Assessment of proxy-reported responses as predictors of motor and sensory peripheral neuropathy in children with B-lymphoblastic leukemia.

Chemotherapy-induced peripheral neuropathy (CIPN), a common condition in children with acute lymphoblastic leukemia, can be challenging to diagnose. Using data from Children's Oncology Group AALL0932 physical function study, we sought to determine if parent/guardian proxy-reported responses from the Pediatric Outcomes Data Collection Instrument could identify children with motor or sensory CIPN diagnosed by physical/occupational therapists (PT/OT). Four variables moderately discriminated between children with and without motor CIPN (c-index 0.76, 95% confidence interval [CI]: 0.64-0.84), but sensory and optimism-corrected models had weak discrimination (c-index sensory models 0.65, 95% CI: 0.54-0.74). New proxy-report measures are needed to identify children with PT/OT diagnosed CIPN.

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.

Prospective patient-reported symptom profiles associated with pediatric acute lymphoblastic leukemia relapse.

PURPOSE: Despite improvements in frontline pediatric acute lymphoblastic leukemia (ALL) treatment, relapse remains a concern. Research in adult cancer patients suggests that patient-reported symptoms may predict survival, but the relationship between symptoms and relapse for pediatric ALL has received little attention. METHODS: Pediatric patients with ALL (age 2-18 years) and/or their primary caregivers completed symptom surveys at the end of induction, start of delayed intensification (DI), start of maintenance cycle 1 (MC1), and start of maintenance cycle 2 (MC2). Symptom clusters for co-occurring fatigue, pain, sleep disruptions, and nausea were defined using latent profile analysis. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between symptom clusters, individual symptoms, and subsequent relapse were calculated using multivariable Cox proportional hazards models, adjusting for clinical and demographic factors. RESULTS: Eligible patients (n = 208) were followed an average of 2.6 years for the incidence of relapse (n = 22). Associations between relapse and symptoms were identified for fatigue at DI (HR = 1.83, 95%CI 1.23-2.73) and MC1 (HR = 2.14, 95%CI 1.62-2.84), pain at DI (HR = 1.80, 95%CI 1.19-2.72), nausea at the end of induction (HR = 1.19, 95%CI 1.01-1.39), and sleep disturbances at the end of induction (HR = 2.00, 95%CI 1.11-3.62), DI (HR = 1.73, 95%CI 1.01-2.96), and MC1 (HR = 2.19, 95%CI 1.10-4.35). Symptom clusters comprised of individuals with a higher average symptom burden at DI were significantly (p < 0.05) associated with relapse. CONCLUSION: Patient-reported symptoms may provide prognostic information to aid in the identification of pediatric ALL patients at increased risk of relapse.

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.

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.

Symptom Clusters, Physical Activity, and Quality of Life: A Latent Class Analysis of Children During Maintenance Therapy for Leukemia.

BACKGROUND: Children undergoing treatment for acute lymphocytic leukemia (ALL) report co-occurring symptoms of fatigue, sleep disturbances, and depression as a symptom cluster. Physical activity (PA) may influence symptom severity and quality of life (QOL). OBJECTIVES: This study examined changes in symptoms and QOL during ALL maintenance in children categorized by symptom cluster and explored the influence of PA and symptoms on QOL. METHODS: Self-report of fatigue, sleep disturbance, and depression; QOL; and PA were measured at the beginning and end of maintenance in 42 children aged 3 to 18 years with ALL. Children were categorized into symptom cluster groups based on measurements at the beginning of maintenance. RESULTS: Two latent classes of symptom clusters (low and high) were identified with significant differences between groups in symptoms at both the beginning and end maintenance (P < .01). Each group's symptom levels did not change during maintenance. Quality-of-life was different between groups at both time points (P < .01) and did not improve. Children with low symptoms and high PA at the beginning of maintenance had better QOL as treatment ended compared with the physically active high-symptom group and the inactive high-symptom group (P < .01). CONCLUSIONS: Children with higher symptoms did not experience an improvement with time. Symptom and PA levels may influence QOL at the end of treatment. IMPLICATIONS FOR PRACTICE: Maintenance therapy is a long time (1.5 years) in a child's life. Symptom assessment is needed early in maintenance; interventions are needed for children with high levels.

Persistence of Chemotherapy-Induced Peripheral Neuropathy Despite Vincristine Reduction in Childhood B-Acute Lymphoblastic Leukemia.

BACKGROUND: Children with B-acute lymphoblastic leukemia (B-ALL) are at risk for chemotherapy-induced peripheral neuropathy (CIPN). Children's Oncology Group AALL0932 randomized reduction in vincristine and dexamethasone (every 4 weeks vs 12 weeks during maintenance in the average-risk subset of National Cancer Institute standard-B-ALL (SR AR B-ALL). We longitudinally measured CIPN, overall and by treatment group. METHODS: AALL0932 standard-B-ALL patients aged 3 years and older were evaluated at T1-T4 (end consolidation, maintenance month 1, maintenance month 18, 12 months posttherapy). Physical and occupational therapists (PT/OT) measured motor CIPN (hand and ankle strength, dorsiflexion and plantarflexion range of motion), sensory CIPN (finger and toe vibration and touch), function (dexterity [Purdue Pegboard], and walking efficiency [Six-Minute Walk]). Proxy-reported function (Pediatric Outcome Data Collection Instrument) and quality of life (Pediatric Quality of Life Inventory) were assessed. Age- and sex-matched z scores and proportion impaired were measured longitudinally and compared between groups. RESULTS: Consent and data were obtained from 150 participants (mean age = 5.1 years [SD = 1.7], 48.7% female). Among participants with completed evaluations, 81.8% had CIPN at T1 (74.5% motor, 34.1% sensory). When examining severity of PT/OT outcomes, only handgrip strength (P < .001) and walking efficiency (P = .02) improved from T1-T4, and only dorsiflexion range of motion (46.7% vs 14.7%; P = .008) and handgrip strength (22.2% vs 37.1%; P = .03) differed in vincristine and dexamethasone every 4 weeks vs vincristine and dexamethasone 12 weeks at T4. Proxy-reported outcomes improved from T1 to T4 (P < .001), and most did not differ between groups. CONCLUSIONS: CIPN is prevalent early in B-ALL therapy and persists at least 12 months posttherapy. Most outcomes did not differ between treatment groups despite reduction in vincristine frequency. Children with B-ALL should be monitored for CIPN, even with reduced vincristine frequency.

