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Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment 1 . Yet, response rates are still limited, and tumour progression commonly occurs 2 . Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity. Recently, growth differentiation factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with antitumour immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1-mediated checkpoint inhibition 3 . In a first-in-human phase 1-2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Here we show that durable and deep responses were achieved in some patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently immunosuppressed by GDF-15 in an in silico screening of approximately 10,000 tumour samples in The Cancer Genome Atlas database. Increased levels of tumour infiltration, proliferation, interferon-γ-related signalling and granzyme B expression by cytotoxic T cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer., Competing Interests: Competing interests: M.H. and J.W. are co-founders and stock owners of CatalYm. A.d.S., M. Rüdiger, P.L’H., M.H., J.A., A.D., A.A., A.G., F.H., M.A., M.L., D.R., C.S.-W., F.S.L., P.F., K.K., F.H., B.R. and E.L. are current or former employees of and/or hold stock options in Catalym. R.D., M.H., J.W., K.K., E.L., F.H., M. Rüdiger and C.S.-W. are inventors on patents related to visugromab and anti-GDF-15 treatment (WO2014049087, WO2015144855, WO2017055613, WO2022101263, WO2024052532, WO2024126808 and unpublished). I. Melero, H.H., R.B., R.D., J.W., F.J.K., A.M.M.E., W.H.F., T.F.G., P.L., M.M., S.S., A.T. and J.R. have received research funding or consulting or advisory fees from CatalYm. Several authors and investigators declare potentially competing interests (grants or contracts and/or royalties or licences, stock or stock options, consulting fees, honoria, travel or meeting support, or advisory or data safety monitoring board participation) apart from their relationship with CatalYm: I. Melero (Agenus, Alligator, Allmiral, AstraZeneca, Biontech, BMS, Boehringer Ingelheim, Bright Peak, Crescendo Biologics, Curon, Dynamicure, F-Star, Genmab, Highlight Therapeutics, HotSpot, Merck Serono, MSD, Merus, Mestag, Numab, PharmaMar, Pieris, Pierre Fabre, Pioneering Medicines, Roche, Sanofi and Servier); G.d.V. (Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen MSD, Merck Serono, Pfizer and Roche); E.G. (Anaveon, BeiGene, Boehringer Ingelheim, Ellipses Pharma, F-Star Therapeutics, Hengrui, Incyte, Janssen Global Services, MabDiscovery, Medscape, MSD, Novartis, Seattle Genetics, Sanofi, Roche, SeaGen, Taiho and Thermo Fisher); J.M.-L. (Astellas, BMS, Highlight Therapeutics, Merck Serono, MSD, Novartis, Ipsen, Roche, Sanofi and Pierre Fabre); M.J. (Adoram, AstraZeneca, Debiopharm, Novartis, Roche, Sanofi and Takeda); M.-E.G. (BMS, Janssen, Novartis and Roche); M.S. (Amgen, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, MSD, Novartis, Roche, Sanofi and Tacalyx); D.K. (AstraZeneca, Amgen, BMS, Merck Serono, MSD, Mirati, PharmaMar, Sanofi and Swiss Oncology in Motion); R.D. (Alligator, Amgen, BMS, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Takeda, Sanofi, Second-Genome, Regeneron, T3 Pharma, MaviVax, Pfizer, Simcere and touchIME); M. Reig (AstraZeneca, Bayer, BMS, Boston Scientific, Biotoscana Pharma, Engitix Therapeutics, Eli Lilly, Geneos, Gilead, Ipsen, Merck, Roche and Universal DC); M.-E.R.R. (BMS, Imcore-Roche, Roche and Highlight Therapeutics); E.C. (Achilles, Adcendo, Alkermes, Amunix, Anaveon, Amcure, AstraZeneca, BeiGene, BMS, Boehringer, Chugai, Debiopharm, Diaccurate, Ellipses, Incyte, iTeos, Janssen, Merus, MonTa, MSD, Nanobiotix, Nouscom, Novartis, OncoDNA, PharmaMar, PsiOxus Therapeutics, Roche/Genentech, Sanofi, Servier, Shionogi, Syneos Health, TargImmune, T-knife and Tolremo); J.E.-V. (BMS, MSD and Pfizer); J.J.S.-C. (Eisai, Novartis, Pfizer and Seagen); K.-L.K. (Janssen and Takeda); O.S. (Affimed); C.S. (BMS, Eli Lilly and Boehringer Ingelheim); E.R. (BMS, Eli Lilly, Kyowa Kirin, Leo Pharma, MSD, Pierre Fabre and Sanofi); A.L.-M. (Incyte, Merck, PharmaMar, Pfizer, Roche, Rovi and Sanofi); I. Moreno (Digicore Initiative, Fondacion Intheos, Exafield, Guidepoint and Ellipses Pharma); A.H.-C. (BMS, Gilead, Kyowa Kirin, Merus and MSD); D.H. (Novartis and Roche); M.S.-Z. (Bayer, Instituto de Salud Carlos III (grant FI19/00222), BTG, MSD and Roche); A.V.-L. (AstraZeneca, BMS, Health in Code and Roche); J.T. (Amgen, AstraZeneca, Bristol Myers Squibb, Eisai, EXACT Therapeutics, Institut für Qualitätssicherung und Transparenz im Gesundheitswesen, Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, Ipsen, Lilly ImClone, medupdate, Merck Serono, Merck Sharp & Dome, Oncolytics Biotech, onkowissen.de, Roche, Servier and streamedup!); C.K. (AstraZenca, BMS, DGVS, Incyte, MCI Deutschland, MSD, Servier, Ipsen, Merck Serono and Roche); P.R.G. (AstraZeneca, Bayer, BMS, Boston Scientific, Eisai, Guerbet, Ipsen, MSD, Lilly, Roche and Sirtex); F.F. (AstraZeneca, BMS, Eisai, Merck Serono, Servier and Roche); Z.T. (Boehringer Ingelheim); H.H. (Secarna); F.J.K. (German Cancer Aid (Deutsche Krebshilfe)); H. Reis (AstraZeneca, BMS, Boehringer Ingelheim, Chop GmbH, Diaceutics, GSK, HUeG, Janssen, MCI, Merck, Novartis, Roche Pharma and Sanofi); M.M. (LYO-X AG and TATAA Biocenter); T.G. (Allogene, Bicara, BMS, Merck, Pyxis and Samyang); W.H.F. (Anaveon, Atreca, Incendia, Ichnos Sciences, Genenta, OSE Immunotherapeutics, Oxford Biotherapeutics, Mestag, Novartis, Roche and Tabby); A.M.M.E. (Acetra, Agenus, BMS, Boehringer Ingelheim, BioInvent, BioNTech, Ellipses, Galecto, GSK, IO Biotech, IQVIA, Isa Pharmaceuticals, Merck & Co, MSD, Pfizer, Pierre Fabre, Sairopa, Sellas, SkylineDX, TigaTx and Trained Immunity); R.B. (Amgen, Avencell); J.R. (Astellas, AstraZeneca, BMS, Daiichi Sankyo, GSK, MSD, Merck and Sanofi); F.H. (Thermosome); P.F. (Curevac); J.W. (Bayrische Forschungsstiftung (FORTiTher) and the German Ministry for Education & Research (Transcan-3)). The remaining authors declare no competing interests., (© 2024. The Author(s).)

Background: An increasing number of HCC develops in the context of metabolic dysfunction-associated steatotic liver disease and its inflammatory form, metabolic dysfunction-associated steatohepatitis, even in the absence of cirrhosis. Chronic metabolic inflammation is the driving force of metabolic dysfunction-associated steatotic liver disease progression and a key factor in hepatocarcinogenesis. Given the prominent role of IL-1 signaling in inflammation and metabolic diseases, we investigated the relevance of the hepatocyte-specific IL-1 receptor type 1 knockout in metabolic dysfunction-associated steatohepatitis-related noncirrhotic HCC., Methods: For HCC induction, Il1r1Hep-/- mice received a single i.p. injection of diethylnitrosamine at 2 weeks and were fed with high-fat plus high-carbohydrate diet, starting from 4 weeks. After 18 weeks of diet intervention, mice were sacrificed, and macroscopic and microscopic tumor loads were assessed., Results: Knockout of the hepatic IL-1 receptor type 1 pathway significantly reduced liver tumor growth. Il1r1Hep-/- mice were also less susceptible to hepatic steatosis, insulin resistance, and associated hepatic c-Jun N-terminal kinase activation than their wild-type (WT) littermates. Reduced Ki-67 and cyclin D1 levels, as well as decreased phosphorylation of signal transducer and activator of transcription 3, occur in Il1r1Hep-/- livers, lowering cancer cell proliferation and growth. Additionally, in Il1r1Hep-/- livers, the chemokine (C-X-C motif) ligand 1/2-driven accumulation of myeloid-derived suppressor cells and CD8+ T-cell infiltration were reduced compared to the wild type., Conclusions: Metabolic inflammation mediated by the hepatocytic IL-1 receptor type 1 is a cofactor in mutagenic hepatocarcinogenesis. Targeting IL-1 signaling could be an adjunct strategy to the current immunomodulatory HCC treatments., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Age-related cognitive decline has become an increasingly relevant public health issue. However, risk and protective factors of cognitive decline have yet to be investigated prospectively taking into account genetic, lifestyle, physical and mental health factors. Population-based data from middle-aged (40 to 59 years; N = 2,764) and older individuals (60 to 80 years; N = 1,254) were drawn from a prospective community cohort study using the Tower of London (TOL) planning task. Assessments were repeated at a 5-year interval to investigate age-related changes in planning performance and to determine the impact of risk and protective factors. Planning performance improved in middle-aged, but declined in older participants over 5 years. SNPs affecting the dopamine system (COMT, DRD2) and APOE polymorphisms differentially predicted cognitive performance in older vs. middle-aged individuals. For older individuals, high alcohol consumption, antidepressant medication and living without a partner had additional negative predictive power on cognition. In contrast, undiagnosed hypertension, no obstructive lung disease, and fewer years of education predicted cognitive decline in the middle-aged group. The results inform screening for individuals particularly vulnerable to cognitive decline and interventions (e.g., focusing on lifestyle factors) to help maintain cognitive performance into old age., (© 2024. The Author(s).)

