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... Show moreBackground: 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. Show less
Background Hepatocellular carcinoma (HCC) recurrence rates following locoregional treatment are high. As multireceptor tyrosine kinase inhibitors targeting vascular endothelial growth factor... Show moreBackground 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. Show less
Objective Knowledge on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in liver transplant recipients is lacking, particularly in terms of severity of the disease. The aim of... Show moreObjective Knowledge on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in liver transplant recipients is lacking, particularly in terms of severity of the disease. The aim of this study was to describe the demographic, baseline clinical characteristics and early outcomes of a European cohort of liver transplant recipients with SARS-CoV-2 infection. Design We conducted an international prospective study across Europe on liver transplant recipients with SARS-CoV-2 infection confirmed by microbiological assay during the first outbreak of COVID-19 pandemic. Baseline characteristics, clinical presentation, management of immunosuppressive therapy and outcomes were collected. Results 57 patients were included (70% male, median (IQR) age at diagnosis 65 (57-70) years). 21 (37%), 32 (56%) and 21 (37%) patients had one cardiovascular disease, arterial hypertension and diabetes mellitus, respectively. The most common symptoms were fever (79%), cough (55%), dyspnoea (46%), fatigue or myalgia (56%) and GI symptoms (33%). Immunosuppression was reduced in 22 recipients (37%) and discontinued in 4 (7%). With this regard, no impact on outcome was observed. Forty-one (72%) subjects were hospitalised and 11 (19%) developed acute respiratory distress syndrome. Overall, we estimated a case fatality rate of 12% (95% CI 5% to 24%), which increased to 17% (95% CI 7% to 32%) among hospitalised patients. Five out of the seven patients who died had a history of cancer. Conclusion In this European multicentre prospective study of liver transplant recipients, COVID-19 was associated with an overall and in-hospital fatality rate of 12% (95% CI 5% to 24%) and 17% (95% CI 7% to 32%), respectively. A history of cancer was more frequent in patients with poorer outcome. Show less
Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease in the world, affecting more than 25% of the adult population. NAFLD covers a spectrum including simple steatosis... Show moreNonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease in the world, affecting more than 25% of the adult population. NAFLD covers a spectrum including simple steatosis, in which lipid accumulation in hepatocytes is the predominant histological characteristic, and nonalcoholic steatohepatitis (NASH), which is characterized by additional hepatic inflammation with or without fibrosis. Liver biopsy is currently the reference standard to discriminate between hepatic steatosis and steatohepatitis. Since liver biopsy has several disadvantages, noninvasive diagnostic methods with high sensitivity and specificity are desirable for the analysis of NAFLD. Improvements in magnetic resonance imaging (MRI) technology are continuously being implemented in clinical practice, specifically multiparametric MRI methods such as proton density fat-fraction (PDFF), T-2*, and T(1)mapping, along with MR elastography. Multiparametric imaging of the liver has a promising role in the clinical management of NAFLD with quantification of fat content, iron load, and fibrosis, which are features in NAFLD. In the present article, we review the utility and limitations of multiparametric quantitative imaging of the liver for diagnosis and management of patients with NAFLD. Level of Evidence 5. Technical Efficacy Stage 3. Show less
Background & Aims Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation of cirrhosis (AD), organ failure(s) and high risk of short-term mortality with bacterial... Show moreBackground & Aims Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation of cirrhosis (AD), organ failure(s) and high risk of short-term mortality with bacterial infection frequently as precipitating event. Innate immune pattern recognition receptors and members of the lectin pathway of complement activation are crucial to the innate immune response to pathogens. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) of innate immune components are associated with the occurrence of bacterial infections or mortality in patients with cirrhosis hospitalized for AD or ACLF.Methods Twenty-one innate immunity SNPs with known functional implications were genotyped in 826 AD/ACLF patients included in the CANONIC study. Associations between baseline characteristics of the patients, the occurrence of bacterial infections and survival rate at 90 days of follow-up in relation to the innate immunity genetic variants were analysed.Results The NOD2-G908R genetic variant was associated with mortality (HR 2.25, P = .004) independently of age and MELD Score. This association was also found in a predefined subgroup analysis in patients with bacterial infections (HR 2.78, P < .001) along with MBL_Yx (HR 1.72, P = .008) and MASP2_371 (HR 1.67, P = .012) genetic variants. None of the analysed SNPs were significantly associated with the occurrence of acute bacterial infections or spontaneous bacterial peritonitis in particular.Conclusions Innate immune system-specific NOD2-G908R, MBL_Yx and MASP2_371 genetic variants were independently associated with increased risk of short-term mortality in AD/ACLF patients with bacterial infection. Show less
Introduction Cirrhotic patients with portal hypertension can suffer from variceal bleeding or refractory ascites and can benefit from a transjugular intrahepatic portosystemic shunt (TIPS). Post... Show moreIntroduction Cirrhotic patients with portal hypertension can suffer from variceal bleeding or refractory ascites and can benefit from a transjugular intrahepatic portosystemic shunt (TIPS). Post-TIPS hepatic encephalopathy (HE) is a common (20%-54%) and often severe complication. A prophylactic strategy is lacking.Methods and analysis The Prevention of hepatic Encephalopathy by Administration of Rifaximin and Lactulose in patients with liver cirrhosis undergoing placement of a TIPS (PEARL) trial, is a multicentre randomised, double blind, placebo controlled trial. Patients undergoing covered TIPS placement are prescribed either rifaximin 550 mg two times per day and lactulose 25 mL two times per day (starting dose) or placebo 550 mg two times per day and lactulose 25 mL two times per day from 72 hours before and until 3 months after TIPS placement. Primary endpoint is the development of overt HE (OHE) within 3 months (according to West Haven criteria). Secondary endpoints include 90-day mortality; development of a second episode of OHE; time to development of episode(s) of OHE; development of minimal HE; molecular changes in peripheral and portal blood samples; quality of life and cost-effectiveness. The total sample size is 238 patients and recruitment period is 3 years in six hospitals in the Netherlands and one in Belgium.Ethics and dissemination This study protocol was approved in the Netherlands by the Medical Research Ethics Committee of the Academic Medical Centre, Amsterdam (2018-332), in Belgium by the Ethics Committee Research UZ/KU Leuven (S62577) and competent authorities. This study will be conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Study results will be submitted for publication in a peer-reviewed journal. Show less
Helm, D. van der; Barnhoorn, M.C.; Jonge-Muller, E.S.M. de; Molendijk, I.; Hawinkels, L.J.A.C.; Coenraad, M.J.; ... ; Verspaget, H.W. 2019
