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Background & Aims: Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow‐up strategies in PSC with the hypothesis that regular imaging improves survival. Methods: We collected retrospective data from 2975 PSC patients from 27 centres. Patients were followed from the start of scheduled imaging or in case of clinical follow‐up from 1 January 2000, until death or last clinical follow‐up alive. The primary endpoint was all‐cause mortality. Results: A broad variety of different follow‐up strategies were reported. All except one centre used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centres used scheduled endoscopic retrograde cholangiopancreatography (ERCP) in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow‐up, was 0.61 (0.47–0.80) for scheduled imaging with and without ERCP; 0.64 (0.48–0.86) for US/MRI and 0.53 (0.37–0.75) for follow‐up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high‐grade dysplasia as a time‐dependent covariate, HR 0.57 (0.44–0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years of follow‐up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed. Conclusions: Follow‐up strategies vary considerably across centres. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumour detection and increased endoscopic treatment of asymptomatic benign biliary strictures. [ABSTRACT FROM AUTHOR]

Background: In recent years substantial progress has been made in the treatment, surveillance and understanding of the pathogenesis of primary sclerosing cholangitis (PSC); however, in most cases liver transplantation (LTX) is still the only curative option for cancer or end-stage liver disease (ELD). In rare cases a partial liver resection is a possible curative treatment of a PSC-associated cholangiocellular carcinoma (CCC). These operations represent a significant additional burden for PSC patients. Objective: Due to the rarity of PSC detailed studies regarding hepato-pancreato-biliary (HPB) surgery are lacking. The aim of this study was to analyze the surgical indications and prognosis of PSC patients. Patients and methods: A single center retrospective cohort study from 1990 to 2020 was carried out. In this study patients with PSC were included and investigated with respect to factors associated with surgery and the prognosis. Results: As a consequence of PSC-associated conditions, in 62 patients (36%) a major HPB operation or explorative laparotomy was necessary. The prevalence of chronic inflammatory bowel disease was significantly higher in these patients (P < 0.019). An LTX was carried out in 46 patients (73%) because of ELD. A liver resection (LR) was performed in 8 patients (11%) and 9 patients only underwent an explorative laparotomy. The overall survival in the LTX subgroup was significantly longer than patients who underwent LR and explorative laparotomy (258 months; 95% confidence interval, CI 210–306 months vs. 88 months; 95% CI 16–161 months vs. 13 months; 95% CI 3–23 months; p < 0.05, respectively). Conclusion: The majority of patients with PSC have to be operated on because of the disease with substantial risks for morbidity and mortality. Curative treatment options are lacking, thus underlining the need for effective early detection and treatment strategies for PSC-CCC. [ABSTRACT FROM AUTHOR]

Background and aims: Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease without a curative medical therapy. The human UDP‐glucuronosyltransferases 1A play a major role in the detoxification and elimination of bilirubin, bile acids and xenobiotics. Whether genetic UGT1A variants determine course and outcome of PSC has not yet been described. Methods: A large cohort of German PSC patients with a long‐term‐follow‐up was genotyped for UGT1A variants including UGT1A1*28, UGT1A3‐66 T>C and UGT1A7 p.N129K/p.R131K using TaqMan 5'‐nuclease assays. Results were correlated with clinical characteristics and transplant‐free survival. Results: About 331 patients with PSC were included in the study (69.9% male, mean age at diagnosis 32.6 years). Median transplant‐free survival was 14.9 years. Patients with wild‐type alleles of all three UGT1A genes had a longer transplant‐free survival (17.2 vs. 14.4 years, P =.048) than patients carrying a homozygous or heterozygous SNP variant in at least one of the UGT1A1, UGT1A3 or UGT1A7 genes. Additionally, we found that patients carrying wild‐type alleles of all three UGT1A genes had lower serum bilirubin (25 vs. 38 µmol/L, P =.02) and serum cholesterol (195 vs. 223 mg/dL), P =.035) at first presentation. Furthermore, inflammatory bowel disease was found to be associated with wild‐type UGT1A alleles (82.2% vs. 68.4%, P =.046). Conclusions: This large cohort shows an association with single nucleotide polymorphisms of the UGT1A1, UGT1A3 and UGT1A7 genes and outcome in PSC. Thus, UGT1A variants may represent a tool for the prognostic stratification of PSC patients and establish a link between disease progression and the regulation of detoxification by glucuronidation in PSC. [ABSTRACT FROM AUTHOR]

