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Background: Nonresectable gastric cancer develops rapidly; thus, monitoring disease progression especially in patients receiving nivolumab as late-line therapy is important. Biomarkers may facilitate the evaluation of nivolumab treatment response. Herein, we assessed the utility of serum-based inflammatory indicators for evaluating tumor response to nivolumab., Methods: This multicenter retrospective cohort study included 111 patients treated with nivolumab monotherapy for nonresectable advanced or recurrent gastric cancer from October 2017 to October 2021. We measured changes in the C-reactive protein (CRP)-to-albumin ratio (CAR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) in serum from baseline to after the fourth administration of nivolumab. Furthermore, we calculated the area under the receiver operating characteristic curves (AUC ROCs) for CAR, PLR, and NLR to identify the optimal cutoff values for treatment response. We also investigated the relationship between clinicopathologic factors and disease control (complete response, partial response, and stable disease) using the chi-squared test., Results: The overall response rate (complete and partial response) was 11.7%, and the disease control rate was 44.1%. The median overall survival (OS) was 14.0 (95% CI 10.7‒19.2) months, and the median progression-free survival (PFS) was 4.1 (95% CI 3.0‒5.9) months. The AUC ROCs for CAR, PLR, and NLR before nivolumab monotherapy for patients with progressive disease (PD) were 0.574 (95% CI, 0.461‒0.687), 0.528 (95% CI, 0.418‒0.637), and 0.511 (95% CI, 0.401‒0.620), respectively. The values for changes in CAR, PLR, and NLR were 0.766 (95% CI, 0.666‒0.865), 0.707 (95% CI, 0.607‒0.807), and 0.660 (95% CI 0.556‒0.765), respectively. The cutoff values for the treatment response were 3.0, 1.3, and 1.4 for CAR, PLR, and NLR, respectively. The PFS and OS were significantly longer when the treatment response values for changes in CAR, PLR, and NLR were below these cutoff values (CAR: OS, p < 0.0001 and PFS, p < 0.0001; PLR: OS, p = 0.0289 and PFS, p = 0.0302; and NLR: OS, p = 0.0077 and PFS, p = 0.0044)., Conclusions: Measurement of the changes in CAR, PLR, and NLR could provide a simple, prompt, noninvasive method to evaluate response to nivolumab monotherapy., Trial Registration: This study is registered with number K2023006., (© 2024. The Author(s).)

Competing Interests: The authors declare that they have no conflict of interest.

Background: The family history of gastric cancer holds important implications for cancer surveillance and prevention, yet existing evidence predominantly comes from case-control studies. We aimed to investigate the association between family history of gastric cancer and gastric cancer risk overall and by various subtypes in Asians in a prospective study., Methods: We included 12 prospective cohorts with 550,508 participants in the Asia Cohort Consortium. Cox proportional hazard regression was used to estimate study-specific adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between family history of gastric cancer and gastric cancer incidence and mortality, then pooled using random-effects meta-analyses. Stratified analyses were performed for the anatomical subsites and histological subtypes., Results: During the mean follow-up of 15.6 years, 2258 incident gastric cancers and 5194 gastric cancer deaths occurred. The risk of incident gastric cancer was higher in individuals with a family history of gastric cancer (HR 1.44, 95% CI 1.32-1.58), similarly in males (1.44, 1.31-1.59) and females (1.45, 1.23-1.70). Family history of gastric cancer was associated with both cardia (HR 1.26, 95% CI 1.00-1.60) and non-cardia subsites (1.49, 1.35-1.65), and with intestinal- (1.48, 1.30-1.70) and diffuse-type (1.59, 1.35-1.87) gastric cancer incidence. Positive associations were also found for gastric cancer mortality (HR 1.30, 95% CI 1.19-1.41)., Conclusions: In this largest prospective study to date on family history and gastric cancer, a familial background of gastric cancer increased the risk of gastric cancer in the Asian population. Targeted education, screening, and intervention in these high-risk groups may reduce the burden of gastric cancer., (© 2024. The Author(s).)

Background: Evidence suggests a possible link between diabetes and gastric cancer risk, but the findings remain inconclusive, with limited studies in the Asian population. We aimed to assess the impact of diabetes and diabetes duration on the development of gastric cancer overall, by anatomical and histological subtypes., Methods: A pooled analysis was conducted using 12 prospective studies included in the Asia Cohort Consortium. Among 558 981 participants (median age 52), after a median follow-up of 14.9 years and 10.5 years, 8556 incident primary gastric cancers and 8058 gastric cancer deaths occurred, respectively. Cox proportional hazard regression models were used to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) and pooled using random-effects meta-analyses., Results: Diabetes was associated with an increased incidence of overall gastric cancer (HR 1.15, 95% CI 1.06-1.25). The risk association did not differ significantly by sex (women vs men: HR 1.31, 95% CI 1.07-1.60 vs 1.12, 1.01-1.23), anatomical subsites (noncardia vs cardia: 1.14, 1.02-1.28 vs 1.17, 0.77-1.78) and histological subtypes (intestinal vs diffuse: 1.22, 1.02-1.46 vs 1.00, 0.62-1.61). Gastric cancer risk increased significantly during the first decade following diabetes diagnosis (HR 4.70, 95% CI 3.77-5.86), and decreased with time (nonlinear p < .01). Positive associations between diabetes and gastric cancer mortality were observed (HR 1.15, 95% CI 1.03-1.28) but attenuated after a 2-year time lag., Conclusion: Diabetes was associated with an increased gastric cancer incidence regardless of sex, anatomical subsite, or subtypes of gastric cancer. The risk of gastric cancer was particularly high during the first decade following diabetes diagnosis., (© 2024 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Cancer cachexia is a complex metabolic disorder accounting for ~20% of cancer-related deaths, yet its metabolic landscape remains unexplored. Here, we report a decrease in B vitamin-related liver enzymes as a hallmark of systemic metabolic changes occurring in cancer cachexia. Metabolomics of multiple mouse models highlights cachexia-associated reductions of niacin, vitamin B6, and a glycine-related subset of one-carbon (C1) metabolites in the liver. Integration of proteomics and metabolomics reveals that liver enzymes related to niacin, vitamin B6, and glycine-related C1 enzymes dependent on B vitamins decrease linearly with their associated metabolites, likely reflecting stoichiometric cofactor-enzyme interactions. The decrease of B vitamin-related enzymes is also found to depend on protein abundance and cofactor subtype. These metabolic/proteomic changes and decreased protein malonylation, another cachexia feature identified by protein post-translational modification analysis, are reflected in blood samples from mouse models and gastric cancer patients with cachexia, underscoring the clinical relevance of our findings., (© 2023. Springer Nature Limited.)

