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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.
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Background and Objective: Rescue Helicobacter pylori eradication can be challenging. Rifabutin (RBT) demonstrates high activity against Helicobacter pylori and is incorporated into various rescue eradication regimens. This exploratory study was performed to evaluate the efficacy and safety of a rescue regimen comprising RBT, metronidazole (MNZ), and vonoprazan (VPZ). Methods: This prospective, single-center, single-arm, interventional study was performed in Japan. Eligible patients were those who underwent failed primary eradication treatment (7-day treatment with three drugs: VPZ or a proton pump inhibitor [PPI], amoxicillin [AMPC], and clarithromycin) and secondary eradication treatment (7-day treatment with three drugs: VPZ or a PPI, AMPC, and MNZ) and those who were unable to receive first- and second-line therapy because of penicillin allergy. Twenty Helicobacter pylori-positive patients were treated with RBT (150 mg twice daily), MNZ (250 mg twice daily), and VPZ (20 mg twice daily) for 10 days (RBT-MNZ-VPZ therapy). Eradication success was evaluated using the urea breath test. Drug susceptibility test results were available in 16 patients. This study is registered in the Japan Registry of Clinical Trials (jRCT031220504). Results: The intention-to-treat (ITT) and per-protocol (PP) eradication rates of RBT-MNZ-VPZ therapy were 70% (90% confidence interval [CI]: 49.2%-86.0%) and 72.2% (95% CI: 50.2%-88.4%), respectively. In the MNZ-susceptible subgroup, the ITT (n = 8) and PP (n = 7) eradication rates were 100% (90% CI: 68.8%-100%) and 100% (90% CI: 65.2%-100%). In the MNZ-resistant subgroup, the ITT (n = 8) and PP (n = 7) eradication rates were both 62.5% (90% CI: 28.9%-88.9%). All infections were RBT-susceptible. Conclusions: These findings suggest that RBT-MNZ-VPZ therapy may be a promising rescue regimen, especially in MNZ- and RBT-susceptible infections or patients with penicillin allergy.
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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.
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Fibroblastos Asociados al Cáncer , Carcinoma Ductal Pancreático , Proteínas de la Membrana , Neoplasias Pancreáticas , Animales , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Ratones , Fibroblastos Asociados al Cáncer/metabolismo , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Humanos , Xantonas/farmacología , Línea Celular Tumoral , Linfocitos T Citotóxicos/inmunologíaRESUMEN
In clinical cases of pancreas divisum, endoscopic retrograde cholangiopancreatography often necessitates cannulation of the pancreatic duct through the minor papilla. Nevertheless, this procedure can be challenging because of the small size of the minor papilla and the difficulty in visualizing the ductal orifice. A new image-enhanced endoscopy technique called texture and color enhancement imaging (TXI) has been developed, which enhances texture, brightness, and color compared with white-light imaging, resulting in subtle differences in the surface mucosa. Herein, we describe the case of a 73-year-old man with pancreas divisum in whom TXI was useful in identifying the orifice of the minor papilla. He was referred to our hospital with repetitive acute exacerbation of chronic pancreatitis. Since contrast-enhanced computed tomography revealed a pancreatic stone in the main pancreatic duct, endoscopic retrograde cholangoepancreatography was performed as a therapeutic intervention. Despite the initial difficulty in identifying the orifice of the minor papilla on white-light imaging, TXI enhanced its visibility successfully, enabling dorsal pancreatic duct cannulation via the minor papilla. Subsequently, endoscopic pancreatic sphincterotomy was performed and a 6Fr plastic stent was placed. Post-endoscopic therapy, the patient's abdominal pain was relieved. TXI was useful in identifying the minor papilla orifice and led to successful cannulation.
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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.
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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.