Background & Aims: Current guidelines recommend immunosuppressive treatment (IT) in patients with primary sclerosing cholangitis (PSC) and elevated aminotransferase levels more than five times the upper limit of normal and elevated serum IgG-levels above twice the upper limit of normal. Since there is no evidence to support this recommendation, we aimed to assess the criteria that guided clinicians in clinical practice to initiate IT in patients with previously diagnosed PSC. Methods: This is a retrospective analysis of 196 PSC patients from seven German hepatology centers, of whom 36 patients had received IT solely for their liver disease during the course of PSC. Analyses were carried out using methods for competing risks. Results: A simplified autoimmune hepatitis (AIH) score >5 (HR of 36, p<0.0001) and a modified histological activity index (mHAI) greater than 3/18 points (HR 3.6, p = 0.0274) were associated with the initiation of IT during the course of PSC. Of note, PSC patients who subsequently received IT differed already at the time of PSC diagnosis from those patients, who did not receive IT during follow-up: they presented with increased levels of IgG (p = 0.004) and more frequently had clinical signs of cirrhosis (p = 0.0002). Conclusions: This is the first study which investigates the parameters associated with IT in patients with PSC in clinical practice. A simplified AIH score >5 and a mHAI score >3, suggesting concomitant features of AIH, influenced the decision to introduce IT during the course of PSC. In German clinical practice, the cutoffs used to guide IT may be lower than recommended by current guidelines. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) after liver transplantation (LT) has a strong impact on transplant and patient survival. After LT, a significant proportion of patients develop renal dysfunction with a high risk to progress to end-stage renal disease (ESRD). Because of the multifactorial nature of CKD in the post-transplant period, the ability to accurately identify patients at risk and the development of preventative strategies remain unsolved issues. In some patients, the pretransplant kidney function significantly declines within the first year post-LT. Until now, no user-friendly and reliable prediction scores exist to identify these patients early on. Data from 328 consecutive adult patients receiving their first LT between 2004 and 2008 at Hannover Medical School were analyzed to develop a prediction model using ordinal logistic regression. We developed a concise risk score identifying the five most important predictors and performed a temporal validation using a prospectively monitored patient cohort of 120 patients from our transplant center. Based on those five parameters, we developed a pocket guide card for clinical use that could be a useful tool for instant identification of patients at high risk as well as patients more suitable for combined liver and kidney transplantation (CLKT). [ABSTRACT FROM AUTHOR]

Objective. Primary sclerosing cholangitis (PSC) is an autoimmune cholestatic liver disease of unknown etiology. The role of antineutrophil cytoplasmic antibodies (ANCAs) in the serum of patients with PSC remains unclear. We hypothesized that ANCA may be detectable in bile, potentially providing diagnostic and prognostic information. Methods. Serum and bile were prospectively collected during endoscopic retrograde cholangiography (ERC) in 72 patients with PSC and other non-PSC obstructive biliary diseases. ANCA measurements were performed by indirect immunofluorescence (IIF). Results. Immunoglobulin G (IgG) ANCA was detected significantly more often in the bile of PSC patients (15/39; 38%) than without (2/33; 6%) ( p = 0.001). IgG ANCA in bile was associated with a ten times higher risk of PSC ( p = 0.005). In addition, IgG ANCA positivity in bile was associated with the presence of dominant strictures ( p = 0.03), cholangiographic severity ( p = 0.004), number of ERC ( p = 0.01) and interventions performed ( p = 0.03). However, IgG ANCA in bile did not correlate with transplantation, cholangiocarcinoma or death. No association was observed between ANCA positivity in sera and ANA and ASCA positivity in sera or bile with the above-mentioned clinical features. Conclusions. The presence of ANCA in the bile of patients with PSC is a novel finding and highly suggestive of PSC. Biliary IgG ANCA correlates with the severity of bile duct strictures and the ensuing number of ERCs and interventions. Therefore, a positive ANCA status in bile may serve as a diagnostic and prognostic marker of the disease progression and biliary complications. [ABSTRACT FROM AUTHOR]

The indication for mandatory screening colonoscopies in liver transplant candidates is controversial. Since the introduction of MELD-based allocation, patients with advanced liver disease and often severe comorbidities are prioritized for liver transplantation ( LT). This study evaluated safety and outcome of colonoscopy in this high-risk patient group. During a two-yr period, we performed 243 colonoscopies in potential LT candidates. Endoscopic findings were registered in a standardized form, and correlations with biochemical or clinical parameters were analyzed using Mann- Whitney U-test and chi-square test. Only 57 patients (23.5%) had an endoscopically normal colon. Main findings were polyps (45.7%), hypertensive colopathy (24.3%), diverticulosis (21%), rectal varices (19.8%), and hemorrhoids (13.6%). In 21% of all patients, the removed polyps were diagnosed as adenomas. The prevalence of neoplastic polyps increased significantly with age: 13.6% (patients <50 yr) vs. 25% (patients ≥50 yr) (p = 0.03). Advanced neoplasia was found only in patients older than 40 yr. No major complications were observed; post-interventional hemorrhage was observed in 1.7% and controlled by clipping or injection therapy. In conclusion, lower gastrointestinal endoscopy is safe and effective in LT candidates. Due to the age dependency of neoplastic polyps, a screening colonoscopy should be performed in LT candidates older than 40 yr or with symptoms or additional risk factors. [ABSTRACT FROM AUTHOR]

