Background Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. Methods In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. Findings Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15.2 months (IQR 5.7-28.0) for the nivolumab group and 13.4 months (5.7-25.9) in the sorafenib group. Median overall survival was 16.4 months (95% CI 13.9-18.4) with nivolumab and 14.7 months (11.9-17.2) with sorafenib (hazard ratio 0.85 [95% CI 0.72-1.02]; p=0.075; minimum follow-up 22.8 months); the protocol-defined significance level of p=0.0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. Interpretation First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

ZusammenfassungRheumatologische und hepatologische Erkrankungen haben einige Überschneidungen, die für Behandler aus beiden Disziplinen relevant sind. In dieser Übersicht wird ein Schlaglicht auf 2 Erkrankungen geworfen, die sich an der Schnittstelle befinden: Arthropathie bei Hämochromatose und Systemische Sklerose bei Primär Biliärer Cholangitis. Daneben werden hepatologische Fragestellungen bei rheumatologischer Therapie beleuchtet.

Rheumatology and hepatology overlap in a number of conditions that are relevant for physicians in both fields. This review highlights 2 disorders at the interface: arthropathy in haemochromatosis and systemic sclerosis in primary biliary cholangitis. Furthermore, hepatological effects of rheumatological therapies are illuminated.

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.1-3 Data on retreatment of DAA failure patients using first-generation DAAs are limited.4-7 Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.8 However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy.

Background and Aims. Systemic treatment with sorafenib has been the standard of care (SOC) in patients with advanced Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) for more than a decade. TACE has been reported to allow better local tumor control in selected patients with BCLC stage C HCC. Methods. A retrospective analysis of patients with BCLC stage C HCC that were treated with sorafenib and TACE was conducted; they were compared to BCLC stage C patients treated either with TACE or sorafenib in the same period of time outside a clinical trial. Results. A total of 201 patients with BCLC stage C were identified, who were treated with either sorafenib and TACE (group A; n = 54), sorafenib (group B; n = 82) or TACE (group C; n = 65). No significant difference in baseline characteristics was observed. Time to progression was 7.0 months (95% CI: 4.3–9.7), 4.1 months (95% CI: 3.6–4.7) and 5.0 months (95% CI: 2.9–7.1) in groups A, B and C, respectively, and overall survival was 16.5 months (95% CI: 15.0–18.1), 8.4 months (95% CI: 6.0–10.8) and 10.5 months (95% CI: 7.5–13.6), respectively (group A vs. group B: p < 0.001; group A vs. group C: p = 0.0023). Adverse events of grade 3/4 occurred in 34% of patients in group A. Conclusions. Although sorafenib is a SOC in patients with BCLC stage C HCC, TACE is frequently used as an additional locoregional treatment in selected patients. This combined approach resulted in a significant overall survival benefit in selected patients, although randomized trials have not yet proven this benefit.

