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Brain tumors are the most common cause of cancer-related deaths among the pediatric population. Among these, pediatric glioblastomas (GBMs) comprise 2.9% of all central nervous system tumors and have a poor prognosis. The purpose of this study is to determine whether the imaging findings can be a prognostic factor for survival in children with GBMs.The imaging studies and clinical data from 64 pediatric patients with pathology-proven GBMs were evaluated. Contrast enhancement patterns were classified into focal, ring-like, and diffuse, based on preoperative postcontrast T1-weighted magnetic resonance images. We used the Kaplan-Meier method and Cox proportional hazard regression to evaluate the prognostic value of imaging findings.Patients with ring-enhanced GBMs who underwent gross total resection or subtotal resection were found to have a significantly shorter progression-free survival (P = 0.03) comparing with other enhancing and nonenhancing glioblastomas.In this study, we analyzed survival factors in children with pediatric glioblastomas. In the group of patients who underwent gross total resection or subtotal resection, those patients with focal-enhanced GBMs had significantly longer progression-free survival (P = 0.03) than did those with other types of enhancing GBMs (diffuse and ring-like).

Tectal gliomas (TGs) are rare tumors that involve critical locations in the brainstem, including the superior and inferior colliculi and the Sylvian aqueduct. The rarity of these tumors and the lack of large clinical studies have hindered adequate understanding of this disease. We sought to determine the association between imaging characteristics of TG and progression-free survival (PFS).In this retrospective cohort study, impact of imaging characteristics (contrast enhancement, calcifications, cystic changes, presence of hydrocephalus) on survival was analyzed for 39 patients with TG. We used the Kaplan-Meier survival analysis method for determining the association between imaging characteristics and PFS. Progression-free survival was measured from time of diagnosis to radiographic or pathological disease progression during observation period. Progression was defined as more than 25% increase of the lesion in size, per response assessment in neuro-oncology, together with clinical deterioration and/or a need for intervention. Progression-free survival differences by various imaging characteristics were assessed using the log-rank test and univariable Cox proportional hazard regression. Because most of the studies in the current literature tend to overrepresent pediatric patients, we aimed to determine the association between TG tumors' imaging characteristics and PFS in both adult and pediatric patients. All statistical analyses were performed using STATA version 16.1 (Stata Corp, College Station, Tex).Of the 39 patients, radiographic tumor progression was observed in 15 cases (38.5%). Median PFS for 39 patients during observation was 21.8 years. Tectal gliomas that showed contrast enhancement initially or developed contrast enhancement during surveillance on magnetic resonance imaging had significantly lower PFS than those without (hazard ratio, 3.55; 95% confidence interval, 1.09-11.58; log-rank P value, 0.02).Analysis of this patient population showed that contrast-enhancing TGs should not be categorically defined as benign lesions. This subgroup of patients should be followed closely for signs of progression.

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.

H3K27M and H3.3G34R/V mutations have been identified in pediatric high-grade gliomas (pHGG), though extraneural metastases are rarely reported and poorly characterized. Three pHGG patients from two institutions were identified with extraneural metastasis, harboring histone mutations. Their clinical, imaging and molecular characteristics are reported here. A 17-year old female presented with supratentorial H3.3G34R-mutant glioma with metastatic osseous lesions in the spine, pelvis, bone marrow, pleural effusion and soft tissue of pelvis. Bone marrow biopsy and soft tissue of pelvis biopsy showed neoplastic cells positive for P53. A 20-year old female was diagnosed with H3F3A H3K27M-mutant thalamic glioma. She developed diffuse sclerotic osseous lesions. Biopsy of an osseous lesion was non-diagnostic. A 17-year old female presented with a H3F3A H3K27M-mutant diffuse midline glioma with diffuse spinal cord metastasis. She further developed multifocal chest lymphadenopathy, pleural effusions, and a soft tissue mass in the abdominal wall. The latter was positive for H3K27M mutation. We present the first case series of pHGG with H3F3A mutation and diffuse extraneural dissemination, describing their clinical and molecular profile.