Since the introduction of model for end-stage liver disease (MELD) in 2006, post-orthotopic liver transplantation (OLT) survival in Germany has declined. The aim of this study was to evaluate risk factors and prognostic scores for outcome. All adult OLT recipients in seven German transplant centers after MELD implementation (December 2006-December 2007) were included. Recipient data were analyzed for their influence on 1-year outcome. A total of 462 patients (mean calculated MELD = 20.5, follow-up: 1 year) were transplanted for alcoholic cirrhosis (33.1%), hepatocellular carcinoma (26.6%), Hepatitis-C (17.1%), Hepatitis-B (9.5%), primary sclerosing cholangitis (5.6%) and late graft-failure after first OLT before December 2006 (8.7%). 1-year patient survival was 75.8% (graft survival 71.2%) correlating with MELD parameters and serum choline esterase. MELD score >30 [odds ratio (OR) = 4.17, confidence interval: 2.57-6.78, 12-month survival = 52.6%, c-statistic = 0.669], hyponatremia (OR = 2.07), and pre-OLT hemodialysis (OR = 2.35) were the main death risk factors. In alcoholic cirrhosis ( n = 153, mean MELD = 21.1) and hepatocellular carcinoma ( n = 123, mean MELD = 13.5), serum bilirubin and the survival after liver transplantation score were independent outcome parameters, respectively. MELD >30 currently represents a major risk factor for outcome. Risk factors differ in individual patient subgroups. In the current German practice of organ allocation to sicker patients, outcome prediction should be considered to prevent results below acceptable standards. [ABSTRACT FROM AUTHOR]

Introduction of the model of end-stage liver disease (MELD) for organ allocation has changed the waiting-list management. Despite reports of unaffected survival after orthotopic liver transplantation (OLT) in the MELD era, survival rates have decreased in our center. The aim of this study was to identify factors contributing to reduced survival. Three-month survival, recipient and graft parameters of all 323 OLT between 2004 and 2008, which fall into a pre- ( N = 220) and a post-MELD ( n = 103) era, were analysed by Kaplan–Meier-, Mann–Whitney- and Fisher tests. After the introduction of MELD, mean scores at OLT increased (14.8 vs. 18.6, P = 0.002). The main indications for OLT were not statistically different between eras. Post-MELD recipients were older (47.9 vs. 50.9 years, P = 0.025), donors younger (NS), cold ischemia time shorter (696 vs. 635 min., P = 0.001), and duration of surgery longer (218 vs. 245 min., P = 0.001). Procedure time significantly correlated with MELD and international normalized ratio (INR). Three-month survival dropped (from 88.6% to 79.6%, P = 0.03). Independent variables of survival were creatinine, urea and duration of surgery. Reduced 3-month survival was associated with longer surgery duration, higher creatinine and urea likely reflecting higher recipient morbidity. Survival probability should be incorporated into MELD-based graft allocation. [ABSTRACT FROM AUTHOR]

Objective. Score-based medical urgency criteria are used for necessity-oriented liver transplantation (OLT) but lead to an increasing number of complications in patients with reduced post-OLT survival. A prediction of outcome would improve preoperative patient selection and management. Material and methods. One-hundred-and-thirty-three consecutive adult patients (63.9% men, mean age 47.4±11.2 years) given transplants between May 2004 and November 2005 at the Hannover Medical School were analysed retrospectively using univariate and multivariate methods. Results. Indications were: 27.1% viral hepatitis, 19.6% primary sclerosing cholangitis, 15.0% alcoholic liver disease, 7.5% metabolic liver disease, 6.8% primary biliary cirrhosis. Overall, 12-month patient survival was 81.2%. The mean MELD score at OLT was 14.5±5.3 and 12-month survival with MELD >16 (71.7%) and <16 (86.2%) differed significantly (p=0.041). Predictors of 12-month mortality included age (53.2±9.4 versus 46.1±11.2 years; p=0.004), lower cholinesterase (2.9±1.88 versus 3.7±2.02 kU/l; p=0.026) and serum creatinine (160.4±186.8 versus 77.7±31.6 µmol/l; p=0.007), with creatinine and cholinesterase as independent parameters. Based on these parameters, a model for predicting patient survival after liver transplantation was calculated and validated in a second independent cohort of 87 OLT patients. This score identified a high-risk group and a low-risk group (overall survival 47.4 versus 91.2%; p<0.001) with a specificity of 87.3% and a sensitivity of 68.75%. Conclusion. Age, pre-OLT creatinine and cholinesterase are predictors of short-term post-OLT survival and may be helpful as a bedside score in pre-OLT clinical management, outcome prediction and decision-making. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by inflammation of the intra‐ and extrahepatic bile ducts. Pathogenesis of PSC is still enigmatic but is likely to be multifactorial. Recently, we identified an interleukin‐6 (IL‐6)‐dependent signal transducer and activator of transcription 3 (STAT3) activation in CD4+ TH1 and TH17 cells in PSC. The IL‐6/STAT3 pathway was shown to be regulated by protease‐activated receptor 1 (PAR1) contributing to inflammation. The role of the PAR1 −506 deletion/insertion (Del/Ins) polymorphism in PSC has not yet been investigated.Two hundred eighty four PSC patients (200 patients with inflammatory bowel diseases [IBD] and 84 without IBD) and 309 healthy controls were genotyped for PAR1 rs11267092 (−506 Del/Ins −13 bp). Results were correlated with clinical characteristics and transplant‐free survival.The frequency of PAR1 –506 Ins allele carriers (Del/Ins and Ins/Ins) was significantly higher in PSC patients (57.0%) compared to healthy controls (39.8%). Furthermore, carriers of PAR1 −506 Ins allele were more likely to have PSC than noncarriers (odds ratio 2.01; 95% confidence interval, 1.45–2.79). Patients with PSC carrying the PAR1 −506 Ins allele showed significantly higher alanine aminotransferase serum levels (p = 0.0357) and a trend toward shorter transplant‐free survival time compared to noncarriers (8.9 ± 6.6 years vs. 10.5 ± 7.1 years; p = 0.076).Our study shows that PAR1 −506 Ins is significantly more frequent in people with PSC. As PAR1 −506 Ins allele carriers tended to have a shorter transplant‐free survival, PAR1 might play a role in the development and course of PSC. [ABSTRACT FROM AUTHOR]

