MASLD/MetALD and mortality in individuals with any cardio-metabolic risk factor: A population-based study with 26.7 years of follow-up.

BACKGROUND AND AIMS: A new term, metabolic dysfunction-associated steatotic liver disease (MASLD), has been proposed by a multi-society expert panel. However, it remains unclear whether hepatic steatosis per se in MASLD contributes to an increased risk of mortality in individuals with any cardio-metabolic risk factor (CMRF), which is also a significant risk factor for increased mortality. This study aimed to compare all-cause and cause-specific mortality between the "MASLD/MetALD" and "no steatotic liver disease (SLD)" groups in individuals with any CMRF. APPROACH AND RESULTS: A population-based cohort study was conducted using 10,750 participants of the Third National Health and Nutrition Examination Survey. All-cause and cause-specific (cardiovascular, cancer, diabetes, and liver) mortality risks were compared between the "MASLD," "MetALD," and "no SLD" groups using the Cox proportional hazards model with complex survey design weights, adjusted for confounders. Over 26 years, the "MASLD" group did not show significantly increased all-cause (adjusted HR 1.04[95% CI: 0.95-1.14], p = 0.413), cardiovascular (0.88 [0.75-1.04], p = 0.139), or cancer (1.06[0.84-1.33], p = 0.635) mortality risk compared to the "no SLD" group in individuals with any CMRF. The MetALD group was associated with increased all-cause (1.41 [1.05-1.89], p = 0.022), cancer (2.35 [1.33-4.16], p = 0.004), and liver (15.04 [2.96-76.35], p = 0.002) mortality risk compared with the no SLD group. This trend was more pronounced in the MetALD group with advanced fibrosis assessed by Fibrosis-4 (FIB-4). CONCLUSIONS: In individuals with CMRF, the presence of steatotic liver disease (MASLD) alone did not increase the risk of mortality, except in cases with more alcohol consumption (MetALD). Therefore controlling metabolic risk factors and reducing alcohol consumption in people with MASLD or MetALD will be crucial steps to improve long-term health outcomes.

Incidence of liver cancer in young adults according to the Global Burden of Disease database 2019.

BACKGROUND AND AIMS: The worldwide burden of cancer is increasing in younger populations. However, the epidemiology of primary liver cancer remains understudied in young adults compared to other cancer forms. APPROACH AND RESULTS: This study analyzed data from the Global Burden of Disease study between 2010 and 2019 to assess the age-standardized incidence, mortality, and disability-adjusted life years associated with primary liver cancer in the young (15-49 y), stratified by region, nation, sociodemographic index, and sex. The study found a global estimate of 78,299 primary liver cancer cases, 60,602 deaths, and 2.90 million disability-adjusted life years in the young population. The Western Pacific region exhibited the highest burden in 2019, showing the most significant increase compared to other regions between 2010 and 2019. More than half of the countries worldwide have undergone an increase in primary liver cancer incidence rates in young adults. Around 12.51% of deaths due to primary liver cancer occur in young individuals. Throughout the study period, there was a significant decline in primary liver cancer mortality due to most etiologies, except for metabolic dysfunction-associated steatotic liver disease-attributable primary liver cancer (annual percentage change + 0.87%, 95% CI: 0.70%-1.05%) and alcohol-attributable primary liver cancer (annual percentage change + 0.21%, 95% CI: 0.01%-0.42%). The limitations of the Global Burden of Disease database include reliance on the quality of primary data and possible underestimation of alcohol consumption. CONCLUSIONS: Over the past decade, there has been a marked increase in the burden of primary liver cancer, especially that originating from steatotic liver disease. This trend calls for the development of urgent and comprehensive strategies to mitigate this rising burden globally.

Hepatocellular Carcinoma Surveillance Patterns and Outcomes in Patients With Cirrhosis.

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.

The Burden of Overweight and Obesity-Associated Gastrointestinal Cancers in Low and Lower-Middle-Income Countries: A Global Burden of Disease 2019 Analysis.

INTRODUCTION: Obesity is associated with cancer, including gastrointestinal (GI). Data from low (LICs) and lower-middle-income countries (MICs) are limited. METHODS: We utilized data from the Global Burden of Disease Study 2019 to determine the mortality from GI cancer risk of high body mass index (BMI) in these countries. RESULTS: Mortality rates of GI cancers from high BMI increased in LICs and lower MICs, while burdens decreased or remained stable in high and middle-income countries. DISCUSSION: The GI cancer-related burden from high BMI increased in LICs and lower MICs, necessitating a concerted effort to tackle the obesity pandemic.

