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Abraham, Anna, and L. Appaji. "Cognitive assessment of children with acute lymphoblastic leukemia: Preliminary findings." Indian Journal of Medical and Paediatric Oncology 30, no. 1 (2009): 14. http://dx.doi.org/10.4103/0971-5851.56330.
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Hooke, Mary C., Daniel Hatch, Marilyn J. Hockenberry, Susan Whitman, Ida Moore, David Montgomery, Kari Marano, et al. "The Longitudinal Parallel Process Analysis of Biomarkers of Oxidative Stress, Symptom Clusters, and Cognitive Function in Children With Leukemia." Journal of Pediatric Oncology Nursing 37, no. 4 (March 6, 2020): 244–54. http://dx.doi.org/10.1177/1043454220909785.
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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.
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Waber, Deborah P., Lewis B. Silverman, Lori Catania, William Mautz, Montse Rue, Richard D. Gelber, Donna E. Levy, et al. "Outcomes of a Randomized Trial of Hyperfractionated Cranial Radiation Therapy for Treatment of High-Risk Acute Lymphoblastic Leukemia: Therapeutic Efficacy and Neurotoxicity." Journal of Clinical Oncology 22, no. 13 (July 1, 2004): 2701–7. http://dx.doi.org/10.1200/jco.2004.10.173.
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Purpose We evaluated 8-year survival and late neuropsychologic toxicity in children with acute lymphoblastic leukemia treated in a randomized clinical trial to test whether hyperfractionated (twice daily) cranial radiation therapy (CRT) can reduce incidence and severity of late toxicities associated with 18 Gy of CRT. Patients and Methods Between 1987 and 1995, 369 children treated on two consecutive Dana-Farber Cancer Institute Consortium protocols for high-risk acute lymphoblastic leukemia were randomly assigned to conventionally fractionated CRT (CFX) or hyperfractionated CRT (HFX) to a total dose of 18 Gy. Neuropsychologic testing was completed for 125 of 287 children in continuous complete remission. Event-free and overall survival, as well as neuropsychologic function, were compared for the two arms of the protocol. Results Eight-year event-free survival (± SE) was 80% ± 3% for children randomly assigned to CFX and 72% ± 3% for HFX (P = .06). Overall survival was 85% ± 3% for CFX and 78% ± 3% for HFX (P = .06). CNS relapses occurred in 2.8% of patients receiving CFX and 2.7% receiving HFX (P = .99). Cognitive function for both groups was solidly in the average range, with no group differences in intelligence, academic achievement, visuospatial reasoning, or verbal learning. Children on the HFX arm exhibited a modest advantage for visual memory (P < .05). Conclusion HFX provides no benefit in terms of cognitive late effects and may compromise antileukemic efficacy. HFX should not be substituted for conventionally dosed CRT in children who require radiation therapy for treatment of acute lymphoblastic leukemia.
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Wright, Marilyn J., Vicky Galea, and Ronald D. Barr. "Proficiency of Balance in Children and Youth Who Have Had Acute Lymphoblastic Leukemia." Physical Therapy 85, no. 8 (August 1, 2005): 782–90. http://dx.doi.org/10.1093/ptj/85.8.782.
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Abstract Background and Purpose. As the survival rate for acute lymphoblastic leukemia (ALL) in childhood increases, long-term sequelae are a growing concern. This cross-sectional, descriptive study compared the balance skills of children and youth who have had ALL with those of comparable subjects and explored associations with demographics, therapy, physical activity, and health-related quality of life (HRQL). Subjects. Ninety-nine subjects treated previously for ALL and 89 comparison subjects were examined. Methods. Measures included the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP) balance subtest, the Children's Self-perceptions of Adequacy in and Predilection for Physical Activity Scale (CSAPPA), and the Health Utilities Index (HUI), a measure of HRQL. Results. The children and youth who had ALL had poorer balance than the comparison subjects (BOTMP=10.55 and 16.30, respectively) and lower CSAPPA scores (57.72 and 63.72, respectively) and HUI scores (0.86 and 0.97, respectively). Regression analyses identified exposure to cranial irradiation, being overweight, lower CSAPPA scores for adequacy, and lower HUI single-attribute scores for cognition as predictors of lower balance scores in subjects who had ALL. Discussion and Conclusion. Balance abilities in subjects treated for ALL were compromised, and several factors were associated with this deficit.
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Warris, Lidewij T., Marry M. van den Heuvel-Eibrink, Ingrid M. Ariës, Rob Pieters, Erica L. T. van den Akker, and Monique L. Den Boer. "Hydrocortisone does Not Influence in Vitro Glucocorticoid Sensitivity of Acute Lymphoblastic Leukemia Blasts." Blood 124, no. 21 (December 6, 2014): 5228. http://dx.doi.org/10.1182/blood.v124.21.5228.5228.
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Abstract Introduction: Dexamethasone-induced neuropsychological side effects on mood, behavior and cognition seriously affect quality of life in children with acute lymphoblastic leukemia (ALL) during a long treatment period. Based on recent studies in animals, we hypothesized that these neuropsychological side effects are mediated by dexamethasone-induced cortisol depletion of the mineralocorticoid receptor (MR) in the brain. Therefore, we hypothesize that these side effects could be ameliorated by an intervention with hydrocortisone. For clinical application settings however, an absolute prerequisite is that MR activation does not interfere with the efficacy of the glucocorticoids, dexamethasone and prednisolone, on ALL cells. Materials and Methods: To investigate responsiveness of leukemic cell lines and fresh patients’ leukemic cells to dexamethasone and prednisolone in the presence of hydrocortisone, MTT-assays were performed. In addition MR and the glucocorticoid receptor (GR) expression on leukemic cells of different ALL subtypes was studied with a microarray-based gene expression profiling and validated by quantitative real-time PCR. Results: Leukemic cells expressed the MR at a very low level with a significantly higher (P≤0.001) expression in ETV6-RUNX1+ patients (median: 160.7 [AU] of fluorescence intensity, range: 38.1 - 760.6 [AU]) versus other ALL subtypes (median: 41.8 [AU] of fluorescence intensity, range: 25.1 - 276.2 [AU]). MR expression did not differ between glucocorticoid resistant and sensitive patients’ cells. Hydrocortisone addition did not affect glucocorticoid sensitivity of leukemic cell lines and patients’ leukemic cells of different leukemic subtypes also including ETV6-RUNX1+. Glucocorticoid sensitive patients’ cells became significantly more sensitive by hydrocortisone addition (prednisolone: P≤0.01, dexamethasone: P≤0.05). Conclusion: This present study shows that hydrocortisone does not interfere with efficacy of dexamethasone and prednisolone in vitro. These findings support a clinical randomized trial to study whether addition of hydrocortisone decreases the neuropsychological side effects of dexamethasone in children with ALL. Acknowledgments: The financial support of the KiKa® (Kinderen Kankervrij) foundation is highly appreciated. Disclosures No relevant conflicts of interest to declare.
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Waber, Deborah P., Sarah C. Carpentieri, Neil Klar, Lewis B. Silverman, Molly Schwenn, Craig A. Hurwitz, Phyllis J. Mullenix, Nancy J. Tarbell, and Stephen E. Sallan. "Cognitive Sequelae in Children Treated for Acute Lymphoblastic Leukemia With Dexamethasone or Prednisone." Journal of Pediatric Hematology/Oncology 22, no. 3 (May 2000): 206–13. http://dx.doi.org/10.1097/00043426-200005000-00004.
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Williams, Kelli S., Judith Ochs, J. Michael Williams, and Raymond K. Mulhern. "Parental Report of Everyday Cognitive Abilities Among Children Treated For Acute Lymphoblastic Leukemia." Journal of Pediatric Psychology 16, no. 1 (1991): 13–26. http://dx.doi.org/10.1093/jpepsy/16.1.13.
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Yildiz Kabak, Vesile, Yasin Ekinci, Songul Atasavun Uysal, Mualla Cetin, and Tulin Duger. "Motor and Basic Cognitive Functions in Children with Acute Lymphoblastic Leukemia Undergoing Induction or Consolidation Chemotherapy." Perceptual and Motor Skills 128, no. 3 (March 17, 2021): 1091–106. http://dx.doi.org/10.1177/00315125211002065.
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Children with acute leukemia (ALL) often suffer from several disease and treatment related side-effects during treatment. The aim of the present study was to determine the gross and fine motor functioning and basic cognitive performance of children (n = 25) with ALL who were undergoing induction or consolidation chemotherapy and to compare these characteristics to a normative group (n = 21) of age-matched typically developing children. We assessed the children’s motor functions with the Bruininks-Oseretsky Test of Motor Proficiency Second Edition-Short Form and the Nine-hole Peg Test, and we used the Modified Mini-Mental State Exam (MMSE) to evaluate their cognitive performance. Compared to the normative group, children with ALL had lower scores on total motor proficiency and sub-tests scores of motor functions ( p < .05), and on the Nine-hole Peg Test performance ( p < .05); but their cognitive performance on the MMSE was not significantly different. Children with ALL would likely benefit from structured exercise and rehabilitative interventions during chemotherapy to prevent and/or ameliorate ALL-related motor dysfunction. We also suggest that their cognitive functioning should be further investigated with more extensive well-validated neurocognitive tests for children (e.g., the Wechsler intelligence scales).
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Tremolada, Marta, Livia Taverna, Sabrina Bonichini, Marta Pillon, and Alessandra Biffi. "The Developmental Pathways of Preschool Children with Acute Lymphoblastic Leukemia: Communicative and Social Sequelae One Year after Treatment." Children 6, no. 8 (August 13, 2019): 92. http://dx.doi.org/10.3390/children6080092.
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Early childhood is considered to be a period of rapid development, with the acquisition of abilities predicting future positive school competences. Motor, cognitive, and social difficulties related to cancer therapies heavily impact the development of children with cancer. This study focused on two main aims: To assess the developmental pathways of preschool children with acute lymphoblastic leukemia one year post-treatment and to compare these abilities both with those of a control group of healthy peers and with Italian norms. Forty-four children and their families, recruited through the Hematology-Oncologic Clinic of the Department of Child and Woman Health (University of Padua), agreed to participate in this study. The children’s mean age was 4.52 years (SD = 0.94, range = 2.5–6 years), equally distributed by gender, all diagnosed with acute lymphoblastic leukemia. Matched healthy peers were recruited through pediatricians’ ambulatories. Each family was interviewed adopting the Vineland adaptive behavior scales. Paired sample Wilcoxon tests revealed that children were reported to have significantly more developmental difficulties than their healthy peers. When compared with Italian norms, they scored particularly low in verbal competence, social, and coping skills. No significant association was found between treatment variables and developmental abilities. These findings suggest that the creation of specialized interventions, both for parents and children, may fill the possible delays in children’s development probably due to stress, lack of adequate stimulation, or difficult adaptation.
