Background.: This study compares selection criteria for liver transplant (LT) for hepatocellular carcinoma (HCC) for inclusivity and predictive ability to identify the most permissive criteria that maintain patient outcomes. Methods.: The Scientific Registry of Transplant Recipients (SRTR) database was queried for deceased donor LT’s for HCC (2003–2020) with 3-y follow-up; these data were compared with a 2-center experience. Milan, University of California, San Francisco (UCSF), 5-5-500, Up-to-seven (U7), HALT-HCC, and Metroticket 2.0 scores were calculated. Results.: Nationally, 26 409 patients were included, and 547 at the 2 institutions. Median SRTR-follow-up was 6.8 y (interquartile range 3.9–10.1). Three criteria allowed the expansion of candidacy versus Milan: UCSF (7.7%, n = 1898), Metroticket 2.0 (4.2%, n = 1037), and U7 (3.5%, n = 828). The absolute difference in 3-y overall survival (OS) between scores was 1.5%. HALT-HCC (area under the curve [AUC] = 0.559, 0.551–0.567) best predicted 3-y OS although AUC was notably similar between criteria (0.506 < AUC < 0.527, Mila n = 0.513, UCSF = 0.506, 5-5-500 = 0.522, U7 = 0.511, HALT-HCC = 0.559, and Metroticket 2.0 = 0.520), as was Harrall’s c-statistic (0.507 < c-statistic < 0.532). All scores predicted survival to P < 0.001 on competing risk analysis. Median follow-up in our enterprise was 9.8 y (interquartile range 7.1–13.3). U7 (13.0%, n = 58), UCSF (11.1%, n = 50), HALT-HCC (6.4%, n = 29), and Metroticket 2.0 (6.3%, n = 28) allowed candidate expansion. HALT-HCC (AUC = 0.768, 0.713–0.823) and Metroticket 2.0 (AUC = 0.739, 0.677–0.801) were the most predictive of recurrence. All scores predicted recurrence and survival to P < 0.001 using competing risk analysis. Conclusions.: Less restrictive criteria such as Metroticket 2.0, UCSF, or U7 allow broader application of transplants for HCC without sacrificing outcomes. Thus, the criteria for Model for End-stage Liver Disease-exception points for HCC should be expanded to allow more patients to receive life-saving transplantation.

Hepatocellular carcinoma (HCC) remains a health concern characterized by heterogeneity and high mortality. Surgical resection, radiofrequency ablation, trans-arterial chemoembolization, and liver transplantation offer potentially curative treatments for early-stage disease, but recurrence remains high. Most patients present with advanced-stage HCC, where locoregional therapies are less effective, and systemic treatments-primarily multi-kinase inhibitors and immune checkpoint inhibitors-often yield limited responses. Precision medicine aims to tailor therapy to molecular and genetic profiles, yet its adoption in HCC is hindered by inter-/intra-tumoral heterogeneity and limited biopsy availability. Advances in molecular diagnostics support reintroducing tissue sampling to better characterize genetic, epigenetic, and immunological features. Liquid biopsy offers a minimally invasive method for capturing real-time tumor evolution, overcoming spatial and temporal heterogeneity. Artificial intelligence and machine learning are revolutionizing biomarker discovery, risk stratification, and treatment planning by integrating multi-omics data. Immunological factors such as tumor-infiltrating lymphocytes, natural killer cells, macrophages, and fibroblasts have emerged as determinants of HCC progression and treatment response. Conversion therapy-combining systemic agents with locoregional treatments-has showndemonstrated promise in downstaging unresectable HCC. Ongoing efforts to refine biomarker-driven approaches and optimize multi-modality regimens underscore precision medicine's potential to improve outcomes. PubMed (January 2002-February 2025) was searched for relevant studies.

The current liver allocation system may be disadvantaging younger adult recipients as it does not incorporate the donor-recipient age difference. Given the longer life expectancy of younger recipients, the influences of older donor grafts on their long-term prognosis should be elucidated. This study sought to reveal the long-term prognostic influence of the donor-recipient age difference in young adult recipients. Adult patients who received initial liver transplants from deceased donors between 2002 and 2021 were identified from the UNOS database. Young recipients (patients 45 years old or below) were categorized into 4 groups: donor age younger than the recipient, 0–9 years older, 10–19 years older, or 20 years older or above. Older recipients were defined as patients 65 years old or above. To examine the influence of the age difference in long-term survivors, conditional graft survival analysis was conducted on both younger and older recipients. Among 91,952 transplant recipients, 15,170 patients were 45 years old or below (16.5%); these were categorized into 6,114 (40.3%), 3,315 (21.9%), 2,970 (19.6%), and 2,771 (18.3%) for groups 1–4, respectively. Group 1 demonstrated the highest probability of survival, followed by groups 2, 3, and 4 for the actual graft survival and conditional graft survival analyses. In younger recipients who survived at least 5 years post-transplant, inferior long-term survival was observed when there was an age difference of 10 years or above (86.9% vs. 80.6%, log-rank p<0.01), whereas there was no difference in older recipients (72.6% vs. 74.2%, log-rank p=0.89). In younger patients who are not in emergent need of a transplant, preferential allocation of younger aged donor offers would optimize organ utility by increasing postoperative graft survival time.

