{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T15:45:42Z","timestamp":1793375142878,"version":"4.5.0"},"reference-count":113,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2016,8,5]],"date-time":"2016-08-05T00:00:00Z","timestamp":1470355200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"National Institutes of Health Cancer Center","award":["CA-21765"],"award-info":[{"award-number":["CA-21765"]}]},{"DOI":"10.13039\/100012524","name":"American Lebanese Syrian Associated Charities","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012524","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg\/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%\u201312% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated.<\/jats:p>","DOI":"10.1634\/theoncologist.2015-0164","type":"journal-article","created":{"date-parts":[[2016,8,5]],"date-time":"2016-08-05T22:49:01Z","timestamp":1470437341000},"page":"1471-1482","source":"Crossref","is-referenced-by-count":827,"title":["Preventing and Managing Toxicities of High-Dose Methotrexate"],"prefix":"10.1093","volume":"21","author":[{"given":"Scott C.","family":"Howard","sequence":"first","affiliation":[{"name":"School of Health Studies, University of Memphis, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"McCormick","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, St. Jude Children\u2019s Research Hospital, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Hon","family":"Pui","sequence":"additional","affiliation":[{"name":"Department of Oncology, St. Jude Children\u2019s Research Hospital, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall K.","family":"Buddington","sequence":"additional","affiliation":[{"name":"School of Health Studies, University of Memphis, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Donald","family":"Harvey","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,8,5]]},"reference":[{"key":"2021122309580965900_B1","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1634\/theoncologist.11-6-694","article-title":"Understanding and managing methotrexate nephrotoxicity","volume":"11","author":"Widemann","year":"2006","journal-title":"The Oncologist"},{"key":"2021122309580965900_B2","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1056\/NEJM197709222971203","article-title":"Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity","volume":"297","author":"Stoller","year":"1977","journal-title":"N Engl J Med"},{"key":"2021122309580965900_B3","first-page":"1088","article-title":"Effectiveness of high-dose infusions of methotrexate followed by leucovorin in carcinoma of the head and neck","volume":"28","author":"Mitchell","year":"1968","journal-title":"Cancer Res"},{"key":"2021122309580965900_B4","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1200\/JCO.1998.16.3.859","article-title":"Long-term survival in primary CNS lymphoma","volume":"16","author":"Abrey","year":"1998","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B5","doi-asserted-by":"crossref","first-page":"4321","DOI":"10.1002\/cncr.27378","article-title":"Resumption of high-dose methotrexate after acute kidney injury and glucarpidase use in pediatric oncology patients","volume":"118","author":"Christensen","year":"2012","journal-title":"Cancer"},{"key":"2021122309580965900_B6","doi-asserted-by":"crossref","first-page":"3979","DOI":"10.1200\/JCO.2009.25.4540","article-title":"Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: Clinical and pharmacologic factors affecting outcome","volume":"28","author":"Widemann","year":"2010","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B7","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.semnephrol.2010.09.005","article-title":"Nephrotoxicity from chemotherapeutic agents: Clinical manifestations, pathobiology, and prevention\/therapy","volume":"30","author":"Perazella","year":"2010","journal-title":"Semin Nephrol"},{"key":"2021122309580965900_B8","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.3109\/10428194.2013.840780","article-title":"High incidence of methotrexate associated renal toxicity in patients with lymphoma: A retrospective analysis","volume":"55","author":"May","year":"2014","journal-title":"Leuk Lymphoma"},{"key":"2021122309580965900_B9","doi-asserted-by":"crossref","first-page":"3762","DOI":"10.1093\/ndt\/gfn503","article-title":"Severe acute renal failure following high-dose methotrexate therapy in adults with haematological malignancies: A significant number result from unrecognized co-administration of several