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Biliary tract cancer, the second most common type of liver cancer, remains a therapeutic challenge due to its late diagnosis and poor prognosis. In recent years, it has become evident that classical chemotherapy might not be the optimal treatment for patients with biliary tract cancer, especially after failure of first-line therapy. Finding new treatment options and strategies to improve the survival of these patients is therefore crucial. With the rise and increasing availability of genetic testing in patients with tumor, novel treatment approaches targeting specific genetic alterations have recently been proposed and have demonstrated their safety and efficacy in numerous clinical trials. In this review, we will first consider chemotherapy options and the new possibility of combining chemotherapy with immune checkpoint inhibitors in first-line treatment. We will then provide an overview of genomic alterations and their potential for targeted therapy especially in second-line therapy. In addition to the most common alterations such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, fibroblast growth factor receptor 2 (FGFR2) fusions, and alterations, we will also discuss less frequently encountered alterations such as BRAF V600E mutation and neurotrophic tyrosine kinase receptor gene (NTRK) fusion. We highlight the importance of molecular profiling in guiding therapeutic decisions and emphasize the need for continued research to optimize and expand targeted treatment strategies for this aggressive malignancy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Iron deficiency anemia (IDA) is the most common form of anemia worldwide, resulting in a high burden of disease. Accumulating evidence suggests that IDA is associated with the development of gastrointestinal (GI) cancers., Methods: Data from the IDA database (IQVIA) of primary care practices in Germany of adult patients first diagnosed with IDA between January 2005 and December 2021 were retrospectively analyzed and compared with a 1:1 propensity score-adjusted cohort without IDA. Study outcomes were first stomach cancer or colorectal cancer (CRC) diagnosis up to 10 years after the index date as a function of IDA., Results: A total of 122,502 individuals with IDA and 122,502 individuals without IDA were included. The 10-year cumulative incidence of CRC was 1.4% in the IDA patients compared to 0.8% in the cohort without IDA (p < 0.001). Regression analysis revealed a significant association between IDA and subsequent CRC (HR 2.05; 95% CI 1.83-2.30). Stomach cancer was diagnosed in 0.3% of IDA patients compared to 0.2% in the non-IDA cohort during the 10-year follow-up period (p = 0.002). However, this was significant only in the age group > 80 years (HR 2.73; 95% CI 1.60-4.67) and in men (HR 1.90; 95% CI 1.38-2.61)., Conclusion: These findings add to the literature and suggest an association between IDA and GI cancers. The extent to which this association is due to GI bleeding or other pathophysiological processes that may be caused by IDA requires further investigation, particularly experimental studies., (© 2024. The Author(s).)

Purpose: Sleep disorders are among the most common health problems worldwide and are linked to a variety of physical and mental health problems. Recently, there has been increasing evidence of an association between sleep disorders and cancer risk. We aimed to investigate this association specifically for cancers of the gastrointestinal (GI) tract., Methods: Using the DA database (IQVIA), adult patients diagnosed with GI cancer between January 2010 and December 2022 were retrospectively compared to a 1:1 propensity score-matched cohort of patients without cancer. The outcome of the study was the association between sleep disorders and subsequent diagnosis of GI cancer. To determine whether sleep disorders were more common in patients with GI cancer than in patients without GI cancer, logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI)., Results: After matching, 37,161 cases with GI cancer and 37,161 controls without cancer were available for analysis. No association with cancer was found for sleep disorders in the overall history before the index date (OR 1.04; 95% CI 0.96-1.12), but considering sleep disorders documented within 1 year before the index date showed a positive association with GI cancer overall (OR 1.20; 95% CI 1.08-1.34). Stratified analyses by cancer site revealed higher odds of sleep disorders prior to diagnosis of gastric, pancreatic, and colorectal cancer., Conclusion: Our findings suggest that sleep disorders might be indicative of short-term health outcomes, including GI cancer, suggesting a role for sleep disorder screening in the context of cancer prevention efforts., (© 2023. The Author(s).)

