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Rim Masmoudi,1 Faten Hadj Kacem,2 Maroua Bouattour,3 Fatma Guermazi,1 Rim Sellami,1 Ines Feki,1 Mouna Mnif,2 Jawaher Masmoudi,1 Imen Baati,1 Mohamed Abid2 1Psychiatry “A” Department, Hedi Chaker University Hospital, Sfax, Tunisia; 2Department of Endocrinology, Hedi Chaker University Hospital, Sfax, Tunisia; 3Department of Family Medicine, Faculty of Medicine of Sfax, University of Sfax, Sfax, TunisiaCorrespondence: Rim Masmoudi, Psychiatry “A” Department, Hedi Chaker University Hospital, Sfax, 3029, Tunisia, Tel +216 74 244 511, Email rim19masmoudi@gmail.comPurpose: Diabetes distress (DD) refers to the negative emotions and burden of living with diabetes. Illness perceptions are among the factors that can influence self-management and psychological distress in diabetics. This study aimed to determine the prevalence and the associated factors of DD in Tunisian patients with type 2 diabetes mellitus. We also studied the relationship between DD and illness perceptions in diabetics.Patients and Methods: This was a cross-sectional study conducted among individuals with type 2 diabetes, followed up at the outpatient endocrinology unit at the Hedi Chaker University Hospital, Tunisia. DD was assessed using the Diabetes Distress Scale (DDS-17). The Brief Illness Perception Questionnaire (Brief-IPQ) was used to assess diabetes illness perceptions. Multivariate logistic regression was used to determine independent factors associated with the presence of DD.Results: A total of 103 patients were recruited. The mean age was 59.31 (± 10.83) years; 54.4% were female. In total, 70.9% had DD. Using regression analysis, we demonstrated that the illness perceptions of personal control, HbA1C, absence of comorbidities, lower age at diabetes diagnosis, and socioeconomic status were significantly associated with DD.Conclusion: This study sheds light on the high prevalence of DD among patients with type 2 diabetes in Tunisia. Illness perception-focused psychological intervention would be efficacious in reducing diabetes distress in patients with type 2 diabetes mellitus.Keywords: diabetes mellitus, type 2, distress, illness perception, Tunisian patients

Romain Coriat,1 Sandrine J Faivre,2 Olivier Mir,3 Chantal Dreyer,2 Stanislas Ropert,3 Mohammed Bouattour,2 Robert Desjardins,4 François Goldwasser,3 Eric Raymond5 1Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris Cité, Paris, 2Department of Medical Oncology, Beaujon Teaching Hospital, Université Paris Diderot, Paris 7, Clichy, 3Department of Medical Oncology, Cochin Teaching Hospital, Université Paris Descartes Sorbonne Paris Cité, Paris, France; 4Drais Pharmaceuticals, Bridgewater, NJ, USA; 5Groupe Hospitalier Paris Saint-Joseph, Paris, France Background: DTS-108 is a hydrosoluble prodrug, where the SN-38 moiety is covalently linked to a 20-amino acid vector peptide by a specific esterase-sensitive cross-linker, releasing 7-ethyl-10-hydroxycampthotecin (SN-38) by esterase bond cleavage. Methods: The pharmacokinetics of DTS-108, adverse events graded according to NCI-CTCv3.1, dose-limiting toxicities at cycle 1, the maximum tolerated dose (MTD), and the recommended Phase II dose (RP2D) of intravenous DTS-108 (1–2 hours) every 2 weeks were evaluated in a first-in-human Phase I study in patients with advanced/metastatic carcinomas, according to an accelerated dose escalation design. SN-38 and SN-38 glucuronide (SN-38G) levels were evaluated with fluorescence high-performance liquid chromatography (HPLC) test, then liquid chromatography–tandem mass spectrometry (LC/MS/MS) methods. Results: Forty-two patients received DTS-108 across 14 dosing cohorts (range 3–416 mg/m2). At 416 mg/m2, three out of six patients had grade 4 neutropenia thereby defining the MTD and the RP2D at 313 mg/m2. Fluorescence HPLC was inaccurate to quantify DTS-108 and its metabolites (SN-38 and SN-38G). New processes and analytical LC/MS/MS methods for testing SN-38 were implemented. At a dose of 313 mg/m2, mean DTS-108, SN-38, and SN-38G area under the plasma concentration–time curve to infinity (coefficients of variation %) were 439,293 (24%), 1,992 (34%), and 4,538 (46%) h·ng/mL. Stable disease (according to Response Evaluation Criteria in Solid Tumors) was observed in nine patients. Conclusion: Assessing SN-38 concentration using fluorescence HPLC is questionable since this method failed to monitor dose escalation of DTS-108, a new topoisomerase I inhibitor, due to ex vivo degradation. LC/MS/MS methods were consistent in evaluating SN-38 exposures allowing drug monitoring. The maximum tolerated dose of DTS-108 was 416 mg/m2. The RP2D for intravenous DTS-108 was 313 mg/m2 every 2 weeks in patients with advanced/metastatic solid tumors. Keywords: Phase I, topoisomerase I inhibitor, irinotecan, fluorescence HPLC

