Adjustment in Childhood Brain Tumor Survival: Child, Mother, and Teacher Report

Examined the adjustment of 6- to 18-year-old children and adolescents(n = 38) 2 to 5 years postdiagnosis of brain tumor with respectto standardized measures of anxiety and depression; self-perceptions;and adaptive living skills. Child, mother, and teacher reportdata were used. Maternal adjustment (anxiety and depression,parenting stress) was also assessed. Children and adolescentssurviving brain tumors reported themselves to be generally withinthe normal range. However, maternal ratings of social problemswere higher than normative scores and significantly lower thannorms on social problems, scholastic competence, and communicationskills. Teacher ratings on the Teacher Rating Form were allwithin normal limits. Maternal adjustment measures were withinthe normal range, although the Parent-Child Dysfunctional Interactionsubscale of the Parenting Stress Index was elevated. No differencesin scores were found between children in regular and specialeducation, or between children who had received radiation andthose who did not. This sample of survivors of pediatric braintumors and their mothers had relatively mild problems in adjustment,supporting a competency-based view of the adaptation of pediatricpatients and their families.     

Cognitive effects of childhood leukemia therapy: a case for four specific deficits

Prophylactic treatment of the central nervous system (CNS) with cranial irradiation and antineoplastic drugs has made childhood acute lymphoblastic leukemia (ALL) a survivable disease, but at the same time there have been many reports of iatrogenic effects, including deficits in cognitive functioning. Previous research suggests a particular effect on the Freedom from Distractibility factor of the WISC-R, memory, and attention. These particular abilities are tested in a group of 43 ALL survivors, with comparisons against solid tumor as well as sibling controls. The results indicate that four cognitive processes are affected by CNS prophylaxis for ALL: short-term memory, speed of processing, visuomotor coordination, and sequencing ability. Younger children have a more severe speed of processing deficit and children treated with a less rigorous protocol appear to be slightly less affected generally. The specific cognitive deficits found are related to neurological evidence on both theoretical and empirical grounds. Results suggest that children who have received CNS prophylaxis are able to learn, but may be slower to acquire new material and may benefit from bimodal presentation.     

Behavioral Adkjustmnet and Social Functioning of Long-Term, Survivors of Childhood Leukemia: Parent and Teacher Reports

Obtained parent and teacher reports of behavior and social competencefor children who were survivors of acute lymphoblastic leukemia(ALL). At followup, children were 5–18 years of age, 48months postdiagnosis, in first continuous remission, and ofchemotherapy. Each child had been randomized to receive either1,800 cGY whole brain radiation therapy (WBRT) plus intrathecalmethotrexate (IT MTX), or IT MTX alone as central nervous systemprophylaxis, and one of four chemotherapy regimenss that variedin treatment intensity. Scores on standardized measures (CBCL-P/Tand PIC) were generally similar to instrument, norms. Parents,but not teachers, reported heightened child somatic concerns.There was no effect of WBRT or chemotherapy regimen on ratingsof behavioral adjustment. Results indicate minimal psychosocialmorbidity among long-term survivors of ALL and suggest thatthe stressful life envents associated with cancer and its treatmentdo not cause significant behavioral or emotional diffculties.     

Intellectual, neuropsychological, and academic functioning in long-term survivors of leukemia

OBJECTIVE: To assess the effects of treatment for acute lymphoblastic leukemia (ALL) on children's cognitive functioning. METHOD: Participants were long-term survivors of ALL treated with cranial irradiation and central nervous system (CNS) chemotherapy (n = 20), or CNS chemotherapy only (n = 21), healthy children (n = 21), and children with chronic asthma (n = 21). The groups were compared on measures of intellectual, neuropsychological, and academic functioning. RESULTS: CNS chemotherapy, with and without cranial irradiation, was associated with significantly lower levels of intellectual and academic functioning. Children with chronic asthma obtained lower scores than healthy controls, but these differences were not significant. Tests of neuropsychological functioning did not consistently separate the groups. CONCLUSIONS: CNS chemotherapy and, to a lesser extent, chronic illness both contribute to the poorer performance of long-term survivors of ALL on measures of intellectual and academic functioning.     

Elevated asymmetric dimethylarginine in young adult survivors of childhood acute lymphoblastic leukemia: A preliminary report

Background: Adult survivors of childhood malignancy are predisposed to late cardiovascular (CV) complications. Our aim was to estimate plasma levels of the endogenous nitric oxide formation inhibitor asymmetric dimethylarginine (ADMA), in long-term survivors of childhood acute lymphoblastic leukemia (ALL) treated with only chemotherapy. Methods: ADMA and its isomer symmetric dimethylarginine (SDMA) were measured in 25 former ALL patients (aged 18–28 years) who had survived without recurrent disease ≥ 5 years from completing chemotherapy without cranial irradiation, and in 20 healthy controls (aged 20–31 years). Results: Characteristics of the both groups were similar, except for lower high-density lipoproteins-cholesterol (HDL-C) in ALL survivors. Compared to controls, the former ALL patients exhibited significant, albeit small, rises in levels of ADMA (0.63 ± 0.09 [SD] vs. 0.57 ± 0.07 μmol/L; p = 0.016), but not SDMA, with a consequently increased ADMA to SDMA ratio (1.08 ± 0.22 vs. 0.91 ± 0.16; p = 0.004). The effect of former ALL on ADMA was attenuated (intergroup p = 0.10 [ANCOVA]) upon adjustment for HDL-C (ADMA vs. HDL-C regression coefficient: −0.065 ± 0.030 [SEM]; p = 0.03). Conclusions: ADMA is elevated in adult childhood ALL survivors, which can reflect late detrimental chemotherapy effects, partially related to minor lipid profile changes. Whether these subtle ADMA elevations might herald future CV morbidity, remains to be elucidated.     

The contribution of neurocognitive situation,physical capacity and daily life activities to quality of life in childhood acute lymphoblastic leukemia survivors

Background/aim There are no extensive studies on the QL in children who completed acute lymphoblastic leukemia (ALL) treatment and currently living without any disease in Turkey. Our study aimed to analyze both the QL and the effects of physical, neurocognitive capacities on QL in childhood ALL survivors aged 7–12 years at the time of recruitment.Materials and methodsPedsQL cancer module 3.0 child and proxy report, for ages 5–7 and 8–12 years, WeeFIM scale, BOTMP Short Form, RPM, reading, writing, and mathematics assessment tools, sociodemographic information form were carried out to the children and their family.Results There was no effect of the months since the completion of therapy on pain, anxiety, cognitive problems, perceived physical appearance, and the total QL scores of children and proxy reports (p > 0.05).Children’s physical capacities were significantly worse than healthy controls and have not reached the level of healthy children even after a long time since completion of ALL therapy. There was a significant association between physical capacity and daily independent living status (p < 0.001). Reading, writing, and mathematical skills were significantly associated with the mean time off-treatment (p < 0.001), and the total score of RPM and PedsQL of those with mathematical difficulties were significantly lower than those without any difficulty (p < 0.05).ConclusionThe months after the treatment (off-treatment time) have not affected total and subunit QL scores. As motor skills difficulties will lead to low academic achievement, early recognition direct the parents for immediate intervention. lead to low academic achievement, early recognition could direct the parents for immediate intervention. Planning psychosocial support programs for physical activity and age-appropriate development of patients from the initiation of treatment will increase the QL in childhood ALL with a survival rate of 80% or more.     

Cognitive status of children treated with central nervous system prophylactic chemotherapy for acute lymphocytic leukemia.

Treatment-related cognitive impairments have been reported for survivors of childhood leukemia following prophylactic central nervous system (CNS) treatment with craniospinal radiation. We examined the neurocognitive status of 46 children with acute lymphocytic leukemia (ALL) to assess the impact of a regimen consisting of systemic chemotherapy and prophylactic CNS chemotherapy. By comparing three groups of ALL children (i.e., patients whose diagnosis was recent, patients 1 year postdiagnosis currently receiving CNS prophylactic chemotherapy, and off-therapy patients who had been treated with chemotherapy for 3 years) and their healthy siblings on measures of sequential and simultaneous processing, we were able to examine the effects of CNS prophylactic and systemic chemotherapy at various points during treatment. Results indicate that the children who had received a 3-year course of chemotherapy (off-therapy patients) were more impaired on tasks involving right-hemisphere simultaneous processing than were sibling controls or ALL children whose diagnosis was recent and whose treatment had just begun. Age at diagnosis did not interact with the effects of chemotherapy. These findings support the need for continued evaluation of cognitive functioning in ALL, children receiving CNS prophylactic chemotherapy to identify potential harmful neurocognitive sequelae of treatment.     

Scholarly literature review: management of neurocognitive late effects with stimulant medication

OBJECTIVE: To examine the extant literature on stimulant drug therapy for survivors of childhood cancer during the late-effects period. METHODS: A review of literature is provided on the mechanism of and cognitive toxicities for children and adolescents treated for acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT) as well as the pharmacotherapy of stimulant medications, with a specific review of literature on the efficacy and safety of the stimulants for children with ALL and BT. RESULTS: Only four studies were found that have examined the effects of stimulant medication on the cognitive toxicities of childhood survivors of cancer during the late-effects period and only two of these investigations were controlled clinical trials. Findings suggest efficacy of the stimulants on parent and teacher ratings of attention and putative tasks of attention and executive functioning. CONCLUSIONS: Although there is some preliminary support for the efficacy and safety of the stimulants for survivors of ALL and BT, more research is needed concerning the long-term effects of the stimulants among cancer survivors.     

Brief report: sluggish cognitive tempo among pediatric survivors of acute lymphoblastic leukemia

OBJECTIVE: The purpose of the present study was to assess sluggish cognitive tempo (SCT) behavioral symptoms among pediatric survivors of acute lymphoblastic leukemia (ALL) and to determine the relationship of these behaviors with cognitive late effects. METHODS: ALL survivors (n = 80) and a sibling control group (n = 19) were administered intelligence (IQ) testing, achievement testing and SCT behavioral items. Group differences (patients vs. siblings) were examined on the SCT behaviors and partial correlations were conducted to explore the relationship of the SCT behaviors with IQ and achievement, while controlling for age at treatment and time since treatment. RESULTS: ALL survivors exhibited significantly more SCT symptoms than the sibling control group and increased SCT symptoms were associated with lower IQ and achievement scores. CONCLUSIONS: ALL survivors are vulnerable to SCT symptoms and these behaviors are associated with cognitive late effects. SCT symptoms may represent a behavioral component of cognitive late effects.     

DNA methylation and obesity in survivors of pediatric acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study

Because survivors of pediatric acute lymphoblastic leukemia (ALL) are more likely to be obese than unaffected contemporaries, we compared DNA methylation profiles between normal‐weight and obese survivors at adiposity‐associated CpG sites previously‐reported by epigenome‐wide association studies (EWAS) of body mass index (BMI) in the general population. We selected 96 ALL survivors from the Childhood Cancer Survivor Study: 48 obese and 48 normal weight. The Illumina HumanMethylation450 BeadChip was used to compare DNA methylation at 211 loci identified in EWAS of BMI in the general population. Thirty‐nine loci were associated (false discovery rate <0.05) with obesity among survivors who only received chemotherapy (n = 49). No loci were significantly associated with obesity among CRT‐exposed survivors (n = 47). Our results suggest that previously identified BMI‐DNA methylation loci are associated with obesity in ALL survivors who were spared CRT, while no loci were significantly associated with obesity in survivors who received CRT.     

Age and Gender Differences in School-Age Children's Appraisals of Injury Risk

Objective: To examine age and gender differences in children'sperception of injury risk and to evaluate cognitive factorsthat relate to their appraisal of risk. Methods: The participants were 120 children (6 to 10 years ofage), who used a series of photographs, which depicted playactivities that varied from no to high risk, to appraise injuryrisk. Results: Children were able to distinguish varying degrees ofinjury risk. Boys rated risk as lower than girls, and 6-year-oldchildren identified fewer risk factors and did so more slowlythan 10-year-old children. For girls, perceived vulnerabilityto injury was the best predictor of injury risk ratings, whereasfor boys it was judged severity of potential injury. Conclusions: Children's appraisal of risk and age and genderdifferences in related factors highlight important componentsfor injury prevention programs.     

Effects of Maternal Intelligence, Marital Status, Income, and Home Environment on Cognitive Development of Low Birthweight Infants

Objective: To examine direct and mediated effects of maternalIQ, marital status, family income, and quality of the home environmenton the cognitive development of low birthweight infants. Methods: Secondary analyses on a large dataset using hierarchicalregression identified factors correlated with cognitive outcomesin children at 3 years of age who were bom at low birthweight. Results: Maternal IQ was a critical variable, because it washighly correlated with child IQ and because maternal intelligenceinfluenced patterns of relationships among other predictor variablesincluding marital status, income level, and home environmenton child IQ. Analyses revealed that effects of these variableson child IQ interacted with maternal IQ. Conclusions: Early childhood intervention programs should targetthose low birthweight infants most at risk for impaired cognitivedevelopment. Children at greatest risk are those living withunmarried, low IQ mothers.     

