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Abstract Alcohol consumption increases oxidative stress and imbalances in the antioxidant system, even with ethanol (EtOH) exposure at a young age. This study assessed changes in the antioxidant system following young EtOH exposure in peripheral immunity and measured sensitive indicators of heavy alcohol consumption. We used peripheral blood mononuclear cells (PBMCs) from 197 male university students without smoking habits to examine changes in antioxidant-related gene expression in vitro and in PBMCs. In vitro, the antioxidant system was impaired by EtOH. Next, we examined the expression of 84 antioxidant-related genes in the PBMCs of 162 young adults, among which the superoxide dismutase (SOD) 1 expression was most negatively correlated with alcohol consumption degree. The plasma SOD1 level had the highest area under the curve value (0.806) for heavy alcohol consumption. Our data demonstrated that a decreased SOD1 level is a sensitive indicator of an impaired antioxidant system and heavy alcohol consumption with early EtOH exposure.

With increasing global life expectancy, the significance of geriatric assessment parameters has increased. Sarcopenia is a crucial assessment parameter and is defined as the age-related loss of muscle mass and strength. Sarcopenia is widely acknowledged as a risk factor for postoperative complications in diverse advanced malignancies and has a detrimental effect on the long-term prognosis. While most studies have primarily concentrated on the correlation between sarcopenia and advanced cancer, more recent investigations have focused on the relationship between sarcopenia and early-stage cancer. Endoscopic submucosal dissection (ESD), which is less invasive than surgical intervention, is extensively employed in the management of early-stage cancer, although it is associated with complications such as bleeding and perforation. In recent years, several reports have revealed the adverse consequences of sarcopenia in patients with early-stage cancer undergoing ESD. This literature review briefly summarizes the recent studies on the association between sarcopenia and ESD.

Background: Previous studies demonstrate an association between metabolic factors and Helicobacter pylori-related gastric cancer. However, the association of gastric atrophy or intestinal metaplasia (IM) with these factors remains unknown. Methods: Data on 1603 Helicobacter pylori-positive patients who underwent esophagogastroduodenoscopy between 2001 and 2021 were evaluated. The outcome measures were endoscopic atrophy, IM grade, and the incidence of endoscopically diagnosed and pathologically confirmed gastric neoplasms. Clinical factors associated with these findings were also determined. Results: Advanced age; successful Helicobacter pylori eradication; and comorbidities including diabetes mellitus (DM), hypertension, dyslipidemia, and fib4 index were significantly associated with endoscopic gastric atrophy grade. Male sex; advanced age; and comorbidities including DM, hypertension, dyslipidemia, hyperuricemia, fatty liver, aortic calcification, and fib4 index were also significantly associated with endoscopic IM grade, whereas advanced age, successful Helicobacter pylori eradication, DM, fatty liver, and fib4 index were significantly associated with the incidence of gastric neoplasms. Conclusion: Several metabolic disorders, including DM, hypertension, dyslipidemia, hyperuricemia, and fatty liver disease, are risk factors for advanced-grade gastric atrophy, intestinal metaplasia, and gastric neoplasms. Risk stratification according to these factors, particularly those with metabolic disorders, would affect EGD surveillance for Helicobacter pylori-positive patients.

Background and Aim: The diagnostic accuracy for cholangiocarcinoma (CCA) is inadequate, necessitating the exploration of novel diagnostic approaches. Protoporphyrin IX (Pp IX), a metabolic product of 5-aminolevulinic acid (5-ALA), emits red fluorescence upon blue light exposure. Because it accumulates selectively in cancer cells, photodynamic diagnosis using 5-ALA (5-ALA-PDD) has been integrated into clinical practice for diverse cancer types. Nevertheless, there is currently no device capable of capturing Pp IX-derived fluorescence for real-time 5-ALA-PDD within the biliary tract, largely due to challenges in device miniaturization. Methods: To investigate the feasibility of real-time 5ALA-PDD in CCA, we developed two essential components of the cholangioscopy system: a small-diameter flexible camera and a light guide for emitting blue light. We evaluated the detectability of Pp IX fluorescence using these devices in experimental gels and animal models. Results: Our camera and light guide were smoothly inserted into the lumen of existing cholangioscopes. Incorporating a long-pass filter at the camera tip enabled efficient detection of red fluorescence without significantly impacting white-light observation. The integration of these devices facilitated clear visualization of red fluorescence from gels containing Pp IX at concentrations of 5 μM or higher. Additionally, when observing subcutaneous human CCA tumor models in nude mice treated with 5-ALA, we successfully demonstrated distinct red fluorescence from Pp IX accumulation in tumors compared to peritumoral subcutaneous areas. Conclusion: The integration of our device combination holds promise for real-time 5-ALA-PDD in human CCA, potentially enhancing the diagnostic accuracy for this complex condition.

Abstract The number of cancer cases diagnosed during the coronavirus disease 2019 (COVID-19) pandemic has decreased. This study investigated the impact of the pandemic on the clinical practice of hepatocellular carcinoma (HCC) using a novel nationwide REgistry for Advanced Liver diseases (REAL) in Japan. We retrieved data of patients initially diagnosed with HCC between January 2018 and December 2021. We adopted tumor size as the primary outcome measure and compared it between the pre-COVID-19 (2018 and 2019) and COVID-19 eras (2020 and 2021). We analyzed 13,777 patients initially diagnosed with HCC (8074 in the pre-COVID-19 era and 5703 in the COVID-19 era). The size of the maximal intrahepatic tumor did not change between the two periods (mean [SD] = 4.3 [3.6] cm and 4.4 [3.6] cm), whereas the proportion of patients with a single tumor increased slightly from 72.0 to 74.3%. HCC was diagnosed at a similar Barcelona Clinic Liver Cancer stage. However, the proportion of patients treated with systemic therapy has increased from 5.4 to 8.9%. The proportion of patients with a non-viral etiology significantly increased from 55.3 to 60.4%. Although the tumor size was significantly different among the etiologies, the subgroup analysis showed that the tumor size did not change after stratification by etiology. In conclusion, the characteristics of initially diagnosed HCC remained unchanged during the COVID-19 pandemic in Japan, regardless of differences in etiology. A robust surveillance system should be established particularly for non-B, non-C etiology to detect HCC in earlier stages.

