Analysis of treatment benefits and prognostic factors for Post-Transplant hepatocellular carcinoma recurrence in a large Euro-American-Asian cohort.

BACKGROUND: Post-transplant 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 disease is needed. METHODS: In this retrospective study across six 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. Efficacy of tyrosine kinase inhibitors was evaluated through propensity score matching. RESULTS: In our study, 431 of 3349 (14%) transplanted HCC patients developed recurrence within a median interval of 18 (IQR:9-32) months. 147 (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 median survival of 45 (95%CI:36-63) months and 1/3/5-year survival of 90%/56%/43% compared to those receiving non-curative treatments (median: 11 (95%CI:10-13) months, 1/3/5-year survival of 46%/10%/7%, log-rank p<0.001). Patients with recurrence diagnosed in the era 2018-2022 showed improved survival over 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 AFP 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 three prognosis groups. Both propensity score-matched analysis and multivariable regression indicated that lenvatinib was not statistically superior to sorafenib in terms of efficacy. CONCLUSION: Curative-intent treatments should be advocated for patients with post-transplant recurrence whenever possible. Prognostic factors linked to aggressive tumor biology significantly influence survival. Advancements in HCC management have improved survival outcomes over the past five years.

Waiting list mortality and 5-year transplant survival benefit of patients with MASLD: An Italian liver transplant registry study.

Background & Aims: International consensus has recently introduced a new definition of metabolic dysfunction-associated steatotic liver disease (MASLD). We sought to analyse epidemiological trends, prognostic features, and transplant survival benefits of patients with MASLD and without MASLD waiting for liver transplantation (LT) in Italy. Methods: Using the Italian Liver Transplant Registry database, we analysed data from adult patients listed for primary LT attributable to end-stage chronic liver disease between January 2012 and December 2022. Independent multivariable waiting lists and post-transplant survival models were developed for patients with and without hepatocellular carcinoma (HCC). A Monte Carlo simulation was used to create 5-year transplant benefit distributions based on the presence of MASLD, HCC, and model for end-stage liver disease (MELD)-sodium values. Results: A total sample of 1,941 patients with MASLD and 11,201 patients without MASLD was considered. A significant increase in the prevalence of MASLD as an indication for LT was observed from 2012 to 2022, for both cohorts with HCC (from 17.7 to 30%) and without HCC (from 9.5 to 11.8%) cohorts. Projections suggest that, as early as next year, MASLD will overcome HCV as the second most common indication for transplantation after alcoholic liver disease in Italy. According to univariate and multivariate analyses, MASLD was not an independent predictive factor for patient survival after transplantation. However, it increased the risk of death for patients on the waiting list without HCC (hazard ratio 1.62, p <0.001). At the same MELD-sodium, the 5-year transplant benefit was higher in patients with non-HCC MASLD, followed by patients with HCC, whereas it was lower in patients without HCC and without MASLD. Conclusions: Patients with non-HCC MASLD had an increased waitlist mortality and 5-year transplant survival benefit compared with other candidates. Impact and implications: The present research addresses the critical need to understand the evolving landscape of liver transplantation indications, mainly focusing on metabolic dysfunction-associated steatotic liver disease (MASLD) in Italy. Given the significant rise in MASLD cases, these findings highlight that patients with non-HCC MASLD face increased waitlist mortality and benefit more from liver transplantation within 5 years compared with other candidates. The significance of these results lies in their emphasis on the necessity of focusing on patients with MASLD on waiting lists to improve outcomes. By tailoring transplant eligibility criteria and resource allocation, the study provides actionable insights to improve patient survival and optimise liver transplantation practices.

Are there any benefits of prolonged hypothermic oxygenated perfusion? - Results from a national retrospective study.

BACKGROUND: 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. METHODS: We performed a national retrospective cohort study of 177 liver transplants from 12 Italian centers preserved with DHOPE for ≥4h between 2015 and 2022. A control group of 177 DHOPEs of <4h during the same period was created using 1:1 propensity score matching. The impact of risk profiles and preservation times on the outcomes was assessed using univariable and multivariable regression models. RESULTS: No significant differences in post-transplant outcomes were found between prolonged and short DHOPEs. However, the prolonged group had a significantly lower incidence of post-transplant acute kidney injury (AKI) compared to the short group (30.5% vs. 44.6%, p=0.008). Among prolonged DHOPEs, no differences in transplant outcomes were observed according to donor risk index (DRI), Eurotransplant definition for marginal grafts, and balance of risk (BAR) score. DHOPE duration was associated with a lower risk of AKI in multivariable models adjusted for DRI, Eutrotransplant marginal grafts, and BAR score. Prolonged HOPE 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]. CONCLUSIONS: 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 post-transplant AKI. These results provide further insight into the important role of DHOPE in preventing post-transplant complications.

