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.

Racial and ethnic differences and the role of unfavorable social determinants of health across steatotic liver disease subtypes in the United States.

BACKGROUND: The global liver community established a more precise criteria to characterize steatotic liver disease (SLD), specifically metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated and alcohol-associated liver disease (MetALD). We aimed to estimate the burden of SLD subtypes and unfavorable social determinants of health (SDOH) in US adults and whether clinical and social factors drive disparities across racial/ethnic subgroups. METHODS: We evaluated 4263 persons aged 20 years or older from the National Health and Nutrition Examination Survey 2017-2018. We estimated the weighted age-adjusted prevalence and severity of SLD, examined the prevalence of SDOH across SLD subtypes, and performed stepwise regression analysis to evaluate associations between race/ethnicity and SLD, accounting for metabolic risks, alcohol use, and SDOH. RESULTS: Hispanic adults had the highest prevalence of MASLD (22.3%), MASLD-predominant MetALD (10.3%), alcohol-associated liver disease (ALD)-predominant MetALD (5.6%), and ALD (5.4%). Hispanic adults with MASLD had the highest prevalence of high-risk metabolic dysfunction-associated steatohepatitis (18.0%) and advanced fibrosis (21.1%), whereas non-Hispanic (NH) White adults with MetALD had the highest prevalence of high-risk metabolic dysfunction-associated steatohepatitis (19.3%), advanced fibrosis (19.5%), and cirrhosis (8.1%). Adults with ALD-predominant MetALD and ALD had an increased burden of unfavorable SDOH than those with MASLD, particularly food insecurity, limited health care access, and single living. In stepwise regression, the odds of SLD in Hispanic adults decreased after adjusting for metabolic risks (OR 1.40, 95% CI, 1.06-1.84) and alcohol use (OR 1.36, 95% CI, 1.01-1.82). Differences did not persist after adjusting for cumulative SDOH and nativity status (OR 1.22, 95% CI, 0.89-1.68). CONCLUSIONS: We found substantial disparities in the burden of unfavorable SDOH across SLD subtypes, particularly among those with ALD-predominant MetALD and ALD. Population-based approaches targeting SDOH may mitigate racial/ethnic differences among US adults with SLD.

Decreasing incidence of hepatocellular carcinoma among most racial groups: SEER-22, 2000-2019.

BACKGROUND: Hepatocellular carcinoma (HCC) incidence was rising in the United States. Previously, using data collected by the Surveillance, Epidemiology, and End Results (SEER) Program through 2017, we found that overall incidence had begun to decline, although not in Black and American Indian/Alaska Native (AI/AN) populations. Utilizing expanded SEER data encompassing ~50% of the population, we examined secular trends and demographic differences in HCC incidence through 2019. METHODS: We included cases of HCC diagnosed in adults aged ≥20 years residing in SEER-22 registry areas. We examined case counts, incidence rates (per 100,000 person-years), annual percent changes (APCs), and calendar years when APCs changed significantly. RESULTS: HCC incidence increased from 5.56 in 2000 to 8.89 in 2009 (APC, 5.17%), then rose more slowly during 2009-2015 (APC, 2.28%). After peaking at 10.03 in 2015, incidence fell to 9.20 in 2019 (APC, -2.26%). In Asian/Pacific Islanders (A/PI), the decline began in 2007 and accelerated in 2015 (APCs: 2007-2015, -1.84%; 2015-2019, -5.80%). In 2014, incidence began to fall in the White (APC: 2014-2019, -1.11%) and Hispanic populations (APC: 2014-2019, -1.72%). In 2016, rates began to fall in Black individuals (APC: 2016-2019, -6.05%). In the AI/AN population, incidence was highest in 2017, although the subsequent decline was not statistically significant. In 2019, population-specific rates were: White, 6.94; Black, 10.74; A/PI, 12.11; AI/AN, 14.56; Hispanic, 15.48. CONCLUSION: HCC incidence is now decreasing in most US racial/ethnic populations, including among Black individuals. The onset of decline differed among racial/ethnic groups and wide disparities in HCC rates remain.