Effects of early middle ear effusion on child intelligence at three, five, and seven years of age

Objective: This study tested the hypothesis that children withprolonged middle ear effusion (MEE) during the first 3 yearsof life are at risk for cognitive delays or deficits. Method: A prospective study enrolled 698 children from diversebackgrounds and controlled for eight demographic and environmental factors. Participants were recruited at birth and monitoredfor ear status frequently in the home; 379 children were assessedfor cognition with the Stanford-Binet, 4th ed., at 3 yearsof age, 294 at 5 years, and 198 at 7 years. Results: Using the SAS General Linear Models (GLM) procedure,we found a significant direct relation between duration of bilateral MEE and Stanford-Binet Composite and Nonverbal Reasoning/VisualizationFactor scores at age 3, but not at age 5 or age 7. Statisticalclustering analysis revealed four groups with different temporal patterns of MEE: Low MEE, Early MEE (peaking at 0-6 months),Later MEE (peaking at 6-12 months), and High MEE. GLM analysesrevealed no direct effects, but several moderated effects,of MEE cluster on cognitive development at 3 years, but noneat 5 or 7 years. In general, children in the Later MEE andHigh MEE groups appeared to be more adversely affected by bilateralMEE at 3 years, but effects were moderated in complex ways by socioeconomic status or home stimulation. Growth curve modelingacross the three assessment periods showed no effects of totalduration of MEE but did indicate that children in the LaterMEE cluster had low scores at age 3 but caught up at ages 5and 7. Conclusions: Prolonged MEE, especially between 6 and 12 months,may put children at risk for cognitive delays at 3 years, butthe risk effect is not strong and effects are no longer detectableat 5 or 7 years.     

Acute neurocognitive response to methylphenidate among survivors of childhood cancer: a randomized, double-blind, cross-over trial

OBJECTIVE: To investigate the acute efficacy and adverse side effects of methylphenidate (MPH) among survivors of childhood cancer [acute lymphoblastic leukemia (ALL) or brain tumor (BT)] with learning impairments. METHODS: Participants (N = 122) completed a two-day, in-clinic, double-blind, cross-over trial during which they received MPH (0.60 mg/kg of body weight) and placebo that were randomized in administration order across participants. Performance was evaluated using measures of attention, memory, and academic achievement. RESULTS: A significant MPH versus placebo effect was revealed on a measure of attention, cognitive flexibility, and processing speed (Stroop Word-Color Association Test). Male gender, older age at treatment, and higher intelligence were predictive of better medication response. No significant differences were found for number or severity of adverse side effects as a function of active medication. CONCLUSIONS: MPH shows some neurocognitive benefit and is well tolerated by the majority of children surviving ALL and BT.     

Cognitive–affective strategies and cortisol stress reactivity in children and adolescents: Normative development and effects of early life stress

This study examined cognitive–affective strategies as predictors of hypothalamic–pituitary–adrenal (HPA) axis responses to a social-evaluative stressor in adolescence as compared to late childhood as a function of early life experiences. Participants included 159 children (9–10 years) and adolescents (15–16 years) divided into two groups based on early care experiences: non-adopted youth raised in their birth families (n = 81) and post-institutionalized youth internationally adopted from orphanage care (n = 78). Youth completed a version of the Trier Social Stress Test modified for use with children and reported on their trait emotion regulation and coping strategies. Children reported more use of suppression and disengagement than adolescents, while adolescents reported more engagement coping strategies. Non-adopted and post-institutionalized youth did not differ in reported strategies. Cognitive reappraisal predicted higher cortisol reactivity in non-adopted children and adolescents, and was not associated with reactivity in the post-institutionalized group. This study has implications for efforts aimed at promoting self-regulation and adaptive stress responses during the transition to adolescence for both typically developing children and children who experienced adverse early care.     

Postirradiation Treatment Outcomes for Children with Acute Lymphocytic Leukemia: Clarification of Risks

Developmental and educational consequences of treatment foracute lymphocytic leukemia (ALL) were examined in a group of26 elementary school children who were survivors of the disease.All of the survivors had received cranial irradiation as partof their treatment. Risks were assessed by comparing each ALLsurvivor to one normal sibling on a comprehensive battery oftests and on measures of behavior and school performance. Consistentwith previous findings, the ALL group performed less well thantheir siblings on tests of IQ, neuropsychological skills, andacademic achievement. Analysis of ratings by parents and teachersrevealed that the ALL group was less able to meet the academicdemands of school but did not differ from the sibling groupin behavioral adjustment. A greater number of children fromthe ALL group obtained borderline to low-average full-scaleIQ scores; and more received special educational assistanceat school. However, none of these children met criteria formental retardation. The present findings help to clarify therisks associated with treatment protocols that include prophylactic irradiation.     