Fairness and pitfalls of the Italian waiting list for elective liver transplantation: The ECALITA registry study.

BACKGROUND: The challenge of transplant waiting-lists is to provide organs for all candidates while maintaining efficiency and equity. AIMS: We investigated the probability of being transplanted or of waiting-list dropout in Italy. METHODS: Data from 12,749 adult patients waitlisted for primary liver-transplantation from January 2012 to December 2022 were collected from the National Transplant-Registry.The cohort was divided into Eras:1 (2012-2014);2 (2015-2018);and 3 (2019-2022). RESULTS: The one-year probability of undergoing transplant increased (67.6 % in Era 1vs73.8 % in Era 3,p < 0001) with a complementary 46 % decrease in waiting-list failures. Patients with hepatocellular-carcinoma were transplanted more often than cirrhotics[at model for end-stage liver-disease (MELD)-15:HR = 1.28,95 %CI:1.21-1.35;at MELD-25:HR = 1.04,95 %CI:0.92-1.19) and those with other indications (at MELD-15:HR = 1.27,95 %CI:1.11-1.46) across all eras. Candidates with Hepatitis-B-virus (HBV)related disease had a greater probability of transplant than those with Hepatitis-C virus-related (HR = 1.13,95 %CI:1.07-1.20), alcohol-related (HR = 1.13,95 %CI:1.05-1.21), and metabolic-related (HR = 1.18,95 %CI:1.09-1.28)disease. Waiting-list failures increased by 27 % every 5 MELD-points and by 14 % for every 5-year increase in recipient-age and decreased by 10 % with each 10-cm increase in stature. Blood-group O patients showed the highest probability of waiting-list failure (HR = 1.28,95 %CI:1.15-1.43). CONCLUSIONS: Liver-transplantation waiting-list success-rates have significantly improved in Italy, with patients with hepatocellular-carcinoma and/or HBV-related diseases being favored. High MELD-score, old-age, short-stature, and blood-group O were significant risk-factors for waiting-list failure. Efforts to improve organ-allocation and prioritization-policies are underway.

The Italian experience on liver transplantation for unresectable peri-hilar cholangiocarcinoma: a national survey and future perspectives.

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.

Long-term outcomes after hypothermic oxygenated machine perfusion and transplantation of 1,202 donor livers in a real-world setting (HOPE-REAL study).

BACKGROUND & AIMS: Despite strong evidence for improved preservation of donor livers by machine perfusion, longer post-transplant follow-up data are urgently needed in an unselected patient population. We aimed to assess long-term outcomes after transplantation of hypothermic oxygenated machine perfusion (HOPE)-treated donor livers based on real-world data (i.e., IDEAL-D stage 4). METHODS: In this international, multicentre, observational cohort study, we collected data from adult recipients of HOPE-treated livers transplanted between January 2012 and December 2021. Analyses were stratified by donation after brain death (DBD) and donation after circulatory death (DCD), sub-divided by their respective risk categories. The primary outcome was death-censored graft survival. Secondary outcomes included the incidence of primary non-function (PNF) and ischaemic cholangiopathy (IC). RESULTS: We report on 1,202 liver transplantations (64% DBD) performed at 22 European centres. For DBD, a total number of 99 benchmark (8%), 176 standard (15%), and 493 extended-criteria (41%) cases were included. For DCD, 117 transplants were classified as low risk (10%), 186 as high risk (16%), and 131 as futile (11%), with significant risk profile variations among centres. Actuarial 1-, 3-, and 5-year death-censored graft survival rates for DBD and DCD livers were 95%, 92%, and 91%, vs. 92%, 87%, and 81%, respectively (log-rank p = 0.003). Within DBD and DCD strata, death-censored graft survival was similar among risk groups (log-rank p = 0.26, p = 0.99). Graft loss due to PNF or IC was 2.3% and 0.4% (DBD), and 5% and 4.1% (DCD). CONCLUSIONS: This study shows excellent 5-year survival after transplantation of HOPE-treated DBD and DCD livers with low rates of graft loss due to PNF or IC, irrespective of their individual risk profile. HOPE treatment has now reached IDEAL-D stage 4, which further supports its implementation in routine clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05520320. IMPACT AND IMPLICATIONS: This study demonstrates the excellent long-term performance of hypothermic oxygenated machine perfusion (HOPE) treatment of donation after circulatory and donation after brain death liver grafts irrespective of their individual risk profile in a real-world setting, outside the evaluation of randomised-controlled trials. While previous studies have established safety, feasibility, and efficacy against the current standard, according to the IDEAL-D evaluation framework, HOPE treatment has now reached the final IDEAL-D stage 4, which further supports its implementation in routine clinical practice.

