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Abstract Objectives The whole picture of the disturbance in endoscopy performance caused by the coronavirus disease 2019 (COVID‐19) pandemic in Japan remains to be clarified. Therefore, the Japan Gastroenterological Endoscopy Society‐Tohoku conducted this questionnaire survey in Tohoku region of Japan. Methods A questionnaire on the number of diagnostic endoscopy procedures and resulting diagnosed cancers in 2019 and 2020 was sent to all guidance/guidance cooperation hospitals in the Japan Gastroenterological Endoscopy Society who worked in the Tohoku region. The percentage change was calculated by comparing the numbers in 2020 with those in 2019 (the pre‐COVID‐19 period). Results Among the applicable 89 guidance/guidance cooperation hospitals, 83 (94%) returned the questionnaire. The number of endoscopy procedures promptly decreased to the nadir in April and May 2020 (during the first state of emergency in Japan); however, it recovered relatively quickly, within a few months after the state of emergency was lifted. Consequently, the annual reduction in the number of endoscopy procedures in 2020 (in comparison to 2019) was 10.1% for esophagogastroduodenoscopy and 7.9% for colonoscopy. The reduction in the number of diagnostic endoscopy procedures led to a 5.5% reduction in esophagogastric cancer and 2.7% in colorectal cancer. Conclusions This is the most comprehensive survey on the impact of the COVID‐19 pandemic on the performance of endoscopy and the resulting diagnosis of cancer in Japan. Understanding the magnitude of the decline in endoscopic examinations and cancer detection due to the pandemic is critical to understanding how many people will ultimately be affected and establishing a strategy for providing endoscopy during national emergencies.

This study aimed to investigate the effect of Japanese dietary patterns on metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis. After excluding factors affecting the diagnosis of hepatic steatosis, 727 adults were analyzed as part of the Health Promotion Project. The dietary patterns of the participants were classified into rice, vegetable, seafood, and sweet based on their daily food intake. Liver stiffness measurements and controlled attenuation parameters were performed using FibroScan. Energy and nutrient intake were calculated using the Brief-type Self-administered Diet History Questionnaire. Univariate and multivariate analyses were used to identify the risk factors for liver fibrosis within the MASLD population. The vegetable group had significantly lower liver fibrosis indicators in the MASLD population than the rice group. The multivariate analysis identified a body mass index ≥ 25 kg/m2 (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.01–1.83; p = 0.047) and HOMA-IR ≥ 1.6 (OR, 3.18; 95% CI, 1.74–5.78; p < 0.001) as risk factors for liver fibrosis, and vegetable group membership was a significant low-risk factor (OR, 0.38; 95% CI, 0.16–0.88; p = 0.023). The multivariate analysis of nutrients in low-risk foods revealed high intake of α-tocopherol (OR, 0.74; 95% CI, 0.56–0.99; p = 0.039) as a significant low-risk factor for liver fibrosis. This study suggests that a vegetable-based Japanese dietary pattern, through the antioxidant effects of α-tocopherol, may help prevent liver fibrosis in MASLD and the development of MASLD.

Functional dyspepsia is distinguishable from Helicobacter pylori-associated dyspepsia. However, distinguishing H. pylori-associated dyspepsia from functional dyspepsia before H. pylori eradication is difficult. Therefore, in the present study, we aimed to investigate whether serum pepsinogen levels before H. pylori eradication are associated with the amelioration of dyspepsia after successful H. pylori eradication. Additionally, we examined the usefulness of serum pepsinogen levels and other factors in predicting dyspepsia outcomes. H. pylori eradication was effective in 14 patients (Responders) and ineffective in 19 patients (Non-responders). The pepsinogen I/II ratio in Responders (3.4 ± 1.2) and Non-responders (2.3 ± 1.0) differed significantly (p = 0.006). The optimal cut-off pepsinogen I/II value was 2.3. Multivariate logistic regression analysis showed that the adjusted odds ratio for Non-responders was 26.1 (95% confidence interval: 2.0–338.0, p = 0.012) for a pepsinogen I/II ratio ≤ 2.3 and 8.10 (95% confidence interval: 1.1–57.6, p = 0.037) for smoking habits. The pepsinogen I/II ratio and smoking habits were associated with the effects of H. pylori eradication on dyspeptic symptoms. Thus, the pepsinogen I/II ratio cut-off value can be used to identify patients likely to respond to H. pylori eradication after the resolution of dyspeptic symptoms.

Abstract Narrow band imaging (NBI) has been extensively utilized as a diagnostic tool for colorectal neoplastic lesions. This study aimed to develop a trial deep learning (DL) based four-class classification model for low-grade dysplasia (LGD); high-grade dysplasia or mucosal carcinoma (HGD); superficially invasive submucosal carcinoma (SMs) and deeply invasive submucosal carcinomas (SMd) and evaluate its potential as a diagnostic tool. We collected a total of 1,390 NBI images as the dataset, including 53 LGD, 120 HGD, 20 SMs and 17 SMd. A total of 598,801 patches were trimmed from the lesion and background. A patch-based classification model was built by employing a residual convolutional neural network (CNN) and validated by three-fold cross-validation. The patch-based validation accuracy was 0.876, 0.957, 0.907 and 0.929 in LGD, HGD, SMs and SMd, respectively. The image-level classification algorithm was derived from the patch-based mapping across the entire image domain, attaining accuracies of 0.983, 0.990, 0.964, and 0.992 in LGD, HGD, SMs, and SMd, respectively. Our CNN-based model demonstrated high performance for categorizing the histological grade of dysplasia as well as the depth of invasion in routine colonoscopy, suggesting a potential diagnostic tool with minimal human inputs.

