The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia
Open accessAbstract
Purpose: Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods: Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results: Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion: MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Transient lesions in the white matter (leukoencephalopathy) due to chemotherapy are well‐documented in ALL survivors (Bhojwani et al., 2014; Reddick, Glass, Johnson, Laningham, & Pui, 2009; Reddick et al., 2005);”
From Brain structure, working memory and response inhibition in childhood leukemia survivors (2017) · cites this paper as Bhojwani et al., 2014
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“however, these lesions do not show a clear relationship with functional abilities (Bhojwani et al., 2014; Pääkkö et al., 2000) and are therefore unlikely to account for the full range of deficits in ALL survivors.”
From Brain structure, working memory and response inhibition in childhood leukemia survivors (2017) · cites this paper as Bhojwani et al., 2014
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Inference of Population Structure Using Multilocus Genotype Data
Pritchard, J. K., Stephens, M., & Donnelly, P. (2000) · Genetics · doi:10.1093/genetics/155.2.945 · Cited by 33,871
Classification and Regression Trees.
Gordon, A. D., Breiman, L., Friedman, J. H., Olshen, R. A., & Stone, C. J. (1984) · Biometrics · doi:10.2307/2530946 · Cited by 23,867
Classification and Regression Trees.
Ryzin, J. V., Breiman, L., Friedman, J. H., Olshen, R. A., & Stone, C. J. (1986) · Journal of the American Statistical Association · doi:10.2307/2288003 · Cited by 21,030
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes
Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S., Zhang, H., Estes, A., Brune, C. W., Bradfield, J. P., et al. (2009) · Nature · doi:10.1038/nature07953 · Cited by 1,421
Treating Childhood Acute Lymphoblastic Leukemia without Cranial Irradiation
Pui, C.-H., Campana, D., Pei, D., Bowman, W. P., Sandlund, J. T., Kaste, S. C., Ribeiro, R. C., Rubnitz, J. E., Raimondi, S. C., Onciu, M., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0900386 · Cited by 1,215
Self-citationMöricke, A., Reiter, A., Zimmermann, M., Gadner, H., Stanulla, M., Dördelmann, M., Löning, L., Beier, R., Ludwig, W.-D., Ratei, R., et al. (2008) · Blood · doi:10.1182/blood-2007-09-112920 · Cited by 611
g:Profiler—a web server for functional interpretation of gene lists (2011 update)
Reimand, J., Arak, T., & Vilo, J. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr378 · Cited by 506
Rare Copy Number Variation Discovery and Cross-Disorder Comparisons Identify Risk Genes for ADHD
Lionel, A. C., Crosbie, J., Barbosa, N., Goodale, T., Thiruvahindrapuram, B., Rickaby, J., Gazzellone, M. J., Carson, A. R., Howe, J., Wang, Z., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002464 · Cited by 374
Treviño, L. R., Shimasaki, N., Yang, W., Panetta, J. C., Cheng, C., Pei, D., Chan, D., Sparreboom, A., Giacomini, K. M., Pui, C., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.20.4156 · Cited by 353
Self-citationGenome-wide association analysis identifies susceptibility loci for migraine without aura
Freilinger, T. M., Anttila, V., de Vries, B., Malik, R., Kallela, M., Terwindt, G. M., Pozo‐Rosich, P., Winsvold, B. S., Nyholt, D. R., van Oosterhout, W. P. J., et al. (2012) · Nature Genetics · doi:10.1038/ng.2307 · Cited by 350
