Time of day of liver transplant reperfusion as a predictor of disease-free and overall survival in patients with advanced hepatocellular carcinoma.

Abstract

e16282 Background: Circadian rhythms moderate cancer biology by regulating cell cycle progression, DNA activity, immune surveillance, and metastatic potential. We aim to assess the relevance of circadian rhythms for the prognosis of patients (pts) undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). Methods: This retrospective study included pts with curative-intent liver transplantation for HCC. The time of day (ToD) of each graft reperfusion was recorded, and its impact on disease-free survival (DFS) and overall survival (OS) was analysed using time-slot stratification and restricted cubic spline Cox modelling. Baseline characteristics were compared to assess group comparability. Results: From 2015 to 2020, 200 consecutive patients, including 79% males with a median age of 61.4 ± 7.1 yrs underwent liver transplant for HCC at a single centre. Mean (±SD) of waiting time on list, MELD score, and alpha-fetoprotein level (AFP) were 267 ± 293 days, 14.7 ± 7.5 UI and 18.9 ± 59.1 ng/mL, respectively. Pts were allocated to four 6-hour time slots according to graft reperfusion ToD, namely 01:00-07:00 (Night, N = 20), 07:00-13:00 (Morning, N = 49), 13:00-19:00 (Afternoon, N = 69), 19:00-01:00 (Evening, N = 62). Pts characteristics were similar for MELD Score, AFP, tumour numbers, largest tumour diameter, and time elapsed between last treatment and liver transplant in the 4 ToD slots. Median follow-up was 5years [IQR 3.3-5.0]. Recurrence occurred in 33 patients (Night N = 7, 21.2%; Morning N = 2, 6%; Afternoon N = 14, 42.4%; Evening N = 10; 30.3%). DFS differed across reperfusion ToD slots (log-rank p = 0.041), with the most favourable outcomes in the Morning slot, whose pts had improved DFS compared with the three other ToD slots (log-rank p = 0.048). Morning reperfusion was associated with a markedly lower recurrence risk compared to Night reperfusion (HR 0.17, [95% CI, 0.04–0.64]), with consistent trends for afternoon and evening reperfusion. Restricted cubic spline modelling confirmed a circadian pattern, with a nadir of recurrence risk in the early-to-mid afternoon (13:00-15:00) and higher risk estimates toward nighttime reperfusion. Finally, OS differed across reperfusion ToD slots (log-rank p = 0.043), with the most favourable outcomes in the Morning ToD slot. Conclusions: Pts with liver transplant for HCC reperfused in the morning hours had a longer DFS and OS compared to those reperfused at other ToDs. Thus, ToDs could account for significant changes in the recipient’s susceptibility to post-transplant HCC recurrence, possibly resulting from changes in immune responses and/or tumour cell seeding and implantation. These clinically relevant findings warrant further validation in retrospective and prospective pt cohorts and may impact surgical oncology practice.