Background: Professional guidelines recommend HCC screening in at-risk patients using semi-annual ultrasound with or without alpha-fetoprotein (AFP); however, this strategy has limited effectiveness due to low adherence and sensitivity. Increasing data support the potential role of blood-based biomarker panels, which could improve both aspects. The biomarker panel GALAD, comprised of sex, age, and 3 blood biomarkers (AFP, AFP-L3, and des-carboxy prothrombin des-carboxy prothrombin), has shown high sensitivity and specificity in biomarker phase II (case-control) and phase III (retrospective cohort) validation studies. However, prospective validation in a large phase IV biomarker clinical utility trial is necessary before its adoption in practice. Methods: The National Liver Cancer Screening Trial is an adaptive pragmatic randomized phase IV trial, which began enrollment in January 2024, comparing ultrasound-based versus biomarker-based screening in 5500 patients with chronic hepatitis B infection or cirrhosis from any etiology. Eligible patients are randomly assigned in a 1:1 ratio to semi-annual screening with ultrasound ± alpha-fetoprotein (arm A) or semi-annual screening with GALAD (arm B). Randomization is stratified by enrollment site, liver disease severity (per Child-Pugh class), liver disease etiology (viral, nonviral, and noncirrhotic HBV), and sex. Patients are being recruited from 15 sites (a mix of tertiary care academic referral centers, safety-net health systems, and large community health systems) over a 3-year period, and the primary endpoint, reduction in late-stage HCC, will be assessed at the end of year 5.5. Discussion: The results of this trial will inform the best strategy for HCC screening and early-stage detection in patients with chronic liver diseases. If GALAD shows superiority, HCC screening would primarily shift from an ultrasound-based strategy to the adoption of the biomarker panel. Trial Registration: NCT06084234. Trial Status: The TRACER Study is actively enrolling. Export

High-density lipoproteins (HDLs) are promising targets for predicting and treating atherosclerotic cardiovascular disease (ASCVD), as they mediate removal of excess cholesterol from lipid-laden macrophages that accumulate in the vasculature. This functional property of HDLs, termed cholesterol efflux capacity (CEC), is inversely associated with ASCVD. HDLs are compositionally diverse, associating with >250 different proteins, but their relative contribution to CEC remains poorly understood. Our goal was to identify and define key HDL-associated proteins that modulate CEC in humans. The proteomic signature of plasma HDL was quantified in 36 individuals in the multi-ethnic population-based Dallas Heart Study (DHS) cohort that exhibited persistent extremely high (>=90th%) or extremely low CEC (<=10th%) over 15 years. Levels of apolipoprotein (Apo)A-I associated ApoC-II, ApoC-III, and ApoA-IV were differentially correlated with CEC in high (r = 0.49, 0.41, and −0.21 respectively) and low (r = −0.46, −0.41, and 0.66 respectively) CEC groups (p for heterogeneity (pHet) = 0.03, 0.04, and 0.003 respectively). Further, we observed that levels of ApoA-I with ApoC-III, complement C3 (CO3), ApoE, and plasminogen (PLMG) were inversely associated with CEC in individuals within the low CEC group (r = −0.11 to −0.25 for subspecies with these proteins vs. r = 0.58 to 0.65 for subspecies lacking these proteins; p < 0.05 for heterogeneity). These findings suggest that enrichment of specific proteins on HDLs and, thus, different subspecies of HDLs, differentially modulate the removal of cholesterol from the vasculature.

Background: Abdominal ultrasound is prone to hepatocellular carcinoma (HCC) surveillance failure, particularly in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) or alcohol-associated liver disease (ALD), prompting growing interest in blood-based biomarkers as an alternative strategy. Methods: We conducted a case–control study evaluating two blood-based biomarker panels, GAAD and GALAD, for detection of early-stage HCC (Barcelona Clinic Liver Cancer (BCLC) stage 0 or A) in patients with MASLD or ALD cirrhosis. Blood specimens were collected within 6 months of HCC diagnosis (cases); controls were patients with cirrhosis but without HCC. GAAD and GALAD scores were measured using the Roche Elecsys platform, applying validated cutoffs of 2.57 and 2.47, respectively. Sensitivity and specificity were compared between the panels and versus ultrasound plus alpha fetoprotein (AFP) using McNemar’s chi square test. Results: Of 152 patients (56.6% men), 46.7% had HCC (54.9% BCLC 0/A) and 53.3% had cirrhosis without HCC. GAAD and GALAD each achieved a sensitivity of 87.2% for early-stage HCC, with specificities of 69.1% and 67.9%, respectively. In paired analyses (n = 90), GAAD had higher sensitivity for any-stage HCC (89.5% vs. 68.4%, p = 0.046) but lower specificity (71.8% vs. 93.0%, p = 0.006) than ultrasound plus AFP. GAAD and GALAD demonstrated consistently higher sensitivity than ultrasound plus AFP across subgroups by age, sex, cirrhosis etiology, and Child Pugh class. Conclusion: In this case–control study of patients with non-viral cirrhosis, GAAD and GALAD demonstrated high sensitivity for early-stage HCC. These findings highlight the potential of blood-based biomarkers to improve HCC surveillance in contemporary populations.

Background: The sensitivity of ultrasound plus alpha-fetoprotein (AFP) for early-stage hepatocellular carcinoma (HCC) detection remains suboptimal, prompting interest in blood-based biomarkers as an alternative strategy. The ASAP [age, sex, AFP, PIVKA-II] score has promising performance, although validation in contemporary Western populations is needed. Methods: We conducted a case–control study in which the cases were patients with HCC and the controls had cirrhosis without HCC. AFP, PIVKA-II, LG2m, and GP73 were measured using the Abbott Alinity platform, and ASAP scores were calculated. Sensitivity and specificity for early-stage HCC (BCLC stage 0/A) were compared between ASAP and ultrasound plus AFP using McNemar’s chi-square test. Results: Among 294 patients (median age of 61 years, 67.7% men), 50.7% had HCC (69.1% BCLC 0/A), and 49.3% had cirrhosis. The performance of individual biomarkers for early-stage HCC was moderate to poor (AUROC: AFP 0.71, PIVKA-II 0.73, LG2m 0.51, and GP73 0.53). ASAP, at a cutoff of ≥0.526, demonstrated a sensitivity of 88.3% for early-stage HCC, with specificity of 54.5%. Sensitivity was higher in men and viremic HCV, whereas specificity was higher in younger individuals, women, and Child–Pugh A cirrhosis. In subgroup analysis (n = 178), ASAP had comparable sensitivity to ultrasound plus AFP (85.5% vs. 90.3%; p = 0.51) but lower specificity (53.4% vs. 93.1%; p < 0.001). Using the Youden-optimized cutoff (≥0.804) improved specificity to 83.4% while maintaining a sensitivity of 68.0% for early-stage HCC. Conclusions: ASAP demonstrated high sensitivity for early-stage HCC detection but low specificity. These findings suggest a need for optimized cutoffs prior to implementation in clinical practice.