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]

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.)

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.)

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.)

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.)

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).)

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.)

Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) and progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported., Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), assessed per RECIST v1.1 by BICR, and safety., Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7-48.8) months for pembrolizumab and 39.8 (31.7-47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4-22.5%) for pembrolizumab and 11.7% (6.8-17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3-13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0-23.4%) for pembrolizumab and 4.4% (1.6-9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported., Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC., Competing Interests: P. Merle reports receiving grants from Ipsen and other financial or non-financial interests for advisory board participation from Roche, AstraZeneca, Eisai, MSD, Ipsen, Eli Lilly, and Bayer. M. Kudo reports receiving support for the present manuscript from MSD, grants or contracts from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, EA Pharma, AbbVie, and Eisai, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Eli Lilly, Bayer, Eisai, Chugai, Takeda, and MSD. J. Edeline reports no conflicts of interest. M. Bouattour reports receiving consulting fees from Roche, Eisai, AstraZeneca, Bayer, Ipsen, Sirtex Medical, Servier, MSD, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Roche, AstraZeneca, Bayer, Ipsen, Sirtex Medical, and Servier, and support for attending meetings and/or travel from Roche, AstraZeneca, Bayer, and Sirtex Medical. A-L. Cheng reports receiving consulting fees from Eisai, Ono Pharmaceutical, Ipsen Innovation, Bayer Healthcare, and Merck Sharp and Dohme, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from F. Hoffmann-La Roche Ltd., Chugai Pharmaceutical, Bayer Yakuhin, Ltd., Novartis, Eisai, Ono Pharmaceutical, and Amgen Taiwan, support for attending meetings and/or travel from Bayer Yakuhin, Ltd., Eisai, and IQVIA, and participation on a data safety monitoring board or advisory board for Novotech. S.L. Chan reports receiving grants or contracts from Bayer, Ipsen, and Sirtex, consulting fees from AstraZeneca, Eisai, Ipsen, and MSD, and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from AstraZeneca, Eisai, Roche, and MSD. T. Yau reports no conflicts of interest. M. Garrido reports receiving payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from MSD, Bristol Myers Squibb, Roche, Pfizer, and Merck, payment for expert testimony from Bristol Myers Squibb, and support for attending meetings and/or travel from MSD. J. Knox reports receiving a grant for an investigator-initiated trial from Merck, consulting fees from Merck, Eisai, and AstraZeneca, and payment for expert testimony from Incyte and AstraZeneca. B. Daniele reports receiving payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Eisai, Ipsen, Eli Lilly, Bayer, MSD, Roche, Amgen, Merck Serono, and AstraZeneca, support for attending meetings and/or travel from AstraZeneca, Sanofi, Celgene, and Bristol Myers Squibb, and participating in a data safety monitoring board or advisory board for Sanofi. V. Breder reports receiving consulting fees from Eisai, Novartis, and Bayer, honoraria for lectures, presentations, and educational events from Bristol Myers Squibb, Roche, Eisai, Ipsen, and Bayer, and support for attending meetings and/or travel from Bristol Myers Squibb, Ipsen, and Roche. H. Y. Lim reports receiving payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Roche, and participation on a data safety monitoring board or advisory board for Bayer, Eisai, and Roche. S. Ogasawara reports receiving grants or contracts from Bayer, AstraZeneca, Eli Lilly, Eisai, and Chugai, consulting fees from Chugai and AstraZeneca, and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bayer, AstraZeneca, Eli Lilly, Eisai, Chugai, and MSD. S. Cattan reports no conflicts of interest. Y. Chao reports no conflicts of interest. A.B. Siegel is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. I. M-Forero is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. Z. Wei was an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA at the time of the analysis. C-C. Liu is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. R. S. Finn reports receiving support for the present manuscript from Merck, consulting fees and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from AstraZeneca, Bayer, Bristol Myers Squibb, CStone, Eisai, Exelixis, Eli Lilly, Pfizer, Merck, and Roche/Genentech, payment for expert testimony from Bayer AS, grants paid to his institution from Merck, Eisai, Pfizer, Bristol Myers Squibb, Roche/Genentech, Eli Lilly, Adaptimmune, and Bayer, stock/stock options from CStone, and reports participating on a data safety monitoring board or advisory board from AstraZeneca and Hengrui., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

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.)

