Search

Background: Acute on chronic pancreatitis (ACP) is a relatively common condition, but there are significant gaps in our knowledge on the definition, incidence, diagnosis, treatment and prognosis. Methods: A systematic review that followed PICO (Population; Intervention; Comparator; Outcome) recommendation for quantitative questions and PICo (Population, Phenomenon of Interest, Context) for qualitative research was done to answer 10 of the most relevant questions about ACP. Quality of evidence was judged by the GRADE criteria (Grades of Recommendation, Assessment, Development and Evaluation). The manuscript was sent for review to 12 international experts from various disciplines and continents using a Delphi process. Results: The quality of evidence, for most statements, was low to very low, which means that the recommendations in general are only conditional. Despite that, it was possible to reach strong levels of agreement by the expert panel for all 10 questions. A new consensus definition of ACP was reached. Although common, the real incidence of ACP is not known, with alcohol as a major risk factor. Although pain dominates, other non-specific symptoms and signs can be present. Serum levels of pancreatic enzymes may be less than 3 times the upper limit of normal and cross-sectional imaging is considered more accurate for the diagnosis in many cases. It appears that it is less severe and with a lower mortality risk than acute pancreatitis.Conclusions: Although the evidence base is poor, this position statement provides a foundation from which to advance management of ACP.(c) 2023 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Genetic alterations in digestive enzymes have been associated with chronic pancreatitis (CP). Recently, chymotrypsin like elastase 3B (CELA3B) emerged as a novel risk gene. Thus, we evaluated CELA3B in two European cohorts with CP.We analyzed all 8 CELA3B exons in 550 German non-alcoholic CP (NACP) patients and in 241 German controls by targeted DNA sequencing. In addition, we analyzed exons 6 and 7 by Sanger sequencing and the c.129+1GA variant by melting curve analysis in 1078 further German controls. As replication cohort, we investigated up to 243 non-German European NACP patients and up to 1665 controls originating from Poland, Hungary, and Sweden. We assessed the cellular secretion and the elastase activity of recombinant CELA3B variants.In the German discovery cohort, we detected a splice-site variant in intron 2, c.129+1GA, in 9/550 (1.64%) CP patients and in 5/1319 (0.38%) controls (P=0.007, OR=4.4, 95% CI=1.5-13.0). In the European replication cohort, this variant was also enriched in patients (9/178 [5.06%]) versus controls (13/1247 [1.04%]) (P=0.001, OR=5.1, 95% CI=2.1-12.0). We did not find the two previously reported codon 90 variants, p.R90C and p.R90L.Our data indicate that CELA3B is a susceptibility gene for CP. In contrast to previous reports suggesting that increased CELA3B activity is associated with CP risk, the splice-site variant identified here is predicted to cause diminished CELA3B expression. How reduced CELA3B function predisposes to pancreatitis remains to be elucidated.

OBJECTIVE: Non-alcoholic chronic pancreatitis (NACP) frequently develops in the setting of genetic susceptibility associated with alterations in genes that are highly expressed in the pancreas. However, the genetic basis of NACP remains unresolved in a significant number of patients warranting a search for further risk genes. DESIGN: We analyzed CUZD1, which encodes the CUB and zona pellucida-like domains 1 protein that is found in high levels in pancreatic acinar cells. We sequenced the coding region in 1,163 European patients and 2,018 European controls. In addition, we analyzed 297 patients and 1,070 controls from Japan. We analyzed secretion of wild-type and mutant CUZD1 from transfected cells using Western blotting. RESULTS: In the European cohort, we detected 30 non-synonymous variants. Using different prediction tools (SIFT, CADD, PROVEAN, PredictSNP) or the combination of these tools, we found accumulation of predicted deleterious variants in patients (p-value range 0.002–0.013; OR range 3.1–5.2). No association was found in the Japanese cohort, in which 13 non-synonymous variants were detected. Functional studies revealed >50% reduced secretion of 7 variants, however, these variants were not significantly enriched in European CP patients. CONCLUSION: Our data indicate that CUZD1 might be a novel susceptibility gene for chronic pancreatitis. How these variants predispose to pancreatitis remains to be elucidated.