Incidence and Risk Factors for Hepatocellular Carcinoma in Cirrhosis: The Multicenter Hepatocellular Carcinoma Early Detection Strategy (HEDS) Study.

BACKGROUND & AIMS: Worldwide, hepatocellular carcinoma (HCC) is a common malignancy. We aimed to prospectively determine the incidence and risk factors of HCC in a U.S. METHODS: The multicenter Hepatocellular Carcinoma Early Detection Strategy study of the National Institutes of Health prospectively enrolled patients with cirrhosis who underwent standard surveillance for HCC. Demographics, medical and family history, etiology of liver disease, and clinical features were evaluated for associations with HCC. RESULTS: Between April 10, 2013 and December 31, 2021, 1723 patients were enrolled and confirmed eligible. During median follow-up of 2.2 years (range, 0-8.7 years), there were 109 incident cases of HCC for an incidence rate of 2.4 per 100 person-years: 88 (81%) patients with very early/early Barcelona Clinic Liver Cancer stage (0, A), 20 (18%) intermediate stage (B), and 1 (1%) unknown stage. Risk factor analyses were restricted to 1325 patients, including 95 incident HCC, with at least 6 months of follow-up. The majority were men (53.2%), obese or severely obese (median body mass index, 30.2 kg/m2), and white (86.3%); 42.0% had history of hepatitis C virus infection, 20.7% had alcoholic liver disease, and 24.9% had nonalcoholic fatty liver disease. Fourteen risk factors for HCC were significant (P < .05) in univariate analyses, and a multivariate subset was selected using stepwise logistic regression. The multivariate subset contained gender (P < .001; male; odds ratio [OR], 2.47; 95% confidence interval [CI], 1.54-4.07), years with cirrhosis (P = .004; OR, 1.06; 95% CI, 1.02-1.1), family history of liver cancer (P = .02; yes; OR, 2.69; 95% CI, 1.11-5.86), age (per 5 years; P = .02; OR, 1.17; 95% CI, 1.03-1.33), obesity (P = .02; yes; OR, 1.7; 95% CI, 1.08-2.73), aspartate aminotransferase (log(1+AST); P = .06; OR, 1.54; 95% CI, 0.97-2.42), alpha-fetoprotein (log(1+AFP); P = .07; OR, 1.32; 95% CI, 0.97-1.77), and albumin (P = .10; OR, 0.7; 95% CI, 0.46-1.07). CONCLUSIONS: Thus far, this is the largest prospective and geographically diverse study of a U.S. cohort of patients with cirrhosis that validates known risk factors for HCC (gender, age, obesity, years with cirrhosis, family history of liver cancer, baseline AFP, albumin, and AST). The incidence of HCC was 2.4% per 100 person-years.

Risk Stratification Model for Hepatocellular Cancer in Patients With Cirrhosis.

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.

Risk stratification for hepatocellular cancer among patients with cirrhosis using a hepatic fat polygenic risk score.

