Vatche G. Agopian

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Calcineurin inhibitors (CNIs) remain the cornerstone of immunosuppression after liver transplantation (LT) but contribute to chronic renal failure, increasing long-term morbidity and mortality. Strategies to minimize CNI exposure and preserve renal function are necessary to improve long-term outcomes in high-acuity LT recipients. We conducted a single-center, prospective, randomized trial of adult LT recipients requiring pre-LT renal replacement therapy (RRT). Patients were randomized to: (1) basiliximab induction and delayed tacrolimus starting postoperative day (POD) 5 (BAS); (2) basiliximab induction, tacrolimus starting POD5, and everolimus starting POD31, followed by tacrolimus minimization (BAS-EVR); (3) standard immunosuppression (control). RRT independence, renal function, rejection, graft and patient survival, and adverse events were assessed. Seventy patients were analyzed (BAS n=30; BAS-EVR n=28; control n=12). Median MELD was 40, and 55.7% of patients required mechanical ventilation or vasopressor support pre-LT. Overall, 68.6% of patients achieved RRT independence by 24 weeks: 73.3% (BAS), 75.0% (BAS-EVR), and 41.7% (control). Basiliximab ( p =0.04) and shorter duration of pre-LT RRT ( p =0.02) were significantly associated with RRT independence; basiliximab remained significant after adjusting for duration of pre-LT RRT [OR 3.87 (95% CI 1.01–14.74), p =0.048]. Among patients who achieved RRT independence, median eGFR trended higher in the BAS-EVR group (67 mL/min/1.73 m ² ) than in BAS (52 mL/min/1.73 m ² ) and control groups (50 mL/min/1.73 m ² ) at 24 weeks. Patient and graft survival were comparable across groups. Adverse events were similar, although diarrhea ( p =0.004) and acute kidney injury ( p =0.01) were more frequent in the BAS-EVR group. Basiliximab induction therapy with delayed tacrolimus promotes RRT independence in high-acuity LT recipients. Addition of everolimus to minimize tacrolimus may further preserve renal function without compromising graft or patient survival.

Background: Hepatic stellate cells (HSCs) drive cirrhosis and hepatocellular carcinoma (HCC). Statin use decreases cirrhosis and HCC through unclear mechanisms. We aimed to uncover statin-responsive pathways preventing activation of HSC subpopulations in human MASLD-HCC. Methods: We used single-nucleus RNA-sequencing and spatial imaging on matched human MASLD-HCC samples in cirrhotic and non-cirrhotic livers, along with RNA-sequencing of human primary HSCs to identify Yes-Associated Protein (YAP) as a statin-responsive pathway, which was assessed for cellular localization and function, that is, downstream gene expression after statin exposure. We used pharmacologic inhibitors, gene silencing, pharmacological repletion, and direct quantification by UPLC-MS/MS to interrogate the mevalonate pathway as a statin-responsive YAP regulator. Results: We identified an HCC-HSC subcluster enriched in activated and deactivated marker genes. Spatial resolution of each cell type revealed that myofibroblast-like HSC subpopulations and YAP-effector genes colocalized in the peritumoral pseudocapsule. In fact, although Rho GTPases were differentially expressed across most cell types, YAP-effector genes were largely upregulated in HCC-HSCs by single-nucleus RNA sequencing. Bulk RNA-sequencing of statin-treated activated human primary HSCs showed decreased expression of YAP-related genes and downregulation of Rho GTPase pathways in response to statins. Statins reduced GGPP levels in LX2 HSCs, determined by direct measurement of intracellular GGPP, which was associated with cytoskeletal restructuring, YAP cytosolic retention, and reduced YAP-effector gene expression. Exogenous GGPP repletion reversed these effects. GGPP synthase 1 knockdown and direct Rho inhibition recapitulated the cellular responses of YAP following statin exposure. Conclusions: Upregulation of YAP-effector genes was largely restricted to HCC-HSCs. Our mechanistic studies support that statins lower GGPP, reduce Rho GTPases prenylation, cause YAP cytosolic retention, and decrease YAP nuclear activity. This study expands on the chemoprotective mechanisms of statins in HCC.

