Search

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate; therefore, the development of effective treatments is a priority. The stimulator of interferon genes (STING) pathway enhances tumor immunity by inducing the production of type 1 interferon (IFN) and proinflammatory cytokines and chemokines and promoting the infiltration of cytotoxic T cells. To assess the function of STING on pancreatic tumorigenesis, Ptf1aER-Cre/+ LSL-KrasG12D/+ p53loxP/loxP mice (KPC mice) and Ptf1aER-Cre/+ LSL-KrasG12D/+ p53loxP/loxP/STING−/− mice (KPCS mice) were generated. However, STING deletion did not affect pancreatic tumorigenesis in mice. Because STING is expressed not only in immune cells but also in cancer-associated fibroblasts (CAFs), we evaluated the STING function in PDAC CAFs. A mouse STING agonist 5,6-Dimethyl-9-oxo-9H-xanthene-4-acetic acid (DMXAA) was administered to KPC mice and CAFs from KPC mice and the resulting immune response was evaluated. DMXAA activated STING in PDAC CAFs in KPC mice, promoting cytotoxic T cell infiltration by secreting proinflammatory cytokines and enhancing tumor immunity. We next generated STING-deficient PDAC cells and subcutaneous tumors in which STING was expressed only in CAFs by performing bone marrow transplantation and assessed the antitumor effect of STING-activated CAFs. The administration of DMXAA to subcutaneous tumors expressing STING only in CAFs sustained the antitumor effect of DMXAA. About half of human PDACs lacked STING expression in the cancer stroma, suggesting that STING activation in PDAC CAFs exerts an antitumor effect, and STING agonists can be more effective in tumors with high than in those with low STING expression in the stroma. [ABSTRACT FROM AUTHOR]

Background: In the absence of Helicobacter pylori (HP) infection, a characteristic gastric mucus adhesion may appear during the use of vonoprazan. We named this novel characteristic mucus "web-like mucus" (WLM). This study aimed to determine the incidence and risk factors for WLM. Methods: Between January 2017 and January 2022, 5665 patients were enrolled in this study. The patients were divided into a proton-pump inhibitor (PPI)-prescribed group (n = 2000), a vonoprazan-prescribed group (n = 268), and a no-PPI/vonoprazan-prescribed (n = 3397) group, and the presence of WLM was examined. After excluding four patients with autoimmune gastritis, the remaining 264 patients in the vonoprazan group were divided into WLM and non-WLM groups, and their clinical features were analyzed. Results: A total of 55 (21%) patients had WLM, all in the vonoprazan-prescribed group. There were no significant differences in factors such as, sex, age, chronic kidney disease, diabetes mellitus, HP eradication history, smoking, or alcohol consumption between the WLM and non-WLM groups. The median duration from the start of vonoprazan administration to the endoscopic detection of WLM was 2 (1–24) months. Conclusions: WLM appears to be a characteristic feature in patients treated with vonoprazan. [ABSTRACT FROM AUTHOR]

Background and Aim: To date, no randomized trials have compared the efficacy of 7‐day vonoprazan, amoxicillin, and metronidazole triple therapy (VAM) versus 7‐day vonoprazan, amoxicillin, and clarithromycin triple therapy (VAC) as a first‐line treatment for Helicobacter pylori eradication. This study was performed to compare the efficacy of VAM and VAC as first‐line treatments. Methods: This prospective multicenter randomized trial was performed in Japan and involved 124 H. pylori‐positive patients without a history of eradication. Patients without antibiotic resistance testing of H. pylori were eligible. The patients were randomized to receive either VAC (vonoprazan 20 mg + amoxicillin 750 mg + clarithromycin 200 or 400 mg twice a day) or VAM (vonoprazan 20 mg + amoxicillin 750 mg + metronidazole 250 mg twice a day) for 7 days, with stratification by age and sex. Eradication success was evaluated using the 13C‐urea breath test. We evaluated safety using patient questionnaires (UMIN000025773). Results: The intention‐to‐treat and per‐protocol eradication rates of VAM were 91.3% (95% confidence interval [CI], 82.0–96.7%) and 92.6% (95% CI, 83.7–97.6%), respectively, and those of VAC were 89.1% (95% CI, 77.8–95.9%) and 96.1% (95% CI, 86.5–99.5%), respectively. No significant difference was observed between VAM and VAC in either analysis (P = 0.76 and P = 0.70, respectively). Abdominal fullness was more frequent in patients who received VAM than VAC. Conclusions: These findings suggest that VAM as a first‐line treatment in Japan can be categorized as grade B (intention‐to‐treat cure rate of 90–95%) and have potential as a first‐line national insurance ‐approved regimen. [ABSTRACT FROM AUTHOR]

Background and Aim: The incidence of metachronous gastric cancer (MGC) after endoscopic treatment for early gastric cancer (EGC) is high, but a method of risk assessment for MGC based on endoscopic findings has not been established. In this study, we focused on endoscopic intestinal metaplasia (IM) and investigated the risk for MGC after endoscopic submucosal dissection (ESD) for EGC. Methods: This retrospective observational study involved patients who underwent curative ESD for EGC from April 2015 to January 2021. We assessed endoscopic IM using the pretreatment endoscopic examination images. The severity of endoscopic IM was classified into four levels: 0 (none), 1 (mild), 2 (moderate), and 3 (severe). Four different gastric areas were evaluated. We divided the patients into a low‐score group and a high‐score group, and compared the cumulative incidence of MGC. Results: In total, 156 patients who met the inclusion criteria were followed up for at least 12 months after ESD, and MGC developed in 14 patients during a mean period oof 41.5 months. The endoscopic IM scores in the lesser curvature of the antrum, lesser curvature of the corpus, and greater curvature of the corpus were higher in patients with MGC than in those without MGC. In the corpus, the 5‐year cumulative incidence of MGC was significantly higher in the high‐score group than in the low‐score group (29.8% vs 10.0%, P = 0.004). Conclusion: The severity of endoscopic corpus IM was associated with MGC. Thus, patients with severe corpus IM at the time of ESD require careful examination and intensive follow‐up. [ABSTRACT FROM AUTHOR]