BACKGROUND: Polygenic risk scores (PRS) hold the promise to refine prognostication in hepatocellular cancer (HCC). The few available HCC PRS include germline risk variants identified among individuals of mostly European ancestry, but data are lacking on the transportability of these PRS in multiethnic U.S patients with cirrhosis from multiple etiologies. METHODS: We used data from 1644 patients with cirrhosis enrolled in two prospective cohort studies in the U.S. Patients were followed until HCC diagnosis, death, liver transplantation, or last study visit through June 30, 2021. The high-risk variants in PNPLA3-MBOAT7-TM6SF2-GCKR were combined in a PRS and we evaluated its association with HCC. Discriminatory accuracy was assessed using the C-statistic. RESULTS: During 4,759 person-years of follow-up, 93 patients developed HCC. Mean age was 59.8 years, 68.6% were male, 27.2% Hispanic, 25.1% non-Hispanic Black, 25.7% had NAFLD, 42.1% had heavy alcohol use, and 19.5% had active HCV. HCC risk increased by 134% per unit increase in PRS (HR = 2.30; 95% CI, 1.35-3.92). Compared to cirrhosis patients in the lowest tertile of the PRS, those in the highest tertile had 2-fold higher risk of HCC (HR = 2.05; 95% CI, 1.22-3.44). The PRS alone had modest discriminatory ability (C-statistic = 0.58; 95% CI, 0.52-0.63); however, adding PRS to a predictive model with traditional HCC risk factors had a C-statistic of 0.70 (95% CI, 0.64-0.76), increasing from 0.68 without the PRS (p = 0.0012). CONCLUSIONS: Our findings suggest that PRS may enhance risk prediction for HCC in contemporary U.S. cirrhosis patients.

Risk factors for HCC in contemporary cohorts of patients with cirrhosis.

BACKGROUND AND AIMS: Etiological risk factors for cirrhosis have changed in the last decade. It remains unclear to what extent these trends in cirrhosis risk factors have changed HCC risk. APPROACH AND RESULTS: We used data from two contemporary, prospective multiethnic cohorts of patients with cirrhosis: the Texas Hepatocellular Carcinoma Consortium Cohort and the Houston Veterans Administration Cirrhosis Surveillance Cohort. Patients with cirrhosis were enrolled from seven US centers and followed until HCC diagnosis, transplant, death, or June 30, 2021. We calculated the annual incidence rates for HCC and examined the effects of etiology, demographic, clinical, and lifestyle factors on the risk of HCC. We included 2733 patients with cirrhosis (mean age 60.1 years, 31.3% women). At enrollment, 19.0% had active HCV, 23.3% had cured HCV, 16.1% had alcoholic liver disease, and 30.1% had NAFLD. During 7406 person-years of follow-up, 135 patients developed HCC at an annual incidence rate of 1.82% (95% CI, 1.51-2.13). The annual HCC incidence rate was 1.71% in patients with cured HCV, 1.32% in patients with alcoholic liver disease, and 1.24% in patients with NAFLD cirrhosis. Compared to patients with NAFLD, the risk of progression to HCC was 2-fold higher in patients with cured HCV (HR, 2.04; 95% CI, 1.24-3.35). Current smoking (HR, 1.63; 95% CI, 1.01-2.63) and overweight/obesity (HR, 1.79; 95% CI, 1.08-2.95) were also associated with HCC risk. CONCLUSIONS: HCC incidence among patients with cirrhosis was lower than previously reported. HCC risk was variable across etiologies, with higher risk in patients with HCV cirrhosis and lower risk in those with NAFLD cirrhosis. Current smoking and overweight/obesity increased HCC risk across etiologies.

ACR Appropriateness Criteria® Management of Liver Cancer: 2022 Update.

The treatment and management of hepatic malignancies can be complex because it encompasses a variety of primary and metastatic malignancies and an assortment of local and systemic treatment options. When to use each of these treatments is critical to ensure the most appropriate care for patients. Interventional radiologists have a key role to play in the delivery of a variety of liver directed treatments including percutaneous ablation, transarterial embolization with bland embolic particles alone, transarterial chemoembolization (TACE) with injection of a chemotherapeutic emulsion, and transarterial radioembolization (TARE). Based on 9 clinical variants, the appropriateness of each treatment is described in this document. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Clinical outcomes of patients with Liver Imaging Reporting and Data System 3 or Liver Imaging Reporting and Data System 4 observations in patients with cirrhosis: A systematic review.

