Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage III gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In Asia, adjuvant chemotherapy after gastrectomy with D2 or more extensive lymph-node dissection is standard treatment for people with pathological stage III gastric or gastro-oesophageal junction (GEJ) cancer. We aimed to assess the efficacy and safety of adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy administered in this setting. METHODS: ATTRACTION-5 was a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial conducted at 96 hospitals in Japan, South Korea, Taiwan, and China. Eligible patients were aged between 20 years and 80 years with histologically confirmed pathological stage IIIA-C gastric or GEJ adenocarcinoma after gastrectomy with D2 or more extensive lymph-node dissection, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and available tumour tissue for PD-L1 expression analysis. Patients were randomly assigned (1:1) to receive either nivolumab plus chemotherapy or placebo plus chemotherapy via an interactive web-response system with block sizes of four. Investigational treatment, either nivolumab 360 mg or placebo, was administered intravenously for 30 min once every 3 weeks. Adjuvant chemotherapy was administered as either tegafur-gimeracil-oteracil (S-1) at an initial dose of 40 mg/m2 per dose orally twice per day for 28 consecutive days, followed by 14 days off per cycle, or capecitabine plus oxaliplatin consisting of an initial dose of intravenous oxaliplatin 130 mg/m2 for 2 h every 21 days and capecitabine 1000 mg/m2 per dose orally twice per day for 14 consecutive days, followed by 7 days off treatment. The primary endpoint was relapse-free survival by central assessment. The intention-to-treat population, consisting of all randomly assigned patients, was used for analysis of efficacy endpoints. The safety population, defined as patients who received at least one dose of trial drug, was used for analysis of safety endpoints. This trial is registered with ClinicalTrials.gov (NCT03006705) and is closed. FINDINGS: Between Feb 1, 2017, and Aug 15, 2019, 755 patients were randomly assigned to receive either adjuvant nivolumab plus chemotherapy (n=377) or adjuvant placebo plus chemotherapy (n=378). 267 (71%) of 377 patients in the nivolumab group and 263 (70%) of 378 patients in the placebo group were male; 110 (29%) of 377 patients in the nivolumab group and 115 (31%) of 378 patients in the placebo group were female. 745 patients received assigned treatment (371 in the nivolumab plus chemotherapy group; 374 in the placebo plus chemotherapy group), which was the safety population. Median time from first dose to data cutoff was 49·1 months (IQR 43·1-56·7). 3-year relapse-free survival was 68·4% (95% CI 63·0-73·2) in the nivolumab plus chemotherapy group and 65·3% (59·9-70·2) in the placebo plus chemotherapy group; the hazard ratio for relapse-free survival was 0·90 (95·72% CI 0·69-1·18; p=0·44). Treatment-related adverse events occurred in 366 (99%) of 371 patients in the nivolumab plus chemotherapy group and 364 (98%) of 374 patients in the placebo plus chemotherapy group. Discontinuation due to adverse events was more frequent in the nivolumab plus chemotherapy group (34 [9%] of 371 patients) than the placebo plus chemotherapy group (13 [4%] of 374 patients). The most common treatment-related adverse events were decreased appetite, nausea, diarrhoea, neutrophil count decreased, and peripheral sensory neuropathy. INTERPRETATION: The results of this trial do not support the addition of nivolumab to postoperative adjuvant therapy for patients with untreated, locally advanced, resectable gastric or GEJ cancer. FUNDING: Ono Pharmaceutical and Bristol Myers Squibb.

Five-year follow-up of a randomized clinical trial comparing bursectomy and omentectomy alone for resectable gastric cancer (JCOG1001).

BACKGROUND: Bursectomy, the total resection of the bursa omentalis, is a standard procedure in gastrectomy for resectable gastric cancer. A phase III trial (JCOG1001) comparing bursectomy and omentectomy alone was terminated early at the interim analysis. The final results of the updated analysis after a minimum follow-up of 5 years are reported here. METHODS: Patients with histologically proven adenocarcinoma of the stomach (cT3-T4a) were randomized (1 : 1) during surgery to bursectomy or omentectomy-alone groups and then underwent D2 gastrectomy. The primary endpoint was overall survival, analysed on an intention-to-treat basis. RESULTS: A total of 1204 patients (602 bursectomy and 602 omentectomy alone) were enrolled between June 2010 and March 2015. The bursectomy group had a significantly higher incidence of Clavien-Dindo grade III-IV intra-abdominal abscess than the omentectomy-alone group (5.5 versus 2.5 per cent respectively; P = 0.008). The updated 5-year overall survival rates were 74.9 (95 per cent c.i. 71.2 to 78.2) per cent in the bursectomy group and 76.5 (72.8 to 79.7) per cent in the omentectomy-alone group; the adjusted HR for death in the bursectomy group was 1.03 (95 per cent c.i. 0.83 to 1.27) (1-sided P = 0.598). Bursectomy did not decrease peritoneal recurrence (12.1 versus 12.3 per cent respectively; P = 1.000). In a multivariable analysis, old age (above 65 years), tumour located in the lower third or posterior wall of the stomach, macroscopic type 3/5, total gastrectomy, and cT4a were independent predictors of poor overall survival, but omentectomy alone was not. CONCLUSION: In D2 gastrectomy, bursectomy is not recommended as a standard procedure for cT3-T4a gastric cancer. Registration number: UMIN000003688 (https://www.umin.ac.jp/ctr/).

