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Background & Aims: In patients with cirrhosis, continued heavy alcohol consumption and obesity may increase risk of hepatocellular carcinoma (HCC). We examined whether germline susceptibility to hepatic steatosis not only independently predisposes to HCC but may also act synergistically with other risk factors., Methods: We analyzed data from 1911 patients in 2 multicenter prospective cohort studies in the United States. We classified patients according to alcohol consumption (current heavy vs not current heavy), obesity (body mass index ≥30 vs <30 kg/m2), and PNPLA3 I148M variant status (carrier of at least one G risk allele vs noncarrier). We examined the independent and joint effects of these risk factors on risk of developing HCC using Cox regression with competing risks., Results: Mean age was 59.6 years, 64.3% were male, 28.7% were Hispanic, 18.3% were non-Hispanic Black, 50.9% were obese, 6.2% had current heavy alcohol consumption, and 58.4% harbored at least 1 PNPLA3 G-allele. One hundred sixteen patients developed HCC. Compared with PNPLA3 noncarriers without heavy alcohol consumption, HCC risk was 2.65-fold higher (hazard ratio [HR], 2.65; 95% confidence interval [CI], 1.20-5.86) for carriers who had current heavy alcohol consumption. Compared with noncarrier patients without obesity, HCC risk was higher (HR, 2.40; 95% CI, 1.33-4.31) for carrier patients who were obese. PNPLA3 and alcohol consumption effect was stronger among patients with viral etiology of cirrhosis (HR, 3.42; 95% CI, 1.31-8.90). PNPLA3 improved 1-year risk prediction for HCC when added to a clinical risk model., Conclusions: The PNPLA3 variant may help refine risk stratification for HCC in patients with cirrhosis with heavy alcohol consumption or obesity who may need specific preventive measures., (Copyright © 2024. Published by Elsevier Inc.)

Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP-1c activation. In summary, PKD1 mutations exert adaptive functionality on the organ level without increasing transformation risk., Competing Interests: Declaration of interests H.Z. is an academic co-founder of Quotient Therapeutics and Jumble Therapeutics, has sponsored research agreements with Alnylam Pharmaceuticals and Chroma Medicines, and serves on the scientific advisory boards of Newlimit and Ubiquitix. A.S.L.Y. has served as a consultant or advisory board member for Regulus, Calico, Otsuka, Navitor, Palladio, and Reata. A.G.S. serves as a consultant for Verve Therapeutics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/aims: Patients with hepatocellular cancer (HCC) are vulnerable to psychological distress given a new cancer diagnosis superimposed on pre-existing chronic liver disease. We aimed to characterise the psychiatric burden in HCC, risk factors for incident diagnosis and treatment patterns over time., Methods: Using IQVIA PharMetrics® Plus for Academics-a nationally representative claims database of the commercially insured US population-we identified psychiatric diagnoses and treatment among patients with newly diagnosed HCC. Multivariable logistic regression modelling identified factors associated with psychiatric diagnosis and treatment., Results: Of 11,609 patients with HCC, 2166 (18.6%) had a psychiatric diagnosis after cancer diagnosis with depression (58.3%) and anxiety (53.0%) being most common. Women (aOR 1.33, 95% CI [1.19-1.49]), pre-existing psychiatric diagnoses (aOR 9.12 [8.08-10.3]) and HCC treatment type (transplant: aOR 2.15 [1.66-2.77]; locoregional therapies: aOR 1.74 [1.52-1.99]; hospice: aOR 2.43 [1.79-3.29]) were significantly associated with psychiatric diagnosis. Female sex, ascites, higher comorbidity and treatment type were associated with incident psychiatric diagnosis. Pharmacotherapy was used in 1392 (64.3%) patients with a psychiatric diagnosis, with antidepressants (46.2%) and anxiolytics (32.8%) being most common. Psychiatric diagnoses increased from 14.8% in 2006-2009 to 21.1% in 2018-2021 (p < 0.001). In almost 20% of patients with pre-existing psychiatric conditions, therapy was discontinued after HCC diagnosis., Conclusions: Nearly 2 of 10 patients with HCC were diagnosed with a psychiatric condition after cancer diagnosis with unique sociodemographic and clinical risk factors identified. This highlights a risk for increased psychological burden in need of early evaluation and treatment among patients with newly diagnosed HCC., (© 2024 John Wiley & Sons Ltd.)

Introduction: Underutilization of hepatocellular cancer (HCC) surveillance has been reported, although data evaluating interventions to improve surveillance are sparse. We assessed the effect of a population-based HCC surveillance program on HCC surveillance utilization and outcomes., Methods: In this retrospective cohort study, we assessed preinclusion and postinclusion HCC surveillance patterns among 597 patients with hepatitis C virus cirrhosis enrolled in a program at an integrated health system between 2013 and 2020. Adequate surveillance was defined as at least 5 surveillance studies within 36 months pre-enrollment and postenrollment; a secondary outcome was proportion of time covered by surveillance over 36 months. Tumor size, stage, and receipt of curative therapy were compared between HCC detected on the first imaging examination (prevalent HCC) and surveillance-detected HCC (incident HCC). We performed Kaplan-Meier analysis and multivariable competing risk analysis to characterize the association between surveillance and mortality., Results: The surveillance program significantly improved surveillance completion (77.6% vs 5.0%, P < 0.001) and proportion time covered (80.9% vs 15.8%, P < 0.001). Compared with prevalent HCC, surveillance-detected cases were more likely unifocal (77.8% vs 44.8%, P < 0.001), early-stage (85.2% vs 44.8%, P < 0.001), with smaller maximum diameter (median 2.3 vs 3.2 cm), and more likely to undergo curative therapy (92.5% vs 72.4% P = 0.010). Survival was improved compared with prevalent cases hazard ratio (HR) 0.23 (0.11-0.51) after adjusting for age and Model for End Stage Liver Disease score., Discussion: Implementation of a population-based program resulted in significant improvement in HCC surveillance use and clinical outcomes among patients with hepatitis C virus cirrhosis. These findings may inform similar interventions by other healthcare systems., (Copyright © 2024 by The American College of Gastroenterology.)

