paediatrics Brussels 17

Neuro-Oncology 15(3):360–369, 2013. doi:10.1093 / neuonc / nos303 Advance Access publication January 14, 2013

NEURO - ONCOLOGY

Association between radiation dose to neuronal progenitor cell niches and temporal lobes and performance on neuropsychological testing in children: a prospective study Kristin J. Redmond, E. Mark Mahone, Stephanie Terezakis, Omar Ishaq, Eric Ford, Todd McNutt, Lawrence Kleinberg, Kenneth J. Cohen, Moody Wharam, and Alena Horska Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University, Baltimore, Maryland (K.J.R., S.T., O.I., T.M., L.K., M.W.); Department of Neuropsychology, Kennedy Krieger Institute, Baltimore, Maryland (E.M.M.); Department of Radiation Oncology, University of Washington, Seattle, Washington (E.F.); Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland (K.J.C.); Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University, Division of Neuroradiology, Baltimore, Maryland (A.H.)

at Universitaet Leipzig, Institut fuer Informatik/URZ, Bibliothek on August 25, 2014 http://neuro-oncology.oxfordjournals.org/ Downloaded from

children. Performance on motor speed / dexterity de- creased with increasing dose to hippocampus ( P , .05) and temporal lobes ( P , .035). There was also a signifi- cant relationship between (i) reduced performance on verbal learning and increasing dose to the cerebrum ( P ¼ .022) and (ii) reduced performance on visual per- ception and increasing dose to the left temporal lobe ( P ¼ .038). There was no association between radiation dose to evaluated structures and performance on vocab- ulary or visuospatial working memory. Conclusions. These prospective data demonstrate a significant association between increasing RT dose to hippocampus and temporal lobes and decline in neuro- cognitive skills following cranial irradiation. These find- ings have important implications for trials, including RTOG 0933 (hippocampal-sparing whole brain radia- tion therapy for brain metastases). Keywords: brain irradiation, brain tumor, neural progenitor cell niches, neuropsychological performance. R adiation therapy (RT) is integral to the manage- ment of a wide variety of both pediatric and adult brain tumors. However, RT to the brain is associated with neurocognitive toxicity. 1 – 7 The etiology of radiation injury to the brain is likely multifactorial, but data suggest that injury to neural progenitor cells (NPCs) plays a role. 8 – 14 Within the mammalian brain, NPCs are known to reside in 2 areas, or NPC niches: the subventricular

Background. Neurocognitive toxicity from radiation therapy (RT) for brain tumors may be related to damage to neural progenitor cells that reside in the sub- ventricular zone and hippocampus. This prospective study examines the relationship between RT dose to neural progenitor cell niches, temporal lobes, and cere- brum and neurocognitive dysfunction following cranial irradiation. Methods. Standardized assessments of motor speed / dexterity, verbal memory, visual perception, vocabulary, and visuospatial working memory were conducted in 19 pediatric patients receiving cranial RT and 55 controls at baseline and 6, 15, and 27 months following completion of RT. Prescription doses ranged from 12 Gy to 59.4 Gy. Linear mixed effects regression model analyses were used to examine the relationships among neuropsycho- logical performance, age, and radiation dose to the subventricular zone, hippocampus, temporal lobes, and cerebrum. Results. Performance on all neuropsychological tests, except vocabulary, was significantly reduced in patients relative to controls, particularly among younger

Received August 8, 2012; accepted October 30, 2012.

Presented in part at the American Society for Radiation Oncology 2011 Annual Meeting in Miami, FL and at the Society for Neuro-Oncology 2011 Annual Meeting in Anaheim, CA. Corresponding Author: Kristin J. Redmond, MD, MPH, 401 North Broadway, Suite 1440, Baltimore, MD 21231 (kjanson3@jhmi.edu).

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