Impact of tumor-related factors and inter-institutional heterogeneity on preoperative T staging for gastric cancer.

Background: To improve the diagnostic accuracy of preoperative T staging in gastric cancer, the authors evaluated tumor-related factors that might affect the diagnosis. Materials & methods: The authors analyzed the data of cT2-4b gastric cancer patients enrolled in the prospective, multicenter JCOG1302A study. They used contrast-enhanced computed tomography to analyze the association between tumor-related factors and the diagnostic accuracy of T3-4b staging for gastric cancer. Results: Among 876 cT3-4b tumors, the diagnostic accuracy was relatively low in the lower third of the stomach compared with those in the upper or middle. A multivariable analysis revealed that accuracy was higher in the lesser curvature or entire circumference region than in other areas (p < 0.001), in macroscopic types 3/5 than in types 0/1/2 (p = 0.003) and in the undifferentiated histological type than in the differentiated type (p = 0.011). Conclusion: The authors found tumor-related factors affecting preoperative T staging by enhanced computed tomography.

Additional chemotherapy before surgery is expected to have potentially beneficial effects on prognosis compared with chemotherapy only after surgery for advanced gastric cancer. The consideration of chemotherapy before surgery depends on preoperative diagnosis of the depth of tumor invasion in the stomach wall. Overdiagnosis of the depth of tumor invasion may lead to unnecessary administration of chemotherapy that is harmful to the patient. Tumor-related factors such as tumor location, macroscopic type and histological type may affect the diagnosis. Therefore, these factors should be considered with special care for the diagnosis, which may lead to higher accuracy in diagnosing the depth of tumor invasion in gastric cancer.

Cisplatin Plus Capecitabine After Adjuvant S-1 in Metastatic Gastric Cancer: A Phase II T-CORE1102 Trial.

BACKGROUND/AIM: This phase II study assessed the efficacy of capecitabine plus cisplatin in patients with advanced gastric cancer refractory to adjuvant S-1. PATIENTS AND METHODS: This single-arm, open-label, multicenter, phase II study was conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE) in Japan. Patients aged ≥20 years with advanced HER2-negative gastric cancer that was refractory to S-1 were enrolled. Patients received 80 mg/m2 cisplatin on day 1 intravenously and 1,000 mg/m2 capecitabine twice daily from day 1 to day 14, in 3-week cycles. The primary endpoint was progression-free survival (PFS). The threshold overall response rate (ORR) was estimated to be 15%. The secondary endpoints were overall survival (OS), time to treatment failure, ORR, and toxicities. RESULTS: In total, 21 patients were enrolled from seven hospitals. The median patient age was 63 years. Nineteen patients received the protocol treatment. Median PFS was 3.7 months [90% confidence interval (CI)=2.7-5.6 months], which did not reach the predefined threshold of 4.0 months. ORR was 5.9% (95%CI=0.0-17.1%). Median OS was 11.9 months (95% CI 6.3-19.4 months). Febrile neutropenia was observed in 5.3% of patients. The most frequently observed grade 3 non-hematologic toxicities were nausea (15.8%) and hyponatremia (15.8%). CONCLUSION: The addition of a fluoropyrimidine to a platinum agent after adjuvant therapy is not suitable for gastric cancer.

Randomized phase II study of CPT-11 versus PTX versus each combination chemotherapy with S-1 for advanced gastric cancer that is refractory to S-1 or S-1 plus CDDP: OGSG0701.