Role of biomarkers in the diagnosis and management of HCC.

For many cancers, biomarkers have served as an important tool across the cancer care continuum from risk stratification and early detection to diagnosis and treatment. Alpha fetoprotein (AFP) remains one of the few validated biomarkers for patients with hepatocellular carcinoma (HCC). Although AFP has shown potential for each of these steps, its performance when used alone has often been suboptimal. There continues to be discordant recommendations about AFP's value when combined with ultrasound for surveillance as well as its role in diagnostic algorithms. Conversely, high AFP levels are associated with aggressive tumor biology and survival, so it remains a key factor for selection of liver transplant candidates. There have been immense efforts to identify and validate additional biomarkers for each of these steps in the HCC care continuum. Indeed, biomarker panels have shown promising data for HCC risk stratification and surveillance among patients with cirrhosis, as well as prognostication and detection of minimal residual disease in patients undergoing HCC treatment. Several large prospective studies to evaluate the role of these emerging biomarkers in clinical practice are currently ongoing.

Risk stratification and early detection biomarkers for precision HCC screening.

Hepatocellular carcinoma (HCC) mortality remains high primarily due to late diagnosis as a consequence of failed early detection. Professional societies recommend semi-annual HCC screening in at-risk patients with chronic liver disease to increase the likelihood of curative treatment receipt and improve survival. However, recent dynamic shift of HCC etiologies from viral to metabolic liver diseases has significantly increased the potential target population for the screening, whereas annual incidence rate has become substantially lower. Thus, with the contemporary HCC etiologies, the traditional screening approach might not be practical and cost-effective. HCC screening consists of (i) definition of rational at-risk population, and subsequent (ii) repeated application of early detection tests to the population at regular intervals. The suboptimal performance of the currently available HCC screening tests highlights an urgent need for new modalities and strategies to improve early HCC detection. In this review, we overview recent developments of clinical, molecular, and imaging-based tools to address the current challenge, and discuss conceptual framework and approaches of their clinical translation and implementation. These encouraging progresses are expected to transform the current "one-size-fits-all" HCC screening into individualized precision approaches to early HCC detection and ultimately improve the poor HCC prognosis in the foreseeable future.

Machine learning models are superior to noninvasive tests in identifying clinically significant stages of NAFLD and NAFLD-related cirrhosis.

BACKGROUND AND AIMS: We assessed the performance of machine learning (ML) models in identifying clinically significant NAFLD-associated liver fibrosis and cirrhosis. APPROACH AND RESULTS: We implemented ML models including logistic regression (LR), random forest (RF), and artificial neural network to predict histological stages of fibrosis using 17 demographic/clinical features in 1370 patients with NAFLD who underwent liver biopsy, FibroScan, and labs within a 6-month period at multiple U.S. centers. Histological stages of fibrosis (≥F2, ≥F3, and F4) were predicted using ML, FibroScan liver stiffness measurements, and Fibrosis-4 index (FIB-4). NASH with significant fibrosis (NAS ≥ 4 + ≥F2) was assessed using ML, FibroScan-AST (FAST) score, FIB-4, and NAFLD fibrosis score (NFS). We used 80% of the cohort to train and 20% to test the ML models. For ≥F2, ≥F3, F4, and NASH + NAS ≥ 4 + ≥F2, all ML models, especially RF, had primarily higher accuracy and AUC compared with FibroScan, FIB-4, FAST, and NFS. AUC for RF versus FibroScan and FIB-4 for ≥F2, ≥F3, and F4 were (0.86 vs. 0.81, 0.78), (0.89 vs. 0.83, 0.82), and (0.89 vs. 0.86, 0.85), respectively. AUC for RF versus FAST, FIB-4, and NFS for NASH + NAS ≥ 4 + ≥F2 were (0.80 vs. 0.77, 0.66, 0.63). For NASH + NAS ≥ 4 + ≥F2, all ML models had lower/similar percentages within the indeterminate zone compared with FIB-4 and NFS. Overall, ML models performed better in sensitivity, specificity, positive predictive value, and negative predictive value compared with traditional noninvasive tests. CONCLUSIONS: ML models performed better overall than FibroScan, FIB-4, FAST, and NFS. ML could be an effective tool for identifying clinically significant liver fibrosis and cirrhosis in patients with NAFLD.

