Ann Surg Oncol (2018) 25:1961–1969 https://doi.org/10.1245/s10434-018-6505-7 OR IG INA L A R TIC L E – BO NE AN D S OFT T IS SU E S A RCOM A S Clinicopathological Features and Prognosis of Primary GISTs with Tumor Rupture in the Real World 1,2,3 4,5 6 2,3 7 8 Toshirou Nishida , Haruhiko Cho , Seiichi Hirota , Toru Masuzawa , Gaku Chiguchi , Toshimasa Tsujinaka , and the Kinki GIST Study Group 1 2 Department of Surgery, National Cancer Center Hospital, Tokyo, Japan; Department of Surgery, Osaka Police Hospital, 3 4 Osaka, Japan; Department of Surgery, Kansai Rosai Hospital, Amagasaki, Japan; Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan; Department of Surgery, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, Tokyo, Japan; Department of Surgical Pathology, Hyogo College of Medicine, 7 8 Nishinomiya, Japan; Department of Gastroenterology, Yokohama Rosai Hospital, Yokohama, Japan; Department of Gastrointestinal Surgery, Kaizuka City Hospital, Kaizuka, Japan ABSTRACT Recurrence rates were higher and median recurrence-free Background. Patients with ruptured gastrointestinal stro- survival (RFS) and overall survival (OS) were shorter with mal tumor (GIST) are recommended for imatinib adjuvant ruptured than nonruptured GIST. Tumor rupture was one of therapy; however, their clinicopathological features and the independent prognostic factors for RFS, but not OS, prognosis in the era of imatinib are unknown. according to multivariate analysis. Patients and Methods. The study cohort included 665 Conclusions. Ruptured GISTs were symptomatic larger patients with histologically proven primary GISTs who tumors with high mitotic activity, frequent relapse, and underwent R0 or R1 surgery between 2003 and 2007; the shorter RFS. Tumor rupture was an independent prognostic validation cohort included 182 patients between 2000 and factor for RFS, but not for OS, in the era of imatinib. 2014. The deﬁnitions of tumor rupture in the study inclu- ded perforation at tumor site, tumor fracture, piecemeal Gastrointestinal stromal tumor (GIST) is a potentially resection including open biopsy, and macroscopic injuries to the pseudocapsule. malignant tumor and the most frequent sarcoma of the gastrointestinal tract. Currently, complete resection (R0) of Results. Tumor rupture occurred in 21 (3.2%) of 665 and 5 (2.9%) of 182 patients in the study and validation cohort, primary GIST offers the only potentially permanent cure for GIST patients. After complete resection, 60% of respectively. Ruptured GISTs were more symptomatic, patients with localized GISTs are cured, while the other were larger in size, and had higher mitotic count than 1–3 nonruptured GISTs but were not associated with tumor 40% experience disease recurrence during follow-up. Prognostic factors for recurrence after R0 surgery have location or laparoscopic surgery. GISTs with intraoperative rupture had clinicopathological features and prognostic been rigorously investigated, and four factors are recog- nized as independent prognostic factors: tumor size (cm), outcomes similar to those with preoperative rupture. mitosis (/50 HPF or/5 mm ), location (gastric versus non- 3–13 gastric), and rupture. Several risk stratiﬁcations have 4–8 been proposed based on these four factors. Among these four prognostic factors, tumor rupture is Electronic supplementary material The online version of this article (https://doi.org/10.1245/s10434-018-6505-7) contains the most ominous and is a subjective factor clinically supplementary material, which is available to authorized users. 