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: To evaluate the cost-effectiveness of the extended use of ablation for the treatment of hepatocellular carcinoma (HCC) with cirrhosis in an expert ablation center when compared to the non-extended use of ablation in equivalent tertiary care centers., Methods: Consecutive cirrhotic patients with non-metastatic HCC, no prior treatment, and referred to three tertiary care centers between 2012 and 2016 were retrospectively identified. The Bondy group, including all of the patients treated at Jean Verdier Hospital, where the extended use of ablation is routinely performed, was compared to the standard of care (SOC) group, including all of the patients treated at the Beaujon and Mondor Hospitals, using propensity score matching. A cost-effectiveness analysis was carried out from the perspective of French health insurance using a Markov model on a lifetime horizon., Results: 532 patients were matched. The Bondy group led to incremental discounted lifetime effects of 0.8 life-years gained (LYG) (95% confidence interval: 0.4, 1.3) and a decrease in lifetime costs of EUR 7288 (USD 8016) (95% confidence interval: EUR 5730 [USD 6303], EUR 10,620 [USD 11,682]) per patient, compared with the SOC group, resulting in a dominant mean incremental cost-effectiveness ratio (ICER). A compliance with the Barcelona Clinic Liver Classification (BCLC) guidelines for earlier stage contributed to the greater part of the ICER., Conclusion: The extended use of ablation in cirrhotic patients with HCC was more effective and less expensive than the non-extended use of the ablation strategy.

Purpose: The purpose of this study was to compare the value of contrast-enhanced computed tomography (CT) to that of magnetic resonance imaging obtained with extracellular contrast agent (ECA-MRI) for the diagnosis of a tumor capsule in hepatocellular carcinoma (HCC) using histopathologic findings as the standard of reference., Materials and Methods: This retrospective study included patients with pathologically-proven resected HCCs with available preoperative contrast-enhanced CT and ECA-MRI examinations. Two blinded radiologists independently reviewed contrast-enhanced CT and ECA-MRI examinations to assess the presence of an enhancing capsule. The histopathological analysis of resected specimens was used as reference for the diagnosis of a tumor capsule. The sensitivity and specificity of CT and ECA-MRI for the diagnosis of a tumor capsule were determined, and an intra-individual comparison of imaging modalities was performed using McNemar test. Inter-reader agreement was assessed using Kappa test., Results: The study population included 199 patients (157 men, 42 women; mean age: 61.3 ± 13.0 [SD] years) with 210 HCCs (mean size 56.7 ± 43.7 [SD] mm). A tumor capsule was present in 157/210 (74.8%) HCCs at histopathologic analysis. Capsule enhancement was more frequently visualized on ECA-MRI (R1, 68.6%; R2, 71.9%) than on CT (R1, 44.3%, P < 0.001; R2, 47.6%, P < 0.001). The sensitivity of ECA-MRI was better for the diagnosis of histopathological tumor capsule (R1, 76.4%; R2, 79.6%; P < 0.001), while CT had a greater specificity (R1, 84.9%; R2, 83.0%; P < 0.001). Inter-reader agreement was moderate both on CT (kappa = 0.55; 95% confidence interval [CI]: 0.43-0.66) and ECA-MRI (kappa = 0.57; 95% CI: 0.45-0.70)., Conclusion: Capsule enhancement was more frequently visualized on ECA-MRI than on CT. The sensitivity of ECA-MRI was greater than that of CT, but the specificity of CT was better than that of ECA-MRI., (Copyright © 2021 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Background & Aims: The histopathological subtypes of hepatocellular carcinoma (HCC) are associated with distinct clinical features and prognoses. This study aims to report Liver Imaging Reporting and Data System (LI-RADS)-defined imaging features of different HCC subtypes in a cohort of resected tumours and to assess the influence of HCC subtypes on computed tomography (CT)/magnetic resonance imaging (MRI) LI-RADS categorisation in the subgroup of high-risk patients., Methods: This retrospective institutional review board-approved study included patients with resected HCCs and available histopathological classification. Three radiologists independently reviewed preoperative CT and MRI exams. The readers evaluated the presence of imaging features according to LI-RADS v2018 definitions and provided a LI-RADS category in patients at high risk of HCC. Differences in LI-RADS features and categorisations were assessed for not otherwise specified (NOS-HCC), steatohepatitic (SH-HCC), and macrotrabecular-massive (MTM-HCC) types of HCCs., Results: Two hundred and seventy-seven patients (median age 64.0 years, 215 [77.6%] men) were analysed, which involved 295 HCCs. There were 197 (66.7%) NOS-HCCs, 62 (21.0%) SH-HCCs, 23 (7.8%) MTM-HCCs, and 13 (4.5%) other rare subtypes. The following features were more frequent in MTM-HCC: elevated α-foetoprotein serum levels ( p <0.001), tumour-in-vein ( p <0.001 on CT, p ≤0.052 on MRI), presence of at least 1 LR-M feature ( p ≤0.010 on CT), infiltrative appearance ( p ≤0.032 on CT), necrosis or severe ischaemia ( p ≤0.038 on CT), and larger size ( p ≤0.006 on CT, p ≤0.011 on MRI). SH-HCC was associated with fat in mass ( p <0.001 on CT, p ≤0.002 on MRI). The distribution of the LI-RADS major features and categories in high-risk patients did not significantly differ among the 3 main HCC subtypes., Conclusions: The distribution of LI-RADS major features and categories is not different among the HCC subtypes. Nevertheless, careful analysis of tumour-in-vein, LR-M, and ancillary features as well as clinico-biological data can provide information for the non-invasive diagnosis of HCC subtypes., Lay Summary: In high-risk patients, the overall distribution of LI-RADS major features and categories is not different among the histological subtypes of hepatocellular carcinoma, but tumour-in-vein, presence of LR-M features, and ancillary features can provide information for the non-invasive diagnosis of hepatocellular carcinoma subtypes., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

