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Background: Primary sclerosing cholangitis (PSC) is a progressive liver disease associated with inflammatory bowel disease (IBD). The percentage of PSC patients diagnosed with concomitant IBD varies considerably between studies. This raises the question whether all PSC patients would show intestinal inflammation if screened thoroughly, even in the absence of symptoms., Methods: To address this question, we collected intestinal biopsies of healthy controls (n = 34), PSC (n = 25), PSC-IBD (n = 41), and IBD (n = 51) patients in a cross-sectional study and carried out cytokine expression profiling, 16S sequencing, in-depth histology, and endoscopy scoring., Results: We found that the vast majority of PSC patients even without clinically manifest IBD showed infiltration of immune cells and increased expression of IL17A and IFNG in intestinal biopsies. However, expression of IL10 and FOXP3 were likewise increased, which may explain why these PSC patients have intestinal inflammation only on a molecular level. This subclinical inflammation in PSC patients was focused in the distal colon, whereas PSC-IBD patients showed inflammation either at the distal colon or on the right side of the colon and the terminal ileum. Furthermore, we observed that PSC patients without IBD showed signs of dysbiosis and exhibited a distinct microbial profile compared with healthy controls., Conclusions: We found a gradient of intestinal inflammation in the vast majority of PSC patients even in the absence of IBD. Thus, further studies evaluating the effect of anti-inflammatory therapies in PSC patients and their impact on the emergence of clinically manifest IBD and colorectal cancer development are needed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation of the biliary mucosa. Bile ducts in PSC are often colonized with bacteria. Although accumulating evidence demonstrates the importance of microbiota for mucosal immunity, little is known about the impact of bile duct colonization with bacteria on the clinical course of PSC., Methods: Bile samples were sent to culture during endoscopic retrograde cholangio-pancreatography before the administration of peri-interventional antibiotics. Procedures during overt bacterial cholangitis or with prior antibiotic treatment were excluded. The primary endpoint was defined as a composite clinical endpoint of decompensated cirrhosis and/or liver transplantation or death., Results: A cohort of 189 patients with 591 bile fluid cultures was included. In multivariable Cox regression analysis, the presence of Enterococci (present in 28% of the patients), but not of other bacterial species, conferred risk of disease progression with a hazard ratio of 3.61 (95% confidence interval, 1.6-8.11; P = .002) to reach the composite clinical endpoint. Fungobilia, present in 19.6% of patients, was confirmed to associate with disease progression with a hazard ratio of 3.25 (95% confidence interval, 1.87-5.66; P < .001) to reach the composite clinical endpoint., Conclusions: The novel association of biliary colonization by Enterococci with disease progression underlines the importance of microbiota-mucosal interplay for the pathogenesis of PSC. These results should stimulate further mechanistic studies on the role of microbiota in PSC and highlight potential new therapeutic targets for a disease without effective treatment options., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: Acute pancreatitis (AP) is a frequent indication for hospitalization and may present with varying degrees of severity. AP often coincides with hepatic disease, yet the impact of liver cirrhosis (LC) on the course of AP is uncertain, and early identification of patients at risk for complications remains challenging. We aimed to assess the impact of LC on the development of pancreatic and extra-pancreatic complications of AP, and to identify predictors of adverse outcomes in cirrhotic patients., Methods: All adult patients with LC and AP (LC-AP, n = 52) admitted to our institution between 01/2011-03/2020 were subjected to a 1:2 matched-pair analysis with patients with AP but without LC (NLC-AP, n = 104)., Results: At hospital admission, Glasgow-Imrie and Ranson scores as well as markers of systemic inflammation were comparable in LC-AP and NLC-AP patients, and both groups had similar rates of necrotizing AP. Infectious complications were more prevalent, and medical interventions were performed more often and with higher complication rates in LC-AP patients. While only 12.5% of NLC-AP patients developed organ failures, 48% of LC-AP patients developed single (7.7%) or multiple organ failure (40.4%), resulting in 44% of LC-AP patients with acute-on-chronic liver failure (ACLF). Patients with overt portal hypertension were particularly prone for decompensation. Mortality was higher among LC-AP compared to NLC-AP patients (6-month mortality 25% vs. 1.9%, p < 0.001), and SOFA and MELD scores at admission most accurately predicted outcomes in LC-AP., Conclusion: Among AP patients, concomitant cirrhosis substantially increases the risk for infections, periprocedural complications, multiorgan failure and death., (Copyright © 2022. Published by Elsevier B.V.)

