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Audrey Debaillon Vesque,1 Marie Decraecker,1 Jean-Frédéric Blanc1,2 1Department of Oncology, CHU Bordeaux, Hospital Haut Leveque, Pessac 33604 France; 2INSERM U1053, BaRITOn, University Victor Segalen, Bordeaux, FranceCorrespondence: Jean-Frédéric Blanc Email jean-frederic.blanc@chu-bordeaux.frAbstract: Management of advanced hepatocellular carcinoma is challenging. With an increasing number of options for the first and second-line treatment, understanding and developing optimal systemic treatment strategies are crucial. In second line, two tyrosine kinase inhibitors (TKI) and one monoclonal antibody have been approved after sorafenib by both the European Medicines Agency and the Food and Drug Administration based on the results of phase 3 trials: cabozantinib, regorafenib and ramucirumab. Cabozantinib has demonstrated an improved overall survival and progression-free survival in the phase 3 CELESTIAL study in second and third line, in patients in good general condition (performance status 0– 1) and with a normal liver function Child-Pugh class A. Analysis of subgroups has shown that even elderly patients over 65 years, or patients with high baseline alpha-fetoprotein ≥ 400 ng/mL benefit from cabozantinib. The choice in second-line between the three drugs should be based on factors such as previous tolerance of sorafenib, safety profile of drugs and quality of life. In this review, we will analyze clinical data available on cabozantinib, clarifying the choice between the different possible treatments. However, the upcoming of a new standard in first line with the combination atezolizumab and bevacizumab will change the game and will warrant further investigations to define the accurate subsequent sequence of TKIs. Cabozantinib is also actually tested in first-line in combination with atezolizumab, results of the phase 3 COSMIC trial are eagerly awaited.Keywords: advanced hepatocellular carcinoma, cabozantinib, MET, alpha-fetoprotein, AFP, tyrosine kinase inhibitor

We prospectively assessed contrast-enhanced sonography for evaluating the degree of liver fibrosis as diagnosed via biopsy in 99 patients. The transit time of microbubbles between the portal and hepatic veins was calculated from the difference between the arrival time of the microbubbles in each vein. Liver biopsy was obtained for each patient within 6 months of the contrast-enhanced sonography. Histological fibrosis was categorized into two classes: (1) no or moderate fibrosis (F0, F1, and F2 according to the METAVIR staging) or (2) severe fibrosis (F3 and F4). At a cutoff of 13 s for the transit time, the diagnosis of severe fibrosis was made with a specificity of 78.57%, a sensitivity of 78.95%, a positive predictive value of 78.33%, a negative predictive value of 83.33%, and a performance accuracy of 78.79%. Therefore, contrast-enhanced ultrasound can help with differentiation between moderate and severe fibrosis. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. The POLO trial showed that olaparib (PARP inhibitor) improved progression-free survival (PFS) but not overall survival (OS), when used as maintenance therapy after ≥ 16 weeks of disease control with first-line platinum-based chemotherapy in patients with germline (g) BRCA 1 or 2 pathogenic variants (PV) metastatic PDAC. However, real-world data on the effectiveness of olaparib are missing., Methods: Patients with unresectable PDAC associated with somatic (s) or (g)BRCA1/2 and (g)non-BRCA-HRD PV (i.e. other homologous recombination deficiency/HRD genes) who were treated with olaparib between 2020-2023 were included. The primary objective was to describe treatment patterns. Secondary exploratory objectives included OS and PFS in patients treated with olaparib according to the POLO trial or not, OS and PFS in patients with (g)HRD PV-associated PDAC versus (s)PVs, olaparib safety profile and factors associated with olaparib poor outcomes., Results: Among 85 patients, 45.9 % received olaparib as defined by the POLO trial. No difference in OS and PFS was observed between patients who received olaparib according to the POLO trial versus not. Patients with (g)HRD PV-associated PDAC had better OS compared to others (22.3 versus 10.5 months, p = 0.038). Factors associated with olaparib poor outcomes included a high neutrophil-to-lymphocyte ratio and the use of olaparib outside the recommendations of the POLO trial. Few grade ≥ 3 adverse events were reported (9.4 %)., Conclusion: Patients with (g)HRD PV-associated PDAC had longer OS than those with (s)HRD PV. Olaparib use beyond the scope of the POLO trial was associated with poor outcomes., Competing Interests: Declaration of Competing Interest APe declares speaker’s engagement from Servier; consulting/advisory role for Amgen; travel grant from Ipsen, Merk and Servier. DT reports consultancy, advisory fees, honoraria from Servier, Pierre Fabre, Merck Serono, MSD, BMS, AZ, Roche, Sanofi; research funding from Sandoz, Astra Zenenca, Servier, MSD; travel grants from Pierre Fabre, MSD, Servier, Roche. JT has received honoraria as a speaker and/or in an advisory role from: AMGEN, Astellas, Astra Zeneca, BMS, Boehringer Ingelheim, Merck KGaA, MSD, Novartis, ONO pharmaceuticals, Pierre Fabre, Roche Genentech, Sanofi, Servier, Takeda. MM reports consultancy, advisory fees, honoraria from Pierre Fabre, Merck Serono, MSD, Takeda; travel grants from Pierre Fabre, Servier. OB reports consultancy, advisory fees, honoraria from Servier, Amgen, Pierre Fabre, Merck Serono, MSD, Takeda, Deciphera; travel grants from Pierre Fabre, Servier, MSD., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant primary liver cancer. iCCA may develop on an underlying chronic liver disease and its incidence is growing in relation with the epidemics of obesity and metabolic diseases. In contrast, perihilar cholangiocarcinoma (pCCA) may follow a history of chronic inflammatory diseases of the biliary tract. The initial management of CCAs is often complex and requires multidisciplinary expertise. The French Association for the Study of the Liver wished to organize guidelines in order to summarize the best evidence available about several key points in iCCA and pCCA. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe the epidemiology of CCA as well as how patients with iCCA or pCCA should be managed from diagnosis to treatment. The most recent developments of personalized medicine and use of targeted therapies are also highlighted., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Current systemic therapies for metastatic pancreatic ductal adenocarcinoma are associated with poor outcomes with a 5-year overall survival rate under 5%. We aimed to assess the safety and antitumour activity of mitazalimab, a human CD40 agonistic IgG1 antibody, with modified FOLFIRINOX (mFOLFIRINOX; fluorouracil, leucovorin, oxaliplatin, and irinotecan), in chemotherapy-naive patients with metastatic pancreatic ductal adenocarcinoma., Methods: OPTIMIZE-1 was a single-arm, multicentre, phase 1b/2 study which enrolled adults with histologically-confirmed metastatic pancreatic ductal adenocarcinoma and European Cooperative Oncology Group performance status 0 or 1 in 14 university hospitals in Belgium, France, and Spain. The primary endpoint of phase 1b was to determine the recommended phase 2 dose of intravenous mitazalimab (450 μg/kg or 900 μg/kg) when combined with intravenous mFOLFIRINOX (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , irinotecan 150 mg/m 2 , fluorouracil 2400 mg/m 2 ). In the first 21-day treatment cycle, mitazalimab was administered on days 1 and 10, and mFOLFIRINOX on day 8. In subsequent 14-day cycles mitazalimab was administered 2 days after mFOLFIRINOX. The phase 2 primary endpoint was objective response rate. Activity and safety analyses were conducted on the full analysis set (all patients who received the combination of mitazalimab at the recommended phase 2 dose and mFOLFIRINOX for at least two treatment cycles) and safety set (all patients who received any study treatment), respectively. Enrolment is complete, and data represents a primary analysis of the ongoing trial. The trial is registered at Clinicaltrials.gov (NCT04888312)., Findings: Between Sept 29, 2021, and March 28, 2023, 88 patients were screened and 70 patients were enrolled (40 [57%] were female and 30 [43%] were