BACKGROUND: To compare irinotecan-alone, paclitaxel-alone, and each combination chemotherapy with S-1 in patients with advanced gastric cancer (AGC) that is refractory to S-1 or S-1 plus cisplatin (SP). METHODS: Patients with AGC after first-line chemotherapy with S-1 or SP, or patients during adjuvant chemotherapy or within 26 weeks after adjuvant chemotherapy completion with S-1 with confirmed disease progression were eligible. Patients were randomly divided into four groups based on treatment: irinotecan-alone (irinotecan; 150 mg/m2, day 1, q14 days), paclitaxel-alone (paclitaxel; 80 mg/m2, days 1, 8, 15, q28 days), S-1 plus irinotecan (irinotecan; 80 mg/m2, days 1, 15, S-1; 80 mg/m2, days 1-21, q35 days), and S-1 plus paclitaxel (paclitaxel; 50 mg/m2, day1, 8, S-1; 80 mg/m2, days 1-14, q21 days). The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS), response rate, and safety. RESULTS: From July 2008 to March 2012, 127 patients were enrolled. No difference in median OS was observed in the irinotecan vs. paclitaxel groups or in the monotherapy groups vs. the S-1 combination therapy groups. Median PFS was longer in the paclitaxel group compared with the irinotecan group (4.1 vs. 3.6 months, p = 0.035), although no difference was observed when comparing monotherapy vs. S-1 combination. The most common grade 3 to 4 hematological adverse events were neutropenia with no difference in incidence rate across the treatment groups. CONCLUSIONS: There was no difference in OS between irinotecan and paclitaxel no in OS prolongation of S-1 combination therapy in second-line chemotherapy.

A Randomized Phase II Study to Evaluate Prolonged Prophylactic Antibacterial Drug Treatment for Patients with Elevated Drain Amylase Concentration After Gastrectomy with D2 Lymph Node Dissection (REDUCED2).

INTRODUCTION: After D2 gastrectomy for advanced gastric cancer, patients with a high drainage fluid amylase level (d-AMY) on the first postoperative day (1POD) have an especially high risk of severe abdominal infectious complications (AICs), which could be fatal. On the hypothesis that prolonged antibiotic administration could reduce the incidence of severe AICs, we conducted a randomized phase II study to evaluate the optimal treatment duration of prophylactic antibiotics for patients who underwent D2 gastrectomy and had elevated d-AMY on 1POD. METHODS: Patients whose d-AMY was >3000 IU/L on 1POD after D2 gastrectomy for gastric cancer were randomly assigned to normal prophylactic antibiotic treatment given only on the day of surgery (Group A) or to prolonged antibiotic treatment given for 1 week after surgery (Group B). The primary endpoint was the incidence of severe AICs (Clavien-Dindo grade IIIa or higher). This trial was registered as UMIN000012152. RESULTS: This study was started in December 2013 and stopped in February 2019 because of poor patient accrual. Finally, 35 and 37 patients were assigned to groups A and B, respectively. The incidences of AICs were 22.9% (eight of 35) in group A and 13.5% (five of 37) in group B. One-sided P value of the Fisher exact test was 0.234. No adverse reactions to antibiotic prophylaxis were observed in any of the patients. CONCLUSIONS: Prolonged prophylactic antibiotic administration had a marginal benefit in preventing grade III or higher AICs and caused no treatment-related morbidities.

Comparison of Postoperative Quality of Life among Three Different Reconstruction Methods After Proximal Gastrectomy: Insights From the PGSAS Study.

BACKGROUND: Proximal gastrectomy (PG) has become an increasingly preferred procedure for early cancer in the upper third of the stomach, owing to reportedly superior quality of life (QOL) after PG when compared with total gastrectomy. However, various methods of reconstruction have currently been proposed. We compared the postoperative QOL among the three different reconstruction methods after PG using the Postgastrectomy Syndrome Assessment Scale-45 (PGSAS-45) questionnaire. METHODS: Post Gastrectomy Syndrome Assessment Study (PGSAS), a nationwide multi-institutional survey, was conducted to evaluate QOL using the PGSAS-45 among various types of gastrectomy. Of the 2,368 eligible data from the PGSAS survey, data from 193 patients who underwent PG were retrieved and used in the current study. The PGSAS-45 consists of 45 items including 22 original gastrectomy specific items in addition to the SF-8 and GSRS. These were consolidated into 19 main outcome measures pertaining postgastrectomy symptoms, amount of food ingested, quality of ingestion, work, and level of satisfaction for daily work, and the three reconstruction methods (n = 193; 115 esophago-gastrostomy [PGEG], 34 jejunal interposition [PGJI], and 44 jejunal pouch interposition [PGJPI]) were compared using PGSAS-45. RESULTS: Size of the remnant stomach was significantly larger in PGEG, and significantly smaller in PGJI and PGJPI (P < 0.05). There was no difference in other patient background factors among the groups. EGJPI tended to be superior to PGEG in several of the 19 main outcome with marginal significance (P = 0.047-0.076). CONCLUSION: PGJPI appears to be the most favorable of the three reconstruction methods after PG especially when the size of remnant stomach is rather small. TRIAL REGISTRATION NUMBER: UMIN-CTR #000002116 entitled as "A study to observe correlation between resection and reconstruction procedures employed for gastric neoplasms and development of postgastrectomy syndrome".

