The Clinical Practice Guidelines for post-ERCP pancreatitis (PEP) 2023 provide updated recommendations for the prevention, diagnosis, and management of PEP. Endoscopic retrograde cholangiopancreatography (ERCP), a valuable procedure for diagnosing and treating pancreatobiliary diseases, can result in PEP as the most common adverse event. Since the first guidelines were published in 2015, advances in techniques and new research findings have necessitated this revision. The guidelines developed using the GRADE methodology target adult patients undergoing ERCP. They offer a comprehensive framework for clinicians to minimize the risk of PEP. For high-risk patients, endoscopic ultrasound before ERCP is recommended to avoid unnecessary procedures. The guidelines also discuss procedural and patient-related risk factors for PEP, highlighting that operator experience does not significantly affect PEP rates if performed under the supervision of skilled endoscopists. The diagnostic criteria include monitoring serum pancreatic enzyme levels postprocedure, and early computed tomography is advised in suspected cases. For treatment, the guidelines recommend following acute pancreatitis protocols. Key preventive measures include the use of temporary pancreatic duct stents and rectal nonsteroidal anti-inflammatory drugs, both of which are supported by strong evidence for reducing the incidence of PEP. Overall, these guidelines aim to enhance clinical outcomes by reducing PEP incidence and improving its management through evidence-based practices.

ABSTRACT Background Serum zinc levels decrease in chronic liver disease (CLD), but their effects on liver reserve function, tyrosine, skeletal muscle mass, handgrip strength (HGS), and hepatocellular carcinoma (HCC) development remain poorly understood. Methods A retrospective, cross‐sectional study was conducted on 516 CLD cases. Patients were divided into a low zinc group (< 80 μg/dL) and a high zinc group (≥ 80 μg/dL). Serum zinc levels were analyzed with liver reserve function (assessed by modified albumin‐bilirubin [mALBI] grade), tyrosine, branched‐chain amino acid/tyrosine ratio (BTR), and HCC development. In 180 cases, the relationship between serum zinc levels and skeletal muscle characteristics, including sarcopenia and HGS, was investigated. Results Tyrosine levels increased significantly with mALBI grade progression. Patients in the low zinc group had higher tyrosine levels (76.9 vs. 67.2 μmol/L, p < 0.001), a greater proportion of high tyrosine levels (5.3% vs. 1.7%, p < 0.001), and more HCC cases (10.5% vs. 3.7%, p < 0.005). Zinc levels were lower with more severe CLD (81 μg/dL [mALBI grade 1] vs. 35.2 μg/dL [grade 3], p < 0.001). Tyrosine levels were higher in HCC patients than in non‐HCC patients (93.1 vs. 70.7 μmol/L, p < 0.001). Sarcopenia prevalence did not differ between groups (56.6% vs. 52.0%, p = 0.344), but low HGS was more frequent in low zinc patients (61.2% vs. 46.3%, p = 0.032). In a subset of patients with low zinc levels (n = 12), zinc supplementation reduced tyrosine levels after 3 months (86.3 vs. 73.3 μmol/L, p = 0.017). Conclusion Hypozincemia is linked to elevated tyrosine levels, reduced HGS, increased HCC incidence, and CLD progression.

OBJECTIVES: This retrospective multicenter study aimed to clarify the clinical impact of endotherapy for painless pancreatic duct (PD) stones compared with that in patients who received conservative treatment without endotherapy. METHODS: We enrolled 268 patients suffering from chronic pancreatitis with painless PD stones (145 with endotherapy and 123 without endotherapy) and evaluated the impact of endotherapy for painless PD stones on clinical and radiological outcomes. RESULTS: When conservative treatment without endotherapy was set as a reference, complete clearance of the targeted PD stones decreased the relative risk for atrophy of pancreatic parenchyma after inclusion (hazard ratio [HR] 0.42; 95% confidence interval [CI] 0.21-0.84). Incomplete clearance of the targeted PD stones was identified as a risk factor for new-onset or worsening of diabetes (HR 2.08; 95% CI 1.10-3.91) and inducement of pain attack (HR 4.03; 95% CI 1.45-11.19), although complete clearance was not correlated with these outcomes. CONCLUSION: In chronic pancreatitis patients with painless PD stones, endotherapy with complete stone clearance allows the maintenance of pancreatic parenchymal volume. However, if complete clearance fails, endotherapy could lead to aggravation of glucose tolerance and pain attacks during follow-up.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are classified into three epithelial types with distinct biological behaviors. However, their effects on the postoperative outcomes remain unclear. METHODS: This multicenter retrospective study included 556 patients with IPMNs who underwent surgical resection. The epithelial types were categorized into the gastric (n = 323), intestinal (n = 160), and pancreatobiliary (n = 73) types. Their associations with the development of extrapancreatic lesions; remnant high-risk lesions (HRLs), including metachronous pancreatic ductal adenocarcinoma (PDAC); and disease-specific survival (DSS) were analyzed. RESULTS: Fifty-one patients (9.2%) developed extrapancreatic lesions. The 10-year cumulative incidence rates for the gastric, intestinal, and pancreatobiliary types were 9.3%, 9.1%, and 32.0%, respectively (P < 0.001). Multivariate analysis identified invasive carcinoma, the gastric, and pancreatobiliary types as independent predictors. Among 516 patients who did not undergo total pancreatectomy, 40 (7.8%) and 13 (2.5%) developed HRLs and metachronous PDAC, respectively. The 10-year cumulative incidence rates of HRLs and metachronous PDAC for the gastric, intestinal, and pancreatobiliary types were 7.0%, 16.2%, and 37.2% and 1.8%, 3.7%, and 22.7%, respectively (P = 0.001 and P = 0.012). In multivariate analysis, the pancreatobiliary type was an independent predictor of metachronous PDAC. Five-year DSS rates for the gastric, intestinal, and pancreatobiliary types were 92.5%, 96.0%, and 76.1% (P < 0.001), respectively. Multivariate analysis identified invasive carcinoma, the gastric, and pancreatobiliary types as independent prognostic factors for DSS. CONCLUSIONS: IPMN epithelial type can independently affect postoperative outcomes. In particular, the pancreatobiliary type has significant impact on the development of metachronous PDAC. Therefore, postoperative surveillance should be tailored according to the epithelial type.

BACKGROUND AND AIM: Although IgG4-related autoimmune hepatitis (IgG4-AIH) and IgG4-hepatopathy have been proposed as hepatic phenotypes of IgG4-related disease (IgG4-RD), their definitions and concepts remain insufficiently established. This study aims to conduct a clinicopathological investigation of cases reported as potential IgG4-AIH or IgG4-hepatopathy. METHODS: In previous nationwide epidemiological studies conducted in 2015 and 2018, we registered 1096 cases of IgG4-sclerosing cholangitis (IgG4-SC). Among these, 19 cases were identified as potential IgG4-AIH by the attending physicians, and other 20 cases as potential IgG4-hepatopathy with available liver histology were further evaluated using immunohistochemistry to assess the possibility of IgG4-AIH or IgG4-hepatopathy. For this purpose, we provisionally established diagnostic criteria for IgG4-AIH and IgG4-hepatopathy, primarily based on the comprehensive diagnostic criteria for IgG4-RD, which include IgG4 + cell count > 10/HPF and an IgG4 + /IgG ratio > 40%. RESULTS: Of the 19 cases, 2 were diagnosed as IgG4-AIH, with IgG4 + cell counts/HPF of 25.3 and 18.7, and IgG4 + /IgG ratios of 310.2% and 53.4%, respectively. Neither storiform fibrosis nor obliterative phlebitis was observed in the liver of these cases, and both responded excellently to corticosteroid treatment. In addition, from other 20 cases, we diagnosed 8 cases as IgG4-hepatopathy, with IgG4-SC and autoimmune pancreatitis being present in 7 and 2 cases, respectively. CONCLUSION: This study identified two cases of IgG4-AIH and eight cases of IgG4-hepatopathy. Further studies are necessary to explore the occurrence of IgG4-AIH using these diagnostic criteria in the AIH cohort. The presence of IgG4-hepatopathy may facilitate the diagnosis of IgG4-SC.

BACKGROUND/AIMS: Radial incision and cutting (RIC) is an alternative dilation method for stenosis of the lower gastrointestinal tract. However, its safety and efficacy for the small intestine requiring balloon-assisted enteroscopy (BAE) remain limited. Therefore, this pilot study aimed to evaluate the safety and efficacy of RIC using BAE. METHODS: We included 10 patients with Crohn's disease and performed 12 sessions of RIC for 10 lesions. The rate of adverse events 1 month after RIC was the primary outcome, whereas short- and long-term prognoses and improvements in subjective symptoms that were evaluated using a visual analog scale were the secondary outcomes. RESULTS: The technical success rate for RIC, defined as scope passage immediately following the procedure, was 100% (12/12). The rates of delayed bleeding and perforation were 0% (0/12). One patient developed restenosis because of the worsening of Crohn's disease and underwent surgery 2 months after RIC. The cumulative restenosis-, reintervention-, and surgery-free rates at 1 year after RIC were 67.5%, 78.7%, and 90.0%, respectively. Abdominal pain, abdominal bloating, nausea, and difficulties in defecation significantly improved 4 weeks after RIC. CONCLUSIONS: RIC for small intestine using BAE has the potential to be safe and effective for relieving symptoms (jRCT identifier jRCTs022200040).

Large-scale population cohort studies that collect genomic information are tasked with returning an assessment of genetic risk for hereditary cancers to participants. While several studies have applied to return identified genetic risks to participants, comprehensive surveys of participants' understanding, feelings, and behaviors toward cancer risk remain to be conducted. Here, we report our experience and surveys of returning genetic risks to 100 carriers of pathogenic variants for hereditary cancers identified through whole genome sequencing of 50 000 individuals from the Tohoku Medical Megabank project, a population cohort study. The participants were carriers of pathogenic variants associated with either hereditary breast and ovarian cancer (n = 79, median age=41) or Lynch syndrome (n = 21, median age=62). Of these, 28% and 38% had a history of cancer, respectively. We provided information on cancer risk, heritability, and clinical actionability to the participants in person. The comprehension assessment revealed that the information was better understood by younger (under 60 years) females than by older males. Scores on the cancer worry scale were positively related to cancer experiences and general psychological distress. Seventy-one participants were followed up at Tohoku University Hospital; six females underwent risk-reducing surgery triggered by study participation and three were newly diagnosed with cancer during surveillance. Among first-degree relatives of hereditary breast and ovarian cancer carriers, participants most commonly shared the information with daughters. This study showed the benefits of returning genetic risks to the general population and will provide insights into returning genetic risks to asymptomatic pathogenic variant carriers in both clinical and research settings.

Hepatitis B virus (HBV) can be transmitted within a family, but an interspousal transmission in elderly cases is rare and the change of viral quasispecies during the event is unclear. We experienced two acute hepatitis B males (AH1 and AH2, 67 and 71 years old, respectively) whose HBV was transmitted from their wives with chronic HBV infection (CH1 and CH2, 67 and 66 years old, respectively). To clarify the characteristics of HBV quasispecies in such cases, we performed long-read deep sequencing of HBV preS1/preS2/S domain using samples from the 2 couples. HBV full-genome sequences determined with direct sequencing showed that the HBV sequences belonged to subgenotype B1. AH1 was 98.0-99.2 % identical to CH1, and AH2 was 98.5-99.5 % identical to CH2, whereas the identity between AH1 and AH2 was 96.9 %. The long-read deep sequencing of amplicons including preS1/preS2/S domains with PacBio Sequel IIe showed the numbers of nucleotides with >5 % substitution frequencies in AH1, AH2, CH1 and CH2 were 0 (0 %), 4 (0.31 %), 39 (3.06 %) and 28 (2.20 %), respectively, indicating that CH1 and CH2 were more heterogeneous than AH1 and AH2. From a phylogenetic analysis based on the deep sequencing, minor CH1/CH2 clones that were close to AH1/AH2 clones were considered to be substantially distinct from the major populations in CH1/CH2. The major population formed during chronic infection under the immune pressure might not be suitable to establish new infection and this might be one of the reasons why the transmission had not occurred for a long time after marriage.

BACKGROUND: The patients taking direct oral anticoagulants (DOACs) are at high risk for developing ischemic stroke and delayed bleeding in upper gastrointestinal endoscopic submucosal dissection (ESD). We aimed to identify the optimal DOAC based on both adverse events in upper gastrointestinal ESD. METHODS: A retrospective population-based cohort study was conducted using the Diagnosis Procedure Combination database in Japan. We included patients on a DOAC undergoing upper gastrointestinal ESD between 2012 and 2021. The primary outcomes were ischemic stroke occurring after upper gastrointestinal ESD and delayed bleeding in gastroduodenal and esophageal ESD. Inverse probability weightings were applied to balance the four DOAC groups (dabigatran, rivaroxaban, apixaban, and edoxaban), and logistic regression analyses were performed to compare the outcomes. RESULTS: We analyzed 9729 patients on a DOAC undergoing upper gastrointestinal ESD. Ischemic stroke developed after upper gastrointestinal ESD in 1.4%, 0.7%, 0.6%, and 0.8% of patients taking dabigatran, rivaroxaban, apixaban, and edoxaban, respectively, after weighting. Rivaroxaban and apixaban showed significantly lower risk of ischemic stroke compared with dabigatran (odds ratio, 0.15 and 0.12, respectively) in standard doses. The delayed bleeding developed after gastroduodenal ESD in 7.6%, 14.6%, 19.2%, and 17.3% of patients taking each DOAC, respectively, with the lowest risk in dabigatran, followed by rivaroxaban. A similar pattern was observed in delayed bleeding in esophageal ESD (3.2%, 5.4%, 7.5%, and 5.5% in each DOAC), but with no significant results. CONCLUSIONS: Rivaroxaban might be an optimal DOAC for upper gastrointestinal ESD showing a lower risk for both ischemic stroke and delayed bleeding.

Pancreatic ductal adenocarcinoma (PDAC) characterized by an abundant cancer stroma is an aggressive malignancy with a poor prognosis. Periostin (Pn) is a key extracellular matrix (ECM) protein in various tumor progression. Previously, we described the role of Pn alternative splicing variants (ASVs) with specific functional features in breast cancer. Pn is known to associate with a chemoresistance of PDAC, but the functions of the Pn-ASVs remain largely unknown. In this study, we focused on physiological and pathological Pn-ASVs, and examined the characteristics of Pn-expressing cells and the difference in function of each ASV. We found that cancer-associated fibroblasts (CAFs) are a main source of Pn synthesis, which selectively secrete pathological Pn-ASVs with exon 21 both in mouse and human samples. RNA sequencing identified a gene signature of Pn-positive CAFs associated with ECM-related genes and chemokines, factors that shape the chemoresistance tumor microenvironment (TME). Additionally, only pathological Pn-ASVs interacted with heat shock protein 70-1a (HSP70-1a), leading to significant rescue of gemcitabine-induced PDAC apoptosis. In silico analysis revealed that the presence or absence of exon 21 changes the tertiary structure of Pn and the binding sites for HSP70-1a. Altogether, Pn-ASVs with exon 21 secreted from CAFs play a key role in supporting tumor growth by interacting with cancer cell-derived HSP70-1a, indicating that Pn-ASVs with exon 21 might be a potential therapeutic and diagnostic target in PDAC patients with rich stroma.

Breast cancer is a prevalent hormone-dependent malignancy, and estrogens/estrogen receptor (ER) signaling are pivotal therapeutic targets in ER-positive breast cancers, where endocrine therapy has significantly improved treatment efficacy. However, the emergence of both de novo and acquired resistance to these therapies continues to pose challenges. Additionally, androgens are produced locally in breast carcinoma tissues by androgen-producing enzymes, and the androgen receptor (AR) is commonly expressed in breast cancer cells. Intratumoral androgens play a significant role in breast cancer progression and are closely linked to resistance to endocrine treatments. The tumor microenvironment, consisting of tumor cells, immune cells, fibroblasts, extracellular matrix, and blood vessels, is crucial for tumor progression. Stromal cells influence tumor progression through direct interactions with cancer cells, the secretion of soluble factors, and modulation of tumor immunity. Estrogen and androgen signaling in breast cancer cells affects the tumor microenvironment, and the expression of hormone receptors correlates with the diversity of the stromal cell profile. Notably, various stromal cells also express ER or AR, which impacts breast cancer development. This review describes how sex steroid hormones, particularly estrogens and androgens, affect stromal cells in the breast cancer microenvironment. We summarize recent findings focusing on the effects of ER/AR signaling in breast cancer cells on stromal cells, as well as the direct effects of ER/AR signaling in stromal cells.

Liquid biopsy (LB) is an essential tool for obtaining tumor-derived materials with minimum invasion. Bile has been shown to contain much higher free nucleic acid levels than blood plasma and can be collected through endoscopic procedures. Therefore, bile possesses high potential as a source of tumor derived cell-free DNA (cfDNA) for bile duct cancers. In this study, we show that a multigene panel for plasma LB can also be applied to bile cfDNA for comparing driver gene mutation detection in other sources (plasma and tumor tissues of the corresponding patients). We collected cfDNA samples from the bile of 24 biliary tract cancer cases. These included 17 cholangiocarcinomas, three ampullary carcinoma, two pancreatic cancers, one intraductal papillary mucinous carcinoma, and one insulinoma. Seventeen plasma samples were obtained from the corresponding patients before surgical resection and subjected to the LiquidPlex multigene panel LB system. We applied a machine learning approach to classify possible tumor-derived variants among the prefiltered variant calls by a LiquidPlex analytical package with high fidelity. Among the 17 cholangiocarcinomas, we could detect cancer driver mutations in the bile of 10 cases using the LiquidPlex system. Of the biliary tract cancer cases examined with this method, 13 (54%) and 4 (17%) resulted in positive cancer driver mutation detection in the bile and plasma cfDNAs, respectively. These results suggest that bile is a more reliable source for LB than plasma for multigene panel analyses of biliary tract cancers.

We started a registry for cases of immunoglobulin (Ig)G4-related disease (IgG4-RD) in December 2019 to clarify the clinical profile of IgG4-RD. In this study, clinical information from 854 cases registered by February 16, 2024 was analyzed from multiple perspectives. Diagnosis of IgG4-RD was made in 808 cases, comprising 638 definite, 38 probable, and 132 possible. The mean ± SD age at time of enrollment of the 808 cases was 67.9 ± 11.3 years, with 68.8% being male. The pancreas was the most frequently affected organ (49.8%), followed by the submandibular glands (46.2%) and lacrimal glands (30.6%). This study reconfirmed the pancreas and head-and-neck region as major affected areas in IgG4-RD. Clinically, submandibular adenitis and autoimmune pancreatitis often occur together in the same patient, but no association between the two organs was observed in our analysis. Regarding diagnosis, the comprehensive diagnostic criteria were most commonly used (63.6%). Storiform fibrosis and phlebitis obliterans were detected at different frequencies in different organs. In summary, this registry study identified clinical, imaging, hematologic, and pathologic findings in 808 Japanese patients with IgG4-RD. The frequency of affected organs and their characteristic pathological findings will be particularly useful for future practice.

BACKGROUND/OBJECTIVE: Elevated serum IgG4 (sIgG4) is a useful diagnostic marker of type 1 autoimmune pancreatitis (AIP). This study aimed to clarify the clinicopathological characteristics of the type 1 AIP patients without elevated sIgG4 levels. METHODS: We analyzed the clinical data of patients registered in a nationwide epidemiological survey in Japan. AIP was diagnosed according to the International Consensus Diagnostic Criteria. Patients with sIgG4 levels ≥135 mg/dl at the diagnosis were classified as sIgG4-positive AIP, and those with sIgG4 levels <135 mg/dl were as sIgG4-negative AIP. RESULTS: A total of 1285 patients with AIP were enrolled in this study; 1128 (87.8 %) had sIgG4-positive AIP and 157 (12.2 %) had sIgG4-negative AIP. Compared to patients with sIgG4-positive AIP, those with sIgG4-negative AIP more frequently experienced inflammatory bowel diseases (3.8 % vs. 0.4 %), and less frequently developed extrapancreatic lesions (53.5 % vs. 72.3 %), including sclerosing cholangitis (30.6 % vs. 40.7 %) and sialadenitis/dacryoadenitis (5.1 % vs. 24.7 %). Histopathological examinations were performed more frequently in patients with sIgG4-negative AIP. The criterion of abundant IgG4-positive plasma cells was less frequently fulfilled by patients with sIgG4-negative AIP (28.0 % vs. 43.1 %). A Kaplan-Meier analysis showed that relapse occurred less frequently in patients with sIgG4-negative AIP (P = 0.006). Results were similar even if the patients with AIP-not otherwise specified (n = 45) were excluded. CONCLUSIONS: Patients with sIgG4-negative type 1 AIP and those with sIgG4-positive type 1 AIP present with different clinicopathological features which suggests heterogeneity of patients with type 1 AIP. Low serum IgG4 levels could indicate low disease activity in type 1 AIP.

A 70-year-old woman had been taking steroids for granulomatosis with polyangiitis since the age of 60 years and warfarin for deep vein thrombosis since the age of 63 years. She was admitted to the emergency unit of our hospital in a shock vital with complaints of sudden onset of epigastralgia, nausea, and melena. Laboratory data revealed anemia, hypoalbuminemia, and coagulation disorders. Enhanced computed tomography demonstrated extravasation in the middle part of the gastric body in an extensive submucosal hematoma extending from the upper esophagus to the entire gastric body. Emergency esophagogastroduodenoscopy depicted a large submucosal hematoma and a large amount of fresh blood in the stomach; however, active bleeding was not identified. Two sessions of interventional radiology treatment in the emergency department, followed by an intensive care, successfully treated the patient without any complications. We report a unique case of a sudden-onset esophagogastric submucosal hematoma with hemorrhagic shock requiring an intensive care and interventional radiology treatment. In this case, the extensive warfarization and the fragility in vascular and connective tissue components in the submucosa due to the long-term steroid therapy and the granulomatosis with polyangiitis-related alteration might comprehensively cause severe esophagogastric submucosal hematoma even without any apparent triggers.

A de novo whitish subepithelial lesion (SEL) with irregular vascular hyperplasia was detected in the lower thoracic esophagus during endoscopic surveillance. Special types of esophageal cancer were suspected; however, endoscopic biopsy specimens were inadequate for a diagnosis. Ten days later, endoscopic ultrasound showed a 7-mm homogeneously hypoechoic round mass in the submucosa, and a biopsy confirmed a histological diagnosis of esophageal neuroendocrine carcinoma (eNEC). Based on the clinical diagnosis of cT2N0M0, subtotal esophagectomy followed by adjuvant chemotherapy was performed immediately after endoscopic reexamination revealing a 20-mm reddish SMT. We herein report the marked changes in endoscopic findings of eNEC within 1.5 months.

Abstract <p>Little is known about how blood free amino acids (FAAs) change in metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to identify the imbalance of FAAs in MASLD and explore its correction as a potential therapeutic targets. We analyzed plasma FAAs data from 23,036 individuals with steatosis information from a biobank in Japan, and 310 patients with MASLD were enrolled. According to diagnostic criteria for steatotic liver disease (SLD) or cardiometabolic criteria (CC), we divided the subjects into five groups: MASLD, metabolic dysfunction and alcohol-associated liver disease (MetALD), CC-SLD-, CC + SLD-, and CC-SLD+. Twenty FAAs were compared among these groups, and among MASLD patients with pathological information. Among the 20 FAAs, the levels of 16 FAAs increased in CC + SLD- according to the number of matches with CC items associated with insulin resistance (IR). Steatosis enhanced most of these changes but serine (Ser) and threonine (Thr) were unaffected. Glycine (Gly), Ser and Thr were significantly decreased in patients according to steatosis grade. We investigated the association between these FAAs imbalances and pathogenesis using MASLD mouse models. In mice fed high-fat, fructose and cholesterol (FFC) diet, metabolomics and RNA sequencing analyses indicated that abnormality in Gly, Ser, and Thr metabolism in liver was associated with mitochondrial dysfunction and enhanced glycolysis via pyruvate. High-Gly, Ser, and Thr diet ameliorated pathogenesis of MASLD in leptin-deficient mice. Most FAAs increase due to cardiometabolic abnormalities, particularly IR. However, interventions targeting metabolism of Gly, Ser, and Thr have potential to improve MASLD.</p>

Imaging tests, tumor marker (TM) screening, and biochemical tests provide a definitive diagnosis of hepatocellular carcinoma (HCC). However, some patients with HCC may present TM-negative results, warranting a need for developing more sensitive and accurate screening biomarkers. Various diseases exhibit increased blood levels of bile acids, biosynthesized from cholesterol in the liver, and they have been associated with HCC. Herein, we analyzed plasma bile acids using liquid chromatography/tandem mass spectrometry and integrated them with conventional biomarkers to develop a diagnostic screening model for HCC. Plasma samples were obtained from patients diagnosed with chronic hepatitis, hepatic cirrhosis (HC), and HCC. A QTRAP 6500 mass spectrometer and a Nexera liquid chromatograph with a YMC-Triart C18 analytical column were used. The mobile phase A was a 20 mmol/L ammonium formate solution, and mobile phase B was a methanol/acetonitrile mixture (1:1, v/v) with 20 mmol/L ammonium formate. After determining the concentrations of 32 bile acids, statistical analysis and diagnostic screening model development were performed. Plasma concentrations of bile acids differed between sample groups, with significant differences observed between patients with HC and HCC. By integrating bile acid results with conventional biochemical tests, a potential diagnostic screening model for HCC was successfully developed. Future studies should increase the sample size and analyze the data in detail to verify the diagnostic efficacy of the model.

OBJECTIVES: Endoscopic pancreatic stenting (EPS) is an effective treatment modality for painful chronic pancreatitis. However, little is known about the factors that cause pain recurrence after stent removal, and there are no clear criteria for stent removal. We aimed to develop a prediction model for pain recurrence by identifying its risk factors. METHODS: We retrospectively reviewed 95 patients who underwent EPS due to pain for the first time using a single plastic stent between January 2007 and July 2022 at our institute. Univariate and multivariate stepwise Cox proportional hazards models were used to identify the risk factors for pain recurrence, and a prediction model was developed based on the identified factors. RESULTS: Of the 95 enrolled patients, 89 (93.7%) achieved pain relief and 73 (76.8%) did stent removal. Of the 69 patients with a follow-up period ≥6 months after stent removal, 29 (42.0%) had pain recurrence during the median follow-up period of 59 months. Serum lipase level (p = 0.034) and pancreatic parenchymal thickness (p = 0.022) on computed tomography or magnetic resonance imaging were identified as independent risk factors for pain recurrence. The prediction model based on the identified factors had good discrimination ability, with a concordance index of 0.74, and could stratify pain recurrence rates. CONCLUSIONS: We identified the risk factors and developed a new prediction model for pain recurrence following stent removal. This model might be useful for decision-making in pancreatic stent management, such as deciding whether to remove a pancreatic stent, continue EPS, or convert to surgery.

BACKGROUND: The natural history of branch-duct intraductal papillary mucinous cystic neoplasms (BD-IPMNs) in the pancreas remains unclear. This study aimed to answer this clinical question by focusing on the development of concomitant pancreatic ductal adenocarcinomas (cPDAC). METHODS: The Japan Pancreas Society conducted a prospective multicenter surveillance study of BD-IPMN every six months for five years. The primary endpoints were progression of BD-IPMN, progression to high-grade dysplasia/invasive carcinoma (HGD/IC), and cPDAC. Factors predicting the progression of BD-IPMN to HGD/IC and development of cPDAC were also assessed as secondary endpoints. RESULTS: Among the 2104 non-operated patients, 348 (16.5 %) showed progression of primary BD-IPMN. Cumulative incidences of BD-IPMN with HGD/IC and cPDAC during the 5.17-year surveillance period were 1.90 % and 2.11 %, respectively, and standard incidence ratios of BD-IPMN with HGD/IC and cPDAC were 5.28 and 5.73, respectively. Of 38 cPDACs diagnosed during surveillance, 25 (65.8 %) were resectable. The significant predictive characteristics of BD-IPMN for progression to HGD/IC were larger cyst size (p = 0.03), larger main pancreatic duct size (p < 0.01), and mural nodules (p = 0.02). Significant predictive characteristics for the development of cPDAC were male sex (p = 0.03) and older age (p = 0.02), while the size of IPMN was not significant. CONCLUSION: Careful attention should be given to "dual carcinogenesis" during BD-IPMN surveillance, indicating the progression of BD-IPMN to HGD/IC and development of cPDAC distinct from BD-IPMN, although the establishment of risk factors that predict cPDAC development remains a challenge (UMIN000007349).

BACKGROUND: Patients with isolated IgG4-related sclerosing cholangitis (IgG4-SC) often undergo unnecessary resection. The aim of this study was to validate the revised Japanese diagnostic criteria for isolated IgG-4-SC and to improve awareness about this condition in the population. METHODS: This was a Japanese retrospective multicenter study. We focused on the data and diagnostic yield obtained using the Japanese diagnostic criteria published initially in 2012 and revised later in 2020 for the diagnosis of isolated IgG4-SC. RESULTS: Patients with isolated IgG4-SC could be classified into two groups based on the primary location of the lesion: the hilar type (n = 40) and the extrahepatic type (n = 13). In total, 10 patients with the hilar type had undergone unnecessary resection. The revised 2020 criteria are useful for the diagnosis of extrahepatic lesions, which are not included in the 2012 criteria. The need for a steroid trial was reduced from 37.7% when the diagnosis was based on the 2012 criteria to 7.6% when the diagnosis was based on the revised 2020 criteria. The diagnostic specificity also improved from 58.5% for the 2012 criteria to 88.7% for the revised 2020 criteria. CONCLUSION: Our validation of the 2020 criteria for the diagnosis of IgG4-SC could contribute to avoiding unnecessary resection in patients with isolated IgG4-SC, which can be classified into the hilar and extrahepatic types. The 2020 criteria can enhance the diagnosis rate of isolated IgG4-SC and uncover this tough-to-diagnose entity based on inclusion of the imaging findings and decrease the dependence on a steroid trial.

A 68-year-old woman was diagnosed with leiomyosarcoma (LMS) based on preoperative biopsy of the gastric body. As tumor invasion confined to the submucosa with no breaking of the submucosal layer was confirmed on endoscopic ultrasonography (EUS), the patient underwent endoscopic submucosal dissection (ESD) for gastric LMS, resulting in complete tumor resection. No apparent recurrence was observed in the 2.5 years after treatment. This is an extremely rare case of gastric LMS that underwent ESD after a precise preoperative diagnosis, with no signs of recurrence after treatment. ESD may be an acceptable option for gastric LMS when EUS findings allow this treatment method.

BACKGROUND AND AIMS: Sarcopenia is associated with the prognosis of patients with liver cirrhosis and hepatocellular carcinoma (HCC). Given their diverse physiological activities, we hypothesized that plasma fatty acids might influence the progression of sarcopenia. This study aimed to clarify the association between fatty acids and sarcopenia in cirrhotic patients with HCC. METHODS: In this single-center retrospective study, we registered 516 cases and analyzed 414 cases of liver cirrhosis and HCC. The skeletal muscle mass index was measured using a transverse computed tomography scan image at the third lumbar vertebra. The cutoff value for sarcopenia followed the criteria set by the Japan Society of Hepatology. Fatty acid concentrations were measured by gas chromatography. RESULTS: Fatty acid levels, particularly omega-3 (n-3) polyunsaturated fatty acid (PUFA), were lower in patients with poor liver function (Child-Pugh grade B/C) and were negatively correlated with the albumin-bilirubin score (p<0.0001). The prognosis of HCC patients with low PUFA levels was significantly worse. Among the different fatty acid fractions, only n-3 PUFAs significantly correlated with skeletal muscle mass index (p=0.0026). In the multivariate analysis, the n-3 PUFA level was an independent variable associated with sarcopenia (p=0.0006). CONCLUSIONS: A low level of n-3 PUFAs was associated with sarcopenia in patients with liver cirrhosis and HCC.

Acetaminophen (APAP) is an over-the-counter (OTC) drug known worldwide for its safety and efficacy. However, in Japan, OTC drug overdose has become a prominent social problem in recent years due to stricter regulations for other drugs, especially among young people, and APAP is an increasing cause of acute liver injury due to overdose. This report describes three consecutive cases of acute liver failure in young women (22, 22 and 19 years old) due to APAP overdose in December 2023. Despite severe liver injury, indicated by high ALT levels and coagulopathy, these cases recovered without requiring liver transplantation. This report discusses three cases of acute liver failure in young Japanese women following APAP overdose, reflecting a national increase in such cases due to increased misuse of OTC drugs and societal factors. Key findings include the need for early treatment with N-acetylcysteine (NAC) and the importance of mental health assessment in the management of overdose patients. The cases underscore the need for prompt team-based care to prevent serious outcomes and highlight the complexity of liver transplantation decisions in Japan, highlighting the need for comprehensive strategies to address the escalating problem of APAP overdose.

BACKGROUND AND AIM: Although sleep disorders are associated with the pathogenesis of inflammatory bowel disease, the causal relationship is unclear. Therefore, in this study we aimed to clarify the causal relationship between them. METHODS: We administered the Pittsburgh Sleep Questionnaire to participants during regular visits to evaluate their sleep condition and prospectively observed the participants. Participants were divided into poor sleep and non-poor sleep groups according to their first and second questionnaire scores. We compared inflammatory bowel disease relapse rates between the two groups. RESULTS: The study population included 139 patients with inflammatory bowel disease, including 60 with chronic poor sleep. Disease relapse rate was significantly higher in the poor sleep group than in the non-poor sleep group (28.3% vs. 8.9%; P=0.0033). Ulcerative colitis relapse rate was significantly higher in the poor sleep group than in the non-poor sleep group (34.5% vs. 10.3%, P=0.031). Multivariate analysis identified chronic poor sleep as a clinical factor that affected inflammatory bowel disease relapse (OR=6.69, 95% CI: 2.23-20.0, P=0.0007) and ulcerative colitis relapse (OR=8.89, 95% CI: 1.57-50.2, P=0.014). The Kaplan-Meier curve showed significantly lower cumulative treatment retention rates in the poor sleep group than in the non-poor sleep group (all patients, P=0.0061; ulcerative colitis, P=0.025). CONCLUSIONS: Concomitant chronic poor sleep may have a negative influence on the disease activity in patients with inflammatory bowel disease, especially in those with ulcerative colitis.

INTRODUCTION: Cell-free DNA (cfDNA) is expected to contribute to the decision for treatment and prediction of effects with minimally invasion. We investigated the correlation between gene mutations before and after lenvatinib (LEN) treatment and its effectiveness, in order to find advanced hepatocellular carcinoma (HCC) patients who would benefit greatly from the therapy. METHODS: We analyzed cfDNA before and 6-8 weeks after the start of treatment in 20 advanced HCC patients started LEN. A next-generation sequencer was used for CTNNB1 and TP53. Concerning TERT promoter, -124C&gt;T and -146C&gt;T mutations are researched using digital PCR. In addition, we examined liver tumor biopsy tissues by the same method. CT evaluation was performed at 6-8 weeks and 3-4 months, to assess the efficacy. RESULTS: Frequencies of TERT promoter, CTNNB1 and TP53 mutations in pretreatment cfDNA were 45%, 65% and 65%, but 53%, 41% and 47% in HCC tissues, respectively. There were no clear correlations between these gene mutations and the disease-suppressing effect or progression-free survival. Overall, there were many cases showing a decrease in mutations after LEN treatment. Integrating the reduction of CTNNB1 and TP53 genetic mutations increased the potential for disease suppression. CONCLUSION: This study suggests that analysis of cfDNA in advanced HCC patients may be useful for identifying LEN responders and determining therapeutic efficacy. Furthermore, it has potential for selecting responders for other molecular-targeted drugs.

A 62-year-old male with a history of stent graft replacement for an infectious aortic aneurysm, followed by multiple interventions for postoperative complications, was admitted with melena and anemia. Enhanced computed tomography (eCT) demonstrated fluffing and hyperdensities surrounding the graft, despite no evidence of an aortoenteric fistula (AEF). Emergency esophagogastroduodenoscopy (EGD) showed a massive bleeding in the reconstructed tract and the protruding lesion of postoperative granulation tissue with clots at the end of the blind pouch. Thereafter, hemorrhage temporarily reoccurred several times; however, the source could not be identified using eCT or EGD. Finally, on the third attempt, we performed gel immersion endoscopy (GIE) with manual injection of VISCOCLEARⓇ, and it showed purulent blood flowing from one side of the protruding lesion in the pouch. Based on the eCT findings showing exudation of the contrast agent from the graft into the pouch, we made a diagnosis of an AEF. However, radical surgery was not performed because of the patient's poor general condition. During conservative management, he died of uncontrolled bleeding from the AEF on the 5th day of hospitalization. This is the first case in which the GIE might provide tips to identify herald bleeding from a lethal AEF.

Chronic infection of Helicobacter pylori is considered the principal cause of gastric cancers, but evidence has accumulated regarding the impact of tobacco smoking and alcohol consumption on the development of gastric cancers. Several possible mechanisms, including the activation of nicotinic acetylcholine receptors, have been proposed for smoking-induced gastric carcinogenesis. On the other hand, local acetaldehyde exposure and ethanol-induced mucosal inflammation have been proposed as the mechanisms involved in the development of gastric cancers in heavy alcohol drinkers. In addition, genetic polymorphisms are also considered to play a pivotal role in smoking-related and alcohol-related gastric carcinogenesis. In this review, we will discuss the molecular mechanisms involved in the development of gastric cancers in relation to tobacco smoking and alcohol consumption.

OBJECTIVE: This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection. SUMMARY BACKGROUND DATA: Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown. METHODS: Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated. RESULTS: These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways. CONCLUSION: Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs.

The optimal immunosuppressive therapy for elderly patients with ulcerative colitis (UC) remains unclear. We aimed to evaluate clinical practice and prognosis in elderly patients with UC through comparing between those with elderly-onset UC (EOUC) and those with long-standing elderly UC (LEUC). In this retrospective single-center cohort study, we evaluated elderly patients with UC aged ≥ 60 in August 2022 through collecting medical record data from the time of diagnosis of UC until August 2022. The patients were divided into two groups based on age at disease onset: EOUC (age at onset, ≥ 60 years) and LEUC (age at onset, < 60 years). We assessed the cumulative rates of systemic steroid and molecular targeted drug (MTD) initiation, and colectomy. We enrolled 97 eligible patients (EOUC group, n = 30; LEUC group, n = 67). The cumulative rates of initiating systemic steroid (46% vs. 22% at 1 year, respectively; P = 0.002) and MTD (17% vs. 5% at 1 year, respectively; P = 0.002) were higher in the EOUC group than in the LEUC group. In multivariate analysis, elderly onset was significantly associated with systemic steroid (hazard ratio [HR] 2.74, 95% confidence interval [CI] 1.43-5.29; P = 0.003) and MTD (HR 2.76, 95% CI 1.30-5.87; P = 0.008) initiation. Cumulative colectomy rates did not differ significantly between the two groups. Patients with EOUC were initiated on systemic steroids and MTDs sooner following disease onset than patients with LEUC. Our findings suggest rapid progression and refractoriness in patients with EOUC.

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>It is crucial to pinpoint the metabolites that cause Crohn’s disease (CD) and ulcerative colitis (UC) to comprehend their pathogenesis and identify possible targets for therapy. To achieve this goal, we performed the first metabolome-wide Mendelian randomization (MR) study of Japanese patients with CD and UC.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>As exposure datasets, genetic instruments with blood-circulating metabolites were obtained from the Tohoku Medical Megabank Organization, which includes 204 metabolites from the genome-wide association study data of 7843 Japanese individuals. As outcome datasets, we enrolled Japanese patients with CD (n = 1803), Japanese patients with UC (n = 1992), and healthy controls (n = 2022). The main analysis utilized the inverse variance–weighted method, while stability of the findings was evaluated through sensitivity analyses.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>After single nucleotide polymorphism (SNP) filtering, 169 SNPs for 45 metabolites were available for MR. Genetically predicted elevated circulating trans-glutaconic acid and tryptophan were associated with a lower CD risk (odds ratio [OR], 0.68; P = 5.95 × 10−3; and OR, 0.64; P = 1.90 × 10−2, respectively). Genetically predicted elevated caffeic acid was associated with a lower UC risk (OR, 0.67; P = 4.2 × 10−4), which remained significant after multiple testing correction. We identified a causal link between UC and 3-hydroxybutyrate (OR, 2.21; P = 1.41 × 10−2), trans-glutaconic acid (OR, 0.72; P = 1.77 × 10−2), and 2-hydroxyvaleric acid (OR, 1.31; P = 4.23 × 10−2). There was no evidence of pleiotropy or reverse causal effects for these candidate metabolites.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>In our metabolome-wide MR study, we discovered a notable protective effect of caffeic acid against UC.</jats:p> </jats:sec>

The gastrointestinal (GI) tract harbors trillions of microorganisms known to influence human health and disease, and next-generation sequencing (NGS) now enables the in-depth analysis of their diversity and functions. Although a significant amount of research has been conducted on the GI microbiome, comprehensive metagenomic datasets covering the entire tract are scarce due to cost and technical challenges. Despite the widespread use of fecal samples, integrated datasets encompassing the entire digestive process, beginning at the mouth and ending with feces, are lacking. With this study, we aimed to fill this gap by analyzing the complete metagenome of the GI tract, providing insights into the dynamics of the microbiota and potential therapeutic avenues. In this study, we delved into the complex world of the GI microbiota, which we examined in five healthy Japanese subjects. While samples from the whole GI flora and fecal samples provided sufficient bacteria, samples obtained from the stomach and duodenum posed a challenge. Using a principal coordinate analysis (PCoA), clear clustering patterns were identified; these revealed significant diversity in the duodenum. Although this study was limited by its small sample size, the flora in the overall GI tract showed unwavering consistency, while the duodenum exhibited unprecedented phylogenetic diversity. A visual heat map illustrates the discrepancy in abundance, with Fusobacteria and Bacilli dominating the upper GI tract and Clostridia and Bacteroidia dominating the fecal samples. Negativicutes and Actinobacteria were found throughout the digestive tract. This study demonstrates that it is possible to continuously collect microbiome samples throughout the human digestive tract. These findings not only shed light on the complexity of GI microbiota but also provide a basis for future research.

BACKGROUND/AIMS: During endoscopy, white spots (WS) are sometimes observed around benign or malignant colorectal tumors; however, few reports have investigated WS, and their significance remains unknown. Therefore, we investigated the significance of WS from clinical and pathological viewpoints and evaluated its usefulness in endoscopic diagnosis. METHODS: Clinical data of patients with lesions diagnosed as epithelial tumors from January 1, 2019, to December 31, 2020, were analyzed (n=3,869). We also performed a clinicopathological analysis of adenomas or carcinomas treated with endoscopic resection (n=759). Subsequently, detailed pathological observations of the WS were performed. RESULTS: The positivity rates for WS were 9.3% (3,869 lesions including advanced cancer and non-adenoma/carcinoma) and 25% (759 lesions limited to adenoma and early carcinoma). Analysis of 759 lesions showed that the WS-positive lesion group had a higher proportion of cancer cases and larger tumor diameters than the WS-negative group. Multiple logistic analysis revealed the following three statistically significant risk factors for carcinogenesis: positive WS, flat lesions, and tumor diameter ≥5 mm. Pathological analysis revealed that WS were macrophages that phagocytosed fat and mucus and were white primarily because of fat. CONCLUSIONS: WS are cancer-related findings and can become a new criterion for endoscopic resection in the future.

Although esophageal cancers invading the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic resection (ER) are associated with a risk of lymph node metastasis, details of metastatic recurrence after additional treatment remain unknown. We aimed to identify the risk factors for metastatic recurrence and recurrence patterns in patients receiving additional treatment after ER for esophageal cancer. Between 2006 and 2017, patients with pT1a-MM/pT1b-SM esophageal cancer who underwent ER with additional treatment (esophagectomy, chemoradiotherapy [CRT], and radiation therapy) at 21 institutions in Japan were enrolled. We evaluated the risk factors for metastatic recurrence after ER with additional treatment. Subsequently, the rate and pattern (locoregional or distant) of metastatic recurrence were investigated for each additional treatment. Of the 220 patients who received additional treatment, 57, 125, and 38 underwent esophagectomy, CRT, and radiation therapy, respectively. In the multivariate analysis, lymphatic invasion was the sole risk factor for metastatic recurrence after additional treatment (hazard ratio, 3.50; P = 0.029). Although the risk of metastatic recurrence with additional esophagectomy was similar to that with CRT (hazard ratio, 1.01; P = 0.986), the rate of locoregional recurrence tended to be higher with additional esophagectomy (80.0% (4/5) vs. 36.4% (4/11)), leading to a better prognosis in patients with metastatic recurrence after additional esophagectomy than CRT (survival rate, 80.0% (4/5) vs. 9.1% (1/11)). Patients with lymphatic invasion have a high risk of metastatic recurrence after ER with additional treatment for pT1a-MM/pT1b-SM esophageal cancer. Additional esophagectomy may result in a better prognosis after metastatic recurrence.

BACKGROUND AND AIM: The number of older patients with ulcerative colitis is increasing; however, limited data exist regarding the differences between elderly- and non-elderly-onset ulcerative colitis. We aimed to compare the clinical practice and course of elderly-onset ulcerative colitis with those of non-elderly-onset ulcerative colitis. METHODS: We selected older patients with ulcerative colitis and divided them into the elderly- and non-elderly-onset ulcerative colitis groups according to their age at onset. We compared the cumulative systemic steroid-free, molecular targeting drug-free, and surgery-free rates between the two groups. We performed a multivariate analysis to identify the clinical factors related to systemic steroid administration, the use of molecular targeting drugs, surgery, and death. RESULTS: We collected data of 2669 and 277 elderly and non-elderly-onset ulcerative colitis patients, respectively. The cumulative systemic steroid-free rate of elderly-onset ulcerative colitis was significantly lower than that of non-elderly-onset ulcerative colitis. However, no difference was observed in the cumulative molecular targeting drugs and surgery-free rates between the two groups. Elderly-onset ulcerative colitis significantly increased the risk of systemic steroid administration and death but not the use of molecular targeting drugs and surgery. CONCLUSION: The disease severity of ulcerative colitis and clinical practice may not differ between the elderly- and non-elderly-onset groups. However, elderly-onset ulcerative colitis was associated with increased mortality risk. Thus, we need to pay attention to the patients' condition and appropriate timing of surgery for patients with elderly-onset ulcerative colitis.