3,10–12 judged by surgeons. Previous reports indicate that most ruptured GISTs are associated with recurrence during The Author(s) 2018. This article is an open access publication follow-up and that patients with ruptured GIST have sig- First Received: 8 February 2018; niﬁcantly shorter recurrence-free survival (RFS) than those 14–16 Published Online: 11 May 2018 without rupture. The deﬁnition of ruptured GIST, T. Nishida however, was not consistent among researchers until a e-mail: email@example.com 1962 T. Nishida et al. recent provisional deﬁnition was proposed. The term time of diagnosis and individuals whose date of surgery, ‘‘ruptured GIST’’ may include heterogeneous entities; age, gender, and/or outcomes were missing (Supplemen- hence, in some reports, rupture may include tumor pene- tary Fig. 1). This study was reviewed and approved by the tration into the peritoneum (T4a) and microscopic Steering Committee of the Kinki GIST Study Group and by pseudocapsule injuries. Incidence of rupture has been the institutional review board (IRB) of Osaka Police 3,7,10,12,16–18 reported to vary from 2 to 22%. Some reports Hospital and Kanagawa Cancer Center. have suggested that tumor rupture is an independent Tumor rupture was considered to be subjectively 3,5,10,12,16 prognostic factor, whereas others have determined by each surgeon at that time, so we conducted a 19,20 disagreed. retrospective survey of the concept of rupture by ques- Recent clinical trials show that patients at high risk of tionnaire. Questionnaire entries included perforation at the recurrence may beneﬁt from 3 years of adjuvant therapy tumor site, tumor fracture with blood-tinged ascites, with imatinib (Gleevec, Novartis Pharmaceuticals, Basel, piecemeal resection during surgery (including open 17,18 Switzerland) after R0 resection. It may be argued that biopsy), and macroscopic injuries to the pseudocapsule patients with ruptured GIST require prolonged adjuvant exposing tumor cells into the peritoneal cavity (Supple- therapy for longer than 3 years. Few studies have examined mentary Table 1). These were similar to the deﬁnitions of which tumors are more likely to rupture or which surgical rupture proposed by Holmebakk et al. Completeness of procedures, open or laparoscopic, may potentially increase surgical resection was assessed by local surgeons as fol- the risk of rupture. In this retrospective study, we ana- lows: R0, no detectable residual tumor; R1, microscopic lyzed real-world data obtained from two registry studies residual tumor; R2, macroscopic residual tumor. Patients conducted in Japan and clariﬁed the clinicopathological with R2 resection were excluded from the analysis. features and prognostic effects of rupture in the era of imatinib. Statistical Analysis Statistical analyses were performed using the Chi PATIENTS AND METHODS squared test, Fisher’s exact test, Student’s t test, and Mann– Study Design Whitney U test. RFS was calculated from date of surgery to date of ﬁrst tumor recurrence or date of death, excluding The study included both study and validation cohorts. living patients without recurrence at time of data collec- The former data were obtained from the GIST registry tion. Overall survival (OS) was calculated from date of study conducted by the Kinki GIST Study Group, and the surgery to date of any death, excluding living patients. RFS latter from the Kanagawa registry study. The GIST registry and OS were compared between the groups using the designed by the Kinki GIST Study Group was reported Kaplan–Meier life-table method with the log-rank test. Cumulative recurrence probability was estimated by previously. This retrospective observational study was designed to collect clinical and pathological data of cumulative incidence competing risk