AbstractBackground and AimsThe IMbrave150 trial established atezolizumab–bevacizumab as the new standard of care for hepatocellular carcinoma (HCC). However, evidence on its applications in real‐world patients is limited. We report the efficacy and safety of atezolizumab–bevacizumab in a Chinese cohort of HCC patients ineligible for clinical trials.MethodsElectronic medical records of patients diagnosed with HCC and with pharmacy orders of atezolizumab and bevacizumab between 2019 and 2021 were retrospectively reviewed. Patients' demographics, performance status, stage, treatment received, adverse events and death time (if any) were recorded.ResultsThirteen eligible patients were included. mOS of HCC patients was 18.6 months [6.8–30.4], while mPFS was 9.3 months [0–19.4]. No grade 5 adverse events were reported.ConclusionsThis real‐world study provides real‐world experiences of atezolizumab–bevacizumab as first‐line and subsequent therapy in patients with unresectable HCC. Further validation on the efficacy and safety of atezolizumab–bevacizumab as second‐line or later lines of treatment should be conducted.

AbstractBackground and AimCabozantinib is a molecular targeted agent (MTA) used for treatment of advanced hepatocellular carcinoma (HCC). Although its superiority over placebo has been proven, its effectiveness and risk factors in real‐world practice are needed to be elucidated.MethodsThis study retrospectively enrolled 54 advanced HCC patients, who were treated with cabozantinib. The effectiveness of cabozantinib, adverse events (AE) and risk factors for survival was analysed.ResultsMajority of the patients (88.9%) were treated with two or more MTAs before starting cabozantinib and atezolizumab plus bevacizumab was the most prevalent MTA used (59.3%). The median overall survival and progression‐free survival (PFS) were 6.9 and 4.4 months, respectively. The objective response rate and disease control rate were 3.7% and 40.7%, respectively. Grade 3/4 AE occurred in 37.0% of the patients; however, unpredictable AE was not observed. Multivariate analysis revealed that high neutrophil–lymphocyte ratio (NLR, >4) was a risk factor for survival (hazard ratio for death, 2.35; 95% confidence interval [CI], 1.41–4.82; p = 0.020). Moreover, the occurrence of Grade 3/4 AE was a negative risk factor for both survival (hazard ratio for death, 0.36; 95% CI, 0.16–0.83; p = 0.016) and PFS (hazard ratio for disease progression or death, 0.33; 95% CI, 0.15–0.73; p = 0.006). Neither preceding therapy with atezolizumab/bevacizumab nor a reduced starting dose correlated with patient survival.ConclusionsCabozantinib can be used safely in real‐world practice. The study identified high NLR as a positive risk factor and the occurrence of Grade 3/4 AE as a negative risk factor for survival.

AbstractHepatocellular carcinoma (HCC) poses a significant global burden, with most patients being diagnosed at an advanced stage, leading to poor prognosis due to the lack of systemic treatment. The approval of oral tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors, and anti‐angiogenic agents has rapidly expanded the treatment prospects for HCC. However, the use of these drugs has also increased the incidence of portal hypertension (PHT) and upper gastrointestinal variceal bleeding in HCC patients. The diagnosis, screening, emergency treatment, and secondary prevention of upper gastrointestinal variceal rebleeding in advanced HCC patients undergoing oral TKIs therapy have become clinically urgent and critical issues. This review provides an overview of the existing understanding regarding the uses and limitations of transjugular intrahepatic portosystemic shunt (TIPS) insertion for managing HCC in cirrhosis patients with PHT and variceal hemorrhage. Additionally, it explores the potential of TIPS in managing acute upper gastrointestinal bleeding and preventing rebleeding in advanced HCC patients undergoing TKIs therapy. The placement of TIPS within the treatment hierarchy is determined by the specific clinical environment and the individual attributes of the patient.

