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.

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.

Managing painful procedures in children with cancer.

Children with cancer experience repeated invasive and painful medical procedures. Pain and distress does not decrease with repeated procedures and may worsen if pain is not adequately managed. In 1990, the first recommendations on the management of pain and anxiety associated with procedures for children with cancer were published. Guiding principles described in the recommendations continue to hold true today: maximize comfort and minimize pain, use nonpharmacologic and pharmacologic interventions, prepare the child and family, consider the developmental age of the child, support family and child involvement, assure provider competency in performing procedures and sedation, and use appropriate monitoring to assure safety. This article reviews these key components for managing painful procedures in children and reviews the latest pharmacological and nonpharmacological interventions most effective in minimizing pain and discomfort.

Carnitine plasma levels and fatigue in children/adolescents receiving cisplatin, ifosfamide, or doxorubicin.

Fatigue is the most frequent symptom experienced by children/adolescents with cancer. One mechanism contributing to cancer-related fatigue involves abnormalities in adenosine triphosphate synthesis caused by carnitine deficiency. The purpose of this study was to examine fatigue and carnitine in children/adolescents before and after ifosfamide, cisplatin, or doxorubicin chemotherapy. Sixty-seven patients from 2 children's cancer centers participated. Fatigue and carnitine measures were obtained before chemotherapy and a week later. Newly diagnosed children/adolescents had significantly higher free (P=0.018) and total carnitine levels (P=0.017) compared with those who received prior chemotherapy. There was a significant increase in free and total carnitine levels after treatment for patients receiving doxorubicin than patients receiving cisplatin or ifosfamide. Increased fatigue and decreased carnitine were significantly correlated a week after chemotherapy in children/adolescents who had received prior chemotherapy. Increased carnitine in newly diagnosed patients is likely associated with rapid tissue release into the bloodstream, replacing carnitine lost by chemotherapy metabolism. Decreased carnitine and increased fatigue occurred after 1 to 2 courses of chemotherapy. This study provides support for a relationship between carnitine and fatigue in children/adolescents with cancer.

Intensity, location, and quality of pain in Spanish-speaking children with cancer.

Spanish speaking children with cancer were asked to describe their pain during the previous week prior to an oncology clinic appointment. Data showed that 41% of the children were experiencing pain and the overall mean pain intensity rating among these children was 5.7 +/- 2.7. Among those children with moderate to severe pain, the most frequently marked locations on the body outline diagram was the abdomen (53.8%), lower back (46.2%), and upper chest (30.8%). The higher percentage of children complaining of abdominal pain may be attributed to the high percentage (63.6%) of children reporting oral chemotherapy at home. Some children experienced pain that was unrecognized and undetected, and therefore were not receiving medications. To minimize the risk of under-treatment of pain, children and parents may be taught to use the Spanish version of the Adolescent Pediatric Pain Tool to communicate the child's pain to clinicians.

Clinical field testing of an enhanced-activity intervention in hospitalized children with cancer.

This prospective, two-site, randomized, controlled pilot study assessed the feasibility of an enhanced physical activity (EPA) intervention in hospitalized children and adolescents receiving treatment for a solid tumor or for acute myeloid leukemia (AML), and assessed different statistical techniques to detect the intervention's sleep and fatigue outcomes. Twenty-nine patients (25 with a solid tumor and 4 with AML) participated. Data were collected from actigraph; patient, parent, and staff nurse reports of patient fatigue; parent sleep diaries; and patient charts. The intervention was successfully implemented 85.4% of the scheduled times. We used two different statistical methods to analyze the longitudinal data. Using an ANOVA model, sleep was significantly more efficient in the experimental arm than in the control arm when daily differences from baseline sleep efficiency values were averaged and compared (F=4.17, P=0.053). However, in a mixed model (repeated measures) analysis, sleep duration (F=0.54, P=0.47) and sleep efficiency (F=0.04, P=0.85) were not seen to differ between study arms. We conclude that an inpatient intervention of EPA can be delivered to children and adolescents receiving chemotherapy. Our findings identify design and statistical considerations for a future effectiveness study of the EPA intervention in hospitalized pediatric oncology patients.

