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

Advances in primary therapy for childhood acute lymphoblastic leukemia (ALL) have resulted in increased five-year survival, which currently approaches 90% (Hunger et al., 2012). Increased overall survival has led to better appreciation of therapy-related morbidity and impaired quality of life (Barr, Feeny, Furlong, Weitzman, & Torrance, 1995; Krull et al., 2008). In contrast to the recognition of childhood cancer–related neurocognitive complications, limited research exists investigating the trajectory of fine motor and visual-motor difficulties and its impact on behavior and emotional function among children with cancer. Even less understanding exists of physiologic risk profiles for neurobehavioral problems in children with leukemia. This study investigated the influence of the oxidative stress pathway on fine and visual-motor skills, as well as behavioral adjustment in children treated for ALL. Oxidative stress results from an imbalance in the production of reactive oxygen species (ROS) and antioxidant defense systems. ROS are formed as byproducts of cellular metabolism, which in excess can result in damage to cellular structures, and antioxidant systems are the body’s first line of defense against cellular injury (Roberts et al., 2010; Stenzel et al., 2010). Brain tissue is particularly vulnerable to oxidative stress because of limited antioxidant capacity, higher energy requirements, and higher concentration of lipids (Floyd, 1999).

A child’s motor system experiences rapid development during the first two to five years of life, the time when ALL most commonly occurs in children. Childhood ALL treatment increases the risk for long-term fine motor problems that include peripheral neuropathy, sensory loss, reduced deep tendon reflexes, and motor function changes. Vainionpää, Kovala, Tolonen, and Lanning (1995) were among the first to describe problems in the peripheral nervous system during childhood ALL treatment; significant prolongation of the median nerve peripheral conduct time caused by vincristine (Oncovin®) therapy was discovered in a group of 38 children receiving ALL therapy. Evidently, motor changes are not restricted to the peripheral nervous system and may cause deficits throughout the motor circuitry, including the central motor system (Harila-Saari, Huuskonen, Tolonen, Vainionpää, & Lanning, 2001). Reduced motor competence is demonstrated by greater handwriting difficulties, as well as deficits in manual dexterity and strength.

Motor and sensory-perceptual function is an important indicator in determining severity of a neurologic insult and extension of impairment across specific regions of the brain. Although motor and sensory perceptual signs are often deemed “soft signs,” they can be important indicators of a compromised central nervous system (CNS). Examination of fine motor function can assist in understanding the effects of ALL treatment on the brain and the long-term impact of therapy on development. Although most studies demonstrated some evidence of fine motor problems associated with manual dexterity problems during treatment (Dowell, Copeland, & Judd, 1989; Green, Knight, McCarthy, & De Luca, 2013; Jansen et al., 2005; Kingma et al., 2001; Reinders-Messelink et al., 1996, 1999, 2001; van Brussel et al., 2006), inconsistencies existed in findings following completion of ALL treatment. Many of the neurotoxic treatment-related problems disappear over time, but findings from several studies demonstrate that gross and fine motor deficits continue to be evident five years after completing therapy (Galea, Wright, & Barr, 2004; Hartman, van den Bos, Stijnen, & Pieters, 2006; Jansen et al., 2008; Kingma et al., 2001; Lehtinen et al., 2002; Marchese & Chiarello, 2004; Reinders-Messelink et al., 1996, 1999; Wright, Galea, & Barr, 2005; Wright, Halton, Martin, & Barr, 1998). Behavior difficulties, including attention problems, anxiety, depression, and social problems, among childhood cancer survivors have been reported (Brown et al., 1992; Buizer, de Sonneville, van den Heuvel-Eibrink, & Veerman, 2005, 2006). However, inter-individual differences exist in neurobehavioral outcomes that could be associated with physiologic and/or psychological factors. A previous study by the current research team found that, in children with ALL, symptoms of hyperactivity decreased over time for participants with low oxidative stress levels but remained stable over time for participants with high oxidative stress levels (Stenzel et al., 2010).

