Hepatic and cardiac hemodynamics and systemic inflammation in cirrhosis: It takes three to tango

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Response to letter: Multiparametric magnetic resonance imaging in patients with nonalcoholic fatty liver disease

Cardiovascular Aspects of Radiolog

Definition, diagnosis and epidemiology of acute-on-chronic liver failure

This narrative review addresses the definition of acute-on-chronic liver failure, a condition associated with high short-term mortality in patients with chronic liver disease and/or cirrhosis. We provide two major points of view: the East and the West perspective. Both definitions vary regarding the underlying patient population and organ failure(s) definition. Nevertheless, all the definitions have their clinical utility: from the core concept of having the "liver" as a conditio sine qua non, the syndrome cannot exist (Asian Pacific Association for the Study of the Liver); a data-driven, robust definition (European Association for the Study of the Liver); a bedside tool that can quickly identify patients at high risk of dying (North American Consortium for the Study of End-stage Liver Disease [NACSELD]). In each section, we provide the overall definitions, the criteria of organ failure(s), and some epidemiological data illustrating how these apply in each area of the world.Horizon 2020 (H2020)825694 and 945096Cellular mechanisms in basic and clinical gastroenterology and hepatolog

In Reply: Neoadjuvant TKI Study in Early- and Intermediate Stage Hepatocellular Carcinoma

This letter to the editor responds to comments from Rizzo et al on recently reported results of a phase II study of dovitinib therapy for hepatocellular carcinoma.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Oncofetal Protein CRIPTO Is Involved in Wound Healing and Fibrogenesis in the Regenerating Liver and Is Associated with the Initial Stages of Cardiac Fibrosis

Oncofetal protein, CRIPTO, is silenced during homeostatic postnatal life and often re-expressed in different neoplastic processes, such as hepatocellular carcinoma. Given the reactivation of CRIPTO in pathological conditions reported in various adult tissues, the aim of this study was to explore whether CRIPTO is expressed during liver fibrogenesis and whether this is related to the disease severity and pathogenesis of fibrogenesis. Furthermore, we aimed to identify the impact of CRIPTO expression on fibrogenesis in organs with high versus low regenerative capacity, represented by murine liver fibrogenesis and adult murine heart fibrogenesis. Circulating CRIPTO levels were measured in plasma samples of patients with cirrhosis registered at the waitlist for liver transplantation (LT) and 1 year after LT. The expression of CRIPTO and fibrotic markers (alpha SMA, collagen type I) was determined in human liver tissues of patients with cirrhosis (on a basis of viral hepatitis or alcoholic disease), in cardiac tissue samples of patients with end-stage heart failure, and in mice with experimental liver and heart fibrosis using immuno-histochemical stainings and qPCR. Mouse models with experimental chronic liver fibrosis, induced with multiple shots of carbon tetrachloride (CCl4) and acute liver fibrosis (one shot of CCl4), were evaluated for CRIPTO expression and fibrotic markers. CRIPTO was overexpressed in vivo (Adenoviral delivery) or functionally sequestered by ALK4Fc ligand trap in the acute liver fibrosis mouse model. Murine heart tissues were evaluated for CRIPTO and fibrotic markers in three models of heart injury following myocardial infarction, pressure overload, and ex vivo induced fibrosis. Patients with end-stage liver cirrhosis showed elevated CRIPTO levels in plasma, which decreased 1 year after LT. Cripto expression was observed in fibrotic tissues of patients with end-stage liver cirrhosis and in patients with heart failure. The expression of CRIPTO in the liver was found specifically in the hepatocytes and was positively correlated with the Model for End-stage Liver Disease (MELD) score for end-stage liver disease. CRIPTO expression in the samples of cardiac fibrosis was limited and mostly observed in the interstitial cells. In the chronic and acute mouse models of liver fibrosis, CRIPTO-positive cells were observed in damaged liver areas around the central vein, which preceded the expression of alpha SMA-positive stellate cells, i.e., mediators of fibrosis. In the chronic mouse models, the fibrosis and CRIPTO expression were still present after 11 weeks, whereas in the acute model the liver regenerated and the fibrosis and CRIPTO expression resolved. In vivo overexpression of CRIPTO in this model led to an increase in fibrotic markers, while blockage of CRIPTO secreted function inhibited the extent of fibrotic areas and marker expression (alpha SMA, Collagen type I and III) and induced higher proliferation of residual healthy hepatocytes. CRIPTO expression was also upregulated in several mouse models of cardiac fibrosis. During myocardial infarction CRIPTO is upregulated initially in cardiac interstitial cells, followed by expression in alpha SMA-positive myofibroblasts throughout the infarct area. After the scar formation, CRIPTO expression decreased concomitantly with the alpha SMA expression. Temporal expression of CRIPTO in alpha SMA-positive myofibroblasts was also observed surrounding the coronary arteries in the pressure overload model of cardiac fibrosis.Furthermore, CRIPTO expression was upregulated in interstitial myofibroblasts in hearts cultured in an ex vivo model for cardiac fibrosis. Our results are indicative for a functional role of CRIPTO in the induction of fibrogenesis as well as a potential target in the antifibrotic treatments and stimulation of tissue regeneration.Therapeutic cell differentiatio

