Nicolas Noriega

Relapse occurs in 10%–20% of children with hepatoblastoma and is associated with inferior outcomes, yet standardized management remains limited. Defining risk factors and relapse patterns, as well as the role of surgery, particularly transplantation, is critical to optimizing survival. A retrospective review was performed of patients aged 0–18 years diagnosed with hepatoblastoma from 2007 to 2024. Demographics, tumor characteristics, treatment course, relapse patterns, and outcomes were collected. Analyses included univariable and multivariable logistic regression, Kaplan–Meier survival estimation, and log‐rank testing. Among 135 patients, 98 (72.6%) achieved remission without relapse, 32 (23.7%) relapsed, and 5 (3.7%) experienced primary progression without remission. Older age, PRETEXT (pretreatment extent of disease) IV, metastatic disease at diagnosis, and macrovascular invasion were associated with relapse on univariable analysis, but only older age remained independently associated with relapse (adjusted odds ratio 1.27 per year, 95% confidence interval 1.05–1.53); PRETEXT IV and metastatic disease were not significantly associated with overall survival. Lung‐only relapse demonstrated favorable survival (100% alive), whereas combined liver and lung or extrahepatic relapse had poorer outcomes (40%–44% alive), although survival did not differ significantly across relapse sites ( p = 0.15). Of 54 liver transplant recipients, 44 underwent upfront transplantation, and 10 underwent salvage transplantation, with no significant difference in overall survival ( p = 0.90), although the salvage group was small. Relapse or progression after upfront transplantation occurred in 27% of recipients; lung‐only relapse again conferred favorable survival. Long‐term survival is achievable in relapsed hepatoblastoma, particularly for isolated pulmonary relapse. Older age, likely a surrogate for adverse tumor biology, was associated with relapse but did not preclude survival when aggressive multimodal therapy was used. Salvage transplantation achieved durable survival in selected patients and should be considered for unresectable intrahepatic relapse when extrahepatic disease is absent or controlled.

Background: Survival in pediatric liver transplantation (PLT) has significantly improved in infants under 1 year, but < 10 kg and < 6 months continue to have poor outcomes with a paucity of information on ultra‐low weight (ULW) infants (< 5 kg). We compared intraoperative vasopressor use in < 5 kg versus 5–< 9.9 kg PLT recipients. Methods: We conducted a single‐center retrospective review of all PLT recipients < 10 kg at time of transplant from 2009 to 2022, excluding multi‐organ transplantation. We collected data on demographics, diagnosis, intraoperative vasoactive infusions, blood loss and requirements, and abdominal closure timing. Outcomes data include total mechanical ventilation, intensive care and hospital length of stay days, 1‐year patient and graft survival and thrombotic complications. Results: ULW < 5 kg and 5–9.9 kg patients showed average weight of 4.53 versus 7.30 kg ( p ‐value < 0.0001) and average age of transplant 3.36 versus 7.90 months ( p ‐value 0.0002). The most common etiology of liver disease for ULW versus 5–9.9 kg was neonatal acute liver failure (3 of 5) versus biliary atresia (41 of 63). No significant difference in anhepatic time, abdominal closure, blood products transfused/kg, estimated blood loss/kg was noted. Total days of mechanical ventilation, ICU and hospital LOS were similar between groups. ULW trends toward higher doses of vasopressors during PLT, most notably at end of case compared to 5–9.9 kg ( p = 0.06). Overall, 1‐year graft and patient survival were 91% and 94%, respectively. HAT and PVT did not appear to be associated with VIS by phase of surgery, but PVT occurred relatively more in the < 5 kg group (2 vs. 4) and HAT in the 5–9.9 kg group (0 vs. 3). Conclusions: Results show etiology of liver failure differs and < 5 kg trends to an increased amount of vasopressor use, especially at end of case, suggesting more hemodynamic instability requiring support; however, this did not correlate with measured hospital metrics. Split graft PLT recipients have more blood loss and require more transfusions. PVT was observed more in the < 5 kg cohort. Etiology, not just size or early age, may contribute to the higher and sustained pressor requirements and possible PVT risk in ULW infants.

Background and Aims: Restitution of the extrahepatic biliary luminal epithelium in cholangiopathies is poorly understood. Prominin-1 (Prom1) is a key component of epithelial ciliary body of stem/progenitor cells. Given that intrahepatic Prom1-expressing progenitor cells undergo cholangiocyte differentiation, we hypothesized that Prom1 may promote restitution of the extrahepatic bile duct (EHBD) epithelium following injury. Approach and Results: Utilizing various murine biliary injury models, we identified Prom1-expressing cells in the peribiliary glands of the EHBD. These Prom1-expressing cells are progenitor cells which give rise to cholangiocytes as part of the normal maintenance of the EHBD epithelium. Following injury, these cells proliferate significantly more rapidly to re-populate the biliary luminal epithelium. Null mutation of Prom1 leads to significantly >10-fold dilated peribiliary glands following rhesus rotavirus–mediated biliary injury. Cultured organoids derived from Prom1 knockout mice are comprised of biliary progenitor cells with altered apical-basal cellular polarity, significantly fewer and shorter cilia, and decreased organoid proliferation dynamics consistent with impaired cell motility. Conclusions: We, therefore, conclude that Prom1 is involved in biliary epithelial restitution following biliary injury in part through its role in supporting cell polarity.

Background and Aims: Biliary atresia (BA), a congenital cholestatic liver disease, commonly culminates in end-stage liver disease. We previously demonstrated in BA that Prominin-1 (Prom1)-expressing hepatic progenitor cells (HPCs) expand within regions of developing fibrosis, giving rise to cholangiocytes within biliary ductular reactions. Null mutation of Prom1 or ablation of cells expressing Prom1 significantly diminishes fibrogenesis. FN14, the receptor for TNF-like weak inducer of apoptosis (TWEAK), is expressed by HPCs. TWEAK/FN14 signaling promotes fibrosis in multiple organ systems. Therefore, we hypothesized that TWEAK/FN14 signaling mediates Prom1-expressing HPC proliferation leading to profibrogenic ductular reactions in BA. Approach and Results: The experimental mouse model of BA mediated by perinatal rhesus rotavirus (RRV) infection resulted in increased co-expression of Fn14 in Prom1-expressing HPCs within regions of ductular reactions. FN14 antagonist L524-0366 decreased ductular reactions, biliary fibrosis and periportal fibroblast activation in RRV injury. L524-0366 inhibition also demonstrated loss of downstream noncanonical NF-kB signaling expression in RRV injury. Murine HPC organoids demonstrated accelerated organoid growth and proliferation when treated with recombinant TWEAK. Increased organoid proliferation with recombinant TWEAK was lost when also treated with L524-0366. Analysis of a large publicly available RNA sequencing database of BA and normal control patients revealed significant increases in expression of PROM1, FN14, and genes downstream of TNF signaling and noncanonical NF-κB signaling pathways in BA infants. Infants who failed to achieve bile drainage after hepatoportoenterostomy had higher relative levels of FN14 expression. Conclusion: TWEAK/FN14 signaling activation in Prom1-expressing HPCs contributes to proliferation of profibrogenic ductular reactions in BA.