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Precancerous metaplasia progression to dysplasia can increase the risk of gastric cancers. However, effective strategies to specifically target these precancerous lesions are currently lacking. To address this, we aimed to identify key signaling pathways that are upregulated during metaplasia progression and critical for stem cell survival and function in dysplasia. To assess the response to chemotherapeutic drugs, we used metaplastic and dysplastic organoids derived from Mist1-Kras mice and 20 human precancerous organoid lines established from patients with gastric cancer. Phospho-antibody array analysis and single-cell RNA-sequencing were performed to identify target cell populations and signaling pathways affected by pyrvinium, a putative anticancer drug. Pyrvinium was administered to Mist1-Kras mice to evaluate drug effectiveness in vivo. Although pyrvinium treatment resulted in growth arrest in metaplastic organoids, it induced cell death in dysplastic organoids. Pyrvinium treatment significantly downregulated phosphorylation of ERK and signal transducer and activator of transcription 3 (STAT3) as well as STAT3-target genes. Single-cell RNA-sequencing data analyses revealed that pyrvinium specifically targeted CD133+/CD166+ stem cell populations, as well as proliferating cells in dysplastic organoids. Pyrvinium inhibited metaplasia progression and facilitated the restoration of normal oxyntic glands in Mist1-Kras mice. Furthermore, pyrvinium exhibited suppressive effects on the growth and survival of human organoids with dysplastic features, through simultaneous blocking of the MEK/ERK and STAT3 signaling pathways. Through its dual blockade of MEK/ERK and STAT3 signaling pathways, pyrvinium can effectively induce growth arrest in metaplasia and cell death in dysplasia. Therefore, our findings suggest that pyrvinium is a promising chemotherapeutic agent for reprogramming the precancerous milieu to prevent gastric cancer development. [Display omitted] Pyrvinium effectively induced cell death in precancerous cells through a dual blockade of 2 different signaling pathways. Our results suggest that pyrvinium may have potential as a therapeutic agent for treatment of gastric precancerous lesions and prevention of gastric cancer development. [ABSTRACT FROM AUTHOR]

With the introduction of new therapeutic options for gastric cancer treatment, more precise preoperative staging of gastric cancer is needed. The purpose of this study was to evaluate the role of endoscopic ultrasonography (EUS) for improving the accuracy of clinical T staging by computed tomography (CT) for gastric cancer. A total of 2636 patients underwent stomach protocol CT (S-CT) and EUS, followed by gastrectomy for primary gastric adenocarcinoma between September 2012 and February 2018 at Seoul National University Hospital. The results of preoperative S-CT and EUS were compared to the postoperative pathologic staging. The overall accuracy of S-CT and EUS for T staging were 69.4% and 70.4%, respectively. When T staging was divided into T1-2 and T3-4 for clinically advanced gastric cancer (AGC), the positive predictive value for T3-4 using S-CT, EUS, and a combination of both modalities was 73.8%, 79.3%, and 85.6%, respectively. In 114 cases of indeterminate lesions between cT1 and cT2 by S-CT, EUS had a better prediction rate than the final decision based on endoscopy or the agreement between the two experts (Match rate: EUS vs. final decision, 69.3% vs. 58.8%). EUS can be a complementary diagnostic tool to clinical T staging of gastric cancer by CT for selecting T3-4 lesion. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to evaluate the nationwide benefit and cost of the national cancer screening program (NCSP) for gastric cancer treatment. Methods: For this nationwide, population‐based study, the Korean National Health Insurance Big Data Base, which included gastric cancer–related treatment information and the costs for all patients with gastric cancer who were 40 years old or older between 2004 and 2013, was restructured. Patients with gastric cancer who participated in the NCSP at least once (the screening group) were compared with those who did not participate in the NCSP (the nonscreening group). Results: The screening group (n = 116,775) spent significantly less on medical care expenses than the nonscreening group (n = 74,927) during the 5 years since the initial treatment (P <.0001). The screening group presented a significantly better prognosis for 5 and 9 years than the nonscreening group (P <.0001). The screening group revealed a 41% decreased hazard ratio (P <.0001) for death in comparison with the nonscreening group; the prognostic benefit became more obvious when treatment was started within the first 4 months after screening. The age‐standardized mortality rate ratio of the screening group versus the nonscreening group was 0.62 (P <.0001). The NCSP for gastric cancer required an average of 22,169,769 Korean Republic won (US $20,309) for 1 life‐year saved, which was less than the average gross domestic product (GDP) per capita in Korea. Conclusions: The screening group had significantly lower medical care expenses and showed a significantly better prognosis than the nonscreening group. On the basis of the GDP per capita, the NCSP for gastric cancer was cost‐effective for treatment prognosis. The nationwide, population‐based health insurance big database in Korea, where a national cancer screening program for gastric cancer was introduced in 2002, reveals that a screening group has lower medical care expenses and presents with a better prognosis than a nonscreening group even after stratification of the treatment group. On the basis of medical care expenses and screening costs, the national cancer screening program for gastric cancer is cost‐effective. [ABSTRACT FROM AUTHOR]

Objectives Malignant ascites is a sign of peritoneal seeding, which is one of the most frequent forms of incurable distant metastasis. Because the development of malignant ascites is associated with an extremely poor prognosis, determining whether it resulted from peritoneal seeding has critical clinical implications in diagnosis, choice of treatment, and active surveillance. At present, the molecular characterizations of malignant ascites are especially limited in case of gastric cancer. We aimed to identify malignant ascites-specific proteins that may contribute to the development of alternative methods for diagnosis and therapeutic monitoring and also increase our understanding of the pathophysiology of peritoneal seeding. Design & methods First, comprehensive proteomic strategies were employed to construct an in-depth proteome of ascitic fluids. Label-free quantitative proteomic analysis was subsequently performed to identify candidates that can differentiate between malignant ascitic fluilds of gastric cancer patients from benign ascitic fluids. Finally, two candidate proteins were verified by ELISA in 84 samples with gastric cancer or liver cirrhosis. Results Comprehensive proteome profiling resulted in the identification of 5347 ascites proteins. Using label-free quantification, we identified 299 proteins that were differentially expressed in ascitic fluids between liver cirrhosis and stage IV gastric cancer patients. In addition, we identified 645 proteins that were significantly expressed in ascitic fluids between liver cirrhosis and gastric cancer patients with peritoneal seeding. Finally, Gastriscin and Periostin that can distinguish malignant ascites from benign ascites were verified by ELISA. Conclusions This study identified and verified protein markers that can distinguish malignant ascites with or without peritoneal seeding from benign ascites. Consequently, our results could be a significant resource for gastric cancer research and biomarker discovery in the diagnosis of malignant ascites. [ABSTRACT FROM AUTHOR]