male). In phase 1b, 900 μg/kg mitazalimab was determined as the recommended phase 2 dose. Overall, five patients received 450 μg/kg mitazalimab; 65 received 900 μg/kg mitazalimab. No dose-limiting toxicities were observed at 450 μg/kg, and one dose-limiting toxicity was observed at 900 μg/kg. 57 patients were evaluated for activity, and all 70 patients were included in the safety set. At data cutoff on Nov 14, 2023, median follow-up was 12·7 months (95% CI 11·1-15·7). Of the 57 patients, 29 (51%) remained on study and 18 (32%) remained on treatment. The primary endpoint (objective response rate >30%) was met (objective response rates in 23 [40%]; one-sided 90% CI ≥32 of 57 patients). The most common grade 3 or worse adverse events were neutropenia (18 [26%] of 70 patients), hypokalaemia (11 patients [16%]), and anaemia and thrombocytopenia (eight patients [11%]). Serious adverse events were reported in 29 (41%) of 70 patients, the most common being vomiting (five [7%] of 70 patients), decreased appetite (four [6%]), and diarrhoea and cholangitis (three [4%] of 70 patients for each), none considered related to mitazalimab. No treatment-related deaths were reported., Interpretation: Mitazalimab with mFOLFIRINOX demonstrated manageable safety and encouraging activity, warranting continued development in a phase 3, randomised, controlled trial. The results from OPTIMIZE-1 pave the way for further exploration and confirmation of a novel immunotherapy treatment regimen for metastatic pancreatic ductal adenocarcinoma, which is a complex and aggressive cancer with very low survival rates and restricted treatment options., Funding: Alligator Bioscience., Competing Interests: Declarations of interests J-LVL, IB, HP, AL, EM, JFeB, LP, JFB, IG, and MRG declare no competing interests. KPG has received honoraria from Ipsen, Servier, Merck, Bristol Myers Squibb (BMS), Serb, and Nordic Pharma; support for attending meetings or travel from Ipsen, and Servier, and MSD; has participated on a data safety monitoring board or advisory board for Servier, BMS, MSD, and AstraZeneca; and is Vice President for Belgian Group of Digestive Oncology. PAC has received honoraria from BMS, Boehringer Ingelheim, Brenus Pharma, Scenic Biotech; research funding to institution from AbbVie, Adlai Nortye, Alligator, Amgen, Astex, AstraZeneca, Boehringer Ingelheim, Bleuprint, C4 Therapeutics, Dragonly, Daiichi Sankyo, Exelixis, GSK, Incyte, Iteos, Janssen, Kinnate, Kazia, Lilly/Loxo, Merus, Molecular Partners, MSD, Novartis, OSE Immunotherapeutics, Pierre Fabre, Relay, Roche/Genentech, Sotio, Taiho, Tango, Toray, Turning Point/BMS, and Transgene. RAP-C received support from Alligator Bioscience for the present manuscript and reports consulting fees from Roche, BMS/Celgene, Eisai Europe, AstraZeneca Spain, Astellas Pharma, Servier, and Ipsen; payments for honoraria from BMS, Servier, AstraZeneca Spain, Astellas Pharma; payment for expert testimony from Servier; support for attending meetings or travel from Lilly, Roche, BMS; participation on data safety monitoring board or advisory board from Roche, BMS/Celgene, AstraZeneca Spain, and Servier. KES, PE, SVA, and YPdC are all employees of and have stock or stock options in Alligator Bioscience. PE is an inventor on the patents relating to mitazalimab, and KES is a co-author of patents for mitazalimab (patents owned by Alligator Bioscience). TM reports grants or contracts from MSD, Novocure, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, Zymeworks, AbbVie Farmaceútica, Ability Pharmaceuticals, Agios Pharmaceuticals, Amgen, Aslan Pharmaceuticals, AstraZeneca, Basilea Pharmaceutica International, Bayer, BeiGene, BioKeralty Research Institute, BioLineRx, Blueprint Medicines, Boston Biomedical, BMS, Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-La Roche, FibroGen, Halozyme, Incyte, Ipsen Bioscience, Ipsen Pharma, Lilly, Loxo Oncology, MedImmune, Merck Sharp & Dohme, Nelum, Novartis, Novocure, OncoMed Pharmaceuticals, QED Therapeutics, VCN Biosciences, and Zymeworks; consulting fees from Ability Pharmaceuticals, Arcus Bioscience, AstraZeneca, Basilea Pharma, Baxter, BioLineRX, Celgene, Eisai, Incyte, Ipsen Bioscience; payment for honoraria from Janssen, Lilly, Esteve, Daïchi, Biontech, Novartis, Jazz Pharmaceuticals; payment for attending meetings or travel from Servier, AstraZeneca, Sanofi, Incyte, Lilly, MSD, and Roche; participation on a data safety monitoring board or advisory board for Ability Pharmaceuticals, Arcus Bioscience, AstraZeneca, Basilea Pharma, Baxter, BioLineRX, Celgene, Eisai, Incyte, and Ipsen Bioscience., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: Sonic hedgehog hepatocellular adenoma (shHCA) is a new hepatocellular adenoma (HCA) subgroup characterized by high risk of hemorrhage. ShHCA account for below 10% of all HCA cases and are often associated with female gender, obesity, and non-alcoholic steatohepatitis. No specific MRI characteristics have been described to date. The objective of this study was to assess the value of using MRI to identify shHCA, and correlate MRI findings with histology., Methods: We retrospectively collected MRI scans of 29 patients with shHCA from our center and from different liver referral centers to include 35 lesions. Diagnosis of shHCA was assessed by immunohistochemical overexpression of argininosuccinate synthase 1 or prostaglandin D2 synthase, then confirmed by molecular analysis of sonic hedgehog pathway activation and/or by proteomic analysis., Results: In 46% (n = 16/35) of shHCA cases, we detected intralesional fluid-filled cavities defined on MR images as fluid-like foci markedly hyperintense on T2-weighted sequences, and hypointense on T1-weighted sequences, with or without delayed enhancement. Pathologically, these cavities were observed in 54% of cases as vacuoles filled with blood at different stages of degradation. Hemorrhage and/or necrosis were detected among 71% of cases by MRI analysis (n = 25/35) versus 82% pathologically. Seventeen percent of shHCA cases (n = 6/35) were completely homogeneous via MRI and pathological analysis. No MRI criteria was found in favor of focal nodular hyperplasia, HNF1A-mutated HCA, or typical inflammatory HCA., Conclusion: We reveal the presence of intralesional fluid-filled cavities among 46% of our shHCA cases that represent a new MRI finding possibly helpful for shHCA diagnosis., Clinical Relevance Statement: This multicenter study is the first clinical study about the radiological aspect of this new hepatocellular adenoma subgroup. This highlights a strong correlation between MRI and histological analysis, with a specific pattern emerging for diagnosis., Key Points: • Sonic hedgehog hepatocellular adenoma is a new hepatocellular adenoma subgroup associated with high risk of hemorrhage, but imaging features of this subgroup remain unknown. • Analysis of MR images and correlation with pathology revealed intralesional fluid-filled cavities and necrotic-hemorrhagic changes. • Intralesional fluid-filled cavities have not yet been described in other adenoma subtypes and represent a new MRI finding for sonic hedgehog hepatocellular adenoma., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Introduction: The effectiveness of percutaneous radiofrequency ablation (RFA) in intrahepatic cholangiocarcinomas (iCCA) remains insufficiently studied., Methods: We conducted a retrospective study including patients with histologically proven iCCA within Milan criteria treated by percutaneous RFA from 2000 to 2022. The primary outcome was overall survival in treatment-naive patients and secondary outcomes included ablation completeness, adverse events, local and distant recurrence. A total of 494 patients with hepatocellular carcinoma (HCC) on cirrhosis treated by RFA were included as a comparison group. Oncological events were analysed using Kaplan-Meier, log-rank and univariate/multivariate Cox models., Results: The main population included 71 patients, mostly cirrhotic (80%) with solitary tumours (66%) of a median size of 24 mm. Local recurrence was 45% at 5 years, lower in multibipolar versus monopolar RFA (22% vs. 55%, p = .007). In treatment-naive patients (n = 45), median overall and recurrence-free survivals were 26 and 11 months, respectively. Tumour size (p = .01) and Child-Pugh B (p = .001) were associated with death. The rate of distant recurrence was 59% at 5 