The effect of body mass index (BMI) on esophageal and gastric carcinogenesis might be heterogeneous, depending on subtype or subsite. However, findings from prospective evaluations of BMI associated with these cancers among Asian populations have been inconsistent and limited, especially for esophageal adenocarcinoma and gastric cardia cancer. We performed a pooled analysis of 10 population-based cohort studies to examine this association in 394,247 Japanese individuals. We used Cox proportional hazards regression to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs), then pooled these estimates to calculate summary HRs with a random effects model. During 5,750,107 person-years of follow-up, 1569 esophageal cancer (1038 squamous cell carcinoma and 86 adenocarcinoma) and 11,095 gastric (728 cardia and 5620 noncardia) cancer incident cases were identified. An inverse association was observed between BMI and esophageal squamous cell carcinoma (HR per 5-kg/m 2 increase 0.57, 95% CI 0.50-0.65), whereas a positive association was seen in gastric cardia cancer (HR 1.15, 95% CI 1.00-1.32). A nonsignificant and significant positive association for overweight or obese (BMI ≥25 kg/m 2 ) relative to BMI <25 kg/m 2 was observed with esophageal adenocarcinoma (HR 1.32, 95% CI 0.80-2.17) and gastric cardia cancer (HR 1.24, 95% CI 1.05-1.46), respectively. No clear association with BMI was found for gastric noncardia cancer. This prospective study-the largest in an Asian country-provides a comprehensive quantitative estimate of the association of BMI with upper gastrointestinal cancer and confirms the subtype- or subsite-specific carcinogenic impact of BMI in a Japanese population., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Despite growing evidence of the effectiveness of minimally invasive surgery (MIS) for primary gastric cancer, MIS for remnant gastric cancer (RGC) remains controversial due to the rarity of the disease. This study aimed to evaluate the surgical and oncological outcomes of MIS for radical resection of RGC., Patients and Methods: Patients with RGC who underwent surgery between 2005 and 2020 at 17 institutions were included, and a propensity score matching analysis was performed to compare the short- and long-term outcomes of MIS with open surgery., Results: A total of 327 patients were included in this study and 186 patients were analyzed after matching. The risk ratios for overall and severe complications were 0.76 [95% confidence interval (CI): 0.45, 1.27] and 0.65 (95% CI: 0.32, 1.29), respectively. The MIS group had significantly less blood loss [mean difference (MD), -409 mL; 95% CI: -538, -281] and a shorter hospital stay (MD, -6.5 days; 95% CI: -13.1, 0.1) than the open surgery group. The median follow-up duration of this cohort was 4.6 years, and the 3-year overall survival were 77.9% and 76.2% in the MIS and open surgery groups, respectively [hazard ratio (HR), 0.78; 95% CI: 0.45, 1.36]. The 3-year relapse-free survival were 71.9% and 62.2% in the MIS and open surgery groups, respectively (HR, 0.71; 95% CI: 0.44, 1.16)., Conclusions: MIS for RGC showed favorable short- and long-term outcomes compared to open surgery. MIS is a promising option for radical surgery for RGC., (© 2023. Society of Surgical Oncology.)

Background: Cancer detection is a global research focus, and novel, rapid, and label-free techniques are being developed for routine clinical practice. This has led to the development of new tools and techniques from the bench side to routine clinical practice. In this study, we present a method that uses Raman spectroscopy (RS) to detect cancer in unstained formalin-fixed, resected specimens of the esophagus and stomach. Our method can record a clear Raman-scattered light spectrum in these specimens, confirming that the Raman-scattered light spectrum changes because of the histological differences in the mucosal tissue., Aim: To evaluate the use of Raman-scattered light spectrum for detecting endoscop-ically resected specimens of esophageal squamous cell carcinoma (SCC) and gastric adenocarcinoma (AC)., Methods: We created a Raman device that is suitable for observing living tissues, and attempted to acquire Raman-scattered light spectra in endoscopically resected specimens of six esophageal tissues and 12 gastric tissues. We evaluated formalin-fixed tissues using this technique and captured shifts at multiple locations based on feasibility, ranging from six to 19 locations 200 microns apart in the vertical and horizontal directions. Furthermore, a correlation between the obtained Raman scattered light spectra and histopathological diagnosis was performed., Results: We successfully obtained Raman scattered light spectra from all six esophageal and 12 gastric specimens. After data capture, the tissue specimens were sent for histopathological analysis for further processing because RS is a label-free methodology that does not cause tissue destruction or alterations. Based on data analysis of molecular-level substrates, we established cut-off values for the diagnosis of esophageal SCC and gastric AC. By analyzing specific Raman shifts, we developed an algorithm to identify the range of esophageal SCC and gastric AC with an accuracy close to that of histopathological diagnoses., Conclusion: Our technique provides qualitative information for real-time morphological diagnosis. However, further in vivo evaluations require an excitation light source with low human toxicity and large amounts of data for validation., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Valvuloplastic esophagogastrostomy (VEG) using the double flap technique (DFT) after proximal gastrectomy (PG) represents a promising procedure for the prevention of reflux oesophagitis. We aimed to retrospectively investigate the efficacy of minimally invasive PG followed by VEG-DFT in preventing reflux oesophagitis among patients who require intra-mediastinal anastomosis., Methods: A total of 80 patients who underwent reconstruction with DFT after LPG from November 2013 to January 2021 were enrolled in the present study. Data were obtained through a review of our prospectively maintained database. At 1 year after surgery, multivariate analyses were performed to identify risk factors for gastroesophageal reflux disease of Los Angeles (LA) classification grade B or higher., Results: The incidence of LA grade B or higher reflux oesophagitis 1 year after surgery was 10%. Multivariate analyses revealed that the longitudinal length of the resected oesophagus of > 20 mm was the only significant risk factor for reflux oesophagitis. Patients with a longitudinal length of the resected oesophagus > 20 mm (group-L, n = 35) had a significantly longer total operative time and a higher rate of complications within 30 days of surgery than those with a length of ≤ 20 mm (group-S, n = 45). LA grade B or higher reflux oesophagitis was significantly higher in group-L than in group-S (20% vs. 2.2%; P = 0.011)., Conclusions: There is a need for surgical procedures with improved efficacy for the prevention of reflux oesophagitis in patients requiring oesophageal resection of > 20-mm., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This prospective study aimed to evaluate presepsin use as a biomarker of on postoperative infectious complications after gastrectomy, compared to C-reactive protein (CRP), white blood cells (WBCs), and neutrophils (Neuts). Overall, 108 patients were enrolled between October 2019 and December 2020. Presepsin, CRP, WBC, and Neut levels were measured preoperatively and on postoperative days (PODs) 1, 3, 5, and 7, using a postoperative morbidity survey. Grade II or higher infectious complications occurred in 18 patients (16.6%). Presepsin levels on all evaluated PODs were significantly higher in the infectious complication group than in the non-complication group (p = 0.002, p < 0.0001, p < 0.0001, and p = 0.025, respectively). The area under the curve (AUC) values were the highest for presepsin on PODs 3 and 7 (0.89 and 0.77, respectively) and similar to that of CRP, with a high value > 0.8 (0.86) on POD 5. For presepsin, the optimal cut-off values were 298 pg/mL (sensitivity, 83.3%; specificity, 83.3%), 278 pg/mL (sensitivity, 83.3%; specificity, 82.2%), and 300 pg/mL (sensitivity, 83.3%; specificity, 82%) on PODs 3, 5, and 7, respectively. Presepsin levels on PODs 3, 5, and 7 after gastrectomy is a more useful biomarker of postoperative infectious complications compared to CRP, WBCs, and Neuts, with a high sensitivity and specificity., (© 2022. The Author(s).)

Background: Laparoscopic gastrectomy (LG) is performed widely, but whether LG is the optimal treatment for sarcopenic gastric cancer patients is unclear. This study aimed to determine whether LG is particularly beneficial for gastric cancer patients with sarcopenia., Methods: We collected data concerning 604 consecutive patients who underwent gastrectomy for gastric cancer between January 2003 and December 2019. After adjustment using one-to-one propensity score matching, short-term and long-term outcomes were compared between LG and open gastrectomy (OG) groups among patients with sarcopenia and those without., Results: Among patients with and without sarcopenia, the LG group had a significantly longer operative time but less blood loss than the OG group. The two groups showed no significant differences regarding complications. Although 5-year overall and disease-specific survival were similar between LG and OG groups among patients with and without sarcopenia, LG was associated with greater 5-year non-gastric cancer-related survival than OG among patients with sarcopenia (88.3% vs. 78.1%, P = 0.048), but not those without., Conclusion: LG for resectable gastric cancer was not inferior to OG regarding complications and outcomes in patients with or without sarcopenia. No difference in overall survival was evident between these approaches, but LG may lessen mortality from conditions unrelated to gastric cancer in sarcopenic patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nivolumab is an immune-checkpoint inhibitor (ICI) that can induce unique treatment-related toxicities, such as immune-related adverse events (irAEs). Myocarditis is a serious irAE with an incidence between 0.06% and 1.14%. Although the peak onset of irAE is generally within three months from the start of treatment, we experienced an autopsy case of late-onset fulminant myocarditis caused by nivolumab in Epstein Barr virus-associated gastric cancer. Pathological complete remission of the primary lesion was confirmed by the autopsy. We should consider possible complications of cardiac irAEs, especially fulminant myocarditis, even beyond three months after starting ICI therapy.