drugs","volume":"23","author":"De Miguel","year":"2008","journal-title":"Nephrol Dial Transplant"},{"key":"2021122309580965900_B10","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/j.1365-2125.2008.03303.x","article-title":"Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy","volume":"67","author":"Suzuki","year":"2009","journal-title":"Br J Clin Pharmacol"},{"key":"2021122309580965900_B11","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/pbc.24393","article-title":"Pharmacokinetic interaction between methotrexate and chloral hydrate","volume":"60","author":"Dao","year":"2013","journal-title":"Pediatr Blood Cancer"},{"key":"2021122309580965900_B12","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1177\/1060028013511951","article-title":"Drug-drug interaction between methotrexate and levetiracetam resulting in delayed methotrexate elimination","volume":"48","author":"Bain","year":"2014","journal-title":"Ann Pharmacother"},{"key":"2021122309580965900_B13","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1002\/pbc.24371","article-title":"Drug-drug interaction between methotrexate and levetiracetam in a child treated for acute lymphoblastic leukemia","volume":"60","author":"Parentelli","year":"2013","journal-title":"Pediatr Blood Cancer"},{"key":"2021122309580965900_B14","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1177\/0897190012442717","article-title":"Suspected methotrexate toxicity from omeprazole: a case review of carboxypeptidase G2 use in a methotrexate-experienced patient with methotrexate toxicity and a review of the literature","volume":"25","author":"McBride","year":"2012","journal-title":"J Pharm Pract"},{"key":"2021122309580965900_B15","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1634\/theoncologist.2011-0431","article-title":"Accumulating evidence for a drug-drug interaction between methotrexate and proton pump inhibitors","volume":"17","author":"Bezabeh","year":"2012","journal-title":"The Oncologist"},{"key":"2021122309580965900_B16","doi-asserted-by":"crossref","first-page":"e180","DOI":"10.1200\/JCO.2010.32.8245","article-title":"High-dose methotrexate-induced renal dysfunction: is glucarpidase necessary for rescue?","volume":"29","author":"Meyers","year":"2011","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B17","doi-asserted-by":"crossref","first-page":"4189","DOI":"10.1200\/JCO.2010.34.4614","article-title":"Antiemetics: American Society of Clinical Oncology clinical practice guideline update","volume":"29","author":"Basch","year":"2011","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B18","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1200\/JCO.1987.5.12.2017","article-title":"High-dose methotrexate: A critical reappraisal","volume":"5","author":"Ackland","year":"1987","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B19","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1200\/JCO.2013.53.0808","article-title":"Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia","volume":"32","author":"Bhojwani","year":"2014","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B20","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1097\/IAE.0b013e31828ac07d","article-title":"Intraocular methotrexate can induce extended remission in some patients in noninfectious uveitis","volume":"33","author":"Taylor","year":"2013","journal-title":"Retina"},{"key":"2021122309580965900_B21","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2174\/1871528112666131230013059","article-title":"Methotrexate-induced pneumonitis: Heterogeneity of bronchoalveolar lavage and differences between cancer and rheumatoid arthritis","volume":"13","author":"D\u2019Elia","year":"2014","journal-title":"Inflamm Allergy Drug Targets"},{"key":"2021122309580965900_B22","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1155\/2013\/527912","article-title":"Methotrexate-induced pulmonary toxicity","volume":"20","author":"Jakubovic","year":"2013","journal-title":"Can Respir J"},{"key":"2021122309580965900_B23","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s10067-011-1758-6","article-title":"How common is methotrexate pneumonitis? A large prospective study investigates","volume":"31","author":"Sathi","year":"2012","journal-title":"Clin Rheumatol"},{"key":"2021122309580965900_B24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s13318-012-0113-x","article-title":"Effect of ketoprofen and indomethacin on methotrexate pharmacokinetics in mice plasma and tumor tissues","volume":"38","author":"Elmorsi","year":"2013","journal-title":"Eur