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The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.

PURPOSE: Children’s Oncology Group study ACNS1123 tested the efficacy of reduced dose and field of radiation therapy (RT) for patients with localized nongerminomatous germ cell tumors (NGGCT) who achieved a complete (CR) or partial response (PR) to chemotherapy. Here, we evaluate the quality of RT and patterns of failure for patients eligible for reduced RT in this phase 2 trial. METHODS AND MATERIALS: Patients with localized NGGCT with CR/PR after induction chemotherapy received reduced RT to 30.6 Gy whole ventricular irradiation and 54 Gy tumor-bed total dose. An atlas was provided to assist with complex RT volumes. Early interventional review was performed for the initial RT plan. Complete RT plans for all patients and images of relapsed patients were centrally reviewed at completion of therapy. RESULTS: Between May 2012 and September 2016, 107 eligible patients were enrolled and 66 achieved a CR/PR after induction chemotherapy (± second-look surgery) and were eligible for reduced RT. Median follow-up was 4.4 years. Median age was 11.0 years (3.7–21.6), and 75% were male. Progression-free survival and overall survival at 4 years were 87.9% ± 4.0% and 92.4% ± 3.3% for 66 evaluable patients, respectively. Eight patients relapsed: 6 with isolated spinal relapse and 2 with disease in the brain and spine. After central review, 62 (94%) patients had RT targets contoured and dose delivered per protocol. None of the patients with deviations (n = 4) have progressed. CONCLUSIONS: Patterns of failure suggest the spine is at risk for recurrence for patients with localized NGGCT who receive reduced RT after a CR/PR to induction chemotherapy. Although survival data are encouraging, the pattern of failure has influenced the next prospective trial design. RT compliance was excellent despite complexity of radiation volumes, suggesting that providing visual guidance in the form of an online atlas contributes to higher quality RT plans.

Background: Understanding the effect of selumetinib on FASI may help elucidate the biology, proliferative potential, and role in neurocognitive changes for these NF1-associated lesions. Methods: Patients with NF1-associated LGG and FASI treated with selumetinib on PBTC-029B were age-matched to untreated patients with NF1-associated FASI at Cincinnati Children’s Hospital Medical Center. Paired bidirectional measurements were compared over time using nonparametric tests. Results: Sixteen age-matched pairs were assessed (age range: 2.8–16.9 years, 60% male). Initial FASI burden was not different between groups (median range 138.7 cm2 [88.4–182.0] for the treated subjects vs. 121.6 cm2 [79.6—181.9] for the untreated subjects; p = 0.98). Over a mean follow-up of 18.9 (±5.9) months, the LGG size consistently decreased with treatment while no consistent change among the treated or untreated FASI size was seen. At the paired time points, the median treated LGG decreased significantly more than the treated FASI (−41.3% (LGG) versus −10.7% (FASI), p = 0.006). However, there was no difference in the median size change in the treated versus untreated FASI (−10.7% (treated FASI) versus −17.9% (untreated FASI), p = 0.08). Among the treated subjects, there was no correlation between the change in LGG and FASI (r = −0.04, p = 0.88). Conclusions: Treatment with selumetinib did not affect the overall FASI size in children with NF1 treated for progressive low-grade glioma.

PURPOSE The US Food and Drug Administration–expanded access program (EAP) uses a single patient use (SPU) mechanism to provide patient access to investigational agents in situations where no satisfactory or comparable therapy is available. Genomic profiling of de novo and relapsed or refractory childhood cancer has led to increased identification of new drug targets in the last decade. The aim of this study is to examine the SPU experience for genomically targeted therapies in patients with pediatric cancer. PATIENTS AND METHODS All genomically targeted therapeutic SPUs obtained over a 5-year period were evaluated at four large pediatric cancer programs. Data were collected on the type of neoplasm, agents requested, corresponding molecularly informed targets, and clinical outcomes. RESULTS A total of 45 SPUs in 44 patients were identified. Requests were predominantly made for CNS and solid tumors (84.4%) compared with hematologic malignancies (15.6%). Lack of an available clinical trial was the main reason for SPU initiation (64.4%). The median time from US Food and Drug Administration submission to approval was 3 days (range, 0-12 days) and from Institutional Review Board submission to approval was 5 days (range, 0-50 days). Objective tumor response was seen in 39.5% (15 of 38) of all evaluable SPUs. Disease progression was the primary reason for discontinuation of drug (66.7%) followed by toxicity (13.3%). CONCLUSION SPU requests remain an important mechanism for pediatric access to genomically targeted agents given the limited availability of targeted clinical trials for children with high-risk neoplasms. Furthermore, this subset of SPUs resulted in a substantial number of objective tumor responses. The development of a multi-institutional data registry of SPUs may enable systematic review of toxicity and clinical outcomes and provide evidence-based access to new drugs in rare pediatric cancers.

Homogeneous and common objective disease assessments and standardised response criteria are important for better international clinical trials for CNS germ cell tumours. Currently, European protocols differ from those of North America (the USA and Canada) in terms of criteria to assess radiological disease response. An international working group of the European Society for Paediatric Oncology Brain Tumour Group and North American Children's Oncology Group was therefore established to review existing literature and current practices, identify major challenges regarding imaging assessment, and develop consensus recommendations for imaging response assessment for patients with CNS germ cell tumours. New clinical imaging standards were defined for the most common sites of CNS germ cell tumour and for the definition of locoregional extension. These new standards will allow the evaluation of response to therapy in patients with CNS germ cell tumours to be more consistent, and facilitate direct comparison of treatment outcomes across international studies.

INTRODUCTION: Panobinostat is an oral HDAC inhibitor with pre-clinical activity against DIPG. The phase I study in children with progressive DIPG (stratum 1) defined the maximum-tolerated dose (MTD) as 10 mg/m2 administered 3x/week, 3 weeks on/1 week off. Herein, we report results of stratum 2, involving children with non-progressive DIPG/DMG using an alternative schedule. Primary objectives were to describe the toxicity profile and define the MTD; secondary objectives were to describe progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Patients with non-progressive DIPG or H3K27M-mutated thalamic DMG were eligible >14 days following standard radiation therapy only. Panobinostat was given every other day, 3x/week, on alternate weeks. Patients who received at least one dose of panobinostat were evaluable for toxicity. Four dose levels (DL) were evaluated: DL1 (16mg/m2/dose), DL2 (22 mg/m2/dose), DL3 (28 mg/m2/dose) and DL4 (36 mg/m2/dose). Dose escalation was determined by a continuous reassessment method. Correlative studies included pharmacokinetics obtained on course 1, day 1, and day 3 prior to subsequent dosing. RESULTS: Thirty-four eligible patients (median age, 7.6 [3-16] years) were enrolled with 29 evaluable for dose finding; DL1, n=3; DL2, n=10; DL3, n=11; DL4, n=5. The primary toxicities were myelosuppression and gastrointestinal. Eight DLTs occurred: DL2, Grade 3 thrombocytopenia (n=1); DL3, Grade 4 neutropenia (n=3), Grade 4 neutropenia and Grade 4 thrombocytopenia, (n=1); DL4, Grade 2 nausea (n=1), Grade 3 increased ALT (n=1), Grade 4 thrombocytopenia (n=1). Median PFS from drug initiation was 4.4 (1-11.2) months; median OS from diagnosis was 11.7 (4.5-25) months. These did not significantly differ from the PBTC historical cohort (PFS, p-value 0.4967; OS, p-value 0.6457). CONCLUSION: The MTD of panobinostat administered on this schedule to children with non-progressive DIPG/DMG is 22 mg/m2/dose. The primary DLT was myelosuppression. There was no significant improvement in PFS or OS in this cohort.

