Background. Perihilar cholangiocarcinoma (phCCA) has excellent outcomes following liver transplantation (LT). Neoadjuvant radiation-based locoregional therapy is standard-of-care. Gemcitabine and cisplatin (gem/cis) combination systemic therapies have improved outcomes in advanced settings, but their efficacy pre-LT has not been studied. Methods. We review our experience following neoadjuvant gem/cis alone versus radiation-based approaches. Patients with phCCA undergoing LT at a single center between January 2008 and February 2023 were identified retrospectively. Neoadjuvant therapy was categorized as gem/cis systemic therapy (ST) alone, or any ST and radiotherapy (RT). Outcomes were posttransplant overall survival (OS), recurrence-free survival (RFS), waitlist time, and pathologic tumor response. Results. During study period, 27 phCCA patients underwent LT. One patient decompensated with neoadjuvant therapy and was excluded. Median age was 61 y (interquartile range, 53–68 y) and 14 (54%) were male. Of 26 patients, 12 (46%) received ST and 14 (54%) RT. Six RT patients received gem/cis ST. Median waitlist time was 199 d (interquartile range, 98–405 d) and did not differ by neoadjuvant regimen. Explanted tumors were predominantly T1 stage, without lymphovascular invasion or nodal involvement. Neither pathologic features nor percent tumor necrosis differed by regimen. OS probabilities at 1 and 3 y were 84% and 55% for the cohort. There was no significant difference in OS and RFS when stratified by regimen. Conclusions. Post-LT OS, RFS, waitlist time, and tumor response were similar in the 2 groups. Patients with phCCA who do not undergo RT may still be considered for LT under appropriate institution-based protocols that adhere to other established criteria.

Primary liver malignancies, specifically hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), present a substantial global health burden with rising incidence and mortality rates. While surgical interventions offer curative potential, most patients eventually require systemic therapy. Traditional treatments, such as kinase inhibitors and cytotoxic chemotherapy, have historically provided limited efficacy and significant toxicity. Recently, immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 and CTLA-4 pathways have revolutionized the management of advanced liver cancers, demonstrating superior overall survival and durable responses in landmark trials such as IMbrave150 and TOPAZ-1. This review evaluates the biological rationale and emerging clinical evidence for the use of immunotherapy in the peri-liver transplant (peri-LT) setting. In the pre-LT setting, ICIs have shown promise for tumor downstaging and as a bridge to transplantation, with high objective response rates and successful conversion to transplant eligibility in some cohorts. However, the integration of immunotherapy into transplant protocols presents a unique challenge of balancing potent anti-tumor immunity with the need for post-transplant immunosuppression to prevent allograft rejection. Current data from retrospective series indicate allograft rejection rates between 26% and 28%, which are largely comparable to general transplant populations, though the clinical severity of these episodes, including potential graft loss, remains a concern. The duration of the washout period between the last ICI dose and transplantation is a critical determinant of safety, with longer intervals (typically >30 to 90 days) associated with a reduced risk of rejection. In the post-LT setting, ICIs may be considered for systemic recurrence, though they carry a high risk of rejection, potentially mitigated by biomarkers like graft PD-L1 expression. Standardized, evidence-based guidelines are necessary to optimize the safety and efficacy of immunotherapy in transplant oncology.

BACKGROUND:Cholangiocarcinoma (CCA) has rising incidence and mortality rates. Outcomes from combination systemic, loco-regional therapy (LRT) and liver transplantation (LT) are improving, but more granular data are needed to inform evidence-based management, including patient selection and immunosuppression. METHODS:Patients with peri-hilar (PH) and intrahepatic (IH) CCA who underwent LT at a single center between January 2008 and February 2023 were reviewed retrospectively. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS) with significance determined by Cox proportional hazards model. RESULTS:During the study period, 53 patients underwent LT for either PH (n = 27), or IH (26). Cohort had mean age 58.5 years old (IQR, 47.0-63.0), body mass index (BMI) 25.9 (IQR, 22.9-30.0) kg/m2, and mean biologic MELD 9 (IQR, 7-17). Most frequent etiology was PSC (n = 12, 22.6%). Forty-nine patients (92.5%) received neoadjuvant therapy, including systemic (n = 48, 90.6%) and locoregional therapy (LRT) (n = 22, 41.5%), to which PH tumors were both most and least responsive (P = .03). On explant pathology, tumor were a median size of 3.5 cm and lympho-vascular invasion (LVI) was present in 13 (24.5%) cases. Median follow-up post-transplant was 910 days (IQR, 407-1509). Probabilities of OS and RFS at 3-years post-LT were 69.2% (95% CI, 56.9%-84.2%) and 57.4% (95% CI, 43.7%-75.4%). In multivariable analysis, OS was associated with tumor type and LVI, and RFS with age, BMI, PSC and LRT. After a median post-LT period of 38 days (IQR, 27-79.5), 39 (71.7%) patients started mTOR inhibition with lowered tacrolimus goal. Cox proportional hazard model showed significant association of OS with mTOR inhibition, though this was not validated by a time-dependent co-variate approach. CONCLUSIONS:In this single center cohort of CCA, post-LT outcomes were significantly greater for patients with IH tumors and no LVI. Immunosuppression with mTOR inhibition was not consistently associated with outcomes.

