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Background and aims: Extrahepatic cholangiocarcinoma (eCCA) remains a malignancy with a dismal prognosis. The first-line standard of care includes systemic chemotherapy (SC) and biliary drainage through stenting. Endobiliary ablative techniques, such as photodynamic therapy (ePDT) and radio-frequency ablation (eRFA), have demonstrated feasibility and favorable survival data. This study aimed to compare the oncologic outcome in patients treated with SC and concomitant eRFA or ePDT. Method: All patients with eCCA were evaluated for study inclusion. Sixty-three patients receiving a combination of SC and at least one endobiliary treatment were retrospectively compared. Results: Patients were stratified into three groups: SC + ePDT (n = 22), SC + eRFA (n = 28), and SC + ePDT + eRFA (n = 13). The median overall survival (OS) of the whole cohort was 14.2 months with no statistically significant difference between the three therapy groups but a trend to better survival for the group receiving ePDT as well as eRFA, during SC (ePDT + SC, 12.7 months; eRFA + SC, 13.8 months; ePDT + eRFA + SC, 20.2 months; p = 0.112). The multivariate Cox regression and subgroup analysis highlighted the beneficial effect of eRFA on OS. Overall, combined therapy was well tolerated. Only cholangitis occurred more often in the SC + eRFA group. Conclusion: Additional endobiliary ablative therapies in combination with SC were feasible. Both modalities, eRFA and ePDT, showed a similar benefit in terms of survival. Interestingly, patients receiving both regimes showed the best OS indicating a possible synergism between both ablative therapeutic techniques. [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 & 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]

Primary sclerosing cholangitis is an important reason for liver transplantation. Hepatic alveolar echinococcosis (AE) is caused by Echinococcus multilocularis and presents characteristic calcified conglomerates detected by ultrasound or computed tomography scan of the liver. Symptoms of AE only occur after a long period of infection when cholestasis or cholangitis becomes apparent. Here, we report on a patient with presumed autoimmune hepatitis and primary sclerosing cholangitis. After liver transplantation, alveolar echinococcosis was diagnosed in the liver explant. [ABSTRACT FROM AUTHOR]

Patients with acute-on-chronic liver failure (ACLF) show excess mortality in MELD-Na based organ allocation for liver transplantation (LT). Whether MELD-based allocation in the Eurotransplant region similarly underprioritizes ACLF patients is unknown. 428 patients listed for LT from 01/2010 to 02/2021 at a tertiary center in Germany were screened and 209 patients included as derivation (n = 123) and validation cohort (n = 86). Competing risk analysis for waitlist mortality and LT as competing events was performed. 90-day waitlist mortality for patients with MELD < and ≥ 25 at baseline was 9% vs. 33%, respectively (p = 0.009). Competing risk analysis shows significantly higher 90-day waitlist mortality in patients listed with ACLF compared to those without ACLF (p = 0.021) in the low MELD stratum. Probability of LT was similar between the two groups (p = 0.91). In the high MELD group, 90-day waitlist mortality and rates of LT were not significantly different between patients with and without ACLF (31% vs. 20%, p = 0.55 and 59% vs. 60%, p = 0.72, respectively). Post-transplant survival was similar between patients with and without ACLF. This result was confirmed in the validation cohort. MELD-based organ allocation in the Eurotransplant region underestimates waitlist mortality in patients with ACLF in lower MELD ranges. [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]

Objective: Prognosis of patients with irresectable cholangiocarcinoma is still poor. The ABC-02 trial established the current first line (1L) standard systemic chemotherapy (CT) with gemcitabine/platinum derivate for advanced cholangiocarcinoma. However, the majority of patients needed therapy adaptions. Thus, the aim of this study was to evaluate 1L and second line (2L) therapy regimens and the impact of therapy adaptions in an unselected real-life cohort of patients with advanced cholangiocarcinoma. Materials and Methods: This is a single institution retrospective analysis of patients with irresectable cholangiocarcinoma who were treated with gemcitabine/platinum derivate from 2010 to 2018. Overall survival (OS), progression-free survival (PFS) and toxicity were analyzed for all patients, especially with regard to CT de-escalation. Results: Fifty-eight patients receiving gemcitabine/platinum derivate were included in the analysis. Median OS and PFS were 12.2 and 6.9 months. Interestingly, 41 patients (71%) needed therapy de-escalation. However, despite reduced CT exposition, there was no-significant difference in OS (10.8 months vs. 15.6 months, p = 0.127), and patients suffered from less adverse events during CT. 21 (36%) patients reached 2L CT, most often with FOLFIRI (57%). Survival beyond the end of 1L CT was 7.1 months with 2L CT vs. 2.9 months with BSC. Conclusion: In our study, the combination of gemcitabine/platinum derivate showed similar OS and PFS as randomized prospective phase II/III trials. Therapy regimen adaptions were needed in the majority of patients. However, individualized modifications of the therapy regimen allowed better tolerance as well as continuation of therapy and did not significantly influence median OS. Furthermore, our study revealed a potential survival benefit with 2L CT for selected patients. [ABSTRACT FROM AUTHOR]

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]

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]

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: 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]

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]

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]

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]