Non-conventional dysplasias of the tubular gut: a review and illustration of their histomorphological spectrum.

The increasing use of gastrointestinal endoscopic procedures has led to the recognition by histopathologists of non-conventional (or special-type) dysplasias of the gastrointestinal tract. These lesions can be recognised in association with prevalent underlying gastrointestinal conditions, such as Barrett oesophagus, chronic atrophic gastritis, and inflammatory bowel disease. The diagnosis of these special types can be challenging, and their biological behaviours are not fully characterised. The aim of this review is to provide a global view of non-conventional dysplastic lesions observed in the various segments of the tubular gastrointestinal tract and describe their salient features. Furthermore, as the clinical implications of these various subtypes have not been broadly tested in practice and are not represented in most management guidelines, we offer guidance on the best management practices for these lesions.

Comparison of pancreatic volume and fat amount linked with glucose homeostasis between healthy Caucasians and Koreans.

AIM: To compare pancreatic volume and fat amount, and their associations with glucose homeostasis, in a Korean and a white population. MATERIALS AND METHODS: In 43 healthy Korean and 43 healthy white people, matched for age (±3 years) and body mass index (BMI; ±1 kg/m2 ), we measured pancreatic volume and fat amount in the pancreas and abdomen using computed tomography. Pancreatic ß-cell function and insulin resistance were estimated according to biochemical characteristics and a 75-g oral glucose tolerance test. Body composition and resting energy expenditure (REE) were examined using bioimpedance and indirect calorimetry, respectively. RESULTS: The mean ±SD age of the participants was 29.9 ± 5.9 years and 30.0 ± 5.2 years, and BMI was 24.0 ±3.7 and 24.1 ±3.2 kg/m2 in the white participants and the Korean participants, respectively. Pancreatic volume in the white participants was greater than that in Korean participants (77.8 ±11.6 vs 68.2 ±12.1 cm3 ; P < .001). Pancreatic fat content in Korean participants was 22.8% higher than in white participants (P = .051). Insulinogenic index, disposition index, muscle mass and REE were significantly lower in Korean participants. Pancreatic volume was positively associated with indices linked to ß-cell function; fat content in the pancreas was negatively associated with such indices, and positively with insulin resistance after adjusting for relevant variables including REE. CONCLUSIONS: A smaller pancreas and higher fat deposition might be crucial determinants of vulnerability to diabetes in Korean people compared with white people with similar BMI and body fat levels.

A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.

We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.

The p65 subunit of nuclear factor-kappaB is a molecular target for radiation sensitization of human squamous carcinoma cells.

The transcription factor nuclear factor-kappaB (NF-kappaB) is activated in response to various stimuli including ionizing radiation. Disruption of NF-kappaB activation by mutant forms of the NF-kappaB inhibitor IkappaB-alpha or by proteasome inhibitors enhances both sensitivity to radiation and radiation-induced apoptosis. Human squamous carcinoma SCC-35 cells stably expressing a fragment (residues 1 to 84) of human p65 have been shown to exhibit down-regulation of both endogenous p65 mRNA and its protein. The mutant protein also inhibited radiation-induced NF-kappaB activation by preventing the proteolysis of IkappaB-alpha. This resulted in enhancement of cellular radiosensitivity and radiation-induced apoptosis. The NH(2)-terminal region of p65 is thus a potential molecular target for disruption of NF-kappaB activation and sensitization of tumors to radiotherapy.

Pyloric gland adenoma in Lynch syndrome.

The prevalence of gastric cancer associated with Lynch syndrome (LS) is highly variable, and the underlying histologic pathway or molecular mechanisms remain unclear. From 1995 to 2012, 15 patients had been treated for both gastric and colonic adenocarcinomas and diagnosed as LS. In all cases, pathologic review, immunohistochemical analysis for mismatch-repair proteins, and microsatellite instability (MSI) tests were performed. To confirm LS, germline mutation tests and multiplex ligation-dependent probe amplification were performed. All gastric and colonic carcinomas were MSI-high and lost expressions of MLH1/PMS2 in 11 (73%) cases and MSH2/MSH6 in 4 (27%) cases. Remarkably, in a patient with LS and germline mutation of MLH1 gene, pyloric gland adenoma (PGA) transformed to adenocarcinoma during follow-up. In 2 additional cases, PGA was found adjacent to advanced gastric cancers. All PGAs in LS patients were MSI-high and lost expression of mismatch-repair proteins (MLH1/PMS2 in 2 cases and MSH2/MSH6 in 1 case), whereas none of the 14 sporadic PGAs was MSI-high or had lost expression of mismatch-repair proteins. On the basis of these observations, although very rare, we suggest the possibility that PGA may be a precursor lesion to gastric adenocarcinoma in LS and that the mismatch-repair deficient pathway of carcinogenesis is involved early in the gastric carcinogenesis pathway.