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Background and Aims: The European Reference Network on Hepatological Diseases (ERN RARE‐LIVER) launched the prospective, multicentre, quality‐controlled R‐LIVER registry on rare liver diseases. The aim of this study was to assess the presentation and outcome of autoimmune hepatitis (AIH) after 1 year of treatment. Methods: Data were prospectively collected at the time of diagnosis and after 6 and 12 months follow‐up. Complete biochemical response (CBR) was defined as normalization of alanine aminotransferase (ALT) and immunoglobulin G (IgG) serum levels. Results: A total of 231 patients from six European centres were included in the analysis. After 6 months of treatment 50% (106/212), and after 12 months 63% (131/210) of patients reached CBR with only 27% (56/211) achieving a steroid‐free CBR within the first year. Overall, 16 different treatment regimens were administered. Change of treatment, mostly due to intolerance, occurred in 30.4% within the first 6 months. In multivariate analysis, younger age at diagnosis (odds ratio [OR] = 1.03 [95% confidence interval (CI) 1.01–1.05]; p =.007), severe fibrosis (OR.38 [95%.16–.89], p =.026) and change of treatment within the first 6 months (OR.40 [95% CI.2–.86]; p =.018) were associated with a lesser chance of ALT normalization at 12 months follow‐up. Conclusion: The landscape of AIH treatment in Europe is highly heterogeneous, even between expert centres. The results from this first European multicentre prospective registry reveal several unmet needs, highlighted by the overall low rates of CBR and the frequent failure to withdraw corticosteroids. [ABSTRACT FROM AUTHOR]

Purpose: Listeria monocytogenes causes severe bacterial infections with the highest mortality rate among foodborne pathogens in Europe. Combination treatment with ampicillin and gentamicin is recommended for invasive manifestations. However, evidence to support this treatment approach remains limited due to a lack of randomised controlled trials. To explore this critical issue further, we conducted this retrospective, single-center study. Methods: We identified all patients hospitalized with invasive listeriosis at the University Medical Center Hamburg-Eppendorf between 2009 and 2020 and analyzed the effect of gentamicin combination treatment versus monotherapy on 90-day mortality. Results: In total, 36 patients with invasive listeriosis were included, of which 21 patients received gentamicin combination treatment and 15 received monotherapy. The mean age-adjusted Charlson Comorbidity Index (aaCCI) value was lower in the gentamicin combination treatment group (5.4 vs. 7.4). Neurolisteriosis was more common in the gentamicin group (81% vs. 20%). The 90-day mortality was with significantly lower in the gentamicin combination treatment group (10%) compared to the monotherapy group (60%). Multivariable cox regression analysis, adjusted for a propensity score computed based on neurolisteriosis, aaCCI and sex, revealed a significantly reduced hazard ratio of 0.07 (95% CI: 0.01–0.53, p = 0.01) for 90-day mortality for the gentamicin combination treatment. Conclusion: This retrospective study highlights the benefit of gentamicin combination treatment in reducing the 90-day mortality rate among patients with invasive listeriosis. The high prevalence of monotherapy in this study cohort raises concerns about the adequacy of antibiotic therapy in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Despite the recent advances in cancer treatment, the therapeutic options for patients with biliary tract cancer are still very limited and the prognosis very poor. More than 50% of newly diagnosed patients with biliary tract cancer are not amenable to curative surgical treatment and thus treated with palliative systemic treatment. Malignant bile duct obstructions in patients with perihilar and/or ductal cholangiocarcinoma (CCA) represents one of the most important challenges in the management of these patients, owning to the risk represented by developing life-threatening cholangitis which, in turn, limits the use of systemic treatment. For this reason, endoscopic stenting and/or bile duct decompression is the mainstay of treatment of these patients. Data on efficacy and safety of adding radiofrequency ablation (RFA) to biliary stenting is not conclusive. The aim of this multicenter, randomized trial is to evaluate the effect of intraductal RFA prior to bile duct stenting in patients with unresectable perihilar or ductal CCA undergoing palliative systemic therapy. Methods/Design: ACTICCA-2 is a multicenter, randomized, controlled, open-label, investigator-initiated trial. 120 patients with perihilar or ductal CCA with indication for biliary stenting and systemic therapy will be randomized 1:1 to receive either RFA plus bile duct stenting (interventional arm) or bile duct stenting alone (control arm). Patients will be stratified by trial site and tumor location (perihilar vs. ductal). Both arms receive palliative systemic treatment according to the local standard of care determined by a multidisciplinary tumorboard. The primary endpoint is time to first biliary event, which is determined by an increase of bilirubin to > 5 mg/dl and/or the occurrence of cholangitis leading to premature stent replacement and/or disruption of chemotherapy. Secondary endpoints include overall survival, safety according to NCI CTCAE v5, quality of life assessed by questionnaires (EORTC QLQ-C30 and QLQ-BIL21), clinical event rate at 6 months after RFA and total days of over-night stays in hospital. Follow-up for the primary endpoint will be 6 months, while survival assessment will be continued until end of study (maximum follow-up 30 month). All patients who are randomized and who underwent endoscopic stenting will be used for the primary endpoint analysis which will be conducted using a cause-specific Cox proportional hazards model with a frailty for trial site and fixed effects for the treatment group, tumor location, and stent material. Discussion: ACTICCA-2 is a multicenter, randomized, controlled trial to assess efficacy and safety of adding biliary RFA to bile duct stenting in patients with CCA receiving palliative systemic treatment. Trial registration: The study is registered with ClinicalTrials.gov (NCT06175845) and approved by the local ethics committee in Hamburg, Germany (2024-101232-BO-ff). This manuscript reflects protocol version 1 as of January 9th, 2024. [ABSTRACT FROM AUTHOR]

