Neurocognitive Outcomes in Multiethnic Pediatric Brain Tumor Patients Treated With Proton Versus Photon Radiation.

BACKGROUND: We analyzed post-radiation (RT) neurocognitive outcomes in an ethnically diverse pediatric brain tumor population undergoing photon radiotherapy (XRT) and proton radiotherapy (PRT). PROCEDURE: Post-RT neurocognitive outcomes from 49 pediatric patients (37% Hispanic/Latino) with primary brain tumors were analyzed. Tests included cognitive outcomes, behavioral outcomes, and overall intelligence. For each outcome, proportion of patients with cognitive impairment (scores <1.5 SD) was calculated. The Fisher exact tests compared proportion of patients with impairment and t tests compared T-scores between XRT (n=32) and PRT (n=17) groups. Linear regression assessed associations between radiation modality and outcomes. RESULTS: Median follow-up was 3.2 and 1.8 years in the XRT and PRT groups, respectively. The median RT dose was 54.0 Gy. We found impairment in 16% to 42% of patients across most neurocognitive domains except executive function. There was no difference in scores between XRT and PRT groups. Regression analyses revealed no association of neurocognitive outcomes with radiation modality. Non-Hispanic patients had better Verbal Comprehension Index and General Ability Index scores than Hispanic patients ( P <0.05). CONCLUSIONS: Among pediatric patients with brain tumors receiving RT, all cognitive domains were affected except executive function. Radiation modality was not associated with neurocognitive outcomes. Hispanic patients may be more vulnerable to posttreatment cognitive effects that warrant further study.

Long-term decline in intelligence among adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation.

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy (CRT) are at risk for cognitive impairment, although whether impairment progresses with age into adulthood is unknown. We report change in intelligence for 102 adult survivors of childhood ALL (age range, 26.6-54.7 years) during a median interval of 28.5 years. Survivors demonstrated lower Performance intelligence (mean, 95.3; standard deviation, 16.5; P = .005) but not Verbal IQ (mean, 97.4; standard deviation, 15.44; P = .09) at initial testing. Verbal intelligence declined an average of 10.3 points (P < .0001) during the follow-up interval with no decline in Performance intelligence. Decline was associated with current attention problems (P = .002) but not gender, CRT dose, age at CRT exposure, or years between testing. Results suggest long-term survivors of childhood ALL treated with CRT are at risk for progressive decline in verbal intellect, which may be driven by attention deficits. This trial was registered at clinicaltrials.gov as no. NCT00760656.

No clinically relevant effect on cognitive outcomes after low-dose radiation to the infant brain: a population-based cohort study in Sweden.

UNLABELLED: While the detrimental effects of cranial radiotherapy on the developing brain are well known, the effects on cognitive performance of low doses of ionizing radiation is less studied. We performed a population-based cohort study to determine whether low doses of ionizing radiation to the brain in infancy affects cognitive function later in life. Further we hypothesized that the dose to the hippocampus predicts cognitive late side effects better than the anterior or the posterior brain doses. MATERIAL AND METHODS: During 1950-1960 3860 boys were treated with radiation in Sweden for cutaneous hemangiomas before the age of 18 months. Of these, 3030 were analyzed for military test scores at the age of 18 years and 2559 for the highest obtained educational level. RESULTS: Logical, spatial and technical test scores were not affected by increasing irradiation doses. The verbal test scores displayed a significant trend for decreasing scores with increasing doses to the hippocampus (p = 0.005). However, the absolute mean difference between the zero dose and the highest dose category (median 680 mGy) was very small, only 0.64 stanine points, and the significance was dependent on the highest dose category, containing few subjects. The educational level was not affected by brain irradiation. Overall, the hippocampal dose was a better predictor of late cognitive side effects than the doses to the anterior or the posterior brain. In conclusion, there was no decrease in logical, spatial and technical verbal or global test scores after ionizing radiation doses up to 250 mGy, but a subtle decrease in verbal test scores if the highest dose category was included (median 680 mGy). However, the clinical relevance of this decline in the highest dose group is questionable, since we could not find any effect on the highest obtained educational level.

Association between radiation dose, thyroid hormone, and IQ levels in children exposed to radiation in utero after the Chernobyl accident.

