TY - JOUR
AB - ATRT ATRT 1. CLAUDIN 6 IS A POSITIVE MARKER FOR ATYPICAL TERATOID/RHABDOID TUMORS Diane Birks,1 Andrew Donson,1 Sean Mcnatt,2 Nicholas Foreman,2 and Michael Handler2; 1University of Colorado Health Sciences Center, Aurora, CO, USA; 2The Children's Hospital, Aurora, CO, USA. Atypical teratoid/rhabdoid tumors (AT/RTs) are highly aggressive malignant CNS tumors of early childhood. Prognosis is extremely poor with median survival times ranging from 6 to 17 months. It has been recognized since the late 1990s that both AT/RTs and malignant rhabdoid tumors of the kidneys and other soft tissues are characterized by a loss of INI1 (aka SMARCB1, BAF47, hSNF5), a component of the SWI/SNF protein complex that regulates transcriptional activity through chromatin remodeling. In fact, loss of INI1 protein, as determined through immunohistochemistry, has become the de facto standard for diagnosis of AT/RTs. Any pediatric brain tumor showing loss of INI1 will generally be diagnosed as an AT/RT, regardless of histological characteristics. However, loss of INI1 has been found in other tumor types, including schwannomas and epithelioid sarcomas. Also, INI1 is not absent in approximately 15% of pediatric brain tumors that show diagnostic histological features for AT/RTs. Thus, INI1 may not be wholly specific to malignant rhabdoid tumors or AT/RTs. To identify potential diagnostic markers specific to AT/RT, 110 pediatric and adult brain tumor samples and 66 normal brain samples were analyzed for gene expression using Affymetrix U133Plus2 GeneChip microarrays. These arrays measure the expression of >54,000 probe sets, including all known human genes. The tumor samples analyzed included eight AT/RTs, as well as glioblastoma, medulloblastoma, large-cell medulloblastoma, ependymoma, pilocytic astrocytoma, rhabdomyosarcoma, meningioma, and radiation-induced tumors. AT/RT expression was compared individually to each other tumor type as well as to normal samples; p-values were adjusted using a false discovery rate of 0.05 which took into account all tests both within and across all groups. Fifty-nine unique genes were found to be overexpressed in the AT/RT samples when compared to all other groups (including normal); five genes were underexpressed. While generally INI1 was expressed at lower levels in AT/RTs than in all other samples, this did not achieve statistical significance for two groups (normal and meningioma). This result is not surprising, because microarrays measure mRNA levels rather than protein levels. Of the 59 genes statistically overexpressed in AT/RTs, 58 showed overlap in their range of expression with other tumor types. However, one gene was found that was consistently expressed in AT/RTs but showed almost no overlap in its range of expression compared to the tumor or normal samples: claudin 6 (CLDN6), a key component of tight junctions. There was an average difference of >50-fold between CLDN6 levels in AT/RTs versus all other tumors and similarly versus normal samples. Compared to medulloblastomas, the most difficult tumor type to discriminate from AT/RTs, CLDN6 was expressed >53-fold higher in AT/RTs with no overlap at all in expression levels. Analysis of protein abundance using Western blotting confirmed the microarray results. Thus the combination of INI1 as a negative marker and CLDN6 as a positive marker may be useful in defining AT/RTs for diagnostic purposes. ATRT 2. CLINICAL FEATURES OF ATYPICAL TERATOID/RHABDOID TUMOR IN JAPAN Hidehiro Oka1 and Kiyotaka Fujii1; 1Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. Introduction: The clinical features of atypical teratoid/rhabdoid tumors (AT/RTs) in Japan and the importance of the differential diagnosis from PNET/medulloblastoma and germ cell tumor are described. Methods: Forty-one patients with AT/RTs in Japan were analyzed for clinicopathological features. Results: The 41 patients with AT/RTs (23 male and 18 female) had ages ranging from 1 month to 37 years (mean, 2.9 years). They had tendency to show increased intracranial pressure by obstructive hydrocephalus and/or tumor volume. Tumors were located in the posterior fossa (63%), brain hemispheres (22%), spinal (12%), and pineal region (3%). Interestingly, AT/RTs of younger patients (<2 years) tended to be located in the posterior fossa or spinal region. Leptomeningeal dissemination was present in >50% of AT/RT cases. Histologically, AT/RT is defined as a polymorphous neoplasm often featuring rhabdoid, PNET, epithelial, and mesenchymal components. AT/RTs usually include PNET components and occur mainly in the posterior fossa, mimicking medulloblastoma. AT/RT is characterized by the cytogenetic finding of monosomy 22 rather than i(17q). The tumor is similarly mistaken for PNET because of supratentorial immunophenotypic diversity, particularly features indicative of epithelial and mesenchymal differentiation. Nonetheless, the remarkable spectrum of tissues typical for teratoma are absent in AT/RT. The prognosis of this tumor is far less favorable than that of PNET/medulloblastoma or germ cell tumor. Conclusions: This study describes the clinicopathological features of 41 AT/RTs in Japan, and we emphasize the necessity for distinguishing this unique tumor from other pediatric CNS neoplasms. ATRT 3. CNS ATYPICAL TERATOID RHABDOID TUMOR (ATRT) IN CHILDREN LESS THAN 36 MONTHS: A CANADIAN PEDIATRIC BRAIN TUMOR CONSORTIUM (CPBTC) EXPERIENCE Lucie Lafay-Cousin,1 Daniel Keene,2 Anne-Sophie Carret,3 Bruce Crooks,4 David Eisenstat,5 Chris Fryer,6 Donna Johnston,7 Valerie Larouche,8 Albert Mograbi,3 Beverly Wilson,9 Anthony Whitton,10 Shayna Zelcer,11 and Eric Bouffet12; 1University of Calgary, Calgary, AB, Canada; 2Children's Hospital of Eastern Ontario, Ottawa, ON, Canada; 3Montreal, QC, Canada; 4Halifax, NS, Canada; 5Winnipeg, MB, Canada; 6Vancouver, BC, Canada; 7Ottawa, AB, Canada; 8Quebec City, QC, Canada; 9Edmonton, AB, Canada; 10Hamilton, ON, Canada; 11London, ON, Canada; 12Toronto, ON, Canada. Background: CNS ATRTs are extremely rare and agressive tumors occuring primiraly in very young children. Data on this relatively recent entity remain limited to institutional experience or single registry report. Rationale/aim of the study: To provide a population-based review on this entity to better define incidence, demographic, outcome data, and potential prognostic factors. Methods: Subgroup analysis of patients with pathology confirmed diagnosis of ATRT found as part of a larger retrospective review of CNS tumors in children <36 months of age diagnosed between 1990 and 2005 in Canada. Results: Data were obtained from 14 out of 16 Canadian centers. ATRT was listed as histological diagnosis in 24 of the 531 reported cases of CNS tumors (4.5%). Seventeen patients (71%) were male. Mean age at diagnosis was 12.6 months (±9.44). Tumors were infratentorial in 58.4%, supratentorial in 33.4%, and spinal in 8.3%. Ten patients (41.7%) had evidence of metastatic disease on imaging at diagnosis. Gross total resection was achieved in five patients (21%). One third of the patients did not receive postoperative therapy. Sixteen patients (66.7%) received adjuvant chemotherapy, combined with radiation in 37.5%. High-dose chemotherapy (HDC) with stem cell rescue was administered in five children (31.5%). Median time to progression was 9.1 months (0–35) and median survival time for the 16 treated patients was 14 months (10.1–12.9). One and 2-year overall survival were 50% (±10.2%) and 18.8% (±8.6%), respectively. The metastatic status, the use of radiation, or high-dose chemotherapy were not found to be significant prognostic factors. Patients who underwent a resection greater than 90% had a better survival (p = 0.006). At completion of the survey, three patients remain alive (20, 21, and 78 months from diagnosis). All underwent resection greater than 90%; one was irradiated, and two received HDC. Conclusion: Our study confirms the poor prognosis of CNS ATRTs in infants. However, aggressive surgery may favorably alter the outcome of a subset of patients. Cooperative prospective studies are needed to define the respective role of systemic chemotherapy, intrathecal chemotherapy and radiation. ATRT 4. DE NOVO INI-1 GENE GERMINAL MUTATION CAUSING SYNCHRONIC CONGENITAL PINEAL REGION AND KIDNEY AT/RT: CASE REPORT AND REVIEW OF THE LITERATURE Ramon Navarro,1 Astrid Laguna,2 Noelia Pérez,3 Carmen De Torres,2 Parareda Andreu,2 Jaume Mora,2 and Ofelia Cruz4; 1Pediatric Neurosurgery, Hospital Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Barcelona, Spain; 2Pediatric Oncology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain; 3Pathology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain; 4Pediatric Oncology, University of Barcelona, Esplugues del Llobregat-Barcelona, Spain. Introduction: Rhabdoid tumors are rare but highly aggressive CNS malignancies. The management of these tumors remains very challenging, especially as they are usually diagnosed in early childhood. Overall prognosis is dismal, and there is no consensus on their treatment. Molecular genetic studies have led to the identification of a rhabdoid suppressor gene (INI1/hSNF5) at 22q11.2. Germline mutations in this gene predispose children to the development of atypical teratoid rhabdoid tumor (AT/RT), the so-called rhabdoid predisposition syndrome. Case Report: We present a 6-month-old Chinese female with an initial diagnosis of kidney rhabdoid tumor that had a simultaneous asymptomatic pineal region mass. She was initially managed with complete abdominal surgery and chemotherapy (alternating courses of ifosphamide, VP-16, and carboplatin with vincristine, doxorrubicine, and ciclophosphamide). A partial response of the pineal mass to this regimen was obtained. The simultaneous occurrence in our patient of a renal rhabdoid tumor and a CNS mass was highly suggestive of constitutional mutation in the INI-1 gene which was confirmed by identification of a common C472T in exon 4 mutation in her blood cells. The sequence analysis suggested that there was loss of heterozygosity, so there was only the mutant allele left in the renal tumor. Her parents and siblings did not share the germinal mutation. The patient subsequently underwent cranial surgery with complete resection of the pineal tumor. Histology of the CNS mass confirmed the AT/RT diagnosis. After surgery, maintenance treatment with irinotecan and cisplatin, together with tamoxifen was given. In addition, the CNS tumor was locally consolidated with fractionated stereotactic radiation therapy (4.500 cGy) given to the tumor bed region at the age of 16 months. Currently she is 20 months old, in complete continuous remission and receiving maintenance treatment with tamoxifen. Commentary: The rhabdoid predisposition syndrome offers an added challenge to the management of these patients. There is still no consensus as to the best approach for AT/RT treatment. The ability to achieve complete surgical resection seems to be a significant prognostic factor in determining overall survival, but it is not enough for cure. Radiation therapy is controversial since most patients are infants. However, the fact that long-term survivors, especially in older patients, were more likely to have had initial radiation favors the use of radiotherapy. As for chemotherapy, these patients have received a variety of regimens, mainly using platinum or alkylating agents, and even high-dose chemotherapy. Temozolomide and intrathecal therapy have been also assayed with some encouraging results. In our patient, we could demonstrate some degree of chemosensitivity to the VAC/ICE alternating regimen. New approaches are needed, and some future avenues might be offered with inmunotherapy or biologically driven therapies. Our patient is on tamoxifen chemopreventive therapy based on the fact that INI1/hSNF5 represses transcription of cyclin D1. ATRT 5. DELAYED METHOTREXATE EXCRETION IN AN INFANT WITH ATYPICAL TERATOID RHABDOID TUMOR AND A LARGE POSTOPERATIVE INTRACRANIAL PSEUDOCYST: PHARMACOKINETIC ANALYSIS AND IMPLICATIONS FOR BRAIN TUMOR TREATMENT Robert Sanders,1 Paula Schaiquevich,2 Frederick Boop,3 Deborah Ward,2 Zoltan Patay,4 Amar Gajjar,1 and Clinton Stewart2; 1Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; 2Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA; 3Department of Neurosurgery, St. Jude Children's Research Hospital, Memphis, TN, USA; 4Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA. High-dose intravenous methotrexate (HDMTX) has activity against medulloblastoma and is included in several current clinical trials for young children with brain tumors. Experience with other tumor types has shown that sequestration of methotrexate within pathological fluid collections (e.g., pleural effusions) may lead to delayed excretion and an increased risk of systemic toxicity. The similar effect of intracranial fluid collections on methotrexate pharmacokinetic parameters has not been studied. We report the case of an infant with a right frontoparietal atypical teratoid rhabdoid tumor (ATRT) who postoperatively developed a large extracerebral fluid-filled pouch at the tumor resection site. After he experienced delayed methotrexate excretion during his first cycle of HDMTX, an Ommaya reservoir was placed into the pseudocyst, permitting matched plasma and cerebrospinal fluid MTX pharmacokinetic studies during his second course. Pharmacokinetic analysis demonstrated that systemic MTX clearance was within the expected range for his age but that the terminal half-life was prolonged, creating the potential for delayed systemic toxicity. Through careful monitoring, hydration, and leucovorin administration, significant toxicity was avoided. We conclude that patients with intracranial fluid collections are at risk for increased toxicity with HDMTX administration but demonstrate that this drug can be safely administered to such patients with vigilant clinical management. ATRT 6. DIAGNOSTIC AND TREATMENT PITFALLS OF ATYPICAL TERATOID/RHABDOID TUMOR (AT/RT) Ai Muroi,1 Shingo Takano,1 Takashi Fukushima,2 Tetsuya Yamamoto,1 Atsushi Saito,1 and Akira Matsumura1; 1Department of Neurosurgery, University of Tsukuba, Tsukuba City, Ibaraki, Japan; 2Department of Pediatrics, University of Tsukuba, Tsukuba City, Ibaraki, Japan. Purposes: The prognosis of the patients with AT/RT younger than 3 years old is very poor. We reviewed six cases of AT/RT in patients younger than 3 years old treated in Tsukuba University in order to investigate the diagnostic and treatment pitfalls. Materials and Methods: Six cases (two male; four female) were pathologically diagnosed as AT/RT; age ranged from 6 to 36 months. Tumor location was infratentorial in two, intraventricular in two, supratentorial in one, and spinal in one. Initial symptoms were increased intracranial pressure with intracranial AT/RT and paraparesis with spine AT/RT. Dissemination was observed at initial in two cases. Total resection was achieved only in one and subtotal resection in others. After histological confirmation, chemotherapy (ifosfamide, cisplatin and etoposide) radiotherapy was initiated. Stem cells were harvested from bone marrow in four cases and high-dose chemotherapy was done in three cases with stem cell rescue. Results: Pathologically, typical rhabdoid cells were not observed in two cases, where immunohistochemistry with EMA, SMA, vimentin, and INI-1 was definitely useful to diagnosis. Prognosis of six cases was dead in three cases (3, 9, and 14 months) and alive in three cases (4, 4, and 38 months). Long-term survivors (>38 months alive) have dissemination at initial presentation, but high-dose chemotherapy with stem cell rescue and whole brain and whole spine irradiation (3 months after the diagnosis at the age of 34 months) resulted in complete response for 20 months. In another case of a 4-month-old girl, salvage irradiation was quite useful for intracranial extension. Conclusion: Diagnostic and therapeutic pitfalls of AT/RT were as follows: (1) Immunohistochemistry for EMA, SMA, and vimentin is important in case of scant rhabdoid cells and prominent PNET features. (2) High-dose chemotherapy could be useful in selected cases; therefore, preparing stem cells should be designed as the initial treatment. (3) cerebrospinal fluid dissemination should be avoided by intrathecal administration of chemotherapy and seamless chemotherapy. (4) Radiotherapy and salvage therapy could be planned as an initial therapy before the age of 3 years. ATRT 7. GERMAN PEDIATRIC ATYPICAL TERATOID/RHABDOID TUMORS: INTERIM ANALYSIS OF THE ATRT-CNS PILOT STUDY AND RETROSPECTIVE ANALYSIS Ove Peters,1 Beatrix Heinzelmann,1 Jörg Marienhagen,2 Monika Friedrich,3 Odo-Winfried Ullrich,3 Torsten Pietsch,4 Kortmann Rolf-Dieter,5 Monika Warmuth-Metz,6 Brigitte Wrede,1 Petra Turowski,1 Gerda Demleitner,1 and Johannes Wolff7; 1Pediatric Oncology, Children's Hospital, Regensburg, Germany; 2Center of Clinical Trials, University Regensburg, Regensburg, Germany; 3Neurosurgery, University Regensburg, Regensburg, Germany; 4Neuropathology, University Bonn, Bonn, Germany; 5Radiology, University Leipzig, Germany; 6Radiology, University Würzburg, Germany; 7Houston, TX, USA. Background: Atypical teratoid/rhabdoid tumors (ATRT) account for <1% of all CNS tumors. Usually newborns and infants are affected. The outcome is dismal (median overall survival, 6–11 months). We present a retrospective analysis of the German historic pediatric ATRT patients (n = 63) from 1988 to 2008, a meta-analysis of international ATRT-outcome data of treated children (406 case reports) from 1985 to 2008, and an interim analysis of the novel ATRT-CNS pilot study (anthracycline-based multimodality therapy). Methods: The retrospective analysis of the German historic pediatric ATRT-patients (n = 58) from 1988 to 2002 and the meta-analysis of international ATRT-outcome data of treated children (401 case reports) from 1985 to 2002 served as the backbone for the development of the ATRT-CNS pilot study. Children were enrolled in this study after the diagnosis of ATRT was confirmed by the German Neuropathology Reference Center. After two induction chemotherapy cycles (each 3 weeks: doxorubicin 25 mg/m2 12-h i.v., d1–3; dactinomycin 45 μg/kg i.v. push, d1; cisplatin 70 mg/m2 6-h i.v., d4; vincristine [VCR] 1.5 mg/m2 i.v. push, d8, 15; MTX 2 mg iventr., d1–4) conventional local 3D radiation therapy (54 Gy) with simultaneous chemotherapy (carboplatin 80 mg/m2 6 h i.v., d1–4) was given. Thereafter, reinduction chemotherapy (same as first/second cycle) was implemented, followed by consolidation chemotherapy (6 cycles/9 months: CCNU 75 mg/m2, d1; cisplatin 70 mg/m2 6 h i.v., d1; VCR 1.5 mg/m2 i.v. push, d1, 8, 15; MTX 2 mg iventr., d1–4). Results: Eleven out of 30 children were excluded from the analysis (eight foreign patients, and three patients due to therapy violation). Nineteen German patients (15 male, 4 female; median age, 22 months) have been treated according to the study criteria. Tumor site: 10 hemispheric (one bifocal), 6 cerebellum, 1 pineal, 1 cerebellopontine angle, and 1 spinal. Additionally, in 32% of the children leptomeningeal dissemination/malignant pleocytosis was present. Primary surgery: one complete, five subtotal, nine partial resections, and four biopsy only. Response to the two primary doxorubicin-based cycles (induction) could be evaluated in 19 children: 1 continued complete response, 2 complete response, 13 partial response, and 3 stable disease. The event-free survival and overall survival is 79% (mean survival time, 50 months; CI, 38–63 months) compared to 27% (mean survival time, 12 months; CI, 9–15 months) of the German historic ATRT group and 28% (mean survival time, 24 months; CI, 19–29 months) of the international ATRT-patient group (meta-analysis). Main toxicity (NCIVers.2) in 19 children after the induction/reinduction chemotherapy: grade III–IV mucositis and infection in 42% and 37%, respectively. Reported neurotoxicity: one transient transverse myelits, one cerebral edema with seizures 2 weeks after local radiochemotherapy, and one postoperative death after ventriculoperitoneal shunt implantation. No encephalomyelopathy has been reported so far. Conclusion: This anthracycline-based induction regimen shows that ATRTs are chemosensitive but has significant toxicity. The survival data are significantly improved compared to the German historic ATRT outcome data of treated children. ATRT 8. INI1 PROTEIN EXPRESSION IN PRIMARY MALIGNANT EMBRYONAL PEDIATRIC CNS TUMORS FROM EAST DENMARK Astrid Sehested,1 Karsten Nysom,1 Lars Bøgeskov,2 John Hauerberg,2 Henning Laursen,3 and Helle Broholm3; 1Paediatric Oncology, Rigshospitalet, Copenhagen, Denmark; 2Neurosurgery, Rigshospitalet, Copenhagen, Denmark; 3Neuropathology, Rigshospitalet, Copenhagen, Denmark. Atypical teratoid/rhabdoid tumors (AT/RT) of the CNS are rare, highly malignant primary CNS neoplasms seen predominantly in very young children and infants. The definition as a clinical and neuropathological entity is relatively recent, and the differentiation from PNET may be difficult. Analysis of nuclear expression of INI1 protein in tumor cells by immunohistochemistry shows negative staining (lack of expression) in nearly all AT/RT tumors. Negative staining may also be seen in a small fraction of primitive neuroectodermal tumors without rhabdoid phenotype, and when seen in such cases is associated with a poorer prognosis. There is growing consensus that such tumors should be classified and treated as AT/RT tumors and that INI1 staining should be carried out in all pediatric malignant embryonal tumors. Ninety tumor specimens from 87 children with primary malignant embryonal CNS neoplasms treated at our institution from 1971 to 2007 inclusive were examined for expression of nuclear INI1 protein by immunohistochemistry. Four tumor specimens from four patients could not be stained due to poor specimen quality (all were medulloblastoma patients, three are long-term survivors). Positive INI1 staining in tumor cells was seen in 82 specimens from 79 patients, whereas four tumor specimens from four patients demonstrated lack of nuclear INI1 protein in tumor cells. Concerning these last four patients, the first was a girl diagnosed in 1991 13 months of age with a central supratentorial PNET and treated with radical tumor resection, chemotherapy, and radiotherapy; she died of disease 7 months postdiagnosis. The second was a girl diagnosed in 1992 18 months of age with a supratentorial central tumor and histology described as malignant anaplastic tumor, possibly sarcoma; the patient was treated with tumor resection, chemotherapy, and radiotherapy but succumbed to disease 6.5 months postdiagnosis with widespread systemic metastases. The third was a boy diagnosed in 1992 at age 22 months with a supratentorial central PNET; he died postoperatively due to surgical complications. Pathological review of these three patients now shows AT/RT in all three, although the last patient did not have rhabdoid morphology. The fourth is a girl diagnosed in 2007 at age 6 with a tumor in the cerebello-pontine angle, where histopathology was compatible with AT/RT but without specific rhabdoid features. Here the INI1 analysis was part of her work-up, and she is at present undergoing intensive treatment with chemotherapy and radiotherapy and has stable disease. Of the 79 patients with tumors that showed normal expression of INI1 by immunohistochemistry, the diagnoses were medulloblastoma in 69 patients (29 patients diagnosed between 1971 and 1989, with 8 long-term survivors, and 40 patients diagnosed between 1990 and 2007, with 22 patients surviving today); PNET in six patients (three survivors); and CNS Ewing sarcoma in three patients, all alive with disease, and ependymoblastoma in one patient (DOD). In conclusion, we confirm that a negative INI1 stain is a rare finding (4 of 83 patients), and in three of four cases was associated with young age and poor prognosis despite aggressive treatment in two cases. ATRT 9. INSIGHTS INTO THE EPIGENETICS OF ATYPICAL TERATOID RHABDOID TUMORS: THE POTENTIAL FOR TREATMENT WITH HISTONE DEACETYLASE INHIBITORS David Ashley,1 Andrea Muscat,2 Vinod Dagar,3 Christian H. Rickert,4 Cw Chow,5 J.A. Biegel,6 Paul Ekert,7 Richard Saffery,2 Jeff Craig,2 Ricky Johnstone,8 and Elizabeth Algar7; 1Royal Children's Hospital, Murdoch Children's Research Institute, Parkville, Victoria, Australia; 2Murdoch Children's Research Institute, Victoria, Australia; 3Murdoch Children's Research Institute, Victoria, Australia; 4Paediatric Pathology/Neuropathology, Royal Children's Hospital, Victoria, Australia; 5Royal Children's Hospital, Victoria, Australia; 6Division of Human Genetics, The Children's Hospital of Philadelphia, PA, USA; 7Royal Children's Hospital, Murdoch Children's Research Institute, Victoria, Australia; 8Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia. Background: Atypical teratoid rhabdoid tumor (ATRT) is an aggressive but rare tumor of infancy and early childhood resistant to conventional chemotherapies and radiotherapy. The majority of afflicted children succumb to their disease within a year of diagnosis. SMARCB1 (INI1) is part of an ATP dependent SWI/SNF chromatin-remodeling complex and is frequently deleted in rhabdoid tumor. We hypothesized that the oncogenic pathway in ATRT may involve epigenetic silencing of key cell cycle regulators as a consequence of altered chromatin-remodeling function attributable to loss of SMARCB1 and that such effects may be reversed by treatment with histone deacetylase inhibitors (HDACi). Methods and Results: In this study we demonstrated, using an inducible expression system, that the imprinted cell cycle inhibitor CDKN1C is a downstream target for SMARCB1 and that it is transcriptionally activated by increased histone H3 acetylation at its promoter, thereby revealing a novel aspect of SMARCB1 function. The histone deacetylase inhibitor (HDACi) Romidepsin, also known as Depsipeptide, restored CDKN1C expression in rhabdoid tumor cells through promoter histone H3 and H4 acetylation, recapitulating the effect of SMARCB1 on CDKNIC transcription and allelic expression. Significantly, treatment with HDACi induced cell cycle arrest in the rhabdoid tumor cell lines, G401 and STM91-01. Most importantly, CDKN1C expression was absent or negligible in clinical specimens, suggesting that CDKN1C silencing is a common event in ATRT. Conclusion: We propose that the aberrant epigenetic regulation of the transcription of key cell cycle regulators such as CDKN1C may be fundamental to ATRT biology. Romidepsin and related compounds should be further explored as therapeutic reagents for the treatment of ATRT and that measuring the reversal of epigenetic changes by such compounds may provide unique methods for monitoring disease response. ATRT 10. MULTIFOCAL NECROTIZING LEUKOENCEPHALOPATHY: A COMPLICATION OF ATYPICAL TERATOID RHABDOID TUMOR THERAPY—PROMPT DETECTION, DIAGNOSIS, AND TREATMENT IS REQUIRED Michael Palumbo,1 Sean Quinlan-Davidson,2 Jean-Pierre Farmer,2 Jose-Luis Montes,2 Jeffrey Atkinson,2 Carolyn Freeman,2 Steffen Albrecht,2 Christine Saint-Martin,2 and Anne-Sophie Carret3; 1McGill University, Montreal, QC, Canada; 2Montreal, QC, Canada; 3Montreal Children's Hospital, Montreal, QC, Canada. We describe a case of multifocal necrotizing leukoencephalopathy (MNL) as a treatment-related complication in a child treated for an atypical teratoid/rhabdoid tumor (ATRT) of the CNS. To the best of our knowledge, MNL has been rarely described in children treated for malignancies. The patient was diagnosed at 20 months of age with an ATRT of the left middle cranial fossa for which she underwent macroscopically complete resection. Urgent radiotherapy (total dose 10.8 Gy) was given 14 days following surgical excision due to rapidly progressive recurrence in the surgical cavity. The patient then underwent two cycles of induction chemotherapy with a combination of high-dose methothrexate, vincristine, etoposide, cyclophosphamide, and cisplatin followed by involved-field radiotherapy (50.4 Gy total dose) resulting in complete tumor regression. This was followed by two cycles of consolidation chemotherapy consisting of high-dose carboplatin and thiotepa with peripheral blood stem cell rescue. Although the protocol calls for three such cycles of consolidation, the child was severely immunosuppressed and experienced severe sepsis along with very subtle signs of neurological impairment (intermittent right eye strabismus and ptosis and bilateral papilledema) following the second cycle. An MRI revealed enlarged ventricles with impressive changes in the pons and mid brain consisting of a “butterfly” diffuse increased signal on flair and T2 images, while the architecture was maintained. A stereotactic biopsy of the lesion, however, revealed white matter necrosis consistent with the diagnosis of MNL. The third cycle of consolidation was omitted, and the patient was started on high-dose steroids and weekly intravenous immunoglobulin (IV-IG) for 4 weeks, which resulted in partial regression of the necrotizing lesion on MRI and marginal improvement in the patient's neurological status. Within a month following the initiation of steroid tapering, the patient presented with worsening neurological symptoms and blindness. A repeat MRI demonstrated necrosis progression. The patient was restarted on high-dose steroids and IV-IG, and although the repeat MRI after the end of steroid therapy demonstrated a more circumscribed necrotic area, there was also evidence of multiple nodular disease in the optic chiasma, left cerebellum, pons, and inferior left temporal lobe. While on palliative care, the patient improved, and the last MRI 1 year following the last cycle of consolidation showed disappearance of both the necrotic area and multiple nodules. With recent use of more aggressive therapies, we document some prolongation of the natural history of this tumor but also significant treatment-related morbidity such as MNL. Combination of severe immunosuppression, sepsis, high-dose chemotherapy, and early radiotherapy can cause MNL probably mediated by an excessive systemic inflammatory response. As early stage can be difficult to detect, prompt investigations and biopsy may help with differential diagnosis. Early initiation of steroids and IVIG may help. ATRT 11. ORTHOTOPIC ATRT XENOGRAFT PANEL APPROACH FOR THERAPEUTIC TESTING C. David James,1 Scott Vandenberg,2 Nalin Gupta,1 Michael Prados,3 Anuradha Banerjee,3 and Mitchel Berger4; 1Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; 2Pathology, University of California, San Francisco, San Francisco, CA, USA; 3University of California, San Francisco, San Francisco, CA, USA; 4Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. Atypical teratoid rhabdoid tumors (ATRTs) may well be the most malignant type of primary brain cancer. For children afflicted with ATRT the duration of symptoms is generally brief due to the incredibly high proliferative rate of the tumor cells. This characteristic, however, has not facilitated the identification of effective therapies, cytotoxic or other, for achieving improved treatment of ATRT patients. In addition to the unfortunate biological and clinical behavior of ATRT, the low incidence of this cancer complicates progress in treatment through clinical trial activity: a high-throughput animal model test system could greatly expedite the discovery of more effective therapies for improved treatment of children with ATRT. The same characteristics that confer high-grade malignancy to ATRT also contribute to the ability of these tumors to grow in athymic mice as human tumor xenografts, and in spite of the relative rarity of this cancer, we and others have been successful in establishing ATRT xenografts that can be indefinitely sustained in athymic mice. The development and molecular characterization of an ATRT xenograft panel is therefore feasible, and such a panel would allow preclinical trial assessments of novel therapies in rodents. These studies would more rapidly reach conclusion than corresponding patient clinical trials, and since an ATRT xenograft panel would consist of multiple unique tumors, results from testing several xenografts would allow one to assess whether a particular treatment approach is generally effective or limited to a molecularly-defined subset of ATRT. Here we present results from the histopathologic, immunohistochemical, and orthotopic (intracranial) therapy response characterization of ATRT xenografts that have been modified for bioluminescence imaging. Histopathologically, ATRT xenografts show a uniformly rhabdoid appearance, in spite of being derived from corresponding patient tumors with typical heterogeneous cell populations. Immunohistochemical characterization shows the intracranial xenografts as being BAF47 negative, with immunohistochemistry results in total supporting the ability to compare treated versus untreated tumors for biomarkers of interest. Mice receiving orthotopic injection of ATRT cells experience relatively short periods of symptom-free survival (30–50 days), which is a time frame that facilitates rapid assessment of therapeutic efficacy in therapy-response experiments. Finally, we show through longitudinal bioluminescence monitoring that intracranial ATRT xenografts can be examined for response to therapy in living animals, as well as for acquisition of resistance to therapy. In total, our results support the utility of ATRT xenografts for studying the molecular and cellular biology, as well as therapeutic response, of these tumors. ATRT 12. RESULTS FROM A SINGLE-ARM, MULTIINSTITUTIONAL PHASE II STUDY OF MULTIAGENT INTRATHECAL AND SYSTEMIC CHEMOTHERAPY WITH AGE- AND RISK-ADAPTED RADIATION THERAPY FOR CHILDREN WITH NEWLY DIAGNOSED CNS ATYPICAL TERATOID/RHABDOID TUMOR (DFCI 02-294) Susan Chi,1 William Fletcher,1 Xiaopan Yao,1 Kenneth Cohen,2 Michael Fisher,3 Jaclyn Biegel,3 Anna Janss,4 Stewart Goldman,5 Daniel Bowers,6 Peter Manley,7 Claire Masewski,4 Anne Bendel,8 Joshua Rubin,9 Christopher D. Turner,1 Charles Roberts,1 Karen Marcus,10 Liliana Goumnerova,11 Nicole Ullrich,11 Christine Chordas,1 Mary Ann Zimmerman,1 and Mark W. Kieran1; 1Dana-Farber Cancer Institute, Boston, MA, USA; 2Johns Hopkins University, Baltimore, MD, USA; 3Children's Hospital of Philadelphia, Philadelphia, PA, USA; 4Emory University, Decatur, GA, USA; 5Children's Memorial Hospital, Chicago, IL, USA; 6University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA; 7Hasbro Children's Hospital, Providence, RI, USA; 8Children's Hospitals and Clinics, Minneapolis, MN, USA; 9Washington University in St. Louis, St. Louis, MO, USA; 10Joint Center for Radiation Oncology, Dana-Farber Cancer Institute/Children's Hospital, Boston, MA, USA; 11Children's Hospital, Boston, MA, USA. Background: Atypical teratoid/rhabdoid tumor (ATRT) of the CNS is a highly malignant neoplasm primarily affecting young children, with a median survival ranging from 6.5 to 10 months. Based on a small successful pilot series of patients with newly diagnosed and recurrent disease (Zimmerman et al. J Neurooncol. 2005;72:77), a multiinstitutional trial was conducted using a modified IRS-III regimen for patients with newly diagnosed CNS AT/RT (DFCI 02-294). Methods: Treatment was divided into five phases: preirradiation induction chemotherapy (weeks 1–6); chemoradiation (weeks 7–12); consolidation (weeks 13–18); maintenance (weeks 19–44); and continuation therapy (weeks 45–51). Intrathecal chemotherapy administration alternated between the intralumbar and intra-Ommaya routes. Patients with M0 stage received conformal radiation therapy at the prescribed time to a total dose of 5,400 cGy. For patients >3 years of age with M+ disease at diagnosis, craniospinal irradiation at 3,600 cGy was prescribed, with boost to primary sites of disease to total dose of 5,400 cGy. Results: Between February 2004 and February 2007, 25 children were enrolled, of whom 22 were evaluable (2 ineligible, 1 withdrawal). There were nine males and 13 females; median age at diagnosis was 2.5 years (range, 2.4 months to 19.5 years). Primary tumors were located in the supratentorial compartment in 12 patients and in the posterior fossa in 10 patients. Gross total resections (GTR) of the primary tumor were achieved in approximately 50% of patients. Sixteen patients had M0 disease at diagnosis, one had M2 disease, and five had M3 disease. Twelve patients completed prescribed treatment. Ten patients came off study for the following reasons: toxic death (one), progressive disease ranging from weeks 2–33 (five), radiation recall (one), transverse myelitis (one), second malignancy (one, M7 AML in a patient with trisomy 21), and noncompliance (one). All patients received some intrathecal therapy. Seventeen patients received radiation therapy, 12 conformal focal radiation therapy, and five craniospinal radiation therapy. Significant toxicities for this treatment regimen included bone marrow suppression; febrile neutropenia; infection; gastrointestinal, electrolyte, and hepatic function disturbances; neuropathies; transverse myelitis; and high-frequency hearing loss. Also notable were two patients who experienced radiation recall. There was one toxic death from pneumococcal sepsis. The planned 51-week treatment plan required 52–78 weeks to complete. Of the 14 patients evaluable for chemotherapeutic response (pre-RT), the objective response rate (CR + PR) was 62%. The objective response rate from radiation therapy was 38%. The 1-year event-free survival (EFS) and overall survival (OS) are 68 ± 10% and 77 ± 9%, respectively, and the 2-year EFS and OS are 48 ± 13% and 67 ± 10%, respectively. Sites of relapse include local (three patients), distant metastases (two), disseminated (three), and unknown (one). Median OS has not yet been reached. Fifteen tumors have been centrally reviewed as ATRT; four additional tumors demonstrated deletion of INI-1/Baf47 by immunohistochemistry; the remaining three tumors are being collected for review. Conclusions: For this rapidly fatal disease, significant progress has been made in terms of improving survival. A future study is planned to incorporate growing biologic data. ATRT 13. SELECTIVE INHIBITORS OF HISTONE DEACETYLASES (HDI)—A NOVEL AVENUE FOR THE TREATMENT OF RHABDOID TUMORS Kornelius Kerl,1 Manfred Jung,2 Heribert Juergens,1 and Michael C. Fruehwald1; 1University of Muenster, Muenster, Germany; 2Department of Medicinal Chemistry, University of Freiburg, Germany. Atypical teratoid rhabdoid tumors (AT/RTs) are rare, but highly aggressive, rather chemoresistant neoplasms. The dismal prognosis has not significantly improved since their first description. The epigenetic structure of DNA and its lesions have gained major interest in the discussion on novel therapeutic strategies for AT/RT. The two most important, closely connected mechanisms of epigenetic regulation are DNA methylation and histone deacetylation. The distinct effects of histone deacetylase (HDAC) inhibitors (HDIs) in studies on neuroblastoma and medulloblastoma cells prompt investigation into the effect these substances have on AT/RT. HDAC are divided into four major groups; class III are termed sirtuins (NAD-dependent HDAC). Previously we have presented unselective HDIs as promising compounds in cell culture models for the treatment of rhabdoid-derived cells (GI50: from nM to μM). Several unselective HDIs are currently in phase I and II clinical trials. Strategies are being developed to implement HDI in the treatment of AT/RT. Furthermore, in vitro survival of AT/RT seems critically dependent on the presence of cyclin D1. We used an array of seven selective HDI and sirtuins (ST 13 → HDAC 1+6; ST 80 → HDAC 6; PE 24/8 → HDAC8; PE 11/5 → HDAC 8; Sirtinol → SIRT 1+2; Hydrazon → Sirt 2; PU 46 → SIRT 2; RN 128 → SIRT 2), which were designed by one of us, for the treatment of rhabdoid cell lines in vitro. Additionally a combination treatment with cyclin D inhibitors (4HPR and 4OHTam) was used. Our results indicate the following: (1) selective HDIs inhibit the growth of rhabdoid tumor cells in culture models. Effective drug concentrations for the different selective HDI vary from 1 μmol/liter to 100 μmol/liter (GI50 values). (2) HDI of class I HDAC (ST13; GI50: 1 μmol/liter) and SIRT II (Hydrazon 1 μmol/liter) seem to be more effective than other selective HDI. (3) The combination of selective (and unselective) HDI with fenretinide (4HPR; cyclin D1 inhibitor) exerts a synergistic inhibitory effect on the growth of rhaboid cells in vitro. These synergisms have not been described in any other tumor cell lines before. Selective HDIs are effective in treating AT/RT cell lines in vitro. The combination of HDI with cyclin D inhibitors acts synergistically. Both HDI alone and in combination are interesting tools to be employed in vivo for the treatment of patients with AT/RT and other rhabdoid tumors. Supported by the Karl Bröcker and the Sonja Wasowicz Stiftung, Germany. BIOLOGY BIO 1. ACQUIRED RESISTANCE TO THE HSP90 INHIBITOR 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN (17-AAG) IN ADULT AND PEDIATRIC GLIOBLASTOMA CELL LINES Nathalie Gaspar,1 Swee Sharp,1 Simon Pacey,1 Chris Jones,2 Mike Walton,1 Gilles Vassal,3 Andrew Pearson,4 and Paul Workman1; 1Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK; 2Paediatric Oncology, Institute of Cancer Research, Sutton, Surrey, UK; 3Institut Gustave Roussy, Villejuif, Paris, France; 4Paediatric Oncology, Royal Marsden Hospital, Sutton, Surrey, UK. Introduction: The molecular chaperone HSP90 has emerged as an exciting anticancer drug target due to its role in maintaining the stability and function of numerous oncogenic client proteins. The inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the intrinsic HSP90 ATPase activity, which is essential for HSP90 function, and is in phase I and II clinical trials in children and adults, respectively. HSP90 inhibitors have been shown to inhibit cell growth in both adult and pediatric glioblastoma (GB) cell lines. The ability for these primary brain tumors to develop drug resistance probably accounts for their high recurrence rate and poor curability. Exploring the mechanism of acquired resistance to HSP90 inhibitors in GB is an important goal for the potential development of these agents as part of the therapeutic arsenal against GB. Methods and Results: By continuous exposure to increasing 17-AAG concentrations, in vitro acquired resistance to 17-AAG has been successfully generated in four GB cell lines from both adult (SF268, U87MG) and pediatric (SF188 and KNS42) origins. High levels of resistance with resistance indices (RI = IC50 of resistant line/IC50 of parental line, as determined by sulforhodamine B assay) of 20–137 were obtained rapidly (2–8 weeks). RIs were higher in adult (RI 104–137) than in pediatric resistant lines (RI 20–23). After cessation of 17-AAG, RIs were decreased (6–25), except for the pediatric line KNS42, where RI increased from 20 to 33, then RI stabilized in all cell lines for several weeks (7–26 weeks). Cross-resistance was found with other ansamycin benzoquinones (17-DMAG, 17-AG) but not with structurally unrelated HSP90 inhibitors, radicicol, and the inhouse synthetic potent resorcinylic pyrazole/isoxazole amide compounds (VER-49009, VER-50589), ruling out general mechanisms of resistance to HSP90 inhibition. We further demonstrated that NAD(P)H:quinone oxidoreductase 1 (NQO1/DT-diaphorase) was involved in 17-AAG acquired resistance of all GB lines. NQO1 has been reported to metabolize ansamycin benzoquinones to their more active hydroquinone counterparts and has been implicated in 17-AAG primary resistance. NQO1 protein levels were depleted in all resistant lines (by Western blot analysis) to a greater extent under 17-AAG pressure than after cessation of 17-AAG. A significant inverse correlation between NQO1 enzymatic activity and 17-AAG IC50 was observed with the resistant lines. Finally, the NQO1 inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines, confirming the major role of NQO1 in 17-AAG resistance. However, after 17-AAG cessation in the pediatric resistant line SF188-RA6, NQO1 protein/activity returned to parental level despite continued insensitivity to 17-AAG, suggesting an additional mechanism of resistance, albeit restricted to ansamycin benzoquinones. The NQO1 mRNA levels (as measured by quantitative RT-PCR) were also inversely correlated with 17-AAG IC50 in the adult resistant lines, but no mRNA level modification was observed in the pediatric resistant lines, suggesting different mechanisms of NQO1 depletion between adult and pediatric cell lines. Interestingly, generation of acquired resistance cell lines was unsuccessful with the resorcinylic pyrazole/isoxazole amide agents in these four GB lines. Conclusion: Low NQO1 activity is not only a mechanism of primary resistance, but also a likely mechanism of acquired resistance to 17-AAG in both adult and pediatric GB and possibly in other cell types (e.g., melanoma), underlining the problematic metabolism of 17-AAG. Interestingly, mechanisms of NQO1 depletion seemed to be different between adult and pediatric cell lines. New series of HSP90 inhibitors with improved metabolic properties such as the resorcinylic pyrazole/isoxazole amide analogues, which are able to circumvent the NQO1 mechanism of resistant, provide additional support for new clinical development. BIO 2. BRAF GENE DUPLICATIONS AND ACTIVATING MUTATIONS CAUSE ABERRANT MAPK PATHWAY ACTIVATION IN PEDIATRIC LOW-GRADE ASTROCYTOMAS Marc Remke,1 Wibke G. Janzarik,2 Aurélie Ernst,1 Andreas Kulozik,3 Astrid Gnekow,4 Guido Reifenberger,5 Andrey Korshunov,6 Wolfram Scheurlen,7 Heymut Omran,8 Peter Lichter,1 and Stefan Pfister1; 1Molecular Genetics, German Cancer Research Center, Heidelberg, Germany; 2Department of Neurology, University Hospital Freiburg, Freiburg, Germany; 3Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany; 4Children's Hospital, Klinikum Augsburg, Augsburg, Germany; 5Neuropathology, Heinrich-Heine University, Düsseldorf, Germany; 6Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia; 7Cnopfsche Kinderklinik, Nürnberg, Germany; 8Pediatric Neurology and Muscle Disorders, University Hospital Freiburg, Freiburg, Germany. Astrocytomas (WHO grade I and II) comprise the most common pediatric brain tumors. However, molecular mechanisms of tumor development and recurrence remain poorly understood. In the present study, we performed array-based comparative genomic hybridization (array-CGH) analysis of 66 pediatric astrocytomas of WHO malignancy grades I and II. The most frequent genomic aberration was a circumscribed duplication of the BRAF locus at 7q34 present in 30 of 66 (45%) cases. Activating mutations of the BRAF gene were identified in 4 of 66 (6%) tumors, exclusively affecting cases without BRAF duplication and indicating different mechanisms for BRAF activation. Tumors with BRAF duplication showed significantly increased mRNA and protein levels of BRAF as compared to tumors without duplication. In addition, we observed mRNA abundance of CCND1, a well-established downstream target of BRAF, in tumors with DNA copy-number gains of the BRAF locus. Fluorescence in situ hybridization (FISH) analysis of 36 low-grade astrocytomas from adult patients also revealed a high frequency of duplications restricted to the BRAF locus (24%), as well as larger gains of chromosome arm 7q (35%). Elevated BRAF protein expression in the tumor was associated with favorable prognosis in adult patients. Proliferation of cell lines derived from low-grade gliomas was effectively blocked by stable knockdown of the BRAF gene using lentivirus-mediated transduction of BRAF-specific shRNAs as well as by pharmacological inhibition of MEK1/2, the immediate downstream target of BRAF. Cell cycle analysis revealed a G2/M arrest in cells treated either with shRNAs targeting the BRAF gene or MEK1/2 inhibitors. Overall, our findings implicate aberrant activation of the mitogen-activated protein kinase (MAPK) pathway due to gene duplication or activating mutation of BRAF as a common event in the tumorgenesis of low-grade astrocytomas and provide a promising novel target for future therapeutic strategies. BIO 3. CHARACTERISATION OF THE 4Q12 AMPLICON IN PEDIATRIC GLIOMAS Lara Perryman,1 Dorine Bax,1 Suzanne Little,1 Nathalie Gaspar,2 Lynley Marshall,1 Gilles Vassal,3 Paul Workman,2 Andrew Pearson,4 Michael Taylor,5 Richard Grundy,6 Suzanne Baker,7 Darren Hargrave,4 David Ellison,8 and Chris Jones1; 1Paediatric Oncology, Institute of Cancer Research, Sutton, Surrey, UK; 2Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK; 3Institut Gustave Roussy, Villejuif, Paris, France; 4Paediatric Oncology, Royal Marsden Hospital, Sutton, Surrey, UK; 5Developmental Biology, The Hospital for Sick Children, ON, Canada; 6Children's Brain Tumour Research Centre, Queens Medical Centre, Nottingham, UK; 7Developmental Neurobiology, St. Jude Children's Research Hospital, TN, USA; 8Neuropathology, St. Jude Children's Research Hospital, TN, USA. The genomic locus at chromosome 4q12 harbors the known oncogenes PDGFRA, KIT, and KDR (VEGFR2) and has been found to be amplified in human glioma samples. Combinations of these genes are targeted by novel small molecule tyrosine kinase inhibitors such as imatinib and AZD2171, thus providing a strong impetus for understanding the frequency and nature of this genomic event. Estimates of gene dosage and protein expression for these and other genes at this locus are equivocal in adult glioma and lacking in pediatric cases. We have sought to clarify this in the high-grade gliomas (HGGs) of childhood by mapping the amplicon by means of targeted FISH probes and Agilent 44K oligonucleotide array CGH, as well as investigating protein expression in the tumors by immunohistochemistry. In our retrospective study of formalin-fixed, paraffin-embedded cases, we observed three patterns of DNA copy gain at 4q12 in pediatric HGG. First was high-level amplification (>10 copies) of a locus as focal as 985 kb harboring PDGFRA and the proximal genes CHIC2 and LNX1, but not extending further distally. Second was an extended amplicon, as wide as 3.1 Mb, which was also high level and included these genes as well as KIT. Finally, was a low-level copy number gain of between three and six copies of a large (>8 Mb) region spanning up to 36 genes and including PDGFRA, KIT, and KDR/VEGFR2. By mining the publicly available datasets for DNA copy number profiling in adult glioblastoma multiforme, we observed an identical pattern of amplification/gain encompassing the same three discrete events. It is noteworthy that in both primary tumors and cell lines, receptor overexpression was seen in the absence of gene amplification. Of key interest was a pediatric astrocytoma cell line Res259/UW467 that harbored a complex rearrangement at 4q12 involving both focal amplification of PDGFRA and KIT as well as a low-level gain of the larger region encompassing KDR/VEGFR2. These data highlight the different amplification events present at 4q12 in pediatric HGGs and provide evidence for a uniquely useful in vitro model for mechanistic and preclinical investigations of this locus and drugs targeting the products encoded by genes therein. BIO 4. COMBINATION OF A POLY(ADP-RIBOSE) POLYMERASE (PARP) INHIBITOR AND TEMOZOLOMIDE (TMZ) SUPPRESSES GROWTH OF PEDIATRIC GLIOBLASTOMA MULTIFORME (GBM) AND MEDULLOBLASTOMA (MB) IN ORTHOTOPIC MOUSE XENOGRAFTS Jack Su,1 Li-Tiang Yu,1 Qin Shu,1 Adekunle Adesina,2 Torsten Pietsch,3 Joy Bauch,4 Brian Dayton,4 Vincent Giranda,4 Susan Blaney,1 Ching Lau,1 and Xiao-Nan Li1; 1Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA; 2Department of Pathology, Baylor College of Medicine, Houston, TX, USA; 3Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany; 4Abbott Laboratories, Abbott Park, IL, USA. Background: PARP is a nuclear enzyme that detects DNA breaks and activates DNA repair proteins in the base-excision repair (BER) and the nonhomologous end-joining (NHEJ) repair pathways. As the majority of TMZ-induced DNA adducts are repaired by the BER mechanism, it has been hypothesized that increased PARP activity may mediate tumor resistance to DNA alkylating agents such as TMZ. We demonstrated PARP overexpression in pediatric GBM and MB specimens, and we confirmed that PARP inhibition enhanced in vivo TMZ efficacy against pediatric GBM and MB xenografts in mice. Design and Methods: PARP expression in 18 pediatric GBM and 59 MB specimens was evaluated by immunohistochemistry (IHC) using an antibody detecting full-length PARP (Trevigen). Intracranial orthotopic MB and GBM xenografts in SCID mice were established using two MB cell lines (Daoy and MHH-MED1) and two patient-derived pediatric GBM cell lines. Two weeks after tumor injection, TMZ (q.d. × 5 days) and/or ABT-888 (b.i.d. × 5 days), an orally bioavailable PARP inhibitor from Abbott Laboratories, were administered. All treated animals received two courses of treatment (5 days of study drugs, followed by 23 days of rest). Survival durations were compared by log-rank analysis. Plasma and CNS concentrations of ABT-888 were measured by LC-MS. PARP and methylguanine methyltransferase (MGMT) activity was quantitated using published techniques. Ku70, BRCA1, MLH1, and MSH2 protein levels were measured by Western blot analysis. Results: Intense (3+) nuclear PARP IHC staining was detected in 61% (11 of 18) of GBM and 81% (48 of 59) of MB specimens, and intermediate (2+) PARP staining was seen in 28% (5 of 18) of GBM and 13% (8 of 59) of MB specimens. Normal pediatric cerebrum and cerebellum, in contrast, showed only faint (1+) cytoplasmic staining. TMZ and ABT-888 treatment moderately prolonged the survival of mice with Daoy xenografts (p = 0.054) and significantly prolonged the survival of mice with MHH-MED1 xenografts (p = 0.038), compared to the TMZ-only group. Combining ABT-888 and TMZ led to a similar improvement in survival in the two GBM models (p = 0.179 and p = 0.026). The brain:plasma ratio of ABT-888 concentration ranged from 15% to 69% (mean, 34% ± 17%), indicating good CNS penetration. Pretreatment PARP activity was comparable in the two MB xenografts, and ABT-888 treatment resulted in 20- to 50-fold reductions in PARP activity. Pretreatment MGMT activity and MLH1 and MSH2 protein levels were comparable in all four xenograft models and unaffected by ABT-888. However, Ku-70 and BRCA1 protein levels were reduced in the GBM xenografts after ABT-888 treatment. Conclusion: We demonstrated differential PARP expression in pediatric MB and GBM tumors versus normal brain tissue. Combining ABT-888 with TMZ dramatically reduced PARP activity and improved survival in mice with MB and GBM xenografts, independent of MGMT activity and mismatch repair proficiency. Reduction of key proteins in the NHEJ and homologous recombination repair pathways was observed in GBM xenografts after ABT-888 treatment. Our data support the addition of ABT-888 to radiation and DNA-damaging drugs to improve the treatment outcome for pediatric CNS tumors. BIO 5. COMPARISON OF THE WNT PATHWAY STATUS IN SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL TUMORS (SPNET) AND MEDULLOBLASTOMA Hazel Rogers,1 Suzanne Miller,1 James Lowe,2 Keith Robson,2 Marie-Anne Brundler,3 Beth Coyle,1 and Richard Grundy1; 1University of Nottingham, Nottingham, UK; 2Nottingham, UK; 3Birmingham, UK. Supratentorial primitive neuroectodermal tumors (sPNETs) are high-grade, predominantly pediatric, brain tumors. Although relatively rare, accounting for 3%–7% of pediatric CNS tumors, sPNETs are aggressive with a poor prognosis. Due to their rarity, relatively little research has been undertaken to understand the molecular genetic mechanisms involved. Previously sPNETs have been grouped together with medulloblastomas, due to their histological similarities. A number of developmental signaling pathways have been shown to be deregulated in medulloblastoma, which may suggest potential candidate genes to investigate in sPNETs. One such pathway is the WNT signaling pathway, which has a key role in cellular proliferation, differentiation, migration and adhesion. Pathway activation through the stabilization and nuclear accumulation of beta-catenin (CTNNB1) has been demonstrated in sporadic medulloblastomas. In the majority of cases this was caused by activating mutations in exon 3 of CTNNB1. Mutations occurred at or adjacent to residues that are phosphorylated to target the protein for degradation. A small study identified a single mutation in CTNNB1 exon 3 in one out of four sPNETs, however, no further research has been undertaken in sPNET. In this study WNT pathway status was investigated in 24 sPNETs and 40 medulloblastomas using immunohistochemistry of CTNNB1, enabling the determination of the cellular location of the protein. This serves as a marker for pathway status, where nuclear staining represents the active state and cytoplasmic inactive. The mutational status of exon 3 of CTNNB1 was also investigated by sequencing of DNA samples extracted from a subset of the tumors and correlated with the IHC results. Nuclear staining and therefore pathway activation was seen in 8 out of 24 (33%) sPNETs. However, mutation of exon 3 of CTNNB1 was seen in only one sample (4%) suggesting pathway activation was caused by an alternative mechanism or factor. The medulloblastoma samples displayed an equivalent percentage of nuclear staining of 35%. The mutation rate of CTNNB1 exon 3 found in sPNETs of 4% was lower than the rate found in medulloblastomas of 19%. The levels of pathway activation and mutation seen in the medulloblastomas agree with previously published results. WNT pathway activation has been demonstrated in 33% of sPNETs, which is equivalent to percentages seen in medulloblastoma. However, only one sPNET contained a mutation of exon 3 of CTNNB1, suggesting the pathway is activated by an alternative means. BIO 6. CONCURRENT ACTIVATION OF NOTCH CELL SIGNALING AND DELETION OF INK4A/ARF IN RADIAL GLIA CAUSES CEREBRAL EPENDYMOMA Nicholas G. Gottardo,1 Helen Poppleton,1 Robert Johnson,1 Sarah Sherr,1 David W Ellison,1 Karen Wright,1 Twala L. Hogg,1 and Richard J. Gilbertson1; 1St. Jude Children's Research Hospital, Memphis, TN, USA. Ependymoma is the third most common pediatric intracranial tumor; yet little is known about the biology of this disease. Up to 40% of children eventually succumb to their disease since total resection is required to ensure cure, and the disease is chemoresistant. Novel treatment strategies are urgently needed for ependymoma, but there has been a lack of validated molecular targets for therapeutic development. We previously reported that ependymomas are likely to arise from neural progenitor cells termed radial glia (RG) that are susceptible to anatomic site-specific genetic alterations (Taylor et al. Cancer Cell. 2005). As an example, we showed that all cerebral ependymomas activate NOTCH signaling and delete INK4a/ARF. To further test the hypothesis that cerebral RG are transformed by concurrent activation of NOTCH and inactivation of INK4a/ARF, we generated a Blbp-NICD transgenic mouse that expresses the intracellular domain of NOTCH1 in RG throughout the CNS. We bred these mice with Ink4a/Arf null mice. Blbp-NICD mice developed classical ependymomas that phenocopy the human disease precisely to include pseudorosettes, glial differentiation, and electron microscopic features of ependymomas. These tumors arise in both Blbp-NICD-Ink4a/Arf+/+ and Blbp-NICD-Ink4a/Arf–/– mice. Tumors develop with much longer latency in the Blbp-NICD-Ink4a/Arf+/+ mice (approx. 16 months) compared to approximately 6 months in Blbp-NICD-Ink4a/Arf–/– mice. Remarkably, tumors in Blbp-NICD-Ink4a/Arf+/+ mice spontaneously delete Ink4a/Arf. No tumors were observed outside the cerebrum despite the expression of the transgene in the hind brain and spine. Our data strongly support the hypothesis that RG are susceptible to transformation in site specific-forms of ependymoma; in the cerebrum this includes aberrant Notch signaling and concurrent Ink4a/Arf loss. This model represents the first spontaneous mouse model of ependymoma and should prove extremely useful for future biological studies and the development of new treatments. BIO 7. CONTRASTING TELOMERE DYNAMICS BETWEEN NEURONAL AND GLIAL PEDIATRIC BRAIN TUMORS (ON BEHALF OF CCLG BIOLOGICAL STUDIES COMMITTEE) Ruman Rahman,1 Lee Ridley,1 Siobhan Quinn,1 Beth Coyle,1 and Richard Grundy1; 1Childrens Brain Tumour Research Centre, University of Nottingham, Nottingham, UK. Telomeres are nucleoprotein structures consisting of highly repetitive DNA that cap chromosomal termini of human cells. Telomere length at birth ranges from 5 to 15 kb and upon successive rounds of cell division, telomeres erode, due in part to the inability of the lagging strand to faithfully replicate its ends. Eventually, telomere attrition triggers replicative senescence and subsequent widespread apoptosis. Thus telomeres are regarded as a cellular “mitotic clock,” representing a primitive tumor suppressor mechanism. Eroded telomeres are replenished, however, in highly proliferative cells, germ cells, and tumor cells by a homeostatic mechanism governed by the enzyme telomerase. Telomeric repeats are synthesized at the telomere substrate by telomerase using an intrinsic RNA component (hTERC) as template in a reverse transcription reaction catalyzed by its protein component (hTERT). Telomerase is active in approximately 90% of human tumors, stimulating a plethora of cancer therapeutic strategies targeting telomerase. We and others have previously demonstrated telomerase-mediated telomere maintenance as a key mechanism facilitating tumor progression in childhood Ependymoma. However, telomerase and telomere status of pediatric glioblastoma multiforme (GBM), sPNET, and PNET primary tissue has not been forthcoming, with only limited current data, derived from cell lines. Here we report a comprehensive descriptive characterization of telomerase activity and telomere length from isolated tumor tissue and explore the amenability of targeting telomerase in these tumors. Telomerase activity was evident in 7 of 7 GBM, 8 of 18 sPNET, and 20 of 20 PNET tumors, consistent with high tumor grade. Telomere length for sPNET DNA (mean, 5.2 kb; median, 4.8 kb; n = 15) was significantly shorter than those of patient-matched blood (mean and median, 6.3 kb; n = 5). Telomere dynamics were similar for PNET tumor DNA with telomere length significantly shorter (mean, 4.4 kb; median, 3.8 kb; n = 15) than those of blood (mean, 6.9 kb; median, 6.6 kb; n = 3). This was in contrast to mean GBM telomere length (mean, 8.3 kb; median, 8.6 kb; n = 7), comparable to telomere length from blood (mean, 8.5 kb; median, 8.5 kb; n = 4). Longer telomere length observed for GBM tumors is consistent with our previous findings in ependymoma (mean telomere length, 10.9 kb; median, 10.0 kb; n = 20). Hence we observe telomere length in primary tumors of neuroectodermal origin (4.9 kb ± 0.3) to be significantly shorter than glial tumor telomere length (8.8 kb ± 0.5) (p < 0.001). Furthermore, no significant difference was observed for mean and median age at diagnosis between neuroectodermal (5.8 years; 5.5 years; range, 0.2–12.0 years) and glial tumors (4.7 years; 4.0 years; range, 0.1–8.8 years). This intriguing contrast between embryonal (poorly differentiated) and further differentiated tumors hints at a fundamental difference in early neurogenesis with respect to cellular replicative history. Our results encourage consideration of varying telomere length dynamics when devising therapeutic strategies to achieve telomerase inhibition in pediatric brain tumors. We would predict the onset of replicative senescence and apoptosis to occur more rapidly in sPNET and PNET tumors upon inhibition. Histone deacteylase (HDAC) inhibitors are a category of telomerase inhibitors being studied as a treatment for cancer and neurodegenerative diseases and proposed to be associated with silencing of gene promoters, including that of hTERT. Induction of apoptosis and telomerase inhibition has recently been documented in adult GBM and medulloblastoma using TSA treatment. We are currently investigating this proof of concept using the HDAC inhibitor Trichostatin A on representative tumor lines, assaying for telomerase inhibition, cell viability, cell proliferation, and apoptosis. BIO 8. CROSS-TALK BETWEEN TUMOR CELLS AND ENDOTHELIUM TRIGGERS A STRONG CHEMOTACTIC SIGNAL RECRUITING T LYMPHOCYTES TO DISTANT MEDULLOBLASTOMA DEPOSITS Nabil Ahmed,1 Vita Salsman,2 Donald R Shaffer,2 Kadikoy Huseyin,3 Xiao-Nan Li,4 Laszlo Perlaky,4 Meenakshi Bhattacharjee,5 Cliona Rooney,6 Helen Heslop,6 and Stephen Gottschalk2; 1Texas Children's Cancer Center, Center for Cell and Gene Therapy, Houston, TX, USA; 2TX, USA; 3Baylor College of Medicine, TX, USA; 4Baylor College of Medicine, Houston, TX, USA; 5Pathology, Baylor College of Medicine, TX, USA; 6Houston, TX, USA. Background: Failure of local control is a poor prognostic factor that heralds incurable disease recurrence in medulloblastoma. In addition, recurrence is multifocal in up to 60% of patients, adding to the dismal prognosis of these patients. We have shown that genetically modified T-cells expressing engineered HER2-specific chimeric antigen receptors (HER2-T cells) induce regression of HER2-positive human medulloblastomas growing in the brains of mice after intratumoral injection. The objective of this project was to study the ability of HER2-T cells to achieve locoregional control in medulloblastoma. Methods: Mice with established human HER2-positive medulloblastoma xenografts (Daoy) were stereotactically injected into the contralateral hemisphere with HER2-T cells expressing the firefly luciferase (luc) gene to determine T-cell migration and expansion in vivo using bioluminesence imaging. To determine the antitumor activity of T-cells, unmodified HER2-T cells were injected into mice bearing luc-expressing Daoy tumors in the contralateral hemisphere. Chemokine expression and chemokine receptor profiles were determined by standard techniques and transwell assays were used to study T-cell migration ex vivo. Results: HER2-T cells migrated within the brain to distant primary medulloblastoma and Daoy xenografts as judged by bioluminescence imaging. Within 48 h of injection HER2-T cells clustered at the tumor site and proliferated as judged by imaging as well as immunohistochemistry for the non-G0 marker Ki-67. HER2-T cells had potent antitumor activity after injection into the contralateral hemisphere of tumor bearing mice, inducing tumor regression, which resulted in a survival advantage of treated animals. To investigate the mechanism of in vivo T-cell migration, we analyzed the chemokine expression profile of Daoy cells and primary medulloblastoma cells, revealing only the presence of chemokines like CXCL-8 (IL-8) and MIF for which HER2-T cells did not have chemokine receptors on their cell surface. Consistent with this finding, supernatants from Daoy cells failed to induce T-cell migration in transwell migration assays. To determine if brain tumor endothelial cells trigger T-cell migration we used supernatants from the murine glioma endothelial cells (b.END.3) as a chemoattractant but also did not observe T-cell migration. However, supernatants derived from cocultures of Daoy and b.END.3 cells induced strong T-cell migration. Chemokine expression analysis revealed high levels of human RANTES (CCL5), for which HER2-T cells expressed the corresponding chemokine receptor. Conclusions: We have shown that HER2-T cells migrate to tumor sites within the CNS, expand at tumor sites, and induce regression of medulloblastoma xenografts in vivo. Our results also suggest that “cross-talk” between tumor and tumor endothelium plays a major role in creating a chemotactic gradient for T-cell migration. Hence, the adoptive transfer of HER2-T cells represents a promising immunotherapeutic approach to control locoregionally advanced, incompletely resected and/or drop-metastatic medulloblastoma. BIO 9. CYCLIN-DEPENDENT KINASE 6 IS REGULATED BY MICRORNA 124 IN MEDULLOBLASTOMA Jessica Pierson,1 Rong Fan,1 and Rajeev Vibhakar1; 1Department of Pediatrics, University of Iowa, Iowa City, IA, USA. Background: Medulloblastoma comprises approximately 20% of all primary pediatric brain tumors. Despite advances in treatment with surgery, radiation, and chemotherapy, patients with high-risk and infant tumors continue to do poorly. Recently increased expression of cyclin-dependent kinase 6 (CDK6) was identified as an adverse prognostic marker in medulloblastoma. Genomic amplification accounts for some but not all of the CDK6 overexpression. MicroRNAs are a large family of small, noncoding RNAs with gene regulatory functions. They consist of 18–22 nucleotide RNA molecules with posttranscriptional gene silencing activity. In addition to their role in normal development, microRNAs are also associated with carcinogenesis. Hypothesis: CDK6 expression is regulated by microRNAs in medulloblastoma. Methods: Medulloblastoma cell lines Daoy, D283 Med, and D341 Med were cultured under standard conditions. Primary cell cultures were derived from biopsy specimens of medulloblastoma patients. Total RNA was isolated from medulloblastoma cell lines or brain tissues using the mirVANA RNA isolation kit (Ambion, Austin, TX, USA). MicroRNA expression was measured by quantitative RT-PCR with MicroRNA primers and probes from Applied Biosystems on an ABI 7700 cycler. Luciferase experiments were done using the the siCHECK dual luciferase system (Promega, Madison, WI, USA). The putative miR 124a target sites from the CDK6 3' UTR were cloned into the 3' UTR of the Renilla luciferase gene. Target sites were amplified by PCR and mutations introduced by alternate primers. Cells were transfected with 0.5 μg siCHECK using LT1(Mirus, Madison, WI, USA), and Renilla luciferase activity was measured 48 h after transfection and normalized to firefly luciferase. Some cells were cotransfected with 50 or 100 nM miR 124a microRNA oligonucleotide (Ambion). Western blotting was performed per standard methods. Cell proliferation was measured at 48 h using Cell Titer AQeous (Promega), and apoptosis was measured by caspase activation using the Caspase-Glo 3/7 assay kit (Promega) according to the manufacturer's instructions. Results: We identified putative miR sites in the CDK6 UTR by using three well-known bioinformatic algorithms (TargetScan v4.0, PICTAR, and miRBase). Among the potential microRNA (miR) sites was microRNA 124a, a brain-enriched microRNA. Expression of miR 124a was significantly decreased in Daoy, D283 Med, and D341 Med cell lines and in primary cells compared to normal adult cerebellar RNA. To establish a functional association between miR 124a and CDK6 in medulloblastoma we performed analysis of the putative miR 124a binding sites from the CDK6 3' UTR using luciferase assays. Cotransfection of siCHECK-CDK6 with miR 124a oligonucleotides (100 nM) decreased firefly luciferase activity to 34% of vector alone control. Mutation of both target sites restored luciferase activity to 93% of control. Additionally, re-expression of miR 124a in Daoy medulloblastoma cells decreased expression of CDK6 protein levels. Transient transfection of miR124 RNA oligonucleotide significantly decreases D283 medulloblastoma cell growth but does not alter apoptosis. Furthermore, in patient samples expression of miR 124a is significantly decreased. Conclusions: Our data strongly indicate that CDK6 is regulated by microRNA 124 in medulloblastoma. MiR124 expression is significantly decreased in medulloblastoma, and re-expression of miR 124 in medulloblastoma cells significantly decreases proliferation. BIO 10. DETECTION OF HUMAN HERPESVIRUS 6 VARIANTS IN PEDIATRIC BRAIN TUMORS: ASSOCIATION OF VIRAL REPLICATION IN LOW-GRADE GLIOMAS John Crawford,1 Mariarita Santi,2 Hallidora Thorarinsdottir,3 Robert Cornelison,4 Elisabeth Rushing,3 Steve Jacobson,5 and Tobey Macdonald3; 1George Washington University, Washington, DC, USA; 2Children's National Medical Center, Washington, DC, USA; 3DC, USA; 4Bethesda, MD, USA; 5MD, USA. Human herpesvirus 6 (HHV6) has been implicated in the pathogenesis of encephalitis, epilepsy, and multiple sclerosis. Since HHV6 is a common virus acquired during childhood, we screened a series of pediatric brain tumors with known clinical information for HHV6 DNA by nested PCR and in situ hybridization. HHV6 major capsid protein DNA was detected in 53% (n = 64) of paraffin-embedded and 58% (n = 24) of fresh frozen tumors compared to 22% (n = 32) of age-matched nontumor brain (p = 0.0008). HHV6 large tegument protein DNA was found in 73% of paraffin-embedded, 71% of fresh frozen, and 38% of control brain (p = 0.019); 73% of tumors were HHV6 variant A compared to 33% of control brain. In situ hybridization for HHV6 was found in 54% of brain tumors (n = 137) and 31% control brain (n = 32; p = 0.021), and was not limited to areas exclusively containing tumor on surgical resection. To establish the presence of active HHV6, immunohistochemistry was performed using HHV6 variant nonspecific gp116/54/64 antibody; 40% (n = 124) of tumors were positive compared to 18% (n = 32) of controls (p = 0.013). Interestingly, 58% of low-grade gliomas were immunopositive compared to 19% of high-grade gliomas (p = 0.002) and 25% of nongliomas (n = 36). Immunofluorescence microscopy confirmed the association of HHV6 antigen in cells of glial origin through colocalization with glial fibrillary acidic protein. There was no association between HHV6 immunopositivity and patient age at diagnosis (p = 0.12), gender (p = 0.22), or progression-free survival (p = 0.861). We provide the first reported association between HHV6 and pediatric brain tumors; these findings may provide insight into potential disease mechanisms. BIO 11. DIFFERENTIAL EXPRESSION OF CELL DIVISION CONTROL PROTEINS IN PEDIATRIC VERSUS ADULT EPENDYMOMAS AND COMPARISON TO OTHER INFILTRATING GLIOMAS: PRELIMINARY RESULTS Jose Otero,1 and Tarik Tihan1; 1Pathology, UCSF, San Francisco, CA, USA. Background: Ependymomas are glial tumors thought to be derived from the ependymal cells or their precursors and are among the most common tumors in the pediatric age group. Prognosis in ependymomas is influenced by a number of factors, such as age at diagnosis, extent of resection, and histological grade. Recent studies also suggest a negative correlation between proliferative rate of ependymomas and their survival probability, which raises the possibilities that cell cycle regulation may be differentially regulated in ependymomas with high proliferation rates and differ between pediatric and adult ependymomas. Methods: In order the determine the activation of a critical cell cycle checkpoint, we examined the activity of cdc2, a cyclin dependent kinase whose activity is required for the G2-M phase transition. We have analyzed 20 ependymomas (nine pediatric cases and 11 adult cases) by immunohistochemical staining for the activated and inhibited forms of cdc2 and its downstream targets in tissue microarrays and compared the results to oligodendrogliomas (20 WHO grade II and 17 WHO grade III tumors, including two patients 15 and 17 months of age), and glioblastomas (45 newly diagnosed and 15 recurrent). Results: Most ependymomas showed low staining for activated and inhibited cdc2. However, all cases showing elevated staining for activated cdc2 were found within the pediatric population. Most GBMs showed higher staining of both inhibited and activated cdc2 relative to oligodendrogliomas and ependymomas. Conclusion: In this preliminary study, recognition of increased activation through cdc2 can account for the increase in the proliferative rate of pediatric ependymomas. Mitotic cells positive for inhibited cdc2 were detected in GBM and anaplastic oligodendroglioma, suggesting that these tumors transitioned from G2-M phase despite inhibited cdc2. Since our study did not have sufficient power to correlate cdc2 activation with outcome in a reasonable fashion, a larger study is under way to determine the exact relationship of this pathway with patient outcome. BIO 12. DIFFERENTIAL MECHANISMS OF TEMOZOLOMIDE RESISTANCE IN PEDIATRIC GLIOMA CELL LINES Nathalie Gaspar,1 Lynley Marshall,2 Dorine Bax,2 Marta Viana-Pereira,3 Suzanne Little,2 Lara Perryman,2 Gilles Vassal,4 Andrew Pearson,5 Paul Workman,1 Rui Reis,3 Darren Hargrave,5 and Chris Jones2; 1Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK; 2Paediatric Oncology, Institute of Cancer Research, Sutton, Surrey, UK; 3Life and Health Science Research Institute (ICVS), University de Minho, Portugal; 4Institut Gustave Roussy, Villejuif, Paris, France; 5Paediatric Oncology, Royal Marsden Hospital, Sutton, Surrey, UK. The alkylating agent temozolomide (TMZ) has been demonstrated to have antitumor activity in glioblastoma multiforme (GBM), although sensitivity is restricted to a subset of patients. Resistance to TMZ in adult GBM patients is associated with two major mechanisms: lack of promoter methylation of the gene encoding the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) and deficiencies in mismatch repair (MMR) enzymes. In the pediatric setting, concurrent with the limited clinical and biological data is a paucity of preclinical information in model systems derived from pediatric glioma patients. We have screened a series of 11 glioma cell lines (six adult high grade, three pediatric high grade, and two pediatric low grade) for TMZ efficacy in vitro and have investigated the differential mechanisms of TMZ resistance involved. The cell line panel comprised adult GBM (LN229, A172, U118MG, U138MG, U87MG, SF268), pediatric GBM (SF188, KNS42), pediatric anaplastic astrocytoma (UW479), pediatric grade II astrocytoma (Res259/UW467), and juvenile pilocytic astrocytoma (Res186/Res199). Response to TMZ was assessed in triplicate by the SRB assay. Three adult GBMs (SF268, LN229, A172) and a pediatric grade II line (Res259/UW467) were sensitive to TMZ, with mean IC50 values ranging from 11.3 to 20.9 μM. The remaining resistant lines had IC50 values of 407.8–949.3 μM. MGMT protein expression was assessed by Western blotting and promoter methylation by methylation specific (MS)-PCR and MS-MLPA. There was a direct relationship between MGMT promoter methylation by both assays and protein expression, and in the majority of cases a lack of methylation, and subsequent overexpression, was linked to TMZ resistance (U118MG, U138MG, SF188, UW479, Res186/Res199). The two exceptions were the adult GBM line U87MG and the pediatric GBM line KNS42. We further screened by Western blotting and MS-MPLA the MMR proteins MLH1, MLH3, MSH2, MSH3, MSH6, and PMS2, however, there were no deficiencies observed in U87MG or KNS42. The U87MG cells are PTEN null, which may explain in part the TMZ resistance due to constitutive Akt activation, however, the KNS42 cells are PTEN wild-type. They do, however, harbor a homozygous TP53 mutation (R342*), although the link between mutant p53 and TMZ resistance is controversial. In order to investigate alternative mechanisms of TMZ resistance in these cells, we carried out expression profiling by Affymetrix U133 Plus2.0 microarrays. Among 52 differentially expressed genes between sensitive and resistant cell lines was an enrichment of genes associated with phosphodiesterase activity, significantly dysregulated in KNS42, and thus providing a link between TMZ resistance and the base excision repair pathway. These data provide an extensive characterization of the in vitro efficacy of TMZ in pediatric glioma model systems and demonstrate that novel mechanisms of resistance may be active in childhood GBM. BIO 13. DISABLING THE PROLIFERATIVE AND THE REPLICATIVE ABILITY OF MEDULLOBLASTOMA AND TERATOID/RHABDOID CNS TUMOR CELLS BY A NOVEL TELOMESTATIN DERIVATIVE Tarek Shalaby,1 Andre Von Bueren,1 Marie-Louise Hürlimann,2 Giulio Fiaschetti,2 Deborah Castelletti,2 Kazuo Shin-Ya,3 Alexandre Arcaro,1 and Michael Grotzer4; 1Department of Oncology, University Children's Hospital of Zurich, Switzerland, Zurich, Switzerland; 2Department of Oncology, University Children's Hospital of Zurich, Switzerland, Switzerland; 3National Institute of Advanced Industrial Science and Technology, Tokyo, Japan; 4University Children's Hospital of Zurich, Zurich, Switzerland. Small molecules that stabilize the G-quadruplex structure in c-myc promoter sequences have shown potential as a new opportunity for cancer therapy. Employing this innovative line of attack to cancer cells, we investigated the effects of S2T1-60TD, a novel telomestatin derivative that specifically targets c-myc promoter, on a representative panel of medulloblastoma (MB) and atypical teratoid/rhabdoid (AT/RT) children's brain cancer cell lines. In remarkable contrast to control cells, treatment (72 h) with S2T1-60TD exhibited a clear antiproliferative effect in all cell lines tested, in a dose- and time-dependent manner and with IC50 at submicromolar levels (0.25–0.39 μM). Importantly, S2T1-60TD demonstrated significantly less cytotoxic effects on normal (not cancer) fibroblast MCR-5 cells (IC50 for MCR-5 was 5× more than the IC50 of MB and AT/RT cells). Seventy-two–hour treatment with S2T1-60TD reduced the mRNA and protein expressions of c-myc and hTERT—that is, transcriptionally regulated by c-myc—and decreased both genes activities. Under conditions where inhibition of both proliferation and c-myc activity were observed, S2T1-60TD treatment decreased the protein expression of the cell cycle activator CDK2 and resulted in cell cycle arrest. Long-term treatment with nontoxic concentrations of S2T1-60TD resulted in time-dependent telomere shortening, which was accompanied by cell growth arrest (starting on day 28) and was followed by cell senescence and induction of apoptosis at day 35 in all of the five cell lines investigated. In this study, we present evidence showing that the use of S2T1-60TD compound to target both c-myc deactivation and telomere maintenance disruption has resulted in the obstruction of proliferation of the MB and AT/RT cancer cells and disabled their ability to replicate. Upon in vivo animal testing, S2T1-60TD may well represent a potential effective and innovative therapeutic strategy for childhood brain tumors. BIO 14. DISTINCTIVE MOLECULAR PROFILE OF RADIATION-INDUCED GLIOBLASTOMA Andrew Donson,1 Nicole Erwin,2 B.K. Demasters,3 Diane Birks,4 and Nicholas Foreman4; 1University of Colorado Health Sciences Center (UCHSC), Aurora, CO, USA; 2Pediatrics, UCHSC, CO, USA; 3UCHSC, CO, USA; 4Aurora, CO, USA. Radiation-induced glioblastomas (RIGs) represent a significant proportion of glioblastomas (GBMs) seen in children and young adults and manifest poor prognosis. Little is known about their underlying biology, although limited studies have suggested no unique histological or cytogenetic characteristics to distinguish them from de novo GBMs. In this study, we investigated RIGs using gene expression microarray profiling and Western blot analysis. Despite the inability of histological and molecular genetic studies to identify distinguishing features between RIGs and pediatric GBMs, gene microarrays showed significant differences between these two tumor types. Greater overlap was detected in gene expression patterns between RIGs and pilocytic astrocytomas (PAs) than between RIGs and pediatric GBMs, medulloblastomas, ependymomas, atypical teratoid/rhabdoid tumors, or rhabdomyosarcoma, suggesting a common precursor cell for RIG and PA. Examination of the genes that constitute the RIG profile showed that a number of clinically relevant molecules are overexpressed in RIG relative to pediatric GBM. Specifically, we showed that platelet-derived growth factor receptor alpha (PDGFRa) and ErbB3 were strongly expressed at both the RNA and protein levels. These proteins may provide a therapeutic target for novel small molecule inhibitors. As an example of how this information can be applied, we used the unique RIG gene expression profile in order to elucidate the etiology in the case of a GBM arising in the site of a treated medulloblastoma. It was debated whether the new astrocytic tumor represented a progression of the medulloblastoma or a radiation-induced neoplasm. Gene microarray assessment showed that the original tumor clustered with other standard medulloblastomas. However, the secondary tumor manifested a genetic expression profile concordant with other radiation-induced glioblastomas and dissimilar to pediatric GBM or standard medulloblastomas studied in our laboratory. In conclusion, the characterization of the molecular pathology of RIG provides a diagnostic tool as well as insight into the etiology of these neoplasms and rationale for design of novel therapeutic regimens for this highly aggressive tumor. BIO 15. DO ALL GLIAL TUMORS OF THE CHILD CONTAIN CANCER-INITIATING CELLS? Barbara Bessette,1 Pascale Varlet,2 Sebastien Dubleumortier,1 Christelle Dufour,3 Josette Cadusseau,4 Catherine Daumas-Duport,2 Jacques Grill,3 Christian Sainte-Rose,5 Herve Chneiweiss,1 Stephanie Puget,5 and Marie-Pierre Junier1; 1Inserm U752, Paris, France; 2Department of Pathology–Neuro-Oncology, Sainte-Anne Hospital, Paris, France; 3Institut Gustave Roussy Villejuif, Villejuif, France; 4Inserm U841, Creteil, France; 5Necker Sick Children's Hospital, Paris, France. Background: Physiopathological understanding of malignant high-grade gliomas in children is made difficult by their heterogeneous appearances, and the variability in clinical evolutions of patients bearing tumors of similar histopathological aspects. Recent isolation of tumor-initiating cells (TICs) having some of the properties of neural stem cells in medulloblastomas and adult gliomas opens novel insights into the development and therapeutic resistance of primitive brain tumors. Data being scarce with respect to pediatric gliomas, we aimed at isolating TIC from 18 of these tumors and from four embryonal tumors. Our approach was based on the fact that TICs can be isolated upon their ability to develop in defined medium supplemented with EGF and bFGF under the form of floating cellular spheres (FS), to self-renew and to be clonally derived. Material and Methods: Tumors corresponded to nine low-grade glial or neuronal-glial tumors (one pilocytic astrocytoma, two ANET, six gangliogliomas), nine high-grade glial tumors (four ependymomas III, one oligoastrocytoma III and its reccurence, one brainstem glioblastoma, two infiltrating brainstem astrocytomas). Six of these high-grade gliomas and one clear-cell ependymoma had the characteristics of malignant glioneuronal tumors according to Hospital Sainte-Anne's classification. Embryonal tumors comprise three medulloblastomas and one ATRT. One cavernoma and one biopsy taken at distance from a pilocytic astrocytoma were used as nontumoral control tissues. Culture ages range from 25 days to >3 months at this time. Results: Viable cells anchored to the culture dish were observed in all cases. No FS were observed in the ATRT, and nontumoral tissue-derived cultures up to 30 DIV (days in vitro). As expected, all medulloblastoma-derived cultures contained FS within 10 DIV. FS developed in 66% of the low-grade glial and glioneuronal tumors and 100% of high-grade glial tumors within 7 DIV. Medulloblastoma-derived FS self-renewed for at most 2.3 months prior to death, the numbers of FS doubling each 6.4 ± 0.9 days (rate of self-renewal, mean ± SEM). No significant difference was noted with respect of rates of renewal between low- and high-grade tumors (7.9 ± 1.3 days for gangliogliomas over 3 months, vs. 8.1 ± 1.4 rate for ependymomas III over 2–3 months). Brainstem glioma–derived FS are ongoing self-renewal at a rate of 5.5–13.3 days. At this time, 50% of the low-grade tumors, all accounted for by gangliogliomas, and 78% of high-grade glial tumors are still undergoing self-renewal. Conclusion: Further characterizations will indicate if the pediatric glial tumor derived–FS contain TICs. They will include determination of their karyotype, of their proteomic profile, and, most importantly, of their capability upon grafting in immunodeficient mice brain to generate tumor exhibiting morpho-phenotypes alike to the original tumor. BIO 16. DUAL-SPECIFIC ANTIBODY, D2C7 (SCDSFV)-PE38KDEL FOR BRAIN TUMOR THERAPY Vidyalakshmi Chandramohan,1 Charles N. Pegram,1 Scott E. Szafranski,1 Stephen T. Keir,1 Ira Pastan,2 Chien-Tsun Kuan,1 and Darell D. Bigner1; 1Pediatric Brain Tumor Foundation Institute, Duke University Medical Center, Durham, NC, USA; 2National Cancer Institute, Bethesda, MD, USA. Brain tumors are the second most frequent malignancy among children, comprising about 17% of all pediatric cancer cases. In the United States, approximately 2,200 children are diagnosed annually with invasive brain tumors, of which astrocytomas account for about 52%, primitive neuroectodermal tumors 21%, other gliomas 15%, and ependymomas 9%. The epidermal growth factor receptor (EGFR) is expressed by normal epithelial cells in most tissues but overexpressed in gliomas: 27%–57% in astrocytomas, 71%–94% in anaplastic astrocytomas, and 60%–90% in glioblastoma multiforme (GBMs). In addition, 58%–61% of all GBMs also express the EGFR variant III mutant (EGFRvIII), which is not found in normal tissues. Monoclonal antibodies targeting either the wild-type EGFR (EGFRwt) or EGFRvIII have been developed, and one of them, D2C7, a murine IgG1κ, recognizes both the EGFRwt and tumor-specific EGFRvIII receptors. In the present study, we have demonstrated cloning of a novel, recombinant single-chain variable-region antibody fragment from the D2C7 hybridoma and have engineered a disulfide-stabilized linkage between variable heavy and light domains to generate D2C7 (scdsFv). The D2C7 (scdsFv) is connected to a truncated variant of Pseudomonas exotoxin A, carrying a C-terminal KDEL peptide for improved intracellular transport (PE38KDEL). The binding affinity of D2C7 (scdsFv)-PE38KDEL for the EGFRwt and the EGFRvIII extracellular domain (ecd) was 6.3 × 108 (mol/liter)–1 and 7.8 × 108 (mol/liter)–1, respectively, as measured by surface plasmon resonance. Flow cytometry of EGFRwt-transfected (NR6W), EGFRvIII-transfected (NR6M), and parental NR6 cells, a mouse 3T3 fibroblast cell line that naturally lacks EGFR expression, further confirmed the dual specificity of D2C7 (scdsFv)-PE38KDEL for the two forms of transfected cells. The immunotoxin was highly cytotoxic, with an IC50 of 1 ng/ml and 3 ng/ml, respectively, on cells expressing the EGFRwt (NR6W) and EGFRvIII (NR6M) receptors. There was no cytotoxic activity at 1,000 ng/ml on the parental NR6 cells. The cytotoxicity of D2C7 (scdsFv)-PE38KDEL on the pediatric GBM cell line D2159MG, expressing both the EGFRwt and EGFRvIII receptors, was 3 ng/ml. The combination of good affinity and cytotoxicity makes this immunotoxin a promising candidate for further evaluation for treatment of pediatric astrocytic tumors. BIO 17. DUPLICATION OF 7Q34 IN PEDIATRIC LOW-GRADE ASTROCYTOMAS DETECTED BY HIGH-DENSITY SNP-BASED GENOTYPING A.J. Sievert,1 E.M. Jackson,2 X. Gai,3 H. Hakonarson,4 A.R. Judkins,5 A.C. Resnick,2 T.H. Shaikh,4 and J.A. Biegel4; 1Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; 2Department of Neurosurgery, University of Pennsylvania School of Medicine, PA, USA; 3Center for Biomedical Informatics, The Children's Hospital of Philadelphia, PA, USA; 4Division of Human Genetics, The Children's Hospital of Philadelphia, PA, USA; 5Department of Pathology, The Children's Hospital of Philadelphia, PA, USA. Pediatric low-grade astrocytomas are a heterogeneous group of tumors whose pathogenesis is not well understood. Histological diagnosis can be subjective. Moreover, the molecular characteristics of the tumors are not well described. A gain of chromosome 7 is the most commonly detected abnormality by cytogenetic analysis; however, this is found in only a minority of patient samples. More recently, studies utilizing comparative genomic hybridization have also failed to consistently find a unique genetic signature pattern for this set of tumors. We sought to identify novel genetic abnormalities such as duplications, deletions, loss of heterozygosity, and copy number variations, using high-density SNP-based microarray technology. DNA was extracted from snap-frozen specimens of 24 pediatric low-grade astrocytomas collected in our institution from 1998 through 2006. DNA samples were analyzed using the Illumina HumanHap 550K microarray platform. The microarray data were analyzed for copy number alterations using our Bioinformatics Core-Copy Number Analysis, Annotation, and Visualization tool. Results were compared to a database of known, common copy number variations seen in healthy controls. We found a consistent and unique duplication in the 7q34 region, previously not described. The 7q34 duplication was found in 13 of 15 (86.7%) juvenile pilocytic astrocytoma samples, one of which also had a whole chromosome copy number gain, and in 5 of 8 (62.5%) fibrillary astrocytoma samples. The sole astrocytoma, NOS sample did not have this duplication but did have a whole chromosome 7 copy number gain. Fluorescence in situ hybridization analysis using 7q and 7 centromere probes confirmed the 7q34 duplications. The 7q34 duplication was not identified in a set of 12 ganglioglioma, 20 ependymoma, and 3 anaplastic astrocytoma samples or a set of 3,000 normal control DNAs analyzed with the Illumina HumanHap 550K platform. We found >30 genes in the duplicated region using the UCSC genome browser; however, the homeodomain protein kinase 2 (HIPK2) gene seemed the most likely candidate given the recent body of literature describing its role not only in apoptosis but also in neuron cell survival. Mutation analysis of all 15 exons of HIPK2 yielded only known single nucleotide polymorphisms and alternative splice sites. Immunohistochemistry of 11 matched paraffin-embedded samples both with and without the 7q34 duplication using a commercially available HIPK2 antibody (Abcam) demonstrated normal nuclear staining. There was no cytoplasmic localization, which has been previously described with HIPK2 gene mutations. Real-time PCR and Western blot analysis did not show any differences in gene or protein expression between the different tumors. In summary, we have described a novel 7q34 duplication in a majority of pediatric low-grade astrocytoma samples that appears to be unique to this group of tumors. Our exploration of HIPK2 as a potential candidate gene failed to yield abnormalities by mutation analysis and/or gene expression; however, it is an intriguing gene as it has multiple transcriptional and p53 interactions. The 7q34 duplication is a novel genetic abnormality and further evaluation of genes in this region may help to explain the pathogenesis of juvenile pediatric astrocytomas and fibrillary astrocytomas. BIO 18. EFFECTIVENESS OF A RODENT BRAINSTEM GLIOMA MODEL FOR THERAPEUTIC TESTING Rintaro Hashizume,1 Tomoko Ozawa,1 Eduard Dinca,1 Anuradha Banerjee,1 Michael Prados,1 C. David James,1 and Nalin Gupta1; 1University of California, San Francisco, San Francisco, CA, USA. Introduction: The prognosis for brainstem tumors remains extremely poor. Therapeutic testing of new agents and delivery strategies is limited by the lack of well-characterized model systems. In this study, we demonstrate the morphologic features and growth kinetics of an orthotopic brainstem tumor model in athymic rats. Tumor growth was quantitatively determined by in vivo bioluminescence imaging (BLI). Effectiveness of the model system was tested by comparing oral and intra-nasal delivery of temozolomide. Distribution studies for intranasal delivery using fluorescence-labeled liposomes were also performed. Methods: U87MG glioblastoma cells were implanted into the pontine tegmentum of athymic rats. This cell line was modified to constitutively express luciferase by lentivirus infection. Survival time, location of the tumor, and time to development of symptoms were measured. In vivo BLI was performed using the Xenogen Lumina Imaging Station (Caliper Life Sciences) coupled to a data-acquisition PC running Livingimage software. Results: Histopathologic analysis and BLI showed progressive tumor growth in all animals, with symptoms indicative of tumor burden between 26 and 31 days. Animals were euthanized at the onset of symptoms. BLI correlated with tumor volume calculated by three-dimensional measurements from serial histologic sections. For efficacy experiments, rats in one group received temozolomide delivered by oral gavage (50 mg/kg for 12 days), while the other group received intranasal delivery (10 mg/kg in 65 μl for 12 days). Animals treated with temozolomide, either by oral or intra nasal route, survived >50 days after implantation. Longitudinal BLI revealed a sustained decrease in luminescence of temozolomide-treated animals. Intranasal delivery with fluorescent liposomes showed accumulation of fluorescence in the pons 6 h after treatment. Conclusions: This orthotopic brainstem tumor model system allows a reproducible assessment of survival defined by time to development of symptoms and should facilitate testing of preclinical therapeutic agents and novel delivery strategies. Tumor response to therapeutic agents can be noninvasively measured using BLI. Intranasal delivery may be an effective noninvasive method for the treatment of brainstem glioma. BIO 19. EGFRVIII DELETION MUTATIONS IN PEDIATRIC HIGH-GRADE GLIOMA AND RESPONSE TO ERLOTINIB IN PEDIATRIC GLIOMA CELL LINES Dorine Bax,1 Nathalie Gaspar,2 Lynley Marshall,1 Suzanne Little,1 Marie Regairaz,3 Lara Perryman,1 Jorge Reis-Filho,4 Safa Al-Sarraj,5 Gilles Vassal,3 Andrew Pearson,6 Darren Hargrave,6 Paul Workman,2 David Ellison,7 and Chris Jones1; 1Pediatric Oncology, Institute of Cancer Research, Sutton, Surrey, UK; 2Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK; 3Institut Gustave Roussy, Villejuif, Paris, France; 4Breakthrough Breast Cancer, Institute of Cancer Research, London, UK; 5Neuropathology, Kings College Hospital, London, UK; 6Paediatric Oncology, Royal Marsden Hospital, Sutton, Surrey, UK; 7St. Jude Children's Research Hospital, TN, USA. Erlotinib (Tarceva, OSI-774) is a selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase and has shown activity in adult high-grade glioma (HGG) patients. A differential therapeutic response has been reported in these cases, with a variety of factors reported to be predictive for treatment efficacy, including activating mutations of EGFR and a wild-type PTEN. EGFR has been considered to play a less important role in pediatric glioma, although extensive data is lacking. We have sought to clarify the molecular pathology of EGFR in pediatric HGG and to assess the in vitro sensitivity of pediatric glioma cell line models to erlotinib. We retrospectively studied a total of 76 formalin-fixed, paraffin-embedded (FFPE) pediatric HGG specimens for EGFR overexpression, amplification, and mutation; 37% of cases demonstrated protein expression by immunohistochemistry. Gene amplification was detected by chromogenic in situ hybridization (CISH) in 18% cases, with a corresponding overexpression of the receptor. These cases had a shorter median overall survival time than those without amplification/overexpression (p < 0.05, log-rank test). None of the 76 samples contained mutations in either the extracellular (exons 2–8) or the tyrosine kinase domains (exons 18–21) of EGFR, as assessed by direct sequencing. By contrast, the exon 2–7 deletion mutation EGFRvIII was detected by RT-PCR and direct sequencing in 6 of 33 (18%) samples from which RNA was available. Seven pediatric glioma cell lines (three high grade: SF188, KNS42, UW479; two low grade: Res259/UW467, Res186/Res199) and two adult high-grade lines (U87MG, SF268) were assessed in triplicate for erlotinib efficacy in vitro by the MTS assay. Of note were the pediatric GBM lines—SF188 was sensitive to EGFR inhibition by erlotinib, with an IC50 of 7 μM, while KNS42 was relatively resistant. Neither these, nor any other pediatric cell lines demonstrated appreciable EGFR protein expression by Western blot, and no activating mutations were found. We further created clones of U87MG (adult GBM, PTEN null) and SF188 (pediatric GBM, PTEN wild-type) stably transduced with either wild-type EGFR or EGFRvIII. Sensitivity to erlotinib was enhanced in clones containing the EGFRvIII construct in both cell lines, but not those overexpressing the wild-type receptor. These data identify an elevated frequency of EGFR gene amplification and EGFRvIII mutation in pediatric high-grade glioma than previously recognized and demonstrate the potential of treatments targeting the receptor in deletion mutant-positive cases. BIO 20. EPIDERMAL PATHWAY GROWTH FACTORS IN CHILDHOOD EPENDYMOMA Juliette Hukin,1 Tami Yamashita,2 Stephen Yip,3 Tamir Ailon,4 Michael Sargent,4 Ashtosh Singhal,4 Ruth Milner,4 Chris Fryer,5 Glenda Hendson,4 John Maguire,4 Cynthia Hawkins,6 and Sandra Dunn7; 1University of British Columbia, Vancouver, BC, Canada; 2University of Kingston, Ontario, ON, Canada; 3MA, USA; 4BC, Canada; 5British Columbia's Children's Hospital, Vancouver, BC, Canada; 6ON, Canada; 7Departments of Pediatrics, Experimental Medicine, and Medical Genetics, Child and Family Research Institute, Vancouver, BC, Canada. Introduction: The overall survival rate of childhood ependymoma is 30%–50%, inferior to that of adult ependymoma. Unfortunately, the current WHO grading system for intracranial ependymoma is not predictive of outcome. In other childhood malignancies, biologic characteristics of the tumors identify clinically relevant subsets of high-, intermediate-, or low-risk patients. Hypothesis: Signaling components of the HER family: EGFR, HER-2, and YB-1 will provide a better risk stratification than the current histologically based classification system. Methods: We performed a retrospective review of all children <17 years of age at diagnosis of ependymoma in British Columbia since 1982. The charts were reviewed, and the imaging and pathology were centrally evaluated. Tissue microarray (TMA) slides were constructed using cases in which the specimen was successfully retrieved. Each case was represented by triplicate (3) formalin-fixed, paraffin-embedded core biopsies on positively charged slides. TMA slides were immunostained for YB-1, EGFR, and HER-2. The TMA slides were incubated with either anti-YB-1 (1:250 dilution, Dr. Colleen Nelson from UBC), anti-EGFR (1:100 dilution, Stress-Gen Bioreagents) or anti-HER-2 (1:100 dilution, Lab Vision Corporation). For the YB-1 immunostain, each core was scored for both nuclear and cytoplasmic staining intensity and for EGFR and HER-2 generalized staining intensity on a scale from 0 to 3. Scores from the triplicate cores were averaged for each case. For YB-1 nuclear staining and HER-2, cases with an average score greater than 0 were considered positive. For YB-1 cytoplasmic and EGFR staining, cases with an average score ⩾2 were considered positive. Kaplan-Meier overall survival was performed using SPSS software (Sutherland, Oncogene 2005). Results: We reviewed the clinical data, centrally reviewed the pathology and radiology, and obtained cores for TMA in 46 of 59 patients diagnosed in this time period. The median age of this group is 5.3 years (range, 0.2–14.3). Three patients were WHO grade I, 29 grade II, and 14 grade III. The primary tumor location for 39 of 46 patients was the posterior fossa. The WHO grade was not predictive of survival. EGFR staining of ⩾2 was considered positive. All patients with a positive EGFR (23 of 23) arose from the posterior fossa, 19 of 23 had at least a gross total resection (>95%), and two had evidence of dissemination at diagnosis. The median age of the patients with a positive result was 4.9 years (0.2–14.3), and 10 were female. Positive EGFR correlated with a worse 35% 5-year overall survival compared with 75% for those who were negative for EGFR (p < 0.05). No correlation was found relating positive immunostain for either nuclear or cytoplasmic YB-1 or HER-2 individually to overall survival. Conclusion: This study suggests that positive immunostaining for EGFR in childhood ependymoma is a molecular prognostic indicator of poor survival. Positive EGFR may be limited to primary location in the posterior fossa, it is unrelated to age at presentation. There was no predictive value with positive YB-1 or HER-2 alone with respect to survival, however, this may be related to small numbers. Further studies are required to evaluate these and other molecular markers for their prognostic value. BIO 21. ESTABLISHMENT AND CHARACTERIZATION OF CELL LINES AND TRANSPLANTABLE XENOGRAFTS FROM PEDIATRIC BRAIN TUMORS Nidhi Srivastava,1 Tracy Warr,2 Charles Pegram,1 Stephen Keir,1 Ahmed Rasheed,1 Roger Mclendon,1 Chien-Tsun Kuan,1 and Darell Bigner1; 1Pediatric Brain Tumor Foundation Institute, Duke University Medical Center, Durham, NC, USA; 2Institute of Neurology, London, UK. Brain tumors are the leading cause of cancer-related mortality in children. Each year approximately 3,400 new cases are diagnosed in the United States alone. Although there are >120 different types of pediatric brain tumors, low-grade astrocytomas are the most common, accounting for approximately 40% of all pediatric cerebral tumors. Brain tumors in children are often located in the brainstem and cerebellum and are heterogeneous in regard to histology and clinical course. Improving survival rate in pediatric brain tumor patients continues to be a challenge, and for this we still need to understand the molecular pathways involved in the genesis, progression, and biological and clinical behavior of the pediatric brain tumors. Establishing stable cell lines and xenograft models provides access to continuous availability of representative tumors. We are establishing pediatric brain tumor cell lines and xenografts for various tumor types, including medulloblastomas, supratentorial primitive neuroectodermal tumors (PNET), and grade III and IV astrocytomas. Two glioblastoma multiforme (GBM) cell lines, D2159 MG and D2368 MG, and a grade II pleomorphic xanthoastrocytoma cell line are beyond passage level 60 in neural stem cell medium. We are also growing six new medulloblastoma cell lines, D2319 Med, D2341 Med, D2344 Med, D2377 Med, D2352 Med, and D2385 Med; one grade I desmoplastic infantile ganglioglioma cell line, D2378 DIG; one grade IV teratoid/rhabdoid cell line, D2376 ATRT; one grade I pilocytic astrocytoma cell line, D2384 GPA; one grade II pleomorphic xanthoastrocytoma cell line, D2388 PXA; and another GBM cell line, D2360 MG; all of these are in passage level 15–30 in neural stem cell medium. All of the above-reported cell lines are also growing into conventional zinc option (ZO) medium at different passage levels, except D2159 MG. Another GBM cell