Project Summary/Abstract: Castleman disease (CD) describes a group of rare and poorly understood hematologic disorders that share characteristic histopathologic alterations, lymphadenopathy, and systemic inflammation but vary in etiology, symptomatology, treatments, and outcomes. Approximately 2,000 individuals of all ages are diagnosed with CD each year in the US. Unicentric CD (UCD) involves one region of enlarged lymph nodes and typically milder inflammatory symptoms; the three currently-recognized subtypes of multicentric CD (MCD) result from different etiologies but involve progressive episodes of systemic inflammatory symptoms and life-threatening cytokine- driven multi-organ dysfunction, such as the liver, kidneys, and bone marrow. The underlying mechanisms and therapeutic targets are not well understood. While various treatments are often tried for CD, systematic evaluations of these treatments have not been performed, the optimal treatments for each subtype are not known, and biomarkers to identify patients likely to respond to certain treatments are needed. New treatment approaches are also needed, but no validated, patient-centric treatment response criteria or biomarkers exist to consistently evaluate promising treatment approaches in clinical trials. Further, clinical data had not been centralized and no evidence-based diagnostic or treatment guidelines existed until recently. To address these barriers, we established an international longitudinal natural history study of CD in 2016 through a 5-year collaborative partnership between the Castleman Disease Collaborative Network, Janssen Pharmaceuticals, and the University of Pennsylvania (lead institution). Developed by a team of physicians, researchers, and patients, ACCELERATE utilizes an innovative patient-powered study design whereby CD patients in the US and globally self-enroll online and our study team obtains and systematically extracts complete medical record data into a central database. The use of common data standards, rigorous data extraction protocols, and expert adjudication of each case ensure that the data is of high quality and interpretability. We have enrolled over 500 CD patients and collected extensive, longitudinal data on approximately one-half that have been leveraged to characterize the spectrum of CD, support the development of evidence-based treatment guidelines, and advance translational research. Despite these advances, significant unmet needs remain for the majority of CD patients who do not have an effective FDA-approved therapy. Unfortunately, our 5-year funded study has ended. We are seeking funding to leverage the data collected from our 5-year collaborative partnership, build upon infrastructure from this multi- stakeholder collaboration, and continue enrollment and data collection to identify clinically-meaningful patient subtypes, clinical outcome measures, and novel treatment approaches. Our proposed studies have the potential to transform care ...