years significantly lower for single tumours of less than 2 (p = .002) or 3 cm (p = .02). In cirrhotic patients naïve of previous treatment (n = 40), overall survival was shorter than in HCC (26 vs 68 months, p < .0001), with more local recurrences (p < .0001). Among distant recurrences, 50% were extrahepatic metastases compared to 12% in HCC (p < .001)., Conclusion: Multibipolar RFA provides better results in terms of tumour recurrence than monopolar RFA and could be used to treat small iCCA (<3 cm). Adjuvant chemotherapy should be discussed due to the frequent extra-hepatic metastasis at recurrence., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1., Methods: In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m 2 gemcitabine and 25 mg/m 2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration-ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration-and adjusted mean change from baseline in patient-reported outcomes., Findings: Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI -0·71 to 3·16) in the durvalumab group and 0·35 (-1·63 to 2·32) in the placebo group., Interpretation: The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer., Funding: AstraZeneca., Competing Interests: Declaration of interests HABIII reports consulting or advisory fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, FORMA Therapeutics, GRAIL, Incyte, Novartis, Pfizer, and Vincerx, and and research funding from AbbVie, Agios, Arch, ARMO Biosciences, Array BioPharma, Arvinas, AstraZeneca, Bayer, BIND Therapeutics, BioAtla, BioMed Valley, Biotheryx, Boehringer Ingelheim, Bristol-Myers Squibb, Cancer and Leukemia Group B, Ciclomed, Coordination Pharmaceuticals, CytomX, eFFECTOR Therapeutics, EMD Serono, Foundation Medicine, Gossamer Bio, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Jiangsu Hengrui, Incyte, Infinity, Janssen, Jounce, Kymab, Lilly, MacroGenics, MedImmune, Merck, Millennium, Takeda, miRNA Therapeutics, Moderna, NGM Biopharmaceuticals, Novartis, Pfizer, Revolution Medicine, Roche, Genentech, Ryvu, Seattle Genetics, TESARO, TG Therapeutics, Verastem, Vertex, XBiotech, and Zymeworks. TO reports honoraria from AbbVie, AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Nihon Servier, Novartis, ONO, Taiho, Takeda, Teijin, and Yakult; consulting or advisory fees from AstraZeneca, Bayer Yakuhin, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Sumitomo, Eisai, Eli Lilly Japan, Incyte, Meiji Seika Pharma, Mundipharma, Nihon Servier, Nippon Shinyaku, Novartis, ONO, Pfizer, Shire, Taiho, Takara Bio, and Takeda; and research funding from AstraZeneca, Baxter, Bristol-Myers Squibb, Chugai, Sumitomo, Eisai, Eli Lilly Japan, Kyowa Hakko Kirin, Merck, Sharp, & Dohme, Nano Carrier, Novartis, ONO, Pfizer, Syneos Health, and Taiho. AV reports honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, British Technology Group, Eisai, GlaxoSmithKline, Imaging Equipment, Incyte, Ipsen, Lilly, Merck, Novartis, Pierre Fabre, Roche, Sanofi, Servier, Sirtex, and Terumo; and consulting or advisory fees from AstraZeneca, Bayer, Bristol-Myers Squibb, British Technology Group, Eisai, GlaxoSmithKline, Imaging Equipment, Incyte, Ipsen, Lilly, Merck, Novartis, Pierre Fabre, Roche, Sanofi, Servier, Sirtex, and Terumo. HT reports honoraria from Daiichi Sankyo, Mylan, Taiho, and Yakult, and research funding from AstraZeneca, Daiichi Sankyo, and Taiho. VB reports honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb Russia, Eisai, Merck, Sharp, & Dohme, Novartis, Pfizer, Roche Russia, and Takeda, and travel or accommodation expenses from Bayer, Bristol-Myers Squibb Russia, Merck, Sharp, & Dohme, and Roche Russia. J-FB reports honoraria from AstraZeneca, Bayer, Eisai, Ipsen, Merck, Sharp, & Dohme, and Roche, and consulting or advisory fees from AstraZeneca, Bayer, Eisai, Ipsen, Merck, Sharp, & Dohme, and Roche. MB reports honoraria for participating in patient advisory boards, review of patient materials, and speaking engagements from AstraZeneca, Boehringer Ingelheim, CRC Oncology, EMD Serono, Incyte, Kinnate, Merck, QED Clinical Services, Taiho, and TriSalus. MŻ is an employee of AstraZeneca. JA was an employee of IQVIA at the time of the study and reports consulting or advisory fees from AstraZeneca. NP, JW, MA, NR, and GC are employees of, and hold stock in, AstraZeneca. D-YO reports consulting or advisory fees from ASLAN, AstraZeneca, Basilea, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Roche, Halozyme, Merck Serono, Novartis, Taiho, Turning Point, Yuhan, and Zymeworks, and research funding from Array, AstraZeneca, BeiGene, Eli Lilly, Handok, Merck, Sharp, & Dohme, Novartis, and Servier. All other others declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: This document is a summary of the French intergroup guidelines of the management of biliary tract cancers (BTC) (intrahepatic, perihilar and distal cholangiocarcinomas, and gallbladder carcinomas) published in September 2023, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org)., Methods: This collaborative work was conducted under the auspices of French medical and surgical societies involved in the management of BTC. Recommendations were graded in three categories (A, B and C) according to the level of scientific evidence until August 2023., Results: BTC diagnosis and staging is mainly based on enhanced computed tomography, magnetic resonance imaging and (endoscopic) ultrasound-guided biopsy. Treatment strategy depends on BTC subtype and disease stage. Surgery followed by adjuvant capecitabine is recommended for localised disease. No neoadjuvant treatment is validated to date. Cisplatin-gemcitabine chemotherapy combined to the anti-PD-L1 inhibitor durvalumab is the first-line standard of care for advanced disease. Early systematic tumour molecular profiling is recommended to screen for actionable alterations (IDH1 mutations, FGFR2 rearrangements, HER2 amplification, BRAF V600E mutation, MSI/dMMR status, etc.) and guide subsequent lines of treatment. In the absence of actionable alterations, FOLFOX chemotherapy is the only second-line standard-of-care. No third-line chemotherapy standard is validated to date., Conclusion: These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice. Each individual BTC case should be discussed by a multidisciplinary team., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gael Roth declares consulting or advisory role or invitation as a speaker for Servier, AstraZeneca, Bristol-Myers Squibb, MSD, Amgen, Ipsen, Accord Healthcare, Pierre Fabre, Incyte, Netris Pharma and Alpha Tau, as well as travel accommodations, or expenses from Servier, AstraZeneca, Bristol Myers Squibb, MSD, Roche, Amgen, Viatris, Pierre Fabre and Ipsen. Research funding by Genoscience Pharma, Netris Pharma. Matthieu Sarabi declares consultancy/honoraria AstraZeneca, Servier, Roche and accommodations or expenses from Ipsen. Jean-Frédéric Blanc declares honoraria from incyte, servier, AZ, Roche, Tahio oncology, MSD. Anne-Laure Bretagne-Bignon declares consulting for Astra Zeneca, Servier, Ipsen and accommodations or congress registration support for Merck and Ipsen. Romain Coriat declares honoraria for lectures and Advisory board for: BAYER, Servier, Pierre Fabre, AAA, Merck, Amgen. Christelle de la Fouchardière declares holding an advisory role with Amgen, Bayer, BMS, Daichi-Sankyo, Eisai, Imescia, Incyte, Lilly, Merck, MSD, Pierre Fabre Oncologie, Roche, and Servier; receiving grants from Pierre Fabre and Servier outside of the submitted work; receiving fees from Ipsen, Eisai, Pierre Fabre, Servier, being an invited speaker outside of the submitted work. Julien Edeline declares consulting or advisory role for BTG, Bristol Myers Squibb, AstraZeneca, Bayer, Ipsen, AstraZeneca, MSD, Eisai, Boston Scientific, Roche, Basilea, Merck Serono, Servier; research Funding from Bristol Myers Squibb (Inst), BeiGene (Inst); travel, accommodations or expenses from Amgen, Bristol Myers Squibb, Roche. Astrid Lièvre declares honoraria for lectures from Amgen, Astellas, Astra-Zeneca, Bayer, BMS, Incyte, Ipsen, Leo-pharma, Mylan, Novartis, Pierre Fabre, Roche, Servier and Viatris; consulting/advisory relationship from AAA, Astellas, Bayer, BMS, Incyte, Pierre Fabre and Servier; travel, accommodations or congress registration support from Bayer, Boehringer, Ipsen, Mylan, MSD, Pierre Fabre, Roche and Servier; research funding from