line, D456 MG has been established in ZO medium and carried out to passage number 84. Using athymic nude mice, we have established new subcutaneous xenografts with three different pediatric GBMs, D2159 MG, D2224 MG, D2234 MG; one xenograft from a grade IV intracranial sarcoma, D2339 SARC; one from a grade IV supratentorial primitive neuroectodermal tumor, D2216 PNET; and one from a grade II pleomorphic xanthoastrocytoma, D2363 PXA. Cells were used to establish the xenografts in most of the cases, except for D2363 PXA and D2339 SARC, where tissue was used for tumor transplantation. Subcutaneous tumor growth rates (reported in days to grow from inoculation to 1,000 mm3) were 32, 35, 24, 28, 120, and 47 days, respectively, for the above-named xenografts. Doubling time for xenograft D2159 MG was 7.43 days, and for xenograft D2224 MG it was 7.20 days. The consistent availability of these established cell lines and xenografts will aid both basic and preclinical pediatric brain tumor research. BIO 22. EXPRESSION OF GLIOMA-ASSOCIATED ANTIGENS IN PEDIATRIC BRAINSTEM AND NONBRAINSTEM GLIOMAS Ian Pollack,1 Hideho Okada,1 Keri Low,2 and Ronald Hamilton1; 1University of Pittsburgh, Pittsburgh, PA, USA; 2Pittsburgh, PA, USA. Background: The outcome for children with diffuse intrinsic pontine gliomas and incompletely resected nonbrainstem gliomas is poor with conventional therapies. In view of these discouraging results, there is a strong need for new therapeutic approaches that target those features of the tumor cell that distinguish it from surrounding normal cells. Vaccine strategies targeting glioma-associated antigens (GAAs) hold particular promise in that regard. In recent years, we have examined the applicability of a series of tumor cell-based immunization approaches for adult patients with gliomas. Although promising results have been achieved by us and others, a limitation of this strategy is the need for autologous tumor to generate a patient-specific vaccine, which delays instituting therapy and precludes use altogether in patients with unresectable lesions. In contrast, vaccines in the form of synthetic peptides encoding T-cell epitopes in GAAs would eliminate the need for autologous fresh glioma explants to generate clinical grade vaccines and facilitate timely vaccine production. To this end, we have focused attention on the identification and characterization of therapeutically applicable human GAA-derived cytotoxic T-lymphocyte (CTL) epitope targets. Methods: We investigated the protein expression of three potential GAAs in pediatric brainstem glioma (BSG) and nonbrainstem glioma (NBSG) cases with a view to their possible use in immunotherapy. Expression of EphA2, IL-13Rα2 and Survivin were studied by immunohistochemistry on paraffin-embedded tissues using a series of 15 archival BSG cases and 12 NBSG cases. Results: Thirteen of 15 BSGs and all 12 NBSGs overexpressed at least one of the GAAs. Seven of 15 BSGs were positive for EphA2, as were all NBGs; 10 of 15 BSGs and 7 of 9 NBSGs were positive for IL-13Rα2; and 8 of 15 BSGs and 8 of 12 NBSGs were positive for Survivin. In total, 7 of 15 BSGs and 9 of 12 NBSGs expressed at least two of these GAAs at significantly higher levels than nonneoplastic brain. There was no association between the tumor grade and levels of GAA expression. Although many cases demonstrated diffuse expression of GAAs throughout the tumor specimen, partial or patchy expression was noted in a small number of cases, supporting the need for targeting multiple GAAs in immunotherapy. Conclusion: These results suggest that EphA2, IL-13Rα2 and Survivin are commonly overexpressed in pediatric malignant gliomas and constitute suitable targets for developing vaccine-based strategies for these tumors. A clinical trial to test this hypothesis has been developed and will be discussed. BIO 23. EXPRESSION OF THE NOTCH PATHWAY EFFECTORS HES-1 AND HES-5 IS ASSOCIATED WITH FAVORABLE OUTCOME IN MEDULLOBLASTOMA Mi Rim Choi,1 Elisabeth Rushing,2 Mary Rita Santi,1 Robert Cornelison,3 and Tobey Macdonald1; 1Children's National Medical Center, Washington, DC, USA; 2Armed Forces Institute of Pathology, Washington, DC, USA; 3National Institutes of Health, Bethesda, MD, USA. Background: Medulloblastoma (MB), an embryonal tumor of the cerebellum, is thought to arise from precursor cells of the cerebellar external granule layer. Signaling pathways such as Wnt, Hedgehog, PDGF, and Notch, which control the specification, proliferation, and survival of normal neuronal precursors of the developing cerebellum, are also aberrantly activated in MB. The role of Notch in tumorigenesis is less clear, but studies have demonstrated Notch overexpression in a variety of human cancers, including MB. However, reports in limited sample sizes of MB have described discrepant results in the expression patterns of two receptors, Notch-1 and Notch-2 (Cancer Res. 2004;64:7787; Cancer Res. 2004;64:7794). Due to the potentially important role of the Notch signaling pathway in MB and the limited existing information, we sought to determine the expression pattern of the Notch pathway using a robust MB sample size. Methods: Immunohistochemistry analysis for the Notch receptors (Notch-1–4), the Notch ligands (Delta-1 and Jagged-1), the Notch antagonist (Numb) and the downstream targets (Hes-1 and Hes-5) was performed using tissue microarrays constructed from 205 childhood brain tumors, including 144 MB, with >95% of the specimens obtained at diagnosis prior to treatment. Protein expression of each marker was then compared to clinical and tumor characteristics. Results: Of the evaluable specimens, 90% were positive for Notch-1 and 89% for Notch-2. Delta-1 and Jagged-1 were positive in less proportion (49% and 42%, respectively), while Hes-1 was positive in 34% and Hes-5 in 42% of the samples. The relative level of Notch pathway member expression did not correlate with any histologic subtype. All MB with documented metastatic disease at diagnosis (n = 11) were positive for Notch-1 (100%), while Notch-2 expression was seen in 90%. Similarly, all MB patients who had died of tumor progression (n = 20), had 100% Notch-1 positivity, while Notch-2 was seen in 93% of the samples. Interestingly, only 27% of all evaluable tumors were positive for both Hes-1 and Hes-5, but of these, 81% (22 of 27) are still alive, regardless of histology. Furthermore, the 20 specimens that were positive for both Hes-1 and Hes-5, as well as positive for either Notch ligand (Delta and/or Jagged) had a 95% survival rate (19 of 20) compared to 57% (4 of 7) of the samples that were positive for Hes-1 and Hes-5 and negative for both Notch ligands. Conclusions: Our results represent the largest series of human MB investigated for the protein expression of Notch and demonstrate that although Notch-1 and Notch-2 are ubiquitously expressed at relatively high levels in MB, activity of the pathway, as evidenced by detectable expression of the downstream targets Hes-1 and Hes-5, is observed in a much smaller subset of tumors. Importantly, Notch pathway activation appears to be associated with a more favorable outcome independent of histology. This finding could have important implications for targeted therapeutics specifically directed against Notch in MB. BIO 24. EXPRESSION PATTERN OF CHEMORESISTANCE-RELATED GENES IN PEDIATRIC BRAIN TUMORS Iacopo Sardi,1 Piergiorgio Modena,2 Valentina Cetica,3 Gabriella Bernini,3 Maurizio Aricò,3 Maura Massimino,2 and Lorenzo Genitori4; 1Neurosurgery/Pediatrics Oncology, A. Meyer Children's Hospital, Florence, Italy; 2Pediatrics, National Tumor Institute, Milan, Italy; 3Pediatrics Oncology, A. Meyer Children's Hospital, Florence, Italy; 4Neurosurgery, A. Meyer Children's Hospital, Florence, Italy. Chemotherapy in solid tumors is poorly effective, partly due to intrinsic or acquired drug resistance of tumor cells, which leads to unsatisfactory outcome. Resistance to chemotherapy in pediatric brain tumors, in particular, is complex and may involve multiple mechanisms. In this work we investigated the expression of some chemoresistance-related genes, alkylated repair protein alkB homolog 2 and 3 (ALKBH2, ALKBH3), O6-methylguanine-DNA methyltransferase (MGMT), P-glycoprotein (ABCB1/MDR), multidrug resistance-associated protein 1 (ABCC1/MRP), topoisomerase 2a (TOPO2a), and glutathione-S-transferase (GSTP1) in malignant pediatric brain tumors. We analyzed 58 bioptic samples identified histologically as 42 ependymomas, six medulloblastoma/PNETs, five low-grade gliomas, one glioblastoma, and four nonneoplastic brain tissues. Quantitative real-time PCR was performed on the corresponding cDNA synthesized from each sample and was repeated in triplicate. The different expression of the target genes normalized to GAPDH and HPRT housekeeping genes were calculated using δδCt method. We used Universal Standard Reference RNA and brain nonneoplastic autoptic samples as calibrators. Expression levels of each of the analyzed genes were generally higher in brain tumors than in nonneoplastic brain tissues. ALKBH2 and ALKBH3 had a similar expression pattern in normal tissue while almost all the tumors showed higher ALKBH2 expression. There was a positive correlation among expression of ALKBH2, GSTP1, and ABCB1. The ABCC1/MRP gene was expressed at low level in controls; while tumor samples showed an increased expression. Anaplastic astrocytomas and medulloblastoma showed an increased expression of GSTP1 gene while TOPO2a presented a marked increment in the ependymoma, with suggestive statistical correlation with WHO grading. Our analysis showed a correlation between the absence of clinical response and the increased expression of chemoresistance-related genes. Additional correlations with clinical parameters will be investigated. This work represents a preliminary study on the expression pattern of genes possibly related to drug resistance in pediatric brain tumors; validation of these results on a higher number of samples, for each tumor histology, would contribute to define a better characterization of brain tumor chemo-responsive phenotype. BIO 25. GANGLIOSIDE EXPRESSION IN PEDIATRIC BRAIN TUMOR XENOGRAFT LINES Hailan Piao,1 Charles N. Pegram,1 Darell D. Bigner,1 and Chien-Tsun Kuan1; 1Pediatric Brain Tumor Foundation Institute, Duke University Medical Center, Durham, NC, USA. Gangliosides are component molecules of the outer leaflet of the plasma membrane that are believed to play a role in tumor formation and progression. These sialylated glycosphingolipids constitute the major class of glycoconjugates on neurons and carry the majority of the sialic acid within the CNS. They are involved in various cellular functions, including signal transduction, regulation of cell proliferation and differentiation, cell-cell recognition and adhesion, and cell death. Two gangliosides, 3′-isoLM1 and 3′,6′-isoLD1, have been characterized and validated as molecular targets for the treatment of malignant gliomas, especially glioblastoma multiforme (GBM). These oncofetal gangliosides are attractive candidates because they are not expressed in the normal adult brain tissue or the CNS. We assessed the reactivity of previously prepared, highly specific monoclonal IgMs: SL50, specific for only 3′-isoLM1; DMAb 14, specific for both 3′-isoLM1 and 3′,6′-isoLD1; and DMAb 21 and DMAb22, specific for only 3′,6′-isoLD1. ELISA and BIAcore analyses showed that SL50 binds to 3′iso LM1 (Kd = 7.9 nM) and that DMab22 binds to 3′,6′-isoLD1 (Kd = 56 nM). In this study, we found that gangliosides 3′-isoLM1 and 3′,6′-isoLD1 were also expressed in pediatric brain tumor xenograft lines. Flow cytometry revealed that these IgMs reacted with several pediatric brain tumor cell lines and xenografts and showed cell-surface binding. Specifically, our results showed that the following pediatric brain tumor lines express 3′-isoLM1 and 3′,6′-isoLD1 on the cell surface: DAOY, D341MED, D283MED, D324MED, D2159MG, and D2224MG. SL50 reacted with approximately 90% of the viable DAOY cell population and reacted with 20%–45% of the cell populations of the five other pediatric cell lines listed; DMAb22 was 80% positive with the DAOY line and 20%–30% positive with the other pediatric lines for cell-surface binding, as indicated by flow cytometry. The significant cell-surface expression of 3′-isoLM1 and 3′,6′-isoLD1 on pediatric brain tumor cells, the low to no expression on normal brain cells, and the tumor antigen involvement in the migratory and invasive aspects of GBM cells demonstrate that these gangliosides are good candidates for antibody-based targeting. Elimination of cells expressing 3′-isoLM1 and 3′,6′-isoLD1 should result in significant survival increases in pediatric brain tumor patients. In addition, since the IgM-type MAbs are unsuitable for therapy, we have begun to prepare high-affinity IgG MAbs against the gangliosides 3′-isoLM1 and 3′,6′-isoLD1. We have successfully cloned the VH and VL fragment sequences from hybridomas SL50, DMAb21, and DMAb14 individually by isolation of mRNA and by RACE-PCR (rapid amplification of cDNA ends–PCR). We have constructed single-chain Fvs (scFvs) by connecting VH and VL sequences with a 15-amino-acid peptide linker (Gly4Ser)3 by PCR splicing technology. The scFv was expressed well in Escherichia coli BL21(λDE3) cultures harboring the corresponding expression plasmid. After characterization of each scFv, the scFvs will undergo affinity maturation. The scFv with the highest affinity will then be converted into an intact human IgG1 with antibody-dependent cellular cytotoxicity or will be used to prepare PE38 immunotoxin for preclinical testing. BIO 26. GENE EXPRESSION ANALYSIS OF SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL TUMORS (SPNETs) Hazel Rogers,1 Suzanne Miller,1 James Lowe,2 Keith Robson,2 MarieAnne Brundler,3 Beth Coyle,1 and Richard Grundy1; 1University of Nottingham, Nottingham, UK; 2Nottingham, UK; 3Birmingham, UK. sPNETs are high-grade, predominantly pediatric tumors found within the cerebrum or suprasellar region of the brain and are composed of poorly differentiated neuroepithelial cells. Although relatively rare, sPNETs are highly malignant with a poor prognosis. Relatively little research has been undertaken to elucidate the molecular basis of sPNETs, and previous studies have often grouped them with the histologically similar tumor medulloblastoma. The aim of this study was to use global gene expression analysis of a set of sPNET samples to try to better understand their molecular basis. RNA was extracted from a cohort of histologically verified tumors that included 15 sPNETs, six medulloblastomas, and a fetal brain sample (Clonetech). The samples were hybridized to Affymetrix U133 plus two arrays. The expression data generated was initially analyzed using clustering methods, separating the tumors into distinct subgroups. Candidate gene lists distinguishing these groups were identified. The majority of the sPNETs divided into two groups, which were found to correlate with metastatic status. Genes differentially expressed included a number of extracellular matrix genes, such as type 3 and type 5 collagen, which have previously been linked to metastasis. These genes were up-regulated in the group of tumors where the majority had metastasized. Genes up-regulated in the nonmetastatic group included oligodendrocyte myelin glycoprotein (OMG), oligodendrocyte transcription factor 1 (OLIG1), and oligodendrocyte lineage transcription factor 2 (OLIG2), suggesting the presence of cells of the oligodendroglial lineage. A number of tumors clustered with fetal brain. Lower expression of genes involved in DNA replication and the cell cycle was seen in this group, suggesting these samples have a phenotype closer to normal brain. Hematoxylin- and eosin-stained smears of the frozen sections used confirmed this. Cell cycle genes significantly up-regulated in the tumors included topoisomerase (DNA) II alpha 170 kDa (TOP2A). Differential expression between sPNETs and medulloblastomas was also demonstrated, including genes linked to cerebellum development such as mab-21-like 1 (MAB21L1) and somatostatin receptor 2 (SSTR2). Putative tumor suppressors dachshund homolog 1 (DACH1) and early B-cell factor 3 (EBF3) were down-regulated in sPNETs only. Global gene expression analysis has enabled the identification of candidate genes and pathways that will help to elucidate the molecular basis of sPNETs. Differential expression has also been demonstrated between sPNET and medulloblastoma. BIO 27. GENETIC AND GENOMIC ANALYSIS OF CHOROID PLEXUS TUMORS REVEALS DISTINCT MOLECULAR PHENOTYPES AND CAN BE TRACED TO THE GERMLINE Uri Tabori,1 Adam Shlien,2 Berivan Baskin,2 Sarah Levitt,2 Jodi Lees,2 Cynthia Hawkins,2 and David Malkin2; 1University of Toronto, Toronto, ON, Canada; 2ON, Canada. Choroid plexus carcinomas (CPCs) and papillomas (CPPs) are rare pediatric brain neoplasms with variable clinical course. Insufficient understanding of the biological processes governing behavior of these tumors leads to inconsistent therapeutic approaches and poor outcomes. CPCs are frequently observed in Li-Fraumeni syndrome (LFS) families in which germline mutations in the TP53 tumor suppressor gene is associated with a high rate of multiple early onset cancers. In an attempt to determine the role of dysfunction in the TP53 pathway and genomic instability in choroids plexus tumors, we used genetic analysis of known polymorphisms in the pathway combined with high-throughput microarray platforms to examine complex molecular alterations. TP53 mutation and MDM2 SNP309 polymorphism analysis were performed on both tumors and paired germline (blood) samples. SNP array was applied to blood and available frozen samples using the Affymetrix 250K GeneChip to explore genomewide alterations. Twenty-two tumors and germline analysis revealed that all TP53 mutated tumors belonged to families with full LFS phenotype. All CPC and CPP patients without LFS phenotype were TP53 wild type in the germline. Interestingly, all tumors negative for TP53 mutation harbored the combination of the MDM2 SNP309 and TP53 codon 72 polymorphisms (p = 0.016) suggesting an alternative mechanism of p53 dysfunction. Single nucleotide polymorphism (SNP) analysis revealed extremely high copy number variation (CNV) in LFS-related tumors compared to wild-type tumors and CPP (p = 0.009). Strikingly, germline SNP analysis revealed the same pattern of very high CNV in CPC patients compared to controls (p = 0.04). Furthermore, CNV in tumors were not random but rather were extensions and propagations of germline CNV in these patients. In summary, our results revealed that while germline TP53 mutations was not consistently observed in CPC, alternative mechanisms of p53 functional abnormalities contributed to CPC tumorigenesis. CNV may possibly differentiate molecular and phenotypic subtypes in this family of tumors. The use of multiplex molecular genotyping may eventually lead to novel prognostic and therapeutic markers for choroid plexus tumors. BIO 28. GENETIC REGULATION OF CNS STEM CELL DIFFERENTIATION AND MIGRATION: ROLE OF DLX HOMEOBOX GENES Trung Le,1 Molly Pind,2 and David Eisenstat3; 1Biochemistry and Medical Genetics, Winnipeg, MB, Canada; 2Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Winnipeg, MB, Canada; 3Pediatrics and Child Health, Human Anatomy and Cell Science, Manitoba Institute of Cell Biology, Winnipeg, MB, Canada. Introduction: Stem cells are present in the developing and mature CNS as well as in neuroepithelial tumors. These stem cells divide symmetrically to produce two daughter stem cells and asymmetrically to repopulate the pool of stem cells or become committed CNS progenitors. These progenitors leave the cell cycle, commit to a neuronal or glial (astrocytic or oligodendroglial) cell fate, and migrate. This process is highly regulated by a combinatorial code of transcription factors, such as basic helix-loop helix (bHLH) or homeobox genes, expressed during defined developmental time periods and/or in specific neuroanatomical regions. Four Dlx homeobox genes (Dlx1, 2, 5, and 6) are expressed in the developing forebrain. In the Dlx1/Dlx2 double knockout mouse there is loss of tangential interneuron migration from the basal forebrain to the neocortex; these interneurons express the inhibitory neurotransmitter GABA. Furthermore, progenitors transplanted from Dlx1/Dlx2 mutant ventral telencephalon differentiate into myelinating oligodendrocytes, supporting a role for Dlx-mediated repression of oligodendrocyte precursor cell formation during forebrain development. In humans, Dlx2 is expressed in transit amplifying cells of the embryonic and adult subventricular zone (SVZ). Methods: In order to understand the function of Dlx2 during CNS development, we have optimized chromatin immunoprecipitation (ChIP) technologies in embryonic tissues to identify Dlx2 transcriptional targets in vivo, including neuropilin-2, the receptor for Semaphorins 3A and 3F, that inhibit interneuron migration to the neocortex, and TrkB, the receptor for the neurotrophin BDNF. Subsequently, we have subcloned genomic DNA fragments bound to Dlx2 in E13.5 ganglionic eminences and generated a ChIP library of candidate Dlx2 targets (ChIP cloning). In addition, we have combined the ChIP assay with CpG island microarrays to identify putative Dlx2 transcriptional targets (ChIP-chip). Results: The ChIP-cloning and ChIP-chip technologies may be complementary, with only partial convergence of data. To date, we have identified molecules associated with axonal guidance, the cytoskeleton, transcriptional regulation, G-protein signaling, neurotransmitter signaling, and ion channels. These candidate Dlx2 targets have been subjected to repeat ChIP analysis to confirm binding to Dlx2 in vivo, reporter gene assays to assess the functional significance of their regulation by DLx2 in vitro, as well as gene expression assays (quantitative PCR, in situ hybridization, and immunohistochemistry) in wild-type and Dlx1/Dlx2 mutant mouse forebrain. We are particularly focused on identification of oligodendroglial targets that may be repressed by Dlx2, including genes critical to myelination in the developing nervous system. Conclusion: Before application of stem cell and/or novel differentiation therapies to CNS tumors of the developing nervous system, it will be necessary to understand the network of transcription factors and their target genes required for terminal differentiation and migration of committed CNS progenitors. BIO 29. GENETICALLY ENGINEERED MOUSE MODEL OF BRAINSTEM GLIOMA Oren Becher,1 Dolares Hambardzumyan,2 Timothy Gershon,1 and Eric Holland3; 1Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 2Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Cancer Biology and Genetics, Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Using the RCAS/tv-a technology for somatic cell gene transfer we have recently observed that we can generate brainstem gliomas (BSGs) by infecting nestin expressing neural stem cells in the posterior fossa of neonatal pups with PDGF, or by coinfection with Kras and AKT. As previously described for cortical gliomas, PDGF-induced BSGs are oligodendrglial in histology while Kras and AKT induced BSGs are astrocytic in histology. Cooperating genetic alterations such as INK4A-ARF loss can accelerate tumorigenesis (penetrance of >90% and latency of <8 weeks). These BSGs are highly aggressive, have high-grade histological characteristics such as microvascular proliferation and pseudopalisading necrosis, and can invade around the basilar artery. Interestingly, overexpression of Kras, AKT, as well as PDGFR has been noted in human samples of pediatric BSGs. This BSG model which recapitulates the genetic alterations of the human disease, and forms in its native environment may serve as an excellent preclinical model to better understand the biology of these tumors as well as to test novel agents for the treatment of pediatric brainstem gliomas. BIO 31. GLOBAL ANALYSIS OF THE MEDULLOBLASTOMA EPIGENOME IDENTIFIES DISEASE SUBGROUP-SPECIFIC INACTIVATION OF COL1A2 Steven Clifford,1 Jennifer Anderton,1 Janet Lindsey,1 Meryl Lusher,1 Richard Gilbertson,2 Simon Bailey,1 and David Ellison2; 1University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, UK; 2St. Jude Children's Research Hospital, Memphis, TN, USA. Candidate gene investigations have indicated a significant role for epigenetic events in the pathogenesis of medulloblastoma, the most common malignant brain tumor of childhood. To assess the nature of the medulloblastoma epigenome more comprehensively, we undertook a genomewide investigation to identify genes that display evidence of methylation-dependent regulation. Expression microarray analysis of medulloblastoma cell lines following treatment with a DNA methyltransferase inhibitor revealed the methylation-dependent regulation of multiple transcripts (3%–6% of probes per cell line). Eighteen independent genes demonstrated >3-fold reactivation in all cell lines tested and were selected for detailed characterization. Bisulphite sequence analysis revealed dense CpG island methylation associated with transcriptional silencing for 12 of these genes. Analysis of the methylation status of these genes in primary tumors and the normal cerebellum revealed three major classes of epigenetically regulated genes in medulloblastomas: (1) normally methylated genes (DAZL, ZNF157, ASN), whose methylation in tumors reflects somatic patterns observed in the cerebellum; (2) X-linked genes (MSN, POU3F4, HTR2C), which show complex disruption of their normal sex-specific methylation patterns in tumors; and (3) tumor-specific methylated genes (COL1A2, S100A10, S100A6, HTATIP2, CDH1, LXN), which display enhanced methylation levels in tumors compared to the cerebellum. Detailed analysis of COL1A2 supports a key role in medulloblastoma tumorigenesis; dense biallelic methylation was observed in 46 of 60 cases (77%) and was associated with silencing of mRNA and protein expression. Moreover, COL1A2 status distinguished infant medulloblastomas of the desmoplastic histopathological subtype, indicating a distinct molecular pathogenesis may underlie these tumors and their more favorable prognosis. These data (1) reveal a more diverse and expansive medulloblastoma epigenome than previously understood; (2) identify novel molecular events in its pathogenesis; and (3) provide strong evidence that the methylation status of specific genes provide biological markers for the discrimination of specific disease subgroups. BIO 32. HIGH-RESOLUTION GENOMIC ANALYSIS IDENTIFIES DISTINCT GROUPS OF PEDIATRIC SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL BRAIN TUMORS Kyle Lee,1 Meihua Li,2 Charles Eberhart,3 Ching Lau,4 Scott Pomeroy,5 Peter Collins,6 Piergiorgio Modena,7 Amar Gajjar,8 Eric Bouffet,9 Michael Taylor,2 Cynthia Hawkins,2 and Annie Huang9; 1University of Toronto, Toronto, ON, Canada; 2ON, Canada; 3Johns Hopkins University, Baltimore, MD, USA; 4Houston, TX, USA; 5Boston, MA, USA; 6UK; 7Pediatrics, National Tumor Institute, Milan, Italy; 8Memphis, TN, USA; 9Toronto, ON, Canada. Primitive neuroectodermal tumors (PNETs) of the supratentorial region are rare, highly malignant embryonal brain tumors affecting young children. Although supratentorial PNETs (sPNET) are histologically indistinguishable from infratentorial PNETs/medulloblastomas, they are characterized by more aggressive clinical phenotypes that suggest sPNET represent distinct biological entities from medulloblastoma. In contrast to considerable progress in understanding the signaling pathways involved in medulloblastoma biology, little is known about which genes contribute to sPNET pathogenesis. Prior studies with low-resolution comparative genomic hybridization (CGH) techniques indicate sPNETs have frequent genomic imbalances and copy number aberrations (CNAs). We have utilized the ultrahigh resolution of the Affymetrix 500K single nucleotide polymorphism (SNP) array and gene expression profiling in order to map potential disease-related genes within CNAs and obtain a more comprehensive characterization of the molecular aberrations underlying sPNET development and tumor progression. Genomic DNA from 41 primary and 4 recurrent sPNET samples were analyzed using the Affymetrix 500K SNP genotyping microarrays. All tumors with available material were tested for expression of the INI1 protein to exclude tumors that may represent rhabdoid tumors. Preliminary data analysis reveals frequent CNAs across the sPNET genome, which encompasses both large and focal chromosome segments. Tumors can be segregated into at least two groups based on DNA copy number changes: tumors with frequent CNAs and tumors with relatively few or no CNAs detected. In addition, as reported in prior studies, we observed a lack of isochromosome 17q in all sPNET, an abnormality found in approximately a third of medulloblastomas. We observed large regions of copy number gains on 1q (27% of samples), as well as amplifications at 12q14.1 (5%) and 13 additional amplification events in distinct genomic loci. Frequent regions with DNA copy number losses included 10q and 13q (21% for each), 22q (17%), as well as a germline deletion at 21q21.1 and homozygous deletions at 13q14.2, 14q31.2, and 16q23.3. Correlations of specific CNAs with gene expression data indicate frequent aberrations of cellular adhesion pathways in sPNET. Further characterization and validation of these loci are underway and may direct future developments in therapy. BIO 33. IDENTIFICATION AND CHARACTERIZATION OF A NOVEL DE NOVO GERMLINE P53 MUTATION WITH A FULMINANT CLINICAL COURSE Mathew Schneiderjan,1 Bahig Shehata,2 Timothy Mapstone,3 Fredrick Barr,4 Robert Marcus,2 Nadia Esiashvili,2 Catherine Stockwell,2 and Anna Janss5; 1Neuropathology, Emory University, Atlanta, GA, USA; 2GA, USA; 3OK, USA; 4PA, USA; 5Emory University, Decatur, GA, USA. Introduction: We present a case of a child with a unique germline p53 mutation who died with three concurrent malignancies. Clinical Course: A 14-year-old male presented with escalating nausea and vomiting over 1 week and was found to have increased intracranial pressure due to a right frontal tumor and left intraventricular tumor. Neither lesion had been present in a brain CT scan performed 2 years prior. Staging showed no evidence of leptomeningeal dissemination. Pathologic diagnosis on the right frontal tumor was of a primitive neuroectodermal tumor (PNET). The second lesion, resected 1 month later, was a choroid plexus carcinoma. Identification of synchronous distinct brain tumors prompted genetic testing for predisposition to malignancy and systemic evaluation for cancer including bone scan and MRI of the chest, abdomen, and pelvis. Results were negative for other tumors. The child underwent craniospinal radiation (36 Gy) with boosts to primary tumors (20 Gy), followed by chemotherapy using cisplatin, vincristine, and CCNU. Within 5 months of presentation the child developed hip pain and subsequent surveillance imaging of his CNS revealed tumoral infiltration of the vertebral bodies, pelvis, hips, and liver. Staging procedures could not be performed due to hepatic failure with hyperammonemia and coagulopathy. The child died of respiratory failure 6 months after presentation. His systemic cancer was evaluated by autopsy. Family History: The patient was survived by two parents, a younger brother, paternal grandparents, and maternal grandmother, all without history of malignancy. An older sibling was stillborn. Pathology: Right frontal tumor—PNET, pleomorphic, poorly differentiated malignant neoplasm composed predominantly of small cells with scant cytoplasm, vesicular chromatin, and prominent nucleoli. There were multiple areas of necrosis and numerous tumor giant cells. Tumor cells stained positive for neurofilament, GFAP (focal), synaptophysin (focal), and p53 and negative for pan-cytokeratin (AE 1/3) and EMA. MIB-1 proliferation index was 80%–90%. Intraventricular tumor—choroid plexus carcinoma, pleomorphic epithelial cells with a high nuclear:cytoplasmic ratio and irregular, hyperchromatic nuclei arranged in papillary and solid patterns. Tumor cells were reactive for AE 1/3, GFAP (focal), and p53 and negative for CEA (monoclonal). Hepatic and bone tumor—alveolar rhabdomyosarcoma, clusters of large pleomorphic cells with hyperchromatic nuclei with high nuclear:cytoplasmic ratio arranged in an alveolar pattern. Tumor cells were reactive for myogenin and desmin and were negative for CD3, CD20, CD45, myeloperoxidase, AE 1/3, vimentin, lysozyme, EMA, synaptophysin, GFAP, and S-100. Cytogenetic analysis demonstrated a translocation, t(2;13)(q35;q14), characteristic of alveolar rhabdomyosarcoma. Genetic Analysis: Sequencing of patient DNA showed a previously undescribed p53 allele with a premature stop codon in the oligomerization/nuclear export signal (NES) domain (R342ter). The patient's brother tested negative for p53 mutations. The patient's parents are untested for p53 mutations but have no malignancy to date. Conclusions: This case identifies a novel germline p53 mutation and shows a more fulminant course than typical cases of Li-Fraumeni syndrome. We discuss potential causes for the unusually aggressive course of this patient's illness and suggest that the aggressive course may be due to the nature of the mutation. BIO 34. IDENTIFICATION OF ANTIGENS ON CANCER STEM CELLS FOR BRAIN TUMOR THERAPY Vidyalakshmi Chandramohan,1 Charles N. Pegram,1 Stephen T. Keir,1 Chien-Tsun Kuan,1 and Darell D. Bigner1; 1Pediatric Brain Tumor Foundation Institute, Duke University Medical Center, Durham, NC, USA. Approximately 26,000 children have brain tumors and >3,000 new pediatric brain tumor cases are diagnosed every year in the United States alone. Brain tumors are the leading cause of cancer death for children <20 years, and there are >120 different types of childhood brain tumors. Recent findings in human leukemia and breast cancer strongly implicate cancer stem cells as the undercurrent that fuels the growth of many human cancers, and the concept of cancer stem cells has been extended to brain tumors. The discovery of brain tumor stem cells (BTSCs), which have biological properties that are distinct from the bulk of tumor cells, has identified new targets for brain tumor treatment. In the present study, we demonstrated screening of pediatric brain tumors for the presence of BTSCs and further analyzed the expression of known brain tumor antigens on these cancer stem cells. BTSCs are known to proliferate and generate multipotent clones of cells in vitro, termed neurospheres, in the presence of growth factors such as epidermal growth factor and basic fibroblast growth factor 2. Neurospheres were isolated from the pediatric xenografts D456MG, D2159MG, and D2224MG and were found to be positive for the expression of the stem cell marker CD133. The CD133-positive BTSCs were further screened for the expression of known brain tumor–associated antigens: wild-type epidermal growth factor receptor (EGFRwt), mutant EGFR variant III (EGFRvIII), chondroitin sulfate proteoglycan (CSPG), interleukin 13 receptor alpha 2 (IL13Rα2), glycoprotein nonmetastatic melanoma protein B (GPNMB), 3′,6′-iso-LD1, 3′-iso-LM1, and multidrug resistance protein 3 (MRP3). The D2159MG cells that were positive for the tumor antigens EGFRwt (20%), EGFRvIII (35%), CSPG (17%), and MRP3 (8%) were also positive for CD133. The overexpression of EGFRwt (24-fold) and MRP3 (22-fold) mRNA was confirmed by Q-PCR in D2159MG neurospheres. Analysis revealed that the EGFRvIII mRNA was expressed only in the D2159MG neurospheres and not in the normal human neural progenitor population, confirming it as a tumor specific antigen. The expression of EGFRwt and EGFRvIII proteins in the D2159MG neurospheres was further demonstrated by Western blot analysis. Next, 13% of the D456MG cells were found to express both CD133 antigen and the tumor antigen CSPG. Finally, analysis of the D2224MG cells revealed the coexpression of CD133 and the tumor antigens 3′,6′-iso-LD1 (85%), 3′-iso-LM1 (94%), CSPG (91%), and IL13Rα2 (71%). Thus, using specific immunotoxins or radioimmunotherapy to target the identified tumor antigens expressed by BTSCs should result in significant survival increases in pediatric brain tumor patients. BIO 35. IDENTIFICATION OF MEDULLOBLASTOMA SUBTYPES WITH DISTINCT GENETIC PROFILES, PATHWAY SIGNATURES, AND CLINICOPATHOLOGICAL FEATURES Marcel Kool,1 Jan Koster,1 Jens Bunt,1 Dirk Troost,2 Netteke Schouten-Van Meeteren,3 Bauke Ylstra,4 Wieslawa Grajkowska,5 Wolfgang Hartmann,6 Torsten Pietsch,6 David Ellison,7 Steven Clifford,8 and Rogier Versteeg1; 1Human Genetics, Academic Medical Center, Amsterdam, Netherlands; 2Neuropathology, Academic Medical Center, Amsterdam, Netherlands; 3Pediatric Oncology, Academic Medical Center, Amsterdam, Netherlands; 4Pathology, VU University Medical Center, Amsterdam, Netherlands; 5Pathology, Children's Memorial Health Institute, Warsaw, Poland; 6Neuropathology, University of Bonn, Bonn, Germany; 7St. Jude Children's Research Hospital, Memphis, TN, USA; 8Northern Institute for Cancer Research, Newcastle-upon-Tyne, UK. Medulloblastoma is the most common malignant brain tumor in children. We established gene expression profiles of 62 medulloblastomas using Affymetrix HG-U133 plus 2.0 GeneChips, and 52 of them were also analyzed by comparative genomic hybridization (CGH) using 30K oligonucleotide arrays. Five molecular subtypes were identified, characterized by WNT pathway activation (type A, 9 cases), sonic hedgehog pathway activation (type B, 15 cases), neuronal differentiation genes (types C and D, 16 and 11 cases, respectively) and photoreceptor genes (types D and E, both 11 cases). Activation of the WNT pathway in type A tumors was in all nine cases caused by mutations in the beta-catenin gene. No beta-catenin mutations were found in tumors of other subtypes. PTCH1 mutations, which lead to activation of the sonic hedgehog pathway, were identified in 4 of 15 type B tumors, but not in tumors of the other subtypes. Also, several fully or partly subtype-specific chromosomal aberrations were found, such as loss of chromosome 6 only in type A tumors, loss of 9q sequences in type B tumors, or loss of chrom 8 and gain of 17q in type C and D tumors. RNA expression levels for genes located on these chromosomes faithfully reflected the identified chromosomal copy number changes. We also found several striking associations between the molecular subtypes and clinicopathological parameters. Metastatic disease at diagnosis was associated with subtypes C and D and most strongly with subtype E (p = 0.005). Also, age at diagnosis was significantly different among the five subtypes (p = 0.006). All patients <3 years of age had either type B or DE tumors (p = 0.0006). Type B contained most desmoplastic cases (p = 0.046). We validated and confirmed these molecular subtypes and the associated clinicopathological parameters using data of a previously published series of 46 medulloblastomas (Thompson et al. J Clin Oncol. 2006;24). Medulloblastoma patients have a poor prognosis. Despite recent improvements in cure rates, survivors suffer from serious side-effects caused by the intensive therapy. Recent data showed that patients with WNT-activated tumors respond very well to current therapies (Ellison et al. J Clin Oncol. 2005;23; Gaijar et al. Lancet Oncol. 2006;7), suggesting that these patients can be treated less severely, thereby reducing the side effects. These results demonstrate the need of a correct classification of medulloblastoma patients and a detailed knowledge of oncogenic signaling pathways in each subtype. The medulloblastoma subtypes presented in our study will therefore be of great importance for a better understanding of this heterogeneous disease and for a better selection of patients for future clinical trials of new molecular-targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life. BIO 36. IDENTIFICATION OF NOVEL CHROMOSOMAL ALTERATIONS SPECIFIC TO PEDIATRIC HIGH-GRADE ASTROCYTOMAS Karine Jacob,1 Huiqi Qu,2 Olivier Delattre,3 Alexandre Montpetit,2 Lauren Solomon,4 Peter Hauser,3 Miklos Garami,3 László Bognár,5 Zoltan Hansely,3 Constantin Polychronakos,6 Cynthia Hawkins,4 and Nada Jabado6; 1Human Genetics, Montreal Children's Hospital, Montreal, QC, Canada; 2QC, Canada; 3France; 4ON, Canada; 5Neurosurgery, University of Debrecen, OEC, Debrecen, Hungary; 6Montreal, QC, Canada. Background: Brain tumors are the largest group of solid neoplasms in children and are currently the leading cause of cancer-related mortality and morbidity in the pediatric years. Pediatric glioblastoma (pGBM) is a rare but devastating brain tumor. Several studies suggest that pGBMs may be biologically distinct from their adult counterparts, despite being histologically identical. In contrast to GBM in adults (aGBM), relatively little is known in children about the molecular mechanisms underlying its development and progression, and the low number of clinical samples available has resulted in very few studies of this cancer. Available data on genetic events in pediatric high-grade astrocytomas (pHGAs) are scarce. This has traditionally been a major impediment to understanding the pathogenesis of this tumor and to developing ways for more effective management. The aim of this study is to chart DNA copy number aberrations (CNAs) in pHGAs and get insight into genetic pathways involved in gliomagenesis in children. Methods: Using the Illumina Infinium Human1 bead chip array (100K SNPs), we genotyped 19 pediatric and 6 adult HGAs. Results were compared to BAC-array profiles harvested on 16 of the same pHGAs to an independent data set of 9 pHGAs analyzed on Affymetrix 204K SNP arrays and to existing data sets on HGA. CNAs were additionally validated by real-time quantitative PCR in a set of genes in pHGA. Results: Our results show an unexpected low frequency of genetic amplification and complete deletions and high frequency of loss of heterozygozity in a high-grade rapidly dividing tumor. The most common copy number alterations were LOH on chromosome 10q22, 15q15, 17p13, and 22q12. Despite commonalities, most CNAs in pHGAs were distinct from CNAs in aHGAs. Novel genomic regions identified with nonrandom clustering of CNAs, suggest that alterations in tumor suppressors and genes involved in the regulation of RNA processing and the cell cycle are major events in the pathogenesis of pHGA. To further characterize this tumor, integrative studies comparing those genomic results with previous results obtained through a transcriptional analysis are now being performed. Conclusions: This first complete profiling of the tumor cell genome using high-resolution SNP arrays fills an important gap in studies on pHGA and may ultimately guide mapping of oncogenic networks unique to pHGA. It further shows that pHGA and aHGA are two diametrically different disease contexts. Our findings suggest that alterations in tumor suppressor genes involved in the regulation of the cell cycle are major events in pHGA pathogenesis and may ultimately lead to a search for more specific molecular therapeutic targets. BIO 37. IDENTIFICATION OF PATHWAYS INVOLVED IN THE PATHOGENESIS OF CHOROID PLEXUS PAPILLOMAS Martin Hasselblatt,1 Sonja Mertsch,1 Astrid Jeibmann,1 Barbara Riesmeier,1 Heike Stegemann,2 Brigitte Wrede,3 Johannes Wolff,4 and Werner Paulus1; 1Institute of Neuropathology, University Hospital Muenster, Muenster, Germany; 2Integrated Functional Genomics, IZKF, University Hospital Muenster, Muenster, Germany; 3Department of Pediatric Oncology, University of Regensburg, Regensburg, Germany; 4The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. The pathogenesis of choroid plexus papillomas, intraventricular papillary neoplasms predominantly occurring in children and young adults, remains uncertain. In order to identify genes differentially expressed in choroid plexus papillomas, gene expression profiles obtained from laser-microdissected choroid plexus papilloma cells (n = 7) were compared to those of normal choroid plexus epithelial cells laser-microdissected from human autopsy tissue (n = 8). On DNA microarray data analysis, a total of 55 probe sets were found to be differentially expressed in choroid plexus papilloma tumor cells (>7-fold), up-regulation of TWIST1, TRPM3, BCLAF1, AJAP1, WIF1, and TAC1; down-regulation of IL6ST and SPACL1 was also confirmed using quantitative RT-PCR. Knockdown of TWIST1 gene expression in the rat choroid plexus epithelial cell line Z310 reduced proliferation as assessed by MTT assay, whereas cell migration was not significantly affected. To conclude, TWIST1 is among the genes differentially expressed in choroid plexus papillomas and promotes proliferation in vitro. The functional role of other identified genes is currently being examined. BIO 38. IMMUNOMODULATORY EFFECTS OF GLIOBLASTOMA CELLS: INFLUENCE ON MONOCYTE EXPRESSION OF THE GRANZYME B INHIBITOR PROTEINASE INHIBITOR 9 (PI-9) Carl Classen1; 1University Children's Hospital Rostock, Rostock, Germany. Glioblastomas are known to influence the immune system in many ways; this is of particular interest since vaccine strategies increasingly show promising results in glioblastoma therapy. Proteinase inhibitor 9 (PI-9)— the only known endogeneous natural antagonist of the lymphocyte protease granzyme B (GrB)—is an intracellular serpin expressed in lymphocytes and in monocyte-derived cells. By intracellular flow cytometry, we have previously shown that ex vivo stimulation by lipopolysaccharides (LPS) leads to up-regulation of PI-9 within 24 h in the monocyte, but not the lymphocyte fraction; this can be inhibited by the NF-kappaB inhibitor pyrrolidin dithiocarbamate (PTDC). Here, we studied the influence of the glioblastoma cell lines GMS-10 and U-138-MG on the spontaneous and LPS-induced expression of PI-9 in monocytes in a coincubation assay. We found that the presence of glioblastoma cells in a 10:1 and even a 1:100 ratio with PBMC lead to PI-9 up-regulation in monocytes, similar to the up-regulation induced by LPS. Combination of coincubation with LPS did not further enhance PI-9 expression. It seems that the effect does not require cell-cell contact, since the supernatant of GMS-10 cells was sufficient to induce PI-9 up-regulation. Since it has been shown that PI-9 overexpression in antigen presenting cells (e.g., dendritic cells) leads to an enhanced immune response by protection of cells from activation-induced or bystander kill, our findings may be relevant for specific immune therapy. Understanding the regulation of PI-9 expression in monocyte-derived cells in glioblastomas might help to optimize the strategies in dendritic cell-based vaccine therapies. BIO 39. INDUCIBLE CRE RECOMBINASE ACTIVITY IN MOUSE MATURE ASTROCYTES AND ADULT NEURAL PRECURSOR CELLS: DEVELOPING NOVEL ANIMAL MODELS FOR GLIOMA Lionel Chow,1 Junyuan Zhang,1 and Suzanne Baker1; 1St. Jude Children's Research Hospital, Memphis, TN, USA. Astrocytes are the most abundant glial cell type in the mammalian brain and play important roles in all aspects of the developing and mature organ. They are proposed to be at the root of numerous pathological processes and may be the cell of origin for the most common primary brain tumor, glioma. The availability of the appropriate molecular tools to manipulate gene expression in vivo in this specific cell type is therefore critical to further our understanding of gliomagenesis. Many genetically engineered models for human disease currently employ the bacteriophage P1 creatine (Cre) recombinase-LoxP system, which enables gene manipulation in a tissue- and cell-specific manner. A large number of brain-specific Cre mouse strains have been developed, including those using the glial fibrillary acidic protein (GFAP) promoter to drive astrocyte-specific expression of Cre. Because Cre-mediated recombination is irreversible, embryonic expression in neural precursor cells directed by the GFAP promoter and/or aberrant expression resulting from transgene insertion effects have resulted in substantial Cre-mediated recombination in mature neurons as well as glial cells in all GFAP-Cre mice characterized to date. Therefore, the ability to restrict Cre activity during embryogenesis could greatly mitigate neuronal Cre-mediated recombination in GFAP-Cre mice and allow for the study of gene function in mature astrocytes without disruption of function in neurons. Cre activity can be regulated in a temporal fashion by engineering a fusion protein with the ligand-binding domain of a steroid hormone receptor, such as the estrogen receptor. Furthermore, a specific point mutation within the ligand-binding domain termed ERTM abolishes the binding to endogenous steroid hormones while retaining its interaction with synthetic estrogen analogs such as tamoxifen. The fusion protein, CreERTM, is inactive while sequestered in the cytoplasm by heat shock protein complexes. Binding of tamoxifen releases CreERTM from this complex allowing ligand-dependent translocation to the nucleus where the fusion protein is active and directs recombination between loxP sites. Two transgenic mouse lines expressing an inducible form of the Cre recombinase (CreERTM) under the control of the human GFAP promoter have been generated and characterized. In adult mice, expression of the fusion protein is largely confined to astrocytes in all regions of the CNS. Minimal spontaneous Cre activity was detected and recombination was efficiently induced by intraperitoneal administration of tamoxifen in adult mice. The pattern of recombination closely mirrored that of transgene expression. The percentage of astrocytes undergoing recombination varied from region to region ranging from 35% to 70% while a much smaller portion (<1%) of oligodendrocytes and neural precursor cells showed evidence of Cre activity. The degree of recombination varied directly and consistently with the dose of tamoxifen administered to mice. Using these new Cre mouse strains, we have also engineered several novel models for spontaneously arising gliomas. BIO 40. MAGIC ANGLE SPINNING METABOLITE PROFILES CHARACTERIZE GLIAL AND PRIMITIVE NEUROECTODERMAL TUMORS Martin Wilson,1 Marie-Anne Brundler,2 Carmel Mcconville,3 Richard Grundy,4 and Andrew Peet5; 1University of Birmingham, Edgbaston, Birmingham, West Midlands, UK; 2Pathology, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK; 3Birmingham, Western Australia, Australia; 4Children's Brain Tumour Research Centre, Queens Medical Centre, Nottingham, Nottinghamshire, UK; 5Academic Paediatrics and Child Health, University of Birmingham, Edgbaston, Birmingham, West Midlands, UK. Introduction: 1H high-resolution magic angle spinning NMR spectroscopy (MAS) is a technique that measures concentrations of multiple metabolites in small pieces of tissue leaving the sample remains intact. The metabolite profiles provide a powerful characteristic of tumor tissue and reflect tumor biology. The metabolic pathways implicated in specific tumors provide targets for new agents. Small sample size, minimal sample preparation, and the potential for rapid analysis also makes the technique a novel candidate for rapid intraoperative diagnosis. In this study, MAS is combined with automated analysis to explore differences between glial and primitive neuroectodermal tumors (PNET) in children. Methods: Forty tissue samples were collected from a total of 29 children at diagnostic and therapeutic operations. Each sample was obtained prior to the patient receiving adjuvant treatment. The PNET group comprised nine medulloblastomas, one supratentorial PNET, and seven neuroblastoma cases. The glial tumors comprised 10 juvenile pilocytic astrocytomas and 2 ependymomas (grade II). Biopsy tissue (5–20 mg) was snap frozen in liquid nitrogen shortly after resection and stored at –80°C. MAS was performed on a Varian 600-MHz spectrometer using a 4-mm gHX nanoprobe. The probe temperature was set to 0.1°C, giving a sample temperature of 6.7°C, and the sample was spun at 2,500 Hz. A standard pulse and acquire sequence was used with water presaturation giving a total acquisition time of 28 min. The TARQUIN algorithm was used to fit the metabolite components of the signal, automatically quantifying a range of metabolites. Metabolites were normalized to the real part of their fitted spectral contribution between 0.5 and 4.5 ppm. A principal component analysis was performed on the standardized metabolite quantities and a two-tailed t-test performed to determine significant differences between the metabolite quantities in glial tumors versus PNETs and medulloblastomas versus neuroblastomas. Results: Glial and PNET tumors formed two distinct groups in the principal component analysis showing that the two tumor groups have characteristic MAS metabolite profiles. The principal component analysis also showed that the medulloblastomas formed a group that was distinct from neuroblastomas. Statistically significant differences (p < 0.05) between PNET and glial tumor specimens were found in 7 of the 17 metabolites analyzed. Taurine was found to be significantly elevated in PNETs, and the ratio of phosphocholine:glycerophosphocholine was higher in PNETs. Significant differences were also found in 8 of the 17 metabolites between medulloblastoma and neuroblastoma specimens. Conclusion: MAS combined with automated analysis can provide rapid information on the biochemistry of childhood tumor tissue. MAS metabolite profiles are a powerful characteristic of tumor type for PNETs and glial tumors and can detect significant differences between medulloblastomas and neuroblastomas despite their similar morphology demonstrating the potential of the technique as a rapid diagnostic aid. Key differences are seen in taurine and choline metabolism in PNETs compared with glial tumors, in keeping with in vivo magnetic resonance spectroscopy findings and demonstrating that MAS can identify key molecular pathways in these tumors. BIO 41. MOLECULAR AND PHENOTYPIC CHARACTERIZATION OF PEDIATRIC HIGH-GRADE GLIOMA CELL LINES AS MODELS FOR PRECLINICAL DRUG DEVELOPMENT Dorine Bax,1 Lynley Marshall,1 Nathalie Gaspar,2 Lara Perryman,1 Suzanne Little,1 Marta Viana-Pereira,3 Gilles Vassal,4 Rui Reis,3 Sue Eccles,2 Paul Workman,2 Andrew Pearson,5 David Ellison,6 Darren Hargrave,5 and Chris Jones1; 1Paediatric Oncology, Institute of Cancer Research, Sutton, Surrey, UK; 2Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK; 3Life and Health Science Research Institute (ICVS), University de Minho, Portugal; 4Institut Gustave Roussy, Villejuif, Paris, France; 5Paediatric Oncology, Royal Marsden Hospital, Sutton, Surrey, UK; 6Neuropathology, St. Jude Children's Research Hospital, Memphis, TN, USA. Although pediatric high-grade gliomas resemble their adult counterparts in many ways, there appear to be distinct clinical and biological differences. Understanding and exploiting these similarities and differences is an important strategy for the development of new targeted therapies. One important factor hampering this is the relative lack of cell lines derived from childhood glioma patients, as it is unclear whether the well-established adult lines commonly used are representative of the underlying molecular genetics of childhood tumors. We have carried out a detailed molecular and phenotypic characterization of a series of pediatric high-grade glioma cell lines in comparison to routinely used adult lines. The panel comprised two patients with pediatric glioblastoma multiforme (GBM) (SF188: 8 years old, male; KNS42: 16 years old, male); one with pediatric anaplastic astrocytoma (UW479: 13 years old, female); and six with adult GBMs (LN229, A172, U118MG, U138MG, U87MG, SF268). All lines proliferate as adherent monolayers with doubling times of 26–48 h and express glial fibrillary acidic protein (GFAP), S100 protein, synaptophysin, and/or vimentin. Classical cytogenetics revealed highly complex karyotypes for all three pediatric lines, underpinned by copy number profiling using Affymetrix 500K SNP and Agilent 44K CGH arrays. SF188 harbored multiple high-level amplifications including MYC, CCND1, and CDK4, which were confirmed by fluorescence in situ hybridization on metaphase spreads. KNS42 contained numerous low-level gains, such as at 3q26 harboring the PIK3CA oncogene, and losses including 13q13-q14, encompassing the BRCA2 and RB1 loci. UW479 was highly rearranged and harbored a homozygous deletion of the CDKN2A locus, among others, as well as extensive gene promoter hyper methylation, as assessed by methylation-specific MLPA. Constitutive protein expression by Western blot analysis showed Akt pathway activation in all pediatric and adult lines, although the pediatric lines were all PTEN wild-type. This was in contrast to a lack of phosphorylated GSK3beta and S6 kinase in the pediatric lines compared with the majority of the adult lines. KNS42 demonstrated high levels of phospho-ERK, not observed in SF188 and UW479. Expression profiling using Affymetrix U133 Plus2.0 arrays revealed 301 differentially expressed genes that we were able to distinguish between the adult and pediatric high-grade cell lines. These included overexpression in pediatric lines of kinases of the Src family, including YES1 and LYN, and low levels of the receptor tyrosine kinase AXL, highly expressed in adult lines. All three pediatric lines were successfully grown as subcutaneous xenografts in nude mice. These data demonstrate that high-grade glioma cell lines derived from pediatric patients show key molecular differences to those from adults, some of which are well known, while others may provide novel targets for evaluation in primary tumors. We thus provide the rationale and demonstrate the practicability of using pediatric high-grade glioma cell lines for in vitro and in vivo preclinical and mechanistic studies. BIO 42. MOLECULAR INVERSION PROBES (MIPS) IDENTIFY NOVEL COPY NUMBER CHANGES IN PEDIATRIC ASTROCYTOMAS Joshua Schiffman,1 Scott Vandenberg,2 Paul Fisher,1 James Ford,1 Hanlee Ji,1 and Graeme Hodgson2; 1Stanford University, Palo Alto, CA, USA; 2University of California, San Francisco, San Francisco, CA, USA. Background: Childhood brain tumors (CBTs) are the most common solid pediatric cancer and the leading cause of pediatric cancer mortality. More than half of all CBTs are gliomas, but little is known about the genetic events that contribute to the development and progression of these tumors. To address this, we used molecular inversion probes (MIPs) to identify recurrently amplified or deleted genomic loci in advancing stages of pediatric astrocytomas (PAs). This study takes important steps toward a molecular classification of PAs, which is critical for the development of biomarkers and patient-specific therapeutic approaches for disease treatment. Methods: DNA was extracted from 14 flash-frozen PA biopsies (WHO grade II [n = 3, mean age, 7 years]; grade III [n = 2, mean age, 6 years], grade IV [n = 9, mean age, 12 years]). DNA was also extracted from five adult-gliosis biopsies to use as nonneoplastic controls. The MIP assay was run using 37 ng genomic DNA sample on a customized Affymetrix 24K Cancer Panel representing oncogenes, tumor suppressor, DNA repair, cell growth, and metabolism genes. Copy number (CN) changes were identified by comparing probe signal intensity between tumors and controls. Results: We observed the full spectrum of genomic CN aberrations including regions of single copy gain and loss, homozygous deletions, and high-level focal amplifications. Grade III and IV tumors showed more CN alterations relative to grade II tumors. Regions of high-level amplification (CN>5) involved chromosome bands: 7q34–36 (10.8 Mb) and 12p13 (4.7 Mb) in one grade III tumor; 1q32 (3.1Mb), 3q13 (2.8 Mb), and 8q24 (1.1 Mb) in one grade IV tumor; and 4q12 (0.65 Mb) in two grade IV tumors. At least 218 known genes map within these amplicons, including well-established oncogenes such as MYCC (8q24), PDGFRA, KIT (4q12), and CCND2 (12p13). Other amplified genes include those that have been previously implicated in glioma development such as the Forkhead transcription factor FOXM1, and those that are known to regulate Wnt-signaling (WNT5B) and p53 activity (MDM4). Further studies will help delineate the extent to which these genes contribute to PA development, and the utility of these genes as biomarkers and therapeutic targets for PA treatment. Conclusions: The MIP platform enabled the identification of low-level (1–4 copies) and high-level (>5 copies) copy number aberrations in pediatric astrocytomas from relatively small amounts of genomic DNA. Pediatric astrocytomas displayed marked heterogeneity in genomic copy number, suggesting that a comprehensive assessment of copy number aberrations will be required to enable accurate molecular subclassification of PAs. The MIP platform is well suited for such large-scale analyses because of its compatibility with formalin-fixed paraffin-embedded specimens. BIO 43. MOLECULAR PORTRAITS OF EPENDYMOMA RECURRENCE Matthieu Peyre,1 Frederic Commo,1 Carmela Dantas-Barbosa,1 Stephanie Puget,2 Ranjeev Bhangoo,1 Ludovic Lacroix,1 Francoise Drusch,1 Pierre Varlet,3 Veronique Scott,1 Philippe Dessen,1 Christian Sainte-Rose,2 Gilles Vassal,1 and Jacques Grill1; 1Institut Gustave Roussy, Villejuif, France; 2Necker Sick Children's Hospital, Paris, France; 3Saint Anne Hospital, Paris, France. Purpose: Recurrence is a frequent phenomenon in intracranial childhood ependymomas. To gain new insights into this process and identify pathways associated with recurrence, we compared the genomic and gene expression profiles of local recurrences with the corresponding initial tumors. Experimental Design: We studied 27 relapses in 17 patients by comparing their gene expression profile to the one obtained at diagnosis in the same child. Recurrences analyzed occurred after surgery alone in seven cases, surgery plus chemotherapy in 10 cases, and any treatment plus radiotherapy in 11 cases. For each recurrence, gene expression levels were compared in relation to the gene's corresponding initial tumor by dual color competitive hybridization on Agilent 44K gene expression microarrays. Statistical analysis was performed after initial filtering which retained only sequences differentially expressed (p = 0.05) in at least 50% of experiments. Filtering criteria as well as the research of a common signature in recurrences and group comparisons (tumor location, treatment, delay between diagnosis and recurrence) were performed with Rosetta Resolver software. Real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry were next performed on genes of interest. In parallel, genomic profiling at diagnosis and at recurrence was performed using Agilent 44K oligo-CGH DNA microarrays, and expression signatures were compared according to gene copy number changes. Results: A subset of 298 sequences appeared to be significantly associated with recurrences (p < 0.01). Forty-eight of them did so in 60% or more of the studied recurrences. Among genes up-regulated at recurrence, some belonged to the Wnt (SFRP1, SFRP2, FZD2, FZD8, and WNT10B) and Notch (DLL1) pathways. In addition, several genes involved in proliferation were up-regulated (Ki67, 4 genes of the G2/M checkpoint and 10 genes of the kinetochore and mitotic spindle). Metallothioneins were the genes most frequently down-regulated at recurrence (60%–85% depending on the isotype). RT-PCR and IHC data on selected genes confirmed the microarray results. Most frequent copy number changes were 3p and 6p losses and 9q and 1q gains and were present in at least 20% of patients. Copy number changes increased at recurrence compared with diagnosis in nine patients and remained stable or decreased in eight patients. Comparison of microarray data with genomic imbalances revealed that most of the modifications in gene expression were not related to copy number changes. We identified one patient with amplifications at 2p (containing the N-myc gene that was overexpressed) and 11p both at diagnosis and at recurrence. Conclusion: The most frequent events associated with ependymoma relapse include increased proliferation associated with overexpression of kinetochore proteins and down-regulation of metallothioneins. Targeting of these pathways may offer novel therapeutic options in these refractory brain tumors. BIO 44. MOLECULAR UNDERSTANDING OF SENSITIVITY TO CHEMOTHERAPEUTIC AGENTS IN MEDULLOBLASTOMA Daniel Meley,1 David Spiller,1 Michael White,1 Heather Mcdowell,2 Barry Pizer,2 and Violaine See1; 1Centre for Cell Imaging, University of Liverpool, Liverpool, Merseyside, UK; 2Oncology, Royal Liverpool Children's Hospital, Liverpool, UK. Introduction: Neuronal proliferation, differentiation, and migration are coordinated during cerebellar development. Disruption of these processes can lead to medulloblastoma (MB), the most common malignant pediatric brain tumor. Despite recent advances in understanding the pathogenesis of MB, the specific genetic alterations involved in the majority of these tumors are still ill defined. Here, we elucidated the specific tuning of NF-kB– and p53-dependent transcription upon chemotherapeutic treatment in MB and its correlation to resistance/sensitivity to the treatment. Methods and Results: (1) We first determined the sensitivity of different cell lines to different chemotherapeutic agents. We used four different MB cell lines (DAOY, D283-MED together with MHH-Med-1 and MEB-Med-8A, kindly provided by Prof. Torsten Pietsch) and compared their resistance to chemotherapeutic drugs. We tested the viability of these cell lines with a time and dose response to cisplatin, methothrexate, and etoposide. The four cell lines had different sensitivity to chemotherapy. The D283-MED and DAOY cells were more sensitive than the MHH-Med-1 and MEB-Med-8A. (2) To explain these different sensitivities, we decided to further explore the activity of key transcription factors involved in death/survival balance in basal conditions and on exposure to chemotherapeutic drugs. We looked at the activity of NF-kB– and p53-dependent pathways at basal levels in the different cell lines and their activation in response to etoposide. We showed that the four cell lines displayed different sensitivity to etoposide depending on the status of both p53 and NF-kB molecules. One interesting finding was that, in all cell lines that were not p53 mutated, we observed an induction of CD95 (also called Fas) upon exposure to etoposide. (3) We then investigated the activation of CD95, a death receptor that might be responsible for the observed etoposide-induced delayed NF-kB activation. We confirmed the p53-dependent transcription of CD95 using a p53 inhibitor, Pifithrin a. The D283-MED cells were very sensitive to etoposide and displayed a proapoptotic delayed NF-kB upon etoposide treatment. The Med-1 cells activated CD95 transcription, but the NF-kB pathway was impaired in this cell line resulting in a medium sensitivity to etoposide. Conversely, the Med-8 cells had a normal NF-kB signaling, but no activity was observed upon etoposide treatment, probably due to a mutation in p53 response and the absence of CD95 activation. This was associated with a high level of resistance to chemotherapeutic agents. Conclusion: We have demonstrated that depicting the mutation status of key transcription factors in MB could lead to enhancement of response to chemotherapy. Elucidation of etoposide-induced genes in cell lines that are not mutated in p53 may allow to target them directly and independently of p53 using specific agents and therefore improve treatment of MB that are p53 mutated. BIO 45. NOTCH 1 MUTATIONS IN PEDIATRIC POSTERIOR FOSSA EPENDYMOMAS Carmela Dantas-Barbosa,1 Ludovic Lacroix,1 Matthieu Peyre,1 Stephanie Puget,2 Ranjeev Bhangoo,1 Patrick Saulnier,1 Felipe Andreiuolo,1 Alexander Valent,1 Pascale Varlet,3 Christian Sainte-Rose,2 Gilles Vassal,1 and Jacques Grill1; 1Institut Gustave Roussy, Villejuif, France; 2Necker Sick Children's Hospital, Paris, France; 3Sainte Anne Hospital, Paris, France. Purpose: A comparative genomic hybridization (CGH) array study of pediatric ependymomas revealed a significant increase of 9q34 gain in recurrent tumors compared to diagnostic tissue. Up-regulation of one of the candidate genes located on 9q34 (Notch-1) was found in most of the samples. The implications of Notch 1 mutations in others tumors such as T-ALL and breast cancer prompted us to analyze mutations in Notch pathway. In addition, we also studied the tumor suppressor gene Fbxw7/hCDC4 mutated in several cancers and involved in Notch-1 ubiquitin-dependent proteolysis. Experimental Design: Notch sequencing of exons 26, 27, and 34 was performed in 72 ependymoma samples from 42 patients: 33 diagnosis and 39 recurrences as well as Fbxw7 sequencing of exons 5, 6, 7, 8, and 9. The tumor location was posterior fossa in 45 samples and supratentorial in 20 and 7 other localizations. 9q.34 gain was confirmed by fluorescence in situ hybridization (FISH) and measure of expression levels of Notch pathway genes, such as HES-1 by RT-PCR, and immunohistochemistry. Results: Notch1 mutation was found in six samples from three distinct patients (8.3% of the whole samples and 20% of the samples with 9q34 gain on CGHarray); for two patients, it was found at diagnosis and recurrence; for the other, in two subsequent recurrences. All Notch-1 mutations were found among posterior fossa ependymomas samples, 6 of 45 (13.3%). Both samples from the same patient presented the same mutation: in the HD domain for one patient (V1671I) and TAD domain for the two others (G2152R and A2279V). 9q gain region was observed in 21 samples (29.2%). FISH confirmed increased copy number of the 9q34 at relapse compared to diagnosis. For the patient for whom we disposed only of relapses, 30% of cells from the first and 100% in the second recurrence presented 9q gain. Functional analysis of Notch pathway revealed Notch 1 overexpression as well as downstream Notch-regulated genes such as HES1. The Fbxw7 gene analysis did not show any mutations. Conclusion: The presence of Notch-1 mutation at diagnosis, even in the absence of detectable 9q34 gain in CGHarray suggest that it is an early event in posterior fossa oncogenesis. The overexpression of Notch-1 was not due to this increased half-life as a consequence of FBXW7 mutations, a negative regulator of the Notch-1 by mediating its ubiquitin dependent proteolisis, since none mutation on this gene was observed. On the other hand, the Notch-1 activation can be explained, at least in the patient that presents the HD mutations, since alterations in this domain render the protein susceptible to be cleaved in a ligand-independent manner that generally results in Notch-1 activation. This is the first report of recurrent mutations in oncogene in pediatric ependymomas. The frequency of Notch-1 mutations in posterior fossa ependymomas is comparable to PTCH mutations in posterior fossa PNET/medulloblastoma. BIO 46. P53 INDEPENDENT ABROGATION OF G1 ARREST IN MURINE BRAIN TUMOR–DERIVED STEM LIKE CELLS AFTER IONIZING RADIATION Andrew Foy,1 Hong Ye,2 and Cynthia Wetmore3; 1Mayo Foundation for Medical Education and Research, Rochester, MN, USA; 2Mayo Clinic, Rochester, MN, USA; 3Rochester, MN, USA. Treatment and cure of medulloblastoma continues to be disappointing. Approximately 30% of cases recur, and even when a cure is achieved, the treatment is highly morbid to the developing brain. Recent evidence suggests that many solid tumors are sustained by a population of cells with stem cell–like properties that have extensive capacity for self-renewal. Tumor stem cells (TSC) are also thought to have increased radio- and chemoresistance and may be responsible for treatment failures. Mechanisms of DNA damage response have not been explored previously in neural stem cells. Identifying novel therapeutic targets that spare normal neural stem cells while eradicating the tumor-derived stem cell population is a long-term goal. Additionally, insight into mechanisms of DNA damage repair in the population of self-renewing neural stem cells will allow for an improved understanding into how the nervous system maintains its molecular integrity. TSCs were isolated from medulloblastomas that spontaneously arose in mice haplo-insufficient for Patched (Ptc), a component of the sonic hedgehog receptor, and cultured in serum-free media as free-floating spheres. Neural stem cells were derived from the early postnatal hippocampus and cerebellum of wild-type and Ptc+/– mice. Cultures were exposed to 2 Gy of ionizing radiation, and cell cycle progression was characterized with flow cytometery. We found that normal neural stem cells had a similar phenotype with sustained accumulation in G1 within 2 h of irradiation. In contrast, we found that TSCs failed to arrest in G1 and showed a marked but unsustained G2/M arrest 8 h after radiation. By 48 h after irradiation, TSCs had reentered the cell cycle. The level of apoptosis was unchanged compared to controls. We repeated these experiments at 10 Gy of radiation and in the TSCs found a large increase in apoptosis over time. Accumulation of TSCs in G2/M was again noted at 8 h, however the G2/M arrest was sustained at 24 and 48 h after irradiation. Preliminary analysis shows that p53 is wild-type in TSCs, suggesting that the abrogated G1 arrest is not due to mutation or deletion of p53. We have characterized the cell-cycle and DNA damage response of murine NSCs and found that this population of undifferentiated cells undergo cell cycle arrest in G1 after DNA damage. This is in contrast to embryonic stem cells that lack a G1 checkpoint and do not initiate cell cycle arrest and undergo apoptosis after exposure to ionizing radiation. Additionally, we found that TSCs have escaped the G1 checkpoint in a p53-independent manner and proceed to replicate their DNA without adequate repair that likely contributes to genomic instability and propagation of new therapy-resistant clones. These data suggest that TSC and normal neural stem cells have distinct responses to ionizing radiation and DNA damage. Studies are ongoing to determine the molecular basis for the distinct phenotype observed in response to radiation in normal and neoplastic stem cells and to specifically increase the sensitivity of TSCs to apoptosis after DNA damage. Supported by Neurosurgery Research and Education Foundation (A.F.), Sontag Foundation (C.W.), and Waterman Foundation for Cancer Genetics (C.W.) BIO 47. PRIMARY TUMOR-BASED ORTHOTOPIC XENOGRAFT MOUSE MODELS OF PEDIATRIC EPENDYMOMA ARE CLINICALLY RELEVANT AND PRESERVE CANCER STEM CELL POOL Litian Yu,1 Eastwood Leung,1 Adekunle Adesina,1 Tsz-Kwong Man,1 Qin Shu,1 Jack Su,1 Patricia Baxter,1 Lazlo Perlaky,1 Murali Chintagumpala,1 Ching C. Lau,1 Susan M. Blaney,1 Pulivarthi H. Rao,1 and Xiao-Nan Li1; 1Baylor College of Medicine, Houston, TX, USA. Animal models play crucial roles in both biological and preclinical studies of human cancers. For ependymomas, which are the second most common malignant brain tumors of childhood, the availability of tumor models that reliably recapitulate the biology of this neoplasm is extremely limited. To create mouse models that would faithfully mimic histopathological, immunophenotypical, and genetic characteristics of human ependymomas, we injected fresh surgical specimen from an anaplastic ependymoma into cerebrum of SCID mice. The developed xenografts have since been serially passaged in mouse brains for three generations while maintaining constant tumorigenicity rate (100%) with as few as 25,000 cells. Detailed characterization of the xenograft tumors revealed that they shared nearly identical histological features with the original tumor and expressed broadly similar immunohistochemical profiles. Although the xenograft tumor formed a clear-cut edge toward the adjacent nervous tissue, isolated tumor cells invading into mouse brain were detected with immunohistochemical staining using human specific antibodies. Gene expression profiling revealed strong similarity between xenograft tumor and the original patient tumor. To determine the presence of cancer stem cells, we utilized antibodies against CD133 to detect and isolate CD133+ cells with FACS. We found that the CD133+ cells only constitute a very small fraction (<1%) of tumor population. In the presence of EGF and FGF, the isolated CD133+ cells formed neurospheres that have be maintained in vitro for >6 months, although spontaneous differentiation as evidenced by the growth of attached cells was occasionally seen. Expression of glial and neuronal markers was detected in the attached cells induced to differentiation. In summary, we have developed a novel orthotopic xenograft ependymoma model that accurately replicated the histopathological, genetic, and behavioral features of anaplastic ependymoma in children. BIO 48. PROGENITOR CELLS IN THE FLOOR OF THE IV VENTRICLE ARE SUSCEPTIBLE TO TRANSFORMATION BY ACTIVATING MUTATIONS IN BETA CATENIN (CTNNB1) RESULTING IN THE FORMATION OF A DISTINCT SUBGROUP OF MEDULLOBLASTOMA Paul Gibson,1 Yiai Tong,1 Margaret Thompson,1 David Ellison,1 and Richard Gilbertson1; 1St. Jude Children's Research Hospital, Memphis, TN, USA. Evidence suggests that subgroups of histologically similar brain tumors arise from different populations of neural progenitor cells (NPCs). We have shown that medulloblastomas (MBs) comprise at least three subgroups that display distinct clinical and molecular characteristics (Thompson et al. J Clin Oncol. 2006). Tumors containing mutations in the sonic hedgehog (SHH) pathway that occur in younger patients frequently display a desmoplastic histology, have a relatively poor outcome, and most likely arise from cerebellar granule neuron precursors (GNPCs). In contrast, tumors that contain activating mutations in CTNNB1 display monosomy 6, classic histology, and excellent clinical outcome and tend to occur in older patients. We hypothesized that CTNNB1-mutant medulloblastomas are clinically and molecularly distinct from SHH-mutant tumors because they arise from progenitor cells outside the GNPC lineage. In support of this hypothesis, we used in situ hybridization to show that signature genes of human SHH pathway-mutant medulloblastoma (n = 71 genes) are expressed in the rhombic lip and GNPC of the developing cerebellum, while CTNNB1-mutant tumor signature genes (n = 72 genes) are expressed in the primary germinal layer and floor of the IV ventricle. Using transgenic mouse technology we show further that Cre-dependent activation of Ctnnb1 in neural progenitor cells of the developing mouse results in the formation of tumors that mimic the human CTNNB1-mutant disease. These tumors arise from the floor of the IV ventricle and primary germinal zone but not the GNPC lineage. Indeed, we show that transgenic expression of mutant Ctnnb1 in GNPC under the Math 1 promoter does not induce medulloblastoma. Our data provide strong evidence that subgroups of medulloblastoma are distinct diseases with different cellular and molecular origins. Of particular note we show for the first time that medulloblastomas can arise outside the GNPC linage and provide the first mouse model of CTNNB1-mutant medulloblastoma. BIO 49. RHABDOID TUMORS: GENE EXPRESSION PATTERNS PROVIDE CLUES TO THE CELL OF ORIGIN, PATHOGENESIS, AND POTENTIAL THERAPEUTIC TARGETS Simone Sredni,1 Samantha Gadd,1 Ching-Chiang Huang,1 and Elizabeth Perlman1; 1Northwestern University, Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, IL, USA. Background: Rhabdoid tumors (RTs) are highly aggressive tumors first described in the kidney of young children. Although they can arise in a variety of extrarenal sites, the most frequent location is the CNS where they are called atypical teratoid/rhabdoid tumors (AT/RTs). More than 90% of the patients with AT/RT are <5 years of age at diagnosis, and 70% present with high-stage disease. The highly aggressive nature of these tumors associated with the absence of effective treatment results in a very poor overall survival of no more than 20% at 3 years. Although the etiology of these tumors is unknown, RT at all sites have a common genetic abnormality: the mutation or deletion of the hSNF5/INI-1 gene located at chromosome 22q11. Aims: This study seeks to clarify the pathogenesis of RT and to uncover potential therapeutic targets. Methods: Gene expression (GE) analysis was performed using oligonucleotide arrays that include >22,000 probe sets (affymetrix U133A). The GE of 10 RTs was compared with the GE of 43 pediatric tumors (12 cellular mesoblastic nephromas, 16 clear cell sarcomas of the kidney, and 15 Wilms tumors). Verification methods included immunohistochemistry, immunoblotting, and quantitative RT-PCR. Results: One hundred fourteen genes were differentially expressed in RT (p < 0.001, fold change >2 or <0.5). INI-1 and genes previously reported to be associated with INI-1 were down-regulated (ATP1B1, PTN, DOCK4, SPARC, PLOD1, PTP4A2, and PTPRK). CDKN1A, CDKN2A, CDKN1C, and CCND1 showed low to no expression in RTs, and MYC was up-regulated, suggesting that RTs gain a proliferative advantage through loss of cyclin-dependent kinase inhibition and up-regulation of c-MYC (both of which may be directly due to INI-1 loss). Twenty-three of the 114 top genes were involved with neural development and were all sharply down-regulated in RT (including PTN, CDH2, FYN, HES1, NOTCH2, NCAM1, SOX11, PTPRK, and LEF1); additionally, RT showed Nestin expression by immunohistochemistry. These findings strongly suggest that RT may arise in neural crest stem cells during a critical developmental window. Differentially expressed genes associated with tumor suppression, invasion, and metastasis were documented. These included up-regulation of SPP1, MMP12, TFRC1, SERPINF1, LGALS1, NCOA3, and ZNF217 and down-regulation of COL18A1 (endostatin), PTPRK, SELENBP1, and DOCK4. Conclusions: RT may arise within neural crest stem cells. During a crucial developmental stage, loss of INI-1 in these cells can result in striking repression of neural development. The inactivation of INI-1 may also be the cause of the loss of the cyclin-dependent kinase inhibition, which gives a proliferative advantage to the affected cells. The identification of abnormal regulation of several genes involved in aggressive behavior provides promising therapeutic targets. BIO 50. ROLE OF SNX3 ON ENDOSOMAL TRAFFICKING AND SIGNALING OF RECEPTOR TYROSINE KINASES IN GLIOBLASTOMA CELL LINES Takrima Haque,1 Carol Nahn,2 Damien Faury,3 and Nada Jabado3; 1McGill University, Montreal, QC, Canada; 2QC, Canada; 3Montreal, QC, Canada. Background: Pediatric glioblastomas (pGBMs) have dismal prognosis and, unlike adult GBMs (aGBMs), little is known about molecular events driving oncogenesis in children. We previously established in primary pGBM samples that there are at least two subtypes of pGBM; both were molecularly distinct from aGBM: one was associated with Ras/Akt-activation and a poor prognosis and the other with no obvious Ras/Akt activation and a better outcome. Aberrant Ras activation in GBM is driven by upstream events including aberrant signaling through receptor tyrosine kinases (RTKs) that are amplified, mutated, or rearranged in a large proportion of aGBMs. However, unlike primary aGBMs, which harbor amplification of EGFR in approximately two-thirds of tumors, pGBMs show no genetic amplification/mutation of RTKs. Data from our microarray analysis identified Sorting Nexin 3 (SNX3) as one of the genes to be exclusively overexpressed in the pGBM subset associated with Ras activation. SNX3 belongs to a family of proteins involved in the regulation of intracellular trafficking of membrane receptors. It is associated with early endosomes through a novel motif (PX domain) following its interaction with phosphatidylinositol-3-phosphate. Overexpression of SNX3 in A431 cells has been shown to delay EGFR degradation prolonging signaling of EGF-EGFR complexes from within the endosomes. This study investigates the role of SNX3 in endosomal trafficking of RTKs in GBM. Our working hypothesis is that overexpressed/overactivated SNX3 prevents/delays RTK degradation in a subset of pGBMs thus generating prolonged RTK-signaling, aberrant Ras activation, and increased cell proliferation/survival/invasion. Methods: Overexpression of SNX3 was validated by qRT-PCR and immunohistochemistry on the same pGBM samples. We stably overexpressed MYC-tagged SNX3 in pGBM cell lines (SF188 and SJ-G2) and transiently in an adult GBM cell line (U87), which had similar endogenous levels of SNX3 and active PI3K-pathway. In parallel, we transiently knocked-down SNX3 in SF188 cells. Effects of overexpression and silencing of SNX3 on cell signaling (Ras and Akt pathways), RTK expression (EGFR/MET/PDGFR), and cell proliferation and invasion were investigated. Results: Myc-tagged-SNX3 localized similar to the endogenous protein within early endosomes in all cell lines. SNX3 overexpression led to a more sustained and stronger activation of Ras pathway and to delayed degradation of EGFR following EGF stimulation in all cell lines as compared to empty-vector (EV) transfectants. No effect was observed on the Akt pathway. Silencing SNX3 in SF188 decreased EGFR baseline level and Ras pathway activation. Preliminary experiments indicate that cell proliferation rate correlates with the level of EGFR expression and Ras pathway activation following SNX3 overexpression or silencing. Conclusion: RTKs are major oncogenes particularly in GBM. Our results suggest that SNX3 modulates EGFR signaling by preventing/delaying its degradation, thus helping sustain Ras activation in GBM cell lines. We are currently studying the role of SNX3 in the endosomal trafficking of other receptors including PDGFR, FGFR, or MET to ascertain that the effect we observe on EGFR targets multiple RTKs or if it is focused to specific membrane receptors. We also are investigating the role of aberrant PI3K activation in sustaining SNX3 function and delay in lysosomal degradation of these RTKs. BIO 51. THE CSF PROTEOME OF MEDULLOBLASTOMA Meena Rajagopal,1 Yetrib Hathout,1 Tobey Macdonald,1 and Brian Rood1; 1Children's National Medical Center, Washington, DC, USA. Identification of medulloblastoma biomarkers in readily accessible body fluids like cerebrospinal fluid (CSF) would be useful for diagnosis, treatment monitoring, and recurrence detection. CSF is an attractive potential source of brain tumor biomarkers given the intimate association between the CSF compartment and brain tumors. In this pilot study, cerebrospinal fluid samples from patients diagnosed with medulloblastoma and control individuals were collected and subjected to two-dimensional gel electrophoresis. Seventy-five micrograms of total CSF protein from each sample were loaded using the criterion 2-DE. Gel analysis was carried out using Ludesi software, and proteins were identified after in-gel trypsin proteolysis using matrix-assisted laser desorption ionization time of flight/time of flight mass spectrometry (MALDI-TOF/TOF). Twenty-one protein spots were found to be altered ⩾2.5-fold in CSF from medulloblastoma patients (p < 0.01). Unsupervised hierarchical clustering was able to differentiate the tumor samples from control samples indicating a potential use in diagnostics and recurrence detection. We also found a significant alteration of the isoform profile of prostaglandin D2 synthase (PGD2S), a brain specific glycoprotein that is synthesized by the choroid plexus. Five isoforms of PGD2S including three acidic, one neutral, and one basic isoform were all at least twofold down-regulated in tumor samples. Our findings further suggest the importance of posttranslational modifications as a source of potential biomarkers. BIO 52. THE EXPRESSION PROFILE OF THE MULTIDRUG-RESISTANCE GENES DIFFERS BETWEEN PEDIATRIC BRAIN TUMOR CELLS AFTER IN VITRO SHORT-TERM EXPOSURE TO VINBLASTINE Elvis Terci Valera,1 Maria Angelica Abdalla De Freitas Cortez,2 Fabio Morato Oliveira,2 Nada Jabado,3 Damien Faury,3 Michael S. Bobola,4 Helio Rubens Machado,5 Carlos Alberto Scrideli,1 and Luiz Gonzaga Tone1; 1Pediatric Oncology, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; 2Department of Genetics, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; 3Department of Pediatrics, Montreal Children's Hospital Research Institute/McGill University Health Center, Montreal, QC, Canada; 4Department of Neurological Surgery, University of Washington, Seattle, WA, USA; 5Surgery and Anatomy, Division of Neurosurgery, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. Background: Drug resistance is a major cause of treatment failure in the pediatric brain cancer setting. The multidrug resistance (MDR) phenotype can be mediated by the superfamily of adenosine-triphosphate binding cassette (ABC) transporters. The dynamics of expression of the MDR genes after exposure to chemotherapy, especially the comparison between pediatric brain tumors of different histologies, are poorly described. Objectives: To compare the mRNA expression profile of the ABCB1, ABCC1, and ABCG2 genes from neuroepithelial pediatric brain tumors prior and following short-term culture with vinblastine (10 and 60 nM for 24 and 72 h) by real-time PCR. Methods: Immortalized cell lines from pylocitic astrocytoma (R286), anaplasic astrocytoma (UW467), glioblastoma (SF188), and medulloblastoma (UW3) were cultured at 37°C in a 5% CO2 atmosphere using HAM-F10 media supplemented with 10% fetal bovine serum, 1% L-glutamine, and 5% antibiotic-antimycotic solution. Cells were used between passage numbers of 20–40. After subculture at 90% confluence, vinblastine sulphate was added at final concentration of either 10 or 60 nM. Cells were harvest after 24 or 72 h of vinblastine exposure by trypsine (0.25%)/EDTA. Total RNA was extracted from each cell line using the TRIzol reagent. cDNA were obtained with the High Capacity kit. The RQ-PCR was performed with the SYBR Green PCR Master MIX kit. mRNA levels were normalized by GUS-β housekeeping gene. Relative amounts of expression were compared between cell lines and normal human brain tissue. Results: As expected, the mRNA levels of expression for ABCB1 gene have augmented in parallel of increasing concentration and time of exposure to vinblastine for R286, UW467, and UW3 cell lines. Interestingly, the SF188 glioblastoma cell line has diminished the ABCB1 expression when exposed to vinblastine. Following chemotherapy, ABCB1 expression has lowered in all cell lines other then glioblastoma; actually, ABCB1 expression of SF188 increased after 24-h exposure to 60 nM of vinblastine. The expression of ABCG2 gene was not influenced by vinblastine exposure. Conclusions: Pediatric glioblastoma cell lines show a different pattern of mRNA expression of MDR genes when stimulated by vinblastine. To validate these findings, evaluation of ABC transporters at proteic and functional levels is ongoing. The resistance to chemotherapy frequently observed in pediatric glioblastoma might be mediated by other genetic or epigenetic events other than ABCB1 overexpression. These preliminary findings may be useful in determining novel strategies of treatment for neuroepithelial pediatric brain tumors. Supported by FAPESP grant 2007/04065-9. BIO 53. THE GENE EXPRESSION, AMPLIFICATION, AND PROMOTER METHYLATION OF NOTCH2 IN EPENDYMOMAS Hehuang Xie,1 Veena Rajaram,2 Tange Yuichi,3 Chris D. Mccabe,4 Wendy Stellpflug,5 Stewart Goldman,6 Tadanori Tomita,7 and Marcelo Bento Soares3; 1Northwestern University, Chicago, IL, USA; 2Plaza, IL, USA; 3IL, USA; 4Molecular Diagnosis, CMH, IL, USA; 5Chicago, IL, USA; 6Hematology/Oncology, Children's Memorial Hospital, Chicago, IL, USA; 7Pediatric Neurosurgery, Children's Memorial Hospital, Chicago, IL, USA. Based on the origins of tumors, ependymomas are classified as supratentorial, infratentorial, and spinal ependymomas. Recent studies suggest these three subclasses of ependymomas have distinct genetic features and gene expression patterns. Some studies have shown distinct genes/pathways associated with these subclasses. IFG-1 and HOX homeobox genes were shown to be overexpressed in infratentorial ependymomas; while Notch signaling pathway was associated with the development of supratentorial ependymomas. Our in-house microarray data demonstrated that genes in Notch signal pathways were also up-regulated in infratentorial ependymomas. In this study, we examined Notch2 expression, gene amplification, and promoter methylation status in a subset of fresh frozen tissues of infratentorial ependymomas. Notch2 expression was determined by quantitative RT-PCR, the gene dosage by quantitative PCR, and the methylation status of Notch2 promoter was determined with pyrosequencing technology. We observed Notch2 overexpression in five infratentorial ependymomas examined. Amplification of Notch2 gene was observed in two out of seven infratentorial ependymomas. Notch2 promoter was found to be hypo-methylated in both normal brain tissues and ependymomas. Conclusion: Our preliminary data suggested Notch signaling pathway may play a role in the development of infratentorial ependymoma in addition to supratentorial ependymomas demonstrated in previous studies. The mechanism of Notch2 overexpression could not be fully explained by gene amplification. In addition, compared to normal human brain, no significant methylation alteration on Notch2 promoter was observed for ependymomas. Further studies for Notch2 amplification by other techniques such as fluorescence in-situ hybridization and expression studies on additional tumor samples from all locations may help understand the role of Notch signaling pathway in the pathogenesis of ependymomas. This study was supported by The Everett/O'Connor Charitable Trust; Dr. Ralph and Marian C. Falk Medical Research Trust; Gus Foundation; The Maeve McNicholas Memorial Foundation; and Medical Research Institute Council. BIO 54. THE INTEGRATION OF “OMICS” DATA ON BRAIN TUMORS Min Wang,1 Hehuang Xie,2 Wendy Stellpflug,2 Jared Bischof,2 Maria De Fatima Bonaldo,2 Chris Mccabe,2 Veena Rajaram,3 Stewart Goldman,4 Tadanori Tomita,5 and Marcelo Bento Soares2; 1Northwestern University, Chicago, IL, USA; 2IL, USA; 3Plaza, IL, USA; 4Hematology/Oncology, Children's Memorial Hospital and Northwestern University, Chicago, IL, USA; 5Pediatric Neurosurgery, Children's Memorial Hospital, Chicago, IL, USA. The identification of molecular markers for early diagnosis and better prognosis has been a focus for recent brain tumor studies. Numerous genes and pathways have been associated with brain tumor genesis and progression. In spite of many large-scale gene expression studies, underlying molecular mechanisms leading to the malfunction of these genes and associated networks are still far from clear. Global hypomethylation and localized hypermethylation are two concurrent phenomena frequently observed in tumors that can significantly affect transcription of cellular genes. However, little is known with respect to epigenomic alterations in brain tumors and their impact on the transcriptome. To assist in the identification of epigenetic and genetic factors that contribute to altered gene expression in brain tumors, an integrated brain tumor epigenomics/genomics at Children's Memorial Hospital database (BTECH) was designed and implemented. Using molecular-based integration, the genomics, transcriptomics, and epigenomics data on brain tumors are combined in this database. On top of the database, a genome browser was developed to allow synchronized visualization of gene expression, methylation, and various annotated features. This integrated platform facilitates a systematic understanding of the interactions of various genetic and epigenetic factors associated with brain tumor development. This study was supported by The Everett/O'Connor Charitable Trust; Dr. Ralph and Marian C. Falk Medical Research Trust; Gus Foundation; The Maeve McNicholas Memorial Foundation and Medical Research Institute Council. BIO 55. THE ONCOGENIC ROLE OF OTX2 IN MEDULLOBLASTOMA PATHOGENESIS AND ITS CLINICAL IMPLICATIONS AS A TUMOR MARKER AND THERAPEUTIC TARGET Hai Yan,1 Cory Adamson,2 Qun Shi,2 Chunhui Di,2 Chris Duncan,1 Roger Mclendon,3 and Darell Bigner2; 1Duke University, Durham, NC, USA; 2NC, USA; 3Durham, NC, USA. OTX2 is a developmentally regulated homeodomain-containing transcription factor that plays extraordinarily important roles in early morphogenesis of the CNS. We previously identified OTX2 amplification in medulloblastoma, one of the most aggressive pediatric brain tumors. However, the mechanism of genetic activation of OTX2, its clinical implication, and its role in medulloblastoma pathogenesis remain unknown. In our studies, we demonstrated that OTX2 amplification and overexpression in medulloblastoma associated with tumor anaplasia and worse survival. We have shown that knockdown of OTX2 by small interfering RNA reduced medulloblastoma cell growth, and that the cells with high levels of OTX2 expression were sensitive to treatment with retinoic acid (RA). Exogenous retinoids, when exogenously applied, have been shown to displace or repress OTX2 expression in the embryonic nervous system and also in embryonal carcinoma cells through cis-acting elements of the OTX2 promoter. In our studies, we observed that RA abrogated cell proliferation in every OTX2-expressing cell line in a dose-dependent manner. These studies lay the conceptual framework for clinical trials of retinoids in the treatment of a commonly lethal pediatric brain tumor. Furthermore, we have investigated the OTX2 molecular signaling pathway and demonstrated that another medulloblastoma oncogene c-Myc was transcriptionally regulated by OTX2. We expect the studies to advance our knowledge on the pathogenesis of medulloblastoma, which could make significant contributions to the therapeutic intervention in this frequently lethal cancer. BIO 56. THE SMO/SMO MOUSE MODEL: SHH-INDUCED MEDULLOBLASTOMA WITH 90% INCIDENCE AND LEPTOMENINGEAL SPREAD Beryl Hatton,1 Elizabeth Villavicencio,1 and James Olson1; 1Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Toward the goal of generating a mouse medulloblastoma (MB) model with increased tumor incidence, we developed a homozygous version of our ND2:SmoA1 model. MBs form in 93% of homozygous Smo/Smo mice by 2 months of age. Tumor formation is thus predictable by age, prior to the symptomatic appearance of larger lesions. This high incidence and early onset of tumors is ideal for preclinical studies because mice can be enrolled before symptom onset and with a greater latency period before late-stage disease. Smo/Smo tumors also display leptomeningeal dissemination of neoplastic cells to the brain and spine, which occurs in many human cases. Despite an extended proliferation of granule neuron precursors (GNPs) in the postnatal external granular layer (EGL), the internal granular layer (IGL) formed normally in Smo/Smo mice and tumor formation occurred only in localized foci on the superficial surface of the molecular layer. Thus, tumor formation is not simply the result of overproliferation of GNPs within the EGL. Moreover, Smo/Smo MBs were transplantable and serially passaged in vivo, demonstrating the aggressiveness of tumor cells and their transformation beyond a hyperplastic state. The Smo/Smo model is the first mouse medulloblastoma model to demonstrate leptomeningeal spread. The adherence to human pathology, high incidence, and early onset of tumors thus make Smo/Smo mice an efficient model for preclinical studies. Results from initial drug testing studies will be presented. We recently published a manuscript describing “Tumor Paint,” a bioconjugate of chlorotoxin and Cy5.5 that binds to brain cancer cells and illuminates them so that surgeons can distinguish brain tumors from normal tissue (Cancer Res. 2007;67:6882). Studies are currently underway to determine the limits of detection in Smo/Smo mice and these data will also be presented. BIO 57. UP-REGULATION OF WW DOMAIN-CONTAINING OXIDOREDUCTASE WOX1 IN CERTAIN TYPES OF NERVOUS SYSTEM TUMORS Ming-Fu Chiang,1 Shur-Tzu Chen,2 and Nan-Shan Chang3; 1Neurosurgery, Mackay Memorial Hospital, Taipei, Taiwan; 2Department of Cell Biology and Anatomy, Nation Cheng Kung University, Tainan, Taiwan; 3Institute of Molecular Biology, Institute of Molecular Biology, Tainan, Taiwan. Human WWOX gene, located on a chromosomal fragile site FRA16D, encodes a tumor suppressor WW domain-containing oxidoreductase WOX1, also known as WWOX or FOR. Homozygous deletion of human WWOX gene has been observed in several different cancers, indicating the chromosome fragile WWOX gene plays an important role in tumorigenesis. WWOX mRNA expression profile in epithelial ovarian cancer also supports the WWOX variant 1 as a tumor suppressor. Down- or up-regulation of WWOX expression has been detected in various tumor tissues, such as hematopoitic malignancies, stomach cancer, and squamous cell carcinoma. The goal of these studies is to evaluate WOX1 protein expression levels in brain tumors and further investigate whether WWOX expression in certain types of meningomas and glioblastromas is functionally colocalized with neurofibromatosis type 2 (NF2). In this study, we have demonstrated that the differential expression of WWOX appears in normal controls and different types of brain tumors. By immunohistochemistry, WWOX expression is low in normal cortical neurons, mainly distributed on the axon fibers, whereas moderate immunoreactivity is present in the cytosol of small fibroblast-like cells of meningioma. In the microcystic meningoma case, WWOX is highly expressed in moderate to large cells. By in situ hybridization, the staining pattern and intensity of WWOX mRNA in different types of meningioma resembles that of WWOX expression. Notably, electron microscopical immunohistochemistry indicates WOX1 and NF2/merlin colocalized in certain tumors. Further, astrocytoma stained moderately to strongly positive for WOX1 protein. WOX1 expression is present in small condense cells and neuritis. Although WWOX is located at a common fragile region, FRA16D, we are unable to detect the loss of heterozygosity in our collected cases (n = 3). In conclusion, we have demonstrated that the differential expression of WOX1 on different types of meningoma, astrocytoma amd glioblastoma. Alterative expression of WOX1 is possibly to correspond to tumor development and metastsis. BRAINSTEM GLIOMA BSG 1. A CANADIAN MULTICENTER PILOT STUDY OF EXTENDED LOW-DOSE TEMOZOLOMIDE AND RADIATION THERAPY IN PEDIATRIC BRAINSTEM GLIOMA Diana Stempak,1 Janet Gammon,1 Derek Stephens,2 Anne Feltis,1 Ute Bartels,1 Chris Fryer,3 Juliette Hukin,3 David Eisenstat,4 Donna Johnston,5 Yvan Samson,6 Eric Bouffet,1 and Sylvain Baruchel1; 1Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada; 2Child Health Evaluative Sciences Program, Hospital for Sick Children, Toronto, ON, Canada; 3British Columbia's Children's Hospital, Vancouver, BC, Canada; 4Cancer Care Manitoba, Winnipeg, MB, Canada; 5Children's Hospital of Eastern Ontario, Ottawa, ON, Canada; 6CHUQ (Centre Hospitalier Universitaire de Québec), Quebec, QC, Canada. Background: Brainstem gliomas (BSGs) constitute 10% of all pediatric CNS tumors and have an extremely poor prognosis, with 90% of children succumbing within 18 months of diagnosis. Temozolomide is an orally administered cytotoxic alkylating agent with activity against primary brain tumors, including high-grade gliomas. We evaluate here which, in combination with radiation therapy, is the standard therapy for the treatment of pediatric BSGs. Objectives: (1) To evaluate the survival rate in newly diagnosed pediatric BSG patients when treated with the combination of concomitant extended low-dose oral temozolomide and radiation therapy. (2) To evaluate the antiangiogenic activity of this regimen by analyzing soluble plasma proteins as surrogate markers and to correlate these biomarkers with response to metronomic temozolomide and radiation Methods: This is a Canadian multicenter nonrandomized pilot study. Temozolomide (85 mg/m2 daily for 6 weeks) was administered in combination with standard radiotherapy followed by maintenance therapy of temozolomide alone (6 weeks/cycle with 1 week rest between cycles). Blood was collected pretreatment and before each new cycle for the analysis of angiogenic proteins in the plasma as potential surrogate markers of angiogenesis. bFGF, VEGF, VCAM-1, ICAM-1, and endoglin were measured using commercially available ELISA kits. Results: Between April 2005 and July 2007, 15 patients were enrolled in five centers (6 males, 9 females; median age, 6.4 years; range, 2.4–12.3 years). A median of three cycles was received (range, 1–5). The median progression-free survival (PFS) was 5 months, and the median overall survival (OS) of these patients was 11 months. Dose-limiting thrombocytopenia led to treatment discontinuation in three patients. Of the potential surrogate markers evaluated, plasma bFGF, VCAM-1, and ICAM-1 did not demonstrate any statistically significant changes over time. While the patient numbers are too small to reach statistical significance, several interesting trends were observed for plasma VEGF and endoglin. Both tended to decrease during the first two cycles of therapy, after which VEGF tended to rise in those patients who remained on therapy, while endoglin concentrations appeared to plateau. Further analysis demonstrated that patients with a longer PFS tended to have a greater decrease in VEGF concentrations than patients with a shorter PFS, but no other correlations between VEGF or endoglin concentrations and PFS or OS were observed. Conclusions: This combination therapy does not appear to improve the PFS or OS of BSG patients when compared to historical controls. With respect to the surrogate markers, there were several limitations including small sample size and high interpatient variation, however the initial decrease in both VEGF and endoglin during the combination phase of therapy (radiation + temozolomide) may suggest antiangiogenic activity. BSG 2. ANAPLASTIC TECTAL GLIOMA IN A 6-YEAR-OLD GIRL: A CASE REPORT Howard Chang,1 Reuben Cuison,2 Renuka Gera,3 Elna Saah,3 and Ajovi Scott-Emuakpor3; 1Neurology and Ophthalmology, Michigan State University, East Lansing, MI, USA; 2Laboratories, Sparrow Health System, Lansing, MI, USA; 3Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA. Tectal glioma is a topographical diagnosis consisting of a heterogeneous group of gliomas in children, with relatively benign clinical course in most previous case reports. We present a case of a tectal glioma with histological features of anaplastic mixed oligoastrocytoma that continues to progress despite chemotherapy and radiation therapy. Case report: A 6-year-old African American girl presented with severe headache for several days associated with vomiting, neck stiffness, fever, and