The CATSINDO Trial - Clinical and Translational Study in Newly Diagnosed Osteosarcoma

Pre-Enrollment Criteria: 1. Suspected diagnosis of high-grade osteosarcoma based on clinical and radiographic findings. 2. Informed consent (and assent, if applicable) obtained, per institutional guidelines. 3. Participants must be ≤ 22 years of age at the time of consent. Inclusion Criteria: 1. Participants with localized or metastatic high-grade osteosarcoma. 2. Participants must be ≤ 22 years of age at the time of consent. 3. Participants must have a body surface area of greater than or equal to 0.8 m2. 4. Participants receiving or planning to receive induction/neoadjuvant MAP chemotherapy with HD-MTX given at the standard dose of 12 gm/m2 (maximum 20 gm). NOTE: Participants may be participating on other clinical studies such as the COG trial AOST2032 or any other clinical trial as long as their treatment includes MAP chemotherapy with the standard HD-MTX dose of 12 gm/m2 (maximum 20 gm). 5. Participants may receive other chemotherapy agents in their treatment provided that drug(s) are not known to interfere with HD-MTX clearance when given concurrently. Medications known to interfere with HD-MTX clearance are listed in Appendix A. 6. Participants must meet minimum organ function requirements to receive HD-MTX: * Adequate liver function defined as: total bilirubin ≤ 1.5x upper limit of normal (ULN) for age at the time of consent and alanine aminotransferase (ALT/SGPT) ≤ 135 U/L for age at the time of consent. * Adequate renal function defined as: a serum creatinine based on age/gender OR - a 24-hour urine Creatinine clearance ≥ 70 mL/min/1.73 m2, OR - an estimated glomerular filtration rate (GFR) of greater than or equal to 70 mL/min/1.73 m2 for age at the time of consent. * Adequate bone marrow function defined as: peripheral absolute neutrophil count (ANC) ≥ 1000/µL, platelet count ≥ 100,000/µL (transfusion independent, defined as not receiving platelet transfusions within a 7-day period prior to enrollment), and hemoglobin ≥ 8.0 g/dL (transfusion independent, defined as not receiving red blood cell transfusions within a 7-day period prior to enrollment) 7. Adequate cardiac function, defined as a left ventricular ejection fraction (LVEF) ≥ 50%, assessed per institutional standard of care using non-invasive imaging modalities such as a Multi-Gated Acquisition (MUGA) scan or echocardiogram (echo). NOTE: Cardiac function assessment will be performed as part of routine clinical care. No additional imaging or procedures will be mandated by the research protocol. 8. Informed consent, and assent when appropriate, must be obtained, per institutional guidelines. 9. Participants can enroll after initiation of induction MAP chemotherapy so long as they are enrolled prior to the second cycle of chemotherapy (prior to week 6 cisplatin and doxorubicin). 10. Participants must be willing and able to comply with all study procedures for the entire length of the study. Exclusion Criteria: 1. Female participants who are pregnant and/or lactating and breast feeding their infant(s). NOTE: Pregnancy testing will follow institutional standard of care practice and is not mandated by the protocol. 2. Sexually active participants of reproductive potential who have not agreed to use an effective contraceptive method for the duration of protocol therapy, at the discretion of the investigator.