Bayer (Inst), Lilly (Inst). Sylvain Manfredi declares travel accommodation from MSD, AMGEN. Cindy Neuzillet declares Honoraria and consulting from Amgen, AstraZeneca, Baxter, Bristol-Myers Squibb, Fresenius Kabi, Incyte Biosciences, Merck, MSD, Mundipharma, Novartis, Nutricia, OSE Immunotherapeutics, Pierre Fabre, Roche, Sanofi, Servier, Viatris, as well as research funding AstraZeneca, Bristol-Myers Squibb, Fresenius Kabi, Nutricia, OSE Immunotherapeutics, Roche, Servier, Viatris. Valérie Paradis declares honoraria for lectures from Incyte. Anthony Turpin declares personal fees from Servier, Viatris, Incyte Bioscience, BMS, Merck and grants and personal fees from AstraZeneca and MSD. Olivier Bouché declares consulting or advisory role for Pierre Fabre, Amgen, Bayer, Servier, MSD, Deciphera, Apmonia Therapeutics and Merck outside the submitted work. David Malka declares honoraria for Roche, Amgen, Bayer, Merck Serono, Servier, Sanofi, Pierre Fabre, Viatris, Bristol Myers Squibb, MSD Oncology, LEO Pharma, Incyte, AstraZeneca; consulting or advisory role: Roche, Sanofi, Merck Serono, MSD, Servier, Bayer, Incyte, Amgen, Bristol Myers Squib, Taiho Oncology, AbbVie, AstraZeneca, Pierre Fabre; travel, accommodations or expenses from Roche, Bayer, Sanofi, Merck Serono, Amgen, Servier, Pierre Fabre, Bristol Myers Squibb/Pfizer, MSD, Viatris. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Non-invasive subtyping of hepatocellular adenomas (HCA) remains challenging for several subtypes, thus carrying different levels of risks and management. The goal of this study is to devise a multivariable diagnostic model based on basic clinical features (age and sex) combined with MRI-radiomics and to evaluate its diagnostic performance., Methods: This single-center retrospective case-control study included all consecutive patients with HCA identified within the pathological database from our institution from January 2003 to April 2018 with MRI examination (T2, T1-no injection/injection-arterial-portal); volumes of interest were manually delineated in adenomas and 38 textural features were extracted (LIFEx, v5.10). Qualitative (i.e., visual on MRI) and automatic (computer-assisted) analysis were compared. The prognostic scores of a multivariable diagnostic model based on basic clinical features (age and sex) combined with MRI-radiomics (tumor volume and texture features) were assessed using a cross-validated Random Forest algorithm., Results: Via visual MR-analysis, HCA subgroups could be classified with balanced accuracies of 80.8 % (I-HCA or ß-I-HCA, the two being indistinguishable), 81.8 % (H-HCA) and 74.4 % (sh-HCA or ß-HCA also indistinguishable). Using a model including age, sex, volume and texture variables, HCA subgroups were predicted (multivariate classification) with an averaged balanced accuracy of 58.6 %, best=73.8 % (sh-HCA) and 71.9 % (ß-HCA). I-HCA and ß-I-HCA could be also distinguished (binary classification) with a balanced accuracy of 73 %., Conclusion: Multiple HCA subtyping could be improved using machine-learning algorithms including two clinical features, i.e., age and sex, combined with MRI-radiomics. Future HCA studies enrolling more patients will further test the validity of the model., Competing Interests: 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., (© 2024 The Authors.)

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.)

Hepatocellular carcinoma (HCC) is an inflammation-associated cancer arising from viral or non-viral etiologies including steatotic liver diseases (SLDs). Expansion of immunosuppressive myeloid cells is a hallmark of inflammation and cancer, but their heterogeneity in HCC is not fully resolved and might underlie immunotherapy resistance. Here, we present a high-resolution atlas of innate immune cells from patients with HCC that unravels an SLD-associated contexture characterized by influx of inflammatory and immunosuppressive myeloid cells, including a discrete population of THBS1 + regulatory myeloid (M reg ) cells expressing monocyte- and neutrophil-affiliated genes. THBS1 + M reg cells expand in SLD-associated HCC, populate fibrotic lesions, and are associated with poor prognosis. THBS1 + M reg cells are CD163 + but distinguished from macrophages by high expression of triggering receptor expressed on myeloid cells 1 (TREM1), which contributes to their immunosuppressive activity and promotes HCC tumor growth in vivo. Our data support myeloid subset-targeted immunotherapies to treat HCC., Competing Interests: Declaration of interests M.D. is co-founder, chief scientific officer, and employee of Inotrem SA, a French company that develops TREM1 inhibitors., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: MET amplification ( MET amp) has been reported in 1%-5% of patients with hepatocellular carcinoma (HCC) and may be sensitive to MET inhibition. Tepotinib, a selective MET inhibitor, has shown promising activity in HCC with MET overexpression. We investigated the preclinical and clinical activity of tepotinib in HCC with MET amp ( MET gene copy number [GCN] ≥5), including high-level MET amp ( MET GCN ≥10)., Methods: Preclinical antitumor activity of tepotinib 100 mg/kg (orally, days 1-5, every 7 days, 3-5 weeks; 3-12 replicates) was evaluated according to MET amp status, as determined using the nCounter platform (NanoString), in 37 HCC patient-derived xenografts (PDXs) in immunodeficient mice. Clinical outcomes were evaluated in patients with MET amp by fluorescence in situ hybridization who received tepotinib 500 mg (450 mg active moiety) in two phase Ib/II trials in HCC with MET overexpression., Results: Across the PDX models, tepotinib induced complete or near-complete tumor regression in the only two models with high-level MET amp. Median tumor volume reductions were 100% and 99.8% in models with MET GCN 47.1 and 44.0, respectively. Across the two clinical trials, 15/121 patients had MET amp. Disease control was achieved by 11/15 patients with MET amp (complete response [CR], n = 1; partial response [PR], n = 4; stable disease [SD], n = 6) and 4/4 with high-level MET amp (CR, n = 1; PR, n = 2; SD, n = 1). All three patients with high-level MET amp and objective response received treatment for >1 year, including one patient who received first-line tepotinib for >6 years., Conclusion: High-level MET amp may be an oncogenic driver in HCC that is sensitive to MET inhibitors such as tepotinib.

Hepatocellular carcinoma (HCC) is one of the most common neoplasms worldwide and the third most common cause of cancer-related death. Several liver-targeted intra-arterial therapies are available for unresectable HCC, including selective internal radiation therapy (SIRT) and trans-arterial chemoembolization (TACE). Those two are the most used treatment modalities in localized non-operable HCC. TACE is the treatment option for patients with stage B, according to the BCLC staging system. In contrast, SIRT does not have an official role in the treatment algorithm, but recent studies showed promising outcomes in patients treated with SIRT. Although TACE is globally a safe procedure, it might provoke several vascular complications such as spasms, inflammatory constriction, and, in severe cases, occlusion, dissection, or collateralization. Hence, it is acclaimed that those complications could restrain the targeted response of the radio-embolization when we use it as second-line therapy post TACE. In this study, we will assess the efficacity of SIRT using Yttrium 90 Microspheres post incomplete or failure response to TACE. In our retrospective study, we had 23 patients who met the inclusion criteria. Furthermore, those patients have been followed radiologically and biologically. Then, we evaluated the therapeutic effect according to the mRECIST criteria, in addition to the personalized dose analysis. We found 8 patients were treated with TheraSphere ® , with a median tumor absorbed dose of 445 Gy, while 15 received SIR-Spheres ® treatment with a mean tumor dose of 268 Gy. After radiological analysis, 56.5% of the patients had a complete response, and 17.3% showed partial response, whereas 13% had stable disease and 13% had progressive disease. For patients treated with SIRT after an incomplete response or failure to TACE, we found an objective response rate of 73.8%. Despite the known vascular complications of TACE, SIRT can give a favorable response.

