Ida M. Moore

Cognitive function in children with leukemia. Effect of radiation dose and time since irradiation

The effect of two cranial radiation (CRTX) doses and the time since radiation therapy on cognitive functioning were studied in 35 children who completed therapy for acute lymphoblastic leukemia (ALL). The patients were grouped according to CRTX dose (2400 or 1800 cGy) and evaluated for general intelligence, academic achievement, and visual motor integration. Those who received 2400 cGy (n = 20) scored ten points below those treated with 1800 cGy (n = 15) on verbal intelligence quotient and achievement tests of reading, spelling, and arithmetic. The effect of time since radiation therapy on these measures of cognitive function was significant (P = 0.001 to 0.03); the effect of CRTX dose was not. Visual motor integration scores in both groups fell below the 33rd percentile. The effect of CRTX dose and time since radiation therapy on visual motor integration and performance intelligence quotient were not significant. Thus, the interval between treatment and the emergence of cognitive impairments may be longer after lower CRTX doses, and deficits in nonverbal areas such as visual motor integration may appear first. A larger study is needed to confirm these findings from a limited sample of long‐term survivors of ALL.

Math Weaknesses in Survivors of Acute Lymphoblastic Leukemia Compared to Healthy Children

Difficulties in math are the most frequently reported area of academic deficit in survivors of acute lymphoblastic leukemia (ALL) and the most frequent academic complaint among parents of ALL survivors. However, previous studies that included measures of math skills have been limited by the use of only a single measure of math skills, most often a measure of written calculations, without any assessment of math reasoning or math application skills. Further, the nature of these math difficulties has not been adequately investigated. The purpose of this study was to examine the performance of ALL survivors using multiple measures of math skills. Performance was compared to a group of healthy controls matched for age and sex as well as to normative levels. Other measures of neuropsychological function were also administered, and the relationships between these measures and the math measures were explored. Converging evidence for math difficulties in ALL survivors compared to healthy controls and normative levels was found. While ALL survivors generally performed within the average range on measures of math skills, math performance was mostly related to memory function and dominant-hand psychomotor speed. By contrast, math performance of healthy children was mostly related to basic reading skills and visual-motor integration. These findings shed light on the nature of math difficulties in ALL survivors and have implications for intervention.

Oxidative stress and executive function in children receiving chemotherapy for acute lymphoblastic leukemia.

Neurocognitive sequelae following treatment for pediatric acute lymphoblastic leukemia (ALL) has been reported in a significant proportion of survivors, including those treated only with chemotherapy. Early identification of children “at risk” for neurocognitive problems is not yet reliable. Biomarkers of oxidative stress (e.g., oxidated phosphatidylcholine) in cerebral spinal fluid (CSF) have been correlated with intensity of methotrexate (MTX) treatment, suggesting an association with acute central nervous system toxicity.

Absence of white matter changes on magnetic resonance imaging in children treated with CNS prophylaxis therapy for leukemia

Previous studies have shown that magnetic resonance imaging (MRI) is sensitive to white matter changes in children receiving cranial radiation of 3000 cGy or greater. The current study used MRI to investigate the integrity of white matter in children receiving 1800 to 2400 cGy of cranial radiation. Ten survivors of acute lymphoblastic leukemia (ALL) who received intrathecal methotrexate (MTX) and either 1800 or 2400 cGy of cranial radiation were studied with MRI and neuropsychologic testing. Magnetic resonance (MR) scans were normal in nine of ten patients. One patient had prominent and asymmetrical lateral ventricles and mildly enlarged cortical sulci. White matter tracts were normal in appearance. However, seven of nine children had below average intellectual functioning. Results indicate that children receiving less than 2500 cGy of cranial radiation fail to show white matter changes on MRI, despite evidence of cognitive impairment.

Behavioral Adjustment of Children and Adolescents With Cancer: Teacher, Parent, and Self-Report

PURPOSE/OBJECTIVES To describe behavioral adjustment in children and adolescents with acute lymphoblastic leukemia (ALL) and to determine whether behavioral adjustment is correlated with cognitive and academic abilities. DESIGN Descriptive, cross-sectional design. SETTING Two pediatric oncology treatment centers. SAMPLE 47 children and adolescents who had been receiving ALL therapy for at least one year or who were off therapy for no more than three years and their parents and teachers. Wechsler Intelligence Scale for Children-Revised (WISC-R) and Wide Range Achievement Test-Revised (WRAT-R) data were available on a subset of 17 subjects. METHODS Parent, teacher, and self-report Behavioral Assessment System for Children (BASC) ratings were used to measure behavioral adjustment. WISC-R measured cognitive abilities, and WRAT-R measured academic abilities. Demographic, family, and treatment-related data also were collected. MAIN RESEARCH VARIABLES Behavioral adjustment and cognitive and academic abilities. FINDINGS At least 20% of teacher ratings for somatization, learning problems, leadership, and study skills; parent ratings for somatization, adaptability, attention problems, withdrawal, anxiety, social skills, and depression; and self-report ratings for anxiety and attitude to school were in the at-risk range (i.e., presence of significant problems that require treatment). The majority of teacher BASC ratings were correlated significantly with WISC-R and WRAT-R scores. Self-report depression and social stress ratings were correlated significantly with some WISC-R and WRAT-R scores. Treatment-related experiences such as body image alterations and mental and emotional problems were associated with problematic behaviors, including depression, somatization, withdrawal, and social stress. CONCLUSIONS Youth with ALL are at risk for some behavioral adjustment problems, particularly anxiety, somatization, adaptability, attention, and withdrawal. Cognitive and academic abilities are associated with some dimensions of behavioral adjustment. IMPLICATIONS FOR NURSING Findings suggest the need for ongoing assessment of behavioral adjustment and cognitive and academic abilities of children with ALL. Behavioral interventions that target at-risk mannerisms, such as somatization, depression, anxiety, and social stress, are needed. Central nervous system treatment may contribute to behavioral adjustment problems, as well as to cognitive and academic problems. Strategies to improve academic abilities also may have a positive effect on behavioral adjustment.

