Lenvatinib radiofrequency ablation sequential therapy offers survival benefits for patients with unresectable hepatocellular carcinoma at intermediate stage and the liver reserve of Child-Pugh A category: A multicenter study.

AIM: This study aims to evaluate the efficacy and safety of lenvatinib radiofrequency ablation (RFA) sequential therapy for certain hepatocellular carcinoma (HCC) patients. METHODS: One hundred and nineteen patients with unresectable HCC in the intermediate stage with Child-Pugh A were retrospectively recruited in a multicenter setting. Those in the lenvatinib RFA sequential therapy group received lenvatinib initially, followed by RFA and the retreatment with lenvatinib. The study compared overall survival (OS), progression-free survival (PFS), tumor response, and adverse events (AEs) between patients undergoing sequential therapy and lenvatinib monotherapy. RESULTS: After propensity score matching, 25 patients on sequential therapy and 50 on monotherapy were evaluated. Independent factors influencing OS were identified as sequential therapy, modified albumin-bilirubin (mALBI) grade, and relative dose intensity (%) with hazard ratios (HRs) of 0.381 (95% confidence interval [CI], 0.186-0.782), 2.220 (95% CI, 1.410-3.493), and 0.982 (95% CI, 0.966-0.999), respectively. Stratified analysis based on mALBI grades confirmed the independent influence of treatment strategy across all mALBI grades for OS (HR, 0.376; 95% CI, 0.176-0.804). Furthermore, sequential therapy was identified as an independent factor of PFS (HR, 0.382; 95% CI, 0.215-0.678). Sequential therapy significantly outperformed monotherapy on survival benefits (OS: 38.27 vs. 18.96 months for sequential therapy and monotherapy, respectively, p = 0.004; PFS: 13.80 vs. 5.32 months for sequential therapy and monotherapy, respectively, p < 0.001). Sequential therapy was significantly associated with complete response by modified Response Evaluation Criteria in Solid Tumors (odds ratio, 63.089). Ten of 119 patients experienced grade 3 AEs, with no AE beyond grade 3 observed. CONCLUSION: Lenvatinib RFA sequential therapy might offer favorable tolerability and potential prognostic improvement compared to lenvatinib monotherapy.

The Origin of Epithelium with Low-Grade Atypia in Early Gastric Cancer.

INTRODUCTION: Helicobacter pylori (HP) infection causes chronic inflammation and atrophy of the gastric mucosa and thus a high risk of gastric cancer (GC). With the increasing success of HP infection treatment, a larger number of GCs that develop after eradication can be assessed. Several studies have shown that epithelium with low-grade atypia (ELA) is a frequent characteristic of these GCs, but the origin of this condition is unknown. In this study, we compared the mucin phenotype, cellular proliferation, and p53 staining in ELA and cancerous tissues obtained from patients with GC with and without HP eradication. METHODS: The study population consisted of 23 patients with GC that developed after successful HP eradication therapy (eradicated group) and 24 patients with GC and HP infection (infected group). The prevalence of ELA was determined by hematoxylin and eosin staining. Tumor tissue and ELA samples were further analyzed by immunohistochemical staining for Muc5AC, Muc2, p53, and Ki-67. RESULTS: The ELA coverage rate was significantly higher in the eradicated group than in the infected group. Gastric-type mucin was frequently expressed by the ELA, and the mucin phenotypes of ELA and cancerous areas differed in 75% of cases. The Ki-67 labeling index was consistently lower in ELA than in the cancerous mucosa. Fourteen of 21 (66.7%) cancerous lesions, but only 3 ELA samples, were p53-positive. CONCLUSION: In most cases, ELA on the surfaces of GCs seems to have originated from normal gastric cells, not from cancer cells.

NAFLD exacerbates cholangitis and promotes cholangiocellular carcinoma in mice.

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.

Quantitative monitoring of circulating tumor DNA in patients with advanced pancreatic cancer undergoing chemotherapy.

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.