J Drug Metab Pharmacokinet"},{"key":"2021122309580965900_B25","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1093\/toxsci\/kfu156","article-title":"Increased susceptibility to methotrexate-induced toxicity in nonalcoholic steatohepatitis","volume":"142","author":"Hardwick","year":"2014","journal-title":"Toxicol Sci"},{"key":"2021122309580965900_B26","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/BF00689044","article-title":"Pharmacokinetics of different doses of methotrexate at steady state by in situ microdialysis in a rat model","volume":"36","author":"Ekstr\u00f8m","year":"1995","journal-title":"Cancer Chemother Pharmacol"},{"key":"2021122309580965900_B27","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1080\/08880010050211358","article-title":"Leucovorin and maximum tolerated dose toxicity of methotrexate in rats","volume":"17","author":"Fuskev\u00e5g","year":"2000","journal-title":"Pediatr Hematol Oncol"},{"key":"2021122309580965900_B28","first-page":"1003","article-title":"Protective effect of pentoxyfilline in renal toxicity after methotrexate administration","volume":"15","author":"Asvadi","year":"2011","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"2021122309580965900_B29","doi-asserted-by":"crossref","first-page":"3134","DOI":"10.1007\/s10620-013-2826-3","article-title":"Protective effect of amifostine on high-dose methotrexate-induced small intestinal mucositis in mice","volume":"58","author":"Chen","year":"2013","journal-title":"Dig Dis Sci"},{"key":"2021122309580965900_B30","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/cbf.1676","article-title":"Melatonin attenuates methotrexate-induced oxidative stress and renal damage in rats","volume":"28","author":"Abraham","year":"2010","journal-title":"Cell Biochem Funct"},{"key":"2021122309580965900_B31","doi-asserted-by":"crossref","first-page":"130","DOI":"10.3109\/08923973.2014.884135","article-title":"Protective effect of peroxisome proliferator activator receptor (PPAR)-\u03b1 and -\u03b3 ligands against methotrexate-induced nephrotoxicity","volume":"36","author":"Ibrahim","year":"2014","journal-title":"Immunopharmacol Immunotoxicol"},{"key":"2021122309580965900_B32","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1172\/JCI108308","article-title":"7-Hydroxymethotrexate as a urinary metabolite in human subjects and rhesus monkeys receiving high dose methotrexate","volume":"57","author":"Jacobs","year":"1976","journal-title":"J Clin Invest"},{"key":"2021122309580965900_B33","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/239395b0","article-title":"Enzymatic cleavage of methotrexate provides a method for prevention of drug toxicity","volume":"239","author":"Chabner","year":"1972","journal-title":"Nature"},{"key":"2021122309580965900_B34","first-page":"621","volume-title":"Acute Renal Failure","author":"Garnick","year":"1988"},{"key":"2021122309580965900_B35","first-page":"43","article-title":"Clinical trial of high-dose methotrexate (nsc-740) with citrovorum factor (nsc-3590)-toxicologic and therapeutic observations","volume":"6","author":"Pitman","year":"1975","journal-title":"Cancer Chemother Rep"},{"key":"2021122309580965900_B36","first-page":"695","article-title":"Weekly methotrexate-calcium leucovorin rescue: effect of alkalinization on nephrotoxicity; pharmacokinetics in the CNS; and use in CNS non-Hodgkin\u2019s lymphoma","volume":"61","author":"Pitman","year":"1977","journal-title":"Cancer Treat Rep"},{"key":"2021122309580965900_B37","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1191\/1078155205jp148oa","article-title":"Polyuria associated with high-dose methotrexate in two patients with acute lymphoblastic leukaemia","volume":"11","author":"Lau","year":"2005","journal-title":"J Oncol Pharm Pract"},{"key":"2021122309580965900_B38","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/nrneph.2009.97","article-title":"Chemotherapy-associated renal dysfunction","volume":"5","author":"Sahni","year":"2009","journal-title":"Nat Rev Nephrol"},{"key":"2021122309580965900_B39","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s00280-013-2319-2","article-title":"Serum creatinine and creatinine clearance for predicting plasma methotrexate concentrations after high-dose methotrexate chemotherapy for the treatment for childhood lymphoblastic malignancies","volume":"73","author":"Xu","year":"2014","journal-title":"Cancer Chemother Pharmacol"},{"key":"2021122309580965900_B40","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0305-7372(95)90010-1","article-title":"Anticancer drug renal toxicity and elimination: Dosing guidelines for altered renal function","volume":"21","author":"Kintzel","year":"1995","journal-title":"Cancer Treat Rev"},{"key":"2021122309580965900_B41","first-page":"48","volume":"4","author":"Aronoff","year":"1999","journal-title":"Drug prescribing in renal failure: Dosing guidelines for adults"},{"key":"2021122309580965900_B42","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1007\/s00280-011-1751-4","article-title":"The role of MTHFR and RFC1 polymorphisms on toxicity and outcome of adult patients with hematological malignancies treated with high-dose methotrexate followed by leucovorin rescue","volume":"69","author":"Chiusolo","year":"2012","journal-title":"Cancer Chemother Pharmacol"},{"key":"2021122309580965900_B43","doi-asserted-by":"crossref","first-page":"5972","DOI":"10.1200\/JCO.2008.20.4156","article-title":"Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects","volume":"27","author":"Trevi\u00f1o","year":"2009","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/gr.129668.111","article-title":"Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition","volume":"22","author":"Ramsey","year":"2012","journal-title":"Genome Res"},{"key":"2021122309580965900_B45","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1182\/blood-2012-08-452839","article-title":"Genome-wide study of methotrexate clearance replicates SLCO1B1","volume":"121","author":"Ramsey","year":"2013","journal-title":"Blood"},{"key":"2021122309580965900_B46","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s00280-014-2614-6","article-title":"Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections","volume":"75","author":"Wright","year":"2015","journal-title":"Cancer Chemother Pharmacol"},{"key":"2021122309580965900_B47","first-page":"999","article-title":"Raised plasma methotrexate concentrations following intrathecal administration in children with renal dysfunction","volume":"5","author":"Gregory","year":"1991","journal-title":"Leukemia"},{"key":"2021122309580965900_B48","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1097\/01.AOG.0000172374.72125.3e","article-title":"A cautionary tale: fatal outcome of methotrexate therapy given for management of ectopic pregnancy","volume":"107","author":"Kelly","year":"2006","journal-title":"Obstet Gynecol"},{"key":"2021122309580965900_B49","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1681\/ASN.2012070653","article-title":"Retooling the creatinine clearance equation to estimate kinetic GFR when the plasma creatinine is changing acutely","volume":"24","author":"Chen","year":"2013","journal-title":"J Am Soc Nephrol"},{"key":"2021122309580965900_B50","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1002\/phar.1360","article-title":"Efficacy of glucarpidase (carboxypeptidase g2) in patients with acute kidney injury after high-dose methotrexate therapy","volume":"34","author":"Widemann","year":"2014","journal-title":"Pharmacotherapy"},{"key":"2021122309580965900_B51","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1200\/JCO.1994.12.8.1667","article-title":"Patient characteristics associated with high-risk methotrexate concentrations and toxicity","volume":"12","author":"Relling","year":"1994","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B52","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1007\/BF00689708","article-title":"Acetazolamide for alkalinisation of urine in patients receiving high-dose methotrexate","volume":"28","author":"Shamash","year":"1991","journal-title":"Cancer Chemother Pharmacol"},{"key":"2021122309580965900_B53","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/BF00262416","article-title":"Pharmacokinetic monitoring of high-dose methotrexate. Early recognition of high-risk patients","volume":"3","author":"Evans","year":"1979","journal-title":"Cancer Chemother Pharmacol"},{"key":"2021122309580965900_B54","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1373\/clinchem.2010.144824","article-title":"Difficulty measuring methotrexate in a patient with high-dose methotrexate-induced nephrotoxicity","volume":"56","author":"Al-Turkmani","year":"2010","journal-title":"Clin Chem"},{"key":"2021122309580965900_B55","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1002\/pbc.25137","article-title":"Assessment of renal function during high-dose methotrexate treatment in children with acute lymphoblastic leukemia","volume":"61","author":"Ylinen","year":"2014","journal-title":"Pediatr