Association Between Brain Substructure Dose and Cognitive Outcomes in Children With Medulloblastoma Treated on SJMB03: A Step Toward Substructure-Informed Planning.

PURPOSE: To characterize the association between neurocognitive outcomes (memory and processing speed) and radiation (RT) dose to the hippocampus, corpus callosum (CC), and frontal white matter (WM) in children with medulloblastoma treated on a prospective study, SJMB03. PATIENTS AND METHODS: Patients age 3-21 years with medulloblastoma were treated at a single institution on a phase III study. The craniospinal RT dose was 23.4 Gy for average-risk patients and 36-39.6 Gy for high-risk patients. The boost dose was 55.8 Gy to the tumor bed. Patients underwent cognitive testing at baseline and once yearly for 5 years. Performance on tests of memory (associative memory and working memory) and processing speed (composite processing speed and perceptual speed) was analyzed. Mixed-effects models were used to estimate longitudinal trends in neurocognitive outcomes. Reliable change index and logistic regression were used to define clinically meaningful neurocognitive decline and identify variables associated with decline. RESULTS: One hundred and twenty-four patients were eligible for inclusion, with a median neurocognitive follow-up of 5 years. Mean right and left hippocampal doses were significantly associated with decline in associative memory in patients without posterior fossa syndrome (all P < .05). Mean CC and frontal WM doses were significantly associated with decline in both measures of processing speed (all P < .05). Median brain substructure dose-volume histograms were shifted to the right for patients with a decline in associative memory or processing speed. The odds of decline in associative memory and composite processing speed increased by 23%-26% and by 10%-15% for every 1-Gy increase in mean hippocampal dose and mean CC or frontal WM dose, respectively. CONCLUSION: Increasing RT dose to the CC or frontal WM and hippocampus is associated with worse performance on tests of processing speed and associative memory, respectively. Brain substructure-informed RT planning may mitigate neurocognitive impairment.

Fetal Exposure to MR Imaging: Long-Term Neurodevelopmental Outcome.

BACKGROUND AND PURPOSE: Very few studies have investigated long-term neurodevelopment of children exposed to MR imaging antenatally. Thus, the purpose of our study was to evaluate long-term neurodevelopmental outcomes of children exposed to MR imaging during pregnancy. MATERIALS AND METHODS: We conducted a historical prospective cohort study in a single tertiary medical center. Women exposed to 1.5T noncontrast MR imaging for maternal or fetal indications were matched to unexposed controls. Long-term neurodevelopmental outcomes were evaluated of their children, 2.5 to 6 years of age, according to the Vineland-II Adaptive Behavior Scale. The Vineland-II Adaptive Behavior Scale assesses communication, daily living skills, socialization, and motor skills. A composite score summarizes these 4 domains. RESULTS: A total of 131 exposed women matched our inclusion criteria and were included in the study group, and 771 unexposed women, in the control group. No difference was identified in the Vineland-II Adaptive Behavior Scale composite score between the children of the study and control groups (mean, 110.79 versus 108.18; P = .098). Differences were also not observed between the children of the 2 groups in 3 of the 4 questionnaire domains: communication (108.84 versus 109.10; P = .888), daily living skills (109.51 versus 108.28; P = .437), and motor skills (105.09 versus 104.42; P = .642). However, the socialization score was favorable for the study group (112.98 versus 106.47; P < .001). CONCLUSIONS: Exposure to 1.5T noncontrast MR imaging during pregnancy had no harmful effects on long-term neurodevelopmental outcomes. This study contributes to understanding the safety of MR imaging during pregnancy.

Child development at 6 years after maternal cancer diagnosis and treatment during pregnancy.