Background & Aims: Atezolizumab/bevacizumab (A/B) is now a standard first-line treatment for advanced hepatocellular carcinoma (HCC), but the optimal second-line regimen is not known. We evaluated real-world treatment patterns and outcomes to investigate factors associated with post-progression survival (PPS)., Methods: In this multicenter, international, retrospective study, we examined clinical characteristics and outcomes of patients with advanced HCC who progressed on first-line A/B. The primary outcome of PPS was defined as time from first radiographic progression on A/B to death., Results: A total of 406 patients alive after progression on first-line A/B were included in the final analysis, of whom 45.3% (n = 184) received best supportive treatment (BST) and 54.7% (n = 222) continued active systemic treatment. In the second line, 155 patients were treated with tyrosine kinase inhibitors (TKIs), 45 with immune checkpoint inhibitor (IO)-based regimens, and 3 had missing data. Median PPS of the whole cohort (mPPS) was 6.0 months (95% CI 5.2-7.2). On multivariate Cox regression analysis, absence of portal vein tumor thrombus, ECOG <2, and continued active treatment were predictors of better PPS. mPPS was significantly longer for patients who continued active treatment vs. BST (9.7 vs. 2.6 months; HR 0.41, p < 0.001). In the second-line setting, patients treated with TKIs had a numerically shorter mPPS compared to those treated with IO (8.4 vs. 14.9 months; HR 1.37, p = 0.256)., Conclusions: Continuation of active therapy after A/B progression was independently associated with better survival even after adjusting for baseline disease characteristics. mPPS with IO-based therapy exceeded a year, suggesting that IO continuation post-progression may retain benefit. The precise sequencing of TKI and IO regimens warrants further investigation., Impact and Implications: There is currently a lack of level 1 data on second-line treatment options for patients with advanced hepatocellular carcinoma who progress after frontline atezolizumab plus bevacizumab, as all second-line approvals were established during the frontline sorafenib era. Our study aims to fill in some of the knowledge gap by investigating real-world patient outcomes in the second-line treatment setting. Findings from this study show that patients who continued active treatment had improved post-progression survival compared to those who received best supportive care, and medication regimens incorporating tyrosine kinase inhibitors as well as immunotherapy agents were active. These results can help inform clinicians of possible treatment options for patients who progress after frontline atezolizumab plus bevacizumab while we await maturing data from randomized-controlled trials., Competing Interests: Celina Ang has received compensation for participating in advisory boards for Bayer and Caris Life Sciences. Lorenz Balcar has served as a speaker for Chiesi and Gilead. Ciro Celsa has received speaker fees or been on the advisory boards of AstraZeneca, MSD/Eisai, Ipsen and has received travel support from Roche. Hong Jae Chon holds consulting or advisory roles with Eisai, Roche, Bayer, ONO, MSD, BMS, Celgene, Sanofi, Servier, AstraZeneca, SillaJen, Menarini, and GreenCross Cell, and has received research grants from Roche, Dong-A ST, and Boryung Pharmaceuticals. Alessio Cortellini received grants for consultancies/advisory boards: BMS, MSD, OncoC4, IQVIA, Roche, GSK, AstraZeneca, Access Infinity, Ardelis Health and REGENERON. He also received speaker fees from AstraZeneca, EISAI, MSD, SANOFI/REGENERON and Pierre-Fabre. Antonio D’Alessio received educational support for congress attendance from Roche, and consultancy fees from Roche, Astrazeneca, and Chugai. Johann von Felden received honoraria from Roche and AstraZeneca. Friedrich Foerster has received honoraria for lectures from AstraZeneca, Lilly, MSD, Pfizer and Roche. He has served as advisory board member to AstraZeneca, BMS, Eisai and Roche and has received travel support from Merck KGaA and Servier. Peter Galle reports honoraria for advisory boards and lectures from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen. Wei-Fan Hsu received speaker fees from AstraZeneca, Eisai, and Roche. Ahmed O Kaseb received research support from Genentech, BMS, Merck, Eisai, Exelixis, AdaptImmune and Tvardi and has been on the advisory board/has received honoraria from/been a consultant for: Genentech, BMS, Merck, Eisai, Exelixis. Masatoshi Kudo has received lecture fees from Eisai and Chugai and has served as an advisor for Roche, BMS, Ono, AstraZeneca, MSD, and Eisai. Neehar Parikh has served as a consultant or advisor for Genentech, Astra Zeneca, Exact Sciences, Eisai, Fujifilm Medical, and Gilead. Matthias Pinter received speaker honoraria from Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he is a consultant/advisory board member for AstraZeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he received grants from AstraZeneca, Bayer, BMS, Eisai, and Roche; he received travel support from Bayer, BMS, Ipsen, and Roche. Tiziana Pressiani received consulting fees from Bayer, Ipsen, and AstraZeneca; institutional research funding from Roche, Bayer, Astra Zeneca; travel expenses from Roche. Lorenza Rimassa received consulting fees from AbbVie, AstraZeneca, Basilea, Bayer, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, BMS, Incyte, Ipsen, Roche, Servier; travel expenses from AstraZeneca; research grants (to Institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Zymeworks. Anwaar Saeed reports a leadership role with Autem therapeutics, Exelixis, KAHR medical and Bristol-Myers Squibb; consulting or advisory board role with AstraZeneca, Bristol-Myers Squibb, Merck, Exelixis, Pfizer, Xilio therapeutics, Taiho, Amgen, Autem therapeutics, KAHR medical, and Daiichi Sankyo; institutional research funding from AstraZeneca, Bristol-Myers Squibb, Merck, Clovis, Exelixis, Actuate therapeutics, Incyte Corporation, Daiichi Sankyo, Five prime therapeutics, Amgen, Innovent biologics, Dragonfly therapeutics, Oxford Biotherapeutics, Arcus therapeutics, and KAHR medical; and participation as a data safety monitoring board chair for Arcus therapeutics. Bernhard Scheiner received grant support from AstraZeneca and Eisai, speaker honoraria from Eisai as well as travel support from AbbVie, AstraZeneca, Ipsen and Gilead. Kornelius Schulze received honoraria from MSD, Roche, and AstraZeneca. Amit Singal has served as a consultant or been on advisory boards for Genentech, AstraZeneca, Eisai, Bayer, Exelixis, Merck, Boston Scientific, Sirtex, HistoSonics, FujiFilm Medical Sciences, Exact Sciences, Glycotest, and Roche. Susanna V Ulahannan reports advisory board roles with Eisai, Astra Zeneca, and IGM biosciences. She has received institutional support for research from AbbVie, Adlai Nortye, Artios Pharma, ArQule, Inc, Astra Zeneca, Atreca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Corporation, Ciclomed, Eisai, Erasca, Evelo Biosciences, Exelexis, G1 Therapeutics, GlaxoSmithKline, IGM biosciences, Immunitas Therapeutics, Incyte, Isofol, Jazz Pharmaceuticals, Klus Pharma, Macrogenics, Merck, Mersana Therapeutics, Omega Therapeutics, OncoMed Pharmaceuticals, Pfizer, Purple, Regeneron, Revolution Medicines, Synermore Biologics, Takeda, Tarveda Therapeutics, Tesaro, Tempest Therapeutics, Theradex, Totos Medicines, Tvardi Therapeutics, Vigeo Therapeutics Inc. Arndt Vogel reports consultancy, speaker and advisory roles at: AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, EISAI, Incyte, Ipsen, MSD, PierreFabre, Roche, Servier, and Tahio. Arndt Weinmann received compensations as a member of scientific advisory boards for AstraZeneca, Bayer, BMS, MSD, Eisai, Servier and Sanofi. He served as a speaker for Leo Pharma, Eisai, Ipsen, Abbvie, AstraZeneca and Roche and received travel support from Merck and Servier. Reports no COI: Claudia AM Fulgenzi, Joshua Glover, Yi-Hsiang Huang, Angelo Pirozzi, Giulia F Manfredi, Yehia Mohamed, Naoshi Nishida, Alessandro Parisi, Natascha Roehlen, Martin Schönlein, Marianna Silletta, Bernardo Stefanini, Y. Linda Wu, Meng Wu. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Authors.)

People with type 2 diabetes mellitus (T2DM) show a high prevalence of steatotic liver disease (SLD), and especially metabolic dysfunction-associated steatotic liver disease (MASLD), with liver fibrosis. Their health-related quality of life (HRQL) is affected by multiple in part overlapping factors and aggravated by metabolic and liver-related comorbidities, including liver fibrosis stage. The aim of this study was to investigate the effect size of advanced fibrosis (AF) on the HRQL in people with T2DM. A total of 149 individuals with T2DM treated at a primary care provider within the German disease management program (DMP) were included in the final analysis. Vibration-controlled transient elastography (VCTE) was used to non-invasively detect steatosis and AF. The EQ-5D-3L questionnaire was used to assess the HRQL. Uni- and multivariable linear regression models were used to identify independent predictors of impaired HRQL. The majority was male (63.1%), and the median age was 67 years (IQR 59; 71). In the entire cohort, the prevalence of MASLD and AF was 70.7% and 19.5%, respectively. People with T2DM and AF had an overall lower HRQL in comparison to those without AF (p < 0.001). Obesity (β: - 0.247; 95% CI - 0.419, - 0.077) and AF (β: - 0.222; 95% CI - 0.383, - 0.051) remained independent predictors of a poor HRQL. In turn, T2DM-related comorbidities were not predictive of an impaired HRQL. Obesity and AF negatively affect the HRQL in patients with SLD and T2DM in primary care. Awareness of liver health and specific interventions may improve patient-reported and liver-related outcomes in people with T2DM., (© 2024. The Author(s).)

Background & Aims: Elevated liver stiffness has been associated with atrial fibrillation (AFib) in the general population. The mechanism underlying this association is unclear., Methods: Participants were recruited from the general population and prospectively enrolled with follow-up for 5 years. The fibrosis-4 (FIB-4) index was used as a surrogate marker for liver fibrosis. Proteomics analysis was performed using the 92-target Olink inflammation panel. Validation was performed using the NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet index (APRI), and repeat confirmation proteomics., Results: A sample of 11,509 participants with a mean age of 54.0 ± 11.1 years, 51.3% women, and a median FIB-4 index of 0.85 (0.65/1.12), was used. The FIB-4 index was predictive for prevalent (FIB-4 index adjusted odds ratio (aOR) per SD: 1.100 with 95% CI 1.011-1.196; p  = 0.026), but not incident AFib (log[FIB-4 index]) adjusted hazard ratio: 1.125 with 95% CI 0.943-1.342, p  = 0.19). Elastic net regularized regression identified CCL20, DNER, and CXCL10 for prevalent AFib, and AXIN1, CXCL10, and Flt3L for the log(FIB-4 index) (per SD) as most important in common regulated proteins. The relationship between the FIB-4 index, the identified proteins, and AFib was relevant and reproduced at the 5-year follow-up for CXCL10 after adjusting for confounders (log[FIB-4 index] per SD - CXCL10 [per SD] adjusted β 0.160 with 95% CI 0.127-0.194, p <0.0001; CXCL10 [per SD] - AFib aOR 1.455 with 95% CI 1.217-1.741, p <0.0001), reproduced using the NFS and APRI, and corresponding to increased serum levels., Conclusions: CXCL10 is linked to liver fibrosis, as determined by the FIB-4 index, and to prevalent AFib., Impact and Implications: How elevated liver stiffness relates to atrial fibrillation in the general population remains to be clarified. We hypothesized that systemic inflammation against a background of liver fibrosis produced from metabolic dysfunction-associated steatotic liver disease (MASLD), is involved in the pathophysiology of atrial fibrillation. Using large-scale targeted proteomics, we found that CXCL10 is related to both liver fibrosis, as defined by the fibrosis-4 index, and to atrial fibrillation. These results can aid evidence-based drug development for patients with atrial fibrillation and MASLD-related liver fibrosis., (© 2024 The Author(s).)

Preliminary work has shown that portal hypertension plays a key role for the prognosis in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Specifically, the presence of ascites appears to be a strong negative predictor for these patients. However, it remains unclear whether different ascites volumes influence prognosis. Therefore, the aim of this work was to investigate the influence of different ascites volumes on survival for patients with HCC undergoing TACE. A total of 327 treatment-naïve patients with HCC undergoing initial TACE at our tertiary care center between 2010 and 2020 were included. In patients with ascites, the fluid was segmented, and the volume quantified by slice-wise addition using contrast-enhanced CT imaging. Median overall survival (OS) was calculated and univariate and multivariate Cox regression analysis has been performed. Ascites was present in 102 (31.9%) patients. Ascites volume as continuous variable was significantly associated with an increased hazard ratio in univariate analysis (p < 0.001) and remained an independent predictor of impaired median OS in multivariate analysis (p < 0.001). Median OS without ascites was 17.1 months, and therefore significantly longer than in patients with ascites (6.4 months, p < 0.001). When subdivided into groups of low and high ascites volume in relation to the median ascites volume, patients with low ascites volume had a significantly longer median OS (8.6 vs 3.6 months, p < 0.001). Ascites in patients with HCC undergoing TACE is strongly associated with a poor prognosis. Our results show that not only the presence but also the amount of ascites is highly relevant. Therefore, true ascites volume as opportunistic quantitative biomarker is likely to impact clinical decision-making once automated solutions become available., (© 2024. The Author(s).)

