Endoscopic papillectomy for ampullary lesions of minor papilla.

BACKGROUND AND AIMS: Ampullary lesions (ALs) of the minor duodenal papilla are extremely rare. Endoscopic papillectomy (EP) is a routinely used treatment for AL of the major duodenal papilla, but the role of EP for minor AL has not been accurately studied. METHODS: We identified 20 patients with ALs of minor duodenal papilla in the multicentric database from the Endoscopic Papillectomy vs Surgical Ampullectomy vs Pancreatitcoduodenectomy for Ampullary Neoplasm study, which included 1422 EPs. We used propensity score matching (nearest-neighbor method) to match these cases with ALs of the major duodenal papilla based on age, sex, histologic subtype, and size of the lesion in a 1:2 ratio. Cohorts were compared by means of chi-square or Fisher exact test as well as Mann-Whitney U test. RESULTS: Propensity score-based matching identified a cohort of 60 (minor papilla 20, major papilla 40) patients with similar baseline characteristics. The most common histologic subtype of lesions of minor papilla was an ampullary adenoma in 12 patients (3 low-grade dysplasia and 9 high-grade dysplasia). Five patients revealed nonneoplastic lesions. Invasive cancer (T1a), adenomyoma, and neuroendocrine neoplasia were each found in 1 case. The rate of complete resection, en-bloc resection, and recurrences were similar between the groups. There were no severe adverse events after EP of lesions of minor papilla. One patient had delayed bleeding that could be treated by endoscopic hemostasis, and 2 patients showed a recurrence in surveillance endoscopy after a median follow-up of 21 months (interquartile range, 12-50 months). CONCLUSIONS: EP is safe and effective in ALs of the minor duodenal papilla. Such lesions could be managed according to guidelines for EP of major duodenal papilla.

Endoscopic papillectomy for ampullary lesions in patients with familial adenomatous polyposis compared with sporadic lesions: a propensity score-matched cohort.

BACKGROUND: Familial adenomatous polyposis (FAP) is a rare inherited syndrome that predisposes the patient to cancer. Treatment of FAP-related ampullary lesions is challenging and the role of endoscopic papillectomy has not been elucidated. We retrospectively analyzed the outcomes of endoscopic papillectomy in matched cohorts of FAP-related and sporadic ampullary lesions (SALs). METHODS: This retrospective multicenter study included 1422 endoscopic papillectomy procedures. Propensity score matching including age, sex, comorbidity, histologic subtype, and size was performed. Main outcomes were complete resection (R0), technical success, complications, and recurrence. RESULTS: Propensity score matching identified 202 patients (101 FAP, 101 SAL) with comparable baseline characteristics. FAP patients were mainly asymptomatic (79.2 % [95 %CI 71.2-87.3] vs. 46.5 % [95 %CI 36.6-56.4]); P < 0.001). The initial R0 rate was significantly lower in FAP patients (63.4 % [95 %CI 53.8-72.9] vs. 83.2 % [95 %CI 75.8-90.6]; P = 0.001). After repeated interventions (mean 1.30 per patient), R0 was comparable (FAP 93.1 % [95 %CI 88.0-98.1] vs. SAL 97.0 % [95 %CI 93.7-100]; P = 0.19). Adverse events occurred in 28.7 %. Pancreatitis and bleeding were the most common adverse events in both groups. Severe adverse events were rare (3.5 %). Overall, 21 FAP patients (20.8 % [95 %CI 12.7-28.8]) and 16 SAL patients (15.8 % [95 %CI 8.6-23.1]; P = 0.36) had recurrence. Recurrences occurred later in FAP patients (25 [95 %CI 18.3-31.7] vs. 2 [95 %CI CI 0.06-3.9] months). CONCLUSIONS: Endoscopic papillectomy was safe and effective in FAP-related ampullary lesions. Criteria for endoscopic resection of ampullary lesions can be extended to FAP patients. FAP patients have a lifetime risk of relapse even after complete resection, and require long-time surveillance.

Endoscopic and Surgical Management of Non-Metastatic Ampullary Neuroendocrine Neoplasia: A Multi-Institutional Pancreas2000/EPC Study.

