Recurrence of symptoms may indicate the presence of a Morel-Lavallée lesion of the knee: A case report and literature review.

Case: An 81 year old male with four failed aspirations presented with recurrent knee swelling following irrigation and debridement, which suggested the presence of a Morel-Lavallée lesion (MLL). This diagnosis was intraoperatively confirmed by separation of the tissue layers forming a space with accumulated fluid. Treatment consisted of doxycycline sclerodesis and tight closure of the tissue layers. The patient had a satisfactory outcome at 4 months. Conclusion: Resolution of Morel-Lavallée lesions requires prompt recognition and appropriate treatment. In the presence of a different diagnosis, recurrence of symptoms following treatment may indicate an MLL. Surgical treatment with doxycycline sclerodesis resulted in resolution of symptoms.

Developmental patterns of CBF and BOLD responses to visual stimulus.

To investigate the developmental changes of cerebral blood flow (CBF) and hemodynamic responses to changing neural activity, we used the arterial spin label (ASL) technique to measure resting CBF and simultaneous CBF / blood-oxygen-level dependent (BOLD) signal changes during visual stimulation in 97 typically developing children and young adults (age 13.35 [6.02, 25.25] (median [min, max]) years old at the first time point). The longitudinal study protocol included three MRIs (2.7 ± 0.06 obtained), one year apart, for each participant. Mixed-effect linear and non-linear statistical models were used to analyze age effects on CBF and BOLD signals. Resting CBF decreased exponentially with age (p = 0.0001) throughout the brain, and developmental trajectories differed across brain lobes. The absolute CBF increase in visual cortex during stimulation was constant over the age range, but the fractional CBF change increased with age (p = 0.0001) and the fractional BOLD signal increased with age (p = 0.0001) correspondingly. These findings suggest that the apparent neural hemodynamic coupling in visual cortex does not change after age six years, but age-related BOLD signal changes continue through adolescence primarily due to the changes with age in resting CBF.

Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only.

Importance: Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL). Objective: To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network. Design, Setting, and Participants: This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020. Exposure: ALL treatment using chemotherapy-only protocols. Main Outcomes and Measures: This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. ß values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm3/1 SD in z score for cerebellum, mm3/[g×hr/L] for dexamethasone and methotrexate AUC, and mm3/intrathecal count for total intrathecal count). Results: Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of both sexes showed decreased mean (SD) cerebellar volumes compared with the control population (female: 70 568 [6465] mm3 vs 75 134 [6780] mm3; P < .001; male: 77 335 [6210] mm3 vs 79 020 [7420] mm3; P < .001). In female survivors, decreased cerebellar volume was associated with worse performance in Rey-Osterrieth complex figure test (left cerebellum: ß = 55.54; SE = 25.55; P = .03; right cerebellum: ß = 52.57; SE = 25.50; P = .04) and poorer dominant-hand motor processing speed (ie, grooved pegboard performance) (left cerebellum: ß = 82.71; SE = 31.04; P = .009; right cerebellum: ß = 91.06; SE = 30.72; P = .004). In female survivors, increased number of intrathecal treatments (ie, number of separate injections) was also associated with Worse Rey-Osterrieth test performance (ß = -0.154; SE = 0.063; P = .02), as was increased dexamethasone exposure (ß = -0.0014; SE = 0.0005; P = .01). Executive dysfunction was correlated with increased global efficiency between smaller brain regions (Pearson r = -0.24; P = .01) compared with individuals without dysfunction. Anatomical connectivity showed differences between impaired and nonimpaired survivors. Analysis of variance of effective-connectivity weights identified a significant interaction association (F = 3.99; P = .02) among the direction and strength of connectivity between the cerebellum and DLPFC, female sex, and executive dysfunction. Finally, no effective connectivity was found between the precuneus and DLPFC in female survivors with executive dysfunction. Conclusions and Relevance: These findings suggest that dexamethasone exposure was associated with smaller cerebello-thalamo-cortical regions in survivors of ALL and that disruption of effective connectivity was associated with impairment of executive function in female survivors.

Neuroanatomical abnormalities related to dexamethasone exposure in survivors of childhood acute lymphoblastic leukemia.

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy only are at risk for neurocognitive impairment. Regions of interest were identified a priori based on glucocorticoid receptor distribution, and sex-stratified multivariable linear regression models were used to test associations between brain MRI morphology and total number of intrathecal injections, and serum concentration of dexamethasone and methotrexate. Compared with controls, ALL survivors have persistently smaller volumes in the bilateral cerebellum (P < 0.005), hippocampal subregions (P < 0.03), temporal lobe regions (P < 0.03), frontal lobe regions (P < 0.04), and parietal lobe regions (precuneus; P < 0.002). Long-term problems with learning may be related to residual posttreatment brain differences.

