Background and objective About 9% of gastric carcinomas have Epstein–Barr virus (EBV) in the tumour cells, but it is unclear whether viral presence influences clinical progression. We therefore examined a large multicentre case series for the association of tumour EBV status with survival after gastric cancer diagnosis, accounting for surgical stage and other prognostic factors. Methods We combined individual-level data on 4599 gastric cancer patients diagnosed between 1976 and 2010 from 13 studies in Asia (n=8), Europe (n=3), and Latin America (n=2). EBV positivity of tumours was assessed by in situ hybridisation. Mortality HRs for EBV positivity were estimated by Cox regression models stratified by study, adjusted for distributions of sex (71% male), age (mean 58 years), stage (52% tumour-node-metastasis stages III or IV), tumour histology (49% poorly differentiated, 57% Lauren intestinal-type), anatomic subsite (70% non-cardia) and year of diagnosis. Variations by study and continent were assessed using study-specific HRs for EBV positivity. Results During median 3.0 years follow-up, 49% of patients died. Stage was strongly predictive of mortality, with unadjusted HRs (vs stage I) of 3.1 for stage II, 8.1 for stage III and 13.2 for stage IV. Tumour EBV positivity was 8.2% overall and inversely associated with stage (adjusted OR: 0.79 per unit change). Adjusted for stage and other confounders, EBV positivity was associated with lower mortality (HR, 0.72; 95% CI 0.61 to 0.86), with low heterogeneity among the study populations (p=0.2). The association did not significantly vary across patient or tumour characteristics. There was no significant variation among the three continent-specific HRs (p=0.4). Conclusions Our findings suggest that tumour EBV positivity is an additional prognostic indicator in gastric cancer. Further studies are warranted to identify the mechanisms underlying this protective association.

PURPOSE In the CLASSIC and MAGIC trials, microsatellite instability (MSI)–high status was a favorable prognostic and potential negative predictive factor for neoadjuvant/adjuvant chemotherapy in resectable gastric cancer (GC). Given the low prevalence of MSI-high status in GC and its association with other positive prognostic variables, large data sets are needed to draw robust evidence of its prognostic/predictive value. PATIENTS AND METHODS We performed a multinational, individual-patient-data meta-analysis of the prognostic/predictive role of MSI in patients with resectable GC enrolled in the MAGIC, CLASSIC, ARTIST, and ITACA-S trials. Prognostic analyses used multivariable Cox models (MVM). The predictive role of MSI was assessed both in an all-comer population and in MAGIC and CLASSIC trials by MVM testing of the interaction of treatment (chemotherapy plus surgery v surgery) with MSI. RESULTS MSI status was available for 1,556 patients: 121 (7.8%) had MSI-high status; 576 were European, and 980 were Asian. In MSI-high versus MSI-low/microsatellite stable (MSS) comparisons, the 5-year disease-free survival (DFS) was 71.8% (95% CI, 63.8% to 80.7%) versus 52.3% (95% CI, 49.7% to 55.1%); the 5-year overall survival (OS) was 77.5% (95% CI, 70.0% to 85.8%) versus 59.3% (95% CI, 56.6% to 62.1%). In MVM, MSI was associated with longer DFS (hazard ratio [HR], 1.88; 95% CI, 1.28 to 2.76; P < .001) and OS (HR, 1.78; 95% CI, 1.17 to 2.73; P = .008), as were pT, pN, ethnicity, and treatment. Patients with MSI-low/MSS GC benefitted from chemotherapy plus surgery: the 5-year DFS compared with surgery only was 57% versus 41% (HR, 0.65; 95% CI, 0.53 to 0.79), and the 5-year OS was 62% versus 53% (HR, 0.75; 95% CI, 0.60 to 0.94). Conversely, those with MSI-high GC did not: the 5-year DFS was 70% versus 77% (HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12). CONCLUSION In patients with resectable primary GC, MSI is a robust prognostic marker that should be adopted as a stratification factor by clinical trials. Chemotherapy omission and/or immune checkpoint blockade should be investigated prospectively in MSI-high GCs according to clinically and pathologically defined risk of relapse.

Gastrointestinal stromal tumor is characterized by a gain of function mutation of KIT gene and the expression of c-kit protein, but in 5% of cases, c-kit expression is negative although histological findings of gastrointestinal stromal tumor are most suspicious. The existence of c-kit-negative gastrointestinal stromal tumors points to the need of additional markers for making the diagnosis. In this study, we studied the expression of PKCh and correlated their expression with other immunohistochemical profiles of gastrointestinal stromal tumors and evaluated their usability as a diagnostic marker. For this purpose, 220 gastrointestinal stromal tumors were immunohistochemically stained for PKCh, c-kit, CD34, a-smooth muscle actin and S-100 protein. Additionally, genetic studies of KIT and PDGFRA genes were performed using c-kit-negative or PKCh-negative cases. All the 220 masses were either PKCh-positive or c-kit-positive. PKCh was positive in 212 (96%) cases and c-kit was positive in 216 (98%) cases in the cytoplasm of tumor cells with a diffuse staining pattern. Out of 212 PKChpositive GISTs, 208 (98%) cases were c-kit-positive, 174 (82%) cases were CD34-positive, 62 (29%) cases were SMA-positive and S-100 protein was positive in 54 cases (26%). Genetic analyses on eight PKCh-negative cases showed exon 11 mutations of KIT gene in four cases. Two PKCh-positive and c-kit-negative GISTs showed mutations of PDGFRA gene. Our study shows that PKCh is a useful marker and it may play a role in the development of gastrointestinal stromal tumors. Together with c-kit, PKCh immunostaining can be used as an important diagnostic tool in the pathologic diagnosis of gastrointestinal stromal tumors with its high specificity and sensitivity.

ESD for expanded indication of EGC had acceptable clinical outcomes. ESD can be applied safely to properly selected patients with EGC.