Background The study aimed to evaluate whether simplified chemotherapy followed by dose-reduced irradiation was effective for treating patients (ages 3–21 years) with localized germinoma. The primary endpoint was 3-year progression-free survival (PFS) rate. Methods Patients with a complete response to chemotherapy with carboplatin and etoposide received 18 Gy WVI + 12 Gy boost to the tumor bed. Patients with partial response proceeded to 24 Gy WVI + 12 Gy. Longitudinal cognitive functioning was evaluated prospectively on ALTE07C1 and was a primary study aim. Results One hundred and fifty-one patients were enrolled; 137 were eligible. Among 90 evaluable patients, 74 were treated with 18 Gy and 16 with 24 Gy WVI. The study failed to demonstrate noninferiority of the 18 Gy WVI regimen compared to the design threshold of 95% 3-year PFS rate, where, per design, patients who could not be assessed for progression at 3 years were counted as failures. The Kaplan-Meier (KM)-based 3-year PFS estimates were 94.5 ± 2.7% and 93.75 ± 6.1% for the 18 Gy and 24 Gy WVI cohorts, respectively. Collectively, estimated mean IQ and attention/concentration were within normal range. A lower mean attention score was observed at 9 months for patients treated with 24 Gy. Acute effects in processing speed were observed in the 18 Gy cohort at 9 months which improved at 30-month assessment. Conclusions While a failure according to the prospective statistical noninferiority design, this study demonstrated high rates of chemotherapy responses, favorable KM-based PFS and OS estimates in the context of reduced irradiation doses and holds promise for lower long-term morbidities for patients with germinoma.

Gliomas are the most common primary central nervous system tumors occurring in children and adults with neurofibromatosis type 1 (NF1). Over the past decade, discoveries of the molecular basis of low-grade gliomas (LGGs) have led to new approaches for diagnosis and treatments. However, these new understandings have not been fully applied to the management of NF1-associated gliomas. A consensus panel consisting of experts in NF1 and gliomas was convened to review the current molecular knowledge of NF1-associated low-grade “transformed” and high-grade gliomas; insights gained from mouse models of NF1-LGGs; challenges in diagnosing and treating older patients with NF1-associated gliomas; and advances in molecularly targeted treatment and potential immunologic treatment of these tumors. Next steps are recommended to advance the management and outcomes for NF1-associated gliomas.

PURPOSE Stratum 1 of ACNS1123 (ClinicalTrials.gov identifier: NCT01602666 ), a Children’s Oncology Group phase II trial, evaluated efficacy of reduced-dose and volume of radiotherapy (RT) in children and adolescents with localized nongerminomatous germ cell tumors (NGGCTs). The primary objective was to evaluate the impact of reduced RT on progression-free survival (PFS) with a goal of preserving neurocognitive function. PATIENTS AND METHODS Patients received six cycles of chemotherapy with carboplatin and etoposide alternating with ifosfamide and etoposide, as used in the Children’s Oncology Group predecessor study (ACNS0122; ClinicalTrials.gov identifier: NCT00047320 ). Patients who achieved a complete response (CR) or partial response (PR) with or without second-look surgery were eligible for reduced RT, defined as 30.6 Gy whole ventricular field and 54 Gy tumor-bed boost, compared with 36 Gy craniospinal irradiation plus 54 Gy tumor-bed boost used in ACNS0122. RESULTS A total of 107 eligible patients were enrolled. Median age was 10.98 years (range, 3.68 to 21.63) and 75% were male. Sixty-six of 107 (61.7%) achieved a CR or PR and proceeded to reduced RT. The 3-year PFS and overall survival and standard error values were 87.8% ± 4.04% and 92.4% ± 3.3% compared with 92% and 94.1%, respectively, in ACNS0122. There were 10 recurrences, prompting early study closure; however, after a retrospective central review, only disease in eight of 66 (12.1%) patients eligible for reduced RT subsequently progressed; six patients had distant spinal relapse alone and two had disease with combined local plus distant relapse. Serum and CSF α-fetoprotein and β-human chorionic gonadotropin levels were not associated with PFS. CONCLUSION Patients with localized NGGCT who achieved a CR or PR to chemotherapy and received reduced RT had encouraging PFS similar to patients in ACNS0122 who received full-dose craniospinal irradiation. However, the patterns of failure were distinct, with all patients having treatment failure in the spine.

BackgroundSurvivors of pediatric brain tumors are at risk for impaired development in multiple neuropsychological domains. The purpose of this study was to compare neuropsychological outcomes of pediatric brain tumor patients who underwent X-ray radiotherapy (XRT) versus proton radiotherapy (PRT).MethodsPediatric patients who underwent either XRT or PRT and received posttreatment age-appropriate neuropsychological evaluation—including measures of intelligence (IQ), attention, memory, visuographic skills, academic skills, and parent-reported adaptive functioning—were identified. Multivariate analyses were performed to assess differences in neuropsychological outcomes and included tests for interaction between treatment cohort and follow-up time.ResultsBetween 1998 and 2017, 125 patients with tumors located in the supratentorial (17.6%), midline (28.8%), or posterior fossa (53.6%) compartments received radiation and had posttreatment neuropsychological evaluation. Median age at treatment was 7.4 years. The PRT patient cohort had higher estimated SES and shorter median time from radiotherapy completion to last neuropsychological evaluation (6.7 vs 2.6 y, P < 0.001). On multivariable analysis, PRT was associated with higher full-scale IQ (β = 10.6, P = 0.048) and processing speed (β = 14.4, P = 0.007) relative to XRT, with trend toward higher verbal IQ (β = 9.9, P = 0.06) and general adaptive functioning (β = 11.4, P = 0.07). Planned sensitivity analyses truncating follow-up interval in the XRT cohort re-demonstrated higher verbal IQ (P = 0.01) and IQ (P = 0.04) following PRT, with trend toward improved processing speed (P = 0.09).ConclusionsPRT is associated with favorable outcomes for intelligence and processing speed. Combined with other strategies for treatment de-intensification, PRT may further reduce neuropsychological morbidity of brain tumor treatment.

Rare Brain Tumor Registry., [Background] Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease., [Methods] Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors., [Findings] 159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18–36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 [73%] of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47–68) at 6 months and 31% (21–42) at 2 years; overall survival was 29% (20–38) at 2 years and 27% (18–37) at 4 years. Overall survival was associated with non-metastatic disease (HR 0·48, 95% CI 0·28–0·80; p=0·0057) and non-brainstem location (0·42 [0·22–0·81]; p=0·013) on univariate analysis, as well as with gross total resection (0·30, 0·16–0·58; p=0·0014), high-dose chemotherapy (0·35, 0·19–0·67; p=0·0020), and radiotherapy (0·21, 0·10–0·41; p, [Interpretation] Prompt molecular diagnosis and post-surgical treatment with intensive multi-modal therapy tailored to patient-specific risk features could improve ETMR survival., Canadian Institute of Health Research, Canada Research Chair Awards, Australian Lions Childhood Cancer Research Foundation, Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía, Miracle Marnie, Phoebe Rose Rocks, Tali's Funds, Garron Cancer Centre, Grace's Walk, Meagan's Hug, Brainchild, Nelina's Hope, and Jean Martel Foundation.