INTRODUCTION: Ampullary neuroendocrine neoplasia (NEN) is rare and evidence regarding their management is scarce. This study aimed to describe clinicopathological features, management, and prognosis of ampullary NEN according to their endoscopic or surgical management. METHODS: From a multi-institutional international database, patients treated with either endoscopic papillectomy (EP), transduodenal surgical ampullectomy (TSA), or pancreaticoduodenectomy (PD) for ampullary NEN were included. Clinical features, post-procedure complications, and recurrences were assessed. RESULTS: 65 patients were included, 20 (30.8%) treated with EP, 19 (29.2%) with TSA, and 26 (40%) with PD. Patients were mostly asymptomatic (n = 46; 70.8%). Median tumor size was 17 mm (12-22), tumors were mostly grade 1 (70.8%) and pT2 (55.4%). Two (10%) EP resulted in severe American Society for Gastrointestinal Enterology (ASGE) adverse post-procedure complications and 10 (50%) were R0. Clavien 3-5 complications did not occur after TSA and in 4, including 1 postoperative death (15.4%) of patients after PD, with 17 (89.5%) and 26 R0 resection (100%), respectively. The pN1/2 rate was 51.9% (n = 14) after PD. Tumor size larger than 1 cm (i.e., pT stage >1) was a predictor for R1 resection (p < 0.001). Three-year overall survival and disease-free survival after EP, TSA, and PD were 92%, 68%, 92% and 92%, 85%, 73%, respectively. CONCLUSION: Management of ampullary NEN is challenging. EP should not be performed in lesions larger than 1 cm or with a endoscopic ultrasonography T stage beyond T1. Local resection by TSA seems safe and feasible for lesions without nodal involvement. PD should be preferred for larger ampullary NEN at risk of nodal metastasis.

Postoperative three-dimensional endoanal ultrasound findings and relation to anal fistula plug failure.

OBJECTIVES: To explore the utilization of three-dimensional (3D) endoanal ultrasound (EAUS) for the follow-up of the anal fistula plug (AFP), describe morphological findings in postoperative 3D EAUS, and evaluate if postoperative 3D EAUS combined with clinical symptoms can predict AFP failure. MATERIALS AND METHODS: A retrospective analysis of 3D EAUS examinations performed during a single-centre study of prospectively included consecutive patients treated with the AFP between May 2006 and October 2009. Postoperative assessment by clinical examination and 3D EAUS was performed at 2 weeks, 3 months and 6-12 months ("late control"). Long-term follow-up was carried out in 2017. The 3D EAUS examinations were blinded and analysed by two observers using a protocol with defined relevant findings for different follow-up time points. RESULTS: A total of 95 patients with a total of 151 AFP procedures were included. Long-term follow-up was completed in 90 (95%) patients. Inflammation at 3 months, gas in fistula and visible fistula at 3 months and at late control, were statistically significant 3D EAUS findings for AFP failure. The combination of gas in fistula and clinical finding of fluid discharge through the external fistula opening 3 months postoperatively was statistically significant (p < 0.001) for AFP failure with 91% sensitivity and 79% specificity. The positive predictive value was 91%, while the negative predictive value was 79%. CONCLUSIONS: 3D EAUS may be utilized for the follow-up of AFP treatment. Postoperative 3D EAUS at 3 months or later, especially if combined with clinical symptoms, can be used to predict long-term AFP failure.ClinicalTrials.gov identifier NCT03961984.

Heparin-binding protein is significantly increased in acute pancreatitis.

BACKGROUND: Most patients with acute pancreatitis (AP) experience mild, self-limiting disease with little or no need for hospital care. However, 20-25% of patients develop a more severe and potentially life-threatening condition with progressive systemic inflammatory response syndrome (SIRS) and multiorgan failure, resulting in high morbidity and mortality rates. Predicting disease severity at an early stage is important, as immediate supportive care has been demonstrated to reduce the incidence of SIRS and organ failure, improving patient outcome. Several studies have demonstrated elevated levels of heparin-binding protein (HBP) in patients with sepsis and septic shock, and HBP is believed to play a part in endothelial dysfunction leading to vascular leakage. As HBP levels increase prior to other known biomarkers, HBP has emerged as a promising early predictor of severe sepsis with organ dysfunction. METHODS: Patients admitted to Skåne University Hospital in Malmö between 2010 and 2013 fulfilling the criteria for AP were identified in the emergency department and prospectively enrolled in this study. The primary outcome was measured levels of HBP upon hospital admission in patients with confirmed AP. Correlations among HBP concentrations, disease severity and fluid balance were considered secondary endpoints. The correlation between HBP levels and fluid balance were analysed using Pearson correlation, and the ability of HBP to predict moderately severe/severe AP was assessed using a receiver operating characteristic (ROC) curve. RESULTS: The overall median HBP level in this study was 529 (307-898) ng/ml. There were no significant group differences in HBP levels based on AP severity. Fluid balance differed significantly between patients with mild versus moderately severe and severe pancreatitis, but we found no correlation between HBP concentration and fluid balance. CONCLUSIONS: HBP levels are dramatically increased in patients with AP, and these levels far exceed those previously reported in other conditions. In this study, we did not observe any significant correlation between HBP levels and disease severity or the need for intravenous fluid. Additional studies on HBP are needed to further explore the role of HBP in the pathogenesis of AP and its possible clinical implications.

