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CNS-Directed Therapy for Childhood Leukemia

CNS-Directed Therapy for Childhood Leukemia. Neurodevelopmental Consequences of Neurologic Injury. BRAIN Initiative. The Brain in Action dynamic picture of the functioning brain molecular genetics Advancing Human Neuroscience

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CNS-Directed Therapy for Childhood Leukemia

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  1. CNS-Directed Therapy for Childhood Leukemia Neurodevelopmental Consequences of Neurologic Injury

  2. BRAIN Initiative • The Brain in Action • dynamic picture of the functioning brain • molecular genetics • Advancing Human Neuroscience • maximize collection of human samples for research on mechanisms of human brain disorders • 3. Human Neural Technology • technology to restore lost function

  3. Acute Lymphoblastic Leukemia • One in 330 children is diagnosed with cancer by age 20 • One in 530 young adults 20 to 39 years of age is a childhood cancer survivor • Most prevalent cancer among children & adolescents is ALL • once fatal • 5 year survival approaches 90%

  4. Improved Survival from ALL • Use of multi-agent therapy • Know risk factors for recurrence • minimal residual disease • treatment intensity matched to recurrence risk • Aggressive CNS-directed treatment for subclinical disease in the brain • primary site of initial disease relapse

  5. What are the Consequences of CNS-Directed Therapy? • Neurodevelopmental and academic problems • 2. Experienced by up to 60% of ALL survivors • Memory • Visual spatial abilities • fine motor speed • attention • processing speed • academic achievement • 3. Associated with secondary effects on • psychological well being (anxiety, depression) • social & adaptive skills • vocational success

  6. Cognitive Abilities Over Time * reported as Z scores with mean of 0 and SD of 1

  7. Cognitive Abilities can Impact Academic Outcomes

  8. Why do children with ALL have long-term neurodevelopmental & academic problems?

  9. CNS Directed Chemotherapy Model of Neurologic Injury : Oxidative Stress & Apoptosis

  10. Oxidative Stress & Apoptosis Biomarkers • Oxidized phospholipids by HPLCwith diode array detection • 206 detects unoxidized phospholipids • 234 detects oxidized phospholipids • Caspaseenyzme activity by PromegaGlo™ assays • capase 8 & 9 initiate apoptosis • caspase 3/7 execute apoptosis

  11. CSF Phospholipid Composition in Children

  12. Unoxidized Phospholipids 206nm PI PC Oxidized Phospholipids 234nm PI PC

  13. Oxidized PC by Treatment Phase F = 22.135; df = 4; p < 0.001

  14. Oxidized PI by Treatment Phase F = 16.747; df = 4; p < 0.001

  15. Oxidative Stress Biomarkers of Neurologic Injury

  16. Human Neural Technology Development Can we restore cognitive and academic abilities in children with ALL?

  17. Improving Academic Outcomes: Math Intervention Determine if Math Intervention prevents declines in academic math scores in children with ALL

  18. Nonverbal Working Memory: Changes over Time by Group F [2, 29] = 5.53, p < =.009

  19. Math Skills in Intervention Group: Changes Over Time F [2, 29] = 12.47, p <0.001

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