unsteady gait. Physical examination was otherwise unremarkable. She was recently treated for otitis media approximately 1 week ago. Mother reported that the patient had frequent headaches and incontinent of bowel and bladder during the past year. A lumbar puncture showed high CSF protein but no signs of infection. CT and MRI of the brain showed obstructive hydrocephalus with a 2.3 cm nonenhancing pineal region mass attached to the tectum. An MRI of the spinal cord at this time was negative. She underwent craniotomy with biopsy and partial resection of the tumor. The histopathology revealed a moderately hypercellular tumor with small cells containing scant cytoplasm and round to oval nuclei with fine chromatin, embedded in a loose myxoid fibrillary matrix. The cells have long thin processes. No definitive eosinophilic granular bodies or Rosenthal fibers are seen. There are no significant mitoses. Immunocytochemistry shows that most tumor cell nuclei are positive for S-100. The matrix has many GFAP-positive processes but the cell bodies appear negative for GFAP. Many neurofilament protein and synaptophysin positive processes are also found in the background. Immunostain for Ki67 shows generally low labeling index, but it is positive in up to 20% of tumor cells focally. The overall features are suggestive of an anaplastic mixed oligoastrocytoma. Fluorescence in situ hybridization study, however, showed no evidence of chromosomes 1p and 19q deletions. The slides were reviewed by an external expert consultant who indicated that this could be a low-grade astrocytoma most consistent with a “low-grade tectal glioma.” Clinical Course: The patient had no neurological deficits including ataxia, headache, nausea or vomiting at the time of initial discharge. She was initially treated with oral temozolomide but showed progression as she developed back pain and had several episodes of urinary incontinence about 2 months after the surgery. MRI revealed extensive coating of the cauda equina and the distal thecal sac consistent with drop metastases. The residual original tectal lesion appeared unchanged. She then received fractional radiation therapy involving the whole brain (3,600 cGy), a boost to the tumor bed (5,400 cGy), cervical spine (4,600 cGy), and thoracic-lumbar spine (4,600 cGy). When it was noted that she continued to progress on this treatment, chemotherapy was resumed with one cycle of PCV. However, she continues to deteriorate at 6 months after initial presentation with MRI evidence of leptomeningeal gliomatosis. BSG 3. DIFFUSE INTRINSIC PONTINE GLIOMAS OF CHILDHOOD: HIROSHIMA UNIVERSITY EXPERIENCE Kazuhiko Sugiyama1; 1Department of Neurosurgery, Hiroshima University, Hiroshima, Japan. To evaluate the overall survival of pediatric patients with diffuse intrinsic potine gliomas treated with conventional radiotherapy concurrently with ACNU-vincristine chemotherapy followed by oral etoposide. Patients between 5 and 20 years of age with typical diffuse intrinsic potine gliomas on MRI/MRS or histologically proven grade III/IV astrocytoma in pons from 2003 to 2007 were eligible. Induction treatment consisted of ACNU (80 mg/m2 × days 1 and 36) and vincristine (1.5 mg/m2 × days 1, 8, 15, 22, 29, 36, and 43) chemotherapy combined with conventional 54-Gy radiotherapy. After this treatment, patients received monthly oral etoposide chemotherapy consisting of daily dose of 25 mg/m2 (days 1–10) for 12 months or until performance status deterioration. Twelve patients were enrolled (five males and seven females; median age, 6 years). Surgical procedure included three biopsies. The most frequent adverse effects were gastrointestinal and hematologic. There were no toxic deaths. The response to combined treatment included no complete response, three partial response, four stable disease, and five partial response, four stable disease, and five progressive disease. Ten tumors progressed locally, and these 10 patients died; two patients with stable disease are alive. The overall median survival was 332 days, ranging from 135 to 818 days. Our treatment to diffuse intrinsic potine gliomas of childhood did not improve survival. The treatment was well tolerated and should be evaluated for more chemosensitive pediatric malignancies. BSG 4. PATTERNS OF FAILURE FOR DIFFUSE INFILTRATING BRAINSTEM GLIOMA: NEW GUIDELINES FOR RADIOTHERAPY PLANNING Andrew Chang1 and Thomas Merchant1; 1St. Jude Children's Research Hospital, Memphis, TN, USA. Introduction: Diffuse infiltrating brainstem glioma (DIBG) is a uniformly fatal diagnosis for the pediatric patient. Radiation therapy remains an integral component of current treatment regimens that seek to improve symptoms and test new agents in a combined modality approach. To make progress and compare results among treatment regimens requires uniform and consistent guidelines for irradiation. Because there is not agreement on target volume definitions for conformal treatment planning, we undertook a review of all patients treated at St. Jude Children's Research Hospital after CT-based treatment planning to determine patterns of failure with respect to the targeted volume. Methods: Between 1994 and 2006, 84 patients with median age of 6.4 years (range, 1.5–14 years) and diagnosis of DIBG were treated with radiation therapy and subsequently progressed and died. Fifty-nine of these patients had postirradiation MRI available for the pattern of failure analysis. Postirradiation MRI was performed at an average of 2.2 months (range, 1–4) until death. The first MRI to demonstrate treatment failure was imported into the treatment planning system for registration with the original three-dimensional treatment plan. First failures were recorded as local, regional, or distant. The definition for local failure was tumor progression within the contoured gross tumor volume (GTV). Regional failure was defined as any component of tumor progression beyond the confine of the contoured GTV. Distant failure was defined as neuraxis metastastic disease. Results: T2-weighted MR imaging was used to demonstrate treatment failure in all cases and showed the propensity of DIBG to extend along neuronal tracts in all dimensions. Regional failure involved superior spread into the cerebral peduncles and thalamus. Axial spread involved posterior extension into the cerebellar peduncles; there were no cases where the tumor progressed beyond the confines of the normal anatomy. Median progression-free and overall survivals were 7.0 and 12.2 months, respectively. At the time of first failure, 29 had local failure, 25 had regional failure, two had regional and distant failure, and three had distant failure alone. Considering the 27 patients with a component of regional failure, 21 had a component of superior progression, four a component of inferior progression, and 18 a component of lateral progression. The average distances from the contoured GTV were determined: superior, 1.1 cm (0.3–2.75 cm); inferior, 0.4 cm (0.1–0.6 cm); lateral, 1.1 cm (0.3–2.0 cm). Superior failure occurred in 13 patients from 0.3 to 1 cm, five patients from 1.0 cm to 2.0 cm, and two patients >2.0 cm. Conclusions: For DIBG, we recommend new target volume guidelines. The GTV should include identifiable tumor on T1- (postcontrast) and T2-weighted MRI. The CTV should include a 2-cm anatomical expansion in the transverse and inferior dimensions and 3-cm anatomical expansion in the superior dimension. Tumors confined to the pons should have the CTV expanded superiorly to cover the midbrain. PTV margins should be individualized (0.3–0.5 cm) but not less than the MR image section thickness used for treatment planning. Treatment planning MRI should include the upper cervical spinal cord. BSG 5. PEDIATRIC BRAINSTEM GLIOMA: HYPOFRACTIONATED ACCELERATED IRRADIATION, A SINGLE INSTITUTION'S EXPERIENCE Christelle Dufour,1 Christine Levy-Piedbois,2 Jacques Grill,1 Jean-Louis Habrand,1 Chantal Kalifa,1 and Frederic Dhermain1; 1Institut Gustave Roussy, Villejuif, France; 2Institut de Radiotherapie, Bobigny, France. Purpose: To prospectively evaluate efficacy and side effects of hypofractionated irradiation in children affected with brainstem glioma. Methods and Materials: Between April 1996 and January 2004, 22 patients with brainstem glioma were enrolled in this study after radiological diagnosis of rapidly progressing, diffusely infiltrating pontine lesions. They underwent radiotherapy at once-daily fraction of 3 cGy, achieving the total dose of 45 cGy. Treatments were delivered over a 3-week period using five daily fractions per week. Results: Median age at diagnosis was 5.9 years. Median duration of irradiation was 22 days (range, 8–63 days). Acute toxicity was limited to increased signs of intracranial hypertension in eight patients. This was corrected by increasing the steroid dose, but five patients received a modified therapy that consisted of conventional fraction (1.5 cGy) instead of 3 cGy. One child died during radiotherapy, probably due to progressive disease. The median time to disease progression was 5.6 months (range, 1.4–16 months). At time of report, 17 patients died of disease, one due to intratumoral hemorrhage (15 months after end of radiotherapy), and four patients were lost at follow-up. The median duration of survival for 18 patients was 7.38 months. Conclusion: Hypofractionated radiotherapy can be used for children with brainstem glioma to reduce conventional radiotherapy overall treatment time. This treatment seems not to increase toxicity. BSG 6. PHASE II TRIAL OF TIPIFARNIB IN CHILDREN WITH NEWLY DIAGNOSED INTRINSIC DIFFUSE BRAINSTEM GLIOMAS Daphne Haas-Kogan,1 Anuradha Banerjee,1 Mehmet Kocak,2 Michael Prados,1 Russell Geyer,3 Maryam Fouladi,2 Tracy Mcknight,1 Tina Young Poussaint,4 Alberto Broniscer,2 Susan Blaney,5 James Boyett,6 and Larry Kun6; 1University of California, San Francisco, San Francisco, CA, USA; 2St. Jude Children's Research Hospital, Memphis, TN, USA; 3Seattle, WA, USA; 4Department of Radiology, Dana Farber, Boston, MA, USA; 5Houston, TX, USA; 6Memphis, TN, USA. Background: Signals that emanate from growth factor receptors such as epidermal growth factor receptor (EGFR) activate Ras, a small guanosine triphosphatase (GTPase) that requires FTase-mediated posttranslational modifications for its activity. FTase inhibitors (FTIs) impede Ras functions, including promotion of oncogenesis and radiation resistance. FTIs sensitize human cancer cells to radiation, supporting the hypothesis that FTIs will augment tumor response to radiation. We performed a phase II study to assess the efficacy of tipifarnib (Tarceva), a farnesyltransferase (FTase) inhibitor, administered concurrently with radiation therapy (RT) in children with newly diagnosed intrinsic diffuse brainstem gliomas (BSG). Patients and Methods: Children from 3 through 21 years of age with newly diagnosed nondisseminated intrinsic diffuse BSG were treated with concurrent tipifarnib and RT, followed by adjuvant tipifarnib. Tipifarnib was taken orally twice daily, 125 mg/m2/dose, continuously, for the entire duration of RT, followed by a 2-week break. Post-RT tipifarnib, 200 mg/m2/dose, was administered twice daily for 21 consecutive days, in 28-day cycles. Results: In the phase I portion of this Pediatric Brain Tumor Consortium (PBTC) study, the MTD of tipifarnib with concurrent RT was established at 125 mg/m2/dose, twice daily. Forty eligible patients were treated at the MTD dose of 125 mg/m2/dose of tipifarnib (six treated during the phase I portion of the trial are included with 35 treated on the Phase II component; one patient had been declared ineligible). Median age was 5.5 years (range, 3.3–16.5); there were 25 females and 15 males. The progression-free and overall survival at 1 year will be compared to the PBTC contemporary BSG experience. Toxicities that were at least grade 3 in severity and were considered related to tipifarnib consisted of one grade 5, seven grade 4, and 37 grade 3 events: one grade 5 CNS hemorrhage; one grade 4 seizure, one grade 4 encephalopathy, one grade 4 low-serum bicarbonate, one grade 4 leukopenia, one grade 4 lymphopenia, and two grade 4 neutropenias; among grade 3 toxicities the majority were hematologic but also included three transaminase elevations, two hypokalemia, two febrile neutropenias, two infections with normal ANC, and one of each of the following: urinary obstruction, hyponatremia, hypomagnesemia, skin rash, and nausea/vomiting. Conclusion: The MTD of tipifarnib with concurrent radiation (125 mg/m2/dose, administered twice daily) was tested in a phase II trial of efficacy with comparison to progression-free and overall survival in the contemporary PBTC BSG experience. When administered concurrently with radiation, tipifarnib exhibited significant toxicities, involving primarily neurologic, hematologic, and metabolic systems. BSG 7. PHASE II TRIAL THALIDOMIDE AND CARBOPLATIN FOR THE TREATMENT OF BRAINSTEM GLIOMA (CNS1099) Stewart Goldman,1 Tadanori Tomita,2 Maryanne Marymont,3 Stephanie Hannon,1 Monica Newmark,3 Joanna Weinstein,1 Anne Bendel,4 Michael Etzl,5 Lauren Evans,1 Molly Fouts,1 and Jason Fangusaro6; 1Children's Memorial Hospital, Chicago, IL, USA; 2Pediatric Neurosurgery, Children's Memorial Hospital, Chicago, Armed Forces Middle East, USA; 3IL, USA; 4Minneapolis, MN, USA; 5AZ, USA; 6Northwestern University, Chicago, IL, USA. Brainstem gliomas account for approximately 10% of pediatric CNS tumors. Multiple clinical trials of radiation with standard cytotoxic regimens have failed to increase survival. This protocol incorporates an antiangiogenic agent (thalidomide) with carboplatin and radiation therapy to increase PFS. Materials and Methods: Forty-five patients with pontine glioma age 3.1–19.8 years (mean, 7.7 years) were treated on a protocol, which included thalidomide and carboplatin. Thirty-eight patients were enrolled in the study at the time of diagnosis with seven entered after first progression. The newly diagnosed patients received 54–60 Gy irradiation concurrent with the start of this protocol. Demographics for the 45 patients revealed 24 females, 21 males (28 Caucasian, 9 Hispanic, 3 African American, 2 Native American, and 3 other) have been enrolled. The lesions were intrinsic in all with eight having partially extrinsic tumors. Carboplatin was administered at a dose of 560 mg/m2; thalidomide dosed at 300 mg/m2 escalating to 700 mg/m2 daily. Results: Best response data are available for 38 of 45 patients. Of the 34 evaluable for response treated at diagnosis: 2 complete response, 12 partial response, 17 stable disease, and 3 progressive disease. Best response for those treated with progression: four stable disease and two progressive disease. Two newly diagnosed patients remain progression free at ⩾320 and ⩾2,914 days. Mean time to progression (TTP) for newly diagnosed: 343 days (median, 185 days); 1- and 2-year projected overall survival is approximately 50% and 11%, respectively. Of the six with recurrent tumor mean TTP of 118 days. Three patients progressed with disseminated disease while maintaining local control. One patient was ineligible, two inevaluable, four were removed from study without progressive disease per family wishes, and six went off study with toxicity. Toxicities included Pseudomonas exotoxin (1), Stevens-Johnson syndrome (1), TIA/CVA (1), and colitis (1). Rash, constipation, and somnolence was seen in most patients but easily controlled with prophylactic regimens and titration of dose. Conclusions: This outpatient regimen is feasible and generally well tolerated. This regimen compares favorably with historical controls and could be incorporated into future trials. BSG 8. POSTTHERAPEUTIC METABOLIC CHANGES IN DIFFUSE INTRINSIC BRAINSTEM GLIOMA: INITIAL EXPERIENCE Ashok Panigrahy,1 Jonathan Finlay,2 Girish Dhall,2 Mark Krieger,3 Marvin Nelson,4 and Stefan Bluml2; 1Childrens Hospital Los Angeles, Los Angeles, CA, USA; 2Los Angeles, CA, USA; 3Neurosurgery, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 4CA, USA. Background and Purpose: Among pediatric brain tumors, diffuse intrinsic brainstem gliomas (DIBSGs) carry the worst prognosis. These tumors are inoperable and highly resistant to chemo- and radiation therapy. Thus, without effective treatment, the majority of the patients die within 6–18 months after diagnoses. Noninvasive MR imaging—considered the gold standard for diagnoses of DIBSG—is often of limited value to assess disease progression or response to therapy. This lack of appropriate monitoring tools compromises clinical research and there has been no improvement in mean survival time over the last several decades. The goal of this study was to compare metabolic changes in patients that undergo a newly developed therapy with changes observed in previous patients that underwent the standard therapy. Methods: A trial to evaluate a novel treatment (radiation therapy, daily carboplatin, and etoposide followed by temodar, irinotecan, and avastin = TRnew) for DIBSG has commenced at our institution. Thirteen prospective MR spectroscopy studies performed in four subjects prior to and following therapy were evaluated. Data were compared with changes observed in five subjects (17 studies) that were treated with standard therapy (radiation therapy followed by temodar and irinotecan = TRstd) (Panigrahy et al. Neuro-Oncology, e-pub Nov. 14, 2007). All spectra were acquired using a single-voxel PRESS sequence (repetition time = 1.5 s, echo time = 45 ms). LCModel software (S. Provencher Inc.) was used for processing and absolute concentrations of metabolites and metabolite concentrations ratios were determined. Diffusion tensor and perfusion MR imaging was also performed. Results: An increase of N-acetyl-aspartate (NAA) concentrations and NAA/tCho (tCho = total choline) relative to baseline levels was observed in four of four newly enrolled patients in the first posttreatment study. This was observed only in one of five subjects treated with TRstd. Discussion and Conclusion: The observed changes in newly enrolled subjects could be interpreted as a decreased density of neoplastic tissue within the region of interest and thus more effective therapy compared to the cohort of patients treated with the standard therapy. Follow-up and correlation with survival times are necessary to determine whether metabolic changes observed immediately after initial therapy are of predictive value for clinical course. If confirmed, MRS could serve as an early surrogate for the effectiveness of therapy and speed-up clinical trials significantly. BSG 8: Table 1. Comparison of N-acetyl-aspartate (NAA) and NAA to total choline (NAA/tCho) levels in previously followed subjects and in subjects undergoing a combined radiation and chemotherapy as described above . Control, TRstd (n = 5) Baseline . Control, TRstd (n = 5) after Radiation Therapy . TRnew (n = 4) Baseline . TRnew (n = 4) after Radiation Therapy . NAA (mmol/kg) 2.9 ± 0.9 2.0 ± 0.9 2.0 ± 0.6 3.1 ± 0.9 (100%) (70%) (100%) (155%) NAA/tCho 1.5 ± 0.7 0.8 ± 0.3 1.4 ± 0.8 1.6 ± 0.8 (100%) (53%) (100%) (114%) . Control, TRstd (n = 5) Baseline . Control, TRstd (n = 5) after Radiation Therapy . TRnew (n = 4) Baseline . TRnew (n = 4) after Radiation Therapy . NAA (mmol/kg) 2.9 ± 0.9 2.0 ± 0.9 2.0 ± 0.6 3.1 ± 0.9 (100%) (70%) (100%) (155%) NAA/tCho 1.5 ± 0.7 0.8 ± 0.3 1.4 ± 0.8 1.6 ± 0.8 (100%) (53%) (100%) (114%) Open in new tab BSG 8: Table 1. Comparison of N-acetyl-aspartate (NAA) and NAA to total choline (NAA/tCho) levels in previously followed subjects and in subjects undergoing a combined radiation and chemotherapy as described above . Control, TRstd (n = 5) Baseline . Control, TRstd (n = 5) after Radiation Therapy . TRnew (n = 4) Baseline . TRnew (n = 4) after Radiation Therapy . NAA (mmol/kg) 2.9 ± 0.9 2.0 ± 0.9 2.0 ± 0.6 3.1 ± 0.9 (100%) (70%) (100%) (155%) NAA/tCho 1.5 ± 0.7 0.8 ± 0.3 1.4 ± 0.8 1.6 ± 0.8 (100%) (53%) (100%) (114%) . Control, TRstd (n = 5) Baseline . Control, TRstd (n = 5) after Radiation Therapy . TRnew (n = 4) Baseline . TRnew (n = 4) after Radiation Therapy . NAA (mmol/kg) 2.9 ± 0.9 2.0 ± 0.9 2.0 ± 0.6 3.1 ± 0.9 (100%) (70%) (100%) (155%) NAA/tCho 1.5 ± 0.7 0.8 ± 0.3 1.4 ± 0.8 1.6 ± 0.8 (100%) (53%) (100%) (114%) Open in new tab BSG 9. PSEUDOPROGRESSION IN PEDIATRIC DIFFUSE PONTINE GLIOMA TREATED WITH RADIATION AND CONCOMITANT TEMOZOLOMIDE Lucie Lafay-Cousin,1 Jason Feniak,2 Beverly Wilson,3 Xingchang Wei,4 Carmen Rotaru,4 Eric Bouffet,5 and Douglas Strother4; 1University of Calgary, Calgary, AB, Canada; 2Calgary, AB, Canada; 3Edmonton, AB, Canada; 4Calgary, AB, Canada; 5Toronto, ON, Canada. Background: The concept of pseudoprogression (PsP) has been recently described in adult glioblastoma multiforme (GBM) treated with a combination of radiation (RT) and temozolomide (TMZ). It is defined by evidence of progressive disease on imaging early after RT, with or without supporting clinical signs, subsequently followed by improvement or stabilization of initial findings. PsP has often been mentioned in pediatric high-grade glioma (HGG) trial using RT and TMZ, however the incidence in children is unknown. Aim of the Study: Estimation of the incidence of PsP in children with DPG treated with RT ± chemotherapy. Secondary objective was to identify potential predisposing factors for PsP (e.g., TMZ). Methods: Retrospective review of clinical and radiological responses of pediatric DPG diagnosed in the province of Alberta from 1995 to 2007. MRIs from diagnosis, early after completion of RT and every 3 months thereafter were reviewed. Initial clinical symptoms, clinical response at similar time points of MRI evaluation, use of steroids, and survival data were collected separately. Results: Thirteen cases (7 females) were evaluated in the study. Median age at diagnosis was 6.7 years (range, 4.3–16.4). Six patients received RT and TMZ, three had RT and other chemotherapy, and four received RT alone. Median times to clinical and radiological progression from end of RT were 5.5 months (0.7–14.7) and 5.7 months (0.7–15.6), respectively. Median survival time from completion of RT was 10.5 months (1.5–20.2). After completion of RT, six patients showed decrease in size of their lesions, three had stable disease, and four (31%) showed evidence of MRI and clinical progression at a mean time of 1.1 months from RT (early progression). Three of the six patients treated with TMZ showed sign of early progression compared to one of seven who did not receive TMZ. Two of these four patients with early progression remained clinically stable at 4.9 and 4.3 months post-RT with a documented partial response on MRI in one patient. None of the patients were on steroids at the time of clinical stabilization. The two patients later showed clinical and radiologic progression at 5.9 and 6.0 months post-RT. These two cases were felt to be in keeping with PsP. The occurrence of two PsP led to TMZ discontinuation in one case. Conclusion: In this small series of DPG, 4 of 13 (31%) patients presented signs of early progression. Among them, 50% were in keeping with the entity of pseudoprogression. However given the short progression-free survival time of DPG, PsP may not be as recognized as in adult GBM and may require different definition criteria. Our two cases were associated with the use of TMZ. A larger, multiinstitution study extended to all pediatric HGG is ongoing. BSG 9: Table 1. Pseudoprogression according to type of treatment Treatment . n . Early Progression . PsP . Radiation therapy + temozolomide 6 3 2 Radiation + other chemotherapy 3 0 0 Radiation therapy alone 4 1 0 Treatment . n . Early Progression . PsP . Radiation therapy + temozolomide 6 3 2 Radiation + other chemotherapy 3 0 0 Radiation therapy alone 4 1 0 Open in new tab BSG 9: Table 1. Pseudoprogression according to type of treatment Treatment . n . Early Progression . PsP . Radiation therapy + temozolomide 6 3 2 Radiation + other chemotherapy 3 0 0 Radiation therapy alone 4 1 0 Treatment . n . Early Progression . PsP . Radiation therapy + temozolomide 6 3 2 Radiation + other chemotherapy 3 0 0 Radiation therapy alone 4 1 0 Open in new tab BSG 10. RADIOLOGICAL CHANGES FOLLOWING COMBINED TEMOZOLOMIDE AND RADIATION IN CHILDREN WITH DIFFUSE BRAINSTEM GLIOMAS Eric Bouffet,1 Lucie Lafay-Cousin,2 Annie Huang,3 Uri Tabori,4 Sylvain Baruchel,4 Darren Hargrave,5 and Ute Bartels4; 1Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; 2University of Calgary, Calgary, AB, Canada; 3Toronto, ON, Canada; 4University of Toronto, Toronto, ON, Canada; 5Sutton, UK. Background: Evaluation of response in children with diffuse pontine gliomas is based on repeated clinical assessment, evaluation of steroid requirements, and radiological changes. At the end of the radiotherapy period, previous studies have reported clinical improvement in 70%–90% of patients, discontinuation of steroids in 60%, and radiological response in 40%–45% of the patients, with 45% stabilization and 15%–20% worsening (Hargrave et al. Lancet Oncol. 2006). The aim of this study was to compare radiological changes observed after radiation combined with temozolomide (TMZ) with those observed in a cohort of patients treated without TMZ. Method: Retrospective clinical and radiological review of data in patients with diffuse pontine glioma seen at the Hospital for Sick Children between 2000 and 2007 who had two MRI evaluations (i.e., one baseline and one evaluation postradiation). Comparison of radiological changes on FLAIR and T2 images in TMZ versus non-TMZ patients. Results: Twenty-five patients were identified (12 males and 13 females; median age, 6.6 years; range, 3.1–11.5), and three were excluded (no postradiation evaluation). Ten patients received radiation with TMZ, eight received radiation only, and four received radiation combined with motexafin gadolinium. The postradiation MRI was performed at 39 days (range, 9–66) after completion of radiation in the non-TMZ group versus 34 days (7–44) in the TMZ group. In the non-TMZ group, nine patients experienced clinical improvement, two had no change, and one had evidence of clinical progression. In the TMZ group, six patients experienced improvement, two had no change, and three had clinical deterioration. Radiological measurement showed a 48% median decrease (range, –85% to 256%) in 3D dimension in the TMZ group compared to a median 16% increase (range, –71% to 366%) in 3D dimensions in the TMZ patients. Radiological progression was observed in five patients in the TMZ group versus one patient in the non-TMZ group. The median survival time between the two groups did not significantly differ (10.3 vs. 10 months in TMZ vs. non-TMZ patients, respectively). Conclusion: Half of the patients treated with TMZ and radiation show evidence of radiological progression on FLAIR/T2 on the early postradiation MRI. However, these changes are not correlated with clinical response and do not seem to predict a shorter survival span. BSG 11. SPONTANEOUS REGRESSION OF BRAINSTEM GLIOMA IN AN INFANT Monica Koehn1; 1Department of Neurology/Pediatric Neurology, Marshfield Clinic, Marshfield, WI, USA. A 40-day-old term female presented with neonatal onset of neurologic symptoms including feeding difficulties, failure to thrive, and progressive irritability. Examination demonstrated a cachectic neonate with 10% weight loss since birth, uncoordinated swallow, stridorous respirations with regurgitation upon feeding, profound irritability, bifacial and tongue weakness, and suck-swallow incoordination. Infectious and traumatic evaluations were unremarkable. CT head demonstrated a nonenhancing brainstem mass extending throughout pons and medulla. MRI brain and cervical spine showed a large 3.3 × 3.1 cm, well-defined, completely intrinsic, nonenhancing mass extending from pons through C1 levels with signal intensities decreased on T1 and increased on T2-weighted images, all features consistent with brainstem glioma. The mass produced mild compression of the fourth ventricle without hydrocephalus. No brainstem biopsy was felt appropriate. No chemotherapy or radiation initated. Tube feeds resulted in weight gain. Dexamethasone 2 mg/kg/day initiated. Over the subsequent 6 weeks, dexamethasone was tapered very slowly to 0.5 mg/kg/day with dosage based on balancing perceived adverse effects of steroid-induced excessive irritability and clinical response of improved lower cranial nerve dysfunction. Follow-up MRI 7 weeks following the first study demonstrated a dramatic reduction in the size of the nonenhancing brainstem mass with no alteration in imaging features when compared to the initial study, no ventricular obstruction, and no new abnormalities. Steroid taper continued very slowly. Transition to exclusive oral feeding was successful. Neurologic examination and developmental assessment at 4 months of age was normal. This case reiterates the importance of considering the possibility of spontaneous regression in the presentation of brainstem glioma in a young infant. Although the dramatic improvement in neuroimaging and clinical features in this case is unusual relative to the typical clinical course of steady progression of neurologic decline in this diagnosis, spontaneous regression should be considered a rare but real possibility when discussing the very limited treatment options in this age group with a mass lesion involving this inoperable location. BSG 12. THE ROLE OF RADICAL HYPOFRACTIONATION RADIOTHERAPY FOR DIFFUSE INTRINSIC BRAINSTEM GLIOMA IN CHILDREN: A PILOT STUDY Geert Janssens,1 Corrie Gidding,2 Erik Van Lindert,3 Foppe Oldenburger,4 Corrie Erasmus,5 Antoinette Schouten-Van Meeteren,6 and Johannes Kaanders1; 1Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands; 2Department of Paediatric Oncology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; 3Department of Neurosurgery, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; 4Department of Radiation Oncology, Academic Medical Centre Amsterdam, Amsterdam, Netherlands; 5Department of Paediatric Neurology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; 6Department of Paediatric Oncology, Academic Medical Centre Amsterdam, Amsterdam, Netherlands. Background and Purpose: Despite aggressive approaches in many clinical trials done over the last three decades, the prognosis for children with diffuse intrinsic brainstem glioma remains dismal, and most will die within 1 year of diagnosis. As an alternative to the standard conventional radiotherapy schedule (30 fractions of 1.8 Gy over 6 weeks), we propose a radical hypo-fractionation schedule, 13 fractions given over 3 weeks, to limit outpatient department transfers and overall treatment time. Materials and Methods: Between July 2004 and October 2007, nine children, ages 3–13 years, were treated in the radiotherapy departments of Nijmegen (seven patients) and Amsterdam (two patients) by a hypofractionation schedule consisting of 13 fractions of 3 Gy (eight patients) or 6 fractions of 5.5 Gy (one patient) given over 3 weeks (range, 18–22 days). All patients include, had symptoms for <3 months (mean, 6.3 weeks) and at least two signs of the neurological triad (long tract signs, ataxia, cranial nerve deficit). On MR imaging, there was bilateral involvement of the pons in eight of nine patients, encasement of the basilary artery in seven of nine patients and extension into the cerebellar peduncle in six of nine patients. Because of doubt, a stereotactic biopsy was obtained in four patients, all confirming a WHO grade IV astrocytoma. Results: Symptom improvement occurred in all patients within 2 weeks after start of radiotherapy. Median time to progression (TTP) from diagnosis was 4.9 months. At a mean follow-up time of 15 months (range, 3–41 months), seven patients have died. Six out of seven patients died of local disease progression; one patient died of CNS infection but with tumor progression as proven by MRI. Median time to death (OS) from diagnosis was 8.6 months. Median time to death after progression was 3.6 months. These results are not different from what is reported in the literature. According to a recently published review of clinical trials, the median TTP, OS, and time between progression and death ranged from 5 to 8.8, 7 to 16, and 1 to 4.5 months, respectively, with conventional, accelerated or hyperfractionated schedules and other experimental treatment combinations (Hargrave et al. Lancet Oncol. 2006;7:241). Conclusion: With this radical hypofractionation schedule, the median TTP, OS, and time to death after progression are within the range of published data. In our opinion, 13 fractions of 3 Gy, given over 3 weeks, are a good alternative to the conventional radiotherapy schedules of 54 Gy in 30 fractions over 6 weeks for diffuse intrinsic brainstem glioma. This treatment offers patients a quick symptom relief and a temporary improvement of neurological signs and symptoms with minimal toxicity and overall treatment time and maximal escape from outpatient department transfers and/or hospital stay. BSG 13. USE OF IMAGING IN RESPONSE CRITERIA FOR PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPGs) Robert Hayward,1 Robyn Bent,2 Emilie Steffen-Smith,2 Jonathan Wiest,2 and Katherine Warren3; 1NIH, Bethesda, MD, USA; 2MD, USA; 3National Institutes of Health (NIH), Bethesda, MD, USA. Background: DIPGs are devastating tumors that represent 80% of brainstem gliomas in the pediatric population. Standard treatment includes the use of radiation therapy. These patients are diagnosed and followed by magnetic resonance imaging (MRI). Significant decrease in the size of DIPGs (e.g., 50% as per definition of response using 2D criteria), even after radiation, is not typical. Because of their dismal prognosis with median survival <1 year, many patients enter investigational trials. Investigational trials determine the activity of new agents by a reduction in tumor size, as defined by MRI. It has been demonstrated previously that measurement of DIPG by MRI is complicated because definition of tumor boundaries and distinguishing active tumor from radiation effects is difficult. In addition, methods of measuring can differ among radiologists and institutions. Objective: To assess the variability in practice in the methods for MRI measurements and definition of response for patients with DIPG. Methods: A sample of pediatric oncologists and neuro-oncologists in North America were asked to answer 10 questions by electronic survey regarding importance and use of imaging in the clinical management of pediatric patients with DIPG. Subjects were asked to rate likelihood or importance based on a 1–5 scale. In addition, the definition of response for clinical trials for which patients with DIPG were eligible over the past decade were reviewed. Results: Fifty-nine responses were obtained from the survey. Eighty-five percent of respondents have treated >10 patients with DIPG. Significant variability in responses was noted for use and importance of MRI in different clinical situations. For comparing MRI scans, 51% chose the scan immediately prior to current scan as most important, while 38% chose the best response scan and 11% chose the diagnostic scan. Twenty-five percent of respondents were not likely to use the definition of progression by imaging to remove a DIPG patient from protocol. The majority of respondents do not routinely use FDG-PET studies to follow patients with DIPG and only 14% rated FDG-PET as important for clinical decision making. A total of 34 investigational studies for which DIPG patients were eligible over the past decade were reviewed (phase I, n = 19; phase II, n = 11; phase I/II, n = 4). Definitions of response varied and included RECIST, standard two-dimensional criteria only, standard two-dimensional criteria with instructions on how to measure, use of steroids, and requirement for response to be maintained over a specific length of time. No study included quality of life as a measure of response. Conclusion: Patients with DIPG frequently enter clinical trials and are followed for response by MRI. The method of tumor measurement and definition of response is variable. The importance of MRI scans and sequences in clinical decision making is variable. The role of MRI in the management of patients with DIPG should be reviewed. At minimum, standard criteria for response for patients with DIPG enrolled on clinical trials need to be defined, and additional measurements of response, such as quality of life measures, should be included. BSG 14. YOUNG AGE PREDICTS A BETTER OUTCOME FOR CHILDREN WITH DIFFUSE PONTINE GLIOMA Alberto Broniscer,1 Fred Laningham,2 Robert Sanders,2 Larry Kun,3 David Ellison,3 and Amar Gajjar2; 1St. Jude Children's Research Hospital, Memphis, TN, USA; 2TN, USA; 3TN, USA. Background: Since diffuse pontine glioma (DPG) is rare among young children, the outcome of affected patients is unknown. Methods: We reviewed clinical and radiological characteristics of all children <3 years with diffuse pontine glioma (DPG) evaluated at our institution. Inclusion followed standard magnetic resonance imaging criteria for diagnosis of DPG. Results: Median age at diagnosis in ten patients was 2.2 years (range, 0.8–2.7 years). Median interval from onset of symptoms and diagnosis was 2.5 months. All patients presented with cranial nerve palsy with (n = 7) or without (n = 3) other neurological deficits attributable to brainstem involvement. All patients had pons-based tumors involving >50% of this brainstem segment. Histological confirmation was attempted in two patients who had atypical radiological features at diagnosis. Original diagnosis was low-grade astrocytoma in both cases. Four patients were initially observed only. All patients have required therapy consisting of radiation therapy (RT; n = 2), RT and chemotherapy (n = 6), or chemotherapy only (n = 2). Median dose of RT dose was 54 Gy (range, 50.4–55.8 Gy). Three patients were younger than 2 years at the time of start of RT. Four patients have died of tumor progression after a median of 0.7 years (range, 0.5–3.7 years). Six patients have survived for a median of 2.3 years (range, 0.6–8 years). The 3-year progression-free and overall survival were 60% ± 22% and 69% ± 19%, respectively. Conclusion: Children <3 years with DPG can potentially fare better than older patients with the same diagnosis despite use of similar therapy. Our results suggest that DPG in younger children may be biologically distinct from similar tumors in older age groups. CHOROID PLEXUS TUMORS CPT 1. ABERRANT MGMT (O6-METHYLGUANINE-DNA METHYLTRANSFERASE) PROMOTER METHYLATION IS A FREQUENT EVENT IN CHOROID PLEXUS TUMORS Martin Hasselblatt,1 Joerg Muehlisch,2 Brigitte Wrede,3 Birgit Kallinger,2 Astrid Jeibmann,1 Ove Peters,3 Johannes Wolff,4 Werner Paulus,1 and Michael Fruehwald2; 1Institute of Neuropathology, University Hospital Münster, Münster, Germany; 2Department of Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany; 3Department of Pediatric Oncology, University of Regensburg, Regensburg, Germany; 4University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. Promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) DNA-repair gene is a surrogate marker for response to chemotherapy with alkylating agents (e.g., temozolomide) in the treatment of malignant gliomas. Because a role of temozolomide in the treatment of relapsing choroid plexus tumors is currently being considered, MGMT promoter methylation status was assessed in a retrospective series of 16 choroid plexus papillomas, 12 atypical choroid plexus papillomas, and seven choroid plexus carcinomas using combined bisulfite restriction analysis. MGMT promoter methylation was detected in 81% of choroid plexus papillomas, 58% of atypical choroid plexus papillomas, and 43% of choroid plexus carcinomas. Upon a median follow-up of 34 months, relapses had occurred in one of the choroid plexus papillomas, two of the atypical choroid plexus papillomas, and three of the choroid plexus carcinomas. Even though MGMT promoter methylation status tended to be associated with a higher probability of recurrence on univariate analysis, histopathological grading was the only independent predictor of outcome (p = 0.018). In conclusion, MGMT promoter methylation is frequent in choroid plexus tumors. Determination of MGMT promoter methylation status is warranted for stratification of patients for alklylator-based treatment in prospective future clinical trials. CPT 2. CLINICAL FEATURES OF THE NEW WHO ENTITY OF ATYPICAL CHOROID PLEXUS PAPILLOMA: A SUBGROUP ANALYSIS OF THE INTERNATIONAL RANDOMIZED CPT-SIOP-2000 STUDY Brigitte Wrede,1 Ove Peters,1 Peter F. Thall,2 Georg Ebetsberger,3 Michaela Nathrath,4 Norbert Jorch,5 Martin Hasselblatt,6 Adela Cañete,7 and Johannes Wolff8; 1Pediatric Oncology/Hematology, University of Regensburg, Regensburg, Germany; 2Department of Biostatistics and Applied Math, M.D. Anderson Cancer Center, Houston, TX, USA; 3Pediatrics, Landes-Frauen- und Kinderklinik, Linz, Austria; 4Pediatric Oncology, University Children's Hospital Munich, Munich, Germany; 5Pediatric Oncology, Ev. Krankenhaus, Bielefeld, Germany; 6Institute of Neuropathology, University Hospital Münster, Münster, Germany; 7Pediatric Oncology, Hospital Infantil La Fe, Valencia, Spain; 8Pediatric Neuro-Oncology, M.D. Anderson Cancer Center, Houston, TX, USA. Introduction: Atypical choroid plexus papilloma (APP) is a novel entity proposed by the World Health Organization in 2007 with intermediate features between low-grade choroid plexus papilloma (CPP) and high-grade choroid plexus carcinoma (CPC). APP are histologically defined by increased mitotic activity compared to CPP, but their clinical features have not been elucidated in detail. We report on an APP subgroup analysis of the CPT-SIOP-2000 study, an international randomized trial for choroid plexus tumors (CPT), initially designed to identify risk factors and to determine the effectiveness of carboplatinum versus cyclophosphamide treatment in CPT. Methods: A worldwide registration of children and adults with CPT and a randomized trial for patients requiring postoperative treatment were started in 2000. For APP, maximal surgical resection was performed. Patients with completely resected tumors were observed, whereas incompletely resected or metastasized APP were treated with six chemotherapy courses (VP16 100 mg/m2, d1–5, vincristine 1.5 mg/m2, d1, and either carboplatinum 350 mg/m2, d1,2, or cyclophosphamide 1,000 mg/m2, d1,2), and additional irradiation after the second course for patients older than 3 years of age. Results: Until January 2008, 21 nations had registered 123 patients (45 CPC, 32 APP, 46 CPP). Of these, 49% were male. Patients with APP had a median age of 0.7 years and were thus significantly younger than patients with CPP (2.3 years) or CPC (2.7 years). 84% of APP were located in the lateral ventricles. Primary metastases were observed in 13% of the patients (5% in CPP, 19% in CPC). Complete resection was achieved in 69% of APP patients. In the observational group, no death was seen. In the APP group receiving further treatment, early response was similar to CPC with partial response or stable disease in seven of eight patients. The APP patients had an intermediate 5-year event-free survival of 70% ± 14 SD (CPP, 95% ± 4 SD; CPC, 45% ± 14 SD). 14% of the APP patients had a relapse (5% CPP, 33% CPC) and two of those showed transformation to CPC. Conclusion: The average age of patients with atypical choroid plexus tumors was lower than that of patients with other choroid plexus tumors. In other aspects, the intermediate position of APP defined by histology was also clinically reflected by the rate of metastases, relapse, and survival between CPP and CPC. Radiochemotherapy of incomplete resected APP may yield similar results compared to CPC, but more patients are required. CPT 3. GENETIC ASPECTS OF CHOROID PLEXUS TUMORS (CPTS): THE EXPERIENCE AT A SINGLE INSTITUTION IN ITALY Maria Luisa Garrè,1 Gilberto Fronza,2 Claudia Milanaccio,1 Liliana Varesco,3 Alessandro Raso,4 Samantha Mascelli,4 Andrea Rossi,5 Salvina Barra,6 Guia Hanau,1 Paolo Nozza,7 Alessandro Consales,4 Armando Cama,4 and Valeria Capra4; 1Haemato-Oncology, Giannina Gaslini Children's Research Hospital, Genoa, Italy; 2Molecular Mutagenesis and Translational Oncology, National Cancer Research Institute (IST), Genoa, Italy; 3Genetics, National Cancer Research Institute (IST), Genoa, Italy; 4Neurosurgery, Giannina Gaslini Children's Research Hospital, Genoa, Italy; 5Neuroradiology, Giannina Gaslini Children's Research Hospital, Genoa, Italy; 6Radiation Oncology, National Cancer Research Institute (IST), Genoa, Italy; 7Pathology, Giannina Gaslini Children's Research Hospital, Genoa, Italy. Choroid plexus tumors (CPTs) are rare CNS tumors; prognosis of the malignant type, choroid plexus carcinoma (CPC), remains poor. CPTs have been reported as tumors occurring in Li-Fraumeni syndrome (LFS), although the frequency of occurrence of LFS in large series of prospectively treated patients with CPTs is not reported yet. We have investigated the clinicopathological characteristics, genetic profile, treatment, and outcome of 21 consecutive cases of CPTs diagnosed and treated at a single large institution in Italy in the period 1990–2006. Eleven were males, 10 females; age at diagnosis ranged from 2 months to 15 years (median, 26 months). There were 10 choroid plexus papillomas (CPP), 3 atypical CPP (ACPP), 9 CPC; lateral ventricles were involved in 17 cases (80%); IV and III ventricles were involved in 2 cases each (10%). Six cases (30%) had metastasis at diagnosis (five CPC, one APP). Treatment consisted of surgical approach with radical intent in all cases; preoperative chemotherapy in four cases (2 CPC, 2 APP); postoperative chemotherapy in 10 cases (9 CPC, 1 ACPP); 2 patients with CPC were irradiated. No relapses were observed in the CPP and ACPP subgroups. Outcome was very poor in CPC: six of nine dead of disease (66%). One patient with ACPP developed a second brain tumor (glioblastoma) at 5 years after discontinuation of treatment, and at that time this patient was found to present constitutional P53 mutation. Concerning the frequency of LFS, it was clearly present in one-third of cases with CPC (three of nine cases) and ACPP (one of three cases). One case in the CPP was reported to have Aicardi syndrome. Conclusions: CPC and ACPP are frequently (30% of cases) associated with LFS in our study. Therefore, cases of CPC should probably be investigated at diagnosis for constitutional mutations of TP53, at least in families with positive history; genetic counseling should be offered to the families. Cases cured for CPTs should be followed for a prolonged period for occurrence of other cancers, and family history frequently updated. Impact of up-front genetic evaluation on treatment strategy of CPC should also be discussed in the plan of large international cooperative studies. CPT 4. WHAT IS THE DEVELOPMENTAL FUTURE OF YOUNG CHILDREN WITH CHOROID PLEXUS PAPILLOMAS? Silvia Gatscher,1 Dianne Gumley2; 1Neurosciences, Great Ormond Street Hospital, London, UK; 2Pediatric Psychology, Great Ormond Street Hospital, London, UK. Introduction: Psychometric evaluation is nowadays part of routine follow-up in children who have been treated with radiotherapy for a CNS tumor. Regular developmental and psychological assessment has provided us with enormous insight regarding long-term side effects. This has sparked our interest in assessing the developmental progress in children who have only undergone a surgical resection for their brain tumor and to look at the consequences of a major neurosurgical procedure, in particular at an early age. We decided to carry out developmental assessments in children with choroid plexus papillomas (CPP), since CPPs usually present at an early age and surgery is the curative treatment. Methods: Between September 2005 and March 2007, 10 children were admitted to Great Ormond Street Hospital with CPP and underwent a complete surgical resection. Eight children were less then 3 years old at the time of presentation; two were 11 and 14, respectively, at the time of diagnosis. One child was lost to follow-up. Seven children were <5 years of age when assessed and were evaluated with the Vineland Adaptive Behavior Scale and the Mullen scales. In the two older children, 12 and 15 at the time of follow-up, we used the Wechsler Intelligence Scales for Children Fourth UK Edition and the Children's Memory Scales. We also asked the parents to complete the Social Development Questionnaire and the Behavior Rating Inventory of Executive Function. Results: We evaluated social and emotional development in both patient groups and executive function skills in the older group. The outcome from the initial assessment of the younger group was particularly encouraging. Developmental progress was within average range in five of seven patients, and five were making good progress with social and adaptive skills. The two older children also performed as expected for their age group. Conclusion: We feel it is important to continue monitoring these children, to see whether their cognitive profile continues to progress as expected, and to observe their emotional and behavioral development. CASE REPORTS CR 1. A HIGHLY UNDIFFERENTIATED TUMOR IN THE POSTERIOR FOSSA IN A YOUNG CHILD WITH CUTANEOUS PIGMENT LESIONS Joris Verlooy,1 Caroline Van Den Broecke,2 Edward Baert,3 Tom Boterberg,4 Valerie Meersschaut,5 Els Vandecruys,1 Yves Benoit1; 1Pediatric Oncology/Hematology, Ghent University Hospital, Ghent, Belgium; 2Department of Pathology, Ghent University Hospital, Ghent, Belgium; 3Neurosurgery, Ghent University Hospital, Ghent, Belgium; 4Radiotherapy, Ghent University Hospital, Ghent, Belgium; 5Radiology, Ghent University Hospital, Ghent, Belgium. We describe the case of a boy presenting at 7 months of age with signs of intracranial hypertension due to a posterior fossa tumor. Two months earlier three truncal large cutaneous pigment lesions had been removed and microscopy revealed several deep penetrating nevi, without evidence of malignancy. The boy underwent a macroscopically total resection confirmed by postoperative MRI. Microscopical examination revealed a highly undifferentiated tumor with small cells having a hyperchromatic nucleus and very little cytoplasm. There were no rosettes to be found, and no signs of glial or neuronal differentiation. Immunohistochemistry showed no positive markers for medulloblastoma (CD 56 and synaptophysin negative). GFAP, CD 99, desmin, keratins, and LCA were all negative. INI 1 staining of tumor cell nuclei was normal. Because of the atypical clinical picture of an intracranial mass and cutaneous lesions, markers for melanocytic lineage were also performed on the CNS tumor: Melan A and NKI-C3 were negative. HMB45 showed a dotlike staining pattern in the cytoplasm of some tumor cells. Staining with MITF-1 was, however, clearly positive. Based on this staining pattern, the diagnosis of a highly undifferentiated tumor with evidence of melanocytic differentiation was put forward. Genetic analysis for nevoid basal cell carcinoma syndrome was negative, and no other genetic anomalies were found. The boy was treated with a chemotherapy regimen consisting of vincristine, carboplatin, cyclophosphamide, and etoposide (SIOP PNET 3), but showed a massive regrowth of the tumor under this treatment at the age of 12 months. A second total resection was performed and because of the melanocytic aspect of the disease he was treated with a combination of irradiation on the posterior fossa, temozolomide, and dendritic cell vaccination. During this therapy he developed a significant number of new cutaneous lesions. MRI examination after irradiation revealed several spinal drop metastases. Therapy was intensified with intrathecal etoposide, but the spinal lesions grew massively and all treatment was ceased. In this child the combination of dermal nevi and CNS melanocytic lesions is suggestive of a neurocutaneous melanosis refractory to a combination of treatments. CR 2. BONE MARROW TRANSPLANTATION (BMT) FOR APLASTIC ANEMIA SECONDARY TO TEMOZOLOMIDE THERAPY IN A LONG-TERM SURVIVOR WITH GLIOBLASTOMA MULTIFORME (GBM) Brannon Morris,1 Ulrike Reiss,2 Kimberly Kasow,2 and Alberto Broniscer1; 1St. Jude Children's Research Hospital, Memphis, TN, USA; 2St. Jude Children's Research Hospital, TN, USA. Introduction: Radiotherapy plus concomitant/adjuvant temozolomide is standard treatment for glioblastoma multiforme (GBM) in adults. Although myelosuppression is a recognized dose-limiting toxic effect, temozolomide is generally considered to be well tolerated. More recently, several patients with irreversible bone marrow aplasia after treatment with temozolomide have been reported. We report the unusual case of an adolescent patient with GBM who underwent bone marrow transplantation (BMT) for treatment of presumed temozolomide-related aplastic anemia. Case History: This patient was an otherwise healthy 16-year-old girl until she presented with a left frontoparietal intraparenchymal hemorrhage in April 2004. The source of hemorrhage was presumed to be an arterialvenous malformation, and she was followed until a second bleed occurred in July 2004. At this time, she underwent a biopsy and was subsequently referred to our institution for subtotal resection of a tumor that proved to be GBM. She was enrolled in August 2004 on CNS126, a phase II study utilizing cranial irradiation with concurrent temozolomide. By day 24 of therapy she became pancytopenic and temozolomide was discontinued. Radiation therapy continued, and the patient received a total dose of 59.4 Gy. The patient's pancytopenia worsened and ultimately she became red blood cell dependent and platelet transfusion dependent with an absolute neutrophil count (ANC) of zero. Bone marrow aspirate at this time revealed a hypocellular marrow with no dysplasia, infection, or neoplasm. A diagnosis of severe aplastic anemia was made, and she received filgrastim therapy from December 2004 to March 2005. Although her ANC responded with consistent levels >500, she remained transfusion-dependent with weekly red cell infusions to keep her hemoglobin count >8 g/dl and biweekly platelet transfusions to maintain her counts >20,000/mm3 due to frequent epistaxis. A bone marrow aspirate in September 2005 revealed cellularity <5% and no morphologic evidence of microorganisms or malignancy. Cytogenetics was not completed because no metaphases were available for analysis. Subsequent chromosome breakage analysis (diepoxybutane-induced) was within normal range and paroxysmal nocturnal hemoglobinuria screen was negative. In March 2006 she was diagnosed with significant iron overload (serum ferritin >5,000 ng/ml and liver iron concentration 30 mg/g). All the while, surveillance neuroimaging demonstrated stable residual tumor. In June 2006, 26 months after her sentinel bleed and 22 months after diagnosis of GBM, she began intensive immunosuppression therapy with antithymocyte globlulin, cyclosporine, and corticosteroids. Unfortunately, she did not have an adequate response to this therapy. In February 2007, after >30 months of stable neuroimaging, the patient underwent a matched unrelated donor BMT with the hope of improving her quality of her life by becoming transfusion independent. Unfortunately, despite studies showing her donor status to be 100% (T-cell chimerism = 98%), her graft function remained quite poor. In July 2007, she underwent additional immunosuppression followed by another infusion of her original donor stem cells. Currently, this patient is back at home with stable neuroimaging. Although she still requires blood and platelet transfusions two to three times per month, she has enrolled in her local community college with a reduced load of classes. CR 3. CASE REPORT: GERMINOMA PRESENTING AS GRANULOMATOUS INFLAMMATION IN THE PINEAL GLAND Veena Rajaram,1 Nicholas Slimack,1 and Arthur Dipatri1; 1Children's Memorial Hospital, Chicago, IL, USA. Germ cell tumors, more specifically germinomas, are the most frequently encountered neoplasms in the pineal region in adolescents. In the absence of elevated serum and/or cerebrospinal fluid markers for alpha-fetoprotein and human chorionic gonadotrophin, tissue diagnosis is necessary in many cases before initiating therapy. Biopsy finding of a granulomatous inflammation generates a wide differential including infection, Langerhans cell histiocytosis, and juvenile xanthogranuloma. Germinomas presenting as a granulomatous inflammatory process have been reported and if this entity is not considered in the differential it may lead to the institution of inappropriate therapy. Case Report: A previously healthy 15-year-old boy presented with a 1-week history of vertical diplopia, blurred vision, and intermittent headaches. An MRI of the brain revealed a heterogeneously enhancing mass originating in the pineal region with acute hydrocephalus. An endoscopic third ventriculostomy was performed. Tumor within the posterior portion of the third ventricle could not be visualized, so a biopsy was not obtained. Serum and cerebrospinal fluid (CSF) alpha-fetoprotein and human chorionic gonadotrophin levels were all in the normal range. Cytological examination of the CSF was negative for malignant cells. The patient's visual symptoms improved and the hydrocephalus resolved. Ten days later a craniotomy was performed for biopsy. At surgery the mass appeared to arise in the pineal region and extend superiorly along the posterior surface of the splenium until it collided with the falx. It then continued along the lateral surfaces of the falx. Multiple tissue samples were taken from the superficial and deep parts of the lesion. Histologically, sections showed extensive inflammation with lymphocytes and numerous multinucleated giant cells admixed with clusters of small blue cells with extensive crush artifact. Some of these cells had large nuclei and scant cytoplasm. Immunohistochemistry studies showed focal positivity in the crushed area and in rare single tumor cells for placental alkaline phosphatase with diffuse positivity in the cell clusters for CD117 (C-KIT). The multinucleated giant cells were positive for CD68, which also stains the admixed histiocytes. Synaptophysin and GFAP were negative. Special stains for microorganisms (acid-fast bacilli and fungus) were negative. The histology, background, and immunostaining pattern was most consistent with a germinoma with an extensive reactive, granulomatous response. We present this case to increase awareness of an atypical presentation of this entity. CR 4. CASE REPORT: PAPILLARY MENINGIOMA (PM) PRESENTING AS LOSS OF MILESTONES IN A TODDLER Stewart Goldman,1 Robin Bowman,2 Wendy Stellpflug,3 Tara Goei,3 and Veena Rajaram1; 1Children's Memorial Hospital, Northwestern University, Chicago, IL, USA; 2Neurosurgery, Children's Memorial Hospital, Northwestern University, Chicago, IL, USA; 3Children's Memorial Hospital, Chicago, IL, USA. Introduction: Papillary meningioma (PM) is a rare malignant variant of meningioma with a propensity for intracranial recurrence and pulmonary metastasis. PM was first described by Cushing and Eisenhardt in 1938. Meningioma accounts for 13%–19% of intracranial tumors of adulthood; papillary meningiomas make up only 1%–2.5% of meningiomas in adulthood and have been rarely reported in children. Case Report: We report a 20-month-old who presented to her MD with changes in balance and decrease in her ability to walk; she developed emesis and lethargy followed by acute decompensation. Emergency MRI revealed hydrocephalus and a large post fossa mass. She underwent gross total resection of her left cerebellar hemispheric mass. On histological examination, the tumor showed sheets of discohesive cells with large vesicular nuclei, occasional nucleoli, and moderate amount of eosinophilic cytoplasm arranged as clusters and perivascular papillary/pseudorosette-like structures. Occasional intranuclear pseudoinclusion was identified. Mitosis was easily identified and there were areas of tumor necrosis. Immunohistochemical studies showed focal weak positivity for epithelial membrane antigen and rare tumor nuclei positivity for progesterone receptor. Ultrastructural studies showed tumor cells with numerous highly interdigitating cellular processes, occasional intercellular junctions consistent with desmosomes, and no zipperlike junctions, ciliary bodies, or microvilli. The ultrastructural findings are suggestive of meningothelial differentiation and the histology was that of a papillary meningioma. Six weeks postoperative she had local recurrence. Workup following a second resection prior to focal proton beam therapy revealed multiple pulmonary and liver metastases. She underwent chemotherapy with ifosfamide, carboplatin, and etoposide (ICE) with significant decrease of her systemic metastasis after the first cycle and obtained complete response after 2 courses. Further cycles of ICE alternating with cycles of doxorubicin, vincristine, and cytoxan were given over 6 months; she then completed high-dose chemotherapy and peripheral-blood stem cells with a carboplatin, thiotepa, and etoposide preparatory regimen; presently she remains with no evidence of disease with short follow-up. This case is presented to increase awareness of this extremely rare entity in young children. CR 5. CLINICAL AND RADIOGRAPHIC CHARACTERIZATION OF RADIATION RECALL IN THE DEVELOPING CNS Anna Janss,1 Nadia Esiashvili,2 Mark Kieran,3 and Susan Chi4; 1Emory University, Decatur, GA, USA; 2GA, USA; 3MA, USA; 4Boston, MA, USA. Radiation recall describes an acute inflammatory reaction in previously irradiated areas after the administration of inciting systemic agents which include several cytotoxic drugs. The skin is the tissue where the phenomenon was first described, but it has been reported in other organ systems. Radiographic and clinical features of radiation recall in the CNS have not been well described. We present a case report of radiation recall affecting the CNS during treatment protocol for children with newly diagnosed CNS atypical teratoid/rhabdoid tumor (AT/RT), DFCI 02-294. This 51-week treatment regimen includes the following systemic agents: vincristine, cisplatin, etoposide, cyclophosphamide, doxorubicin, dactinomycin, and temozolomide. Intrathecal therapy (methotrexate, cytarabine, and hydrocortisone) is administered throughout the regimen. Radiation therapy is given during weeks 7–12; for this patient, conformal 54 Gy in 180 cGy fractions was delivered. Case: A 3-year-old girl with a subtotally resected pineal AT/RT received induction chemotherapy, chemoradiation (conformal RT), and consolidation therapy, with complications limited to constipation, anemia, and neutropenia. Evaluation performed at week 19 showed tumor regression on imaging and a normal neurological examination. On week 24 of therapy she developed partial seizures featured by right arm shaking and altered mental status, in the absence of systemic illness or metabolic abnormality. Seizures were controlled with benzodiazepines, then levetiracetam. Neuroimaging revealed stable tumor in the pineal gland and dorsal midbrain with new T2 signal abnormality in the posterior mesiotemporal lobes, thalami, mid-brain, and medial cerebellum. This distribution closely matched the high-voltage regions in her radiation dosimetry maps. After this episode the child developed ataxia, nystagmus, vertical skew, tremor, and right hemiparesis. These symptoms gradually improved but did not completely resolve. Imaging over the ensuing 6 months revealed regression of the T2 signal abnormality, replaced by transient patchy enhancement. Dactinomycin, doxorubicin, and intrathecal medications were held or reduced for the remainder of her therapy. The child remains on anticonvulsants without evidence of recurrence 6 months after completion of therapy. This case highlights an example of the radiographic features and prolonged neurological consequences of radiation recall in the developing nervous system, contrasting with the more classic and temporary findings typically seen in radiation recall. Recognition of radiation recall within the brain and differentiation from other treatment-related changes will require a better understanding of their presentation and etiology. CR 6. EXTRACRANIALLY METASTATIC PNET PRESENTING WITH ABDOMINAL PAIN Arja Harila-Saari,1 Hannu Tuominen,2 Sakari Knuutila,3 Merja Mottonen,1 Ritta Herva,2 and Satu Lehtinen1; 1Department of Pediatrics, Oulu University Hospital, Oulu, Finland; 2Department of Pathology, Oulu University Hospital, Oulu, Finland; 3Department of Pathology, Laboratory of Cytomolecular Genetics, Helsinki, Finland. A 6-year-old boy was admitted into our hospital because of a 2-week history of abdominal pain. He was febrile and unable to walk because of the pain, but his physical examination was otherwise unremarkable. CRP was high (120 mg/liter), as were also ferritin (1,890 μg/liter) and LD (4,216 U/liter). Subtle anemia (Hb 9.0 g/dl), leukocytosis (22 × 109/liter), thrombocytopenia (94 × 109/liter), and clear eosinophilia (45%) were found. Splenomegaly and enlarged abdominal and hilar thoracal lymph nodes were observed in CT. Bone marrow was nearly filled with nonleukemic small blastlike malignant cells. Immunohistochemisty was not compatible with Ewing's sarcoma, and the test for translocation t(11;22) was negative. The disease progressed and the patient's condition deteriorated so rapidly that a course of chemotherapy (VAC) had to be started before the final diagnosis. FDG-PET scan showed increased glucose uptake in the bone marrow, lungs, pleura, abdomen, and brain. MRI revealed a huge frontal brain tumor. No malignant cells were shown in CSF, and the patient did not have any neurological symptoms or findings. The tumor was operated as soon as the patient's condition improved. PAD was best compatible with atypical PNET. Molecular caryotyping showed gene amplifications in the entire chromosome 18 and chromosome 19, especially in the 19q arm. The chromosome 9p gene CDKN2A was deleted. These findings fit the diagnosis of PNET. Despite two additional chemotherapy courses, the disease progressed, and the patient died 3 months later. At autopsy, the tumor was found to have metastasized diffusely within the CNS and all over the body. Such an aggressive brain PNET with disseminated disease at diagnosis is extremely rare and seems to be associated with rapid progression and poor prognosis CR 7. HIGH-GRADE CONGENITAL PRIMITIVE NEUROEPITHELIAL TUMOR: A CASE STUDY Wendy Beaudoin,1 Diane Arndt,2 Vivek Mehta,2 and Lothar Resh2; 1Stollery Children's Hospital, Edmonton, AB, Canada; 2AB, Canada. A 9-day-old female infant was admitted after a 2-day history of nonbilious projectile vomiting and dehydration. Head circumference at that time was 37.5 cm. The infant was born of a 30-year-old mother at 40 weeks gestational age via scheduled C-section. Apgars were 8 at 1 min and 10 at 5 min. Two prenatal ultrasounds had been done at 22 weeks and 34 weeks gestation. Both were reported to be unremarkable. On day 2 of admission a head ultrasound was completed, revealing a very large heterogeneous mass within the right cerebral hemisphere. A CT and MRI of the head were obtained and revealed a mass that was centered within the right frontal lobe but crossed midline and extended into the right middle cranial fossa. The tumor measured 8.0 × 6.6 × 6.0 cm. At 13 days of age, a right frontal craniotomy with drainage of cyst and tumor biopsy was performed. Intraoperative frozen section was described to be consistant with astrocytoma. On postoperative day 1, the patient developed tongue fasciculations and lip smacking and was started on phenobarbital; CT scan showed some improvement in size of the cyst and less mass effect on the right lateral ventricle. A family conference was held day 13 postoperatively to review pathology, and palliative chemotherapy was offered. The family declined any intervention, and on postoperative day 17 the child was discharged home on phenobarbital and tube feeds with home care and the palliative care team was involved. The patient died peacefully at home 3 months later. The incidence of congenital brain tumors is rare. The definition is controversial. The two main criteria for classifying a brain tumor as congenital are (1) the age of the patient at presentation of clinical manifestations and (2) the histopathological characteristics of the tumor. These tumors account for only 0.5%–1.5% of all childhood brain tumors, but for 5% of all neonatal deaths. CR 8. IDIOPATHIC INTRACRANIAL PACHYLEPTOMENINGITIS IN A CHILD TREATED FOR ATYPICAL TERATOID/RHABDOID TUMOR (ATRT) Lidija Kitanovski1 and Martina BüRger Lazar1; 1Department of Hematooncology, University of Ljubljana, University Children's Hospital Ljubljana, Ljubljana, Slovenia. A now 5-year-old boy was diagnosed with multifocal atypical theratoid rhabdoid tumor (ATRT) at the age of 2 years. The infratentorial tumor was surgically removed. He was treated intensively according to German ATRT-ZNS 2004 protocol for 14 months, including chemotherapy, intraventricular methotrexate, and local radiotherapy. During induction treatment he experienced persistent nausea and vomiting with ventricular dilatation. Diamox had no effect. VP drainage was done; thereafter consciousness disturbances appeared. Dexamethasone was introduced, followed by significant improvement of nausea and vomiting, which reappeared immediately after its discontinuation. MRI revealed diffuse pachymeningeal thicknening and mild leptomeningeal (especially along folia cerebelli) enhancement. Diagnostic workup did not detect any infectious agents or malignant cells in the CSF. Chemotherapy has continued. Later convulsions with consciousness disturbances appeared on two occasions and responded poorly to anticonvulsants, except dexamethasone. Nausea and vomiting again considerably improved during dexamethasone use, and regression of MRI meningeal findings was observed. Hystological examination of two consequent meningeal biopsies (after considerable regression of MRI findings following dexamethasone and at the time of supratentorial tumor removal) revealed no abnormalities. After second convulsive status, dexamethasone was continuously used for 1.5 years; periodic MRIs have revealed persistent pachymeningeal and slight leptomeningeal thickness, while nausea and vomiting have been considerably controlled. Due to severe side effects, dexamethasone was replaced by methylprednisolone and gradually tapered to very low dose. Nausea and vomiting reappeared, left facial nerve paresis worsened, and progression of MRI findings with diffuse bone thickness of calvaria was found. Immunological workup revealed increased IgM level (1.99 g/liter) and positive ANCA-BPI antibodies. ANA, anti-ENA, s-ACE, LA, and ACA were normal. Elevated erythrocyte sedimentation rate (ESR) and CSF protein concentration were detected on several occasions. A third meningeal biopsy (at the site of a chronic subdural hematoma) did not confirm pachymeningitis. The child received 2 courses of high-dose methylprednisolone, nausea and vomiting diminished again, ESR decreased, and ANCA antibodies were no longer detected. Recently azathioprine was added to methylprednisolone to try to considerably reduce or even omit corticosteroids in the future since they significantly compromise the quality of life of the child, who walks with assistance and has severe osteoporosis, marked cushingoid appearance, and progressive cerebral atrophy. Psychological assessment of his cognitive, physical, language, and psychosocial development show mental and motor developmental delay. Most delayed mental areas are complex language and mathematical concept formation, construction, spatial problem-solving and planning, memory, discrimination, and abstract thinking. The main motor disabilities are balance, coordination of large muscles, finer manipulatory skills of hands and fingers, dynamic movement, and visual-motor integration. His mood is very unstable and varies from depressive to euphoric. We believe we are dealing with idiopathic intracranial pachyleptomeningitis in a child treated for multifocal ATRT, who currently (2 years after treatment conclusion) has no signs of tumor relapse. Persistent clinical and occasional MRI findings of improvements after corticosteroids and persistently elevated ESR favor our diagnosis, despite its not being hystologically confirmed. In our patient idiopathic pachyleptomeningitis might be MPO-ANCA associated and provoked by intravenous or intraventricular chemotherapy in the past. CR 9. INCREASED NONCLONAL CHROMOSOME ABERRATIONS IN A PATIENT WITH GLIOSARCOMA AND SECONDARY ACUTE MYELOID LEUKEMIA Zhihong Wang,1 Kanta Bhambhani,1 Merlin Hamre,1 Guo Liu,2 Christine Ye,2 and Henry Heng2; 1Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA; 2Center for Molecular Medicine and Genetics, Wayne State University, MI, USA. The theory that genome aberrations rather than gene mutations cause the majority of cancers has gained increasing support from recent experimental data (Heng et al. Genome. 2006;49:195; Heng. BioEssays. 2007;29:783). Genomic instability–generated nonclonal chromosome aberrations (NCCAs) are believed to be a key driving force in cancer progression (Heng et al. J Cell Physiol. 2006;208:461). Both chromosome fragmentation and defective mitotic figures (DFMs) are newly identified forms of chromosome aberrations. In vitro data indicated that frequencies of chromosome fragmentation correlate to levels of genomic instability of cell lines; and many chemotherapeutic agents can generate increased frequency of chromosome fragmentation (Stevens et al. Cancer Res. 2007;67:7686). We report here a patient who developed secondary acute myeloid leukemia (AML) within a year after completion of treatment for gliosarcoma. Significantly increased chromosome fragmentation and NCCAs were detected when he was receiving chemotherapy for gliosarcoma. The patient is a 13-year-old African American male who initially presented with seizures, which led to the evaluation and diagnosis of malignant gliosarcoma of the left frontal region. He had a complete resection of the left frontal mass followed by involved field radiation and chemotherapy with CCNU and temozolamide per COG study ACNS0423. He completed treatment per protocol without major complications. He had an unremarkable past medical history and no family history of brain tumors or other cancers. Nine months after completion of treatment, he developed a forearm hematoma following minor trauma. Workup revealed moderate anemia and severe thrombocytopenia, which prompted bone marrow evaluation and diagnosis of AML with features of extensive myeloid displasia. He had complex cytogenetic abnormalities including 45,XY, del(5)(q13), del(7)(q22q36), r(11)(p15q25), and add(17)(p12). There was no evidence of translocation or deletion of MLL/11q23 by FISH. His AML was refractory to multiple rounds of chemotherapy including arabinoside, daunorubicin, and etoposide (ADE), gemtuzumab, and clofarabine. As part of a pilot study to determine the clinical significance of nonclonal chromosome aberrations, tests for chromosome fragmentation, DMFs, and NCCAs were performed when he was receiving chemotherapy for gliosarcoma. The results showed that he had >20% chromosome fragmentation and 36% NCCAs, both the highest degree among the 15 brain tumor patients we have tested. He also had significantly increased DMFs (>5%) and free chromatin. It is likely that increased chromosome aberrations induced by chemotherapy in this patient contributed to his secondary malignancy. It is uncertain whether he had inherent genome instability, as pretreatment testing was not performed. Nevertheless, we believe that the increased genome instability as demonstrated by increased NCCAs and increased chromosome fragmentation contributed to the rapid onset of secondary malignancy. Although this is only an anecdotal case, it raised some interesting issues. First is whether we can use these tools to monitor the degree of chromosome aberrations and determine the levels of genome instability in patients with high risk of developing cancers. Second is whether the severity of nonclonal chromosome aberration as reflected by NCCAs, chromosome fragmentation, and DNFs could be used as an indicator of increased susceptibity to secondary malignancies. CR 10. INTRACAVITARY CHEMOTHERAPY WITH LIPOSOMAL CYTARABINE: A CASE REPORT Benedikt Weiß,1 Petra Turowski,1 Gerda Demleitner,1 Brigitte Wrede,1 and Ove Peters1; 1Children's Hospital, Regensburg, Germany. Background: We present a white male patient 17 years of age at diagnosis of an alveolar rhabomyosarcoma (T4/pN2c/M0) of the paranasal sinuses with a tumor cyst (6.6 × 5.6 × 4.1 cm; volume 76 cm3) extending per continuity into the left frontal cerebral lobe. This cyst had no contact with the cerebrospinal fluid (CSF) system. In addition to the sarcoma chemotherapy, we locally treated the tumor cyst with repeated intracavitary liposomal cytarabine (DepoCyt) injections. Liposomal cytarabine has been developed as an alternative for the intrathecal chemotherapy of neoplastic meningitis. The drug is composed of the pyrimidine analog cytarabine, encapsulated in multivesicular, lipid-based particles. After a single intrathecal injection, these particles spread throughout the CSF and account for a sustained release of cytarabine, maintaining cytotoxic concentrations up to 14 days. Procedure: On the third day of the sarcoma chemotherapy (CWS 2002-P: i.v. doxorubicin, ifosfamide/vincristine/dactinomycin, and ITH prednisolone/cytarabine/methotrexate), the intracranial tumor cyst volume increased, resulting in symptoms of elevated intracranial pressure (ICP). We decreased the cyst volume by serial punctures due to an implanted Rickham reservoir. The symptoms of ICP improved rapidly. Each extracted cystic fluid showed a massive amount of rhabdomyosarcoma cells. Because of the recurrent increase in cyst volume, we additionally started an intracavitary chemotherapy by injection of DepoCyt via the implanted Rickham reservoir. The injections were given at days 24 (1 mg), 28 (5 mg), 35 (5 mg), and 49 (5 mg) after initiation of the sarcoma chemotherapy. DepoCyt trough concentrations of the cystic fluid were determined before the injection. Meanwhile, the sarcoma chemotherapy was continued, with interposition of a local irradiation (52.2 Gy) of all primary tumor sites starting 73 days after primary diagnosis. Results: After four intracavitary DepoCyt injections and concomitant sarcoma chemotherapy within 26 days, a partial shrinkage of the cyst volume and of the primary tumor sites was observed by MRI/sonography before irradiation was started. After the third DepoCyt injection no more rhabdomyosarcoma cells of the cystic fluid were microscopically seen. Since the tumor cyst collapsed completely 53 days after the diagnosis, we terminated the DepoCyt injections. Directly prior to the first DepoCyt injection 24 days after the chemotherapy initiation, the cytarabine concentration of the cystic fluid was zero. Thereafter, the lowest DepoCyt concentration was 2.1 mg/liter 5 days after the first injection (1 mg). The highest concentration was 7.0 mg/liter 8 days after the second injection (5 mg). These DepoCyt trough concentrations are in the range of those of the ventricular CSF after an intraventricularly injected dose of 75 mg DepoCyt in adults. The patient received a total of four DepoCyt injections without consequential side effects or Rickham reservoir complications. Unfortunately, he experienced a multifocal relapse 2 months after termination of the chemotherapy. He died 14 months after the primary diagnosis despite a cytostatic and biologic treatment attempt. At time of relapse, no residual of the tumor cyst was observed. Conclusion: We conclude that the intracavitary liposomal cytarabine contributed to the disappearance of the intracranial rhabdomyosarcoma cyst and that inoperable or chemotherapy-resistant intracranial malignant cysts could locally be treated with the described strategy. CR 11. INTRACRANIAL EWING SARCOMA/PERIPHERAL PRIMITIVE NEUROECTODERMAL TUMOR: A REPORT OF TWO CASES Kazuaki Shimoji,1 Makoto Hishii,1 Naoaki Horinaka,1 Masakazu Miyajima,2 and Hajime Arai2; 1Department of Neurosurgery, Juntendo Nerima Hospital, Nerima City, Tokyo, Japan; 2Department of Neurosurgery, Juntendo University School of Medicine, Bunkyo City, Tokyo, Japan. Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) is a malignant tumor with a pathological appearance of small round cells. It is commonly seen outside the central and sympathetic nervous system such as bone and soft tissue. This tumor may have different characteristics from central PNETs originating in the CNS, which have been described by Hart and Earle. Recently in this tumor, positive immunostaining for MIC2 and characteristic translocation; t(11;22)q(24;q12) related to chromosome 22q12 has been reported. Thus, it has been accepted as a single category. Two cases that had been diagnosed as intracranial ES/pPNET were treated in our institute. Case 1: An 18-month-old girl was admitted to our hospital suffering from left abducens palsy. The MR image disclosed a cudgel-shaped mass just adjacent to the left pons. She underwent surgery via subtemporal approach. The tumor was partially resected and histological examination showed small round cells with rich chromatin. Homer-Wright rosettes and Flexner-Wintersteiner rosettes were also seen. Immunohistochemical staining revealed positive reaction to MIC2, which led to a diagnosis of intra cranial ES/pPNET. This girl unfortunately died 1 month after surgery despite craniospinal radiation therapy and chemotherapy. Case 2: A 5-year-old boy was referred to our hospital because his consciousness level had deteriorated to lethargy. The MR image showed a huge mass located at the temporal lobe adjacent to the dura matter. Tumor resection was conducted followed by radiation and chemotherapy. Histological examination was similar to case 1. This boy is still followed up 4 years after surgery without recurrence. In this case expression of EWS/FLI-1 chimeric gene was seen. In the literature, only four reports of intracranial ES/pPNET with histological confirmation are reported. Therefore, this tumor is considered a rare tumor. However, if we focus on the positive reaction of MIC2 in immunohistochemical staining and expression of EWS/FLI-1 chimeric gene, this tumor may not be extremely rare. We would like to discuss the clinical course of our two cases with a review of the literature. CR 12. MEDULLOBLASTOMA IN A BOY WITH SEPTO-OPTIC DYSPLASIA: CAUSAL RELATIONSHIP? Antoinette Schouten-Van Meeteren,1 Jeroen Vermeulen,2 Huib Caron,3 Rogier Versteeg,4 and Marcel Kool4; 1Pediatric Oncology, Emma Children's Hospital AMC, Amsterdam, Netherlands; 2Pediatric Neurology, VU University Medical Center, Netherlands; 3Pediatric Oncology, Emma Children's Hospital AMC, Netherlands; 4Human Genetics, Academic Medical Center, Amsterdam, Netherlands. Background: The combination of developmental abnormalities of the eye and medulloblastoma is rare and has been described earlier in Gorlin syndrome, Gardner syndrome, and Turcot syndrome. The mutations in these syndromes are detected in the PTCH1 and APC genes, which also have been found in sporadic cases of medullloblastoma. We present a case of a 3.5-year-old boy with medulloblastoma. Staging of the disease showed tumor cells in the cerebrospinal fluid. The treatment consisted of complete resection of the tumor, craniospinal radiotherapy at 54/36 Gy, and chemotherapy with vincristine, lomustine, and cisplatinum for eight courses. Complete remission has been sustained for 5 years now. The medical history of the boy mentioned strabismus at 11 months of age, caused by unilateral optic hypoplasia. Further analysis of this feature revealed optic hypoplasia visible at fundoscopy showing a small pupil with abnormal pigment at the nasal side of the retina, while other sides of the eye were completely normal in development. At physical examination no signs of optic hypoplasia were present, nor were there any doubts about the psychosocial development of the boy, which was normal until the diagnosis of the brain tumor. The endocrine axis showed no abnormalities. MRI revealed absence of the septum pellucidum and the optic nerve was extremely thin, so septo-optic dysplasia was diagnosed. Expression profiling of the tumor tissue of this patient showed that several retina-specific transcription factors such as NRL, CRX, and OTX2 were expressed at high levels. These transcription factors are important for normal eye development, but their role in medulloblastoma pathogenesis is still unclear. Retina-specific gene expression in a medulloblastoma of a patient with optic hypoplasia may suggest that a genetic defect is responsible for both the abnormal eye development and the tumor. In conclusion it is important to examine dysmorphic features in all children with medulloblastoma. Physical examination should be completed with MRI to detect subtle abnormalities of the brain and eye as well. Increased awareness of a possible relationship between neurogenic and oncogenic factors might be helpful. CR 13. MENINGIOANGIOMATOSIS IN THE BASAL GANGLIA Takayuki Inagaki,1 Yasuo Yamanouchi,1 and Keiji Kawamoto1; 1Neurosurgery, Kansai Medical University, Moriguchi, Osaka, Japan. Introduction: Meningioanigomatosis (MA) is a rare benign disorder. It is a focal lesion involving the leptomeninges and underlying cortex. It was originally described in association with von Recklinghause disease. However, according to Ibrahim Omesis et al., <15% of the cases are associated with neurofibromatosis (NF). MA located at the basal ganglia has not been described previously. We report a case of sporadic MA located in the basal ganglia. Case presentation: The patient was referred to our hospital after head trauma at the age of one. On computer-assisted tomography, a calcified lesion was found on the left basal ganglion without mass effect or peripheral edema. Because he had no clinical signs he was followed at outpatient clinic. He visited our institute at the age of eight because of slight headache. Follow-up MRI at that time revealed slightly increased size of the mass. The mass was enhanced with Gd. The relationship between the mass and his headache was unclear. Since the tumor was increasing in size, we performed stereotactic biopsies. The first biopsy revealed calcification with normal brain. However, the second biopsy revealed a cluster of meningeal cells which had a whirl formation. The pathological diagnosis of meningioangiomatosis was made. Because of the pathological diagnosis, neither irradiation nor chemotherapy was given. The boy started to have seizures at the age of 10, which were controlled with medication. Discussion: There are approximately 100 reported cases of MA so far in the English literature. Sixteen cases are associated with NF. The others were thought to be sporadic cases. In both sporadic and NF cases, the lesion was usually located in the leptomeningeal and underlying cortex. There in no report of MA located in the basal ganglia. Total removal of the tumor was recommended in case of leptomeningeal MA. It is not possible in this case because of the location of the mass. CR 14. RARE EXTRANEURAL METASTASIS FROM A PRIMARY SPNET: DIAGNOSIS AND MANAGEMENT Jason Fangusaro,1 Yasmin Gosiengfiao,1 David Jacobsohn,1 and Tadanori Tomita2; 1Pediatric Hematology/Oncology and Stem Cell Transplantation, Children's Memorial Hospital, Northwestern University, Chicago, IL, USA; 2Pediatric Neurosurgery, Children's Memorial Hospital, Chicago, IL, USA. Although CNS tumors are the most common solid tumor in pediatrics, it is exceedingly rare for a primary brain tumor to spread outside the CNS. When this rare finding does occur, it is often after multiple relapses and is almost universally fatal. We present the case of a 2-year-old female who presented with typical signs of increased intracranial pressure, including emesis and headache. Imaging revealed a large mass in the left occipital region. A near total resection was performed revealing a tumor consistent with a supratentorial primitive neuroectodermal tumor (sPNET). Postoperatively, the patient developed respiratory difficulty, and a chest x-ray and chest CT were performed revealing a paraspinal mass and lung nodules. A biopsy was performed of the paraspinal mass, again revealing a PNET tumor. The tumor samples from both operations were sent for translocation studies and were both negative for the commonly known Ewing sarcoma translocations. Bone scan, abdominal/pelvic CT, spine MRI, lumbar puncture,and bone marrow evaluations were all negative for any other sites of disease. This patient was treated initially using a Ewing's protocol, since the translocation results were yet unknown and Ewing's metastasis to the CNS would be more commonly seen than metastasis outside the CNS. Her lung disease responded completely as seen by imaging, and her CNS disease showed some response of the residual tumor. She subsequently underwent tandem autologous hematopoietic cell rescue after high-dose chemotherapy followed by focal brain radiation. She is currently alive 12 months from diagnosis with a good quality of life. This case demonstrates that extraneural metastasis from primary CNS tumors can occur, and with aggressive treatment, a prolonged event-free survival can be achieved. CR 15. RETINOBLASTOMA DISPERSION AFTER CHEMOTHERAPY: AN UNREPORTED AND UNDESIRABLE RESPONSE Reut Parness-Yossifon,1 Paul Bryar,2 Joanna L. Weinstein,3 Janice Lasky Zeid,1 and Marilyn B. Mets1; 1Ophthalmology, Children's Memorial Hospital, Chicago, IL, USA; 2Ophthalmology, Northwestern University Medical School, Chicago, IL, USA; 3Hematology/Oncology, Children's Memorial Hospital, Chicago, IL, USA. Introduction: Retinoblastoma, the most common intraocular tumor in children, is a highly curable malignancy whose management has changed dramatically over the past decade. Historically, external beam radiation and enucleation were the primary treatment modalities for advanced intraocular retinoblastoma while chemotherapy was reserved for extraocular disease. The morbidity and risk for secondary malignancies associated with external beam radiation prompted further investigation into alternative globe-preserving therapies. In the 1990s promising results with chemoreduction were reported. Chemoreduction refers to the use of chemotherapy to reduce the tumor's volume; the shrunken tumor is then amenable to focal therapy, including cryotherapy, laser photocoagulation, thermotherapy, or plaque radiotherapy. Today, chemoreduction has become the most common approach in moderate to advanced disease. Various uncommon vitreoretinal complications have been reported after treatment. One rare complication reported after focal laser therapy is tumor dispersion, leading to active seeds in the subretinal space and vitreous. This is a devastating complication because vitreous seeds are very difficult to treat and often result in enucleation. Purpose: To present three cases of retinoblastoma that demonstrated an unusual response to chemotherapy. Patients: One girl and two boys presented at 8, 28, and 40 months of age, respectively, with large unilateral retinoblastomas. At presentation, cases 1 and 2 had no evidence of vitreous or subretinal seeds; case 3 had a few distant retinal seeds but no vitreous seeds. Shortly after the diagnosis, chemotherapy was started with carboplatin and etoposide in cases 1 and 3, and carboplatin, etoposide, and vincristine in case 2. In all cases examination after one cycle of chemotherapy revealed extensive vitreous seeding. All the eyes were enucleated. Histopathologic exam revealed in all cases either viable tumor cells in the vitreous or significant invasion of the ciliary body, choroid, and inner sclera. Conclusions: We present three cases of unilateral retinoblastoma that demonstrated an atypical response to chemotherapy with intraocular dissemination. This response has not been previously described in the literature. In all cases the clinical picture changed dramatically in a very brief period of time following chemotherapy, a fact that emphasizes the need for close follow-up. An analysis of Shields et al. found an association between the absence of subretinal fluid, vitreous seeds, or subretinal seeds and the success of chemoreduction. In our cases only one had few subretinal seeds at presentation. We hypothesize that in addition to the clinical characteristics, the histopathologic features, like microscopic seeding, also may have an impact on the tumor's response to chemotherapy. A sudden increase in tumor necrosis in response to chemotherapy may lead to loss of integrity of the tumor mass and dispersion of the tumor debris. However, the close relationship of the initiation of chemotherapy to the tumor dissemination, though suggestive, does not prove a causal relationship. Although these events have not been previously described in the literature, we cannot rule out the possibility that the intraocular dissemination may represent the natural history of these tumors. CR 16. SPINAL TANYCYTIC EPENDYMOMA PRESENTING AS MENINGITIS Samuel Blackman,1 Elizabeth Bundock,2 and Mark Kieran1; 1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 2Office of the Chief Medical Examiner, Commonwealth of Massachusetts, Boston, MA, USA. Tanycytic ependymoma is a rare variant of ependymoma that most frequently presents in the spine or periventricular area. While distinct from myxopapillary ependymoma, the prognosis for this disease appears favorable. We report a case of tanycytic intramedullary ependymoma of the spinal cord (TE). This case was unusual because the patient presented with findings of meningitis. A 13-year-old boy presented to the hospital for a syncopal episode following several days of back pain radiating to the legs. Physical findings were initially consistent with muscle strain. Over the next several days the patient's pain intensified, accompanied by neck stiffness and headache. Several days later he suffered another syncopal episode and was reevaluated, at which time nuchal rigidity and photophobia were noted. A lumbar puncture yielded purulent fluid containing 90% neutrophils. Cerebrospinal fluid (CSF) cultures were ultimately negative. He was treated with antibiotics and dexamethasone, but several hours later had severe pain, emesis, and paresthesias in both legs. Because of concern for an epidural abscess, an MRI was obtained. This revealed a T1-isointense 3 × 1 cm ovoid lesion at L1–L2 with areas of high T2-signal and enhancement following gadolinium administration. After resolution of the meningitis, the patient underwent extensive resection of the lesion. Two satellite lesions were found on the filum terminale. Pathologic analysis and electron microscopy revealed histologic and ultrastructural features consistent with a TE, characterized by monotonous cells with oval nuclei and fibrillary tanycytic-like processes arranged in loose fascicles and cultures. No areas of hypercellularity or visible mitoses were seen. Of note, the tumor was infiltrated with CD68-positive macrophages and LCA-positive lymphocytes. Based on the extent of resection, histologic analysis, and absence of tumor cells in the CSF, no further treatment was proposed. The patient has been free of disease for >2 years, with no neurologic sequelae. The diagnostic features, pathology, and neuroradiology, and decision making with regard to treatment of TE are discussed. We also review the literature involving presentation of CNS tumors as meningitis. CR 17. SPONTANEOUS REGRESSION OF A DIFFUSE BRAINSTEM LESION IN AN INFANT Sofia Nunes,1 Duarte Salgado,2 Gabriela Caldas,3 and Mário Chagas3; 1Unidade de Neuro-Oncologia Pediátrica, Instituto Português de Oncologia de Lisboa, Lisboa, Portugal; 2Unidade de Neuro-Oncologia Pediátrica, Instituto Português de Oncologia, Portugal; 3Department of Child and Adolescent Oncology, Instituto Português de Oncologia de Lisboa, Portugal. The authors report a case of a 3-month-old child who presented with a diffuse brainstem lesion that regressed without treatment. He was born after an uneventful full-term pregnancy and his development was considered normal until that time. At 3 months of age, abnormal opsoclonus-like ocular movements were noted for a transient period of about 2 weeks. His physical examination was otherwise normal. MRI showed a large intrinsic expansive lesion centered on the medulla, hypointense on T1, hyperintense on T2 weighted images and without contrast enhancement, consistent with a glioma. Laboratory investigation, including neuroblastoma screening, was inconclusive. Due to age and normal neurological examination, no treatment was considered and surveillance scanning was agreed upon with the parents' consent. Serial MRI taken every 3 months in the first year of follow-up and 6 months apart in the second year showed a clear trend toward regression of the lesion. He is now 2.5 years old, his intellectual and motor development are considered normal for his age, and no neurological deficits have been found so far except for a mild hypertonia of the lower limbs during the first year of follow-up. The spontaneous remission of diffuse brainstem tumors is very rare, although some cases have been reported in patients with neurofibromatosis. To our knowledge only three cases of children <12 months of age have been reported, all diagnosed in the neonatal period and all showing clinical signs of neurological impairment. CR 18. TRIGEMINAL TROPHIC SYNDROME IN PEDIATRIC BRAIN TUMOR PATIENTS: RECURRENT UNILATERAL FACIAL AND CORNEAL ULCERATIONS Gesina F. Keating,1 Francine Kim,2 Anthony J. Mancini,3 Zibute G. Zaparackas,4 and Tadanori Tomita5; 1Neurology, Children's Memorial Hospital, Chicago, IL, USA; 2Radiology, Children's Memorial Hospital, Chicago, IL, USA; 3Dermatology, Children's Memorial Hospital, Chicago, IL, USA; 4Ophthalmology, Children's Memorial Hospital, Chicago, IL, USA; 5Neurosurgery, Children's Memorial Hospital, Chicago, IL, USA. We report three children with brain tumors who developed facial skin ulcerations and corneal irritation during the course of treatment. Trigeminal trophic syndrome (TTS) is a rare condition in which persistent or recurrent skin ulcerations, most typically in the ala nasi region, occur following an insult to the trigeminal nerve, thereby causing altered sensory perception to the face. The resultant anesthesia and paresthesias, combined with self-induced trauma, are believed to lead to the ulcerations, which may become chronic. TTS is typically reported in adults, with the most common etiologies related to stroke or treatment of trigeminal neuralgia. In adults, few reported cases have a history of brain tumor, with reported tumor types including astrocytoma, meningioma, and acoustic neuroma. Aside from the three children with TTS reported here, there are only two others in the literature, neither with brain tumor. All of our patients had benign brain tumors whose location included the cerebellopontine angle, where the trigeminal nerve emerges from the brainstem. They subsequently developed ipsilateral facial and corneal lesions of varying degrees and duration. Although in adults the time to develop TTS ranges from weeks to years, these children all developed lesions within 1 month following surgery. Skin findings in these patients included characteristic crescent-shaped ulcers and crusted plaques at the ala nasi as well as other facial areas, including the chin, cheek, and periorbital region. Treatments included wound care with topical antibiotic ointments and wound dressings, oral antibiotics for secondary superinfection, and the use of elbow-wrist immobilizers while sleeping to minimize manipulation and further trauma to the sites. Although little is discussed elsewhere regarding eye involvement in TTS, neurotrophic keratitis was observed in all three patients here, and ranged from mild and transient to severe and recurrent. In one patient, changes were severe enough to require consultation with a corneal specialist, who recommended using a bandage contact lens to provide protection and promote healing. The child developed a central corneal opacity which decreased his visual acuity to 20/80. Recurrence of lesions has occurred in all three children, though both the frequency and severity have decreased over time. TTS is an important condition for clinicians caring for pediatric brain tumor patients to recognize, so that appropriate diagnosis and intervention can be made in a timely manner. Although TTS may be unpreventable in such patients, prompt recognition may prevent further morbidity, including permanent facial and visual impairment. CR 19. TURCOT SYNDROME IN CHILDREN: TWO CASES ILLUSTRATING THE DIFFERENT MOLECULAR DIAGNOSES AND COMPLEX MANAGEMENT OF THIS RARE SYNDROME Helen Toledano,1 Liora Kornreich,2 Shalom Michowiz,3 Eyal Fenig,4 Rivka Shapiro,5 Baruch Brenner,6 Isaac Yaniv,1 and Ian J. Cohen1; 1Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petach Tikva, Israel; 2Department of Imaging, Schneider Children's Medical Center, Petach Tikva, Israel; 3Department of Neurosurgery, Rabin Medical Center, Petach Tikva, Israel; 4Radiation Oncology Unit, Rabin Medical Center, Israel; 5Gastrointestinal Unit, Schneider Children's Medical Center, Petach Tikva, Israel; 6Gastrointestinal Oncology Unit, Rabin Medical Center, Israel. Several inherited syndromes are associated with brain tumors, including neurofibromatosis, Gorlin's syndrome, and Von Hippel-Lindau, among others. Turcot syndrome, first described in 1959, describes the association between hereditary adenomatous polyps of the colorectum and a primary brain tumor. It has subsequently been established that in fact two different molecular mechanisms underlie Turcot syndrome. The first, classified as Turcot syndrome type I, is caused by mutations in one of the mismatch repair genes involved in hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, while Turcot syndrome type II is caused by mutations in the familial adenomatous polyposis gene (FAP). Apart from the colonic manifestations, which include polyposis and a tendency to develop colorectal cancer, both syndromes are associated with a variety of extracolonic manifestations including a tendency to other malignancies. One of these is a predisposition to developing brain tumors, in FAP usually a medulloblastoma, in HNPCC usually a glioma. We present here two children with a brain tumor recently treated at our center, one subsequently revealed as having FAP and the other with HNPCC, that illustrate the differences and similarities of the two brain tumor polyposis syndromes. The first child had papillary carcinoma of the thyroid, pinealoblastoma, and multiple colonic polyps and FAP, while the second had simultaneous rectal carcinoma and malignant glioma; polyposis coli and microsatellite instability was detected in the rectal tumor. We present the complex management decisions involved in caring for patients with a familial syndrome, brain tumor, colonic polyps, and multiple malignancies, whether synchronously or metanchronously, and present the molecular diagnosis of the families in both cases with discussion of the literature. CRANIOPHARYNGIOMA CRANIO 1. CRANIOPHARYNGIOMA: A CHALLENGE BETWEEN TOTAL RESECTION AND NEUROLOGICAL COMPLICATIONS Hassan Kadri1; 1Pediatric Neurosurgery, Moassat University Hospital, Damascus, Syria. Some neurosurgeons believe that craniopharyngioma, a benign tumor, needs total resection to reduce recurrence rate and consequently improve the quality of life for the affected children. Other neurosurgeons suggest that total resection of craniopharyngioma should be abandoned because of some complications related to hypothalmus damage and/or optic nerve incidental surgical injury. We analyzed our data of 66 patients operated on for craniopharyngioma in our unit of pediatric neurosurgery. Subtotal removal was planned in 16 cases while total resection by microsurgical technique assisted by endoscopy was planned in 50. In the latter group the total resection was achieved in 43 patients (85%). We compared the quality of life between patients who underwent a total resection and those who underwent a subtotal removal of the tumor. We found that the microsurgical technique assisted by endoscopy is the best technique for craniopharyngioma and that those who had partial resection did not have a better quality of life than those who had total resection. CRANIO 2. CRANIOPHARYNGIOMA PATIENTS ARE AT INCREASED RISK FOR OBESITY AFTER THERAPY Patricia Baxter,1 Hikmet Oktay,2 Arnold Paulino,3 William Whitehead,4 Robert Dauser,4 David Kornguth,5 Anita Mahajan,5 Jane Edmond,6 M. Fatih Okcu,1 and Murali Chintagumpala1; 1Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA; 2Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey; 3Department of Radiation Oncology, Baylor College of Medicine, TX, USA; 4Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA; 5Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 6Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA. Background: Craniopharyngiomas are a rare group of CNS tumors derived from Rathke's pouch. These tumors are histologically benign. However growth of the tumors in this location and their management can have devastating long-term consequences. Therapeutic options remain controversial, and optimal management is still elusive. Methods: We reviewed medical records of patients diagnosed with craniopharyngioma between 1992 and 2008. We collected the following information: presenting symptoms, endocrine outcomes, surgical interventions, radiation therapy, cyst therapy, and visual outcomes. Two-sample t, chi-square, and paired t-tests were used for comparison. All statistical tests were two-sided and we considered a p value of <0.05 significant. Results: Of the 53 patients who were identified, 43 were available for analysis. Median age at diagnosis was 7.1 years, and 26 were female. Patients were treated with a combination of therapies including surgery, radiation therapy (proton and conformal), cyst aspiration, and intracystic therapy with either chemotherapy or P32. There were 29 (76.3%) patients who received both surgery and radiation and eight (21.1%) who received surgery alone. Progression was defined as any enlargement, either cystic or solid, as noted on diagnostic imaging. There were 14 (35%) patients with cystic progression alone, one with solid and six (15%) with both cystic and solid progression. With a median follow-up of 53.3 months (range, 0.8–135 months) in survivors, the estimated 3-year progression-free survival was 40.3% (SE 9%) and the overall 3-year survival for this group was 94.2% (SE 4%). At the time of diagnosis, 11.1% of the patients had a body mass index (BMI) that was >25 (median, 