Longitudinal investigation of suicidal ideation and associated factors during pediatric acute lymphoblastic leukemia chemotherapy.

OBJECTIVE: This study describes the prevalence of suicidal ideation (SI) during acute lymphoblastic leukemia (ALL) therapy and investigates the influence of clinical factors and physical symptoms on SI. METHODS: The Children's Depressive Inventory (CDI-2) was administered to ALL patients (diagnosed 2012-2017) at start of consolidation, delayed intensification (DI), maintenance cycle 1 (MC1), and maintenance cycle 2 (MC2) in a multi-site study. SI was present if patients endorsed the item "I want to kill myself." Logistic regression models evaluated associations between SI and sociodemographic factors; depressive symptoms; and below average, average, and above average symptom clusters identified using latent class analysis of pain, nausea, fatigue, and sleep. RESULTS: Participants (n = 175) were 51% male, 75% high-/very high-risk disease, with a median age of 11.2 years at diagnosis (range: 7-18 years). Overall, 14.9% of patients (75% under age 12 years) endorsed SI during treatment, including 4% at start of consolidation, 9% at DI, 8% at MC1, and 4% at MC2. Non-Hispanic Other patients were 10.9-times (95% CI: 2.30-53.40) more likely than non-Hispanic Whites to endorse SI (p = 0.003). The frequency of SI was higher in patients experiencing above average (53.3%) compared to below average (4.1%, p = 0.003) symptoms. Depressive symptoms were consistently associated with SI. CONCLUSIONS: SI during the initial year of childhood ALL was more prevalent in children under the age of 12 years, from ethnic groups not typically associated with increased risk, and who endorsed increased physical and depressive symptoms. Findings highlight the need for improved screening of mental health problems to mitigate symptoms of distress.

Association between fatigue and sleep disturbances during treatment for pediatric acute lymphoblastic leukemia and posttreatment neurocognitive performance.

BACKGROUND: Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk of neurocognitive weakness in the areas of attention, executive function, and processing speed. Although fatigue and sleep disturbances are frequent complications of ALL therapy and associated with cognitive functions, the impact of fatigue and sleep profiles during active ALL treatment on posttreatment neurocognitive performance has received limited attention. METHODS: Pediatric patients (n = 120) with ALL (diagnosed 2011-2016) who completed fatigue and sleep questionnaires at four time points during active treatment were enrolled in a study of neurocognitive performance. Latent class growth analysis identified subgroups of patients with similar sleep and fatigue profiles during treatment. Neurocognitive performance collected >6 months post treatment on 40 participants was compared between latent classes using multivariable linear regression models. RESULTS: Participants (57.5% male and 79.1% Hispanic or non-Hispanic White) were classified into one of two fatigue and sleep profiles: Class 1 characterized by mild fatigue and sleep disturbances during treatment (50.8%), and Class 2 characterized by higher levels of fatigue and sleep disturbances (49.2%). Posttreatment cognitive performance was in the normal range for most measures, but significantly below normative means for executive function, verbal short-term memory, attention, and distractability measures. Compared to Class 1, Class 2 demonstrated significantly (p < .05) poorer posttreatment neurocognitive performance, particularly in measures of attention. CONCLUSIONS: Our findings indicate that fatigue and sleep disturbances during the first year of pediatric ALL therapy may impact long-term neurocognitive performance. Sleep and fatigue may be targets for intervention to preserve cognitive functioning in survivors.

Influence of age at seizure onset on the acquisition of neurodevelopmental skills in an SCN8A cohort.

OBJECTIVE: To characterize a cohort of patients with SCN8A-related epilepsy and to perform analyses to identify correlations involving the acquisition of neurodevelopmental skills. METHODS: We analyzed patient data (n = 91) submitted to an online registry tailored to characteristics of children with SCN8A variants. Participants provided information on the history of their child's seizures, medications, comorbidities, and developmental skills based on the Denver II items. Spearman rank tests were utilized to test for correlations among a variety of aspects of seizures, medications, and neurodevelopmental progression. RESULTS: The 91 participants carried 71 missense variants (41 newly reported) and three truncating variants. Ages at seizure onset ranged from birth to >12 months of age (mean ± SD = 5 months 21 days ± 7 months 14 days). Multiple seizure types with multimodal onset times and developmental delay were observed as general features of this cohort. We found a positive correlation between a developmental score based upon percentage of acquired skills and the age at seizure onset, current seizure freedom, and initial febrile seizures. Analyses of cohort subgroups revealed clear distinctions between patients who had a single reported variant in SCN8A and those with an additional variant reported in a gene other than SCN8A, as well as between patients with different patterns of regression before and at seizure onset. SIGNIFICANCE: This is the first study of an SCN8A patient cohort of this size and for which correlations between age at seizure onset and neurodevelopment were investigated. Our correlation studies suggest that variants of uncertain significance should be considered in assessing children with SCN8A-related disorders. This study substantially improves the characterization of this patient population and our understanding of the neurodevelopmental effects associated with seizures for SCN8A patients, and provides a clinical context at initial presentation that may be prognostic for developmental outcome.