OXIDATIVE CHANGES IN CEREBRAL SPINAL FLUID PHOSPHATIDYLCHOLINE DURING TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA

Central nervous system (CNS) treatment contributes to improved long-term disease-free survival from childhood acute lymphoblastic leukemia (ALL) by sigificantly decreasing the rate of disease relapse. Methotrexate (MTX), a drug commonly used for CNS treatment, has been associated with cognitive and academic problems, white-matter changes, perfusion defects, and brain atrophy. This study investigated oxidative stress as a possible mechanism of chemotherapyinduced CNS injury. Unoxidized and oxidized components of phosphatidylcholine (PC), the most prevalent phospholipid in CNS cellular membranes, were measured in cerebral spinal fluid (CSF) samples obtained from 21 children diagnosed with low (n = 7), standard (n= 7), or high (n= 7) risk ALL. Children with high-risk ALL received the most MTX, especially during the most intensive phase of treatment (consolidation). Phospholipids were extracted from CSF samples obtained at diagnosis and during the induction, consolidation, and continuation treatment phases. Unoxidized and oxidized PC were measured by normalphase high-performance liquid chromatography at 2 ultraviolet wavelengths (206 and 234 nm, respectively). Data were analyzed by 2-way repeated-measures analysis of variance. Results support the hypotheses that the highest levels of oxidized PC would be observed during the most intensive phase of ALL therapy and in the high-risk ALL group. Findings provide preliminary evidence for chemotherapy-induced oxidative stress inCNSmembrane phospholipids.

Mathematics intervention for prevention of neurocognitive deficits in childhood leukemia

Despite evidence that CNS treatment is associated with cognitive and academic impairment, interventions to prevent or mitigate these problems are limited. The purpose was to determine if early intervention can prevent declines in mathematics abilities.

Psychosomatic symptoms in parents 2 years after the death of a child with cancer

Forty-five mothers and 30 fathers, representing 58 families, completed the Symptom Checklist 90-Revised, a measure of current psychological and somatic symptoms, 24 months after the death of a child with cancer. The mean scores from six symptom dimensions (somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, and hostility) and a global measure of the depth of symptomatology, the Global Severity Index, were contrasted with those of the nonpatient and psychiatric outpatient norms reported by Derogatis (1983). Two years after the childs death parents showed a symptom profile reflecting significantly greater distress than that reported by nonbereaved, nonpatient adults. The results highlight important distinctions between bereaved parents and psychiatric outpatients.

Methotrexate causes apoptosis in postmitotic endothelial cells.

Methotrexate (MTX) is a commonly used chemotherapy agent for a variety of cancers. However, therapeutic levels are associated with numerous untoward effects such as central nervous system damage in children with acute lymphoblastic leukemia. The purpose of this study was to determine if MTX caused injury to endothelial cells using cultured bovine pulmonary artery endothelial cells as a model. Light microscopy showed gaps between cells and reduced numbers of endothelial cells after exposure to MTX (10 M), a range consistent with therapeutic drug levels. Proliferation and viability of subconfluent and confluent MTX-treated endothelial cells were measured by colorimetric (MTS) assay. There was a significant decline in cell numbers in MTX-treated subconfluent (growing) cells cultured after 4 days of MTX exposure compared to controls, as expected. However, there was also an unexpected decline in cell numbers in MTX-treated postmitotic endothelial cells after 1, 3, and 4 days of drug exposure. This suggested that MTX induced endothelial cell death. Fluorescent ApoAlert™ Enhanced Annexin-V binding demonstrated apoptosis in endothelial cells after 1 day of MTX exposure. Apoptosis was confirmed by a DNA fragment assay. This is apparently the first report of MTX-induced apoptosis of postmitotic, cultured endothelial cells. The findings suggest that apoptosis may be one mechanism of MTX-induced injury to endothelial cells.

Oxidative stress and neurobehavioral problems in pediatric acute lymphoblastic leukemia patients undergoing chemotherapy.

Neurobehavioral problems after chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL) have been a recent focus of investigation. This study extended previous research that suggested oxidative stress as a potential mechanism for chemotherapy-induced central nervous system injury by examining early markers of oxidative stress in relation to subsequent neurobehavioral problems. Oxidized and unoxidized components of phosphatidylcholine (PC) were measured in the cerebrospinal fluid of 87 children with ALL at diagnosis, induction, and consolidation. Behavioral assessments were conducted postconsolidation and at the end of chemotherapy. Results revealed a significant association between physiologic reactivity (high vs. low PC changes from diagnosis) and behavioral outcomes (high vs. low pathology). Elevated oxidized PC fraction change was predictive of increased problems with aggression at the end of therapy as well as postconsolidation adaptability. Furthermore, symptoms of hyperactivity systematically changed over time in relation to both unoxidized PC and oxidized PC fraction reactivity. These findings suggest that symptoms of behavioral problems occur early in the course of chemotherapy and that increases in the cerebrospinal fluid PC markers of oxidative stress during induction and consolidation may help to predict certain future behavioral problems.