George Vincent Mazariegos

Background: Initiation or augmentation of pediatric liver transplant programs in the United States faces challenges of limited expertise, small volumes, and regional variation in access to care. PACH launched a prospective plan of pediatric liver program development at two sites (VAUV and FLFH) with the goals of comprehensive multidisciplinary program support, consistent surgical leadership from one team, consensus protocol development, and standardization of perioperative and postoperative care, and comprehensive long‐term follow‐up care plans. A third center, NCCM, was launched in June 2024. Methods: Between January 2016 and December 31, 2024, 140 children received pediatric liver transplants at one of the collaborative sites. A total of 215 PLT were performed at PACH during the same period. Results: Patient and graft survival were 94.4% and 93.2% respectively, with current follow‐up of 1674 ± 1037 days. Overall patient demographics, complications, and patient outcomes were similar among all institutions. Conclusions: A paradigm of systematically extending center experience directly to facilitate safe and high‐quality pediatric liver program establishment has been demonstrated, with the additional benefit of increased split liver graft utilization benefiting both adults and children. The success of this model has implications for optimizing pediatric liver transplant care in the United States.

Background: Normothermic machine perfusion (NMP) is an emerging strategy for pediatric liver transplantation, but pediatric‐specific viability criteria remain undefined. Lactate clearance, extrapolated from adult protocols, is a central marker of allograft function. In our pediatric NMP (pNMP) experience, we observed a novel pattern: initial clearance followed by secondary rise, termed rebound lactic acidosis. Methods: We retrospectively reviewed pediatric liver allografts preserved on the TransMedics Organ Care System at two centers (January 2025 through June 2026). After excluding donors > 35 kg, 18 perfusions (17 transplants) were classified as rebound lactic acidosis (lactate rise > 0.5 mmol/L after initial clearance) or sustained clearance. Rebound cases were characterized by lactate kinetics, perfusion parameters, acid–base status, bile production, histology, and recipient outcomes. Results: Six allografts demonstrated rebound, with onset 1.0–6.6 h into perfusion. All sustained bile production throughout perfusion. Circuit alkalosis temporally correlated with rebound in three cases and improved with gas flow reduction. The first allograft was discarded; the remaining five were transplanted, including one perfused for 35.5 h. Recipients had elevated POD1 transaminases and INR that normalized by POD7; three are discharged home and two remain hospitalized, all with functioning allografts (follow‐up up to 312 days). Conclusions: Rebound lactic acidosis during pNMP may not indicate allograft nonviability and may be ameliorated by modifying circuit perfusion or pH. Lactate kinetics should be interpreted within a multiparametric viability framework incorporating perfusion adequacy, acid–base status, bile production, liver function, and histology. Pediatric‐specific criteria are needed to safely expand the donor pool.

Background: Hepatoblastoma exhibits variable therapeutic response that is not fully explained by current risk stratification. While prior studies have characterized tumor composition, the role of spatial organization in determining outcome, particularly in unresectable disease requiring transplantation under immunosuppression, remains unclear. Methods: We integrated spatial transcriptomics using the 10x Genomics Visium platform ( n = 11 tumors) with single-cell spatial molecular imaging using NanoString CosMx ( n = 3 tumors) on post-chemotherapy explant specimens across clinically defined groups (relapse-prone unresectable, non-relapse unresectable, and resectable hepatoblastoma). Spatial deconvolution, module scoring, spatial co-localization, and cell-cell interaction analyses were used to define region-level transcriptional programs and their underlying cellular organization. Results: We identified three spatial architectures associated with clinical outcome. Relapse-prone tumors exhibited a centralized, TME-dominated organization enriched for progenitor-like, cycling, and stress-responsive tumor cell states co-localized with SPP1+ TAMs and CAFs, with enrichment of hypoxia response, extracellular matrix remodeling, and Midkine (MDK-LRP1) signaling. Non-relapse tumors displayed a distributed architecture with compartmentalized tumor-immune interactions, increased immune engagement, and preserved epithelial differentiation, including inflammatory hepatocyte-like states. Resection samples showed reduced tumor cell state heterogeneity and more uniform TME-immune organization. Conclusions Integration of regional and single-cell spatial transcriptomics across two platforms reveals that the chemo-remodeled tumor architecture of hepatoblastoma encodes spatially organized tumor cell-TME interactions as central determinants of therapeutic response. Translational Relevance: Current risk stratification in hepatoblastoma — principally based on staging and clinical features — does not reliably predict therapeutic response, particularly in unresectable disease. Our findings identify that spatial tumor-microenvironment (TME) organization is a key determinant of patient outcome. Specifically, our analysis reveals that disease relapse is driven by specialized macrophage-fibroblast signaling networks that promote an immune-cold, therapy-resistant niche. We define a spatially derived gene signature capturing this high-risk TME, which demonstrates strong prognostic value across independent cohorts, highlighting its potential utility as a biomarker for refined patient stratification. These results strongly suggest that incorporating spatial biomarkers into clinical assessment can improve the choice of therapy. Furthermore, the identification of Midkine (MDK) signaling and macrophage-stromal crosstalk as key components of relapse-associated architecture provides a direct rationale for targeting TME communication to combat therapeutic resistance. Together, this work supports a crucial shift from composition-based to spatially informed approaches for risk assessment and therapeutic targeting in hepatoblastoma.

