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Sulfation of metabolites is the second highest phase II modification in humans, which plays a critical role in the xenobiotics clearance process and gut microbiota-host co-metabolism. Besides the main function to remove xenobiotics from the body, sulfated metabolites have also been linked to inflammation, bacterial pathogenesis and metabolic disorders. A better understanding of how these metabolites impact the human body has turned into an important research area. Analytical methods for selective identification of this metabolite class are scarce. We have recently developed an assay utilizing the arylsulfatase from Helix pomatia due to a high substrate promiscuity combined with state-of-the-art metabolomics bioinformatic analysis for the selective identification of O-sulfated metabolites in human samples. This enzyme requires a multistep purification process as highest purity is needed for the developed mass spectrometric assay. In this study, we have utilized a new and recombinant overexpressed arylsulfatase (ASPC) for the selective identification of organic sulfate esters in human urine samples. We have compared the substrate conversion in urine samples and substrate specificity of this enzyme with purified arylsulfatase from Helix pomatia. Our analysis of urine samples revealed that both enzymes can be utilized for the selective analysis and discovery of sulfated metabolites with high promiscuity as demonstrated by equal hydrolysis of 108 substrates including sulfated conjugates of 27 metabolites of microbial origin. Importantly, we also identified 21 substrates in human urine samples that are exclusively hydrolyzed by ASPC and application of this enzyme increases the discovery of unknown sulfated metabolites with a higher scaffold diversity.

Introduction: Treatment of autoimmune pancreatitis (AIP) is based solely on consensus and has yet to become standardized. Consequently, therapeutic regimens vary greatly between countries and centers, and largely depend on the experience of the physician. At this moment, the optimal regimen for inducing disease remission and preventing relapse is unknown. Objectives: The primary objective of this study is to describe current treatment regimens used in Europe, and to compare their effectiveness in inducing remission and preventing and treating relapse. The secondary objectives are: to identify risk factors for relapse; to assess the diagnostic accuracy of the Unified-AIP criteria; to assess the performance of the M-ANNHEIM score for predicting relapse; and to assess long-term outcomes including pancreatic exocrine insufficiency and pancreatic cancer. Methods: This is an international, retrospective, observational cohort study, performed in over 40 centers from 16 European countries. Eligible are all patients diagnosed with AIP from 2005 onwards, regardless of the used diagnostic criteria. Data on study subjects will be retrieved from the hospital's electronic medical records and registered with a standardized, web-based, electronic case report form (eCRF). To compare the effectiveness of treatment regimens in inducing remission, preventing relapse, and treating relapse, subjects will be stratified in groups based on: type of therapy; initial therapy dose; cumulative therapy dose; therapy tapering speed and duration; and having received maintenance therapy or not. Ethics and Dissemination: Ethical and/or institutional review board approvals are obtained by all participating centers according to local regulations. The study complies with the General Data Protection Regulation (GDPR). All manuscripts resulting from the study will be submitted to peer-reviewed journals. Conclusion: This is the first pan-European retrospective registry for AIP. It will produce the first large-scale data on treatment of European patients with AIP, providing answers on the use and effectiveness of treatment regimens. In the future, this collaboration may provide a network for continuation into a prospective European registry.

Metabolites with ketone or aldehyde functionalities comprise a large proportion of the human metabolome, most notably in the form of sugars. However, these reactive molecules are also generated through oxidative stress or gut microbiota metabolism and have been linked to disease development. The discovery and structural validation of this class of metabolites over the large concentration range found in human samples is crucial to identify their links to pathogenesis. Herein, we have utilized an advanced chemoselective probe methodology alongside bioinformatic analysis to identify carbonyl-metabolites in urine and fecal samples. In total, 99 metabolites were identified in urine samples and the chemical structure for 40 metabolites were unambiguously validated using a co-injection procedure. We also describe the preparation of a metabolite-conjugate library of 94 compounds utilized to efficiently validate these ketones and aldehydes. This method was used to validate 33 metabolites in a pooled fecal sample extract to demonstrate the potential for rapid and efficient metabolite detection over a wide metabolite concentration range. This analysis revealed the presence of six metabolites that have not previously been detected in either sample type. The constructed library can be utilized for straightforward, large-scale, and expeditious analysis of carbonyls in any sample type.

Patients with chronic pancreatitis have an impaired quality of life and are at risk for several long-term complications. It is important to diagnose and treat these patients to minimize the effects of the disease. Clinical manifestations of chronic pancreatitis include a wide range of symptoms and patients are managed differenth between medical centers. In recent years, there have been improvements in knowledge about treatment and management of patients with chronic pancreatitis. This is a short report of the recently published Swedish guidelines for chronic pancreatitis, which are based on international guidelines as well as original publications and are related to the Swedish healthcare system.

Background According to the European evidence-based consensus, published by European Crohn's and Colitis Organization (ECCO), diseases of the pancreas are included as extra-intestinal manifestations in IBD in the forms of acute pancreatitis (AP), chronic pancreatitis (CP), autoimmune pancreatitis (AIP), pancreatic duct abnormalities and pancreatic exocrine insufficiency (PEI). Presence of pancreatic autoantibodies directed against the exocrine of the pancreas has been reported in about one-third of CD. However, association between CD and PEI is not fully elucidated. Methods Patients with a diagnosis of CD were recruited at the Department for Digestive Diseases at Karolinska University Hospital in Stockholm, Sweden. Demographic, clinical and laboratory data were analyzed. Fecal elastase-1 (FE-1) measurements were performed using the enzyme-linked immunosorbent assay (ELISA) method. Results There were 20 patients included in the study, 13 (65%) males and 7 (35%) females, mean age 48.3±1.4 years (range 29-67 years). Mean duration of CD was 15.7±2.1 years (range 1-40 years). There were 11 (55%) patients without history of bowel surgery and 9 (45%) patients after ileocecal resection. FE-1 test was normal in all patients, among them 15 (75%) patients with the values of FE-1>500. Conclusions Fecal elastase-1 level was normal in all patients with CD strongly indicated absence of PEI in this group of patients.

Background: Chronic pancreatitis is a long-standing, inflammatory condition of the pancreas that leads to the progressive damage and loss of function of pancreatic parenchyma and to the development of possible locoregional and systemic medical complications. Materials and methods: In this review, we tried to summarize the current evidence on non-surgical treatment trying to suggest a practical approach to the management of chronic pancreatitis. Results: Besides the unclear pathophysiological mechanism and a poorly unknown epidemiology, chronic pancreatitis is a complex syndrome that displays different possible challenges for physicians. Despite being traditionally considered as a benign disease, chronic pancreatitis encompasses 10-year mortality rates which are superior to the ones reported for some of the most common cancers. Conclusions: Chronic pancreatitis encompasses the management of multiple and complex medical co-morbidities that needs to be understood and addressed in a multidisciplinary specialist context.