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Balsamo, Lyn M., Kyaw J. Sint, Joseph Philip Neglia, and Nina Kadan-Lottick. "Assessment of executive function (EF) among pediatric survivors of acute lymphoblastic leukemia (ALL)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 9584. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.9584.
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9584 Background: Childhood ALL survivors are at increased risk of impaired EF. Both parent ratings and performance-based measures are used to identify vulnerable patients. We seek to assess the association between these modalities to 1) each other, and 2) need for special education and stimulants. Methods: This 22-site cross-sectional study included 256 children in remission for standard-risk precursor-B ALL previously enrolled on legacy Children's Oncology Protocols from 1993 - 2000. Patients had no history of CNS leukemia, cranial radiation, or pre-existing neurodevelopmental disorders; were ≥1 year off-therapy; and were 6-16 years at evaluation. Patients were administered performance-based measures of working memory, Digit Span (DS) and Letter-Number Sequencing (LNS) comprising the Working Memory Index (WMI) from the Wechsler Intelligence Scales for Children - Fourth Edition. Patients completed the Controlled Oral Word Association Test (COWAT). Parents completed demographic surveys and a Likert-scale assessment of executive processes, Behavior Rating Inventory of Executive Function (BRIEF). Results: There were modest correlations between BRIEF-WM scale and WMI (r=-0.20, p<0.01) and subscales, DS (r=-0.17, p<0.01) and LNS (r=-0.19, p<0.01). BRIEF-Initiate and COWAT (r=-0.22, p<0.01) were correlated. However, impaired classification based on performance-based measures was a poor predictor of parent assessment classification. The WMI and BRIEF-WM independently predicted receipt of special education (p=0.0017 and 0.0003). The BRIEF-WM and Initiate scales predicted stimulant medication use (p<0.0001 and p=0.0037); however, performance-based measures did not. Conclusions: Rater and performance-based measures provide related, but different information about EF indicating the need for both. Both measurement modalities capture educational difficulties; however, only parent ratings are associated with stimulants. This may reflect the medication's success in modifying cognition in controlled environments and the BRIEF's sensitivity to the child's ability to execute tasks in the real-world setting.
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Waber, Deborah P., Gerald Gioia, Jeanne Paccia, Barbara Sherman, David Dinklage, Natalie Sollee, David K. Urion, Nancy J. Tarbell, and Stephen E. Sallan. "Sex Differences in Cognitive Processing in Children Treated with CNS Prophylaxis for Acute Lymphoblastic Leukemia." Journal of Pediatric Psychology 15, no. 1 (1990): 105–22. http://dx.doi.org/10.1093/jpepsy/15.1.105.
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Chen, Yu-Chieh, Jiunn-Ming Sheen, Su-Chen Wang, Mei-Hsin Hsu, Chih-Cheng Hsiao, Kow-Aung Chang, and Li-Tung Huang. "Methotrexate Neurotoxicity Is Related to Epigenetic Modification of the Myelination Process." International Journal of Molecular Sciences 22, no. 13 (June 23, 2021): 6718. http://dx.doi.org/10.3390/ijms22136718.
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With the improvement of the survival rate of acute lymphoblastic leukemia (ALL) in children, some children ALL survivors reveal inferior intellectual and cognition outcome. Methotrexate (MTX), while serving as an essential component in ALL treatment, has been reported to be related to various neurologic sequelae. Using combined intrathecal (IT) and intraperitoneal (IP) MTX model, we had demonstrated impaired spatial memory function in developing rats, which can be rescued by melatonin treatment. To elucidate the impact of MTX treatment on the epigenetic modifications of the myelination process, we examined the change of neurotrophin and myelination-related transcriptomes in the present study and found combined IT and IP MTX treatment resulted in altered epigenetic modification on the myelination process, mainly in the hippocampus. Further, melatonin can restore the MTX effect through alterations of the epigenetic pathways.
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Yao, Hisayuki, Trevor Price, Lindsey Olivere, Matthew Warner, Stacey Tannheimer, and Dorothy A. Sipkins. "PI3Kδ Inhibition Suppresses Central Nervous System Involvement of Acute Lymphoblastic Leukemia." Blood 128, no. 22 (December 2, 2016): 282. http://dx.doi.org/10.1182/blood.v128.22.282.282.
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Abstract The majority of children and adults who experience relapse of acute lymphoblastic leukemia (ALL) will die from the disease. The presence of leukemic blasts within the cerebrospinal fluid (CSF) is an important predictor of disease recurrence in both the bone marrow (BM) and central nervous system (CNS), a frequent site of disease involvement. In the absence of intrathecal chemotherapy or craniospinal irradiation, 30%‒50% of patients will in fact develop CNS disease. All patients therefore receive CNS prophylaxis. High-risk patients require intensive CNS-directed treatment that causes toxic side effects and can impact cognitive development in children. Patients who develop recurrence in the CNS have limited treatment options and an extremely poor prognosis. The enzyme PI3K plays an important role in many biological effects including cell proliferation, migration, and apoptosis. The d isoform of PI3K is specifically expressed in immune cells. The PI3Kd inhibitor idelalisib is approved for use in combination with rituximab for the treatment of chronic lymphocytic leukemia (CLL). However, little is known about the efficacy of PI3Kd inhibition in ALL. Here, the PI3Kd inhibitor GS-649443, a potent and specific in vivo tool compound, was evaluated in a xenograft mouse model. The in vivo effects of GS-649443 were investigated in a Nalm-6 pre-B ALL SCID model. At approximately 40 days postengraftment, untreated mice all developed symptoms of CNS involvement and displayed hind limb paralysis. Hind limb paralysis is the clinical endpoint for sacrifice, occurring prior to death from progressive BM disease. Mice were treated with GS-649443 by oral gavage beginning on postengraftment day 1 and continuing until the development of clinical symptoms requiring sacrifice (hind limb paralysis, weight loss >20%, respiratory or other distress). Only 17% of GS-649443‒treated mice developed hind limb paralysis at their clinical endpoint, while 100% of vehicle-treated mice showed hind limb paralysis. In addition, mice treated with GS-649443 or vehicle control were paired. When either mouse in a treatment pair reached a clinical endpoint, both were sacrificed so disease burden in individual organs could be compared at matched time points. There was no difference in tumor burden or leukemic cell apoptotic rate in the BM of treated vs vehicle control groups. In contrast, there was a significant decrease in the number of leukemic blasts harvested from the CSF of treated mice (Fig. 1). Consistent with the inhibition of CNS disease progression, GS-649443 significantly prolonged the survival of treated mice (Fig. 2). While compromised blood-brain barrier in leukemic mice may allow therapeutic targeting of CNS disease, it is unknown whether GS-649443 enters the CNS in healthy rodents. Given the well-described effects of idelalisib on CLL cell migration, we hypothesized that PI3Kd blockade impacts disease in this ALL model by impairing leukemia migration into the CNS. To investigate the in vitro effect of GS-649443 on ALL cell migration, transwell migration assays with SDF-1 as chemoattractant were performed. Both GS-649443 and idelalisib suppressed migration of Nalm-6 and primary human ALL cells toward SDF-1. Lastly, the effects of GS-649443 in combination with conventional chemotherapy were examined. GS-649443 alone did not cause significant cytotoxicity of Nalm-6 in vitro, however, treatment with GS-649443 after cytarabine significantly increased apoptosis. Leukemic mice (20 days post-engraftment) were then treated with cytarabine (days 1‒5) in combination with GS-649443 or cytarabine alone (days 1‒7) for 1 cycle. In contrast to the single-agent study, significant decreases in the number of leukemic blasts harvested from both the BM and CSF of treated mice were observed, suggesting that PI3Kd inhibition sensitized ALL cells to cytarabine chemotherapy (Fig. 3). This decrease in residual disease after combination therapy led to significantly prolonged survival in GS-649443‒treated mice (Fig. 4). Taken together, this study provides evidence that PI3Kd inhibition prevents ALL progression in the CNS. In addition, GS-649443 and conventional chemotherapy appear to synergize to decrease residual BM disease. The potential for PI3Kd inhibition to improve chemotherapy response and impede development of CNS disease in ALL warrants further investigation in a translational clinical study. Disclosures Yao: Gilead Sciences, Inc.: Research Funding. Price:Gilead Sciences, Inc.: Research Funding. Olivere:Gilead Sciences, Inc.: Research Funding. Warner:Gilead Sciences, Inc.: Research Funding. Tannheimer:Gilead Sciences: Employment. Sipkins:Gilead Sciences, Inc.: Research Funding.
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Miketova, Petra, Kris Kaemingk, Marilyn Hockenberry, Alice Pasvogel, John Hutter, Kevin Krull, and Ida M. (Ki) Moore. "Oxidative Changes in Cerebral Spinal Fluid Phosphatidylcholine during Treatment for Acute Lymphoblastic Leukemia." Biological Research For Nursing 6, no. 3 (January 2005): 187–95. http://dx.doi.org/10.1177/1099800404271916.
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Central nervous system (CNS) treatment contributes to improved long-term disease-free survival from childhood acute lymphoblastic leukemia (ALL) by sigificantly decreasing the rate of disease relapse. Methotrexate (MTX), a drug commonly used for CNS treatment, has been associated with cognitive and academic problems, white-matter changes, perfusion defects, and brain atrophy. This study investigated oxidative stress as a possible mechanism of chemotherapyinduced CNS injury. Unoxidized and oxidized components of phosphatidylcholine (PC), the most prevalent phospholipid in CNS cellular membranes, were measured in cerebral spinal fluid (CSF) samples obtained from 21 children diagnosed with low (n = 7), standard (n= 7), or high (n= 7) risk ALL. Children with high-risk ALL received the most MTX, especially during the most intensive phase of treatment (consolidation). Phospholipids were extracted from CSF samples obtained at diagnosis and during the induction, consolidation, and continuation treatment phases. Unoxidized and oxidized PC were measured by normalphase high-performance liquid chromatography at 2 ultraviolet wavelengths (206 and 234 nm, respectively). Data were analyzed by 2-way repeated-measures analysis of variance. Results support the hypotheses that the highest levels of oxidized PC would be observed during the most intensive phase of ALL therapy and in the high-risk ALL group. Findings provide preliminary evidence for chemotherapy-induced oxidative stress inCNSmembrane phospholipids.