Emerging evidence supports oxidative stress as an underlying biologic process responsible for progressive neurologic injury following chemotherapy. Growing evidence exists that alkylating agents and antimetabolites increase ROS production (Illingworth & Glover, 1971; Roberts et al., 2010; Stenzel et al., 2010). Oxidative stress induced by methotrexate (MTX) (Rasuvo®, Otrexup®, Trexall® ) has been observed in tumor tissue, cell cultures, rat liver and brain, and children with ALL (Babiak, Campello, Carnieri, & Oliveira, 1998; Cetinkaya, Bulbuloglu, Kurutas, & Kantarceken, 2006; Hockenberry et al., 2013; Jahovic, Cevik, Sehirli, Yegen, & Sener, 2003; Mazor, Abucoider, Meyerstein, & Kapelushnik, 2008; Oktem et al., 2006; Rouse, Nwokedi, Woodliff, Epstein, & Klimberg, 1995; Sener et al., 2006). Oxidative stress may also be responsible for fine motor dexterity problems observed in children with ALL.

The current study assessed fine motor dexterity, visual processing, and visual-motor integration in children during chemotherapy and examined associations with behavioral outcomes and cerebrospinal fluid (CSF) markers of oxidative stress. In addition, the authors expected oxidative stress within the CNS to be associated with fine motor problems.

Methods

A prospective, longitudinal design was used to investigate a model for examining associations among CSF biomarkers of oxidative stress, fine motor, visual-motor, and behavioral adjustment in children treated for ALL. The study was approved by the University of Arizona Human Subjects Protection Program in Tuscon, Arizona, and the Baylor College of Medicine Institutional Review Board in Houston, Texas. Parent consent and child assent (for children aged 7–15 years) were obtained.

Patients

Eligibility requirements included children diagnosed with pre-B or pre-T cell ALL and being treated on or according to an existing Children’s Oncology Group protocol. For continuity and validity of longitudinal neurocognitive assessments, patients were aged 2 years and 9 months to 15 years at the time of diagnosis and were English-language dominant. Exclusion criteria included children with CNS leukemia, a preexisting neurologic disorder (e.g., seizures), subsequent brain injury associated with an alteration of consciousness, or a neurodevelopmental disability (e.g., Down syndrome).

The ALL therapeutic protocols included the induction, postinduction, and continuation therapy treatments. Induction therapy involved weekly treatment with vincristine and daunomycin (DaunoXome®) (for high-risk ALL), a corticosteroid and a dose of pegylated L-asparaginase (Oncaspar®), and two intrathecal (IT) MTX (Rasuvo, Otrexup) treatments (Days 8 and 29). Postinduction therapy (6–8 months) involved several courses of asparaginase (Elspar®), high- or intermediate-dose IV MTX depending on ALL protocol assignment, vincristine, doxorubicin (Adriamycin®), corticosteroid, cytarabine (Depocyt®), mercaptopurine (Purinethol®), and IT MTX. Continuation therapy consisted of daily mercaptopurine and weekly oral MTX (Trexall), with monthly pulses of vincristine and a corticosteroid, and an IT MTX treatment every 12 weeks for 2.5 years (female) to 3 years (male).

Procedures

Baseline measures were collected during postinduction therapy and during two follow-up sessions. The first follow-up occurred during continuation, about one year from date of baseline evaluation, and the second follow-up occurred at the end of continuation therapy, about two years from baseline. The test battery included measures of fine motor dexterity (Tiffin, 1968), visual-motor integration (Beery, Buktenica, & Beery, 2010), visual processing speed (Woodcock, McGrew, & Mather, 2001), and visual-spatial perception and construction (Korkman, Kirk, & Kemp, 2007), as well as parental ratings of behavioral functioning (Reynolds & Kamphaus, 2004).

CSF was obtained during scheduled therapeutic lumbar punctures (LPs), with the first sample collected during the diagnostic LP. Subsequent CSF samples were collected during the LP for each IT MTX treatment but prior to injection of any chemotherapy. Samples were obtained during the induction, postinduction, and continuation phases of therapy. Biomarkers of oxidative stress in the CSF consisted of oxidized phosphatidylinositol (PI) and F₂-isoprostanes (F₂-Is). Unoxidized PI, a biomarker of cell membrane disruption, was also measured (Chauhan & Chauhan, 2006; Folch, Lees, & Sloane Stanley, 1957).

CSF samples were placed on ice immediately after collection, centrifuged for 10 minutes at 1,750 x g to remove any cellular debris, and then stored at –80°C to limit degradation. PI was extracted from CSF samples using a modified method developed by Folch et al. (1957) and separated by high-performance liquid chromatography (HPLC) with a normal-phase gradient. Lipids were extracted from the aqueous CSF with 4 ml of chloroform; methanol (2:1, v/v) was vortexed for one minute and centrifuged at 10,000 rpm for 20 minutes. The organic phase was collected and stored on ice. A second extraction of the aqueous phase with chloroform-methanol (9:1, v/v) was done to ensure complete extraction of the less polar phospholipids. The organic fractions were combined, evaporated to dryness under nitrogen, and resuspended in hexane-isopropanol (1:1, v/v) prior to HPLC separation. This method recovers 98% of phospholipids.

