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SARS-CoV-2 and HCoV-OC43 belong to the same β genus of the Coronaviridae family. SARS-CoV-2 was responsible for the recent COVID-19 pandemic, and HCoV-OC43 is the etiological agent of mild upper respiratory tract infections. SARS-COV-2 and HCoV-OC43 co-infections were found in children with respiratory symptoms during the COVID-19 pandemic. The two β-coronaviruses share a high degree of homology between the 3CLpro active sites, so much so that the safer HCoV-OC43 has been suggested as a tool for the identification of new anti-SARS-COV-2 agents. Compounds 5 and 24 inhibited effectively both Wuhan and British SARS-CoV-2 patient isolates in Vero E6 cells and the HCoV-OC43 in MRC-5 cells at low micromolar concentrations. The inhibition was apparently exerted via targeting the 3CLpro active sites of both viruses. Compounds 5 and 24 at 100 μM inhibited the SARS-CoV-2 3CLpro activity of 61.78 and 67.30%, respectively. These findings highlight 5 and 24 as lead compounds of a novel class of antiviral agents with the potential to treat SARS-COV-2 and HCoV-OC43 infections.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths and remains a major burden on healthcare systems worldwide. The incidence of HCC continues to rise globally, despite preventative efforts being made., Aims: This study aimed to investigate epidemiological changes observed in the etiology and survival outcomes of HCC patients at Klinikum Klagenfurt am Wörthersee between 2012 and 2023., Methods: This was a retrospective, single-center cohort study. Two time-periods (2012-2017 and 2018-2023) were created to enable comparison between the respective intervals. IBM SPSS was used to analyze statistical data., Results: More patients were diagnosed with HCC during the second time period ( n = 128, n = 148). The median age of diagnosis was 72.5 years (SD 8.6). Patients were on average 2 years younger in the second time period compared to the first ( p = 0.042). Alcohol remained the leading underlying etiology of HCC and no statistically significant change was seen over time ( p = 0.353). Nevertheless, a clear upward trend in the number of NASH cases was evident over time ( n = 15, n = 28, respectively). Nearly half of the patient population had a normal AFP (<7 µg/L) level at the time of diagnosis ( n = 116, 42.6%). The survival time for HCC patients remained similar between time periods, with a median overall survival time of 20.5 months (95% CI 16.8-24.2, p = 0.841), despite improvements in management strategies and the availability of new systemic treatments. More advanced-stage HCC cases were documented in the second period (BCLC-C, n = 23 to n = 46, p = 0.051). An increased number of HCC patients without liver cirrhosis were identified during the second time period ( n = 22, n = 47, respectively, p = 0.005). NASH was the most common underlying etiology in patients without liver cirrhosis (50%) compared to alcohol use in being the primary cause in cirrhotic patients (65%, p < 0.001)., Conclusion: HCC continues to be an important health concern in our society. The number of HCC patients without liver cirrhosis is steadily increasing, with NAFLD/NASH, due to underlying lifestyle diseases playing an important etiological role. Continued efforts should be made to prevent HCC and to screen at-risk population groups. Preventative strategies and screening techniques should be adjusted in light of the changing epidemiological landscape of HCC, where more focus will have to be placed on detecting HCC in patients without underlying cirrhosis.