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Annett, Robert D., Sarah Hile, Edward Bedrick, Alicia S. Kunin-Batson, Kevin R. Krull, Leanne Embry, Willliam E. MacLean, and Robert B. Noll. "Neuropsychological functioning of children treated for acute lymphoblastic leukemia: impact of whole brain radiation therapy." Psycho-Oncology 24, no. 2 (June 2, 2014): 181–89. http://dx.doi.org/10.1002/pon.3586.
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Waber, D. P., N. J. Tarbell, D. Fairclough, K. Atmore, R. Castro, P. Isquith, F. Lussier, I. Romero, P. J. Carpenter, and M. Schiller. "Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice." Journal of Clinical Oncology 13, no. 10 (October 1995): 2490–96. http://dx.doi.org/10.1200/jco.1995.13.10.2490.
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PURPOSE We evaluated cognitive sequelae of treatment for childhood acute lymphoblastic leukemia (ALL). CNS therapy consisted of cranial irradiation (CRT) or no radiation. Children were also randomized to single intravenous high-dose methotrexate (HD-MTX) or conventional-dose methotrexate (CD-MTX) during induction, and all patients received intrathecal (IT) and systemic continuation chemotherapy. PATIENTS AND METHODS Sixty-six patients treated for ALL on Dana-Farber Cancer Institute protocol 87-01 were evaluated by standardized cognitive and achievement tests. These children had been assigned at diagnosis to a standard-risk (SR) or high-risk (HR) group and received no CRT or 18 Gy CRT, respectively. All patients were randomized to receive MTX during remission induction, either as CD-MTX (40 mg/m2) or HD-MTX (4 g/m2) with leucovorin rescue. RESULTS There was no difference in cognitive outcomes between radiated and unirradiated patients (P > .4). However, the HD-MTX/CRT combination was associated with decreased intelligence quotient (IQ estimate, 9.3 points) for girls only (P < .08). A specific deficit in verbal coding and memory was documented for all patients (P < .0001). CONCLUSION We conclude the following: (1) 18 Gy CRT per se was not an independent toxic agent for cognitive outcome; (2) HD-MTX during induction was associated with IQ decline in girls, but only when it was followed by CRT; and (3) impairment of verbal memory and coding was a consistent finding that was independent of CRT, which implicates some component of chemotherapy, possibly prednisone, as a CNS toxin.
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Moore, Ida M. (Ki), Petra Miketova, Marilyn Hockenberry, Kevin Krull, Alice Pasvogel, Marissa Carey, and Kris Kaemingk. "Methotrexate-Induced Alterations in Beta-Oxidation Correlate With Cognitive Abilities in Children With Acute Lymphoblastic Leukemia." Biological Research For Nursing 9, no. 4 (April 2008): 311–19. http://dx.doi.org/10.1177/1099800407313268.
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Treatment advances, including central nervous system (CNS) treatment with methotrexate, have led to significant gains in disease-free survival from childhood acute lymphoblastic leukemia (ALL). However, methotrexate has been associated with neurological problems such as declines in cognitive and academic abilities. The purpose of this study was to investigate methotrexate-induced changes in beta-oxidation in children with ALL receiving methotrexate for CNS treatment. Specific aims were to investigate effects of methotrexate on beta-oxidation of the two most prevalent fatty acids (palmitic acid and stearic acid) in cerebrospinal fluid (CSF) samples and correlate the ratio of monounsaturation to saturation of these fatty acids with cognitive and academic abilities. The sample included 12 females and 14 males with low-risk ( n = 7), standard-risk ( n = 13), or high-risk ( n = 6) ALL. Mean age at diagnosis was 94.1 months ( SD = 34.4). CSF samples were obtained in conjunction with diagnostic lumbar punctures; subsequent samples were obtained prior to intrathecal methotrexate administration during the induction, consolidation, and continuation phases of treatment. Fatty acids were analyzed by gas chromatography. Results showed a significant increase in the ratio of monounsaturation to saturation of both fatty acids, which was greatest during the most intensive phase of treatment. Ratios of monounsaturated to saturated fatty acids were negatively correlated with full-scale IQ, verbal IQ, and math calculations. Findings suggest that methotrexate alters beta-oxidation and that the resulting increase in fatty acid monounsaturation is related to declines in some domains of cognitive ability.
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Wright, Marilyn J., Victoria Galea, and Ronald D. Barr. "Self-Perceptions of Physical Activity in Survivors of Acute Lymphoblastic Leukemia in Childhood." Pediatric Exercise Science 15, no. 2 (May 2003): 191–201. http://dx.doi.org/10.1123/pes.15.2.191.
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Participation in physical activity has important beneficial effects on physical and psychological health. Many outcomes associated with physical activity are typically compromised in survivors of childhood cancer. The purpose of this study was to describe self-perceptions of physical activity in survivors of acute lymphoblastic leukemia (ALL) and to explore the relationships of these findings with quality of life measures and clinical descriptors. 62 children and adolescents treated previously for ALL and 71 comparable healthy subjects completed the Children’s Self-perceptions of Adequacy in and Predilection for Physical Activity (CSAPPA) scale and the Health Utilities Index (HUI). The ALL subjects had significantly poorer self-perceptions of their adequacy in and predilection for physical activity than the comparison group. Stepwise regression analyses identified high risk for relapse, female gender, and older age, but not body-mass-index, age, age at diagnosis, length of time off therapy, or cranial irradiation as significant predictors of CSAPPA total scores in the ALL group. HUI overall scores and single attribute scores for emotion, cognition and pain had significant positive correlations with various CSAPPA scores. Results suggest that survivors of ALL are less inclined to participate in physical activity and physical activity scores are related to quality of life scores. Long-term follow-up should include education and programming to promote participation in physical activity.
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Protas, Piotr T., Katarzyna Muszynska-Roslan, Adam Holownia, Aleksandra Grabowska, Przemyslaw Wielgat, Maryna Krawczuk-Rybak, and Jan J. Braszko. "Negative correlation between cerebrospinal fluid tau protein and cognitive functioning in children with acute lymphoblastic leukemia." Pediatric Blood & Cancer 53, no. 1 (July 15, 2009): 105–8. http://dx.doi.org/10.1002/pbc.22029.
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Halberg, F. E., J. H. Kramer, I. M. Moore, W. M. Wara, K. K. Matthayi, and A. R. Ablin. "Prophylactic cranial irradiation dose effects on late cognitive function in children treated for acute lymphoblastic leukemia." International Journal of Radiation Oncology*Biology*Physics 22, no. 1 (January 1992): 13–16. http://dx.doi.org/10.1016/0360-3016(92)90976-o.
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Umaretiya, Puja J., Victoria B. Koch, Kristen E. Stevenson, Peter D. Cole, Lisa M. Gennarini, Justine Kahn, Kara M. Kelly, et al. "Household material hardship and parental distress in a multicenter clinical trial for pediatric acute lymphoblastic leukemia." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 10025. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.10025.
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10025 Background: Poverty is associated with inferior psychosocial function among parents of children with cancer. Severe parental distress during treatment predicts future poor mental health for both parents and children. It is also associated with impaired parental cognitive bandwidth and executive function, which may have implications for treatment adherence. Efforts to identify poverty-exposures amenable to intervention are essential to improving survivorship quality of life for the > 90% of children with acute lymphoblastic leukemia (ALL) who will be long-term survivors. Household material hardship (HMH) is a targetable poverty exposure defined as at least 1 of 3 unmet basic needs including food, housing, or utilities. Dana-Farber Cancer Institute (DFCI) ALL Consortium trial 16-001 is the first pediatric oncology clinical trial to systematically evaluate HMH. We investigated the hypothesis that HMH exposure independently predicts severe parent psychological distress during ALL therapy. Methods: Patients with newly diagnosed ALL ages 1-17 years were enrolled on the DFCI 16-001 embedded HMH cohort study at 8 U.S. and Canadian centers. Secondary interim analyses used baseline (within 32-days of trial enrollment) and 6-mos parent-reported sociodemographic data, the Kessler-6 (K6) Psychological Distress scale, and trial-collected child and disease data. Severe psychological distress was defined as a K6 > = 13. Multivariable cox regression evaluated baseline HMH-exposure and parent distress at baseline and 6-mos adjusting for child’s initial ALL risk group (Very High Risk (VHR) vs other) and marital status (single vs dual parent). Results: Among 258 families with evaluable data, 34% reported baseline HMH. Families were predominantly English-speaking (54%) dual parent households (71%). Children were a median of 5.7 years (IQR 1.0-17.99) at diagnosis and predominantly non-Hispanic white (66%) with expected disease distribution by immunophenotype (84% B-cell). HMH (odds ratio (OR) 2.18, 95% confidence interval (CI) 1.0-4.31, p = 0.025) and VHR initial risk group (OR 2.32; 95% CI 1.06-5.06, p = 0.035) were independently associated with baseline severe psychological distress. Only HMH was independently associated with 6-mos severe psychological distress (OR 4.93, 95% CI 1.80-13.48, p = 0.002). Future analyses will investigate race and ethnicity associations with parental distress pending trial accrual for statistical power. Conclusions: HMH, a modifiable poverty exposure, is significantly associated with severe parent psychological distress at diagnosis that persists 6-months into pediatric ALL therapy. These findings identify a cohort at high risk of inferior mental health outcomes, and affirm the need for HMH-targeted interventions to support children and parents during cancer treatment to reduce poverty-associated outcome disparities in survivorship.
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Hockenberry, M. J., K. Krull, I. M. Moore, A. Pasvogel, M. Gregurich, and K. Kaemingk. "Longitudinal evaluation of fine motor deficits in children with leukemia." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 8559. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.8559.