Background: Growing evidence suggests that liver disease originates in early life. Antihistamines cross the placenta and are frequently prescribed to pregnant women to treat nausea and vomiting, as well as allergy and asthma symptoms. Exposure to antihistamines in utero may impact the developing liver by reprogramming or inducing epigenetic changes in fetal hepatocytes., Methods: We examined in utero exposure to antihistamines and the risk of HCC in the Child Health and Development Studies, a multigenerational cohort that enrolled pregnant women in the East Bay, CA, between 1959 and 1966 (n=14,507 mothers and 18,751 liveborn offspring). We reviewed mothers' medical records to identify those prescribed antihistamines during pregnancy, and diagnoses of HCC in adult (age ≥18 y) offspring were identified by linkage with a population-based cancer registry. Cox proportional hazard models were used to estimate adjusted hazard ratios, with follow-up accrued from birth through cancer diagnosis, death, or last contact., Results: About 15% of offspring (n=2759 of 18,751) were exposed in utero to antihistamines. Chlorpheniramine (51.8%) and diphenhydramine (15.4%) were the 2 most commonly prescribed antihistamines. Any in utero exposure was not associated with HCC (adjusted hazard ratio: 2.76, 95% CI: 0.70, 10.89), but the association differed by timing of exposure. Offspring exposed to antihistamines in the first or second trimester had a higher risk of HCC compared to offspring not exposed (adjusted hazard ratio: 4.64, 95% CI: 1.21, 17.78). Similarly, incidence rates were 4.3 per 100,000 (95% CI: 0.9, 12.6) for offspring exposed in the first or second trimester compared to 1.0 per 100,000 (95% CI: 0.3, 2.1) for offspring not exposed., Conclusions: In utero exposure to antihistamines in early pregnancy may increase the risk of HCC in adulthood., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Introduction: Access to hepatocellular carcinoma (HCC) surveillance and treatments were disrupted during the coronavirus disease 2019 (COVID-19) pandemic. We aimed to characterize the impact of the pandemic on HCC incidence and mortality rates, treatment, and outcomes in the United States., Methods: Two nationwide databases, the United States Cancer Statistics and the National Vital Statistics System, were used to investigate HCC incidence and mortality between 2001 and 2020. Trends in age-adjusted incidence rate (aIR) and adjusted mortality rate (aMR) were assessed using joinpoint analysis. The 2020 aIR and aMR were projected based on the prepandemic data and compared with actual values to assess the extent of underdiagnosis. We assessed differences in HCC characteristics, treatment, and overall survival between 2020 and 2018-2019., Results: The aIR of HCC in 2020 was significantly reduced compared with 2019 (5.22 vs 6.03/100K person-years [PY]), representing a 12.2% decrease compared with the predicted aIR in 2020 (5.94/100K PY). The greatest extent of underdiagnosis was observed in Black (-14.87%) and Hispanic (-14.51%) individuals and those with localized HCC (-15.12%). Individuals staged as regional or distant HCC were also less likely to receive treatment in 2020. However, there was no significant difference in short-term overall survival in 2020 compared with 2018-2019, with HCC mortality rates remaining stable (aMR: 2.76 vs 2.73/100K PY in 2020 vs 2019)., Discussion: The COVID-19 pandemic resulted in underdiagnosis of HCC, particularly early stage disease and racial ethnic minorities, and underuse of HCC-directed treatment. Longer follow-up is needed to determine the impact of the COVID-19 pandemic on HCC-related mortality., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background and Aims: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP)., Approach and Results: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC., Conclusions: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Surgical therapies in patients with early-stage HCC can afford long-term survival but are often limited by the continued risk of recurrence, underscoring an interest in (neo)adjuvant strategies. Prior attempts at adjuvant therapy using tyrosine kinase inhibitors failed to yield significant improvements in recurrence-free survival or overall survival. Advances in the efficacy of systemic therapy options, including the introduction of immune checkpoint inhibitors, have fueled renewed interest in this area. Indeed, the IMBrave050 trial recently demonstrated significant improvements in recurrence-free survival with 1 year of adjuvant atezolizumab plus bevacizumab in high-risk patients undergoing surgical resection or ablation, with several other ongoing trials in this space. There is a strong rationale for consideration of the administration of these therapies in the neoadjuvant setting, supported by early clinical data demonstrating high rates of objective responses, although larger trials examining downstream outcomes are necessary, particularly considering the possible risks of this strategy. In parallel, there has been increased interest in using systemic therapies as a bridging or downstaging strategy for liver transplantation. Current data suggest the short-term safety of this approach, with acceptable rates of rejection, so immunotherapy is not considered a contraindication to transplant; however, larger studies are needed to evaluate the incremental value of this approach over locoregional therapy. Conversely, the use of immunotherapy is currently discouraged after liver transplantation, given the high risk of graft rejection and death. The increasing complexity of HCC management and increased consideration of (neo)adjuvant strategies highlight the critical role of multidisciplinary care when making these decisions., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: High financial burden for patients has been reported for multiple types of cancer, but there are limited data in those with HCC. We aimed to describe the financial burden for patients diagnosed with HCC and identify correlates of high financial burden., Methods: We used the IQVIA PharMetrics Plus for Academics database to identify commercially insured patients diagnosed with HCC between 2006 and 2021. Patient financial liability was defined as the difference between allowed and paid amounts from adjudicated insurance claims. We reported total and HCC-related financial liabilities (i.e., cost for HCC-related claims), with high total financial liability defined as ≥$3000 annually and high HCC-related financial liability as ≥$1000 annually. We used multivariable logistic regression modeling to identify factors associated with high total and HCC-related financial liability., Results: Among 11,609 patients with HCC, the median total financial liability during the year after HCC diagnosis was $2955 (Q1-Q3: $972-$6293). Nearly half (45%) of patients experienced high total financial liability, with the greatest liability incurred in the 3-month period immediately following HCC diagnosis. Older age, increased comorbidity, and cirrhosis-related complications were associated with higher total patient liability. Patient liability also varied by type of HCC treatment, with systemic therapy and liver transplantation having the highest financial liability in multivariable analysis. However, only 66.7% of the patients experienced HCC-related liability., Conclusions: Patients with HCC experience significant financial liability underscoring a need for price transparency as well as financial counseling in this population., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Liver transplantation is the curative therapy of choice for patients with early-stage HCC. Locoregional therapies are often employed as a bridge to reduce the risk of waitlist dropout; however, their association with posttransplant outcomes is unclear. We conducted a systematic review using Ovid MEDLINE and EMBASE to identify studies published between database inception and August 2, 2023, which reported posttransplant recurrence-free survival and overall survival among patients transplanted for HCC within Milan criteria, stratified by receipt of bridging therapy. Pooled HRs were calculated for each outcome using the DerSimonian and Laird method for a random-effects model. We identified 38 studies, including 19,671 patients who received and 20,148 patients who did not receive bridging therapy. Bridging therapy was not associated with significant differences in recurrence-free survival (pooled HR: 0.91, 95% CI: 0.77-1.08; I2 =39%) or overall survival (pooled HR: 1.09, 95% CI: 0.95-1.24; I2 =47%). Results were relatively consistent across subgroups, including geographic location and study period. Studies were discordant regarding the differential strength of association by pretreatment tumor burden and pathologic response, but potential benefits of locoregional therapy were mitigated in those who received 3 or more treatments. Adverse events were reported in a minority of studies, but when reported occurred in 6%-15% of the patients. Few studies reported loss to follow-up and most had a risk of residual confounding. Bridging therapy is not associated with improvements in posttransplant recurrence-free or overall survival among patients with HCC within Milan criteria. The risk-benefit ratio of bridging therapy likely differs based on the risk of waitlist dropout., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Abdominal US is currently the best-validated surveillance strategy for hepatocellular carcinoma (HCC) in at-risk patients. It is the only modality shown to have completed all five phases of validation and can achieve high sensitivity and specificity for HCC detection, especially when conducted by expert sonographers in high-volume centers. However, US also has limitations, including operator dependency and varying sensitivity in clinical practice. Further, the sensitivity of US for early-stage HCC detection is lower in patients with obesity or nonviral liver disease, increasingly common populations undergoing surveillance. Imaging-based and blood-based surveillance strategies, including abbreviated MRI and biomarker panels, may overcome some limitations of US-based surveillance. Both strategies have promising test performance in phase II and phase III biomarker studies and are undergoing prospective validation. Considering the variation in HCC risk and test performance between patients, there will likely be a shift away from a one-size-fits-all approach and toward precision screening, in which the "best" test is selected based on individual patient characteristics. In this upcoming era of precision HCC screening among patients with cirrhosis, US will likely continue to have an important, albeit reduced, surveillance role., (© RSNA, 2024.)