Cognitive Performance, Aerobic Fitness, Motor Proficiency, and Brain Function Among Children Newly Diagnosed With Craniopharyngioma.

OBJECTIVES: Craniopharyngioma survivors experience cognitive deficits that negatively impact quality of life. Aerobic fitness is associated with cognitive benefits in typically developing children and physical exercise promotes recovery following brain injury. Accordingly, we investigated cognitive and neural correlates of aerobic fitness in a sample of craniopharyngioma patients. METHODS: Patients treated for craniopharyngioma [N=104, 10.0±4.6 years, 48% male] participated in fitness, cognitive and fMRI (n=51) assessments following surgery but before proton radiation therapy. RESULTS: Patients demonstrated impaired aerobic fitness [peak oxygen uptake (PKVO2)=23.9±7.1, 41% impaired (i.e., 1.5 SD<normative mean)], motor proficiency [Bruininks-Oseretsky (BOT2)=38.6±9.0, 28% impaired], and executive functions (e.g., WISC-IV Working Memory Index (WMI)=96.0±15.3, 11% impaired). PKVO2 correlated with better executive functions (e.g., WISC-IV WMI r=.27, p=.02) and academic performance (WJ-III Calculation r=.24, p=.04). BOT2 correlated with better attention (e.g., CPT-II omissions r=.26, p=.04) and executive functions (e.g., WISC-IV WMI r=.32, p=.01). Areas of robust neural activation during an n-back task included superior parietal lobule, dorsolateral prefrontal cortex, and middle and superior frontal gyri (p<.05, corrected). Higher network activation was associated with better working memory task performance and better BOT2 (p<.001). CONCLUSIONS: Before adjuvant therapy, children with craniopharyngioma demonstrate significantly reduced aerobic fitness, motor proficiency, and working memory. Better aerobic fitness and motor proficiency are associated with better attention and executive functions, as well as greater activation of a well-established working memory network. These findings may help explain differential risk/resiliency with respect to acute cognitive changes that may portend cognitive late effects. (JINS, 2019, 25, 413-425).

Disseminability of computerized cognitive training: Performance across coaches.

Cogmed is a computerized cognitive intervention utilizing coaches who receive standardized instruction in analyzing training indices and tailoring feedback to remotely monitor participant's performance. The goal of this study was to examine adherence, satisfaction, and efficacy of Cogmed across coaches. Survivors of pediatric brain tumors and acute lymphoblastic leukemia (N = 68) were randomized to intervention (Cogmed) or waitlist control. The intervention group was matched with one of two coaches. Cognitive assessments were completed before and after intervention, and participants and caregivers in the intervention group completed satisfaction surveys. T-tests showed no differences in adherence across coaches (number of sessions completed p = .38; d = .32). Noninferiority statistics were not consistently equivalent for satisfaction, but equivalence was supported for caregiver perceptions of pragmatic utility and participant perceptions of logistical ease of Cogmed. Equivalence was not consistently suggested for cognitive outcomes, but was supported on measures tapping relevant cognitive domains (attention, working memory, processing speed, academic fluency). This study suggests adherence can be maintained across coaches. While aspects of satisfaction and cognitive outcomes were equivalent, the possible influence of coach-based variables cannot be ruled out. Findings highlight challenges in standardizing the coaching component of multicomponent computerized interventions and the need for ongoing research to establish dessiminability.

Brain Activity Associated With Attention Deficits Following Chemotherapy for Childhood Acute Lymphoblastic Leukemia.

