Project Summary/Abstract A diagnosis of pediatric cancer is uniquely disquieting for children and adolescents, and the long-term management of complex treatment protocols, repeated hospitalizations, and unpredictable complications generates persistent stress, often spanning many years. Stressful early life experiences have enduring consequences on long-term physical and mental health and may impair emotional processing. How youth respond to stress is meaningfully linked to ability to regulate emotions and cultivate resilience, which have important implications for long-range development, including development of a range of internalizing and externalizing symptoms of psychopathology although resilience emerges as robust protective factor. One way the brain governs the immune system is via cortisol, a glucocorticoid hormone released during stress and in part responsible for the up- and down-regulation of pro-inflammatory cytokine activity. Executive control is also often undermined during a stress response. The long-term goal of Dr. Cosgrove's research program is to study the psychology and biology of how youth with cancer and their families respond to stress in order to identify those at elevated risk for poor psychosocial and neurocognitive outcomes, in turn informing allocation of mental health services in pediatric oncology. The specific objective of this NCI K08 Award resubmission application is to determine whether immune responses to stress induction in youth recently diagnosed with blood, brain, or other central nervous system cancers predict impairment in emotion regulation, low quality of life, and neurocognitive (executive control) outcomes at follow-up. We will recruit 70 youth in close proximity (2-10 months) to diagnosis and study longitudinal relationships between baseline psychobiological stress vulnerability and psychosocial/neurocognitive outcomes at 6- and 12-month follow-ups. This K08 Award will provide Dr. Cosgrove with the necessary training and mentorship to: (1) develop expertise in pediatric psycho- oncology, with a subspecialty emphasis on multidirectional stress-immune-emotion regulation relationships; (2) understand ways to increase emotion regulation and promote quality of life outcomes in pediatric medical illnesses; (3) develop expertise in affective science as applied within pediatric oncology, including measurement of executive control with neurocognitive assessments; (4) study ethical considerations involved with conducting research in pediatric oncology, a uniquely vulnerable population; (5) advance skills in scientific writing, including federal/foundation/intramural grants and peer-reviewed scientific manuscripts. To accomplish these training goals, she has organized a strong mentorship team (Korey Hood, Ph.D.; Matthew Hocking, Ph.D.; David Spiegel, M.D., Laura Roberts, M.D., M.S.) and advisory committee (Sheri Spunt, M.D., Cynthia Gerhardt, Ph.D., Holden Maecker, Ph.D., and Christine Blasey, Ph.D.), with expertise in pediatric and adult psycho-oncology, pediatric psychology and oncology, neurocognitive assessment, biostatistics, and clinical research with vulnerable populations.

Project Narrative Findings from this study may ultimately enable providers in pediatric oncology to discern, via simple pen-and- paper screening, information about a child's immune response to stress and related risk for psychosocial or neurocognitive deficits linked to impairment in emotion regulation. In this way, both psychosocial interventions targeted at improving emotion regulation or neurocognition could be combined with immune-targeted pharmacological interventions in a true model of child-centered precision medicine. Given that eventual long- term survivorship is anticipated for more than 85% of pediatric oncology patients, understanding the nature and long-term psychological and biological impact of stress in pediatric cancer is critical for enabling maximal quality of life into young adulthood and beyond.