Immunosuppression in adult liver transplant recipients: a 2024 update from the Italian Liver Transplant Working Group.

PURPOSE: Advances in surgical procedures and immunosuppressive therapies have considerably improved the outcomes of patients who have undergone liver transplantation in the past few decades. In 2020, the Italian Liver Transplant Working Group published practice-oriented algorithms for immunosuppressive therapy (IT) in adult liver transplant (LT) recipients. Due to the rapidly evolving LT field, regular updates to the recommendations are required. This review presents a consensus- and evidence-based update of the 2020 recommendations. METHODS: The Italian Liver Transplant Working Group set out to address new IT issues, which were discussed based on supporting literature and the specialists' personal experiences. The panel deliberated on and graded each statement before consensus was reached. RESULTS: A series of consensus statements were formulated and finalized on: (i) oncologic indications for LT; (ii) management of chronic LT rejection; (iii) combined liver-kidney transplantation; (iv) immunosuppression for transplantation with an organ donated after circulatory death; (v) transplantation in the presence of frailty and sarcopenia; and (vi) ABO blood group incompatibility between donor and recipient. Algorithms were updated in the following LT groups: standard patients, critical patients, oncology patients, patients with specific etiology, and patients at high immunologic risk. A steroid-free approach was generally recommended, except for patients with autoimmune liver disease and those at high immunologic risk. CONCLUSION: The updated consensus- and evidence-based 2024 recommendations for immunosuppression regimens in adult patients with ABO-compatible LT address a range of clinical variables that should be considered to optimize the choice of the immunosuppression treatment in clinical practice in Italy.

Cornerstones and divergencies in the implementation and use of liver hypertrophy techniques: results from a nationwide survey for the set-up of the prospective registry.

BACKGROUND: The aim of this national survey on liver hypertrophy techniques was to track the trends of their use and implementation in Italy and to detect analogies and heterogeneities among centers. METHODS: In December 2022, Italian centers with liver resection activity were specifically contacted and asked to fill an online questionnaire composed of 6 sections including a total of 51 questions. RESULTS: 46 Italian centers filled the questionnaire. The proportion of major/total number of liver resections was 27% and the use of hypertrophy techniques was required in 6,2% of cases. The most frequent reason of drop out was disease progression in 58.5% of cases. Most frequently used techniques were PVE and ALPPS with an increasing use of hepatic venous deprivation (HVD). Heterogeneous answers were provided regarding the cutoff values to indicate the need for hypertrophy techniques. Criteria to allocate a patient to different hypertrophy techniques are not standardized. CONCLUSIONS: The use of hypertrophy techniques is deep-rooted in Italy, documenting the established value of their role in improving resectability rate. While an evolution of techniques is detectable, still significant heterogeneity is perceived in terms of cutoff values, indications and managing protocols.

Estimation of lifetime costs for patients receiving a transplant: the case of liver transplantation related to hepatitis B in Italy.

