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This paper proposes simultaneous estimation of states and sensor faults of Takagi-Sugeno (T-S) fuzzy models in the presence of bounded disturbances. The method uses the technique of singular systems by considering sensor faults as an auxiliary state variable. An H∞ fuzzy singular observer is proposed to simultaneously estimate system state and sensor faults. Then a controller based observer for active fault tolerant control (FTC) system is designed in terms of linear matrix inequality (LMI). Finally, a numerical example is given to demonstrate the effectiveness of the proposed method. [ABSTRACT FROM AUTHOR]

A total of 24 Murciano-Granadina dairy goats milked once daily throughout lactation were used to study the effects of including soybean oil (SBO) in the diet on lactational performance and milk fatty acid (FA) content, particularly conjugated linoleic acid (CLA) and trans-vaccenic acid (trans- 11 C 18:1, TVA). Three weeks after parturition, goats were allocated to 2 balanced groups according to lactation number, body weight, and daily milk yield, and were kept in separate pens. The experiment consisted of a 2-period (28 d each) crossover with 2 dietary treatments: control and SBO (6% as fed in the concentrate). Goats were fed dehydrated fescue (ad libitum), alfalfa pellets (0.5 kg/d), and concentrate (1 kg/d) to which the SBO was or was not added. Forage was fed in the pens, and concentrate was fed individually in 2 equal portions at milking (0900 h) and in the afternoon (1700 h). Final SBO content in the consumed SBO diet was 2.5% (dry matter basis). Diets were isonitrogenous (17.4% crude protein), but their total FA content varied from 2.2% (control) to 4.6% (SBO). There was no effect of SBO on dry matter intake, milk yield, energy-corrected milk, body weight, or body condition score. Compared with the control diet, feeding SBO increased milk fat content (4.57 vs. 5.24%) and yield as well as total solids content. Soybean oil had no effect on milk crude and true protein contents, but it reduced milk casein content (2.48 vs. 2.34%). Short- and medium-chain FA decreased by feeding SBO, whereas long-chain FA increased. Feeding preformed linoleic acid through SBO increased milk concentrations of linoleic, oleic, and stearic FA but reduced levels of linolenic and palmitic FA. As a consequence, feeding SBO decreased the saturated-to-unsaturated FA ratio and the atherogenicity index. Compared with the control treatment, milk contents of cis-9, trans-11 CLA (0.68 vs. 2.03%) and TVA (2.04 vs. 6.41%) in the SBO treatment increased by approximately 200%. In conclusion, feeding a moderate dose of SBO to dairy goats was a useful way to increase milk fat, CLA, and TVA contents in milk and to reduce the atherogenicity index without negative effects on intake, milk yield, and protein content. [ABSTRACT FROM AUTHOR]

A total of 24 Lacaune dairy ewes milked twice daily were used to study the effects of adding whole safflower seeds (WSF) to their concentrate, on dairy performances, milk, fatty acids (FA) profile and CLA. Ewes were allocated to two balanced groups according to number of lactation, BW and daily milk yield, and kept in two separate pens. TMR fed to ewes was a mixture of 55% forage (dehydrated fescue:alfalfa hay; 1:1), and 45% concentrate, to which the WSF was or not added. Dietary treatments were: C (control) and WSF (16.2% in the concentrate). Ether extract in the two experimental concentrates were similar (8.01%) due to the incorporation of calcium soaps of palm oil FA (6.25%) to the control concentrate. The experiment consisted of a two periods crossover design (20d each), during which the TMR was offered ad libitum in the pens (09:00 and 18:00). Addition of WSF decreased (P<0.05) DMI (2.42 vs. 2.34 kg/d), milk yield (1.58 vs. 1.48 L/d), ECM (1.47 vs. 1.34 L/d) and milk conversion rate (0.60 vs. 0.57 L/kg DM), but did not modify milk fat (6.7%), protein (5.3%), casein (4.19%) and TS (17.9%) contents. True protein content was increased (5.16 vs. 5.43%; P<0.0001) and fat (108 vs. 96g) and protein (83 vs. 73) yields were decreased (P<0.05) by WSF, mainly because of the milk yield depression. The WSF treatment increased (P<0.05) ewes BCS (3.11 vs. 3.24) but decreased (P<0.05) blood concentrations of cholesterol (96.2 vs. 84.5 mg/dL) and glucose (51.6 vs. 44.9 mg/dL). Safflower addition increased (P<0.0001) LCFA (35.2 vs. 45.4%) and MUFA (24.4 vs. 27.1%), and decreased MCFA (49.3 vs. 39.9%), but no changes were observed in SCFA (12.7%), PUFA (4.1%), n3 (0.86%) and n6 (3.25%). In contrast, the addition of WSF increased (P<0.01) the concentration of cis 9- trans 11 C18:2 (CLA, 0.62 vs. 0.93%), reduced (P<0.05) the saturated/unsaturated ratio (2.52 vs. 2.12) and the atherogenicity index (2.75 vs. 2.2), which is positive in terms of human health. [ABSTRACT FROM AUTHOR]

This study was performed to investigate the effects of feeding whole linseed (WLS) or linseed oil (LSO) to dairy ewes on lactational performances, and milk fatty acids profile and CLA content. Thirty Lacaune dairy ewes were blocked in 3 pens of 10 animals, and used in a 3 × 3 Latin square (20 d periods). Ewes were fed a TMR with 55% forage (alfalfa and fescue dehydrated mixture, 1:1) and 45% concentrate. Treatments were: 1) C (control); 2) WLS (8.2% of TMR, DM basis); and, 3) LSO (2.7%). Diets were isonitrogenous (18.5% CP), and had the same level of fat (5.3% EE), being a 6.3% of calcium soap of palm oil included in the control concentrate. Feed intake (C: 2.65; WLS: 2.72; LSO: 2.7 kg DM/d) was increased (P<0.05) by WLS, but milk yield (1.9 L/d), ECM (1.6 L/d) and milk protein (5.23%) and casein (4.1%) contents were unaffected by treatments. In contrast, true protein content (5.2; 5.11; 4.97%) was reduced and milk fat (5.7; 5.85; 6.08%) content and yield (107; 107; 114 g/d) and total solids content (16.3; 16.6;16.9%) where increased (P<0.05) by LSO. Regarding blood metabolites, both linseed treatments increased (P<0.01) triglycerides concentration (12.7; 19.2; 17.6%) but did not affect glucose (53.6 mg/dL), cholesterol (100.6 mg/dL), NEFA (0.11 mmol/L), HDL (1.78 mmol/L) or LDL (0.67 mmol/L) concentrations. Both linseed treatments increased (P<0.01) SCFA and LCFA, but decreased (P<0.0001) MCFA. The cis 9- trans 11 C18:2 (CLA) was only improved by LSO (0.65; 0.6; 1.23%) and no changes were observed in C18:1 (23.4%) and MUFA (24.6%), while PUFA (4.03; 4.68; 4.54) were higher (P<0.05), and saturated FA (70.02; 67.6; 68.8%) and atherogenicity index (2.66; 2.31; 2.35%) lower (P<0.05) in linseed treatments than in control. In conclusion, LSO was more effective than WLS to increase CLA in milk, but both linseed treatments were useful to increase PUFA and reduce atherogenicity index of milk fat. [ABSTRACT FROM AUTHOR]