Patients with advanced hepatocellular carcinoma (aHCC) not amenable to surgical resection or locoregional therapy may be treated with multitargeted kinase inhibitors or immuno-oncology–based combination therapy. Sorafenib is approved as first-line (1L) therapy but provides only a modest survival benefit. Despite approved 1L therapies for aHCC, there remains an unmet need to prolong survival while improving treatment tolerability. The phase 3 CheckMate 459 study compared 1L nivolumab versus sorafenib in patients with aHCC; initial efficacy and safety data were previously presented (Yau et al. ESMO 2019; NCT02576509). The protocol-defined statistical significance threshold for overall survival (OS) was not met, although nivolumab showed clinical benefit. Here, we present long-term follow-up results from CheckMate 459. In CheckMate 459, 743 systemic therapy–naive patients ≥ 18 years of age with aHCC and Child-Pugh A liver function were randomized 1:1 to nivolumab (240 mg intravenous every 2 weeks; n = 371) or sorafenib (400 mg oral twice daily; n = 372). The primary endpoint was OS. Secondary endpoints were objective response rate and progression-free survival by blinded independent central review per Response Evaluation Criteria in Solid Tumors v1.1; efficacy by programmed death ligand 1 (PD-L1) tumor cell expression; and safety. At a minimum follow-up of 33.6 months, nivolumab demonstrated a clinically meaningful improvement in OS versus sorafenib (median OS, 16.4 months [95% CI, 14.0–18.5] vs 14.8 months [95% CI, 12.1–17.3], respectively; hazard ratio [HR], 0.85 [95% CI, 0.72–1.00]; nominal P value = 0.0522). The 33-month OS rates for nivolumab and sorafenib were 29% (95% CI, 25–34) and 21% (95% CI, 17–25), respectively. A consistent benefit was observed with nivolumab regardless of baseline PD-L1 expression (PD-L1 ≥ 1% HR, 0.80 [95% CI, 0.54–1.17]; PD-L1 < 1% HR, 0.84 [95% CI, 0.70–1.01]). Median OS (mOS) in patients with PD-L1 ≥ 1% was longer with nivolumab versus sorafenib (16.1 months [95% CI, 8.4–22.3] vs 8.6 months [95% CI, 5.7–16.3], respectively). Among patients with hepatitis C virus (HCV) and hepatitis B virus (HBV) etiology, mOS was numerically longer with nivolumab versus sorafenib (17.5 vs 12.7 months; HR, 0.72 [95% CI, 0.51–1.02] for HCV and 16.1 vs 10.4 months; HR 0.79 [95% CI, 0.59–1.07] for HBV, respectively). Nivolumab demonstrated greater liver function preservation over time than sorafenib as evidenced by albumin-bilirubin levels and Child-Pugh scores. Seven patients (2%) in the nivolumab arm and 77 patients (21%) in the sorafenib arm received subsequent immuno-oncology therapy. Nivolumab demonstrated a more favorable safety profile compared with sorafenib, with grade 3–4 treatment-related adverse events occurring in 82 patients (22.3%) and 180 patients (49.6%), respectively. At a minimum follow-up of 33.6 months, 1L nivolumab monotherapy continued to demonstrate clinically meaningful survival benefit in aHCC. Nivolumab had a more favorable and manageable safety profile and greater preservation of liver function over time compared with sorafenib, consistent with previous reports, with no new or unexpected safety signals observed.

Background and aims Discontinuation of long-term suppression of HBV replication with nucleos(t)ide analogues (NUCs) can result in durable immune control of hepatitis B virus (HBV) replication in HBeAg negative patients. We have assessed the effect of NUC discontinuation in HBeAg negative patients in a prospective, multicenter, randomized trial (the Stop-NUC study).

Hepatocellular carcinoma (HCC) is a leading cause of cancer death. The multikinase inhibitor sorafenib is widely used for systemic therapy in advanced HCC. Sorafenib might affect epoxyeicosanoids, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of epoxides derived from long-chain polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding diols. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) showed that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this pilot study, we assessed the effect of sorafenib treatment on the presence of lipid mediators, such as EETs, in blood of the patients with HCC using the lipidomics technology. We found a significant increase in 11,12-EET and 14,15-EET levels in HCC patients treated with sorafenib. Furthermore, while not significant in this small sample set, the data presented indicate that sorafenib can also increase the level of omega-3 DHA-derived 19,20-EDP. While the effect on EETs might hamper the anti-tumor effect of sorafenib, we hypothesize that supplementation of DHA in sorafenib-treated HCC patients could increase the level of 19,20-EDP and thereby enhance its anti-tumor effect.

Bei vorbehandelten aHCC-Patienten, führte Cabozantinib (C) in Phase-3 der CELESTIAL-Studie (NCT01908426; N = 707) zu verlängertem Gesamtüberleben und progressionsfreiem Überleben im Vgl. zu Placebo (P). Die vorliegende Post-hoc-Analyse beschreibt die qualitätskorrigierten Lebensjahre (QALYs) im Verlauf der Studie.

