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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)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A 73-year-old man was presented with epigastric pain and indicated high CA19-9 levels, and computed tomography detected a tumor in the uncinate process of the pancreas infiltrated duodenum and superior mesenteric artery. The patient was diagnosed with borderline resectable pancreatic carcinoma and received neoadjuvant chemotherapy with gemcitabine and S-1. During neoadjuvant chemotherapy, the patient also received radiotherapy to control duodenal bleeding. After neoadjuvant chemotherapy, stable disease(SD)was proven on the Response Evaluation Criteria in Solid Tumors(RECIST), and subtotal stomach-preserving pancreaticoduodenectomy was performed. The pathological findings showed pancreatic adenosquamous carcinoma. After 7 days postoperatively, hepatic metastasis was detected, and after 78 days postoperatively, the patient died.

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., (© 2022. The Author(s).)

In Japan, with the increasing prevalence of gastroesophageal reflux disease (GERD) and growing public interest, the Japanese Society of Gastroenterology issued Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009 and a revised 2nd edition in 2015. A number of studies on GERD were subsequently conducted in Japan and abroad, and vonoprazan, a potassium-competitive acid blocker (P-CAB), became available for the first time in Japan in February 2015. The revised 3rd edition (Japanese edition), which incorporates new findings and information, was published in April 2021. These guidelines are summarized herein, particularly sections related to the treatment of GERD. The important clinical issues addressed in the present revision are (i) the introduction of treatment algorithms that classify GERD into reflux esophagitis and non-erosive reflux disease, (ii) the clarification of treatment algorithms based on to the severity of reflux esophagitis, and (iii) the positioning of vonoprazan in the treatment for GERD. The present guidelines propose vonoprazan as the initial/maintenance treatment for severe reflux esophagitis. They also recommend vonoprazan or PPI as an initial treatment for mild reflux esophagitis and recommended PPI and proposed vonoprazan as maintenance treatment. These updated guidelines offer the best clinical strategies for GERD patients in Japan and hope that they will be of global use for the diagnosis and treatment for GERD., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

Background: Functional dyspepsia (FD) is a disorder that presents with chronic dyspepsia, which is not only very common but also highly affects quality of life of the patients. In Japan, FD became a disease name for national insurance in 2013, and has been gradually recognized, though still not satisfactory. Following the revision policy of Japanese Society of Gastroenterology (JSGE), the first version of FD guideline was revised this time., Method: Like previously, the guideline was created by the GRADE (grading of recommendations assessment, development and evaluation) system, but this time, the questions were classified to background questions (BQs, 24 already clarified issues), future research questions (FRQs, 9 issues cannot be addressed with insufficient evidence), and 7 clinical questions that are mainly associated with treatment., Results and Conclusion: These revised guidelines have two major features. The first is the new position of endoscopy in the flow of FD diagnosis. While endoscopy was required to all cases for diagnosis of FD, the revised guidelines specify the necessity of endoscopy only in cases where organic disease is suspected. The second feature is that the drug treatment options have been changed to reflect the latest evidence. The first-line treatment includes gastric acid-secretion inhibitors, acetylcholinesterase (AChE) inhibitors (acotiamide, a prokinetic agent), and Japanese herbal medicine (rikkunshito). The second-line treatment includes anxiolytics /antidepressant, prokinetics other than acotiamide (dopamine receptor antagonists, 5-HT4 receptor agonists), and Japanese herbal medicines other than rikkunshito. The patients not responding to these treatment regimens are regarded as refractory FD., (© 2022. The Author(s).)

Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non-viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease (CVD) event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow-up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary provides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan., (© 2021. The Author(s).)

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)., (© 2020 Japan Gastroenterological Endoscopy Society.)

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH., (© 2021. The Author(s).)

Inflammatory bowel disease (IBD) is a general term for chronic or remitting/relapsing inflammatory diseases of the intestinal tract and generally refers to ulcerative colitis (UC) and Crohn's disease (CD). Since 1950, the number of patients with IBD in Japan has been increasing. The etiology of IBD remains unclear; however, recent research data indicate that the pathophysiology of IBD involves abnormalities in disease susceptibility genes, environmental factors and intestinal bacteria. The elucidation of the mechanism of IBD has facilitated therapeutic development. UC and CD display heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management depends on the understanding and tailoring of evidence-based interventions by physicians. In 2020, seventeen IBD experts of the Japanese Society of Gastroenterology revised the previous guidelines for IBD management published in 2016. This English version was produced and modified based on the existing updated guidelines in Japanese. The Clinical Questions (CQs) of the previous guidelines were completely revised and categorized as follows: Background Questions (BQs), CQs, and Future Research Questions (FRQs). The guideline was composed of a total of 69 questions: 39 BQs, 15 CQs, and 15 FRQs. The overall quality of the evidence for each CQ was determined by assessing it with reference to the Grading of Recommendations Assessment, Development and Evaluation approach, and the strength of the recommendation was determined by the Delphi consensus process. Comprehensive up-to-date guidance for on-site physicians is provided regarding indications for proceeding with the diagnosis and treatment.