Background & Aims: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line., Methods: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events., Results: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively., Conclusions: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials., Impact and Implications: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy., Competing Interests: BS received travel support from AbbVie, Ipsen and Gilead. DR has received advisory fees from Bayer and speakers fees as well as travel grants from Ipsen. He is an investigator for Bayer, BMS, Lilly, AstraZeneca and Roche. SP has nothing to disclose. ML has nothing to disclose. KP has nothing to disclose. TP received consulting fees from IQVIA and Bayer; and institutional research funding from Lilly, Roche, Bayer. AC has nothing to disclose. TWF has nothing to disclose. JVF has received advisory board fees from Roche. KS served as consultant for Ipsen and Bayer, and conducts studies for Bayer, Roche, Lilly, MSD, and BMS. VH has nothing to disclose. FF received travel support from Abbvie and Novartis, and speaker fees from Abbvie and MSD. AD has nothing to disclose. ARS has served at advisory boards and received consulting honoraria from AMGEN, AAA, Bayer, BMS, IPSEN, Lilly, Merck, MSD, Pfizer, Roche, Sanofi, and Servier. KS has nothing to disclose. PR has nothing to disclose. BiS has nothing to disclose. MPE received consulting honoraria from BMS and MSD. AT received consulting honoraria and/or lecture fees from Bayer, IPSEN, Lilly, BMS, Eisai Novartis, Roche, Intercept, Falk, AbbVie, and Gilead. He received travel grants from IPSEN, AbbVie, and Gilead. He is an investigator for IPSEN and GILEAD. AngD received advisory board fees from Roche and BMS, and travel support from Roche and Ipsen. FH received travel support from Bayer, Abbvie, and Gilead. LB has nothing to disclose. ABP has nothing to disclose. DH received research support from Pfizer. MV received speaker fees from Nordic Pharma, Ipsen, Merck Serono, Bayer Vital, Lilly, AstraZeneca, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), and Sirtex, advisory board fees from Roche, Ipsen, Lilly, Nordic Pharma, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Eisai, AstraZeneca and Amgen, research grants from Sirtex. FS has nothing to disclose. MT received speaker fees from Bristol-Myers Squibb (BMS), Falk Foundation, Gilead, Intercept and Merck Sharp & Dohme (MSD); advisory board fees from Abbvie, Albireo, Boehringer Ingelheim, BiomX, Falk Pharma GmbH, GENFIT, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Regulus and Shire; travel grants from AbbVie, Falk, Gilead, and Intercept; and research grants from Albireo, CymaBay, Falk, Gilead, Intercept, MSD, and Takeda. He is also coinventor of patents on the medical use of norUDCA filed by the Medical University of Graz. ADA received travel support and consultancy fees from Roche. CAMF has nothing to disclose. DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, Eisai, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra, Mursla, Exact Sciences and Astra Zeneca; research funding (to institution) from MSD and BMS. MPR is advisor/consultant for Astra Zeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he served as a speaker for Bayer, Eisai, Ipsen, Lilly, and Roche; he is an investigator for Bayer, BMS, Eisai, Exelixis, Lilly, and Roche. JFD received compensations as a member of scientific advisory boards of Abbvie, Bayer, Bristol–Myers Squibb, Falk, Galapagos, Genfit, Genkyotex, Gilead Sciences, HepaRegenix, Intercept, Lilly, Merck, and Novartis. AW received compensations as a member of scientific advisory boards for BMS, Wako and Sanofi. He served as a speaker for Leo Pharma, Eisai, Ipsen and Roche and received travel support from Merck and Servier. AEK has received consulting fees from Abbvie, AstraZeneca, Bayer, CymaBay, Escient, FMC, Gilead, GSK, Guidepoint, Intercept, Mirum, Medscape, MSD, Myr, Viofor; lecture fees from Abbvie, AOP Orphan, Bayer, BMS, CMS, CymaBay, Eisai, Falk, Gilead, GSK, Intercept, Janssen, Newbridge, Novartis, Lilly, MSD, Zambon; and institutional research funding from Intercept. AGS served on advisory boards and as a consultant for Genentech, AstraZeneca, Eisai, Bayer, Exelixis, TARGET RWE, FujiFilm Medical Sciences, Glycotest, Exact Sciences, GRAIL, and Freenome. ENDT has