BACKGROUND: Data on the long-term effects of prenatal exposure to maternal cancer and its treatment on child development are scarce. METHODS: In a multicenter cohort study, the neurologic and cardiac outcomes of 6-year-old children born to women diagnosed with cancer during pregnancy were compared with the outcome of children born after an uncomplicated pregnancy. Assessment included clinical evaluation, comprehensive neuropsychological testing, electrocardiography and echocardiography. RESULTS: In total, 132 study children and 132 controls were included. In the study group, 97 children (73.5%) were prenatally exposed to chemotherapy (alone or in combination with other treatments), 14 (10.6%) to radiotherapy (alone or in combination), 1 (0.8%) to trastuzumab, 12 (9.1%) to surgery alone and 16 (12.1%) to no treatment. Although within normal ranges, statistically significant differences were found in mean verbal IQ and visuospatial long-term memory, with lower scores in the study versus control group (98.1, 95% confidence interval [CI]: 94.5-101.8, versus 104.4, 95% CI: 100.4-108.4, P = 0.001, Q < 0.001 [Q refers to the false discovery rate adjusted P value], and 3.9, 95% CI: 3.6-4.3, versus 4.5, 95% CI: 4.1-4.9, P = 0.005, Q = 0.045, respectively). A significant difference in diastolic blood pressure was found, with higher values in chemotherapy-exposed (61.1, 95% CI: 59.0 to 63.2) versus control children (56.0, 95% CI 54.1 to 57.8) (P < 0.001, Q < 0.001) and in a subgroup of 59 anthracycline-exposed (61.8, 95% CI: 59.3 to 64.4) versus control children (55.9, 95% CI: 53.6 to 58.1) (P < 0.001, Q = 0.02). CONCLUSIONS: Children prenatally exposed to maternal cancer and its treatment are at risk for lower verbal IQ and visuospatial long-term memory scores and for higher diastolic blood pressure, but other cognitive functions and cardiac outcomes were normal at the age of 6 years. CLINICAL TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov, NCT00330447.

Neurocognitive, academic and functional outcomes in survivors of infant ependymoma (UKCCSG CNS 9204).

PURPOSE: This is the first UK multi-centre case-controlled study with follow-up in excess of 10 years to report the neurocognitive, academic and psychological outcomes of individuals diagnosed with a brain tumour in early childhood. Children enrolled into the UKCCSG CNS 9204 trial, diagnosed with intracranial ependymoma when aged ≤ 36 months old, who received a primary chemotherapy strategy to defer or avoid radiotherapy, were recruited. METHODS: Outcomes of those who relapsed and subsequently received radiotherapy (n = 13) were compared to those enrolled who did not relapse (n = 16), age-matched controls-diagnosed with solid non-central nervous system (SN-CNS; n = 15) tumours or low-grade posterior fossa pilocytic astrocytoma (PFPA; n = 15), and normative data. Analyses compared nine neurocognitive outcomes as primary measures with quality of survival as secondary measures. RESULTS: Relapsed ependymoma participants performed significantly worse than their non-relapsed counterparts on measures of Full Scale IQ, Perceptual Reasoning, Word Reading and Numerical Operations. The relapsed ependymoma group performed significantly worse than SN-CNS controls on all primary measures, whereas non-relapsing participants only differed significantly from SN-CNS controls on measures of Processing Speed and General Memory. Relapsed ependymoma participants fared worse than all groups on measures of quality of survival. CONCLUSIONS: The relapsed irradiated ependymoma group demonstrated the most significantly impaired neurocognitive outcomes at long-term follow-up. Non-relapsing participants demonstrated better outcomes than those who relapsed. Results tentatively suggest avoiding radiotherapy helped preserve neurocognitive and learning outcomes of individuals diagnosed with ependymoma when aged ≤ 36 months old. Prospective neurocognitive surveillance is required. Recommendations for clinical and research practice are provided.

Early Axial Growth Outcomes of Pediatric Patients Receiving Proton Craniospinal Irradiation.