BACKGROUND: The impact of contemporary chemotherapy treatment for childhood acute lymphoblastic leukemia on central nervous system activity is not fully appreciated. METHODS: Neurocognitive testing and functional magnetic resonance imaging (fMRI) were obtained in 165 survivors five or more years postdiagnosis (average age = 14.4 years, 7.7 years from diagnosis, 51.5% males). Chemotherapy exposure was measured as serum concentration of methotrexate following high-dose intravenous injection. Neurocognitive testing included measures of attention and executive function. fMRI was obtained during completion of two tasks, the continuous performance task (CPT) and the attention network task (ANT). Image analysis was performed using Statistical Parametric Mapping software, with contrasts targeting sustained attention, alerting, orienting, and conflict. All statistical tests were two-sided. RESULTS: Compared with population norms, survivors demonstrated impairment on number-letter switching (P < .001, a measure of cognitive flexibility), which was associated with treatment intensity (P = .048). Task performance during fMRI was associated with neurocognitive dysfunction across multiple tasks. Regional brain activation was lower in survivors diagnosed at younger ages for the CPT (bilateral parietal and temporal lobes) and the ANT (left parietal and right hippocampus). With higher serum methotrexate exposure, CPT activation decreased in the right temporal and bilateral frontal and parietal lobes, but ANT alerting activation increased in the ventral frontal, insula, caudate, and anterior cingulate. CONCLUSIONS: Brain activation during attention and executive function tasks was associated with serum methotrexate exposure and age at diagnosis. These findings provide evidence for compromised and compensatory changes in regional brain function that may help clarify the neural substrates of cognitive deficits in acute lymphoblastic leukemia survivors.

Ultrashort echo time imaging for quantification of hepatic iron overload: Comparison of acquisition and fitting methods via simulations, phantoms, and in vivo data.

BACKGROUND: Current R2*-MRI techniques for measuring hepatic iron content (HIC) use various acquisition types and fitting models. PURPOSE: To evaluate the accuracy and precision of R2*-HIC acquisition and fitting methods. STUDY TYPE: Signal simulations, phantom study, and prospective in vivo cohort. POPULATION: In all, 132 patients (58/74 male/female, mean age 17.7 years). FIELD STRENGTH/SEQUENCE: 2D-multiecho gradient-echo (GRE) and ultrashort echo time (UTE) acquisitions at 1.5T. ASSESSMENT: Synthetic MR signals were created to mimic published GRE and UTE methods, using different R2* values (25-2000 s-1 ) and signal-to-noise ratios (SNR). Phantoms with varying iron concentrations were scanned at 1.5T. In vivo data were analyzed from 132 patients acquired at 1.5T. R2* was estimated by fitting using three signal models. Accuracy and precision of R2* measurements for UTE acquisition parameters (SNR, echo spacing [ΔTE], maximum echo time [TEmax ]) and fitting methods were compared for simulated, phantom, and in vivo datasets. STATISTICAL TESTS: R2* accuracy was determined from the relative error and by linear regression analysis. Precision was evaluated using coefficient of variation (CoV) analysis. RESULTS: In simulations, all models had high R2* accuracy (error <5%) and precision (CoV <10%) for all SNRs, shorter ΔTE (≤0.5 msec), and longer TEmax (≥10.1 msec); except the constant offset model overestimated R2* at the lowest SNR. In phantoms and in vivo, all models produced similar R2* values for different SNRs and shorter ΔTEs (slopes: 0.99-1.06, R2 > 0.99, P < 0.001). In all experiments, R2* results degraded for high R2* values with longer ΔTE (≥1 msec). In vivo, shorter and longer TEmax gave similar R2* results (slopes: 1.02-1.06, R2 > 0.99, P < 0.001) for the noise subtraction model for 25≤R2*≤2000 s-1 . However, both quadratic and constant offset models, using shorter TEmax (≤4.7 msec) overestimated R2* and yielded high CoVs up to ∼170% for low R2* (<250 s-1 ). DATA CONCLUSION: UTE with TEmax ≥ 10.1 msec and ΔTE ≤ 0.5 msec yields accurate R2* estimates over the entire clinical HIC range. Monoexponential fitting with noise subtraction is the most robust signal model to changes in UTE parameters and achieves the highest R2* accuracy and precision. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1475-1488.

Brain Network Connectivity and Executive Function in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia.

Chemotherapeutic agents used to treat acute lymphoblastic leukemia (ALL), the most common cancer affecting young children, have been associated with long-term cognitive impairments that reduce quality of life. Executive dysfunction is one of the most consistently observed deficits and can have substantial and pervasive effects on academic success, occupational achievement, psychosocial function, and psychiatric status. We examined the neural mechanisms of executive dysfunction by measuring structural and functional connectomes in 161 long-term survivors of pediatric ALL, age 8-21 years, who were treated on a single contemporary chemotherapy-only protocol for standard/high- or low-risk disease. Lower global efficiency, a measure of information exchange and network integration, of both structural and functional connectomes was found in survivors with executive dysfunction compared with those without dysfunction (p < 0.046). Patients with standard/high- versus low-risk disease and those who received greater number of intrathecal treatments containing methotrexate had the lowest network efficiencies. Patients with executive dysfunction also showed hyperconnectivity in sensorimotor, visual, and auditory-processing regions (p = 0.037) and poor separation between sensorimotor, executive/attention, salience, and default mode networks (p < 0.0001). Connectome disruption was consistent with a pattern of delayed neurodevelopment that may be associated with reduced resilience, adaptability, and flexibility of the brain network. These findings highlight the need for interventions that will prevent or manage cognitive impairment in survivors of pediatric acute lymphoblastic leukemia.

Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.

Parent perspectives and preferences for strategies regarding nonsedated MRI scans in a pediatric oncology population.

PURPOSE: Children with cancer frequently require MRI scans for clinical purposes. Sedation with general anesthesia (GA) is often used to promote compliance, reduce motion, and alleviate anxiety. The use of GA for MRI scans is costly in terms of time, personnel, and medications. In addition, prominent risks are associated with anesthesia exposure in patients with complex medical conditions. Successful behavioral interventions have been implemented in clinical research settings to promote scan success and compliance. To our knowledge, parent/caregiver acceptability of behavioral interventions to promote nonsedated MRI has not been systematically investigated in a medically complex population. As a first step toward developing a protocol-based intervention to promote nonsedated scanning, we conducted a survey to explore parental perspectives regarding acceptability of nonsedated scanning and to gain information regarding preference for specific behavioral interventions to facilitate nonsedated MRI exams. METHODS: Parents or guardians of 101 patients diagnosed with childhood cancer participated in a semi-structured survey via telephone. The sample was stratified by age group (8-12 years; 13-18 years), gender, and diagnosis (solid tumor (ST), brain tumor (BT), and acute lymphoblastic leukemia (ALL)). RESULTS: The majority of parents indicated that nonsedated MRI scans would be acceptable. Reduced anesthesia exposure was the most frequently identified benefit, followed by decreased irritability post-MRI scan, and shorter appointment time. Challenges included fear of movement and noise during scans and change in routine, with parents of younger children and those with a history of sedated exams identifying more challenges. Behavioral intervention preference differed by patient age and gender; however, education was ranked as most preferred overall. CONCLUSION: Parents of children treated for cancer consider behavior interventions to promote nonsedated scanning as acceptable. Patient characteristics should be considered when tailoring behavioral interventions. Results can inform future studies of behavioral interventions to promote nonsedated MRI scans. Future research should also investigate the risks associated with failed exams, both in terms of patient medical care and cost effectiveness.

Overlapping Representation of Primary Tastes in a Defined Region of the Gustatory Cortex.

Both physiological and imaging approaches have led to often-disparate conclusions about the organization of taste information in gustatory cortex (GC). In this study, we used neuroanatomical and imaging approaches to delineate the likely area of insular cortex given to gustatory function and to characterize taste responses within this delineated area in female and male C57BL/6J mice. Anterograde tracers were injected into the taste thalamus (the medial parvicellular portion of the ventral posterior medial division, VPMpc) of mice and the thalamic terminal field was investigated across the cortex. Working within the delineated area, we used two-photon imaging to measure basic taste responses in >780 neurons in layer 2/3 located just posterior to the middle cerebral artery. A nonbiased, hierarchical cluster analysis revealed multiple clusters of cells responding best to either individual or combinations of taste stimuli. Taste quality was represented in the activity of taste-responsive cells; however, there was no apparent spatial organization of primary taste qualities in this region.SIGNIFICANCE STATEMENT Recent studies investigating taste coding within the gustatory cortex have reported highly segregated, taste-specific regions containing only narrowly tuned cells responding to a single taste separated by large non-taste-coding areas. However, focusing on the center of this area, we found a large number of taste responsive cells ranging from narrowly to broadly responsive with no apparent local spatial organization. Further, population analysis reveals that activity in the neuronal population in this area appears to be related to measures of taste quality or hedonics.

Disrupted development and integrity of frontal white matter in patients treated for pediatric medulloblastoma.

