Preferences for survivorship education and delivery among Latino and non-Latino childhood cancer survivors and caregivers.

PURPOSE: To assess survivor and parent perceptions of the long-term survivor visit and preferences regarding accessing health information, survivorship education, and support networks in rural and metropolitan regions of Texas. METHODS: Leveraging the multi-institutional Survivorship and Access to Care for Latinos to Understand Disparities (SALUD) cohort, we administered a 26-item bilingual survey to adult survivors of childhood cancer and parents of younger survivors. Characteristics and responses were compared between survivors vs. parents and Latinos vs. non-Latinos using a t test or Fisher exact test. Odds ratios for the outcomes of interest were calculated with 95% confidence intervals. RESULTS: We received 138 responses from 59 survivors and 79 parents of survivors treated at three Texas pediatric cancer hospitals/clinics. Parents were more likely than survivors to seek survivorship information from other survivors or parents of survivors (OR=6.32, 95% CI 1.78, 22.47), and non-Latinos preferred social media as an educational resource (OR=3.70, CI 1.58, 8.68). Survivors, particularly Latino survivors, preferred short videos as a mode of survivorship education delivery. Highest topic priorities for survivorship education were 'risk for second cancers' and 'diet, nutrition, and exercise.' All parents and survivors who rated survivor physical and mental health as 'fair' or 'poor' identified as Latino. CONCLUSIONS: These results highlight differences in perceived health status between Latino and non-Latino survivors and support the development of adapted survivorship education content to address the specific needs of Latino survivors. Implications for Cancer Survivors Results of this study suggest a need for survivorship educational materials in multiple formats and that are tailored to the style, content, language preferences, and health literacy status of the target population.

Identification of USP9X as a leukemia susceptibility gene.

We recently reported that children with multiple birth defects have a significantly higher risk of childhood cancer. We performed whole-genome sequencing on a cohort of probands from this study with birth defects and cancer and their parents. Structural variant analysis identified a novel 5 kb de novo heterozygous inframe deletion overlapping the catalytic domain of USP9X in a female proband with multiple birth defects, developmental delay, and B-cell acute lymphoblastic leukemia (B-ALL). Her phenotype was consistent with female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F). Genotype-phenotype analysis including previously reported female probands (n = 42) demonstrated that MRXS99F probands with B-ALL (n = 3) clustered with subjects with loss-of-function (LoF) USP9X variants and multiple anomalies. The cumulative incidence of B-ALL among these female probands (7.1%) was significantly higher than an age- and sex-matched cohort (0.003%) from the Surveillance, Epidemiology, and End Results database (P < .0001, log-rank test). There are no reports of LoF variants in males. Males with hypomorphic missense variants have neurodevelopmental disorders without birth defects or leukemia risk. In contrast, in sporadic B-ALL, somatic LoF USP9X mutations occur in both males and females, and expression levels are comparable in leukemia samples from both sexes (P = .54), with the highest expressors being female patients with extra copies of the X-chromosome. Overall, we describe USP9X as a novel female-specific leukemia predisposition gene associated with multiple congenital, neurodevelopmental anomalies, and B-ALL risk. In contrast, USP9X serves as a tumor suppressor in sporadic pediatric B-ALL in both sexes, with low expression associated with poorer survival in patients with high-risk B-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.

Ethnic-specific predictors of neurotoxicity among patients with pediatric acute lymphoblastic leukemia after high-dose methotrexate.

BACKGROUND: High-dose methotrexate (HD-MTX; 5000 mg/m2 ) is an important component of curative therapy in many treatment regimens for high-risk pediatric acute lymphoblastic leukemia (ALL). However, methotrexate therapy can result in dose-limiting neurotoxicity, which may disproportionately affect Latino children. This study evaluated risk factors for neurotoxicity after HD-MTX in an ethnically diverse population of patients with ALL. METHODS: The authors retrospectively reviewed the medical records of patients who were diagnosed with ALL and treated with HD-MTX at Texas Children's Cancer Center (2010-2017). Methotrexate neurotoxicity was defined as a neurologic episode (e.g., seizures or stroke-like symptoms) occurring within 21 days of HD-MTX that resulted in methotrexate treatment modifications. Mixed effects multivariable logistic regression was used to estimate the odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between clinical factors and neurotoxicity. RESULTS: Overall, 351 patients (58.1% Latino) who received 1183 HD-MTX infusions were evaluated. Thirty-five patients (10%) experienced neurotoxicity, 71% of whom were Latino. After adjusting for clinical risk factors, the authors observed that serum creatinine elevations ≥50% of baseline were associated with a three-fold increased odds (OR, 3.32; 95% CI, 0.98-11.21; p = .05) for neurotoxicity compared with creatinine elevation <25%. Notably, predictors of neurotoxicity differed by ethnicity. Specifically, Latino children experienced a nearly six-fold increase in neurotoxicity odds (OR, 5.80; 95% CI, 1.39-24.17; p = .02) with serum creatinine elevation ≥50% compared with creatinine elevation <25%. CONCLUSIONS: The current findings indicate that serum creatinine elevations ≥50% may be associated with an increased risk for neurotoxicity among Latino children with ALL and may identify potential candidates for therapeutic or supportive care interventions.