19; range, 16–35); after therapy, 48.7% had a BMI that was >25 (median, 24; range, 15–39). On average patients had an increase in BMI of 3.8 points after therapy, (p = 0.001). Patients who developed diabetes insipidus (DI) after therapy (n = 31, 72.1%) had BMIs that were 4.2 points higher (p = 0.04) than those without DI (21.1 vs. 25.3, respectively), and patients with adrenal insufficiency after therapy had an average increase of 4.8 points in their BMI after treatment (21 vs. 25.8, respectively, p = 0.02). Conclusions: While overall survival is excellent for patients with craniopharyngioma, there is increased risk for obesity after diagnosis and therapy. Such patients will have significantly increased risk for comorbid conditions and require long-term follow-up to assure adequate screening for associated health risks. CRANIO 3. CYSTIC CRANIOPHARYNGIOMA FLUID DURING INTERFERON-ALPHA TREATMENT: DETECTION OF ALPHA-DEFENSINS 1–3 Benedetta Ludovica Pettorini,1 Massimo Caldarelli,1 Luca Massimi,2 Gianpiero Tamburrini,1 Rosanna Inzitari,1 Chiara Fanali,1 Tiziana Cabras,1 Irene Messana,1 Massimo Castagnola,1 and Concezio Di Rocco1; 1Catholic University Medical School, Rome, Italy; 2Rome, Italy. Craniopharyngiomas consist of a tumor wall composed by squamous epithelium often associated to a cystic component filled with secreted fluid, cholesterol crystals, and epithelial cells. The tumor cyst can be used to deliver chemotherapeutic and radiotherapeutic agents to obtain tumor shrinkage. Although most of these agents have been proved to be effective, they are burdened by severe complications in case of diffusion through the brain parenchyma. Recently, favorable results have been reported with the intracystic administration of interferon-alpha (INF-alpha), a cytotoxic agent against the squamous epithelium but without toxic side effects toward the cerebral tissue. Very few studies are currently available about the mechanisms of action of INF-alpha, except for a preliminary investigation showing an increased apoptosis associated with its administration. The goal of the present study was to identify the most significant peptides contained in the fluid of cystic craniopharyngiomas, both under physiological conditions and following the administration of intracystic INF-alpha. The acidic soluble proteins contained in the fluid of a patient with cystic craniopharyngioma treated with intratumoral IFN-alpha was analyzed by reversed-phase high-performance chromatography coupled to ion-trap mass spectrometry (RP-HPLC ESI-IT MS). The multifunctional antimicrobial peptides alpha-defensins 1–3 were detected in the cystic fluid before the intratumoral treatment. These peptides are important for innate immunity and are usually released from azurophilic granules of neutrophils. The concentration of these peptides in the cystic fluid sensibly decreased during IFN-alpha pharmacological treatment. The presence of antimicrobial peptides in the cyst of craniopharyngioma allows us to hypothesize the involvement of the innate immune response in the presence of a cystic craniopharyngioma and that inflammation may play a role in the cyst formation and enlargement. Moreover, the reduction of antimicrobial and cytotoxic peptides, such as defensins, after IFN-alpha treatment, could represent its indirect anti-inflammatory effect on the squamous epithelial cells of the craniopharyngioma, as well as its oncolytic potency. Additional studies are necessary to establish the exact role of the molecules involved in the pathogenesis of craniopharyngioma, and further investigations are required to improve the efficacy of the antitumoral activity of INF-alpha. CRANIO 4. FIRST EXPERIENCES WITH LAPAROSCOPIC ADJUSTABLE GASTRIC BANDING FOR THE TREATMENT OF MORBID OBESITY IN PATIENTS WITH CHILDHOOD CRANIOPHARYNGIOMA Hermann Muller,1 Ursel Gebhardt,1 Verena Wessel,1 Sabine Schroder,1 Reinhard Kolb,2 Niels Sorensen,3 Jorn Maroske,4 and Ernst Hanisch5; 1Department of Pediatrics, Klinikum Oldenburg gGmbH, Oldenburg, Germany; 2Oldenburg, Germany; 3Department of Pediatric Neurosurgery, University Hospital Wurzburg, Wurzburg, Germany; 4Department of Surgery, Neu Ulm, Germany; 5Germany. Craniopharyngiomas (CP) are benign embryogenic malformations which arise from ectoblastic remnants of Rathke's pouch and can be found anywhere along the development path of Rathke's pouch in hypothalamic and pituitary regions—both of importance in endocrine regulation and satiety modulation. According to the ongoing German multicenter surveillance study on childhood CP (KRANIOPHARYNGEOM 2000), obesity is present postoperatively in up to 52% of patients, with at least half of these patients having severe difficulty controlling their desire to eat. Experience with bariatric surgery (adjustable gastric banding) in extremely obese patients with childhood CP is limited. We are reporting on four patients with childhood CP diagnosed at age 2, 12, 12, and 20 years. Body mass index-standard deviation score (BMI-SDS) at diagnosis of CP was +0.8, +4.97, +4.7, and +0.1 SD according to Rolland-Cachera. During follow-up, all patients developed severe obesity (BMI-SDS: +12.35, +10.36, +11.4, +7.3) so that 11, 5, 9, and 3 years after diagnosis of CP flexible gastric bandings were performed. Bariatric surgery was well tolerated. After a follow-up of 3.5, 0.5, 1.0, and 0.5 years after bariatric surgery, the BMI decreased slowly and continuously in all patients (BMI-SDS decrease 5.1, 1.1, 3.6, 1.8 SD during follow-up). The patients' eating behavior changed profoundly in three of four patients. Addiction to food and especially sweets significantly improved based on self-assessment. We conclude that adjustable gastric banding could be feasible and effective in weight reduction of severely obese patients with CP due to hypothalamic disorders. Further evaluation on long-term effects is warranted and part of the ongoing German multicenter prospective surveillance study KRANIOPHARYNGEOM 2007. CRANIO 5. GROWTH HORMONE REPLACEMENT AND HIGH RECURRENCE RATES IN PATIENTS WITH CHILDHOOD CRANIOPHARYNGIOMA: RESULTS OF THE GERMAN MULTICENTER PROSPECTIVE TRIAL KRANIOPHARYNGEOM 2000 Hermann Muller,1 Ursel Gebhardt,1 Sabine Schroder,1 Fabian Pohl,2 Rolf-Dieter Kortmann,3 Andreas Faldum,4 Monika Warmuth-Metz,5 Thorsten Pietsch,6 and Niels Sorensen7; 1Department of Pediatrics, Klinikum Oldenburg gGmbH, Oldenburg, Germany; 2Department of Radiooncology, University Hospital Regensburg, Regensburg, Germany; 3Radiation Oncology, University of Leipzig, Leipzig, Germany; 4University Mainz, Institute for Medical Biometry, Epidemiology and Informatics, Mainz, Germany; 5Institute of Neuroradiology, University of Wuerzburg, Wuerzburg, Germany; 6Department of Neuropathology, University Hopital Bonn, Bonn, Germany; 7Department of Pediatric Neurosurgery, University Hospital Wurzburg, Wurzburg, Germany. Background: Growth hormone (GH) has been used successfully in the treatment of short stature secondary to GH deficiency in survivors of childhood craniopharyngioma (CP). There has been concern that GH replacement might increase the risk of tumor recurrence and progression. In the German multicenter prospective trial KRANIOPHARYNGEOM 2000 we analyzed the impact of GH replacement on the incidence and time course of relapses after complete resection (CR) and tumor progressions after incomplete resection (IR) in patients with CP. Results: Between 2001 and 2006, 117 patients (57 female/60 male) with CP were recruited at a median age of 10.0 years at diagnosis (range, 1–17 years. The histological diagnosis and the assessment of tumor progression/recurrence were prospectively confirmed by a reference panel in all patients. The impact of GH replacement on tumor progression/recurrence could be evaluated in 115 patients at a median time of 2.9 years after diagnosis (range, 0.2–6.5 years). In 51 of 115 patients (44%) GH replacement was initiated 0.8 years (0.1–3.6 years) after diagnosis and had been performed for a period of 2.8 years (0.0–5.9 years) at the time of evaluation. In the total group of 115 patients we observed a 3-year event-free survival (EFS) of 0.44 ± 0.06, indicating high recurrence rates after CR (n = 45; 3-year EFS, 0.62 ± 0.09) and high progression rates after IR (n = 64; 3-year EFS, 0.30 ± 0.07). Of these, 23 patients (51%) received GH replacement after CR, 27 patients (43%) after IR. Patients with GH replacement after CR had similar 3-year EFS (n = 23; 0.58 ± 0.12) when compared with non-GH treated patients after CR (n = 22; 0.73 ± 0.13). No difference in EFS was found between 27 patients with GH replacement after IR (2-year EFS, 0.30 ± 0.09) and 36 non-GH-treated patients after IR (2-year EFS, 0.29 ± 0.09). Similar results were also observed in the subgroups of nonirradiated patients after CR (GH-treated: n = 20; 3-year EFS, 0.70 ± 0.12; vs. non-GH-treated: n = 22; 3-year EFS, 0.73 ± 0.13) and in nonirradiated patients after IR (GH-treated: n = 11; 2-year EFS, 0.27 ± 0.16; vs. nonirradiated and non-GH-treated patients after IR: n = 21; 2-year EFS, 0.21 ± 0.12). Conclusions: In our prospective, multicenter trial we observed high recurrence rates after CR and high progression rates after IR in childhood craniopharyngioma. However, GH replacement had no significant impact on relapse and progression rates in irradiated and nonirradiated patients. GH replacement was safe and not related to the high risk of tumor relapse and progression. Further studies on biological markers and risk factors for tumor growth in childhood craniopharyngioma are part of the prospective, randomized, multicenter trial KRANIOPHARYNGEOM 2007 (www.kinderkrebsinfo.de/kranio 2007). Supported by Deutsche Kinder-krebsstiftung, Bonn, Germany. CRANIO 6. HIGH RATES OF RELAPSES AFTER COMPLETE RESECTION AND TUMOR PROGRESSIONS AFTER INCOMPLETE RESECTION OF CHILDHOOD CRANIOPHARYNGIOMA: UPDATE AFTER THREE YEARS OF PROSPECTIVE EVALUATION IN KRANIOPHARYNGEOM 2000 AND STUDY DESIGN OF KRANIOPHARYNGEOM 2007 Hermann Muller,1 Ursel Gebhardt,1 Sabine Schroder,1 Fabian Pohl,2 Rolf-Dieter Kortmann,3 Angela Emser,4 Andreas Faldum,5 Monika Warmuth-Metz,6 Thorsten Pietsch,7 and Niels Sorensen8; 1Department of Pediatrics, Klinikum Oldenburg gGmbH, Oldenburg, Germany; 2Department of Radiooncology, University Hospital Regensburg, Regensburg, Germany; 3Radiation Oncology, University of Leipzig, Leipzig, Germany; 4Institute of Biostatistics, IMBEI, University of Mainz, Mainz, Germany; 5University Mainz, Institute for Medical Biometry, Epidemiology and Informatics, Mainz, Germany; 6Institute of Neuroradiology, University of Wuerzburg, Wuerzburg, Germany; 7Department of Neuropathology, University Hopital Bonn, Bonn, Germany; 8Department of Pediatric Neurosurgery, University Hospital Wurzburg, Wurzburg, Germany. In our multicenter cross-sectional study HIT-Endo we collected data on therapy and outcome of 306 patients with childhood craniopharyngioma (CP). The survival rates were 94% ± 4% in irradiated and 93% ± 5% in nonirradiated patients. The German multicenter prospective study KRANIOPHARYNGEOM 2000 (www.kraniopharyngeom.de) was initiated in order to collect data on incidence and time course of relapses after complete resection and tumor progressions after incomplete resection. Furthermore, the impact of irradiation (XRT) on relapse and recurrence rates was analyzed. Since 2001, 96 patients with newly diagnosed CP were recruited. With a high degree of completeness (80%–90%), data on neurosurgery, neuroradiology and XRT could be collected prospectively. Complete resection was achieved in 43%, subtotal resection in 45%. XRT was performed in 22 of 96 CP patients: in 18% immediately after subtotal resection, in 53% after progression of residual tumor, and in 14% after (second surgery of) relapse. Data on XRT modalities were evaluable in 17 of 22 patients. XRT was performed at a median age of 11 years (4–18 years) and a mean interval of 10 months after first diagnosis. All patients got a three-dimensional CT-planning of XRT. The mean total dose was 52.5 Gy. An interim evaluation on event-free survival rates (EFS) after 3 years of follow-up showed a high rate of early events (EFS, 0.22. ± 0.06) in terms of tumor progression after subtotal resection (n = 48) and relapses (EFS, 0.60 ± 0.10) after complete resection (n = 37) during the first 3 years of follow-up. A high rate of early events (EFS, 0.57. ± 0.15) was also found for patients after XRT (two cystic progressions, four progressions of solid tumor parts after XRT). We conclude that progression after subtotal resection and relapse after complete resection of CP are frequent and early events even in irradiated patients during the first 3 years after diagnosis. Regular monitoring of cerebral imaging and clinical status is recommended in follow-up of patients with CP. There is controversial discussion on the adequate time point of irradiation after incomplete resection. Accordingly, the multicenter prospective study KRANIOPHARYNGEOM 2007 will focus on this issue. Patients at age ⩾5 years at diagnosis will be randomized after incomplete resection for the time point of irradiation (immediate XRT after surgery versus XRT at progression of residual tumor). End points of the study will be quality of life (PEDQOL domain: physical function), progression-free survival, and overall survival). The time point of evaluation will be 3 years after randomization. Supported by Deutsche Kinderkrebsstiftung, Bonn, Germany. CRANIO 7. HISTORY AND CLINICAL MANIFESTATIONS AT PRIMARY DIAGNOSIS OF CHILDHOOD CRANIOPHARYNGIOMA IN 311 PATIENTS Hermann L. Muller,1 Ursel Gebhardt,1 Sabine Schroder,1 and Niels Sorensen2; 1Department of Pediatrics, Klinikum Oldenburg gGmbH, Oldenburg, Germany; 2Department of Pediatric Neurosurgery, University Hospital Wurzburg, Wurzburg, Germany. Caniopharyngioma are connatal embryogenic midline malformations of low-grade malignancy developing from remnants of Rathke's pouch; 30–50% of all cases are diagnosed during childhood and adolescence, with a peak of incidence at an age of 8 years. In spite of a high overall survival rate (92%) the long-term prognosis is severely impaired by late effects of tumor and treatment. The records of 311 patients with childhood craniopharyngioma recruited in HIT-Endo and KRANIOPHARYNGEOM 2000 were evaluated in regard to clinical manifestations and history before primary diagnosis of childhood craniopharyngioma. Results: The diagnosis of craniopharyngioma was incidental without any observed symptoms and complaints in the history of 3% of all patients. First symptoms and duration of history until diagnosis of craniopharyngioma were headache (52%; median duration of history, 24 months [range, 0.5–96]), visual impairment (18%; 6 months [1–48]), growth retardation (15%; 33 months [12–96]), impairment of vigilance (8%; 2 months [0.1–6]), polyuria/polydypsia as a symptom of diabetes insipidus neurohormonalis (5%; 26 months [12–48]), and weight gain (5%; 24 months [24–48]). Median duration of history in 311 patients was 12 months (range, 0.5–96). The long duration of history could be confirmed by analysis of anthropometric data collected in 90 patients before diagnosis of childhood craniopharyngioma in a nationwide health survey (Vorsorgeuntersuchungen). Already at the time point U6 (10–12 months of age), a significantly and persistently impaired growth rate was found especially for patients with hypothalamic involvement of craniopharyngioma. The correlation between duration of history and functional capacity (Fertigkeitenskala Münster-Heidelberg) as a parameter of quality of life did not reach statistical significance. Conclusions: A combination of the symptoms headache, visual impairment, polyuria/polydypsia, and growth impairment should lead differential diagnostic efforts toward craniopharyngioma. Monitoring of growth is of essential importance in early diagnosis of childhood craniopharyngioma. A long history before diagnosis does not seem to have significant impact on long-term prognosis and functional capacity in these patients. Supported by Deutsche Kinderkrebsstiftung, Bonn, Germany. CRANIO 8. KRYPTONITE FOR CYSTIC CRANIOPHARYNGIOMA Sergio Cavalheiro,1 Daniela Ierardi,2 Maria Aparecida Pinhal,3 João Roberto Martins,4 Miriam Jasiulionis,5 Fernanda Molognoni,5 Nasjla Silva,6 Maria José Fernandes,1 and Silvia Toledo7; 1Department of Neurology and Neurosurgery, São Paulo Federal University, São Paulo, Brazil; 2São Paulo, Brazil; 3Biochemistry Department, São Paulo Federal University, São Paulo, Brazil; 4Division of Endocrinology, Department of Medicine, São Paulo Federal University, São Paulo, Brazil; 5Microbiology, Imunology, and Parasitology Department, São Paulo Federal University, São Paulo, Brazil; 6Pediatric Oncology Institute GRAACC, São Paulo Federal University, São Paulo, Brazil; 7Genetic Laboratory/Pediatric Oncology Institute GRAACC, São Paulo Federal University, São Paulo, Brazil. Objectives: To verify the behavior of apoptotic factors during the treatment of craniopharyngiomas with interferon alpha 2a (IFN-α2a). Patients and Methods: From 2000 to 2007, 25 patients diagnosed with predominantly cystic craniopharyngioma (age range, 1–19 years), were treated with intratumoral chemotherapy with IFN-α2a at the São Paulo Federal University. After insertion of a catheter intratumorally connected to an Ommaya reservoir, 3 MUI of the drug were administered every other day, totaling 36 MUI in the end of a cycle. The intratumoral liquid removed was used to quantify the apoptotic factor FAS ligand, hyaluronic acid, and nitric oxide. Results: In 80% of the cases, it was possible to control the craniopharyngioma growth with a single cycle and without surgical resection. Only two patients had surgical resection. None of the patients presented with endocrinological deterioration after the treatment. All patients analyzed presented an increase of FAS ligand level and a decrease of hyaluronic acid and nitric oxide levels. Conclusion: The IFN-α2a weakens the proliferation activity of the craniopharyngioma as a kryptonite, controlling tumor growth by minimally invasive approach. The increase of FAS ligand as well as the decrease of hyaluronic acid and the nitric oxide levels show the increase of the apoptotic process during treatment. New studies should be done to clarify the apoptotic pathway involved in craniopharyngioma intratumoral chemotherapy with IFN-α2a. Financial support: FAPESP/GRAACC. CRANIO 9. PEDIATRIC CRANIOPHARYNGIOMAS: SURGICAL ALGORITHMS FOR DIFFERENT AGE GROUPS Nejat Akalan,1 Burcak Bilginer,1 and Aysegul Cila2; 1Department of Neurosurgery, Hacettepe University, Ankara, Turkey; 2Department of Radiology, Hacettepe University, Ankara, Turkey. Craniopharyngioma treatment is one of the most controversial topics in current neurosurgical practice. Their benign histological nature and extraaxial origin make them an ideal tumor to attempt to “cure” by total tumor removal. While their location leads to enthusiasm for total resection with a variety of surgical approaches and advanced microsurgical techniques supported by excellent diagnostic tools, significant morbidity due to intimate relationship to neighboring anatomical structures prevents a unified treatment algorithm. For craniopharyngiomas in children, acceptable morbidity figures following total resection and cure for adults may become intolerable. Obesity, hyperphagia, and neuropsychological disorders are serious side effects of pituitary and hypothalamic dysfunction exclusive to children. Accumulated data from large centers create a dilemma between “cure” and poor quality of life as the cost of aggressive resection. Moreover, high recurrence rates following attempted total resection resulted in moving to limited surgery followed by radiotherapy in a subgroup of children with craniopharyngiomas. While improved diagnostic tools provide early diagnosis, this brings further questions concerning the optimal treatment in those with very young age and apparently normal endocrine function. Based upon a single institution experience in Hacettepe University on >120 pediatric craniopharyngiomas for the last two decades, we have tried to stratify treatment within the subgroup of children of different age groups and clinical presentation. The treatment modalities comprised nearly all available techniques from total tumor removal to endoscopic approach, Ommaya reservoir, and bleomycin therapy to stereotactic aspiration. The aim of this presentation is to give an idea of the decision-making process in pediatric craniopharyngiomas based upon various variables like age, clinical presentation, size, and extension of the tumor. CRANIO 10. PROTON IRRADIATION FOR CRANIOPHARYNGIOMA: EARLY EVALUATION OF THE FIRST SIX PATIENTS TREATED AT THE MIDWEST PROTON RADIOTHERAPY INSTITUTE, BLOOMINGTON, INDIANA Markus Fitzek,1 Andrew Chang,1 Kim Roach,2 Avril O'Ryan-Blair,2 and Allan Thornton2; 1Indiana University Purdue University Indianapolis, Bloomington, IN, USA; 2Midwest Proton Radiotherapy Institute, Bloomington, IN, USA. Purpose: Protons can minimize dose to nontarget structures compared to photons by means of their better physical dose distribution. As a result, we expect to see fewer unwanted dose-dependent side effects such as radiation-associated secondary tumors, neurocognitive damage, and late hormonal changes. The present study evaluates early tumor response patterns and the acute effects of proton radiotherapy in children with craniopharyngioma treated with proton radiation therapy at the Midwest Proton Radiotherapy Institute (MPRI). Materials and Methods: Between 2005 and 2007, six children of median age 11 years (range, 5–18 years) with craniopharyngioma were treated at MPRI in Bloomington, Indiana, with the 206 MeV fixed horizontal beam line supplied by the Indiana University Cyclotron Facility. Median dose prescribed to the tumor was 54 cobalt Gy equivalent (CGE, 1 proton Gy = 1.1 CGE), with a range of 50.4–54 CGE. Median tumor volume was 17 cc (range, 3–54 cc). Patients were treated after they had developed recurrence following initial surgical treatment or after initial subtotal resection. Results: With a median observation period of 18 months (range, 3–28 months) from radiotherapy, all six patients are alive without tumor progression. One child required repeat cyst drainage during the course of radiotherapy. Proton radiotherapy was well tolerated; no child required a treatment break. Acute toxicity was limited to intermittent headaches, partial alopecia, and fatigue. Four of the six tumors showed regression early during follow-up. Conclusion: Our experience indicates excellent acute tolerability and tumor responses compatible with the doses delivered. No deterioration in the quality of life has thus far been observed attributable to radiotherapy. The expected decrease in late CNS effects requires longer observation times to manifest itself. CRANIO 11. PROTON THERAPY FOR CRANIOPHARYNGIOMA IN CHILDREN. Claire Alapetite,1 Jean-Louis Habrand,2 George Noel,3 Catherine Nauraye,4 Stephanie Puget,5 Christian Sainte-Rose,5 Hervé Brisse,6 Nathalie Boddaert,5 Anne Laurent Vannier,7 Michel Zerah,5 Jacques Grill,2 François Doz,6 and Pierre Bey1; 1Radiation Oncology Department-Paris and Proton Therapy Center-Orsay, Institut Curie, Paris, France; 2Institut Gustave Roussy, France; 3Centre Paul Strauss, France; 4Institut Curie Centre de Protonthérapie d'Orsay, France; 5Necker-Enfants Malades Hospital, France; 6Institut Curie, France; 7Hôpital National Saint Maurice, France. Craniopharyngioma is associated with severe morbidity including hypothalamic dysfunction related to tumor growth and/or postoperative damage, visual impairment, and endocrinological deficiency. After incomplete resection, radiotherapy (RT) substantially reduces recurrence rate although its place is debated especially in younger children. Improving dose-gradient to critical structures (optic pathway) and reducing developing brain dose exposure, proton therapy (PT) optimizes the radiotherapeutic index and may contribute to reconsidering postoperative RT according to clinical presentation. Eighty-seven children were treated at Institut Curie Centre de Protonthérapie d'Orsay (ICPO), from 1994 to 2006, among whom were 23 craniopharyngioma (26.4%; median age, 9 years; range, 4–16.1 years). Irradiation was performed at relapse in 11 cases, and as part of a prospective conservative approach following incomplete surgery in 12 patients with hypothalamic involvement (starting 2004). Only one patient required general anesthesia. Multidisciplinary follow-up includes serial imaging and neuropsychological evaluation in all recent cases. A total dose of 54–55 CGE, conventionally fractionated, was delivered until 2004, using a combined photon-proton approach; technical improvements now allow for proton therapy only. Potential benefit was examined through comparative dosimetry (3DCRT/IMRT/protons) in two cases, showing benefit with proton beams for critical organs at some distance of CTV (nonabutting chiasma, cochlea, brainstem); surrounding parenchyma (temporal lobe); and whole-brain exposure. At median follow-up, 18 months (9–114), no relapse was observed. In three cases, increase of the cystic component was observed during or shortly after completion of proton therapy. These patients were carefully monitored, and experienced subsequent shrinkage of their cysts (follow-up 7, 16, and 114 months). All children had hypopituitarism with diabetes insipidus prior to RT. No additional RT-related optic neuropathy or hypothalamic morbidity was observed. Neuropsychological evaluation in children irradiated at relapse emphasized altered short-term memory, social and emotional functioning, and significant school difficulties. Delineation of relevant anatomofunctional structures (e.g., hippocampus, trigone), during treatment planning might help document dose-effect relationships and possibly help refine proton-beam access routes providing further preservation of memory, emotion, and cognition. To further identify primary determinants of adverse radiation sensitivity in children, longitudinal analysis of neuropsychological and behavioral impairments in craniopharyngioma, together with follow-up using new imaging parameters, would be necessary. With the potential to reduce the risks of late sequelae and second malignancies, proton therapy is a promising technique, especially in younger children, as part of a conservative approach, particularly when hypothalamic involvement is present. CRANIO 12. PSEUDOTUMOR CEREBRI TRIGGERED BY ESCALATION OF TESTOSTERONE IN ADOLESCENT WITH CRANIOPHARYNGIOMA AND PANHYPOPITUITARISM Gesina F. Keating,1 Reema Habiby,2 and Tadanori Tomita3; 1Neurology, Children's Memorial Hospital, Chicago, IL, USA; 2Endocrinology, Children's Memorial Hospital, Chicago, IL, USA; 3Pediatric Neurosurgery, Children's Memorial Hospital, Chicago, IL, USA. Pseudotumor cerebri developed in a 14-year-old boy >5 years after diagnosis of craniopharyngioma and initiation of hormone replacement for panhypopituitarism, including recombinant human growth hormone (rhGH). This was manifested by intractable vomiting and headaches. Episodes of vomiting occurred up to five times daily immediately following testosterone injection in 2 consecutive months. Clinical examination was stable with monocular blindness and bilateral optic atrophy, without papilledema. MRI of the brain showed no disease recurrence or hydrocephalus. Gastroenterology evaluation was unremarkable. A change to transdermal testosterone resulted in minimal improvement. Symptoms promptly resolved following lumbar puncture, with opening pressure of 230 mm H2O and normal cerebrospinal fluid. Both rhGH and testosterone were stopped, with reintroduction of only rhGH at a lower dose 2 weeks later. Vomiting returned 4 months later with increasing rhGH dosage. Neither acetazolamide nor discontinuation of rhGH provided adequate relief. Lumbar puncture again provided complete resolution of symptoms. Although an opening pressure of >250 mm H2O is considered a diagnostic criterion for pseudotumor cerebri in adults, amelioration following both lumbar punctures supports symptomatic intracranial hypertension in our patient. Papilledema, another diagnostic criterion, is unlikely to occur in the setting of optic atrophy; thus this clinical finding cannot be relied upon to assist in the diagnosis here. There is a known association of rhGH treatment and pseudotumor cerebri, also referred to as benign intracranial hypertension (BIH) or idiopathic increased hypertension (IIH). The latency for its development is typically within 8 weeks of initiation of rhGH; however, longer latencies up to 5 years have been noted. This child had tolerated rhGH therapy without side effects for 5 years. Within 6 months of initiation of testosterone therapy, however, the patient developed intermittent headaches and vomiting. This was thought to be migraine but responded poorly to prophylaxis measures. Subsequent escalation of testosterone dosage led to dramatic clinical worsening. The temporal association of these events and the diagnosis of pseudotumor cerebri led us to suspect that testosterone triggered this known adverse effect of rHGH. This case also highlights an important alternative cause for vomiting and headache in the brain tumor population, particularly in patients requiring hormone replacement. CRANIO 13. QUALITY OF LIFE IN CHILDHOOD CRANIOPHARYNGIOMA: CURRENT STATUS OF THE PROSPECTIVE MULTICENTER STUDY KRANIOPHARYNGEOM 2000 AND RESULTS OF A RETROSPECTIVE STUDY ON 185 LONG-TERM SURVIVORS Hermann Muller,1 Ursel Gebhardt,1 Sabine Schroder,1 Carmen Teske,2 Reinhard Kolb,3 and Gabriele Calaminus2; 1Department of Pediatrics, Klinikum Oldenburg gGmbH, Oldenburg, Germany; 2Department of Pediatrics, University Hospital Munster, Germany; 3Oldenburg, Germany. Patients with craniopharyngioma (CP), an intracranial tumor of low-grade malignancy, frequently suffer from severe acute and long-term adverse effects related to pituitary and hypothalamic alterations. The spectrum includes endocrine deficiencies, obesity, and sleeping disorders. Such morbidities influence quality of life (QoL). Within the German multicenter prospective study KRANIOPHARYNGEOM 2000 as well as in a retrospective investigation of patients with childhood CP, we evaluated health-related QoL to answer the question whether operation, treatment, and appearance of endocrine deficiencies have impact on QoL. We retrospectively analyzed 185 children with CP at least 2 years off treatment. Questionnaires (KINDL, PEDQOL, EORTC-QIQ-30) were used and patients were grouped according to degree of surgery, irradiation, and body mass index (BMI-SDS). There were 77 data sets available. Generally compared to healthy controls, CP patients showed an impaired QoL in respect to cognition and social functioning with friends. In addition, patients with a BMI >3 SD gave a more negative rating of body image, social functioning with friends, and physical abilities. Over time, emotional functioning was rated negatively. Within the prospective setting, 70 patients are so far registered in KRANIOPHARYNGEOM 2000, of whom 41 patients gave complete information on their QoL. After the operative intervention most patients valued their QoL positive. During follow-up, problems with friends, body image, and physical functioning were constantly detectable. Parents rated their children's QoL more negatively. Over time, the ratings (self/proxy) converged to each other. We conclude that QoL in children with CP is influenced by endocrine deficiencies and severe obesity. QoL changes over time. Integration within peer groups, acceptance of body structures, and emotional status are relevant problems. Patients with CP need a good network structure of medical and psychosocial care to cope with the disease and its long-term effects. This work was supported by the Deutsche Kinder-krebsstiftung, Bonn, Germany CRANIO 14. QUALITY OF LIFE IN CHILDHOOD CRANIOPHARYNGEOMA PATIENTS WITH AND WITHOUT HYPOTHALAMIC INVOLVEMENT Andreas Wiener,1 Hermann L. Müller,2 Ursel Gebhardt,2 and Gabriele Calaminus1; 1Pediatric Hematology and Oncology, University of Munster, Münster, Germany; 2Department of Pediatrics, Klinikum Oldenburg gGmbH, Oldenburg, Germany. Objective: Craniopharyngeomas are benign malformations located in the hypothalamic and pituitary region. Treatment consists of surgery (OP) alone or in combination with mainly irradiation in case of progression. Although the overall survival rate is good, patients frequently suffer from adverse effects often related to hypothalamic involvement, for example, hyperphagia, severe obesity, and increased daytime sleepiness. In addition, cognitive deficiencies (e.g., attention, memory) as well as dysfunctional behavior (irritability, bursts of rage) are observed. These findings can severely QoL. Therefore it is expected that patients without hypothalamic involvement (non-HI) are reporting a better QoL than patients with HI. Methods: As secondary objective of the German KRANIOPHARYNGEOM 2000 treatment protocol, QoL was evaluated using the Pediatric Quality of Life Questionnaire (PEDQoL), which covers the following domains: familial interactions (FAM), interactions with friends (FR), autonomy (AUT), body image (BI), and emotional (EF), physical (PF), and cognitive functioning (CF). Twenty-four HI patients and 14 non-HI patients (age range, 6–18 years) as well as their parents filled in this cancer-specific questionnaire 1 year and 3 years after surgery. Results: One year after surgery, non-HI patients reported better QoL compared to the HI group. While this applies to all domains, a tendency toward significance was observed for the domain EF (p = 0.10; Mann-Whitney U-test). Three years after surgery, non-HI patients also reported better QoL except for the domain BI. In addition, a tendency toward significance was found for the domain CF (p = 0.1) with better ratings in the non-HI group. One year after surgery, parents of the non-HI group reported QoL equal to or better than did HI parents. This difference tends toward significance for the domains BI and PF (p = 0.10). Three years after surgery, parents of the non-HI group reported better QoL compared to the parents of the HI group for the domains FR, BI, EF, and CF but not for FAM and PF. Moreover, parents' ratings for the domain AUT were significantly better in the non-HI group (p = 0.05; Mann-Whitney). When comparing the self and parent ratings no significant difference was observed. Conclusion: Even if no significant differences were observed in patients, the non-HI patients reported better QoL in general. The value of the differences was found to change over time but no cluster of systematic changes was detectable over the several domains. Parents of the patients who had no primary hypothalamic involvement rated the QoL of their children better, too. This was the case for almost all the domains during the whole follow-up. Thus, the subjective appraisal of QoL mirrors the differences in clinical burden and also highlights the utility of QoL data when planning rehabilitation efforts. CRANIO 15. REDUCED SYMPATHETIC METABOLITES IN URINE OF OBESE PATIENTS WITH CRANIOPHARYNGIOMA Hermann Muller,1 Ursel Gebhardt,1 Sabine Schroder,1 Donald Hunneman,2 and Christian Roth3; 1Department of Pediatrics, Klinikum Oldenburg gGmbH, Oldenburg, Germany; 2Department of Pediatrics, University Hospital, Gottingen, Germany; 3Division of Neuroscience, Oregon Health and Science University, Beaverton, OR, USA. In patients suffering from craniopharyngioma (CP), a tumor of low histological malignancy located in the pituitary and hypothalamic regions, severe posttreatment obesity is a major problem. In the present study, we aimed to test the hypothesis that hypothalamic damage leads to reduction of the overall sympathetic tone and physical activity. We measured the major catecholamine metabolites, homovanillinic acid (HVA) and vanillylmandelic acid (VMA), which arise from epinephrin and norepinephrin and their precursor dopamine, in morning voided urine of 93 CP patients of the German pediatric craniopharyngioma study (KRANIOPHARYNGEOM 2000). The results were compared to age-matched HVA and VMA values in urine of 900 pediatric control patients representing a usual hospital pediatric population proven not to have a catecholamine-secreting tumor. Furthermore, the self-estimated daily physical activity of participating CP patients has been recorded using a questionnaire (scores from –2: activity much less, to +2: activity much more, compared to healthy people of same age). In patients suffering from obesity (BMI >2 SD), HVA and VMA values as well activity scores were significantly lower compared to CP patients with normal BMI. Patients with hypothalamic CP had higher BMI values and lower HVA, VMA, and activity scores than CP patients without hypothalamic involvement (BMI-SDS, 4.3 ± 0.4 vs. 1.4 ± 0.3; ratio HVAcp/HVA control, 0.77 ± 0.06 vs. 1.06 ± 0.07; ratio VMAcp/VMA control, 0.81 ± 0.06 vs. 0.88 ± 0.05; activity score, –1.11 ± 0.1 vs. –0.21 ± 0.15; mean ± SEM, p < 0.01, for all comparisons). These findings support the hypothesis of disturbed sympatoadrenergic regulation leading to reduced physical activity and severe obesity in patients with craniopharyngioma, especially in those with hypothalamic tumor. A disturbed sympathetic tone should be considered in further studies investigating treatment options for hypothalamic obesity. This work was supported by the Deutsche Kinder-krebsstiftung, Bonn, Germany. CRANIO 16. SEVERAL TIPS TO AVOID COMPLICATIONS OF INTRACYSTIC CHEMOTHERAPY WITH BLEOMYCIN FOR CRANIOPHARYNGIOMA IN CHILDREN Akira Gomi,1 Hiroshi Takahashi,2 Toshihiro Mashiko,1 and Eiju Watanabe1; 1Department of Neurosurgery, Jichi Medical University, Tochigi, Japan; 2Department of Neurosurgery, Nippon Medical School Musashikosugi Hospital, Kanagawa, Japan. Objectives: We have reported the effectiveness of intracystic chemotherapy with bleomycin for cystic craniopharyngiomas. This result has been confirmed by the following reports. However, relevant complications, including cerebral ischemia, visual and hypothalamic damages, associated with local bleomycin therapy have been also reported. We have, so far, experienced no such significant complications with our methods. Here we report a way to avoid such complications. Methods and Results: Intracystic bleomycin administration has been performed on 14 children since 1988 in our institutes. When radiological examinations indicated cystic craniopharyngioma, we partially removed the cyst wall to confirm the pathological diagnosis and then placed the Ommaya reservoir tube into the tumor cavity. It is important to place all the side holes of the tube within the cyst cavity and to tighten its entrance so as to avoid leakage of infused bleomycin. Bleomycin was administrated 2 weeks postoperatively via the Ommaya reservoir connected to the tube. Cystography should be performed prior to bleomycin administration. A smaller dose (5 mg or less) per injection or infrequent (every other day) injections would lessen complications. In addition, the concentration of bleomycin in the cyst is very important. If the dilution of bleomycin is not enough, the drug may leak through the wall of the cyst. We suggest an appropriate concentration of bleomycin solution of 1 mg/ml or less and injection timing immediately after aspiration of cystic fluid. In nine children the cysts have almost disappeared and the children have achieved a good school life. Four children are also achieving good quality of life after additional stereotactic radiosurgery. No severe complications were obeserved. Conclusion: We recommend several tips for appropriate usage of bleomycin to avoid complications and achieve a good result. CRANIO 17. THE TREATMENT OF CRANIOPHARYNGIOMA: THE UNIVERSITY OF WASHINGTON EXPERIENCE 1980–2002 James Douglas,1 Zachary Weber,2 Jeffrey Ojemann,3 Anthony Avellino,3 Olson James,4 Richard Ellenbogen,5 and J. Russell Geyer4; 1Radiation Oncology, Pediatrics, and Neurological Surgery, University of Washington, Seattle, WA, USA; 2Radiation Oncology, University of Washington, Seattle, WA, USA; 3Neurological Surgery, Children's Hospital and Regional Medical Center, Seattle, WA, USA; 4Hematology/Oncology, Children's Hospital and Regional Medical Center, Seattle, NH, USA; 5University of Washington, Seattle, WA, USA. Purpose: To examine the outcomes of patients treated for craniopharyngioma at our institution over a 22-year period. Materials and Methods: The records of 43 consecutive patients diagnosed with craniopharyngioma from 1980 through 2002 were examined. Median age at diagnosis was 7.6 years (range, 1–18 years); male to female ratio was 1.4:1. Endocrinopathies were found preoperatively in 37% of patients, with growth hormone deficiency being the most common (65%) followed by TSH (24%), ACTH (22%), VP (20%), and GnRH (11%). Sixty-seven percent had calcifications on imaging studies; 76% had cyst formation; 65% had documented visual field loss at diagnosis. Seventy-nine percent underwent subtotal resections; the remaining 21% had gross total resections as judged by postoperative imaging and the surgeon's report. Irradiation was administered in the immediate postoperative period in 47% of patients, delayed irradiation for recurrence in 21%, no irradiation in 32%. Median dose was 5,040 cGy (range, 5,000–5,580 cGy). Results: The 10-year Kaplan-Meier estimated local control probability was 72% for the entire group. We could find no statistically improved local control comparing those patients having a gross total versus subtotal resections (p = 0.75) or immediate versus delayed irradiation (p = 0.71). Visual field testing deficits improved postoperatively compared to diagnostic testing in 55% of patients. Endocrinopathies were much more common postoperatively compared to those present at diagnosis. Conclusions: Local control of craniopahryngioma was excellent at 10 years. These data suggest that there is no difference in local control between gross total resection without radiotherapy and subtotal resection with either immediate or delayed irradiation. Delaying irradiation did not compromise local control. EPENDYMOMA EPEN 1. TREATMENT AND OUTCOME OF CHILDREN WITH RELAPSED EPENDYMOMA: A MULTIINSTITUTIONAL RETROSPECTIVE ANALYSIS Stergios Zacharoulis,1 Susan Ashley,2 Darren Hargrave,3 Jean Claude Gentet,4 Uri Tabori,5 Maura Massimino,6 and Didier Frappaz7; 1Royal Marsden Hospital, Sutton, Surrey, UK; 2Biostatistics, Royal Marsden Hospital, Sutton, Surrey, UK; 3Sutton, UK; 4Hôpital de la Timone, Marseille, France; 5University of Toronto, Toronto, ON, Canada; 6Pediatrics, National Tumor Institute, Milan, Italy; 7Oncology, Centre Léon Bérard, Lyon, France. Current therapeutic options for relapsed ependymoma are limited. We analyzed retrospectively clinical data (treatment and outcome) for 66 children treated for relapsed ependymoma from European and Canadian institutions. Median age at diagnosis was 4 years (10 months–19 years), 39 were female, 80% had infratentorial tumors, and half had anaplastic histology (reviewed centrally as part of their treatment protocols at diagnosis). There were three patients with metastatic disease at presentation. Patients were treated according to institutional protocols at diagnosis. Of the group, 62% had local recurrence only, 16% had distant recurrence, and 21% had both local and distant recurrence. Following the first relapse, treatment included surgery only (n = 6), irradiation only (n = 8), chemotherapy only (n = 7), irradiation and chemotherapy (n = 4), surgery and irradiation (n = 17), surgery and chemotherapy (n = 13), and all three modalities (n = 11). Reirradiation was used in 19 patients. Five-year overall survival (OS) following the first relapse was 24% (95% confidence interval [CI], 12%–36%). Median time to second relapse was 12 months (95% CI, 28 weeks–18 months). Late relapses and deaths (>5 years from diagnosis) were observed. Complete resection of the relapsed tumors was associated with statistically significant better 5-year progression-free survival (PFS) and OS, for patients with incompletely resected relapsed tumors (8% and 37%, p = 0.04, p = 0.01, respectively). Median PFS for patients who received chemotherapy at first relapse was 8 months (5–11 months) versus 14 months (8–20 months) for patients who received surgery and/or irradiation (p = 0.1) without chemotherapy. Objective responses to chemotherapy for evaluable patients were rare (n = 4), with response duration between 6 and 16 months; these patients had regimens containing either platinum or etoposide. Median PFS for patients who received irradiation at the time of first relapse was 15 months (9–20 months) compared to 8 months for patients who did not receive irradiation. Of the 19 patients who were reirradiated with variable doses with either craniospinal (n = 5), or focal irradiation (n = 10), or stereotactic radiosurgery (n = 4), five patients were survivors; three of these had complete resections of their tumors. Multivariate analysis of potential prognostic factors predicting survival following relapse revealed that the extent of resection and initial tumor grade were independent predictors of overall survival. In conclusion, and given the limitations of a multi-institutional retrospective analysis of patients treated heterogeneously, survival for patients who relapse with ependymoma is possible provided surgical resection and/or irradiation/reirradiation is feasible. Complete resection if possible even at the time of relapse should be encouraged. New agents are urgently needed to be tested against this disease since cytotoxic chemotherapy has failed to provide substantial benefit, at least following relapse. EPEN 2. CONFORMAL RADIATION THERAPY FOR PEDIATRIC EPENDYMOMA: THE ST. JUDE EXPERIENCE Thomas Merchant,1 Frederick Boop,1 Fred Laningham,1 Amar Gajjar,2 Larry Kun,1 and Robert Sanford1; 1Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA; 2Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA. Introduction: Successful therapy for ependymoma requires aggressive surgical intervention, accurate evaluation to determine the extent of disease, and radiation therapy administered using methods that minimize the risk of side effects. During the past decade, 153 children with ependymoma have been prospectively treated and followed at St. Jude Children's Research Hospital to determine the benefit of conformal radiation therapy. Methods: Between July 1997 and December 2007, 153 pediatric patients (median age, 2.9 ± 0.4 years) with localized ependymoma received conformal or intensity-modulated radiation therapy at St. Jude Children's Research Hospital. Doses of 59.4 (n = 131) or 54.0 Gy (n = 22) were administered to the postoperative tumor bed using a 10 mm clinical target volume and 3–5 mm planning target volume margin. Patients were followed with MR imaging every 3–4 months during the first 2–3 years, semiannually through 5 years, and yearly through 10 years. The patients were characterized based on anaplastic tumor grade (n = 75), infratentorial tumor location (n = 122), history of chemotherapy administered prior to irradiation (n = 35), extent of resection (gross total = 141, near total = 12, subtotal = 12), number of attempts at resection (one = 87, two = 51, three = 11, four = 4), gender (female = 58), race (white = 126), age at time of irradiation (age <3 years = 80), and time from initial surgery to start of irradiation. Prognostic factors for disease control were determined based on univariate and multivariate analyses with end points of local tumor control, progression-free survival, and disease-specific survival. Results: There were 18 disease-related deaths and 35 patients experienced progression, including 19 with local failure. The data were current on December 31, 2007, and no patients were lost to follow-up. Median (±SE) follow-up was 58.6 ± 3.1 months among patients who had disease control at the time of analysis. The 7-year local control, progression-free, and overall survival were 84% ± 4%, 72% ± 4% and 84% ± 4%, respectively. Univariate analysis demonstrated favorable local control and progression-free survival rates based on lower tumor grade, female gender, fewer attempts at resection, and more extensive resection. Lower tumor grade, female gender, extensive resection, and treatment without chemotherapy improved overall survival. Multivariate analysis showed that progression-free and overall survival were influenced by tumor grade, extent of resection, gender, and race. Local control was influenced by gender and extent of resection. Local control (87% ± 4%, p = 0.02) and progression-free (78% ± 5%, p = 0.05) survival were improved for the 110 patients treated with radiation therapy within 135 days of first surgery compared to those observed for longer periods or treated with chemotherapy for any time period. When these patients were considered separately, local control, progression-free, and overall survival were influenced by tumor grade and extent of resection; gender was marginally significant. Conclusions: The results from this study establish new, long-term disease control benchmarks for children treated with ependymoma using aggressive surgery and high-dose postoperative conformal radiation therapy. Excellent outcomes for patients with differentiated tumors, and less favorable outcomes for patients with anaplastic or incompletely resected tumors, suggest that future investigations may be risk-adapted to reduce or intensify therapy, respectively. EPEN 3. EXPERIENCE WITH PEDIATRIC EPENDYMOMAS OVER 10 YEARS Jennifer Madden,1 Michael Handler,2 Molly Hemenway,3 Arthur Liu,4 and Nicholas Foreman5; 1The Children's Hospital; University of Colorado at Denver, Aurora, CO, USA; 2CO, USA; 3University of Colorado at Denver, Aurora, CO, USA; 4Radiation Oncology, University of Colorado at Denver, CO, USA; 5The Children's Hospital, University of Colorado, Denver, CO, USA. Although the overall survival rate of ependymoma at our institution is similar to the nationally accepted survival rate, the relapse rate continues to be unacceptable. At our tertiary care pediatric hospital, we have found that long-term survival may be possible after first relapse. In the 10-year period between 1995 and 2005, we have seen 39 patients with ependymoma, ages 6 months to 19 years (median, 4.2 years) at presentation. For almost all of this period, a national front-line study did not exist. Our standard therapy at diagnosis consists of aggressive surgery. If complete resection is not possible at diagnosis, patients undergo two rounds of chemotherapy (carboplatin/etoposide) followed by second-look surgery to pursue complete resection. Complete resection is followed by conventional conformal radiation. Our standard therapy at relapse has consisted of complete tumor resection and reirradiation using hypofractionated stereotactic radiotherapy. We typically deliver three 8-Gy fractions to the tumor bed. Of the 39 patients treated, 9 have died. Overall actuarial survival (OS) from presentation is 72% and event-free survival (EFS) from presentation is 26%; both at 5 years. From first relapse, OS is 55% and EFS is 43%; both at 5 years. Our policy of aggressive surgery with computerized conformational radiation at relapse may give better 5-year survival rates (55% in our series) than with previous first relapse therapies. However the possibility of further relapses continues even after 5 years, and it is likely the 10-year survival will be substantially lower. Survival from second relapse is poor. Children with ependymoma may survive longer now even after relapse, but the survival figures must be looked at with caution as there are late relapses. Very long-term follow-up (>10 years) is needed to ascertain true EFS. EFS is still unsatisfactory for children with ependymoma (both at diagnosis and at first relapse) evidenced only by very long-term follow-up. In spite of the addition of second-look surgery, aggressive surgery, and hypofractionated stereotactic radiotherapy at relapse, the addition of novel therapies at both diagnosis and relapse is warranted. EPEN 4. HISTOPATHOLOGICAL GRADING OF INTRACRANIAL PEDIATRIC EPENDYMOMAS David Ellison,1 Mehmet Kocak,1 Dominique Figarella-Branger,2 Felice Giangaspero,3 Catherine Godfraind,4 Torsten Pietsch,5 Zhao Wei,1 Didier Frappaz,6 Maura Massimino,7 James Boyett,1 and Richard Grundy8; 1St. Jude Children's Research Hospital, Memphis, TN, USA; 2Service d'Anatomie Pathologique et de Neuropathologie, Hôpital de la Timone, Marseilles, France; 3University of Rome La Sapienza, Rome, Italy; 4Université Catholique de Louvain, Brussels, Belgium; 5Institut für Neuropathologie, Universität Bonn, Bonn, Germany; 6Centre Léon Bérard, Lyon, France; 7Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; 8Paediatric Oncology, University of Nottingham, Nottingham, UK. Histopathological grading of pediatric ependymoma has been controversial with respect to its reproducibility and clinical significance. We have reviewed intracranial ependymomas from four European trial cohorts of infants (two trials) and older children (two trials) to assess both diagnostic concordance among five neuropathologists and the prognostic value of grading, before and after defining a consensus grading scheme. At the first meeting, the pathologists, without first discussing any issue related to grading ependymomas, reviewed and graded ependymomas from three trial cohorts. Diagnosis of grade II ependymoma was less frequent than grade III. This difference increased when the same tumors were reassessed at a subsequent meeting, during which the pathologists discussed ependymoma grading, jointly reviewed all tumors in one trial cohort, and defined a novel grading scheme based on histopathological features that are regarded as significant for grading in the WHO 2007 classification of nervous system tumors. Second review was associated with a significant increase in concordance on grading. Extent of tumor resection was the only clinical variable to be significantly associated with progression-free survival (PFS). Strength of consensus on grade was significantly associated with PFS in only one (noninfant) trial cohort. The scoring of individual histopathological features (necrosis, angiogenesis, cell density, and mitotic activity) and consensus on these features correlated with PFS only in the same trial cohort, but in none of the others. No individual pathologist was shown to apply the scheme significantly better than another in terms of correlation with outcome. This is the only study of its kind, utilizing a novel grading scheme, derived from histopathological consensus, across four trial cohorts. We conclude that histopathological grading needs further refinement before it can be reliably used in therapeutic stratification of children with intracranial ependymoma. EPEN 5. IMMUNE RESPONSE GENE OVEREXPRESSION IS PREDICTIVE FOR RESPONSE TO THERAPY IN EPENDYMOMA Andrew Donson,1 Diane Birks,1 Michael Handler,2 Wei Qi,3 and Nicholas Foreman4; 1University of Colorado Health Sciences Center, Aurora, CO, USA; 2CO, USA; 3Molecular Pathology, The Children's Hospital Denver, CO, USA; 4Aurora, CO, USA. Ependymoma (EPN), the third most common brain tumor of children, is routinely treated by surgical removal and radiation therapy. Unfortunately, this therapy will not cure all patients. More than 50% will suffer from tumor recurrence, which will ultimately result in death. This high failure rate represents one of the most significant problems in pediatric neurooncology. Despite the severity of this disease, little progress has been made in treatment or understanding of the factors underlying EPN recurrence. In order to address this problem, we performed microarray analysis of tumor from initial presentation of EPN that later recurred (n = 8) and EPN that did not recur (n = 7). Gene expression profiles were analyzed using Gene-Spring and R microarray analysis packages and those genes that in nonrecurrent EPN were >2-fold overexpressed and statistically significant (p < 0.05) versus recurrent EPN were identified. These genes were then analyzed using the web resource DAVID (Database for Annotation, Visualization, and Integrated Discovery), which provides a rapid means to reduce large lists of genes into functionally related groups. DAVID helps to unravel the biological content captured by high-throughput technologies. Analysis of those genes that were overexpressed in nonrecurrent EPN showed that there was a striking and significant (p = 2.7 × 10–9: false discovery rate adjusted) enrichment of immune response genes. These data imply that a preexisting immune response prior to radiation predicts a complete response to that therapy, that is, no tumor recurrence. Examination of the immune response genes up-regulated in the nonrecurrent EPN revealed a number of genes that were interferon-induced, including multiple components of the MHC class-II pathway and CD4, toll-like receptors, and viral-response genes. Earlier research had identified SV40-like sequences in approximately 50% of EPN. We performed quantitative PCR for SV40, BK, and JC virus in recurrent and nonrecurrent EPN and found very low expression of SV40 in 9 of 18 EPN. However, no correlation between SV40 and clinical outcome was observed. Differential gel electrophoresis proteomic and immunohistochemical studies are currently being conducted to further characterize the immune response mechanism. Exploration of the nonrecurrent EPN immune response, and how it combines with radiation therapy to result in complete tumor eradication, may provide new strategies to identify those EPN that will recur and how to effectively treat them. EPEN 6. INTRACRANIAL EPENDYMOMAS IN CHILDREN: THE S.F.O.P. EXPERIENCE WITH HYPERFRACTIONATED POSTOPERATIVE FOCAL RADIOTHERAPY Cécile Conter,1 Christian Carrie,2 Valérie Bernier,3 Anne Geoffray,4 Dominique Plantaz,5 Jean Claude Gentet,6 Sylvie Chabaud,7 Marie Madeleine Ruchoux,8 and Didier Frappaz9; 1Centre Léon Bérard, Lyon, France; 2Radiotherapy, Centre Léon Bérard, Lyon, France; 3CHU, Nancy, France; 4Fondation Lenval, Nice, France; 5CHU, Grenoble, France; 6CHU Timone, Marseille, France; 7Centre Léon Bérard, Lyon, France; 8CHU, Lille, France; 9Neurooncology, Centre Léon Bérard, Lyon, France. Objective: To prospectively investigate the role of focal hyperfractionated radiotherapy (HFRT) in the treatment of intracranial ependymomas in children, after surgical resection. Materials and Methods: Postoperative focal HFRT was proposed for every child (>5 years of age at diagnosis) with localized intracranial ependymoma. Sixty gray in case of complete (CR) and 66 Gy in case of incomplete resection (IR) was delivered in two daily fractions of 1 Gy, according to early postoperative imaging. Results: From November 1996 to December 2002, 24 children with infratentorial (20) or supratentorial (4) intracranial ependymomas were included. Median age was 8.6 years (range, 5–17 years). WHO grade was anaplasic in 10 of the 24 patients (nonassessable in 1). After retrospective central review CR was reported in 16, IR in 4, and doubtful resection in 4. Dose of radiotherapy were 60 Gy in 18 cases (1 in IR), 66 Gy in 5 cases (1 in CR), and 54 Gy in 1 case (CR). Five-year overall survival is 74.8%, and progression-free, survival 54.2%. Eleven patients had a relapse; seven were local, and four were metastatic and local. Histological grade and extent of resection were not found to be prognostic factors. More than 12 of 16 children had no sequelae of radiotherapy after a median follow-up of 7 years (confidence interval 95%: 66.4–90.0 months). Conclusion: HFRT is a safe procedure, but provides no benefit when compared to other strategies of radiotherapy, such as conformal radiotherapy. EPEN 7. LATE RECURRENCES OF INTRACRANIAL EPENDYMOMA Juliette Hukin,1 Tamir Ailon,2 Stephen Yip,3 Tami Yamashita,4 Michael Sargent,2 Ashtosh Singhal,2 Glenda Hendson,2 Chris Fryer,5 and Karen Goddard2; 1University of British Columbia, Vancouver, BC, Canada; 2BC, Canada; 3MA, USA; 4University of Kingston Ontario, ON, Canada; 5Vancouver, BC, Canada. Background: Ependymomas comprise 6%–12% of pediatric brain tumors and are the third most common overall. In contrast to the majority of pediatric CNS tumors, for which remission at 5 years is considered a cure, late recurrences are not uncommon in ependymoma. We assessed the long-term outcome in pediatric patients with ependymoma with a focus on the incidence and clinical characteristics of late relapses. Methods: A population-based, retrospective study was made of all patients between 1970 and 2005 in British Columbia. Patients diagnosed before 17 years of age were reviewed with respect to incidence of relapse greater than 5 years after initial diagnosis; this included chart review, imaging, and pathology. Near total resection was defined as 95%–99% resection. Results: Of the 78 patients identified, median age at diagnosis was 4.6 years and male to female ratio was 45:33. Five-year progression-free survival (PFS) and overall survival (OS) were 46.5% and 63% respectively. Three patients were identified to have late relapses at 125, 170, and 314 months (10.4, 14.2, and 26.2 years). Two had posterior fossa (PF) tumors and the third a myxopapillary ependymoma of the lumbar spine (SP). All three had a near total resection at diagnosis; two had involved field radiation, one craniospinal radiation. Two had metastatic disease at relapse (SP/PF), one relapsed at the primary site. The PF patient with a localized relapse was treated with an incomplete resection followed by involved field radiation; this patient is alive at 39 months postrelapse. The two patients with metastatic disease at relapse were treated with biopsy, involved field radiotherapy, and chemotherapy; the PF relapse died at 7 months postrelapse; the SP was still alive at 5 years postrelapse. Conclusions: Although the majority of recurrences occurred within the first 5 years, three patients had late recurrences despite an aggressive resection and radiation at diagnosis. This highlights the need for continued surveillance of long-term survivors of both intracranial and spinal pediatric ependymoma. EPEN 8. MONITORING EPIGENOMIC ALTERATIONS IN EPENDYMOMAS Hehuang Xie,1 Maria De Fatima Bonaldo,2 Min Wang,3 Veena Rajaram,4 Chris D. McCabe,5 Wendy Stellpflug,3 Stewart Goldman,6 Tadanori Tomita,7 and Marcelo Bento Soares8; 1Northwestern University, Chicago, IL, USA; 2Cancer Biology and Epigenomics, CMRC, IL, USA; 3Chicago, IL, USA; 4Plaza, IL, USA; 5Molecular Diagnosis, CMH, IL, USA; 6Hematology/Oncology, Children's Memorial Hospital, Chicago, IL, USA; 7Pediatric Neurosurgery, Children's Memorial Hospital, Chicago, IL, USA; 8IL, USA. Ependymomas, occurring predominantly in children and adolescents, are the third most frequent pediatric brain tumors. Children diagnosed with ependymomas have a 5-year overall survival rate of approximately 50%, and no significant improvement in the prognosis has been made over decades. This, at least in part, reflects a poor understanding of the molecular mechanisms underlying genesis and progression of ependymomas. Global hypomethylation has been recognized as a hallmark in the early stage in tumorigenesis. Such loss of DNA methylation may result in genome instability and the activation of oncogenes, thus promoting tumor progression. Unfortunately, no genomewide methylation data have been generated for ependymomas. In this study, we conducted a comprehensive analysis to uncover genomewide methylation aberrations in ependymomas. The methylation status of CpG dinucleotides in repetitive elements, and of Alu repeats in particular since they contribute to approximately 30% of the total CpG methylation content of the human genome, has been utilized for assessment of global levels of cytosine methylation. We designed a set of primers targeting Alu elements rich in CpG dinucelotides. Along with the pyrosequencing technology, we took advantage of these primers to determine the global levels of DNA methylation in a number of ependymomas. We observed highly variable methylation in ependymoma tissues. In addition, significant loss of DNA methylation was observed in the tissues from patients who had been subject to chemotherapy. Interestingly, DNA remethylation was observed after termination of chemotherapy. We plan to exploit this strategy to study the impact of various chemotherapeutic agents on global methylation and genomic instability. This study was supported by The Everett/O'Connor Charitable Trust; Dr. Ralph and Marian C. Falk Medical Research Trust; Gus Foundation; The Maeve McNicholas Memorial Foundation and Medical Research Institute Council. EPEN 9. PRELIMINARY RESULTS OF THE SECOND AIEOP PROTOCOL FOR INTRACRANIAL EPENDYMOMA (EPD) Maura Massimino,1 Lorenza Gandola,2 Maria Luisa Garré,3 Lorenzo Genitori,4 Piergiorgio Modena,1 Geraldina Poggi,5 Marco Forni,6 Giovanni Scarzello,7 Maurizio Mascarin,8 Iacopo Sardi,4 and Felice Giangaspero9; 1Istituto Nazionale Tumori, Milano, Italy; 2Milano, Italy; 3Genova, Italy; 4Ospedale Pediatrico Meyer, Firenze, Italy; 5Lecco, Italy; 6Pathology, Ospedale Pediatrico Regina Margherita, Torino, Italy; 7Radiotherapy, Università di Padova, Padova, Italy; 8Radiotherapy, Centro di Riferimento Oncologico, Aviano, Italy; 9Rome/Pozzilli, Italy. After the results of our first protocol on intracranial ependymoma (EPD), we launched a second study stratifying patients according to the two main prognostic subgroups determined by surgical results (no evidence of disease [NED] vs. evidence of disease [ED]) and histology (grade 2 vs. grade 3) as after frontal central pathology review. NED patients with grade 2 tumors were to be focally irradiated with a 3D-conformal technique 1.8 Gy/d up to 59.4 Gy, while NED grade 3 received also four VEC (CTX, VP16, VCR) courses after irradiation. ED patients received four VEC courses, second-look surgery whenever possible, and 59.4 Gy irradiation followed by a 8-Gy boost into two fractions on surgical residue. Children >1 and <3 years received the same treatment, except for those grade 2 unequivocally NED, who received only six VEC courses and strict follow-up. As of November 2007, study cases were 65 (male/female, 40/25); median age, 6 years; posterior fossa origin in 39 (1 plus metastasis), supratentorial in 26. After surgery, NED patients were 40 of 65, with grade 3 assessed in 35. Front-line histopathological central review determined modified diagnoses in 20% of cases. Second-look surgery rendered 7 of 16 children NED without additional severe morbidity. Radiotherapy boost obtained complete or partial response in five of nine with macroscopic residue; for three children evaluation is too early. At a median follow-up of 36 months, overall survival was 81% and progression-free survival (PFS) was 63% with no toxic deaths or serious adverse events. With respect to the previous study, PFS of ED patients seems improved (63% vs. 50%, p = 0.09), as well of NED grade 3 patients (60% vs, 37%, p = 0.07). Patient accrual is satisfactory. Front-line pathology review, second-look surgery, and confomal radiation plus boost were feasible on a national basis, without unexpected toxicity. Preliminary results suggest a prognostic amelioration in ED and grade 3 patients. EPEN 10. RESPONSE OF RECURRENT EPENDYMOMA TO TAMOXIFEN WITH OR WITHOUT ORAL ETOPOSIDE Myriam Ben Arush,1 Sergey Postovsky,1 Dorit Goldsher,2 Joseph Guilburd,3 and Shlomi Constantini4; 1Pediatric Hematology Oncology, Meyer Children's Hospital, Rambam Medical Center, Haifa, Israel; 2MRI Department, Rambam Medical Center, Haifa, Israel; 3Pediatric Neurosurgery, Rambam Medical Center, Haifa, Israel; 4Pediatric Neurosurgery, Dana Children's Hospital, Tel Aviv Souraski Medical Center, Tel Aviv, Israel. Surgery remains the best therapeutic option for recurrent ependymoma, but therapeutic options in unresectable ependymoma recurring after radiotherapy and standard chemotherapy are unset. The purpose of this study was to deliver tamoxifen with or without oral etoposide (VP) to children with recurrent progressive brain ependymoma. Three children diagnosed with brain ependymoma developed recurrences which occurred after combined multimodalities of treatment, including repeated surgical excisions, local radiotherapy (conventional and/or stereotactic-radiosurgery), and first- and second-line chemotherapy protocols. The decision to deliver tamoxifen to the three children was made when no other therapeutic options were possible. Tamoxifen was delivered as a single drug at a dose of 60 mg/m2 per day in one patient and together with oral VP 16 at a dose of 50 mg/m2 in two children. Results: Stable disease was obtained for 30 months in a 5-year-old girl, 24 months in an 8-year-old boy, and 16 months in a 13-year-old boy who is still on therapy. No therapeutic complication was observed. Conclusions: These observations raise the question of a possible benefit of tamoxifen in unresectable malignant ependymoma recurring after radiotherapy and standard chemotherapy. EPEN 11. RESULTS OF TREATMENT OF ANAPLASTIC EPENDYMOMA PATIENTS: EXPERIENCE OF POLISH NEUROONCOLOGY STUDY GROUP (PNOSG) Danuta Perek,1 Monika Drogosiewicz,1 Marta Perek-Polnik,1 Bozena Dembowska-Bagiñska,1 Wieslawa Grajkowska,2 Jaroslaw Peregud-Pogorzelski,3 Tomasz Urasinski,3 Mariusz Wysocki,4 Beata Zalewska-Szewczyk,5 Dorota Wojcik,6 and Alicja Chybicka6; 1Department of Oncology, The Children's Memorial Health Institute, Warsaw, Poland; 2Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland; 3Pediatric Oncology and Hematology, Medical Academy Szczecin, Poland; 4Pediatric Oncology and Hematology, Medical Academy Bydgoszcz, Poland; 5Pediatric Oncology and Hematology, Medical Academy Lodz, Poland; 6Pediatric Oncology and Hematology, Medical Academy Wroclaw, Poland. The aim of the study was to analyze treatment results of patients with anplastic ependymoma treated with PNOSG protocol in six centers. Material and Methods: Thirty-one patients, 12 girls and 19 boys, 6 months to 17 years 9 months of age (mean, 7 years 4 months; median, 5 years), were treated according to the Polish Neuroncology Study Group (PNOSG) protocol. Central pathological verification of tumors was performed. There were 12 patients <3 years of age, who received 18 months of chemotherapy consisting of vincristine (VCR), etoposide (VP-16), cytotoxin (CTX), and cisplatinum (CDDP) after surgery, and 19 patients >3 years of age, who were operated on, then received preirradiation chemotherapy (4 courses of VP-16, IF alternating with ADM, IF), were irradiated and received maintenance chemotherapy (eight courses of Philadelphia protocol). Tumor location, stage of disease, type of resection, response to treatment, and outcome were analyzed. Five-year event-free and overall survival were evaluated. Results: There were 16 infratentorial tumors, 14 supratentorial, and 1 in the cervical spine. Five (16%) patients had disseminated disease at diagnosis (two single metastases to the spine, infratentorial localization; three multiple metastases to the spine and brain, supratentorial localization). All patients regardless of stage underwent surgery; 23 (74.1%) primary tumors were resected totally or near totally, and 8 (25.8%) were resected partially or had biopsy only. In 10 patients who had visible tumor (residual of primary lesion or metastases), eight had accessible data allowing to assess tumor response to treatment (chemotherapy or chemo- + radiotherapy). There were four complete response (CR), two partial response (PR), two progressive disease (PD), two CR and four PR after chemotherapy alone; three patients with PR had further regression after radiotherapy. One patient with PD died of disease; the other had second-line chemotherapy and is alive with disease. One patient with CR relapsed and is now in third CR. In the whole group there were four relapses, in two patients <3 years of age and two over this age. Patients who had local disease at diagnosis presented with local relapses; patients who had disseminated relapse had dissemination at diagnosis. In relapsed patients, three tumors were located infratentorially, one supratentorially. Up to now one patient, <3 years of age, with disseminated disease at diagnosis, died from disease that did not respond to treatment. Five-year event-free and overall survival are 85.7% and 96.3%, respectively. Comments: Results obtained in our series are very promising but longer follow-up of these patients is needed to confirm it. Our material showed that anaplastic epenymoma responds to chemotherapy, and this should be included in the treatment strategy of this tumor. EPEN 12. SURGICAL RESECTABILITY OF INFANT EPENDYMOMA IN THE FIRST UKCCSG/SIOP STUDY Meharpal Sangra,1 Connor Mallucci,1 Jerard Ross,1 Donald Macarthur,2 Kling Chong,3 Richard Hayward,4 Richard Grundy,5 and Tim Cox6; 1Neurosurgery, Royal Liverpool Children's Hospital NHS Trust, Liverpool, UK; 2Neurosurgery, Nottingham University Hospitals NHS Trust, Nottingham, UK; 3Department of Radiology, Great Ormond Street Hospital, UK; 4London, UK; 5Nottingham, UK; 6United Kingdom. Objective: To evaluate those factors that influence “second-look” surgery in those with residual disease following resection of intracranial ependymoma in the infant population. Subjects: Data were used from patients enrolled in the UKCCSG/SIOP study (Grundy et al. Lancet Oncol. 2007;8:696) looking at primary postoperative chemotherapy following resection of intracranial ependymoma in children <3 years of age. The imaging was reviewed (44 patients with incomplete resection, 45 with complete) on data collected from 19 centers in the United Kingdom, Ireland, Denmark, and Holland. Tumors were evaluated for site, size, and location by an independent neuroradiologist. A panel of assessors, all pediatric neurosurgeons, evaluated location of residual disease, perceived chance of complete resection, and risk of cranial nerve injury and this was compared to action taken. Frequency of surgery, progression of disease, and overall outcome were investigated. Results and Conclusions: The extent of surgical resection has already been shown to influence progression-free as well as overall survival. Outcome from the 44 patients (age range, 4–35 months) with residual disease in whom imaging is available are discussed and within the entire group we look at those factors predisposing to less than total resection. The decision to offer second-look surgery can be predicted on the basis of tumor location and perceived risks of surgery. This has a direct influence on outcome. EPEN 13. TELOMERE MAINTENANCE AND DYSFUNCTION PREDICT RECURRENCE IN PEDIATRIC EPENDYMOMA Uri Tabori,1 Jing Ma,2 Mary Shago,2 Noa Alon,2 James Rutka,2 Eric Bouffet,3 Ute Bartels,2 David Malkin,2 and Cynthia Hawkins2; 1University of Toronto, Toronto, ON, Canada; 2ON, Canada; 3Toronto, ON, Canada. Pediatric ependymomas lack reliable biological markers of risk and molecular therapeutic due in part to a lack of representative preclinical models. We took advantage of the unique treatment for these tumors, which entails multiple resections performed over time, to examine the role of telomere dysfunction and telomerase activity in tumor progression and survival. We examined different aspects of telomere biology in 133 ependymomas from 83 pediatric patients. These were then correlated against conventional pathological markers and clinical outcome measures of tumor progression and response to therapy. In all 133 tumors, hTERT expression correlated with proliferative markers including MIB-1 index (p < 0.0001) and mitotic index (p = 0.001) as well as tumor grade (p = 0.002), but not with markers of anaplasia. While telomere length was not associated with telomerase activity or survival, we did observe an inverse correlation between hTERT expression and telomere dysfunction as measured by γH2AX expression (p = 0.011). Surprisingly, neither prior radiation nor chemotherapy-induced DNA damage affected telomere maintenance in recurrent tumors. Tumors that continued to progress invariably reactivated telomerase. However, late recurrences had higher γH2AX expression, indicating some telomere erosion with time (p = 0.0015). Combining γH2AX and hTERT expression could segregate tumors into three different survival groups (log rank, p < 0.0001). This study provides evidence that telomere dysfunction evolves with tumor progression over time, and emphasizes the importance of telomere biology as a prognostic tool and telomerase inhibition as a therapeutic target for pediatric ependymoma. Further, we have demonstrated that analyzing tumors as they progress in vivo is a viable approach to studying tumor biology in humans. EPEN 14. TEMOZOLAMIDE IN THE TREATMENT OF HIGH-RISK OR RECURRENT EPENDYMOMA Nichole Bryant,1 John Fiveash,1 John Wellons,1 Jeffrey Blount,1 Jerry Oakes,1 and Alyssa Reddy1; 1University of Alabama at Birmingham, Birmingham, AL, USA. Temozolamide is an alkylating agent shown in numerous adult trials to have efficacy against malignant gliomas. Although temozolomide has been evaluated in recurrent pediatric solid tumors, including CNS tumors, its efficacy for specific diseases in the pediatric population is not well established. Ependymomas are tumors for which effective therapeutic options are limited. Surgery and radiation are accepted as standard front-line treatment. Prognosis is poor for patients with incompletely resected tumors, disseminated disease, or recurrence. Multiple chemotherapeutic agents and regimens have been studied as up-front therapy and as salvage therapy for ependymomas. However, no chemotherapy regimen has had significant impact on event-free or overall survival. Temozolamide is an attractive treatment option for many reasons. It is an oral agent that crosses the blood-brain barrier and is known to be well tolerated in the pediatric population. This case series reports five pediatric patients with high-risk ependymoma at the University of Alabama at Birmingham. The table shows the characteristics of these five patients, including other therapy, response, and outcome. Although there were some mild side effects, including hematopoietic and gastrointestincal toxicity, none of the patients treated with temozolomide had side effects severe enough to discontinue the drug. Further, several patients have had surprisingly prolonged survival. All four patients who were treated for at least a year were alive with at least stable disease at the one-year mark. Patient 5 is currently 6 months into therapy with near complete radiographic response. Patient 4 is the only patient with progressive disease. Patients 1 and 2 were considered high-risk at diagnosis. They were treated with temozolomide as part of up-front therapy and are both alive with no evidence of disease progression at 30 months and 5 years from diagnosis, respectively. These results show that therapy with temozolamide is a promising adjunct to the currently accepted standards of surgery and radiation in the treatment of high-risk ependymoma. Although the data are limited, this approach appears safe and well tolerated and warrants further study. (See EPEN 14: Table 1, p. 516.) EPEN 14: Table 1. Characteristics of ependymoma patients treated with temozolomide Patient Number . Age at Time of Temozolomide Therapy . Up-Front/Recurrence . Risk Factors . Anaplasia . Prior Therapy . Concurrent Treatment with Temozolomide . Time on Temozolamide . Response . Current Status . 1 29 months Up-front Brainstem infiltration – None Surgery, chemotherapy, radiation 15 months Complete response Alive with PFS 30 months from diagnosis 2 16 years Up-front Diffuse spinal dissemination – None Surgery, radiation 13 months Near complete response Alive with PFS 5 years from diagnosis 3 39 months First recurrence Brainstem infiltration + Surgery, chemotherapy, radiation Radiation 12 months Stable disease Alive with PFS 13 months from recurrence 4 19 years Third recurrence Dissemination + Surgery, radiation, gamma knife Radiation 13 months Progressive disease after 13 months DOD 5 17 years Fourth recurrence + Surgery, radiation, chemotherapy, gamma knife Surgery, bevacizumab 6 months Near complete response Alive with PFS 6 months from recurrence Patient Number . Age at Time of Temozolomide Therapy . Up-Front/Recurrence . Risk Factors . Anaplasia . Prior Therapy . Concurrent Treatment with Temozolomide . Time on Temozolamide . Response . Current Status . 1 29 months Up-front Brainstem infiltration – None Surgery, chemotherapy, radiation 15 months Complete response Alive with PFS 30 months from diagnosis 2 16 years Up-front Diffuse spinal dissemination – None Surgery, radiation 13 months Near complete response Alive with PFS 5 years from diagnosis 3 39 months First recurrence Brainstem infiltration + Surgery, chemotherapy, radiation Radiation 12 months Stable disease Alive with PFS 13 months from recurrence 4 19 years Third recurrence Dissemination + Surgery, radiation, gamma knife Radiation 13 months Progressive disease after 13 months DOD 5 17 years Fourth recurrence + Surgery, radiation, chemotherapy, gamma knife Surgery, bevacizumab 6 months Near complete response Alive with PFS 6 months from recurrence Open in new tab EPEN 14: Table 1. Characteristics of ependymoma patients treated with temozolomide Patient Number . Age at Time of Temozolomide Therapy . Up-Front/Recurrence . Risk Factors . Anaplasia . Prior Therapy . Concurrent Treatment with Temozolomide . Time on Temozolamide . Response . Current Status . 1 29 months Up-front Brainstem infiltration – None Surgery, chemotherapy, radiation 15 months Complete response Alive with PFS 30 months from diagnosis 2 16 years Up-front Diffuse spinal dissemination – None Surgery, radiation 13 months Near complete response Alive with PFS 5 years from diagnosis 3 39 months First recurrence Brainstem infiltration + Surgery, chemotherapy, radiation Radiation 12 months Stable disease Alive with PFS 13 months from recurrence 4 19 years Third recurrence Dissemination + Surgery, radiation, gamma knife Radiation 13 months Progressive disease after 13 months DOD 5 17 years Fourth recurrence + Surgery, radiation, chemotherapy, gamma knife Surgery, bevacizumab 6 months Near complete response Alive with PFS 6 months from recurrence Patient Number . Age at Time of Temozolomide Therapy . Up-Front/Recurrence . Risk Factors . Anaplasia . Prior Therapy . Concurrent Treatment with Temozolomide . Time on Temozolamide . Response . Current Status . 1 29 months Up-front Brainstem infiltration – None Surgery, chemotherapy, radiation 15 months Complete response Alive with PFS 30 months from diagnosis 2 16 years Up-front Diffuse spinal dissemination – None Surgery, radiation 13 months Near complete response Alive with PFS 5 years from diagnosis 3 39 months First recurrence Brainstem infiltration + Surgery, chemotherapy, radiation Radiation 12 months Stable disease Alive with PFS 13 months from recurrence 4 19 years Third recurrence Dissemination + Surgery, radiation, gamma knife Radiation 13 months Progressive disease after 13 months DOD 5 17 years Fourth recurrence + Surgery, radiation, chemotherapy, gamma knife Surgery, bevacizumab 6 months Near complete response Alive with PFS 6 months from recurrence Open in new tab EPIDEMIOLOGY EPI 1. A DETAILED ANALYSIS OF THE PRESENTATION OF PEDIATRIC CNS TUMORS: THE 5-YEAR EXPERIENCE OF A UK CENTER Reena Kundu,1 Elisabeth Jameson,1 Ian Kamaly-Asl,2 Rao Gattamaneni,3 and Eddy Estlin1; 1Royal Manchester Children's Hospital, Manchester, Greater Manchester, UK; 2Manchester, UK; 3Young Oncology Unit, Christie Hospital NHS Foundation Trust, Manchester, UK. Objectives: To study the demographics and presentation of pediatric CNS tumors according to histological type. Design: Retrospective notes review from January 2001 to December 2005. Setting: A UK tertiary paediatric oncology department. Patients: One hundred seventy patients aged from 5 months to 16 years 8 months, of which 156 sets of notes were available. The patient list and histological tumor type were obtained from the North West Children's Cancer Registry. Results: There were nine histological types defined. The overall male to female ratio was 1.19:1. The “high-grade astrocytoma” group had a predominant male bias with a ratio of 4.5:1. The “pilocytic astrocytoma” and “other glioma” categories had a slight female dominance. The overall mean age of presentation was 8.1 years (range, 5 months to 16 years 8 months). The “choroid plexus” group had the youngest overall age and the “miscellaneous” category the oldest. The majority (60%) had a symptom history of between 0 and 2.9 months, of which 38% had a history of <1 month's duration. Those with the shortest history were the “other glioma” (including brainstem glioma) and “high-grade astrocytoma” groups, while the “miscellaneous” and “low-grade astrocytoma” groups generally had the longest. Of all tumors, 9.6% were incidental findings during routine screening, such as in tuberous sclerosis or investigation of an underlying condition (e.g., developmental delay); this was especially true of the “choroid plexus” group. Headache and/or vomiting were seen in two-thirds of all cases. Headache and vomiting were particularly dominant in the “other PNET,” “ependymoma,” and “pilocytic astrocytoma” groups. “medulloblastoma” was associated with vomiting being predominant over headache. Visual disturbance was seen in 42% of all cases, being a common feature of the “pilocytic astrocytoma” (a diagnostic category the encompasses visual pathway astrocytomas), “high-grade astrocytoma,” and “miscellaneous” groups, often in combination with headache and vomiting. Presentation with growth/pubertal concerns was seen in the “miscellaneous” group. Seizures were seen in 25% of all cases but were particularly seen in the “other glioma” group, especially in those with the diagnosis of DNET. There were a multitude of other nonspecific symptoms in all categories. In total, 27 children (15.9%) died, of whom approximately a third had “other glioma” and a third “high-grade astrocytoma.” Conclusions: This study highlights the epidemiology and presentation of the various CNS tumors. While the classic presentation of headache and vomiting is well known among health professionals, it highlights the multitude of other presentations and the importance of investigating the child with unusual neurology or poorly controlled seizures. It also draws attention to the fact that while the majority of CNS tumors have a short symptom history, there is a significant proportion that has a more insidious onset. The prompt recognition of symptoms can lead to early diagnosis and treatment, which may aid in reducing the relatively high mortality associated with pediatric CNS malignancy. EPI 2. A POPULATION-BASED EPIDEMIOLOGICAL STUDY OF CHILDHOOD LOW-GRADE GLIOMA Katrin Scheinemann,1 Ute Bartels,2 Annie Huang,3 Cynthia Hawkins,4 Eric Bouffet,3 and Uri Tabori5; 1The Hospital for Sick Children, Toronto, ON, Canada; 2University of Toronto, Toronto, ON, Canada; 3Toronto, ON, Canada; 4ON, Canada; 5University of Toronto, ON, Canada. Background: Low-grade gliomas (PLGGs) are the most common CNS tumors in children. However, lack of epidemiological studies result in confusing data regarding the significance of pathological and location subtypes especially in relation to age and gender in this heterogeneous group of neoplasms. Furthermore, ongoing discussions still exist regarding optimal treatment and outcome for these patients. Methods: We performed a retrospective, population-based (catchment area of 5 million people) study of the MRI era (1985–2007). All children (<18 years old) diagnosed and treated for PLGGs at the Hospital for Sick Children in Toronto were identified. We collected all relevant demographic and clinical data and analyzed treatment details and outcome. Results: A total of 635 patients were identified. Fifteen percent had an underlying diagnosis NF-1. Median follow-up time was 5.43 years (range, 0–17.94 years). Diagnosis relied on pathology in 83% of patients; 66% of tumors were histologically grade I astrocytoma. Only 2% were adult type diffuse astrocytomas. Other noted pathologies were 4% ganglioglioma and 3.5% mixed astrocytomas. Overall, male preference (57%) was noted. Interestingly, diagnosis of ganglioglioma and tectal and thalamic location were clearly dominated by males, whereas supracellar tumors and pilomyxoid astrocytomas were predominantly found in females. The most common tumor location was posterior fossa (28%), followed by optic pathway (22%), brainstem (10%), thalamus (7%), and spine (5%). Four different age/location patterns were observed: posterior fossa tumors showed a peak age at 2–4 years followed by a plateau until the age of 16. Spinal and optic gliomas peaked at the age of 0–2 and 2–4 years, respectively. Brainstem tumors showed two peaks at age 0–2 years and at age 10–12 years, and thalamic tumors a late peak at age 12–14 years with no diagnosis before the age of 2 years. Further tumor progression was observed in 23% of patients. In 10 patients (1.5%) the tumor transformed to high-grade glioma. Twenty-eight (4%) of the patients died (70% of whom had a midline tumor). Tumor progression was the cause of death in only seven (1%) patients (five with location in the brainstem). Other causes included secondary malignancy, malignant transformation, and health issues attributed to PLGG morbidity. Conclusion: This large epidemiological population-based study of PLGGs shows lower than expected adult type pathologies and intriguing associations between age and location of tumors suggesting different biological patterns. The very low mortality but high morbidity associated with PLGGs supports that treatment should be adapted to the natural progression of these tumors. Specifically, biological markers and new, less harming treatment strategies should be implemented. EPI 3. AN ANALYSIS OF PROGNOSTIC FACTORS IN PEDIATRIC POSTERIOR FOSSA EPENDYMOMAS: CHALLENGES IN THE STUDY OF PROGNOSTIC FACTORS IN CHILDHOOD BRAIN TUMORS AND A PLEA FOR A NOVEL APPROACH Tarik Tihan,1 Lloyd Morgan,2 Patricia Buffler,3 Melissa Bondy,4 Roberta Mckean-Cowdin,5 and Margaret Wrensch6; 1University of California, San Francisco, CA, USA; 2CBTRUS, Berkeley, CA, USA; 3Epidemiology, University of California, Berkeley, CA, USA; 4University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 5University of Southern California, CA, USA; 6University of California, San Francisco, San Francisco, CA, USA. Background: Ependymomas are among the most common neoplasms in children, and the majority of ependymomas originate in the posterior fossa. There have been significant variations in the conclusions of the studies on the prognostic value of clinicopathological variables in pediatric posterior fossa ependymomas. Specifically, it is not clear which set of clinicopathological variables should be considered prognostically relevant and influence treatment decisions. Design: We have reviewed all publications between 1990 and 2007, including our experience, to identify significant prognostic factors. We have included all studies that provided specific prognostic analysis of pediatric ependymomas and only included patients younger than 20 years. Studies that included adults, diagnoses other than typical ependymomas, review papers, and case reports were excluded. Results: We identified 35 studies between 1990 and 2007. The total number of patients studied was 1,625 with 979 tumors located in the posterior fossa. Some studies included the same patients, thus the total number of patients was lower. Male/female ratio ranged between 0.7 and 2.2 (mean ratio, 1.2) suggesting no particular gender predilection. The studies included patients from a range of 2–45 years diagnosed between 1951 and 2005. Among 35 studies, 22 identified extent of resection, 14 identified age, 10 identified histological grade, and six identified tumor location as independent prognostic factor. Conclusion: Single institution and limited consortia studies fall short of providing definitive answers in defining prognostic factors in posterior fossa ependymomas. The challenges of limited number of patients with markedly different characteristics often prevent an objective assessment of prognostic factors. It appears that a more comprehensive effort could have provided answers at probably a fraction of the overall cost and effort. The implications of this study in terms of determining risk factors in epidemiological studies are even more serious. We propose a national consortia-based study model for a more objective and effective means of analyzing critical parameters in childhood brain tumors. EPI 4. BLOOD SPOTS AS A RESOURCE FOR GENETIC STUDIES OF PEDIATRIC BRAIN TUMORS Beatrice Malmer1; 1Oncology, Umea University, Umea, Sweden. In Sweden and also in other countries, blood spots are taken on Guthrie cards on all newborns to screen for phenylketonuria, a disease that could be fatal if undetected but could be treated if found. In Sweden the Guthrie cards have been saved since 1975 and onward and could potentially be used as a resource for DNA-based studies. However, the ethical considerations for using a biorepository of this kind must be addressed, and a linkage through different national registries must be performed to identify the subjects. In most cases subjects must give informed consent for participation, depending on what level of information is needed from each subject. Another concern when choosing correct genetic analytical methods is the fact that DNA degrades over time, and this consideration will be addressed in the presentation. Blood spots are a unique source and have large potential as a resource for a large number of samples for analysis in a case controls study or for studies of prognostic factors. As the material is sparse it is very important to use the samples in an effective way, getting as much genetic information as possible while saving part of the Guthrie card for future research as technology is constantly developing. The concept of using blood spots and the troubleshooting of the planned Swedish study will be presented. EPI 5. BRAINSTEM TUMORS IN INFANTS <3 YEARS OLD IN CANADA 1990–2005: REPORT OF THE CANADIAN PEDIATRIC BRAIN TUMOR CONSORTIUM Bruce Crooks,1 Daniel Keene,2 Anne-Sophie Carret,3 Ute Bartels,4 David Eisenstat,5 Christophe Fryer,6 Lucie Lafay-Cousin,7 Valerie Larouche,8 Albert Moghrabi,9 Mariana Silva,10 Shayna Zelcer,11 and Eric Bouffet4; 1Dalhousie University, Halifax, NS, Canada; 2Children Hospital of Eastern Ontario, Ottawa, ON, Canada; 3Montreal, QC, Canada; 4University of Toronto, Toronto, ON, Canada; 5Winnipeg, MB, Canada; 6British Columbia's Children's Hospital, Vancouver, BC, Canada; 7University of Calgary, Calgary, AB, Canada; 8Hematology-Oncology, Centre Hospitalier Universitaire de Québec, Quebec, QC, Canada; 9Ste Justine Hospital, Montreal, QC, Canada; 10Queen's University, ON, Canada; 11London, ON, Canada. Introduction: Infant brain tumors are rare, with brainstem tumors representing a very small subgroup. As with other rare tumors, even major centers see only 1–2 cases per year, and large case series do not exist. This limits understanding of the biology, natural history, treatment, and outcomes of these tumors. Lack of outcome and treatment data limits approaches to management and our ability to counsel parents regarding the decisions they need to make in planning care for their children. The Canadian Paediatric Brain Tumour Consortium (CPBTC) represents all 17 Canadian pediatric oncology centers and allows collaborative studies, including collection of population-based data about specific tumors. Methods: The CPBTC surveyed all 17 Canadian pediatric oncology centers for cases of brain tumors in children <3 years diagnosed between 1990 and 2005. Data were collected regarding epidemiology, presenting features, tumor site and pathology, treatments, and outcomes; 531 cases were collected into an ongoing database. A subset of patients with brainstem tumors were extracted and reported here. Results: Of 531 reported infant brain tumors, 43 (8.1%) were brainstem tumors. Annual incidence in Canada is estimated at 2.9 cases/year. Median age at diagnosis was 19 months, and 27 of 43 (62.8%) occurred in males. Commonest presenting features were vomiting (23%), squint (18.6%), developmental regression (16.3%), and abnormal gait (16.3%). Commonest tumor types were low-grade astrocytoma (17), intrinsic pontine glioma (14), and high-grade astrocytoma (3). Other tumors represented 1–2 cases only. Surgical resection was complete in three cases, near complete in four, and incomplete in 14. Seven were biopsied, and 15 had no surgical intervention. Ten tumors were metastatic at presentation. Additional treatment was given in 19 (44.2%) cases only. Nineteen received chemotherapy, seven received radiotherapy to the tumor bed, and one underwent HSCT. Thirty (69.8%) cases were progressive, or recurred after treatment. Median time to progression was 21.5 months from diagnosis. Of 30 progressive tumors, 13 (30.2%) received supportive care only, seven had additional chemotherapy, six had further surgery, two had chemotherapy and radiotherapy, and two had chemotherapy and surgery. Twenty-four of 43 (55.8%) cases were alive at the time of survey, including 16 of 17 low-grade astrocytoma, 2 of 3 high-grade astrocytoma, and 1 of 2 ganglioglioma. No patients with ependymoma, medulloblastoma, PNET, or rhabdoid tumors survived. Conclusions: Infantile brainstem tumors are heterogeneous with variable outcome. Low-grade astrocytomas are the commonest subgroup, with very good survival. Other histological subgroups fared worse, including intrinsic pontine gliomas and embryonal tumors. Many (55.8%) families chose not to pursue active therapy. These data help to improve global knowledge of infantile brainstem tumors and help to guide management. More research is needed to improve outcomes. EPI 6. CHALLENGES TO EPIDEMIOLOGY STUDIES OF BRAIN TUMORS (REPORT FROM THE BRAIN TUMOR EPIDEMIOLOGY CONSORTIUM [BTEC]) Melissa Bondy1; 1University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. Brain tumor epidemiologists have largely reached consensus about areas where further research is warranted. Many risk factors have been examined; however, studies have been largely inconclusive due to small sample sizes, lack of studies of synergistic effects, and consideration of possible confounders. The group agreed that there is a need for more research in genetics and molecular epidemiology and for an active role for BTEC in promoting needed areas of investigation, in particular pediatric brain tumors, and the etiology of tumor subtypes, as well as encouraging researchers to enter promising areas of study at the genetic and molecular level. A barrier to conclusive studies is the paucity of cases of the relatively rare tumor types and the resulting need for interinstitutional data pooling and cooperative, collaborative studies. There is also a need for more researchers in the BT epidemiologic effort, especially junior investigators. Aside from rare genetic syndromes and high doses of ionizing radiation, risk factors accounting for a majority of brain tumors have not been identified. Although the epidemiologic literature on brain tumors is, in many areas, inconclusive, there are many promising areas that need to be pursued for future research, including (1) conduct large-scale genotyping studies (genomewide association studies; whole genome enriched for candidates); (2) research in the role of immunology, infectious agents, viruses, methylation, epigenetics, and imprinting; (3) understand routes of exposure—biology related to the blood-brain barrier; (4) translate research findings; and (5) improve study design and methodology. Since brain tumors are a rare disease, a consensus emerged from this meeting for the need to inform, communicate, and collaborate at a level far more comprehensive than currently achieved by the scientific community. This reality is valid for all brain tumors but particularly for childhood brain tumors (CBTs), where the numbers to conduct a sufficiently large study are limited in single geographic areas. Many factors that may have etiological associations with CBTs are being recognized and better defined: the role of viral pathogenesis, the importance of comprehensive genomics, the role of immune response, and host immunological status; and the need to assess the effect of physical and chemical agents using objective measures such as biomarkers of exposure to complement self-reported exposures insofar as possible. There is still much more to be learned, and many associations have yet to be established. The role of genetic and nongenetic factors in both adult and childhood brain tumors can be better understood with the increasing ability to diagnose and treat and to perform large-scale genetic and epigenetic analyses, high-throughput assays, computations, and data analyses, and, most importantly, increasing collaboration and communication. There is also a need to improve methods of exposure assessment in epidemiologic studies using biomarkers. The fundamental challenges inherent in the study of brain tumors are no longer insurmountable in the age of high-speed electronic communications, genomics, and bioinformatics. We believe it is time to consider comprehensive collaborations at the national and international levels that would not have been possible for earlier generations. Not unlike the efforts to accumulate worldwide human experience in combating climate change, there is a real opportunity to gather comprehensive information; most importantly, studies of CBTs are tantamount to enable us to compare information gathered in the same fashion from many more children across the nation and the globe. EPI 7. DEFINING THE ROLE OF ALL PRIMARY BRAIN AND CNS TUMORS AS A LEADING CAUSE OF CHILDHOOD CANCER MORTALITY (1985–2004) Vanessa Ramirez,1 Jennifer Propp,2 and Bridget Mccarthy1; 1Epidemiology/Biostatistics, University of Illinois at Chicago, Chicago, IL, USA; 2University of Illinois at Chicago, Chicago, IL, USA. As survival rates for leukemias have improved considerably over time, controversy has occurred regarding whether leukemia or brain/CNS tumors are the leading cause of cancer death in children. Rates vary based on the data source, the ages included in the definition of “childhood,” how tumors are classified, and which histologies are included in the analyses. To examine in further detail the mortality rates and frequencies of cancer-related deaths in children (0–19 years of age), incidence-based mortality data from NCI's Surveillance, Epidemiology, and End Results Program (SEER) from 1985 to 2004, stratified by age of diagnosis and year of death, were analyzed using SEER*Stat 6.3.6 software. To begin to account for deaths attributable to both nonmalignant and malignant brain tumors, data from 2004 (the first year of data collection for all primary brain tumors) were analyzed separately in children who were both diagnosed and died in 2004, thus representing deaths from the most aggressive tumors. The International Classification of Childhood Cancer (ICCC) classification scheme was used for defining leukemias. As the ICCC classification for brain tumors excludes tumors of the pituitary, pineal, brain lymphomas, intracranial germ cell tumors, and others, brain/CNS tumors were classified using the CBTRUS definition according to site (any histology in the ICD-O-3 site codes: C70.0–C72.9, C75.1–C75.3). Overall, leukemias were the leading cause of cancer mortality in children (0.39/100,000) followed by brain/CNS tumors (0.32/100,000). Of 6,757 cancer deaths, most were attributed to leukemias (28.8%), brain/CNS tumors (24.0%), and lymphomas (12.6%). Brain/CNS tumors exhibited the highest mortality rates in children <1 year of age (0.93/100,000) and ages 5–9 (1.23/100,000) compared to leukemias (0.56 and 1.13, respectively). Leukemia mortality rates in children diagnosed between the ages of 10–14 and 15–19 (1.17 and 1.41/100,000) were higher than the mortality rates seen in children dying from CNS/brain tumors in these same age at diagnosis groups (0.86 and 0.70/100,000). In those who were both diagnosed and died in 2004, all primary CNS/brain tumors were the leading cause of cancer death with mortality rates of 0.075/100,000 and leukemias were the second highest cause of cancer death (0.068/100,000); of 50 deaths, 38% were due to CNS/brain tumors and 32% from leukemias. While, overall, leukemia remains the leading cause of childhood cancer death in children ages 0–19, differences in mortality rates exist within specific age groups. Brain/CNS tumors account for more deaths in the <1 year and 5–9 year age groups, while children >10 years of age are disproportionately affected by leukemia deaths. Additional analyses will incorporate 2 years (2004–2005) of SEER nonmalignant brain tumor data and use of the U.S. mortality public-use data tapes to analyze data for all primary brain tumors. EPI 8. DESCRIPTIVE EPIDEMIOLOGY OF NONPINEAL CNS GERM CELL TUMORS Bridget Mccarthy,1 Jennifer Propp,1 and J. Lee Villano2; 1University of Illinois at Chicago, Chicago, IL, USA; 2Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA. Germ cell tumors of the CNS have not been well described epidemiologically. Germ cell tumors of the pineal region are the most common, and a descriptive review of these tumors has recently been completed by these authors. The goal of this abstract was to describe a population-based series of nonpineal germ cell tumors located in brain and CNS site codes (ICD-O-3 site codes: C70.0–C72.9 and C75.1–C75.3). Data on all primary (malignant and nonmalignant) CNS germ cell tumors from the Central Brain Tumor Registry of the United States (CBTRUS) for cases diagnosed between 2000 and 2004 and data from all malignant germ cell tumors from the Surveillance, Epidemiology, and End Results (SEER) for cases diagnosed between 1992 and 2004 were analyzed. From the CBTRUS data, 370 germ cell tumors were identified. Of these, 132 (35.7%) were located in the pineal region (C75.3). For the remainder of the germ cell tumors (n = 238), the most common site was brain, NOS (31.1%), followed by the ventricles (18.1%), the pituitary (13.9%), and the cerebrum (10.1%). The majority of nonpineal CNS germ cell tumors were found in those 0–14 years of age (45.8%), followed by those 15–29 years of age (38.7%), with adults >30 years of age having the lowest frequency (15.5%). Males had a greater frequency of nonpineal germ cell tumors (59.7%) than females (40.3%). However, by age group, the male:female ratio differed, with children (0–14 years) having a male:female ratio of 1.2:1, young adults (15–29 years) a ratio of 2.4:1, and adults (⩾30 years of age) a ratio of 0.9:1. For both children and young adults, the majority of their tumors were malignant (87.2% and 89.1%, respectively), while for adults, more than half of the germ cell tumors were nonmalignant (56.8%). Germinoma (ICD-O-3 histology 9064; 58.4%) was the most frequent diagnosis, followed by teratoma (9080; 19.3%) and mixed germ cell tumor (9085; 8.8%). From the SEER data, 504 malignant germ cell tumors were identified in CNS site codes. Of these, 270 (53.6%) were nonpineal, with the most common site being brain, NOS (34.4%), followed by pituitary and cerebrum (14.8% each) and ventricles (11.9%). Sixty percent of nonpineal malignant CNS germ cell tumors occurred in males, with a male:female ratio of 1.5:1. Overall relative survival for all nonpineal CNS malignant germ cell tumors was 87.0% at 2 years, 79.4% at 5 years, and 68.5% at 10 years. At 5 years postdiagnosis, relative survival rates by site did not differ significantly from each other, nor did survival differ by gender or race. In conclusion, previous studies that have not stratified for nonpineal CNS tumors have suggested greater gender disparity. This analysis illustrates that nonpineal CNS tumors show no significant gender preference. Further descriptive statistics will be presented. EPI 9. DESCRIPTIVE EPIDEMIOLOGY OF PILOCYTIC ASTROCYTOMAS Bridget Mccarthy1 and Peter Burger2; 1Epidemiology/Biostatistics, University of Illinois at Chicago, Chicago, IL, USA; 2Johns Hopkins University, Baltimore, MD, USA. Although pilocytic astrocytomas are one of the most common brain tumor histologies in childhood, they remain understudied because of their relatively benign nature. Surveillance, Epidemiology, and End Results (SEER) public-use population-based data from 13 registries were used to provide a detailed description of the frequency, incidence, and survival of pilocytic astrocytomas. Pilocytic astrocytomas (ICD-O-3 histology code 9421) that occurred in a brain or CNS site (ICD-O-3 site codes: C70.0–C72.9, C75.1–C75.3) and were diagnosed between 1992 and 2004 were included for analysis. Data were analyzed using SEER*Stat 6.3.6, and 1,445 pilocytic astrocytomas were identified. 