Mawatari and Murakami (1998) developed an HPLC method for detecting peroxidation of phospholipids in a single chromatic elution. The current authors modified that method to optimize detection using normal-phase HPLC for separation of phospholipid classes. Details of this method have been previously reported (Hockenberry et al., 2013; Ki Moore et al., 2015).

F₂-Is are a sensitive index of oxidative stress in vivo and were measured by a competitive enzyme-linked immunoassay kit. The immunoassay was validated in human urine samples with gas chromatography/mass spectrometry following solid-phase extraction, with an intra-assay correlation of r > 0.8. Detailed methods for F₂-I have been previously reported (Hockenberry et al., 2013).

Statistical Analysis

Descriptive statistics were calculated for patient demographics and treatment variables. Scores on measures of fine motor dexterity, visual-motor integration, visual processing speed, and visual-spatial abilities were converted to age-adjusted z-scores (mean = 0, SD = 1) using national population norms. For behavioral adjustment, t-scores (mean = 50, SD = 10) were used, which is the format given by the computerized scoring program. The authors calculated a 95% confidence interval (CI) around each mean z-score and t-score, and those intervals that did not contain the population mean (0 or 50, respectively) were interpreted as being significantly different from the normal population. Pearson correlation was used to test for associations among measures of motor abilities and CSF biomarkers. Some motor and visual-motor problems recovered after the postinduction phase of therapy. Therefore, Pearson correlation was used to determine associations between performance on motor measures at the first follow-up and behavioral measures at the end of therapy (second follow-up). All analyses were conducted using SPSS®, version 20.

Results

Table 1 presents demographic and clinical characteristics of the 89 participants. Participants were aged an average of 7.1 years at diagnosis, and 49 participants were female. Patients received an average cumulative IV MTX dose of 9.4 g/m², and number of IT MTX injections ranged from 13–24.

Participants’ scores were significantly lower than the population means for fine motor dexterity symptoms at baseline following induction therapy (see Table 2). Performance improved during the course of therapy; scores for nondominant (mean = –0.2, 95% CI [–0.51, 0.1]) and both hands (mean = –0.25, 95% CI [–0.58, 0.09]) were within the average range at the second follow-up by the end of therapy. Performance for the dominant hand remained significantly below expectations by the end of therapy (mean = –0.39, 95% CI [–0.7, –0.09]). Visual processing speed demonstrated a pattern of low performance following induction (mean = –0.24, 95% CI [–0.45, –0.03]) and postinduction (mean = –0.26, 95% CI [–0.5, –0.03]) therapy, but performance was within the expected range by the end of therapy (mean = –0.03, 95% CI [–0.26, 0.21]). Visual-motor integration was also below expectations following induction therapy (mean = –0.22, 95% CI [–0.42, –0.02]) and remained that way until the end of therapy (mean = –0.37, 95% CI [–0.57, –0.18]). No difficulties were observed in spatial perception or construction during the course of treatment.

Following induction, parental rating of hyperactivity was below the norm (mean = 47.95, 95% CI [46.02, 49.88]), and rating of somatic complaints was elevated (mean = 59.9, 95% CI [57.18, 62.62]). Following postinduction therapy, rating of hyperactivity (mean = 47.64, 95% CI [45.39, 49.89]) and aggressive behavior (mean = 47.52, 95% CI [45.2, 49.83]) were below norms, and rating of somatic complaints (mean = 57.84, 95% CI [55.04, 60.65]) remained elevated above norms. This pattern continued until the end of therapy. No differences were noted in ratings of emotional or social behaviors.

F₂-I, oxidized PI, and unoxidized PI levels in the diagnostic CSF samples were not associated with motor dexterity, visual processing speed, or visual-motor integration at any of the three assessment points. CSF concentration of F₂-I during induction was negatively correlated with motor dexterity symptoms (r = –0.29, p < 0.05) and visual-motor integration problems (r = –0.23, p < 0.05) at the postinduction assessment. CSF concentration of F₂-I during postinduction therapy was significantly associated with motor dexterity symptoms at the second follow-up at the end of therapy (r = –0.339, p < 0.05). As shown in Table 3, oxidized and unoxidized PI concentrations during induction, postinduction, and continuation were negatively correlated with motor dexterity problems at the end of therapy. The number of IT MTX injections received was not associated with performance on the motor dexterity, visual processing speed, or visual-motor integration measures. However, greater total dose of IV MTX received was significantly and negatively associated with visual-motor integration abilities at the first (r = –0.213, p < 0.05) and second (r = –0.24, p < 0.05) follow-up assessments.