Extracellular cold-inducible RNA-binding protein regulates neutrophil extracellular trap formation and tissue damage in acute pancreatitis.

Neutrophil extracellular traps (NETs) play a key role in the development of acute pancreatitis (AP). In the present study, we studied the role of extracellular cold-inducible RNA-binding protein (eCIRP), a novel damage-associated-molecular-pattern molecule, in severe AP. C57BL/6 mice underwent retrograde infusion of taurocholate into the pancreatic duct. C23, an eCIRP inhibitor, was given 1 h prior to induction of AP. Pancreatic, lung, and blood samples were collected and levels of citrullinated histone 3, DNA-histone complexes, eCIRP, myeloperoxidase (MPO), amylase, cytokines, matrix metalloproteinase-9 (MMP-9), and CXC chemokines were quantified after 24 h. NETs were detected by electron microscopy in the pancreas and bone marrow-derived neutrophils. Amylase secretion was analyzed in isolated acinar cells. Plasma was obtained from healthy individuals and patients with mild and moderate severe or severe AP. Taurocholate infusion induced NET formation, inflammation, and tissue injury in the pancreas. Pretreatment with C23 decreased taurocholate-induced pancreatic and plasma levels of eCIRP and tissue damage in the pancreas. Blocking eCIRP reduced levels of citrullinated histone 3 and NET formation in the pancreas as well as DNA-histone complexes in the plasma. In addition, administration of C23 attenuated MPO levels in the pancreas and lung of mice exposed to taurocholate. Inhibition of eCIRP reduced pancreatic levels of CXC chemokines and plasma levels of IL-6, HMGB-1, and MMP-9 in mice with severe AP. Moreover, eCIRP was found to be bound to NETs. Coincubation with C23 reduced NET-induced amylase secretion in isolated acinar cells. Patients with severe AP had elevated plasma levels of eCIRP compared with controls. Our novel findings suggest that eCIRP is a potent regulator of NET formation in the inflamed pancreas. Moreover, these results show that targeting eCIRP with C23 inhibits inflammation and tissue damage in AP. Thus, eCIRP could serve as an effective target to attenuate pancreatic damage in patients with AP.

Anthropometric and reproductive factors and risk of esophageal and gastric cancer by subtype and subsite: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Obesity has been associated with upper gastrointestinal cancers; however, there are limited prospective data on associations by subtype/subsite. Obesity can impact hormonal factors, which have been hypothesized to play a role in these cancers. We investigated anthropometric and reproductive factors in relation to esophageal and gastric cancer by subtype and subsite for 476,160 participants from the European Prospective Investigation into Cancer and Nutrition cohort. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models. During a mean follow-up of 14 years, 220 esophageal adenocarcinomas (EA), 195 esophageal squamous cell carcinomas, 243 gastric cardia (GC) and 373 gastric noncardia (GNC) cancers were diagnosed. Body mass index (BMI) was associated with EA in men (BMI ≥30 vs. 18.5-25 kg/m2 : HR = 1.94, 95% CI: 1.25-3.03) and women (HR = 2.66, 95% CI: 1.15-6.19); however, adjustment for waist-to-hip ratio (WHR) attenuated these associations. After mutual adjustment for BMI and HC, respectively, WHR and waist circumference (WC) were associated with EA in men (HR = 3.47, 95% CI: 1.99-6.06 for WHR >0.96 vs. <0.91; HR = 2.67, 95% CI: 1.52-4.72 for WC >98 vs. <90 cm) and women (HR = 4.40, 95% CI: 1.35-14.33 for WHR >0.82 vs. <0.76; HR = 5.67, 95% CI: 1.76-18.26 for WC >84 vs. <74 cm). WHR was also positively associated with GC in women, and WC was positively associated with GC in men. Inverse associations were observed between parity and EA (HR = 0.38, 95% CI: 0.14-0.99; >2 vs. 0) and age at first pregnancy and GNC (HR = 0.54, 95% CI: 0.32-0.91; >26 vs. <22 years); whereas bilateral ovariectomy was positively associated with GNC (HR = 1.87, 95% CI: 1.04-3.36). These findings support a role for hormonal pathways in upper gastrointestinal cancers.