analysis as described previously. A forward stepwise Cox proportional hazards patients with pathologically proven GIST diagnosed in each participating hospital and treated between January model was used for multivariate analysis to identify risk 2003 and December 2007. Data on risk stratiﬁcations factors associated with RFS and OS. P values were two- classiﬁed according to the modiﬁed National Institutes of sided, and P values less than 0.05 were considered sig- Health (NIH) consensus criteria and the Armed Forces niﬁcant. Data were analyzed using the Statistical Package Institute of Pathology (AFIP) criteria were collected, in of IBM SPSS Statistics 25, version 25.0 (IBM Corp., addition to information regarding preoperative and intra- Armonk, NY, USA). operative ruptures. The Kanagawa registry study collected similar patient data retrospectively and prospectively since RESULTS January 2001 to December 2016 from the two hospitals in Kanagawa Prefecture. The hospitals participating in each In total, 665 patients with primary GIST who underwent registry are listed at the end of the manuscript. R0 or R1 surgery were included in the study cohort and 172 Using data obtained from the GIST registry database, patients in the validation cohort. The clinicopathological eligible patients were selected (Supplementary Fig. 1). features of the patients analyzed in the study and validation Eligibility criteria included tumor morphology compatible cohorts are presented in Table 1. The study cohort included with GIST, KIT positivity on immunohistochemistry, and 506 gastric, 119 small intestinal, 26 colorectal, 10 eso- macroscopically complete resection of the primary tumor. phageal, and 4 extra-gastrointestinal GISTs. The study We excluded patients with metastatic or recurrent GIST at sample included 339 males and 326 females with median Features of Ruptured GISTs in Clinical Practice 1963 TABLE 1 Patient Factor Study cohort (N = 665) Validation cohort (N = 172) characteristics Age (Median; years) 66.0 (18–93) 62.5 (17–89) Gender Male 339 (51.0%) 100 (58.1%) Female 326 (49.9%) 72 (41.9%) Cancer association Cancer history 113 (17.0%) 37 (21.5%) No cancer history 536 (80.6%) 135 (78.5%) Unavailable 16 (2.4%) 0 (0%) Location Esophagus 10 (1.5%) 2 (1.2%) b b b Stomach 506 (76.1%) 120 (69.4%) b b b Small intestine 119 (17.9%) 37 (21.5%) Colon and rectum 26 (3.9%) 14 (8.1%) Others 4 (0.6%) 0 (0%) Tumor size (median; cm) 4.0 (0.1–35) 5.0 (1.1–25) Mitosis (median;/50 HPF) 2.6 (0.0–250.0) 5.0 (0.0–250.0) Symptoms at diagnosis Yes 257 (38.6%) No 407 (61.2%) Unavailable 1 (0.2%) Neoadjuvant Yes 9 (1.3%) 15 (8.7%) No 648 (97.4%) 157 (91.3%) Unavailable 8 (1.3%) 0 (0%) Adjuvant Yes 37 (5.6%) 30 (17.4%) No 627 (94.3%) 142 (82.6%) Unavailable 1 (0.1%) 0 (0%) Surgery Open 459 (69.0%) 116 (67.4%) Laparoscopy 200 (30.1%) 51 (29.7%) Local 6 (0.9%) 5 (2.9%) Completeness of surgery R0 661 (99.4%) 162 (94.2%) R1 4 (0.6%) 10 (5.8%) Tumor rupture No 644 (96.8%) 167 (97.1%) Yes 21 (3.2%) 5 (2.9%) Preoperative 12 3 Intraoperative 9 2 Histological type Spindle 538 (80.9%) 83 (48.3%) Epithelioid 22 (3.3%) 2 (1.2%) Mixed 35 (5.3%) 7 (4.1%) Unavailable 70 (10.5%) 80 (46.4%) Recurrence No recurrence 570 (87.5%) 124 (72.1%) Recurrence 95 (12.5%) 47 (27.9%) Estimated 5-year RFS (median ? SE) 78.6 ? 1.8% 72.5 ? 3.9% Overall survival Alive 600 (90.2%) 151 (87.8%) Death 65 (9.8%) 21 (12.2%) Estimated 5-year OS (median ? SE) 91.5 ? 1.2% 92.2 ? 