The Japanese diet is a healthy dietary pattern, and the oral or gut microbiota have been identified as the main factors underlying the beneficial effects of the Japanese diet. However, epidemiological studies on Japanese dietary patterns calculated from daily eating habits in the general population yielded inconsistent findings. This study aimed to determine the association between the 12-component modified Japanese Diet Index (mJDI12) and the oral and gut microbiota in the general population of a rural area in Japan. After propensity-score matching, 396 participants (198 each in the low and high mJDI12 groups) were picked out. One year after the follow up survey, we reclassified the subjects and compared the low and high mJDI12 groups again. Participants with a high mJDI12 had a higher relative abundance of butyric acid-producing bacteria in their gut microbiota. Moreover, the significantly higher dietary fiber intake in the high mJDI12 group suggested that the high intake of dietary fiber contributed to an increase in butyric acid-producing bacteria in the gut. In contrast, in individuals with a high mJDI12, only Allpprevotella was decreased in the oral microbiota. Thus, the Japanese dietary pattern can have beneficial effects by improving the oral and gut microbiota.

Surgery avoidance is an important goal in Crohn’s disease (CD) treatment and predicting the risk of subsequent surgery is important to determine adequate therapeutic strength for patients with newly diagnosed CD. Herein, we aimed to construct a prediction model for the risk of subsequent surgery based on disease characteristics at the patients’ initial visit. We retrospectively collected disease characteristic data from 93 patients with newly diagnosed CD. A logistic regression model with a brute force method was used to maximize the area under the receiver operating characteristic curve (auROC) by employing a combination of potential predictors from 14 covariates (16,383). The auROC remained almost constant when one to 12 covariates were considered, reaching a peak of 0.89 at four covariates (small-bowel patency, extensive small-bowel lesions, main lesions, and the number of poor prognostic factors), and it decreased with increasing covariate size. The most significant predictors were small-bowel patency, extensive small-bowel lesions, and age or major lesions. Therefore, this prediction model using covariates may be helpful in determining the likelihood that a patient with newly diagnosed CD will require surgery, which can aid in appropriate treatment selection for high-risk patients.

Abstract Objectives Gastrointestinal endoscopy increases the risk of bacterial exposure to endoscopists. However, before 2019, most endoscopists did not pay attention to microorganism transmission from patients. This study aimed to investigate the incidence of bacterial exposure to endoscopists’ faces during gastrointestinal endoscopic procedures using the bacterial culture method. Methods This was a single‐centered, retrospective study including endoscopists who performed various gastrointestinal endoscopy procedures at the Division of Endoscopy, Hirosaki University Hospital between August 31 and October 6, 2020. Endoscopists wore surgical masks and affixed pre‐sterilized films over them. Following the gastrointestinal endoscopic procedures, attached microbes were collected from the endoscopists’ surface films using sterilized swabs. Collected microorganisms were cultured on tryptic soy agar and 5% sheep blood agar, and the incidence of bacterial exposure was determined by bacterial culture positivity. Cultured bacteria were identified by gram staining and 16S rRNA gene sequencing. Results Bacterial culture positivity was 12.6%, and it was significantly higher in therapeutic than in diagnostic endoscopy. Notably, therapeutic endoscopy increased bacterial culture positivity in colonoscopy, but not in esophagogastroduodenoscopy. Staphylococci, including Staphylococcus epidermidis and Staphylococcus capitis, were the most commonly found bacteria in samples identified through 16S rRNA gene sequencing. Conclusions The risk of bacterial exposure to the endoscopist's face was increased in colonoscopy treatment procedures. Therefore, endoscopists should be aware of the significant risk of microbial infection from scattering fluid that comes from the endoscopy's working channel.

Abstract Sarcopenia is associated with poor prognosis of patients with hepatocellular carcinoma (HCC). We investigated the association of skeletal muscle volume (SMV) and its change in HCC patients taking lenvatinib. In 130 HCC patients, psoas mass index (PMI) was calculated as the left–right sum of the major × minor axis of psoas muscle at the third lumbar vertebra, divided by height squared. Patients were classified into two groups (low and normal PMI) based on indices of

Abstract Gut microbiomics is based on analysis of both live and dead cells in the stool. However, to understand the ecology of gut microbiota and their symbiotic relationships with hosts, spatial distribution of live bacteria must be examined. Here, we analyzed the live composition of luminal microbiota (LM) and mucosa-associated microbiota (MAM) in the ascending and descending colons and the rectums of 10 healthy adults and compared it with the total composition. The abundance of Lachnospiraceae in live LM decreased along the gut length and was significantly lower than that in total LM. Contrastingly, the abundance of Bacteroidaceae and Bifidobacteriaceae in live LM was higher than that in total LM, suggesting differences in death rate during gut migration. Live Enterobacteriaceae levels in MAM were significantly higher in rectum than in the ascending and descending colons and in LM. High-performance liquid chromatographic analysis of luminal bile acids revealed that 7α-dehydroxylation occurred towards the rectum. In live LM where a bile acid-inducible gene could be detected, 7α-dehydroxylation rates were higher than those in the group without the gene. Overall, we showed differences in live bacteria composition among three gut sites and between LM and MAM, highlighting the importance of understanding their spatial distribution.