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AIM: This was a prospective, multicenter, single-arm intervention, against historical controls, study of the efficacy of a vonoprazan-based 7-day triple regimen with metronidazole (VPZ-AMPC-MNZ) as a first-line therapy for eradicating clarithromycin-resistant Helicobacter pylori (H. pylori). METHODS: We enrolled 35 patients positive for clarithromycin-resistant H. pylori, as assessed by culture, without a history of eradication. These 35 patients were prospectively eradicated with VPZ-AMPC-MNZ. As historical controls, we also assessed 98 patients with clarithromycin-resistant H. pylori from our prior prospective studies, who achieved H. pylori eradication with a 7-day triple regimen including clarithromycin (VPZ-AMPC-CAM). A preplanned analysis was performed as a superiority study against the historical controls (VPZ-AMPC-MNZ compared to VPZ-AMPC-CAM). In each regimen, vonoprazan was used at 20 mg bid, amoxicillin at 750 mg bid, metronidazole at 250 mg bid, and clarithromycin at 200 mg or 400 mg bid for 7 days. We assessed the outcome of eradication therapy using a 13C-urea breath test or H. pylori stool antigen test. We evaluated safety using patient questionnaires. RESULTS: The intention-to-treat (ITT) and per-protocol (PP) eradication rates of VPZ-AMPC-MNZ were both 100% (95% confidence interval (95% CI) 90.0-100%, n = 35). The eradication rates of VPZ-AMPC-CAM were 76.5% (95% CI 66.9-84.5%, n = 98) in the ITT analysis and 77.3% (95% CI 67.7-85.2%, n = 97) in the PP analysis. The eradication rate of VPZ-AMPC-MNZ was significantly higher than that of VPZ-AMPC-CAM in both the ITT (p = 0.00052) and PP (p = 0.00095) analyses. CONCLUSIONS: The findings suggest that 7-day VPZ-AMPC-MNZ was superior to 7-day VPZ-AMPC-CAM as a first-line regimen for eradicating clarithromycin-resistant H. pylori. We suggest VPZ-AMPC-MNZ as the standard first-line regimen for eradication of clarithromycin-resistant H. pylori in Japan.
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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.
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Vonoprazan (VPZ), a new potassium-competitive acid blocker, has been approved and used for Helicobacter pylori eradication in Japan. To date, many studies, as well as several systematic reviews and meta-analyses (MAs), have compared VPZ-based 7-day triple therapy with proton pump inhibitor (PPI)-based therapy. An MA of randomized controlled trials (RCTs) comparing first-line VPZ- with PPI-based triple therapy, the latter featuring amoxicillin (AMPC) and clarithromycin (CAM), found that approximately 30% of patients hosted CAM-resistant H. pylori; however, the reliability was poor because of high heterogeneity and a risk of selection bias. VPZ-based triple therapy is superior to PPI-based triple therapy for patients with CAM-resistant H. pylori, but not for those with CAM-susceptible H. pylori. An MA of non-RCTs found that second-line VPZ-based triple therapies were slightly (~2.6%) better than PPI-based triple therapies (with AMPC and metronidazole). However, the reliability of that MA was also low because of selection bias, confounding variables and a risk of publication bias; in addition, it is difficult to generalize the results because of a lack of data on antibiotic resistance. VPZ-based triple therapy (involving AMPC and sitafloxacin) was more effective than PPI-based triple therapy in a third-line setting, but a confirmatory RCT is needed. Non-RCT studies indicated that VPZ-based triple therapy involving CAM and metronidazole may be promising. Any further RCTs must explore the antibiotic-resistance status when evaluating the possible superiority of a potassium-competitive acid blocker.
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Infecciones por Helicobacter , Helicobacter pylori , Amoxicilina/uso terapéutico , Antibacterianos/uso terapéutico , Claritromicina/uso terapéutico , Quimioterapia Combinada , Infecciones por Helicobacter/tratamiento farmacológico , Humanos , Metronidazol/uso terapéutico , Potasio/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND AND AIM: To assess the efficacy and safety of 7-day Helicobacter pylori rescue treatment consisting of a vonoprazan (VPZ), metronidazole (MNZ), and sitafloxacin (STFX) regimen (VPZ-MNZ-STFX therapy) in patients with penicillin allergy. METHODS: This was a registered prospective intervention study. Patients with penicillin allergy who were diagnosed with H. pylori infection and had a history of H. pylori eradication were eligible for inclusion. Seventeen patients were prospectively treated with VPZ 20 mg bid, MNZ 250 mg bid, and STFX 100 mg bid for 7 days. Safety was evaluated using a questionnaire on adverse effects. RESULTS: The eradication rate of 7-day VPZ-MNZ-SFTX therapy was 88.2% (95% confidence interval: 63.6-98.5%; n = 17) in both intention-to-treat and per-protocol analyses. On the questionnaire, 25% of patients reported experiencing diarrhea, with a score of 2 or 3. All patients undergoing VPZ-MNZ-STFX therapy completed 100% of their medication course. CONCLUSION: Rescue H. pylori eradication with VPZ-MNZ-STFX therapy is effective and well tolerated in patients with penicillin allergy (UMIN000016335, jRCTs031180133).
