Increase in oxidative stress as measured by cerebrospinal fluid lipid peroxidation during treatment for childhood acute lymphoblastic leukemia.

Five-year survival from childhood acute lymphoblastic leukemia (ALL) approaches 90%, but 40% of survivors experience central nervous system (CNS) treatment-related cognitive problems. Despite considerable evidence for cognitive problems, less is known about mechanisms of neurological injury. Our purpose was to investigate oxidative stress, measured by lipid peroxidation, as a mechanism of CNS treatment-related neurological injury. The sample included 55 children (mean age at diagnosis=6.84 y, SD=3.40) who received intrathecal and intravenous chemotherapy for CNS-directed treatment according to Children's Oncology Group protocols. Glycerophospholipids were extracted from cerebrospinal fluid samples obtained at diagnosis and during intrathecal chemotherapy administration. Unoxidized and oxidized phosphatidylcholine (PC) and phosphatidylinositol (PI) were measured by normal phase high-performance liquid chromatography with diode array detection, and analyzed with a general linear model for repeated measures analysis of variance. Compared with the diagnostic cerebrospinal fluid sample, unoxidized and oxidized PC and PI increased significantly across treatment phases. Amount of intravenous methotrexate received was significantly correlated with oxidized PI, and age at time of ALL diagnosis was significantly associated with oxidized PC. These findings support our hypothesis that oxidative stress is a mechanism of neurological injury associated with CNS-directed treatment for ALL.

Symptom self-management strategies in patients with non-metastatic prostate cancer.

AIMS AND OBJECTIVES: To explore the association between symptoms, symptom distress and symptom self-management and to identify effective strategies of symptom self-management in men with non-metastatic prostate cancer following radical prostatectomy or radiation therapy. BACKGROUND: Men receiving treatments for localised prostate cancer experience symptoms of urinary incontinence, urinary obstruction/irritation, bowel difficulties and sexual dysfunction. Understanding patients' symptom experiences and identifying strategies that they use to manage these symptoms are imperative for symptom management planning. DESIGN: A descriptive, cross-sectional study was conducted with a sample of 53 men, who were within three months of the initiation of their treatment. METHODS: The Symptom Indexes and the Strategy and Effectiveness of Symptom Self-Management questionnaires were used to measure symptoms, symptom distress and symptom self-management. Descriptive statistics, t-tests, correlations and multiple regressions were used to analyse the data. RESULTS: Symptoms were significantly correlated with symptom-related distress (r = 0·67, p < 0·01). Frequency of symptoms was significantly associated with symptom self-management strategies for urinary (ß = 0·50, p < 0·01), bowel (ß = 0·71, p < 0·01) and sexual problems (ß = 0·28, p = 0·05). The most effective strategies were as follows: pads and doing Kegel exercise for managing urinary problems, rest and endurance for bowel symptoms, and expressing feelings and finding alternative ways to express affection for management of sexual dysfunction. CONCLUSIONS: Assessing symptom self-management among men with newly diagnosed prostate cancer can help healthcare providers develop strategies that will enhance health-related quality of life. RELEVANCE TO CLINICAL PRACTICE: Results provide information on effective strategies that patients with prostate cancer found to reduce their symptoms. The strategies used provide a foundation for developing and testing interventions for personalised symptom management.

Mathematics intervention for prevention of neurocognitive deficits in childhood leukemia.

BACKGROUND: 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. PROCEDURES: Fifty-seven children with ALL were enrolled and randomized to a Mathematics Intervention or Standard Care. Subjects completed neurocognitive assessments prior to the intervention, post-intervention, and 1 year later. Parents received written results and recommendations for use with their school. The Mathematics Intervention was based on Multiple Representation Theory and delivered individually over 1 year. RESULTS: Thirty-two of 57 subjects completed the study and were included in data analyses. These 32 subjects completed all neurocognitive assessments and, for those in the Intervention Group, 40-50 hours of the Mathematics Intervention. There were no group differences on relevant demographic variables; risk stratification; number of intrathecal methotrexate injections; or high dose systemic methotrexate. Significant improvements in calculation and applied mathematics from Baseline to Post-Intervention (P = 0.003 and 0.002, respectively) and in visual working memory from Baseline to 1 year Follow-up (P = 0.02) were observed in the Intervention but not the Standard Care Group. Results from repeated measures ANOVA demonstrated significant between group differences for applied mathematics [F(2,29) = 12.47, P < 0.001] and visual working memory [F(2,29) = 5.53, P = 0.009]. CONCLUSIONS: The Mathematics Intervention improved mathematics abilities and visual working memory compared to standard care. Future studies are needed to translate the Mathematics Intervention into a "virtual" delivery method more readily available to parents and children.