Background/aim The use of lamivudine for the treatment of chronic hepatitis B (CHB) is limited by high rates of lamivudine resistance. However, it is still in use in many regions. Factors associated with lamivudine resistance development have been studied in only a few European cohorts. The aim of our study was to assess the rate and risk factors for lamivudine resistance in a large real-life European cohort. Patients and methods We retrospectively analyzed patients with CHB treated in three German University centers over up to 12 years. Lamivudine resistance was defined as virologic breakthrough and presence of genotypic lamivudine resistance. The probability of resistance was estimated by Kaplan-Meier analysis and resistance predictors by Cox regression. Results A total of 227 patients were included into the analysis (hepatitis B envelope antigen positive or negative). Rates of lamivudine resistance by years 1-7 were 7, 26, 35, 41, 46, 53, and 55%, respectively. Interestingly, two hepatitis B envelope antigen-negative patients developed resistance during the year 12 of treatment. Independent risk factors for resistance development were hepatitis B virus DNA levels of at least 10(7) copies/ml before and detectable hepatitis B virus DNA by month 6 of treatment. Conclusion Even after long-term response to lamivudine more than 10 years, resistance may still develop. Our findings further discourage the use of lamivudine for the treatment of CHB.

Background SOR is approved as 1L therapy for pts with aHCC, but there is still an unmet need to prolong survival and improve tolerability. This phase III study compared clinical efficacy and safety of NIVO with SOR as 1L therapy in pts with aHCC. Methods Systemic therapy–naive pts aged ≥18 years with aHCC were randomized 1:1 to NIVO (240mg IV Q2W) or SOR (400mg oral BID). Primary endpoint was overall survival (OS). Additional endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review per RECIST v1.1, efficacy by tumor programmed death ligand 1 (PD-L1) expression, and safety. Results 743 pts with aHCC were randomized to NIVO (n=371) or SOR (n=372) with minimum follow-up of 22.8 months at data cutoff. OS did not meet the predefined threshold of statistical significance (HR 0.84, P=0.0419). Median OS (mOS) was 16.4mo for NIVO and 14.7mo for SOR (HR 0.85 [95% CI: 0.72–1.02]; P=0.0752). Clinical benefit was observed across predefined subgroups, including hepatitis infection status, presence of vascular invasion and/or extrahepatic spread, and region (Asia vs non-Asia). ORR was 15% for NIVO (14 pts with complete response [CR]) and 7% for SOR (5 pts with CR; Table). Grade 3/4 treatment-related adverse events were reported in 81 pts (22%) in the NIVO arm and 179 pts (49%) in the SOR arm and led to discontinuation in 16 (4%) and 29 (8%) pts, respectively. No new safety signals were observed with NIVO. 140 pts (38%) in the NIVO arm and 170 pts (46%) in the SOR arm received subsequent therapy. Additional OS analyses and patient-reported outcomes will be presented to support the benefit of NIVO.Table: LBA38_PREfficacy resultsTable: LBA38_PRNIVOSORn=371n=372Median OS (95% CI), mo16.4 (13.9–18.4)14.7 (11.9–17.2)12-mo OS rate, % (95% CI)59.7 (54.4–64.6)55.1 (49.8–60.1)24-mo OS rate, % (95% CI)36.8 (31.8–41.8)33.1 (28.3–38.0)Median PFS, mo (95% CI)3.7 (3.1–3.9)3.8 (3.7–4.5)ORR, n (%)57 (15)26 (7)BOR, n (%)Complete response14 (4)5 (1)Partial response43 (12)21 (6)ORR by baseline tumor PD-L1 expression, n/n (%)PD-L1 ≥1%20/71 (28)6/64 (9)PD-L1 Conclusions Though the primary endpoint of OS did not achieve statistical significance vs SOR, NIVO showed clinically meaningful improvements in OS, ORR, and CR rate as 1L treatment for aHCC. NIVO demonstrated a favorable safety profile consistent with previous reports. Clinical trial identification NCT02576509. Editorial acknowledgement Writing and editorial assistance was provided by Andrea L. Hammons of Parexel International (Waltham, MA, USA) and funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure T. Yau: Honoraria (institution), Advisory / Consultancy: Bristol-Myers Squibb. R.S. Finn: Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eisai; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli-Lilly; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Honoraria (self), Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Honoraria (self), Speaker Bureau / Expert testimony: Roche/ Genentech. A. Cheng: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ono Pharmaceutical; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Nucleix Ltd.; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: IQVIA; Advisory / Consultancy: Merck Sharp Dohme; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Yakuhin; Speaker Bureau / Expert testimony: Amgen Taiwan; Advisory / Consultancy: Ispen; Advisory / Consultancy: Bayer Schering Pharma; Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy: Merck Serono; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis. P. Mathurin: Honoraria (self), Speaker Bureau / Expert testimony: Ipsen; Honoraria (self), Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Speaker Bureau / Expert testimony: MSD; Honoraria (self), Speaker Bureau / Expert testimony: Bayer Healthcare ; Honoraria (self), Speaker Bureau / Expert testimony: AbbVie; Honoraria (self), Speaker Bureau / Expert testimony: Gilead; Honoraria (self), Speaker Bureau / Expert testimony: Servier; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi. J. Edeline: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau / Expert testimony: MSD; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony: IPSEN; Honoraria (self), Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Speaker Bureau / Expert testimony: Bayer; Travel / Accommodation / Expenses: Amgen. M. Kudo: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: Ono; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Medico's Hirata; Research grant / Funding (institution): Otsuka; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): EA Pharma; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Gilead. J.J. Harding: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Speaker Bureau / Expert testimony: Exelexis; Honoraria (self), Speaker Bureau / Expert testimony: Elly Lilly ; Honoraria (self), Speaker Bureau / Expert testimony: CytomX; Honoraria (self), Speaker Bureau / Expert testimony: QED. P. Merle: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): IPSEN; Advisory / Consultancy: Eisai; Advisory / Consultancy: Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck; Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: AstraZeneca. O. Rosmorduc: Honoraria (self): Bayer; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Sirtex; Honoraria (self): Eisai. L. Wyrwicz: Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Beigene; Research grant / Funding (self): Eisai. E. Schott: Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Bayer. S.P. Choo: Honoraria (self), Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy: Sirtex; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Ipsen. R.K. Kelley: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Honoraria (self), Speaker Bureau / Expert testimony, IDMC membership: Genentech/Roche; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): AstraZeneca. D. Begic: Full / Part-time employment: Bristol-Myers Squibb. J. Neely: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. J. Anderson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. B. Sangro: Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: BTG; Advisory / Consultancy: H3 Biomedicine; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: Onxeo; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sirtex Medical; Advisory / Consultancy: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Terumo. All other authors have declared no conflicts of interest.

