Clinicopathological and prognostic features of Epstein-Barr virus infection, microsatellite instability, and PD-L1 expression in gastric cancer.

BACKGROUND AND OBJECTIVES: Gastric cancer (GC) has recently been categorized in molecular subtypes, which include Epstein-Barr (EBV)-positive and microsatellite instability (MSI) tumors. This distinction may provide prognostic information and identifies therapeutic targets. The aim of this study was to evaluate EBV, MSI, and PD-L1 immunoexpression in GC and its relationship with clinicopathological characteristics and patient's prognosis. METHODS: We evaluated 287 GC patients who underwent D2-gastrectomy through immunohistochemistry for DNA mismatch repair proteins and PD-L1, and in situ hybridization for EBV detection utilizing tissue microarray. RESULTS: EBV-positive and MSI were identified in 10.5% and 27% of the GCs, respectively. EBV positivity was associated to male gender (P = 0.032), proximal location (P < 0.001), undetermined Lauren type (P < 0.001), poorly differentiated histology (P = 0.043) and severe inflammatory infiltrate (P < 0.001). MSI-tumors were associated to older age (P = 0.002), subtotal gastrectomy (P = 0.004), pN0 (P = 0.024) and earlier TNM stage (P = 0.020). PD-L1-positive was seen in 8.8% of cases, with predominant expression in EBV-positive GC (P < 0.001). MSI was associated to better survival outcomes. CONCLUSION: EBV-positive GCs had increased PD-L1 expression, while MSI GC had better survival outcome. EBV and MSI subgroups are distinct GC entities, their recognition is feasible by conventional techniques, and it may help individualize follow-up and guide adjuvant therapy.

Do colorectal cancer resections improve diabetes in long-term survivors? A case-control study.

BACKGROUND: A clinical study was designed that aimed to analyze whether resection of the large bowel in cancer patients might benefit diabetes mellitus. METHODS: This prospective case-control study included retrospective information. Patients (n = 247) included diabetic and euglycemic groups with colorectal cancer operations (n = 60), cancer gastrectomy (n = 72), exclusive chemoradiotherapy for rectal cancer (n = 46), and noncancer clinical controls (n = 69). Follow-up periods were, respectively, 79.2 ± 27.4, 86.8 ± 25.1, 70.0 ± 26.3, and 85.1 ± 18.2 months (NS). Diabetes groups included patients with prediabetes. RESULTS: Diabetes remission, defined as conversion from diabetes to prediabetes or from this condition to normal, was documented in, respectively, 32.4 % (11 of 34), 41.2 % (14 of 34), 7.1 % (1 of 14), and 7.7 % (3 of 39) in the four cohorts (P = 0.004). Within the same period, progression of euglycemic participants to diabetes occurred in 30.8 % (8 of 26), 63.2 % (24 of 38), 25.0 (8 of 32), and 20.0 % (6 of 30) (P = 0.028). Diabetes amelioration was associated with weight loss in gastrectomy patients but not in the other groups. Dietary intake, estimated in the two surgical populations, did not predict outcome. CONCLUSIONS: Diabetes amelioration after colorectal interventions was demonstrated, but progression of euglycemic patients toward prediabetes was not changed in comparison with nonsurgical controls. It is speculated that reshaping of the bowel microbiome or hormone changes after colorectal interventions underlay the improvement in diabetes. Body weight fluctuations could not be incriminated in this investigation.

Does Roux-en-Y gastrectomy for gastric cancer influence glucose homeostasis in lean patients?