Introduction: In Italy, post-liver transplant (LT) hepatitis B virus (HBV) reinfection prophylaxis is frequently based on a combined regimen of anti-HBV immunoglobulin (HBIG) and oral antivirals. However, little information is available at the national level on the cost of LT and the contribution of HBV prophylaxis. This study aimed to quantify the direct healthcare cost for adult patients undergoing LT for HBV-related disease over a lifetime horizon and from the perspective of a National Healthcare Service. Methods: A pharmaco-economic model was implemented with a 4-tiered approach consisting of 1) preliminary literature research to define the research question; 2) pragmatic literature review to retrieve existing information and inform the model; 3) micro-simulated patient cycles; and 4) validation from a panel of national experts. Results: The average lifetime healthcare cost of LT for HBV-related disease was €395,986. The greatest cost drivers were post-transplant end-stage renal failure (31.9% of the total), immunosuppression (20.6%), and acute transplant phase (15.8%). HBV reinfection prophylaxis with HBIG and antivirals accounted for 12.4% and 6.4% of the total cost, respectively; however, lifetime HBIG prophylaxis was only associated with a 6.6% increase (~€422 k). Various sensitivity analyses have shown that discount rates have the greatest impact on total costs. Conclusion: This analysis showed that the burden of LT due to HBV is not only clinical but also economic.

The long-term follow-up of the living liver donors.

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.

Full-left/Full-right Liver Splitting With Middle Hepatic Vein and Caval Partition During Dual Hypothermic Oxygenated Machine Perfusion.

BACKGROUND: Split liver transplantation is a valuable means of mitigating organ scarcity but requires significant surgical and logistical effort. Ex vivo splitting is associated with prolonged cold ischemia, with potentially negative effects on organ viability. Machine perfusion can mitigate the effects of ischemia-reperfusion injury by restoring cellular energy and improving outcomes. METHODS: We describe a novel technique of full-left/full-right liver splitting, with splitting and reconstruction of the vena cava and middle hepatic vein, with dual arterial and portal hypothermic oxygenated machine perfusion. The accompanying video depicts the main surgical passages, notably the splitting of the vena cava and middle hepatic vein, the parenchymal transection, and the venous reconstruction. RESULTS: The left graft was allocated to a pediatric patient having methylmalonic aciduria, whereas the right graft was allocated to an adult patient affected by hepatocellular carcinoma and cirrhosis. CONCLUSIONS: This technique allows ex situ splitting, counterbalancing prolonged ischemia with the positive effects of hypothermic oxygenated machine perfusion on graft viability. The venous outflow is preserved, safeguarding both grafts from venous congestion; all reconstructions can be performed ex situ, minimizing warm ischemia. Moreover, there is no need for highly skilled surgeons to reach the donor hospital, thereby simplifying logistical aspects.

Liver Transplantation from Elderly Donors (≥85 Years Old).

BACKGROUND: Despite the ongoing trend of increasing donor ages in liver transplantation (LT) setting, a notable gap persists in the availability of comprehensive guidelines for the utilization of organs from elderly donors. This study aimed to evaluate the viability of livers grafts from donors aged ≥85 years and report the post-LT outcomes compared with those from "ideal" donors under 40 years old. METHODS: Conducted retrospectively at a single center from 2005 to 2023, this study compared outcomes of LTs from donors aged ≥85 y/o and ≤40 y/o, with the propensity score matching to the recipient's gender, age, BMI, MELD score, redo-LT, LT indication, and cause of donor death. RESULTS: A total of 76 patients received grafts from donors ≥85 y/o and were compared to 349 liver grafts from donors ≤40 y/o. Prior to PSM, the 5-year overall survival was 63% for the elderly group and 77% for the young group (p = 0.002). After PSM, the 5-year overall survival was 63% and 73% (p = 0.1). A nomogram, developed at the time of graft acceptance and including HCC features, predicted 10-year survival after LT using a graft from a donor aged ≥85. CONCLUSIONS: In the context of organ scarcity, elderly donors emerge as a partial solution. Nonetheless, without proper selection, LT using very elderly donors yields inferior long-term outcomes compared to transplantation from very young donors ≤40 y/o. The resulting nomogram based on pre-transplant criteria allows for the optimization of elderly donor/recipient matching to achieve satisfactory long-term results, in addition to traditional matching methods.

Recipient hepatectomy technique may affect oncological outcomes of liver transplantation for hepatocellular carcinoma.