Guidelines on proton craniospinal irradiation (p-CSI) target volume selection in children are lacking. We examined the impact of target volume selection on growth of children receiving p-CSI at a institution. Records of 58 patients who received p-CSI were reviewed. Median age at treatment initiation was 8 years (range, 2 to 18 y). Spinal target volumes included whole vertebral body (WVB) in 67% and partial vertebral body (PVB) in 33%. Height z-scores before and after p-CSI were assessed using Centers for Disease Control and Prevention stature-for-age charts. Maximal Cobb angle and height z-score change were compared for WVB versus PVB p-CSI using a t test. Among 93% of patients with detailed data, median follow-up was 19 months (range, 2 to 58 mo) after radiation therapy initiation. Quantitative growth evaluations were available for 64% of patients. Median change in height z-score was -0.5 (range, -2.1 to +0.7) after treatment, representing a decrease (P<0.001) in age-adjusted height. WVB patients had significantly greater reduction in height z-score versus PVB patients (P=0.004) but no difference in Cobb angle change (P>0.05). Despite reluctance surrounding its use in younger patients, PVB p-CSI was associated with similar spinal curvature and less growth suppression as compared with WVB p-CSI; a trial comparing WVB versus PVB in children may be warranted.

Electromagnetic Fields, Pulsed Radiofrequency Radiation, and Epigenetics: How Wireless Technologies May Affect Childhood Development.

Mobile phones and other wireless devices that produce electromagnetic fields (EMF) and pulsed radiofrequency radiation (RFR) are widely documented to cause potentially harmful health impacts that can be detrimental to young people. New epigenetic studies are profiled in this review to account for some neurodevelopmental and neurobehavioral changes due to exposure to wireless technologies. Symptoms of retarded memory, learning, cognition, attention, and behavioral problems have been reported in numerous studies and are similarly manifested in autism and attention deficit hyperactivity disorders, as a result of EMF and RFR exposures where both epigenetic drivers and genetic (DNA) damage are likely contributors. Technology benefits can be realized by adopting wired devices for education to avoid health risk and promote academic achievement.

Influence of light exposure at nighttime on sleep development and body growth of preterm infants.

Previous studies have demonstrated that a light-dark cycle has promoted better sleep development and weight gain in preterm infants than constant light or constant darkness. However, it was unknown whether brief light exposure at night for medical treatment and nursing care would compromise the benefits brought about by such a light-dark cycle. To examine such possibility, we developed a special red LED light with a wavelength of >675 nm which preterm infants cannot perceive. Preterm infants born at <36 weeks' gestational age were randomly assigned for periodic exposure to either white or red LED light at night in a light-dark cycle after transfer from the Neonatal Intensive Care Unit to the Growing Care Unit, used for supporting infants as they mature. Activity, nighttime crying and body weight were continuously monitored from enrolment until discharge. No significant difference in rest-activity patterns, nighttime crying, or weight gain was observed between control and experimental groups. The data indicate that nursing care conducted at 3 to 4-hour intervals exposing infants to light for <15 minutes does not prevent the infants from developing circadian rest-activity patterns, or proper body growth as long as the infants are exposed to regular light-dark cycles.

Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy.

BACKGROUND: Data on the long-term outcome of children who are exposed to maternal cancer with or without treatment during pregnancy are lacking. METHODS: In this multicenter case-control study, we compared children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis. We used a health questionnaire and medical files to collect data regarding neonatal and general health. All children were prospectively assessed (by means of a neurologic examination and the Bayley Scales of Infant Development) at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months. RESULTS: A total of 129 children (median age, 22 months; range, 12 to 42) were included in the group whose mother had cancer (prenatal-exposure group) with a matching number in the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings. CONCLUSIONS: Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment. (Funded by Research Foundation-Flanders and others; ClinicalTrials.gov number, NCT00330447.).

[Physical and mental development of preschool children in South Municipal County of Moscow, residing near objects with potential radiation jeopardy].