Importance: Surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is underused. Identifying potentially modifiable factors to address barriers in HCC surveillance is critical to improve patient outcomes., Objective: To evaluate clinician-level factors contributing to underuse of HCC surveillance in patients with cirrhosis., Design, Setting, and Participants: This survey study included primary care clinicians (PCCs) and gastroenterology and hepatology clinicians at 5 safety-net health systems in the US. Clinicians were surveyed from March 15 to September 15, 2023, to assess knowledge, attitudes, beliefs, perceived barriers, and COVID-19-related disruptions in HCC surveillance in patients with cirrhosis. Data were analyzed from October to November 2023., Main Outcome and Measures: HCC surveillance knowledge was assessed with 6 questions querying the respondent's ability to correctly identify appropriate use of HCC surveillance. Attitudes, perceived barriers, and beliefs regarding HCC surveillance and perceived impact of the COVID-19 pandemic-related disruptions with HCC surveillance were assessed with a series of statements using a 4-point Likert scale and compared PCCs and gastroenterology and hepatology clinicians., Results: Overall, 347 of 1362 clinicians responded to the survey (25.5% response rate), among whom 142 of 237 (59.9%) were PCCs, 48 of 237 (20.3%) gastroenterology and hepatology, 190 of 236 (80.5%) were doctors of medicine and doctors of osteopathic medicine, and 46 of 236 (19.5%) were advanced practice clinicians. On HCC knowledge assessment, 144 of 270 (53.3%) scored 5 or more of 6 questions correctly, 37 of 48 (77.1%) among gastroenterology and hepatology vs 65 of 142 (45.8%) among PCCs (P < .001). Those with higher HCC knowledge scores were less likely to report barriers to HCC surveillance. PCCs were more likely to report inadequate time to discuss HCC surveillance (37 of 139 [26.6%] vs 2 of 48 [4.2%]; P = .001), difficulty identifying patients with cirrhosis (82 of 141 [58.2%] vs 5 of 48 [10.4%]; P < .001), and were not up-to-date with HCC surveillance guidelines (87 of 139 [62.6%] vs 5 of 48 [10.4%]; P < .001) compared with gastroenterology and hepatology clinicians. While most acknowledged delays during the COVID-19 pandemic, 62 of 136 PCCs (45.6%) and 27 of 45 gastroenterology and hepatology clinicians (60.0%) reported that patients with cirrhosis could currently complete HCC surveillance without delays., Conclusions and Relevance: In this survey study, important gaps in knowledge and perceived barriers to HCC surveillance were identified. Effective delivery of HCC education to PCCs and health system-level interventions must be pursued in parallel to address the complex barriers affecting suboptimal HCC surveillance in patients with cirrhosis.

Introduction: Hepatocellular carcinoma (HCC) surveillance is associated with improved early tumor detection, but effectiveness is limited by underuse. We characterized adherence to HCC surveillance using proportion of time covered (PTC) and estimated its association with clinical outcomes among patients with cirrhosis., Methods: We conducted a retrospective cohort study of patients diagnosed with HCC between January 2008 and December 2022 at 2 large US health systems. We characterized PTC by imaging in the 12 and 24 months before HCC diagnosis. We used multivariable logistic and Cox regression analyses to assess the association between PTC and early HCC detection, receipt of curative treatment, and overall survival., Results: Among 2,027 patients with HCC, 331 (51.4% Barcelona Clinic Liver Cancer 0/A) had been followed up for at least 12 months before diagnosis. The median PTC was 24.9% (interquartile range 1.1%-50.7%), with only 16.0% having semiannual imaging and 42.0% having annual surveillance. Semiannual and annual surveillance decreased to 6.3% and 29.6% when assessed over 24 months, although the median PTC remained unchanged at 24.9%. Receipt of gastroenterology/hepatology care had the strongest association with PTC, with median PTC of 36.7% and 3.8% for those with and without gastroenterology/hepatology care, respectively. PTC was independently associated with improved early HCC detection, curative treatment receipt, and overall survival. The median survival was 15.7, 26.8, and 32.7 months among those with PTC of <25% (n = 168 patients), PTC 25%-50% (n = 69 patients), and PTC >50% (n = 94 patients), respectively., Discussion: The proportion of time covered by HCC surveillance in patients with cirrhosis remains low, highlighting a need for multilevel interventions., (Copyright © 2023 by The American College of Gastroenterology.)

Background: Racial and ethnic disparities in hepatocellular carcinoma (HCC) prognosis exist, partly related to differential failures along the cancer care continuum. We characterized racial and ethnic disparities in treatment receipt among patients with HCC in the United States., Methods: We searched Medline, Embase, and CINAHL databases to identify studies published between January 2012 and March 2022 reporting HCC treatment receipt among adult patients with HCC, stratified by race or ethnicity. We calculated pooled odds ratios for HCC treatment using random effects models., Results: We identified 15 studies with 320,686 patients (65.8% White, 13.9% Black, 10.4% Asian, and 8.5% Hispanic). Overall, 33.2% of HCC patients underwent any treatment, and 22.7% underwent curative treatment. Compared with White patients, Black patients had lower odds of any treatment (OR 0.67, 95% CI 0.55-0.81) and curative treatment (OR 0.74, 95% CI 0.71-0.78). Similarly, Hispanic patients had lower pooled odds of curative treatment (OR 0.79, 95% CI 0.73-0.84)., Conclusions: There were significant racial and ethnic disparities in HCC treatment receipt, with Black patients having lower odds of receiving any and curative treatment while Hispanic patients having lower odds of curative treatment., Impact: Racial and ethnic differences in treatment receipt serve as an intervention target to reduce disparities in HCC prognosis., (©2024 American Association for Cancer Research.)

Importance: Cohort studies demonstrating an association of hepatocellular carcinoma (HCC) screening with reduced mortality are prone to lead-time and length-time biases., Objective: To characterize the clinical benefits of HCC screening, adjusting for lead-time and length-time biases, in a diverse, contemporary cohort of at-risk patients., Design, Setting, and Participants: This retrospective cohort study of patients with HCC was conducted between January 2008 and December 2022 at 2 large US health systems. Data analysis was performed from September to November 2023., Main Outcomes and Measures: The primary outcome was screen-detected HCC, defined by abnormal screening-intent abdominal imaging or α-fetoprotein level within 6 months before diagnosis. Cox regression analysis was used to characterize differences in overall survival between patients with screen-detected and non-screen-detected HCC; lead-time and length-time adjustments were calculated using the Duffy parametric formula., Results: Among 1313 patients with HCC (mean [SD] age, 61.7 [9.6] years; 993 male [75.6%]; 739 [56.3%] with Barcelona Clinic Liver Cancer stage 0/A disease), HCC was screen-detected in 556 (42.3%) and non-screen detected in 757 (57.7%). Patients with screen-detected HCC had higher proportions of early-stage HCC (393 patients [70.7%] vs 346 patients [45.7%]; risk ratio [RR], 1.54; 95% CI, 1.41-1.70) and curative treatment receipt (283 patients [51.1%] vs 252 patients [33.5%]; RR, 1.52; 95% CI, 1.34-1.74) compared with patients with non-screen-detected HCC. The screen-detected group had significantly lower mortality, which persisted after correcting for lead-time bias (hazard ratio, 0.75; 95% CI, 0.65-0.87) in fully adjusted models. Both groups had similar tumor doubling times (median [IQR], 3.8 [2.2-10.7] vs 5.6 [1.7-11.4] months) and proportions of indolent tumors (28 patients [35.4%] vs 24 patients [38.1%]; RR, 0.93; 95% CI, 0.60-1.43). Adjustment for length-time bias decreased survival estimates, although 3-year and 5-year survival for patients with screen-detected HCC remained longer than that for patients with non-screen-detected HCC., Conclusions and Relevance: The findings of this cohort study suggest that HCC screening is associated with reduced mortality even after accounting for lead-time and length-time biases. However, these biases should be considered in future studies.

Liver cancer, specifically hepatocellular carcinoma (HCC), is the sixth most common cancer and the third leading cause of cancer mortality worldwide. The development of effective systemic therapies, particularly those involving immune-checkpoint inhibitors (ICIs), has substantially improved the outcomes of patients with advanced-stage HCC. Approximately 30% of patients are diagnosed with early stage disease and currently receive potentially curative therapies, such as resection, liver transplantation or local ablation, which result in median overall survival durations beyond 60 months. Nonetheless, up to 70% of these patients will have disease recurrence within 5 years of resection or local ablation. To date, the results of randomized clinical trials testing adjuvant therapy in patients with HCC have been negative. This major unmet need has been addressed with the IMbrave 050 trial, demonstrating a recurrence-free survival benefit in patients with a high risk of relapse after resection or local ablation who received adjuvant atezolizumab plus bevacizumab. In parallel, studies testing neoadjuvant ICIs alone or in combination in patients with early stage disease have also reported efficacy. In this Review, we provide a comprehensive overview of the current approaches to manage patients with early stage HCC. We also describe the tumour immune microenvironment and the mechanisms of action of ICIs and cancer vaccines in this setting. Finally, we summarize the available evidence from phase II/III trials of neoadjuvant and adjuvant approaches and discuss emerging clinical trials, identification of biomarkers and clinical trial design considerations for future studies., (© 2024. Springer Nature Limited.)