IntroductionTreatment of recurrent primary pediatric brain tumors remains a major challenge, with most children succumbing to their disease. We conducted a prospective phase 2 study investigating the safety and efficacy of pomalidomide (POM) in children and young adults with recurrent and progressive primary brain tumors.MethodsPatients with recurrent and progressive high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), ependymoma, or medulloblastoma received POM 2.6 mg/m2/day (the recommended phase 2 dose [RP2D]) on days 1-21 of a 28-day cycle. A Simon’s Optimal 2-stage design was used to determine efficacy. Primary endpoints included objective response (OR) and long-term stable disease (LTSD) rates. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety.Results46 patients were evaluable for response (HGG, n = 19; DIPG, ependymoma, and medulloblastoma, n = 9 each). Two patients with HGG achieved OR or LTSD (10.5% [95% CI, 1.3%-33.1%]; 1 partial response and 1 LTSD) and 1 patient with ependymoma had LTSD (11.1% [95% CI, 0.3%-48.2%]). There were no ORs or LTSD in the DIPG or medulloblastoma cohorts. The median PFS for patients with HGG, DIPG, ependymoma, and medulloblastoma was 7.86, 11.29, 8.43, and 8.43 weeks, respectively. Median OS was 5.06, 3.78, 12.02, and 11.60 months, respectively. Neutropenia was the most common grade 3/4 adverse event.ConclusionsTreatment with POM monotherapy did not meet the primary measure of success in any cohort. Future studies are needed to evaluate if POM would show efficacy in tumors with specific molecular signatures or in combination with other anticancer agents.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT03257631; EudraCT, identifier 2016-002903-25.

BACKGROUND: ETV and tumor biopsy are central to the surgical management of children with primary CNS GCT. An ETV creates a communication between the intraventricular compartment and the subarachnoid spaces and decompartmentalizes the ventricular system. “Tumor spill” or shedding may result from surgical interventions, such as biopsy. ETV with simultaneous biopsy may impart a greater tendency for dissemination and possible distant relapse. This is a concern in CNS GCT given the attempts of irradiation field and dose reduction following chemotherapy. METHODS: We performed a retrospective review of the prospective database for the Children’s Oncology Group (COG) ACNS1123 study. Possible associations were explored among ETV, endoscopic biopsy, and combined ETV+biopsy with relapse, distant relapse, progression free survival (PFS), and time to distant relapse. RESULTS: Among 244 eligible patients, 97 ETV+/-biopsies were performed, and 30 relapses occurred. There were no associations among ETV and/or biopsy with relapse (Cochran-Mantel-Haenszel [CMH] test, with histology (germinoma vs. nongerminomatous germ cell tumor (NGGCT)) as stratification variable: ETV: p=0.3167, biopsy: p=0.3375, combined: p=0.3066), distant relapse (CMH test, ETV: p=0.4631, ETV+biopsy: p=0.6795), PFS (log-rank test, ETV: NGGCT p=0.1632, germinoma p=0.9288; biopsy: NGGCT p=0.1682, germinoma p=0.9701; ETV+Biopsy: NGGCT p=0.1306, germinoma p=0.7758), or time to distant relapse with death/local relapse as competing risk (Gray’s test, ETV: NGGCT p=0.5694, germinoma p=0.2327; biopsy: NGGCT p=0.3505, germinoma p=0.5747; ETV+Biopsy: NGGCT p=0.3988, germinoma p=0.6839). CONCLUSIONS: Based on a secondary analysis of prospective data from the ACNS1123 trial, ETV and biopsy did not impart a greater likelihood of relapse in children with primary CNS GCT treated with combined chemotherapy and irradiation. However, three tract recurrences did occur (all germinoma), suggesting that they may affect pattern of relapse. Current and future prospective trials should continue to explore associations among these variables and relapse, including patterns of relapse.

BACKGROUND: A greater understanding of the Ras-MAP kinase pathway in pediatric low-grade glioma (LGG) paired with the availability of selective inhibitors has enhanced the ability to target this pathway with therapeutic intent. METHODS: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/progressive LGG assigned to 6 strata and treated at a dose of 25 mg/m2/dose PO BID for up to two years. Here we present stratum 5 which enrolled children without NF1, non-OPG and non-pilocytic LGG harboring either a BRAFV600E mutation or BRAF-KIAA1549 fusion. RESULTS: Twenty-four of 25 children enrolled were eligible; 23 were evaluable for the primary radiologic response endpoint. Enrollment stopped early due to slow accrual and initiation of COG ACNS1931. The most common histologies were ganglioglioma (42%) and astrocytoma NOS (33%). Thirteen tumors (54%) had BRAF-KIAA1549 fusion; 11 (46%) had the BRAFV600E mutation. Five of 23 (22%) evaluable patients achieved a centrally confirmed partial response (PR), 12 (52%) had stable disease and 6 (26%) had progression with a 2-year progression-free survival of 75 + 9%. Four of 11 (36%) patients with a BRAFV600E mutation and 1/12 (8%) with a BRAF-KIAA1549 fusion achieved a PR. The 2-year PFS did not significantly differ between tumors with BRAFV600E mutation (82 + 12%) versus BRAF-KIAA1549 fusion (68 + 13%) (n=24, p=0.548). No patient remains on therapy. The most common attributable toxicities were grade 1/2 ALT/AST elevation, dry skin and leukopenia. Rare grade 3/4 toxicities included elevated CPK, rash, paronychia, fever, weight gain and sinus tachycardia. CONCLUSIONS: Despite lower than planned accrual, selumetinib met the design threshold for success in treating children with recurrent/progressive non-pilocytic, non-OPG LGG without NF1 that harbored the common BRAF aberrations. Ongoing phase 3 prospective studies will better determine the role of this agent in this population.

BACKGROUND: Central Nervous System- Non-Germinomatous Germ Cell Tumors (CNS-NGGCT) are rare but curable tumors. Due to their rarity, treatment failures remain a poorly characterized disease with unfavorable outcomes. In this study, we sought to characterize the treatment failures in a large cohort of prospectively treated patients. METHODS: European and North American clinical trials for patients with CNS-NGGCT (SIOP-GCT96, SFOP-TGM TC 90/92, COG-ACNS0122 and COG-ACNS1123) were pooled for analysis. Additionally, patients included and treated in the UK and France national registries under strict protocol-guidelines were included as an independent, non-overlapping cohort. RESULTS: A total of 118 patients experienced a treatment failure. Twenty-four patients had progressive disease during therapy and additional eleven patients were diagnosed with growing teratoma syndrome (GTS). Patients with GTS are significantly younger and present with local failures and negative tumor markers. Eighty-three individuals experienced disease relapses after treatment ended. Patients’ metastatic relapses presented significantly earlier than local relapses and were associated with tumor marker elevation (OR: 4.39; p=0.026). In our analysis, focal or whole ventricular (WVI) radiation therapy was not associated with an increased risk of metastatic relapses. CONCLUSIONS: Herein, we present the largest pooled dataset of prospectively treated patients with relapsed CNS-NGGCT. Our study identified younger age and negative tumor markers to be characteristic of GTS. Additionally, we elucidated that metastatic relapses occur earlier than local relapses, are associated with elevated tumor markers, and are not associated with the field of radiation therapy. These findings are of utmost importance for the planning of future clinical trials and the implementation of surveillance strategies in these patients.

