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Background Medulloblastoma in adults is rare and treatment decisions are largely driven from pediatric literature. We sought to characterize recurrent medulloblastoma in adults. Methods From a single-institution dataset of 200 adult patients diagnosed with medulloblastoma during 1978–2017, those with recurrence were analyzed for clinical features, treatment, and outcome. Results Of the 200 patients, 82 (41%) with median age of 29 years (18–59) had recurrence after a median follow-up time of 8.4 years (95% CI = 7.1, 10.3). Of these, 30 (37%) were standard-risk, 31 (38%) were high-risk, and 21 (26%) had unknown-risk diseases at the time of initial diagnosis. Forty-eight (58%) presented with recurrence outside the posterior fossa, of whom 35 (43%) had distant recurrence only. Median Progression-free survival (PFS) and OS from initial surgery were 33.5 and 62.4 months, respectively. Neither PFS nor OS from initial diagnosis differed between the standard-risk and high-risk groups in those who experience recurrence (P = .505 and .463, respectively). Median OS from first recurrence was 20.3 months, also with no difference between the standard-risk and high-risk groups (P = .518). Recurrences were treated with combinations of re-resection (20 patients; 25%), systemic chemotherapy (61 patients; 76%), radiation (29 patients; 36%), stem cell transplant (6 patients; 8%), and intrathecal chemotherapy (4 patients; 5%). Patients who received radiation at recurrence had better OS (32.9 months) than those who did not (19.2 months) (P = .034). Conclusions Recurrent medulloblastoma in adults has a poor prognosis irrespective of initial risk stratification. Recurrence commonly arises outside the posterior fossa years after initial diagnosis.

Background ONC201, a dopamine receptor D2 (DRD2) antagonist and caseinolytic protease P (ClpP) agonist, has induced durable tumor regressions in adults with recurrent H3 K27M-mutant glioma. We report results from the first phase I pediatric clinical trial of ONC201. Methods This open-label, multi-center clinical trial (NCT03416530) of ONC201 for pediatric H3 K27M-mutant diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) employed a dose-escalation and dose-expansion design. The primary endpoint was the recommended phase II dose (RP2D). A standard 3 + 3 dose escalation design was implemented. The target dose was the previously established adult RP2D (625 mg), scaled by body weight. Twenty-two pediatric patients with DMG/DIPG were treated following radiation; prior lines of systemic therapy in addition to radiation were permitted providing sufficient time had elapsed prior to study treatment. Results The RP2D of orally administered ONC201 in this pediatric population was determined to be the adult RP2D (625 mg), scaled by body weight; no dose-limiting toxicities (DLT) occurred. The most frequent treatment-emergent Grade 1-2 AEs were headache, nausea, vomiting, dizziness and increase in alanine aminotransferase. Pharmacokinetics were determined following the first dose: T1/2, 8.4 h; Tmax, 2.1 h; Cmax, 2.3 µg/mL; AUC0-tlast, 16.4 hµg/mL. Median duration of treatment was 20.6 weeks (range 5.1-129). Five (22.7%) patients, all of whom initiated ONC201 following radiation and prior to recurrence, were alive at 2 years from diagnosis. Conclusions The adult 625 mg weekly RP2D of ONC201 scaled by body weight was well tolerated. Further investigation of ONC201 for DMG/DIPG is warranted.

Background Primary spinal high-grade gliomas (S-HGG) are rare aggressive tumors; radiation therapy (RT) often plays a dominant role in management. We conducted a single-institution retrospective review to study the clinicopathological features and management of S-HGGs. Methods Patients with biopsy-proven S-HGG who received RT from 2001 to 2020 were analyzed for patient, tumor, and treatment characteristics. Kaplan–Meier estimates were used for survival analyses. Results Twenty-nine patients were identified with a median age of 25.9 years (range 1–74 y). Four patients had GTR while 25 underwent subtotal resection or biopsy. All patients were IDH wildtype and MGMT-promoter unmethylated, where available. H3K27M mutation was present in 5 out of 10 patients tested, while one patient harbored p53 mutation. Median RT dose was 50.4 Gy (range 39.6–54 Gy) and 65% received concurrent chemotherapy, most commonly temozolomide. Twenty-three (79%) of patients had documented recurrence. Overall, 16 patients relapsed locally, 10 relapsed in the brain and 8 developed leptomeningeal disease; only 8 had isolated local relapse. Median OS from diagnosis was 21.3 months and median PFS was 9.7 months. On univariate analysis, age, gender, GTR, grade, RT modality, RT dose and concurrent chemotherapy did not predict for survival. Patients with H3K27M mutation had a poorer PFS compared to those without mutation (10.1 m vs 45.1 m) but the difference did not reach statistical significance (P = .26). Conclusions The prognosis of patients with spinal HGGs remains poor with two-thirds of the patients developing distant recurrence despite chemoradiation. Survival outcomes were similar in patients ≤ 29 years compared to adults > 29 years. A better understanding of the molecular drivers of spinal HGGs is needed to develop more effective treatment options.

Background The goal of this study was to evaluate extent of surgical resection, and timing and volume of re-irradiation, on survival for children with locally recurrent ependymoma. Methods Children with locally recurrent ependymoma treated with a second course of fractionated radiotherapy (RT2) from 6 North American cancer centers were reviewed. The index time was from the start of RT2 unless otherwise stated. Results Thirty-five patients were included in the study. The median doses for first radiation (RT1) and RT2 were 55.8 and 54 Gy, respectively. Median follow-up time was 5.6 years. Median overall survival (OS) for all patients from RT2 was 65 months. Gross total resection (GTR) was performed in 46% and 66% of patients prior to RT1 and RT2, respectively. GTR prior to RT2 was independently associated with improved progression-free survival (PFS) for all patients (HR 0.41, P = 0.04), with an OS benefit (HR 0.26, P = 0.03) for infratentorial tumors. Median PFS was superior with craniospinal irradiation (CSI) RT2 (not reached) compared to focal RT2 (56.9 months; log-rank P = 0.03). All distant failures (except one) occurred after focal RT2. Local failures after focal RT2 were predominantly in patients with less than GTR pre-RT2. Conclusions Patients with locally recurrent pediatric ependymoma should be considered for re-treatment with repeat maximal safe resection (ideally GTR) and CSI re-irradiation, with careful discussion of the potential side effects of these treatments.

BACKGROUND The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral PARP1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy. Preclinical data indicates that veliparib crosses the blood-brain-barrier and enhances the efficacy of radiotherapy and temozolomide in IDH mutant and wild-type HGG models. ACNS1721 was a single-arm, non-randomized phase 2 clinical trial designed to determine whether treatment with veliparib and radiotherapy, followed by the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and temozolomide, improves progression-free survival (PFS) in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features. METHODS Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients without somatic H3 K27M or BRAF mutations were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant). Protocol radiochemotherapy consisted of involved field radiotherapy with concurrent veliparib at 65 mg/m2 twice daily. Adjuvant chemotherapy consisted of up to 10 cycles of veliparib 25 mg/m2 twice daily and temozolomide 135 mg/m2 once daily for 5 days every 4 weeks. RESULTS Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year progression-free survival (PFS) was 0.29 (SE = 0.09) and 1-year overall survival (OS) was 0.67 (SE = 0.10). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year PFS was 0.57 (SE = 0.15) and 1-year OS was 0.90 (SE = 0.09). CONCLUSION Rapid central pathology review and molecular testing was feasible. The protocol therapy was well tolerated but failed to improve outcome compared to clinically and molecularly matched historical control cohorts.