Background: The overall value of hepatocellular carcinoma screening is defined by the balance of benefits and harms. Studies have only reported physical harms with none describing financial harms., Methods: We conducted a multicenter pragmatic randomized clinical trial of hepatocellular carcinoma screening outreach among 2872 patients with cirrhosis from March 2018 to April 2021. Patients with positive or indeterminate results and matched patients with negative results completed surveys at baseline and at follow-up measuring financial harms via Cancer Self-Administered Questionnaire and financial burden via Comprehensive Score for Financial Toxicity Functional Assessment of Chronic Illness Therapy. Univariable and multivariable longitudinal regression analyses were performed to compare changes in financial harms across groups: true positive, true negative, false positive, and indeterminate. Semistructured interviews were conducted in a subset of patients, sampled by center and test result., Results: Of 311 patients who completed at least 1 follow-up survey (75% response rate), 37 had true positive, 133 true negative, 64 false positive, and 77 indeterminate results. Financial harms increased in true positive and false positive patients with no significant changes noted among those with true negative or indeterminate results. At follow-up, 21.8% of patients reported moderate-severe financial burden, which was not significantly associated with test results. Semistructured interviews revealed variation in the frequency and severity of financial harms based on test results, with increased harm in those with false positive results., Conclusions: Financial harms of hepatocellular carcinoma screening vary by test result and can pose a barrier that must be considered when determining the optimal screening program., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma as single agents. Targeting membranous phosphatidylserine may induce pro-inflammatory and -immune stimulating effects that enhance immunotherapy activity. This hypothesis was tested in a single-arm phase 2 trial evaluating frontline bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab (anti-PD-1) in patients with unresectable hepatocellular carcinoma (NCT03519997). The primary endpoint was investigator-assessed objective response rate among evaluable patients, and secondary end points included progression-free survival, incidence of adverse events, overall survival, and duration of response. Among 28 evaluable patients, the confirmed response rate was 32.1%, which met the pre-specified endpoint, and the median progression-free survival was 6.3 months (95% CI, 1.3-11.3 months). Treatment related-adverse events of any grade occurred in 45.7% of patients, with grade 3 or greater adverse events in 14.3% of patients. Adverse events of any cause were observed in 33 patients (94.3%), with grade 3 or greater adverse events in 11 patients (31.4%). Prespecified exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the presence of fibrotic tissue and expression of immune checkpoints in stroma was associated with tumor response. These results suggest that targeting phosphatidylserine may lead to synergistic effects with PD-1 blockade without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the pre-treatment tumor microenvironment., (© 2024. The Author(s).)

Background & Aims: Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours., Methods: Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure., Results: In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p <0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p = 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96)., Conclusions: Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes., Impact and Implications: Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: Hepatocellular carcinoma (HCC) surveillance is associated with improved early detection and reduced mortality, although practice patterns and effectiveness vary in clinical practice. We aimed to characterize HCC surveillance patterns in a large, diverse cohort of patients with HCC., Methods: We conducted a retrospective cohort study of patients diagnosed with HCC between January 2008 and December 2022 at 2 large US health systems. We recorded imaging receipt in the year before HCC diagnosis: ultrasound plus α-fetoprotein (AFP), ultrasound alone, multiphasic contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI), and no liver imaging. We used multivariable logistic and Cox regression analysis to compare early tumor detection, curative treatment receipt, and overall survival between surveillance strategies., Results: Among 2028 patients with HCC (46.7% Barcelona Clinic Liver Cancer stage A), 703 (34.7%) had ultrasound plus AFP, 293 (14.5%) had ultrasound alone, 326 (16.1%) had multiphasic CT/MRI, and 706 (34.8%) had no imaging in the year before HCC diagnosis. Over the study period, proportions without imaging were stable, whereas use of CT/MRI increased. Compared with no imaging, CT/MRI and ultrasound plus AFP, but not ultrasound alone, were associated with early stage HCC detection and curative treatment. Compared with ultrasound alone, CT/MRI and ultrasound plus AFP were associated with increased early stage detection., Conclusions: HCC surveillance patterns vary in clinical practice and are associated with differing clinical outcomes. While awaiting data to determine if CT or MRI surveillance can be performed in a cost-effective manner in selected patients, AFP has a complementary role to ultrasound-based surveillance, supporting its adoption in practice guidelines., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Coronavirus Disease 2019 disrupted cancer-related care in early 2020., Methods: We used population-based cancer registry data to estimate incidence and mortality rates of gastrointestinal cancers between 2016 and 2020., Results: Incidence rates were unchanged from 2016 to 2019 but decreased in 2020, with the largest declines for colorectal cancer (rate ratio [RR] 0.88; 95% confidence interval [CI] 0.87-0.90) and hepatocellular carcinoma (RR 0.85; 95% CI 0.82-0.88). Mortality rates of colorectal cancer (RR 1.06; 95% CI 1.04-1.08) and esophageal adenocarcinoma (RR 1.06; 95% CI 1.00-1.13) increased in 2020., Discussion: Incidence and mortality rates of gastrointestinal cancers may increase in the future given pandemic-related delays in 2020., (Copyright © 2023 by The American College of Gastroenterology.)

Background and Aims: The value of HCC surveillance is determined by the balance between benefits and harms; however, no studies have enumerated psychological harms., Approach and Results: We fielded surveys measuring psychological harms to patients with cirrhosis in a multicenter randomized trial of HCC surveillance outreach. All patients with positive or indeterminate surveillance results and matched patients with negative results were invited to complete surveys measuring (1) depression through the Patient Health Questionnaire-ninth version, (2) anxiety through State-Trait Anxiety Inventory, (3) HCC-specific worry through Psychological Consequences Questionnaire, and (4) decisional regret. Patients were classified into 4 groups: true positive (TP), false positive (FP), indeterminate, and true negative (TN). Multivariable longitudinal regression analysis using the generalized estimating equation method was performed to compare the means of measures across groups. We conducted 89 semistructured interviews in a subset of patients stratified by health system and test results. Of 2872 patients in the trial, 311 completed 1+ follow-up survey (63 FP, 77 indeterminate, 38 TP, and 133 TN). Moderate depression decreased in TN patients, increased in TP, and had intermittent but mild increases in those with FP and indeterminate results. High anxiety temporarily increased in patients with TP results but resolved over time and was stable in those with FP and indeterminate results. Decisional regret was low and did not differ across groups. In semistructured interviews, patients reported apprehension, anxiety, emotional distress, and coping related to HCC surveillance., Conclusions: Psychological harms of HCC surveillance appear mild but differ by test result. Future research should determine the impact of psychological harms on the value of HCC surveillance programs., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Hepatocellular carcinoma (HCC) surveillance is recommended by professional society guidelines given a consistent association with reduced HCC-related mortality. HCC surveillance should be performed using semiannual abdominal ultrasound and alpha-fetoprotein, although this combination has suboptimal sensitivity and can miss more than one-third of HCC at an early stage. There are promising emerging blood-based and imaging-based strategies, including abbreviated MRI and biomarker panels; however, these require further validation before routine use in clinical practice. HCC surveillance is underused in clinical practice due to patient-related and provider-related barriers, highlighting a need for interventions to improve surveillance utilization in clinical practice., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background & Aims: Widespread use of direct-acting antivirals for hepatitis C virus infection has been paralleled with increased numbers of patients with hepatocellular carcinoma (HCC) after achieving sustained virologic response (post-SVR HCC) worldwide. Few data compare regional differences in the presentation and prognosis of patients with post-SVR HCC., Methods: We identified patients with advanced fibrosis (F3/F4) who developed incident post-SVR HCC between March 2015 and October 2021 from 30 sites in Europe, North America, South America, the Middle East, South Asia, East Asia, and Southeast Asia. We compared patient demographics, liver dysfunction, and tumor burden by region. We compared overall survival by region using Kaplan-Meier analysis and identified factors associated with survival using multivariable Cox regression analysis., Results: Among 8796 patients with advanced fibrosis or cirrhosis who achieved SVR, 583 (6.6%) developed incident HCC. There was marked regional variation in the proportion of patients detected by surveillance (range: 59.5%-100%), median maximum tumor diameter (range, 1.8-5.0 cm), and the proportion with multinodular HCC (range, 15.4%-60.8%). The prognosis of patients highly varied by region (hazard ratio range, 1.82-9.92), with the highest survival rates in East Asia, North America, and South America, and the lowest survival rates in the Middle East and South Asia. After adjusting for geographic region, HCC surveillance was associated with early stage detection (Barcelona Clinic Liver Cancer stage 0/A, 71.0% vs 21.3%; P < .0001) and lower mortality rates (adjusted hazard ratio, 0.29; 95% CI, 0.18-0.46)., Conclusions: Clinical characteristics, including early stage detection, and prognosis of post-SVR HCC differed significantly across geographic regions. Surveillance utilization appears to be a high-yield intervention target to improve prognosis among patients with post-SVR HCC globally., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) mortality rates are increasing globally, and particularly in the Western world. Cirrhosis remains the predominant risk factor for HCC. However, epidemiological shifts in the incidence of HCC from patients with virus-related liver disease to those with non-viral aetiologies, including alcohol-associated and metabolic dysfunction-associated steatotic liver disease, have important implications for prevention, surveillance and treatment. Hepatitis B vaccination and antiviral therapy for hepatitis B and C are effective for primary prevention of virus-related HCCs, but chemoprevention strategies for non-viral liver disease remain an unmet need. Emerging data suggest associations between aspirin, statins, metformin and coffee and reduced HCC incidence, although none has been proved to be causally related. Secondary prevention of HCC via semi-annual surveillance is associated with improvements in early detection and thus reduced mortality; however, current tools, including abdominal ultrasonography, have suboptimal sensitivity for the detection of early stage HCC, particularly in patients with obesity and/or non-viral liver disease. Promising blood-based or imaging-based surveillance strategies are emerging, although these approaches require further validation before adoption in clinical practice. In the interim, efforts should be focused on maximizing use of the existing surveillance tools given their prevalent underuse globally. Remarkable advances have been made in the treatment of HCC, including expanded eligibility for surgical therapies, improved patient selection for locoregional treatments and increased systemic treatment options, including immune-checkpoint inhibitors. In this Review, we discuss trends in the epidemiology of HCC and their implications for screening, prevention and therapy., (© 2023. Springer Nature Limited.)