Neuroendocrine tumours (NET) are rare tumours of the gastrointestinal tract. Many of these are diagnosed incidentally during routine upper and lower GI endoscopy. Complete surgical resection is the treatment of choice for localised tumours. For small tumours with no associated risk factors for metastases, endoscopic resection can be performed with curative intent. This endoscopic approach is standard of care for gastric, duodenal and rectal NET. In contrast, NET of the jejunum and ileum should not be treated endoscopically, as they exhibit a high rate of metastases independent of tumour size. The feasibility of an endoscopic resection is defined by the technical possibility of achieving an R0 resection, the complication rate of the procedure and the suspected rate of lymph node metastases. In general, endoscopic resection is recommended for tumours less than 1 cm in size, since they can be successfully endoscopically resected without major complications and carry a low risk of metastases. All tumours above 2 cm should be surgically resected, as endoscopic R0 resection is unlikely and risk of lymph node metastases is high. Tumours of between 1 cm and 2 cm could be approached by both surgical or endoscopic resection. A novel approach for these "in between" tumours is a combined endoscopic-laparoscopic rendezvous to achieve limited organ-sparing resection with maximal safety. This approach is particularly useful for duodenal NET as the risk of perforation is high for endoscopic resection., Competing Interests: J. Schrader hat Vortragshonorare von Novartis, AAA und Ipsen, Forschungsförderung von Novartis und Riemser und Beraterhonorare von Novartis und Advanz erhalten. Die anderen Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

BACKGROUND : Following endoscopic resection of early-stage Barrett's esophageal adenocarcinoma (BEA), further oncologic management then fundamentally relies upon the accurate assessment of histopathologic risk criteria, which requires there to be sufficient amounts of submucosal tissue in the resection specimens. METHODS : In 1685 digitized tissue sections from endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) performed for 76 early BEA cases from three experienced centers, the submucosal thickness was determined, using software developed in-house. Neoplastic lesions were manually annotated. RESULTS : No submucosa was seen in about a third of the entire resection area (mean 33.8 % [SD 17.2 %]), as well as underneath cancers (33.3 % [28.3 %]), with similar results for both resection methods and with respect to submucosal thickness. ESD results showed a greater variability between centers than EMR. In T1b cancers, a higher rate of submucosal defects tended to correlate with R1 resections. CONCLUSION : The absence of submucosa underneath about one third of the tissue of endoscopically resected BEAs should be improved. Results were more center-dependent for ESD than for EMR. Submucosal defects can potentially serve as a parameter for standardized reports., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background and Aims: Endoscopic resection has been established as curative therapy for superficial cancer arising from Barrett's oesophagus (BE); recurrences are very rare. Based on a case series with unusual and massive early recurrences, we analyse the issue of tumour cell reimplantation., Methods: This hypothesis was developed on the basis of two out of seven patients treated by circumferential (n=6) or nearly circumferential (n=1) en bloc and R0 endoscopic resection of T1 neoplastic BE. Subsequently, a prospective histocytological analysis of endoscope channels and accessories was performed in 2 phases (cytohistological analysis; test for cell viability) in 22 different oesophageal carcinoma patients undergoing endoscopy. Finally, cultures from two oesophageal adenocarcinoma cell lines were incubated with different triamcinolone concentrations (0.625-10 mg/mL); cell growth was determined on a Multiwell plate reader., Results: Cancer regrowth in the two suspicious cases (male, 78/71 years) occurred 7 and 1 months, respectively, after curative tumour resection. Subsequent surgery showed advanced tumours (T2) with lymph node metastases; one patient died. On cytohistological examinations of channels and accessories, suspicious/neoplastic cells were found in 4/10 superficial and in all 5 advanced cancers. Further analyses in seven further advanced adenocarcinoma cases showed viable cells in two channel washing