Background: This study was performed to investigate the association between body mass index (BMI) and gastric cancer in East and Southeast Asia where most of gastric cancer is non-cardia gastric cancer., Methods: On the basis of 8,997 gastric cancer cases among the Asia Cohort Consortium participants from China, Japan, Korea, and Singapore (N = 538,835), we assessed gastric cancer risk according to BMI by calculating hazard ratios (HR) and 95% confidence intervals (CI) using the Cox proportional hazard regression model., Results: A U-shaped associations between BMI and gastric cancer risk were observed. Gastric cancer risks in underweight group (&lt;18.5 kg/m2) and in obesity group (≥27.5 kg/m2) were higher than reference BMI group (23-24.9 kg/m2; HR, 1.15; 95% CI, 1.05-1.25 for underweight; HR, 1.12; 95% CI, 1.03-1.22 for obesity, respectively). The associations of underweight and obesity with gastric cancer risk were consistent in the analyses for non-cardia gastric cancer, intestinal-type gastric cancer, and late-onset gastric cancer. No significant association of underweight and obesity with the risk of cardia gastric cancer, diffuse-type gastric cancer, and early-onset gastric cancer was observed. In addition, we found that the U-shaped association between BMI and gastric cancer risk remained in nonsmokers, while only underweight was related to increased gastric cancer risk in smokers., Conclusions: BMI has a U-shaped association with gastric cancer risk in East and Southeast Asian population, especially for the non-cardia gastric cancer, intestinal-type gastric cancer, and late-onset gastric cancer., Impact: Future studies with consideration of anatomic location and histology of gastric cancer are needed to establish the association of underweight as well as obesity with gastric cancer risk., (©2022 American Association for Cancer Research.)

Objective: Gastric-type mucinous carcinoma (GAS) is a novel variant of uterine cervix mucinous carcinoma. GAS is a distinct entity that can be distinguished from typical endocervical adenocarcinoma (UEA). In Japan, postoperative adjuvant therapy for cervical cancer includes not only radiation therapy (RT) or concurrent chemoradiotherapy (CCRT) but also chemotherapy in many cases. However, no previous studies have analyzed adjuvant therapy for GAS. In the present study, we investigated the efficacy of adjuvant therapy for GAS., Methods: This was a preplanned secondary analysis of a dataset from previous nationwide, retrospective, observational study. The study population comprised women with stage I-II GAS who underwent surgery. Progression-free survival (PFS) and overall survival (OS) were compared among patients who did and did not receive adjuvant therapy using the Kaplan-Meier method., Results: Data were analyzed for a total of 102 enrolled patients, who were classified as low- (17 patients), intermediate- (37 patients), or high risk (48 patients) based on the risk of postoperative cervical cancer recurrence. In the intermediate-risk group, median survival could not be assessed due to a lack of sufficient events, but the no-adjuvant and RT groups tended to exhibit better prognoses. In contrast, within the high-risk group, patients in the RT subgroup exhibited a trend towards better PFS and OS than those in the CCRT and chemotherapy groups., Conclusions: The prognosis of GAS was confirmed to be poor, even in cases of early-stage cancer and following surgical resection. Chemotherapy strategies, including CCRT as postoperative adjuvant therapy, tend to have a poor prognosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Day of the week when elective gastrointestinal surgery is performed may be influenced by various background and tumor-related factors. Relationships between postoperative outcome and when in the week gastrectomy is performed remain controversial. We undertook this study to evaluate whether weekday of gastrectomy influenced outcomes of gastric cancer treatment ("weekday effect")., Methods: Patients who underwent curative surgery for gastric cancer between 2004 and 2017 were included in this retrospective study. To obtain 2 cohorts well balanced for variables that might influence clinical outcomes, patients whose gastrectomy was performed early in the week (EW group) were matched 1:1 with others undergoing gastrectomy later in the week (LW group) by use of propensity scores., Results: Among 554 patients, 216 were selected from each group by propensity score matching. Incidence of postoperative complications classified as Clavien-Dindo grade II or higher was similar between EW and LW groups (20.4% vs. 24.1%; P = 0.418). Five-year overall and recurrence-free survival were 86.0% and 81.9% in the EW group, and 86.2% and 81.1% in the LW group (P = 0.981 and P = 0.835, respectively)., Conclusions: Short- and long-term outcomes were comparable between gastric cancer patients who underwent gastrectomy early and late in the week., (© 2022. The Author(s).)

