Transarterial chemoembolization versus sorafenib in patients with hepatocellular carcinoma and extrahepatic disease

BackgroundSorafenib is the recommended treatment for advanced hepatocellular carcinoma (HCC), but transarterial chemoembolization (TACE) is performed in individual cases with limited extrahepatic spread. The aim of this study was to compare the outcome of patients with HCC and extrahepatic disease (EHD) treated with sorafenib and TACE.MethodsA total of 172 patients with HCC and EHD treated with sorafenib (n = 98) or TACE (n = 74) at three German referral centers (Hannover, Mainz and Hamburg) were included in this study. In order to reduce selection bias, patients were matched for significant demographic differences using a propensity score analysis.ResultsPatients with liver cirrhosis, high…

Validation of the simplified Animal Naming Test as primary screening tool for the diagnosis of covert hepatic encephalopathy

Diagnosis of covert hepatic encephalopathy (CHE) is time consuming in clinical practice. Recently, a new diagnostic tool - the simplified Animal Naming Test (S-ANT1) - was presented with promising results in an Italian cohort. The aim of the present study was to validate S-ANT1 in a cohort of cirrhotic patients from a German tertiary referral centre.143 cirrhotic patients and 37 healthy controls were enrolled. Hepatic encephalopathy (HE) grade 1 (HE1) was clinically diagnosed according to the West-Haven Criteria. Critical flicker frequency and Psychometric Hepatic Encephalopathy Score were used to detect minimal HE (MHE). All participants were additionally examined by S-ANT1.58 (40.6%) pati…

Predictors of advanced fibrosis in non-cirrhotic non-alcoholic fatty liver disease in Germany

BACKGROUND Advanced fibrosis has been established as the most important predictor of overall mortality in patients with non-alcoholic fatty liver disease (NAFLD). In contrast to cirrhosis, advanced, non-cirrhotic NAFLD is difficult to identify and data from Germany are lacking. AIM To identify clinical factors associated with advanced, non-cirrhotic fibrosis. METHODS Patients were recruited in the prospectively enrolling European NAFLD Registry. Clinical characteristics and the performance of non-invasive surrogate scores compared with vibration-controlled transient elastography are reported. RESULTS Two hundred and sixty-one patients with non-cirrhotic NAFLD on liver biopsy (mean age 51 ye…

Guidelines are silver, but a multidisciplinary team discussion may be golden?

Drug Treatment for Chronic Hepatitis C Infection and Cancer Risk

BACKGROUND In patients with chronic hepatitis C infection, a sustained virologic response (SVR) to interferon-based therapy markedly decreases the incidence of hepatocellular carcinoma (HCC) over the long term. This is also true for patients who have hepatic cirrhosis, as well as for those with HCC-with or without cirrhosis-who have undergone resection or ablation with curative intent. Recent publications, however, have reported a higher incidence of HCC among patients in both of these subgroups who were treated with direct antiviral agents (DAA) rather than interferon-based therapy. METHODS A selective search for pertinent literature was carried out in the PubMed database with the search t…

Use of inhibitors of the renin-angiotensin system is associated with longer survival in patients with hepatocellular carcinoma.

Inhibition of the renin-angiotensin system (RAS) was associated with longer survival in patients with different solid malignancies.The objective of this study was to investigate the effect of RAS inhibitor (RASi) treatment (angiotensin-converting enzyme inhibitors or angiotensin-II-receptor blockers) on survival of patients with hepatocellular carcinoma (HCC).Patients diagnosed with HCC and Child-Pugh A between 1992 and 2013 who received sorafenib, experimental therapy, or best supportive care were eligible for the Vienna cohort. The Mainz cohort included patients with HCC and Child-Pugh A who received sorafenib treatment between 2007 and 2016. The association between RASi and overall survi…

Navigating the new landscape of second‐line treatment in advanced hepatocellular carcinoma

