Real-world virological efficacy and safety of daclatasvir/asunaprevir/beclabuvir in patients with chronic hepatitis C virus genotype 1 infection in Japan Abstract Background The virological efficacy and safety of the direct-acting antiviral (DAA) regimen consisting of daclatasvir, asunaprevir, and beclabuvir (DCV/ASV/BCV) for patients chronically infected with hepatitis C virus (HCV) genotype 1 have not been previously evaluated in Japanese real-world settings. Methods In a Japanese nationwide multicenter study, the rate of sustained virologic response (SVR) and safety were analyzed in 91 patients who started the DCV/ASV/BCV regimen between November 2016 and July 2017. SVR rates were compared based on baseline patient characteristics. Results More than 60% of patients had a history of failure to achieve SVR with interferon (IFN)-free DAA therapy. Overall, 50 of 91 patients (54.9%) achieved SVR. Multivariate analysis identified a history of failure with IFN-free DAA therapy and pretreatment HCV RNA levels as factors significantly associated with treatment failure. Whereas the SVR rate in patients without a history of IFN-free DAA therapy was 91.7% (33 of 36 patients), it was only 30.9% (17 of 55 patients) among patients with a history of IFN-free DAA therapy. The rate of discontinuation due to an adverse event was 4.4%. Conclusions Many patients treated with the DCV/ASV/BCV regimen have a history of a failure to achieve SVR with previous IFN-free DAA therapy. SVR rate was not as high as that in pre-approval clinical trial of this regimen in IFN-free DAA-naïve patients. In addition, most patients with a history of failure with IFN-free DAA therapy, particularly the DCV/ASV regimen, showed resistance to this regimen.

Molecular subtype switching in early-stage gastric cancers with multiple occurrences Abstract Background Multiple gastric cancers at the same time (synchronous) or recurrence after 1 year (metachronous) are frequently encountered. Since their genetic profiles were not well elucidated, we molecularly subtyped the genetic events of synchronous and metachronous early-stage gastric cancers. Methods We studied mismatch repair (MMR) genes in 84 tumors from 31 patients (15 synchronous and 16 metachronous) by immunohistochemistry. We performed microsatellite instability analysis and targeted sequencing of 58 significantly mutated genes (SMGs) in 35 tumors from thirteen patients. Genomic data from TCGA were used for comparisons with advanced-stage cancers. Results Among the 31 patients, at least one deficient-MMR (dMMR) tumor was observed in eight (26%). Of eight patients, seven showed a mixture of proficient-MMR (pMMR) and dMMR tumors. The one case with only dMMR had six recurrent tumors within 2 years. To further subtype, we sequenced 58 SMGs in 35 samples (25 pMMR and 10 dMMR) from thirteen patients. In 35 samples, 163 mutations were identified, but none matched in almost cases, strongly indicating different clonal origins, whether synchronous or metachronous occurrences. Of the 25 pMMR cases, 1 belonged to Epstein–Barr virus (EBV), 24 belonged to chromosomal instability (CIN) subtypes. Of the thirteen cases, repetitive CIN, a mixture of CIN and MSI, a mixture of CIN and EBV, and repetitive MSI were observed in nine (70%), two (15%), one (8%) and one (8%), respectively. Conclusions Despite multiple tumors occurring in the same patient simultaneously or several years apart, clonal origin was totally different. ‘Switching’ or ‘mixing’ of dMMR and pMMR, EBV or CIN occurred, which had clinical relevance with regard to immunotherapy.

