Episodes of acute methotrexate-related neurotoxicity linked to compromised long-term neurocognitive function.

Methotrexate is a critical component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL), but is associated with neurotoxicity. Information on long-term outcomes following an acute neurotoxic event is limited. Therefore, this report compares neurocognitive performance more than 12 months post diagnosis (mean = 4 years) between ALL patients with (n = 25) and without (n = 146) a history of acute neurotoxicity. Compared to children with no documented on-treatment neurotoxic event, children who experienced a neurotoxic event during treatment exhibited poorer performance on measures of fine motor function (p = .02) and attention (p = .02). Children with ALL who experience acute neurotoxicity may be candidates for early neuropsychological screening and intervention.

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.

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.

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.

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.

Influence of Nitrosative Stress on Fatigue During Childhood Leukemia Treatment.

The focus on a cure for childhood leukemia over the last three decades has resulted in survival rates of more than 80%. However, efforts to manage leukemia-treatment symptoms have not kept pace with new therapies. Symptom toxicity during treatment can result in complications, treatment delays, and therapy dose reductions. Compromise in therapy can negatively influence the quality of life and, even more notably, jeopardize chances for long-term survival. This study examined biologic mechanisms that influence fatigue caused by increased reactive oxidative species (ROS) or actual failure of the antioxidant defense system due to genetic variation by investigating reactive nitrosative species, a "downstream" consequence of ROS. The specific aims of this study were to characterize the trajectory of nitrosative stress during acute lymphoblastic leukemia treatment and evaluate the influence of nitrosative stress on fatigue. A repeated measures design was used to evaluate the fatigue experienced by 186 children and adolescents, 3-18 years of age, with a diagnosis of leukemia during the most intense phase of treatment. An established biomarker of nitrosative stress, protein 3-nitrotyrosine (3NT) residues in the cerebral spinal fluid, was evaluated at diagnosis, postinduction, and consolidation phases of treatment. Higher fatigue was associated with higher 3NT levels at the beginning of treatment. Two distinct groups of children experienced either consistently high or consistently low 3NT levels across the treatment trajectory, from diagnosis to 12 months postinduction. Findings from this study support continued exploration into the phenotypic biochemical mechanisms that influence a reactive response to childhood cancer treatment.

Changes in Oxidant Defense, Apoptosis, and Cognitive Abilities During Treatment for Childhood Leukemia.

Aggressive central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia (ALL), the most prevalent cancer among children and adolescents, prevents metastasis of leukemia cells into the brain. Up to 60% of survivors experience cognitive problems, but knowledge about risk factors for and mechanisms of neurologic injury is lacking. Objectives of the present study were to (1) quantify changes in oxidant defense and apoptosis over the course of ALL therapy and (2) elucidate risk factors for long-term cognitive problems. The sample included 71 children with ALL. Cerebrospinal fluid (CSF) samples were collected at diagnosis and during intrathecal chemotherapy administration. Oxidant defense was measured by reduced glutathione (GSH), oxidized glutathione (GSSG), and the ratio of GSH:GSSG. Apoptosis was measured by activity of several cysteine-dependent aspartate-specific protease (abbreviated as caspase) enzymes that initiate (caspases 8 and 9) or execute (caspases 3/7) apoptosis. Cognitive abilities were assessed by standardized measures of short-term memory, visual-motor integration, and attention 3 years after ALL diagnosis. GSH and GSSG concentration increased significantly during ALL therapy, and a low GSH:GSSG ratio was indicative of an oxidized extracellular environment. Caspase enzyme activity increased significantly, and caspases 3/7 activity was significantly and negatively associated with performance on measures of cognitive abilities. Younger age at time of ALL diagnosis was associated with some measures of attention. Efflux of glutathione into CSF maintains oxidant defense by scavenging free radicals and other reactive oxygen species and is an early event in apoptosis. These mechanisms may be involved in neurologic injury associated with CNS-directed treatment and subsequent cognitive problems.

Declines Noted in Cognitive Processes and Association With Achievement Among Children With Leukemia.