Moscow State Unitary Enterprise--united ecological, scientific and research centre of decontamination of radioactive waste (RAW) and environmental protection SUE SIA "Radon"; Territorial department of the Moscow Administration of the Federal service on customers' rights protection and human well-being surveillance in the South Administrative district of Moscow Study covered physical and mental development of 2733 children aged 4-7 years, residing in South Moscow Municipal County with objects of potential radiation jeopardy. Findings are that residence near that objects causes no negative influences on physical and mental development of the preschoolers. Share of children with lower functional parameters and arrested development was smaller and that of children with weight deficit was higher in the area with objects of potential radiation jeopardy. The differences revealed result from socio-economic conditions in the families and from general educational and physical training programs level at the preschool institutions.

[Clinical immunological disorders in children from various observation cohorts exposed to radiation factor during various stages of oncogenesis].

The immune status disorders and features depending on the radiation impact type in various cohorts of radiation observations long after the Chernobyl (CNPP) disaster and the possible role of these disorders in development of chronic somatic pathology in children are shown. Lymphocyte depletion, T-cell immunity component disorders in the form of cell contraction with CD3, CD4, CD8 markers and the B-cell immunity component disorders in the form of reducing the quantity of CD10, CD23 marker cells were observed in children subject to combined chronic irradiation by 131I, 137Cs, 90Sr radionuclides. The descendants of irradiated parents (the 1st generation; children of the Chernobyl accident consequences liquidators, children of the citizens of radiation contaminated territories with various 137Cs levels) had immunity disorders of different type. A change in the total amount of NK-cells (CD16(+)-lymphocytes) is the general sign for all radiation risk groups; however, people subject to direct radiation impact demonstrated reduction of the antitumor protection potency, whereas descendants of irradiated ones demonstrated its activation with typically increasing number of CD16(+)-lymphocytes. In all radiation risk groups, a tendency to reduction of a number of cells involved in the leukocytal activation with the "pluripotential activation" marker (CD38 marker cells), proliferating cells (CD71 marker cells) and the increase of relative amount of cells with apoptosis marker (CD95(+)-lymphocytes). Immune disorder markers under the radiation impact in various cohorts of children's observation are suggested: antigens: CD4, CD8, CD10, CD23, CD16, CD38, CB71, CD95.

Prenatal cell phone use and developmental milestone delays among infants.

OBJECTIVE: The aim of this study was to examine if prenatal use of cell phones by pregnant mothers is associated with developmental milestones delays among offspring up to 18 months of age. METHODS: Our work is based upon the Danish National Birth Cohort (DNBC), which recruited pregnant mothers from 1996-2002, and was initiated to collect a variety of detailed information regarding in utero exposures and various health outcomes. At the end of 2008, over 41,000 singleton, live births had been followed with the Age-7 questionnaire, which collected cell phone use exposure for mothers during pregnancy. Outcomes for developmental milestones were obtained from telephone interviews completed by mothers at age 6 and 18 months postpartum. RESULTS: A logistic regression model estimated the odds ratios (OR) for developmental milestone delays, adjusted for potential confounders. Less than 5% of children at age 6 and 18 months had cognitive/language or motor developmental delays. At 6 months, the adjusted OR was 0.8 [95% confidence interval (95% CI) 0.7-1.0] for cognitive/language delay and 0.9 (95% CI 0.8-1.1) for motor development delay. At 18 months, the adjusted OR were 1.1 (95% CI 0.9-1.3) and 0.9 (95% CI 0.8-1.0) for cognitive/language and motor development delay, respectively. CONCLUSIONS: No evidence of an association between prenatal cell phone use and motor or cognitive/language developmental delays among infants at 6 and 18 months of age was observed. Even when considering dose-response associations for cell phone, associations were null.

