Liquid Biopsy in Ewing Sarcoma and Osteosarcoma as a Prognostic And Response Diagnostic: LEOPARD

Inclusion Criteria:

* 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.

Exclusion Criteria:

* For Part A, subjects must not meet any of the following exclusion criteria.
* Patients with distant metastatic disease.
* Patients with known Ewing-like sarcoma (e.g., BCOR-CCNB3 or CIC-DUX4 translocated small round cell sarcomas) are not eligible.
* Patients who are enrolled with an initial diagnosis of Ewing sarcoma and subsequently found to have Ewing-like sarcoma will be replaced. Samples obtained prior to removal from study will be analyzed and reported descriptively. Patients with Ewing-like tumors may continue to provide samples and clinical data until they meet off-study criteria per protocol.
* Patients weighing \< 5 kg at time of diagnosis
* Patients with a second malignant neoplasm
* Patients without detectable tumor at the time of study enrollment (ie, complete tumor resection prior to study enrollment)
* Patients already receiving tumor-directed therapy at the time of study enrollment except when a pre-treatment baseline sample has already been obtained under a local banking study in DFCI Pediatrics that would be eligible for analysis under this study.
* Patients with osteosarcoma with a pelvic primary tumor site Pregnancy
* For Part B, subjects must not meet any of the following exclusion criteria.
* Patients with known Ewing-like sarcoma (e.g., BCOR-CCNB3 or CIC-DUX4 translocated small round cell sarcomas) are not eligible.
* Samples obtained prior to removal from study will be analyzed and reported descriptively. Patients with Ewing-like tumors may continue to provide samples and clinical data until they meet off-study criteria per protocol
* Patients weighing \< 5 kg at time of enrollment
* Patients diagnosed with relapsed disease and/or having started therapy directed at disease relapse
* Pregnancy
* Resides outside of the United States
* For Part B, providers at non-study centers will not be eligible to receive the provider survey.