Abstract Sorafenib and lenvatinib are approved for first‐line treatment of patients with advanced hepatocellular carcinoma (HCC), and the efficacy of atezolizumab plus bevacizumab has been demonstrated versus sorafenib. Over time, first‐line treatment frequently fails, and regorafenib, cabozantinib, ramucirumab (for patients with alpha fetoprotein ≥400 ng/mL), nivolumab, pembrolizumab and ipilimumab plus nivolumab are approved for use after sorafenib (but not lenvatinib) treatment in advanced HCC. Given the considerable complexity in the therapeutic landscape, the objective of this review was to summarize the clinical evidence for second‐line agents and provide practical guidance for select…

Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre

BACKGROUND: The recurrence of hepatocellular carcinoma (HCC) is the strongest survival-limiting factor after liver transplantation (LT) in patients with HCC. In the face of donor organ shortage, it is necessary to identify factors associated with HCC recurrence in order to maximize the utility of the available grafts. OBJECTIVE: To study the phenomenon of HCC recurrence after LT at a European transplantation centre over the past 20 years. METHODS: Data from 304 HCC patients who underwent LT were prospectively recorded. Clinical and pathological factors were assessed for their association with recurrence. RESULTS: Fifty-one patients (16.8%) had HCC recurrence after LT. Patients exceeding the…

Impact of non-selective ß-blockers on hepatic encephalopathy in patients with liver cirrhosis

Non-selective β-blockers (NSBB) are frequently used for the treatment of portal hypertension and gastroesophageal varices in patients with liver cirrhosis; however prospective studies investigating the potential association between NSBB use and hepatic encephalopathy (HE) are still scarce. We investigated the potential association between NSBB use and the presence of covert HE (CHE) as well as the development of overt HE (OHE).224 patients with liver cirrhosis were included into this cohort study at two German centers and followed for a median of 364 days. CHE was diagnosed by pathological results in the PHES. Predictors for the presence of CHE or the development of OHE were analyzed using …

The Addition of Transarterial Chemoembolization to Palliative Chemotherapy Extends Survival in Intrahepatic Cholangiocarcinoma

Incidence and mortality of intrahepatic cholangiocarcinoma (iCCA) have been increasing continuously. Recent studies suggest that the combination of palliative chemotherapy (pCTX) and transarterial chemoembolization (TACE) improves overall survival (OS). This study aimed to evaluate the outcome of patients treated with TACE and pCTX in unresectable iCCA at our tertiary care center. A group of 14 patients was treated with both pCTX and TACE. The non-randomized control group of 59 patients received pCTX alone. Patients received a median of two pCTX lines in both groups. Those treated with TACE underwent a median number of 3.5 sessions. Median OS from the time of unresectability was 26.2 months…

A young patient with type 2 diabetes associated non-alcoholic steatohepatitis, liver cirrhosis, and hepatocellular carcinoma.

The rising prevalence of the metabolic syndrome has led to an increase of non-alcoholic fatty liver disease (NAFLD), and its progressive-inflammatory form called non-alcoholic steatohepatitis (NASH). In recent years, NAFLD and NASH have become major risk factors for developing liver cirrhosis and hepatocellular carcinoma (HCC). In this case, we report a 46-year-old patient with type 2 diabetes mellitus and metabolic comorbidities including obesity and arterial hypertension, who was referred because of rising liver enzymes. After clinical and diagnostic evaluation, the patient was diagnosed with NASH-associated liver cirrhosis, Child-Pugh stage B. A normal blood sugar level was difficult to …

Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation

Regorafenib is one option for second-line treatment of hepatocellular carcinoma (HCC), improving overall survival (OS) of sorafenib-tolerant patients who develop progression. We aim to evaluate the safety and outcomes of regorafenib as second-line treatment for HCC recurrence after liver transplantation (LT). This is a retrospective, multicenter, international study including regorafenib-treated LT patients (2015-2018), with analysis of baseline characteristics and evolutionary events during sorafenib/regorafenib treatment. Twenty-eight LT patients (57 years, 7% cirrhotics, 54% performance status 1) were included. Median time from LT to regorafenib initiation was 3.9 (1.1-18.5) years; media…

Raised serum Interleukin-6 identifies patients with liver cirrhosis at high risk for overt hepatic encephalopathy