Mahoney, D. H., Shuster, J. J., Nitschke, R., Lauer, S. J., Steuber, C. P., Winick, N. J., & Camitta, B. M. (1998) · Journal of Clinical Oncology · doi:10.1200/jco.1998.16.5.1712 · Cited by 289
Biochemical and Clinical Aspects of Methotrexate Neurotoxicity
Vezmar, S., Becker, A., Bode, U., & Jaehde, U. (2003) · Chemotherapy · doi:10.1159/000069773 · Cited by 272
Kawedia, J. D., Kaste, S. C., Pei, D., Panetta, J. C., Cai, X., Cheng, C., Neale, G. A. M., Howard, S. C., Evans, W. E., Pui, C., et al. (2010) · Blood · doi:10.1182/blood-2010-10-311969 · Cited by 260
Self-citationAncestry and pharmacogenetics of antileukemic drug toxicity
Kishi, S., Cheng, C., French, D., Pei, D., Das, S., Cook, E. H., Hijiya, N., Rizzari, C., Rosner, G. L., Frudakis, T. N., et al. (2007) · Blood · doi:10.1182/blood-2006-10-054528 · Cited by 204
Self-citationInaba, H., Khan, R. B., Laningham, F. H., Crews, K. R., Pui, C., & Daw, N. C. (2007) · Annals of Oncology · doi:10.1093/annonc/mdm466 · Cited by 197
Self-citationHomocysteine, Pharmacogenetics, and Neurotoxicity in Children With Leukemia
Kishi, S., Griener, J. C., Cheng, C., Das, S., Cook, E. H., Pei, D., Hudson, M. M., Rubnitz, J. E., Sandlund, J. T., Pui, C., et al. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.07.056 · Cited by 191
Self-citationWilson, P. M., Fryer, R. H., Fang, Y., & Hatten, M. E. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0032-10.2010 · Cited by 169
Case-Control Genome-Wide Association Study of Attention-Deficit/Hyperactivity Disorder
Neale, B. M., Medland, S. E., Ripke, S., Anney, R., Asherson, P. J., Buitelaar, J. K., Franke, B., Gill, M., Kent, L., Holmans, P., et al. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2010.06.007 · Cited by 169
Aminophylline for methotrexate-induced neurotoxicity
Bernini, J. C., Fort, D. W., Griener, J. C., Kane, B. J., Chappell, W. B., Kamen, B. A., & Kamen, B. A. (1995) · The Lancet · doi:10.1016/s0140-6736(95)90464-6 · Cited by 164
Conklin, H. M., Krull, K. R., Reddick, W. E., Pei, D., Chen, C., & Pui, C. (2012) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djs344 · Cited by 162
Self-citationRollins, N. K., Winick, N. J., Bash, R. O., & Booth, T. N. (2004) · PubMed Central · Cited by 158
Rubnitz, J. E., Relling, M. V., Harrison, P., Sandlund, J. T., Ribeiro, R., Rivera, G. K., Thompson, S., Evans, W., & Pui, C.-H. (1998) · Leukemia · doi:10.1038/sj.leu.2401098 · Cited by 128
Self-citation(2005) · PubMed Central · Cited by 117
Self-citationBuizer, A. I., de Sonneville, L. M. J., van den Heuvel‐Eibrink, M. M., & Veerman, A. J. P. (2006) · Cancer · doi:10.1002/cncr.21820 · Cited by 113
Unexpected Acute Neurologic Toxicity in the Treatment of Children With Acute Lymphoblastic Leukemia
Winick, N. J., Bowman, W. P., Kamen, B. A., Roach, E. S., Rollins, N. K., Jacaruso, D., & Buchanan, G. R. (1992) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/84.4.252 · Cited by 100
Diep, D. B., Hoen, N., Backman, M., Machoň, O., & Krauss, S. J. K. (2004) · Developmental Brain Research · doi:10.1016/j.devbrainres.2004.09.008 · Cited by 96
Genetic Mediators of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia
Krull, K. R., Bhojwani, D., Conklin, H. M., Pei, D., Cheng, C., Reddick, W. E., Sandlund, J. T., & Pui, C. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.46.7944 · Cited by 96