2.3% Median follow-up: 4.67 years for study cohort and 5.12 years for validation cohort RFS recurrence-free survival, OS overall survival, SE standard error Not available in validation cohort One duplicated patient with gastric and small intestinal GISTs in each cohort age of 66 years. Median tumor size was 4.0 cm, and the (N = 12) or intraoperatively (N = 9). In the validation median mitotic count was 2.6/50 HPF; 21 (3.2%) patients cohort, there were 120 gastric, 37 small intestinal, 14 were reported to have tumor rupture, either preoperatively colorectal, and 2 esophageal GISTs. Median age was 1964 T. Nishida et al. 62.5 years, with 100 male and 72 female patients in the nonrupture group (Supplementary Fig. 2). RFS of (Table 1). Median tumor size was 5.0 cm, the median patients with intraoperative ruptured GIST was not differ- mitotic count was 5.0/50 HPF, and only ﬁve patients ent from that of patients with preoperative rupture (Fig. 2; (2.9%) had tumor rupture, of whom three had preoperative P = 0.6709). In the study cohort, recurrence in patients and two intraoperative rupture. Most patients in both with ruptured GIST was more frequent in the peritoneum cohorts underwent R0 surgery, by either open or laparo- and local lesions compared with those in patients with scopic procedure. Nearly all patients received imatinib nonruptured GIST (Table 2). Median OS of patients with therapy after relapse. A small fraction of patients with ruptured GIST (6.4 years; 95% CI 5.5–7.3 years) was high-risk features received neoadjuvant (1.3 and 8.7%), signiﬁcantly shorter than that of those with nonruptured while a relatively larger number of patients received GIST in the study cohort (11.9 years; 95% CI adjuvant therapy (5.6 and 17.4%) in the study and valida- 10.7–13.0 years; P = 0.0218); this was not conﬁrmed in tion cohort, respectively. the validation cohort, likely because of the low statistical A questionnaire to participating surgeons indicated the power and higher rate of imatinib adjuvant therapy. following results (Supplementary Table 1): most surgeons Multivariate analyses using the Cox proportional haz- considered that tumor fracture and perforation, piecemeal ards model indicated that location, tumor size, mitotic resection, open biopsy, and macroscopic injuries to the count, and rupture were independent prognostic factors for pseudocapsule exposing tumor cells represented rupture; in RFS and that age, gender, and mitotic count were inde- contrast, they considered that core and needle biopsy pendent prognostic factors for OS in the study cohort without complications, luminal perforation of tumors, (Table 3). In the validation cohort, independent prognostic peritoneal tumor penetration, and microscopic injuries to factors for recurrence included tumor size, mitotic count, the pseudocapsule did not represent rupture. rupture, and use of adjuvant therapy, and those for OS were Tumor size was larger and mitotic count was higher in gender, tumor size, and mitotic count (Supplementary ruptured GISTs than in nonruptured tumors in the study Table 4). In the combined analysis of both cohorts, tumor cohort (Table 2). Patients with ruptured GIST were more size, mitotic count, location, rupture, and gender were symptomatic at admission, regardless of preoperative or independent prognostic factors for RFS, and age, gender, intraoperative rupture (Table 2, Supplementary Table 3). and mitotic count were independent prognostic factors for Among the nine patients who had neoadjuvant therapy, one OS. patient experienced tumor rupture during surgery. Inci- dence of rupture was not different between open and DISCUSSION laparoscopic surgery in either group. Location (gastric and nongastric) was not correlated with GIST rupture in either This study found that ruptured GIST was seen in nearly the study or validation cohort. There was no signiﬁcant 3% of primary GISTs, being