Background & Aims: Malignant transformation of hepatocellular adenoma (MT-HCA) may occur in up to 5% of tumours. However, the prognostic value of this event remains poorly described. In this study, we aimed to analyse the long-term outcomes of patients undergoing liver resection (LR) for MT-HCA compared to those of patients resected for hepatocellular carcinoma (HCC) occurring on normal liver parenchyma (NP-HCC)., Methods: This single-centre retrospective study included all patients who underwent LR for MT-HCA at Beaujon Hospital between 2001 and 2019. MT-HCAs were classified as small foci of malignant transformation HCA (SF-HCA) and as malignant HCA (M-HCA) in cases of predominant HCC foci. Recurrence-free survival (RFS) of MT-HCA was compared with that of NP-HCC after propensity score matching., Results: Forty patients (24 men, 16 women) underwent LR for MT-HCA, including 23 with SF-HCA and 17 with M-HCA. Of these cases, 16/40 (40%) had β-catenin mutations, 19/40 (47.5%) were inflammatory, 1 was HNF1α-mutated HCA and 4 (10%) were unclassified HCA. Microvascular invasion (12% vs. 0%, p = 0.091) and satellite nodules (25% vs. 4%, p = 0.028) were more frequently observed in M-HCA than in SF-HCA. After a median follow-up of 67 months, 10 (25%) patients with MT-HCA had tumour recurrence, including 9 with M-HCA and 1 with SF-HCA ( p = 0.007). M-HCA was linked to significantly poorer 1-, 3-, 5- and 10-year RFS rates than SF-HCA (76%, 63%, 39%, 37% vs. 100%, 100%, 100%, 91%, p = 0.003). Multivariate analysis showed that SF-HCA was independently associated with improved RFS (hazard ratio 0.064; 95% CI 0.008-0.519; p = 0.01). After propensity score matching, NP-HCC was associated with significantly poorer 1-, 3-, 5- and 10-year RFS rates than MT-HCA ( p = 0.01)., Conclusions: HCA with malignant transformation yields a better long-term prognosis than NP-HCC. Among MT-HCA, SF-HCA is associated with a better prognosis than M-HCA., Lay Summary: The prognostic relevance of malignant transformation of hepatocellular adenoma (HCA) remains unknown. Thus, the aim of our study was to compare the outcomes of patients undergoing liver resection for malignant transformation to those of patients undergoing liver resection for hepatocellular carcinoma (HCC). The main long-term risk after resection for carcinoma is recurrence. In this study, 10/40 patients with malignant transformation of HCA relapsed after resection and we identified age >55 years, presence of satellite nodes, and microvascular invasion as risk factors for long-term recurrence. Compared to patients with HCC, patients who underwent liver resection for HCA with malignant transformation had better long-term survival., Competing Interests: The authors declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