Background: The Japanese Society of Gastroenterology (JSGE) published ''Daicho Polyp Shinryo Guideline 2014'' in Japanese and a part of this guideline was published in English as "Evidence-based clinical practice guidelines for management of colorectal polyps" in the Journal of Gastroenterology in 2015. A revised version of the Japanese-language guideline was published in 2020, and here we introduce a part of the contents of revised version., Methods: The guideline committee discussed and drew up a series of clinical questions (CQs). Recommendation statements for the CQs were limited to items with multiple therapeutic options. Items with established conclusions that had 100% agreement with previous guidelines (background questions) and items with no (or old) evidence that are topics for future research (future research questions: FRQs) were given descriptions only. To address the CQs and FRQs, PubMed, ICHUSHI, and other sources were searched for relevant articles published in English from 1983 to October 2018 and articles published in Japanese from 1983 to November 2018. The Japan Medical Library Association was also commissioned to search for relevant materials. Manual searches were performed for questions with insufficient online references., Results: The professional committee created 18 CQs and statements concerning the current concept and diagnosis/treatment of various colorectal polyps, including their epidemiology, screening, pathophysiology, definition and classification, diagnosis, management, practical treatment, complications, and surveillance after treatment, and other colorectal lesions (submucosal tumors, nonneoplastic polyps, polyposis, hereditary tumors, ulcerative colitis-associated tumors/carcinomas)., Conclusions: After evaluation by the moderators, evidence-based clinical practice guidelines for management of colorectal polyps were proposed for 2020. This report addresses the therapeutic related CQs introduced when formulating these guidelines.

Managing irritable bowel syndrome (IBS) has attracted international attention because single-agent therapy rarely relieves bothersome symptoms for all patients. The Japanese Society of Gastroenterology (JSGE) published the first edition of evidence-based clinical practice guidelines for IBS in 2015. Much more evidence has accumulated since then, and new pharmacological agents and non-pharmacological methods have been developed. Here, we report the second edition of the JSGE-IBS guidelines comprising 41 questions including 12 background questions on epidemiology, pathophysiology, and diagnostic criteria, 26 clinical questions on diagnosis and treatment, and 3 questions on future research. For each question, statements with or without recommendations and/or evidence level are given and updated diagnostic and therapeutic algorithms are provided based on new evidence. Algorithms for diagnosis are requisite for patients with chronic abdominal pain or associated symptoms and/or abnormal bowel movement. Colonoscopy is indicated for patients with one or more alarm symptoms/signs, risk factors, and/or abnormal routine examination results. The diagnosis is based on the Rome IV criteria. Step 1 therapy consists of diet therapy, behavioral modification, and gut-targeted pharmacotherapy for 4 weeks. For non-responders, management proceeds to step 2 therapy, which includes a combination of different mechanistic gut-targeted agents and/or psychopharmacological agents and basic psychotherapy for 4 weeks. Step 3 therapy is for non-responders to step 2 and comprises a combination of gut-targeted pharmacotherapy, psychopharmacological treatments, and/or specific psychotherapy. These updated JSGE-IBS guidelines present best practice strategies for IBS patients in Japan and we believe these core strategies can be useful for IBS diagnosis and treatment globally.

Aim: Acute liver failure (ALF) patients with coma need to be revived not only for spontaneous recovery but also as a bridge to liver transplantation. We developed a new high-volume plasma purification system using an on-line continuous hemodiafiltration (CHDF) system, and evaluated its safety and efficacy in a multicenter study., Methods: A single arm interventional study using the new apparatus was undertaken in the six major liver centers in Japan. The primary end-point was the proportion of patients who regained consciousness within 10 days, which was compared with a historical control (47%). Nine ALF patients were enrolled and treated with the new machine. One patient was excluded because of the need for artificial respiration support according to the established protocol., Results: Seven of eight (87.5%) patients regained consciousness during the on-line CHDF session, with five of those seven waking within 4 days. After waking, one patient spontaneously recovered, three received liver transplantation, two died of liver failure, and one died of another disease. The plasma ammonia levels significantly decreased after the start of on-line CHDF from 182.5 ± 64.8 μg/dL (mean ± SD) on day 0 to 87.0 ± 38.9 μg/dL on the last day of the session (P < 0.001). Similarly, the plasma glutamine level also significantly decreased from 2069 ± 1234 μmol/L to 628 ± 193 μmol/L. Although seven severe adverse events occurred during on-line-CHDF, no causal relationship with liver support was recognized., Conclusions: The newly developed on-line CHDF system showed high efficacy for regain of consciousness and excellent therapeutic safety for managing ALF., (© 2020 The Japan Society of Hepatology.)