Recently, hepatitis E virus (HEV, Paslahepevirus balayani) particles were detected for the first time in the ejaculate of two chronically infected patients. Since then, we have been able to detect HEV in ejaculate in five further patients, and thus in a total of seven out of nine (78%) chronically infected men (age 36–67 years, median 56 years). In five patients, the HEV RNA concentration was more than 100‐fold higher compared to the serum, while in two patients, the viral load was more than 10‐fold lower. However, it has remained unclear whether viral particles shed in the ejaculate were infectious, as a previous cell culture model had failed to demonstrate the infectivity. In the current study, we employed an optimized HEV cell culture system based on overconfluent PLC/PRF/5 cells to investigate the infectivity of HEV particles from ejaculate and other body fluids. With this approach, we were able to show for the first time that HEV particles in the ejaculate from several patients were infectious. HEV replicated to high viral loads of 1e9 HEV RNA copies per ml. This indicates that HEV‐positive ejaculate could bear a risk of infection for sexual partners. [ABSTRACT FROM AUTHOR]

Literature investigating the impact of COVID-19 on healthcare professionals barely addresses predictors of somatic symptom burden during the COVID-19 pandemic. As biopsychosocial models propose that not only the disease but also sociodemographic and psychosocial factors contribute to the development and maintenance of symptoms, this study investigates the predictive value of these factors for bothersome somatic symptoms in SARS-CoV-2 negative healthcare professionals. German healthcare professionals were assessed with self-rating questionnaires and underwent SARS-CoV-2 IgG antibody tests at baseline and 8 weeks later between April and August 2020. Differences in psychosocial variables between the time points were analyzed and regression analyses were performed to predict somatic symptoms at follow-up. 1185 seronegative healthcare professionals completed both assessments. Previous somatic symptom burden, higher levels of anxiety, being a nurse, younger age, higher psychological symptom burden, lower efficiency, and higher fatigability at baseline predicted somatic symptom burden at follow-up. Comparisons between baseline and follow-up showed a significant improvement in psychological impairment and deterioration of physical exhaustion. Our study applies a biopsychosocial perspective to bothersome somatic symptoms during the COVID-19 pandemic and contributes to the identification of potential risk factors as a starting point for future interventions that could support the handling of symptoms. [ABSTRACT FROM AUTHOR]

Autoreactive B cells are considered pathogenic drivers in many autoimmune diseases; however, it is not clear whether autoimmune B cells are invariably pathogenic or whether they can also arise as bystanders of T cell‐driven autoimmune pathology. Here, we studied the B cell response in an autoantigen‐ and CD4+ T cell‐driven model of autoimmune hepatitis (AIH), the Alb‐iGP_Smarta mouse in which expression of a viral model antigen (GP) in hepatocytes and its recognition by GP‐specific CD4+ T cells causes spontaneous AIH‐like disease. T cell‐driven AIH in Alb‐iGP_Smarta mice was marked by autoantibodies and hepatic infiltration of plasma cells and B cells, particularly of isotype‐switched memory B cells, indicating antigen‐driven selection and activation. Immunosequencing of B cell receptor repertoires confirmed B cell expansion selectively in the liver, which was most likely driven by the hepatic GP model antigen, as indicated by branched networks of connected sequences and elevated levels of IgG antibodies to GP. However, intrahepatic B cells did not produce increased levels of cytokines and their depletion with anti‐CD20 antibody did not alter the CD4+ T cell response in Alb‐iGP_Smarta mice. Moreover, B cell depletion did not prevent spontaneous liver inflammation and AIH‐like disease in Alb‐iGP_Smarta mice. In conclusion, selection and isotype‐switch of liver‐infiltrating B cells was dependent on the presence of CD4+ T cells recognizing liver antigen. However, recognition of hepatic antigen by CD4+ T cells and CD4+ T cell‐mediated hepatitis was not dependent on B cells. Thus, autoreactive B cells can be bystanders and need not be drivers of liver inflammation in AIH. [ABSTRACT FROM AUTHOR]

Autoimmune hepatitis (AIH) is a rare autoimmune liver disease that is characterised by a chronic inflammatory immune reaction directed against hepatocytes. The disease results in a substantial reduction in quality of life and potentially leads to liver‐related complications or death. The International Autoimmune Hepatitis Group (IAIHG) initiated a series of research workshops to uncover the scientific gaps and opportunities in AIH. This review summarises the results of the latest workshop in Maastricht in 2022 and reviews the current challenges in adult AIH, particularly in relation to four important aspects of AIH: diagnostics; new immunomodulatory therapies; clinical trial design; and unmet clinical needs. This review also summarises the progress made since the AIH workshop in 2017. Patients and patient representatives were actively involved in the parallel working groups alongside clinicians and researchers. Despite 40 years of experience with diagnosing and treating AIH, false diagnoses occur and treatment is still based on nonselective immunosuppression. In addition to the need for more specific diagnostic tests, prognostic markers and tailor‐based treatments, a major unmet clinical need was identified in areas of care delivery and health‐related quality of life. [ABSTRACT FROM AUTHOR]