Background/Aims Thiopurines are key drugs for inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). Recently, NUDT15 polymorphism (R139C, c.415C > T) has been shown to be associated with thiopurine-induced adverse events in Asian populations. In patients with the C/T genotype, low-dose thiopurine treatment is recommended, but its long-term efficacy and tolerability remain unclear. This study aimed to uncover the long-term efficacy and appropriate dosage of thiopurine for IBD patients with the C/T genotype. Methods A total of 210 patients with IBD (103 UC and 107 CD) determined to have NUDT15 R139C variants were enrolled. Clinical data were retrospectively reviewed from medical records. Results Of 46 patients (21.9%) with the C/T genotype, 30 patients (65.2%) were treated with thiopurines. Three of whom (10.0%) discontinued thiopurine treatment due to adverse events and 27 of whom continued. The median maintenance dosage of 6-mercaptopurine was 0.25 mg/kg/day (range, 0.19–0.36 mg/kg/day), and 6-thioguanine nucleotides level was 230 (104–298) pmol/8 × 108 red blood cells. Cumulative thiopurine continuation rates for 120 months for patients with the C/C and C/T genotypes were not significantly different (P = 0.895). Cumulative non-relapse rates in the patients with UC treated with thiopurine monotherapy and surgery-free rates in CD patients treated with combination therapy (thiopurines and anti-tumor necrosis factor-α agents) for maintenance remission were not significantly different at 60 months (C/C vs. C/T, P = 0.339 and P = 0.422, respectively). Conclusions Low-dose thiopurine treatment is an effective and acceptable treatment for patients with C/T genotype.

A novel treatment method for achalasia of the esophagus and related disorders is known as peroral endoscopic myotomy (POEM). This study aimed to calculate the resting energy expenditure (REE) and evaluated the degree of physical invasiveness based on metabolic changes during the perioperative period of POEM. Fifty-eight patients who underwent POEM were prospectively enrolled; REE, body weight (BW), and basal energy expenditure were measured on the day of POEM, postoperative day 1 (POD 1), and three days after POEM (POD 3). The median REE/BW increased from 19.6 kcal/kg on the day of POEM to 24.5 kcal/kg on POD 1. On POD 3, it remained elevated at 20.9 kcal/kg. The stress factor on POD 1 was 1.20. Among the factors, including the Eckardt score, operation time, and the length of myotomy, the length of myotomy was associated with changes in REE/BW. During the perioperative period of POEM, the level of variation in energy expenditure was lower than that of esophageal cancer surgeries performed under general anesthesia. However, because the length of myotomy is a factor affecting changes in energy expenditure, careful perioperative management is desirable for patients with longer myotomy lengths.

The association between liver fibrosis and oral or gut microbiota has been studied before. However, epidemiological studies in the general population are limited owing to the difficulty of noninvasive liver-fibrosis assessment. FibroScan–asparate aminotransferase (FAST) scores can be used to accurately and non-invasively evaluate liver fibrosis. This study aimed to determine the association between liver fibrosis and oral or gut microbiota using the FAST score in the general population. After propensity score matching of 1059 participants based on sex, age, body mass index, homeostasis model assessment of insulin resistance, and triglyceride levels, 125 (non-liver-fibrosis group, 100; liver fibrosis group, 25) were included. The diversity of gut microbiota differed significantly between the two groups; however, no significant differences were noted in their oral microbiota. The liver fibrosis group showed an increase in the relative abundance of Fusobacteria strains and a decrease in the relative abundance of Faecalibacterium, with the presence of Fusicatenibacter in the gut microbiota. Feacalibacterium was not identified as an independent factor of liver fibrosis in adjusting the fatty liver index. In the general population, gut microbiota may be more involved in liver fibrosis than oral microbiota.

Patients with lean nonalcoholic fatty liver disease (NAFLD) may have different metabolic profiles than those with NAFLD. Estrogenic activity is associated with NAFLD pathogenesis. We evaluated the production ability of equol, which has estrogenic activity, in lean NAFLD and assessed their gut microbiota in relation to their equol-producing ability. Among 684 adult participants, 276 (40%) had NAFLD and 293 (43%) were equol producers. The rates of equol producers in the normal and NAFLD groups were 43% and 42%, respectively. Among the patients with NAFLD, 55 (20%) had lean NAFLD of which 18 (33%) were equol producers. The rate of equol production in men with lean NAFLD was 8%, which was the lowest, while the corresponding rate in the other participants was approximately 40%. The gut microbiota composition of equol producers and nonproducers showed many significant differences. The gut microbiota of men with lean NAFLD showed increased abundance of Caulobacter and decreased abundances of Slackia and Terrisporobacter . Thus, almost all men with lean NAFLD lacked equol-producing ability, and their gut microbiota showed a reduced abundance of Slackia , which is related to equol production. The pathology of lean NAFLD in men may be strongly associated with equol-producing ability and gut microbiota.

Indigo naturalis, a herbal medicine purified from indigo-containing plants, such as Strobilanthes cusia, Isatis tinctoria, and Polygonum tinctorium, has been reported to be useful in the treatment of ulcerative colitis by activating the aryl hydrocarbon receptor. However, the aryl hydrocarbon receptor pathway causes crucial side effects, such as pulmonary arterial hypertension. Although P. tinctorium is one of the plant derivatives of indigo naturalis, it is not identical to it. To date, the pure leaves of P. tinctorium have not been reported to ameliorate ulcerative colitis. Therefore, we investigated the effect of pure P. tinctorium leaves, which are consumed in some regions, on experimental colitis induced in mice using sodium dextran sulfate. We found that P. tinctorium leaves ameliorated weight loss (P

Abstract A 66‐year‐old man presented with worsening dyspnea. A colonoscopy revealed an elevated lesion at the rectosigmoid junction. The biopsy specimen and bone marrow aspiration demonstrated adenocarcinoma, leading to a diagnosis of disseminated carcinomatosis of the bone marrow. Because chemotherapy proved effective, he survived until 333 days after admission.