Situs inversus totalis (SIT) is a rare congenital anomaly in which all viscera are transposed to the opposite side of the body. This uncommon anatomy causes technical difficulties in endoscopic treatment. A 98-year-old woman with SIT was admitted to our hospital complaining of upper abdominal pain and fever. Blood examinations and findings of abdominal computed tomography imaging confirmed the diagnosis of acute pancreatitis and cholangitis associated with biliary stones. After recovering from pancreatitis and cholangitis with conservative treatment, she underwent therapeutic endoscopic retrograde cholangiopancreatography (ERCP) to remove the common bile duct (CBD) stones. The patient and the endoscopist were positioned in the usual ERCP position, and the scope was inserted into the duodenum with an approach in the direction opposite to the routine practice. Biliary cannulation was performed in the direction of 1 o'clock, and the cholangiography showed remarkably dilated CBD filled with numerous stones. Endoscopic papillary large balloon dilation was performed, and the CBD stones were successfully removed. There were no complications, such as bleeding, pancreatitis, or perforation. Over 3 years of follow-up, she had no recurrence of cholangitis or pancreatitis.

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., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

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., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

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., (© 2020 The Author(s). Published by S. Karger AG, Basel.)

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.

Purposes: The aim of this study was to clarify the impact of a board certification system and the implementation of clinical practice guidelines for pancreatic cancer (PC) on the mortality of pancreaticoduodenectomy in Japan., Methods: By a web questionnaire survey via the National Clinical Database (NCD) for departments participating in the NCD, quality indicators (QIs) related to the treatment for PC, namely the board certification systems of various societies and the adherence to clinical practice guidelines for PC, were investigated between October 2014 and January 2015. A multivariable logistic regression analysis was performed to evaluate the relationship between the QIs and mortality of pancreaticoduodenectomy., Results: Of 1415 departments that registered at least 1 pancreaticoduodenectomy between 2013 and 2014 in NCD, 631 departments (44.6%), which performed pancreaticoduodenectomy for a total of 11,684 cases, answered the questionnaire. The mortality of pancreaticoduodenectomy was positively affected by the board certification systems of the Japanese Society of Gastroenterological Surgery, Japanese Society of Hepato-Biliary-Pancreatic Surgery, Japanese Society of Gastroenterology, and Japanese Society of Medical Oncology as well as by institutions that used magnetic resonance imaging of ≥ 3 T for the diagnosis of PC in principle., Conclusions: The measurement of the appropriate QIs is suggested to help improve the mortality in pancreaticoduodenectomy. Masamichi Mizuma and Hiroyuki Yamamoto equally contributed.

Background/objectives: This paper is part of the international consensus guidelines on chronic pancreatitis, presenting for interventional endoscopy., Methods: An international working group with experts on interventional endoscopy evaluated 26 statements generated from evidence on 9 clinically relevant questions. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to evaluate the level of evidence. To determine the level of agreement, a nine-point Likert scale was used for voting on the statements., Results: Strong consensus was obtained for 15 statements relating to nine questions including the recommendation that endoscopic intervention should be offered to patients with persistent severe pain but not to those without pain. Endoscopic decompression of the pancreatic duct could be used for immediate pain relief, and then offered surgery if this fails or needs repeated endoscopy. Endoscopic drainage is preferred for portal-splenic vein thrombosis and pancreatic fistula. A plastic stent should be placed and replaced 2-3 months later after insertion. Endoscopic extraction is indicated for stone fragments remaining after ESWL. Interventional treatment should be performed for symptomatic/complicated pancreatic pseudocysts. Endoscopic treatment is recommended for bile duct obstruction and afterwards surgery if this fails or needs repeated endoscopy. Surgery may be offered if there is significant calcification and/or mass of the pancreatic head. Percutaneous endovascular treatment is preferred for hemosuccus pancreaticus. Surgical treatment is recommended for duodenal stenosis due to chronic pancreatitis., Conclusions: This international expert consensus guideline provides evidenced-based statements concerning indications and key aspects for interventional endoscopy in the management of patients with chronic pancreatitis., Competing Interests: Declaration of competing interest All authors have no conflict of interest of these consensus guidelines., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

