Autologous and allogeneic hematopoietic stem cell transplantation (HCT) are potential curative therapy for solid tumors and cancers of the blood and bone marrow. However, the efficacy of this procedure has been impeded by several transplant-related-mortality (TRM) due to complications including complications involving damage of the endothelium in the really early phase of HCT (day 0 to 14 post-HCT) (1, 2). Sinusoidal obstruction syndrome (SOS), also called veno-occlusive disease of the liver, is one of these complications of endothelial origin that appears early after HCT but also other intensive chemotherapy regimen with irradiation of the abdomen such as in patients with neuroblastoma. Despite its relatively lower incidence in the recent years due to less aggressive conditioning regimen, the cases of SOS that evolve to multiorgan failure (MOF) have a mortality rate higher than 80%. Pre-transplant clinical or transplant characteristics have minimal ability to predict SOS incidence and outcomes. No biomarkers currently in clinical use are suitable for stratifying patients according to risk of developing SOS. Our objective in this proposal is to validate early biomarkers of SOS in a prospective multicenter trial for use in a future preemptive trial. Our central hypothesis is that SOS development can be predicted from analysis of defined biomarkers. This hypothesis is based on our preliminary data characterizing a panel of three early biomarkers: L-Ficolin, hyaluronic acid (HA), and suppression of tumorigenicity-2 (ST2) which permit diagnosis of SOS prior to appearance of clinical signs. The rationale for this study is that once we are able to identify patients who are at particularly high risk for subsequent SOS; we will propose preemptive, customized treatment plans that could ultimately avert the development of SOS and improve survival. The hypothesis will be tested through three specific aims: 1) In a prospective multicenter study including Texas Children, University of Michigan, National Children's, and Indiana University, evaluate L-Ficolin, HA, and ST2 as early proteomic predictors of SOS to allow future preemptive intervention with an efficient treatment: defibrotide. 2) Using the same prospective multicenter cohort as Aim 1, also evaluate responders and nonresponders to defibrotide using our proteomic markers panel (L-Ficolin, HA, and ST2) as well as with discovery of new markers via our well-established proteomic workflow. 3) Identify and validate genomics candidate biomarkers of endothelial dysfunction in pediatric patients receiving high intensity chemotherapy/irradiation using approximately 1000 DNA samples from patients accrued in our retrospective IU HCT cohort, the multicenter HCT cohort, and this new cohort, the latter being enriched three times for complications. This approach is significant and innovative because it sets the grounds for a novel approach to SOS using biomarkers as a guide for starting treatment in a preemptive manner. Furthermore, this prospective multicenter study will allow defining a single algorithm for SOS prognosis, systematically addressing the problems associated with center effects.