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Purpose : Accurate detection of leptomeningeal metastasis (LM) is critical for risk stratification and treatment of pediatric brain tumors. Poor-quality staging MRI has been associated with decreased survival in this population, but technical factors differentiating good from poor quality screening MRIs remain undefined. To test the hypothesis that key technical factors are associated with accurate MRI diagnosis of leptomeningeal metastasis in children with leptomeningeal seeding brain tumors. Methods: MRIs acquired at outside facilities and repeated in our institution within 35 days for 75 children with leptomeningeal seeding tumors were assessed for slice thickness and gap; use of T2 FLAIR + Contrast, acquisition plane of 3DT1WI + Contrast (brain); axial T1 + Contrast sequence, and use of pre-contrast T1 images (spine). Reported findings were recorded as positive, negative, or equivocal for LM and classified as true positive (TP; unequivocal metastasis), false negative (FN; not reported), false positive (FP; resolved without treatment), or true negative. Wilcoxon signed-rank and Fisher's exact test were used to assess technical differences between TP and FN MRIs. Results: Rate of LM detection was greater with smaller interslice gap in brain (P = 0.003) and spine (P = 0.002); use of T2 FLAIR + Contrast (P = 0.005) and sagittal plane for 3DT1WI + Contrast (P = 0.028) in brain; and use of alternatives to axial TSE/FSE in spine (P = 0.048). Slice thickness was not significant. Pre-contrast T1WI did not contribute to LM diagnosis in spine. Conclusion: Using post-contrast T2 FLAIR and sagittal 3DT1 in brain, small/no interslice gap, and avoiding TSE/FSE axials in spine may facilitate leptomeningeal metastasis detection in children with brain tumors. [ABSTRACT FROM AUTHOR]

Purpose: To generate synthetic relative proton stopping power (sRPSP) images from magnetic resonance imaging (MRI) sequence(s) and develop an online quality assurance (QA) tool for sRPSP to facilitate safe integration of magnetic resonance (MR)‐only proton planning into clinical practice. Materials and methods: Planning computed tomography (CT) and MR images of 195 pediatric brain tumor patients were utilized (training: 150, testing: 45). Seventeen consistent‐cycle generative adversarial network (ccGAN) models were trained separately using paired CT‐converted RPSP and MRI datasets to transform a subject's MRI into sRPSP. T1‐weighted (T1W), T2‐weighted (T2W), and FLAIR MRI were permutated to form 17 combinations, with or without preprocessing, for determining the optimal training sequence(s). For evaluation, sRPSP images were converted to synthetic CT (sCT) and compared to the real CT in terms of mean absolute error (MAE) in Hounsfield units (HU). For QA, sCT was deformed and compared to a reference template built from training dataset to produce a flag map, highlighting pixels that deviate by >100 HU and fall outside the mean ± standard deviation reference intensity. The gamma intensity analysis (10%/3 mm) of the deformed sCT against the QA template on the intensity difference was investigated as a surrogate of sCT accuracy. Results: The sRPSP images generated from a single T1W or T2W sequence outperformed that generated from multi‐MRI sequences in terms of MAE (all p < 0.05). Preprocessing with N4 bias and histogram matching reduced MAE of T2W MRI‐based sCT (54 ± 21 HU vs. 42 ± 13 HU, p = 0.002). The gamma intensity analysis of sCT against the QA template was highly correlated with the MAE of sCT against the real CT in the testing cohort (r = ‐0.89 for T1W sCT; r = ‐0.93 for T2W sCT). Conclusion: Accurate sRPSP images can be generated from T1W/T2W MRI for proton planning. A QA tool highlights regions of inaccuracy, flagging problematic cases unsuitable for clinical use. [ABSTRACT FROM AUTHOR]

Microstructural asymmetry of the brain can provide more direct causal explanations of functional lateralization than can macrostructural asymmetry. We performed a cross-sectional diffusion imaging study of 314 patients treated for childhood acute lymphoblastic leukemia (ALL) at a single institution and 92 healthy controls. An asymmetry index based on diffusion metrics was computed to quantify brain microstructural asymmetry. The effects of age and the asymmetry metrics of the two cohorts were examined with t-tests and linear models. We discovered two new types of microstructural asymmetry. Myelin-related asymmetry in controls was prominent in the back brain (89% right), whereas axon-related asymmetry occurred in the front brain (67% left) and back brain (88% right). These asymmetries indicate that white matter is more mature and more myelinated in the left back brain, potentially explaining the leftward lateralization of language and visual functions. The asymmetries increase throughout childhood and adolescence (P = 0.04) but were significantly less in patients treated for ALL (P<0.01), especially in younger patients. Our results indicate that atypical brain development may appear long before patients treated with chemotherapy become symptomatic. [ABSTRACT FROM AUTHOR]