INTRODUCTION: Endoscopic third ventriculostomy and endoscopic tumor biopsy have become integral to the surgical management of children with primary CNS GCTs. Observing ependymal tumor dissemination at the time of endoscopic surgery has been anecdotally reported. The incidence and impact of this finding in CNS GCT has not been reported. METHODS: Baseline neurosurgery data capture forms and operative reports from the Children’s Oncology Group (COG) ACNS1123 study were reviewed for ventriculoscopic findings of suspected tumor dissemination. The association between these findings and relapse was determined using Fisher’s exact test for each stratum and the Cochran-Mantel-Haenszel test for the entire cohort. Progression-free survival (PFS) was defined as time from enrollment to relapse, progression, death, or last follow-up; and survival probabilities were estimated using the Kaplan-Meier method with log-rank tests for outcome comparisons. RESULTS: 110/244 patients (45.1%) underwent endoscopic neurosurgery. Twelve patients (10.9%) had a documented observation suggestive of metastatic disease within the ventricular compartment. Ten were in the third ventricle and two were in the lateral ventricle. Nine of 12 were nongerminomatous germ cell tumors (NGGCTs) and three were germinoma. Ventriculoscopic findings of metastatic tumor were not significantly associated with relapse in NGGCT (p=0.4091), germinoma (p=0.1832), or overall (p=0.1540); odds ratio 2.57 (95%CI:0.66–10.11). PFS was not influenced in NGGCT (Log-rank test, p=0.1953) but was negatively impacted in germinoma (p=0.0250) when tumor dissemination was found during ventriculoscopy. CONCLUSIONS: Ventriculoscopic observation of tumor dissemination was reported in 10.9% of cases. This may negatively influence outcomes in children with germinoma, though due to the small number of relapses, more data is needed to verify these findings. Ventriculoscopic observation of tumor dissemination may contribute toward more accurate staging and influence future therapy, but a larger sample size is needed. Prospective studies should routinely integrate documentation of endoscopic observation in the study protocol.

INTRODUCTION: Autophagy is a highly conserved process by which intracellular components are degraded and recycled promoting cell survival. Preclinically, autophagy has been implicated as a resistance mechanism in BRAF-mutant glioma cells treated with MAPK-pathway inhibitors. HCQ, an oral autophagy inhibitor, has been evaluated preclinically and clinically to overcome resistance. METHODS: PBTC-055 (NCT04201457) is a phase I/II trial of HCQ combined with trametinib (BRAF-fusion or NF1-associated gliomas) or trametinib and dabrafenib (BRAFV600E gliomas) in patients < 30 years with progressive glioma. Prior treatment with RAF and/or MEK inhibitor with sub-optimal response (no response or response followed by progression on therapy) was required. Here, we present phase I data combining trametinib with HCQ utilizing a rolling-6 design. HCQ was administered at escalating dose levels (8, 15, or 20 mg/kg/day divided BID) in combination with standard pediatric trametinib dosing. All patients received prior MEK inhibitor therapy; 5/18 (28%) exhibited no response and 13/18 (72%) progressed on active therapy. RESULTS: Eighteen eligible/evaluable subjects were enrolled. Median age was 9.6 years (2.5-20.4 years); 10 were male. There were 2 dose-limiting toxicities (both grade 3 rash one each at DL1 and DL3). The highest dose level of HCQ (20 mg/kg/day divided BID) was declared the RP2D. Grade 3 adverse events possibly related to therapy included skin infection, rash, cardiac ejection fraction decrease, weight loss, and anorexia. There were no grade 4 or 5 attributable toxicities. Preliminarily, combination pharmacokinetic assessment revealed similar metabolism of trametinib to that reported as a single agent; HCQ demonstrated more rapid clearance compared to adults. Pharmacodynamic assessments are ongoing. CONCLUSIONS: The combination of trametinib and HCQ is safe with a RP2D of HCQ of 20 mg/kg/day divided BID. Currently, subjects are enrolling on the phase II portion evaluating the efficacy of this novel combination.

Background Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type 1) optic pathway and hypothalamic gliomas (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes. Methods We present results from children with recurrent/progressive OPHGs treated on a PBTC (Pediatric Brain Tumor Consortium) phase II trial evaluating efficacy of selumetinib (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase II dose (25mg/m2/dose BID) for a maximum of 26 courses. Results Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%), and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia, and rash. Conclusions Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS, and visual outcomes.

Selumetinib, a highly specific mitogen-activated protein kinase 1/2 inhibitor, is approved for children older than 2 years of age with neurofibromatosis 1 who have inoperable plexiform neurofibromas. By selectively binding to mitogen-activated protein kinase 1/2 proteins, selumetinib can arrest the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway that regulates critical cellular responses. Selumetinib has shown promising results as a single agent or in combination with conventional chemotherapy and other targeted therapies both preclinically and clinically, in multiple cancers including pediatric low-grade glioma, non-small cell lung cancer, and melanoma, among others. The pharmacokinetic profiles of selumetinib and its active metabolite N-desmethyl selumetinib have been well characterized in both adults and children. Both compounds exhibited rapid absorption and mean terminal elimination half-lives of about 7.5 h, with minimal accumulation at steady state. Three population pharmacokinetic models have been developed in adults and children, characterizing large inter- and intra-patient variabilities, and identifying significant covariates including food intake on selumetinib absorption, weight metrics, age, co-administration of cytochrome modulators, and Asian ethnicity on selumetinib apparent oral clearance. The most common side effects associated with selumetinib are dermatologic, gastrointestinal toxicities, and fatigue. Most toxicities are mild or moderate, generally tolerated and manageable. Cardiovascular and ocular toxicities remain less frequent but can be potentially more severe and require close monitoring. Overall, selumetinib exhibits a favorable safety profile and pharmacokinetic properties, with promising activity in multiple solid tumors, supporting current and further evaluation in combination with conventional chemotherapy and other targeted agents.