Background: Surgical resection (SR) is a potentially curative treatment of hepatocellular carcinoma (HCC) hampered by high rates of recurrence. New drugs are tested in the adjuvant setting, but standardised risk stratification tools of HCC recurrence are lacking., Objectives: To develop and validate a simple scoring system to predict 2-year recurrence after SR for HCC., Methods: 2359 treatment-naïve patients who underwent SR for HCC in 17 centres in Europe and Asia between 2004 and 2017 were divided into a development (DS; n = 1558) and validation set (VS; n = 801) by random sampling of participating centres. The Early Recurrence Score (ERS) was generated using variables associated with 2-year recurrence in the DS and validated in the VS., Results: Variables associated with 2-year recurrence in the DS were (with associated points) alpha-fetoprotein (<10 ng/mL:0; 10-100: 2; >100: 3), size of largest nodule (≥40 mm: 1), multifocality (yes: 2), satellite nodules (yes: 2), vascular invasion (yes: 1) and surgical margin (positive R1: 2). The sum of points provided a score ranging from 0 to 11, allowing stratification into four levels of 2-year recurrence risk (Wolbers' C-indices 66.8% DS and 68.4% VS), with excellent calibration according to risk categories. Wolber's and Harrell's C-indices apparent values were systematically higher for ERS when compared to Early Recurrence After Surgery for Liver tumour post-operative model to predict time to early recurrence or recurrence-free survival., Conclusions: ERS is a user-friendly staging system identifying four levels of early recurrence risk after SR and a robust tool to design personalised surveillance strategies and adjuvant therapy trials., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFβ inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC., Methods: This Phase 2 open-label study enrolled patients with metastatic PDAC who progressed after 1-2 prior therapies. Patients were enrolled in a safety lead-in (abemaciclib plus galunisertib) followed by a 2-stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib-containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression-free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics., Results: One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4-1.8), 1.8 months (95% CI: 1.3-1.9), and 3.3 months (95% CI: 1.1-5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified., Conclusion: In patients with pretreated metastatic PDAC, abemaciclib-based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC., (© 2023 The Authors. Cancer Medicine published by 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 & Aims: Hepatocellular adenomas (HCAs) are rare, benign, liver tumours classified at the clinicopathological, genetic, and proteomic levels. The β-catenin-activated (b-HCA) subtypes harbour several mutation types in the β-catenin gene ( CTNNB1 ) associated with different risks of malignant transformation or bleeding. Glutamine synthetase is a surrogate marker of β-catenin pathway activation associated with the risk of malignant transformation. Recently, we revealed an overexpression of glutamine synthetase in the rims of exon 3 S45-mutated b-HCA and exon 7/8-mutated b-HCA compared with the rest of the tumour. A difference in vascularisation was found in this rim shown by diffuse CD34 staining only at the tumour centre. Here, we aimed to characterise this tumour heterogeneity to better understand its physiopathological involvement., Methods: Using mass spectrometry imaging, genetic, and proteomic analyses combined with laser capture microdissection, we compared the tumour centre with the tumour rim and with adjacent non-tumoural tissue., Results: The tumour rim harboured the same mutation as the tumour centre, meaning both parts belong to the same tumour. Mass spectrometry imaging showed different spectral profiles between the rim and the tumour centre. Proteomic profiling revealed the significant differential expression of 40 proteins at the rim compared with the tumour centre. The majority of these proteins were associated with metabolism, with an expression profile comparable with a normal perivenous hepatocyte expression profile., Conclusions: The difference in phenotype between the tumour centres and tumour rims of exon 3 S45-mutated b-HCA and exon 7/8-mutated b-HCA does not depend on CTNNB1 mutational status. In a context of sinusoidal arterial pathology, tumour heterogeneity at the rim harbours perivenous characteristics and could be caused by a functional peripheral venous drainage., Impact and Implications: Tumour heterogeneity was revealed in β-catenin-mutated hepatocellular adenomas (b-HCAs) via the differential expression of glutamine synthase at tumour rims. The combination of several spatial approaches (mass spectrometry imaging, genetic, and proteomic analyses) after laser capture microdissection allowed identification of a potential role for peripheral venous drainage underlying this difference. Through this study, we were able to illustrate that beyond a mutational context, many factors can downstream regulate gene expression and contribute to different clinicopathological phenotypes. We believe that the combinations of spatial analyses that we used could be inspiring for all researchers wanting to access heterogeneity information of liver tumours., Competing Interests: The authors declare that they have no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

Introduction: The calculation of resin yttrium-90 ( 90 Y-) microspheres activity for selective internal radiotherapy (SIRT) needs to be investigated., Methods and Materials: Analyses using Simplicit 90 Y (Boston Scientific, Natick, Massachusetts, USA) dosimetry software were performed to determine the concordance between the absorbed doses to the tumor (D T1 and D T2 ) and healthy liver (D N1 and D N2 ) during the pre-treatment and the post-treatment phases. An optimized calculation of the activity of 90 Y-microspheres performed using dosimetry software was applied retrospectively to assess the impact of this calculation method on the treatment., Results: D T1 ranged from 38.8 to 372 Gy, with a mean value of 128.9 ± 73.6 Gy and median of 121.2 Gy [interquartile range (IQR): 81.7-158.8 Gy]. The median D N1 and D N2 was 10.5 Gy (IQR: 5.8-17.6). A significant correlation was between D T1 and D T2 ( r  = 0.88, P  < 0.001) and D N1 and D N2 ( r  = 0.96, P  < 0.001). The optimized activities were calculated; the target dose to the tumor compartment was 120 Gy. No activity reduction was applied in accordance with the tolerance of the healthy liver. Optimization of the microspheres dosages would have resulted in a significant increase in activity for nine treatments (0.21-2.54 GBq) and a reduction for seven others (0.25-0.76 GBq)., Conclusions: The development of customized dosimetry software adapted to clinical practice makes it possible to use dosimetry to optimize the dosage for each patient., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: The aim of this analysis was to describe the nationwide distribution of patients with newly diagnosed hepatocellular carcinoma (HCC) according to treatment patterns, aetiologies, and outcomes in France., Method: A retrospective cohort of patients with newly diagnosed HCC was selected over the period 2015-2017 in a French claims database covering 99% of the population. Treatment patterns were described using an algorithm based on a ranking of curative and palliative HCC treatments identified. Survival was analyzed using Kaplan-Meier curves according to major treatments and aetiologies., Results: A total of 20,083 incident patients were identified with a mean age of 69.2 years (SD: 11.0) and 82.4% of men. The mean duration of follow-up was 10.0 months (SD: 9.7). At least one HCC risk factor could be identified in 87.0% of patients. The most frequent aetiologies were alcohol-related liver disease present in 50.8% of patients, a metabolic disease (NAFLD, NASH or diabetes) without alcohol or viral hepatitis (44.5%) and viral hepatitis (20.0%). Only 32.7% of patients received a curative therapy, with a 1-year survival of 89.5%, while 38.0% of patients received only best supportive care, with a 1-year survival of 12.9%. The highest rates of curative treatments were found in patients with viral hepatitis, associated or not with another risk factor., Conclusion: Hepatocellular carcinoma was still most often diagnosed at an advanced disease stage as shown by the low rate of curative treatment observed and the very poor prognosis. Viral aetiology was associated with the best survival., Competing Interests: Declaration of Competing Interest Philippe Mathurin: MSD, Ipsen, Eisai, Abbvie, Sanofi, Gilead Sciences, Pfizer, Evive Biotech, Novo Nordisk, Bayer Healthcare, Surrozen, Intercept; Marie de Zélicourt: Employee of CEMKA; Caroline Laurendeau: Employee of CEMKA; Manel Dhaoui: Employee of Ipsen; Nadia Kelkouli: Employee of Ipsen; Jean Frédéric Blanc: Bayer, ESAI, MSD, IPSEN, Roche, Astra-Zeneca, BMS, AMGEN., (Copyright © 2023. Published by Elsevier Masson SAS.)

