We report long-term intention-to-treat outcome of 118 patients with hepatocellular carcinoma (HCC) undergoing down-staging to within Milan/UNOS T2 criteria before liver transplantation (LT) since 2002, and compare the results with 488 patients listed for LT with HCC meeting T2 criteria at listing in the same period. The down-staging subgroups include 1 lesion >5 cm and ≤8 cm (n=43), 2 or 3 lesions at least one >3 cm and ≤5 cm with total tumor diameter ≤8 cm (n=61), or 4 to 5 lesions each ≤3 cm with total tumor diameter ≤8 cm (n=14). In the down-staging group, 64 patients (54.2%) had received LT, and 5 (7.5%) developed HCC recurrence. Two of the 5 patients with HCC recurrence had 4–5 tumors at presentation. The 1- and 2-year cumulative probabilities for dropout (competing risk) were 24.1% and 34.2% in the down-staging group, versus 20.3% and 25.6% in the T2 group (p=0.04). The Kaplan-Meier 5-year post-transplant survival and recurrence-free probabilities were 77.8% and 90.8%, respectively, in the down-staging group, versus 81% and 88%, respectively, in the T2 group (p=0.69 and p=0.66, respectively). The 5-year intention-to-treat survival was 56.1% in the down-staging group, versus 63.3% in the T2 group (p=0.29). Factors predicting dropout in the down-staging group included pre-treatment alpha-fetoprotein ≥1000 ng/mL (multivariate HR 2.42, p=0.02) and Child’s B versus Child’s A cirrhosis (multivariate HR 2.19, p=0.04). Conclusion: Successful down-staging of HCC to within T2 criteria was associated with a low rate of HCC recurrence and excellent post-transplant survival, comparable to those meeting T2 criteria without down-staging. Due to the small number of patients with 4–5 tumors, further investigations are needed to confirm the efficacy of down-staging in this subgroup.

Background Cirrhosis is characterized by muscle wasting, malnutrition, and functional decline that confer excess mortality not well quantified by the MELDNa score. We aimed to develop a frailty index to capture these extrahepatic complications of cirrhosis and enhance mortality prediction in cirrhotics. Methods Consecutive outpatients listed for LT at a single transplant center without MELD exceptions were assessed with candidate frailty measures. Best subset selection analyses with Cox regression identified subsets of frailty measures that predicted waitlist mortality (=death or delisting due to sickness). We selected the Frailty Index by balancing statistical accuracy with clinical utility. The net reclassification index (NRI) evaluated the %patients correctly reclassified by adding the Frailty Index to MELDNa. Results Included were 536 cirrhotics with median MELDNa of 18. 107(20%) died/were delisted. The final Frailty Index consisted of: grip strength, chair stands, and balance. The ability of MELDNa and the Frailty Index to correctly rank patients according to their 3-mo waitlist mortality risk (i.e., C-statistic) was 0.80 and 0.76, respectively, but 0.82 for MELDNa + Frailty Index together. Compared with MELDNa alone, MELDNa + Frailty Index correctly re-classified 16% of deaths/delistings (p=0.005) and 3% of non-deaths/delistings (p=0.17) with a total NRI of 19% (p<0.001). Compared to those with robust Frailty Index scores (<20%ile), cirrhotics with poor Frailty Index Scores (>80%ile) were more impaired by gait speed, IADL difficulty, exhaustion, and low physical activity [p<0.001 for each]. Conclusions Our Frailty Index for cirrhotics, comprised of 3 performance-based metrics, has construct validity for the concept of frailty and improves risk prediction of waitlist mortality over MELDNa alone.

In a retrospective analysis of 147 patients who underwent early LT (before 6 months of abstinence) for severe AH, we found that most patients survive for 1 year (94%) and 3 years (84%), similar to patients receiving liver transplants for other indications. Sustained alcohol use after LT was infrequent but associated with increased mortality. Our findings support the selective use of LT as a treatment for severe AH. Prospective studies are needed to optimize selection criteria, management of patients after LT, and long-term outcomes.