Background & Aims: Preoperative low skeletal muscle mass and obesity have been identified as poor prognostic factors after gastrectomy for cancer, but the predictive value of combined quantitation of skeletal muscle mass and obesity remains unclear. This study examined the impact of combined body compositions on outcomes after gastrectomy for cancer., Methods: 518 patients who had undergone gastric resection for cancer between 2004 and 2017 were analyzed retrospectively. Skeletal muscle mass (skeletal muscle mass index (SMI)) and visceral obesity (visceral fat area) were measured in preoperative computed tomographic images to categorize patients as outlined below. Impacts of these body compositions on outcomes after gastrectomy were investigated., Results: Body composition was classified as high SMI without obesity in 231 patients (45%), high SMI with obesity in 202 (39%), low SMI without obesity in 55 (11%), and low SMI with obesity in 30 (6%). Postoperative complications developed in 128 patients (25%). Multivariate analysis identified low SMI with obesity as an independent risk factor for postoperative complications (odds ratio, 3.27; P = 0.010). Moreover, patients with low SMI without obesity had lower 5-year overall survival rates than patients with high SMI without obesity (64.4% vs. 88.0%; P < 0.001) and worse 5-year relapse-free survival rates (61.3% vs. 81.3%; P = 0.002). Multivariate analysis identified low SMI without obesity as a significant risk factor for overall survival (hazard ratio, 3.033; P < 0.001) and relapse-free survival (hazard ratio, 2.144; P = 0.008) after gastrectomy., Conclusion: Preoperative low SMI with obesity was an independent risk factor for postoperative complications, while low SMI without obesity was an independent risk factor for overall and relapse-free survival following gastrectomy for cancer., Competing Interests: Conflict of Interest The authors have no conflict of interest to disclose., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The number of overweight gastric cancer patients who are undergoing laparoscopic gastrectomy (LG) has increased in Japan. However, the relationship between obesity and surgical outcomes of LG remains unclear. Therefore, this study aimed to evaluate the effect of visceral fat area (VFA) on surgical outcomes of LG for gastric cancer compared to the body mass index (BMI)., Methods: This study was a retrospective, cohort study that included 587 patients who underwent LG in our institution between January 2015 and December 2019. The patients were divided into two groups according to VFA (< 100 cm 2 and ≥ 100 cm 2 ) and BMI (< 25 kg/m 2 and ≥ 25 kg/m 2 ) values, respectively. Surgical outcomes and postoperative complications were compared between the low and high groups for each VFA and BMI value. Propensity score matching was used to minimize potential selection bias., Results: After propensity score matching, 144 pairs of patients in the VFA group and 82 pairs of patients in the BMI group were extracted. Operative time (p = 0.003), intraoperative blood loss (p = 0.0006), and CRP levels on postoperative day 1 (p = 0.002) and on postoperative day 3 (p = 0.004) were significantly higher in the high-VFA group than in the low-VFA group. However, these surgical outcomes were not significantly different between the high-BMI and low-BMI groups. There was no strong correlation between VFA and BMI (R 2  = 0.64). There were no significant differences in postoperative complications between the high and low groups for both VFA and BMI values. On multivariate analysis, high VFA was an independent predictor of operative time, but it was not significantly associated with the incidence of postoperative complications., Conclusion: VFA is a better indicator of longer operative time than BMI. However, increased VFA did not affect postoperative complications., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In Helicobacter pylori-driven gastric cancer, mucosal colonization induces chronic inflammation that may variably progress to cancer. Prospective studies of circulating inflammation-related proteins have suggested weak associations with gastric cancer risk. To assess potential utility as a screening tool in clinical settings, we examined circulating levels of a wide range of key inflammation molecules for associations with early-stage gastric cancer., Methods: We used pretreatment EDTA plasma from 239 individuals with early-stage noncardia gastric cancer (203 stage I and 36 stage II) and 256 age-frequency-matched H. pylori-seropositive cancer-free controls within the Hospital-based Epidemiologic Research Program at Aichi Cancer Center. Levels of 92 biomarkers were measured by proximity extension assays using Olink's Proseek Immuno-oncology Panel. Odds ratios (ORs) for association with gastric cancer risk were calculated for quantiles (two to four categories) of each biomarker from unconditional logistic regression models, adjusted for age, sex, smoking and alcohol consumption. Two-sided P values <0.05 were considered as significant. The false discovery rate (FDR) was used to correct for multiple comparisons., Results: Of 83 evaluable biomarkers, lower levels of TNFRSF12A (per quartile OR, 0.82; nominal P-trend = 0.02) and ADGRG1 (per quartile OR, 0.84; nominal P-trend = 0.03) were associated with early-stage gastric cancer but were not statistically significant after FDR correction., Conclusion: Our study did not identify any inflammation-related biomarkers that may be useful for early disease detection. To date, this is the first assessment of circulating inflammation-related proteins in early-stage gastric cancer. Given the complex inflammation processes preceding malignant transformation, further investigation of other biomarkers is warranted., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The association between alcohol intake and stomach cancer risk remains controversial. We undertook a pooled analysis of data from six large-scale Japanese cohort studies with 256 478 participants on this topic. Alcohol intake as ethanol was estimated using a validated questionnaire. The participants were followed for incidence of stomach cancer. We calculated study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for stomach cancer according to alcohol intake using a Cox regression model. Summary HRs were estimated by pooling the study-specific HRs using a random-effects model. During 4 265 551 person-years of follow-up, 8586 stomach cancer cases were identified. In men, the multivariate-adjusted HRs (95% CIs) of stomach cancer were 1.00 (0.87-1.15) for occasional drinkers, and 1.00 (0.91-1.11) for <23 g/d, 1.09 (1.01-1.18) for 23 to <46 g/d, 1.18 (1.09-1.29) for 46 to <69 g/d, 1.21 (1.05-1.39) for 69 to <92 g/d, and 1.29 (1.11-1.51) for ≥92 g/d ethanol in regular drinkers compared with nondrinkers. In women, the multivariate-adjusted HRs were 0.93 (0.80-1.08) for occasional drinkers, and 0.85 (0.74-0.99) for <23 g/d, and 1.22 (0.98-1.53) for ≥23 g/d in regular drinkers compared with nondrinkers. The HRs for proximal and distal cancer in drinkers vs nondrinkers were 1.69 (1.15-2.47) and 1.24 (0.99-1.55) for ≥92 g/d in men, and 1.60 (0.76-3.37) and 1.18 (0.88-1.57) for ≥23 g/d in women, respectively. Alcohol intake increased stomach cancer risk in men, and heavy drinkers showed a greater point estimate of risk for proximal cancer than for distal cancer., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The incidence of remnant gastric cancer (RGC) after distal gastrectomy is 1-5%. However, as the survival rate of patients with gastric cancer improves due to early detection and treatment, more patients may develop RGC. There is no consensus on the surgical and postoperative management of RGC, and the clinicopathological characteristics correlated with the long-term outcomes remain unclear. Therefore, we investigated the clinicopathological factors associated with the long-term outcomes of RGC., Methods: We included 65 consecutive patients who underwent gastrectomy for RGC from January 2000 to December 2015 at the Osaka Medical and Pharmaceutical University Hospital, Japan. The Kaplan-Meier method was used to create survival curves, and differences in survival were compared between the groups (clinical factors, pathological factors, and surgical factors) using the log-rank test. Multivariate analyses using the Cox proportional hazard model were used to identify factors associated with long-term survival., Results: No significant differences were noted in the survival rate based on clinical factors (age, body mass index, diabetes mellitus, hypertension, cardiovascular disease, pulmonary complications, liver disease, diet, history of alcohol drinking, and history of smoking) or the type of remnant gastrectomy. Significant differences were noted in the survival rate based on pathological factors and surgical characteristics (intraoperative blood loss, operation time, and the number of positive lymph nodes). Multivariate analysis revealed that the T stage (hazard ratio, 5.593; 95% confidence interval [CI], 1.183-26.452; p = 0.030) and venous invasion (hazard ratio, 3.351; 95% CI, 1.030-10.903; p = 0.045) were significant independent risk factors for long-term survival in patients who underwent radical resection for RGC., Conclusions: T stage and venous invasion are important prognostic factors of long-term survival after remnant gastrectomy for RGC and may be keys to managing and identifying therapeutic strategies for improving prognosis in RGC., (© 2021. The Author(s).)

Background: The short- and long-term efficacy of laparoscopic surgery for elderly patients with gastric cancer has not been evaluated. We aimed to use propensity score matching to clarify the efficacy of laparoscopic gastrectomy (LG) for elderly patients with gastric cancer aged ≥80 years., Methods: We retrospectively collected data from 159 consecutive patients with gastric cancer aged ≥80 years who underwent gastrectomy with curative intent at our institution between 2004 and 2015. Propensity score matching was applied to compare the open gastrectomy (OG) and LG. Short- and long-term outcomes were evaluated between the propensity-matched groups., Results: Patients' backgrounds and surgical factors were similar in both groups except for blood loss. The median time to first flatus was significantly shorter in the LG group than in the OG group (P = 0.002). The postoperative hospital stay was significantly shorter in the LG group (P = 0.014). The complication rate of Clavien-Dindo grade III or higher was significantly lower in the LG group (3% vs. 23%, P = 0.023). The 5-year overall survival and 5-year disease-specific survival rates were better in the LG group than in the OG group, but the differences were not significant (45% vs. 42% and 67% vs 57%, respectively)., Conclusion: LG was associated with good short-term outcomes and acceptable oncologic outcomes compared with OG in these propensity-matched patients aged ≥80 years., (© 2021. Société Internationale de Chirurgie.)

Purpose: It is known that sarcopenia affects the overall short- and long-term outcomes of patients with gastric cancer (GC); however, the effect of muscle quality on infectious complications after gastrectomy for GC remains unclear. We investigated the associations between the preoperative quantity and quality of skeletal muscle on infectious complications following gastrectomy for GC., Methods: The subjects of this retrospective study were 353 GC patients who underwent radical gastrectomy between 2009 and 2018. We examined the relationships between their clinical factors, including skeletal muscle mass index and intramuscular adipose tissue content (IMAC), and infectious complications after gastrectomy., Results: Infectious complications developed in 59 patients (16.7%). The independent risk factors for infectious complications identified by multivariate analysis were male gender (P < 0.001), prognostic nutritional index below 45 (P = 0.006), and high IMAC (P = 0.011). Patients with a high IMAC were older and had a higher body mass index, as well as a greater age-adjusted Charlson comorbidity index, than those with low or normal IMAC., Conclusions: Low skeletal muscle quality defined by a high IMAC is a risk factor for infectious complications following gastrectomy. When feasible, preoperative nutritional intervention and rehabilitation aiming to improve muscle quality could reduce infectious complications after gastrectomy for GC.

Background: In Japan, there are ongoing efforts to shift the gastric cancer prevention and control policy priorities from barium-based screening to Helicobacter pylori (H. pylori)-oriented primary prevention. A comprehensive summary of the evidence regarding the effects of H. pylori eradication on the risk of gastric cancer could inform policy decisions., Methods: We conducted a systematic review and meta-analysis of published studies evaluating the effectiveness of H. pylori eradication for the prevention of gastric cancer in otherwise healthy individuals (primary prevention) and early gastric cancer patients (tertiary prevention)., Results: In total, 19 studies were included. Three moderate-quality observational cohort studies showed that H. pylori eradication may be associated with a decreased risk of gastric cancer in healthy asymptomatic Japanese people. There is moderate certainty regarding the effectiveness of H. pylori eradication in patients with gastrointestinal diseases, such as peptic ulcers. A meta-analysis of 10 observational studies with otherwise healthy individuals (mainly peptic ulcer patients) yielded an overall odds ratio of 0.34 (95% CI: 0.25-0.46). Regarding tertiary prevention, the overall odds ratio for developing metachronous gastric cancer was 0.42 (95% CI: 0.35-0.51) in the eradication group in a meta-analysis of nine studies involving early gastric cancer patients who underwent endoscopic resection., Conclusion: H. pylori eradication is effective in preventing gastric cancer in the Japanese population, regardless of symptoms. Well-designed, large cohort studies are warranted to determine the long-term efficacy and safety of H. pylori eradication in the context of reducing the gastric cancer burden through population-based screening and treatment., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A 55-year-old man complained of abdominal distention. Gastroscopy showed a submucosal tumor in the upper-third portion of the stomach, with a biopsy diagnosis of gastrointestinal stromal tumor(GIST). Because abdominal contrast- enhanced CT findings suspected the invasion of the tumor into the pancreatic tail, preoperative imatinib therapy was performed. After 2 weeks of treatment, the tumor had shrunk to 44% of its starting volume. Six months later, CT findings suggestive of the tumor invasion had disappeared. Therefore, the laparoscopic local resection of the stomach was performed. The postoperative course was uneventful. A pathological diagnosis was c-kit-positive GIST, with less than 5/50 HPF of mitotic counts. Imatinib was restarted 2 weeks after the operation. The patient is alive 8 months after the operation, with no obvious recurrence. Preoperative imatinib therapy can be a useful option for large GIST tumors.