Biomarkers and Cognitive Function in Children and Adolescents During Maintenance Therapy for Leukemia.

OBJECTIVES: To explore the relationship between biomarkers of oxidative stress and inflmmation in cerebrospinal fluid (CSF) and cognitive function in children receiving maintenance therapy for acute lymphocytic leukemia (ALL). SAMPLE & SETTING: 30 participants aged 4-17 years receiving ALL maintenance therapy at two pediatric cancer centers in the United States. METHODS & VARIABLES: F2-isoprostane (F2-ISoP) and interleukin-8 (IL-8) were evaluated in CSF samples, and cognitive function measures were completed during the first and last cycles of ALL maintenance. The Flanker Inhibitory Control and Attention Test (Flanker) and Dimensional Change Card Sort were completed during the last cycle. RESULTS: During maintenance therapy, IL-8 decreased, and parent reports of children's cognitive function improved. Higher IL-8 was associated with better parent reports of children's cognitive function at each timepoint. Higher F2-ISoP levels were associated with lower Flanker scores. IMPLICATIONS FOR NURSING: F2-ISoP may be a useful biomarker in evaluating cognitive dysfunction in children with ALL and merits further investigation.

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.

Parental perceptions of risk and protective factors associated with the adaptation of siblings of children with cystic fibrosis.

When a child is diagnosed with a chronic, life-threatening illness, there is a significant impact on the healthy siblings. Few studies have addressed the adaptation of well siblings in diagnoses other than cancer. The purpose of this descriptive correlational study was to examine the relationships between the risk and protective factors that affect the psychological adaptation of healthy siblings of a child with cystic fibrosis. Findings from this study suggest family environment, especially parental stress and perceived social support, may affect the adaptation of the well sibling. Adolescent well siblings were more at risk for environmental influences than their younger counterparts.

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

BACKGROUND: 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. PROCEDURE: This study examined the association between oxidized CSF phospholipids and executive functions throughout chemotherapy. Measures of oxidative stress and executive functions were examined in 88 children newly diagnosed with ALL. The children were followed over 3 years with neurocognitive testing and parent ratings of executive functions. RESULTS: Results demonstrated an association between increased oxidative stress following induction and consolidation and decreased executive function 2 years later. Younger age at diagnosis was associated with both an increase in oxidative stress and in executive dysfunction; younger age was associated with poorer ability to organize materials in one's environment (r(48) = 0.28, P < 0.05) and with greater oxidated phosphatidylcholine in CSF at the end of chemotherapy (r(48) = -0.27, P < 0.05). As such, younger age appears to be the most prominent moderator of neurocognitive decline. CONCLUSIONS: These results link functional changes to CSF biomarkers and underscore the importance of monitoring cognitive development in young children treated for ALL. Children with less advanced central nervous system development may be particularly vulnerable to the effects of chemotherapy.

Introduction to the special section on school-related outcomes and success for youth with chronic medical conditions.

Chronic medical conditions permeate our schools with estimates showing that between 15% and 25% of students present with an ongoing illness or disease. Treatments for the most prevalent of these conditions (e.g., diabetes, epilepsy, cancer, juvenile arthritis, and asthma) include hospitalizations, home treatments, and frequent physician appointments-all of which are highly disruptive to children and families. Given the potential medical, cognitive/academic, social-emotional, and behavioral challenges encountered by students with chronic medical conditions, school psychologists are in a unique position to both identify and support the educational experiences of these students. Further, schools provide an ideal forum for outcomes research and intervention programs. This Introduction to the Special Issue on School-Related Outcomes and Success for Youth With Chronic Medical Conditions addresses definitional issues, identifies challenges, reviews the 7 empirical articles in this issue, and discusses areas for future research. This special issue includes scientifically rigorous papers, which feature innovative studies that emphasize real-time, momentary assessments; positive psychology frameworks; and intervention approaches. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Impact of Childhood Leukemia Treatment on Attention Measured by the Continuous Performance Test Factor Structure.

