Integrated analysis of circRNAs and mRNAs expression profile revealed the involvement of hsa_circ_0007919 in the pathogenesis of ulcerative colitis Abstract Background Ulcerative colitis (UC) is characterized by chronic inflammation in the colon and epigenetic factors underlying the occurrence. Circular RNAs (circRNAs) have been under intensive focus due to the circular construct and gene-regulating functions. However, the changes and roles of circRNAs in UC remain unknown. Methods Microarrays were used to detect the differentially expressed genes, and quantitative real-time PCR was used to identify the changes in UC. In silico analyses were performed to predict the functions of circRNAs and mRNAs. In vitro, epithelial cell lines were stimulated by pro-inflammation effectors to test the alterations in circRNAs. CircRNAs–microRNAs–mRNAs network clarified the potential mechanisms underlying circRNAs in UC. The binding site between hsa_circ_0007919 and miR-138 or let-7a was verified using dual-luciferase assay. Results A total of 264 significantly dysregulated circRNAs and 1869 differentially expressed mRNAs in inflamed mucosa were compared with the non-inflamed mucosa in UC. Hsa_circ_0004662 and hsa_circ_0007919 were altered largely in UC tissues. Hsa_circ_0007919 was reduced persistently after inflammatory treatments, and it was relevant to Mayo endoscopic subscores and the expression of tight junction molecules. Finally, hsa_circ_0007919 could harbor miR-138, and let-7a to regulate the targeted mRNAs EPC1 and VIPR1. Conclusions Several circRNAs were differentially expressed in UC. Hsa_circ_0007919 is related to clinical characteristics and epithelial integrity by binding to hsa-let-7a, hsa-miR-138 to regulate the target genes. CircRNAs, especially hsa_circ_0007919, are associated with the pathogenesis and development of UC, with potential diagnostic and therapeutic implications.

Epstein–Barr virus status is a promising biomarker for endoscopic resection in early gastric cancer: proposal of a novel therapeutic strategy Abstract Background Epstein–Barr virus-positive gastric cancer (EBVGC) is associated with a low prevalence of lymph node metastasis (LNM); however, EBV status is not considered in the indication of endoscopic resection (ER). We aimed to clarify the implication of EBV status for ER of pT1b GC. Methods Consecutive cases of pT1b GCs treated with surgery between 2005 and 2014 were retrospectively analyzed. Clinicopathological factors and LNM status were compared between EBVGC and non-EBVGC groups. Results EBVGC accounted for 7.9% (71 of 898) cases. Compared to non-EBVGC, EBVGC was more frequent in males (p = 0.0055), the upper third region (p < 0.0001), showed elevated growth features (p = 0.0059), and was associated with a lower frequency of accompanying ulceration (p = 0.002), greater depth of submucosal invasion (p = 0.017), and lower frequency of lymphatic invasion (p < 0.0001). Frequency of LNM was significantly lower in EBVGC than in non-EBVGC (4.2% vs. 21.9%, p < 0.0001). In EBVGC, tumors without lymphovascular invasion showed significantly lower frequency of LNM than those with lymphovascular invasion (0 of 50, 0%; vs 3 of 21, 14.3%; p = 0.023). Histologically, 84.5% (60 of 71) of EBVGC included carcinomas with lymphoid stroma and/or lace pattern components. Conclusions pT1b EBVGC is a convincing candidate for ER, regardless of risk factors other than lymphovascular invasion.

The course of elderly patients with persistent hepatitis C virus infection without hepatocellular carcinoma Abstract Background Little is known about the course of elderly patients with persistent hepatitis C virus (HCV) infection. We investigated the course of HCV infection in this patient population. Methods Among 9,126 HCV antibody-positive patients who visited our hospital between 1995 and 2015, there were 453 patients with continuous follow-up who survived to age 80. They were included in the study following the inclusion criteria: confirmed persistent detection of HCV RNA, no HCV eradication if anti-HCV therapy occurred before enrollment, and no development of hepatocellular carcinoma (HCC) before enrollment. For all study patients, baseline was defined as the date when they turned 80. Mortality rates after the age of 80 years and cause of death were analyzed. Results During the study period, 155 patients (34.2%) died. Median survival time (MST) after age 80 was 8.8 years, which was comparable to that of the general population (10.1 years). Among 155 deceased patients, the majority (115 patients, 74.2%) died due to non-liver-related disease, followed by HCC (28 patients, 18.1%) and liver-related disease other than HCC (12 patients, 7.7%). Patients with advanced liver fibrosis (FIB-4 index > 3.25, n = 245) had shorter MST than patients with mild liver fibrosis (FIB-4 index ≤ 3.25, n = 208) (7.1 vs. 10.2 years; p = 0.020) due to a higher mortality rate from liver-related complications, including HCC. Conclusion Most elderly HCV patients die from non-liver-related disease, especially those with less advanced liver fibrosis.