Introduction: Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) in IMbrave150. Efficacy and safety in patient subpopulations with Vp4 portal vein tumor thrombosis (PVTT) and other high-risk prognostic factors are reported., Methods: IMbrave150 was a global, randomized (2:1), open-label, phase 3 study in systemic treatment-naive patients with unresectable HCC; OS and PFS were co-primary endpoints. Exploratory analyses compared the efficacy and safety of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg every 3 weeks versus sorafenib 400 mg twice daily in patients (i) with and without Vp4 PVTT alone and (ii) with and without high-risk prognostic factors., Results: In patients with Vp4 PVTT, median OS was 7.6 months (95% CI: 6.0-13.9) with atezolizumab plus bevacizumab ( n = 48) and 5.5 months (95% CI: 3.4-6.7) with sorafenib ( n = 25; HR 0.62 [95% CI: 0.34-1.11]; descriptive p = 0.104). Median PFS in the respective arms was 5.4 months (95% CI: 3.6-6.9) and 2.8 months (95% CI: 1.5-5.3; HR 0.62 [95% CI: 0.35-1.09]; descriptive p = 0.094). In patients without Vp4, median OS was 21.1 months (95% CI: 18.0-24.6) with atezolizumab plus bevacizumab ( n = 288) and 15.4 months (95% CI: 12.6-18.6) with sorafenib ( n = 140; HR 0.67 [95% CI: 0.51-0.88]; descriptive p = 0.003). Median PFS in the respective arms was 7.1 months (95% CI: 6.1-9.6) and 4.7 months (95% CI: 4.2-6.1; HR 0.64 [95% CI: 0.51-0.81]; descriptive p < 0.001). The high-risk versus non-high-risk populations had similar outcome patterns. In the respective treatment arms, grade ≥3 treatment-related adverse events occurred in 43% and 48% of patients with Vp4 and 46% and 47% of patients without Vp4., Conclusion: Regardless of VP4 PVTT or other high-risk features of unresectable HCC, which have often resulted in exclusion from other front-line trials, patients benefited from atezolizumab and bevacizumab versus sorafenib., Competing Interests: Richard S. Finn reports receiving consulting fees from AstraZeneca, Bayer, CStone Pharmaceuticals, Eisai, Eli Lilly, Exelixis, F. Hoffmann-La Roche Hengrui, Merck, and Pfizer; research funding to institution from Adaptimmune, Bristol Myers Squibb, Eisai, Eli Lilly, Merck, Pfizer, and F. Hoffmann-La Roche Ltd; and is an Editorial Board Member of Liver Cancer. Peter R. Galle reports receiving consulting fees from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp and Dohme, and Sirtex Medical; honoraria from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp and Dohme, and Sirtex Medical; advisory fees from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp and Dohme, and Sirtex Medical; and research funding to institution from Bayer and F. Hoffmann-La Roche Ltd. Michel Ducreux reports receiving honoraria, consulting fees, or advisory fees to self from Amgen, AstraZeneca, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Serono, Pierre Fabre, and Servier; travel support from Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Sharp & Dohme, and Servier; speaker bureau participation for Amgen, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, and Merck Serono; and research funding to institution from Bayer and F. Hoffmann-La Roche Ltd. Ann-Lii Cheng reports receiving research funding to institution from F. Hoffmann-La Roche Ltd. Alan Nicholas is an employee and stockholder of Roche/Genentech. Philippe Merle has had a consulting or advisory role for Bayer, Ipsen, Lilly, Eisai, AstraZeneca, Bristol Myers Squibb, and MSD; received institutional research funding from Ipsen; and travel and accommodation expenses from Bayer and Ipsen. Riad Salem is a consultant for Boston Scientific, Eisai, Genentech, Cook, Sirtex and AstraZeneca. Daneng Li has received honoraria and advisory/consultancy fees from AstraZeneca, Ipsen, Eisai, Exelixis, Coherus, Genentech, QED, Merck, Adagene, Delcath, Servier, Sumitomo, Transthera, and TerSera; and received institutional research funding from Brooklyn Immunotherapeutics and AstraZeneca. Valeriy Breder has received advisory/consultancy fees from F. Hoffmann-La Roche, MSD, Eisai, Bristol Myers Squibb, and Ipsen; and travel and accommodation expenses from F. Hoffmann-La Roche, MSD, Eisai, Bristol Myers Squibb, and Bayer. Ning Ma is an employee and stockholder of Roche/Genentech. Sairy Hernandez is an employee and stockholder of Roche/Genentech., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Minimal hepatic encephalopathy, defined by the portosystemic hepatic encephalopathy score (PHES), is associated with a higher risk of subsequent OHE. It remains unclear if there is a stepwise increase in OHE risk with worse PHES results., Methods: In this multicenter study, patients with minimal hepatic encephalopathy, as defined by abnormal PHES, were followed for OHE development., Results: In all, 207 patients were included. There was no stepwise increase in OHE risk with worse PHES results., Conclusions: Abnormal PHES is associated with a higher OHE risk, but we found no stepwise increase in OHE risk with worse PHES results below the established cutoff., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: The current management of metabolic dysfunction-associated steatotic liver disease (MASLD) relies on lifestyle intervention. Prior studies have shown that nutritional wheat amylase trypsin inhibitors (ATI) activate toll-like receptor 4 on intestinal myeloid cells to enhance intestinal and extra-intestinal inflammation, including the promotion of murine MASLD, insulin resistance and liver fibrosis., Aims: We aimed to assess the impact of ATI (gluten)-free diet in liver as well as metabolic parameters of biopsy-proven MASLD patients., Methods: We performed a 6-week, proof-of-concept 1:1 randomised controlled trial of an ATI-free diet. The controls followed a balanced diet recommended by the German Nutrition Society. We assessed changes in controlled attenuation parameter (CAP), body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA-IR). Patient-reported outcomes were assessed by the CLDQ-NASH questionnaire. Forty-five patients were consecutively enrolled (21 in the intervention arm and 24 in the control arm)., Results: Three patients from each arm discontinued the study. In the ATI-free diet group, a significant decrease in BMI (p = 0.018), CAP (p = 0.018) and HOMA-IR (p = 0.042) was observed at 6 weeks. The mean difference in CAP between the two arms at week 6 was 30.5 dB/m (p = 0.039), with a delta significantly higher in the ATI-free diet group (p = 0.043). Only an ATI-free diet could achieve a significant improvement in CLDQ-NASH domains (p value for total scoring: 0.013)., Conclusions: A short-term ATI-free diet leads to significant improvements in liver and metabolic parameters, as well as patient-reported outcomes with good tolerability. A larger follow-up study is justified to corroborate these findings., Clinical Trial Number: NCT04066400., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: Data on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting, and data from multicentre studies are scarce. The aim of this study was to dissect the potential association between PPI use and minimal (MHE) and overt HE (OHE)., Methods: Data from patients with cirrhosis recruited at seven centres across Europe and the US were analysed. MHE was defined by the psychometric hepatic encephalopathy score (PHES). PPI use was recorded on the day of testing with PHES. Patients were followed for OHE development and death/liver transplantation., Results: A total of 1,160 patients with a median MELD of 11 were included (Child-Pugh stages: A 49%/B 39%/C 11%). PPI use was noted in 58% of patients. Median follow-up time was 18.1 months, during which 230 (20%) developed an OHE episode, and 224 (19%) reached the composite endpoint of death/liver transplantation. In multivariable analyses, PPI use was neither associated with the presence of MHE at baseline nor OHE development during follow-up. These findings were consistent in subgroup analyses of patients with Child-Pugh A or B cirrhosis and after excluding patients with a history of OHE. PPI use was also not associated with a higher risk of OHE, neither in patients with an indication for treatment nor in patients without an indication., Conclusions: PPI use is not associated with a higher risk of HE in patients with cirrhosis. Based on these findings, at present, a prescription should not be prohibited in case of a generally accepted indication., Impact and Implications: Data on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting. In this study, PPI use was not associated with a higher risk of minimal HE at baseline or overt HE during follow-up in patients with cirrhosis. Based on these findings, prescription of a PPI for a generally accepted indication should not be prohibited in patients with cirrhosis., (© 2024 The Author(s).)

Background and Aims: Minimal hepatic encephalopathy (MHE) is a frequent complication in patients with liver cirrhosis. Its impact on predicting the development of overt hepatic encephalopathy (OHE) and survival has not been studied in large multicenter studies., Methods: Data from patients recruited at eight centers across Europe and the United States were analyzed. MHE was detected using the psychometric hepatic encephalopathy score (PHES). A subset was also tested with the simplified animal naming test (S-ANT1). Patients were followed for OHE development and death/liver transplantation (LTx)., Results: A total of 1462 patients with a median model of end-stage liver disease of 11 were included (Child-Pugh (CP) stages: A 47%/B 41%/C 12%). Median follow-up time was 19 months, during which 336 (23%) patients developed an OHE episode and 464 (32%) reached the composite end point of death/LTx (369 deaths, 95 LTx). In multivariable analyses, MHE (defined by PHES) was associated with the development of OHE (subdistribution hazard ratio 1.74, p < 0.001) and poorer LTx-free survival (hazard ratio 1.53, p < 0.001) in the total cohort as well as in the subgroup of patients without a history of OHE. In subgroup analyses, MHE (defined by PHES) was associated with OHE development in patients with CP B, whereas there was no association in patients with CP A or C. In the subgroup of patients with available S-ANT1, MHE (defined by S-ANT1) was independently associated with OHE development. Combined testing (PHES+S-ANT1) was superior to single testing for predicting OHE and poorer LTx-free survival., Conclusions: This large multicenter study demonstrates that screening for MHE is a useful tool for predicting OHE and poorer survival., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background: Type 2 diabetes mellitus (T2DM) is a major risk factor for advanced liver disease. The aim of this prospective cohort study was to assess the prevalence and associated risk factors of liver fibrosis and cirrhosis in primary care centers participating in the diabetes disease management program (DMP) in Germany., Methods: A total of 175 participants with the diagnosis of T2DM were enrolled in two primary care centers. Steatotic liver disease (SLD; hepatic steatosis, ≥275 dB/m), fibrosis (≥8 kPa), and cirrhosis (≥15 kPa) were assessed non-invasively using vibration-controlled transient elastography. Multivariable logistic regression analysis was performed to identify clinical predictors of fibrosis and cirrhosis. The AUDIT questionnaire was used to screen for alcohol consumption, and a score ≥8 was considered harmful alcohol consumption., Results: The majority of participants were male (62%), and the median age was 66 years (interquartile range 59; 71). The median body mass index was 31.1 kg/m 2 , with 58.9% of the participants being obese. Harmful alcohol consumption was prevalent in 8.0% and 20.0% of the entire cohort and in those with cirrhosis, respectively. The prevalence of SLD, fibrosis, and cirrhosis was 77.1%, 42.3%, and 12.0%, respectively. In multivariable logistic regression analysis, obesity, and harmful alcohol consumption were associated with the highest odds of fibrosis (odds ratio [OR] 5.198, 95% confidence interval [CI] 2.269-11.908) and cirrhosis (OR 5.615, 95% CI 1.274-24.756), respectively., Conclusion: The prevalence of fibrosis and cirrhosis in patients seen in the diabetes DMP in Germany is high. Obesity and harmful alcohol consumption increase the risk of fibrosis and cirrhosis in people with T2DM. Screening for advanced liver disease and associated risk factors within the DMP program may reduce the liver disease burden in this high-risk population., (© 2024 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known., Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS)., Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes., Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted., Impact and Implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised., Systematic Review Registration: PROSPERO CRD42023429625., Competing Interests: The authors have nothing to disclose regarding the work under consideration for publication. The following authors disclose conflicts of interests outside the submitted work: L.B. has nothing to disclose. B.Sc. received travel support from AbbVie, AstraZeneca, Gilead and Ipsen as well as grant support from AstraZeneca. C.A.M.F. has nothing to disclose. A.D. is supported by the National Institute for Health Research (NIHR) Imperial BRC, by grant funding from the European Association for the Study of the Liver (2021 Andrew Burroughs Fellowship) and from Cancer Research UK (RCCPDB- Nov21/100008). A.D. received educational support for congress attendance and consultancy fees from Roche. K.P. has nothing to disclose. M.B.R. has nothing to disclose. E.L.M. is a salaried employee of Berry Consultants. J.C. has nothing to disclose. N.N. has nothing to disclose. P.-C.L. has nothing to disclose. L.W. has nothing to disclose. C.A. has nothing to disclose. A.K. has nothing to disclose. An.S. has nothing to disclose. B.St. has nothing to disclose. A.Ca. has nothing to disclose. T.P. has nothing to disclose. Y.I.A. has nothing to disclose. S.C. has nothing to disclose. B.W. has nothing to disclose. A.P. has nothing to disclose. Y.-H.H. has nothing to disclose. S.P. has nothing to disclose. C.V. has nothing to disclose. F.S. has nothing to disclose. G.M. has nothing to disclose. D.B. has nothing to disclose. A.V. has nothing to disclose. J.v.F. has received advisory board fees from Roche. K.S. has nothing to disclose. M.S. has nothing to disclose. M.T. served as a speaker and/or consultant and/or advisory board member for Albireo, BiomX, Falk, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Hightide, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens and Shire, and received travel support from AbbVie, Falk, Gilead, and Intercept as well as grants/research support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid. Ad.S. is supported by grant funding from CRUK, served as a speaker for Merck and Chugai and received grants from Histosonics, Transgene, Oncolytics and Theolytics. H.W. has received lecture and consulting fees from AstraZeneca, Roche, and Eisai. F.P. has received honoraria for advisory board or lecturing from Astrazeneca, Bayer, Bracco, ESAOTE, EISAI, Exact Sciences, GE, IPSEN, MSD, Roche, Samsung, Siemens Healthineers. P.R.G. received honoraria from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen and Daiichi-Sankyo. R.S. has nothing to disclose. M.K. received lecture fees from Eli Lilly, Bayer, Eisai, Chugai, Takeda, AstraZeneca as well as grant support from Taiho, Otsuka, EA Pharma, AbbVie, Eisai, Chugai, GE Healthcare; and acts on advisory boards from Chugai, Roche, AstraZeneca, Eisai. A.G.S. has served as a consultant or on advisory boards for Genentech, AztraZeneca, Eisai, Exelixis, Bayer, Boston Scientific, FujiFilm Medical Sciences, Exact Sciences, Roche, Glycotest, Freenome, and GRAIL. Dr. Singal’s research is conducted with support from National Cancer Institute R01 MD012565 and R01 CA256977. A.I. has nothing to disclose. S.V.U. has served on advisory boards for Eisai, Astra Zeneca, IgM biosciences and received institutional support for research from AbbVie, Inc, Adlai Nortye, ArQule, Inc, AstraZeneca, Atreca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Corporation, Ciclomed LLC, Erasca, Evelo Biosciences, Inc, Exelexis, G1 Therapeutics, Inc, GlaxoSmithKline GSK, IGM biosciences, Incyte, Isofol, Klus Pharma, Inc, Macrogenics, Merck Co. Inc, Mersana Therapeutics, OncoMed Pharmaceuticals, Inc, Pfizer, Regeneron, Inc, Revolution Medicines, Inc, Synermore Biologics Co, Takeda, Tarveda Therapeutics, Tesaro, Tempest, Vigeo Therapeutics Inc. (all funds to institution). N.D.P. serves as a consultant for Exact Sciences, Eli Lilly, Freenome, Astra Zeneca and has served on advisory boards of Genentech, Eisai, Bayer, Exelixis, Wako/Fujifilm and has received research funding from Bayer, Target Pharmasolutions, Exact Sciences, and Glycotest. A.Co. served as consultant/advisory role for AstraZeneca, BMS, MSD, Roche, IQVIA and OncoC4. He also received speaker’s fees from AstraZeneca, Pierre-Fabre, EISAI. A.K. has nothing to disclose. L.R. reports consulting fees from AstraZeneca, Basilea, Bayer, BMS, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, Eisai, Gilead, Incyte, Ipsen, Merck, Serono, Roche, Sanofi, Servier; travel expenses from AstraZeneca; research grants (to Institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. H.J.C. has nothing to disclose. D.J.P. is supported by grant funding from the Wellcome Trust Strategic Fund (PS3416) and acknowledges grant support from the Cancer Treatment and Research Trust (CTRT); the NIHR Imperial Biomedical Research Centre; and the AIRC MFAG Grant No. 25697, Associazione Italiana per la Ricerca sul Cancro Foundation, Milan, Italy. D.J.P. acknowledges the following COIs: Lecture fees: Bayer Healthcare, Astra Zeneca, EISAI, Bristol-Myers-Squibb, Roche, Ipsen; Travel expenses: Bristol-Myers-Squibb, Roche, Bayer Healthcare; Consulting fees: Mina Therapeutics, Boeringer Ingelheim, Ewopharma, EISAI, Ipsen, Roche, H3B, Astra Zeneca, DaVolterra, Mursla, Avammune Therapeutics, LiFT Biosciences, Exact Sciences; Research funding (to institution): MSD, BMS, GSK. M.P. served as a speaker and/or consultant and/or advisory board member for Astra Zeneca, Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Lilly, MSD, and Roche, and received travel support from Bayer, Bristol-Myers Squibb, Ipsen, and Roche. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background: Spleen stiffness measurement (SSM) performed by transient elastography at 100 Hz is a novel technology for the evaluation of portal hypertension in advanced chronic liver disease, but technical aspects are lacking. We aimed to evaluate the intraexamination variability of SSM and to determine the best transient elastography protocol for obtaining robust measurements to be used in clinical practice., Methods: We analyzed 253 SSM exams with up to 20 scans for each examination, performed between April 2021 and June 2022. All SSM results were evaluated according to different protocols by dividing data into groups of n measurements (from 2 to 19). Considering as reference the median SSM values across all the 20 measurements, we calculated the distribution of the absolute deviations of each protocol from the reference median. This analysis was repeated 1,000 times by resampling the data. Distributions were also stratified by etiology (chronic liver disease versus clinically significant portal hypertension) and different SSM ranges: < 25 kPa, 25-75, and > 75 kPa., Results: Overall, we observed that the spleen stiffness exam had less variability if it exceeded 12 measurements, i.e., absolute deviations ≤ 5 kPa at 95% confidence. For exams with higher SSM values (> 75 kPa), as seen in clinically significant portal hypertension, at least 15 measurements are highly recommendable., Conclusions: Fifteen scans per examination should be considered for each SSM exam performed at 100 Hz to achieve a low intraexamination variability within a reasonable time in clinical practice., Relevance Statement: Performing at least 15 scans per examination is recommended for 100 Hz SSM in order to achieve a low intraexamination variability, in particular for values > 75 kPa compatible with clinically significant portal hypertension., Key Points: • Spleen stiffness measurement by transient elastography is used for stratification in patients with portal hypertension. • At 100 Hz, this method may have intraexamination variability. • A minimum of 15 scans per examination achieves a low intraexamination variability., (© 2023. The Author(s).)