Introduction The number of people aged 60 and above will rise from 46 million in 2015 to 157 in 2050 million, exceeding 30% of the population in many western countries. Consequently, the demand for oncological therapy for elderly patients will increase within the next decades. Currently, sufficient data on neoadjuvant therapy (NTx) of pancreatic cancer in elderly patients are lacking. Methods Data of a multinational, retrospective database were screened for patients having received preoperative FOLFIRINOX (FFx) or Gemcitabine/nab-paclitaxel (GNP) for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC) before June 2017. Data were included in an intention-to-treat-analysis and outcomes were compared between non-aged and elderly patients using a cut-off age of 63 (comparison 1) and 70 years (comparison 2). Results Of 165 patients receiving NTx, 76 and 33 were older than 63 and 70 years. Baseline characteristics revealed that elderly patients preferably undergo GNP (comparison 1: p = 0.063; comparison2: p = 0.005), with less cycles of NTx (comparison 1: p = 0.057). Whereas reductions of NTx dosage was more common in elderly patients in comparison 1 (p = 0.003), resection rates (p = 0.575; p = 1.000) and median survival (p = 0.406; p = 0.499) were not different. Whereas resected patients showed no differences in survival (p = 0.328; p = 0.132), patients aged >70 years showed a decreased progression-free survival (p = 0.019). Conclusion Elderly patients treated with NTx show encouragingly high resection rates. If comorbidities allow for FFx or GNP, elderly patients with LAPC/BRPC can offered NTx with the prospect of survival comparable to younger patients.

Introduction: Immunoglobulin G4-related disease (IgG4-RD) is a systemic immune-mediated disease characterised pathologically by the infiltration of IgG4-bearing plasma cells into the involved organs. Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis with a heavy lymphocytic infiltration and two distinct histopathological subtypes, namely: lymphoplasmacytic sclerosing pancreatitis (AIP type 1) and idiopathic duct-centric pancreatitis (AIP type 2). Lung involvement and aortic involvement have been reported in 12% and 9% of patients with systemic IgG4-RD, respectively. In series including patients with AIP, both lung and aortic involvement were described in 2% of the patients. Most of the epidemiological data come from Japan, and there is a lack of information from Europe, especially the Scandinavian countries. Patients and methods: We performed a single-centre retrospective study on a prospectively collected cohort of patients diagnosed with AIP at the Department for Digestive Diseases at Karolinska University Hospital in Stockholm, Sweden, from 2004 to 2019. Demographic and clinical data were collected from the medical charts. Results: One hundred and thirty-three patients with AIP were analysed. Six patients were excluded because they lacked some of the clinical data relevant to the study. Demographic and clinical features of 127 patients were presented. There were 98 patients with AIP type 1-35 (35.7%) female and 63 (64.3%) male, with a mean age of 55.4 ± 18.2. Among them, 15 (15.3%) patients had lung and/or cardiovascular involvement-11 (11.2%) patients had lung involvement, 10 (10.2%) patients had cardiovascular involvement (six patients had both). Most of them (67.0%) had never smoked. The mean follow-up time of the patients with AIP type 1 was 49 months. Conclusions: Lung and/or cardiovascular involvement were diagnosed in 15 (15.3%) patients in our historical cohort of patients with AIP type 1. Most of the lung involvement was presented in the form of nodular lesions in the lungs, non-specific infiltrates, “ground-glass” appearance with pleura thickening, and effusion. Aortic involvement was a major form of vascular involvement in patients with AIP, as in previous published studies on patients with IgG4-RD.

Background and study aims Conventional endoscopic retrograde cholangiopancreatography (ERCP) is hampered by two-dimensional visualization, post-procedural adverse events (AEs), and exposure to ionizing radiation. Bimodal ERCP might mitigate these challenges, but no reports of its use are available to date. The aim of this study was to explore the feasibility of bimodal ERCP, while investigating its potential clinical yield. Patients and methods This was a retrospective observational study of patients that underwent bimodal ERCP in a single tertiary academic referral center. Thirteen patients undergoing conventional ERCP had a previously T2-weighted isotropic 3 D TSE MRCP sequence aligned and fused with the two-dimensional image generated from the fluoroscopy c-arm unit in real time. Results Over a 2-month period, 13 patients with a mean age of 54 underwent bimodal ERCP for bile duct stricture (61.5 %), complex cholelithiasis (7.7 %) and ductal leakage (30.1 %). Bimodal ERCP was feasible in all 13 cases, and image quality was assessed as “good” in 11 patients (84.6 %). Bimodal ERCP aided in visualizing the lesion of interest (76.9 %), assisted in understanding the 3 D anatomy of the biliopancreatic ductal system (61.5 %), and aided in finding a favorable position for the c-arm (38.4 %) for subsequent therapeutic intervention. Conclusions This first report on bimodal ERCP proves its feasibility and suggests that it may assist in increasing both the diagnostic and therapeutic yield of ERCP, while at the same time decreasing AEs during and after ERCP. Its main application might lie in treatment of complex intrahepatic disease.

Background Pancreatic ductal adenocarcinoma is a devastating disease with poor outcome, generally characterized by an excessive stroma component. The purpose of this study was to develop a simple and reproducible in vitro 3D-assay employing the main constituents of pancreatic ductal adenocarcinoma, namely pancreatic stellate and cancer cells. Method A spheroid assay, directly co-culturing human pancreatic stellate cells with human pancreatic tumour cells in 3D was established and characterized by electron microscopy, immunohistochemistry and real-time RT-PCR. In order to facilitate the cell type-specific crosstalk analysis by real-time RT-PCR, we developed a novel in vitro 3D co-culture model, where the participating cell types were from different species, human and mouse, respectively. Using species-specific PCR primers, we were able to investigate the crosstalk between stromal and cancer cells without previous cell separation and sorting. Results We found clear evidence for mutual influence, such as increased proliferation and a shift towards a more mesenchymal phenotype in cancer cells and an activation of pancreatic stellate cells towards the myofibroblast phenotype. Using a heterospecies approach, which we coined virtual sorting, confirmed the findings we made initially in the human-human spheroids. Conclusions We developed and characterized different easy to set up 3D models to investigate the crosstalk between cancer and stroma cells for pancreatic cancer.