INTRODUCTION: We investigated the factors associated with synchronous multiple early gastric cancers and determined their localization. METHODS: We analyzed 8191 patients who underwent endoscopic submucosal dissection for early gastric cancers at 33 hospitals in Japan from November 2013 to October 2016. Background factors were compared between single-lesion (n=7221) and synchronous multi-lesion cases (n=970) using univariate and multivariate analyses. We extracted cases with two synchronous lesions (n=832) and evaluated their localization. RESULTS: Significant independent risk factors for synchronous multiple early gastric cancer were older age (≥75 years old) (OR=1.257), male sex (OR=1.385), severe mucosal atrophy (OR=1.400), tumor localization in the middle (OR=1.362) or lower region (OR=1.404), and submucosal invasion (OR=1.528 (SM1), 1.488 (SM2)). Depressed macroscopic type (OR=0.679) and pure undifferentiated histology OR=0.334) were more common in single early gastric cancers. When one lesion was in the upper region, the other was more frequently located in the lesser curvature of the middle region. When one lesion was in the middle region, the other was more frequently located in the middle region or the lesser curvature of the lower region. When one lesion was in the lower region, the other was more frequently located in the lesser curvature of the middle region or the lower region. CONCLUSION: Factors associated with synchronous multiple early gastric cancer included older age, male sex, severe mucosal atrophy, tumor localization in the middle or lower region, and tumor submucosal invasion. Our findings provide useful information regarding specific areas that should be examined carefully when one lesion is detected.

Pancreatic cancer is characterized by a densely fibrotic stroma. The fibrotic stroma hinders the intratumoral penetration of nanomedicine and diminishes therapeutic efficacy. Fibrosis is characterized by an abnormal organization of extracellular matrix (ECM) components, namely the abnormal deposition and/or orientation of collagen and fibronectin. Abnormal ECM organization is chiefly driven by pathological signaling in pancreatic stellate cells (PSCs), the main cell type involved in fibrogenesis. However, whether targeting signaling pathways involved in abnormal ECM organization improves the intratumoral penetration of nanomedicines is unknown. Here, we show that targeting transforming growth factor-β (TGFβ)/Rho-associated kinase (ROCK) 1/2 signaling in PSCs normalizes ECM organization and concomitantly improves macromolecular permeability of the fibrotic stroma. Using a 3-dimensional cell culture model of the fibrotic pancreatic cancer microenvironment, we found that pharmacological inhibition of TGFβ or ROCK1/2 improves the permeation of various macromolecules. By using an isoform-specific pharmacological inhibitor and siRNAs, we show that targeting ROCK2, but not ROCK1, alone is sufficient to normalize ECM organization and improve macromolecular permeability. Moreover, we found that ROCK2 inhibition/knockdown attenuates Yes-associated protein (YAP) nuclear localization in fibroblasts co-cultured with pancreatic cancer cells in 3D. Finally, pharmacological inhibition or siRNA-mediated knockdown of YAP normalized ECM organization and improved macromolecular permeability. Our results together suggest that the TGFβ/ROCK2/YAP signaling axis may be therapeutically targeted to normalize ECM organization and improve macromolecular permeability to augment therapeutic efficacy of nanomedicines in pancreatic cancer.

BACKGROUND AND AIM: We previously identified that ever-smoking and severe gastric atrophy in pepsinogen are risk factors for synchronous gastric cancers (SGCs). This study aimed to determine the association of alcohol drinking status or alcohol-related genetic polymorphism with SGCs and also stratify their risk. METHODS: This multi-center prospective cohort study included patients who underwent endoscopic submucosal dissection for the initial early gastric cancers at 22 institutions in Japan. We evaluated the association of alcohol drinking status or alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase 2 (ALDH2) genotypes with SGCs. We then stratified the risk of SGCs by combining prespecified two factors and risk factors identified in this study. RESULTS: Among 802 patients, 130 had SGCs. Both the ADH1B Arg and ALDH2 Lys alleles demonstrated a significant association with SGCs on multivariate analysis (odds ratio, 1.77), although alcohol drinking status showed no association. The rates of SGCs in 0-3 risk factors in the combined evaluation of three risk factors (ever-smoking, severe gastric atrophy in pepsinogen, and both the ADH1B Arg and ALDH2 Lys alleles) were 7.6%, 15.0%, 22.0%, and 32.1%, respectively. The risk significantly increased from 0 to 3 risk factors on multivariate analysis (P for trend <0.001). CONCLUSIONS: Both the ADH1B Arg and ALDH2 Lys alleles were at high risk for SGCs. The risk stratification by these three factors may be a less invasive and promising tool for predicting their risk.

Situs inversus totalis is a rare congenital malformation in which organs are positioned in a mirror-image relationship to normal conditions. It often presents with vascular and biliary malformations. Only a few reports have pointed out the surgical difficulties in patients with situs inversus totalis, especially in those with perihilar cholangiocarcinoma. This report describes a 66-year-old male patient who underwent left hemihepatectomy (S5, 6, 7, and 8) with combined resection of the caudate lobe (S1), extrahepatic bile duct, and regional lymph nodes for perihilar cholangiocarcinoma with situs inversus totalis. Cholangiocarcinoma was mainly located in the perihilar area and progressed extensively into the bile duct. Surgery was performed after careful evaluation of the unusual anatomy. Although several vascular anomalies required delicate manipulation, the procedures were performed without major intraoperative complications. Postoperatively, bile leakage occurred, but the patient recovered with drainage treatment. The patient was discharged on the 29th postoperative day. Adjuvant chemotherapy with S-1 was administered for approximately 6 months. There was no recurrence 15 months postoperatively. Appropriate imaging studies and an understanding of unusual anatomy make surgery safe and provide suitable treatment for patients with situs inversus totalis.

BACKGROUND: This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. METHODS: A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status. RESULTS: Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users. CONCLUSIONS: NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

Clinical evidence has revealed that high-level activation of NRF2 caused by somatic mutations in NRF2 (NFE2L2) is frequently detected in esophageal squamous cell carcinoma (ESCC), whereas that caused by somatic mutations in KEAP1, a negative regulator of NRF2, is not. Here, we aspire to generate a mouse model of NRF2-activated ESCC using the cancer-derived NRF2L30F mutation and cancer driver mutant TRP53R172H. Concomitant expression of NRF2L30F and TRP53R172H results in formation of NRF2-activated ESCC-like lesions. In contrast, while squamous-cell-specific deletion of KEAP1 induces similar NRF2 hyperactivation, the loss of KEAP1 combined with expression of TRP53R172H does not elicit the formation of ESCC-like lesions. Instead, KEAP1-deleted cells disappear from the esophageal epithelium over time. These findings demonstrate that, while cellular NRF2 levels are similarly induced, NRF2 gain of function and KEAP1 loss of function elicits distinct fates of squamous cells. The NRF2L30F mutant mouse model developed here will be instrumental in elucidating the mechanistic basis leading to NRF2-activated ESCC.

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.

A 69-year-old woman, a long-term survivor of subtotal stomach-preserving pancreatoduodenectomy with the splenic vein resection for pancreatic cancer, visited our hospital with a chief complaint of bloody stools. Previously, she was diagnosed with varices in the ascending colon due to left-sided portal hypertension after pancreatoduodenectomy by computed tomography and colonoscopy. After emergency hospitalization, she went into shock, and blood tests showed acute progression of severe anemia. Computed tomography showed a mosaic-like fluid accumulation from the ascending colon to the rectum. She was diagnosed with ruptured varices in the ascending colon. Emergency colonoscopy was performed, and treatment with endoscopic injection sclerotherapy using N-butyl-2-cyanoacrylate was successful. Ectopic varices occur at any location other than the esophagus and stomach, and colonic varices are rare among them. They are mostly caused by portal hypertension due to liver cirrhosis. However, with the trend of improving the prognosis for patients with pancreatic cancer, we should occasionally pay attention to the development of ectopic varices including colonic varices in patients who have undergone pancreatoduodenectomy with superior mesenteric and splenic veins resection. Treatment methods for colonic varices varied from case to case, including conservative therapy, interventional radiology, and endoscopic procedure. In this case, endoscopic injection sclerotherapy was successfully performed without any complications. To the best of our knowledge, this is the first study to report successful treatment with endoscopic injection sclerotherapy for varices in the ascending colon caused by left-sided portal hypertension after pancreatoduodenectomy. Colonic varices should be considered in patients with obscure gastrointestinal bleeding after pancreatoduodenectomy.

BACKGROUND AND AIM: Inflammatory bowel disease (IBD) frequently affects younger patients and poses various challenges concerning pregnancy and childbirth. Maintaining good disease control throughout pregnancy is crucial, but expectant and pregnant patients may worry about the fetal impact of medications, leading to treatment discontinuation due to uncertainty about this issue. This study investigated the real-world drug-prescribing practices for pregnant patients with IBD in Japan and their potential connection to major congenital malformations (MCMs). METHODS: Overall, 277 female IBD patients who gave birth between 2010 and 2019 were selected from the JMDC claims database. The prescribing patterns of IBD medications and MCMs in the patients' offspring were analyzed. RESULTS: Among pregnant IBD patients, 74.4% received at least one medication from 90 days before pregnancy to 90 days after delivery. Trends in medication prescriptions during pregnancy in 2010-2019 revealed consistent use of oral 5-ASA, variable use of topical medications, a decrease in systemic steroids, and an increase in biologics. The prevalence of MCMs in children born to IBD-affected mothers did not differ significantly between those who did and did not receive IBD medications (8.6% vs 6.8%). Although circulatory system MCMs were slightly more common in the IBD medication group (4.9% vs 1.4%), this difference was not significant. Logistic regression analysis did not reveal an association between MCM risk and first-trimester use of IBD medications, including corticosteroids and biologics. CONCLUSIONS: This study provides insights into medication patterns in pregnant IBD patients and suggests no increased risk of MCMs associated with first-trimester IBD medication use.

BACKGROUND/AIMS: Vedolizumab (VDZ) is a gut-selective agent with a favorable safety profile. We aimed to assess the feasibility of elective switch from other advanced therapies to VDZ and subsequent live-attenuated vaccination while continuing VDZ in patients with inflammatory bowel diseases (IBD). METHODS: We measured antibody titers specific for measles, rubella, mumps, and varicella viruses in IBD patients under immunosuppressive therapy. Those with negative titers and without vaccination history were judged unimmunized. Patients were administered vaccines while continuing VDZ or switched to VDZ if receiving other advanced therapies and then administered vaccines. Co-primary outcomes were the rate of maintaining disease severity after vaccination and the rate without vaccine-induced infection. RESULTS: Among 107 unimmunized patients, 37 agreed to receive live-attenuated vaccines while continuing VDZ (17 patients) or after switching to VDZ (20 patients). In the 20 patients who electively switched to VDZ, disease severity was maintained except for 1 patient who developed intestinal infection. After 54 weeks, 18 patients (90%) continued to receive VDZ, excluding 2 patients who reverted to their originally administered biologics. In all 37 patients administered live-attenuated vaccines under VDZ treatment, disease severity was maintained after vaccination. Antibody titers became positive or equivocal in 34 patients (91.9%). There were no cases of vaccine-induced infection during a median observation period of 121 weeks. CONCLUSIONS: While live-attenuated vaccines are contraindicated under immunosuppressive therapy, they may be safely administered while receiving VDZ immunotherapy. Switching from other advanced therapies to VDZ and subsequently receiving live-attenuated vaccines may be a safe alternative in unimmunized patients.

BACKGROUND: The branched-chain amino acids (BCAAs) to tyrosine (Tyr) ratio (BTR) test is used to evaluate the progression of chronic liver disease (CLD). However, the differences across sex, age, body mass index (BMI) and etiologies are still unclear. METHODS: We retrospectively reviewed data from 2,529 CLD cases with free amino acids (FAAs) in peripheral blood from four hospitals and 16,421 general adults with FAAs data from a biobank database. In total, 1,326 patients with CLD (covering seven etiologies) and 8,086 healthy controls (HCs) were analyzed after exclusion criteria. We investigated the change of BTR in HCs by sex, age and BMI and then compared these to patients divided by modified ALBI (mALBI) grade after propensity score matching. RESULTS: BTR is significantly higher in males than females regardless of age or BMI and decreases with aging in HCs. In 20 types of FAAs, 7 FAAs including BCAAs were significantly decreased, and 11 FAAs including Tyr were significantly increased by mALBI grade in total CLD. The decreasing timings of BTR were at mALBI grade 2b in all CLD etiologies compared to HCs, however in chronic hepatitis C (CHC), chronic hepatitis B (CHB) and alcoholic liver disease (ALD), BTR started to decrease at 2a. There was a positive correlation between BCAAs and albumin among parameters in BTR and mALBI. The correlation coefficients in PBC, ALD and MASLD were higher than those of other etiologies. CONCLUSIONS: BTR varies by sex and age even among healthy adults, and decreasing process and timing of BTR during disease progression is different among CLD etiologies.

BACKGROUND: Lower gastrointestinal tract stenosis is commonly diagnosed and is typically treated with surgery or endoscopic balloon dilation (EBD). Radial incision and cutting (RIC) is a novel treatment approach that has several benefits compared with EBD and surgery. Although RIC has demonstrated a high technical success rate and has been shown to improve subjective symptoms, previous studies revealed that restenosis after RIC remain unsolved. Herein, we report the design of a prospective, multicenter, single-arm, interventional, phase II trial to evaluate the safety of local triamcinolone acetonide (TA) administration and its feasibility in preventing restenosis after RIC for lower gastrointestinal tract stenosis. METHODS: The major inclusion criteria are age 20-80 years and the presence of benign stenosis in the lower gastrointestinal tract accessible by colonoscope. We will perform RIC followed by local administration of TA to 20 participants. The primary outcome is the safety of local TA administration, which will be assessed by determining the frequency of adverse events of special interest. The secondary outcomes are the technical success rate of RIC, duration of procedure, improvement in subjective symptoms, and duration of hospitalization. The outcomes, improvement in subjective symptoms, and long-term results will be evaluated using descriptive statistics, Student's t-test, and Kaplan-Meier curve, respectively. DISCUSSION: This explorative study will provide useful information regarding the safety of TA administration after RIC, which may contribute to further investigations.

OBJECTIVES: Narrow light observation is currently recommended as an alternative to Lugol chromoendoscopy (LCE) to detect esophageal squamous cell carcinoma (ESCC). Studies revealed little difference in sensitivity between the two modalities in expert settings; however, these included small numbers of cases. We aimed to determine whether blue light imaging (BLI) without magnification is satisfactory for preventing misses of ESCC. METHODS: This was a post-hoc analysis of a multicenter randomized controlled trial targeting patients at high risk of ESCC in expert settings. In this study, BLI without magnification followed by LCE was performed. The evaluation parameters included: (i) the diagnostic abilities of ESCC; (ii) the endoscopic characteristics of lesions with diagnostic differences between the two modalities; and (iii) the color difference between cancerous and noncancerous areas in BLI and LCE. RESULTS: This study identified ESCC in 49 of 699 cases. Of these cases, nine (18.4%) were missed by BLI but detected by LCE. In per-patient analysis, the sensitivity of BLI was lower than that of LCE following BLI (83.7% vs. 100.0%; P = 0.013), whereas the specificity and accuracy of BLI were higher (88.2% vs. 81.2%; P < 0.001 and 87.8% vs. 82.5%; P < 0.001, respectively). No significant endoscopic characteristics were identified, but the color difference was lower in BLI than in LCE (21.4 vs. 25.1; P = 0.003). CONCLUSION: LCE following BLI outperformed BLI in terms of sensitivity in patients with high-risk ESCC. Therefore, LCE, in addition to BLI, would still be required in screening esophagogastroduodenoscopy even by expert endoscopists.

Abstract Pancreatic cancer (PC) is a challenging malignancy to treat. Mac‐2‐binding protein glycan isomer (M2BPGi) is a novel serum marker of liver fibrosis and hepatocellular carcinoma and is secreted by hepatic stellate and stroma cells. Serum M2BPGi levels are upregulated in PC patients. We measured the expression of M2BPGi in the serum of 27 PC patients and determined whether M2BPGi affects the malignant potential of PC cells in vitro. We also examined the effect of M2BP on PC tumor growth and gemcitabine sensitivity in vivo. Serum M2BPGi levels in PC patients were higher compared with those of healthy subjects. M2BPGi extraction in cancer‐associated fibroblasts (CAFs) was higher compared with that of PC cells. M2BPGi treatment promoted the proliferation and invasion of PC cells. The suppression of galectin‐3, which binds to M2BPGi, did not affect the proliferation‐promoting effect of M2BPGi in PC cells. The suppression of M2BP reduced tumor growth and enhanced gemcitabine sensitivity in PC‐bearing xenograft mice. CAF‐derived M2BPGi promotes the proliferation and invasion of PC cells. Targeting M2BPGi may represent a new therapeutic strategy to circumvent refractory PC.

BACKGROUND: The association between thiopurine use and testicular reproductive functions remains unclear. In this study, we investigated whether thiopurines affect testicular functions based on the NUDT15 genotypes using Nudt15R138C knock-in mice. METHODS: The male Nudt15R138C knock-in mice (9-12 weeks) were treated with mercaptopurine (MP: 0.5 mg/kg/day) for 4 or 12 weeks. To examine reversibility, some mice were maintained for a further 12 weeks under MP-free condition. RESULTS: After MP treatment for 4 weeks, Nudt15R138C/R138C mice exhibited a significant reduction of testis weight compared to Nudt15+/+ mice and Nudt15+/R138C mice. The epithelial height and diameter of seminiferous tubules were significantly reduced in Nudt15R138C/R138C mice compared to Nudt15+/+ and Nudt15+/R138C mice. Apoptotic cells were significantly increased in Nudt15R138C/R138C mice, and most of apoptotic cells were spermatogonia. There were no significant changes in sperm counts and sperm morphology in MP-treated Nudt15R138C/R138C mice after 4-week MP treatment. On the other hand, after MP treatment for 12 weeks, the Nudt15+/R138C mice, but not Nudt15+/+ mice, exhibited a significant reduction in the testis weight and atrophic changes of seminiferous tubules, but these changes disappeared after 12-week rearing under MP-free condition. Despite a significant increase in abnormal sperm rate, there were no changes in the ability to conceive. No differences in serum levels of follicle-stimulating hormone or testosterone were observed between MP-treated Nudt15+/R138C and Nudt15+/+ mice after 12-week MP treatment. CONCLUSIONS: Thiopurines exert harmful effects on testicular reproductive function according to host NUDT15 genotypes.

AIM: Nucleos(t)ide analogs do not completely prevent hepatocellular carcinoma (HCC) in chronic hepatitis B virus infection. This study aimed to evaluate the dynamics of a non-invasive liver fibrosis marker, the Fibrosis-4 (FIB-4) index, for predicting HCC development. METHODS: Among a total of 882 chronically hepatitis B virus infection-infected patients who were treated with nucleos(t)ide analogs, 472 patients without HCC history whose FIB-4 at baseline and 1 year of treatment was obtained were evaluated for the incidence of HCC. RESULTS: The median FIB-4 was 2.00 at baseline and was significantly reduced to 1.58 at 1 year (P < 0.001), but the reduction was small at 2 years or later. When a receiver operating characteristic analysis of FIB-4 was performed to predict HCC within 5 years, the area under the curve of FIB-4 at 1 year was higher than that at baseline (0.676 vs. 0.599). The HCC incidence was significantly higher in patients with FIB-4 ≥1.58 than in those with FIB-4 <1.58 (14.8% vs. 3.6% at 10 years, P < 0.001). Additionally, an abnormal alanine aminotransferase (≥31 U/L) at 1 year was an independent risk for HCC. When a fibrosis and alanine aminotransferase-1 (FAL-1) score was evaluated as an applicable number of FIB-4 ≥1.58, and alanine aminotransferase ≥31 as 0, 1, and 2, the HCC risk in patients with score 2 was significantly higher than in those with score 1 or score 0 (24.1% vs. 9.8% vs. 0.7% at 10 years, P < 0.001). CONCLUSIONS: FIB-4 ≥1.58 and alanine aminotransferase ≥31 at 1 year of nucleos(t)ide analog was an independent risk factor for HCC development, and a score using these factors stratified the risk of HCC.

A 46-year-old Japanese man was referred to our hospital because of a marked increase in his eosinophil count (22,870/μL) and elevated liver enzyme levels. Computed tomography (CT) showed thrombi measuring approximately 8 cm in both femoral veins. A liver biopsy revealed eosinophilic infiltration, hepatocyte necrosis, fibrosis, and multiple thrombi. We suspected acute liver injury and deep vein thrombosis associated with hypereosinophilic syndrome and initiated steroids and heparin treatment. Four days after starting treatment, the patient experienced sudden chest pain and cardiopulmonary arrest. CT revealed bilateral pulmonary artery thrombosis, and despite administration of a tissue plasminogen activator, the patient died.

BACKGROUND/OBJECTIVES: The association between autoimmune pancreatitis (AIP) and pancreatic cancer (PC) remains controversial. This study aimed to clarify the long-term prognosis and risk of malignancies in AIP patients in Japan. METHODS: We conducted a multicenter retrospective cohort study on 1364 patients with type 1 AIP from 20 institutions in Japan. We calculated the standardized incidence ratio (SIR) for malignancies compared to that in the general population. We analyzed factors associated with overall survival, pancreatic exocrine insufficiency, diabetes mellitus, and osteoporosis. RESULTS: The SIR for all malignancies was increased (1.21 [95 % confidence interval: 1.05-1.41]) in patients with AIP. Among all malignancies, the SIR was highest for PC (3.22 [1.99-5.13]) and increased within 2 years and after 5 years of AIP diagnosis. Steroid use for ≥6 months and ≥50 months increased the risk of subsequent development of diabetes mellitus and osteoporosis, respectively. Age ≥65 years at AIP diagnosis (hazard ratio [HR] = 3.73) and the development of malignancies (HR = 2.63), including PC (HR = 7.81), were associated with a poor prognosis, whereas maintenance steroid therapy was associated with a better prognosis (HR = 0.35) in the multivariate analysis. Maintenance steroid therapy was associated with a better prognosis even after propensity score matching for age and sex. CONCLUSIONS: Patients with AIP are at increased risk of developing malignancy, especially PC. PC is a critical prognostic factor for patients with AIP. Although maintenance steroid therapy negatively impacts diabetes mellitus and osteoporosis, it is associated with decreased cancer risk and improved overall survival.

Background and study aims: Endoscopic hemostasis is a life-saving procedure for gastrointestinal bleeding; however, its training is often performed on real patients and during urgent situations that put patients at risk. Reports of simulation-based training models for endoscopic hemostasis are scarce. Herein, we developed a novel simulator called “Medical Rising STAR-Ulcer type” to practice endoscopic hemostasis with hemoclips and coagulation graspers. This study aimed to evaluate the reproducibility of the clinical difficulty of this model and the effectiveness of simulation-based training for clipping hemostasis.Patients and methods: This was a prospective educational study. Fifty gastroenterology resident doctors from Japan and Canada were recruited to participate in a simulation-based training program. The primary outcome was the success rate of clipping hemostasis. We measured differences in trainees’ subjective assessment scores and evaluated the co-occurrence network based on comments after training.Results: The hemostasis success rate of the trainees significantly increased after instruction (64% vs. 86%, p&lt;0.05). The success rate for ulcers in the upper body of the stomach (59%), a high-difficulty site, was significantly lower than that for ulcers in the antrum, even after feedback and instruction. Trainees’ self-perceived proficiency and confidence significantly improved after simulation-based training (p&lt;0.05). Co-occurrence network analysis showed that trainees valued a structured learning approach, acknowledged the simulator’s limitations, and recognized the need for continuous skill refinement. Conclusions: Our study demonstrates the potential of our simulation-based training model as a valuable tool for improving technical skills and confidence in trainees learning to perform endoscopic hemostasis.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy (EST) are essential skills for endoscopic cholangio-pancreatic procedures. However, these procedures have a high incidence of adverse events, and most training is currently patient-based. Herein, we aimed to develop an ERCP/EST simulator model to address the need for safer training alternatives, especially for learners with limited ERCP experience. METHODS: The model was designed to facilitate the use of actual endoscopic devices, supporting learning objectives that align with the components of the validated Bethesda ERCP Skill Assessment Tool (BESAT). BESAT focuses on skills such as papillary alignment and maintenance of duodenoscope position, gentle and efficient cannulation, controlled sphincterotomy in the correct trajectory, and guidewire manipulation. Thirty gastroenterology trainees used the simulator between May 2022 and March 2023, and their satisfaction was assessed using a visual analog scale (VAS) and pre- and post-training questionnaires. RESULTS: The novel simulator model comprises a disposable duodenal papillary portion, suitable for incision with an electrosurgical knife, alongside washable upper gastrointestinal tract and bile duct portions, designed for repeated use. The duodenal papillary portion enabled reproduction of a realistic endoscope position and the adverse bleeding events due to improper incisions. The bile duct portion allowed for the reproduction of fluoroscopic-like images, enabling learners to practice guidewire guidance and insert other devices. After training, the median VAS score reflecting the expectation for model learning significantly increased from 69.5 (interquartile range [IQR]:55.5-76.5) to 85.5 (IQR: 78.0-92.0) (P<0.01). All participants expressed their desire for repeated simulator training sessions. CONCLUSIONS: This innovative simulator serves as a practical educational tool, particularly beneficial for novices in ERCP. It facilitates hands-on practice with actual devices, enhancing procedural fluency and understanding of precise incisions to minimize the risk of bleeding complications during EST.

For pancreatic masses, an evaluation of their vascularity using contrast-enhanced ultrasonography can help improve their characterization. This study was designed to evaluate the utility and safety of contrast-enhanced transabdominal ultrasonography (CE-TUS) and endoscopic ultrasonography (CE-EUS) in the diagnosis of pancreatic masses including solid or cystic masses. This multi-center comparative open-label superiority study is designed to compare Plain (P)-TUS/EUS alone with P-TUS/P-EUS plus CE-TUS/CE-EUS. Three hundred and one patients with a total of 232 solid pancreatic masses and 69 cystic masses were prospectively enrolled. The primary endpoints are to compare the diagnostic accuracy between P-TUS/P-EUS alone and P-TUS/P-EUS plus CE-TUS/CE-EUS for both the TUS and EUS of solid pancreatic masses, and to compare the diagnostic accuracy between P-EUS alone and P-EUS plus CE-EUS in cystic pancreatic masses. The secondary endpoints are to compare the diagnostic sensitivity and specificity of P-TUS/P-EUS alone and P-TUS/P-EUS plus CE-TUS/CE-EUS for pancreatic solid/cystic masses, and the accuracy of P-TUS alone and P-TUS plus CE-TUS for pancreatic cystic masses. Other secondary endpoints included comparing the diagnostic sensitivity, specificity, and accuracy of CE-TUS, CE-EUS and CE-computed tomography (CT) for solid/cystic pancreatic masses. The safety, degree of effective enhancement, and diagnostic confidence obtained with CE-TUS/CE-EUS will also be assessed.

BACKGROUND/OBJECTIVE: Previous studies have demonstrated that sarcopenia is frequently observed in patients with chronic pancreatitis (CP). However, most studies have defined sarcopenia solely based on skeletal muscle (SM) loss, and muscle weakness such as grip strength (GS) reduction has not been considered. We aimed to clarify whether SM loss and reduced GS have different associations with clinical characteristics and pancreatic imaging findings in patients with CP. METHODS: One hundred two patients with CP were enrolled. We defined SM loss by the SM index at the third lumbar vertebra on CT (<42 cm2/m2 for males and <38 cm2/m2 for females), and reduced GS by < 28 kg for males and <18 kg for females. RESULTS: Fifty-seven (55.9 %) patients had SM loss, 21 (20.6 %) had reduced GS, and 17 (16.7 %) had both. Patients with SM loss had lower body mass index, weaker GS, higher Controlling Nutritional Status score, lower serum lipase level, and lower urinary para-aminobenzoic acid excretion rate, suggesting worse nutritional status and pancreatic exocrine insufficiency. On CT, main pancreatic duct dilatation and parenchymal atrophy were more frequent in patients with SM loss than in those without it. Patients with reduced GS were older and had worse nutritional status than those without it. CONCLUSIONS: SM loss was associated with pancreatic exocrine insufficiency, low nutritional status, and pancreatic imaging findings such as parenchymal atrophy and main pancreatic duct dilatation, whereas older age and low nutritional status led to additional reduced GS.

Introduction: Although endoscopic balloon dilation (EBD) is a common therapeutic approach for managing strictures associated with Crohn's disease (CD), the clinical application and complication rates of EBD remain unclear. Methods: We collected admission data for patients who underwent EBD using a nationwide database. We compared EBD outcomes between ileal and colonic strictures, CD and ulcerative colitis, and CD and anastomotic strictures arising from cancer-related surgery. Subsequently, propensity score matching was employed to facilitate comparisons between each group. Results: The median duration of hospital stay was 4 days. Endoscopic hemostasis and urgent surgery rates after EBD for CD-related strictures were considerably low (0.035% and 0.11%, respectively). Most patients with CD underwent only one EBD procedure during a single admission. Although no significant differences in patient backgrounds and severe complications were observed between ileal and colonic stricture in CD, multiple EBD procedures were more commonly performed for ileal strictures than for colonic stricture. Moreover, EBD for ileal stricture was more frequently conducted in high-volume centers than in low-volume centers. Regarding severe complications after EBD, no significant differences were observed between CD-related strictures and ulcerative colitis or anastomotic strictures related to cancer surgery. Conclusion: Our findings support the safe and effective use of EBD for both ileal and colonic strictures associated with CD. The clinical practice and safety outcomes of EBD for CD-related strictures were comparable to those for strictures stemming from other etiologies.

Objective This study assessed the impact of dietary therapy and reduced body weight on the loss of skeletal muscle in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods This was a single-center retrospective observational study. We enrolled 129 patients with MASLD who had undergone dietary therapy at our facility. We assessed skeletal muscle mass using a bioelectrical impedance analysis (BIA) at the start of dietary treatment and 12 months after the first assessment. Variables related to muscle reduction were analyzed using a logistic regression model. Results One hundred and eighteen cases were analyzed, excluding those with missing data. In the muscle reduction group, there were more subjects with body weight reduction than in the control group (68% and 40%, respectively, p =0.002), and their body mass index (BMI) was decreased (-0.7 kg/m2 and +0.3 kg/m2, respectively, p =0.0003). There was a significant correlation between the changes in the BMI and muscle mass (R =0.48, p <0.0001). We standardized muscle mass change by dividing it by weight change to analyze the severe decrease in muscle mass compared to weight change. A logistic regression analysis revealed that type 2 diabetes mellitus (T2DM) was an independent variable related to severe skeletal muscle loss (odds ratio, 2.69; 95% CI: 1.13-6.42, p =0.03). Conclusion Weight loss is associated with skeletal muscle loss during dietary treatment for MASLD. T2DM is a risk factor for severe skeletal muscle loss.

BACKGROUND AND PURPOSE: Colorectal cancer progression from adenoma to cancer is a time-intensive process; however, the interaction between normal fibroblasts (NFs) with early colorectal tumors, such as adenomas, remains unclear. Here, we analyzed the response of the microenvironment during early tumorigenesis using co-cultures of organoids and NFs. MATERIALS AND METHODS: Colon normal epithelium, adenoma, cancer organoid, and NFs were established and co-cultured using Transwell inserts. Microarray analysis of NFs was performed to identify factors expressed early in tumor growth. Immunostaining of clinical specimens was performed to localize the identified factor. Functional analysis was performed using HCT116 cells. Serum DKK1 levels were measured in patients with colorectal cancer and adenoma. RESULTS: Colorectal organoid-NF co-culture resulted in increased organoid diameter and cell viability in normal epithelial and adenomatous organoids but not in cancer organoids. Microarray analysis of NFs revealed 18 genes with increased expression when co-cultured with adenoma and cancer organoids. Immunohistochemical staining revealed DKK1 expression in the tumor stroma from early tumor growth. DKK1 stimulation reduced HCT116 cell proliferation, while DKK1 silencing by siRNA transfection increased cell proliferation. Serum DKK1 level was significantly higher in patients with advanced cancer and adenoma than in controls. Serum DKK1 level revealed area-under-the-curve values of 0.78 and 0.64 for cancer and adenoma, respectively. CONCLUSION: These findings contribute valuable insights into the early stages of colorectal tumorigenesis and suggest DKK1 as a tumor suppressor. Additionally, serum DKK1 levels could serve as a biomarker to identify both cancer and adenoma, offering diagnostic possibilities for early-stage colon tumors. The present study has a few limitations. We considered using DKK1 as a candidate gene for gene transfer to organoids and NFs; however, it was difficult due to technical problems and the slow growth rate of NFs. Therefore, we used cancer cell lines instead. In addition, immunostaining and ELISA were based on the short-term collection at a single institution, and further accumulation of such data is desirable. As described above, most previous reports were related to advanced cancers, but in this study, new findings were obtained by conducting experiments on endoscopically curable early-stage tumors, such as adenomas.

INTRODUCTION: Limited data exist regarding the prevalence and clinical practice involving generic drugs and biosimilars for treating ulcerative colitis (UC) in Japan. We aimed to clarify the clinical usage of these generic drugs and biosimilars for UC treatment in Japan using a nationwide database. METHODS: We collected data from 30,675 UC cases, along with their prescriptions for both generic drugs or biosimilars and their original counterparts, using a medical claim database provided by DeSC Healthcare, Inc. We calculated the prescription and penetration rates of generic drugs and biosimilars and demonstrated the transition of these rates. Additionally, the cumulative retention rates between infliximab originator and biosimilar were compared using the Kaplan-Meier method. RESULTS: The prescription rate of generic mesalazine increased from approximately 10% in 2015 to over 30% in 2021. Although the prescription rate of generic molecular targeting drugs (MTDs) also increased from approximately 0.15% in 2014 to 2.5% in 2021, the increment was lower than that of generic mesalazine. The penetration rates of generic 5-aminosalicylic acid and tacrolimus ranged from over 30% to approximately 50%. Infliximab biosimilar achieved an approximate 20% penetration rate, whereas adalimumab achieved <5%. The cumulative retention rates did not differ between infliximab originator and biosimilar. CONCLUSIONS: The penetration rates of generics and biosimilars for UC treatment are relatively low compared with those for treatment in other fields and the goal of the Ministry of Health, Labor, and Welfare. Several countermeasures are necessary for the widespread use of generics and biosimilars, ultimately contributing to cost-effective and sustainable healthcare delivery.

INTRODUCTION: Limited data exist on the efficacy of combination therapy with ustekinumab and budesonide in patients with Crohn's disease. Our objective was to compare the clinical outcomes of ustekinumab and budesonide combination therapy with those of ustekinumab monotherapy. METHODS: In this phase 2 single-center, double-blind, randomized controlled trial, we assigned 19 patients with Crohn's disease with a Crohn's disease activity index (CDAI) equal to or greater than 220 and less than 450 in a 1:1 ratio to receive ustekinumab and budesonide or ustekinumab for 32 weeks. The primary endpoint was the clinical remission rate at 8 weeks. The secondary endpoints were the clinical remission rate at 32 weeks and mucosal healing rates at 8 and 32 weeks. RESULTS: Of 19 patients, the mean age was 37.8 years, and 42.1% were women (CDAI ≥220 and <450). There was no difference between combination therapy and ustekinumab monotherapy in terms of clinical remission rates (50.0% vs. 30.0%, p = 0.39 at 8 weeks and 37.5% vs. 20.0%, p = 0.41) and mucosal healing rates (75.0% vs. 90.0%, p = 0.40 and 37.5% vs. 60.0%, p = 0.34 at 8 and 32 weeks, respectively). The most common adverse event was an exacerbation of Crohn's. There were no differences in safety profiles between the two groups. CONCLUSIONS: Our study showed no difference between ustekinumab monotherapy and ustekinumab and budesonide combination therapy in terms of the induction and maintenance of remission (trial registration number: jRCTs021200013).

BACKGROUND: We compared the results of preoperative pancreatic juice cytology (PJC) and final pathological diagnosis after resection in patients who underwent resection of intraductal papillary mucinous neoplasm (IPMN) of the pancreas to determine whether preoperative PJC can help determine therapeutic strategies. METHODS: Of 1130 patients who underwent surgical resection IPMN at 11 Japanese tertiary institutions, the study included 852 patients who underwent preoperative PJC guided by endoscopic retrograde cholangiopancreatography (ERCP). RESULTS: The accuracy of preoperative PJC for differentiation between cancerous and noncancerous lesions were 55% for IPMN overall; 59% for the branch duct type; 49% for the main pancreatic duct type; 53% for the mixed type, respectively. On classifying IPMN according to the diameters of the mural nodule (MN) and main pancreatic duct (MPD), the corresponding values for diagnostic performance were 40% for type 1 (MN ≥5 mm and MPD ≥ 10 mm); 46% for type 2 (MN ≥5 mm and MPD < 10 mm); 61% for type 3 (MN < 5 mm and MPD ≥ 10 mm); 72% for type 4 (MN < 5 mm and MPD < 10 mm), respectively. CONCLUSIONS: PJC in IPMN is not a recommended examination because of its low overall sensitivity and no significant difference in diagnostic performance by type, location, or subclassification. Although the sensitivity is low, the positive predictive value is high, so we suggest that pancreatic juice cytology be performed only in cases where the patient is not sure about surgery.

A 53-year-old female patient, who had been treated for Crohn's disease for approximately 20 years, was admitted to our hospital with a chief complaint of persistent bloody stools. Colonoscopy, computed tomography, and magnetic resonance enterography revealed two stenoses of the ileum and multiple enlarged lymph nodes around the oral-side ileal stenosis. We accordingly performed transoral double-balloon enteroscopy and found ileal stenosis with an irregular mucosal surface. Based on pathological examination of the stenosis, adenocarcinoma of the small bowel was diagnosed for the oral-side stenosis. The stenosis on the anal side was benign. The two stenoses were resected simultaneously, and lymph node dissection was performed on the cancerous lesion. The diagnosis of the cancerous lesion was pStage IIIB, and immunohistochemical staining was positive for tumor protein 53. Patients with Crohn's disease are at a high risk of small bowel cancer, but no surveillance protocol has been established to date. We encountered a case of Crohn's disease in which radical surgery was possible, owing to preoperative pathological diagnosis, by using balloon-assisted enteroscopy. In this paper, we report a case that suggests the importance of performing balloon-assisted enteroscopy when small bowel stenosis is detected in patients with Crohn's disease.

It is difficult to determine whether an individual therapy contributes to the elongation of survival because of the difficulty of organizing clinical research in patients who receive multiple treatments in HCC. We aimed to establish a new model of survival prediction in patients with intermediate stage HCC to establish standards in the recent and coming multi-MTA era. This analysis was prepared using a data set of 753 patients diagnosed HCC prior to 2017. Multiple regression analysis showed age, naïve or recurrence, the size of the largest tumor nodule, the number of nodules, total bilirubin, albumin and α-fetoprotein as independent predictors of survival. A Weibull model had the best fit and, based on these predictors, we established a new predicted survival model. The survival duration can be predicted the proposed model; EXP (4.02580 + (- 0.0086253) × age + (- 0.34667) × (naïve/recurrence) + (- 0.034962) × (number of nodules) + (- 0.079447) × (the size of the largest nodule) + (- 0.21696) × (total bilirubin) + 0.27912 × (albumin) + (- 0.00014741) × (α-fetoprotein)) × (- natural logarithm(0.5))^0.67250. This model is useful for the planning and evaluating the efficacy of recent sequential therapies in multi-MTA era.

Objectives For preoperative biliary drainage (PBD) of malignant hilar biliary obstruction (MHBO), current guidelines recommend endoscopic nasobiliary drainage (ENBD) due to the higher risk of cholangitis after endoscopic biliary stenting (EBS) during the waiting period before surgery. However, few studies have supported this finding. Therefore, we aimed to compare the outcomes of preoperative ENBD and EBS in patients with MHBO. Methods Patients with MHBO who underwent laparotomy for radical surgery after ENBD or EBS were included from retrospectively collected data from 13 centers (January 2014 to December 2018). We performed a 1:1 propensity score matching between the ENBD and EBS groups. These patients were compared for the following: cholangitis and all adverse events (AEs) after endoscopic biliary drainage (EBD) until surgery, time to cholangitis development after EBD, postsurgical AEs, and in‐hospital death after surgery. Results Of the 414 patients identified, 355 were analyzed in this study (226 for ENBD and 129 for EBS). The matched cohort included 63 patients from each group. The proportion of cholangitis after EBD was similar between the two groups (20.6% vs. 25.4%, P = 0.67), and no significant difference was observed in the time to cholangitis development. The proportions of surgical site infections, bile leaks, and in‐hospital mortality rates were similar between the groups. Conclusion For PBD of MHBO, the proportion of AEs, including cholangitis, after EBD until surgery was similar when either ENBD or EBS was used.

BACKGROUND: Recent epidemiological studies suggested correlation between gastric cancer (GC) and periodontal disease. AIMS: We aim to clarify involvement of lipopolysaccharide of Porphyromonas gingivalis (Pg.), one of the red complex periodontal pathogens, in the GC development. METHODS: To evaluate barrier function of background mucosa against the stimulations, we applied biopsy samples from 76 patients with GC using a Ussing chamber system (UCs). K19-Wnt1/C2mE transgenic (Gan) mice and human GC cell-lines ± THP1-derived macrophage was applied to investigate the role of Pg. lipopolysaccharide in inflammation-associated carcinogenesis. RESULTS: In the UCs, Pg. lipopolysaccharide reduced the impedance of metaplastic and inflamed mucosa with increases in mRNA expression of toll-like receptor (TLR) 2, tumor necrosis factor (TNF) α, and apoptotic markers. In vitro, Pg. lipopolysaccharide promoted reactive oxidative stress (ROS)-related apoptosis as well as activated TLR2-β-catenin-signaling on MKN7, and it increased the TNFα production on macrophages, respectively. TNFα alone activated TLR2-β-catenin-signaling in MKN7, while it further increased ROS and TNFα in macrophages. Under coculture with macrophages isolated after stimulation with Pg. lipopolysaccharide, β-catenin-signaling in MKN7 was activated with an increase in supernatant TNFα concentration, both of which were decreased by adding a TNFα neutralization antibody into the supernatant. In Gan mice with 15-week oral administration of Pg. lipopolysaccharide, tumor enlargement with β-catenin-signaling activation were observed with an increase in TNFα with macrophage infiltration. CONCLUSIONS: Local exposure of Pg. lipopolysaccharide may increase ROS on premalignant gastric mucosa to induce apoptosis-associated barrier dysfunction and to secrete TNFα from activated macrophages, and both stimulation of Pg. lipopolysaccharide and TNFα might activate TLR2-β-catenin-signaling in GC.

OBJECTIVES: We aimed to clarify the clinical utility of measuring serum pancreatic enzymes after endoscopic retrograde cholangiopancreatography (ERCP) for the purpose of predicting post-ERCP pancreatitis (PEP) by a meta-analysis of diagnostic test accuracy studies. METHODS: Studies on the prediction accuracy of PEP by serum amylase or lipase measured at 2, 3, and 4 h after ERCP were collected. A literature search was performed in PubMed and the Cochrane Library database for studies published between January 1980 and March 2023. The quality of individual studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. Data were analyzed using Meta-DiSc 2.0 software. RESULTS: We searched the databases and identified 20 observational studies (12,313 participants). PEPs were defined according to criteria by Cotton or modified Cotton, revised Atlanta criteria, or the Japanese criteria. Meta-analysis of eight studies (4389 participants) showed a pooled sensitivity of 71.1% (95% confidence interval [CI] 56.1-82.5) and pooled specificity of 91.2% (95% CI 85.9-94.6) for the serum amylase cut-off value at 3 times the upper limit of normal (ULN). Another meta-analysis of five studies (1970 participants) showed a pooled sensitivity of 85.8% (95% CI 61.9-95.7) and pooled specificity of 85.3% (95% CI 81.9-88.1) for the serum lipase cut-off value at 3 times ULN. CONCLUSION: Despite a high risk of bias due to various reference standards, this updated meta-analysis and the utility assessment by a decision tree showed the utility of serum amylase or lipase levels more than 3 times ULN measured 2-4 h after ERCP for predicting PEP.

The usefulness of NUDT15 genotyping as a pharmacogenomic test for thiopurine has been established. The first such test developed to date, NUDT15 genotyping was approved for reimbursement in Japan in February 2019 for all indicated patients. We retrospectively examined claims data in Japan and confirmed that the proportion of patients who undergo genotyping before initiating a new thiopurine regimen has increased; furthermore, genotyping has improved the rate of treatment continuation and reduced on-treatment hospitalization. However, the genotyping rate before thiopurine induction was >50% for patients with inflammatory bowel disease and <20% for those with other immune-related diseases, indicating significant variation by disease field. Additionally, over 10% of tests were found to have been performed inappropriately, such as multiple genotyping of the same patient or testing more than 2 weeks after starting treatment. Although NUDT15 genotyping for patients requiring thiopurine treatment has been shown to improve thiopurine treatment continuation rate, measures are required to address the systematic issues identified in our analysis.

INTRODUCTION: The efficacy of antibiotics for diverticulitis without abscess or peritonitis (uncomplicated diverticulitis) is controversial. We aimed to investigate the effectiveness of antibiotics for uncomplicated diverticulitis. METHODS: We collected admission data for patients with acute uncomplicated diverticulitis using a nationwide database. We divided eligible admissions into two groups according to antibiotic initiation within 2 days after admission (antibiotic group vs. nonantibiotic group). We conducted propensity score matching and compared the rates of surgery (intestinal resection and stoma creation), in-hospital death, and medical costs between the groups. We also performed multivariate analysis to identify the clinical factors that affect surgery. RESULTS: We enrolled 131,936 admissions; among these, we obtained 6,061 pairs after propensity score matching. Rates of both intestinal resection and stoma creation in the antibiotic group were lower than those in the nonantibiotic group (0.61 vs. 3.09%, p &lt; 0.0001, and 0.08 vs. 0.26%, p = 0.027, respectively). Median costs in the antibiotic group were higher than those in the nonantibiotic group (315,820 JPY vs. 300,175 JPY, p &lt; 0.0001, respectively). Multivariate analysis showed that non-initiation of antibiotics within 2 days after admission was a clinical factor that increased the risk of intestinal resection (odds ratio [OR] = 5.19, 95% confidence interval [CI]: 4.38-6.16, p &lt; 0.0001) and stoma creation (OR = 2.68, 95% CI: 1.53-4.70, p = 0.0006). CONCLUSION: Our results indicated that antibiotics for uncomplicated diverticulitis expected to have moderate to severe disease activity may reduce the risk of intestinal resection and stoma creation. Further investigations are warranted.