Healthy lifestyle and the risk of pancreatic cancer in the EPIC study.

Pancreatic cancer (PC) is a highly fatal cancer with currently limited opportunities for early detection and effective treatment. Modifiable factors may offer pathways for primary prevention. In this study, the association between the Healthy Lifestyle Index (HLI) and PC risk was examined. Within the European Prospective Investigation into Cancer and Nutrition cohort, 1113 incident PC (57% women) were diagnosed from 400,577 participants followed-up for 15 years (median). HLI scores combined smoking, alcohol intake, dietary exposure, physical activity and, in turn, overall and central adiposity using BMI (HLIBMI) and waist-to-hip ratio (WHR, HLIWHR), respectively. High values of HLI indicate adherence to healthy behaviors. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and 95% confidence intervals (CI). Sensitivity analyses were performed by excluding, in turn, each factor from the HLI score. Population attributable fractions (PAF) were estimated assuming participants' shift to healthier lifestyles. The HRs for a one-standard deviation increment of HLIBMI and HLIWHR were 0.84 (95% CI: 0.79, 0.89; ptrend = 4.3e-09) and 0.77 (0.72, 0.82; ptrend = 1.7e-15), respectively. Exclusions of smoking from HLIWHR resulted in HRs of 0.88 (0.82, 0.94; ptrend = 4.9e-04). The overall PAF estimate was 19% (95% CI: 11%, 26%), and 14% (6%, 21%) when smoking was removed from the score. Adherence to a healthy lifestyle was inversely associated with PC risk, beyond the beneficial role of smoking avoidance. Public health measures targeting compliance with healthy lifestyles may have an impact on PC incidence.

Helicobacter pylori infection, chronic corpus atrophic gastritis and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort: A nested case-control study.

The association between H. pylori infection and pancreatic cancer risk remains controversial. We conducted a nested case-control study with 448 pancreatic cancer cases and their individually matched control subjects, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, to determine whether there was an altered pancreatic cancer risk associated with H. pylori infection and chronic corpus atrophic gastritis. Conditional logistic regression models were applied to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs), adjusted for matching factors and other potential confounders. Our results showed that pancreatic cancer risk was neither associated with H. pylori seropositivity (OR = 0.96; 95% CI: 0.70, 1.31) nor CagA seropositivity (OR = 1.07; 95% CI: 0.77, 1.48). We also did not find any excess risk among individuals seropositive for H. pylori but seronegative for CagA, compared with the group seronegative for both antibodies (OR = 0.94; 95% CI: 0.63, 1.38). However, we found that chronic corpus atrophic gastritis was non-significantly associated with an increased pancreatic cancer risk (OR = 1.35; 95% CI: 0.77, 2.37), and although based on small numbers, the excess risk was particularly marked among individuals seronegative for both H. pylori and CagA (OR = 5.66; 95% CI: 1.59, 20.19, p value for interaction < 0.01). Our findings provided evidence supporting the null association between H. pylori infection and pancreatic cancer risk in western European populations. However, the suggested association between chronic corpus atrophic gastritis and pancreatic cancer risk warrants independent verification in future studies, and, if confirmed, further studies on the underlying mechanisms.

IL-6 and CRP are superior in early differentiation between mild and non-mild acute pancreatitis.

BACKGROUND: The revised Atlanta classification on acute pancreatitis (AP) presents distinct criteria for severity categorization. Due to the lack of reliable prognostic markers, a majority of patients with AP are currently hospitalized and initially managed identically. As incidence and financial costs are rising the need for early severity differentiation will increase. This study aimed to investigate the capacity of biomarkers to stratify AP patients during the initial course of the disease. METHODS: Patients with AP were prospectively enrolled and dichotomized into mild or non-mild (moderately severe and severe AP) according to the revised Atlanta classification. Serum samples taken within 13-36 h after onset of disease were analyzed for 20 biomarkers. Through receiver operating curves cut-off levels were set for 5 biomarkers whose stratifying ability was further analyzed. Additionally, the patients were classified according to the harmless acute pancreatitis score (HAPS). RESULTS: Among the 175 patients, 70.9% had mild and 29.1% non-mild AP. CRP and IL-6 combined, with cut-off levels 57.0 and 23.6 respectively, demonstrated superior discriminative capacity with an area under the curve of 0.803, sensitivity 98%, specificity 54% and a positive and negative likelihood ratio of 2.1 and 0.06 for the non-mild group. Regarding the mild group likelihood ratios were positive 26.5 and negative 0.48. The identification potential of the HAPS was generally inferior when compared to CRP plus IL-6. CONCLUSIONS: In this study CRP and IL-6 demonstrate a clinically relevant capacity to differentiate mild from non-mild AP early in the course of AP.