As summarized in Table 4, fine motor dexterity problems at the first follow-up assessment were associated with a range of behavioral problems, including anxiety, somatic complaints, atypicality (i.e., behaviors commonly considered odd or strange), and attention problems, at the second follow-up assessment at the end of therapy. Poor visual processing speed at Year 1 was associated with increased attention problems (r = –0.29, p < 0.05) at the end of therapy, and poor visual-motor integration was associated with higher hyperactivity (r = –0.23, p < 0.05) and lower functional communication (r = 0.29, p < 0.05) at the end of therapy.

Discussion

Results of the current study demonstrate that children undergoing chemotherapy for ALL experience fine motor dexterity problems within months of diagnosis, which persist throughout the course of therapy. Visual processing speed was also initially lower than expected but improved and normalized by the end of therapy. Visual-motor integration, a relatively complex task dependent on visual-spatial perception and fine motor dexterity, followed a similar pattern as motor dexterity and worsened with time. Because spatial perception and construction tasks did not show impairment at any time during treatment, visual-motor integration problems are likely directly related to poor motor dexterity.

Symptoms of impairment in fine motor dexterity appear to be related to oxidative stress and associated disruption in cell membrane integrity in the CNS. F₂-Is are prostaglandin-like compounds formed by free radical peroxidation of arachidonic acid and are established markers of oxidative injury (Frere, Chang-Ileto, & Di Paolo, 2012). Although F₂-I is a gold standard measure of oxidative stress, phospholipids were more strongly associated with fine motor problems in the current study.

F₂-I levels in CSF increased from the diagnostic LP to the induction sample, and further increased following induction and postinduction therapy. Although F₂-I concentration at diagnosis was not associated with motor dexterity, levels in CSF during and following induction significantly correlated with subsequent motor dexterity problems. MTX has been observed to induce oxidative stress. Given the timing between increased F₂-I and treatment phase in the current study, MTX may be responsible for oxidative stress and subsequent impaired motor dexterity.

Arachidonic acid is a polyunsaturated fatty acid found in PI and other phospholipids that comprise cellular membranes in the brain, muscle, and liver. In the current study, the authors found an increase in CSF levels of oxidized and unoxidized PI over time compared to the diagnostic CSF sample. This pattern is suggestive of oxidative injury, resulting in disruption of cellular membranes within the CNS, and is likely because of the mediating effect of F₂-I (Milne, Musiek, & Morrow, 2005; Montuschi, Barnes, & Roberts, 2004). Although phosphoinositides are quantitatively a minor class of lipids, they have a crucial role in synaptic function. In addition, dysregulation of PI metabolism has been implicated in synaptic malfunction associated with a variety of brain disorders. Oxidized and unoxidized PI following induction were predictive of impaired motor dexterity at the end of therapy, supporting the notion that CNS-based injury is responsible for fine motor dexterity problems that could potentially involve dysregulation of neurotransmission (Frere et al., 2012).

Motor functioning following postinduction therapy was related to behavioral adjustment at the end of therapy. Fine motor dexterity was significantly correlated with anxiety and somatic complaints at the end of therapy, and visual-motor integration was associated with hyperactivity and poor functional communication. Visual-motor integration is a complex task that involves perception of visual-spatial relations combined with fine motor dexterity required to reproduce designs and patterns. In the current study, impaired visual-motor integration following postinduction therapy was associated with symptoms of increased hyperactivity and reduced functional communication at the end of therapy. Hyperactivity is often viewed as reduced control over motor systems. Functional communication includes not only expressive language and speech, but also written communication. Therefore, early deficits in complex motor control can affect functional behavior as children continue to develop. This association suggests that behavioral problems that emerge over time are related to neurocognitive limitations as opposed to social or environmental interactions. Further research is needed to evaluate this connection between neurocognitive deficits and behavioral problems.

Slowed visual processing speed following postinduction therapy was associated with increased attention problems at the end of therapy. Attention is a cognitive construct that is heavily dependent on processing speed because slower rates of information processing require more sustained attentional effort. In the current study, visual processing speed appears to normalize by the end of therapy, but the impact on the broader domain of attention remains. That finding is consistent with work by Krull et al. (2013), demonstrating that many children treated with chemotherapy for ALL have sustained attention problems on direct assessment at the end of therapy.