BACKGROUND: /Objectives: Pediatric acute pancreatitis (AP) is not as rare as previously thought, and an increased incidence thereof has been reported. We aimed to clarify the trends and clinical characteristics of pediatric AP in Japan. METHODS: We utilized the Japanese Diagnosis Procedure Combination inpatient database for patients admitted between April 2012 and March 2021, and extracted the data of patients whose principal diagnosis was AP (ICD-10 code K85) or in whom AP accounted for most of the medical expenses. Patients were classified into pediatric (≤18 years) and adult (age >18 years) groups. RESULTS: We included 3941 AP cases in pediatrics and 212,776 in adults. AP cases accounted for 0.08 % of all admissions in pediatrics and 0.33 % in adults, with upward trends during the study period. The proportion of AP patients among all admissions was increased with advancing age in pediatrics. Compared to adults, pediatric AP patients had a smaller proportion of severe cases (22.9 % vs. 28.7 %; P < 0.001), fewer interventions for late complications (0.2 % vs. 1.3 %; P < 0.001), shorter hospital stays (mean 16.6 days vs. 18.0 days; P = 0.001), lower overall mortality (0.7 % vs. 2.9 %; P < 0.001), and lower mortality in severe cases (1.3 % vs. 5.6 %; P < 0.001). Pediatric cases were more frequently transferred from other institutions and treated at academic hospitals than adults (both P < 0.001). CONCLUSIONS: There was an upward trend in the proportion of AP among all admissions in pediatrics, with a lower risk of complications and mortality than adult cases.

BACKGROUND AND AIM: There is a scarcity of data on long-term outcomes in patients with new-onset ulcerative colitis (UC) in the era of biologics. We aimed to clarify the long-term prognosis of UC and the clinical practice of prescriptions for UC. METHODS: We collected 6689 new-onset UC cases using a medical claim database provided by DeSC Healthcare, Inc. We investigated the surgery-free, systemic steroid-free, and molecular targeting drug-free rates and compared their differences based on UC-onset age. We used multivariate analysis to identify clinical factors affecting long-term prognosis and investigated the transition of prescriptions for UC. RESULTS: The surgery-free, systemic steroid-free, and molecular targeting drug-free rates at 5 years post-UC diagnosis were 98.5%, 61.0%, and 88.7%, respectively. Pediatric patients had higher surgery-free rates compared with elderly patients and non-pediatric/non-elderly patients (P = 0.022), whereas the systemic steroid-free and molecular targeting drug-free rates were significantly lower (P< 0.0001, P < 0.0001, respectively). The retention rate of the first molecular targeting drug did not differ between drugs. The prescription rates of systemic steroid, immunomodulator, and molecular targeting drug increased from the second quarter in 2014 to the fourth quarter in 2021 (29.8%-39.1%, 6.8%-17.7%, and 7.6%-16.4%, respectively). CONCLUSIONS: We clarified the long-term prognosis and clinical practice of new-onset UC cases. The long-term outcome after UC onset might improve because of increasing use of new therapeutic agents. Further investigations are warranted.

INTRODUCTION: Cyclosporine or infliximab (IFX) have been used to avoid surgery in patients with severe refractory ulcerative colitis (UC). Tacrolimus (Tac) is occasionally used as an alternative to cyclosporine; however, the comparative efficacy of Tac and IFX has not been reported. We aimed to compare the effectiveness of Tac and IFX in hospitalized UC patients. METHODS: In a propensity score (PS)-matched cohort derived from a large nationwide database, 4-year effectiveness was compared between patients initiated on Tac or IFX. The primary outcome was the colectomy rate during the index hospitalization. We also analyzed the cumulative medication discontinuation, UC-related re-hospitalization, and colectomy rates after discharge. RESULTS: Among 29,239 hospitalized patients, 4,565 were extracted for eligibility, of whom 2,170 were treated with Tac and the remaining 2,395 with IFX. After PS matching, 1,787 patients were selected for each group. During the index hospitalization, excluding patients who switched to another molecular-targeted agent, the colectomy rate was higher in the Tac group than the IFX group (7.8% vs 4.2%, P <0.01). Among patients discharged without colectomy, the cumulative medication discontinuation (28.4% vs 17.1%, P <0.01) and re-hospitalization (22.4% vs 15.4%, P <0.01) rates were higher in the Tac group than the IFX group; however, there was no difference in the cumulative colectomy rate (3.3% vs 2.7%). CONCLUSIONS: Although Tac and IFX were effective for avoiding surgery in hospitalized UC patients, IFX was more effective than Tac. IFX also had higher long-term effectiveness. Future prospective studies comparing the efficacy of Tac and IFX is warranted.

Dual-specificity phosphatase 6 (DUSP6) is a specific phosphatase for mitogen-activated protein kinase (MAPK). In this study, we used a high-fat diet (HFD)-induced murine nonalcoholic fatty liver disease model to investigate the role of DUSP6 in this disease. Wild-type (WT) and Dusp6-haploinsufficiency mice developed severe obesity and liver pathology consistent with nonalcoholic fatty liver disease when exposed to HFD. In contrast, Dusp6-knockout (KO) mice completely eliminated these phenotypes. Furthermore, primary hepatocytes isolated from WT mice exposed to palmitic and oleic acids exhibited abundant intracellular lipid accumulation, whereas hepatocytes from Dusp6-KO mice showed minimal lipid accumulation. Transcriptome analysis revealed significant down-regulation of genes encoding cytochrome P450 4A (CYP4A), known to promote ω-hydroxylation of fatty acids and hepatic steatosis, in Dusp6-KO hepatocytes compared with WT hepatocytes. Diminished CYP4A expression was observed in the liver of Dusp6-KO mice compared with WT and Dusp6-haploinsufficiency mice. Knockdown of DUSP6 in HepG2, a human liver-lineage cell line, also promoted a reduction of lipid accumulation, down-regulation of CYP4A, and up-regulation of phosphorylated/activated MAPK. Furthermore, inhibition of MAPK activity promoted lipid accumulation in DUSP6-knockdown HepG2 cells without affecting CYP4A expression, indicating that CYP4A expression is independent of MAPK activation. These findings highlight the significant role of DUSP6 in HFD-induced steatohepatitis through two distinct pathways involving CYP4A and MAPK.

Abstract Background The development of synchronous multiple primary cancers is one of the major causes of death in patients with head and neck cancer. Herein, we report a case of synchronous intraductal papillary mucinous carcinoma (IPMC), invasive in a patient with maxillary gingival carcinoma. Case presentation A 73-year-old female visited our hospital complaining of a mass on the left side of the maxillary gingiva. Intraorally, an exophytic tumor, 50 × 25 mm in size, was found on the gingiva of the left maxillary posterior, and a diagnosis of squamous cell carcinoma was revealed by cytology. Emission tomography/ computed tomography with 18 Fluorodeoxyglucose-Positron (18FDG- PET/ CT) showed increased accumulation in the left maxillary gingiva, the left side of cervical lymph nodes, and the main pancreatic duct. The pancreatic ductal tumor was performed the biopsy at esophagogastroduodenoscopy (EGD) and resulted in a pathological diagnosis of IPMC, invasive. The patient was diagnosed as synchronous double primary cancers consisting of maxillary gingival carcinoma cT4aN2bM0 and IPMC, invasive cT3N0M0. She refused radical treatment, and died 11 months later. Conclusion 18FDG- PET/ CT, EGD and multidisciplinary approach is required for the detection and determining the treatment strategy of synchronous double primary cancers.

Several pancreatitis-related genetic variants have been identified. Recently, the association of loss-of-function variants in the transient receptor potential cation channel subfamily V member 6 (TRPV6) gene and early-onset non-alcoholic chronic pancreatitis (CP) has been reported. However, detailed clinical presentation of the cases carrying TRPV6 variants remains largely unknown. We report a case of early CP carrying a TRPV6 variant in which recurrent attacks of pancreatitis were successfully managed by pancreatic duct stenting. A 12-year-old boy with CP was referred to our hospital for further investigation. He had experienced recurrent pancreatitis attacks since he was 11 years old. Pancreatic ductal anomalies were not identified on magnetic resonance cholangiopancreatography. Genetic analysis revealed that the patient had a loss-of-function TRPV6 c.1448G > A (p.R483Q) variant in a heterozygous form. Conservative treatments were not effective; thus, we placed pancreatic duct stent by endoscopic intervention, and the frequency of relapses have dramatically decreased. We present the first pediatric report of early CP associated with the TRPV6 variant that was successfully treated with pancreatic duct stenting. This case suggests that pancreatic duct stenting is effective in preventing the relapse of pancreatitis related to the TRPV6 variant.

Immune checkpoint inhibitors (ICIs) sometimes induce immune-mediated hepatotoxicity (IMH), and corticosteroids and mycophenolate mofetil (MMF) are recommended for the treatment of IMH. However, there is no consensus on the treatment of IMH refractory to these drugs. Here, we report a case of refractory IMH that was successfully treated with tacrolimus. A 69-year-old man presented with liver injury after receiving durvalumab, an ICI, for lung cancer. He was diagnosed with IMH and received corticosteroids including methylprednisolone pulses and MMF, but his liver damage did not improve. Liver histology showed infiltration of inflammatory cells, mainly CD8 + T cells, in the portal area. Tacrolimus was added to corticosteroid and MMF to suppress mainly T cells. After the tacrolimus administration, the liver damage promptly improved. Since IMH is thought to be caused by activated CD8 + T-cell infiltration, T-cell suppression may be an effective treatment. This case suggests that tacrolimus may be an effective option for IMH refractory to corticosteroids or MMF if CD8 + T-cell infiltration is confirmed in the liver tissue.

Recently, the HLA-DQA1*05 (rs2097432) genetic variation has been reported to be linked to early infliximab (IFX) treatment failure in the Caucasian Crohn's disease (CD) population, but that evidence is scarce in the Asian population. This study aimed to investigate the relationship between rs2097432 and the cumulative discontinuation-free time of IFX (IFX persistence) in 189 Japanese biologics-naive CD patients. We also performed a genome-wide association study (GWAS) to discover novel genetic predictors for IFX persistence. The C allele of rs2097432 significantly increased the risk of early discontinuation of IFX [Hazard ratio (HR) = 2.23 and P-value = 0.026]. In GWAS, one locus tagged by rs73277969, located upstream of PPARGC1B which attenuates macrophage-mediated inflammation, reached genome-wide significance (HR = 6.04 and P-value = 7.93E-9). Pathway analysis suggested association of signaling by PDGF and FCGR activation signaling with IFX persistence (P-value = 8.56E-5 and 5.80E-4, respectively).

Genetic analysis of inflammatory bowel disease has identified many disease susceptibility genes in a large number of cases, mainly in Europe and North America. However, because of the ethnic differences in genetic background, analysis in various ethnic groups is needed. Although genetic analysis in East Asia began at the same time as in the West, the total number of patients analyzed has remained limited in Asia. To address these issues, meta-analyses across East Asian countries are underway, and the genetic analysis of inflammatory bowel disease in East Asians is entering a new phase. New findings on the genetic background factors associated with inflammatory bowel disease originating from East Asia have also been made, such as the association between chromosomal mosaic alteration and this disease. Genetic analysis has been conducted mainly through studies that consider patients as a group. Some of these results, such as the identified relationship between the NUDT15 gene and thiopurine-related adverse events, are beginning to be applied to the actual treatment of individuals. Meanwhile, genetic analyses of rare diseases have focused on the development of diagnostic methods and therapies by identifying causative gene mutations. Recently, genetic analysis has been moving from research on populations and pedigrees to the stage of identifying and using personal genetic information of each patient, which is important for personalized medical care. To achieve this, close collaboration between specialists in complex genetic analysis and clinicians will be critical.

BACKGROUND: The anti-diabetic drugs sodium glucose cotransporter 2 inhibitors (SGLT2is) and thiazolidinediones have beneficial effects on the liver dysfunction of patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus (T2DM). We aimed to determine the efficacy of these drugs for the treatment of liver disease in patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and T2DM. METHODS: We performed a retrospective study of 568 patients with MAFLD and T2DM. Of these, 210 were treating their T2DM with SGLT2is (n=95), 86 with pioglitazone, and 29 with both. The primary outcome was the change in fibrosis (FIB)-4 index between baseline and 96 weeks. RESULTS: At 96 weeks, the mean FIB-4 index had significantly decreased (from 1.79 ± 1.10 to 1.56 ± 0.75) in the SGLT2i group, but not in the pioglitazone group. The aspartate aminotransferase to platelet ratio index (APRI), serum aspartate and alanine aminotransferase (ALT), hemoglobin A1c, and fasting blood sugar significantly decreased in both groups (ALT: SGLT2i group, -17 ± 3 IU/L; pioglitazone group, -14 ± 3 IU/L). The body weight of the SGLT2i group decreased, but that of the pioglitazone group increased (-3.2 kg and +1.7kg, respectively). When the participants were allocated to two groups according to their baseline ALT (>30 IU/L), FIB-4 index significantly decreased in both groups. In patients taking pioglitazone, the addition of SGLT2i improves liver enzymes but not FIB-4 index for 96 weeks. CONCLUSIONS: SGLT2i treatment causes a larger improvement in FIB-4 index than pioglitazone in patients with MAFLD over 96 weeks. This article is protected by copyright. All rights reserved.

[BACKGROUND] Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein that contributes to the progression of various cancers, including pancreatic cancer. The higher expression of CTHRC1 in tumor tissues is associated with poorer survival outcomes. However, its specific roles in tumor extracellular matrix (ECM) remodeling remain unclear. Our study aims to investigate the influences of CTHRC1 on pancreatic stellate cells (PSCs), a main source of ECM production in pancreatic cancer. [METHODS AND RESULTS] The analyses of the publicly available pancreatic cancer patient data revealed that CTHRC1 is mainly expressed in cancer stroma and highly correlated with ECM-related genes. An in vitro study showed that more than 40% of these genes can be upregulated by CTHRC1. CTHRC1 specifically activated PSC into myofibroblast-like cancer-associated fibroblasts (myCAFs), which are characterized by a significantly upregulated POSTN gene expression. Periostin (coded by the POSTN gene) has a central role in the CTHRC1-PSCs-cancer metastasis axis. Furthermore, CTHRC1 promoted pancreatic cancer cell proliferation through PSC activation to a greater extent than via direct stimulation. Proof-of-concept experiments showed that the long-term (4-week) inhibition of CTHRC1 led to significant tumor suppression and ECM reduction, and also resulted in an unexpected shift in the CAF subtype from myCAFs to inflammatory CAFs (iCAFs). [CONCLUSION] PSC activation was demonstrated to be the key molecular mechanism responsible for the tumor-promoting effects of CTHRC1, and CTHRC1 has a critical role in CAF subtype differentiation and tumor microenvironment (TME) remodeling. The inhibition of CTHRC1 as a therapeutic strategy for the treatment of pancreatic cancer warrants further investigation.

Introduction Tramadol, a weak opioid anesthetic, is used for pain management in patients with cancer, but the effects of tramadol on cancer via µ-opioid receptor are still unknown. We assessed the effects of tramadol on pancreatic ductal adenocarcinoma using transgenic mice (LSL-Kras^G12D/+; Trp53^flox/flox; Pdx-1^cre/+). Methods Six-week-old transgenic mice were orally administered 10 mg/kg/day tramadol (n=12), 10 mg/kg/day tramadol and 1 mg/kg/day naltrexone (n=9), or vehicle water (n=14) until the humane endpoint. Cancer-related pain and plasma cytokine levels were assessed by the mouse grimace scale and cytokine array, respectively. Tumor status was determined histopathologically. Tramadol’s effects on proliferation and invasion in pancreatic ductal adenocarcinoma cell lines were studied in vitro. Results Tramadol with/without naltrexone improved mouse grimace scale scores while decreasing inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. Proliferative Ki-67 and cyclins decreased by tramadol, while local M1-like tumor-associated macrophages increased by tramadol, which was blocked by naltrexone. Meanwhile, tramadol with/without naltrexone reduced juxta-tumoral cancer-associated fibroblasts and M2-like tumor-associated macrophages. Tumor-associated neutrophils, natural killers, and cytotoxic T cells were not altered. Tramadol decreased the proliferative and invasive potentials of pancreatic ductal adenocarcinoma cell lines via decreasing cyclins/cyclin-dependent kinases, which was partially reversed by naltrexone. Conclusions These findings imply that tramadol might be a useful anesthetic for pancreatic ductal adenocarcinoma: inhibiting the proliferation and invasion along with increasing antitumor M1-like tumor-associated macrophages via the µ-opioid receptor, while improving cancer-associated pain possibly through the antitumor effects with the decrease of inflammatory cytokines.

OBJECTIVES: Clinical outcomes of endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) with esophageal varices (EVs) are obscure. We aimed to elucidate the clinical outcomes of ESD for ESCC with EVs in a multicenter, retrospective study. METHODS: We established a retrospective cohort of 30 patients with ESCC complicating EVs, who underwent ESD at 11 Japanese institutions. Rates of en bloc resection and R0 resection, procedure time, and adverse events were evaluated as indicators of the feasibility and safety of ESD. Additional treatment, recurrence, and metastasis of the lesions were evaluated as indicators of the long-term efficacy of ESD. RESULTS: Portal hypertension was caused by cirrhosis, of which alcohol was the most common cause. En bloc resection was achieved in 93.3% and R0 resection in 80.0% of the patients. The median procedure time was 92 min. Adverse events included a case of uncontrolled intraoperative bleeding leading to discontinuation of ESD and a case of esophageal stricture due to extensive resection. During the follow-up period of a median for 42 months, a patient with local recurrence and another patient with liver metastasis were observed. One patient died of liver failure after receiving chemoradiotherapy as an additional treatment after ESD. No patient died of ESCC. CONCLUSION: This multicenter, retrospective cohort study demonstrated the safety and efficacy of ESD for ESCC with EVs. Further studies are needed to establish appropriate treatment methods for EVs before ESD and additional treatments for patients with insufficient ESD.

Acquired hemophilia A (AHA) is a coagulation disorder related to the factor VIII inhibitors, which might cause intractable bleeding of gastrointestinal tracts. However, its scarcity makes it difficult to recognize AHA as a pitfall of endoscopic hemostasis failure. An 81-year-old female with a history of endoscopic treatment for colon polyps visited a local hospital with chief compliments of bloody stool and severe anemia. During several examinations for the bleeding origin, esophagogastroduodenoscopy depicted a 5 mm-sized hemorrhagic angioectasia of the duodenum, followed by treatment with argon plasma coagulation. However, hemostasis was not achieved by multiple sessions of endoscopic hemostasis and transcatheter arterial embolization, so blood transfusion was repeatedly done and she was transferred to our hospital. Laboratory data showed severe anemia with coagulation disorder. Based on the results of von Willebrand factor activity, factor VIII activity and factor VIII inhibitor, we diagnosed AHA as a comorbidity. Endoscopic hemostasis was confirmed only after improvement of APTT level and negative for the factor VIII inhibitor by hemostatic bypass treatment with recombinant active factor VII and immunosuppressive therapy with prednisolone and cyclophosphamide. In case of refractory bleeding of gastrointestinal tract, we should suspect of a comorbidity of coagulation disorder like AHA.

BACKGROUND/OBJECTIVES: The detection of malignancy is a major concern in the management of intraductal papillary mucinous neoplasm (IPMN). The height of the mural nodule (MN), estimated using endoscopic ultrasound (EUS) and computed tomography (CT), has been considered crucial for predicting malignant IPMN. Currently, whether surveillance using CT or EUS alone is sufficient for detecting MNs remains unclear. This study aimed to compare the ability of CT and EUS to detect MNs in IPMN. METHODS: This multicenter, retrospective observational study was conducted in 11 Japanese tertiary institutions. Patients who underwent surgical resection of IPMN with MN after CT and EUS examinations were eligible to participate. The MN detection rates between CT and EUS were examined. RESULTS: Two-hundred-and-forty patients who underwent preoperative EUS and CT had pathologically confirmed MNs. The MN detection rates of EUS and CT were 83% and 53%, respectively (p < 0.001). Additionally, the MN detection rate of EUS was significantly higher than that of CT regardless of morphological type (76% vs. 47% in branch-duct-type IPMN; 90% vs. 54% in mixed IPMN; 98% vs. 56% in main-duct-type IPMN; p < 0.001). Further, pathologically confirmed MNs ≥5 mm were more frequently observed on EUS than on CT (95% vs. 76%, p < 0.001). CONCLUSIONS: EUS was superior to CT for the detection of MN in IPMN. EUS surveillance is essential for the detection of MNs.

Duodenal varices are detected infrequently, and their rupture is very rare. We encountered an 87-year-old man who developed duodenal varices rupture during chemotherapy with atezolizumab and bevacizumab (ATZ/BV) for hepatocellular carcinoma. We identified massive bleeding of a ruptured varix in the horizontal portion of the duodenum with emergency esophagogastroduodenoscopy (EGD). Successful hemostasis was achieved by endoscopic injection sclerotherapy with Histoacryl. Although ATZ/BV can cause esophageal varices rupture, there have been no cases of duodenal varices rupture. We should take care to check the duodenal varices as well as esophagogastric varices before ATZ/BV treatment.

Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract with the following two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). To date, most IBD genetic associations were derived from individuals of European (EUR) ancestries. Here we report the largest IBD study of individuals of East Asian (EAS) ancestries, including 14,393 cases and 15,456 controls. We found 80 IBD loci in EAS alone and 320 when meta-analyzed with ~370,000 EUR individuals (~30,000 cases), among which 81 are new. EAS-enriched coding variants implicate many new IBD genes, including ADAP1 and GIT2. Although IBD genetic effects are generally consistent across ancestries, genetics underlying CD appears more ancestry dependent than UC, driven by allele frequency (NOD2) and effect (TNFSF15). We extended the IBD polygenic risk score (PRS) by incorporating both ancestries, greatly improving its accuracy and highlighting the importance of diversity for the equitable deployment of PRS.

Crosstalk among organs/tissues is important for regulating systemic metabolism. Here, we demonstrate inter-organ crosstalk between hepatic insulin and hypothalamic leptin actions, which maintains survival during food shortages. In inducible liver insulin receptor knockout mice, body weight is increased with hyperphagia and decreased energy expenditure, accompanied by increased circulating leptin receptor (LepR) and decreased hypothalamic leptin actions. Additional hepatic LepR deficiency reverses these metabolic phenotypes. Thus, decreased hepatic insulin action suppresses hypothalamic leptin action with increased liver-derived soluble LepR. Human hepatic and circulating LepR levels also correlate negatively with hepatic insulin action indices. In mice, food restriction decreases hepatic insulin action and energy expenditure with increased circulating LepR. Hepatic LepR deficiency increases mortality with enhanced energy expenditure during food restriction. The liver translates metabolic cues regarding energy-deficient status, which is reflected by decreased hepatic insulin action, into soluble LepR, thereby suppressing energy dissipation and assuring survival during food shortages.

BACKGROUND AND AIMS: Data about the detail of post-endoscopic submucosal dissection (ESD) bleeding in patients with early gastric cancer (EGC) who take antiplatelet agents (APAs), particularly in those taking thienopyridine and cilostazol, are lacking. We aimed to clarify the association between the status of APA medication and post-ESD bleeding risk. METHODS: This study is a secondary analysis using data from a recently conducted nationwide multicenter study in Japan. We retrospectively reviewed patients treated with APAs or on no antithrombotic therapy recruited from 33 institutions who underwent ESD for EGC between November 2013 and October 2016. The primary outcome of this study was the relationship between the rate of post-ESD bleeding and the status of each APA medication. RESULTS: A total of 9736 patients were included in the analysis. Among aspirin users (n=665), the continuation group was significantly associated with post-ESD bleeding (odds ratio [OR], 2.79; 95% confidence interval (CI), 1.77-4.37). Among thienopyridine users (n=227), the aspirin or cilostazol replacement group was not significantly associated with post-ESD bleeding (OR, 1.85; 95% CI, 0.72-4.78). Among cilostazol users (n=158), there was no significant association with post-ESD bleeding, irrespective of medication status. The rate of post-ESD bleeding was approximately 10-20% irrespective of the status of APA administration among dual antiplatelet therapy users. No patients experienced thromboembolic events in this study. CONCLUSIONS: Replacement of thienopyridine with aspirin/cilostazol may be acceptable for minimizing both the risk of post-ESD bleeding and thromboembolism in patients with EGC. In patients on cilostazol monotherapy undergoing ESD, continuation of therapy may be acceptable.

BACKGROUND: No studies have evaluated the relationship between lifestyle and synchronous gastric cancers (SGCs) in patients with endoscopic submucosal dissection (ESD) for early gastric cancers (EGCs). Using data from the Tohoku gastrointestinal (GI) study, we aimed to identify factors associated with SGCs. METHODS: Tohoku GI study is a multicenter prospective cohort study investigating the relationship between lifestyle and metachronous gastric cancers. Patients who had a schedule to undergo ESD for primary EGCs were enrolled. We used logistic regression analysis to examine the relationship of 15 candidate factors, including lifestyle, with the prevalence of SGCs in this study. RESULTS: Of 850 patients between 2016 and 2019, 16.0% (136 patients) had SGCs. In multivariate analysis, smoking history (odds ratio [OR], 1.93; p = 0.048) and severe atrophic gastritis assessed by pepsinogen (OR, 1.92; p = 0.004) were risk factors for the prevalence of SGCs. Regarding smoking, current smoking (OR, 2.33; p = 0.021), but not former smoking (OR, 1.76; p = 0.098), was a significant risk factor for its prevalence. In the stratified analysis, severe atrophic gastritis assessed by pepsinogen was a risk factor in patients without Helicobacter pylori (H. pylori) eradication (OR, 2.10; p = 0.002), but not a risk factor in those with H. pylori eradication (OR, 0.75; p = 0.737). CONCLUSION: Smoking history was a risk factor for the prevalence of SGCs in patients with ESD for EGCs, and severe atrophic gastritis assessed by pepsinogen was also a risk factor when H. pylori was not eradicated.

Relevant protein expression of GATA6, CK5, vimentin, and mucins using immunohistochemistry was assessed for predicting the prognosis of and chemotherapy efficacy in patients with pancreatic cancers (PCs). The protein expression was examined in 159 PCs resected after neoadjuvant chemotherapy (NAC-PCs) and compared with that of 120 matched biopsy specimens taken before NAC. KRAS mutations were assessed by digital PCR. NAC-PCs were classified by GATA6 expression initially and CK5 expression subsequently into 4 types: classical-type (n = 22) with GATA6-high (≥50%)/CK5-low (<10%) PCs; hybrid-type (n = 45) with GATA6-high/CK5-high (≥10%) PCs; basal-like-type (n = 53) with GATA6-low (<50%)/CK5-high (≥30%) PCs; and null-type (n = 39) with GATA6-low/CK5-low (<30%) PCs, which resulted in clear stratification of patient prognosis. The classical-type was associated with the most favorable prognosis, whereas the null-type was associated with the worst prognosis (multivariate hazard ratio: 3.56; 95% CI: 1.63-7.77; P = .0015). The hybrid and basal-like types correlated with in-between levels of prognosis. The risk of hepatic recurrence was lower in the classical-type than in null (multivariate odds ratio [mOR]: 0.18; 95% CI: 0.04-0.96; P = .0449) and basal-like (mOR: 0.24; 95% CI: 0.05-1.16; P =.0750) types. By contrast, the risk of locoregional recurrence was higher in the classical-type than in the basal-like-type (mOR: 5.03; 95% CI: 1.20-21.1; P = .0272). The hybrid-type was subclassified into transition and coexpression patterns with different gastric mucin expression levels. High levels of vimentin (≥10%, n = 30) in pre-NAC-PC tissues was associated with poor prognosis (P = .0256). Phenotypic transitions between pre-NAC and post-NAC-PCs were common (73/120; 61%). PCs with NAC regression grades 2 and 3 showed a transition to poorer prognostic phenotypes (P = .0497). KRAS mutations were not associated with these phenotypes. In conclusion, GATA6 and CK5 immunohistochemical expression phenotypes may stratify the survival of patients with NAC-PCs and reflect post-NAC phenotypic transitions associated with poor prognosis. Prompt evaluation of immunohistochemical phenotypes may contribute to designing a precision therapeutic strategy for patients with PCs.

BACKGROUND: Although additional treatment is considered for patients with esophageal squamous cell carcinoma (ESCC) invading into the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic submucosal dissection (ESD), the actual benefits of this method remain to be elucidated. AIMS: We aimed to evaluate the prognostic benefits of additional treatment in such patients. METHODS: Between 2006 and 2017, we enrolled patients with pT1a-MM/pT1b-SM ESCC after ESD at 21 institutions in Japan. Overall survival (OS) and disease-specific survival (DSS) were compared between the additional treatment and follow-up groups after propensity score matching, to reduce the bias of baseline characteristics. A subgroup analysis was performed according to the pathological findings: category A, pT1a-MM but negative for lymphovascular invasion (LVI) and vertical margin (VM); category B, tumor invasion into the submucosa ≤ 200 μm but negative for LVI and VM; category C, others. RESULTS: Of 593 patients with pT1a-MM/pT1b-SM ESCC after ESD, 101 matched pairs were extracted after propensity score matching. The OSs were similar between the additional treatment and follow-up groups (80.6% vs. 78.6% in 5 years; P = 0.972). In a subgroup analysis, the OS in the additional treatment group was significantly lower than that in the follow-up group (65.7% vs. 95.2% in 5 years; P = 0.037) in category A, whereas OS did not significantly differ in category C (76.8% vs. 69.5% in 5 years; P = 0.360). CONCLUSIONS: Additional treatment after ESD in patients with pT1a-MM/pT1b-SM ESCC was not associated with an improved prognosis.

BACKGROUND: We attempted to determine the indications and limitations of steroid therapy as the 1st line therapy in patients with autoimmune pancreatitis (AIP) with cyst formation (ACF). METHODS: This Japanese multicenter survey was conducted to examine the merits/demerits of steroid treatment as the initial therapy for ACF. RESULT: Data of a total of 115 patients with ACF were analyzed. Complete remission was achieved in 86% (86/100) of patients who had received steroid treatment, but only 33.3% (5/15) of patients who had not received steroids. Relapse after the remission (n=86) occurred in 7.6% (6/86) of patients who had received steroid therapy, but 40% (2/5) of patients who had not received steroid therapy. Multivariate analysis identified adoption of the wait&watch approach without steroid treatment (odds ratio=0.126, p<0.001) as a significant and independent negative predictor of remission of ACF. As for predictors of relapse, the presence of varix (odds ratio=5.83, p=0.036) was identified as an independent risk factor. CONCLUSION: Steroid therapy plays an important role as 1st line therapy in AIP patients with pancreatic cyst formation, however, varix formation, besides the diameter of the cyst(s), is a risk factor for refractoriness to steroid therapy.

BACKGROUND: The guidelines recommend additional gastrectomy after noncurative endoscopic resection for early gastric cancers (EGCs). However, no additional treatment might be acceptable in some patients aged ≥ 85 years. We aimed to identify this patient group using the data in a highly aged area. METHODS: We enrolled patients aged ≥ 85 years after noncurative endoscopic resection for EGCs at 30 institutions of the Tohoku district in Japan between 2002 and 2017. Treatment selection and prognosis after noncurative endoscopic resection were investigated. Fourteen candidates were evaluated using the Cox model to identify risk factors for poor overall survival (OS) in patients with no additional treatment. RESULTS: Of 1065 patients aged ≥ 85 years, 143 underwent noncurative endoscopic resection. Despite the guidelines' recommendation, 88.8% of them underwent no additional treatment. The 5-year OS rates in those with additional gastrectomy and those with no additional treatment were 63.1 and 65.2%, respectively. Multivariate analysis showed independent risk factors for poor OS in patients with no additional treatment were the high-risk category in the eCura system (hazard ratio [HR], 2.91), Charlson comorbidity index (CCI) ≥ 3 (HR, 2.78), and male (HR, 2.04). In patients with no additional treatment, nongastric cancer-specific survival was low (69.0% in 5 years), whereas disease-specific survival rates were very high in the low- and intermediate-risk categories of the eCura system (100.0 and 97.1%, respectively, in 5 years). CONCLUSIONS: No additional treatment may be acceptable in the low- and intermediate-risk categories of the eCura system in patients aged ≥ 85 years with noncurative endoscopic resection for EGCs.

OBJECTIVE: IgG4-related sclerosing cholangitis (IgG4-SC) is recognized as a benign steroid-responsive disease; however, little is known about the risk of development of cancer in patients with IgG4-SC and about how to counter this risk. DESIGN: We conducted a retrospective review of the data of 924 patients with IgG4-SC selected from a Japanese nationwide survey. The incidence, type of malignancy, and risk of malignancy in these patients were examined. Then, the standardized incidence ratio (SIR) of cancer in patients with IgG4-SC was calculated. RESULTS: Relapse was recognized in 19.7% (182/924) of patients, and cancer development was noted in 15% (139/924) of patients. Multivariate analysis identified only relapse as an independent risk factor for the development of cancer. In most of these patients with pancreato-biliary cancer, the cancer developed within 8 years after the diagnosis of IgG4-SC. The SIR for cancer after the diagnosis of IgG4-SC was 12.68 (95% confidence interval [CI] 6.89-8.79). The SIRs of cancers involving the biliary system and pancreas were 27.35 and 18.43, respectively. The cumulative survival rate was significantly better in the group that received maintenance steroid treatment (MST) than in the group that did not; thus, MST influenced the prognosis of these patients. CONCLUSION: Among the cancers, the risk of pancreatic and biliary cancers is the highest in these patients. Because of the elevated cancer risk, surveillance after the diagnosis and management to prevent relapse are important in patients with IgG4-SC to reduce the risk of development of cancer.

An otherwise healthy 45-year-old woman had been experiencing intermittent right upper abdominal pain for the past 1 year. Computed tomography showed pneumobilia and pancreatic duct emphysema despite a normal duodenal papilla. Magnetic resonance cholangiopancreatography and endoscopic ultrasound confirmed bile duct dilation but without a pancreaticobiliary maljunction. Duodenoscopy detected a slightly sunken, unfixed, and spontaneously enlarged duodenal papilla. During the cholangiogram, the Oddi sphincter was relaxed and the catheter could be easily inserted into the bile duct. Further, no findings suggestive of pancreaticobiliary maljunction were observed, and the contrast medium leaked spontaneously from the duodenal papilla. As biliary amylase level was high, we surmised the occurrence of occult pancreaticobiliary reflux due to relaxation of the Oddi sphincter. However, as there are no guidelines on the management of this condition, we did not offer any treatment. Nevertheless, the patient continued to experience similar symptoms and was retested 1 year later with similar results. As occult pancreaticobiliary reflux was reconfirmed, we suggested that the patient undergo laparoscopic extrahepatic bile duct resection and cholecystectomy, which is the standard treatment for pancreaticobiliary maljunction. Pathological evaluation revealed fibrous thickening of the bile duct wall and chronic cholecystitis, which are typical findings of pancreaticobiliary reflux. Even though pancreaticobiliary reflux is mainly observed in pancreaticobiliary maljunction, it has also been reported in normal patients. Here, we describe a novel mechanism of pancreaticobiliary reflux, namely, a relaxed or defective Oddi sphincter.

BACKGROUND: Although live-attenuated vaccines are contraindicated under immunosuppression, the immune status of patients with inflammatory bowel disease (IBD) has not been fully assessed prior to immunosuppressive therapy. AIMS: To investigate antiviral serostatus against viruses requiring live vaccines for prevention in IBD patients undergoing immunosuppressive therapy. METHODS: This multicenter study included IBD patients who were aged <40 years and were treated with thiopurine monotherapy, molecular-targeted monotherapy, or combination therapy. Gender- and age-matched healthy subjects (HS) living in the same areas were included as control group. Antibody titers against measles, rubella, mumps, and varicella were measured by enzyme-linked immunosorbent assays. RESULTS: A total of 437 IBD patients (163 ulcerative colitis [UC] and 274 Crohn's disease [CD]) and 225 HS were included in the final analysis. Compared with HS, IBD patients had lower seropositivity rates for measles (IBD vs. HS = 83.91% vs. 85.33%), rubella (77.55% vs. 84.89%), mumps (37.50% vs. 37.78%), and varicella (91.26% vs. 96.44%). Gender- and age-adjusted seropositivity rates were lower in UC patients than in both CD patients and HS for measles (UC, CD, and HS = 81.60%, 85.29%, and 85.33%), rubella (76.40%, 78.23%, and 84.89%), mumps (27.16%, 43.70%, and 37.78%), and varicella (90.80%, 91.54%, and 96.44%); the difference was significant for all viruses except measles. Divided by the degree of immunosuppression, there were no significant differences in seropositivity rates among IBD patients. CONCLUSIONS: IBD patients, especially those with UC, exhibit reduced seropositivity rates and may benefit from screening prior to the initiation of immunosuppressive therapy.

The expression of T-box transcription factor 3 (TBX3) has been identified in various cancers, including gastric cancers. Its role in breast cancers and melanomas has been intensively studied, and its contribution to the progression of cancers through suppressing senescence and promoting epithelial-mesenchymal transition has been reported. Recent reports on the role of TBX3 in gastric cancers have implied its involvement in gastric carcinogenesis. Considering its pivotal role in the initiation and progression of cancers, TBX3 could be a promising therapeutic target for gastric cancers.

Abstract Background and Aims Perianal lesion is a refractory phenotype of Crohn’s disease [CD] with significantly diminished quality of life. We evaluated the clinical characteristics of perianal lesions in newly diagnosed CD patients and the impact of perianal lesions on the quality of life in Japanese patients with CD. Methods Patients newly diagnosed with CD after June 2016 were included between December 2018 and June 2020 from the Inception Cohort Registry Study of Patients with CD [iCREST-CD]. Results Perianal lesions were present in 324 [48.2%] of 672 patients with newly diagnosed CD; 71.9% [233/324] were male. The prevalence of perianal lesions was higher in patients aged &amp;lt;40 years vs ≥40 years, and it decreased with age. Perianal fistula [59.9%] and abscess [30.6%] were the most common perianal lesions. In multivariate analyses, male sex, age &amp;lt;40 years and ileocolonic disease location were significantly associated with a high prevalence of perianal lesions, whereas stricturing behaviour and alcohol intake were associated with low prevalence. Fatigue was more frequent [33.3% vs 21.6%] while work productivity and activity impairment-work time missed [36.3% vs 29.5%] and activity impairment [51.9% vs 41.1%] were numerically higher in patients with than those without perianal lesions. Conclusions At the time of CD diagnosis, approximately half of the patients had perianal lesions; perianal abscesses and perianal fistulas were the most common. Young age, male sex, disease location and behaviour were significantly associated with the presence of perianal lesions. The presence of perianal lesion was associated with fatigue and impairment of daily activities. Clinical trials registry University Hospital Medical Information Network Clinical Trials Registry System [UMIN-CTR, UMIN000032237].

INTROODUCTION: Primary sclerosing cholangitis (PSC) is a rare disease, especially in Asian countries. PSC often develops during ulcerative colitis (UC). Little is known about the severity of PSC in patients with UC. Thus, this study aimed to investigate the impact of concomitant UC on the clinical course of patients with PSC using a nationwide database in Japan. METHODS: We collected data on patients who were admitted for PSC using a nationwide database and divided eligible admissions according to concomitant UC (PSC-UC group vs. PSC-alone group). We conducted propensity score matching and compared the rates of liver transplantation, biliary drainage, and other clinical events between the two groups. We also conducted a multivariate analysis to identify the clinical factors that affect biliary drainage, cholangiocarcinoma, and liver transplantation. RESULTS: We enrolled 672 patients after propensity score matching. The rate of liver transplantation in the PSC-UC group was lower than that in the PSC-alone group (2.2 vs. 5.4%, p = 0.002), whereas the rate of biliary drainage did not differ between the two groups (38.1 vs. 33.8%, p = 0.10). On multivariate analysis, concomitant UC was identified as a clinical factor that decreased the risk of liver transplantation (odds ratio = 0.40, 95% confidence interval: 0.23-0.68, p = 0.0007). DISCUSSION: Concomitant UC in patients with PSC may decrease the risk of liver transplantation. The milder disease activity of PSC with UC is more likely compared to that of PSC without UC.

BACKGROUND: Based on the Japan Adjuvant Study Group of Pancreatic Cancer 01 study, the standard duration of adjuvant chemotherapy with S-1 (an oral 5-fluorouracil prodrug consisting of tegafur, gimeracil, and oteracil) in patients with resected pancreatic ductal adenocarcinoma (PDAC) was considered to be 6 months, but the impact of increasing its duration on postoperative survival was unknown. Here, the authors investigated this question by reviewing real-world data from a large cohort of patients with PDAC. METHODS: In total, 3949 patients who underwent surgery for PDAC during the study period followed by S-1 adjuvant chemotherapy in board-certified institutions were included. Based on the duration of S-1 chemotherapy, two subgroups were defined: a standard-duration group that included patients who were treated for 180 ± 30 days and a longer duration group that included patients who received treatment for >210 days. RESULTS: The median duration of S-1 chemotherapy was 167 days, with a mean ± standard deviation of 200 ± 193 days. After excluding patients who had a recurrence within 210 days after the initiation of adjuvant chemotherapy, postoperative recurrence-free survival (RFS) and overall survival (OS) in the standard-duration group (n = 1473) and the longer duration group (n = 975) were compared. RFS and OS did not differ significantly between the standard-duration and longer duration groups (5-year RFS: 37.8% vs. 36.2% respectively; p = .6186; 5-year OS: 52.8% vs. 53.4%, respectively; p = .5850). The insignificant difference was verified by multivariate analysis and propensity-score matching analysis. CONCLUSIONS: The current findings suggest that extending S-1 adjuvant chemotherapy beyond 6 months has no significant additional effect on survival in patients with PDAC. This could be useful in determining whether to extend S-1 chemotherapy in patients who have completed the standard 6-month treatment.

There have been many reports on serologic autoantibodies in inflammatory bowel diseases (IBD),1 consisting of ulcerative colitis (UC) and Crohn's disease (CD), and recently Kuwada et al2 reported a new autoantibody against integrin αvβ6 with high sensitivity and specificity for UC. Concurrently, we had discovered autoantibodies against endothelial protein C receptor (EPCR) in Takayasu arteritis (TAK), which is sometimes complicated by UC.3 Interestingly, this autoantibody was found in most patients with TAK associated with UC, and we found that the positivity rate in patients with UC without TAK was also high, suggesting that anti-EPCR antibody is a candidate autoantibody useful for the diagnosis of UC.4 To clarify the diagnostic usefulness of anti-EPCR antibodies in patients with IBD and their relationship to several disease subphenotypes and their disease activities, we analyzed the serum samples from patients with IBD and non-IBD control subjects in Japan and the United States.

OBJECTIVES: Blue light imaging (BLI) and linked color imaging (LCI) are superior to conventional white light imaging for detecting esophageal squamous cell carcinoma (ESCC). Hence, we compared their diagnostic performances in ESCC screening. METHODS: This open-labeled, randomized controlled trial was performed at seven hospitals. Patients with a high risk of ESCC were randomly assigned to the BLI group (BLI followed by LCI) and LCI group (LCI followed by BLI). The primary endpoint was the detection rate of ESCC in the primary mode. The main secondary endpoint was its miss rate in the primary mode. RESULTS: In total, 699 patients were enrolled. The detection rate of ESCC did not significantly differ between the BLI and LCI groups [4.0% (14/351) vs. 4.9% (17/348); p = 0.565]; however, the number of patients with ESCC tended to be smaller in the BLI group (19 vs. 30). Notably, the miss rate of ESCC was lower in the BLI group [26.3% (5/19) vs. 63.3% (19/30); p = 0.012] and LCI detected no ESCCs missed by BLI. The sensitivity was higher in BLI (75.0% vs. 47.6%; p = 0.042); on the other hand, the positive predictive value in BLI tended to be lower (28.8% vs. 45.5%; p = 0.092). CONCLUSIONS: The detection rates of ESCC did not significantly differ between BLI and LCI. Although BLI may have a potential to be advantageous over LCI for the diagnosis of ESCC, it is still unclear whether BLI is superior to LCI, and a further large-scale study is needed.

Pancreatic cancer is notorious for its dismal prognosis. The enhanced permeability and retention (EPR) effect theory posits that nanomedicines (therapeutics in the size range of approximately 10-200 nm) selectively accumulate in tumors. Nanomedicine has thus been suggested to be the "magic bullet"-both effective and safe-to treat pancreatic cancer. However, the densely fibrotic tumor microenvironment of pancreatic cancer impedes nanomedicine delivery. The EPR effect is thus insufficient to achieve a significant therapeutic effect. Intratumoral fibrosis is chiefly driven by aberrantly activated fibroblasts and the extracellular matrix (ECM) components secreted. Fibroblast and ECM abnormalities offer various potential targets for therapeutic intervention. In this review, we detail the diverse strategies being tested to overcome the fibrotic barriers to nanomedicine in pancreatic cancer. Strategies that target the fibrotic tissue/process are discussed first, which are followed by strategies to optimize nanomedicine design. We provide an overview of how a deeper understanding, increasingly at single-cell resolution, of fibroblast biology is revealing the complex role of the fibrotic stroma in pancreatic cancer pathogenesis and consider the therapeutic implications. Finally, we discuss critical gaps in our understanding and how we might better formulate strategies to successfully overcome the fibrotic barriers in pancreatic cancer.

