Brief alcohol interventions are underutilized in persons with nonalcohol-associated chronic liver diseases.

BACKGROUND: Brief alcohol interventions use patient-provider communication to promote alcohol cessation. We characterized the receipt of this intervention in chronic liver disease (CLD). METHODS: We surveyed patients with CLD for weekly drinking patterns and examined associations with patient-provider communication receipt. RESULTS: Among 840 participants, 82.1% and 56.5% reported ≥1 standard drink weekly and excessive alcohol consumption, respectively. Patient-provider communication was lower in noncirrhotic (adjusted odds ratio:0.34, 95% CI: 0.22-0.54) and nonalcohol-associated CLD (adjusted odds ratio: 0.22, 95% CI: 0.15-0.34) among individuals drinking ≥1 standard drink weekly, and similarly in noncirrhotic CLD (adjusted odds ratio: 0.45, 95% CI: 0.21-0.95) among those with excessive drinking. CONCLUSIONS: Brief alcohol interventions are underutilized in noncirrhotic and nonalcohol-associated CLD.

Defining the Role of Social Vulnerability in Treatment and Survival in Localized Colon Cancer: A Retrospective Cohort Study.

OBJECTIVE: To determine whether variations in Social Vulnerability Index (SVI) are associated with disparities in colon cancer surgery and mortality. SUMMARY BACKGROUND DATA: Colon cancer mortality is influenced by health care access, which is affected by individual and community-level factors. Prior studies have not used the SVI to compare surgical access and survival in localized colon cancer patients. Further, it is unclear if those above 65 years are more vulnerable to variations in SVI. METHODS: We queried the Texas and California Cancer Registries from 2004-2017 to identify patients with localized colonic adenocarcinoma and categorized patients into <65 and ≥65 years. Our outcomes were survival and access to surgical intervention. The independent variable was census tract social vulnerability index, with higher scores indicating more social vulnerability. We used multivariable logistic regression and Cox proportional hazards for analysis. RESULTS: We included 73,923 patients with a mean age of 68.6 years (SD 13.0), mean SVI of 47.2 (SD 27.6), and 51.1% male. After adjustment, increasing SVI was associated with reduced odds of undergoing surgery (OR 0.996; 95% CI 0.995-0.997; P < 0.0001 and increased mortality (HR 1.002; 95% CI 1.001-1.002; P < 0.0001). Patients < 65 years were more sensitive to variation in SVI. CONCLUSIONS: Increased social vulnerability was associated with reduced odds of receiving surgery for early-stage colon cancer as well as increased mortality. These findings amplify the need for policy changes at the local, state, and federal level to address community-level vulnerability to improve access to surgical care and reduce mortality.

The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial.

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.

Racial and ethnic disparities in alcohol-associated liver disease in the United States: A systematic review and meta-analysis.

BACKGROUND: Alcohol-associated liver disease (ALD), encompassing alcohol-associated hepatitis and alcohol-associated cirrhosis, is rising in the United States. Racial and ethnic disparities are evident within ALD; however, the precise nature of these disparities is poorly defined. METHODS: We conducted a search of the PubMed/MEDLINE and EMBASE databases to identify studies published from inception through September 2023 that reported ALD incidence, prevalence, and mortality within the United States, stratified by race and ethnicity. We calculated pooled prevalence and incidence by race and ethnicity, including risk ratios and ORs for ALD pooled prevalence and alcohol-associated hepatitis/alcohol-associated cirrhosis pooled proportions, and OR for ALD mortality using the DerSimonian and Laird method for random-effect models. RESULTS: We identified 25 relevant studies (16 for quantitative meta-analysis), comprising 76,867,544 patients. ALD prevalence was highest in Hispanic (4.5%), followed by White (3.1%) and Black (1.4%) individuals. Pooled risk ratios of ALD prevalence were 1.64 (95% CI: 1.12-2.39) for Hispanic and 0.59 (95% CI: 0.35-0.87) for Black compared to White individuals. Mortality among those with ALD did not significantly differ between White and Hispanic (OR: 1.54, 95% CI: 0.9-2.5; I2=0%), Black (OR: 1.2, 95% CI: 0.8-1.6; I2=0%), or Native American (OR: 2.41, 95% CI: 0.9-2.9) individuals, while there was a significant difference between White and Asian (OR: 0.1; 95% CI: 0.03-0.5) individuals. Most data were cross-sectional and assessed to be of poor or fair quality. CONCLUSIONS: Differences were observed in ALD epidemiology, including higher prevalence among Hispanic and lower prevalence among Black individuals, although there were smaller differences in ALD mortality. Differences in ALD prevalence and prognosis remain poorly defined based on existing data, highlighting a need for higher-quality epidemiological studies in this area.