Trajectories of Obesity and Overweight Rates Among Survivors of Childhood Acute Lymphoblastic Leukemia.

PURPOSE/OBJECTIVES: To describe the trajectories of obesity/overweight rates by age group among survivors of childhood acute lymphoblastic leukemia (ALL) from diagnosis through several years post-therapy. DESIGN: Longitudinal, descriptive. SETTING: Hematology/oncology clinic in the southwestern United States. SAMPLE: 62 child and adolescent ALL survivors receiving treatment and follow-up care from 1999-2013. METHODS: Retrospective chart review of height, weight, and body mass index. MAIN RESEARCH VARIABLES: Annual obesity/overweight rates and developmental age groups. FINDINGS: Different trajectories of obesity/overweight rates existed among age groups. Forty-seven percent of adolescents met the Centers for Disease Control and Prevention criteria for obesity/overweight status at some point following diagnosis, compared to 68% of school-age and 73% of preschool children. Preschool children demonstrated the most rapid rate increase following diagnosis, with a particularly susceptible period in the years immediately following therapy. Obesity/overweight persistence was most characteristic of school-age children. CONCLUSIONS: Important variations in rate and pattern of weight status trajectories exist by age group, demonstrating that children diagnosed with ALL during the preschool and school-age developmental years have the greatest vulnerability of developing obesity/overweight status. IMPLICATIONS FOR NURSING: Obesity/overweight prevention efforts are greatly needed in children with ALL, and efforts should occur before ALL treatment completion in preschool and school-age children.

Evaluation of Biomarkers of Oxidative Stress and Apoptosis in Patients With Severe Methotrexate Neurotoxicity: A Case Series.

Central nervous system (CNS) treatment is an essential part of acute lymphocytic leukemia (ALL) therapy, and the most common CNS treatment is intrathecal (IT) and high-dose intravenous (IV) methotrexate (MTX). Treatment with MTX may cause neurotoxicity, which is often accompanied by neurologic changes, delays in treatment, and prolonged hospital stays. This article reports clinical presentations of 3 patients with severe MTX toxicity as well as levels of oxidative stress and apoptosis biomarkers in cerebrospinal fluid (CSF). Oxidative stress was measured by oxidized phosphatidylcholine (PC), oxidized phosphatidylinositol (PI), and F2 isoprostanes; apoptosis was measured by caspase 3/7 activity. Most consistent biomarker changes in all 3 cases were increases in caspase 3/7 and F2 isoprostanes prior to acute toxicity while increases in oxidized phospholipids occurred slightly later. Progressive increases in F2 isoprostanes and caspase 3/7 activity prior to and/or during acute toxicity suggests MTX induces oxidative stress and an associated increase in apoptosis. These findings support the role of oxidative stress in MTX-related neurotoxicity.

F2-isoprostanes: a measure of oxidative stress in children receiving treatment for leukemia.

Acute lymphoblastic leukemia (ALL) is the most prevalent and curable cancer among children and adolescents less than 15 years of age in the United States. Essential for cure of childhood ALL is prophylactic treatment of the central nervous system (CNS), with methotrexate (MTX) being the most widely used drug in this treatment. While CNS treatment has contributed to long-term disease-free survival, resulting declines in academic abilities have been reported. There is growing evidence that CNS treatment with MTX increases oxidative stress, a potential mechanism of CNS injury. This article reports changes in oxidative stress, measured by the biomarker F2-isoprostane (F2-IsoP), in the cerebrospinal fluid (CSF) in 47 children with ALL during the first 18 months of treatment. The number of CSF samples ranged from 5 to 14 during postinduction and from 1 to 9 during continuation. Total doses of intrathecal MTX during postinduction were significantly correlated with the mean and highest concentrations of F2-IsoP during postinduction and the mean concentration of F2-IsoP during continuation. F2-IsoP concentrations during postinduction and continuation were higher in children who received more than six doses of intrathecal MTX. New therapies for a highly curable disease such as childhood leukemia have the potential to be individualized in the future, requiring reliable molecular and biochemical markers, such as oxidative stress indicators. Innovative use of biomarkers has the potential to increase our understanding of treatment-related toxicities and associated symptoms and to inform future therapeutic approaches for optimizing cure and quality of life among children with leukemia.