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: 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., Competing Interests: Declaration of competing interest MK declares that he has received payment of lecture fee from Olympus Co. Ltd. DCW declares that he serves as a consultant to AbbVie, Abbott, Ariel Precision Medicine, and Regeneron; Samsung, and is a co-founder of Ariel Precision Medicine; and may have equity. SV is a consultant for Boston Scientific, Creo Medical, Medtronic and Olympus. The remaining authors declared that they did not have any conflicts of interest., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Patients with chronic pancreatitis (CP) have an increased risk of pancreatic cancer. We present the international consensus guidelines for surveillance of pancreatic cancer in CP., Methods: The international group evaluated 10 statements generated from evidence on 5 questions relating to pancreatic cancer in CP. The GRADE approach was used to evaluate the level of evidence available per statement. 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: In the following domains there was strong consensus: (1) the risk of pancreatic cancer in affected individuals with hereditary pancreatitis due to inherited PRSS1 mutations is high enough to justify surveillance; (2) the risk of pancreatic cancer in patients with CP associated with SPINK1 p. N34S is not high enough to justify surveillance; (3) surveillance should be undertaken in pancreatic specialist centers; (4) surveillance should only be introduced after the age of 40 years and stopped when the patient would no longer be suitable for surgical intervention. All patients with CP should be advised to lead a healthy lifestyle aimed at avoiding risk factors for progression of CP and pancreatic cancer. There was only moderate or weak agreement on the best methods of screening and surveillance in other types of environmental, familial and genetic forms of CP., Conclusions: Patients with inherited PRSS1 mutations should undergo surveillance for pancreatic cancer, but the best methods for cancer detection need further investigation., Competing Interests: Declaration of competing interest JPN reports grants from NUCANA, Stiftung Deutsche Krebshilfe and Heidelberger Stiftung Chirurgie all outside of the submitted work; DCW is co-founder of Ariel Precision Medicine and may have equity., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: The aim was to evaluate the various operative techniques and outcomes used to manage the pancreatic transection plane (or stump) during a left (distal) pancreatectomy and to develop expert consensus guidelines., Methods: Evidence-based, clinically relevant questions were discussed and then were circulated among members of the International Study Group of Pancreatic Surgery. After agreement on the questions and statements, voting in a 9-point Likert scale was used to gauge the level of objective support for each., Results: Studies using the International Study Group of Pancreatic Surgery definition of postoperative pancreatic fistula including 16 randomized trials were reviewed to generate a series of statements set into 14 domains. There was strong consensus in the following statements: there was no difference in the postoperative pancreatic fistula rate after left pancreatectomy between the handsewn and stapler techniques; a stapling technique could not be used in all cases of left pancreatectomy; the use of an energy-based tissue sealant or a chemical sealant device or combinations of these did not impact the postoperative pancreatic fistula rate; there was no difference in the postoperative pancreatic fistula rate between the open, laparoscopic, or robotic approaches; and there are 1 or more clinically important, patient-related risk factors associated with the postoperative pancreatic fistula rate. There was weak or conditional agreement on the use of prophylactic somatostatin analogs, stents, stump closure, stump anastomosis, and the role of abdominal drains., Conclusion: Areas of strong consensus suggests a change in clinical practice and priority setting. Eight domains with lower agreement will require novel approaches and large multicenter studies to determine future key areas of practice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose related to this work., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Advances in our understanding of total pancreatectomy with islet autotransplantation (TPIAT) have been made. We aimed to define indications and outcomes of TPIAT., Methods: Expert physician-scientists from North America, Asia, and Europe reviewed the literature to address six questions selected by the writing group as high priority topics. A consensus was reached by voting on statements generated from the review., Results: Consensus statements were voted upon with strong agreement reached that (Q1) TPIAT may improve quality of life, reduce pain and opioid use, and potentially reduce medical utilization; that (Q3) TPIAT offers glycemic benefit over TP alone; that (Q4) the main indication for TPIAT is disabling pain, in the absence of certain medical and psychological contraindications; and that (Q6) islet mass transplanted and other disease features may impact diabetes mellitus outcomes. Conditional agreement was reached that (Q2) the role of TPIAT for all forms of CP is not yet identified and that head-to-head comparative studies are lacking, and that (Q5) early surgery is likely to improve outcomes as compared to late surgery., Conclusions: Agreement on TPIAT indications and outcomes has been reached through this working group. Further studies are needed to answer the long-term outcomes and maximize efforts to optimize patient selection., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)