Defining molecular patterns underlying pediatric end-stage liver disease and its treatment with liver transplantation requires rich datasets spanning a multitude of diagnoses and transplant outcomes. Here, we describe the spatial molecular landscape of approximately five million liver cell profiles from 98 liver tissue samples. The samples span donor liver, used here as a reference tissue, and end-stage diseases including biliary atresia, progressive familial intrahepatic cholestasis, hepatoblastoma, acute liver failure, and gestational alloimmune liver disease. Post-transplant liver allograft biopsies include those without and with T-cell-mediated and antibody-mediated rejection, mixed pathology, and outcome groups from immunosuppression withdrawal studies. Samples were profiled using the CosMx Human Universal Cell Characterization RNA Panel (1K) and the CosMx Human 6K Discovery Panel (6K). Preliminary exploratory analyses include cellular composition and gene abundance and variability across clinical cohorts. A twelve-gene signature comprising the genes with the highest variance implicates acute-phase response genes (e.g., SAA1 ) and profibrotic genes (e.g., COL1A1 ) as a shared link across these otherwise distinct conditions. This injury-repair-remodeling gene network warrants further investigation through higher-resolution, zone-specific spatial mapping to help clarify disease pathogenesis.

Background: Gestational alloimmune liver disease is the most common cause of acute liver failure in neonates. Treatment includes exchange transfusion and IVIG, though a subset of neonates requires liver transplantation for survival. Methods: We conducted a retrospective study using the Organ Procurement and Transplantation Network database and an institutional case series to characterize waitlist outcomes and patient survival among transplanted patients with gestational alloimmune liver disease. Results: 81 candidates were registered on the liver transplant waitlist with a neonatal hemochromatosis diagnosis code from October 1987 through March 2025. Of these, 36 (44.4%) received a liver transplant. Re‐transplantation was required in 6 (16.7%) patients. Four patients developed graft failure within the first year of transplant, 3 (75%) of which were due to hepatic artery thrombosis. Patient survival was 88.8% at 30 days, 82.7% at 1 year, and 79.5% at 5 years. Of the 45 candidates (55.6%) who did not receive a transplant, 20 (24.7% of all listed) died on the waitlist, 15 (18.5%) experienced improvement and ultimately did not need transplant, 8 (9.9%) were too sick to transplant, 1 (1.2%) was removed for other reasons, and 1 (1.2%) was transferred to another center. Among the institutional case series, three neonates presented with acute liver failure with workup consistent with GALD. All three were listed as status 1A, underwent successful liver transplant, and are alive present day. Conclusions: Liver transplant should be offered without hesitation for treatment‐refractory GALD. Early referral to a transplant center should occur simultaneously with initiation of medical therapy.

Biliary reconstruction is often considered the Achilles’ heel of liver transplantation, yet risk factors and outcomes remain poorly defined, particularly in pediatric living donor liver transplantation (LDLT). This international multicenter study aims to identify predictors of biliary complications and evaluate their impact on long-term outcomes. The study included 2665 pediatric patients who underwent LDLT between January 2019 and December 2023 across 19 centers. Multivariable logistic regression was performed to identify risk factors, while time-dependent Cox models were used to assess the impact on survival. The median recipient age was 11 months (IQR: 6.3–34.6), and biliary atresia was the most common diagnosis (59.7%). Bile leak and anastomotic stricture occurred in 3.6% (n=97) and 1.9% (n=51) of patients, respectively. For bile leak, higher donor BMI was an independent predictor (OR 1.09 per kg/m ² , 95% CI: 1.02–1.17). For anastomotic strictures, longer cold ischemia time was a significant predictor (OR 1.36 per hour, 95% CI: 1.03–1.79). Bile leak (aHR 4.39, 95% CI: 1.04–18.60) and biliary stricture (aHR 6.26, 95% CI: 1.58–24.80) were associated with worse graft survival. Patient survival was not significantly impacted by bile leak and stricture. Early complications more often required surgery, but survival and failure-to-rescue rates were similar regardless of treatment approach. Ultimately, bile leak and anastomotic stricture remain significant threats to graft survival. The identified risk factors offer insights for risk stratification and prevention strategies aimed at improving outcomes in children undergoing LDLT.