BACKGROUND: The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral PARP1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy. Preclinical data indicates that veliparib crosses the blood-brain-barrier and enhances the efficacy of radiotherapy and temozolomide in IDH mutant and wild-type HGG models. ACNS1721 was a single-arm, non-randomized phase 2 clinical trial designed to determine whether treatment with veliparib and radiotherapy, followed by the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and temozolomide, improves progression-free survival (PFS) in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features. METHODS: Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients without somatic H3 K27M or BRAF mutations were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant). Protocol radiochemotherapy consisted of involved field radiotherapy with concurrent veliparib at 65 mg/m2 twice daily. Adjuvant chemotherapy consisted of up to 10 cycles of veliparib 25 mg/m2 twice daily and temozolomide 135 mg/m2 once daily for 5 days every 4 weeks. RESULTS: Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year progression-free survival (PFS) was 0.29 (SE = 0.09) and 1-year overall survival (OS) was 0.67 (SE = 0.10). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year PFS was 0.57 (SE = 0.15) and 1-year OS was 0.90 (SE = 0.09). CONCLUSION: Rapid central pathology review and molecular testing was feasible. The protocol therapy was well tolerated but failed to improve outcome compared to clinically and molecularly matched historical control cohorts.

Background Despite advances in care, the 5 year overall survival for patients with relapsed and or metastatic sarcoma remains as low as

BACKGROUND: H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS: Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (>20 years old) and seven pediatric (

BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults; no effective systemic therapy is available. ONC201, a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 and agonist of the mitochondrial protease ClpP. ONC201 monotherapy demonstrated durable objective responses in adults with recurrent H3 K27M-mutant glioma. This phase 1 trial will evaluate ONC201±radiotherapy (RT) in pediatric patients with H3 K27M-mutant midline glioma DIPG. METHODS This multicenter, open-label, dose escalation and expansion phase 1 study of ONC201 is comprised of eight arms that will evaluate the recommended phase 2 dose (RP2D) of ONC201, biomarkers, and pharmacokinetics (PK) of ONC201±RT in various treatment settings (NCT03416530). Arm G previously defined the RP2D for twice-weekly ONC201 on consecutive days. Arm H, for which enrollment is ongoing, will estimate the influence of tumor location and blood-brain barrier integrity on PK and intratumoral ONC201 exposure in biopsy-eligible pediatric tumors (DIPG or contrast-enhancing thalamic glioma). Patients eligible for Arm H will be aged 2-≤19 years, ≥2 weeks from last RT administration, and have a KPS/LPS ≥50; prior confirmation of H3 K27M mutation is not required. In Arm H, single-agent ONC201 administration will occur twice-weekly on consecutive days during each 21-day cycle at the RP2D defined in Arm G. Arm H has a planned enrollment of 27 patients (DIPG, n=15; thalamic glioma, n=12), with three patients undergoing a single biopsy at each of the following time points: 1-3 h post-first dose, 22-26 h post-second dose, 1-3 h post-first dose, 6-10 h post-second dose, and 22-26 h post-second dose. The 22-26 h post-first dose biopsy in thalamic glioma was previously collected and will not be assessed in this treatment arm. Plasma for PK analysis will be collected from all patients.

BACKGROUND Primary spinal high-grade gliomas(S-HGG) are rare, aggressive tumors and radiation therapy(RT) plays a dominant role in the management given their infiltrative nature. We conducted a single-institution retrospective review to study the clinicopathological features and management of S-HGGs. METHODS Patients with biopsy-proven S-HGG who received RT from 2001-2020 were analyzed for patient, tumor, and treatment characteristics. Kaplan-Meier estimate and Cox proportional hazard regression method were used for survival analyses. RESULTS Twenty-nine patients were identified with a median age of 25.9 years (range 1-74y). Four patients had gross total resection(GTR) while 25 underwent subtotal resection or biopsy. Nineteen patients had WHO grade 4 tumor. IDH1 mutation and MGMT promoter methylation were analyzed in 14 and four patients respectively; all were IDH wildtype and MGMT-promoter unmethylated. H3K27M mutation was present in five out of 10 patients tested. Twenty-two patients received photon-based radiation and 7 received proton therapy. Median RT dose was 50.4 Gy (range 39.6-54Gy) with 79% receiving >45Gy. 65% patients received concurrent chemotherapy, most commonly temozolomide. Twenty-three (79%) patients had documented recurrence. Overall, 16 patients relapsed locally, 10 relapsed in the brain and 8 developed leptomeningeal disease; only 8(35%) had isolated local relapse. Median OS from diagnosis was 21.3 months and median PFS after RT was 9.7 months. On univariate analysis, age, sex, GTR, grade, RT modality, RT dose and concurrent chemotherapy did not predict for survival. Patients with H3K27M mutation had a poorer median PFS after RT compared to those without the mutation but the difference did not reach statistical significance (p = 0.26). CONCLUSIONS Although 86% of patients had gross disease at RT and received a lower median RT dose than typically used in cerebral high-grade gliomas, only 55% of patients failed locally. H3K27M mutation may portend worse survival; future studies to improve the therapeutic approach in these patients are warranted.

Purpose/Objective(s) Brainstem toxicity after radiation is a devastating complication and a particular concern with proton radiation (RT), given the biological differences and range uncertainties at the distal edge of proton beam. Data from St. Jude's found a 3.7% risk of brainstem necrosis after photon-based RT, while the incidence with protons ranges from 0.7% - 31% across studies. We investigated the incidence and clinical correlates of brainstem injury in pediatric brain tumors treated with proton therapy. Materials/Methods All patients 30 Gy and/or Dmax > 50.4 Gy were included. We excluded patients with primary brainstem tumors. Symptomatic brainstem injury (SBI) was defined as any new or progressive cranial neuropathy, ataxia, dysmetria and/or motor weakness with corresponding radiographic abnormality within the brainstem and was graded per the NCI Common Terminology Criteria for Adverse Events v5.0 (Grade 2: moderate symptoms, corticosteroids indicated; Grade 3: severe symptoms, medical intervention indicated; Grade 4: life-threatening; urgent intervention; and Grade 5: death). Results A total of 595 patients were reviewed and 362 (medulloblastoma = 209, ependymoma = 86, ATRT = 43, pineoblastoma = 9, others = 15) met our inclusion criteria. Median age at RT was 5 years (range 0.7 – 17.9 years) and median prescribed RT dose was 54 CGyE (range 39.6 – 59.4 CGyE). Median follow up was 40 months (range 1 – 152). Ten patients (2.7%) developed SBI, at a median of 4 months after RT (range 1-6). Grades 2,3,4 and 5 brainstem injuries were seen in 3, 4, 2 and 1 patient respectively. Mean brainstem Dmax in SBI and non-SBI patients was 55.9 Gy and 54.8 Gy (P = 0.30), while the mean Dmean was 43.3 Gy and 43.2 Gy (P = 0.48) respectively. Most common symptoms of SBI were ataxia, slurred speech, 6th cranial nerve palsy and bulbar palsy. All SBI patients required steroids for 1-5 months, while grade 3-5 injuries were also treated with bevacizumab and/or hyperbaric oxygen therapy. Asymptomatic imaging changes within brainstem were seen in 47 patients (13%) at a median of 4 months after RT, most common findings being increased T2 flair, focal enhancement and encephalomalacia. In 2014, our institution started using strict brainstem dose constraints (Dmax ≤ 57 Gy, Dmean ≤ 52.4 Gy and V54 ≤ 10%). The incidence of SBI has decreased from 4.2% (2007-2013) to 0.7% (2014-2019) (P = 0.047) while asymptomatic imaging changes remain similar (11.6% vs 15.1%, P = 0.33). Patients with SBI had a higher V45, V50-52 and D15 -D50; while the Dmax, Dmean, V53-60 and D1- D10 were similar. Conclusion Our results suggest that there is a low risk of SBI after proton therapy for pediatric brain tumors. A lower incidence of SBI was seen after the use of strict brainstem dose constraints. Volumetric doses to brainstem may play a significant role in determining the risk of SBI and developing a dose response nomogram is warranted.