A Helicobacter pylor i screening and treatment program to eliminate gastric cancer among junior high school students in Saga Prefecture: a preliminary report Abstract Background To present the strategies and preliminary findings of the first 3 years after implementing a Helicobacter pylori screening and eradication program to prevent gastric cancer in Saga Prefecture. Methods A screening and treatment program to eradicate H. pylori from third-grade junior high students was started in Saga Prefecture in 2016, using local governmental grants. Screening was with urinary anti-H. pylori antibody tests, followed by H. pylori stool antigen tests for students who were antibody positive. Those positive on both tests underwent H. pylori eradication by triple therapy based on a potassium-competitive acid blocker. Results From 2016 to 2018, the participation rate was 83.1% and the H. pylori infection rate was 3.1% (660/21,042). The participation rates were higher in 2017 (85.4%) and 2018 (85.9%) compared with 2016 (78.5%) (P < 0.0001), and the infection rate also decreased in a time-dependent manner (2016: 3.6%, 2017: 3.3%, 2018: 2.5%, P = 0.0001). In total, 501 students positive for H. pylori received eradication therapy (85.1% success) and adverse events occurred in 20 of these (4.0%). However, no serious complications occurred. Conclusions The H. pylori screening and eradication project for school students in Saga Prefecture has started successfully and we have seen both a steady increase in the participation rate and a steady decrease in the infection rate, without major safety concerns.

Pathological risk factors and predictive endoscopic factors for lymph node metastasis of T1 colorectal cancer: a single-center study of 846 lesions Abstract Background Determining the depth of invasion of early stage colorectal cancer has been emphasized as a means of improving endoscopic diagnostic accuracy. Recent studies have focused on other pathological risk factors for lymph node metastasis (LNM). We investigated the significance of depth of invasion and predictive properties of other endoscopic findings. Methods We retrospectively investigated 846 patients with submucosal invasive (T1) colorectal cancer who received an accurate pathological diagnosis and were treated between January 2005 and December 2016. Pathological risk factors associated with LNM were reviewed. We divided patients into groups: low-risk T1 colorectal cancer (LRC; no risk factors) and high-risk T1 colorectal cancer (HRC; exhibiting lymphovascular invasion, tumor budding grade of 2/3, and/or poor differentiation) and studied predictive endoscopic factors for HRC. Results Significant risk factors for LNM in multivariate analysis were lymphovascular invasion [odds ratio (OR) 8.09; 95% confidence interval (CI) 3.84–17.1], tumor budding (OR 1.89; 95% CI 1.09–3.29), and histological differentiation (OR 2.09; 95% CI 1.12–3.89). The LNM-positive rate with only deep submucosal invasion was 1.6%. Significant predictive factors for HRC in multivariate analysis identified rectal tumor location (OR 1.92; 95% CI 1.35 –2.72, depression (OR 2.73; 95% CI 1.96 –3.80), protuberance within the depression (OR 2.58; 95% CI 1.39– 4.78), expansiveness (OR 2.39; 95% CI 1.27– 4.50), and loss of mucosal patterns (OR 1.90; 95% CI 1.20 –3.01) as significant factors. Conclusions Rectal tumor location, depression, protuberance within the depression, expansiveness, and loss of mucosal patterns could be predictive factors for HRC.

Integrated analysis of 8-week glecaprevir/pibrentasvir in Japanese and overseas patients without cirrhosis and with hepatitis C virus genotype 1 or 2 infection Abstract Background Chronic hepatitis C virus (HCV) infection with genotypes (GT) 1 and 2 accounts for over 50% of HCV infections globally, including over 97% of all HCV infections in Japan. Here, we report an integrated analysis of efficacy and safety of 8-week treatment with the all-oral, fixed-dose combination of the direct acting antivirals (DAA), glecaprevir and pibrentasvir (G/P), in DAA-naïve Japanese and overseas patients without cirrhosis and with HCV GT1 or GT2 infection. Methods Data from 899 DAA-naïve patients without cirrhosis and with HCV GT1 or GT2 infection treated with G/P (300/120 mg) for 8 weeks in the six Phase 2 or 3 overseas or Japan-only clinical trials were included. All patients who received ≥ 1 dose of G/P were included in an intent-to-treat (ITT) analysis. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and safety of the 8-week regimen in the ITT population. Results Overall, SVR12 was achieved by 98.9% (889/899) of DAA-naïve patients without cirrhosis, including 99.2% (597/602) of GT1-infected and 98.3% (292/297) of GT2-infected patients. Less than 1% (2/899) of patients overall and no Japanese patients experienced virologic failure. SVR12 rate was > 97% for patients regardless of baseline characteristics, and common comorbidities or co-medications. Overall, < 1% (2/899) discontinued G/P due to an adverse event (AE) and 1.6% (14/899) of patients experienced a serious AE. Conclusions 8-week G/P treatment is safe and efficacious in DAA-naive patients without cirrhosis and with HCV GT1 or GT2 infection, demonstrating high SVR12 rates regardless of baseline patient and disease characteristics. ClinicalTrials.gov identifiers The trials discussed in this paper were registered with ClinicalTrials.gov as follows: NCT02707952 (CERTAIN-1), NCT02723084 (CERTAIN-2), NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02738138 (EXPEDITION-2).