Vitamin A ensures intestinal homeostasis, impacting acquired immunity and epithelial barrier function; however, its role in innate immunity is mostly unknown. Here, we studied the impact of vitamin A in different dextran sulfate sodium (DSS)-induced colitis animal models. Interestingly, more severe DSS-induced colitis was observed in vitamin A-deficient (VAD) mice than in vitamin A-sufficient (VAS) mice; the same was observed in VAD severe combined immunodeficient mice lacking T/B cells. Remarkably, IL-1β production, LC3B-II expression, and inflammasome activity in the lamina propria were significantly elevated in VAD mice. Electron microscopy revealed numerous swollen mitochondria with severely disrupted cristae. In vitro, non-canonical inflammasome signaling-induced pyroptosis, LC3B-II and p62 expression, and mitochondrial superoxide levels were increased in murine macrophages (RAW 264.7) pretreated with retinoic acid receptor antagonist (Ro41-5253). These findings suggest that vitamin A plays a crucial role in the efficient fusion of autophagosomes with lysosomes in colitis.

Abstract Objectives Cancer patients treated with immune checkpoint inhibitors occasionally show persistent diarrhea accompanied by endoscopic features of ulcerative colitis. The endoscopic mucosal inflammation may appear mild in some patients compared to the clinical severity, which can make choosing a treatment challenging. In this study, we evaluated the factors that support the continuation of chemotherapy by assessing the endoscopic and histopathological characteristics of patients who experienced diarrhea after immune checkpoint inhibitor administration. Methods This study included eight patients who were diagnosed with collagenous colitis based on pathological assessments. We retrospectively investigated these patients’ backgrounds, laboratory data, and computed tomography images that were extracted from their medical records. We also summarized their endoscopic and pathologic findings. Results All eight patients were being treated with anti‐programmed cell death‐1/programmed cell death‐ligand 1 therapeutic agents and had a recent history of oral proton pump inhibitor therapy. The anti‐programmed cell death‐1‐related collagenous colitis in these cases was characterized by endoscopically mild mucosal inflammation, high fecal calprotectin levels, and a lower frequency of intestinal wall thickening on computed tomography. Histological assessments showed CD8+ lymphocytes predominantly infiltrating the lamina propria and crypts of the colonic mucosa. Suspending the proton pump inhibitor therapy relieved the patients’ symptoms and allowed the continuation of the anti‐programmed cell death‐1/programmed cell death‐ligand 1 therapy. Conclusions Anti‐programmed cell death‐1‐related collagenous colitis is reversible; appropriate diagnosis of adverse events is crucial for the continuation of immune checkpoint inhibitor therapy.

Probiotic products have been shown to have beneficial effects on human hosts, but what happens in the gastrointestinal tract after its ingestion remains unclear. Our aim was to investigate the changes within the small intestines after a single intake of a fermented milk product containing a probiotic. We have periodically collected the small-intestinal fluids from the terminal ileum of seven healthy subjects for up to 7 h after ingestion by small-intestinal fluid perfusion using an endoscopic retrograde bowel insertion technique. The bacterial composition of the terminal ileum clearly revealed that the ingested probiotics (Lactobacillus casei strain Shirota: LcS and Bifidobacterium breve strain Yakult: BbrY) occupied the ileal microbiota for several hours, temporarily representing over 90% of the ileal microbiota in several subjects. Cultivation of ileal fluids showed that under a dramatic pH changes before reaching the terminal ileum, a certain number of the ingested bacteria survived (8.2 ± 6.4% of LcS, 7.8 ± 11.0% of BbrY). This means that more than 1 billion LcS and BbrY cells reached the terminal ileum with their colony-forming ability intact. These results indicate that there is adequate opportunity for the ingested probiotics to continuously stimulate the host cells in the small intestines. Our data suggest that probiotic fermented milk intake affects intestinal microbes and the host, explaining part of the process from the intake of probiotics to the exertion of their beneficial effects on the host.

Objective: There is limited information regarding the benefits of Lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for unresectable hepatocellular carcinoma (u-HCC). We compared the efficacy and safety of LEN-TACE sequential therapy to LEN monotherapy and investigated the factors contributing to the LEN-TACE sequential therapy deep response. Methods: We enrolled a multi-center cohort of 247 patients with u-HCC treated with LEN between 2018 and 2020. Propensity score matching identified sixty-three matching pairs of patients with well-balanced characteristics. We retrospectively compared the clinical outcomes, including overall survival (OS), progression-free survival (PFS), and incidence of adverse events (AEs), between the LEN-TACE and LEN monotherapy groups. Additionally, we evaluated the tumor response, change in albumin-bilirubin (ALBI) score, factors affecting PFS and OS, and independent predictors contributing to the LEN-TACE sequential therapy deep response. In this study, at eight weeks after resumption of LEN after initial TACE, "deep response" was defined as achieving CR or PR on mRECIST, and at least a 30% decrease in the sum of diameters of target lesions, taking the baseline sum diameters as the reference. Results: The OS and PFS in the LEN-TACE group were significantly higher than those in the LEN monotherapy group (P = 0.002 and P = 0.037, respectively). The incidence of AEs related to LEN was not significantly different between the two groups. In LEN-TACE sequential therapy, the objective response rate was 61.9%, and the disease control rate was 74.6%, according to the mRECIST criteria. No significant change in the ALBI score was observed during sequential LEN-TACE therapy. Multivariable analyses revealed that deep response was independently associated with the outcome of the initial response to LEN by mRECIST: PR (odds ratio: 13.75, 95% CI: 0.41–1.32, P