served as a paid consultant for AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co, MSD, Mallinckrodt, Omega, Pfizer, IPSEN, Terumo and Roche. He has received reimbursement of meeting attendance fees and travel expenses from Arqule, Astrazeneca, BMS, Bayer, Celsion and Roche, and lecture honoraria from BMS and Falk. He has received third-party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly, and IPSEN and Roche. LR has received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, Zymeworks; lectures fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi, Servier; travel expenses from AstraZeneca; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. MP is an investigator for Bayer, BMS, Eisai, Ipsen, Lilly, and Roche; he received speaker honoraria from Bayer, BMS, Eisai, Lilly, MSD, and Roche; he is a consultant for Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he received travel support from Bayer, BMS, and Roche. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Using national registries, we investigated the epidemiological trends of hepatobiliary carcinomas in Austria between 2010 and 2018 and compared them to those reported for the periods of 1990-1999 and 2000-2009. In total, 12,577 patients diagnosed with hepatocellular carcinoma ( n = 7146), intrahepatic cholangiocarcinoma ( n = 1858), extrahepatic cholangiocarcinoma ( n = 1649), gallbladder carcinoma ( n = 1365), and ampullary carcinoma ( n = 559), between 2010 and 2018, were included. The median overall survival of all patients was 9.0 months. The best median overall survival was observed in patients with ampullary carcinoma (28.5 months) and the worst median overall survival was observed in patients with intrahepatic carcinoma (5.6 months). The overall survival significantly improved in all entities over the period 2010-2018 as compared with over the periods of 2000-2009 and 1990-1999. Age-adjusted incidence and mortality rates remained stable for most entities in both, men and women; only in gallbladder carcinoma, the incidence and mortality rates significantly decreased in women, whereas, in men, the incidence rates remained stable and mortality rates showed a decreasing trend. We showed that age-adjusted incidence and mortality rates were stable in most entities, except in gallbladder carcinoma. The overall survival improved in almost all entities as compared with those during 1990-2009.

Vericiguat is a soluble guanylate cyclase stimulator. The pharmacokinetics, absorption, metabolism, and excretion properties of vericiguat in rats and dogs and the distribution in rats are reported. [ 14 C]-labelled vericiguat was studied in intact and bile duct-cannulated rats (oral and intravenous administration), and dogs (oral administration).Vericiguat reached maximum plasma concentrations at 1-3 h after oral administration. Absolute bioavailability was moderate in rats and high in dogs. Vericiguat was the most abundant component in plasma of rats and dogs.After oral administration to rats, radioactivity was widely distributed. Penetration into the brain was minimal. Elimination was rapid from most tissues in rats. Most of the radioactivity was excreted in faeces (rat: 81%, dog: 89%), while low amounts were excreted in urine (rat: 11%, dog: 4%). Clearance routes in both species were unchanged excretion and metabolism via glucuronidation and oxidative reactions. After intravenous administration to bile duct-cannulated rats, a relevant proportion of the dose (30%) underwent direct excretion into the gastrointestinal tract as unchanged vericiguat.

Background & Aims: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need., Methods: Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204)., Results: Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response., Conclusions: The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation., Lay Summary: The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers., Competing Interests: Conflict of interest B.S. received travel support from AbbVie, Ipsen and Gilead. K.P. nothing to disclose. M.K. received honoraria from BMS and AstraZeneca as consultant and is an investigator for AstraZeneca. F.H. received travel support from Bayer, Abbvie, and Gilead. F.F. received travel support from Abbvie and Novartis, and speaker fees from Abbvie and MSD. O.W. served as consultant for