BACKGROUND: Treatment of pediatric medulloblastoma is associated with known neurocognitive deficits that we hypothesize are caused by microstructural damage to frontal white matter (WM). METHODS: Longitudinal MRI examinations were collected from baseline (after surgery but before therapy) to 36 months in 146 patients and at 3 time points in 72 controls. Regional analyses of frontal WM volume and diffusion tensor imaging metrics were performed and verified with tract-based spatial statistics. Age-adjusted, linear mixed-effects models were used to compare patient and control images and to associate imaging changes with Woodcock-Johnson Tests of Cognitive Abilities. RESULTS: At baseline, WM volumes in patients were similar to those in controls; fractional anisotropy (FA) was lower bilaterally (P < 0.001) and was associated with decreased Processing Speed (P = 0.014) and Broad Attention (P = 0.025) performance at 36 months. During follow-up, WM volumes increased in controls but decreased in patients (P < 0.001) bilaterally. Smaller WM volumes in patients at 36 months were associated with concurrent decreased Working Memory (P = 0.026) performance. CONCLUSIONS: Lower FA in patients with pediatric medulloblastoma compared with age-similar controls indicated that patients suffer substantial acute microstructural damage to supratentorial frontal WM following surgery but before radiation therapy or chemotherapy. Additionally, this damage to the frontal WM was associated with decreased cognitive performance in executive function 36 months later. This early damage also likely contributed to posttherapeutic failure of age-appropriate WM development and to the known association between decreased WM volumes and decreased cognitive performance.

Long-Term Efficacy of Computerized Cognitive Training Among Survivors of Childhood Cancer: A Single-Blind Randomized Controlled Trial.

Objective: To investigate the long-term efficacy of computerized cognitive training in improving cognitive outcomes among childhood cancer survivors. Methods: Sixty-eight survivors of childhood acute lymphoblastic leukemia (ALL) or brain tumor (BT) were randomly assigned to computerized cognitive intervention (23 ALL/11 BT, age = 12.21 ± 2.47) or a waitlist control group (24 ALL/10 BT, age = 11.82 ± 2.42). Cognitive assessments were completed pre-, immediately post-, and 6 months postintervention. Results: A prior report showed training led to immediate improvement in working memory, attention and processing speed. In the current study, piecewise linear mixed effects modeling revealed that working memory and processing speed were unchanged from immediate to 6 months postintervention (intervention ß = -.04 to .01, p = .26 to .95; control ß = -.06 to .01, p = .23-.97), but group differences on an attention measure did not persist. Conclusion: Cognitive benefits are maintained 6 months following computerized cognitive training, adding to potential clinical utility of this intervention approach.

Chemotherapy Pharmacodynamics and Neuroimaging and Neurocognitive Outcomes in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia.

PURPOSE: To examine associations among methotrexate pharmacodynamics, neuroimaging, and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy-only protocol. PATIENTS AND METHODS: This longitudinal study linked pharmacokinetic assays collected during therapy to neurocognitive and brain imaging outcomes during long-term follow-up. A total of 218 (72.2%) of 302 eligible long-term survivors were recruited for outcome studies when they were more than 5 years post-diagnosis and older than 8 years of age. At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis, and 51% were male. Neurocognitive testing, functional magnetic resonance imaging (MRI) during an executive function task, and structural MRI with diffusion tensor imaging were conducted. Generalized linear models were developed to identify predictors, and models were adjusted for age at diagnosis, sex, and parent education. RESULTS: Intelligence was within normal limits (mean, 98; standard deviation, 14) compared with population expectations (mean, 100; standard deviation, 15), though measures of executive function, processing speed, and memory were less than population means (all P < .02 after correction for false discovery rates). Higher plasma concentration of methotrexate was associated with a poorer executive function score (P < .02). Higher plasma methotrexate was also associated with higher functional MRI activity, with thicker cortices in dorsolateral prefrontal brain regions, and with white matter microstructure in the frontostriatal tact. Neurocognitive impairment was associated with these imaging findings as well. Associations did not change after adjustment for age or dose of leucovorin rescue. CONCLUSION: Survivors of childhood acute lymphoblastic leukemia treated on contemporary chemotherapy-only protocols demonstrate executive dysfunction. A higher plasma concentration of methotrexate was associated with executive dysfunction as well as with a thicker cortex and higher activity in frontal brain regions, regions often associated with executive function.

Investigating the Role of Hypothalamic Tumor Involvement in Sleep and Cognitive Outcomes Among Children Treated for Craniopharyngioma.

OBJECTIVE: Despite excellent survival prognosis, children treated for craniopharyngioma experience significant morbidity. We examined the role of hypothalamic involvement (HI) in excessive daytime sleepiness (EDS) and attention regulation in children enrolled on a Phase II trial of limited surgery and proton therapy. METHODS: Participants completed a sleep evaluation (N = 62) and a continuous performance test (CPT) during functional magnetic resonance imaging (fMRI; n = 29) prior to proton therapy. RESULTS: EDS was identified in 76% of the patients and was significantly related to increased HI extent (p = .04). There was no relationship between CPT performance during fMRI and HI or EDS. Visual examination of group composite fMRI images revealed greater spatial extent of activation in frontal cortical regions in patients with EDS, consistent with a compensatory activation hypothesis. CONCLUSION: Routine screening for sleep problems during therapy is indicated for children with craniopharyngioma, to optimize the timing of interventions and reduce long-term morbidity.