From the perspective of diversity in the medical field, the relationship between physicians and medical staff is one of the important factors. In this study, a survey was conducted on female doctors for 136 medical staff who are deeply involved in gastroenterology. Furthermore, another survey was conducted on 10 female doctors in gastroenterology regarding their relationship with the medical staff and their work-life balance. Consequently, 89% of the medical staff had experienced a situation where they relied on female doctors. Seventy-eight percent felt a necessity for female doctors, and it was observed that the demand for female doctors in gastroenterology would remain high in the future. Conversely, regarding the necessity of female doctors, 22% responded "neither agree nor disagree," and several of them believed that the personal qualities of a doctor were the most significant versus being a female. Moreover, it was noted that the idea of genderless thinking is becoming prevalent in the medical field. In addition, half of the female doctors considered gastroenterology to be a workplace that is easy for female doctors. The most common reason was that it broadens the options for working styles because skills, including gastrointestinal endoscopy and ultrasonography, can be acquired. Ninety percent of female doctors had no experience of trouble with medical staff due to being female. Conversely, 80% responded that they could work smoothly with staff in their interactions with female patients. Since medical treatment is based on gender differences, it is difficult not to be aware of them. Creating an environment wherein female doctors are freed from gender stereotypes and can utilize being female as one of their abilities while responding to the needs of patients and the medical field will be necessary.

Objective The use of a proton pump inhibitor (PPI) reduces rebleeding and mortality in patients with upper gastrointestinal bleeding (UGIB). Vonoprazan is a novel oral agent with strong and sustained acid-inhibitory activity. We clarified the effect of vonoprazan compared with oral PPIs in such patients. Methods We analyzed the Diagnosis Procedure Combination database. The primary outcome was rebleeding, and secondary outcomes were in-hospital mortality and in-hospital mortality after rebleeding. Propensity score matching was performed to balance the comparison groups, and logistic regression analyses were used to compare the outcomes between vonoprazan and oral PPIs. Patients Patients on vonoprazan or oral PPIs who underwent endoscopic hemostasis for UGIB between 2014 and 2019 were included. Results We enrolled 78,964 patients, of whom 27,101 and 51,863 were prescribed vonoprazan and a PPI, respectively. After propensity score matching, the rebleeding rate of vonoprazan did not significantly differ from that of oral PPIs [6.4% vs. 6.1%; odds ratio (OR), 1.05; 95% confidence interval (CI), 0.98-1.13]; similarly, the in-hospital mortality rate (1.4% vs. 1.5%; OR, 0.91; 95% CI, 0.79-1.05) and in-hospital mortality after rebleeding (0.3% vs. 0.2%; OR, 1.09; 95% CI, 0.78-1.54) also did not significantly differ between the groups. The acquired findings were robust across dose-restricted analyses and several sensitivity analyses. Conclusion Rebleeding and in-hospital mortality risks in patients on vonoprazan were similar to those in patients on oral PPIs. Considering the higher cost of vonoprazan, oral PPIs might be an optimal oral agent as an acid-suppressive therapy in such patients.

BACKGROUND: PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition. METHODS: We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction. RESULTS: We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77-0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression. CONCLUSIONS: The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection.

Palmoplantar pustulosis (PPP) is a chronic skin inflammatory disease in which blisters and pustules repeatedly develop on palms and soles. PPP is often refractory to topical therapy, oral therapy, phototherapy, and biologics that are usually applied for PPP. We report a patient with PPP improved by vedolizumab (anti-α4β7 integrin antibody) treatment for ulcerative colitis, suggesting the possibility of a new molecular target for PPP therapy.

Some patients present gastro-duodenal eosinophilia without abdominal symptoms. Nine cases with gastro-duodenal eosinophilia were seen at the Tohoku University Hospital between January 2011 and June 2022. Seven (78%) patients had a background of allergic or hyper-eosinophilic disease. Esophagogastroduodenoscopy showed erosions (n=6), discoloration (n=4), ulcers (n=3), erythema (n=3), muskmelon-like appearance (n=2), and cracks (n=1). Two cases were asymptomatic with eosinophilic gastroenteritis (EGE)-like endoscopic findings, and two were symptomatic with normal endoscopic findings. The discrepancy between the abdominal symptoms and esophagogastroduodenoscopy findings suggests that clinicians should assess patients for background allergic disease, regardless of abdominal symptoms.

BACKGROUND AND AIM: Acute pancreatitis (AP) is a rare extraintestinal manifestation of inflammatory bowel disease (IBD). Several studies from Western countries have reported that the severity of AP in patients with IBD is similar to that in the general population; however, its severity in patients from Eastern countries in the era of biologics remains unclear. This study aimed to investigate the severity of AP in patients with IBD and the effect of biologics on the severity of AP using a nationwide database. METHODS: We divided 1138 eligible AP admissions from the Diagnosis Procedure Combination database system into IBD and non-IBD groups after propensity score matching, and compared the severity of AP. We divided the IBD group into ulcerative colitis (UC) and Crohn's disease (CD) subgroups and compared each with the non-IBD group. Logistic regression analysis was conducted to identify the clinical factors affecting acute pancreatitis. RESULTS: IBD and UC groups had lower rate of severe AP compared to the non-IBD group (13.7% vs 28.3%, P < 0.0001 and 11.0% vs 28.3%, P < 0.0001, respectively). There were no differences in the rates of severe AP between the CD and non-IBD groups. Multivariate analysis showed that biologics did not affect the severity of AP. CONCLUSION: The severity of AP in patients with IBD may be lower than that in the general population; biologics for IBD may not worsen its severity. Further prospective studies are required to clarify the severity of AP in patients with IBD.

BACKGROUND/OBJECTIVES: Proper assessment of disease activity and prediction of relapse are crucial for the management of autoimmune pancreatitis (AIP). The M-ANNHEIM-AiP-Activity-Score (MAAS) has been proposed to determine disease activity and predict relapse in German and Swedish patients with AIP. MAAS is calculated using six categories: pain report, pain control, exocrine insufficiency, endocrine insufficiency, imaging, and complications. This study aimed to clarify the usefulness of MAAS to predict relapse in Japanese patients with type 1 AIP. METHODS: We retrospectively analyzed 117 patients with type 1 AIP undergoing initial and maintenance steroid treatments at our institute between April 2006 and March 2021. AIP was diagnosed according to the Japanese Diagnostic Criteria for AIP 2018. We examined the association of MAAS with relapse during and after maintenance treatment. RESULTS: MAAS (median, 8 points) at the start of the initial treatment was reduced after treatment (median, 4 points; P < 0.001). A MAAS ≥11 points at the start of the initial treatment was associated with relapse. The initial treatment-induced reduction of MAAS<60% was more frequent in patients with relapse (75.0%) than in patients without relapse (37.6%; P = 0.007). MAAS at the start of maintenance treatment was higher for patients with relapse (median, 5 points) than that for patients without relapse (median, 4 points; P = 0.007). MAAS ≥4 points at the start of maintenance treatment was associated with subsequent relapse. CONCLUSIONS: MAAS is useful for predicting relapse in patients with type 1 AIP undergoing maintenance therapy.

BACKGROUND: The genetic background of inflammatory bowel diseases (IBDs) has been explored using genetic analysis techniques, such as genome-wide association studies for the population and whole-exome sequencing analyses of family lineages in cases of very early onset. SUMMARY: The results of genetic analysis for IBD indicated the involvement of innate and adaptive immune system variations and epithelial abnormalities in the pathogenesis of IBD. Several associated genes were also reported, indicating that IBD occurs in a heterogeneous population with an extremely diverse background. The genetic background of IBDs is currently being studied to understand not only its onset but also its prognosis, response to treatment, and adverse effects. In the future, it will be possible to use an individual's genetic information for determining appropriate treatment. In Japan, the NUDT15 polymorphism test is performed before administering thiopurine preparations. However, because of racial differences in genetic analysis, biased analysis toward some racial groups may result in overlooking important genetic backgrounds of IBD. KEY MESSAGE: Studies of IBDs in a more diverse range of races are expected to elucidate genetic factors through a transethnic analysis, thereby aiding the development of novel treatments and precision medicine for IBDs.

BACKGROUND: Recent advances in human genome research have provided evidence for genotype-phenotype associations, pathogenicity, and clinical actionability of variants and genomic risk prediction of disease. However, the return of individual genomic results to healthy individuals is fraught with ethical and practical complexity. METHODS: Individual genomic results were returned to BRCA1/2 pathogenic variant (PV) carriers of the Tohoku Medical Megabank cohort study participants with an information on hereditary breast and ovarian cancer syndrome (HBOC). One hundred and eighty participants, including 9 BRCA1/2 PV carriers, were asked about their willingness to receive individual genomic results, without revealing the gene name and related disorders, prior to the study. Of the 142 participants who responded, 103 showed willingness to know their genomic information. Each of the six BRCA1/2 PV carriers who consented to participate in the study received information about HBOC in person and underwent validation testing with blood resampling. RESULTS: All participants were in their 60s or 70s; of the four females and two males, two had a history of breast cancer and five had a family history of HBOC-related cancers. All participants appreciated the information, without remarkable negative psychological impact of the return, and intended to undergo clinical risk surveillance. Five participants were accompanied by family members while receiving the results, and three first-degree female relatives wished to undergo genomic testing at the hospital. CONCLUSIONS: Our results suggest that returning actionable genomic information to participants in a population-based genome cohort study is beneficial for preventing or providing early-stage intervention for associated diseases.

BACKGROUND: Coronavirus disease 2019 (COVID-19) vaccination is recommended for patients with inflammatory bowel disease (IBD); however, suppressed immune responses have been reported for fully vaccinated patients under immunosuppressive therapy, mainly from Western countries. We prospectively analyzed antibody titers of IBD patients in Asia induced by two-dose and additional dose of messengerRNA COVID-19 vaccine. METHODS: After measuring high-affinity antibody titers, factors associated with antibody titers were identified by multiple regression analyses using the following covariates: sex, age (≥60 or <60 years), disease type (Crohn's disease or ulcerative colitis), vaccine type (BNT162b2 or mRNA-1273), time from second/third vaccination, molecular-targeted agent (anti-tumor necrosis factor [TNF] agents, ustekinumab, vedolizumab, tofacitinib, or no molecular-targeted agents), thiopurine, steroid, and 5-aminosalicylic acid. RESULTS: Among 409 patients analyzed, mean titer was 1316.7 U/mL (SD, 1799.3); 403 (98.5%) were judged to be seropositive (≥0.8 U/mL), and 389 (95.1%) had neutralizing antibodies (≥15 U/mL). After the third vaccination, mean titer raised up to 21 123.8 U/mL (SD, 23 474.5); all 179 were seropositive, and 178 (99.4%) had neutralizing antibodies. In 248 patients with genetic data, there was no difference in mean titer after two/third doses between carriers and non-carriers of HLA-A24 associated with severe disease during COVID-19 infection. A multiple regression analyses using covariates revealed that older age, vaccine type (BNT162b2), time from second/third dose, anti-TNF agent, tofacitinib, and thiopurine were independently associated with lower antibody titers. CONCLUSIONS: Our findings further support the recommendation for COVID-19 vaccination in patients under immunosuppressive therapy, especially additional third dose for patients receiving anti-TNF agents and/or thiopurine or tofacitinib.

Mirogabalin, a selective voltage-gated calcium channel α2δ ligand, improves peripheral neuropathic pain; however, its effects on patients with cancers including pancreatic ductal adenocarcinoma (PDAC) remain unknown. We analyzed the effects of mirogabalin on a KPPC ( LSL-KrasG12D/+; Trp53flox/flox; Pdx-1cre/+ ) mouse model of PDAC. Six-week-old KPPC mice received oral mirogabalin (10 mg/kg/day) (n = 10) or vehicle water (n = 14) until the humane endpoint. Cancer-associated pain was evaluated using the scores of hunching and mouse grimace scale (MGS). Tumor status and plasma cytokine levels were determined using histopathological analysis and cytokine array, respectively. The effects of mirogabalin on the proliferative ability of PDAC cell lines were determined. The scores of the hunching and MGS improved after mirogabalin administration with a decrease in the plasma levels of inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interferon-γ. Although no significant difference in the survival rate was observed, mirogabalin significantly increased pancreatic tumor size and proliferative index of Ki-67 and cyclins. Local arginase-1 + M2-like tumor-associated macrophages and CD31 + tumor blood vessels increased after mirogabalin administration. In contrast, the number of α-smooth muscle actin weak+ cancer-associated fibroblasts, desmoplastic stroma, and CD8 + T cells decreased. Local myeloperoxidase + tumor-associated neutrophils and CD45R + B cells were unaltered. Mirogabalin enhanced the proliferative ability of PDAC cell lines with the upregulation of cyclins and CDKs; however, it inhibited the potential of pancreatic stellate cells in vitro . Therefore, our results suggest that mirogabalin improves cancer-associated pain but enhances the proliferative potential of PDAC in vitro and in vivo .

BACKGROUND AND AIM: The incidence and prevalence of psychiatric disorders are elevated in patients with inflammatory bowel disease (IBD). Whether psychiatric disorders could affect the clinical course of IBD is uncertain and controversial. We aimed to evaluate the impact of psychiatric disorders, particularly depression, on the clinical course of IBD using a nationwide database in Japan. METHODS: We collected data on admissions with IBD using the Diagnosis Procedure Combination database system introduced in Japan. We divided eligible admissions into IBD with and without depression groups using propensity score matching and compared the rates of surgery, use of molecular targeted drugs and biologics, systemic steroid administrations, and in-hospital death. We also conducted a logistic regression analysis to identify clinical factors affecting surgery, the use of molecular targeted drugs and biologics, and systemic steroid administrations. RESULTS: The rates of surgery, use of two or more molecular targeted drugs, systemic steroid administrations, and in-hospital deaths in the ulcerative colitis (UC) with depression group were higher than in the UC without depression group. Multivariate analysis of UC showed that depression increased the odds of systemic steroid administrations, use of two or more molecular targeted drugs, and surgery. However, analysis of Crohn's disease showed that only steroid administrations were associated with depression. CONCLUSION: Our study demonstrated an association between a worse clinical course of UC and depression. Although this result indicates that depression might be associated with increased disease activity in patients with UC, the causal relationship is still unclear. Further prospective studies are warranted.

Nucleos(t)ide analogues (NAs) suppress hepatitis B virus (HBV) replication, but the risk of hepatocellular carcinoma still remains. The presence of detectable HBV DNA in the serum during NA therapies for chronic hepatitis B patients has been reported to be associated with the risk of hepatocellular carcinoma. In this study, we investigated the antiviral effect of switching from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in chronic hepatitis B patients who had detectable HBV DNA in the serum at least once within a year. Among a total of 77 cases in 7 hospitals that switched NAs from ETV to TAF, 23 patients with detectable HBV DNA in a year before switching were analyzed. When the detection frequencies of HBV DNA in the 1st and 2nd years after switching to TAF were analyzed, they were significantly lower than those in the year before switching (68.8% vs. 34.1% for the 1st year and 21.3% for the 2nd year, P < 0.001 for both). The HBsAg decline tended to be larger after switching than before (-2.5% vs. -3.0% for 1st year and -3.1% for 2nd year), but the difference was not significant. One patient died of a cardiovascular event 11 months after the treatment switch, but no adverse effects due to TAF including renal function were observed. In conclusion, it was suggested that switching from ETV to TAF might be effective to suppress the HBV DNA level further in patients whose HBV DNA is detectable, even if at a very low level.

An unidentified cause of functional dyspepsia (FD) is closely associated with medication resistance. Acid suppression is a traditional and preferential method for the treatment of FD, but the efficacy of this treatment varies between epigastric pain syndrome (EPS) and postprandial syndrome (PDS): it is efficient in the former but not much in the latter. Transepithelial electrical resistance (TEER), a surrogate of mucosal barrier function, was measured under pH 3 and pH 5 acidic conditions using duodenal biopsy specimens obtained from the patients with EPS and PDS and asymptomatic healthy controls. The infiltration of inflammatory cells to the duodenal mucosa was accessed by immunohistochemical analysis. The duodenal mucosal TEER in EPS patients was decreased by exposure to the acidic solution compared to that of the controls and the PDS patients. The decrease in TEER of the EPS patients was observed even under pH 5 weak acidic condition and was correlated to degree of the epigastric pain. Moreover, the duodenal mucosa of EPS patients presented an increase in mast cells and plasma cells that expressed Ig-E. Duodenal mucosal vulnerability to acid is likely to develop EPS.

The type 2 Ca²⁺-dependent activator protein for secretion (CAPS2/CADPS2) regulates dense-core vesicle trafficking and exocytosis and is involved in the regulated release of catecholamines, peptidergic hormones, and neuromodulators. CAPS2 is expressed in the pancreatic exocrine acinar cells that produce and secrete digestive enzymes. However, the functional role of CAPS2 in vesicular trafficking and/or exocytosis of non-regulatory proteins in the exocrine pancreas remains to be determined. Here, we analyzed the morpho-pathological indicators of the pancreatic exocrine pathway in Cadps2-deficient mouse models using histochemistry, biochemistry, and electron microscopy. We used whole exosome sequencing to identify CADPS2 variants in patients with chronic pancreatitis (CP). Caps2/Cadps2-knockout (KO) mice exhibited morphophysiological abnormalities in the exocrine pancreas, including excessive accumulation of secretory granules (zymogen granules) and their amylase content in the cytoplasm, deterioration of the fine intracellular membrane structures (disorganized rough endoplasmic reticulum, dilated Golgi cisternae, and the appearance of empty vesicles and autophagic-like vacuoles), as well as exocrine pancreatic cell injury, including acinar cell atrophy, increased fibrosis, and inflammatory cell infiltration. Pancreas-specific Cadps2 conditional KO mice exhibited pathological abnormalities in the exocrine pancreas similar to the global Cadps2 KO mice, indicating that these phenotypes were caused either directly or indirectly by CAPS2 deficiency in the pancreas. Furthermore, we identified a rare variant in the exon3 coding region of CADPS2 in a non-alcoholic patient with CP and showed that Cadps2-dex3 mice lacking CAPS2 exon3 exhibited symptoms similar to those exhibited by the Cadps2 KO and cKO mice. These results suggest that CAPS2 is critical for the proper functioning of the pancreatic exocrine pathway, and its deficiency is associated with a risk of pancreatic acinar cell pathology.

Video 1Demonstration of novel simulator of endoscopic hemostasis.

BACKGROUND: Ustekinumab (UST), an antibody against the p40 subunit of interleukin-12/23, has been proven to be effective in patients with Crohn's disease (CD). However, large, long-term comparative studies of UST against anti--tumor necrosis factor (TNF) agents are lacking. We compared the effectiveness of anti-TNF agents and UST in CD patients without prior use of biologics. METHODS: We used a large nationwide anonymized Japanese database containing administrative medical claims data and various related patient data. In a propensity score-matched cohort with similar clinical characteristics, 2-year effectiveness was compared between patients treated with infliximab or adalimumab (anti-TNF group) and those treated with UST (UST group). Primary outcomes were cumulative rates of hospitalization, surgery, and persistence. RESULTS: Among 53 540 CD patients, 7047 were extracted for eligibility, of which 5665 were treated with an anti-TNF agent and 1382 with UST. After propensity score matching, the cumulative hospitalization rates were comparable between anti-TNF and UST groups (P = 0.85; 25.3% vs 26.5% at 1 year, 33.8% vs 39.8% at 2 years). The cumulative surgery rates were also comparable between these groups (P = 0.46; 5.5% vs 5.1% at 1 year, 8.3% vs 8.4% at 2 years). The persistence rate at 1 year was higher in UST group (90.8% vs 92.5%), and that at 2 years was higher in anti-TNF group (81.2% and 74.6%); however, there was no significant difference in the cumulative persistence rate (P = 0.55). CONCLUSIONS: Anti-TNF agents and UST appear to have comparable effectiveness for CD patients without prior use of biologics.

OBJECTIVES: We aimed to clarify the prognostic factors for patients with esophageal squamous cell carcinoma (ESCC) invading into the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic submucosal dissection (ESD). METHODS: This retrospective study enrolled such patients at 21 institutions in Japan between 2006 and 2017. We evaluated 15 factors, including pathological risk categories for ESCC-specific mortality, six non-cancer-related indices, and treatment strategies. RESULTS: In the analysis of 593 patients, the 5-year overall and disease-specific survival rates were 83.0% and 97.6%, respectively. In a multivariate Cox analysis, male sex (hazard ratio [HR] 3.56), Charlson comorbidity index (CCI) ≥3 (HR 2.53), ages of 75-79 (HR 1.61) and ≥80 years (HR 2.04), prognostic nutrition index (PNI) <45 (HR 1.69), and pathological intermediate-risk (HR 1.63) and high-risk (HR 1.89) were prognostic factors. Subsequently, we developed a clinical risk classification for non-ESCC-related mortality based on the number of prognostic factors (age ≥75 years, male sex, CCI ≥3, PNI <45): low-risk, 0; intermediate-risk, 1-2; and high-risk, 3-4. The 5-year non-ESCC-related mortality rates for patients without additional treatment were 0.0%, 10.2%, and 45.8% in the low-, intermediate-, and high-risk groups, respectively. Meanwhile, the 5-year ESCC-specific mortality rates for the pathological low-, intermediate-, and high-risk groups were 0.3%, 5.3%, and 18.2%, respectively. CONCLUSIONS: We clarified prognostic factors for patients with pT1a-MM/pT1b-SM ESCC after ESD. The combined assessment of non-ESCC- and ESCC-related mortalities by the two risk classifications might help clinicians in deciding treatment strategies for such patients.

BACKGROUND: There has been an increasing number of elderly patients with intraductal papillary mucinous neoplasm (IPMN), who are surgically intolerant and require less invasive treatment options, which are limited. In the present study, we report a case of IPMN presenting with acute recurrent pancreatitis (ARP), in which radiation therapy effectively prevented further attacks of ARP and reduced tumor volume. CASE SUMMARY: An 83-year-old man was referred to our hospital with an asymptomatic incidental pancreatic cyst. Endoscopic ultrasound imaging and magnetic resonance cholangiopancreatography revealed a multiloculated tumor in the head of the pancreas, with dilated pancreatic ducts and mural nodules. The patient was diagnosed with mixed-type IPMN, and five years later, he developed ARP. Several endoscopic pancreatic ductal balloon dilatations failed to prevent further ARP attacks. Surgery was considered clinically inappropriate because of his old age and comorbidities. He was referred to our department for radiation therapy targeted at those lesions causing intraductal hypertension and radiation was administered at a dose of 50 Gy. An magnetic resonance imaging scan taken ten weeks after treatment revealed a decrease in tumor size and improvement of pancreatic duct dilatation. Fourteen months later, he remains symptom-free from ARP. CONCLUSION: This case highlights the important role of radiation therapy in mitigating the signs and symptoms of ARP in patients with inoperable IPMN.

BACKGROUND: The appropriate method of preoperative endoscopic biliary drainage (EBD) for cholangiocarcinoma with hilar biliary obstruction remains controversial. The inside-stent technique is a method of placing plastic stents entirely inside the bile duct. Several studies of patients with unresectable stage have reported longer stent patency compared with conventional endoscopic biliary stenting (EBS). Inside-stent techniques have been introduced as a bridge-to-surgery option and as an alternative to conventional EBS. AIMS: We aimed to evaluate the clinical outcomes of inside stent use and conventional EBS. METHODS: During this retrospective multicenter study, we reviewed consecutive patients with cholangiocarcinoma who underwent radical surgery after conventional EBS or inside-stent insertion. Adverse event (AE) rates after EBD and post-surgical AEs were compared. A multivariable analysis was performed to identify factors affecting cholangitis after EBD. RESULTS: Conventional EBS and inside-stent procedures were performed for 56 and 73 patients, respectively. Patient backgrounds were similar between groups, except for percutaneous transhepatic portal vein embolization. The waiting time before surgery was similar between groups (28.5 days vs. 30 days). There were no significant differences in the cholangitis rate (21.4% vs. 26.0%; P = 0.68) and all AEs (25.0% vs. 30.1%; P = 0.56) between groups. The post-surgical AE rate was similar between the groups. The multivariable analysis found that preprocedural cholangitis was a risk factor for cholangitis after EBD (odds ratio: 5.67; 95% confidence interval: 1.61-19.9). CONCLUSIONS: The outcomes of inside-stent techniques and conventional EBS for the management of preoperative EBD are comparable for patients with cholangiocarcinoma.

Aging is considered a risk factor for various diseases including cancers. In this aging society, there is an urgent need to clarify the molecular mechanisms involved in aging. Wnt signaling has been shown to play a crucial role in the maintenance and differentiation of tissue stem cells, and intensive studies have elucidated its pivotal role in the aging of neural and muscle stem cells. However, until recently, such studies on the gastrointestinal tract have been limited. In this review, we discuss recent advances in the study of the role of Wnt signaling in the aging of the gastrointestinal tract and aging-related carcinogenesis.

In Japan, type 1 autoimmune pancreatitis (AIP) is the most common type of AIP; type 2 AIP is rare. The aim of this study was to clarify the usefulness of endoscopic ultrasound-guided fine-needle aspiration and biopsy (EUS-FNAB) for the diagnosis of type 2 AIP. We analyzed the tissue specimens of 10 patients with suspected type 2 AIP who underwent EUS-FNAB at our hospital between April 2009 and March 2021 for tissue volume and histopathological diagnostic performance. The male-to-female ratio of the patients was 8:2, and the patient age (mean ± standard deviation) was 35.6 ± 15.5 years. EUS-FNAB provided sufficient tissue volume, with high-power field &gt;10 in eight patients (80.0%). Based on the International Consensus Diagnostic Criteria (ICDC), four patients (40.0%) had histological findings corresponding to ICDC level 1, and five patients (50.0%) had histological findings corresponding to ICDC level 2. The results of this study show that EUS-FNB can be considered an alternative method to resection and core-needle biopsy for the collection of tissue samples of type 2 AIP.

Barrett esophagus (BE) is a precursor to a life-threatening esophageal adenocarcinoma (EAC). Surveillance endoscopy with random biopsies is recommended for early intervention against EAC, but its adherence in the clinical setting is poor. Dysplastic lesions with flat architecture and patchy distribution in BE are hardly detected by high-resolution endoscopy, and the surveillance protocol entails issues of time and labor and suboptimal interobserver agreement for diagnosing dysplasia. Therefore, the development of advanced imaging technologies is necessary for Barrett's surveillance. Recently, non-endoscopic or endoscopic technologies, such as cytosponge, endocytoscopy, confocal laser endomicroscopy, autofluorescence imaging, and optical coherence tomography/volumetric laser endomicroscopy, were developed, but most of them are not clinically available due to the limited view field, expense of the equipment, and significant time for the learning curve. Another strategy is focused on the development of molecular biomarkers, which are also not ready to use. However, a combination of advanced imaging techniques together with specific biomarkers is expected to identify morphological abnormalities and biological disorders at an early stage in the surveillance. Here, we review recent developments in advanced imaging and molecular imaging for Barrett's neoplasia. Further developments in multiple biomarker panels specific for Barrett's HGD/EAC include wide-field imaging systems for targeting 'red flags', a high-resolution imaging system for optical biopsy, and a computer-aided diagnosis system with artificial intelligence, all of which enable a real-time and accurate diagnosis of dysplastic BE in Barrett's surveillance and provide information for precision medicine.

INTRODUCTION: Few studies have focused on bleeding following endoscopic submucosal dissection (ESD) in surgically altered stomach. We aimed to reveal the bleeding risk in surgically altered stomach following ESD for early gastric cancer (EGC). METHODS: We enrolled patients with ESD for EGC at 33 institutions between 2013 and 2016. In study 1, we evaluated bleeding risk following ESD in surgically altered stomach, compared with whole stomach. In study 2, we evaluated factors associated with bleeding following ESD in patients with surgically altered stomach. RESULTS: Of 11,452 patients, 445 patients had surgically altered stomach with the bleeding rate following ESD of 4.9%. In study 1, the bleeding risk in surgically altered stomach was not significant (odds ratio [OR], 1.37; 95% confidence interval [CI], 0.87-2.17) in the multivariate logistic regression analysis. No significant results were obtained when the surgically altered stomach was subdivided into various types. In study 2, the multivariate logistic regression analysis revealed that independent risk factors for bleeding following ESD were ischemic heart disease (OR, 7.52; 95% CI, 2.00-28.25) and P2Y12 receptor antagonist (OR, 4.81; 95% CI, 1.21-19.14). DISCUSSION/CONCLUSION: In this nationwide study, we found that the bleeding risk of surgically altered stomach following ESD for EGC did not significantly differ from that of whole stomach. The risk factors for ESD in patients with surgically altered stomach were ischemic heart disease and P2Y12 receptor antagonist.

Gastrinoma may cause refractory esophageal stricture due to gastro-esophageal reflux disease (GERD), but imaging technologies have limited power in its diagnosis. A 74-year-old female with a history of peptic ulcers suffered from repeated epigastralgia, and she visited a local hospital. An esophago-gastro-duodenoscopy (EGD) demonstrated severe reflux esophagitis and multiple peptic ulcers. Blood examination revealed a high value of fasting serum gastrin. Multi-detector computed tomography showed a hypervascular and tiny nodule in duodenal bulb, although other imaging technologies did not. Short-term medication with a proton pump inhibitor or potassium-competitive acid blocker was intermittently provided, but dysphagia was repeatedly worsened, and she was referred to our division. Serum hypergastrinemia was retained, and EGD reexamination depicted esophageal stricture, treated by multiple sessions of endoscopic balloon dilatation. Primary tumor was not identified by the morphological imaging technologies, but a selective arterial secretagogue injection test suggested its existence in the duodenum or pancreatic head. Pancreaticoduodenectomy was performed, and histological study identified 2 mm-sized microgastrinoma buried in Brunner`s glands on the posterior wall of the duodenum bulb. We reported a case with difficulty in diagnosis of the smallest sporadic gastrinoma of the duodenum, which might cause refractory GERD-associated stricture.

BACKGROUND: Chronic pancreatitis (CP) is defined according to the recently proposed mechanistic definition as a pathological fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental, and/or other risk factors who develop persistent pathological responses to parenchymal injury or stress. METHODS: The clinical practice guidelines for CP in Japan were revised in 2021 based on the 2019 Japanese clinical diagnostic criteria for CP, which incorporate the concept of a pathogenic fibro-inflammatory syndrome in the pancreas. In this third edition, clinical questions are reclassified into clinical questions, background questions, and future research questions. RESULTS: Based on analysis of newly accumulated evidence, the strength of evidence and recommendations for each clinical question is described in terms of treatment selection, lifestyle guidance, pain control, treatment of exocrine and endocrine insufficiency, and treatment of complications. A flowchart outlining indications, treatment selection, and policies for cases in which treatment is ineffective is provided. For pain control, pharmacological treatment and the indications and timing for endoscopic and surgical treatment have been updated in the revised edition. CONCLUSIONS: These updated guidelines provide clinicians with useful information to assist in the diagnosis and treatment of CP.

Loss of function in the BRCA2 gene exacerbates ovarian, breast, and pancreatic ductal cancer risk. Despite being implicated in the pancreatic ductal epithelium carcinogenesis, the involvement of a germline BRCA2 mutation in acinar and endocrine cells is less reported. A 45-year-old woman with a history of breast cancer was referred to our hospital for a detailed examination of epigastric pain. Her father had pancreatic cancer, and her paternal aunt had a history of breast cancer. Contrast-enhanced computed tomography revealed a round tumor with a contrast effect in the pancreatic head. The patient underwent pancreaticoduodenectomy, and postoperative pathology and genetic testing revealed amphicrine-type mixed acinar-neuroendocrine carcinoma with a germline BRCA2 mutation. Recent studies have reported the BRCA2 mutation in genome sequencing of pancreatic acinar cell carcinoma and neuroendocrine tumor; perhaps, genetic testing for the BRCA2 mutation is feasible for patients with mixed neuroendocrine-non-neuroendocrine neoplasm.

BACKGROUNDS: Entecavir (ETV) and tenofovir alafenamide fumarate (TAF) have been used widely to treat patients with chronic hepatitis B virus (HBV) infection, but it is still unclear how best to use these drugs. Although some studies compared the efficacies of treatment switch from ETV to TAF, there has been no randomized study. METHODS: We performed a prospective multicenter randomized controlled study in which subjects were enrolled from April 2018 to June 2019 and observed for 2 years until March 2021 to clarify the efficacy and safety of switching from ETV to TAF. RESULTS: Thirty-three patients were enrolled and randomized into 2 groups, and a total of 30 patients were evaluated; a TAF-switching group (n = 16) and an ETV-continuing group (n = 14). The mean age of the 30 patients was 61 years old and 18 patients (60%) were male. The serum HBV DNA in all patients were below detection limit. The mean change in hepatitis B surface antigen (HBsAg) levels after 2 years was not significantly different between the TAF and ETV groups (-0.08 vs -0.20 log IU/mL, P = .07). Comparing the group with a HBsAg decline (≤ -0.1 log IU/mL) and a group without a HBsAg decline in an overall analysis, the prior ETV duration was significantly shorter in the HBsAg-declined group (49 vs 92 months, P = .03). Although the eGFR levels tended to decrease in the TAF group compared to ETV (-6.15 vs -2.26 mL/min/1.73 m2, P = .09), no significant differences were observed in patients with baseline eGFR < 60 (-2.49 vs 0.40 mL/min/1.73 m2, P = .25). CONCLUSION: The efficacy and safety were comparable in the TAF-switching group and the ETV-continuing group. Because the present study was conducted in limited patients, a larger study will be required.

BACKGROUND AND AIM: The usefulness of fecal calprotectin (FC) and serum leucine-rich alpha-2 glycoprotein (LRG) assessing the activity of Crohn's disease (CD) remains to be fully demonstrated in Asia. The present study aimed to elucidate whether FC and LRG could predict endoscopic remission (ER) in Japanese patients with CD. METHODS: Between October 2018 and July 2021, we prospectively observed treatment courses of CD patients treated with biologic agents. The optimal cutoff values of Crohn's Disease Activity Index (CDAI), serum C-reactive protein (CRP), serum albumin (Alb), FC, and LRG levels for predicting ER at week 52 were calculated using receiver operating characteristic (ROC) curves. We also analyzed the correlations between the achievement of clinical remission (CR) or biomarker remission (BR) at week 12/24/52 and ER at week 52. RESULTS: Among 53 patients who completed 52 weeks of observation, 20 (37.7%) achieved ER at week 52. Using the calculated cutoff values, patients who achieved CR (CDAI ≤ 112) or BR (CRP ≤ 0.42 mg/dL, Alb ≥ 3.8 g/dL, FC ≤ 287 μg/g, or LRG ≤ 13.6 μg/mL) at week 12/24/52 had a higher ER rate at week 52. FC-BR at week 12/24 showed low sensitivity (0.58/0.60) but high specificity (0.78/0.74) for predicting ER; LRG-BR at week 12/24 also showed low sensitivity (0.68/0.74) but high specificity (0.87/0.78). However, FC-BR and LRG-BR at week 52 had improved sensitivity (0.80/0.84) while specificity remained (0.79/0.85). CONCLUSIONS: From the early phase of biologic treatment, both FC and LRG had high specificity for predicting ER at week 52. LRG showed higher sensitivity than FC.

Interactions between pancreatic cancer cells and pancreatic stellate cells (PSCs) play an important role in the progression of pancreatic cancer. Recent studies have shown that cellular senescence and senescence-associated secretory phenotype factors play roles in the progression of cancer. This study aimed to clarify the effects of senescence-induced PSCs on pancreatic cancer cells. Senescence was induced in primary-cultured human PSCs (hPSCs) through treatment with hydrogen peroxide or gemcitabine. Microarray and Gene Ontology analyses showed the alterations in genes and pathways related to cellular senescence and senescence-associated secretory phenotype factors, including the upregulation of C-X-C motif chemokine ligand (CXCL)-1, CXCL2, and CXCL3 through the induction of senescence in hPSCs. Conditioned media of senescent hPSCs increased the proliferation-as found in an assessment with a BrdU incorporation assay-and migration-as found in an assessment with wound-healing and two-chamber assays-of pancreatic cancer AsPC-1 and MIAPaca-2 cell lines. SB225002, a selective CXCR2 antagonist, and SCH-527123, a CXCR1/CXCR2 antagonist, attenuated the effects of conditioned media of senescent hPSCs on the proliferation and migration of pancreatic cancer cells. These results suggest a role of CXCLs as senescence-associated secretory phenotype factors in the interaction between senescent hPSCs and pancreatic cancer cells. Senescent PSCs might be novel therapeutic targets for pancreatic cancer.

A 69-year-old woman with multiple neuroendocrine neoplasms (NENs) was referred to our hospital. Although she had extreme hypergastrinemia (11,675 pg/mL), no findings that indicated types I to III gastric NENs were found. Although gastric corpus atrophy was suspected on conventional white-light imaging, findings on magnifying endoscopy with narrow-band imaging indicated no severe atrophy. A biopsy from the background fundic gland mucosa revealed no atrophic changes, parietal cells with vacuolated cytoplasm and negative findings for H+K+-ATPase [please check this carefully]. Thus, this case was diagnosed as multiple NENs with parietal cell dysfunction. Neither progression nor metastasis has been confirmed during two-year follow-up.

According to the European and Japanese guidelines, additional treatment is recommended for cases of superficial esophageal squamous cell carcinoma (ESCC) and early gastric cancer (EGC) that do not meet the curability criteria for endoscopic resection (ER), i.e., non-curative ER, owing to the risk of lymph node metastasis (LNM). However, the rates of LNM in such cases were relatively low (e.g., 8% for EGC). Several recent advances have been made in this field. First, pathological risk stratification for metastatic recurrence following non-curative ER without additional treatment was developed for both superficial ESCC and EGC. Second, the pattern of metastatic recurrence and prognosis after recurrence following non-curative ER without additional treatment was found to be considerably different between superficial ESCC and EGC. Third, a combination of ER and selective chemoradiotherapy was developed as a minimally invasive treatment method for clinical T1b-SM ESCC. These findings may help clinicians decide the treatment strategy for patients following non-curative ER; however, for optimal therapeutic decision-making in such patients, it is also important to predict the prognosis other than SESCC or EGC and impaired quality of life. Thus, a novel algorithm that considers these factors, as well as metastatic recurrence, should be developed.

BACKGROUND AND AIM: The standard therapies for benign gastrointestinal stenosis are endoscopic balloon dilation or surgery; each have their advantages and disadvantages. In contrast, radial incision and cutting (RIC) is a novel approach for such stenosis. This study aimed to investigate the feasibility, safety, and effectiveness of RIC. METHODS: We enrolled 20 patients with benign stenosis of the lower gastrointestinal tract developed by various causes and conducted RIC. We evaluated the re-intervention free rate 52 weeks after RIC, technical success rate, adverse events, procedure time, and improvement of symptoms using a visual analog scale. RESULTS: We performed 20 sessions of first RIC for 20 lesions and seven sessions of additional RIC due to re-stenosis. The cumulative re-intervention-free survival rate 52 weeks after the first RIC was 55.8%. The technical success rate of the first RIC was 100% (20/20) while that of the additional RIC was 85.7% (6/7). One case developed perforation during the additional RIC and urgent surgery was performed. The additional RIC tended to show worse results in adverse events and procedure time compared with the first RIC. The patients' symptoms including abdominal bloating and dyschezia were significantly improved. CONCLUSIONS: Although RIC demonstrated a higher technical success rate for lower gastrointestinal stricture and subsequent improvement of patient symptoms, several issues including preventing delayed bleeding, perforation, and the long-term prognosis should be solved and clarified in further investigations.

As pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs) are the two major cell types that comprise the immunosuppressive tumor microenvironment of pancreatic cancer, we aimed to investigate the role of conditioned medium derived from PCCs and PSCs co-culture on the viability of lymphocytes. The conditioned medium (CM) collected from PCCs and/or PSCs was used to treat peripheral blood mononuclear cells (PBMCs) to determine CM ability in reducing lymphocytes population. A proteomic analysis has been done on the CM to investigate the differentially expressed protein (DEP) expressed by two PCC lines established from different stages of tumor. Subsequently, we investigated if the reduction of lymphocytes was directly caused by CM or indirectly via CM-induced MDSCs. This was achieved by isolating lymphocyte subtypes and treating them with CM and CM-induced MDSCs. Both PCCs and PSCs were important in suppressing lymphocytes, and the PCCs derived from a metastatic tumor appeared to have a stronger suppressive effect than the PCCs derived from a primary tumor. According to the proteomic profiles of CM, 416 secreted proteins were detected, and 13 DEPs were identified between PANC10.05 and SW1990. However, CM was found unable to reduce lymphocytes viability through a direct pathway. In contrast, CM that contains proteins secreted by PCC and/or PSC appear immunogenic as they increase the viability of lymphocytes subtypes. Lymphocyte subtype treated with CM-induced MDSCs showed reduced viability in T helper 1 (Th1), T helper 2 (Th2), and T regulatory (Treg) cells, but not in CD8+ T cells, and B cells. As a conclusion, the interplay between PCCs and PSCs is important as their co-culture displays a different trend in lymphocytes suppression, hence, their co-culture should be included in future studies to better mimic the tumor microenvironment.

Abstract Aging is a risk factor for cancers in various organs. Recent advances in the organoid culturing system have made it viable to investigate the influence of aging utilizing these mini organs. In this study, we aimed to examine the implications of aging for gastric carcinogenesis. Gastric organoids established from aged mice grew larger, proliferated vigorously, and survived longer than that from young mice. Since Wnt/b-catenin signaling was intensified in the aged organoids and since removal of Wnt-related factors diminished their proliferation, we investigated for Wnt target gene that contributed to enhanced proliferation and discovered that the aged organoids expressed the transcription factor T-box3 (Tbx3), which has been reported to suppress cellular senescence. Indeed, cellular senescence was suppressed in the aged organoids, and this resulted from enhanced G2/M transition. As for the mechanism involved in the intensified Wnt/b-catenin signaling, we identified that Dickkopf3 (Dkk3) expression was reduced in the aged organoids due to methylation of the Dkk3 gene. Finally, the expression of TBX3 was enhanced in human atrophic gastritis and even more enhanced in human gastric cancers. In addition, its expression correlated positively with patients' age. These results indicated that the emergence of anti-senescent property in aged gastric organoids due to enhanced Tbx3 expression led to accelerated cellular proliferation and organoid formation. Since the enhanced Tbx3 expression seen in aged gastric organoids was also observed in human gastric cancer tissues, this Dkk3-Wnt-Tbx3 pathway may be involved in aging-related gastric carcinogenesis.

BACKGROUND AND AIMS: Self-expandable metallic stent (SEMS) is widely used for obstructive colorectal cancer (OCC). Both SEMS and urgent surgery have several merits and demerits. This study aimed to clarify the efficacy of SEMS by comparing the mortality rate after the hospitalization between SEMS and urgent surgery for OCC. METHODS: We collected OCC patients' data using the Diagnosis Procedure Combination (DPC) database system. We divided eligible patients into the SEMS and urgent surgery groups using propensity score matching and compared in-hospital death rates, length of hospitalization, and medical costs. We also conducted logistic regression analysis to identify clinical factors affecting in-hospital deaths. RESULTS: We enrolled 17 140 cases after propensity score matching. SEMS reduced the in-hospital death rate compared with urgent surgery (2.0% vs 3.6%, P < 0.0001). Length of hospitalization was shorter in the SEMS group than in the urgent surgery group (16 vs 25 days, P < 0.0001). Medical costs were lower in the SEMS group than in the urgent surgery group (1 663 550 vs 2 424 082 JPY, P < 0.0001). Multivariate analysis also showed that SEMS reduced in-hospital death (odds ratio = 0.58, 95% confidence interval: 0.50-0.70, P < 0.0001). CONCLUSION: Self-expandable metallic stent placement for OCC might reduce the mortality rate in short term and shorten the length of hospitalization. These results facilitate considering SEMS with careful judgment for its indication when treating OCC patients.

BACKGROUND: While an association between esophago-gastric junctional adenocarcinomas (EGJACs) and obesity, especially visceral obesity, has been suggested in Western countries, the association remains unclear in Asia, including Japan. In this population-based case-control study, we investigated the association between EGJACs and obesity. METHODS: To perform near-population-based data collection for all early-stage EGJACs occurring in Akita Prefecture from 2014 to 2019, clinical data, including endoscopic and computed tomography (CT) findings, were collected from 11 cancer treatment base hospitals in the area. Age- and gender-matched controls were extracted at a case-to-control ratio of 1:2 from healthy subjects who received health checkups in the same area. The visceral fat area (VFA) was calculated using CT images. Logistic regression analyses were performed to investigate the associations between EGJACs and obesity-related parameters. RESULTS: In total, 74 EGJAC cases (62 males, median age of 70 years old) and 148 controls were extracted. Multivariable analyses showed a significantly negative association between the BMI and EGJACs and a significantly positive association between the VFA and EGJACs with odds ratios (ORs) (95% confidence intervals [CIs]) of 0.65 (0.53-0.80) and 1.01 (1.01-1.02), respectively. These findings were confirmed in another dataset (40 EGJACs and 80 controls). In addition, as a categorical variable, VFA ≥ 100 cm2 showed a significantly positive association with EGJACs (OR [95% CI] 1.96 [1.02-3.76]). CONCLUSIONS: We found paradoxical associations between EGJACs and obesity-related parameters (BMI vs. VFA) in a Japanese population, suggesting a potentially pivotal role of the VFA rather than the BMI as a risk factor for EGJACs.

BACKGROUND: Cavernous transformation of the portal vein (CTPV) due to extrahepatic portal vein obstruction is a rare vascular anomaly. Since its symptoms usually appear in childhood, most of the adult cases are detected unexpectedly with other diseases. Only a few reports have described surgical difficulties in patients with CTPV. We report a case of pancreatic head cancer with CTPV in a patient who underwent pancreaticoduodenectomy. CASE PRESENTATION: A 77-year-old man with epigastric and back pain was referred to our hospital. Computed tomography revealed a tumor in the pancreatic head and a CTPV near the hepatic hilum. CTPV consisted of two main collateral vessels connected by multiple surrounding small vessels. Also, portal vein obstruction was observed near the hepatic hilum, which was far from the pancreatic head tumor. After confirming that there was no distant metastasis by a thorough whole-body search, we performed a pancreaticoduodenectomy following neoadjuvant chemotherapy. During the operation, we carefully manipulated the area of the CTPV and omitted lymph node dissection in the hepatoduodenal ligament to prevent massive venous bleeding and intestinal congestion. Pancreaticoduodenectomy was performed without any intraoperative complications and the postoperative course was uneventful. Complete tumor resection was histologically confirmed. CONCLUSION: Although pancreaticoduodenectomy for patients with CTPV involves many surgical difficulties, we successfully performed it by determining specific treatment strategies tailored to the patient and following careful and delicate surgical procedures.