Few studies have explored the effects of n utero radiation exposure on human health and cognition and none have taken into account thyroid hormone levels (T3), which have shown to affect cognitive performance. We investigated mechanisms of possible radiation effects on IQ in two cohorts of 250 persons each: exposed n utero after the Chernobyl accident: a 'higher exposure group (HEG)', whose mothers resided in more heavily contaminated territories at the time of the Chernobyl accident, and a 'lesser exposure group (LEG)' whose mothers resided in less contaminated areas. The dataset included information on estimated prenatal thyroid radiation dose, gestation week at the time of the accident (ATA); thyroid hormones: T3 (triiodothyronine) and T4 (thyroxine) levels measured at age 11-12 years and general IQ measured at three time points: t1: 6-7 years old; t2: 11-12 years old and t3: 15-16 years old. Descriptive and inference analyses were used to explore the dynamic of changes through time and the associations between key variables at the three time points. Estimated radiation doses to the thyroid gland were substantially higher in the HEG than in the LEG (mean 391 vs 25 mGy respectively). Significant differences in thyroid hormones levels were observed between the two groups, with lower values in T3 (higher in T4) in the LEG. At t1, the general IQ, as well as verbal and non-verbal IQ scores, were lower in the HEG than in the LEG. In the HEG, analyses adjusting simultaneously for radiation dose, gestational week ATA and T3 levels suggest that all three variables are associated with IQ, with the latter being highest among those exposed later during gestation and decreasing with increasing level of dose and of T3. No significant association was observed between IQ and T4 levels. No effect of exposure on IQ was seen in the LEG. Further investigation of this hypothesis will be important to understand the relation between n utero exposure radiation dose to thyroid, thyroid hormone levels and IQ, taking into account effects of potential confounding factors (physiological stress, maternal anxiety related evacuation).

We followed up persons exposed in utero to radiation from the Chernobyl accidentAmong the most highly exposed, IQ was higher among those exposed later during gestationAmong the most highly exposed, IQ also decreased with increasing level of dose and of T3No such relation was seen in those with lower exposureOur study provides insights into the possible relation between prenatal radiation dose and IQ and the factors which may modify it.

Intellectual and academic outcome following two chemotherapy regimens and radiotherapy for average-risk medulloblastoma: COG A9961.

PURPOSE: Assess the intellectual and academic outcomes as well as risk factors associated with treatment for average-risk medulloblastoma in childhood using 23.4 Gy of craniospinal radiotherapy plus adjuvant chemotherapy. METHODS: From an overall sample of 379 enrolled in the parent study (COG A9961), 110 patients received a total of 192 assessments over more than 5 years with standardized IQ and academic achievement tests. Random coefficient models of the various outcomes were developed that incorporated covariates including chemotherapy regimen, age at diagnosis, sex, initial Full Scale IQ, and mutism. RESULTS: Participants in this study were found to be comparable to the overall sample in all demographic, disease, and treatment factors, except there were more gross total resections in the subsample undergoing intellectual and academic assessment. Major findings include significant decline in both intellectual and academic domains over time that were greater in children who were younger at diagnosis and had higher initial intelligence test scores. Children with mutism were at higher risk for initial effects on intelligence. No effects of sex were found. CONCLUSION: These results show progressive decline over several years post-treatment in standardized intellectual and academic scores. Despite recent improvements in therapies for these children, most notably a decrease dose of craniospinal radiation, they remain at risk. The pursuit of less toxic treatments, particularly for younger children, should continue. Neuropsychological surveillance should be routine at centers treating children with brain tumors.

Genetic susceptibility to cognitive decline following craniospinal irradiation for pediatric central nervous system tumors.