Patients with indeterminate liver nodules, classified as LR-3 and LR-4 observations per the Liver Imaging Reporting and Data System, are at risk of developing hepatocellular carcinoma (HCC), but risk estimates remain imprecise. We conducted a systematic review of Ovid MEDLINE, EMBASE, and Cochrane databases from inception to December 2021 to identify cohort studies examining HCC incidence among patients with LR-3 or LR-4 observations on computed tomography (CT) or magnetic resonance imaging (MRI). Predictors of HCC were abstracted from each study, when available. Of 13 total studies, nine conducted LR-3 observation-level analyses, with the proportions of incident HCC ranging from 1.2% to 12.5% at 12 months and 4.2% to 44.4% during longer study follow-up. Among three studies with patient-level analyses, 8%-22.2% of patients with LR-3 lesions developed LR-4 observations and 11.1%-24.5% developed HCC. Among nine studies conducting LR-4 observation-level analyses, incident HCC ranged from 30.8% to 44.0% at 12 months and 30.9% to 71.0% during study follow-up; conversely, 6%-42% of observations were downgraded to LR-3 or lower. Patient-level factors associated with HCC included older age, male sex, higher alpha-fetoprotein levels, viral etiology, and prior history of HCC; observation-level factors included maximum diameter, threshold growth, T2 hyperintensity, and visibility on ultrasound. Studies were limited by small sample sizes, inclusion of patients with prior HCC, short follow-up duration, and failure to account for clustering of observations in patients or competing risks of transplantation and death. LR-3 and LR-4 observations have elevated but variable risks of HCC. Higher quality studies are necessary to identify high-risk patients who warrant close CT or MRI-based follow-up.

Severe Cholestatic Jaundice (Stauffer Syndrome) as a Rare Paraneoplastic Manifestation in Adrenocortical Carcinoma.

Background: Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. While ACC can be associated with adrenal hormone excess syndromes, classic paraneoplastic syndromes are rarely seen. Stauffer syndrome, a paraneoplastic phenomenon characterized by reversible cholestasis in the absence of liver metastases, has been described with renal carcinoma and other malignancies but has not been previously reported in ACC. Case Presentation: A 38-year-old man presented with emesis, painless jaundice, pruritus, and weight loss. Laboratory evaluation demonstrated elevated total bilirubin of 8.7 mg/dL (N < 1.3 mg/dL). Computed tomography revealed a 20.4-cm left adrenal mass without evidence of liver metastases. The patient's condition deteriorated rapidly with progressive renal failure and worsening hyperbilirubinemia. The patient underwent left adrenalectomy, nephrectomy, ureterolysis, and wedge liver biopsy. Histopathology showed necrotic ACC with tumor invasion into the adrenal capsule, no lymphovascular invasion, uninvolved margins, and Ki-67 of 40%. Kidney parenchyma exhibited diffuse pigment casts. The liver specimen contained diffuse bile deposits and minimal chronic inflammation in the portal tracts. He tested positive for the pathogenic variant of folliculin (FLCN) gene consistent with Birt-Hogg-Dube syndrome. Renal function recovered after surgery, and bilirubin level normalized after several weeks. Based on clinical presentation and absence of other etiologies, reversible cholestatic jaundice was attributed to Stauffer syndrome. Conclusion: This is the first report of a unique presentation of paraneoplastic-related hyperbilirubinemia in the setting of ACC. While extremely rare, Stauffer syndrome should still be considered in differential diagnosis in patients with ACC with liver dysfunction and jaundice without evidence of liver metastases.

Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease.

Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1+ dendritic cells and dysfunctional CD8+ T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.

HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: A meta-analysis.