Reducing external ventricular drain associated ventriculitis: An improvement project in a level 1 trauma center.

BACKGROUND: External ventricular drain (EVD)-associated infections have a negative impact on healthcare cost and patient outcomes. Practice variation in EVD management may place patients at increased risk for EVD-associated infection. This project aimed to evaluate the impact of implementing an interprofessional evidence-based EVD bundle of care on reduction of EVD-related ventriculitis rates. METHODS: An interprofessional team developed an evidence based EVD care bundle and order set to eliminate practice inconsistencies. Standardization of EVD equipment and optimization of the electronic health record occurred. Education and competency validation were completed with neurosurgical providers and nurses. Interprofessional rounds occur weekly for observation, recognition, and in-the-moment education. RESULTS: A pre/post intervention design was used to show that the rate of EVD-associated ventriculitis decreased from 8.8 per reported EVD days in 2019 to 0 per reported EVD days in 2021 after implementation of the EVD care bundle. CONCLUSION: Through an interprofessional team approach, reduction in EVD-associated infection rates is feasible with implementation of an evidence based EVD care bundle.

A Prospective Evaluation of Fatigue in Pediatric Brain Tumor Patients Treated With Radiation Therapy.

Background: Fatigue is a well-established consequence of cranial radiotherapy in survivors of pediatric brain tumor, but less is known about acute fatigue during radiotherapy treatment. This study aimed to longitudinally evaluate fatigue in newly diagnosed pediatric patients with brain tumors during treatment. Methods: Primary caregivers of pediatric patients with brain tumors completed the proxy-reported Parent Fatigue Scale assessments prior to radiotherapy and weekly during radiotherapy treatment. The association between clinical factors and fatigue at each assessment was evaluated with multiple linear regressions. A comparison of fatigue between radiation modalities was also analyzed. Results: A total of 33 caregivers completed pre-radiation fatigue assessments, with 29 reporting fatigue during radiotherapy. Patients were aged 3 to 16 years (M = 8.32) at diagnosis and diagnosed with medulloblastoma (n = 23), primitive neuroectodermal tumor (n = 2), ependymoma (n = 1), germ cell tumor (n = 1), pineoblastoma (n = 1), atypical teratoid rhabdoid (n = 1), and other unspecific tumors (n = 3). Moderate-to-severe fatigue was reported for the majority of patients (31/33; 94%) during treatment. Craniospinal irradiation dose was the only significant predictor of fatigue (p < .05), but this association was restricted to the first week of therapy and was attenuated by therapy completion. Discussion: Although fatigue is often considered a long-term consequence of cranial radiotherapy, this pilot study demonstrates that moderate-to-severe fatigue is pervasive prior to radiotherapy and persists throughout treatment in pediatric patients with brain tumors, regardless of radiation modality or clinical factors. Additional research is warranted to establish a link between acute and long-term fatigue and develop interventions to mitigate this adverse outcome.

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.

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.

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.

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.

Comparison of the blood, bone marrow, and cerebrospinal fluid metabolomes in children with b-cell acute lymphoblastic leukemia.

Metabolomics may shed light on treatment response in childhood acute lymphoblastic leukemia (ALL), however, most assessments have analyzed bone marrow or cerebrospinal fluid (CSF), which are not collected during all phases of therapy. Blood is collected frequently and with fewer risks, but it is unclear whether findings from marrow or CSF biomarker studies may translate. We profiled end-induction plasma, marrow, and CSF from N = 10 children with B-ALL using liquid chromatography-mass spectrometry. We estimated correlations between plasma and marrow/CSF metabolite abundances detected in ≥ 3 patients using Spearman rank correlation coefficients (rs). Most marrow metabolites were detected in plasma (N = 661; 81%), and we observed moderate-to-strong correlations (median rs 0.62, interquartile range [IQR] 0.29-0.83). We detected 328 CSF metabolites in plasma (90%); plasma-CSF correlations were weaker (median rs 0.37, IQR 0.07-0.70). We observed plasma-marrow correlations for metabolites in pathways associated with end-induction residual disease (pyruvate, asparagine) and plasma-CSF correlations for a biomarker of fatigue (gamma-glutamylglutamine). There is considerable overlap between the plasma, marrow, and CSF metabolomes, and we observed strong correlations for biomarkers of clinically relevant phenotypes. Plasma may be suitable for biomarker studies in B-ALL.

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.

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.

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.

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.

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.

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.