Problem Behaviors and Personality of Children and Adolescents With Prader-Willi Syndrome

Objective: Compare behavioral and emotional problems of childrenand adolescents with Prader-Willi Syndrome (PWS) and clientsconsulting mental health centers (MHC) and related behavioraland emotional problems to the children's personality in thePWS group. Methods: Participants were 39 children with PWS and 585 matchedMHC dlents. Child Behavior Checklist (CBCL) syndromes were relatedto the Big-Five personality factors measured with the CaliforniaChild Q-sort (CCQ). Results: Mean CBCL Total Problems scores were not differentfor the PWS and MHC groups, but differences were found for severalof the CBCL subscales. Patterns of correlations among CBCL scaleswere similar In both groups, although coefficients were generallyhigher in the PWS group, indicating higher comorbidity or co-absenceof CBCL syndromes in children and adolescents with PWS. Personalityprofiles were specific for Internalizing and Externalizing problemsof children and adolescents with PWS.     

Sex differences in cognitive processing in children treated with CNS prophylaxis for acute lymphoblastic leukemia

Evaluated cognitive processing in 51 children (27 female, 24 male) who had been treated for acute lymphoblastic leukemia (ALL) with CNS prophylaxis (cranial radiation in combination with intrathecal chemotherapy) and were continuously disease-free for 5 to 12 years. The control group comprised 15 children treated for Wilm's tumor. Functions assessed included visuoperceptual skills, generation of organizational strategies, sensitivity to organizational structure, and attention. The ALL group showed performance deficits relative to the solid tumor controls in appreciating the organization inherent in complex visuospatial material and alertness, with females more severely affected than males. Sex differences favoring males on IQ and academic achievement were related to these cognitive processes.     

Cytogenetics of long‐term survivors of ETV6‐RUNX1 fusion positive acute lymphoblastic leukemia

This study describes the cytogenetics of 33 children with ETV6‐RUNX1 positive acute lymphoblastic leukemia (ALL) who had been in continuous complete remission for a minimum of 8.8 years [median event‐free survival (EFS) 10.9 years]. The results were compared with a published series of 16 fusion positive patients treated on the same childhood ALL trial, who had relapsed (median EFS, 2.3 years). Interphase fluorescence in situ hybridization (FISH) at diagnosis showed deletion of the second ETV6 signal from all fusion positive cells in 45% of the long‐term survivors but in none of the relapsed patients, whereas patients with mixed populations with retained or lost second signals were more frequent among those who had relapsed (69%) than the long‐term survivors (21%). Interphase populations with two fusion signals in 18% of the long‐term survivors and 31% of relapsed patients were smaller in the long‐term survivors (median, 4% of total cells) than in the relapsed patients (median, 84%). The additional copy of chromosome 21 in 30% of long‐term survivors and in 69% of relapsed patients was a derived chromosome 21 in 20% and 55% of patients, respectively. Metaphase FISH for 26 long‐term survivors and 15 relapsed patients revealed complex karyotypes in both groups. Variant translocations involved different chromosome arms between the long‐term survivors and relapsed patients. It appears that the two groups have some distinguishing cytogenetic features at the time of diagnosis, which may provide pointers to relapse that are worthy of more detailed study. © 2009 Wiley‐Liss, Inc.     

Intellectual functioning of childhood leukemia survivors - relation to Tau protein - a marker of white matter injury

PurposeChemo- and radiotherapy used in acute lymphoblastic leukemia (ALL) can influence on brain functioning in the future. In a prospective study we analysed the cognitive functions of ALL survivors in relation to Tau protein as a marker of white matter injury.Material and methodsThirty-one survivors of childhood ALL (6.3 years after diagnosis); without the signs of CNS involvement, treated with chemotherapy alone, rested in first remission; underwent Intelligence tests- Wechsler Intelligence Scales (WISC-R, WAIS-R). Their results were analyzed in relation to the levels of Tau in cerebrospinal fluid (CSF) obtained during the treatment.ResultsThe analysis showed that all survivors attained the average scores in intelligence tests. A negative correlation was found between methotrexate (MTX) doses and Freedom from Distractibility (FFD). Females had higher values of Performance Intelligence Quotient (PIQ) than males. A negative correlation was noted of Tau protein levels obtained from the last CSF with: Total and Verbal Intelligence Quotient, PIQ, Perceptual Organisation Index and FFD but not with Verbal Comprehension Index.ConclusionOur results suggest the possibility of white matter injury during the treatment for ALL with chemotherapy alone. Elevated Tau protein level in CSF at the end of treatment might indicate future difficulties in neurocognitive functioning.