Resections for intraductal papillary mucinous neoplasia (IPMN) have increased dramatically during the last decade. Recurrence pattern and impact of adjuvant chemotherapy for solid pancreatic ductal adenocarcinoma (PDAC) is well known, but not for invasive IPMN (inv-IPMN).To elucidate the impact of spatio-temporal recurrence pattern and adjuvant chemotherapy on overall survival for inv-IPMN compared with PDAC.We conducted a retrospective single-center observational study of consecutive patients ≥18 years of age who underwent resection for inv-IPMN or PDAC at Karolinska University Hospital, between 2009 and 2018. Different initial recurrence sites and time frames as well as predictors for death were assessed with multivariable Cox and logistic regressions. Survival analyses were performed using the Kaplan-Meier model and log rank test.Of 396 resected patients, 92 were inv-IPMN and 304 PDAC. Both recurrence rate and death rate within three-years were lower for inv-IPMN compared to PDAC (p = 0.006 and p = 0.007 respectively). Across the whole cohort, the most common recurrence patterns were multi-site (25%), single-site liver (21%) and single-site locoregional (10%) recurrence. The most prominent predictors for death in multivariable Cox regression, especially if occurred within the first year, were multi-site (HR 17.0), single-site peritoneal (HR 13.6) and single-site liver (HR 13.1) recurrence. These predictors were less common in inv-IPMN compared to PDAC (p = 0.007). The effect of adjuvant chemotherapy was similar in the two groups.Resected inv-IPMN exhibits a less aggressive recurrence pattern than PDAC that translates into a more favorable overall survival.

Background/objectives: There is scarce information about risk factors for exocrine pancreas insufficiency (EPI) in chronic pancreatitis (CP), and how it associates with other complications. The aim of the present study was to examine risk factors for EPI and associations to procedures and other CP related complications in a large, Northern European cohort.Patients and methods: We retrieved cross-sectional data on demographics, status on EPI, aetiological risk factors for CP, CP related complications as well as surgical and endoscopic treatment from the Scandinavian Baltic Pancreatic Club Database. Associations were assessed by univariate and multivariate logistic regression analyses. Results are presented as odds ratios (OR) with 95% confidence intervals.Results: We included 1869 patients with probable or definitive CP in the study. Exocrine pancreas insufficiency was present in 849 (45.4%) of patients. In multivariate analyses, EPI associated with smoking aetiology (OR 1.47 (1.20-1.79), p < 0.001), and nutritional/metabolic aetiology (OR 0.52 (0.31-0.87), p = 0.01) to CP. Pancreatic or common bile duct stenting procedure and pancreatic resection were both associated with EPI (ORs 1.44 (1.15-1.80), p = 0.002 and 1.54 (1.02-2.33), p = 0.04, respectively). The presence of diabetes mellitus (OR 2.45 (1.92-3.15), p < 0.001), bile duct stenosis (OR 1.48 (1.09-2.00), p = 0.02) and underweight (2.05 (OR 1.40-3.02), p < 0.001) were all associated with presence of EPI.Conclusions: Smoking, bile duct stenosis, previous stenting and resection procedures are all associated with EPI in patients with CP. Presence of EPI were also associated with malnutrition and diabetes mellitus. Hence, intensive nutritional surveillance is needed in these patients. (C) 2022 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC.

IntroductionDespite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency.MethodsAn online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years.ResultsOverall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency.ConclusionThis survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence. Introduction: Despite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency. Methods: An online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years. Results: Overall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency. Conclusion: This survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence.

Transforming growth factor-β (TGF-β)-mediated accumulation of extracellular matrix proteins such as collagen I is a common feature of fibrosis. Pancreatic stellate cells play an integral role in the pathogenesis of pancreatitis, and their profibrotic ability is mainly mediated by TGF-β signaling. To specifically address the role of fibrogenic cells in experimental pancreatic fibrosis, we deleted Smad7, the main feedback inhibitor of TGF-β signaling in this cell type in mice.A mouse strain harboring a conditional knockout allele of Smad7 (Smad7fl/fl) with the tamoxifen-inducible inducible Col1a2-CreERT allele was generated and compared with wild-type mice challenged with the cerulein-based model of chronic pancreatitis.Pancreatic stellate cells lacking Smad7 had significantly increased collagen I and fibronectin production and showed a higher activation level in vitro. Surprisingly, the fibrotic index in the pancreata of treated conditional knockout mice was only slightly increased, without statistical significance. Except for fibronectin, the expression of different extracellular matrix proteins and the numbers of fibroblasts and inflammatory cells were similar between Smad7-mutant and control mice.There was no clear evidence that the lack of Smad7 in pancreatic stellate cells plays a major role in experimental pancreatitis, at least in the mouse model investigated here.