specimens. Finally, cell culture experiments demonstrated enhanced tumour cell growth by triamcinolone after 24 hours compared with controls., Conclusions: Tumour cell reimplanation from contaminated endoscopes and accessories is a possible cause of local recurrence after curative endoscopic therapy for superficial Barrett carcinoma; also, corticosteroid injection could have promoted tumour regrowth in these cases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The current therapy of neoplastic Barrett's esophagus (BE) consists of endoscopic resection plus ablation, with radiofrequency ablation as the best studied technique. This prospective trial assesses a potential alternative, namely hybrid argon plasma ablation., Methods: Consecutive patients with neoplastic BE undergoing ablation after curative endoscopic resection (89.6%) or primarily were included into this prospective trial in 9 European centers. Up to 5 ablation sessions were allowed for complete eradication of BE (initial complete eradication of intestinal metaplasia [CE-IM]), by definition including BE-associated neoplasia, documented by 1 negative endoscopy with biopsies. The main outcome was the rate of initial CE-IM in intention-to-treat (ITT) and per-protocol (PP) samples at 2 years. The secondary end points were the rate of recurrence-free cases (sustained CE-IM) documented by negative follow-up endoscopies with biopsies and immediate/delayed adverse events., Results: One hundred fifty-four patients (133 men and 21 women, mean age 64 years) received a mean of 1.2 resection and 2.7 ablation sessions (range 1-5). Initial CE-IM was achieved in 87.2% of 148 cases in the PP analysis (ITT 88.4%); initial BE-associated neoplasia was 98.0%. On 2-year follow-up of the 129 successfully treated cases, 70.8% (PP) or 65.9% (ITT) showed sustained CE-IM; recurrences were mostly endoscopy-negative biopsy-proven BE epithelium and neoplasia in 3 cases. Adverse events were seen in 6.1%., Discussion: Eradication and recurrence rates of Barrett's intestinal metaplasia and neoplasia by means of hybrid argon plasma coagulation at 2 years seem to be within expected ranges. Final evidence in comparison to radiofrequency ablation can only be provided by a randomized comparative trial., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background and Aims: Endoscopic resection is considered a curative treatment for early upper GI cancers under certain histologic (low-risk) criteria. In tumors not completely fulfilling these criteria but resected R0 endoscopically, esophagectomy is still advised because of an increased risk of lymph node (LN) metastases (LNM). However, the benefit-risk ratio, especially in elderly patients at higher risk for radical surgery, can be debated. We now present the outcome of our case series of laparoscopic LN sampling (LLS) in patients with T1 esophagogastric junction tumors, which had been completely resected by endoscopy but did not fulfill the low-risk criteria (G1/2, m, L0, V0)., Methods: Retrospective review was done of all patients with T1 cancer undergoing LLS with at least 1 high-risk parameter after endoscopic resection during an 8-year period. Repeated endoscopy with biopsy and abdominothoracic CT had been performed before. The patients were divided into 2 periods: before (n = 8) and after (n = 12) the introduction of an extended LLS protocol (additional resection of the left gastric artery). In cases of positive LN, patients underwent conventional oncologic surgery; if negative, follow-up was performed. The main outcome was the number of harvested LNs by means of LLS and the percentage of positive LNs found., Results: Twenty patients with cardia (n = 1) and distal esophageal/Barrett's cancer (n = 19) were included. The LN rate with use of the extended LLS technique increased by 12% (period 1: median 12 [range, 5-19; 95% CI, 3.4-15.4] vs period 2: median 17.5 [range, 12-40; 95% CI, 12.8-22.2]; P = .013). There were 2 adverse events: 1 inadvertent chest tube removal and 1 postoperative pneumonia. In 15% of cases, patients had positive LNs. and in 2 cases there was local recurrence at the endoscopic resection site, all necessitating surgery., Conclusions: An extended technique of laparoscopic LN sampling appears to provide adequate LN numbers and is a safe approach with short hospital stay only. Only long-term follow-up of larger patient numbers will allow conclusions about miss rate as well as oncologic adequacy of this concept., (Copyright © 2021. Published by Elsevier Inc.)