Screening Implications for Distribution of Colorectal Cancer Subsite by Age and Role of Flexible Sigmoidoscopy.

Objectives: The effectiveness of colonoscopy to reduce colorectal cancer (CRC) mortality is extrapolated from cohort studies in the absence of randomized controlled trial (RCT) data, whereas flexible sigmoidoscopy is supported by RCT data and may be easier to implement in practice. We characterized the anatomic distribution of CRC to determine the proportion that is visible with sigmoidoscopy. Methods: Patients with a primary diagnosis of colorectal adenocarcinoma were identified in the Surveillance, Epidemiology, and End Results program (2000-2020). Tumors from the rectum to the descending colon were categorized as visible by sigmoidoscopy, whereas more proximal tumors required colonoscopy. Differential prognosis between tumor locations, stratified by age groups and stage, was assessed using the overall restricted mean survival time (RMST) at 2, 5, and 10 years. Results: Among 309,466 patients, 58% had tumors visible by sigmoidoscopy, including 73% of those under age 50 (OR 2.10, 95% CI 2.03-2.16 age < 45, OR 2.20, 95% CI 2.13-2.27 age 45-49 versus age ≥ 50). Male sex (OR 1.54, 95% CI 1.51-1.56) and Asian or Pacific Islander race (OR 1.60, 95% CI 1.56-1.64) were also positively associated with tumors visualizable by sigmoidoscopy. Across age groups, for local disease, RMST was comparable for tumors visible versus not visible on sigmoidoscopy. For regional and metastatic cancer, patients with tumors visible by sigmoidoscopy had improved RMST versus those with more proximal tumors. Conclusions: 58% of CRC arises in locations visible by flexible sigmoidoscopy. Flexible sigmoidoscopy should be considered as a viable option for CRC screening, particularly in younger patients unwilling or unable to undergo colonoscopy.

Pan-cancer molecular signatures connecting aspartate transaminase (AST) to cancer prognosis, metabolic and immune signatures.

Background: Serum aspartate transaminase (sAST) level is used routinely in conjunction with other clinical assays to assess liver health and disease. Increasing evidence suggests that sAST is associated with all-cause mortality and has prognostic value in several cancers, including gastrointestinal and urothelial cancers. Here, we undertake a systems approach to unravel molecular connections between AST and cancer prognosis, metabolism, and immune signatures at the transcriptomic and proteomic levels. Methods: We mined public gene expression data across multiple normal and cancerous tissues using the Genotype Tissue Expression (GTEX) resource and The Cancer Genome Atlas (TCGA) to assess the expression of genes encoding AST isoenzymes (GOT1 and GOT2) and their association with disease prognosis and immune infiltration signatures across multiple tumors. We examined the associations between AST and previously reported pan-cancer molecular subtypes characterized by distinct metabolic and immune signatures. We analyzed human protein-protein interaction networks for interactions between GOT1 and GOT2 with cancer-associated proteins. Using public databases and protein-protein interaction networks, we determined whether the subset of proteins that interact with AST (GOT1 and GOT2 interactomes) are enriched with proteins associated with specific diseases, miRNAs and transcription factors. Results: We show that AST transcript isoforms (GOT1 and GOT2) are expressed across a wide range of normal tissues. AST isoforms are upregulated in tumors of the breast, lung, uterus, and thymus relative to normal tissues but downregulated in tumors of the liver, colon, brain, kidney and skeletal sarcomas. At the proteomic level, we find that the expression of AST is associated with distinct pan-cancer molecular subtypes with an enrichment of specific metabolic and immune signatures. Based on human protein-protein interaction data, AST physically interacts with multiple proteins involved in tumor initiation, suppression, progression, and treatment. We find enrichments in the AST interactomes for proteins associated with liver and lung cancer and dermatologic diseases. At the regulatory level, the GOT1 interactome is enriched with the targets of cancer-associated miRNAs, specifically mir34a - a promising cancer therapeutic, while the GOT2 interactome is enriched with proteins that interact with cancer-associated transcription factors. Conclusions: Our findings suggest that perturbations in the levels of AST within specific tissues reflect pathophysiological changes beyond tissue damage and have implications for cancer metabolism, immune infiltration, prognosis, and treatment personalization.