The current study is not without limitations. The sample size is relatively small compared to other reported ALL outcome studies; however, the vast majority of those studies are cross-sectional and do not include longitudinal data beginning shortly after diagnosis. All children received vincristine, a known neurotoxic agent, and the contributions of this agent to changes in dexterity were not evaluated. The children also received oral corticosteroids, which can cause behavioral problems. However, corticosteroid therapy was most intense during the induction and postinduction phases of treatment and consisted of only monthly pulses during continuation when the first and second follow-up sessions were completed. The battery of assessment measures is also brief and more focused than other reports in the literature, a consequence of limited choices and time for assessment of young children during treatment of a major medical condition.

Implications for Nursing and Conclusions

The current study demonstrates that children undergoing chemotherapy for childhood ALL are at risk for early onset and persistence of fine motor dexterity and visual-motor problems that appear to be related to CNS treatment-related neurotoxicity. Pediatric oncology nurses are in an ideal position to advocate for ongoing assessment of motor abilities among children receiving CNS-directed treatment and referral for physical or occupational therapy when appropriate. Early assessment of motor abilities is important because problems with fine motor dexterity and visual-motor integration appear to affect development of functional behavior. Early interventions designed to improve fine motor dexterity and visual-motor integration are lacking. Findings from the current study support the need to test the efficacy of early interventions designed to improve fine motor dexterity and prevent future problems with visual-motor integration and behavior. The association between early motor symptoms and CNS biomarkers of oxidative stress suggest the potential role of antioxidants in limiting the cascade of reactive oxygen species and peroxidation injury of lipid membranes. However, prior to any clinical trial, preclinical studies are necessary to ensure that antioxidants do not limit the efficacy of the primary cancer therapy.

The number of IT MTX doses was not associated with any measures of motor function, and total dose of IV MTX received was associated only with visual-motor integration at the first and second follow-ups. These findings suggest that there may be individual differences in susceptibility to chemotherapy-related CNS injury. Differences in susceptibility could be because of epigenetic changes in regulation of gene activity and expression involved in oxidative stress and oxidant defense that could be linked to diminished motor abilities among children with ALL. Additional studies are needed to characterize epigenetic factors that could identify children with ALL who are at greatest risk for fine and visual-motor skills, as well as behavioral adjustment problems.

References

Babiak, R.M., Campello, A.P., Carnieri, E.G., & Oliveira, M.B. (1998). Methotrexate: Pentose cycle and oxidative stress. Cell Biochemistry and Function, 16, 283–293. doi:10.1002/(SICI)1099-0844(1998120)16:4<283::AID-CBF801>3.0.CO;2-E

Barr, R.D., Feeny, D., Furlong, W., Weitzman, S., & Torrance, G.W. (1995). A preference-based approach to health-related quality-of-life for children with cancer. International Journal of Pediatric Hematology/Oncology, 2, 305–315.

Beery, K.E., Buktenica, N.A., & Beery, N.A. (2010). The Beery-Buktenica Developmental Test of Visual-Motor Integration (6th ed.). San Antonio, TX: PsychCorp.

Brown, R.T., Madan-Swain, A., Pais, R., Lambert, R.G., Sexson, S., & Ragab, A. (1992). Chemotherapy for acute lymphocytic leukemia: Cognitive and academic sequelae. Journal of Pediatrics, 121, 885–889. doi:10.1016/S0022-3476(05)80333-6

Buizer, A.I., de Sonneville, L.M., van den Heuvel-Eibrink, M.M., & Veerman, A.J. (2005). Chemotherapy and attentional dysfunction in survivors of childhood acute lymphoblastic leukemia: Effect of treatment intensity. Pediatric Blood and Cancer, 45, 281–290. doi:10.1002/pbc.20397

Buizer, A.I., de Sonneville, L.M., van den Heuvel-Eibrink, M.M., & Veerman, A.J. (2006). Behavioral and educational limitations after chemotherapy for childhood acute lymphoblastic leukemia or Wilms tumor. Cancer, 106, 2067–2075. doi:10.1002/cncr.21820

Cetinkaya, A., Bulbuloglu, E., Kurutas, E.B., & Kantarceken, B. (2006). N-acetylcysteine ameliorates methotrexate-induced oxidative liver damage in rats. Medical Science Monitor, 12(8), BR274–BR278.