Blood Cancer"},{"key":"2021122309580965900_B56","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.2165\/00003088-200645120-00007","article-title":"Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia","volume":"45","author":"Aumente","year":"2006","journal-title":"Clin Pharmacokinet"},{"key":"2021122309580965900_B57","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1007\/s00280-007-0550-4","article-title":"A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia","volume":"60","author":"Plard","year":"2007","journal-title":"Cancer Chemother Pharmacol"},{"key":"2021122309580965900_B58","doi-asserted-by":"crossref","first-page":"2690","DOI":"10.1182\/blood-2004-04-1616","article-title":"Improved outcome for children with acute lymphoblastic leukemia: Results of Total Therapy Study XIIIB at St Jude Children\u2019s Research Hospital","volume":"104","author":"Pui","year":"2004","journal-title":"Blood"},{"key":"2021122309580965900_B59","article-title":"Statistical analysis of relation between plasma methotrexate concentration and toxicity in high-dose methotrexate therapy of childhood nonHodgkin lymphoma","volume-title":"Pediatr Blood Cancer","author":"Tsurusawa","year":"2014"},{"key":"2021122309580965900_B60","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1001\/jama.291.20.2471","article-title":"Establishment of a pediatric oncology program and outcomes of childhood acute lymphoblastic leukemia in a resource-poor area","volume":"291","author":"Howard","year":"2004","journal-title":"JAMA"},{"key":"2021122309580965900_B61","first-page":"335","article-title":"In vitro and in vivo protein binding of methotrexate assessed by microdialysis","volume":"34","author":"Maia","year":"1996","journal-title":"Int J Clin Pharmacol Ther"},{"key":"2021122309580965900_B62","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s00467-002-0946-7","article-title":"Effective removal of methotrexate by high-flux hemodialysis","volume":"17","author":"Saland","year":"2002","journal-title":"Pediatr Nephrol"},{"key":"2021122309580965900_B63","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1016\/S0272-6386(96)90384-4","article-title":"Effective clearance of methotrexate using high-flux hemodialysis membranes","volume":"28","author":"Wall","year":"1996","journal-title":"Am J Kidney Dis"},{"key":"2021122309580965900_B64","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1200\/JCO.1997.15.5.2125","article-title":"Carboxypeptidase-G2, thymidine, and leucovorin rescue in cancer patients with methotrexate-induced renal dysfunction","volume":"15","author":"Widemann","year":"1997","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B65","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1002\/1097-0142(19880901)62:5<884::AID-CNCR2820620506>3.0.CO;2-A","article-title":"Removal of methotrexate, leucovorin, and their metabolites by combined hemodialysis and hemoperfusion","volume":"62","author":"Relling","year":"1988","journal-title":"Cancer"},{"key":"2021122309580965900_B66","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1093\/rheumatology\/kep023","article-title":"Liver fibrosis in patients with psoriasis and psoriatic arthritis on long-term, high cumulative dose methotrexate therapy","volume":"48","author":"Lindsay","year":"2009","journal-title":"Rheumatology (Oxford)"},{"key":"2021122309580965900_B67","first-page":"207","article-title":"Transient acute hepatotoxicity of high-dose methotrexate therapy during childhood","volume-title":"NCI Monogr","author":"Weber","year":"1987"},{"key":"2021122309580965900_B68","first-page":"49","article-title":"High-dose methotrexate administration and acute liver damage in children treated for acute lymphoblastic leukemia. A prospective study","volume":"77","author":"Locasciulli","year":"1992","journal-title":"Haematologica"},{"key":"2021122309580965900_B69","first-page":"511","article-title":"Liver biopsies from psoriatics related to methotrexate therapy. 