Immune checkpoint blockade (ICB) treatment improves the prognosis of several types of solid tumors, however, responsiveness to ICB therapy remains low in pancreatic ductal adenocarcinoma (PDACs), which has a rich tumor microenvironment (TME). The TME is composed of various stromal cells, including cancer-associated fibroblasts (CAFs), which contribute to the establishment of an immunosuppressive microenvironment. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate immune pathway that results in the upregulation of immune cell recruiting-cytokines and anti-tumor efficacy. In this study, we aimed to investigate the impact of cGAS-STING expression and the presence of CAFs upon immune cell infiltration in PDACs. cGAS and STING co-expressing PDAC cases showed favorable survival, with many cytotoxic CD8 + T cell infiltrations from the stromal component adjacent to the cancer cells toward cancer cells, but not in cGAS-STING signaling defected PDAC cases. The signatures of tumor-restrain CAFs were expressed in tumors with cGAS-STING signaling. Finally, transwell co-culture experiments demonstrated that immune cell infiltration was impeded by the presence of CAFs, but not by activation of cGAS-STING signaling. In conclusion, pro-infiltration signals, such as cGAS-STING, and characterization of CAFs are crucial in defeating CAF barricades and encouraging immune cell infiltration in PDACs.

Inflammatory bowel disease (IBD) diagnoses are increasing in Japan. Some patients have symptoms that are difficult to control, and further research on IBD is needed. Claims databases, which have a large sample size, can be useful for IBD research. However, it is unclear whether the International Classification of Diseases, Tenth Revision (ICD-10) codes alone can correctly identify IBD. We aimed to develop algorithms to identify IBD in claims databases. We used claims data from the Department of Gastroenterology, Tohoku University Hospital from 1 January 2016 to 31 December 2020. We developed 11 algorithms by combining the ICD-10 code, prescription drug, and workup information. We had access to the database which contains all the information for Crohn's disease and ulcerative colitis patients who visited our department, and we used it as the gold standard. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value for each algorithm. We enrolled 19,384 patients, and among them, 1012 IBD patients were identified in the gold standard database. Among 11 algorithms, Algorithm 4 (ICD-10 code and ≥1 prescription drugs) showed a strong performance (PPV, 94.8%; sensitivity, 75.6%). The combination of an ICD-10 code and prescription drugs may be useful for identifying IBD among claims data.

Vaccination against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently underway across countries worldwide. However, the prevalence and characteristics of prolonged adverse events lasting for several months after receiving the vaccine remain largely unknown. We herein report a 46-year-old woman with prolonged diarrhea and vomiting after receiving the BNT162b2 mRNA vaccine for COVID-19. She had no notable medical history, including that of gastrointestinal diseases. She developed vomiting several hours after receiving the first vaccine dose and further developed severe diarrhea after 7 days. Several days after the second vaccine dose, her condition deteriorated, unrelieved by symptomatic therapies, including anti-diarrheal drugs. Abdominal computed tomography (CT) revealed inflammatory changes in the entire segment of the small intestine with wall thickening. The upper and lower gastrointestinal and capsule endoscopies were unremarkable. The patient's symptoms persisted for more than 6 months after the second vaccine dose. A Vaccine Adverse Event Reporting System (VAERS) database search suggested that diarrhea is observed in approximately 3% of all vaccine recipients, but a literature review indicated that prolonged gastrointestinal symptoms lasting for several months is very rare. In summary, a case of prolonged unexplained gastrointestinal symptoms, possibly based on inflammatory changes in the small intestine, is described. A literature search revealed that this type of manifestation is very rare, and further evidence is needed to determine the causality between vaccination and gastrointestinal symptoms.

PURPOSE: Little is known about the prognostic factors for survival after endoscopic submucosal dissection (ESD) in elderly patients with early gastric cancer (EGC). The aim of this study is to determine prognostic factors and a prediction model of 3-year survival after ESD for EGC in patients aged ≥ 85 years. METHODS: We retrospectively evaluated the clinical outcomes of 740 patients with EGC aged ≥ 85 years, who were treated by ESD at 30 institutions in Japan. Overall survival (OS) and disease-specific survival (DSS) were calculated with the Kaplan-Meier method. Prediction models for 3-year OS after ESD were estimated using the Cox proportional hazards model based on Uno's C-statistics. RESULTS: During the follow-up period, 309 patients died of any cause and 10 patients died of gastric cancer. OS and DSS after 3 years were 82.7% and 99.2%, respectively. No significant differences in OS were found among curability categories. The Cox proportional hazards model revealed the geriatric nutritional risk index (GNRI) and the Charlson comorbidity index (CCI) to be predictors of 3-year survival. We established a final model (EGC-2 model) expressed by GNRI - (2.2×CCI) with a cutoff value of 96. The overall survival rate was significantly lower in the model value < 96 group than in the model value ≥ 96 group (P < 0.001). CONCLUSIONS: The prediction model using GNRI and CCI will be useful to support decision-making for the treatment of EGC in elderly patients aged ≥ 85 years.

BACKGROUND AND AIMS: Mosaic chromosomal alterations (mCAs) increase the risk for hematopoietic malignancies and may be risk factors for several other diseases. Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are associated with mCAs, and patients may be at risk for hematopoietic malignancy development and/or modification of IBD phenotypes. In the present study, we screened patients with IBD for the presence of mCAs and explored the possible pathophysiological and genetic risk factors for mCAs. METHODS: We analyzed mCAs in peripheral blood from 3,339 patients with IBD and investigated the clinical and genetic risk factors for mCAs. RESULTS: CD and exposure to thiopurines before the age of 20 years were identified as novel independent risk factors for mCAs (odds ratio = 2.15 and 5.68, P = 1.17e-2 and 1.60e-3, respectively). In contrast, there were no significant associations of disease duration, anti-tumor necrosis factor alpha antibodies, or other clinical factors with mCAs. Gene ontology enrichment analysis revealed that genes specifically located in the mCAs in patients with CD were significantly associated with factors related to mucosal immune responses. A genome-wide association study revealed that ERBIN, CD96, and AC068672.2 were significantly associated with mCAs in patients with CD (P = 1.56e-8, 1.65e-8, and 4.92e-8, respectively). CONCLUSION: The difference in mCAs between patients with CD and UC supports the higher incidence of hematopoietic malignancies in CD. Caution should be exercised when using thiopurines in young patients with IBD, particularly CD, in light of possible chromosomal alterations.

OBJECTIVES: Endoscopic ultrasound-guided tissue acquisition (EUS-TA) plays a crucial role in the diagnosis of pancreatic tumors. The present study aimed to investigate the current status of needle tract seeding (NTS) after EUS-TA of pancreatic tumors based on a nationwide survey in Japan. METHODS: Patients who underwent surgical resection of primary pancreatic tumors after EUS-TA performed between April 2010 and March 2018 were surveyed. The incidence rates of NTS were determined, and compared in patients with pancreatic ductal adenocarcinomas (PDACs) and other tumors, and in patients who underwent transgastric and transduodenal EUS-TA of PDACs. The detailed features and prognosis of patients with NTS were also assessed. RESULTS: A total of 12,109 patients underwent surgical resection of primary pancreatic tumors after EUS-TA. The overall incidence rate of NTS was 0.330%, and the NTS rate was significantly higher in patients with PDAC than in those with other tumors (0.409% vs. 0.071%, P=0.004). NTS was observed in 0.857% of patients who underwent transgastric EUS-TA, but in none of those who underwent transduodenal EUS-TA. Of the patients with NTS of PDACs, the median time from EUS-TA to occurrence of NTS and median patient survival were 19.3 and 44.7 months, respectively, with 97.4% of NTS located in the gastric wall and 65.8% of NTS resected. The patient survival was significantly longer in patients who underwent NTS resection than in those without NTS resection (P=0.037). CONCLUSIONS: NTS appeared only after transgastric not after transduodenal EUS-TA. Careful follow-up provides an opportunity to remove localized NTS lesions by gastrectomy.

Patients with a chronic hepatitis B virus (HBV) infection who are treated with nucleos(t)ide analogues (NAs) are still at risk for hepatocellular carcinoma (HCC), and it has been clinically questioned whether patients with a high risk of HCC can be identified efficiently. We aimed to clarify the risk factors associated with the development of HCC during NA therapies. A total of 611 chronically HBV-infected patients without a history of HCC, who were treated with NAs for more than 6 months (median 72 months), from 2000 to 2021, were included from 16 hospitals in the Tohoku district in Japan. Incidences of HCC occurrence were analyzed with clinical factors, including on-treatment responses. Alanine aminotransferase (ALT) normalization, based on the criteria of three guidelines, was analyzed with other parameters, including the age−male−ALBI−platelets (aMAP) risk score. During the observation period, 48 patients developed HCC, and the cumulative HCC incidence was 10.6% at 10 years. Non-achievement of ALT normalization at 1 year of therapy was mostly associated with HCC development when ALT ≤ 30 U/L was used as the cut-off (cumulative incidence, 19.9% vs. 5.3% at 10 years, p < 0.001). The effectiveness of the aMAP risk score at the start of treatment was validated in this cohort. A combination of an aMAP risk score ≥ 50 and non-achievement of ALT normalization could stratify the risk of HCC significantly, and notably, there was no HCC development in 103 patients without these 2 factors. In conclusion, non-achievement of ALT normalization (≤30 U/L) at 1 year might be useful in predicting HCC during NA therapies and, in combination with the aMAP risk score, could stratify the risk more precisely.

OBJECTIVE: The acceptable duration of steroid therapy for patients with IgG4-sclerosing cholangitis (SC) has been under debate. Our aim is to clarify the feasible duration of steroid treatment. DESIGN: We retrospectively reviewed the data of patients with IgG4-SC and analyzed the following: biliary status during the steroid therapy, incidence of remission, relapse, relapse-free survival rate, and steroid-related complications (SRCs). RESULTS: Remission was achieved 99.5% (763/767) of patients who received steroid therapy, while remission rate dropped to 63.6% (78/129) of patients who didn't receive it. Relapse was noted in 19.7% (151/763) of the patients who received steroid. Besides, relapse rate went up 38.4% (30/78) of the counterpart. Normalization of the serum total bilirubin and serum alkaline phosphatase (ALP) levels were achieved at two weeks regardless of biliary drainage. Multivariate analysis identified younger onset, MST less than three years, immunosuppressant, and steroid cessation as independent risk factors for relapse. Steroid-free was achieved in the patients underwent MST only 3.4% over 54 months. SRCs were recorded in a total of 99 patients (12.9%) despite sufficient preemptive medications. Multivariate analysis identified history of malignancy and immunosuppressant as independent risk factors for SRCs. CONCLUSION: Steroid therapy should be continued for no less than three years to reduce the risk of relapse, with use of preemptive measures taken around five years. The biliary drainage might not be mandatory. Steroid as 1st line therapy could serve as a bridge to further promising treatments.

BACKGROUND: Small benign intestinal stenosis is usually treated by endoscopic balloon dilation (EBD) or surgery. Although EBD and surgery are able to resolve the stenosis in most cases, they are associated with several problems such as insufficient dilation and surgical stress, respectively. On the contrary, a novel approach called radial incision and cutting (RIC) is reported to have several benefits when compared to EBD and surgery. We can currently adopt RIC only for the strictures in the colon or terminal ileum and not for those stenotic lesions present further in the small intestine where balloon-assisted endoscopy is utilized, because the long-type electric knife is currently not approved for use in Japan. We will herein conduct a pilot study to investigate the safety and feasibility of RIC for treating the benign stenoses of the small intestine using the long-type electric knife. METHODS: This will be a single-center, single-arm, interventional trial. The major criteria for inclusion will be age ranging from 20 to 80 years and the presence of benign stenosis in the small intestine. We will perform RIC on 10 participants. The primary outcome is the safety of this procedure, which will be assessed by measuring the frequency of adverse events of special interest. The secondary outcomes will be technical success rate, improvement in subjective symptoms, procedure time, and duration of hospitalization. DISCUSSION: This pilot study will provide useful information that will aid in adopting RIC for treating the benign strictures present in the small intestine. TRIAL REGISTRATION: jRCT Identifier, jRCTs022200040 . Registered on 1 March 2021.

INTRODUCTION: Pharmacogenomic (PGx) testing results provide valuable information on drug selection and appropriate dosing, maximization of efficacy, and minimization of adverse effects. Although the number of large-scale, next-generation-sequencing-based PGx studies has recently increased, little is known about the risks and benefits of returning PGx results to ostensibly healthy individuals in research settings. METHODS: Single-nucleotide variants of three actionable PGx genes, namely, MT-RNR1, CYP2C19, and NUDT15, were returned to 161 participants in a population-based Tohoku Medical Megabank project. Informed consent was obtained from the participants after a seminar on the outline of this study. The results were sent by mail alongside sealed information letter intended for clinicians. As an exception, genetic counseling was performed for the MT-RNR1 m.1555A > G variant carriers by a medical geneticist, and consultation with an otolaryngologist was encouraged. Questionnaire surveys (QSs) were conducted five times to evaluate the participants' understanding of the topic, psychological impact, and attitude toward the study. RESULTS: Whereas the majority of participants were unfamiliar with the term PGx, and none had undergone PGx testing before the study, more than 80% of the participants felt that they could acquire basic PGx knowledge sufficient to understand their genomic results and were satisfied with their potential benefit and use in future prescriptions. On the other hand, some felt that the PGx concepts or terminology was difficult to fully understand and suggested that in-person return of the results was desirable. CONCLUSIONS: These results collectively suggest possible benefits of returning preemptive PGx information to ostensibly healthy cohort participants in a research setting.

BACKGROUND: In preparing the Japanese (JPN) guidelines for the management of acute pancreatitis 2021, the committee focused the issues raised by the results of nationwide epidemiological survey in 2016 in Japan. METHOD: In addition to a systematic search using the previous JPN guidelines, papers published from January 2014 to September 2019 were searched for the contents to be covered by the guidelines based on the concept of GRADE system. RESULTS: Thirty-six clinical questions (CQ) were prepared in 15 subject areas. Based on the facts that patients diagnosed with severe disease by both Japanese prognostic factor score and contrast-enhanced computed tomography (CT) grade had a high fatality rate and that little prognosis improvement after 2 weeks of disease onset was not obtained, we emphasized the importance of Pancreatitis Bundles, which were shown to be effective in improving prognosis, and the CQ sections for local pancreatic complications had been expanded to ensure adoption of a step-up approach. Furthermore, on the facts that enteral nutrition for severe acute pancreatitis was not started early within 48 h of admission and that unnecessary prophylactic antibiotics was used in almost all cases, we emphasized early enteral nutrition in small amounts even if gastric feeding is used and no prophylactic antibiotics are administered in mild pancreatitis. CONCLUSION: All the members of the committee have put a lot of effort into preparing the extensively revised guidelines in the hope that more people will have a common understanding and that better medical care will be spread.

INTRODUCTION: Under the current pandemic situation of the coronavirus disease 2019 (COVID-19), we have newly developed a commercially available device named Endomask to prevent the diffusion of droplets from subjects undergoing esophagogastroduodenoscopy (EGD). Herein, we evaluate the efficacy and safety of the device, and also evaluate the stress of the device on the operators and the subjects of EGD. METHODS: The efficacy of the device was evaluated using an experimental model that simulated the environment of EGD. The safety of the device was evaluated clinically by means of measuring the oxygen saturation and the expiratory carbonic dioxide partial pressure of subjects with our device during EGD. The stress of the device on the operability of the endoscopists and the respiration of the subjects were evaluated using questionnaires. RESULTS: In the experiments with Endomask, the percentage of the area with simulated droplets was significantly reduced compared to that without our device (median, 0.24% vs. 6.96%, p = 0.009). The saturation of oxygen and the expiratory carbonic dioxide partial pressure of subjects with the device did not show significant change at any recording times. Neither the operators nor the subjects felt serious stress from examination with the device. CONCLUSIONS: Endomask could remarkably and safely prevent the diffusion of droplets without serious stress. Endomask is expected to contribute to a reduction of the infectious risk of SARS-CoV-2 in endoscopy units during COVID-19 pandemic.

Prospective studies in western countries have shown that the obvious risk factors for Barrett's esophageal cancer are male sex, smoking habit, a longer length of Barrett's esophagus, and low-grade dysplasia. However, few reports have prospectively examined risk factors for adenocarcinoma development from Barrett's esophagus in Japan. In the West, where adenocarcinoma is common among esophageal cancer, endoscopic surveillance of Barrett's esophagus every 2-5 years is recommended for early detection of adenocarcinoma. However, there is no established surveillance method in Japan. In recent years, the incidence of adenocarcinoma from long-segment Barrett's esophagus and short-segment Barrett's esophagus longer than 2 cm in Japan has been reported to be similar to the West. For surveillance of adenocarcinoma arising from Barrett's esophagus, recognizing the characteristics of superficial adenocarcinoma and carefully observing the entire Barrett's esophagus are needed. It has been reported that representative characteristics of Barrett's adenocarcinoma are a reddish area or a lesion located on the anterior to the right sidewall. It is necessary to establish surveillance methods for Barrett's esophagus sooner in Japan.

BACKGROUND: Anaesthesia and perioperative management contribute to long-term outcomes of patients with cancer, including pancreatic ductal adenocarcinoma. We assessed the antitumour, anti-inflammatory, and analgesic effects of midazolam on LSL-KrasG12D/+;Trp53flox/flox;Pdx-1cre/+ transgenic mice with pancreatic ductal adenocarcinoma. METHODS: Six-week-old transgenic mice were administered midazolam 30 mg kg-1 day-1 p.o. (n=13); midazolam 30 mg kg-1 day-1 with 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline carboxamide (PK11195) 3 mg kg-1 day-1 i.p., a peripheral benzodiazepine receptor antagonist (n=10); or vehicle (water; n=14) until the humane endpoint. Cancer-associated pain was evaluated using hunching score and mouse grimace scale. Tumour stage and immuno-inflammatory status were determined histopathologically. Anti-proliferative and apoptotic potentials of midazolam were investigated using mouse pancreatic ductal adenocarcinoma cell lines. RESULTS: Midazolam significantly inhibited tumour size and proliferative index of Ki-67 and cyclins in pancreatic ductal adenocarcinoma, which was blocked by administration of PK11195. Local myeloperoxidase+ tumour-associated neutrophils, arginase-1+ M2-like tumour-associated macrophages, and CD11b+Ly-6G+ polymorphonuclear myeloid-derived suppressor cells were reduced by midazolam, which was antagonised by administration of PK11195. Hunching and mouse grimace scale were improved by midazolam, whereas the scores increased with midazolam+PK11195 treatment. Plasma pro-inflammatory cytokines, such as interleukin-6 and CC chemokine ligand (CCL)2, CCL3, and CCL5, were reduced by midazolam, whereas these cytokines increased with PK11195. Midazolam inhibited pancreatic ductal adenocarcinoma proliferation through downregulation of cyclins and cyclin-dependent kinases and induced apoptosis in vitro. CONCLUSIONS: These results suggest that midazolam inhibits pancreatic ductal adenocarcinoma proliferation and local infiltration of tumour-associated neutrophils, tumour-associated macrophages, and polymorphonuclear myeloid-derived suppressor cells, thereby inhibiting pancreatic ductal adenocarcinoma progression.

In response to the latest knowledge and the amendment of the Japanese diagnostic criteria for autoimmune pancreatitis (AIP) in 2018, the Japanese consensus guidelines for managing AIP in 2013 were required to be revised. Three committees [the professional committee for developing clinical questions (CQs) and statements by Japanese specialists; the expert panelist committee for rating statements by the modified Delphi method; and the evaluating committee of moderators] were organized. Twenty specialists in AIP extracted the specific clinical statements from a total of 5218 articles (1963-2019) from a search in PubMed and the Cochrane Library. The professional committee made 14, 9, 5, and 11 CQs and statements for the current concept and diagnosis, extra-pancreatic lesions, differential diagnosis, and treatment, respectively. The expert panelists regarded the statements as valid after a two-round modified Delphi approach with individually rating these clinical statements, in which a clinical statement receiving a median score greater than 7 on a 9-point scale from the panel was regarded as valid. After evaluation by the moderators, the amendment of the Japanese consensus guidelines for AIP has been proposed in 2020.

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and early diagnosis is challenging. Because patients who present with symptoms generally have advanced-stage diseases, analysis of asymptomatic PDAC provides invaluable information for developing strategies for early diagnosis. Here, we reviewed 577 patients with PDAC (372 diagnosed with symptoms [symptomatic group] and 205 without symptoms [asymptomatic group]) diagnosed at our institute. Among the 205 asymptomatic PDAC patients, 109 were detected during follow-up/work-up for other diseases, 61 because of new-onset or exacerbation of diabetes mellitus, and 35 in a medical check-up. Asymptomatic PDAC is characterized by smaller tumor size, earlier disease stage, and higher resectability than those of symptomatic PDAC. In 22.7% of asymptomatic cases, indirect findings, e.g., dilatation of the main pancreatic duct, triggered PDAC detection. Although pancreatic tumors were less frequently detected, overall abnormality detection rates on imaging studies were nearly 100% in asymptomatic PDAC. Asymptomatic PDAC had a better prognosis (median survival time, 881 days) than symptomatic PDAC (342 days, P < 0.001). In conclusion, diagnosis of PDAC in the asymptomatic stage is associated with early diagnosis and a better prognosis. Incidental detection of abnormal findings during the follow-up/work-up for other diseases provides important opportunities for early diagnosis of asymptomatic PDAC.

BACKGROUND AND AIM: Despite the widespread use of endoscopic submucosal dissection (ESD) for early gastric cancer, post-ESD bleeding remains a significant problem. Intragastric pH plays an important role in intragastric bleeding. Because gastric acid secretion contributes to intragastric pH, both the presence or absence of Helicobacter pylori infection and the degree of gastric mucosal atrophy may affect bleeding. The present study aimed to clarify the relationship between post-ESD bleeding and the degree of gastric mucosal atrophy based on H. pylori infection status. METHODS: We included 8170 patients who underwent ESD for early gastric cancer at 33 hospitals in Japan from November 2013 to October 2016. We analyzed the risk factors contributing to post-ESD bleeding. RESULTS: There were 3935 H. pylori-positive patients and 4235 H. pylori-negative patients. A nonsevere degree of gastric mucosal atrophy was an independent risk factor for post-ESD bleeding in H. pylori-negative patients (odds ratio: 1.51, P = 0.007), but not in H. pylori-positive patients (odds ratio: 0.91, P = 0.600). Further, in H. pylori-negative, but not H. pylori-positive, patients, the rate of post-ESD bleeding increased in a stepwise manner for patients continuing antithrombotic drug use, patients who withdrew antithrombotic drug use, and antithrombotic drug nonusers. CONCLUSIONS: Nonsevere gastric mucosal atrophy was a risk factor for post-ESD bleeding in early gastric cancer in H. pylori-negative patients but not in H. pylori-positive patients.

The management of non-functioning pancreatic neuroendocrine neoplasms (NF-PanNENs) is still controversial. This study aimed to develop a new scoring system for treatment decisions at initial diagnosis based on the identification of the predictive factors for aggressive NF-PanNENs. Seventy-seven patients who had been pathologically diagnosed with NF-PanNENs were enrolled. We retrospectively reviewed 13 variables that could be assessed preoperatively. Univariate and multivariate stepwise logistic regression analyses were performed to identify factors for the aggressiveness of NF-PanNENs, and a scoring system was developed by assigning weighted points proportional to their β regression coefficient. Tumor size > 20 mm on contrast-enhanced computed tomography, tumor non-vascularity, and Ki-67 labeling index ≥5% on endoscopic ultrasound-guided fine-needle aspiration specimens were identified as independent factors for predicting the aggressiveness of NF-PanNENs. The new scoring system, developed using the identified factors, had an excellent discrimination ability, with area under the curve of 0.92 (95% CI, 0.85-0.99), and good calibration (p = 0.72, Hosmer-Lemeshow test). Ten-year overall survival rates in low-risk (0 point), intermediate-risk (1 to 2 points), and high-risk (3 to 4 points) groups were 100%, 90.9%, and 24.3%, respectively. This new scoring system would be useful for treatment decisions and prognostic prediction at initial diagnosis.

The recent discovery of TRPV6 as a pancreatitis susceptibility gene served to identify a novel mechanism of chronic pancreatitis (CP) due to Ca2+ dysregulation. Herein, we analyzed TRPV6 in 81 probands with hereditary CP (HCP), 204 probands with familial CP (FCP), and 462 patients with idiopathic CP (ICP) by targeted next-generation sequencing. We identified 25 rare nonsynonymous TRPV6 variants, 18 of which had not been previously reported. All 18 variants were characterized by a Ca2+ imaging assay, with 8 being identified as functionally deficient. Evaluation of functionally deficient variants in the three CP cohorts revealed two novel findings: (i) functionally deficient TRPV6 variants appear to occur more frequently in HCP/FCP patients than in ICP patients (3.2% vs. 1.5%) and (ii) functionally deficient TRPV6 variants found in HCP and FCP probands appear to be more frequently coinherited with known risk variants in SPINK1, CTRC, and/or CFTR than those found in ICP patients (66.7% vs 28.6%). Additionally, genetic analysis of available HCP and FCP family members revealed complex patterns of inheritance in some families. Our findings confirm that functionally deficient TRPV6 variants represent an important contributor to CP. Importantly, functionally deficient TRPV6 variants account for a significant proportion of cases of HCP/FCP.

Pancreatic cancer is intractable due to early progression and resistance to conventional therapy. Dense fibrotic stroma, known as desmoplasia, is a characteristic feature of pancreatic cancer, and develops through the interactions between pancreatic cancer cells and stromal cells, including pancreatic stellate cells. Dense stroma forms harsh tumor microenvironments characterized by hypoxia, few nutrients, and oxidative stress. Pancreatic cancer cells as well as pancreatic stellate cells survive in the harsh microenvironments through the altered expression of signaling molecules, transporters, and metabolic enzymes governed by various stress response mechanisms. Hypoxia inducible factor-1 and KEAP1-NRF2, stress response mechanisms for hypoxia and oxidative stress, respectively, contribute to the aggressive behaviors of pancreatic cancer. These key molecules for stress response mechanisms are activated, both in pancreatic cancer cells and in pancreatic stellate cells. Both factors are involved in the mutual activation of cancer cells and stellate cells, by inducing cancer-promoting signals and their mediators. Therapeutic interventions targeting these pathways are promising approaches for novel therapies. In this review, we summarize the roles of stress response mechanisms, focusing on hypoxia inducible factor-1 and KEAP1-NRF2, in pancreatic cancer. In addition, we discuss the potential of targeting these molecules for the treatment of pancreatic cancer.

&lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; 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. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We enrolled a multicenter cohort of 247 patients with u-HCC treated with LEN between 2018 and 2020. Propensity score matching identified 63 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 complete response or partial response (PR) on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and at least a 30% decrease in the sum of diameters of target lesions, taking the baseline sum diameters as the reference. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The OS and PFS in the LEN-TACE group were significantly higher than those in the LEN monotherapy group (&lt;i&gt;p&lt;/i&gt; = 0.002 and &lt;i&gt;p&lt;/i&gt; = 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: 5.176, 95% confidence interval: 1.528–17.537, &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.001). &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; LEN-TACE sequential therapy may provide more clinical benefits than LEN monotherapy in u-HCC patients who responded to initial LEN treatment. Objective response according to mRECIST to initial LEN is an independent factor contributing to LEN-TACE sequential therapy deep response.

Patients with esophageal squamous cell carcinoma (ESCC) might have a specific mechanism for the carcinogenesis by alcohol consumption in the background esophageal mucosa, and nuclear factor erythroid 2-related factor 2 (NRF2), which plays a protective role against esophageal carcinogenesis, and barrier dysfunction might be associated with this phenomenon. This study aimed to confirm this hypothesis. Twenty patients with superficial ESCCs (ESCC patients) and 20 age- and sex-matched patients without ESCC (non-ESCC patients) were enrolled. Biopsy samples were obtained from non-neoplastic esophageal mucosa: one for histological evaluation, one for quantitative real-time polymerase chain reaction (PCR), and two for the mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) and, thereafter, for PCR. The TEER after acetaldehyde or both acetaldehyde and ethanol exposure did not differ significantly between ESCC and non-ESCC patients. Unlike non-ESCC patients, mRNA levels of NRF2 target genes and claudin4 in ESCC patients tended to decrease after the exposure, with a significant difference between no exposure and both acetaldehyde and ethanol exposure in NRF2 target genes (p < 0.05). Furthermore, in ESCC patients, the decreased tendency of mRNA levels of NRF2 target genes after the exposure was more pronounced in high-risk states, such as aldehyde dehydrogenase 2 (ALDH2) Lys alleles (Glu/Lys + Lys/Lys), Lugol-voiding lesion grade C, and drinking history. In conclusion, the protective role of NRF2 against carcinogenesis from alcohol exposure might be disrupted in the background esophageal mucosa of ESCC patients, which might lead to a high incidence of metachronous ESCC.

BACKGROUND AND AIMS: Surgery is recommended in early gastric cancer (EGC) after noncurative endoscopic submucosal dissection (ESD), although observation can be an alternative. We aimed to develop a tailor-made treatment strategy for noncurative EGCs by comparing the lymph node metastasis risk (LNMR) and the surgical risk. METHODS: We retrospectively identified 485 patients with differentiated-type, noncurative EGCs removed by ESD and classified them into two groups: a surgery-preferable group and an observation-preferable group, according to the clinical courses. Subsequently, LNMR and surgery-related death risk were assessed using a published scoring system and a risk calculator for gastrectomy, respectively. Finally, we investigated the optimal cutoff value of the risk difference (LNMR minus surgery-related death risk) to efficiently allocate these cases into either of two groups, surgery-preferable or observation-preferable. RESULTS: In 485 patients (surgery in 322, observation in 163), 57 and 428 patients were classified into the surgery-preferable group and the observation-preferable group, respectively. The optimal cutoff value of the risk difference (LNMR minus surgery-related death risk) to allocate the cases to the two preferable groups was 7.85 with the highest area under the curve (0.689). When cases with >7.85 LNMR over the surgery-related death risk were allocated into the surgery-preferable group and vice versa, the discriminability was 73.2%, which was sufficiently higher than that in the clinical decision (44.5%). CONCLUSION: Personalized comparison of LNMR and surgery-related death risk is helpful to provide a favorable treatment option for each patient with EGCs after noncurative ESD.

Barrett's esophagus arises in the process of wound healing in distal esophageal epithelium damaged by gastroesophageal reflux disease. Differentiation of fibroblast into myofibroblasts, a smooth muscle cell-like phenotype and tissue contraction are crucial processes in wound healing. No study has evaluated mechanism by which luminal esophageal nitric oxide (NO) affect Rho-associated coiled coil-forming protein kinase (Rho-ROCK) signaling pathway, a key factor of tissue contraction, in stromal fibroblasts to develop Barrett's esophagus. Using esophageal fibroblasts, we performed collagen-based cell contraction assays and evaluated influence of Rho-ROCK signaling in the exposure to acidic bile salts and NOC-9, which is an NO donor. We found that enhanced cell contraction induced by acidic bile salts was inhibited by NO, accompanied by decrease in phosphorylated myosin light chain expression and stress fiber formation. NO directly S-nitrosylated GTP-RhoA and consequently blocked Rho-ROCK signaling. Moreover, exposure to NO and Y27632, a Rho-ROCK signaling inhibitor, decreased α-SMA expression and increased bone morphogenetic protein-4 (BMP4) expression and secretion. These findings could account for the increased expression of BMP4 in the columnar epithelial cells and stromal fibroblasts in human Barrett's esophagus. NO could impair wound contraction by blocking the Rho-ROCK signaling pathway and promote the development of Barrett's esophagus.NEW & NOTEWORTHY Barrett's esophagus is the condition where esophageal epithelium damaged by gastroesophageal reflux disease (GERD) is abnormally healed via replacing of metaplastic columnar epithelium, but very few studies have conducted focusing wound healing in the development of Barrett's esophagus. Esophageal luminal nitric oxide inhibits Rho-ROCK signaling pathway in esophageal fibroblasts, which leads to delay tissue contraction, a pivotal step in proper wound healing. Moreover, this inhibition increases tissue BMP4 expression. Impaired wound healing could be related to Barrett's esophagus.

Aims: Primary sclerosing cholangitis (PSC) is a relatively common complication of ulcerative colitis (UC). Only a few studies have investigated the impact of PSC on the clinical course of UC, and their conclusions are contradictory. Therefore, we aimed to compare the disease activity of UC with and without PSC. Methods and Results: We collected UC patient data using the Diagnosis Procedure Combination database system in Japan and classified eligible admissions into two groups based on their diagnosis of either UC alone or UC associated with PSC. We then compared therapeutic details (medical treatment and surgery) between the two groups. Multivariable logistic regression analysis and propensity score matching was also performed. The rates of systemic steroid injection and infliximab administration in patients with PSC were lower than those in patients without PSC (21% vs. 28%, P = 0.012, 9.6% vs. 16%, P = 0.01, respectively). The rates of surgery, colorectal cancer, duration of hospital stay, and in-hospital mortality did not differ between the two groups. Multivariable analysis revealed that concomitant PSC was a clinical factor that reduced the odds of systemic steroid injection (odds ratio [OR] = 0.66, 95% confidence interval [CI]: 0.49-0.90, P = 0.008) and infliximab (OR = 0.48, 95% CI: 0.32-0.74, P = 0.0008) administration. Conclusion: UC patients with PSC might have less UC disease activity than those with UC alone.

BACKGROUND: In Crohn's disease, postoperative endoscopic activity of small bowel lesions outside the scope of ileocolonoscopy has been insufficiently studied. AIMS: We aimed to assess this postoperative activity using capsule endoscopy (CE) and analyze the association between treatment optimization based on CE findings and the long-term course. METHODS: In patients who underwent intestinal resection, we performed CE and assessed the endoscopic activity using the Lewis score within 3 months postoperatively (1st CE) and during follow-up. Postoperative treatments were adjusted according to clinical symptoms or CE findings (severity of 1st CE or worsening of follow-up CEs). Hospitalization, repeat surgery, or endoscopic dilation defined the primary outcome. RESULTS: Among the CE group (N = 48), 85.7% (1st CE) and 79.2% (2nd CE) exhibited endoscopic activities indicating residual or recurrent lesions. Postoperative treatments were adjusted according to clinical symptoms in the non-CE group (N = 57) and clinical symptoms or CE findings in the CE group. Compared to the non-CE group, the CE group had significantly fewer primary outcomes. Patients with treatment adjustments based on CE findings had even lower primary outcome rate. Multivariate analysis identified the CE group as an independent protective factor (hazard ratio = 0.45, 95% confidence interval = 0.20-0.96). Treatment adjustments based on CE findings showed a stronger protective effect (0.30, 0.10-0.75). CONCLUSIONS: Postoperative repeated CE enabled us to assess residual and recurrent lesions accurately before clinical symptoms appeared. The regular assessment of endoscopic activity and subsequent treatment optimization have the potential for improving postoperative course.

We report a case of reconstruction of the portal vein(PV)and superior mesenteric vein(SMV)using a superficial femoral vein graft in total pancreatectomy for pancreatic cancer. A 62-year-old man visited a previous hospital due to epigastric pain and bilirubinuria and was diagnosed with pancreatic cancer. The patient was referred to our hospital for further examination and treatment. Abdominal CT scan revealed a 30 mm pancreatic head tumor with an abutment of almost 360 degrees around the superior mesenteric artery(SMA)and extensive involvement from the PV to branches of the SMV, radiologically classified as locally advanced unresectable pancreatic cancer. Although gemcitabine plus nab-paclitaxel combination therapy(GnP)was performed, the patient developed drug-induced lung injury after 3 courses. GnP was stopped, and chemoradiation therapy with S-1 was performed. After chemoradiation therapy, the tumor shrank to 14 mm, while no change of the abutment around SMA was observed. After 8 months from the initial diagnosis, total pancreatectomy and resection of the PV/SMV were performed. Approximately 70 mm of the PV/SMV was surgically removed and was reconstructed using a graft from the left superficial femoral vein in consideration of the length and diameter. Although delayed gastric emptying was postoperatively observed, the patient was discharged 39 days after operation, then received adjuvant therapy with S-1. The patient is alive without recurrence and the patency of PV/SMV was well maintained.

BACKGROUND AND AIMS: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is used for the histopathological diagnosis of any type of gastrointestinal disease. Few adverse events are experienced with this procedure; however, the actual rate of adverse events remains unclear. This study aimed to clarify the current status of cases that experienced adverse events related to the EUS-FNA procedure used for histopathologic diagnoses. METHODS: A retrospective analysis of cases with EUS-FNA-related adverse events in Japanese tertiary centers was conducted by assessing the following clinical data: basic case information, FNA technique, type of procedural adverse events, and prognosis. RESULTS: Of the 13,566 EUS-FNA cases overall, the total number of cases in which adverse events related to EUS-FNA occurred was 234. The incidence of EUS-FNA-related adverse events was ~1.7%. Bleeding and pancreatitis cases accounted for ~49.1% and 26.5% of all adverse events, respectively. Bleeding was the most common adverse event with only seven cases requiring blood transfusion. In cases with neuroendocrine tumors, pancreatitis was the most frequent adverse event. Needle tract seeding because of EUS-FNA was observed during the follow-up period in only ~0.1% of cases with pancreatic cancer. There was no mortality because of adverse events caused by EUS-FNA. CONCLUSIONS: This study revealed that the adverse events-related EUS-FNA for histopathologic diagnoses were not severe conditions, and had low incidence.

Blue light imaging (BLI) and narrow-band imaging (NBI) are two modalities that enable narrow-band light observation. We aimed to compare the diagnostic ability of magnifying endoscopy with BLI (ME-BLI) and NBI (ME-NBI) for determining the invasion depth of superficial esophageal squamous cell carcinoma (SESCC) by the Japanese Esophageal Society's intrapapillary capillary loop (IPCL) classification. We enrolled 81 patients between 2014 and 2018, and the still endoscopic images for diagnosing the invasion depth at the same part in ME-BLI and ME-NBI were registered. Two blinded investigators reviewed them and diagnosed the invasion depth by the IPCL classification. Subsequently, the diagnostic yields in two modalities were compared. The overall accuracies for the invasion depth by the IPCL classification in ME-BLI and ME-NBI did not differ significantly (67.9-71.6% vs. 72.8-74.1%). In the analysis based on the invasion depth, the sensitivities and positive predictive values in tumors invading the muscularis mucosa or submucosa ≤200 µm were low (23.1-30.8% and 16.7-25.0%, respectively) in both modalities. In conclusion, the diagnostic ability for determining the invasion depth of SESCC by the IPCL classification was relatively similar in ME-BLI and ME-NBI, but diagnosis by magnifying endoscopy alone might not be satisfactory.

OBJECTIVES: Although many patients with early gastric cancers (EGCs) die of non-gastric cancer-related causes, the association of the risk categories of lymph node metastasis (LNM) with all-cause mortality remains unclear. We aimed to clarify the predictors of early and late mortality, separately. METHODS: Patients with endoscopic resection or gastrectomy for EGCs between 2003 and 2017 were retrospectively enrolled. We analyzed predictors for early and late mortality, including risk categories of LNM, treatment method, and nine non-cancer-related indices, separately, with a cut-off value of 3 years. RESULTS: We enrolled 1439 patients with a median follow-up period of 79 months. The 5-year overall survival rate was 86.8%. In the multivariate Cox analysis, the most important predictors for early and late mortality were age ≥85 years (hazard ratio [HR] 2.88 and 4.54, respectively) and Eastern Cooperative Oncology Group Performance Status ≥2 (HR 3.00 and 4.19, respectively). Charlson comorbidity index ≥2 (HR 2.76 and 1.99, respectively), American Society of Anesthesiologists Physical Status ≥3 (HR 2.35 and 1.79, respectively), and C-reactive protein/albumin ratio ≥0.028 (HR 2.30 and 1.58, respectively) were also predictors for both early and late mortality. Male (HR 2.26), intermediate- (HR 2.12)/high-risk (HR 1.85) of LNM in eCura system, and sarcopenia evaluated by the psoas muscle mass index (HR 1.70) were predictors for early mortality. CONCLUSION: The combined assessment of multiple predictors might help to predict early and/or late mortality in patients with EGCs. The eCura system was associated with early mortality.

BACKGROUND: With the ongoing growth of the aged population, the number of elderly patients suffering from gastric cancer has increased in Japan. Since the frequency of lymph node metastasis (LNM) in patients after endoscopic submucosal dissection (ESD) with endoscopic curability (eCura) C-2 for early gastric cancer (EGC) is relative low, the following question can be raised: "Is additional gastrectomy required for elderly patients with such criteria for ESD?" SUMMARY: For therapeutic decision-making after ESD with eCura C-2, the risk of all-cause mortality and impaired quality of life (QoL) should thus be evaluated. Risk stratification of LNM and gastric cancer-specific mortality was established by the eCura system; however, it remains unclear how much these categories and treatment selection affect all-cause mortality. The contribution of prognostic tools for predicting all-cause mortality was noted to vary across the studies of patients with EGC; thus, further studies that investigate comprehensive geriatric assessment (CGA) may be required. Regarding the QoL, studies on elderly patients remain to be lacking. Furthermore, one of the issues with CGA and QoL tools is that they are time consuming. Key Messages: Combined evaluation of risk stratification of gastric cancer-specific mortality by the eCura system and risk of nongastric cancer-related mortality and impaired QoL may be the current optimal method to decide treatment strategy after ESD with eCura C-2 for EGC among elderly patients. A large-scale prospective study that investigates CGA domains is required to identify predictors of all-cause mortality and impaired QoL, and a more easily usable tool should be developed.

BACKGROUND: Although post-bulbar duodenal ulcers (PBDUs) could become a source of upper gastro-intestinal bleeding, the whole picture of the disease is unknown. We compared the characteristic features and treatment outcomes after endoscopic hemostasis between PBDUs and bulbar duodenal ulcers (BDUs). METHODS: Data on duodenal ulcers with evidence of endoscopically-active bleeding were extracted from the data that were retrospectively collected at 12 institutes in Japan between 2011 and 2018. Rebleeding and in-hospital mortality were compared between patients with PBDUs and those with BDUs by logistic regression analyses. RESULTS: Among 468 consecutive patients with bleeding duodenal ulcers, 96 (20.5%) had endoscopically-confirmed PBDUs. PBDUs were more frequently observed in patients with a poor general condition in comparison to BDUs. The rates of rebleeding and in-hospital mortality in patients with PBDUs were approximately 3 times higher than those in patients with BDUs (PBDU vs. BDU: 29.2% vs. 10.2% [p<0.0001] and 14.6% vs. 5.1% [p=0.0029], respectively). Although the high in-hospital mortality in PBDUs could be explained, to a lesser extent, by the likelihood of rebleeding, and, to a greater extent, by the patients' poor general condition, the presence of a PBDU itself was largely responsible for the high rebleeding rates in PBDUs. CONCLUSIONS: This is the first study focusing on the nature and treatment outcomes of bleeding PBDUs. PBDUs were associated with much higher rebleeding and mortality rates in comparison to BDUs, and the likelihood of rebleeding may be derived from their unique anatomic location.

Several case reports have described severe postoperative enteritis shortly after total colectomy for ulcerative colitis. The very low incidence of this condition makes diagnosis and treatment difficult, and the appropriate treatment strategy is unclear. We report two cases of enteritis after surgery for ulcerative colitis, which were treated with anti-tumor necrosis factor-α therapy. Case 1 involved a 22-year-old man with symptoms, such as nausea 40 days after total colectomy. Gastrointestinal endoscopy revealed patchy obliteration of the vascular pattern, erosions in the duodenum, and superficial ulcers in the small intestine. His symptoms and endoscopic findings immediately improved upon administration of infliximab; clinical remission lasted 5 years with continuous administration. Case 2 involved a 64-year-old man, who had a large amount of watery diarrhea from ileostomy that increased 5 days after total colectomy; gastrointestinal endoscopy revealed extensive ulcers in the small intestine. Symptoms and endoscopic findings improved with prednisolone, but relapsed with tapering of the corticosteroid. Administration of adalimumab resulted in marked improvement of enteritis. However, the small intestine developed a pinhole stricture, and partial resection of the small intestine was performed. Our experience with two cases indicates that anti-tumor necrosis factor-α therapy may play an important role in ulcerative colitis-related postoperative enteritis.

As the central regulator of the oxidative stress response, nuclear factor erythroid 2-related factor 2 (Nrf2) is attracting great interest as a therapeutic target for various cancers, and the possible clinical applications of novel Nrf2 inhibitors have been explored in Nrf2-activated cancers. In the present study, we specifically investigated halofuginone, which is derived from a natural plant alkaloid. We found that halofuginone administration decreased the number of pancreatic intraepithelial neoplasias in pancreas-specific Kras and p53 mutant (KPC) mice. In Nrf2-activated pancreatic cancer cell lines established from KPC mice, halofuginone rapidly depleted Nrf2 in Nrf2-activated cancer cells. Both in vitro and in vivo, it sensitized Nrf2-activated pancreatic cancer cells to gemcitabine, which is the first-line chemotherapy in clinical practice. In our mechanistic study, we found that halofuginone downregulated aldehyde dehydrogenase 3a1 (ALDH3A1) in mouse pancreatic cancer cells. The Nrf2 inducer diethyl maleate upregulated ALDH3A1, and knockdown of Aldh3a1 sensitized Nrf2-activated cancer cells to gemcitabine, strongly suggesting that ALDH3A1 is regulated by Nrf2 and that it contributes to gemcitabine resistance. The current study demonstrated the therapeutic benefits of halofuginone in Nrf2-activated pancreatic cancers. SIGNIFICANCE STATEMENT: We identified nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target aldehyde dehydrogenase 3a1 (ALDH3A1) as novel therapeutic targets in pancreatic cancer. They negatively affect the efficacy of a conventional chemotherapeutic agent, gemcitabine. We confirmed that Nrf2 plays a pivotal role in the induction of ALDH3A1.