What Is This Summary About?: This is a summary of results from a phase 3 clinical study called HIMALAYA. HIMALAYA looked at treatment with one dose of a medication called tremelimumab combined with multiple doses of a medication called durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone. These treatments were compared with a medication called sorafenib in participants with unresectable hepatocellular carcinoma (HCC). HCC is a type of liver cancer that is difficult to treat because it is often diagnosed when it is unresectable, meaning it can no longer be removed with surgery. Sorafenib has been the main treatment for unresectable HCC since 2007. However, people who take sorafenib may experience side effects that can reduce their quality of life, so alternative medicines are being trialed. Tremelimumab and durvalumab are types of drugs called immunotherapies, and they both work in different ways to help the body's immune system fight cancer., What Were the Results of the Study?: Participants who took STRIDE lived longer than participants who took sorafenib, whilst participants who took durvalumab alone lived a similar length of time as participants who took sorafenib. Participants who took STRIDE or durvalumab had a lower relative risk of experiencing worsening in their quality of life than participants who took sorafenib. The side effects that participants who received STRIDE or durvalumab experienced were expected for these types of treatments and could mostly be managed., What Do the Results of the Study Mean?: Overall, STRIDE is more effective than sorafenib for people with unresectable HCC.

Background: Systemic inflammation with elevated inflammatory cytokines is a hallmark in patients with cirrhosis and the main driver of decompensation. There is insufficient data on whether inflammatory cytokine levels differ between hepatic and jugular veins, which may have implications for further immunological studies., Methods: Blood from the hepatic and jugular veins of 40 patients with cirrhosis was collected during hepatic venous pressure gradient (HVPG) measurements. Serum levels of 13 inflammatory cytokines (IL-1 β , Int- α 2, Int- γ , TNF- α , MCP-1, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23, and IL-33) were quantified by cytometric bead array., Results: Cytokine levels of IFN- α 2, IFN- γ , TNF- α , IL-6, IL-8, IL-10, IL-17A, IL-18, IL-23, and IL-33 were significantly elevated in patients with decompensated cirrhosis compared to patients with compensated cirrhosis. When comparing patients with clinically significant portal hypertension (CSPH, HVPG ≥ 10 mmHg) to patients without CSPH, there were significantly enhanced serum levels of IL-6 and IL-18 in the former group. There was no significant difference between cytokine serum levels between blood obtained from the jugular versus hepatic veins. Even in subgroup analyses stratified for an early cirrhosis stage (Child-Pugh (CP) A) or more decompensated stages (CP B/C), cytokine levels were similar., Conclusion: Cytokine levels increase with decompensation and increasing portal hypertension in patients with cirrhosis. There is no relevant difference in cytokine levels between hepatic and jugular blood in patients with cirrhosis., Competing Interests: The authors declare no competing interests., (Copyright © 2023 Leonard Kaps et al.)