Background: The use of older donors after circulatory death(DCD) for liver transplantation(LT) has increased over the past decade. This study examined whether outcomes of LT using older DCD(≥50 y) have improved with advancements in surgical/perioperative care and normothermic machine perfusion(NMP) technology. Method: 7,602 DCD LT cases from the UNOS database(2003-2022) were reviewed. The impact of older DCD donors on graft survival(GS) was assessed using Kaplan-Meier and hazard ratio(HR) analyses. Results: 1,447 LT cases(19.0%) involved older DCD donors. Although there was a decrease in their use from 2003-2014, a resurgence was noted post-2015 and reached 21.9% of all LT in the last four years(2019-2022). Initially, 90-day and one-year GS for older DCDs were worse than younger DCDs, but this difference decreased over time and there was no statistical difference after 2015. Similarly, HRs for graft loss in older DCD have recently become insignificant. In older DCD LT, NMP usage has increased recently, especially in cases with extended donor-recipient distances, while the median time from asystole to aortic cross-clamp has decreased. Multivariable Cox regression analyses revealed that in the early phase, asystole to cross-clamp time had the highest HR for graft loss in older DCD LT without NMP, while in the later phases, the CIT(>5.5 h) was a significant predictor. Conclusion: LT outcomes using older DCD donors have become comparable to those from young DCD donors, with recent HRs for graft loss becoming insignificant. The strategic approach in the recent period could mitigate risks, including managing CIT(≤5.5 h), reducing asystole to cross-clamp time, and adopting NMP for longer distances. Optimal use of older DCD donors may alleviate the donor shortage. Export

With increasing metabolic dysfunction–associated steatotic liver disease, the use of steatotic grafts in liver transplantation (LT) and their impact on postoperative graft survival (GS) needs further exploration. Analyzing adult LT recipient data (2002–2022) from the United Network for Organ Sharing database, outcomes of LT using steatotic (≥30% macrosteatosis) and nonsteatotic donor livers, donors after circulatory death, and standard-risk older donors (age 45–50) were compared. GS predictors were evaluated using Kaplan-Meier and Cox regression analyses. Of the 35,345 LT donors, 8.9% (3,155) were fatty livers. The initial 30-day postoperative period revealed significant challenges with fatty livers, demonstrating inferior GS. However, the GS discrepancy between fatty and nonfatty livers subsided over time (p = 0.10 at 5 y). Long-term GS outcomes showed comparable or even superior results in fatty livers relative to nonsteatotic livers, conditional on surviving the initial 90 postoperative days (p = 0.90 at 1 y) or 1 year (p = 0.03 at 5 y). In the multivariable Cox regression analysis, the high body surface area (BSA) ratio (≥1.1) (HR 1.42, p = 0.02), calculated as donor BSA divided by recipient BSA, long cold ischemic time (≥6.5 h) (HR 1.72, p < 0.01), and recipient medical condition (intensive care unit hospitalization) (HR 2.53, p < 0.01) emerged as significant adverse prognostic factors. Young (<40 y) fatty donors showed a high BSA ratio, diabetes, and intensive care unit hospitalization as significant indicators of a worse prognosis (p < 0.01). Our study emphasizes the initial postoperative 30-day survival challenge in LT using fatty livers. However, with careful donor-recipient matching, for example, avoiding the use of steatotic donors with long cold ischemic time and high BSA ratios for recipients in the intensive care unit, it is possible to enhance immediate GS, and in a longer time, outcomes comparable to those using nonfatty livers, donors after circulatory death livers, or standard-risk older donors can be anticipated. These novel insights into decision-making criteria for steatotic liver use provide invaluable guidance for clinicians.

Despite being the standard treatment for end-stage liver disease, liver transplantation has limitations like donor scarcity, high surgical costs, and immune rejection risks. Mesenchymal stem cells (MSCs) and their derivatives offer potential for liver regeneration and transplantation. MSCs, known for their multipotency, low immunogenicity, and ease of obtainability, can differentiate into hepatocyte-like cells and secrete bioactive factors that promote liver repair and reduce immune rejection. However, the clinical application of MSCs is limited by risks such as aberrant differentiation and low engraftment rates. As a safer alternative, MSC-derived secretomes and extracellular vesicles (EVs) offer promising therapeutic benefits, including enhanced graft survival, immunomodulation, and reduced ischemia–reperfusion injury. Current research highlights the efficacy of MSC-derived therapies in improving liver transplant outcomes, but further studies are necessary to standardize clinical applications. This review highlights the potential of MSCs and EVs to address key challenges in liver transplantation, paving the way for innovative therapeutic strategies.