Randomized trial of vonoprazan-based versus proton-pump inhibitor-based third-line triple therapy with sitafloxacin for Helicobacter pylori.

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.

Switch to miriplatin for multinodular hepatocellular carcinoma unresponsive to transarterial chemoembolization with epirubicin: a prospective study.

OBJECTIVE: The aim of this prospective study was to evaluate the efficacy of transarterial chemoembolization using miriplatin, a platinum-based anticancer drug, as a retreatment regimen for hepatocellular carcinoma (HCC) unresponsive to chemoembolization using epirubicin. METHODS: Between April 2013 and December 2014, we enrolled 57 consecutive chamoembolization-naïve patients with unresectable HCC, and performed chemoembolization with epirubicin. Treatment effect, necrotizing rate of the target nodules, was evaluated at 1-3 months after treatment using contrast-enhanced CT or MRI. We subsequently included retreatment chemoembolization with miriplatin for patients whose treatment effect was <50% after chemoembolization with epirubicin. The treatment effect after chemoembolization with miriplatin and the liver function before and after chemoembolization were evaluated. RESULTS: Eighteen patients of the 57 showed a treatment effect <50% after chemoembolization with epirubicin, and were switched to chemoembolization with miriplatin. The treatment effect after chemoembolization with miriplatin was ≥50% in four (22%) patients. Four of the remaining 14 (78%) patients who had <50% necrosis exhibited deterioration of the liver function after chemoembolization with miriplatin. Univariate analysis indicated that an alpha-fetprotein-L3 level <10% and a serum albumin level ≥3.6 g/dl were predictive factors of therapeutic response after chemoembolization with miriplatin (P < 0.05). However, there was no predictive factor regarding the deterioration of liver function after chemoembolization with miriplatin. CONCLUSIONS: In unresectable HCC patients who were unresponsive to chemoembolization with epirubicin, switching the chemotherapeutic regimen to a platinum-based anticancer drug in retreatment chemoembolization should be considered as a treatment option. Trial registration: UMIN 000015887.

Unexpected Side Effects of a High S-1 Dose: Subanalysis of a Phase III Trial Comparing Gemcitabine, S-1 and Combinatorial Treatments for Advanced Pancreatic Cancer.

OBJECTIVE: In this subanalysis of a phase III trial using three categorized doses of S-1, the influence of the actual doses on safety and efficacy was evaluated. METHODS: We compared the efficacy and safety of the S-1 or gemcitabine plus S-1 combination (GS) arm between the top 10% group and the bottom 10% group according to the initial doses of S-1: ≥77.6 versus ≤65.9 mg/m2/day (n = 28 vs. 28) in the S-1 arm, and ≥65.1 versus ≤53.8 mg/m2/day (n = 27 vs. 28) in the GS arm. RESULTS: Overall and progression-free survival were not significantly different between these two groups: hazard ratios of 0.818 and 0.761 with p values of 0.498 and 0.330 in the S-1 arm, and hazard ratios of 0.836 and 0.759 with p values of 0.557 and 0.323 in the GS arm, respectively. Incidences of grade 3-4 hematological toxicities were significantly higher in the top 10% group than in the bottom 10% group: 42.9 versus 14.3 and 85.2 versus 57.1%, with p values of 0.037 and 0.037 in the S-1 and the GS combination arm, respectively. CONCLUSIONS: Higher actual doses of S-1 were associated with a higher incidence of hematological toxicity even in the same dose setting.

Duodenal stenting followed by systemic chemotherapy for patients with pancreatic cancer and gastric outlet obstruction.