Recurrence risk evaluation in T1N1M0/T2N0M0/T3N0M0 gastric cancer with TP53 codon 72 polymorphisms.

BACKGROUND: Postoperative adjuvant chemotherapy is not indicated for T1N1M0/T2N0M0/T3N0M0 gastric cancer. However, approximately 10% to 30% of these patients experience recurrence and metastasis. METHODS: Among 658 patients with gastric cancer who received gastrectomy with curative intent, 130 T1N1M0/T2N0M0 and 73 T3N0M0 patients were enrolled. Overall survival (OS) and relapse-free survival (RFS) were analyzed based on TP53 codon 72 polymorphisms Arg/Arg, Arg/Pro, and Pro/Pro. The hazard ratio (HR) for each subgroup was compared by TP53 codon 72 polymorphisms. RESULTS: Of the 189 patients for whom polymorphism analysis results were available, the 5- and 10-year OS was 84.9% and 65.1%, respectively. The 5- and 10-year RFS was 81.8% and 65.4%, respectively. When the study cohort was divided into two groups according to polymorphism status (ie, "Arg/Arg and Arg/Pro" vs Pro/Pro), both the OS (HR, 2.799; 95% confidence interval [CI], 1.071-7.315; P = .036) and RFS (HR, 2.639; 95% CI, 1.025-6.794; P = .044) of the Pro/Pro group were significantly lower than those for the Arg/Arg and Arg/Pro groups across the entire observation period. CONCLUSIONS: The TP53 codon 72 Pro/Pro polymorphism may isolate a relatively high-risk patient group in T1N1M0/T2N0M0/T3N0M0 gastric cancer.

An integrated analysis of two phase II trials (JCOG0001 and JCOG0405) of preoperative chemotherapy followed by D3 gastrectomy for gastric cancer with extensive lymph node metastasis.

BACKGROUND: Gastric cancer with extensive lymph node metastasis is commonly regarded as unresectable, while preoperative chemotherapy followed by gastrectomy has been tested since 2000 in JCOG (JCOG0001 and JCOG0405). The survivals were quite different between the trials despite the similar eligibility criteria. The aim of this study was to investigate if survival is still better in JCOG0405 after adjusting baseline factors and if there is any subset of patients who benefit more from either treatment. METHODS: Eligibility criteria for both trials included histologically proven gastric adenocarcinoma; bulky nodal involvement around the celiac artery and its major branches (bulky N) and/or para-aortic lymph node (PAN); cM0 (except PAN); negative lavage cytology; not linitis plastica type; PS of 0 or 1. Patients received two or three cycles of preoperative chemotherapy of irinotecan plus cisplatin in JCOG0001, or S-1 plus cisplatin in JCOG0405, followed by D3 gastrectomy. Multivariable analysis for overall survival adjusting baseline and treatment factors was performed with the Cox regression model. RESULTS: After adjusting baseline factors, S-1 plus cisplatin was superior to irinotecan plus cisplatin for overall survival (HR = 0.39: 95% CI 0.22-0.67). The 5-year overall survival was poor for patients with bulky N+/PAN+ (19.2%) compared with bulky N+/PAN- (50.7%) or bulky N-/PAN+ (43.5%). CONCLUSIONS: S-1 plus cisplatin was shown to be a favorable preoperative treatment for gastric cancer with extensive lymph node metastasis by multivariable analysis, while poor prognosis in patients having both bulky N+ and PAN+ may necessitate further treatment improvement.

Four courses versus eight courses of adjuvant S-1 for patients with stage II gastric cancer (JCOG1104 [OPAS-1]): an open-label, phase 3, non-inferiority, randomised trial.