Background & Aims: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). Herein, we evaluated whether the schedule of LC screening or procedures has been interrupted or delayed because of the COVID-19 pandemic., Methods: An international survey evaluated the impact of the COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international, and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave., Results: Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia, and Africa (73.7%, 17.1%, 5.3%, 2.6%, and 1.3% per continent, respectively). Eighty-seven percent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening programme, 50% cancelled curative and/or palliative treatments for LC, and 41.7% modified the liver transplantation programme. Forty-five out of 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service before the COVID-19 pandemic (n = 19/37)., Conclusions: The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with liver cancer. Modifications in screening, diagnostic, and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision-making., Lay Summary: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems globally. Herein, we assessed the impact of the first wave pandemic on patients with liver cancer and found that routine care for these patients has been majorly disrupted, which could have a significant impact on outcomes., Competing Interests: SM.-M.: Speaker fees from Bayer and travel funding from 10.13039/100004326Bayer and 10.13039/501100014382Eisai. V.S.: Travel grants from 10.13039/100004326Bayer. A.F.: Lecture fees from Bayer, Gilead and MSD; consultancy fees from Bayer, AstraZeneca, Roche and Guerbert. J-C.N.: Received research grant from 10.13039/100004326Bayer for Inserm UMR1138. L.R.: Reports receiving consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, Celgene, Eisai, Exelixis, Hengrui, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi; lectures fees from AbbVie, Amgen, Eisai, Gilead, Incyte, Ipsen, Lilly, Roche, Sanofi; travel fees from Ipsen; and institutional research funding from Agios, ARMO BioSciences, 10.13039/100004325AstraZeneca, BeiGene, 10.13039/501100003769Eisai, 10.13039/100010544Exelixis, 10.13039/100006591Fibrogen, Incyte, 10.13039/501100014382Ipsen, 10.13039/100004312Lilly, 10.13039/100007054MSD, 10.13039/100004337Roche. B.S.: Reports consultancy fees from Adaptimmune, AstraZeneca, Bayer, BMS, BTG, Eli Lilly, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo; and research grants from 10.13039/100002491BMS and Sirtex Medical. J. Bruix: Consultancy: AbbVie, ArQule, Astra, Basilea, Bayer, BMS, Daiichi Sankyo, GlaxoSmithKline, Gilead, Kowa, Lilly, Medimune, Novartis, Onxeo, Polaris, Quirem, Roche, Sanofi-Aventis, Sirtex, Terumo/Grants: 10.13039/100004326Bayer and 10.13039/501100014382Ipsen. M.S.Z.: Received speaker fees and travel grants from 10.13039/100004326Bayer and 10.13039/100014869BTG, 10.13039/100007054MSD. M.B.: Consultant and Advisory Board for: Bayer Pharma, Ipsen, BMS, Eisai, Roche, AstraZeneca, Sirtex Medical. D.J.P.: Received lecture fees from ViiV Healthcare and Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, and AstraZeneca; received research funding (to institution) from MSD and BMS. T.M.: Consultancy: Eisai, Roche, BTG, Ipsen, Bayer, Adaptimmune. Research funding: Bayer, BTG. H.W.: Served as speaker for Bayer, Eisai, and Ipsen, and as a consultant for Bayer, Eisai, Lilly, BMS, Roche, and Ipsen. B.M.: Consultancy: Bayer-Shering Pharma /Speaker fees: Eisai, MSDG. C. Consultancy fees from Bayer, Ipsen. P.R.G.: Bayer, BMS, MSD, AstraZeneca, Adaptimmune, Sirtex, Lilly Ipsen, Roche, Eisai. M.R.A.S.: Has received Research grants, advisory board or speaker fees for 10.13039/100006483AbbVie, 10.13039/100004326Bayer, Biolab, Intercept, 10.13039/501100014382Ipsen, 10.13039/100008799Gilead, 10.13039/100009947MSD, 10.13039/100004336Novartis, and 10.13039/100004337Roche. J.T.: Has received research grants from 10.13039/100004337Roche and 10.13039/501100014382Ipsen. He has received speaker and consulting honoraria from AstraZeneca, Amgen, Bayer Healthcare, Bristol Myers-Squibb, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, and Roche. J. Bridgewater: Consultancy Bayer, BMS, Incyte, Taiho, Roche, MSD and Merck Serono. Research funding from Incyte. G.C.: Consultancy fees from Bayer, Ipsen. A.L.: Consultancy CAScination, Advisory Board Neuwave and Histosonics. H.T.: Speaker fees from AbbVie, Gilead, MSD, and Bayer. R.V.: Research grant from 10.13039/100006483Abbvie. A.M.M.P.: Speaker honorarium from Bayer, BMS, Boston Scientific and EISAI. Consulting honorarium from Bayer, AstraZeneca and EISAI. Advisory honorarium from Bayer, AstraZeneca and EISAI. Grants from 10.13039/100004326Bayer and 10.13039/100008497Boston Scientific. M.D.: Has received consulting and training fees from Bayer and Eisai. B.B.: Reports Consultancy for GenMab (paid to Institution); Advisory Boards for Roche (paid to Institution), Eisai Europe Limited (paid to Institution), research grant from 10.13039/100006436Celgene Ltd (paid to Institution), Speakers Bureau for Eisai Europe Limited (paid to Institution), Travel and registration for Congress from Bayer. L.d.F.: Lectures fees from BMS, Roche and Bayer. B.M.M.: Advisory/Speaker: Amgen, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Merck, Roche, Sanoffi Genzyme, Taiho. Expert Testimony: Eisai, Roche. Travel: Eisai, Merck. Research: Sillajen (Individual); AstraZeneca, H3/Eisai, Galera, GSK, Exelixis (Institution). M.S.: Travel/ accommodation/meeting expenses: Bayer. Eisai. Speaker fees: Bayer. C.R.L.: Travel grants from 10.13039/100004326Bayer. M.R-G.: Reports grants from Intercept, grants from 10.13039/100005564Gilead-Sciences, personal fees from Shionogi, personal fees from Alfa-Wasserman, personal fees from Prosciento, personal fees from Kaleido, personal fees from Novonrdisk, personal fees from MSD, personal fees from BMS, personal fees from Allergan, personal fees from Boehriger-Ingelheim, personal fees from Zydus, personal fees from Intercept Pharma, personal fees from Gilead-Sciences, outside the submitted work. F.P.: Disclosures: Received speaker honoraria from Bayer, Roche, LKM-Biotoscana, RAFFO. Research Grants from INC Argentinean 10.13039/100013137National Institute of Corrections, 10.13039/100004337Roche. V.M.: Lectures sponsored by Bayer. G.B.: Advisory board Eli-Lilly and Incyte. M. Vergara: Travel grants from 10.13039/100004326Bayer, 10.13039/100008799Gilead, 10.13039/100009947MSD and 10.13039/100006483Abbvie. Lectures sponsored by Gilead, Abbvie, Intercept, and MSD. M.L.: Lectures and educational presentations: Abbvie. Travel/accommodation, meeting expenses covered by Bayer, Gilead, Abbvie. M.I.: Received speaker honoraria from Bayer, Gilead Sciences, BMS, Janssen, Ipsen, MSD, BTG-Boston Scientific, AbbVie, EISAI, and was consultant for BTG-Boston Scientific, Bayer, and Guerbet. M.R.: Consultancy: Bayer-Schering Pharma, BMS, Roche, Ipsen, AstraZeneca, Lilly, BTG/Paid conferences: Bayer-Schering Pharma, BMS, Gilead, Lilly/Research Grants: 10.13039/100004326Bayer-Schering Pharma, 10.13039/501100014382Ipsen. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