It was previously identified that systemic Nrf2 deletion attenuates pancreatic cancer progression in a mutant K-ras/p53-expressing mouse model (KPC mouse). In this study, the type of cell that is responsible for the retarded cancer progression was elucidated. Human pancreatic cancers were first examined, and elevated expression of NRF2-target gene products in α-smooth muscle actin-positive cells was found, suggesting that pancreatic stellate cells (PSCs) are involved in this process. Closer examination of primary cultured PSCs from Nrf2-deleted mice revealed that the cells were less proliferative and retained a lower migration capacity. The conditioned medium of Nrf2-deleted PSCs exhibited reduced growth-stimulating effects in pancreatic cancer cells. KPC mouse-derived pancreatic cancer cells coinjected with wild-type PSCs developed significantly larger subcutaneous tumors in immunodeficient mice than those coinjected with Nrf2-deleted PSCs. These results demonstrate that Nrf2 actively contributes to the function of PSCs to sustain KPC cancer progression, thus, suggesting that Nrf2 inhibition in PSCs may be therapeutically important in pancreatic cancer.NEW & NOTEWORTHY This study identified that Nrf2 contributes to PSC activation. Nrf2 deletion in PSCs resulted in attenuation of cancer-promoting role. Nrf2 in PSCs could be an attractive therapeutic target in pancreatic cancer.

The effectiveness of azathioprine (AZA) in preventing relapse and maintaining autoimmune pancreatitis (AIP) remission has been reported; however, most of these studies are case series with no randomized control trials available in the literature. Therefore, this study performed a systematic review and meta-analysis of the existing literature on this subject to determine the clinical efficacy of AZA as maintenance therapy for AIP patients. A systematic search was performed to identify studies on the clinical efficacy of AZA as maintenance therapy in AIP patients. The crude multiple relapse rate was estimated to assess the ability of AZA to control relapses in AIP. Pooled estimates were obtained using a random-effects model with the DerSimonian-Laird method. We identified AIP patients who did not respond to initial steroid treatment, experienced steroid weaning failure, or those who relapsed during remission as refractory cases. After reviewing the studies, ten articles fulfilled the inclusion criteria and were selected for meta-analysis. Of all 4504 patients, 3534 patients were treated with steroids, and 346 patients were treated with AZA for relapsed AIP. In this meta-analysis, 14/73 (19.2%) patients receiving AZA for refractory AIP relapsed. Meanwhile, 14/47 (29.8%) patients without AZA experienced relapse. The integrated odds ratio for relapse risk in patients receiving AZA was estimated to be 0.52 (p = 0.15). This systematic review and meta-analysis demonstrated the efficacy of AZA in preventing relapse of AIP, which supports the use of AZA as a maintenance treatment in patients with AIP who relapse upon withdrawal of steroid therapy.

OBJECTIVES: Post-operative bleeding is the most common adverse event in endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). Patients taking antithrombotic agents has increased. We evaluated the influence of antithrombotic agents on delayed bleeding in ESD for EGC. METHODS: This was a post hoc analysis of nationwide, multicentre, retrospective cohort study in Japan. Altogether, 11452 patients who underwent ESD for EGC in 33 institutions between November 2013 and October 2016 were enrolled. The primary outcome was the incidence of delayed bleeding in patients with or without antithrombotic agents. The secondary outcome was the incidence of delayed bleeding in those who took each antithrombotic agent and the cessation status of its use compared with each matched pair of patients. We used propensity matching and inverse probability of treatment weighting (IPTW) analyses. RESULTS: There were 1353 matched pairs of patients. The incidence of delayed bleeding was 2.8% and 10.7% in those without and with antithrombotic agents, respectively (odds ratio [OR], 4.15; 95% confidence interval [CI], 2.88-5.99; p<0.001). The IPTW analysis showed similar results (OR, 4.21; 95% CI, 3.48-5.08; p<0.001). Antiplatelets, anticoagulants, and their combination increased such incidence. Heparin bridging therapy had high OR (8.80), and the continuation (OR, 3.46) and cessation (OR, 2.95) of antithrombotic agent use had similar risk. CONCLUSIONS: Antithrombotic agents increased the incidence of delayed bleeding in patients who underwent ESD for EGC. Continuing antithrombotics may be more appropriate than heparin bridging therapy.

INTRODUCTION: As the aging of people in a society advances, the number of elderly patients older than 80 years in Japan with gastric cancer continues to increase. Although delayed ulcer bleeding is a major adverse event after endoscopic submucosal dissection (ESD), little is known about characteristic risk factors for bleeding in elderly patients undergoing ESD. This study aimed to evaluate risk factors for delayed bleeding after ESD for gastric cancer in elderly patients older than 80 years. METHODS: We retrospectively evaluated the incidence of delayed bleeding after ESD in 10,320 patients with early-stage gastric cancer resected by ESD between November 2013 and January 2016 at 33 Japanese institutions and investigated risk factors for delayed bleeding in elderly patients older than 80 years. RESULTS: The incidence of delayed bleeding in elderly patients older than 80 years was 5.7% (95% confidence interval [CI]: 4.6%-6.9%, 95/1,675), which was significantly higher than that in nonelderly (older than 20 years and younger than 80 years) patients (4.5%, 4.1%-5.0%, 393/8,645). Predictive factors for ESD-associated bleeding differed between nonelderly and elderly patients. On multivariate analysis of predictive factors at the time of treatment, risk factors in elderly patients were hemodialysis (odds ratio: 4.591, 95% CI: 2.056-10.248, P < 0.001) and warfarin use (odds ratio: 4.783, 95% CI: 1.689-13.540, P = 0.003). DISCUSSION: This multicenter study found that the incidence of delayed bleeding after ESD in Japanese patients older than 80 years was high, especially in patients receiving hemodialysis and taking warfarin. Management of ESD to prevent delayed bleeding requires particular care in patients older than 80 years.

Pancreatic ductal adenocarcinoma (PDAC) accounts for the majority of all pancreatic cancers and is highly lethal. Focal parenchymal atrophy (FPA) of the pancreas has been reported as a characteristic imaging finding of early PDAC. Here, we reviewed 76 patients with PDAC who underwent computed tomography (CT) between 6 months and 3 years before PDAC diagnosis, as well as 76 sex- and age-matched controls without PDAC on CT examinations separated by at least 5 years. FPA was observed corresponding to the location of the subsequent tumor on pre-diagnostic CT in 14/44 (31.8%) patients between 6 months and 1 year, 14/51 (27.5%) patients between 1 and 2 years, and 9/41 (22.0%) patients between 2 and 3 years before PDAC diagnosis. Overall, FPA was more frequently observed in patients with PDAC (26/76; 34.2%) on pre-diagnostic CT than that in controls (3/76; 3.9%) (p < 0.001). FPA was observed before the appearance of cut-off/dilatation of the main pancreatic duct, suggesting that FPA might be the earliest sign of PDAC. FPA was less frequently found in tumors in the pancreatic head (3/27; 11.1%) than in those in the body (14/30; 46.7%) or tail (9/19; 47.4%). FPA may predict the subsequent PDAC diagnosis, serving as an important imaging sign for the early diagnosis of pancreatic cancer.

BACKGROUND: Information on whether there is a relationship between hospital volume and bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is limited. This study aimed to compare the bleeding rates after ESD for EGC according to the hospital volume. METHODS: Patients who underwent ESD for EGC at 33 institutions in Japan between November 2013 and October 2016 were included in this multicenter retrospective study. Hospital volume was categorized into three groups, based on the average annual number of ESD procedures: low- and medium-volume group (LMVG), high-volume group (HVG), and very high-volume group (VHVG). The bleeding rate after ESD for EGC was compared between the three hospital volume groups after propensity score matching. RESULTS: A total of 10,320 patients, including 2797 patients in the LMVG, 4646 patients in the HVG, and 2877 patients in the VHVG, were identified. Propensity score matching yielded 2002 patients in each hospital volume group, with an improved balance of confounding variables between the three groups. The bleeding rates in the LMVG, HVG, and VHVG were 4.3%, 3.7%, and 4.9%, respectively, and no significant difference was noted between the three groups. CONCLUSIONS: The bleeding rate after ESD for EGC did not differ between hospitals in Japan. The finding indicated that ESD for EGC is equally feasible across Japanese hospitals of different volumes regarding bleeding after ESD.

Background: New therapeutic agents, including biologics and small-molecule drugs, are widely used to treat ulcerative colitis (UC). This study evaluates long-term prognosis in Japanese patients treated with these agents and the association between prognosis and genetic susceptibility to UC. Methods: We evaluated surgery-free rates using the Kaplan-Meier method in the total cohort and in patients treated with prednisolone and new therapeutic agents. Multivariate analysis was performed to identify clinical factors affecting surgical rates using Cox's proportional hazard model. The rate of use of new therapeutic agents was compared using the Kaplan-Meier method, and multivariate analysis was conducted to investigate the correlation between the single-nucleotide polymorphism (SNP) rs117506082 and long-term prognosis. Results: Surgery-free survival decreased over time. There was no significant difference in this parameter between patients who were administered prednisolone and those who were administered new therapeutic agents. Poor response to prednisolone and treatment without topical 5-aminosalicylic acid were poor prognostic factors. Shorter time from diagnosis to initiation of treatment with new therapeutic agents was a risk factor for colectomy. The AA genotype of SNP rs117506082 was associated with a shorter time to surgery and increased use of new therapeutic agents. Conclusions: The use of new therapeutic agents might improve long-term prognosis in patients with more severe UC. Previously identified genetic risk factors were not significantly associated with a higher rate of colectomy.

Immune response involving various immunoglobulin (Ig) isotypes and subtypes to microbiome is involved in the pathogenesis and disease activity of inflammatory bowel diseases (IBDs). To clarify the presence of Ig-coated bacteria in the intestine and its association with disease activity in ulcerative colitis (UC) and Crohn's disease (CD), we extracted and classified Ig-coated bacteria from fecal samples of 42 patients with IBD and 12 healthy controls (HCs) using flow cytometry and 16S ribosomal RNA sequence analysis. The percentage of bacteria coated with IgA and IgM was higher in patients with IBD than in HCs, and IgG-coated bacteria were found only in patients with IBD. Moreover, the percentages of bacteria coated with IgG1, IgG2, IgG3, and IgM in UC samples and IgG3, IgG4, and IgM in CD samples were correlated with disease activities. The proportions of Bacteroides ovatus and Streptococcus increased during the active phase of CD. Hence, the detailed analysis of Ig-coated bacteria and Ig subtypes using flow cytometry could aid in developing useful indicators of disease activity and identifying more disease-related bacteria, which could become novel treatment targets for IBDs.

Background and Aim: The number of elderly patients with ulcerative colitis (UC) is increasing worldwide. The clinical practice of associated treatment is still unclear. Therefore, we aimed to analyze clinical treatment realities and mortality in elderly and non-elderly patients with UC. Methods: We collected UC patients' data using the diagnosis procedure combination (DPC) database system and divided eligible patients into elderly (≥65 years) and non-elderly (≤64 years) groups. We investigated and compared their therapeutic histories (medical treatments vs. surgery). Logistic regression analysis was conducted to identify clinical factors affecting surgery and in-hospital death in each group. Results: The rates of systemic steroid injection, molecular targeting drug usage, and surgery were not different between the two age groups. Meanwhile, the rate of in-hospital death in elderly patients was higher than that in non-elderly patients (2.7% vs. 0.19%, P < 0.0001). Multivariate analysis revealed that lower body mass index, treatment at an academic hospital, smoking history, molecular targeting drug use, and treatment with systemic steroid injection affected the rate of surgery in the elderly group. Multivariate analysis also revealed that male and older age affected the rate of in-hospital death in the elderly group. Similar tendencies were also recognized in the non-elderly group. Conclusions: The clinical practice of treating elderly patients with UC is overall not different from treating non-elderly patients with UC. Although the form of medical treatment and surgery rate for elderly patients with UC may not be significantly different from non-elderly patients, the rate of in-hospital death for elderly patients is higher.

Hepatitis C virus (HCV) infection has an adverse impact on outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). It is recommended that HSCT candidates infected with HCV receive the treatment prior to transplantation. Although the recent approval of direct-acting antivirals (DAAs) has led to great advances in the treatment of HCV infection, little information is available on the efficacy and safety of DAA therapy in patients receiving allogeneic HSCT. Herein, we report the clinical course of an umbilical cord blood (UCB) recipient treated with DAAs for HCV infection. The patient achieved HCV RNA negativity with glecaprevir and pibrentasvir after consolidation therapy for acute myeloid leukemia (AML), and underwent transplantation before confirming sustained virological response (SVR) at 12 weeks. The HCV viral load became detectable on day +28 after transplantation and second HCV treatment with sofosbuvir, velpatasvir, and ribavirin was required. It is important to confirm SVR prior to transplantation, but it is often difficult. If early transplantation is required, close monitoring of HCV RNA after transplantation is needed. Further investigation is required to clarify the optimal management of HCV infection for allogeneic HSCT recipients in the DAA era.

Currently, the hepatocellular trafficking pathways that are used by the hepatitis B virus (HBV) during viral infection and shedding are poorly defined. It is known that the HBV uses late endosomal and multivesicular body (MVB) compartments for assembly and release. The intraluminal vesicles (ILVs) generated within MVBs have also been implicated in the late synthesis stages of a variety of pathogenic viruses. We recently observed that the HBV within infected hepatocytes appears to associate with the tetraspanin protein CD63, known to be a prominent and essential component of ILVs. Immunofluorescence microscopy of HBV-expressing cells showed that CD63 colocalized with HBV proteins (large hepatitis B surface antigens [LHBs] and hepatitis B core) and labeled an exceptionally large number of secreted extracellular vesicles of uniform size. Small interfering RNA (siRNA)-mediated depletion of CD63 induced a substantial accumulation of intracellular LHBs protein but did not alter the levels of either intracellular or extracellular HBV DNA, nor pregenomic RNA. Consistent with these findings, we found that markedly less LHBs protein was associated with the released HBV particles from CD63 siRNA-treated cells. Importantly, the HBV viral particles that were shed from CD63-depleted cells were substantially less infective than those collected from control cells with normal CD63 levels. Conclusion: These findings implicate the tetraspanin protein CD63 as a marker and an important component in the formation and release of infectious HBV particles.

BACKGROUND: Pancreatic serous cystic neoplasm (SCN) is an uncommon exocrine neoplasm, which is believed to be a benign entity. However, some of these neoplasms may occasionally attain metastatic ability. Von Hippel-Lindau disease (VHL) manifests a dominantly inherited systemic syndrome accompanied by several benign or malignant tumors, including cystic tumors, in various organs. We describe here a long-term survival case who underwent surgical resection for metachronous liver metastases of pancreatic SCN associated with VHL disease. CASE PRESENTATION: A 35-year-old woman with VHL underwent total pancreatectomy and right nephrectomy for pancreatic SCN and renal cell carcinoma, respectively. At the 4th year follow-up examination after the resection, contrast-enhanced computed tomography (CT) and gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) showed arterially hyper-enhanced neoplastic lesions in the segment VI and VIII of the liver. Partial resections of the liver were performed 53 months after the initial surgery. At the 6th month follow-up examination from the second surgery, one and two tumors located in the liver segment III, and VIII, respectively, were detected by contrast-enhanced CT and Gd-EOB-DTPA-enhanced MRI. Anterior segmentectomy and partial resection of the segment III were performed 66 months after the initial surgery and 13 months after the second, respectively. The tumors were pathologically diagnosed as liver metastases of pancreatic SCN synonymous with serous cystadenocarcinoma. She remains disease-free without recurrence 6.5 years after the last operation. CONCLUSIONS: This is the first report of a case of metastatic SCN associated with VHL. Surgical resection might confer a favorable prognosis in patients of pancreatic SCN with liver metastases.

BACKGROUND: No prediction scores for the mortality of both inpatients and outpatients who developed nonvariceal upper gastrointestinal bleeding (UGIB) without endoscopic findings have been established. We aimed to derive and validate a novel prediction score for in-hospital mortality. METHODS: We conducted a three-stage, multicenter retrospective study. In the derivation stage, patients with nonvariceal UGIB at six institutions were enrolled to derive the prediction score by logistic regression analysis. External validation of the score was performed to analyze discrimination by patients at six other institutions. Then the performance of this score was compared with that of four existing scores. RESULTS: We enrolled 1380 and 825 patients in the derivation and validation cohorts, respectively. A prediction score (CHAMPS-R Score) comprising seven variables (Charlson Comorbidity Index ≥ 2, in-hospital onset, albumin < 2.5 g/dL, altered mental status, Eastern Cooperative Oncology Group performance status ≥ 2, steroids, and rebleeding) with equal-weight scores was established, with high discriminative ability in both derivation and validation cohorts (c statistic, 0.91 and 0.80, respectively). When rebeeding was excluded from the score (an onset model; CHAMPS Score), this score also achieved high discriminative ability (c statistic, 0.90 and 0.81, respectively). The prediction scores had significantly higher discriminative ability than the Glasgow Blatchford Score, AIMS65, ABC Score, and clinical Rockall Score in both cohorts (all, p < 0.05). CONCLUSIONS: We derived and externally validated prediction scores for in-hospital mortality in patients with nonvariceal UGIB. The CHAMPS Score might be optimal for managing such patients. Its mobile application is freely available ( https://apps.apple.com/app/id1565716902 for iOS and https://play.google.com/store/apps/details?id=hatta.CHAMPS for Android).

The envelope of hepatitis B virus (HBV), which is required for the entry to hepatocytes, consists of a lipid bilayer derived from hepatocyte and HBV envelope proteins, large/middle/small hepatitis B surface antigen (L/M/SHBs). The mechanisms and host factors for the envelope formation in the hepatocytes are being revealed. HBV-infected hepatocytes release a large amount of subviral particles (SVPs) containing L/M/SHBs that facilitate escape from the immune system. Recently, novel drugs inhibiting the functions of the viral envelope and those inhibiting the release of SVPs have been reported. LHBs that accumulate in ER is considered to promote carcinogenesis and, especially, deletion mutants in the preS1/S2 domain have been reported to be associated with the development of hepatocellular carcinoma (HCC). In this review, we summarize recent reports on the findings regarding the biological characteristics of HBV envelope proteins, their involvement in HCC development and new agents targeting the envelope.

Amyloidosis is classifiable as systemic, with amyloid deposition in organs throughout the body, or localized, involving only one organ. Amyloidosis localized in the intestinal tract is rare. This report describes three cases of localized AL amyloidosis in the intestinal tract and presents their clinical characteristics, endoscopic findings, and prognoses. All three cases were asymptomatic, and were found accidentally during endoscopy for closer examination after a positive fecal occult blood test. Endoscopic findings included patchy redness and meandering dilated vessels of the lesion. Using autofluorescence (AFI) endoscopy, the lesion of amyloid deposition was enhanced as bright green. We used fluorescence microscopy to observe unstained specimens obtained from an amyloid deposition site with excitation light. Autofluorescence was detected with the broad excitation wavelength at amyloid deposition lesion sites of the specimen. Results revealed that AL amyloid has autofluorescence that engenders its detection by AFI endoscopy as bright green. In none of the three cases was systemic amyloidosis or organ failure observed. The long-term course of all the cases was favorable.

BACKGROUND AND AIM: Although colonic diverticular bleeding (CDB) is considered to have good prognosis with conservative therapy, some cases are severe. The efficacy of urgent colonoscopy for CDB and clinical factors affecting CDB prognosis are unclear. This study aimed to evaluate the efficacy of urgent colonoscopy for CDB and identify risk factors for unfavorable events, including in-hospital death during admission, owing to CDB. METHODS: We collected CDB patients' data using the Diagnosis Procedure Combination database system. We divided eligible patients into urgent and elective colonoscopy groups using propensity score matching and compared endoscopic hemostasis and in-hospital death rates and length of hospital stay. We also conducted logistic regression analysis to identify clinical factors affecting CBD clinical events, including in-hospital death, a relatively rare CDB complication. RESULTS: Urgent colonoscopy reduced the in-hospital death rate (0.35% vs 0.58%, P = 0.033) and increased the endoscopic hemostasis rate (3.0% vs 1.7%, P < 0.0001) compared with elective colonoscopy. Length of hospitalization was shorter in the urgent than in the elective colonoscopy group (8 vs 9 days, P < 0.0001). Multivariate analysis also revealed that urgent colonoscopy reduced in-hospital death (odds ratio = 0.67, 95% confidence interval: 0.46-0.97, P = 0.036) and increased endoscopic hemostasis (odds ratio = 1.84, 95% confidence interval: 1.53-2.22, P <  0.0001). CONCLUSION: Urgent colonoscopy for CDB may facilitate identification of the bleeding site and reduce in-hospital death. The necessity and appropriate timing of urgent colonoscopy should be considered based on patients' condition.

A 72-year-old man without any symptoms was referred to our hospital. Esophagogastroduodenoscopy revealed an elevated esophageal lesion that was covered with normal mucosa. The examination of biopsy specimens from the lesion revealed amyloid light-chain (AL) (λ) type amyloid deposits, but there were no amyloid deposits elsewhere in the gastrointestinal tract. Further examinations did not indicate systemic amyloidosis. Thus, this case was diagnosed as a localized esophageal amyloidosis. As the clinical outcome of localized amyloidosis is favorable, this case was scheduled for close follow-up. Localized amyloidosis should be considered in the differential diagnosis of esophageal submucosal tumors.

Hepatitis C virus reactivation (HCVr) was defined previously as an increase in HCV RNA level of ≥ 1 log10 IU/mL from baseline HCV RNA level after chemotherapies or immunosuppressive therapies, but HCVr during a steroid monotherapy has rarely been reported. Here we report a 75-year-old Japanese female with chronic hepatitis C (genotype 2a) who developed HCVr after the administration of prednisolone for interstitial pneumonia. She experienced alanine aminotransferase (ALT) flare with icterus, but after the tapering of prednisolone and a liver supporting therapy, levels of HCV RNA and ALT were gradually decreased. Then, she received an anti-viral therapy with sofosbuvir/ledipasvir. Although HCV relapsed 4 weeks after the therapy, a second therapy with glecaprevir/pibrentasvir was successful. This case suggests that HCVr with hepatitis flare can occur even after a steroid monotherapy, and we should pay attention to HCVr when we administer prednisolone for patients with HCV chronic infection.

INTRODUCTION: MicroRNAs (miRNAs) can serve as tumor biomarkers; however, their role in evaluating colorectal adenoma (CRA) is unclear. Recently, the organoid culture system enabled long-term expansion of human colon epithelium. This study aimed to examine the potential of exosomal miRNAs extracted from CRA organoids as biomarkers in the clinical liquid biopsy CRA test. METHODS: We established organoid cultures from normal colon and CRA using resected specimens. Exosomes were isolated from the conditioned medium organoids. MiRNAs were isolated from the exosomes, and their expression profiles were compared using microarray analysis. To identify miRNA candidates for liquid biopsy, we prospectively compared changes in their expression in serum and exosomes before and after endoscopic resection in 26 patients with CRA. RESULTS: Seven exosomal miRNAs were overexpressed in CRA organoids: miR-4323, miR-4284, miR-1268a, miR-1290, miR-6766-3p, miR-21-5p, and miR-1246. The expression levels of 4 exosomal miRNAs (miR-4323, miR-4284, miR-1290, and miR-1246) and 2 serum miRNAs (miR-1290 and miR-1246) were significantly lower in posttreatment sera. The combined expression of 4 exosomal miRNAs could identify both CRA and large-size (>12.6 cm2) CRA with respective areas under the curve of 0.698 (95% confidence interval [CI] = 0.536-0.823) and 0.834 (95% CI = 0.660-0.929). Combinations of 2-serum miRNA expression values could identify both CRA and large-size CRA with respective area under the curves of 0.691 (95% CI = 0.528-0.817) and 0.834 (95% CI = 0.628-0.938). DISCUSSION: We found that exosomal miRNAs derived from the CRA organoid culture could be potential diagnostic biomarkers for CRA.

BACKGROUND AND AIM: This study aimed to reveal the timing of bleeding and thromboembolism associated with endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). METHODS: We retrospectively reviewed  10,320 patients who underwent ESD for EGC during November 2013-October 2016. We evaluated overall bleeding rates and their inter-group differences. Factors associated with early/late (cut-off 5 days) bleeding and thromboembolism frequency and its association with the intake of antithrombotic agents were investigated. RESULTS: Overall, the post-ESD bleeding rate was 4.7% (489/10 320); the median time to post-ESD bleeding was 4 days. The post-ESD bleeding rates were 3.2%, 8.7%, 15.5%, and 29.9% in those not taking antithrombotic agents, those taking antiplatelet agents, those taking anticoagulants (ACs), and those taking antiplatelet agents and ACs. Warfarin (odds ratio [OR], 9.16), direct oral ACs (OR, 4.16), chronic kidney disease with hemodialysis (OR, 2.93), thienopyridine (OR, 2.25), aspirin (OR, 1.66), tumor size >30 mm (OR, 1.86), multiple tumors' resection (OR, 1.54), and tumor in the lower third of the stomach (OR, 1.40) were independent risk factors for early bleeding. The independent risk factors for late bleeding were direct oral ACs (OR, 7.42), chronic kidney disease with hemodialysis (OR, 4.99), warfarin (OR, 3.90), thienopyridine (OR, 3.09), liver cirrhosis (OR, 2.43), cilostazol (OR, 1.93), aspirin (OR, 1.92), ischemic heart disease (OR, 1.77), and male sex (OR, 1.65). There were three (0.03%) thromboembolic events (cerebral infarction = 2, transient ischemic attack = 1). CONCLUSION: We revealed the timing of bleeding and risk factors for early/late bleeding and showed the thromboembolism frequency associated with ESD for EGC.

BACKGROUND: We aimed to elucidate the risk of metastatic recurrence after endoscopic resection (ER) without additional treatment for esophageal squamous cell carcinomas (ESCCs) with tumor invasion into the muscularis mucosa (pT1a-MM) or submucosa (T1b-SM). METHODS: We retrospectively enrolled patients with pT1a-MM/pT1b-SM ESCC after ER at 21 institutions in Japan between 2006 and 2017. We compared metastatic recurrence between patients with and without additional treatment, stratified into category A (pT1a-MM with negative lymphovascular invasion [LVI] and vertical margin [VM]), B (tumor invasion into the submucosa ≤ 200 µm [pT1b-SM1] with negative LVI and VM), and C (others). Subsequently, using multivariate Cox analysis, we evaluated risk factors for metastatic recurrence after ER without additional treatment. RESULTS: We enrolled 593 patients, and metastatic recurrence occurred in 38 patients. Metastatic recurrence after additional treatment was significantly lower than that after no additional treatment in category C (9.1% vs. 23.6% in 5 years, p = 0.001), whereas no significant difference was noted in categories A (0.0% vs. 2.6%) and B (0.0% vs. 4.3%). In patients without additional treatment after ER, risk factors for metastatic recurrence were lymphatic invasion (hazard ratio [HR], 5.61), positive VM (HR, 4.55), and tumor invasion into the submucosa > 200 μm (HR, 3.25), and, but near half of the patients with metastatic recurrence had no further recurrence after salvage treatment, resulting in excellent 5-year disease-specific survival in categories A (99.6%) and B (100.0%). CONCLUSIONS: Closed follow-up with no additional treatment may be an acceptable option after ER in pT1a-MM/pT1b-SM1 ESCC with negative LVI and VM.

BACKGROUND: Delayed bleeding is the major adverse event in upper gastrointestinal endoscopic treatment (UGET). We aimed to investigate the efficacy of vonoprazan, which is the novel strong antisecretory agent, to reduce the risk for delayed bleeding in comparison with proton pump inhibitors (PPIs) in UGET. METHODS: This retrospective population-based cohort study used the Diagnosis Procedure Combination database in Japan. We included patients on vonoprazan or PPI in UGET between 2014 and 2019. The primary outcome was delayed bleeding. We conducted propensity score matching to balance the comparison groups, and logistic regression analyses to compare the bleeding outcomes. RESULTS: We enrolled 124,422 patients, in which 34,822 and 89,600 were prescribed with vonoprazan and PPI, respectively. After propensity score matching, the risk for delayed bleeding was lower in vonoprazan than in PPI (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.71-0.80), consistent with sensitivity analysis results. In the subgroup analyses of seven UGET procedures, vonoprazan was significantly advantageous in esophageal endoscopic submucosal dissection (E-ESD) (OR, 0.71; 95% CI, 0.54-0.94) and gastroduodenal endoscopic submucosal dissection (GD-ESD) (OR, 0.70; 95% CI, 0.65-0.75), although correction for multiple testing of the outcome data removed the significance in E-ESD. These results were also consistent with sensitivity analysis results. In the five other procedures, no significant advantage was found. CONCLUSIONS: This nationwide study found that, compared with PPI, vonoprazan can reduce delayed bleeding with approximately 30% in GD-ESD. Vonoprazan has the possibility to become a new treatment method for preventing delayed bleeding in this procedure.

An 83-year-old man without specific symptoms was referred to our hospital for further evaluation and treatment of apparent double primary tumors of the cystic duct and common bile duct. Computed tomography showed contrast-enhanced solid tumors in the cystic duct and common bile duct. Magnetic resonance imaging showed that the bile duct tumor was isointense on T1-weighted images and had low intensity on T2-weighted images. In addition, the bile duct tumor showed high intensity on diffusion-weighted images. Endoscopic ultrasonography revealed the tumor of the common bile duct and endoscopic retrograde cholangiopancreatography demonstrated a filling defect in the bile duct. The cystic duct was not identified on endoscopic ultrasonography or endoscopic retrograde cholangiopancreatography. Transpapillary biopsy of the bile duct tumor showed adenocarcinoma. The patient was diagnosed with double primary tumors of the cystic duct and the common bile duct and underwent subtotal stomach-preserving pancreaticoduodenectomy. Microscopic examination with molecular profiling of the tumors revealed a high-grade noninvasive intracholecystic papillary neoplasm of the cystic duct extending into the common bile duct and forming a tubulopapillary neoplasm with invasion of the common bile duct.

OBJECTIVE: Sarcopenia worsens the prognosis of patients with hepatocellular carcinoma (HCC). The aim of this study was to elucidate the plasma free amino acids (PFAAs) associated with sarcopenia or myosteatosis in the course of HCC recurrence. METHODS: In this cross-sectional study, 187 patients were enrolled retrospectively. All patients experienced more than one hospitalization (mean times, 2.65) owing to HCC recurrence. The skeletal muscle index (SMI) and muscle attenuation (MA) were measured by a transverse computed tomography (CT) scan image at the third lumbar vertebra (L3). The changes in the concentration of 24 PFAAs, SMI, and MA in the same patient between recurrences were defined as Δ. The associations between sarcopenia, myosteatosis, and PFAAs were evaluated by a logistic regression model. The ΔSMI and ΔMA were compared between the patients who received branched-chain amino acids (BCAAs) formulation and those who did not. RESULTS: Patients with sarcopenia showed lower survival rate; the 1-, 3-, and 5-y survival rates were 85%, 42%, and 9%, respectively. Multivariate analysis revealed that the level of total BCAAs was significantly associated with sarcopenia. The correlation coefficient value between the change of leucine (ΔLeu) and ΔSMI was highest (R = 0.256; P < 0.001) among the PFAAs. In the Child-Pugh grade B or C, the decrease of SMI was significantly more suppressed in the patients with the BCAAs formulation than in those without BCAAs formulation (ΔSMI: mean change -0.98 versus -3.45 cm²/m²; P = 0.038). CONCLUSION: Among the PFAAs, the level of BCAAs was associated with sarcopenia in the course of HCC recurrence.

PURPOSE: To evaluate the diagnostic performance of apparent diffusion coefficient (ADC) parameters by region of interest (ROI) methods in differentiating mass-forming autoimmune pancreatitis (AIP) from pancreatic ductal adenocarcinoma (PDAC). METHODS: The institutional review board approved this retrospective study and the requirement for informed consent was waived. Twenty-three patients with mass-forming AIP and 144 patients with PDAC underwent diffusion-weighted imaging with b-values of 0 s/mm2 and 800 s/mm2. The minimum, maximum, and mean ADC values obtained by placing ROIs within lesions and percentile ADC values (10th, 25th, 50th, 75th, and 90th) from entire-lesion histogram analysis were compared between the two groups by using Mann-Whitney U tests. The diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: The minimum, maximum, and mean ADC values were significantly different between mass-forming AIP and PDAC groups. ROC curve analysis showed that the maximum ADC had the highest diagnostic performance (0.92), while the minimum ADC value had the lowest diagnostic performance (0.72). The AUC of minimum ADC was significantly lower than that of maximum or mean ADC (P < 0.0001, P < 0.0001). The AUC was lowest in 10th percentile ADC value and highest in 90th percentile value. The AUC increased along with the increase of percentile values. CONCLUSION: Either the maximum or mean ADC value was effective in differentiating mass-forming AIP from the PDAC group, while the minimum ADC value might not be recommended.

A 31-year-old man with Crohn's disease in remission after 6-year treatment with infliximab developed nasopharyngeal diffuse large B cell lymphoma. Infliximab was discontinued, and complete remission was achieved following chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. However, the patient subsequently experienced severely symptomatic Crohn's disease relapse. Therapy with adalimumab was initiated, and the patient attained remission. However, after 3 months, he suffered a recurrence of the lymphoma. Adalimumab was discontinued, and the patient received further chemotherapy (with rituximab, etoposide, cisplatin, methylprednisolone, and high-dose cytarabine) treatment and underwent allogeneic hematopoietic stem cell transplantation. Following the procedure, Crohn's disease and lymphoma have remained in complete remission for 5 years. There are limited reports on Crohn's disease remission after allogeneic hematopoietic stem cell transplantation. Therefore, we present this case report and a review of the existing literature on allogeneic stem cell transplantation for Crohn's disease.

A 66-year-old man with a history of diabetes and dilated cardiomyopathy underwent the implantation of a ventricular assist device (VAD) at the age of 62. He suffered from epigastralgia for a month and then visited our hospital with complaints of severe epigastralgia and hematemesis. A physical examination revealed abdominal distension without rigidity. Laboratory data showed severe systemic inflammation, multiple organ failure, and disseminated intravascular coagulation. Computed tomography showed multifocal thickness of the gastroduodenal wall with surrounding panniculitis, gas in a portal vein and a perigastric vein. Emergency esophago-gastro duodenoscopy (EGD) demonstrated a large erosion in the antrum of the stomach, and penetration surrounded by circumferentially ischemic mucosa in the second and third portions of the duodenum. Based on informed consent, conservative therapy was performed, and his condition improved enabling the start of oral intake on the 37th hospital day. However, 7 days later, there was a relapse of epigastralgia after a meal. Gastrointestinal series and EGD revealed a 10-mm-long pinhole-like stricture at the site. After laparoscopic gastro-jejunal bypass surgery, he has remained in a good condition for 2 years. We demonstrated a rare case of penetration due to severe ischemic duodenitis 4 years after VAD implantation.

A 64-year-old man was admitted to our hospital to undergo examination of a pancreatic tumor accompanied by sudden epigastric pain. The tumor had a well-defined oval shape that was mostly less enhanced, with the exception of part of the tumor on the pancreatic head side, on contrast enhanced (CE)-CT. However, CE-CT performed one-month later revealed that the viable part of the tumor grew toward the pancreatic tail with the reduction of necrotic tissue. We performed distal pancreatectomy and the tumor was diagnosed as acinar cell carcinoma (ACC). One important characteristic of ACC is that it may develop morphological changes within a short period of time.

Nonalcoholic fatty liver disease (NAFLD) is a lipotoxic disease wherein hepatic steatosis and oxidative stress are key pathogenic features. However, whether free amino acids (FAAs) are associated with the oxidative stress response against lipotoxicity has yet to be determined. We hypothesized that an imbalance of FAAs aggravates hepatic steatosis by interfering with the oxidative stress sensor. C57BL/6 mouse immortalized hepatocytes, primary hepatocytes and organoids were employed. Steatotic hepatocytes treated with oleic acid (OA) were cultured under FAAs-modifying media based on the concentrations of FAAs in the hepatic portal blood (HPB) of wild type mice (WT). As in vivo experiments, WT, Hepatocyte-specific Keap1 knock out (KO) mice (Keap1∆hepa ) and Cre- control mice (Keap1fx/fx ) were fed high fat (HF) diets with modified amino acid content. The correlations were analyzed between the areas of lipid droplets (LDs) around central vein and plasma OA / FAAs ratio in 61 patients with NAFLD. Mice fed a HF, Met restricted and Tyr deficient diet showed the NAFLD-like phenotype in which the nuclear translocation of Nrf2, triglyceride-rich VLDL and fumarate were decreased in liver but Keap1∆hepa ameliorated these phenomena. Reactive oxygen species and LDs induced by the deprivation of Met and Tyr were prevented in hepatic organoids generated from Keap1∆hepa . Dimethyl fumarate, a Nrf2 inducer ameliorated the steatosis and increased the hepatic fumarate reduced by the deprivation of Met and Tyr in vitro. OA / Met or Tyr ratio in peripheral blood were associated with the hepatic steatosis in NAFLD patients. CONCLUSION: An imbalance between free fatty acids and Met and Tyr induces hepatic steatosis by disturbing the VLDL assembling via the Keap1-Nrf2 system.

Several years have passed since the clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2012 were published. New findings and knowledge have accumulated since then. The Research Committees for IgG4-related Diseases and for Intractable Diseases of the Liver and Biliary Tract, in association with the Ministry of Health, Labor, and Welfare of Japan and the Japan Biliary Association, have established a working group consisting of researchers specializing in IgG4-SC and have drawn up new clinical diagnostic criteria for IgG4-SC 2020. The diagnosis of IgG4-SC is based on a combination of the following six criteria: (a) narrowing of the intra- or extrahepatic bile duct; (b) thickening of the bile duct wall; (c) serological findings; (d) pathological findings; (e) other organ involvement; and (f) effectiveness of steroid therapy. These new diagnostic criteria for IgG4-SC are useful in practice for general physicians and other non-specialists.

INTRODUCTION: Exosomes are membrane-enclosed nanovesicles, which are increasingly being recognized as important cell communication components for their role in transmitting microRNAs (miRNAs). No previous study has addressed the exosomal miRNA profile in colorectal adenomas (CRAs) because the long-term culture of CRA is challenging. This study aimed to identify the miRNA signature in organoid exosomes derived from human CRA and colorectal cancer (CRC) samples. METHODS: Organoid cultures were developed from resected colorectal tissues of patients with CRA or CRC undergoing surgery or endoscopic mucosal resection. Exosomes were prepared from the conditioned medium of the organoids. miRNAs were prepared from the exosomes and their source organoids. The miRNA expression profiles were compared using microarray analysis. The impact of alteration of miRNA expression on cell proliferation was examined using miRNA mimics or inhibitors in HT-29 human CRC cells. RESULTS: We established 6 organoid lines from CRC and 8 organoid lines from CRA. Exosomal miRNA signatures were different between the organoids derived from CRA and CRC. Both exosomal and cellular miR-1246 expressions were upregulated in CRC-derived organoids compared to their expression in CRA-derived organoids. Alteration of miR-1246 expression by the miR-1246 mimic or inhibitor increased or decreased cell proliferation in HT-29 cells, respectively. CONCLUSIONS: We report for the first time the miRNA profiles of exosomes in CRA- and CRC-derived organoids. The upregulation of miR-1246 might play a role in increased cell proliferation in the process of CRA-carcinoma transition.

BACKGROUND: The clinical characteristics of IgG4-related sclerosing cholangitis (IgG4-SC) especially without autoimmune pancreatitis (AIP) have not been investigated in a large cohort. AIMS: To clarify the clinical characteristics of IgG4-SC and IgG4-SC without AIP. METHODS: We retrospectively reviewed imaging, serology, other organ involvement (OOI) and histology of 872 patients with IgG4-SC who participated in a Japanese nationwide survey in 2019, and compared these items between IgG4-SC with and without AIP. RESULTS: AIP was present in 83.7% (730/872) of IgG4-SC. In IgG4-SC, bile duct wall thickening was observed on ultrasound (528/650; 81.2%), computed tomography (375/525; 71.4%) and magnetic resonance imaging or cholangiopancreatography (290/440; 65.9%). An elevated serum IgG4 level (≥ 135 mg/dL) was found in 88.0% (322/366). IgG4-related OOI other than AIP was observed in 25.2% (211/836). The proportion of females was significantly higher in IgG4-SC without AIP (28.9% vs. 20.1%; p = 0.025). Hilar stricture was the most common cholangiographic type in IgG4-SC without AIP (39/107; 36.4%).There were no significant differences between IgG4-SC with and without AIP in the rates of bile duct wall thickening, elevated serum IgG4 level, or IgG4-related OOI. CONCLUSIONS: The clinical characteristics of IgG4-SC was similar between IgG4-SC with and without AIP in a large cohort.

OBJECTIVE: Bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is a frequent adverse event after ESD. We aimed to develop and externally validate a clinically useful prediction model (BEST-J score: Bleeding after ESD Trend from Japan) for bleeding after ESD for EGC. DESIGN: This retrospective study enrolled patients who underwent ESD for EGC. Patients in the derivation cohort (n=8291) were recruited from 25 institutions, and patients in the external validation cohort (n=2029) were recruited from eight institutions in other areas. In the derivation cohort, weighted points were assigned to predictors of bleeding determined in the multivariate logistic regression analysis and a prediction model was established. External validation of the model was conducted to analyse discrimination and calibration. RESULTS: A prediction model comprised 10 variables (warfarin, direct oral anticoagulant, chronic kidney disease with haemodialysis, P2Y12 receptor antagonist, aspirin, cilostazol, tumour size >30 mm, lower-third in tumour location, presence of multiple tumours and interruption of each kind of antithrombotic agents). The rates of bleeding after ESD at low-risk (0 to 1 points), intermediate-risk (2 points), high-risk (3 to 4 points) and very high-risk (≥5 points) were 2.8%, 6.1%, 11.4% and 29.7%, respectively. In the external validation cohort, the model showed moderately good discrimination, with a c-statistic of 0.70 (95% CI, 0.64 to 0.76), and good calibration (calibration-in-the-large, 0.05; calibration slope, 1.01). CONCLUSIONS: In this nationwide multicentre study, we derived and externally validated a prediction model for bleeding after ESD. This model may be a good clinical decision-making support tool for ESD in patients with EGC.

OBJECTS: Although anti-thrombotic use is recognized as a risk factor for upper gastrointestinal bleeding (UGIB), there has been no clear evidence that it worsens the outcomes after the bleeding. The aim of this study is to investigate the effects of anti-thrombotic agents on in-hospital mortality following UGIB. METHODS: Information on clinical parameters, including usage of anti-thrombotic agents, was retrospectively collected from consecutive patients with UGIB at 12 high-volume centers in Japan between 2011 and 2018. The all-cause in-hospital mortality rate was evaluated according to the usage of anti-thrombotic agents. RESULTS: Clinical data were collected from 2205 patients with endoscopically confirmed UGIB. Six hundred and forty-five (29.3%) patients used anti-thrombotic agents. The all-cause in-hospital mortality rate was 5.7% (125 deaths). After excluding 29 cases in which death occurred due to end-stage malignancy, 96 deaths (bleeding-related, n = 22 ; non-bleeding-related, n = 74) were considered "preventable." Overall, the "preventable" mortality rate in anti-thrombotic users was significantly higher than that in non-users (6.0% vs. 3.7%, P < 0.05). However, the "preventable" mortality of anti-thrombotic users showed a marked improvement over time; although the rate in users remained significantly higher than that in non-users until 2015 (7.3% vs. 4.2%, P < 0.05), after 2016, the difference was no longer statistically significant (4.8% vs. 3.5%). CONCLUSIONS: Although the usage of anti-thrombotic agents worsened the outcomes after UGIB, the situation has recently been improving. We speculate that the recent revision of the Japanese guidelines on the management of anti-thrombotic treatment after UGIB may have partly contributed to improving the survival of users of anti-thrombotic agents.

BACKGROUND Anaplastic carcinoma of the pancreas (ACP) is a rare type of cancer with an extremely poor prognosis. Hereditary pancreatitis is a rare autosomal-dominant disease. It progresses to chronic pancreatitis at a young age, increasing the risk of pancreatic cancer. CASE REPORT A 39-year-old woman was diagnosed with chronic pancreatitis at the age of 18 years. The patient was referred to our hospital for epigastralgia and jaundice. We identified a tumor mass at the head of the pancreas using contrast computed tomography (CT) and endoscopic ultrasound (EUS) of the abdomen. Tissue biopsy revealed ACP of the spindle cell type. We started the patient on combination chemotherapy using gemcitabine and nanoparticle albumin-bound (nab) -paclitaxel, but she died 1 month after her first visit. An autopsy revealed a mixture of tubular adenocarcinoma and anaplastic carcinoma. We performed genetic analysis using DNA samples from the biopsy tissues but did not find mutations in the PRSS1 and SPINK1 genes associated with hereditary pancreatitis. CONCLUSIONS The risk of pancreatic cancer generally increases in patients with hereditary pancreatitis after 50 years of age. However, in this case, the development of pancreatic cancer occurred at a younger age, suggesting the importance of early detection in such cases. Furthermore, this case suggests that EUS is a useful method for monitoring patients with hereditary pancreatitis and the diagnosis of ACP.

We herein report an extremely rare case of localized gastric amyloidosis (LGA) with morphological changes during the follow-up. A 71-year-old woman who had a depressed lesion with central elevation in the gastric lower body was diagnosed with LGA. Esophagogastroduodenoscopy at 10 years after the initial examination showed that the lesion had grown and changed morphologically, exhibiting a submucosal tumor-like appearance. Since the lesion was confined to the submucosa, the patient underwent endoscopic submucosal dissection. The final pathological diagnosis was amyloid light-chain (AL)-type LGA. This case may provide useful information regarding the natural history of AL-type LGA.

Pancreatic cancer remains intractable owing to the lack of effective therapy for unresectable cases. Activating mutations of K-ras are frequently found in pancreatic cancers, but these have not yet been targeted by cancer therapies. The Keap1-Nrf2 system plays a crucial role in mediating the oxidative stress response, which also contributes to cancer progression. Nrf2 activation reprograms the metabolic profile to promote the proliferation of cancer cells. A recent report suggested that K-ras- and Nrf2-active lung cancer cells are sensitive to glutamine depletion. This finding led to the recognition of glutaminase inhibitors as novel anticancer agents. In the current study, we used murine pancreatic cancer tissues driven by mutant K-ras and p53 to establish cell lines expressing constitutively activated Nrf2. Genetic or pharmacological Nrf2 activation in cells via Keap1 deletion or Nrf2 activation sensitized cells to glutaminase inhibition. This phenomenon was confirmed to be dependent on K-ras activation in human pancreatic cancer cell lines harboring mutant K-ras, i.e., Panc-1 and MiaPaCa-2 in response to DEM pretreatment. This phenomenon was not observed in BxPC3 cells harboring wildtype K-ras. These results indicate the possibility of employing Nrf2 activation and glutaminase inhibition as novel therapeutic interventions for K-ras mutant pancreatic cancers.

