Observations reported in the mid-1980's described the occurrence of cognitive impairments subsequent to prophylactic cranial radiation in children with leukemia. Waber and her collaborators in this IDDRC followed up on this initial observation (Dev. Med. Child Neurol., 1990). Cognitive function and physical growth were measured in 51 children who had been treated for acute lymphoblastic leukemia with the combination of chemotherapy, cranial radiation and intrathecal methotrexate and were continuously disease-free for 5 to 12 years. A comparison group of children treated for a solid tumor, Wilms tumor, also was studied. The rates of cognitive impairment and growth retardation were found to be clearly higher among the acute lymphoblastic leukemia group. Of particular significance was the finding that females were at greater risk for central nervous system toxicity from therapy than males. Both cognitive impairment and short stature were more prevalent among females. In addition, the younger the child at diagnosis and treatment, the greater the risk. These observations are important because the combined therapeutic approach to acute lymphoblastic leukemia has resulted in very high cure rates for this once fatal disease so that prevention of subsequent cognitive deficits in the survivors has become a critical future challenge. This work spawned a study of the sex- dependent relationship between chemotherapy and cognitive impairment in an animal model and led to an expanded investigation of neuro-oncological issues in our IDDRC, including recent work that describes stroke and other vascular disorders as late effects of cranial irradiation ( Pomeroy and Waber ).