Pediatric, adolescent and young adult (AYA) patients receiving novel cancer immunotherapies may develop associated toxicities with overlapping signs and symptoms that are not always easily distinguished from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection/clinical sequelae. We describe 2 diagnostically challenging cases of SARS-CoV-2 and Multi-Inflammatory Syndrome-Adult (MIS-A), in patients with a history of acute lymphoblastic leukemia following cellular therapy administration and review evolving characterization of both the natural course of SARS-CoV-2 infection and toxicities experienced in younger cancer immunotherapy patients. Vigilant monitoring for unique presentations and epidemiologic surveillance to promptly detect changes in incidence of either condition may be warranted.

BACKGROUND/PURPOSE: Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) deliver highly conformal, ablative doses of radiation over 1–5 treatments, while minimizing dose to surrounding normal tissues. To document toxicities and outcomes of these treatments in children, our updated institutional experience with SRS or SRT for intracranial targets in pediatric patients was reviewed. METHODS: On an IRB approved study, institutional databases were reviewed to identify pediatric patients with intracranial lesions treated with SRS or SRT from October 2009 to July 2021. Medical records were retrospectively reviewed for patient and treatment characteristics. Outcomes were analyzed for symptomatic radionecrosis and CNS progression. RESULTS: Thirty SRS or SRT treatment courses in 26 patients age 3.2 to 17.8y (median, 15.6y) at the time of SRS or SRT were identified. Twenty-two patients had one treatment and four had two treatments. Sixteen patients had brain metastases from extracranial primary disease; 10 had recurrence of a primary CNS tumor. Fifteen patients had prior fractionated radiation to the brain. Nineteen treatments used Gamma Knife (GK) with Leksell frame, three used GK ICON with mask, and eight used linear accelerator with volumetric modulated arc therapy with thermoplastic mask. All patients (10 treatments in nine patients) treated since July 2016 received mask-based radiation. Twelve of 26 (46%) patients were treated with anesthesia. With 9.6-month median follow up (range, 0.1-96.2m), five patients had progression of treated lesions, eight had distant CNS failure, and one had both local and distant failure, for a crude local failure rate of 6/26 (23%) and a crude distant failure rate of 9/26 (35%). There were no skull fractures or other complications from Leksell frame placement. One patient developed symptomatic radionecrosis requiring surgery. CONCLUSION: SRS and SRT can be safely performed in pediatric patients with intracranial lesions. Mask-based immobilization provides an alternative to frame-based treatments.

Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor of the pons and brainstem. Therefore, there is a desperate need for new therapeutics. Genomic profiling of tumors identified a highly prevalent dominant negative somatic mutation at lysine (K)-27 in histone genes HIST1H3B and H3F3A. Clonal evolution modeling suggests these mutations are truncal, and studies have demonstrated their contribution to tumorigenesis. ONC201, a first-in-class DRD2 antagonist and ClpP agonist is an anticancer drug developed by Oncoceutics, which targets the unfolded protein response (UPR) and integrated stress response (ISR) signaling and is actively being investigated in patients with recurrent H3 K27M-mutant gliomas. In adults with recurrent glioma, single agent studies showed benign-safety, no dose-limiting toxicities and a durable objective response when administered orally. In addition, intra-tumoral drug levels exceeded therapeutic thresholds, and induced tumor cell apoptosis. Based on this and response seen in a pediatric patient with DIPG for whom compassionate use of ONC201 was approved, a multi-arm, non-randomized multi-institutional Phase I clinical trial (NCT03416530) is actively accruing patients. However, the strength of UPR and ISR in DIPGs and their effect on DIPG response to ONC201 is not known. Our group employed bulk/single cell transcriptomic and single cell proteomic approaches to demonstrate substantial heterogeneity in UPR and ISR signaling in human DIPG samples. Consistent with this, DIPG cell lines exhibited considerable variability in sensitivity to ONC201. Single cell profiling identified tumor sub-populations with significant proliferative capacity even after ONC201 exposure. Incomplete response promotes recurrence. To target these cells, we performed a synthetic lethality screen with a library of 360 FDA-approved CNS penetrant compounds, which identified HDAC inhibitors and DNA damage-inducing chemotherapy as having synergy with ONC201. Thus, we suggest that tumor heterogeneity impacts sensitivity to ONC201 and that this can be reduced by combination treatments.

BackgroundDiffuse midline gliomas (DMG), including brainstem diffuse intrinsic pontine glioma (DIPG), are incurable pediatric high-grade gliomas (pHGG). Mutations in the H3 histone tail (H3.1/3.3-K27M) are a feature of DIPG, rendering them therapeutically sensitive to small-molecule inhibition of chromatin modifiers. Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) is clinically relevant but has not been carefully investigated in pHGG or DIPG.MethodsPatient-derived DIPG cell lines, orthotopic mouse models, and pHGG datasets were used to evaluate effects of LSD1 inhibitors on cytotoxicity and immune gene expression. Immune cell cytotoxicity was assessed in DIPG cells pretreated with LSD1 inhibitors, and informatics platforms were used to determine immune infiltration of pHGG.ResultsSelective cytotoxicity and an immunogenic gene signature were established in DIPG cell lines using clinically relevant LSD1 inhibitors. Pediatric HGG patient sequencing data demonstrated survival benefit of this LSD1-dependent gene signature. Pretreatment of DIPG with these inhibitors increased lysis by natural killer (NK) cells. Catalytic LSD1 inhibitors induced tumor regression and augmented NK cell infusion in vivo to reduce tumor burden. CIBERSORT analysis of patient data confirmed NK infiltration is beneficial to patient survival, while CD8 T cells are negatively prognostic. Catalytic LSD1 inhibitors are nonperturbing to NK cells, while scaffolding LSD1 inhibitors are toxic to NK cells and do not induce the gene signature in DIPG cells.ConclusionsLSD1 inhibition using catalytic inhibitors is selectively cytotoxic and promotes an immune gene signature that increases NK cell killing in vitro and in vivo, representing a therapeutic opportunity for pHGG.Key Points1. LSD1 inhibition using several clinically relevant compounds is selectively cytotoxic in DIPG and shows in vivo efficacy as a single agent.2. An LSD1-controlled gene signature predicts survival in pHGG patients and is seen in neural tissue from LSD1 inhibitor–treated mice.3. LSD1 inhibition enhances NK cell cytotoxicity against DIPG in vivo and in vitro with correlative genetic biomarkers.

INTRODUCTION: Supratentorial pediatric high-grade gliomas (pHGGs) are aggressive malignancies that lack effective treatment options. Deep genomic sequencing by multiple groups has revealed that the primary alterations unique to pHGGs occur in epigenetic and kinase genes. These mutations, fusions, and deletions present a therapeutic opportunity by use of small molecules targeting epigenetic modifiers and kinases that contribute to pHGG growth. METHODS: Using a targeted search of the pre-clinical literature and clinicaltrials.gov for kinase and epigenetic pathways in pHGG, we collectively describe how these mechanisms are being targeted in pre-clinical animal models and in current clinical trials, as well as propose unexplored therapeutic possibilities for future investigations. RESULTS: Relevant pHGG kinases are targetable by several FDA-approved or clinical-stage kinase inhibitors, including altered BRAF/MET/NTRK/ALK and wild-type PI3K/EGFR/PDGFR/VEGF/AXL. Epigenetic proteins implicated in pHGG are also clinically targetable and include histone erasers, writers and readers such as HDACs, demethylases LSD1/JMJD3, methyltransferase EZH2, chromatin reader bromodomains, and chromatin remodeler subunit BMI-1. Crosstalk between these pathways can occur involving kinases such as EGFR and AMPK interacting with epigenetic modifiers such as HDACs or EZH2. Single agent trial results of kinase inhibitors or epigenetic targets alone are underwhelming and hampered by poor pharmacokinetics, adaptive resistance, and broad inclusion criteria. CONCLUSIONS: The genetic and phenotypic diversity of pHGGs is now well characterized after large-scale sequencing studies on patient tissue. However, clinical treatment paradigms have not yet shifted in response to this information. Combination therapies targeting multiple kinases or epigenetic targets may hold more promise, especially if attempted in selected patient populations with hemispheric pHGG tumors and relevant targeted therapeutic biomarkers.