BACKGROUND & AIMS: There is controversy regarding the overall value of hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis given the lack of data from randomized-controlled trials. To address this issue, we conducted a systematic review and meta-analysis of cohort studies evaluating the benefits and harms of HCC surveillance in patients with cirrhosis. METHODS: We performed a search of the Medline and EMBASE databases and national meeting abstracts from January 2014 through July 2020 for studies reporting early-stage HCC detection, curative treatment receipt, or overall survival, stratified by HCC surveillance status, among patients with cirrhosis. Pooled risk ratios (RRs) and hazard ratios, according to HCC surveillance status, were calculated for each outcome using the DerSimonian and Laird method for random effects models. RESULTS: We identified 59 studies including 145,396 patients with HCC, which was detected by surveillance in 41,052 (28.2%) cases. HCC surveillance was associated with improved early-stage detection (RR 1.86, 95% CI 1.73-1.98; I2 = 82%), curative treatment receipt (RR 1.83, 95% CI 1.69-1.97; I2 = 75%), and overall survival (hazard ratio 0.67, 95% CI 0.61-0.72; I2 = 78%) after adjusting for lead-time bias; however, there was notable heterogeneity in all pooled estimates. Four studies examined surveillance-related physical harms due to false positive or indeterminate surveillance results, but no studies examined potential financial or psychological harms. The proportion of patients experiencing surveillance-related physical harms ranged from 8.8% to 27.5% across studies, although most harms were mild in severity. CONCLUSION: HCC surveillance is associated with improved early detection, curative treatment receipt, and survival in patients with cirrhosis, although there was heterogeneity in pooled estimates. Available data suggest HCC surveillance is of high value in patients with cirrhosis, although continued rigorous studies evaluating benefits and harms are still needed. LAY SUMMARY: There has been ongoing debate about the overall value of hepatocellular carcinoma (HCC) screening in patients with cirrhosis given the lack of data from randomized-controlled trials. In a systematic review of contemporary cohort studies, we found that HCC screening is associated with improved early detection, curative treatment receipt, and survival in patients with cirrhosis, although there were fewer data quantifying potential screening-related harms. Available data suggest HCC screening is of high value in patients with cirrhosis, although continued studies evaluating benefits and harms are still needed.

Cachexia is Prevalent in Patients With Hepatocellular Carcinoma and Associated With Worse Prognosis.

BACKGROUND & AIMS: Cancer cachexia is a wasting syndrome associated with functional impairment and reduced survival that impacts up to 50% of patients with gastrointestinal cancers. However, data are limited on the prevalence and clinical significance of cachexia in patients with hepatocellular carcinoma (HCC). METHODS: We performed a retrospective cohort study of patients diagnosed with HCC at 2 United States health systems between 2008 and 2018. Patient weights were recorded 6 months prior to and at time of HCC diagnosis. Cachexia was defined as >5% weight loss (or >2% weight loss if body mass index <20 kg/m2), and precachexia was defined as 2% to 5% weight loss. We used multivariable logistic regression models to identify correlates of cachexia and multivariable Cox proportional hazard models to identify factors associated with overall survival. RESULTS: Of 604 patients with HCC, 201 (33.3%) had precachexia and 143 (23.7%) had cachexia at diagnosis, including 19.0%, 23.5%, 34.7%, and 34.0% of patients with Barcelona Clinic Liver Cancer stages 0/A, B, C, and D, respectively. Patients with cachexia were less likely to receive HCC treatment (odds ratio, 0.38; 95% confidence interval, 0.21-0.71) and had worse survival than those with precachexia or stable weight (11.3 vs 20.4 vs 23.5 months, respectively; P < .001). Cachexia remained independently associated with worse survival (hazard ratio, 1.43; 95% confidence interval, 1.11-1.84) after adjusting for age, sex, race, ethnicity, Child Pugh class, alpha-fetoprotein, Barcelona Clinic Liver Cancer stage, and HCC treatment. CONCLUSIONS: Nearly 1 in 4 patients with HCC present with cachexia, including many with compensated cirrhosis or early stage tumors. The presence of cancer-associated weight loss appears to be an early and independent predictor of worse outcomes in patients with HCC.

GALAD demonstrates high sensitivity for HCC surveillance in a cohort of patients with cirrhosis.