Neutrophil Extracellular Traps Induce Trypsin Activation, Inflammation, and Tissue Damage in Mice With Severe Acute Pancreatitis.

BACKGROUND & AIMS: Neutrophils are involved in the development of acute pancreatitis (AP), but it is not clear how neutrophil-induced tissue damage is regulated. In addition to secreting antimicrobial compounds, activated neutrophils eliminate invading microorganisms by expelling nuclear DNA and histones to form extracellular web-like structures called neutrophil extracellular traps (NETs). However, NETs have been reported to contribute to organ dysfunction in patients with infectious diseases. We investigated whether NETs contribute to the development of AP in mice. METHODS: AP was induced in C57BL/6 mice by infusion of taurocholate into the pancreatic duct or by intraperitoneal administration of L-arginine. Pancreata were collected and extracellular DNA was detected by Sytox green staining, levels of CXC chemokines, histones, and cytokines also were measured. Cell-free DNA was quantified in plasma samples. Signal transducer and activator of transcription 3 phosphorylation and trypsin activation were analyzed in isolated acinar cells. NETs were depleted by administration of DNase I to mice. Plasma was obtained from healthy individuals (controls) and patients with severe AP. RESULTS: Infusion of taurocholate induced formation of NETs in pancreatic tissues of mice and increased levels of cell-free DNA in plasma. Neutrophil depletion prevented taurocholate-induced deposition of NETs in the pancreas. Administration of DNase I to mice reduced neutrophil infiltration and tissue damage in the inflamed pancreas and lung, and decreased levels of blood amylase, macrophage inflammatory protein-2, interleukin 6, and high-mobility groups protein 1. In mice given taurocholate, DNase I administration also reduced expression of integrin α M (macrophage-1 antigen) on circulating neutrophils. Similar results occurred in mice with L-arginine-induced AP. Addition of NETs and histones to acinar cells induced formation of trypsin and activation of signal transducer and activator of transcription 3; these processes were blocked by polysialic acid. Patients with severe AP had increased plasma levels of NET components compared with controls. CONCLUSIONS: NETs form in the pancreata of mice during the development of AP, and NET levels are increased in plasma from patients with AP, compared with controls. NETs regulate organ inflammation and injury in mice with AP, and might be targeted to reduce pancreatic tissue damage and inflammation in patients.

Significant inter-observer variation in the diagnosis of extrapancreatic necrosis and type of pancreatic collections in acute pancreatitis - An international multicenter evaluation of the revised Atlanta classification.

BACKGROUND: For consistent reporting and better comparison of data in research the revised Atlanta classification (RAC) proposes new computed tomography (CT) criteria to describe the morphology of acute pancreatitis (AP). The aim of this study was to analyse the interobserver agreement among radiologists in evaluating CT morphology by using the new RAC criteria in patients with AP. METHODS: Patients with a first episode of AP who obtained a CT were identified and consecutively enrolled at six European centres backwards from January 2013 to January 2012. A local radiologist at each center and a central expert radiologist scored the CTs separately using the RAC criteria. Center dependent and independent interobserver agreement was determined using Kappa statistics. RESULTS: In total, 285 patients with 388 CTs were included. For most CT criteria, interobserver agreement was moderate to substantial. In four categories, the center independent kappa values were fair: extrapancreatic necrosis (EXPN) (0.326), type of pancreatitis (0.370), characteristics of collections (0.408), and appropriate term of collections (0.356). The fair kappa values relate to discrepancies in the identification of extrapancreatic necrotic material. The local radiologists diagnosed EXPN (33% versus 59%, P < 0.0001) and non-homogeneous collections (35% versus 66%, P < 0.0001) significantly less frequent than the central expert. Cases read by the central expert showed superior correlation with clinical outcome. CONCLUSION: Diagnosis of EXPN and recognition of non-homogeneous collections show only fair agreement potentially resulting in inconsistent reporting of morphologic findings.

Predictive Capacity of Biomarkers for Severe Acute Pancreatitis.