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Introduction: Cancer-associated fibroblasts (CAF) have been identified as relevant contributors to cancer progression and drug resistance in many tumors. Although neuroendocrine tumors (NET) are often associated with a strong stromal reaction, no study has addressed whether CAF are involved in progression and therapeutic resistance in NET. The aim of this study was to characterize the role of CAF in NET. Methods: We established primary CAF cultures derived from NET liver metastases to study the effect on NET cell lines NT-3 and BON. Immunohistochemistry was performed on tissue sections of primary and metastatic NET tissue. Results: Immunohistochemistry identified CAF dispersed in between tumor cells and within fibrotic bands separating tumor cell clusters in NET. Stimulating NET cells with CAF decreased expression of SSTR2 and chromogranin A and induced expression of CXCR4. CAF induced a 2.3-fold increase in proliferation and completely reversed the response to everolimus in NT-3 cells. We identified STAT3 as the main signaling pathway induced by CAF. STAT3 targeting by small interfering RNA knockdown and inhibitors prevented CAF-induced proliferation and restored everolimus responsiveness. STAT3 activation in NET tissue was associated with decreased chromogranin A expression, increased Ki-67 index, and decreased 5-year overall and progression-free survival. CAF directly influence proliferation and therapeutic response in NET cells. Conclusion: Identifying STAT3 as the contributing pathway of this so far neglected tumor-stroma interaction has the potential to become a new therapeutic target to halt tumor growth and to restore therapeutic responsiveness in NET. [ABSTRACT FROM AUTHOR]

Backgrounds/Aims: Liver diseases may affect the liver heterogeneously, especially in autoimmune hepatitis (AIH). Hence, the aim of this study was to assess the added benefit of double biopsy of both liver lobes during minilaparoscopy in guiding treatment decisions in patients with AIH. Methods: We identified all patients with AIH or variant syndromes (AIH/PBC and AIH/PSC) at our center, who underwent a double biopsy of both liver lobes via minilaparoscopy between 01/2016 and 12/2020. Results: A total of 114 patients received a biopsy of both liver lobes (AIH: N = 83, AIH/PBC: N = 26, AIH/PSC: N = 7). Differences in inflammatory activity as assessed by Ishaks's modified hepatitis activity index (mHAI) were observed in 72 (63%) patients. The difference was ≥2/18 points and ≥3/18 points in 32 (28%) and 11 (10%) patients, respectively. Starting or intensification of immunosuppression should be discussed at a mHAI of 4–5, while a mHAI≥6 prompts intensified immunosuppression in most cases. In 19/114 (17%) and 17/114 (15%) patients mHAI ≥4 or ≥6 was found in only one liver lobe, respectively. In ten patients, severe fibrosis (≥F3) was only found in one liver biopsy. Overall, therapeutically relevant histological differences were observed in 39/114 (34%) patients, which had a direct impact on treatment decisions in 24 patients (21%). No major adverse outcome occurred by taking biopsies from both liver lobes. Conclusions: Obtaining a double biopsy of both liver lobes is a safe procedure during minilaparoscopy that results in more accurate grading and staging and that may impact on treatment decisions in patients with AIH. [ABSTRACT FROM AUTHOR]

Sarcopenia, the loss of muscle mass and quality, contributes to worse clinical outcome in patients with end-stage liver disease, but its impact on short- and long-term survival remains insufficiently understood. The aim of this study was to evaluate the development of computed tomography (CT) muscle parameters and their impact on short-term and long-term survival after liver transplantation. This retrospective study included patients with liver transplantation between 2011 and 2015 and a pre-transplant CT scan. Clinical characteristics, CT muscle mass and density were assessed pre-transplant, and in available CT scans at short-term (11 months) and long-term follow-up (56 months). Overall, 93/152 (61%) patients (109 male, 55 ± 10 years) suffered from sarcopenia pre-transplant. In short- (n = 50) and long-term follow-up (n = 52) the muscle mass (− 2.65 cm2/m2 95% CI [− 4.52, − 0.77], p = 0.007; − 2.96 cm2/m2 [− 4.7, − 1.23], p = 0.001, respectively), and muscle density (− 3 HU [− 6, − 1], p = 0.007; − 2 HU [− 4, 0], p = 0.069) decreased. Myosteatosis was associated with a higher post-transplant mortality (survival probability: 3 months 72% vs. 95%, 1 year 63% vs. 90%, 5 years 54% vs. 84%, p = 0.001), while muscle mass was not. In conclusion, muscle mass and quality did not improve after transplant. Muscle quality predicts short- and long-term survival and could help to identify a patient's risk profile. [ABSTRACT FROM AUTHOR]