Polyethylene glycol 3350 plus electrolytes for chronic constipation: a 2-week, randomized, double-blind, placebo-controlled study with a 52-week open-label extension Abstract Background Although polyethylene glycol 3350 plus electrolytes (PEG3350 + E) is the most widely used osmotic laxative in Europe, prospective data on its long-term (over 6 months) safety and efficacy are not available to date. Methods Japanese patients with chronic constipation were randomized to receive PEG3350 + E or placebo for 2 weeks orally. Following this, the patients received PEG3350 + E in the 52-week extension study. The starting dose was 13.7 g/day dissolved in 125 mL of water, and dose titration was allowed (upper limit 41.1 g/day) according to the patient’s bowel condition. The primary efficacy endpoint was the change from baseline in frequency of spontaneous bowel movements (SBMs) at week 2 in the double-blind study. Secondary endpoints and adverse events were assessed. Safety and efficacy were also assessed in the extension study. Results Among 204 patients who provided informed consent, 156 were randomized and included in the full analysis. The frequency of SBMs was significantly higher with PEG3350 + E [least squares mean (LSM) 4.3, 95% confidence interval (CI) 3.6–4.9] compared with placebo (LSM 1.6, 95% CI 1.2–2.1; P < 0.0001). A total of 153 patients entered the extension study; PEG3350 + E led to a sustained improvement in bowel function. The common adverse drug reactions during the entire study period were mild gastrointestinal disorders (abdominal pain 4.5%, diarrhea 3.8%, nausea 3.2%, abdominal distension 2.6%). Conclusions Treatment with PEG3350 + E resolved constipation in the short term, was well tolerated, and led to sustained improvement in bowel function in the long-term treatment of Japanese patients with chronic constipation. Clinical trial registration number Japic CTI-163167.

Time trends in the incidence of esophageal adenocarcinoma, gastric adenocarcinoma, and superficial esophagogastric junction adenocarcinoma Abstract Background In Japan, the incidence of esophageal adenocarcinoma (EAC) and esophagogastric junction (EGJ) adenocarcinoma is expected to increase and that of gastric adenocarcinoma (GAC) is expected to decrease due to Westernization of the diet and the decreasing prevalence of Helicobacter pylori infection. However, few reports about these trends have included the latest data, and no reports about the time trend in the incidence of EGJ adenocarcinoma have focused on the etiologies (gastric cardia adenocarcinoma or EAC, including Barrett’s adenocarcinoma). We therefore investigated the time trends in the incidence of these cancers by including the latest data. Methods First, we investigated the time trends in EAC and GAC using population-based cancer registry data in Osaka Prefecture (1985–2014). We then investigated the time trend in superficial EGJ adenocarcinoma with clinicopathological features at Osaka International Cancer Institute (2006–2017). Results From 1985 to 2014 in Osaka Prefecture, the incidence of EAC gradually increased in both sexes, while that of GAC in men did not significantly change and that in women decreased. The ratio of the EAC/GAC incidence increased 3.5 times in men and 1.8 times in women. In the secondary time trend survey for EGJ adenocarcinoma, the numbers of patients with endoscopic Barrett’s esophagus and those without gastric mucosal atrophy increased, and the number of patients with lesions located above the EGJ line and histologically diagnosed as Barrett’s adenocarcinoma increased. Conclusions The incidence of EAC and superficial EGJ adenocarcinoma with characteristics similar to those of EAC, including Barrett’s adenocarcinoma, might be increasing.

A simple and practical index predicting the prognoses of the patients with well-differentiated pancreatic neuroendocrine neoplasms Abstract Background The prognostic importance of the neuroendocrine (NE) markers involving neural cell adhesion molecule (NCAM) has been unclear enough to be adopted for WHO classification in patients with pancreatic neuroendocrine neoplasms (Pan-NENs). This study aimed to elucidate whether the three NE markers such as chromogranin A, synaptophysin, and NCAM decide prognoses for patients with well-differentiated tumors. Methods Between April 2002 and October 2018, 217 patients were included in this study. Tissue samples from tumors of Pan-NENs were immunochemically stained for the aforementioned NE markers. Diffuse and intense staining was defined as positive, while faint or focal staining and non-staining were considered negative. Results The median age of patients was 55 years. The median observation period was 1415 days. In multivariate analysis of progression-free survival (PFS), liver metastasis, Ki-67 index, and triple-positive staining of NE markers were risk factors. The 5-year PFS rate of patients with and without triple-positive NE markers was 56.3% and 23.8%, respectively (P < 0.0001). In multivariate analysis of overall survival (OS), R0 resection, Ki-67 index and triple-positive NE markers (hazard ratio 0.4, P = 0.02) were the risk factors. The 5-year OS rate of patients with and without triple-positive NE markers was 88.8% and 66.4%, respectively (P = 0.014). The tumors of patients without triple-positive NE markers were associated with large tumor size, a high mitotic rate and high Ki-67 index. Conclusions Triple-positive NE marker staining was a simple and practical indicator of prognoses in patients with well-differentiated Pan-NETs.