INTRODUCTION: Although pancreatic tuberculosis (TB) is traditionally considered to be a rare clinical entity, in recent times, an increase in the number of reports of pancreatic TB has been noted. We conducted a systematic review in order to summarise currently available data on pancreatic TB. METHODS: A comprehensive literature search of Medline, Scopus and ISI Web of Science databases was conducted in order to identify papers reporting cases of pancreatic TB. The eligibility criteria for inclusion in the review required that the studies reported patient(s) affected by pancreatic TB and that individual data on age, sex, clinical presentation and outcome were available. RESULTS: In total, 116 studies reporting data on 166 patients were included in the analysis. The majority of patients were males (62.1%) diagnosed at a mean age of 41.61 ± 13.95 years. Most cases were diagnosed in Asia (50.0%), followed by North America (22.9%), Europe (20.5%), Africa (4.2%) and South America (2.4%). Human immunodeficiency virus (HIV) infection was diagnosed in 25.3% of those affected. Pancreatic TB most frequently presented itself in the form of a pancreatic mass (79.5%) localised mainly in the head (59.0%) and less frequently in the body (18.2%) and tail (13.4%). Extrapancreatic TB involvement most frequently affected the peripancreatic lymph nodes (47.3%). More than half of patients (55.2%) were subjected to laparotomy, while 21.08% underwent endoscopic ultrasound fine-needle aspiration biopsy. The presence of TB was identified most frequently through histological analysis (59.6%), followed by culture (28.9%), staining (27.7%) and, in a smaller number, by polymerase chain reaction (9.6%) and cytology (6.6%). Almost all patients received anti-tubercular pharmacological therapy (98.2%), while 24.1% underwent surgery. Despite treatment, 8.7% of patients died. CONCLUSION: Increased awareness of pancreatic TB is needed, not only in endemic areas but especially in relation to HIV infection and other clinical conditions associated with immunoincompetence.

Supplemental material, sj-pdf-1-ueg-10.1177_2050640620934911 for European Guideline on IgG4-related digestive disease – UEG and SGF evidence-based recommendations by J-Matthias Löhr, Ulrich Beuers, Miroslav Vujasinovic, Domenico Alvaro, Jens Brøndum Frøkjær, Frank Buttgereit, Gabriele Capurso, Emma L Culver, Enrique de-Madaria, Emanuel Della-Torre, Sönke Detlefsen, Enrique Dominguez-Muñoz, Piotr Czubkowski, Nils Ewald, Luca Frulloni, Natalya Gubergrits, Deniz Guney Duman, Thilo Hackert, Julio Iglesias-Garcia, Nikolaos Kartalis, Andrea Laghi, Frank Lammert, Fredrik Lindgren, Alexey Okhlobystin, Grzegorz Oracz, Andrea Parniczky, Raffaella Maria Pozzi Mucelli, Vinciane Rebours, Jonas Rosendahl, Nicolas Schleinitz, Alexander Schneider, Eric FH van Bommel, Caroline Sophie Verbeke, Marie Pierre Vullierme, Heiko Witt and the UEG guideline working group in United European Gastroenterology Journal

Supplemental material, UEG902353 Supplemental Material for Pancreatic tuberculosis: A systematic review of symptoms, diagnosis and treatment by Nikola Panic, Hartwig Maetzel, Milutin Bulajic, Mihailo Radovanovic and J-Matthias Löhr in United European Gastroenterology Journal

Background Autoimmune pancreatitis is a special form of chronic pancreatitis with strong lymphocytic infiltration and two histopathological distinct subtypes, a lymphoplasmacytic sclerosing pancreatitis and idiopathic duct centric pancreatitis. Immunoglobulin G4‐associated cholangitis may be present at the time of autoimmune pancreatitis type 1 diagnosis or occur later over the course of the disease. Immunoglobulin G4 is considered reliable but not an ideal marker for diagnosis of autoimmune pancreatitis type 1 with reported sensitivity between 71–81%. It is essential to differentiate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis as the treatment and prognosis of the two diseases are totally different. It was the aim of the study to find a marker for immunoglobulin G4‐associated cholangitis that would distinguish it from primary sclerosing cholangitis. Patients and methods We performed a retrospective analysis of patients with autoimmune pancreatitis at our outpatient clinic. Patients from the primary sclerosing cholangitis registry were taken as a control group. Blood samples for the measurement of immunoglobulin subclasses were analysed at the time of diagnosis. Results Patients with autoimmune pancreatitis and immunoglobulin G4‐associated cholangitis had higher values of immunoglobulin G2 when compared to autoimmune pancreatitis alone or primary sclerosing cholangitis with a high specificity (97%) and high positive predictive value (91%). In patients with normal or low immunoglobulin G2 or immunoglobulin G4, a high level of immunoglobulin G1 indicated primary sclerosing cholangitis. Conclusion Immunoglobulin G1 and immunoglobulin G2 can distinguish patients with immunoglobulin G4‐associated cholangitis from those with primary sclerosing cholangitis.

Objectives: Post-endoscopic retrograde cholangiopancreatography (ERCP) acute pancreatitis (PEP) is a frequent complication of this endoscopic procedure. Chronic statin intake has been linked to lower incidence and severity of acute pancreatitis (AP). Periprocedural rectal administration of non-steroidal anti-inflammatory drugs is protective against PEP, but the role of chronic acetylsalicylic acid (ASA) treatment is unclear. We aimed to investigate whether statins and chronic ASA intake are associated with lower risk of PEP. Methods: An international, multicenter, prospective cohort study. Consecutive patients undergoing ERCP in seven European centers were included. Patients were followed-up to detect those with PEP. Multivariate analysis by means of binary logistic regression was performed, and adjusted odds ratios (aORs) were calculated. Results: A total of 1150 patients were included, and 70 (6.1%) patients developed PEP. Among statins users, 8.1% developed PEP vs. 5.4% among non-users (P=0.09). Multivariate analysis showed no association between statin use and PEP incidence (aOR 1.68 (95% CI 0.94–2.99, P=0.08)). Statin use had no effect on severity of PEP, being mild in 92.0% of statin users vs. 82.2% in non-statin users (P=0.31). Chronic ASA use was not associated with PEP either (aOR 1.02 (95% CI 0.49–2.13), P=0.96). Abuse of alcohol and previous endoscopic biliary sphincterotomy were protective factors against PEP, while >1 pancreatic guidewire passage, normal bilirubin values, and duration of the procedure >20minutes, were risk factors. Conclusions: The use of statins or ASA is not associated with a lower risk or a milder course of PEP.

Most models for predicting malignant pancreatic intraductal papillary mucinous neoplasms were developed based on logistic regression (LR) analysis. Our study aimed to develop risk prediction models using machine learning (ML) and LR techniques and compare their performances. This was a multinational, multi-institutional, retrospective study. Clinical variables including age, sex, main duct diameter, cyst size, mural nodule, and tumour location were factors considered for model development (MD). After the division into a MD set and a test set (2:1), the best ML and LR models were developed by training with the MD set using a tenfold cross validation. The test area under the receiver operating curves (AUCs) of the two models were calculated using an independent test set. A total of 3,708 patients were included. The stacked ensemble algorithm in the ML model and variable combinations containing all variables in the LR model were the most chosen during 200 repetitions. After 200 repetitions, the mean AUCs of the ML and LR models were comparable (0.725 vs. 0.725). The performances of the ML and LR models were comparable. The LR model was more practical than ML counterpart, because of its convenience in clinical use and simple interpretability.