Background: Epstein-Barr virus (EBV)-positive gastric cancers have clinicopathologic differences from EBV-negative tumors and lack TP53 mutation. Serologic profiles may inform viral contribution to carcinogenesis., Methods: We compared humoral responses of EBV-positive ( n = 67) and EBV-negative ( n = 137) patients with gastric cancer from the International EBV-Gastric Cancer Consortium. Serum antibodies against four EBV proteins, nuclear (EBNA), viral capsid (VCA), early-diffuse (EA-D), and Zta replication activator (ZEBRA), and to p53 were assessed by multiplex assays. OR of antibody level tertiles (T1-T3) were adjusted by logistic regression. We also conducted a meta-analysis of reported anti-p53 seropositivity in gastric cancer., Results: Consistent with EBV's ubiquity, 99% of patients were seropositive for anti-EBNA and 98% for anti-VCA, without difference by tumor EBV status. Seropositivity varied between patients with EBV-positive and EBV-negative tumors for anti-EA-D (97% vs. 67%, respectively, P < 0.001) and anti-ZEBRA (97% vs. 85%, respectively, P = 0.009). Adjusted ORs (vs. T1) for patients with EBV-positive versus EBV-negative tumors were significantly elevated for higher antibodies against EBNA (2.6 for T2 and 13 for T3), VCA (1.8 for T2 and 2.4 for T3), EA-D (6.0 for T2 and 44 for T3), and ZEBRA (4.6 for T2 and 12 for T3). Antibodies to p53 were inversely associated with EBV positivity (3% vs. 15%; adjusted OR = 0.16, P = 0.021). Anti-p53 prevalence from the literature was 15%., Conclusions: These serologic patterns suggest viral reactivation in EBV-positive cancers and identify variation of p53 seropositivity by subtype., Impact: Anti-EBV and anti-p53 antibodies are differentially associated with tumor EBV positivity. Serology may identify EBV-positive gastric cancer for targeted therapies., (©2019 American Association for Cancer Research.)

A 69-year-old woman, who complained of loss of appetite, was admitted to our hospital and diagnosed with clinical Stage Ⅳgastric cancer and paraaortic lymph node metastases(cT4aN3M1[#16b1LYM], cStage Ⅳ). She underwent 2 cycles of SP therapy(combination of S-1 and CDDP). A partial response of the primary tumor was noted, with no distant metastases, except for the paraaortic lymph nodes. She underwent robotic total gastrectomy with D2 plus paraaortic lymph node dissection. Histopathology showed no residual tumor cells in the stomach or lymph nodes. Postoperatively, the patient underwent 3 cycles of SOX therapy(combination of S-1 and oxaliplatin)and survived for over 6 postoperative months, with no recurrences. For advanced gastric cancers with paraaortic lymph node dissection with no evidences of other distant metastases, gastrectomy with paraaortic lymph node dissection combined with chemotherapy could be a therapeutic option to achieve R0 resection.

Purposes: Laparoscopic gastrectomy using ultrasonic devices occasionally causes postoperative pancreatic fistula. Robotic gastrectomy using monopolar scissors may reduce intraoperative injury to the pancreas. We evaluated the safety and feasibility of robotic gastrectomy., Methods: A multicenter prospective study was conducted to evaluate the surgical outcomes of robotic gastrectomy. The primary endpoints were the incidence of intraoperative and postoperative complications and operative mortality., Results: A total of 115 patients were enrolled. The clinical T stages were T1 in 68 patients and T2 or higher in 47 patients. The types of surgery included distal gastrectomy (n = 72), total gastrectomy (n = 39), and proximal gastrectomy (n = 4). Two patients developed intraoperative complications (1.7%), but no cases required conversion to open surgery. The amylase concentration in drainage fluid was higher in cases with pancreatic compression, especially in those with compression for longer than 20 min. Postoperative complications of Clavien-Dindo grade ≥ II occurred in 11 patients (9.6%). There was no mortality. A multivariate analysis indicated that a high body mass index and pancreatic compression by an assistant for longer than 20 min were independent risk factors for postoperative complications (P = 0.029 and P = 0.010)., Conclusions: Robotic gastrectomy using monopolar scissors is safe and feasible. Robotic dissection without compression of the pancreas may reduce postoperative complications.

A 63-year-old man was diagnosed with gastric cancer. Distal gastrectomywas performed in November 2011. The pathologic finding was pT3N2M0, Stage ⅢA. S-1 was administered as adjuvant chemotherapy. However, in August 2012, computed tomographyrevealed a tumor measuring 3 cm in size in the dorsal pancreas. Based on endoscopic ultrasound-guided fine- needle aspiration, he was diagnosed with lymph node recurrence of gastric cancer. Injection chemotherapy of CDDP/CPT-11 was initiated in November 2012. In January 2013, the patient developed fever owing to a ruptured abscess from the posterior wall in the stomach. In the 6 years since, although the patient has not undergone chemotherapy, recurrence has not been observed.

Infection with Helicobacter pylori (H. pylori) is associated with an increased risk of gastric malignant lymphoma. The chronic inflammation of gastric mucosa by H. pylori infection induces lymphomagenesis. Although this chronic mucosal inflammation also results in atrophic gastritis, evidence supporting the possible significance of atrophic gastritis in gastric lymphomagenesis is scarce. Here, to evaluate the association between gastric mucosal atrophy and the risk of gastric lymphoma, we conducted a matched case-control study at Aichi Cancer Center focusing on the attribution of H. pylori infection status and pepsinogen (PG) serum levels. In total, 86 patients with gastric lymphoma (including 49 cases of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and 24 cases of diffuse large B cell lymphoma (DLBCL)) and 1720 non-cancer controls were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were assessed by conditional logistic regression analysis with adjustment for potential confounders. Results failed to show a statistically significant association between atrophic gastritis and the risk of gastric lymphoma. The adjusted ORs of positive atrophic gastritis relative to negative for overall gastric lymphoma, MALT lymphoma, DLBCL, and other lymphomas were 0.77 (95% CI 0.45-1.33), 0.65 (0.30-1.39), 1.03 (0.38-2.79), and 0.84 (0.22-3.29), respectively. In contrast, a positive association between overall gastric lymphoma and H. pylori infection was observed (OR = 2.14, 95% CI 1.30-3.54). A consistent association was observed for MALT lymphoma, DLBCL, and other lymphomas with ORs of 1.96 (1.00-3.86), 1.92 (0.74-4.95), and 5.80 (1.12-30.12), respectively. These findings suggest that H. pylori infection triggers gastric lymphoma but that epithelial changes due to atrophic gastritis do not inherently affect the development of gastric lymphoma.