Background/objectives: Resections for intraductal papillary mucinous neoplasm (IPMN) have increased last decades. Overall survival (OS) for conventional pancreatic ductal adenocarcinoma (PDAC) is well known but OS for invasive IPMN (inv-IPMN) is not as conclusive. This study aims to elucidate potential differences in clinicopathology and OS between these tumor types and to investigate if the raised number of resections have affected outcome. Methods: Consecutive patients ≥18 years of age resected for inv-IPMN and PDAC at Karolinska University Hospital between 2009 and 2018 were included. Clinicopathological variables were analyzed in multivariable regression models. Outcome was assessed calculating two-year OS, estimating OS using the Kaplan-Meier model and comparing survival functions with log-rank test. Results: 513 patients were included, 122 with inv-IPMN and 391 with PDAC. During the study period both the proportion resected inv-IPMN and two-year OS, irrespective of tumor type, increased (2.5%–45%; p < 0.001 and 44%–57%; p = 0.005 respectively). In Kaplan-Meier survival analysis inv-IPMN had more favorable median OS (mOS) compared to PDAC (33.6 months vs 19.3 months, p = 0.001). However, in multivariable Cox Regression analysis, tumor type was not a predictor for death, but so were resection period, tumor subtype and N-stage (all p < 0.001). Conclusion: In this large single center observational cohort study, inv-IPMN seemed to have favorable survival outcome compared to PDAC, but after adjusting for predictors for death this benefit vanished. The combination of a pronounced increase in resected inv-IPMN and a concurrent hazard abatement for death within 2 years during the study period proved to be a principal factor.

Contains fulltext : 238998.pdf (Publisher’s version ) (Open Access) BACKGROUND: Pancreatic duct disruption or disconnection is a potentially severe complication of necrotizing pancreatitis. With no existing treatment guidelines, it is unclear whether there is any consensus among experts in clinical practice. We evaluated current expert opinion regarding the diagnosis and treatment of pancreatic duct disruption and disconnection in an international case vignette study. METHODS: An online case vignette survey was sent to 110 international expert pancreatologists. Expert selection was based on publications in the last 5 years and/or participation in development of IAP/APA and ESGE guidelines on acute pancreatitis. Consensus was defined as agreement by at least 75% of the experts. RESULTS: The response rate was 51% (n = 56). Forty-four experts (79%) obtained a MRI/MRCP and 52 experts (93%) measured amylase levels in percutaneous drain fluid to evaluate pancreatic duct integrity. The majority of experts favored endoscopic transluminal drainage for infected (peri)pancreatic necrosis and pancreatic duct disruption (84%, n = 45) or disconnection (88%, n = 43). Consensus was lacking regarding the treatment of patients with persistent percutaneous drain production, and with persistent sterile necrosis. CONCLUSION: This international survey of experts demonstrates that there are many areas for which no consensus existed, providing clear focus for future investigation.

