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.

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.

Physical Activity, the Childhood Cancer Symptom Cluster-Leukemia, and Cognitive Function: A Longitudinal Mediation Analysis.

BACKGROUND: Children undergoing leukemia treatment report co-occurring symptoms of fatigue, sleep disturbances, pain, nausea, and depression as a symptom cluster. Physical activity (PA) is essential for development and may influence symptom severity. Children with leukemia are at risk of cognitive impairments from central nervous system therapies. Using a longitudinal parallel-process model, relationships among function and symptom clusters were explored. OBJECTIVE: This study examined the longitudinal mediation effects of PA on cognition via a symptom cluster during leukemia treatment. METHODS: Symptoms, PA, and cognitive function of 327 children aged 3 to 18 years were measured over 4 intervals during the first year of leukemia treatment. Children 7 years or older self-reported and parents reported for younger children. Parents completed cognitive function measurements for all children. The influence of the first time point and the subsequent change between all 4 time points of PA on the symptom cluster were explored. Analysis determined whether the symptom cluster mediated the effect of cognition over the treatment period. RESULTS: Patients with a higher PA at time 1 reduced their symptom cluster severity over the measurements. However, when PA increased over the measurements, symptom cluster severity also increased. When the symptom cluster was more severe at time 1, cognitive function was lower at time 1, and cognitive function decreased over time. When symptoms became more severe over time, cognitive function declined. CONCLUSIONS: The symptom cluster acted as a mediator between PA and cognition. IMPLICATIONS FOR PRACTICE: Symptom management during treatment may be an additional strategy for protecting cognitive function.

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.

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.

Symptom Trajectories in Children Receiving Treatment for Leukemia: A Latent Class Growth Analysis With Multitrajectory Modeling.

CONTEXT: Cancer treatment symptoms play a major role in determining the health of children with cancer. Symptom toxicity often results in complications, treatment delays, and therapy dose reductions that can compromise leukemia therapy and jeopardize chances for long-term survival. Critical to understanding symptom experiences during treatment is the need for exploration of "why" inter-individual symptom differences occur; this will determine who may be most susceptible to treatment toxicities. OBJECTIVES: This study examined specific symptom trajectories during the first 18 months of childhood leukemia treatment. Symptom measures included fatigue, sleep disturbances, pain, nausea, and depression. METHODS: Symptom trajectories of 236 children with leukemia three to 18 years old were explored prospectively over four periods: initiation of post-induction therapy, four and eight post-induction therapy, and the last time point was at the beginning of maintenance/continuation therapy. Latent class growth analysis was used to classify patients into distinctive groups with similar symptom trajectories based on patients' response patterns on the symptom measures over time. RESULTS: Three latent classes of symptom trajectories were identified and classified into mild, moderate, and severe symptom trajectories. The only demographic characteristic with a significant relationship to membership in the latent class symptom trajectories was race/ethnicity. All other demographic characteristics including leukemia risk levels showed no significant relationships. CONCLUSION: This study is unique in that groups of patients with similar symptoms were identified rather than groups of symptoms. Further research using latent class growth analysis is needed.

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.

Differences in Transitional Care Provided to Mexican American and Non-Hispanic White Older Adults.

BACKGROUND: Transitional care, assisting patients to move safely through multiple health care settings, may be insufficient for older Hispanic patients. PURPOSE: Describe home health care services referral rates for Hispanic and non-Hispanic White (NHW) patients and factors that influence case managers' (CMs') discharge planning processes. DESIGN: Organized by the Ethno-Cultural Gerontological Nursing Model, health records were reviewed ( n = 33,597 cases) and supplemented with qualitative description ( n = 8 CMs). FINDINGS: Controlling for gender, insurance type, age, and hospital length of stay, NHW older adults received more home health care services referrals (odds ratio = 1.23). Insurance coverage was the most frequent determinant of CMs' post-hospital care choices, rather than patients' being Hispanic. NHW older adults were more likely to have insurance than Hispanic older adults. IMPLICATIONS: Insurance coverage being CMs' primary consideration in determining patients' dispositions is a form of systems-level discrimination for Hispanic vulnerable groups, which combined with other hospital-level constraints, should be addressed with policy-level interventions.

Multifaceted Prospective Memory Intervention to Improve Medication Adherence.