Background and Aims: Deterioration of liver function is a leading cause of death in patients with advanced hepatocellular carcinoma (HCC). We evaluated the impact of immune checkpoint inhibitor (ICI)-treatment on liver function and outcomes., Method: HCC patients receiving ICIs or sorafenib between 04/2003 and 05/2024 were included. Liver function (assessed by Child-Pugh score [CPS]) was evaluated at the start of ICI-treatment (baseline, BL) and 3 and 6 months thereafter. A ≥1 point change in CPS was defined as deterioration (-) or improvement (+), while equal CPS points were defined as stable (=)., Results: Overall, 182 ICI-treated patients (66.8 ± 11.8 years; cirrhosis: n = 134, 74%) were included. At BL, median CPS was 5 (IQR: 5-6; CPS-A: 147, 81%). After 3 months, liver function improved/stabilized in 102 (56%) and deteriorated in 61 (34%) patients, while 19 (10%) patients deceased/had missing follow-up (d/noFU). Comparable results were observed at 6 months (+/=: n = 82, 45%; -: n = 55, 30%; d/noFU: n = 45, 25%). In contrast, 54 (34%) and 33 (21%) out of 160 sorafenib patients achieved improvement/stabilization at 3 and 6 months, respectively. Radiological response was linked to CPS improvement/stabilization at 6 months (responders vs. non-responders, 73% vs. 50%; p = 0.007). CPS improvement/stabilization at 6 months was associated with better overall survival following landmark analysis (6 months: +/=: 28.4 [95% CI: 18.7-38.1] versus -: 14.2 [95% CI: 10.3-18.2] months; p < 0.001). Of 35 ICI-patients with CPS-B at BL, improvement/stabilization occurred in 16 (46%) patients, while 19 (54%) patients deteriorated/d/noFU at 3 months. Comparable results were observed at 6 months (CPS +/=: 14, 40%, -: 8, 23%). Importantly, 6/35 (17%) and 9/35 (26%) patients improved from CPS-B to CPS-A at 3 and 6 months., Conclusion: Radiological response to ICI-treatment was associated with stabilization or improvement in liver function, which correlated with improved survival, even in patients with Child-Pugh class B at baseline., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

The tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) is complex and plays a role in prognosis and resistance to treatments. We aimed to decipher the iCCA TME phenotype using multiplex sequential immunohistochemistry (MS-IHC) to investigate which cell types and their spatial location may affect its prognosis. This was a retrospective study of 109 iCCA resected samples. For all cases, we used an open-source software to analyse a panel of markers (αSMA, FAP, CD8, CD163) by MS-IHC for characterize the different TME cells and their location. RNA sequencing was performed to determine the main iCCA transcriptomic classes. The association of the TME composition with overall survival (OS) was assessed by univariate and multivariate analyses. A high proportion of activated fibroblasts (FAP +) was significantly associated with poor OS (HR = 2.33, 95%CI = 1.43-3.81, p = 0.001). CD8 T lymphocytes excluded from the epithelial compartment were significantly associated with worse OS (HR = 1.86, 95% CI = 1.07-3.22, p = 0.014). The combination of a high proportion of FAP + fibroblasts and CD8 T lymphocytes excluded from the epithelial compartment, observed in 21 cases (19%), was significantly associated with poor OS on univariate (HR = 2.49, 95% CI = 1.44-4.28, p = 0.001) and multivariate analyses (HR = 2.77, 95% CI = 1.56-4.92, p < 0.001). In these cases, CD8 T lymphocytes were predominantly located at the tumour/non-tumour interface (19/21, 90%), and an association with the transcriptomic inflammatory stroma class was observed (10/21, 48%). Our results confirm the TME prognostic role in iCCA, highlighting the impact in the process of spatial heterogeneity, especially cell colocalization of immune and fibroblastic cells creating a peritumoural fibro-immune interface., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis., Methods: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m 2 ) and cisplatin (25 mg/m 2 ) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235., Findings: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%])., Interpretation: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer., Funding: AstraZeneca., Competing Interests: Declaration of interests D-YO reports advisory fees from Arcus Biosciences, Aslan Pharmaceuticals, AstraZeneca, Basilea, Bayer, BeiGene, Bristol Myers Squibb/Celgene, Genentech/Roche, Halozyme, IQVIA, Merck Serono, Novartis, Taiho Pharmaceutical, Turning Point Therapeutics, Yuhan, and Zymeworks; and institutional research funding from Array BioPharma, AstraZeneca, BeiGene, Eli Lilly, Handok, MSD, Novartis, and Servier. ARH reports consulting fees from AstraZeneca, Bristol Myers Squibb, and Genentech/Roche; research funding from Genentech and Merck; and speakers bureau fees from Eisai and Bristol Myers Squibb. MB reports consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, MSD, Roche, and Sirtex Medical; speakers bureau fees from Bayer, Eisai, and Roche; and support for travel and attending meetings from AstraZeneca, Bayer, and Sirtex Medical. TO reports advisory fees from AstraZeneca, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Incyte, Meiji Seika Pharma, Mundipharma, Nihon Servier, Nippon Shinyaku, Pfizer, Taiho Pharmaceutical, and Takara Bio; and speaker fees from AstraZeneca, Baxter, Bayer, Bristol Myers Squibb, Chugai Pharma, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, MSD, Nihon Servier, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Teijin Pharma, and Yakult Honsha. L-TC reports personal speaker fees from Bristol Myers Squibb, CStone, Eli Lilly, Ipsen, Ono Pharmaceutical, Novartis, PharmaEngine, and TTY; fees for medical monitoring for clinical trials for Taivex; fees received as a data and safety monitoring committee member for clinical trials for OBI Pharma; advisory fees from AstraZeneca, MSD, and SynCoreBio; speaker fees from AstraZeneca, HuniLife Biotechnology, Ono Pharmaceutical, ScinoPharm Taiwan, SynCoreBio, and TTY; and research funding from Celgene. MK reports research funding from AbbVie and Takeda; and honoraria from EA Pharma and AstraZeneca. JWK reports research funding from inno.N and Jeil Pharmaceutical; and consulting fees from AstraZeneca, BeiGene, BeyondBio, Bristol Myers Squibb/Celgene, Eisai, GC Cell, MSD Ono, Sanofi-Aventis, Servier, and TCUBEit. TS reports speaker fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Baxter, Eli Lilly, Mundipharma (Thailand), Janssen, MSD, Novartis, Roche, and Takeda; and advisory fees from Novartis and Roche. MI reports grant or research support from Aslan Pharmaceuticals, AstraZeneca, Bayer, Bristol Myers Squibb, Chiome Bioscience, Chugai Pharma, Delta-Fly Pharma, EA Pharma, Eisai, Eli Lilly Japan, J-Pharma, Merck, Merus NV, Nihon Servier, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Yakult; fees or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas Pharma, Bayer, Bristol Myers Squibb, Chugai Pharma, Eisai, Eli Lilly Japan, MSD, Nihon Servier, Novartis, Otsuka, Dainippon Sumitomo Pharma, Taiho Pharmaceutical, Takeda, Teijin Pharma, and Yakult; and fees for participation on a data safety monitoring board or advisory board from Aslan Pharmaceuticals, Bayer, Bristol Myers Squibb, Chugai Pharma, Eisai, Eli Lilly Japan, GlaxoSmithKline, Nihon Servier, Novartis, and Takeda. J-SC reports grant or research support from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Janssen, Eli Lilly, Merck KGaA, MSD, MSD Oncology, Oncologie, Ono Pharmaceutical, Roche, Senhwa Biosciences, SynCore, and TTY; and consulting fees from Ono Pharmaceutical. PP reports personal fees for an advisory board from AstraZeneca, Sanofi-Aventis, Bristol Myers Squibb, Janssen Oncology, MSD, Pierre Fabre, Roche, and Servier; personal fees as an invited speaker from AstraZeneca, Ipsen, Pierre Fabre, and Merck; and being a principal investigator for AstraZeneca and Roche. HAB reports research funding from AbbVie, Agios, Arch Pharmalabs, ARMO BioSciences, Array BioPharma, Arvinas, AstraZeneca, Bayer, BIND Therapeutics, BioAtla, BioMed Valley Discoveries, Biotheryx, Boehringer Ingelheim, Bristol Myers Squibb, CALGB, CicloMed, Coordination Pharmaceuticals, CytomX, eFFECTOR Therapeutics, Eli Lilly, EMD Serono, Foundation Medicine, Gossamer Bio, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Infinity Pharmaceuticals, Janssen, Jiangsu Hengrui Pharmaceuticals, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck, Millennium/Takeda, miRNA Therapeutics, Moderna, NGM Bio, Novartis, Pfizer, Revolution Medicine, Roche/Genentech, Ryvu Therapeutics, Seattle Genetics, Tesaro, TG Therapeutics, Verastem Oncology, Vertex Pharmaceuticals, XBiotech, and Zymeworks; and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Forma