50.8% of these tumors were found in males, demonstrating a male:female ratio of 1.03:1. The overall incidence for pilocytic astrocytomas was 0.286/100,000 person-years (0.287 in males, and 0.285 in females). The incidence rate was the highest in the youngest age groups (0–4 and 5–9 years, 0.80/100,000 person-years) and declined with age (10–14 years, 0.72; 15–19 years, 0.45; ⩾20 years, 0.12). Pilocytic astrocytomas were reported most frequently in the cerebellum (35.7%), while 13.1% were coded to one of the four lobes of the brain, 10.8% to the brainstem, 4.8% to the spinal cord/cauda equina, and 3.8% to the optic nerve; 17.1% were coded to brain, NOS, and overlapping brain sites. Cerebellum was the most frequently coded site for all age groups. Pilocytic astrocytomas coded to the optic nerve were most common in the youngest age group (0–4 years) and decreased in both frequency and incidence with age. Conversely, pilocytic astrocytomas coded to the lobes of the brain increased in frequency with age. Overall 10-year relative survival for pilocytic astrocytomas was 90.0%. Survival did not differ among the childhood age groups (0–4 years, 94.3%; 5–9 years, 95.9%, 10–14 years, 94.6%; 15–19 years, 94.5%), but 10-year relative survival (78.6%) was significantly lower in adults (⩾20). By site, the highest 10-year relative survival was found for tumors of the cerebellum (95.5%), and the lowest 10-year relative survival was found for tumors in the cerebrum (77.2%). Ten-year survival estimates were 93.5% for tumors found in the optic nerve and 87.1% for tumors in the spinal cord/cauda equina. For pilocytic tumors located in the cerebellum, 10-year relative survival was similar for the 0–4 year (100%), 5–9 year (100%), 10–14 year (96.4%), and 15–19 year (98.2%) age groups, while survival was significantly lower for the ⩾20 age group (84.3%). Ten-year relative survival estimates did not significantly differ between males and females either overall or by site or age group. Overall, 10-year survival for pilocytic astrocytomas on a population-based level is quite good; however, long-term survival data and quality of life measurements will be necessary to more accurately define the clinical aspects of the disease. EPI 10. DIFFERENCES IN THE DISTRIBUTION OF BRAIN TUMORS BY PRIMARY SITE IN CHILDREN, YOUNG ADULTS, AND ADULTS Bridget Mccarthy1 and Jennifer Propp1; 1University of Illinois at Chicago, Chicago, IL, USA. Pediatric brain tumors are known to differ from adult brain tumors in terms of most common histologies. In addition, pediatric brain tumors occur in specific brain sites with different frequencies than adult brain tumors. In an effort to document the primary site differences among children (0–14 years), young adults (15–29 years), and adults (⩾30 years) in a population-based manner, data on all primary brain tumors from the Central Brain Tumor Registry of the United States for the years 2000–2004 were analyzed. Of 74,825 primary brain tumors, 4,551 tumors (3,510 malignant and 1,041 nonmalignant) were found in children, 5,124 tumors (2,547 malignant and 2,577 nonmalignant) were found in young adults, and 65,150 tumors (27,283 malignant and 37,867 nonmalignant) were found in adults. A difference of greater than 5% in the frequency of all tumors by primary site was found for the meninges (0–14: 1.5%; 15–29: 8.7%; ⩾30: 29.4%), the frontal lobe (0–14: 5.4%; 15–29: 12.1%; ⩾30: 11.6%), the cerebellum (0–14: 18.4%; 15–29: 7.4%; ⩾30: 2.2%), the brainstem (0–14: 14.1%; 15–29: 3.9%; ⩾30: 1.0%), brain NOS (0–14: 14.6%; 15–29: 7.2%; ⩾30: 8.1%), and the pituitary (0–14: 2.0%; 15–29: 18.4%; ⩾30: 8.6%). For malignant tumors, adults had a higher frequency of tumors in the frontal, temporal, and parietal lobes and overlapping brain sites and a lower frequency of tumors in the cerebellum and brainstem than children. Adults had a higher frequency of tumors of the temporal and parietal lobes than young adults. Young adults had a higher frequency of tumors of the temporal lobe and a lower frequency of tumors in the cerebellum and brainstem than children. For nonmalignant tumors, both adults and young adults had higher frequencies of tumors in the meninges and pituitary and acoustic nerve tumors but lower frequencies of tumors in the temporal lobe, ventricles, brain NOS, and craniopharyngeal duct than children. The highest frequency of tumors in the pituitary was found in young adults compared to either adults or children. By histology, the astrocytic tumors were more frequent in children in the cerebrum and brainstem than in adults, but more frequent in the lobes in adults compared to children. Ependymomas were more frequent in the brainstem and brain NOS in children compared to adults, but there was a higher frequency of these tumors in the spinal cord in young adults and adults compared to children. While tumors of the meninges were most frequently reported in the cerebral meninges in all three age groups, children had a greater frequency of these tumors reported in the spinal meninges than adults or young adults. Further differences in brain tumor frequency by primary site will be presented. EPI 11. EPIDEMIOLOGY AND TREATMENT OUTCOME OF CHILDHOOD EPENDYMOMA: REPORT FROM THE HONG KONG PEDIATRIC HEMATOLOGY ONCOLOGY STUDY GROUP Chi Fung Godfrey Chan,1 Matthew Ming-Kong Shing,2 Hui-Leung Yuen,3 Anselm Chi-Wai Lee,4 Chi-Keung Li,5 Chung-Wing Luk,3 Shau-Yin Ha,1 and Chi-Kong Li2; 1Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, China; 2Paediatrics and Adolescent Medicine, Chinese University of Hong Kong, Hong Kong, China; 3Paediatrics and Adolescent Medicine, Queen Elizabeth Hospital, Hong Kong, China; 4Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Hong Kong, China; 5Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China. Objective: Ependymoma is the fourth commonest childhood brain tumor, but there was little information on its epidemiology and outcome in Chinese children. We reviewed our data and provide some insight in this aspect. Materials and Methods: Prospective collection of childhood cancer data was performed since early 1990s from the five major public hospitals, which captured almost all children with cancers locally. Standard data accrual was performed by designated data managers. The data was further crosschecked with the Hong Kong Cancer Registry database, which collected all the local pathology reports for cancers. Chemotherapy regimen was baby-POG before 2005 and SIOP-99 after 2004. Results: From January 1995 to December 2006 (12 years), a total of 20 cases of childhood (⩽18 years) ependymoma were diagnosed. Their median age was 3.4 years (range, 0.5–16.3 years), and male:female ratio was 8:12. Excluding one non-Chinese and one >15 years, the incidence of ependymoma was 1.3/1,000,000 per year for children ⩽15 years. The distribution was fairly even between the cerebral (n = 9) and posterior fossa (n = 9), and two were in the spinal cord region. Chemotherapy was given to 10 children, mostly for children <3 years in order to delay cranial radiation therapy (RT) (n = 6) or for children with incomplete surgical excision (n = 4). The 5-year overall survival rate was 69% but was 87.5% for cerebral and 53.3% for posterior fossa location (p = 0.14), mainly because seven of nine (77%) children with posterior fossa ependymoma were <3 years (median age, 1.5 years; range, 0.5–5.1 years) and RT was postponed. On the contrary, only two of nine children with cerebral ependymomas were <3 years (median, 5.8 years; range, 2.3–16.3 years). Eight of 10 patients with either cerebral or posterior fossa ependymoma who did not receive upfront cranial RT (<3 years or parents refused) relapsed, irrespective of the completeness of the initial surgical resection or chemotherapy used. The two patients with spinal ependymoma were treated with surgery alone, and one relapsed; he was successfully re-treated with surgery plus local RT. Conclusion: Ependymoma is less common among Chinese children, and the majority of our children with posterior fossa ependymoma were <3 years. Without upfront cranial RT, 80% of our cerebral or cerebellar ependymomas relapsed. The data managers were supported by the Children's Cancer Foundation of Hong Kong. EPI 12. EPIDEMIOLOGY OF PEDIATRIC CNS GERM CELL TUMORS: A CALIFORNIA CANCER REGISTRY STUDY Sonia Partap,1 Julie Von Behren,2 Jane Maclean,1 Paul Fisher,1 and Peggy Reynolds2; 1Stanford University, Palo Alto, CA, USA; 2Northern California Cancer Center, Berkeley, CA, USA. Background: Pediatric CNS germ cell tumors (GCTs) are reported to comprise 2%–4% of childhood brain tumors, with an even greater prevalence in Asians. In the United States GCTs have historically been separated from other brain tumors when sorted by the International Classification of Childhood Cancer and thus are often neglected in analyses. Past Western studies of GCTs have also been limited by small sample sizes. Methods: We aimed to perform a rigorous, descriptive analysis of childhood CNS GCTs, using data from the population-based California Cancer Registry. Results: We obtained data on 4,070 CNS cancers, diagnosed from 1988 through 2004 in children ages 0–14 years; 214 (5.3% of sample) primary intracranial and intraspinal germ cell tumors were identified. Mean age at diagnosis was 9.1 years, and 68% of tumors occurred in males. The most common tumor location was the pineal gland (93 cases, 43%) with 7.5% of cases in the sellar region. Of the cases, 43% were Hispanic children, 35% white, 16% Asian, and 6% African American, compared to general California childhood population ethnic frequencies of approximately 42% Hispanic, 37% white, 10% Asian, and 7% African American. Histologically, 131 cases (61%) were reported as germinomas, with the remainder distributed among various pathologic classifications. The overall frequency of CNS GCTs in our cohort was 5.3%, with 11% of cases occurring between ages 0 and 1 year and 62% between ages 10 and 14 years. Children <1 year most often had malignant teratomas, with more females than males (16 vs. 7, p ⩽ 0.001, chi-square test). GCT incidence increased starting at age 7 and continued to rise at age 14. The proportion seen in males was greater than twofold that in females (p < 0.05). Conclusion: With the largest pediatric intracranial and intraspinal germ cell tumor series in the United States to date, our study reveals that CNS GCTs may be more prevalent among Western pediatric brain tumors than initially reported. Overall these tumors were more common among males; however, female infants were affected more than males, a difference that has not been previously reported. While our sample might be influenced by a high proportion of Asian Americans, the patterns observed differ from Asian series. EPI 13. GLUTATHIONE S-TRANSFERASE M1 POLYMORPHISM MAY PREDICT INTELLECTUAL IMPAIRMENT IN CHILDREN WITH MEDULLOBLASTOMA Mehmet Okcu,1 Nadia Barahmani,2 Sarah Carpentieri,3 Xiao-Nan Li,3 Tao Wang,4 Yumei Cao,5 Laura Howe,6 Lindsay Kilburn,7 Murali Chintagumpala,8 and Ching Lau9; 1Pediatrics Hematology Oncology, Baylor College of Medicine, Houston, TX, USA; 2Pediatric Hematology Oncology, Baylor College of Medicine, Houston, TX, USA; 3Houston, TX, USA; 4Pediatric, Baylor College of Medicine, Houston, TX, USA; 5M.D. Anderson Cancer Center, Houston, TX, USA; 6Pearland, TX, USA; 7Pediatric Hematology Oncology, Baylor College of Medicine, Houston, TX, USA; 8Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA; 9Pediatrics, Baylor College of Medicine, Houston, TX, USA. Background: Glutathione S-transferases (GSTs) are polymorphic enzymes that catalyze the glutathione conjugation of alkylating agents, platinum compounds, and free radicals formed by radiation used to treat medulloblastoma. We hypothesized that GST polymorphisms may be responsible, in part, for individual differences in response and cognitive outcomes in pediatric medulloblastoma. Methods: We investigated the relationship between GSTM1 and GSTT1 polymorphisms and survival and cognitive impairment in 42 children with medulloblastoma diagnosed and treated at Texas Children's Cancer Center between 1996 and 2005. We conducted Kaplan-Meier analyses to determine if the GST polymorphisms were related to progression-free survival (PFS) and performed t-tests to compare the within-subject slopes to explore associations between GST polymorphisms and changes in full-scale, performance, and verbal IQ scores. All statistical tests were two-sided and we considered a p value of <0.05 as significant. Results: The median follow-up for the 29 survivors was 3.7 years (range, 2–8.6 years). Fourteen patients had a progression, and 13 died, resulting in an estimated 4-year PFS of 68% ± 7% and 4-year overall survival rate of 76% ± 7%. In patients treated with high-dose chemotherapy followed by stem cell rescue (n = 24) patients with GSTM1 null genotype had an estimated 4-year PFS of 44% ± 16% compared to 79% ± 10% in GSTM1 nonnull patients (p = 0.12). In GSTM1 null patients the mean slopes for full-scale, performance, and verbal IQ scores were, –8.4, –11.1, and –4, respectively, whereas mean slopes in patients with the GSTM1 nonnull genotype were 4.5, 6.6, and 2.6, respectively (p = 0.001, 0.004, and 0.009, respectively). At 1 year after radiation, compared to patients with GSTM1 nonnull genotype, patients with the GSTM1 null genotype had significantly lower average full-scale (90.8 vs. 65.3, respectively, p = 0.04), performance (92.9 vs. 65.5, respectively, p = 0.08), and verbal (90.6 vs. 70.8, respectively, p = 0.04) IQ scores. Conclusion: GSTM1 polymorphism may predict intellectual impairment in children with medulloblastoma. A larger study to validate these findings is under way. EPI 14. INCIDENCE AND SURVIVAL TRENDS IN CHILDREN AND ADOLESCENTS WITH LOW- AND HIGH-GRADE GLIOMAS: ANALYSIS OF THE 1973–2002 SEER DATA Wendy Woods-Swafford,1 John Kuttesch,2 and Jill Barnholtz-Sloan3; 1Vanderbilt University, Nashville, TN, USA; 2Nashville, TN, USA; 3Case Western Reserve University, Cleveland, OH, USA. Background: Gliomas are the most common brain tumor in childhood accounting for >50% of all pediatric CNS tumors. Prior investigations of treatment effects and long-term prognosis are limited by single institutional reviews with small sample sizes. We examined trends in incidence and survival of pediatric gliomas in the United States using population-based data from the Surveillance, Epidemiology, and End Results (SEER) program. Methods: Study subjects from the SEER public-use database included 2,799 pediatric and adolescent patients diagnosed with microscopically confirmed primary glial tumors from 1973 to 2002 with follow-up through December 31, 2004. Overall frequencies of prognostic variables of interest were calculated. Frequencies of prognostic variables were assessed for differences by time period (1973–1979, 1980–1989, and 1990–2002) using chi-square tests. Survival analyses were performed using Kaplan-Meier models. Differences in survival by time period were examined using multivariable Cox regression models. Results: The number of black and other race children diagnosed increased over time. The number of children with astrocytoma NOS decreased over time, while WHO grade I/II and oligodendrogliomas increased over time. Children with WHO grade III/IV and glioma histology types had worse survival compared to those with astrocytoma NOS for all three time periods. In the most recent period, black children had an increased risk of death compared to white children (HR = 1.51, CI 1.06, 2.14). Treatment with surgery alone was consistently and significantly associated with improved survival, while treatment with radiation alone following biopsy or biopsy alone was associated with worse survival compared to those who received a combination of surgery and radiation. Further investigation showed any surgical intervention decreased the risk of death (∼80% decreased risk of death), whereas any combination of radiation with surgery increased this risk. Conclusions: Gliomas treated with radiation alone following biopsy had increased risk of death. Any surgical intervention significantly decreased the risk of death. However, radiation therapy in combination with surgery eliminated this survival advantage. Further investigation into the role of radiation therapy in this population is necessary. EPI 15. LOW-GRADE ASTROCYTOMA IN CHILDREN: SINGLE INSTITUTIONAL EXPERIENCE IN 143 PATIENTS Ofelia Cruz,1 Noelia Pérez,2 Eva Rodriguez,3 Marylin Medina,4 Mariona Suñol,2 Cusi Victoria,2 Carmen De Torres,1 Gemma Garcia-Fructuoso,5 Antonio Guillen,5 Ramon Navarro,5 Josep Maria Costa,5 Andreu Parareda,1 and Jaume Mora1; 1Pediatric Oncology, University of Barcelona, Esplugues de Llobregat-Barcelona, Spain; 2Pediatric Pathology, University of Barcelona, Esplugues de Llobregat-Barcelona, Spain; 3Pediatric Oncology, University of Barcelona, Esplugues de Llobregat-Barcelona, Spain; 4Pediatric Pathology, University of Barcelona, Esplugues de Llobregat-Barcelona, Spain; 5Pediatric Neurosurgery, University of Barcelona, Esplugues de Llobregat-Barcelona, Spain. Introduction: Astrocytomas are the most frequent brain tumors in children, consisting mainly of low-grade neoplasias. They represent a very heterogeneous group of CNS tumors, with variable natural history, therapeutic response, and outcome. Aim: To review the clinical experience with low-grade astrocytomas (LGAs), their histopathological and clinical features, therapeutic approach, and their prognostic features. Patients and Methods: A retrospective study of children (0–18 years), diagnosed with LGA within a 30-year period (1974–2004) was performed. Histology variables included histological pattern, tumor classification (edited WHO version), and inmunohistochemistry (IHC) in a tissue microarray for GFAP, WT1, p53, and ki67 expression. Statistical analysis was performed using the SPSS 15.0 package. Results: A total of 143 patients managed at our institution for LGA were included. Average age at diagnosis was 7.4 years (SD 4.3). Seventy-three (51%) patients were male. Neurofibromatosis was documented in 11 cases (8.1%). Initial symptoms were headache (35.8%), seizures (20.9%), motor deficit (16.4%), visual (10.4%), and ataxia (9.7%). Eighty-four tumors (58.7%) were infratentorial. Primary sites were cerebellum (41.2%), hemispheres (21.3%), optic pathway (14%), brainstem (14%), spine (6.6%), or mesencephalon (2.9%). Fifty tumors (39.7%) sited at midline and 30% each were right and left. Hydrocephalus was present in 61 patients (42.7%) and a mixed solid-cystic pattern was seen in 80% of cases. Only four patients had metastases (2.9%). Surgery was complete in 60 patients (45.1%). Twenty-seven patients had two or more resections (18.9%). A derivative procedure for hydrocephalus was required in 37 patients (27.4%), 31 of them currently device-dependent (23.1%). Pathological review classified 93 tumors as WHO grade 1 (73.8%), and 33 as grade 2 tumors (13 as fibrillary and three as pleomorhic xantoastrocytomas). IHQ for p53 was negative, save for five patients, all grade-2 tumors; Ki67 expression was >5% in 92.6% of cases, WT1 (nuclear) in 59.7%, and focal citoplasmatic in 6.9%. No significant differences in survival was found among histological subtypes or IHQ pattern, but a trend for higher mortality in WT1-positive tumors was appreciated. Neurological complications were the most frequent in the immediate postoperative period (41 [31.3%]). Adjuvant therapy was given in 53 (37%) cases: radiation therapy in 36 patients (25%) and chemotherapy in 22 patients (15.3%). Currently, 15 (11.3%) patients have died of disease, 67 (50.4%) patients are alive with no evidence of disease, and 51 (38.3%) patients are alive with disease, with a median follow-up of 200 months. An age younger than 12 months was a prognosis factor, as four of five infants have died. Long-term secondary effects (LTSEs) have been documented in 54 (37.8%) patients, 17 with more than one sequel. Predominant LTSEs were motor in 25 patients (45.5% of sequels), sensorial in 11 (20%), cognitive in eight (14.55%), and endocrine in three patients. Forty-nine (35.5%) cases were lost to follow-up since they were discharged to adult care specialist. Conclusion: LGAs in infants have an unfavorable prognosis. We are not aware of the current status of the eldest patients; long-term follow-up is necessary but is unfeasible in the actual health setting. EPI 16. MALIGNANT BRAIN TUMORS IN CHILDHOOD AND CHEMICAL EXPOSURES Dora Il'Yasova1; 1Duke University, Durham, NC, USA. Malignant brain tumors are the second most common type of pediatric cancer and the leading cause of cancer death in children. Etiology of childhood brain tumors is largely unknown. Animal experiments clearly demonstrate that the developing brain in the prenatal and early postnatal periods is much more sensitive to chemical carcinogens compared to the adult brain. Many environmental chemical exposures are suspected to play a role in the etiology of childhood brain tumors. We will summarize and discuss (1) animal data on brain carcinogens and their relation to childhood tumors specifically and (2) published epidemiological studies of the associations between chemical exposures and the risk of childhood brain tumors, including parental exposures. These exposures include N-nitroso compounds. We will focus on the existing gaps in the literature and methodological issues. EPI 17. OPPORTUNITIES FOR IMPROVED EXPOSURE ASSESSMENT IN BRAIN TUMOR RESEARCH Patricia Buffler1; 1University of California, Berkeley, Berkeley, CA, USA. Well-designed epidemiological studies are the desired approach for defining the relationships between environmental exposures and human disease. This is largely because human health studies provide the research framework for addressing issues of individual susceptibility to exposure and disease and they obviate the need for data extrapolation from laboratory studies with nonhuman models. The lack of accurate, quantitative measures of exposure and information about their relationship to one another and to disease is the greatest source of uncertainty in epidemiological studies, limiting the power of such studies to make definitive conclusions about the association between exposure and disease. New technologies are available for improving exposure assessment in future epidemiologic studies of brain tumors. One recent novel method utilizes the residual use of archived residual newborn dried blood spots (DBS) from state newborn screening programs. In recent years, investigators have also used these stored DBS for various other purposes, including epidemiologic surveys of infectious diseases, population-based studies of environmental and pharmacologic exposures, etiologic studies of birth defects and developmental disabilities, and population-based studies of haplotype and allele frequencies for genetic disorders and potentially significant gene polymorphisms. In general, any analyte that can be measured from whole blood, serum, or plasma can be measured from dried blood on filter paper. The dried blood matrix stabilizes many analytes, including DNA, which allows one to measure both phenotype (biochemical marker) and genotype (mutation or polymorphism) from one specimen, or to conduct multiplex DNA amplification for the detection of multiple gene mutations. Broin and Gunter (1999) combined the advantages of a microbiological assay and DBS in an assay for erythrocyte folate. Using newly collected blood samples, we can measure levels of >30 volatile hydrocarbons in the blood. Chemicals form stable adducts with albumin and other blood proteins that, unlike DNA adducts, are not repaired. Thus, adducts to blood proteins are stable biomarkers of cumulative exposure over the residence time of the protein, which for albumin is around 21 days and for hemoglobin 120 days. By means of personal monitoring and biomarkers of internal dose such as albumin adducts, it should be possible to characterize individual exposure and identify air pollution sources with relevant biological effects. EPI 18. PEDIATRIC BRAIN TUMORS IN ISRAEL: REASONS FOR DELAY IN DIAGNOSIS (DID) Vered Shay,1 Liana Beni,1 and Shlomi Constantini1; 1Dana Children's Hospital, Tel Aviv Medical Center, Tel Aviv, Israel. Background: There are several objective reasons for delays in pediatric clinical care in general and with pediatric brain tumor (PBT) diagnosis in particular. The importance of early diagnosis of PBTs is not obvious. Theoretical aspects that may be considered significant in early diagnosis include precluding acute situations, minimizing irreversible damage, preventing tumor spread, shortening time of suffering, and economic savings. Goals: Characterize the incidence and reasons for DID of PBTs in Israel. Identify risk-factors for such delays and relationship to other clinical variables. Provide a feedback to the system for improved education. Methods: Survey population: 330 children with PBTs. Data collection: files and telephone interviews. Results: Average age at presentation: 8 years. Most tumors were gliomas; 50% were infratentorial. Most common symptoms were headache and vomiting. Fifty percent of diagnosed children had normal physical exam. Papiledema in only 19%. Average time from the beginning of symptoms to imaging: 8 months. We found DID in about 50% of cases; 27% were defined as “unacceptable delay.” Major reasons for DID were “classical symptoms with a wrong diagnosis” and “delayed imaging despite clear indication.” Risk factors for late diagnosis were torticollis, ataxia, and motor dysfunction. Interestingly, examination by specialists such as ophthalmologists or neurologists was also found to be a risk factor for DID. Summary: Delay in diagnosis for PBTs in Israel is common and worrisome. Similar trend in other countries is probable. Delays can be minimized with lowering imaging threshold and better education and knowledge of symptoms and signs associated with PBTs. EPI 19. PERINATAL RISK FACTORS FOR CHILDHOOD BRAIN TUMORS: A CALIFORNIA CASE–CONTROL STUDY Jane Maclean,1 Julie Von Behren,2 Sonia Partap,3 Paul Fisher,1 and Peggy Reynolds4; 1Stanford University, Palo Alto, CA, USA; 2Northern California Cancer Center, Fremont, CA, USA; 3Stanford University, CA, USA; 4CA, USA. Background: Many studies have investigated various birth characteristics as possible risk factors for childhood brain tumors. High birth weight has been of particular interest because it may be a marker for increased cell division, in utero hormone levels, or insulin-like growth factor, stimulating cell proliferation. These are all factors that could influence cancer risk. While most prior research has not found any birth weight differences between brain tumor cases and controls, these studies have had small samples and did not differentiate by tumor subtype. Birth order and number of siblings have also been of interest because they may serve as proxies for infectious exposure. Methods: Using data from the population-based California Cancer Registry we obtained information on 4,070 CNS cancers diagnosed from 1988 through 2004 in children ages 0–14 years. We are in the process of linking the cases with state birth certificate files, using probabilistic record linkage. For each linked case we will select four controls, matched on date of birth and gender. Using the data from the linked birth certificates, we will analyze the risk for childhood brain tumors by demographic factors and birth characteristics, including high birth weight, gestational age, birth order, race, ethnicity, and parental age. Results: The two most common tumor types were astrocytoma (1,712 cases, 42%), with medulloblastoma the second most common (546 cases, 13%). In this ethnically diverse population, 48% of the cases were white, 36% Hispanic, 8% Asian, and 7% black. We will present full, preliminary results of our case–control study after analyzing the data from the linked medical records and birth certificates. Conclusion: As the largest case–control study of childhood brain tumors conducted to date, we will have enough cases to stratify our analyses by tumor type, thus accounting for the enormous heterogeneity of childhood brain tumors. EPI 20. PREVALENCE OF CHILDREN AFFECTED BY BRAIN TUMORS IN THE UK WEST MIDLANDS Martin English,1 Sheila Parkes,2 Davies Paul,3 and Andrew Peet4; 1Oncology Department, Birmingham Children's Hospital, Birmingham, UK; 2West Midlands Regional Children's Tumour Registry, Birmingham Children's Hospital, Birmingham, UK; 3Institute of Child Health, Birmingham Children's Hospital, Birmingham, UK; 4Child Life and Health, University of Birmingham and Birmingham Children's Hospital, Birmingham, UK. Introduction: Children who have had brain tumors are more likely to require additional educational, psychological, and other support. The incidence of brain tumors in childhood is well described, but it is more difficult to identify the prevalence of school age children who have had a brain tumor. The West Midlands Regional Children's Tumour Registry is a population-based registry that has data on all neoplasms since 1957 for all children in a population of 5.3 million (2001 census), thus covering >10% of the children in England. The majority of patients are treated at Birmingham Children's Hospital. We analyzed the registry to identify the prevalence of CNS tumors in children at ages 0–3, 4–6, 7–11, 12–16, and >16 that correspond with the following educational stages in England: pre school, key stage 1, key stage 2, key stage 3–4, and 16 plus in the 11-year period 1996–2006. Methods: Incidence, survival, and cumulative prevalence were calculated for the period 1996–2006 for patients in each age group and for the disease subtypes optic pathway glioma, posterior fossa low-grade glioma, other low-grade glioma, medulloblastoma, pineoblastoma, nonpineal supratentorial primitive neuroectodermal tumor, ependymoma, germ cell tumor, high-grade glioma, craniopharyngioma, spinal tumor (all histologies), and others. Patients diagnosed before 1996 were not included in this part of the analysis so annual prevalence in each age group was not stable in the early part of the time period. Survival by disease subtype was also compared between 1996–2006 and 1986–1995. Results: Between 1986 and 1995, 301 children were diagnosed, and 408 were diagnosed between 1996 and 2006. Five-year overall survival (OS) was 59% and 71% and 10-year OS was 56% and 66% respectively. Substantial improvements in 5-year OS were seen for other low-grade gliomas (not optic pathway or posterior fossa), 55%–99%; all supratentorial PNET, 20%–32%; ependymoma, 37%–80%; and germ cell tumors, 40%–92%. No improvements were seen in other tumor groups, most strikingly in medulloblastoma, where the 5-year survival was 52% and 54% in each period (43 and 63 patients, respectively). Between 2001 and 2006 the mean number of children who have had a brain tumor is as follows: 0–3 years, 16 per year; 4–6 years, 29 per year; 7–11 years, 65 per year; 12–16 years, 58 per year; >16 years, 51 per year. The figures for 12–16 years have not yet stabilized as some younger patients will not have reached that age group, and the >16 figures do not include patients diagnosed before 1996. Extrapolating these figures nationally, the number of children in England ⩽16 years of age who have been affected by brain tumors will be >1,700 each year. Discussion: This analysis is helpful in predicting numbers of school-age and preschool children affected by brain tumors in the UK, and within individual treatment centers in the UK. Improvements in survival have been seen for a number of tumors. The lack of improvement in survival for medulloblastoma requires further scrutiny. EPI 21. SECOND MALIGNANT NEOPLASM (SMN) OCCURRING IN THREE CHILDREN IN THE CNS AFTER TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) Dorota Wojcik,1 Ewa Niedzielska,1 and Dorota Sega-Pondel2; 1Medical University, Wroclaw, Poland; 2Medical University, Poland. SMNs occurring after completion of chemotherapy for anticancer treatment are increasingly reported, especially in combination with radiotherapy. During the last 30 years we observed eight children in our center treating 90 children/year for pediatric malignancies. The most common localization for SMNs was the CNS. Here we present three children after completion of ALL treatment according to BFM protocol diagnosed with SMNs in the CNS in 1988, 1995, and 2007: astrocytoma (2) and PNET (1). The tumor (astrocytoma) developed shortly after completion of chemotherapy in two cases (22 and 45 months, respectively), while prophylactic CNS radiotherapy (18 Gy) was included in the primary treatment course of one child only. Tumor excision was performed in both cases. Both children died due to rapid disease progression 3 months after surgery. Chemotherapy was not administered. The third child developed PNET 8 years after completion of chemotherapy with previous radiotherapy (24 Gy). This boy is in partial remission 10 months after partial tumor resection staying in good clinical condition while still on chemotherapy after having accomplished the intensive part of the treatment protocol including external CNS irradiation (36 Gy). SMNs are rare events after completion of ALL therapy and should be reported in order to be aware of this problem. Progress in oncology will hopefully offer an additional chance for curing children who develop SMNs. EPI 22. SPINAL CORD TUMORS IN INFANCY: A CANADIAN PEDIATRIC BRAIN TUMOR CONSORTIUM REPORT Shayna Zelcer,1 Daniel Keene,2 Anne-Sophie Carret,3 Bruce Crooks,4 David Eisenstat,5 Donna Johnston,6 Chris Fryer,7 Lucie Lafay-Cousin,8 Valerie Larouche,9 Albert Moghrabi,10 Beverly Wilson,11 Anthony Whitton,12 and Eric Bouffet13; 1Children's Hospital London Health Sciences Center, London, ON, Canada; 2Ottawa, ON, Canada; 3Montreal, QC, Canada; 4Dalhousie University, Halifax, NS, Canada; 5Winnipeg, MB, Canada; 6Children's Hospital of Eastern Ontario, Ottawa, ON, Canada; 7Vancouver, BC, Canada; 8Canada; 9Quebec City, QC, Canada; 10MB, Canada; 11Edmonton, AB, Canada; 12Hamilton, ON, Canada; 13AB, Canada. Background: Tumors of the spinal cord are exceedingly rare in infancy and only a paucity of literature exists describing the spectrum of this disease and its management. The objectives of our study were to describe the demographic characteristics of spinal cord tumors (SCT) in children <3 years of age at diagnosis and to review their treatment. Methods: A national retrospective chart review was conducted across Canada of patients <3 years of age diagnosed with a primary tumor of the CNS between 1990 and 2005. Inclusion criteria were age <3 years, histologic confirmation of the diagnosis, and residency in Canada. Data collected included age and year of diagnosis, pathological diagnosis, and evidence of disseminated disease, treatment, and overall outcome. A centralized database was created. From this central data registry, information regarding spinal cord tumors was extracted. Results: Twenty-four of 531 patients (4.5%) in the data bank had a SCT. Median age at diagnosis was 16.5 months (range, 0–32 months), and 54% were male. Histological diagnoses showed that 15 (62.5%) patients had lowgrade astrocytoma, 3 (12.5%) had PNET, and 2 (8.4%) had rhabdoid tumor, along with a single case each of ganglioglioma, schwannoma, lipoblastoma, and meningeal sarcoma. The median duration of symptoms prior to diagnosis was 6 weeks (range, 0–52 weeks). Presenting symptoms included gait disorder (62.5%) and developmental delay or regression (25%). Leptomeningeal dissemination based on neuroradiologic imaging was present in 3 of 24 (12.5%) of patients. Cerebrospinal fluid cytology was positive for malignant cells in only two patients (8.4%). The degree of surgical resection was >90% (complete/near complete) in 37.5% of patients, and 10%–90% (incomplete) in 50% of patients. The majority of patients (62.5%) did not receive adjuvant radiotherapy or chemotherapy after surgical intervention. Of those who received frontline treatment (9 of 24, 37.5%), seven patients received chemotherapy, and five patients received local (one), spinal (two), or craniospinal (two) radiotherapy. Seventeen of 24 (70.8%) patients developed recurrent or progressive disease. Treatment (if any) at the time of relapse or progression included surgery, chemotherapy, or both. The mean relapse-free and overall survival rates were 60.24 ± 15.12 (95% CI, 36.12–96.18) and 127.25 ± 16.3 (95% CI, 95.3–159.21) months, respectively. Conclusions: Relapse and/or progression of disease in patients <3 years of age with spinal cord tumors is frequent. However, prolonged survival with further therapy is possible. EPI 23. THE CANADIAN PEDIATRIC BRAIN TUMOR CONSORTIUM NATIONAL SURVEY OF CNS TUMORS IN CHILDREN UNDER 3 YEARS OF AGE Daniel Keene,1 Lucie Lafay-Cousin,2 Anne-Sophie Carret,3 Bruce Crooks,4 David Eisenstat,5 Chris Fryer,6 Donna Johnston,1 Valerie Larouche,7 Albert Moghrabi,8 Mariana Silva,9 Barbara Wilson,10 Shayna Zelcer,11 and Eric Bouffet12; 1Children's Hospital of Eastern Ontario, Ottawa, ON, Canada; 2University of Calgary, Calgary, AB, Canada; 3Montreal, QC, Canada; 4Dalhousie University, Halifax, NS, Canada; 5Winnipeg, MB, Canada; 6BC Children's Hospital, BC, Canada; 7Hematology-Oncology, Centre Hospitalier Universitaire de Québec, Quebec, QC, Canada; 8Ste Justine Hospital, Montreal, QC, Canada; 9Queen's University, ON, Canada; 10University of Alberta, AB, Canada; 11London, ON, Canada; 12Division of Hematology/Oncology, Hospital for Sick Children, ON, Canada. Background: Brain tumors in children <3 years of age are rare. Studies in this group of patients remain problematic as most reports have been based on single institution reviews. Therefore, accurate incidence figures are not available. Objectives: (1) To determine the incidence of brain tumors in children diagnosed in the first 3 years of life. (2) To describe the demographic characteristics of children <3 years of age with tumors of the CNS. Methods: A retrospective review of patients who were diagnosed with a primary tumor of the CNS was done. Children who were residing in Canada between 1990 and 2005 and were <3 years of age at time of diagnosis were included. Histological confirmation of diagnosis either at the time of initial surgery or at the time of autopsy had to be available for inclusion in the study, except for intrinsic brainstem and anterior optic pathway tumors. Case ascertainment was through the Canadian Pediatric Brain Tumor Consortium, a national group with representation from all the Canadian university-affiliated teaching hospitals. Most of the children with brain tumors in Canada are treated at one of these centers. Descriptive statistics for each of the demographic variables (age, sex, anatomic location of tumor, and histological diagnosis) were obtained. Yearly incidence rates per million children <3 years of age were calculated based on Statistics Canada Census data. Results: There were 531 cases ascertained. Nineteen cases (4%) were occurred in first 28 days of life; 186 (35%) before 1 year of age; 168 (32%) between 1 and 2 years of age; and 174 (33%) >2 years. Of the cases, 53.7% were female. The histological diagnoses were astrocytic tumors 161 (30%), embryonal 140 (26%), ependymal 69 (13%), mixed neuronal 42 (8%), choroid plexus 33 (6%), craniopharyngioma 11(2%), mesenchymal nonmeningothelial 10 (2%), germ cell 6 (1%), pineal parenchymal 4 (0.7%), melanoma 3 (0.6%), oligodendroglioma 2 (0.4%), mixed glioma 1 (0.2%), meningioma 1 (0.2%), and hemangiomablastoma 1 (0.2%). The overall mean yearly incidence was 32.17% ± 1.94% (95% confidence interval [CI], 28.03%–36.32%). The mean yearly incidence rate for persons <1 year of age was 34.43% ± 10.05% (95% CI, 29.08%–39.78%); between 1 and 2 years of age 30.09% ± 8.33% (95% CI, 25.65%–34.53%); and >2 years of age 31.23% ± 24.0% (95% CI, 25.0%–37.47%). The mean yearly incidence of supratentorial tumors was 14.89% ± 1.01% (95% CI, 12.72%–17.05%): hemispheric 5.55% ± 2.45% (95% CI, 4.26%–6.85%), axial 7.14% ± 0.69% (95% CI, 5.66%–8.62%), and optic pathway 2.19% ± 1.01% (95% CI, 1.65%–2.74%). The mean yearly incidence of infratentorial tumors was 15.79% ± 1.5% (95% CI, 12.59%–18.99%): cerebellum 13.2% ± 5% (95% CI, 10.53%–15.87%), brainstem 2.6% ± 2.1% (95% CI, 1.48%–3.70%). The mean yearly incidence for spinal cord tumors was 1.44% ± 0.99% (95% CI, 0.9%–1.97%). A significant trend of increase in yearly incidence rate of tumors in cerebellum was found, but this was not seen for other anatomical locations or age. Conclusions: The incidence of brain tumors in children <3 years of age is low. Except for tumors occurring in the cerebellar region, the incidence rate for this age group has remained stable. EPI 24. UNDERSTANDING HETEROGENEITY OF CHILDHOOD BRAIN TUMORS FOR EPIDEMIOLOGIC STUDIES Patricia Buffler1 and Tarik Tihan2; 1University of California, Berkeley, Berkeley, CA, USA; 2University of California, San Francisco, San Francisco, CA, USA. Brain tumors are the second most common tumors in children and constitute the most common solid tumor type in this age group. Childhood brain tumors (CBTs) are more prevalent within the cerebellum, and malignant tumors are roughly 20% of all pediatric malignancies. CBT is the leading cause of death from solid tumors in children. There is a modest, but statistically significant, increase in incidence rates for specific types of CBTs over the last decade. The increase in the rates of some CBTs such as pilocytic astrocytoma has been the subject of many reports. While it has been suggested that changes in environmental exposure may be responsible, there is no evidence to support this hypothesis or provide a satisfactory explanation. Unlike recent trends, previous incidence increase of CBTs between 1970 and 1980 has been attributed to improved diagnosis and reporting. This explanation may still be valid for the current increase as well, but this remains unknown. The only known risk factors for CBTs include ionizing radiation and familial genetic syndromes such as neurofibromatosis, Turcot syndrome, and Li-Fraumeni syndrome. While sex has been listed as a “known risk factor” for some types of brain tumors, how gender influences incidence of these tumors is unknown. A number of factors have been suggested as potential risk factors for CBT. Among them, maternal diet during pregnancy, family history of cancer, exposure to electromagnetic radiation, pesticides or N-nitroso compounds, paternal occupation, history of head injury, and history of seizures have been studied. However, none of these factors has been clearly associated with an increased risk of CBT. Factors other than those listed have also been analyzed, but the interpretation of these studies is difficult and the limitations are substantial. Studies of risk factors for CBTs can be plagued by confounding factors that may not be readily apparent yet are likely to influence the results. The validity of the study design, reliability of data collection, and the use of analytical procedures can all be affected by the heterogeneities inherent in the biological properties of CBTs. In multicenter trials or large population studies, heterogeneity of this nature can result in statistically significant results even though the factor may be of little biological consequence. The challenges of heterogeneity of CBTs may exist at a number of levels. In this presentation, we will focus on three such challenges: (1) study design, (2) data collection, and (3) data analysis. The challenges of inherent heterogeneity in biological, phenotypical, genetic, and ecological factors in CBTs that need to be addressed are formidable in studies that focus on risk factors in individual patients, single center studies or case series, and even more so in large epidemiologic studies. The clinical approach to understanding risk factors and etiological agents in CBTs needs to be modified to incorporate a comprehensive model of causality at a national level. GERM CELL TUMOR GCT 1. CHALLENGES AND DIFFICULTIES IN MANAGEMENT OF PATIENTS WITH INTRACRANIAL GERM CELL TUMOR HAVING DIABETES INSIPIDUS TREATED WITH CISPLATIN- AND/OR IFOSFAMIDE-BASED CHEMOTHERAPY Samina Afzal,1 Diane Wherrett,2 Ute Bartels,3 Uri Tabori,3 Annie Huang,4 Derek Stephens,5 and Eric Bouffet6; 1Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; 2Endocrinology, The Hospital for Sick Children, Toronto, ON, Canada; 3University of Toronto, Toronto, ON, Canada; 4Toronto, ON, Canada; 5Child Health Evaluative Sciences Program, Hospital for Sick Children, Toronto, ON, Canada; 6The Hospital for Sick Children, Toronto, ON, Canada. Background: Patients with suprasellar germ cell tumors often present with central diabetes insipidus (CDI), anterior pituitary dysfunction, visual fields defects, headache, and vomiting. Recent treatment protocols have used preradiation chemotherapy including a combination of etoposide and ifosfamide and/or cisplatin. Management of diabetes insipidus (DI) in these patients may be challenging and requires vigilant monitoring of electrolytes and fluids during chemotherapy administration. Methods: All consecutive patients treated with chemotherapy for an intracranial germ cell tumor during the period 1990–2007 at the Hospital for Sick Children, Toronto, were reviewed. Three protocols were used during the time period: POG9530, SIOP-CNS GCT 96, and ACNS0122. Out of 31 patients who received chemotherapy, 20 had DI and 11 had no DI. Twenty-five patients had germinoma, five mixed germ cell tumor, and one immature teratoma. Only cycles containing cisplatin and/or ifosfamide and hyperhydration were analyzed. DI and non-DI patients were compared for each cycle of chemotherapy. Patients were studied for number of days in hospital during each cycle of chemotherapy, daily fluid input and output, changes in dose, schedule and route of administration of DDAVP before and during chemotherapy, daily variations in sodium level, electrolytes monitoring requirements per day, and complications related to fluid and electrolytes disturbances. Patients with DI were managed in oncology units with full supervision of endocrinologist. Results: Fifty-four cycles of chemotherapy in DI patients were compared to 25 in non-DI patients. All 20 patients with DI required daily change in dosage and schedule of DDAVP. Eight patients required change of route either from oral to subcutaneously or oral to intravenous as per requirement. Average daily monitoring of sodium level ranged from two to seven times in DI patients versus once per day in non-DI patients. Marked variations in daily sodium (Na) level were observed in the DI group with minimum of 122 to maximum 162, a median variation between maximum and minimum daily Na values of 6 mM in DI patients (range, 0–22) versus 1 mM in non-DI patients (range, 0–3). Seventeen courses required prolonged admission in the DI group (one in the non-DI), and the number of days of admission differed significantly between the two groups (median = ⩾2.1 days in DI patients). Despite vigilant monitoring, four patients had serious complications related to electrolyte imbalance (tremors and hyperreflexia with sodium level of 162, generalized seizure and agitation with sodium of 124, seizures with a sodium of 122, and significant tachycardia and hypotonia in the absence of sepsis requiring discontinuation of chemotherapy with a Na value of 126). Conclusions: The presence of DI is a risk factor for chemotherapy-related complications when cisplatin- and/or ifosfamide-based protocols are used. Despite careful electrolyte monitoring and DDAVP dose adjustment, significant variations in Na level occur that can be associated with clinical manifestations. The role of cisplatin and ifosfamide in the management of intracranial germ cell tumors should be carefully reviewed and guidelines for management of DI established. GCT 2. CHILDHOOD INTRACRANIAL GERM CELL TUMORS: EXPERIENCE IN A MULTIRACIAL ASIAN POPULATION OVER 18 YEARS Wan-Yee Teo,1 Ah-Moy Tan,1 Mei-Yoke Chan,1 Vk Sethi,2 and Wan-Tew Seow3; 1Department of Paediatric Subspecialties, Haemato-Oncology Service, KK Women's and Children's Hospital, Singapore, Singapore; 2Department of Radiation Oncology, National Cancer Centre, Singapore General Hospital, Singapore, Singapore; 3Department of Neurosurgery, KK Women's and Children's Hospital, Singapore, Singapore. Background: Incidence of primary intracranial germ cell tumors (ICGCTs) is higher in Asia compared to the West. ICGCTs account for 11.8% of childhood intracranial tumors in Singapore and 16.5% in Japan, but only 2% in the West. Objective: To analyze survival outcome of childhood ICGCTs in a multiracial Asian population treated in Singapore. Methods: Patients were retrieved from the Singapore Children's Cancer Registry. This is a retrospective study of 34 patients diagnosed with ICGCTs between January 1989 and January 2007 (18-year period). Data were collected up to January 2008 (period of 19 years). SPSS v13.0 software was used. For overall survival (OS), event of interest was death, whereas for event-free survival (EFS), event of interest was disease progression, relapse, or death. Craniospinal radiotherapy was delivered in two phases. In phase 1, radiotherapy doses of 30–36 Gy in 1.6–1.8 Gy per fraction, five fractions a week, was given to the whole brain. Phase 2 cranial field was a boost to the primary site with margin. In last 3 years, local radiotherapy included the ventricular system. Results: Median age at diagnosis was 12.1 years (range, 5.7–17.5 years); 53% were between 10 and 14 years. Majority (88.2% [30 of 34]) of patients were Chinese; 67.6% (23 of 34) were males. Majority (64.7% [22 of 34]) were germinomas, and 35.3% (12 of 34) were nongerminomatous germ cell tumor (NGGCT). Diagnosis was made on both tumor histology and evaluation of tumor markers. In patients with significant marker elevation, B-HCG >50 IU/liter, AFP ⩾25 ng/ml (serum/cerebrospinal fluid [CSF]), a histological evaluation was not necessary before starting therapy. Serum markers were measured in 82.3% (28 of 34) patients, but only 20 (58.8%) of these had CSF markers measured. For the germinoma group (n1 = 22), median follow-up was 5.9 years (range, 0–19 years) with three deaths. Eighteen cases received chemotherapy (seven cases treated according to SIOP 96 protocol, five JEB regimen, and three BEP regimen). Thirteen cases received chemoradiotherapy, three received surgery and RT, three chemotherapy and surgery, and three surgery alone. Five-year OS and EFS were 89.8% and 75.5%, respectively, while 10-year OS and EFS were 82.9% and 68.7%, respectively. Five cases (22.7%) relapsed, of which two died; 78.9% who are still alive had received chemotherapy while 66.7% of deaths did not receive chemotherapy as part of primary treatment. For NGGCT group (n2 = 12), median follow-up was 2.7 years (range, 0.5–9.6 years) with four deaths and one patient with pineal gland secreting germinoma who was lost to follow-up after he relapsed after chemotherapy and radiotherapy at 15.4 months and left for treatment overseas. All received chemotherapy (six cases treated according to SIOP 96 protocol, two JEB regimen, three BEP regimen, and one PEI); eight received chemoradiotherapy with surgery, two chemoradiotherapy, and two chemotherapy alone. Five-year OS and EFS were 66.7% and 58.3%, respectively. Six cases relapsed, median relapse-free survival was 8.8 years from diagnosis. Of six cases that relapsed, three died. One patient received transplant. Conclusions: Our center shows good results. It appears that the majority of survivors had received chemotherapy as part of primary treatment. Combined chemoradiotherapy is recommended to improve survival rate of ICGCT. Combined modality of chemoradiotherapy will decrease long-term neurological sequelae of radiotherapy in young children with ICGCT. GCT 3. GERMINOMA WITH BILATERAL FRONTAL LOBE INVOLVEMENT Tomoyuki Koga,1 Kazuhiko Mishima,2 Ryo Nishikawa,2 Masaaki Usui,3 and Masao Matsutani2; 1Department of Neurosurgery, University of Tokyo Hospital, Tokyo, Japan; 2Department of Neurosurgery and Neuro-Oncology, Saitama Medical University International Medical Center, Japan; 3Department of Neurosurgery, Toranomon Hospital, Japan. Central nervous system germinoma affecting the bilateral frontal lobes is rare. No case of germinoma extending to the frontal lobes in both sides has been reported previously. We encountered three patients with germinoma involving the bilateral frontal lobe parenchyma surrounding lateral ventricles. Tumors in these cases were pathologically diagnosed as germinoma by surgical specimens. Chemotherapy and radiotherapy were performed on these patients, and complete or partial remission was achieved. Case 1 was a 17-year-old male presenting with polydypsia, polyuria, and epilepsy attack. MRI revealed enhanced mass lesion in pineal region, pituitary stalk, and white matter beneath the wall of lateral ventricles. The lesion in the left frontal lobe contained cystic component. Obstructive hydrocephalus, which was improved by endoscopic third ventriculostomy performed simultaneously with open biopsy of the left frontal lesion, could be also seen. The lesion was diagnosed as pure germinoma, and complete remission was obtained by performing chemotherapy using carboplatin and etoposide and 24 Gy of extended ventricular irradiation. Case 2 was a 15-year-old male presenting with headache and vomiting. MRI showed enhanced lesion in pineal region and bilateral frontal lobe without enlargement of ventricular system. Lesions in the frontal lobes contained cysts as seen in the previous case. Open biopsy of the left frontal lesion was done, and this case was also diagnosed as pure germinoma. Chemotherapy using carboplatin and etoposide, which was followed by radiotherapy, yielded partial remission in this case. Case 3 was a 32-year-old male presenting with general convulsion. MRI showed hemorrhagic cysts in the bilateral frontal lobes and an enhanced mass in the suprasellar region. The specimen was obtained from the wall of the cyst in the right frontal lobe and was pathologically diagnosed as germinoma with STGC. Chemotherapy with ifosfamide, cisplatin, and etoposide and 30 Gy of craniospinal irradiation with 30 Gy boost radiation yielded complete remission. In these three cases, the lesions were distributed to brain parenchyma around the anterior horns of the lateral ventricles and pineal or suprasellar region, which seemed not to be continuous. It is notable that germ cell tumors could show such unique radiological presentation. Furthermore, it is interesting to consider whether this unique distribution resulted from dissemination or multicentric origin of the tumor. GCT 4. GROWING TERATOMA SYNDROME Cho Byung-Kyu1; 1Seoul National University, Seoul, South Korea. Growing teratoma syndrome (GTS) shows that tumors are growing even during chemoradiotherapy, so urgent surgical resection has to be performed to save lives. It is not well known why differentiating or maturing teratomatous lesions grow so rapidly during treatment. The aims of this study were to clarify the clinical characteristics, responses to chemotherapy and/or radiotherapy, pathologic changes with tumor markers, and outcomes of GTS. We experienced eight cases of GTS between January 1997 and July 2007. Retrospective analysis was performed. The mean age was 13.4 years (range, 6–25 years), with seven males and one female. Locations of the tumor were pineal in three, suprasellar in three, and basal ganglia in two. Primary pathology was imature teratoma in three (38%), mixed germ cell tumor in three, germinoma in one, and yolk sac tumor in one. Tumor marker studies showed elevated serum AFP in seven (median, 118 ng/ml; range, 13–12,080) and elevated beta-HCG in three (median, 399 mIU/ml; range, 56–1,350). Serum AFP value was higher than CSF in all cases. In contrast, beta-HCG value was higher in CSF than in serum. MRI showed hydrocephalus in all cases, and the mass was heterogeneously contrast-enhancing cystic and solid large tumor in general. Honeycomb appearance was characteristic finding of GTS. Two patients died of disease progression, and four patients were alive with no evidence of recurrence. Two patients were alive with tumor recurrence. Primary complete surgical excision should be reconsidered instead of primary chemoradiotherapy for the immature teratoma, which shows high incidence of GTS with poor response to the primary treatment. Early detection and complete surgical excision of GTS is crucial to avoid rapid clinical deterioration during chemoradiotherapy. Close surveillance of the treated GTS is necessary to detect the possible recurrent GTS. GCT 5. GROWING TERATOMA SYNDROME IN YOUNG CHILDREN WITH PINEAL SECRETING GERM-CELL TUMORS Sofia Nunes,1 Ana Azevedo,2 Duarte Salgado,3 Filomena Pereira,4 Ana Neto,4 and Mário Chagas4; 1Pediatric Neuro-Oncology Unit, Instituto Português de Oncologia, Lisboa, Portugal; 2Pediatric Neuro-Oncology Unit, Instituto Português de Oncologia de Lisboa, Lisboa, Portugal; 3Unidade de Neuro-Oncologia Pediátrica, Instituto Português de Oncologia, Portugal; 4Department of Child and Adolescent Oncology, Instituto Português de Oncologia de Lisboa, Portugal. Introduction: The growing teratoma syndrome was initially described in metastatic mixed germ-cell tumors of the testis. We found only six cases in the literature reporting this entity in primary intracranial nongerminomatous germ-cell tumors. It is defined as increase in tumor mass volume during or after chemotherapy for germ-cell tumor in the absence of tumor marker levels elevation. After surgical resection mature teratoma is found at histological analysis. We report two cases of growing teratoma syndrome in young children with pineal secreting germ-cells tumors treated with chemotherapy. Case reports: Two female patients, 15 and 3 months old, presented with volumous pineal secreting germ-cell tumors. The younger child underwent subtotal resection and the histological examination revealed an immature teratoma. They were treated with platinum-based chemotherapy. After four cycles the imaging studies showed tumor enlargement, with none or slight neurological deterioration and normal tumor marker levels. Gross total removals of the tumors were preformed, and the histological analysis disclosed mature teratoma. They are both in remission after 3 and 2.5 years of follow-up. Conclusion: To our knowledge, these are the first reported cases of intracranial growing teratoma syndrome in children <2 years of age. This is a very rare phenomenon, but the clinicians should be aware of its existence to be able to recognize and properly manage these patients. Complete surgical resection is the treatment of choice. GCT 6. LOCALIZED AND METASTATIC NONGERMINOMA TREATED ACCORDING TO THE SIOP CNS GCT 96 PROTOCOL: UPDATE ON RISK PROFILES AND OUTCOME Gabriele Calaminus,1 Didier Frappaz,2 Rolf-Dieter Kortmann,3 Maria Luisa Garré,4 Claire Alapetite,5 Umberto Ricardi,6 Frank Saran,7 and James Nicholson8; 1University of Muenster, Muenster, Germany; 2Oncology, Centre Léon Bérard, Lyon, France; 3Radiation Oncology, University of Leipzig, Germany; 4Genova, Italy; 5Radiooncology, Institute Curie, Paris, France; 6Radiooncology, University of Turin, Turin, Italy; 7London, UK; 8Department of Pediatric Oncology, Addenbrooke's Hospital, Cambridge, UK. Objective: The SIOP CNS GCT 96 protocol aimed to standardize diagnostics and treatment of intracranial nongerminomatous germ cell tumors (NGGCTs). Diagnosis was made by imaging and markers in serum and CSF (AFP and β-HCG). Only in cases of negative markers in both compartments was histological diagnosis necessary. After diagnosis patients received four courses of chemotherapy followed by radiotherapy tailored to the extent of disease. Patients and Treatment: Up to December 31, 2005, 130 protocol patients with NGGCT were registered. The age range was 0–29 years (median, 12 years), and 106 were boys. NGGCTs were localized in 102 (60 pineal, 28 suprasellar, 6 bifocal, 8 other), and 28 were metastatic. Patients with localized disease received four courses of cisplatin/etoposide/ifosfamide (PEI) followed by focal radiotherapy of 54 Gy. Patients with metastases received 4× PEI followed by 30 Gy craniospinal radiotherapy (CSI) and 24 Gy boosts to tumor and macroscopic metastatic sites of disease. Results: Progression-free survival (PFS) of patients with chemotherapy plus focal radiotherapy was 0.67% ± 0.06%, and of those with chemotherapy and CSI 0.72% ± 0.05% (median follow-up, 39 months for both groups). There were 25 relapses after chemotherapy plus focal radiotherapy (n = 102) including 17 local, two ventricular, one distant, and five combined. Two patients progressed on treatment and died, and one patient in complete remission committed suicide 5 years after therapy. Eight relapses were observed after CSI (n = 28), including two local, one distant, and five combined. Fifteen patients had an AFP ⩾1,000 ng/ml (serum and/or CSF), of whom nine relapsed (PFS 0.33% ± 0.13%). At the end of radiotherapy a residual tumor was found in 34 of the 130 patients; 16 of these patients relapsed (PFS 0.37% ± 0.12%). Conclusion: Two-thirds of patients with malignant NGGCT treated according to SIOP CNS GCT 96 can be cured. AFP ⩾1,000 ng/ml and residual disease are independent risk factors that indicate the need for treatment intensification in these subgroups. Supported in part by Deutsche Krebshilfe. GCT 7. MALIGNANT CNS GERM CELL TUMORS (CNS-GCT): SINGLE INSTITUTION RESULTS FOLLOWING THE GUIDELINE OF CNS-SIOP 96 PROTOCOL Daniel Alderete,1 Vicente Cuccia,2 Elsa Raslawski,3 Fabiana Lubienieki,4 Jaqueline Avalos Gomez,5 Pedro Zubizarreta,5 and Walter Cachavilano5; 1Hematooncology, Hospital Nacional de Pediatria JP Garrahan, Buenos Aires, Argentina; 2Neurosurgery, Hospital Garrahan, Buenos Aires, Argentina; 3Radiotherapy, Hospital Garrahan, Buenos Aires, Argentina; 4Pathology, Hospital Garrahan, Buenos Aires, Argentina; 5Hematooncology, Hospital Garrahan, Buenos Aires, Argentina. Objective: To evaluate the results of a protocol in children with CNS-GCT, treated according to CNS-SIOP 96 for secreting tumors (sGCT) and germinoma tumor (G). Patients and Methods: Between January 2000 and December 2006, 21 consecutive patients with CNS-GCT were registered at our institution. Patients with G were treated with two-course chemotherapy (CHT) consisting of carboplatin 600 mg/m2 day 1, etoposide 150 mg/m2 days 1–3 and 22–24, and ifosfamide 1.8 g/m2 days 22–26, after receiving focal radiotherapy (RT). Patients with sGCT received four courses of cisplatin 20 mg/m2 days 1–5, etoposide 100 mg/m2 days 1–5, and ifosfamide 1.5 g/m2 days 1–5; in addition, craniospinal RT tumor boost was applied. Patients were considered G with markers alpha-fetoprotein and human chorionic gonadotropin (AFP/HCG) <25 ng/ml and <50 IU/liter in serum/cerebrospinal fluid respectively and biopsy (bx)/resection. Results: The tumors were located in the suprasellar (S) region in seven patients and in the pineal region in six patients. Four patients had a double S-P location, and the other four patients had tumors in other locations (one spina cauda, two thalamic, and one frontal). Sixteen patients were G and five sGCT. Germinoma group: the median age was 154 months (range, 45–194 months); 10 patients were male, and six were female. Two patients were disseminated at diagnosis (dx) in the 3° and lateral ventricle (both patients received craniospinal RT after CHT). The diagnosis was obtained by tumor resection in nine patients, stereotactic bx in two, and endoscopy bx in five. Median follow-up (FU) is 40 months (range, 1–89 months). The 3-year event-free survival (EFS) is 59%, and the overall survival (OS) is 85.3%. Five patients in this group had events: two patients relapsed with sGCT-elevated AFP (one disseminated and one local); one patient relapsed intraventricle outside of radiation limit; one patient died from infection complication; and the other patient had acute nonlymphoblast leukemia. sGCT group: the median age was 136 months (range, 32–178 months). Three patients were male, and two were female. Only one patient was dx by markers because other the four patients have a very large tumors. The median FU is 50 months (range, 10–84 months). The 3-year EFS is 60%, and the OS is 75%. Two patients, both with elevated AFP ⩾ 3,000 ng/ml at dx were refractory to the CHT and RT. Conclusion: We can not obtain results similar to another report with same protocol in the germinoma group. sGCT with AFP ⩾ 3,000 ng/ml probably needs another strategy like chemoradiotherapy. GCT 8. METACHRONOUS INTRASELLAR MIXED GERM CELL TUMOR OCCURRING 4 YEARS AFTER A MATURE TERATOMA OF THE PINEAL GLAND Antonello Podda,1 Macello Maciel,2 Noelina Lewis,2 and Julio Barredo2; 1Pediatric Hematology-Oncology, University of Miami, Miami, FL, USA; 2Pediatric Hematology-Oncology, University of Miami, FL, USA. A 15-year-old boy from Ecuador presented in December 2004 at the University of Miami School of Medicine with headaches and left VI cranial nerve palsy caused by a mixed germ cell intrasellar tumor occurring 4 years after total resection of a mature teratoma of the pineal region. At his first diagnosis in December 2000, the patient presented with acute onset of headaches and occasional vomiting. An MRI showed a posterior third ventricular enhancing and multiloculated cystic lesion of 1.5 × 1.5 × 1.8 cm in diameter with obstructive hydrocephalus. Tumor markers beta-human chorionic gonadotropin (beta-HCG) and alpha-fetoprotein (AFP) were negative. After complete resection of the mass through a paraoccipital craniotomy that revealed a diagnosis of mature teratoma, the child was followed up semiannually with MRI scans. The patient then presented 4 years later, in December 2004, with mild recurrent headaches and sudden onset diplopia with left esotropia from abducent nerve palsy. An MRI revealed an intrasellar tumor with minimal suprasellar extension and left cavernous sinus invasion. The adolescent underwent a trans-sphenoidal subtotal resection of the mass and the histological examination revealed a mixed germ cell tumor with a predominant component of embryonal cell carcinoma. Laboratory examination revealed an elevated serum level of beta-HCG (555 mIU/ml) and an elevated serum level of AFP (26 ng/ml). As adjuvant treatment, the patient received a chemotherapy regiment based on three cycles of carboplatin and etoposide alternating with three cycles of ifosfamide and etoposide followed by radiation therapy (54 Gy to the tumor bed and 36 Gy craniospinal irradiation). The adolescent continues presently to remain in complete remission. This patient developed two germ cell tumors (GCT) of different histological types, in two different sites, with a long interval between occurrences. The second tumor was therefore considered to be a de novo metachronous germ cell tumor. Metachronous germ cell tumors in the CNS are an exceptional occurrence; only seven such cases have been reported so far in the literature. In all cases the initial tumor was a mature teratoma mostly of the pineal area, as in our case. The oncogenetic mechanism of metachronous GCT in not known; it is speculated that these tumors originate from the transformation of two primordial germ cell groups that have strayed into the midline brain structures, including the pineal area and the neurohypophyseal region. On the other hand, a germline genetic predisposition of the patient, like a mutation of the INK4a tumor suppressor gene (detected in up to 71% of analyzed GCT) or others genetic abnormalities, could be speculated to be at the origin of GCT that develop metachronously in the CNS. GCT 9. MICRO-RNA PROFILING SUGGESTS INTRACRANIAL MALIGNANT GERM CELL TUMORS (MGCTS) ARE BIOLOGICALLY DISTINCT FROM THEIR EXTRACRANIAL COUNTERPARTS Matthew Murray,1 Roger Palmer,1 Balaji Muralidhar,1 Claire Thornton,2 James Nicholson,3 and Nicholas Coleman1; 1Medical Research Council Cancer Cell Unit, Cambridge, UK; 2Department of Pathology, Royal Group of Hospitals, Belfast, UK; 3Department of Pediatric Oncology, Addenbrooke's Hospital, Cambridge, UK. Introduction: Pediatric malignant germ cell tumors (MGCTs) occur at numerous midline anatomical sites, including the gonads and CNS. Despite their heterogeneous nature they are considered to share a common origin from primordial germ cells (PGCs), resulting in the “germ cell theory” of tumorigenesis. Recently, endogenous CNS neural progenitor cells have been proposed as the cell of origin of intracranial MGCTs, termed the “brain cell theory” (Scotting. Neuropathol Appl Neurobiol. 2006;32). Micro-RNAs (miRNAs) are short, non–protein-coding RNAs that act posttranscriptionally as negative regulators of gene expression and are reported to be diagnostic and prognostic markers in certain cancers. Additionally, miRNAs have been shown to distinguish the developmental lineage and differentiation status of tumors more accurately than expression profiling of protein-coding genes (Lu et al. Nature. 2005;435:834). Previously, we have demonstrated that such protein-coding gene profiling segregates MGCTs on the basis of histological subtype rather than anatomical site. By performing miRNA profiling on a cohort of MGCTs we aimed to test the hypothesis that miRNA expression may better classify these tumors. Methods: Following histological verification and nucleic acid extraction, total RNA quality and integrity from 48 MGCTs and controls was determined by spectrophotometry and microelectrophoresis. Of these, 25 samples were germinomas (three intracranial, 10 extracranial) or yolk sac tumors (YSTs) (one intracranial, 11 extracranial). miRNA profiling was performed using the Exiqon miRCURYTM LNA microarray platform, covering 585 known human miRNAs, and data analysis was undertaken using DNA-chip analyzer (dChip) software. Results: Unsupervised hierarchical clustering demonstrated that MGCTs largely clustered according to histological subtype. However, three of the four intracranial tumors did not associate with the main cluster for their particular histology. Supervised hierarchical clustering of the three intracranial germinomas, compared to the 10 extracranial germinomas, generated a list of eight miRNAs most significantly differentially expressed between the two groups (p < 0.001, one-way ANOVA). Of these, miR-451 (p < 0.00004), miR-302c* (p < 0.0001), and miR-491-3p (p < 0.0002) were most discriminatory. When compared with the 11 extracranial YSTs, the intracranial YST demonstrated relative overexpression of miR-515-5p and miR-520g (5.0- and 3.8-fold change, respectively). In contrast, extracranial MGCTs of the same histological subtype were indistinguishable from one another, based upon anatomical site. Confirmation of these results with Taqman quantitative polymerase chain reaction and miRNA fluorescent insitu hybridization probes is currently being performed. Conclusions: The differential miRNA profiles identified suggests that intracranial MGCTs are biologically distinct from their extracranial counterparts. This lends credence to the recent “brain cell theory” of tumorigenesis, where intracranial MGCTs arise from endogenous CNS neural progenitor cells rather than PGCs. Furthermore, it is not possible, on the basis of miRNA profiles, to distinguish extracranial tumors of identical histology, consistent with the “germ cell theory” of tumor development. These novel findings suggest new approaches to the study of intracranial MGCTs are warranted. Moreover, the miRNAs identified may represent targets for development of new therapeutic agents. GCT 10. NEUROCOGNITIVE OUTCOMES IN PEDIATRIC PATIENTS WITH CNS GERMINOMA TREATED WITH CHEMOTHERAPY PRIOR TO IRRADIATION Sharon O'Neil,1 Jonathan Finlay,2 Jaye Azoff,3 Richard Sposto,4 Stephen Sands,5 Shulamit Steinlauf,3 Aarti Nasta,3 Mark Krieger,1 Gordon Mccomb,6 Arthur Olch,7 and Lavey Robert4; 1Childrens Hospital of Los Angeles, Los Angeles, CA, USA; 2Los Angeles, CA, USA; 3CA, USA; 4Childrens Hospital Los Angeles, CA, USA; 5New York, NY, USA; 6Neurosurgery, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 7Radiation Oncology, Childrens Hospital Los Angeles, Los Angeles, CA, USA. Study Purpose: Evaluation of neurocognitive outcomes following a combined chemotherapy and reduced-dose irradiation strategy for primary CNS germinoma. Methods: Neuropsychological evaluations including measures of verbal and nonverbal intellectual functioning, working memory, processing speed, verbal and nonverbal memory, and executive functioning were analyzed for 25 patients with histologically diagnosed pure CNS germinoma, evaluated at a mean of 2.8 years from diagnosis. Six patients received two to four cycles of carboplatin/etoposide chemotherapy at 3–4 week intervals, followed by focal irradiation at a dose of 30 Gy. Nineteen patients received four cycles of the same chemotherapy, followed by ventricular field irradiation to 22.5–24 Gy with simultaneous integrated boost to the primary site(s), to a focal dose of 30 Gy; t-tests were performed for ventricular field versus no ventricular field irradiation, tumor location (pineal vs. suprasellar vs. other), age at diagnosis (8 patients <12 years; 17 patients >12 years), and English as primary or secondary language. Results: No significant differences were found by treatment type or tumor location. The 25 patients performed as a group in the average range on all neurocognitive measures administered when compared to a nonmedical normative group. Although within the average range, processing speed scores were significantly lower than verbal and nonverbal intellectual functioning scores and working memory scores overall. Patients <12 years of age at diagnosis performed significantly lower than patients >12 years on measures of verbal and nonverbal intellectual functioning, although still within the average range. Patients with English as a second language, despite all patients being English dominant, performed significantly lower than patients with English as a first language on measures of verbal intellectual functioning, though still in the average range. Conclusions: For pediatric patients with newly diagnosed CNS germinoma, modest chemotherapy followed by either reduced-dose ventricular field with reduced-dose boost irradiation or focal field irradiation alone at the same dose, are associated with overall preservation of neurocognitive functioning. Weakness in processing speed, relative to verbal and nonverbal intellectual functioning, is a potential area for remediation/educational planning to promote educational achievement in these patients. English language psychometric measures may underestimate verbal intelligence for bilingual patients, even when English is the dominant language. GCT 11. OUTCOME OF LOCALIZED AND METASTATIC GERMINOMA TREATED ACCORDING TO SIOP CNS GCT 96 Gabriele Calaminus,1 Claire Alapetite,2 Didier Frappaz,3 Rolf-Dieter Kortmann,4 Maria Luisa Garré,5 Frank Saran,6 Umberto Ricardi,7 and James Nicholson8; 1University of Munster, Munster, Germany; 2Radiooncology, Institute Curie, Paris, France; 3Oncology, Centre Léon Bérard, Lyon, France; 4Radiation Oncology, University of Leipzig, Leipzig, Germany; 5Genova, Italy; 6Sutton, UK; 7Radiooncology, University of Turin, Turin, Italy; 8Department of Pediatric Oncology, Addenbrooke's Hospital, Cambridge, UK. Objective: The SIOP CNS GCT 96 protocol aimed to standardize diagnostic and treatment for germinoma on an international multicenter basis, as part of a study of all intracranial germ cell tumor subtypes. Diagnosis of germinoma was made by imaging and biopsy, in the presence of negative markers in serum and CSF (AFP and β-HCG), measured in order to exclude nongerminomatous (secreting) elements. After diagnosis of germinoma and no sign of dissemination (negative CSF, negative imaging), two treatment options based on national preference were offered: patients either received two courses of carboplatin/etoposide alternating with two of etoposide/ifosfamide, followed by focal irradiation with 40 Gy, or radiotherapy (RT) alone at a dose of 24 Gy to the craniospinal axis and 16 Gy tumor boost. In cases of metastatic disease, patients received 24 Gy craniospinal RT with 16 Gy boost to the primary site and metastases. Patients: Up to December 31, 2005, 223 protocol patients with germinoma were registered, of which 165 were boys, 0–42 years of age (median, 14 years); 179 were localized (87 pineal, 53 suprasellar, 31 bifocal, and eight other sites), and 44 metastatic. Results: Event-free survival (EFS) of patients with localized disease and chemotherapy + focal radiotherapy (n = 64) was 0.85% ± 0.05% (median follow-up, 40 months), and overall survival (OS) 0.94% ± 0.03%. Events included eight relapses (three local, two local and ventricular, two ventricular, and one spinal), and one fatal case of meningitis in a girl in complete remission (CR) 4 years after treatment. EFS of patients with localized disease and craniospinal radiotherapy (n = 115) was 0.96% ± 0.02%, and OS 0.97% ± 0.03%. Events included four relapses, all at the primary site, one death 5 years after diagnosis in CR following a neurosurgical intervention, one second malignancy, and one death in CR from an endocrine decompensation 3 years after treatment. EFS in metastatic patients was 0.98% ± 0.02% (median follow-up, 44 months); one patient with diabetes insipidus died following metabolic decompensation during radiotherapy. Conclusion: The survival of CNS germinoma is excellent. Craniospinal radiotherapy effectively controls metastatic disease in germinoma. Spinal RT can be omitted in localized germinoma given chemotherapy. Focal RT after chemotherapy is insufficient to prevent recurrences in the ventricles, which need to be included in an extended radiotherapy field. Supported in part by Deutsche Krebshilfe. GCT 12. THERAPEUTIC ADVANCEMENT FOR PEDIATRIC GERM CELL TUMORS Shingo Takano,1 Satoru Osuka,1 Ai Muroi,1 Ryota Mashiko,1 Tetsuya Yamamoto,1 and Akira Matsumura1; 1University of Tsukuba, Tsukuba City, Ibaraki, Japan. Purposes: Intracranial germ cell tumors are composed of various degrees of malignancies, therefore treatment strategy is important. Therapeutic advancement for pediatric germ cell tumors is retrospectively investigated. Materials and Methods: Germ cell tumors treated in Tsukuba University since 1980 were 50 cases. Among them, 23 pediatric cases (<15 years of age, 15 males and 8 females) were retrospectively examined for treatment strategy. There were 17 cases of germinoma and 6 cases of nongerminomatous tumor (two immature teratomas, one yolk sac tumor, one choriocarcinoma, one malignant germ cell tumor, and one teratoma). Tumors were located in pineal lesion (11), neurohypophysial lesion (nine), basal ganglia lesion (two), and frontal lobe (one). Each case was classified into a subgroup based on treatment strategy. Germinoma: (1) G1 group (∼1994, n = 7, follow-up 147 months): histology not confirmed, whole brain (51.4 Gy) and whole spine (30.6 Gy) irradiation; (2) G2 group (∼2002, n = 5, follow-up 91 months): histology confirmed, chemotherapy (cisplatin + etoposide) and whole-ventricle (30.6 Gy) + local (19.8 Gy) irradiation; (3) G3 group (∼2003, n = 5, follow-up 30 months): histology confirmed (endoscopic biopsy and third ventriculostomy for pineal lesion tumors), chemotherapy (carboplatin + etoposide) and whole ventricle (24 Gy) + local (16 Gy) irradiation. Nongerminomatous tumor: (1) NG1 group (∼2002, n = 3): tumor removal with craniotomy followed by chemoradiotherapy; (2) NG2 group (∼2003, n = 3): diagnosed by tumor marker or biopsy followed by chemoradiotherapy and salvage surgery if needed. Results: Germinoma—recurrence was observed in only one case (34 months) in G2 group. Death was observed in only one case located in basal ganglia (89 months) in G1 group. Hormonal replacement for neurohypophysial tumors (n = 7) is needed for all cases except for one case in G1 group. KPS in each case was 100% except for two cases in G1 group (70% with lung fibrosis and 0% death). Nongerminomatous tumor—median survival time in NG1 group was 34 months. In NG2 group, recurrence-free time was >36 months. Conclusion: (1) Pediatric germinomas could be well treated with diminished dose of radiation, whole ventricle 24 and local 16 Gy combined with chemotherapy. (2) Neoadjuvant chemoradiotheraphy before excision of residual tumors dramatically improved the prognosis of the pediatric patients with nongerminomatous germ cell tumors. GCT 13. TREATMEMT OF INTRACRANIAL GERM CELL TUMORS: THE SECOND PHASE II STUDY OF JAPANESE GCT STUDY GROUP Masao Matsutani1; 1Neuro-Oncology, Saitama International Medical Center, Saitama Medical University, Hidaka, Saitama, Japan. We conducted a phase II study for intracranial germ cell tumors from 1995 to 2003 and evaluated 228 patients with the median follow-up period of 6.3 years. After analyzing the results, we will start the second phase II study for intracranial germ cell tumors in this year. (1) 123 patients with germinoma were generally treated by CARE (carboplatin 450 mg/m2 on day 1, etoposide 150 mg/m2 on days 1–3) followed by local irradiation (24 Gy). The 5-year overall survival rate was 98%, but 16 patients (13%) showed recurrent tumors. Analysis of recurrent patients indicated a critical factor of the radiation volume. In patients with tumors around the third ventricle, 75% of recurrences developed in the ventricle, and a half of those in the basal ganglia were outside ventricles. In the next protocol, we will treat germinoma patients around the third ventricle with the combination of CARE and 24 Gy of whole ventricular irradiation and those in the basal ganglia with the combination of CARE and whole brain irradiation. (2) 38 patients with HCG or HCG-beta secreting germinomas were treated in the same strategy as the intermediate prognosis group because of their high recurrent rate. In spite of five recurrences, the 5-year OSR was 100%. There were no statistical differences in serum HCG or HCG-beta titers between recurrent and nonrecurrent patients. Analysis of recurrent patients, the radiation volume was a critical factor for recurrence as in pure germinomas. We found abnormally high titer of HCG-beta in the cerebrospinal fluid in all patients with germinomas. We will treat all types of germinoma without any nongerminoma components with a same regimen consisting of three cycles of CARE and whole ventricular irradiation with 24 Gy in the next step. (3) In 40 patients in the intermediate prognosis group were treated by CARE followed by local irradiation (50 Gy). They received additional chemotherapy five times. The 5-year overall survival rate was 97%. The recurrent rate was significantly different between disease-free patients (4.8%) and those with residual tumors after the initial treatment (31.6%). In CR patients at the end of the initial treatment, there was no difference in the recurrent rate between groups with fewer than four cycles and groups with more than five cycles. There was no indicative correlation among radiation volumes, histology, and recurrence rate. In the next step, we will observe CR patients without delivering chemotherapy after the initial treatment. But we deliver CARE chemotherapy for non-CR patients same as in the present regimen. We recommend salvage surgery for non-CR patients. (4) In 27 patients with poor prognostic group, the 5-year overall and progression-free survival rate was 60%, respectively, which is better than our expected 3-year survival rate of 50%. As the number of patients is too small, we could not find any risk factors for recurrence. However, we can say that obtaining CR or near CR will be necessary for good control of disease. GCT 14. TREATMENT OF CNS GERMINOMA BY CHEMORADIATION Chen Kan Tseng,1 Tang Her Jaing,2 Ping Ching Pai,3 and Shinn-Yn Lin4; 1Department of Radiation Oncology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan; 2Department of Pediatric Hemato-Oncology, Chang Gung Children Hospital, Taiwan; 3Department of Radiation Oncology, Chang Gung Memorial Hospital, Taiwan; 4Department of Radiation Oncology, Chang Gung Memorial Hospital, Taoyuan, Taiwan. Between January 2002 and June 2007, 17 patients younger than 20 years old were diagnosed with primary CNS germinoma in our hospital: 15 by histology, 1 by tumor marker of beta-HCG, and 1 by therapeutic try. Of these, 15 are males and 2 are females with a median age of 14.6 years (range, 7.6–19.6 months). Pretreatment workup by brain MRI (15) or CT (two) showed 10 pineal tumors, six suprasellar, two basal ganglion, and three at other periventricular areas; 14 showed only one tumor focus, but three have multifoci tumors. All patients had spinal MRI workup, and only one got positive finding; five with additional CSF cytological examinations were negative. Two patients had elevated beta-HCG at diagnosis. In order to reduce the long-term complication from radiotherapy, the treatment design in our pilot study consisted of two cycles of CDDP, VP-16–based chemotherapy, and 2,340 cGy low-dose radiotherapy to whole brain or whole ventricle. Due to five patients' refusal to receive chemotherapy, there were actually 12 patients enrolled in this study. The median time of follow-up for these patients is 32 months (range, 6–70 months). Eight of 12 total patients completed whole treatment as scheduled; four others did not. The first enrolled patient did not qualify for the additional four cycles of postradiation chemotherapy. The second patient was treated without histological proof of germinoma, therefore, radiotherapy was used first as therapeutic try; the volume and dose adhered to the treatment protocol, witnessing the brisk tumor response after radiotherapy favoring germinoma, followed by four cycles of chemotherapy. The third patient, the one with spinal seeding lesion, received one course of chemotherapy and acute hepatitis happened soon after that, so we decided to withdraw further chemotherapy and shift the treatment to craniospinal radiotherapy for tumor control. The last patient received whole ventricular radiotherapy (2,340 cGy) first, followed by chemotherapy; having an aversion to the side effects of chemotherapy, this patient refused to go on second-course chemotherapy. Even though there were some variations in the treatment received, all 12 patients survived without failure in the brain, spine, or other distant sites, and only one patient developed new complication of persistent hypopituitarism 8 months after treatment. In summary, the short courses of chemotherapy combined with low-dose whole brain or whole ventricular radiotherapy is feasible in our small pilot study and has comparable 3-year disease-free and overall survival as conventional treatments. (See GCT 14: Table 1, p. 516.) GCT 14: Table 1. Characteristics of chemoradiation-treated patients No. . Gender . Age (Years) . Tumor(s) . RT Volume . RT Dose (cGy) . C/T Rx . Induction C/T . Adjuvant C/T . Status . Survival (Months) . 1 M 9.2 PN WB 2,340 PE ×2 ×4 NED 70 2 M 19.0 PN WB 2,340 PEB ×2 0 NED 62 3 F 10.6 SS WV 2,340 PE 0 ×4 NED 48 4 M 17.3 SS WV 2,340 PEB ×2 0 NED 46 5 M 13.7 PN WV 2,340 PE ×2 0 NED 43 6 M 15.0 SS WV 3,060 PE ×2 0 NED 36 7 M 18.6 Seeding CSI + TB 3,600 + 1,400 PEB ×1 0 NED 34 12 M 14.7 PN WB 2,340 PE ×2 0 NED 19 13 M 12.2 PV WV + TB 2,340 + 1,620 PE 0 ×1 NED 20 15 F 14.6 SS WV 2,340 PE ×2 0 NED 13 16 M 14.8 PN + PV WB 2,340 PE ×2 0 NED 9 17 M 19.6 PN + SS WV 2,340 PE ×2 0 NED 6 No. . Gender . Age (Years) . Tumor(s) . RT Volume . RT Dose (cGy) . C/T Rx . Induction C/T . Adjuvant C/T . Status . Survival (Months) . 1 M 9.2 PN WB 2,340 PE ×2 ×4 NED 70 2 M 19.0 PN WB 2,340 PEB ×2 0 NED 62 3 F 10.6 SS WV 2,340 PE 0 ×4 NED 48 4 M 17.3 SS WV 2,340 PEB ×2 0 NED 46 5 M 13.7 PN WV 2,340 PE ×2 0 NED 43 6 M 15.0 SS WV 3,060 PE ×2 0 NED 36 7 M 18.6 Seeding CSI + TB 3,600 + 1,400 PEB ×1 0 NED 34 12 M 14.7 PN WB 2,340 PE ×2 0 NED 19 13 M 12.2 PV WV + TB 2,340 + 1,620 PE 0 ×1 NED 20 15 F 14.6 SS WV 2,340 PE ×2 0 NED 13 16 M 14.8 PN + PV WB 2,340 PE ×2 0 NED 9 17 M 19.6 PN + SS WV 2,340 PE ×2 0 NED 6 Open in new tab GCT 14: Table 1. Characteristics of chemoradiation-treated patients No. . Gender . Age (Years) . Tumor(s) . RT Volume . RT Dose (cGy) . C/T Rx . Induction C/T . Adjuvant C/T . Status . Survival (Months) . 1 M 9.2 PN WB 2,340 PE ×2 ×4 NED 70 2 M 19.0 PN WB 2,340 PEB ×2 0 NED 62 3 F 10.6 SS WV 2,340 PE 0 ×4 NED 48 4 M 17.3 SS WV 2,340 PEB ×2 0 NED 46 5 M 13.7 PN WV 2,340 PE ×2 0 NED 43 6 M 15.0 SS WV 3,060 PE ×2 0 NED 36 7 M 18.6 Seeding CSI + TB 3,600 + 1,400 PEB ×1 0 NED 34 12 M 14.7 PN WB 2,340 PE ×2 0 NED 19 13 M 12.2 PV WV + TB 2,340 + 1,620 PE 0 ×1 NED 20 15 F 14.6 SS WV 2,340 PE ×2 0 NED 13 16 M 14.8 PN + PV WB 2,340 PE ×2 0 NED 9 17 M 19.6 PN + SS WV 2,340 PE ×2 0 NED 6 No. . Gender . Age (Years) . Tumor(s) . RT Volume . RT Dose (cGy) . C/T Rx . Induction C/T . Adjuvant C/T . Status . Survival (Months) . 1 M 9.2 PN WB 2,340 PE ×2 ×4 NED 70 2 M 19.0 PN WB 2,340 PEB ×2 0 NED 62 3 F 10.6 SS WV 2,340 PE 0 ×4 NED 48 4 M 17.3 SS WV 2,340 PEB ×2 0 NED 46 5 M 13.7 PN WV 2,340 PE ×2 0 NED 43 6 M 15.0 SS WV 3,060 PE ×2 0 NED 36 7 M 18.6 Seeding CSI + TB 3,600 + 1,400 PEB ×1 0 NED 34 12 M 14.7 PN WB 2,340 PE ×2 0 NED 19 13 M 12.2 PV WV + TB 2,340 + 1,620 PE 0 ×1 NED 20 15 F 14.6 SS WV 2,340 PE ×2 0 NED 13 16 M 14.8 PN + PV WB 2,340 PE ×2 0 NED 9 17 M 19.6 PN + SS WV 2,340 PE ×2 0 NED 6 Open in new tab GCT 15. TREATMENT OF PRIMARY CNS GERMINOMATOUS GERM CELL TUMORS (GCT) WITH CHEMOTHERAPY PRIOR TO REDUCED-DOSE VENTRICULAR FIELD IRRADIATION: THE CHILDRENS HOSPITAL LOS ANGELES EXPERIENCE 2003–2007 Jonathan Finlay,1 Mark Krieger,2 Arti Nasta,1 Ignacio Gonzalez-Gomez,3 Rima Jubran,1 Anat Erdreich-Epstein,1 Araz Marachelian,1 Girish Dhall,1 Gordon Mccomb,2 Arthur Olch,4 Barbara Britt,1 Richard Sposto,1 and Robert Lavey4; 1Oncology, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 2Neurosurgery, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 3Pathology, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 4Radiation Oncology, Childrens Hospital Los Angeles, Los Angeles, CA, USA. Study Purpose: Evaluation of a uniform treatment strategy for newly diagnosed primary CNS germinomas. Methods: Since October 2003, 20 patients at Childrens Hospital Los Angeles (CHLA) with histologically diagnosed pure germinomas (n = 19) or germinomas with mature components (n = 1) received four cycles of carboplatin (300 mg/m2 days 1 and 2) and etoposide (150 mg/m2 days 1, 2, and 3) at 3-week intervals, followed by ventricular field irradiation to 22.4–24.0 Gy with simultaneous integrated boost to the primary site(s), to a focal dose of 30 Gy in 15 fractions. Mean age at diagnosis was 15.5 years. Fifteen patients were males. Primary tumor locations were suprasellar (n = 6), pineal (n = 11), basal ganglia (n = 2), and cerebellar (n = 1). No patient had metastases at diagnosis. Elevated HCG-beta levels (>50 mIU/ml) were documented in the serum (2 of 20) or CSF (4 of 20) at diagnosis. No patient (of 20 tested) had serum AFP elevations. One patient (of 18 tested) had CSF AFP elevated at 2.9 ng/ml. Minimal endoscopic biopsies were obtained in 12 patients, partial or gross total resections in eight. Second-look surgery was advocated for patients with radiographic residual following chemotherapy; this was undertaken in two patients, revealing either scar tissue or mature teratoma. All but one remaining patient achieved a complete or near-complete radiographic response to chemotherapy; a single patient with the “Growing Teratoma Syndrome” after one cycle of chemotherapy underwent gross total resection of a mature teratoma without residual germinoma, and then proceeded directly to irradiation. Results: All but two patients continue without evidence of residual or recurrent tumor, at a median follow-up of 40 months from diagnosis. One patient, with elevated CSF AFP at diagnosis, developed radiographic recurrence with AFP and HCG-beta elevations 18 months from diagnosis. A second patient, with serum and CSF HCG-beta of 323 mIU/ml and 101 mIU/ml at diagnosis, achieved a rapid complete response to the induction chemotherapy, but promptly recurred prior to irradiation both radiographically and with rapidly and markedly rising HCG-beta, consistent with choriocarcinoma. The EFS and OS for all 20 patients are 89.5% and 100%. Conclusions: Modest chemotherapy followed by reduced-dose ventricular field and boost irradiation produces outstanding EFS for patients with unequivocal diagnoses of CNS germinoma. Patients with even minimal AFP elevations, despite biopsy of pure germinoma, require more intensive regimens for nongerminomatous GCT. More representative diagnostic tissue will be required to determine which patients with modest elevations of HCG-beta >50 mIU/mL are truly pure germinomas or else patients with mixed malignant GCT. While the latter clearly require more intensive therapy, the former are at risk of being needlessly assigned and treated with more intensive chemotherapy and irradiation regimens. The risks of more radical surgical intervention will need to be carefully weighed against the risks of long-term morbidity of more intensive chemotherapy and irradiation and against the risks of undertreatment, as in our CHLA experience. HIGH-DOSE CHEMOTHERAPY HDCT 1. ANZCCSG BABYBRAIN 99: INTENSIFIED SYSTEMIC CHEMOTHERAPY, SECOND LOOK SURGERY, AND INVOLVED FIELD RADIATION IN YOUNG CHILDREN WITH CNS MALIGNANCY David Ashley,1 Pratiti Bandopadhayay,2 Maria Kirby,3 Michael Sullivan,4 Jennifer Houlihan,5 Richard Cohn,6 and Timothy Hassall7; 1Royal Children's Hospital, Murdoch Childrens Research Institute, Parkville, Victoria, Australia; 2Royal Children's Hospital, Melbourne; Murdoch Childrens Research Institute, Melbourne, Victoria, Australia; 3Womens and Childrens Hospital Adelaide, South Australia, Australia; 4Christchurch Hospital, New Zealand; 5Children's Cancer Centre, Royal Children's Hospital, Melbourne, Victoria, Australia; 6Sydney Children's Hospital, New South Wales, Australia; 7Royal Children's Hospital, Queensland, Queensland, Australia. Background: The prognosis for young children with brain tumors has been poor, and survivors often have long-term cognitive deficits. Recent studies have suggested that intensification of chemotherapy may offer promising results. ANZCCSG BabyBrain99 is a recently completed trial of intensive systemic chemotherapy with dual stem cell–supported treatment, second-look surgery, and involved field radiation for children <4 years of age with malignant CNS tumors. Methods: Following primary resection, treatment included two courses of chemotherapy with cisplatin and oral etoposide, a third course of mobilizing chemotherapy (vincristine, etoposide, and cyclophosphamide) with stem cell harvest, and a fourth intensive stem cell–supported chemotherapy with high-dose cyclophosphamide, etoposide, and vincristine. At the completion of this “induction” therapy children were then evaluated for the role of second resection prior to proceeding to a second high-dose stem cell–supported consolidation therapy in the form of melphalan and carboplatin. Patients then received involved field radiation therapy. Primary outcome measures were aimed to measure feasibility and toxicity, response rates to induction, and 5-year event-free survival. Results: Thirty-three children <4 years of age (median age, 20.4 months) with high-grade or malignant CNS tumors received treatment according to the study. Histological diagnosis included medulloblastoma (27%), ependymoma (18%), atypical teratoid rhabdoid tumor (18%), glioma (18%), primitive neuroectodermal tumor (9%), and others. Nine percent of children had metastatic disease at diagnosis, with either spinal metastasis or malignant cells in cerebrospinal fluid. Of the 33 children enrolled, 19 children completed treatment including irradiation. At the end of induction therapy the event-free survival was 70% (54%–86%); 51% of children had a complete response, 15% of children had stable disease, and 3% of children had a partial response. There was one treatment-related death of overwhelming adenovirus infection following course 4 of chemotherapy. Three children underwent second resection prior to consolidation therapy. Five-year overall survival was 40% (22%–56%) and event-free survival was 33% (17%–50%). Chemotherapy was generally well tolerated. In particular there were 22 courses of stem cell–supported carboplatin and melphalan consolidation therapy administered. Eighty-six percent of these children had grade 3 or 4 bone marrow toxicity, and there were 12 admissions with either febrile neutropenia or sepsis, however there were no treatment-related deaths during this phase of therapy. Conclusions: This study demonstrates that intensive systemic chemotherapy with dual stem cell–supported treatment can be safely administered to children with CNS tumors and may be incorporated into future studies. HDCT 2. HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANT (HDC/AHSCT) IN CHILDREN WITH RECURRENT MEDULLOBLASTOMA OR SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL TUMORS (MB/ST-PNET) Anna Butturini,1 Mary Jacob,2 Araz Marachelian,2 and Jonathan Finlay2; 1Childrens Hospital Los Angeles, Los Angeles, CA, USA; 2CA, USA. HDC/AHSCT as a part of the initial therapy is an effective treatment in young children with MB/ST-PNET. Its role after recurrence is controversial. At Childrens Hospital Los Angeles, 12 children with MB and 5 with ST-PNET received HDC/AHSCT after recurrence from 1992 to 2006. Six were female. Ten were Caucasian and seven Hispanic. Median age at diagnosis was 3.8 (range, 1.1–15.2) years. Nine of the 17 patients received radiotherapy as part of the initial therapy. HDC/AHSCT was performed at the time of the first recurrence in 15 patients and later in two, at a median age of 7 (1.7–18) years. Recurrences were within the CNS in 15 patients and in bone and/or bone marrow in two. Conditioning regimens included thiotepa and carboplatin: 12 patients received a single cycle of high-dose chemotherapy and five multiple cycles. Bone marrow or blood-derived AHSC were given in eight patients each; one patient received graft of both origins. Nine patients received radiotherapy after transplants. Five patients (29%) died of toxic complications within 100 days posttransplant; one of them had already relapsed. All but one toxic deaths occurred in children who had received craniospinal irradiation. An additional five patients had posttransplant disease recurrence; four of them died. The probabilities of survival and event-free survival 3 years after transplant were 49% ± 12% and 39% ± 12%. Males' sex (p = 0.01), Hispanic race (p = 0.02), localized disease at diagnosis (p = 0.01), and no radiotherapy in the initial treatment (p = 0.044) predicted improved survival. Recurrence at the primary sites (p = 0.08) and the use of radiotherapy after transplant (p = 0.07) had borderline effects; in contrast no transplant-related variable (single vs. multiple cycles of high-dose therapy or origin of graft) had effect on outcome. The limited number of patients precludes multivariate analyses, however, most of the variables associated with survival were more common in children initially treated without radiotherapy. In particular, patients who did not receive initial radiotherapy were more likely younger (p = 0.002), Hispanic (p = 0.004), had localized disease at diagnosis (p = 0.04), and, as a trend, relapsed in the primary site (p = 0.07) and received radiotherapy after relapse (p = 0.2). The probability of surviving 3 years after transplant was 75% ± 15% versus 26% ± 15% in patients who did not receive versus those who received initial radiotherapy. The latter group had increased probability of both posttransplant relapse and toxic death. In conclusion, HDC/AHSCT cures three-quarters of the children with MB/ST-PNET who relapsed after surgery and chemotherapy only. Results are inferior in those who relapsed after radiotherapy; additional approaches are especially necessary in this last setting, including posttransplant creative re-irradiation and/or metronomic therapy and biological modifiers. HDCT 3. NO SALVAGE WITH HIGH-DOSE CHEMOTHERAPY REIRRADIATION FOR RECURRENT ALREADY IRRADIATED MEDULLOBLASTOMA Maura Massimino,1 Filippo Spreafico,1 Roberto Luksch,1 Fabio Simonetti,2 Graziella Cefalo,1 Marta Podda,1 Michela Casanova,1 Andrea Ferrari,1 Monica Terenziani,1 Cristina Meazza,1 Daniela Polastri,1 Geraldina Poggi,3 Franca Fossati Bellani,1 and Lorenza Gandola1; 1Fondazione IRCCS Istituto dei Tumori, Milan, Italy; 2Milan, Italy; 3Lecco, Italy. Introduction: High-dose chemotherapy and autologous hemopoietic stem cell rescue (HDCT/ASCR) is used as salvage therapy in several solid tumors. This strategy has been particularly attractive in the last two decades for relapsing embrional CNS tumors such as medulloblastoma. We here report on our institutional experience during the years 1997–2002. Methods: The protocol included sequential intensive-dose chemotherapy reinduction with HDMTX, HDVP16, HDCTX, and HDCBDCA (as for de novo metastatic medulloblastoma), and two HDthiotepa/ASCR courses. If the patients had initially received the above-mentioned regimen at diagnosis, reinduction included CDDP/VP16 for two to four courses. Mobilization of hemopoietic precursors followed HDVP16 or HDCTX or the first CDDP/VP16 course. Each recurrent case had to be discussed with the referral neurosurgeon and radiotherapist. Before or soon after the myeloablative phase the possible re-irradiation was prescribed. Results: Of 17 patients enrolled, 13 were male (in the same 5-year time span 75 newly diagnosed children affected by medulloblastoma have been treated at our institute). All patients had already received craniospinal irradiation (19–36 Gy) with posterior fossa or tumor bed boosted, and 16 also with chemotherapy: 15 were at first relapse, 1 at the second, and 1 at third. Progression-free survival for the 15 patients at first relapse was 17–93 months (median, 28 months); site of recurrence in this cohort was leptomeningeal (eight), single spine nodule (four), and posterior fossa (three). Three patients had been resubmitted to surgery with complete posterior fossa nodules excision; 10 received the sequential schedule as above described, six CDDP/VP16, and one HDCT/ASCR after complete resurgery. Nine patients received reirradiation at some point of their salvage treatment. Thirteen of 14 cases with initial tumor evidence displayed partial or complete response after reinduction phase, four progressed, and two of them did not go forward to the myeloablative phase. No toxic deaths were registered. Remission duration was 9–45 months (median, 22 months). Further relapses in the 15 patients continuing the treatment included leptomeningeal dissemination in eight and posterior fossa and one single supratentorial site in four and one patients, respectively. Thirteen of the 15 patients who received HDCT died of tumor progression, one for pneumonia at 13 months after relapse. The only long-term survivor in continuous remission at 64 months after relapse had a single spine metastasis that was excised and irradiated. Survival of the whole series after relapse was 11–60 months, with a median of 27 months. Conclusions: Excluding exceptional cases, second-line therapy based on HDCT/ASCR strategies, despite the high rate of response and the extensive adoption of surgery and reirradiation, did not obtain cure. A second-line therapy for medulloblastoma that could pursue cure still has to be looked for. HDCT 4. PHASE II PROSPECTIVE STUDY OF SEQUENTIAL MYELOABLATIVE CHEMOTHERAPY WITH STEM CELL RESCUE FOR THE TREATMENT OF SELECTED HIGH-RISK CNS TUMORS AND RECURRENT CNS TUMORS Amy Rosenfeld,1 Alfred Rademaker,2 Colleen Schaefer,1 Molly Fouts,1 Reggie Duerst,1 David Jacobsohn,1 Morris Kletzel,1 and Goldman Stewart1; 1Hematology/Oncology/Transplantation, Children's Memorial Hospital, Chicago, IL, USA; 2Preventative Medicine, Northwestern University, Chicago, IL, USA. Background: Therapy for high-risk and recurrent CNS tumors often results in poor outcome. HSCR has been proposed as salvage therapy for these patients. Methods: Eighteen patients participated in this study between June 1998 and November 2007 with a median age of 7.1 years (range, 2 months to 17 years) at diagnosis, and evidence of a recurrent posterior fossa medulloblastoma (n = 9), recurrent germ cell tumor (n = 4), high-grade astrocytoma (n = 2), supratentorial PNET (sPNET) (n = 1), or pineoblastoma (n = 2). Patients demonstrated chemosensitivity and had stem cell mobilization during conventional relapse therapies. A minimum of 2 × 108 MNC/kg and 2 × 106 CD34+ stem cells/kg were required for each rescue. The preparatory regimen for the first stem cell rescue consisted of carboplatin (500 mg/m2/day) for 3 days, followed by etoposide (250 mg/m2/day), and thiotepa (300 mg/m2/day), each for 3 days. Patients who achieved an unsupported ANC >1,000 within 50 days of HSCR 1, without evidence of neuroradiographic progression or excessive