The influence of oxidative stress on symptom occurrence, severity, and distress during childhood leukemia treatment.

PURPOSE/OBJECTIVES: To explore the symptom trajectory during the first 16 months of childhood leukemia treatment and any associations with the oxidative stress pathway measured by cerebrospinal fluid (CSF) concentration of oxidized phosphatidylcholine (PC), the predominant glycerophospholipid in the brain and cell membranes. DESIGN: Prospective, longitudinal design. SETTING: Two cancer centers in the southwestern United States. SAMPLE: 36 children (aged 3-14 years) newly diagnosed with acute lymphoblastic leukemia. METHODS: Symptoms were measured using the Memorial Symptom Assessment Scale at six specific time points during treatment. Biochemical changes in oxidative stress were measured by oxidized PC in the CSF. MAIN RESEARCH VARIABLES: Childhood cancer symptoms, oxidized PC. FINDINGS: Significant differences were found in the number of symptoms experienced during the three phases of treatment. Symptom trajectory changes and influence of the oxidative stress pathway on symptom experiences were identified. CONCLUSIONS: Symptoms experienced during treatment for childhood leukemia are associated with increased oxidative stress. IMPLICATIONS FOR NURSING: Children with leukemia experience symptoms throughout treatment. Physiologic measures indicate the influence of oxidative stress on symptoms.

An outpatient Urgent Care Bay within a pediatric cancer and hematology center.

Time-sensitive medical care is essential for pediatric patients undergoing treatment for a hematologic or oncologic condition. Such patients commonly experience acute symptoms related to routine childhood illness and/or their underlying disease or therapy. An Urgent Care Bay (UCB) staffed by a designated nurse and medical provider was established within Texas Children's Cancer Center Outpatient Clinic to provide time-sensitive, same-day diagnostic and therapeutic medical care during clinic hours for patients with acute, non-life-threatening symptoms. The number of patients seen in UCB, chief complaint, underlying diagnosis, and disposition was reviewed. To establish timeliness of care, the authors reviewed the time of referral to the UCB provider or nurse, time of arrival to UCB, time evaluated by providers, and time of initiation of treatment. The addition of an UCB to Texas Children's Cancer Center Outpatient Clinic has shown to allow for rapid assessment and initiation of treatment while avoiding unnecessary emergency room care.

Using improvement science to promote evidence-based practice in a childhood cancer and hematology center.

A major children's cancer and hematology center established a Quality Transformation (QT) Core to develop and monitor empirical outcomes that demonstrate excellence in clinical care. The QT Core, based on the Institute of Medicine's domains of quality health care, aims to ensure that care is safe, effective, patient centered, timely, efficient, and equitable. Specific goals for the first year of the QT Core were to develop a team of improvement science experts, engage faculty and staff in QT initiatives, promote accountability for excellence in clinical care, and establish specific metrics to evaluate process, structure, and outcomes for QT Core projects. The purpose of this article is to discuss the successful development of a quality transformation core within a pediatric subspecialty and demonstrate the principles of improvement science through an actual quality transformation project designed to implement an evidence-based guideline for procedural sedation for children with cancer. The QT Core within this subspecialty was founded on principles of successful transformation of patient care that includes motivation to change, leaders committed to quality, active engagement of staff in meaningful problem-solving initiatives, alignment with organization goals with resource allocation, and integration to bridge boundaries throughout an organization. These key principles are demonstrated through the discussion of the development of the QT Core and implementation of an evidence-based procedure sedation guideline. Pediatric and pediatric subspecialty groups can be on the forefront of national initiatives that promote quality health care, exemplified by the QT Core developed within the cancer and hematology center.