Therapeutics, Grail, Incyte, Novartis, Pfizer, and Vincerx Pharma. VO reports grant or research support from Dr Reddy's Laboratories and Zydus Cadila; institutional fees for advisory board participation from AstraZeneca, Panacea Biotec, Dr Reddy's Laboratories, and Zydus Cadila; travel reimbursement as an invited speaker from AstraZeneca; other institutional financial interests with Alkem Laboratories, Eisai, Intas Pharmaceuticals, and Micro Labs; and non-financial interests with the Indian Association of Supportive Care in Cancer. ST reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, MSD, Novartis, and Roche; speaker fees from Bristol Myers Squibb, Ipsen, and Novartis; and non-financial interests with AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, and Roche. CM reports institutional grant or research support from AstraZeneca, Daiichi Sankyo, Eisai, J-Pharma, Hitachi, Merck BioReliance, MSD, Kyowa Kirin, Ono Pharmaceutical, Taiho Pharmaceutical, and Yakult Honsha; personal fees for advisory board participation from AstraZeneca, Boehringer Ingelheim, Merck BioReliance, MSD, Servier, Taiho Pharmaceutical, and Yakult; and personal fees received as an invited speaker from AstraZeneca, Eisai, Kyowa Kirin, MSD, Novartis, Servier, Taiho Pharmaceutical, Teijin Pharma, and Yakult Honsha. REZ reports speaker fees from Bristol Myers Squibb, Ipsen, and Novartis; and travel grants from Pierre Fabre. MGM reports grant or research support from Ipsen, NuCana, and Servier; consulting fees from AstraZeneca and Incyte; and honoraria from Advanced Accelerator Applications and AstraZeneca. AA reports research funding from Amgen, Bayer, and Bristol Myers Squibb; and advisory fees from AstraZeneca, Amgen, Eisai, and MSD. JEC reports advisory fees from MSD; and fees as an invited speaker for AstraZeneca, Boehringer Ingelheim, Takeda, and Roche. VB reports consulting fees from Bayer, Bristol Myers Squibb Russia, Eisai, MSD, Novartis, Pfizer, Roche Russia, and Takeda; and travel expenses from Bayer, Bristol Myers Squibb Russia, MSD, and Roche Russia. BT reports research funding from Adaptimmune, AstraZeneca, Bristol Myers Squibb, and Exelixis. SS reports grant or research support from Delta-Fly Pharma and Incyte. DT reports personal fees for advisory board participation from Amgen, AstraZeneca, MSD, Pierre Fabre, Roche, Sanofi, and Servier. LE reports personal fees for advisory board participation from Amgen, Merk, MSD, and Servier. MP reports personal fees for advisory board participation from Roche and Servier; personal fees as an invited speaker from AstraZeneca, Ewopharma, and Takeda; and non-financial interests with AstraZeneca and Sanofi. DBZ reports advisory fees from Cornerstone Pharmaceuticals, Ipsen, Jazz Pharmaceuticals/Zymeworks, and QED Therapeutics; and research funding from AstraZeneca, Bayer, Bristol Meyers Squibb, Cornerstone Pharmaceuticals, Daiichi Sankyo, Eli Lily, Ipsen, Roche/Genentech, Legend Biotech, Merck, and Seagen. VGG holds stock in RPG Life Sciences and Zydus Lifesciences. FD reports grant or research support from Amgen, AstraZeneca, Bristol Myers Squibb, Exelixis, Genentech, Ipsen, Signatera, and Taiho Pharmaceutical; consulting fees from AstraZeneca, Eisai, Exelixis, Genentech, and Ipsen; and payment or honoraria from Astellas, Eisai, Exelixis, Ipsen, Servier, and Sirtex Medical. JOP reports advisory board fees from Adicet Bio, AstraZeneca, Bristol Myers Squibb (Celgene), MediRama, MedPacto, Merck Serono, and Servier; support for travel to meetings from Minneamrita Therapeutics; and grant or research support from ABL Bio, Bristol Myers Squibb (Celgene), Eutilex, MedPacto, and Servier. HK, CM, and MŻ are employees of AstraZeneca. JW and NR are employees of and hold stock in AstraZeneca. AV reports speaker fees from BeiGene, Bristol Myers Squibb, Eisai, Imaging Equipment, Incyte, Ipsen, Jiangsu Hengrui Pharmaceuticals, Eli Lilly, MSD, Novartis, Pierre Fabre, and Roche; and advisory fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Daiichi Sankyo, Eisai, Ipsen, Incyte, Lilly, MSD, Pierre Fabre, Roche, and Sirtex Medical. JWV reports advisory fees from Agios, AstraZeneca, Autem Therapeutics, Baxter, Hutchison MediPharma, Image Equipment, NuCana, QED Therapeutics, Sirtex Medical, Servier, and Zymeworks; speaker fees from Incyte, Ipsen, and Mylan; and research funding from AstraZeneca and Redx. All other authors declare no competing interests., (2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Backgrounds: The efficacy of atezolizumab/bevacizumab has never been reported in patients with metastatic/unresectable combined hepatocellular-cholangiocarcinoma (cHCC-CCA)., Patients and Methods: We retrospectively included patients with a histological diagnosis of unresectable/metastatic cHCC-CCA and treated with atezolizumab/bevacizumab (2020-2022) in 7 centers. Clinical and radiological features were collected at the beginning of atezolizumab/bevacizumab. We reported the radiological response using RECIST criteria, overall survival (OS) and progression-free survival (PFS)., Results: Sixteen patients with cHCC-CCA were included and were predominantly male (75%) with advanced fibrosis/cirrhosis (69%). Nine patients received atezolizumab/bevacizumab as a first-line systemic treatment, 5 as a second line, 1 as a third line and 1 as a fifth line. Severe digestive bleeding occurred in 2 patients. Among the 9 patients treated in the first line, 4 experienced radiological progression, 3 partial response and 1 had stable disease. Patients treated with atezolizumab/bevacizumab in the first line had a median OS of 13 months and a median PFS of 3 months. Among the 7 patients receiving atezolizumab/bevacizumab as a second line or more, 4 patients harbored a stable disease, 2 a partial response, and 1 a progressive disease., Conclusions: The combination of atezolizumab and bevacizumab showed signs of anti-tumor efficacy in patients with unresectable/metastatic cHCC-CCA., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Purpose: Steatohepatitic hepatocellular carcinoma (SH-HCC) is characterized by intratumoral fat with > 50% inflammatory changes. However, intratumoral fat (with or without inflammation) can also be found in not-otherwise specified HCC (NOS-HCC). We compared the imaging features and outcome of resected HCC containing fat on pathology including SH-HCC (> 50% steatohepatitic component), NOS-HCC with < 50% steatohepatitic component (SH-NOS-HCC), and fatty NOS-HCC (no steatohepatitic component)., Material and Methods: From September 2012 to June 2021, 94 patients underwent hepatic resection for fat-containing HCC on pathology. Imaging features and categories were assessed using LIRADS v2018. Fat quantification was performed on chemical-shift MRI. Recurrence-free and overall survival were estimated., Results: Twenty-one patients (26%) had nonalcoholic steatohepatitis (NASH). The median intra-tumoral fat fraction was 8%, with differences between SH-HCC and SH-NOS-HCC (9.5% vs. 5% p = 0.03). There was no difference in major LI-RADS features between all groups; most tumors were classified as LR-4/5. A mosaic architecture on MRI was rare (7%) in SH-HCC, a fat in mass on CT was more frequently depicted (48%) in SH-HCC. A combination of NASH with no mosaic architecture on MRI or NASH with fat in mass on CT yielded excellent specificity for diagnosing SH-HCC (97.6% and 97.7%, respectively). The median recurrence-free and overall survival were 58 and 87 months, with no difference between groups (p = 0.18 and p = 0.69)., Conclusion: In patients with NASH, an SH-HCC may be suspected in L4/LR-5 observations with no mosaic architecture at MRI or with fat in mass on CT. Oncological outcomes appear similar between fat-containing HCC subtypes., (© 2024. Italian Society of Medical Radiology.)