BACKGROUND: Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to eight courses) is standard care for stage II gastric cancer. Whether the duration of S-1 could be shortened to 6 months (corresponding to four courses) without worsening survival is unclear. The aim of this study was to investigate the non-inferiority of four courses of S-1 compared with eight courses of S-1 for patients with stage II gastric cancer. METHODS: We did a phase 3, open-label, randomised controlled, non-inferiority trial at 59 hospitals in Japan. Patients aged 20-80 years with stage II adenocarcinoma of the stomach were randomly assigned (1:1) to eight courses or four courses of S-1. Randomisation was done by the Japan Clinical Oncology Group Data Center website, using a minimisation method with a random component using institution, stage (IIA vs IIB), age (<70 years vs ≥70 years), and mode of operation (open gastrectomy with bursectomy vs open gastrectomy without bursectomy vs laparoscopic gastrectomy) as adjustment factors. One course was 80 mg/day per m2 of S-1 administered for 4 weeks followed by a rest for 2 weeks. The primary endpoint was relapse-free survival, analysed by intention to treat, with a non-inferiority margin for the hazard ratio (HR) set at 1·37. This study is registered at UMIN-Clinical Trial Registry, number UMIN000007306. FINDINGS: Between Feb 16, 2012, and March 19, 2017, 590 patients were enrolled (295 per group). 528 (89%) patients were analysed at the first planned interim analysis in March, 2017, at which time the point estimate of HR for the four-course group compared with the eight-course group was 2·52 (95% CI 1·11-5·77), which exceeded 1·37 and met the prespecified criteria for early termination. Predictive probability for showing non-inferiority at the final analysis was calculated to be 2·9%. The study was stopped for futility. Updated 3-year relapse-free survival analysed in May, 2017, was 93·1% (95% CI 87·8-96·1) for the eight-course group and 89·8% (84·2-93·5) for the four-course group (HR 1·84, 95% CI 0·93-3·63). The most common grade 3-4 adverse event was neutropenia, observed in 46 (16%) patients in the eight-course group and 51 (17%) patients in the four-course group. INTERPRETATION: S-1 for 1 year should remain as standard adjuvant chemotherapy for stage II gastric cancer. FUNDING: Japan Agency for Medical Research and Development; the Ministry of Health, Labour and Welfare of Japan; the National Cancer Center Research and Development Fund, Japan.

Questionnaire survey on adjuvant chemotherapy for elderly patients after gastrectomy indicates their vulnelabilities.

BACKGROUND: In Japan, S-1 adjuvant chemotherapy for 1 year is the standard of care for the treatment of stage II and III patients under 80 years old with gastric cancer after curative operation. However, the feasibility of S-1 chemotherapy in patients over 80 years old has not yet been elucidated. METHODS: To clarify the current treatment situation and feasibility of S-1 treatment in patients over 80 years old, a questionnaire survey of the patients treated from January 2011 to December 2012 was conducted at 58 member institutions of the Stomach Cancer Study Group of the JCOG (Japan Clinical Oncology Group). RESULTS: Gastrectomy was performed in 15,573 patients of all ages, and 1,660 (10.7%) patients were over 80 years of age. Of these elderly patients, 661 (4.2%) were diagnosed as stage II and III. While S-1 adjuvant chemotherapy was recommended to 248 (37.5%) of the stageII/III patients, only 99 (15.0%) of them actually received S-1. Interestingly, the creatinine clearance rate was between 30 and 80 mL/min in 87 (87.9%) of the patients suggesting that S-1 dose modification should be considered. Moreover, S-1 compliance was poor in patients with more than 15% body weight loss. CONCLUSION: In general practice, surgery alone can be regarded as the standard of care for stage II and III gastric cancer patients over 80 years old. The feasibility and efficacy of S-1 adjuvant chemotherapy should be elucidated in a randomized control trial considering the vulnerabilities of the elderly.

Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated advanced gastric cancer: an exploratory analysis of the phase III ABSOLUTE trial.

BACKGROUND: In the ABSOLUTE trial, weekly nanoparticle albumin-bound paclitaxel (w-nab-PTX) showed non-inferiority to weekly solvent-based paclitaxel (w-sb-PTX) for overall survival (OS). Thus, w-nab-PTX might be an option for second-line chemotherapy in advanced gastric cancer (AGC). However, predictive factors for efficacies of these agents have not been evaluated. METHODS: Patients previously enrolled in the ABSOLUTE trial were divided into apparent peritoneal metastasis group (PM group) and no apparent peritoneal metastasis group (no PM group) based on baseline imaging evaluated by RECIST ver. 1.1 criteria and amount of ascites. OS, progression-free survival, and overall response rate were compared between two arms in each group. RESULTS: This study included 240 and 243 patients in the w-nab-PTX and w-sb-PTX arms, respectively. In the PM group, the w-nab-PTX arm (n = 88) had longer OS than the w-sb-PTX arm (n = 103), and median survival time (MST) of 9.9 and 8.7 months [hazard ratio (HR) 0.63; 95% CI 0.45-0.88; P = 0.0060], respectively. In the no PM group, the w-nab-PTX arm (n = 140) had shorter OS than the w-sb-PTX arm (n = 152), and MST of 11.6 and 15.7 months (HR 1.40; 95% CI 1.06-1.86; P = 0.0180), respectively. After adjusting for prognostic factors, the HR for OS in the w-nab-PTX arm versus the w-sb-PTX arm was 0.59 (95% CI 0.42-0.83; P = 0.0023; PM group) and 1.34 (95% CI 1.01-1.78; P = 0.0414; no PM group), with significant interaction between treatment efficacy and presence of peritoneal metastasis (P = 0.0003). CONCLUSIONS: The presence of apparent peritoneal metastasis might be a predictive factor for selecting w-nab-PTX for pretreated AGC patients. TRIAL REGISTRATION NUMBER: JapicCTI-132059.