Background: Patients with primary sclerosing cholangitis (PSC) display an altered colonic microbiome compared with healthy controls. However, little is known on the bile duct microbiome and its interplay with bile acid metabolism in PSC., Methods: Patients with PSC (n=43) and controls without sclerosing cholangitis (n=22) requiring endoscopic retrograde cholangiography were included prospectively. Leading indications in controls were sporadic choledocholithiasis and papillary adenoma. A total of 260 biospecimens were collected from the oral cavity, duodenal fluid and mucosa and ductal bile. Microbiomes of the upper alimentary tract and ductal bile were profiled by sequencing the 16S-rRNA-encoding gene (V1-V2). Bile fluid bile acid composition was measured by high-performance liquid chromatography mass spectrometry and validated in an external cohort (n=20)., Results: The bile fluid harboured a diverse microbiome that was distinct from the oral cavity, the duodenal fluid and duodenal mucosa communities. The upper alimentary tract microbiome differed between PSC patients and controls. However, the strongest differences between PSC patients and controls were observed in the ductal bile fluid, including reduced biodiversity (Shannon entropy, p=0.0127) and increase of pathogen Enterococcus faecalis (FDR=4.18×10 -5 ) in PSC. Enterococcus abundance in ductal bile was strongly correlated with concentration of the noxious secondary bile acid taurolithocholic acid (r=0.60, p=0.0021)., Conclusion: PSC is characterised by an altered microbiome of the upper alimentary tract and bile ducts. Biliary dysbiosis is linked with increased concentrations of the proinflammatory and potentially cancerogenic agent taurolithocholic acid., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Biliary stenoses represent a differential diagnostic challenge. Diagnostic methods to clarify the underlying dignity are often invasive, and provide high specificity beside insufficient sensitivity. In many cases, an accurate diagnosis is only possible over time, and therefore limits curative treatment options. This article provides an overview of the diagnostic challenges and treatment options for unclear biliary stenosis., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background & Aims: High IgG levels are considered a hallmark of autoimmune hepatitis (AIH). A subgroup of patients with AIH has IgG within the normal range despite evidence of clinical disease activity. The clinical significance of this biomarker has not been explored., Methods: In a European multicentre study we compared biochemical, clinical and histological features from patients with AIH and normal IgG-values at diagnosis to an age- and sex-matched control group of patients with typical AIH presenting with elevated IgG. Data were assessed at diagnosis, after 12 months of therapy and at last follow-up., Results: Out of 1,318 patients with AIH, 130 (10%) had normal IgG at presentation. Histological and biochemical parameters at diagnosis, as well as treatment response, showed no difference between groups. Stable remission off treatment was achieved more commonly in the normal IgG group than in the typical AIH group (24 vs. 8%; p  = 0.0012). Patients of the control group not only had higher IgG levels (29.5 ± 5.8 vs. 12.5 ± 3.2 g/L; p <0.0001), but also a higher IgG/IgA ratio (9.3 ± 6.9 vs. 5.4 ± 2.4; p  <0.0001) at diagnosis. The IgG/IgA ratio only declined in patients with typical AIH and was no longer different between groups after 12 months (6.3 ± 4.3 vs. 5.5 ± 2.2; p  = 0.1), indicating a selective increase of IgG in typical AIH and its suppression by immunosuppression. Autoantibody titres were higher in the typical AIH group, but not when controlled for IgG levels., Conclusions: Compared to AIH with typical biochemical features, patients with normal IgG levels at diagnosis (i) show similar biochemical, serological and histological features and comparable treatment response, (ii) appear to lack the selective elevation of serum IgG levels observed in typical active AIH disease, (iii) may represent a subgroup with a higher chance of successful drug withdrawal., Lay Summary: A characteristic feature of autoimmune hepatitis (AIH) is an elevation of immunoglobulin G (IgG), which is therefore used as a major diagnostic criterion, as well as to monitor treatment response. Nevertheless, normal IgG does not preclude the diagnosis of AIH. Therefore, we herein assessed the features of patients with AIH and normal IgG in a large multicentre study. This study demonstrates that about 10% of all patients with AIH have normal IgG; these patients are indistinguishable from other patients with AIH with respect to biochemical markers, liver histology, disease severity and treatment response, but might represent a subgroup with a higher chance of remission after drug withdrawal., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).)