AbstractBackground and AimsHepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. This study considers the geographical trends in incidence and mortality from HCC.MethodsData were obtained for each EU15+ country from the Global Burden of Disease Study database. Age‐standardised incidence rates (ASIRs), mortality rates (ASMRs) and disability‐adjusted life years (DALYs) were extracted for each year from 1990 to 2019. Data were subdivided into males and females. Mortality‐to‐incidence ratios (MIRs) were calculated. All Indices were reported per 100 000 population, and trends were described using Joinpoint regression.ResultsASIRs increased in 17/19 countries in females and 18/19 countries in males between 1990 and 2019. ASMRs increased in all countries except Italy (for both sexes) and Sweden (for females). MIR decreased in all countries except Denmark in males (+8.0) and females (+1.2). Ireland saw the greatest decline in MIR among females (−15.0%) and the United Kingdom for males (−16.4%). DALYs increased in all countries except Italy for males and females and Sweden for females.ConclusionsThe incidence of and mortality from hepatocellular carcinoma are increasing in the majority of EU15+ countries. The rise in mortality and fall in MIR may suggest that outcomes from HCC are improving, despite an increased disease burden.

AbstractThere is no consensus on which substances and which method should be used for transarterial chemoembolization. A publication commissioned by CIRSE 2021 attempted to formulate recommendations. However, only the spectrum of currently implemented procedures is outlined but no recommendation was made. In this article, therefore, basic considerations regarding the technique of chemoembolization are presented, and the authors discuss fundamental considerations about the embolic materials used, the cytostatic drugs and their dosage, as well as about pain therapy during treatment. Then, a technique is presented which used degradable starch microspheres as an embolic agent. This technique enables multiple treatments over a longer period. However, this proposal is not only evidence‐based but also eminence‐based. What we need are controlled studies that systematically compare different treatment techniques in a sufficient number of patients. This will hopefully help to find the best method for individual patients. Until then, the technique proposed by the authors can be applied.

AbstractBackground and AimsNon‐alcoholic steatohepatitis (NASH) is a common cause of hepatocellular carcinoma (HCC) worldwide. Emerging data suggests NASH‐induced HCC could be associated with less response to immune checkpoint inhibitor (ICI)‐based therapy. Metformin has been associated with improved outcomes in cancers like melanoma treated with ICIs, but its impact on HCC is not well defined. The purpose of this study was to examine the effect of metformin on clinical outcomes in patients with advanced HCC treated with ICIs.MethodsWe retrospectively analysed patients with advanced HCC treated with ICIs in first and later‐line settings between 2015 and 2021. The primary endpoints were overall survival (OS), progression‐free survival (PFS), and objective response rate (ORR) as assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Patients were stratified based on their usage of metformin.ResultsOur study included 18 patients in the metformin group and 93 patients in the non‐metformin group. The most common causes of HCC were viral hepatitis (52%), NASH (29%), and alcohol (8%). ORR was 5.6% in the metformin group vs 22.6% in the non‐metformin group (P = .0987). Median OS was 10.8 months versus 45.9 months (HR = 1.99, 95% CI = 0.95–4.21, P = .065) and median PFS was 2.5 months versus 6.6 months (P = .077) in the metformin and non‐metformin groups, respectively. Regardless of metformin usage, OS was significantly worse in patients with poor ECOG performance status, HCC aetiology of NASH, MELD score 10–23, AFP >= 400, and use of ICIs in later lines of therapy.ConclusionsMetformin use was associated with a trend, although not statistically significant, toward a worse ORR, OS and PFS in advanced HCC patients treated with ICIs.