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.

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.

Cerebrospinal Fluid Metabolomic Profiles Associated With Fatigue During Treatment for Pediatric Acute Lymphoblastic Leukemia.

CONTEXT: Cancer-related fatigue (CRF) is one of the most distressing and persistent symptoms reported during pediatric acute lymphoblastic leukemia (ALL) therapy; however, information on the pathways underlying CRF severity is limited. OBJECTIVES: We conducted global metabolomics profiling of cerebrospinal fluid (CSF) samples to provide insight into the underlying mechanisms of CRF. METHODS: Fatigue in pediatric ALL patients (2012-2017) was assessed during postinduction therapy approximately six months after diagnosis. Postinduction CSF was collected from 171 participants, comprising discovery (n = 86) and replication (n = 85) cohorts. We also conducted secondary validation using diagnostic CSF from 48 replication cohort participants. CSF metabolomic profiling was performed using gas chromatography-mass spectrometry (MS) and liquid chromatography-MS/MS. Kendall's rank correlation was used to evaluate associations between metabolite abundance and CRF. False discovery rate was used to account for multiple comparisons. RESULTS: Participants were 56% males and 59% Hispanic with a mean age at diagnosis of 8.5 years. A total of 274 CSF-derived metabolites were common to the discovery and replication cohorts. Eight metabolites were significantly associated with fatigue in the discovery cohort (P < 0.05), of which three were significant in the replication cohort, including false discovery rate-corrected associations with gamma-glutamylglutamine (Pcombined = 6.2E-6) and asparagine (Pcombined = 3.5E-4). Notably, the abundance of gamma-glutamylglutamine in diagnostic CSF samples was also significantly associated with fatigue (P = 0.0062). CONCLUSION: The metabolites identified in our assessment have been implicated in neurotransmitter transportation and glutathione recycling, suggesting that glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF. This information could inform targeted therapies for reducing CRF in at-risk individuals.

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.

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.

Improving Transitional Care: The Role of Handoffs and Discharge Checklists in Hematologic Malignancies.

BACKGROUND: Transitional care from inpatient to outpatient settings is a high-risk time for medical errors and missed follow-up appointments. Discharge checklists and handoffs are effective tools that lead to improved quality of care and outcomes. OBJECTIVES: The purpose of this project was to implement an evidence-based discharge checklist and handoff template to improve and standardize transitional care from hospital to home for patients with hematologic malignancies. METHODS: The advanced practice providers (APPs) completed the discharge checklist at least 24 hours prior to discharge. The APPs requested appointments through the electronic health record using the discharge handoff tool. Chi-square analysis and descriptive statistics were used to analyze the data. FINDINGS: Implementation of the discharge checklist resulted in a statistically significant increase in the number of patients who had a follow-up appointment scheduled prior to discharge. The discharge handoff tool standardized communication between inpatient and outpatient providers.

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.

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.

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.

Disparities in Neurotoxicity Risk and Outcomes among Pediatric Acute Lymphoblastic Leukemia Patients.

Purpose: Methotrexate chemotherapy can be associated with neurologic complications during therapy and long-term neurologic deficits. This study evaluated demographic and clinical factors associated with incidence of methotrexate neurotoxicity and described the impact of neurotoxicity on acute lymphoblastic leukemia (ALL) therapy in pediatric patients.Experimental Design: Patients were enrolled between 2012 and 2017 from three pediatric cancer treatment centers in the United States. Medical records for suspected cases of methotrexate neurotoxicity, defined as an acute neurologic event following methotrexate therapy, were reviewed. Cox proportional hazards models were used to estimate the association between race/ethnicity and methotrexate neurotoxicity. Multivariable linear regression models compared treatment outcomes between patients with and without methotrexate neurotoxicity.Results: Of the 280 newly diagnosed patients enrolled, 39 patients (13.9%) experienced methotrexate neurotoxicity. Compared with non-Hispanic whites, Hispanic patients experienced the greatest risk of methotrexate neurotoxicity (adjusted HR, 2.43; 95% CI, 1.06-5.58) after accounting for sex, age at diagnosis, BMI Z-score at diagnosis, and ALL risk stratification. Patients who experienced a neurotoxic event received an average of 2.25 fewer doses of intrathecal methotrexate. Six of the 39 cases of neurotoxicity (15.4%) experienced relapse during the study period, compared with 13 of the 241 (2.1%) patients without neurotoxicity (P = 0.0038).Conclusions: Hispanic ethnicity was associated with increased risk of methotrexate neurotoxicity, which was associated with treatment modifications and relapse. Understanding the mechanism and predictors of methotrexate neurotoxicity is important to improving treatment outcomes in pediatric ALL. Clin Cancer Res; 24(20); 5012-7. ©2018 AACR.

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.