Background & Aims: Colorectal cancer (CRC) is the third most common cancer in the world. Gut microbiota has recently been implicated in the development of CRC. Actinomyces odontolyticus is one of the most abundant bacteria in the gut of patients with very early stages of CRC. A odontolyticus is an anaerobic bacterium existing principally in the oral cavity, similar to Fusobacterium nucleatum, which is known as a colon carcinogenic bacterium. Here we newly determined the biological functions of A odontolyticus on colonic oncogenesis. Methods: We examined the induction of intracellular signaling by A odontolyticus in human colonic epithelial cells (CECs). DNA damage levels in CECs were confirmed using the human induced pluripotent stem cell-derived gut organoid model and mouse colon tissues in vivo. Results: A odontolyticus secretes membrane vesicles (MVs), which induce nuclear factor kappa B signaling and also produce excessive reactive oxygen species (ROS) in colon epithelial cells. We found that A odontolyticus secretes lipoteichoic acid-rich MVs, promoting inflammatory signaling via TLR2. Simultaneously, those MVs are internalized into the colon epithelial cells, co-localize with the mitochondria, and cause mitochondrial dysfunction, resulting in excessive ROS production and DNA damage. Induction of excessive DNA damage in colonic cells by A odontolyticus-derived MVs was confirmed in the gut organoid model and also in mouse colon tissues. Conclusions: A odontolyticus secretes MVs, which cause chronic inflammation and ROS production in colonic epithelial cells, leading to the initiation of CRC.

Background and Aims: Cancer-associated venous thromboembolism (VTE) is a frequent complication associated with high mortality in patients with cancer, particularly pancreatic cancer. While biological factors such as coagulation factors released from cancer cells may underlie the mechanisms of cancer-associated VTE, the detailed mechanisms have not been determined. Here, we aimed to determine whether extracellular vesicles carrying a glycan sialyl-Lewisa, known as carbohydrate antigen 19-9 (CA19-9), which is a clinically used serum tumor marker and selectin ligand, are a significant cause of cancer-associated VTE. Methods: Risk factors for cancer-associated VTE were determined using clinical data. EVs derived from CA19-9-deficient or overexpressing pancreatic cancer cells were characterized. The protein levels of coagulation factors on the surface of the EVs were quantified using our newly developed sensitive method. Results: Higher CA19-9 levels in the sera of patients were significantly associated with the occurrence of VTE. Using CA19-9-negative or overexpressing pancreatic cancer cells, we found that EVs derived from these cells interacted with E-selectin of endothelial cells in a CA19-9-dependent manner in cell-based assays and in vitro blood vessel models. EVs derived from cancer cells have higher tissue factor levels on their surfaces, and increased tissue factor activity is induced locally, where CA19-9-positive EVs bind to activated endothelial cells. Conclusion: These results suggest that the binding between CA19-9-positive EVs released from cancer cells and endothelial cell E-selectin explains the increased frequency of VTE in patients with pancreatic cancer.

Abstract Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here we treat male STAM (STelic Animal Model) mice, which develop diabetes, NASH and HCC associated with dysbiosis upon low-dose streptozotocin and high-fat diet (HFD), with insulin or phlorizin. Although both treatments ameliorate hyperglycemia and NASH, insulin treatment alone lead to suppression of HCC accompanied by improvement of dysbiosis and restoration of antimicrobial peptide production. There are some similarities in changes of microflora from insulin-treated patients comorbid with diabetes and NASH. Insulin treatment, however, fails to suppress HCC in the male STAM mice lacking insulin receptor specifically in intestinal epithelial cells (ieIRKO), which show dysbiosis and impaired gut barrier function. Furthermore, male ieIRKO mice are prone to develop HCC merely on HFD. These data suggest that impaired gut insulin signaling increases the risk of HCC, which can be countered by restoration of insulin action in diabetes.

Abstract Alterations in KRAS, CDKN2A (p16), TP53, and SMAD4 genes have been major drivers of pancreatic carcinogenesis. The clinical course of patients with pancreatic cancer in relation to these driver alterations has not been fully characterised in large populations. We hypothesised that pancreatic carcinomas with different combinations of KRAS mutation and aberrant expression of CDKN2A, p53, and SMAD4 might show distinctive recurrence patterns and post‐operative survival outcomes. To test this hypothesis, we utilised a multi‐institutional cohort of 1,146 resected pancreatic carcinomas and assessed KRAS mutations by droplet digital polymerase chain reaction and CDKN2A, p53, and SMAD4 expression by immunohistochemistry. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease‐free survival (DFS) and overall survival (OS) were computed according to each molecular alteration and the number of altered genes using the Cox regression models. Multivariable competing risks regression analyses were conducted to assess the associations of the number of altered genes with specific patterns of recurrence. Loss of SMAD4 expression was associated with short DFS (multivariable HR, 1.24; 95% CI, 1.09–1.43) and OS times (multivariable HR, 1.27; 95% CI, 1.10–1.46). Compared to cases with 0–2 altered genes, cases with three and four altered genes had multivariable HRs for OS of 1.28 (95% CI, 1.09–1.51) and 1.47 (95% CI, 1.22–1.78), respectively (ptrend

Abstract Background Previous studies have revealed an association between probiotic use and effectiveness of immune checkpoint inhibitors in renal and lung cancers. However, little is known regarding other cancers, including gastrointestinal cancer. Methods To address this issue, we conducted a multicenter retrospective cohort study and the duration of nivolumab treatment for various cancers was compared between probiotic users and non‐users. Results and Conclusions In total, 488 patients who received nivolumab therapy were included. In all cancers, no significant differences in treatment duration of nivolumab were observed between probiotic users and non‐users (median 62.0 vs. 56.0, hazard ratio = 1.02, p = 0.825), whereas probiotic use, compared with non‐use, in patients with gastric cancer was significantly associated with a longer duration of nivolumab treatment (55.0 vs. 31.0 days, hazard ratio = 0.69, p = 0.039). In conclusion, probiotics may improve the response to nivolumab and potentially prolong progression‐free survival in patients with gastric cancer.