OBJECTIVES: Endoscopic duodenal stenting has recently been proposed as a substitute for surgical gastrojejunostomy for the treatment of gastric outlet obstruction. We aimed to evaluate the efficacy and safety of duodenal stenting followed by systemic chemotherapy for patients with advanced pancreatic cancer with gastric outlet obstruction. METHODS: This was a single-center, retrospective cohort study, conducted at an academic medical center, of 71 patients with advanced pancreatic cancer and gastric outlet obstruction (mean age: 67.6 years; range: 31-92 years) who underwent duodenal stenting with or without subsequent chemotherapy. Overall survival, duration of oral intake of foods, the rate of introduction of chemotherapy, progression-free survival, and adverse events were evaluated. RESULTS: Stent placement was technically successful in 69 (97%) patients. Thirty-six (51%) patients were treated with chemotherapy: 17 with gemcitabine alone, 15 with S-1 alone, 3 with FOLFIRINOX, and 1 with paclitaxel. Median progression-free survival and overall survival after chemotherapy were 2.6 months (95% confidence interval: 1.3-3.9 months) and 4.7 months (95% confidence interval: 2.6-6.8 months), respectively. Cases of grade 3 anemia were frequently observed during chemotherapies following duodenal stenting (32%). Tumor stage, performance status, neutrophil-to-lymphocyte ratio, and introduction of chemotherapy were independent prognostic factors for survival (hazard ratios of 3.73, 2.21, 2.69, and 1.85 with p-values of <0.001, 0.010, <0.001, and 0.045, respectively). CONCLUSIONS: The findings of this study suggest that endoscopic duodenal stenting is an advantageous treatment in advanced pancreatic cancer patients with gastric outlet obstruction regarding its safety and smooth conduction of subsequent chemotherapies.

Potential prognostic significance of a new proteomic profile in patients with advanced pancreatic adenocarcinoma.

OBJECTIVES: Seven-signal proteomic approach has recently been developed as a new proteomic profile measured by matrix-assisted laser desorption/ionization mass spectrometry. The aim of this study was to evaluate prognostic significance of this proteomic value in patients with pancreatic adenocarcinoma. METHODS: Blood samples from the patients with pancreatic adenocarcinoma were prospectively collected before treatments including surgical resection and systemic chemotherapies. The seven-signal proteomic profiles of the samples were measured, and the prognostic significance of the proteomic value was evaluated through comparison with other existing prognostic markers. RESULTS: Cut-off value of the proteomic profiles at 52 stratified overall prognosis of the patients (6.5 months vs. 10.9 months with the values ≥52 vs. <52, p = 0.020). In subgroup analyses of inoperable cases with carcinoembryonic antigen level of <5 ng/ml or performance status of 0-1, the proteomic value at 52 stratified their prognosis (p = 0.002 and p = 0.006, respectively). CONCLUSIONS: The new seven-signal proteomics showed useful prognostic significance for patients with pancreatic adenocarcinoma. Further studies with a large sample size would be required to evaluate whether this proteomic approach possibly complements the existing parameters, such as carcinoembryonic antigen and performance status.

Enhancement of radiofrequency ablation of the liver combined with transarterial embolization using various embolic agents.

PURPOSE: Reducing blood flow in the liver during radiofrequency ablation causes enlargement of the ablation area. In this animal study, we evaluated the extended effects of radiofrequency ablation combined with transarterial embolization using various embolic agents. METHODS: We treated 38 radiofrequency ablation lesions after embolization in 13 pigs using the following embolic agents: gelatin sponge (Group A); iodized oil followed by gelatin sponge (Group B); 700-900 µm calibrated microspheres (Group C); and 100-300 µm calibrated microspheres (Group D). Lesion size and pathological evaluations of these ablation lesions were compared with those receiving radiofrequency ablation alone (control). RESULTS: Both the long- and short-axis diameters of the ablation lesions for Groups A, B, C, and D were significantly longer than those of controls (long axis/short axis for Groups A, B, C, D, and controls were 27.2/23.2, 30.2/26.0, 28.2/22.2, 32.0/24.4, and 23.2 mm/18.5 mm, respectively) (P < 0.05). The long-axis of the ablation lesion for Group D was significantly longer than those for both Groups A and C (P < 0.05). At pathological examination, the central ablation lesions showed coagulative necrosis with a surrounding hemorrhagic rim, and the microspheres were fitted to occlude the small arteries in peripheral liver parenchyma in Groups C and D. CONCLUSIONS: The extended effects of embolization with small microspheres may be stronger than those with large microspheres and were equal to those with iodized oil followed by gelatin sponge.

