Luciano De Carlis

Objective: To investigate the impact of cumulative liver age on graft survival in liver transplant recipients. Summary of Background Data: Organ shortage has led to increased use of elderly donor livers for an ageing group of recipients, particularly in Europe. We hypothesized that hypothermic oxygenated perfusion (HOPE) enhances graft resilience against aging in livers from elderly donors. Methods: This post-hoc analysis of the multicenter European HOPE-REAL study (NCT05520320) examined liver age in adult recipients of HOPE-treated brain-dead donor (DBD) livers. Cumulative liver age was defined as the sum of donor age and post-transplant graft survival. HOPE-treated DBD liver transplants were compared with a single-center control cohort of non-perfused DBD livers using propensity score matching to adjust for confounders. Results: The median cumulative liver age was significantly higher in the HOPE-treated (n=768) cohort than in the non-perfused (n=863) group (69 vs. 61 years, PPPP<0.001). Conclusions: HOPE treatment appears to mitigate the risks associated with transplanting elderly DBD livers, leading to excellent long-term survival in an ageing recipient population. These findings support broader adoption of HOPE to improve utilization of older donor livers and expand the donor pool.

Total hepatectomy and liver transplantation has emerged as a game-changing strategy in the treatment of several liver-confined primary or metastatic tumors, opening the new era of transplant oncology. However, the expansion of indications is going to worsen the chronic scarcity of organs, and new strategies are needed to enlarge the donor pool. A possible source of organs could be developing split liver transplantation (SLT) programs. We propose to refer donors aged 18-50 years unsuitable for pediatric patients and donors aged 50-60 years for split evaluation. This will generate new small left lateral grafts that can be used for RAPID procedures, based on a national waiting list specifically for non-HCC oncologic patients. Centralized imaging review will streamline the donor-recipient matching process and address organizational challenges. Additionally, adopting an ex-situ splitting technique during hypothermic oxygenated machine perfusion could further enhance logistical efficiency and improve graft viability. The proposed protocol (ALERT 50) will therefore promote the development of oncologic indications without affecting the standard waiting list and without competing with urgent or pediatric patients. Export

Posttransplant HCC recurrence significantly impacts survival, yet its management is challenging due to limited evidence. With recent advancements in HCC treatment, updated data on managing recurrent diseases are needed. In this retrospective study across 6 centers (2000–2022), we employed Cox proportional-hazards regression and log-rank tests to assess survival differences. A prognostic score model was developed to categorize patient survival. The efficacy of tyrosine kinase inhibitors was evaluated through propensity score matching. In our study, 431 of 3349 (14%) patients with HCC who underwent transplantation developed recurrence within a median interval of 18 (IQR: 9–32) months. One hundred forty-seven (34%) underwent curative-intent treatments, 207 (48%) received palliative treatments, and 77 (18%) were given best-supportive care. Patients undergoing curative-intent treatments had better survival from the time of recurrence with a median survival of 45 (95% CI: 36–63) months and 1/3/5-year survival of 90%/56%/43% compared to those receiving noncurative treatments (median: 11 [95% CI: 10–13] mo, 1/3/5-y survival of 46%/10%/7%, log-rank p < 0.001). Patients with recurrence diagnosed in the era 2018–2022 showed improved survival over the previous era (HR 0.64 [95% CI: 0.47–0.86]). Multivariable analysis identified 5 prognostic factors: ineligibility for curative-intent treatment (HR: 3.5 [95% CI: 2.7–4.6]), recurrence within 1 year (HR: 1.7 [95% CI: 1.3–2.1]), poor tumor differentiation (HR: 1.5 [95% CI: 1.1–1.9]), RETREAT score ≥3 (HR: 1.4 [95% CI: 1.1–1.8]), and alpha-fetoprotein at recurrence ≥400 ng/mL (HR: 1.4 [95% CI: 1.1–1.9]). These factors contributed to a prognostic scoring system (0–9) that stratified patients into 3 prognosis groups. Both propensity score-matched analysis and multivariable regression indicated that lenvatinib was not statistically superior to sorafenib in terms of efficacy. Curative-intent treatments should be advocated for patients with posttransplant recurrence whenever possible. Prognostic factors linked to aggressive tumor biology significantly influence survival. Advancements in HCC management have improved survival outcomes over the past 5 years.