BACKGROUND Systemic inflammation is a driving force for the development of hepatic encephalopathy and recent studies demonstrated that elevated Interleukin-6 (IL-6) serum levels are associated with the presence of minimal hepatic encephalopathy in patients with liver cirrhosis. AIM To test the hypothesis that IL-6 is a suitable marker to identify patients with liver cirrhosis at high risk for the development of overt hepatic encephalopathy. METHODS 201 patients were included into this prospective cohort study and were followed for a mean time of 322 days. Covert hepatic encephalopathy was diagnosed according to the West-Haven criteria (hepatic encephalopathy grade 1) and with the portosyste…

Association between diabetes mellitus and hepatic encephalopathy in patients with cirrhosis

Background Diabetes mellitus may lead to increased serum ammonia and systemic inflammation thereby promoting hepatic encephalopathy (HE). Aim To investigate the potential association between diabetes mellitus/glycaemic control and the presence of covert HE as well as the development of overt HE in a prospective setting. Methods A total of 240 patients with liver cirrhosis were included into this prospective cohort study and followed for a median of 17 months. Covert HE was diagnosed by pathological results in the Portosystemic Hepatic Encephalopathy Score. Predictors for the presence of covert HE or the development of overt HE were analysed using logistic regression or Cox-regression models…

Epidemiology of hepatic encephalopathy in german hospitals – the EpHE study

Abstract Background Hepatic encephalopathy (HE) is a serious complication of liver cirrhosis. The proportion of patients with liver cirrhosis attending German hospitals suffering from HE is unknown. Methods In the first part of the study, data of 14 community hospitals and 5 university hospitals covering the years 2010 and 2011 were analyzed retrospectively for the DRG codes of liver cirrhosis and hepatic encephalopathy. In the second prospective part of the multicenter observational study, all patients with liver cirrhosis attending the departments of gastroenterology of 16 participating community hospitals within a study period of 3 months were included and screened for HE clinically acco…

Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.

Abstract Background Recurrence of hepatocellular carcinoma after orthotopic liver transplantation not amenable to surgical approaches is associated with poor outcome. Aims Retrospective evaluation of the safety and efficacy of sorafenib in patients with post-transplant hepatocellular carcinoma recurrence. Methods Patients with post-transplant hepatocellular carcinoma recurrence were treated with sorafenib. Adverse events were assessed using National Cancer Institute Common Toxicity Criteria of AEs version 3.0, tumour response was evaluated according to Response Evaluation Criteria in Solid Tumours. Results First-line therapy after recurrence was surgery ( n  = 6), radiation therapy ( n  = 1…

Clinicopathologic features and prognosis of young patients with hepatocellular carcinoma in a large German cohort.

GOALS AND BACKGROUND Hepatocellular carcinoma in non-hepatitis B virus endemic areas is rare in patients younger than 40 years of age. The aim of this study was to characterize young patients in a large German cohort in comparison with older patients with regard to underlying liver disease, clinical management, and survival. STUDY We analyzed the clinical data and medical records of 1108 consecutive patients with confirmed hepatocellular carcinoma. Twenty-five patients (2%) were younger than 40 years of age. We compared this subgroup with patients older than 40 years of age. RESULTS Underlying chronic liver disease was less common in young patients and detectable in only 56% of patients. Fi…

Patient prioritisation in HCC treatment: All (good) things come in threes.

Reply to: “Response to ‘the flexible therapeutic approach to the BCLC B stage’: Time for scoring systems?”

Health-related quality of life in patients with compensated and decompensated liver cirrhosis.

Compensated (Child-Pugh [CP] A) and decompensated (CP B/C) liver cirrhosis significantly differs in terms of impairment of health-related quality of life (HRQoL). However, sufficient data on potentially treatable factors associated with HRQoL in both stages of the disease are still lacking. Consequently, aims of this study were to determine differences in HRQoL between patients with compensated and decompensated liver cirrhosis and to identify potentially treatable factors associated with HRQoL.218 patients with liver cirrhosis were enrolled into this study. Chronic Liver Disease Questionnaire (CLDQ) was used to assess HRQoL. Covert hepatic encephalopathy (CHE) was diagnosed according to a …

Prescription rates of common medications in patients with decompensated cirrhosis in Germany

Adequate pharmacological treatment is of pivotal importance to improve prognosis in patients with decompensated liver cirrhosis. We studied the adherence to recommended pharmacological treatments as secondary prevention in cirrhotic patients following a first decompensation in German primary care.Using the Disease Analyzer Database, the current study sample included patients with liver cirrhosis who had an initial diagnosis of a first decompensation event between 2015 and 2018 (index date) and a follow-up time of at least 6 months after the index date. Pharmacological treatments following the 6 months after the index date were studied.The study included 1538 patients with a first decompensa…

Association Between Serum Levels of Neurofilament Light Chains and Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis.