Background: Pemigatinib is approved for patients with pretreated, locally advanced or metastatic CCA harboring FGFR2 rearrangements or fusions. We aim to assess the effectiveness and safety of pemigatinib in real-world setting., Material and Methods: A joint analysis of two multicentre observational retrospective cohort studies independently conducted in France and Italy was performed. All consecutive FGFR2-positive patients affected by CCA and treated with pemigatinib as second- or further line of systemic treatment in clinical practice, within or outside the European Expanded Access Program, were included., Results: Between July 2020 and September 2022, 72 patients were treated with pemigatinib in 14 Italian and 25 French Centres. Patients had a median age of 57 years, 76% were female, 81% had ECOG-PS 0-1, 99% had intrahepatic CCA, 74% had ≥ 2 metastatic sites, 67% had metastatic disease at diagnosis, while 38.8% received ≥ 2 previous lines of systemic treatment. At data cut-off analysis (April 2023), ORR and DCR were 45.8% and 84.7%, respectively. Median DoR was 7 months (IQR: 5.8-9.3). Over a median follow-up time of 19.5 months, median PFS and 1-year PFS rate were 8.7 months and 32.8%. Median OS and 1-year OS rate were 17.1 months and 60.6%. Fatigue (69.4%), ocular toxicity (68%), nail toxicities (61.1%), dermatologic toxicity (41.6%) hyperphosphataemia (55.6%), stomatitis (48.6%), and diarrhea (36.1%) were the most frequent, mainly G1-G2 AEs. Overall incidence of G3 AEs was 22.2%, while no patient experienced G4 AE. Dose reduction and temporary discontinuation were needed in 33.3% and 40.3% of cases, with 1 permanent discontinuation due to AEs., Conclusions: These results confirm the effectiveness and safety of pemigatinib in a real-world setting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: No head-to-head trials compared the efficacy of transarterial radioembolization (TARE, also known as selective internal radiation therapy) to combination immunotherapy in hepatocellular carcinoma (HCC). The analysis objective was to compare effectiveness outcomes of TARE using Y-90 resin microspheres and atezolizumab-bevacizumab (AB) in advanced unresectable HCC., Methods: Patient-level data from SARAH randomized controlled trial for TARE and aggregate real-world data from AB-real study were used in an unanchored matching-adjusted indirect comparison. The basecase analysis used per-protocol data from SARAH; intention-to-treat data were used in sensitivity analyses. The following prognostic variables and effect modifiers were identified from literature: cause of disease, macrovascular invasion, Eastern Cooperative Oncology Group Performance Status, alpha-fetoprotein level and albumin-bilirubin score. Weights were assigned to patients from SARAH to balance baseline characteristics across studies and reflect characteristics of AB-real patients. Overall survival (OS), progression-free survival (PFS) and response rates (overall response rates [ORR]) were calculated and compared., Results: The analysis of OS and PFS included 140 patients receiving TARE and 131 for the analysis of response rates, compared to 202 receiving AB. Median OS was 15.0 and 14.9 months for TARE and AB, respectively (HR=0.980; 95% confidence interval [CI]: 0.658-1.461; p-value=0.922). Median PFS was 4.4 and 6.8 months for TARE and AB, respectively (HR=0.745; 95%CI: 0.544-1.022; p-value=0.068). ORR were 19.8% and 25% with TARE and AB, respectively (OR for AB=1.386, 95%CI: 0.746-2.668; p-value=0.306). Sensitivity analyses generated similar results., Conclusion: In HCC patients receiving treatment, TARE using Y-90 resin microspheres may achieve comparable effectiveness outcomes compared with AB., Competing Interests: Declaration of Competing Interest IA, VKB, PLC, SS and NA were full-time employees of Sirtex Medical at the time of manuscript preparation. MB received speaker fees from Bayer, MSD; Sirtex Medical, Roche, Advisory board fees from Bayer, MSD, Sirtex Medical, Eisai, AstraZeneca, Ipsen, Servier, Taiho, BMS. DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, Astra Zeneca, Roche, IPSEN and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, Astra Zeneca, LiFT biosciences, DaVolterra, Exact Sciences, Mursla, Avamune, BMS; received research funding (to institution) from MSD, BMS, GSK. VV reports personal fees from Sirtex during the period the study was conducted. AD received educational support for congress attendance and consultancy fees from Roche and Astrazeneca., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To measure the performance and variability of a radiomics-based model for the prediction of microvascular invasion (MVI) and survival in patients with resected hepatocellular carcinoma (HCC), simulating its sequential development and application., Methods: This study included 230 patients with 242 surgically resected HCCs who underwent preoperative CT, of which 73/230 (31.7%) were scanned in external centres. The study cohort was split into training set (158 patients, 165 HCCs) and held-out test set (72 patients, 77 HCCs), stratified by random partitioning, which was repeated 100 times, and by a temporal partitioning to simulate the sequential development and clinical use of the radiomics model. A machine learning model for the prediction of MVI was developed with least absolute shrinkage and selection operator (LASSO). The concordance index (C-index) was used to assess the value to predict the recurrence-free (RFS) and overall survivals (OS)., Results: In the 100-repetition random partitioning cohorts, the radiomics model demonstrated a mean AUC of 0.54 (range 0.44-0.68) for the prediction of MVI, mean C-index of 0.59 (range 0.44-0.73) for RFS, and 0.65 (range 0.46-0.86) for OS in the held-out test set. In the temporal partitioning cohort, the radiomics model yielded an AUC of 0.50 for the prediction of MVI, a C-index of 0.61 for RFS, and 0.61 for OS, in the held-out test set., Conclusions: The radiomics models had a poor performance for the prediction of MVI with a large variability in the model performance depending on the random partitioning. Radiomics models demonstrated good performance in the prediction of patient outcomes., Clinical Relevance Statement: Patient selection within the training set strongly influenced the performance of the radiomics models for predicting microvascular invasion; therefore, a random approach to partitioning a retrospective cohort into a training set and a held-out set seems inappropriate., Key Points: • The performance of the radiomics models for the prediction of microvascular invasion and survival widely ranged (AUC range 0.44-0.68) in the randomly partitioned cohorts. • The radiomics model for the prediction of microvascular invasion was unsatisfying when trying to simulate its sequential development and clinical use in a temporal partitioned cohort imaged with a variety of CT scanners. • The performance of the radiomics models for the prediction of survival was good with similar performances in the 100-repetition random partitioning and temporal partitioning cohorts., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Introduction and Objectives: The lockdown policy introduced in 2020 to minimize the spread of the COVID-19 pandemic, significantly affected the management and care of patients affected by hepatocellular carcinoma (HCC). The aim of this follow-up study was to determine the 12 months impact of the COVID-19 pandemic on the cohort of patients affected by HCC during the lockdown, within six French academic referral centers in the metropolitan area of Paris., Materials and Methods: We performed a 12 months follow-up of the cross-sectional study cohort included in 2020 on the management of patients affected by HCC during the first six weeks of the COVID-19 pandemic (exposed), compared to the same period in 2019 (unexposed). Overall survival were compared between the groups. Predictors of mortality were analysed with Cox regression., Results: From the initial cohort, 575 patients were included (n = 263 Exposed&#95;COVID, n = 312 Unexposed&#95;COVID). Overall and disease free survival at 12 months were 59.9 ± 3.2% vs. 74.3 ± 2.5% (p<0.001) and 40.2 ± 3.5% vs. 63.5 ± 3.1% (p<0.001) according to the period of exposure (Exposed&#95;COVID vs. Unexposed&#95;COVID, respectively). Adjusted Cox regression revealed that the period of exposure (Exposed&#95;COVID HR: 1.79, 95%CI (1.36, 2.35) p<0.001) and BCLC stage B, C and D (BCLC B HR: 1.82, 95%CI (1.07, 3.08) p = 0.027 - BCLC C HR: 1.96, 95%CI (1.14, 3.38) p = 0.015 - BCLC D HR: 3.21, 95%CI (1.76, 5.85) p<0.001) were predictors of death., Conclusions: Disruption of routine healthcare services because of the pandemic translated to reduced 1 year overall and disease-free survival among patients affected by HCC, in the metropolitan area of Paris, France., Competing Interests: Declaration of interests None., (Copyright © 2023. Published by Elsevier España, S.L.U.)