Background: Psychosocial support is a crucial component of adequate rare disease care, but to date psychosocial support needs of this patient population are insufficiently met. Within Q.RARE.LI, we strive to evaluate the effectiveness of a structured, transdiagnostic, and location-independent psychosocial support intervention in routine care of patients with rare autoimmune liver diseases in five countries and prepare its implementation. Methods: Within an effectiveness-implementation hybrid trial, we aim to a) investigate the effectiveness of the intervention in routine care in five diverse healthcare systems and b) assess implementation outcomes, examine and prepare the implementation context, and develop country-specific implementation strategies. To assess effectiveness, we will include N = 240 patients with rare autoimmune liver diseases. Within a two-armed randomized controlled trial (allocation ratio 1:1), we will compare structured and peer-delivered psychosocial support in addition to care-as-usual (CAU) with CAU alone. Outcomes will be assessed via electronic database entry prior to intervention, directly after, and at a three-month follow-up. Our primary effectiveness outcome will be mental health-related quality of life at post-assessment. Secondary outcomes include depression and anxiety severity, perceived social support, helplessness, and disease acceptance. Implementation outcomes will be assessed within a mixed-methods process evaluation. In a quantitative cross-sectional survey, we will examine perceived acceptability and feasibility in patients, peer-counselors, and healthcare providers involved in delivery of the intervention. In qualitative focus groups, we will analyze the implementation context and determine barriers and facilitators for implementation with different stakeholders (patients and/or representatives, peer-counselors, healthcare providers, health insurers). Based on these results, we will derive country-specific implementation strategies and develop a concrete implementation plan for each country. Discussion: The intervention is expected to help patients adjust to their disease and improve their mental quality of life. The transdiagnostic and location-independent program has the potential to reach patients for psychosocial support who are usually hard to reach. By preparing the implementation in five countries, the project can help to make low-threshold psychosocial support available to many patients with rare diseases and improve comprehensive healthcare for an often neglected group. Trial registration: ISRCTN15030282 [ABSTRACT FROM AUTHOR]

Background: Predictors of poor outcome associated with variceal bleeding remain suboptimal. In patients with cirrhosis, serum lactate combined with Model for End-Stage Liver Disease (MELD-LA) improved prediction across heterogeneous populations. However, prognostic properties have not yet been assessed in the context of variceal bleeding. Aims: We aimed to evaluate the predictive performance of MELD-LA compared to MELD, lactate, and nadir hemoglobin in cirrhosis patients with variceal bleeding. Methods: In this multicenter study, we identified 472 patients with variceal bleeding from a German primary cohort (University Hospitals Hamburg/Frankfurt/Cologne), and two independent external validation cohorts [Veterans Affairs (VA), Baylor University]. Discrimination for 30-day mortality was analyzed and scores were compared. MELD-LA was evaluated separately in validation cohorts to ensure consistency of findings. Results: In contrast to nadir hemoglobin, MELD and peak-lactate at time of bleeding were significantly higher in 30-day non-survivors in the primary cohort (p = 0.708; p < 0.001). MELD-LA had excellent discrimination for 30-day mortality (AUROC 0.82, 95% CI 0.76–0.88), better than MELD and peak-lactate (AUROC 0.78, 95% CI 0.71–0.84; AUROC 0.73, 95% CI 0.66–0.81). MELD-LA predicted 30-day mortality independently of age, sex, severity of liver disease and vasopressor support (HR 1.29 per 1-point-increase of MELD-LA; 95% CI 1.19–1.41; p < 0.001). Similarly, MELD-LA demonstrated excellent discrimination for 30-day mortality in the VA (AUROC = 0.86, 95% CI 0.79–0.93) and Baylor cohort (AUROC = 0.85, 95% CI 0.74–0.95). Conclusions: MELD-LA significantly improves discrimination of short-term mortality associated with variceal bleeding, compared to MELD, peak-lactate and nadir hemoglobin. Thus, MELD-LA might represent a useful and objective marker for risk assessment and therapeutic intervention in patients with variceal bleeding. [ABSTRACT FROM AUTHOR]

Objectives: Abdominal tuberculosis (TB) is a "great mimic," and diagnosis remains challenging even for experienced clinicians. While mini-laparoscopy has already been demonstrated to be an efficient diagnostic tool for a variety of diseases, we aimed to demonstrate the feasibility of this technique in diagnosing abdominal TB. Methods: We retrospectively included patients who underwent mini-laparoscopy at the University Medical Center Hamburg-Eppendorf between April 2010 and January 2022 for suspected abdominal TB. Demographic, clinical, and laboratory data, radiological findings as well as macroscopic, histopathologic, and microbiologic results were analyzed by chart review. Results: Out of 49 consecutive patients who underwent mini-laparoscopy for suspected abdominal TB, the diagnosis was subsequently confirmed in 29 patients (59%). Among those, the median age was 30 years (range 18–86 years) and the majority were male (n = 22, 76%). Microbiological diagnosis was established in a total of 16 patients. The remaining patients were diagnosed with abdominal TB either by histopathological detection of caseating granulomas (n = 3), or clinically by a combination of typical presentation, mini-laparoscopic findings, and good response to anti-tuberculous treatment (n = 10). Bleeding from the respective puncture site occurred in 19 patients (66%) and either resolved spontaneously or was arrested with argon plasma coagulation alone (n = 10) or in combination with fibrin glue (n = 1). Minor intestinal perforation occurred in 2 patients and was treated conservatively. Conclusions: Mini-laparoscopy is a useful and safe modality for the diagnosis of abdominal TB. [ABSTRACT FROM AUTHOR]