Abstract Aim Comprehensive genomic profiling (CGP) test for solid tumors is now increasingly utilized in clinical practice, especially in pancreatobiliary cancer, and specimens obtained by endoscopic ultrasound‐guided tissue acquisition (EUS‐TA) are often submitted for tissue‐based CGP test. In this study, we evaluated the feasibility of EUS‐TA using a 22‐gauge Franseen needle for the CGP test. Methods Consecutive patients with solid tumors who underwent EUS‐TA using a 22‐gauge Franseen needle, and whose tissue samples were pre‐checked for suitability for CGP test, were included in this single‐center, retrospective analysis. The success rates of appropriate sample collection for CGP evaluated by pathologists (1st quality control) and CGP test (2nd quality control) were evaluated. In addition, The EUS‐TA slides were evaluated for the tissue area and tumor area content, using the image software. Results A total of 50 cases, with 78% of pancreatic cancer, were included in the analysis. A median of 3 passes of EUS‐TA were performed with an adverse event rate of 4%. The success rates for 1st and 2nd quality control for CGP tests were 86% and 76%, respectively. The image analyses suggested EUS‐TA specimen did not always fulfill CGP test criteria, with 18% of tissue area ≥16 mm2 and 38% of tumor area content ≥20%, even in cases with successful CGP tests. The suction method yielded a significantly larger amount of DNA but without a significant difference in the multivariate analysis. Conclusions The present study demonstrated the feasibility of EUS‐TA using a 22‐gauge Franseen needle for CGP test.

Abstract Obstructive colitis is an acute condition caused by colorectal strictures and requires a combination of therapeutic strategies, including surgery, endoscopic interventions, and medications. Here, we describe the case of a 69‐year‐old man who developed severe obstructive colitis owing to diverticular stenosis of the sigmoid colon. We immediately performed endoscopic decompression to avoid perforation. The mucosa of the dilated colon appeared black, suggesting severe ischemia. We considered surgical total colectomy owing to the extensive colitis. However, considering the invasiveness of the emergent surgery, we adopted a conservative approach as enhanced computed tomography demonstrated colonic dilation with maintained blood flow in the deeper layer of the colonic wall and no signs of colonic necrosis, such as peritoneal irritation sign or elevation of deviation enzymes, were observed. Moreover, the patient preferred a conservative approach, and surgeons in our team agreed with this conservative approach. While relapses of colonic dilation occurred several times, antibiotic treatment and repeated endoscopic decompression successfully suppressed the dilation and systemic inflammation. The colonic mucosa healed gradually, and we performed a colostomy without resecting a large portion of the colorectum. In conclusion, severe obstructive colitis with maintained blood flow can be treated with endoscopic decompression instead of emergent resection for a wide portion of the colorectum. Moreover, endoscopic images of improved colitic mucosa obtained through repeated colorectal procedures are rare and noteworthy.

Abstract Background Endoscopic ultrasound‐guided fine needle aspiration (EUS‐FNA) is widely used for the pathological diagnosis of solid pancreatic lesions but in cases with obstructive jaundice, transpapillary sampling can be performed during endoscopic retrograde cholangiopancreatography with transpapillary biliary stent placement. Thus, it is still controversial whether EUS‐FNA should be performed prior to endoscopic retrograde cholangiopancreatography with biliary stent placement or only after negative transpapillary sampling. Methods The accuracy, sensitivity, and specificity of EUS‐FNA for solid pancreatic lesions with or without indwelling biliary stents were retrospectively studied in patients undergoing EUS‐FNA between January 2017 and December 2021. We also conducted a meta‐analysis including our data to compare the accuracy and sensitivity of EUS‐FNA with or without biliary stents. Results A total of 509 patients (40 with biliary stents and 469 without biliary stents) were included. The accuracy (77.5% vs. 94.5%, p < 0.001) and sensitivity (71.0% vs. 91.7%, p < 0.001) were lower in EUS‐FNA with biliary stents. A meta‐analysis confirmed that accuracy (odds ratio [OR] of 0.43, 95% confidence interval [CI] 0.29–0.62, p < 0.001) and sensitivity (OR of 0.46, 95% CI 0.33–0.64, p < 0.001) were lower in EUS‐FNA with biliary stents. There were no statistically significant differences between plastic stents and self‐expandable metallic stents for accuracy or sensitivity. Conclusions The presence of biliary stents had a negative impact on the diagnostic performance of EUS‐FNA, and EUS‐FNA prior to endoscopic retrograde cholangiopancreatography with biliary stent placement should be considered in cases with obstructive jaundice.

Abstract Background Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease. This study aimed to clarify the status of HRS in Japan by analyzing the Japanese Diagnosis Procedure Combination database. Methods Patients hospitalized for cirrhosis and HRS from July 2010 to March 2019 were sampled. They were divided into two groups according to their prognosis upon discharge: the transplant-free survival group and the death or liver transplantation group. The two groups’ baseline patient characteristics and treatments were compared. Results The mean age of the 1,412 participants was 67.3 years (standard deviation: 12.3 years), and 65.4% were male. The Child–Pugh grades was B and C in 18.8% and 81.2%, respectively. Hepatocellular carcinoma was present in 27.1% of the patients, and the proportion of spontaneous bacterial peritonitis was 2.3%. Albumin, noradrenaline, and dopamine were administered to 57.9%, 8.0%, and 14.9% of the patients, respectively; 7.0% of the patients underwent renal replacement therapy; and 5.0% were admitted to the intensive care unit. Intravenous antibiotics were administered to 30.8% of the patients. A total of 925 patients (65.5%) died or underwent liver transplantation. In addition to a higher proportion of patients with poor baseline liver function, the death or liver transplantation group included more males, patients with hepatocellular carcinoma, and those with spontaneous bacterial peritonitis. Conclusions HRS in Japan has a high mortality rate. Albumin was administered to over 50% of participants. Although noradrenaline is recommended in Japanese clinical guidelines, dopamine was more frequently used as a vasoconstrictor in clinical practice.