Magnetic resonance elastography-based prediction model for hepatic decompensation in NAFLD: A multicenter cohort study.

BACKGROUND AND AIMS: Magnetic resonance elastography (MRE) is an accurate, continuous biomarker of liver fibrosis; however, the optimal combination with clinical factors to predict the risk of incident hepatic decompensation is unknown. Therefore, we aimed to develop and validate an MRE-based prediction model for hepatic decompensation for patients with NAFLD. APPROACH AND RESULTS: This international multicenter cohort study included participants with NAFLD undergoing MRE from 6 hospitals. A total of 1254 participants were randomly assigned as training (n = 627) and validation (n = 627) cohorts. The primary end point was hepatic decompensation, defined as the first occurrence of variceal hemorrhage, ascites, or HE. Covariates associated with hepatic decompensation on Cox-regression were combined with MRE to construct a risk prediction model in the training cohort and then tested in the validation cohort. The median (IQR) age and MRE values were 61 (18) years and 3.5 (2.5) kPa in the training cohort and 60 (20) years and 3.4 (2.5) kPa in the validation cohort, respectively. The MRE-based multivariable model that included age, MRE, albumin, aspartate aminotransferase, and platelets had excellent discrimination for the 3- and 5-year risk of hepatic decompensation (c-statistic 0.912 and 0.891, respectively) in the training cohort. The diagnostic accuracy remained consistent in the validation cohort with a c-statistic of 0.871 and 0.876 for hepatic decompensation at 3 and 5 years, respectively, and was superior to Fibrosis-4 in both cohorts ( p < 0.05). CONCLUSIONS: An MRE-based prediction model allows for accurate prediction of hepatic decompensation and assists in the risk stratification of patients with NAFLD.

Implications of drug intoxication on donor utilization and outcomes in liver transplantation.

INTRODUCTION: This study evaluates the implications of drug intoxication (DI) on donor utilization and outcomes in liver transplantation (LT). METHODS: The UNOS STAR database was evaluated for all potential donors and adult, first-time, whole LT between 2005 and 2019. Logistic regression analyses evaluated liver utilization; proportional hazards modeling assessed risk of 1-year graft loss. RESULTS: A total of 132 783 potential donors (10 205, 7.7% from DI), and 90 612 adult LT were identified (7490, 8.3% from DI). DI donors had median age 32 years (IQR 26-40 years, p < .001), were 42.6% female (n = 4346), and 15.5% were DCD donors (n = 1583). Utilization of DI donors changed over time, such that by 2015-2019 they were the most likely donor cause of death (COD) to be utilized. Among LT recipients, there were insignificant differences (<2% variance) in age, gender, ethnicity, and etiology of liver disease according to donor COD. Recipients with MELD scores >30 more frequently received grafts from donors with trauma (23.8%) and DI (21.8%) versus cardiovascular (20.0%) and CVA/stroke (19.9%, p < .001). Among DBD donors, DI-COD was associated with superior 1-year graft survival compared to donors from trauma (HR 1.172, 95% CI 1.057-1.300) and CVA/stroke (HR 1.404, 95% CI 1.264-1.561, p < .001). Donor COD was not significantly associated with 1-year graft loss among DCD donors. CONCLUSIONS: There is an increased likelihood of donor utilization when COD is drug overdose and an increased likelihood of 1-year graft survival compared to donors from trauma, CVA/stroke, and other COD.

Heterozygous midnolin knockout attenuates severity of nonalcoholic fatty liver disease in mice fed a Western-style diet high in fat, cholesterol, and fructose.

Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery that the knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this antitumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease (NAFLD) which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first functional global midnolin knockout mouse model. Although the overwhelming majority of global homozygous midnolin knockout mice demonstrated embryonic lethality, heterozygous knockout mice were observed to be similar to wild-type mice in their viability and were used to determine the effect of reduced midnolin expression on NAFLD. We found that global heterozygous midnolin knockout attenuated the severity of NAFLD in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism. Collectively, our results support a role for midnolin in regulating cholesterol/lipid metabolism in the liver. Thus, midnolin may represent a novel therapeutic target for NAFLD. Finally, our observation that midnolin was essential for survival underscores the broad importance of this gene beyond its role in liver biology.NEW & NOTEWORTHY We have developed and now report on the first functional global midnolin knockout mouse model. We found that global heterozygous midnolin knockout attenuated the severity of nonalcoholic fatty liver disease (NAFLD) in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism.