[A Case of Sarcoidosis Associated with Esophageal Cancer].

A 67-year-old man was diagnosed with esophageal cancer. Computed tomography(CT)revealed multiple sites of bilateral mediastinal lymph node swelling. Serum levels of soluble interleukin-2 receptor(sIL-2R)were elevated; however, serum levels of angiotensin-converting enzyme(ACE)were normal. Thus, we could not confirm a diagnosis of sarcoidosis. Esophagectomy with neck lymph node dissection was performed. The resected specimen, comprising the mediastinal lymph nodes, showed noncaseating epithelioid cell granuloma; this supported the diagnosis of sarcoidosis. Cases of sarcoidosis associated with esophageal cancer are rare. It is difficult to distinguish between metastasis and sarcoid-like reactions from swollen lymph nodes using preoperative CT or positron emission tomography(PET). It is possible to differentiate lymph node metastasis from its sarcoid reaction it the patient received.

Bursectomy versus omentectomy alone for resectable gastric cancer (JCOG1001): a phase 3, open-label, randomised controlled trial.

BACKGROUND: The role of bursectomy, in which the peritoneal lining covering the pancreas and the anterior plane of the transverse mesocolon are dissected, has long been controversial for preventing peritoneal metastasis. We investigated the survival benefit of bursectomy in patients with resectable gastric cancer. METHODS: This phase 3, open-label, randomised controlled trial was done at 57 hospitals in Japan. Patients aged 20-80 years who had cT3(SS)-cT4a(SE) histologically proven gastric adenocarcinoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 and body-mass index less than 30 kg/m2 and who did not have distant metastasis or bulky lymph nodes were randomly assigned (1:1) during surgery to receive omentectomy alone (non-bursectomy) or bursectomy. Randomisation was done by telephone or website to the Japan Clinical Oncology Group Data Center and used a minimisation method with a random component to adjust for institution, cT status (T3 vs T4a), and type of gastrectomy (distal vs total). Both groups had total or distal gastrectomy with D2 lymphadenectomy. The primary endpoint was overall survival, analysed in the intention-to-treat population. The study is registered with UMIN-CTR, number UMIN000003688. FINDINGS: Between June 1, 2010, and March 30, 2015, 1503 patients were enrolled based on preoperative inclusion and exclusion criteria. Intraoperative inclusion and exclusion criteria were met in 1204 patients, of which 602 were allocated to the non-bursectomy group and 602 were allocated to the bursectomy group. At the planned second interim analysis on Sept 17, 2016, the JCOG Data and Safety Monitoring Committee independently reviewed the results and recommended their early publication on the basis of futility because overall survival was lower in the bursectomy group than the non-bursectomy group, and because the predictive probability of overall survival being significantly higher in bursectomy than non-bursectomy patients at the final analysis was only 12·7%. 5-year overall survival was 76·7% (95% CI 72·0-80·6) in the non-bursectomy group and 76·9% (72·6-80·7) in the bursectomy group (hazard ratio 1·05, 95% CI 0·81-1·37, one-sided p=0·65). 64 (11%) of 601 in the non-bursectomy group and 77 (13%) of 600 patients in the bursectomy group had grade 3-4 operative morbidity. Pancreatic fistula was significantly more common in the bursectomy group than in the non-bursectomy group (29 [5%] vs 15 [2%]; p=0·032). Six deaths occurred either in hospital or within 1 month of surgery: five in the non-bursectomy group and one in the bursectomy group. INTERPRETATION: Bursectomy did not provide a survival advantage over non-bursectomy. D2 dissection with omentectomy alone should be done as a standard surgery for resectable cT3-T4a gastric cancer. FUNDING: Japan Agency for Medical Research and Development, the Ministry of Health, Labour and Welfare of Japan, and the National Cancer Centre Research and Development Fund.