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Surveillance for HCC is critical for early detection and treatment, but fewer than one-quarter of individuals at risk of HCC undergo surveillance. Multiple failures across the screening process contribute to the underutilization of surveillance, including limited disease awareness among patients and health-care providers, knowledge gaps, and difficulty recognizing patients who are at risk. Non-alcoholic fatty liver disease and alcohol-associated liver disease are the fastest-rising causes of HCC-related death worldwide and are associated with unique barriers to surveillance. In particular, more than one-third of patients with HCC related to non-alcoholic fatty liver disease do not have cirrhosis and therefore lack a routine indication for HCC surveillance on the basis of current practice guidelines. Semi-annual abdominal ultrasound with measurement of α-fetoprotein levels is recommended for HCC surveillance, but the sensitivity of this approach for early HCC is limited, especially for patients with cirrhosis or obesity. In this Review, we discuss the current status of HCC surveillance and the remaining challenges, including the changing aetiology of liver disease. We also discuss strategies to improve the utilization and quality of surveillance for HCC., (© 2023. Springer Nature Limited.)

Introduction: The efficacy and safety of combined immunotherapy and transarterial radioembolization (TARE) were suggested in preclinical and early-phase trials, but these were limited by small sample sizes. We sought to compare the efficacy of combined therapy and immunotherapy alone in patients with advanced hepatocellular carcinoma (HCC)., Methods: The National Cancer Database was used to identify patients with advanced HCC diagnosed between January 1, 2017, and December 31, 2019. We included patients who received combined therapy or immunotherapy alone as first-line treatment. Multivariable logistic regression was conducted to determine predictors of combined therapy. Kaplan-Meier and Cox regression approaches were used to identify predictors of overall survival and to compare hazards of mortality between the patients who received combined therapy and immunotherapy alone., Results: Of 1,664 eligible patients with advanced-stage HCC, 142 received combined TARE/immunotherapy and 1,522 received immunotherapy alone. Receipt of combination therapy was associated with care at an academic center and inversely associated with racial/ethnic minority status (Hispanic and Black individuals). The median overall survival was significantly higher in the combination group than in the immunotherapy alone group (19.8 vs 9.5 months). In multivariable analysis, combined therapy was independently associated with reduced mortality (adjusted hazard ratio 0.50, 95% confidence interval: 0.36-0.68, P < 0.001). Results were consistent across subgroups and in sensitivity analyses using propensity score matching and inverse probability of treatment weighting., Discussion: The combination of TARE and immunotherapy was associated with improved survival compared with immunotherapy alone in patients with advanced-stage HCC. Our findings underly the importance of large clinical trials evaluating combination therapy in these patients., (Copyright © 2023 by The American College of Gastroenterology.)

Background & Aims: The available risk stratification indices for hepatocellular cancer (HCC) have limited applicability. We developed and externally validated an HCC risk stratification index in U.S. cohorts of patients with cirrhosis., Methods: We used data from 2 prospective U.S. cohorts to develop the risk index. Patients with cirrhosis were enrolled from 8 centers and followed until development of HCC, death, or December 31, 2021. We identified an optimal set of predictors with the highest discriminatory ability (C-index) for HCC. The predictors were refit using competing risk regression and its predictive performance was evaluated using the area under the receiver-operating characteristic curve (AUROC). External validation was performed in a cohort of 21,550 patients with cirrhosis seen in the U.S Veterans Affairs system between 2018 and 2019 with follow-up through 2021., Results: We developed the model in 2431 patients (mean age 60 years, 31% women, 24% cured hepatitis C, 16% alcoholic liver disease, and 29% nonalcoholic fatty liver disease). The selected model had a C-index of 0.77 (95% confidence interval [CI], 0.73-0.81), and the predictors were age, sex, smoking, alcohol use, body mass index, etiology, α-fetoprotein, albumin, alanine aminotransferase, and platelet levels. The AUROCs were 0.75 (95% CI, 0.65-0.85) at 1 year and 0.77 (95% CI, 0.71-0.83) at 2 years, and the model was well calibrated. In the external validation cohort, the AUROC at 2 years was 0.70 with excellent calibration., Conclusion: The risk index, including objective and routinely available risk factors, can differentiate patients with cirrhosis who will develop HCC and help guide discussions regarding HCC surveillance and prevention. Future studies are needed for additional external validation and refinement of risk stratification., (Copyright © 2023. Published by Elsevier Inc.)