To date, caval sparing (CS) and total caval replacement (TCR) for recipient hepatectomy in liver transplantation (LT) have been compared only in terms of surgical morbidity. Nonetheless, the CS technique is inherently associated with an increased manipulation of the native liver and later exclusion of the venous outflow, which may increase the risk of intraoperative shedding of tumor cells when LT is performed for HCC. A multicenter, retrospective study was performed to assess the impact of recipient hepatectomy (CS vs. TCR) on the risk of posttransplant HCC recurrence among 16 European transplant centers that used either TCR or CS recipient hepatectomy as an elective protocol technique. Exclusion criteria comprised cases of non-center-protocol recipient hepatectomy technique, living-donor LT, HCC diagnosis suspected on preoperative imaging but not confirmed at the pathological examination of the explanted liver, HCC in close contact with the IVC, and previous liver resection for HCC. In 2420 patients, CS and TCR approaches were used in 1452 (60%) and 968 (40%) cases, respectively. Group adjustment with inverse probability weighting was performed for high-volume center, recipient age, alcohol abuse, viral hepatitis, Child-Pugh class C, Model for End-Stage Liver Disease score, cold ischemia time, clinical HCC stage within Milan criteria, pre-LT downstaging/bridging therapies, pre-LT alphafetoprotein serum levels, number and size of tumor nodules, microvascular invasion, and complete necrosis of all tumor nodules (matched cohort, TCR, n = 938; CS, n = 935). In a multivariate cause-specific hazard model, CS was associated with a higher risk of HCC recurrence (HR: 1.536, p = 0.007). In conclusion, TCR recipient hepatectomy, compared to the CS approach, may be associated with some protective effect against post-LT tumor recurrence.

Portal vein thrombosis and liver transplantation: management, matching, and outcomes. A retrospective multicenter cohort study.

BACKGROUND AND AIMS: Besides the increased risk of perioperative morbidity, graft failure, and mortality, the majority of PVT are diagnosed at liver transplantation (LT). Improving preoperative management and patient selection may lead to better short-term and long-term outcomes and reduce the risk of a futile LT. The authors aimed to identify predictors of adverse outcomes after LT in patients with nonmalignant portal vein thrombosis (PVT) and improve donor to recipient matching by analyzing the results of the Italian cohort of LT recipients. METHODS: Adult patients who underwent LT in Italy between January 2000 and February 2020 diagnosed with PVT pre-LT or at time of LT were considered eligible for inclusion. Based on a survey encompassing all 26 surgeons participating in the study, a binary composite outcome was defined. Patients were classified as having the composite event if at least one of these conditions occurred: operative time more than 600 min, estimated blood loss greater than 5000 ml, more than 20 ICU days, 90 days mortality, 90 days retransplant. RESULTS: Seven hundred fourteen patients were screened and 698 met the inclusion criteria. The analysis reports the results of 568 patients that fulfilled the criteria to enter the composite outcome analysis.Overall, 156 patients (27.5%) developed the composite outcome. PVT stage 3/4 at transplant and need for any surgical correction of PVT are independent predictors of the composite outcome occurrence. When stratified by PVT grade, overall survival at 1-year ranges from 89.0% with PVT grade 0/1 to 67.4% in patients with PVT grade 3/4 at LT ( P <0.001). Nevertheless, patients with severe PVT can improve their survival when identified risk factors are not present. CONCLUSIONS: Potential LT candidates affected by PVT have a benefit from LT that should be adequately balanced on liver function and type of inflow reconstruction needed to mitigate the incidence of adverse events. Nonetheless, the absence of specific risk factors may improve the outcomes even in patients with PVT grades 3-4.

Recent outcomes of liver transplantation for Budd-Chiari syndrome: A study of the European Liver Transplant Registry (ELTR) and affiliated centers.

