INTRODUCTION:Donation after circulatory death (DCD) graft use has become a standard practice globally to increase access to liver transplantation (LT). Machine preservation strategies have been widely adopted to improve graft quality, mitigate ischemia-reperfusion injury, expand organ utilization and enable organ viability assessment. However, the various approaches to MP have never been directly compared, particularly in the DCD cohort which might experience the greatest benefit. METHODS:All cases of adult DCD-LT 2014-2024 preserved MP were collected from centers in Italy, The Netherlands, Switzerland, UK, and USA. DCD grafts preserved with cold storage (SCS) alone from previously established DCD-benchmarking cohorts served as comparators. Core Outcome Sets methodology was employed for standardized outcome analysis, comparing the impact of MP technologies in DCD grafts within established "benchmark" criteria to those with extended risk factors outside benchmarks. RESULTS:Data were collected for 1538 perfused DCD-LT from >30 transplant centers; 995 (65%) were outside-benchmark criteria. Nearly half received NRP alone or combined with ex-situ perfusion (49%). Inside benchmark, nonanastomotic biliary strictures (NAS) were equally common in upfront NMP (14%) and back-to-base (B-t-B) NMP (14%). NRP (1%) and NRP+HOPE (2%) were protective (P<0.001). Outside benchmark, NAS was least frequent in the NRP+HOPE (2%), and NRP-alone (4%) group, and most common in the B-t-B NMP (18%, P<0.001) cohort. Upfront NMP demonstrated a lower observed NAS incidence than B-to-B NMP (9% vs. 18%). NRP, NRP+HOPE, and HOPE demonstrated a pattern of convergence in outcomes between inside- and outside-benchmark grafts in multivariable analyses. Binary logistic mixed-effects modelling demonstrated NAS-reduction with NRP+HOPE (OR=0.201, 95% CI= 0.075-0.569) and NRP alone (OR=0.281, 0.105-0.569). Other preservation modalities did not differ, including upfront NMP, which was similar to B-t-B NMP and SCS. Increasing donor age was detrimental to NAS rates (OR=1.02, 95% CI= 1.004-1.036). Donor and preservation factors demonstrated a 19% impact on NAS versus recipient factors (labMELD, age, BMI), which contributed with only 3% (Conditional Pseudo-R2=0.201, Marginal=0.187). Similar trends were observed regarding actuarial 1-year GS. CONCLUSIONS AND RELEVANCE:Machine preservation strategies were associated with differences in outcomes in DCD LT and with lower observed NAS incidence and favorable adjusted survival estimates in DCD LT. NMP-based preservation was not associated with statistically significant reductions in NAS compared with benchmark SCS cohorts.

BACKGROUND:Liver surgery carries a significant risk of perioperative bleeding. This randomized clinical trial compared the safety and efficacy of ETHIZIA, a novel, highly adaptable hemostatic patch, to the current standard of care during open liver surgery. METHODS:Adult subjects (N = 132) were randomized 2:1 to ETHIZIA or TachoSil to treat one or more target bleeding sites (TBS) on the liver transection plane. The objective was to demonstrate non-inferiority (margin 10%) and subsequently, superiority, of ETHIZIA to TachoSil in hemostatic success at 3 min post-application. RESULTS:For the first-treated TBS (Per protocol set, ETHIZIA N = 87, TachoSil N = 43), 3-min hemostatic success was both non-inferior (p < 0.0001) and superior (p = 0.0038) for ETHIZIA (93.1%) compared to TachoSil (76.7%); the median time to hemostasis was significantly shorter (0.5 versus 3.0 min, respectively (p < 0.0001)). Failure and rescue rates were lower for ETHIZIA (1.1% and 3.4%) than for TachoSil (7.0% and 11.6%). Efficacy results including additionally treated TBS were similar (ETHIZIA N = 139 TBS, TachoSil N = 59 TBS). Bile/non-bile fluid collections were more frequent in ETHIZIA-treated subjects, but multivariable regression indicated a multifactorial surgical basis and no association with hemostatic device. CONCLUSION:Fast and robust hemostasis supports ETHIZIA as a valuable and safe new hemostatic agent during open liver surgery. CLINICAL TRIAL REGISTRATION:The trial was registered at ClinicalTrials.gov as NCT05385952.