Chauhan, A., & Chauhan, V. (2006). Oxidative stress in autism. Pathophysiology, 13, 171–181. doi:10.1016/j.pathophys.2006.05.007

Dowell, R.E., Jr., Copeland, D.R., & Judd, B.W. (1989). Neuropsychological effects of chemotherapeutic agents. Developmental Neuropsychology, 5, 17–24. doi:10.1080/87565648909540419

Floyd, R.A. (1999). Antioxidants, oxidative stress, and degenerative neurological disorders. Proceedings of the Society for Experimental Biology and Medicine, 222, 236–245. doi:10.1046/j.1525-1373.1999.d01-140.x

Folch, J., Lees, M., & Sloane Stanley, G.H. (1957). A simple method for the isolation and purification of total lipides from animal tissues. Journal of Biological Chemistry, 226, 497–509.

Frere, S.G., Chang-Ileto, B., & Di Paolo, G. (2012). Role of phosphoinositides at the neuronal synapse. Sub-Cellular Biochemistry, 59, 131–175. doi:10.1007/978-94-007-3015-1_5

Galea, V., Wright, M.J., & Barr, R.D. (2004). Measurement of balance in survivors of acute lymphoblastic leukemia in childhood. Gait and Posture, 19, 1–10. doi:10.1016/S0966-6362(03)00014-6

Green, J.L., Knight, S.J., McCarthy, M., & De Luca, C.R. (2013). Motor functioning during and following treatment with chemotherapy for pediatric acute lymphoblastic leukemia. Pediatric Blood and Cancer, 60, 1261–1266. doi:10.1002/pbc.24537

Harila-Saari, A.H., Huuskonen, U.E., Tolonen, U., Vainionpää, L.K., & Lanning, B.M. (2001). Motor nervous pathway function is impaired after treatment of childhood acute lymphoblastic leukemia: A study with motor evoked potentials. Medical and Pediatric Oncology, 36, 345–351. doi:10.1002/mpo.1084

Hartman, A., van den Bos, C., Stijnen, T., & Pieters, R. (2006). Decrease in motor performance in children with cancer is independent of the cumulative dose of vincristine. Cancer, 106, 1395–1401. doi:10.1002/cncr.21706

Hockenberry, M.J., Taylor, O.A., Gundy, P.M., Ross, A.K., Pasvogel, A., Montgomery, D., . . . Moore, I. (2013). F2–isoprostanes: A measure of oxidative stress in children receiving treatment for leukemia. Biological Research for Nursing, 16, 303–309. doi:10.1177/1099800413498507

Hunger, S.P., Lu, X., Devidas, M., Camitta, B.M., Gaynon, P.S., Winick, N.J., . . . Carroll, W.L. (2012). Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: A report from the children’s oncology group. Journal of Clinical Oncology, 30, 1663–1669. doi:10.1200/JCO.2011.37.8018

Illingworth, D.R., & Glover, J. (1971). The composition of lipids in cerebrospinal fluid of children and adults. Journal of Neurochemistry, 18, 769–776. doi:10.1111/j.1471-4159.1971.tb12006.x

Jahovic, N., Cevik, H., Sehirli, A.O., Yegen, B.C., & Sener, G. (2003). Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats. Journal of Pineal Research, 34, 282–287. doi:10.1034/j.1600-079X.2003.00043.x

Jansen, N.C., Kingma, A., Schuitema, A., Bouma, A., Veerman, A.J., & Kamps, W.A. (2008). Neuropsychological outcome in chemotherapy-only-treated children with acute lymphoblastic leukemia. Journal of Clinical Oncology, 26, 3025–3030. doi:10.1200/Jco.2007.12.4149

Jansen, N.C., Kingma, A., Tellegen, P., van Dommelen, R.I., Bouma, A., Veerman, A., & Kamps, W.A. (2005). Feasibility of neuropsychological assessment in leukaemia patients shortly after diagnosis: Directions for future prospective research. Archives of Disease in Childhood, 90, 301–304. doi:10.1136/adc.2004.051839

Ki Moore, I.M., Gundy, P., Pasvogel, A., Montgomery, D.W., Taylor, O.A., Koerner, K.M., . . . Hockenberry, M.J. (2015). Increase in oxidative stress as measured by cerebrospinal fluid lipid peroxidation during treatment for childhood acute lymphoblastic leukemia. Journal of Pediatric Hematology/Oncology, 37, E86–E93. doi:10.1097/mph.0000000000000258

Kingma, A., van Dommelen, R.I., Mooyaart, E.L., Wilmink, J.T., Deelman, B.G., & Kamps, W.A. (2001). Slight cognitive impairment and magnetic resonance imaging abnormalities but normal school levels in children treated for acute lymphoblastic leukemia with chemotherapy only. Journal of Pediatrics, 139, 413–420. doi:10.1067/mpd.2001.117066

Korkman, M., Kirk, U., & Kemp, S. (2007). NEPSY–II: Clinical and interpretive manual (2nd ed.). San Antonio, TX: PsychCorp.