What is causing the rising incidence of esophageal adenocarcinoma in the West and will it also happen in the East? Abstract In the West, the incidence of esophageal adenocarcinoma, which is a long-term complication of damage by gastroesophageal reflux, has been rising over recent decades. Two main factors are likely to account for this increase. The first is the rising incidence of central obesity which promotes gastroesophageal reflux. The second is the falling incidence of H. pylori infection and associated atrophic gastritis which reduces the acidity and peptic activity of gastric juice, the main factors damaging to the esophageal mucosa. The rise in esophageal adenocarcinoma has been mirrored by a fall in gastric cancer consistent with H. pylori atrophic gastritis protecting from the former and predisposing to the latter. The incidence of gastric cancer in Japan is still above the level at which a rise in esophageal adenocarcinoma became apparent in the West. Esophageal adenocarcinoma is likely to rise in Japan also as the incidence of gastric cancer falls but the degree of rise will depend on a variety of other environmental and genetic factors.

Noninvasive diagnostic criteria for nonalcoholic steatohepatitis based on gene expression levels in peripheral blood mononuclear cells Abstract Background Nonalcoholic fatty liver disease (NAFLD) consists of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH); the latter progresses to liver cirrhosis and hepatocellular carcinoma. Discriminating NASH from NAFL typically involves liver biopsy. The mechanism of NASH progression is unclear but may involve immunological pathways. In this study, we examined expression levels of cytokine- and chemokine-encoding genes in peripheral blood mononuclear cells (PBMCs) from NAFLD patients and established immunological criteria for discriminating NASH from NAFL. Methods PBMCs were obtained from 54 patients diagnosed histologically with NAFLD (NAFL, 18; NASH, 36). mRNA was extracted from PBMCs, and expression levels of cytokine- and chemokine-encoding genes were determined by quantitative real-time PCR. Statistical analysis was performed by nonparametric test. Results Expression levels of interferon (IFN)γ, interleukin (IL)2, IL15, C–C-motif chemokine ligand (CCL)2, IL10, and C-X-C-motif chemokine ligand (CXCL)11 were significantly upregulated in NASH patients compared with NAFL patients. Moreover, their expression levels were positively correlated with the degree of ballooning of hepatocytes but not of steatosis or lobular inflammation. We focused on those encoding IL10, IFNγ, and CCL2, and developed a scoring system to discriminate NASH from NAFL. The discriminatory power of the criteria was validated in an independent cohort. Conclusions Expression levels of the cytokine- and chemokine-encoding genes in PBMCs were positively correlated with ballooning, suggesting their utility for the diagnosis of NASH. The data indicate that peripheral as well as intrahepatic immunity is involved in the progression of NASH. Our findings afford new insight into immunological mechanisms of NASH and will facilitate its noninvasive diagnosis.