Background: 2017 International and 2018 European guidelines are the most recent guidelines for intraductal papillary mucinous neoplasms management. Aim: to evaluate the diagnostic accuracy of these guidelines in identifying malignant IPMN. Methods: data from resected patients with IPMN were collected in two referral centers. Features of risk associated to cancerous degeneration described in International and European guidelines were retrospectively applied. Sensitivity, specificity, positive and negative predictive value in detecting malignant disease were calculated. Results: the study includes 627 resected patients. European guidelines suggest resection in any patient with at least one feature of moderate-risk. International guidelines suggest that patients with moderate risk features undergo endoscopic ultrasound before surgery. European guidelines had a higher sensitivity (99.2% vs. 83%) but a lower positive predictive value (59.5% vs. 65.8%) and Specificity (2% vs. 37.5%). European guidelines detected almost all malignancies, but 40% of resected patients had low-grade dysplasia. 297 patients underwent endoscopic ultrasound before surgery. 31/116 (26.7%) tumors radiologically classified as "worrisome features" were reclassified as "high-risk stigmata" by endoscopic ultrasound and 24/31 were malignant IPMN. Conclusions: European and International guidelines have a relatively low diagnostic accuracy, being European guidelines more aggressive. Endoscopic ultrasound can improve guidelines accuracy in patients with moderate-risk features. (c) 2021 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Background: The clinical importance of intraductal papillary mucinous neoplasm (IPMN) have increased last decades. Long-term survival after resection for invasive IPMN (inv-IPMN) compared to conventional pancreatic ductal adenocarcinoma (PDAC) is not thoroughly delineated. Objective: This study, based on the Swedish national pancreatic and periampullary cancer registry aims to elucidate the outcome after resection of inv-IPMN compared to PDAC. Methods: All patients ≥18 years of age resected for inv-IPMN and PDAC in Sweden between 2010 and 2019 were included. Clinicopathological variables were retrieved from the national registry. The effect on death was assessed in two multivariable Cox regression models, one for patients resected 2010–2015, one for patients resected 2016–2019. Median overall survival (OS) was estimated using the Kaplan-Meier method. Results: We included 1909 patients, 293 inv-IPMN and 1616 PDAC. The most important independent predictors of death in multivariable Cox regressions were CA19-9 levels, venous resection, tumour differentiation, as well as T-, N-, M-stage and surgical margin. Tumour type was an independent predictor for death in the 2016–2019 cohort, but not in the 2010–2015 cohort. In Kaplan-Meier survival analysis, inv-IPMN was associated with longer median OS in stage N0-1 and in stage M0 compared to PDAC. However, in stage T2-4 and stage N2 median OS was similar, and in stage M1 even shorter for inv-IPMN compared to PDAC. Conclusion: In this population-based nationwide study, outcome after resected inv-IPMN compared to PDAC is more favourable in lower stages, and similar to worse in higher.

Adenomatous neoplasia in the papilla of Vater needs to be resected in order not to progress. It can be challenging to distinguish between early ampullary malignant lesions and non-invasive adenomas, due to the overlap in symptoms and radiological findings. This retrospective study describes the different findings and treatment decisions taken prior to endoscopic and/or surgical resection of ampullary adenomatous lesions. Patients treated with endoscopic and/or surgical resection for suspected or verified ampullary adenomatous neoplasia, between January 2006 and July 2018, where pre-interventional cross-sectional imaging could not discern an obvious invasive, malignant tumor, were included. Findings were compared against the final diagnosis of the histopathological analysis on the resected specimen. In total, 172 met the inclusion criteria. Patients were treated with either surgical resection (n = 96), endoscopic papillectomy (EP) (n = 55) or both (n = 21). The final diagnosis was in 48% ampullary adenocarcinoma, and the remaining had either ampullary adenoma (38%) or non-neoplastic lesions (14%). In patients where symptoms and cross-sectional imaging were suspicious for malignancy, but with no tissue samples that confirmed neoplasia prior to surgical resection, only 47% had adenocarcinoma. The remaining had either adenoma (9%) or non-neoplastic lesions (44%). Adenocarcinoma was revealed in 27% of the patients where endoscopic biopsies had shown adenoma. Patients with adenoma, treated with EP, were cured in 59%. However, 28% were after EP sent for further surgery due to ductal invasion or a finding of adenocarcinoma. In patients with a suspicion of ampullary neoplasia on imaging, attempts should be made to get endoscopic tissue samples before deciding on a treatment strategy. If biopsies show ampullary adenoma, patients should be considered for EP, unless there are clear radiologic or endoscopic signs of malignancy. Patients with adenocarcinoma on endoscopic biopsies should undergo surgical resection.