Amgen, Bayer, BMS, Celgene, Eisai, Merck, Novartis, Roche, Servier, and Shire. He served as a speaker for Abbvie, Bayer, BMS, Celgene, Falk, Ipsen, Novartis, Roche, and Shire. He received travel support from Abbvie, BMS, Ipsen, Novartis, and Servier. V.H. has nothing to disclose. K.S. Served as consultant for Ipsen and Bayer, and conducts studies for Bayer, Roche, Lilly, MSD, and BMS. J.v.F. has received advisory board fees from Roche. T.W.F. has nothing to disclose. M.S. has nothing to disclose. H.H. received compensations as a member of a scientific advisory board of Lilly. K.S. has nothing to disclose. S.S. has nothing to disclose. P.R. has nothing to disclose. A.R.S. has served at advisory boards and received consulting honoraria from AMGEN, AAA, Bayer, BMS, IPSEN, Lilly, Merck, MSD, Pfizer, Roche, Sanofi, and Servier. J.C.M. has received consulting honoraria from Abbvie, Astra Zeneca, Bayer, BMS, Eisai, Gilead, Incyte, Intercept, MSD, Sanofi, Vifor for work performed outside the current study. N.N.R. has nothing to disclose. F.K. received speakers' fees from Bayer, Ipsen, MSD, Eisai, Shire, Sirtex and has received travel grants from Eisai, Janssen, Ipsen and Novartis. D.T.W. served as speaker/expert testimony for AstraZeneca, Eisai, BMS, Celgene, Incyte, Ipsen, Falk, Novartis, Roche Pharma AG, Servier, Shire Baxelta, and Sirtex; he received travel support from Bayer Health Pharma, Celgene, Ipsen, Novartis, and SIRTEX, and research grants/funding from Servier. M.P.E. received consulting honoraria from BMS and MSD. A.T. received consulting honoraria and /or lecture fees from Bayer, IPSEN, Lilly, BMS, Eisai Novartis, Roche, Intercept, Falk, AbbVie, and Gilead. He received and travel grants from IPSEN, AbbVie, and Gilead. He is an investigator for IPSEN and GILEAD. S.D.D. received consulting honoraria from Amgen, Bayer, BMS, IPSEN, Lilly, Merck, BMS, Novartis, Pfizer, Roche, Sanofi, and Servier, and travel grants from Amgen, BMS, IPSEN, Roche, and Servier. D.J.P. received lecture fees from ViiV Healthcare, Bayer Healthcare, Falk, BMS, EISAI and Roche; travel expenses from BMS, MSD and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, H3B, Roche, Astra Zeneca, and DaVolterra; research funding (to institution) from MSD, BMS. T.P. received consulting fees from IQVIA and Bayer; and institutional research funding from Lilly, Roche, Bayer. T.M. has nothing to disclose. L.B. has nothing to disclose. C.M. has nothing to disclose. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Collective Acumen, Gilead, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. T.R. received speaker fees from Boehringer Ingelheim, Roche, W.L. Gore and MSD, grant support from Boehringer Ingelheim, Boston Scientific, Cook Medical, Gilead, Guerbet, Abbvie, Phenex Pharmaceuticals, Philips, W.L. Gore, and MSD, served as a consultant for Abbvie, Bayer, Boehringer Ingelheim, Gilead, Intercept and MSD and received travel support from Gilead, Roche, MSD, and Gore. M.T. received speaker fees from Bristol-Myers Squibb (BMS), Falk Foundation, Gilead, Intercept and Merck Sharp & Dohme (MSD); advisory board fees from Abbvie, Albireo, Boehringer Ingelheim, BiomX, Falk Pharma GmbH, GENFIT, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Regulus and Shire; travel grants from AbbVie, Falk, Gilead, and Intercept; and research grants from Albireo, CymaBay, Falk, Gilead, Intercept, MSD, and Takeda. He is also coinventor of patents on the medical use of norUDCA filed by the Medical University of Graz. N.P. received consulting fees from Amgen, Merck Serono, Servier; lectures fees from AbbVie, Gilead, Lilly; travel fees from Amgen, ArQule; and institutional research funding from Basilea, Merck Serono, Servier. L.R. has received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Zymeworks; lectures fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. M.B. received compensations as a member of scientific advisory boards of Bayer, Bristol–Meyers Squibb, EISAI, IPSEN, and MSD. J.T. served as consultant for Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche, received travel support from BMS and Ipsen, and speaking fees from Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche. He is also an investigator for Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche. A.W. received compensations as a member of scientific advisory boards for