INTRODUCTION: Serum biomarkers for the diagnosis of minimal hepatic encephalopathy (MHE) in patients with liver cirrhosis would be desirable. In this proof-of-concept study, we investigated the association between MHE and serum levels of neurofilament light chains (sNfL) in patients with liver cirrhosis. METHODS: sNfL were studied in patients with liver cirrhosis (with or without MHE) and controls (patients with ischemic stroke, transitory ischemic attack, and healthy individuals). MHE was diagnosed using the Psychometric Hepatic Encephalopathy Score. RESULTS: Patients with MHE showed higher sNfL than patients without MHE and controls. In multivariable analyses, higher sNfL were independent…

Liver injury in patients with severe acute respiratory syndrome coronavirus-2 infection: a systematic review and meta-analysis.

OBJECTIVE: Coronavirus disease-19 (COVID-19) infection is a global health threat. To inform the liver community on the potential relevance of COVID-19, we performed a systematic review and meta-analysis of published data on liver injury in patients with COVID-19 infection. METHODS: We searched PubMed and Google Scholar through 22 March according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled data were analyzed by using random-effects meta-analyses. RESULTS: A total of 14 studies combining data from 2.871 patients were identified. The prevalence of pre-existing liver disease was reported at 3.1%. The pooled prevalence of elevated aspartate aminot…

Impact of Individual Components of the Metabolic Syndrome on the Outcome of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib

<b><i>Background/Aim:</i></b> Individual components of the metabolic syndrome (MS) such as obesity or diabetes mellitus impair the prognosis of patients with hepatocellular carcinoma (HCC) following curative treatment approaches or transarterial therapies. The aim of this retrospective study was to assess the impact of these factors on the overall survival (OS) of patients with advanced HCC treated with sorafenib. <b><i>Methods:</i></b> Univariate and multivariate analyses were performed to assess the impact of individual components of the MS on the OS of 152 consecutive patients with advanced HCC treated with sorafenib. <b><i>Resu…

Development and Validation of a Prognostic Score to Predict Covert Hepatic Encephalopathy in Patients With Cirrhosis.

Diagnosis of covert hepatic encephalopathy (CHE) is challenging and often neglected in clinical practice. The aim of this study was to develop an easy-to-perform score to predict CHE in patients with cirrhosis.For the development or validation cohort of the proposed clinical CHE score, 142 or 96 consecutive patients with cirrhosis were prospectively enrolled. The Psychometric Hepatic Encephalopathy Score was used to detect minimal hepatic encephalopathy. All patients were examined with the simplified animal naming test and were asked to complete the Chronic Liver Disease Questionnaire. We followed the TRIPOD guideline for development, validation, and reporting of the proposed score.The clin…

How COVID-19 kick-started online learning in medical education-The DigiMed study.

Background The coronavirus disease 2019 (COVID-19) pandemic led to far-reaching restrictions of social and professional life, affecting societies all over the world. To contain the virus, medical schools had to restructure their curriculum by switching to online learning. However, only few medical schools had implemented such novel learning concepts. We aimed to evaluate students’ attitudes to online learning to provide a broad scientific basis to guide future development of medical education. Methods Overall, 3286 medical students from 12 different countries participated in this cross-sectional, web-based study investigating various aspects of online learning in medical education. On a 7-…