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.)

Background & Aims: Transcatheter arterial chemoembolisation (TACE) is recommended for patients with hepatocellular carcinoma devoid of macrovascular invasion or extrahepatic spread but not eligible for curative therapies. We compared the efficacy and safety of the combination of a single TACE and external conformal radiotherapy (CRT) vs . classical TACE., Methods: TACERTE was an open-labelled, randomised controlled trial with a 1:1 allocation rate to two or three TACE (arm A) or one TACE + CRT (arm B). Participants had a mean age of 70 years, and 86% were male. The aetiology was alcohol in 85%. The primary endpoint was liver progression-free survival (PFS) in the intention-to-treat population. The typical CRT schedule was 54 Gy in 18 sessions of 3 Gy., Results: Of the 120 participants randomised, 64 were in arm A and 56 in arm B; 100 participants underwent the planned schedule and defined the 'per-protocol' group. In intention-to-treat participants, the liver PFS at 12 and 18 months were 59% and 19% in arm A and 61% and 36% in arm B (hazard ratio [HR] 0.69; 95% CI 0.40-1.18; p  = 0.17), respectively. In the per-protocol population, treated liver PFS tended to be better in arm B (HR 0.61; 95% CI 0.34-1.06; p  = 0.081) than in arm A. Liver-related grade III-IV adverse events were more frequent in arm B than in arm A. Median overall survival reached 30 months (95% CI 23-35) in arm A and 22 months (95% CI 15.7-26.2) in arm B., Conclusions: Although TACE + CRT tended to improve local control, this first Western randomised controlled trial showed that the combined strategy failed to increase PFS or overall survival and led more frequently to liver-related adverse effects., Impact and Implications: Hepatocellular carcinoma is frequently treated by arterial embolisation of the tumour and more recently by external radiotherapy. We tried to determine whether combination of the two treatments (irradiation after embolisation) might produce interesting results. Our results in this prospective randomised study were not able to demonstrate a beneficial effect of combining embolisation and irradiation in these patients. On the contrary, we observed more adverse effects with the combined treatment., Clinical Trials Registration: NCT01300143., Competing Interests: CF, LC, IA, XM, ER, CP, LM, FO, YT, JG, HR, JE, AR, PH, JFB, ENK, DA, AGP, EF-P, and HA did not receive any grants or funding. P Merle reports grants or funding from Roche, AstraZeneca, MSD, Eisai, Bayer, and Ipsen. P Mathurin reports grants or funding from Ipsen, Eisai, Abbvie, Sanofi, Gilead Sciences, Pfizer, Evive Biotech, Novo Nordisk, Bayer Healthcare, Surrozen, and Intercept. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

The standard of care of first-line systemic therapy for advanced hepatocellular carcinoma (HCC) is currently changing with the results of the IMbrave150 trial which are demonstrating superiority of the atezolizumab-bevacizumab combination over sorafenib, modifying this line of treatment for the first time in over 10 years. Recently, other immunotherapy-based combinations (durvalumab-tremelimumab, lenvatinib-pembrolizumab, cabozantinib-atezolizumab, and camrelizumab-rivoceranib) reported results in phase III studies, and might challenge this new standard of care. This revolution will lead to a considerable change in practice, and highlight challenges for future drug development. In this review, we will, firstly, describe results of the different combinations, and discuss the difficulties in selecting the first-line treatment. We will then present the different recommendations about second-line treatment following the first-line immunotherapy-based combination, discussing the rationale for the differences in existing recommendations. We will finally discuss the challenges for future drug development in advanced HCC.

Introduction: Tislelizumab (anti-programmed cell death protein 1 antibody) showed preliminary antitumor activity and tolerability in patients with advanced solid tumors, including hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of tislelizumab in patients with previously treated advanced HCC., Methods: The multiregional phase 2 study RATIONALE-208 examined single-agent tislelizumab (200 mg intravenously every 3 weeks) in patients with advanced HCC with Child-Pugh A, Barcelona Clinic Liver Cancer stage B or C, and who had received one or more prior lines of systemic therapy. The primary endpoint was objective response rate (ORR), radiologically confirmed per Response Evaluation Criteria in Solid Tumors version 1.1 by the Independent Review Committee. Safety was assessed in patients who received ≥1 dose of tislelizumab., Results: Between April 9, 2018, and February 27, 2019, 249 eligible patients were enrolled and treated. After a median study follow-up of 12.7 months, ORR was 13% ( n = 32/249; 95% confidence interval [CI], 9-18), including five complete and 27 partial responses. The number of prior lines of therapy did not impact ORR (one prior line, 13% [95% CI, 8-20]; two or more prior lines, 13% [95% CI, 7-20]). Median duration of response was not reached. The disease control rate was 53%, and median overall survival was 13.2 months. Of the 249 total patients, grade ≥3 treatment-related adverse events were reported in 38 (15%) patients; the most common was liver transaminase elevations in 10 (4%) patients. Treatment-related adverse events led to treatment discontinuation in 13 (5%) patients or dose delay in 46 (19%) patients. No deaths were attributed to the treatment per investigator assessment., Conclusion: Tislelizumab demonstrated durable objective responses, regardless of the number of prior lines of therapy, and acceptable tolerability in patients with previously treated advanced HCC., Competing Interests: Zhenggang Ren reports consulting support from AstraZeneca, F. Hoffmann-La Roche Ltd., and Merck. Michel Ducreux reports research support to the institution from F. Hoffmann-La Roche, Ltd., Merck, Keocyt, and Bayer and receives consulting support from AMGEN, F. Hoffmann-La Roche Ltd., Ipsen, Merck, MSD, Bayer, BeiGene, Ltd., Hutchinson, AstraZeneca, Eli Lilly, Keocyt, and Celgene. Ghassan K. Abou-Alfa reports research support to the institution from Arcus, Agios, AstraZeneca, Bayer, BioNTech, BMS, Celgene, Flatiron, Genentech/Ltd./F. Hoffmann-La Roche Ltd., Genoscience, Incyte, Polaris, Puma, QED, Sillajen, and Yiviva and receives consulting support from Agios, Alnylam, AstraZeneca, Autem, Bayer, BeiGene, Ltd., Berry Genomics, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech Ltd./F. Hoffmann-La Roche Ltd., Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Merck, MINA, QED, Redhill, Sillajen, Surface Oncology, Therabionics, Twoxar, Vector, and Yiviva. Philippe Merle reports grants from Ipsen and Genosciences and receives advisory board fees from F. Hoffmann-La Roche Ltd., BMS, AstraZeneca, Bayer, Eisai, MSD, Ipsen, Lilly, and Genosciences. Weijia Fang, Zhiwei Li, Julien Edeline, Lihua Wu, Sheng Hu, Tao Zhang, Jean-Frédéric Blanc, Hongming Pan, Chia-Jui Yen, Albert Tran, Guoliang Shao, Mohamed Bouattour, Yajin Chen, Jinlin Hou, Yuxian Bai, Ming-Mo Hou, and Zhiqiang Meng declare no competing interests. Eric Assenat reports research support to the institution from F. Hoffmann-La Roche Ltd. and Bayer and receives consulting support from AMGEN, F. Hoffmann-La Roche Ltd., Ipsen, Bayer, AstraZeneca, and Boston. Lorenza Rimassa reports receiving consulting support from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, F. Hoffmann-La Roche Ltd., Sanofi, Servier, Taiho Oncology, and Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, F. Hoffmann-La Roche Ltd., and Sanofi; travel expenses from AstraZeneca; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Ltd., Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, F. Hoffmann-La Roche Ltd., and Zymeworks. Paul Ross reports grants from Bayer and Sanofi. Tim Meyer is supported by the NIHR ULCH Biomedical Research Centre. David Tougeron reports receiving consulting support from Amgen, AstraZeneca, Bayer, BMS, Ipsen, MSD, Sanofi, Servier, and Merck Serono and institutional research funding from AstraZeneca, MSD, F. Hoffmann-La Roche Ltd., and Ipsen. John Wu reports employment with BeiGene, Ltd. Vincent Li reports employment and stocks with BeiGene, Ltd. Sandra Chica-Duque reports employment with BeiGene, Ltd., and