Background Recurrent pediatric medulloblastoma and ependymoma have a grim prognosis. We report a first-in-human, phase I study of intraventricular infusions of ex vivo expanded autologous natural killer (NK) cells in these tumors, with correlative studies. Methods Twelve patients were enrolled, 9 received protocol therapy up to 3 infusions weekly, in escalating doses from 3 × 106 to 3 × 108 NK cells/m2/infusion, for up to 3 cycles. Cerebrospinal fluid (CSF) was obtained for cellular profile, persistence, and phenotypic analysis of NK cells. Radiomic characterization on pretreatment MRI scans was performed in 7 patients, to develop a non-invasive imaging-based signature. Results Primary objectives of NK cell harvest, expansion, release, and safety of 112 intraventricular infusions of NK cells were achieved in all 9 patients. There were no dose-limiting toxicities. All patients showed progressive disease (PD), except 1 patient showed stable disease for one month at end of study follow-up. Another patient had transient radiographic response of the intraventricular tumor after 5 infusions of NK cell before progressing to PD. At higher dose levels, NK cells increased in the CSF during treatment with repetitive infusions (mean 11.6-fold). Frequent infusions of NK cells resulted in CSF pleocytosis. Radiomic signatures were profiled in 7 patients, evaluating ability to predict upfront radiographic changes, although they did not attain statistical significance. Conclusions This study demonstrated feasibility of production and safety of intraventricular infusions of autologous NK cells. These findings support further investigation of locoregional NK cell infusions in children with brain malignancies.

Advances in genomic, transcriptomic and epigenomic profiling now identifies pediatric ependymoma as a defined biological entity. Molecular interrogation has segregated these tumors into distinct biological subtypes based on anatomical location, age and clinical outcome, which now defines the need to tailor therapy even for histologically similar tumors. These findings now provide reasons for a paradigm shift in therapy, which should profile future clinical trials focused on targeted therapeutic strategies and risk-based treatment. The need to diagnose and differentiate the aggressive variants, which include the posterior fossa group A and the supratentorial RELA fusion subtypes, is imperative to escalate therapy and improve survival.

Metachronous neoplasms have rarely been reported in patients with neuroblastoma. This report presents the clinical case of a 23-month-old child who was diagnosed with an anaplastic medulloblastoma 5 months after completing treatment for stage IV neuroblastoma. The patient was treated with complete surgical resection and adjuvant chemoradiation followed by maintenance chemotherapy at an outside institution and came to our institution for further management. A pathologic diagnosis and review of both the suprarenal and posterior fossa masses were performed, as well as a genetic analysis of both cerebellar tumor tissue and blood using next-generation gene sequencing. At our institution, the patient was submitted to induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation and remains free of disease 2 years after completion of treatment. Genetic analysis revealed multiple somatic copy number variations with most deleted genes located in 2q37, a region which harbors genes involved in epigenetic regulation and tumor suppression. A homozygous deletion was found in the TSC2 gene, which is a clinically actionable gene, and patients with activating deletions in TSC2 can potentially be eligible for basket clinical trials with mTOR inhibitors. Germline single nucleotide variants were also identified in multiple genes involved in cancer (ALK, FGFR3, FLT3/4, HNF1A, NCOR1, and NOTCH2/3), cancer predisposition (TP53, TSC1, and BRCA1/2), and genes involved in DNA repair (MSH6, PMS2, POLE, and ATM). Metachronous neoplasms are rare and challenging to treat, hence genetic analysis and referral are needed to exclude hereditary cause. DNA sequencing of the tumor and germline can help identify alterations that increase predisposition or can be used to guide treatment decisions on recurrence and when standard options fail.

Case Presentation A 3-year-old female with insignificant past medical history presented with 6 weeks of headaches, emesis, and lethargy. MR imaging identified a heterogeneously enhancing right cerebellar hemispheric mass and obstructive hydrocephalus. Gross total resection was performed without complications; pathology revealed classical WHO grade 4 medulloblastoma (MB). MR imaging of the spine and cerebrospinal fluid testing were negative for disseminated disease. Treatment for standard risk medulloblastoma was initiated, comprising proton craniospinal irradiation with posterior fossa boost and concurrent vincristine, followed by adjuvant chemotherapy with vincristine, lomustine, cisplatin, and cyclophosphamide as standard of care. Next generation sequencing of the tumor tissue performed using a high-multiplex PCR-based NGS panel was negative for alteration of the SMO, PTCH1 and CTBNN1 genes. Further molecular characterization via methylation profiling demonstrated the sonic hedgehog (SHH) molecular subtype. Prior to initiation of chemotherapy, renal ultrasound was performed and identified congenitally absent right kidney; audiology evaluation was unremarkable. Discussion In patients with Gorlin syndrome, cases of unilateral renal agenesis in association with germline SHH-pathway mutations have been reported [1]. SHH signaling is implicated in multiple steps in the development of the urinary system [2]. Outside Gorlin syndrome, however, to the best of our knowledge unilateral renal agenesis coinciding with SHH-driven MB has not been reported. Our patient notably lacks any clinical stigmata of Gorlin syndrome (skeletal abnormalities, skin pits, macrocephaly) and does not exhibit the characteristic germline genetic abnormalities that define GS (PTCH1 mutation or 9q22.3 microdeletion). There are important treatment implications for patients with the constellation of abnormalities we describe here, particularly regarding the requisite frequent monitoring of renal function during multi-agent chemotherapy courses. Our patient tolerated chemoradiation well, and is currently on maintenance chemotherapy with favorable course to date.

ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. The recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated in adult and pediatric populations. Radiographic regressions with single agent ONC201 have been reported in recurrent H3 K27M-mutant glioma patients. In another study, twice/week dosing was explored in adult patients and deemed to be safe (no DLTs observed). This warranted exploration of twice/week dosing in pediatric patients and will be discussed in this presentation. This multi-arm, dose-escalation and dose-expansion trial (ONC014; NCT03416530) determined the pediatric RP2D of ONC201 administered once per week and twice per week on two consecutive days. ONC201 was orally administered and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with two 125mg capsules less than the adult RP2D equivalent. Twelve children (8 females; 4 males) with H3 K27M-mutant gliomas (pons: 8; thalamus: 2; spinal cord: 2) aged 4-19 years have been treated post-radiation: 3 at dose level -1; 3 at dose level 1; 6 as part of the dose expansion cohort on dose level 2. Median KPS was 90 (range 70-100). One treatment cycle was 21 days (6 doses), which also defined the DLT window. Patients were on-treatment for a median length of 4 cycles (range: 2-11). Twice weekly dosing of ONC201 was tolerated well, as observed with weekly dosing, with no instance of DLT. A total of 4 SAEs were reported, none of which were related to the study drug. The most common AEs (regardless of relatedness) included headache, facial nerve disorder, abducens nerve disorder, nausea, fatigue and ataxia. Additional safety data, PK, and clinical outcomes from this arm will be reported.