BACKGROUND: Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI. METHODS: Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (n = 241). Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common variants (minor allele frequency > 1%) associated with cognitive performance change. Novel variants associated with cognitive decline (P < 5 × 10-5) in individuals of European ancestry (n = 163) were considered replicated if they demonstrated consistent genotype-by-time interactions (P < .05) in individuals of non-European ancestries (n = 78) and achieved genome-wide statistical significance (P < 5 × 10-8) in a meta-analysis across ancestry groups. RESULTS: Participants were mostly males (65%) diagnosed with embryonal tumors (98%) at a median age of 8.3 years. Overall, 1150 neurocognitive evaluations were obtained (median = 5, range: 2-10 per participant). One of the five loci previously associated with cognitive outcomes in pediatric CNS tumors survivors demonstrated significant time-dependent IQ declines (PPARA rs6008197, P = .004). Two variants associated with IQ in the general population were associated with declines in IQ after Bonferroni correction (rs9348721, P = 1.7 × 10-5; rs31771, P = 7.8 × 10-4). In genome-wide analyses, we identified novel loci associated with accelerated declines in IQ (rs116595313, meta-P = 9.4 × 10-9), WM (rs17774009, meta-P = 4.2 × 10-9), and PS (rs77467524, meta-P = 1.5 × 10-8; rs17630683, meta-P = 2.0 × 10-8; rs73249323, meta-P = 3.1 × 10-8). CONCLUSIONS: Inherited genetic variants involved in baseline cognitive functioning and novel susceptibility loci jointly influence the degree of treatment-associated cognitive decline in pediatric CNS tumor survivors.

Intellectual development after treatment in children with acute leukemia and brain tumor.

BACKGROUND: The influence of central nervous system (CNS)-directed chemotherapy on intelligence remains controversial. In this study, we investigated the influence of treatment on intellectual development in acute lymphoblastic leukemia (ALL) and brain tumor patients undergoing CNS-directed treatments. METHODS: Among patients treated in the Department of Pediatrics, St Luke's International Hospital between April 2000 and March 2009, the subjects were 38 patients with ALL or brain tumors who underwent regular Wechsler intelligence tests. RESULTS: The subjects consisted of 26 patients with ALL and 12 with brain tumors. Prophylactic cranial irradiation was not performed in patients with ALL, whereas it was done for all those with brain tumor. In patients with ALL, the IQ 1 year later was not changed from the start of treatment. In those with brain tumors, the verbal IQ 1 year later was significantly lower than that at the start of treatment. In patients with ALL, intelligence tests were performed 3 years after the start of treatment and there were no marked changes between the two time-points (n = 11). In those with a brain tumor, intellectual functions further decreased after the completion of treatment to as late as 5 years after the initiation of treatment (n = 7). CONCLUSIONS: There is no intellectual impairment in any patient with ALL at post-treatment follow-up 3 years after the start of treatment, while intelligence is serially reduced in brain tumor patients. An innovative intervention may be needed for this group of patients.

Hearing loss and intellectual outcome in children treated for embryonal brain tumors: Implications for young children treated with radiation sparing approaches.

PURPOSE: We investigate the impact of severe sensorineural hearing loss (SNHL) and for the first time evaluate the effect of unilateral versus bilateral SNHL on intellectual outcome in a cohort of children with embryonal brain tumors treated with and without radiation. METHODS: Data were from 94 childhood survivors of posterior fossa (PF) embryonal brain tumors who were treated with either: (1) chemotherapy alone (n = 16, 7.11 [3.41] years, 11M/5F), (2) standard-dose craniospinal irradiation (CSI) and/or large boost volumes (n = 44, 13.05 [3.26] years, 29M/15F), or (3) reduced-dose CSI with a boost restricted to the tumor bed (n = 34, 11.07 [3.80] years, 19M/15F). We compared intellectual outcome between children who: (1) did and did not develop SNHL and (2) developed unilateral versus bilateral SNHL. A Chang grade of ≥2b that required the use of a hearing aid was considered severe SNHL. Comparisons were made overall and within each treatment group separately. RESULTS: Patients who developed SNHL had lower full scale IQ (p = 0.007), verbal comprehension (p = 0.003), and working memory (p = 0.02) than patients without SNHL. No differences were observed between patients who had unilateral versus bilateral SNHL (all p > 0.05). Patients treated with chemotherapy alone who developed SNHL had lower mean working memory (p = 0.03) than patients who did not develop SNHL. Among patients treated with CSI, no IQ indices differed between those with and without SNHL (all p > 0.05). CONCLUSIONS: Children treated for embryonal brain tumors who develop severe SNHL have lower intellectual outcome than patients with preserved hearing: this association is especially profound in young children treated with radiation sparing approaches. We also demonstrate that intellectual outcome is similarly impaired in patients who develop unilateral versus bilateral SNHL. These findings suggest that early intervention to preserve hearing is critical.

Effect of low dose ionizing radiation exposure in utero on cognitive function in adolescence.