her immediate family member reports a relationship with Turning Point Therapeutics. Ann-Lii Cheng reports and receives consulting support from Bristol Myers Squibb, Bayer, Eisai, Ono Pharmaceutical, AstraZeneca, Genentech Ltd./F. Hoffmann-La Roche Ltd., MSD, BeiGene, Ltd., Exelixis Ltd., Ipsen Innovation, and F. Hoffmann-La Roche Ltd., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Background & Aims: Acute intermittent porphyria (AIP), caused by heterozygous germline mutations of the heme synthesis pathway enzyme HMBS (hydroxymethylbilane synthase), confers a high risk of hepatocellular carcinoma (HCC) development. Yet, the role of HMBS in liver tumorigenesis remains unclear., Methods: Herein, we explore HMBS alterations in a large series of 758 HCC cases, including 4 patients with AIP. We quantify the impact of HMBS mutations on heme biosynthesis pathway intermediates and we investigate the molecular and clinical features of HMBS-mutated tumors., Results: We identify recurrent bi-allelic HMBS inactivation, both in patients with AIP acquiring a second somatic HMBS mutation and in sporadic HCC with 2 somatic hits. HMBS alterations are enriched in truncating mutations, in particular in splice regions, leading to abnormal transcript structures. Bi-allelic HMBS inactivation results in a massive accumulation of its toxic substrate porphobilinogen and synergizes with CTNNB1-activating mutations, leading to the development of well-differentiated tumors with a transcriptomic signature of Wnt/β-catenin pathway activation and a DNA methylation signature related to ageing. HMBS-inactivated HCC mostly affects females, in the absence of fibrosis and classical HCC risk factors., Conclusions: These data identify HMBS as a tumor suppressor gene whose bi-allelic inactivation defines a homogenous clinical and molecular HCC subtype., Lay Summary: Heme (the precursor to hemoglobin, which plays a key role in oxygen transport around the body) synthesis occurs in the liver and involves several enzymes including hydroxymethylbilane synthase (HMBS). HMBS mutations cause acute intermittent porphyria, a disease caused by the accumulation of toxic porphyrin precursors. Herein, we show that HMBS inactivation is also involved in the development of liver cancers with distinct clinical and molecular characteristics., Competing Interests: Conflict of interest The authors declare that they have no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to evaluate the capabilities of radiomics using magnetic resonance imaging (MRI) data in the assessment of treatment response to 90 yttrium transarterial radioembolization (TARE) in patients with locally advanced hepatocellular carcinoma (HCC) by comparison with predictions based on European Association for the Study of the Liver (EASL) criteria., Patients and Methods: Twenty-two patients with HCC (19 men, 3 women; mean age: 66.7 ± 9.8 [SD]; age range: 37-82 years) who underwent contrast-enhanced MRI 4 ± 1 weeks before and 4 ± 4 weeks after TARE, were enrolled in this retrospective study. Regions of interest were placed manually along the contours of the treated tumor on each axial slice of arterial and portal phase images using the ITK-SNAP post-processing software. For each MRI, the Pyradiomics Python package was used to extract 107 radiomics features on both arterial and portal phases, and resulting delta-features were computed. The Mann-Whitney U test with Bonferroni correction was used to select statistically different features between responders and non-responders (i.e., those with progressive or stable disease) at 6-month follow-up, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Finally, for each selected feature, univariable logistic regression with leave-one-out cross validation procedure was used to perform receiver operating characteristic (ROC) curve analysis and compare radiomics parameters with MRI variables., Results: According to mRECIST, 14 patients (14/22; 64%) were non-responders and 8 (8/22; 36%) were responders. Four radiomics parameters (long run emphasis, minor axis length, surface area, and gray level non-uniformity on arterial phase images) were the only predictors of early response. ROC curve analysis showed that long run emphasis was the best parameter for predicting early response, with 100% sensitivity (95% CI: 68-100) and 100% specificity (95% CI: 78-100). EASL morphologic criteria yielded 75% sensitivity (95% CI: 41-96%) and 93% specificity (95% CI: 69-100%)., Conclusion: Radiomics allows identify marked differences between responders and non-responders, and could aid in the prediction of early treatment response following TARE in patients with HCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial or personal relationships that could be viewed as influencing the work reported in this paper., (Copyright © 2022 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Backgrounds and Aims: Even if no systemic treatment is currently validated for unresectable hepatocellular-cholangiocarcinoma (cHCC-CCA), tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy are frequently used in clinical practice. Our study aims to describe the effectiveness of first-line systemic treatments in patients with cHCC-CCA., Patients and Methods: Patients with histological diagnosis of unresectable or metastatic cHCC-CCA confirmed by a centralized review (WHO classification 2019) and who received systemic treatment from 2009 to 2020 were included retrospectively in 11 centers. The outcomes of patients with cHCC-CCA were compared with patients with hepatocellular carcinoma (HCC) treated by sorafenib ( n = 117) and with intrahepatic cholangiocarcinoma (iCCA, n = 94) treated mainly by platinum-based chemotherapy using a frailty Cox model. The efficacy of TKIs and platinum-based chemotherapies in patients with cHCC-CCA was assessed using a doubly robust estimator., Results: A total of 83 patients with cHCC-CCA were included and were predominantly male (72%) with underlying cirrhosis (55%). 67% of patients had extrahepatic metastases and 31% macrovascular tumor invasion. cHCC-CCAs were more often developed on cirrhosis (55.4%) than iCCA (26.6%) but less frequently than HCC (80.2%) ( p < 0.001). Both HCC (36.8% and cHCC-CCA (66.2%) had less frequent extrahepatic metastases than iCCA (81%) ( p < 0.001). Unadjusted overall survival (OS) was better in iCCA (13 months) compared to cHCC-CCA (12 months) and HCC (11 months) ( p = 0.130). In multivariable analysis, after adjustment by a Cox frailty model, patients with cHCC-CCA had the same survival as HCC and iCCA (HR = 0.67, 95% CI: 0.37-1.22, p = 0.189 and HR = 0.66, 95% CI: 0.43-1.02, p = 0.064, respectively). ALBI score (HR = 2.15; 95% CI: 1.23-3.76; p = 0.009), ascites (HR = 3.45, 95% CI: 1.31-9.03, p = 0.013), and tobacco use (HR = 2.29, 95% CI: 1.08-4.87, p = 0.032) were independently associated with OS in patients with cHCC-CCA. Among patients with cHCC-CCA, 25 patients treated with TKI were compared with 54 patients who received platinum-based chemotherapies. Patients treated with TKI had a median OS of 8.3 months compared to 11.9 months for patients treated with platinum-based chemotherapy ( p = 0.86). After a robust doubly adjustment on tumor number and size, vascular invasion, ALBI, MELD, and cirrhosis, the type of treatment did not impact OS (HR = 0.92, 95% CI: 0.27-3.15, p = 0.88) or progression-free survival (HR = 1.24, 95% CI: 0.44-3.49, p = 0.67)., Conclusions: First-line systemic treatments with TKIs or platinum-based chemotherapies have similar efficacy in patients with unresectable/metastatic cHCC-CCA. The ALBI score predicts OS., Competing Interests: E.G. received travel and congress fees from Bayer, Gilead, and Ipsen; M.B. received consulting fees from Bayer, BMS, Ipsen, Roche, Eisai, Sirtex, Servier, MSD, and AstraZeneca; M.R. received honoraria from Servier, GE Healthcare, Ipsen, Canon-Toshiba, Alexion Pharmaceuticals, Guerbet, and Sirtex; A.Z. received consulting and advisory board fees from Amgen, Lilly, Merck, Roche, Sanofi, Servier, Baxter, MSD, Pierre Fabre, Havas Life, Alira Health, and Zymeworks; D.T. received consulting fees from Amgen, Merck, Novartis, BMS, MSD, AstraZeneca, Sanofi, Roche, Bayer, Servier, and Ipsen; J.E. received consulting fees from MSD, Eisai, BMS, AstraZeneca, Bayer, Roche, Ipsen, Basilea, Merck Serono, Incyte, and Servier and also received travel fees from Amgen and research funding (institutional) from BMS, Beigene; J.