Development and validation of a dynamic survival prediction model for patients with acute-on-chronic liver failure

Background & aims: Acute-on-chronic liver failure (ACLF) is usually associated with a precipitating event and results in the failure of other organ systems and high short-term mortality. Current prediction models fail to adequately estimate prognosis and need for liver transplantation (LT) in ACLF. This study develops and validates a dynamic prediction model for patients with ACLF that uses both longitudinal and survival data.Methods: Adult patients on the UNOS waitlist for LT between 11.01.2016-31.12.2019 were included. Repeated model for end-stage liver disease-sodium (MELD-Na) measurements were jointly modelled with Cox survival analysis to develop the ACLF joint model (ACLF-JM). Model validation was carried out using separate testing data with area under curve (AUC) and prediction errors. An online ACLF-JM tool was created for clinical application.Results: In total, 30,533 patients were included. ACLF grade 1 to 3 was present in 16.4%, 10.4% and 6.2% of patients, respectively. The ACLF-JM predicted survival significantly (p <0.001) better than the MELD-Na score, both at baseline and during follow-up. For 28- and 90-day predictions, ACLF-JM AUCs ranged between 0.840-0.871 and 0.833-875, respectively. Compared to MELD-Na, AUCs and prediction errors were improved by 23.1%-62.0% and 5%-37.6% respectively. Also, the ACLF-JM could have prioritized patients with relatively low MELD-Na scores but with a 4-fold higher rate of waiting list mortality.Conclusions: The ACLF-JM dynamically predicts outcome based on current and past disease severity. Prediction performance is excellent over time, even in patients with ACLF-3. Therefore, the ACLF-JM could be used as a clinical tool in the evaluation of prognosis and treatment in patients with ACLF.Lay summary: Acute-on-chronic liver failure (ACLF) progresses rapidly and often leads to death. Liver transplantation is used as a treatment and the sickest patients are treated first. In this study, we develop a model that predicts survival in ACLF and we show that the newly developed model performs better than the currently used model for ranking patients on the liver transplant waiting list. (C) 2021 The Author(s). Published by Elsevier B.V.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Hemodynamic response to primary prophylactic therapy with nonselective beta-blockers is related to a reduction of first variceal bleeding risk in liver cirrhosis: a meta-analysis

Development and application of statistical models for medical scientific researc

Copeptin is an independent prognostic factor for transplant-free survival in cirrhosis

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Neoadjuvant treatment with angiogenesis-inhibitor dovitinib prior to local therapy in hepatocellular carcinoma: a phase II study