However, the en bloc resection rate was higher in patients with SAL (81.2 %) compared with those with FAP (68.3 %; I P i = 0.04), and patients with FAP received more submucosal injection (47.5 % vs. 32.7 %; I P i = 0.03). Methods Patients This study assessed endoscopic papillectomy outcomes in patients with FAP compared with those in patients with SAL based on propensity score matching. As patients with FAP were regularly screened for neoplastic lesions of the upper gastrointestinal tract, patients with FAP-related ampullary lesions are often younger than patients with SAL [6]. [Extracted from the article]

BACKGROUND: Gastrointestinal dysfunctions are common in Parkinson's disease. Their management is still challenging and new treatment options are needed. OBJECTIVE: To test whether transcutaneous vagal nerve stimulation can improve gastrointestinal dysfunction in patients with Parkinson's disease. METHODS: We performed a randomized double-blind pilot study enrolling patients suffering from Parkinson's disease with gastroenteric complaints. Patients were randomized to use either a sham-device or to stimulate the vagal nerve with an electric device over the course of four weeks with four stimulations per day. Ten patients (aged 69.6±4.6 years) were randomized for the intervention group, and nine patients (aged 67.2±6.3 years) used a sham-device. Clinical outcome was evaluated using the Gastrointestinal Symptom Rating Scale whereas gastrointestinal motility was measured with the 13C-octanoic acid breath test. RESULTS: In the treatment group, vagal nerve stimulation improved the Gastrointestinal Symptom Rating Scale comparing before and after stimulation (before, 8.7±6.09; after 5.67±3.08; p-value 0.48). This improvement was not observed in the sham group (before, 7.44±4.85; after, 5.67±3.08; p-value 0.16). In the 13C-octanoic acid breath test no significant changes were detectable. CONCLUSIONS: Vagal nerve stimulation is well tolerated with no side effects and may be a promising non-invasive therapy option to improve gastroenteric symptoms in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, characterized by progressive inflammation and fibrosis of the bile ducts, resulting in biliary cirrhosis and is associated with a high risk of cholangiocarcinoma. The majority of patients are young, male and have coexisting inflammatory bowel disease. PSC is found with a prevalence of 10/100,000 in Northern European populations. The pathophysiology of PSC is a complex multistep process including immunological mechanisms, immunogenetic susceptibility and disorders of the biliary epithelia. The diagnosis is primarily based on endoscopic cholangiography although magnetic resonance imaging is increasingly used; biochemistry and immunoserology as well as histology play only a minor role. Due to the high risk of developing cholangiocarcinoma and also other tumours of the GI tract, surveillance strategies are essential, however they have yet to be established and evaluated. Biochemical parameters, clinical risk factors, endoscopic procedures and imaging techniques contribute to the early identification of patients at risk. Since medical therapy of PSC with ursodeoxycholic acid does not improve survival, to date, liver transplantation is the only option with a cure potential; if transplantation is accurately timed, transplanted PSC patients have an excellent rate of survival. However if cholangiocarcinoma is detected, a curative treatment is not possible in the majority of cases. The present review critically summarizes the current knowledge on the aetiopathogenesis of PSC and gives an overview of the diagnostic approaches, surveillance strategies and therapeutic options. Primary sclerosing cholangitis is a disease of unknown aetiology and without any further curative treatment options apart from liver transplantation. Therefore it may be regarded as the greatest challenge in hepatology today. [Copyright &y& Elsevier]

Background: Endoscopic vacuum therapy (EVT) has become a standard treatment method for esophageal perforations in adults. However, experience with EVT in infants is scarce. In this retrospective case series, we report on four very young infants who were successfully treated with EVT for esophageal perforations of different etiology.Methods: Four infants were diagnosed with esophageal perforations on day 7, 32, 35 and 159 of life, respectively. The youngest one was prematurely born in the 31st week of pregnancy weighing 980 g only. Three infants had perforations due to foreign body insertion (nasogastric tube or pulling through of percutaneous endoscopic gastrostomy (PEG) tube through the esophagus). One child had an anastomotic dehiscence after Foker's surgery for atresia. In three children EVT was applied as first-line therapy for perforation, in one child EVT was a rescue therapy due to persisting leakage after surgical closure involving thoracotomy. Depending on the esophageal diameter, either an open-pore drainage film or polyurethane sponge was attached to a single-lumen 8 Fr suction catheter, endoscopically (or fluoroscopically by wire-guidance) placed into the esophagus (intraluminal EVT) and supplied with continuous negative pressure (ranging between 75 and 150 mmHg). The EVT system was exchanged twice per week.Results: Complete closure of the perforation/leakage could be achieved in all four infants (100%) after 22 days of continuous EVT (median value; range 7-39) and 4.5 EVT exchanges (median value; range 1-12). No serious adverse events occurred.Conclusions: EVT is an effective and safe addition to our therapeutic armamentarium in the management of esophageal perforations irrespective of its etiology. Here we prove the feasibility of EVT even in very young infants. The use of an extra thin vacuum open-pore drainage film is helpful to cope with the small esophageal diameter. EVT settings and exchange rates similar to those known from adult treatment were used. [ABSTRACT FROM AUTHOR]