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs)., Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs. A-2). PFS was evaluated per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated., Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 versus A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs. 9.7 months) per IRF-HCC mRECIST for group A-1 versus A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis., Discussion/conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab., Competing Interests: Masatoshi Kudo reports the following conflicts of interest: honoraria payment to self from Bayer, Chugai Pharmaceutical Co. Ltd., Eli Lilly, Eisai, and Takeda; research funding to institution from AbbVie, Chugai Pharmaceutical Co. Ltd., EA Pharma, Eisai, F. Hoffmann-La Roche Ltd, GE HealthCare, Gilead Sciences, Otsuka, Sumitomo Dainippon Pharma, Taiho, and Takeda; and Editor in Chief of Liver Cancer. Kaoru Tsuchiya reports the following conflicts of interest: advisory/consultancy fees to self from Chugai Pharmaceutical Co. Ltd. and Eisai; speakers bureau participation for Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, and Takeda; and research funding to institution from F. Hoffmann-La Roche Ltd. Yu-Yun Shao reports the following conflicts of interest: honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd, Ipsen, Merck, and Ono. Richard S. Finn reports the following conflicts of interest: consulting fees to self from AstraZeneca, Bayer, CStone Pharmaceuticals, Eisai, Eli Lilly, Exelixis, F. Hoffmann-La Roche Ltd., Hengrui, Merck, and Pfizer; research funding to institution from Adaptimmune, Bristol Myers Squibb, Eisai, Eli Lilly, Merck, Pfizer, and F. Hoffmann-La Roche Ltd.; and Editorial Board Member of Liver Cancer. Peter R. Galle reports the following conflicts of interest: consulting fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; honoraria payment to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; advisory fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; and research funding to institution from Bayer and F. Hoffmann-La Roche Ltd. Michel Ducreux reports the following conflicts of interest: honoraria, consulting fees, or advisory fees to self from Amgen, AstraZeneca, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Serono, Pierre Fabre, and Servier; travel support from Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Sharp & Dohme, and Servier; speakers bureau participation for Amgen, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, and Merck Serono; and research funding to institution from Bayer and F. Hoffmann-La Roche Ltd. Ann-Lii Cheng reports the following conflicts of interest: research funding to institution from F. Hoffmann-La Roche Ltd. Tatsuya Yamashita reports the following conflicts of interest: speakers bureau participation for Bayer and Chugai Pharmaceutical Co. Ltd. and research funding to institution from F. Hoffmann-La Roche Ltd. Hironori Koga reports the following conflicts of interest: research funding to institution from AbbVie, Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo, and F. Hoffmann-La Roche Ltd. Ryosuke Take, Kyoko Yamada, Takashi Asakawa, and Yuki Nakagawa reports the following conflicts of interest: employment by Chugai Pharmaceutical Co. Ltd. Masafumi Ikeda reports the following conflicts of interest: honoraria to self from Bayer, Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, and Takeda; advisory/consulting fees to self from Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, Merck Sharp & Dohme, and Takeda; and research funding to institution from Bayer, Bristol Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Merck Sharp & Dohme, and Takeda., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: A well-recognized class effect of immune checkpoint inhibitors (ICI) is immune-related adverse events (IrAEs) ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI. Deaths are reported in < 5% of patients treated with ICI. There are, however, no reliable markers to predict the onset and severity of IrAEs. We tested the association between neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) at baseline with development of clinically significant IrAEs (grade ≥ 2) in hepatocellular carcinoma (HCC) patients treated with ICI., Aim: To test the association between NLR and PLR at baseline with development of clinically significant IrAEs (grade ≥ 2) in HCC patients treated with ICI., Methods: Data was extracted from an international database from a consortium of 11 tertiary-care referral centers. NLR = absolute neutrophil count/absolute lymphocyte count (ALC) and PLR = platelet count/ALC. Cutoff of 5 was used for NLR and 300 for PLR based on literature. We also tested the association between antibiotic and steroid exposure to IrAEs., Results: Data was collected from 361 patients treated between 2016-2020 across the United States (67%), Asia (14%) and Europe (19%). Most patients received Nivolumab ( n = 255, 71%). One hundred sixty-seven (46%) patients developed at least one IrAE, highest grade 1 in 80 (48%), grade ≥ 2 in 87 (52%) patients. In a univariable regression model PLR > 300 was significantly associated with a lower incidence of grade ≥ 2 IrAEs (OR = 0.40; P = 0.044). Similarly, a trend was observed between NLR > 5 and lower incidence of grade ≥ 2 IrAEs (OR = 0.58; P = 0.097). Multivariate analyses confirmed PLR > 300 as an independent predictive marker of grade ≥ 2 IrAEs (OR = 0.26; P = 0.011), in addition to treatment with programmed cell death ligand 1 (PD-1)/cytotoxic T lymphocyte-associated protein-4 (OR = 2.57; P = 0.037) and PD-1/tyrosine kinase inhibitor (OR = 3.39; P = 0.01) combinations. Antibiotic use was not associated with IrAE incidence (OR = 1.02; P = 0.954). Patients treated with steroids had a > 2-fold higher incidence of grade ≥ 2 IrAEs (OR = 2.74; P < 0.001), although 74% were prescribed steroids for the treatment of IrAEs., Conclusion: Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs, lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI. This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs., Competing Interests: Conflict-of-interest statement: Rimassa L report consulting fees from AstraZeneca, Basilea, Bayer, BMS, Eisai, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, Merck Serono, Roche, Servier; travel expenses from AstraZeneca; research grants (to institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. Pressiani T reports consulting fees from Bayer, Ipsen, AstraZeneca; travel expenses from Roche; research grants (to institution) from Roche, Bayer, Astra Zeneca. Personeni N reports consulting fees from Amgen, Merck KGaA, Boehringer Ingelheim, IQVIA, Servier, Sanofi Aventis; lecture fees from Janssens, Astra Zeneca, Incyte; research grants (to institution) from Servier, Basilea; travel expenses from Amgen, Servier. Pinter M 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. Scheiner B received travel support from AbbVie, Ipsen and Gilead. Bettinger D received consulting fees from Bayer Healthcare, Boston Scientific, and Shionogi. Lectures: Falk Foundation. A.C. received consulting fees from MSD, BMS, AstraZeneca, and Roche; speakers’ fee from AstraZeneca, MSD, Novartis, and Astellas. Pinato DJ received lecture fees from ViiV Healthcare and Bayer Healthcare, and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, and Astra Zeneca; and received research funding (to institution) from MSD and BMS. Saeed A receives consulting fee from AstraZeneca; Bristol-Myers Squibb; Daiichi Sankyo/Astra Zeneca; Exelixis; Five Prime Therapeutics; Pfize, speakers fee from Daiichi Sankyo/Astra Zeneca and research funding from Actuate Therapeutics (Inst); Astellas Pharma (Inst); AstraZeneca/MedImmune (Inst); Bristol-Myers Squibb (Inst); Clovis Oncology (Inst); Daiichi Sankyo/UCB Japan (Inst); Exelixis (Inst); Five Prime Therapeutics (Inst); KAHR Medical (Inst); Merck Sharp and Dohme (Inst); Seattle Genetics (Inst). Khan U receives honoraria from Cardinal Health, consulting fee from Bard Peripheral Vascular and travel expenses paid for by Bard Peripheral Vascular; Cardinal Health. Huang YH is a consultant for Bayer; Bristol-Myers Squibb; Eisai; Gilead Sciences; Lilly; MSD; Roche and received speaker honoraria from Bayer; Bristol-Myers Squibb; Eisai; Gilead Sciences; Lilly; MSD; Roche. Kesab AO receives honoraria from AstraZeneca; Bayer Health; Bristol-Myers Squibb; Eisai; Exelixis; Genentech/Roche; Merck and research funding from Adaptimmune (Inst); Bayer/Onyx (Inst); Bristol-Myers Squibb (Inst); Genentech (Inst); Hengrui Pharmaceutical (Inst); Merck (Inst). Pillai A received consulting fee from AstraZeneca; Eisai; Exelixis; Genentech; Replimune, research funding from Target Pharmasolutions and speaker honoraria from Simply Speaking PAH. All remaining authors have declared no conflicts of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Patients with cirrhosis and especially those with HE may have impaired driving skills and may be prone to car accidents. This proof-of-concept study aimed to develop and evaluate the applicability of a virtual reality (VR)-based driving test in patients with cirrhosis. Additionally, the association between the results in the VR test and car accidents was investigated., Methods: A short driving test using a VR head-mounted display (HTC Vive Pro Eye) was developed to simulate five hazardous situations. The patient has to pull the brake when the hazardous situations occur. The time from triggering the event to pressing the brake is recorded as reaction time. Total reaction time (TRT) is defined as the combined reaction time to all 5 events. Car accidents were assessed retrospectively (previous 12 months) and patients were followed prospectively for 6 months. Minimal HE (MHE) was diagnosed using Psychometric Hepatic Encephalopathy Score., Results: In total, 112 outpatients with cirrhosis and 52 controls without cirrhosis were recruited. MHE was detected in 14% (n = 15). Patients with cirrhosis and MHE (5.67 s) had higher TRTs compared to patients without MHE (5.02 s) and controls without cirrhosis above the age of 50 (4.98 s) (MHE vs. no MHE or controls p<0.01, no MHE vs. controls: not significant). Seven patients reported car accidents during the twelve months prior to study inclusion. TRTs were numerically higher in patients with reported car accidents (p = 0.099). When patients who stopped driving for HE-related/cirrhosis-related reasons (n = 14) were added to the group of patients with accidents, then a longer TRT was significantly associated with the modeled outcome in univariable (p<0.01) and multivariable analyses (OR 2.83, p<0.01). Two car accidents occurred during follow-up. Both patients had TRTs above the 90th percentile., Conclusions: The VR driving test is easy and rapid to perform in patients with cirrhosis and could be helpful as a point-of-care tool for predicting car accidents., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Objective: This study aimed to explore psychosocial consequences of (false) positive liver screening results and to identify influencing factors for perceived strain within a multistage screening programme for liver cirrhosis and fibrosis in Germany., Methods: Between June 2018 and May 2019, all positively screened patients were asked to participate in the study (n = 158). N = 11 telephone interviews and n = 4 follow-up interviews were conducted. Semi-structured telephone interviews were carried out. The analysis followed a structuring content analysis approach. Thereby, categories were first defined deductively. Second, the categories were revised inductively based on the data., Results: The main themes found regarding the consequences of the screening were categorised in emotional reactions and behavioural reactions. Few respondents described negative emotional consequences related to screening. Those seem to be mostly driven by suboptimal patient-provider communication and might be worsened when transparent information transfer fails to happen. As a result, patients sought information and support in their social environment. All patients reported positive attitudes towards liver screening., Conclusion: To reduce the potential occurrence of psychosocial consequences during the screening process, medical screening should be performed in the context of transparent information. Regular health communication on the side of health professionals and increasing patients' health literacy might contribute to avoiding negative emotions in line with screening., Patient or Public Contribution: This study recognises the wide-ranging patients' perspectives regarding the consequences of liver screening which should be taken into consideration when implementing a new screening programme to ensure a patient-centred approach., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Introduction: Intratumoral administration of pexa-vec (pexastimogene devacirepvec), an oncolytic and immunotherapeutic vaccinia virus, given to patients with hepatocellular carcinoma (HCC), is associated with both local and distant tumor responses. We hypothesized subsequent treatment with sorafenib could demonstrate superior efficacy., Methods: This random phase III open-label study evaluated the sequential treatment with pexa-vec followed by sorafenib compared to sorafenib in patients with advanced HCC and no prior systemic treatment. The primary endpoint is overall survival (OS). Key secondary endpoints included time to progression (TTP), progression-free survival, overall response rate (ORR), and disease control rate (DCR). Safety was assessed in all patients who received ≥1 dose of study treatment., Results: The study was conducted at 142 sites in 16 countries. From December 30, 2015, to the interim analysis on August 2, 2019, 459 patients were randomly assigned (pexa-vec plus sorafenib: 234, sorafenib: 225). At the interim analysis, the median OS was 12.7 months (95% CI: 9.89, 14.95) in the pexa-vec plus sorafenib arm and 14.0 months (95% CI: 11.01, 18.00) in the sorafenib arm. This led to the early termination of the study. The median TTP was 2.0 months (95% CI: 1.77, 2.96) and 4.2 months (95% CI: 2.92, 4.63); ORR was 19.2% (45 patients) and 20.9% (47 patients); and DCR was 50.0% (117 patients) and 57.3% (129 patients) in the pexa-vec plus sorafenib and sorafenib arms, respectively. Serious adverse events were reported in 117 (53.7%) patients in the pexa-vec plus sorafenib and 77 (35.5%) patients in the sorafenib arm. Liver failure was the most frequently reported in both groups., Conclusion: Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The advent of the added value of checkpoint inhibitors should direct any further development of oncolytic virus therapy strategies., Competing Interests: Ghassan K. Abou-Alfa reports research support from Arcus, Astra Zeneca, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Silenseed, Yiviva, and consulting support from Adicet, Alnylam, Astra Zeneca, Autem, Beigene, Berry Genomics, Boehringer Ingelheim, Celgene, Cend, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Helsinn, Incyte, Ipsen, Merck, Nerviano, Newbridge, Novartis, QED, Redhill, Rafael, Servier, Silenseed, Sobi, Vector, Yiviva, plus patent PCT/US2014/031545 filed on March 24, 2014, and priority application Serial No.: 61/804,907; filed: March 25, 2013. Peter R. Galle reports research support from Bayer and Roche and consulting support from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, and Ipsen. Joseph Erinjeri reports consulting support from AztraZeneca. Jeong Heo received grants/research support from Roche, Yuhan, and Gilead and participates on trials steering committee for Sillajen, Oncolys, Gilead, and AstraZeneca. Mitesh J. Borad report research support from Senhwa Pharmaceuticals, Adaptimmune, Agios Pharmaceuticals, Halozyme Pharmaceuticals, Celgene Pharmaceuticals, EMD Merck Serono, Toray, Dicerna, Taiho Pharmaceuticals, Sun Biopharma, Isis Pharmaceuticals, Redhill Pharmaceuticals, Boston Biomed, Basilea, Incyte Pharmaceuticals, Mirna Pharmaceuticals, Medimmune, Bioline, Sillajen, ARIAD Pharmaceuticals, PUMA Pharmaceuticals, Novartis Pharmaceuticals, QED Pharmaceuticals, Pieris Pharmaceuticals, and consulting support from ADC Therapeutics, Exelixis Pharmaceuticals, Inspyr Therapeutics, G1 Therapeutics, Immunovative Therapies, OncBioMune Pharmaceuticals, Western Oncolytics, Lynx Group, Genentech, Merck, Huya. James Burke is employed by CG Oncology and is consultant for Oncomyx, Kalivir, Western Oncolytics, Sonata, and Amped. Adina Pelusio is employed by Kalivir Immunotherapeutics and reports previous employment by SillaJen Biotherapeutics and Turnstone Biologics, Corp. Delphine Agathon reports previous employment by Transgene. Caroline Breitbach is an inventor on SillaJen patents. Edward Gane is a member of the Scientific Advisory Boards as an advisor and/or speaker for AbbVie, Abbott Diagnostics, Aligos, Arbutus, Arrowhead, Assembly, Dicerna, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Novartis, Roche, Surrozen, The Liver Company, Vaccitech, Virion Therapeutics, and Vir Bio and is on Speakers’ Bureau for AbbVie and Abbott Diagnostics. Yee Chao, Angelo Luca, Monika Lusky, and Shukui Qin report no conflicts of interest., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Postembolization syndrome (PES) represents the most frequent complication after transarterial chemoembolization (TACE) in patients with HCC. Given the vague definition as a symptom complex comprising abdominal pain, fever, and nausea, PES is diagnosed in heterogeneous patient cohorts with symptoms ranging from mild pain to severe deterioration of their general condition. This study aimed to evaluate predictive factors and the prognostic impact of PES with regard to different severity grades., Methods: A total of 954 patients treated with TACE for HCC at the University Medical Centres Mainz and Freiburg were included in this study. PES disease severity was graded as mild, moderate, or severe according to a predefined combination of symptoms. Logistic regression models were used to identify independent predictors of PES. The prognostic impact of PES was evaluated by competing risk analyses considering liver transplantation as a competing risk., Results: PES occurred in 616 patients (64.5%), but only 56 patients (5.9%) had severe PES, defined as moderate to severe abdominal pain requiring opioids in combination with fever and nausea. The largest tumor diameter was the strongest independent predictor of PES (OR = 1.21, 95% CI = 1.13-1.28), and severe PES (OR = 1.23, 95% CI = 1.14-1.33, p < 0.0001). Presence of liver cirrhosis was protective against PES (OR = 0.48, 95% CI = 0.27-0.84, p = 0.01). Furthermore, PES was independently associated with an impaired disease control rate (OR = 0.33, 95% CI = 0.16-0.69, p = 0.003) and severe PES with poor overall survival (subdistribution HR = 1.53, 95% CI = 0.99-2.36, p = 0.04)., Conclusions: Tumor size and absence of liver cirrhosis are predictors of severe PES and associated with impaired prognosis in HCC patients after TACE., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), remains a significant contributor to cancer-related mortality worldwide. Oxidative stress and lipid peroxidation play a key role in chronic liver diseases and have been shown to be pivotal for tumor initiation and progression. 4-hydroxy-nonenal (4-HNE), one of the major mediators of oxidative stress and a well-established biomarker for lipid peroxidation, can act as a signal transducer, inducing inflammation and exerting carcinogenic effects. However, the role of 4-HNE in primary liver cancer remains poorly explored. In this study, we investigated 4-HNE levels in 797 liver carcinomas, including 561 HCC and 236 iCCA, by immunohistochemistry. We then correlated 4-HNE levels with comprehensive clinical data and survival outcomes. In HCC, lower expression levels of 4-HNE were associated with vascular invasion, a high tumor grade, a macrotrabecular-massive HCC subtype, and poor overall survival. Concerning iCCA, large duct iCCA showed significantly higher 4-HNE levels when compared to small duct iCCA. Yet, in iCCA, 4-HNE levels did not correlate with known prognostic parameters or survival outcomes. To conclude, in HCC but not in iCCA, low amounts of 4-HNE predict unfavorable survival outcomes and are associated with aggressive tumor behavior. These findings provide insights into the role of 4-HNE in liver cancer progression and may enable novel therapeutic strategies.

Hepatocytes exert pivotal roles in metabolism, protein synthesis and detoxification. Non-parenchymal liver cells (NPCs), largely comprising macrophages, dendritic cells, hepatic stellate cells and liver sinusoidal cells (LSECs), serve to induce immunological tolerance. Therefore, the liver is an important target for therapeutic approaches, in case of both (inflammatory) metabolic diseases and immunological disorders. This review aims to summarize current preclinical nanodrug-based approaches for the treatment of liver disorders. So far, nano-vaccines that aim to induce hepatitis virus-specific immune responses and nanoformulated adjuvants to overcome the default tolerogenic state of liver NPCs for the treatment of chronic hepatitis have been tested. Moreover, liver cancer may be treated using nanodrugs which specifically target and kill tumor cells. Alternatively, nanodrugs may target and reprogram or deplete immunosuppressive cells of the tumor microenvironment, such as tumor-associated macrophages. Here, combination therapies have been demonstrated to yield synergistic effects. In the case of autoimmune hepatitis and other inflammatory liver diseases, anti-inflammatory agents can be encapsulated into nanoparticles to dampen inflammatory processes specifically in the liver. Finally, the tolerance-promoting activity especially of LSECs has been exploited to induce antigen-specific tolerance for the treatment of allergic and autoimmune diseases.

The prevalence of metabolic risk factors and non-alcoholic fatty liver disease (NAFLD) is high among people living with HIV (PLWH). Data on the recently proposed definition of metabolic dysfunction-associated fatty liver disease (MAFLD) in PLWH receiving antiretroviral therapy (ART) remains unknown. A total of 282 PLWH were included in this cross-sectional cohort study. Vibration-controlled transient elastography (VCTE) was used to assess hepatic steatosis and fibrosis. MAFLD and its subgroups (overweight/obese, lean/normal weight, and type 2 diabetes) were defined according to a recently published international consensus statement. The majority of this cohort was male (n = 198, 70.2%), and the median age was 51.5 years. The median BMI was 25 kg/m 2 , and obesity was prevalent in 16.2% (n = 44). A total of 207 (73.4%) PLWH were classified as non-MAFLD while 75 (26.6%) qualified as MAFLD. The median CAP in the MAFLD group was 320 dB/m. PLWH with MAFLD showed a higher median LSM (p < 0.008) and were older (p < 0.005) compared to the non-MAFLD group. Overall, the metabolic risk profile was comparable between MAFLD and NAFLD. The majority of PLWH and MAFLD were overweight or obese (n = 58, 77.3%). The highest median LSM values were observed in the subgroup with MAFLD and type 2 diabetes. HIV-related parameters did not differ between non-MAFLD and MAFLD. The prevalence of MAFLD in PLWH is high and comparable to NAFLD. PLWH may be characterized according to the novel MAFLD criteria and its subgroups to identify patients at risk for chronic liver disease., (© 2023. The Author(s).)