MRI-AST (MAST) Score Accurately Predicts Major Adverse Liver Outcome, Hepatocellular Carcinoma, Liver Transplant, and Liver-Related Death.

BACKGROUND & AIMS: The MRI-AST (MAST) score accurately identifies patients with at-risk nonalcoholic steatohepatitis, defined as nonalcoholic steatohepatitis with nonalcoholic fatty liver disease activity score ≥4 and fibrosis stage ≥2 at highest risk for disease progression. It is important to determine the robustness of the MAST score in predicting major adverse liver outcomes (MALO), hepatocellular carcinoma (HCC), liver transplant, and death. METHODS: This retrospective analysis included patients with nonalcoholic fatty liver disease from a tertiary care center who underwent magnetic resonance imaging proton density fat fraction, magnetic resonance elastography, and laboratory testing within 6 months from 2013 to 2022. Other causes of chronic liver disease were excluded. Hazard ratios between logit MAST and MALO (ascites, hepatic encephalopathy, or bleeding esophageal varices), liver transplant, HCC, or liver-related death were computed using a Cox proportional hazards regression model. We computed the hazard ratio of MALO or death associated with MAST scores 0.165-0.242 and 0.242-1.000, using MAST scores 0.000-0.165 as the reference group. RESULTS: Among 346 total patients, average age was 58.8 years with 52.9% females and 34.4% with type 2 diabetes. Average alanine aminotransferase was 50.7 IU/L (24.3-60.0 IU/L), aspartate aminotransferase was 38.05 IU/L (22.00-41.00 IU/L), platelets were 242.9 × 109/L (193.8-290.0 × 109/L), proton density fat fraction was 12.90% (5.90%-18.22%), and liver stiffness on magnetic resonance elastography was 2.75 kPa (2.07-2.90 kPa). Median follow-up was 29.5 months. Fourteen had adverse outcomes, including 10 MALO, 1 HCC, 1 liver transplant, and 2 liver-related deaths. The Cox regression of MAST versus adverse event rate had a hazard ratio of 2.01 (95% confidence interval, 1.59-2.54; P < .0001) for each 1 logit unit increases in MAST. The corresponding Harrell concordance statistic (C statistic) was 0.919 (95% confidence interval, 0.865-0.953). The MAST score ranges of 0.165-0.242 and 0.242-1.0, respectively, had adverse event rate hazard ratio of 7.75 (1.40-42.9; P = .0189) and 22.11 (6.59-74.2; P < .0000) relative to MAST 0-0.165. CONCLUSIONS: The MAST score noninvasively identifies at-risk nonalcoholic steatohepatitis and accurately predicts MALO, HCC, liver transplant, and liver-related death.

Clinical Characteristics and Outcomes of Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma in the United States.

BACKGROUND & AIMS: The extent to which nonalcoholic fatty liver disease (NAFLD) contributes to hepatocellular carcinoma (HCC) prevalence in contemporary practices and whether there are any etiologic differences in surveillance receipt, tumor stage, and overall survival (OS) remain unclear. We aimed to estimate the burden of NAFLD-related HCC and magnitude of associations with surveillance receipt, clinical presentation, and outcomes in a contemporary HCC cohort. METHODS: In a cohort of HCC patients from the Surveillance, Epidemiology and End Results-Medicare database between 2011 and 2015, we used multivariable logistic regression to identify factors associated with surveillance receipt, early-stage tumor detection, and curative treatment. Cox regression was used to identify factors associated with OS. RESULTS: Among 5098 HCC patients, NAFLD was the leading etiology, accounting for 1813 cases (35.6%). Compared with those with hepatitis C-related HCC, NAFLD was associated with lower HCC surveillance receipt (adjusted odds ratio, 0.22; 95% confidence interval [CI], 0.17-0.28), lower early-stage HCC detection (adjusted odds ratio, 0.49; 95% CI, 0.40-0.60), and modestly worse OS (adjusted hazard ratio, 1.20; 95% CI, 1.09-1.32). NAFLD subgroup analysis showed that early-stage HCC, absence of ascites/hepatic encephalopathy, surveillance, and curative treatment receipt were associated with improved OS. NAFLD patients with coexisting liver disease were more likely to have surveillance, early-stage detection, curative treatment, and improved OS than NAFLD patients without coexisting liver diseases. CONCLUSIONS: NAFLD is the leading etiology of HCC among Medicare beneficiaries. Compared with other etiologies, NAFLD was associated with lower HCC surveillance receipt, early-stage detection, and modestly poorer survival. Multifaceted interventions for improving surveillance uptake are needed to improve prognosis of patients with NAFLD-related HCC.