BACKGROUND The authors analyzed the incidence and types of second malignant neoplasms (SMNs) in patients treated for medulloblastoma. METHODS The authors compared the incidence of SMNs after radiotherapy (RT) for medulloblastoma in patients treated in 1973-2014 with the incidence in the general population with the multiple primary-standardized incidence ratio function of Surveillance, Epidemiology, and End Results 9. Observed-to-expected incidence (O/E) ratios and 95% confidence intervals (CIs) were reported for the entire cohort and by disease site according to age at diagnosis, treatment era, and receipt of chemotherapy. P values < .05 were considered statistically significant. RESULTS Of the 1294 patients with medulloblastoma who received RT, 68 developed 75 SMNs. The O/E ratio for SMNs among all patients was 4.49 (95% CI, 3.53-5.62; P < .05). The site at highest risk was the central nervous system (CNS; O/E, 40.62; 95% CI, 25.46-61.51), which was followed by the endocrine system (O/E, 15.95; 95% CI, 9.12-25.91), bone (O/E, 14.45; 95% CI, 1.75-52.21), soft tissues (O/E, 9.01; 95% CI, 1.09-32.56), the digestive system (O/E, 5.03; 95% CI, 2.51-9.00), and the lymphatic/hematopoietic system (O/E, 3.37; 95% CI, 1.35-6.94). The O/E ratio was higher for patients given chemotherapy and RT (O/E, 5.52; 95% CI, 3.75-7.83) than for those given RT only (O/E, 3.96; 95% CI, 2.88-5.32). CONCLUSIONS Patients with medulloblastoma are at elevated risk for SMNs in comparison with the general population. Variations in O/E for SMNs by organ systems were found for treatment modality, age at diagnosis, and time of diagnosis. The most common site, the CNS, was involved more often in younger patients and those given chemotherapy with RT.

Introduction: We report 2 cases of medulloblastoma maturing into gangliocytoma after receiving multimodal therapy. Here we present 2 cases of diagnosed medulloblastoma which on re-resection were noted to be gangliocytoma without heterogeneity, which is an extremely rare occurrence. Case Presentation: The first patient, an 11-year-old boy diagnosed with high-risk (non-WNT, non-SHH) medulloblastoma, was treated with near-total surgical resection followed by craniospinal radiation therapy with weekly vincristine. He then received maintenance chemotherapy with vincristine, cyclophosphamide, and cisplatin. On surveillance MR imaging studies residual tumor in the lateral aspect of the tumor bed was noted to be slowly growing, eliciting gross-total resection of the residual tumor. Histopathology showed benign gangliocytoma without residual medulloblastoma. The second patient, a 3-year-old girl, was diagnosed with medulloblastoma, desmoplastic nodular variant. She was initially treated with gross total resection and chemotherapy with etoposide, carboplatin, and high-dose methotrexate. At 4 months off therapy, she was noted to have local recurrence along the resection cavity. Second-line therapy was started with irinotecan and temozolomide, but MRI assessment during treatment showed further disease progression. She then received craniospinal radiation. Eleven months off therapy, further radiographic progression was noted, and the patient underwent second-look surgery, with pathology showing gangliocytoma and treatment-related gliosis. Discussion/Conclusion: The maturation of medulloblastoma into a ganglion cell-rich lesion is very rare, with few well-characterized previous reports. Given the rare nature of this entity, it would be of great value to understand the process of posttreatment maturation and the genetic and treatment factors which contribute to this phenomenon.

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.

Purpose/Objective(s) 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. Materials/Methods Children with locally recurrent ependymoma treated with a second course of fractionated radiotherapy (RT2) from six North American cancer centers were reviewed. The index time was from the start of RT2 unless otherwise stated. Results 35 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 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. Conclusion Patients with locally recurrent pediatric ependymoma should be considered for re-treatment with repeat maximal safe resection (ideally GTR) and CSI re-irradiation.

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.