BACKGROUND: Early prediction of severe acute pancreatitis (SAP) substantially improves treatment of patients. A large amount of biomarkers have been studied with this objective. The aim of this work was to study predictive biomarkers using preset cut-off levels in an unselected population of patients with acute pancreatitis (AP). METHODS: 232 patients (52.2% males, median age 66 years) with AP admitted to Skåne University Hospital, Malmö, were consecutively enrolled. Blood samples were collected upon admission and clinical data were gathered both prospectively at inclusion and through review of medical notes. Cut-off levels were defined based on the reports of prior studies, and through their results eight biomarkers (IL-1ß, IL-6, IL-8, IL-10, TNF-α, MCP-1, procalcitonin and D-dimer) were selected for analysis. RESULTS: Of the patients, 83.2% had mild AP and 16.8% had SAP. Levels of IL-1ß, IL-6 and IL-10 were significantly (p < 0.05) higher upon admission in the group with SAP. When applying the preset cut-off levels on our material, sensitivity and specificity for prediction of severity were low. Receiver operating characteristic curves showed that selected cut-off levels were acceptable, but areas under the curves were inferior compared to other studies. The results did not improve when using the revised Atlanta 2012 classification. CONCLUSIONS: Previous studies on severity prediction of AP are difficult to compare due to large variations in setups and outcomes. Calculated cut-offs in our cohort were in acceptable range from preset levels, however areas under the curves were low, indicating suboptimal biomarkers for the unselected population investigated. For comparable results and possible clinical implementations, future studies need large consecutive series with a reasonable percentage of severe cases. Additionally, novel biomarkers need to be explored.

Histone deacetylase regulates trypsin activation, inflammation, and tissue damage in acute pancreatitis in mice.

BACKGROUND: The onset of acute pancreatitis (AP) is characterized by early protease activation followed by inflammation and organ damage, but the mechanisms are poorly understood. AIMS: We hypothesized that histone deacetylase (HDAC) inhibition might exert protective effects on AP and investigated the role of HDAC in trypsin activation, inflammation, and tissue damage in severe AP. METHODS: Male C57Bl/6 mice were treated i.p. with the HDAC inhibitor trichostatin A (2 mg/kg) prior to retrograde infusion of taurocholic acid (5 %) into the pancreatic duct. Serum levels of amylase and interleukin (IL)-6, pancreatic levels of macrophage inflammatory protein-2 (MIP-2) as well as tissue morphology and myeloperoxidase activity in the pancreas and lung were determined 24 h after taurocholate challenge. Trypsin activation was analyzed in isolated acinar cells. Quantitative RT-PCR was used to examine the expression of pro-inflammatory mediators in the pancreas. RESULTS: Pretreatment with trichostatin A decreased amylase levels by 70 % and protected against tissue injury in the pancreas. Moreover, HDAC inhibition reduced systemic IL-6 by more than 95 % and pulmonary myeloperoxidase activity by 75 %. Notably, inhibition of HDAC abolished taurocholate-induced gene expression of cyclooxygenase-2, MIP-2, monocyte chemotactic protein-1, IL-6, and IL-1ß in the pancreas. In addition, HDAC inhibition reduced cerulein-induced trypsinogen activation in isolated acinar cells. CONCLUSION: Our findings show that HDAC regulates trypsin activation, inflammation, and tissue damage in AP. Thus, targeting HDAC could serve as novel therapeutic approach in the management of severe AP.

Human thrombin-derived host defense peptides inhibit neutrophil recruitment and tissue injury in severe acute pancreatitis.

Severe acute pancreatitis (AP) is characterized by leukocyte infiltration and tissue injury. Herein, we wanted to examine the potential effects of thrombin-derived host defense peptides (TDPs) in severe AP. Pancreatitis was provoked by infusion of taurocholate into the pancreatic duct or by intraperitoneal administration of l-arginine in C57BL/6 mice. Animals were treated with the TDPs GKY20 and GKY25 or a control peptide WFF25 30 min before induction of AP. TDPs reduced blood amylase levels, neutrophil infiltration, hemorrhage, necrosis, and edema formation in the inflamed pancreas. Treatment with TDPs markedly attenuated the taurocholate-induced increase in plasma levels of CXCL2 and interleukin-6. Moreover, administration of TDPs decreased histone 3, histone 4, and myeloperoxidase levels in the pancreas in response to taurocholate challenge. Interestingly, administration of TDPs abolished neutrophil expression of Mac-1 in mice with pancreatitis. In addition, TDPs inhibited CXCL2-induced chemotaxis of isolated neutrophils in vitro. Fluorescent-labeled TDP was found to directly bind to isolated neutrophils. Finally, a beneficial effect of TDPs was confirmed in l-arginine-induced pancreatitis. Our novel results demonstrate that TDPs exert protective effects against pathological inflammation and tissue damage in AP. These findings suggest that TDPs might be useful in the management of patients with severe AP.