BACKGROUND AND AIMS: Management of Budd-Chiari syndrome (BCS) has improved over the last decades. The main aim was to evaluate the contemporary post-liver transplant (post-LT) outcomes in Europe. APPROACH AND RESULTS: Data from all patients who underwent transplantation from 1976 to 2020 was obtained from the European Liver Transplant Registry (ELTR). Patients < 16 years, with secondary BCS or HCC were excluded. Patient survival (PS) and graft survival (GS) before and after 2000 were compared. Multivariate Cox regression analysis identified predictors of PS and GS after 2000. Supplemental data was requested from all ELTR-affiliated centers and received from 44. In all, 808 patients underwent transplantation between 2000 and 2020. One-, 5- and 10-year PS was 84%, 77%, and 68%, and GS was 79%, 70%, and 62%, respectively. Both significantly improved compared to outcomes before 2000 ( p < 0.001). Median follow-up was 50 months and retransplantation rate was 12%. Recipient age (aHR:1.04,95%CI:1.02-1.06) and MELD score (aHR:1.04,95%CI:1.01-1.06), especially above 30, were associated with worse PS, while male sex had better outcomes (aHR:0.63,95%CI:0.41-0.96). Donor age was associated with worse PS (aHR:1.01,95%CI:1.00-1.03) and GS (aHR:1.02,95%CI:1.01-1.03). In 353 patients (44%) with supplemental data, 33% had myeloproliferative neoplasm, 20% underwent TIPS pre-LT, and 85% used anticoagulation post-LT. Post-LT anticoagulation was associated with improved PS (aHR:0.29,95%CI:0.16-0.54) and GS (aHR:0.48,95%CI:0.29-0.81). Hepatic artery thrombosis and portal vein thrombosis (PVT) occurred in 9% and 7%, while recurrent BCS was rare (3%). CONCLUSIONS: LT for BCS results in excellent patient- and graft-survival. Older recipient or donor age and higher MELD are associated with poorer outcomes, while long-term anticoagulation improves both patient and graft outcomes.

Liver transplantation with uncontrolled versus controlled DCD donors using normothermic regional perfusion and ex-situ machine perfusion.

In Italy, 20 minutes of continuous, flat-line electrocardiogram are required for death declaration, which significantly increases the risks of donation after circulatory death (DCD) LT. Despite prolonged warm ischemia time, Italian centers reported good outcomes in controlled donation after circulatory death LT by combining normothermic regional and end-ischemic machine perfusion. However, data on uncontrolled DCD (uDCD) LT performed by this approach are lacking. This was a multicenter, retrospective study performed at 3 large-volume centers comparing clinical outcomes of uncontrolled versus controlled DCD LT. The aim of the study was to assess outcomes of sequential normothermic regional perfusion and end-ischemic machine perfusion in uncontrolled DCD liver transplantation (LT). Of 153 DCD donors evaluated during the study period, 40 uDCD and 59 donation after circulatory death grafts were transplanted (utilization rate 52% vs. 78%, p = 0.004). Recipients of uDCD grafts had higher MEAF (4.9 vs. 3.5, p < 0.001) and CCI scores at discharge (24.4 vs. 8.7, p = 0.026), longer ICU stay (5 vs. 4 d, p = 0.047), and a trend toward more severe AKI. At multivariate analysis, 90-day graft loss was associated with recipient BMI and lactate downtrend during normothermic regional perfusion. One-year graft survival was lower in uDCD (75% vs. 90%, p = 0.007) but became comparable when non-liver-related graft losses were treated as censors (77% vs. 90%, p = 0.100). The incidence of ischemic cholangiopathy was 10% in uDCD versus 3% in donation after circulatory death, p = 0.356. uDCD LT with prolonged warm ischemia is feasible by the sequential use of normothermic regional perfusion and end-ischemic machine perfusion. Proper donor and recipient selection are key to achieving good outcomes in this setting.

Computed Tomography and Magnetic Resonance Imaging Signs of Chronic Liver Rejection: A Case-Control Study.

OBJECTIVE: In liver transplantation, chronic rejection is still poorly studied. This study aimed to investigate the role of imaging in its recognition. METHODS: This study is a retrospective observational case-control series. Patients with histologic diagnosis of chronic liver transplant rejection were selected; the last imaging examination (computed tomography or magnetic resonance imaging) before the diagnosis was evaluated. At least 3 controls were selected for each case; radiological signs indicative of altered liver function were analyzed. χ 2 Test with Yates correction was used to compare the rates of radiologic signs in the case and control groups, also considering whether patients suffered chronic rejection within or after 12 months. Statistical significance was set at P < 0.050. RESULTS: A total of 118 patients were included in the study (27 in the case group and 91 in the control group). Periportal edema was appreciable in 19 of 27 cases (70%) and in 6 of 91 controls (4%) ( P < 0.001); ascites and hepatomegaly were present in 14 of 27 cases (52%) and 12 of 27 cases (44%), respectively, and in 1 of 91 controls (1%) ( P < 0.001); splenomegaly was present in 13 of 27 cases (48%) and in 8 of 91 controls (10%) ( P < 0.001); and biliary tract dilatation was present in 13 of 27 cases (48%) and in 11 of 91 patients controls (5%) ( P < 0.001). In the controls, periportal edema was significantly less frequent beyond 12 months after transplant (1% vs 11%; P = 0.020); the other signs after 12 months were not significant. CONCLUSIONS: The identification of periportal edema, biliary dilatation, ascites, and hepatosplenomegaly can serve as potential warning signs of ongoing chronic liver rejection. It is especially important to investigate periportal edema if it is present 1 year or more after orthotopic liver transplantation.