What Is This Summary About?: This is a summary describing the results of a Phase III study called TOPAZ-1. The study looked at treatment with durvalumab (a type of immunotherapy) and chemotherapy to treat participants with advanced biliary tract cancer (BTC). Advanced BTC is usually diagnosed at late stages of disease, when it cannot be cured by surgery. This study included participants with advanced BTC who had not received previous treatment, or had their cancer come back at least 6 months after receiving treatment or surgery that aimed to cure their disease. Participants received treatment with durvalumab and chemotherapy or placebo and chemotherapy. The aim of this study was to find out if treatment with durvalumab and chemotherapy could increase the length of time that participants with advanced BTC lived, compared with placebo and chemotherapy., What Were the Results of the Study?: Participants who took durvalumab and chemotherapy had a 20% lower chance of experiencing death at any point in the study compared with participants who received placebo and chemotherapy. The side effects experienced by participants were similar across treatment groups, and less than 12% of participants in either treatment group had to stop treatment due to treatment-related side effects., What Do the Results of the Study Mean?: Overall, these results support durvalumab and chemotherapy as a new treatment option for people with advanced BTCs. Based on the results of this study, durvalumab is now approved for the treatment of adults with advanced BTCs in combination with chemotherapy by government organizations in Europe, the United States and several other countries.

Aims: According to the last WHO classification, steatohepatitic hepatocellular carcinoma (SH-HCC) is recognized as a distinct HCC subtype, even though a consensual definition is still lacking. The objectives of the study were to carefully describe the morphological features of SH-HCC and evaluate its impact on prognosis., Methods and Results: We conducted a single-centre retrospective study including 297 surgically resected HCC. Pathological features including SH criteria (steatosis, ballooning, Mallory-Denk bodies, fibrosis, and inflammation) were assessed. SH-HCC was defined by the presence of at least four of the five SH criteria and the SH component represented >50% of the tumour area. According to this definition, 39 (13%) HCC cases corresponded to SH-HCC and 30 cases (10%) corresponded to HCC with an SH component (<50%). SH criteria in SH-HCC and non-SH-HCC were distributed as follows: ballooning (100% versus 11%), fibrosis (100% versus 81%), inflammation (100% versus 67%), steatosis (92% versus 8%), and Mallory-Denk bodies (74% versus 3%). Inflammation markers (c-reactive protein [CRP] and serum amyloid A [SAA]) were significantly more expressed in SH-HCC compared to non-SH-HCC (82% versus 14%, P = <0.001). Five-year recurrence-free survival (RFS) and 5-year overall survival (OS) were similar for SH-HCC and non-SH-HCC (P = 0.413 and P = 0.866, respectively). The percentage of SH component does not impact OS and RFS., Conclusion: We confirm in a large cohort the relatively high prevalence (13%) of SH-HCC. Ballooning is the most specific criteria for this subtype. The percentage of the SH component does not impact prognosis., (© 2023 John Wiley & Sons Ltd.)

Background and Objectives: Hepatocellular carcinoma epidemiological data are limited in France. The Epidemio Liver Immunotherapy Tecentriq outcome research (ELITor) retrospective study, based on real-world data from the Carcinome HépatocellulaIrE en France (CHIEF) French cohort of hepatocellular carcinoma patients, aimed to get insight into the treatment patterns, the sociodemographic, clinical, biological, and etiological characteristics, and the quality of life of patients with unresectable hepatocellular carcinoma., Methods and Results: Between 1 September 2019 and 4 December 2020, 367 patients from the CHIEF cohort received at least one locoregional (52.8%) chemoembolization or radioembolization or systemic treatment (88.3%) and were selected for ELITor. Most patients had a Barcelona Clinic Liver Cancer (BCLC) C (93.2%) hepatocellular carcinoma stage and were affected by cirrhosis (67.7%). Alcohol was confirmed as the main etiology both as a single etiology (29.1%) and in association with other risk factors (26.9%), mainly metabolic disorders (16.2%).Tyrosine-kinase inhibitors, mainly sorafenib, were the most administered systemic treatments in first line. Patients who received at least one combination of atezolizumab and bevacizumab during the study period ( N  = 53) had a better performance status and less portal hypertension frequency than the overall population and more hepatitis B virus infection and fewer metabolic disorders as single etiology. Overall, the global health score before treatment (62.3 ± 21.9) was in line with that of reference cancer patients and worsened in 51.9% of the cases after first-line palliative-intent treatment., Conclusion: This study provided real-life data on advanced hepatocellular carcinoma characteristics and treatment patterns and described the first patients to receive the atezolizumab-bevacizumab combination before it became the new standard of care for advanced hepatocellular carcinoma., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Sarcopenia is a common problem in patients with HCC. We aimed to evaluate the prognostic and predictive value of baseline transversal psoas muscle thickness (TPMT) measurement in patients with HCC undergoing immunotherapy., Methods: HCC patients treated with programmed death ligand 1-based therapies between June 2016 and October 2022 at the Vienna General Hospital (n = 80) and the Hôpital Beaujon Clichy (n = 96) were included and followed until April 2023. TPMT at the level of the third lumbar vertebra was measured independently by 2 radiologists to evaluate interreader reliability. TPMT <12 mm/m in men and <8 mm/m in women indicated sarcopenia., Results: Overall, 176 patients (age: 66.3±11.7 y; male: n=143, 81%, Barcelona-Clinic Liver Cancer C: n=121, 69%) were included, of which 131 (74%) exhibited cirrhosis. Interreader agreement for the diagnosis of sarcopenia based on TPMT was 92.6%, and Cohen κ showed a "strong agreement" [κ = 0.84 (95% CI: 0.75-0.92)]. Sarcopenia, present in 58 patients (33%), was associated with shorter median overall survival [7.2 (95% CI: 5.0-9.5) vs. 22.6 (95% CI: 16.4-28.8 months); p < 0.001] and median progression-free survival [3.4 (95% CI: 0.2-6.8) vs. 7.9 (95% CI: 5.8-9.9 months), p = 0.001], and an independent predictor of overall [adjusted HR: 1.63 (95% CI: 1.07-2.48)] and progression-free mortality [adjusted HR: 1.54 (95% CI: 1.06-2.23)] in multivariable analyses. The objective response rate [evaluable in 162 subjects (92.0%)] per modified Response Evaluation Criteria In Solid Tumors (mRECIST) in patients with and without sarcopenia was 22% and 39%, respectively (p = 0.029). Survival and radiological responses were worse in patients with sarcopenia and systemic inflammation [median overall survival: 6.1 (95% CI: 3.6-8.6) mo; median progression-free survival: 2.8 (95% CI: 2.1-3.4) mo; objective response rate=16%; disease control rate=39%]., Conclusions: Evaluation of sarcopenia using TPMT measurement is reliable and identifies HCC patients with a dismal prognosis and response to immunotherapy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: In patients with advanced hepatocellular carcinoma (HCC) progressing after atezolizumab and bevacizumab, the optimal therapeutic sequence is still unclear and no second-line agent has proven its efficacy., Objectives: The aim of this retrospective multicenter real-world cohort study was to provide an evaluation of the efficacy and safety of the use of second-line tyrosine kinase inhibitors (TKIs) in this population., Methods: All patients with advanced HCC, treated in first-line setting by atezolizumab-bevacizumab, and who received at least one dose of treatment with TKI were included in this study. All the data were retrospectively collected from medical records. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), overall global survival (OGS), and safety. A total of 82 patients were included in this study., Results: Patients were assigned to the regorafenib group ( n  = 29, 35.4%) or other TKI (sorafenib n  = 41, lenvatinib n  = 8, or cabozantinib n  = 4) group ( n  = 53). PFS was not significantly different between the two groups [2.6 versus 2.8 months, HR 1.07 (95% CI: 0.61-1.86), p  = 0.818]. Median PFS rates were 2.6, 4.4, and 2.8 months in sorafenib-, lenvatinib-, and cabozantinib group, respectively. OS was statistically different between the regorafenib group and other TKI group [15.8 versus 7.0 months, HR 0.40 (95% CI: 0.20-0.79), p  = 0.023]. When adjusting on confounding factors, there was still a difference in OS favoring the regorafenib group (adjusted hazard ratio 0.35, p  = 0.019). OGS of patients who received regorafenib was improved compared to other TKI [18.6 versus 15.0 months, HR 0.42 (95% CI: 0.22-0.84), p  = 0.036]. Twenty percent of patients had grade 3 and none had grade 4 or 5 adverse events. In patients who experienced disease progression and fit for a third-line treatment, 80% and 50% received cabozantinib in regorafenib group and other TKI group, respectively., Conclusion: Efficacy of any TKI in the second-line setting was not affected by atezolizumab-bevacizumab treatment as first-line therapy. The safety profile in the second-line setting was consistent with the results shown in pivotal studies. PFS rates of patients were similar, regardless of TKI type. Regorafenib was associated with better OS and OGS rates compared to other TKI. These data need to be confirmed in prospective comparative studies., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

The safety and effectiveness of hepatic transarterial embolic locoregional therapy (LRT) was assessed, including transarterial chemoembolization (TACE) and transarterial radioembolization (TARE), in patients who underwent portal vein embolization (PVE) before major hepatectomy in whom surgery was then contraindicated. Adverse events (AEs) were graded according to the Society of Interventional Radiology classification of AEs. Tumor response was assessed based on the Response Evaluation Criteria In Solid Tumors 1.1. Overall survival (OS) and progression-free survival (PFS) were estimated. Fifteen patients underwent 37 transarterial LRTs (25 TACEs, 11 TAREs, and 1 bland embolization), most (73%) with hepatocellular carcinoma. Eleven AEs occurred in 7 patients, including 2 Grade 3/5 (severe) and 2 Grade 4/5 (life-threatening) events. The best response was partial response in 4 (27%) and stable disease in 10 (66%) patients. The median OS and PFS were 42 (95% CI, 35-49 months) and 33 months (95% CI, 24-42 months), respectively. In conclusion, hepatic transarterial LRT can be considered as a therapeutic option in patients with contraindicated liver surgery after PVE., (Copyright © 2023 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Several cancer immunotherapies that target the PD-L1/PD-1 pathway show promising clinical activity in patients with hepatocellular carcinoma (HCC). However, the standard of care in first-line treatment with atezolizumab (anti-PD-L1 therapy) in combination with bevacizumab is associated with a limited objective response rate. Telomerase reverse transcriptase (TERT) activation meets the criteria of oncogenic addiction in HCC and could be actionable therapeutic target and a relevant tumor antigen. Therefore we hypothesized that combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine might be an attractive therapy in HCC. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (human TERT). UCPVax has been evaluated in a multicenter phase I/II study in non-small cell lung cancers and has demonstrated to be safe and immunogenic, and is under evaluation in combination with atezolizumab in a phase II clinical trial in tumors where telomerase reactivation contributes to an oncogene addiction (HPV +  cancers). The aim of the TERTIO study is to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer anti-telomerase vaccine (UCPVax) with atezolizumab and bevacizumab in unresectable HCC in a multicenter randomized phase II study., Methods: Patients with locally advanced, metastatic or unresectable HCC who have not previously received systemic anti-cancer treatment are eligible. The primary end point is the objective response rate at 6 months. Patients will be allocated to a treatment arm with a randomization 2:1. In both arms, patients will receive atezolizumab at fixed dose of 1200 mg IV infusion and bevacizumab at fixed dose of 15 mg/kg IV infusion, every 3 weeks, according to the standard of care. In the experimental arm, these treatments will be combined with the UCPVax vaccine at 0.5 mg subcutaneously., Discussion: Combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine gains serious consideration in HCC, in order to extend the clinical efficacy of anti-PD-1/PD-L1. Indeed, anti-cancer vaccines can induce tumor-specific T cell expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. Thus, there is a strong rational to combine immune checkpoint blockade therapy and anticancer vaccine (UCPVax) in order to activate antitumor T cell immunity and bypass the immunosuppression in the tumor microenvironment in HCC. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a CD4 Th1-inducer cancer vaccine derived from telomerase (UCPVax) and atezolizumab plus bevacizumab in unresectable HCC, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials., Trial Registration: NCT05528952., (© 2023. The Author(s).)

Using the TYDL causality test, this paper attempts (i) to investigate the existence of shift contagion among a large spectrum of financial markets during recent stress and stress-free periods and (ii) to propose a new approach of portfolio management based on the minimization of the causal intensity. During the COVID-19 crisis period, the shift contagion analysis not only reveal a tripling of the causal links between the markets studied, but also a change in the causal structure. Beyond the initial impact of the COVID-19 crisis on financial markets, policy interventions seem to have helped in reassuring market participants that the further spread of financial stress would be mitigated. However, the Russian-Ukrainian conflict, and the high degree of uncertainty it entailed, has again exacerbated the interdependencies between financial markets. In terms of portfolio analysis, our minimum-causal-intensity approach records a lower (respectively higher) reward-to-volatility ratio than the Markowitz (1952 & 1959) minimum-variance traditional approach during the pre-COVID-19 (respectively pre-war) period. On the other hand, both approaches, the one we propose in this paper and the minimum-variance approach, record negative reward-to-volatility ratios during crisis periods., Competing Interests: There is no conflict of interest., (© 2023 Elsevier Inc. All rights reserved.)