Neurocognitive late effects are unfortunately common following treatment for pediatric medulloblastoma. While radiation therapy is an essential component of treatment for most pediatric medulloblastoma patients, it is associated with neurocognitive compromise. Effects include deficits in cognitive speed and performance efficiency, aspects of attention, as well as working memory. Yet long after treatment it is difficult to tease apart relative contributions of other risk factors to neurocognitive functioning beyond radiation. We examined neurocognitive functioning in a sample of pediatric medulloblastoma patients prior to radiation therapy, including investigation of neurocognitive risk factors such as hydrocephalus, presence of posterior fossa syndrome, and duration of neurological symptoms prior to diagnosis. Results indicated that the sample functioned in the average range in terms of overall IQ (n=34, X̅=103). Patients also functioned in the normal range in terms of language-based ability (X̅=106), nonverbal ability (X̅=104), and working memory (X̅=103). However, the sample performed statistically significantly lower than the general population in terms of cognitive speed and efficiency (z=-2.026, p=.043). The sample was also rated by parents as exhibiting more attention problems relative to the general population (z=1.988, p=.047). There was no specific association with hydrocephalus, duration of symptoms, or history of posterior fossa syndrome. Results suggest weaknesses in attention and processing speed may exist in some pediatric medulloblastoma patients prior to radiation therapy secondary to tumor and related complications. Implications for future research are presented, along with difficulties inherent to “baseline” assessment with pediatric brain tumor survivors.

INTRODUCTION Spinal myxopapillary ependymoma (MPE) is a rare histological variant of ependymoma, classified as WHO grade I tumor. Further interrogation of the molecular and clinical profile is warranted, to better understand the biology and clinical phenotype. We summarize our institutional experience with spinal MPE including methylation-profiling. METHODS A retrospective analysis of charts during the period of 2001 to 2019 of histologically proven MPE was done. We performed methylation profiling for 12 patients by Infinium MethylationEPIC Kit. RESULTS 26 patients with spinal MPE were identified, median age of diagnosis was 34.2 years with a range of 11 to 59.9 years. Ten patients were below 30 years of age, lumbar spine location was commonest and 6 had leptomeningeal spread at diagnosis. All the patients underwent surgery and 11 received radiation following surgery. Eight patients below the age of 30 received radiation due to residual disease or metastases. Methylation profiling revealed 11,752 CpGs differentially methylated between the younger and older patients (p < 0.05), however only one CpG cg22496254 associated with gene NCAPG/DCAF16 (role in promoting mitosis) was detectable with FDR < 0.25 that overly methylated in the younger age group. This is a new finding in MPE. CONCLUSIONS Spinal MPE is a rare spinal tumor. Our study though limited by numbers, showed younger patients had aggressive phenotype, most requiring radiation. Methylation profiling reaffirmed this finding and trend in the younger patients. Prospective studies in a larger cohort of patients with methylation profiling are needed to identify prognostic variables and new targets for treatment.

INTRODUCTION We report the first known cases of pediatric glioblastoma (GBM) with prior clinical NF1 diagnoses, one with concurrent germline Lynch syndrome (LS) and NF1, and the other with somatic NF1 mutation and germline constitutional mismatch repair deficiency (CMMRD). METHODS Two pediatric GBM cases with prior NF1 clinical diagnoses based on neurocutaneous criteria were reviewed. Next generation sequencing and immunohistochemical staining were used for somatic and germline NF1 and MMR gene mutation detection, and for MMR protein expression, respectively. RESULTS Sixteen year old male with prior NF1 clinical diagnosis had resection of right frontal GBM revealing somatic mutations of POLE and PMS2, but not NF1. His father had confirmed LS with MSH2 mutation and no neurocutaneous stigmata. Patient’s germline testing revealed both pathogenic MSH2 plus NF1 mutations confirming LS and NF1. Treatment consisted of chemoradiation with temozolomide followed by adjuvant temozolomide with stable disease at 8 cycles. Nineteen year old male with former NF1 clinical diagnosis had 2 GBMs, first in left midbrain biopsied revealing somatic PMS2 and NF1 mutations underwent radiation then 7 cycles of temozolomide, then new left frontal GBM underwent resection followed by radiation and 5 cycles of pembrolizumab stable at 5th cycle. CONCLUSION Children with NF1 stigmata and GBM can have concurrent NF1 and LS, or CMMRD with NF1 somatic mutations. Our patients tolerated alkylating agents, despite risk for secondary malignancies as upfront therapy and at recurrence checkpoint inhibitors. Upfront therapy in GBM with mismatch repair syndrome with checkpoint inhibitors should be studied.

BACKGROUND Diffuse intrinsic pontine glioma (DIPG) constitutes 80% of pediatric brain stem tumors with a median survival of 12 months. The PI3K/AKT/mTOR pathway is a key oncogenic driver of this tumor. Targeting the chromatin dysregulation through HDAC inhibition, demonstrated benefit in vivo and vitro studies. We completed the first study as a multi-targeted therapy using SAHA and temsirolimus in pediatric DIPG. METHODS After receiving institutional IRB approval, we enrolled 6 patients on this phase I study using a 3 + 3 statistical design. Patients were divided into stratum 1 and stratum 2, based on newly diagnosed or relapsed DIPG respectively. Stratum I patients received radiation therapy concurrently with vorinostat, followed by maintenance therapy with vorinostat and temsirolimus for 10 cycles (28 day cycle), while in stratum II patients received vorinostat and temsirolimus for 12 cycles. Neuroimaging including diffusion tensor imaging were evaluated where feasible. RESULTS Three patients were enrolled in each of the stratum. One patient in stratum 1 completed therapy, 2 other demonstrated progressive disease (PD) after 4th and 1st cycle of maintenance therapy respectively. In stratum 2 all patients progressed 2 months after the start of therapy. However no dose-limiting toxicity (DLT) was noted. The patient in stratum 1 who completed therapy, remained free of PD 21 months after diagnosis with continued improvements in the volume of enhancing and T2 hyperintense disease. CONCLUSION Although no significant benefit was seen as compared to historical controls during this study, no dose limiting toxicity was noticed with this treatment.

BACKGROUND Predicting neurocognitive outcomes in pediatric brain tumor (PBT) patients is challenging. Rarity of PBT makes inclusion of detailed risk factors (e.g., treatment modality, intensity, individual complications) difficult when sample sizes are small. The Neurological Predictor Scale (NPS) summarizes complications and treatment factors associated with neurocognitive risks and has modest validation. Recently, the Pediatric Neuro-Oncology Rating of Treatment Intensity (PNORTI) was developed to evaluate the impact of treatment intensity on psychosocial outcomes but has not been compared to neurocognitive outcomes. This study compared the NPS and PNORTI in terms of relationship to neurocognitive outcomes known to be at risk in PBT survivors. METHODS 88 PBT survivors’ neuropsychological outcomes were retrospectively analyzed in relation to the NPS and PNORTI. Variables of interest included IQ, working memory, and processing speed. RESULTS NPS associated with lower IQ (rs=-.476, p=.001), lower working memory (rs=-.323, p=.010), and lower processing speed (rs=-.389, p=.007) in patients diagnosed at a younger age, but only processing speed for children diagnosed after age 7 years (rs=-.262, p=.036). PNORTI was not correlated with neurocognitive variables for either group. CONCLUSION NPS has value in predicting neurocognitive outcomes, though much more in a younger age at diagnosis group compared to older patients. The PNORTI did not demonstrate predictive value for these neurocognitive domains in our sample. Given the potential clinical and research value of a summary rating of treatment burden relating to long-term outcome, future research should include relationship to psychosocial outcomes and quality of life.

Although BRAF inhibition has demonstrated activity in BRAFV600–mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAFV600-mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated.