Management of hepatic encephalopathy in Germany: a survey among physicians

 Hepatic encephalopathy (HE) is a severe complication of liver cirrhosis with impairment of quality of life and prognosis. Management patterns among physicians have not been investigated yet. A questionnaire containing 17 questions was sent out to 1468 gastroenterologists and 120 general practitioners (GPs). It included questions regarding diagnostic, therapeutic, and management strategies used in patients with overt HE (OHE) and covert HE (CHE). The response rate was 12 % (n = 172) for gastroenterologists and 45 % (n = 54) for GPs. Of gastroenterologists, 26.7 % examine patients with an initial diagnosis of liver cirrhosis regarding HE. Gastroenterologists favored a combination of differen…

Proton pump inhibitors increase risk of bone fractures in men with cirrhosis: a population-based study

Bone fractures are a frequent complication in patients with cirrhosis. Proton pump inhibitors (PPIs) are among the most frequently prescribed medications and may impair bone quality and quantity.To investigate whether PPI use predisposes patients with cirrhosis to bone fractures.We performed a population-based case-control study exploring a sample of patients with cirrhosis derived from the Disease Analyzer database. In total, 1795 cirrhotic patients with fractures were compared to 10 235 cirrhotic patients without fractures. PPI use overall and the cumulative PPI dose 5 years prior to the index date were analysed. To estimate the association between PPI use and fractures, logistic regressi…

Letter: diabetes mellitus increases the risk of hepatic encephalopathy in patients with cirrhosis-authors’ reply

Validation of the Clinical Frailty Scale for the Prediction of Mortality in Patients With Liver Cirrhosis

Introduction Frailty is a common but often underestimated complication in patients with liver cirrhosis. The Clinical Frailty Scale (CFS) allows the assessment of frailty within a short period of time but has only been investigated in a Canadian cohort of outpatients. The aim of the current study was to evaluate the ability of the CFS to predict mortality in outpatients and nonelectively hospitalized German patients. Methods Two hundred outpatients and 99 nonelectively hospitalized patients with liver cirrhosis were prospectively enrolled. Outpatients/inpatients were followed for a median of 364/28 days regarding the primary outcome of death or liver transplantation. Eighty-seven patients o…

Hepatitis C virus: Current steps toward elimination in Germany and barriers to reaching the 2030 goal

Abstract Hepatitis C virus (HCV) affects over 70 million people globally, with an estimated 399 000 HCV‐related deaths in 2016. The World Health Organization (WHO) has set a goal to eliminate HCV by 2030. Despite the availability of direct‐acting antivirals—highly effective and well‐tolerated therapies for HCV—many patients infected with HCV in Germany have not initiated treatment, including a majority of those who are aware of their positive diagnosis. Barriers to screening, diagnosis, and treatment are major factors taking many countries off track for HCV elimination by 2030. Identifying country‐specific barriers and challenges, particularly in at‐risk populations such as people who injec…

Supplemental material for Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre

Supplemental Material for Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre by Friedrich Foerster, Maria Hoppe-Lotichius, Johanna Vollmar, Jens U Marquardt, Arndt Weinmann, Marcus-Alexander Wörns, Gerd Otto, Tim Zimmermann and Peter R Galle in United European Gastroenterology Journal

Systemic therapy and synergies by combination.

After years of therapeutic nihilism due to the inefficacy of conventional cytotoxic chemotherapy, the multikinase inhibitor sorafenib was the first agent to demonstrate a significant improvement in the survival of patients with advanced hepatocellular carcinoma (HCC). However, survival benefits on sorafenib treatment remain modest in clinical practice and developing more effective systemic therapies is challenging. No other targeted agent or regimen has proven efficacy to improve survival in a phase III trial in the first- or second-line setting, and no standard treatment option currently exists outside of clinical trials for patients with acquired resistance or intolerance to sorafenib. In…

Outcome Prediction of Covert Hepatic Encephalopathy in Liver Cirrhosis: Comparison of Four Testing Strategies

INTRODUCTION: Despite the negative impact of covert hepatic encephalopathy on the outcome of patients with liver cirrhosis, data regarding the ability of different testing strategies to predict overt hepatic encephalopathy (OHE) development and mortality are limited. This study aimed to compare the ability of Psychometric Hepatic Encephalopathy Score (PHES), critical flicker frequency (CFF), simplified animal naming test (S-ANT1), and clinical covert hepatic encephalopathy (CCHE) score to predict OHE development and mortality. METHODS: A total of 224 patients with liver cirrhosis were tested with different testing strategies and prospectively followed up regarding clinically relevant outcom…