Gastric cancer is the third leading cause of cancer mortality in Japan and worldwide. Although previous studies identify various genetic variations associated with gastric cancer, host genetic factors are largely unidentified. To identify novel gastric cancer loci in the Japanese population, herein, we carried out a large-scale genome-wide association study using 6171 cases and 27 178 controls followed by three replication analyses. Analysis using a total of 11 507 cases and 38 904 controls identified two novel loci on 12q24.11-12 (rs6490061, P = 3.20 × 10 -8 with an odds ratio [OR] of 0.905) and 20q11.21 (rs2376549, P = 8.11 × 10 -10 with an OR of 1.109). rs6490061 is located at intron 19 of the CUX2 gene, and its expression was suppressed by Helicobacter pylori infection. rs2376549 is included within the gene cluster of DEFB families that encode antibacterial peptides. We also found a significant association of rs7849280 in the ABO gene locus on 9q34.2 (P = 2.64 × 10 -13 with an OR of 1.148). CUX2 and ABO expression in gastric mucosal tissues was significantly associated with rs6490061 and rs7849280 (P = 0.0153 and 8.00 × 10 -11 ), respectively. Our findings show the crucial roles of genetic variations in the pathogenesis of gastric cancer., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms have a strong impact on carcinogenic acetaldehyde accumulation after alcohol drinking. To date, however, evidence for a significant ALDH2-alcohol drinking interaction and a mediation effect of ALDH2/ADH1B through alcohol drinking on gastric cancer have remained unclear. We conducted two case-control studies to validate the interaction and to estimate the mediation effect on gastric cancer., Methods: We calculated odds ratios (OR) and 95% confidence intervals (CI) for ALDH2/ADH1B genotypes and alcohol drinking using conditional logistic regression models after adjustment for potential confounding in the HERPACC-2 (697 cases and 1372 controls) and HERPACC-3 studies (678 cases and 678 controls). We also conducted a mediation analysis of the combination of the two studies to assess whether the effects of these polymorphisms operated through alcohol drinking or through other pathways., Results: ALDH2 Lys alleles had a higher risk with increased alcohol consumption compared with ALDH2 Glu/Glu (OR for heavy drinking, 3.57; 95% CI 2.04-6.27; P for trend = 0.007), indicating a significant ALDH2-alcohol drinking interaction (P interaction  = 0.024). The mediation analysis indicated a significant positive direct effect (OR 1.67; 95% CI 1.38-2.03) and a protective indirect effect (OR 0.84; 95% CI 0.76-0.92) of the ALDH2 Lys alleles with the ALDH2-alcohol drinking interaction. No significant association of ADH1B with gastric cancer was observed., Conclusion: The observed ALDH2-alcohol drinking interaction and the direct effect of ALDH2 Lys alleles may suggest the involvement of acetaldehyde in the development of gastric cancer.

Background: Image recognition using artificial intelligence with deep learning through convolutional neural networks (CNNs) has dramatically improved and been increasingly applied to medical fields for diagnostic imaging. We developed a CNN that can automatically detect gastric cancer in endoscopic images., Methods: A CNN-based diagnostic system was constructed based on Single Shot MultiBox Detector architecture and trained using 13,584 endoscopic images of gastric cancer. To evaluate the diagnostic accuracy, an independent test set of 2296 stomach images collected from 69 consecutive patients with 77 gastric cancer lesions was applied to the constructed CNN., Results: The CNN required 47 s to analyze 2296 test images. The CNN correctly diagnosed 71 of 77 gastric cancer lesions with an overall sensitivity of 92.2%, and 161 non-cancerous lesions were detected as gastric cancer, resulting in a positive predictive value of 30.6%. Seventy of the 71 lesions (98.6%) with a diameter of 6 mm or more as well as all invasive cancers were correctly detected. All missed lesions were superficially depressed and differentiated-type intramucosal cancers that were difficult to distinguish from gastritis even for experienced endoscopists. Nearly half of the false-positive lesions were gastritis with changes in color tone or an irregular mucosal surface., Conclusion: The constructed CNN system for detecting gastric cancer could process numerous stored endoscopic images in a very short time with a clinically relevant diagnostic ability. It may be well applicable to daily clinical practice to reduce the burden of endoscopists.

Background: Individual participant data pooled analyses allow access to non-published data and statistical reanalyses based on more homogeneous criteria than meta-analyses based on systematic reviews. We quantified the impact of publication-related biases and heterogeneity in data analysis and presentation in summary estimates of the association between alcohol drinking and gastric cancer., Methods: We compared estimates obtained from conventional meta-analyses, using only data available in published reports from studies that take part in the Stomach Cancer Pooling (StoP) Project, with individual participant data pooled analyses including the same studies., Results: A total of 22 studies from the StoP Project assessed the relation between alcohol intake and gastric cancer, 19 had specific data for levels of consumption and 18 according to cancer location; published reports addressing these associations were available from 18, 5 and 5 studies, respectively. The summary odds ratios [OR, (95%CI)] estimate obtained with published data for drinkers vs. non-drinkers was 10% higher than the one obtained with individual StoP data [18 vs. 22 studies: 1.21 (1.07-1.36) vs. 1.10 (0.99-1.23)] and more heterogeneous (I 2 : 63.6% vs 54.4%). In general, published data yielded less precise summary estimates (standard errors up to 2.6 times higher). Funnel plot analysis suggested publication bias., Conclusion: Meta-analyses of the association between alcohol drinking and gastric cancer tended to overestimate the magnitude of the effects, possibly due to publication bias. Additionally, individual participant data pooled analyses yielded more precise estimates for different levels of exposure or cancer subtypes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

As a result of the RAINBOW trial, ramucirumab plus paclitaxel was established as a second-line treatment of advanced gastric cancer. Regarding the safety of ramucirumab plus paclitaxel in the Japanese, a subgroup analysis of the RAINBOW trial was conducted. The incidence of neutropenia was higher in Japanese patients. However, information is lacking concerning the safety of ramucirumab after marketing in Japanese patients. Therefore, the aim of this study was to evaluate the safety of ramucirumab in Japanese patients with advanced gastric cancer. The inclusion criteria were patients diagnosed with advanced gastric cancer who had commenced treatment with ramucirumab plus paclitaxel or paclitaxel only at Ogaki Municipal Hospital (Gifu, Japan) between January 2015 and December 2016. There were 26 patients in the ramucirumab plus paclitaxel group and 22 patients in the paclitaxel only group. Treatment-related adverse events were documented in 100.0% of the patients in the ramucirumab plus paclitaxel group (Grade 3-4, 73.1%) and 90.9 % of the patients in the paclitaxel only group (Grade 3-4, 45.5 %). The most frequently observed adverse event in both treatment groups was anemia. The second common adverse event was neutropenia. The incidence of neutropenia of Grade ≥3 was significantly higher in the ramucirumab plus paclitaxel group than in the paclitaxel only group. In conclusion, the incidence of neutropenia is high. However, we believe that ramucirumab plus paclitaxel can be safely administered.

Tobacco smoking is one of the main risk factors for gastric cancer, but the magnitude of the association estimated by conventional systematic reviews and meta-analyses might be inaccurate, due to heterogeneous reporting of data and publication bias. We aimed to quantify the combined impact of publication-related biases, and heterogeneity in data analysis or presentation, in the summary estimates obtained from conventional meta-analyses. We compared results from individual participant data pooled-analyses, including the studies in the Stomach Cancer Pooling (StoP) Project, with conventional meta-analyses carried out using only data available in previously published reports from the same studies. From the 23 studies in the StoP Project, 20 had published reports with information on smoking and gastric cancer, but only six had specific data for gastric cardia cancer and seven had data on the daily number of cigarettes smoked. Compared to the results obtained with the StoP database, conventional meta-analyses overvalued the relation between ever smoking (summary odds ratios ranging from 7% higher for all studies to 22% higher for the risk of gastric cardia cancer) and yielded less precise summary estimates (SE ≤2.4 times higher). Additionally, funnel plot asymmetry and corresponding hypotheses tests were suggestive of publication bias. Conventional meta-analyses and individual participant data pooled-analyses reached similar conclusions on the direction of the association between smoking and gastric cancer. However, published data tended to overestimate the magnitude of the effects, possibly due to publication biases and limited the analyses by different levels of exposure or cancer subtypes.