Racial and Ethnic Disparities in Years of Potential Life Loss Among Patients With Cirrhosis During the COVID-19 Pandemic in the United States.

INTRODUCTION: Our aim was to evaluate the impact of race/ethnicity on cirrhosis-related premature death during the COVID-19 pandemic. METHODS: We obtained cirrhosis-related death data (n = 872,965, January 1, 2012-December 31, 2021) from the US National Vital Statistic System to calculate age-standardized mortality rates and years of potential life lost (YPLL) for premature death aged 25-64 years. RESULTS: Significant racial/ethnic disparity in cirrhosis-related age-standardized mortality rates was noted prepandemic but widened during the pandemic, with the highest excess YPLL for the non-Hispanic American Indian/American Native (2020: 41.0%; 2021: 68.8%) followed by other minority groups (28.7%-45.1%), and the non-Hispanic White the lowest (2020: 20.7%; 2021: 31.6%). COVID-19 constituted >30% of the excess YPLLs for Hispanic and non-Hispanic American Indian/American Native in 2020, compared with 11.1% for non-Hispanic White. DISCUSSION: Ethnic minorities with cirrhosis experienced a disproportionate excess death and YPLLs in 2020-2021.

Immunotherapy and Transarterial Radioembolization Combination Treatment for Advanced Hepatocellular Carcinoma.

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.

CS-iCCA, A New Clinically Based Staging System for Intrahepatic Cholangiocarcinoma: Establishment and External Validation.

INTRODUCTION: Intrahepatic cholangiocarcinoma (iCCA) is a primary liver malignancy with poor prognosis. Current prognostic methods are most accurate for patients with surgically resectable disease. However, a significant proportion of patients with iCCA are not surgical candidates. We aimed to develop a generalizable staging system based on clinical variables to determine prognosis of all patients with iCCA. METHODS: The derivation cohort included 436 patients with iCCA seen between 2000 and 2011. For external validation, 249 patients with iCCA seen from 2000 to 2014 were enrolled. Survival analysis was performed to identify prognostic predictors. All-cause mortality was the primary end point. RESULTS: Eastern Cooperative Oncology Group status, tumor number, tumor size, metastasis, albumin, and carbohydrate antigen 19-9 were incorporated into a 4-stage algorithm. Kaplan-Meier estimates for 1-year survival were 87.1% (95% confidence interval [CI] 76.1-99.7), 72.7% (95% CI 63.4-83.4), 48.0% (95% CI 41.2-56.0), and 16% (95% CI 11-23.5), respectively, for stages I, II, III, and IV. Univariate analysis yielded significant differences in risk of death for stages II (hazard ratio [HR] 1.71; 95% CI 1.0-2.8), III (HR 3.32; 95% CI 2.07-5.31), and IV (HR 7.44; 95% CI 4.61-12.01) compared with stage I (reference). Concordance indices showed the new staging system was superior to the TNM staging for predicting mortality in the derivation cohort, P < 0.0001. In the validation cohort, however, the difference between the 2 staging systems was not significant. DISCUSSION: The proposed independently validated staging system uses nonhistopathologic data to successfully stratify patients into 4 stages. This staging system has better prognostic accuracy compared with the TNM staging and can assist physicians and patients in treatment of iCCA.

Racial and ethnic disparities in early treatment with immunotherapy for advanced HCC in the United States.