Sickness behavior clustering in children with cancer.

Despite knowing that pediatric cancer patients experience multiple concurrent symptoms, most research focuses on individual symptoms. This study is a secondary data analysis from previous research evaluating symptom clusters and carnitine plasma levels in 67 children and adolescents aged between 7 and 18 years, before and after receiving ifosfamide, doxorubicin, or cisplatin chemotherapy. In preparation for cluster analysis, fatigue, nausea and vomiting, depression, and performance status symptoms were rated in categories of none, mild, moderate, or severe. A conceptual approach was used to evaluate the identification of unique patterns of symptoms that cluster as well as what subgroup members of pediatric oncology patients assemble together. Comparison of symptoms is made with the recent literature on sickness behavior symptoms. The hierarchical agglomerative cluster analysis was used to identify and classify variables into groups based on similarities they possess. This cluster analysis increases awareness of sickness behavior symptoms, patterns, interaction, and synergy. Increasing knowledge of the complex symptom experiences of pediatric oncology patients provides the scientific basis for new directions in symptom intervention.

Improving care for children with sickle cell disease/acute chest syndrome.

BACKGROUND: Acute chest syndrome (ACS) is a leading cause of hospitalization and death of children with sickle cell disease (SCD). An evidence-based ACS/SCD guideline was established to standardize care throughout the institution in February 2008. However, by the summer of 2009 use of the guideline was inconsistent, and did not seem to have an impact on length of stay. As a result, an implementation program was developed. OBJECTIVE: This quality-improvement project evaluated the influence of the development and implementation of a clinical practice guideline for children with SCD with ACS or at risk for ACS on clinical outcomes. METHODS: Clinical outcomes of 139 patients with SCD were evaluated before and after the development of the implementation program. Outcomes included average length of stay, number of exchange transfusions, average cost per SCD admission, and documentation of the clinical respiratory score and pulmonary interventions. RESULTS: Average length of stay decreased from 5.8 days before implementation of the guideline to 4.1 days after implementation (P = .033). No patients required an exchange transfusion. Average cost per SCD admission decreased from $30 359 before guideline implementation to $22 368. Documentation of the clinical respiratory score increased from 31.0% before implementation to 75.5%, which is an improvement of 44.5% (P < .001). Documentation of incentive spirometry and positive expiratory pressure increased from 23.3% before implementation to 50.4%, which is an improvement of 27.1% (P < .001). CONCLUSIONS: Implementation of a guideline for children with SCD with ACS or at risk for ACS improved outcomes for patients with SCD.

Symptom clusters in children and adolescents receiving cisplatin, doxorubicin, or ifosfamide.

PURPOSE/OBJECTIVES: To examine the influence of the proposed symptom cluster of fatigue, nausea and vomiting, and sleep disturbances on clinical outcomes defined as behavior changes, depression, and performance status in children and adolescents before and after receiving cisplatin, doxorubicin, or ifosfamide chemotherapy. DESIGN: A prospective, descriptive, within-group, before-and-after-chemotherapy design was used. SETTING: Two major childhood cancer treatment hospitals in the United States. SAMPLE: 67 patients aged 7-18 years who were receiving chemotherapy courses of cisplatin, doxorubicin, or ifosfamide. METHODS: Fatigue, depression, behavior, and performance assessments were completed on the first day of cisplatin, doxorubicin, or ifosfamide therapy and one week later. Patients wore a wrist actigraph on the nondominant hand during the course of therapy and for 48 hours after discharge from the hospital. Nausea and vomiting were measured every 24 hours during the course of therapy and for 48 hours after discharge. A linear mixed model was used to evaluate the influence of the symptom cluster. Regression analysis was used to examine the associations between performance status and the symptom cluster. Principal component analysis with varimax rotation was used to produce the correlation of sleep symptoms. MAIN RESEARCH VARIABLES: Fatigue, nausea and vomiting, sleep disturbances, behavior, depression, and performance. FINDINGS: Adolescents with the cluster of increased fatigue and sleep disturbances experienced more depressive symptoms and behavior changes. Children with higher levels of fatigue had increased depressive symptoms. The more fatigue parents perceived in their children or adolescents, the more behavior and emotional difficulties were reported. CONCLUSIONS: Fatigue, sleep disturbance, and nausea and vomiting, when clustered, impacted depressive symptoms and behavior changes in adolescents after chemotherapy. In children, fatigue alone impacted depressive symptoms and behavior changes. IMPLICATIONS FOR NURSING: Symptom clusters can have a significant impact on children's and adolescents' quality of life during cancer treatment. Early recognition and intervention for these symptoms are an important nursing role.