Dual hypothermic oxygenated perfusion (DHOPE) is increasingly being used to extend liver preservation to improve transplant logistics. However, little is known about its benefits in high-risk liver grafts. This study aimed to investigate whether prolonged DHOPE provides benefits other than improved logistics in all liver types. We performed a national retrospective cohort study of 177 liver transplants from 12 Italian centers preserved with DHOPE for ≥4 hours between 2015 and 2022. A control group of 177 DHOPEs of p= 0.008). Among prolonged DHOPEs, no differences in transplant outcomes were observed according to donor risk index, Eurotransplant definition for marginal grafts, and balance of risk score. DHOPE duration was associated with a lower risk of AKI in multivariable models adjusted for donor risk index, Eutrotransplant marginal grafts, and balance of risk score. Prolonged hypothermic oxygenated perfusion confirmed its protective effect against AKI in a multivariable model adjusted for donor and recipient risk factors [OR: 0.412, 95% CI: 0.200–0.850,p= 0.016]. Prolonged DHOPE is widely used to improve transplant logistics, provides good results with high-risk grafts, and appears to be associated with a lower risk of posttransplant AKI. These results provide further insight into the important role of DHOPE in preventing posttransplant complications.

Liver transplantation (LT) was considered an ineffective treatment for perihilar cholangiocarcinoma (pCCA) until the successful experience of the Mayo Clinic, proposing a protocol with strict inclusion criteria and neoadjuvant radio-chemotherapy. Since 2015, pCCA is considered an indication for LT in Italy only in the context of controlled prospective studies. We performed a survey among the 22 Italian Liver Transplant Centers to assess the results of LT for pCCA. Eight centers reported 53 cases from 1986 to 2021 (Bologna 12, Padova 10, Niguarda 10, Milano Tumori 8, Torino 5, Pisa 4, Ancona 2, Modena 2). Patients were divided according to whether they recieved neoadjuvant radio-chemotherapy (Group 1, 25 cases) or not (Group 2, 28 cases). Eleven patients were transplanted without neoadjuvant treatment after 2015. Overall survival at 1, 3 and 5 years was 83.8%, 56.6% and 50.6% in Group 1 and 72.4%, 41.4% and 35.5% in Gropu 2 (p = 0.13). Recurrence-free survival at 1, 3, and 5 years was 91.2%, 61.1% and 47.2% in Group 1 and 58.2%, 42.2%, and 36.1% in Group 2 (p = 0.16). A competing risk regression analysis showed a 5-year risk of cancer-related death of 19% for patients in Group 1 against 62.3% in Group 2, with a hazard ratio of 0.31 (95%CI [0.10–0.98], p 0.047). This survey promoted a discussion about the limitations of the Mayo protocol and set the basis for the adoption of a new nationwide protocol (LITHALICA–NCT06125769), having the same inclusion criteria but proposing standard of care chemotherapy as neoadjuvant regimen.

Living donor liver transplantation (LDLT) has been proposed in many countries to reduce organ shortage. While the early postoperative outcomes have been well investigated, little is known about the long-term follow-up of the living donors. We, therefore, designed a systematic review of the literature to explore long-term complications and quality of life among living donors. We searched MEDLINE and EMBASE registries for studies published since 2013 that specifically addressed long-term follow-up following living-donor liver donation, concerning both physical and psychological aspects. Publications with a follow-up shorter than 1 year or that did not clearly state the timing of outcomes were excluded. A total of 2505 papers were initially identified. After a thorough selection, 17 articles were identified as meeting the eligibility criteria. The selected articles were mostly from North America and Eastern countries. Follow-up periods ranged from 1 to 11.5 years. The most common complications were incision site discomfort (13.2–38.8%) and psychiatric disorders (1–22%). Biliary strictures occurred in 1–14% of cases. Minimally invasive donor hepatectomy could improve quality of life, but long-term data are limited. About 30 years after the first reported LDLT, little has been published about the long-term follow-up of the living donors. Different factors may contribute to this gap, including the fact that, as healthy individuals, living donors are frequently lost during mid-term follow-up. Although the reported studies seem to confirm long-term donor safety, further research is needed to address the real-life long-term impact of this procedure. Graphical abstract