Background Hepatocellular carcinoma (HCC) recurrence rates following locoregional treatment are high. As multireceptor tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFRs) are effective in advanced HCC, we assessed the efficacy and safety of neoadjuvant systemic treatment with dovitinib in early- and intermediate-stage HCC. Materials and Methods Twenty-four patients with modified Child-Pugh class A early- and intermediate-stage HCC received neoadjuvant oral dovitinib 500 mg daily (5 days on/2 days off) for 4 weeks, followed by locoregional therapy. Primary endpoints were objective response rates and intratumoral blood flow changes. Secondary endpoints were safety, pharmacodynamical plasma markers of VEGFR-blockade, time to progression (TTP), and overall survival (OS). Results Modified RECIST overall response rate was 48%, including 13% complete remission, and despite dose reduction/interruption in 83% of patients, intratumoral perfusion index decreased significantly. Grade 3-4 adverse events, most frequently (on-target) hypertension (54%), fatigue (25%), and thrombocytopenia (21%), occurred in 88% of patients. Plasma VEGF-A, VEGF-D, and placental growth factor increased significantly, whereas sTie-2 decreased, consistent with VEGFR-blockade. Following neoadjuvant dovitinib, all patients could proceed to their original planned locoregional treatment. No delayed toxicity occurred. Seven patients (three early, four intermediate stage) underwent orthotopic liver transplant after median 11.4 months. Censoring at transplantation, median TTP and OS were 16.8 and 34.8 months respectively; median cancer-specific survival was not reached. Conclusion Already after a short 4-week dovitinib treatment period, intratumoral blood flow reduction and modest antitumor responses were observed. Although these results support use of systemic neoadjuvant strategies, the poor tolerability indicates that dovitinib dose adaptations are required in HCC. Implications for Practice Orthotopic liver transplantation may cure early and intermediate-stage hepatocellular carcinoma. Considering the expected waiting time >6 months because of donor liver scarcity, there is an unmet need for effective neoadjuvant downsizing strategies. Angiogenesis inhibition by dovitinib does not negatively affect subsequent invasive procedures, is safe to administer immediately before locoregional therapy, and may provide a novel treatment approach to improve patient outcomes if tolerability in patients with hepatocellular carcinoma can be improved by therapeutic drug monitoring and personalized dosing.MTG4Molecular tumour pathology - and tumour genetic

Thermal ablation combined with transarterial chemoembolization for hepatocellular carcinoma: what is the right treatment sequence?

Background: The combination treatment regimen of thermal ablation (TA) and transarterial chemoembolization (TACE) has gained a place in treatment of hepatocellular carcinoma (HCC) lesions > 3 cm unsuitable for surgery. Despite a high heterogeneity in the currently used treatment protocols, the pooled results of combined treatments seem to outperform those of TA or TACE alone. TACE preceding TA has been studied extensively, while results of the reverse treatment sequence are lacking. In this retrospective cohort study we compared the two treatment sequences. Patients and methods: 38 patients (median age: 68.5 yrs (range 40-84), male: 34, liver cirrhosis: 33, early stage HCC: 21, intermediate stage HCC: 17) were included in two tertiary referral centers, of whom 27 were treated with TA and adjuvant TACE (TA + TACE). The other 11 patients received TA with neoadjuvant TACE (TACE + TA). Overall survival (OS), time to progression (TTP) and local tumor progression (LTP) free survival were determined for the entire cohort and compared between the two treatment sequences. Results: The median OS of all patients was 52.7 months and the median time to LTP was 11.5 months (censored for liver transplantation). No differences were found with respect to OS between the two treatment sequences. Median time to LTP for TACE + TA was 23.6 months and 8.1 months for TA + TACE (p = 0.19). Discussion: No statistical differences were found for OS, TTP and time to LTP between patients treated with TA combined with neoadjuvant or adjuvant TACE.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas