Early-life nutrition is associated with processing speed at age 5 in children born preterm with very low birth weight.

OBJECTIVE: Processing speed is suboptimal among preterm-born children which is of concern as it is a foundational skill supporting higher-level cognitive functions. The study objective was to evaluate associations between early-life nutrition and processing speed in childhood. METHODS: Macronutrient and human milk (mother's own, donor) intakes from 137 children born preterm with very low birth weight enrolled in a nutrition feeding trial were included. Processing speed was evaluated at age 5 using the Wechsler Preschool and Primary Scale of Intelligence-fourth edition Processing Speed Index. Associations between early-life nutrition and processing speed were explored through linear regression. RESULTS: Children had a mean (standard deviation [SD]) birth gestational age of 28.1 (2.5) weeks, weight of 1036 (260) g and 52% were male. The mean (SD) assessment age was 5.7 (0.2) years. Sex-dependent relationships were identified between first postnatal month protein, lipid and energy intakes and processing speed at 5 years. For females, lower protein (per 0.1 g/kg/d: -0.88, 95% confidence interval [CI]: -1.53, -0.23; p = 0.01) and energy (per 10 kcal/kg/d: -2.38, 95% CI: -4.70, -0.05; p = 0.03) intakes were related to higher processing speed scores. Mother's milk provision was positively associated (per 10% increase: 0.80, 95% CI: 0.22, 1.37; p = 0.01) and donor milk was negatively associated (per 10% increase: -1.15, 95% CI: -2.22, -0.08; p = 0.04) with processing speed scores; no sex differences were observed. CONCLUSIONS: First postnatal month nutrition was related to processing speed at age 5 in children born preterm with very low birth weight. Early-life nutrition that supports processing speed may be leveraged to improve later cognitive outcomes for this vulnerable population.

Incidence of pulmonary embolism in COVID-19 infection in the ED: ancestral, Delta, Omicron variants and vaccines.

PURPOSE: This retrospective review examines the incidence of pulmonary embolism (PE) during computed tomography pulmonary angiography (CTPA) exams performed in the emergency room setting of a tertiary care center over dominant periods of the ancestral, Delta, and Omicron variants of COVID-19. MATERIALS/METHODS: Demographic information, patient comorbidities and risk factors, vaccination status, and COVID-19 infection status were collected from patient's charts. Incidence of PE in COVID positive patients was compared between variant waves. Subgroup analysis of vaccination effect was performed. RESULTS: CTPA was ordered in 18.3% of COVID-19 positive patients during the ancestral variant period, 18.3% during the Delta period and 17.3% during the Omicron wave. PE was seen in 15.0% of the ancestral COVID-19 variant cohort, 10.6% in the Delta COVID cohort and 9.23% of the Omicron cohort, reflecting a 41% and 60% increased risk of PE with ancestral variants compared to Delta and Omicron periods respectively. The study however was underpowered and the difference in rate of PE did not reach statistically significance (p = 0.43 and p = 0.22). Unvaccinated patients had an 2.75-fold increased risk of COVID-associated PE during the Delta and Omicron periods (p = .02) compared to vaccinated or recovered patients. CONCLUSION: Vaccination reduces the risk of COVID-19 associated PE. Patients infected with the Delta and Omicron COVID-19 variants may have a lower incidence of pulmonary embolism, though a larger or multi-institution study is needed to prove definitively.

PPAR and GST polymorphisms may predict changes in intellectual functioning in medulloblastoma survivors.

PURPOSE: Advances in the treatment of pediatric medulloblastoma have led to improved survival rates, though treatment-related toxicity leaves children with significant long-term deficits. There is significant variability in the cognitive outcome of medulloblastoma survivors, and it has been suggested that this variability may be attributable to genetic factors. The aim of this study was to explore the contributions of single nucleotide polymorphisms (SNPs) in two genes, peroxisome proliferator activated receptor (PPAR) and glutathione-S-transferase (GST), to changes in general intellectual functioning in medulloblastoma survivors. METHODS: Patients (n = 44, meanage = 6.71 years, 61.3% males) were selected on the basis of available tissue samples and neurocognitive measures. Patients received surgical tumor resection, craniospinal radiation, radiation boost to the tumor site, and multiagent chemotherapy. Genotyping analyses were completed using the Illumina Human Omni2.5 BeadChip, and 41 single nucleotide polymorphisms (SNPs) were assessed across both genes. We used a machine learning algorithm to identify polymorphisms that were significantly associated with declines in general intellectual functioning following treatment for medulloblastoma. RESULTS: We identified age at diagnosis, radiation therapy, chemotherapy, and eight SNPs associated with PPARs as predictors of general intellectual functioning. Of the eight SNPs identified, PPARα (rs6008197), PPARγ (rs13306747), and PPARδ (rs3734254) were most significantly associated with long-term changes in general intellectual functioning in medulloblastoma survivors. CONCLUSIONS: PPAR polymorphisms may predict intellectual outcome changes in children treated for medulloblastoma. Importantly, emerging evidence suggests that PPAR agonists may provide an opportunity to minimize the effects of treatment-related cognitive sequelae in these children.

Unique and shared areas of cognitive function in children with intractable frontal or temporal lobe epilepsy.

OBJECTIVE: Previous findings have been mixed in terms of identifying a distinct pattern of neuropsychological deficits in children with frontal lobe epilepsy (FLE) and in those with temporal lobe epilepsy (TLE). The current study investigated the neuropsychological similarities and differences across these two pediatric medically intractable localization-related epilepsies. METHOD: Thirty-eight children with FLE, 20 children with TLE, and 40 healthy children (HC) participated in this study. A comprehensive battery of standardized tests assessed five neuropsychological domains including intelligence, language, memory, executive function, and motor function. A principal component analysis (PCA) was used to distill our neuropsychological measures into latent components to compare between groups. RESULTS: Principal component analysis extracted 5 latent components: executive function (F1), verbal semantics (F2), motor (F3), nonverbal cognition/impulsivity (F4), and verbal cognition/attention (F5). The group with FLE differed from the HC group on F1, F2, F4, and F5, and had worse performance than the group with TLE on F1; the group with TLE had lower performance relative to the HC group on F2. CONCLUSION: Our findings suggest that, in comparison with neurotypically developing children, children with medically intractable FLE have more widespread neuropsychological impairments than do children with TLE. The differences between the two patient groups were greatest for the factor score most clearly related to executive function. The results provide mixed support for the concept of specificity in neuropsychological dysfunction among different subtypes of localization-related medically intractable childhood epilepsies.

Verbal memory after temporal lobe epilepsy surgery in children: Do only mesial structures matter?

OBJECTIVE: Previous findings have been mixed regarding verbal memory outcome after left temporal lobectomy in children, and there are few studies comparing verbal memory change after lateral versus mesial temporal lobe resections. We compared verbal memory outcome associated with sparing or including the mesial structures in children who underwent left or right temporal lobe resection. We also investigated predictors of postsurgical verbal memory change. METHODS: We retrospectively assessed verbal memory change approximately 1 year after unilateral temporal lobe epilepsy surgery using a list learning task. Participants included 23 children who underwent temporal lobe surgery with sparing of the mesial structures (13 left), and 40 children who had a temporal lobectomy that included resection of mesial structures (22 left). RESULTS: Children who underwent resection from the left lateral and mesial temporal lobe were the only group to show decline in verbal memory. Furthermore, when we considered language representation in the left temporal resection group, patients with left language representation and spared mesial structures showed essentially no change in verbal memory from preoperative to follow-up, whereas those with left language representation and excised mesial structures showed a decline. Postoperative seizure status had no effect on verbal memory change in children after left temporal lobe surgery. Finally, we found that patients with intact preoperative verbal memory experienced a significant decline compared to those with below average preoperative verbal memory. SIGNIFICANCE: Our findings provide evidence of significant risk factors for verbal memory decline in children, specific to left mesial temporal lobe epilepsy. Children who undergo left temporal lobe surgery that includes mesial structures may be most vulnerable for verbal memory decline, especially when language representation is localized to the left hemisphere and when preoperative verbal memory is intact.

Visualization and segmentation of reciprocal cerebrocerebellar pathways in the healthy and injured brain.

Detailed information regarding the neuroanatomy of reciprocal cerebrocerebellar pathways is based on well-documented animal models. This knowledge has not yet been fully translated to humans, in that the structure of reciprocal cerebrocerebellar pathways connecting the cerebellum with frontal lobe has not been shown in its entirety. We investigated the impact of injury and age on cerebrocerebellar pathway microstructure using diffusion tensor imaging (DTI) and probabilistic tractography. We used medulloblastoma (MB) as an injury model due to the known impact of tumor/treatment on the cerebellum, one of the main nodes of cerebrocerebellar pathways. We delineated and segmented reciprocal cerebrocerebellar pathways connecting the cerebellum with frontal lobe in 38 healthy children (HC) and 34 children treated for MB, and compared pathway segment DTI measures between HC and MB and across three age cohorts: childhood, early adolescence, and late adolescence. Pathway compromise was evident for the MB group compared to HC, particularly within posterior segments (Ps<0.01). Though we found no age effect, group differences in microstructure were driven by pathway segment (posterior) and age cohort (adolescence), which may reflect the extent of injury to the posterior fossa following treatment for MB and age cohort differences in radiation treatment protocol in our sample. We have examined the microstructure of reciprocal cerebrocerebellar connections in the pediatric brain and have found that these pathways are injured in MB, a clinical population treated with surgery, radiation, and chemotherapy. Our findings support the late effects literature describing white matter injury emergence in the years following treatment for MB.

Evaluation of behavioral outcomes in children 1 year after epilepsy surgery.

OBJECTIVE: Children with epilepsy have elevated rates of behavior problems. Research findings on the impact of epilepsy surgery on children's behavior have been mixed, with some studies showing improvements in behavior 3 to 18 months after surgery and other studies finding no change within this time interval. We examined behavior in a large surgical sample and in a nonsurgical comparison group. We also examined for potential effects of epilepsy-related and cognitive/linguistic variables. METHODS: Behavior was assessed by parent report in 147 children who underwent epilepsy surgery and 40 children who did not, using the Child Behavior Checklist (CBCL). For the surgical group, the CBCL was completed prior to surgery (baseline) and approximately 1 year after surgery (follow-up); ratings of the nonsurgical group were also conducted twice, at comparable intervals. RESULTS: At baseline, the groups did not differ on age, sex, age at seizure onset, antiepileptic drugs (AEDs), or intelligence quotient (IQ). Baseline Social and Attention Problems were higher in the nonsurgical group. At follow-up, 65% of the surgical group and 20% of the nonsurgical group were seizure-free. Behavioral change was not related to surgical status or seizure outcome. Children with temporal lobe seizure focus had more Externalizing Behaviors compared to those with frontal or multilobar foci. Attention was poorer in children who underwent frontal lobe excisions relative to temporal or multilobar excisions. Baseline IQ did not predict behavioral change. SIGNIFICANCE: Our results suggest that surgery and seizure outcome do not affect behavior in the first year following surgery; it may be the abnormal neural substrate and not seizure control that influences behavior in children with epilepsy. If changes are to occur due to seizure freedom, they may require a longer time to emerge. Some behaviors may be resistant to change in children with epilepsy or may require even longer intervals for improvement.

Unraveling Temporal Dynamics of Multidimensional Statistical Learning in Implicit and Explicit Systems: An X-Way Hypothesis.

Statistical learning enables humans to involuntarily process and utilize different kinds of patterns from the environment. However, the cognitive mechanisms underlying the simultaneous acquisition of multiple regularities from different perceptual modalities remain unclear. A novel multidimensional serial reaction time task was developed to test 40 participants' ability to learn simple first-order and complex second-order relations between uni-modal visual and cross-modal audio-visual stimuli. Using the difference in reaction times between sequenced and random stimuli as the index of domain-general statistical learning, a significant difference and dissociation of learning occurred between the initial and final learning phases. Furthermore, we used a negative and positive occurrence-frequency-and-reaction-time correlation to indicate implicit and explicit learning, respectively, and found that learning simple uni-modal patterns involved an implicit-to-explicit segue, while acquiring complex cross-modal patterns required an explicit-to-implicit segue, resulting in a X-shape crossing of regularity learning. Thus, we propose an X-way hypothesis to elucidate the dynamic interplay between the implicit and explicit systems at two distinct stages when acquiring various regularities in a multidimensional probability space.

Embolization of pulmonary artery aneurysms in a patient with Behçet's disease complicated by coil erosion into the airway.

Behçet's disease is an inflammatory vasculitis with the unique feature of pulmonary artery aneurysms. We describe a patient with Behçet's disease and pulmonary artery aneurysms who presented with massive hemoptysis treated by coil embolization. Although there was immediate resolution of hemoptysis and improvement in hemodynamic status, 2 months later the patient reported a refractory cough and feeling of foreign body in her throat. Imaging demonstrated partial coil migration into the bronchus and trachea. Although endovascular intervention is the first-line treatment for massive hemoptysis, in patients with Behçet's disease, active inflammation and chronic steroid use may increase the risk of coil erosion and migration.

Diet Quality and Cognitive Performance in Children Born Very Low Birth Weight.

Children born very low birth weight (VLBW, <1,500 g) are at high risk for cognitive and academic difficulties later in life. Although early nutrition (e.g., breastfeeding) is positively correlated with IQ in children born VLBW, the association between dietary intake in childhood and cognitive performance is unknown. Thus, our study is the first to investigate the relationship between diet quality, as measured by the Healthy Eating Index-2010 (HEI-2010) and cognitive performance in a Canadian cohort of 5-year-old children born VLBW (n = 158; 47% female). Diet quality was measured using two 24-h diet recalls obtained from parents and cognitive performance was assessed using the Wechsler Preschool and Primary Scale of Intelligence-IV (WPPSI-IV). To account for additional sociodemographic factors that could influence neurodevelopment, linear regression analyses were adjusted for sex, household income above/below the poverty line, maternal education, birth weight and breastfeeding duration. Mean ± SD HEI-2010 score was 58.2 ± 12.4, with most children (67%) having diets in "need of improvement" (scores 51-80). HEI-2010 scores were not significantly associated with IQ or any other WPPSI-IV composite score. Significant predictors of IQ in our model were birth weight, sex, and maternal education. Our findings emphasize the important role of maternal education and other sociodemographic factors on neurodevelopment in children born VLBW. Further, despite not finding any significant association between HEI-2010 scores and IQ, our results highlight the need to improve diet quality in young children born VLBW. Further research is needed to confirm the impact of diet quality on cognitive performance in this vulnerable population.

Eating Behaviors, Caregiver Feeding Interactions, and Dietary Patterns of Children Born Preterm: A Systematic Review and Meta-Analysis.