Development of reading skills is vulnerable to disruption in children treated for brain tumors. Interventions, remedial and prophylactic, are needed to mitigate reading and other learning difficulties faced by survivors. A functional magnetic resonance imaging (fMRI) study was conducted to investigate long-term effects of a prophylactic reading intervention administered during radiation therapy in children treated for medulloblastoma. The fMRI study included 19 reading-intervention (age 11.7 ± 0.6 years) and 21 standard-of-care (age 12.1 ± 0.6 years) medulloblastoma survivors, and 21 typically developing children (age 12.3 ± 0.6 years). The survivors were 2.5 [1.2, 5.4] years after completion of tumor therapies and reading-intervention survivors were 2.9 [1.6, 5.9] years after intervention. Five fMRI tasks (Rapid Automatized Naming, Continuous Performance Test using faces and letters, orthographic and phonological processing of letter pairs, implicit word reading, and story reading) were used to probe reading-related neural activation. Woodcock-Johnson Reading Fluency, Word Attack, and Sound Awareness subtests were used to evaluate reading abilities. At the time of fMRI, Sound Awareness scores were significantly higher in the reading-intervention group than in the standard-of-care group (p = 0.046). Brain activation during the fMRI tasks was detected in left inferior frontal, temporal, ventral occipitotemporal, and subcortical regions, and differed among the groups (p < 0.05, FWE). The pattern of group activation differences, across brain areas and tasks, was a normative trend in the reading-intervention group. Standardized reading scores and patterns of brain activation provide evidence of long-term effects of prophylactic reading intervention in children treated for medulloblastoma. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the feasibility and accuracy of magnetic resonance imaging (MRI)-based treatment planning using pseudo CTs generated through atlas registration. Methods: A pseudo CT, providing electron density information for dose calculation, was generated by deforming atlas CT images previously acquired on other patients. The authors tested 4 schemes of synthesizing a pseudo CT from single or multiple deformed atlas images: use of a single arbitrarily selected atlas, arithmetic mean process using 6 atlases, and pattern recognition with Gaussian process (PRGP) using 6 or 12 atlases. The required deformation for atlas CT images was derived from a nonlinear registration of conjugated atlas MR images to that of the patient of interest. The contrasts of atlas MR images were adjusted by histogram matching to reduce the effect of different sets of acquisition parameters. For comparison, the authors also tested a simple scheme assigning the Hounsfield unit of water to the entire patient volume. All pseudo CT generating schemes were applied to 14 patients with common pediatric brain tumors. The image similarity of real patient-specific CT and pseudo CTs constructed by different schemes was compared. Differences in computation times were also calculated. The real CT in the treatment planning system was replaced with the pseudo CT, and the dose distribution was recalculated to determine the difference. Results: The atlas approach generally performed better than assigning a bulk CT number to the entire patient volume. Comparing atlas-based schemes, those using multiple atlases outperformed the single atlas scheme. For multiple atlas schemes, the pseudo CTs were similar to the real CTs (correlation coefficient, 0.787-0.819). The calculated dose distribution was in close agreement with the original dose. Nearly the entire patient volume (98.3%-98.7%) satisfied the criteria of chi-evaluation (<2% maximum dose and 2 mm range). The dose to 95% of the volume and the percentage of volume receiving at least 95% of the prescription dose in the planning target volume differed from the original values by less than 2% of the