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality. Optimal treatment decisions are challenging, and existing treatment allocation frameworks may not fully reflect the evolving therapeutic landscape or contemporary clinical practices in North America. Using a modified Delphi process, a multidisciplinary panel of 20 North American experts in hepatology, medical oncology, surgery, radiology, and radiation oncology developed a consensus-based treatment framework for HCC, termed the BEACON-HCC system. The framework was informed by current evidence and expert opinion through iterative discussion and voting. In a pilot study using 29 real-world patient cases, we assessed concordance between external expert recommendations and BEACON-HCC recommendations and Barcelona Clinic Liver Cancer (BCLC) 2025 treatment recommendations. The BEACON-HCC treatment allocation framework diverges from prior frameworks by incorporating nuanced clinical features such as the degree of intrahepatic tumor burden and vascular invasion, and adverse tumor prognostic markers, to align treatment allocation with tumor biology and therapeutic potential. Key innovations include the incorporation of emerging modalities such as external beam radiation therapy (EBRT), transarterial radioembolization (TARE), and systemic–locoregional combination therapies. In the pilot exercise, expert treatment decisions showed 96.6% concordance with BEACON-HCC recommendations and 72.4% concordance with BCLC recommendations. In conclusion, BEACON-HCC is a consensus-based framework for treatment allocation that incorporates the expanding range of therapeutic options available to patients in the North American HCC population. Expert treatment decisions showed a high concordance with the BEACON-HCC system; further validation using empiric clinical data is planned through the HCC-Live Consortium.

The survival benefit of liver transplantation (LT) for hepatocellular carcinoma (HCC) varies by waitlist dropout risk, yet allocation policy applies uniform prioritization, and center practices remain poorly characterized. We performed a retrospective cohort study using the United Network for Organ Sharing database, including LT candidates with HCC between February 4, 2020, and October 1, 2024. Low-dropout-risk (LDR) HCC was defined as MELDp <0.001). Waitlist outcomes for LDR candidates and post-transplant survival did not differ by center type. These findings suggest substantial center variation exists for LDR HCC and may disadvantage access among higher-need candidates despite similar post-transplant survival.

Background: Semi-annual abdominal ultrasound plus alpha-fetoprotein (AFP) is recommended for HCC surveillance but has limited performance, particularly in patients with metabolic dysfunction–associated steatotic liver disease. We aimed to validate a blood-based test combining cell-free DNA methylation profiling with AFP to improve HCC detection in at-risk individuals. Methods: Between September 1, 2023, and April 30, 2025, 135 patients with HCC and 167 at risk for HCC were prospectively recruited at 2o medical centers; archived samples (46 HCC and 32 at-risk) were also included. A cell-free DNA methylation assay was performed to generate methylation scores, and AFP testing was conducted as part of standard of care. A pretrained model integrated methylation scores and AFP levels for HCC detection. Results: The combination of methylation and AFP tests achieved an AUC of 0.94 (95% CI, 0.92–0.96) for detecting HCC in at-risk individuals, significantly outperforming both methylation alone (AUC: 0.92, 95% CI, 0.89–0.95; p =0.001) and AFP alone (AUC: 0.83, 95% CI, 0.79–0.87; p p =0.002) and AFP alone (AUC: 0.81, 95% CI, 0.76–0.86; p p =0.025) for methylation alone and 52% (95% CI, 43%–62%; p <0.0001) for AFP alone. Sensitivity improvements were consistent across major demographic and etiologic subgroups. Conclusions: The combination of cell-free DNA methylation with AFP shows promising performance for early-stage HCC detection in this case-control validation study and warrants further validation.

Plasma cell-free DNA (cfDNA), originating from multiple organs, holds significant potential for noninvasive diagnostics and prognostics. Current cfDNA methylation assays primarily focus on single clinical indications by targeting specific genomic loci. In contrast, comprehensive profiling of cfDNA methylome can enable simultaneous detection of multiple diseases by capturing organ-specific methylation signatures, thereby offering a holistic view of health, when disease etiology is unclear or when conventional biochemical diagnostics are unavailable. However, deep sequencing required for sensitive detection of methylation abnormalities remains prohibitively expensive, limiting widespread clinical use. To overcome this barrier, we developed MethylScan , a highly cost-effective approach for cfDNA methylome sequencing. We demonstrated its broad clinical utility in a cohort of 1,061 individuals across diverse applications, including multicancer detection in general population, liver cancer surveillance in high-risk individuals, liver disease classification, identification of organ abnormalities, and race prediction from cfDNA. In multicancer detection (liver, lung, ovarian, and stomach cancers), MethylScan achieved an area under the receiver operating characteristic curve (AUROC) of 0.938 (95% CI: 0.920 to 0.954), with a sensitivity of 63.3% (95% CI: 58.9 to 67.9%) at 98.0% specificity for all cancer stages. For early-stage cancers, the AUROC was 0.916 (95% CI: 0.890 to 0.940), with 55.3% sensitivity (95% CI: 49.1 to 62.1%) at the same specificity. In liver cancer surveillance, MethylScan achieved an AUROC of 0.927 (95% CI: 0.889 to 0.959), with 79.6% sensitivity (95% CI: 70.6 to 87.8%) at 90.4% specificity. The assay also demonstrated strong performance in additional diagnostic tasks, supporting its potential as a versatile platform for comprehensive cfDNA-based health monitoring.