BACKGROUND AND AIMS: Most patients with HCC are diagnosed at a late stage, highlighting the need for more accurate surveillance tests. Although biomarkers for HCC early detection have promising data in Phase 2 case-control studies, evaluation in cohort studies is critical prior to adoption in practice. We leveraged a prospective cohort of patients with Child-Pugh A or B cirrhosis who were followed until incident HCC, liver transplantation, death, or loss to follow-up. We used a prospective specimen collection, retrospective, blinded evaluation design for biomarker evaluation of GALAD (gender × age × log alpha-fetoprotein [AFP] × des-gamma-carboxy prothrombin), longitudinal GALAD, and the HCC Early Detection Screening (HES) algorithm-compared to AFP-using patient-level sensitivity and screening-level specificity. APPROACH AND RESULTS: Of 397 patients with cirrhosis, 42 developed HCC (57.1% early stage) over a median of 2.0 years. Longitudinal GALAD had the highest c-statistic for HCC detection (0.85; 95% CI, 0.77-0.92) compared to single-time point GALAD (0.79; 95% CI, 0.71-0.87), AFP (0.77; 95% CI, 0.69-0.85), and HES (0.76; 95% CI, 0.67-0.83). When specificity was fixed at 90%, the sensitivity for HCC of single-time point and longitudinal GALAD was 54.8% and 66.7%, respectively, compared to 40.5% for AFP. Sensitivity for HCC detection was higher when restricted to patients with biomarker assessment within 6 months prior to HCC diagnosis, with the highest sensitivities observed for single-time point GALAD (72.0%) and longitudinal GALAD (64.0%), respectively. Sensitivity of single-time point and longitudinal GALAD for early-stage HCC was 53.8% and 69.2%, respectively. CONCLUSION: GALAD demonstrated high sensitivity for HCC detection in a cohort of patients with cirrhosis. Validation of these results is warranted in large Phase 3 data sets.

Early Survivorship After Liver Transplantation: A Qualitative Study Identifying Challenges in Recovery From the Patient and Caregiver Perspective.

Survivorship after liver transplantation (LT) is a novel concept providing a holistic view of the arduous recovery experienced after transplantation. We explored components of early survivorship including physical, emotional, and psychological challenges to identify intervention targets for improving the recovery process of LT recipients and caregivers. A total of 20 in-person interviews were conducted among adults 3 to 6 months after LT. Trained qualitative research experts conducted interviews, coded, and analyzed transcripts to identify relevant themes and representative quotes. Early survivorship comprises overcoming (1) physical challenges, with the most challenging experiences involving mobility, driving, dietary modifications, and medication adherence, and (2) emotional and psychological challenges, including new health concerns, financial worries, body image/identity struggles, social isolation, dependency issues, and concerns about never returning to normal. Etiology of liver disease informed survivorship experiences including some patients with hepatocellular carcinoma expressing decisional regret or uncertainty in light of their post-LT experiences. Important topics were identified that framed LT recovery including setting expectations about waitlist experiences, hospital recovery, and ongoing medication requirements. Early survivorship after LT within the first 6 months involves a wide array of physical, emotional, and psychological challenges. Patients and caregivers identified what they wish they had known prior to LT and strategies for recovery, which can inform targeted LT survivorship interventions.

Dynamic Changes in Ultrasound Quality for Hepatocellular Carcinoma Screening in Patients With Cirrhosis.

