British Journal of Cancer

Lopez-Serra, L; Esteller, M

doi: 10.1038/sj.bjc.6604374pmid: 18542062

DNA methylation and the machinery involved in epigenetic regulation are key elements in the maintenance of cellular homeostasis. Epigenetic mechanisms are involved in embryonic development and the establishment of tissue-specific expression, X-chromosome inactivation and imprinting patterns, and maintenance of chromosome stability. The balance between all the enzymes and factors involved in DNA methylation and its interpretation by different groups of nuclear factors is crucial for normal cell behaviour. In cancer and other diseases, misregulation of epigenetic marks is a common feature, also including DNA methylation and histone post-translational modifications. In this scenario, it is worth mentioning a family of proteins characterized by the presence of a methyl-CpG-binding domain (MBDs) that are involved in interpreting the information encoded by DNA methylation and the recruitment of the enzymes responsible for establishing a silenced state of the chromatin. The generation of novel aberrantly hypermethylated regions during cancer development and progression makes MBD proteins interesting targets for their biological and clinical implications.

Le, N H; Franken, P; Fodde, R

doi: 10.1038/sj.bjc.6604401pmid: 18506144

Sporadic cases of colorectal cancer are primarily initiated by gene mutations in members of the canonical Wnt pathway, ultimately resulting in β-catenin stabilisation. Nevertheless, cells displaying nuclear β-catenin accumulation are nonrandomly distributed throughout the tumour mass and preferentially localise along the invasive front where parenchymal cells are in direct contact with the stromal microenvironment. Here, we discuss the putative role played by stromal cell types in regulating β-catenin intracellular accumulation in a paracrine fashion. As such, the tumour microenvironment is likely to maintain the cancer stem cell phenotype in a subset of cells, thus mediating invasion and metastasis.

van As, N J; Gilbert, D C; Money-Kyrle, J; Bloomfield, D; Beesley, S; Dearnaley, D P; Horwich, A; Huddart, R A

doi: 10.1038/sj.bjc.6604280pmid: 18542063

Testicular germ cell tumours (TGCTs) are the most common cause of cancer in men between the ages of 15 and 40 years, and, overall, the majority of patients should expect to be cured. The European Germ Cell Cancer Consensus Group has provided clear guidelines for the primary treatment of both seminoma and nonseminomatous germ cell tumours. There is, however, no international consensus on how best to follow patients after their initial management. This must promptly and reliably identify relapses without causing further harm. The standardising of follow-up would result in optimising risk-benefit ratios for individual patients, while ensuring economic use of resources. We have identified the seven common scenarios in managing seminomas and nonseminomas of the various stages and discuss the pertinent issues around relapse and follow-up. We review the available literature and present our comprehensive TGCT follow-up guidelines. Our protocols provide a pragmatic, easily accessible user-friendly basis for other centres to use or to adapt to suit their needs. Furthermore, this should enable future trials to address specific issues around follow-up giving meaningful and useful results.

Ream, E; Quennell, A; Fincham, L; Faithfull, S; Khoo, V; Wilson-Barnett, J; Richardson, A

doi: 10.1038/sj.bjc.6604406pmid: 18506142

Men with prostate cancer have various treatment options depending upon their stage of disease, age and presence of comorbidity. However, these treatments typically induce side effects, which generate currently ill-defined supportive care needs. This study examined the supportive care needs of men with prostate cancer within England. A postal questionnaire survey was conducted in six acute NHS Trusts. Seven hundred and forty-one men with prostate cancer participated. They had been diagnosed 3–24 months prior to the survey and had received various treatments. Men surveyed had specific and significant unmet supportive care needs. Areas of greatest need are related to psychological distress, sexuality-related issues and management of enduring lower urinary tract symptoms. High levels of psychological distress were reported, and those reporting psychological distress reported greater unmet supportive care needs. Unmet sexuality-related need was highest in younger men following radical prostatectomy. Lower urinary tract symptoms were almost universal in the sample. Perceived quality of life varied; men unsure of their remission status reported lowest quality of life. Psychological distress impacts significantly on perceived unmet need and is currently not being assessed or managed well in men living with prostate cancer in England.