Association between bridging therapy and posttransplant outcomes in patients with HCC within Milan criteria: A systematic review and meta-analysis.

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.

Artificial intelligence in liver cancer research: a scientometrics analysis of trends and topics.

Background and aims: With the rapid growth of artificial intelligence (AI) applications in various fields, understanding its impact on liver cancer research is paramount. This scientometrics project aims to investigate publication trends and topics in AI-related publications in liver cancer. Materials and Methods: We employed a search strategy to identify AI-related publications in liver cancer using Scopus database. We analyzed the number of publications, author affiliations, and journals that publish AI-related publications in liver cancer. Finally, the publications were grouped based on intended application. Results: We identified 3950 eligible publications (2695 articles, 366 reviews, and 889 other document types) from 1968 to August 3, 2023. There was a 12.7-fold increase in AI-related publications from 2013 to 2022. By comparison, the number of total publications on liver cancer increased by 1.7-fold. Our analysis revealed a significant shift in trends of AI-related publications on liver cancer in 2019. We also found a statistically significant consistent increase in numbers of AI-related publications over time (tau = 0.756, p < 0.0001). Eight (53%) of the top 15 journals with the most publications were radiology journals. The largest number of publications were from China (n=1156), the US (n=719), and Germany (n=236). The three most common publication categories were "medical image analysis for diagnosis" (37%), "diagnostic or prognostic biomarkers modeling & bioinformatics" (19%), and "genomic or molecular analysis" (18%). Conclusion: Our study reveals increasing interest in AI for liver cancer research, evidenced by a 12.7-fold growth in related publications over the past decade. A common application of AI is in medical imaging analysis for various purposes. China, the US, and Germany are leading contributors.

Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma.

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.

Implementation of a Hepatocellular Carcinoma Surveillance Program in a Community-Based Integrated Health System in Patients With Hepatitis C Cirrhosis.

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.

Serum biomarker signature is predictive of the risk of hepatocellular cancer in patients with cirrhosis.

BACKGROUND: Inflammatory and metabolic biomarkers have been associated with hepatocellular cancer (HCC) risk in phases I and II biomarker studies. We developed and internally validated a robust metabolic biomarker panel predictive of HCC in a longitudinal phase III study. METHODS: We used data and banked serum from a prospective cohort of 2266 adult patients with cirrhosis who were followed until the development of HCC (n=126). We custom designed a FirePlex immunoassay to measure baseline serum levels of 39 biomarkers and established a set of biomarkers with the highest discriminatory ability for HCC. We performed bootstrapping to evaluate the predictive performance using C-index and time-dependent area under the receiver operating characteristic curve (AUROC). We quantified the incremental predictive value of the biomarker panel when added to previously validated clinical models. RESULTS: We identified a nine-biomarker panel (P9) with a C-index of 0.67 (95% CI 0.66 to 0.67), including insulin growth factor-1, interleukin-10, transforming growth factor ß1, adipsin, fetuin-A, interleukin-1 ß, macrophage stimulating protein α chain, serum amyloid A and TNF-α. Adding P9 to our clinical model with 10 factors including AFP improved AUROC at 1 and 2 years by 4.8% and 2.7%, respectively. Adding P9 to aMAP score improved AUROC at 1 and 2 years by 14.2% and 7.6%, respectively. Adding AFP L-3 or DCP did not change the predictive ability of the P9 model. CONCLUSIONS: We identified a panel of nine serum biomarkers that is independently associated with developing HCC in cirrhosis and that improved the predictive ability of risk stratification models containing clinical factors.

Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

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.

Accessibility to ERCP-performing hospitals among patients with pancreatic cancer living in SEER regions.

BACKGROUND AND AIMS: The two most common interventions used to treat painless jaundice from pancreatic cancer are endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic biliary drainage (PTBD). Our study aimed to characterize the geographic distribution of ERCP-performing hospitals among patients with pancreatic cancer in the United States and the association between geographic accessibility to ERCP-performing hospitals and biliary interventions patients receive. METHODS: This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database for pancreatic cancer from 2005 to 2013. Multilevel models were used to examine the association between accessibility to ERCP hospitals within a 30- and 45-min drive from the patient's residential ZIP Code and the receipt of ERCP treatment. A two-step floating catchment area model was used to calculate the measure of accessibility based on the distribution across SEER regions. RESULTS: 7464 and 782 patients underwent ERCP and PTBD, respectively, over the study period. There were 808 hospitals in which 8246 patients diagnosed with pancreatic cancer in SEER regions from 2005 to 2013 received a procedure. Patients with high accessibility within both 30- and 45-min drive to an ERCP-performing hospital were more likely to receive an ERCP (30-min adjusted odds ratio [aOR]: 1.53, 95% confidence interval [CI]: 1.17-2.01; 45-min aOR: 1.31, 95% CI: 1.01-1.70). Furthermore, in the adjusted model, Black patients (vs. White) and patients with stage IV disease were less likely to receive ERCP than PTBD. CONCLUSIONS: Patients with pancreatic cancer and high accessibility to an ERCP-performing hospital were more likely to receive ERCP. Disparities in the receipt of ERCP persisted for Black patients regardless of their access to ERCP-performing hospitals.

Racial and Ethnic Disparities in Hepatocellular Carcinoma Treatment Receipt in the United States: A Systematic Review and Meta-Analysis.

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.

A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.

Effect of Hospital Cancer Designation on use of Multimodal Therapy and Survival of Metastatic Colorectal Cancer: A State-Wide Analysis.

BACKGROUND: Stage IV colorectal cancer (CRC) often requires multidisciplinary approach. However, multimodal treatment options (receipt of > 1 type of treatment) may not be uniformly delivered across health systems. We characterized the association between center-level cancer center designation and receipt of multimodal treatment and survival. METHODS: The Texas Cancer Registry was used to identify patients diagnosed with stage IV CRC from 2004-2017. We identified those who received care at either: a National Cancer Institute-designated (NCI-D), an American College of Surgeons-Commission on Cancer-designated (ACS-D), or an undesignated facility. We used multivariable logistic regression and Cox regression for analysis to assess receipt of one or more treatment modality and 5-year overall survival. RESULTS: Of 19,355 patients with stage IV CRC, 2955 (15%) received care at an NCI-D facility and 5871 (30%) received multimodal therapy. Both NCI-D (odds ratio [OR] 1.64; 95% confidence interval [CI] 1.49-1.81) and ACS-D (OR 1.37; 95% CI 1.27-1.48) were associated with increased likelihood of multimodal therapy compared with undesignated centers. NCI-D also was associated with significantly improved survival (hazard ratio [HR] 0.74; 95% CI 0.70-0.78), although ACS-D was associated with a modest improvement in survival (HR 0.95; 95% CI 0.92-0.99). Receipt of multimodal therapy was strongly associated with improved survival (HR 0.61; 95% CI 0.59-0.63). CONCLUSIONS: In patients with stage IV CRC, treatment at ACS-D and NCI-D facilities was associated with increased use of multimodality therapy and improved survival. However, only a small proportion of patients have access to these specialized centers, highlighting a need for expanded access to multimodal therapies at other centers.

Proportion of Time Covered by Hepatocellular Carcinoma 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.

Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours.

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.