Background and Aims: Although Helicobacter pylori is the most important bacterial carcinogen in gastric cancer (GC), GC can emerge even after H. pylori eradication. Studies suggest that various constituents of the gastric microbiome may influence GC development, but the role of individual pathogens is unclear. Methods: Human gastric mucosal samples were analyzed by 16SrRNA sequencing to investigate microbiome composition and its association with clinical parameters, including GC risk. Identified bacteria in the stomach were cocultured with gastric epithelial cells or inoculated into mice, and transcriptomic changes, DNA damage, and inflammation were analyzed. Bacterial reads in GC tissues were examined together with transcriptomic and genetic sequencing data in the cancer genome atlas dataset. Results: Patients after Helicobacter pylori eradication formed 3 subgroups based on the microbial composition revealed by 16SrRNA sequencing. One dysbiotic group enriched with Fusobacterium and Neisseria species was associated with a significantly higher GC incidence. These species activated prooncogenic pathways in gastric epithelial cells and promoted inflammation in mouse stomachs. Sugar chains that constitute gastric mucin attenuate host-bacteria interactions. Metabolites from Fusobacterium species were genotoxic, and the presence of the bacteria was associated with an inflammatory signature and a higher tumor mutation burden. Conclusion: Gastric microbiota in the dysbiotic stomach is associated with GC development after H. pylori eradication and plays a pathogenic role through direct host-bacteria interaction.

Abstract The objective of this study was to elucidate the molecular background of sessile serrated adenoma/polyp (SSA/P) endoscopically resected with comprehensive gene expression analysis. Gene expression profiling was performed for 10 tumor‐normal pairs of SSA/P. Cluster analysis, gene set enrichment analysis (GSEA), and consensus molecular subtype (CMS) classification of colorectal cancer (CRC) were applied to our transcriptome analysis. Unsupervised cluster analysis showed that the gene expression profile of SSA/Ps is different from that of adjacent normal epithelial cells, even in the very early stage of tumorigenesis. According to the CMS classification, our microarray data indicated that SSA/Ps were classified as CMS1. GSEA demonstrated a strong association between SSA/P and microsatellite instability‐high (MSI‐H) CRC (p

Abstract A non-invasive method to evaluate the fibrosis stage and the risk stratification of non-alcoholic fatty liver disease (NAFLD) is required. A total of 416,066 generally healthy subjects who underwent health check-ups between 1990 and 2019 were investigated. Fatty liver prevalence greatly increased from the 1990s (21.9%) to the 2000s (37.1%) but showed no considerable change between 2001–2010 (39.2%) and 2011–2019 (35.5%). During the 30 years, the rate of high FIB-4 index (≥2.67) and mean body mass index (BMI) did not markedly change. Fatty liver was significantly associated with BMI, but not with alcohol intake or FIB-4 index. Cox regression analyses for development of chronic hepatitis or liver cirrhosis identified that the risk of developing chronic hepatitis and liver cirrhosis was higher in subjects without fatty liver than in those with it (hazard ratio [HR]=0.09; 95% confidence interval [CI], 0.03–0.22, p

Abstract This study aimed to evaluate the feasibility and efficacy of Endoscopic ultrasound elastography-guided fine needle biopsy (EUS-EG-FNB) for the diagnosis of pancreatic mass lesions. EUS-EG images were classified into heterogeneous and homogeneous groups. For the heterogeneous group, EUS-FNB was separately performed in both hard areas and soft areas. Only samples obtained during the first two passes (hard/soft areas) were used to compare the diagnostic accuracy as well as the quality and quantity of the specimens. We investigated the association of EUS-EG findings using strain histogram analysis with the histological findings. Fifty-five patients were enrolled including 25 patients with heterogeneous group. The homogeneous group had significantly lower mean strain value (hard) lesions. The adequate sampling rates from hard and soft areas were 88 and 92%, respectively (P = 0.6374). Comparison of the diagnostic accuracy and the quality and quantity of the histological core between hard and soft areas showed no significant differences. In pancreatic adenocarcinoma cases, the proportion of fibrous stroma in the core tissue was significantly correlated with the elasticity of the region. (R2 = 0.1226: P = 0.0022) EUS-EG may reflect tissue composition in pancreatic tumors, however, EUS-EG did not affect either the quality and quantity of the tissues obtained. Clinical Trial Registry No: UMIN-000033073.

Abstract The prognostic impact of direct‐acting antivirals (DAAs) on patients with hepatitis C‐related hepatocellular carcinoma (C‐HCC) is still unclear. This study aimed to evaluate the prognosis of C‐HCC in the DAA era. We enrolled 1237 consecutive patients with treatment‐naive C‐HCC who underwent radical radiofrequency ablation between 1999 and 2019. We also enrolled 350 patients with nonviral HCC as controls. We divided these patients into three groups according to the year of initial treatment: 1999–2005 (cohort 1), 2006–2013 (cohort 2), and 2014–2019 (cohort 3). The use of antiviral agents and their effect in patients with C‐HCC was investigated. Overall survival was evaluated for each cohort using the Kaplan‐Meier method and a multivariable Cox proportional hazards regression model. Sustained virologic response (SVR) was achieved in 52 (10%), 157 (26%), and 102 (74%) patients with C‐HCC in cohorts 1–3, respectively. The 3‐ and 5‐year survival rates of patients with C‐HCC were 82% and 59% in cohort 1; 80% and 64% in cohort 2; and 86% and 78% in cohort 3, respectively (p = 0.003). Multivariable analysis adjusted for age, liver function, and tumor extension showed that the prognosis of C‐HCC improved in cohort 3 compared to cohort 1 (adjusted hazard ratio [aHR], 0.49; 95% confidence interval [CI], 0.32–0.73; p