Background: Social adversity contributes to poor health outcomes for children after liver transplantation (LT), including greater morbidity and mortality. Although social risk screening is standard practice in pediatric primary care, its adoption in pediatric LT (pLT) remains limited, despite the significant prevalence of social risks among these families. Objectives: To evaluate barriers and facilitators to social risk screening implementation in pLT settings across a multicenter learning health network. Research Design: A mixed-methods study utilizing surveys and semistructured interviews. Subjects: Health care practitioners involved in pLT care across North American centers in the Starzl Network for Excellence in Pediatric Transplantation (SNEPT) Network. Participants included multidisciplinary team members, notably transplant physicians, social workers, and research coordinators. Measures: We surveyed center leads to identify center-level implementation challenges. We conducted 1-on-1 interviews with transplant team members to identify barriers and facilitators. We analyzed qualitative data using the Capability, Opportunity, Motivation-Behavior model, an implementation science model for developing targeted interventions. Results: We surveyed 10 centers, of which 40% of liver transplant clinics reported actively screening patients for Social Determinants of Health (SDoH). Most practitioners indicated reliance on social workers and cited limited resources as barriers to implementation. We also conducted interviews with 18 practitioners across 11 centers. Reported barriers included uncertainty about the tool’s added value, time and space constraints during patient encounters, and challenges with data entry and sharing across a multicenter network. Facilitators included institutional support, interdisciplinary collaboration, and integration into electronic health records. Conclusion: Efforts to increase adoption should focus on improving practitioners’ experiences with the tool as well as further assessing and disseminating its potential value in improving outcomes. Strategies for addressing logistical challenges to adapting workflows and simplifying network data management should be considered. This study establishes a foundation for improving screening rates and data capacity.

Antibody‐mediated rejection (AMR) is an important but infrequent cause of pediatric liver allograft injury. There is a lack of standardized guidance, and treatment approaches vary across institutions. A writing group from the Society of Pediatric Liver Transplantation conducted a comprehensive review of the published literature and collected institutional guidance documents from pediatric transplant centers across the United States to synthesize current diagnostic and management approaches to AMR in pediatric liver transplant recipients. AMR is diagnosed by the presence of characteristic histologic injury, C4d deposition, circulating donor‐specific antibody (DSA), and exclusion of alternative causes of graft dysfunction, including T cell–mediated rejection. Management strategies focus on reducing circulating DSA through therapeutic plasma exchange and suppressing ongoing immune activation with corticosteroids and intravenous immunoglobulin. In severe or refractory cases, targeted therapies such as rituximab, bortezomib, and eculizumab may be considered. A stepwise diagnostic and management algorithm is presented. This resource outlines a practical approach to the diagnosis and management of AMR in pediatric liver transplantation, serving as a reference for busy clinicians who may encounter this serious but underrecognized cause of graft dysfunction and loss.

Background and Aims: Liver transplantation is a lifesaving, standard of care intervention for infants, children, and adolescents with liver tumors, inborn errors of metabolism, and irreversible liver disease caused by a wide spectrum of liver conditions. The American Association for the Study of Liver Diseases (AASLD) last published guidelines for the evaluation and selection of pediatric liver transplant candidates in 2014. This 2026 update aims to provide evidence-based recommendations that reflect current best practices and evolving clinical knowledge. Methods: A multidisciplinary writing group of pediatric liver transplant experts and a medical librarian was convened by AASLD, with guidance by its Practice Guidelines Development Policy, and in collaboration with the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the American Society of Transplantation (AST). We conducted a systematic global literature review, formulated key clinical questions, and developed recommendations. Each recommendation was graded using the Oxford Centre for Evidence-Based Medicine framework and categorized by strength through a consensus voting process. Conclusion: This document provides clear, evidence-based guidelines on the transplant evaluation process and journey in infants, children, and adolescents. It outlines indications, contraindications, and barriers to transplantation based on robust, relevant published data. It offers best practices for pre-transplant assessment, organ allocation, and strategies to optimize survival, while allowing flexibility for individual clinical scenarios.