-F.B. received consulting fees from Bayer, BMS, Ipsen, Eisai, MSD, Roche, and AstraZeneca; J.-C.N. received research grants from Ipsen and Bayer; and E.T. received research support from Gilead and speaker fees from Abbvie. The other authors have no conflicts of interest to declare., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Background: Deregulation of FGF19-FGFR4 signaling is found in several cancers, including hepatocellular carcinoma (HCC), nominating it for therapeutic targeting. FGF401 is a potent, selective FGFR4 inhibitor with antitumor activity in preclinical models. This study was designed to determine the recommended phase 2 dose (RP2D), characterize PK/PD, and evaluate the safety and efficacy of FGF401 alone and combined with the anti-PD-1 antibody, spartalizumab., Methods: Patients with HCC or other FGFR4/KLB expressing tumors were enrolled. Dose-escalation was guided by a Bayesian model. Phase 2 dose-expansion enrolled patients with HCC from Asian countries (group1), non-Asian countries (group2), and patients with other solid tumors expressing FGFR4 and KLB (group3). FGF401 and spartalizumab combination was evaluated in patients with HCC., Results: Seventy-four patients were treated in the phase I with single-agent FGF401 at 50 to 150 mg. FGF401 displayed favorable PK characteristics and no food effect when dosed with low-fat meals. The RP2D was established as 120 mg qd. Six of 70 patients experienced grade 3 dose-limiting toxicities: increase in transaminases (n = 4) or blood bilirubin (n = 2). In phase 2, 30 patients in group 1, 36 in group 2, and 20 in group 3 received FGF401. In total, 8 patients experienced objective responses (1 CR, 7 PR; 4 each in phase I and phase II, respectively). Frequent adverse events (AEs) were diarrhea (73.8%), increased AST (47.5%), and ALT (43.8%). Increase in levels of C4, total bile acid, and circulating FGF19, confirmed effective FGFR4 inhibition. Twelve patients received FGF401 plus spartalizumab. RP2D was established as FGF401 120 mg qd and spartalizumab 300 mg Q3W; 2 patients reported PR., Conclusions: At biologically active doses, FGF401 alone or combined with spartalizumab was safe in patients with FGFR4/KLB-positive tumors including HCC. Preliminary clinical efficacy was observed. Further clinical evaluation of FGF401 using a refined biomarker strategy is warranted., Trial Registration: NCT02325739 ., (© 2022. The Author(s).)

Background and Aims: Non-O blood group promotes deep vein thrombosis and liver fibrosis in both general population and hepatitis C. We aimed to evaluate the influence of Non-O group on the outcome of Child-Pugh A cirrhotic patients., Methods: We used two prospective cohorts of Child-Pugh A cirrhosis due to either alcohol or viral hepatitis. Primary end point was the cumulated incidence of 'Decompensation' at 3 years, defined as the occurrence of ascites , hydrothorax, encephalopathy, gastrointestinal bleeding related to portal hypertension, or bilirubin >45 μmol/L. Secondary end points were the cumulated incidences of (1) 'Disease Progression' including a « decompensation» or « the occurrence of one or more parameters » among: prothrombin time (PT) <45%, albumin <28 g/L, Child-Pugh worsening (B or C vs A or B, C vs B), hepatorenal syndrome, and hepato-pulmonary syndrome, (2) other events such as non-malignant portal vein thrombosis (nmPVT), and (3) overall survival., Results: Patients (n = 1789; 59.9% Non-O group; 40.1% group O) were followed during a median of 65.4 months. At 3 years cumulated incidence of Decompensation was 8.3% in Non-O group and 7.2% in group O (P = .27). Cumulated incidence of Disease Progression was 20.7% in Non-O group and 18.9% in group O (P = .26). Cumulated incidence of nmPVT was 2.7% in Non-O group and 2.8% in group O (P = .05). At 3 years overall survival was 92.4% in Non-O group and 93.4% in group O (P = 1)., Conclusion: Non-O group does not influence disease outcome in Child-Pugh A cirrhotic patients. Clinicals trial number NCT03342170., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Oncogene activation leads to replication stress and promotes genomic instability. Here we combine optical mapping and whole-genome sequencing (WGS) to explore in depth the nature of structural variants (SV) induced by replication stress in cyclin-activated hepatocellular carcinomas (CCN-HCC). In addition to classical tandem duplications, CCN-HCC displayed frequent intra-chromosomal and interchromosomal templated insertion cycles (TIC), likely resulting from template switching events. Template switching preferentially involves active topologically associated domains that are proximal to one another within the 3D genome. Template sizes depend on the type of cyclin activation and are coordinated within each TIC. Replication stress induced continuous accumulation of SVs during CCN-HCC progression, fostering the acquisition of new driver alterations and large-scale copy-number changes at TIC borders. Together, this analysis sheds light on the mechanisms, dynamics, and consequences of SV accumulation in tumors with oncogene-induced replication stress., Significance: Optical mapping and whole-genome sequencing integration unravels a unique signature of replication stress-induced structural variants that drive genomic evolution and the acquisition of driver events in CCN-HCC., (©2022 American Association for Cancer Research.)

Objective: Infection by HBV is the main risk factor for hepatocellular carcinoma (HCC) worldwide. HBV directly drives carcinogenesis through integrations in the human genome. This study aimed to precisely characterise HBV integrations, in relation with viral and host genomics and clinical features., Design: A novel pipeline was set up to perform viral capture on tumours and non-tumour liver tissues from a French cohort of 177 patients mainly of European and African origins. Clonality of each integration event was determined with the localisation, orientation and content of the integrated sequence. In three selected tumours, complex integrations were reconstructed using long-read sequencing or Bionano whole genome mapping., Results: Replicating HBV DNA was more frequently detected in non-tumour tissues and associated with a higher number of non-clonal integrations. In HCC, clonal selection of HBV integrations was related to two different mechanisms involved in carcinogenesis. First, integration of viral enhancer nearby a cancer-driver gene may lead to a strong overexpression of oncogenes. Second, we identified frequent chromosome rearrangements at HBV integration sites leading to cancer-driver genes ( TERT, TP53, MYC ) alterations at distance. Moreover, HBV integrations have direct clinical implications as HCC with a high number of insertions develop in young patients and have a poor prognosis., Conclusion: Deep characterisation of HBV integrations in liver tissues highlights new HBV-associated driver mechanisms involved in hepatocarcinogenesis. HBV integrations have multiple direct oncogenic consequences that remain an important challenge for the follow-up of HBV-infected patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hepatocellular benign liver tumours are mainly developed on normal liver and include hepatic hemangioma, focal nodular hyperplasia and hepatocellular adenoma from the most frequent to the less frequent. The diagnosis of hepatic hemangioma and of simple hepatic biliary cysts can be performed using non-invasive criteria using liver ultrasonography or contrast enhanced MRI. Most of the time the diagnosis of focal nodular hyperplasia can be achieved using contrast-enhanced ultrasonography or contrast enhanced MRI with an additional value of hepatobiliary contrast-agent in this setting. Rarely, if a doubt persists, a tumour and non-tumour liver biopsy can be required in order to establish the diagnosis. As hepatic hemangioma, simple hepatic biliary cysts and focal nodular hyperplasia are not associated with complications, they don't require any treatments or follow-up. Hepatocellular adenomas are mainly diagnosed at histology on surgical samples or liver biopsy even if some radiological features are highly suggestive of several subtypes of hepatocellular adenomas. Finally, the management of hepatocellular adenomas should be guided according to the tumour size, gender but also to the molecular subtypes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)