The mesenchymal stem cell secretome as an acellular regenerative therapy for liver disease Abstract The use of mesenchymal stem cells (MSC) for tissue repair has garnered much interest and has been evaluated in several disease settings. Recent evidence indicates that the beneficial effects observed with MSC-based therapy can be mediated through the paracrine release of extracellular vesicles and other soluble proteins or biologically active molecules, which collectively constitute the MSC secretome. In this concise overview, we highlight results from preclinical and other studies that demonstrate the therapeutic efficacy of the MSC secretome for diseases that are characterized by liver injury or fibrosis. The potential for the use of the MSC secretome as an acellular regenerative therapy and approaches for the isolation of a secretome product for therapeutic applications are highlighted. The use of the MSC secretome as an acellular therapeutic agent could provide several advantages over the use of cell-based therapies for liver diseases.

Internet survey on the actual situation of constipation in the Japanese population under 70 years old: focus on functional constipation and constipation-predominant irritable bowel syndrome Abstract Background In Japan, the prevalence of constipation-predominant irritable bowel syndrome (IBS-C) and functional constipation (FC) diagnosed by the Rome III criteria is unclear, as are the demographic profile, quality of life (QOL), and habits of persons with IBS-C or FC. Methods We performed an internet survey of constipation. After extracting 3000 persons fitting the composition of the general Japanese population, we investigated demographic factors, lifestyle, defecation, and laxatives. IBS-C and FC were diagnosed by Rome III criteria. Respondents also completed the Japanese IBS severity index (IBS-SI-J), Japanese IBS QOL scale (IBS-QOL-J), SF-8, Hospital Anxiety and Depression Scale (HADS), and Japanese Health Practice Index (JHPI). Results There were 262 respondents with FC (8.73%) [73 men and 189 women; mean age: 49.8 ± 13.1 years; mean body mass index (BMI): 21.0 ± 3.3 g/m2] and 149 respondents with IBS-C (4.97%) (76 men and 73 women; mean age; 41.6 ± 13.7 years; mean BMI: 20.8 ± 3.0 kg/m2). Total IBS-QOL-J score were significantly lower in the IBS-C group than the FC group. With regard to SF-8, score of mental component summary (MCS) was significantly lower in the IBS-C group. The total IBS-SI-J score and item scores, except for satisfactory defecation, were significantly higher in the IBS-C group than the FC group. HADS showed a significant increase of anxiety and depression in both the groups, and the JHPI revealed insufficient sleep. Conclusions In Japan, among the population of under 70 years old, the prevalence of IBS-C and FC (Rome III criteria) was 4.97% and 8.76%, respectively. IBS-C caused more severe symptoms than FC, resulting in impairment of QOL.

Cost-utility analysis of a ‘vonoprazan-first’ strategy versus ‘esomeprazole- or rabeprazole-first’ strategy in GERD Abstract Background Gastroesophageal reflux disease (GERD) can be treated using a vonoprazan-first strategy (first-line treatment with vonoprazan), or esomeprazole-first/rabeprazole-first strategies (first-line treatment with proton-pump inhibitors [PPIs], esomeprazole/rabeprazole, followed by a switch to vonoprazan). This cost-utility analysis used long-term simulation modeling to evaluate the cost-effectiveness of a vonoprazan-first strategy compared with the esomeprazole-first and rabeprazole-first strategies. Methods A Markov simulation model was developed to evaluate the cost-effectiveness of vonoprazan-first, esomeprazole-first, and rabeprazole-first strategies, comprising healing and maintenance therapies, over 5 years (4-week cycles). Healing therapy began with the administration of a normal dose of drug per real-world practice. If patients were not healed endoscopically, either a longer duration of healing therapy was provided (vonoprazan), the dose was increased (rabeprazole), or patients were switched to vonoprazan (immediately for esomeprazole, and after dose-escalation for rabeprazole, respectively). Healed patients received maintenance (lower/same dose as healing therapy). Recurrence resulted in re-challenge with healing therapy. Transition probabilities were derived from the results of indirect comparisons (network meta-analysis) and costs calculated from the Japanese payer perspective. Outcomes were defined as quality-adjusted life years (QALYs), with utilities based on published values. Results Expected costs of the vonoprazan-, esomeprazole-, and rabeprazole-first strategies were ¥36,194, ¥76,719, and ¥41,105, respectively, over 5 years. QALY gains for vonoprazan-first strategy versus the esomeprazole- and rabeprazole-first strategies were 0.014 and 0.003, respectively. Both estimated incremental cost-effectiveness ratios were dominant and robust to two sensitivity analyses. Conclusions Vonoprazan-first strategy increased QALYs and appeared to be cost-effective for GERD patients compared with the esomeprazole- or rabeprazole-first strategies.

Correction to: Management of elderly ulcerative colitis in Japan Management of elderly ulcerative colitis in Japan