Tobacco smoking is a known cause of gastric cancer, but several aspects of the association remain imprecisely quantified. We examined the relation between cigarette smoking and the risk of gastric cancer using a uniquely large dataset of 23 epidemiological studies within the 'Stomach cancer Pooling (StoP) Project', including 10 290 cases and 26 145 controls. We estimated summary odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) by pooling study-specific ORs using random-effects models. Compared with never smokers, the ORs were 1.20 (95% CI: 1.09-1.32) for ever, 1.12 (95% CI: 0.99-1.27) for former, and 1.25 (95% CI: 1.11-1.40) for current cigarette smokers. Among current smokers, the risk increased with number of cigarettes per day to reach an OR of 1.32 (95% CI: 1.10-1.58) for smokers of more than 20 cigarettes per day. The risk increased with duration of smoking, to reach an OR of 1.33 (95% CI: 1.14-1.54) for more than 40 years of smoking and decreased with increasing time since stopping cigarette smoking (P for trend<0.01) and became similar to that of never smokers 10 years after stopping. Risks were somewhat higher for cardia than noncardia gastric cancer. Risks were similar when considering only studies with information on Helicobacter pylori infection and comparing all cases to H. pylori+ controls only. This study provides the most precise estimate of the detrimental effect of cigarette smoking on the risk of gastric cancer on the basis of individual data, including the relationship with dose and duration, and the decrease in risk following stopping smoking.

Rationale: We report a very rare case of safely resectable giant gastrointestinal stromal tumor (GIST) with preoperative three-dimensional computed tomography (3D-CT) angiography in spite of no neoadjuvant treatment., Patient's Concern: A 71-year-old woman presented to our hospital with an abdominal giant tumor. As this giant tumor could not be accurately diagnosed by preoperative investigation, we had to perform her surgical treatment without neoadjuvant treatment. However, preoperative 3D-CT angiography clearly showed that the tumor was supplied by the right gastroepiploic artery (RGA). Based on the preoperative information, a surgical procedure was undertaken., Diagnosis: Giant tumor of stomach with suspicion of GIST., Interventions: Laparotomy guided by 3D-CT imaging including angiography., Outcome: The giant tumor originated from the greater curvature of the distal stomach and was supplied by the RGA, as expected. The tumor was resected easily under the accurate preoperative anatomical information. The tumor measured 20 cm × 20 cm in size and weighed 2500 g (Fig. 2C and D). Histopathological examination showed evidence of growth of spindle-shaped cells and a low mitotic index (3 per 50 high-power field, Fig. 3B). Immunohistochemical examination showed positive immunoreactions for KIT, CD34, and DOG1 (Fig. 3 C-E), but negative ones for SMA and S-100 protein (Fig. 3F and G). Consequently, we made a final diagnosis of an extra luminal GIST of the stomach. The post-operative course was uneventful, and so the patient was discharged on postoperative day 13., Lessons: Making full use of an imaging procedure such as 3D-CT angiography is one of the effective tools for the surgical management of giant-size tumors including giant GISTs.

An association between heavy alcohol drinking and gastric cancer risk has been recently reported, but the issue is still open to discussion and quantification. We investigated the role of alcohol drinking on gastric cancer risk in the "Stomach cancer Pooling (StoP) Project," a consortium of epidemiological studies. A total of 9,669 cases and 25,336 controls from 20 studies from Europe, Asia and North America were included. We estimated summary odds-ratios (ORs) and the corresponding 95% confidence intervals (CIs) by pooling study-specific ORs using random-effects meta-regression models. Compared with abstainers, drinkers of up to 4 drinks/day of alcohol had no increase in gastric cancer risk, while the ORs were 1.26 (95% CI, 1.08-1.48) for heavy (>4 to 6 drinks/day) and 1.48 (95% CI 1.29-1.70) for very heavy (>6 drinks/day) drinkers. The risk for drinkers of >4 drinks/day was higher in never smokers (OR 1.87, 95% CI 1.35-2.58) as compared with current smokers (OR 1.14, 95% CI 0.93-1.40). Somewhat stronger associations emerged with heavy drinking in cardia (OR 1.61, 95% CI 1.11-2.34) than in non-cardia (OR 1.28, 95% CI 1.13-1.45) gastric cancers, and in intestinal-type (OR 1.54, 95% CI 1.20-1.97) than in diffuse-type (OR 1.29, 95% CI 1.05-1.58) cancers. The association was similar in strata of H. pylori infected (OR = 1.52, 95% CI 1.16-2.00) and noninfected subjects (OR = 1.69, 95% CI 0.95-3.01). Our collaborative pooled-analysis provides definite, more precise quantitative evidence than previously available of an association between heavy alcohol drinking and gastric cancer risk., (© 2017 UICC.)

Cytochrome P450 (CYP) 1A1 and glutathione S-transferases (GST) M1 and T1 are major enzymes in the carcinogen metabolizing pathway. We examined the association between single nucleotide polymorphisms (SNPs) of CYP1A1 (rs4646421, rs4646422 and rs1048943), GSTM1 and GSTT1 and gastric cancer risk in Japan. This is a nested case-control study (457 cases and 457 matched controls) of our population-based cohort involving 36,745 subjects who answered a baseline questionnaire and supplied blood samples. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated using conditional logistic regression models. We found that CYP1A1 (rs4646422) variant allele was associated with a statistically significant increased risk of gastric cancer compared with the homozygous wild-type genotype (OR = 1.65; 95% CI = 1.17-2.32). GSTM1 null, GSTT1 null and GSTM1/T1 both or either null genotypes were associated with increased risk, but not statistically significantly. Combination of the CYP1A1 (rs4646422) variant allele and GSTM1/T1 both or either null genotypes was associated with a statistically significant increased risk compared with the combination of the CYP1A1 homozygous wild-type genotype and the GSTM1/T1 both active genotypes. In addition, compared with CYP1A1 (rs4646422) homozygous wild-type genotypes in those who were never-smokers, CYP1A1 variant alleles in those who smoked ≥30 pack-years were associated with an increased risk; neither gene-gene nor gene-environment interactions were significant. The CYP1A1 (rs4646422) polymorphism might be involved in gastric carcinogenesis among the Japanese population., (© 2016 UICC.)

Background: Helicobacter pylori is the primary cause of gastric cancer, but about 9% of cases harbor Epstein-Barr virus (EBV) in the tumor cells. There is limited evidence on the possible interaction or antagonism between these infectious agents in gastric carcinogenesis., Methods: We compared H. pylori serologic profiles of EBV-positive (n = 58) and EBV-negative (n = 111) noncardia gastric cancer patients from the United States National Cancer Institute's International EBV-Gastric Cancer Consortium. EBV positivity of tumors was assessed by in situ hybridization. Serum levels of 15 antibodies to immunogenic proteins of H. pylori (Cad, CagA, Cagδ, CagM, Catalase, GroEL, HcpC, HP0231, HP0305, HpaA, HyuA, NapA, Omp, UreA, VacA) were assessed using bead-based multiplex serology. Logistic regression models were used to adjust odds ratios (OR) for country, age, sex, and year of diagnosis., Results: Seropositivity to individual proteins ranged up to 90% overall. Antibodies to Catalase were borderline associated with tumor EBV positivity (adjusted OR = 3.15, p = .0024, Bonferroni corrected p = .036). Distributions of other antibodies did not vary by tumor EBV status., Conclusion: Similarity of host-response indicates the essential etiological role of H. pylori in EBV-positive gastric cancer., Competing Interests: none reported, (© 2015 John Wiley & Sons Ltd.)

Gastric cancer is the fourth most common cancer worldwide. Although it is important to identify patients at high risk for a poor outcome, factors correlating with prognosis in gastric cancer are largely unknown. Here, we focus on the correlations among expression of Polo-like kinase 1 (PLK1), DNA ploidy, and clinical outcome in gastric cancer patients. Gastric cancer specimens were analyzed from 207 consecutive patients. Patients were classified into two groups according to tumor PLK1 expression and DNA content, and an analysis of their clinical outcomes was carried out. Prognoses of patients with PLK1-high tumors were worse than those of patients with PLK1-low tumors, but the differences were not statistically significant. In cell lines, overexpression of PLK1 induced centrosome amplification and multipolar spindles, potentially leading to DNA aneuploidy. Indeed, high expression of PLK1 was also associated with DNA aneuploidy in clinical gastric cancer specimens. Patients with both high PLK1 expression and DNA aneuploidy had poor recurrence-free survival, whereas PLK1 expression and DNA ploidy status alone were not significantly associated with outcome. Here, we provide clinical evidence that high expression of PLK1 could have detrimental effects in tumors with DNA aneuploidy, which may increase the risk of recurrence in gastric cancer patients., (© 2016 S. Karger AG, Basel.)