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8559 Background: Fine motor assessments are important tools to use in screening children undergoing treatment for acute lymphoblastic leukemia (ALL) that may provide decisive data that can reveal subtle changes in neurodevelopment over time. Methods: Fine motor and visual-motor skills were assessed longitudinally in a group of 83 children receiving treatment for ALL. Children in this study had the first fine motor assessment at an average of 8 weeks into treatment and had already received several doses of Vincristine. Fine motor and visual-motor skills assessments were repeated at years 1 and 2 into therapy. The mean age at time of first assessment was 7.2 years and 58% were female. Results: Fine motor speed deficits were evident at the first assessment, and for many, continued to be problematic at Years 1 and 2. In addition to fine motor speed deficits, a significant decline in visual motor integration skills was noted from the baseline level (p = 0.019). Visual motor integration skills observed at Years 1 and 2 were predicted by the baseline performance on the Purdue Pegboard test. Our results indicate that the factors underlying these declines in higher-level skills begin within six months of the onset of chemotherapy. Conclusions: Early reductions in fine motor speed, possibly due to Vincristine, steroids and/or acute Methotrexate toxicity, may lead to reduced visual motor integration and construction abilities. The reduced fine motor skills, which predict eventual declines in visual motor integration, may be part of the underlying process for reduced perceptual abilities and nonverbal intellect often reported in long-term follow-up studies. For children with ALL, motor and sensory-perceptual examinations during treatment may identify those most at risk for significant long-term effects interfering with integration of visual spatial construction. These basic processing skills are necessary elements to the development of higher-level cognitive abilities, including nonverbal intelligence and academic achievement, particularly in arithmetic and written language. Early identification of reduced processing skills can provide an opportunity to identify at risk patients and intervene prior to reduction in these higher-level skills. Supported by NIH/NICHD RO-1 Funding: Grant number HD 37816 No significant financial relationships to disclose.
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Halberg, F. E., J. H. Kramer, I. M. Moore, W. M. Wara, K. K. Matthay, and A. R. Ablin. "Cranial radiotherapy (RT) dose effects on late cognitive function in children treated for acute lymphoblastic leukemia (ALL)." International Journal of Radiation Oncology*Biology*Physics 19 (January 1990): 177. http://dx.doi.org/10.1016/0360-3016(90)90751-5.
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Zajac-Spychala, Olga, Mikolaj Pawlak, Katarzyna Karmelita-Katulska, Jakub Pilarczyk, Katarzyna Derwich, and Jacek Wachowiak. "Long-Term Brain Status and Cognitive Functioning In Children With Acute Lymphoblastic Leukemia Treated According To ALL IC-BFM 2002." Blood 122, no. 21 (November 15, 2013): 2637. http://dx.doi.org/10.1182/blood.v122.21.2637.2637.
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Abstract Background Acute lymphoblastic leukemia (ALL) comprises about 85% of all leukemias in children and is the most frequent malignancy of childhood. Long-term side effects of applied therapy according to ALL IC-BFM 2002 (with prophylactic CNS radiotherapy dose reduced to 12 Gy given in combination with high-dose methotrexate intra venous and methotrexate alone or in combination with cytarabine and prednisolone intra thecally) are still unknown. Aim The aim of this cross-sectional study is to assess the long-term side effects of central nervous system (CNS) prophylaxis (high-dose chemotherapy i.v. alone vs. high dose chemotherapy i.v. combined with prophylactic CNS radiotherapy) according to ALL IC-BFM 2002 by the whole brain magnetic resonance and assessment the neuropsychological functioning. Patients and Methods Out of 150 children treated in 2002-2010 because of ALL, 58 children (23 girls and 35 boys) aged 6.4 - 19.9 years (median: 14.4) have been previously studied, including 26 children treated with chemotherapy alone, 21 - treated with chemo- and radiotherapy, and 11 - before treatment (control group). The structural assessment included evaluation of the segmentation of brain and calculation of the volume of white and gray matter as well as segmentation of subcortical structures. The neuropsychological assessment included the Wechsler Intelligence Test for Children (WISC-R; IQ assessment and long-term memory), Rey Auditory Verbal Learning Test (RAVLT; evaluation of short term memory), Benton Visual Retention Test (evaluation of visual memory), Verbal Fluency Test (evaluation of verbal memory), the Stroop test (evaluation of reaction time and executive) and Wisconsin Card Sorting Test (WSCT; evaluation of executive functions). Results Patients treated with high-dose chemotherapy and CNS radiotherapy had a lower volume of the hippocampus (6.7 cm³) and basal ganglia (29 cm³) compared to the group treated with chemotherapy alone (8 cm³ and 31 cm³, respectively) and the control group (8 cm³ and 32 cm³). All patients treated due to ALL had smaller total volume of brain ventricles (12 cm³ in the group treated with chemo-and radiotherapy, and 13 cm³ in the group treated with chemotherapy alone), compared to the control group (18 cm³). In patients, who that received chemo-and radiotherapy the average intelligence quotient was lower (IQ - 101), visual-spatial memory was worse (Benton test – 6 correct reproductions), auditory-verbal memory was worse (6, 7, 9, 9, 11) and lower verbal fluency (10 for phonemic category and 13 for semantic one) as compared to patients treated with chemotherapy alone (respectively: IQ - 116, Benton test - 7; RAVLT -7, 7, 10, 12, 13; verbal fluency – 12 and 16) and to patients in the control group (IQ - 116, Benton test - 9; RAVLT - 9, 11 , 13, 13, 14; verbal fluency – 15 and 19). The group treated with chemo-and radiotherapy (WSCT - 3.2 classified category, the rate of correct answers - 0.48, Stroop test - 3.2) and the group treated with chemotherapy alone (WSCT - 4.1 category, the rate of correct answers - 0.59; Stroop test - 2.9) performed significantly worse on measures of executive functioning in comparison to the control group (WSCT - 5.2 category, the rate of correct answers - 0.71; Stroop test - 2.5). Conclusions In children treated for ALL according to the ALL IC-BFM 2002 both CNS structural changes and cognitive impairment may be observed. These abnormalities are even more pronounced in children who received chemotherapy in combination with CNS radiotherapy. This work was supported by grant from the National Science Centre (DEC-2012/05/N/NZ5/00879). Disclosures: No relevant conflicts of interest to declare.
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Kingma, Annette, Rieneke I. Van Dommelen, Eduard L. Mooyaart, Jan T. Wilmink, Betto G. Deelman, and Willem A. Kamps. "No Major Cognitive Impairment in Young Children With Acute Lymphoblastic Leukemia Using Chemotherapy Only: A Prospective Longitudinal Study." Journal of Pediatric Hematology/Oncology 24, no. 2 (February 2002): 106–14. http://dx.doi.org/10.1097/00043426-200202000-00010.
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Cole, Peter D., Yaron Finkelstein, Kristen E. Stevenson, Traci M. Blonquist, Veena Vijayanathan, Lewis B. Silverman, Donna S. Neuberg, Stephen E. Sallan, Philippe Robaey, and Deborah P. Waber. "Polymorphisms in Genes Related to Oxidative Stress Are Associated With Inferior Cognitive Function After Therapy for Childhood Acute Lymphoblastic Leukemia." Journal of Clinical Oncology 33, no. 19 (July 1, 2015): 2205–11. http://dx.doi.org/10.1200/jco.2014.59.0273.
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Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) exhibit increased rates of neurocognitive deficits. This study was conducted to test whether interpatient variability in neurocognitive outcomes can be explained by polymorphisms in candidate genes conferring susceptibility to neurocognitive decline. Methods Neurocognitive testing was conducted in 350 pediatric leukemia survivors, treated on Dana-Farber Cancer Institute ALL Consortium Protocols 95-01 or 00-01. Genomic DNA was isolated from bone marrow collected at remission. Candidate polymorphisms were selected on the basis of prior literature, targeting genes related to drug metabolism, oxidative damage, altered neurotransmission, neuroinflammation, and folate physiology. Single nucleotide polymorphisms were detected using either a customized multiplexed Sequenom MassARRAY assay or polymerase chain reaction–based allelic discrimination assays. Multivariable logistic regression models were used to estimate the effects of genotype on neurocognitive outcomes, adjusted for the effects of demographic and treatment variables. False-discovery rate correction was made for multiple hypothesis testing, indicated as a Q value. Results Inferior cognitive or behavioral outcomes were associated with polymorphisms in three genes related to oxidative stress and/or neuroinflammation: NOS3 (IQ, Q = 0.008; Vocabulary Q = 0.011; Matrix Reasoning Q = 0.008), SLCO2A1 (IQ Q = 0.043; Digit Span Q = 0.006; Block Design Q = 0.076), and COMT (Behavioral Assessment System for Children-2 Attention Q = 0.080; and Hyperactivity Q = 0.084). Survivors homozygous for NOS3 894T, with at least one SLCO2A1 variant G allele or with at least one GSTP1 variant allele, had lower mean estimated IQ scores than those without these genotypes. Conclusion These data are consistent with the hypothesis that oxidative damage contributes to chemotherapy-associated neurocognitive decline among children with leukemia.
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Bava, Laura, Alexis Johns, David R. Freyer, and Kathleen Ruccione. "Development of a Culturally Competent Service to Improve Academic Functioning for Latino Survivors of Acute Lymphoblastic Leukemia: Methodological Considerations." Journal of Pediatric Oncology Nursing 34, no. 3 (November 26, 2016): 222–29. http://dx.doi.org/10.1177/1043454216676837.
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Many survivors of childhood acute lymphoblastic leukemia (ALL) develop neurocognitive deficits that compromise academic functioning, especially in the presence of sociodemographic risk factors. The extent to which these risk factors coexist for Latino ALL survivors is not well described, but with shifts in U.S. demographics and improved survival in ALL, culturally competent interventions are needed. The Achieving Best Cognitive Successes after Cancer service was designed and implemented by a team representing nursing, medicine, psychology, and social work. Service components include neurocognitve assessment and individualized intervention for treatment-related risks and improving academic success for school-aged ALL survivors. Interventions are child-focused and parent-directed, recognizing that parents are major sources of support and advocates for their children within school systems. The service was designed to be culturally appropriate for the predominantly Latino patient population at our center, based on (1) linguistic competency of children and parents; (2) multicultural and ecological considerations for urban, low socioeconomic status, and migrant populations; (3) literacy barriers; and (4) contextual factors. This report describes methodological considerations and practice implications relevant to the design and implementation of similar culturally competent services for Latino pediatric cancer survivors.