We report about a proctitis and ileitis terminalis, leading to the misdiagnosis of Chron's disease, in a male patient who has sex with men. Molecular multiplex analysis identified Entamoeba histolytica as the underlying cause. We provide diagnostic images, clues and pitfalls for diagnosis of E. histolytica associated proctitis., Competing Interests: All authors declare that they have no conflicts of interest in the context of this work., (© 2023 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Both the Chronic Liver Failure Consortium (CLIF-C) organ failure score (OFs) and the CLIF-C acute-on-chronic-liver failure (ACLF) score (ACLFs) were developed for risk stratification and to predict mortality in patients with liver cirrhosis and ACLF. However, studies validating the predictive ability of both scores in patients with liver cirrhosis and concomitant need for intensive care unit (ICU) treatment are scarce. The aim of the present study is to validate the predictive ability of the CLIF-C OFs and CLIF-C ACLFs regarding the rationale of ongoing ICU treatment and to investigate their predictive ability regarding 28-days (short-), 90-days (medium-), and 365-days (long-term) mortality in patients with liver cirrhosis treated in an ICU. Patients with liver cirrhosis and acute decompensation (AD) or ACLF and concomitant need for ICU treatment were retrospectively analyzed. Predictive factors for mortality, defined as transplant-free survival, were identified using multivariable regression analyses and the predictive ability of CLIF-C OFs, CLIF-C ACLFs, MELD score, and AD score (ADs) was assessed by determining the AUROC. Of 136 included patients, 19 patients presented with AD and 117 patients with ACLF at ICU admission. In multivariable regression analyses, CLIF-C OFs as well as CLIF-C ACLFs were independently associated with higher short-, medium-, and long-term mortality after adjusting for confounding variables. The predictive ability of the CLIF-C OFs in the total cohort in short-term was 0.687 (95% CI 0.599-0.774). In the subgroup of patients with ACLF, the respective AUROCs were 0.652 (95% CI 0.554-0.750) and 0.717 (95% CI 0.626-0.809) for the CLIF-C OFs and for the CLIF-C ACLFs, respectively. ADs performed well in the subgroup of patients without ACLF at ICU admission with an AUROC of 0.792 (95% CI 0.560-1.000). In the long-term, the AUROCs were 0.689 (95% Cl 0.581-0.796) and 0.675 (95% Cl 0.550-0.800) for CLIF-C OFs and CLIF-C ACLFs, respectively. The predictive ability of CLIF-C OFs and CLIF-C ACLFs was relatively low to predict short- and long-term mortality in patients with ACLF with concomitant need for ICU treatment. However, the CLIF-C ACLFs may have special merit in judging futility of further ICU treatment.

Primary liver cancer is the third leading cause of cancer-related death worldwide. An increasing body of evidence suggests that the Hippo tumor suppressor pathway plays a critical role in restricting cell proliferation and determining cell fate during physiological and pathological processes in the liver. Merlin (Moesin-Ezrin-Radixin-like protein) encoded by the NF2 (neurofibromatosis type 2) gene is an upstream regulator of the Hippo signaling pathway. Targeting of Merlin to the plasma membrane seems to be crucial for its major tumor-suppressive functions; this is facilitated by interactions with membrane-associated proteins, including CD44 (cluster of differentiation 44). Mutations within the CD44-binding domain of Merlin have been reported in many human cancers. This study evaluated the relative contribution of CD44- and Merlin-dependent processes to the development and progression of liver tumors. To this end, mice with a liver-specific deletion of the Nf2 gene were crossed with Cd44 -knockout mice and subjected to extensive histological, biochemical and molecular analyses. In addition, cells were isolated from mutant livers and analyzed by in vitro assays. Deletion of Nf2 in the liver led to substantial liver enlargement and generation of hepatocellular carcinomas (HCCs), intrahepatic cholangiocarcinomas (iCCAs), as well as mixed hepatocellular cholangiocarcinomas. Whilst deletion of Cd44 had no influence on liver size or primary liver tumor development, it significantly inhibited metastasis formation in Nf2 -mutant mice. CD44 upregulates expression of integrin β2 and promotes transendothelial migration of liver cancer cells, which may facilitate metastatic spreading. Overall, our results suggest that CD44 may be a promising target for intervening with metastatic spreading of liver cancer.

Background: Clinically significant portal hypertension (CSPH) has been identified as an important prognostic factor in patients with hepatocellular carcinoma (HCC) undergoing curative treatment. This study aimed to assess PH estimates as prognostic factors in patients with HCC treated with immunotherapy., Methods: All patients with HCC treated with an immunotherapeutic agent in first or subsequent lines at our tertiary care center between 2016 and 2021 were included (n = 50). CSPH was diagnosed using the established PH score for non-invasive PH estimation in pre-treatment CT data (cut-off ≥ 4). Influence of PH on overall survival (OS) and progression-free survival (PFS) was assessed in uni- and multivariable analyses., Results: Based on the PH score, 26 patients (52.0%) were considered to have CSPH. After treatment initiation, patients with CSPH had a significantly impaired median OS (4.1 vs 33.3 months, p < 0.001) and a significantly impaired median PFS (2.7 vs 5.3 months, p = 0.02). In multivariable Cox regression, CSPH remained significantly associated with survival (HR 2.9, p = 0.015) when adjusted for established risk factors., Conclusions: Non-invasive assessment of CSPH using routine CT data yielded an independent prognostic factor in patients with HCC and immunotherapy. Therefore, it might function as an additional imaging biomarker to detect high-risk patients with poor survival and possibly for treatment decision making., (© 2023. The Author(s).)

Background: Microvascular invasion (MVI) can only be assessed on a full surgical specimen. We aimed at evaluating, whether the histology of the primary tumor is predictive of MVI in a hepatocellular carcinoma (HCC) recurrence., Methods: Patients, who underwent liver resection or orthotopic liver transplantation (OLT) for recurrent HCC from January 2001 until June 2018 were eligible for this retrospective analysis. Resected specimens were evaluated for HCC subtype/morphology, vessels encapsulating tumor clusters (VETC)-pattern and MVI. Dichotomous parameters were analyzed using χ 2 -test and ϕ-values, with P values <0.05 being considered significant., Results: Of 230 HCC recurrences, 37 (16.1%) underwent repeated liver resection (n=22) or OLT (n=15). Of these, 67.6% initially exceeded the Milan criteria. MVI correlated Milan criteria (P=0.005), tumor size (P=0.015) and VETC-pattern (P=0.034) in the primary specimen. The recurrences shared many features of the primary HCC such as tumor grade (P=0.002), VETC-pattern (P=0.035), and MVI (P=0.046). In recurrences, however, only the concordance with the Milan criteria correlated with MVI (P=0.018). No patient without MVI in the primary HCC revealed MVI on early recurrence (<2 years) (P=0.035)., Conclusions: HCC recurrences share many biological features of the primary tumor. Moreover, early recurrences of MVI-negative HCC never revealed MVI. This finding offers novel concepts, e.g., patient selection for salvage OLT., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-346/coif). HL serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. JUM participated in advisory boards for Bayer, Eisai, AstraZeneca, Roche. PRG receives consulting fees from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen; and payment or honoraria from Bayer Adaptimmune, Sirtex, Lilly, Roche, Ipsen. The other authors have no conflicts of interest to declare., (2023 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Hepatic encephalopathy (HE) is one of the most important complications of patients with liver cirrhosis. In addition, HE is associated with a dismal prognosis and has detrimental effects on patients' quality of life. Thus, it is of pivotal importance to identify patients at high risk for overt HE (OHE) in whom primary prophylaxis may be justified. In this narrative review, we aim to provide insight into predictors and prediction tools for a first-time episode of OHE and to scrutinize the current level of evidence of primary prophylaxis. In recent decades, several cognitive tests, composite scores, and blood-based biomarkers have been demonstrated to be predictive of a first-time episode of OHE. Among the best validated are the established tests for minimal HE, such as the Psychometric Hepatic Encephalopathy Score, determination of the critical flicker frequency, Stroop EncephalApp, or the Animal Naming Test. Individualized risk stratification using blood-based biomarkers and cross-sectional imaging (sarcopenia and spontaneous portosystemic shunts) is coming to the fore, but validation in larger multicenter cohorts is often lacking. On the basis of current evidence, a recommendation for primary prophylaxis of a first episode of OHE cannot be made in general. Only 2 studies have investigated the prevention of a first-time OHE episode as the primary endpoint. In this narrative review, we provide a concise overview of the current evidence levels on prediction tools and pharmacological prevention of a first episode of OHE. In addition, we give an outlook on future research targets to improve knowledge on this important topic., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon., Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D., Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events., Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment., Impact and Implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment., Competing Interests: CD has received travel support from Gilead. FT has received grants or contracts from any entity from Allergan, BMS, Inventiva, Gilead; consulting fees from Allergan, Bayer, Gilead, BMS, Boehringer, Intercept, Ionis, Inventiva, Merz, Pfizer, Alnylam, NGM, CSL Behring, Novo Nordisk, Novartis; payment for expert testimony from Alnylam; support for attending meetings and/or travel from Gilead; participation on a Data Safety Monitoring Board or Advisory Board from Pfizer. CZ has no COI. MD has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead and MYR, support for attending meetings and/or travel from Gilead; participation on a Data Safety Monitoring Board or Advisory Board from Gilead and MYR. HS has no COI. CS received support for attending meetings and/or travel from Abbvie and Gilead, participation on a Data Safety Monitoring Board or Advisory Board form Gilead. KW has no COI. CL has received consulting fees from CSL Behring, Boston Scientific, Astra Zeneca, Eisai, Shionogi, Sobi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Gilead, Falk, BSL Behring, Eisai; support for attending meetings and/or travel from Gilead and Abbvie. SW received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Falk and Abbvie; support for attending meetings and/or travel form Orphalan, Falk, Abbvie. GD received consulting fees from Alexion, Gilead, Intercept, Novartis, Orphalan, Univar; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Falk Foundation, Gilead, Intercept, Novartis, Orphalan; support for attending meetings and/or travel support form Gilead and Intercept. CB received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead; and support for attending meetings and/or travel from Gilead. JG has no COI. UM received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from CSL Behring, MSD, Falk, Univar, Microbiotica; support for attending meetings and/or travel from Gilead; participation on a Data Safety Monitoring Board or Advisory Board from Takeda, Gilead, CSL Behring; AO has no COI; SZ reports speaker’s bureau and/or consultancy for Abbvie, BioMarin, Gilead, GSK, Intercept, Janssen, Madrigal, MSD/Merck, NovoNordisk, SoBi and Theratechnologies, GSK, Gilead, Intercept; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, BioMarin, Janssen, MSD/Merck; payment for expert testimony and support for attending meetings and/or travel from Gilead. KS received grants from Gilead; honoraria for lectures from Gilead, Abbvie and MSD; support for attending meetings and/or travel from Gilead and Abbvie; participated in advisory boards from Gilead. TB received grants or contracts from any entity from Abbvie, BMS, Gilead, MSD/Merck, Humedics, Intercept, Merz, Novartis, Sequana Medical, received consulting fees from Abbvie, Alexion, Bayer, Gilead, Eisai, GSK, Intercept, Ipsen, Janssen, MSD/Merck, Novartis, Roche, Sequana Medical, and Shionogi; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Alexion, Bayer, Gilead, Eisai, Intercept, Ipsen, Janssen, MedUpdate GmbH, MSD/Merck, Novartis, and Sequana Medica; has received support for attending meetings and/or travel Gilead, Abbvie, Intercept, Janssen. FB received grants or contracts from any entity from Gilead, Ipsen, Roche, Janssen; consulting fees from Gilead, Janssen, Astra Zeneca, MSD, Janssen, Advanz Pharma; support for attending meetings and/or travel from Advanz Pharma and Gilead, reports participation on a Data Safety Monitoring Board or Advisory Board from Janssen. JW has no COI. TH received author honoraria from Falk. TS has no COI. EZ has no COI. ND has no COI. RT has no COI. CNH received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Gilead, GSK, MSD, Falk Foundation. PG has no COI. MS participated in advisory boards from Gilead. AL received consulting fees from Roche, reports participation in advisory boards from Roche, MSD and Genfit. JSW received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and travel support from Gilead. JK has no COI. AG received payment for expert testimony from AbbVie, Alexion, Bayer, BMS, Eisai, Gilead, Intercept, Ipsen, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Sequana. FR received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and support for attending meetings and/or travel from Falk Foundation, Novartis, Ipsen and Gilead. BS received honoraria for lectures from Gilead and Alnylam, received consulting fees from Gilead and Univar, received travel support from Abbvie and Gilead. JG has no COI. WH received speakers honoraria from Gilead, Abbvie, Intercept, Norgine, Novo Nordisk, Falk; support for attending meetings and/or travel from Abbvie and Gilead. PB received consulting fees from Gilead; received payment for speakers bureau from AbbVie, Falk, Gilead, Roche, MSD, Myr; support for attending meetings and/or travel from Abbvie and Gilead. JK has no COI. KP has no COI. BM received grants or contracts from any entity from Roche Diagnostics and Fujirebio; consulting fees from Abbvie, Roche, Luvos; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Roche, Gilead, Norgine, Fujirebio, Merck/MSD, Medical Tribune Forum; support for attending meetings and/or travel from Abbvie and Gilead; holds stocks or stock options from Biontech. MC received consulting fees from Abbvie, AiCuris, Gilead, GlaxoSmithKline, Janssen-Cilag, MSD Sharp & Dohme, Spring Bank Pharmaceuticals, Swedish Orphan Biovitrum AB (SOBI); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Gilead, GlaxoSmithKline, MSD Sharp & Dohme, Falk; reports participation on a Data Safety Monitoring Board or Advisory Board from Novartis; HW received grants or contracts from any entity from AbbVie, Biotest, BMS, Gilead, Merck/MSD, Novartis, Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbott, AbbVie, Altimmune, Biotest, BMS, BTG, Dicerna, Gilead, Janssen, Merck/MSD, MYR GmbH, Novartis, Roche, Siemens. KD has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead, Falk, Abbvie, MSD/Merck and Alnylam. Please refer to the accompanying ICMJE disclosure forms for further details., (.)