BACKGROUND: Cancer gastrectomy seems to benefit type 2 diabetes; however, results are conflicting. In a prospective protocol, including retrospective information, the aim was assessment of changes in glucose profile in patients with both normal and deranged preoperative glucose homeostasis. METHODS: Patients (N = 164) with curative subtotal or total Roux-en-Y gastrectomy for gastric cancer (n = 92), or Roux-en-Y gastric bypass for morbid obesity (RYGB, n = 72) were preoperatively classified into diabetes (including prediabetes) and control group. Postoperative diabetes outcome was stratified as responsive or refractory, and results in controls were correspondingly defined as stable or new-onset diabetes (NOD), according to fasting blood glucose and HbA1c. Dietary intake and biochemical profile was documented. Statistical methods included analysis of variance, multivariate logistic regression, and propensity score matching according to postoperative weight loss. RESULTS: Age of cancer cases was 67.9 ± 11.5 years, 56.5 % males, initial body mass index (BMI) 24.7 ± 3.7, current BMI 22.6 ± 3.8 kg/m(2), and follow-up 102.1 ± 51.0 months, whereas in bariatric individuals age was 51.4 ± 10.1 years, 15.3 % males, initial BMI 56.7 ± 12.2, current BMI 34.8 ± 8.1 kg/m(2), and follow-up 104.1 ± 29.7 months. Refractory disease corresponded to 62.5 % (cancer) versus 23.5 % (bariatric) (P = 0.019), whereas NOD represented 69.2 versus 23.8 % respectively (P = 0.016). Weight loss (ΔBMI) was associated with diabetes response in cancer patients but not with NOD. No difference between subtotal and total gastrectomy was detected. Divergent outcomes (refractory vs. responsive) were confirmed in BMI-similar, propensity-matched cancer gastrectomy patients with preoperative diabetes, consistent with weight-dependent and -independent benefits. CONCLUSIONS: Diabetes response was confirmed, however with more refractory cases than in bariatric controls, whereas high proportions of NOD occurred. Such dichotomous pattern seems unusual albeit consistent with previous studies.

Clinicopathologic and immunohistochemistry characterization of synchronous multiple primary gastric adenocarcinoma.

The aim of this investigation was to evaluate clinicopathologic and immunohistochemical characteristics of synchronous primary gastric adenocarcinomas. Immunohistochemistry for p53 (suppressor pathway) and for hMLH1, hMSH2, and hMSH6 (mutator pathway) was performed using ABC-technique amplification by biotinylated tyramide. Synchronous primary gastric adenocarcinomas were detected in 19/553 (3.43%) of the patients. The tumors were localized in distal stomach in 22, body in 14, and proximal in five. There was a predominance of intestinal type in the group of synchronic tumors compared to the solitary lesions, 73.2 vs 37.3%, p = 0.001. Synchronous neoplasias were diagnosed in earlier stage than solitary neoplasias, T1-T2 = 60.9% vs T1-T2 = 28.4%, p = 0.0001; and N0 = 68.4% vs N0 = 26.2%, p = 0.001. p53 was detected in 52.6% of the patients with synchronous tumors. Altered hMLH1 immunoexpression occurred in 26.3% of the patients and hMSH6 in 5.3%. hMSH2 immunoreactivity was positive in all tumors. p53 was solely detected in 17 tumors, while hMLH1 was altered in 10/24 negative p53 tumors, p = 0.01. Synchronous gastric adenocarcinomas presented higher frequency of intestinal type and early gastric cancer in comparison to solitary gastric cancer. Two routes of carcinogenesis, mutator, and suppressor appear to be involved independently in the development of synchronous tumors.

Prognostic value of immunohistochemistry in gastric neuroendocrine (carcinoid) tumors.

UNLABELLED: Three subtypes of enterochromaffin-like cell tumors (carcinoids) have been described: type I, associated with chronic atrophic gastritis; type II, multiple endocrine neoplasia 1 and Zollinger-Ellison syndrome; and type III, sporadic tumors. OBJECTIVES: (i) To investigate the immunoexpression of Ki-67, p53 and Bcl-2 proteins in enterochromaffin-like cell (carcinoid) tumors and (ii) to evaluate the prognostic value of these markers. METHODS: Fifty-four samples from 21 patients with gastric carcinoid tumors were sectioned and immunostained using avidin-biotin peroxidase method. RESULTS: The mean age was 62.2+/-11.4 years (36-83 years-old) and 13 (61.9%) were women. Type I lesions were detected in 61.9% and type III in 38.1%. Tumors were single in 10 (47.6%) and were multiple and/or multicentric in 11 (52.4%). Nuclear p53 immunoreactivity was observed in 6/21 patients (28.6%), and all of them were type III tumors (6/8), compared with no p53 expression in type I (0/13), P=0.0002. p53 expression was also associated with high degree of cell proliferation (Ki-67-positive nuclear cells), P=0.00001. Bcl-2 expression was either unreactive or weakly positive in all tumor lesions. The mean follow-up period was 50.4 months (SD=45.2), varying from 6 to 144 months. Overall survival time of patients with positive p53 expression and high proliferative rate was significantly lower than that of negative patients (14.4 vs 123 months, P=0.0007). CONCLUSIONS: (i) p53 immunoexpression associated with high proliferative rate was useful to distinguish between type I and type III gastric carcinoid tumors and (ii) these markers were able to predict a shorter survival.