Nocturnal awakenings, sleep environment interruptions, and fatigue in hospitalized children with cancer.

PURPOSE/OBJECTIVES: To describe nocturnal awakenings and sleep environment interruptions experienced by children and adolescents hospitalized for two to four days to receive chemotherapy and to assess the relationships among nocturnal awakenings, sleep environment interruptions, sleep duration, and fatigue. DESIGN: Longitudinal, descriptive design. SETTING: St. Jude Children's Research Hospital and Texas Children's Cancer Center. SAMPLE: 25 patients with solid tumors and 4 with acute myeloid leukemia. METHODS: Actigraphy, fatigue instruments, sleep diary, room entry and exit checklists, and blood samples. MAIN RESEARCH VARIABLES: Nocturnal awakenings, sleep environment interruptions, sleep duration, and fatigue. FINDINGS: The number of nocturnal awakenings per night as measured by actigraphy ranged from 0-40. The number of room entries and exits by a staff member or parent was 3-22 times per eight-hour night shift. The number of nocturnal awakenings was related to fatigue by patient report; patients who experienced 20 or more awakenings had significantly higher fatigue scores than those with fewer awakenings. Nocturnal awakenings also were significantly associated with sleep duration by patient and parent report. CONCLUSIONS: Hospitalized pediatric patients with cancer who experience more nocturnal awakenings are more fatigued and sleep longer. IMPLICATIONS FOR NURSING: Nurses may be able to control some of the factors that contribute to nocturnal awakenings and sleep environment interruptions that affect fatigue and sleep duration in hospitalized pediatric patients with cancer.

Dexamethasone alters sleep and fatigue in pediatric patients with acute lymphoblastic leukemia.

BACKGROUND: Dexamethasone improves the cure rate of childhood acute lymphoblastic leukemia (ALL) but causes physical and behavioral adverse events. The objective of the current study was to determine the effect of dexamethasone exposure on sleep and fatigue in pediatric patients with ALL. METHODS: One hundred pediatric patients with low-risk or standard-risk ALL were enrolled on 1 of 3 protocols (St. Jude Total XV, Children's Oncology Group [COG] 9904, or COG 9905) at 3 institutions. The mean age of the cohort was 9.24 +/- 3.23 years (range, 5.03-18.14 years). The majority of patients were white (79%) males (62%) with standard-risk ALL (63%). The cohort was divided into 4 subgroups: St. Jude low-risk, St. Jude standard-risk, COG low-risk, and COG standard-risk. Patients wore a wrist actigraph to monitor sleep activity during 2 consecutive 5-day periods: During the first period, they did not receive dexamethasone; and, during the second period, they did. Patients and their parents completed fatigue instruments on Days 2 and 5 of each period, and parents completed sleep diaries. RESULTS: Actual sleep minutes, sleep duration, total daily nap minutes, and fatigue increased significantly during the dexamethasone treatment for 3 to 4 of the subgroups. Total daily nap minutes increased significantly for both standard-risk groups during the dexamethasone treatment. Parents reported significant increases in their child's nighttime awakenings, restless sleep, and nap time during dexamethasone treatment. CONCLUSIONS: Dexamethasone treatment during continuation therapy for childhood ALL significantly and adversely altered sleep and fatigue, confirming that sleep and fatigue are behavioral responses to dexamethasone.