Introduction: Atezolizumab + bevacizumab showed survival benefit in patients with unresectable hepatocellular carcinoma (HCC) versus sorafenib in the Phase III IMbrave150 study. This exploratory analysis examined the prognostic impact of a baseline albumin-bilirubin (ALBI) score., Methods: Patients with treatment-naïve unresectable HCC, ≥1 measurable untreated lesion, and Child-Pugh class A liver function were randomized 2:1 to receive atezolizumab 1,200 mg + bevacizumab 15 mg/kg every 3 weeks or sorafenib 400 mg twice daily. Overall survival (OS) and progression-free survival (PFS) were assessed in the intention-to-treat population by ALBI/modified (m)ALBI grade. Time to deterioration (TTD; defined as time to 0.5-point increase from the baseline ALBI score over 2 visits or death) of liver function and safety were investigated., Results: Of 501 enrolled patients, 336 were randomized to receive atezolizumab + bevacizumab (ALBI grade [G] 1: n = 191; G2: n = 144 [mALBI G2a: n = 72, G2b: n = 72]; missing ALBI grade: n = 1) and 165 to sorafenib (ALBI G1: n = 87; G2: n = 78 [mALBI G2a: n = 37; G2b: n = 41]). Median follow-up was 15.6 months. OS and PFS improved with atezolizumab + bevacizumab versus sorafenib in patients with ALBI G1 (OS HR: 0.50 [95% CI: 0.35, 0.72]; PFS HR: 0.61 [95% CI: 0.45, 0.82]). In patients with ALBI G2 or mALBI G2a or G2b, PFS was numerically longer with atezolizumab + bevacizumab versus sorafenib, but no OS benefit was seen. Median TTD in the intention-to-treat population was 10.2 months (95% CI: 8.0, 11.0) with atezolizumab + bevacizumab versus 8.6 months (95% CI: 6.2, 11.8) with sorafenib (HR: 0.82 [95% CI: 0.65, 1.03]). Safety profiles of atezolizumab and bevacizumab were consistent with previous analyses, regardless of ALBI grade., Conclusion: ALBI grade appeared to be prognostic for outcomes with both atezolizumab + bevacizumab and sorafenib treatment in patients with HCC. Atezolizumab + bevacizumab preserved liver function for a numerically longer duration than sorafenib., Competing Interests: Masatoshi Kudo reports the following conflicts of interest: honoraria payment to self from Bayer, Chugai Pharmaceutical Co., Ltd., Eli Lilly, Eisai, and Takeda; research funding to institution from AbbVie, Chugai Pharmaceutical Co., Ltd., EA Pharma, Eisai, F. Hoffmann-La Roche Ltd., GE Healthcare, Gilead Sciences, Otsuka, Sumitomo Dainippon Pharma, Taiho, and Takeda; Editor-in-Chief of Liver Cancer. Richard S. Finn reports the following conflicts of interest: consulting fees to self from AstraZeneca, Bayer, CStone Pharmaceuticals, Eisai, Eli Lilly, Exelixis, F. Hoffmann-La Roche Hengrui, Merck, and Pfizer; research funding to institution from Adaptimmune, Bristol Myers Squibb, Eisai, Eli Lilly, Merck, Pfizer, and F. Hoffmann-La Roche Ltd; Editorial Board Member of Liver Cancer. Ann-Lii Cheng reports the following conflicts of interest: research funding to institution from F. Hoffmann-La Roche Ltd. Andrew X. Zhu reports the following conflicts of interest: consulting fees to self from Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., and Sanofi-Aventxis; research funding to the institution from F. Hoffmann-La Roche Ltd. Michel Ducreux reports the following conflicts of interest: honoraria, consulting fees, or advisory fees to self from Amgen, AstraZeneca, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Serono, Pierre Fabre, and Servier; travel support from Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Sharp & Dohme, and Servier; speaker bureau participation for Amgen, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, and Merck Serono; research funding to institution from Bayer and F. Hoffmann-La Roche Ltd. Peter R. Galle reports the following conflicts of interest: consulting fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; honoraria payment to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; advisory fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; research funding to institution from Bayer and F. Hoffmann-La Roche Ltd. Naoya Sakamoto reports the following conflicts of interest: honoraria payment to self from AbbVie, Eisai, Gilead Sciences, and Otsuka; research funding to institution from Astellas Pharmaceutical, Bayer, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, F. Hoffmann-La Roche Ltd., Gilead Sciences, Otsuka, and Takeda. Naoya Kato reports the following conflicts of interest: honoraria payment to self from Bayer and Chugai Pharmaceutical Co., Ltd.; research funding to institution from Bayer, Chugai Pharmaceutical Co., Ltd., and F. Hoffmann-La Roche Ltd. Michitaka Nakano reports the following conflicts of interest: employment by Chugai Pharmaceutical Co., Ltd. Jing Jia reports the following conflicts of interest: employment by F. Hoffmann-La Roche Ltd. Arndt Vogel reports the following conflicts of interest: consulting fees to self from AstraZeneca, Bayer, Böhringer Ingelheim, Bristol Myers Squibb, BTG Limited, Eisai, F. Hoffmann-La Roche Ltd., Imaging Equipment Ltd. (AAA), Ipsen, Merck Sharp & Dohme, Servier Laboratories, Sirtex Medical, and Terumo; honoraria payment to self from AstraZeneca, Bayer, Böhringer Ingelheim, Bristol Myers Squibb, BTG Limited, Eisai, F. Hoffmann-La Roche Ltd., Imaging Equipment Ltd. (AAA), Ipsen, Merck Sharp & Dohme, Servier Laboratories, Sirtex Medical, and Terumo; travel support from Bayer, Bristol Myers Squibb, and F. Hoffmann-La Roche Ltd.; advisory fees to self from AstraZeneca, Bayer, Bristol Myers Squibb, BTG Limited, Eli Lilly, Eisai, F. Hoffmann-La Roche Ltd., Imaging Equipment Ltd. (AAA), Ipsen, Merck Sharp & Dohme, Sirtex Medical, Servier Laboratories, and Terumo; research funding to institution from F. Hoffmann-La Roche Ltd., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background and Aims: Hepatorenal syndrome is a major complication in patients with cirrhosis and associated with high mortality. Predictive biomarkers for therapy response are largely missing. Cytokeratin18-based cell death markers are significantly elevated in patients with complications of chronic liver disease, but the role of these markers in patients with HRS treated with vasoconstrictors and albumin is unknown., Methods: We prospectively analyzed a total of 138 patients with HRS, liver cirrhosis without HRS and acute kidney injury treated at the University Medical Center Mainz between April 2013 and July 2018. Serum levels of M30 and M65 were analyzed by ELISA and clinical data were collected. Predictive ability was assessed by Kaplan-Meier curves, logistic regression and c-statistic. Primary endpoint was response to therapy., Results: M30 and M65 were significantly increased in patients with HRS compared to non-HRS controls (M30: p < 0.0001; M65: p < 0.0001). Both serum markers showed predictive ability for dialysis- and LTX-free survival but not overall survival. Logistic regression confirmed M30 and M65 as independent prognostic factors for response to therapy. A novel predictive score comprising bilirubin and M65 showed highest predictive ability to predict therapy response., Conclusions: Serum levels of M30 and M65 can robustly discriminate patients into responders and non-responders to terlipressin therapy with a good predictive ability for dialysis- and LTX-free survival in cirrhotic patients. Cell death parameters might possess clinical relevance in patients with liver cirrhosis and HRS., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Background & Aims: Blood biomarkers facilitating the diagnosis of covert hepatic encephalopathy (CHE) in patients with cirrhosis are lacking. Astrocyte swelling is a major component of hepatic encephalopathy. Thus, we hypothesised that glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes, might facilitate early diagnosis and management. This study aimed to investigate the utility of serum GFAP (sGFAP) levels as a biomarker of CHE., Methods: In this bicentric study, 135 patients with cirrhosis, 21 patients with ongoing harmful alcohol use and cirrhosis, and 15 healthy controls were recruited. CHE was diagnosed using psychometric hepatic encephalopathy score. sGFAP levels were measured using a highly sensitive single-molecule array (SiMoA) immunoassay., Results: In total, 50 (37%) people presented with CHE at study inclusion. Participants with CHE displayed significantly higher sGFAP levels than those without CHE (median sGFAP, 163 pg/ml [IQR 136; 268] vs . 106 pg/ml [IQR 75; 153]; p <0.001) or healthy controls ( p <0.001). sGFAP correlated with results in psychometric hepatic encephalopathy score (Spearman's ρ = -0.326, p <0.001), model for end-stage liver disease score (Spearman's ρ = 0.253, p  = 0.003), ammonia (Spearman's ρ = 0.453, p  = 0.002), and IL-6 serum levels (Spearman's ρ = 0.323, p  = 0.006). Additionally, sGFAP levels were independently associated with the presence of CHE in multivariable logistic regression analysis (odds ratio 1.009; 95% CI 1.004-1.015; p <0.001). sGFAP levels did not differ between patients with alcohol-related cirrhosis vs. patients with non-alcohol-related cirrhosis or between patients with ongoing alcohol use vs. patients with discontinued alcohol use.Conclusions: sGFAP levels are associated with CHE in patients with cirrhosis. These results suggest that astrocyte injury may already occur in patients with cirrhosis and subclinical cognitive deficits and that sGFAP could be explored as a novel biomarker., Impact and Implications: Blood biomarkers facilitating the diagnosis of covert hepatic encephalopathy (CHE) in patients with cirrhosis are lacking. In this study, we were able to demonstrate that sGFAP levels are associated with CHE in patients with cirrhosis. These results suggest that astrocyte injury may already occur in patients with cirrhosis and subclinical cognitive deficits and that sGFAP could be explored as a novel biomarker., Competing Interests: The authors disclose no potential financial or non-financial conflict of interests regarding this study. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background & Aims: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1., Methods: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response., Results: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy., Conclusion: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: The literature on liver transplantation (LT) for cirrhosis-associated hepatocellular carcinoma (cirr-HCC) in elderly patients (≥65 years of age) is scarce. The aim of this study was therefore to analyze the outcome after LT for cirr-HCC in elderly patients in our single-center experience., Methods: All consecutive patients who underwent LT for cirr-HCC at our center were identified from our prospectively collected LT database and stratified into an elderly (≥65 years) and a younger (<65 years) cohort. Perioperative mortality as well as Kaplan-Meier estimations of overall (OS) and recurrence-free survival (RFS) were compared between age strata. A subgroup analysis was performed for patients with HCC only inside Milan criteria. For further oncological comparison, outcome in the subgroup of elderly LT recipients with HCC inside Milan was also compared to a group of elderly patients undergoing liver resection for cirr-HCC inside Milan extracted from our institutional liver resection database., Results: Out of 369 consecutive patients with cirr-HCC who underwent LT between 1998 and 2022 at our center, we identified 97 elderly (with a subgroup of 14 septuagenarians) and 272 younger LT patients. 5- and 10-year OS in elderly compared to younger LT patients was 63% and 52% versus 63% and 46% ( p = 0.67), respectively, while 5- and 10-year RFS was 58% and 49% versus 58% and 44% ( p = 0.69). 5-/10-year OS and RFS in 50 elderly LT recipients with HCC inside Milan were 68%/55% and 62%/54%, respectively, which compared to 46%/38% ( p = 0.07) and 26%/14% ( p < 0.0001) in elderly patients after liver resection for cirr-HCC inside Milan., Conclusion: Our results in almost 100 elderly patients after LT for cirr-HCC show that older age per se should not be considered a contraindication to LT and that selected elderly patients older than 65 and even 70 years benefit from LT as much as younger ones., Competing Interests: None of the authors has any conflict of interest to disclose with regard to this study. Arndt Weinmann received compensations as a member of scientific advisory boards for BMS, Wako, and Sanofi and received travel support from Merck and Servier. Roman Kloeckner consults and advises for Boston Scientific, Bristol-Myers Squibb, Guerbet, Roche, and SIRTEX and is on the speakers' bureau for BTG, Eisai, Guerbet, Ipsen, MSD Sharp & Dohme, and SIRTEX. PRG reports receiving consulting and lectures fees from Adaptimmune, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, Roche, and SIRTEX., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Background: Ramucirumab is indicated for patients with advanced hepatocellular carcinoma (HCC) and α-fetoprotein (AFP) ≥400 ng/mL following sorafenib. Here, we prospectively studied ramucirumab following non-sorafenib systemic therapies., Materials and Methods: This open-label, non-comparative cohort of REACH-2 enrolled patients with advanced HCC, Child-Pugh class-A liver disease, and AFP ≥400 ng/mL who had received 1-2 lines of therapy, excluding sorafenib or chemotherapy. Ramucirumab was administered 8 mg/kg intravenously Q2W. The primary endpoint was safety. Secondary endpoints were overall survival, progression-free survival, objective response rate (RECIST v1.1), time to progression, pharmacokinetics, and patient-reported outcomes. Final analysis occurred after all enrolled patients completed ≥3 treatment cycles or discontinued treatment., Results: Between April 27, 2018, and March 29, 2021, 47 patients were treated at 21 investigative sites in Asia, Europe, and USA. The most frequently reported grade ≥3 adverse events, regardless of causality, were hypertension (11%), proteinuria (6%), hyponatremia (6%), and AST increased (6%). Two patients died from adverse events (myocardial infarction and upper gastrointestinal hemorrhage), deemed related to treatment. Median progression-free survival, time to progression, and overall survival were 1.7 months, 2.8 months, and 8.7 months, respectively. The objective response rate was 10.6% with a median duration response of 8.3 months. Median time to deterioration in FHSI-8 total score was 4.4 months., Conclusion: Ramucirumab demonstrated consistent and meaningful clinical activity with no new safety signals following non-sorafenib therapies in patients with advanced HCC and AFP ≥400 ng/mL. This represents one of the first sequencing studies for patients with advanced HCC not treated with sorafenib., (© The Author(s) 2022. Published by Oxford University Press.)