Supplemental material, sj-pdf-1-ueg-10.1177_2050640620916027 for Immunoglobulin G subtypes-1 and 2 differentiate immunoglobulin G4-associated sclerosing cholangitis from primary sclerosing cholangitis by Miroslav Vujasinovic, Pia Maier, Hartwig Maetzel, Roberto Valente, Raffaella Pozzi-Mucelli, Carlos F Moro, Stephan L Haas, Karouk Said, Caroline S Verbeke, Patrick Maisonneuve and J-Matthias Löhr in United European Gastroenterology Journal

Background To date, there still is a lack of specific acute pancreatitis markers and specifically an early marker that can reliably predict disease severity. The inflammatory response in acute pancreatitis is mediated in part through oxidative stress and calcineurin-NFAT (Nuclear Factor of Activated T-cells) signaling, which is inducing its own negative regulator, regulator of calcineurin 1 (RCAN1). Caerulein induction is a commonly used in vivo model of experimental acute pancreatitis. Caerulein induces CN-NFAT signaling, reactive oxygen species and inflammation. Methods To screen for potential markers of acute pancreatitis, we used the caerulein model of experimental acute pancreatitis (AP) in C57Bl/6 J mice. Pancreata from treated and control mice were used for expression profiling. Promising gene candidates were validated in cell culture experiments using primary murine acinar cells and rat AR42J cells. These candidates were then further tested for their usefulness as biomarkers in mouse and human plasma. Results We identified a number of novel genes, including Regulator of calcineurin 1 (Rcan1) and Sestrin 2 (Sesn2) and demonstrated that they are induced by oxidative stress, by stimulation with H2O2 and by inhibiting caerulein stimulated expression with the antioxidant N-acetylcysteine. We found Rcan1 protein to be significantly elevated in AP-induced mouse plasma as well as in plasma from AP patients. Conclusion We demonstrated that Rcan1 is regulated by oxidative stress and identified RCAN1 as a potential diagnostic marker of AP.

While metabolites derived from gut microbiota metabolism have been linked to disease development in the human host, the chemical tools required for their detailed analysis and the discovery of biomarkers are limited. A unique and multifunctional chemical probe for mass spectrometric analysis, which contains p-nitrocinnamyloxycarbonyl as a new bioorthogonal cleavage site has been designed and synthesized. Coupled to magnetic beads, this chemical probe allows for straightforward extraction of metabolites from human samples and release under mild conditions. This isolation from the sample matrix results in significantly reduced ion suppression, an increased mass spectrometric sensitivity, and facilitates the detection of metabolites in femtomole quantities. The chemoselective probe was applied to the analysis of human fecal samples, resulting in the discovery of four metabolites previously unreported in this sample type and confirmation of the presence of medically relevant gut microbiota-derived metabolites.

Background/objectives: Smoking and alcohol abuse are established risk factors for chronic pancreatitis (CP). Few studies have examined how exposure to smoking and alcohol abuse act as risk factors for complications in CP. Our aim was to examine associations between patient reported exposure to smoking and alcohol abuse and complications in CP in a large cohort of patients from the Scandinavian and Baltic countries. Methods: We retrieved data on demographics, CP related complications and patients’ histories of exposure to smoking and alcohol abuse from the Scandinavian Baltic Pancreatic Club database. Associations were investigated by univariate and multivariate logistic regression analyses. Results are presented as odds ratios (OR) with 95% confidence intervals. Results: A complete history of smoking and alcohol exposure was available for 932 patients. In multivariate regression analyses, the presence of pain and exocrine pancreatic insufficiency were both significantly associated with history of smoking (OR 1.94 (1.40–2.68), p < 0.001 and OR 1.89 (1.36–2.62), p < 0.001, respectively) and alcohol abuse (OR 1.66 (1.21–2.26), p = 0.001 and 1.55 (1.14–2.11), p = 0.005, respectively). Smoking was associated with calcifications (OR 2.89 (2.09–3.96), p < 0.001), moderate to severe ductal changes (OR 1.42 (1.05–1.92), p = 0.02), and underweight (OR 4.73 (2.23–10.02), p < 0.001). History of alcohol abuse was associated with pseudocysts (OR 1.38 (1.00–1.90) p = 0.05) and diabetes mellitus (OR 1.44 (1.03–2.01), p = 0.03). There were significantly increased odds-ratios for several complications with increasing exposure to smoking and alcohol abuse. Conclusion: Smoking and alcohol abuse are both independently associated with development of complications in patients with CP. There seems to be a dose-dependent relationship between smoking and alcohol abuse and complications in CP.

Introduction: With high-throughput DNA analysis with next-generation sequencing (NGS), a new area of comprehensive molecular diagnostics is entering clinic. The profile of biomarkers (mutations and...

Senior people constitute the fastest growing segment of the population. The elderly are at risk for malnutrition, thought to be caused by reduced food intake or involution of the physiological capacity of the GI tract. Age-related changes are well known in other secretory organs such as liver, kidney and intestine. The pancreas, representing a metabolically active organ with uptake and breakdown of essential nutritional components, changes its morphology and function with age. During childhood, the volume of the pancreas increases, reaching a plateau between 20 and 60 years, and declines thereafter. This decline involves the pancreatic parenchyma and is associated with decreased perfusion, fibrosis and atrophy. As a consequence of these changes, pancreatic exocrine function is impaired in healthy older individuals without any gastrointestinal disease. Five per cent of people older than 70 years and ten per cent older than 80 years have pancreatic exocrine insufficiency (PEI) with a faecal elastase-1 below 200 μg g-1 stool, and 5% have severe PEI with faecal elastase-1 below 100 μg g-1 stool. This may lead to maldigestion and malnutrition. Patients may have few symptoms, for example steatorrhoea, diarrhoea, abdominal pain and weight loss. Malnutrition consists of deficits of fat-soluble vitamins and is affecting both patients with PEI and the elderly. Secondary consequences may include decreased bone mineral density and results from impaired absorption of fat-soluble vitamin D due to impaired pancreatic exocrine function. The unanswered question is whether this age-related decrease in pancreatic function warrants therapy. Therapeutic intervention, which may consist of supplementation of pancreatic enzymes and/or vitamins in aged individuals with proven exocrine pancreas insufficiency, could contribute to healthy ageing.