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Iuvone, Laura, Paolo Mariotti, Cesare Colosimo, Francesco Guzzetta, Antonio Ruggiero, and Riccardo Riccardi. "Long-term cognitive outcome, brain computed tomography scan, and magnetic resonance imaging in children cured for acute lymphoblastic leukemia." Cancer 95, no. 12 (December 3, 2002): 2562–70. http://dx.doi.org/10.1002/cncr.10999.
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Feeny, D., W. Furlong, R. D. Barr, G. W. Torrance, P. Rosenbaum, and S. Weitzman. "A comprehensive multiattribute system for classifying the health status of survivors of childhood cancer." Journal of Clinical Oncology 10, no. 6 (June 1992): 923–28. http://dx.doi.org/10.1200/jco.1992.10.6.923.
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PURPOSE A multiattribute health status classification system was devised to describe comprehensively the health status of survivors of childhood cancer. METHODS The system consists of seven attributes: sensation, mobility, emotion, cognition, self-care, pain, and fertility. Three to five levels of functioning are defined for each attribute. Any specific combination of seven attribute levels constitutes a health state. In the first survey, the system was used to classify the health status of 20 children currently undergoing therapy for high-risk acute lymphoblastic leukemia (ALL), Wilms' tumor, or neuroblastoma, and eight who had completed treatment. A second survey consisted of 13 children with brain tumors on active treatment. RESULTS In general, independent ratings by clinicians were in agreement, and consensus was readily achieved in 1 to 2 minutes per patient. Children on therapy experienced a higher burden of morbidity than those off treatment. Brain tumor patients experienced more morbidity than patients in the first survey. CONCLUSION The multiattribute system provides a compact but comprehensive tool for long-term follow-up of survivors of childhood cancer. It captures both multiple sequelae and varying levels of severity. By using a mathematical utility function, a single summary score of health-related quality of life may be assigned to each health state. Additional studies to establish reproducibility, validity, responsiveness, and generalizability are indicated.
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Moore, Ida M. (Ki), Kari M. Koerner, Patricia M. Gundy, David W. Montgomery, Kathleen C. Insel, Lynnette L. Harris, Olga A. Taylor, and Marilyn J. Hockenberry. "Changes in Oxidant Defense, Apoptosis, and Cognitive Abilities During Treatment for Childhood Leukemia." Biological Research For Nursing 20, no. 4 (March 7, 2018): 393–402. http://dx.doi.org/10.1177/1099800418763124.
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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.
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Montour-Proulx, Isabelle, Sally M. Kuehn, Daniel L. Keene, Nicholas J. Barrowman, Elizabeth Hsu, Mary-Ann Matzinger, Hal Dunlap, and Jacqueline M. Halton. "Cognitive Changes in Children Treated for Acute Lymphoblastic Leukemia With Chemotherapy Only According to the Pediatric Oncology Group 9605 Protocol." Journal of Child Neurology 20, no. 2 (February 2005): 129–33. http://dx.doi.org/10.1177/08830738050200020901.
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Hearps, Simone, Marc Seal, Vicki Anderson, Maria McCarthy, Madeleine Connellan, Peter Downie, and Cinzia De Luca. "The relationship between cognitive and neuroimaging outcomes in children treated for acute lymphoblastic leukemia with chemotherapy only: A systematic review." Pediatric Blood & Cancer 64, no. 2 (October 3, 2016): 225–33. http://dx.doi.org/10.1002/pbc.26188.
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Meeske, Kathleen A., Stuart E. Siegel, Denise R. Globe, Wendy J. Mack, and Leslie Bernstein. "Prevalence and Correlates of Fatigue in Long-Term Survivors of Childhood Leukemia." Journal of Clinical Oncology 23, no. 24 (August 20, 2005): 5501–10. http://dx.doi.org/10.1200/jco.2005.03.210.
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Purpose To estimate the prevalence of fatigue, identify the factors associated with fatigue, and to explore the relationship between fatigue and quality of life (QOL) in long-term survivors of childhood acute lymphoblastic leukemia (ALL). Methods One hundred sixty-one ALL survivors diagnosed at Childrens Hospital Los Angeles (Los Angeles, CA) before age 18 years and between January 1, 1975 and December 31, 1995, participated in a structured telephone interview. Participants were aged 18 to 41 years and off treatment for an average of 14 years. Four measures of fatigue, including the Revised–Piper Fatigue Scale, were used to assess fatigue; depression was assessed using the Center for Epidemiological Studies Depression Scale. Multivariate logistic regression models were developed to identify factors associated with fatigue and depression. Results Prevalence of fatigue (30%) fell within the general population normal limits. Fatigue and depression were highly correlated (Pearson r = 0.75). Fatigue was associated with marriage (OR = 0.11; 95% CI, 0.02 to 0.50), having children (OR = 5.80; 95% CI, 1.30 to 25.82), sleep disturbances (OR = 6.15; 95% CI, 2.33 to 16.22), pain (OR = 5.56; 95% CI, 2.13 to 14.48), obesity (OR = 3.80; 95% CI, 1.41 to 10.26), cognitive impairment (OR = 2.56; 95% CI, 1.02 to 6.38), and exercise-induced symptoms (OR = 2.98; 95% CI, 1.11 to 8.02). Four factors associated with fatigue were also associated with depression: sleep disturbances, pain, obesity, and cognitive impairment. Fatigue was inversely related to QOL. Conclusion Some survivors of childhood ALL experience fatigue many years after treatment. Fatigued survivors represent a high-risk subgroup as they report more depression and poorer QOL than nonfatigued survivors and their peers.
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Waber, D. P., N. J. Tarbell, C. M. Kahn, R. D. Gelber, and S. E. Sallan. "The relationship of sex and treatment modality to neuropsychologic outcome in childhood acute lymphoblastic leukemia." Journal of Clinical Oncology 10, no. 5 (May 1992): 810–17. http://dx.doi.org/10.1200/jco.1992.10.5.810.
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PURPOSE Long-term adverse neurobehavioral sequelae frequently are observed in pediatric patients treated for acute lymphoblastic leukemia (ALL). To clarify the relative contribution of cranial irradiation (CRT) therapy and drug therapy to these outcomes, we evaluated neuropsychologic outcomes associated with different doses of CRT and intravenous (IV) methotrexate (MTX) in long-term survivors. PATIENTS AND METHODS Fifty-one patients treated for ALL on Dana-Farber Cancer Institute protocol 81-01 were evaluated by standardized cognitive and academic achievement tests. These children had been assigned at diagnosis to a standard-risk (SR) or high-risk (HR) group and received 1,800 cGy or 2,800 cGy CRT, respectively. A subgroup of these patients was randomized to receive MTX during remission induction, either as a single low dose (LD; 40 mg/m2) or a single high dose (HD; 4 g/m2) with leucovorin rescue. RESULTS Sex and MTX randomization jointly predicted the intelligence quotient (IQ). Fifty percent of girls versus 14% of boys exhibited low IQ (less than 90; P = .01); 80% of girls who received HD MTX versus 25% of girls who received LD MTX exhibited low IQ (P = .03). In contrast, risk group better predicted performance on tasks sensitive to verbal memory and/or coding. CONCLUSIONS We conclude that (1) significant neurotoxicity occurred principally in girls; (2) increased dose intensity of IV MTX was associated with lower IQ, but only in girls; and (3) increased dose of CRT may have been associated with impairment of verbal memory and coding.
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Meshref, M. M., N. Elshazly, M. Nasr, and R. Abdelhai. "Effect of prophylactic cranial irradiation dose on CNS relapse, late cognitive decline and learning disabilities in children treated for acute lymphoblastic leukemia." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 9032. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.9032.
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9032 Background: Prophylactic cranial irradiation is still standard in treatment of high risk childhood acute lymphoblastic leukemia. In this study we assessed the effect of cranial irradiation dose of 1,800 cGy and 1200 cGy on CNS relapse as well as the late cognitive decline and learning disabilities in both groups versus a control group using neurophysiologic and psychometric studies. Methods: 42 patients treated from acute lymphoblastic leukemia and categorized to be at high risk of relapse were assessed in this study. 28 patients received prophylactic cranial irradiation at a dose of 1,800 cGy and 14 received a dose of 1,200 cGy. A control group of 42 age and sex matched normal children was also assessed. Visual and auditory P300 studies were carried out to assess high visual and auditory processing functions. Several selected subscales of Wechsler Intelligence scale for children were applied to both subgroups as well as the control group. Results: Mean age at receiving irradiation was 5.7 years. Mean testing age was 10 years. Mean follow up period was 4.6 years.There was one CNS relapse in the group who received 1,800 cGy (3.5%) and one in the group who received 1,200 cGy (7%). As compared to the control group the group of patient who received 1,800 cGy showed a high statistically significant delay in the latency and significant reduction in the amplitude of the Visual P300 (p <0.001, =0.01 respectively). The Auditory P300 showed a significant delay in latency (p=0.01). In the group receiving 1,200 cGy only the latency of the visual P300 was significantly affected(p=0.01). The other parameters in the 1,200 cGy subgroup were not significantly affected. As for the psychometric studies there were significant differences in several subscales between controls and 1,800 cGy subgroup namely in similarities, total performance and picture compilation which were not found between controls and 1,200 cGy subgroup. Conclusions: These findings reflects that there is impairment in the intellectual abilities as well as visual and auditory processing functions in the subgroup receiving 1,800 cGy compared to the controls which was much less in the subgroup receiving 1,200 cGy at no significant increased protection from CNS relapse. No significant financial relationships to disclose.
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Waber, Deborah P., Jennifer Turek, Lori Catania, Kristen Stevenson, Philippe Robaey, Ivonne Romero, Heather Adams, et al. "Neuropsychological Outcomes From a Randomized Trial of Triple Intrathecal Chemotherapy Compared With 18 Gy Cranial Radiation As CNS Treatment in Acute Lymphoblastic Leukemia: Findings From Dana-Farber Cancer Institute ALL Consortium Protocol 95-01." Journal of Clinical Oncology 25, no. 31 (November 1, 2007): 4914–21. http://dx.doi.org/10.1200/jco.2007.10.8464.