Background. Alcohol use disorder (AUD) incidence is increasing, and alcohol-associated liver disease is the leading indication for liver transplantation (LT) in the United States. Many centers have adopted “early LT” (ELT) for patients with <6 mo of abstinence. This study evaluates whether ELT outcomes in acutely ill recipients are equivalent to standard LT (SLT). Methods. We retrospectively analyzed LTs for alcohol-associated liver disease in patients with AUD at a single center between January 2019 and December 2021. Patients were categorized as ELT (<6 mo) or SLT (≥6 mo). Alcohol relapse was categorized as “abstinent,” “slip,” or “harmful,” with use defined by phosphatidylethanol or self-reported consumption. Outcomes were post-LT relapse, graft, and patient survival. Results. Of 183 patients (ELT: 99 [54.1%]; SLT: 84 [45.9%]), ELT recipients were younger, had higher model for end-stage liver disease scores, shorter waitlist times, and were more frequently in intensive care unit pre-LT. Multivariable analysis showed no association in time to post-LT relapse, graft, or patient survival. Intensive care unit status was associated with lower relapse risk (hazard ratio, 0.17; 95% confidence interval, 0.07-0.43; P < 0.001), whereas higher education levels were associated with higher risk (hazard ratio, 2.31; 95% confidence interval, 1.18-4.49; P = 0.014). Conclusions. Pre-LT alcohol abstinence duration does not significantly impact post-LT relapse or survival. ELT should be considered for acutely ill patients with AUD.

Background. Hepatocellular carcinoma (HCC) has a rising incidence and mortality in North America. Liver transplantation (LT) with adjunctive therapies offers excellent outcomes. However, HCC recurrences are associated with high mortality. We investigate whether adjuvant systemic therapy can reduce recurrence, as shown with other malignancies. Methods. Medical records of patients undergoing LT for HCC at a single center between January 2016 and December 2022 were retrospectively reviewed. Patients were stratified into 3 groups: (1) recipients of adjuvant sorafenib, (2) nonrecipients at high recurrence risk, and (3) nonrecipients at low risk by explant pathology features. The outcomes were overall survival (OS) and recurrence-free survival (RFS). Adjuvant sorafenib recipients were also propensity score matched 1:2 to nonadjuvant recipients based on recurrence risk features. Results. During the study period, 273 patients with HCC underwent LT and 16 (5.9%) received adjuvant sorafenib therapy. Adjuvant sorafenib recipients were demographically similar to nonrecipients and, on explant pathology, had greater tumor burden, lymphovascular invasion, and poorer differentiation (all P < 0.001). Adverse events were observed in 12 adjuvant sorafenib recipients (75%). OS was similar among the 3 groups (P = 0.2), and adjuvant sorafenib was not associated with OS in multivariable analysis (hazard ratio, 1.31; 95% confidence interval, 0.45-3.78; P = 0.62). RFS was significantly lower in sorafenib patients (hazard ratio, 6.99; 95% confidence interval, 2.12-23.05; P = 0.001). Following propensity matching, adjuvant sorafenib use was not associated with either OS (P = 0.24) or RFS rates (P = 0.65). Conclusions. In this single-center analysis, adjuvant sorafenib was not associated with OS. Recipients were observed to have shorter RFS, likely due to the increased prevalence of high-risk features, and sorafenib use was associated with high frequencies of adverse events.