BMS, Wako, Sanofi and. He served as a speaker for Leo Pharma, Eisai, Ipsen and Roche and received travel support from Merck and Servier. H.W. served as speaker for Bayer, Eisai, Ipsen, and Roche, and as a consultant for Bayer, Eisai, Lilly, BMS, Roche, and Ipsen. He conducts studies for Bayer, Roche, Lilly, MSD, and BMS. J.F.D. received compensations as a member of scientific advisory boards of Abbvie, Bayer, Bristol-Myers Squibb, Falk, Galapagos, Genfit, Genkyotex, Gilead Sciences, HepaRegenix, Intercept, Lilly, Merck, and Novartis. M.P.R. is advisor/consultant for Astra Zeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he served as a speaker for Bayer, Eisai, Ipsen, Lilly, and Roche; he is an investigator for Bayer, BMS, Eisai, Exelixis, Lilly, and Roche. A.V. served as consultant for Roche, Bayer, Lilly, BMS, Eisai, and Ipsen, and received speaking fees form Roche, Bayer, Lilly, BMS, Eisai, and Ipsen. He is also an investigator for Roche, Bayer, Lilly, BMS, Eisai, and Ipsen. M.P. is an investigator for Bayer, BMS, Lilly, and Roche, he received speaker honoraria from Bayer, BMS, Eisai, and MSD, he is a consultant for Bayer, BMS, Ipsen, Eisai, Lilly, Roche, and MSD, and he received travel support from Bayer, BMS, and Roche. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: To assess the adherence to treatment, sustained virologic response (SVR) rate, and reinfection rate in hepatitis C patients with and without intravenous drug use., Methods: This retrospective study included hepatitis C patients, evaluated and treated in our hepatology outpatient clinic between January 2014 and October 2019. The following information was extracted from the patient's file: the presence of positive viral load for hepatitis C virus (HCV), active and recent (in the last 6 months) use of i.v. drugs, HCV genotype, treatment regimen, SVR, HCV reinfection rate, coinfection with human immunodeficiency virus (HIV) and ongoing opioid substitution therapy (OST)., Results: We included 431 hepatitis C patients, 234 people who inject drugs (PWID) and 197 non-PWID. Most patients were treated with direct-acting antivirals (DAA) only. The rate of documented SVR by treated patients was significantly higher in the non-PWID cohort (91.5% vs. 61.5%, p < 0.0001), while noncompliance (did not show up to start treatment) rate or refusal of treatment was significantly higher in the PWID cohort (19.4% vs. 8.9%, p = 0.004). In the PWID cohort, younger age and recent (in the last 6 months) or ongoing i.v. drug use was associated with noncompliance: 31.1 ± 8.4 years vs. 35.8 ± 10.6 years (p = 0.02) and 33.3% vs. 12.8% (p = 0.0008), respectively. Ongoing OST was associated with better compliance: 61.1% vs. 46.1% (p = 0.04)., Conclusion: To achieve elimination of hepatitis C better treatment strategies are needed, especially in PWIDs., (© 2021. Springer-Verlag GmbH Austria, part of Springer Nature.)

Hepatocellular carcinoma (HCC) can have viral or non-viral causes 1-5 . Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need 6,7 . Here we report the progressive accumulation of exhausted, unconventionally activated CD8 + PD1 + T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8 + PD1 + T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8 + PD1 + CXCR6 + , TOX + , and TNF + T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 + T cells or TNF neutralization, suggesting that CD8 + T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8 + PD1 + T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Background and Aims: The heterogeneity of intermediate-stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable., Approach and Results: Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological responses (as assessed by modified Response Evaluation Criteria in Solid Tumors [mRECIST]) were also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A pre-TACE model ("Pre-TACE-Predict") and a post-TACE model ("Post-TACE-Predict") that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. The median OS was 19.9 months. The factors influencing survival were tumor number and size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, cause, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared with existing models (the hepatoma arterial embolization prognostic score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7 months to more than 4 years., Conclusions: A TACE-specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient-level prognostication., (© 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