Infants born preterm (<37 weeks of gestation) often experience feeding problems during hospitalization. Whether difficulties persist or have long-term sequelae on childhood eating is unclear. We aimed to describe the oromotor eating skills (e.g., chewing/swallowing), eating behaviors (e.g., food neophobia), food parenting practices (e.g., pressure to eat), and dietary patterns of preterm children during late infancy (6-12 mo) and early childhood (>12 mo-7 y) and to determine whether these differed from those of term-born peers. We identified 67 articles (57 unique studies) for inclusion. We used random-effects meta-analysis of proportions to examine the prevalence of oromotor eating skill and eating behavior challenges among preterm children, standard meta-analysis for comparisons with term-born peers, and the Grading of Recommendations, Assessment, Development and Evaluation approach to assess the certainty of evidence. Forty-three percent (95% CI: 24%, 62%) of infants and 25% (95% CI: 17%, 33%) of children born preterm experienced oromotor eating difficulties and 16% (95% CI: 4%, 27%) and 20% (95% CI: 11%, 28%), respectively, exhibited challenging eating behaviors. During late infancy and early childhood, oromotor eating difficulties (OR: 2.86; 95% CI: 1.71, 4.77; I2 = 67.8%) and challenging eating behaviors (OR: 1.52; 95% CI: 1.11, 2.10; I2 = 0.0%) were more common in those born preterm than in those born term: however, the certainty of evidence was very low. Owing to the low number and heterogeneity of studies, we narratively reviewed literature on food parenting and dietary patterns. Mothers of preterm infants appeared to have heightened anxiety while feeding and utilized coercive food parenting practices; their infants reportedly received less human milk, started solid foods earlier, and had poorer diet quality than term-born peers. In conclusion, meta-analyses show preterm children experience frequent oromotor eating difficulties and challenging eating behaviors throughout the early years. Given preterm birth increases risk of later obesity and diet-related chronic disease, research examining the effects of caregiver-child interactions on subsequent diet is warranted. This review was registered at www.crd.york.ac.uk/prospero/ as CRD42020176063.

Social-emotional functioning and dietary intake among children born with a very low birth weight.

Very low birth weight (VLBW, <1500 g)  infants are at an elevated risk of neurodevelopmental disorders, later obesity and cardiometabolic disease; if and how neurodevelopmental disorders impact chronic disease risk is poorly understood. The most common neurodevelopmental disorders experienced by VLBW children are those of social-emotional functioning. We compared dietary patterns and body composition between VLBW children with poor vs. typical social-emotional functioning using linear mixed models adjusted for sex, gestational age, cognitive impairment, parental education, and body mass index (BMI). VLBW children (n=158) attending the Donor Milk for Improved Neurodevelopmental Outcomes trial with 5.5-year follow-up participated. Poor social-emotional functioning was based on standardized parent-rated questionnaires and/or parent-reported physician diagnosis of autism spectrum or attention-deficit/hyperactivity disorders. Most children had diets categorized as "needs improvement" (67%) or "poor" (27%) and 29% of children exhibited poor social-emotional functioning. Poor social-emotional functioning was positively associated with 100% fruit juice (ß=0.3 cup equivalents/day; 95% CI 0.1, 0.5) and energy intake (ß=118.1 kcal/day; 95% CI 0.9, 235.2). Children with poor social-emotional functioning were more likely to have a limited food repertoire (p=0.02), but less likely to exceed dietary fat recommendations (p=0.04). No differences in overall diet quality or body composition were observed. Diet counselling and research are essential to improving the nutrition of VLBW children to mitigate chronic disease risk. Trial registration - Optimizing Mothers' Milk for Preterm Infants Program of Research: Study 1 - Impact of Donor Milk at Kindergarten, NCT02759809, https://clinicaltrials.gov/ct2/show/NCT02759809. Novelty: Overall diet quality and body composition did not differ between VLBW children with poor vs. typical social-emotional functioning. Most had diets "needing improvement" or "poor" according to the Healthy Eating Index-2010. Diet counselling may help mitigate chronic disease risk in this vulnerable population.

Cerebello-thalamo-cerebral connections in pediatric brain tumor patients: impact on working memory.