Portal vein infiltration (PVI) is a typical complication of HCC. Once diagnosed, it leads to classification as BCLC C with an enormous impact on patient management, as systemic therapies are henceforth recommended. Our aim was to investigate whether radiomics analysis using imaging at initial diagnosis can predict the occurrence of PVI in the course of disease. Between 2008 and 2018, we retrospectively identified 44 patients with HCC and an in-house, multiphase CT scan at initial diagnosis who presented without CT-detectable PVI but developed it in the course of disease. Accounting for size and number of lesions, growth type, arterial enhancement pattern, Child-Pugh stage, AFP levels, and subsequent therapy, we matched 44 patients with HCC who did not develop PVI to those developing PVI in the course of disease (follow-up ended December 2021). After segmentation of the tumor at initial diagnosis and texture analysis, we used LASSO regression to find radiomics features suitable for PVI detection in this matched set. Using an 80:20 split between training and holdout validation dataset, 17 radiomics features remained in the fitted model. Applying the model to the holdout validation dataset, sensitivity to detect occurrence of PVI was 0.78 and specificity was 0.78. Radiomics feature extraction had the ability to detect aggressive HCC morphology likely to result in future PVI. An additional radiomics evaluation at initial diagnosis might be a useful tool to identify patients with HCC at risk for PVI during follow-up benefiting from a closer surveillance.

Currently, there are only few data on health literacy in patients with chronic gastrointestinal diseases such as gastrointestinal cancer, inflammatory bowel disease (IBD) and, in particular, liver cirrhosis available. Moreover, head-to-head comparisons between patients with these different diseases are lacking. In this study, 379 patients were enrolled. Of these, 102 patients had gastrointestinal cancer, 86 had IBD, and 191 had cirrhosis. Health literacy was quantified using the Health Literacy Questionnaire (HLQ) developed by Osborne et al. (Swinburne University, Australia) and was compared between these three groups. Patients with cancer had the best health literacy across all nine subscales of the HLQ, while patients with cirrhosis had the poorest. In detail, patients with cirrhosis had significantly poorer health literacy than patients with cancer or IBD in subscales such as "feeling understood and supported by healthcare providers", "having sufficient information to manage my health", "appraisal of health information", "ability to actively engage with healthcare providers" or "understanding health information well enough to know what to do" (p < 0.05 for cirrhosis versus IBD or cancer, respectively). In conclusion, health literacy differs remarkably between patients with chronic gastrointestinal diseases such as cirrhosis, IBD or gastrointestinal cancers., (© 2022. The Author(s).)

Background: While chronic exposure to high levels of noise was demonstrated to increase the risk of various cardiovascular diseases, the association between noise annoyance and risk of cardiovascular disease remains still inconsistent. Recently, we showed that noise annoyance is associated with prevalent atrial fibrillation in the general population. However, the association between noise annoyance and risk of incident atrial fibrillation as well as potential sex-differences remain still elusive., Methods and Results: 15,010 subjects from a German population-based cohort were examined at baseline (2007 to 2012) and follow-up five years later (2012 to 2017) to investigative the association between noise annoyance due to multiple sources and prevalent and incident atrial fibrillation. After multivariable adjustment, the results from logistic regression analyses revealed overall consistent and positive associations between noise annoyance and prevalent and incident atrial fibrillation in men, whereas this association was weaker in women, in particular with respect to incident atrial fibrillation. For instance, industrial noise annoyance was associated with 21% (95% confidence interval (CI) 9-34%) and 18% (8-29%) higher odds of prevalent atrial fibrillation in men and women, respectively. In prospective analysis, this association remained stable in men (odds ratio (OR) 1.25, 1.07-1.44), while in women no association was observed (OR 1.03, 0.89-1.18)., Conclusions: The findings suggest that noise annoyance can increase the risk of incident atrial fibrillation in a large population-based cohort and that men may be more sensitive to the adverse effects of noise annoyance with regard to the risk of atrial fibrillation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hahad, Beutel, Gilan, Chalabi, Schuster, Gianicolo, Lackner, Lieb, Galle, Wild, Daiber and Münzel.)

The Fibrosis-4 index (FIB-4) is a recommended noninvasive fibrosis test in patients at risk of liver fibrosis. Chronic liver diseases are often associated with kidney diseases. This study aimed to investigate the association between FIB-4 and the development of renal failure among the general population. For this study, we used the Disease Analyzer database, which includes diagnoses and basic medical and demographic data of patients followed in general practices in Germany. Using these data, we extensively matched patients with a FIB-4 index ≥ 1.3 (n = 66,084) to patients with a FIB-4 index < 1.3 (n = 66,084). The primary outcome was the incidence of renal failure or chronic renal failure during a 10-year period. Within 10 years of the index date, 9.2% of patients with a FIB-4 < 1.3 and 10.6% of patients with a FIB-4 ≥ 1.3 were diagnosed with renal failure (p = 0.007). The endpoint chronic renal failure was reached by 7.9% with a FIB-4 < 1.3 and 9.5% with a FIB-4 ≥ 1.3 (p < 0.001). A FIB-4 index ≥ 1.3 was associated with a slight increase in renal failure incidence (hazard ratio [HR]: 1.08, p = 0.009). There was an increasing association between an increase in FIB-4 index and the incidence of renal failure with the strongest association for a FIB-4 index ≥ 2.67 (HR: 1.34, p = 0.001). In sensitivity analyses, a significant association was found for the age group of 51-60 years (HR: 1.38, p < 0.001), patients with arterial hypertension (HR: 1.15, p < 0.001), obese patients (HR: 1.25, p = 0.005), and patients with lipid metabolism disorders (HR:1.22, p < 0.001). Conclusion: A higher FIB-4 index is associated with an increased incidence of renal failure. Therefore, the FIB-4 index may be useful in identifying patients who are at risk not only for liver-related events but also for renal disease., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis reports efficacy and safety results in patients with baseline Barcelona Clinic Liver Cancer (BCLC) stage B disease., Methods: Patients with systemic treatment-naive unresectable HCC and Child-Pugh class A liver function were randomized 2:1 to receive 1,200 mg of atezolizumab plus 15 mg/kg of bevacizumab or 400 mg of sorafenib. Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 in the BCLC stage B subgroup. Patients in this analysis had BCLC stage B disease at baseline per electronic case report form. Secondary efficacy endpoints included the objective response rate (ORR) and change in the sum of longest diameters (SLD) of target lesions from baseline per IRF RECIST 1.1 and modified RECIST (mRECIST) for HCC., Results: Of 501 enrolled patients, 74 (15%) had BCLC stage B disease at baseline (atezolizumab + bevacizumab, n = 49; sorafenib, n = 24). For this group, median follow-up was 19.7 months. A trend toward improved OS and PFS per IRF RECIST 1.1 was observed with atezolizumab + bevacizumab versus sorafenib (OS: hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.29, 1.34; PFS: HR: 0.64; 95% CI: 0.36, 1.12). ORRs per IRF RECIST 1.1 and HCC mRECIST were 43% and 50% with atezolizumab + bevacizumab and 26% and 30% with sorafenib, respectively. Percentage change in SLD of target lesions from baseline per IRF RECIST 1.1 and HCC mRECIST showed durable responses with atezolizumab + bevacizumab treatment. Safety data were consistent with known profiles of atezolizumab and bevacizumab, as seen in the overall study population., Discussion/conclusion: Efficacy benefits were observed with atezolizumab + bevacizumab in patients with baseline BCLC stage B disease, consistent with the intention-to-treat population., Competing Interests: Masatoshi Kudo reports the following conflicts of interest: honoraria payment to self from Bayer, Chugai Pharmaceutical Co. Ltd., Eli Lilly, Eisai, Merck Sharp & Dohme, and Takeda; research funding to the institution from AbbVie, Chugai Pharmaceutical Co. Ltd., EA Pharma, Eisai, F. Hoffmann-La Roche Ltd., GE Healthcare, Gilead Sciences, Otsuka, Sumitomo Dainippon Pharma, Taiho, and Takeda; Editor-in-Chief of Liver Cancer. Richard S. Finn reports the following conflicts of interest: consulting fees to self from AstraZeneca, Bayer, CStone Pharmaceuticals, Eisai, Eli Lilly, Exelixis, F. Hoffmann-La Roche Ltd., Jiangsu Hengrui Pharmaceuticals, Merck, and Pfizer; research funding to the institution from Adaptimmune, Bristol Myers Squibb, Eisai, Eli Lilly, Merck, Pfizer, and F. Hoffmann-La Roche Ltd; Editorial Board Member of Liver Cancer. Peter R. Galle reports the following conflicts of interest: consulting fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; honoraria payment to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; advisory fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; research funding to the institution from Bayer and F. Hoffmann-La Roche Ltd. Andrew X. Zhu reports the following conflicts of interest: consulting fees to self from Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., and Sanofi-Aventis; research funding to the institution from F. Hoffmann-La Roche Ltd. Michel Ducreux reports the following conflicts of interest: honoraria, consulting fees, or advisory fees to self from Amgen, AstraZeneca, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Serono, Pierre Fabre, and Servier; speaker bureau participation for Amgen, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, and Merck Serono; travel support from Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Sharp & Dohme, and Servier; research funding to the institution from Bayer and F. Hoffmann-La Roche Ltd. Ann-Lii Cheng reports the following conflicts of interest: research funding to the institution from F. Hoffmann-La Roche Ltd. Masafumi Ikeda reports the following conflicts of interest: honoraria to self from Bayer, Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, and Takeda; advisory/consulting fees to self from Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, Merck Sharp & Dohme, and Takeda; research funding to the institution from Bayer, Bristol Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Merck Sharp & Dohme, and Takeda. Kaoru Tsuchiya reports the following conflicts of interest: advisory/consultancy fees to self from Chugai Pharmaceutical Co. Ltd., and Eisai; speaker bureau participation for Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, and Takeda; research funding to the institution from F. Hoffmann-La Roche Ltd. Ken-ichi Aoki reports the following conflicts of interest: employment by Chugai Pharmaceutical Co. Ltd. Jing Jia reports the following conflicts of interest: employment by F. Hoffmann-La Roche Ltd. Riccardo Lencioni reports the following conflicts of interest: advisory/consultancy fees to self from AstraZeneca, Bayer, Eisai, and F. Hoffmann-La Roche Ltd.; research funding to the institution from F. Hoffmann-La Roche Ltd., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Systemic inflammation is a key risk factor for hepatocellular carcinoma (HCC) progression and poor outcomes. Inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) may have prognostic value in HCC treated with standard of care atezolizumab plus bevacizumab (Atezo-Bev). We conducted a multicenter, international retrospective cohort study of patients with unresectable HCC treated with Atezo-Bev to assess the association of NLR and PLR with overall survival (OS), progression-free survival (PFS), and objective response rates. Patients with NLR ≥ 5 had a significantly shorter OS (9.38 vs. 16.79 months, p < 0.001) and PFS (4.90 vs. 7.58 months, p = 0.03) compared to patients with NLR < 5. NLR ≥ 5 was an independent prognosticator of worse OS (HR 2.01, 95% CI 1.22−3.56, p = 0.007) but not PFS. PLR ≥ 300 was also significantly associated with decreased OS (9.38 vs. 15.72 months, p = 0.007) and PFS (3.45 vs. 7.11 months, p = 0.04) compared to PLR < 300, but it was not an independent prognosticator of OS or PFS. NLR and PLR were not associated with objective response or disease control rates. NLR ≥ 5 independently prognosticated worse survival outcomes and is worthy of further study and validation.