Renal toxicity associated with weekly cisplatin and gemcitabine combination therapy for treatment of advanced biliary tract cancer.

OBJECTIVE: A combination of weekly cisplatin plus gemcitabine is a new standard regimen for patients with advanced biliary tract cancer (BTC). This regimen does not require prolonged hydration schedules; however, the long-time safety profile has not been evaluated so far. In particular, the aim of this study was to evaluate the renal function during this regimen. METHODS: We reviewed 79 consecutive patients with BTC who received the weekly cisplatin plus gemcitabine regimen. The incidence of adverse events was evaluated by CTCAE v4.0. RESULTS: A total of 402 courses were administered. The median cumulative dose of cisplatin was 250 mg (range: 25-825). The renal function was exacerbated gradually throughout the treatment course. The incidence of a decreased glomerular filtration rate (GFR) at <50 ml/min was significantly related to a pretreatment GFR at <80 ml/min and a total dose of cisplatin>400 mg [p=0.011, odds ratio (OR) 58.2, 95% confidence interval (CI): 2.5-1334.0 and p=0.021, OR 18.3, 95% CI: 1.6-215.5]. CONCLUSIONS: The combination of weekly cisplatin and gemcitabine for advanced BTC gradually affected the renal function, and it was highly recommended to focus on both the change of GFR and total dose of cisplatin during this regimen.

Single-Arm, Prospective, Interventional Study of Helicobacter pylori Eradication Rescue Therapy with Rifabutin, Metronidazole, and Vonoprazan.

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.

A Novel Characteristic Gastric Mucus Named "Web-like Mucus" Potentially Induced by Vonoprazan.

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.

The usefulness of texture and color enhancement imaging to identify the minor papilla orifice.

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.

Novel 8-wire basket catheter is useful for endoscopic removal of common bile duct stones up to 10 mm: A multicenter prospective study.

BACKGROUND/PURPOSE: Endoscopic treatment of common bile duct (CBD) stones involves the use of basket or balloon catheters; however, what is the appropriate device remains controversial. In this study we aimed to prospectively evaluate the usefulness of a novel 8-wire helical basket (8WB) catheter made of Nitinol for the removal of CBD stones ≤10 mm. METHODS: We conducted a multicenter prospective trial. Patients with CBD stones ≤10 mm were enrolled. The primary endpoint was the rate of complete stone removal within 10 min using the 8WB. The number of cases was determined using a previous study of stone removal by a conventional basket catheter as a historical control. RESULTS: A total of 155 patients were enrolled and 139 were ultimately included in the analysis. Patients with a single stone were the most common (84 cases, 60.4%), with a median maximum stone diameter of 5 mm. The median stone removal time using the 8WB was 6 min. The complete stone removal rate was 95.0% (132/139). Adverse events were observed in 14 patients (10.1%). CONCLUSIONS: The novel 8WB catheter is useful in the treatment of CBD stones ≤10 mm, presenting a high complete stone removal rate in this study. TRIAL REGISTRATION NUMBER: jRCT1032200324.

Activation of STING in pancreatic cancer-associated fibroblasts exerts an antitumor effect by enhancing tumor immunity.

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.

Comparison of metronidazole versus clarithromycin in first-line vonoprazan-based triple therapy for Helicobacter pylori: A multicenter randomized trial in Japan.

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.

Prospective Study of Vonoprazan-Based First-Line Triple Therapy with Amoxicillin and Metronidazole for Clarithromycin-Resistant Helicobacter pylori.

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.

Vonoprazan and high-dose amoxicillin dual therapy for Helicobacter pylori first-line eradication: A single-arm, interventional study.

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.

Risk assessment of metachronous gastric cancer after endoscopic submucosal dissection based on endoscopic intestinal metaplasia.

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.