Assessing Patient Radiation Exposure in Endoscopic Retrograde Cholangiopancreatography: A Multicenter Retrospective Analysis of Procedural Complexity and Clinical Factors.

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) procedures can result in significant patient radiation exposure. This retrospective multicenter study aimed to assess the influence of procedural complexity and other clinical factors on radiation exposure in ERCP. METHODS: Data on kerma-area product (KAP), air-kerma at the reference point (Ka,r), fluoroscopy time, and the number of exposures, and relevant patient, procedure, and operator factors were collected from 2641 ERCP procedures performed at four university hospitals. The influence of procedural complexity, assessed using the American Society for Gastrointestinal Endoscopy (ASGE) and HOUSE complexity grading scales, on radiation exposure quantities was analyzed within each center. The procedures were categorized into two groups based on ERCP indications: primary sclerosing cholangitis (PSC) and other ERCPs. RESULTS: Both the ASGE and HOUSE complexity grading scales had a significant impact on radiation exposure quantities. Remarkably, there was up to a 50-fold difference in dose quantities observed across the participating centers. For non-PSC ERCP procedures, the median KAP ranged from 0.9 to 64.4 Gy·cm2 among the centers. The individual endoscopist also had a substantial influence on radiation dose. CONCLUSIONS: Procedural complexity grading in ERCP significantly affects radiation exposure. Higher procedural complexity is typically associated with increased patient radiation dose. The ASGE complexity grading scale demonstrated greater sensitivity to changes in radiation exposure compared to the HOUSE grading scale. Additionally, significant variations in dose indices, fluoroscopy times, and number of exposures were observed across the participating centers.

Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort.

General obesity has been positively associated with risk of liver and probably with biliary tract cancer, but little is known about abdominal obesity or weight gain during adulthood. We used multivariable Cox proportional hazard models to investigate associations between weight, body mass index, waist and hip circumference, waist-to-hip and waist-to-height ratio (WHtR), weight change during adulthood and risk of hepatocellular carcinoma (HCC), intrahepatic (IBDC) and extrahepatic bile duct system cancer [EBDSC including gallbladder cancer (GBC)] among 359,525 men and women in the European Prospective Investigation into Cancer and Nutrition study. Hepatitis B and C virus status was measured in a nested case-control subset. During a mean follow-up of 8.6 years, 177 cases of HCC, 58 cases of IBDC and 210 cases of EBDSC, including 76 cases of GBC, occurred. All anthropometric measures were positively associated with risk of HCC and GBC. WHtR showed the strongest association with HCC [relative risk (RR) comparing extreme tertiles 3.51, 95% confidence interval (95% CI): 2.09-5.87; p(trend) < 0.0001] and with GBC (RR: 1.56, 95% CI: 1.12-2.16 for an increment of one unit in WHtR). Weight gain during adulthood was also positively associated with HCC when comparing extreme tertiles (RR: 2.48, 95% CI: 1.49-4.13; <0.001). No statistically significant association was observed between obesity and risk of IBDC and EBDSC. Our results provide evidence of an association between obesity, particularly abdominal obesity, and risk of HCC and GBC. Our findings support public health recommendations to reduce the prevalence of obesity and weight gain in adulthood for HCC and GBC prevention in Western populations.

NFATc3 regulates trypsinogen activation, neutrophil recruitment, and tissue damage in acute pancreatitis in mice.

BACKGROUND & AIMS: The signaling mechanisms that regulate trypsinogen activation and inflammation in acute pancreatitis (AP) are unclear. We explored the involvement of the calcium- and calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in development of AP in mice. METHODS: We measured levels of myeloperoxidase and macrophage inflammatory protein 2 (CXCL2), trypsinogen activation, and tissue damage in the pancreas 24 hours after induction of AP by retrograde infusion of taurocholate into the pancreatic ducts of wild-type, NFAT luciferase reporter (NFAT-luc), and NFATc3-deficient mice. We isolated acinar cells and measured NFAT nuclear accumulation, trypsin activity, and expression of NFAT-regulated genes. RESULTS: Infusion of taurocholate increased the transcriptional activity of NFAT in the pancreas, aorta, lung, and spleen of NFAT-luc mice. Inhibition of NFAT with A-285222 blocked taurocholate-induced activation of NFAT in all organs. A-285222 also reduced taurocholate-induced increases in levels of amylase, myeloperoxidase, and CXCL2; activation of trypsinogen; necrosis of acinar cells; edema; leukocyte infiltration; and hemorrhage in the pancreas. NFATc3-deficient mice were protected from these effects of taurocholate. Similar results were obtained using an l-arginine-induced model of AP. Reverse-transcription polymerase chain reaction and confocal immunofluorescence analyses showed that NFATc3 is expressed by acinar cells. NFATc3 expression was activated by stimuli that increase intracellular calcium levels, and activation was prevented by the calcineurin blocker cyclosporin A or A-285222. Activation of trypsinogen by secretagogues in acinar cells was prevented by pharmacologic inhibition of NFAT signaling or lack of NFATc3. A-285222 also reduced expression of inflammatory cytokines such as CXCL2 in acinar cells. CONCLUSIONS: NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice and might be a therapeutic target.