prescription dose (root-mean-square, RMS < 1%). The PRGP scheme did not perform better than the arithmetic mean process with the same number of atlases. Increasing the number of atlases from 6 to 12 often resulted in improvements, but statistical significance was not always found. Conclusions: MRI-based treatment planning with pseudo CTs generated through atlas registration is feasible for pediatric brain tumor patients. The doses calculated from pseudo CTs agreed well with those from real CTs, showing dosimetric accuracy within 2% for the PTV when multiple atlases were used. The arithmetic mean process may be a reasonable choice over PRGP for the synthesis scheme considering performance and computational costs. [ABSTRACT FROM AUTHOR]

Purpose: To characterize respiration-induced abdominal organ motion in children receiving radiation treatment with a 4-dimensional (4D) magnetic resonance imaging (MRI) method.Methods and Materials: We analyzed free-breathing coronal 4D MRI datasets acquired from 35 patients (aged 1-20 years) with abdominal tumors. A deformable image registration of the 4D MRI datasets was performed to derive motion trajectories of selected anatomic landmarks, from which organ motions were quantified. The association between organ motion and patient characteristics was investigated and compared with previous studies. The relation between patient height and organ motion was further investigated to predict organ motion in prospective patients.Results: Organ motion and its individual variation were reduced in younger patients (eg, kidney peak-to-peak motion <5 mm for all but 1 patient aged ≤8 years), although special motion management may be warranted in some adolescents. The liver and spleen exhibited greater motion than did the kidneys, while intraorgan variation was present. The motions in the liver and kidneys agreed with those reported by the previous 4D computed tomography studies. Individual variations of organ motion in younger patients were due, in part, to changes in respiration rate, which ostensibly reflected the effect of anesthesia. The prediction of organ motion was limited by large individual variations, particularly for older patients.Conclusions: The 4D MRI acquisition method and motion analysis described in this study provide a nonionizing approach to understand age-associated organ motion, which aids in the planning of abdominal radiation therapy for pediatric patients. Use of 4D MRI facilitates monitoring of changes in target motion patterns during treatment courses and in various studies of the effect of organ motion on radiation treatment. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study was to determine radiation dose effect on the structural integrity of cerebral white matter in craniopharyngioma patients receiving surgery and proton therapy. Methods and Materials Fifty-one patients (2.1-19.3 years of age) with craniopharyngioma underwent surgery and proton therapy in a prospective therapeutic trial. Anatomical magnetic resonance images acquired after surgery but before proton therapy were inspected to identify white matter structures intersected by surgical corridors and catheter tracks. Longitudinal diffusion tensor imaging (DTI) was performed to measure microstructural integrity changes in cerebral white matter. Fractional anisotropy (FA) derived from DTI was statistically analyzed for 51 atlas-based white matter structures of the brain to determine radiation dose effect. FA in surgery-affected regions in the corpus callosum was compared to that in its intact counterpart to determine whether surgical defects affect radiation dose effect. Results Surgical defects were seen most frequently in the corpus callosum because of transcallosal resection of tumors and insertion of ventricular or cyst catheters. Longitudinal DTI data indicated reductions in FA 3 months after therapy, which was followed by a recovery in most white matter structures. A greater FA reduction was correlated with a higher radiation dose in 20 white matter structures, indicating a radiation dose effect. The average FA in the surgery-affected regions before proton therapy was smaller ( P =.0001) than that in their non–surgery-affected counterparts with more intensified subsequent reduction of FA ( P =.0083) after therapy, suggesting that surgery accentuated the radiation dose effect. Conclusions DTI data suggest that mild radiation dose effects occur in patients with craniopharyngioma receiving surgery and proton therapy. Surgical defects present at the time of proton therapy appear to accentuate the radiation dose effect longitudinally. This study supports consideration of pre-existing surgical defects and their locations in proton therapy planning and studies of treatment effect. [ABSTRACT FROM AUTHOR]