Background: Previous studies have found variations in cancer types, tumor progression, and disease outcomes between men and women. However, there is limited knowledge of the effect of sex on gastrointestinal neuroendocrine neoplasms (GI-NENs)., Methods: We identified 1354 patients with GI-NEN from the IQVIA's Oncology Dynamics database. Patients were derived from four European countries (Germany, France, the United Kingdom (UK), Spain). Clinical and tumor related characteristics including patients' age, tumor stage, tumor grading and differentiation, frequency and sites of metastases, as well as co-morbidities were analyzed as a function of patients´ sex., Results: Among the 1354 included patients, 626 were female and 728 were male. The median age was similar between both groups (w: 65.6 years, SD: 12.1 vs. m: 64.7 years; SD: 11.9; p = 0.452). UK was the country with the most patients, however, there was no differences in the sex ratio between the different countries. Among documented co-morbidities, asthma was more often diagnosed in women (7.7% vs. 3.7%), while COPD was more prevalent in men (12.1% vs. 5.8%). The ECOG performance states was comparable between females and males. Of note, the patients´ sex was not associated with tumor origin (e.g., pNET or siNET). Females were overrepresented among G1 tumors (22.4% vs. 16.8%), however, median proliferation rates according to Ki-67 were similar between both groups. In line, no differences in tumor stages was found and rates of metastases as well as the specific sites of metastases were similar between males and females. Finally, no differences in the applied tumor specific treatments between the both sexes became apparent., Conclusion: Females were overrepresented among G1 tumors. No further sex-specific differences became apparent, highlighting that sex-related factors might play a rather subordinate role in the pathophysiology of GI-NENs. Such data may help to better understand the specific epidemiology of GI-NEN., (© 2023. The Author(s).)

Liver diseases represent a significant global health burden, necessitating the development of reliable biomarkers for early detection, prognosis, and therapeutic monitoring. Extracellular vesicles (EVs) have emerged as promising candidates for liver disease biomarkers due to their unique cargo composition, stability, and accessibility in various biological fluids. In this study, we present an optimized workflow for the identification of EVs-based biomarkers in liver disease, encompassing EVs isolation, characterization, cargo analysis, and biomarker validation. Here we show that the levels of microRNAs miR-10a, miR-21, miR-142-3p, miR-150, and miR-223 were different among EVs isolated from patients with nonalcoholic fatty liver disease and autoimmune hepatitis. In addition, IL2, IL8, and interferon-gamma were found to be increased in EVs isolated from patients with cholangiocarcinoma compared with healthy controls. By implementing this optimized workflow, researchers and clinicians can improve the identification and utilization of EVs-based biomarkers, ultimately enhancing liver disease diagnosis, prognosis, and personalized treatment strategies.

Locoregional therapy options for CCA are used, in particular, for non-resectable tumors and aim to reduce tumor viability or delay tumor growth and ultimately prolong overall survival. In addition to local ablative procedures such as radiofrequency- or microwave-ablation, transarterial procedures such as transarterial embolization (TAE), transarterial chemoembolization (TACE), or selective internal radiotherapy (SIRT) play a major role. In particular, in combination with advances in molecular medicine and immunotherapy, there has been a further development in the therapy of primary malignant liver tumors in recent years. In this review, we analyze data from recent studies and examine the implications for therapy of CCA, particularly with regard to the combination of locoregional therapies with modern systemic therapies.