Background and Aims: Data on the effectiveness of atezolizumab plus bevacizumab (atezo-bev) after failure of multikinase inhibitor (MKI) therapy in patients with advanced hepatocellular carcinoma are scarce., Methods: This retrospective multicentre study included all consecutive patients treated with atezo-bev after failing one or more MKI treatments in the setting of an early access program. The primary endpoint was the objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1). Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan‒Meier method., Results: Fifty patients were included in this analysis. Atezo-bev was started between April 2020 and November 2021 (median follow-up, 18.21 months). The investigator-assessed ORR was 14% (95% CI 5.37-22.63%), with 7 patients displaying a tumour response, and the disease control rate was 56% (95% CI 51.21-60.8%). After starting atezo-bev, the median OS was 17.1 months (95% CI 10.58-22.01), and the median PFS was 7.99 months (95% CI 4.78-10.50). Treatment-related adverse events led to treatment discontinuation in 7 patients., Conclusions: Atezo-bev every three weeks showed clinical benefit for a proportion of patients previously treated with one or multiple lines of MKIs., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer., Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m 2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m 2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636., Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7-30·4). Median overall survival was 12·7 months (95% CI 11·5-13·6) in the pembrolizumab group versus 10·9 months (9·9-11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72-0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events., Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA., Competing Interests: Declaration of interests RKK, MU, CY, RSF, JF, ZR, TY, H-JK, SLC, MO, CV, MB, JOP, OB, UP, JWV, JE, and AV report funding to their institution from Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA (MSD), to support conduct of this study. All authors received medical writing and editorial support for the preparation of this manuscript from MSD. RKK additionally reports advisory committee membership for MSD; grants or contracts to their institution from Agios, AstraZeneca, Bayer, BMS, Eli Lilly, EMD Serono, Genentech/Roche, Loxo Oncology, MSD, Novartis, Partner Therapeutics, QED, Relay Therapeutics, Surface Oncology, and Taiho; consulting fees (advisory board payments) to themself from Compass Therapeutics, Kinnate, Exact Sciences, Regeneron, and Tyra Biosciences; consulting fees (advisory board or steering committee payments) to their institution from Agios, AstraZeneca, Exelixis, Ipsen, and MSD; travel support from AstraZeneca and MSD; participation on a data safety monitoring board (uncompensated) for Genentech/Roche and MSD; being a scientific and medical advisory board co-chair (uncompensated) for the Cholangiocarcinoma Foundation; and member of governance board (uncompensated) for the International Liver Cancer Association. MU additionally reports grants or contracts to their institution from Taiho Pharmaceutical, AstraZeneca, Merck Biopharma, MSD, Astellas Pharma, Eisai, Ono Pharmaceutical, Daiichi Sankyo, Novartis, Boehringer Ingelheim, and J-pharma; and payment or honoraria to themself from Taiho Pharmaceutical, AstraZeneca, Yakult Honsha, MSD, Nihon Servier, Ono Pharmaceutical, Incyte, Chugai Pharmaceutical, Boehringer Ingelheim, J-pharma, Takeda Pharmaceutical, Mylan EPD, Delta-Fly Pharma, and Novartis. CY additionally reports grants or contracts to themself from Servier, Bayer, AstraZeneca, Ono Pharmaceuticals, Celgene, Ipsen, Boryung Pharmaceuticals, Ildong Pharmaceuticals, CKD Pharmaceuticals, and HK inno.N; consulting fees to themself from Servier, Bayer, AstraZeneca, MSD, Eisai, Celgene, Bristol Myers Squibb, Debiopharm, Ipsen, Kyowa Kirin, Novartis, Boryung Pharmaceuticals, Merck Serono, Mundipharma, Roche, and Janssen; and payment or honoraria to themself from Servier, Bayer, AstraZeneca, MSD, Eisai, Celgene, Bristol Myers Squibb, Debiopharm, Ipsen, Kyowa Kirin, Novartis, Boryung Pharmaceuticals, Merck Serono, Mundipharma, Roche, and Janssen. RSF additionally reports grants or contracts to their institution from Adaptimmune, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Pfizer, Roche, and Genentech; consulting fees to themself from AstraZeneca, Bayer, Bristol Myers Squibb, Exelixis, Cstone, Hengrui, Eisai, Eli Lilly, MSD, Pfizer, Roche, and Genentech; payment or honoraria to themself from Genentech; and participation on a data safety monitoring or advisory board from AstraZeneca, and Hengrui. JF additionally reports grants or contracts from Astellas, AstraZeneca, Incyte Biosciences Japan, Eisai, MSD, Ono Pharmaceutical, Sanofi, J-Pharma, Daiichi Sankyo, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, Delta-Fly Pharma, and Chugai Pharma; payment or honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, Incyte Biosciences Japan, Eisai, Eli Lilly Japan, AstraZeneca, Yakult Honsha, Servier Japan, MSD, Novartis Pharma, Takeda, Bayer, Taiho Pharmaceutical, EA Pharma, Teijin Pharma, Daiichi Sankyo, and Terumo; and participation on a data safety monitoring board or advisory board from Onco Therapy Science, Chugai Pharma, Astellas, AstraZeneca, Takara Bio, Merck Bio, MSD, and Taiho Pharmaceutical. ZR additionally reports consulting fees from MSD, AstraZeneca, and Roche and payment or honoraria for lectures from Bayer, MSD, and Roche. TY additionally reports consulting fees from BMS, MSD, AstraZeneca, Eisai, and Ipsen; support for attending meetings or travel from Roche and Bayer; stock or stock options in Moderna; medical writing support from Taiho and Ispen; and payments to their institution for clinical trial investigatorship from BMS, MSD, Exelixis, Eli Lilly, AstraZeneca, Roche, and Taiho. H-JK additionally reports payment or honoraria to their institution from MEDtalks and Ipsen and payments made to their institution for participation on an advisory board from AstraZeneca, Janssen, MSD, and Ipsen. SLC additionally reports consulting fees to themself from MSD, AstraZeneca, Eisai, Roche, and Bayer; payment or honoraria to themself from MSD, AstraZeneca, Eisai, Roche, and Bristol Myers Squibb; and support for attending meetings or travel from Ipsen and Novartis. MO additionally reports payment or honoraria from Taiho Pharmaceutical, Yakult Honsha, MSD, Ono Pharmaceutical, Nihon, Servier, Bayer, and Pfizer. CV additionally reports consulting fees from Bayer, MSD, Roche, Ipsen, and AstraZeneca; and payment or honoraria from Bayer, MSD, Roche, Ipsen, and AstraZeneca. MB additionally reports consulting fees from Bayer Pharma, MSD, Eisai, Sirtex Medical, BMS, Roche, and AstraZeneca; and payment or honoraria from Bayer Pharma, MSD, Sirtex Medical, BMS, Roche, and AstraZeneca. JOP additionally reports grants or contracts from BMS (Celgene), Servier, MedPacto, Eutilex, and ABL Bio; support for attending meetings or travel from Minneamrita Therapeutics; and participation on a data safety monitoring board or advisory board for AstraZeneca, Adicet, and Merck Serono. JWV additionally reports consulting fees to themself from Ipsen, Novartis, AstraZeneca, Merck, Pfizer, PCI Biotech, Incyte, Keocyt, QED Therapeutics, Pieris Pharmaceuticals, Genoscience Pharma, Mundipharma, Wren Laboratories, Nucana, Debiopharm Group, Imaging Equipment Limited, Hutchison MediPharma, Zymeworks, Aptitude Health, Sirtex Medical, Baxter, Medivir, Cantargia AB, Autem Medical, Taiho Oncology, Servier, and Boehringer Ingelheim; payments to themself for speakers bureaus from Novartis, Ipsen, Nucana, Imaging Equipment Limited, Mylan, Incyte, Servier, and Delcath Systems; and support for attending meetings or travel from Nucana, Lilly, Roche, and AstraZeneca/MedImmune. LY reports salary for full-time employment from MSD. UM reports salary for full-time employment from MSD and stock ownership in Merck & Co, Rahway, NJ, USA. ABS reports salary for full-time employment from MSD and stock ownership