Background and Aims Current scoring systems accurately predict risk of pre-liver transplant (LT) mortality but fall short in estimation of post-LT survival. This study seeks to identify biomarkers of pre-LT immune dysfunction that predict mortality following LT. Methods From 10/1/13 − 3/23/21, 279 cirrhotic patients underwent assessment of plasma biomarker (Luminex) and clinical variables immediately prior to LT (T0). Results Cox-proportional hazards modeling identified HCV IgG, Fractalkine, and MMP3 as multivariate predictors of 1-year mortality, with covariate selection by clinical importance and LASSO methodology. These were utilized to comprise the novel Liver Immune Frailty Index (LIFI), which stratifies recipients into -low, -moderate, and –high risk tertiles. One-year mortality was 1.4%, 12.7%, and 58.3% for LIFI-low, -moderate, and -high, respectively. Internal validation through bootstrap resampling with 2000 replicates demonstrates LIFI predicts early post-LT mortality with C-statistic = 0.84 and Brier score of 0.04. LIFI-high is not dependent upon HCV status. The relative contribution of the continuous variables in the LIFI calculation exceeded the discrete HCV IgG binary variable contribution. Stratification into either LIFI-high or moderate requires cumulative contribution of elevated MMP3 and Fractalkine levels. Excluding HCV IgG+ as a covariate similarly stratifies patients at high-, moderate-, and low-risk of early futility after LT based only on MMP3 and Fractalkine levels (C-statistic 0.83). Conclusions LIFI may identify patients at risk for persistent severe immune dysfunction and early mortality following LT.

BACKGROUND:Although Hispanic patients have high rates of end-stage liver disease and liver cancer, for which liver transplantation (LT) offers the best long-term outcomes, they are less likely to receive LT. Studies of end-stage renal disease patients and kidney transplant candidates have shown that targeted, culturally relevant interventions can increase the likelihood of Hispanic patients receiving kidney transplant. However, similar interventions remain largely unstudied in potential LT candidates. METHODS:Referrals to a single center in Texas with a large Hispanic patient population were compared before (01/2018-12/2019) and after (7/2021-6/2023) the implementation of a targeted outreach program. Patient progress toward LT, reasons for ineligibility, and differences in insurance were examined between the two eras. RESULTS:A greater proportion of Hispanic patients were referred for LT after the implementation of the outreach program (23.2% vs 26.2%, p = 0.004). Comparing the pre-outreach era to the post-outreach era, more Hispanic patients achieved waitlisting status (61 vs 78, respectively) and received a LT (971 vs 82, respectively). However, the proportion of Hispanic patients undergoing LT dropped from 30.2% to 20.3%. In the post-outreach era, half of the Hispanic patients were unable to get LT for financial reasons (112, 50.5%). CONCLUSIONS:A targeted outreach program for Hispanic patients with end-stage liver disease effectively increased the total number of Hispanic LT referrals and recipients. However, many of the patients who were referred were ineligible for LT, most frequently for financial reasons. These results highlight the need for additional research into the most effective ways to ameliorate financial barriers to LT in this high-need community.

BACKGROUND:The deceased donor shortage in the United States has led to increased utilization extended criteria donor (ECD) liver grafts. Centers often utilize ECD grafts in patients with low Model for End-Stage Liver Disease (MELD) scores, like patients with hepatocellular carcinoma (HCC). However, few studies have directly examined the outcomes of using ECD grafts in patients with HCC. METHODS:Adults receiving liver transplantation (LT) for HCC between 2010 and 2020 were identified in the Organ Procurement and Transplantation Network database. Recipients were categorized according to donor type: standard criteria donor (SCD), extended criteria donor, donation after brain death (ECD-DBD), and donation after circulatory death (DCD). Multivariable Cox regression analysis identified variables associated with overall or graft survival at 3 years post-LT. RESULTS:Most patients received ECD-DBD grafts (51.4%); only 8.3% received DCD grafts. The time on the waitlist was similar for ECD and SCD recipients (P = .79). SCD recipients had higher 5-year overall survival post-LT than ECD-DBD or DCD recipients (79.1%, 77.1%, and 76.8%, respectively, P < .001). Similarly, 5-year graft survival was also highest in SCD recipients (SCD = 77.8%, ECD-DBD = 75.7%, and DCD = 72.2%, P < .001). In multivariable analysis, DCD grafts increased mortality risk (hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 1.12-1.57, P = .001), but ECD-DBD grafts did not (HR = 1.10, 95% CI = 1.00-1.22, P = .052). CONCLUSIONS:DCD and ECD-DBD recipients had significantly lower overall and graft survival. However, the survival benefit of LT for patients with HCC greatly outweighs the small differences in patient and graft survival from using ECD grafts. Further research should investigate whether treatment of ECD grafts with machine perfusion may ameliorate this discrepancy.