Prognosis of patients with advanced extrahepatic cholangiocarcinoma (eCCA) is poor. The current standard first-line treatment is systemic chemotherapy (CT) with gemcitabine and a platinum derivate. Additionally, endobiliary radiofrequency ablation (eRFA) can be applied to treat biliary obstructions. This study aimed to evaluate the additional benefit of scheduled regular eRFA in a real-life patient cohort with advanced extrahepatic cholangiocarcinoma under standard systemic CT. All patients with irresectable eCCA treated at University Hospital Bonn between 2010 and 2020 were eligible for inclusion. Patients were stratified according to treatment: standard CT (n = 26) vs. combination of eRFA with standard CT (n = 40). Overall survival (OS), progression free survival (PFS), feasibility and toxicity were retrospectively analyzed using univariate and multivariate approaches. Combined eRFA and CT resulted in significantly longer median OS (17.3 vs. 8.6 months, p = 0.004) and PFS (12.9 vs. 5.7 months, p = 0.045) compared to the CT only group. While groups did not differ regarding age, sex, tumor stage and chemotherapy treatment regimen, mean MELD was even higher (10.1 vs. 6.7, p = 0.015) in the eRFA + CT group. The survival benefit of concomitant eRFA was more evident in the subgroup with locally advanced tumors. Severe hematological toxicities (CTCAE grades 3 – 5) did not differ significantly between the groups. However, therapy-related cholangitis occurred more often in the combined treatment group (p = 0.031). Combination of eRFA and systemic CT was feasible, well-tolerated and could significantly prolong survival compared to standard CT alone. Thus, eRFA should be considered during therapeutic decision making in advanced eCCA. [ABSTRACT FROM AUTHOR]

Background and aims: Immunoglobulin G4‐associated cholangitis (IAC) is characterized by distinctly elevated immunoglobulin G4 in serum (sIgG4) and responds well to corticosteroid therapy. Primary Sclerosing Cholangitis (PSC) is a progressive liver disease without causal treatment options usually not responding to immunosuppression. Increased serum levels of sIgG4 in patients with PSC, that do not meet criteria of IAC, have been reported in 10%‐25%. Therefore, we aimed to characterize this subgroup of patients in a retrospective, multicenter study. Methods: sIgG4 values of 289 patients with PSC from three German university hospitals were analysed. Patients with elevated sIgG4 levels were identified and further characterized by clinical and biochemical parameters and by cholangiographic presentation. Clinical endpoints, death and liver transplantation were compared between groups. Parameters associated with outcome were identified with Cox regression analysis. Results: 14.5% of patients with PSC showed increased sIgG4 levels (PSC‐IgG4), presented with significantly higher (P <.02) albumin, aspartate‐aminotransferase, bilirubin and alkaline phosphatase and had a significant lower prevalence of a concomitant autoimmune hepatitis (P =.025). Cholangiogram obtained via ERC showed extrahepatic dominant strictures more often in the PSC‐IgG4 subgroup (P =.047). The disease severity models Amsterdam‐Oxford‐Score (P =.018) and Mayo‐Risk‐Score (P =.025) predicted lower survival rates for the PSC‐IgG4 subgroup. Transplant‐free survival after first diagnosis of PSC was shorter in patients with elevated sIgG4 (11.6 vs 15.1 years, P =.001). Conclusion: Patients with PSC and elevated sIgG4 should be considered as a distinct subgroup, characterized by different clinical and cholangiographical features and are associated with an inferior outcome. [ABSTRACT FROM AUTHOR]

Background: Pylorus-preserving pancreatoduodenectomy (PPPD) with pancreatogastrostomy is a standard surgical procedure for pancreatic head tumors, duodenal tumors and distal cholangiocarcinomas. Post-operative pancreatic fistulas (POPF) are a major complication causing relevant morbidity and mortality. Endoscopic vacuum therapy (EVT) has become a widely used method for the treatment of intestinal perforations and leakages. Here we report on a pilot single center series of 8 POPF cases specifically caused by dehiscences of the pancreatogastric anastomosis (PGD), successfully managed by EVT.Methods: We included all patients with PGD after PPPD, who were treated with EVT between 07/2017 and 08/2020. For EVT a vacuum drainage film (EVT film) or open-pore polyurethane foam sponge (EVT sponge) was fixed to a 14Fr or 16Fr suction catheter and placed endoscopically within the PGD for intracavitary EVT with continuous suction between - 100 and - 150 mmHg. The EVT film/sponge was exchanged twice per week. EVT was discontinued when the PGD was sufficiently healed.Results: PGD closure was achieved in 7 of 8 patients after a mean EVT time of 16 days (range 8-38) and 3 EVT film/sponge exchanges (range 1-9). One patient died on day 18 after PPPD from acute hemorrhagic shock, unlikely related to EVT, before effectiveness of EVT could be fully achieved. There were no adverse events directly attributable to EVT.Conclusions: EVT could be an effective and safe addition to our therapeutic armamentarium in the management of POPF with PGD. Unless prospective comparative studies are available, EVT as minimally invasive therapeutic alternative should be considered individually by an interdisciplinary team involving endoscopists, surgeons and radiologists. [ABSTRACT FROM AUTHOR]

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Although ruxolitinib contributes to immunomodulation and can lead to severe infections, it seems a feasible treatment strategy for patients with polycythemia vera and myelofibrosis after liver transplantation. [ABSTRACT FROM AUTHOR]

Purpose: Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease that leads to severe fibrosis and cirrhosis. The aim of this study was to determine the diagnostic value of T1 and T2 mapping as well as extracellular volume fraction (ECV) for non-invasive assessment of liver fibrosis in AIH patients. Methods: In this prospective study, 27 patients (age range: 19–77 years) with AIH underwent liver MRI. T1 and T2 relaxation times as well as ECV were quantified by mapping techniques. The presence of significant fibrosis (≥ F2) was defined as magnetic resonance elastography (MRE)-based liver stiffness ≥ 3.66 kPa. MRE was used as reference standard, against which the diagnostic performance of MRI-derived mapping parameters was tested. Diagnostic performance was compared by utilizing receiver-operating characteristic (ROC) analysis. Results: MRE-based liver stiffness correlated with both, hepatic native T1 (r = 0.69; P < 0.001) as well as ECV (r = 0.80; P < 0.001). For the assessment of significant fibrosis, ECV yielded a sensitivity of 85.7% (95% confidence interval (CI): 60.1–96.0%) and a specificity of 84.6% (CI 60.1–96.0%); hepatic native T1 yielded a sensitivity of 85.7% (CI 60.1–96.0%); and a specificity of 76.9% (CI 49.7–91.8%). Diagnostic performance of hepatic ECV (area under the curve (AUC): 0.885), native hepatic T1 (AUC: 0.846) for assessment of significant fibrosis was similar compared to clinical fibrosis scores (APRI (AUC: 0.852), FIB-4 (AUC: 0.758), and AAR (0.654) (P > 0.05 for each comparison)). Conclusion: Quantitative mapping parameters such as T1 and ECV can identify significant fibrosis in AIH patients. Future studies are needed to explore the value of parametric mapping for the evaluation of different disease stages. [ABSTRACT FROM AUTHOR]

Introduction: Gastrointestinal (GI) malignancies, such as cholangiocarcinoma, pancreatic carcinoma, and metastatic colorectal carcinoma, have a poor prognosis and effective therapeutic approaches are still challenging. Checkpoint inhibition with PD-1 or PDL-1 antibodies revealed promising results in different tumor entities; however, only few patients with GI tumors can potentially benefit from PD1/PDL1 inhibiting immunotherapy. Further immunotherapeutic strategies for GI malignancies are urgently needed. The aim of this study was to demonstrate that in vitro activation of the immune checkpoint CD40/CD40L can improve DC action towards bile duct, pancreas, and colorectal carcinoma. Methods: Human DC were isolated from buffy coats from healthy donors, pulsed with tumor lysates and then transduced with adenoviruses encoding human CD40L (Ad-hCD40L). Using transwell assays, the effects of (m)CD40L on DC immunoactivation compared to (s)CD40L were analyzed. Surface marker and cytokine/chemokine expression were measured by flow cytometry, ELISA and cytokine arrays. Capacity of Ad-hCD40L-transduced DC to induce tumor-specific effector cells was tested using MTT proliferation assay and cytotoxicity assays. Apoptosis induction on tumor cells after culturing with supernatants of Ad-hCD40L-transduced DC was analyzed by flow cytometry. Results: Ad-hCD40L transduction induced a high expression of (s)CD40L and (m)CD40L on DC and seemed to induce a strong cellular CD40/CD40L interaction among DC, leading to the formation of cell aggregates. Due to the CD40/CD40L interaction, a significant upregulation of DC maturation markers and a Th1-shift on cytokines/chemokines in the supernatant of DC were achieved. Interestingly, a pure Th1-shift was only achieved, when a cellular CD40/CD40L interaction among DC took place. (s)CD40L induced almost no upregulation of maturation markers and rather resulted in a Th2-cytokine expression, such as IL-10. Correspondingly, (m)CD40L-expressing DC led to significant proliferation and stimulation of tumor-specific effector cells with increased cytotoxicity towards pancreatic, bile duct and colorectal tumor cells. Supernatants of Ad-hCD40L-transduced DC could also induce apoptosis in the different tumor cells in vitro. Conclusion: Stimulation of the immune checkpoint CD40L/CD40 by endogenous expression of (m)CD40L provokes a cellular interaction, which increases the immunomodulatory capacity of DC. A Th1 cytokine/chemokine expression is induced, leading to a significant proliferation and enabling cytotoxicity of effector cells towards human bile duct, pancreatic and colorectal tumor cells. The present data point to the promising approach for DC-based immunotherapy of gastrointestinal malignances by activating the CD40/CD40L immune checkpoint. [ABSTRACT FROM AUTHOR]