3. Findings in post-methotrexate liver biopsies from 160 psoriatics","volume":"85","author":"Nyfors","year":"1977","journal-title":"Acta Pathol Microbiol Scand [A]"},{"key":"2021122309580965900_B70","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.ajem.2005.05.001","article-title":"2004 annual report of the American Association of Poison Control Centers toxic exposure surveillance system","volume":"23","author":"Watson","year":"2005","journal-title":"Am J Emerg Med"},{"key":"2021122309580965900_B71","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1002\/art.1780370304","article-title":"Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity","volume":"37","author":"Kremer","year":"1994","journal-title":"Arthritis Rheum"},{"key":"2021122309580965900_B72","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1200\/JCO.1998.16.5.1712","article-title":"Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: An association with intermediate-dose intravenous methotrexate and intrathecal triple therapy\u2013a Pediatric Oncology Group study","volume":"16","author":"Mahoney","year":"1998","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B73","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/sj.leu.2401098","article-title":"Transient encephalopathy following high-dose methotrexate treatment in childhood acute lymphoblastic leukemia","volume":"12","author":"Rubnitz","year":"1998","journal-title":"Leukemia"},{"key":"2021122309580965900_B74","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1172\/JCI116884","article-title":"The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation","volume":"92","author":"Cronstein","year":"1993","journal-title":"J Clin Invest"},{"key":"2021122309580965900_B75","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/S0140-6736(95)90464-6","article-title":"Aminophylline for methotrexate-induced neurotoxicity","volume":"345","author":"Bernini","year":"1995","journal-title":"Lancet"},{"key":"2021122309580965900_B76","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S1368-8375(97)00053-5","article-title":"Mucositis as a biological process: A new hypothesis for the development of chemotherapy-induced stomatotoxicity","volume":"34","author":"Sonis","year":"1998","journal-title":"Oral Oncol"},{"key":"2021122309580965900_B77","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/nrc1318","article-title":"The pathobiology of mucositis","volume":"4","author":"Sonis","year":"2004","journal-title":"Nat Rev Cancer"},{"key":"2021122309580965900_B78","first-page":"21","article-title":"A biological approach to mucositis","volume":"2","author":"Sonis","year":"2004","journal-title":"J Support Oncol"},{"key":"2021122309580965900_B79","first-page":"492","article-title":"Prevention of high dose L-PAM-induced mucositis by cryotherapy","volume":"14","author":"Dumontet","year":"1994","journal-title":"Bone Marrow Transplant"},{"key":"2021122309580965900_B80","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1023\/A:1006026928733","article-title":"Phase I trial of edatrexate plus carboplatin in advanced solid tumors: Amelioration of dose-limiting mucositis by ice chip cryotherapy","volume":"16","author":"Edelman","year":"1998","journal-title":"Invest New Drugs"},{"key":"2021122309580965900_B81","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0266-4356(90)90128-8","article-title":"Local benefit of prostaglandin E2 in radiochemotherapy-induced oral mucositis","volume":"28","author":"Matejka","year":"1990","journal-title":"Br J Oral Maxillofac Surg"},{"key":"2021122309580965900_B82","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1093\/annonc\/mdn179","article-title":"Use of palifermin for the prevention of high-dose methotrexate-induced oral mucositis","volume":"19","author":"Schmidt","year":"2008","journal-title":"Ann Oncol"},{"key":"2021122309580965900_B83","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1742-7843.2009.00400.x","article-title":"Protective effects of amifostine and cyclooxygenase-1 inhibitor against normal human epidermal keratinocyte toxicity induced by methotrexate and 5-fluorouracil","volume":"105","author":"Maiguma","year":"2009","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"2021122309580965900_B84","first-page":"CD000978","article-title":"Interventions for preventing oral mucositis for patients with cancer receiving treatment","volume":"4","author":"Worthington","year":"2011","journal-title":"Cochrane Database Syst Rev"},{"key":"2021122309580965900_B85","first-page":"CD001973","article-title":"Interventions for treating oral mucositis for patients with cancer receiving treatment","volume":"8","author":"Clarkson","year":"2010","journal-title":"Cochrane Database Syst Rev"},{"key":"2021122309580965900_B86","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1743-7075-11-17","article-title":"Glutamine attenuates the inhibitory effect of methotrexate on TLR signaling during intestinal chemotherapy-induced mucositis in a rat","volume":"11","author":"Sukhotnik","year":"2014","journal-title":"Nutr Metab (Lond)"},{"key":"2021122309580965900_B87","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1007\/s00280-013-2238-2","article-title":"Disruption of ZO-1\/claudin-4 interaction in relation to inflammatory responses in methotrexate-induced intestinal mucositis","volume":"72","author":"Hamada","year":"2013","journal-title":"Cancer Chemother Pharmacol"},{"key":"2021122309580965900_B88","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.clnu.2012.10.002","article-title":"Reduced absorption of long-chain fatty acids during methotrexate-induced gastrointestinal mucositis in the rat","volume":"32","author":"Fijlstra","year":"2013","journal-title":"Clin Nutr"},{"key":"2021122309580965900_B89","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/BF00262419","article-title":"Evaluation of 24-hour infusion of high-dose methotrexate\u2013pharmacokinetics and toxicity","volume":"3","author":"Goh","year":"1979","journal-title":"Cancer Chemother Pharmacol"},{"key":"2021122309580965900_B90","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1002\/1097-0142(19950801)76:3<521::AID-CNCR2820760325>3.0.CO;2-M","article-title":"Carboxypeptidase-G2 rescue in a patient with high dose methotrexate-induced nephrotoxicity","volume":"76","author":"Widemann","year":"1995","journal-title":"Cancer"},{"key":"2021122309580965900_B91","first-page":"4418","article-title":"The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides","volume":"36","author":"Pinedo","year":"1976","journal-title":"Cancer Res"},{"key":"2021122309580965900_B92","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1158\/1055-9965.EPI-13-0036","article-title":"Glomerular function time trends in long-term survivors of childhood cancer: A longitudinal study","volume":"22","author":"Mulder","year":"2013","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"2021122309580965900_B93","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1634\/theoncologist.12-11-1299","article-title":"Glucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy","volume":"12","author":"Schwartz","year":"2007","journal-title":"The Oncologist"},{"issue":"suppl","key":"2021122309580965900_B94","doi-asserted-by":"crossref","first-page":"6530","DOI":"10.1200\/jco.2012.30.15_suppl.6530","article-title":"Clinical trial and compassionate use experience with glucarpidase for methotrexate toxicity","volume":"30","author":"Widemann","year":"2012","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B95","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/sj.bjc.6602337","article-title":"Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure","volume":"92","author":"Buchen","year":"2005","journal-title":"Br J Cancer"},{"key":"2021122309580965900_B96","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1159\/000365725","article-title":"The weaned pig as a model for Doxorubicin-induced mucositis","volume":"60","author":"Martin","year":"2014","journal-title":"Chemotherapy"},{"key":"2021122309580965900_B97","doi-asserted-by":"crossref","first-page":"940","DOI":"10.3892\/ol.2014.2773","article-title":"Mechanisms of methotrexate resistance in osteosarcoma cell lines and strategies for overcoming this resistance","volume":"9","author":"Wang","year":"2015","journal-title":"Oncol Lett"},{"key":"2021122309580965900_B98","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1038\/sj.leu.2402526","article-title":"Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: The JALSG-ALL93 study","volume":"16","author":"Takeuchi","year":"2002","journal-title":"Leukemia"},{"key":"2021122309580965900_B99","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1200\/JCO.2002.07.116","article-title":"Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia","volume":"20","author":"Linker","year":"2002","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B100","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1046\/j.1365-2141.2003.04738.x","article-title":"Successful treatment without cranial radiotherapy of children receiving intensified chemotherapy for acute lymphoblastic leukaemia: Results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI (ISRC TN 16757172)","volume":"124","author":"Hill","year":"2004","journal-title":"Br J Haematol"},{"key":"2021122309580965900_B101","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1002\/pbc.25191","article-title":"Impact of SLCO1B1 521T&gt;C variant on leucovorin rescue and risk of relapse in childhood acute lymphoblastic leukemia treated with high-dose methotrexate","volume":"61","author":"Zhang","year":"2014","journal-title":"Pediatr Blood