PURPOSE:Liver transplantation is the definitive treatment for hepatocellular carcinoma (HCC) in eligible patients with cirrhosis. Bridging liver-directed therapies are critical for maintaining transplant eligibility during long wait times. However, due to the fear of decompensation, many advanced cirrhotic patients are excluded from receiving liver-directed therapies. This prospective pilot clinical trial evaluated the feasibility, safety, and efficacy of stereotactic body radiation therapy (SBRT) as a bridging therapy in an advanced cirrhotic HCC population. METHODS AND MATERIALS:HCC patients with Child-Pugh B8 or worse cirrhosis and eligible for liver transplant were enrolled. SBRT to 40 Gy in 5 fractions was delivered to a single HCC as a bridging strategy. The primary endpoint was the proportion of patients who were transplant eligible up to 1 year following SBRT. Secondary endpoints included disease control per modified Response Evaluation Criteria in Solid Tumors, proportion of patients that proceeded to transplant, incidence of nonclassical radiation-induced liver disease (RILD) within 1 week to 3 months after SBRT, and incidence of liver toxicity per Common Terminology Criteria for Adverse Events v5.0. RESULTS:Between 2019 and 2023, 9 patients with Child-Pugh B8 or worse cirrhosis were enrolled. Median follow-up was 11.2 months with a 22% death rate. Six patients (67%) were transplanted or remained transplant eligible 1 year after SBRT. Three patients (33%) failed to receive a liver transplantation: 2 due to factors unrelated to SBRT or tumor progression, and 1 patient experienced minimal tumor progression outside of Milan criteria. Per modified Response Evaluation Criteria in Solid Tumors, the local control rate was 100% and the incidence of intrahepatic and extrahepatic disease progression was 0%. Within 1 week to 3 months after SBRT, 1 patient (11%) experienced liver toxicity (Common Terminology Criteria for Adverse Events grade 4 acidosis, acute hepatic encephalopathy, and hepatic failure), but there were no instances of nonclassical RILD. CONCLUSIONS:Bridging SBRT in patients with HCC and advanced cirrhosis may safely maintain transplant eligibility without increasing the risk of nonclassical RILD.

Study Purpose Cytomegalovirus (CMV) is a common opportunistic viral infection among liver transplant (LT) recipients. This study evaluated the status of current CMV prophylaxis, treatment and associated antiviral side effects in LT patients. Procedures This single-center, retrospective study of 570 adult LT recipients from January 1, 2013, to December 31, 2023 compared CMV infection, disease, antiviral side effects and survival among high- (D+/R-, n = 157), intermediate- (D-/R+, D+/R+, n = 341), and low-CMV risk patients (D-/R-, n = 72). Maintenance immunosuppression was tacrolimus, mycophenolate or azathioprine (Imuran), and prednisone. High-risk patients received valganciclovir 900 mg daily for 6 months, and intermediate-risk patients received valganciclovir 450 mg daily for 3 months. Low-risk recipients received acyclovir 400 mg BID for 3 months. Findings Overall, 92 (16 %) patients developed CMV infection, and 64 (11 %) developed CMV disease. The high-risk group had the highest rates of CMV infection (50.3 % vs. 3.2 % vs. 2.8 %; p < 0.001) and disease (37.6 % vs. 1.2 % vs. 1.4 %; p < 0.001) compared to intermediate- and low-risk groups. Of those with CMV disease, 90.6 % received antiviral treatment, while 9.4 % resolved their disease without treatment. During prophylaxis, the high-risk group experienced higher rates of leukopenia (65.6 % vs. 45.7 % vs. 18.1 %; p < 0.001), antiviral-associated neutropenia (AAN; 48.4 % vs. 16.1 % vs. 8.3 %; p < 0.001), and uptrend in AAN requiring G-CSF (28.0 % vs. 8.7 % vs. 2.8 %; p = 0.802). Notably, more intermediate-risk recipients developed AAN requiring G-CSF during prophylaxis than developed CMV disease (8.7 % vs. 1.2 %). Conclusion This study demonstrates the need for revised antiviral prophylactic and treatment algorithms that effectively manage CMV disease while minimizing antiviral side effects such as AAN.

IntroductionLiver transplant recipients may have pre-formed anti-HLA antibodies directed to mismatched HLA of the liver donor (donor specific antibodies, DSA) or not directed to the liver donor (non-donor specific, non-DSA). We observed the fate of these antibodies (DSA and non-DSA) at 12 months after transplant.MethodsPatients transplanted between 4/2015 and 12/2018 (N = 216) who had anti-HLA antibody measurements at both transplant and 12 months posttransplant (N = 124) and with DSAs at transplant (N = 31) were considered informative for a paired analysis of the natural history of DSA and non-DSA following liver transplantation.ResultsClass I DSAs and non-DSAs decreased between transplant and 12 months; however, Class I DSAs essentially disappeared by 12 months while Class I non-DSAs did not. Anti-HLA Class II DSAs performed differently. While there was a significant drop in values between transplant and 12 months, these antibodies mostly persisted at a low level.DiscussionOur study demonstrated a significant difference in the kinetics of DSA compared to non-DSA following liver transplantation, most profoundly for anti-HLA Class I antibodies. Class I DSAs were mostly absent at 12 months while Class II DSAs persisted, although at lower levels. The mechanisms of reduction in anti-HLA antibodies following liver transplantation are not completely understood and were not pursued as a part of this study. This detailed analysis of Class I and Class II DSAs and non-DSAs represents and important study to explore the change in antibodies at one year from liver transplantation.