Self-citationImpact of childhood cancer on the mental health of parents
Dockerty, J. D., Williams, S., McGee, R. O., & Skegg, D. C. G. (2000) · Medical and Pediatric Oncology · doi:10.1002/1096-911x(20001101)35:5 · Cited by 88
Zhao, Z., Wang, Z., Gu, Y., Feil, R., Hofmann, F. B., & Ma, L. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.3770-08.2009 · Cited by 81
The Trio family of guanine-nucleotide-exchange factors: regulators of axon guidance
Bateman, J. R., & Vactor, D. V. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.11.1973 · Cited by 80
Prognostic value of breast cancer aromatase
Lipton, A., Santen, R. J., Santner, S. J., Harvey, H. A., Sanders, S. I., & Matthews, Y. L. (1992) · Cancer · doi:10.1002/1097-0142(19921001)70:7 · Cited by 80
Vezmar, S., Schüsseler, P., Becker, A., Bode, U., & Jaehde, U. (2008) · Pediatric Blood & Cancer · doi:10.1002/pbc.21827 · Cited by 63
Oka, M., Terae, S., Kobayashi, R., Sawamura, Y., Kudoh, K., Tha, K. K., Yoshida, M., Kaneda, M., Suzuki, Y., & Miyasaka, K. (2003) · Neuroradiology · doi:10.1007/s00234-003-0983-3 · Cited by 62
Chu, C. W., Chik, K.-W., Chan, Y.-L., Yeung, D. K. W., Roebuck, D. J., Howard, R. G., Li, C. K., & Metreweli, C. (2003) · Radiology · doi:10.1148/radiol.2293021550 · Cited by 56
Spectrin and Ankyrin-Based Cytoskeletons at Polarized Domains in Myelinated Axons
Susuki, K., & Rasband, M. N. (2008) · Experimental Biology and Medicine · doi:10.3181/0709-mr-243 · Cited by 55
Dufourg, M., Landman‐Parker, J., Auclerc, M.-F., Schmitt, C., Pérel, Y., Michel, G., Lévy, P., Couillault, G., Gandemer, V., Tabone, M., et al. (2006) · Leukemia · doi:10.1038/sj.leu.2404495 · Cited by 53
Mikkelsen, T. S., Sparreboom, A., Cheng, C., Zhou, Y., Boyett, J. M., Raimondi, S. C., Panetta, J. C., Bowman, W. P., Sandlund, J. T., Pui, C., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.32.5340 · Cited by 53
Self-citationPauley, J. L., Panetta, J. C., Crews, K. R., Pei, D., Cheng, C., McCormick, J., Howard, S. C., Sandlund, J. T., Jeha, S., Ribeiro, R. C., et al. (2013) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-013-2206-x · Cited by 50
Self-citationFolate Homeostasis in Cerebrospinal Fluid During Therapy for Acute Lymphoblastic Leukemia
Cole, P. D., Beckwith, K. A., Vijayanathan, V., Roychowdhury, S., Smith, A. K., & Kamen, B. A. (2008) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2008.09.005 · Cited by 45
Gene expression in mouse brain following chronic hypoxia: role of sarcospan in glial cell death
Zhou, D., Wang, J., Zapala, M. A., Xue, J., Schork, N. J., & Haddad, G. G. (2007) · Physiological Genomics · doi:10.1152/physiolgenomics.00147.2007 · Cited by 45
Reddick, W. E., Glass, J. O., Helton, K. J., Langston, J. W., Li, C., & Pui, C. (2005) · PubMed Central · Cited by 43
Self-citationVagace, J. M., Marzal, C. C., Jimenez, M., Casado, M. S., de Murillo, S. G., & Gervasini, G. (2010) · American Journal of Hematology · doi:10.1002/ajh.21897 · Cited by 36
Impact of acute lymphoblastic leukemia therapy on attention and working memory in children
Reddick, W. E., & Conklin, H. M. (2010) · Expert Review of Hematology · doi:10.1586/ehm.10.65 · Cited by 31
Self-citationRuehs, H., Becker, A., Drescher, A., Panetta, J. C., Pui, C., Relling, M. V., & Jaehde, U. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046015 · Cited by 29
Self-citationNecrotising leukoencephalopathy complicating treatment of childhood leukaemia.