Background: Platelets have been reported to influence tumor biology and may promote metastasis. Traditionally, thrombocytopenia, a hallmark of cirrhosis, was associated with hepatocellular carcinoma (HCC) development. However, the impact of platelet count on outcome in patients with established HCC is not well studied., Methods: Outcomes of patients with cirrhosis diagnosed with HCC between 1995 and 2013 (derivation cohort) and 2000-2016 (validation cohort) who were not eligible for surgical treatment and did not receive antiplatelet therapy were retrospectively studied. Thrombocytopenia was defined as platelet count < 150 g/L. High mean platelet volume (MPV) was defined as ≥median value of the respective cohort (derivation cohort: ≥11 fL; validation cohort: ≥10.6 fL)., Results: Among 626 patients with unresectable HCC, thrombocytopenia was present in 378 (60.4%) and was associated with favorable baseline tumor characteristics: lower diameter of the largest nodule (5.6 ± 3.2 vs. 7.6 ± 4.2 cm), less extrahepatic spread (9.5 vs. 20.2%, both p < 0.001), less macrovascular invasion (21.2 vs. 31.0%, p = 0.005), and lower BCLC stages (63.0 vs. 73.4% BCLC C/D; p = 0.007) as compared to patients with normal platelet count. On univariate analysis, thrombocytopenia and larger MPV were associated with longer overall survival (OS) (thrombocytopenia: median OS [95% CI], 11.5 [9.3-13.8] vs. 5.5 [3.8-7.1] months; p = 0.001; MPV ≥11 fL: 11.7 [9.1-14.2] vs. 6.0 [4.4-7.6] months; p < 0.001). In multivariate analysis, the combined variable of thrombocytopenia and larger MPV was independently associated with longer OS (HR [95% CI], 0.80 [0.65-0.98]; p = 0.029). These results were confirmed in an independent external validation cohort of 525 patients with cirrhosis and HCC. Again, patients with thrombocytopenia and high MPV had significantly longer OS (15.3 [11.7-18.9] vs. 9.3 [7.4-11.2] months; p < 0.001)., Conclusions: Thrombocytopenia and higher MPV are associated with better outcome in patients with advanced HCC. These findings may prompt further clinical research on additive antiplatelet therapy in the prevention and management of HCC.

Background: Programmed cell death protein-1-targeted immunotherapy has shown promising results in phase II studies of hepatocellular carcinoma., Aim: To evaluate safety and efficacy of nivolumab and pembrolizumab in an international, multicentre, real-world cohort of patients with advanced hepatocellular carcinoma., Methods: Sixty-five patients treated with nivolumab (n = 34) or pembrolizumab (n = 31) between July 10, 2015 and December 31, 2018 (data cut-off) across six centres in Austria and Germany were retrospectively analysed., Results: Child-Pugh class A/B/C was 32 (49%)/28 (43%)/5 (8%). Immunotherapy was used as systemic first-/second-/third-/fourth-line treatment in 9 (14%)/27 (42%)/26 (40%)/3 (5%) patients. Fifty-four patients had at least one follow-up imaging and were, therefore, available for radiological response assessment. The overall response and disease control rates were 12% and 49% respectively. Of 52 evaluable patients, four (8%) had hyperprogressive disease. Median time to progression was 5.5 (95% CI, 3.5-7.4) months, median progression-free survival was 4.6 (95% CI, 3.0-6.2) months, and median overall survival was 11.0 (95% CI, 8.2-13.8) months. Most common adverse events were infections (n = 7), rash (n = 6), pruritus (n = 3), fatigue (n = 3), diarrhoea (n = 3) and hepatitis (n = 3). Efficacy and safety results were comparable between Child-Pugh A and B patients; however, median overall survival (OS) was shorter in Child-Pugh B patients (16.7 vs 8.6 months; P = 0.065). There was no difference in terms of efficacy and adverse events between patients who received immunotherapy as first-/second-line and third-/fourth-line respectively., Conclusions: Programmed cell death protein-1-targeted immunotherapy with nivolumab or pembrolizumab showed promising efficacy and safety in patients with advanced hepatocellular carcinoma, including subjects with Child-Pugh stage B and patients with intensive pretreatment., (© 2019 The Authors. Alimentary Pharmacology & Therapeutics Published by John Wiley & Sons Ltd.)