OBJECTIVES: Delayed bleeding is a major adverse event in endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). Some patients may experience rebleeding after successful hemostasis for delayed bleeding, yet the details of rebleeding remain unclear. We aimed to clarify the frequency and risk factors of rebleeding. METHODS: Among 11,452 patients who underwent ESD for EGC at 33 institutions in Japan between 2013 and 2016, we analyzed 489 patients showing delayed bleeding. The rate of rebleeding was investigated. Subsequently, 15 candidate variables were evaluated for their influence on the risk of rebleeding via logistic regression analysis. RESULTS: Rebleeding occurred in 11.2% (55/489) of the enrolled patients. Multivariate analysis revealed that warfarin [odds ratio (OR), 2.71; 95% confidence interval (CI), 1.26-5.84] and a resection size >40 mm (OR, 1.99; 95% CI, 1.08-3.67) were independent risk factors for rebleeding. In the analysis of the management of warfarin after index bleeding, only warfarin discontinuation (OR, 3.66; 95% CI, 1.37-9.78) was significantly associated with rebleeding in comparison with no use of warfarin. However, many rebleeding events (75.0%) occurred following the resumption of warfarin. The rebleeding rate during discontinuation status and that in taking warfarin (continuation or resumption) were 6.1% and 20.0%, respectively. CONCLUSIONS: Rebleeding was not a rare event in patients experiencing delayed bleeding after ESD for EGC. In addition to having a resection size >40 mm, warfarin usage placed patients at high risk for rebleeding, especially at the timing of its resumption following discontinuation as well as its continuation.

Although hepatitis B surface antigen (HBsAg) removal is considered the goal of chronic hepatitis B treatment, it can rarely be achieved with nucleos(t)ide analogues (NAs). It has been reported that tenofovir disoproxil fumarate (TDF) is superior in reducing HBsAg compared with entecavir (ETV) in treatment-naïve patients; however, the effect of TDF in patients who have received NAs is still unclear. The aim of the present study was to evaluate the efficacy of switching from ETV to TDF in patients who were already receiving ETV. A pilot randomized controlled study for 2 years in patients who had been treated with ETV for >1 year and did not exhibit drug resistance was performed (Clinical trial registration: UMIN000021948, UMIN-CTR, May 1, 2016). A total of 20 patients were enrolled and 19 patients were randomized into 2 groups, a TDF-switching group (n=12) or an ETV-continuing group (n=7). The mean change in HBsAg levels after 2 years was greater in the TDF group compared with the ETV group, but the difference was not significant (-0.25 vs. -0.06 log IU/ml). In the TDF group, hepatitis B e antigen (HBeAg)-positive patients at baseline showed significantly greater changes in HBsAg (-0.63 vs. -0.03 log IU/ml; P=0.030). In contrast, no difference between HBeAg-positive and HBeAg-negative patients was observed in the ETV group. No significant differences of estimated glomerular filtration rate and inorganic phosphorus changes were observed among the TDF and ETV groups. In conclusion, a significant HBsAg decrease was not achieved after switching from ETV to TDF in the overall analysis, but HBeAg-positive patients showed a larger HBsAg decrease after switching treatment.

A 71-year-old man underwent surgery for a pancreatic neuroendocrine tumor. Follow-up imaging showed swelling of the remnant pancreas, and he was histologically diagnosed with autoimmune pancreatitis based on endoscopic ultrasonography-guided fine-needle aspiration specimens. After two years, a tumor appeared on the liver surface. Although we planned to perform laparoscopic partial hepatectomy, the intraoperative findings showed that the tumor was located in the diaphragm. Partial resection of the diaphragm was performed, and the final diagnosis was an immunoglobulin G4-related inflammatory pseudotumor in the diaphragm. To our knowledge, this is the first reported case of an immunoglobulin G4-related diaphragmatic inflammatory pseudotumor.

Appropriate management of constipation in hemodialysis patients has not been established, although constipation is the most frequent gastrointestinal complication in dialysis patients. We herein report the efficacy and safety of polyethylene glycol in constipated hemodialysis patients assessed prospectively. Seven patients using stimulant laxatives participated in this study. Polyethylene glycol was administered to reduce stimulant laxatives during the six-week intervention period. The amount of stimulant laxatives decreased and spontaneous bowel movements with ideal stool consistency increased significantly after the intervention. No serious adverse effects were observed throughout this study. In conclusion, polyethylene glycol can be a useful tool for managing constipated hemodialysis patients.

We herein report the first case of foveolar-type gastric adenocarcinoma that developed after the initiation of vonoprazan (VPZ). A 51-year-old man had heartburn at the first visit and reflux esophagitis endoscopically, so he started taking VPZ. An approximately 5-mm-sized reddish polyp with a raspberry-like morphology was detected at the anterior wall of the upper body of the stomach 156 weeks after starting maintenance therapy with VPZ 10 mg/day. It was diagnosed as foveolar-type gastric adenocarcinoma based on a biopsy. Another approximately 4-mm-sized foveolar-type gastric adenocarcinoma was also detected at the posterior wall of the middle body of the stomach.

BACKGROUND AND AIMS: The largest cause of mortality in patients with inflammatory bowel disease (IBD) remains thromboembolic disease (TED). Recent reports have demonstrated that both monogenic and polygenic factors contribute to TED and 10% of healthy subjects are genetically at high risk for TED. Our aim was to utilize whole-exome sequencing and genome-wide genotyping to determine the proportion of IBD patients genetically at risk for TED and investigate the effect of genetic risk of TED in IBD. METHODS: The TED polygenic risk score was calculated from genome-wide genotyping. Thrombophilia pathogenic variants were extracted from whole-exome sequencing. In total, 792 IBD patients had both whole-exome sequencing and genotyping data. We defined patients at genetically high risk for TED if they had a high TED polygenic risk score or carried at least 1 thrombophilia pathogenic variant. RESULTS: We identified 122 of 792 IBD patients (15.4%) as genetically high risk for TED. Among 715 of 792 subjects whose documented TED status were available, 63 of the 715 patients (8.8%) had TED events. Genetic TED risk was significantly associated with increased TED event (odds ratio, 2.5; P = .0036). In addition, we confirmed an additive effect of monogenic and polygenic risk on TED (P = .0048). Patients with high TED genetic risk more frequently had thrombosis at multiple sites (78% vs 42%, odds ratio, 3.96; P = .048). CONCLUSIONS: Genetic risk (both poly- and monogenic) was significantly associated with TED history. Our results suggest that genetic traits identify approximately 1 in 7 patients with IBD who will experience 2.5-fold or greater risk for TED.

INTRODUCTION: The purpose of this study is to clarify the clinical features of temozolomide (TMZ)-related hepatitis B virus (HBV) reactivation and to identify HBV reactivation predictive factors. METHOD: We retrospectively reviewed the clinical course of 145 patients newly diagnosed or with recurrent malignant glioma treated with TMZ. Before treatment, we screened patients for HB surface antigen (HBsAg) positivity (HBV carrier) and HBsAg negativity. Patients were also screened for antibody for HB core antigen (anti-HBc) positivity and/or for HB surface antigen positivity (resolved HBV infection). The patients were monitored by HBV DNA, alanine, and aspartate aminotransaminase during and after the completion of TMZ. HBV carriers and those with resolved HBV infections with HBV reactivation received preemptive entecavir treatment. In those with resolved HBV infections, we analyzed clinical characters for the predictive factors for HBV reactivation. RESULTS: In one of two HBV carriers, HBV DNA turned positive 8 months after the completion of TMZ and entecavir. In four (16.7%) of 24 resolved HBV infections, HBV DNA turned detectable at completion of concomitant radiation and TMZ or during monthly TMZ. HBV DNA turned negative with entecavir in all patients without liver dysfunction. In resolved HBV infections, those with a high anti-HBc titer had significantly higher incidence of HBV reactivation than those with low anti-HBc titers (60% vs. 5.3%: p = 0.018). CONCLUSION: Screenings, monitoring, and preemptive entecavir were important for preventing TMZ-related HBV reactivations. Anti-HBc titers could be the predictive markers for HBV reactivation in the those with resolved HBV infections.

BACKGROUND: Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called "mesalamine allergy," which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD. METHODS: Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance. RESULTS: In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn's disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%). CONCLUSIONS: Mesalamine allergy was more common in ulcerative colitis than in Crohn's disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.

Objective Linked-color imaging (LCI), a new technology for image-enhanced endoscopy, emphasizes the color of the mucosa, and its practicality in the detection of early gastric and colon cancers has been reported. However, whether or not LCI is useful for the diagnosis of Barrett's adenocarcinoma (BA) has been unclear. In this study, we explored whether or not LCI enhances the color difference between a BA lesion and the surrounding mucosa. Methods Twenty-one lesions from 20 consecutive patients with superficial BA who underwent endoscopic submucosal dissection between November 2014 and September 2017 were retrospectively examined. The color differences (ΔE*) between the inside and outside of the lesion were evaluated retrospectively using white-light imaging (WLI), blue-light imaging (BLI), and LCI objectively, based on a Commission Internationale de l'Eclairage (CIE) lab color system. Furthermore, we compared the morphology, color, and circumferential location of the lesion. Results The median values of the color difference (ΔE*) in WLI and BLI were 9.1 and 5.8, respectively, and no difference was observed. In LCI, the median color difference was 17.6, which was higher than that of WLI and BLI. Regardless of the morphology, color, and circumferential location of BA lesions, the color difference was larger in LCI than in WLI. Conclusion LCI increases the color difference between the BA and the surrounding Barrett's mucosa.

Objectives: The objectives of the study was to evaluate the diagnostic performance of findings on T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and magnetic resonance cholangiopancreatography (MRCP) separately and to identify an optimal Boolean interpretation model for discriminating patients with small pancreatic ductal adenocarcinoma (PDAC) from control groups in clinical practice. Material and Methods: We retrospectively enrolled 30 patients with surgery confirmed small PDAC (≤20 mm) and 302 patients without pancreatic abnormality between April 2008 and February 2020. The presence of masses was evaluated by T1WI, T2WI, and DWI. Abnormality of the main pancreatic duct (MPD) was evaluated by T2WI and MRCP. Multivariate logistic regression analysis was performed to select significant sequences for discriminating the small PDAC and control groups. Boolean operators "OR" or "AND" were used to construct sequence combinations. Diagnostic performances of these sequences and combinations were evaluated by X 2 tests. Results: The sensitivity of T2WI was lowest (20%) for detecting masses. For evaluating MPD abnormality, sensitivity was higher for MRCP than for T2WI (86.7% vs. 53.3%). Multivariate logistic regression analysis showed that T1WI and DWI for detecting the presence of masses and MRCP for evaluating MPD abnormality were significantly associated with differentiation between the two groups (P = 0.0002, P = 0.0484, and P < 0.0001, respectively). Seven combinations were constructed with T1WI, DWI, and MRCP. The combination of findings on "T1WI or DWI or MRCP" achieved the highest sensitivity of 96.7% and negative predictive value of 99.6%. Conclusion: The combination of findings on "T1WI or DWI or MRCP" might be an optimal interpretation model for discriminating small PDAC from control groups in clinical practice.

In esophageal squamous cell carcinoma (ESCC) comprising 90% of cases with esophageal cancer, endoscopic resection (ER) is recommended for patients with negligible risk of ESCC-related mortality. In fact, a main cause of death in patients underwent ER is not ESCC. We thus aimed to clarify the predictors for early and late mortality among patients underwent ER of ESCC between 2005 and 2018 at our institution. In this retrospective cohort study, we investigated the prognosis and predictors of early and late mortality with the cut-off value of 3 years. We enrolled 407 patients with a median 69 months follow-up. The 5-year overall survival and disease-specific survival, an indicator of ESCC-related mortality, were 83.4% and 98.4%, respectively. In multivariate Cox analyses, Eastern Cooperative Oncology Group performance status (ECOG-PS), consisting of six grades by a patient's level of activity, ≥ 2 was a predictor for early and late morality [hazard ratio (HR), 7.21 (P = 0.007) and 15.62 (P = 0.021), respectively]. Charlson comorbidity index (CCI), which is an index for predicting mortality by comorbid conditions, ≥ 2 was also a predictor for both mortality [HR, 2.97 (P = 0.017) and 1.90 (P = 0.019), respectively]. However, age was a predictor only for late mortality [HR, 3.08 (P = 0.010) in 80-84 years and 8.38 (P < 0.001) in ≥ 85 years]. Considering the predictive ability for early mortality, we propose that ECOG-PS and/or CCI are better indices compared with age in deciding treatment strategy after ER for ESCC.

INTRODUCTION: Weakly acidic reflux has been reported to be the major cause of symptoms in patients with proton pump inhibitor (PPI)-refractory nonerosive reflux disease (NERD) undergoing PPI treatment. We previously reported that reflux at pH 4-5 was the main factor that induced symptoms in such patients. The present study aimed to elucidate the symptom-ameliorating effect of vonoprazan (VPZ) by evaluating the change in the pH value of the refluxate using multichannel intraluminal impedance and pH (MII-pH) monitoring. METHODS: We retrospectively evaluated the records of MII-pH monitoring in 29 symptom index (SI) and/or symptom association probability (SAP)-positive patients with PPI-refractory NERD. After switching to VPZ 20 mg/day, we performed MII-pH monitoring again. We assessed the change in the score of the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG), the pH value of the refluxate, and the percent times of intragastric pH <4 or <5 before and after switching. We divided the patients into the following 2 groups according to the FSSG score after switching: effective and noneffective groups. RESULTS: Among of the 29 SI/SAP-positive patients, 16 underwent switching to VPZ. Furthermore, of these 16 patients, 10 underwent MII-pH monitoring again after switching. The FSSG score decreased, the pH value of the refluxate increased, and the percent times of intragastric pH <4 or <5 reduced after switching when compared with the findings before switching. In the effective group, both the proportion of reflux at pH <4 and that of reflux at pH 4-5 decreased while taking VPZ when compared with the findings while taking double-dose PPI. In the noneffective group, the proportion of reflux at pH <4 decreased but that of reflux at pH 4-5 increased and that of reflux at pH <5 did not change overall while taking VPZ. In addition, the percent times of intragastric pH <5 values were low in the effective group. CONCLUSION: Symptom suppression appears to be inadequate in patients with persistent reflux at pH 4-5 even with VPZ 20 mg/day. Strong acid suppressive therapy with VPZ to increase the pH value of the refluxate to ≥5 is useful for symptom improvement.

BACKGROUND: Submucosal fibrosis observed during colorectal endoscopic submucosal dissection (ESD) is an important factor related to incomplete resection. Biopsy is generally accepted as having the potential to elicit submucosal fibrosis, but few reports have presented definitive proof. This study investigated the relation between submucosal fibrosis and colorectal ESD outcomes and assessed factors related to fibrosis, including pretreatment biopsy. METHODS: After reviewing 369 records of colorectal ESD performed between January 2011 and December 2016, we assessed the relation between fibrosis and ESD outcomes. Multiple logistic regression analysis revealed fibrosis risk factors. RESULTS: Severe fibrosis was related significantly to ESD outcomes such as the mean procedure time (p < 0.001), en bloc resection rate (p < 0.001), and R0 resection rate (p = 0.011). Multivariate analyses indicated residual lesions (ORs 175.4, p < 0.001), pretreatment biopsy (ORs 8.30, p = 0.002), nongranular-type laterally spreading tumors (LST-NG; ORs 5.86, p = 0.025), and invasive carcinoma (ORs 5.83, p = 0.03) as independent risk factors of severe fibrosis. In each macroscopic type, LST-NG was more strongly related to fibrosis induced by pretreatment than granular-type laterally spreading tumors with adjust ORs of 50.8 and 4.69. CONCLUSIONS: Pretreatment biopsy causes submucosal fibrosis resulting in prolonged procedure times and incomplete resection. These findings suggest important benefits of avoiding biopsy before ESD.

BACKGROUND AND OBJECTIVE: Weakly acidic reflux reaching to the proximal esophagus is closely related to the perception of gastroesophageal reflux in patients with nonerosive reflux disease despite treatment with a proton pump inhibitor (PPI). However, little is known about the involvement of the patients' mucosal integrity of the proximal esophagus. METHODS: We recruited 15 symptomatic nonerosive gastroesophageal reflux disease (GERD) patients with a positive symptom index despite PPI treatment and 11 healthy asymptomatic volunteers as controls. The biopsy specimens obtained from the proximal and distal esophagus were applied to a mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) against a pH 4 weak acid. The esophageal biopsy samples were subjected to quantitative real-time PCR and immunohistochemical analysis. RESULTS: In the proximal esophagus, the weak acid exposure reduced the TEER in the PPI-refractory patients compared to that in the controls. The frequency of the reflux extending to the proximal esophagus had a significant correlation with the reduction in the proximal esophageal TEER in the patients. The reduced TEER in the proximal esophagus was accompanied by an increase in IL-8 and IL-1β mRNA and a decrease in occludin mRNA levels. The proximal esophageal mucosa in the patients presented infiltration of CD3-positive lymphocytes and an increased expression of solute carrier organic anion transporter family member 2A1 (SLCO2A1), a passage gate of reflux symptom-evoking molecules. CONCLUSIONS: The reflux perception is related to an impairment of the proximal esophageal mucosal integrity in patients with nonerosive reflux disease despite PPI.

OBJECTS: Although a recent study showed the cancer incidence of Barrett's esophagus (BE) to be 1.2%/year in 251 patient-years in Japan, the long-term outcomes remain unclear. The present study estimated the cancer risk of BE in Japan using our original prospective multicenter cohort. METHODS: A total of 98 patients with BE of maximum length of ≥2 cm were enrolled during the period of 2010-2012 and received at least one follow-up endoscopy over 5 years thereafter. Cancer incidence rates with 95% confidence interval for occurrence of esophageal adenocarcinoma (EAC) were calculated as the number of events divided by patient-years of follow-up and were expressed as %/year. RESULTS: Overall, the median endoscopic follow-up period was 59.9 (first and third quartiles, 48.5-60.8) months, constituting a total of 427 patient-years of observation. Since two EAC cases developed, the cancer incidence was 0.47% (0.01%-1.81%)/year. The cancer incidence was 0.39% (-0.16% to 2.44%) in 232 patient-years and 0.31% (-0.13% to 1.95%)/year in 318 patient-years for 55 cases with specialized intestinal metaplasia and 70 with BE ≥3 cm (maximum), respectively. At the end of follow-up, 12 of 92 patients (13.0%) died, but none died from EAC. CONCLUSION: This is the largest prospective follow-up study with endoscopy to investigate the incidence of EAC in unequivocal BE with the maximum length of ≥2 cm in Japan. Although a further large-scale study will be required to validate our results, the cancer risk of BE in Japan would be lower than previously reported (0.47% vs 1.2%/year).

Gastric squamous-cell carcinoma (SqCC) metastasized form the cervix is rarely detected in endoscopic examination, although cervical carcinoma is the second most common in gynecologic malignancy. A 59-year-old female visited a clinic for anorexia, and an esophago-gastro-duodenoscopy (EGD) revealed multiple submucosal tumors (SMTs) of the stomach. After she was referred, an image-enhanced endoscopy enhanced multiple SMTs with white spots, whose findings were irregular micro-vascular patterns in the mucosa with irregular/absent micro-surface pattern. We took endoscopic biopsies, whose histological diagnoses were SqCC in the layer of the lamina propria under normal epithelium. Positron emission tomography-CT, CT and magnetic resonance imaging revealed an irregularly enhanced mass of the cervix, the irregularly thickening wall of the stomach and peritoneal nodules. Palliative care alone was administered based on poor condition associated with the Stage IV cervical carcinoma. In this case, endoscopic detection of gastric SqCC might provide a tip to make final diagnosis of primary site of cervical SqCC. The numbers of endoscopic examination become increasing, so further deep awareness of such patterns of metastasis in cervical cancer are required.

Background and Aim: TL1A (TNFSF15) is a major Crohn's disease (CD) susceptibility gene, especially in the East Asian population, and is also known to be associated with some clinical phenotypes, such as stricturing and penetrating behavior. This study aims to investigate the association between TL1A genotype and the long-term therapeutic outcomes of infliximab and adalimumab in Japanese CD patients. Methods: We investigated 119 biologic-naïve CD patients treated with infliximab or adalimumab. TL1A -358C/T (rs6478109) was genotyped as a tag single nucleotide polymorphism (SNP) for CD risk or nonrisk haplotype of TL1A (the -358C allele is a risk allele for CD development). We compared the long-term therapeutic outcomes of anti-tumor necrosis factor (TNF) antibodies between the TL1A -358C/C group and the C/T+T/T group. Results: Sixty-nine cases (58.0%) were homozygous for the risk allele (TL1A -358C/C group), and 50 cases (42.0%) were heterozygous for the risk allele or homozygous for the protective allele (TL1A -358C/T+T/T group). No significant differences were found in the cumulative retention rates and the relapse-free survival between the TL1A genotypes. However, the surgery-free survival was significantly lower in the TL1A -358C/C group than in the C/T+T/T group (log-rank test, P < 0.05). Multivariate analysis showed that TL1A -358C/C was identified as an independent risk factor for surgery (hazard ratio, 4.67; 95% confidence interval, 1.39-22.1; P = 0.025). Conclusion: An association was found between the TL1A genotype and the therapeutic outcomes of anti-TNF therapy. Our data indicate that the design of customized therapy with anti-TNF antibodies using TL1A genomic information could be effective in the future.

Pancreatic ductal adenocarcinoma (PDAC), which accounts for majority of pancreatic cancers, is one of the most lethal human malignancies. Most patients are diagnosed at an advanced stage after symptom development. Early diagnosis of PDAC in asymptomatic subjects is important to improve prognosis. Diabetes mellitus (DM) is a risk factor for PDAC, and DM, especially new-onset DM, has attracted attentions as a diagnostic clue to PDAC. However, the impact of DM as a diagnostic opportunity on the prognosis of PDAC is unclear. We here retrospectively reviewed 489 PDAC patients and compared the clinical characteristics and prognosis according to the opportunities for PDAC diagnosis. PDAC was diagnosed upon presentation of symptoms, such as pain and jaundice, in 318 cases including 151 DM patients, upon new-onset or exacerbation of long-standing DM in 53 asymptomatic patients, and upon incidental detection by medical check-up or follow-up/work-up of other diseases in 118 asymptomatic patients. Asymptomatic patients including those with DM had smaller tumors, earlier disease stage, and higher resectability rates than symptomatic patients. Asymptomatic patients diagnosed in association with DM had better prognosis (median survival time, 771 days) than those diagnosed due to symptoms (343 days, P < 0.001), and similar to those diagnosed by incidental detection (869 days). The survival advantage was not evident in symptomatic patients with DM-associated signs. In conclusion, patients diagnosed in association with DM at asymptomatic stages had better prognosis than those diagnosed with symptoms. DM-associated signs might provide a clue to the early diagnosis of PDAC among asymptomatic subjects.

This work summarizes new and emerging metrics and tools in esophageal function testing and their potential clinical impact. Because the diagnostic sensitivity and reliability of conventional impedance-pH variables are suboptimal, several novel impedance parameters, such as the postreflux swallow-induced peristaltic wave index and the mean nocturnal baseline impedance, as well as mucosal impedance, are entering a validation stage prior to general clinical use. The accurate diagnosis of behavioral disorders in patients with rumination syndrome and supragastric belching using ambulatory multiple intraluminal impedance-pH can lead directly to behavioral interventions in patients with refractory gastroesophageal reflux disease (GERD). New provocative measures, such as multiple rapid swallows and the rapid drink challenge, have been developed to overcome the limitations of standard high-resolution esophageal manometry, aiming at further clarifying esophageal dysmotility. Furthermore, the current diagnostic and therapeutic challenges in patients with esophageal involvement in Sjogren's syndrome and scleroderma, who tend to have severe forms of GERD, are entering a new investigative and clinical phase.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. Patients with inoperative PDAC require effective chemotherapy and pain control to increase their quality of life. We investigated whether duloxetine, a serotonin-noradrenaline reuptake inhibitor, improves quality of life in a KPPC (LSL-Kras;Trp53;Pdx1-cre) mouse model of PDAC. Six-week-old KPPC mice were orally administered 4 mg/kg/d duloxetine (n = 12); 4 mg/kg/d duloxetine with 0.15 mg/kg/d atipamezole, a synthetic α2 adrenergic receptor antagonist (n = 9); or vehicle water (n = 11). Body weight and food intake were measured daily, and cancer pain was evaluated by the hunching score and mouse grimace scale. At the endpoint, the tumor status, angiogenesis, and immunoinflammatory condition were analyzed. The pain level using the hunching and mouse grimace scale scores improved by duloxetine in KPPC mice (P < 0.01), whereas the scores that had been reduced by duloxetine were elevated by administration of atipamezole. Kaplan-Meier analysis demonstrated that duloxetine-treated mice had significantly prolonged survival (P < 0.05) with delayed appetite loss, cachexia, and body weight loss. Duloxetine inhibited the proliferation of PDAC cells and cancer-associated fibroblasts in vivo with a shift into an antitumor immunoinflammatory condition and the corresponding plasma cytokine levels. The migrative/invasive potentials of PDAC were inhibited by duloxetine in vitro. Meanwhile, atipamezole did not inhibit the antitumor effects of duloxetine in vitro and in vivo. Therefore, our results indicate that duloxetine mainly improves cancer-associated pain by enhancement of the noradrenergic pathway rather than the serotonergic pathway, whereas duloxetine modulates antitumor effects on PDAC without involvement of the noradrenergic pathway.

A hepatic cyst is usually asymptomatic but, in some cases, can be associated with various complications. Here we report a rare case with rapid enlargement of a hepatic hilar cyst that induced bile duct obstruction after an acute exacerbation of chronic hepatitis B. The case is a 60-year old female who discontinued entecavir by herself. Hyperbilirubinemia was prolonged along with bile duct obstruction due to an enlarged cyst. After the administration of entecavir and steroid pulse therapy, biliary drainage and punctuation of the cyst were performed. There was no evidence of malignancy in the cyst. The therapies were not effective enough, probably due to the prior liver damage, and she died of acute on chronic liver failure. This case suggests that a hepatic hilar cyst in a patient with acute hepatitis or an acute exacerbation of chronic hepatitis can become enlarged and may affect the clinical course of hepatitis. In such a case, the size of the cyst should be monitored frequently and bile duct obstruction should be treated early if it occurs.

A 38-year-old Japanese man who had been diagnosed with appendiceal carcinoid and undergone ileocecal resection 8 years before presented with duodenal obstruction caused by a submucosal tumor-like appearance. He was diagnosed with long-term recurrence of appendiceal goblet cell carcinoid (GCC) with a multi-morphological pattern based on the histological assessment of a duodenal biopsy and his previously resected appendix. He underwent subtotal stomach-preserving pancreaticoduodenectomy combined with resection of an ileo-colic anastomotic lesion. The GCC recurred at the nearby ileo-colic anastomosis and invaded the duodenum. This late recurrence might have resulted from the unique features of his GCC, which contained cells with different degrees of malignancy.

Early stage of esophageal squamous cell carcinoma (ESCC) is known to be accompanied by angiogenesis and morphological changes of microvessels. Transcription factor Sox2 is amplified in various cancers including ESCC, but the role of Sox2 in the carcinogenesis and angiogenesis has not been determined. Hence, we aimed to investigate the role of Sox2 in the early stage of ESCC. We found that the expression of Sox2 was significantly higher in early-stage ESCC tissues than that in their adjacent normal tissues. We then established Sox2-inducible normal human esophageal squamous cell line (HetSox2) to investigate the role of Sox2 in esophageal carcinogenesis and angiogenesis in vitro. Sox2 overexpression led to increased cell proliferation and spheroid formation. The culture supernatant of Sox2-overexpressing HetSox2 induced migration and sprouting of endothelial cell line HUVEC (human umbilical vein endothelial cell). As for the mechanism, we found that the expression of secreted protein Suprabasin was directly induced by Sox2. Suprabasin enhanced proliferation of normal human esophageal squamous cells when added to the culture. Moreover, Suprabasin enhanced migration and sprouting of HUVEC cells, which were observed with the culture supernatant of Sox2-overexpressing HetSox2. This angiogenic effect of Suprabasin was abolished by inhibiting AKT phosphorylation, which suggested its dependence on AKT signaling. Finally, we showed that Suprabasin expression and the density of microvessels were significantly higher in ESCC tissues with high Sox2 expression. Our study suggested that increased Sox2 expression in esophageal squamous cells induced Suprabasin expression, and as a result initiated the carcinogenesis via increased cell proliferation and angiogenesis.

OBJECTIVES: To provide updated clinico-epidemiological information on chronic pancreatitis (CP) in Japan. METHODS: We conducted a two-stage nationwide epidemiological survey; the number of CP patients was estimated in the first-stage survey, and their clinical features were examined in the second-stage survey. We surveyed patients with CP who had visited hospitals in 2016 and were diagnosed according to the Japanese diagnostic criteria 2009 (DC2009). Furthermore, we validated the new Japanese diagnostic criteria (DC2019) in patients with early CP diagnosed according to DC2009. RESULTS: The number of patients with definite/probable CP in 2016 was 56,520 (prevalence, 44.5 per 100,000 persons), and that of early CP was 4470 (prevalence, 3.5 per 100,000 persons). We obtained detailed clinical information of 2150 patients with definite/probable CP and 249 patients with early CP. Compared with the early CP cases, the definite/probable CP cases had higher proportions of male (4.8 vs. 1.3), alcohol-related etiology (72.0% vs. 45.8%), smoking history (69.6% vs. 41.0%), diabetes mellitus (42.3% vs. 19.3%), and past history of acute pancreatitis (AP) (50.4% vs. 22.1%). Among the patients with early CP diagnosed according to DC2009, 93 (37.3%) were diagnosed with early CP according to DC2019, but the diagnosis of the remaining 156 (62.7%) patients was downgraded. Alcohol-related etiology, smoking history, early disease onset, and past history of AP were associated with the maintenance of early CP diagnosis in DC2019. CONCLUSION: We clarified the current status of CP in Japan. Further validation studies are warranted to clarify the diagnostic utility of DC2019.

BACKGROUND: Supragastric belching (SGB) may play a role in the pathophysiology of proton pump inhibitors (PPIs)-refractoriness in gastroesophageal reflux disease (GERD). SGB may be present in up to 40% of reflux symptoms in PPI-refractory GERD. Most reports on SGB have come from Western countries, and little is known about the prevalence and relevance of SGB in Asian refractory GERD patients. This study aimed at comparing the role of SGB in GERD patients in Japan and the UK. METHODS: We re-analyzed impedance-pH monitoring tracings from patients who were referred to tertiary centers in Japan and the UK due to PPI-refractory reflux symptoms. The prevalence of excessive SGB and the impact of SGB on reflux symptoms were compared between the two countries. RESULTS: Impedance-pH tracings from124 Japanese and 83 British patients were re-analyzed. Japanese patients were significantly younger and had smaller body mass index than the British (P < 0.001). Japanese patients had significantly lower prevalence of excessive SGB (18.5%) than the UK (36.1%) irrespective of reflux phenotype (P = 0.006). Logistic regression analysis showed that the geographical/cultural difference was the only factor associated with the different prevalence of SGB (odds ratio; 2.91, 95% CI 1.09-7.73, P = 0.032). SGB were related to typical reflux symptoms very rarely in Japan [0% (0-4.9)] compared to the UK [35% (0-54.1)] (P = 0.071). CONCLUSIONS: The prevalence of SGB and their impact on reflux symptoms is significantly lower in Japan compared to the UK. The difference is not related to reflux parameters but might come from ethnic/cultural factors to be further characterized.

Generally, reactivation of hepatitis B virus (HBV) infection is induced by the administration of immunosuppressants or anticancer agents, but reactivation without such drugs has rarely been reported. Here we report an elder case with spontaneous reactivation of HBV replication accompanied by hepatitis B surface antigen (HBsAg) mutations. A 69-year-old man with a history of diabetes mellitus and chronic kidney disease (CKD) was found to be positive for HBsAg (0.072 IU/ml) in June 2018. In May 2019, marked hepatic dysfunction and increased HBsAg (2533.2 IU/ml) were observed when he visited the hospital due to diarrhea and worsening of CKD. At that time, hepatitis B surface antibody (HBsAb) was positive (268.9 mIU/ml) and HBV DNA was 6.0 log IU/ml. After treatment with entecavir, HBV DNA and HBsAg rapidly decreased. Full-genome HBV sequence analysis revealed that the patient was infected with HBV of subgenotype B1 and it had an "a" determinant mutation M133L in the S gene coding HBsAg. Notably, both HBsAg and HBsAb were positive at the time of HBV reactivation, suggesting that the HBV with these mutations escaped from neutralization by HBsAb. This case suggests that immune escape mutations could play an important role in spontaneous HBV reactivation.

Methotrexate-related lymphoproliferative disorder (MTX-LPD) is known to be a side effect of MTX, but its involvement in the liver has been rarely reported. We herein report a 70-year-old woman with autoimmune hepatitis and rheumatoid arthritis who developed multiple liver tumors. We initially considered that she had developed rapid-growing hepatocellular carcinoma (HCC) in the cirrhotic liver based on imaging tests. A tumor biopsy and transcatheter arterial chemoembolization were thus performed. The tumors were then diagnosed as diffuse large B-cell lymphoma pathologically and considered to be MTX-LPD. This case indicates that MTX-LPD should be considered even in cirrhotic patients with liver tumors resembling HCC.

Pancreatic cancer is one of the most dangerous solid tumors, but its early diagnosis is difficult. The abnormality of the main pancreatic duct (MPD), such as a single localized stricture and upstream dilatation, might be useful in the early detection of pancreatic cancer. However, these findings are often observed in benign inflammatory cases. This study aimed to clarify whether early pancreatic cancer presenting MPD abnormalities has characteristic features different from those of benign cases. This is a single-center, retrospective study. We analyzed 20 patients who underwent pancreatectomy presenting with a single, localized MPD stricture without identifiable masses on imaging: 10 patients with pancreatic ductal adenocarcinoma (cancer group; 6 with stage 0 and 4 with stage I) and 10 patients with benign strictures (benign group; 8 with inflammation and 2 with low-grade pancreatic intraepithelial neoplasms). Pancreatectomy was performed in these benign cases because high-grade intraepithelial neoplasm was suspected. Although the proportion of patients with diabetes mellitus tended to be higher in the cancer group (6/10) than that in the benign group (1/10) (P = 0.058), other clinical characteristics were not different between the groups. Preoperative cytological malignancies were detected in four patients in the cancer group (4/10) but not in the benign group (P = 0.09). Focal parenchymal atrophy and fat replacement were more frequently detected on computed tomography in the cancer group (7/10) than in the benign group (1/10) (P = 0.02). In conclusion, focal parenchymal atrophy and fat replacement may provide clues for the early diagnosis of pancreatic cancer.

PURPOSE: To clarify the usefulness of cancer-related inflammation, hypermetabolism, and subsequent host malnutrition biomarkers for predicting the histological grades of intraductal papillary mucinous neoplasms of the pancreas (IPMNs). METHODS: The systemic immune-inflammation index (SII), prognostic nutritional index (PNI), and maximum standardized uptake value (SUVmax) on fluorodeoxyglucose-positron emission tomography were compared across 171 resected IPMN cases of different histological grades. The diagnostic performance of each marker and of their combinations for predicting IPMN with high-grade dysplasia (HGD)/associated invasive carcinoma (INV) was also tested. RESULTS: Of the 171 IPMNs, the IPMN cases with HGD showed significantly higher values of SII (median 406 vs. 340; P = 0.041) and SUVmax (median 2.5 vs. 2.0; P = 0.001) than those with low-grade dysplasia (LGD). On a multivariate analysis, the SII and SUVmax were both independent markers for predicting HGD/INV. A combination analysis including the tumor- and host-derived markers in combination with imaging findings showed an improved diagnostic performance (area under the curve 0.824; sensitivity 75.9%; specificity 80.0%). CONCLUSIONS: The combination of multiple markers of host-derived inflammation and tumor-derived focal hypermetabolism can serve as a predictor for the presence of HGD/INV.

With the ongoing increase in the aging population in Japan, the number of elderly patients among the total population with upper gastrointestinal (GI) neoplasia has also been increasing. As elderly patients present unique age-related variations in their physical condition, the therapeutic approach for upper GI neoplasia should be differentiated between elderly and nonelderly patients. According to the existing guidelines, additional treatment is the standard therapy in patients who undergo endoscopic resection (ER) with a possible risk of lymph node metastasis (LNM) for upper GI neoplasia. However, due to the relatively low rate of LNM, applying additional treatment in all elderly patients may be excessive. Although additional treatment has the advantage of reducing cancer-specific mortality, its disadvantages include deteriorated quality of life, complications, and mortality in surgery. In patients with early gastric cancer, we propose treatment decisions be made using a risk-scoring system for LNM and upon considering the physical condition of the patient after ER with curability C-2. In those with superficial esophageal squamous cell carcinoma with a possible risk of LNM after ER, selective chemoradiotherapy may be a less-invasive treatment option, although the present standard treatment is esophagectomy. When considering the treatment decision, achieving a "cure" of the tumor has been regarded as critical. However, as the main cause of mortality in elderly patients with ER for upper GI neoplasia is noncancer-related death, both achieving a "cure" and also a good level of "care" is important in the management of elderly patients.

Background and Aim: The T-cell receptor (TCR) repertoire was assessed in response to various antigens and was considered to be associated with the pathogenesis of inflammatory bowel disease (IBD). Thus, we performed TCR repertoire analysis to examine the pathology of IBD from changes in the TCR repertoire of memory T cells in the intestinal lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs) of patients with IBD. Methods: LPMCs in the surgical specimens and PBMCs were isolated from 12 patients with IBD (5 patients with ulcerative colitis [UC] and 7 patients with Crohn's disease [CD]). PBMCs were collected from 10 healthy individuals as controls. Comprehensive TCR sequence analyses of adaptor-ligation polymerase chain reaction (PCR) products were performed using MiSeq. Results: The diversity of TCR-α and TCR-β in PBMCs was significantly lower in patients with IBD than that in controls (P = 0.00084 and 0.0013, respectively). Comparisons of TCR diversity in LPMCs and PBMCs between CD and UC showed that the diversity in LPMC was not affected by diseases, whereas that in PBMCs was significantly lower in CD than in UC (P = 0.045 and 0.049, respectively). Some TCR clones may have shown a specific increase or decrease in CD and UC, and many clones were common to both LPMCs and PBMCs in the same patients. Conclusion: The diversity of TCR clones in LPMCs and PBMCs in patients with IBD was significantly lower than that of PBMCs in controls. TCR diversity in PBMCs was particularly low in patients with CD.

The frequency of HBV genomic methylation in the liver was reported to vary among patients, but the detailed mechanism is still unknown. In this study, the effects of HBV genome methylation on HBV replication were investigated in vitro. A total of 6 plasmids containing 1.24-fold the HBV genome of different genotypes (subgenotypes A1, A2, B1, and C2) were purified after in vitro methylation with CpG methyltransferase (M.SssI) and transfected into HepG2 cells. In genotype B and C strains, methylation markedly decreased the amount of hepatitis B e antigen (HBeAg) in the culture supernatant. A reduction of hepatitis B surface antigen (HBsAg) was found in some HBV strains but the reduction was smaller than that of HBeAg. There was no significant difference in particle-associated HBV DNA in the culture supernatant. These findings suggest that HBV genomic methylation might be involved in the HBeAg decline in genotype B and C, in part, and that the reduction of HBsAg was less than that of HBeAg. In conclusion, this study showed that the effect of HBV genomic methylation differs among HBV genotypes, suggesting a potential explanation for the different clinical outcomes of genotypes A, B, and C.

BACKGROUND: Additional surgery for all patients with noncurative resection after endoscopic resection (ER) for early gastric cancer (EGC) may be excessive due to the relatively low rate of lymph node metastasis (LNM) in such patients. However, the prevalence and risk factors for LNM after noncurative ER have not been consistent across studies. METHODS: We performed a systematic review of electronic databases through August 10, 2018 to identify cohort studies with patients who underwent additional surgery after noncurative ER for EGC. The prevalence of LNM in such patients was extracted for all studies. Odds ratios (ORs) were combined using random-effects meta-analyses to assess the risk of LNM, when possible. RESULTS: We identified 24 studies comprising 3877 patients with 311 having LNM (pooled prevalence, 8.1%). The risk of LNM was significantly increased in lymphatic invasion (OR [95% confidence interval] = 4.22 [2.88-6.19]), lymphovascular invasion (LVI) (4.17 [2.90-5.99]), vascular invasion (2.38 [1.65-3.44]), positive vertical margin (2.16 [1.59-2.93]), submucosal invasion depth of ≥ 500 μm (2.14 [1.48-3.09]), and tumor size > 30 mm (1.77 [1.31-2.40]). In contrast, there was no significant association between undifferentiated-type or ulceration (scar) and LNM. When studies were restricted to those that evaluated the adjusted OR, the risk of vascular invasion for LNM did not reach statistical significance. CONCLUSIONS: Several pathological factors, most notably lymphatic invasion and LVI, were associated with LNM in patients with noncurative resection after ER for EGC. Lymphatic and vascular invasion should be assessed separately instead of LVI (PROSPERO CRD42018109996).

BACKGROUND: To clarify the genetic background of ulcerative colitis (UC) in the Japanese population, we conducted a genome-wide association study (GWAS) using a population-specific single nucleotide polymorphism (SNP) array. METHODS: We performed a GWAS and replication study including 1676 UC patients and 2381 healthy controls. The probability of colectomy was compared between genotypes of rs117506082, the top hit SNP at HLA loci, by the Kaplan-Meier method. We studied serum expression of miR-622, a newly identified candidate gene, from 32 UC patients and 8 healthy controls by quantitative reverse-transcription polymerase chain reaction. RESULTS: In the GWAS, only the HLA loci showed genome-wide significant associations with UC (rs117506082, P = 6.69E-28). Seven nominally significant regions included 2 known loci, IL23R (rs76418789, P = 6.29E-7) and IRF8 (rs16940202, P = 1.03E-6), and 5 novel loci: MIR622 (rs9560575, P = 8.23E-7), 14q31 (rs117618617, P = 1.53E-6), KAT6B (rs12260609, P = 1.81E-6), PAX3-CCDC140-SGPP2 (rs7589797, P = 2.87E-6), and KCNA2 (rs118020656, P = 4.01E-6). Combined analysis revealed that IL23R p.G149R (rs76418789, P = 9.03E-11; odds ratio [OR], 0.51) had genome-wide significant association with UC. Patients with GG genotype of rs117506082 had a significantly lower probability of total colectomy than those with the GA+AA genotype (P = 1.72E-2). Serum expression of miR-622 in patients with inactive UC tended to be higher than in healthy controls and patients with active UC (inactive UC vs healthy controls, P = 3.03E-02; inactive UC vs active UC, P = 6.44E-02). CONCLUSIONS: IL23R p.G149R is a susceptibility locus for UC in Japanese individuals. The GG genotype of rs117506082 at HLA loci may predict a better clinical course.

Endoscopic submucosal dissection (ESD) has become the standard treatment method for early gastric cancers (EGCs) due to the negligible risk for lymph node metastasis (LNM) in Eastern Asian countries. According to the guidelines, the curability of EGC after endoscopic resection was classified into three groups: curative resection, expanded curative resection, and noncurative resection. In Eastern Asian countries, a structured follow-up schedule is needed for patients undergoing curative resection and expanded curative resection. Conversely, in Western countries, additional surgery may be recommended for some patients undergoing expanded curative resection (ulcerated, undifferentiated, or slight submucosal invasion) due to the potential risk for LNM, even though specimens of ESD and surgery may not be handled with the same methodology as that used in Japan, which may lead to this slightly higher risk. In noncurative resection, additional surgery is the standard method after ESD because of the risk for LNM. However, in elderly patients and/or those with severe underlying diseases, the advantages and disadvantages of additional surgery should be considered when selecting a post-ESD treatment strategy for patients undergoing noncurative resection. Risk-scoring systems for LNM may facilitate clinical decisions for these patients. However, it should be noted that when recurrence was detected in patients who were followed up with no additional treatment after ESD with noncurative resection, most of them had a poor prognosis. To select an appropriate treatment method, especially in elderly patients undergoing ESD with noncurative resection, a new tool for evaluating the condition of patients should be established.

OBJECTIVES: The objective of this study was to clarify the role of pancreatectomy for patients with resectable and borderline resectable pancreatic ductal adenocarcinoma aged 80 years or older using a nationwide audit by the Japan Pancreas Society. METHODS: Data were collected from 39 institutions from 2007 to 2014. The primary endpoint was overall survival, and secondary endpoints were surgical outcomes and predictive factors for prognosis. RESULTS: Data were obtained from 556 octogenarians who underwent pancreatectomy (n = 369, 66%), chemo(radio)therapy (n = 99, 18%), and palliative therapy (n = 88, 16%). Median survival times were 20.6, 18.6, and 8.8 months in each group, respectively. Even after propensity score matching, median survival time in the surgery group (22.8 months) was significantly higher than that in the chemotherapy group (18.5 months; hazard ratio, 0.64 [95% confidence interval, 0.44-0.93]; P = 0.020). Significant independent prognostic factors were body mass index, lymph node metastasis, and tumor diameter in the surgery group, and serum albumin level, American Society of Anesthesiologists classification, body mass index, modified Glasgow prognostic score, second-line chemotherapy, and tumor diameter in the chemotherapy group. CONCLUSIONS: Octogenarians with resectable/borderline resectable pancreatic ductal adenocarcinoma can be recommended for pancreatectomy according to mental and physical fitness for surgical procedures.

BACKGROUND: Chronic pancreatitis (CP) is a complex inflammatory disease with variable presentations and outcomes. This statement is part of the international consensus guidelines on CP, specifically on the diagnostic role of endoscopic ultrasound (EUS). METHODS: An international working group with experts on the role of diagnostic EUS in the management of CP from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated two key statements generated from evidence on two questions deemed to be the most clinically relevant. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available for each statement. To determine the level of agreement, the working group voted on each statement for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: Strong consensus was obtained for both of the following statements [1]. The ideal threshold number of EUS criteria necessary to diagnose CP has not been firmly established, but the presence of 5 or more and 2 or less strongly suggests or refutes the diagnosis, respectively. The Rosemont scoring system standardizes the reporting of EUS signs indicative of chronic pancreatitis, but further studies are needed to demonstrate an overall improvement of its diagnostic accuracy over conventional scoring [2]. Specificity, inter- and intra-observer variability and pre-test probability limit the reliability and utility of EUS to help diagnose CP especially early stages of the disease. CONCLUSIONS: The presence of 5 or more and 2 or less EUS criteria strongly suggests or refutes the diagnosis of CP, respectively. Intra-observer variability still limits the role of EUS in diagnosing CP especially early stage disease.