Radiation from the Chernobyl nuclear power plant meltdown greatly affected several Norwegian counties. The cognitive consequences of in utero exposure to radiation from the Chernobyl accident have been intensely debated. This study examines the cognitive outcomes for those Norwegians who were exposed as fetuses to the fallout from Chernobyl. The participants, 84 adolescents who were exposed in utero to radiation from the most contaminated areas in Norway and 94 adolescents from areas not contaminated by the radiation, were tested on verbal and nonverbal IQ. Two data analyses were conducted. First, using a control-group design, the IQ scores of exposed and unexposed adolescents were compared. Second, in a timing-of-exposure design, those exposed during the most sensitive period were contrasted with those exposed later in gestation. Adolescents exposed to low-dose ionizing radiation in utero scored significantly lower in full-scale IQ than unexposed adolescents. The difference was restricted to verbal IQ and was not evident for nonverbal IQ. The effect was not observed in exposed adolescents who had passed the most sensitive gestational period prior to the accident and thus were exposed to the radiation from Chernobyl exclusively after gestational week 16. These participants performed as well as the controls. Although the results should be interpreted cautiously due to the study's nonrandomized design, the data add new and important support to the hypothesis that the Chernobyl accident may have had a subtle effect on the cognitive functioning of those exposed to low-dose ionizing radiation in utero during the most sensitive gestational period.

Superior Intellectual Outcomes After Proton Radiotherapy Compared With Photon Radiotherapy for Pediatric Medulloblastoma.

PURPOSE: Proton radiotherapy (PRT) may lessen the neuropsychological risk traditionally associated with cranial radiotherapy for the treatment of pediatric brain tumors by reducing the dose to normal tissue compared with that of photon radiotherapy (XRT). We examined the change in intellectual scores over time in patients with pediatric medulloblastoma treated with craniospinal PRT versus XRT. METHODS: Intelligence test scores were obtained for a sample of pediatric patients treated between 2007 and 2018 on the same medulloblastoma protocols that differed only in radiotherapy modality (PRT v XRT). Growth curve analyses compared change in scores over time since diagnosis between groups. RESULTS: Longitudinal intelligence data from 79 patients (37 PRT, 42 XRT) were examined. Groups were similar on most demographic/clinical variables, including sex (67.1% male), age at diagnosis (mean, 8.6 years), craniospinal irradiation dose (median, 23.4 Gy), length of follow-up (mean, 4.3 years), and parental education (mean, 14.3 years). Boost dose (P < .001) and boost margin (P = .001) differed between groups. Adjusting for covariates, the PRT group exhibited superior long-term outcomes in global intelligence quotient (IQ), perceptual reasoning, and working memory compared with the XRT group (all P < .05). The XRT group exhibited a significant decline in global IQ, working memory, and processing speed (all P < .05). The PRT group exhibited stable scores over time in all domains with the exception of processing speed (P = .003). CONCLUSION: To our knowledge, this is the first study to compare intellectual trajectories between pediatric patients treated for medulloblastoma with PRT versus those treated with XRT on comparable, contemporary protocols. PRT was associated with more favorable intellectual outcomes in most domains compared with XRT, although processing speed emerged as a vulnerable domain for both groups. This study provides the strongest evidence to date of an intellectual sparing advantage with PRT in the treatment of pediatric medulloblastoma.

Exclusive Hyperfractionated Radiation Therapy and Reduced Boost Volume for Standard-Risk Medulloblastoma: Pooled Analysis of the 2 French Multicentric Studies MSFOP98 and MSFOP 2007 and Correlation With Molecular Subgroups.

PURPOSE: Medulloblastoma has recently been characterized as a heterogeneous disease with 4 distinct molecular subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4, with a new definition of risk stratification. We report progression-free survival, overall survival, and long-term cognitive effects in children with standard-risk medulloblastoma exclusively treated with hyperfractionated radiation therapy (HFRT), reduced boost volume, and online quality control, and we explore the prognostic value of biological characteristics in this chemotherapy-naïve population. METHODS AND MATERIALS: Patients with standard-risk medulloblastoma were enrolled in 2 successive prospective multicentric studies, MSFOP 98 and MSFOP 2007, and received exclusive HFRT (36 Gy, 1 Gy/fraction twice daily) to the craniospinal axis followed by a boost at 68 Gy restricted to the tumor bed (1.5 cm margin), with online quality assurance before treatment. Patients with MYC or MYCN amplification were not excluded at the time of the study. We report progression-free survival and overall survival in the global population, and according to molecular subgroups as per World Health Organization 2016 molecular classification, and we present cognitive evaluations based on the Wechsler scale. RESULTS: Data from 114 patients included in the MSFOP 98 trial from December 1998 to October 2001 (n = 48) and in the MSFOP 2007 from October 2008 to July 2013 (n = 66) were analyzed. With a median follow-up of 16.2 (range, 6.4-19.6) years for the MSFOP 98 cohort and 6.5 (1.6-9.6) years for the MSFOP 2007 cohort, 5-year overall survival and progression-free survival in the global population were 84% (74%-89%) and 74% (65%-81%), respectively. Molecular classification was determined for 91 patients (WNT [n = 19], SHH [n = 12], and non-WNT/non-SHH [n = 60]-including group 3 [n = 9], group 4 [n = 29], and not specified [n = 22]). Our results showed more favorable outcome for the WNT-activated subgroup and a worse prognosis for SHH-activated patients. Three patients had isolated extra-central nervous system relapse. The slope of neurocognitive decline in the global population was shallower than that observed in patients with a normofractionated regimen combined with chemotherapy. CONCLUSIONS: HFRT led to a 5-year survival rate similar to other treatments combined with chemotherapy, with a reduced treatment duration of only 6 weeks. We confirm the MSFOP 98 results and the prognostic value of molecular status in patients with medulloblastoma, even in the absence of chemotherapy. Intelligence quotient was more preserved in children with medulloblastoma who received exclusive HFRT and reduced local boost, and intelligence quotient decline was delayed compared with patients receiving standard regimen. HFRT may be appropriate for patients who do not consent to or are not eligible for prospective clinical trials; for patients from developing countries for whom aplasia or ileus may be difficult to manage in a context of high cost/effectiveness constraints; and for whom shortened duration of RT may be easier to implement.

Gender differences in facial expression recognition in survivors of pediatric brain tumors.

OBJECTIVE: To examine the relation between gender, history of cranial radiation therapy (CRT) and facial expression recognition (FER) skill in survivors of pediatric brain tumors. METHODS: Fifty-three survivors (27 females) completed a measure of FER and an intelligence test. RESULTS: There was a significant interaction between gender and CRT on ability to interpret low-intensity facial expressions, such that females who had not had CRT made fewer errors than either females who had CRT or males. CONCLUSION: A history of CRT has a notable effect on FER skill in females: girls who received CRT performed significantly more poorly than girls who did not.

Differential trajectories of neurocognitive functioning in females versus males following treatment for pediatric brain tumors.

BACKGROUND: Female and male trajectories of cerebellar and lobar brain structures are sexually dimorphic, making sex a potential candidate moderator of neurocognitive late effects from radiation treatment. We sought to evaluate longitudinal neurocognitive functioning in male versus female children treated for posterior fossa brain tumors. METHODS: Fifty-one female and 63 male survivors of posterior fossa tumors completed neuropsychological testing at 2 timepoints. We included patients treated with surgical resection, chemotherapy, and radiation therapy. Multilevel mixed modeling was used to predict IQ score as a function of patient sex following treatment (~2 or ~4 years post treatment). Effect sizes were used as a measure of clinical significance. RESULTS: Multilevel models resulted in a significant sex by time interaction (F = 6.69, P = 0.011). Females' cognitive scores were considerably higher compared with males at 4 years posttreatment. Females demonstrated an average improvement of 7.61 standard score IQ points compared with a decline of 2.97 points for males at 4 years follow-up. Effect sizes for female IQ compared with male IQ at 4 years posttreatment were between 0.8 and 0.9. CONCLUSION: Trajectories of neurocognitive functioning following posterior fossa tumor treatment differed between female and male children. Sexual dimorphism in radiation late effects may alter treatment decisions in children. Research into sex-specific neuroprotective mechanisms underlying neurocognitive development following pediatric brain tumor treatments is warranted.

Maintenance of multidomain neurocognitive functions in pediatric patients after proton beam therapy: A prospective case-series study.

Proton Beam Therapy (PBT) was developed to minimize the harmful results of radiation therapy as treatment for brain tumors. This study examined the neurocognitive outcomes of PBT in pediatric patients. A total of 8 patients, who received either PBT or photon radiotherapy (XRT), were evaluated with multiple cognitive functions, which include intelligence, memory, executive functions, and attention. Most of patients performed average-to-superior levels of neurocognitive functions (NCF), except that a deterioration of executive functions was revealed in two patients receiving XRT. This study might be the first one to show the maintenance of multidomain NCF after PBT.

Improved neuropsychological outcomes following proton therapy relative to X-ray therapy for pediatric brain tumor patients.

BACKGROUND: Survivors of pediatric brain tumors are at risk for impaired development in multiple neuropsychological domains. The purpose of this study was to compare neuropsychological outcomes of pediatric brain tumor patients who underwent X-ray radiotherapy (XRT) versus proton radiotherapy (PRT). METHODS: Pediatric patients who underwent either XRT or PRT and received posttreatment age-appropriate neuropsychological evaluation-including measures of intelligence (IQ), attention, memory, visuographic skills, academic skills, and parent-reported adaptive functioning-were identified. Multivariate analyses were performed to assess differences in neuropsychological outcomes and included tests for interaction between treatment cohort and follow-up time. RESULTS: Between 1998 and 2017, 125 patients with tumors located in the supratentorial (17.6%), midline (28.8%), or posterior fossa (53.6%) compartments received radiation and had posttreatment neuropsychological evaluation. Median age at treatment was 7.4 years. The PRT patient cohort had higher estimated SES and shorter median time from radiotherapy completion to last neuropsychological evaluation (6.7 vs 2.6 y, P < 0.001). On multivariable analysis, PRT was associated with higher full-scale IQ (ß = 10.6, P = 0.048) and processing speed (ß = 14.4, P = 0.007) relative to XRT, with trend toward higher verbal IQ (ß = 9.9, P = 0.06) and general adaptive functioning (ß = 11.4, P = 0.07). Planned sensitivity analyses truncating follow-up interval in the XRT cohort re-demonstrated higher verbal IQ (P = 0.01) and IQ (P = 0.04) following PRT, with trend toward improved processing speed (P = 0.09). CONCLUSIONS: PRT is associated with favorable outcomes for intelligence and processing speed. Combined with other strategies for treatment de-intensification, PRT may further reduce neuropsychological morbidity of brain tumor treatment.

Prospective, longitudinal comparison of neurocognitive change in pediatric brain tumor patients treated with proton radiotherapy versus surgery only.

BACKGROUND: Proton radiotherapy (PRT) reduces the volume of normal tissue receiving radiation dose, which may lead to better neurocognitive outcomes. We examined change in neurocognitive scores over time in pediatric brain tumor patients treated with proton craniospinal irradiation (CSI), proton focal RT, or surgery only. METHODS: Patients received annual neurocognitive evaluations for up to 6 years. We examined Full Scale IQ (FSIQ), Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI) scores. General linear mixed models examined change in scores over time by treatment group, adjusting for significant covariates. RESULTS: Scores from 93 patients treated between 2012 and 2017 (22 proton CSI, 31 proton focal, and 40 surgery only) were examined. Treatment groups were similar on gender (51.6% male), age at treatment (median = 9.7 y), and length of follow-up (median = 2.9 y). The surgery only group had proportionately more gliomas (P < 0.001), and the proton CSI group had more infratentorial tumors (P = 0.001) and higher total RT dose (P = 0.004). The proton focal and surgery only groups exhibited stable neurocognitive scores over time across all indexes (all P > 0.05). In the proton CSI group, WMI, PSI, and FSIQ scores declined significantly (P = 0.036, 0.004, and 0.017, respectively), while VCI and PRI scores were stable (all P > 0.05). CONCLUSIONS: Focal PRT was associated with stable neurocognitive functioning into survivorship. Outcomes were similar whether patients received focal PRT or no radiotherapy, even in neurocognitive domains known to be particularly radiosensitive. Proton CSI emerged as a neurocognitive risk factor, consistent with photon outcomes research.

Trajectories of psychosocial and cognitive functioning in pediatric patients with brain tumors treated with radiation therapy.

