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BackgroundGastric adenocarcinoma of fundic-gland type (GA-FG) is a rare variant of gastric neoplasia. However, the etiology, classification, and clinicopathological features of gastric epithelial neoplasm of fundic-gland mucosa lineage (GEN-FGML; generic term of GA-FG related neoplasm) are not fully elucidated. We performed a large, multicenter, retrospective study to establish a new classification and clarify the clinicopathological features of GEN-FGML.MethodsOne hundred GEN-FGML lesions in 94 patients were collected from 35 institutions between 2008 and 2019. We designed a new histopathological classification of GEN-FGML using immunohistochemical analysis and analyzed via clinicopathological, immunohistochemical, and genetic evaluation.ResultsGEN-FGML was classified into 3 major types; oxyntic gland adenoma (OGA), GA-FG, and gastric adenocarcinoma of fundic-gland mucosa type (GA-FGM). In addition, GA-FGM was classified into 3 subtypes; Type 1 (organized with exposure type), Type 2 (disorganized with exposure type), and Type 3 (disorganized with non-exposure type). OGA and GA-FG demonstrated low-grade epithelial neoplasm, and GA-FGM should be categorized as an aggressive variant of GEN-FGML that demonstrated high-grade epithelial neoplasm (Type 2 > 1, 3). The frequent presence of GNAS mutation was a characteristic genetic feature of GEN-FGML (7/34, 20.6%; OGA 1/3, 33.3%; GA-FG 3/24, 12.5%; GA-FGM 3/7, 42.9%) in mutation analysis using next-generation sequencing.ConclusionsWe have established a new histopathological classification of GEN-FGML and propose a new lineage of gastric epithelial neoplasm that harbors recurrent GNAS mutation. This classification will be useful to estimate the malignant potential of GEN-FGML and establish an appropriate standard therapeutic approach.

Gut commensal microbes affect the development and activation of the mucosal and systemic immune systems. However, the exact molecular mechanism of these microbes that is involved in the development of colitis remains unclear. The present study was conducted to determine the distinct role of the innate immune system in the development of a dextran sulfate sodium (DSS) colitis model in MyD88(-/-) mice, because myeloid differentiation protein (MyD88) is a major adaptor molecule essential for signaling via Toll-like receptors (TLRs). To this end, MyD88(-/-) and wild-type (WT) mice received sterile distilled water containing 1.2% DSS for 8 days. The survival rate, total clinical score (body weight loss, stool consistency, and rectal bleeding), colon length, and histological score were assessed. The expression of surface markers (F4/80 and CD4) on infiltrating lamina propria mononuclear cells was analyzed immunohistochemistrically. MyD88(-/-) mice exhibited increased susceptibility to DSS-induced colitis, as reflected by significantly higher lethality and higher clinical and histological scores, and more severe colonic shortening compared to WT mice. Immunohistochemical analysis revealed a significant increase of both F4/80+ macrophages and CD4+ T cells in the inflamed mucosa in DSS-fed MyD88(-/-) mice compared to DSS-fed WT mice. These findings suggest that, via MyD88 signaling, the innate immune system in the gut plays an important protective role in colitis.

Background The effectiveness of esophagogastroduodenoscopy (EGD) screening in cohorts with low Helicobacter pylori prevalence is unknown. This study aimed to develop an optimally efficient EGD screening strategy for detecting H. pylori -naïve gastric neoplasms (HpNGNs). Methods EGD data of 12 institutions from 2016 to 2022 were retrospectively analyzed. Age-related HpNGN prevalence, tumor growth rate, missing rate, and detection threshold size were calculated from the databases. Subsequently, using clinical data, a novel mathematical model that simultaneously simulated demographic changes and HpNGN detection was developed. Screening strategies using different starting ages (40/45/50 years) and intervals (2/5/10 years) were also compared. The detection rates of all tumors occurring within the virtual cohort and number-needed-to-test (NNT) were measured as outcomes. Results Data of 519,368 EGDs and 97 HpNGNs (34 pure signet ring cell carcinomas, 26 gastric adenocarcinomas of the fundic gland type, 30 foveolar gastric adenoma-Raspberry type, and seven undifferentiated-type cancer cases) were analyzed. A virtual cohort with a 70-year time horizon was used to simulate the occurrence, growth, and detection of 346,5836 people. Among the strategies with detection rate > 50%, the screening strategy with a 5-year interval starting at 45 years of age had the lowest NNT. Adopting this strategy, most HpNGNs were detected at < 20 mm in size, and the deep submucosal invasion rate was less than 30%. Conclusions A mathematical simulation model revealed that screening every 5 years starting at 45 years of age could efficiently assist in identifying HpNGNs at an early stage.

INTRODUCTION: In recent years, new molecularly defined tumor groups have been reported among tumors previously considered unclassifiable. Among them, gene fusions involving the CREB family of transcription factors, including cAMP-responsive element modulator (CREM), with genes encoding FET family RNA-binding proteins, such as Ewing sarcoma breakpoint region 1 (EWSR1), have recently been shown to be implicated in driving the pathogenesis of various tumor types. Here, we report our experience with a gastric mesenchymal tumor with epithelioid histology and an EWSR1::CREM fusion, which is rare but requires caution.CASE PRESENTATION: A 58-year-old man with epigastric pain underwent esophagogastroduodenoscopy, which revealed a submucosal tumor, 40 × 30 mm in size, at the greater curvature of the upper gastric body. Surgical resection was scheduled because of easy bleeding from the tumor and because biopsy could not establish a diagnosis. The tumor was clinically considered benign because there was no significant accumulation on positron emission tomography scans. Therefore, we performed a local resection of the stomach. Histologically, the tumor consisted of a proliferation of keratin-positive, relatively uniform epithelioid cells arranged in sheets, with a scattering of lymphoid follicles in the surrounding area. Based on a pathology consultation, the tumor was diagnosed as a mesenchymal tumor with EWSR1::CREM fusion.CONCLUSION: We experienced a gastric epithelioid mesenchymal tumor with EWSR1::CREM fusion genes. Since a malignant course has been reported in similar tumors in the stomach and abdominal cavity, such patients require careful follow-up.

Based on Pasteur's work on the microbial nature of fermentation, it was widely believed that the presence of bacteria in the intestine was essential for the life of the host. It has also been known for decades that gut commensal microbes effect the activation and development of the systemic immune system through gut-associated lymphoid tissues (GALT). Recent extensive studies have shown that recognition of microbes is mediated by a set of germline-encoded receptors, Toll-like receptors (TLRs), in mammals. This article reviews the role of the innate immunity system in the development of GALT and the pathogenesis of inflammatory bowel diseases (IBD).