Background & Aims: Patients affected by hepatocellular carcinoma (HCC) represent a vulnerable population during the COVID-19 pandemic and may suffer from altered allocation of healthcare resources. The aim of this study was to determine the impact of the COVID-19 pandemic on the management of patients with HCC within 6 referral centres in the metropolitan area of Paris, France., Methods: We performed a multicentre, retrospective, cross-sectional study on the management of patients with HCC during the first 6 weeks of the COVID-19 pandemic (exposed group), compared with the same period in 2019 (unexposed group). We included all patients discussed in multidisciplinary tumour board (MTB) meetings and/or patients undergoing a radiological or surgical programmed procedure during the study period, with curative or palliative intent. Endpoints were the number of patients with a modification in the treatment strategy, or a delay in decision-to-treat., Results: After screening, n = 670 patients were included (n = 293 exposed to COVID, n = 377 unexposed to COVID). Fewer patients with HCC presented to the MTB in 2020 ( p  = 0.034) and fewer had a first diagnosis of HCC (n = 104 exposed to COVID, n = 143 unexposed to COVID, p  = 0.083). Treatment strategy was modified in 13.1% of patients, with no differences between the 2 periods. Nevertheless, 21.5% vs. 9.5% of patients experienced a treatment delay longer than 1 month in 2020 compared with 2019 ( p <0.001). In 2020, 7.1% (21/293) of patients had a diagnosis of an active COVID-19 infection: 11 (52.4%) patients were hospitalised and 4 (19.1%) patients died., Conclusions: In a metropolitan area highly impacted by the COVID-19 pandemic, we observed fewer patients with HCC, and similar rates of treatment modification, but with a significantly longer treatment delay in 2020 vs.  2019., Lay Summary: During the coronavirus disease 2019 (COVID-19) pandemic era, fewer patients with hepatocellular carcinoma (HCC) presented to the multidisciplinary tumour board, especially with a first diagnosis of HCC. Patients with HCC had a treatment delay that was longer in the COVID-19 period than in 2019., Competing Interests: JCN received a research grant from Bayer for INSERM UMR1138. The other authors declare no conflicts of interest that pertain to this study. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)

