Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.

The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK:

Between early and established chronic pancreatitis: A proposal of "acinar-ductal hybrid mechanism".

BACKGROUND/OBJECTIVES: The recently proposed "new mechanistic definition of chronic pancreatitis (CP)" categorized early CP as a reversible condition. However, there is no clear explanation regarding the pathological condition of early CP, the reason for the development of the disease in only a small portion of the patients with risk factors, and the mechanism for transition from a reversible pathological condition to an irreversible one. METHODS: Based on the available information, a mechanism that could provide answers to the queries associated with CP was proposed. RESULTS: Acinar-ductal coordination is very important for the physiological secretion of pancreatic juice. Inflammation originating from acinar cells undermines the function of proximal ducts and leads to a vicious cycle of sustained inflammation by increasing the viscosity and decreasing the alkalinity of pancreatic juice. Persistent elevation of ductal pressure due to stagnation of pancreatic juice caused by protein plugs, stones, or fibrous scar of ducts converts the reversible pathological condition of early CP to an irreversible one. Diagnostic criteria for early CP proposed by Japanese researchers have enabled to the recognition of patients showing a progression from early to established CP. However, most patients diagnosed with early CP do not experience progression of the disease, suggesting the inadequate specificity of the criteria. CONCLUSION: The "acinar-ductal hybrid mechanism" may explain the pathological condition and progression of early CP. To diagnose early CP more accurately, it is essential to discover specific biomarkers that can discriminate "early CP" from "acute pancreatitis (AP)/recurrent acute pancreatitis (RAP)" and "established CP." Therapeutic intervention in clinical practices through various new approaches is expected to improve the prognosis of patients with CP.

[A Case of Resected Pancreatic Adenosquamous Carcinoma with Early Hepatic Metastatic Recurrence].

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.

Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis.

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.

Multicenter study on the consciousness-regaining effect of a newly developed artificial liver support system in acute liver failure: An on-line continuous hemodiafiltration system.

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.

Evidence-based clinical practice guidelines for liver cirrhosis 2020.

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 Japanese 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.

Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020.

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 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 pro- vides 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.

Impaired Mucosal Integrity in Proximal Esophagus Is Involved in Development of Proton Pump Inhibitor-Refractory Nonerosive Reflux Disease.

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-1ß 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.

Factors Associated with Fibrosis during Colorectal Endoscopic Submucosal Dissection: Does Pretreatment Biopsy Potentially Elicit Submucosal Fibrosis and Affect Endoscopic Submucosal Dissection Outcomes?

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.

Comprehensive Analysis of microRNA Profiles in Organoids Derived from Human Colorectal Adenoma and Cancer.

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.

Long-term endoscopic surveillance for Barrett's esophagus in Japan: Multicenter prospective cohort study.

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).

Small Interfering RNA Screening for the Small GTPase Rab Proteins Identifies Rab5B as a Major Regulator of Hepatitis B Virus Production.

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.

Clinical practice of acute pancreatitis in Japan: An analysis of nationwide epidemiological survey in 2016.

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.

Guidelines on the histopathology of chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and the European Pancreatic Club.

BACKGROUND: Chronic pancreatitis is a complex multifactorial fibro-inflammatory disease. Consensus guidelines are needed for the histopathological evaluation of non-autoimmune chronic pancreatitis (CP). METHODS: An international working group with experts on the histopathology of CP evaluated 15 statements generated from evidence on seven key clinically relevant questions. 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 the statements for strength of agreement, using a nine-point Likert scale, and Cronbach's alpha reliability coefficients were calculated. RESULTS: Strong consensus was obtained for 12 statements relating to all seven key questions including that: the cardinal features of CP are the triad of fibrosis, loss of acinar tissue and duct changes; there are no unique histopathological features that distinguish the different aetiologies of CP; clinical history and laboratory investigations, including genetic testing, are important in establishing the aetiology of CP; there is no reproducible and universally accepted histological grading system for assessing severity of CP, although classification as "mild", "moderate" and "severe" is usually applied; scoring systems for fibrosis are not validated for clinical use; asymptomatic fibrosis is a common finding associated with ageing, and not necessarily evidence of CP; there are no obvious diagnostic macroscopic features of early CP; histopathology is not the gold standard for the diagnosis of CP; and cytology alone is not a reliable method for the diagnosis of CP. CONCLUSIONS: Cardinal histopathological features of CP are well-defined and internationally accepted and pathological assessment is relevant for the purpose of differential diagnosis with other pancreatic diseases, especially cancer. However, a reliable diagnosis of CP requires integration of clinical, laboratory and imaging features and cannot be made by histology alone.

International consensus guidelines on the role of diagnostic endoscopic ultrasound in the management of chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

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.

International consensus guidelines on interventional endoscopy in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

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.

International Consensus Guidelines for Risk Factors in Chronic Pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

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.

The role of total pancreatectomy with islet autotransplantation in the treatment of chronic pancreatitis: A report from the International Consensus Guidelines in chronic pancreatitis.

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.

International consensus guidelines on surveillance for pancreatic cancer in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

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.

Effect of viral DNA methylation on expression of hepatitis B virus proteins depends on the virus genotype.

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.