TPS496 Background: Liver cancer is the third most common cause of cancer related death worldwide, and hepatocellular carcinoma (HCC) accounts for 90% of all primary liver cancers, with pre-existing cirrhosis being a very strong risk factor for HCC development. Liver transplantation (LTx) is the best treatment for patients with HCC and advanced cirrhosis as both conditions can be very effectively treated at once. As LTx wait-lists can be many months, liver-directed therapies (LDT), including stereotactic body radiation therapy (SBRT) to one or few lesions are essential as oncologic temporizing measures to bridge patients to LTx and prevent progression outside of LTx criteria. However, due to the fear of further hepatic decompensation, many patients with advanced cirrhosis are excluded from receiving LDT. Rather, recent studies suggest that SBRT be of safe and practical use in this fragile patient population with advanced cirrhosis and HCC, and thereby reduce the rate of transplantation drop-out. This pilot prospective study will assess the feasibility, safety and efficacy of bridge-to-transplantation SBRT for patients with advanced cirrhosis and HCC. Methods: Patients with non-metastatic and unresectable HCC and Child-Pugh (CP)-B8 or worse cirrhosis who are within Milan criteria (one tumor ≤ 5 cm in diameter or no more than 3 tumors each ≤ 3 cm in diameter) and have been listed or recommended to be listed for liver transplantation will be eligible for participation. Eligible participants will undergo SBRT consisting of 40 Gy to be given in 5 fractions every other day to the only or largest lesion, provided that criteria for normal organ constraints are met. In cases where normal organ constraints are not met, the dose will be iteratively de-escalated to two dose levels (35 Gy in 5 fractions, then 30 Gy in 5 fractions). If normal organ constraints are unable to be met at 30 Gy in 5 fractions, the participant will be considered ineligible for SBRT and considered a screen failure. The primary endpoint is the proportion of participants who are transplanted or with localized disease control that meets Milan criteria within a year of SBRT. Secondary endpoints will include localized control rate (mRECIST), incidence of intra- or extra-hepatic progressive disease (mRECIST), overall survival, incidence of liver toxicity per CTCAE v5.0, incidence of non-classical radiation-induced liver disease (defined as CTCAE grade 4 AST/ALT elevation or an increase in CP score of ≥ 2 within 3 months of SBRT) and quality of life scores per QLQ-C30 and FACT-Hep questionnaires. The study is open, aiming to enroll 15 patients with 8 patients enrolled at time of submission. Clinical trial information: NCT03812289.

Cell-free RNA (cfRNA) in plasma reflects phenotypic alterations of both localized sites of cancer and the systemic host response. Here we report that cfRNA sequencing enables the discovery of messenger RNA (mRNA) biomarkers in plasma with the tissue of origin-specific to cancer types and precancerous conditions in both solid and hematologic malignancies. To explore the diagnostic potential of total cfRNA from blood, we sequenced plasma samples of eight hepatocellular carcinoma (HCC) and ten multiple myeloma (MM) patients, 12 patients of their respective precancerous conditions, and 20 non-cancer (NC) donors. We identified distinct gene sets and built classification models using Random Forest and linear discriminant analysis algorithms that could distinguish cancer patients from premalignant conditions and NC individuals with high accuracy. Plasma cfRNA biomarkers of HCC are liver-specific genes and biomarkers of MM are highly expressed in the bone marrow compared to other tissues and are related to cell cycle processes. The cfRNA level of these biomarkers displayed a gradual transition from noncancerous states through precancerous conditions and cancer. Sequencing data were cross-validated by quantitative reverse transcription PCR and cfRNA biomarkers were validated in an independent sample set (20 HCC, 9 MM, and 10 NC) with AUC greater than 0.86. cfRNA results observed in precancerous conditions require further validation. This work demonstrates a proof of principle for using mRNA transcripts in plasma with a small panel of genes to distinguish between cancers, noncancerous states, and precancerous conditions.