Autoimmune pancreatitis (AIP) is a rare etiological type of chronic pancreatitis. The clinical and radiological presentation of AIP often resembles that of pancreatic cancer. Identifying non-invasive markers for their early distinction is of utmost importance to avoid unnecessary surgery or a delay in steroid therapy. Thus, this systematic review was conducted to revisit all current evidence on the clinical utility of different serum biomarkers in diagnosing AIP, distinguishing AIP from pancreatic cancer, and predicting disease course, steroid therapy response, and relapse. A systematic review was performed for articles published up to August 2021 by searching electronic databases such as MEDLINE, Web of Science, and EMBASE. Among 5123 identified records, 92 studies were included in the qualitative synthesis. Apart from immunoglobulin (Ig) G4, which was by far the most studied biomarker, we identified autoantibodies against the following: lactoferrin, carboanhydrase II, plasminogen-binding protein, amylase-α2A, cationic (PRSS1) and anionic (PRSS2) trypsinogens, pancreatic secretory trypsin inhibitor (PSTI/SPINK1), and type IV collagen. The identified novel autoantigens were laminin 511, annexin A11, HSP-10, and prohibitin. Other biomarkers included cytokines, decreased complement levels, circulating immune complexes, N-glycan profile changes, aberrant miRNAs expression, decreased IgA and IgM levels, increased IgE levels and/or peripheral eosinophil count, and changes in apolipoprotein isoforms levels. To our knowledge, this is the first systematic review that addresses biomarkers in AIP. Evolving research has recognized numerous biomarkers that could help elucidate the pathophysiological mechanisms of AIP, bringing us closer to AIP diagnosis and its preoperative distinction from pancreatic cancer.

Background: The initial management of patients with acute pancreatitis impacts both morbidity and mortality. Point-of-care decisions have been reported to differ from clinical guideline recommendations. Methods: An online anonymous questionnaire was distributed through scientific associations and social media using REDCap. Multivariable logistic regression was used to identify the characteristics of participants associated with compliance with the recommendations. Results: A total of 1054 participants from 94 countries completed the questionnaire; median age (IQR) was 39 (32–47) years; 30.7% were women. Among the participants, 37% opted for nonmoderate flow of i.v. fluid, 31% for fluid type other than Ringer’s lactate; 73.4% were in favor of nil per os to patients who could eat, 75.5% for other than enteral feeding to patients with oral intolerance; 15.5% used prophylactic antibiotic in patients with severe acute pancreatitis, 34.1% in necrotizing acute pancreatitis, and 27.4% in patients with systemic inflammatory response syndrome; 27.8% delayed cholecystectomy after biliary acute pancreatitis. Participants with publications in PubMed on acute pancreatitis showed better compliance (OR, 1.62; 95% CI: 1.15–2.32; P =.007) with recommendations of the clinical guidelines. Conclusions: Feeding and nutrition require the greatest improvement efforts, but also the use of prophylactic antibiotics and timing of cholecystectomy should be improved.

Background Although we previously proposed a nomogram to predict malignancy in intraductal papillary mucinous neoplasms (IPMN) and validated it in an external cohort, its application is challenging without data on tumor markers. Moreover, existing nomograms have not been compared. This study aimed to develop a nomogram based on radiologic findings and to compare its performance with previously proposed American and Korean/Japanese nomograms. Methods We recruited 3708 patients who underwent surgical resection at 31 tertiary institutions in eight countries, and patients with main pancreatic duct > 10 mm were excluded. To construct the nomogram, 2606 patients were randomly allocated 1:1 into training and internal validation sets, and area under the receiver operating characteristics curve (AUC) was calculated using 10-fold cross validation by exhaustive search. This nomogram was then validated and compared to the American and Korean/Japanese nomograms using 1102 patients. Results Among the 2606 patients, 90 had main-duct type, 900 had branch-duct type, and 1616 had mixed-type IPMN. Pathologic results revealed 1628 low-grade dysplasia, 476 high-grade dysplasia, and 502 invasive carcinoma. Location, cyst size, duct dilatation, and mural nodule were selected to construct the nomogram. AUC of this nomogram was higher than the American nomogram (0.691 vs. 0.664, p = 0.014) and comparable with the Korean/Japanese nomogram (0.659 vs 0.653, p = 0.255). Conclusions A novel nomogram based on radiologic findings of IPMN is competitive for predicting risk of malignancy. This nomogram would be clinically helpful in circumstances where tumor markers are not available. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN.

