DESCRIPTION (provided by applicant): Survivors of childhood cancer treated with thoracic radiation therapy (TRT) are at risk for cardiovascular and pulmonary morbidity, though risk is not recognized for Central Nervous System (CNS) pathology. In non- cancer populations, cardiopulmonary health is associated with CNS integrity. Adults with cardiovascular disease demonstrate neurocognitive problems, and small vessel disease reflected through multi-focal white matter hyper intensities (i.e., leukoencephalopathy) on brain magnetic resonance imaging (MRI). Pulmonary disease also increases risk of CNS abnormalities in non-cancer populations, including stroke, leukoencephalopathy, and neurocognitive impairment. We recently identified significant associations between thoracic radiation and brain pathology in 62 adult survivors of Hodgkin lymphoma (mean [range] age = 42.2 [34-55] years; time since diagnosis = 27.1 [18-40] years) who received no CNS chemotherapy and no cranial radiation. These survivors demonstrated high rates of neurocognitive impairment, and brain imaging revealed 53% had leukoencephalopathy and 37% had evidence of cerebrovascular injury consistent with small vessel disease. Thoracic radiation dose was associated with leukoencephalopathy and cortical thickness in numerous brain regions, and these pathologies were associated with neurocognitive impairment. These novel results lead us to propose a more comprehensive follow-up of an expanded cohort to examine the impact of specific treatment characteristics and potential pathophysiological processes involved in CNS outcomes, with the goal of developing an early intervention for CNS risk reduction. We propose to examine the prevalence and predictors of brain integrity in adult survivors of childhood cancer who are at risk for cardiac an pulmonary morbidity, but who have not received cranial radiation or CNS-directed chemotherapies. We will examine neurocognitive and brain imaging outcomes in reference to indices of cardiac, vascular, and pulmonary health. Results of this study have the potential to significantly impact current standard of care and long-term follow-up guidelines, as cancer survivors treated without direct CNS exposure are not presently recommended for screening of neurocognitive function or CNS morbidity. Findings will be used to develop and pilot specific interventions aimed at reducing risk for CNS morbidity, including overt cerebrovascular injury.
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