BACKGROUND Liquid biopsies can be used in castration-resistant prostate cancer (CRPC) to detect androgen receptor splice variant 7 (AR-V7), a splicing product of the androgen receptor. Patients with AR-V7-positive circulating tumor cells (CTCs) have greater benefit of taxane chemotherapy compared with novel hormonal therapies, indicating a treatment-selection biomarker. Likewise, in those with pancreatic cancer (PaCa), KRAS mutations act as prognostic biomarkers. Thus, there is an urgent need for technology investigating the expression and mutation status of CTCs. Here, we report an approach that adds AR-V7 or KRAS status to CTC enumeration, compatible with multiple CTC-isolation platforms. METHODS We studied 3 independent CTC-isolation devices (CellCollector, Parsortix, CellSearch) for the evaluation of AR-V7 or KRAS status of CTCs with in situ padlock probe technology. Padlock probes allow highly specific detection and visualization of transcripts on a cellular level. We applied padlock probes for detecting AR-V7, androgen receptor full length (AR-FL), and prostate-specific antigen (PSA) in CRPC and KRAS wild-type (wt) and mutant (mut) transcripts in PaCa in CTCs from 46 patients. RESULTS In situ analysis showed that 71% (22 of 31) of CRPC patients had detectable AR-V7 expression ranging from low to high expression [1–76 rolling circle products (RCPs)/CTC]. In PaCa patients, 40% (6 of 15) had KRAS mut expressing CTCs with 1 to 8 RCPs/CTC. In situ padlock probe analysis revealed CTCs with no detectable cytokeratin expression but positivity for AR-V7 or KRAS mut transcripts. CONCLUSIONS Padlock probe technology enables quantification of AR-V7, AR-FL, PSA, and KRAS mut/wt transcripts in CTCs. The technology is easily applicable in routine laboratories and compatible with multiple CTC-isolation devices.

Item does not contain fulltext BACKGROUND: In collaboration with United European Gastroenterology, the working group on 'Harmonizing diagnosis and treatment of chronic pancreatitis across Europe' (HaPanEU) developed European guidelines for the management of chronic pancreatitis using an evidence-based approach. METHODS: Recommendations of multidisciplinary review groups based on systematic literature reviews to answer predefined clinical questions are summarised. Recommendations are graded using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Recommendations covered topics related to the clinical management of chronic pancreatitis: aetiology, diagnosis of chronic pancreatitis with imaging, diagnosis of pancreatic exocrine insufficiency, surgical therapy, medical therapy, endoscopic therapy, treatment of pancreatic pseudocysts, pancreatic pain, nutrition and malnutrition, diabetes mellitus and the natural course of the disease and quality of life. CONCLUSIONS: The HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research. This article summarises the HaPanEU recommendations and statements.

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with an extremely poor prognosis, predominantly as a result of chemotherapy resistance and numerous somatic mutations. Consequently, PDAC is a prime candidate for the use of sequencing to identify causative mutations, facilitating subsequent administration of targeted therapy. In a feasibility study, we retrospectively assessed the therapeutic recommendations of a novel, evidence-based software that analyzes next-generation sequencing (NGS) data using a large panel of pharmacogenomic biomarkers for efficacy and toxicity. Tissue from 14 patients with PDAC was sequenced using NGS with a 620 gene panel. FASTQ files were fed into treatmentmap. The results were compared with chemotherapy in the patients, including all side effects. No changes in therapy were made. Known driver mutations for PDAC were confirmed (e.g. KRAS, TP53). Software analysis revealed positive biomarkers for predicted effective and ineffective treatments in all patients. At least one biomarker associated with increased toxicity could be detected in all patients. Patients had been receiving one of the currently approved chemotherapy agents. In two patients, toxicity could have been correctly predicted by the software analysis. The results suggest that NGS, in combination with an evidence-based software, could be conducted within a 2-week period, thus being feasible for clinical routine. Therapy recommendations were principally off-label use. Based on the predominant KRAS mutations, other drugs were predicted to be ineffective. The pharmacogenomic biomarkers indicative of increased toxicity could be retrospectively linked to reported negative side effects in the respective patients. Finally, the occurrence of somatic and germline mutations in cancer syndrome-associated genes is noteworthy, despite a high frequency of these particular variants in the background population. These results suggest software-analysis of NGS data provides evidence-based information on effective, ineffective and toxic drugs, potentially forming the basis for precision cancer medicine in PDAC.

Constitutive depletion of p21-activated kinase 4 (PAK4) in the mouse causes embryonic lethality associated with heart and brain defects. Given that conventional gene depletion of PAK1 or PAK3 caused functional deficits in the mouse pancreas, while gene depletion of PAK5 or PAK6 did not, we asked if PAK4 might have a functional role in pancreas development. We therefore introduced conditional, Pdx1-Cre-mediated, pancreatic PAK4 gene depletion in the mouse, verified by loss of PAK4 protein expression in the pancreas. PAK4 knock-out (KO) mice were born at Mendelian ratios in both genders. Further, morphological and immunohistochemical examinations and quantifications indicated that exocrine, endocrine and ductal compartments retained the normal proportions and distributions upon PAK4 gene depletion. In addition, body weight records and a glucose tolerance test revealed no differences between WT and PAK4 KO mice. Together, this suggests that PAK4 is dispensable for mouse pancreas development. This will facilitate future use of our Pdx1-Cre-driven conditional PAK4 KO mouse model for testing in vivo potential functions of PAK4 in pancreatic disease models such as for pancreatitis and different pancreatic cancer forms.

Background: Many endoscopists acknowledge that the appearance of the papilla of Vater seems to affect biliary cannulation. To assess the association between the macroscopic appearance of the papilla and biliary cannulation and other related clinical issues, a system is needed to define the appearance of the papilla. Objective: The purpose of this study was to validate an endoscopic classification of the papilla of Vater by assessing the interobserver and intraobserver agreements among endoscopist with varying experience. Methods: An endoscopic classification, based on pictures captured from 140 different papillae, containing four types of papillae was proposed. The four types are (a) Type 1: regular papilla, no distinctive features, ‘classic appearance’; (b) Type 2: small papilla, often flat, with a diameter ≤ 3 mm (approximately 9 Fr); (c) Type 3: protruding or pendulous papilla, a papilla that is standing out, protruding or bulging into the duodenal lumen or sometimes hanging down, pendulous with the orifice oriented caudally; and (d) Type 4: creased or ridged papilla, where the ductal mucosa seems to extend distally, rather out of the papillary orifice, either on a ridge or in a crease. To assess the level of interobserver agreement, a web-based survey was sent out to 18 endoscopists, containing 50 sets of still images of the papilla, distributed between the four different types. Three months later a follow-up survey, with images from the first survey was sent to the same endoscopists. Results: Interobserver agreement was substantial (κ = 0.62, 95% confidence interval (CI) 0.58–0.65) and were similar for both experts and non-experts. The intraobserver agreement assessed with the second survey was also substantial (κ = 0.66, 95% CI 0.59–0.72). Conclusion: The proposed endoscopic classification of the papilla of Vater seems to be easy to use, irrespective of the level of experience of the endoscopist. It carries a substantial inter- and intraobserver agreement and now the clinical relevance of the four different papilla types awaits to be determined.