Robain, O., Dulac, O., Dommergues, J. P., Bernaudin, F., Diebler, K., Kalifa, C., & Poirier, J. C. (1984) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.47.1.65 · Cited by 26
Netrin1 is required for neural and glial precursor migrations into the olfactory bulb
Hakanen, J., Duprat, S., & Salminen, M. (2011) · Developmental Biology · doi:10.1016/j.ydbio.2011.04.016 · Cited by 24
Fine mapping of the chromosome 10q11-q21 linkage region in Alzheimer's disease cases and controls
Fallin, M. D., Szymanski, M., Wang, R., Gherman, A., Bassett, S. S., & Avramopoulos, D. (2010) · Neurogenetics · doi:10.1007/s10048-010-0234-9 · Cited by 21
Echovirus 30 Induced Neuronal Cell Death through TRIO-RhoA Signaling Activation
Lee, J.-W., Yeo, S.-G., Kang, B.-H., Lee, H.-K., Kim, J.-W., Lee, S.-H., Kim, K.-S., & Cheon, D.-S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036656 · Cited by 12
Research works printed but not linked: 3
- Rollins N, 2004, AJNR Am J Neuroradiol, 25, 1688
- Reddick WE, 2005, AJNR Am J Neuroradiol, 26, 1263
- Reddick WE, 2005, AJNR Am J Neuroradiol, 26, 2371
Cited by
Sorted by citations
Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration
Pui, C., Yang, J. J. J., Hunger, S. P., Pieters, R., Schrappe, M., Biondi, A., Vora, A. J., Baruchel, A., Silverman, L. B., Schmiegelow, K., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.1636 · Cited by 1,016
Self-citationPreventing and Managing Toxicities of High-Dose Methotrexate
Howard, S. C., McCormick, J., Pui, C., Buddington, R. K., & Harvey, R. D. (2016) · The Oncologist · doi:10.1634/theoncologist.2015-0164 · Cited by 935
Self-citationIn vitro models of medulloblastoma: Choosing the right tool for the job
Ivanov, D. P., Coyle, B., Walker, D. A., & Grabowska, A. M. (2016) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2016.07.028 · Cited by 231
Cheung, Y. T., & Krull, K. R. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.03.016 · Cited by 187
Self-citationLong-Term Cognitive Dysfunction in Cancer Survivors
Országhová, Z., Mego, M., & Chovanec, M. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.770413 · Cited by 196
Metadata
- Authors
- Bhojwani, D., Sabin, N. D., Pei, D., Yang, J. J., Khan, R. B., Panetta, J. C., Krull, K. R., Inaba, H., Rubnitz, J. E., Metzger, M. L., Howard, S. C., Ribeiro, R. C., Cheng, C., Reddick, W. E., Jeha, S., Sandlund, J. T., Evans, W. E., Pui, C.-H., & Relling, M. V.
- Affiliations
- St. Jude Children's Research Hospital (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2014-03-20
- Volume
- 32
- Issue
- 9
- Pages
- 949-959
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC3948096
- OpenAlex
- W2098676147
- Cited by
- 400
- References
- 48
- Citations by year
- 2026: 38 · 2025: 36 · 2024: 40 · 2023: 27 · 2022: 47 · 2021: 40 · 2020: 33 · 2019: 30 · 2018: 27 · 2017: 34 · 2016: 28 · 2015: 16 · 2014: 3
- FWCI
- 26.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 36401, R01CA036401, R01 CA90246, R01CA090246, R37CA036401, P30CA021765)
- National Institute of General Medical Sciences (U01GM092666, GM 92666)
- Topics
- Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Keywords
- methotrexate neurotoxicity, leukoencephalopathy, childhood acute lymphoblastic leukemia, intrathecal methotrexate, methotrexate pharmacokinetics, germline polymorphisms, neurodevelopmental genes, brain MRI
- MeSH terms
- Adolescent, Antimetabolites, Antineoplastic, Antineoplastic Combined Chemotherapy Protocols, Brain, Child, Child, Preschool, Leucovorin, Female, Humans, Magnetic Resonance Imaging, Male, Methotrexate, Polymorphism, Genetic, Prospective Studies, Risk Factors, Logistic Models, Germ-Line Mutation, Genetic Predisposition to Disease, Neurotoxicity Syndromes, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Genome-Wide Association Study, Leukoencephalopathies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