Background: Patient-reported outcomes (PRO) measures relevant to domains most important to patients with HCC who received locoregional therapies are needed to advance patient-centered research. Furthermore, electronic PRO monitoring in clinical care has been shown to reduce hospitalizations and deaths in patients with other cancers. We conducted a qualitative study among patients with HCC who recently received locoregional therapies to (1) identify common and distressing posttreatment symptoms to prioritize PRO domain selection and (2) gauge interest in an electronic PRO symptom monitoring system., Methods: We performed semi-structured telephone interviews among adult patients who received locoregional therapies (median of 26 days after treatment) for treatment-naïve HCC at a single tertiary care center. Interviews were conducted until thematic saturation was reached. Qualitative content analysis was conducted to identify emerging themes and sub-themes., Results: Ten of 26 patients (38%) reported at least 1 symptom before treatment. In contrast, all participants (n = 26) with recently treated HCC reported at least 1 posttreatment physical symptom, with the most common being appetite loss (73%), fatigue (58%), abdominal pain (46%), and nausea (35%). Most participants (77%) stated they saw potential benefits in posttreatment ePRO symptom monitoring., Conclusions: Posttreatment symptoms after HCC locoregional therapies are common and often severe. These data can inform and prioritize PRO domain selection. Patients are interested in ePRO monitoring to monitor and proactively address posttreatment symptoms. Given the clinical benefits in patients with metastatic cancers, ePRO monitoring warrants investigation in patients with HCC., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Since the introduction of the combination treatment of anti-programmed death-ligand 1 antibody atezolizumab and anti-VEGF antibody bevacizumab (AB), median overall survival in HCC has drastically improved. However, evidence on the efficacy and safety of the novel treatment standard in patients with prior exposure to systemic treatment is scarce. The aim of this global, multicenter, observational study was to evaluate the efficacy and safety of AB in patients after previous systemic therapy., Methods: We screened our global, multicenter, prospectively maintained registry database for patients who received any systemic therapy before AB. The primary end point was overall survival; secondary end points were time-to-progression, progression-free survival, objective response rate, and safety (rate and severity of adverse events)., Results: Among 493 patients who received AB for unresectable HCC, 61 patients received prior systemic therapy and were included in this analysis. The median age of the study population was 66 years, with 91.8% males. Predominant risk factors for HCC were viral hepatitis (59%) and alcohol (23%). Overall survival for AB was 16.2 (95% CI, 14.5-17.9) months, time-to-progression and progression-free survival were 4.1 (95% CI, 1.5-6.6) and 3.1 (95% CI, 1.1-5.1) months, respectively. The objective response rate was 38.2% (7.3% with complete and 30.9% with partial response). Overall survival was not influenced by treatment line (2nd vs. >2nd) or previous systemic treatment modality (tyrosine kinase inhibitors vs. immune checkpoint inhibitors). Treatment-related adverse events of all grades according to Common Terminology Criteria for Adverse Events were documented in 42.6% of patients, with only 13.1% of grade ≥3, including one death., Conclusion: In this observational study, AB emerges as a safe and efficacious treatment option in patients with HCC previously treated with other systemic therapy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in the overall sample and among non-Hispanic whites. The results show that among non-Hispanic whites, presence of rare functional variants in ABCC2 was associated with 7-fold higher risk of metabolic HCC (OR = 6.92, 95% CI: 2.38-20.15, P = 0.0004), and this association remained significant when analyses were restricted to functional rare variants observed in ≥2 participants (cases 3.2% versus controls 0.0%, P = 1.02 × 10-5). In the overall multiethnic sample, presence of rare functional variants in ABCC2 was nominally associated with metabolic HCC (OR = 3.60, 95% CI: 1.52-8.58, P = 0.004), with similar nominal association when analyses were restricted to functional rare variants observed in ≥2 participants (cases 2.9% versus controls 0.2%, P = 0.006). A common variant in PNPLA3 (rs738409[G]) was associated with higher HCC risk in the overall sample (P = 6.36 × 10-6) and in non-Hispanic whites (P = 0.0002). Our findings indicate that rare functional variants in ABCC2 are associated with susceptibility to metabolic HCC in non-Hispanic whites. PNPLA3-rs738409 is also associated with metabolic HCC risk., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background & Aims: Black patients with hepatocellular cancer (HCC), often attributed to hepatitis C virus (HCV) infection, have suboptimal survival following liver transplant (LT). We evaluated the impact of direct-acting antiviral (DAA) availability on racial and ethnic disparities in wait list burden post-LT survival for candidates with HCC., Methods: Using the United Network for Organ Sharing registry, we identified patients with HCC who were listed and/or underwent LT from 2009 to 2020. Based on date of LT, patients were categorized into 2 era-based cohorts: the pre-DAA era (LT between 2009 and 2011) and DAA era (LT between 2015 and 2017, with follow-up through 2020). Kaplan-Meier and Cox proportional hazards analyses were used to compare post-LT survival, stratified by era and race and ethnicity., Results: Annual wait list additions for HCV-related HCC decreased significantly in White and Hispanic patients during the DAA era, with no change (P = .14) in Black patients. Black patients had lower 3-year survival than White patients in the pre-DAA era (70.6% vs 80.1%, respectively; P < .001) but comparable survival in the DAA era (82.1% vs 85.5%, respectively; P = .16). 0n multivariable analysis, Black patients in the pre-DAA era had a 53% higher risk (adjusted hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.28-1.84), for mortality than White patients, but mortality was comparable in the DAA era (adjusted HR, 1.23; 95% CI, 0.99-1.52). In a stratified analysis in Black patients, HCV-related HCC carried more than a 2-fold higher risk of mortality in the pre-DAA era (adjusted HR, 2.86; 95% CI, 1.50-5.43), which was reduced in the DAA era (adjusted HR, 1.34; 95% CI, 0.78-2.30)., Conclusions: With the availability of DAA therapy, racial disparities in post-LT survival have improved., (Copyright © 2023 AGA Institute. All rights reserved.)

Background & Aims: Hepatocellular carcinoma (HCC) has an increasing mortality in the United States and is a leading cause of morbidity and mortality in patients with cirrhosis. We aimed to estimate the financial burden related to HCC in a large nationally representative United States cohort., Methods: We used the Surveillance, Epidemiology, and End Results program (SEER)-Medicare database to identify 4525 adult patients who were diagnosed with HCC between 2011 and 2015. We generated a 1:1 propensity score-matched cohort of patients with cirrhosis but no HCC as a comparator group to define incremental HCC-specific costs beyond costs related to underlying cirrhosis. Our main outcomes were patient liabilities and Medicare payments in the first year after HCC diagnosis., Results: Compared with patients with cirrhosis, those with HCC had higher incremental patient liabilities (median +$7166; interquartile range, $2401-$16,099) and Medicare payments (+$50,110; interquartile range, $142,42-$136,239; P < .001 for both) in the first year after diagnosis. Patients with HCC had significantly higher inpatient, outpatient, and physician service costs compared with the matched cohort with cirrhosis (P < .001 for all). Patients with early-stage HCC had lower incremental patient liabilities (median, $4195 vs $8238; P < .001) and Medicare payments (median, $28,207 vs $59,509; P < .001) than those with larger tumor burden. In multivariable median regression analysis, incremental patient liabilities and Medicare payments were significantly associated with the National Cancer Institute comorbidity index, nonalcoholic fatty liver disease etiology, presence of ascites, and presence of hepatic encephalopathy., Conclusions: Patients with HCC suffer from cancer-related financial burden, highlighting a need for policy interventions and financial support systems., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestation, nonalcoholic steatohepatitis (NASH), has a global prevalence of 20-25% and is a major public health problem. Its incidence is increasing in parallel to the rise in obesity, diabetes and metabolic syndrome. Progression from NASH to NASH-related hepatocellular carcinoma (HCC) (~2% of cases per year) is influenced by many factors, including the tissue and immune microenvironment, germline mutations in PNPLA3, and the microbiome. NASH-HCC has unique molecular and immune traits compared with other aetiologies of HCC and is equally prevalent in men and women. Comorbidities associated with NASH, such as obesity and diabetes mellitus, can prevent the implementation of potentially curative therapies in certain patients; nonetheless, outcomes are similar in patients who receive treatment. NASH-HCC at the early to intermediate stages is managed with surgery and locoregional therapies, whereas advanced HCC is treated with systemic therapies, including anti-angiogenic therapies and immune-checkpoint inhibitors. In this Review, we present the latest knowledge of the pathogenic mechanisms and clinical management of NASH-HCC. We discuss data highlighting the controversy over varying responses to immune-checkpoint inhibitors according to underlying aetiology and suggest that the future of NASH-HCC management lies in improved surveillance, targeted combination therapies to overcome immune evasion, and identifying biomarkers to recognize treatment responders., (© 2023. Springer Nature Limited.)