ObjectiveWe evaluated the clinical characteristics of metabolic dysfunction-associated fatty liver disease (MAFLD) to evaluate the usefulness of the MAFLD diagnostic criteria in a resident health survey.MethodsIn 1056 participants of a health survey, we compared obesity, diabetes, metabolic dysregulation, FibroScan-aspartate aminotransferase (FAST) score, dietary habits, and gut microbiota between healthy individuals and participants with MAFLD and Nonalcoholic fatty liver disease (NAFLD).ResultsThe proportion of participants with MAFLD in the fatty liver was higher than that with NAFLD (88.1% vs. 75.5%, respectively). Of 36 participants with a FAST score > 0.35, 29 (80.6%) participants had MAFLD and 23 (63.9%) participants had NAFLD. Of 29 patients with liver fibrosis, 26 (89.7%) participants had obesity and metabolic dysregulation. In the evaluation of diet, the total energy, protein, dietary fiber, and salt intake were significantly higher in participants with MAFLD than those in participants without fatty liver. In the microbiota analysis, the results of the linear discriminant analysis effect size analysis revealed nine bacterial genera that were significantly different in participants with MAFLD in comparison with participants without fatty liver. Of these genera, the relative abundance of Blautia was especially low in participants with MAFLD.ConclusionIn a resident health survey, participants with MAFLD had a higher proportion of fatty liver than those with NAFLD. MAFLD criteria could help in improved screening of participants with liver fibrosis. Therefore, the MAFLD criteria could be a useful diagnostic tool for aggressively identifying participants with a high risk of fatty liver. Additionally, Blautia might be involved in the development of MAFLD.

Capsule endoscopy has been widely used as a non-invasive diagnostic tool for small or large intestinal lesions. In recent years, automated lesion detection systems using machine learning have been devised. This study aimed to develop an automated system for capsule endoscopic severity in patients with ulcerative colitis along the entire length of the colon using ResNet50. Capsule endoscopy videos from patients with ulcerative colitis were collected prospectively. Each single examination video file was partitioned into four segments: the cecum and ascending colon, transverse colon, descending and sigmoid colon, and rectum. Fifty still pictures (576 × 576 pixels) were extracted from each partitioned video. A patch (128 × 128 pixels) was trimmed from the still picture at every 32-pixel-strides. A total of 739,021 patch images were manually classified into six categories: 0) Mayo endoscopic subscore (MES) 0, 1) MES1, 2) MES2, 3) MES3, 4) inadequate quality for evaluation, and 5) ileal mucosa. ResNet50, a deep learning framework, was trained using 483,644 datasets and validated using 255,377 independent datasets. In total, 31 capsule endoscopy videos from 22 patients were collected. The accuracy rates of the training and validation datasets were 0.992 and 0.973, respectively. An automated evaluation system for the capsule endoscopic severity of ulcerative colitis was developed. This could be a useful tool for assessing topographic disease activity, thus decreasing the burden of image interpretation on endoscopists.

Recently, the importance of achieving clinical and deep remissions with mucosal healing (MH) has been demonstrated as a therapeutic goal to avoid Crohn’s disease (CD) surgical operations. Although ileocolonoscopy (CS) is considered the gold standard, there are increasing reports on the benefits of capsule endoscopy (CE) and serum leucine-rich α2-glycoprotein (LRG) for evaluating small-bowel lesions in CD. We evaluated the data of 20 patients with CD who underwent CE in our department between July 2020 and June 2021 and whose serum LRG level was measured within 2 months. Concerning the mean LRG value, there was no significant difference between the CS-MH and CS-non-MH groups. Conversely, the mean LRG level was 10.0 μg/mL in seven patients in the CE-MH group and 15.2 μg/mL in 11 patients in the CE-non-MH group with a significant difference between the two groups (p = 0.0025). This study’s findings show that CE can sufficiently determine total MH in most cases, and LRG is useful for evaluating CD small-bowel MH because of its correlation with CE-MH. Furthermore, satisfying CS-MH criteria and a cut-off value of 13.4 μg/mL for LRG suggests its usefulness as a CD small-bowel MH marker, which could be incorporated into the treat-to-target strategy.

Summary: Schlafen11 (SLFN11) is referred to as interferon (IFN)-inducible. Based on cancer genomic databases, we identified human acute myeloid and lymphoblastic leukemia cells with gain-of-function mutations in the Janus kinase (JAK) family as exhibiting high SLFN11 expression. In these cells, the clinical JAK inhibitors cerdulatinib, ruxolitinib, and tofacitinib reduced SLFN11 expression, but IFN did not further induce SLFN11 despite phosphorylated STAT1. We provide evidence that suppression of SLFN11 by JAK inhibitors is caused by inactivation of the non-canonical IFN pathway controlled by AKT and ERK. Accordingly, the AKT and ERK inhibitors MK-2206 and SCH77284 suppressed SLFN11 expression. Both also suppressed the E26 transformation-specific (ETS)-family genes ETS-1 and FLI-1 that act as transcription factors for SLFN11. Moreover, SLFN11 expression was inhibited by the ETS inhibitor TK216. Our study reveals that SLFN11 expression is regulated via the JAK, AKT and ERK, and ETS axis. Pharmacological suppression of SLFN11 warrants future studies.