[Aortoesophageal Fistula with Infected Thoracic Aortic Aneurysm Rupture;Report of a Case].

A 67-year-old man was referred to our hospital because of fever and discomfort of the throat. Gastrointestinal endoscopy revealed hematoma at the middle thoracic esophagus. Computed tomography revealed posterior mediastinal hematoma extending the descending aorta. Bacillus was detected in the blood culture. Aortoesophageal fistula with an infected thoracic aortic aneurysm rupture was diagnosed. First, thoracic endovascular aortic repair (TEVAR) was performed. Resection of the thoracic esophagus and omentopexy was conducted 15 days after TEVAR. Esophageal reconstruction using a gastric tube was performed 43 days after esophagectomy. He has been doing well since then.

Helicobacter pylori infection is associated with favorable outcome in advanced gastric cancer patients treated with S-1 adjuvant chemotherapy.

BACKGROUND AND OBJECTIVES: Limited information exists regarding beneficial effects of Helicobacter pylori. To examine the effect in advanced gastric cancer, we compared survival for patients treated with surgery-only or adjuvant chemotherapy on the basis of H. pylori infection status. METHODS: A cohort of 491 patients who underwent R0 resection for locally advanced gastric cancer between 2000 and 2009 at 12 institutions in northern Japan was included. H. pylori infection status, was assessed from paraffin-embedded formalin-fixed samples. Overall survival (OS) and disease-free survival (DFS) in surgery-only (Surgery) and adjuvant chemotherapy (S-1) groups were analyzed. A propensity score matching was employed to correct for confounding factors by indication. RESULTS: H. pylori infection was positive in 175 patients and negative in 316 patients. H. pylori-positive patients showed significantly better survival than H. pylori-negative patients in both OS (hazard ratio [HR] 0.593, 95% confidence interval [CI] 0.417-0.843; P = 0.003]) and DFS (HR 0.679, 95%CI 0.492-0.937; P = 0.018). Propensity score matching further confirmed that S-1 was virtually only effective when tumors were H. pylori-positive. CONCLUSIONS: The favorable outcome of H. pylori-positive patients implies that the host immune system is modulated by H. pylori enhancing the chemotherapeutic efficacy.

A prospective multi-institutional validity study to evaluate the accuracy of clinical diagnosis of pathological stage III gastric cancer (JCOG1302A).

BACKGROUND: Neoadjuvant chemotherapy (NAC) followed by radical surgery is a promising strategy to improve survival of patients with stage III gastric cancer, but is associated with the risk of preoperative overdiagnosis by which patients with early disease may receive unnecessary intensive chemotherapy. METHODS: We assessed the validity of a preoperative diagnostic criterion in a prospective multicenter study. Patients with gastric cancer with a clinical diagnosis of T2/T3/T4, M0, except for diffuse large tumors and extensive bulky nodal disease, were eligible. Prospectively recorded clinical diagnoses (cT category, cN category) were compared with postoperative pathological diagnoses (pT category, pN category, and pathological stage). The primary endpoint was the proportion of pathological stage I tumors among those diagnosed as cT3/T4, which we expected to be 5% or less. RESULTS: Data from 1260 patients enrolled from 53 institutions were analyzed. The proportion of pathological stage I tumors in those with a diagnosis of cT3/T4 (primary endpoint) was 12.3%, which was much higher than the prespecified value. The positive predictive value and the sensitivity for pathological stage III tumors were 43.6% and 87.8% respectively. The sensitivity and specificity of contrast-enhanced CT for lymph node metastasis were 62.5% and 65.7% respectively. After exploring several diagnostic criteria, we propose, for future NAC trials in Japan, a diagnosis of "cT3/T4 with cN1/N2/N3," by which inclusion of pathological stage I tumors was reduced to 6.5%, although its sensitivity for pathological stage III tumors decreased to 64.5%. CONCLUSION: Clinical diagnosis of T3/T4 tumors was not an optimal criterion to select patients for intensive NAC trials because more than 10% of patients with pathological stage I disease were included. We propose the criterion "cT3/T4 and cN1/N2/N3" instead.

Randomized Controlled Trial to Evaluate Splenectomy in Total Gastrectomy for Proximal Gastric Carcinoma.