Background Central nervous system (CNS) malignancies are the most common solid tumors among children, and novel therapies are needed to help improve survival. Pomalidomide is an immunomodulatory agent that displays antiangiogenic and cytotoxic activity, making it an appropriate candidate to explore in pediatric CNS tumors. Methods A phase 1 first in pediatric trial of pomalidomide was conducted in children with recurrent, progressive, and refractory CNS tumors. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) when given orally once daily for 21 consecutive days of a 28-day cycle. Once the MTD was established, 12 additional patients were enrolled on expansion cohorts based on age and steroid use. Results Twenty-nine children were enrolled and 25 were evaluable for dose-limiting toxicity (DLT). The MTD was 2.6 mg/m2 (dose level 2). Four DLTs were observed in three patients at dose level 3 (3.4 mg/m2 ) includeding grade 3 diarrhea, grade 3 thrombocytopenia, grade 3 lung infection, and grade 4 neutropenia. The most common adverse events were grade 1 and 2 myelosuppression. One patient with an oligodendroglioma had stable disease for nine cycles, and a second patient with an anaplastic pleomorphic xanthoastrocytoma achieved a sustained partial response. Immunologic analyses suggested that pomalidomide triggers immunomodulation. Conclusions The MTD of pomalidomide is 2.6 mg/m2 . It was well tolerated, and immune correlates showed a serum immune response. These data led to an industry-sponsored phase 2 trial of pomalidomide monotherapy in children with recurrent brain tumors (NCT03257631).

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive glial tumor that occurs in children. The extremely poor median and 5-year survival in children afflicted with DIPG highlights the need for novel biology-driven therapeutics. Here, we have implicated the chromatin remodeler and regulator of brain development called RE1 Silencing Transcription Factor (REST), in DIPG pathology. We show that REST protein is aberrantly elevated in at least 21% of DIPG tumors compared to normal controls. Its knockdown in DIPG cell lines diminished cell growth and decreased their tumorigenicity in mouse intracranial models. DIPGs are vascularized tumors and interestingly, REST loss in DIPG cells also caused a substantial decline in tumor vasculature as measured by a decrease in CD31 and VEGFR2 staining. These observations were validated in vitro, where a significant decline in tube formation by human umbilical vein endothelial cells (HUVEC) was seen following REST-loss in DIPG cells. Mechanistically, REST controlled the secretion of a pro-angiogenic molecule and ligand for VEGFR2 called Gremlin-1 (GREM-1), and was associated with enhanced AKT activation. Importantly, the decline in tube formation caused by REST loss could be rescued by addition of recombinant GREM-1, which also caused AKT activation in HUVECs and human brain microvascular endothelial cells (HBMECs). In summary, our study is the first to demonstrate autocrine and paracrine functions for REST in DIPG development. It also provides the foundation for future investigations on anti-angiogenic therapies targeting GREM-1 in combination with drugs that target REST-associated chromatin remodeling activities.

Ependymoma is the third most common brain tumor in children, but there is a paucity of large studies with more than 10 years of follow-up examining the long-term survival and recurrence patterns of this disease. We conducted a retrospective chart review of 103 pediatric patients with WHO Grades II/III intracranial ependymoma, who were treated at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Chicago’s Ann & Robert H. Lurie Children’s Hospital between 1985 and 2008, and an additional 360 ependymoma patients identified from the Surveillance Epidemiology and End Results (SEER) database. For the institutional cohort, we evaluated clinical and histopathological prognostic factors of overall survival (OS) and progression-free survival (PFS) using the log-rank test, and univariate and multivariate Cox proportional-hazards models. Overall survival rates were compared to those of the SEER cohort. Median follow-up time was 11 years. Ten-year OS and PFS were 50 ± 5% and 29 ± 5%, respectively. Findings were validated in the independent SEER cohort, with 10-year OS rates of 52 ± 3%. GTR and grade II pathology were associated with significantly improved OS. However, GTR was not curative for all children. Ten-year OS for patients treated with a GTR was 61 ± 7% and PFS was 36 ± 6%. Pathological examination confirmed most recurrent tumors to be ependymoma, and 74% occurred at the primary tumor site. Current treatment paradigms are not sufficient to provide long-term cure for children with ependymoma. Our findings highlight the urgent need to develop novel treatment approaches for this devastating disease. Electronic supplementary material The online version of this article (doi:10.1007/s11060-017-2568-8) contains supplementary material, which is available to authorized users.

ETMR, an aggressive disease characterised by C19MC alterations, were previously categorised as various histologic diagnoses. The clinical spectrum and impact of conventional multi-modal therapy on this new WHO diagnostic category remains poorly understood as a majority of ~200 cases reported to date lack molecular confirmation. We undertook comprehensive clinico-pathologic studies of a large molecularly confirmed cohort to improve disease recognition and treatment approaches. Amongst 623 CNS-PNETs patients enrolled in the RBTC registry, 159 primary ETMRs were confirmed based on a combination of FISH (125), methylation analysis (88), SNP and RNAseq (32) analyses; 91% had C19MC amplification/gains/fusions, 9% lacked C19MC alterations but had global methylation features of ETMR NOS. ETMRs arose in young patients (median age 26 months) predominantly as localized disease (M0-72%, M2-3 -18%) at multiple locations including cerebrum (60%) cerebellum (18%), midline structures (6%); notably 10% were brainstem primaries mimicking DIPG. Uni-and multivariate analyses of clinical and treatment details of curative regimens available for 110 patients identified metastatic disease (p=0.002), brainstem locations(p=0.005), extent of surgery, receipt of multi-modal therapy including high dose chemotherapy and radiation (P

BACKGROUND We report the outcomes of patients with pineoblastoma enrolled on the Head Start I-III trials. METHODS Twenty-three children were enrolled between 1991–2009. Treatment included maximal surgical resection followed by five cycles of intensive-chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction. RESULTS The median age was 3.12 years (range:0.44–5.72). Three patients withdrew from the protocols and two patients experienced chemotherapy-related mortality. Eight patients experienced progressive disease (PD) during induction chemotherapy. Ten patients received HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation (CSI) with a median dose of 20.7 Gy (range:18–36 Gy) with boost(s) (median dose 27 Gy, range:18–36 Gy); three received CSI as adjuvant therapy (2 post-HDCx/AuHCR) and four upon progression/recurrence. The 5-year progression-free survival (PFS) and overall survival (OS) were 9.7% (95%,CI:2.6–36.0%) and 13% (95%,CI:4.5–37.5%), respectively. Three patients survived beyond five years. Nineteen patients relapsed in the following sites: local site (n=4), distal site (n=6), local and distal sites (n=9). Favorable OS prognostic factors were CSI (hazard ratio (HR)=0.30 (0.11–0.86), p=0.025), and HDCx/AuHCR (HR=0.40 (0.16–0.99), p=0.047). CONCLUSION CSI and HDCx/AuHCR were statistically associated with improved survival. The overall poor outcomes and high PD rate during later induction cycles and following consolidation chemotherapy warrants consideration of fewer induction cycles before consolidation and the intensification of consolidation with multiple cycles of marrow-ablative chemotherapy.

In this issue of Cancer Cell, Ryall et al. report on the largest clinically and molecularly characterized cohort of pediatric low-grade gliomas (pLGGs) published to date. They provide new insight into the pLGG molecular landscape and a novel risk stratification system with the potential to revolutionize prognostication and impact treatment.

Response criteria for paediatric high-grade glioma vary historically and across different cooperative groups. The Response Assessment in Neuro-Oncology working group developed response criteria for adult high-grade glioma, but these were not created to meet the unique challenges in children with the disease. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric high-grade glioma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric high-grade gliomas to various treatments. For areas in which scientific investigation was scarce, consensus was reached through an iterative process. RAPNO response assessment recommendations include the use of MRI of the brain and the spine, assessment of clinical status, and the use of corticosteroids or antiangiogenics. Imaging standards for brain and spine are defined. Compared with the recommendations for the management of adult high-grade glioma, for paediatrics there is inclusion of diffusion-weighted imaging and a higher reliance on T2-weighted fluid-attenuated inversion recovery. Consensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted.