Ferrandina, G; Petrillo, M; Carbone, A; Zannoni, G; Martinelli, E; Prisco, M; Pignata, S; Breda, E; Savarese, A; Scambia, G

doi: 10.1038/sj.bjc.6604410pmid: 18506140

To our knowledge, very few data about the role of Topoisomerase IIα (TOPO-IIα), an enzyme involved in critical steps of tumour cell proliferation and chemoresistance are currently available in ovarian cancer patients. The aim of this study was to investigate the prognostic value of TOPO-IIα expression in a large, single institution series of 96 primary untreated advanced ovarian cancer patients admitted to the Gynecologic Oncology Unit, Catholic University of Campobasso and Rome. Immunohistochemistry was carried out by using the MoAb anti-human TOPO-IIα antibody (clone Ki-S1). TOPO-IIα immunoreaction was observed in 70 out of 96 cases (72.9%), and the percentages of positively stained cells ranged between 1 and 83% (median=10%). There was no association with clinico-pathological parameters. During the follow up period, progression and death of disease were observed in 76 (79.2%) and 45 (46.9%) cases. A statistically significant direct association between the percentages of positively immunostained tumour cells and the relative risk of death was observed (χ 2=6.6, P-value=0.0101). In multivariate analysis, only platinum resistance, advanced stage of disease and high levels of TOPO-IIα expression retained an independent negative prognostic role for OS. The unfavourable role of high TOPO-IIα expression was maintained only in the subgroup of platinum resistant recurrent ovarian cancer patients, be TOPO-IIα expression evaluated as continuous variable (χ 2=5.1, P-value=0.024), or by means of the defined cutoff point. Our study suggests that the assessment of TOPO-IIα could be helpful to identify poor prognosis platinum-resistant ovarian cancer patients, potentially candidates to investigational agents.

Adamo, V; Lorusso, V; Rossello, R; Adamo, B; Ferraro, G; Lorusso, D; Condemi, G; Priolo, D; Di Lullo, L; Paglia, A; Pisconti, S; Scambia, G; Ferrandina, G

doi: 10.1038/sj.bjc.6604409pmid: 18493232

This multicentre phase II study was aimed at investigating the activity and safety of pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) as front-line therapy in a large series of chemotherapy-naïve recurrent/metastatic breast cancer patients. From June 2003 to December 2006, a total of 71 recurrent/metastatic breast cancer patients were enrolled. Median age was 63 years (range=37–79), and 31 patients (43.7%) were ⩾65 years old. Patients received PLD, 25 mg m−2, day 1, followed by GEM, 800 mg m−2, days 1 and 8, q21. Response was evaluable in 64 cases. Eight complete (12.5%) and 17 partial responses (26.6%) were registered, with an overall response rate of 39.1%. Thirty patients (46.9%) experienced stable disease, with an overall clinical benefit of 85.9%. Median time to progression (TTP) was 11 months, whereas median overall survival (OS) was not reached. The rate of 1- and 2-year OS was 79 and 61%, respectively. A total of 443 courses were evaluable for toxicity: grade 3 and 4 neutropaenia affected 14 patients (20.3%) and 3 patients (4.3%), respectively. Grade 3 and 4 palmar-plantar erythrodysesthesia syndrome was documented in five cases (7.2%) and one case (1.4%), whereas grade 3 and 4 mucositis occurred in six cases (8.7%) and two cases (2.9%), respectively. Grade 2 cardiac toxicity was observed in only one case. Interestingly enough, there was no difference in the percentage and severity of either haematological or non-haematological toxicity according to the age of the patients (<65 vs ⩾65 years). We confirmed in a large, very homogenous study sample of chemotherapy-naïve recurrent/metastatic breast cancer patients the efficacy and safety of PLD/GEM combination, providing response rates, median TTP and OS values comparable with those achieved with more toxic combinations.

Guggenheim, M; Dummer, R; Jung, F J; Mihic-Probst, D; Steinert, H; Rousson, V; French, L E; Giovanoli, P

doi: 10.1038/sj.bjc.6604407pmid: 18506141

Twenty per cent of sentinel lymph node (SLN)-positive melanoma patients have positive non-SLN lymph nodes in completion lymph node dissection (CLND). We investigated SLN tumour load, non-sentinel positivity and disease-free survival (DFS) to assess whether certain patients could be spared CLND. Sentinel lymph node biopsy was performed on 392 patients between 1999 and 2005. Median observation period was 38.8 months. Sentinel lymph node tumour load did not predict non-SLN positivity: 30.8% of patients with SLN macrometastases (⩾2 mm) and 16.4% with micrometastases (⩽2 mm) had non-SLN positivity (P=0.09). Tumour recurrences after positive SLNs were more than twice as frequent for SLN macrometastases (51.3%) than for micrometastases (24.6%) (P=0.005). For patients with SLN micrometastases, the DFS analysis was worse (P=0.003) when comparing those with positive non-SLNs (60% recurrences) to those without (17.6% recurrences). This difference did not translate into significant differences in DFS: patients with SLN micrometastasis, either with (P=0.022) or without additional positive non-SLNs (P<0.0001), fared worse than patients with tumour-free SLNs. The 2-mm cutoff for SLN tumour load accurately predicts differences in DFS. Non-SLN positivity in CLND, however, cannot be predicted. Therefore, contrary to other studies, no recommendations concerning discontinuation of CLND based on SLN tumour load can be deduced.

