Most if not all gastric cancers are associated with chronic infection of the stomach mucosa with Helicobacter pylori cagA-positive strains(1-4). Approximately 10% of gastric cancers also harbour Epstein-Barr virus (EBV) in the cancer cells(5,6). Following delivery into gastric epithelial cells via type IV secretion(7,8), the cagA-encoded CagA protein undergoes tyrosine phosphorylation on the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs initially by Src family kinases (SFKs) and then by c-Abl(9,10). Tyrosine-phosphorylated CagA binds to the pro-oncogenic protein tyrosine phosphatase SHP2 and thereby deregulates the phosphatase activity(11,12), which has been considered to play an important role in gastric carcinogenesis(13). Here we show that the SHP2 homologue SHP1 interacts with CagA independently of the EPIYA motif. The interaction potentiates the phosphatase activity of SHP1 that dampens the oncogenic action of CagA by dephosphorylating the CagA EPIYA motifs. In vitro infection of gastric epithelial cells with EBV induces SHP1 promoter hypermethylation, which strengthens phosphorylation-dependent CagA action via epigenetic downregulation of SHP1 expression. Clinical specimens of EBV-positive gastric cancers also exhibit SHP1 hypermethylation with reduced SHP1 expression. The results reveal that SHP1 is the long-sought phosphatase that can antagonize CagA. Augmented H. pylori CagA activity, via SHP1 inhibition, might also contribute to the development of EBV-positive gastric cancer.

Background The survival impact of the geriatric nutrition risk index (GNRI) has yet to be investigated in patients undergoing gastric carcinoma (GC) surgery. Methods In total, 1166 GC patients who underwent radical gastrectomy were retrospectively reviewed. The predictive and discrimination abilities for overall survival (OS) were compared among GNRI, nutrition indices, and systemic inflammatory markers. Patients were dichotomized by GNRI (GNRI <98, low; GNRI ≥98, high), and the impacts of GNRI on OS and cancer‐specific survival (CSS) were evaluated using Cox hazards analysis. Results GNRI showed superior discrimination and predictive ability for OS as compared with other indices. There were 447 (38.3%) and 719 (61.7%) patients in the low‐ and high‐GNRI groups, respectively. Patients with low GNRI were older and had a higher pStage III disease rate than those with high GNRI (P < .001). OS curves were significantly stratified by GNRI in all patients (P < .001) and those with pStage I (P < .001), II (P < .001), and III (P = .02) disease. Multivariate analysis showed low GNRI to be independently associated with poor OS (hazard ratio [HR], 2.15; 95% CI, 1.612.87; P < .001). Furthermore, low GNRI was an independent predictor of poor CSS (HR, 1.61; 95% CI, 1.072.44; P = .02), as were total gastrectomy (P < .001) and pStage III disease (P < .001). Patients who had low GNRI and underwent total gastrectomy showed quite poor 5‐year OS (54.8%). Conclusion GNRI is useful for predicting survival and oncological outcomes in GC patients.

<b><i>Background:</i></b> Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. GC is a pathologically and molecularly heterogeneous disease. DNA hypermethylation in promoter CpG islands causes silencing of tumor-suppressor genes and thus contributes to gastric carcinogenesis. In addition, various molecular aberrations, including aberrant chromatin structures, gene mutations, structural variants, and somatic copy number alterations, are involved in gastric carcinogenesis. <b><i>Summary:</i></b> Comprehensive DNA methylation analyses revealed multiple DNA methylation patterns in GCs and classified GC into distinct molecular subgroups: extremely high-methylation epigenotype uniquely observed in GC associated with Epstein-Barr virus (EBV), high-methylation epigenotype associated with microsatellite instability (MSI), and low-methylation epigenotype. In The Cancer Genome Atlas classification, EBV and MSI are extracted as independent subgroups of GC, whereas the remaining GCs are categorized into genomically stable (GS) and chromosomal instability (CIN) subgroups. EBV-positive GC, exhibiting the most extreme DNA hypermethylation in the whole human malignancies, frequently shows <i>CDKN2A</i> silencing, <i>PIK3CA</i> mutations, <i>PD-L1/2</i> overexpression, and lack of <i>TP53</i> mutations. MSI, exhibiting high DNA methylation, often has <i>MLH1</i> silencing and abundant gene mutations. GS is generally a diffuse-type GC and frequently shows <i>CDH1/RHOA</i> mutations or <i>CLDN18–ARHGAP</i> fusion. CIN is generally an intestinal-type GC and frequently has <i>TP53</i> mutations and genomic amplification of receptor tyrosine kinases. <b><i>Key Messages:</i></b> The frequency and targets of genetic aberrations vary depending on the epigenotype. Aberrations in the genome and epigenome are expected to synergistically interact and contribute to gastric carcinogenesis and comprehensive analyses of those in GCs may help elucidate the mechanism of carcinogenesis.