AbstractHepatocellular carcinoma (HCC) is a leading cause of cancer‐related death worldwide. Recently, patient care was revolutionized by the introduction of immunotherapy combining anti‐programmed death‐ligand 1 (PD‐L1) checkpoint inhibition with anti‐vascular endothelial growth factor (VEGF) therapy as first‐line treatment for advanced unresectable HCC. Additional promising studies with mono‐ or combination immunotherapy are in advanced phases of clinical testing. Currently, however, our understanding of which patients profit from immunotherapy and how therapy response may be related to the composition of the tumour immune microenvironment remains incomplete. Inhibitory receptors as targets of immune checkpoint inhibitor (ICI) therapies are strongly expressed by T cells in the tumour microenvironment (TME). However, the HCC microenvironment is highly heterogeneous as illustrated by distinct molecular subtypes and subclassifications with an immune‐rich microenvironment representing only a small proportion of HCCs. A better understanding of the tumour immune microenvironment is expected to provide insights for clinically applicable biomarkers to optimize immunotherapies. Recent studies identified subtypes of PD‐1 expressing CD8+ T cells with divergent function in the HCC TME associated with different outcomes, suggesting that specific PD‐1 expressing CD8+ tissue‐resident memory T cells (TRM), but not exhausted CD8+ T cells (TEX), govern positive therapy outcomes. This review discusses the T‐cell response in the HCC TME in the context of its heterogeneity, molecular and immune classifications and implications for ICI therapy and biomarker discovery.

Liver Cancer InternationalVolume 4, Issue 1 p. 1-4 ISSUE INFORMATIONFree Access Issue Information First published: 06 April 2023 https://doi.org/10.1002/lci2.53AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume4, Issue1Special Issue: Hepatocellular Carcinoma: New Knowledge in Diagnosis and TherapiesMarch 2023Pages 1-4 RelatedInformation

AbstractHepatocellular carcinoma (HCC) is a major public health burden with increasing incidence and mortality worldwide. Arising almost exclusively on the background of chronic liver disease, the tumour microenvironment plays a tremendous role in the occurrence and progression of HCC. With the emergence of checkpoint inhibitor‐based combination therapies as first‐line therapy in advanced HCC, the tumour microenvironment has drawn increasing attention as a target for novel therapeutic approaches. In fact, checkpoint‐inhibitor‐based immunotherapies currently dominate clinical studies on HCC therapy. Importantly, whilst checkpoint‐inhibitor‐based immune‐oncology primarily targets T‐cells, the tumour microenvironment consists of a wide variety of different cell populations that show complex interactions with each other and the malignant tumour cells. Stromal cells and representatives of the innate immune system, such as macrophages, neutrophils and natural killer cells hereby orchestrate the initial immune response and thus appear as attractive targets for broad therapeutic effects, less susceptible to immune escape. In this review, we aim to discuss the current knowledge on the role of innate immune cells and stromal cell populations in HCC initiation and progression as well as related novel therapeutic concepts.

AbstractHepatocellular carcinoma (HCC) is a leading cause of cancer‐related mortality and morbidity worldwide. Machine learning (ML) tools have been developed in recent years to generate diagnostic and prognostic molecular biomarkers for this high‐fatality cancer. To delineate the landscape of ML in HCC, we performed a systematic search of Ovid Medline, Ovid Embase, Cochrane Database of Systematic Reviews (Ovid) and Cochrane CENTRAL (Ovid) to identify studies of HCC molecular biomarkers using ML strategies. In total, 75 studies met our inclusion criteria, 53 of which were pertinent to diagnosis of HCC and 22 of which were pertinent to prognostication of HCC. Genomic, transcriptomic, epigenomic, proteomic and metabolomic signatures were derived using various ML techniques (supervised, unsupervised and deep learning approaches) using serum, urine and tissue samples of HCC. The ML algorithms achieved a sensitivity of up to 95% for the diagnosis of HCC. Through pathway analysis of the signatures derived by ML tools, we identified regulators of epithelial‐mesenchymal transition and the cancer pathway Ras/Raf/MAPK as being particularly prognostic of HCC outcome. The application of ML to molecular data in HCC has thus far resulted in the generation of highly sensitive diagnostic and prognostic signatures. In future, development of ML algorithms that incorporate clinical, laboratory, alongside molecular features will be needed to fulfil the promise of personalized HCC diagnosis and treatment.