Background & aims: Mature hepatocytes have limited expansion capability in culture and rapidly loose key functions. Recently however, tissue culture conditions have been developed that permit rodent hepatocytes to proliferate and transform into progenitor-like cells with ductal characteristics in vitro. Analogous cells expressing both hepatic and duct markers can be found in human cirrhotic liver in vivo and may represent an expandable population. Methods: An in vitro culture system to expand epithelial cells from human end stage liver disease organs was developed by inhibiting the canonical TGF-β, Hedgehog and BMP pathways. Results: Human cirrhotic liver epithelial cells became highly proliferative in vitro. Both gene expression and DNA methylation site analyses revealed that cirrhosis derived epithelial liver cells were intermediate between normal hepatocytes and cholangiocytes. Mouse hepatocytes could be expanded under the same conditions and retained the ability to re-differentiate into hepatocytes upon transplantation. In contrast, human cirrhotic liver derived cells had only low re-differentiation capacity. Conclusions: Epithelial cells of intermediate ductal-hepatocytic phenotype can be isolated from human cirrhotic livers and expanded in vitro. Unlike their murine counterparts they have limited liver repopulation potential.

Recombinant adeno-associated viral (rAAV) vectors are considered promising tools for gene therapy directed at the liver. Whereas rAAV is thought to be an episomal vector, its single-stranded DNA genome is prone to intra- and inter-molecular recombination leading to rearrangements and integration into the host cell genome. Here, we ascertained the integration frequency of rAAV in human hepatocytes transduced either ex vivo or in vivo and subsequently expanded in a mouse model of xenogeneic liver regeneration. Chromosomal rAAV integration events and vector integrity were determined using the capture-PacBio sequencing approach, a long-read next-generation sequencing method that has not previously been used for this purpose. Chromosomal integrations were found at a surprisingly high frequency of 1%-3% both in vitro and in vivo. Importantly, most of the inserted rAAV sequences were heavily rearranged and were accompanied by deletions of the host genomic sequence at the integration site.

During pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a prometastatic niche. These data suggest a mechanism for increased liver metastasis in breast cancer patients with recent childbirth. It is unknown whether the human liver changes in size and function during pregnancy and weaning. In this study, abdominal imaging was obtained in healthy women at early and late pregnancy and postwean. During pregnancy time points, glucose production and utilization and circulating bile acids were measured. Independently of weight gain, most women's livers increased in size with pregnancy, then returned to baseline postwean. Putative roles for bile acids in liver growth and regression were observed. Together, the data support the hypothesis that the human liver is regulated by reproductive state with growth during pregnancy and volume loss postwean. These findings have implications for sex-specific liver diseases and for breast cancer outcomes.

The name of one of the co-authors was slightly misspelled. Kristian Enestvedt is listed currently as "Kristian K. Enestvedt" and should be listed instead as "C. Kristian Enestvedt."

Department of Interventional Radiology, Dotter Interventional Institute, Oregon Health and Science University, Portland, OR, USA; Department of Radiation Oncology, Oregon Health and Science University, Portland, OR, USA; Division of Hematology and Medical Oncology, Department of Internal Medicine, Oregon Health and Science University, Portland, OR, USA; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Oregon Health and Science University, Portland, OR, USA Correspondence to: Khashayar Farsad. Dotter Department of Interventional Radiology, 3181 SW Sam Jackson Park Road, L-605, Portland, OR 97239, USA. Email: farsad@ohsu.edu. Comment on: Kim BK, Kim DY, Byun HK, et al. Efficacy and Safety of Liver-Directed Concurrent Chemoradiotherapy and Sequential Sorafenib for Advanced Hepatocellular Carcinoma: A Prospective Phase 2 Trial. Int J Radiat Oncol Biol Phys 2020;107:106-15.

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Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, but unlike other leading causes of cancer death, HCC is increasing in mortality and burden of management. Management of HCC is unique because it usually arises in a diseased liver, which itself may be a driver of mortality. Multidisciplinary teams (MDTs) for the management of complex diseases are becoming more common, but are especially needed in the management of patients with HCC. Liver cancer MDTs are used in most centers providing comprehensive care for patients with HCC, and should be considered the standard of care for these patients.

Adeno-associated virus (AAV) integrates into host genomes at low frequency, but when integration occurs in oncogenic hotspots it can cause hepatocellular carcinoma (HCC). Given the possibility of recombinant AAV (rAAV) integration leading to HCC, common causes of liver inflammation like non-alcoholic fatty liver disease (NAFLD) may increase the risk of rAAV-induced HCC. A rAAV targeting the oncogenic mouse Rian locus was used, and as expected led to HCC in all mice infected as neonates, likely due to growth-related hepatocyte proliferation in young mice. Mice infected with rAAV as adults did not develop HCC unless they were fed a diet leading to NAFLD, with increased inflammation and hepatocyte proliferation. Female mice were less susceptible to rAAV-induced HCC, and male mice with NAFLD treated with estrogen exhibited less inflammation and immune exhaustion associated with oncogenesis compared to those without estrogen. Adult NAFLD mice infected with a non-targeted control rAAV also developed HCC, though only half as frequently as those exposed to the Rian targeted rAAV. This study shows that adult mice exposed to rAAV gene therapy in the context of chronic liver disease developed HCC at high frequency, and thus warrants further study in humans given the high prevalence of NAFLD in the population.