OBJECTIVE: To clarify the role of splenectomy in total gastrectomy for proximal gastric cancer. BACKGROUNDS: Splenectomy in total gastrectomy is associated with increased operative morbidity and mortality, but its survival benefit is unclear. Previous randomized controlled trials were underpowered and inconclusive. METHODS: We conducted a multiinstitutional randomized controlled trial. Proximal gastric adenocarcinoma of T2-4/N0-2/M0 not invading the greater curvature was eligible. During the operation, surgeons confirmed that R0 resection was possible with negative lavage cytology, and patients were randomly assigned to either splenectomy or spleen preservation. The primary endpoint was overall survival (OS) and the secondary endpoints were relapse-free survival, operative morbidity, operation time, and blood loss. The trial was designed to confirm noninferiority of spleen preservation to splenectomy in OS with a noninferiority margin of the hazard ratio as 1.21 and 1-sided alpha of 5%. RESULTS: Between June 2002 and March 2009, 505 patients (254 splenectomy, 251 spleen preservation) were enrolled from 36 institutions. Splenectomy was associated with higher morbidity and larger blood loss, but the operation time was similar. The 5-year survivals were 75.1% and 76.4% in the splenectomy and spleen preservation groups, respectively. The hazard ratio was 0.88 (90.7%, confidence interval 0.67-1.16) (<1.21); thus, the noninferiority of spleen preservation was confirmed (P = 0.025). CONCLUSIONS: In total gastrectomy for proximal gastric cancer that does not invade the greater curvature, splenectomy should be avoided as it increases operative morbidity without improving survival.

Short-term surgical outcomes from a phase III study of laparoscopy-assisted versus open distal gastrectomy with nodal dissection for clinical stage IA/IB gastric cancer: Japan Clinical Oncology Group Study JCOG0912.

BACKGROUNDS: No confirmatory randomized controlled trials (RCTs) have evaluated the efficacy of laparoscopy-assisted distal gastrectomy (LADG) compared with open distal gastrectomy (ODG). We performed an RCT to confirm that LADG is not inferior to ODG in efficacy. METHODS: We conducted a multi-institutional RCT. Eligibility criteria included histologically proven gastric adenocarcinoma in the middle or lower third of the stomach, clinical stage I tumor. Patients were preoperatively randomized to ODG or LADG. This study is now in the follow-up stage. The primary endpoint is relapse-free survival (RFS) and the primary analysis is planned in 2018. Here, we compared the surgical outcomes of the two groups. This trial was registered at the UMIN Clinical Trials Registry as UMIN000003319. RESULTS: Between March 2010 and November 2013, 921 patients (LADG 462, ODG 459) were enrolled from 33 institutions. Operative time was longer in LADG than in ODG (median 278 vs. 194 min, p < 0.001), while blood loss was smaller (median 38 vs. 115 ml, p < 0.001). There was no difference in the overall proportion with in-hospital grade 3-4 surgical complications (3.3 %: LADG, 3.7 %: ODG). The proportion of patients with elevated serum AST/ALT was higher in LADG than in ODG (16.4 vs. 5.3 %, p < 0.001). There was no operation-related death in either arm. CONCLUSIONS: This trial confirmed that LADG was as safe as ODG in terms of adverse events and short-term clinical outcomes. LADG may be an alternative procedure in clinical IA/IB gastric cancer if the noninferiority of LADG in terms of RFS is confirmed.

Factors that minimize postgastrectomy symptoms following pylorus-preserving gastrectomy: assessment using a newly developed scale (PGSAS-45).

BACKGROUND: Pylorus-preserving gastrectomy (PPG) is sometimes performed as a function-preserving surgery for the treatment of early gastric cancer. The aim of this study was to use an integrated assessment scale for postgastrectomy syndrome to determine the appropriate indicators and optimal methods for PPG. METHODS: The Postgastrectomy Syndrome Assessment Study (PGSAS) is a multicenter survey based on an integrated questionnaire (PGSAS-45) consisting of 45 items. Questionnaire responses were retrieved from a total of 2,520 patients, each of whom had undergone one of six different types of gastrectomy procedures; 313 responses from patients who had received PPG were analyzed here. RESULTS: The size of the proximal gastric remnant (less than one-quarter, about one-third, or more than one-half of the original size) significantly influenced the change in body weight, the scores for dissatisfaction at the meal, and dissatisfaction for daily life subscale (P = 0.030, P = 0.005, P = 0.034, respectively). The nausea score in patients who underwent hand-sewn anastomosis was significantly lower than in those who underwent anastomosis with a linear stapler (P = 0.006). The scores for diarrhea subscale, increased passage of stools, and sense of foods sticking differed significantly depending on the length of the preserved pyloric cuff (P = 0.047, P = 0.021, P = 0.046, respectively). CONCLUSIONS: The results suggest that preservation of a sufficient proximal gastric remnant is recommended when utilizing PPG as function-preserving surgery.