Background & Aims: We compare the performance of liver surface nodularity (LSN) and liver stiffness measurements (LSM) using transient elastography (TE) for the detection of clinically significant portal hypertension (CSPH) in patients with cirrhosis and hepatocellular carcinoma (HCC)., Methods: All patients with cirrhosis and HCC who underwent computed tomography, LSM and hepatic venous pressure gradient (HVPG) measurements within 30 days between 2015 and 2018 were included. The estimation of CSPH by LSN and LSM, and the LSM-spleen-size-to-platelet ratio score (LSPS) were evaluated and compared., Results: In total, 140 patients were included (109 men [78%], mean age 63 ± 9 years old), including 39 (28%) with CSPH. LSN measurements were valid in 130 patients (93%) and significantly correlated with HVPG (r = 0.68; p <0.001). Patients with CSPH had higher LSN measurements compared with those without [3.1 ± 0.4 vs . 2.5 ± 0.3, p <0.001; area under the receiver operating characteristic (AUROC): 0.87 ± 0.31]. LSM and LSPS were valid in 132 patients (94%) and significantly correlated with HVPG (r = 0.75, p <0.001; AUROC 0.87 ± 0.04 and r = 0.68, p <0.001; AUROC 0.851 ± 0.04, respectively). There was no significant difference in the diagnostic performance between LSN and LSM-LSPS (DeLong, p  = 0.28, 0.37, and 0.65, respectively) in patients with both valid tests (n = 122). LSN <2.50 had a 100% negative predictive value for CSPH. A 2-step algorithm combining LSN and LSPS for the diagnosis of CSPH classified 108/140 patients (77%) with an 8% error., Conclusions: The diagnostic performance and feasibility of LSN measurements were similar to those of LSM for the detection of CSPH in patients with compensated cirrhosis and HCC. Combining LSN and LSPS accurately detected CSPH in >75% of patients. Such a combination could be useful in centres where the HVPG measurement is unavailable., Lay Summary: The diagnostic performance and feasibility of liver surface nodularity was similar to that of liver stiffness measurement (LSM) for the detection of clinically significant portal hypertension in patients with compensated cirrhosis. Thus, liver surface nodularity could be an option for the preoperative detection of clinically significant portal hypertension in patients with hepatocellular carcinoma. Combining liver surface nodularity with LSM-spleen-size-to-platelet ratio score resulted in the accurate detection of clinically significant portal hypertension in >75% of patients, thus limiting the need for HVPG measurements., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)