Long-Term Follow-up and Risk of Recurrence of Internal Herniation after Roux-en-Y Gastric Bypass.

PURPOSE: Internal herniation (IH) is the most common complication after Roux-en-Y gastric bypass surgery (RYGB). Although primary closure has reduced the incidence, recurrences are a continued problem. This study aimed to investigate long-term follow-up and recurrence risk of IH surgery. METHODS: A retrospective cohort study of laparoscopic RYGB operated patients operated for a first IH between April 2012 and April 2015 at Skåne University Hospital in Malmö, Sweden. Status of primary closure of mesenteric gaps, time since RYGB, and findings at IH surgery were retrieved from medical records. Follow-up until December 31st, 2019, included recurrences of IH, number of computed tomography (CT) scans, emergency visits, readmissions, and other acute surgeries. RESULTS: IH (n = 44) occurred almost equally in Petersen's space (n = 24) and beneath the jejunojejunostomy (n = 20). Long-term follow-up (median 75 months) of 43 patients registered an IH recurrence rate of 14% (n = 6). All recurrences occurred in the other mesenteric gap. One patient suffered a third IH, and one patient had four IH events. During follow-up, 56% (n = 24) had ER visits for abdominal pain, 47% (n = 20) had ≥ 1 abdominal CT scan, and 40% (n = 17) were readmitted. A third of readmitted (6/17) patients suffered a recurrence of internal herniation. Two other patients were readmitted ≥ 10 times for chronic abdominal pain. CONCLUSION: Surgery for IH had a low risk of recurrence at the treated mesenteric gap, but a 14% recurrence risk at the other mesenteric gap, emphasizing the importance of carefully investigating weaknesses or gaps at the other mesenteric defect during surgery for IH.

Laparoscopic transcystic common bile duct exploration versus transgastric endoscopic retrograde cholangiography during cholecystectomy after Roux-en-Y gastric bypass.

BACKGROUND: Treatment of common bile duct (CBD) stones after Roux-en-Y gastric bypass (RYGB) poses a particular challenge given the altered anatomy and inability to perform a standard endoscopic retrograde cholangiogram (ERC). The optimal treatment strategy for intraoperatively encountered CBD stones in post-RYGB patients has not been established. OBJECTIVES: To compare outcomes following laparoscopic transcystic common bile duct exploration (LTCBDE) and laparoscopy-assisted transgastric ERC for CBDs during cholecystectomy in RYGB-operated patients. SETTING: Swedish nationwide multi-registry study. METHODS: The Swedish Registry for Gallstone Surgery and ERCs, GallRiks (n = 215,670), and the Scandinavian Obesity Surgery Registry (SOReg) (n = 60,479) were cross-matched for cholecystectomies with intraoperatively encountered CBD stones in patients with previous RYGB surgery between 2011 and 2020. RESULTS: Registry cross-matching found 550 patients. Both LTCBDE (n = 132) and transgastric ERC (n = 145) were comparable in terms of low rates of intraoperative adverse events (1% versus 2%) and postoperative adverse events within 30 days (16% versus 18%). LTCBDE required significantly shorter operating time (P = .005) by on average 31 minutes, 95% confidence interval (CI) [10.3-52.6], and was more often used for smaller stones <4 mm in size (30% versus 17%, P = .010). However, transgastric ERC was more often used in acute surgery (78% versus 63%, P = .006) and for larger stones >8 mm in size (25% versus 8%, P < .001). CONCLUSIONS: LTCBDE and transgastric ERC have similarly low complication rates for clearance of intraoperatively encountered CBD stones in RYGB-operated patients, but LTCBDE is faster while transgastric ERC is more often used in conjunction with larger bile duct stones.