OBJECTIVES: To describe the impact of central nervous system-directed treatment on attention and its relation to academic outcomes in childhood acute lymphoblastic leukemia (ALL) survivors. SAMPLE & SETTING: 51 children diagnosed with ALL at two pediatric oncology treatment centers in the southwestern United States. METHODS & VARIABLES: A prospective, longitudinal design measured attention after a child was in remission, two years after the start of treatment, and at the end of treatment. Attention measures from the Conners' Continuous Performance Test were grouped into composite subdomains based on a factor structure describing focused attention, hyperactivity/impulsivity, sustained attention, and vigilance. RESULTS: Children treated for ALL exhibited decreased focused attention, sustained attention, and vigilance during and at the end of treatment when compared to age- and gender-normed references. IMPLICATIONS FOR NURSING: Pediatric oncology nurses are in a position to ask patients and parents about neuropsychological difficulties during ALL treatment. Patients who experience these effects are at risk for decreased academic abilities after treatment.

Childhood Cancer Symptom Cluster: Leukemia and Health-Related Quality of Life.

OBJECTIVES: To examine the relationship of the Childhood Cancer Symptom Cluster-Leukemia (CCSC-L) with health-related quality of life (HRQOL). SAMPLE & SETTING: 327 children receiving treatment for acute lymphoblastic leukemia from four pediatric oncology programs across the United States. METHODS & VARIABLES: Participants completed fatigue, sleep disturbance, pain, nausea, and depression symptom questionnaires at four time points; these symptoms comprised the CCSC-L. HRQOL was measured at the start of postinduction therapy and then at the start of maintenance therapy. Relationships between the CCSC-L and HRQOL scores were examined with longitudinal parallel-process modeling. RESULTS: The mean HRQOL significantly increased over time (p < 0.001). The CCSC-L had a significant negative association with HRQOL scores at the start of postinduction therapy (beta = -0.53, p < 0.005) and the start of maintenance therapy (beta = -0.33, p < 0.015). Participants with more severe symptoms in the CCSC-L over time had significantly lower HRQOL at the start of maintenance therapy (beta = -0.42, p < 0.005). IMPLICATIONS FOR NURSING: Nurses are pivotal in providing management strategies to minimize symptom severity that may improve HRQOL.

Cerebrospinal fluid phospholipid changes following traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality, with approximately 1.4 million people suffering a TBI each year. With TBI, a cascade of events is initiated including the activation of phospholipases, which leads to the disruption of the lipid bilayer of the membrane of neurons and neuroglia. The purpose of this study is to describe phospholipid changes following TBI. A total of 39 cerebrospinal fluid samples were obtained from the ventricular catheter system of 10 participants who received a TBI as a result of a motor vehicle crash, being struck by a vehicle as a pedestrian, or a fall. Phospholipids were extracted from samples and measured by normal-phase high-performance liquid chromatography with ultraviolet detector at a wavelength of 206 nm. The highest mean concentration of lysophosphatidylcholine occurred on Day 1 after injury. The concentration of phosphatidylserine was variable, with the highest mean concentration occurring on Day 2 after injury. The highest mean concentrations of phosphatidylethanolamine, phosphatidylcholine, and sphingomyelin occurred on Day 4 after injury. Findings provide preliminary evidence for disruption of central nervous system membrane phospholipids following TBI.

Methotrexate-induced alterations in beta-oxidation correlate with cognitive abilities in children with acute lymphoblastic leukemia.

Treatment advances, including central nervous system (CNS) treatment with methotrexate, have led to significant gains in disease-free survival from childhood acute lymphoblastic leukemia (ALL). However, methotrexate has been associated with neurological problems such as declines in cognitive and academic abilities. The purpose of this study was to investigate methotrexate-induced changes in beta-oxidation in children with ALL receiving methotrexate for CNS treatment. Specific aims were to investigate effects of methotrexate on beta-oxidation of the two most prevalent fatty acids (palmitic acid and stearic acid) in cerebrospinal fluid (CSF) samples and correlate the ratio of monounsaturation to saturation of these fatty acids with cognitive and academic abilities. The sample included 12 females and 14 males with low-risk (n = 7), standard-risk ( n = 13), or high-risk (n = 6) ALL. Mean age at diagnosis was 94.1 months (SD = 34.4). CSF samples were obtained in conjunction with diagnostic lumbar punctures; subsequent samples were obtained prior to intrathecal methotrexate administration during the induction, consolidation, and continuation phases of treatment. Fatty acids were analyzed by gas chromatography. Results showed a significant increase in the ratio of monounsaturation to saturation of both fatty acids, which was greatest during the most intensive phase of treatment. Ratios of monounsaturated to saturated fatty acids were negatively correlated with full-scale IQ, verbal IQ, and math calculations. Findings suggest that methotrexate alters beta-oxidation and that the resulting increase in fatty acid monounsaturation is related to declines in some domains of cognitive ability.