Krull, K.R., Bhojwani, D., Conklin, H.M., Pei, D., Cheng, C., Reddick, W.E., . . . Pui, C.H. (2013). Genetic mediators of neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia. Journal of Clinical Oncology, 31, 2182–2188. doi: 10.1200/JCO.2012.46.7944

Krull, K.R., Okcu, M.F., Potter, B., Jain, N., Dreyer, Z., Kamdar, K., & Brouwers, P. (2008). Screening for neurocognitive impairment in pediatric cancer long-term survivors. Journal of Clinical Oncology, 26, 4138–4143. doi:10.1200/JCO.2008.16.8864

Lehtinen, S.S., Huuskonen, U.E., Harila-Saari, A.H., Tolonen, U., Vainionpää, L.K., & Lanning, B.M. (2002). Motor nervous system impairment persists in long-term survivors of childhood acute lymphoblastic leukemia. Cancer, 94, 2466–2473. doi:10.1002/cncr.10503

Marchese, V.G., & Chiarello, L.A. (2004). Relationships between specific measures of body function, activity, and participation in children with acute lymphoblastic leukemia. Rehabilitation Oncology, 22, 5–9.

Mawatari, S., & Murakami, K. (1998). Analysis of membrane phospholipid peroxidation by isocratic high-performance liquid chromatography with ultraviolet detection. Analytical Biochemistry, 264, 118–123. doi:10.1006/abio.1998.2830

Mazor, D., Abucoider, A., Meyerstein, N., & Kapelushnik, J. (2008). Antioxidant status in pediatric acute lymphocytic leukemia (ALL) and solid tumors: The impact of oxidative stress. Pediatric Blood and Cancer, 51, 613–615. doi:10.1002/pbc.21665

Milne, G.L., Musiek, E.S., & Morrow, J.D. (2005). F2–isoprostanes as markers of oxidative stress in vivo: An overview. Biomarkers, 10(Suppl. 1), S10–S23. doi:10.1080/13547500500216546

Montuschi, P., Barnes, P.J., & Roberts, L.J., II. (2004). Isoprostanes: Markers and mediators of oxidative stress. FASEB Journal, 18, 1791–1800. doi:10.1096/fj.04-2330rev

Oktem, F., Yilmaz, H.R., Ozguner, F., Olgar, S., Ayata, A., Uzare, E., & Uz, E. (2006). Methotrexate-induced renal oxidative stress in rats: The role of a novel antioxidant caffeic acid phenethyl ester. Toxicology and Industrial Health, 22, 241–247. doi:10.1191/0748233706th265oa

Reinders-Messelink, H., Schoemaker, M., Snijders, T., Göeken, L., van den Briel, M., Bökkerink, J., & Kamps, W. (1999). Motor performance of children during treatment for acute lymphoblastic leukemia. Medical and Pediatric Oncology, 33, 545–550. doi:10.1002/(SICI)1096-911X(199912)33:6<545::AID-MPO4>3.0.CO;2-Y

Reinders-Messelink, H.A., Schoemaker, M.M., Hofte, M., Göeken, L.N., Kingma, A., van den Briel, M.M., & Kamps, W.A. (1996). Fine motor and handwriting problems after treatment for childhood acute lymphoblastic leukemia. Medical and Pediatric Oncology, 27, 551–555.

Reinders-Messelink, H.A., Schoemaker, M.M., Snijders, T.A., Göeken, L.N., Bökkerink, J.O., & Kamps, W.A. (2001). Analysis of handwriting of children during treatment for acute lymphoblastic leukemia. Medical and Pediatric Oncology, 37, 393–399. doi:10.1002/mpo.1216

Reynolds, C., & Kamphaus, R. (2004). Behavior assessment scale for children (2nd ed.). San Antonio, TX: PsychCorp.