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Purpose We evaluated late neuropsychological toxicity in children treated for standard-risk acute lymphoblastic leukemia (ALL) who were randomly assigned to receive either cranial radiation therapy (CRT) with double intrathecal (IT) chemotherapy or intensive triple IT chemotherapy (no CRT) as CNS-directed therapy. Patients and Methods Between 1996 and 2000, 164 children with standard-risk ALL treated on Dana-Farber Cancer Institute Consortium Protocol 95-01 were randomly assigned to receive either 18 Gy CRT delivered in twice daily fractions (0.9 Gy) with double IT therapy (methotrexate and cytarabine) or intensive triple IT drug (methotrexate, cytarabine and hydrocortisone) without CRT. Neuropsychological testing was completed at a median 6 years postdiagnosis for 79 children (CRT, n = 39; triple IT, n = 40), all of whom were in continuous complete remission. Results Cognitive function for both groups was solidly in the average range, with no consistent group differences in basic cognitive skills. Children treated on the CRT plus double IT arm did, however, exhibit less fluent output and were less effective at modulating their behavior by parent report. Conclusion This randomized trial revealed only subtle differences 6 years after diagnosis between children who received CNS therapy as CRT plus double IT drug or as intensive triple IT drug. In most situations where comparable therapeutic efficacy can be achieved without CRT, it is preferable to do so. Where therapeutically necessary, however, CRT at lower doses may not add risk for significant neurotoxicity.
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Kadan-Lottick, Nina S., Pim Brouwers, David Breiger, Thomas Kaleita, James Dziura, Haibei Liu, Lu Chen, et al. "A comparison of neurocognitive functioning in children previously randomized to dexamethasone or prednisone in the treatment of childhood acute lymphoblastic leukemia." Blood 114, no. 9 (August 27, 2009): 1746–52. http://dx.doi.org/10.1182/blood-2008-12-186502.
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In previous clinical trials of childhood acute lymphoblastic leukemia (ALL), dexamethasone resulted in higher event-free survival rates than prednisone, presumably due to greater central nervous system penetration. Dexamethasone's association with long-term neurocognitive toxicity is unknown. In this multisite study, we measured neurocognitive functioning in 92 children with standard-risk ALL, 1 to 9.99 years at diagnosis, at a mean of 9.8 years after randomization to prednisone (n = 41) or dexamethasone (n = 51) on Children's Cancer Group (CCG) 1922. No significant overall differences in mean neurocognitive and academic performance scores were found between the prednisone and dexamethasone groups after adjusting for age, sex, and time since diagnosis. The exception was that patients receiving dexamethasone scored one-third of a standard deviation worse on word reading (98.8 ± 1.7 vs 104.9 ± 1.8; P = .02). There were no group differences in the distribution of test scores or the parents' report of neurologic complications, psychotropic drug use, and special education. Further analyses suggested for the dexamethasone group, older age of diagnosis was associated with worse neurocognitive functioning; for the prednisone group, younger age at diagnosis was associated with worse functioning. In conclusion, our study did not demonstrate any meaningful differences in long-term cognitive functioning of childhood ALL patients based on corticosteroid randomization. This study is registered with http://www.clinicaltrials.gov under NCT00085176.
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Kingma, Annette, Rieneke I. van Dommelen, Eduard L. Mooyaart, Jan T. Wilmink, Betto G. Deelman, and Willem A. Kamps. "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, no. 3 (September 2001): 413–20. http://dx.doi.org/10.1067/mpd.2001.117066.
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Kadan-Lottick, Nina S., Pim Brouwers, David Breiger, Thomas Kaleita, James Dziura, Veronika Northrup, Lu Chen, et al. "Comparison of Neurocognitive Functioning in Children Previously Randomly Assigned to Intrathecal Methotrexate Compared With Triple Intrathecal Therapy for the Treatment of Childhood Acute Lymphoblastic Leukemia." Journal of Clinical Oncology 27, no. 35 (December 10, 2009): 5986–92. http://dx.doi.org/10.1200/jco.2009.23.5408.
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Purpose For the majority of children with acute lymphoblastic leukemia (ALL), CNS prophylaxis consists of either intrathecal (IT) methotrexate or triple IT therapy (ie, methotrexate with both cytarabine and hydrocortisone). The long-term neurotoxicities of these two IT strategies have not yet been directly compared. Patients and Methods In this multisite study, 171 children with standard-risk ALL, age 1 to 9.99 years at diagnosis, previously randomly assigned to IT methotrexate (n = 82) or to triple IT therapy (n = 89) on CCG 1952, underwent neurocognitive evaluation by a licensed psychologist at a mean of 5.9 years after random assignment. Results Patients who received IT methotrexate had a mean Processing Speed Index that was 3.6 points lower, about one fourth of a standard deviation, than those who received triple IT therapy (P = .04) after analysis was adjusted for age, sex, and time since diagnosis. Likewise, 19.5% of children in the IT methotrexate group had a Processing Speed Index score in the below-average range compared with 6.9% in the triple IT therapy group (P = .02). Otherwise, the groups performed similarly on tests of full-scale intelligence quotient, academic achievement, attention/concentration, memory, and visual motor integration. The association of treatment with measures of cognitive functioning was not modified by sex or age at diagnosis. In the post-therapy period, there were no group differences in special education services, neurologic events, or use of psychotropic medications. Conclusion This study did not show any clinically meaningful differences in neurocognitive functioning between patients previously randomly assigned to IT methotrexate or triple IT therapy except for a small difference in processing speed in the IT methotrexate group.
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Piette, Caroline, Stefan Suciu, Yves Bertrand, Anne Uyttebroeck, Els Vandecruys, Geneviève Plat, Patrick Lutz, et al. "Prophylactic CNS Therapy (with or without Radiation Therapy) in Medium-High Risk Acute Lymphoblastic Leukemia (ALL) Children: Long-Term Outcome Evaluation of the Randomized BFM-Oriented Trial 58832 (period 1983-1989) of the EORTC Children Leukemia Group." Blood 128, no. 22 (December 2, 2016): 2775. http://dx.doi.org/10.1182/blood.v128.22.2775.2775.
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Abstract Background Cranial radiotherapy (CRT) is associated with early and late side effects. Intrathecal (IT) and systemic chemotherapy could successfully replace CRT in most protocols for standard risk ALL. However, in medium and high risk ALL patients (pts) its omission is still debatable. Aim We investigated the long-term outcome, the occurrence of second malignant neoplasms (SMN) and the incidence of late toxicities in pts randomized for receiving or not CRT in the EORTC 58832 study. Methods From 1983 to 1989, ALL children under 18 years (yrs) were included in EORTC Children Leukemia Group BFM-oriented studies, either 58831, for standard risk pts (Riehm-Langerman Risk Factor (RF) < 1.2), or 58832, for medium risk (RF 1.2-1.69) and high risk pts (RF ≥1.7). Pts with central nervous system (CNS) involvement at diagnosis were ineligible. The present report focusses on pts included in the 58832 trial (randomized for receiving or not prophylactic CRT). Prophylactic CNS therapy consisted of 4 high-dose methotrexate (HD-MTX) injections (2500 mg/m2) during consolidation and 7 IT MTX injections scheduled during the treatment period. Pts still in complete remission (CR) after the end of late intensification were randomized for receiving prophylactic CRT (standard arm) or not (experimental arm) before the start of continuation therapy. Dose of CRT was age dependent: 24 Gy (> 2 yrs), 20 Gy (1-2 yrs) and 16 Gy (< 1 yr). Endpoints were: disease-free survival (DFS) (event: relapse, death in CR), incidence of SMN, event-free survival (EFS) (event: relapse, death in CR, SMN), incidence of late toxicities, and overall survival (OS) from randomization. Results 788 pts were included in the 58831/58832 study. Among them, 189 were randomized in the 58832 study to receive CRT (n=93) or No CRT (n=96). A total of 6 pts did not meet eligibility criteria, 2 had an early relapse, 3 had an early protocol violation and 2 refused allocated treatment. Finally, 176 randomized pts were included in the analyses: 84 in the CRT group and 92 in the No CRT group. The median follow-up was 20 yrs (range 4-32 yrs). Omission of CRT did not increase the 25-yr incidence of isolated CNS relapse, any CNS relapse or non-CNS relapse (4.8 vs 6.5; 11.9 vs 8.7 and 16.7 vs 21.8 in the CRT vs No CRT arms, respectively). No relapses occurred after 10 yrs. The 25-yr DFS rates were similar in both arms: 70.2% with CRT and 67.4% without CRT; No CRT vs CRT hazard ratio (HR)=1.08, 95% CI (0.63, 1.83). CRT was associated with an increase of the 25-yr SMN incidence: 13.2% with CRT and 3.9% without CRT. In the CRT arm, 9 pts (10.7%) developed SMN: 2 acute myeloid leukemias (AML), 1 non-Hodgkin lymphoma, 1 thyroid carcinoma, 4 meningiomas and 1 malignant histiocytosis. One SMN (meningioma) occurred after a CNS combined relapse. Three pts developed second SMN (meningiomas): 1 after an AML and 2 after a first meningioma. In the No CRT arm, 3 pts (3.3%) had SMN: 1 pleomorphic xanthoastrocytoma, 1 melanoma and 1 adenocarcinoma of the ileum. One SMN occurred after a bone marrow (BM) relapse. The 25-yr EFS rates were similar in both arms: 60.3% with CRT and 63.2% without CRT, HR=0.90, 95% CI (0.55, 1.46). CRT was also associated with an increase of late CNS and endocrine toxicities. Five pts (19.2% of the pts with available data) developed leukoencephalopathy in the CRT arm, versus 2 pts (8.7%) in the No CRT arm. Noteworthy, 1 of those 2 pts received CRT for a BM relapse, while the other received total body irradiation for a CNS relapse. Stroke was observed in 2 pts (7.7%) who received CRT. In contrast, there was no clear increase of the incidence of cognitive disturbance after CRT: 33.3% in the CRT arm vs 25.0% in the No CRT arm. Regarding endocrine toxicities, GH deficiency, hypothyroidism and precocious puberty were more frequent in the CRT arm: 53.1% vs 29.6%, 27.8% vs 0% and 29.4% vs 0%, respectively. Finally, the 25-yr OS rates were similar in both arms: 78.5% with CRT and 78.1% without CRT, HR=1.00, 95% CI (0.53, 1.88). Conclusion In medium and high risk pts without CNS involvement at diagnosis and treated with HD-MTX in the EORTC trial 58832 (1983-1989), omission of CRT did not increase the risk of CNS or non-CNS relapse. On long-term evaluation, CRT was associated with a higher incidence of SMN, late CNS and endocrine toxicities. These long-term results indicate that prophylactic CRT can be safely omitted in childhood medium and high risk ALL pts receiving IT and systemic chemotherapy (including HD-MTX) as CNS prophylaxis. Table Table. Disclosures No relevant conflicts of interest to declare.