Systematic review with network meta-analysis: indirect comparison of the efficacy of vonoprazan and proton-pump inhibitors for maintenance treatment of gastroesophageal reflux disease Abstract Background Long-term maintenance treatment of gastroesophageal reflux disease (GERD) is important to prevent relapse. Proton-pump inhibitors (PPIs) are used for both treatment and maintenance therapy of GERD. Recently, a potassium-competitive acid blocker vonoprazan was launched in Japan. We evaluated the comparative efficacy of vonoprazan and other PPIs for GERD maintenance. Methods A systematic literature search was performed using MEDLINE and Cochrane Central Register of Controlled Trials. Double-blind randomized controlled trials (RCTs) of PPIs, vonoprazan, and placebo for GERD maintenance published in English or Japanese were selected. Among them, studies conducted at the recommended dose and for the recommended use, and containing information on maintenance rate based on endoscopic assessment, were included. The comparative efficacies of treatments were estimated by performing a Bayesian network meta-analysis, which assessed the consistency assumption. Outcomes were number or rate of patients who maintained remission. Results Of 4001 articles identified, 22 RCTs were eligible for analysis. One study published as an abstract was hand-searched and added. The consistency hypothesis was not rejected for the analysis. The odds ratio of vonoprazan 10 mg to each PPI was 13.92 (95% credible interval [CI] 1.70–114.21) to esomeprazole 10 mg; 5.75 (95% CI 0.59–51.57) to rabeprazole 10 mg; 3.74 (95% CI 0.70–19.99) to lansoprazole 15 mg; and 9.23 (95% CI 1.17–68.72) to omeprazole 10 mg. Conclusions The efficacy of vonoprazan in GERD maintenance treatment may be higher than that of some PPIs. However, a direct comparison of vonoprazan and PPIs is required to confirm these effects.

Combination treatment with highly bioavailable curcumin and NQO1 inhibitor exhibits potent antitumor effects on esophageal squamous cell carcinoma Abstract Background Esophageal squamous cell carcinoma (ESCC) is one of the most intractable cancers, so the development of novel therapeutics has been required to improve patient outcomes. Curcumin, a polyphenol from Curcuma longa, exhibits various health benefits including antitumor effects, but its clinical utility is limited because of low bioavailability. Theracurmin® (THC) is a highly bioavailable curcumin dispersed with colloidal submicron particles. Methods We examined antitumor effects of THC on ESCC cells by cell viability assay, colony and spheroid formation assay, and xenograft models. To reveal its mechanisms, we investigated the levels of reactive oxygen species (ROS) and performed microarray gene expression analysis. According to those analyses, we focused on NQO1, which involved in the removal of ROS, and examined the effects of NQO1-knockdown or overexpression on THC treatment. Moreover, the therapeutic effect of THC and NQO1 inhibitor on ESCC patient-derived xenografts (PDX) was investigated. Results THC caused cytotoxicity in ESCC cells, and suppressed the growth of xenografted tumors more efficiently than curcumin. THC increased ROS levels and activated the NRF2–NMRAL2P–NQO1 expressions. Inhibition of NQO1 in ESCC cells by shRNA or NQO1 inhibitor resulted in an increased sensitivity of cells to THC, whereas overexpression of NQO1 antagonized it. Notably, NQO1 inhibitor significantly enhanced the antitumor effects of THC in ESCC PDX tumors. Conclusions These findings suggest the potential usefulness of THC and its combination with NQO1 inhibitor as a therapeutic option for ESCC.

Eosinophilic esophagitis: novel concepts regarding pathogenesis and clinical manifestations Abstract This report explores two hypotheses regarding eosinophilic esophagitis (EoE): (1) that the use of proton pump inhibitors (PPIs) might contribute to the pathogenesis of EoE by preventing peptic digestion of food allergens, by increasing gastric mucosal permeability to enable gastric absorption of those undegraded food allergens, and by causing microbial dysbiosis, and (2) that EoE, like eosinophilic gastroenteritis, might have mucosal-predominant and muscle-predominant forms, and that the muscle-predominant form of EoE might cause a variety of esophageal motility disorders including achalasia.