Neoadjuvant chemotherapy has become a powerful tool to convert borderline resectable (BRPC) and locally advanced pancreatic cancers (LAPC) into a resectable scenario. However, data analyzing the optimal type of therapy are scarce. In the present multicenter retrospective study, we evaluated the influence of FOLFIRINOX (FFX) and gemcitabine (GEM)-based neoadjuvant therapy on patient prognosis.Data on 239 patients from 7 centers across Europe was gathered using an online database. Patients having received their first cycle of chemotherapy for BRPC/LAPC before 06/2017, with a minimum follow-up of 12 months, were included in the intention-to-treat analysis.Patients treated with neoadjuvant FFX (n = 135) or gemcitabine + nab-paclitaxel (GNP) (n = 38) had significantly improved radiological response according to RECIST criteria as compared to single-agent GEM (n = 16), with a partial/complete response of 59.3%, 55.3% and 6.25% respectively (p = 0.001). Treatment with FFX (n = 135) and GNP (n = 38) resulted in higher resection rates compared to GEM (73.3%, 81.6% and 43.8%; p = 0.01 and p = 0.005). Regardless of regimen, patients who were resected had significantly prolonged overall survival compared to non-resected patients (p 0.01). Complete pathological responses (ypT0 ypN0) were predominantly observed with FFX (p = 0.01). Adjuvant GNP in addition to successful neoadjuvant therapy and surgery resulted in a trend towards improved median survival as compared to postoperative observation (47.0 vs. 30.1 months, p = 0.06).Representing one of the largest studies published so far, our results reveal that patients with BRPC/LAPC should be offered either FFX or GNP to improve chances of resection and with this also survival.

IgG4-related conditions affecting the digestive tract are part of a multi-organ fibro-inflammatory disorder termed IgG4-related disease (IgG4-RD), with autoimmune pancreatitis and IgG4-related cholangitis being the most prominent manifestations. Gastrointestinal symptoms include jaundice, weight loss, abdominal pain, biliary strictures, and pancreatic and hepatic masses that mimic malignant diseases. IgG4-RD manifestations occur less frequently elsewhere in the digestive tract, namely in the oesophagus, retroperitoneum or intestine. Evidence-based European guidelines frame the current state-of-the-art in the diagnosis and management of IgG4-related digestive tract disease. Diagnosis is based on histology (if available), imaging, serology, other organ involvement and response to therapy (HISORt criteria). Few biomarkers beyond serum IgG4 concentrations are reliable. The first-line therapy (glucocorticoids) is swiftly effective but disease flares are common at low doses or after tapering. Second-line therapy might consist of other immunosuppressive drugs such as thiopurines or rituximab. Further trials, for example, of anti-CD19 drugs, are ongoing. Although an association between IgG4-RD and the development of malignancies has been postulated, the true nature of this relationship remains uncertain at this time.

Background: Patients with chronic pancreatitis (CP) have an increased risk of developing pancreatic ductal adenocarcinoma (PDAC). We present data on PDAC in one of the most extensive European single-centre cohort studies of patients with CP. Methods: Retrospective analysis of prospectively collected data of patients with CP was performed. Aetiology of CP was determined according to the M-ANNHEIM classification system and only patients with definite CP &gt, 18 years at data analysis were included. The final dataset included 581 patients with definite CP diagnosed between 2003 and 2018. Results: At CP diagnosis, there were 371 (63.9%) males and 210 (36.1%) females (median age 57 years, range 2&ndash, 86). During 3423 person-years of observation, six pancreatic cancers were diagnosed (0.2% year). The mean time between diagnosis of CP and the occurrence of PDAC was 5.0 years (range 2.7&ndash, 8.6). None of the cancer patients had a family history of PDAC. Diabetes mellitus (DM) was present in five of six (83.3%) patients with PDAC: in three patients before and in two after CP diagnosis. Clinical/laboratory signs of pancreatic exocrine insufficiency (PEI) were present in five of six (83.3%) patients with PDAC: in two at diagnosis of CP and in three after diagnosis. The mean survival time was 4 months after the diagnosis of PDAC (range 0.5&ndash, 13). PDAC occurred significantly more often (p &lt, 0.001) in two groups of patients without previous acute pancreatitis (AP): 2 of 20 patients (10%) with low body mass index (BMI) and PEI and in 3 of 10 (30%) patients with high BMI and DM at diagnosis of CP. Conclusions: Patients with CP have a high risk of developing PDAC, although risk is low in absolute terms. Our data suggest the possibility of defining subgroups of patients with a particularly elevated risk of PDAC. Such a possibility would open a path to personalised decision making on initiation of PDAC surveillance of patients with no previous episode of AP, (i) with low BMI and PEI, or (ii) elevated BMI and DM.