Summary: Background: Chemotherapy with gemcitabine and cisplatin is the current standard for patients with unresectable cholangiocarcinoma. Local photodynamic therapy has also demonstrated benefit in patients with extrahepatic cholangiocarcinoma. Aim: To evaluate the benefit of photodynamic therapy in combination with systemic chemotherapy in advanced extrahepatic cholangiocarcinoma. Methods: Three hundred and fifty‐three patients diagnosed with cholangiocarcinoma between 2004 and 2016 were treated at the University Hospital of Bonn, Germany. Of these, 96 suffering from unresectable extrahepatic cholangiocarcinoma were included. Patients were stratified according to treatment: combination photodynamic therapy and chemotherapy (36 patients), photodynamic therapy alone (34 patients), and chemotherapy alone (26 patients). Results: Combined photodynamic therapy with chemotherapy resulted in significantly longer overall survival than chemotherapy alone (P = 0.022). Median survival was 20 months in the combination group (95% CI: 16.38‐23.62), 15 months in the photodynamic alone group (95% CI: 10.02‐19.98) and 10 months in the chemotherapy alone group (95% CI: 8.45‐11.55). In multivariate analysis, combination therapy and photodynamic therapy alone (HR: 0.41, 95% CI: 0.22‐0.77, P = 0.006), metal stenting, and radiofrequency ablation were independent predictors of longer survival. Conclusions: Combination photodynamic therapy and chemotherapy was well tolerated and resulted in significantly longer survival than chemotherapy alone. Application of photodynamic therapy significantly correlated with longer survival, demonstrating benefit in advanced cholangiocarcinoma. Thus, photodynamic therapy should be considered during therapeutic decision making in advanced cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Background & Aims Biliary tract cancer is a rare tumour entity characterized by a poor prognosis. We aimed to identify prognostic factors and create a prognostic score to estimate survival. Methods Clinical data of the training set, consisting of 569 patients treated from 2000 to 2010 at Hannover Medical School, were analysed. A prognostic model defining three prognostic risk groups was derived from Cox regression analyses. The score was applied and validated in an independent cohort of 557 patients from four different German centres. Results Median overall survival ( OS) was 14.5 months. If complete resection was performed, the patients had a significantly improved OS (23.9 months; n=242) as compared to patients with non-resectable tumours (9.1 months; n=329, P<.0001). Based on univariable and multivariable analyses of clinical data, a prognostic model was created using variables available before treatment. Those were age, metastasis, C-reactive protein ( CRP), international normalized ratio ( INR) and bilirubin. The prognostic score distinguished three groups with a median OS of 21.8, 8.6 and 2.6 months respectively. The validation cohort had a median OS of 20.2, 14.0 and 6.5 months respectively. The prognostic impact of the score was independent of the tumour site and of treatment procedures. Conclusions Here, we identified prognostic factors and propose a prognostic score to estimate survival, which can be applied to all patients independent of tumour site and before initial treatment. Further validation in prospective trials is required. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Background Diagnosis and curative treatment of cholangiocarcinoma (CC) often comes too late due to the lack of reliable tumour markers especially in patients with primary sclerosing cholangitis (PSC). The authors recently introduced bile proteomic analysis for CC diagnosis. Nevertheless, bile collection depends on invasive endoscopic retrograde cholangiography. The authors therefore evaluated urine proteomic analysis for non-invasive CC diagnosis. Methods Using capillary electrophoresis mass spectrometry the authors established a CC-specific peptide marker model based on the distribution of 42 peptides in 14 CC, 13 PSC and 14 benign biliary disorder (BBD) patients. Results In cross-sectional validation of 123 patients, the urine peptide marker model correctly classified 35 of 42 CC patients and 64 of 81 PSC and BBD patients with an area under the curve value of 0.87 (95% CI 0.80 to 0.92, p=0.0001, 83% sensitivity, 79% specificity). Evaluation of 101 normal controls resulted in 86% specificity. All 10 patients with CC on top of PSC were correctly classified. The majority of sequence-identified peptides are fragments of interstitial collagens with some of them also detected in blood indicating their extra-renal origin. Immunostaining of liver sections for matrix metallopeptidase 1 indicated increased activity of the interstitial collagenase in liver epithelial cells of CC patients. Conclusion The urine test differentiates CC from PSC and other BBD and may provide a new diagnostic noninvasive tool for PSC surveillance and CC detection [ABSTRACT FROM AUTHOR]

Background & Aims: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods: We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results: Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p replication <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p combined =2.1×10−8) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p repl <0.05). FUT2 at chromosome 19q13 (rs602662; p comb =1.9×10−6, rs281377; p comb =2.1×10−6 and rs601338; p comb =2.7× 10−6) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. Conclusions: We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC. [Copyright &y& Elsevier]