The association between alcohol consumption, genetic polymorphisms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) and gastric cancer risk is not completely understood. We investigated the association between ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms, alcohol consumption and the risk of gastric cancer among Japanese subjects in a population-based, nested, case-control study (1990-2004). Among 36 745 subjects who answered the baseline questionnaire and provided blood samples, 457 new gastric cancer cases matched to 457 controls were used in the analysis. The odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated using logistic regression models. No association was observed between alcohol consumption, ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms and gastric cancer risk. However, considering gene-environmental interaction, ADH1C G allele carriers who drink ≥150 g/week of ethanol had a 2.5-fold increased risk of gastric cancer (OR = 2.54, 95% CI = 1.05-6.17) relative to AA genotype carriers who drink 0 to <150 g/week (P for interaction = 0.02). ALDH2 A allele carriers who drink ≥150 g/week also had an increased risk (OR = 2.08, 95% CI = 1.05-4.12) relative to GG genotype carriers who drink 0 to < 150 g/week (P for interaction = 0.08). To find the relation between alcohol consumption and gastric cancer risk, it is important to consider both alcohol consumption level and ADH1C and ALDH2 polymorphisms., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aim: To determine whether the endoscopic findings of depressed-type early gastric cancers (EGCs) could precisely predict the histological type., Methods: Ninety depressed-type EGCs in 72 patients were macroscopically and histologically identified. We evaluated the microvascular (MV) and mucosal surface (MS) patterns of depressed-type EGCs using magnifying endoscopy (ME) with narrow-band imaging (NBI) (NBI-ME) and ME enhanced by 1.5% acetic acid, respectively. First, depressed-type EGCs were classified according to MV pattern by NBI-ME. Subsequently, EGCs unclassified by MV pattern were classified according to MS pattern by enhanced ME (EME) images obtained from the same angle., Results: We classified the depressed-type EGCs into the following 2 MV patterns using NBI-ME: a fine-network pattern that indicated differentiated adenocarcinoma (25/25, 100%) and a corkscrew pattern that likely indicated undifferentiated adenocarcinoma (18/23, 78.3%). However, 42 of the 90 (46.7%) lesions could not be classified into MV patterns by NBI-ME. These unclassified lesions were then evaluated for MS patterns using EME, which classified 33 (81.0%) lesions as MS patterns, diagnosed as differentiated adenocarcinoma. As a result, 76 of the 90 (84.4%) lesions were matched with histological diagnoses using a combination of NBI-ME and EME., Conclusion: A combination of NBI-ME and EME was useful in predicting the histological type of depressed-type EGC.

Aim: To identify the characteristics of gastric tube cancer (GTC) and the complications associated with endoscopic submucosal dissection (ESD) for GTC., Methods: Between 2007 and 2012, 11 individuals with early gastric cancer in the reconstructed gastric tube after esophagectomy who underwent ESD in this hospital were studied. The characteristics of GTC were identified, and the complications of ESD for GTC were analyzed at three phases: preoperative, intraoperative, and postoperative., Results: A total of 11 consecutive patients with 11 GTCs were selected for this study. All cases underwent en bloc resections by ESD. The median procedure time was 142 min. The average GTC diameter was 26.1 mm, and the average size of the resected lesions was 45.5 mm. The histopathological diagnosis in all cases was a differentiated adenocarcinoma. In the preoperative phase, anastomotic strictures (5/11, 45%) and food residues (4/11, 36.4%) in the gastric tube were the main complications. In the intraoperative phase, bleeding was observed in 5 cases (45%). The postoperative complications observed were delayed bleeding in 2 cases (18.2%) and stenosis in one case (9.1%). The case with stenosis was successfully treated using endoscopic balloon dilatation., Conclusion: Minor complications were frequently observed. However, all GTCs underwent en bloc resection with ESD without any serious complications. ESD is considered a useful treatment for GTC.

Gastric cancer affects about one million people per year worldwide, being the second leading cause of cancer mortality. The study of its etiology remains therefore a global issue as it may allow the identification of major targets, besides eradication of Helicobacter pylori infection, for primary prevention. It has however received little attention, given its comparatively low incidence in most high-income countries. We introduce a consortium of epidemiological investigations named the 'Stomach cancer Pooling (StoP) Project'. Twenty-two studies agreed to participate, for a total of over 9000 cases and 23 000 controls. Twenty studies have already shared the original data set. Of the patients, 40% are from Asia, 43% from Europe, and 17% from North America; 34% are women and 66% men; the median age is 61 years; 56% are from population-based case-control studies, 41% from hospital-based ones, and 3% from nested case-control studies derived from cohort investigations. Biological samples are available from 12 studies. The aim of the StoP Project is to analyze the role of lifestyle and genetic determinants in the etiology of gastric cancer through pooled analyses of individual-level data. The uniquely large data set will allow us to define and quantify the main effects of each risk factor of interest, including a number of infrequent habits, and to adequately address associations in subgroups of the population, as well as interaction within and between environmental and genetic factors. Further, we will carry out separate analyses according to different histotypes and subsites of gastric cancer, to identify potential different risk patterns and etiological characteristics.

Background: To evaluate the relationship between methylation status of blood leukocyte DNA and risk of gastric cancer, a population-based study was conducted in Linqu County., Methods: Methylation levels of IGFII and N33 were determined by quantitative methylation-specific PCR. The temporal trend of methylation levels during gastric cancer development was investigated in 133 gastric cancer cases from two cohorts with pre- and/or post-gastric cancer samples. As the references of pre-GCs, 204 intestinal metaplasia (IM) or dysplasia (DYS) subjects who did not progress to gastric cancer during the follow-up period were selected. Meanwhile, 285 subjects with superficial gastritis/chronic atrophic gastritis (SG/CAG) were also selected as controls., Results: IGFII median methylation level was significantly higher in gastric cancer cases than those with SG/CAG (61.47% vs. 49.73%; P < 0.001). IGFII and N33 methylation levels were elevated at least 5 years ahead of clinical gastric cancer diagnosis comparing with SG/CAG (63.38% vs. 49.73% for IGFII, 9.12% vs. 5.70% for N33; all P < 0.001). Furthermore, the frequency of hypermethylated IGFII was markedly increased in IM or DYS subjects who progressed to gastric cancer in contrast to those who remained with IM and DYS, and adjusted ORs were 12.52 [95% confidence interval (CI), 3.81-41.15] for IM and 10.12 (95% CI, 2.68-38.22) for DYS. Similar results were also found for N33 in subjects with IM (OR, 3.77; 95% CI, 1.20-11.86)., Conclusions: Our findings suggested that hypermethylated IGFII and N33 in blood leukocyte DNA were associated with risk of gastric cancer in a Chinese population., Impact: IGFII and N33 methylation status may be related to gastric carcinogenesis., (©2014 American Association for Cancer Research.)

Background: Prospective evidence is inconsistent regarding the association between vegetable/fruit intake and the risk of gastric cancer., Methods: In an analysis of original data from four population-based prospective cohort studies encompassing 191 232 participants, we used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of gastric cancer incidence according to vegetable and fruit intake and conducted a meta-analysis of HRs derived from each study., Results: During 2 094 428 person-years of follow-up, 2995 gastric cancer cases were identified. After adjustment for potential confounders, we found a marginally significant decrease in gastric cancer risk in relation to total vegetable intake but not total fruit intake: the multivariate-adjusted HR (95% CI; P for trend) for the highest versus the lowest quintile of total vegetable intake was 0.89 (0.77-1.03; P for trend = 0.13) among men and 0.83 (0.67-1.03; P for trend = 0.40) among women. For distal gastric cancer, the multivariate HR for the highest quintile of total vegetable intake was 0.78 (0.63-0.97; P for trend = 0.02) among men., Conclusions: This pooled analysis of data from large prospective studies in Japan suggests that vegetable intake reduces gastric cancer risk, especially the risk of distal gastric cancer among men., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)