Intellectual aspects of cognitive performance in children after treatment for medulloblastoma and astrocytoma

The present study investigated the relationship between posterior fossa tumors (astrocytoma and medulloblastoma) and their respective treatments and cognitive performance in Brazilian children by measuring Intelligence Quotient (IQ). Twenty children were enrolled in the study, of whom 13 were diagnosed with astrocytoma (average age at evaluation, 10.2 years; eight girls and five boys) and seven were diagnosed with medulloblastoma (average age at evaluation, 9.2 years; five girls and two boys). The first subgroup underwent exclusively tumor resection surgery, and the second subgroup underwent surgery, chemotherapy (Vincristine, Cisplatine, and Carmustine), and radiotherapy (total dose, 54 Gy). The inclusion criteria for the clinical group were normal social and emotional behavior before the diagnosis and motor and visual performance not excessively deteriorated after surgery. All participants were submitted to the Wechsler Intelligence Scale for Children - third version, and their scores were related to standard norms established for Brazilian children and compared with regard to the diagnosis subgroups and treatment modalities. Statistically significant differences were identified between the two diagnosis subgroups in Performance IQ and Processing Speed scores. The medulloblastoma subgroup presented poorer performance in all domains compared with the astrocytoma subgroup. Time interval between diagnosis and neuropsychological evaluation also had a significant effect on Processing Speed and Freedom from Distractibility in the medulloblastoma subgroup. These results provide empirical evidence of a possible significant effect of radiotherapy exposure on processing speed and global intellectual capacity.(AU)

Intellectual aspects of cognitive performance in children after treatment for medulloblastoma and astrocytoma

The present study investigated the relationship between posterior fossa tumors (astrocytoma and medulloblastoma) and their respective treatments and cognitive performance in Brazilian children by measuring Intelligence Quotient (IQ). Twenty children were enrolled in the study, of whom 13 were diagnosed with astrocytoma (average age at evaluation, 10.2 years; eight girls and five boys) and seven were diagnosed with medulloblastoma (average age at evaluation, 9.2 years; five girls and two boys). The first subgroup underwent exclusively tumor resection surgery, and the second subgroup underwent surgery, chemotherapy (Vincristine, Cisplatine, and Carmustine), and radiotherapy (total dose, 54 Gy). The inclusion criteria for the clinical group were normal social and emotional behavior before the diagnosis and motor and visual performance not excessively deteriorated after surgery. All participants were submitted to the Wechsler Intelligence Scale for Children - third version, and their scores were related to standard norms established for Brazilian children and compared with regard to the diagnosis subgroups and treatment modalities. Statistically significant differences were identified between the two diagnosis subgroups in Performance IQ and Processing Speed scores. The medulloblastoma subgroup presented poorer performance in all domains compared with the astrocytoma subgroup. Time interval between diagnosis and neuropsychological evaluation also had a significant effect on Processing Speed and Freedom from Distractibility in the medulloblastoma subgroup. These results provide empirical evidence of a possible significant effect of radiotherapy exposure on processing speed and global intellectual capacity

Prenatal exposure to cell phone use and neurodevelopment at 14 months.

BACKGROUND: Recently, an association was reported between prenatal and postnatal exposure to cell phones and neurobehavioral problems in children at the age of 7 years. METHODS: A birth cohort was established in Sabadell, Spain between 2004 and 2006. Mothers completed questions about cell phone use in week 32 of the pregnancy (n = 587). Neurodevelopment of their children was tested at age 14 months using the Bayley Scales of Infant Development (n = 530). RESULTS: We observed only small differences in neurodevelopment scores between the offspring of cell phone users and nonusers. Those of users had higher mental development scores and lower psychomotor development scores, which may be due to unmeasured confounding. There was no trend with amount of cell phone use within users. CONCLUSION: This study gives little evidence for an adverse effect of maternal cell phone use during pregnancy on the early neurodevelopment of offspring.

[Mental and physical development of children living in the area of monitoring pollution from a plant for processing and long-term storage of radioactive waste].

Environmental conditions in the area hosting a plant for processing and long storage of low- to moderately-active radioactive waste are described as reasonably safe. Residence in the area does not exert negative influence on the physical and mental development of children. Several indicators of physical development give better estimates than at the control territory. The difference can be accounted for by a better social situation in the study area (housing conditions, financial standing, food patterns, general lifestyle).

Late effects in long-term survivors after treatment for childhood acute leukemia.