Background: Liver diseases and cardiovascular diseases are closely associated. Noninvasive tests (NITs), such as the FIB-4 score, have been recommended by different guidelines to rule out advanced fibrosis and estimate the risk of liver-related outcomes in patients with chronic liver diseases (CLDs). However, the association of an elevated FIB-4 score with the development of myocardial infarction and/or stroke/transient ischemic attack (TIA) is unknown., Methods: By using the Disease Analyzer database (IQVIA), which compiles diagnoses, laboratory values as well as basic medical and demographic data of over 7.5 million patients followed in general practices in Germany, we identified 68 921 patients with available lab values for FIB-4 score calculation between 2005 and 2019. Patients with an FIB-4 score of less than 1.3 were matched 1:1 to patients with an FIB-4 score of at least 1.3 by age, sex and yearly consultation frequency., Results: In regression analysis, the incidence rate ratio (IRR) of myocardial infarction was similar among patients with an FIB-4 score of at least 1.3 compared with patients with a low FIB-4 score of less than 1.3, regardless of whether patients with or without preexisting liver disease were analyzed. Moreover, there was no significant increase in the IRR of stroke/TIA between patients with a high or low FIB-4 score, both in the general population and patients with CLD., Conclusion: Our study suggests that the FIB-4 score is not associated with cardiovascular events both in the general population as well as in patients with CLD., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Recently the incidence of nonalcoholic fatty liver disease (NAFLD) has risen to become the most frequent liver disease worldwide. NAFLD is not a disease limited to the liver, but rather represents a systemic inflammatory disease involving multiple organ systems. Previous studies have suggested an association between NAFLD and coeliac disease, another disease related to inflammation. As the available clinical data is scarce and at least partially contradictory, we aimed at investigating a potential association between NAFLD and celiac disease in outpatients in Germany., Methods: Using the Disease Analyzer database featuring data on diagnoses, prescriptions and demographic variables for 7.49 million cases of patients followed in general practices in Germany, we matched a total of 57 336 patients with NAFLD/diagnosed between 2000 and 2015 to a cohort of equal size without NAFLD by age, sex and index year. Incidence of celiac disease was compared between groups within 10 years from the index date., Results: During the 10-years observation period, we observed a higher incidence of coeliac disease in NAFLD patients compared to patients without NAFLD (11.2 vs. 7.5 cases per 100 000 patients' years). Interestingly, this association was most prominent in men (hazard ratio, 2.02; 95% CI, 1.01-4.04) and patients between 18 and 50 years (hazard ratio, 2.79; 95% CI, 1.12-6.94)., Summary: Our data suggest that NAFLD promotes the development of coeliac disease particularly in young men. This finding argues that coeliac disease should be recognized as another nonliver-related complication of NAFLD and suggests screening of selected NAFLD patients for the presence of coeliac disease., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: The aim of this study was to examine the development of drug purchases over the course of the coronavirus crisis in Germany in 2020., Materials and Methods: The evaluations in this retrospective cross-sectional study are based on the IMS RPM (Regional Pharmaceutical Market) weekly database, which shows weekly purchases by public pharmacies from full-service wholesalers at the time the pharmacy purchase is made in Germany. The outcome of this investigation was the development of cardiovascular drug sales by packing unit over all 52 weeks of 2020., Results: We found an increase of 68% in week 12 compared to the average sales for weeks 2 - 11, 2020 (vs. -2% in week 12, 2019), while the increase in week 51 was 61%, compared to the average sales for weeks 13 - 50, 2020 (vs. 35% in week 51, 2019). The largest increases in week 12 were for calcium channel blockers (64%), and the largest increases in week 51 were for lipid-lowering drugs (67%)., Conclusion: The results of this retrospective cross-sectional study suggest that the COVID-19 lockdown in Germany was associated with a significant surge in pharmacy purchases of cardiovascular drugs, indicating panic buying. Although there were no drug shortages during the first lockdown, this panic buying recurred shortly before the second lockdown, albeit to a lesser extent.

The COVID-19 pandemic represents a huge burden on global health systems. Although far-reaching prevention measures such as the increase of intensive care capacities and drastic restrictions of public life have so far been able to avert an overload of the German health care system, the current situation implies an exceptionally high burden on medical professionals. The current study presents the results of an opinion evaluation among 513 pneumology specialists in Germany in the period from March 27 th to April 11 th , 2020. While the majority of respondents stated that Germany was "well" prepared for the pandemic, this assessment was significantly worse among participants from the outpatient sector compared to the hospital sector (p < 0.001). Furthermore, a lack of medical protective equipment was reported significantly more frequently by respondents from the outpatient sector (p < 0.001). The importance of telemedicine approaches during the COVID-19 pandemic was rated "high" (35.2 %) or "very high" (17.2 %) by most pneumology professionals, with participants from the hospital sector giving a higher rating (p < 0.001). Finally, 45.8 % of the respondents expressed a "negative" influence of the COVID-19 pandemic on their personal mood and 58.3 % expressed "strong" or "very strong" concerns about the health of their fellow human beings. This assessment was significantly stronger among female participants and participants from the nursing sector (p < 0.001). In summary, the current study analyses for the first time the professional and personal impact of the COVID-19 pandemic on pneumology professionals in Germany. The results could help to identify first starting points to better support health professionals during the current and future challenges., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht. A. P. ist Geschäftsführer und Gesellschafter der Clinomic GmbH. L. M. und G. M. sind Gesellschafter der Clinomic GmbH., (Thieme. All rights reserved.)

