{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T08:23:53Z","timestamp":1773563033007,"version":"3.50.1"},"reference-count":25,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp;amp; Cancer"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Methotrexate\u2010associated leukoencephalopathy is poorly documented in osteosarcoma. Since 2007, our institution has monitored osteosarcoma patients with sequential magnetic resonance imaging (MRI) and neuropsychological evaluations during treatment and follow\u2010up.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed data from consecutive osteosarcoma patients younger than 25\u00a0years enrolled at Gustave Roussy in the OS2006 study (2007\u20132015) and treated with high\u2010dose methotrexate (MTX) and etoposide\u2013ifosfamide. Eligible patients received four or more MTX courses and at least one brain MRI. MTX\u2010related neurotoxicity was defined as neurological symptoms attributed to MTX after excluding other causes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MTX\u2010related neurotoxicity occurred in seven (13%) of 53 eligible patients. Additionally, 12 had severe depression, nine reported attention\/memory deficits, and 25 had headaches during MTX infusion. Acute symptoms resolved in all but one. Forty\u2010nine patients had an MRI during treatment, and 47 after. Leukoencephalopathy was found in 44 (83%): Grade 1 in six, Grade 2 in 15, and Grade 3 in 23. Grade 2\u20133 leukoencephalopathy was more frequent in patients with severe depression (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.02) and those receiving more than 12 MTX courses (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.03); no association was found with age, sex, MTX\u2010related neurotoxicity, or cognitive complaints. Among 24 patients with MRI \u22653\u00a0years post\u2010treatment, 20 still showed leukoencephalopathy (12 Grade 1, eight Grade 2). Neurocognitive evaluations showed IQ scores consistent with norms, except for lower processing speed, which improved post\u2010treatment. At last follow\u2010up (median 8.5\u00a0years), most patients had integrated into school or work.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>MTX\u2010associated leukoencephalopathy is frequent in osteosarcoma, even in asymptomatic patients, and often persists after treatment. Serious neurocognitive sequelae appear uncommon, but long\u2010term cognitive monitoring is essential to detect subtle deficits.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pbc.32104","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T05:25:46Z","timestamp":1761110746000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Leukoencephalopathy, a Frequent Complication After High\u2010Dose Methotrexate in Treatment of Osteosarcoma"],"prefix":"10.1002","volume":"73","author":[{"given":"Sandra","family":"Raimbault","sequence":"first","affiliation":[{"name":"Department of Children and Adolescent Oncology Gustave Roussy Cancer Center  Villejuif France"},{"name":"Department of Pediatric and AYA Oncology Centre Oscar Lambret  Lille France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean Louis","family":"Amegnizin","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology Henri Mondor University Hospital  Creteil France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Audrey","family":"Longaud","sequence":"additional","affiliation":[{"name":"Department of Children and Adolescent Oncology Gustave Roussy Cancer Center  Villejuif France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7603-7828","authenticated-orcid":false,"given":"Brice","family":"Fresneau","sequence":"additional","affiliation":[{"name":"Department of Children and Adolescent Oncology Gustave Roussy Cancer Center  Villejuif France"},{"name":"INSERM U1018 CESP, Radiation Epidemiology Team Paris\u2010Saclay University  Villejuif France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie","family":"Gaspar","sequence":"additional","affiliation":[{"name":"Department of Children and Adolescent Oncology Gustave Roussy Cancer Center  Villejuif France"},{"name":"Inserm U1015 Paris Saclay University  Villejuif France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1110-7789","authenticated-orcid":false,"given":"Pablo","family":"Berlanga","sequence":"additional","affiliation":[{"name":"Department of Children and Adolescent Oncology Gustave Roussy Cancer Center  Villejuif France"},{"name":"Inserm U1015 Paris Saclay University  Villejuif France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginie","family":"Kieffer","sequence":"additional","affiliation":[{"name":"Department of Children and Adolescent Oncology Gustave Roussy Cancer Center  Villejuif France"},{"name":"Rehabilitation Department for Children with Acquired Brain Injury Saint Maurice Hospitals  Saint Maurice France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Maraval","sequence":"additional","affiliation":[{"name":"Department 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France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7798-6651","authenticated-orcid":false,"given":"Pierre","family":"Brugieres","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology Henri Mondor University Hospital  Creteil France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blanche","family":"Bapst","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology Henri Mondor University Hospital  Creteil France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurence","family":"Brugieres","sequence":"additional","affiliation":[{"name":"Department of Children and Adolescent Oncology Gustave Roussy Cancer Center  Villejuif 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