toxicity (n = 11), received their second ablation with melphalan (60 mg/m2/day) for 3 days and cytoxan (1,500 mg/m2/day) for 4 days. Results: Eighteen patients were evaluable for this study, all of whom received chemotherapy, radiation, or a combination thereof, prior to their most recent relapse. Eleven patients underwent tandem HSCRs. Seven patients did not proceed to HSCR 2 due to either prolonged bone marrow aplasia (n = 3), parental refusal (n = 2), or transplant-related mortality (TRM) after HSCR 1 (n = 2). For all patients, projected overall survival at 1, 3, and 5 years from HSCT 1 was 56%, 56%, and 50%, respectively. There were a total of five TRMs: 2 of 18 patients (11%) who received a single transplant and 3 of 11 patients (27%) who underwent both transplants. Of the six documented relapses, three occurred after a single transplant and three after undergoing two transplants. Nine patients, five of whom underwent tandem transplants, are alive at last follow-up (median, 546 days), six with no evidence of disease. Toxicity (after one or both regimens) included grade 4 hematologic (n = 18), sepsis or bacteremia (n = 10), veno-occlusive disease (n = 4), grade 4 pulmonary toxicity (n = 4), pancreatitis (n = 1), seizure (n = 2), multisystem organ failure (n = 3), and mucositis (n = 18). Conclusion: Sequential myeloablative chemotherapy in high-risk and recurrent CNS tumors is not feasible, given the significant toxicity, primarily hematologic and infections. While the TRM was greater for patients undergoing two versus one transplants, this study was not designed to evaluate that comparison. Although the number of patients that underwent both transplants is too small to conclude that there is a benefit to performing tandem transplants, given the excessive toxicity seen thus far, this study has been closed to enrollment. The risks associated with tandem transplants performed using this particular conditioning regimen appear to outweigh any clinical benefit. HDCT 5. SEQUENTIAL HIGH-DOSE CHEMOTHERAPY AND REDUCED CRANIOSPINAL IRRADIATION IN YOUNG CHILDREN WITH METASTATIC MEDULLOBLASTOMA Christelle Dufour,1 Dominique Couanet,1 Dominique Figarella-Branger,2 Christian Carrie,3 Francois Doz,4 Didier Frappaz,5 Jean Claude Gentet,6 Pierre Leblond,7 Pascal Chastagner,8 Christian Sainte-Rose,9 Marie-Anne Raquin,1 Jacques Grill,1 and Chantal Kalifa1; 1Institut Gustave Roussy, Villejuif, France; 2Service d'Anatomie Pathologique et de Neuropathologie, Hôpital de la Timone, Marseilles, France; 3Radiotherapy, Centre Léon Bérard, Lyon, France; 4Institut Curie, Paris, France; 5Centre Léon Bérard, Lyon, France; 6Hôpital de la Timone, Marseille, France; 7Centre Oscar Lambret, Lille, France; 8CHU, Nancy, France; 9Necker-Enfants Malades Hospital, Paris, France. Introduction: Prognosis of disseminated medulloblastomas (DMBs) is poor and treatment remains a major challenge in young children because of the late toxicity of standard-dose craniospinal irradiation (CSI). We therefore developed a new strategy based on sequential high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) and reduced-dose CSI. Patients and Methods: Thirty-four children were enrolled in this phase II study. Median age at diagnosis was 3.2 years (range, 0.8–7 years). Chang stages were M1 (6 patients) and M3 (28 patients). After initial surgery, children received two courses of carboplatin-etoposide; then peripheral blood stem cells were harvested. In absence of disease progression, five sequential courses of chemotherapy followed by ASCT were performed: melphalan (100 mg/m2) at day 43, cisplatin (100 mg/m2) at day 64, melphalan at day 85, cisplatin at day 106, and thiotepa (720 mg/m2) at day 127. Children with resectable tumor residue were operated at the end of chemotherapy. Treatment was completed by age-adapted CSI. Results: At the end of the chemotherapy 11 patients were in complete remission, seven in partial remission. Out of the 19 patients who completed the treatment, 13 children are alive in CR1 (median follow-up, 26 months). Delivered doses of CSI were 50 Gy to the posterior fossa and 18 Gy to the brain and spinal canal in three patients, 50 Gy and 24 Gy in six, and 50 Gy and 35 Gy in one. The overall survival is 50% at 30 months. The hematological toxicity was high but manageable; no toxic death was observed. Conclusion: This chemotherapy regimen combined with reduced-dose CSI produced a survival, which compares favorably with published data. A longer follow-up is necessary to assess long-term quality of life. HDCT 6. THIOTEPA/TOPOTECAN/CARBOPLATIN (TTC) WITH AUTOLOGOUS STEM CELL RESCUE (ASCR) IN RECURRENT/REFRACTORY/POOR PROGNOSIS PEDIATRIC MALIGNANCIES OF THE CNS Stephen Gilheeney,1 Ira Dunkel,1 Yasmin Khakoo,1 Mark Souweidane,2 Suzanne Wolden,3 Farid Boulad,1 and Brian Kushner1; 1Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 2Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 3Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Background: Alkylating agents (thiotepa and carboplatin) are known to be active in CNS tumors, with an extensive clinical experience when used at high doses, and with nonoverlapping extramedullary toxicities. Topoisomerase inhibitors appear to potentiate the anticancer effects of alkylating agents and topotecan (a topoisomerase I inhibitor) crosses the blood-brain barrier. We present here the analysis of a group of patients with recurrent, progressive, or poor prognosis CNS malignancies treated on an institutional myeloablative regimen using these three drugs. Methods: Treatment with TTC was as follows: thiotepa 300 mg/m2 on days –8, –7, and –6; topotecan 2 mg/m2 on days –8, –7, –6, –5, and –4; and carboplatin ∼500 mg/m2 (dosed by the Calvert formula: AUC = 7) on days –5, –4, and –3. Stem cell rescue was on day 0. Data collected included basic demographic information, disease type, treatment history, and disease status prior to study entry, toxicity, and current vital status. Results: Between February 1999 and May 2004, 10 patients (three females, seven males) with primary CNS tumors were enrolled. Age at study entry ranged from 2.5 to 20 years old (median age, 13.7 years). Five had medulloblastoma (MB), four had high-grade glioma (HGG), and one had trilateral retinoblastoma/pineoblastoma (tRB/PB). Prior treatment for all patients included surgery and chemotherapy (1–7 regimens; median, 2). Nine patients had received radiation; one patient did not receive radiation therapy as pre- or poststudy therapy. Three patients (all with HGG) had residual disease at the time of transplant. There was one toxic death due to sepsis and no unexpected extramedullary toxicities. Four patients are event-free survivors at a median of 6 years (range, 2.8–7.6 years) after treatment including two of five MB patients, one of four HGG patients, and the tRB/PB patient. One MB patient suffered a late recurrence at 8.5 years. Four of seven patients with no evidence of disease/minimal residual disease status (NED/MRD) at the time of stem cell rescue are long-term survivors versus one of three with measurable disease. Conclusion: TTC appears to have some efficacy in the setting of poor prognosis CNS tumors. Patients with MB/tRB/PB may fare better than those with HGG. Patients in NED/MRD prior to ASCR may fare better than those with measurable disease using this regimen. HDCT 7. UNEXPECTED MORBIDITIES AND MORTALITIES IN YOUNG CHILDREN DURING INDUCTION CHEMOTHERAPY, ENROLLED ON THE “HEAD START III” PROTOCOL FOR NEWLY DIAGNOSED EMBRYONAL TUMORS Kelley Haley,1 Girish Dhall,1 Lingyun Ji,1 Richard Sposto,1 and Jonathan Finlay1; 1Oncology, Childrens Hospital Los Angeles, Los Angeles, CA, USA. Objective: Interim assessment of the toxicities of intensive chemotherapy on the current “Head Start III” protocol for newly diagnosed children with embryonal tumors. Methods: Between March 2003 and January 2007, 95 children <10 years of age were enrolled among participating institutions on the “Head Start III” regimen D for newly diagnosed CNS embryonal tumors (medulloblastomas, other PNET, AT/RT, ependymomas, and choroid plexus carcinomas). Five cycles of induction chemotherapy consisted of three cycles (days 1, 3, and 5) with vincristine (days 0, 7, and 14) and cisplatin (day 0), high-dose cyclophosphamide (65 mg/kg) and etoposide (days 1 and 2) and high-dose methotrexate, 12 g/m2, on day 3, alternating with two cycles (cycles 2 and 4) of vincristine (days 0, 7, and 14), oral etoposide (days 0–9), oral temozolomide (days 0–4), and high-dose cyclophosphamide (65 mg/kg, days 10 and 11). Following recovery from cycle 5, patients with responsive disease were to undergo a single cycle of myeloablative chemotherapy (thiotepa, carboplatin, and etoposide) with autologous hematopoietic progenitor cell rescue. Results: Six children (of 46 enrolled) <24 months of age suffered toxic deaths during induction regimen D. There were no toxic deaths during induction regimen D among 49 patients >24 months of age enrolled. Three deaths occurred during cycle 1: one on day +7 of systemic inflammatory response syndrome secondary to RSV infection; one on day +8 of RSV pneumonitis; and one on day +18 of acute myocarditis secondary to Stevens-Johnson Syndrome. One death occurred on day +19 of cycle 2 of ARDS of unknown etiology. Two deaths occurred during cycle 3; one on day +9 of acute gastric hemorrhage secondary to severe mucositis and thrombocytopenia; one on day +12 of Gram-negative septicemia. Evaluation including toxic morbidities (grades IV and V) revealed expected high incidence of hematologic toxicities, not different between those <18 months and those >18 months of age. Certain nonhematologic toxicities were more prevalent in the younger (<18 months old) population: ARDS (p = 0.0029), GI hemorrhage (p = 0.0031), dyspnea (p = 0.0050), hypoxia (p = 0.0069), typhlitis (p = 0.0227), AST elevation (p = 0.0456), hypotension (p = 0.0468), and infection (p = 0.0468). Among 10 children with grade IV infection-related morbidity, four were <24 months of age: infections included disseminated CMV, HSV with ARDS, ARDS of unknown etiology, and one with simultaneous RSV, HSV, CMV, and rotavirus infections. Of the children >24 months of age, infections included septic shock of unknown etiology; ARDS of unknown etiology; parainfluenza pneurmonia; ARDS and strep viridans; pneumonitis of unknown etiology; and parainfluenza with ARDS. Conclusions: An unexpected increased incidence of both toxic mortality and morbidities was encountered in children <24 months of age enrolled on induction regimen D of the “Head Start” III protocol. These toxicities were largely but not exclusively due to serious infections, including RSV and other viral infections. The mortalities were predominantly encountered during cycles 1 and 3 (six of seven cases), while grade IV morbidities occurred equally during the cycles. The protocol has been amended to include enhanced supportive care guidelines, as well as dose adjustments in cyclophosphamide (65 mg/kg to 55 mg/kg) and methotrexate (12 g/m2 to 8 g/m2) to hopefully minimize these toxicities. HIGH-GRADE GLIOMA HGG 1. AUGMENTING GRK3 FUNCTION ABROGATES CXCL12-INDUCED ASTROCYTOMA GROWTH Mahil Rao,1 Mark Woerner,2 Arie Perry,1 and Joshua Rubin1; 1Washington University in St. Louis, St. Louis, MO, USA; 2MO, USA. Development of more efficacious, less-toxic therapies for malignant gliomas will advance when the critical differences in growth regulation between astrocytoma cells and astrocytes are identified. We found that astrocytoma cells, but not astrocytes, exhibit a growth response to the chemokine CXCL12 that is dependent on prolonged suppression of intracellular cAMP. Here, we report that diminished counter-regulation of signaling through the CXCL12 receptor, CXCR4, occurs in astrocytoma cells and may underlie the sustained suppression of cAMP and the unique growth effects of CXCL12 on astrocytomas. The importance of the CXCR4 pathway to astrocytoma growth in vivo was made evident by the potent antitumor effects of CXCR4 antagonists in treating an intracranial xenograft model of glioblastoma. However, in clinical trials for other indications, prolonged systemic CXCR4 antagonism was not tolerable, and therefore we sought to identify differences in CXCR4 signaling between astrocytes and astrocytomas in order to develop more tumor-specific strategies for antagonizing this pathway. The abnormal CXCL12-induced suppression of cAMP suggested that CXCR4 desensitization was diminished in astrocytoma cells. Desensitization is a counter-regulatory mechanism to limit the duration of heterotrimeric G protein signaling downstream of G protein coupled receptors. It is initiated through phosphorylation of the ligand-bound receptor by a family of receptor kinases, GRKs. In support of our hypothesis we found that ligand-induced phosphorylation of CXCR4 occurs at a much slower rate in astrocytoma cells than in astrocytes. Further, analysis of microarray data indicated that there are significantly lower levels of GRK2, GRK3, and GRK6 expression in grade IV gliomas compared to normal brain. The most significant differences were evident in GRK3 expression, and these were further validated in immunohistochemical studies. Finally, we found that overexpression of GRK3 in U87 astrocytoma cells inhibits SDF-induced growth. Together these studies indicate that a key difference between astrocytomas and normal astrocytes lies in the regulation of CXCR4 signaling through desensitization and suggests that enhancing GRK-mediated CXCR4 desensitization can reestablish normal growth responses and may therefore be an important new approach to malignant glioma therapy. HGG 2. BRAIN TUMORS IN CHILDREN WITH DNA MISMATCH REPAIR DEFICIENCY SYNDROME Patricia Baxter,1 Shweta Dhar,2 Asad Mian,2 Claire Noll,1 Carl Allen,1 Robert Dauser,3 Adekunle Adesina,4 Arnold Paulino,5 Ching Lau,1 Sharon E. Plon,6 and Murali Chintagumpala1; 1Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA; 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; 3Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA; 4Department of Pathology, Baylor College of Medicine, Houston, TX, USA; 5Department of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA; 6Department of Molecular and Human Genetics/Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. DNA mismatch repair (MMR) deficiency syndrome, also referred to as the recessive form of Turcot syndrome, is characterized by childhood onset of CNS tumors, hematologic malignancies, colorectal cancers, and NF1-like cutaneous lesions. Multiple brain tumors have been associated with MMR including medulloblastoma, glioblastoma multiforme (GBM), astrocytoma, oligodendroglioma, and SPNET. Both homozygous and compound heterozygous mutations in the MLH1, MSH2, PMS2, and MSH6 genes have been reported. We describe three families with the clinical diagnosis of MMR deficiency syndrome from one institution. Family 1 is a nonconsanguineous Pakistani family with two children with cafe-au-lait spots (CALS). The son was diagnosed with lymphoma at age 5 and colorectal cancer at age 8, while the daughter was diagnosed with GBM at age 8, related to being homozygous for a nonsense mutation in MSH6. Family 2 is a consanguineous Indian family with a 6-year-old male with CALS and synchronous diagnosis of multifocal GBM and T-cell lymphoblastic lymphoma. This child is homozygous for an intragenic PMS2 deletion. Family 3 is a Mexican/Guatemalan nonconsanguineous family with two children with multiple CALS. The older sibling was diagnosed with T-cell lymphoblastic lymphoma at age 5 years and GBM at age 6 years. A younger sibling, who is now 5 years old, was recently diagnosed with a GBM, and mutation analysis is underway. In all three families there was no evidence for hereditary nonpolyposis colon cancer–associated cancers in obligate heterozygous mutation carriers. This group of patients supports careful skin exams for NF1-associated lesions in newly diagnosed patients with pediatric brain tumors and diagnostic consideration of MMR deficiency syndrome in addition to NF1. Family members and patients with MMR deficiency syndrome are at increased risk for lymphoma and also require screening by colonoscopy for colon cancer risk. Screening guidelines for patients with DNA MMR deficiency, which should include routine colonoscopy, need to be developed. HGG 3. COMPREHENSIVE MAPPING OF PEDIATRIC HIGH-GRADE GLIOMA BY OLIGO ARRAY COMPARATIVE GENOMIC HYBRIDIZATION Jennifer Barrow,1 Martyna Adamowicz-Brice,1 James Lowe,2 Keith Robson,2 Helen Brown,3 Beth Coyle,1 and Richard Grundy1; 1Children's Brain Tumour Research Centre, University of Nottingham, Nottingham, Nottinghamshire, UK; 2Neuropathology, University of Nottingham Medical School, Nottingham, Nottinghamshire, UK; 3University of Warwick, UK. High-grade glioma describes a series of glial tumors with World Health Organization (WHO) classification of grade III (anaplastic astrocytoma and anaplastic oligodendroglioma) or grade IV (glioblastoma). High-grade astrocytomas are highly vascular and frequently rapidly advancing tumors with a poor prognosis in both children and adults. Very young children (children <3 years of age) with high-grade astrocytomas fare better than older children, which suggests different underlying biology. To date, relatively little is known about the underlying genetics of childhood high-grade gliomas. The main aim of this study is therefore to investigate these tumors using molecular cytogenetic techniques. Brainstem gliomas account for up to 20% of pediatric CNS tumors, with a mean age of diagnosis of 7–9 years old. The brainstem describes an area of the brain encompassing the mid-brain, pons, and medulla oblongata. Around 20% of brainstem gliomas are low-grade astrocytomas, and the remaining 80% are diffuse tumors involving the pons. These diffuse pontine gliomas are frequently counted alongside high-grade gliomas due to poor prognosis, although the histological grade may vary. Brainstem gliomas are considered surgically inaccessible due to their anatomical location, and as the diagnosis can be made on MRI, little tumor material is available for research. Little research has been performed on brainstem gliomas, hence the need for further study. Formalin-fixation has been the most common soft tissue preservation method for clinical studies for decades. There is a large cohort of formalin-fixed paraffin embedded (FFPE) pediatric high-grade glioma samples available for study. Unfortunately, DNA isolated from FFPE samples is of poorer quality than freshly extracted DNA due to the extensive cross-links formed between nucleic acids and proteins within cells by the formalin-fixation method. Our pilot studies have shown that DNA isolated from FFPE tissue can, however, be of sufficient quality to produce reliable, reproducible data that is comparable with results generated using DNA isolated from frozen tissue, using Agilent Oligo Array CGH on 244k arrays. We have isolated DNA from 45 pediatric high-grade glioma FFPE samples, including seven brainstem gliomas. The most common aberration in the 20 samples that have been run so far is an amplification at chromosome 11q13, which is seen in 80% of the samples. A region of gain at 12q13 was detected in 60% samples, and in 25% of the samples there is a deleted region at chromosome 9p21. In addition, there were common gains on chromosome 1q and frequent losses on chromosomes 9p and 10. Overall there are more gains than losses, and the number of imbalances differs widely between samples. This study aims to use Oligo Array CGH to facilitate the identification of diagnostic and prognostic markers in pediatric high-grade glioma and identify novel therapy targets. We will present 244k oligo array data and correlate this with clinical markers in order to aid diagnosis, prognostication, and future development of new treatments. HGG 4. FUNCTIONAL SIGNIFICANCE OF DYSREGULATED YB-1 EXPRESSION IN THE ONCOGENESIS OF PEDIATRIC GLIOBLASTOMA Caroline Sollier,1 Damien Faury,1 Yuanyuan Gao,2 David Barnett,1 Sandra Dunn,2 and Jabado Nada3; 1Department of Human Genetics, Montreal Children's Hospital, McGill University Health Centre Research Institute, Montreal, QC, Canada; 2Departments of Pediatrics, Experimental Medicine and Medical Genetics, Child and Family Research Institute, Vancouver, BC, Canada; 3Department of Human Genetics and Pediatrics, Montreal Children's Hospital, McGill University Health Centre Research Institute, Montreal, QC, Canada. Background: Pediatric glioblastomas (pGBMs) have a dismal 3-year survival of <20%. While considerable information is available on adult GBM (aGBM), substantially fewer genetic/molecular data exist for pGBM. We previously established that pGBM are molecularly distinct from aGBM and showed that overexpression of Y-box-protein 1 (YB-1) may help drive oncogenesis in this tumor. YB-1 is broadly expressed throughout development and is mandated for late embryonic development. Its expression level correlates with cell proliferation state and is turned down in quiescent cells including in normal brain. This protein is a major structural component of messenger ribonucleoprotein complexes in the cytoplasm where it acts as a translational regulator. Akt-dependent phosphorylation of YB-1 at Ser102 induces nuclear translocation in the presence of functional p53 and the transcription of genes including EGFR. Nuclear YB-1 interacts with p53 inhibiting p53-induced cell death and has been involved in the oncogenesis of several epithelial cancers, but our study is the first that associates it with brain cancer. We hypothesize that dysregulated YB-1 expression is driving oncogenesis in a subset of pGBM. Methods: We stably overexpressed HA-tagged wild-type (WT) and S102A-YB-1 (preventing nuclear shuttling) in pGBM (SF188) and aGBM (U251) cell lines. In parallel, we stably knocked down YB-1 expression using shRNA in these cell lines. We investigated the effects of overexpression and silencing of YB1 on cell signaling (Ras and Akt pathways), proliferation, invasion, response to chemotherapeutic agents, and EGFR/Met levels in these cell lines. Results: Silencing YB-1 expression in cell lines induced a change in cell morphology and led to a dramatic decrease in the proliferation rate (85%) and invasiveness (60%) of silenced cell lines when compared to empty vector (EV) transfectants. These data correlated with a loss of integrin-linked kinase (ILK) expression. Moreover, inhibiting YB-1 expression enhanced chemosensitivity to taxol in monolayer and soft agar assays relative to the empty vector. Overexpression of WT and nonmutant YB-1 led to increased baseline EGFR expression and sustained activation of the Ras pathway in response to RTK signaling, while no effect was observed on the Akt pathway. Furthermore, expression of mutant YB-1 decreased cell proliferation and invasion similar to shRNA transfectants, while cell lines transfected with WT-YB1 grew similar to control cells. Most recently we have characterized the parental SF188 xenograft model and intend to alter the expression of YB-1 to evaluate changes in tumor growth. Conclusion: Our results suggest that YB-1 modulates EGFR levels, Ras signaling, and cellular proliferation, invasion, and response to chemotherapy based on its nuclear or cytoplasmic localization. This study ascertains the role of YB-1 in driving cell growth and oncogenesis in pGBM and provides much-needed tools that will prove valuable in preclinical trials targeting this factor. HGG 5. IMMUNOTHERAPY FOR RELAPSED HIGH-GRADE GLIOMA: CLINICAL UPDATE OF COHORTS A, B, C, AND D FROM THE COHORT COMPARISON TRIAL HGG-IMMUNO-2003 Stefaan Van Gool,1 Stefan Rutkowski,2 Eckhart Kaempgen,2 Johannes Wolff,3 Sabine Wagner,2 Frank Van Calenbergh,2 Christof Kramm,2 Hilko Ardon,2 and Steven De Vleeschouwer2; 1UZ Leuven, Leuven, Belgium; 2Germany; 3Houston, TX, USA. Purpose: The prognosis of patients with high-grade glioma (HGG) is dismal. We investigate the therapeutic role of vaccination with mature dendritic cells (DCs) loaded with tumor lysates derived from resected tumors at time of relapse. Methods: DCs were injected intradermally according to three different vaccination schedules (cohorts A, B, C). Cohort D consisted of cohort C with addition of local application of imiquimod. Results: One hundred thirty-one patients entered these cohorts. The median age at time of relapse of HGG was 42 years (range, 6–77 years). Fifteen patients dropped out immediately due to tumor progression. Sixteen patients combined immunotherapy with concomitant chemotherapy. In three patients of the last cohort, boosts with lysate were provided earlier due to lack of sufficient monocytes after one leukapheresis procedure to produce DCs. These 34 patients were excluded from the as-treated analysis. The median progression-free (PFS) and overall (OS) survival of 97 patients was 3.6 and 9.9 months (2-year OS = 12.9%). The median PFS and OS of 72 patients >20 years was 3.7 months and m (2-year OS = 7%). The median PFS and OS of 25 patients <20 years was 3 months and 16.9 months (2-year OS = 41.9%). In a univariate analysis, extent of resection influenced the PFS but not the OS. However, one should take into account that at least subtotal resection was required to be included in cohorts B, C, and D. For the subgroup of 71 patients with relapsed GBM, median age was 44 years (range, 7–77 years). The median PFS and OS of the total group was 3.5 and 9.9 months (2-year OS = 16.1%). The median PFS and OS of 14 patients <20 years was 2.4 and 16.9 months (2-year OS = 42.3%). The median PFS and OS of 57 patients >20 years was 3.7 and 9.6 months (2-year OS = 7%). Extent of resection did not influence PFS or OS. By stepwise shortening of the interval between the vaccination from cohort A to C, a significant improvement of the PFS was observed in the total group of adults with relapsed HGG and in the subgroup with relapsed GBM. In both groups, the addition of imiquimod induced a further significant improvement of the PFS. All patients received their vaccinations in an ambulatory setting. There were no adverse events, except in one relapsed patient with gross tumoral disease prior to vaccination who developed repetitive vaccine-related peritumoral edema. Conclusion: Immunotherapy for patients with relapsed HGG is feasible without major adverse events. Especially in young patients, DC vaccination induces obvious tumor control even at time of relapse. The vaccination schedule plays a role in building up the immune-mediated control mechanisms in adults with relapsed HGG or GBM. Further improvement of the PFS in these patients could be realized by stimulating in vivo the ex vivo generated DCs with imiquimod. HGG 6. LOW PARP-1 PROTEIN EXPRESSION AND MGMT METHYLATION, BUT NOT MGMT PROTEIN EXPRESSION, ARE ASSOCIATED WITH IMPROVED SURVIVAL IN GLIOBLASTOMA Valerie Barton,1 Andrew Donson,1 Diane Birks,1 Nicholas Foreman,2 Michael Handler,3 and Arthur Liu1; 1University of Colorado Health Sciences Center, Aurora, CO, USA; 2Aurora, CO, USA; 3CO, USA. Background: Parp-1 and MGMT are DNA repair proteins that may influence the efficacy of chemotherapy and radiotherapy in pediatric and/or adult glioblastoma (GBM). Although Parp-1 is overexpressed in many types of cancer, variations in Parp-1 expression have not been examined in brain tumors. Several small molecule Parp-1 inhibitors have been developed and shown to sensitize GBM cancer cells to DNA damaging agents in vitro and in vivo, suggesting that low Parp-1 expression may be associated with improved survival. MGMT promoter methylation is associated with survival benefit and sensitivity to temozolomide, however, its relationship to MGMT protein expression is unclear. The present study examined the relationships among Parp-1 protein expression, MGMT methylation status, MGMT protein expression, and patient outcome. The utility of Parp-1 and MGMT as predictive markers for response to temozolomide in pediatric and adult GBM was examined and compared. Procedure: Parp-1 and MGMT protein expression were examined retrospectively in 20 GBMs (12 adult, 8 pediatric) by a Western blot analysis. The methylation status of 17 GBMs (11 adult, 6 pediatric) was determined by nested, methylation-specific PCR. The relationships among total MGMT and Parp-1 protein, methylation status, and survival time were evaluated. Results: In temozolomide-treated patients, low Parp-1 expression was associated with improved survival (p = 0.045). In all patients, MGMT methylation corresponded to improved patient outcome (p = 0.063). As a combined predictor, low Parp-1 expression and MGMT methylation showed improved survival in patients treated with temozolomide (p = 0.015). MGMT protein expression was not correlated with methylation status or survival benefit (p = 0.681 and p = 0.934, respectively). No significant difference was found between pediatric and adult patients in Parp-1 expression, MGMT expression, or methylation status (p = 0.121, p = 0.480, and p = 0.387, respectively). Conclusions: The present study provides evidence that low Parp-1 expression may be a marker for temozolomide sensitivity. Methylation of the MGMT promoter is a better indicator of patient outcome than MGMT protein expression in GBM. No significant difference in protein expression or methylation status was observed between adult and pediatric GBM. Analysis in a larger cohort is required and will be performed as more patient data are collected. HGG 7. PEDIATRIC GIANT CELL GLIOBLASTOMA: NEW INSIGHTS INTO A RARE TUMOR ENTITY Michael Karremann,1 Sandra Butenhoff,1 Ulrike Rausche,1 Torsten Pietsch,2 Johannes Wolff,3 and Christof Kramm1; 1University Children's Hospital, Halle (Saale), Germany; 2Department of Neuropathology, University of Bonn, Germany; 3Houston, TX, USA. Only little is known about giant cell glioblastoma in pediatric patients. The present study identified 18 pediatric patients with centrally reviewed giant cell glioblastoma (GCG) from the HIT-GBM/HIT-HGG database of the Gesellschaft für Paediatrische Onkologie und Haematologie (GPOH) in Germany, Austria, and Switzerland. Clinical and epidemiological data were compared with those of 178 pediatric patients with centrally reviewed glioblastoma multiforme (GBM) from the same source. In this unique series, median age, male preference, and median clinical history did not differ significantly between pediatric GCG and GBM patients. Interestingly, no infant of 3 years and younger suffered from GCG. GCG showed a stronger predilection for cerebral hemispheres than GBM, which may only partly explain the higher percentage of gross total tumor resections in GCG patients. Most surprisingly, the widely distributed hypothesis that GCG may imply a better prognosis than GBM could not be substantiated for our pediatric series. Future studies with larger patient numbers and molecular pathological analyses are still needed to corroborate the present findings and further elucidate the biology of GCG in children. HGG 8. PEDIATRIC MALIGNANT GLIOMAS: SPECIFIC GENOMIC ABNORMALITIES CORRELATED WITH DIFFERENT HISTOLOGICAL SUBGROUPS Stephanie Puget,1 Philippe Dessen,2 Bastien Job,3 Veronique Scott,2 Catherine Richon,3 Vladimir Lazar,3 Pascale Varlet,4 Nathalie Boddaert,5 Catherine Miquel,6 Christian Sainte-Rose,5 Francois Doz,4 Jacques Grill,7 and Gilles Vassal2; 1Necker Enfants Malades, Paris, France; 2Institut Gustave Roussy, Villejuif, France; 3France; 4Paris, France; 5Necker Sick Children's Hospital, Paris, France; 6Sainte Anne Hospital, Paris, France; 7Institut Gustave Roussy Villejuif, Villejuif, France. Purpose: Pediatric malignant gliomas (pMGs) are classified into histological subgroups according to the criteria established for adults, but differ from them in terms of prognosis. Histological diagnostic accuracy and reproducibility are suboptimal criteria to predict prognosis. We investigated whether array-CGH (aCGH) can detect pMG-specific genomic abnormalities in order to establish a pediatric pMG classification. Methods: We retrospectively reviewed stored tissue samples of a series of 96 patients undergoing initial surgical procedure affected with histologically confirmed pMG (grade 3–4 according to WHO classification); aCGH analyses were performed on 59 of 96 patients by using Agilent 44k slides. The corresponding histological samples were blindly and independently reviewed by two anatomopathologists and classified according to WHO and Sainte-Anne (SA) classifications. Supervised and unsupervised classifications were performed to evaluate the potential associations of aCGH data to histological features (as assessed by WHO and SA classifications) and to outcome. Results: After revision, nonglial tumors were excluded (four cases), and tumors classified as low-grade gliomas (LGGs, 16% and 7% of the initial cohort according to WHO and SA, respectively) were used as a control group for the aCGH data analyses. Cohort mean age was 7.9 years (range, 5 days to 17 years) with a sex ratio of 1:4. Median follow-up was 19 months (range, 1.8 months to 17 years). Tumors were mainly hemispheric (52.7%), followed by basal ganglia (36.4%), and brainstem (10.9%). Unsupervised clusterization identified four patterns: (a) no or very few aberrations (n = 31); (b) loss of ch10q and gain of 7q (100% of cases; n = 4); (c) gain of 1q and 17q (100% and 75%, respectively; n = 9); and (d) loss of ch13q and 5q (82% and 70%, respectively; n = 11). This clusterization poorly correlated with histological classifications but showed a better 3-year survival rate for group d compared to others (70% vs. <30%). By applying a supervised clusterization, SA classification showed to better discriminate pMG versus LGG compared to WHO classification (i.e., loss of 13q in LGG, p = 0.005). Grade 3 and 4 (WHO classification) differed significantly as ch7p15.2 (encompassing HOXA9) was gained mainly in grade 4 (50% vs. 8%; p = 0.002), and ch16q24 (encompassing CDK10) was gained in grade 4, while lost in grade 3 (p = 0.002). In SA classification, two chromosomal regions could significantly distinguish malignant glioneuronal tumors (MGNT) from other MG: ch14q32.3 (encompassing AKT1) was gained in MGNT and lost in MG (p = 0.0.004); conversely, ch9p24 (encompassing JAK2) was lost in MGNT and gained in MG (p = 0.008). Conclusion: These data suggest that analyses of pMG by aCGH play an important role in correlating with survival. Histological subgroups, especially according to SA classification, are characterized by specific chromosomal regions and potential candidate genes. Further gene-expression analyses need to confirm these data. HGG 9. PHASE I DOSE ESCALATION STUDY OF AUTOLOGOUS TUMOR LYSATE-PULSED DENDRITIC CELL IMMUNOTHERAPY FOR MALIGNANT GLIOMAS IN PEDIATRIC PATIENTS Joseph Lasky,1 Linda Liau,2 Robert Prins,2 and Theodore Moore1; 1Pediatric Hematology Oncology, University of California, Los Angeles, Los Angeles, CA, USA; 2Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA. Introduction: Immunotherapy provides an armamentarium of novel treatment modalities that may prove to be more effective and less toxic means with which to treat pediatric brain tumors. Trials have already been performed in children including using monocyte-derived dendritic cells pulsed with tumor RNA for brain tumors and neuroblastoma and CD40L/IL2 transduced fibroblasts plus leukemic cells for treating relapsed leukemia. However, more remains to be learned with regard to induction and then targeting of these antitumor immune responses. Methods: We are conducting a phase I trial using autologous dendritic cells (DCs) pulsed with a tumor protein lysate as immunotherapy for pediatric patients with primary or recurrent malignant gliomas. The patients are immunized with a series of three biweekly intradermal injections done in an outpatient setting following standard chemotherapy and/or radiation therapy. Peripheral blood (PB) samples are obtained at days –14, 35, 56, and 112, and every 8 weeks thereafter. Brain MRIs are obtained at screening and then every 8 weeks to assess for radiologic evidence of clinical response or stability. Cohorts of three to six patients will receive escalating doses of autologous DCs pulsed with approximately equal amounts of autologous tumor lysate based upon standard protein quantification, allowing for the evaluation of three dose levels of autologous tumor lysate-pulsed DCs (1,000,000 cells/injection, 5,000,000 cells/injection, and 10,000,000 cells/injection). The PB samples will be analyzed for T-cell proliferation in response to the autologous tumor lysate. Samples will also be used to assess cell mediated cytotoxicity using a standard 51-chromium release assay by mixing labeled autologous tumor cells with stimulated peripheral blood mononuclear cells (PBMCs). Results: To date, we have enrolled four patients (see HGG 9: Table 1, p. 516). Adequate amounts of tumor lysate and PBMCs were collected for three vaccine doses for all four patients. However, vaccine administration was only given to patients 1 and 4 as the other two patients had progressive disease prior to being able to receive the vaccinations (see HGG 9: Table 1, p. 516). For both patients who received vaccination, one million dendritic cells per dose were pulsed with 100 μg of peptide prior to intradermal administration. This was repeated for the following two injections without complication. There were no serious or unexpected toxicities related to the vaccine administration. Patient 1 ultimately succumbed from progressive disease. Patient 4 remains without evidence of disease on MRI 8 months from diagnosis. Immunologic assays on the patient samples are in progress. Conclusions: Many questions remain as to the optimal time during which induction of active tumor immunity should take place. These issues are further complicated by the often intensely myelosuppressive therapies that are routinely given to children for the treatment of malignancies. We are encouraged both by the feasibility of producing a dendritic cell vaccine and by the minimal toxicity of DC vaccination in pediatric patients. Completion of this phase I toxicity trial will allow us to move on to further phase II efficacy studies and refinement of the use of active tumor immunotherapy in children. HGG 9: Table 1. Summary of treatment data Patient No. . Age . Gender . Time to Recurrence . Pathology for Trial . DC Dose × 106 . Survival from Recurrence or Diagnosis (for Primary) . Current Status . 1 14 Male 11 months Recurrent Glioblastoma 1 12 months DOD 2 7 Female 7 months Recurrent Glioblastoma n/a 8 months DOD 3 16 Female 12 months Recurrent Glioblastoma n/a 1 month DOD 4 13 Female N/A Primary Glioblastoma 1 8 months Alive, NED Patient No. . Age . Gender . Time to Recurrence . Pathology for Trial . DC Dose × 106 . Survival from Recurrence or Diagnosis (for Primary) . Current Status . 1 14 Male 11 months Recurrent Glioblastoma 1 12 months DOD 2 7 Female 7 months Recurrent Glioblastoma n/a 8 months DOD 3 16 Female 12 months Recurrent Glioblastoma n/a 1 month DOD 4 13 Female N/A Primary Glioblastoma 1 8 months Alive, NED Open in new tab HGG 9: Table 1. Summary of treatment data Patient No. . Age . Gender . Time to Recurrence . Pathology for Trial . DC Dose × 106 . Survival from Recurrence or Diagnosis (for Primary) . Current Status . 1 14 Male 11 months Recurrent Glioblastoma 1 12 months DOD 2 7 Female 7 months Recurrent Glioblastoma n/a 8 months DOD 3 16 Female 12 months Recurrent Glioblastoma n/a 1 month DOD 4 13 Female N/A Primary Glioblastoma 1 8 months Alive, NED Patient No. . Age . Gender . Time to Recurrence . Pathology for Trial . DC Dose × 106 . Survival from Recurrence or Diagnosis (for Primary) . Current Status . 1 14 Male 11 months Recurrent Glioblastoma 1 12 months DOD 2 7 Female 7 months Recurrent Glioblastoma n/a 8 months DOD 3 16 Female 12 months Recurrent Glioblastoma n/a 1 month DOD 4 13 Female N/A Primary Glioblastoma 1 8 months Alive, NED Open in new tab HGG 10. THE TREATMENT OF HIGH-GRADE GLIOMAS IN PEDIATRICS: WHERE HAVE WE BEEN? WHERE ARE WE GOING? Kenneth Cohen1; 1Johns Hopkins University, Baltimore, MD, USA. The prognosis for children with high-grade gliomas (HGGs) including anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) remains poor. In North American trials, the best results reported for this population of patients was the CCG-943 trial on the arm that included irradiation (XRT) followed by adjuvant chemotherapy with prednisone, carmustine, and vincristine, in which the 5-year event-free survival (EFS) was 46%. When this arm of the regimen was repeated in the CCG-945 randomized trial of XRT/pCV versus XRT/“8-in-1” chemotherapy, the 5-year EFS was only 26% for the XRT/pCV arm despite there being no change in the treatment administered. A variety of additional trials followed focusing on neoadjuvant chemotherapy followed, all of which proved to be either too toxic or ineffective. On the basis of these earlier trials the value of upfront resection and upfront XRT has been confirmed. ACNS0126 was the first trial following the merger of CCG and POG and was a single-arm phase 2 trial of chemoradiotherapy with temozolomide followed by 10 additional cycles of adjuvant temozolomide. In comparison to CCG-945, 1-year overall survival (OS) was the same in both groups (68%), but 1-year EFS was worse in ACNS0126 than CCG-945 for the children diagnosed with AA (31% ± 8% vs. 45% ± 6.5%, respectively). One-year EFS for the GBM cohort was similar in both groups (36% ± 7% on ACNS0126 vs. 32% ± 6% on CCG-945). This would suggest that either (1) ACNS0126 therapy was less effective for children with AA, (2) the criteria for the diagnosis of AA have become more stringent over time, or (3) the biologic nature of AA has become more aggressive over the last 30 years. Arguably, the latter two hypotheses could be invoked when comparing the change in outcome for the XRT/pCV regimen on CCG-943 versus CCG-945. While it is conceivable that the biologic behavior of AAs has changed in the last 30 years, it seems more likely that the pathologic criteria for the diagnosis have become more stringent over time. The impact of such an evolving classification would lead to a more aggressive population of tumors being classified as AA, diminishing the utility of historical control cohorts as a comparator group in modern trials. Novel treatment designs are required (e.g., randomized phase 2 studies) that eliminate the necessity for comparison to historical control cohorts. HGG 11. THE TREATMENT OF YOUNG CHILDREN WITH HIGH-GRADE GLIOMAS (HGGs) AND DIFFUSE INTRINSIC BRAINSTEM GLIOMAS (DIBSGs): RESULTS OF AN IRRADIATION-AVOIDING STRATEGY, THE “HEAD START” PROTOCOLS 1991–2007 Neha Patel,1 Adam Showman,2 Kelley Haley,2 Melissa Siegel,2 Sharon Gardner,3 Juliette Hukin,4 Michael Sullivan,5 Albert Cornelius,6 Geoffrey Mccowage,7 Jeffrey Allen,8 Lingyun Ji,9 Richard Sposto,2 and Jonathan Finlay10; 1Childrens Hospital of Los Angeles, Los Angeles, CA, USA; 2Childrens Hospital Los Angeles, Los Angeles, CA, USA; 3New York University Medical Center, New York, NY, USA; 4British Columbia's Children's Hospital, Vancouver, BC, Canada; 5Christchurch Hospital, Christchurch, New Zealand; 6DeVos Children's Hospital, Grand Rapids, MI, USA; 7New South Wales, Australia; 8New York University, New York, NY, USA; 9Division of Hematology-Oncology, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 10Los Angeles, CA, USA. Background: Despite multimodal therapy, the prognosis for young children with HGGs and DIBSGs remains poor. Additionally, effects on the quality of life are dismal when irradiation is given to the developing brain of these young children. Objective: Improvement of both the survival and the quality of life of young children with newly diagnosed HGG and DIBSG through strategies incorporating intensive chemotherapy and avoidance of irradiation. Methods: Fifty-one children <7.5 years of age at diagnosis of either anaplastic astrocytoma (AA) (n = 17), glioblastoma multiforme (GBM) (n = 19), or DIBSG (n = 15) have been enrolled on one of the three sequential “Head Start” protocols since 1991. The treatment plan included maximal surgical resection and three to five cycles of one of the three intensive induction chemotherapy regimens: vincristine, etoposide, cisplatin, and cyclophosphamide (regimen A); prednisone, lomustine, vincristine, and carboplatin (regimen B); or vincristine, carboplatin, and temozolomide (regimen C), followed by consolidation phase with a single cycle of marrow ablative chemotherapy (thiotepa, carboplatin, and etoposide) with autologous hematopoietic progenitor cell rescue (AuHPCR). Irradiation was used only for residual tumor at consolidation or for progressive/recurrent disease. Results: The 5-year event-free survival (EFS) and overall survival (OS) for all patients with HGG and DIBSG treated on regimens A, B, or C were 18% ± 6% and 25% ± 7%, respectively. The 2-year EFS and OS for all patients with GBM (n = 19) were 37% ± 12% and 34% ± 12%. The 2-year EFS and OS for all patients with AA (n = 17) were 14% ± 11% and 64% ± 12%. Patients with DIBSG (n = 15) had the poorest outcome, with a 2-year EFS and OS of 7% ± 6% and 20% ± 10%, respectively. Comparing the three regimens, regimen B was too toxic and ineffective, and all patients treated on this regimen died either of progressive disease or of toxicity; therefore enrollment on this regimen ceased after accrual of just five patients. Regimens A and C were well tolerated in most patients. Six of the 18 (33%) patients treated on regimen A, and 16 of the 28 (57%) patients treated on regimen C achieved minimal residual disease and proceeded to the consolidation phase. Eleven of these 22 patients are alive after the consolidation phase at a median follow-up of 2 years. Patients with HGG when treated on regimen A experienced 2-year EFS and OS of 17% ± 11% and 42% ± 14%, respectively, while HGG patients treated on regimen C experienced 2-year EFS and OS of 42% ± 11% and 58% ± 12%, respectively. Fifteen of the 36 (41%) patients with nonbrainstem HGG enrolled on these “Head Start” protocols are alive, and 9 of these 15 patients did not receive any irradiation at a median follow-up of 2 years. Conclusions: The prognosis for children with HGG and DIBSG remains poor. Children with DIBSG do not benefit from this irradiation-avoiding intensive chemotherapy strategy. Children with HGG may benefit provided that they can achieve minimal tumor burden, through induction chemotherapy or surgical resection, prior to myeloablative chemotherapy with AuHPCR. HGG 12. TREATMENT FAILURES IN CHILDREN WITH HIGH-GRADE GLIOMAS: RESULTS FROM THE POLISH NEURO-ONCOLOGY STUDY GROUP (PNOSG) Danuta Perek,1 Monika Drogosiewicz,1 Bozenna Dembowska-Bagiñska,1 Marta Perek-Polnik,1 Grazyna Sobol,2 Anna Szolkiewicz,3 Anna Balcerska,3 Dorota Wojcik,4 Alicja Chybicka,4 Hanna Wisniewska-Slusarz,5 Jerzy Kowalczyk,5 Beata Zalewska-Szewczyk,6 and Walentyna Balwierz7; 1Department of Oncology, The Children's Memorial Health Institute, Warsaw, Poland; 2Pediatric Oncology and Hematology, Medical Academy Katowice, Poland; 3Pediatric Oncology and Hematology, Medical Academy Gdansk, Poland; 4Pediatric Oncology and Hematology, Medical Academy Wroclaw, Poland; 5Pediatric Oncology and Hematology, Medical Academy Lublin, Poland; 6Pediatric Oncology and Hematology, Medical Academy Lodz, Poland; 7Pediatric Oncology and Hematology, Medical Academy Krakow, Poland. Introduction: Despite progress in the treatment of CNS malignant tumors, the diagnosis of high-grade gliomas (HGGs) still carries a poor prognosis. The aim of our study was to analyze treatment failures in children with HGGs treated according to the PNOSG. Materials: Between 1996 and 2007, 112 patients (52 girls and 60 boys), from 3 to 24 years of age (mean, 10 years 8 months) with HGG were registered and treated according to national protocols, which included surgery, preradiation chemotherapy, radiotherapy, and maintenance chemotherapy. Fifty-two patients were diagnosed with anaplastic astrocytoma (AA) and 60 with glioblastoma multiforme (GBM). To rule out incorrect diagnosis all pathology specimens were reviewed by three independent Polish pathologists. Up until 2005, all specimens were also verified by a German center and, currently, difficult cases are sent there. Method: We analyzed event-free survival (EFS) in the whole group, by age, histopathological diagnosis, surgical radicality (total/subtotal resection vs. partial resection/biopsy), and type of chemotherapy protocols (protocol I consisting of CBDCA,VCR,VP/CTX, VCR, and VP before radiotherapy and VCR, CDDP, and CCNU as maintenance versus protocol II consisting of preradiation IF, VP/IF/DOXO, and VCR, CDDP, CCNU/temozolomide, and CDDP as maintenance). Overall survival (OS) of patients who had progressed/relapsed was assessed and correlated with the time from diagnosis to progression/relapse, type of relapse, and treatment approach. Results: Five-year EFS in the whole group was 34.7%. There were no toxic deaths. Five-year EFS was significantly worse for patients who underwent partial resections or biopsies compared to total resections (17.4% vs. 49.9%, p = 0.0006). Children <15 years of age had a significantly worse 5-year EFS (19.5%) when compared to older ones (66%) (p = 0.001). Patients with AA and GBM had an EFS of 44.2% and 26.6%, respectively (p = 0.31). Patients treated with protocol I had a 5-year EFS of 16.67% and 40.5% with protocol II (p = 0.07). Progression/relapses were observed from 1 month to 5 years 5 months from diagnosis (mean, 9 months). Fifty-two episodes occurred during treatment, 10 after treatment cessation. Twelve were local relapses, 6 solitary metastases, 2 disseminations, and 32 progressions of residual tumors. Five-year OS for relapsed patients was 3.7%, for early relapse; 3-year OS was 0% and for late 30%. When treatment of relapse was undertaken (chemotherapy, surgery), 2-year OS was 17.3%. It concerns two patients who had late-occuring solitary metastases. Conclusions: Of our patients with HGG, 65% failed treatment. Biopsies, partial resections, and younger age (<15 years) were unfavorable prognostic factors. Chemotherapy according to protocol II seemed to (though not statistically) cause better results. Histopathology (AA vs. GBM) in our series did not have an impact on failures; 83.8% of progression/relapses occurred early, suggesting that primary resistance to chemotherapy and radiotherapy and cure of these patients was not possible. NEURO-IMAGING IMAGI 1. 1H-MAGNETIC RESONANCE SPECTROSCOPY AS AN AID TO THE DIAGNOSIS OF BRAINSTEM TUMORS: A MULTICENTER STUDY Lisa Harris,1 Lesley Macpherson,2 Dorothee Auer,3 Theodoros Arvanitis,4 Darren Hargrave,5 Franklin Howe,6 Tim Jaspan,7 Martin Leach,8 Kal Natarajan,9 Paul Morgan,3 Geoffrey Payne,10 Dawn Saunders,11 Richard Grundy,12 and Andrew Peet13; 1University of Birmingham, Edgbaston, Birmingham, West Midlands, UK; 2Birmingham Children's Hospital NHS Foundation Trust, Birmingham, West Midlands, UK; 3Nottingham, UK; 4Electronic, Electric and Computer Engineering, University of Birmingham, Edgbaston, Birmingham, West Midlands, UK; 5Paediatric Oncology, Royal Marsden Hospital, Sutton, Surrey, UK; 6St Georges, University of London, London, UK; 7Department of Radiology, Nottingham University Hospitals Trust, Nottingham, UK; 8Sutton, Surrey, UK; 9Medical Physics and Imaging, University Hospital Birmingham NHS Foundation Trust, Birmingham, West Midlands, UK; 10Royal Marsden Hospital, Sutton, Surrey, UK; 11Great Ormond Street Hospital, London, UK; 12Children's Brain Tumour Research Centre, Queens Medical Centre, Nottingham, Nottinghamshire, UK; 13Academic Paediatrics and Child Health, University of Birmingham, Edgbaston, Birmingham, West Midlands, UK. Background: The diagnosis and management of brainstem tumors presents a major challenge to pediatric oncology. The brainstem is a difficult location to biopsy, and diagnoses are often made on clinical and imaging grounds alone. Noninvasive methods that can improve our understanding of these tumors would be particularly valuable. 1H-magnetic resonance spectroscopy (MRS) provides information on the metabolic characteristics of the tumors that is not available from conventional imaging. As such, MRS may provide novel indicators for the diagnosis, management, and understanding of childhood brainstem tumors. This study investigates MRS in conjunction with conventional MRI to aid diagnosis of tumors of the brainstem. Materials and Methods: Diagnoses were made on the basis of either biopsy or clinical parameters and central radiological review of MRI scans. Radiological diagnosis of brainstem tumors was made by a consensus opinion of two neuroradiologists. Short echo-time (30 ms), single-voxel MRS was performed on 26 children at four centers during routine diagnostic MR imaging for patients with brainstem lesions. The cohort consisted of 13 diffuse pontine gliomas (DPG); four DPGs not confined to the pons referred to here as diffuse glioma (DG); three unbiopsied low-grade gliomas (LGGs); one biopsied ganglioglioma; two biopsied high-grade gliomas (bHGG); one tumor of the tectal plate with nondiagnostic biopsy presumed high-grade glioma due to imaging characteristics and clinical behaviour (TPHGG); and two neurofibromatosis hamartomas in the brainstem (NBO). The bHGGs and TPHGG were grouped together as high-grade gliomas (HGG). MRS data were processed using LCModel to determine metabolite concentrations and lipid levels relative to water and ratios to total choline. Two-tailed t-tests of significance were applied. Results: Diffuse tumors (DPG + DG) had significantly higher creatine/total choline (2.43 vs. 1.17, p = 0.004) and myoinositol/total choline (4.37 vs. 2.05, p = 0.008) ratios compared with the focal tumors. In the group of focal tumors, LGGs had a significantly higher myoinositol/total choline than the HGGs (3.3 vs. 1.5, p = 0.048). DGs showed significantly higher lipid levels at 1.3 ppm when compared with DPGs (36.1 vs. 7.4, p = 0.015). DGs also showed an elevated level of lipids at 0.9 ppm compared with DPGs (9.1 vs. 4.1, p = 0.06). Lipid levels in DGs were comparable to the values found in focal HGGs and were higher than those in the LGG. NBO spectra showed many differences compared with tumor spectra; in particular, there were lower concentrations of myoinositol (4.4 vs. 7.4) and glutamate plus glutamine (4.6 vs. 7.5) in tumor spectra compared with NBO spectra. Conclusions: MRS shows key differences between diffuse and focal tumors in the brainstem with creatine/total choline and myoinositol/total choline being important discriminators. In addition, myoinositol/total choline is a significant discriminator between LGG and HGG. The similarity of the concentrations of lipids in DGs and HGGs is consistent with this tumor group showing a more aggressive nature than DPGs. This study has shown that MRS provides information that may be useful in the diagnosis and characterization of brainstem tumors. Further multicenter studies are required to link these results to specific clinical outcomes and prognostic factors. IMAGI 2. 99MTC-METHOXYISOBUTYLISONITRILE (SESTAMIBI) SPECT IMAGING IN ADULT AND PEDIATRIC MALIGNANT GLIOMA Asma Shah,1 Frank Saran,1 Gary Cook,1 and Darren Hargrave1; 1Royal Marsden Hospital, Sutton, UK. Background: 99mTc-methoxyisobutylisonitrile (MIBI) or Sestamibi SPECT has been reported to be a useful imaging modality in the assessment of adult gliomas. Initially utilized to distinguish between tumor progression and radionecrosis, Sestamibi SPECT has also been documented to correlate with histological grade and act as an early prognostic factor for treated malignant glioma. Only one previous study has reported this imaging modality in pediatric brain tumors. Methods: Patients with a known malignant glioma (after informed consent) were given an intravenous injection of 99mTc-MIBI calculated according to body surface area to result in an equivalent adult dose of 750 MBq. Imaging was initiated 10–15 min later using a triple-head gamma camera with an acquisition time of 30–45 min. The maximum allowed interval between MRI scan and sestamibi SPECT was 2 weeks. The “MIBI index” was calculated by taking the ratio of uptake in tumor versus that in normal parenchyma. If the initial Sestamibi SPECT was positive in the tumor a second SPECT was repeated at the time of MRI to assess treatment response. Results: Over an 18-month period, 16 patients with malignant glioma (nine adults and seven children) underwent Sestamibi SPECT imaging. The mean age of the adult cohort was 55 years (range, 48–62 years); the mean age for the pediatric cohort was 11 years (4.5–16 years). All the patients had a histological verified glioblastoma (GBM) except one of the pediatric patients who radiologically had a classic diffuse intrinsic pontine glioma. All patients had an initial Sestamibi scan; six went on to have a second scan following treatment. Eight patients had a negative initial Sestamibi scan (three of nine [33%] in the adult cohort and five of seven [71%] in the pediatric cohort). The mean MIBI index in the eight positive initial scans was 2.5 (range, 1.7–3.8). For the six patients undergoing a second Sestamibi SPECT scan the ratio decreased in two and increased in four and correlated with MRI tumor response or progression. Mean overall survival was 12.6 months (11.2 pediatrics, 13.7 adults months). For Sestamibi (initial scan) positive patients mean survival was 11.5 months versus 13.7 months for those with a negative SPECT. In one adolescent GBM patient, a whole body Sestamibi SPECT helped to detect extracranial relapse with metastatic bone lesions (confirmed by MRI). Conclusion: This pilot study demonstrated that 50% of malignant gliomas exhibited uptake of Sestamibi at diagnosis and there was correlation with MRI tumor response in these patients after adjuvant therapy. This imaging modality also proved useful in the unusual setting of a patient with extracranial progression of a GBM. However in the pediatric population there was a high false-negative rate (71%), which contrasted with the adult cohort and this would limit the potential utility of this novel imaging modality in children with malignant glioma. IMAGI 3. DIFFUSION TENSOR IMAGING AND FIBERTRACKING IN PEDIATRIC GLIOMAS Ervin Berényi,1 László Novák,2 László Bognár,3 and Péter Molnár4; 1Radiology, University of Debrecen, Medical and Health Sciences Center, Debrecen, Hungary; 2Neurosurgery, University of Debrecen, Debrecen, Hungary; 3Neurosurgery, University of Debrecen, OEC, Debrecen, Hungary; 4Pathology, University of Debrecen, Medical and Health Sciences Center, Debrecen, Hungary. Theoretical Background: Water compartmentalization and diffusion behavior are strongly dependent on the degree of organization of intra- and extracellular structures. The high water content of brain tissue plus its well-organized fiber structure provide optimal basis for studying restricted water movements, which can be described with a tensor. While the structure of the brain is highly ordered, each pathological process destroys this order and hence results in different alterations of the anisotropic water movements along the XYZ coordinates (i.e., within 3D space). With diffusion tensor imaging (DTI) we can visualize this anisotropic pattern of water diffusion in pediatric CNS tumors that often have uniquely ordered histological growth patterns (pilocytic: compact vs. biphasic). DTI is capable of demonstrating water movement properties, since the latter is severely affected by the changes of the intratumoral “milieu intérieur.” Applying the fiber tracking method to DTI data, different brain pathways (i.e., functional connections) can be visualized. Based on these images, disruption, shifting, and destruction of white matter fibers can be avoided while planning the most optimal surgical approaches. Materials and Methods: Pediatric gliomas of various WHO grades have been collected for >2 years now and are continuously being worked up according to a new and ever “revised/improved” (i.e., broadened) protocol. Histopathological workup includes routine stains, a wide panel of immunohistochemical (IHC) reactions, and, in some cases, electron microscopy plus molecular/genetical analysis (1p19q co-deletions [FISH]). Imaging is supplemented with PET/CT studies and image co-registration when it is feasible (FDG, methionin, CT, MRI), and MR spectroscopy has recently been added to the armamentarium. A 1.5 T GE Excite magnet was used. Multiple pulsed gradients were used in 25 different steps (b = 1,000). Fiber tracking was carried out with dTV, Volume One and 3D Slicer, additionally to the commercial GE possibility. Results and Conclusions: We present a series of illustrative cases in which this kind of analysis (1) helped planning surgery (i.e., the often unorthodox surgical approach has been planned based on DTI and fiber tracking features to avoid any possible functional noxae and sequalae); (2) the comparative results obtained by DTI in pilocytic astrocytomas (circumscribed and infiltrating types) and grade II–IV pediatric astrocytomas are rather different. In certain tumors (e.g., those forms in which the palisading arrangement of elongated, bipolar cells seen in a highly ordered, structured pattern dominates), DTI may closely reflect locoregional cellular patterns, but this feature is critically dependent upon proper surgical sampling. This kind of image representation of cellular pattern(s) has not, heretofore, been possible to obtain in grade II–IV tumors. The histological arrangement showed no consistent relationship with IHC and/or molecular characteristics of the tumors. Further experience and more calculations are needed for the precise evaluation of tumor grading (vis-à-vis the new WHO classification) and their clinical/biological behavior. For now, it suffices to state that the method is more than promising. IMAGI 4. FALSE-POSITIVE MRI FINDINGS IN FOLLOW-UP OF PEDIATRIC PATIENTS WITH TUMORS OF THE CNS: THE CHILDRENS HOSPITAL LOS ANGELES (CHLA) EXPERIENCE Satiro De Oliveira,1 Ignacio Gonzalez-Gomez,2 Ashok Panigrahy,3 Mark Krieger,1 Marvin Nelson,4 Gordon Mccomb,5 Robert Lavey,6 Jonathan Finlay,7 and Girish Dhall1; 1Childrens Hospital Los Angeles, Los Angeles, CA, USA; 2Department of Pathology, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 3Childrens Hospital Los Angeles, CA, USA; 4Department of Imaging Services, Children Hospital of Los Angeles, CA, USA; 5Neurosurgery, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 6Childrens Hospital of Los Angeles, Beverly Hills, CA, USA; 7Los Angeles, CA, USA. Background: Management of patients with CNS tumors relies largely on MRI scans to document disease progression or recurrence. The finding of new enhancing lesions always presents the challenge of differentiating among postsurgical changes, radiation necrosis, gliosis, and tumor, submitting these patients to more aggressive therapy and hence more toxicity. Methods: We analyzed the medical records of four patients with malignant CNS tumors treated at Childrens Hospital Los Angeles who had false-positive MRI findings suggestive of tumor recurrence. Results: Patient 1 is a male diagnosed with disseminated choroid plexus carcinoma at 1 year of age. He had a gross total resection (GTR) of the primary lesion in the right lateral ventricle followed by chemotherapy with three cycles of induction chemotherapy with cisplatin, vincristine, cyclophosphamide, and etoposide followed by three cycles of consolidation with thiotepa and carboplatin with autologous hematopoietic progenitor cell rescue (AuHCR), without irradiation. MRI scan at the end of therapy showed persistent marked leptomeningeal enhancement. Therefore, a biopsy of the leptomeninges was undertaken that was interpreted as fibrosis. Follow-up scans 3 years later without further treatment shows stable nodular leptomeningeal enhancement. Patient 2 is a female diagnosed at 15 years of age with myxopapillary ependymoma of the spinal cord from L2 to L4 level. She had a partial resection of the tumor followed by irradiation to the tumor bed. She developed a local recurrence 2 months after completing irradiation. She then had a GTR of the tumor followed by chemotherapy with carboplatin 175 mg/m2 weekly (4 weeks on and 2 weeks off) for seven cycles. While receiving chemotherapy, a follow-up MRI scan showed a new enhancing mass at the level of L3 of the lumbosacral spine. A biopsy of the lesion showed fibrosis with no evidence of tumor recurrence. Patient 3 is a 4-year-old male with disseminated medulloblastoma with gross nodular disease in the spinal cord. He received five cycles of induction chemotherapy using cisplatin, vincristine, etoposide, cyclophosphamide, and high-dose methotrexate followed by AuHCR using thiotepa and carboplatin. He had a marked response to chemotherapy. However, since he had gross residual disease at the beginning of consolidation, he received craniospinal proton beam irradiation with focal boosts followed by low-dose temozolomide and cis-retinoic acid. On a follow-up MRI scan 17 months after diagnosis, interval increase in nodular enhancement in the region of the lower lumbosacral spine consistent with tumor recurrence was noted. Resection of this mass showed gliosis with no evidence of active tumor. Patient 4 is a male who was diagnosed at 3 years of age with posterior fossa ependymoma. He had a GTR of his tumor followed by intensity modulated radiation therapy to the tumor bed. At 16 months after resection, he developed a new 5 mm enhancing nodule on the dorsal medulla. Resection of this mass showed reactive glial tissue with no evidence of recurrent tumor. Conclusion: Not everything that enhances on brain or spine MRI is viable tumor. A biopsy should be considered in the decision-making process in evaluation of potentially recurrent CNS tumors. IMAGI 5. FIESTA MR IMAGING FOR DETECTION OF EARLY RECURRENCE AND INCOMPLETE RESECTION IN CHILDREN WITH INFRATENTORIAL EPENDYMOMA Betty Herrington,1 Michelle Silvera,2 Yen-Lin Chen,3 Liliana Goumnerova,4 Michael Scott,5 Mark Kieran,1 and Nicole Ullrich6; 1Pediatric Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 2Radiology, Children's Hospital Boston, Boston, MA, USA; 3Massachusetts General Hospital, Boston, MA, USA; 4Department of Neurosurgery, Children's Hospital Boston, Boston, MA, USA; 5Neurosurgery, Children's Hospital Boston, Boston, MA, USA; 6Children's Hospital of Boston, Boston, MA, USA. Background and Purpose: Ependymomas in children are aggressive tumors for which gross total resection is considered to be the most significant indicator of clinical outcome. Ependymomas have a predilection for the fourth ventricle and often extend into the cerebellopontine angle (CPA) and through the foramen of Lushka. They also can occur in the supratentorial compartment. Fast imaging employing steady-state acquisition (FIESTA) imaging has been shown to facilitate superior assessment of the cranial nerve anatomy in the cisternal segments where there is high cerebrospinal fluid–nerve contrast with high spatial resolution. In addition, the intensity of many tumor types is increased with FIESTA imaging. We hypothesize that FIESTA imaging may be helpful for preoperative assessment as well as for increased evaluation of extent of resection and detection of early recurrence of ependymoma. Methods: Routine pre- and postoperative MR-imaging studies of patients that included FIESTA imaging were retrospectively reviewed in patients with histologically proven ependymoma. All imaging studies were performed with the 1.5-T scanner using an eight-channel head coil. Imaging studies were assessed for signal intensity, gadolinium enhancement of tumors, and depiction of the relationship between tumor and the cranial nerves and surrounding parenchyma. All patients underwent surgical removal of the tumors, and FIESTA findings were compared with intraoperative observations and postoperative imaging studies. Results: FIESTA imaging was helpful for imaging of posterior fossa ependymoma in several ways. Extent of tumor involvement at the foramen of Luschka and association with cranial nerves was better visualized both pre- and postoperatively. In addition, in several patients, incomplete resection and early evidence for tumor recurrence was detected in patients with both infra- and supratentorial ependymoma, for whom intraoperative observation and postoperative imaging studies were thought to demonstrate gross total resection. By contrast, residual and recurrent tumor was not as well-visualized on standard T1, T1 with contrast, T2, and FLAIR imaging. Tumor recurrence was confirmed by subsequent intraoperative re-resection. Conclusion: Gross total resection for ependymoma remains the cornerstone of therapy. FIESTA MR sequences are a helpful tool preoperatively for evaluation of the cranial nerves affected by tumor. In a selected population of patients with both infra- and supratentorial ependymoma, use of FIESTA MR for postoperative neuroimaging was important for increasing the detection of incomplete tumor resection and for visualization of early recurrence that was not otherwise evident on standard postoperative imaging. We plan a prospective study of FIESTA imaging in patients with supra- and infratentorial ependymoma to determine the overall sensitivity and specificity of this imaging technique. IMAGI 6. HISTOLOGICAL AND RADIOLOGICAL FEATURES IN A SERIES OF PEDIATRIC MALIGNANT GLIOMAS: CORRELATION WITH THE OUTCOME Nathalie Boddaert,1 Stephanie Puget,1 Catherine Miquel,2 Jacques Grill,3 Francis Brunelle,1 Christian Sainte-Rose,1 and Pascale Varlet2; 1Necker Sick Children's Hospital, Paris, France; 2Sainte-Anne Hospital, Paris, France; 3Institut Gustave Roussy, Villejuif, France. Purpose: Pediatric malignant gliomas (pMGs) differ from adult ones in terms of prognosis despite similar histological classification. The diagnostic accuracy and reproducibility of histology are suboptimal to predict prognosis. For pediatric population, prognosis significance of histological classification has to be assessed and specific imaging features have to be correlated with this disease. Material and Methods: We reviewed a selected series of 96 patients undergoing surgical procedure at diagnosis affected with pMG (grade 3 and 4 according to WHO classification). All histological samples have been blindly and independently reviewed by two national anatomopathologists. Additional immunohistological staining was performed when necessary. The patients were classified according to WHO and Sainte-Anne (SA) classifications. Radiological features were reviewed independently by a pediatric neuroradiologist and two pediatric neurosurgeons and included location, tumor size, cyst, necrosis, sharp versus indistinct border, contrast enhancement, ratio of enhancement area versus the hyper-T2 signal area, meningeal attachment, and polycyclic aspect. Statistical analyses were performed to associate clinical, radiological, and histological features (as assessed by WHO and SA classifications) to outcome. Results: Cohort mean age was 7.4 years (range, 5 days to 17 years) with a sex ratio of 1:4. Median follow-up was 19 months (range, 1.8 months to 17 years). Tumors were mainly hemispheric (48.9%), followed by brainstem (26.6%), and basal ganglia (24.5%). After histopathological revision, low-grade gliomas (LGGs), and nonglial tumors were excluded; LGG 5-year overall survival (OS) was significantly better compared to malignant tumors (80% vs. 20%; p = 0.000, log rank). SA classification showed to better discriminate prognosis compared to WHO classification. SA remarked a clear difference in terms of 3-year survival rate among oligodendendroglioma A group, oligodendendroglioma B, glioneuronal tumors, and GBM (75%, 55%, 20%, and 0%, respectively). Tumor location was also associated to 3-year survival rate according to the three groups: hemispheric (60%), basal ganglia (20%), and brainstem (0%) tumors (p = 0.004). Three radiological criteria were found to be significantly associated to better survival: (1) T2 signal area no larger than enhancement area (p = 0.003), (2) meningeal attachment (p = 0.02), and (3) sharp borders (p = 0.01). Conclusions: SA classification seems to better distinguish pMG in terms of outcome compared to WHO classification. We identified imaging features that were correlated to better outcome. This study is a prerequisite to further genomic investigations that may provide additional information to improve pMG classification. IMAGI 7. IN VIVO PROTON MR SPECTROSCOPY OF INTRACRANIAL GERMINOMAS Ashok Panigrahy,1 Jonathan Finlay,2 Marvin Nelson,3 Mark Krieger,4 Ignacio Gonzalez-Gomez,5 Floyd Gilles,1 and Stefan Bluml2; 1Childrens Hospital Los Angeles, Los Angeles, CA, USA; 2Los Angeles, CA, USA; 3CA, USA; 4Neurosurgery, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 5Department of Pathology, Childrens Hospital Los Angeles, Los Angeles, CA, USA. Methods: MR spectra from 20 pediatric patients with pathology-proven intracranial germ cell tumors (13 pure and 7 mixed) were retrospectively reviewed (Table 1). Metabolic features were compared with other common pediatric brain tumors such as medulloblastoma (n = 14), ependymoma (n = 8), astrocytoma (n = 8), and pilocytic astrocytoma (n = 14) that have been previously studied at this institution. All spectra were acquired with a short echo time (TE = 35 ms) PRESS sequence. Spectra were processed with fully automated LCModel software (Stephen Provencher Inc., ON, Canada), and metabolite concentrations of N-acetyl-aspartate (NAA), creatine (Cr), choline (tCho), myo-inositol (mI), taurine (Tau), and lipid intensities were determined. Also reviewed were features of spectra such as the full width at half maximum (FWHM), a measure of homogeneity of the magnetic field in the region of interest. Serum and cerebrospinal fluid (CSF) levels of alpha-fetoprotein and beta–human chorionic gonadotropin were obtained from the clinical records. IMAGI 7: Table 1. Number of patients . Pineal . Suprasellar . Basal Ganglia . Pure 8 2 3 Mixed malignant 3 3 1 . Pineal . Suprasellar . Basal Ganglia . Pure 8 2 3 Mixed malignant 3 3 1 Open in new tab IMAGI 7: Table 1. Number of patients . Pineal . Suprasellar . Basal Ganglia . Pure 8 2 3 Mixed malignant 3 3 1 . Pineal . Suprasellar . Basal Ganglia . Pure 8 2 3 Mixed malignant 3 3 1 Open in new tab Results: Pineal germinoma—MR spectra of pure pineal germinoma showed features generally also found in other tumors such as prominent lipids, low NAA, elevated tCho, and reduced Cr. In addition, Tau (3.6 ± 1.3 mmol/kg, n = 8) was consistently observed. There was no evidence for taurine in mixed pineal tumors (0.0 ± 0.0, n = 3, p < 0.05). But it needs to be acknowledged that the quantitation of taurine was compromised by the larger line width of peaks in mixed tumor spectra (13 ± 6 vs. 7 ± 2 Hz, n.s.). Also, lipids appeared to be more prominent in pure germinoma than in mixed but significance was not reached due to the small number subjects studied. Nonpineal germinoma—pure and mixed germinoma showed a large line width (11 ± 3 Hz) that was significantly higher than the line width observed in other common pediatric brain tumors (5 ± 1, p < 0.001). There was no difference in metabolite or lipid levels between mixed and pure germinoma that occurred outside the pineal region. There was no correlation between serum and CSF tumor markers and MR spectroscopy data. Discussion: This study demonstrated two major MR spectroscopy features of germ cell tumors: (1) pure pineal germinoma present with prominent taurine; and (2) nonpineal germ cell tumors (pure + mixed) demonstrate a high line width that likely reflects the heterogeneity of the lesions. These characteristics may help to differentiate germ cell tumors that cannot be separated by serum and CSF tumor markers and may be useful to distinguish germ cell tumors from other tumors. IMAGI 8. MAGNETIC RESONANCE SPECTROSCOPY IN THE ASSESSMENT OF JUVENILE PILOCYTIC ASTROCYTOMAS Lisa Harris,1 Nigel Davies,1 Lesley Macpherson,2 Shaheen Lateef,2 Kal Natarajan,3 Marie-Anne Brundler,2 Spyros Sgouros,2 Martin English,4 Theodoros Arvanitis,5 Richard Grundy,6 and Andrew Peet1; 1Academic Paediatrics and Child Health, University of Birmingham, Edgbaston, Birmingham, West Midlands, UK; 2Birmingham Children's Hospital NHS Foundation Trust, Birmingham, West Midlands, UK; 3Medical Physics and Imaging, University Hospital Birmingham NHS Foundation Trust, Birmingham, West Midlands, UK; 4Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK; 5Electronic, Electric and Computer Engineering, University of Birmingham, Edgbaston, Birmingham, West Midlands, UK; 6Children's Brain Tumour Research Centre, Queens Medical Centre, Nottingham, Nottinghamshire, UK. Background: Juvenile pilocytic astrocytomas (JPAs) are common pediatric tumors that occur in a variety of locations within the CNS and have a wide range of clinical outcomes. Cerebellar JPAs are usually cured by surgery alone, whereas supratentorial lesions are commonly located in areas not amenable to complete surgical resection and have poorer prognosis. Tumors in the optic pathway and thalami present a considerable management challenge, in part due to current limitations in imaging methods in predicting and assessing tumor response. 1H magnetic resonance spectroscopy (MRS) is a powerful noninvasive tool for assessing brain tumors and can be performed in addition to conventional MRI to provide information on tissue biochemistry. We have investigated the role of MRS in the assessment of JPAs and provide preliminary evidence for biological correlates of tumor behavior. Methods: Single-voxel MRS was performed as part of the routine clinical imaging on two 1.5-T scanners. All voxels were cubic with 1.5 cm or 2.0 cm side length (TE 30 ms, TR 1,500 ms). Raw MRS data was processed using LCModel to determine metabolite concentrations (relative to water) and quality control parameters. For a case to be included, the voxel had to be placed wholly within the tumor, signal-to-noise ratio had to be greater than 5 and full width at half maximum had to be <0.15 ppm, indicating acceptable resolution. Differences in MRS metabolite concentrations for different locations were analyzed using two-tailed t-tests followed by a principal component analysis. Biological correlates of tumor behavior were determined by comparing the MRS profiles of tumors that progressed, based either on clinical and imaging grounds and led to a decision to alter their clinical management plan, with those with stable or responding disease. A set of control spectra were recorded from brain distance to the tumor in 11 children with brain tumors who had received no treatment other than surgery. Results: MRS of acceptable quality was performed on 21 children with JPAs prior to any adjuvant treatment: 9 cerebellar and 12 supratentorial lesions (including four nonbiopsied optic pathway gliomas). The supratentorial tumors had significantly higher myo-inositol (p < 0.01) and glutamate plus glutamine (p = 0.02) than cerebellar tumors, and the tumors formed distinct groups on the principal component analysis. In the control cases, glutamate plus glutamine was significantly higher in the supratentorial regions (p = 0.02), but there was no significant difference in myo-inositol levels (p = 0.6). Out of those with optic pathway or thalamic tumors, the five patients who progressed (average time to progression 12.2 months) had a significantly (p = 0.04) lower myoinositol level than the other six patients (average time of follow-up 30 months). Of these patients, nine had follow-up MRS with a median time between first and second MRS of 2.2 months. Tumors that progressed showed a significant (p = 0.03, paired t-test) drop in the concentration of myoinositol between the two scans. Conclusions: MRS can detect differences between JPAs in the cerebellum and in the supratentorial regions and may provide useful prognostic biomarkers for supratentorial tumors. Further studies, with larger cohorts, are required to verify these findings. IMAGI 9. METABOLITE PATTERNS IN PONTINE GLIOMAS POSTRADIATION: COMPARISON OF SINGLE AND MULTIVOXEL SPECTROSCOPIC TECHNIQUES Emilie Steffen-Smith,1 Paul Albert,1 and Katherine Warren1; 1National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA. Background: Pediatric diffuse intrinsic pontine gliomas (DIPGs) represent a group of poorly understood tumors with a grim prognosis. Conventional magnetic resonance imaging (MRI) findings are used for diagnosis but have no prognostic significance. Magnetic resonance spectroscopic imaging (MRSI) allows noninvasive monitoring of metabolite changes in brain tumors. Elevated choline/N-acetyl aspartate (Cho/NAA) ratios are associated with active tumor in supratentorial gliomas and presumably in DIPGs. Small shifts in Cho/NAA ratios may correlate with changes in tumor status. This study explores the prognostic value of two MRSI techniques by examining metabolic changes in patients with DIPG postradiation therapy. Objective: To assess the agreement in Cho/NAA ratios between two MRSI techniques and the variance of multivoxel data within the tumor region of interest (ROI) relative to radiation therapy. Methods: Eligible patients had a brainstem mass consistent with DIPG based on MRI findings. Spectroscopic data were acquired longitudinally on a 1.5-T magnet using both single and multislice, multivoxel techniques. Single-voxel ROIs included bulk of tumor mass. Multivoxel ROIs were selected to match the size and relative location of the single-voxel ROI for the same time point. Single-voxel Cho/NAA ratios were compared to the maximum Cho/NAA ratio from the corresponding multivoxel imaging study. Data were assessed for (1) agreement between MRSI techniques and (2) the relationship between time since radiation therapy and variation among voxel ratios for multivoxel data. A difference of 0.5 between the two measurements was determined as clinically significant. Dependence of multiple observations from the same individual was addressed using a linear mixed model. Results: Single- and multivoxel MRSI were performed longitudinally on 12 patients. Multivoxel ROIs ranged in size from 6 to 24 voxels (mean = 13 voxels). Of the selected regions, useable voxel data ranged from 20% to 100% (mean = 73%). The mean difference between Cho/NAA measurements was 0.077. Cho/NAA ratios differed by >0.50 for 20 of 38 scans. Results indicated a 72% probability of the absolute value of the difference between the two measurements being >0.50. Eleven patients received radiation therapy and multivoxel MRSI. Imaging studies were acquired between 14 and 763 days postradiation (mean = 242 days). Variance among voxels appeared to decrease over time since radiation therapy, but this trend was not significant (Pearson's correlation coefficient r = –0.36, p = 0.17). Conclusion: Appropriate disease assessment is critical to improving treatment of DIPGs. This study is the first to compare single- and multivoxel metabolite data in these tumors. Disagreement between Cho/NAA ratios was clinically significant for >50% of scans. Comparisons between multivoxel data and time since radiation revealed greater Cho/NAA ratio variance closer to radiation therapy. Further evaluation in a larger population is needed to evaluate this trend. Given the heterogeneous composition of DIPGs, multivoxel MRSI may provide more useful information about tumor infiltration and aggressiveness compared to single-voxel techniques. Such information is needed for biopsy planning. Correlations between MRSI data and patient survival are currently underway to further evaluate the prognostic value of multivoxel techniques. IMAGI 10. NONINVASIVE MEASUREMENT OF ICP USING MRI TECHNIQUE IN PATIENTS WITH HYDROCEPHALUS AND BRAIN TUMORS Roberta Glick,1 Sang Lee,2 John Curran,3 Tadanori Tomita,3 Joy Ito,3 Terry Lichtor,1 and Noam Alperin4; 1John H. Stroger, Jr. Hospital, Chicago, IL, USA; 2IL, USA; 3Children's Memorial Hospital, Chicago, IL, USA; 4University of Illinois at Chicago, Chicago, IL, USA. Hydrocephalus is a common presentation of pediatric brain tumors. The decision regarding the need for a shunt postoperatively is complicated by a number of factors because ventriculomegaly may or may not be associated with elevated intracranial pressure (ICP). In addition, small ventricular size is not always indicative of low pressure. The decision for surgical intervention in such cases is an important one with significant long-term sequelae. Thus, a noninvasive means of determining ICP is urgently needed. We recently reported the potential clinical utility of a new noninvasive MRI-based measurement of ICP (MR-ICP) in a series of symptomatic hydrocephalic patients undergoing surgery for brain tumors. We found that MR-ICP measurement had a strong negative predictive value for surgery (i.e., patients with normal MR-ICP did not require surgical intervention during the 3-month follow-up period). In the present study, we performed validation studies correlating invasive ICP measurements with noninvasive MR-ICP in six pediatric patients with brain tumors associated with hydrocephalus, as a means of determining their future need for a shunt. The patients ranged in age from 6 months to 16 years. The diagnosis was posterior fossa tumor in five, and one patient had a supratentorial thalamic tumor. All patients had an indwelling EVD placed for control of their hydrocephalus. The validation studies were obtained by the simultaneous invasive measurements of ICP, via the indwelling EVD, and measured at the time of the noninvasive MR-ICP determinations. We found excellent correlation between the noninvasively measured MR-ICP and the invasive measurements of ICP in these patients, especially in cases of elevated ICP. This noninvasive means of measuring ICP in hydrocephalic patients will hopefully be a useful clinical tool in guiding therapeutic decisions and may obviate the need for surgery in questionable cases. IMAGI 11. NOVEL MAGNETIC RESONANCE TECHNIQUES DETECT NEUROTOXICITY PROFILES IN PEDIATRIC POSTERIOR FOSSA TUMOR PATIENTS Stefan Rueckriegel,1 Friederike Blankenburg,2 Guenter Henze,2 Harald Bruhn,3 and Pablo Hernaiz Driever1; 1Department of Pediatric Oncology/Hematology, Charité-Universitaetsmedizin Berlin, Berlin, Germany; 2Department of Pediatric Oncology and Hematology, Charité-Universitaetsmedizin Berlin, Berlin, Germany; 3Department of Radiology, Charité-Universitaetsmedizin Berlin, Berlin, Germany. Objectives: Pediatric posterior fossa tumors cause neurologic and neurocognitive long-term deficits in survivors. Sequelae are more pronounced in CNS-irradiated medulloblastoma (MB) patients (WHO IV) than in pilocytic astrocytoma (PA) patients (WHO I). Our goal was to quantify neurotoxicity-associated therapy by comparing MRI-based data of these groups of patients. Methods: Nineteen MB patients (mean age ± SD, 15 years ± 4.8 years) and 16 PA patients (11.8 years ± 4.8 years) were subjected to diffusion tensor imaging (DTI), on a 3T-MR system. Voxelwise statistical analysis of fractional anisotropy (FA) data was carried out using Tract-Based Spatial Statistics of FMRIB Software Library. MR H-1 spectroscopy (MRS) was carried out in 23 MB patients (13 years ± 5.1 years) and 19 PA patients (12.1 years ± 4.8 years). Volumes of interest were set in parietal white (WM) and grey matter (GM) using the PRESS technique (TR/TE/NEX = 6,000 ms/30 ms/64). Metabolite resonances were quantified by the operator-independent LCModel method. Results: A significant decrease of FA was observed in a cluster of voxels in the right lateral occipital white matter of MB patients. In spectroscopy significantly decreased concentrations of NAA, Cho, and Glu were observed in WM of MB patients compared to PA patients (p < 0.05, Mann-Whitney U-test). Conclusion: DTI and 1H spectroscopy proved to be useful tools for objective measures of neurotoxicity in children. Pre- and posttherapy assessments are warranted to detect intraindividual alterations of FA and metabolites. IMAGI 12. O-(2-[18F] FLUOROETHYL)-L-TYROSINE (FET) IN THE DIAGNOSIS OF CNS TUMORS IN CHILDHOOD AND ADOLESCENCE Frederik Grosse,1 Michail Plotkin,2 Andreas Guggemos,1 Guenter Henze,3 and Pablo Hernaiz Driever1; 1Department of Pediatric Oncology/Hematology, Charité-Universitaetsmedizin Berlin, Berlin, Germany; 2Department of Nuclear Medicine, Charité-Universitaetsmedizin Berlin, Berlin, Germany; 3Department of Pediatric Oncology and Hematology, Charité-Universitaetsmedizin Berlin, Berlin, Germany. O-(2-[18F] fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) provides information on amino acid uptake in brain tumors and thus on localization and size of areas with actively proliferating cells. The aim of this retrospective study was to evaluate our experience with FET-PET compared to MRI in terms of specificity and sensitivity in the management of children and adolescents with CNS tumors. Our study includes 11 boys and 4 girls (mean age, 11 years; range, 2–16 years). Each pair of imaging studies (i.e., FET-PET and MRI) were carried out within 4 weeks. Three examinations were made within the context of primary diagnosis, seven examinations prior to starting chemotherapy or irradiation, and nine examinations were used to evaluate remission status. We verified results of PET imaging studies by histology and clinical follow-up. Sensitivity and specificity of FET-PET for detection of viable tumor tissue were calculated. Additionally to the visual analysis, SUVmax (tumor)/SUVmean (brain) of 19 FET-PET images performed on 14 patients were analyzed. SUVmax (tumor) values were defined on FET-PET slices with the highest FET uptake in the suspicious lesion. The calculated average of SUV values in healthy brain tissue on the contralateral side in three adjacent PET slices was used for SUVmean (brain). Histological classification included four glioblastoma multiforme, two medulloblastoma, two pilocytic astrocytoma (WHO I), as well as one anaplastic astrocytoma, DNT, ATRT, oligodendroglioma (WHO II), ganglioglioma (WHO II), and anaplastic ependymoma (WHO III). In one patient a diffuse intrinsic ponsglioma was diagnosed by neuroradiological criteria. Sixteen of 19 MRI results revealed the correct diagnosis (14 true-positive, two true-negative). In two MRI studies a false-negative diagnosis was made. One result was false-positive. For the MRI a sensitivity of 87.5% and a specificity of 66.7% were calculated. Eighteen of 19 FET-PET results contained the correct diagnosis. One study was false-positive. Visual analysis of FET-PET revealed a sensitivity of 100% and a specificity of 66.7%. In the analysis of SUVmax (tumor)/SUVmean (brain) a threshold value of 2.5 led to a lower value for sensitivity (94.4%) and equal value for specificity (66.7%). This result was due to two falsely classified values (one false-positive, one false-negative). The sensitivity of FET-PET for detecting the viable brain tumors in pediatric patients was higher when compared with MRI. A difference in the specificity of both diagnostic tools was not found in our experience. The SUV-based quantification of the FET-PET images was not helpful. To examine the importance of FET-PET in the diagnosis of CNS tumors in childhood and adolescence in a more detailed way a prospective study is warranted. IMAGI 13. RESPONSE ASSESSMENT BY MRI IN PEDIATRIC HIGHLY MALIGNANT BRAIN TUMORS: 1D VERSUS 2D MEASUREMENT OF TUMOR SIZE Mareike Windelberg,1 Monika Warmuth-Metz,2 Udo Bode,1 Ferdinand Bach,3 and Gudrun Fleischhack1; 1Department of Pediatric Hematology/Oncology, Medical Center, University of Bonn, Bonn, Germany; 2Department of Neuroradiology, University of Wuerzburg, Wuerzburg, Germany; 3Oncoscience AG, Wedel, Germany. Background: The Response Evaluation Criteria in Solid Tumors (RECIST) guidelines suggest the use of one-dimensional (1D) measurements of tumor size by magnetic resonance imaging (MRI) to assess tumor response to treatment, while two-dimensional (2D) measurements have been widely used so far (WHO criteria). The aim of this study was to evaluate the use of RECIST for the assessment of treatment response and progression-free survival (PFS) in children with highly malignant brain tumors by comparing the two methods. Patients and Methods: Sixty-seven pediatric patients 3–8 years of age had a total of 175 MRI scans performed before, during, and after treatment (67 baseline scans and 108 follow-up scans; median, 2 scans per patient; range, 2–6) in a phase II and III study with a humanized epidermal growth factor receptor antagonist. Of the 67 patients, 8 had an anaplastic astrocytoma, 10 a glioblastoma multiforme, and 49 a diffuse intrinsic pontine glioma. The tumors were located in the cerebral cortex (n = 8), the thalamus (n = 6), and in the posterior fossa (n = 53). The 2D tumor size was measured only in the axial plane (for comparability to the historical trials) while the 1D measurements were done both in the axial plane and in the plane with the longest diameter of the tumor (if different). The percentage change of tumor size between the baseline or the best response scan and the follow-up scans was used to determine treatment response. Categories used for tumor response were complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Besides tumor size measurements, new lesions, and/or definite clinical progression indicated progressive disease. Results: In the 108 response assessments concordance between the axial 1D and 2D measurements was 94.4%. There was excellent scanwise agreement between the two methods for PD (100%) and PR (94.7%) and a little less agreement for SD (87.8%) when using RECIST as reference. When the 1D measurement was not limited to the axial plane, the concordance between the two methods was still 89%. Both the 1D and 2D measurements showed the same median progression-free survival (PFS) if also definite clinical cardinal symptoms were used in the assessment. Conclusions: If PFS is the end point in a clinical study simple, 1D measurement of the longest tumor diameter as suggested by RECIST together with clinical symptoms can be used instead of 2D measurements for the assessment of treatment response in children with highly malignant brain tumors. If an excellent concordance is needed for each response category, the 1D and 2D measurements should be done in the same plane. IMAGI 14. ROLE OF PET/MRI FUSION IN EVALUATION OF PEDIATRIC BRAIN TUMORS Lorcan O'Tuama1 and Manuel Meza2; 1University of Pittsburgh, Pittsburgh, PA, USA; 2Children's Hospital of Pittsburgh, PA, USA. Introduction: PET/CT provides the pediatric oncologist direct correlation of functional imaging activity with the microstructural detail of the lesion-associated activity. We describe initial deployment of a method of PET/MRI registration to combine advantages of these modalities. Objective: To evaluate PET/CT with diagnostic contrast-enhanced CT component and MRI fusion (PET/CTDCE/MRI) in seven pediatric brain tumor patients showing typical clinical diagnostic and/or management issues. Methods: Blood sugar at time of study ⩽140 mg/dl. Radiopharmaceutical/contrast 18F-fluorodeoxyglucose (FDG) 10 millicuries/kg i.v. Gastroview 600–800 ml p.o. optiray 100–25 ml. Instrumentation: PET/CTDCE (16-head MDCT; 140 kVp/160 mA). PET/CTDCE/MRI fusion PET acquisition (transaxial summed aligned 63 slice series) was opened for rotation and resaving, assuring resliced section slices paralleled orbitomeatal (OM) line. Arbitrary color-encoded scales and contrast settings were elected according to author-imagers preferences. Typically, we chose a spectrum (“rainbow”) scale for the cortical regions (range, deep purple [least metabolically active] to red-white [maximum cortical activation]). MRI-SPGR with short TE sequences showed best triplanar conspicuity. Uptake assessment was visual, double-blind read, and patient population details were assessed semiquantitatively (see Table 1). IMAGI 14: Table 1. Demographic details of the patient population Patient Designation . Age (Years, Months) . Sex . Tumor Histology . Anatomic Sites of Lesions . 1 14,11 F Anaplastic astrocytoma Temporal lobe/insular cortex 2 8,9 M Glioblastoma status postradiation Parietal lobe 3 15,9 F Pontine glioma Brainstem 4 19,7 M Oligodendroglioma Temporal lobe 5 18,4 M Medulloblastoma Posterior cranial fossa 6 6,2 M Ependymoma Posterior cranial fossa 7 8,10 F High-grade glioma Thalamus Patient Designation . Age (Years, Months) . Sex . Tumor Histology . Anatomic Sites of Lesions . 1 14,11 F Anaplastic astrocytoma Temporal lobe/insular cortex 2 8,9 M Glioblastoma status postradiation Parietal lobe 3 15,9 F Pontine glioma Brainstem 4 19,7 M Oligodendroglioma Temporal lobe 5 18,4 M Medulloblastoma Posterior cranial fossa 6 6,2 M Ependymoma Posterior cranial fossa 7 8,10 F High-grade glioma Thalamus Open in new tab IMAGI 14: Table 1. Demographic details of the patient population Patient Designation . Age (Years, Months) . Sex . Tumor Histology . Anatomic Sites of Lesions . 1 14,11 F Anaplastic astrocytoma Temporal lobe/insular cortex 2 8,9 M Glioblastoma status postradiation Parietal lobe 3 15,9 F Pontine glioma Brainstem 4 19,7 M Oligodendroglioma Temporal lobe 5 18,4 M Medulloblastoma Posterior cranial fossa 6 6,2 M Ependymoma Posterior cranial fossa 7 8,10 F High-grade glioma Thalamus Patient Designation . Age (Years, Months) . Sex . Tumor Histology . Anatomic Sites of Lesions . 