more symptomatic and difference in terms of location, symptoms, tumor size, exhibiting aggressive features of larger size and higher mitotic count, or recurrence between preoperative and mitotic count compared with nonruptured tumors. The intraoperative rupture (Supplementary Table 2). reported frequency of tumor rupture varies depending on During median follow-up of 4.67 years, there were 95 the study; population-based studies indicated that it was 7 10 3 11 (12.5%) relapses and 65 (9.8%) deaths in the study cohort, less than 10% (1%, 4.0%, 5.9%, and 7.1% ), while in compared with 47 (27.9%) recurrences and 21 (12.2%) clinical trials, it was higher than 10% (20% of high-risk 17 18 deaths in the validation cohort with median follow-up of GISTs, 11% of intermediate- and high-risk GISTs, and 5.12 years. Recurrence was more frequent for patients with 17% ). The true incidence of tumor rupture is speculated ruptured GISTs than those without rupture in both cohorts to be several percent in clinical practice. Ruptured GISTs (Table 2, Supplementary Table 4). Median RFS of patients were shown to be more symptomatic with high-risk fea- with ruptured GIST [2.4 years; 95% conﬁdence interval tures, including larger tumor size and higher mitotic count, (CI) 1.4–3.4 years in the study cohort; P \ 0.0001, and and were treated by emergency surgery in previous, as well 11,14,15 3.2 years in the validation cohort; 95% CI 1.3–5.8 years; as present, studies. P = 0.0392] was signiﬁcantly shorter than that of patients Tumor rupture occurred both before and during surgery. with nonruptured GIST (8.4 years; 95% CI 8.0–8.8 years, The frequency of preoperative and intraoperative rupture 17,24 and 8.4 years; 95% CI 7.4–9.3 years) in the study and was similar in this registry study. Clinicopathological validation cohort, respectively (Fig. 1). Cumulative inci- features and prognostic outcomes of GISTs with preoper- dence analysis of the study cohort indicated that all events ative rupture were similar to those with intraoperative were recurrence of GIST in the rupture group, whereas rupture, although the sample size was small (Table 2, one-third of events were recurrence of GIST, and deaths Supplementary Table 3). The laparoscopic approach was due to other diseases might account for the other two-thirds Features of Ruptured GISTs in Clinical Practice 1965 TABLE 2 Background of GIST patients with and without tumor rupture (study cohort) Nonruptured (N = 644) Ruptured (N = 21) P value Age (years) 66 (18–93) 68 (55–90) 0.2236 Gender Male 326 (50.6%) 13 (61.9%) 0.3087 Female 318 (49.4%) 8 (38.1%) Primary location Gastric 493 (76.6%) 13 (61.9%) 0.1215 Nongastric 151 (23.4%) 8 (38.1%) Association of cancer No 518 (80.4%) 18 (85.7%) 0.7098 Yes 110 (17.1%) 3 (14.3%) Unavailable 16 (2.5%) 0 (0%) Median tumor size (cm) 4.0 (0.1–35.0) 9.6 (2.6–30.0) 0.0008 Symptoms No 406 (63.0%) 1 (4.7%) \ 0.0001 Yes 237 (36.8%) 20 (95.2%) Unavailable 1 (0.2%) 0 (0%) Neoadjuvant No 629 (97.7%) 19 (90.5%) 0.1561 Yes 8 (1.2%) 1 (5%) Unavailable 7 (1.1%) 1 (5%) Adjuvant therapy No 613 (95.2%) 14 (66.7%) \ 0.0001 Yes 30 (4.7%) 7 (23.3%) Unavailable 1 (0.1%) 0 (0%) Surgery Open 441 (68.5%) 18 (85.7%) 0.2383 Laparoscopic 197 (30.6%) 3 (14.3%) Local 6 (0.9%) 0 (0%) R R0 642 (99.7%) 19 (90.5%) \ 0.0001 R1 2 (0.3%) 2 (9.5%) Median mitosis (/50 HPF) 2.5 (0.0–250) 13.0 (0.0–115) 0.0004 Cell type Spindle 518 (80.4%) 20 (95.2%) 0.3347 Epithelioid 22 (3.4%) 0 (0%) Mixed 35 (5.4%) 0 (0%) Unavailable 69 (10.7%) 1 (4.8%) Median RFS (95% CI; years) 8.4 (8.0–8.9) 2.4 (1.4–3.4) \ 0.0001 Estimated 5-year RFS (median ? SE) 80.7 ? 1.7% 16.4 ? 