Abstract Background Fecal microbiota transplantation (FMT) is a potential treatment for irritable bowel syndrome (IBS), but its efficacy in Japanese IBS patients is unknown. This study aimed to evaluate the efficacy, side effects, and microbiome changes following FMT in Japanese IBS patients. Methods Seventeen Japanese patients with refractory IBS received FMT (4 donors) under colonoscopy. Responders were defined by an improvement in the IBS severity index (IBS-SI) of 50 points or more after 12 weeks. We evaluated the IBS-SI and Bristol Stool Form Scale (BSFS) and compared the diversity and microbiome before and 12 weeks after FMT. For the microbiome, we analyzed the V3–V4 region of the 16S rRNA gene. Results IBS-SI decreased an average of 115.58 points after 12 weeks, and 10 patients (58.8%) were considered responders. Eight patients with diarrhea (66.7%) and three patients with constipation (60.0%) showed improvement in the BSFS. Two patients complained of mild abdominal pain, but there were no cases with severe side-effects. α-diversity was increased only in the responder group (p = 0.017). Patients who closely paralleled the donor microbiome had a higher rate of IBS-SI improvement. The relative abundance of Neisseria and Akkermansia increased and Desulfovibrio and Delftia were decreased in the responder group after FMT. Conclusions Following FMT, about 60% of Japanese patients with IBS showed improvement in both the IBS-SI and BSFS, without severe side effects. Increased α-diversity and similarity to the donor microbiome after FMT may be associated with better treatment effects. Trial registration: This study was registered in the University Hospital Medical Information Network Clinical Trial Registration (UMIN000026363). Registered 31 May 2017, https://rctportal.niph.go.jp/s/detail/um?trial_id=UMIN000026363 . The study was registered prospectively.

Although the mortality rates of gastric cancer (GC) are gradually declining, gastric cancer is still the fourth leading cause of cancer-related death worldwide. This may be due to the high rate of patients who are diagnosed with GC at advanced stages. However, in countries such as Japan with endoscopic screening systems, more than half of GCs are discovered at an early stage, enabling endoscopic resection (ER). Especially after the introduction of endoscopic submucosal dissection (ESD) in Japan around 2000, a high en bloc resection rate allowing pathological assessment of margin and depth has become possible. While ER is a diagnostic method of treatment and may not always be curative, it is widely accepted as standard treatment because it is less invasive than surgery and can provide an accurate diagnosis for deciding whether additional surgery is necessary. The curability of ER is currently assessed by the completeness of primary tumor removal and the possibility of lymph node metastasis. This review introduces methods, indications, and curability criteria for ER of EGC. Despite recent advances, several problems remain unsolved. This review will also outline the latest evidence concerning future issues.

Abstract This study assessed the effect of magnifying endoscopy with narrow-band imaging (M-NBI) on the endoscopic differential diagnosis between intramucosal gastric carcinomas and adenomas with matched characteristics. Associations between magnified endoscopic findings and pathological high-grade cellular and architectural atypia were also investigated. In total, the records of 50 adenomas and 50 intramucosal well-differentiated adenocarcinomas matched by tumor size (≥ 20 mm or

Abstract Sarcopenia is thought to be related to the microbiome, but not enough reports in chronic liver disease (CLD) patients. In addition to the differences in microbiome, the role of the microbiome in the gut is also important to be clarified because it has recently been shown that the microbiome may produce branched-chain amino acids (BCAAs) in the body. In this single-center study, sixty-nine CLD patients were divided by skeletal muscle mass index (SMI) into low (L-SMI: n = 25) and normal (N-SMI: n = 44). Microbiome was analyzed from stool samples based on V3-4 region of bacterial 16S rRNA). L-SMI had a lower Firmicutes/Bacteroidetes ratio than N-SMI. At the genus level, Coprobacillus, Catenibacterium and Clostridium were also lower while the Bacteroides was higher. Predictive functional profiling of the L-SMI group showed that genes related to nitrogen metabolism were enriched, but those related to amino acid metabolism, including BCAA biosynthesis, were lower. The genes related to 'LPS biosynthesis' was also higher. The microbiome of CLD patients with low muscle mass is characterized not only by high relative abundance of gram-negative bacteria with LPS, but also by the possibility of low potential for amino acid synthesis including BCAAs.

Abstract Background Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer. Methods The phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety. The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II. Discussion Strategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma. Trial registration Clinicaltrial.gov: NCT05064618 , registered on 1 October 2021. jRCT: jRCT2041210056 , registered on 27 August 2021.

Abstract Objectives Proton pump inhibitors (PPIs) are widely prescribed medications for gastric acid‐induced diseases. Despite the effectiveness of PPIs, recent evidence suggested an increased risk of various bacterial infections in PPI users. The current study was conducted to evaluate the risk of biliary infection after endoscopic biliary stent placement in regular users of PPIs. Methods Consecutive patients with a native papilla who underwent endoscopic retrograde cholangiopancreatography and stent placement for biliary stricture between January 2010 and August 2019 were included in this retrospective study. The cumulative incidences of biliary infection were compared between regular and non‐regular PPI users. Results During the study period, 270 regular PPI users and 146 non‐regular PPI users were included in the analyses. Age, gender, and indication of endoscopic retrograde cholangiopancreatography were not different between the two groups. The incidences of biliary infection were 43% in regular PPI users and 36% in non‐regular PPI users but the time to biliary infection was significantly shorter in regular PPI users than in non‐regular users (28 vs. 87 days, p = 0.01). The cumulative incidence of biliary infection was significantly higher in regular PPI users compared with non‐regular users (p = 0.008). The multivariable Cox regression analysis also showed a significantly higher hazard ratio of biliary infection in regular PPI users (1.62 [95% confidence interval 1.16–2.26; p = 0.005]). Conclusions Regular PPI use was associated with a higher risk of biliary infection after endoscopic biliary drainage. Inappropriate PPI use should be avoided.