BACKGROUND Pineoblastoma (PB) is a rare but aggressive pediatric brain tumour arising from the pineal gland. Overall survival rates are estimated at 50–70%, with younger patients (< 5 years old) faring much worse (15–40%) despite intensive treatment regimens. Although germline RB1 and DICER1 alterations have been reported in a small proportion of PB, the clinical significance of such alterations and the biology of sporadic cases remains unknown. METHODS We collected tumor tissue from 93 PB cases diagnosed at their referring centres. We undertook global DNA methylation profiling and performed multiple orthogonal consensus clustering analyses to elucidate PB subgroups. Chromosomal copy number alterations were determined using Conumee and GISTIC2, and whole exome or targeted sequencing was completed. Clinical data was analyzed with correlative statistical methods and outcomes were measured by Kaplan-Meier survival estimates. RESULTS PB comprise five epigenetic groups, designated 1, 2, 3, 4A, and 4B. Deleterious, mutually exclusive alterations affecting miRNA biogenesis pathway members (DICER1, DROSHA, and DGCR8) were observed in 12/21 group 1 and 11/11 group 2 samples. Group 4A was characterized by recurrent RB1 loss and gain of the oncogenic miR-17/92, and group 4B by recurrent gain or amplification of MYC. These groups also exhibit distinct clinical features. PB groups 1–3 arose in older children (median ages 5.2–14.0 years) and had intermediate to excellent outcome (5-year OS of 71.9–100%). Group 4A and 4B were restricted to much younger children (median age 1.3–1.4 years) and had dismal prognoses (5-year OS 37.5% and 28.6%, respectively). CONCLUSIONS PB divides into five groups with distinct genetic and clinical profiles. These findings will have important implications for precise patient stratification and form the foundation for preclinical studies of biology-informed therapies.

Background We report the outcomes of patients with pineoblastoma and trilateral retinoblastoma syndrome enrolled on the Head Start (HS) I-III trials. Methods Twenty-three children were enrolled prospectively between 1991 and 2009. Treatment included maximal surgical resection followed by five cycles of intensive chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction. Results Median age was 3.12 years (range, 0.44-5.72). Three patients withdrew from the study treatment and two patients experienced chemotherapy-related death. Eight patients experienced progressive disease (PD) during induction chemotherapy and did not proceed to HDCx/AuHCR. Ten patients received HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation (CSI) with a median dose of 20.7 Gy (range, 18-36 Gy) with boost(s) (median dose 27 Gy; range, 18-36 Gy); three received CSI as adjuvant therapy (two post-HDCx/AuHCR) and four upon progression/recurrence. The five-year progression-free survival (PFS) and overall survival (OS) were 9.7% (95% confidence intervals [CI]: 2.6%-36.0%) and 13% (95% CI: 4.5%-37.5%), respectively. Only three patients survived beyond five years. Favorable OS prognostic factors were CSI (hazard ratio [HR] = 0.30 [0.11-0.86], P = 0.025) and HDCx/AuHCR (HR = 0.40 [0.16-0.99], P = 0.047). Conclusions Within the HS I-III trials, CSI and HDCx/AuHCR were statistically associated with improved survival. The high PD rate during later induction cycles and following consolidation chemotherapy warrants consideration of fewer induction cycles prior to consolidation and the potential intensification of consolidation with multiple cycles of marrow-ablative chemotherapy and irradiation.

BACKGROUND: Pediatric low-grade glioma (pLGG) is the most common CNS tumor of childhood. Progression-free survival (PFS) is much lower than overall survival emphasizing the need for alternative treatments. In addition, many children suffer functional morbidities such as visual and motor disturbances. Recently, there has been an appropriate prioritization of functional outcomes in children with pLGG. METHODS: We present the results of a PBTC phase II trial evaluating selumetinib, (AZD6244, ARRY-142886) a MEK-1/2 inhibitor, in children with recurrent/progressive pLGG on 2 strata, including visual outcomes. RESULTS: Stratum 3 enrolled Neurofibromatosis type 1 (NF1)-associated pLGG. Ten of 25 (40%) eligible patients had partial response (PR), 14/25 (56%) had stable disease (SD) and 1/25 (4%) had progressive disease (PD); 2-year PFS was 96+4%. Ten patients with optic pathway glioma (OPG) were evaluable for visual acuity (VA) at baseline and 1 year. VA improved in 2/10 patients (20%) and was stable in 8/10 (80%). One patient (10%) had improvement in visual fields (VF) and 9 patients (90%) had stable VF. Stratum 4 included patients with non-NF1-associated recurrent/progressive hypothalamic and OPG. Five of 25 (20%) eligible patients had PR, 16/25 (64%) had SD and 4 (16%) had PD; 2-year PFS was 78+8.5%. Nineteen of 25 patients were evaluable for VA. VA improved in 4/19 patients (21%), was stable in 13/19 (68%) and worsened in 2/19 (11%). Five patients (26%) had improved VF and 14 (74%) had stable VF. The most common toxicities included grade 1/2 CPK elevation, diarrhea, hypoalbuminemia and rash. Rare grade 3 toxicities included elevated CPK, rash and paronychia. CONCLUSIONS: Selumetinib was tolerable and effective in treating children with NF1-associated and sporadic recurrent/progressive hypothalamic and OPG based upon radiographic response and PFS. Twenty-seven of 29 (93%) evaluable patients had stable or improved vision based on VA and VF testing.

The PBTC conducted a re-treatment study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/progressive pLGG. Eligible patients must have previously enrolled on PBTC-029 or PBTC-029B and progressed after coming off treatment with selumetinib. Patients must have maintained stable disease (SD) for ≥12 courses or had a sustained radiographic response (partial or complete) during their first exposure to selumetinib. Thirty-five eligible patients (median age: 13.11 years [range 7.96–25.33]) were enrolled, 57% of whom had optic pathway or hypothalamic target lesions. At the time of submission, median duration of treatment was 18 courses (range 2–48) and 21 subjects remained on therapy. Best responses reported to date are 6/35 (17%) partial response, 22/35 (63%) SD and 7/35 (20%) progressive disease with a 2-year progression-free survival of 75.7 + 8.3%, which met the design parameters for success. The most common attributable toxicities were grade 1 diarrhea, elevated AST, hypoalbuminemia, elevated CPK, maculo-papular rash, fatigue, paronychia, ALT elevation, acneiform rash and grade 2 CPK elevation. Rare grade 3 toxicities included CPK elevation (3), lymphopenia (2), paronychia (2) and ALT elevation (2). There was only one grade 4 CPK elevation. Five patients (14%) required dose reductions due to toxicity. There does not appear to be a notable difference in toxicities observed during initial selumetinib therapy versus re-treatment. In pLGG that has recurred/progressed following treatment with selumetinib, re-treatment with selumetinib appears to be effective with 80% of patients again achieving response or prolonged stable disease. Long-term follow-up is ongoing.