Background & aims: To explore the humoral and T‐cell response to the third COVID‐19 vaccination in autoimmune hepatitis (AIH). Methods: Anti‐SARS‐CoV‐2 antibody titers were prospectively determined in 81 AIH patients and 53 healthy age‐ and sex‐matched controls >7 days (median 35) after the first COVID‐19 booster vaccination. The spike‐specific T‐cell response was assessed using an activation‐induced marker assay (AIM) in a subset of patients. Results: Median antibody levels were significantly lower in AIH compared to controls (10 908 vs. 25 000 AU/ml, p <.001), especially in AIH patients treated with MMF (N = 14, 4542 AU/ml, p =.004) or steroids (N = 27, 7326 AU/ml, p =.020). Also, 48% of AIH patients had antibody titers below the 10% percentile of the healthy controls (9194 AU/ml, p <.001). AIH patients had a high risk of failing to develop a spike‐specific T‐cell response (15/34 (44%) vs. 2/16 (12%), p =.05) and showed overall lower frequencies of spike‐specific CD4 + T cells (median: 0.074% vs 0.283; p =.01) after the booster vaccination compared to healthy individuals. In 34/81 patients, antibody titers before and after booster vaccination were available. In this subgroup, all patients but especially those without detectable/low antibodies titers (<100 AU/ml) after the second vaccination (N = 11/34) showed a strong, 148‐fold increase. Conclusion: A third COVID‐19 vaccination efficiently boosts antibody levels and T‐cell responses in AIH patients and even seroconversion in patients with the absent immune response after two vaccinations, but to a lower level compared to controls. Therefore, we suggest routinely assessing antibody levels in AIH patients and offering additional booster vaccinations to those with suboptimal responses. [ABSTRACT FROM AUTHOR]

Background and Aims: Autoimmune liver diseases (AILDs) are associated with impaired health‐related quality of life (HrQoL). The aim of this project was to identify potentially modifiable factors related to HrQoL in a large transnational cohort of patients with AILDs. Methods: A cross‐sectional online survey was conducted on patients with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) or primary sclerosing cholangitis from 15 European countries. HrQoL was measured with EQ‐5D‐5L and EQ visual analogue scale (EQ‐VAS) and analysed in relation to demographic, psychosocial, disease‐ and treatment‐related factors. A Patient Health Questionnaire‐2 score >3 indicated relevant depression. Multivariable linear regression analyses were used to identify potentially modifiable factors associated with HrQoL and confidence in treatment whilst adjusting for known confounders. Results: A group of 1178 European patients (79% female, mean age 48 ± 14 years) participated in the study. HrQoL was impaired in all three diseases (mean EQ‐5D‐5L = 0.75, mean EQ VAS = 68.9), most markedly in PBC (mean EQ‐5D‐5L = 0.73, mean EQ‐VAS = 66.2). Relevant depression, which was detected in 17% of patients, was prominently associated with impaired HrQoL. In the regression analysis, treatment confidence was identified as an important modifiable factor positively contributing to HrQoL. This influence was observable even after adjusting for other covariates including depression. Management in a transplant centre, treatment with azathioprine in AIH, and with ursodeoxycholic acid in PBC, was associated with increased treatment confidence. Finally, improved patient‐physician relationships contributed to treatment confidence. Conclusion: Treatment confidence is a relevant modifiable determinant of HrQoL and should be further investigated to improve the standards of care for patients with AILDs. [ABSTRACT FROM AUTHOR]

At the start of the pandemic, liver transplant recipients (LTR) were at high risk of developing severe COVID-19. Here, the outcomes of breakthrough infections in fully vaccinated LTR (n = 98) during the Omicron wave were assessed. In most patients, a mild disease course was observed, but 11 LTR (11.2%) required hospitalization for COVID-19-related complications. All patients survived. The LTR requiring hospitalization were older (67 years vs. 54 years; p < 0.001), had a higher Charlson comorbidity index (9 vs. 5; p < 0.001), and a lower anti-S RBD titer (Roche Elecsys) prior to infection (508.3 AU/mL vs. 2044 AU/mL; p = 0.03). Long-lasting symptoms for ≥4 weeks were reported by 37.5% of LTR (30/80). Risk factors in LTR included female sex (p = 0.01; Odds Ratio (OR) = 4.92 (95% confidence interval (CI) (1.5–16.5)) and dyspnea (p = 0.009; OR = 7.2 (95% CI (1.6–31.6)) during infection. Post-infection high anti-S RBD antibody levels were observed in LTR, and healthy controls (HC), while the cellular immune response, assessed by interferon-gamma release assay (EUROIMMUN), was significantly lower in LTR compared with HC (p < 0.001). In summary, in fully vaccinated LTR, SARS-CoV-2 breakthrough infections during the Omicron wave led to mild disease courses in the majority of patients and further boosted the humoral and cellular hybrid anti-SARS-CoV-2-directed immune response. While all patients survived, older and multimorbid LTR with low baseline antibody titers after vaccination still had a substantial risk for a disease course requiring hospitalization due to COVID-19-related complications. [ABSTRACT FROM AUTHOR]