1 14,11 F Anaplastic astrocytoma Temporal lobe/insular cortex 2 8,9 M Glioblastoma status postradiation Parietal lobe 3 15,9 F Pontine glioma Brainstem 4 19,7 M Oligodendroglioma Temporal lobe 5 18,4 M Medulloblastoma Posterior cranial fossa 6 6,2 M Ependymoma Posterior cranial fossa 7 8,10 F High-grade glioma Thalamus Open in new tab Findings: Major questions posed by the neuro-oncologist related clinical status of patient and/or specific ancillary imaging (MRI) findings. Specific questions raised by the pediatric oncologist following review of the MRI report were assess posttherapy status; assist with needed restaging; evaluate significance of new gadolinium enhancement on MRI; assess significance of new MRI-enhancing nodule; assess necrotic appearing enhancing mass s/p XRT; and assess probability of tumor persistence/recurrence versus posttreatment effects? In three of seven cases the interpreted PET CT information allowed a definitive exclusion of metabolically significant residual disease. In three of seven cases worsening of local uptake and/or new sites favored progression. In one of seven cases persistent significant residual metabolically active disease with areas of improvement favored a mixed response with partial disease control. Conclusions: Tumor types are representative of age-expected disease. In six of seven cases, studies allowed conclusive determination of presence/absence of significant residual metabolically active disease. In one of seven cases, studies allowed characterization of mixed disease response to therapy. PET/MRI fusion to enhance spatial and functional resolution was fundamental to the high accuracy of the study. Extended studies will assess outcome response to determine the usefulness to the pediatric oncologist of routine PET/CTMRI image fusion for (a) initial diagnostic survey, (b) determination of therapy, (c) disease staging, and (d) therapeutic response assessment. IMAGI 15. SINGLE-CENTER EXPERIENCE WITH FDG-PET TO DIFFERENTIATE BETWEEN TUMOR PROGRESSION AND RADIOTHERAPY EFFECT IN AN ENHANCING LESION ON MRI DURING FOLLOW-UP OF PEDIATRIC BRAIN TUMOR PATIENTS Corrie Gidding,1 Geert Janssens,2 Erik Van Lindert,3 Corrie Erasmus,4 and Wim Oyen5; 1Pediatric Oncology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; 2Radiation Oncology, Radboud University Nijmegen Medical Center, Netherlands; 3Neurosurgery, Radboud University Nijmegen Medical Center, Netherlands; 4Pediatric Neurology, Radboud University Nijmegen Medical Center, Netherlands; 5Nuclear Medicine, Radboud University Nijmegen Medical Center, Netherlands. Goal: MRI scans during the follow-up of a child with a brain tumor treated with radiotherapy often show an increase in the volume of a residual enhancing lesion. On MRI alone we cannot differentiate between tumor progression and radiotherapy effect. A noninvasive method to differentiate between these two would be helpful. FDG PET differentiates between lesions with high and low metabolic activity and might thus differentiate between active tumor growth and radiotherapy effect. Materials and Methods: We studied children with brain tumors treated with radiotherapy and a growing or new lesion on MRI (>1.5 cm), with FDG PET and compared the FDG PET result with outcome. Results: We studied five patients, between 6 and 12 years old, three with ependymoma, one with malignant secreting germ cell tumor, and one with PNET. Four patients had a negative FDG PET, one a positive. The negative predicting value was 2/4. The positive predicting value was 1/1. The three patients in whom the prediction was good all had a growing lesion on MRI within a year after radiotherapy. The two patients in whom the prediction was false had a lesion 2 years after radiotherapy. Conclusion: FDG PET might be helpful in differentiation between tumor progression and radiotherapy effect in children with brain tumors and a growing lesion on MRI, especially if the lesion presents within a year after radiotherapy. More data are needed. IMAGI 16. VOXEL-BASED MORPHOMETRIC STUDY IN MALE SURVIVORS OF CHILDHOOD LEUKEMIA Luciana Porto,1 C. Preibisch,2 M. Kieslich,2 M. Bartels,2 T. Lehrnbecher,2 and F. Zanella2; 1Neuroradiology, Uniklinikum Frankfurt, Frankfurt, Germany; 2Germany. Background and Purpose: Survivors of acute lymphoblastic leukemia (ALL) demonstrate posttreatment neurocognitive deficits in a number of areas. However, it is not known which neuroanatomical structures are involved in survivors of ALL with functional deficits. The aim of this study was to detect morphological changes in neuroanatomical components in male adult survivors of ALL when compared to matched controls. Materials and Methods: We used Voxel-based morphometry (VBM) to examine 10 male survivors of ALL and 11 healthy male-matched controls. All but one survivor of ALL underwent cranial radiation, and all patients received chemotherapy. Imaging was performed on a 3.0-T MRI. Group comparisons of images of grey matter (GM), white matter (WM), and cerebral spinal fluid (CSF) from healthy volunteers and ALL survivors were performed. Results: VBM showed significantly reduced GM concentration within the caudate nucleus and thalamus bilaterally in male survivors of ALL who received intrathecal methotrexate and cranial radiation during childhood. The frontal, mainly periventricular WM concentration was decreased in both hemispheres. Areas of CSF enlargement were seen bilaterally in the frontal horns of lateral ventricles and at the frontobasal subarachnoid space. Conclusions: The present data can reasonably be interpreted as providing persuasive evidence that combined chemotherapy and radiation therapy in children has structural effects on the developing brain. INFANT TUMORS INF 1. A PILOT STUDY OF POSTOPERATIVE INDUCTION CHEMOTHERAPY, FOCAL RADIATION THERAPY, AND HIGH-DOSE CONSOLIDATION CHEMOTHERAPY IN INFANTS WITH MALIGNANT BRAIN TUMORS Mikhail Laskov,1 Igor Dolgopolov,1 George Mentkevich,1 Sergei Ozerov,2 Viktor Glekov,3 Igor Vysochin,1 Leonid Satanin,2 Natasha Subbotina,1 Vasili Boyarshinov,1 Mikhail Budarin,1 Sergei Gorelyshev,2 and Maxim Yankelevich1; 1Pediatric Oncology, N.N. Blokhin Russian Cancer Center, Moscow, Russia; 2N.N. Burdenko Institute for Neurosurgery, Moscow, Russia; 3Radiation Oncology, N.N. Blokhin Russian Cancer Center, Moscow, Russia. Historically, young age significantly reduces overall and event-free survival in pediatric brain tumors. We designed a pilot study for children <4 years old that consists of effective up-to-date treatment modalities: induction chemotherapy, localized radiotherapy, and high-dose chemotherapy with stem cell rescue. From January 2006 until now we enrolled 13 patients with high-risk brain tumors (ependymoma, seven; medulloblastoma, four; AT/RT, one; and CPC, one). The mean age at enrollment was 18 months (range, 5–38 months). In the interim, our goal was to assess toxicity and feasibility of our treatment. One feature of our cohort was that the majority (9 of 13) of enrolled patients had residual tumor at the beginning of chemotherapy. Following surgery and staging, patients were treated with three cycles of cyclophosphamide, etoposide, vincristine, and cisplatin using the same regimen as induction regimen CCG-99703, four cycles of high-dose methotrexate, and focal irradiation (in selected patients only). During induction, peripheral blood stem cells were harvested. Consolidation consisted of two cycles of carboplatin (17 mg/kg), cyclophosphamide (130 mg/kg, cycle 1) or melphalan (3.5 mg/kg, cycle 2), and temozolomide (6.6 mg/kg). We used the following criteria for the radiotherapy: age >12 months, posterior fossa ependymoma, and residual medulloblastoma after induction of chemotherapy if a second-look surgery was not possible. Seven patients completed the treatment. One patient died of treatment-related toxicity; one patient died of progression; and four patients are still on treatment. In evaluable patients (n = 9) we observed one complete response (CPC), five partial responses (four ependymomas; one medulloblastoma), two stable diseases (two medulloblastomas), and one progressive disease (AT/RT) after two cycles of induction therapy. Induction chemotherapy turned out to be more toxic than high-dose chemotherapy with stem cell rescue. Radiotherapy was used in 8 of 13 patients. So far we observed one case of leukoencephalopathy (asymptomatic). In conclusion, the intensive treatment combination of induction chemotherapy, focal radiation therapy, and high-dose tandem consolidation chemotherapy was feasible in infants and young children with high-risk malignant brain tumors. The treatment-related toxicity was acceptable, and there is some evidence that our treatment at least leads to stabilization of tumor growth in the majority of patients. INF 2. BIALLELIC BRCA2 INACTIVATION IN TWO BROTHERS WITH EMBRYONAL CNS TUMORS DIAGNOSED DURING INFANCY Mariko Dewire,1 David Ellison,2 Peter Mckinnon,3 Amar Gajjar,1 and Robert Sanders1; 1Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; 2Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA; 3Department of Genetics/Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. The breast cancer susceptibility gene, BRCA2, has been associated with Fanconi anemia complementation group D1 (FANCD1). Biallelic inactivation of BRCA2 in Fanconi anemia has been reported in a small number of patients with medulloblastoma. We report two siblings diagnosed with CNS embryonal tumors at an early age in association with biallelic BRCA2 inactivation, including the first reported case of spinal cord primitive neuroectodermal tumor (PNET) in a BRCA2/FANCD1 kindred. Sibling 1 was a 15-month-old male who presented with a 2-month history of a bilateral decrease in upper extremity use with anisocoria, right ptosis, and facial weakness. MRI revealed an intramedullary spinal cord lesion extending from C2–T2. Pathological assessment showed a high-grade primary neuroepithelial tumor, consistent with a diagnosis of PNET with focal glial differentiation. He was treated as per the Head Start III protocol. Treatment was complicated by prolonged count recovery, severe mucocitis, fungemia, and bacteremia. His third course of chemotherapy was complicated by development of hepatic venous occlusion resulting in death 3 months after initial diagnosis. Sibling 2 is a 21-month-old male with a history of refusal to walk and progressively worsening emesis without focal neurological findings. MRI revealed a large heterogenous enhancing mass of the right cerebellar hemisphere. The tumor was an unusual variant of medulloblastoma showing both desmoplastic/nodular and anaplastic phenotypes. He was initially treated on a nonprotocol treatment plan including high-dose methotrexate, vincristine, cisplatin, and cyclophosphamide. After the first course of chemotherapy, prolonged pancytopenia was noted. The early age of cancer presentation and unusual chemosensitivity evident in both siblings led to an investigation for a disorder of DNA repair. Diepoxybutane chromosomal fragility testing was consistent with Fanconi anemia, and BRCA2 sequencing revealed bi-allelic mutations in BRCA2*6174delT/886delGT. Further testing confirmed that each parent was a carrier of one BRCA2 mutation. As conventional medulloblastoma therapy was contraindicated, a palliative treatment regimen with limited use of DNA-damaging agents was initiated. This included 4-week cycles of high-dose methotrexate (5 gm/m2/dose), intraventricular methotrexate, and low-dose oral chemotherapy (cyclophosphamide alternating with etoposide). The patient did not tolerate this milder regimen, however, and experienced symptomatic leukoencephalopathy, significant myelosuppression, and sepsis. He is therefore receiving no further antitumor therapy and is currently 7 months from diagnosis with no evidence of disease. All patients in the literature with BRCA2 mutations and medulloblastoma were diagnosed at a young age and have died, either from disease or from complications of therapy. Most cases did not have the typical clinical features of Fanconi anemia, and, as a result, the diagnosis was typically made after extreme chemosensitivity was noted. Clinicians must be aware of this association in order to appropriately treat such patients and avoid potentially fatal treatment toxicity. Clinical features such as early age of presentation (<3 years) in association with markedly delayed count recovery or other evidence of atypical chemosensitivity should warrant further investigation, including chromosomal fragility testing and gene specific BRCA2 analysis. INF 3. BRAIN TUMORS IN CHILDREN <3 YEARS OF AGE: OUTCOME IN 95 CONSECUTIVE PATIENTS TREATED AT THE MEDICAL UNIVERSITY OF VIENNA (1992–2007) Irene Slavc,1 Thomas Czech,2 Mario Brandl,2 Christine Haberler,3 Adelheid Woehrer,4 Andreas Peyrl,5 Karin Dieckmann,6 and Daniela Prayer7; 1Pediatrics, Vienna, Austria; 2Neurosurgery, Vienna, Austria; 3Institute of Neurology, Medical School of Vienna, Vienna, Austria; 4Institute of Neurology, Medical University of Vienna, Vienna, Austria; 5Pediatrics, Medical University of Vienna, Vienna, Austria; 6Radiotherapy, Medical University of Vienna, Vienna, Austria; 7Radiology, Medical University of Vienna, Vienna, Austria. Brain tumors in young children differ in clinical presentation, histopathology, biological behavior, and prognosis from those seen in older children. We reviewed the data of 95 consecutive children <3 years of age who were treated for CNS tumors at our institution over the past 15 years. The aim of the study was to asses the impact of histology, tumor location, and treatment, such as degree of surgical removal, chemo-, and radiotherapy on outcome. Patients: From 1992 to 2007, 95 patients (57 males, 38 females) <3 years of age were treated. Patients with tectum glioma, optic pathway tumors (OPT), and SEGA that were only observed were excluded from the study. Only three patients (one ependymoma [EP] and two atypical teratoid rhabdoid tumors [ATRTs]) were first operated on in another hospital. Histopathology was reviewed for all malignant tumors applying the INI 1 antibody disclosing seven additional ATRTs originally misdiagnosed as other malignant tumors. Corrected histologies and locations were pilocytic OPT (n = 20), EP (n = 16, 15 posterior fossa), supratentorial diffuse glioma (n = 14), ATRT (n = 13, 10 posterior fossa, one midbrain, two spinal), primitive neuroectodermal tumor (PNET) (n = 9, five cerebral hemispheres, two pineal, one supratentorial midline, one brainstem), medulloblastomas (MB) (n = 5, three desmoblastic, two classic), glioblastoma (GBM) (n = 5), plexus papilloma (n = 5, one atypical), cerebellar pilocytic astrocytoma (n = 4), craniopharyngioma (n = 3), and diffuse pontine glioma (n = 1). Twenty-seven of 95 patients were <1 year of age and 4 of 27 had connatal tumors (one GBM, one brainstem glioma, and two PNETs). The diagnoses in the remaining 23 were ATRT (n = 8), OPT (n = 7), PNET (n = 2), plexus papilloma (n = 3), EP (n = 2), and temporal lobe glioma (n = 1). Results: In January 2008, 72 patients (75%) are alive with a median survival time of 6.5 years (range, 3 months to 14 years). All 26 patients with diffuse gliomas, cerebellar astrocytomas, craniopharyngiomas, and plexus papillomas, respectively, are alive after surgery only. Seventeen of 20 patients with OPT, 10 of 16 with EP, 7 of 9 with PNET, 5 of 13 with ATRT, 3 of 5 with GBM, 3 of 5 with MB, and 1 connatal diffuse brainstem glioma are also alive. Except for 2 patients with OPT and 1 with EP, all of these patients received chemotherapy and irradiation, as well for 3 of 7 PNETs, 10 of 10 EPs, 2 of 3 GBMs, and 5 of 5 ATRTs. Except for two patients with connatal tumors of the cerebral hemipheres (one GBM, one PNET) who also suffer from seizures, none of the patients has major cognitive disabilities. Four patients with OPT were either diagnosed with visual loss or lost vision during the course of their disease. No other major neurologic deficits occurred in any of the surviving patients; however, all patients were operated on by a few highly experienced neurosurgeons. Conclusion: Prognosis of brain tumors in young children has improved substantially over the past 15 years. ATRT is much more frequent than previously acknowledged and proper diagnosis is essential for appropriate therapy. The degree of surgery appears to be a major factor in predicting prognosis and maximal safe surgery should be attempted, particularly in EP, ATRTs, PNET, MB, and GBM. INF 4. CNS TUMORS IN THE FIRST 6 MONTHS OF LIFE: THE CHILDRENS HOSPITAL LOS ANGELES EXPERIENCE, 1979–2005 Kathryn Serowka,1 Yvonne Chiu,1 Ignacio Gonzalez-Gomez,2 Floyd Gilles,3 Gordon Mccomb,4 Mark Krieger,4 Robert Lavey,5 Girish Dhall,1 Barbara Britt,1 Lingyun Ji,1 Richard Sposto,1 and Jonathan Finlay1; 1Oncology, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 2Pathology, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 3Pathology, Children's Hospital of Los Angeles, Los Angeles, CA, USA; 4Neurosurgery, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 5Radiation Oncology, Childrens Hospital Los Angeles, Los Angeles, CA, USA. Objective: To review and report the experience at the Childrens Hospital Los Angeles (CHLA) between 1979 and 2005 with children diagnosed with brain tumors <6 months following birth. Methods: CHLA medical records, oncology databases, and pathology files were searched for data on infants diagnosed <6 months following birth with primary CNS tumors. This study was undertaken with institutional IRB approval. Results: A total of 33 children were identified, one of whom had Down syndrome. Twelve (36%) were females. The average age at diagnosis was 93 days (median, 87 days; range prenatal to 200 days). Two patients were diagnosed prenatally by ultrasound, and four patients within 30 days of birth. Nine patients were diagnosed by computed tomography and 22 patients by MRI. The most common presenting signs and symptoms were those of increased intracranial pressure, such as bulging fontanelles, separating sutures, prominent scalp veins and hydrocephalus in 18 patients. Seventeen had eye findings, and 16 had macrocephaly. There were 11 glial tumors (one glioblastoma multiforme, one anaplastic glioma, one unbiopsied pontine tumor, eight low-grade astrocytomas), five choroid plexus papillomas, two atypical choroid plexus papillomas, four supratentorial PNETs, four medulloblastomas, two ATRTs, two choroid plexus carcinomas, and one each of ependymoma, craniopharyngioma, and posterior fossa immature teratoma (in the child with Down syndrome). Tumor locations were as follows: 21 supratentorial (64%), 7 posterior fossa, and 5 additional tumors involving both compartments. Nine patients (27%) had metastatic disease at presentation. Extent of resection included 5 biopsy only, 18 less than gross total resection (GTRx), and 9 GTRx. Fifteen received chemotherapy at some time following diagnosis (45%), and three received irradiation (one at initial diagnosis and two at relapse). Twelve children developed tumor recurrence/progression (36%), two of whom, both with low-grade gliomas, are long-term survivors. The Kaplan-Meier analysis of event-free survival (EFS) and overall survival (OS) for all patients is 21% ± 9% and 35% ± 9% at 5 years. For glioma patients, the 4-year OS is 48% ± 17%, and the 5-year OS for patients with embryonal tumors (medulloblastomas/PNETs/ATRTs) is 12% ± 11% (p = 0.39). The 5-year OS for children achieving a GTRx is 64% ± 21% and for those with, ± 10% (p = 0.08). Conclusions: For infants diagnosed within 6 months of birth with CNS embryonal tumors, radical surgical resection is the mainstay of successful outcome for infants with low-grade CNS tumors. INF 5. DEVELOPMENTAL AND FUNCTIONAL OUTCOME FOLLOWING POSTOPERATIVE CHEMOTHERAPY AND LOCAL CONFORMAL RADIATION IN INFANTS WITH MEDULLOBLASTOMA USING A CENTRALLY ADMINISTERED PHONE-BASED INTERVIEW TECHNIQUE, INITIAL REPORT: A CHILDREN'S ONCOLOGY GROUP STUDY David Ashley,1 Lyon Nancy,2 Bonner Melanie,3 Msall Michael,4 Tianni Zhou,5 Douglas Strother,6 Thomas Merchant,7 Russell Geyer,8 Ian Pollack,9 and Patricia Duffner10; 1Royal Childrens Hospital, Murdoch Childrens Research Institute, Parkville, Victoria, Australia; 2Women and Children's Hospital, Buffalo, Buffalo, NY, USA; 3Duke University Medical Center, NC, USA; 4University of Chicago, IL, USA; 5Children's Oncology Group, Arcadia, CA, USA; 6University of Calgary, AB, Canada; 7St. Jude Children's Research Hospital, Memphis, TN, USA; 8Seattle, WA, USA; 9University of Pittsburgh, Pittsburgh, PA, USA; 10University at Buffalo, Buffalo, NY, USA. Background: Over the past 20 years, the U.S. cooperative groups have developed novel approaches for the treatment of infants and very young children with malignant brain tumors. In most of these, radiation has either been delayed or eliminated in an effort to reduce neurotoxicity. While these studies have had excellent accrual, compliance with neuropsychologic follow-up has been poor. The present study, P9934, used conformal irradiation (RT) limited to the posterior fossa and postoperative tumor bed early in the treatment course. Therefore, it was essential that developmental and functional progress be continuously monitored. Methods: A centrally administered phone-based parent interview about functional skills in self-care, mobility, and social cognition (WeeFIM) and a developmental questionnaire about gross and fine motor, communication, problem solving, and personal-social skills (ASQ) were administered prechemotherapy, preradiation, and at 12, 24, 36, and 48 months following diagnosis. A baseline value, “best ever development achieved prior to illness” was also obtained retrospectively at the time of enrollment with the prechemotherapy assessment. Formal neuropsychological testing was administered pre-RT and at 2 and 4 years following diagnosis. Results: There was 100% compliance with the phone-based interview system in contrast to that achieved with neuropsychologic testing (57% pre-RT and 46% at 2 years). Thirty-three of 59 children had mild to moderate delays at baseline (56%), which then significantly declined by the time of their prechemotherapy assessments (92%). On the ASQ, a significant decline from baseline was identified in all developmental domains. However, when prechemotherapy (postoperative) values were compared with subsequent testing, no developmental declines were noted. Moreover, there was a significant improvement in gross motor skills, compared to their prechemotherapy baseline. Results on self-care, mobility and communicative functioning using the WeeFIM closely mirrored the ASQ (i.e., a significant decline in functional skills compared to baseline but no decline when later values were compared to the prechemotherapy assessment). As in the ASQ, mobility functional skills improved compared to the prechemotherapy assessment. Results of the Bayley pre-RT and at 2 years postdiagnosis also revealed no significant decline in either mental (MDI) or performance (PDI) criteria. Conclusions: To date, no significant or consistent decline in either cognitive or motor functioning as measured by either the phone-based interview technique or formal neuropsychologic assessments could be seen after the delivery of chemotherapy and local conformal RT. Although young children with medulloblastoma continued to make developmental progress and actually improved in gross motor abilities, their scores remained impaired compared to normal children. The significant declines in developmental and functional skills compared to the premorbid “baseline” suggests that surgery and/or the tumor may have more impact on developmental and functional abilities than has previously been recognized. This approach of using a centrally administered phone-based interview technique improved compliance compared to previous studies. Moreover, results of the ASQ and WeeFIM closely mirrored those of standardized neuropsychologic testing. This surveillance strategy appears to be highly useful in the assessments of developmental and functional outcomes in very young children with brain tumors. INF 6. DIFFERENTIATION OF GLIOBLASTOMA MULTIFORME (WHO GRADE IV) INTO GANGLIOCYTOMA (WHO GRADE I) IN AN INFANT: MIRACLE OR NOVEL SUBENTITY? Ronald Straeter,1 Astrid Jeibmann,2 Angela Brentrup,3 Werner Paulus,2 and Michael C. Fruehwald1; 1Paediatric Oncology and Hematology, University Hospital, Muenster, Germany; 2Institute of Neuropathology, University Hospital Muenster, Muenster, Germany; 3Neurosurgery, University Hospital, Germany. Glioblastoma multiforme in neonates and young infants constitutes an infrequent entity with a poor prognosis. Longtime survival is rare, especially in cases with an incomplete neurosurgical resection. Differentiation of malignant brain tumors in children has been reported in individual cases (e.g., medulloblastomas) and is a better characterized phenomenon in other high-grade tumors of childhood such as neuroblastoma. Case Report: Our index case is a currently 13-month-old girl who presented shortly after birth with a large structural anomaly of the left hemisphere with intralesional hemorrhage due to perinatal stroke or tumor. After 8 weeks, the girl was hospitalized with symptoms of increased intracranial pressure and obtunded consciousness. MRI revealed progressive growth of the lesion, suspicious for a malignant CNS tumor. Biopsy revealed the histopathologic diagnosis of a glioblastoma multiforme WHO grade IV, which was confirmed by olacla and reference pathology. In agreement with the parents, an individualized intravenous polychemotherapy approach based on carboplatinum and etoposide was initiated at 3 months of age. Using this regimen, the girl showed an unexpected nearly normal neurological development with no hemiparesis. MRI scans demonstrated a stabilized tumor size with continuous regression of contrast enhancement. In view of the excellent clinical course, a second-look surgery was performed after the patient's first birthday: The histopathology was surprisingly changed to a gangliocytoma WHO grade I. Based on this interesting case report, demonstrating the differentiation of a high-grade glioma to a low-grade glioma, neonates and infants with glioblastoma multiforme may have the chance of an improved prognosis when differentiation can be induced. With respect to our case, therapeutic nihilism should be abandoned, and separate chemotherapy protocols for the subset of infants with glioblastoma should be developed. As demonstrated, the individual course may lead to surprising changes in histopathology and consequently prognosis. INF 7. INCOMPLETELY RESECTED MEDULLOBLASTOMA IN YOUNG CHILDREN: A HIGH-DOSE CHEMOTHERAPY APPROACH WITH FOCAL IRRADIATION Jacques Grill,1 Maria El Kababri,2 Vita Ridola,2 Frederic Dhermain,3 Dominique Valteau-Couanet,3 Stephanie Puget,4 and Dominique Couanet2; 1Institut Gustave Roussy Villejuif, Villejuif, France; 2France; 3Institut Gustave Roussy, Villejuif, France; 4Necker Sick Children's Hospital, Paris, France. Background: Incompletely resected medulloblastomas have a bad prognosis in young children when treated with conventional chemotherapy. Due to the good efficacy of high-dose chemotherapy (HDCT) with stem cell rescue followed by focal irradiation in children with local progression/relapse after conventional chemotherapy, we initiated a pilot study of this approach in children with local residue. Patients and Methods: Eleven children (median age, 31 months; range, 6–56 months) were treated with HDCT after two cycles of conventional chemotherapy. Nine had a classic medulloblastoma, and two had a desmoplastic variant. HDCT consisted of busulfan 600 mg/m2 over 4 days and thiotepa 900 mg/m2 over 3 days followed by autologous stem cells transplantation (ASCT). Posterior fossa (PF) radiotherapy was delivered at doses from 50 to 55 Gy on day 70 after ASCT. Results: The median follow-up period was 36 months (range, 8–134 months). Five of six patients with radiologically evaluable residue responded to the chemotherapy protocol administered before radiotherapy. The 5-year overall survival (OS) for the whole group was 90% (95% CI, 60%–98%), and the 5-year PFS 72% (95% CI, 35%–92%). Acute toxicity consisted mainly of hepatic veno-occlusive disease (n = 5) and septicemias (n = 3). One delayed toxic death from brainstem radionecrosis was reported 14 months after diagnosis. Two patients relapsed to date; both are alive after further chemotherapy/radiotherapy 24 and 53 months after diagnosis. Conclusion: This aggressive regimen seems to offer a survival advantage in young children with incompletely resected medulloblastoma. However, further refinements are warranted to decrease its toxicity. INF 8. INFANTILE BURKITT'S LYMPHOMA PRESENTING WITH A SCALP MASS Sharmin Basher,1 Ramasubramanian Kalpatthi,2 Pierre Giglio,3 Gerald Tuite,1 and Nada Besenski4; 1Neurosurgery, Medical University of South Carolina, Charleston, SC, USA; 2Pediatrics, Medical University of South Carolina, Charleston, SC, USA; 3Medical University of South Carolina, Charleston, SC, USA; 4Radiology, Medical University of South Carolina, Charleston, SC, USA. Non-Hodgkin's lymphoma (NHL) is currently classified as the third most common cause of cancer malignancy to affect children and adolescents. Burkitt's lymphoma (BL) is a histologic subtype of NHL occurring in about 34% of childhood cases. It tends to present with abdominal or head and neck involvement. However, CNS involvement is also noted, and in one large series, BL cases had CNS involvement in 8.8% of cases. Advanced BL with CNS involvement is rarely encountered in infancy. In the United States, the Surveillance, Epidemiology, and End Results Program (SEER) reported that roughly 15–20 such cases are encountered per year in North America in patients younger than 19 years of age, which is 1% of all primary CNS lymphomas. We report a 7-week-old male infant presenting with two progressively enlarging extracranial masses that on neuroimaging were noted to have intracranial extension. A third left frontal mass with intraorbital extension was also noted. A lumbar puncture was found to be positive for malignant cells consistent with malignant lymphoma, and a biopsy of the left scalp mass revealed BL. To our knowledge, this patient is the youngest patient ever reported with BL and presents a very unusual picture of intracranial/extracranial disease. INF 9. MEDULLOBLASTOMA IN CHILDREN UNDER 3 YEARS OF AGE: A RETROSPECTIVE CANADIAN REVIEW Donna Johnston,1 Daniel Keene,2 Ute Bartels,3 Anne-Sophie Carret,4 Bruce Crooks,5 David Eisenstat,6 Chris Fryer,7 Lucie Lafay-Cousin,8 Valerie Larouche,9 Albert Moghrabi,10 Beverly Wilson,11 Shayna Zelcer,12 and Eric Bouffet13; 1Children's Hospital of Eastern Ontario, Ottawa, ON, Canada; 2Children's Hospital of Eastern Ontario, Ottawa, ON, Canada; 3University of Toronto, Toronto, ON, Canada; 4Montreal, QC, Canada; 5Dalhousie University, Halifax, NS, Canada; 6Winnipeg, MB, Canada; 7British Columbia's Children's Hospital, Vancouver, BC, Canada; 8University of Calgary, Calgary, AB, Canada; 9Hematology-Oncology, Centre Hospitalier Universitaire de Québec, Quebec, QC, Canada; 10Ste Justine Hospital, Montreal, QC, Canada; 11Edmonton, AB, Canada; 12London, ON, Canada; 13Toronto, ON, Canada. Background: In children <3 years of age, the most common tumors are primitive neuroectodermal tumors in the first year of life, astrocytomas and ependymomas in the second year of life, and astrocytomas in the third year of life. Medulloblastoma does occur in children <3 years of age, but the median age of diagnosis is 5–7 years. Children <3 years of age with this type of tumor have an inferior survival to older children with this disease. Objective: To review the incidence, characteristics, therapy, and outcome of children <36 months of age diagnosed with medulloblastoma from 1990 to 2005 in Canada. Methods: A data bank was established using data collected from 15 of 17 Canadian pediatric oncology centers on children <3 years of age diagnosed with brain tumors between 1990 and 2005. Cases of medulloblastoma were extracted from this data bank and their characteristics summarized. Survival was analyzed using Kaplan-Meier analysis and significance determined using log-rank test. Results: From the 531 cases in the data bank, 80 cases of medulloblastoma (15%) were identified. The median age at diagnosis was 21.5 months, and 56% of cases were male. At diagnosis, 38% of patients had positive cerebral spinal fluid, 38% of patients had disseminated disease on imaging, and, overall, 45% of patients had metastatic disease. Fifty-two percent of patients had a complete resection, 24% a near-complete (90%–95%) resection, 22% an incomplete (10%–90%) resection, and 1% biopsy only. Therapy consisted of chemotherapy in 91%, stem cell transplant in 14%, and radiation therapy in 23%. At the time of the survey, 40% of patients were alive. The median survival time was 60 ± 12.98 months (95% CI, 34.57–85.43). There was no significant difference in survival when comparing <90% resection versus >90% resection, nor when comparing the presence of metastases at diagnosis versus their absence. There was no increase in incidence over the time period of this study for this tumor type. The incidence was 5.4 ± 2.76 per million children in the population. Conclusions: The median survival time for Canadian children <36 months of age with medulloblastoma was 60 months, which is shorter than is observed in older children with this disease. Interestingly, this survival was not significantly affected by the degree of resection or presence of metastatic disease, something that is observed in older children. This information reinforces the need for improved therapy for young children with medulloblastoma in order to improve their survival. INF 10. METHOTREXATE PHARMACOKINETICS IN CHILDREN LESS THAN 3 YEARS OF AGE WITH EMBRYONAL BRAIN TUMORS Robert Sanders,1 Paula Schaiquevich,2 Alberto Broniscer,1 Brannon Morris,1 Andrea Simmons,1 Amar Gajjar,1 and Clinton Stewart2; 1Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; 2Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA. Background: High-dose methotrexate (MTX) is being used more frequently for the treatment of brain tumors in infants. MTX pharmacokinetics (PK) have been well characterized in children with leukemia, but no studies have evaluated MTX PK in brain tumor patients receiving concomitant nephrotoxic drugs. We studied MTX PK in children <3 years of age who were treated with both high-dose MTX and cisplatin. Methods: Patients received MTX 5 g/m2 administered over 24 h on day 1 of each course. Standard leucovorin (LV) rescue consisted of LV 15 mg/m2 i.v. every 6 h for five doses, starting at hour 42 after the start of the MTX infusion. In cases of toxicity or delayed clearance, the dose and duration of LV were adjusted per institutional practice based on experience with leukemia patients receiving the same MTX dose. Treatment also included vincristine 1 mg/m2 on days 8 and 15, cisplatin 75 mg/m2 on day 8, and cyclophosphamide 1,500 mg/m2 on day 9 of each 28-day course. Serial plasma samples (1–2 ml) for MTX PK studies were collected predose and at 6, 23, 42, 66, and 90 h from the infusion start of MTX. Data sets from patients with complete MTX concentration-time profiles were initially fitted by maximum-likelihood estimation as implemented in ADAPT II. A two-compartment model was used to fit the plasma MTX data. Model parameters estimated included volume of distribution of the central compartment (Vc), elimination rate constant (ke), clearance (CL), and the intercompartmental rate constants between the central and the peripheral compartment (kcp and kpc). The mean and standard deviation were calculated for each parameter. Then, all sets of data were fitted using a maximum a posteriori Bayesian algorithm, and parameters were estimated for all data sets. Results: MTX pharmacokinetic data were available for a total of 19 courses from eight patients (three medulloblastomas, four ATRTs, and one PNET) with a median age at the initiation of therapy of 20 months (range, 4–24 months). The median (range) MTX concentrations at 23 h and 42 h after the start of the infusion were 66.8 μM (41.2–132.6) and 0.58 μM (0.21–4.0), respectively. The median (range) clearance obtained for all courses was 104.6 ml/min/m2 (56.1–164.2). MTX clearance was related to age with children <1 year old having a median (range) MTX clearance of 64.8 ml/min/m2 (56.0–77.8) compared with children >1 year old (median [range] MTX clearance 117.2 ml/min/m2 [60.6–164.2]). An increase in LV dose or duration was required in 10 courses in six patients. Clinically significant toxicity consisted of grade 3 mucositis in a single course. Conclusions: MTX clearance in very young children with brain tumors receiving multiagent nephrotoxic chemotherapy was similar to prior reports from children with leukemia, with lower MTX clearance in children <1 year of age. While patients frequently required an increase in the dose or duration of LV rescue beyond the standard regimen, toxicity was minimal. These results suggest that, with careful clinical management, high-dose MTX can be administered safely to infants receiving concomitant nephrotoxic chemotherapy. INF 11. MULTIAGENT CHEMOTHERAPY AND DEFERRED CRANIOSPINAL RADIOTHERAPY IN CHILDREN YOUNGER THAN 4 YEARS WITH SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL TUMOR (STPNET) Nicolas Gerber,1 Katja Von Hoff,2 Wiebke Treulieb,1 Monika Warmuth-Metz,3 Torsten Pietsch,4 Niels Soerensen,5 Martin Benesch,6 Andreas Faldum,7 Angela Emser,7 Frank Deinlein,1 Rolf-Dieter Kortmann,8 and Stefan Rutkowski1; 1Department of Pediatric Oncology, Children's Hospital, University of Wuerzburg, Würzburg, Germany; 2Department of Pediatric Oncology, Children's Hospital, University of Wuerzburg, Wuerzburg, Germany; 3Department of Neuroradiology, University of Wuerzburg, Wuerzburg, Germany; 4Department of Neuropathology, University of Bonn, Bonn, Germany; 5Department of Pediatric Neurosurgery, University of Wuerzburg, Wuerzburg, Germany; 6Division of Pediatric Hematology and Oncology, Medical University of Graz, Graz, Austria; 7Institute for Medical Biostatistics, Epidemiology, and Informatics, University of Mainz, Mainz, Germany; 8Department of Radiation Oncology, University of Leipzig, Leipzig, Germany. Background: The prognosis for children <4 years of age with stPNET is dismal with 3-year progression-free survival (PFS) rates between 5% and 35% in most published studies. Here we report the results of children younger than 4 years with nonmetastatic stPNET diagnosed between January 2001 and December 2005 and treated within the prospective GPOH-trial HIT 2000. Methods: After surgery, children received three 2-month induction chemotherapy cycles, each consisting of intravenous cyclophosphamide, methotrexate, vincristine, carboplatin, and etoposide. In case of complete remission (CR) after the three cycles, two additional modified cycles were given, followed by craniospinal radiotherapy; patients with residual tumor were given radiotherapy directly after the initial chemotherapy, followed by four cycles of maintenance chemotherapy with CCNU, cisplatin, and vincristine. In very young children, radiotherapy was delayed until the age of 18 months by maintenance chemotherapy following induction chemotherapy. For all children, normofractionated radiotherapy was given, with 24.0 Gy to the craniospial axis and boosts to 54.6 Gy to the extended tumor region and to 60.0 Gy to a residual tumor. After each therapy step, the possibility of resurgery was considered. Results: Nine patients (two with pineoblastoma and seven with nonpineal stPNET) were treated according to the protocol. Age at diagnosis was 1.7 years (range, 0.1–3.9 years). Gross total tumor resection was achieved in four, and partial resection in five cases. All patients showed a tumor progression/relapse (eight local, one distant) during induction chemotherapy (median time to progression, 5.9 months; range, 2.3–8.0 months). Overall survival at 3 years is 22.2% ± 13.9%. In most patients, the planned radiotherapy was advanced due to progression under chemotherapy. After progression, therapy consisted of radiotherapy followed by chemotherapy in three cases, chemotherapy followed by radiotherapy in three cases, and chemotherapy only in two cases. Four patients underwent resurgery. Seven patients died of disease 16.7 months (range, 8.8–28.7 months) after operation. Two patients, both with nonpineal stPNET, were alive at last follow-up (at 34.8 and 72.8 months after relapse, both with complete remission). The first patient had partial resection of the relapsed tumor, which due to young age was initially followed by chemotherapy with carboplatin/etoposide, and two myeloablative high-dose chemotherapies with carboplatin/etoposide and cyclophosphamide/thiotepa, followed by radiotherapy at the age of 21 months. The other patient was treated according to the protocol, with additional four cycles of maintenance chemotherapy. Toxicity of CTC grade 3 or 4 of neoadjuvant chemotherapy (apart from bone marrow suppression, nausea/vomitiing, and mucositis) was reported four times in two patients (two, hepatotoxicity; one, diarrhea; one, infection); no information was obtained from two patients. Conclusion: Postoperative neoadjuvant multiagent chemotherapy as applied in this study did not confer sufficient tumor control. The value of shorter chemotherapy regimens to defer craniospinal radiotherapy should be evaluated in the high-risk group of young children with supratentorial PNET. INF 12. P9934: SYSTEMIC CHEMOTHERAPY, SECOND-LOOK SURGERY AND CONFORMAL RADIATION THERAPY LIMITED TO THE POSTERIOR FOSSA AND PRIMARY SITE FOR CHILDREN >8 MONTHS AND <3 YEARS WITH NONMETASTATIC MEDULLOBLASTOMA: A CHILDREN'S ONCOLOGY GROUP PHASE III STUDY David Ashley,1 Thomas Merchant,2 Tianni Zhou,3 Lee Coleman,1 Ian Pollack,4 Patricia Duffner,5 Peter Burger,6 Douglas Miller,7 Allen Buxton,8 and Strother Douglas9; 1University of Melbourne Parkville, Parkville, Victoria, Australia; 2St. Jude Children's Research Hospital, Memphis, TN, USA; 3Children's Oncology Group, Arcadia, CA, USA; 4University of Pittsburgh, Pittsburgh, PA, USA; 5University at Buffalo, Buffalo, NY, USA; 6Johns Hopkins University, Baltimore, MD, USA; 7Columbia, CO, USA; 8Children's Oncology Group, CA, USA; 9University of Calgary, Calgary, AB, Canada. Background: The prognosis for young children with medulloblastoma has been poor, and survivors often have long-term cognitive deficits. P9934 is a recently completed trial of systemic chemotherapy, second-look surgery, and conformal radiation therapy (cRT) limited to the posterior fossa and primary site for children between 8 months and 3 years with nonmetastatic medulloblastoma. Method: After initial surgery children received four 4-week courses of induction chemotherapy, each consisting of cyclophosphamide, vincristine, cisplatin, and etoposide. This was followed by assessment for second surgical resection, followed by an age- and response-adjusted course of cRT to the tumor bed and posterior fossa (PF). Patients then received maintenance chemotherapy consisting of four alternating cycles of cyclophosphamide and vincristine followed by oral VP-16. Results: From October 2000 until June 2006, we registered 83 children, 78 of whom met eligibility criteria. Preliminary analysis shows that the 3-year event-free survival (EFS) on this study was 50% ± 6%. That compares favorably with a similar group treated on POG9233, in which 3-year EFS was 27% ± 6% (log-rank p = 0.018). In children who had complete resection (55 patients) and residual tumor (14), 3-year EFS and overall survival rates were 58% ± 7% and 77% ± 6% and 36% ± 13% and 50% ± 13%, respectively. Only one patient underwent second-look surgery. There was a striking difference in the pattern of recurrence related to the timing of radiation therapy. Of the eight patients that progressed prior to RT, seven had evidence of involvement of the primary site; in six, the recurrence was confined to the PF. Of the 18 patients with disease progression after cRT, the initial sites of recurrence were either in the region of the frontal lobes or in the spinal leptomeningeal compartment below C2–3 in 15. There was only one recurrence in the PF, and there were no recurrences in the occipital or temporal lobes after cRT. There was one treatment-related death in course 1 from fungal sepsis, but otherwise there were no major instances of unexpected toxicity. Detailed neuro-developmental follow-up has been performed and will be reported separately. Conclusions: Analyses are ongoing, however, the addition to postoperative chemotherapy of cRT limited to the PF and primary site appears to be a promising treatment for nonmetastatic medulloblastoma in infants. INF 13. PEDIATRIC BRAIN TUMORS IN THE FIRST YEAR OF LIFE: A 10-YEAR REVIEW Guirish Solanki,1 Shungu Ushewokunze,1 Martin English,2 Richard Walsh,1 Spyros Sgouros,1 Andrew Kay,1 and Anthony Hockley1; 1Department of Neurosurgery, Birmingham Children's Hospital, Birmingham, UK; 2Department of Oncology, Birmingham Children's Hospital, Birmingham, UK. Introduction: Brain tumors are uncommon in the first year of life and are especially so when children present with symptoms in the first 2 months of life (congenital tumors). Objective: To review the presentation, management, and outcome of children presenting with a brain tumor in the first year of life in a single large pediatric neurosurgical unit. Method: Retrospective review from January 1998 to December 2007 of histologically proven brain tumors identified from the tumor registry. There were 17 (nine boys, eight girls) children. Median age was 6 months (birth to 10 months). Five had congenital tumors. Results: There were six astrocytomas, two ependymomas, one pineoblastoma, one hemangioma, two PNETs, one chordoma, one immature teratoma, one lymphoma, and two rhabdoid/teratoid tumors. Eleven tumors were supratentorial and six infratentorial. Six patients had a complete resection performed, six debulking procedures, and five had a biopsy performed. Nine children received chemotherapy, and two radiotherapy. Seven children died, including four of five with congenital tumors and 3 of 12 with symptoms developing after the first 2 months of life (older infant group). The Fisher exact p-test (two-sided) was 0.04. The odds ratio for mortality between the two groups was 12 (SE = 15.62, p = 0.056). There is a 3× greater probability of death in the congenital group (risk ratio = 3.2; 95% CI, 1.09–9.36, p = 0.033). The overall 12-month survival was 64.7% (congenital group = 20%, older infant group = 83.3%). Three patients have survived >9.5 years; these were all noncongenital tumors. Follow-up ranged to 131 months. Discussion: Poor survival in congenital tumors (one of five) was associated with malignant lesions; the lone survivor was a patient with a metastatic clivus chordoma treated with endoscopic biopsy and chemotherapy. Other factors include delay in diagnosis (low suspicion index) and large tumor volume; both tumor progression and its treatment toxicity effects are more severe at this age. Conclusions: Outcome of brain tumors in infants remains poor and depends on histological type and therapeutic options available. In those children presenting with congenital tumors, the outcome remains very poor despite therapeutic advances. INF 14. PROGNOSTIC FACTORS AND SURVIVAL OF YOUNG CHILDREN WITH MEDULLOBLASTOMA: AN INTERNATIONAL META-ANALYSIS Stefan Rutkowski,1 Katja Von Hoff,2 Angela Emser,3 Maria Luisa Garré,4 David Walker,5 Richard Grundy,5 Girish Dhall,6 Jonathan Finlay,6 and Jacques Grill7; 1Children's University Hospital, University of Wuerzburg, Wuerzburg, Germany; 2Children's University Hospital, University of Wuerzburg, Germany; 3Institute of Biostatistics, IMBEI, University of Mainz, Mainz, Germany; 4Genova, Italy; 5Nottingham, UK; 6Los Angeles, CA, USA; 7Institut Gustave Roussy Villejuif, Villejuif, France. Purpose: To investigate survival and the relevance of clinical and biological prognostic factors (histologic subtype, extent of resection, and staging) in young children with medulloblastoma. Methods: Clinical data sets of children diagnosed March 1987–July 2004 and treated within prospective national trials (HIT, SFOP, AIEOP, UKCCSG, and Head Start) were centrally analyzed by univariable and multivariable analyses. Results: Data of 270 children with medulloblastoma <5 years of age at diagnosis were collected; 253 children with a median age of 1.88 years (range, 0.17–4.97 years) and a median follow-up of 8.0 years (range, 1.2–16.2 years) were eligible for analysis. Rates for 8-year event-free survival (EFS) and overall survival (OS) were 86% and 95% in 21 children with extensive nodularity (MBEN), 48% and 72% in 87 children with desmoplastic medulloblastoma (DMB), 28% and 42% in 145 children with classical medulloblastoma (CMB), and 14% and 14% in seven children with large cell anaplastic medulloblastoma (LCA); p < 0.001. Among 104 children with M0-stage and complete tumor resection, survival was higher in DMB compared to CMB (EFS 63% vs. 42%, OS 85% vs. 67%, p < 0.02). Survival rates were lower in 78 nonmetastatic children with postoperative residual tumor (EFS, 37% DMB and 23% CMB, p = n.s.; OS, 66% DMB and 42% CMB, p = 0.045). Among 71 children with metastatic disease, survival was better in children with DMB (EFS, 56% vs.19%, p = 0.003; OS, 66% vs.19%, p = 0.001). Histology (DMB, HR 0.5, CI 0.35–0.73; MBEN, HR 0.15, CI 0.05–0.48; LCA, HR 3.17, CI 1.32–7.64; p < 0.001 compared to CMB), incomplete resection (HR 1.82, CI 1.31–2.54, p < 0.001), and national group were independent prognostic factors for EFS. Conclusion: Histologic subtypes of medulloblastoma were strong and independent prognostic factors in this age group. Desmoplasia is confirmed as a strong independent favorable prognostic factor in localized and metastatic medulloblastoma of early childhood. This should be considered for planning of future trials and treatment concepts. INF 15. THE MANAGEMENT OF FETAL BRAIN TUMORS: CHALLENGES AND CONTROVERSIES Manabu Natsumeda,1 Junichi Yoshimura,1 Kenichi Nishiyama,1 Takayuki Takachi,2 Chihaya Imai,2 and Yukihiko Fujii1; 1Department of Neurosurgery, Brain Research Institute, University of Niigata, Niigata City, Niigata, Japan; 2Department of Pediatrics, University of Niigata, Niigata City, Niigata, Japan. Objective: To discuss the therapeutic strategy for fetal brain tumors. Methods: From 1982 to 2007, of the 19 congenital brain tumors diagnosed during the first year of life and treated at our institution, three were diagnosed before birth (fetal brain tumors). Surgical procedures and additional postoperative therapies were applied. The management of these patients was discussed retrospectively. Results: The three patients were histologically diagnosed as immature teratoma, PNET, and cavernous angioma (CA). The first patient was diagnosed by fetal MRI at 38 weeks of gestation. Progressive hydrocephalus was observed after birth, and a subtotal removal and external ventricular drainage were performed at 41 days after caesarean section. The histological diagnosis was immature teratoma. Postoperatively, there were epileptic attacks and hydrocephalus with subdural hygroma observed on scans. Ventriculoperitoneal and subduroperitoneal shunts were placed and chemotherapy was administered from 2 months of age. He is now 3 years of age with moderate mental disabilities. There has been no enhancing lesion on follow-up brain and spine MRI scans. The second patient had a mass in the lateral ventricle, diagnosed by fetal MRI at 36 weeks. Emergency removal was performed because of intratumoral hemorrhage and brain herniation on postnatal day 5. The histological diagnosis was PNET. Postoperative hydrocephalus was treated by multiple shunts and endoscopic procedures. Chemotherapy was started at 2 months of age. She is now 2 years old with severe mental disabilities, although there is no recurrence of tumor. The third patient had a mass in the left basal ganglia diagnosed by ultrasonography at 39 weeks. After waiting and scanning, the size of the mass increased, and partial removal was performed at 7 months. The histology was CA. Postoperatively, he received 30.4 Gy of local irradiation. The residual CA is stable at present. He is now 7 years old with mild mental disabilities. The 5-year survival rate of 19 congenital tumors (including fetal brain tumors) is 50.2%. As for the functional outcome of 10 surviving patients, three have shown normal development, two mild to moderate disabilities, and five severe mental disabilities. Discussion and Conclusion: The improvement in prenatal diagnosis and perinatal management has led to the necessity for development of treatment strategies for fetal brain tumors. Radical operation is risky, and some advocate biopsy and shunt placement as initial treatment. However, early shunt placement may lead to intratumoral hemorrhage and limitation of further approach to intraventricular tumors. We propose a case-by-case approach, using radical surgical resection as the initial procedure when possible. Radical resection will keep postoperative chemotherapy and radiation at an absolute minimum, maintaining optimal mental status. The survival rate and functional outcome of fetal brain tumors are not catastrophic in our series. We thus have to face the challenges of treating this clinical entity through collaboration with other specialists including obstetricians, neonatologists, anesthesiologists, and pediatric oncologists. LATE EFFECTS LE 1. ABNORMAL TIMING OF MENARCHE IN SURVIVORS OF CHLDHOOD CNS TUMORS Gregory Armstrong,1 John Whitton,2 Wendy Leisenring,2 Eric Chow,2 Amar Gajjar,1 Larry Kun,1 Leslie Robison,1 and Charles Sklar3; 1St. Jude Children's Research Hospital, Memphis, TN, USA; 2University of Washington, Seattle, WA, USA; 3Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Purpose: Children with CNS tumors who receive radiation therapy (RT) to the hypothalamic-pituitary (H-P) axis are at particular risk for altered timing of puberty or menarche. Early puberty has been well described in childhood acute lymphoblastic leukemia (18–24 Gy). Risk for both early and late menarche after higher dose RT, as used in the treatment of CNS tumors, has not been well described. Patients and Methods: We evaluated 235 female survivors of CNS tumors, diagnosed between 1970 and 1986, and 1,051 sibling controls who were participants in the Childhood Cancer Survivor Study, and provided self-reported data on age at menarche. Logistic regression models were used to estimate various patient and treatment-related risk factors on the risk of early and late menarche. Results: Survivors of CNS tumors were more likely to have onset of menarche before age 10 compared to their siblings (11.9% vs. 1.0%) (odds ratio [OR] = 14.1, 95% confidence interval [CI] = 7.0–30.9). Twenty of the 138 survivors (14.5%) who received RT to the H-P axis had onset of menarche before age 10, compared to 4.3% of those who did not receive RT (OR = 3.8, CI = 1.2–16.8). Notably, 17% of participants receiving >50 Gy to the H-P axis experienced menarche before age 10 (OR = 4.6, CI = 1.2–22.4). Patients diagnosed and treated <4 years of age had a fourfold risk of early menarche (p = 0.002). To further explore the dose–response relationship between CNS RT and early menarche, we combined a previously published cohort of 874 patients treated for acute lymphoblastic leukemia with the current CNS cohort. These data suggest increasing incidence of early menarche with increasing doses of RT (5.4% at 20–30 Gy, 14% at 30–40 Gy, and 17% at >50 Gy). Additionally, survivors of CNS tumors were more likely than their siblings to have onset of menarche after age 16 (10.6% vs. 1.9%) (OR = 6.6, CI = 3.4–11.4). When compared to survivors who had surgery alone for treatment of CNS tumor, participants who received craniospinal RT were at greater risk for late menarche (OR = 7.4, CI = 1.7–51.7) than those who had CNS-directed RT alone (OR = 2.4, CI = 0.5–17.1). However, doses of RT to the H-P axis >50 Gy conferred an increased risk of late menarche (OR = 9.0, 2.3–59.5). Older age (>10) at the time of diagnosis was associated with late menarche (p = 0.01). Conclusions: Survivors of CNS tumors are at risk of both early and late menarche. Radiotherapy to the H-P axis and young age at the time of treatment are major risk factors for early menarche. Craniospinal RT, cranial RT dose >50 Gy, and older age at time of treatment are associated with late menarche. LE 2. AKINETIC AND NONAKINETIC MUTISM AFTER POSTERIOR FOSSA TUMOR RESECTION Adrian Caceres1 and Tadanori Tomita2; 1Neurosurgery, National Childrens Hospital, San José, Costa Rica; 2Pediatric Neurosurgery, Children's Memorial Hospital, Chicago, IL, USA. Mutism after posterior fossa tumor resection was described more than two decades ago, and remains to this day an intriguing clinical phenomenon. We conducted a retrospective analysis of all patients treated at Children's Memorial Hospital from 1983 to 2003, finding 21 cases of cerebellar mutism. Average follow-up was 7.8 years. Tumor histology was compatible in 20 cases with medulloblastoma, with one additional case corresponding to a juvenile pilocytic astrocytoma. Age and symptoms at presentation, surgical approach with particular attention to vermian splitting, extent of resection, and apparent origin as determined during surgery were documented. Special attention was paid to mutism initiation, language breakthrough, orofacial/swallowing compromise, and particularly associated akinesia, hemiparesis, behavioral abnormalities, urinary sphincter dysfunction, and presence of shunted hydrocephalus. We were able to identify two subgroups of mute patients, those who were akinetic (n = 8) and those who continued to move (n = 13). In both groups, mutism started an average of 48 hours after surgery and speech output restarted by 5.4 weeks. There were no statistically significant differences between the two groups in age, sex, extent of tumor resection, initiation of mutism, language breakthrough, or shunted hydrocephalus. We propose that despite these similarities, there are two subgroups of mute patients after posterior fossa tumor removal based on the absolute arrest of movement. Further investigation is warranted in order to understand the complex roles of the cerebellum in motor and cognitive functioning. LE 3. BEHAVIORAL, PSYCHOLOGICAL, AND NEUROLOGICAL OUTCOMES IN CHILDREN TREATED FOR BRAIN TUMORS UNDER THE AGE OF THREE YEARS Catherine Ward,1 Dianne Gumley,1 Kim Phipps,1 and Carlos De Souza1; 1Great Ormond Street Hospital for Children NHS Trust, London, England, UK. Studies of childhood brain tumor outcomes tend to report significant deficits in cognitive functioning among long-term survivors. Younger children are particularly vulnerable to the effects of radiotherapy. Recent guidelines recommend using other treatment options with this group. There have been few published studies examining behavioral outcomes in children treated before the age of 3 years. Aims: We looked at long-term behavioral, psychological, and neurological outcomes in children treated for brain tumors with surgery and/or chemotherapy before the age of 3 years. We also investigated the relationships among tumor/treatment factors, neuropsychological functioning, and behavioral and psychological outcome. Method: We have fully evaluated the 30 children 7–14 years of age with event-free survival, and report on their physical status and psychological and emotional well-being. All were treated before the age of 3 years and had not received radiotherapy. We assessed cognitive functioning (Wechsler Abbreviated Scale of Intelligence), memory (CMS), executive functioning (BADS-C) and verbal fluency (Multilingual Aphasia Exam Controlled Oral Word Association Test). Parents and teachers completed measures of executive functioning (BRIEF), behavior, and psychological functioning (CBCL). Results: Children are making good progress with cognitive and memory skills, with the majority functioning within the normal range. However, behavioral and psychological difficulties were reported in more than half of the children. Conclusions: Although these children appear to be making good progress with cognitive skills, it is important to monitor difficulties with behavioral, social, and emotional development. LE 4. EDUCATING PARENTS AND TEACHERS: INCREASING UNDERSTANDING OF NEUROCOGNITIVE LATE EFFECTS OF CHILDHOOD CANCER SURVIVORS Bonnie Carlson-Green,1 Janet Oliver,2 Marsha Finkelstein,3 Meixia Liu,3 and Song Chen3; 1Children's Hospitals and Clinics of Minnesota, St. Paul, MN, USA; 2Psychology, Children's Hospitals and Clinics of Minnesota, St. Paul, MN, USA; 3MN, USA. Background: With improved survival rates has come increased focus on long-term quality of life for childhood cancer survivors. Unfortunately, specific interventions to address the neurocognitive sequelae of childhood cancer have been few and far between. Pharmacological interventions, such as trials of methylphenidate (e.g., Mulhern et al. 2004), have been undertaken most recently with some benefits. Cognitive rehabilitation (e.g., Butler and Copeland, 2002) may be an additional area of promise. However, ecological interventions such as explaining neuropsychological late effects to patients, parents, and especially teachers (Butler and Mulhern, 2005) may be a more beneficial and cost-effective means of improving quality of life for this population. Childhood cancer survivors whose parents and teachers can help them access special education services may experience improved quality of life and similar educational achievement to children who did not have cancer (Mitby et al. 2003). Objective: We report here four methods of providing information about neurocognitive late effects: in the context of a family retreat, a parent/teacher evening conference in a hospital, a training conference for teachers of children with medical disorders sponsored by a state Department of Education, and a daylong educational program for childhood cancer survivors organized by a national survivors' group. Pre- and post knowledge surveys were collected from participants and the different intervention methods were compared. Summary: Each intervention had its own strengths and weaknesses, but all were effective in delivering important information. In general, self-evaluation of knowledge postworkshop compared to preworkshop demonstrated significant improvements for both parents and teachers regardless of the format or setting. All parents and most teachers indicated strong agreement in recommending the program to others. After completing a daylong seminar, survivors and their families rated themselves as more knowledgeable about appropriate resources, as well as having a better understanding of some of the specific learning problems after cancer treatments. These preliminary results underscore the need and importance of providing education about neurocognitive and social/emotional late effects to parents and teachers of children with cancer, and its importance as an ecological intervention. Future studies on this topic would incorporate techniques other than true/false responses for measuring participants' specific knowledge about late effects. Such information could then be used to design a specific intervention to address knowledge gaps. Studies to address the appropriate timing of the interventions may also be helpful. Long-term follow-up would be beneficial in determining whether or not the interventions ultimately result in improved educational advocacy or services for childhood cancer survivors. Alternatively, future studies could track educational outcomes of children who receive such services compared with those who do not. LE 5. EFFICACY AND TOLERABILITY OF STIMULANT MEDICATION FOR LEARNING-IMPAIRED SURVIVORS OF CHILDHOOD CANCER Heather Conklin,1 Raja Khan,2 Wilburn Reddick,3 Joanne Lawford,1 Scott Howard,4 Brannon Morris,4 Ronald Brown,5 Melanie Bonner,6 Shengjie Wu,7 Xiaoping Xiong,7 and Raymond Mulhern8; 1Division of Behavioral Medicine, St. Jude Children's Research Hospital, Memphis, TN, USA; 2Department of Neurology, University of Tennessee, Memphis, TN, USA; 3Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA; 4Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; 5College of Health Professions, Temple University, Philadelphia, PA, USA; 6Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA; 7Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA; 8Deceased. Background: Children surviving malignant brain tumors (BT) and acute lymphoblastic leukemia (ALL) are at significant risk for developing attention and learning problems. There have been few systematic attempts to study interventions to remediate these cognitive problems. The efficacy of stimulant medications, such as methylphenidate (MPH), is well established in improving attention regulation in otherwise healthy children diagnosed with attention-deficit hyperactivity disorder (ADHD). However, medication response rates and tolerance levels may differ for children with compromised neurological status, and the few studies of MPH in childhood cancer survivors have been limited by small sample sizes, lack of randomized designs, poor characterization of medication response, and short follow-up times. Methods: Long-term survivors of BT and ALL, identified as displaying attention and academic problems, participated in up to three sequential phases of a multicenter, randomized clinical trial of MPH: (1) a 2-day, in-clinic, double-blind crossover trial to evaluate neurocognitive performance and side effects of MPH compared to placebo (n = 122; 61 BT, 61 ALL); (2) a 3-week, home-based, double-blind crossover trial to evaluate attention modulation and social skills on placebo, low-dose MPH, and moderate-dose MPH (n = 83; 43 BT, 40 ALL); and (3) a yearlong, open-label MPH maintenance trial during which attention modulation and social skills are assessed at 1, 3, 6, and 12 months and neurocognitive performance is assessed at 12 months (n = 57; 26 BT, 31 ALL). Results: During the 2-day, in-clinic study phase, a significant MPH versus placebo effect was revealed on a measure of attention, cognitive flexibility, and processing speed (Stroop Word-Color Association Test, p = 0.01). No significant difference was found for mean severity of side effects as a function of active medication (Barkley's Side Effects Rating Scale; MPH vs. placebo, 2.68 ± 1.57 vs. 2.34 ± 1.72, p = 0.46). For the home crossover phase, significant improvement was reported by teachers and parents on measures of attention modulation (Conners' Rating Scales; effect sizes [ES], 0.41–0.73; 79.5% showed clinical improvement) and teachers on the measure of social skills (Social Skills Rating System; ES, 0. 37–0.73). There was no consistent advantage for moderate dose over low dose. Preliminary findings from the ongoing maintenance trial suggest that benefits are sustained at a statistically significant level at least for measures of attention (Conners parent and teacher ratings and Conners Continuous Performance Test), if not academic achievement (Wechsler Individual Achievement Test). Statistically significant but modest weight decline, not height deceleration, was observed during the year-long MPH trial relative to case-matched childhood cancer survivors not taking MPH. Across study phases, there were no significant differences based on cancer diagnoses, BT, or ALL. Conclusions: MPH reduces some attentional and social deficits among survivors of childhood BT and ALL. Improvements were evident in a brief home crossover trial and still evident after a year of treatment. While some childhood cancer survivors demonstrate greater sensitivity to medication side effects, MPH was tolerable for the majority of these children. Demographic and clinical predictors of positive MPH response and MPH side effects will be discussed. LE 6. ENDOCRINE, INTELLECTUAL, AND FUNCTIONAL OUTCOMES IN ADULT SURVIVORS OF CHILDHOOD POSTERIOR FOSSA BRAIN TUMORS Jessica Jackson,1 K. Davies,2 S.S. Khan,1 N. Martin,1 R.J. Greenwood,3 L. Cipolotti,1 and H.A. Spoudeas2; 1Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, London UK; 2Neuroendocrine Division, London Centre for Paediatric Endocrinology, Great Ormond Street and University College Hospitals, London, UK; 3Department of Neurology and Neurorehabilitation, Institute of Neurology, University College, London, UK. Purpose: To evaluate endocrine, cognitive, and functional outcomes in long-term (>9 years) cranially irradiated adult survivors of childhood posterior fossa tumor (PFT). Methods: Sixteen adults (9 male/7 female) of mean age (standard deviation [SD]) 22.3 (4.1) years, surviving childhood PFT at 6.0 (2.8) years, and attending a neuroendocrine surveillance clinic were studied. All had received surgery and 30–35 Gy neuraxial irradiation with 20 Gy tumor boost. Their adult endocrine, neurological, cognitive, and occupational status were recorded. Results: Pituitary growth hormone (GH) deficiency was isolated in all but one patient (who also had TSH and GnRH deficiency). Two females with primary hypothyroidism (one with gonadal failure) and one female with gonadal failure alone had all received adjuvant chemotherapy with spinal irradiation. Two patients had motor deficits and three required anticonvulsants. None had visual impairment, and just one had mild auditory impairment. Patients were educated for 14.4 (2.1) years; five (31%) had education statements and a further six (38%) received some concessions or support; seven (44%) were in paid employment and only one was unemployed; seven were academic students and just one required support in the community. Their mean (SD) Wechsler Adult Intelligence Scale-Revised FIQ was 80.1 (10.9) (range, 61–99) Conclusion: Radiation-based therapeutic strategies for non-centrally positioned childhood brain tumors do not cause significant pituitary dysfunction other than GH deficiency, even at long (16 years) follow-up. Adjuvant chemotherapy increases the risk of primary glandular deficits (hypothyroidism and gonadotoxicity), and sensory and motor late effects. Despite these disabilities and reduced intellectual skills, patients can achieve gainful employment with neuroendocrine rehabilitative support. LE 7. GROWTH HORMONE EXCESS ASSOCIATED WITH HYPOTHALAMIC TUMORS IN CHILDREN Reema Habiby,1 Jami Josefson,1 Donald Zimmerman,1 Mary Kreiter,1 Jason Fangusaro,2 Stewart Goldman,2 Tadanori Tomita,3 Joel Charrow,4 and Robert Listernick4; 1Endocrinology, Children's Memorial Hospital, Chicago, IL, USA; 2Hematology/Oncology, Children's Memorial Hospital, Chicago, IL, USA; 3Neurosurgery, Chicago, IL, USA; 4Children's Memorial Hospital, Chicago, IL, USA. Growth hormone (GH) excess occurs rarely in childhood. Most often, GH excess results from excessive growth hormone secretion from a pituitary adenoma. Growth hormone excess has also been observed in the presence of hypothalamic tumors, though the mechanism is unknown. There are a few sporadic reports in the literature of children with GH excess associated with optic pathway tumors (OPT) involving or contiguous with the hypothalamus. We report five children with hypothalamic tumors and growth hormone excess. The GH excess was diagnosed by the following criteria: linear growth acceleration, elevated IGF-1 and IGFBP-3 levels, and lack of GH suppressibility to <1.0 ng/ml during oral glucose tolerance tests. There were four girls and one boy. The average age at presentation was 3.4 years (range, 2–4 years). Three of the five children also had associated neurofibromatosis type 1. Four of the five children had sex steroid levels in the early pubertal range following stimulation with leuprolide acetate, while the hypothalamic-pituitary-gonadal axis was not assessed in one child. Though early puberty is associated with elevated IGF-1 and IGFBP-3 levels, early puberty has not been shown to cause lack of suppressibility of GH. The precocious puberty was treated in one child and was not associated with lowering of the IGF-1 and IGFBP-3 levels. Three of the children were receiving chemotherapy for their tumors at the time of presentation of GH excess. GH excess has been rarely reported and may be an underrecognized occurrence, especially in the setting of concomitant precocious puberty, where growth is already rapid. The natural history of GH excess in this subset of patients is not known, and a very important concern is the possibility that GH excess may stimulate progressive tumor growth. LE 8. INTELLECTUAL AND PSYCHOLOGICAL OUTCOME IN A GROUP OF CHILDREN TREATED FOR EPENDYMOMA Geraldina Poggi,1 Annarita Adduci,2 Susanna Galbiati,3 Mariarosaria Liscio,4 Maura Massimino,4 and Lorenza Gandola4; 1Scientific Institute E. Medea, Lecco, Italy; 2Acquired Brain Injury, Scientific Institute E. Medea, Bosisio Parini-Lecco, Italy; 3Acquired Brain Injury, Scientific Institute E. Medea-Lecco, Lecco, Italy; 4Italy. Purpose: To evaluate the cognitive and psychological outcome in, and follow-up on, a group of 22 children treated for ependymoma. Methods: All the patients received a cognitive (Wechsler scale) and psychological evaluation (Child Behavior Checklist [CBCL]) and Vineland Adaptive Behavior Scales. After the first assessment, some patients underwent repeat evaluations: 12 patients were assessed only once, 8 were assessed twice, and 5 were assessed three times. The patients were divided into two groups according to age at treatment (< and >5 years) and supra-/subtentorial site. Results: Mean age at diagnosis was 5.87 years and mean age at radiotherapy was 6.32 years. Time between diagnosis and first evaluation was 1.86 years; mean age at initial evaluation was 7.93 years. Sixteen patients had been treated for subtentorial ependymoma and six for supratentorial ependymoma; 10 children were <5 years at radiotherapy and 12 children were >5 years at radiotherapy. At initial assessment mean FIQ was 99, VIQ was 100.06, and PIQ was 95.7. With regard to age at radiotherapy, there is a marked but not significant difference in IQ between the two groups: older children have a lower mean IQ than younger children. This difference between the two age groups was also observed at follow-up. With regard to the supra-/subtentorial distinction, FIQ, VIQ, and PIQ improved in patients with subtentorial ependymoma, while they decreased in patients with supratentorial ependymoma. Regarding the psychological profile, the whole group shows a mild and progressive improvement on the CBCL, although it must be noted that only the mean internalizing score shows a critical psychological and clinical picture. Looking at data according to age, the mean scores of children <5 years are in the normal range, while the mean scores of older children at the second evaluation are closer to the cutoff. In particular, these children scored higher than the cut-off at the Internalizing Scale. Social and Communication skills improved, while Motor and Daily Living skills showed initial deterioration at the second evaluation and later improvement. Children <5 years of age improved on all the domains, while older children showed a marked decrease in Daily Living skills and Motor skills and a milder deterioration of Social and Communication skills, with later improvement. Conclusion: These patients show mild cognitive and psychological impairment. It is important to note that patients with supratentorial ependymoma show worse cognitive and psychological recovery, which is independent of age. Research Implications: Our small sample size does not allow us to draw general conclusions. It would be useful to carry out this study on a larger group of patients and compare its results with results of patients affected by other brain tumors. Clinical Implications: Although these patients do not show a severe cognitive and psychological impairment, it is important to provide appropriate remediation in order to limit its impact on academic performance, psychological development, and social reentry. We gratefully acknowledge the financial support of Associazione Italiana per la Ricerca contro il Cancro. LE 9. IQ VERSUS EXECUTIVE FUNCTION RATINGS AS PREDICTORS OF ADAPTIVE SKILLS IN CHILDREN TREATED FOR LOW-GRADE GLIOMAS ONLY WITH SURGERY Celiane Rey-Casserly,1 Christine Chordas,2 Cori Liptak,2 Nicole Ullrich,1 Scott Pomeroy,1 Liliana Goumnerova,1 Mark Kieran,2 and Christopher Turner2; 1Children's Hospital of Boston, Boston, MA, USA; 2Dana-Farber Cancer Institute, Boston, MA, USA. Objective: Neuropsychological functioning (executive functions and intelligence) was assessed in long-term survivors of pediatric low-grade gliomas (LGG) treated only with surgery as predictors of overall adaptive functioning. Competence in executive functioning was expected to predict effectiveness of adaptive skills over and above any association with IQ. Participants and Methods: Medical, neuropsychological, and psychosocial outcome data were collected through a retrospective chart review of LGG surgery-only patients diagnosed before age 22 who are followed regularly in a multidisciplinary pediatric neurooncology outcomes program. Of the 76 surgery-only LGG survivors reviewed, 33 (15 male, 18 female) had comprehensive neuropsychological assessments that included measures of intellectual ability, executive function, and adaptive skills (median age at testing, 12 years; range, 6–20). The median time since diagnosis was 5 years (range, 1–16). Diagnoses included astrocytomas, gangliogliomas, oligodendrogliomas, and LGG not otherwise specified. Primary locations were posterior fossa/cerebellar (52%), cortical (36%), and other (12%). Intellectual ability (IQ) was assessed with the Wechsler scale appropriate for the patient's age. Executive functions (EF) were measured by the Behavioral Rating Inventory of Executive Function, a rating scale of executive functioning in everyday life, completed by a parent/guardian. Functional level of adaptive behaviors was assessed with a multidimensional questionnaire measure of adaptive ability (Adaptive Behavior Assessment System-II; Scales of Independent Behavior-Revised). The summary score was used for analysis. Hierarchical regression analysis was used to evaluate the contribution of EF to adaptive skills over and above that of IQ. Results: Overall IQ and adaptive skills were within the average range; mean IQ = 96 (range, 60–147; median, 95); mean adaptive skills = 95 (range, 52–143; median, 92). The proportion of individuals with scores at or below 85 for IQ (30%) and adaptive functioning (30%) was higher than expected for the normative population (p = 0.03). Hierarchical regression analysis revealed that IQ accounted for 2% of the variance in adaptive skills (p = 0.47) while EF accounted for an additional 32% of the variance (p = 0.006). Conclusions: LGG surgery-only survivors followed in a survivorship clinic experienced neurobehavioral late effects as assessed with comprehensive neuropsychological evaluation. Although the mean scores were close to the expected population mean on measures of IQ, executive function, and adaptive skills, the proportion of individuals with scores below normal range was higher than expected. Findings indicate that IQ is not predictive of overall adaptive living competence in these patients. A measure of executive function was a far better predictor of adaptive success in this population. The findings suggest that executive functioning may be a particularly important focus for intervention in long-term survivors of LGG whose adaptive skills are compromised. LE 10. LATE EFFECTS FOLLOW-UP OF “HEAD START II” SURVIVORS Stephen Sands,1 Jennifer Oberg,2 Sharon Gardner,3 and Jonathan Finlay4; 1Pediatrics and Psychiatry, Columbia University, New York, NY, USA; 2Pediatrics, Columbia University, New York, NY, USA; 3Pediatrics, New York University, New York, NY, USA; 4University of Southern California, Los Angeles, CA, USA. Purpose: To evaluate the neuropsychological late effects of survivors treated on the “Head Start II” protocol from 1997 to 2003. Methods: Patients <10 years of age diagnosed with a malignant brain tumor underwent baseline neuropsychological assessment prior to autologous stem cell transplantation (AuHCR) and 3 years later. Standard risk patients received five cycles of induction chemotherapy and one cycle of myeloablative consolidation therapy, while patients with neuraxis dissemination also received intensification using i.v. methotrexate (IVMTX). Craniospinal irradiation (CSI) was used to treat residual disease at completion of induction or relapse. Results: Baseline assessments for 49 patients (median age, 38 months; standard deviation [SD] = 25), indicated low-average intelligence (full-scale IQ [FSIQ] = 88.77; SD = 17.7) and low average visual-motor abilities (VMI = 87.69; SD = 9.4); whereas expressive language skills were within the average range (Peabody Picture Vocabulary Test [PPVT] = 102.11; SD = 17.1). Parents reported social-emotional and behavioral functioning within the average range (CBCL T score = 47.59; SD = 9.4). Follow-up testing was obtained on 24 of 30 survivors (80%) at mean follow-up of 39.7 months after transplant (SD = 16.1). Analysis of FSIQ reveals a stable level of intellectual functioning between baseline and follow-up (FSIQ = 89.27, SD = 16). Additionally, learning and memory were within the average range, while academic achievement (reading, spelling, and math), receptive language, and VMI were within the low-average range at time 2. Of the 10 patients (42%) who received CSI, mean radiation delay was 14.3 months (SD = 13.2). There were no significant differences in FSIQ between those who received IVMTX and those who did not. No significant correlations were found between age at diagnosis and intellectual ability, academic achievement, expressive language, or visual-motor skills. Conclusions: Induction and myeloablative consolidation chemotherapy, with or without IVMTX, followed by AuHCR may avoid or delay CSI while preserving neuropsychological functioning, including for patients who were younger at diagnosis. Continued follow-up of these survivors is warranted to determine the stability of their neuropsychological, social-emotional, and behavioral functioning over time. LE 11. LONG-TERM OUTCOME AND QUALITY OF LIFE IN CHILDREN OPERATED ON FOR BRAIN TUMOR Chandra Sd,1 Anit Singh,2 and Vinay Singh3; 1Department of Pediatric Neurology, Govt. Medical College Banglore, Banglore, Karnataka, India; 2India; 3Karnataka, India. Objective: Brain tumors are one of the most common forms of cancer in children. In our hospital, we evaluated quality of life before and after surgical resection, chemotherapy, and radiotherapy. In this study, we established the relationship between brain and behavior in children with various brain tumors, for example, medulloblastoma, oligodendroglioma, and glioma. Neuropsychological sequelae and behavior differ due to disease itself and various modes of treatment available. Long-term studies have revealed serious psychological consequences of the disease. The aim of this study was to evaluate neuropsychological, behavioral, sensorimotor, intellectual, academic, emotional, and social function. Methods: We evaluated 17 children surgically treated for various brain tumors and given radiotherapy and chemotherapy postoperatively. To determine quality of life, behavior, and intellectual status, we evaluated the children's functional status with the help of psychometric assessment using the Luria-Nebraska Neuropsychological Battery, intelligence quotient by the Wechsler Intelligence Scale, and magnetic resonance imaging. In addition, personal interviews of both child and parents were carried out. Result: Serial evaluations were conducted after surgery and 8 months later to see the effect of chemotherapy and radiation on the children's lives. Of 17 children, 12 experienced major problems in academic, motor, sensory, cognitive, and emotional function. Other children had mild disability with intelliegnce quotient greater than 80 and ability to work independently. Children with cognition, behavior, and academic problems were <5 years old and had poor prognosis due to high-grade tumor and tumor recurrence. We noticed mood problems, anxiety, and social withdrawal in all children, to some extent. Conclusions: Cognitive functions were most affected in children with CNS radiation with younger age, high-grade tumor located in midline with atypical features, and family history of brain tumor and mood disorder. Chemotherapy and radiotherapy have certainly improved outcomes in children with certain brain tumors, but with long-term neuropsychological consequences. Neuropsychological status is important to evaluate quality of life in survivors of brain tumors, to make their lives as easy as possible, to combat difficulties of daily routine, and to provide aid to improve living and rehabilitation. LE 12. NEUROLOGICAL AND NEUROPSYCHOLOGICAL OUTCOME OF CHILDREN AND ADOLESCENTS WITH INTRACRANIAL GERM CELL TUMORS: EXPERIENCE IN 17 CONSECUTIVE PATIENTS TREATED AT THE MEDICAL UNIVERSITY OF VIENNA (1991–2007) Amedeo Azizi,1 Ulrike Leiss,1 Anastasia Dressler,1 Astrid Gupper,1 Andreas Peyrl,1 Thomas Czech,2 Karin Dieckmann,3 and Irene Slavc1; 1Pediatrics, Medical University of Vienna, Vienna, Austria; 2Neurosurgery, Medical University of Vienna, Vienna, Austria; 3Radiotherapy, Medical University of Vienna, Vienna, Austria. The optimal management of localized intracranial germ cell tumors remains controversial. Cure rates for these rare CNS tumors are high, and limitation of treatment-related late morbidity is therefore essential. We assessed the neurological and neuropsychological long-term outcome of patients with intracranial germ cell tumors. Patients: From 1991 to 2007, 17 consecutive patients (14 male, 3 female) with intracranial pure germinomas (GCT) (n = 8) and secreting malignant nongerminomatous germ cell tumors (MNGGCT) (n = 9) were treated at our institution. Mean age at diagnosis was 13 years (range, 6–23). Tumor location was pineal in nine patients, suprasellar/third ventricle in five, and multifocal/metastatic in three. Patients with suprasellar tumors presented with various degrees of endocrinopathy, and patients with pineal region tumors experienced increased intracranial pressure due to occlusive hydrocephalus. Surgical intervention at diagnosis consisted of biopsy (n = 9), gross total resection (n = 3), partial resection (n = 1), and marker diagnosis only (n = 4). Second-look surgery was performed in two patients. Treatment according to German protocol Makei 89 (n = 4) or international protocol SIOP CNS-GCT 96 (n = 13) consisted of either craniospinal irradiation alone or local irradiation plus chemotherapy and craniospinal irradiation plus chemotherapy in patients with metastases. Two patients received high-dose chemotherapy followed by peripheral stem cell rescue. Results: All patients are alive for a median of 7 years (range, 5 months to 16.5 years), 15 in first complete cytogenetic remission (CCR), one in second CCR, and one in fourth remission. All patients were evaluable for neurological outcome. No significant differences were found between the examinations before and 3 months after diagnosis; however, statistically significant normalization of cranial nerves I and VI deficits was seen in long-term follow-up (p = 0.037). Fourteen patients were tested repeatedly neuropsychologically over the course of treatment and follow-up. With follow-up ranging from 5 months to 16 years after diagnosis, the latest full-scale IQ scores ranged from 78 to 117. Counting the score differences of every subtest between the first and the last assessment, an average improvement of 0.5–3.7 points on the Wechsler scale was found. Seven patients with detailed information improved their neuropsychological functions over the first 4 years after diagnosis. Improvement over time was seen in subtests evaluating abstract reasoning, level of general knowledge, and visual and spatial perception, including abstract visual processing, and problem solving. A tendency toward loss over time was noticed in digit span, learning and attention, mathematical problem solving, mental speed, and visual/motor coordination. Conclusion: None of our patients showed a worsening of preexisting neurologic deficits after surgery. Intellectual abilities improved in the majority of the 14 evaluable patients over a period of several years after diagnosis. These results might reflect the serious and long-standing impact of the tumor prior to diagnosis with regard to untreated endocrinopathies or increased intracranial pressure. At last follow-up, the mean IQ for the whole cohort reached values almost comparable to the normal population. There was a trend toward lower performance in some subtests; however, numbers were too small to draw conclusions on the impact of different treatment modalities. These data could serve as a benchmark for newer treatment protocols eliminating or reducing radiation. LE 13. NEUROPSYCHOLOGICAL AND BEHAVIORAL OUTCOMES OF UNDER THREE-YEAR-OLD CHILDREN WITH MEDULLOBLASTOMA TREATED WITH SURGERY, CHEMOTHERAPY, AND FOCAL IRRADIATION Dianne Gumley,1 Kim Phipps,2 Maisy Haslop,1 and Antony Michalski3; 1Paediatric Psychology, Great Ormond Street Hospital for Children NHS Trust, London, UK; 2Great Ormond Street Hospital for Children NHS Trust, London, UK; 3Great Ormond Street Hospital for Children NHS Trust, London, UK. Neuropsychological function of very young children treated for medulloblastoma is a key outcome measure. Recent publications have shown improved survival for these children. We report cognitive and behavioral outcomes for 12 children, all of whom were <36 months of age at diagnosis of medulloblastomoa. At follow-up assessment, the children ranged in age from 2 years to 12 years. Cognitive skills (WISC-IV), memory (CMS), and executive function skills (BRIEF) were assessed in children ⩾6 years of age. We also assessed behavioral outcomes. A developmental assessment was carried out with younger children together with a measure of adaptive functioning (Vineland 11, Adaptive Behavior Scales) One child had learning disabilities identified before diagnosis and continues to have difficulties. Two children who were treated at a very young age are functioning below average for their age. Four children have cognitive skills within the normal range. Of the remaining five children, moderate impairments in different neuropsychological and behavioral domains were noted. We can conclude that this protocol is compatible with good neuropsychological and behavioral outcomes in survivors. LE 14. NEUROPSYCHOLOGICAL AND QUALITY OF LIFE OUTCOME OF SURVIVORS OF PEDIATRIC MALIGNANT GLIOMA Stephen Sands,1 Tianni Zhou,2 Zhengjia Chen,2 Sharon O'Neil,3 and Jonathan Finlay3; 1Pediatrics and Psychiatry, Columbia University, New York, NY, USA; 2Preventive Medicine, University of Southern California, Los Angeles, CA, USA; 3Pediatrics, University of Southern California, Los Angeles, CA, USA. Purpose: To evaluate late effects of survivors treated on a pediatric high-grade glioma (HGG) study (CCG-945) from 1985 to 1991. Following maximal surgical resection, children >24 months of age received 5,400 cGy of cranial radiotherapy and were randomly assigned to receive either the “8-in-1” chemotherapy regimen or vincristine, lomustine, and prednisone. Patients with spinal tumors and those <24 months were nonrandomly assigned to the “8-in-1” regimen and did not receive cranial radiotherapy. Methods: Fifty-four of 79 (68%) survivors from 25 institutions across North America were enrolled on companion study COG L991 between 2000 and 2005 to assess their neuropsychological status and quality of life (QoL), as well as their emotional-behavioral functioning by both patient and caregiver report. Results: Median age of the 54 survivors (29 male, 25 female) was 8.8 years (range, 0.2–19.5 years) at diagnosis and 23.6 years (range, 11.3–36.0 years) at time of testing, after a median follow-up of 15.1 years (range, 9.5–19.2 years). Survivors demonstrated mean intelligence and verbal memory in the low-average range, executive functioning between the low-average and borderline ranges, and visual memory in the borderline range. Visual-motor and processing speed were focal areas of impairment. Survivors reported emotional-behavioral functioning and QoL well within the average range. Spinal cord patients performed solidly within the average range, whereas midline and posterior fossa tumor patients displayed lower verbal intelligence (p = 0.02) and processing speed (p = 0.05) than those with hemispheric tumors. Female patients displayed lower verbal intelligence (p = 0.02) and reported poorer physical QoL (p = 0.02), while their family members reported more frequent problems with depression (p = 0.01), somatic complaints (p = 0.03), aggression (p = 0.04), and motor functioning (p = 0.05) than male patients. Patients <3 at diagnosis demonstrated lower full-scale IQ (p = 0.03) and performance IQ (p = 0.03), while their family members reported more depression (p < 0.01), aggression (p = 0.04), and somatic complaints (p = 0.03). Patients with longer follow-up reported higher motor functioning (p = 0.02), fewer somatic problems (p = 0.03), and better communication (p = 0.03) compared to those with shorter follow-up. Conclusions: This is the first pediatric HGG study to examine neuropsychological, QoL, and emotional-behavioral functioning of long-term survivors. Deficits in visual-motor and processing speed are consistent with cranial irradiation sequelae; however, intelligence, verbal memory, and executive functioning are higher than in reports of adult HGG patients. Further research is warranted in the outcomes of patients with HGG that arise in the midline or posterior fossa, as well as for females, which both represent prognostic variables that have not been widely noted in previous research. Attention should also be given to developing treatment regimens for young HGG patients in order to minimize late effects. Last, insight should be gained into the development of normal quality of life amid variable neuropsychological functioning, underscored by the higher emotional-behavioral status of those with longer follow-up. LE 15. NEUROPSYCHOLOGICAL ASSESSMENT AND REHABILITATION IN CHILDHOOD CANCER SURVIVORS Jordi Bernabeu,1 Adela Cañete,2 Concepcion Fournier,2 Gonzalo Almerich,2 Jesus Suarez,2 and Victoria Castel2; 1International Neuropsychological Society, Valencia, Spain; 2Spain. Brain tumor and leukemia survivors have neurocognitive deficits that worsen their quality of life. Our objective is to convey the descriptive results of our research in neuropsychology (evaluation and rehabilitation) in this population in 2006. We follow a standard protocol including specific and general tests measuring cognitive functions and psychopathology (Achenbach). Thirty-five survivors have been evaluated. Brain tumor survivors are the most affected, presenting deficit in dominant and nondominant hand motor skills, flexibility, verbal comprehension, speed of processing, working and visuospatial memory, selective attention, and nonverbal fluency. From the psychopathological point of view, survivors with >5 years of follow-up are the most isolated. We have performed a pharmacological intervention in three patients and home rehabilitation in nine, with satisfactory results. These neuropsychological tools should be included systematically in brain tumor survivor evaluation. LE 16. PUBERTAL DEVELOPMENT IN 32 PATIENTS WITH POSTERIOR FOSSA MEDULLOBLASTOMA AND EPENDYMOMA TREATED ACCORDING TO THE HIT 91 AND HIT 2000 PROTOCOLS Astrid Gupper,1 Sandra Bandion,2 Irene Slavc,3 Karin Dieckmann,4 Georg Schatzl,5 and Gabriele Häusler2; 1University Clinic for Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria; 2University Clinic for Paediatrics and Adolescent Medicine, Medical University of Vienna, Austria; 3Vienna, Austria; 4Radiotherapy, Medical University of Vienna, Vienna, Austria; 5Urology, Medical University of Vienna, Austria. Introduction: Medulloblastoma and ependymoma are the most common malignant brain tumors of childhood; however, there is little published information regarding posttreatment gonadal function of long-term survivors. We report on the gonadal function of 32 patients with posterior fossa medulloblastoma and ependymoma treated during childhood in a similar fashion with chemo- and radiotherapy. Patients and Methods: We reviewed pubertal development and gonadal function of 32 pediatric patients (17 male, 15 female) with medulloblastoma or ependymoma treated according to the HIT 91 and HIT 2000 protocols from 1992 to 2003. Median age at diagnosis was 6.8 years (range, 0.4–21 years) Four patients were lost to follow-up. Twenty-eight patients (13 females, 15 males) available for endocrinological evaluation had a median age of 19.7 years at last follow-up (range, 11–29 years). Median follow-up was 10 years (range, 3–20 years). Patients were assessed for pubertal status, basal and LH-RH, stimulated LH and FSH, and estrogen or testosterone serum levels. Gonadal ultrasound was performed in both sexes, spermanalysis was performed in male patients >18 years, and self-report of menstrual cycle patterns was obtained in females. Results: Eleven of 13 females had normal, 1 of 13 precocious, and 1 of 13 late-onset puberty. Twelve of 15 males had normal pubertal development, one boy developed late puberty, and two are 12 years old and not yet fully evaluable. Nine girls >18 years of age had normal basal LH and estrogen levels. Basal FSH levels were elevated in four of nine, but only one had also stimulated elevated FSH levels. Three of four girls <18 years of age revealed basal elevated LH, but only one of these girls had also stimulated elevated LH. Basal FSH was elevated in two of four girls <18 years, but only one girl had also stimulated elevated FSH levels. Eight of 15 male patients showed pathologic LH-RH tests with elevated basal and stimulated LH and FSH levels, the latter reflecting testicular insufficiency which could be confirmed by sperm analysis in four patients (three oligo-asthenoteratozoospermia syndrome, one azoospermia). The remaining seven showed a higher incidence of elevated basal and stimulated FSH levels, indicating possible germ cell damage and gonadal dysfunction. Gonadal ultrasound was normal in all patients. Conclusion: Overall clinical pubertal development was within normal limits. So far, none of 28 patients developed hyphothalamic-pituitary gonadotropin deficiency. While only one girl showed ovarian insufficiency in LH-RH testing, the incidence of primary testicular insufficiency was high in males. Patient numbers are small, but our data stress the importance to carefully monitor posttreatment endocrine parameters in these patients to detect and avoid problems in later adulthood such as early menopause or osteoporosis. Further studies including larger patient numbers with longer follow-up are necessary to estimate fecundity in survivors of childhood medulloblastoma. LE 17. READING ABILITY IS ASSOCIATED WITH THE INTEGRITY OF WHITE MATTER MICROSTRUCTURE FOLLOWING TREATMENT FOR PEDIATRIC BRAIN TUMORS: A COGNITIVE OUTCOME AND DIFFUSION TENSOR IMAGING STUDY Shawna Palmer,1 Wilburn Reddick,2 John Glass,2 Wallace Dana,3 and Amar Gajjar4; 1Behavioral Medicine, St. Jude Children's Research Hospital, Memphis, TN, USA; 2Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA; 3Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA; 4Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA. Purpose: Previous literature has established a decline in reading ability as well as damage to the white matter of the brain among patients treated for brain tumors in childhood. The purpose of this study is to examine the relationship between reading ability and white matter integrity among patients treated with cranial radiation and high-dose chemotherapy for pediatric medulloblastoma/primitive neuroectodermal tumor, atypical rhabdoid tumor, or pineoblastoma. Patients and Methods: The study included 45 patients, ranging in age from 3.5 to 20 years at diagnosis (median, 9.12 years), treated for infratentorial brain tumors with postsurgical risk-adapted craniospinal irradiation (CSI) followed by four cycles of high-dose chemotherapy (cyclophosphamide, cisplatin, vincristine) with stem cell support. High-risk (HR, n = 11) patients received CSI to 36–39.6 Gy and conformal boost treatment of the primary site to 55.8–59.4 Gy. Average-risk (n = 34) patients received CSI to 23.4 Gy, conformal boost treatment of the posterior fossa to 36 Gy, and primary site to 55.8 Gy. Following treatment, all patients completed a neuropsychology evaluation at 12 months postdiagnosis, including measures of reading ability (Word Attack, Letter Word Identification, and Basic Reading Skills composite score) using the Woodcock Johnson Tests of Academic Achievement (third edition). Patients also received a magnetic resonance imaging study, including diffusion tensor imaging, deriving measures of fractional anisotropy (FA). Results: Reading scores were found to be within the normal range (population mean = 100, standard deviation [SD] = 15; Table 1). After spatial normalization to the ICBM T2-weighted atlas, a voxel-based analysis was performed to derive possible regions of interest (ROI) with an association between FA and Word Attack scores, controlling for age at examination. Two clusters were identified, the first in the left temporoparietal region and the second in the right temporoparietal region, with coordinates (–22, –19, 10) and (18, –11, 13) in Talairach space, respectively (Table 1). Regression models, controlling for age at treatment and risk arm, revealed a significant relationship between the left temporoparietal ROI and Word Attack (r = 0.703, p < 0.001), Letter Word Identification (r = 0.600, p = 0.001), and Basic Reading Skills composite score (r = 0.659, p < 0.001). A significant relationship was also found between the right temporoparietal ROI and Word Attack (r = 0.644, p < 0.001), Letter Word Identification (r = 0.586, p = 0.001), and Basic Reading Skills composite score (r = 0.636, p < 0.001). LE 17: Table 1. Reading scores and fractional anisotropy scores for voxel-based regions of interest (ROI) . n . Mean . Standard Deviation . Word attack 42 101.42 12.12 Letter word ID 43 98.40 12.93 Basic reading 42 99.79 12.78 FA–left ROI 45 0.60 0.12 FA–right ROI 45 0.56 0.12 . n . Mean . Standard Deviation . Word attack 42 101.42 12.12 Letter word ID 43 98.40 12.93 Basic reading 42 99.79 12.78 FA–left ROI 45 0.60 0.12 FA–right ROI 45 0.56 0.12 Open in new tab LE 17: Table 1. Reading scores and fractional anisotropy scores for voxel-based regions of interest (ROI) . n . Mean . Standard Deviation . Word attack 42 101.42 12.12 Letter word ID 43 98.40 12.93 Basic reading 42 99.79 12.78 FA–left ROI 45 0.60 0.12 FA–right ROI 45 0.56 0.12 . n . Mean . Standard Deviation . Word attack 42 101.42 12.12 Letter word ID 43 98.40 12.93 Basic reading 42 99.79 12.78 FA–left ROI 45 0.60 0.12 FA–right ROI 45 0.56 0.12 Open in new tab Conclusions: Fractional anisotropy measures the directional organization of water diffusion within a region and reflects the integrity of white matter microstructure. The integrity of the microstructure in the two regions of interest may contribute to the patient's reading ability by strengthening communication among visual, auditory, and language cortical areas. Specific attention to these areas of the brain during radiation treatment planning may be necessary to reduce treatment-related reading deficits. LE 18. SURVIVORSHIP ISSUES FOR CHILDREN DIAGNOSED WITH TUMORS OF THE CNS: THE EXPERIENCE OF A UK CENTER Gurkirat Panesar,1 Gail Hann,2 Anna Wright,2 Ian Kamaly-Asl,3 Rao Gattamaneni,3 and Eddy Estlin4; 1Royal Manchester Children's Hospital, Manchester, Greater Manchester, UK; 2Greater Manchester, UK; 3Manchester, UK; 4Royal Manchester Children's Hospital, Manchester, UK. Advances in modern treatment methods have resulted in an increase in the number of survivors of childhood CNS tumors, and therefore an increase in the number of patients for whom late sequelae of treatment might give rise to significant issues in relation to survivorship. The aim of this study was to characterize the late effects burden of a cohort of survivors following the diagnosis of a CNS tumor, as an essential benchmarking requirement for future service development at our institutions. More than 150 survivors of a childhood CNS tumor diagnosed between 1990 and 2001 have been identified from the records of the North West Children's Cancer Registry and the records of the Christie Hospital, and are the subject of an ongoing analysis of their late effects burdens. The late effects findings for 64 children who had been diagnosed with a CNS tumor between 1990 and 2001, and identified from the North West Children's Cancer Registry, are presented here. The medical records of the survivors were analyzed to determine demography and tumor type, treatment received, and any long-term problems recorded; the latter were graded using the NCI Common Toxicity Criteria for Adverse Events version 3.0. (Information on sequelae was documented using a data collection sheet and captured the most recent information on each child's motor, visual, hearing, epilepsy, endocrine, psychological, and social functioning.). Of the survivors 39% were found to have some form of memory impairment (most often in the form of short-term memory impairment), 37% showed endocrinopathy (most often in the form of growth hormone deficiency), and 26% had behavioral difficulties. In addition, 23% were documented to have cranial nerve weaknesses, 22% were experiencing problems with visual acuity and/or fields, 22% showed motor impairments, 21% had epilepsy, 20% had ataxia, and 18% demonstrated auditory impairment. The diagnosis of medulloblastoma was most frequently associated with the sequelae of memory, motor, auditory, and ataxia, and the diagnosis of ependymoma and craniopharyngioma with endocrine and memory sequelae. Both age <5 years at diagnosis and previous radiotherapy were more associated with late sequelae, and in particular with survivors who had multiple late effects. Comparable results have been seen in other published series and emphasize the importance of regular and multidisciplinary follow-up for children and adult survivors following diagnosis of a CNS tumor. This may be particularly true for those who experience neuropsychological problems, which can significantly affect their ability to gain employment and live independent lives; further insights into this will be gained from the ongoing analysis of the entire patient cohort. LE 19. THE RELATIONSHIP BETWEEN LEARNING PROBLEMS AND EXECUTIVE DYSFUNCTION IN CHILDREN TREATED FOR BRAIN TUMORS Ellen Vriezen,1 Danielle Cataudella,1 Andrea Downie,1 and A. Elizabeth L. Cairney2; 1Paediatric Psychology, Children's Hospital at London Health Sciences Centre, London, ON, Canada; 2Paediatrics, University of Western Ontario, London, ON, Canada. Purpose: It has been established that children treated for a brain tumor often experience significant cognitive and learning problems (Butler and Haser, 2006; Mulhern et al. 2004). The objective of this study was to determine whether a relationship exists between learning problems and executive function (e.g., holding information in memory during activities; initiating, planning, organizing, and monitoring one's behavior and activities) in children who have been treated for a brain tumor. Methods: Twenty-two children who were diagnosed and treated for a brain tumor at Children's Hospital, London Health Sciences Centre, between 1996 and 2005 were included in this study. Children (11 male, 11 female) ranged in age from 6.25 to 18.75 years (mean = 12.11, SD = 3.22). The parents of these children completed the Behavior Rating Inventory of Executive Function (BRIEF) and a background questionnaire including questions related to learning and school supports (e.g., Does your child have significant learning problems at school? Does your child have an Individual Education Plan?). Tumors were located in the posterior fossa (n = 12; 54%), subcortical region (n = 5; 23%), and cortical region (n = 5; 23%). Two children were treated with chemotherapy only. Of the remaining 20 children, 13 underwent surgery only, 1 received surgery and radiation, 2 received surgery and chemotherapy, and 4 received surgery, chemotherapy, and radiation. Children ranged from 1.04 to 7.47 years since diagnosis (mean = 3.82, SD = 1.78). Results: Thirteen (59%) of the parents identified their child as having significant learning problems. Ten (45%) of the children had Individual Education Plans (IEPs). T-tests indicated that children who were identified as having learning problems had significantly higher scores than children not identified as having learning problems on all of the indices and most of the Scales (six of eight) of the BRIEF, including the Behavioral Regulation Index, Metacognition Index, and General Executive Composite, as well as the Shift, Emotional Control, Initiate, Working Memory, Plan/Organize, and Monitor scales (p < 0.01), with mean scores falling within the clinically significant range (T-scores > 60). Conclusion: Learning problems and a need for individualized learning programs were identified in a high percentage of children treated for brain tumors. The finding that executive dysfunction is more common in children treated for brain tumors who also have significant learning problems suggests that executive dysfunction contributes to their learning difficulties. Future studies will investigate whether interventions designed to remediate executive dysfunction have an impact on learning success in children treated for brain tumors. LEPTOMENINGEAL AND DISSEMINATED DISEASE LEPTO 1. A COMPARISON OF INTRACRANIAL AND LUMBAR CSF CYTOLOGY IN STAGING PEDIATRIC MEDULLOBLASTOMAS, SUPRATENTORIAL PNETS, AND EPENDYMOMAS Sergei Terterov,1 Mark Krieger,2 Jonathan Finlay,3 and Gordon Mccomb4; 1Childrens Hospital Los Angeles, Los Angeles, CA, USA; 2Childrens Hospital Los Angeles, Los Angeles, CA, USA; 3Los Angeles, CA, USA; 4Neurosurgery, Childrens Hospital Los Angeles, Los Angeles, CA, USA. Background and Purpose: Cerebrospinal fluid (CSF) dissemination is an ominous feature of pediatric brain tumors, occurring in at least 25% of medulloblastomas and 11% of ependymomas. Detecting early dissemination is important for determining both treatment and survival. Dissemination can be detected by MRI of the full neuraxis, cytology of CSF obtained via lumbar puncture (LP), and cytology of intracranial CSF. Our objective was to compare the sensitivity and specificity of CSF obtained intracranially (either intraoperatively or via ventriculostomy) and via LP against the rate of dissemination determined by MRI. Methods: Medical records, pathology reports, and radiology reports for 169 patients who had resection of brain tumors (medulloblastoma, n = 101; supratentorial PNET, n = 25; ependymoma, n = 43) in the last 15 years were retrospectively reviewed. Radiology results were compared with the CSF cytology results. Results: Twenty patients (12%) presented with disseminated disease depicted on MR images at presentation. Intracranial CSF cytology had a sensitivity of 57% and specificity of 88% in detection of disseminated disease. Lumbar CSF cytology had a sensitivity of 25% and specificity of 96% in detection of disseminated disease. Conclusions: Based on the results, intracranial CSF cytology is a more sensitive but less specific technique than lumbar CSF cytology for detecting disseminated disease. Treatment protocols should keep these data in mind when evaluating diagnostic results. LEPTO 2. EFFECTIVE INTRATHECAL RADIOIMMUNOTHERAPY-BASED SALVAGE REGIMEN FOR METASTATIC CNS NEUROBLASTOMA (NB) Kim Kramer,1 Brian Kushner,2 Shakeel Modak,3 Neeta Pandit-Taskar,3 Peter Smith-Jones,3 Pat Zanzonico,3 John Humm,3 Suzanne Wolden,3 Mark Souweidane,4 Steven Larson,3 and Nai-Kong Cheung3; 1Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 2Memorial Sloan-Kettering Cancer Center, NY, USA; 3NY, USA; 4Cornell University, Ithaca, NY, USA. Background: Recurrent metastatic NB is difficult to cure, particularly in patients with CNS disease. This complication was uniformly fatal in our previous published experience (median time to death, 6.7 months). We evaluated the addition of antibody-based intrathecal radioimmunotherapy (RIT) targeting minimal residual disease following surgery, craniospinal radiation, and chemotherapy. Methods: Forty-four patients with recurrent CNS NB treated at Memorial Sloan-Kettering Cancer Center over a 20-year period are the subject of this report. Thirty patients (group 1) were treated with various combinations of surgery, chemotherapy, and radiation therapy. Since 2003, 14 patients (group 2) were treated with surgical resection of parenchymal lesions, 1,080–2,160 cGy craniospinal radiation, intravenous irinotecan plus oral temozolomide, intrathecal RIT with 131I-3F8 or 131I-8H9, intravenous anti-GD2 monoclonal antibody plus granulocyte macrophage-colony stimulating factor (GM-CSF), and oral temozolomide. Results: All 30 patients in group 1 died of progressive disease; median time to death was 5.5 months from the CNS event. In contrast, 13 of 14 patients in group 2 are alive and free of NB 6–53 months since CNS event. One patient with leptomeningeal NB died of infection 22 months after the detection of CNS disease; no NB was found at autopsy. One patient remains on treatment for refractory systemic NB. Myelosuppression following craniospinal radiation therapy and chemotherapy was common; five patients received stem cell support to minimize hematologic toxicity. Three patients remain on oral supplements for treatment-related hypothyroidism. One patient with a 7-year history of NB is being treated for MLL-associated secondary leukemia that developed 3.5 years after detection of CNS disease. Conclusion: Effective control of CNS NB is possible with intrathecal RIT-based treatment. This multimodality treatment regimen is well tolerated by young patients despite prior intensive cytotoxic therapies and has the potential to increase survival. LEPTO 3. INTRAVENTRICULAR THERAPY WITH ETOPOSIDE IN RECURRENT METASTATIC BRAIN TUMORS: RESULTS OF A PILOT TRIAL AND INTERIM RESULTS OF A PHASE II STUDY Stefanie Reichling,1 Mareike Windelberg,2 Martina Zimmermann,2 Monika Warmuth-Metz,3 Torsten Pietsch,4 Ulrich Jaehde,5 Stefan Rutkowski,6 Udo Bode,1 and Gudrun Fleischhack2; 1Department of Pediatric Hematology/Oncology, Medical Center, University of Bonn, Bonn, Germany; 2Bonn, Germany; 3Department of Neuroradiology, University of Wuerzburg, Wuerzburg, Germany; 4Institute of Neuropathology, Medical Center, University of Bonn, Bonn, Germany; 5Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany; 6Children's Hospital, University of Wuerzburg, Wuerzburg, Germany. Purpose. As the systemic administration of etoposide is efficacious in brain tumor, a pilot trial was designed to study the feasibility and pharmacokinetics of intraventricularly administered (IVC) etoposide in children and adolescents with relapsed metastatic brain tumors in 1997. Based on the results of this trial, a phase II study was initiated to evaluate the efficacy and safety of IVC administered etoposide in recurrent CNS-PNETs and ependymomas with subarachnoid disease manifestation in 2005. Patients and Methods. In the pilot trial, 70 patients (1.9–34.6 years) were treated with IVC etoposide and systemic chemotherapy simultaneously. Etoposide was administered daily for 5–10 consecutive days every 2–5 weeks over a period of 0.5–20.5 months in doses of 0.25 mg (4 patients, 12 courses), 0.5 mg (34 patients, 159 courses), or 1.0 mg (32 patients, 194 courses). In the phase II study, so far 20 patients (16 medulloblastomas, 1 pineoblastoma, 3 ependymomas; 4.9–26.3 years old) were enrolled and treated with three 5-day cycles of etoposide in a daily dose of 1.0 mg for 5 weeks. In both studies, the tumor response and safety were documented clinically, by CSF cytology and MRI, respectively. Pharmacokinetic (PK) analyses were performed in CSF samples drawn from an Ommaya/Rickham reservoir. Etoposide concentrations in CSF were determined by HPLC with electrochemical detection. PK parameters were estimated by using a two-compartment model with Bayesian curve fitting. Results. In the pilot trial, the efficacy of the intrathecal therapy only could not be assessed because all patients received systemic chemotherapy concomitantly. Clinically, 11 patients showed improvement of neurological symptoms. Ten patients being initially positive for tumor cells cleared their CSF following one to five courses of IVC etoposide. In the phase II study, stable disease as best response could be documented radiologically and cytologically in 6 of 19 evaluable patients (week 6 after start). The side effects in both studies were mostly mild in form of transient headache, nausea, fever, or fatigue. Infectious complications as meningitis were seen in five patients (four in the pilot trial). Two patients with neoplastic meningitis showed a reversible coma. Possible long-term side effects in the pilot study were impairment of concentration, memory, and verbal fluency. The PK of etoposide in the CSF was found to be dose and schedule independent, as no statistically significant differences were found in terminal half-life (t1/2Z), volume of distribution (Vss), or clearance (CL) among the three dosage regimens. An equivalence between the IVC CSF and the lumbar CSF was achieved 4 h after IVC administration. The results indicate linear pharmacokinetics of etoposide in the CSF with high interindividual variability. With all regimens, mean trough levels exceeded the level of 0.1 μg/ml assumed to be cytotoxic. Conclusions. Our data suggest that the repeated IVC etoposide application is well tolerated. It seems to have cytotoxic efficacy in recurrent metastatic brain tumors, especially in medulloblastomas. The continuation of the phase II trial is warranted. LEPTO 4. LEPTOMENINGEAL GLIOMATOSIS: PITFALLS IN DIAGNOSIS AND MANAGEMENT. LESSONS LEARNED FROM AN UNUSUAL CASE Bruce Crooks,1 Daniel Mcneely,2 David Gaskin,3 and Ute Bartels4; 1Dalhousie University, Halifax, NS, Canada; 2Neurosurgery, IWK Health Centre, Halifax, NS, Canada; 3Anatomic Pathology, Dalhousie University, Halifax, NS, Canada; 4University of Toronto, Toronto, ON, Canada. Case Report: A 9-year-old identical twin presented with recurrent acute episodes of headache and loss of consciousness. Episodes were managed with supportive care and high-dose methylprednisolone. MRIs showed communicating hydrocephalus and multiple cerebellar cystic lesions suggestive of neurocysticercosis. VP shunt was inserted, and empiric albendazole given. Symptoms continued and further cystic lesions developed. Dexamethasone was required for symptom control. Biopsy of cerebellar lesion showed reactive changes only, with no evidence of neurological or hematological malignancy. Repeat MRI showed progressive cystic lesions, including spinal cord, and progressive meningeal enhancement. Repeated CSF showed mild leukocytosis with occasional ependymal cells, but no malignant cells. He additionally developed enhancing lesions in multiple vertebral bodies, consistent with multifocal osteomyelitis. Biopsy was inconclusive, but a nongrowing gram-negative bacterium was isolated. Bone marrow biopsies showed no evidence of hematological malignancy. Six months after presentation, raised protein levels and malignant cells were eventually found on repeated lumbar puncture, and a diagnosis of leptomeningeal gliomatosis was made. There was no response either to vincristine and carboplatin or to temozolomide, and he remained dexamethasone dependent for symptomatic relief. Due to progressive symptoms, and worsening leptomeningeal and disseminated cerebral lesions on MRI, he received craniospinal radiotherapy, with dramatic resolution of MRI findings, but no symptomatic relief and worsening debility. Eighteen months after original diagnosis, he was readmitted with sepsis, herpes zoster, and purpura fulminans. He failed to respond adequately to antimicrobials and deteriorated with progressive vasculitic skin rash, hepatosplenomegaly, ascites, pleural and pericardial infusion, and pancytopenia. Active care was withdrawn, and he died. Autopsy showed severe cerebral atrophy and widespread leptomeningeal ganglioglioma. Liver, spleen, and bone marrow were extensively infiltrated and replaced by atypical malignant lymphomatous cells, suggestive of T-cell origin. Discussion: This patient presented with complex, atypical symptoms and MRI findings, with no evidence of malignancy on repeated CSF sampling, brain biopsy, and bone marrow biopsy. He remained steroid dependent throughout his illness, contributing to severe debility. His CNS gliomatosis responded on imaging studies to radiotherapy but not chemotherapy. He developed second primary disseminated hematologic malignancy, possibly due to long-term steroids and chemotherapy. Although initial MRI findings, in retrospect, could be compatible with primary CNS lymphoma, partially treated with recurrent corticosteroids, autopsy proved CNS leptomeningeal ganglioglioma. This case illustrates the difficulty in diagnosing leptomeningeal CNS tumors and pitfalls of chronic high-dose steroid usage, with severe steroid-induced debility and possible second malignancy, in association with chemotherapy. LEPTO 5. LEPTOMENINGEAL OLIGODENDRAL TUMORS WITH PARTIAL RESPONSE TO CHEMOTHERAPY AND LONG-TERM SURVIVAL—REPORT OF TWO CHILDREN Stefan Holm,1 Ingrid Ohlsson,2 Bengt Gustavsson,2 Tommy Stoedberg,1 Abiel Orrego,3 Bjoern Jacobsson,4 and Mikael Mosskin2; 1Karolinska Institutet, Institute for Women and Child Health, Stockholm, Sweden; 2Karolinska Institutet, Institute for Clinical Neuroscience, Stockholm, Sweden; 3Karolinska Institutet, Institute for Oncology and Pathology, Stockholm, Sweden; 4St Goeran's Hospital, Department of Pathology, Stockholm, Sweden. Case 1: A 10-year-old boy with parents from Iran was admitted October 1999 because of irritability, fatigue, balance disturbance, and strabismus. CT revealed hydrocephalus and MRI meningeal contrast enhancement in brain and spinal cord. A VP shunt was inserted. Biopsies from brain and, later, spinal cord were inconclusive. The clinical condition improved. PCR for HHV-6 in CSF was positive in February 2000, and antiviral therapy with ganciclovir and foscarnet led to further improvement. In June 2000, symptoms reappeared. MRI in July showed progression with brain involvement, and biopsy, leptomeningeal oligodendroglioma with HHV-6 DNA in the tumor. Treatment with vincristine and carboplatinum according to SIOP LGG 1995 was started September 2000; antiviral therapy was continued. Because of neuropathia, vincristine was withdrawn February 2001. Carboplatinum was given monthly until May 2002 and stopped because of decrease in glomerular filtration rate. Serial MRIs showed partial regression of the intracranial findings and stable disease in the spine until 2005 and stable disease thereafter. Antiviral therapy was discontinued 2006. The boy has no focal neurological deficits but severe retardation and autism with need for continuous personal assistance. He is fed through gastrostomy and has antiepileptic medication. Case 2: An 11-year-old boy presented February 2002 with 3 months of headache, back pain, morning vomiting, bladder dysfunction, and squint. MRI showed hydrocephalus and leptomeningeal contrast enhancement, and biopsy from contrast-enhancing small nodule in posterior part of medulla at Th 11 showed leptomeningeal oligoastrocytoma. CSV protein was 1.5 g/liter. PCR HHV-6 in CSF was negative. The clinical condition markedly improved, and neurological examination was normal in March 2002. MRI in April 2002 showed progression of supratentorial meningeal changes. Headache developed. In May 2002, vincristine and carboplatinum according to SIOP LGG 1995 was started. Because of anaphylactoid reaction to carboplatinum, November 2002 treatment was changed to vinblastine 6 mg/m2/week (Bouffet et al.). MRI showed partial regression of meningeal enhancement and thereafter stable disease. In October 2003, treatment was stopped after a total of 16 months due to his excellent clinical condition. Lumbar CSF protein in October 2003 was 2.5 g/liter, which increased to 3.85 g/liter May 2005. CSF cytology negative. Lumbar puncture has not been repeated because of good clinical condition. No further therapy was given after October 2003, and repeated MRIs have shown some minor fluctuations in contrast enhancement, and stable disease. No focal neurological findings November 2007; no epilepsy but attention deficit syndrome and some learning difficulties in mainstream school with extra help. Comments: Leptomeningeal oligodendral tumors in childhood are extremely rare. These boys have a partial response to standard chemotherapy, and to date no progression 5.5 and 4 years after end of treatment. The sequelae of the disease are severe in case 1, and mild in case 2. LEPTO 6. LONG-TERM REMISSIONS FOR CNS AND LEPTOMENINGEAL (LM) CANCERS WITH INTRA-OMMAYA 131I-3F8: PRELIMINARY RESULTS OF A PHASE II STUDY Kim Kramer,1 Peter Smith-Jones,2 John Humm,2 Pat Zanzonico,2 Neeta Pandit-Taskar,2 Shakeel Modak,2 Brian Kushner,3 William Gerald,2 Ira Dunkel,4 Yasmin Khakoo,2 Mark Souweidane,5 Steven Larson,2 and Nai-Kong Cheung2; 1Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 2NY, USA; 3Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 4New York, NY, USA; 5Cornell University, Ithaca, NY, USA. Purpose: Tumors metastasizing to the CNS and leptomeninges (LM) are associated with significant mortality. In a phase I study (J Clin Oncol. 