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Huang, I.-Chan, Tara M. Brinkman, Yin Ting Cheung, Ching-Hon Pui, Melissa M. Hudson, and Kevin R. Krull. "Functional consequence of cognitive impairment in survivors of childhood acute lymphoblastic leukemia (ALL): The role of cancer symptoms as mediators." Journal of Clinical Oncology 34, no. 3_suppl (January 20, 2016): 235. http://dx.doi.org/10.1200/jco.2016.34.3_suppl.235.
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235 Background: Although cognitive impairment of childhood cancer survivors affects daily functional status, the mechanisms are less understood. This study aimed to examine the role of cancer symptoms on the association of cognitive impairment with functional status in childhood ALL survivors treated on a chemotherapy only protocol. Methods: 213 survivors (mean age = 14.8 years) were assessed at > 5 years post-diagnosis. Testing included measures of executive function (Delis-Kaplan Executive Function System; Wechsler Intelligence Scale for Children-IV [WISC-IV]), processing speed (WISC-IV; Grooved Pegboard), visual-spatial processing (Wechsler Abbreviated Scale of Intelligence), memory span (WISC-IV), and attention (Conners CPT-II). Symptoms (e.g., pain, worry, cognitive, communication) and daily functional status (physical, emotional, social, school) were reported by parents using the PedsQL. Association of cognitive impairment with symptoms and functional status was tested using regression analyses. The extent to which cognitive impairment influences functional status through symptoms was tested using mediation analyses. Results: Cognitive impairment ( > 1SD below age-adjusted norm) was identified in 18-41% of the survivors. Impaired executive function, processing speed, and memory span were associated with high cancer symptoms (all p’s < 0.05), typically driven by perceived cognitive and communication problems. Impaired executive function, processing speed, visual-spatial processing, and memory span were associated with poor functional status (all p’s < 0.05). In each cognitive domain, impairment was related to poor school function (all p’s < 0.05). Impact of cognitive function (except attention) on overall functional status was mediated by overall cancer symptoms (all p’s < 0.05). Conclusions: Although the frequency of impairment in survivors treated with chemotherapy was less than that seen with cranial irradiation, cognitive impairment is related to elevated cancer symptoms and decreased functional status. Mediation analyses suggest that cognitive function works through cancer symptoms to impact functional status.
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Madhyastha, Sampath, S. N. Somayaji, M. S. Rao, K. Nalini, and K. Laxminarayana Bairy. "Hippocampal brain amines in methotrexate-induced learning and memory deficit." Canadian Journal of Physiology and Pharmacology 80, no. 11 (November 1, 2002): 1076–84. http://dx.doi.org/10.1139/y02-135.
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Intrathecal methotrexate in children with leukemia is known to cause seizures, dementia, leukoencephalo pathy, and cognitive dysfunction after long-term treatment. To investigate the cognitive dysfunction, male Wistar rats were given multiple intracerebroventricular injections of methotrexate. Its effect on behaviour was tested in the two-compartment conditioned avoidance task and darkbright arena test. Levels of brain amines in the hippocampal region of the brain were estimated by HPLC. The qualitative and quantitative histopathological changes in the different regions of the hippocampus were studied by cresyl violet staining. Multiple injections (1 or 2 mg/kg) produced convulsions and learning and memory impairment but did not induce anxiolytic activity. They also reduced concentrations of all three brain amines (norepinephrine, dopamine, and serotonin) and the serotonin metabolite 5-hydroxyindoleacetic acid. The CA4 region of the hippocampus was severely affected by intraventricular methotrexate. Disruption of brain monoamines has been proposed as a cause of brain dysfunction from this chemotherapy, and that disruption may in turn involve cytotoxic effects of methotrexate on brain tissue. The outcomes of this study may have therapeutic implications in the management of cancer conditions, particularly in childhood lymphoblastic leukemia.Key words: methotrexate, hippocampus, norepinephrine, dopamine, serotonin, learning and memory.
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Conklin, Heather M., Robert J. Ogg, Jason M. Ashford, Matthew A. Scoggins, Ping Zou, Kellie N. Clark, Karen Martin-Elbahesh, et al. "Computerized Cognitive Training for Amelioration of Cognitive Late Effects Among Childhood Cancer Survivors: A Randomized Controlled Trial." Journal of Clinical Oncology 33, no. 33 (November 20, 2015): 3894–902. http://dx.doi.org/10.1200/jco.2015.61.6672.
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Purpose Children receiving CNS-directed therapy for cancer are at risk for cognitive problems, with few available empirically supported interventions. Cognitive problems indicate neurodevelopmental disruption that may be modifiable with intervention. This study evaluated short-term efficacy of a computerized cognitive training program and neural correlates of cognitive change. Patient and Methods A total of 68 survivors of childhood acute lymphoblastic leukemia (ALL) or brain tumor (BT) with identified cognitive deficits were randomly assigned to computerized cognitive intervention (male, n = 18; female, n = 16; ALL, n = 23; BT, n = 11; mean age ± standard deviation, 12.21 ± 2.47 years) or waitlist (male, n = 18; female, n = 16; ALL, n = 24; BT, n = 10; median age ± standard deviation, 11.82 ± 2.42 years). Intervention participants were asked to complete 25 training sessions at home with weekly, telephone-based coaching. Cognitive assessments and functional magnetic resonance imaging scans (intervention group) were completed pre- and postintervention, with immediate change in spatial span backward as the primary outcome. Results Survivors completing the intervention (n = 30; 88%) demonstrated greater improvement than controls on measures of working memory (mean ± SEM; eg, Wechsler Intelligence Scale for Children [fourth edition; WISC-IV] spatial span backward, 3.13 ± 0.58 v 0.75 ± 0.43; P = .002; effect size [ES], 0.84), attention (eg, WISC-IV spatial span forward, 3.30 ± 0.71 v 1.25 ± 0.39; P = .01; ES, 0.65), and processing speed (eg, Conners' Continuous Performance Test hit reaction time, −2.10 ± 1.47 v 2.54 ± 1.25; P = .02; ES, .61) and showed greater reductions in reported executive dysfunction (eg, Conners' Parent Rating Scale III, −6.73 ± 1.51 v 0.41 ± 1.53; P = .002; ES, 0.84). Functional magnetic resonance imaging revealed significant pre- to post-training reduction in activation of left lateral prefrontal and bilateral medial frontal areas. Conclusion Study findings show computerized cognitive training is feasible and efficacious for childhood cancer survivors, with evidence for training-related neuroplasticity.
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Rodes, Stephen, Beverly A. Bell, Sharon B. Abish, Jeanette Pullen, Allen Chauvenet, Joanne Kurtzberg, Meenakshi Devidas, Jonathan Shuster, and Bruce M. Camitta. "A Report of the Event-Free Survival (EFS) and Neurotoxicity for Children with Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia (ALL) on Pediatric Oncology Group (POG) Protocol 9405." Blood 106, no. 11 (November 16, 2005): 882. http://dx.doi.org/10.1182/blood.v106.11.882.882.
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Abstract POG 9405, a randomized phase III study for children with standard risk ALL, opened in 1994. The primary objectives were to determine effects on event-free survival (EFS) of: 1) higher (2.5g/m2) vs. standard (1g/m2) dose methotrexate (MTX) infusions during consolidation (in an attempt to obtain a plasma MTX target of 12 μmol) and (2) once vs. twice daily 6- mercaptopurine (MP) dosing during continuation (to improve the efficacy of MP based on its short half-life and S-phase dependence). Following remission induction, patients were randomized to: Regimens (Reg) A/B (MTX 1 g/m2 IV) or C/D (MTX 2.5 g/m2), all with MP 1g/m2 IV, q2 weeks (wk) x 12. Leucovorin 5 mg/m2 q6h x 5 began at hour 48 and continued until MTX level was <0.3μmol. MTX 20 mg/m2/wk IM and MP 75 mg/m2/day p.o. were given on alternate wks. Continuation was MTX 20 mg/m2/wk IM for all patients and MP 75 mg/m2 daily p.o. for A/C and 37.5 mg/m2 p.o. b.i.d for B/D. CNS prophylaxis was age-adjusted triple intrathecal therapy (TIT) for a total of 14–19 doses due to protocol modifications made because of concerns about neurotoxicity. Total treatment duration was 130 wks. 295 patients entered consolidation therapy. Reg A: 77, Reg B: 77, Reg C: 70, Reg D: 71. The overall 6 year EFS for the study was 80% ±2.4% (s.e.). The study closed prematurely in 1996 due to issues pertaining to neurotoxicity. There was no significant difference in EFS between the two 6-MP dosing regimens [once-daily 78% vs. twice-daily 83%; p = 0.222]. Only 36% of patients on Reg C/D received the full 12 courses of higher dose MTX due to above noted protocol modifications. Neither the efficacy nor the toxicity of higher dose MTX can be fully evaluated for this study. 57 Patients (19%) reported one or more grade 2–4 neurotoxicity event using the Common Toxicity Criteria (CTC) version 2.0. These events included: cortical toxicity 37 events (including 33 seizures), cerebellar 15, cognitive dysfunction 6, headaches 4, motor 3, and significant fatigue in 3 children. Preliminary review indicates no difference in neurotoxicity incidence based on MTX dose. This antimetabolite based study highlights the importance of monitoring for neurotoxicity, as well as other unexpected adverse events on subsequent leukemia treatment protocols.
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Druley, Todd E., Mark Valentine, Nicholas Sanchez, and Julie A. Ross. "Matched Exome Sequencing in Mothers and Infants with MLL-Negative Acute Leukemia." Blood 120, no. 21 (November 16, 2012): 536. http://dx.doi.org/10.1182/blood.v120.21.536.536.