Roberts, R.A., Smith, R.A., Safe, S., Szabo, C., Tjalkens, R.B., & Robertson, F.M. (2010). Toxicological and pathophysiological roles of reactive oxygen and nitrogen species. Toxicology, 276(2), 85–94. doi:10.1016/j.tox.2010.07.009

Rouse, K., Nwokedi, E., Woodliff, J.E., Epstein, J., & Klimberg, V.S. (1995). Glutamine enhances selectivity of chemotherapy through changes in glutathione metabolism. Annals of Surgery, 221, 420–426.

Sener, G., Eksioglu-Demiralp, E., Cetiner, M., Ercan, F., Sirvanci, S., Gedik, N., & Yegen, B.C. (2006). L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death. Cell Biology and Toxicology, 22, 47–60. doi:10.1007/s10565-006-0025-0

Smith, M., Arthur, D., Camitta, B., Carroll, A.J., Crist, W., Gaynon, P., . . . Ungerleider, R. (1996). Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. Journal of Clinical Oncology, 14, 18–24.

Stenzel, S.L., Krull, K.R., Hockenberry, M., Jain, N., Kaemingk, K., Miketova, P., & Moore, I.M. (2010). Oxidative stress and neurobehavioral problems in pediatric acute lymphoblastic leukemia patients undergoing chemotherapy. Journal of Pediatric Hematology/Oncology, 32, 113–118. doi:10.1097/MPH.0b013e3181c9af84

Tiffin, J. (1968). Purdue pegboard examiner manual. Chicago, IL: Science Research Associates.

Vainionpää, L., Kovala, T., Tolonen, U., & Lanning, M. (1995). Vincristine therapy for children with acute lymphoblastic leukemia impairs conduction in the entire peripheral nerve. Pediatric Neurology, 13, 314–318. doi:10.1016/0887-8994(95)00191-3

van Brussel, M., Takken, T., van der Net, J., Engelbert, R.H., Bierings, M., Schoenmakers, M.A., & Helders, P.J. (2006). Physical function and fitness in long-term survivors of childhood leukaemia. Pediatric Rehabilitation, 9, 267–274. doi:10.1080/13638490500523150

Woodcock, R.W., McGrew, K.S., & Mather, N. (2001). Woodcock-Johnson® III Normative Update (NU) Tests of Achievement. Itasca, IL: Riverside Publishing.

Wright, M.J., Galea, V., & Barr, R.D. (2005). Proficiency of balance in children and youth who have had acute lymphoblastic leukemia. Physical Therapy, 85, 782–790.

Wright, M.J., Halton, J.M., Martin, R.F., & Barr, R.D. (1998). Long-term gross motor performance following treatment for acute lymphoblastic leukemia. Medical and Pediatric Oncology, 31, 86–90.

About the Author(s)

Marilyn J. Hockenberry, PhD, RN, PPCNP, FAAN, is a professor in the School of Nursing at Duke University in Durham, NC; Kevin R. Krull, PhD, is a member in the Department of Epidemiology and Cancer Control at St. Jude Children’s Research Hospital in Memphis, TN; Kathleen C. Insel, PhD, is a professor in the College of Nursing at the University of Arizona in Tucson; Lynnette L. Harris, PhD, is an associate professor at the Baylor College of Medicine in Houston, TX; Patricia M. Gundy, MS, is a principal research specialist in the College of Nursing at the University of Arizona; Kristin B. Adkins, MA, is a psychological associate at the Baylor College of Medicine; Alice E. Pasvogel, PhD, is an assistant research scientist in the College of Nursing at the University of Arizona; Olga A. Taylor, MPH, is a senior research coordinator at the Baylor College of Medicine; Kari M. Koerner, MPH, is a research specialist, David W. Montgomery, PhD, is a research professor, and Adam K. Ross, BS, is a research technician, all in the College of Nursing at the University of Arizona; Adam Hill, MD, is a palliative care fellow in the Palliative Care Program at Indiana University Health in Bloomington; and Ida (Ki) M. Moore, PhD, is a professor and biobehavioral health science division director in the College of Nursing at the University of Arizona. This study was supported by the National Institute of Nursing Research at the National Institutes of Health (NR010889). Mention of specific products and opinions related to those products do not indicate or imply endorsement by the Oncology Nursing Forum or the Oncology Nursing Society. Moore can be reached at imoore@email.arizona.edu, with copy to editor at ONFEditor@ons.org. (Submitted January 2015. Accepted for publication April 8, 2015.)