BACKGROUND: This is a report of late effects in childhood cancer survivors seen in the follow-up clinic of a single institution. MATERIALS AND METHODS: There were 324 acute leukemia survivors in the database of the Long Term Follow Up Clinic of Children's National Medical Center from January 1, 1997, through June 30, 2005. RESULTS: Of the 324 acute leukemia survivors, 228 were white, 48 black, 20 Hispanic, and 12 other. Their follow-up time was 0 to 25 years (mean 5.3 years). One or more adverse events occurred in 74.1% of the 324 survivors. Defective physical growth was most commonly reported, followed by disturbed neurocognitive function, emotional difficulties, cardiac abnormalities, hypertension, osteoporosis/osteopenia, fractures, and second neoplasms. More black and Hispanic children had acute myeloid leukemia, relapses, cardiac problems, and hypertension than white and other subjects. CONCLUSION: Childhood cancer survivors require lifelong monitoring, with prompt identification and treatment of adverse late effects.

Disrupted development of the dominant hemisphere following prenatal irradiation.

One hundred children, exposed prenatally to radiation after the Chernobyl nuclear power plant accident, and 50 nonexposed classmates were examined between the ages of 11 and 13 years old using neuropsychiatric tests, WISC, EEG, and visual evoked potentials. Individual prenatal radiation doses were reconstructed for all examined children. The exposed children were found to have more neuropsychiatric disorders, left-brain neurological signs, lower full-scale and verbal IQ, IQ discrepancies with verbal decrement, disorganized EEG patterns, an excess of lateralized-to-left frontotemporal region delta and beta power with depression of theta and alpha power, and interhemispheric inversion visual information processing. Mothers' mental health, stress, and prenatal irradiation contributed to these effects, along with several confounding factors.

Growth and endocrine function in patients with Hurler syndrome after hematopoietic stem cell transplantation.

Short stature is characteristic of Hurler syndrome, or mucopolysaccharidosis type IH (MPS IH). Hematopoietic stem cell transplantation (HSCT) is used to treat children with MPS IH. While HSCT corrects some of the metabolic features of MPS IH, its effects on growth are not well delineated. We investigated growth in patients with MPS IH after HSCT and described accompanying endocrine abnormalities. A cohort of 48 patients with MPS IH who had received HSCT between 1983 and 2005 were included. The prevalence of short stature (height <-2 s.d. score, SDS) before HSCT was 9%, and increased to 71% at last follow-up (6.9+/-5.1 years after HSCT). Short stature was positively associated with increased age at HSCT (P=0.002) and TBI (P=0.009). In total, 23% had growth hormone deficiency and/or low insulin-like growth factor-1, one female patient had premature adrenarche, one precocious puberty and 27% had clinical or subclinical hypothyroidism. Growth failure is highly prevalent in children with MPS IH after HSCT. Children who had no TBI exposure and were younger at the time of HSCT had a better height outcome.

Growth and development after hematopoietic cell transplant in children.

Hematopoietic cell transplantation (HCT) following high-dose chemotherapy or chemoradiotherapy for children with malignant or nonmalignant hematologic disorders has resulted in an increasing number of long-term disease-free survivors. The preparative regimens include high doses of alkylating agents, such as CY with or without BU, and may include TBI. These agents impact the neuroendocrine system in growing children and their subsequent growth and development. Children receiving high-dose CY or BUCY have normal thyroid function, but those who receive TBI-containing regimens may develop thyroid function abnormalities. Growth is not impacted by chemotherapy-only preparative regimens, but TBI is likely to result in growth hormone deficiency and decreased growth rates that need to be treated with synthetic growth hormone therapy. Children who receive high-dose CY-only have normal development through puberty, whereas those who receive BUCY have a high incidence of delayed pubertal development. Following fractionated TBI preparative regimens, approximately half of the patients have normal pubertal development. These data demonstrate that the growth and development problems after HCT are dependent upon the preparative regimen received. All children should be followed for years after HCT for detection of growth and development abnormalities that are treatable with appropriate hormone therapy.