Summary Background Bacille Calmette–Guerin (BCG) is the world's most widely distributed vaccine, used against tuberculosis (TB), in cancer immunotherapy, and in autoimmune diseases due to its immunomodulatory properties. To date, the effect of BCG vaccination on antibody responses to host proteins has not been reported. High-content peptide microarrays (HCPM) offer a unique opportunity to gauge specific humoral immune responses. Methods The sera of BCG-vaccinated healthy adults were tested on a human HCPM platform (4953 randomly selected epitopes of human proteins) to detect specific immunoglobulin gamma (IgG) responses. Samples were obtained at 56, 112, and 252 days after vaccination. Immunohistology was performed on lymph node tissue from patients with TB lymphadenitis. Results were analysed with a combination of existing and novel statistical methods. Results IgG recognition of host peptides exhibited a peak at day 56 post BCG vaccination in all study subjects tested, which diminished over time. Primarily, IgG responses exhibited increased reactivity to ion transporters (sodium, calcium channels), cytokine receptors (interleukin 2 receptor β (IL2Rβ), fibroblast growth factor receptor 1 (FGFR1)), other cell surface receptors (inositol, somatostatin, angiopoeitin), ribonucleoprotein, and enzymes (tyrosine kinases, phospholipase) on day 56. There was decreased IgG reactivity to transforming growth factor-beta type 1 receptor (TGFβR1) and, in agreement with the peptide microarray findings, immunohistochemical analysis of TB-infected lymph node samples revealed an overexpression of TGFβR in granulomatous lesions. Moreover, the vesicular monoamine transporter (VMAT2) showed increased reactivity on days 112 and 252, but not on day 56 post-vaccination. IgG to interleukin 4 receptor (IL4R) showed increased reactivity at 112 days post-vaccination, while IgG to IL2Rβ and FGFR1 showed decreased reactivity on days 112 and 252 as compared to day 56 post BCG vaccination. Conclusions BCG vaccination modifies the host's immune landscape after 56 days, but this imprint changes over time. This may influence the establishment of immunological memory in BCG-vaccinated individuals.

Background/Aims: Autoimmune pancreatitis (AIP) has been associated with an increased risk of malignant diseases. We aimed to describe the incidence of malignant diseases in patients with AIP compared to the general population and to characterize the clinical presentation of these patients. Methods: We retrospectively analyzed data from 28 patients with AIP presenting to the clinic (periods 1998 until 2010, 2012 until September 2015). We retrieved the expected cancer incidence of the general population from the German cancer registry. We determined the ratio of patients with malignant disease, characterized the clinical presentation of these patients, and calculated standardized incidence ratios (SIR). Results: We observed 6 malignant diseases in 5 patients with AIP (non-Hodgkin lymphoma, colon cancer, breast cancer and ovarian carcinoma, breast cancer, bladder cancer, n = 5/28, 17.9%) during an overall observation period of 223 person-years (2,675 months). The overall SIR of cancer in patients with AIP was 17.3 (95% CI 5.9-35.8), and the overall incidence rate of malignant diseases in these patients was significantly increased compared to the expected incidence in the German population (Fisher's exact test, p < 0.001). Conclusion: The incidence of malignant diseases in patients with AIP is significantly increased compared to the general population. Careful clinical monitoring is required in individuals with AIP to exclude the occurrence of malignancy.

Endoscopic mucosal dissection (ESD) is a treatment option for oesophagus tumours localized to the mucosa enabling en bloc removal of large lesions. The resulting larger mucosal defects have resulted in an increase in the occurrence of post-treatment strictures. Transplantation of autologous cell sheets, cultured from oral mucosa, has been shown to prevent post-ESD strictures. The aim of the study was to assess the efficacy and safety of cell sheet transplantation after oesophageal ESD in a Western patient population where reflux-associated pre-malignant and malignant conditions predominate.Patients with Barrett's oesophagus associated high-grade dysplasia or early adenocarcinoma where ESD entailed a resection3 cm in length and ≥75% of the circumference were eligible for treatment under hospital exemption. Cell sheets were cultured from buccal mucosa according to Good Manufacturing Practice and were endoscopically applied to the post-ESD defect directly after resection. Patients were followed with weekly endoscopy examinations, including confocal laser microscopy, for a total of four weeks.Five patients were treated. ESD was extensive with resections being circumferential in three patients and 9-10 cm in length in two. The number of transplanted cell sheets ranged from two to six. Three patients developed strictures requiring two to five dilatation sessions.Cell sheet transplantation shows to be safe and feasible in a Western population. Results suggest that transplantation has a protective effect on the mucosal defect after ESD, decreasing both the risk for and extent of stricture formation.

In this issue of the Young GI Angle, we have the opportunity to share the personal experience of four experienced clinicians with a successful career in different fields of gastroenterology. Here, you will find some of their most important decisions that have been a crucial turning point in their life. Many young fellows will face similar situations. Therefore, the testimony of these authors may help those taking difficult decisions during their professional career.

Clinical outcomes of chemotherapy for patients with advanced pancreatic adenocarcinoma in a real-world setting might differ from outcomes in randomized clinical trials (RCTs). Here we show in a single-institution cohort of 595 patients that median overall survival (OS) of patients who received gemcitabine alone (n = 185, 6.6 months (95% CI, 5.5&ndash, 7.7)) was the same as in pivotal RCTs. Gemcitabine/capecitabine (n = 60, 10.6 months (95% CI, 7.8&ndash, 13.3)) and gemcitabine/nab-paclitaxel (n = 66, 9.8 months (95% CI, 7.9&ndash, 11.8)) resulted in a longer median OS and fluorouracil/oxaliplatin/irinotecan (n = 31, 9.9 months (95% CI, 8.1&ndash, 11.7)) resulted in a shorter median OS than previously reported. Fluorouracil/oxaliplatin (n = 35, 5.8 months (95% CI, 4.5&ndash, 7)) and best supportive care (n = 206, 1.8 months (95% CI, 1.5&ndash, 2.1)) could not be benchmarked against any RCTs. The degree of protocol adherence explained differences between real-world outcomes and the respective RCTs, while exposure to second-line treatments did not.

New strategies are required for the discovery of unknown bioactive molecules produced by gut microbiota in the human host. Herein, we utilize a chemoselective probe immobilized to magnetic beads for analysis of carbonyls in human fecal samples. We identified 112 metabolites due to femtomole analysis and an increased mass spectrometric sensitivity by up to six orders of magnitude.