BACKGROUND AND AIMS: Immunotherapy has emerged as an effective treatment for patients with advanced-stage HCC. We aimed to investigate the efficacy of immunotherapy for advanced HCC in a nationwide cohort and racial and ethnic disparities in access to immunotherapy. APPROACH AND RESULTS: We used the US National Cancer Database to identify patients with tumor-node-metastasis stage 3 or 4 HCC between 2017 and 2018. We performed multivariable Cox regression to identify factors associated with overall survival (OS) and logistic regression to identify factors associated with receipt of immunotherapy. Of the 3,990 patients treated for advanced HCC, 3,248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR: 0.76, 95% CI: 0.65-0.88) after adjusting for covariates. There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted OR [aOR]: 0.63, 95% CI: 0.46-0.83) and Black patients (aOR: 0.71, 95% CI: 0.54-0.89) less likely to receive immunotherapy compared with White patients. There was a significant interaction between race-ethnicity and facility type, with higher disparity observed in nonacademic centers (interaction p = 0.004). CONCLUSIONS: Immunotherapy was associated with improved OS compared with chemotherapy in advanced HCC. There are significant disparities in early access to immunotherapy, likely due to differential access to clinical trials and experimental therapies. A comprehensive approach to monitoring and eliminating racial-ethnic disparities in the management of advanced HCC is urgently needed.

Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has one of the highest mortality rates among solid cancers. Late diagnosis and a lack of efficacious treatment options contribute to the dismal prognosis of HCC. Immune checkpoint inhibitor (ICI)-based immunotherapy has presented a new milestone in the treatment of cancer. Immunotherapy has yielded remarkable treatment responses in a range of cancer types including HCC. Based on the therapeutic effect of ICI alone (programmed cell death (PD)-1/programmed death-ligand1 (PD-L)1 antibody), investigators have developed combined ICI therapies including ICI + ICI, ICI + tyrosine kinase inhibitor (TKI), and ICI + locoregional treatment or novel immunotherapy. Although these regimens have demonstrated increasing treatment efficacy with the addition of novel drugs, the development of biomarkers to predict toxicity and treatment response in patients receiving ICI is in urgent need. PD-L1 expression in tumor cells received the most attention in early studies among various predictive biomarkers. However, PD-L1 expression alone has limited utility as a predictive biomarker in HCC. Accordingly, subsequent studies have evaluated the utility of tumor mutational burden (TMB), gene signatures, and multiplex immunohistochemistry (IHC) as predictive biomarkers. In this review, we aim to discuss the current state of immunotherapy for HCC, the results of the predictive biomarker studies, and future direction.

Disparities in curative treatments and outcomes for early stage intrahepatic cholangiocarcinoma in the United States.

BACKGROUND: Curative surgical treatments afford the best prognosis for patients with intrahepatic cholangiocarcinoma (iCCA); however, the comparative effectiveness of treatment options and factors associated with curative treatment receipt for early stage iCCA remain unknown. METHODS: The authors identified patients who were diagnosed with early stage iCCA, defined as a unifocal tumor <3 cm, during 2004-2018 from the National Cancer Database. Multivariable logistic and Cox regression analyses were used to identify the factors associated with curative treatment and overall survival (OS), respectively. RESULTS: The proportion of patients with early stage iCCA increased from 4.5% in 2004 to 7.3% in 2018, with the odds of early stage detection increasing by 3.1% per year (odds ratio [OR], 1.031; 95% CI, 1.015-1.049). Of 1093 patients who had early stage iCCA, 464 (42.5%) underwent resection, 113 (10.3%) underwent ablation, 62 (5.7%) underwent liver transplantation, and 454 (41.5%) received noncurative treatments. Hispanic patients (adjusted OR [aOR], 0.57; 95% CI, 0.33-0.97) and Black patients (aOR, 0.47; 95% CI, 0.28-0.77) were less likely to receive curative treatments than White patients. Compared with patients who underwent surgical resection, those who underwent liver transplantation had a trend toward improved OS (adjusted hazard ratio [aHR], 0.63; 95% CI, 0.37-1.08), whereas those who underwent local ablation (aHR, 1.39; 95% CI, 1.01-1.92) and noncurative treatments (aHR, 3.97; 95% CI, 3.24-4.88) experienced worse OS. CONCLUSIONS: More than one third of patients with early stage iCCA did not receive curative treatment, with Hispanic and Black patients being less likely to receive curative treatments than White patients. Surgical resection and liver transplantation were associated with improved survival compared with local ablation. Future studies should investigate disparities in curative treatment receipt and outcomes for early stage iCCA.

