PURPOSE:Sensorineural hearing loss (SNHL) is associated with intellectual and academic declines in children treated for embryonal brain tumors. This study expands upon existing research by examining core neurocognitive processes that may result in reading difficulties in children with treatment-related ototoxicity.PATIENTS AND METHODS:Prospectively gathered, serial, neuropsychological and audiology data for 260 children and young adults age 3 to 21 years (mean, 9.15 years) enrolled in a multisite research and treatment protocol, which included surgery, risk-adapted craniospinal irradiation (average risk, n = 186; high risk, n = 74), and chemotherapy, were analyzed using linear mixed models. Participants were assessed at baseline and up to 5 years after diagnosis and grouped according to degree of SNHL. Included were 196 children with intact hearing or mild to moderate SNHL (Chang grade 0, 1a, 1b, or 2a) and 64 children with severe SNHL (Chang grade 2b or greater). Performance on eight neurocognitive variables targeting reading outcomes (eg, phonemics, fluency, comprehension) and contributory cognitive processes (eg, working memory, processing speed) was analyzed.RESULTS:Participants with severe SNHL performed significantly worse on all variables compared with children with normal or mild to moderate SNHL (P ≤ .05), except for tasks assessing awareness of sounds and working memory. Controlling for age at diagnosis and risk-adapted craniospinal irradiation dose, performance on the following four variables remained significantly lower for children with severe SNHL: phonemic skills, phonetic decoding, reading comprehension, and speed of information processing (P ≤ .05).CONCLUSION:Children with severe SNHL exhibit greater reading difficulties over time. Specifically, they seem to struggle most with phonological skills and processing speed, which affect higher level skills such as reading comprehension.

Objective: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1).Methods: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8-15 yearswere screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population.Results: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = -0.15, 95% confidence interval -0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval -0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo.Conclusions: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population.ClinicalTrials.gov identifier: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493).Classification of evidence: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.

Purpose: Clinically effective measurement of cognitive toxicity from photon radiation therapy (XRT) should be accurate, sensitive, and specific. This pilot study tested translational findings on phasic changes in children's memory systems that are sensitive and insensitive to toxic XRT effects to identify a possible neuroplastic effect.Methods and Materials: Memory processes were prospectively tested before XRT and at 3 later time points up to 2 years in 35 children with mixed primary brain tumors who had not experienced recurrence. Memory processes were verbal-semantic, visual-semantic, and visual-perceptual, including accuracy, speed to recall, encoding, retrieval, and recognition. The mixed-effects model included time (to estimate slope), covariates (age, tumor locus, XRT field, and medications) as fixed effects, and individual random intercepts. A sensitivity analysis examined the influence of XRT dose to the hippocampi on memory.Results: Retrieval from long-term verbal-semantic memory declined 2 months after completing XRT, as seen in adults, and was lowest at 1 year, which was delayed in comparison with adults. Double dissociation from visual-perceptual memory at baseline and 2 months was found, consistent with adults. Recovery was demonstrated 2 years after XRT. Patterns were unchanged when dose to hippocampus was included in the model.Conclusions: Verbal and semantic long-term retrieval is specifically sensitive to XRT-related cognitive dysfunction, without effect on visual-perceptual memory. Children reached nadir in XRT-sensitive memory 1 year after XRT and recovered by 2 years, which is later than that observed in adults. The protracted period of post-XRT injury may represent the maturation of the human hippocampus and white matter into late adolescence. (C) 2016 Elsevier Inc. All rights reserved.

RO-10. PROSPECTIVE SLOPES OVER EIGHT YEARS IN COGNITIVE MARKERS OF PHOTON RADIOTHERAPY FOR PEDIATRIC BRAIN TUMORS Carol L. Armstrong1,2, Julie Petersen1,3, Michael J. Fisher1,2, Robert A. Lustig1,2, Jane E. Minturn1,2, Jean B. Belasco1,2, Sarah Amedoro1, Cathy Bolton3, Peter C. Phillips1,2, and Christine E. Hill-Kayser1,2; The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Drexel University, Philadelphia, PA, USA PURPOSE: This prospective longitudinal study examined late-delayed effects (pre-treatment to 8y) of IMRT/conformal photon radiotherapy (RT) on cognition in children with brain tumors. We previously demonstrated that memory systems are affected differentially by RT, and investigated the pattern over eight years of these RT-specific cognitive markers. At the latedelayed phase, clinical information suggests a generalized decline in cognition, but no prospective studies report the late phase cognitive toxicity (.5 yr post treatment). METHODS: Participants were 28 patients with mixed primary brain tumors (18 males; age range: 4-17, M 1⁄4 9.04, SD 1⁄4 3.32; 61% had grosstotal resection)whocompletedbaseline andat leastone follow-upassessment frombaseline-8years (115 visits). Verbal-semantic memory wasassessed using a supraspan test of word memory (Rey Auditory Verbal Learning (RAVL, 4-forms)) for encoding, retrieval after interference, and retrieval after a delay. Complex Figure (CF, 2-forms) measured visuoperceptual memory immediately and after delay. Picture Recognition (PR) measured visual-semantic memory (accuracy, speed to recognize). Analyses used age-referenced Z scores in a mixed effects model; whole brain versus focal RT was a covariate. RESULTS: Verbal retrieval indices, but not encoding, were sensitive to the late-effects with progressive decline, and greater detriment in hippocampus-sensitive delayed retrieval. CF recall demonstrated continuous improvement to eight years. Bi-hemispherically processed PR demonstrated no decline over eight years. Dose burden significantly predicted retrieval but not encoding or recognition. CONCLUSIONS: Results evidence significant change over time, with differential changes in cognition, and no general decline. The sensitivity of retrieval infers multi-substrate injury not limited to hippocampus. Neuro-Oncology 18:iii159–iii164, 2016. doi:10.1093/neuonc/now082.10 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Conclusion:The new method based on local structures in 18F-FDG PET images was a feasible approach.This method is more sensitive in terms of providing a clearer 18FDG uptake dose response six weeks after initiation of treatment compared to standard image subtraction, and may be valuable in future studies addressing RILT.