8.6% Recurrence No 565 (87.7%) 5 (23.8%) \ 0.0001 Yes 79 (12.3%) 16 (76.2%) a b b Recurrence site Liver 53 (67.1%) 6 (37.5%) 0.0108 b b Lung 2 (2.5%) 0 (0%) b b Local 8 (10.1%) 4 (25%) b b Peritoneum 24 (30.4%) 14 (87.5%) Median OS (95% CI; years) 11.9 (10.7–13.0) 6.4 (5.6–7.3) 0.0218 Estimated 5-year OS (median ? SE) 88.9 ? 7.4% 91.6 ? 1.2% Overall survival Alive 584 (90.7%) 16 (76.2%) 0.0452 Dead 60 (9.3%) 5 (23.8%) c c Death due to GIST 21 (35%) 5 (100%) c c Death due to other diseases 39 (65%) 0 (0%) RFS recurrence-free survival, OS overall survival, SE standard error, CI conﬁdence interval Duplicated number % of total recurrence in each group % of total death in each group 1966 T. Nishida et al. Recurrence-free Survival Overall Survival A B Non-ruptured (N=643; estimated RFS=8.4 yrs) Non-ruptured (N=643; estimated OS=11.9 yrs) P<0.0001 P=0.0218 Ruptured Ruptured (N=21; estimated median OS=6.4 yrs) (N=21; estimated median RFS=2.4 yrs) 02468 02468 Years after surgery (years) Years 0 2 4 6 8 0 2 4 6 8 Non- 644 499 377 138 31 644 536 422 163 41 ruptured Ruptured 21 7 4 1 0 21 18 16 3 0 Recurrence-free Survival Overall Survival C D Non-ruptured (estimated median RFS=8.3 yrs) P=0.4305 P=0.0392 Non-ruptured (estimated median OS: not reached) Ruptured (estimated median OS: not Ruptured reached) (estimated median RFS=3.2 yrs) 02 4 6 8 10 0 2 4 68 10 Years after surgery (years) 0 2 4 6 8 10 Years 0 2 4 6 8 10 Non-ruptured 167 122 76 38 21 9 167 146 103 64 41 25 5 3 3 2 0 0 Ruptured 5 2 1 1 0 0 FIG. 1 Recurrence-free (a, c) and overall survival (b, d) after surgery for patients with or without tumor rupture in the study (a, b) and validation cohort (c, d) not considered to increase incidence of rupture, nor did Tumor rupture was an independent prognostic factor for neoadjuvant therapy in this study (Table 2, Supplementary both RFS and OS before imatinib. We showed that rup- Table 3). Taken together, rupture might occur in GISTs ture remains an important prognostic factor of RFS, but not with high-risk features regardless of rupture timing; intra- OS, in the era of imatinib. This is likely due to the activity operative rupture might not be due to surgical techniques of imatinib, sunitinib, and/or regorafenib used following but rather due to tumor factors, such as fragility, size, and/ recurrence. In fact, most patients received imatinib and or adhesion to adjacent organs. subsequently sunitinib after recurrence, although patients Tumor rupture may result in peritoneal seeding of tumor receiving adjuvant therapy represented a small fraction. All cells, hence surgery may be considered R1 even if guidelines suggest that patients with high-risk GISTs achieving macroscopic complete resection. This study, should have adjuvant therapy, but only 7 of 21 patients however, revealed that some surgeons considered such (33%) with ruptured GIST received adjuvant therapy in surgery to be R0 after macroscopic complete resection this study. This low rate of adjuvant therapy reﬂects the during the study period (Table 2, Supplementary Table 3). historical background of the registries. Taken together, Survival Rate (%) Survival Rate (%) Features of Ruptured GISTs in Clinical Practice 1967 was viewed as tumor rupture in this study. In our deﬁnition 1.0 of tumor rupture, there was no prognostic difference between preoperative and intraoperative rupture, suggest- P=0.6709 0.8 ing that our deﬁnition might be acceptable. There are some limitations to consider. The study is Preoperative Rupture 0.6 (N=15; estimated median RFS=2.7 yrs) retrospective, and the number of patients was limited, especially in the events of recurrence and death; however, 0.4 it is based on two multi-institutional registry studies. The