ACNS1123 was a Children’s Oncology Group Phase 2 study that was undertaken to determine whether irradiation could be safely reduced without impacting survival in a subgroup of NGGCT patients. Between May 2012-Jan 2017, 107 eligible patients were accrued to Stratum 1 (NGGCT stratum). Sixty-six (61.7%) patients achieved a complete/partial response (CR/PR) to induction chemotherapy and received 30.6Gy whole ventricular field irradiation followed by 54Gy tumor-bed boost achieving a 2-year progression-free survival rate of 89% (95% CI:81%-97%) and overall survival rate of 92% (95% CI:86%- 99%). Eight patients progressed; 6 had a spinal relapse and 2 patients had a local plus spinal relapse. Seven of eight patients had marker elevation at relapse and data was not available in one patient. At diagnosis, location was pineal in six cases, suprasellar in one, and bifocal in one case. Four patients had beta HCGβ and AFP elevation and two each had HCGβ and AFP elevation alone at diagnosis. Only two patients had HCGβ or AFP >1000 (HCGβ 3550 in one patient and AFP of 1340 in another). All eight patients were CR by markers; four had radiographic CR and four had a PR. Five patients had surgery at diagnosis: two had embryonal carcinoma, one germinoma, and two mixed germ cell tumor with malignant elements on histology. A consistent significant risk factor could not be identified to explain excess of spinal failures seen in our cohort.

BACKGROUND COG ACNS 1123 tested reduced radiotherapy (RT) for non-metastatic, non-germinomatous germ cell tumor (NGGCT) patients. The impact of central review on quality of RT and pattern of failure for NGGCT patients is evaluated. METHODS Patients who achieved a complete response (CR) or partial response (PR) to induction chemotherapy were eligible for reduced dose and field RT of 30.6 Gy whole ventricular field (WVI) and 54 Gy tumor-bed total dose. An online contouring atlas was available. Within three days of RT start, WVI plans were submitted for rapid central review. Within one week of RT completion, the complete RT record was submitted. Brain and spine MRIs of relapsed patients were centrally reviewed. RESULTS Between 5/2012–9/2016, 107 eligible patients were accrued and 70 met reduced RT criteria. Rapid RT review was performed for 49 (70%) of 70 patients. Forty-four (89.8%) required no modification. All modifications were completed and plans became compliant. Final central review was performed for 66 evaluable patients: 62 (94%) were per protocol; there were 2 major (1 dose and 1 target) and 2 minor deviations. Eight patients progressed; none had deviations. Median time to progression was 3.54 months (range: 1.7–19.1) from RT start. All failures had a spine component; two also had cranial component: one local progression (within the RT boost volume) and one leptomeningeal disease. CONCLUSION Providing an online contouring atlas and performing a rapid central review lead to high quality radiotherapy on this prospective trial. The deviations did not contribute to the pattern of failure.

INTRODUCTION Pediatric low-grade gliomas (pLGG) show clinical and biological features that are distinct from their adult counterparts. Consequently, additional considerations are needed for response assessment in children compared to the established adult Response Assessment in Neuro-Oncology (RANO) criteria. Standardized response criteria in pediatric clinical trials are lacking, complicating comparisons of responses across studies. We therefore established an international committee of the Radiologic Assessment in Pediatric Neuro-Oncology (RAPNO) working group to develop consensus recommendations for response assessment in pLGG. METHODS The committee consisted of 25 international experts in the areas of Pediatric Neuro-Oncology, Neuroradiology and Neurosurgery. The committee first developed a set of agreed upon topics they deemed necessary to understand the controversies of imaging utilization and assessment in pLGG. These topics were divided up among the committee members who presented all available literature to the entire RAPNO committee via web teleconference. Once presented, the group discussed these data and developed consensus statements and recommendations based on available literature, committee expertise and clinical experience. Each topic was discussed until a consensus was reached. RESULTS Final consensus included recommendations about the following topics: specific imaging sequences, advanced imaging techniques, NF1-associated pLGG, molecular and histologic classification, assessment of cysts, vision and other functional outcomes as well as overall radiologic response assessment. CONCLUSIONS The RAPNO pLGG consensus establishes systemic recommendations that represent an initial effort to uniformly collect and assess response in pLGG. These recommendations should now be evaluated internationally and prospectively in an effort to assess clinical utility, validate and modify as appropriate.

BACKGROUND CD40 is a co-stimulatory molecule expressed on antigen presenting cells (APCs). APX005M is a CD40 agonist monoclonal antibody which stimulates innate and adaptive anti-tumor immunity through activation of APCs, macrophages, and antigen-specific CD8+T-cells. Pediatric Brain Tumor Consortium study PBTC-051 is the first investigation of APX005M in pediatric patients and is evaluating the safety, recommended phase 2 dose (RP2D), pharmacokinetics, and preliminary efficacy of APX005M in children with central nervous system (CNS) tumors. RESULTS Accrual of patients with recurrent/refractory primary malignant CNS tumors (stratum 1) began in March 2018. 16 patients (2 ineligible) have enrolled on this stratum; 14 were treated. Dose escalation through 3 planned dose levels of APX005M was completed without excessive or unanticipated toxicities. The highest dose level (0.6 mg/kg q3 weeks) is the presumptive RP2D, and an expansion cohort is currently enrolling at this dose. 2 patients at dose level 3 have received >12 cycles of therapy. Grade 3 or higher adverse events at least possibly attributable to APX005M include 11 lymphopenia, 5 neutropenia, 5 leukopenia, 3 ALT elevations, 1 AST elevation, 1 thrombocytopenia, and 1 hypoalbuminemia. PK data will be available March 2020. Stratum 2 is now enrolling patients with post-radiation/pre-progression DIPG beginning at dose level 2, with 1 patient currently enrolled. CONCLUSION The CD40 agonistic antibody APX005M has demonstrated preliminary safety in pediatric patients with recurrent/refractory primary malignant CNS tumors and has a likely RP2D of 0.6 mg/kg q3 weeks in this population. Preliminary efficacy data are pending.

BACKGROUND The objective of stratum 2 of COG ACNS1123 was to evaluate children and young adults (3–21 years) with localized central nervous system (CNS) germinoma and investigate whether simplified pre-irradiation chemotherapy followed by response based dose-reduced whole ventricular irradiation (WVI) would maintain a high progression-free survival (PFS) while reducing long term treatment burden. METHODS Pre-irradiation chemotherapy consisted of 4 cycles of carboplatin and etoposide every 21 days followed by response-based irradiation (XRT). Patients with a complete response (CR) to pre-XRT chemotherapy received 18Gy WVI + 12Gy boost to the tumor bed. Patients with partial response (PR) but less than 1.5 cm residual proceeded to 24Gy WVI + 12Gy boost. All patients were also enrolled on COG ALTE07C1 to prospectively evaluate and longitudinally model the cognitive, social and behavioral functioning. RESULTS During a total accrual time of 45.5 months from 05/2012 to 06/2018, 137 eligible patients were enrolled. Median age was 14.09 years (4.95–21.46), 73% were male, and 45.26% had elevated βhCG in serum and/or cerebrospinal fluid. Twenty-nine patients (21.17%) did not have tissue biopsy. Eleven patients underwent second-look surgery; 7 had mature teratoma and 4 had non-viable tumor. Eighty-one patients (59.13%) had a CR. There were 4 relapses in patients receiving 18Gy WVI + boost, but no deaths. No unexpected treatment-related events were observed. The estimated 3-year PFS was 94.4 ±2.7% among 74 evaluable subjects. CONCLUSION This study shows promise in XRT reduction for patients with localized CNS germinoma and CR. Long-term survival outcomes and ALTE07C1 data are being evaluated.