BACKGROUND: Pediatric patients with brain tumors who are treated with radiation therapy (RT) are at risk for neurocognitive and psychosocial late effects. Research to date has primarily examined these outcomes at a group level and in isolation. Advanced statistical techniques allow for person-centered analyses, as well as examination of relationships between domain-specific trajectories. METHODS: Patients with brain tumors (craniopharyngioma, ependymoma, low-grade astrocytoma, high-grade astrocytoma) were enrolled on a phase II clinical trial of RT. Three hundred and fifty patients completed serial neurocognitive assessments as part of their treatment monitoring, including pre-RT baseline, 6 months post-RT, and then yearly for 5 years. This secondary analysis focused on outcomes of cognition (estimated IQ, parent-reported attention problems) and psychosocial effects (parent-reported socialization and social problems) post-RT. RESULTS: Latent growth curve modeling indicated that estimated IQ and socialization were best served by quadratic models, while attention and social problems were best served by linear models. Growth mixture modeling indicated 3-class models were the best fit for IQ and socialization, and 2-class models for attention and social problems. Baseline IQ and socialization scores were associated, but there was no association over time. Young age at diagnosis and pre-RT treatments (surgery, chemotherapy) were associated with class membership. CONCLUSIONS: Person-centered statistical analyses provide rich information regarding the variability in neurocognitive and psychosocial functioning following RT for pediatric brain tumor. While many patients do well over time, a subset are exhibiting significant cognitive and/or psychosocial deficits. Class membership was associated with some medical factors (eg, pre-radiation surgery/chemotherapy, age at diagnosis, shunted hydrocephalus).

Brain magnetic resonance imaging after high-dose chemotherapy and radiotherapy for childhood brain tumors.

PURPOSE: Brain necrosis or other subacute iatrogenic reactions has been recognized as a potential complication of radiotherapy (RT), although the possible synergistic effects of high-dose chemotherapy and RT might have been underestimated. METHODS AND MATERIALS: We reviewed the clinical and radiologic data of 49 consecutive children with malignant brain tumors treated with high-dose thiotepa and autologous hematopoietic stem cell rescue, preceded or followed by RT. The patients were assessed for neurocognitive tests to identify any correlation with magnetic resonance imaging (MRI) anomalies. RESULTS: Of the 49 children, 18 (6 of 25 with high-grade gliomas and 12 of 24 with primitive neuroectodermal tumors) had abnormal brain MRI findings occurring a median of 8 months (range, 2-39 months) after RT and beginning to regress a median of 13 months (range, 2-26 months) after onset. The most common lesion pattern involved multiple pseudonodular, millimeter-size, T1-weighted unevenly enhancing, and T2-weighted hyperintense foci. Four patients with primitive neuroectodermal tumors also had subdural fluid leaks, with meningeal enhancement over the effusion. One-half of the patients had symptoms relating to the new radiographic findings. The MRI lesion-free survival rate was 74%+/-6% at 1 year and 57%+/-8% at 2 years. The number of marrow ablative courses correlated significantly to the incidence of radiographic anomalies. No significant difference was found in intelligent quotient scores between children with and without radiographic changes. CONCLUSION: Multiple enhancing cerebral lesions were frequently seen on MRI scans soon after high-dose chemotherapy and RT. Such findings pose a major diagnostic challenge in terms of their differential diagnosis vis-à-vis recurrent tumor. Their correlation with neurocognitive results deserves further investigation.

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.

Factors related to changes in cognitive, educational and visual motor integration in children who undergo hematopoietic stem cell transplant.

OBJECTIVES: Investigate cognitive, educational, and perceptual motor skills up to 2 years posttransplant of pediatric hematopoietic progenitor cell transplantation (HPCT) survivors and their correlates. METHODS: Survivors were assessed at baseline, 12, and 24 months after transplant. RESULTS: Performance IQ improved over time and was negatively related to maternal depression. Full IQ and educational outcomes were positively related to child's age and mother's age. Low depression scores were associated with high Verbal IQ one and 2 years post-HPCT, and with high visual motor scores 2 years post-HPCT. Poor educational outcomes were related to increased time since diagnosis. Two years post-HPCT, Performance IQ and Processing Speed were above the norm values whereas arithmetic and motor scores were below. CONCLUSIONS: Pediatric HPCT survivors do better cognitively than educationally. Maternal age and depression, child's age, and time since diagnosis are critical factors for these outcomes.