use of two different cohorts may help to check repro- 0.2 ducibility to conﬁrm the obtained results. The median Intra-operative Rupture (N=11; follow-up of the registry studies was 4.7 and 5.1 years for estimated median RFS=2.4yrs) 0.0 the study and validation cohort, respectively, which may be 0 24 68 insufﬁcient to evaluate OS in the era of imatinib, although Years after surgery (years) it may be long enough to determine RFS. Historically, imatinib has been the standard therapy for recurrent dis- Years 0 2 4 6 8 Preoperative 15 5 3 1 0 eases. However, adjuvant therapy was not used sufﬁciently; Operative 11 5 2 1 0 thus, adjuvant imatinib was not an independent prognostic factor as previously suggested. Finally, the deﬁnition of FIG. 2 Recurrence-free survival in patients with pre- or tumor rupture was subjective among surgeons; however, as intraoperative rupture in the study cohort; there is no signiﬁcant mentioned above, participating investigators shared similar difference between them views regarding tumor rupture, indicating that this multi- institutional study is valid. tumor rupture is an independent prognostic factor of recurrence, but not OS, after complete resection in the era This study focused on ruptured GISTs. Tumor rupture may be deﬁned by tumor fracture and perforation at the of imatinib. The deﬁnition of tumor rupture was subjectively deter- tumor site, piecemeal resection, open biopsy, and macro- scopic injuries to the pseudocapsule, whereas core and mined and was not yet agreed upon when patients registered in this study underwent surgery. However, the needle biopsy without complications, luminal perforation of tumors, microscopic peritoneal breaks on tumors, or survey showed that the results appeared to be similar to the deﬁnition of tumor rupture recently proposed by Holme- microscopic breaks of the pseudocapsule on pathological bakk et al. There are some differences; half of surgeons examination are not considered to be tumor rupture. By this did not consider microscopic inﬁltration into neighboring deﬁnition, GISTs with tumor rupture were seen in several structures as tumor rupture when they performed en bloc percent of GISTs in clinical practice, showed aggressive features of larger size and higher mitotic count regardless resection, while macroscopic injury to the pseudocapsule TABLE 3 Multivariate Independent prognostic factor HR (95% CI) P value analysis for RFS and OS (study cohort) Recurrence-free survival (study cohort): Location (Ref: gastric) 1.637 (1.339–2.002) 0.0140 Size (cm) 1.070 (1.055–1.085) \ 0.0001 Mitotic count (/50 HPF) 1.012 (1.010–1.014) \ 0.0001 Rupture (Ref: nonrupture) 4.545 (3.307–6.234) \ 0.0001 Overall survival (study cohort): Age (years) 1.033 (1.018–1.047) 0.0168 Gender (Ref: female) 2.347 (1.738–3.168) 0.0045 Mitotic count (/50 HPF) 1.014 (1.011–1.017) \ 0.0001 Other factors included in the analysis for RFS using a forward stepwise Cox proportional hazards model were age (P = 0.157), gender (P = 0.086), symptoms (P = 0.551), association of NF1 (P = 0.733), neoadjuvant therapy (P = 0.454), adjuvant therapy (P = 0.453), histology (P = 0.177), and R (complete- ness of surgery) (P = 0.887) Other factors included in the analysis for OS were rupture (P = 0.251), tumor location (P = 0.743), symptoms (P = 0.475), association of NF1 (P = 0.311), neoadjuvant therapy (P = 0.821), adjuvant therapy (P = 0.637), histology (P = 0.696), and R (completeness of surgery) (P = 0.763) Survival Rate (%) 1968 T. 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Annals of Surgical Oncology – Springer Journals
Published: May 11, 2018
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