Patients with primary sclerosing cholangitis (PSC) tend to develop progressive liver fibrosis and end-stage liver disease within 10-20 years. 1 The International PSC Study Group declared research on surrogate endpoints a high-priority task not least for ongoing clinical trials on novel treatment options. 2 The spleen in patients with PSC often enlarges even before cirrhosis develops. Transient elastography (TE) has been investigated as a dynamic and prognostic marker in PSC. 3,4 However, TE is not generally accessible, measures only a small part of the right liver, and is prone to errors in obese patients, and liver stiffness is related to postprandial status, liver inflammation, and biliary obstruction. 5 We have recently demonstrated that single-point spleen length (SL) measurement has a prognostic performance similar to liver stiffness measured by TE. 3,4,6 SL measurement is a fast, simple, and ubiquitously available method. However, absolute spleen size depends on body height and sex, 7 and single-point measurement of SL cannot be used to assess the effects of therapeutic interventions. To overcome these issues, we assessed the intra-individual development of spleen size over time (delta spleen length: dSL = SL 2 - SL 1 ) to evaluate its role as a novel surrogate marker, which accounts for the dynamic nature of PSC progression., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Endoscopic retrograde cholangiography (ERC) is a mainstay of therapy in patients with primary sclerosing cholangitis (PSC) and obstructive cholestasis. Patients with liver cirrhosis have an increased risk of surgical complications and are more susceptible to infections. Since PSC often progresses to cirrhosis, we aimed to assess whether ERC is associated with increased risk of complications in patients with PSC and cirrhosis., Methods: Out of 383 patients with PSC, 208 patients received endoscopic treatment between 2009-2017. Seventy patients had cirrhosis when ERC was performed and 138 patients had no signs of cirrhosis. Overall, 663 ERC procedures were analysed, with 250 ERC in patients with cirrhosis and 413 ERC in patients without cirrhosis. Data were analysed retrospectively from a prospectively acquired database using repeated measures logistic regression., Results: Overall, 40 procedure-related complications were documented in 663 ERC interventions (6%). The rate of complications was similar between patients with and without cirrhosis (4.4% vs. 7.0%). First-time ERC was associated with a higher risk of complications (17.5% vs. 4.9%). Biliary sphincterotomy, stent placement and female sex, but not presence of liver cirrhosis, were identified as risk factors for overall complications in multivariate analysis. Patients without cirrhosis showed a significant decline of ALP and bilirubin levels after the first two interventions. In contrast, in patients with cirrhosis, ALP and bilirubin levels did not significantly decline after ERC., Conclusions: In patients with PSC, cirrhosis was not a risk factor for post-ERC complications. Therefore, cirrhosis should not preclude endoscopic intervention in patients with clear clinical indication., Competing Interests: The authors have declared that no competing interests exist.