Background. Liver transplantation cures hepatocellular carcinoma (HCC) if within conventional selection criteria. Expanded criteria are elusive. Loco-regional treatments pursue tumor downstaging from outside Milan criteria to within criteria. No trial investigated HCC-downstaging strategy to expand transplant eligibility. Methods. This multi-center trial aimed at comparing successfully downstaged HCC followed by transplantation vs. non-transplant therapies. Eligible patients had good liver function (Child-Pugh A-B7), HCC beyond Milan, 5-year estimated post-transplant survival ≥50%, no macrovascular or extrahepatic spread. Only partial-complete responses according to modified-RECIST were randomized 1:1 after 3 months observation period, during which sorafenib was allowed. Co-endpoints were survival and timeto-tumor event. We used Kaplan-Meier method, log-rank test, Cox regression for intention-to-treat analysis. Survival benefit was the difference between groups mean survival time. Organ allocation policy changed over time and limited patients' accrual to 4 years. After 4 additional years conditional power calculation estimated the probability that the final results would be statistically significant in the remaining study, given the data observed. ClinicalTrials.gov NCT01387503. Findings. 74 patients were enrolled between March 2011 to March 2015: 29 dropped-out pre-randomization. Downstaging median duration was 6 months (1-17). Success-rate was 73%. Progression during observation was 17%. 45 patients were randomized: 23 transplanted vs. 22 controls. Median followup was 71 months (IQR 60-85). 5-year overall survival was 77.5% (95%CI 61.9-97.1%) in transplants vs. 31.2% (95%CI: 16.6-58.5%) in controls (Cox hazard ratio [HR] 0.22, 95%CI: 0.08-0.61; p=0.004). 5-year tumor eventfree survival was 76.8 (95%CI: 60.8-96.9%) vs. 18.3% (95%CI: 7.1-47.0%) in controls (HR: 0.14, 95%CI: 0.05-0.38; p<0001). 5-year survival-benefit favored transplantation by 14.5 months (95%CI: 3.6-25.3; p=0.009). The trial retained a conditional power of 98.6%. Interpretation. After effective and sustained downstaging of eligible HCCs beyond Milan criteria, liver transplantation is superior to nontransplant therapies. Post-downstaging tumor response should contribute to HCC transplant criteria expansion. Funding. Italian Ministry of Health

Donation after circulatory death (DCD) in Italy constitutes a relatively unique population because of the requirement of a no-touch period of 20 minutes. The first aim of this study was to compare liver transplantations from donors who were maintained on normothermic regional perfusion after circulatory death and suffered extended warm ischemia (DCD group, n = 20) with those from donors who were maintained on extracorporeal membrane oxygenation (ECMO) and succumbed to brain death (ECMO group, n = 17) and those from standard donors after brain death (donation after brain death [DBD] group, n = 52). Second, we conducted an explorative analysis on the DCD group to identify relationships between the donor characteristics and the transplant outcomes. The 1-year patient survival for the DCD group (95%) was not significantly different from that of the ECMO group (87%; P = 0.47) or the DBD group (94%; P = 0.94). Graft survival was slightly inferior in the DCD group (85%) because of a high rate of primary nonfunction (10%) and retransplantation (15%) but was not significantly different from the ECMO group (87%; P = 0.76) or the DBD group (91%; P = 0.20). Although ischemic cholangiopathy was more frequent in the DCD group (10%), this issue did not adversely impact graft survival because none of the recipients underwent retransplantation due to biliary complications. Moreover, the DCD recipients were more likely to develop posttransplant renal dysfunction with the need for renal replacement therapy. Further analysis of the DCD group showed that warm ischemia >125 minutes and an Ishak fibrosis score of 1 at liver biopsy negatively impacted serum creatinine and alanine transaminase levels in the first posttransplant week, respectively. In conclusion, our findings encourage the use of liver grafts from DCD donors maintained by regional perfusion after proper selection.

The DCD livers were allocated according to the Italian allocation policy, primarily on a regional basis. 19 Superurgent patients and candidates with a model for end-stage liver disease (MELD) score ≥30 points were excluded. Most centers preferably selected low-risk recipients and prioritized candidates, for example, with hepatocellular carcinoma (HCC).

COVID‐19 pandemic dramatically impacted transplantation landscape. Scientific societies recommend against the use of donors with active SARS‐CoV‐2 infection. Italian Transplant Authority recommended to test recipients/donors for SARS‐CoV‐2‐RNA immediately before liver transplant (LT) and, starting from November 2020, grafts from deceased donors with active SARS‐CoV‐2 infection were allowed to be considered for urgent‐need transplant candidates with active/resolved COVID‐19. We present the results of the first 10 LTs with active COVID‐19 donors within an Italian multicenter series. Only two recipients had a positive molecular test at LT and one of them remained positive up to 21 days post‐LT. None of the other eight recipients was found to be SARS‐CoV‐2 positive during follow‐up. IgG against SARS‐CoV‐2 at LT were positive in 80% (8/10) of recipients, and 71% (5/7) showed neutralizing antibodies, expression of protective immunity related to recent COVID‐19. In addition, testing for SARS‐CoV‐2 RNA on donors’ liver biopsy at transplantation was negative in 100% (9/9), suggesting a very low risk of transmission with LT. Immunosuppression regimen remained unchanged, according to standard protocol. Despite the small number of cases, these data suggest that transplanting livers from donors with active COVID‐19 in informed candidates with SARS‐CoV‐2 immunity, might contribute to safely increase the donor pool.