Changes in Oxidant Defense, Apoptosis, and Cognitive Abilities During Treatment for Childhood Leukemia.

Aggressive central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia (ALL), the most prevalent cancer among children and adolescents, prevents metastasis of leukemia cells into the brain. Up to 60% of survivors experience cognitive problems, but knowledge about risk factors for and mechanisms of neurologic injury is lacking. Objectives of the present study were to (1) quantify changes in oxidant defense and apoptosis over the course of ALL therapy and (2) elucidate risk factors for long-term cognitive problems. The sample included 71 children with ALL. Cerebrospinal fluid (CSF) samples were collected at diagnosis and during intrathecal chemotherapy administration. Oxidant defense was measured by reduced glutathione (GSH), oxidized glutathione (GSSG), and the ratio of GSH:GSSG. Apoptosis was measured by activity of several cysteine-dependent aspartate-specific protease (abbreviated as caspase) enzymes that initiate (caspases 8 and 9) or execute (caspases 3/7) apoptosis. Cognitive abilities were assessed by standardized measures of short-term memory, visual-motor integration, and attention 3 years after ALL diagnosis. GSH and GSSG concentration increased significantly during ALL therapy, and a low GSH:GSSG ratio was indicative of an oxidized extracellular environment. Caspase enzyme activity increased significantly, and caspases 3/7 activity was significantly and negatively associated with performance on measures of cognitive abilities. Younger age at time of ALL diagnosis was associated with some measures of attention. Efflux of glutathione into CSF maintains oxidant defense by scavenging free radicals and other reactive oxygen species and is an early event in apoptosis. These mechanisms may be involved in neurologic injury associated with CNS-directed treatment and subsequent cognitive problems.

Influence of Nitrosative Stress on Fatigue During Childhood Leukemia Treatment.

The focus on a cure for childhood leukemia over the last three decades has resulted in survival rates of more than 80%. However, efforts to manage leukemia-treatment symptoms have not kept pace with new therapies. Symptom toxicity during treatment can result in complications, treatment delays, and therapy dose reductions. Compromise in therapy can negatively influence the quality of life and, even more notably, jeopardize chances for long-term survival. This study examined biologic mechanisms that influence fatigue caused by increased reactive oxidative species (ROS) or actual failure of the antioxidant defense system due to genetic variation by investigating reactive nitrosative species, a "downstream" consequence of ROS. The specific aims of this study were to characterize the trajectory of nitrosative stress during acute lymphoblastic leukemia treatment and evaluate the influence of nitrosative stress on fatigue. A repeated measures design was used to evaluate the fatigue experienced by 186 children and adolescents, 3-18 years of age, with a diagnosis of leukemia during the most intense phase of treatment. An established biomarker of nitrosative stress, protein 3-nitrotyrosine (3NT) residues in the cerebral spinal fluid, was evaluated at diagnosis, postinduction, and consolidation phases of treatment. Higher fatigue was associated with higher 3NT levels at the beginning of treatment. Two distinct groups of children experienced either consistently high or consistently low 3NT levels across the treatment trajectory, from diagnosis to 12 months postinduction. Findings from this study support continued exploration into the phenotypic biochemical mechanisms that influence a reactive response to childhood cancer treatment.

Association of Asthma Illness Representations and Reported Controller Medication Adherence Among School-Aged Children and Their Parents.

This study examined the relationship between asthma illness representations and reported controller medication adherence of school-aged children (6-11 years) with persistent asthma and their parents. Thirty-four parent-child dyads independently reported on asthma controller medication adherence and asthma illness representations. Hierarchical regression analyses were used to test parent and child illness representation domain variables as predictors of reported medication adherence. Parent beliefs about medication necessity versus concerns was a significant predictor of parent-reported adherence (ß = .55, p < .01), and child treatment control was also a significant predictor of parent-reported adherence (ß = -.50, p < .01). Child beliefs about medication necessity versus concerns was a significant predictor of child-reported adherence (ß = .50, p < .01), and no parent variables reached significance. Although there are similarities between parent and child asthma illness representations, findings indicate that school-aged children develop illness representations somewhat independently from their parents and, therefore, are critical participants in both asthma care and research.