Water-soluble dietary fiber is primarily a substrate for degradation of short chain fatty acids (SCFAs), particularly butyric acid, by gut microbiota. SCFAs have beneficial effects on the whole body. However, epidemiological studies on the association between water-soluble dietary fiber from daily food intake and butyric acid-producing bacteria are inconsistent. The purpose of this study was to determine the association between levels of water-soluble dietary fiber from daily food intake and gut microbiota, particularly butyric acid producers, in middle-aged and older adults in a rural area in Japan. We examined the effects of water-soluble dietary fiber intake on gut microbiota after adjusting for confounding factors. After propensity score matching, 520 subjects (260 in the low-intake group and 260 in the high-intake group) were selected. One year later after a follow-up survey, we re-classified the participants and again compared low- and high-intake groups. As a result, people with a high intake had a higher relative abundance of butyric acid-producing bacteria. It was also revealed that butyric acid-producing bacteria remained high in the group that maintained high intake the next year. We concluded that continuous intake of water-soluble dietary fiber from daily food is necessary to maintain sufficient amounts of butyric acid-producing bacteria.

Myelodysplastic syndromes (MDSs) are a group of myeloid neoplasms characterized by blood cell deformation and dysfunction, and MDS with trisomy 8 is closely linked with intestinal Behçet’s-like diseases. Intestinal Behçet’s-like disease is refractory to conventional therapies, including prednisolone, immunomodulators, and anti-tumor necrosis factor α agents. Here, we describe a 56-year-old woman with intestinal Behçet’s-like disease ascribed to MDS with trisomy 8 who had multiple intractable intestinal ulcers. She presented with periodic fever and abdominal pain. The genetic analysis showed a heterozygous E148Q mutation in the Mediterranean fever gene. The patient did not tolerate treatment with colchicine because of diarrhea; therefore, azacitidine therapy was initiated. One cycle of azacitidine therapy improved the multiple intestinal ulcers, and the periodic fever and abdominal pain gradually disappeared. After eight cycles of azacitidine therapy, ileocolonoscopy, histological assessment and capsule endoscopy revealed mucosal healing. Azacitidine therapy was continued, and mucosal healing was maintained for more than 2 years. This case suggests that azacitidine therapy which has immunoregulatory effects and epigenetic modulations, might control intestinal Behçet’s-like disease associated with MDS involving trisomy 8.

Fever of unknown origin (FUO) is caused by various diseases, making differential diagnosis difficult. This study aimed to determine the clinical features of patients with FUO for use in daily medical practice. Medical records of patients who first visited our department for FUO between January 2008 and December 2017 were reviewed. We classified the diagnostic categories as infection, non-infectious inflammation, neoplasm, others, and unidentified through definitive diagnosis and compared the clinical characteristics of patients who fulfilled the criteria of classical FUO and those who did not. The most prevalent diseases in patients who fulfilled the criteria were adult-onset Still’s disease, Behçet’s disease (BD), and polymyalgia rheumatica, which do not have any specific image inspection or specific serological markers. BD and familial Mediterranean fever were most prevalent in patients who did not fulfill the criteria. All neoplasms fulfilled the criteria of classical FUO. The most useful diagnostic procedure was determined according to the criteria of each disease. The key factor that did not fulfill the criteria was periodic fever continuing for less than 3 weeks. When examining patients with FUO, we should strictly diagnose in accordance with the criteria of each disease and consider diseases that cause periodic fever.

A 45-year-old Japanese male patient who was diagnosed with celiac disease (CeD) developed type I enteropathy-associated T-cell lymphoma (EATL). In 2013, the patient was admitted to our hospital with worsening of diarrhea and weight loss. Pathological examination of biopsy specimens from the duodenum and ileum led to a diagnosis of suspected EATL. A previous total colonoscopy (TCS) indicated villous atrophy in the terminal ileum. The patient was changed to a gluten-free diet, and the nutritional status gradually improved. In September 2014, he experienced acute right lower abdominal pain. He underwent urgent surgery, and a perforation was identified in the ileum. A diagnosis of type I EATL was made following histopathological examination. After eight courses of CHOP therapy, the patient entered complete remission. TCS and esophagogastroduodenoscopy with magnifying narrow-band imaging performed in 2015 identified villous regrowth in the distal ileum and duodenum. Capsule endoscopy also found villous regrowth in the entire small intestine. To our knowledge, this is the first case of type I EATL following CeD with villous atrophy before EATL occurrence in a Japanese HLA-DQ2 carrier. The possibility of type I EATL occurring after CeD should be recognized, although CeD is quite rare in Japan.

Currently, the number of patients treated with immune-checkpoint inhibitor involving nivolumab is increasing. Nevertheless, it causes various immune-related adverse events (irAEs). Here, we report the case of a patient who underwent long-term follow-up after suffering from nivolumab-associated colitis. The patient was a 57-year-old man who underwent resection of a bladder tumor. Following surgery, lymph node metastasis was detected, and he was treated by nivolumab. Two months after treatment with nivolumab, the patient complained of bloody diarrhea. Colonoscopy revealed pancolitis with erosions, loss of vascular pattern and erythema. Pathological findings indicated a disease state of pan-ulcerative colitis. As an irAE by nivolumab, the patient was started with 30 mg of prednisolone. Prednisolone treatment successfully induced clinical remission and mucosal healing. Nevertheless, eight months after stopping the steroid treatment, the colitis relapsed with diarrhea following elevation of fecal immunochemical test (FIT) and fecal calprotectin (CPT). The relapsed colitis was treated by mesalazine, and then diarrhea was improved. Nivolumab-associated colitis relapsed following mucosal healing suggesting that it is necessary to consider maintenance therapy as well as remission induction for long-term survivor. The present case also demonstrates that the FIT and CPT would be effective biomarker to assess the disease activity of nivolumab-associated colitis.