BACKGROUND & AIMS: Identifying patients in whom ultrasound may be inadequate to exclude the presence of hepatocellular carcinoma (HCC) can inform interventions to improve screening effectiveness. We aimed to characterize correlates of suboptimal ultrasound quality and changes in ultrasound quality over time in patients with cirrhosis undergoing HCC screening. METHODS: We performed a retrospective cohort study of patients with cirrhosis who underwent ultrasound examination at 2 large health systems between July 2016 and July 2019. Exam adequacy was graded by radiologists using the LI-RADS Visualization Score (A, B, C); we evaluated changes in visualization over time among patients with >1 ultrasound exams. We performed multivariable logistic regression to identify characteristics associated with limited ultrasound visualization (scores B or C). RESULTS: Of 2053 cirrhosis patients, 1685 (82.1%) had ultrasounds with score A, 262 (12.8%) had score B, and 106 (5.2%) had score C. Limited visualization was associated with alcohol-related or nonalcoholic fatty liver disease cirrhosis and presence of class II-III obesity. Among 1546 patients with >1 ultrasounds, 1129 (73.0%) had the same visualization score on follow-up (1046 score A, 60 score B, 23 score C). However, 255 (19.6%) of 1301 with score A at baseline had limited visualization when repeated (230 score B, 25 score C), and 130 (53.1%) of 245 patients with baseline limited visualization had good visualization when repeated. CONCLUSIONS: Nearly 1 in 5 patients with cirrhosis had moderately-severely limited ultrasound visualization for HCC nodules, particularly those with obesity or alcohol-related or nonalcoholic fatty liver disease cirrhosis. Ultrasound quality can change between exams, including improvement in many patients with limited visualization.

High Neutrophil-Lymphocyte Ratio and Delta Neutrophil-Lymphocyte Ratio Are Associated with Increased Mortality in Patients with Hepatocellular Cancer.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) has been proposed as a prognostic biomarker for cirrhosis and non-liver malignancies. We aimed to evaluate the prognostic value of NLR in a diverse cohort of patients with hepatocellular carcinoma (HCC). METHODS: We performed a retrospective study of patients diagnosed with HCC between 2008 and 2017 at two large US health systems. We used Cox proportional hazard and multivariable ordinal logistic regression models to identify factors associated with overall survival and response to first HCC treatment, respectively. Primary variables of interest were baseline NLR and delta NLR, defined as the difference between pre- and post-treatment NLR. RESULTS: Among 1019 HCC patients, baseline NLR was < 5 in 815 (80.0%) and ≥ 5 in 204 (20.0%). Patients with NLR ≥ 5 had a higher proportion of infiltrative tumors (36.2% vs 22.3%), macrovascular invasion (39.6% vs 25.5%), metastatic disease (20.6% vs 11.4%), and AFP > 200 ng/mL (45.6% vs 33.8%). Baseline NLR ≥ 5 was independently associated with higher mortality (median survival 4.3 vs 15.1 months; adjusted HR 1.70, 95%CI 1.41-2.06), with differences in survival consistent across BCLC stages. After adjusting for baseline covariates including NLR, delta NLR > 0.26 was also independently associated with increased mortality (HR 1.42, 95%CI 1.14-1.78). In a secondary analysis, high NLR was associated with lower odds of response to HCC treatment (20.2% vs 31.6%; adjusted OR 0.55, 95%CI 0.32-0.95). CONCLUSIONS: In a large Western cohort of patients with HCC, high baseline NLR and delta NLR were independent predictors of mortality. IMPACT: NLR is an inexpensive test that may be a useful component of future HCC prognostic models.

Doylestown Plus and GALAD Demonstrate High Sensitivity for HCC Detection in Patients With Cirrhosis.

Hepatocellular carcinoma (HCC) surveillance is associated with early tumor detection and improved survival in patients with cirrhosis.1 Surveillance is performed using semiannual abdominal ultrasound with or without α-fetoprotein (AFP); however, this strategy misses more than one-third of HCC at an early stage.2 These data highlight a need for novel surveillance strategies with higher accuracy for early HCC detection. GALAD and Doylestown Plus are novel biomarker panels that combine multiple biomarkers with patient demographic and clinical characteristics; both demonstrated promising accuracy in phase II case-control studies;3,4 however, case-control studies can overestimate biomarker performance, highlighting a need for phase III cohort and nested case-control studies.5 Our study aimed to compare multiple biomarkers (including AFP, GALAD, and Doylestown Plus) in a nested case-control study of patients with cirrhosis.