Summary: Background: Primary sclerosing cholangitis (PSC) is a progressive bile duct disease associated with inflammatory bowel disease (PSC‐IBD). Aim: To investigate whether patients with PSC‐IBD benefit from a gluten‐free and amylase trypsin inhibitor (ATI)‐free diet (GFD). Methods: We performed a prospective clinical pilot study administering an eight‐week GFD. The primary outcomes were colonic inflammation assessed by proctosigmoidoscopy, and liver stiffness (surrogate for fibrosis, inflammation and cholestasis) measured by transient elastography before and after GFD. Amongst the secondary (exploratory) outcomes were colonic mucosal and serum cytokine/chemokine changes, the intestinal microbiome and transcriptome dynamics, and shifts in serum markers of hepatic fibrogenesis. Results: Fifteen patients with PSC‐IBD completed the study. The study did not meet its primary outcome: the endoscopic score and liver stiffness remained unchanged. However, the expression of pro‐inflammatory mucosal cytokines and chemokines such as IL6, IL8, CCL2, and TNFα was significantly down‐regulated. Two critical markers of liver fibrosis and matrix remodelling, thrombospondin‐2 and ‐4, decreased significantly. The microbiota composition changed slightly, including a decrease in the pathogen Romboutsia ilealis. The intestinal transcriptome indicated a gut barrier improvement. Pruritus, fatigue, overall well‐being, faecal calprotectin levels, and serum alkaline phosphatase did not change significantly. Conclusions: This study did not demonstrate a clinical improvement with short‐term GFD in patients with PSC‐IBD. However, a gluten/ATI‐free diet may improve biomarkers of intestinal inflammation and barrier function in these patients with associated changes in the enteric microbiota. Further investigation of the therapeutic potential of the GFD in PSC‐IBD is warranted. [ABSTRACT FROM AUTHOR]

Purpose: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) form a rare and remarkably heterogeneous group of tumors. Therefore, establishing personalized therapies is eminently challenging. To achieve progress in preclinical drug development, there is an urgent need for relevant tumor models. Methods: We successfully established three gastroenteropancreatic neuroendocrine tumor (GEP-NET) cell lines (NT-18P, NT-18LM, NT-36) and two gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) cell lines (NT-32 and NT-38). We performed a comprehensive characterization of morphology, NET differentiation, proliferation and intracellular signaling pathways of these five cell lines and, in addition, of the NT-3 GEP-NET cell line. Additionally, we conducted panel sequencing to identify genomic alterations suitable for mutation-based targeted therapy. Results: We found that the GEP-NEN cell lines exhibit a stable neuroendocrine phenotype. Functional kinome profiling revealed a higher activity of serine/threonine kinases (STK) as well as protein tyrosine kinases (PTK) in the GEP-NET cell lines NT-3 and NT-18LM compared to the GEP-NEC cell lines NT-32 and NT-38. Panel sequencing revealed a mutation in Death Domain Associated Protein (DAXX), sensitizing NT-18LM to the Ataxia telangiectasia and Rad3 related (ATR) inhibitor Berzosertib, and a mutation in AT-Rich Interaction Domain 1A (ARID1A), sensitizing NT-38 to the Aurora kinase A inhibitor Alisertib. Small interfering RNA-mediated knock down of DAXX in the DAXX wild type cell line NT-3 sensitized these cells to Berzosertib. Conclusions: The newly established GEP-NET and GEP-NEC cell lines represent comprehensive preclinical in vitro models suitable to decipher GEP-NEN biology and pathogenesis. Additionally, we present the first results of a GEP-NEN-specific mutation-based targeted therapy. These findings open up new potentialities for personalized therapies in GEP-NEN. [ABSTRACT FROM AUTHOR]

Introduction: Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms. Surgery is the only curative treatment option. However, our understanding of predictors of survival after surgery remains incomplete. The aim of the study was to evaluate metabolic syndrome (MetS) as a prognostic factor in pNET. Methods: In a retrospective single-center cohort study, we examined the influence of MetS in 120 patients with curative intended resection of pNETs on overall survival (OS), recurrence-free survival, and outcome after recurrence. Results: MetS was present in 32 patients (26.6%). Patients with MetS had an impaired OS after curative intended surgery compared to patients without MetS (median OS 72 months [95% CI 13.3–130.7] vs. not reached, p < 0.001). The shortest survival was observed in patients with MetS in the presence of oligometastatic disease at time of surgery. In a multivariable Cox regression analysis, MetS was identified as an independent risk factor for mortality (hazard ratio [HR] = 4.54, 95% CI [1.88–11.00], p = 0.01). In our dataset, MetS was not associated with tumor recurrence or recurrence-free survival. Nevertheless, in patients with recurrence, MetS was associated with shorter time to recurrence (median 3.4 months, 95% CI [2.48–4.24], vs. 20.1 months, 95% CI [10.8–29.49], p < 0.001), and poor outcome (HR = 5.03, 95% CI [1.25–20.20], p = 0.01). Conclusions: We identified MetS as a negative prognostic factor after curative intended surgery for pNET. In particular, patients with oligometastatic disease might not benefit from extensive surgery in the presence of MetS. Furthermore, MetS had a strong impact on survival after recurrence. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is an aggressive tumor associated with a high rate of recurrence after resection. An important risk factor for recurrence is the presence of occult metasta-ses, which are not radiologically detectable at the time of diagnosis. There are currently no biomarkers for the preoperative assessment of micrometastases. A previous study demonstrated the prognostic relevance of circulating tumor cells (CTC) in patients with advanced CCA but the potential of CTCs as a preoperative marker for detecting occult metastases has not been investigated so far. In this twophase study, we first recruited a cohort of 27 patients with histologically proven, metastatic CCA or gallbladder cancer (GBCA) to assess feasibility (feasibility cohort, FC). CTCs were measured in the peripheral blood using the CellSearch System (CSS) between October 2012 and January 2017. Subsequently, in 11 patients undergoing curative-intended resection for CCA (intrahepatic CCA: n =4; extrahepatic CCA n= 6; gallbladder cancer: n=1), peripheral and central venous blood specimens were obtained to improve detection rate by simultaneous measurement and to elucidate distribution of CTCs in different venous compartments. Presence of CTCs detection was correlated with postoperative TNM-status. In the FC, CTCs (range 1-3 cells, median: 1) were detected in 40% (11/27) patients and were signifi-cantly associated with worse overall survival (hazard ratio: 3.59; 95% CI: 1.79-7.1; p = 0.04). By combined peripheral and central measurement, CTC detection was increased to 54% (6/11) in the resection cohort (RC) and was associated with metastases that were only identified during the surgical procedure (peritoneal carcinoma: n = 1; infiltration of the duodenum: n = 1) or immediately after surgery (evidence of pulmonary metastases by CT scan two days after resection, not evident on initial tumor staging prior resection). Taken together, in this single center pilot study, we demonstrated that CTCs are detectable in CCA patients and are associated with significantly impaired survival in patients at metastatic stage. Detection rate prior to surgery was improved to >50% by combined peripheral and central measurement. Moreover, preoperative CTC detection may indicate existing metastases and could help to stratify patients more accurately. [ABSTRACT FROM AUTHOR]