Declines Noted in Cognitive Processes and Association With Achievement Among Children With Leukemia.

PURPOSE/OBJECTIVES: To assess change in specific cognitive processes during treatment with chemotherapy only among children with acute lymphoblastic leukemia (ALL). 
. DESIGN: A prospective, repeated measures design.
. SETTING: Pediatric oncology treatment centers at Banner-University Medical Center Tucson/Banner Children's-Diamond Medical Center (University of Arizona) and Texas Children's Cancer and Hematology centers (Baylor College of Medicine) in Houston. 
. SAMPLE: 71 children with ALL, with a mean age of 6.18 years at the time of diagnosis. 
. METHODS: Using mixed-effects latent growth curve modeling with time since diagnosis as a fixed effect, age-adjusted standardized measures of working memory, processing speed, executive function, and attention were obtained and repeated about one and two years later. A subsample was tested for academic achievement at the end of treatment.
. MAIN RESEARCH VARIABLES: Verbal working memory, visual spatial memory, processing speed, academic achievement, age, and gender. 
. FINDINGS: A significant main effect was observed for age at diagnosis on decline in verbal working memory during treatment. Planned contrasts revealed greater decline among children who were diagnosed when aged younger than five years compared to those diagnosed when aged five years or older. Decline in verbal working memory and achievement in letter-word identification and calculation skills were associated, and decline in spatial memory was associated with calculation. A main effect of gender was observed on processing speed, with female patients showing greater decline than male patients. 
. CONCLUSIONS: Findings from this study may guide the timing of interventions that could improve school achievement among survivors. 
. IMPLICATIONS FOR NURSING: Children undergoing treatment for ALL may experience issues with verbal working memory and increased difficulty in school. Nurses are in a position to refer parents and children to school resources for additional academic support.

Cytosine arabinoside induces programmed endothelial cell death through the caspase-3 pathway.

The anti-cancer effects of cytosine arabinoside (ARA-C) are well known. However, effects on nonmalignant cells have not been elucidated and may be important to understanding treatment-related toxicity. The purpose of this study was to examine the effect of ARA-C on nondividing vascular endothelial cells. The objectives were to determine the effects of ARA-C on cell viability and to ascertain whether ARA-C caused apoptosis in cultured vascular endothelial cells and hydrocortisone blunted caspase-3-induced apoptosis. Endothelial cells were cultured until confluent and mitotically quiescent then exposed to ARA-C (10(-7)to 10(-3) M) for 1 to 4 days. Some experiments involved cotreatment with hydrocortisone (10(-11),10(-10),10(-4), and 10(-3) M). Light microscopy and the colorimetric MTS assay were used to measure viability. Fluorescent annexin-V and DNA fragmentation assays were used to measure apoptosis, and a fluorescence-based enzymatic assay was used to measure caspase-3 activity, which is one pathway involved in the apoptosis cascade. Two-way ANOVA or the appropriate nonparametric test was used to determine statistical significance in studies of viability and apoptosis. Oneway ANOVA was used to determine statistical significance for caspase-3 activity. Viability was decreased with higher concentrations of ARA-C and increased days of treatment. The percentage of apoptotic cells increased with higher concentrations of ARA-C and increased days of treatment. ARA-C-treated samples showed DNA fragmentation, indicative of apoptosis. Caspase-3 activity increased after ARA-C addition; hydrocortisone blunted this increase. ARA-C caused apoptosis in nondividing endothelial cells in culture. Hydrocortisone may protect against ARA-C-induced apoptosis by reducing caspase-3 activity.

Fatigue and Oxidative Stress in Children Undergoing Leukemia Treatment.