Liver transplant is the definitive treatment of children with end-stage liver disease, select metabolic disorders, and unresectable hepatic malignancies. Radiologists play a central role in the multidisciplinary transplant team, contributing to preoperative assessment, surgical planning, and postoperative surveillance. This article, a report from the Pediatric LI-RADS Working Group in collaboration with pediatric liver transplant surgeons, highlights the unique aspects of pediatric liver transplantation, focusing on critical anatomic, imaging, and surgical considerations specific to children. Use of the Pretreatment Extent of Tumor (PRETEXT) staging system for tumor staging is described, along with anatomic factors relevant to resectability and transplant eligibility. Particular attention is given to technical aspects of transplant, including the frequent use of living donor and segmental grafts in pediatric recipients. Imaging protocols for both donor and recipient evaluations are reviewed, with an emphasis on volumetric analysis, vascular and biliary anatomy, and identification of anatomic variants that may influence surgical decision-making. Postoperative imaging findings, including common vascular and biliary complications, are also discussed. By understanding the unique anatomic and surgical considerations in pediatric liver transplantation, radiologists can enhance diagnostic accuracy, facilitate interdisciplinary communication, and support optimal outcomes for pediatric transplant recipients.

Background:In the United States, no published guidelines promote exposure to technical variants (ie, living donor or split liver) during transplant fellowship. Simulation with hands-on liver models may improve training in transplantation. This pilot study addressed 3 overall goals (material and model creation tools, recruitment rates and assessment of workload, and protocol adherence). Methods:A patient-specific hands-on liver model was constructed from clinical imaging, and it needed to be resilient and realistic. Multiple types of materials were tested between January 2020 and August 2022. Participants were recruited stepwise. A left lateral segmentectomy simulation was conducted between August 2022 and December 2022 to assess protocol adherence. Results:Digital anatomy 3-dimensional printing was considered the best option for the hands-on liver model. The recruitment rate was 100% and 47% for junior attendings and surgical residents, respectively. Ten participants were included and completed all the required surveys. Seven (70%) and 6 (60%) participants "agreed" that the overall quality of the model and the material were acceptable for surgical simulation. Five participants (50%) "agreed" that the training improved their surgical skills. Nine participants (90%) "strongly agreed" that similar sessions should be included in surgical training programs. Conclusions:Three-dimensional hands-on liver models have the advantage of tactile feedback and were rated favorably as a potential training tool. Study enrollment for further studies is possible with the support of leadership. Rigorous multicenter designs should be developed to measure the actual impact of 3-dimensional hands-on liver models on surgical training.

Background. In the paediatric liver transplant programme in Johannesburg, South Africa (SA), tacrolimus is the calcineurin inhibitor of choice, comprising an essential component of the immunosuppression regimen. It is characterised by a narrow therapeutic index and wide interpatient variability, necessitating therapeutic drug monitoring of whole-blood concentrations. Pharmacogenetic research, although not representative of SA population groups, suggests that single-nucleotide polymorphisms within the cytochrome P450 3A5 (CYP3A5) gene contribute to the variability in tacrolimus dosing requirements. The rs776746 polymorphism, CYP3A5*3, results in a splice defect and a non-functional enzyme. Clinically, to reach the same tacrolimus concentration-to-dose ratio (CDR), expressors (CYP3A5*1/*1 and *1/*3) require a higher tacrolimus dose than non-expressors (*3/*3). Objectives. To compare the pharmacokinetics of tacrolimus in paediatric liver transplant recipients with their donors’ CYP3A5 genotypes, considering both donor and recipient characteristics. Methods. Blood samples from 46 living liver donors were collected, their genomic DNA was extracted, and their CYP3A5 genotype was established (polymerase chain reaction and restriction fragment length polymorphism analysis, validated by Sanger sequencing). The relationship of donor and recipient characteristics with the mean tacrolimus CDR was analysed using a general linear model. Non- confounding significant variables were included in a multiple regression model. Results. The study showed that all expressor donors genotyped as CYP3A5*1/*1 were of black African self-reported race and ethnicity. During the first 15 days post-transplant, we found that children who received grafts from donor CYP3A5 expressors (CYP3A5*1/*1 and *1/*3) had significantly lower mean tacrolimus CDRs compared with those who received grafts from donor CYP3A5 non-expressors (*3/*3); the recipients of CYP3A5 expressor grafts therefore require higher doses of oral tacrolimus to achieve the same therapeutic target range. In addition, graft-to-recipient weight ratio and the CYP3A5 donor genotypes were independent factors that significantly (p<0.05) affected mean tacrolimus CDRs in recipients. Conclusion. In this study, we showed that all CYP3A5*1 homozygote donors were of black African self-reported race and ethnicity, and tacrolimus CDRs in paediatric living-donor liver transplant recipients were significantly affected by donor graft size and donor CYP3A5 genotypes. Information from this study may inform the development of an Afrocentric tacrolimus precision-medicine algorithm to optimise recipient safety and graft outcomes.