Preoperative PNI, a score related to nutritional status, is of importance for predicting long-term outcomes in patients with GC and AEG.

Patients with gastric cancer typically face gastrectomies even when few or no nodal metastases are reported. Current procedures poorly predict lymphatic metastases; thus, evaluation of target molecules expressed on cancer cell membranes is necessary for in vivo detection. However, marker development is limited by the intratumoral heterogeneity of gastric cancer cells. In this study, multiple gene expression arrays of 42 systemic normal tissue samples and 56 gastric cancer samples were used to investigate two adhesion molecules, cadherin 17 (CDH17) and claudin 18 (CLDN18), which are intestinal and gastric markers, respectively. Expression of CDH17 and CLDN18 was partially redundant, but overlapped in 50 of 56 cases (89.3%). Tissue microarrays constructed using primary lesions and nodal metastases of 106 advanced gastric cancers revealed CDH17 and CLDN18 expression in 98 positive cases of 106 (92%). Hierarchical clustering classified gastric cancers into three subgroups, CDH17(++)/CLDN18(+/−), CDH17(++)/CLDN18(++) or CDH17(+)/CLDN18(+), and CDH17(−)/CLDN18(++/+/−). Whole tissue sections displayed strong, homogeneous staining for CDH17 and CLDN18. Together, these results indicate that CDH17 and CLDN18 are useful target molecules; moreover, their coupling can aid in the comprehensive detection and localization of gastric cancer metastases in vivo to overcome challenges associated with intratumoral heterogeneity.

Adenocarcinoma of the esophagogastric junction (AEG) has heterogeneous carcinogenic process due to its location straddling the esophagogastric junction. We assessed background mucosal pathology and its correlation with clinicopathological features of each Siewert type of AEG. Clinicopathological and immunohistochemical analyses of 103 AEGs and 58 gastric cancers (GCs) were conducted. Background mucosal features were evaluated according to the updated Sydney System. Siewert classification divided 103 AEGs into three type I, 75 type II, and 25 type III tumors, respectively. Two type I, 9 type II AEGs, and none of type III AEGs were Barrett‐related and were excluded from further analysis. Background mucosa of type III AEGs more frequently showed moderate to marked degree of atrophy and intestinal metaplasia than those of type II AEGs and was very similar to those of GCs. Among type II AEGs, tumors with atrophic background were significantly associated with higher patient age and intestinal‐type histology. Type II AEGs with nonatrophic background, but not those with atrophic background, showed more frequent mismatch repair deficiency, TP53 overexpression, and less frequent intestinal phenotypic markers expression than type III AEG or GC. Type II AEGs with atrophic background involved suprapancreatic nodes more frequently than those without. We demonstrated that chronic atrophic gastritis was a major precancerous condition of AEG in the Japanese population, especially Siewert type III which had background mucosal pathology similar to that of GC. Type II AEGs with and without atrophic background showed some clinicopathological differences, and these observations might represent heterogeneous carcinogenic process within type II AEGs.

Solitary fibrous tumor (SFT) is one of the mesenchymal tumors, which rarely arises in the abdominal space. We report a very rare case of abdominal SFT, mimicking another mesenchymal tumor. A 52-year-old Japanese man was referred to our hospital for further evaluation and treatment of gallbladder polyp. Contrast-enhanced computed tomography (CT) showed an enhanced nodule within the gallbladder, and incidentally, also showed a well-circumscribed mass adjacent to the small intestine. The mass was depicted as slightly high density in plain CT, and with contrast-enhancement, the mass was partially stained in early phase and the stained area spread heterogeneously in delayed phase. Magnetic resonance imaging showed that the abdominal mass was depicted as slightly high intensity on T2-weighted imaging and low intensity on T1-weighted imaging. With double-balloon endoscopy and capsule endoscopy, we did not find any tumor inside the small intestine. These visual findings lead us to diagnose it as gastrointestinal stromal tumor of the small intestine with extraluminal growth. We planned to resect both the gallbladder polyp and the intraperitoneal tumor at the same time for pathologic diagnosis and treatment. When the operation was performed, we found a milk-white lobulated tumor on the greater omentum and the tumor was entirely resected. Microscopically, the gallbladder polyp was diagnosed as tubular adenoma, and the omental tumor was diagnosed as SFT. It is important to bear in mind that omental SFTs sometimes mimic other mesenchymal tumors and should be included in the differential diagnosis of abdominal tumor not revealed by endoscopy.

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