Introduction: Little is known about risk factors for both Long COVID and somatic symptoms that develop in individuals without a history of COVID-19 in response to the pandemic. There is reason to assume an interplay between pathophysiological mechanisms and psychosocial factors in the etiology of symptom persistence. Objective: Therefore, this study investigates specific risk factors for somatic symptom deterioration in a cohort of German adults with and without prior SARS-CoV-2 infection. Methods: German healthcare professionals underwent SARS-CoV-2 IgG antibody testing and completed self-rating questionnaires at baseline and 21 months later between April 2020 and February 2022. Dierences in variables between the time points were analyzed and a regression analysis was performed to predict somatic symptom deterioration at follow-up. Results: Seven hundred fifty-one adults completed both assessments. Until follow-up, n = 58 had contracted SARS-CoV-2 confirmed by serology. Between baseline and follow-up, signs of mental and physical strain increased significantly in the sample. Symptom expectations associated with COVID19 and a self-reported history of COVID-19, but not serologically confirmed SARS-CoV-2 infection, significantly predicted somatic symptom deterioration at follow-up. A further predictor was baseline psychological symptom burden. Conclusions: This study supports a disease-overarching biopsychosocial model for the development of burdensome somatic symptoms during the COVID-19 pandemic and supports research findings that symptom burden may be more related to the psychosocial eects of the pandemic than to infection itself. Future studies on Long COVID should include SARS-CoV-2 negative control groups and consider symptom burden prior to infection in order to avoid an overestimation of prevalence rate. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is an idiopathic cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of intra- and extrahepatic bile ducts. Osteoporosis is a frequent comorbidity in PSC, and we could previously demonstrate that IL17-dependent activation of bone resorption is the predominant driver of bone loss in PSC. Since we additionally observed an unexpected heterogeneity of bone mineral density in our cohort of 238 PSC patients, the present study focused on a comparative analysis of affected individuals with diagnosed osteoporosis (PSCOPO, n = 10) or high bone mass (PSCHBM, n = 7). The two groups were not distinguishable by various baseline characteristics, including liver fibrosis or serum parameters for hepatic function. In contrast, quantification of serum bile acid concentrations identified significant increases in the PSCOPO group, including glycoursodeoxycholic acid (GUDCA), an exogenous bile acid administered to both patient groups. Although cell culture experiments did not support the hypothesis that an increase in circulating bile levels is a primary cause of PSC-associated osteoporosis, the remarkable differences of endogenous bile acids and GUDCA in the serum of PSCOPO patients strongly suggest a yet unknown impairment of biliary metabolism and/or hepatic bile acid clearance in this patient subgroup, which is independent of liver fibrosis. [ABSTRACT FROM AUTHOR]

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Background: Asplenia or functional hyposplenism are risk factors for severe infections, and vaccinations against encapsulated bacteria are advised. There are only limited data regarding the spleen function of cirrhotic patients. Methods: We evaluated spleen function in patients with liver cirrhosis, who were prospectively enrolled in this study. Spleen function was evaluated by the measurement of pitted erythrocytes. Functional hyposplenism was defined as a percentage of PE of >15%. Results: 117 patients, mean age 58.4 years and 61.5% (n = 72) male with liver cirrhosis were included. Functional hyposplenism was diagnosed in 28/117 patients (23.9%). Pitted erythrocytes correlated with albumin (p = 0.024), bilirubin (p<0.001), international normalized ratio (INR; p = 0.004), model of end-stage liver disease (MELD) score (p<0.001) and liver stiffness (p = 0.011). Patients with functional hyposplenism had higher MELD scores (median 13 vs. 10; p = 0.021), liver stiffness (46.4 kPa vs. 26.3 kPa; p = 0.011), INR (1.3 vs. 1.2; p = 0.008) and a higher Child-Pugh stage (Child C in 32.1% vs. 11.2%; p = 0.019) as compared to patients without functional hyposplenism. Functional hyposplenism was not associated with the etiology of cirrhosis. Importantly, 9/19 patients with Child C cirrhosis had functional hyposplenism. Conclusion: A quarter of patients with liver cirrhosis and almost 50% of patients with Child C cirrhosis have functional hyposplenism. Functional hyposplenism is associated with poor liver function and the degree of portal hypertension, which is characterized by higher liver stiffness measurements in transient elastography. [ABSTRACT FROM AUTHOR]