Association between sustained virological response and clinical outcomes in patients with hepatitis C infection and hepatocellular carcinoma.

BACKGROUND: Sustained viral response (SVR) improves survival for patients with hepatitis C (HCV) and hepatocellular carcinoma (HCC) after curative treatment; however, the benefit of SVR in those with active HCC with a significant competing risk of mortality is unknown. This study aimed to evaluate the association between SVR and outcomes in patients with active HCC. METHODS: The authors performed a multicenter, retrospective cohort study including consecutive adults with HCV cirrhosis and treatment-naive HCC diagnosed between 2014 and 2018. Patients were stratified into two groups: active viremia (n = 431) and SVR before HCC diagnosis (n = 135). All patients underwent nonsurgical therapy as their initial treatment and were followed until liver transplantation, last follow-up, or death. The primary outcome was incident or worsening hepatic decompensation within 6 months and the secondary outcome was overall survival. All analyses used inverse probability of treatment weights (IPTW) to account for differences between the nonrandomized cohorts. RESULTS: Post-SVR patients had significantly lower odds of hepatic decompensation compared to viremic patients (odds ratio [OR], 0.18; 95% confidence interval [CI], 0.06-0.59). Results were consistent among subgroups of patients with Child Pugh A cirrhosis (OR, 0.22; 95% CI, 0.04-0.77), Barcelona Clinic Liver Cancer stage B/C HCC (OR, 0.20; 95% CI, 0.04-0.65), and those receiving nonablative HCC therapies (OR, 0.21; 95% CI, 0.07-0.67). However, in IPTW multivariable Cox regression, SVR was not associated with improved survival (hazard ratio, 0.79; 95% CI, 0.56-1.12). CONCLUSIONS: Patients with HCV-related HCC and SVR are less likely to experience hepatic decompensation than viremic patients, suggesting patients with HCC who are undergoing nonsurgical therapies may benefit from DAA treatment.

MRI-based (MAST) score accurately identifies patients with NASH and significant fibrosis.

BACKGROUND & AIMS: Among the large population of patients with non-alcoholic fatty liver disease (NAFLD), identifying those with fibrotic non-alcoholic steatohepatitis (Fibro-NASH) is a clinical priority, as these patients are at the highest risk of disease progression and will benefit most from pharmacologic treatment. MRI-based proton density fat fraction (MRI-PDFF) and MR elastography (MRE) can risk-stratify patients with NAFLD by assessing steatosis and fibrosis, respectively. We developed a highly specific MRI-based score to identify patients with Fibro-NASH. METHODS: This analysis included derivation (n = 103) and validation (n = 244) cohorts of patients who underwent MRI, liver biopsy, transient elastography, and laboratory testing for NAFLD from 2016-2020 in 2 tertiary care centers. To identify Fibro-NASH, a formula was developed based on MRI-PDFF, MRE, and a third variable with highest balanced accuracy per logistic regression. The MRI-aspartate aminotransferase (MAST) score was created and compared to NAFLD fibrosis (NFS), Fibrosis-4 (FIB-4), and FibroScan-aspartate aminotransferase (FAST) scores. RESULTS: The MAST score demonstrated high performance and discrimination in the validation cohort (AUC 0.93; 95% CI 0.88-0.97). In the validation cohorts, the 90% specificity cut-off of 0.242 corresponded to a sensitivity of 75.0%, positive predictive value (PPV) of 50.0% and negative predictive value (NPV) of 96.5%, whereas the 90% sensitivity cut-off of 0.165 corresponded to a specificity of 72.2%, PPV of 29.4%, and NPV of 98.1%. Compared to NFS and FIB-4, MAST resulted in fewer patients having indeterminate scores and an overall higher AUC. Compared to FAST, MAST exhibited a higher AUC and overall better discrimination. CONCLUSION: The MAST score is an accurate, MRI-serum-based score that outperforms previous scores in non-invasively identifying patients at higher risk of Fibro-NASH. LAY SUMMARY: Identifying patients with non-alcoholic steatohepatitis and significant fibrosis - who need treatment and are at risk of clinical liver-related outcomes - is a clinical priority. We developed a more accurate score using MRI-based technologies and a laboratory blood test (aspartate aminotransferase) that outperforms previous non-invasive scores for the identification of patients at higher risk of liver disease progression.