Cancer"},{"key":"2021122309580965900_B102","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/S0140-6736(97)02307-6","article-title":"Randomised trial of two regimens of chemotherapy in operable osteosarcoma: A study of the European Osteosarcoma Intergroup","volume":"350","author":"Souhami","year":"1997","journal-title":"Lancet"},{"key":"2021122309580965900_B103","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1023\/A:1008391103132","article-title":"Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group\u2019s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs","volume":"9","author":"Fuchs","year":"1998","journal-title":"Ann Oncol"},{"key":"2021122309580965900_B104","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1016\/S0959-8049(01)00229-5","article-title":"Neoadjuvant chemotherapy for osteosarcoma of the extremity: Long-term results of the Rizzoli\u2019s 4th protocol","volume":"37","author":"Bacci","year":"2001","journal-title":"Eur J Cancer"},{"key":"2021122309580965900_B105","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1200\/JCO.2003.08.165","article-title":"Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651","volume":"21","author":"Goorin","year":"2003","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B106","doi-asserted-by":"crossref","first-page":"8845","DOI":"10.1200\/JCO.2004.00.5785","article-title":"Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: A joint study by the Italian and Scandinavian Sarcoma Groups","volume":"23","author":"Ferrari","year":"2005","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B107","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1038\/sj.leu.2400861","article-title":"The hyper-CVAD regimen improves outcome in relapsed acute lymphoblastic leukemia","volume":"11","author":"Koller","year":"1997","journal-title":"Leukemia"},{"key":"2021122309580965900_B108","doi-asserted-by":"crossref","first-page":"3803","DOI":"10.1200\/JCO.1998.16.12.3803","article-title":"Hyper-CVAD and high-dose methotrexate\/cytarabine followed by stem-cell transplantation: An active regimen for aggressive mantle-cell lymphoma","volume":"16","author":"Khouri","year":"1998","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B109","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1182\/blood-2003-12-4428","article-title":"Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma","volume":"104","author":"Thomas","year":"2004","journal-title":"Blood"},{"key":"2021122309580965900_B110","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1200\/JCO.2003.03.036","article-title":"Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: A report of NABTT 96-07","volume":"21","author":"Batchelor","year":"2003","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B111","doi-asserted-by":"crossref","first-page":"500","DOI":"10.3109\/10428194.2014.927458","article-title":"What is the optimal dose of high-dose methotrexate in the initial treatment of primary central nervous system lymphoma?","volume":"56","author":"Dalia","year":"2015","journal-title":"Leuk Lymphoma"},{"key":"2021122309580965900_B112","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1200\/JCO.1983.1.3.208","article-title":"Methotrexate-induced renal impairment: Clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine","volume":"1","author":"Abelson","year":"1983","journal-title":"J Clin Oncol"},{"key":"2021122309580965900_B113","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0305-7372(77)80007-8","article-title":"Methotrexate: Clinical pharmacology, current status and therapeutic guidelines","volume":"4","author":"Bleyer","year":"1977","journal-title":"Cancer Treat Rev"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1634\/theoncologist.2015-0164","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1634\/theoncologist.2015-0164","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/21\/12\/1471\/41877230\/oncolo_21_12_1471.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/21\/12\/1471\/41877230\/oncolo_21_12_1471.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T23:48:02Z","timestamp":1640303282000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/21\/12\/1471\/6401616"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,5]]},"references-count":113,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2016,8,5]]},"published-print":{"date-parts":[[2016,12,1]]}},"URL":"https:\/\/doi.org\/10.1634\/theoncologist.2015-0164","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,12,1]]},"published":{"date-parts":[[2016,8,5]]}}}