Liver cirrhosis represents the common end-stage of chronic liver diseases regardless of its etiology. Patients with compensated disease are mostly asymptomatic, however, progression to a decompensated disease stage is common. The available stratification strategies are often unsuitable to identify patients with a higher risk for disease progression and a limited prognosis. SIBLINGs, soluble glycophosphoproteins, are secreted into the blood by immune-cells. While osteopontin, the most prominent member of the SIBLINGs family, has been repeatedly associated with liver cirrhosis, data on the diagnostic and/or prognostic value of bone sialoprotein (BSP) are scarce and partly inconclusive. In this study, we analyzed the diagnostic and prognostic potential of circulating BSP in comparison to other standard laboratory markers in a large cohort of patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt (TIPS). Serum levels of BSP were similar in patients with different disease stages and were not indicative for prognosis. Interestingly, BSP serum levels did correlate inversely with portal pressure, as well as its surrogates such as platelet count, the portal vein cross-sectional area and correlated positively with the portal venous velocity. In summary, our data highlight that BSP might represent a previously unrecognized marker for portal hypertension in patients with liver cirrhosis., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Alterations in miR-155 serum levels have been described in inflammatory and infectious diseases. Moreover, a role for miR-155 in aging and age-related diseases was recently suggested. We therefore analyzed a potential age-dependent prognostic value of circulating miR-155 as a serum-based marker in critical illness., Methods: Concentrations of circulating miR-155 were determined in 218 critically ill patients and 76 healthy controls., Results: By using qPCR, we demonstrate that miR-155 serum levels are elevated in patients with critical illness when compared to controls. Notably, levels of circulating miR-155 were independent on the severity of disease, the disease etiology, or the presence of sepsis. In the total cohort, miR-155 was not an indicator for patient survival. Intriguingly, when patients were subdivided according to their age upon admission to the ICU into those younger than 65 years, lower levels of miR-155 turned out as a strong marker, indicating patient mortality with a similar accuracy than other markers frequently used to evaluate critically ill patients on a medical ICU., Conclusion: In summary, the data provided within this study suggest an age-specific role of miR-155 as a prognostic biomarker in patients younger than 65 years. Our study is the first to describe an age-dependent miRNA-based prognostic biomarker in human diseases.

Background & Aims: We performed an integrated analysis to identify microRNAs (miRNAs) and messenger RNAs (mRNAs) with altered expression in liver tumors from 3 mouse models of hepatocellular carcinoma (HCC) and human tumor tissues., Methods: We analyzed miRNA and mRNA expression profiles of liver tissues from mice with diethylnitrosamine-induced hepatocarcinogenesis, conditional expression of lymphotoxin alpha and lymphotoxin beta, or inducible expression of a Myc transgene (Tet-O-Myc mice), as well as male C57BL/6 mice (controls). miRNA mimics were expressed and miRNAs and mRNAs were knocked down in human (Huh7, Hep3B, JHH2) hepatoma cell lines; cells were analyzed for viability, proliferation, apoptosis, migration, and invasion. Cells were grown as xenograft tumors in nude mice and analyzed. We combined in silico target gene prediction with mRNA profiles from all 3 mouse models. We quantified miRNA levels in 146 fresh-frozen tissues from patients (125 HCCs, 17 matched nontumor tissues, and 4 liver samples from patients without cancer) and published human data sets and tested correlations with patient survival times using Kaplan-Meier curves and the log-rank test. Levels of NUSAP1 mRNA were quantified in 237 HCCs and 5 nontumor liver samples using the TaqMan assay., Results: Levels of the miRNA 193a-5p (MIR193A-5p) were reduced in liver tumors from all 3 mouse tumor models and in human HCC samples, compared with nontumor liver tissues. Expression of a MIR193A-5p mimic in hepatoma cells reduced proliferation, survival, migration, and invasion and their growth as xenograft tumors in nude mice. We found nucleolar and spindle-associated protein 1 (NUSAP1) to be a target of MIR193A-5p; HCC cells and tissues with low levels of MIR193A-5p had increased expression of NUSAP1. Increased levels of NUSAP1 in HCC samples correlated with shorter survival times of patients. Knockdown of NUSAP1 in Huh7 cells reduced proliferation, survival, migration, and growth as xenograft tumors in nude mice. Hydrodynamic tail-vein injections of a small hairpin RNA against NUSAP1 reduced growth of Akt1-Myc-induced tumors in mice., Conclusions: MIR193A-5p appears to prevent liver tumorigenesis by reducing levels of NUSAP1. Levels of MIR193A-5p are reduced in mouse and human HCC cells and tissues, leading to increased levels of NUSAP1, associated with shorter survival times of patients. Integrated analyses of miRNAs and mRNAs in tumors from mouse models can lead to identification of therapeutic targets in humans. The currently reported miRNA and mRNA profiling data have been submitted to the Gene Expression Omnibus (super-series accession number GSE102418)., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Angiogenesis is critically involved in the development of liver fibrosis, portal hypertension (PHT) and hepatocellular carcinoma (HCC). Regorafenib is a novel second-line therapy for HCC, but might also be beneficial in fibrosis and PHT even in absence of HCC. This study investigated the effects of regorafenib in experimental models without HCC., Methods: Fibrosis ( in vivo and in vitro ), inflammation, liver damage (aminotransferases), angiogenesis (matrigel implantation) and in vivo systemic and portal hemodynamics were assessed in different mouse and rat models (bile duct ligation, CCl 4 , partial portal vein ligation) after acute and chronic treatment with regorafenib., Results: Long-term treatment with regorafenib improved portal hypertension most likely due to blunted angiogenesis, without affecting fibrosis progression or regression. Interestingly, acute administration of regorafenib also ameliorated portal hemodynamics. Although regorafenib treatment led to hepatotoxic side effects in long-term treated fibrotic animals, in partial portal vein ligated rats, no liver toxicity due to regorafenib was observed., Discussion: Regorafenib might be especially suitable as therapy in patients with PHT and preserved liver function., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest.

