• For Part A, subjects must meet all of the following eligibility criteria.

• Age: ≥ 12 months of age at time of study enrollment to 50 years of age

• Diagnosis: Patients with histologic diagnosis (by institutional pathologist) of newly diagnosed, localized or regionally disseminated Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) of bone or soft tissue or; Patients with histologic diagnosis (by institutional pathologist) of newly diagnosed, non-pelvic, localized or regionally disseminated high-grade osteosarcoma. NOTE: Staging will be assessed according to standard of care at the treating center.

• Prior Therapy:

‣ Patients should have only previously had a biopsy, and not had prior attempt at tumor resection.

⁃ Not yet started chemotherapy or radiation therapy OR patient has started chemotherapy or radiation therapy, but an appropriate pre-treatment baseline sample was collected and processed for ctDNA under a local banking study in DFCI Pediatrics and is available to use for this study.

• Planned to receive chemotherapy as follows:

• \-- VDC/IE as per COG protocols AEWS0031, AEWS1031 or AEWS1221 (for patients with Ewing sarcoma or PNET); or MAP as per COG protocol AOST0331 (for patients with osteosarcoma).

• For Part B subjects must meet all of the following eligibility criteria.

• Age: ≥ 12 months of age at time of study enrollment

• Diagnosis: Patients with histologic diagnosis (by institutional pathologist) of newly diagnosed Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) of bone or soft tissue

• Prior Therapy:

‣ Patients should have had only frontline therapy as per institutional standard, and maintenance therapy if given (no relapse therapy).

⁃ If frontline systemic therapy already completed (not including maintenance or metastatic site radiation), therapy completed within 6 months of enrollment to Part B.

⁃ Subjects must have a willing physician provider supporting their participation in Part B.

• For Part B, providers are eligible to receive the provider survey if they are listed as the primary provider for the patient at the study site.