Background & Aims: Texas has the highest age-adjusted incidence rate of hepatocellular carcinoma (HCC) in the United States. The Cancer Prevention and Research Institute of Texas has funded the Texas Collaborative Center for Hepatocellular Cancer (TeCH) to facilitate HCC research, education, and advocacy activities with the overall goal of reducing HCC mortality in Texas through coordination, collaboration, and advocacy., Methods: On September 17, 2022, TeCH co-sponsored a multi-stakeholder conference on HCC with the Baker Institute Center for Health and Biosciences. This conference was attended by HCC researchers, policy makers, payers, members from pharmaceutical industry and patient advocacy groups in and outside of Texas. This report summarizes the results of the conference., Results: The goal of this meeting was to identify different strategies for preventing HCC and evaluate their readiness for implementation., Conclusions: We call for a statewide (1) viral hepatitis elimination program; (2) program to increase nonalcoholic steatohepatitis and obesity awareness; (3) research program to develop health care models that integrate alcohol associated liver disease treatment and treatment for alcohol use disorder; and (4) demonstration projects to evaluate the effectiveness of identifying and linking patient with advanced fibrosis and cirrhosis to clinical care., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Combination anti-PD-(L)1/CTLA-4 blockade is approved in patients with hepatocellular carcinoma (HCC) in the first-line setting or after sorafenib, but whether this treatment has efficacy after prior anti-PD-(L)1 therapy is unknown. We performed a multicenter retrospective review of patients with advanced HCC treated with ipilimumab plus nivolumab after prior anti-PD-(L)1 therapy, excluding patients with prior anti-CTLA-4 treatment. Of the 32 patients who met our inclusion criteria, prior anti-PD-(L)1 regimens included atezolizumab plus bevacizumab (50%, n = 16), other anti-VEGF plus anti-PD-(L)1 combinations (31%, n = 10), and anti-PD-(L)1 monotherapy (19%, n = 6). The median number of prior systemic therapies was 2 (range, 1-8). The objective response rate with ipilimumab plus nivolumab by RECIST 1.1 was 22% [1 complete response (3%), 6 partial response (19%), 8 stable disease (25%), 16 progressive disease (50%), and 1 not evaluable (NE) (3%)], and objective response was associated with improved progression-free survival and overall survival. Immune-related adverse events were reported in 13 patients (41%), with no new safety signals. This study demonstrates that ipilimumab plus nivolumab has efficacy in patients with HCC who have received prior anti-PD-(L)1 therapy, suggesting that failure to respond to prior PD-(L)1 blockade should not preclude treatment with salvage ipilimumab plus nivolumab. Prospective studies are needed to define the optimal sequence of therapies., Significance: Anti-PD-(L)1 containing regimens are the preferred first-line treatment for advanced HCC, but whether salvage with PD-(L)1/CTLA-4 blockade is effective in patients who have failed prior anti-PD-(L)1 therapy is unknown. Our study demonstrates that ipilimumab plus nivolumab has clinical activity in patients with advanced HCC previously treated with anti-PD-(L)1 therapy, supporting the continued use of this regimen in the late-line setting after prior anti-PD-(L)1 exposure., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Several breakthroughs in hepatocellular carcinoma (HCC) therapy across tumor stages provide hope to improve its dismal prognosis. Although surgical and local ablative therapies have few significant changes in technique, an improved understanding of tumor biology has facilitated increase numbers of patients who are now eligible to undergo curative-intent procedures. Most notably, acceptable post-transplant outcomes can be achieved in well selected patients whose tumors are downstaged into Milan Criteria. Adjuvant therapy in patients at high risk of recurrence also significantly improves recurrence-free survival after resection or ablation. For patients with liver-localized disease who are not eligible for curative-intent procedures, transarterial chemoembolization (TACE) was historically the treatment modality of choice, regardless of tumor burden; however, there is now increased recognition of patients who are "TACE unsuitable" and may be better treated with systemic therapy. The greatest evolution in HCC treatment options has occurred with systemic therapy, where several new agents are now available in the first- and second-line setting, including immune checkpoint inhibitor combinations. Objective responses are observed in approximately 30% of patients and median survival is approaching 2 years. The availability of immune checkpoint inhibitors has renewed interest in combination therapies for earlier tumor stages, with several phase III trials ongoing. Considering increasing complexities of HCC care, requiring decisions between therapies delivered by different providers, multidisciplinary care is critical and is associated with improved clinical outcomes. In this review, we detail major breakthroughs in HCC therapy, how these breakthroughs can be applied in clinical practice, and remaining areas in need of further research., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background Aims: Early-stage HCC can be treated with thermal ablation or stereotactic body radiation therapy (SBRT). We retrospectively compared local progression, mortality, and toxicity among patients with HCC treated with ablation or SBRT in a multicenter, US cohort., Approach Results: We included adult patients with treatment-naïve HCC lesions without vascular invasion treated with thermal ablation or SBRT per individual physician or institutional preference from January 2012 to December 2018. Outcomes included local progression after a 3-month landmark period assessed at the lesion level and overall survival at the patient level. Inverse probability of treatment weighting was used to account for imbalances in treatment groups. The Cox proportional hazard modeling was used to compare progression and overall survival, and logistic regression was used for toxicity. There were 642 patients with 786 lesions (median size: 2.1 cm) treated with ablation or SBRT. In adjusted analyses, SBRT was associated with a reduced risk of local progression compared to ablation (aHR 0.30, 95% CI: 0.15-0.60). However, SBRT-treated patients had an increased risk of liver dysfunction at 3 months (absolute difference 5.5%, aOR 2.31, 95% CI: 1.13-4.73) and death (aHR 2.04, 95% CI: 1.44-2.88, p < 0.0001)., Conclusions: In this multicenter study of patients with HCC, SBRT was associated with a lower risk of local progression compared to thermal ablation but higher all-cause mortality. Survival differences may be attributable to residual confounding, patient selection, or downstream treatments. These retrospective real-world data help guide treatment decisions while demonstrating the need for a prospective clinical trial., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Hepatocellular cancer (HCC) surveillance is associated with increased curative treatment and improved survival, underscoring its importance in patients with cirrhosis. 1 Surveillance is 1 step in a larger HCC screening continuum, and those with abnormal screening results must undergo diagnostic evaluation with multiphase computed tomography (CT) or magnetic resonance imaging (MRI). 2 The Liver Imaging Reporting and Data System (LI-RADS) classifies liver observations in at-risk patients based on risk of malignancy and HCC, with LR-5 observations having a positive predictive value exceeding 95% for HCC. However, indeterminate liver nodules (ie, LR-3 or LR-4) are commonly observed in clinical practice, associated with heterogenous HCC risk, and have large variations in practice management. 3,4 We previously reported the natural history of LR-3 observations in a multicenter cohort of patients with cirrhosis, demonstrating a high annual incidence for HCC development of 8.4 cases per 100 person-years; 5 however, the natural history of LR-4 observations remains uncertain. Herein, we aimed to characterize clinical outcomes in patients with LR-4 observations in a multicenter cohort., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The effectiveness of ultrasound-based surveillance for HCC in patients with cirrhosis is limited by suboptimal sensitivity for early tumor detection and poor adherence. Emerging blood-based biomarkers have been proposed as an alternative surveillance strategy. We aimed to evaluate the comparative effectiveness of a multitarget HCC blood test (mt-HBT)-with and without improved adherence-against ultrasound-based HCC surveillance., Methods: We developed a Markov-based mathematical model that simulated a virtual trial in patients with compensated cirrhosis comparing potential surveillance strategies: biannual surveillance using ultrasound, ultrasound plus AFP, and mt-HBT with or without improved adherence (+10% increase). We used published data to inform underlying liver disease progression rates, HCC tumor growth patterns, performance characteristics of surveillance modalities, and efficacy of treatments. Primary outcomes of interest were the number of early-stage HCCs detected and life years gained., Results: Per 100,000 patients with cirrhosis, mt-HBT detected 1680 more early-stage HCCs than ultrasound alone and 350 more early-stage HCCs than ultrasound + AFP, yielding an additional 5720 and 1000 life years, respectively. mt-HBT with improved adherence detected 2200 more early-stage HCCs than ultrasound and 880 more early-stage HCCs than ultrasound + AFP, yielding an additional 8140 and 3420 life years, respectively. The number of screening tests needed to detect one HCC case was 139 with ultrasound, 122 with ultrasound + AFP, 119 with mt-HBT, and 124 with mt-HBT with improved adherence., Conclusions: mt-HBT is a promising alternative to ultrasound-based HCC surveillance, particularly given anticipated improved adherence with blood-based biomarkers could increase HCC surveillance effectiveness., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Ultrasound-based surveillance has suboptimal sensitivity for early hepatocellular carcinoma (HCC) detection, generating interest in alternative surveillance modalities. We aim to investigate the association between prediagnostic CT or MRI and overall survival in a contemporary cohort of patients with HCC. Using the Surveillance Epidemiology and End Results (SEER)-Medicare database, we analyzed Medicare beneficiaries diagnosed with HCC between 2011 and 2015. Proportion of time covered (PTC) was defined as the proportion of the 36-month period prior to HCC diagnosis in which patients had received abdominal imaging (ultrasound, CT, MRI). Cox proportional hazards regression was used to investigate the association between PTC and overall survival. Among 5,098 patients with HCC, 3,293 (65%) patients had abdominal imaging prior to HCC diagnosis, of whom 67% had CT/MRI. Median PTC by any abdominal imaging was 5.6% [interquartile range (IQR): 0%-36%], with few patients having PTC >50%. Compared with no abdominal images, ultrasound [adjusted HR (aHR): 0.87, 95% confidence interval (CI): 0.79-0.95] and CT/MRI group (aHR: 0.68, 95% CI: 0.63-0.74) were associated with improved survival. Lead-time adjusted analysis showed improved survival continued to be observed with CT/MRI (aHR: 0.80, 95% CI: 0.74-0.87) but not ultrasound (aHR: 1.00, 95% CI: 0.91-1.10). Increased PTC was associated with improved survival, with a larger effect size observed with CT/MRI (aHR per 10%: 0.93, 95% CI: 0.91-0.95) than ultrasound (aHR per 10%: 0.96, 95% CI: 0.95-0.98). In conclusion, PTC by abdominal images was associated with improved survival in patients with HCC, with potential greater benefit using CT/MRI. Regular utilization of CT/MRI before cancer diagnosis may have potential survival benefit compared to ultrasound in patients with HCC., Significance: Our population-based study using SEER-Medicare database demonstrated that proportion of time covered by abdominal imaging was associated with improved survival in patients with HCC, with potential greater benefit using CT/MRI. The results suggest that CT/MRI surveillance may have potential survival benefit compared with ultrasound surveillance in high-risk patients for HCC. A larger prospective study should be conducted for external validation., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Death rates from primary liver cancer (hepatocellular carcinoma [HCC]) have continued to rise in the United States over the recent decades despite the availability of an increasing range of treatment modalities, including new systemic therapies. Prognosis is strongly associated with tumor stage at diagnosis; however, most cases of HCC are diagnosed beyond an early stage. This lack of early detection has contributed to low survival rates. Professional society guidelines recommend semiannual ultrasound-based HCC screening for at-risk populations, yet HCC surveillance continues to be underused in clinical practice. On April 28, 2022, the Hepatitis B Foundation convened a workshop to discuss the most pressing challenges and barriers to early HCC detection and the need to better leverage existing and emerging tools and technologies that could improve HCC screening and early detection. In this commentary, we summarize technical, patient-level, provider-level, and system-level challenges and opportunities to improve processes and outcomes across the HCC screening continuum. We highlight promising approaches to HCC risk stratification and screening, including new biomarkers, advanced imaging incorporating artificial intelligence, and algorithms for risk stratification. Workshop participants emphasized that action to improve early detection and reduce HCC mortality is urgently needed, noting concern that many of the challenges we face today are the same or similar to those faced a decade ago and that HCC mortality rates have not meaningfully improved. Increasing the uptake of HCC screening was identified as a short-term priority while developing and validating better screening tests and risk-appropriate surveillance strategies., (© The Author(s) 2023. Published by Oxford University Press.)