Brain tumors are the leading cause of death and disability from childhood disease in developed countries. Pediatric posterior fossa tumors are often effectively controlled with a combination of surgery, radiation, and chemotherapy, depending on tumor type. White matter injury following resection of tumor and radiation treatment is associated with cognitive declines, including working memory deficits. We investigated how brain injury following treatment for posterior fossa tumors results in deficits in working memory. We used diffusion tensor imaging and probabilistic tractography to examine the structural integrity of cerebello-thalamo-cerebral tracts in patients and healthy children. We also compared working memory outcome in patients versus controls, and related this function to integrity of cerebello-thalamo-cerebral tracts. Bilateral cerebello-thalamo-cerebral tracts were delineated in all participants. Patients treated with a combination of surgery and radiation had lower mean anisotropy and higher mean radial diffusivity within the cerebellar regions of the cerebello-thalamo-cerebral tract compared to patients treated with surgery only and healthy controls. Poorer working memory scores were observed for the cranial radiation group relative to controls. Reduced anisotropy and higher radial diffusivity within the entire cerebello-thalamo-cerebral pathway predicted lower working memory. Our finding that working memory function is related to the integrity of cerebello-thalamo-cerebral connections is a novel contribution to the understanding of cerebral-cerebellar communication. Identifying differences in the structural integrity of white matter for specific pathways is an essential step in attempting to localize the effects of posterior fossa tumors and their treatment methods.

Texture analysis and machine learning algorithms accurately predict histologic grade in small (< 4 cm) clear cell renal cell carcinomas: a pilot study.

PURPOSE: To predict the histologic grade of small clear cell renal cell carcinomas (ccRCCs) using texture analysis and machine learning algorithms. METHODS: Fifty-two noncontrast (NC), 26 corticomedullary (CM) phase, and 35 nephrographic (NG) phase CTs of small (< 4 cm) surgically resected ccRCCs were retrospectively identified. Surgical pathology classified the tumors as low- or high-Fuhrman histologic grade. The axial image with the largest cross-sectional tumor area was exported and segmented. Six histogram and 31 texture (gray-level co-occurrences (GLC) and gray-level run-lengths (GLRL)) features were calculated for each tumor in each phase. T testing compared feature values in low- and high-grade ccRCCs, with a (Benjamini-Hochberg) false discovery rate of 10%. Area under the receiver operating curve (AUC) was calculated for each feature to assess prediction of low- and high-grade ccRCCs in each phase. Histogram, texture, and combined histogram and texture data sets were used to train and test four algorithms (k-nearest neighbor (KNN), support vector machine (SVM), random forests, and decision tree) with tenfold cross-validation; AUCs were calculated for each algorithm in each phase to assess prediction of low- and high-grade ccRCCs. RESULTS: Zero, 23, and 0 features in the NC, CM, and NG phases had statistically significant differences between low and high-grade ccRCCs. CM histogram skewness and GLRL short run emphasis had the highest AUCs (0.82) in predicting histologic grade. All four algorithms had the highest AUCs (0.97) predicting histologic grade using CM histogram features. The algorithms' AUCs decreased using histogram or texture features from NC or NG phases. CONCLUSION: The histologic grade of small ccRCCs can be accurately predicted with machine learning algorithms using CM histogram features, which outperform NC and NG phase image data.

Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort.

BACKGROUND: Understanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients. METHODS: Seventy-six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered-including molecular subgroup. RESULTS: The majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy-assessed. Self-care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P = .02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P < .05. Patients treated with a gross total resection also had better outcomes for the HUI3 hearing (P = .04). However, those who underwent a gross total resection reported having worse outcomes on the HUI3 vision (P = .02). No differences in HRQL were evident as a function of subgroup. CONCLUSIONS: By examining an international sample of survivors, we characterized the worldwide impact of medulloblastoma. This is a critical first step in developing global standards for evaluating long-term outcomes.

Executive function in paediatric medulloblastoma: The role of cerebrocerebellar connections.