OBJECTIVES: To test whether a multifaceted prospective memory intervention improved adherence to antihypertensive medications and to assess whether executive function and working memory processes moderated the intervention effects. DESIGN: Two-group longitudinal randomized control trial. SETTING: Community. PARTICIPANTS: Individuals aged 65 and older without signs of dementia or symptoms of severe depression who were self-managing prescribed medication. MEASUREMENTS: After 4 weeks of initial adherence monitoring using a medication event monitoring system, individuals with 90% or less adherence were randomly assigned to groups. INTERVENTION: The prospective memory intervention was designed to provide strategies that switch older adults from relying on executive function and working memory processes (that show effects of cognitive aging) to mostly automatic associative processes (that are relatively spared with normal aging) for remembering to take medications. Strategies included establishing a routine, establishing cues strongly associated with medication taking actions, performing the action immediately upon thinking about it, using a medication organizer, and imagining medication taking to enhance encoding and improve cuing. RESULTS: There was significant improvement in adherence in the intervention group (57% at baseline to 78% after the intervention), but most of these gains were lost after 5 months. The control condition started at 68% and was stable during the intervention, but dropped to 62%. Executive function and working memory moderated the intervention effect, with the intervention producing greater benefit for those with lower executive function and working memory. CONCLUSION: The intervention improved adherence, but the benefits were not sustained. Further research is needed to determine how to sustain the substantial initial benefits.

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.

The impact of a telenovela intervention on use of home health care services and Mexican American older adult and caregiver outcomes.

A two-group randomized controlled trial tested a telenovela intervention (i.e., a culturally congruent videotaped dramatization with guided dialogue) to increase Mexican American older adults' and family caregivers' awareness of and confidence in home health care services (HHCS), thereby increasing use of HHCS and improving older adult and caregiver outcomes. Both groups had significant increases in awareness of and confidence in HHCS. The intervention group used HHCS more than the control group (91.1% versus 71.2% of total visits authorized); however, this was not a statistically significant difference (p = 0.18). Use of HHCS was associated with increased older adult and caregiver mutuality (i.e., the quality of the older adult-caregiver relationship) and decreased caregiving burden and depression. The predictive role and measurement of awareness and ways to improve the intervention are discussed. Findings are especially important with today's focus on transitional care to keep older adults at home and prevent unnecessary readmissions.

Recruitment of Older Adults: Success May Be in the Details.

PURPOSE: Describe recruitment strategies used in a randomized clinical trial of a behavioral prospective memory intervention to improve medication adherence for older adults taking antihypertensive medication. RESULTS: Recruitment strategies represent 4 themes: accessing an appropriate population, communication and trust-building, providing comfort and security, and expressing gratitude. Recruitment activities resulted in 276 participants with a mean age of 76.32 years, and study enrollment included 207 women, 69 men, and 54 persons representing ethnic minorities. Recruitment success was linked to cultivating relationships with community-based organizations, face-to-face contact with potential study participants, and providing service (e.g., blood pressure checks) as an access point to eligible participants. Seventy-two percent of potential participants who completed a follow-up call and met eligibility criteria were enrolled in the study. The attrition rate was 14.34%. IMPLICATIONS: The projected increase in the number of older adults intensifies the need to study interventions that improve health outcomes. The challenge is to recruit sufficient numbers of participants who are also representative of older adults to test these interventions. Failing to recruit a sufficient and representative sample can compromise statistical power and the generalizability of study findings.

Oxidative Stress, Motor Abilities, and Behavioral Adjustment in Children Treated for Acute Lymphoblastic Leukemia.

PURPOSE/OBJECTIVES: To examine associations among oxidative stress, fine and visual-motor abilities, and behavioral adjustment in children receiving chemotherapy for acute lymphoblastic leukemia (ALL)
. DESIGN: A prospective, repeated-measures design
. SETTING: Two pediatric oncology settings in the southwestern United States. SAMPLE: 89 children with ALL were followed from diagnosis to the end of chemotherapy. METHODS: Serial cerebrospinal fluid samples were collected during scheduled lumbar punctures and analyzed for oxidative stress biomarkers. Children completed fine motor dexterity, visual processing speed, and visual-motor integration measures at three time points. Parents completed child behavior ratings at the same times. MAIN RESEARCH VARIABLES: Oxidative stress, fine motor dexterity, visual processing, visual-motor integration, and behavioral adjustment
. FINDINGS: Children with ALL had below-average fine motor dexterity, visual processing speed, and visual-motor integration following the induction phase of ALL therapy. By end of therapy, visual processing speed normalized, and fine motor dexterity and visual-motor integration remained below average. Oxidative stress measures correlated with fine motor dexterity and visual-motor integration. Decreased motor functioning was associated with increased hyperactivity and anxiety
. CONCLUSIONS: Oxidative stress occurs following chemo-therapy for childhood ALL and is related to impaired fine motor skills and visual symptoms
. IMPLICATIONS FOR NURSING: Early intervention should be considered to prevent fine motor and visual-spatial deficits, as well as behavioral problems.