Patient description: The patient is a 17-year-old boy complaining of severe migratory pain in the right lower quadrant of his abdomen that started four days ago. The pain is accompanied by nausea and vomiting. He was febrile with tenderness, rebound tenderness and guarding on palpation. His WBC was elevated with dominant neutrophils. CT scan showed evidence of acute perforated appendicitis with free fluid in the pelvis. Diagnostic laparoscopy revealed phlegmon with no other abdominal abnormalities. He is now a candidate for emergent laparoscopic appendectomy under general anesthesia.

Clinical trial eligibility criteria: eligible ages (years): 16.0-999.0,  Glioblastoma Diffuse Midline Glioma H3 K27M Glioma Thalamic Glioma Infratentorial Glioma Basal Ganglia Glioma Histologically confirmed World Health Organization Grade IV glioblastoma. WHO Grade IV gliomas will be allowed on protocol. For Arm D: Must have a WHO Grade IV glioma as per above and tumor must harbor a histone H3 K27M mutation as evidenced by testing any tumor sample with an immunohistochemistry or DNA sequencing test. For Arm E: Must have clinical and/or radiographic evidence of a diffuse midline glioma defined as a WHO Grade IV glioma involving the brainstem, thalamus or spinal cord and be eligible for salvage surgical resection as deemed by the site Investigator. For Arm F: Must have a diffuse midline glioma, defined as a WHO Grade IV glioma involving the brainstem, thalamus or spinal cord, without the H3 K27M mutation or with unknown H3 mutation status. Unequivocal evidence of progressive disease on contrast-enhanced brain computerized tomography (CT) or magnetic resonance imaging (MRI) as defined by Response Assessment in Neuro-Oncology (RANO), or have documented recurrent glioblastoma on diagnostic biopsy. Previous first line therapy with at least radiotherapy and temozolomide. For Arms D, E, and F, previous first line therapy with at least radiotherapy For Arm A or D: Any number of recurrences are allowable. For Arm B: First recurrence (only) WHO Grade glioma. First recurrence is defined as progression following initial therapy (i.e., radiation ± chemotherapy). For participants who had prior therapy with radiation or chemotherapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first recurrence. For patients who did not get additional treatment following surgery and diagnosis of low-grade glioma, surgical diagnosis of high grade glioma will not be considered the first recurrence. Instead, progression after treatment will be considered first recurrence. For Arm C: Patients must have clinical and/or radiographic evidence of first recurrence of glioblastoma and be eligible for salvage surgical resection as deemed by the site Investigator. For Arm E: Patients must have clinical and/or radiographic evidence of recurrence of diffuse midline glioma defined as a WHO Grade IV glioma involving the pons, thalamus or spinal cord, and be eligible for salvage surgical resection as deemed by the site Investigator. Must be 12 weeks from radiotherapy. If patients are within 12 weeks of radiotherapy, then the progressive lesion must be outside of the high-dose radiation target volume or have unequivocal evidence of progressive tumor on a biopsy specimen. From the projected start of scheduled study treatment, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies. All adverse events Grade > 1 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must be resolved, except for alopecia. Male or Female age ≥16 years. Karnofsky Performance Status (KPS) ≥ 60% (see Appendix A). Adequate organ and marrow function as defined below, all screening labs should be performed within 14 days of treatment initiation leukocytes ≥ 3,000/mcL absolute neutrophil count ≥ 1,500/mcL platelets ≥ 100,000/mcL hemoglobin > 8.0 mg/dL total bilirubin < 2.0 x upper limit of normal AST (SGOT)/ALT (SGPT) ≤2.5 × upper limit of normal creatinine OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above normal. CT or MRI within 14 days prior to start of study drug. Corticosteroid dose must be stable or decreasing for at least 5 days prior to the scan. For Arm B: Corticosteroid dose must be stable or decreasing for at least 2 weeks prior to study entry. The effects of ONC201 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Male subjects should agree to use adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of therapy. Archival tissue for evaluation of correlative objectives (if available). Archival tissue is required for Arms B and C. Ability to understand and the willingness to sign a written informed consent document  History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201 or its excipients. Current or planned participation in a study of an investigational agent or using an investigational device. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements. Active infection requiring systemic therapy. Prior stereotactic radiotherapy, convection enhanced delivery (CED) or brachytherapy must have had a biopsy to confirm radiographic progression is consistent with progressive tumor and not treatment-related necrosis. If the recurrent lesion is outside of any prior high-dose radiation target volume or distant from the prior CED or brachytherapy site, subjects will be considered eligible Pregnant women because ONC201 is novel agent with unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ONC201, breastfeeding should be discontinued if the mother is treated with ONC201. Known HIV-positive test on combination antiretroviral therapy. Known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias or bradycardia. Receiving therapeutic agents known to prolong QT interval will be excluded. History of CHF, or MI or stroke in the last 3 months will be excluded. Active illicit drug use or diagnosis of alcoholism. For Arms A, B, C, prior bevacizumab for treatment (allowable for Arms D, E, and F). Tumors with isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations as determined by immunohistochemistry for the IDH1 R132H variant or by direct sequencing. IDH1/2-mutant gliomas have a markedly longer overall survival rate compared to those with IDH1/2-wildtype glioma (Parsons et al., 2008; Yan et al., 2009), indicating IDH1/2-mutant gliomas have a distinct natural history. Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug. Exceptions basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. Any surgery (not including minor diagnostic procedures such as lymph node biopsy) within 2 weeks of baseline disease assessments; or not fully recovered from any side effects of previous procedures. Concomitant use of CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration. Concomitant use of potent CYP3A4/5 inducers, which enzyme inducing antiepileptic drugs (EIAEDs) (see Appendix B), during the treatment phase of the study and within 2 weeks prior to starting treatment. Planned concurrent use Optune™. Prior use of the device is allowable. For Arm D and F: Evidence of leptomeningeal spread of disease