IMPORTANCE Several factors are associated with increased hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT), but no reliable risk score has been established to determine the individual risk for HCC recurrence. OBJECTIVE We aimed to develop and validate a Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score for patients with HCC meeting Milan criteria by imaging. DESIGN, SETTING, AND PARTICIPANTS Predictors of recurrence were tested in a development cohort of 721 patients who underwent LT between 2002 and 2012 at 3 academic transplant centers (University of California–San Francisco; Mayo Clinic, Rochester; and Mayo Clinic, Jacksonville) to create the RETREAT score. This was subsequently validated in a cohort of 341 patients also meeting Milan criteria by imaging who underwent LT at the University of Toronto transplant center using the C concordance statistic and net reclassification index. MAIN OUTCOMES AND MEASURES Characteristics associated with post-LT HCC recurrence. RESULTS A total of 1061 patients participated in the study; 77.8%(825) were men, and the median (IQR) age was 58.2 (53.3–63.9) years in the development cohort and 56.4 (51.7–61.0) years in the validation cohort (P < .001). In the development cohort of 721 patients (542 men), median α-fetoprotein (AFP) level at the time of LT was 8.3 ng/mL; 9.4% had microvascular invasion (n = 68), and 22.1% were beyond Milan criteria on explant (n = 159) owing to understaging by pretransplantation imaging. Cumulative probabilities of HCC recurrence at 1 and 5 years were 5.7% and 12.8%, respectively. On multivariable Cox proportional hazards regression, 3 variables were independently associated with HCC recurrence: microvascular invasion, AFP at time of LT, and the sum of the largest viable tumor diameter and number of viable tumors on explant. The RETREAT score was created using these 3 variables, with scores ranging from 0 to 5 or higher that were highly predictive of HCC recurrence (C statistic, 0.77). RETREAT was able to stratify 5-year post-LT recurrence risk ranging from less than 3%with a score of 0 to greater than 75% with a score of 5 or higher. The validation cohort (n = 340; 283 men) had significantly higher microvascular invasion (23.8% [n = 81], P < .001), explant beyond Milan criteria (37.3% [n = 159], P < .001), and HCC recurrence at 5 years (17.9% [n = 159], P = .03). RETREAT showed good model discrimination (C statistic, 0.82; 95%CI, 0.77–0.86) and superior recurrence risk classification compared with explant Milan criteria (net reclassification index, 0.40; P = .001) in the validation cohort. CONCLUSIONS AND RELEVANCE We have developed and validated a simple and novel prognostic score that may improve post-LT HCC surveillance strategies and help identify patients who may benefit from future adjuvant therapies.

Background & Aims Cirrhosis is characterized by sarcopenia and malnutrition, leading to progressive functional decline. We aimed to objectively measure functional decline in cirrhotics awaiting liver transplantation (LT) and its association with wait-list mortality. Methods Consecutive adults listed for LT with laboratory MELD≥12 at a single center underwent functional status assessments at every outpatient visit using the Short Physical Performance Battery (SPPB; 0=impaired to 12=robust) consisting of gait, chair stands, and balance tests. Joint linear time-to-event analyses modeled the simultaneous impact of longitudinal trajectory of physical function on wait-list mortality (=death/delisted for being too sick for LT). Results Included were 309 LT candidates. Median laboratory MELD was 15, serum albumin was 3.0 g/dL, 28% had ascites, 18% hepatic encephalopathy, and 83% were Child class B/C. At a median follow-up of 14 months, 15% died/were delisted and 28% underwent LT. Average physical function worsened per 3 months on the wait-list: −0.38 kg in grip strength, −0.05 meters/second in gait, 0.03 seconds in chair stands, and −0.16 SPPB points. In joint models of longitudinal trajectories of physical function and wait-list mortality adjusted for MELD-Na, albumin, hepatocellular carcinoma, and baseline physical function, the longitudinal trajectories of each physical function measure were significantly associated with wait-list mortality: grip [hazard ratio (HR)=0.89, 95%CI=0.83–0.95], gait (HR 0.72, 95%CI=0.62–0.84), chair stands (HR=1.17, 95%CI=1.09–1.25), and SPPB<10 (HR=1.45, 95%CI=1.15–2.20). Conclusions LT candidates experience significant functional decline on the wait-list, despite modest wait-time and low baseline MELD. Decline in physical function is associated with an increased risk of death/delisting, independent of liver disease severity.