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Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition, affecting up to 25% of the population worldwide. NAFLD has been linked to several conditions, including hepatic inflammation, fibrosis, and hepatocellular carcinoma (HCC), however the role of NAFLD in cholangitis and the development of cholangiocellular carcinoma (CCC) remains poorly understood. This study investigated whether a high-fat diet (HFD) promotes cholangitis and the development of CCC in mice. We used liver-specific E-cadherin gene (CDH1) knockout mice, CDH1∆Liv , which develop spontaneous inflammation in the portal areas along with periductal onion skin-like fibrosis, similar to that of primary sclerosing cholangitis (PSC). An HFD or normal diet (ND) was fed to CDH1∆Liv mice for 7 mo. In addition, CDH1∆Liv mice were crossed with LSL-KrasG12D mice, fed an HFD, and assessed in terms of liver tumor development. The extent of cholangitis and number of bile ductules significantly increased in mice fed an HFD compared with ND-administered CDH1∆Liv mice. The numbers of Sox9 and CD44-positive stem cell-like cells were significantly increased in HFD mice. LSL-KrasG12D /CDH1∆Liv HFD mice exhibited increased aggressiveness along with the development of numerous HCC and CCC, whereas LSL-KrasG12D /CDH1∆Liv ND mice showed several macroscopic tumors with both HCC and CCC components. In conclusion, NAFLD exacerbates cholangitis and promotes the development of both HCC and CCC in mice.
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Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Colangitis/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Animales , Antígenos CD/metabolismo , Neoplasias de los Conductos Biliares/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Colangiocarcinoma/metabolismo , Colangitis/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Inflamación/metabolismo , Inflamación/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
BACKGROUND & AIMS: E-cadherin (Cdh1) is a key molecule for adherence required for maintenance of structural homeostasis. Loss of E-cadherin leads to poor prognosis and the development of resistance to chemotherapy in pancreatic cancer. Here, we evaluated the physiological and pathologic roles of E-cadherin in the pancreas. METHODS: We crossbred Ptf1a-Cre mice with Cdh1f/f mice to examine the physiological roles of E-cadherin in the pancreas. In addition, we crossbred these mice with LSL-KrasG12D/+ mice (PKC) to investigate the pathologic roles of E-cadherin. We also generated a tamoxifen-inducible system (Ptf1a-CreERT model). Organoids derived from these models using lentiviral transduction were analyzed for immunohistochemical features. Established cell lines from these organoids were analyzed for migratory and invasive activities as well as gene expression by complementary DNA microarray analyses. RESULTS: None of the Ptf1a-Cre mice crossbred with Cdh1f/f mice survived for more than 28 days. We observed aberrant epithelial tubules that resembled the structure of acinar-to-ductal metaplasia after postnatal day 6, showing features of pancreatitis. All of the PKC mice died within 10 days. We observed tumorigenicity with increasing stroma-like aggressive tumors. Ptf1a-CreERT models showed that deletion of E-cadherin led to earlier pancreatic intraepithelial neoplasm formation. Cells established from PKC organoids had greater migratory and invasive activities, and these allograft tumors showed a poorly differentiated phenotype. Gene expression analysis indicated that Hdac1 was up-regulated in PKC cell lines and a histone deacetylase 1 inhibitor suppressed PKC cell proliferation. CONCLUSIONS: Under physiological conditions, E-cadherin is important for maintaining the tissue homeostasis of the pancreas. Under pathologic conditions with mutational Kras activation, E-cadherin plays an important role in tumor formation via the acquisition of tumorigenic activity.
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Cadherinas/deficiencia , Carcinogénesis/patología , Neoplasias Pancreáticas/patología , Pancreatitis/patología , Animales , Cadherinas/genética , Carcinogénesis/genética , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasa 1/metabolismo , Humanos , Metaplasia/genética , Metaplasia/patología , Ratones , Ratones Noqueados , Organoides , Páncreas/patología , Neoplasias Pancreáticas/genética , Cultivo Primario de Células , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Regulación hacia ArribaRESUMEN
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 13 C-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.