2007;25:5465), intra-Ommaya 131I-labeled monoclonal antibody 3F8 was safe with favorable dosimetry. We now report results of an ongoing phase II trial using intra-Ommaya 131I-3F8 for recurrent GD2-expressing CNS disease. Patients and Methods: Only patients with <72 Gy prior radiation to brain parenchyma and 45 Gy to the spinal cord were eligible. Baseline MR brain and spine and CSF cytology were obtained. Thirteen patients with recurrent CNS tumors (neuroblastoma, n = 4; medulloblastoma, n = 5; retinoblastoma, n = 3; ependymoma, n = 1) have been enrolled. Adequate CSF flow was confirmed by pretreatment 111indium-DTPA studies. Patients were given 10 mCi 131I-3F8 per injection every 2–3 weeks for a total of four injections (40 mCi), with a therapeutic goal of two or more injections (>20 mCi). Systemic chemotherapy administered between the second and third injection was permitted for patients with both CNS and systemic malignancy. 131I-3F8 pharmacokinetics was studied by serial CSF and blood samplings. Dosimetry was based on pharmacokinetics and region of interest (ROI) analyses on whole-body gamma camera scans. Tumor response was determined by clinical, radiographic, and cytologic criteria, as well as progression-free survival at 6 months. Results: Eight of 10 patients treated with 131I-3F8 as a consolidative therapy following various chemotherapy or external beam radiotherapy doses remain alive and in cytologic and radiographic remission (⩾3 months, ⩾8 months, ⩾10 months, ⩾12 months, ⩾12 months, ⩾12 months, ⩾18 months, ⩾22 months). Three of these patients had CNS neuroblastoma and remain alive and in remission 11 months, 15 months, and 24 months since detection of CNS disease. This is significant in that the median time to death from the onset of CNS disease was 5.4 months in our previously published non-intra-Ommaya therapy experience. One patient with multiply recurrent medulloblastoma is stable after two injections. One patient with CSF cytology-positive LM retinoblastoma achieved CSF remission after the second injection but had radiographic progression on follow-up MR, currently alive with disease. Three patients with active disease progression at the time of study enrollment all had radiographic progression of disease after one injection. Total absorbed CSF dose was 237–2,239 cGy by sampling. Average dosimetry (cGy/mCi) to the CSF was 42.9 cGy/mCi based on CSF pharmacokinetics and 0.9 cGy/mCi to the blood. Toxicities, included self-limited headache, fever, and vomiting, generally resolved within 24–48 h. No late toxicities have been seen in the five patients who remain in remission off therapy for >1 year since 131I-3F8 injections. Accrual is ongoing. Conclusions: Serial injections of intra-Ommaya 131I-3F8 are generally well tolerated at 10 mCi per injection, and a high CSF:blood ratio is achieved. Prolonged clinical and radiographic remissions in patients with recurrent and metastatic CNS disease have been observed, when 131I-3F8 has been used to treat minimal residual disease. Radioimmunoconjugates targeting GD2 may have clinical utility in the treatment of CNS/LM malignancies. LEPTO 7. LOW-GRADE NEUROEPITHELIAL TUMOR OF LEPTOMENINGES WITH INDOLENT CLINICAL COURSE: UNIFYING RADIOGRAPHIC, PATHOLOGIC, AND CLINICAL FEATURES IN FOUR CHILDREN Anna Janss,1 Wessley Miller,2 Susan Palasis,2 Peter Burger,3 Daniel J. Brat,4 David Wrubel,2 Andrew Reisner,2 Denis Atkinson,2 and Claire Mazewski5; 1Emory University, Decatur, GA, USA; 2GA, USA; 3MD, USA; 4GA, USA; 5Emory University, Atlanta, GA, USA. Introduction: Disseminated low-grade glial tumors of the CNS, while uncommon, have been well described in the literature (Childs Nerv Syst. 2003;19:197). In 2000, a series of children diagnosed at multiple institutions with disseminated low-grade neuroepithelial tumors was presented in abstract form (J Neuropathol Exp Neurol. 2000;59:445). We have identified four children, all diagnosed, treated, and followed at the same institution with this rare entity. Methods: Between January 2001 and January 2007, four children <5 years of age were diagnosed at Children's Healthcare of Atlanta with disseminated low-grade neuroepithelial tumors. Pathologic diagnosis of all four cases was made by at least two neuropathologists. We reviewed radiologic, clinical, and pathologic data. Results: All four children presented with clinical symptoms of increased intracranial pressure and radiographic evidence of hydrocephalus. All four required placement of ventriculoperitoneal shunt. Median age at presentation was 34 months (range, 20–47). MRI revealed diffuse leptomeningeal enhancement of the spinal cord, cauda equina, and intracranial subarachnoid spaces. Three of four children had evidence of nodular tumor extending into the cervical or thoracic spinal cord. Examination of the CSF was nondiagnostic in all four cases. Two children had at least one nondiagnostic biopsy of the leptomeninges prior to their diagnostic biopsy. Diagnosis was made by biopsy of infiltrated spinal arachnoid tissue in all four cases. Pathology was remarkable for thickened arachnoid membrane infiltrated by low-grade neuroepithelial tumor cells. Cells were seen individually and in clusters within the membrane. They were round, stellate, or spindle-shaped cells with clear cytoplasm and round, bland nuclei. In all cases, immunohistochemistry was positive for synaptophysin and S-100, negative or minimal for GFAP, and negative for chromogranin, LCA, c-Kit, Neu-N, EMA, HMB45. Proliferation indices (MIB1 staining) were <8% in all cases (range, 3%–8%). All children are alive with evidence of disease at this time, with median follow-up of 51 months (range, 14–83 months). Three of four children were treated with chemotherapeutic regimens for low-grade tumors, while the child with clinical and radiographic evidence of cord compression was treated with craniospinal radiation and multiagent chemotherapy. Conclusions: Disseminated low-grade neuroepithelial tumors of the CNS represent a rare neoplastic disease of childhood very distinct from primitive neuroectodermal tumors. They most often present as communicating hydrocephalus in young children. Diagnosis is often difficult and cannot be made by examination of the CSF alone. Tumor growth can be controlled with chemotherapy or radiation. We recommend further studies to further define the origin, clinical behavior, and optimal therapy of this disorder. LEPTO 8. PRIMARY LEPTOMENINGEAL GLIONEURONAL TUMORS OF THE CNS Tom Davidson,1 Ignacio Gonzalez-Gomez,2 Ashok Panigrahy,3 Mark Krieger,1 Marvin Nelson,3 Gordon Mccomb,4 Jonathon Finlay,3 and Girish Dhall3; 1Childrens Hospital Los Angeles, Los Angeles, CA, USA; 2Department of Pathology, Childrens Hospital Los Angeles, Los Angeles, CA, USA; 3Los Angeles, CA, USA; 4Neurosurgery, Childrens Hospital Los Angeles, Los Angeles, CA, USA. Background: Mixed glioneuronal tumors are a recently described group of CNS tumors with coexpression of glial and neuronal markers. Primary leptomeningeal glioneuronal tumors are rare neoplasms in this category. Methods: We analyzed the medical records of three patients with a diagnosis of primary leptomeningeal mixed glioneuronal tumor treated at Childrens Hospital Los Angeles. Results: Patient 1 is a 6-year-old boy with Noonan syndrome, who presented with vomiting and altered mental status. MRI of the brain showed diffuse leptomeningeal disease around the brainstem and cerebellum extending down to the spine and T2-hyperintense nodules in the suprasellar region. The patient was diagnosed as diffuse low-grade astrocytoma on biopsy and started treatment with temozolomide. His neurologic symptoms worsened, and a repeat MRI was consistent with disease progression. Leptomeningeal biopsy showed that the tumor cells were diffusely positive for GFAP and neuronal markers such as synaptophysin and protein gene product (PGP), consistent with low-grade glioneuronal tumor. Chemotherapy with carboplatin and vincristine was initiated. The most recent MRIs performed 1 year later show marked regression of tumor in the brain as well as decreased enhancement in the cervicothoracic cord. Patient 2 is a 9-year-old female who presented with seizures and altered mental status. MRI showed diffuse leptomeningeal enhancement and hydrocephalus. A biopsy was nondiagnostic. The patient had stable disease on serial MRI scans. A follow-up MRI of the brain and spine 1 year after initial diagnosis showed disease progression. Leptomeningeal biopsy revealed tumor cells that stained for PGP and synaptophysin and contained GFAP-type filaments on electron microscopy (EM). A diagnosis of mixed glioneuronal tumor was made. She was started on oral temozolomide with disease stabilization for 6 months, at which point she was found to have a new enhancing lesion within the fourth ventricle with neurologic deterioration. Chemotherapy was changed to vincristine and carboplatin. Follow-up scans showed resolution of the fourth ventricular lesion and decrease in leptomeningeal disease. The patient continues to receive chemotherapy and have slow progress in her speech and motor skills. Patient 3 is a 2.5-year-old boy who initially presented with focal seizures, vomiting, and altered mental status. He had diffuse leptomeningeal enhancement and hydrocephalus on the MRI scan. Initial biopsy was negative. After 1 year of continuing symptoms and similar MRI results, he had a second biopsy. Tumor cells were positive for synaptophysin, and EM revealed GFAP-type filaments. A diagnosis of primary leptomeningeal mixed glioneuronal tumor was made, and he was started on carboplatin and vincristine. Patient was switched to temozolomide and celecoxib after 3 months due to carboplatin allergy. Patient continued to have neurological deterioration and increased leptomeningeal enhancement on MRI. He eventually suffered from seizures, cerebral edema, and cardiopulmonary arrest of unknown etiology, which ultimately lead to his death 1 year after diagnosis. Conclusion: Primary leptomeningeal mixed neuroglial tumors are not well described in pediatric literature. Here we describe a series of three patients to better understand the diagnostic challenge as well as the clinical features and treatment of this extremely rare neoplasm. LEPTO 9. SAFETY AND PHARMACOKINETICS OF INTRATHECAL LIPOSOMAL CYTARABINE (DEPOCYTE®) IN CHILDREN 3 YEARS OF AGE WITH MALIGNANT BRAIN TUMORS Andreas Peyrl,1 Robert Sauermann,2 Friederike Traunmueller,2 Amedeo Azizi,1 and Irene Slavc1; 1Pediatrics, Medical University of Vienna, Vienna, Austria; 2Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. Liposomal cytarabine (DepoCyte®) is a slow-release formulation in which cytarabine is encapsulated in microscopic particles ensuring a prolonged exposure. The recommended dose of liposomal cytarabine for adults is 50 mg, leading to a mean elimination half-life of free cytarabine in cerebrospinal fluid (CSF) of 80 h, versus 3.4 h for native cytarabine. Patients between 3 and 21 years of age showed a more rapid elimination of liposomal cytarabine compared with adults treated at similar dose levels. Nonetheless, the duration of CSF exposure to cytotoxic cytarabine levels was at least 8 days. However, children tolerated an overall lower dose than adults leading to a recommended phase II dose of 35 mg. No safety and pharmacokinetic data are available for children <3 years of age. The objective of this study was to determine the feasibility, safety, and pharmacokinetics of cytarabine after intrathecal administration of 25 mg liposomal cytarabine in children 3 years of age with malignant brain tumors. Patients and Methods: Six patients with a mean age of 20 months were assessable for safety and feasibility. The diagnoses were supratentorial PNET (n = 3) and atypical teratoid rhabdoid tumor (ATRT) (n = 3). All six were male. Liposomal cytarabine at a dose of 25 mg was administered intraventricularly in six patients, and by lumbar puncture as well in one patient. Dexamethasone was used concomitantly for 3 days to prevent arachnoiditis. Pharmacokinetic data were available for four patients 13, 16, 24 and 26 months of age. CSF and plasma samples were collected before administration of liposomal cytarabine and 1 h, 12 h, 24 h, 1 week, and 2 weeks postdosing. CSF samples were analyzed for free and encapsulated cytarabine; plasma samples were analyzed for free cytarabine. Results: Liposomal cytarabine was generally well tolerated. Headache grade 2 occurred in one patient. Free and encapsulated cytarabine in the ventricular CSF after intraventricular administration of 25 mg liposomal cytarabine was detectable up to 14 days postdosing above the cytotoxic drug level of 0.1 μg/ml, with an average elimination half-life of 56.67 h for free cytarabine and 59.28 h for encapsulated cytarabine. After intralumbar administration the elimination half-life for free cytarabine measured in the ventricular CSF during two courses in one patient was significantly shorter (32 h). This appears to be in accordance with data published in adult patients and children >3 years of age. Cytarabine concentrations in plasma just above detection level were found in 4 of 48 plasma samples. Conclusion: The administration of 25 mg liposomal cytarabine in children 3 years of age appears to be safe, and well tolerated with concomitant dexamethasone, and shows comparable drug exposure to the administration of 50 mg in adult patients. LEPTO 10. SAFETY OF OMMAYA RESERVOIRS IN CHILDREN WITH BRAIN TUMORS: EXPERIENCE WITH 2,213 INTRAVENTRICULAR DRUG ADMINISTRATIONS IN 58 CONSECUTIVE PATIENTS TREATED AT THE MEDICAL UNIVERSITY OF VIENNA (1992–2007) Irene Slavc,1 Mariella Gruber-Olipitz,1 Elke Minichmayr,1 Andreas Peyrl,1 Amedeo Azizi,1 and Thomas Czech2; 1Pediatrics, Medical University of Vienna, Vienna, Austria; 2Neurosurgery, Medical University of Vienna, Vienna, Austria. The Ommaya reservoir facilitates repetitive delivery of drugs into the CSF and is a pharmacologically rational system for administering intrathecal chemotherapy. As a consequence, some infant brain tumor protocols (e.g., the HIT protocols) routinely require an Ommaya reservoir placement. However, previous studies have found a rate of infection and other complications ranging from 4.8% to 19% in patients treated for various cancers, leading to hesitation in the use Ommaya reservoirs in some countries. We report on a 15-year experience with the use of these devices in 58 consecutive children with brain tumors. Patients and Methods: Between 1992 and 2007, 58 patients aged 4 months to 18 years (27 <3 years) with various poor-prognosis brain tumors received preventive or therapeutic intrathecal chemotherapy via a subcutaneously indwelling Ommaya reservoir. All reservoirs were inserted by experienced neurosurgeons. Stereotaxy was used as needed. A CT scan was obtained in all patients postoperatively to ensure appropriate catheter positioning and confirmed ipsilateral frontal horn placement. All patients received prophylactic antibiotic therapy intraoperatively and for 3 days thereafter. A total of 2,213 chemotherapy administrations via the reservoir were performed, amounting to a median of 35 deliveries per reservoir (range, 2–163). Only personnel undergoing special training were allowed to administer the intrathecal therapy, and no one was allowed to enter or leave the treatment room during the procedure. CSF cell counts and bacterial cultures were obtained at each use of the reservoir. Since most patients received concomitant intensive intravenous chemotherapy as well, blood tests, including C-reactive protein (CRP) and white cell and platelet count, were performed regularly during intrathecal therapy, and intravenous antibiotics were used generously in patients with increased CRP levels to avoid seeding of the reservoir during bacteremia. Results: No cases required reoperation for infection or malpositioning of the ventricular catheter. In one patient, the intraventricular catheter required reassembly due to kinking at the burr hole edge. No hemorrhage or reservoir dysfunction occurred. Thirty-five (60%) of the patients are surviving a median of 4.5 years (range, 3 months to 13.5 years) after reservoir placement. No late-onset Ommaya reservoir infections occurred in any of the long-term survivors. Conclusion: Ommaya reservoirs are safe in immunocompromised children with brain tumors if neurosurgeons experienced with the technique are performing the procedure, physician and nurses administering the drug undergo special training to strictly adhere to aseptic rules and avoid unnecessary handling, and systemic antibiotics are used perioperatively and when CRP levels increase. LOW-GRADE GLIOMA LGG 1. AGE AND LOCALIZATION ARE KEY FACTORS IN LOW-GRADE GLIOMAS: EPIDEMIOLOGY AND PROGNOSTIC FACTORS OF A LARGE POPULATION-BASED CHILDREN'S CANCER AND LEUKAEMIA GROUP (CCLG, FORMERLY UKCCSG) STUDY Tore Stokland,1 Kathryn Robinson,2 Liu Jo Fen,3 Ironside James,4 David Ellison,5 Roger Taylor,6 Jennie Lucas,2 Sue Picton,7 Terence Parker,8 and David Walker9; 1University Hospital of North Norway, Tromso, Norway; 2Children's Cancer and Leukaemia Group, Leicester, Leicestershire, UK; 3Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK; 4National CJD Surveillance Unit, Edinburgh, UK; 5St. Jude Children's Research Hospital, TN, USA; 6Swansea, Wales, UK; 7St James's University Hospital, Leeds, UK; 8University of Nottingham, Nottingham, UK; 9Division of Child Health, University of Nottingham, Nottingham, UK. Low-grade gliomas (LGG) account for 40% of brain tumors in children; they are predominantly pilocytic astrocytoma, which rarely, if ever, undergo malignant transformation. In order to identify factors that influence tumor growth patterns, clinical data from a population-based cohort were analyzed. Hypothesis: Detailed analysis of patient, tumor, and treatment factors will identify the factors affecting the risk of tumor progression Methods: A clinical database of a UK patient population-based cohort with LGG, registered within an international pilot study, was studied. Kaplan-Meier survival analysis and the Cox proportional hazard regression model were used to estimate progression-free survival and hazard ratios. The pilot study incorporated a standardized diagnostic, observation, and treatment strategy (SIOP LGG 1 1997–2003), with which there was high compliance. The cohort was subjected to central pathology review and validation of the tumor localization. Results: Of 798 patients, 639 were eligible for analysis. Sex distribution was equal. There was a bimodal age incidence with peaks at 3–5 and 13–14 years; NF type I affected 15.9%. Locations and median age at presentation (ranked incrementally) were as follows: chiasm/hypothalamus (24.7%, 4.38 years), optic nerve (6%, 5.31 years), other supratentorial midline (6.1%, 6.3 years), spinal (4%, 6.32 years), brainstem (10%, 6.91 years), cerebellum (31.6%, 7.69 years), and cerebral hemispheres/ventricles (16.0%, 11.06 years). Chiasmatic/optic pathway tumors presented younger (OR 1.45, age 1–3 years) and cerebral hemispheres older (OR 1.88, age >10 years). Overall, 3- and 5-year survival rates were 96.7% (CI, 94.9–97.9%) and 94.6% (CI, 92.1–96.4%); progression-free 3- and 5-year survival rates were 73.1% (CI, 69.3–76.5%) and 69.5% (CI, 65.4–73.2%). In univariate analysis progression was predicted for by age (<1 year, p < 0.001), localization (p < 0.001), histology (p < 0.001), and extent of tumor resection (p < 0.001). In multivariate analysis, age was the strongest predictor of progression (<1 and 1–5 years, p < 0.001), followed by diffuse fibrillary histology (p = 0.002). There was an interaction between anatomical site and extent of resection: optic nerve progressed least, and degree of resection interacted with cerebral and cerebellar sites. Finally, the use of chemotherapy predicted progression. Conclusions: Younger children present with hypothalamic/chiasmatic tumors and progress more commonly. Diffuse fibrillary histology identifies a separate group for risk of progression in this study. Near total/total resection is effective at cerebellar and cerebral sites in preventing progression. The use of chemotherapy in this cohort was selected for the youngest and most progressive patients and therefore is an indicator of progression rather than a prognostic factor. This interaction among age, site, and tumor behavior may be an expression of neurobiological factors linked to brain growth and development affecting tumor behavior. LGG 2. CISPLATIN-ETOPOSIDE REDUCED-DOSE REGIMEN FOR CHILDHOOD PROGRESSIVE LOW-GRADE GLIOMA Maura Massimino,1 Filippo Spreafico,2 Felice Giangaspero,3 Lorenza Gandola,4 Daria Riva,5 Geraldina Poggi,6 Veronica Biassoni,7 Carlo Solero,8 Lorenzo Genitori,9 and Michela Casanova1; 1Pediatric Oncology, Istituto Nazionale Tumori, Milano, Italy; 2Italy; 3Rome/Pozzilli, Italy; 4Milano, Italy; 5Neurologic Development, Istituto Neurologico Carlo Besta, Milano, Italy; 6Bosisio Parini, Italy; 7Istituto Nazionale Tumori, Milano, Italy; 8Istituto Neurologico Carlo Besta, Milano, Italy; 9Ospedale Pediatrico Meyer, Firenze, Italy. After obtaining satisfying results by using a regimen with cisplatin (30 mg/m2/d) and etoposide (150 mg/m2/d) applied for 3 days during 10 courses (J Clin Oncol. 20:4209), we launched a new institutional protocol reducing daily dose of cisplatin to 25 mg and etoposide to 100 mg for progressing low-grade gliomas. The primary end point was to maintain the same rate of responses (70%) and progression-free survival at 3 years with lower neurotoxicity—as expressed by audiograms—and myelotoxicity. From December 2000 to November 2006, we treated 29 patients (20 males) with a median age of 6 years (range, 6 months to 14 years); five with NF1. Nineteen had optic-chiasmatic tumors (Dodge 3:18; Dodge 2:1), four mesencephalothalamic, two multinodular brain and spine tumors, one temporal; six cases were metastatic overall. Clinical diagnoses were done in 12; histologic in 17, with pilocytic astrocytoma in 13, ganglioglioma in 3, and fibrillary astrocytoma in 1. Treatment was decided for sure radiological progression in two subsequent MRIs and/or clinical deterioration, mostly represented by visual loss, at a median latency of 15 months after first diagnosis (range, 0–69 months). As in the previous strategy, intervals between the first four cycles were 4 weeks long, the next three cycles had 5-week intervals, and the remaining three had 6-week intervals, the aim being to cover a period of approximately 10–11 months, thus delivering 10 cycles in total. After initial MRI staging, subsequent follow-up during treatment was based on neurologic and clinical examination before each chemotherapy cycle, with MRI of the tumor site after the first three courses and every 3 months thereafter for the first year of treatment. At a median follow-up of 30 months, volume reduction was noted in 19 (PR 5), SD in 9, PD in 1; with maximal responses so far appreciated at 11 months after starting treatment (range, 2–31 months). Three-year EFS and OS were 78% and 100%, respectively, with one boy dying from tumor bleeding at 49 months after relapse and resurgery. Clinical/neurological/functional improvement was appreciated in 18. No child had a WBC nadir <2,000/mmc after the first course; therefore, no CBC was repeated after the other courses. All had only mild alopecia noted after the first three courses. Audiological toxicity was monitored with audiograms, acoustic potentials, and otoemission according to patient age, revealing, in 4 of 26 tested children, Brock G0 alterations in two, G1 in one, and retrocochlear dysfunction in one. The previous protocol had obtained 19 of 28 volume reductions at a median of 8 months after chemotherapy was started (PR + CR, 14), with a PFS/OS at 3 years of 86% and 96%, respectively, being followed in 8 of 25 by audiologic alteration: Brock G2 in one, G1 in five, and G0 in two. Conclusions. Cisplatin/etoposide regimen is an effective regimen independently by dose reduction that is cheaper, easier to administer, and followed by lower acute and long-term morbidity. LGG 3. EPIDEMIOLOGICAL SURVEY OF HISTOLOGICALLY CONFIRMED LOW-GRADE GLIOMAS IN CHILDREN <36 MONTHS OF AGE: A CANADIAN PEDIATRIC BRAIN TUMOUR CONSORTIUM (CPBTC) STUDY Anne-Sophie Carret,1 Daniel Keene,2 Ute Bartels,3 Bruce Crooks,4 David Eisenstat,5 Christophe Fryer,6 Lucie Lafay-Cousin,7 Valerie Larouche,8 Albert Moghrabi,9 Mariana Silva,10 Beverley Wilson,11 Shayna Zelcer,12 and Eric Bouffet13; 1Pediatrics, The Montreal Children's Hospital/McGill University Health Center, Montreal, QC, Canada; 2Children's Hospital of Eastern Ontario, Ottawa, ON, Canada; 3University of Toronto, Toronto, ON, Canada; 4Dalhousie University, Halifax, NS, Canada; 5Winnipeg, MB, Canada; 6British Columbia's Children's Hospital, Vancouver, BC, Canada; 7University of Calgary, Calgary, AB, Canada; 8Hematology-Oncology, Centre Hospitalier Universitaire de Québec, Québec, QC, Canada; 9Hôpital Sainte-Justine, Montreal, QC, Canada; 10University of Puerto Rico, San Juan, Puerto Rico, USA; 11University of Kansas, KS, USA; 12London, ON, Canada; 13Toronto, ON, Canada. Objectives: To determine the incidence and characteristics of low-grade gliomas (LGG) in children <36 months of age who have been diagnosed with CNS tumor in Canada. Method: A national retrospective review of hospital charts was done on all children <3 years with histologically diagnosed LGG between 1990 and 2005. Patients had to be <36 months at the time of diagnosis of LGG and a resident of Canada. Information extracted included age and year of diagnosis, symptoms at presentation, pathological diagnosis, location of tumor, evidence of disseminated disease at time of diagnosis, treatment modalities, and outcome. Results: Among 531 tumors of the CNS diagnosed during this period of time, 137 cases (25.8%) were histologically diagnosed LGG. The yearly incidence rate was 7.9 ± 1.52 per million children (95% CI) with no increase in time. Male predominance was noted (1.35:1). The median age at diagnosis was 18 months with a median duration of symptoms prior to diagnosis of 6 weeks. These symptoms mainly consisted of gait disorder (n = 50), vomiting (n = 44), development delay or regression (n = 22), abnormal eye movement (n = 22), failure to thrive (n = 17), and increased head circumference. The primary locations were predominantly axial (32.1%) for the supratentorial tumors rather than hemispheric (12.4%), and cerebellar (32.8%) rather than in the brainstem (12.4%) for those infratentorial. Only 10.2% were localized in the spinal cord. Eleven patients presented disseminated disease at the time of diagnosis with either CSF or imaging positive. A gross total resection was possible in 39.4% of cases, mainly in supratentorial (n = 17) or cerebellar (n = 32) tumors when 43.7% had an incomplete resection; 16.8% had a biopsy only. Among those who received a treatment after surgery (n = 39), all of them received chemotherapy combined in 3% of cases with radiotherapy. Progression or recurrence happened in 46.3% of the cases, with 86.9% of the patients alive at time of the survey. Conclusion: Low-grade astrocytomas represent a very heterogeneous group of CNS tumors with stable pattern over years. The therapeutic response and outcome are variable when complete surgical resection is not possible. Efforts to improve treatment modalities and outcome should focus on young patients (<3 years) and those with central midline tumors. LGG 4. FEASIBILITY AND EFFICACY OF SECOND-LINE CHEMOTHERAPY AT RECURRENCE FOR PEDIATRIC LOW-GRADE GLIOMAS: A COMPARATIVE POPULATION-BASED STUDY Katrin Scheinemann,1 Ute Bartels,2 Annie Huang,3 Cynthia Hawkins,4 Eric Bouffet,3 and Uri Tabori5; 1The Hospital for Sick Children, Toronto, ON, Canada; 2University of Toronto, Toronto, ON, Canada; 3Toronto, ON, Canada; 4ON, Canada; 5University of Toronto, ON, Canada. Background: Chemotherapy is widely accepted as the first-line therapy for pediatric low-grade gliomas (PLGG). Treatment modalities for further progression are controversial. Radiation therapy is still widely used, but the role for repeated chemotherapy remains unclear. The aim of the study was to determine treatment outcome for PLGG treated by chemotherapy at recurrence. Methods: The study group consisted of patients who received chemotherapy due to progression after initial chemotherapy protocol. These were compared to patients treated with chemotherapy at diagnosis, patients who received chemotherapy at third progression and to patients who received radiotherapy at recurrence. Results: From 1990 to 2007, 80 patients received chemotherapy as first-line treatment for PLGG, 36 received chemotherapy as second line, and 11 at further recurrence; 31 patients were treated with radiation at recurrence. There was no gender preference. Median follow-up time was 6.85 years. Histology revealed grade I astrocytoma in 73%. The most common location was optic pathway with 49%, followed by brainstem and suprasellar (14%) and thalamic and spinal location (11%). The most common initial protocol was vincristine and carboplatin (80%). The most common protocol at relapse was vinblastine (87%). Five-year progression-free survival (PFS) for first-line chemotherapy was 49% ± 6% compared to 41% ± 9% with second-line chemotherapy (p = 0.2). For further chemotherapy, PFS was comparable but so far with shorter follow-up. Five-year PFS for the second-line chemotherapy and radiotherapy group was 41% ± 9% and 78% ± 5%, respectively (p = 0.003). Only four patients died, out of whom only two due to tumor progression. Conclusion: This is the first study to address the role of chemotherapy for recurrent PLGG. In contrast to other tumors, chemotherapy at diagnosis as well as at first recurrence is associated with similar outcome. Nevertheless, in this study radiotherapy was superior to chemotherapy at recurrence. Prospective studies to assess toxicity and long-term outcome are needed. The benign nature of PLGG justifies further consideration of second-line chemotherapy at recurrence. LGG 5. HIGH MORBIDITY BUT LOW MORTALITY IN CHILDHOOD SPINAL CORD GLIOMAS Katrin Scheinemann,1 Ute Bartels,2 Annie Huang,3 Cynthia Hawkins,4 Eric Bouffet,3 and Uri Tabori5; 1The Hospital for Sick Children, Toronto, ON, Canada; 2Division of Hematology/Oncology, Hospital for Sick Children, ON, Canada; 3Toronto, ON, Canada; 4ON, Canada; 5University of Toronto, ON, Canada. Background: Intramedullary spinal cord low-grade gliomas (sPLGG) are rare pediatric CNS neoplasms. There is little information on therapy and outcome of sPLGA. Furthermore most studies are biased by mixed pathology or adult and pediatric data. Methods: We performed a retrospective, population-based, pediatric low-grade glioma study of the MRI era (1985–2007); 31 of 635 PLGA patients were identified as sPLGG (4.9%). Data on demographics as well as treatment details and outcome were collected. Results: Median age at diagnosis was 5.63 years (range, 1.39–14.62 years); median follow-up, 7.29 years (range, 0.02–15.47 years). There was an age peak at 2 years. There was a clear male predominance (69%). Patients presented with back pain (40%), followed by neurological symptoms (30%) and developmental regression (15%). Histology revealed a grade I astrocytoma in 83% of all patients. Interestingly, there was one ganglioglioma and three mixed gliomas. Five-year progression-free survival (PFS) for the total group was 52% ± 9%. Nevertheless, only one patient died, this from a cause unrelated to his tumor. All patients underwent surgery as primary treatment. Gross total resection (GTR) was achieved in 26% patients, of whom only one patient progressed and underwent GTR again. PFS for GTR versus non-GTR was 85% ± 13% and 34% ± 11%, respectively (p = 0.03). Some of the non-GTR patients were treated with chemotherapy (n = 11) or radiation (n = 5). PFS for the chemotherapy and radiation group was 57% and 50%, respectively (p = 0.9). Eighty percent of patients with available data had significant morbidity; 50% needed an orthopedic intervention, and severe neurological sequelae were observed in 68% of patients. Summary: In this most comprehensive study of childhood spinal low-grade glioma, we found low mortality but a high morbidity rate. Surgery still remains the main treatment modality—even at recurrence—but can cause significant morbidity with severe orthopedic as well as neurological long-term sequelae. Biological behavior of sPLGA seems to be different from other CNS locations and should be investigated for better treatment adjustment. LGG 6. MITOCHONDRIAL MUTATIONS IN PILOCYTIC ASTROCYTOMAS Maria Lueth,1 Lena Wronski,2 Guenter Henze,2 Torsten Pietsch,3 Andreas Von Deimling,4 and Pablo Hernaiz Driever5; 1Department of Pediatric Oncology/Hematology, Charité-Universitaetsmedizin Berlin, Berlin, Germany; 2Department of Pediatric Oncology and Hematology, Charité-Universitaetsmedizin Berlin, Berlin, Germany; 3Department of Neuropathology, University of Bonn, Bonn, Germany; 4Department of Neuropathology, University of Heidelberg, Heidelberg, Germany; 5Berlin, Germany. Molecular underpinnings involved in genesis of pilocytic astrocytomas are not yet fully understood. During the last decades, an increasing number of cancer-related mitochondrial defects have been identified. Previously reported observations indicate increasing numbers of somatic mitochondrial mutations in diverse neoplasms, including brain tumors. These observations prompted us to analyze the complete mitochondrial genomes of pilocytic astrocytomas. Long-range PCR and sequence analysis were performed from brain tumor tissue samples of 19 patients with pilocytic astrocytoma and corresponding peripheral lymphocyte DNA. Overall, 34 somatic mitochondrial DNA mutations were detected in 16 of 19 (84%) astrocytomas. Among these mutations, 31 were homoplasmic and 3 were heteroplasmic changes. Thirty somatic mutations were single-base substitutions; the remaining four were insertions in the np 303–315 poly C tract region. Eighteen (53%) mutations were detected in protein coding regions, 12 (35%) in the D-loop region, 1 (3%) in the tRNA region, and 4 (12%) in regions coding for the mitochondrial ribosomes. Three of the mutations of the protein coding region were missing mutations: MxxV in ATP synthase subunit 6, LxxM in cytochrome b, and LxxM in cytochrome c oxidase subunit 1. The other 15 are silent mutations. Two of the missing mutations are not yet reported. Overall, seven somatic mutations were novel, and 269 distinct germline mutations were identified. Most of these variations are known polymorphisms, but 25 are novel. All germline variations were found as homoplasmic changes; 121 (45%) were found in the mRNA protein coding region, 108 (40%) in the D-loop region, 33 (12%) in regions coding for mitochondrial ribosomes, and seven (2.6%) in the tRNA region. Six of the novel germline variations caused a change of amino acids. In conclusion, pilocytic astrocytoma patients presented germline as well as somatic mutations of the mitochondrial genome. In order to eliminate pseudogene mutations, the sample size was strongly reduced. However, a high proportion of mutations affected the redox system. LGG 7. MOLECULAR ANALYSIS OF PILOMYXOID ASTROCYTOMA Nicholas Foreman,1 Diane Birks,2 Valerie Barton,3 and Andrew Donson4; 1UCHSC, Aurora, CO, USA; 2Aurora, CO, USA; 3University of Colorado Health Sciences Center, Denver, CO, USA; 4University of Colorado Health Sciences Center, Aurora, CO, USA. Pilomyxoid astrocytoma (PMA) is a recently identified tumor type characteristically located in the hypothalamus and occurring in young children (<2 years). PMAs were formerly included in large series of pilocytic astrocytomas (PA) until it was realized in 1999 that this differing phenotype tended to manifest a more aggressive biological course. Development of effective therapies for PMA demands a better biological understanding of this newly defined entity. In order to characterize the biology of PMA, we conducted gene expression analysis of surgical specimens (n = 4) using Affymetrix U113plus2 microarray chips. PMA gene expression profiles was contrasted against PA gene expression profiles (n = 7) using GeneSpring and R microarray analysis packages, and those genes that were >2-fold overexpressed and statistically significant (p < 0.05) were identified. These genes were subsequently analyzed using the Web resource DAVID (Database for Annotation, Visualization and Integrated Discovery), which provides a rapid means to reduce large lists of genes into functionally related groups. DAVID helps to unravel the biological content captured by high-throughput technologies. Analysis of those genes that were overexpressed in PMA showed that there was a significant (p = 8.5 × 10–6, false discovery rate adjusted) enrichment of cell cycle genes. Specifically, cell cycle genes up-regulated in PMA included p53 and cyclins b2, d1, d2, and e2. This finding concurs with previous studies that showed elevated MIB staining in PMA. In a second analysis, genes overexpressed in PMA versus PA were ranked according to magnitude in order to identify the most differentially expressed genes. From this, we showed that L1CAM was the most the highest overexpressed gene in PMA compared to PA. This is significant as L1CAM has been shown to be involved in glial growth and invasiveness and as a marker of poor prognosis in other tumors. With relevance to potential therapeutic targets, we found that topoisomerase IIA (TOP2A) was one of the highest overexpressed genes in PMA compared to PA. TOP2A can be inhibited with doxorubicin or etoposide, suggesting that these may be good choices of drug for future clinical studies in PMA. Further molecular studies of the role of p53 and cyclins in the aggressive phenotype of PMA may also lead to a better understanding of the biology of this tumor. LGG 8. OBJECTIVE RESPONSE OF MULTIPLY RECURRENT LOW-GRADE GLIOMAS TO BEVACIZUMAB AND IRINOTECAN Roger Packer,1 Tobey Macdonald,1 Marianna Horn,1 Brian Rood,1 Regina Jakacki,2 Michael Fisher,3 and Bruce Cohen4; 1Children's National Medical Center, Washington, DC, USA; 2Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; 3Children's Hospital of Philadelphia, Philadelphia, PA, USA; 4Cleveland Clinic, Cleveland, OH, USA. Although childhood low-grade gliomas, including pilocytic astrocytomas and grade 2 fibrillary lesions, are often responsive to chemotherapy, these tumors will usually relapse within 3 years of completion of therapy. Objective responses following initial relapse are infrequent and short-lived. Over the past 2 years, seven children between 1.5 and 11.2 years of age (median age, 4.7 years; three <3 years) with multiply relapsed low-grade gliomas were treated with bevacizumab and irinotecan. All had diencephalic low-grade gliomas; two had disseminated disease, and one had neurofibromatosis type 1. All had recurred despite receiving at least three previous drug regimens, which included carboplatin and vincristine (7), temozolomide (6), vinblastine (7), CCNU-containing regimens (2), and phenylacetate (1). Two had progressed despite receiving prior radiotherapy. Bevacizumab was given intravenously at 10 mg/kg, followed immediately with irinotecan at initially 125 mg/m2. The irinotecan was to be escalated to 150 mg/m2 if there was no toxicity after the first course of treatment. Cycles of chemotherapy were repeated every 2 weeks. Five of seven had an objective response to therapy. Partial responses (>50% reduction) were seen in four, based on both the enhanced and nonenhanced MRI (FLAIR) images, and one child had a minor response (30% reduction). Two patients had stable disease. Marked clinical improvement occurred in four patients, including documented improved vision in one, improved hemiparesis in one, and weight gain in two with diencephalic syndrome. No patient, to date, has relapsed on treatment, with patients presently on treatment for ⩾13, ⩾9, ⩾8, ⩾7, ⩾6, and ⩾2 months. One child stopped treatment after 12 months, after achieving a near complete response, and relapsed 4 months later. No child had dose-limiting toxicity, and none has had symptomatic or asymptomatic intracranial or intratumoral bleeding. This early experience demonstrates that bevacizumab and irinotecan are active in recurrent childhood low-grade gliomas and result in objective, durable responses, even in patients with multiple recurrences after treatment with a variety of drug regimens. Further investigation of this regimen is warranted earlier in the course of disease, possibly even in newly diagnosed patients with progressive disease; however, the long-term toxicity and benefit of this regimen are not known. LGG 9. OPTIC PATHWAY GLIOMAS IN ADOLESCENCE Amy Lee Chong,1 Eric Bouffet,2 Annie Huang,2 and Ute Bartels2; 1The Hospital for Sick Children, Toronto, ON, Canada; 2ON, Canada. Background: Optic pathway gliomas (OPGs) account for 5% of all CNS tumors and occur predominantly in the first two decades of life. Historically the standard treatment was radiotherapy. Carboplatin-based chemotherapy (CT) was employed in young children aiming to avoid or delay radiation to the immature brain. National trials have focused on management and outcomes predominantly in the younger child, and children >10 years of age were excluded from studies evaluating the role of CT. The rationale of this retrospective, single-institution study was to describe management strategies and outcomes in children diagnosed with OPG in adolescence and to compare their course of disease with children <10 years of age. Methods: All patients diagnosed with OPGs in adolescence and treated at the Hospital for Sick Children in Toronto between 1990 and 2006 were identified. Data collected included clinical presentation, management regimens, and current status. Findings were evaluated with respect to progression-free survival. Results: Twenty-two adolescent patients (6 males and 16 females) were identified from 123 patients treated with OPG. Mean age at diagnosis was 12 years 3 months (range, 10–14 years 6 months), and patients were followed for a mean of 5 years (range, 1 year to 6 years 8 months). Eleven patients had optic nerve/chiasmatic gliomas, and 11 had involvement of hypothalamus/posterior radiations. Five had a prior diagnosis of NF-1. Histology was available in 77% (17) of patients, obtained at time of presentation or progression, and was consistent with a low-grade glioma. Of the seven patients (5 with NF-1) initially followed by observation, four required no additional therapy (all with NF-1), one was treated at time of progression with radiation alone, and two with surgery and radiation. Eight patients were treated with radiotherapy (± surgery) as first adjuvant therapy. Four (50%) progressed after a mean time of 19 months (range, 5–42 months), requiring further therapy; four are progression free at a mean follow-up of 47 months (range, 9–96 months). Of nine patients who received chemotherapy as first adjuvant therapy or after radiation failed (n = 3), eight are progression free at a mean follow-up of 27 months (range, 2–56 months); only one patient progressed while on chemotherapy. Review of clinical status at time of transfer to adult services identified two patients with deficits: one with impaired short-term memory who had received prior radiotherapy (5,040 cGy), and one who had suffered an ischemic insult post-surgical intervention. Conclusion: Chemotherapy is a valuable treatment modality with achievement of disease control in adolescents. This option should be considered especially in those affected from NF-1, as cranial radiotherapy is associated with significant late effects, including neurocognitive deficits, even beyond 10 years of age and an increased risk of vascular complications (Moya-Moya) as well as secondary malignancies. LGG 10. OPTIC PATHWAY GLIOMAS IN CHILDREN: RETROSPECTIVE ANALYSIS OF 26 CASES —A SINGLE-INSTITUTION STUDY Rejin Kebudi,1 Ozen Ayranci,2 Samuray Tuncer,2 Inci Ayan,3 Gonul Peksayar,4 Ömer Gorgun,5 Emin Darendeliler,5 and Fulya Yaman Agaoglu5; 1Oncology Institute, Istanbul University, Istanbul, Turkey; 2Turkey; 3Istanbul University, Oncology Institute, Istanbul, Turkey; 4Department of Ophthalmology, Istanbul University, Turkey; 5Istanbul University, Oncology Institute, Turkey. Background: Optic pathway gliomas (OPGs) constitute 1%–5% of childhood brain tumors; they can occur in patients with NF1. The aim of this study is to evaluate our patients with optic pathway gliomas through a 17-year period. Methods: We reviewed the medical records of 26 patients treated between December 1990 and December 2007. Results: Fifteen girls and 11 boys (6 months to 19 years of age; median, 5 years) were diagnosed with optic pathway glioma. Fifteen patients (58%) had the diagnosis of neurofibromatosis type 1. Two had diencephalic syndrome. In 11, the tumor extended to the hypothalamus. Two had leptomeningeal disease, both of whom died despite therapy. Mean follow-up time was 56 months (range, 6–147 months). Three patients had stable disease and were followed without treatment; seven patients underwent surgery (five total tumor resection, two ventriculoperitoneal shunt operation, five received no additional therapy). Two patients (14 and 19 years old) were treated with primary radiotherapy, and 16 patients (6 months to 9 years of age), with symptoms or progressive disease, received chemotherapy. Three patients, who had stable disease, remained clinically and radiologically stable throughout the study. Of the five patients who had total tumor resection, four were followed >26 months and had no evidence of the disease; one recurred and had a resection. In two patients, treated with primary radiotherapy because of progressive disease, clinical response was attained and remained stable. Sixteen patients received chemotherapy; 15 had vincristine 1.5 mg/m2 and carboplatinum 560 mg/m2 in 1 day every 28 days. Of these 15 patients, two are still on chemotherapy and have partial response/stable disease; 10 patients had clinical response to systemic chemotherapy and remained stable thereafter. In one patient who also had diencephalic syndrome, and received vincristine, CCNU, CTX, and PCZ, 7 months after achievement of stable disease with chemotherapy, progressive disease occurred, and the patient died. Conclusion: Gliomas of optic pathway are rare childhood CNS tumors. The rarity of these tumors and their variable course make assessment and standardization of treatment methods difficult. Conservative management can be suggested for asymptomatic or stable cases. Based on the primary location of the tumor and age of the patient, surgery, radiotherapy, and chemotherapy can be used as a single treatment modality or in combination. Therefore, treatment should be planned on an individual basis. In young children with progressive disease, chemotherapy with vincristine and carboplatinum once a month seems to be effective and provides a good quality of life. LGG 11. PATHOLOGICALLY DIAGNOSED OPTIC LOW-GRADE GLIOMAS IN CHILDREN: LONG-TERM FOLLOW-UP OF THE MAYO CLINIC EXPERIENCE David Schomas,1 Nadia Laack,2 Paula Schomberg,2 and Paul Brown1; 1Mayo Clinic, Rochester, Rochester, MN, USA; 2MN, USA. Introduction: Low-grade gliomas of the optic tract (OG) are relatively uncommon pediatric tumors. The long-term clinical behavior and the impact of various prognostic factors on outcomes remain to be defined, especially in children with pathologically proven disease. Materials and Methods: The records of 15 pediatric (18 years or younger) patients with low-grade OGs, including pilocytic OGs, diagnosed between 1960 and 1992 at the Mayo Clinic, Rochester, MN were retrospectively reviewed. Lesions were considered OG if they were felt to involve predominantly the optic tract by either radiographic or surgical analysis. Data of clinical outcomes, therapy received, and pertinent prognostic factors were extracted for analysis. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS), as well as to determine the impact of prognostic factors on outcomes. Results: The median age at diagnosis was 4.2 years. The median follow-up was 10.2 years. Four patients (26%) had neurofibromatosis. Operative pathology revealed that the majority were astrocytomas (53%). Pilocytic astrocytomas were found in six patients (40%), and a mixed oligoastrocytoma was seen in a single patient (6.7%). Two patients were deceased at last follow-up. The extent of surgical resection was assessed by operative report, neurosurgeon's impression, and postoperative imaging when available. Gross total resection (GTR) was achieved in a single patient (6.7%), subtotal resection in eight patients (53%), and biopsy only in six patients (50%). Postoperative radiation therapy (RT) was administered to seven patients (47%). The median OS for the entire group was not reached. The 10- and 15-year OS rates were 89% and 71%, respectively. By univariate analysis, no adverse prognostic factors for OS were identified when analyzed for age, sex, size of lesion, extent of resection, histology, or the use of postoperative RT. Progression was determined by review of radiographic reports, clinical notes, or the initiation of additional therapy (e.g., chemotherapy, RT, surgery). The 10-year PFS rate was 48%. Prognostic factors for PFS identified by univariate analysis included histology (pilocytic vs. astrocytoma, p = 0.02) and postoperative RT (p = 0.01). PFS at 10 years was 80% (median PFS not reached) versus 18% (median PFS, 4.5 years) for those that did and did not receive postoperative RT, respectively. On multivariate analysis, postoperative RT remained statistically significant for improvement in PFS. Conclusions: This single-institution retrospective series of pediatric patients with pathologically proven OGs provides evidence that a significant proportion of patients have good long-term prognosis and remain alive with stable disease up to and beyond 10 years after diagnosis. Postoperative RT did not affect OS. However, the use of RT did significantly influence PFS. LGG 12. PHASE II STUDY OF ANTINEOPLASTONS A10 AND AS2-1 (ANP) IN CHILDREN WITH OPTIC PATHWAY GLIOMA: A PRELIMINARY REPORT Stanislaw Burzynski,1 Robert Weaver,1 Tomasz Janicki,1 Marek Walczak,1 Barbara Szymkowski,1 and Shiney Samuel1; 1Burzynski Clinic, Houston, TX, USA. Optic pathway gliomas (OPG) constitute approximately 6% of pediatric brain tumors. Histologically, these tumors are low-grade gliomas and typically occur in children <12 years of age. The treatment for nonresectable OPG remains controversial. Radiation therapy and chemotherapy are appropriate for recurrent and posterior OPG; however, radiotherapy in young children typically results in serious toxicities. Chemotherapy with carboplatin and temozolomide yields a high percentage of initial stable disease (SD), inevitably followed by progressive disease (PD). This report summarizes the treatment with ANP of the first 12 evaluable children treated under study protocol BT-23. The patients' median age was 6 years 3 months and ranged from 7 months to 16 years. Five (42%) had multicentric, and seven (58%) had solitary tumors. Two patients had neurofibromatosis 1. Pilocytic astrocytoma was diagnosed in five (42% of) cases. Four (33% of) patients had low-grade astrocytomas, and three (25% of) patients did not have a biopsy. Only two patients were not treated prior, but developed progressive tumors. In the remaining patients, eight (67%) failed chemotherapy alone, and two (17%) developed progression after surgery. Treatment consisted of intravenous infusions of ANP (antineoplastons A10 and AS2-1) for a median of 16.5 months. The median of average dosage of A10 was 8.36 g/kg/day and of AS2-1 was 0.37 g/kg/day. The responses were assessed by MRIs according to standard criteria. Complete response (CR) was achieved in 25%, partial response (PR) in 17%, SD in 50%, and PD in 8% of patients. Seven patients are alive and well (from 3.5 to 15.2 years postdiagnosis and from 3 to 9.5 years postenrollment). None of the patients were lost to follow-up. The median interval of disease control was 45.4 months. The 5-year overall survival from initiation of treatment was 42% and from the time of diagnosis as 67%. The median overall survival from diagnosis based on Kaplan-Meier survival curve was 13.7 years. There were no grade 3 or 4 toxicities related to ANP. The preliminary results of this study showed favorable responses and survival data in a small group of patients diagnosed with the difficult-to-treat OPG. LGG 13. PHASE II STUDY OF WEEKLY VINBLASTINE IN RECURRENT/REFRACTORY PEDIATRIC LOW-GRADE GLIOMAS Eric Bouffet,1 Regina Jakacki,2 Stewart Goldman,3 Darren Hargrave,4 Manohar Shroff,5 Juliette Hukin,6 Ute Bartels,7 Shannon Farley,8 and Sylvain Baruchel7; 1Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada; 2Pediatric Oncology, Children's Hospital of Pittsburgh, PA, USA; 3Chicago, IL, USA; 4Sutton, UK; 5Diagnostic Imaging, The Hospital for Sick Children, Toronto, ON, Canada; 6British Columbia's Children's Hospital, Vancouver, BC, Canada; 7University of Toronto, Toronto, ON, Canada; 8Haematology/Oncology, The Hospital for Sick Children, Toronto, AB, Canada. Background: Weekly vinblastine was evaluated in a phase II study in children with recurrent or refractory low-grade gliomas. Methods: Vinblastine was given intravenously at a dose of 6 mg/m2 weekly for 52 weeks. Eligible patients were neurofibromatosis (NF1) or non-NF1 patients <18 years old who had previously failed chemotherapy and/or radiation for unresectable low-grade glioma. Responses were assessed every 3 months during vinblastine administration. Results: The study opened in 2003 and accrual was completed in 2006. Fifty-one eligible patients (27 females, 24 males; median age, 7.2 years; range, 1.4–16.8 years) were enrolled on this study; nine patients had NF1. Pathological diagnosis was pilocytic astrocytoma (29), low-grade astrocytoma NOS (9), ganglioglioma (2), and pilomyxoid astrocytoma (1); 10 patients were diagnosed on imaging only. Thirty-seven patients had received a previous line of chemotherapy, 11 two lines, 2 had three lines, and 9 had received previous radiation. Twenty-nine (57%) patients completed 52 weeks of chemotherapy. Three discontinued vinblastine for toxicity (two peripheral neuropathy, one recurrent rash). Main toxicity was hematological, with 27 patients who required transient or permanent dose reduction. Progression during treatment (>25% increase in 2-D or >40% in 3-D tumor size) occurred in 20 patients, including one who eventually showed partial response following further vinblastine administration. Independent central radiology review on the 31 first patients reports one CR, three PR, nine minor responses (MR), 10 stable disease, and 10 progression, with an overall response rate (CR + PR + MR) of 42%. At a median follow-up of 31 months, 19 of 29 patients who completed 52 weeks of therapy are progression free. Conclusions: This is the largest phase II chemotherapy study ever conducted in recurrent/refractory low-grade glioma. This study shows that sustained responses can be achieved with weekly vinblastine used as second-line chemotherapy. The low toxicity profile of this agent and the potential for extended administration (>12 months) without significant cumulative toxicity make this agent a potentially useful drug for the treatment of pediatric low-grade gliomas. Supported by a grant from the Ontario Cancer Research Network. LGG 14. PILOMYXOID ASTROCYTOMA: PRELIMINARY RESULTS OF IMMEDIATE POSTOPERATIVE CHEMOTHERAPY James Garvin,1 Ricardo Komotar,2 Jennifer Levine,1 Richard Anderson,2 and Neil Feldstein2; 1Pediatrics, Columbia University, New York, NY, USA; 2Neurological Surgery, Columbia University, New York, NY, USA. Pilomyxoid astrocytoma (PMA) occurs mainly in the hypothalamic region of young children and is considered a more aggressive variant (grade II) of pilocytic astrocytoma (PA) in the 2007 WHO classification, although this relationship awaits further clarification. Mean progression-free survival (PFS) for PMA is 26 months, distinctly shorter than for PA (Komotar RJ et al. 2004). Postoperative chemotherapy or radiotherapy for PA in children is generally initiated only at tumor progression, but we have treated PMA patients preemptively with vincristine and carboplatin (Packer RJ et al. 1993) with or without temozolomide. Here we report preliminary results of this approach (see LGG 14: Table 1, p. 516). All patients had large suprasellar tumors with mild to moderate hydrocephalus. One of two evaluable patients attained CR to chemotherapy. Patient 3, who had early tumor progression prior to starting chemotherapy, subsequently had transient neurologic deterioration (new contralateral weakness) associated with temozolomide administration, suggestive of temozolomide-associated tumor flare as reported in adults with high-grade gliomas. There were no other unanticipated toxicities of chemotherapy. In conclusion, preemptive postoperative carboplatin-based chemotherapy for PMA appears feasible and may be associated with improved PFS. LGG 14: Table 1. Treatment and outcome Patient . Age (Months) . Tumor Location . Surgery . Chemotherapy . Response (Months) . 1 17 Suprasellar, third ventricle GTR Vcr, Cbp CCR (≥72) 2 16 Suprasellar, thalamus, hypothalamus, brainstem STR Vcr, Cbp CR (≥44) 3 13 Parasellar, temporal lobe, thalamus, brainstem STR Vcr, Cbp, Tmz SD (≥5) Patient . Age (Months) . Tumor Location . Surgery . Chemotherapy . Response (Months) . 1 17 Suprasellar, third ventricle GTR Vcr, Cbp CCR (≥72) 2 16 Suprasellar, thalamus, hypothalamus, brainstem STR Vcr, Cbp CR (≥44) 3 13 Parasellar, temporal lobe, thalamus, brainstem STR Vcr, Cbp, Tmz SD (≥5) Chemotherapy: Vcr, vincristine; Cbp, carboplatin; Tmz, temozolomide Open in new tab LGG 14: Table 1. Treatment and outcome Patient . Age (Months) . Tumor Location . Surgery . Chemotherapy . Response (Months) . 1 17 Suprasellar, third ventricle GTR Vcr, Cbp CCR (≥72) 2 16 Suprasellar, thalamus, hypothalamus, brainstem STR Vcr, Cbp CR (≥44) 3 13 Parasellar, temporal lobe, thalamus, brainstem STR Vcr, Cbp, Tmz SD (≥5) Patient . Age (Months) . Tumor Location . Surgery . Chemotherapy . Response (Months) . 1 17 Suprasellar, third ventricle GTR Vcr, Cbp CCR (≥72) 2 16 Suprasellar, thalamus, hypothalamus, brainstem STR Vcr, Cbp CR (≥44) 3 13 Parasellar, temporal lobe, thalamus, brainstem STR Vcr, Cbp, Tmz SD (≥5) Chemotherapy: Vcr, vincristine; Cbp, carboplatin; Tmz, temozolomide Open in new tab LGG 15. PRIMARY SPINAL CORD ASTROCYTOMAS IN THE PEDIATRIC POPULATION Ruth Bristol,1 Mark Krieger,1 Alexander Taghva,2 Jonathan Finlay,3 and Gordon Mccomb4; 1Childrens Hospital of Los Angeles, Los Angeles, CA, USA; 2Neurosurgery, University of Southern California, Los Angeles, CA, USA; 3Los Angeles, CA, USA; 4Neurosurgery, Childrens Hospital Los Angeles, Los Angeles, CA, USA. Introduction: Intramedullary spinal cord astrocytomas are uncommon tumors in childhood. With the small number of children affected, few data exist on specific therapies and outcomes of spinal astrocytomas in children. Methods: The hospital and clinic charts of 16 patients, 2–13 years of age at presentation, were retrospectively reviewed. Imaging, pathology, and operative reports were also reviewed. All patients were treated at Childrens Hospital of Los Angeles. Results: Weakness was the first sign of disease in 6 of 16 patients. In general, weakness was present for several weeks prior to diagnosis, although one patient had leg weakness for a full year. The remaining patients presented with back pain, scoliosis, and gait changes in equal numbers. One patient who underwent treatment for a syrinx before the tumor at T3–T6 was identified. Mean age at presentation was 9.5 years (range, 2–13). Follow-up ranged from 2 to 104 months (mean, 33 months). Five patients underwent two resections, and one patient underwent a third exploration for cystic loculation with minimal tumor resection. Nine patients exhibited transient neurologic deficits immediately following surgery, with good resolution prior to discharge. Nine patients had lesions that spanned a junctional level (either C7–T1 or T12–L1), and seven developed postoperative spinal deformity, three of whom required fusion. Recurrent disease occurred in six patients, whereas four had stable residual disease, and four had no evidence of disease. All patients with anaplastic astrocytomas exhibited recurrence or progression of residual. In addition, two patients with low-grade lesions experienced recurrence. Six patients underwent Temodar chemotherapy, two of whom also received irinotecan, and one received vincristine/carboplatin. Five patients received spinal radiation from 3,000 to 5,700 cGy. Conclusion: While weakness was the most common presenting symptom, standard evaluation for back pain and scoliosis delayed the diagnosis of tumor by 2–4 months. This supports the need for MRI in scoliosis patients. In addition to surgical resection, chemotherapy and radiation therapy can be employed to improve progression-free survival in patients with higher grade lesions. Low-grade astrocytomas of the spine can be cured with complete resection. Even small residuals can remain unchanged for many years. The high incidence of lesions at junctional levels and postoperative deformities implicate the importance of neural innervation to the spinal musculature and the need for minimally invasive resections. LGG 16. PILOCYTIC ASTROCYTOMAS: A PEDIATRIC CASE SERIES Sofia Nunes,1 Duarte Salgado,2 and Mário Chagas3; 1Pediatric Neuro-Oncology Unit, Instituto Português de Oncologia de Lisboa, Lisboa, Portugal; 2Pediatric Neuro-Oncology Unit, Instituto Português de Oncologia de Lisboa, Portugal; 3Department of Child and Adolescent Oncology, Instituto Português de Oncologia de Lisboa, Portugal. Introduction: Pilocytic astrocytomas constitute about 30% of all primary brain tumors in children. They are commonly located in the optic pathways and hypothalamus, cerebellum, brainstem and more rarely in the cerebral hemispheres. Prognosis is relatively favorable and more dependent on complete resection of tumor, which should be the treatment of choice whenever possible. However, residual or unresectable tumors remain a challenge. The aim of our work was to characterize our cases of pilocytic astrocytomas, including optic pathway gliomas in children with neurofibromatosis, mainly in what concerns the treatment response and survival. Methods: Retrospective study of the patients followed in our unit since 1985. We included all the children with documented pilocytic astrocytoma by histology or children with optic pathway glioma and neurofibromatosis type 1 (NF-1) without biopsy but with typical MRI presentation. Data were collected on age, age of diagnosis, neurofibromatosis or other associated pathology, localization of the tumor, radiologic characteristics, histological diagnosis, type of treatment, response to the treatment, neurological sequelae, and survival. Variables were analyzed using methods of descriptive statistics and survival analyses (Kaplan-Meyer). Results: Sixty-four children were included for analysis (50% male; mean age, 5.7 years). Of these, 15 presented NF-1 and optic pathway gliomas (group 1), 21 optic pathway gliomas without NF-1 (group 2), and 28 pilocytic astrocytomas with other localization (39% in the cerebellum, 14% in brainstem, and 14% in medulla) (group 3). Mean follow-up time was 70.4 months, and mortality rate was 9.3% (n = 6). In group 1, the majority (66%) were treated with a chemotherapy protocol for low-grade gliomas. In group 2, 43% were treated with surgical resection alone or followed by chemotherapy and/or radiotherapy, and 33% were treated with a chemotherapy regimen only. In group 3, 82% were submitted to surgery followed by chemotherapy, and/or radiotherapy schemes and 10.7% were treated only with chemotherapy. Recurrence occurred in 45% (n = 29) of all patients (n = 5 in the neurofibromatosis group, 33%). Survival curves were not significantly different between the groups (between 70% and 100% at 5 years) or between the type of treatment. Conclusion: Our series seems to confirm an overall good prognosis for children harboring a pilocytic astrocytoma as reported in the literature and despite some referral bias in our population. We highlight the important role of chemotherapy in patient management. LGG 17. RADIOLOGICAL CLASSIFICATION OF OPTIC PATHWAY GLIOMAS: EXPERIENCE OF A MODIFIED FUNCTIONAL CLASSIFICATION SYSTEM Timothy Taylor,1 Tim Jaspan,1 Giuseppe Maria Milano,2 Richard Gregson,3 Terence Parker,4 Timothy Ritzmann,4 Charlotte Benson,5 and David Walker6; 1Department of Radiology, Nottingham University Hospitals Trust, Nottingham, UK; 2Pediatric Oncology/Hematology, Ospedale “S. Maria della Misericordia,” San Sisto Perugia, Italy; 3Department of Ophthalmology, Nottingham University Hospitals Trust, Nottingham, UK; 4University of Nottingham, Nottingham, UK; 5University of Medicine, Nottingham, UK; 6Division of Child Health, University of Nottingham, Nottingham, UK. Introduction: Optic pathway gliomas (OPGs) in childhood are associated with neurofibromatosis 1. Dodge's anatomical classification (DC) helps select patients for surgery. Treatments with chemotherapy and radiotherapy are being reevaluated, particularly in young children (<8 years), in response to a perceived threat to vision from tumor growth as their capacity to cooperate with detailed vision testing is poor until late childhood. A modified Dodge classification (MDC) was developed in order to predict visual loss using anatomical criteria. Methods: Paired diagnostic and follow-up MRI scans from a cohort of 72 patients (36.1% NF1+ve) from four centers who had participated in an international pilot study were reviewed by a single supported observer to test the feasibility and applicability of the new classification system, to validate it against DC, and to investigate associations between MDC scoring and patient and tumor characteristics. Analysis of data was performed using SPSS v15.0 (SPSS, Inc.) using the chi-squared test. Results: The application of the MDC was feasible after familiarization. Using the established DC in this cohort, where cases had tumors at multiple sites, 14% were Dodge A (optic nerves), 17% Dodge B (chiasm), and 69% Dodge C. The MDC recorded tumor involvement as optic nerve: unilateral (1a) 19%, bilateral (1b) 28%; optic nerve/chiasmatic junction (1c) 14%; chiasmatic: as centrally placed (2a) 32% and asymmetric (2b) 51%; hypothalamic 40.3%; optic tracts (3) 49% with diffuse involvement (4) 26%. NF1+ve cases more commonly involved both optic nerves (p = 0.021) and other multiple locations (p = 0.001). NF1–ve tumors more commonly involved the central chiasm (p = 0.005) and hypothalamus (P = 0.003). Fewer hypothalamic-positive tumors were associated with optic nerve involvement (p = 0.009), while more were associated with central chiasm involvement (p < 0.001) (see LGG 17: Table 1, p. 516). LGG 17: Table 1. The Dodge classifications Original Dodge Classification (DC) . Modified Dodge Classification (MDC) . Description . Subcategories . Description . A 1a Single optic nerve 1aL/R (left/right) 1b Bilateral optic nerve 1bL/R (left>right/right>left) 1c Cisternal segment optic nerve 1cL/R/B (left/right/bilateral) B 2a Central chiasmatic 2a 2b Asymmetric chiasmatic 2bL/R (left>right/right>left) C 3 Optic tracts 3L/R/B 3b Asymmetric tracts 3bL/R (left>right/right>left) 4 Diffuse posterior tracts 4L/R/B (left/right/bilateral) 4b Asymmetric posterior tracts 4bL/R (left>right/right>left) H+/– Hypothalamic involvement LM+/– Leptomeningeal dissemination NF1+/– Neurofibromatosis type 1 Original Dodge Classification (DC) . Modified Dodge Classification (MDC) . Description . Subcategories . Description . A 1a Single optic nerve 1aL/R (left/right) 1b Bilateral optic nerve 1bL/R (left>right/right>left) 1c Cisternal segment optic nerve 1cL/R/B (left/right/bilateral) B 2a Central chiasmatic 2a 2b Asymmetric chiasmatic 2bL/R (left>right/right>left) C 3 Optic tracts 3L/R/B 3b Asymmetric tracts 3bL/R (left>right/right>left) 4 Diffuse posterior tracts 4L/R/B (left/right/bilateral) 4b Asymmetric posterior tracts 4bL/R (left>right/right>left) H+/– Hypothalamic involvement LM+/– Leptomeningeal dissemination NF1+/– Neurofibromatosis type 1 Open in new tab LGG 17: Table 1. The Dodge classifications Original Dodge Classification (DC) . Modified Dodge Classification (MDC) . Description . Subcategories . Description . A 1a Single optic nerve 1aL/R (left/right) 1b Bilateral optic nerve 1bL/R (left>right/right>left) 1c Cisternal segment optic nerve 1cL/R/B (left/right/bilateral) B 2a Central chiasmatic 2a 2b Asymmetric chiasmatic 2bL/R (left>right/right>left) C 3 Optic tracts 3L/R/B 3b Asymmetric tracts 3bL/R (left>right/right>left) 4 Diffuse posterior tracts 4L/R/B (left/right/bilateral) 4b Asymmetric posterior tracts 4bL/R (left>right/right>left) H+/– Hypothalamic involvement LM+/– Leptomeningeal dissemination NF1+/– Neurofibromatosis type 1 Original Dodge Classification (DC) . Modified Dodge Classification (MDC) . Description . Subcategories . Description . A 1a Single optic nerve 1aL/R (left/right) 1b Bilateral optic nerve 1bL/R (left>right/right>left) 1c Cisternal segment optic nerve 1cL/R/B (left/right/bilateral) B 2a Central chiasmatic 2a 2b Asymmetric chiasmatic 2bL/R (left>right/right>left) C 3 Optic tracts 3L/R/B 3b Asymmetric tracts 3bL/R (left>right/right>left) 4 Diffuse posterior tracts 4L/R/B (left/right/bilateral) 4b Asymmetric posterior tracts 4bL/R (left>right/right>left) H+/– Hypothalamic involvement LM+/– Leptomeningeal dissemination NF1+/– Neurofibromatosis type 1 Open in new tab Conclusion: The MDC records more detailed information than the DC and is proposed as a new research tool for the classification of OPG in clinical trials of new therapies as well as research into the biology of tumor development and its impact on visual outcome. LGG 18. RESULTS OF COG PROTOCOL A9952: A RANDOMIZED PHASE 3 STUDY OF TWO CHEMOTHERAPY REGIMENS FOR INCOMPLETELY RESECTED LOW-GRADE GLIOMA IN YOUNG CHILDREN Joann Ater,1 Emi Holmes,2 Tianni Zhou,2 Claire Mazewski,3 William Roberts,4 Gilbert Vezina,5 Timothy Booth,6 David Freyer,7 Richard Kadota,4 Regina Jakacki,8 Roger Packer,5 Michael Prados,9 and Ian Pollack8; 1Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 2Children's Oncology Group, Arcadia, CA, USA; 3Emory University, Atlanta, GA, USA; 4Children's Hospital of San Diego, San Diego, CA, USA; 5Washington, DC, USA; 6Dallas Children's, Dallas, TX, USA; 7Children's Hospital of Los Angeles, Los Angeles, CA, USA; 8University of Pittsburgh, Pittsburgh, PA, USA; 9University of California, San Francisco, San Francisco, CA, USA. Purpose and Methods: To test the efficacy of chemotherapy as treatment for progressive or symptomatic unresectable low-grade gliomas to delay the need for radiotherapy, 428 children <10 years old were enrolled in COG A9952 between 1997 and 2005. Of these, 27 were ineligible. Previous treatment other than surgery was not allowed, and residual tumor in the brain was required. Of 401 eligible children, 137 were randomized to carboplatin and vincristine (CV); 137 to thioguanine, procarbazine, lomustine (CCNU), and vincristine (TPCV); and 127 children with neurofibromatosis (NF1) and radiographically verified progressive optic pathway gliomas were treated with CV without randomization. The committee neuropathologist performed central review of pathology, and committee neuroradiologists (G.V. and T.B.) performed central review of tumor location, size of residual, response, and progression. The randomization was stratified to assure equal distribution between regimens of pilocytic astrocytoma, hypothalamic/optic pathway tumors, and progressive tumors. The primary end point of this study was event-free survival (EFS). An event for this study was defined as the first occurrence of progressive disease, relapse, death from any cause, or development of second malignancy. The secondary end point was time to death from any cause, from which actuarial survival probability was computed. Results: Of the 401 eligible children, 52% were female, 60% were <5 years of age at enrollment, and 334 (83%) had hypothalamic/optic pathway or juvenile pilocytic astrocytomas in other sites. Centrally reviewed tumor response rates (CR + PR + MR), defined as a decrease in both enhancement and T2 signal on MRI at end of protocol therapy, by regimen were 57% for CV (non-NF), 61% for CV (NF), and 58% for TPCV. Five-year overall survival rates are 86% ± 2.4% for non-NF and 98% ± 1.1% for NF children (p = 0.0017). Five-year EFS for children with NF is also significantly better with 68.7% ± 4.8% EFS versus 41.7% ± 3.4% EFS for non-NF children (p < 0.0001). EFS rates in children with NF are not affected by age. In non-NF children, those >5 years of age have a significantly better 5-year EFS rate (p = 0.0015). Five-year EFS in randomized subjects was 35% ± 4.8% for CV versus 48 ± 4.8% for TPCV (p = 0.11). Toxicity differs between regimens but is manageable for both. There were no treatment-related deaths or second malignant neoplasms. Conclusions: Both regimens showed efficacy in controlling low-grade gliomas, with a median time to progression of 3.2 years for CV and 4.9 years for TPCV, thus allowing delay in radiotherapy. Children with NF had significantly better 5-year EFS and survival than did children without NF. Further follow-up is needed, and CV should not necessarily be considered the best standard regimen. More trials of new agents and regimens for low-grade gliomas are warranted. LGG 19. ROLE OF VISUAL EVOKED POTENTIALS IN FUNCTIONAL ASSESSMENT OF PEDIATRIC OPTIC PATHWAY TUMORS TREATED WITH CARBOPLATIN AND VINCRISTINE CHEMOTHERAPY Su Berrak,1 Ozlem Yenice,2 Cengiz Canpolat,1 and Memet Ozek3; 1Department of Pediatric Hematology-Oncology, Marmara University Medical Faculty, Istanbul, Turkey; 2Department of Ophthalmology, Marmara University Medical Faculty, Istanbul, Turkey; 3Department of Pediatric Neurosurgery, Marmara University Medical Faculty, Istanbul, Turkey. Objects: Biologic activity of optic pathway tumors (OPT) is highly variable, and the most effective screening method is debatable. Methods: Patients were regularly evaluated with neuroradiographic studies and visual evaluation, including VEP testing. Patients' VEPs and ophthalmologic examination results were compared with their corresponding magnetic resonance imaging scans and with age-matched controls. Results: Overall survival and progression-free survival rates at 41 months were 77% ± 8% and 76% ± 10%, respectively. VEP results in terms of amplitude and latency at presentation and at last follow-up correlated with patient's final status according to MRI findings at last follow-up (p = 0.036 and p = 0.003, respectively). Conclusion: The absence of traces in VEP at presentation in our study suggests that VEP can identify which OPT patients are at higher risk for relapse. Thus, patients without any traces in VEPs at presentation should be monitored closer with MRI and ophthalmologic examinations in order to perceive the forthcoming progressive disease earlier. LGG 20. SECOND CHEMOTHERAPY FOR RELAPSED PEDIATRIC LOW-GRADE GLIOMA: THE HIT-LGG 96 EXPERIENCE Uwe Kordes,1 Stephan Von Hornstein,2 Barbara Thieme,2 Sabine Breitmoser-Greiner,3 and Astrid Gnekow4; 1Department of Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany; 2Department of Pediatric Hematology and Oncology, Klinikum Augsburg, Augsburg, Germany; 3Department of Pediatric Hematology and Oncology, Klinikum Augsburg, Germany; 4Augsburg, Germany. Objective: Feasibility and efficiency of salvage chemotherapy for children with low-grade glioma suffering a second relapse after primary treatment with carboplatin/vincristine. Between October 1, 1996, and March 31, 2004, the HIT-LGG 96 study offered a uniform treatment strategy for 1,044 children with low-grade glioma. Here we report the experience with patients who suffered a progression following initial response to chemotherapy and received salvage chemotherapy rather than radiotherapy because of their young age. Nonsurgical treatment was given to 361 patients with severe clinical or ophthalmological problems at diagnosis or upon clinical, ophthalmological, or radiological progression. Age stratification for primary chemotherapy was <5 years initially, although this was raised throughout the course of the study. Two hundred fifteen protocol patients received chemotherapy at a median age of 37 months (10-week induction: VCR 1.5 mg/m2 d1 weeks 1–10, carboplatin 550 mg/m2 d1 weeks 1, 4, 7, and 10, both drugs q 4 weeks from week 13 to week 53). One hundred forty-six protocol patients received primary radiotherapy. There were 94 PD in the chemotherapy group after a median of 19.2 months, at which point 28 patients were irradiated and 27 received chemotherapy. This latter group is the focus of this report. Median age at start of first treatment was 11.8 months; 12 were male, 15 female; four had NF1, eight had leptomeningeal metastasis, nine had diencephalic syndrome. Main localization was supratentorial midline in 22, posterior fossa in five. Six patients were diagnosed clinically; three had a complete resection, five a partial resection, and one a subtotal resection; and six were biopsied. All operated patients had a pilocytic astrocytoma. Median age at start of second treatment was 49 months. For second chemotherapy, 12 patients received a vincristine/platin- and or cyclophosphamide-based regimen, nine patients received vinblastine, three patients received temozolomide, and three patients received other agents. Repeat evaluation for best responses demonstrated reduction of tumor volume in 8 patients, stabilization in 13, progressive disease in 4 (NA in 2). Thirteen patients became progressive again after a median of 15.7 months after start of second therapy. The 3-year PFS of the second-chemotherapy group was 34%. Response rate was highest in those who received carboplatin/VCR, and the time to second progression in this group was 11.4 months. Conclusion: While today we are able to define indications for primary chemotherapy more clearly in children with low-grade glioma, treatment options are less standardized in those who suffer a second progression following this approach at a young age. Clinicians have to recognize, however, that repeat chemotherapy is still able to prolong PFS and further defer RT in this patient group. Repeat administration of the time-tested carboplatin/vincristine combination can be an effective option with tolerable toxicity in young patients who may be poor candidates even for focal radiotherapy. LGG 21. SIOP-LGG 2004: COMPREHENSIVE TREATMENT STRATEGY FOR LOW-GRADE GLIOMA IN CHILDREN AND ADOLESCENTS, INCLUDING A RANDOMIZED CHEMOTHERAPY TRIAL AND A RADIOTHERAPY TRIAL Astrid Gnekow,1 Gian Luca De Salvo,2 Barbara Thieme,3 Stephan Von Hornstein,3 Giorgio Perilongo,4 Tore Stokland,5 Per Eric Sandstrom,6 Irene Slavc,7 Jon Helgestad,8 Heiko Goette,9 Jacques Grill,10 Rolf-Dieter Kortmann,11 and David Walker12; 1Children's Hospital, Augsburg, Germany; 2IOV-IRCCS, Padua, Italy; 3Augsburg, Germany; 4Padua, Italy; 5Tromso, Norway; 6Umea, Sweden; 7Vienna, Austria; 8Aarhus, Denmark; 9IMBEI, Mainz, Germany; 10Villejuif, France; 11Leipzig, Germany; 12Nottingham, UK. Introduction: Low-grade glioma (LGG) accounts for 30%–40% of CNS tumors, comprising a growing number of histologic subgroups with divergent biologic behavior. Although around a third may be cured by surgery alone, a comprehensive treatment strategy has to integrate adjuvant chemotherapy (CT) and radiotherapy (RT) regimens. Up to now, neither the differential indication for these nonsurgical treatments nor the most effective and least toxic strategy has been defined considering improved understanding of childhood brain development and its vulnerability. Trial design: In the SIOP-LGG 2004 trial, activated successively in 11 European countries and 1 Australian hospital since April 1, 2004, children are observed without further therapy after complete tumor resection, or after incomplete resection or radiological diagnosis if their tumor is asymptomatic and/or nonprogressive. Nonsurgical treatment is instituted upon defined clinical and radiological indications. For those <8 years of age and for all neurofibromatosis (NF1) patients, an 18-month chemotherapy of vincristine/single-dose carboplatin is recommended. For non-NF1 patients of any age, a randomized comparison of a two-drug (carboplatin/vincristine) versus a three-drug (carboplatin/vincristine/VP-16) induction therapy is in progress to define the influence of treatment intensity on progression-free survival and the distribution of tumor response at 6 months. Treatment toxicity is closely monitored especially for neurotoxicity and allergy. Radiotherapy using modern planning and treatment techniques is specified and recommended as primary treatment for those >8 years of age. Ophthalmologic, endocrine, neurological, and quality of life data are being collected and will be correlated with radiation dose to CNS organs at risk and the effect of CT and RT treatment. Integral parts of the trial are central review programs for neuropathology and for radioimaging material at defined time points to assess response/progression. Patients and Results: A total of 1,234 patients were entered by January 6, 2008, with 1,121 being evaluable (144 NF1; 605 male/516 female; median age, 76.0 months; range, 0.5–215.7 months). Four hundred sixty tumors were supratentorial midline, 177 hemispheric, 286 cerebellar, 120 brainstem, 43 spinal, 35 others; 45 were disseminated. Surgical resection was complete in 284, subtotal/partial in 337, and consisted of biopsy only in 174; 326 LGG were diagnosed neuroradiologically (113 data incomplete). Histologically, there were 589 WHO grad I tumors (561 pilocytic astrocytoma), 133 grade II tumors, 37 ganglioglioma grade I/II, and 36 others. Currently, 792 children are observed after diagnosis; 442 started nonsurgical treatment 0–150.6 months after diagnosis, with 353 receiving chemotherapy, and 82 radiotherapy (7 data awaited). Of 260 eligible patients, 220 were randomized. Current follow-up time is limited to median 16.8 months (range, 0.2–40.3 months). Conclusion: Compliance with patient recruitment, randomization, age stratification, and multidisciplinary strategy is high. The implementation of programs for quality assessment is feasible. Within this first large international LGG trial, the relevance of predefined indications for the start of nonsurgical treatment will be reexamined, especially the impact of visual impairment. Collection of follow-up data is critical to the trial's future success. LGG 22. STEREOTACTIC RADIOSURGERY FOR PILOCYTIC ASTROCYTOMAS Ajay Niranjan,1 Hideyuki Kano,2 Douglas Kondziolka,2 John Flickinger,2 Ian Pollack,1 Regina Jakacki,3 and L. Dade Lunsford2; 1University of Pittsburgh, Pittsburgh, PA, USA; 2PA, USA; 3Pittsburgh, PA, USA. Object: To assess tumor control, the risk of complications, and the variables that predict outcome in patients who underwent stereotactic radiosurgery for recurrent or unresectable juvenile pilocytic astrocytomas (JPAs) of the brain. Methods. Sixty-two patients (32 male and 29 females) with pilocytic astrocytomas had Gamma knife stereotactic radiosurgery at the University Pittsburgh between 1987 and 2006. The median patient age was 12.0 years (range, 2.0–52.4 years). Forty-six patients had prior surgical resection, while 16 were diagnosed by biopsy. Thirteen patients had received multimodal therapy prior to radiosurgery. The median radiosurgery target volume was 3.0 cc (range, 0.17–33.7 cc), and the median margin dose was 14 Gy (range, 10–22.5 Gy). Results: With mean follow-up of 50.6 months (range, 6.0–171.1 months), 5 patients had died, and 57 were alive. Overall survivals after stereotactic radiosurgery at 1, 5, 10 years were 96.4%, 90.0%, and 77.1%. Tumor control rates for solid tumors were 94.1% and 82.9% at 1 and 5 years. The control rate for tumors with cystic components was 82.2% at 1 year but fell to 15.2% at 5 years. Factors associated with a better progression-free survival included younger age and solid tumors. Conclusions: Stereotactic radiosurgery as a part of multimodal therapy for progressive, recurrent, or unresectable pilocytic astrocytomas provides safe and satisfactory clinical outcomes. Radiosurgery is especially effective in young patients with residual solid tumors. LGG 23. THALAMIC LOW-GRADE GLIOMA (LGG) IN CHILDREN: ANALYSIS OF PROGNOSTIC FACTORS. REPORT OF THE MULTICENTER TRIAL HIT-LGG 1996 Barbara Thieme,1 Stephan Von Hornstein,1 Torsten Pietsch,2 Monika Warmuth-Metz,3 Angela Emser,4 Susanne Berkefeld,4 Rolf-Dieter Kortmann,5 and Astrid Gnekow1; 1Children's Hospital, Augsburg, Germany; 2Department of Neuropathology, University of Bonn, Germany; 3Department of Neuroradiology, University of Wuerzburg, Germany; 4Department of Biostatistics, IMBEI, University of Mainz, Germany; 5Radiation Oncology, University of Leipzig, Germany. Introduction: Thalamic LGG in children are infrequent compared to other sites. It is subject of debate whether they follow a more unfavorable course and whether outcome can be predicted by clinical factors. Thus, large cohorts are needed to evaluate prognosis and to decide if a special treatment approach is necessary in the future. Objective: We analyzed the cohort of children with low-grade thalamic glioma included in the HIT-LGG 1996 trial between October 1, 1996, and March 31, 2004, for prognostic factors. Results: Forty-five children (22 female and 23 male) with a mean age of 6.94 ± 3.49 years (range, 0.58–13.94 years) at diagnosis were followed up for a mean of 5.60 ± 2.85 years (range, 0.51–9.68 years). One patient was diagnosed with neurofibromatosis type 1 (NF1), one with tuberous sclerosis; 39 tumors were unilateral, and 6 bithalamic. Extent of first surgery was 5 complete, 2 subtotal, 11 partial (1 after receiving CT), and 25 biopsy only. Histology included pilocytic astrocytoma (WHO grade I; PAI) in 27 (1 NF1), astrocytoma (WHO grade II; AII) in 11, oligodendroglioma (WHO grade II; OII) in 3, ganglioglioma (WHO grade I) in 1, and SEGA (WHO grade I) in one patient. Two patients did not undergo surgery. Primary nonsurgical therapy, indicated by severe initial symptoms or progression, was chemotherapy (CT) with vincristine/single-dose carboplatin in 11 and radiotherapy (RT) in 19 patients. Eight patients (five RT, three CT) received two or more nonsurgical therapies. Fifteen patients were observed only. Overall survival (OS) was 88.8 ± 4.7% at 5 years and at 8 years; five patients died (one by accident). OS differs from OS of patients with LGG of other tumor sites (HIT-LGG 1996 trial: OS 96.1 ± 0.7% at 5 years) (p = 0.038). Event-free survival (EFS: survival without start of nonsurgical therapy, tumor progression, or death) was 20.7 ± 6.3% at 5 years. Extent of primary surgery was the single predictive factor for EFS with 80.0 ± 17.9% (complete resection), 0% (partial/subtotal resection), and 14.4 ± 7.3% (biopsy only) at 5 years (p < 0.01). Progression-free survival (PFS: survival after start of nonsurgical therapy without progression) did not differ between the CT and RT groups, with 43.6 ± 15.5% at 3 and 5 years following CT and 63.5 ± 12.2% at 3 and 42.3 ± 14.7% at 5 years following RT (p = 0.561). For both groups, PFS was different regarding histologic subtype with 55.3 ± 12.1% (PAI), 71.4 ± 17.1% (AII), and 0% (OII) at 3 years (p < 0.01). No other clinical factor was relevant for PFS (age, gender, bithalamic or unilateral tumor, primary thalamic lesion, or tumor extension into thalamus). Conclusion: Children with histologically confirmed thalamic low-grade glioma represent a clinically distinct subgroup in respect to a low incidence in NF1 patients, a higher percentage of grade II gliomas, and worse overall survival compared to LGG of other tumor sites. However, the 5-year OS of 88.8% in our group is similar to comparable studies, but better than reported in non-histologically verified groups or cohorts mixed for histology and/or age. Since the most important predictive factor for EFS is extent of primary surgery, maximum feasible resection should be attempted, but additional neurologic deficit definitely be avoided. CT and RT according to the HIT-LGG 1996 trial prove to be equivalent in preventing further progression; thus, for young children, RT can be deferred effectively. Currently, we can recommend including children with thalamic lesions in the ongoing treatment strategies for low-grade glioma. LGG 24. TREATMENT OF INFANTS WITH PROGRESSIVE HYPOTHALAMIC GLIOMAS WITH “BABY POG” CHEMOTHERAPY Daniel Bowers,1 Yasmin M. El-Khashab,2 and Lynn Gargan2; 1University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA; 2Children's Medical Center, Dallas, TX, USA. Introduction: Although infants with hypothalamic gliomas are recognized as having a worse prognosis than other children with low-grade gliomas, there is not a standard therapy for pilomyxoid gliomas or for hypothalamic gliomas following tumor progression. Methods: A retrospective chart review of infants with pilomyxoid gliomas or progressive hypothalamic gliomas was performed to describe the progression-free survival following therapy with standard-dose POG 9233 (“baby POG”) chemotherapy, consisting of cyclophosphamide, vincristine, cisplatin, and etoposide. Results: Five patients were identified (100% males; median age at diagnosis, 2.3 years; range, 0.1–2.4 years). Median duration of follow-up for these patients is 4.8 years (range, 2.2–7.8 years). One patient with a pilomyxoid glioma who was initially treated with up-front baby POG has not progressed in 7.8 years after initial diagnosis. Four patients with pilocytic astrocytomas progressed rapidly after initial diagnosis and therapy with carboplatin and vincristine (median interval from diagnosis to initial progression, 0.3 years; range, 0.2–0.3 years). After initial progression, these patients were treated with baby POG chemotherapy. One of four patients remains without tumor progression 2.5 years after beginning baby POG chemotherapy; three of four patients have subsequently experienced tumor progression (median, 2.0 years; range, 1.5–2.1 years). One was subsequently treated with additional chemotherapy, and two with radiation therapy (45 Gy, 54 Gy). At time of most recent follow-up, all patients are alive. Conclusion: For infants with progressive hypothalamic gliomas, the baby POG chemotherapy regimen is one option for salvage therapy and may allow for omission or deferral of radiation therapy for several years. LGG 25. TWO CHILDREN WITH DISSEMINATED LOW-GRADE CNS TUMOR: PRESENTATION, DIAGNOSIS, TREATMENT, AND CLINICAL COURSE Astrid Sehested,1 Karsten Nysom,2 Aase Wagner,3 Lars Bøgeskov,4 John Hauerberg,4 Henning Laursen,5 and Helle Broholm5; 1Rigshospitalet, Copenhagen, Denmark; 2Paediatric Oncology, Rigshospitalet, Copenhagen, Denmark; 3Neuroradiology, Rigshospitalet, Copenhagen, Denmark; 4Neurosurgery, Rigshospitalet, Copenhagen, Denmark; 5Neuropathology, Rigshospitalet, Copenhagen, Denmark. Two patients with primary disseminated low-grade CNS tumors are presented. Both presented with hydrocephalus, spinal tumor, and diffuse leptomeningeal thickening with contrast enhancement on MRI. The first patient was treated for hydrocephalus with VP shunt with multiple shunt revisions for 2 years before the spine was investigated with MRI at the age of 4, disclosing a spinal tumor as well as evidence of widespread leptomeningeal disease. Tumor biopsy showed a rosetted glioneuronal tumor, WHO grade II. The second patient was diagnosed by MRI with both hydrocephalus and spinal tumor with leptomeningeal dissemination at the age of 12. She was treated with VP shunt and thereafter biopsied. Repeated biopsies of a pathologically thickened dura showed only fibrosis and nonspecific inflammatory/reactive changes. Extensive investigation for CNS infection, autoimmune disease, and sarcoidosis were all negative. MRI changes progressed concurrently with increasing neurological symptoms, including epilepsy. High-dose steroid treatment was without effect. The clinical diagnosis of disseminated low-grade glioma was made, and chemotherapy was started. Both patients were treated with chemotherapy (carboplatin, etoposide, and vincristine). In both patients, vincristine was changed to vinblastine due to progressive difficulty in walking with good effect. Both patients improved considerably clinically after the first 3 months of treatment, and MRI during treatment also showed regression of the leptomeningeal changes. The first patient was treated for 18 months and is now with stable disease as evaluated by MRI and continued clinical improvement 6 months after end of treatment. The second patient is still on treatment (14 months). Children presenting with hydrocephalus should be investigated with MRI with contrast, and imaging of the spine should be included. LGG 26. VINORELBINE IN LOW-GRADE GLIOMA: A CASE REPORT Andréa Cappellano,1 Nasjla Saba,1 Eric Bouffet,2 Sergio Cavalheiro,3 and Poliana Carmona1; 1Pediatric Oncology, IOP/GRAACC/Federal University of São Paulo, São Paulo, Brazil; 2Pediatric Oncology, Hospital for Sick Children, São Paulo, Brazil; 3Neurology and Neurosurgery, IOP/GRAACC/Federal University of São Paulo, São Paulo, Brazil. Introduction: Brainstem gliomas constitute 10%–20% of all pediatric CNS tumors, and diffusely infiltrative brainstem gliomas are the most common brainstem tumors associated with a poor prognosis. A small subset of these tumors are benign, showing low-grade features on histology. The role of chemotherapy in the management of these tumors is ill-defined. We report a successful experience of chemotherapy in a 4-month-old girl with a diffuse brainstem pilocytic astrocytoma, treated with vinorelbine, a vinca alkaloid that has shown significant activity against some human childhood high-grade glioma xenografts. Case Report: A 4-month-old girl admitted at IOP/GRAACC/UNIFESP presented with drooling and swallowing difficulties since birth associated with seventh nerve palsy. MRI revealed a diffuse and infiltrative brainstem tumor, hyperintense on fluid attenuated inversion recovery (FLAIR) sequence, and no enhancement after gadolinium administration, with focal area of necrosis and hydrocephalus. The patient underwent a ventriculoperitoneal shunt due to the presence of hydrocephalus and proceeded to surgery, with a partial resection of the tumor. The histological diagnosis of pilocytic astrocytoma was obtained. After the surgery, she remained dependant of noninvasive mechanical ventilation, and a tracheotomy was performed. Chemotherapy was administrated with vinorelbine (4 mg/day at days 0, 8, and 22), with a total of three cycles prior to a first evaluation. The therapy was well tolerated; the patient showed clinical response such as gain of weight, and she could be weaned off mechanical ventilation. The MRI at this point showed an excellent radiologic response, with a 75% decrease in tumor size. The patient is still in treatment at the moment for a total of 12 cycles. Conclusion: The role of chemotherapy in these neonatal low-grade gliomas of the brainstem is still unclear. There are anecdotal reports of spontaneous remission, but the natural history of these tumors does not support a wait-and-see approach. Our experience suggests that vinorelbine may be effective in pediatric low-grade gliomas, since this patient showed significant clinical improvement over a short period of time. A larger cooperative national study is currently ongoing to confirm the role of this agent in pediatric low-grade gliomas. LGG 27. VISION AND CLINICAL DATA: REPORT OF GERMAN PATIENTS WITH VISUAL PATHWAY GLIOMA IN THE CURRENT COOPERATIVE MULTICENTER STUDY FOR CHILDREN AND ADOLESCENTS WITH LOW-GRADE GLIOMA—SIOP-LGG 2004 Barbara Thieme,1 Stephan Von Hornstein,1 Heiko Goette,2 Rolf-Dieter Kortmann,3 and Astrid Gnekow1; 1Children's Hospital, Augsburg, Germany; 2Department of Biostatistics, IMBEI, University of Mainz, Germany; 3Radiation Oncology, University of Leipzig, Germany. Background: Children diagnosed with visual pathway glioma (VPG) often show deterioration of visual acuity or visual fields or appearance of nystagmus. They are at risk to experience further visual impairment. Since surgery faces the risk to induce an even greater visual deficit, nonsurgical therapies have been investigated, one of the aims being to stabilize or improve vision. Within the SIOP-LGG 2004 study, chemotherapy (CT) or radiotherapy (RT) is indicated when children present with severe ophthalmologic symptoms at diagnosis or progression during observation. Objective: Within the German subgroup, we investigated into the clinical data of children with VPG to assess factors determining visual acuity and to follow the changes summarizing visual acuity to three time points (start of therapy/diagnosis, during/after treatment, and follow-up, respectively). Results: The reported ophthalmologic findings of 113 German patients (56 NF1) with VPG (registered 01.04.2004 to 01.08.2007) were evaluated. At present 35 patients are being observed; 17 received RT and 61 CT as first-line therapy.
TI - Abstracts from the Thirteenth International Symposium on Pediatric Neuro-Oncology
JF - Neuro-Oncology
DO - 10.1215/15228517-2008-024
DA - 2008-06-01
UR - https://www.deepdyve.com/lp/oxford-university-press/abstracts-from-the-thirteenth-international-symposium-on-pediatric-whl6y8LnPh
SP - 369
EP - 517
VL - 10
IS - 3
DP - DeepDyve
ER -