Swerdlow, A J; Schoemaker, M J; Higgins, C D; Wright, A F; Jacobs, P A

doi: 10.1038/sj.bjc.6604391pmid: 18506147

The finding of increased risks of specific cancers in individuals with constitutional deletions of chromosomes 11p and 13q led to the discovery of cancer predisposition genes at these locations, but there have been no systematic studies of cancer risks in patients with constitutional deletions, across the chromosome complement. Therefore, we assessed cancer incidence in comparison with national cancer incidence rates in a follow-up of 2561 patients with constitutional autosomal chromosome deletions diagnosed by microscopy or fluorescence in situ hybridisation in Britain during the period 1965–2002. Thirty cancers other than non-melanoma skin cancer occurred in the cohort (standardised incidence ratio (SIR)=2.4, 95% confidence interval (CI) 1.6–3.5). There were significantly increased risks of renal cancer in persons with 11p deletions (SIR=1869, 95% CI 751–3850; P=4 × 10−21), eye cancer with 13q deletions (SIR=1084, 95% CI 295–2775; P=2 × 10−11), and anogenital cancer with 11q deletions (SIR=305, 95% CI 63–890; P=3 × 10−7); all the three latter cancers were in the 11 subjects with 11q24 deletions. The results strongly suggest that in addition to suppressor genes relating to Wilms' tumour risk on 11p and retinoblastoma on 13q, there are suppressor genes around 11q24 that greatly affect anogenital cancer risk.

Mitchell, A J

doi: 10.1038/sj.bjc.6604396pmid: 18506146

The purpose of this study is to examine the value of one or two simple verbal questions in the detection of depression in cancer settings. This study is a systematic literature search of abstract and full text databases to January 2008. Key authors were contacted for unpublished studies. Seventeen analyses were found. Of these, 13 were conducted in late stage palliative settings. (1) Single depression question: across nine studies, the prevalence of depression was 16%. A single ‘depression’ question enabled the detection of depression in 160 out of 223 true cases, a sensitivity of 72%, and correctly reassured 964 out of 1166 non-depressed cancer sufferers, a specificity of 83%. The positive predictive value (PPV) was 44% and the negative predictive value (NPV) 94%. (2) Single interest question: there were only three studies examining the ‘loss-of-interest’ question, with a combined prevalence of 14%. This question allowed the detection of 60 out of 72 cases (sensitivity 83%) and excluded 394 from 459 non-depressed cases (specificity of 86%). The PPV was 48% and the NPV 97%. (3) Two questions (low mood and low interest): five studies examined two questions with a combined prevalence of 17%. The two-question combination facilitated a diagnosis of depression in 138 of 151 true cases (sensitivity 91%) and gave correct reassurance to 645 of 749 non-cases (specificity 86%). The PPV was 57% and the NPV 98%. Simple verbal methods perform well at excluding depression in the non-depressed but perform poorly at confirming depression. The ‘two question’ method is significantly more accurate than either single question but clinicians should not rely on these simple questions alone and should be prepared to assess the patient more thoroughly.

Lewison, G; Sullivan, R

doi: 10.1038/sj.bjc.6604405pmid: 18521087

There has been a substantially increased interest in biomedical research impact assessment over the past 5 years. This can be studied by a number of methods, but its influence on clinical guidelines must rank as one of the most important. In cancer, there are 43 UK guidelines (and associated Health Technology Assessments) published (up to October 2006) across three series, each of which has an evidence base in the form of references, many of which are papers in peer-reviewed journals. These have all been identified and analysed to determine their geographical provenance and type of research, in comparison with overall oncology research published in the peak years of guideline references (1999–2001). The UK papers were cited nearly three times as frequently as would have been expected from their presence in world oncology research (6.5%). Within the United Kingdom, Edinburgh and Glasgow stood out for their unexpectedly high contributions to the guidelines' scientific base. The cited papers from the United Kingdom acknowledged much more explicit funding from all sectors than did the UK cancer research papers at the same research level.