PURPOSE/OBJECTIVES: To assess change in specific cognitive processes during treatment with chemotherapy only among children with acute lymphoblastic leukemia (ALL). 
. DESIGN: A prospective, repeated measures design.
. SETTING: Pediatric oncology treatment centers at Banner-University Medical Center Tucson/Banner Children's-Diamond Medical Center (University of Arizona) and Texas Children's Cancer and Hematology centers (Baylor College of Medicine) in Houston. 
. SAMPLE: 71 children with ALL, with a mean age of 6.18 years at the time of diagnosis. 
. METHODS: Using mixed-effects latent growth curve modeling with time since diagnosis as a fixed effect, age-adjusted standardized measures of working memory, processing speed, executive function, and attention were obtained and repeated about one and two years later. A subsample was tested for academic achievement at the end of treatment.
. MAIN RESEARCH VARIABLES: Verbal working memory, visual spatial memory, processing speed, academic achievement, age, and gender. 
. FINDINGS: A significant main effect was observed for age at diagnosis on decline in verbal working memory during treatment. Planned contrasts revealed greater decline among children who were diagnosed when aged younger than five years compared to those diagnosed when aged five years or older. Decline in verbal working memory and achievement in letter-word identification and calculation skills were associated, and decline in spatial memory was associated with calculation. A main effect of gender was observed on processing speed, with female patients showing greater decline than male patients. 
. CONCLUSIONS: Findings from this study may guide the timing of interventions that could improve school achievement among survivors. 
. IMPLICATIONS FOR NURSING: Children undergoing treatment for ALL may experience issues with verbal working memory and increased difficulty in school. Nurses are in a position to refer parents and children to school resources for additional academic support.

Neurocognitive Predictors of Academic Outcomes Among Childhood Leukemia Survivors.

BACKGROUND: Acute lymphoblastic leukemia is the most common pediatric cancer, and survival approaches 90%. Acute lymphoblastic leukemia survivors are more likely than healthy peers or siblings to experience academic underachievement, yet little is known about neurocognitive predictors of academic outcomes. OBJECTIVES: Objectives were to compare neurocognitive abilities to age-adjusted standardized norms, examine change over time in neurocognitive abilities, and establish neurocognitive predictors of academic outcomes. METHODS: Seventy-one children were followed over the course of therapy. Cognitive abilities were assessed during induction when the child was in remission (baseline) and annually for 3 years (years 1, 2, and 3). Reading and mathematics abilities were assessed at year 3. RESULTS: Fine motor dexterity was significantly below age-adjusted norms at all data points but showed improvement over time. Baseline visual-motor integration was within the reference range but significantly declined by year 3, and mean scores at years 2 and 3 were significantly below age-adjusted norms. Verbal short-term memory was significantly below age-adjusted norms at all assessments. Visual-motor integration predicted reading and mathematics abilities. Verbal short-term memory predicted reading abilities, and visual short-term memory predicted mathematics abilities. CONCLUSIONS: Central nervous system-directed therapy is associated with specific neurocognitive problems. Visual-spatial skills and verbal and visual short-term memory predict academic outcomes. IMPLICATIONS FOR PRACTICE: Early assessment of visual-spatial perception and short-term memory can identify children at risk of academic problems. Children who are at risk of academic problems could benefit from a school-based individual educational program and/or educational intervention.

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.

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

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

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.

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.

Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR.

Phytosterols, components of soy-derived lipids, are among the proposed exacerbants of parenteral nutrition-associated cholestasis (PNAC). We investigated whether phytosterols contribute to bile acid (BA)-induced hepatocyte damage by antagonizing a nuclear receptor (NR) critically involved in hepatoprotection from cholestasis, FXR (farnesoid X receptor, NR1H4). In HepG2 cells, stigmasterol acetate (StigAc), a water-soluble Stig derivative, suppressed ligand-activated expression of FXR target genes involved in adaptation to cholestasis (i.e. BSEP, FGF-19, OSTalpha/beta). Furthermore, StigAc antagonized BA-activated, FXR target genes SHP and BSEP in FXR+/+, but not in FXR-/- mouse hepatocytes. Both Stig and StigAc inhibited BA-activated, FXR-dependent reporter gene expression in transfected HepG2 cells, whereas the most prevalent phytosterol in lipids, beta-sitosterol, had no inhibitory effect. Finally, among six ligand-activated NR-ligand binding domains (LBDs) tested, antagonism by StigAc was specific to only two (FXR and PXR, pregnane X receptor, NR1I2). We demonstrate that Stig, a phytosterol prevalent in soy-derived PN lipid solutions, is a potent in vitro antagonist of the NR for bile acids FXR.