Bone sialoprotein (BSP), a member of the SIBLINGs (for Small Integrin-Binding LIgand, N-linked Glycoproteins) family, has recently be associated to inflammatory and infectious diseases. We therefore measured BSP concentrations in 136 patients at admission to the intensive care unit (ICU) and 3 days of ICU. BSP levels were compared to 36 healthy blood donors and correlated to clinical data. In these analysis, BSP serum levels were strongly elevated at the time point of admission to the ICU when compared to healthy controls. Moreover BSP concentrations were significantly elevated after 3 days of treatment on the intensive care unit. A further increase in BSP levels was detected in patients with higher APACHE-II-scores and in patients with septic disease. While in most patients, BSP levels decreased during the first three days of treatment on a medical ICU, patients with persistently elevated BSP levels displayed an unfavorable outcome. In these patients, persistently elevated BSP concentrations were a superior predictor of mortality than established indicators of patient´ prognosis such as the SAPS2 or the APACHE-II score. In summary, our data argue for a novel utility for BSP as a biomarker in patients treated on a medical ICU.

miR-192-5p has gained increasing relevance in various diseases, however, its function in acute liver injury is currently unknown. We analysed miR-192-5p serum levels and hepatic miR-192-5p expression in mice after hepatic ischaemia and reperfusion (I/R) as well as in toxic liver injury. On a functional level, miRNA levels were analysed in the different hepatic cell-compartments and in the context of tumour necrosis factor (TNF)-dependent liver cell death. We detected increased serum levels of miR-192-5p after hepatic I/R- and carbon tetrachloride (CCl4)-induced liver injury. miR-192-5p levels correlated with the degree of liver damage and the presence of hepatic cell death detected by TUNEL stainings (terminal deoxynucleotidyltransferase-mediated dUTP biotin nick-end labelling stainings). Moreover, expression of miR-192-5p was increased in a hypoxia/reoxygenation (H/R) model of in vitro hepatocyte injury, supporting that the passive release of miR-192-5p represents a surrogate for hepatocyte death in liver injury. In critically ill patients, miR-192-5p levels were elevated selectively in patients with liver injury and closely correlated with the presence of hepatic injury. In contrast with up-regulated miR-192-5p in the serum, we detected a down-regulation of miR-192-5p in both injured mouse and human livers. Deregulation of miR-192-5p in livers was dependent on stimulation with TNF. Functional experiments confirmed a protective effect of down-regulation of miR-192-5p in hepatocytes, suggesting a role of miR-192-5p in limiting liver injury. Finally, we identified Zeb2, an important regulator of cell death, as a potential target gene mediating the function of miR-192-5p Our data suggest that miR-192-5p is involved in the regulation of liver cell death during acute liver injury and might represent a potent marker of hepatic injury., (© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.)

Introduction. Omentin, a recently described adipokine, was shown to be involved in the pathophysiology of inflammatory and infectious diseases. However, its role in critical illness and sepsis is currently unknown. Materials and Methods. Omentin serum concentrations were measured in 117 ICU-patients (84 with septic and 33 with nonseptic disease etiology) admitted to the medical ICU. Results were compared with 50 healthy controls. Results. Omentin serum levels of critically ill patients at admission to the ICU or after 72 hours of ICU treatment were similar compared to healthy controls. Moreover, circulating omentin levels were independent of sepsis and etiology of critical illness. Notably, serum concentrations of omentin could not be linked to concentrations of inflammatory cytokines or routinely used sepsis markers. While serum levels of omentin were not predictive for short term survival during ICU treatment, low omentin concentrations were an independent predictor of patients' overall survival. Omentin levels strongly correlated with that of other adipokines (e.g., leptin receptor or adiponectin), which have also been identified as prognostic markers in critical illness. Conclusions. Although circulating omentin levels did not differ between ICU-patients and controls, elevated omentin levels were predictive for an impaired patients' long term survival.