Background and aims: A relationship between treatment outcomes and intestinal microbiota in patients with inflammatory bowel diseases has been demonstrated. Cyclosporine treatment leads to rapid improvement in severe ulcerative colitis. We hypothesized that the potent effects of cyclosporine would be exerted through relationships between intestinal epithelial cells (IECs) and the host microbiota. The present study was designed to elucidate the effects of cyclosporine on monocarboxylate transporter 1 (MCT1) regulation and butyrate uptake by IECs. Methods: Colitis was induced in C57BL6 mice via the administration of 4% dextran sulfate sodium in drinking water, following which body weights, colon lengths, and histological scores were evaluated. To examine the role of butyrate in the protective effects of cyclosporine, MCT1 inhibitor and an antibiotic cocktail was administered and tributyrin (TB; a prodrug of butyrate) was supplemented; MCT1 protein expression and acetylated histone 3 (AcH3) signals in IECs, as well as the MCT1-membrane fraction of Caco-2 cells, were evaluated. To explore butyrate uptake, as s butyrate derivatives, 3-bromopyruvic acid (3-BrPA) and 1-pyrenebutyric acid were used. Results: Treatment with cyclosporine inhibited body weight loss and colon length shortening. However, treatment with MCT1 inhibitor and the antibiotic cocktail negated the efficacy of cyclosporine, whereas TB supplementation restored its protective effect. Furthermore, cyclosporine upregulated MCT1 expression in the membrane and the AcH3 signal in IECs, while also inducing higher anti-inflammatory cytokine production compared to that in the vehicle-treated mice. The transcription level of MCT1 mRNA in IECs and Caco-2 cells did not increase with cyclosporine treatment; however, cyclosporine treatment increased membrane MCT1 expression in these cells and uptake of butyrate derivative. Conclusion: Cyclosporine treatment modulates butyrate uptake via the post-transcriptional upregulation of membrane MCT1 levels in IECs.

Simple hepatic cysts are common and most often asymptomatic. In symptomatic cases, hemorrhage, rupture, and infection are major complications. However, urinary tract obstruction caused by a simple hepatic cyst is rare. We treated an 82-year-old Japanese man with an infected giant hepatic cyst causing right hydronephrosis who had a past history of left nephrectomy for renal cell carcinoma. The patient underwent ultrasound-guided percutaneous drainage and sclerotherapy with minocycline hydrochloride for the infected hepatic cyst. Right hydronephrosis was relieved, and renal dysfunction improved with regression of the hepatic cyst after treatment. This is the first report of hydronephrosis due to ureteral obstruction caused by compression from a hepatic cyst.

Although decreased calcium absorption, decreased bone formation, alcohol drinking, and smoking have been considered as causes of osteopenia in men, the cause is unknown in half of the cases. Many reports highlighted the association between Helicobacter pylori infection and osteoporosis, mainly in East Asia and Japan. To identify relevant factors of osteoporosis in men, we examined estrogen and calcium intakes and other lifestyle factors together with gastric mucosal atrophy caused by Helicobacter pylori infection. This study is a cross-sectional study design of 268 healthy men who underwent general medical examinations. Multivariate analysis was performed, with age, body mass index, smoking habit, drinking habit, exercise habit, estradiol level, calcium intake, and Helicobacter pylori infection and its associated gastric mucosal atrophy as the independent variables and the presence of osteopenia as the dependent variable. The adjusted odds ratio was 0.74 (95% Confidence Interval [0.29, 1.90], p = .531) and 1.31 (95% Confidence Interval [0.54, 3.21], p = .552), when Helicobacter pylori infection was positive without and with gastric mucosal atrophy, respectively. Helicobacter pylori infection and gastric mucosal atrophy were not significant factors. Low body mass index, smoking habit, and low calcium intake were significantly associated with decreased bone density. In conclusion, Helicobacter pylori infection was not a significant risk, whereas low body mass index, current smoking, and lower calcium intake had a significant influence on the development of osteopenia in men.

Altered amino acid levels have been found in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). However, it is not clear whether this alteration is due to altered hepatic metabolism or insulin resistance. The aim of this study was to clarify the association among amino acid levels, fatty liver, and liver fibrosis while eliminating the influence of insulin resistance. NAFLD and liver fibrosis were diagnosed using transient elastography and subjects were divided into three groups: normal, NAFLD, and liver fibrosis. To exclude the influence of insulin resistance, the subjects were matched using the homeostasis model assessment of insulin resistance (HOMA-IR). The amino acid serum levels were compared among the groups. Of 731 enrolled subjects, 251 and 33 were diagnosed with NAFLD and liver fibrosis. Although significant differences were observed among the groups in the serum levels of most amino acids, all but those of glutamate and glycine disappeared after matching for HOMA-IR. The multivariate logistic regression revealed that glutamate, glycine, and HOMA-IR were independent risk factors for liver fibrosis. The altered serum levels of most amino acids were associated with insulin resistance, while the increase in glutamate and the decrease in glycine levels were strongly associated not only with insulin resistance, but also with altered liver metabolism in patients with liver fibrosis.