Quantitative imaging analysis of posterior fossa ependymoma location in children.

PURPOSE: Imaging descriptions of posterior fossa ependymoma in children have focused on magnetic resonance imaging (MRI) signal and local anatomic relationships with imaging location only recently used to classify these neoplasms. We developed a quantitative method for analyzing the location of ependymoma in the posterior fossa, tested its effectiveness in distinguishing groups of tumors, and examined potential associations of distinct tumor groups with treatment and prognostic factors. METHODS: Pre-operative MRI examinations of the brain for 38 children with histopathologically proven posterior fossa ependymoma were analyzed. Tumor margin contours and anatomic landmarks were manually marked and used to calculate the centroid of each tumor. Landmarks were used to calculate a transformation to align, scale, and rotate each patient's image coordinates to a common coordinate space. Hierarchical cluster analysis of the location and morphological variables was performed to detect multivariate patterns in tumor characteristics. The ependymomas were also characterized as "central" or "lateral" based on published radiological criteria. Therapeutic details and demographic, recurrence, and survival information were obtained from medical records and analyzed with the tumor location and morphology to identify prognostic tumor characteristics. RESULTS: Cluster analysis yielded two distinct tumor groups based on centroid location The cluster groups were associated with differences in PFS (p = .044), "central" vs. "lateral" radiological designation (p = .035), and marginally associated with multiple operative interventions (p = .064). CONCLUSIONS: Posterior fossa ependymoma can be objectively classified based on quantitative analysis of tumor location, and these classifications are associated with prognostic and treatment factors.

Functional MRI in medulloblastoma survivors supports prophylactic reading intervention during tumor treatment.

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.

Computerized Cognitive Training for Amelioration of Cognitive Late Effects Among Childhood Cancer Survivors: A Randomized Controlled Trial.

PURPOSE: Children receiving CNS-directed therapy for cancer are at risk for cognitive problems, with few available empirically supported interventions. Cognitive problems indicate neurodevelopmental disruption that may be modifiable with intervention. This study evaluated short-term efficacy of a computerized cognitive training program and neural correlates of cognitive change. PATIENT AND METHODS: A total of 68 survivors of childhood acute lymphoblastic leukemia (ALL) or brain tumor (BT) with identified cognitive deficits were randomly assigned to computerized cognitive intervention (male, n = 18; female, n = 16; ALL, n = 23; BT, n = 11; mean age ± standard deviation, 12.21 ± 2.47 years) or waitlist (male, n = 18; female, n = 16; ALL, n = 24; BT, n = 10; median age ± standard deviation, 11.82 ± 2.42 years). Intervention participants were asked to complete 25 training sessions at home with weekly, telephone-based coaching. Cognitive assessments and functional magnetic resonance imaging scans (intervention group) were completed pre- and postintervention, with immediate change in spatial span backward as the primary outcome. RESULTS: Survivors completing the intervention (n = 30; 88%) demonstrated greater improvement than controls on measures of working memory (mean ± SEM; eg, Wechsler Intelligence Scale for Children [fourth edition; WISC-IV] spatial span backward, 3.13 ± 0.58 v 0.75 ± 0.43; P = .002; effect size [ES], 0.84), attention (eg, WISC-IV spatial span forward, 3.30 ± 0.71 v 1.25 ± 0.39; P = .01; ES, 0.65), and processing speed (eg, Conners' Continuous Performance Test hit reaction time, -2.10 ± 1.47 v 2.54 ± 1.25; P = .02; ES, .61) and showed greater reductions in reported executive dysfunction (eg, Conners' Parent Rating Scale III, -6.73 ± 1.51 v 0.41 ± 1.53; P = .002; ES, 0.84). Functional magnetic resonance imaging revealed significant pre- to post-training reduction in activation of left lateral prefrontal and bilateral medial frontal areas. CONCLUSION: Study findings show computerized cognitive training is feasible and efficacious for childhood cancer survivors, with evidence for training-related neuroplasticity.

Effects of Surgery and Proton Therapy on Cerebral White Matter of Craniopharyngioma Patients.

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.