Background: Patients with advanced hepatocellular carcinoma (HCC) have a poor prognosis. First-line sorafenib has been the standard of care for a decade, but the treatment landscape is expanding. This review provides a practical overview of current and future systemic treatment options for advanced HCC and their place in clinical practice., Summary: First-line sorafenib and lenvatinib have shown to improve the survival of patients with advanced HCC. In the second line, regorafenib provides benefit for patients who previously tolerated sorafenib. Anti-PD1 antibodies, nivolumab and pembrolizumab, recently became available for second-line use in the US. Ramucirumab (for patients with α-fetoprotein [AFP] levels ≥400) and cabozantinib present potential future second-line treatment options. Combinations of systemic and locoregional treatment, such as radiofrequency ablation or selective internal radiotherapy, require further research. Precision medicine has not yet been translated into clinical practice, as the most common driver mutations ( TERT promoter, CTNNB1 , TP53 , and ARID1A mutations) have not yet been shown to be suitable therapeutic targets. However, our growing understanding of signaling pathways and efforts in drug development are expected to pave the way for precision medicine in HCC in the future. Evaluating the place for the current and novel systemic treatment options in clinical practice can be challenging due to the diverse toxicity profiles of the treatment options and characteristics of the patient population. Sorafenib data elucidate the effect patient characteristics (such as the performance score, Child-Pugh class, AFP, etiology of the underlying disease, and level of macrovascular invasion and extrahepatic spread) may have on outcomes in advanced stages., Key Messages: Lenvatinib is expected to join sorafenib as a preferred first-line treatment in advanced HCC. In the second line, the treatment of choice, regorafenib, is soon expected to be accompanied by cabozantinib and ramucirumab in patients with AFP ≥400 ng/mL, whereas nivolumab and pembrolizumab present second-line alternatives in the US., Competing Interests: M.B. is a consultant for and has received honoraria from Bayer Pharma, Bristol-Myers Squibb, Sitex Medical. A.R.H. is a consultant for and has received honoraria from Bayer Pharma, Bristol-Myers Squibb, Merck. N.M., E.I.C., and J.-C.N. have declared no potential conflicts of interest., (Copyright © 2019 by S. Karger AG, Basel.)

Purpose: Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a novel morphological subtype of HCC associated with early relapse after resection or percutaneous ablation, independently of classical clinical and radiological prognostic factors. The aim of the present study was to identify immunohistochemical markers of MTM-HCC, to ease its diagnosis and implementation into clinical practice., Experimental Design: To identify potential biomarkers of MTM-HCC, we first analyzed gene expression profiling data from The Cancer Genome Atlas study and further selected two candidate biomarkers. Performance of both biomarkers for diagnosis of MTM-HCC was further tested by immunohistochemistry in two independent series of 67 and 132 HCC biopsy samples., Results: Analysis of RNA sequencing data showed that MTM-HCC was characterized by a high expression of neoangiogenesis-related genes. Two candidate biomarkers, Endothelial-Specific Molecule 1 (ESM1) and Carbonic Anhydrase IX (CAIX), were selected. In the discovery series, sensitivity and specificity of ESM1 expression by stromal endothelial cells for the detection of MTM-HCC were 97% (28/29), and 92% (35/38), respectively. Sensitivity and specificity of CAIX were 48% (14/29) and 89% (34/38). In the validation set, sensitivity and specificity of ESM1 for the identification of MTM-HCC were 93% (14/15) and 91% (107/117), respectively. Interobserver agreement for ESM1 assessment was good in both series (Cohen Kappa 0.77 and 0.76)., Conclusions: Using a molecular-driven selection of biomarkers, we identified ESM1 as a reliable microenvironment immunohistochemical marker of MTM-HCC. The results represent a step toward the implementation of HCC morpho-molecular subtyping into clinical practice., (©2019 American Association for Cancer Research.)

This paper investigates the sensor and actuator fault (SAF) estimations and the fault tolerant tracking control (FTTC) problem for uncertain systems represented by Takagi-Sugeno (T-S) fuzzy model affected by Unknown Bounded Disturbance (UBD). A robust descriptor adaptive observer based FTTC is firstly designed to simultaneously estimate the unmeasurable system states and SAF vectors and then to track reference trajectories. Sufficient design conditions are developed in terms of Linear Matrix Inequalities (LMIs). The gains of both observer and fault tolerant controller are computed by solving a set of LMI constraints in single step. Robustness against external disturbances is analysed using the H ∞ performance index to attenuate its effect on the tracking error for bounded reference inputs. Finally, simulation results are illustrated by considering three types of actuator faults. Moreover, two comparisons are presented to show the mentioned process effectiveness., (Copyright © 2018 ISA. Published by Elsevier Ltd. All rights reserved.)