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Abstract Abstract 536 Introduction: Infant leukemia (IL) is an extremely rare, sporadic, but often fatal, form of cancer that is defined as leukemia occurring within the first year of life. Unlike leukemia in older children where survival rates for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are approximately 70% and 85%, respectively, infants have a survival rate of ∼50%. Unfortunately, despite years of research and clinical trials, overall survival for IL hasn't improved substantially since the advent of hematopoietic stem cell transplantation, and those infants that survive are often left with lifelong deficits in cognition, development, end organ function, behavioral milestones and/or other complications due to the intensity of treatment (Pui, NEJM 2003; Chow, J Pediatr 2007). The incidence rate of IL is increasing (Linabery, Cancer 2008) in the US, but cannot be attributed to chromosomal anomalies (Uckun, Blood 1998), environmental exposures (Ross, Epidemiol Rev 1994), or highly penetrant genetic polymorphisms alone. Clearly, a critical component of IL pathophysiology remains undiscovered. Rare variation has been implicated in a host of complex phenotypes and diseases, but the impact of rare germline variants on the etiology and outcome of IL has not been fully explored. The Rare Variant Hypothesis predicts that a population of affected individuals would harbor a diverse collection of functionally significant variants in genes involved in etiologically relevant pathways. Given this model, we hypothesize that the onset of IL requires heritable deleterious germline variants, which act alone or in combination with somatic mutations to induce leukemic transformation. Methods: To explore this possibility, we completed a pilot exome sequencing project on 25 pairs of germline DNA from mothers and their infants with MLL-negative IL collected from the Children's Oncology Group (COG) AE24 “Epidemiology of Infant Leukemia” study. Twelve infants had ALL, 13 had AML and none of the mothers had cancer. We asked if a) infants harbored rare or novel deleterious germline variants in known leukemia genes, b) these variants were inherited from mothers and c) the genes affected by these germline variants fell in common pathways or share common regulatory mechanisms. Results: We found an average of 16,056 variants per exome with an average of 3,082 (19.2%) being novel. Comparing these results to the COSMIC database (http://www.sanger.ac.uk/genetics/CGP/cosmic/), infants with AML had novel, non-synonymous, deleterious germline variants in 82 genes associated with hematologic malignancies, infants with ALL had similar variants in 64 genes, and 42 additional genes (40%) overlapped between ALL or AML. For infants with ALL, 45% of these variants were inherited from healthy mothers compared to only 23% in AML infants. Presumably, the remaining variants were inherited from fathers, but without paternal DNA, we cannot exclude de novo germline mutation, although such mutations are exceedingly rare and would only account for a few non-maternal variants. We used the g:Profiler (http://biit.cs.ut.ee/gprofiler/) algorithm to determine if any of these genes acted in common leukemia-related pathways or shared regulatory mechanisms. We found that many candidate genes were regulated by microRNAs (MIR) previously implicated in cancer, including MIR10a, MIR29c, MIR291b-3p, MIR369-5p, MIR469, MIR519a, MIR721. Five MIRs have been associated with leukemia, four with acute leukemia. Two MIRs, 291b-3p and 721, are also associated with embryonic stem cell cycle regulation and apoptosis, respectively. Ongoing work is focusing on additional exome sequencing, epidemiologic analysis and in vitro functional studies. Conclusion: It is clear that the incidence, clinical behavior and outcomes of IL cannot be explained fully through either environmental exposures or somatic mutations alone. We are leveraging the largest epidemiologic study of IL to date to explore the intersection of functional congenital genetic variation, clinical outcomes and maternal prenatal/pregnancy exposures to augment our understanding of IL. A better understanding of the natural history of IL will aid in future recommendations for pre- and post-natal genetic diagnostics, risk stratification of affected infants and ultimately therapeutic decisions. Disclosures: No relevant conflicts of interest to declare.
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Dwiningsih, Sri Ratna, Samsulhadi Samsulhadi, Arif Tunjungseto, Monika Lijuwardi, and Arsana Wiyasa. "Night Shift Work Accelerates Menopausal Age in Health Workers." Biomolecular and Health Science Journal 4, no. 1 (June 30, 2021): 30. http://dx.doi.org/10.20473/bhsj.v4i1.25361.
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Introduction: Earlier menopause has been associated with increased risk of cardiovascular disease, osteoporosis, shorter life expectancy and even cognitive decline. There are many factors that cause differences in the age of menopause in women, one of these environmental factors is a history of night shift work as a consequence of a job. It is not yet known whether female medical workers, with a history of night shifts, get earlier menopause.Methods: This case control study was conducted among 57 female night workers of the Dr. Soetomo General Academic Hospital. Data collection was conducted from December 2019 - March 2020. The study sample was postmenopausal health workers (nurse and midwife) and administrators. The instrument used in this study was a list of interview questions. The data was processed using SPSS software release 23.Results: The results show that from 45 children diagnosed with ALL, 53% are of the age ≤ 5 years old, with 58% males and 42% females. 13% of the patients are in the high risk group and 87% are in the standard risk group. Nutritional statuses of patients are 2% of them obese experienced remission after induction phase therapy, 56% normal with 80% of them experienced remission. 40% underweight with 89% of them experienced remission and 11% not experienced remission, 2% malnutrition and experienced remission. There is no correlation between the nutritional status of children with acute lymphoblastic leukemia with the outcome of induction phase (p = 0.798).Conclusion: In conclusion, there is no correlation between nutritional status and remission outcome of patients with ALL in the induction phase of therapy. However, high percentage of underweight patients shows nutrition needs special attention to improve therapy outcomes.
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Dal, Borgo P., J. Quintana, V. Beresi, W. Schuh, and Pozo H. Del. "NON-LYMPHOBLASTIC LEUKEMIA IN CHILDREN." Journal of Pediatric Hematology/Oncology 12, no. 1 (1990): 240. http://dx.doi.org/10.1097/00043426-199022000-00034.
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Pui, Ching-Hon. "Acute lymphoblastic leukemia in children." Current Opinion in Oncology 12, no. 1 (January 2000): 3–12. http://dx.doi.org/10.1097/00001622-200001000-00002.
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Hunger, Stephen P., and Charles G. Mullighan. "Acute Lymphoblastic Leukemia in Children." New England Journal of Medicine 373, no. 16 (October 15, 2015): 1541–52. http://dx.doi.org/10.1056/nejmra1400972.
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Gaynes, Jeffrey, Leslie Jonart, Jordan Naumann, Edward Zamora, Nathan Gossai, Maryam Ebadi, and Peter M. Gordon. "The Central Nervous System Microenvironment Influences the Leukemia Transcriptome and Enhances Leukemia Chemo-Resistance." Blood 128, no. 22 (December 2, 2016): 1515. http://dx.doi.org/10.1182/blood.v128.22.1515.1515.
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Abstract Central nervous system (CNS) relapse is a significant cause of treatment failure among patients with acute lymphoblastic leukemia (ALL). Isolated CNS relapse occurs in ~3-8% of children with leukemia and accounts for 30-40% of initial relapses in some clinical trials. In addition, CNS-directed therapies are associated with seizures, secondary neoplasms, encephalopathy, and long-term endocrine, developmental, neurovascular, and cognitive deficits. While many studies have demonstrated that interactions between leukemia cells and components of the bone marrow microenvironment influence leukemia development, maintenance, and chemo-resistance, the role of the CNS microenvironment in leukemia is less well studied. To investigate the influence of the CNS niche in leukemia, we asked whether the CNS niche could impart unique and functionally important gene expression changes in leukemia cells. We transplanted NALM-6 human, pre-B leukemia cells into NSG mice without prior irradiation to avoid perturbing the bone marrow and CNS niches. After systemic leukemia development the mice were euthanized and leukemia cells were isolated from the bone marrow and CNS microenvironments. Gene expression profiling of ~700 cancer-associated genes (NanoString® Technology) identified 36 leukemia genes differentially expressed (30 up-regulated and 6 down-regulated; fold change ≥ 2 and FDR<0.05) in leukemia cells in the CNS microenvironment relative to the bone marrow. Furthermore, functional annotation revealed the up-regulated genes were involved in known leukemia and cancer pathways including MAPK, RAS, and apoptosis. We elected to further examine the gene PBX1 as it is a transcription factor with known roles in hematopoiesis, leukemia, and cancer biology. PBX1 contributes to Evi-1 mediated leukemia development in a murine model of leukemia and is a partner with TCF3 in the t(1;19) translocation that occurs in ~5% of pre-B ALL. Interestingly, this translocation is also associated with an increased risk for CNS relapse. We confirmed PBX1 mRNA up-regulation in leukemia cells either isolated from the CNS or in leukemia cells co-cultured with CNS-derived, murine choroid plexus cells by quantitative PCR. Supporting the generalizability of these results, additional human B-cell leukemia lines SEM and REH also exhibited PBX1 mRNA up-regulation in leukemia cells isolated from the murine CNS niche. Western blots of NALM-6 and SEM leukemia cells isolated from the mouse CNS as well as from leukemia cells co-cultured ex vivo with choroid plexus cells also showed PBX1 up-regulation at the protein level. Finally, culture of leukemia cells in either choroid plexus cell conditioned media or human cerebral spinal fluid (CSF) had minimal effects on PBX1 protein levels, suggesting that direct cell contact, rather than a soluble factor(s), contributes to PBX1 up-regulation in leukemia cells. Following confirmation of PBX1 up-regulation in leukemia cells within the CNS microenvironment, we next ectopically expressed PBX1, or GFP as a control, in leukemia cells to identify functional consequences of PBX1 expression in leukemia cells. Leukemia cells expressing PBX1 exhibited decreased sensitivity to cytarabine relative to control cells as measured by both proliferation and apoptosis assays. Furthermore, shRNA targeting PBX1, but not control shRNA, prevented PBX1 up-regulation in leukemia cells when co-cultured with choroid plexus cells and modestly, but significantly, attenuated the ability of choroid plexus cells to protect leukemia cells from cyatabine-induced apoptosis. Finally, although PBX1 had no effect on leukemia proliferation, it caused enhanced colony-forming ability in semi-solid media, consistent with increased leukemia self-renewal properties. Together these results suggest PBX1 up-regulation in leukemia cells may contribute to both leukemia self-renewal properties and chemo-resistance in the CNS niche. In summary, we believe this work illustrates the unique and functionally important effect that the CNS microenvironment has on leukemia cells. More comprehensive analyses of the leukemia transcriptome, genome, and proteome in the CNS niche will build upon this foundation and provide a more detailed understanding of the role of the CNS niche in leukemia biology. Finally, this approach may identify targetable CNS niche-mediated mechanisms of leukemia chemo-resistance and self-renewal. Disclosures No relevant conflicts of interest to declare.