Background & Aims: Failures have been reported across the cancer care continuum in patients with hepatocellular carcinoma (HCC); however, the impact of treatment delays on outcomes has not been well-characterized. We described the prevalence of treatment delays in a racially and ethnically diverse cohort of patients and its association with overall survival., Methods: Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients diagnosed with HCC between 2001 and 2015. We performed multivariable logistic regression analysis to identify factors associated with treatment delay (ie, receipt of HCC-directed therapy >3 months after diagnosis). Cox proportional hazards regression analysis with a 5-month landmark was used to characterize the association between treatment delay and overall survival, accounting for immortal time bias., Results: Of 8450 patients with treatment within 12 months of HCC diagnosis, 1205 (14.3%) experienced treatment delays. The proportion with treatment delays ranged from 6.8% of patients undergoing surgical resection to 21.6% of those undergoing liver transplantation. In multivariable analysis, Black patients (odds ratio, 1.96; 95% confidence interval [CI], 1.21-3.15) and those living in high poverty neighborhoods (odds ratio, 1.55; 95% CI, 1.25-1.92) were more likely to experience treatment delays than white patients and those living in low poverty neighborhoods, respectively. Treatment delay was independently associated with worse survival (hazard ratio 1.15, 95% CI, 1.05-1.25)., Conclusions: Nearly 1 in 7 patients with HCC experience treatment delays, with higher odds in Black patients and those living in high poverty neighborhoods. Treatment delays are associated with worse survival, highlighting a need for interventions to improve time-to-treatment., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Given the complexity of managing HCC, professional society guidelines advocate multidisciplinary care (MDC) for patients with HCC. However, implementation of MDC programs requires a significant investment of time and resources. We conducted a systematic review and meta-analysis to enumerate potential benefits of MDC for patients with HCC., Methods: We conducted a search of the PubMed/MEDLINE and EMBASE databases and national conference abstracts to identify studies published after January 2005 that reported early-stage presentation, treatment receipt, or overall survival among patients with HCC, stratified by MDC status. We calculated pooled risk ratios and HRs for clinical outcomes according to MDC receipt using the DerSimonian and Laird method for random effects models., Results: We identified 12 studies (n = 15,365 patients with HCC) with outcomes stratified by MDC status. MDC was associated with improved overall survival (HR = 0.63, 95% CI: 0.45-0.88); however, its association with curative treatment receipt was not statistically significant (risk ratio = 1.60, 95% CI: 0.89-2.89) and pooled estimates were limited by high heterogeneity (I2 > 90% for both). Studies (n = 3) were discordant regarding an association between MDC and time-to-treatment initiation. MDC was associated with early-stage HCC (risk ratio = 1.60, 95% CI: 1.12-2.29), suggesting possible referral bias contributing to improved outcomes. Limitations of studies also included risk of residual confounding, loss to follow-up, and data preceding the availability of immune checkpoint inhibitors., Conclusion: MDC for patients with HCC is associated with improved overall survival, underscoring the likely benefit of managing patients with HCC in a multidisciplinary care setting., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Hepatocellular carcinoma (HCC) is a leading cause of death in patients with cirrhosis and has a rising mortality rate in the United States. 1 Racial and ethnic minorities experience a disproportionate burden of HCC, including higher incidence rates, more late-stage diagnoses, and worse survival. 2 , 3 These disparities are complex in nature and can be attributed to many proximal, intermediate, and distal determinants, such as health literacy and behaviors, social support, social needs, social determinants of health, and access to health care. 4 Prior studies have identified racial and ethnic differences in clinical factors, including receipt of HCC surveillance and tumor stage 5 ; however, few studies have examined differences in patient-reported barriers that may partly explain observed disparities. Understanding these data is essential to inform interventions to address and mitigate disparities. Therefore, we described patient-reported barriers to medical care and examined differences in barriers by race and ethnicity in a large, diverse population of patients newly diagnosed with HCC., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)