Background. Children are removed from the liver transplant waitlist because of death or progressive illness. Size mismatch accounts for 30% of organ refusal. This study aimed to demonstrate that 3-dimensional (3D) technology is a feasible and accurate adjunct to organ allocation and living donor selection process. Methods. This prospective multicenter study included pediatric liver transplant candidates and living donors from January 2020 to February 2023. Patient-specific, 3D-printed liver models were used for anatomic planning, real-time evaluation during organ procurement, and surgical navigation. The primary outcome was to determine model accuracy. The secondary outcome was to determine the impact of outcomes in living donor hepatectomy. Study groups were analyzed using propensity score matching with a retrospective cohort. Results. Twenty-eight recipients were included. The median percentage error was –0.6% for 3D models and had the highest correlation to the actual liver explant (Pearson’s R = 0.96, P < 0.001) compared with other volume calculation methods. Patient and graft survival were comparable. From 41 living donors, the median percentage error of the allograft was 12.4%. The donor-matched study group had lower central line utilization (21.4% versus 75%, P = 0.045), shorter length of stay (4 versus 7 d, P = 0.003), and lower mean comprehensive complication index (3 versus 21, P = 0.014). Conclusions. Three-dimensional volume is highly correlated with actual liver explant volume and may vary across different allografts for living donation. The addition of 3D-printed liver models during the transplant evaluation and organ procurement process is a feasible and safe adjunct to the perioperative decision-making process.

BackgroundSupply-demand mismatch in solid organ transplantation is particularly pronounced in small children. For liver transplantation, advanced surgical techniques for reducing deceased and living donor grafts allow access to life-saving transplantation. Living donor left lateral segment liver grafts have been successfully transplanted in small children in our center since 2013, the only program providing this service in Sub-Saharan Africa. This type of partial graft remains too large for children below 6 kg body weight and generally requires reduction. MethodsA left lateral segment graft was reduced in situ from a directed, altruistic living donor to yield a hyperreduced left lateral segment graft. ResultsThe donor was discharged after 6 days without complications. The recipient suffered no technical surgical complications except for an infected cut-surface biloma and biliary anastomotic stricture and remains well 9 months post-transplant. ConclusionsWe report the first known case in Africa of a hyperreduced left lateral segment, ABO incompatible, living donor liver transplant in a 4,5 kg child with pediatric acute liver failure (PALF).

Pharmaceutical companies subject all new molecular entities to a series of in vitro metabolic characterizations that guide the selection and/or design of compounds predicted to have favorable pharmacokinetic properties in humans. Current drug metabolism research is based on liver tissue predominantly obtained from people of European origin, with limited access to tissue from people of African origin. Given the interindividual and interpopulation genomic variability in genes encoding drug-metabolizing enzymes, efficacy and safety of some drugs are poorly predicted for African populations. To address this gap, we have established the first comprehensive liver tissue biorepository inclusive of people of African origin. The African Liver Tissue Biorepository Consortium currently includes three institutions in South Africa and one in Zimbabwe, with plans to expand to other African countries. The program has collected 67 liver samples as of July 2023. DNA from the donors was genotyped for 120 variants in 46 pharmacogenes and revealed variants that are uniquely found in African populations, including the low-activity, African-specific CYP2C9*5 and *8 variants relevant to the metabolism of diclofenac. Larger liver tissue samples were used to isolate primary human hepatocytes. Viability of the hepatocytes and microsomal fractions was demonstrated by the activity of selected cytochrome P450s. This resource will be used to ensure the safety and efficacy of existing and new drugs in African populations. This will be done by characterizing compounds for properties such as drug clearance, metabolite and enzyme identification, and drug-drug and drug-gene interactions. SIGNIFICANCE STATEMENT: Standard optimization of the drug metabolism of new molecular entities in the pharmaceutical industry uses subcellular fractions such as microsomes and isolated primary hepatocytes, being done mainly with tissue from donors of European origin. Pharmacogenetics research has shown that variants in genes coding for drug-metabolizing enzymes have interindividual and interpopulation differences. We established an African liver tissue biorepository that will be useful in ensuring drug discovery and development research takes into account drug responses in people of African origin.

A position statement of the International Pediatric Transplant Association endorsing prioritizing pediatric recipients for deceased donor organ allocation, examining the key ethical arguments that serve as the foundation for that position, and making specific policy recommendations to support prioritizing pediatric recipients for deceased donor organ allocation globally.