INTRODUCTION We report the first known cases of pediatric glioblastoma (GBM) with prior clinical NF1 diagnoses, one with concurrent germline Lynch syndrome (LS) and NF1, and the other with somatic NF1 mutation and germline constitutional mismatch repair deficiency (CMMRD). Pediatric GBMs in NF1 are rare but increase with age. LS and CMMRD differ by inheritance: autosomal dominant with heterozygous germline mutation (LS), or biallelic mutation (CMMRD) of one of the 4 (possibly 5) MMRD genes (MLH1, MSH2, MSH6, PMS2, or MSH3) - both can develop GBM. METHODS Two pediatric GBM cases with prior NF1 clinical diagnoses (neurocutaneous stigmata) were reviewed. Next generation sequencing and immunohistochemical staining were used for somatic and germline NF1 and MMR gene mutation detection, and for MMR protein expression, respectively. RESULTS Sixteen-year-old male with prior NF1 clinical diagnosis had headaches for one year preceding diagnosis and resection of right frontal GBM with somatic mutations of POLE and PMS2, but not NF1. His father had confirmed LS with MSH2 mutation and no neurocutaneous stigmata. Patient’s germline testing revealed pathogenic MSH2 and NF1 mutations, confirming LS and NF1. Current treatment is chemoradiation. Nineteen-year-old male with former NF1 clinical diagnosis had 2 GBMs, first in left midbrain diagnosed and biopsied (after 3 months of right hemiparesis) with somatic PMS2 and NF1 mutations, and a second left frontal lobe tumor diagnosed and resected 11 months later, with 2 pathogenic germline mutations of PMS2, inherited one from each parent, confirming CMMRD without NF1. Treatment was focal radiation administered to both sites followed by adjuvant chemotherapy. CONCLUSION Children with NF1 stigmata and GBM may have either concurrent NF1 and LS, or CMMRD with NF1 somatic mutations. Confirmatory germline and somatic MMR gene and NF1 mutation testing in children with GBM and NF1 stigmata should be considered as the specific diagnosis affects management.

INTRODUCTION Prospective studies for adult medulloblastoma (MB) are scarce and management guidelines are largely derived from pediatric experience and retrospective data. However, adult MB is a distinct disease for which limited data exist regarding clinical characteristic, prognostic factors, outcome based on upfront treatment, or patterns of recurrence. METHODS 200 patients (≥18 years at diagnosis) were identified from 1978 to 2017. Survival analysis was performed using the Kaplan-Meier method. RESULTS Median age at diagnosis 29 (18–63); 111 (55.5%) standard-risk (SR), 59 (29.5%) high-risk (HR), 30 (15%) unknown. 188 (94%) and 97 (48.5%) underwent radiotherapy and upfront chemotherapy, respectively. Median PFS: 6.28 years (4.9–11.2); median OS: 8.8 (7.8–12.4) years. Median time to first recurrence: 8.2 (5.1-not reached); 5-year recurrence-free rate: 71% in SR and 45% in HR patients. Survival after first recurrence: 2 years (1.64–2.4). Documented recurrence and risk group were associated with survival (HR 30.4, p< 0.0001 and 2.33, p< 0.001), but metastatic status and local vs. distant recurrence were not. The effect of upfront chemotherapy on survival did not reach statistical significance in SR patients. The use of chemotherapy regimens with or without vincristine or containing cisplatin vs. carboplatin, did not alter the survival outcome. In a subgroup of 57 SR patients who were seen at initial diagnosis and for whom complete staging and treatment information were available 3 and 5-year PFS were 94% (88%, 100%) and 76% (66%, 86%); OS at 5 years, 94% (87%, 100%). CONCLUSION No statistically significant difference was noted in outcome of patients treated without vincristine or with carboplatin instead of cisplatin, suggesting attenuated upfront regimens could be considered to reduce toxicity. Adult MB patients recur late and have a poor post-recurrence survival, therefore long-term follow-up, development of molecular risk-adjusted upfront treatment, and optimization of rescue treatments are needed.

Introduction Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare diagnosis first incorporated into the WHO Classification of Tumors of the Central Nervous System in 2016. Though historically considered indolent, emerging evidence suggests that the biological behavior of these tumors may be further classified by molecular features of prognostic significance. Methods A retrospective review was conducted in accordance with IRB approval of patients with the histologic diagnosis of DLGNT. Demographic, clinical, and molecular data where abstracted from the medical record when available. Results 10 patients were identified (M = 8, F = 2). Median age at diagnosis was 6 years (range 0.3–21 years), and the most common symptoms at diagnosis were related to obstructive hydrocephalus, for which 3 patients required CSF diversion. MRI findings included diffuse leptomeningeal thickening, nodularity, or coating of the subarachnoid or ependymal surfaces. Histologically, these tumors expressed variable features of neuronal and/or glial differentiation. Four patients (40%) were treated with radiation therapy (all craniospinal), which was upfront for 2 patients. Chemotherapy regimens used included temozolomide, carboplatin and vincristine and vinblastine. NTRK or BRAF-targeted therapy were used upon progression. At follow-up, 6/10 had stable disease (4/6 of whom were on second line therapy), 1 had partial response, 1 passed away from sepsis and 2 were lost to follow-up. The median progression-free survival for the four patients who developed disease progression was 26 months (range 12–34 months). Next generation sequencing of the tumor tissue performed using a high-multiplex PCR-based NGS panel detected BRAF-KIAA1549 (4 patients) and NTRK (1 patient) fusions. Conclusions DLGNT are rare tumors with scarce data about imaging characteristic and standard of care treatment. Our case series reinforces current literature that although these tumors appear low-grade, they can be clinically aggressive. Further study is needed regarding molecular diagnosis and profiling treatment strategies.

BACKGROUND Despite its increasing use, circulating tumor cells (CTCs) have not been studied in pediatric brain tumors. METHODS Cell surface vimentin (CSV) is a marker for CTC detection. We developed an automated CSV-based CTC capture method for pediatric brain tumor using the Abnova Cytoquest platform. PBMCs isolated from blood samples from 52 brain tumor patients were processed to isolate CSV+ CTCs. Captured cells were then stained for CSV and CD45 and scanned to determine the number of CTCs. DIPG samples were additionally examined for H3K27M expression on CSV+ cells. Long term cancer survivors were used as a control cohort. RESULTS 86.4% of all the samples exhibited between 1–13 CSV+ CTCs, with a median of 2 CSV+ CTCs per sample. Using a value of ≥ 1 CTC as a positive result, the sensitivity and specificity of this test was 83.05% and 60.0% respectively. 19 DIPG samples were analyzed and 70% (13 samples) were positive for 1–5 CTCs. Five of these 7 positive CSV+ CTCs DIPG samples were also positive for H3K27M mutations by immunohistochemistry (71%). Mean survival in days for the CTC positive and negative DIPG samples were 114 and 211 days, respectively (p= 0.13). CONCLUSION This is the first study of CTCs in pediatric CNS tumors using an automated approach. Patients with brain tumors can exhibit CSV+ CTCs within peripheral blood. The use of specific molecular markers such as H3K27M can improve the diagnostic capability of liquid biopsies and may enable future disease assessment for personalized therapy.

BACKGROUND Embryonal Tumor with Multilayered Rosettes (ETMR) are rare tumors that are molecularly diagnosed by C19MC amplification. Rarity of this tumor has precluded profiling uniform therapeutic strategy. METHODS Retrospective review after institutional approval, identified 10 pediatric case of ETMR, treated at MD Anderson Cancer Center during the period of 2005 to 2019. RESULTS Median age of at diagnosis was 4.6 years. Tumor sites include frontal or parietal lobes (3), spine (3) and posterior fossa involving the brainstem (4). All patients received a combination of chemotherapy and radiation. 4 patients had metastasis at the presentation. 9 patients received focal radiation but only 6 of them received Craniospinal irradiation (CSI). Average dose of radiation was 50 Gy. Surgical resection was performed in all cases except the brainstem tumors. 7 children had recurrence including all the patients with metastasis at diagnosis (median time: 9.4 months), 1 passed away secondary to hemorrhage in brainstem and data was not available for 2 patients. 5/6 patients who received CSI had recurrence. CONCLUSIONS To-date no well-defined treatment regimens exists for these neoplasms, resulting in poor overall survival. Preclinical drug screen have shown the efficacy of topotecan, actinomycin D, and volasertib as potential new therapeutic candidates, though this has not translated successfully into the clinical arena. Given the limited success with current conventional therapeutic methods, molecular interrogation in addition to histopathological diagnosis are essential upfront, as it could provide clues to targeted therapy. Defining molecularly-based treatment with less toxicities and increased survival are warranted.