Dynamic surgical anatomy using 3D reconstruction technology in complex hepato-biliary surgery with vascular involvement. Results from an international multicentric survey.

INTRODUCTION: Three-dimensional liver modeling can lead to substantial changes in choosing the type and extension of liver resection. This study aimed to explore whether 3D reconstruction helps to better understand the relationship between liver tumors and neighboring vascular structures compared to standard 2D CT scan images. METHODS: Contrast-enhanced CT scan images of 11 patients suffering from primary and secondary hepatic tumors were selected. Twenty-three experienced HBP surgeons participated to the survey. A standardized questionnaire outlining 16 different vascular structures (items) having a potential relationship with the tumor was provided. Intraoperative and histopathological findings were used as the reference standard. The proper hypothesis was that 3D accuracy is greater than 2D. As a secondary endpoint, inter-raters' agreement was explored. RESULTS: The mean difference between 3D and 2D, was 2.6 points (SE: 0.40; 95 % CI: 1.7-3.5; p < 0.0001). After sensitivity analysis, the results favored 3D visualization as well (mean difference 1.7 points; SE: 0.32; 95 % CI: 1.0-2.5; p = 0.0004). The inter-raters' agreement was moderate for both methods (2D: W = 0.45; 3D: W = 0.44). CONCLUSION: 3D reconstruction may give a significant contribution to better understanding liver vascular anatomy and the precise relationship between the tumor and the neighboring structures.

The Italian data on SARS-CoV-2 infection in transplanted patients support an organ specific immune response in liver recipients.

Introduction: The study of immune response to SARSCoV-2 infection in different solid organ transplant settings represents an opportunity for clarifying the interplay between SARS-CoV-2 and the immune system. In our nationwide registry study from Italy, we specifically evaluated, during the first wave pandemic, i.e., in non-vaccinated patients, COVID-19 prevalence of infection, mortality, and lethality in liver transplant recipients (LTRs), using non-liver solid transplant recipients (NL-SOTRs) and the Italian general population (GP) as comparators. Methods: Case collection started from February 21 to June 22, 2020, using the data from the National Institute of Health and National Transplant Center, whereas the data analysis was performed on September 30, 2020.To compare the sex- and age-adjusted distribution of infection, mortality, and lethality in LTRs, NL-SOTRs, and Italian GP we applied an indirect standardization method to determine the standardized rate. Results: Among the 43,983 Italian SOTRs with a functioning graft, LTRs accounted for 14,168 patients, of whom 89 were SARS-CoV-2 infected. In the 29,815 NL-SOTRs, 361 cases of SARS-CoV-2 infection were observed. The geographical distribution of the disease was highly variable across the different Italian regions. The standardized rate of infection, mortality, and lethality rates in LTRs resulted lower compared to NL-SOTRs [1.02 (95%CI 0.81-1.23) vs. 2.01 (95%CI 1.8-2.2); 1.0 (95%CI 0.5-1.5) vs. 4.5 (95%CI 3.6-5.3); 1.6 (95%CI 0.7-2.4) vs. 2.8 (95%CI 2.2-3.3), respectively] and comparable to the Italian GP. Discussion: According to the most recent studies on SOTRs and SARS-CoV-2 infection, our data strongly suggest that, in contrast to what was observed in NL-SOTRs receiving a similar immunosuppressive therapy, LTRs have the same risk of SARS-CoV-2 infection, mortality, and lethality observed in the general population. These results suggest an immune response to SARS-CoV-2 infection in LTRS that is different from NL-SOTRs, probably related to the ability of the grafted liver to induce immunotolerance.