Objective. While marked changes in the frequency of hepatobiliary malignancies, most notably hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), have been observed in different populations, no such data have been reported for Germany. We aimed to provide epidemiological data on recent trends in liver-related mortality, specifically mortality from hepatobiliary malignancies, in Germany. Material and methods. We used incidence and mortality data to determine changes in the frequency of malignant and non-malignant liver disease in Germany over the past 30 years. Results. While overall liver disease mortality has slightly declined in Germany, deaths from hepatobiliary malignancies have declined in women, but remained constant in men. Among hepatobiliary malignancies, ICC stands out, because mortality has more than tripled both in men and women between 1998 and 2008. This is mirrored by a marked increase in new cases reported to local cancer registries, that is, incidence. Over the same time period, HCC and extrahepatic cholangiocarcinoma (ECC) have remained largely constant while gall bladder cancers (GBC) have declined twofold. The rapid rise in ICC is in line with finding from different regions worldwide, but in contrast to recent data from Denmark and France, two of Germany's direct neighbors. Conclusions. The incidence of and mortality from ICC are rising markedly in Germany. The risk factors underlying this trend are as yet unclear. [ABSTRACT FROM AUTHOR]

Biliary tract cancer (BTC) refers to a heterogenous group of epithelial malignancies arising along the biliary tree. The highly aggressive nature combined with its silent presentation contribute to the dismal prognosis of this tumor. Tumor-infiltrating immune cells (TIICs) are frequently present in BTC and there is growing evidence regarding their role as therapeutic targets. In this study, we analyzed the immune cell infiltration in BTC and developed a promising immune signature score to predict prognosis in BTC. Immunohistochemistry (IHC) was carried out on tissue microarray sections from 45 patients with resectable cholangiocarcinoma for the detection of 6-sulfoLacNAc+ monocytes (slanMo), BDCA-2+ plasmacytoid dendritic cells (pDC), CD8+ or CD4+T-lymphocytes, CD103+ cells, GATA3+ cells, Toll-like receptor (TLR) 3, 7 and 9-expressing cells as well as programmed cell death protein 1 and programmed cell death ligand 1 positive cells. Data from the IHC staining were analyzed and correlated with clinicopathological and survival data. High expression of TLR7, TLR9, and GATA3 was associated with improved overall survival (OS, Log-rank p < 0.05). In addition, TLR9 was associated with better disease-free survival (Log-rank p < 0.05). In the multivariate Cox proportional-hazards model for OS, the TLR/TLR9/GATA3 score was found to be an independent prognostic factor for OS ("Score 2" vs. "Score 0": HR 11.17 95% CI 2.27–54.95, p < 0.01). [ABSTRACT FROM AUTHOR]

Biliary tract cancer (BTC) is characterized by an intense stromal reaction and a complex landscape of infiltrating immune cells. Evidence is emerging that tumor-infiltrating neutrophils (TINs) have an impact on carcinogenesis and tumor progression. TINs have also been associated with outcomes in various solid malignant tumors but their possible clinical role in BTC is largely unknown. Tissue samples from patients with sporadic BTC ("spBTC" cohort, N = 53) and BTC in association with primary sclerosing cholangitis ("PSC-BTC" cohort, N = 7) were collected. Furthermore, tissue samples from 27 patients with PSC who underwent liver transplantation ("PSC-LTX" cohort) were investigated. All specimens were assessed for TIN density in invasive and precancerous lesions (biliary intraepithelial neoplasia, BilIN). Most spBTC showed low TIN density (LD, 61%). High TIN density (HD) was detected in 16% of the tumors, whereas 23% were classified as intermediate density (ID); the majority of both HD and ID groups were in T1–T2 tumors (83% and 100%, p = 0.012). TIN density in BilIN lesions did not significantly differ among the three groups. The HD group had a mean overall survival (OS) of 53.5 months, whereas the mean OS in the LD and ID groups was significantly shorter (LD 29.5 months vs. ID 24.6 months, log-rank p < 0.05). The results of this study underline the possible prognostic relevance of TINs in BTC and stress the complexity of the immune cell landscape in BTC. The prognostic relevance of TINs suggests a key regulator role in inflammation and immune landscape in BTC. [ABSTRACT FROM AUTHOR]

Linked Content This article is linked to Gonzalez‐Carmona et al and Srinivasa and Wigmore papers. To view these articles, visit https://doi.org/10.1111/apt.15050 and https://doi.org/10.1111/apt.15093. [ABSTRACT FROM AUTHOR]

The early and definitive diagnosis of malignant bile duct stenoses is essential for a timely and adequate therapy. However, tissue sampling with transpapillary brush cytology (BC) or forceps biopsy (FB) remains challenging. With this study, we aimed to compare the effectiveness and safety of different tissue sampling modalities (BC, FB without/after previous balloon dilatation). Standardized database research identified all patients, who underwent endoscopic retrograde cholangiography with BC and/or FB for indeterminate bile duct stenosis between January 2010 and April 2018 and with a definitive diagnosis. 218 patients were enrolled (149 cases with malignant and 69 with benign disease). FB had a significant higher sensitivity than BC (43% vs. 16%, p < 0.01). Prior balloon dilatation of the stenosis improved the sensitivity of FB from 41 to 71% (p = 0.03), the NPV from 36 to 81% (p < 0.01) and the accuracy from 55 to 87% (p < 0.01). The complication rates did not differ significantly between the modalities. In our center FB turned out to be the diagnostically more effective procedure. Balloon dilatation of the stenosis before FB had a significant diagnostic benefit and was not associated with a higher complication rate. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively). [ABSTRACT FROM AUTHOR]

The article presents a case in which percutaneous transgastral biliodigestive diversion was suggested as a treatment option for benign recurrent intrahepatic cholestasis.