Pancreatic stellate cells (PSCs) are a key component of tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) and contribute to drug resistance. c-MET receptor tyrosine kinase activation plays an important role in tumorigenesis in different cancers including PDAC. In this study, effects of PSC conditioned medium (PCM) on c-MET phosphorylation (by immunocytochemistry enzyme-linked immunosorbent assay (ELISA)) and drug response (by sulforhodamine B assay) were investigated in five primary PDAC cells. In novel 3D-spheroid co-cultures of cyan fluorescence protein (CFP)-firefly luciferase (Fluc)-expressing primary human PDAC cells and green fluorescence protein (GFP)-expressing immortalized PSCs, PDAC cell growth and chemosensitivity were examined by luciferase assay, while spheroids&rsquo, architecture was evaluated by confocal microscopy. The highest phospho-c-MET expression was detected in PDAC5 and its subclone sorted for &ldquo, stage specific embryonic antigen-4&rdquo, (PDAC5 (SSEA4)). PCM of cells pre-incubated with PDAC conditioned medium, containing increased hepatocyte growth factor (HGF) levels, made PDAC cells significantly more resistant to gemcitabine, but not to c-MET inhibitors. Hetero-spheroids containing both PSCs and PDAC5 (SSEA4) cells were more resistant to gemcitabine compared to PDAC5 (SSEA4) homo-spheroids. However, c-MET inhibitors (tivantinib, PHA-665752 and crizotinib) were equally effective in both spheroid models. Experiments with primary human PSCs confirmed the main findings. In conclusion, we developed spheroid models to evaluate PSC&ndash, PDAC reciprocal interaction, unraveling c-MET inhibition as an important therapeutic option against drug resistant PDAC.

OBJECTIVES: Chronic pancreatitis (CP) is characterized by several disease-related complications and multiple etiological risk factors. Past studies of associations between complications and risk factors have mostly been limited to single complications or highly focused on single etiologies. Using an objective data-driven approach (cluster analysis), we characterized complication clusters and their associations with etiological risk factors in a large cohort of patients with CP.METHODS: This was a multicenter, cross-sectional study including 1,071 patients with CP from the Scandinavian and Baltic countries. Complications to CP were classified according to the M-ANNHEIM system, and treelet transform was used to derive complication clusters. Cluster complication frequencies were analyzed for their association with main etiological risk factors (smoking and alcohol).RESULTS: The mean age of participants was 57 years and 66% were men. Alcohol (55%) and smoking (53%) were the most common etiological risk factors and seen in combination in 36% of patients. Cluster analysis identified 3 distinct complication clusters characterized by inflammation, fibrosis, and pancreatic insufficiencies. An independent association between inflammatory complications and alcoholic etiology was seen (odds ratio [OR] 2.00 [95% CI [confidence interval], 1.38-2.90], P < 0.001), whereas smoking was associated with fibrosis-related complications (OR 2.23 [95% CI, 1.56-2.3.20], P < 0.001) and pancreatic insufficiencies (OR 1.42 [95% CI, 1.00-2.01], P = 0.046).DISCUSSION: Three distinctive clusters of complications to CP were identified. Their differing associations with alcoholic and smoking etiology indicate distinct underlying disease mechanisms.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, which is mainly due to late diagnosis and profound resistance to treatment. The latter is to a large extent attributed to the tumor stroma that is exceedingly prominent in PDAC and engages in complex interactions with the cancer cells. Hence, relevant preclinical models of PDAC should also include the tumor stroma. We herein describe the establishment and functional validation of an ex vivo organotypic culture of human PDAC that is based on precision-cut tissue slices from surgical specimens and reproducibly recapitulates the complex cellular and acellular composition of PDAC, including its microenvironment. The cancer cells, tumor microenvironment and interspersed remnants of nonneoplastic pancreas contained in these 350 µm thick slices maintained their structural integrity, phenotypic characteristics and functional activity when in culture for at least 4 days. In particular, tumor cell proliferation persisted and the grade of differentiation and morphological phenotype remained unaltered. Cultured tissue slices were metabolically active and responsive to rapamycin, an mTOR inhibitor. This culture system is to date the closest surrogate to the parent carcinoma and harbors great potential as a drug sensitivity testing system for the personalized treatment of PDAC.

Interventional treatment with stents in pancreatic cancer is a topic that developed during recent years and new fields of palliative stent therapy have evolved. The increasing life expectancy of patients with unresectable pancreatic cancer increases the need for clinical and cost effective therapeutic interventions. Current literature, guidelines, practice and evidence were reviewed. Besides the most obvious biliary stenting via endoscopic retrograde cholangiopancreatography (ERCP), pancreatic and gastroduodenal stenting as well as percutaneous transhepatic cholangiography (PTC) and the rapidly growing field of endosonographic stent implantation in the palliative care of patients with pancreatic cancer are being discussed from several points of view in this review.

Activated pancreatic stellate cells (PSCs) play a central role in the tumor stroma of pancreatic ductal adenocarcinoma (PDAC). Given the limited availability of patient-derived PSCs from PDAC, immortalized PSC cell lines of murine and human origin have been established, however, it is not elucidated whether differences in species, organ disease status, donor age, and immortalization alter the PSC phenotype and behavior compared to that of patient-derived primary PSC cultures. Therefore, a panel of commonly used PSC cultures was examined for important phenotypical and functional features: three primary cultures from human PDAC, one primary from normal human pancreas, and three immortalized (one from human, two from murine pancreas). Growth rate was considerably lower in primary PSCs from human PDAC. Basal collagen synthesis varied between the PSC cultures, and TGF-&beta, stimulation increased collagen synthesis only in non-immortalized cultures. Differences in secretome composition were observed along with a divergence in the DNA synthesis, migration, and response to gemcitabine of PDAC cell lines that were grown in conditioned medium from the various PSC cultures. The findings reveal considerable differences in features and functions that are key to PSCs and in the interactions with PDAC. These observations may be relevant to researchers when selecting the most appropriate PSC culture for their experiments.

ObjectiveIgG4-related disease (IgG4-RD) is a heterogeneous, multiorgan condition of unclear aetiology that can cause organ failure. Difficulty recognising IgG4-RD contributes to diagnostic delays. We sought to identify key IgG4-RD phenotypes.MethodsWe used two cross-sectional studies assembled by an international, multispecialty network of IgG4-RD specialists who submitted 765 cases to derive and replicate phenotypic groups. Phenotype groups of disease manifestations and key covariate distributions across the identified groups were measured using latent class analysis.ResultsIn the derivation cohort (n=493), we identified four groups with distinct manifestations: Group 1 (31%), Pancreato-Hepato-Biliary disease; Group 2 (24%), Retroperitoneal Fibrosis and/or Aortitis; Group 3 (24%), Head and Neck-Limited disease and Group 4 (22%), classic Mikulicz syndrome with systemic involvement. We replicated the identification of four phenotype groups in the replication cohort. Compared with cases in Groups 1, 2 and 4, respectively, cases in Group 3 were more likely to be female (OR 11.60 (95% CI 5.39 to 24.98), 10.35 (95% CI 4.63 to 23.15) and 9.24 (95% CI 3.53 to 24.20)) and Asian (OR 6.68 (95% CI 2.82 to 15.79), 7.43 (95% CI 2.97 to 18.56) and 6.27 (95% CI 2.27 to 17.29)). Cases in Group 4 had a higher median serum IgG4 concentration (1170 mg/dL) compared with groups 1–3 (316, 178 and 445 mg/dL, respectively, pConclusionWe identified four distinctive IgG4-RD phenotypes according to organ involvement. Being Asian or female may predispose individuals to head and neck-limited disease. These phenotypes serve as a framework for identifying IgG4-RD and studying its aetiology and optimal treatment.

Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene‐disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case–control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58–0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21–0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19–0.89, and OR = 0.73, 95%CI 0.53–1.00, respectively). Several inflammatory‐related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC. Grant sponsor: Acción Especial de Genómica, Spain; Grant numbers: #GEN2001-4748-c05-03; Grant sponsor: Swedish ALF; Grant numbers: #SLL20130022; Grant sponsor: Cancer Focus Northern Ireland and Department for Employment and Learning; Grant sponsor: EU H2020 Programme 2014-2020; Grant numbers: 634143 MedBioinformatics676559 Elixir-Excelerate; Grant sponsor: EU-6FP Integrated Project; Grant numbers: #018771-MOLDIAG-PACA; Grant sponsor: EU-FP7-HEALTH; Grant numbers: #256974-EPC-TMNet#259737-ANCERALIA#602783- Cam-Pac; Grant sponsor: Italian Foundation for Cancer Research (FIRC); Grant sponsor: Italian Ministry of Health; Grant numbers: FIMPCUP_J33G13000210001; Grant sponsor: Red Temática de Investigación Cooperativa en Cáncer, Spain; Grant numbers: #RD12/0036/0050#RD12/0036/ 0073(#RD12/0036/0034; Grant sponsor: The work was partially supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III-FEDER, Spain; Grant numbers: #PI0902102#PI11/01542#PI12/00815#PI12/01635#PI13/ 00082CP10/00524PI15/01573; Grant sponsor: World Cancer Research Fund; Grant numbers: WCR #15-0391.

Background Single-operator, per-oral cholangiopancreatoscopy (SOPCP) enables direct biliopancreatic ductal visualization, targeted tissue sampling, and therapeutic intervention. At Karolinska University Hospital, SOPCP was introduced early and has since been extensively utilized according to a standardized protocol. We analysed the clinical value of SOPCP in the diagnosis and treatment of biliopancreatic diseases in a single high volume center. Methods All SOPCP procedures performed between March 2007 and December 2014 were retrospectively reviewed. Each procedure’s diagnostic yield and therapeutic value was evaluated using a predefined 4 grade scale; 1 - no diagnostic or therapeutic value, 2 - information gained did not impact clinical decision-making and in case of a therapeutic intervention, did not alter the clinical course of the patient, 3 - information gained had an impact on clinical decision-making and in the case of a therapeutic intervention, assisted subsequent disease management, and finally, 4 - information gained was essential and critical for clinical decision-making and in case of a therapeutic intervention, solved the clinical problem requiring no further therapeutic actions. Descriptive statistics were used to analyse results, with uni- and multivariate analyses completed to assess risk of adverse events. Results During the study period, 365 SOPCP procedures were performed. We found SOPCP of pivotal importance (grade 4) in 19% of cases, and of great clinical significance (grade 3) in 44% of cases. SOPCP did not affect clinical decision-making or alter clinical course (grade 1 and 2) in 37% of cases. Conclusion SOPCP offers direct access to the biliopancreatic ducts for both diagnostic and therapeutic purposes, adding significant clinical value in 64% of cases. Trial registration As this is a purely observational and retrospectively registered study in which the assignment of the medical intervention was not at the discretion of the investigator, it has not been registered in a registry.

Background The purpose of the current study was to investigate the immunohistochemical (IHC) profile of liver metastases (LM) in patients with pancreatic ductal adenocarcinoma (PDAC). Methods Expression of 15 IHC markers in liver biopsies from 77 patients with PDAC, who were diagnosed between 2010 and 2014, were evaluated. In a separate subgroup analysis (n = 12), paired samples (LM and primary tumor) from the same patient were investigated for IHC profile differences. Results LM samples were classified as pancreatobiliary-type (PB-type) in 72 patients (93.5%), intestinal-type (INT-type) in four patients (5.2%), and squamous in one patient (1.3%). There was no significant difference in overall survival (OS) between LM of the PB-type or INT-type (p = 0.097). In a multivariate analysis, age

BACKGROUND Zinc is a key element in numerous proteins and plays an important role in essential cell functions such as defense against free radicals and DNA damage repair. Chronic pancreatitis (CP) is a chronic inflammation with progressive fibrosis of pancreas ultimately resulting in pancreatic exocrine insufficiency (PEI), which is associated with malnutrition. Studies analyzing zinc levels in patients with CP are sparse and lead to conflicting results. AIM To investigate serum zinc levels in patients with CP of various etiologies. METHODS Between October 2015 and March 2018, patients with a diagnosis of CP were identified and recruited from the Pancreatic Outpatient Clinic at the Karolinska University Hospital in Stockholm, Sweden. Demographic, clinical and laboratory data were analyzed. Etiology of CP was determined according to the M-ANNHEIM classification system into the following etiological subcategories: alcohol consumption, nicotine consumption, hereditary factors, efferent pancreatic duct factors and immunological factors. Pancreatic exocrine function was defined as normal (fecal elastase 1 > 200 μg/g), mildly reduced (100-200 μg/g) and severely reduced (fecal elastase 1 < 100 μg/g). RESULTS A total of 150 patients were included in the analysis. Zinc deficiency (< 11 μmol/L) was present in 39 (26.0%) of patients: 22 females and 17 males. In the group of patients with zinc deficiency, 76.7% of patients had an exocrine pancreatic insufficiency (FE-1 < 200 μg/g). Older age was significantly associated with low zinc levels. Following a univariate analysis, patients aged 60-69 and patients ≥ 70 years of age had a significantly higher prevalence of zinc deficiencies compared to patients < 40 years of age [OR: 3.8, 95%CI (1.08-13.4); P = 0.04]; [OR 6.26, 95%CI (1.94-20.2), P > 0.002]. Smoking and number of pack-years were additionally associated with low zinc levels. The risk of zinc deficiency in current smokers and smokers with ≥ 20 pack-years was approximately three times higher compared to those who had never smoked. Gender, body mass index, etiology of CP, presence of diabetes mellitus, levels of glycated hemoglobin (HbA1c), bone mineral density, alcohol intake and presence of PEI were not associated with low zinc levels. CONCLUSION Zinc deficiency is common in patients with CP and is significantly associated with age ≥ 60, smoking and the number of pack-years, but not with PEI.