Expression quantitative trait locus (eQTL) analyses have enabled us to predict the function of disease susceptibility SNPs. However, eQTL for the effector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn's disease (CD), are not yet available. Thus, we conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n = 20). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confirmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed significant correlation with tenascin-XA (TNXA) expression were significantly associated with CD in GWAS. By TWAS, TNFSF15 (FDR = 1.35e-13) in whole blood, ERV3-1 (FDR = 2.18e-2) in lymphocytes, and ZNF713 (FDR = 3.04e-2) in the sigmoid colon was significantly associated with CD. By conducting integration analyses using GWAS and eQTL data, we confirmed multiple gene transcripts are involved in the development of CD.

BACKGROUND: Chronic pancreatitis (CP) is a complex inflammatory disease with remarkably impaired quality of life and permanent damage of the pancreas. This paper is part of the international consensus guidelines on CP and presents the consensus on factors elevating the risk for CP. METHODS: An international working group with 20 experts on CP from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated 14 statements generated from evidence on four questions deemed to be the most clinically relevant in CP. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available per statement. To determine the level of agreement, the working group voted on the 14 statements for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: Strong consensus and agreement were obtained for the following statements: Alcohol, smoking, and certain genetic alterations are risk factors for CP. Past history, family history, onset of symptoms, and life-style factors including alcohol intake and smoking history should be determined. Alcohol consumption dose-dependently elevates the risk of CP up to 4-fold. Ever smokers, even smoking less than a pack of cigarettes per day, have an increased risk for CP, as compared to never smokers. CONCLUSIONS: Both genetic and environmental factors can markedly elevate the risk for CP. Therefore, health-promoting lifestyle education and in certain cases genetic counselling should be employed to reduce the incidence of CP.

BACKGROUND: To provide updates on clinical practice of acute pancreatitis (AP) in Japan, we conducted a nationwide epidemiological survey. METHODS: This study consisted of a two-staged survey; the number of AP patients was estimated by the first-stage survey and their clinical features were examined by the second-stage survey. We surveyed AP patients who had visited hospitals in 2016. RESULTS: The estimated number of AP patients in 2016 was 78,450, with an overall incidence of 61.8 per 100,000 persons. We obtained detailed clinical information of 2994 AP patients, including 706 (23.6%) severe cases classified according to the Japanese severity criteria. The male-to-female sex ratio was 2.0, and the mean age at onset was 59.9 years in males and 66.5 years in females. Alcohol was the most common etiology (42.8%) in males and gallstones in females (37.7%). The AP-associated mortality was 6.1% in severe AP cases, which was decreased by 40% compared to the 2011 survey. Antibiotics were administered to most cases, with carbapenem being frequently used. Enteral nutrition was given in 31.8% of severe cases, but majority cases received after 48 h. Among the 107 patients who received intervention for walled-off necrosis, five patients received surgery-first approach, 66 received endoscopic ultrasound-guided transluminal drainage, and 19 underwent step-up approach. CONCLUSIONS: We clarified the current status of AP in Japan including the significant reduction of mortality in severe cases, shift to endoscopic approaches for walled-off necrosis, and poor compliance of the recommendations in the guidelines including management of enteral nutrition and antibiotic administration.

BACKGROUND & AIMS: Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca2+-selective ion channel, in an international cohort of patients and in mice. METHODS: We performed whole-exome DNA sequencing from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (control individuals). In replication studies, we sequenced DNA from patients with early-onset CP (20 years or younger) not associated with alcohol consumption from France (n = 470) and Germany (n = 410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca2+ imaging assays. CP was induced by repeated injections of cerulein in TRPV6mut/mut mice. RESULTS: We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3-371.7; P = 2.4 × 10-8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P = 6.2 × 10-8). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese patients vs control individuals (OR, 10.9; 95% CI, 4.5-25.9; P = 7.4 × 10-9 for p.I223T and P = .01 for p.D324N), whereas the p.L299Q was overrepresented in European patients vs control individuals (OR, 3.0; 95% CI, 1.9-4.8; P = 1.2 × 10-5). TRPV6mut/mut mice given cerulein developed more severe pancreatitis than control mice, as shown by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis. CONCLUSIONS: We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca2+ balance in pancreatic cells. TRPV6 regulates Ca2+ homeostasis and pancreatic inflammation.

A 58-year-old man was referred for obstructive jaundice. Imaging modalities revealed the presence of multiple pancreatic tumors and the stenosis of the middle common bile duct due to a hypoenhanced localized tumor. The multiple pancreatic tumors were histopathologically diagnosed as autoimmune pancreatitis by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). To differentiate between IgG4-related sclerosing cholangitis (IgG4-SC) and cholangiocarcinoma, we diagnosed the biliary tumor as IgG4-SC by EUS-FNA because of insufficient pathological materials obtained in a transpapillary manner. We herein report a case of IgG4-SC diagnosed by EUS-FNA.

The presence of antiendothelial cell antibodies (AECAs) has been documented in Takayasu arteritis (TAK), a chronic granulomatous vasculitis. Here, we identify cell-surface autoantigens using an expression cloning system. A cDNA library of endothelial cells is retrovirally transfected into a rat myeloma cell line from which AECA-positive clones are sorted with flow cytometry. Four distinct AECA-positive clones are isolated, and endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) are identified as endothelial autoantigens. Autoantibodies against EPCR and SR-BI are detected in 34.6% and 36.5% of cases, respectively, with minimal overlap (3.8%). Autoantibodies against EPCR are also detected in ulcerative colitis, the frequent comorbidity of TAK. In mechanistic studies, EPCR and SR-BI function as negative regulators of endothelial activation. EPCR has also an effect on human T cells and impair Th17 differentiation. Autoantibodies against EPCR and SR-BI block the functions of their targets, thereby promoting pro-inflammatory phenotype.

The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma.NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.

An 83-year-old woman with severe aortic stenosis was admitted to our hospital due to heart failure with refractory anemia requiring blood transfusions. She had repetitive bleeding episodes from endoscopically proven angiodysplasia in the stomach. Moreover, she repeatedly underwent endoscopic argon plasma coagulation for hemostasis. Importantly, she had a deficiency of the high-molecular-weight (HMW) multimers of von Willebrand factor (VWF), and she was diagnosed with Heyde's syndrome.After she underwent transcatheter aortic valve implantation (TAVI), aortic valve area and mean left ventricular aorta pressure gradient improved. Notably, endoscopy showed cessation of bleeding at 10 days after TAVI and the disappearance of angiodysplasia at 4 months after TAVI. Even at 2 years after TAVI, follow-up endoscopy showed remaining free of angiodysplasia in the stomach. She experienced no episodes of anemia since TAVI procedure. Additionally, analysis of HMW multimers demonstrated immediate and lasting recovery after TAVI.Recovery of HMW multimers of VWF with cessation of gastrointestinal bleeding following aortic valve replacement has been previously reported in a patient diagnosed with Heyde's syndrome. To the best our knowledge, this is the first case to demonstrate that angiodysplasia disappears after TAVI for a long term with endoscopic images in a patient with Heyde's syndrome. Here, we summarized case reports of patients with Heyde's syndrome that required aortic valve intervention. Cessation of gastrointestinal bleeding and anemia after aortic valve intervention for severe aortic stenosis may be attributed not only to recovery of HMW multimers of VWF but also to the disappearance of angiodysplasia.

BACKGROUND: Recent studies reported that impaired proximal duodenal mucosa, assessed by duodenal biopsy, could play an important role in the development of dyspeptic symptoms. The aims of this study were (a) to develop a method to measure "in vivo" duodenal and jejunal baseline impedance (BI) and (b) to assess small bowel mucosal integrity in patients with functional dyspepsia (FD) and healthy controls (HC). METHODS: We recruited 16 patients with FD and 15 HC. All subjects underwent ambulatory duodeno-jejunal manometry combined with impedance (HRM/Z), BI were determined by measuring impedance immediately after the passage of nocturnal migrating motor complex (MMC) phase IIIs. RESULTS: The number of MMC phase IIIs in FD was significantly lower than that in HC (2.6 ± 1.4 vs 4.8 ± 1.7, p < 0.001). The BI in patients was significantly lower than that in HC in D1(164.2 ± 59.8 Ω in FD and 243.1 ± 40.5 Ω in HC, p = 0.0061), D2 (191.2 ± 34.1 and 256.5 ± 91.4 Ω, p = 0.01), D3 (214.0 ± 76.9 and 278.1 ± 45.3 Ω, p = 0.009), D4 (270.8 ± 54.2 and 351.8 ± 50.2 Ω, p < 0.001), and J1 (312.2 ± 55.4 and 379.3 ± 38.3 Ω, p = 0.001). CONCLUSIONS: This is the first study reporting the duodenal and jejunal BI in vivo. The results have shown significantly lowered BI in the proximal small intestine in patients with FD compared to HC. Furthermore it suggests that measurements of small bowel BI could be used as a biomarker for diagnosis and follow up of patients with FD.

A 37-year-old man underwent screening examinations, and a pale-colored submucosal tumor was detected on gastric cardia. Endosonography showed a 15-mm cyst with hypoechoic nodules in the muscularis propria, and endoscopic ultrasound-guided fine-needle aspiration obtained mucinous fluid with atypical spindle cells positive for c-kit, indicating a gastrointestinal stromal tumor. Surgical resection was recommended, but he initially agreed to surveillance. After becoming larger for 8 years, partial gastrectomy was performed for the 22 × 22 × 15-mm capsulized lesion. Surprisingly, its histology was gastric duplication cyst without gastrointestinal stromal tumor. Gastric duplication cyst is a rare entity with the possibility of malignant complications, but careful assessment of endoscopic ultrasound-guided fine-needle aspiration might also be required.

Introduction: The long-term prognosis of Japanese patients with Crohn's disease (CD) treated by switching anti-tumor necrosis factor-α (anti-TNFα) antibodies remains unclear. Objective: This study aimed to clarify the long-term prognosis and clinical factors that affect the long-term prognosis and outcomes of such patients. Methods: This retrospective, observational, single-center cohort study analyzed Japanese patients with CD treated by switching between infliximab and adalimumab in the Tohoku University Hospital between March 2003 and December 2017. Cumulative relapse-free survival and cumulative surgery-free survival rates were analyzed using the Kaplan-Meier method. Clinical factors that affected the long-term outcomes were identified using both a log-rank test and the Cox proportional hazards model. Results: The cumulative relapse-free survival rates were 68.6, 33.7, and 22.9% at 1, 3, and 5 years, respectively. The surgery-free survival rates were 91.7, 75.7, and 57.4% at 1, 3, and 5 years, respectively. The cumulative relapse-free survival rate was significantly higher in the group with ileal lesions (HR = 0.12; 95% CI 0.0066-0.64, p = 0.0086), stricture (HR = 0.24; 95% CI 0.0094-0.59, p = 0.0021), and a penetrating type (HR = 0.34; 95% CI 0.14-0.84, p = 0.020). Intolerance (HR = 0.29; 95% CI 0.12-0.63, p = 0.0013) and switching after surgery (HR = 0.41; 95% CI 0.17-0.87, p = 0.019) were clinical factors that reduced the risk of recurrence. The cumulative surgery-free survival rate was significantly higher in the group that switched after surgery (HR = 0.28; 95% CI 0.074-0.91, p = 0.034) and used concomitant thiopurine (HR = 0.32; 95% CI 0.10-0.90, p = 0.030). Conclusion: We should clarify the reason for switching anti-TNFα antibodies and investigate bowel complications before switching. Surgical reset of bowel complications including stricture and fistula could reduce the risk of recurrence after switching anti-TNFα antibodies. Concomitant thiopurine administration might reduce the risk of bowel surgery after switching anti-TNFα antibodies.

BACKGROUND: In patients with malignant perihilar biliary strictures, preoperative biliary drainage (PBD) of the hepatic lobe to be resected may decrease the liver volume of the future liver remnant (FLR) after percutaneous transhepatic portal vein embolization (PVE). However, evidence of its application is insufficient. This study aimed to clarify the effects of PBD on liver hypertrophy after PVE. METHODS: Between January 2008 and December 2017, 169 patients with malignant perihilar biliary strictures underwent major hepatectomy or palliative surgery at our hospital. Of these, 76 patients who underwent PVE were categorized into two groups: group A (n = 29) who received unilateral PBD of the FLR and group B (n = 47) who received bilateral PBD, including that of the hepatic lobe to be resected. FLR ratios after PVE and liver hypertrophy ratios were retrospectively compared in both groups. RESULTS: Group B exhibited significantly severe biliary stenosis (p = 0.0038) and high serum bilirubin before biliary drainage (p = 0.0037). After PVE, the total liver volumes were 1287 ± 260 ml and 1340 ± 257 ml (p = 0.39), respectively. FLR volumes were 555 ± 135 and 577 ± 113 ml (p = 0.45), respectively. FLR ratios were 43.4 ± 8.2% and 43.4 ± 6.4%, respectively (p = 0.98). Liver hypertrophy ratios were 124.2 ± 17.7% and 129.2 ± 20.9%, respectively (p = 0.28). In addition, an examination which excluded patients with Bismuth type I obtained similar result. CONCLUSIONS: PBD of the hepatic lobe to be resected did not decrease the FLR ratios and hypertrophy ratios. Thus, in patients with poor biliary drainage, additional PBD of the target lobe is acceptable.

Mixed adenoneuroendocrine carcinoma (MANEC) is defined as a tumor composed of both adenocarcinoma and neuroendocrine components. Here, we report the case of a 75-year-old woman with ampullary MANEC. She visited a physician with the chief complaint of dark urine and was diagnosed with advanced jaundice. Subsequently, she was referred to our hospital. Contrast-enhanced computed tomography scan revealed a neoplastic lesion measuring approximately 2 cm with a contrast effect at the duodenal papilla. Upper endoscopy showed a non-exposed tumor at the duodenal papilla. After biliary drainage, a subtotal stomach-preserving pancreaticoduodenectomy was performed. Histopathological examination revealed that the tumor components were composed of circular-to-oval atypical cells admixed with tubular adenocarcinoma tissue. These atypical cells were immunohistochemically positive for synaptophysin and diagnosed as neuroendocrine carcinoma with a Ki-67 labeling index of 63%. The patient was diagnosed with MANEC with a neuroendocrine carcinoma component of approximately 40%. The neuroendocrine carcinoma component had metastasized to the posterior pancreatic lymph nodes. Despite starting adjuvant chemotherapy with S-1, computed tomography revealed the presence of multiple liver metastases within 4 months after surgery. MANEC with neuroendocrine carcinoma is well known to have an extremely poor prognosis. Therefore, establishing a multidisciplinary therapy including chemotherapy is crucial.

Tight control management of Crohn's disease (CD) based on biomarkers is more effective than conventional clinical management; however, fecal calprotectin is not allowed in Asian and some Western countries. To investigate whether tight control management based on readily available serum biomarkers results in better outcomes, we retrospectively reviewed treatment courses of consecutive Japanese CD patients treated with anti-tumor necrosis factor agents between 2003 and 2018. The association between failure of tight control (C-reactive protein (CRP) ≥ 0.5 mg/dL or albumin (Alb) < 3.8 g/dL at week 8 or 24) and subsequent major adverse outcomes (MAOs; hospitalization related to CD worsening, surgery, and discontinuation due to treatment failure) were analyzed. Among 223 patients followed for >8 weeks, 88 patients experienced MAOs. Multivariate analysis identified penetrating type, CRP ≥ 0.5 mg/dL and Alb < 3.8 g/dL at week 8 as independent risk factors (hazard ratios: 2.16, 2.06, and 2.08, respectively). Among 204 patients followed for >24 weeks, 80 patients experienced MAOs. Penetrating type, CRP ≥ 0.5 mg/dL, and Alb < 3.8 g/dL at week 24 were identified as independent risk factors (2.39, 1.90, and 2.20, respectively). Even in settings without fecal calprotectin, tight control management based on serum CRP and Alb may help avoid MAOs.

Background and study aims  Intestinal stricture associated with Crohn's disease (CD) is usually treated by endoscopic balloon dilation (EBD) or stricture plasty. Although EBD is effective and safe for such strictures, refractory stricture after EBD poses a problem. Hence, other novel approaches for these refractory strictures are required. On the other hand, the efficacy of radial incision and cutting (RIC) method for esophageal stricture after esophagogastric surgery is reported. In this pilot study, we adopted the RIC technique for five CD patients with refractory intestinal stricture to dilate their strictures. We conducted the RIC procedure using an electric needle knife with a ceramic tip on the top of the needle. Four cases were of anastomotic stricture after ileocecal resection and the remaining one case was of stricture due to mucosal healing. The RIC procedure was successful for all five patients. Average procedure time was 18.6 minutes. One patient developed delayed bleeding after RIC. There were no cases of perforation. RIC could be an alternative therapy for intestinal stricture associated with CD. Further studies should be conducted to clarify its efficacy and safety.

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BACKGROUND AND OBJECTIVES: Weakly acidic reflux has been reported as the major cause of symptom occurrence in patients with proton pump inhibitor (PPI)-refractory non-erosive reflux disease (NERD). This study is aimed at clarifying whether the pH value of weakly acidic reflux affects the induction of symptoms. METHODS: We retrospectively evaluated the records of combined multichannel intraluminal impedance and pH monitoring in 57 patients with PPI-refractory NERD. Weakly acidic refluxes were divided into 3 categories based on the pH value of the refluxate: pH 4-5, 5-6, and 6-7. RESULTS: A total of 29 patients were positive in the symptom index. The symptom provocation rate in reflux of pH 4-5 (19%) was much higher than in that of pH 5-6 (11%) and pH 6-7 (12%). In the reflux at pH 4-5, the symptom provocation rate in the proximal reflux was higher than that in the distal reflux (p < 0.05), whereas the reflux at pH 5-6 and pH 6-7 was not significantly different in the symptom provocation rate between the proximal and distal refluxes. CONCLUSION: Reflux at pH <5 reaching the proximal esophagus was the main factor in the induced symptoms of patients with PPI-refractory NERD.

BACKGROUND: There has been no study that has directly measured the esophageal reflux factors in Barrett's adenocarcinoma (BA) using 24-h multichannel intraluminal impedance-pH monitoring (24-h MII-pH). We aimed to clarify the esophageal reflux factors in Barrett's esophagus (BE) and BA and the factors that determine the location of BA with 24-h MII-pH. METHODS: We performed 24-h MII-pH in 26 patients with superficial BA treated endoscopically (BA group) and 13 patients with BE (BE group) and examined the esophageal reflux factors (esophageal acid exposure time [AET], bolus exposure (acid, weakly acid, and alkaline), and number of reflux episodes. In the BA group, there were 16 cases in which the lesions were localized in an area in contact with the esophagogastric junction (EGJ; EGJ group), and 10 cases in which the lesions were proximal to the BE and separated from the EGJ (non-EGJ group). RESULTS: Total reflux in the bolus exposure in the BA group showed higher values compared to that in the BE group. The total of acid and weakly acid reflux of bolus exposure was significantly higher in the BA group than that in the BE group. The BA group also had greater numbers of total reflux episodes than the BE group. As for the cancer locations in BE, the cases in which the lesions were located proximally and separated from the EGJ had more AET and total reflux and acid reflux indicated by bolus exposure compared to the lesions adjacent to the EGJ. CONCLUSIONS: Stronger gastro-esophageal reflux appeared to be an important factor in the development of adenocarcinoma from BE. In addition, the cancer location in BE may be related to the intensity of esophageal reflux.

Japanese guidelines for gastric cancer treatment were first published in 2001 for the purpose of showing the appropriate indication for each treatment method, thereby reducing differences in the therapeutic approach among institutions, and so on. With the accumulation of evidence and the development and prevalence of endoscopic submucosal dissection (ESD), the criteria for the indication and curability of endoscopic resection (ER) for early gastric cancer (EGC) have expanded. However, several problems still remain. Although a risk-scoring system (eCura system) for predicting lymph node metastasis (LNM) may help treatment decision in patients who do not meet the curative criteria for ER of EGC, which is referred to as eCura C-2 in the latest guidelines, additional gastrectomy with lymphadenectomy may be excessive for many patients, even those at high risk for LNM. Less-invasive function-preserving surgery, such as non-exposed endoscopic wall-inversion surgery with laparoscopic sentinel node sampling, may overcome this problem. In addition, further less-invasive treatment, such as ER with chemotherapy, should be established for patients who prefer not to undergo additional gastrectomy.

We report a case of locally advanced unresectable(UR-LA)pancreatic cancer in a patient who underwent conversion surgery after FOLFIRINOX and proton beam therapy(PBT)combined with S-1. A 68-year-old woman was referred to our hospital for a pancreatic tumor. The abdominal CT scan revealed a 40mm pancreatic body tumor with an abutment(>180°) of the celiac artery and the superior mesenteric artery. Moreover, the tumor was classified as UR-LA with a contact to the abdominal aorta. The tumor was histologically diagnosed as adenocarcinoma via an endoscopic ultrasound-guided fine-nee- dle aspiration. After 2 courses of FOLFIRINOX, PBT(50 GyE/25 Fr)combined with S-1 were administered. The tumor shrunk to 30mm at the CT scan. After 5 courses of FOLFIRINOX, the tumor reduced to 20 mm. No distant metastasis or malignant cells in abdominal washing cytology was detected using staging laparoscopy. Then, distal pancreatectomy with celiac axis resection(DP-CAR)was performed. According to the General Rules for the Study of Pancreatic Cancer(7th edition)from Japan Pancreas Society, the histological findings were suggestive of ypT3, ypN0, R0, and Grade 3 histological effect. The patient had a Grade A delayed gastric emptying post-operation. He was discharged 35 days after the surgery and has been alive without recurrence on imaging for 11 months post-operation.

BACKGROUND: The importance of peritoneal washing cytology status both as a sign of irresectability and as a prognostic factor for pancreatic ductal adenocarcinoma remains controversial. The purpose of this nationwide, cancer registry-based study was to clarify the clinical implications of operative resection in patients who had positive cytology status. METHODS: Clinical data from 1,970 patients who underwent tumor resection were collected from the Pancreatic Cancer Registry in Japan. Clinicopathologic factors and overall survival curves were analyzed, and multivariate Cox proportional hazard models were evaluated. RESULTS: Among the 1,970 patients analyzed, positive cytology status was found in 106 patients and negative cytology status was found in 1,864 patients. The positive cytology status group had a greater frequency of pancreatic body and tail cancer and greater preoperative serum carbohydrate antigen 19-9 levels than the negative cytology status group (P < .001 each). The ratio of peritoneal recurrence tended to be greater in the positive cytology status group (14% vs 43%; P < .001). Overall median survival times were less in the positive cytology status group (17.5 months vs 29.4 months; P < .001). The 5-year survival rates were 13.7% and 31.1% in the positive cytology status and negative cytology status groups, respectively. Multivariate analysis of positive cytology status patients revealed that adjuvant chemotherapy was an independent prognostic factor. CONCLUSION: Positive cytology status was an adverse prognostic factor in patients who underwent resection for pancreatic ductal adenocarcinoma but did not preclude attempted curative resection. Curative resection followed by adjuvant chemotherapy may contribute to long-term prognosis in patients with positive cytology status.

AIM: Hepatitis B virus genotype B (HBV/B) has been reported to have less risk of liver cirrhosis and hepatocellular carcinoma (HCC), but long-term observation has rarely been reported. We aimed to clarify the characteristics of HBV/B in nucleos(t)ide analog-treated patients in an area where HBV/B is more prevalent than in other areas of Japan. METHODS: A total of 498 chronically HBV-infected patients treated with nucleos(t)ide analog (lamivudine, entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide fumarate) for >6 months (mean 70.6 months) were included from nine hospitals in northeast Japan. The frequencies of hepatitis B surface antigen loss and HCC occurrence were analyzed. RESULTS: Among 427 patients whose genotype could be determined, 34.0% and 64.4% were infected with HBV/B and genotype C (HBV/C), respectively. The age of patients with HBV/B was significantly older than those with HBV/C (57.7 vs. 48.1). The cumulative rate of hepatitis B surface antigen loss was significantly higher in HBV/B than in HBV/C (3.6% vs. 0.7% at 10 years). Among 480 patients without HCC history, HCC occurrence was found in 40 patients (13.4% at 10 years). There was no cumulative rate difference of HCC occurrence among the genotypes, but after propensity score matching for age/sex, it was significantly lower in HBV/B than in HBV/C (5.3% vs. 18.5% at 10 years). CONCLUSIONS: Although a lower rate of HCC occurrence in HBV/B was shown by an age/sex-matched analysis than that in HBV/C, patients with HBV/B were significantly older and had a comparative risk of HCC occurrence in nucleos(t)ide analog-treated patients.

Cancer-associated fibroblasts (CAF) constitute a major component of the tumor microenvironment. Recent observations in genetically engineered mouse models and clinical studies have suggested that there may exist at least two functionally different populations of CAFs, that is, cancer-promoting CAFs (pCAF) and cancer-restraining CAFs (rCAF). Although various pCAF markers have been identified, the identity of rCAFs remains unknown because of the lack of rCAF-specific marker(s). In this study, we found that Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis of 71 human PDAC tissues revealed that the infiltration of Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, Meflin deficiency led to significant tumor progression with poorly differentiated histology in a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs suppressed the growth of xenograft tumors. Lineage tracing revealed that Meflin-positive cells gave rise to α-smooth muscle actin-positive CAFs that are positive or negative for Meflin, suggesting a mechanism for generating CAF heterogeneity. Meflin deficiency or low expression resulted in straightened stromal collagen fibers, which represent a signature for aggressive tumors, in mouse or human PDAC tissues, respectively. Together, the data suggest that Meflin is a marker of rCAFs that suppress PDAC progression. SIGNIFICANCE: Meflin marks and functionally contributes to a subset of cancer-associated fibroblasts that exert antitumoral effects.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5367/F1.large.jpg.

BACKGROUND: Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas. Early diagnosis and intervention, before CP becomes established and irreversible, are essential to improve the long-term outcomes. The world's first diagnostic criteria for early CP were proposed in Japan in 2009, but their clinical utility remains elusive. This study aimed to clarify whether patients with early CP progress to definite CP. METHODS: This is a multicenter, prospective study. Patients diagnosed as having early CP according to the Japanese diagnostic criteria were prospectively followed for 2 years. Clinical profiles including symptoms, drinking and smoking status, laboratory data, imaging findings and treatments were analyzed. RESULTS: Among the 83 patients who completed the 2-year follow-up period, four (4.8%) patients progressed to definite CP. The diagnosis of 48 (57.8%) patients was unchanged, and that of 31 (37.3%) patients was downgraded. All the four progressive patients were male, alcohol-related, smokers (3 current and 1 ever), and continued drinking. Comparison of the clinical profiles between the progression group (n = 4) and non-progression group (n = 79) revealed that etiology (alcohol-related), smoking status and presence of acute pancreatitis episodes were associated with the progression to definite CP. CONCLUSIONS: The Japanese diagnostic criteria could identify some patients before the progression to definite CP, while the majority of the patients did not progress. TRIAL REGISTRATION NUMBER: UMIN000015992.

BACKGROUND: When a lesion does not meet the curative criteria of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC), referred to as non-curative resection or curability C-2 in the guidelines, an additional surgery is the standard therapy because of the risk of lymph node metastasis (LNM). OBJECTIVE: This study aimed to identify high-risk patients for recurrence after additional surgery for curability C-2 ESD of EGC. METHODS: This multicenter retrospective cohort study enrolled 1064 patients who underwent additional surgery after curability C-2 ESD for EGC. We evaluated the recurrence rate and the risk factors for recurrence after additional surgery in these patients. RESULTS: The 5-year recurrence rate after additional surgery was 1.3%. Multivariate Cox analysis revealed that the independent risk factors for recurrence after additional surgery were LNM (hazard ratio [HR] 32.47; p < 0.001) and vascular invasion (HR 4.75; p = 0.014). Moreover, patients with both LNM and vascular invasion had a high rate of recurrence after additional surgery (24.6% in 5 years), with a high HR (119.32) compared with those with neither LNM nor vascular invasion. Among patients with no vascular invasion, a high rate of recurrence was observed in those with N2/N3 disease according to the American Joint Committee on Cancer TNM staging system (27.3% in 5 years), in contrast with no recurrence in those with N1 disease. CONCLUSIONS: Patients with both LNM (N1-N3) and vascular invasion, as well as those with N2/N3 disease but no vascular invasion, would be candidates for adjuvant chemotherapy after additional surgery for curability C-2 ESD of EGC.

BACKGROUND AND AIM: Pooling of liquid in the esophageal lumen can worsen the field of vision and cause liquid reflux to the mouth, which leads to aspiration pneumonia, in esophageal endoscopic submucosal dissection (ESD). We developed a continuous liquid-suction catheter attachment for the endoscope (CLCA) that has multiple tiny holes and can suction the liquid without causing mucosal injury. Thus, we aim to show the efficacy of CLCA in esophageal ESD. METHODS: This was a single-blinded, randomized controlled trial involving patients with superficial esophageal cancer. The enrolled patients were randomly assigned to the conventional ESD (C-ESD) or ESD with CLCA (CLCA-ESD) groups. Primary endpoint was volume of liquid reflux to the mouth during the ESD procedure. Secondary endpoints were incidence of aspiration pneumonia and procedure time. RESULTS: Fifty patients were enrolled in this trial. Volume of liquid reflux to the mouth was significantly lower in the CLCA-ESD group than in the C-ESD group (mean: 10 vs 73 mL, P = 0.010). Furthermore, the incidence of aspiration pneumonia on computed tomography (CT) scan between the two groups was also significantly different (4.0% vs 32.0%, P = 0.023), although no significant difference was observed through chest radiography. In addition, procedure time tended to be shorter in the CLCA-ESD group (P = 0.054). CONCLUSION: This study first showed that use of CLCA in esophageal ESD reduced the volume of liquid reflux to the mouth and contributed to decreased incidence of aspiration pneumonia on CT scan (UMIN000018167).

The present report describes an extremely rare case of Barrett's adenocarcinoma (BAC) with a squamous cell carcinoma (SCC) component. A 55-year-old man was diagnosed with esophageal adenocarcinoma on Barrett's esophagus. The patient underwent endoscopic submucosal dissection, but the pathology revealed deep submucosal invasive, moderately differentiated tubular adenocarcinoma and focal SCC with vascular invasion. In addition, morphological transition between adenocarcinoma and SCC components was confirmed. The patient underwent additional surgery, which revealed lymph node metastasis, and then received S-1 adjuvant chemotherapy. Based on the pathological findings, the transdifferentiation process may have a role in the histogenesis of this tumor.

AIM: Macrovesicular steatosis around the central vein (zone 3) is one of the pathological features of non-alcoholic fatty liver disease or steatohepatitis (NAFLD/NASH). The aim of this study is to elucidate precisely the association between the area of lipid droplets (LDs) and the plasma metabolic parameters in patients with NAFLD/NASH. METHODS: Eighty patients with NAFLD/NASH diagnosed by needle biopsy were enrolled. The LDs around zone 3 were counted automatically by image processing software, the total area of LDs (TLDs), the maximum area of LDs (MAXLDs), the average area of LDs (AVELDs) and the heterogeneity by the coefficient of variation (CV [%]) were quantified. The correlations between these values and plasma metabolic parameters were analyzed. We evaluated the association between branched chain amino acids (BCAAs) and the heterogeneity of LDs in hepatocytes in vitro and in vivo. RESULTS: The MAXLDs was significantly correlated with more metabolic parameters than AVELDs and TLDs. The level of BCAAs was independently associated with the CV among the metabolic parameters. In early stage NAFLD, aspartate and alanine aminotransferase were significantly higher in the high CV group than in the low CV group. The high concentration of BCAAs increased the CV of LDs in hepatocytes accompanied by the expression of phosphor-p70 S6 kinase and sterol regulatory element-binding protein 1 in vitro. A high BCAA diet induced high heterogeneity of LDs around zone 3 in ob/ob mice. CONCLUSIONS: The levels of BCAAs were associated with the LD heterogeneity of hepatocytes around zone 3 in patients with NAFLD/NASH.

Selective immunoglobulin M deficiency (SIGMD) is an uncommon primary immunodeficiency disorder. We herein report an SIGMD patient with autoimmune hepatitis. A 21-year-old Japanese man was transferred to our hospital because of acute liver dysfunction. His serum IgM level was low, whereas those of IgG and IgA were normal, indicating that he had SIGMD. We diagnosed him with acute-onset autoimmune hepatitis, and his liver function test findings gradually recovered with corticosteroid administration. Although SIGMD with autoimmune diseases has been reported, the clinical features and pathogenesis have not yet been clarified. We have summarized previous reports on SIGMD patients with autoimmune diseases.

Viruses are considered to use vesicular trafficking in infected cells, but the details of assembly/release pathways of hepatitis B virus (HBV) are still unknown. To identify key regulators of HBV production, we performed short interfering RNA (siRNA) screening for Rab proteins, which are considered to act as molecular switches in vesicular trafficking using HepG2.2.15 cells. Among 62 Rab proteins, the suppression of Rab5B most significantly increased HBV DNA in the culture supernatant. Surprisingly, 5 days after the transfection of Rab5B siRNA, HBV DNA in the supernatant was increased more than 30-fold, reflecting the increase of infectious HBV particles. Northern blotting showed that transcription of 2.4/2.1-kb mRNA coding envelope proteins containing large hepatitis B surface protein (LHBs) was increased. Analysis of hepatocyte nuclear factors (HNFs) showed that transcription of HNF4α, which is known to enhance 2.4-kb mRNA transcription, was regulated by Rab5B. Also, it was revealed that LHBs had accumulated in the endoplasmic reticulum (ER) after Rab5B depletion but not in the multivesicular body (MVB), which is thought to be an organelle utilized for HBV envelope formation. Therefore, it was considered that Rab5B is required for the transport of LHBs from the ER to MVB. Immunofluorescent microscopy showed that HBs proteins, including LHBs, colocalized with HBc in the ER of Rab5B-depleted cells, suggesting that HBV envelopment occurs not only in the MVB but also in the ER. In conclusion, Rab5B is a key regulator of HBV production and could be a target of antiviral therapy.IMPORTANCE HBV infection is a worldwide health problem, but the mechanisms of how HBV utilizes cellular machinery for its life cycle are poorly understood. In particular, it has been unclear how the viral components and virions are transported among the organelles. The HBV budding site has been reported to be the ER or MVB, but it has not been clearly determined. In this study, siRNA-based screening of Rab proteins using HBV-expressing cells showed that Rab5B, one of the Rab5 isoforms, has important roles in late steps of the HBV life cycle. Although Rab5 is known to work on early endosomes, this study showed that Rab5B plays a role in the transport of LHBs between the ER and MVB. Furthermore, it affects the transcription of LHBs. This is the first report on the mechanisms of HBV envelope protein transport among the organelles, and the results provide important insights into the therapeutic control of HBV infection.

A 60-year-old man with a medical history of diabetes, liver cirrhosis, and distal gastrectomy was referred for further examination of a 10-mm pale-colored submucosal tumor around 40 cm from the incisors. Narrow band imaging-magnifying endoscopy revealed the lesion covered by smooth epithelium with irregular microvascular architecture in a sparse distribution. Endosonography showed an irregular-shaped hypoechoic lesion in the submucosa. With no evidence of metastases, we performed en bloc endoscopic submucosal dissection, whose specimen revealed esophageal lymphoepithelioma-like carcinoma invading up to 500 μm in the submucosa, a rare disease entity. Despite no additional treatment, he was alive without recurrence for longer than 88 months.

Vasohibin-2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL-KrasG12D ; LSL-Trp53R172H ; Pdx-1-Cre (KPC) mice, a mouse model of pancreatic ductal adenocarcinoma (PDAC), and cells isolated from them (KPC cells). Knockdown of Vash2 from PDAC cells did not affect their proliferation, but decreased their migration. When Vash2-knockdown PDAC cells were orthotopically inoculated, liver metastasis and peritoneal dissemination were reduced, and the survival period was significantly prolonged. When KPC mice were crossed with Vash2-deficient mice, metastasis was significantly decreased in Vash2-deficient KPC mice. VASH2 was recently identified to have tubulin carboxypeptidase activity. VASH2 knockdown decreased, whereas VASH2 overexpression increased tubulin detyrosination of PDAC cells, and tubulin carboxypeptidase (TCP) inhibitor parthenolide inhibited VASH2-induced cell migration. We next clarified its role in the tumor microenvironment. Tumor angiogenesis was significantly abrogated in vivo when VASH2 was knocked down or deleted. We further examined genes downregulated by Vash2 knockdown in KPC cells, and found chemokines and cytokines that were responsible for the recruitment of myeloid derived suppressor cells (MDSC). Indeed, MDSC were accumulated in PDAC of KPC mice, and they were significantly decreased in Vash2-deficient KPC mice. These findings suggest that VASH2 plays an essential role in the metastasis of PDAC with multiple effects on both cancer cells and the tumor microenvironment, including tubulin detyrosination, tumor angiogenesis and evasion of tumor immunity.

OBJECTIVES: Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intrapancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase emerged as a trypsin-independent risk gene. Here, we evaluated pancreatic lipase (PNLIP) as a potential novel susceptibility gene for CP. METHODS: We analyzed all 13 PNLIP exons in 429 nonalcoholic patients with CP and 600 control subjects from Germany, in 632 patients and 957 controls from France, and in 223 patients and 1,070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 patients with CP and 1,849 controls originating from Germany, United States, and India. We assessed the cellular secretion, lipase activity, and proteolytic stability of recombinant PNLIP variants. RESULTS: In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P = 0.02, odds ratio [OR] = 5.7, 95% confidence interval [CI] = 1.1-38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) vs controls (1/957 [0.1%]) (P = 0.04, OR = 7.6, 95% CI = 0.9-172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1,163 cases (1.1%) and in 3/3,000 controls (0.1%) (OR = 11.3, 95% CI = 3.0-49.9, P < 0.0001). CONCLUSIONS: Our data indicate that protease-sensitive PNLIP variants are novel genetic risk factors for the development of CP.

Reactivation of hepatitis B virus (HBV) is a major problem in patients receiving chemotherapy for malignant diseases or immunosuppression therapies. It has been thought that a reduction in the immune responses might result in the reactivation of HBV replication from covalently closed circular DNA (cccDNA) residing in hepatocytes. However, not only the host's immune status, but also viral mutations have been reported to be associated with reactivation. Especially, several case reports about amino acid mutations in hepatitis B surface antigen (HBsAg) that escape from immune reactions have been reported, and recent reports showed that the frequencies of such mutations are higher than previously expected. In this review, we summarize the characteristics of viral mutations, including immune escape mutations in HBV-reactivated patients, and discuss their significance.

BACKGROUND AND AIMS: Genome-wide association studies [GWASs] of European populations have identified numerous susceptibility loci for Crohn's disease [CD]. Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array [JPA] and subsequent imputation with the 1KJPN reference panel. METHODS: Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population, followed by a meta-analysis. Two additional replication sets [254 + 516 CD patients and 287 + 565 controls] were analysed for top hit single nucleotide polymorphisms [SNPs] from novel genomic regions. RESULTS: Genotype data of 4 335 144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10-26, odds ratio [OR] = 2.10), HLA-DQB1 [rs184950714, pmeta = 3.56 × 10-19, OR = 2.05], ZNF365, and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci [p <1 × 10-6], and rs488200 located upstream of RAP1A was significantly associated with CD [pcombined = 4.36 × 10-8, OR = 1.31]. Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression. CONCLUSIONS: RAP1A is a novel susceptibility locus for CD in the Japanese population.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. PDAC is the fourth leading cause of death in the United States and Japan based on epidemiological data. Early detection of PDAC is very important to improve the prognosis of PDAC. Early detection of pancreatic ductal adenocarcinoma (PDAC) requires further examination after selecting cases with risk factors for the condition, such as family history, hereditary pancreatic carcinoma syndrome, intraductal papillary mucinous neoplasms, or chronic pancreatitis. The Japan Study Group on the Early Detection of Pancreatic Cancer has investigated and clarified the clinicopathological features for the early diagnosis of PDAC. In Japan, an algorithm for the early diagnosis of PDAC, which utilized the cooperation of local clinics and regional general hospitals, has been a breakthrough in the detection of early-stage PDAC. Further approaches for the early diagnosis of PDAC are warranted.

Desmoplasia is a hallmark of pancreatic cancer and consists of fibrotic cells and secreted extracellular matrix (ECM) components. Various in vitro three-dimensional (3D) models of desmoplasia have been reported, but little is known about the relevant thickness of the engineered fibrotic tissue. We thus measured the thickness of fibrotic tissue in human pancreatic cancer, as defined by the distance from the blood vessel wall to tumor cells. We then generated a 3D fibrosis model with a thickness reaching the clinically observed range using pancreatic stellate cells (PSCs), the main cellular constituent of pancreatic cancer desmoplasia. Using this model, we found that Collagen fiber deposition was increased and Fibronectin fibril orientation drastically remodeled by PSCs, but not normal fibroblasts, in a manner dependent on Transforming Growth Factor (TGF)-β/Rho-Associated Kinase (ROCK) signaling and Matrix Metalloproteinase (MMP) activity. Finally, by targeting Secreted Protein, Acidic and Rich in Cysteine (SPARC) by siRNA, we found that SPARC expression in PSCs was necessary for ECM remodeling. Taken together, we developed a 3D fibrosis model of pancreatic cancer with a clinically relevant thickness and observed aberrant SPARC-dependent ECM remodeling in cancer-derived PSCs.

BACKGROUND: Rapid urinary trypsinogen-2 dipstick test and levels of urinary trypsinogen-2 and trypsinogen activation peptide (TAP) concentration have been reported as prognostic markers for the diagnosis of acute pancreatitis. AIM: To reconfirm the validity of all these markers in the diagnosis of acute pancreatitis by undertaking a multi-center study in Japan. METHODS: Patients with acute abdominal pain were recruited from 17 medical institutions in Japan from April 2009 to December 2012. Urinary and serum samples were collected twice, at enrollment and on the following day for measuring target markers. The diagnosis and severity assessment of acute pancreatitis were assessed based on prognostic factors and computed tomography (CT) Grade of the Japanese Ministry of Health, Labour, and Welfare criteria. RESULTS: A total of 94 patients were enrolled during the study period. The trypsinogen-2 dipstick test was positive in 57 of 78 patients with acute pancreatitis (sensitivity, 73.1%) and in 6 of 16 patients with abdominal pain but without any evidence of acute pancreatitis (specificity, 62.5%). The area under the curve (AUC) score of urinary trypsinogen-2 according to prognostic factors was 0.704, which was highest in all parameter. The AUC scores of urinary trypsinogen-2 and TAP according to CT Grade were 0.701 and 0.692, respectively, which shows higher than other pancreatic enzymes. The levels of urinary trypsinogen-2 and TAP were significantly higher in patients with extended extra-pancreatic inflammation as evaluated by CT Grade. CONCLUSION: We reconfirmed urinary trypsinogen-2 dipstick test is useful as a marker for the diagnosis of acute pancreatitis. Urinary trypsinogen-2 and TAP may be considered as useful markers to determine extra-pancreatic inflammation in acute pancreatitis.

BACKGROUND/AIMS: Few reports have described the long-term treatment outcomes of the anti-tumor necrosis factor-α antibody for Japanese Crohn's disease (CD) patients. The aim of this study was to evaluate them and clarify the clinical factors that affect the long-term prognosis of the anti-tumor necrosis factor-α treatments. METHODS: This was a retrospective, observational, single-center cohort study. Japanese CD patients treated with either infliximab or adalimumab as a first-line therapy were analyzed. The cumulative retention rates of the biologics, relapse-free survival, and surgery-free survival were analyzed using Kaplan-Meier methods. The clinical factors associated with the long-term outcomes were estimated by both the log-rank test and Cox proportional hazard model. RESULTS: The cumulative retention rate was significantly higher in the group with a concomitant elemental diet of ≥900 kcal/day, baseline C-reactive protein (CRP) levels <2.6 mg/dL, and baseline serum albumin levels ≥3.5 g/dL, respectively. The baseline serum albumin levels were also associated with both relapse-free and surgery-free survival. The lack of concomitant use of an elemental diet ≥900 kcal/day was identified as the only independent risk factor for the withdrawal of the biologics. CONCLUSIONS: Baseline CRP levels and serum albumin levels could affect the long-term outcomes in CD patients. Concomitant elemental diet of ≥900 kcal/day could have a positive influence on clinical treatment course.

Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. Cancer-associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)-6, IL-8, C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.

OBJECTIVES: The microRNA (miRNA) let-7d is linked to the formation of pancreatic cancer-related fibrosis. In this study, the mechanism by which let-7d regulates the activation of the human pancreatic stellate cell (hPSC) was evaluated. METHODS: The transient transfection of a let-7d mimic in the hPSCs was performed, and the altered thrombospondin 1 (THBS1) expression was confirmed by western blotting and real-time qPCR. Targeting of the 3'-untranslated region (UTR) of THBS1 by let-7d was investigated by the luciferase assays. After hPSC transfection using THBS1 siRNA, the fibrosis markers (α-SMA and collagen 1A1) were evaluated by western blotting and real-time qPCR. The correlation between tumor fibrosis and let-7d or THBS1 was estimated using the data from The Cancer Genome Atlas project. Finally, the effects of genistein on the hPSCs were evaluated. RESULTS: We found that a let-7d mimic inhibits THBS1 expression by targeting its 3'-UTR. THBS1 inhibition by siRNA inhibited hPSC activation. An in silico analysis revealed that let-7d and THBS1 expression are negatively correlated. Additionally, let-7d was negatively correlated with the stromal score, while THBS1 was positively correlated with this score. Genistein substantially induced let-7d and decreased the expression of fibrosis marker along with the inhibition of THBS1. CONCLUSIONS: Let-7d inhibited hPSC activation by targeting THBS1. Genistein induced the expression of let-7d and might modulate pancreatic fibrosis.