Background and study aims Although endoscopic transpapillary gallbladder drainage (ETGBD) is reportedly useful in patients who have acute cholecystitis, its efficacy has not been compared to that of percutaneous transhepatic gallbladder drainage (PTGBD). We retrospectively compared the efficacy and safety of ETGBD and PTGBD in patients with acute cholecystitis. Patients and methods We studied 75 patients who required gallbladder drainage for acute cholecystitis between January 2014 and December 2016. Using propensity score matching analysis, we compared the clinical efficacy and length of hospitalization in patients successfully treated with ETGBD and PTGBD. Moreover, we assessed the predictive factors for hospitalization period

BackgroundSuppression of gastric acid by proton pump inhibitors is associated with the increase of Lactobacillus in human gut microbiota. Gastric acid secretion is also suppressed by Helicobacter pylori infection and following atrophic gastritis. However, few studies have examined the association between H. pylori infection and Lactobacillus species in gut microbiota particularly in Japan.MethodsA total of 1,123 adult subjects who participated in a health survey in Hirosaki City were studied. Infection of H. pylori was defined by both serum antibody and stool antigen test. The presence and the severity of atrophic gastritis were defined by the serum level of serum pepsinogens. Using 16S ribosomal RNA amplification from fecal samples, the relative abundance of Lactobacillus was calculated, and the composition ratio of each Lactobacillus species was surveyed.ResultsThe relative abundance of the Lactobacillus in H. pylori-infected subjects with severe atrophic gastritis was higher comparing with those in subjects with mild atrophic gastritis and without atrophic gastritis (0.591 vs 0.068% and 0.033%, respectively; p

Background: The relationship between Helicobacter pylori infection and iron metabolism has not been well studied in Japan. We examined the association of H. pylori infection and its eradication to iron metabolism. Methods: A total of 654 adults who completed a health survey in 2012 were enrolled. H. pylori stool antigen was tested and serum antibody titer and serum iron, ferritin and pepsinogen levels were estimated. Subjects reported on their daily intake of the diets to calculate daily intake of iron and vitamin C. Among the H. pylori-infected patients surveyed in 2012, 177 patients completed the same health survey in 2014. For these patients, the change of daily intake of iron and vitamin C and serum iron and ferritin levels were examined. Results: In 2012, 244 subjects (37.3%) were considered as infected with H. pylori. In male subjects aged 35–64 years, serum level of ferritin was 77.5 (SD 53.1) ng/mL in infected patients and 130.6 (114.3) ng/mL in non-infected subjects (p

To assess the influence of biliary drainage to cholangitis on modified Glasgow Prognostic Score (mGPS) in patients with pancreatic cancer.mGPS was calculated before and after biliary drainage in 47 consecutive patients with inoperable pancreatic cancer who were receiving chemotherapy. Biliary drainage was indicated for malignant obstructive jaundice that prevented the administration of chemotherapy. To elucidate mGPS values, serum levels of CRP and albumin were measured at the time of diagnosis (before biliary drainage). Overall survival was evaluated and risk factors, which contribute to overall survival, were examined.Biliary drainage was performed in 15 patients. Using values obtained before biliary drainage, there were no significant differences in median survival time between patients with a mGPS of 0 and those with a mGPS of 1 or 2 (10.7 vs. 9.4 months; p = 0.757). However, using values obtained after biliary drainage, median survival time was significantly higher in patients with a mGPS of 0 than in those with a mGPS of 1 or 2 (11.4 vs. 4.7 months; p = 0.002). Multivariate analysis revealed that a mGPS of 1 or 2 (HR: 3.38; 95% CI: 1.35-8.46, p = 0.009), a carbohydrate antigen 19-9 >1000 U/mL (2.52; 1.22-5.23, p = 0.013), a performance status of 2 (7.68; 2.72-21.28, p = 0.001), carcinoembryonic antigen level >10 ng/mL (2.29; 1.13-4.61, p = 0.021) were independently associated with overall survival.mGPS values obtained after biliary drainage appear to be a more reliable indicator of overall survival in patients with inoperable pancreatic cancer.

Equol is a metabolite of isoflavone daidzein and has an affinity to estrogen receptors. Although equol is produced by intestinal bacteria, the association between the status of equol production and the gut microbiota has not been fully investigated. The aim of this study was to compare the intestinal bacteria responsible for equol production in gut microbiota between equol producer and non-producer subjects regarding the intake of daidzein. A total of 1044 adult subjects who participated in a health survey in Hirosaki city were examined. The concentration of equol in urine was measured by high-performance liquid chromatography. The relative abundances of 8 bacterial species responsible for equol production in the gut microbiota was assessed using 16S rRNA amplification. There were 458 subjects identified as equol producers. The proportion of equol production status and the intake of daidzein increased with age. Daily intake of daidzein was larger in equol-producer. The intestinal bacteria, which convert daidzein to equol were present in both equol producers and non-producers. However, the relative abundance and the prevalence of Asaccharobacter celatus and Slackia isoflavoniconvertens were significantly higher in equol producers than those in equol non-producers. The intestinal bacteria that convert daidzein to equol are present in not only the equol producers but also in the non-producers. The daidzein intake is associated with the equol production status through an increase of A. celatus and S. isoflavoniconvertens in the gut microbiota.

The aim of this study was to characterize the effects of rebamipide on the oxidative burst of human neutrophils. The neutrophil oxidative burst was measured in the presence of rebamipide and cimetidine using lucigenin- or luminol-dependent chemiluminescence (LgCL or LmCL). Rebamipide inhibited the LmCL response stimulated with opsonized zymosan, 12-myristate 13-acetate phorbol, and calcium ionophore in a dose-dependent manner, but the LgCL response was inhibited when neutrophils were stimulated with opsonized zymosan. LmCL response was also dose-dependently attenuated by rebamipide even in the presence of cimetidine. Thus, addition of rebamipide to H2-receptor antagonists can be considered for the treatment of gastric mucosal injury associated with oxidative stress.