BACKGROUND & AIMS:Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the efficacy and safety of a combination of sorafenib and selective internal radiation therapy (SIRT) - with yttrium-90 (90Y) resin microspheres - to sorafenib alone in patients with advanced HCC. METHODS:SORAMIC is a randomised controlled trial comprising diagnostic, local ablation and palliative cohorts. Based on diagnostic study results, patients were assigned to local ablation or palliative cohorts. In the palliative cohort, patients not eligible for TACE were randomised 11:10 to SIRT plus sorafenib (SIRT + sorafenib) or sorafenib alone. The primary endpoint was overall survival (OS; Kaplan-Meier analysis) in the intention-to-treat (ITT) population. RESULTS:In the ITT cohort, 216 patients were randomised to SIRT + sorafenib and 208 to sorafenib alone. Median OS was 12.1 months in the SIRT + sorafenib arm, and 11.4 months in the sorafenib arm (hazard ratio [HR] 1.01; 95% CI 0.81-1.25; p = 0.9529). Median OS in the per protocol population was 14.0 months in the SIRT + sorafenib arm (n = 114), and 11.1 months in the sorafenib arm (n = 174; HR 0.86; p = 0.2515). Subgroup analyses of the per protocol population indicated a survival benefit of SIRT + sorafenib for patients without cirrhosis (HR 0.46; 0.25-0.86; p = 0.02); cirrhosis of non-alcoholic aetiology (HR 0.63; p = 0.012); or patients ≤65 years old (HR 0.65; p = 0.05). Adverse events (AEs) of Common Terminology Criteria for AE Grades 3-4 were reported in 103/159 (64.8%) patients who received SIRT + sorafenib, 106/197 (53.8%) patients who received sorafenib alone (p = 0.04), and 8/24 (33.3%) patients who only received SIRT. CONCLUSION:Addition of SIRT to sorafenib did not result in a significant improvement in OS compared with sorafenib alone. Subgroup analyses led to hypothesis-generating results that will support the design of future studies. LAY SUMMARY:Sorafenib given orally is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). In selective internal radiation therapy (SIRT), also known as radioembolisation, microscopic, radioactive resin or glass spheres are introduced into the blood vessels that feed the tumours in the liver. This study found that the addition of SIRT with 90yttrium-loaded resin microspheres to sorafenib treatment in people with advanced HCC did not significantly improve overall survival compared with sorafenib treatment alone. However, the results give an indication of how future studies using this combination therapy in people with advanced HCC could be designed. STUDY REGISTRATION:EudraCT 2009-012576-27, NCT0112 6645.

Acute hepatitis C virus (HCV) infection has been associated with altered phenotypes and function of several immune cell populations and soluble inflammatory mediators (SIM). Successful treatment of chronic hepatitis C with DAA"s has been associated with alterations of SIM. However, no complete SIM restoration was observed. We hypothesized that early DAA treatment of symptomatic acute hepatitis C with DAAs may normalize most SIM – in contrast to treatment of persistent infection.

Die CELSTIAL Studie zeigt, das Cabozantinib sowohl das das Gesamtüberleben (10,2 Monate (C) vs. 8,0 Mon (P); (HR 0,76; 95% CI; 0,63 – 0,92; P = 0,0049), als auch das progressionsfreie Überleben (C): 5,2 M vs. 1,9 M (P) (HR 0,44; 95% CI); 0,36 – 0,52; P < 0,0001) verbessert, bei einer Ansprechrate von 4% (C, vs. 0,4% (P) (P = 0,0086) gemäß RECIST-Kriterien). In dieser Auswertung untersuchen wir Tumoransprechen (Änderungen Durchmesser Zielläsion, SOD), AFP-Serumspiegel und Zeit bis zur Tumorprogression (TPP).

Background: In pivotal studies with direct-acting antivirals (DAAs), rates of sustained virological response in hepatitis C genotype 1 infection are >90%. Objective: The objective of this article is to assess real-world safety and effectiveness of DAA treatment in a prospective multicenter registry study. Methods: The German Hepatitis C-Registry includes 6606 patients with genotype 1 from 246 centers, treated between February 2014 and June 2016 at the discretion of the physician. Results: A total of 4846 patients completed treatment and follow-up; 51% of these patients were treatment experienced and 28% had liver cirrhosis. Comorbidities were reported in 76% of patients, including HIV co-infection in 8%. SVR12 was 92% with 91% in GT1a and 93% in GT1b. HIV co-infected patients (n=247) had an SVR12 of 92%. Treatment was discontinued prematurely in 2.5%. In multivariate analysis, SVR12 was dependent on the choice of antiviral regimen (OR 1.33 (1.24-1.43); p<0.001), negatively associated with presence of liver cirrhosis (OR 0.71 (0.56-0.89); p<0.003) and positively associated with female gender (OR 1.52 (1.21-1.91); p<0.001). Conclusion: Data from this real-world registry show SVR12 rates close to those obtained in clinical studies. Discontinuation rates are low, confirming good tolerance of the regimens and good adherence of patients(Trial registration number DRKS00009717, German Clinical Trials Register, DRKS).