Abstract Objectives This study aimed to objectively evaluate the water‐jet‐functioned electrosurgical knife injection performances in a desktop experiment. Methods Five types of water‐jet‐functioned electrosurgical knives, including two injection styles of sheath‐type (A: DualKnife J, KD‐655L; B: FlushKnife, DK2620‐J‐B20S; C: Splash M‐Knife, DN‐D2718B; D: ISSEN, SN1650‐20) and tip‐type (E: ORISE ProKnife, M00519361) were evaluated. These knives were compared with an injection needle (Control: SuperGrip 25G) as a control. The injection speed under constant pressure and the injection efficiency for each knife against prepared porcine stomach mucosa were evaluated. The additional clear gel injections using an injection needle were observed using an indigo blue‐colored gel to evaluate the difference between the locations of water‐jet holes. Results Four types of knives, except for A, showed significantly higher water‐jet speeds (A: 0.79 ± 0.03 g/20 s, B: 2.56 ± 0.05 g/20 s, C: 3.09 ± 0.06 g/20 s, D: 2.86 ± 0.05 g/20 s, and E: 1.79 ± 0.03 g/20 s) compared to that of the control (1.21 ± 0.03 g/20 s). Meanwhile, significantly higher efficacy of injection was found in the tip‐type water‐jet function knife, second to the injection needle (Control: 37.2% ± 35.5%, A: 20.9% ± 20.2%, B: 1.1% ± 2.2%, C: 6.2% ± 12.6%, D: 12.5% ± 15.6%, and E: 33.3% ± 32.2%). An additional injection experiment revealed that the injection with a piercing tip into the gel could achieve sufficient additional injection inside the stacked clear gel. Conclusions The tip‐type water‐jet function electrosurgical knife is preferable for effective submucosal injection during endoscopic treatments.

Abstract The gut microbiota interacts with infectious diseases and affects host immunity. Liver disease is also reportedly associated with changes in the gut microbiota. To elucidate the changes in the gut microbiota before and after hepatitis C virus (HCV) eradication through direct-acting antiviral (DAA) treatment in patients with chronic hepatitis C (CHC), we investigated 42 samples from 14 patients who received DAA therapy for HCV. Fecal samples were obtained before treatment (Pre), when treatment ended (EOT), and 24 weeks after treatment ended (Post24). The target V3–4 region of the 16S rRNA gene from fecal samples was amplified using the Illumina Miseq sequencing platform. The diversity of the gut microbiota did not significantly differ between Pre, EOT, and Post24. Principal coordinates analysis showed that for each patient, the values at Pre, EOT, and Post24 were concentrated within a small area. The linear discriminant analysis of effect size showed that the relative abundances of Faecalibacterium and Bacillus increased at EOT, further increased at Post24, and were significantly increased at Post24 compared to Pre. These suggest that changes in the gut microbiota should be considered as among the various effects observed on living organisms after HCV eradication.

Circular RNAs are single-stranded RNAs with a covalently closed structure formed by the process of back-splicing. Aberrant expression of circular RNAs contributes to the pathogenesis of a wide range of cancers. Pancreatic cancer is one of the most lethal cancers due to diagnostic difficulties and limited therapeutic options. Circular RNAs are emerging as novel diagnostic biomarkers and therapeutic targets for pancreatic cancer. Moreover, recent advances in the therapeutic application of engineered circular RNAs have provided a promising approach to overcoming pancreatic cancer. This review discusses the roles of circular RNAs in the pathogenesis of pancreatic cancer and in potential treatment applications and their usefulness as diagnostic biomarkers.

Abstract Non-alcoholic steatohepatitis (NASH) occurrence has been increasing and is becoming a major cause of liver cirrhosis and liver cancer. However, effective treatments for NASH are still lacking. We examined the benefits of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) on a murine non-alcoholic steatohepatitis (NASH) model induced by a combination of Western diet (WD) and repeated administration of low doses of carbon tetrachloride intraperitoneally, focusing on the gut-liver axis. We showed that repeated intravenous administration of SHED-CM significantly ameliorated histological liver fibrosis and inflammation in a murine NASH model. SHED-CM inhibited parenchymal cell apoptosis and reduced the activation of inflammatory macrophages. Gene expression of pro-inflammatory and pro-fibrotic mediators (such as Tnf-α , Tgf-β, and Ccl-2) in the liver was reduced in mice treated with SHED-CM. Furthermore, SHED-CM protected intestinal tight junctions and maintained intestinal barrier function, while suppressing gene expression of the receptor for endotoxin, Toll-like receptor 4, in the liver. SHED-CM promoted the recovery of Caco-2 monolayer dysfunction induced by IFN-γ and TNF-α in vitro. Our findings suggest that SHED-CM may inhibit NASH fibrosis via the gut-liver axis, in addition to its protective effect on hepatocytes and the induction of macrophages with unique anti-inflammatory phenotypes.