Executive functions (EFs) are involved in the attainment, maintenance, and integration of information; these functions may play a key role in cognitive and behavioural outcomes in children treated for medulloblastoma (MB). At present, it remains unclear which EFs are most sensitive to the treatment effects for MB and whether damage to cerebrocerebellar circuitry is associated with EF. We completed a comprehensive evaluation of EF in 24 children treated for MB and 20 age-matched healthy children (HC) and distilled these measures into components. Six components (C1-C6) were extracted from our model, reflecting dissociable constructs of EF: C1 = cognitive efficiency; C2 = planning/problem-solving; C3 = positive cognitive emotion regulation; C4 = working memory; C5 = negative cognitive emotion regulation; and C6 = mixed cognitive emotion regulation. Group differences were found for C1, C2, C3, and C4; the MB group showed poorer performance on EF tasks and made less use of positive cognitive emotion regulation strategies relative to HC. Compromise to cerebrocerebellar microstructure - cerebro-ponto-cerebellar and cerebello-thalamo-cerebral pathways - was evident in children treated for MB compared to HC. We found that cerebrocerebellar circuitry has a mediating effect on one component of EF following treatment for MB - working memory.

Vulnerability of white matter to insult during childhood: evidence from patients treated for medulloblastoma.

OBJECTIVE Craniospinal irradiation damages the white matter in children treated for medulloblastoma, but the treatment-intensity effects are unclear. In a cross-sectional retrospective study, the effects of treatment with the least intensive radiation protocol versus protocols that delivered more radiation to the brain, in addition to the effects of continuous radiation dose, on white matter architecture were evaluated. METHODS Diffusion tensor imaging was used to assess fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity. First, regional white matter analyses and tract-based spatial statistics were conducted in 34 medulloblastoma patients and 38 healthy controls. Patients were stratified according to those treated with 1) the least intensive radiation protocol, specifically reduced-dose craniospinal irradiation plus a boost to the tumor bed only (n = 17), or 2) any other dose and boost combination that delivered more radiation to the brain, which was also termed the "all-other-treatments" group (n = 17), and comprised patients treated with standard-dose craniospinal irradiation plus a posterior fossa boost, standard-dose craniospinal irradiation plus a tumor bed boost, or reduced-dose craniospinal irradiation plus a posterior fossa boost. Second, voxel-wise dose-distribution analyses were conducted on a separate cohort of medulloblastoma patients (n = 15). RESULTS The all-other-treatments group, but not the reduced-dose craniospinal irradiation plus tumor bed group, had lower fractional anisotropy and higher radial diffusivity than controls in all brain regions (all p < 0.05). The reduced-dose craniospinal irradiation plus tumor bed boost group had higher fractional anisotropy (p = 0.05) and lower radial diffusivity (p = 0.04) in the temporal region, and higher fractional anisotropy in the frontal region (p = 0.04), than the all-other-treatments group. Linear mixed-effects modeling revealed that the dose and age at diagnosis together 1) better predicted fractional anisotropy in the temporal region than models with either alone (p < 0.005), but 2) did not better predict fractional anisotropy in comparison with dose alone in the occipital region (p > 0.05). CONCLUSIONS Together, the results show that white matter damage has a clear association with increasing radiation dose, and that treatment with reduced-dose craniospinal irradiation plus tumor bed boost appears to preserve white matter in some brain regions.

White matter and information processing speed following treatment with cranial-spinal radiation for pediatric brain tumor.

OBJECTIVE: We compared the structure of specific white matter tracts and information processing speed between children treated for posterior fossa tumors with cranial-spinal radiation (n = 30), or with surgery +/- focal radiation (n = 29), and healthy children (n = 37). METHOD: Probabilistic diffusion tensor imaging (DTI) tractography was used to delineate the inferior longitudinal fasciculi, optic radiation, inferior frontal occipital fasciculi, and uncinate fasciculi bilaterally. Information processing speed was measured using the coding and symbol search subtests of the Wechsler Intelligence Scales, and visual matching, pair cancellation, and rapid picture naming subtests of the Woodcock-Johnson Test of Cognitive Ability, 3rd revision. We examined group differences using repeated measures MANOVAs and path analyses were used to test the relations between treatment, white matter structure of the tracts, and information processing speed. RESULTS: DTI indices of the optic radiations, the inferior longitudinal fasciculi, and the inferior fronto-occipital fasciculi differed between children treated with cranial-spinal radiation and children treated with surgery +/- focal radiation, and healthy controls (p = .045). Children treated with cranial-spinal radiation also exhibited lower processing speed scores relative to healthy control subjects (p = .002). Notably, we observed that group differences in information processing speed were related to the structure of the right optic radiation (p = .002). CONCLUSION: We show that cranial-spinal radiation may have a negative impact on information processing speed via insult to the right optic radiations. (PsycINFO Database Record

Intellectual Outcome in Molecular Subgroups of Medulloblastoma.