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.

Symptoms, Physical Activity, and Biomarkers in Children at the End of Leukemia Maintenance Therapy.

Background: Symptoms in children with acute lymphocytic leukemia (ALL) change over the trajectory of treatment but little is known about their symptoms as treatment ends. Physical activity may help decrease symptom distress and is vital for ongoing development. The role of biomarkers in symptom science is emerging. The purpose of the study was to explore relationships between self-report of symptoms and physical activity, actigraphy measures, and cerebrospinal fluid (CSF) biomarkers. Methods: Participants were children who were ages 3 to 18 years at the time of ALL diagnosis and were now in the last 12-week cycle of ALL maintenance. Self-reports of fatigue, sleep disturbance, depressive symptoms, and physical activity were completed by participants and parents of younger children. Participants wore a wrist actigraph continuously for the 7 days before other measurements. F2-isoprostanes and interleukin-8 were evaluated in CSF samples. Results: Among the 15 participants, self-report of symptoms and physical activity indicated levels similar to healthy peers. F2-isoprostane had a strong positive correlation with fatigue levels and with depressive symptoms. Fatigue, sleep disturbance, and depressive symptoms positively correlated with each other. Actigraph measures showed children met the CDC guidelines for 60 min of daily moderate to vigorous activity; sleep time was slightly less than healthy norms. Discussion: During maintenance therapy, most children return to healthy norms in symptom burden and physical activity. F2-isoprostane in the CSF is a biomarker for fatigue and depressive symptoms. Children who had persistent symptoms experienced them as a cluster, which confirms previous symptom cluster research.

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.

The Longitudinal Parallel Process Analysis of Biomarkers of Oxidative Stress, Symptom Clusters, and Cognitive Function in Children With Leukemia.

Background: During treatment for acute lymphoblastic leukemia (ALL), children report co-occurring symptoms of fatigue, sleep disturbance, pain, nausea, and depression as a symptom cluster. Central nervous system-directed ALL therapies also put children at risk for cognitive impairments. Cancer therapies can cause an increase in oxidative stress, which may contribute to treatment-related symptoms. This study examined the longitudinal relationships between biomarkers of oxidative stress in the cerebrospinal fluid, the Childhood Cancer Symptom Cluster-Leukemia (CCSC-L), and cognition, in children over the first year of ALL treatment. Methods: Glutathione (GSH) biomarkers of oxidative stress were measured in cerebrospinal fluid collected during treatment lumbar punctures. GSH biomarkers, symptoms, and cognitive function of 132 children aged 3 to 18 years were evaluated at four time points during the first year of leukemia treatment. Participants, 7 years and older, completed self-report measures, and parents reported for younger children. Cognitive function measurements for all participants were completed by parents. A longitudinal parallel-process model was used to explore the influence of the initial measurement and the subsequent change over four time points of the GSH biomarkers on the CCSC-L and cognition. Results: GSH biomarkers increased over the four time points indicating decreasing oxidative stress. When GSH biomarkers were higher (less oxidative stress) at the initial measurement, the CCSC-L severity was lower, cognition was better, and cognition improved over the four measurements. Screening children for high levels of oxidative stress would be a foundation for future intervention studies to address symptom distress and cognitive impairments.

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.

Influence of Inflammatory and Oxidative Stress Pathways on Longitudinal Symptom Experiences in Children With Leukemia.

PURPOSE: The purpose of this study was to explore the influence of oxidative stress (F2-isoprostanes) and inflammatory (interleukin [IL]-8) biomarkers on symptom trajectories during the first 18 months of childhood leukemia treatment. METHOD: A repeated-measures design was used to evaluate symptoms experienced by 218 children during treatment. A symptom cluster (fatigue, pain, and nausea) was explored over four time periods: initiation of post-induction therapy, 4 and 8 months into post-induction therapy, and the beginning of maintenance therapy (12 months postinduction). F2-isoprostanes and IL-8 were evaluated in cerebrospinal fluid (CSF) samples collected at baseline (diagnosis) and then at the four time periods. The longitudinal relationships of these biomarkers with the symptom cluster were examined using the longitudinal parallel process. RESULTS: Pain and fatigue levels were highest during the post-induction phases of treatment and decreased slightly during maintenance therapy, while nausea scores were relatively stable. Even in the later phases of treatment, children continued to experience symptoms. CSF levels of the biomarkers increased during the post-induction phases of treatment. Early increases in the biomarkers were associated with more severe symptoms during the same period; patients who had increased biomarkers over time also experienced more severe symptoms over time. CONCLUSIONS: Findings reveal that children experienced symptoms throughout the course of leukemia treatment and support hypothesized longitudinal relationships of oxidative stress and inflammatory biomarkers with symptom severity. Activation of the biomarker pathways during treatment may explain underlying mechanisms of symptom experiences and identify which children are at risk for severe symptoms.

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.