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 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.

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.

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.

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.

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.

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.

Background: Acute pancreatitis (AP) is the most common complication after endoscopic retrograde cholangiopancreatography (ERCP). Statins have been traditionally associated to an increased risk of AP, however, recent evidence suggests that statins may have a protective role against this disease. Aims: Our primary aim is to investigate whether the use of statins has a protective effect against post-ERCP pancreatitis (PEP). Secondary outcomes are: to evaluate the effect of other drugs on the incidence of PEP; to ascertain the relationship between the use of statins and the severity of PEP; and to evaluate the effect of other risk and protective factors on the incidence of PEP. Methods: STARK is an international multicenter prospective cohort study. Centers from Spain, Italy, Croatia, Finland and Sweden joined this study. The total sample size will include about 1016 patients, which was based on assuming a 5% incidence of PEP among non-statin (NSt) users, a 1-3 ratio of statin (St) and NSt consumers respectively, a 70% decrease in PEP among St consumers, an alpha-error of 0.05 and beta-error of 0.20. All patients aged >18 years scheduled for ERCP will be offered to enter the study. Discussion: STARK study will ascertain whether statins, a safe, widely used and inexpensive drug, can modify the incidence of PEP. (C) 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Autoimmune pancreatitis (AIP) is a pancreatic inflammatory process characterized by a strong inflammatory cell infiltration and two histopathologically distinct subtypes: type 1 and type 2. Diagnosis is often challenging and requires a combination of clinical, laboratory and imaging data. AIP can mimic pancreatic tumours leading to unnecessary resections if not correctly diagnosed. Short- and long-term outcomes of AIP have been poorly investigated so far and no large series have been previously reported from Sweden.A single-centre, retrospective, cohort study of patients with histologically confirmed or highly probable diagnosis of AIP according to ICDC criteria. Demographic, clinical and radiological characteristics, type of treatment and its outcomes were collected and analysed.Seventy-one patients with AIP (87% with type 1), were evaluated at Karolinska University Hospital between 2004 and 2018; 49% males, mean age 49 years (range 44-53). Among them, 28% were histologically confirmed, 35% presented with jaundice, 22% with acute pancreatitis, 39% had non-specific symptoms such as weight loss or abdominal pain, 84% showed other organ involvement (OOI). Radiologically, 76% showed a focal pancreatic enlargement, 27% diffuse enlargement, 27% signs of acute pancreatitis and 10% of chronic pancreatitis. Overall, 58 patients (81%) underwent treatment with different medications: 46 (79%) cortisone, 7 (12%) azathioprine, 5 (8%) other immunosuppressive drugs. Twenty-six (36%) underwent biliary stenting and 12 (16%) were given surgery. In total, 47% of patients developed pancreatic exocrine insufficiency (PEI), of whom 76% had a severe form (faecal elastase-1 100 μg/g) and 21% of patients developed diabetes mellitus (pancreatic endocrine insufficiency), of whom 73% required insulin.AIP is a challenging disease for diagnosis and treatment. Cortisone treatment is generally successful and provides clinical remission in the large majority of patients (90%). In the further course of the disease, a considerable number of patients develop PEI and diabetes. Only one-quarter of patients exhibit on imaging the characteristic "sausage-like" pancreas (diffuse enlargement), approximately three-quarters had a focal mass that could be misdiagnosed as pancreatic malignancy.