Clinical Frailty Scale for Risk Stratification in Patients with Sars-Cov-2 Infection

Predictive factors for adverse outcomes in patients with COVID-19 are urgently needed. Data related to the applicability of the Clinical Frailty Scale (CFS) for risk stratification in patients with COVID-19 are currently lacking. We investigated the ability of CFS to predict need for mechanical ventilation and the duration of hospital stays in European patients with COVID-19. In total, 42 patients with confirmed COVID-19 infection admitted to the University Medical Center Mainz between March 3 and April 15 2020 were included into this validation study and data were retrospectively analyzed. CFS was assessed at admission in all patients. Patients were followed for need for mechanical ventil…

Clinical Predictors for Poor Quality of Life in Patients With Covert Hepatic Encephalopathy.

Background Current EASL/AASLD guidelines recommend treatment of covert hepatic encephalopathy (HE) only in symptomatic patients, for example, in those with impaired quality of life or with affected driving abilities. Goals Because testing for impaired quality of life is time consuming, the aim of the present study was to identify simple clinical predictors for poor quality of life in patients with covert HE (CHE). Study In total, 139 cirrhotic in- and outpatients without a history of overt hepatic encephalopathy were enrolled. Diagnosis of HE grade 1 (HE1) was diagnosed clinically according to the West-Haven Criteria. Critical flicker frequency and the Psychometric Hepatic Encephalopathy Sc…

Two large steps forward, one small step back

In 2017, the FDA approved regorafenib and nivolumab for the treatment of patients with hepatocellular carcinoma following prior sorafenib treatment, opening the door for an effective systemic second-line therapy in advanced disease. By contrast, the addition of sorafenib to transarterial chemoembolization with drug-eluting beads did not improve progression-free survival in the intermediate disease stage.

Efficacy and safety of glecaprevir/pibrentasvir in renally impaired patients with chronic HCV infection

Background and aims Chronic hepatitis C virus (HCV) infection increases the risk of incident chronic kidney disease (CKD) and progression to end-stage renal disease (ESRD). Previously available direct-acting antiviral regimens are not approved for patients with advanced CKD across all HCV genotypes. Methods EXPEDITION-5 is a phase 3 study to evaluate efficacy and safety of the fixed-dose combination of glecaprevir and pibrentasvir (G/P) for chronic HCV infection (genotype 1 through 6) in adults without cirrhosis or with compensated cirrhosis and with stage 3b, 4 or 5 CKD. Patients received approved duration of G/P according to HCV genotype, cirrhosis status and prior HCV treatment experienc…

International and multicenter real‐world study of sorafenib‐treated patients with hepatocellular carcinoma under dialysis

Background & Aims: Information on safety and efficacy of systemic treatment in patients with hepatocellular carcinoma (HCC) under dialysis are limited due to patient exclusion from clinical trials. Thus, we aimed to evaluate the rate, prevalence, tolerability, and outcome of sorafenib in this population. Methods: We report a multicenter study comprising patients from Latin America and Europe. Patients treated with sorafenib were enrolled; demographics, dose modifications, adverse events (AEs), treatment duration, and outcome of patients undergoing dialysis were recorded. Results: As of March 2018, 6156 HCC patients were treated in 44 centres and 22 patients were concomitantly under dial…

HCC therapies--lessons learned.

The antiangiogenic multikinase inhibitor sorafenib was the first systemic agent to demonstrate a significant improvement in the overall survival of patients with advanced hepatocellular carcinoma (HCC), thereby introducing molecularly-targeted therapy in a therapeutic field of unmet needs. However, survival benefits for patients on sorafenib treatment are modest in clinical practice and advancing the field is far more challenging than initially anticipated. Molecular and clinical heterogeneity diminishes signals of potential activity in unselected populations, and underlying liver cirrhosis seals the fate of many novel targeted agents by causing relevant toxicity and mortality. The failure …

Reply to: “Performance status in patients with HCC: New kid on the block”

Immune oncology in hepatocellular carcinoma-hype and hope.