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Amoxicilina/administración & dosificación , Antibacterianos/administración & dosificación , Fluoroquinolonas/administración & dosificación , Gastritis/tratamiento farmacológico , Gastritis/microbiología , Inhibidores de la Bomba de Protones/administración & dosificación , Pirroles/administración & dosificación , Sulfonamidas/administración & dosificación , Anciano , Claritromicina/administración & dosificación , Quimioterapia Combinada , Esomeprazol/administración & dosificación , Femenino , Humanos , Lansoprazol/administración & dosificación , Masculino , Metronidazol/administración & dosificación , Persona de Mediana Edad , Estudios Prospectivos , Rabeprazol/administración & dosificación , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND/AIM: Although IL-6-mediated activation of the signal transduction and activator of transcription 3 (STAT3) axis is involved in inflammation and cancer, the role of STAT3 in Helicobacter-associated gastric inflammation and carcinogenesis is unclear. This study investigated the role of STAT3 in gastric inflammation and carcinogenesis and examined the molecular mechanism of Helicobacter-induced gastric phenotypes. METHODS: To evaluate the contribution of STAT3 to gastric inflammation and carcinogenesis, we used wild-type (WT) and gastric epithelial conditional Stat3-knockout (Stat3Δgec ) mice. Mice were infected with Helicobacter felis and euthanized at 18 months postinfection. Mouse gastric organoids were treated with recombinant IL-6 (rIL-6) or rIL-11 and a JAK inhibitor (JAKi) to assess the role of IL-6/STAT3 signaling in vitro. RESULTS: Inflammation and mucous metaplasia were more severe in WT mice than in Stat3Δgec mice. The epithelial cell proliferation rate and STAT3 activation were increased in WT mice. Application of rIL-6 and rIL-11 induced expression of intestinal metaplasia-associated genes, such as Tff2; this induction was suppressed by JAKi administration. CONCLUSIONS: Loss of STAT3 signaling in the gastric mucosa leads to decreased epithelial cell proliferation, atrophy, and metaplasia in the setting of Helicobacter infection. Therefore, activation of STAT3 signaling may play a key role in Helicobacter-associated gastric carcinogenesis.
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Pancreatic ductal adenocarcinoma (PDA) has a 5-year survival rate of less than 5% and is the sixth leading cause of cancer death. Although KRAS mutations are one of the major driver mutations in PDA, KRAS mutation alone is not sufficient to induce invasive pancreatic cancer in mice model. HER2, also known as ERBB2, is a receptor tyrosine kinase, and overexpression of HER2 is associated with poor clinical outcomes in pancreatic cancer. However, no report has shown whether HER2 and its downstream signaling contributes to the pancreatic cancer development. By immunohistochemical analysis in human cases, HER2 protein expression was detected in 40% of PDAs and 29% of intraductal papillary mucinous carcinomas, another type of pancreatic cancer. In a mouse model, we showed overexpression of activated HER2 (HER2 NT ) in the pancreas, in which cystic neoplastic lesions resembling intraductal papillary mucinous neoplasm-like lesions in humans had developed. We also found that HER2 NT cooperated with oncogenic Kras to accelerate the development of pancreatic intraepithelial neoplasms. In addition, using pancreatic organoids in 3D cultures, we found that organoids cultured from HER2 NT /Kras double transgenic mice showed proliferative potential and tumorigenic ability cooperatively. HER2-signaling inhibition was suggested to be an new therapeutic target in some types of PDAs.
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Adenocarcinoma Mucinoso/genética , Adenocarcinoma Papilar/genética , Carcinoma Ductal Pancreático/genética , Transformación Celular Neoplásica/genética , Expresión Génica , Páncreas/metabolismo , Receptor ErbB-2/genética , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Papilar/metabolismo , Adenocarcinoma Papilar/patología , Animales , Biomarcadores de Tumor , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Modelos Animales de Enfermedad , Inmunohistoquímica , Ratones , Mutación , Páncreas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismoRESUMEN
BACKGROUND: Vonoprazan affords more clinical benefits than proton pump inhibitors (PPIs) during the healing of gastroduodenal ulcers. However, it remains controversial whether vonoprazan is more effective than PPIs when used to heal artificial ulcers arising after endoscopic submucosal dissection (ESD). AIM: This study investigated the effects of vonoprazan compared with esomeprazole on the healing of post-ESD artificial ulcers. METHODS: Sixty patients who underwent gastric ESD between May 2015 and May 2017 were randomized to treatment with vonoprazan (V group) or esomeprazole (E group) for 8 weeks. Upper endoscopy was performed at 4 and 8 weeks after ESD, and drug effects were estimated based on the ulcer healing rates and shrinkage rates. RESULTS: Fifty-three patients were analyzed. The respective 4- and 8-week ulcer healing rates did not differ significantly between V and E groups (8.0 versus 11.5%, P = 0.669; 88.9 versus 84.6%, P = 0.420). Similarly, the respective 4- and 8-week ulcer shrinkage rates did not differ significantly between V and E groups (96.8 versus 97.5%, P = 0.656; 100 versus 100%, P = 0.257). CONCLUSION: The healing of artificial ulcers after ESD did not differ using vonoprazan or esomeprazole. Both vonoprazan and esomeprazole were effective when used to promote artificial ulcer healing after ESD.
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CORRECTION: Unfortunately, the original article [1] contained an error incorporated during production. A duplicated version of Table 1 was published in place of Table 2. Table 2 has been corrected in the original article and is also included correctly below.
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BACKGROUND: The eradication rate of vonoprazan-based first-line triple therapy (combined with clarithromycin and amoxicillin) (V-AC) was reported to be 97.6% in patients with clarithromycin (CAM)-susceptible Helicobacter pylori in a phase III study, whereas our real-world, prospective, multicenter cohort study yielded an eradication rate <90%. OBJECTIVE: To validate the eradication rate of V-AC using CAM-susceptible testing in a multicenter, prospective, randomized trial. METHODS: We included 147 treatment-naïve H. pylori-positive patients [41 with CAM-resistant infections and 106 with CAM-susceptible infections]. The CAM-susceptible group patients were randomized to either the V-AC group (vonoprazan 20 mg bid, amoxicillin 750 mg bid, and clarithromycin 200 or 400 mg bid) or PPI-AC group (lansoprazole 30 mg, rabeprazole 10 mg, or esomeprazole 20 mg bid; amoxicillin 750 mg bid; and clarithromycin 200 or 400 mg bid). All CAM-resistant H. pylori were eradicated by V-AC, as measured by the urea breath test around 8 weeks after eradication. Safety was evaluated by patient questionnaires. RESULTS: The intention-to-treat and per-protocol eradication rates of V-AC in the CAM-susceptible H. pylori-infected patients were 87.3% (95% confidence interval 75.5%-94.7%) and 88.9% (77.4%-95.8%). The respective eradication rates of PPI-AC were 76.5% (62.5%-87.2%) and 86.7% (73.2%-94.9%). No significant difference was observed between the V-AC and PPI-AC regimes in terms of the intention-to-treat (P = .21) or per-protocol (P = .77) analyses. The questionnaire scores did not differ significantly between the groups. Both the intention-to-treat and per-protocol eradication rates of V-AC in the CAM-resistant patients were 82.9% (67.9%-92.8%). CONCLUSION: The eradication rate of V-AC treatment in the CAM-susceptible H. pylori-infected patients was <90%, as was that by PPI-AC, thus V-AC is not ideal regimen in CAM-susceptible H. pylori. However, the 82.9% eradication rate of V-AC in the CAM-resistant infections may indicate the potential of V-AC with modified dose, dosing interval, and treatment duration. (UMIN000016337).
Asunto(s)
Claritromicina/uso terapéutico , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/patogenicidad , Inhibidores de la Bomba de Protones/uso terapéutico , Pirroles/uso terapéutico , Sulfonamidas/uso terapéutico , Anciano , Femenino , Infecciones por Helicobacter/microbiología , Helicobacter pylori/efectos de los fármacos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Although Helicobacter-induced gastric inflammation is the major predisposing factor for gastric carcinogenesis, the precise mechanism by which chronic gastritis causes gastric cancer remains unclear. Intestinal and spasmolytic polypeptide-expressing metaplasia (SPEM) is considered as precancerous lesions, changes in epithelial tissue stem/progenitor cells after chronic inflammation has not been clarified yet. In this study, we utilized three-dimensional gastric epithelial cell culture systems that could form organoids, mimicking gastric epithelial layer, and characterized the changes in epithelial cells after chronic Helicobacter felis infection. METHODS: We used three mice model; 1) long-term H. felis infection, 2) H. felis eradication, and 3) MNU chemical carcinogenesis model. We performed cRNA microarray analysis after organoid culture, and analyzed the effects of chronic gastric inflammation on tissue stem cells, by the size of organoid, mRNA expression profile and immunohistochemical analysis. RESULTS: The number of organoids cultured from gastric epithelial cells was significantly higher in organoids isolated from H. felis-infected mice compared with those from uninfected gastric mucosa. Based on the mRNA expression profile, we found that possible stem cell markers such as Cd44, Dclk1, and genes associated with the intestinal phenotype, such as Villin, were increased in organoids isolated from H. felis-infected mucosa compared with the control. The upregulation of these genes were cancelled after H. felis eradication. In a xenograft model, tumors were generated only from organoids cultured from carcinogen-treated gastric mucosa, not from H. felis infected mucosa or control organoids. CONCLUSIONS: Our results suggested that, as a possible mechanism of gastric carcinogenesis, chronic inflammation induced by H. felis infection increased the number of tissue stem/progenitor cells and the expression of stem cell markers. These findings suggest that chronic inflammation may alter the direction of differentiation toward undifferentiated state and that drawbacks may enable cells to redifferentiate to intestinal metaplasia or neoplasia.