Purpose To evaluate intellectual functioning and the implications of limiting radiation exposure in the four biologically distinct subgroups of medulloblastoma: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Patients and Methods A total of 121 patients with medulloblastoma (n = 51, Group 4; n = 25, Group 3; n = 28, SHH; and n = 17, WNT), who were treated between 1991 and 2013 at the Hospital for Sick Children (Toronto, Ontario, Canada), Children's National Health System (Washington, DC), or the Lucile Packard Children's Hospital (Palo Alto, CA), had intellectual assessments. First, we compared intellectual trajectories between subgroups. Next, we evaluated the effect of treatment with reduced-dose craniospinal irradiation (CSI) plus a tumor bed boost versus treatments that deliver higher CSI doses and/or larger boost volumes to the brain (all other treatments) within subgroups. Linear mixed modeling was used to determine the stability or change in intelligence scores over time. Results Intellectual outcomes declined comparably in each subgroup except for processing speed; SHH declined less than Group 3 ( P = .04). SHH had the lowest incidence of cerebellar mutism and motor deficits. Treatment with reduced-dose CSI plus a tumor bed boost was associated with preserved intellectual functioning in WNT and Group 4 patients considered together (ie, subgroups containing patients who are candidates for therapy de-escalation), and not in Group 3 or SHH. Across all subgroups, patients in the all other treatments group declined over time (all P < .05). Conclusion SHH patients appear to have the most distinct functional (ie, motor deficits and mutism) outcomes and a unique processing speed trajectory. Only WNT and Group 4 patients seem to benefit from limiting radiation exposure. Our findings highlight the value of conducting subgroup-specific analyses, and can be used to inform novel biologically based treatment protocols for patients with medulloblastoma.

Impact of craniospinal dose, boost volume, and neurologic complications on intellectual outcome in patients with medulloblastoma.

PURPOSE: To examine the impact of radiation (ie, craniospinal irradiation [CSR] dose and boost volume) and complications (ie, hydrocephalus and other neurologic complications, including mutism) on patterns of change in intellectual functioning in medulloblastoma survivors. PATIENTS AND METHODS: We conducted a retrospective review of 113 patients treated for medulloblastoma between 1983 and 2011 who were seen for neuropsychological assessment, including longitudinal follow-up of intellectual function. Patients were treated with either standard-dose CSR with a posterior fossa (PF) boost (n=51), standard-dose CSR plus tumor bed (TB) boost (n=9), reduced-dose CSR plus PF boost (n=28), or reduced-dose CSR plus TB boost (n=23), with or without chemotherapy. A subset of patients developed hydrocephalus that required cerebrospinal fluid (CSF) diversion (n=54) and/or other neurologic complications (n=40), more than half of which were postoperative mutism (n=25). Growth curve analysis was used to determine stability or change in intelligence scores over time. RESULTS: Patients treated with reduced-dose CSR plus TB boost showed stable intellectual trajectories, whereas patients treated with higher doses and larger boost volumes experienced intellectual declines. Presence of complications was associated with worse intellectual outcome; however, hydrocephalus requiring CSF diversion and mutism differed in their pattern of decline. CONCLUSION: These results improve our understanding of factors that impair intellectual outcome in patients treated for medulloblastoma. Lower doses of CSR and smaller boost volumes seem to mitigate intellectual decline. Our findings validate the use of TB boost and suggest PF boost should be reconsidered.