Abstract Background Pancreatic exocrine insufficiency (PEI) is associated with the outcome of pancreatic disease. However, there is no method for assessing PEI that can be used noninvasively and easily for outpatient. It has been reported that changes in intestinal bacteria caused by PEI may increase breath hydrogen concentration (BHC) levels during glucose or lactose loading. We have evaluated the usefulness of fasting breath hydrogen concentration (FBHC) measurement without glucose loading for the evaluation of PEI. Methods Sixty patients underwent FBHC measurement, BT-PABA testing, and microbiome analysis. They were classified into PEI group (PABA excretion rate

Abstract Background Endoscopic papillectomy of duodenal papillary tumors (PT) is indicated for adenomas or well-differentiated adenocarcinomas that do not involve the sphincter of Oddi. However, there is currently no reliable pre-operative method to diagnose the infiltration in the sphincter of Oddi.’ Insulin-like growth factor 2 mRNA protein 3 (IMP3) staining is reportedly associated with advanced disease stage and clinical outcomes in many carcinomas. The aim of this retrospective study was to investigate the ability of diagnosing sphincter of Oddi involvement in PT and predicting the prognoses using IMP3 immunohistochemistry. Methods Twenty-five resected specimens from patients with PT and 24 biopsy specimens from the same patients excluding one were immunostained for IMP3. The percentage of positive cells in the tumor was evaluated and compared with the final pathological diagnosis and prognosis. Results The final pathological diagnoses were adenoma in 5 patients and adenocarcinoma in 20 patients (no sphincter of Oddi involvement in 5 and involvement in 15). The ability to diagnose sphincter of Oddi involvement based on the percentage of IMP3-positive cells in resected specimens and tissue biopsies was the area under the curve 0.8 and 0.78, respectively, of the receiver operating characteristic curve, and the accuracies were 80.0% and 75.0% (cutoff value: 10%), respectively. Moreover, patients with an IMP3-positive cell rate of ≥ 10% had a significantly worse prognosis (log-rank test P = 0.01). Conclusion IMP3 immunostaining of resected and biopsy specimens from PT patients enables the diagnosis of sphincter of Oddi involvement objectively and is also effective in predicting the prognosis.

Abstract Shear wave elastography (SWE) is a technique to non-invasively and quantitatively evaluate tissue stiffness. We aimed to investigate whether we can differentiate pancreatic cancer (PC) from normal pancreatic parenchyma (NPP) by SWE using transabdominal ultrasound. We investigated a total of 106 patients (84 with NPP and 22 with PC) whose pancreatic elastic modulus was measured by two-dimensional SWE (2D-SWE). Intra-rater reliability in this study was examined, and three measurements were sufficiently reliable. There were no differences between the two groups in factors that could affect SWE measurements. The median value of the elastic modulus was 5.70 kPa in the PC patients and 5.66 kPa in the NPP group, which was not significantly different (P = 0.785). On the contrary, the range was 8.64 kPa and 4.72 kPa, with a significantly greater range in the PC patients (P = 0.001). In conclusion, the median elastic modulus measured by 2D-SWE was not significantly different between PC and NPP, and evaluating the obtained elastic modulus itself is not useful in differentiation. However, the variability was significantly greater in PC than in NPP. Evaluating the range of elasticities will provide additional information in SWE, which may be useful in the diagnosis of PC.

Abstract Background Crohn’s disease (CD) can involve the upper gastrointestinal (GI) tract as well as the small and large bowel. PillCam colon capsule endoscopy (PCCE-2) enables observation of the whole GI tract, but its diagnostic yield for CD lesions in the whole GI tract remains unknown. Aim To elucidate the diagnostic yield of PCCE-2 in patients with CD. Methods Patients with CD who underwent PCCE-2 and double-balloon endoscopy (DBE) using oral and anal approaches were evaluated for CD lesions in the whole GI tract. We divided the small bowel into three segments (jejunum, ileum, and terminal ileum), and the large bowel into four segments (right colon, transverse colon, left colon, rectum). Detection of ulcer scars, erosion, ulcers, bamboo joint-like appearance, and notch-like appearance was assessed in each segment. The diagnostic yield of PCCE-2 was analyzed based on the DBE results as the gold standard. Results Of the total 124 segments, the sensitivities of PCCE-2 for ulcer scars, erosion, and ulcers were 83.3%, 93.8%, and 88.5%, respectively, and the specificities were 76.0%, 78.3%, and 81.6%, respectively. For the 60 small bowel segments, the sensitivities were 84.2%, 95.5%, and 90.0%, respectively, and the specificities were 63.4%, 86.8%, and 87.5%, respectively. For the 64 large bowel segments, the sensitivities were 80.0%, 90.0%, and 83.3%, respectively, and the specificities were 84.7%, 72.2%, and 77.6%, respectively. Conclusion PCCE-2 provides a high diagnostic yield for lesions in the whole GI tract of patients with CD. Thus, we recommend its use as a pan-enteric tool in clinical settings.

Enhanced de novo lipogenesis mediated by sterol regulatory element–binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage–activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.

Background and study aims Snare devices play an important role in treatment of intestinal polyps. However, there are no objective measurements for the characteristics of the various types of snare devices. Materials and methods Seven types of snare devices from four manufacturers were evaluated based on original measurements. The evaluated factors were stiffness, cutting quality, and change in force required for cutting depending on sheath shape. The latter two factors were evaluated by measuring the force required to cut 20 % gelatin cylinders, which simulated intestinal polyps. The cutting sharpness was evaluated by observing the sectional surface of cut gelatin cylinders using a stereomicroscope. The correlations between these measurements and characteristics of the snare devices were investigated. Results A strong positive correlation, with an R2 value of 0.863, was shown between the force required to cut gelatin cylinders and loop wire diameter. Loop wire diameter also had a strong correlation, with an R2 value of 0.7997, with the change in force required for cutting gelatin cylinders depending on sheath shape. No correlations were detected between loop stiffness and characteristics of snare devices. The edge-enhanced image revealed that the rougher surfaces of the gelatin cylinders were cut by snares with a thicker diameter. Conclusions Thinner loop wire may provide higher performance in cold snare polypectomy in an experimental model.