in Merck & Co, Rahway, NJ, USA. JE additionally reports grants or contracts from BMS, Beigene, and Boston Scientific; and payment or honoraria from MSD, Eisai, BMS, AstraZeneca, Bayer, Roche, Ipsen, Basilea, Merck Serono, Incyte, Servier, Beigene, Taiho, and Boston Scientific. AV additionally reports consulting fees to themself from AstraZeneca, Amgen, Beigene, Böhringer Mannheim, BMS, BTG, Daiichi Sankyo, Eisai, Incyte, Ipsen, MSD, Pierre Fabre, Roche, Servier, Sirtex, Taiho, and Terumo; payment or honoraria to themself from AstraZeneca, Amgen, Beigene, Böhringer Mannheim, BMS, BTG, Daiichi Sankyo, Eisai, GSK, Imaging Equipment (AAA), Incyte, Ipsen, Jiangsu Hengrui Medicines, MSD, Pierre Fabre, Roche, Servier, Sirtex, Taiho, and Terumo; and participation on a data safety monitoring board or advisory board from AstraZeneca, Amgen, Beigene, Böhringer Mannheim, BMS, BTG, Daiichi Sankyo, Eisai, Incyte, Ipsen, MSD, Pierre Fabre, Roche, Servier, Sirtex, Taiho, and Terumo. OB and UP report no additional competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In this debate, the authors consider whether patients with hepatocellular carcinoma (HCC) and portal vein tumour thrombosis are candidates for liver transplantation (LT). The argument for LT in this context is based on the premise that, following successful downstaging treatment, LT confers a much greater clinical benefit in terms of survival outcomes than the available alternative (palliative systemic therapy). A major argument against relates to limitations in the quality of evidence for LT in this setting - in relation to study design, as well as heterogeneity in patient characteristics and downstaging protocols. While acknowledging the superior outcomes offered by LT for patients with portal vein tumour thrombosis, the counterargument is that expected survival in such patients is still below accepted thresholds for LT and, indeed, the levels achieved for other patients who receive transplants beyond the Milan criteria. Based on the available evidence, it seems too early for consensus guidelines to recommend such an approach, however, it is hoped that with higher quality evidence and standardised downstaging protocols, LT may soon be more widely indicated, including for this population with high unmet clinical need., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

A substantial proportion of patients with hepatocellular carcinoma have to face up, sooner or later, to systemic therapy. The current standards as first line systemic therapies are either atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGF), or durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4). However, the median overall survival remains below 20 months, and a minority of patients become long-term survivors. Of interest in immune-oncology strategies for hepatocellular carcinoma, the objective response seems to be the most reliable surrogate marker of better overall survival. TRIPLET-HCC (NCT05665348) is a multicentre, randomised, open-label phase II-III trial designed to evaluate efficacy and safety of the triple combination by the addition of ipilimumab (anti-CTLA-4) to atezolizumab/bevacizumab, versus the double atezolizumab/bevacizumab combination. The main inclusion criteria are histologically proven BCLC-B/C HCC without previous systemic therapy. The primary objective of the phase II is the objective response rate in the triple arm, and OS in the triple versus double arms in the phase III. Secondary endpoints common to the phases II and III are the comparisons of progression-free survival, objective response rates, tolerance and quality of life. In addition, genetic and epigenetic studies from tissue and circulating DNA/RNA will be conducted to assess their prognostic or predictive value., Competing Interests: Conflict of interest • B.G. has participated in consulting and/or advisory boards for Roche, AstraZeneca, BMS, Bayer, Ipsen, and received research grant from Roche. • C.C. has participated in consulting and/or advisory boards for Ipsen, Gilead, Abbvie, Intercept and received research grant from Gilead. • D.T. has participated in consulting and/or advisory boards for AstraZeneca, Pierre Fabre, Ipsen, MSD, BMS, Servier, Sirtex Medical, Novartis and AMGEN • E.A.: Consulting: BMS, AstraZeneca, Bayer, Roche, Ipsen, Incyte, Servier, Boston Scientific, AAA; Travel expense: IPSEN, MSD • H.S. report lecture fee, board membership, or consultancy from Amgen, Fresenius, IPSEN, Actial, Astellas, Danone, THAC, Biose, BiomX, Eligo, Immusmol, Adare, Nestle, Ferring, MSD, Bledina, Pfizer, Biocodex, BMS, Bromatech, Gilead, Janssen, Mayoli, Roche, Sanofi, Servier, Takeda, Abbvie, has stocks from Enterome bioscience and is co-founder of Exeliom Biosciences. • J.C.N. has received research grants from Ipsen and Bayer. • J.E.: Consulting: MSD, Eisai, BMS, AstraZeneca, Bayer, Roche, Ipsen, Basilea, Merck Serono, Incyte, Servier, Beigene, Taiho, Boston Scientific; Travel expense: Amgen; Research funding (institutional): BMS, Beigene, Boston Scientific • J.F.B.: Bayer, Ipsen, Esai, Astra-Zeneca, Roche, BMS, Servier, Incyte, Tahio Oncology • J.M.P. has participated in consulting and/or advisory boards for Roche, AstraZeneca, Eisai, MSD, Bayer, Ipsen, Lilly • K.L.M.: No conflict of interests • M.A. has participated in consulting and/or advisory boards for AstraZeneca, Bayer and Roche. • M.B. has participated in consulting and/or advisory boards for Bayer, AstraZeneca, Roche, Ipsen, MSD, BMS, Servier, Sirtex Medical, Eisai, Taiho • M.G.: No conflict of interests • P.M. has participated in consulting and/or advisory boards for Roche, AstraZeneca, Eisai, MSD, Bayer, Ipsen, and received research grants from Genosciences and Ipsen. • P.L.P.: is a consultant/advisory board member for Merck Serono, AstraZeneca Amgen, Boehringer Ingelheim, Biocartis, Roche, Bristol-Myers Squibb, Pierre Fabre, Servier, and MSD. • T.A.: has participate in consulting and/or advisory boards for Servier, Pierre Fabre, MSD and BMS and received grant from Amgen, (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: The purpose of this study was to assess the performance of a reinforced analgesic protocol (RAP) on pain control in patients undergoing conventional trans-arterial chemoembolization (cTACE) for hepatocellular carcinoma (HCC)., Materials and Methods: Eighty-one consecutive patients (57 men, 24 women) with a mean age of 69 ± 10 (standard deviation) years (age range: 49-92 years) underwent 103 cTACEs. Standard antalgic protocol (50 mg hydroxyzine, 10 mg oxycodone, 8 mg ondansetron, and lidocaine for local anesthesia) was prospectively compared to a RAP (standard + 40 mg 2-h infusion nefopam and 50 mg tramadol). The individual pain risk was stratified based on age, the presence of cirrhosis and alcoholic liver disease, and patients were assigned to a low-risk group (standard protocol) or high-risk group (RAP). The primary endpoint was severe periprocedural abdominal pain (SAP), defined as a visual analog scale score ≥30/100. A predefined intermediate analysis was performed to monitor the benefit-risk of the RAP. Based on the intermediate analysis, all patients were treated with the RAP., Results: The intermediate analysis performed after 52 cTACE showed that 2/17 (12%) high-risk patients (i.e., those receiving the RAP) experienced SAP compared to 15/35 (43%) low-risk patients (odds ratio [OR] = 0.18; 95% confidence interval [CI]: 0.02-0.98; P = 0.03). Analysis of all procedures showed that 12/67 (18%) patients in cTACE receiving the RAP experienced SAP compared to 15/36 (42%) patients who did not receive it (OR = 3.27; 95% CI: 1.32-8.14; P = 0.01). There were no statistical differences in adverse events, particularly for nausea, between groups., Conclusion: Reinforcing the analgesic protocol by combining non-opioid and opioid molecules reduces perioperative pain in patients undergoing cTACE for HCC., Competing Interests: Declaration of Competing Interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article., (Copyright © 2022 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)