Purpose: Optimal radiation therapy (RT) target margins for diffuse intrinsic pontine glioma (DIPG) are unknown. We sought to define disease progression patterns in a contemporary cohort treated with conformal RT using different clinical target volume (CTV) margins.Methods and Materials: We reviewed 105 patients with newly diagnosed DIPG treated with conformal conventionally fractionated RT at our institution from 2006 to 2014. CTV margins were classified as standard (1 cm) for 60 patients and extended (2-3 cm) for 45 patients. Survival and cumulative incidence of progression in treatment groups were compared by log-rank and Gray's tests, respectively. Cox proportional hazard models identified predictors of survival.Results: For 97 patients evaluated with magnetic resonance imaging at progression, the cumulative incidences of isolated local, isolated distant, and synchronous disease progression at 1 year were 62.6%, 12.3%, and 7.2%, respectively, and did not differ significantly according to the CTV margin. Central dosimetric progression (Vprogression95% ≥95%) was observed in 80 of 81 evaluable patients. Median progression-free survival and overall survival (OS) were 7.6 months (95% confidence interval, 6.9-8.2) and 11.3 months (95% confidence interval, 10.0-12.8), respectively, and did not differ significantly according to margin status. DIPG survival prediction risk group (standard vs high, P = .02; intermediate vs high, P = .009) and development of distant metastasis (P = .003) were independent predictors of OS. For the 41 patients (39%) with a pathologic diagnosis, H3.3 K27M mutation was associated with shorter OS (hazard ratio [HR], 0.41; P =.02), whereas H3.1 K27M and ACVR1 mutations were associated with longer OS (HR, 3.56; P =.004 and HR, 2.58; P =.04, respectively).Conclusions: All patients who experienced local failure showed progression within the high-dose volume, and there was no apparent survival or tumor-control benefit to extending the CTV margins beyond 1 cm. Given the increasing use of reirradiation, standardizing the CTV margin to 1 cm may improve retreatment tolerance. [ABSTRACT FROM AUTHOR]

Purpose: We sought to investigate the pattern of treatment failure with respect to anatomic extent, radiation dose, and criteria for failure according to the Response Assessment in Neuro-Oncology (RANO). We evaluated the corresponding prognostic significance of these factors in patients with pediatric high-grade glioma (pHGG).Methods and Materials: Fifty-six patients with pHGG were enrolled in an institutional phase 1 to 2 prospective trial that included maximal safe resection and radiation therapy with concurrent and adjuvant erlotinib. The radiation therapy dose administered was 54 to 59.4 Gy at 1.8 Gy/d. Tumor progression was defined according to clinical symptoms and imaging features and was classified in relation to the original extent of the tumor, radiation prescription target volume coverage, and RANO criteria (RANOc).Results: With a median follow-up period of 90 months (range, 70-124 months), progression occurred in 48 patients (85.7%) while 8 (14.3%) were without progression. Central failure represented 42.6% of the total cohort, while in-field, marginal, and distant failures occurred in 7.4%, 9.3%, and 22.2%, respectively. Patients with biopsy or subtotal resection had increased rates of central failure and represented 14.81% and 16.67% of the total cohort, respectively. Tumor progression was classified as local, local plus distant, or distant. Among patients with local failure as a component of failure, 5 were considered to have marginal failure. Patients with frontal, temporal, and parietal disease had the highest rates of multifocal failure. A comparison between responses defined by RANOc demonstrated varied time to death (TTD) from progression.Conclusions: Pediatric high-grade glioma was shown to have high rates of central failure, particularly in cases with limited resection. Patients with central failure had a trend toward more prolonged TTD from failure relative to other failure patterns. The low marginal failure rates seen in this group suggest that less conservative radiation target margins may be possible. TTD from failure varied according to RANO type, suggesting that adult RANOc require modification before being applied to pHGG. [ABSTRACT FROM AUTHOR]