Background & Aims: To provide an adequate treatment strategy for chronic hepatitis B, it is essential to know which patients are expected to have a good prognosis and which patients do not require therapeutic intervention. Previously, we identified the substitution of isoleucine to leucine at amino acid 97 (I97L) in the hepatitis B core region as a key predictor among patients with stable hepatitis. In this study, we attempted to identify the point at which I97L affects the hepatitis B virus (HBV) life cycle and to elucidate the underlying mechanisms governing the stabilization of hepatitis. Methods: To confirm the clinical features of I97L, we used a cohort of hepatitis B e antigen–negative patients with chronic hepatitis B infected with HBV-I97 wild-type (wt) or HBV-I97L. The effects of I97L on viral characteristics were evaluated by in vitro HBV production and infection systems with the HBV reporter virus and cell culture-generated HBV. Results: The ratios of reduction in hepatitis B surface antigen and HBV DNA were higher in patients with HBV-I97L than in those with HBV-I97wt. HBV-I97L exhibited lower infectivity than HBV-I97wt in both infection systems with reporter HBV and cell culture-generated HBV. HBV-I97L virions exhibiting low infectivity primarily contained a single-stranded HBV genome. The lower efficiency of cccDNA synthesis was demonstrated after infection of HBV-I97L or transfection of the molecular clone of HBV-I97L. Conclusions: The I97L substitution reduces the level of cccDNA through the generation of immature virions with single-stranded genomes. This I97L-associated low efficiency of cccDNA synthesis may be involved in the stabilization of hepatitis.

Abstract Autoimmune pancreatitis (AIP) is recognized as the pancreatic manifestation of a systemic IgG4-related disease that can involve various organs, including the kidney. However, renal lesions tend to be overlooked when AIP is diagnosed, and the clinical characteristics and long-term prognosis of AIP with renal lesions are unclear. We retrospectively reviewed 153 patients with AIP diagnosed at our hospital with a median follow-up period of 41 months (interquartile range, 10–86) and classified them into two groups: the KD group (n = 17), with characteristic renal imaging features, and the non-KD group (n = 136). Serum IgG4 levels were significantly higher in the KD group (663 vs. 304.5 mg/dl, P = 0.014). No differences were observed between the two groups in terms of steroid treatment [14/17 (82.4%) vs. 112/136 (82.4%), P = 1] or in the number of patients who exhibited exacerbation of renal function during treatment [1/17 (5.9%) vs. 8/136 (5.9%), P = 1]. However, the cumulative relapse rate was significantly higher in the KD group [61% vs. 21.9% (3 years), P

Abstract Background In cases of Hirschsprung disease, complete and reproducible resection of the aganglionic bowel is ideal to achieve good postoperative bowel function. Reliable identification of the upper margin of the surgical anal canal, which is the squamous-columnar junction, is necessary during transanal pull-through. Here, we describe a novel staining technique using Lugol’s iodine stain to visualize the upper margin of the surgical anal canal. Methods Lugol’s iodine staining was performed in five patients with Hirschsprung disease treated using a single-stage laparoscopic transanal pull-through modified Swenson procedure. In two of these patients, endocytoscopic observation with ultra-high magnification was performed using methylene blue and crystal violet to mark the border of the squamous epithelium at 1 week before surgery. The alignment between the incisional line, which was revealed using Lugol’s iodine staining and endocytoscopic marking, was evaluated. Complications, including postoperative bowel dysfunction, were evaluated. Results In all cases, Lugol’s iodine staining produced a well-demarcated line. The endocytoscopic marking of the upper margin of the surgical anal canal was aligned with the line revealed by Lugol’s iodine staining. There were no complications associated with the transanal pull-through procedure, including postoperative bowel dysfunction. Conclusions Lugol’s iodine staining could be a safe and practical method to visualize the upper margin of the surgical anal canal intraoperatively. This finding may be useful for surgeons to make a consistent removal of the aganglionic bowel during surgery for Hirschsprung disease.

Abstract Background and Aim Commonly used classifications for colorectal lesions (CLs) include the Narrow Band Imaging (NBI) International Colorectal Endoscopic (NICE) and Japan NBI Expert Team (JNET) classifications. However, both lack a sessile serrated adenoma/polyp (SSA/P) category. This has been addressed by the modified Sano's (MS) and Workgroup serrAted polypS and Polyposis (WASP) classifications. This study aims to compare the accuracy of wNICE and wJNET (WASP added to both) with the stand‐alone MS classification. Methods Patients undergoing colonoscopy at an Australian tertiary hospital who had at least one CL detected were prospectively enrolled. In the exploratory phase, CLs were characterized in real time with NBI and magnification using all classifications. In the validation phase, CLs were assessed with both NBI and Blue Laser Imaging (BLI) by four external endoscopists in Japan. The primary outcome was the comparison of wJNET and MS. Secondary outcomes included comparisons among all classifications and the calculation of interrater reliability. Results A total of 483 CLs were evaluated in real time in the exploratory phase, and four sets of 30 CL images (80 on NBI and 40 on BLI) were scored in the validation phase. For high‐confidence diagnoses, MS accuracy was superior to wJNET in both the exploratory (86% vs 79%, P

Background and Aim Endoscopic submucosal dissection (ESD) is a challenging procedure. A dissection speed of ≥9 cm2/h has been acknowledged as a mark for expertise, alongside a complication rate of ≤5% and en bloc resection rate of ≥90%. However, there is lack of objective information on whether the three measures correlate with each other. This study aims to evaluate the dissection speed, safety, and efficacy of colorectal ESDs performed by experts and trainees. Methods Consecutive patients undergoing colorectal ESD at a Japanese hospital (2006–2017) were included in a prospectively collected database. Information on patient demographics, proceduralist, and intra‐/postprocedure data was retrieved. The primary outcome was the comparison in dissection speed. The secondary outcomes included differences in safety and efficacy. Log‐linear regression models adjusted for confounders (e.g. R0 resection) were used to assess the differences in dissection speed. Results Five hundred ninety procedures (514 patients) performed by 26 endoscopists were analyzed. Experts performed a higher number of difficult lesions (e.g. F2 fibrosis) but achieved higher dissection speed (10.3 vs 6.7 cm2/h). The difference was statistically significant for both unadjusted and adjusted models (P