We describe large-scale demographic, initial treatment, and outcomes data for pediatric grade II gliomas included in the National Cancer Database from 2004 to 2014.Our cohort included cases less than 21 years of age with pathology-confirmed disease. Logistic regressions were used to evaluate the use of chemotherapy (CT) and radiation therapy (RT). Overall survival (OS) rates were determined using Kaplan-Meier estimates and the log-rank test.We identified 803 cases with astrocytoma (56.2%), oligodendroglioma (26.0%), and mixed glioma/glioma NOS (17.8%) histologies. Most cases underwent surgical resection (n = 661). Whereas cases 16 to 21 years of age were more likely than cases 0 to 5 years to receive RT (OR = 7.38, 95% CI 3.58-15.21, p0.001), they were less likely to receive CT (OR = 0.34, 95% CI 0.22-0.52, p0.001). The 5-year OS rates for all cases, cases that underwent surgical resection, and cases managed with biopsy were 87.5%, 92.7%, and 63.6%, respectively.In one of the largest series of pediatric grade II gliomas, astrocytoma was the most common histology. Patterns of care and OS outcomes were similar to grade I gliomas, with surgical resection being the most common initial treatment and associated with a favorable rate of OS. Younger patients were more likely to receive post-operative CT and the use of RT increased with age.

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.

Nuclear medicine studies have previously been utilized to assess for blockage of cerebrospinal fluid (CSF) flow prior to intraventricular chemotherapy infusions. To assess CSF flow without nuclear medicine studies, we obtained cine phase-contrast MRI sequences that assess CSF flow from the fourth ventricle down to the sacrum. In three clinical trials, 18 patients with recurrent malignant posterior fossa tumors underwent implantation of a ventricular access device (VAD) into the fourth ventricle, either with or without simultaneous tumor resection. Prior to infusing therapeutic agents into the VAD, cine MRI phase-contrast CSF flow sequences of the brain and total spine were performed. Velocity encoding (VENC) of 5 and 10 cm/s was used to confirm CSF flow from the fourth ventricular outlets to the cervical, thoracic, and lumbar spine. Qualitative CSF flow was characterized by neuroradiologists as present or absent. All 18 patients demonstrated CSF flow from the outlets of the fourth ventricle down to the sacrum with no evidence of obstruction. One of these patients, after disease progression, subsequently showed obstruction of CSF flow. No patient required a nuclear medicine study to assess CSF flow prior to initiation of infusions. Fourteen patients have received infusions to date, and none has had neurological toxicity. CSF flow including the fourth ventricle and the total spine can be assessed noninvasively with phase-contrast MRI sequences. Advantages over nuclear medicine studies include avoiding both an invasive procedure and radiation exposure.

Diffuse midline glioma, H3-K27M mutant (DMG-K27M) is a newly described, molecularly distinct infiltrative glioma that almost exclusively arises in midline CNS structures, including the brain stem, especially the pons, as well as the thalamus and spinal cord with rare examples seen in the cerebellum, third ventricle, and hypothalamus. To our knowledge, only 1 case of a molecularly confirmed DMG-K27M arising in the pineal region has been previously reported. We present the second occurrence of a tissue-confirmed DMG-K27M of the pineal region, which, to our knowledge, is the first case reported in a child and the first case with documented preoperative MRI. This case, in addition to a prior report described in an adult, defines the lower end of a broad age range of DMG-K27M onset (12-65 years) and establishes the pineal gland as a bona fide site of origin for this newly codified midline glioma.

Nearly 20 years ago, the concept of targeting the proteasome for cancer therapy began gaining momentum. This concept was driven by increased understanding of the biology/structure and function of the 26S proteasome, insight into the role of the proteasome in transformed cells, and the synthesis of pharmacological inhibitors with clinically favorable features. Subsequent in vitro, in vivo, and clinical testing culminated in the FDA approval of three proteasome inhibitors—bortezomib, carfilzomib, and ixazomib —for specific hematological malignancies. However, despite in vitro and in vivo studies pointing towards efficacy in solid tumors, clinical responses broadly have been evasive. For brain tumors, a malignancy in dire need of new approaches both in adult and pediatric patients, this has also been the case. Elucidation of proteasome-dependent processes in specific types of brain tumors, the evolution of newer proteasome targeting strategies, and the use of proteasome inhibitors in combination strategies will clarify how these agents can be leveraged more effectively to treat central nervous system malignancies. Since brain tumors represent a heterogeneous subset of solid tumors, and in particular, pediatric brain tumors possess distinct biology from adult brain tumors, tailoring of proteasome inhibitor-based strategies to specific subtypes of these tumors will be critical for advancing care for affected patients, and will be discussed in this review.

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.