BACKGROUND Pseudoprogression after proton therapy of CNS tumors is a challenging clinical situation. The rate of pseudoprogression after proton therapy of pediatric spinal tumors is unknown. METHODS Records of pediatric patients with spinal pilocytic astrocytoma (sPA; n = 9) or myxopapillary ependymoma (MPE; n = 6) with gross disease treated with proton therapy with at least 6 months of follow up from completion of proton therapy were retrospectively reviewed for demographics, treatment characteristics, and occurrence of pseudoprogression. Pseudoprogression was defined as a post-radiation increase in tumor size with subsequent decrease in size without additional tumor-directed therapy. RESULTS The median age at radiation for sPA patients was 10.1y (range, 7.0 – 16.2y) and 12.7y (range, 7.9 – 14.4y) for MPE patients. The median prescribed dose was 45 GyRBE (range, 39.6 – 50.4 GyRBE) for sPA patients and 50.4 GyRBE (range, 45 – 54 GyRBE) for MPE patients. One sPA patient received concurrent vincristine. Median follow up after proton therapy was 44 months (range, 9 – 99 months). Six of nine sPA patients (67%) had pseudoprogression occurring at a median of 81 days (range, 34 – 136 days) after proton therapy; no MPE patients developed pseudoprogression (0%; p < 0.03). Two sPA patients with pseudoprogression were symptomatic and improved with medical therapy. CONCLUSION Preliminary analysis suggests that pseudoprogression occurs frequently within 6 months after proton therapy for sPA and infrequently after proton therapy for MPE.

H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no effective treatments. ONC201 efficacy has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adults with recurrent H3 K27M-mutant gliomas. These observations led to a Phase I pediatric clinical trial of ONC201 dosed by body weight. This multi-center, open-label, 3 + 3 dose-escalation and dose-expansion clinical trial (NCT03416530) for H3 K27M-mutant glioma or non-biopsied DIPG has 6 arms: arms A and E determine the RP2D in pediatric post-radiation (recurrent or not-recurrent) H3 K27M-mutant glioma patients with ONC201 administered as an oral capsule as well as a liquid formulation, respectively. Both arms have completed accrual. The study is currently enrolling newly diagnosed DIPG patients to determine the RP2D for ONC201 in combination with radiation (arm B). Dedicated assessment of intratumoral ONC201 concentrations in midline gliomas patients (arm C) and the effects of ONC201 in H3K27M DNA levels in circulating CSF (arm D) are currently enrolling patients. ONC201 as a single agent in patients with progressive H3K27M mutant tumors following irradiation (excluding DIPG/spinal cord tumors) was recently opened (arm F). Once the RP2D is confirmed, there is a dose-expansion cohort to confirm the safety, radiographic efficacy and survival with ONC201. The primary endpoints of arms A, B, and E have been established with the RP2D of 625mg scaled by body weight as a capsule or liquid formulation administered alone or in combination with radiation without incidence of dose-limiting toxicity.

Pediatric low-grade gliomas (pLGG) account for one third of all central nervous system (CNS) tumors. MRI is the preferred imaging modality for diagnosis and response evaluation. This study aims to evaluate if radiographic characteristics of pLGG at diagnosis are prognostic. Medical records of 700 pLGG patients were reviewed who were seen between 1998- 2019 at our institution. Summary statistics were provided to describe patient demographic and clinical characteristics. 603 patients were not eligible because incomplete records, 97 patients were identified and eligible for the review. There were 45 females and 52 males with the mean age of 6.5 years at diagnosis. Patients were categorized based on contrast enhancement to 2 groups; none/mild versus moderate/high with 65 and 32 patients respectively. 31 patients had infiltrative glioma (32.3%) with more than one lobe involved at diagnosis. Fifteen patients (15.46%) had hydrocephalous at initial diagnosis. 32 patients (32.9%) did not have any treatment and remained stable while 65(67.0%) had either surgery, chemotherapy or radiation or combination. 21 patients had neurofibromatosis type-1(NF-1) with better outcome comparing to non-NF1 as previously reported. No statistically significant difference in outcome was found based on the imaging characteristics at diagnosis including contrast enhancement, hydrocephalus, tumor size, presence of cyst or infiltrative tumors. The 5 years PFS rate for the entire cohort was 47%. Our study results are limited by low patient number, hence collaborative multi-institutional studies are warranted to delineate consensus and investigate prognostic factors to improve the outcome of pLGG.

Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor. Current standard of care has shown no improvements in survival. Here, we report our study of ONC201, a first-in-class small molecule developed by Oncoceutics, Inc., against a panel of DIPG cells in vitro and in mouse orthotopic models. ONC201 inhibits signaling through dopamine receptor D2 (DRD2), a G protein-coupled receptor (GPCR). MTT assays revealed a delayed but more robust response to ONC201, as measured by IC50 values, in DIPGs with histone H3.3-K27M expression compared to cells expressing wildtype (WT) or K27M mutant histone H3.1. Interestingly, transcriptomic profiling identified an association of this response delay with an elevation of genes controlling the cellular unfolded protein response, lysosomal and vacuole organization, and a decline in nucleic acid biosynthetic genes. These cells were also more committed to neuronal and oligodendrocytic lineage specification. By contrast, WT-H3 DIPGs that survived ONC201 treatment were stem-like and exhibited altered expression of genes controlling cell proliferation and apoptosis induction, respectively. Single cell proteomics validated the increase in anti-apoptotic proteins in these cells. Intraperitoneal administration of ONC201 for 7-weeks in mice bearing pontine xenografts of histone H3.1-K27M mutant DIPGs, caused a complete blockade of tumor growth relative to untreated controls. However, identical treatment of animals with forebrain tumors resulted only in a partial reduction in tumor burden, suggesting that the tumor microenvironment may be involved in the differential effect. These data indicate that tumor intrinsic and extrinsic factors may contribute to the response of DIPG tumors to ONC201.

DNA mismatch repair machinery is an integral part of the human genome and its defect has been involved in tumorigenesis and treatment resistance. Heterozygous monoallelic germline loss of function in MLH-1, MSH-2, MSH-6 or PMS-2 is involved in Lynch syndrome, whereas biallelic mutations cause constitutional mismatch repair deficiency (CMMRD) which is associated with hematologic malignancies and glioblastoma. We report here the clinical characterization and molecular analyses of 7 patients who presented with gliomas and MMR machinery aberrations. Two patients had a clinical diagnosis of NF-1 with dermatologic stigmata, of whom one patient has CMMRD and the other has Lynch syndrome. Two patients had a known family history of Lynch syndrome upon their diagnosis of glioma. Three patients with high-grade glioma and negative family history, 2 had germline mutations in MMR genes, and one had numerous mutations including MMR genes with microsatellite instability. Patients were initially treated with chemotherapy and radiation for high-grade gliomas (HGG); 5/7 had progression. Median time to progression was 12 months (range: 5–52), and median time from progression to death was 7 months (range: 2–25). One patient had low-grade glioma initially but progressed to HGG and is currently on therapy. Another patient treated with temozolomide and radiation is currently receiving maintenance therapy without any disease recurrence. Although the literature data on brain tumors with MMR deficiency is limited, these consistently show that MMRD-associated gliomas are treatment-resistant and have a dismal outcome. Collaborative efforts are needed to better understand this subgroup of pediatric HGG and to define optimal treatment strategy.