Fatigue is a frequent and distressing symptom in children undergoing leukemia treatment; however, little is known about factors influencing this symptom. Antioxidants such as glutathione can decrease symptom severity in adult oncology patients, but no study has evaluated antioxidants' effects on symptoms in pediatric oncology patients. This study describes fatigue patterns and associations of fatigue with antioxidants represented by reduced glutathione (GSH) and the reduced/oxidized glutathione (GSH/GSSG) ratio among children receiving leukemia treatment. A repeated measures design assessed fatigue and antioxidants among 38 children from two large U.S. cancer centers. Fatigue was assessed among school-age children and by parent proxy among young children. Antioxidants (GSH and GSH/GSSG ratio) were assessed from cerebrospinal fluid at four phases during leukemia treatment. Young children had a steady decline of fatigue from the end of induction treatment through the continuation phase of treatment, but no significant changes were noted among the school-age children. Mean antioxidant scores varied slightly over time; however, the GSH/GSSG ratios in these children were significantly lower than the normal ratio. Mean GSH/GSSG ratios significantly correlated to fatigue scores of the school-age children during early phases of treatment. Children with low mean GSH/GSSG ratios demonstrated oxidative stress. The low ratios noted early in therapy were significantly correlated with higher fatigue scores during induction and postinduction treatment phases. This finding suggests that increased oxidative stress during the more intensive phases of therapy may explain the experience of fatigue children report.

Effects of Intraventricular Methotrexate on Neuronal Injury and Gene Expression in a Rat Model: Findings From an Exploratory Study.

Central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia, used to prevent disease recurrence in the brain, is essential for survival. Systemic and intrathecal methotrexate, commonly used for CNS-directed treatment, have been associated with cognitive problems during and after treatment. The cortex, hippocampus, and caudate putamen, important brain regions for learning and memory, may be involved in methotrexate-induced brain injury. Objectives of this study were to (1) quantify neuronal degeneration in selected regions of the cortex, hippocampus, and caudate putamen and (2) measure changes in the expression of genes with known roles in oxidant defense, apoptosis/inflammation, and protection from injury. Male Sprague Dawley rats were administered 2 or 4 mg/kg of methotrexate diluted in artificial cerebrospinal fluid (aCSF) or aCSF only into the left cerebral lateral ventricle. Gene expression changes were measured using customized reverse transcription (RT)(2) polymerase chain reaction arrays. The greatest percentage of degenerating neurons in methotrexate-treated animals was in the medial region of the cortex; percentage of degenerating neurons in the dentate gyrus and cornu ammonis 3 regions of the hippocampus was also greater in rats treated with methotrexate compared to perfusion and vehicle controls. There was a greater percentage of degenerating neurons in the inferior cortex of control versus methotrexate-treated animals. Eight genes involved in protection from injury, oxidant defense, and apoptosis/inflammation were significantly downregulated in different brain regions of methotrexate-treated rats. To our knowledge, this is the first study to investigate methotrexate-induced injury in selected brain regions and gene expression changes using a rat model of intraventricular drug administration.

Neurocognitive Predictors of Academic Outcomes Among Childhood Leukemia Survivors.

BACKGROUND: Acute lymphoblastic leukemia is the most common pediatric cancer, and survival approaches 90%. Acute lymphoblastic leukemia survivors are more likely than healthy peers or siblings to experience academic underachievement, yet little is known about neurocognitive predictors of academic outcomes. OBJECTIVES: Objectives were to compare neurocognitive abilities to age-adjusted standardized norms, examine change over time in neurocognitive abilities, and establish neurocognitive predictors of academic outcomes. METHODS: Seventy-one children were followed over the course of therapy. Cognitive abilities were assessed during induction when the child was in remission (baseline) and annually for 3 years (years 1, 2, and 3). Reading and mathematics abilities were assessed at year 3. RESULTS: Fine motor dexterity was significantly below age-adjusted norms at all data points but showed improvement over time. Baseline visual-motor integration was within the reference range but significantly declined by year 3, and mean scores at years 2 and 3 were significantly below age-adjusted norms. Verbal short-term memory was significantly below age-adjusted norms at all assessments. Visual-motor integration predicted reading and mathematics abilities. Verbal short-term memory predicted reading abilities, and visual short-term memory predicted mathematics abilities. CONCLUSIONS: Central nervous system-directed therapy is associated with specific neurocognitive problems. Visual-spatial skills and verbal and visual short-term memory predict academic outcomes. IMPLICATIONS FOR PRACTICE: Early assessment of visual-spatial perception and short-term memory can identify children at risk of academic problems. Children who are at risk of academic problems could benefit from a school-based individual educational program and/or educational intervention.