Background: To date, no interventional trial has assessed the efficacy and safety of vonoprazan and high‐dose (500 mg four times daily, 2000 mg/day) amoxicillin dual therapy in terms of Helicobacter pylori eradication. We explored whether this was an appropriate first‐line treatment. Methods: This prospective, dual‐center, single‐arm interventional study was performed in Japan. Twenty H. pylori‐positive patients lacking any eradication history were treated with vonoprazan 20 mg twice daily and amoxicillin 500 mg four times daily (qid) for 7 days. Eradication was evaluated using a stool H. pylori antigen test. We evaluated safety using patient questionnaires. This study was registered in the jRCT database (jRCT031200128). Results: The intention‐to‐treat and per‐protocol eradication rates were 90% (95% confidence interval [CI] 68.3–98.8%, n = 20) and 94.4% (95% CI 72.7–99.9%, n = 18) respectively. No significant adverse event was recorded. Conclusion: Vonoprazan/high‐dose amoxicillin dual therapy can be a safe standard first‐line therapy. We are now undergoing a randomized controlled trial comparing dual therapy and vonoprazan‐based triple therapy. [ABSTRACT FROM AUTHOR]

According to cancer genome sequences, more than 90% of cases of pancreatic ductal adenocarcinoma (PDAC) harbor active KRAS mutations. Digital PCR (dPCR) enables accurate detection and quantification of rare mutations. We assessed the dynamics of circulating tumor DNA (ct‐DNA) in patients with advanced PDAC undergoing chemotherapy using dPCR. KRAS G12/13 mutation was assayed by dPCR in 47 paired tissue‐ and ct‐DNA samples. The 21 patients were subjected to quantitative ct‐DNA monitoring at 4 to 8‐week intervals during chemotherapy. KRAS mutation was detected in 45 of those 47 patients using tissue DNA. In the KRAS mutation‐negative cases, next‐generation sequencing revealed KRAS Q61K and NRAS Q61R mutations. KRAS mutation was detected in 23/45 cases using ct‐DNA (liver or lung metastasis, 18/19; mutation allele frequency [MAF], 0.1%‐31.7%; peritoneal metastasis, 3/9 [0.1%], locally advanced, 2/17 [0.1%‐0.2%]). In the ct‐DNA monitoring, the MAF value changed in concordance with the disease state. In the 6 locally advanced cases, KRAS mutation appeared concurrently with liver metastasis. Among the 6 cases with liver metastasis, KRAS mutation disappeared during the duration of stable disease or a partial response, and reappeared at the time of progressive disease. The median progression‐free survival was longer in cases in which KRAS mutation disappeared after an initial course of chemotherapy than in those in which it was continuously detected (248.5 vs 50 days, P <.001). Therefore, ct‐DNA monitoring enables continuous assessment of disease state and could have prognostic utility during chemotherapy. [ABSTRACT FROM AUTHOR]

Background and Aim: This was a prospective, randomized trial of the efficacy of vonoprazan‐based and proton‐pump inhibitor‐based 7‐day triple regimens with amoxicillin and sitafloxacin as a third‐line therapy for eradicating Helicobacter pylori after failure of clarithromycin‐based and metronidazole‐based first‐line and second‐line therapy. Methods: We enrolled 63 patients positive for H. pylori in whom first‐line and second‐line regimens for eradicating failed. Patients were randomized to the V‐AS group (vonoprazan 20‐mg bid, amoxicillin 750‐mg bid, and sitafloxacin 100‐mg bid for 7 days) or PPI‐AS group (esomeprazole 20‐mg bid, rabeprazole 10‐mg bid, or lansoprazole 30‐mg bid; amoxicillin 750‐mg bid; and sitafloxacin 100‐mg bid for 7 days). We assessed the outcome of eradication therapy using the 13C‐urea breath test. We evaluated safety using patient questionnaires. This study was registered in the UMIN Clinical Trials Registry (UMIN000016336). Results: The intention‐to‐treat and per‐protocol eradication rates of V‐AS were 75.8% (95% confidence interval [CI]: 57.7–88.9%) and 83.3% (95% CI: 65.3–94.4%), respectively. The respective eradication rates of PPI‐AS were 53.3% (95% CI: 34.3–71.7%) and 57.1% (95% CI: 37.2–75.5%). In per‐protocol analyses, the eradication rate of the V‐AS group was significantly higher than that of the PPI‐AS group (P = 0.043); however, no significant differences were observed in intention‐to‐treat analyses (P = 0.071). Questionnaire scores did not differ significantly between the groups. Conclusions: The findings suggest that 7‐day triple therapy with vonoprazan, amoxicillin, and sitafloxacin is more effective than proton‐pump inhibitor, amoxicillin, and sitafloxacin as a third‐line regimen for eradicating H. pylori. [ABSTRACT FROM AUTHOR]