BACKGROUND Pediatric GBMs are rare, accounting for 3% of all pediatric CNS tumors. Despite advances in treatment, the outcomes for pediatric glioblastomas (GBM) have not significantly improved. Research suggests a link between enhancement patterns and survival in adult patients with glial tumors. We sought to study this relationship in a cohort of pediatric GBMs. METHODS A radiology database was searched for cases < 22 years, pathology proven brain glioblastoma, and pre-surgical MR imaging available for review. Based on pre-treatment, T1-contrast enhanced MR images, size, and contrast enhancement patterns were characterized as focal, diffuse, or ring-like. The extent of resection was assessed by comparing pre- and post-surgery T2 hyperintensity and contrast enhancement. RESULTS 64 eligible patients (age 2-21y, 14.6 + 5.4) were identified. The majority of lesions demonstrated enhancement on gadolinium-enhanced T1 imaging. (n=58/64; 90%). The lesions were categorized into six (9.4%) cases with focal enhancement, 37 (57.8%) cases with diffuse enhancement, and 15 (23.4%) with ring-like enhancement. Patients who received GTR/subtotal resection (STR) and had focal-enhanced GBMs had a significantly longer progression-free survival (PFS) – 14.1 months (p = 0.0308), comparing to diffuse and ring-like enhancing glioblastomas which had respectively 13.9 and 5.5 months of PFS. DISCUSSION Our data suggests that the contrast enhancement pattern is a significant prognostic factor for survival in pediatric GBM. Patients with GTR/STR who had focal-enhancing GBMs had a significantly longer progression-free survival (p=0.03) comparing to other enhancement patterns.

An 11 y.o. female presented to a GI specialist with complaints of morning vomiting and periumbilical abdominal pain for several months. Had progressing symptoms with GI work-up for ~1 year. She developed diplopia and worsening headaches. Imaging revealed a T2/FLAIR hyperintense mass in the 4th ventricle with heterogeneous enhancement and obstructive hydrocephalus. Three T2 bright, non-enhancing, subcentimeter masses identified in the right cerebellum. Due to poor differentiation between tumor and normal tissue at brainstem, only partial resection (PR) was feasible. Pathology initially called pilocytic astrocytoma (PA). All symptoms resolved after PR. Slow progression in the tumor and “satellite” lesions noted over two years. Second opinion and molecular typing reclassified the tumor as rosette-forming glioneuronal tumor (RFGNT) with a mutation in PIK3CA. Therapy started with vinblastine and carboplatin with stable disease x 7 months, discontinued due to allergic reaction to carboplatin. Initiated therapy with everolimus, an mTOR inhibitor. The tumor’s characteristics on imaging changed with initial growth and increase in peripheral enhancement in one satellite and the primary tumor. Nevertheless, we persevered. When comparing pre-treatment MRI to most recent 7 months later, there has been an overall decrease in volume of expansile heterogenous tumor along the margins of the fourth ventricle. The degree of peripheral enhancement associated with the mass has increased. RFGNT is a rare tumor included in WHO classification since 2007. Ellezam et al identified recurrent PIK3CA mutations. To our knowledge, this is the only report of treatment targeting the mutation. We report a radiographic response despite initial growth.

Pediatric chordomas are exceedingly rare and there are limited data to guide treatment decisions. We report a retrospective analysis of 19 patients with chordomas who received treatment at our institution from 2001–2020. Of the 19 patients, 15 had clival (79%), 3 cervical and 1 sacral chordoma. There were 9 males (47%). Median age at diagnosis of 10.6 years. Eight patients had gross total (42%) and 11 (58%) had sub-total resection. As front line therapy 15 patients (79%) underwent surgery followed by radiation (1 photon and 14 proton), 3 patients (16%) received surgery and chemotherapy (anaplastic histology) and 1 patient received only surgery. For patients treated with radiation therapy the average prescribed dose was 70 Gy (range: 52–74). Post-surgery and radiation, 14 of 15 patients remained in remission. Five (26%) patients had progressive disease (PD) with median time to progression of 13 months of whom 3 died of disease at median of 18 months. Treatment of PD consisted of chemotherapy and radiation for 3, re-resection with radiation for 1 and chemotherapy alone for 1 patient. The patients with metastatic and anaplastic disease mean survival is 21 month versus 45 for the rest of the cohort. In summary, post-operative adjuvant radiation provided an overall good outcome in majority of patients. Patients with anaplastic pathology and metastasis at diagnosis had worse outcome. Those who relapsed, subsequent treatment was palliative at best with short survival. Molecular analysis is warranted in future for better disease stratification.

ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. In adults, the recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated. Radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. This multi-arm, dose-escalation and dose-expansion trial determined the pediatric RP2D of ONC201 administered as an oral capsule (Arm A) or liquid formulation (Arm E) in post-radiation H3 K27M-mutant glioma (Arm A) or in newly diagnosed DIPG (Arm B) patients. Molecular assessments include intratumoral ONC201 concentrations (Arm C) and CSF H3 K27M DNA levels (Arm D). Enrollment as of April 30, 2020 is complete in Arm A (22) and Arm E (26) and continues in Arm B (18/24), Arm C (5/12), and Arm D (22/24). The RP2D of weekly 625mg ONC201 scaled by body weight was confirmed when administered as a capsule or a liquid formulation as a single agent or in combination with radiation without dose-limiting toxicity. The most frequent adverse events regardless of attribution to the drug were predominantly low grade: ONC201 capsule alone was headache (54.5%), nausea (36.4%), and fatigue (36.4%); ONC201 liquid formulation was vomiting (31.8%), headache (22.7%), VIth nerve disorder (22.7%); ONC201 capsules in combination with radiation (Arm B) was headache (47.1%), vomiting (52.9%), nausea (41.2%). Pharmacokinetic analysis in plasma of Arm A patients revealed T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL, with similar exposure across body weights. In conclusion, when scaled by body weight the ONC201 capsule or liquid formulation alone or in combination with radiation were associated with safety and pharmacokinetic profiles in pediatric H3 K27M-mutant diffuse midline glioma patients that are similar to the experience in adults.

Although BRAF inhibition has demonstrated activity in BRAFV600–mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAFV600-mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated.

BACKGROUND: Brain tumors are the second most common malignancy in children, and are the leading cause of death from childhood cancer. Although significant strides have been achieved in improving survival of most childhood malignancies, the outcome for children with brain tumors has remained poor. Advanced imaging techniques can reduce diagnostic uncertainty, but the need to identify better disease markers is immense and remains unmet. In that regard, analysis of circulating biomarkers is a novel and promising avenue for monitoring disease status. Despite increasing use in tumor research, circulating tumor cells (CTCs) have not been studied in pediatric brain tumor and only scarcely investigated in adult brain tumors. METHOD: Based on previous research showing cell surface vimentin (CSV) as a key surface marker for CTC detection, we developed an automated CSV-based CTC capture method for pediatric brain tumor using the Abnova CytoQuest CR CTC isolation platform. With this platform, we processed PBMCs isolated from whole blood samples through the automated system to trap CSV-positive CTCs on to a chip. Captured cells are then stained for CSV and CD45 before automated scanning and detection to determine CTC yield per sample. RESULT: Ten patients were consented on the study, nine patients (3 high grade glioma, 3 brain stem glioma, 1 pineoblastoma, 1 medulloblastoma, 1 atypical teratoid rhabdoid tumor) had an adequate samples for testing, of those 7 had CTC detected from PBMCs. Our results show that brain tumors patients can and do exhibit CSV+ CTCs. These findings do not distinguish between various types of brain malignancies as evidenced by positive CTC isolation in multiple types of gliomas and embryonal tumors. CONCLUSION: Overall, we present the first study of CTCs in pediatric tumors using an automated approach. This is a promising methodology for future tumor risk stratification and treatment response monitoring.