Introduction: Acute Pancreatitis (AP) is the most frequent complication after Endoscopic Retrograde Cholangiopancreatography (ERCP). Some prophylactic strategies are the use of pancreatic stents or peri-procedural nonsteroidal anti-inflammatory drugs (NSAIDs). Statins are widely used lipid-lowering drugs. Recent studies suggest that chronic statin intake may be associated to a lower incidence of AP. Methods: Our aim is to investigate whether chronic statin and/or acetylsalicylic acid (ASA) intake is associated to a lower incidence of PEP. Stark project is an international, multicenter, prospective, cohort study, developed under the auspices of “Pancreas 2000”. Consecutive patients undergoing ERCP in seven european centers, older than 18, were included prospectively. Demographic and medical data were retrieved by anamnesis. Patients were followed-up to detect those with PEP. The sample size was estimated to be 1, 016 participants. A univariate analysis and multivariate analysis (binary logistic regression) were performed. Results: 1150 patients were included. Mean age was 68.4 years (SD 14.5). 561 (48.8%) patients were female. 70 patients developed post-ERCP-AP (PEP) (6.1%) ; 25 patients (8.1%) under chronic statin treatment versus 45 patients (5.4%) who do not (p= 0.086). Multivariate analysis showed an aOR of 1.679 (0.941-2.994), p 0.079 for PEP incidence in statin users. Regarding ASA consumption, 11 patients (6.6%) under ASA treatment versus 59 patients (6%) who were not consuming ASA, developed PEP (p= 0.753). Multivariate analysis showed an aOR of 1.017 (0.487-2.127), p=0.963 for PEP incidence among ASA users. Conclusion: Our data suggest that chronic statin and/or ASA intake isnt statistically associated to an increase incidence of PEP.

Background and objective Even when advanced cross-sectional imaging modalities have been employed, endoscopic evaluation of intraductal papillary mucinous neoplasms (IPMN) is often required in order to assess the final character and extent of lesions. The current study addresses the use of SpyGlass single-operator peroral pancreatoscopy in suspected IPMN. Design A prospective, non-randomized exploratory cohort study. Setting Single-center. Patients and intervention A prospective study-cohort of 44 consecutive patients in a single tertiary referral center who underwent ERCP and peroral pancreatoscopy, was prospectively collected between July 2007 and March 2013 because of a radiological signs of IPMN. These IPMN-findings were discovered incidentally in 44% of the cases. Main outcome measurements Diagnostic accuracy (specificity & sensitivity) and complications. Results The targeted region of the pancreatic duct was reached with the SpyGlass system in 41 patients (median age 65 years, 41% female). Three patients were excluded from analysis because of failed deep cannulation of the pancreatic duct. Brush cytology was taken in 88% and direct biopsies in 41%. IPMN with intermediate or high-grade dysplasia was the main final diagnosis (76%) in 22 patients who had surgery. Out of the 17 patients with a final diagnosis of MD-IPMN, 76% were correctly identified by pancreatoscopy. Of the 9 patients with a final diagnosis of BD-IPMN, the pancreatoscopy identified 78% of the cases correctly.The incidence of post-ERCP pancreatitis was 17%. Pancreatoscopy was found to have provided additional diagnostic information in the vast majority of the cases and to affect clinical decision-making in 76%. Limitations Single-center study. Conclusions Single-operator peroral pancreatoscopy contributed to the clinical evaluation of IPMN lesions and influenced decision-making concerning their clinical management. The problem of post-procedural pancreatitis needs further attention.

Autoimmune pancreatitis (AiP) is treated by immunosuppressive therapy. Exact description of disease activity of AiP is essential in clinical practice and research, but a score to describe the disease activity is missing. Thus, we aimed to establish an activity score of AiP.We retrospectively studied long-term disease courses of 29 patients with AiP (Mannheim, Germany), receiving corticosteroid treatment (CST) by analyzing 613 treatment appointments. Two assumptions were made: First, disease activity is higher at emergency treatments; second, disease activity drops under CST. In all patients, we evaluated established activity- and classification-systems of chronic pancreatitis (cP). Based on the most suitable system, we established an activity score of AiP by including AiP-specific parameters identified from our long-term disease courses and the literature. The new AiP-specific activity score was validated in an external cohort of 14 patients with AiP (Stockholm, Sweden).Within published activity indexes of cP, the M-ANNHEIM-classification most significantly correlated with emergency- and treatment-dependent disease activities (p 0.001 and p 0.01, conditional-logistic-regression-analysis). Significant correlations of disease activity were found for several clinical parameters (biliary involvement, extrapancreatic lesions, acute pancreatitis, focal pancreatic mass, pancreatic sausage/mass, focal enlargement, ascites; p 0.05, Wilcoxon-signed-rank-test). Based on these data and disease features from the literature, the M-ANNHEIM-AiP-Activity-Score (MAAS) was established. CST-induced reduction of MAAS disease activity of more than 60% was associated with lower relapse rates (p 0.05; Chi-Square-test). The results were validated in the external patient cohort.The MAAS might represent a useful tool to monitor AiP.