Background: The immunogenicity of different COVID-19 vaccine regimens and combinations in naïve and convalescent individuals has not been formally tested in controlled studies, and real-life observational studies are scarce. Methods: We assessed the SARS-CoV-2 infection and COVID-19 vaccination-induced immunity of 697 hospital workers at the University Medical Center Hamburg-Eppendorf between 17 and 31 January 2022. Results: The overall prevalence of anti-NC-SARS-CoV-2 antibodies indicating prior infection was 9.8% (n = 68) and thus lower than the seroprevalence in the general population. All vaccinated individuals had detectable anti-S1-RBD-SARS-CoV-2 antibodies (median AU/mL [IQR]: 13,891 [8505–23,543]), indicating strong protection against severe COVID-19. Individuals who received three COVID-19 vaccine doses (median AU/mL [IQR]: 13,856 [8635–22,705]) and those who resolved a prior SARS-CoV-2 infection and had received two COVID-19 vaccine doses (median AU/mL [IQR] 13,409 [6934–25,000]) exhibited the strongest humoral immune responses. Conclusions: The current study indicates that three exposures to the viral spike protein by either SARS-CoV-2 infection or COVID-19 vaccination are necessary to elicit particularly strong humoral immune responses, which supports current vaccination recommendations. [ABSTRACT FROM AUTHOR]

B cells are central for the adaptive immune system to mount successful immune responses not only as antibody producers but also as regulators of cellular immunity. These multifaceted features are also reflected in autoimmunity where autoreactive B cells can fuel disease by production of cytotoxic autoantibodies, presentation of autoantigens to autoreactive T cells, and secretion of cytokines and chemokines that either promote detrimental immune activation or impair regulatory T and B cells. The role of B cells and autoantibodies in autoimmune hepatitis (AIH) have been controversially discussed, with typical autoantibodies and hypergammaglobulinemia indicating a key role, while strong HLA class II association suggests T cells as key players. In this review, we summarize current knowledge on B cells in AIH and how different B cell subpopulations may drive AIH progression beyond autoantibodies. We also discuss recent findings of B cell-directed therapies in AIH. [ABSTRACT FROM AUTHOR]

Introduction: Incidence of pancreatic neuroendocrine tumours (pNETs) is on the rise. The only curative treatment is surgical resection in localized or oligo-metastatic disease. However, patients may present with locally advanced or unresectable primary tumours. So far, no conversion therapy to achieve resectability has been established, which is partly due to lack of data on primary tumour response to therapies. Here, we specifically evaluate the primary tumour response to streptozocin/5-FU in a large cohort of metastatic pNET patients. Methods: Five ENETS centres in Germany contributed 84 patients to the study cohort for retrospective analysis. Results: Overall response rate (ORR) in primary tumours was 34% and disease control rate (DCR) 88%. ORR was different in metastases at 44% and DCR at 70%. Partial remission in primary tumours was more frequent among those located in pancreatic tail than that in pancreatic head (49% vs. 14%, p = 0.03). Correspondingly, metastases from tumours originating from pancreatic tail responded more frequently than metastases originating from pancreatic head (88.5% vs. 41.7%, p = 0.005). The median PFS of the primary tumours was longer than that in metastases (31 months vs. 16 months; p = 0.04). Considerable downsizing of the primary tumour was rare and occurred primarily in tumours located in the pancreatic tail. Conclusion: STZ/5-FU can achieve disease stabilization in a high proportion of metastatic pNET patients. In the majority of cases however it does not induce substantial downsizing of the primary tumour, thus possibly limiting its potential as conversion chemotherapy. Furthermore, the difference in response rate observed between different primary tumour locations warrants further exploration. [ABSTRACT FROM AUTHOR]

Background & Aims: Diagnostic histological criteria for autoimmune hepatitis (AIH) have not been clearly established. Previously published criteria focused mainly on chronic AIH, in which inflammatory changes mainly occur in portal/periportal regions and may not be applicable to acute presentation of AIH, in which inflammatory changes are typically predominantly lobular in location. International consensus criteria for the diagnosis and assessment of disease severity in both acute and chronic AIH are thus urgently needed. Methods: Seventeen expert liver pathologists convened at an international workshop and subsequently used a modified Delphi panel approach to establish consensus criteria for the histopathological diagnosis of AIH. Results: The consensus view is that liver biopsy should remain standard for diagnosing AIH. AIH is considered likely, if there is a predominantly portal lymphoplasmacytic hepatitis with more than mild interface activity and/or more than mild lobular hepatitis in the absence of histological features suggestive of another liver disease. AIH is also considered likely if there is predominantly lobular hepatitis with or without centrilobular necroinflammation and at least one of the following features: portal lymphoplasmacytic hepatitis, interface hepatitis or portal‐based fibrosis, in the absence of histological features suggestive of another liver disease. Emperipolesis and hepatocellular rosettes are not regarded as being specific for AIH. Conclusions: The criteria proposed in this consensus statement provide a uniform approach to the histological diagnosis of AIH, which is relevant for patients with an acute as well as a chronic presentation and to more accurately reflect the current understanding of liver pathology in AIH. [ABSTRACT FROM AUTHOR]

Background: Proton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication. Methods: The STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallelgroup trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021. Discussion: The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis. [ABSTRACT FROM AUTHOR]