Introduction: The Food and Drug Administration (FDA) expanded access program uses a single-patient use (SPU) mechanism to provide patient access to investigational agents prior to FDA approval and outside clinical trials, in situations where no satisfactory or comparable therapy is available. Genomic profiling of both newly diagnosed and relapsed/refractory childhood cancer has increased in the last decade, resulting in identification of new drug targets for pediatric malignancies. Recently, a review of SPU use in adult and pediatric patients at a single institution (Feit, JAMA Oncology 2019) showed that a markedly higher percentage of pediatric patients receive access through SPUs compared with adult patients, identifying this as an important means of pediatric drug access. However, little is known about the pediatric use and efficacy of SPUs in children. The aim of this study is to examine the SPU experience in pediatric and adolescent and young adult (AYA) cancer patients—specifically obtained for targeted therapies at three large pediatric cancer centers. Methods: All therapeutic SPUs obtained between January 1, 2014 and January 1, 2019 were evaluated at the Aflac Cancer & Blood Disorders Center (Atlanta, GA), Cincinnati Children’s Hospital (Cincinnati, OH), and the Memorial Sloan Kettering Cancer Center (New York, NY). Data were collected on the type of malignancy, agents requested, and corresponding molecularly informed targets, if applicable. Results: A total of 61 SPUs were approved in the five-year period, with 34 (55%) of them specific for access to agents based on somatic tumor mutations identified by genomic profiling. Among the disease groups, SPUs were most often requested for tumors affecting the central nervous system (CNS) (48%), followed by solid tumors (bone, liver, and kidney tumors) (26%), hematologic malignancies (leukemia/lymphoma) (21%), and other rare tumors (5%). Kinase inhibitors were the most frequently requested agents in the genomically defined category (n=34), specifically, FGFR (fibroblast growth factor receptor) inhibitors followed by drugs targeting NTRK 1/2/3 (tropomyosin receptor kinase (Trk) receptors). Most patients within this genomically targeted group (18/34) are currently receiving therapy with these agents. Conclusions: We found that SPUs represent an important means of access to therapeutic agents in the pediatric and AYA populations, with more than half of all SPUs based on rearrangements identified by genomic profiling. A broad range of agents were requested across CNS, solid tumor, and hematologic types. Furthermore, more than half of the patients remain on their respective SPU-approved drug. We are currently performing a more detailed analysis of clinical responses, as well as a time analysis from SPU initiation to approval for all patients in this cohort. Establishment of this cohort of patients across institutions will serve as the basis for a formal registry of pediatric SPUs, which will enable us to study their use and efficacy over time. Citation Format: Himalee Sabnis, Benjamin Mizukawa, Julia Glade-Bender, Jason Fangusaro, Stephen Roberts, Chanta Whitlow, Marilyn Winchester, Maureen O’Brien, Laura Agresta, Brian Turpin, Daniel Wechsler, Sharon Castellino, Neerav Shukla. Targeted therapies for children and young adults with cancer: Single-patient use (SPU) experience at three large pediatric cancer programs [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A50.

BACKGROUND: Pediatric low-grade glioma (pLGG) is the most common central nervous system tumor of childhood. Although overall survival is very good, many children suffer from multiple progressions and functional morbidities. There is no one universally accepted therapy for children with recurrent disease, however, standard cytotoxic chemotherapies are often utilized by most practitioners. The Pediatric Brain Tumor Consortium conducted a multi-institutional phase II study evaluating selumetinib (AZD6244, ARRY-142886), a MAP/ERK Kinase I/II inhibitor, in patients with recurrent, refractory or progressive pLGG assigned to numerous strata. The aim of the study was to evaluate the efficacy of selumetinib in these patients. METHODS: Eligibility required age 3–21 y/o, a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory or progressive pLGG after at least one standard therapy. Stratum 1 included children with World Health Organization (WHO) grade I pilocytic astrocytoma (PA) harboring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAF(V600E) mutation). Stratum 3 included children with any neurofibromatosis type 1 (NF1)-associated pLGG (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase II dose of 25 mg/m(2) twice daily. The primary endpoint was stratum-specific objective response rate assessd by the local site and sustained for at least 8 weeks. All responses were reviewed centrally and statistical analyses were done as per protocol. Although the trial (NCT01089101) is still ongoing in other strata, enrollment and planned follow-up is compete on both strata 1 and 3. FINDINGS: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable children were accrued to stratum 1, and between August 28, 2013, and June 25, 2015, 25 eligible and evaluable children were accrued to stratum 3. On stratum 1, 9/25 (36%) patients achieved a partial response (PR). The median follow-up for the 11 patients who have not yet experienced an event is 36.4 months (4.4–50.5; IQR=23.9). On stratum 3, 10/25 (40%) patients achieved a PR with a median follow-up of 48.6 months (8.6–59.1; IQR=12.2) for the 17 subjects without progressions. All patients evaluable for visual acuity had improved or stable vision. The most common attributable toxicities on both strata were grade 1 and 2 CPK elevation, hypoalbuminemia, dyspnea, rash, duodenal ulcer, anemia, dry skin, fatigue and diarrhea. Rare grade 3 toxicities included elevated CPK (n=5), maculopapular rash (n=5), neutropenia (n=3), nausea (n=3), paronychia (n=3), acneiform rash (n=2), diarrhea (n=2), elevated ALT (n=1), decreased ejection fraction (n=1), gastric hemorrhage (n=1), headache (n=1), skin infection (n=1), tooth infection (n=1) and weight gain (n=1). There was only one grade 4 toxicity, lymphopenia. There were no treatment-realted deaths. Patient reported outcomes and quality of life assessments were not part of the current study. INTERPRETATION: Selumetinib is active against recurrent, refractory or progressive PA harboring common BRAF aberrations and NF1-associated pLGG. To our knowledge, this is one of the first prospectively tested and successful molecularly-targeted agents in pLGG. These data not only provide an alternative to standard chemotherapy for these subgroups of patients, but this success has led to an interest in exploring efficacy in patients as a first-line therapy. In fact, these data have directly led to the development of two Children’s Oncology Group phase III studies in newly diagnosed pLGG patients both with and without NF1 comparing standard chemotherapy to selumetinib. The current trial was funded by a National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) PBTC U01 Grant: 2UM1CA081457 (UM1) and by the American Lebanese Syrian Associated Charities.

2503 Background: CNS-NGGCT are rare tumors that have been successfully treated with multimodal therapies. With a 5-yr EFS and OS of 72-84% and 82-93% respectively, surveillance and relapse detection is essential. Tumor marker (TM) elevation has proven to be a highly sensitive method of relapse detection in extra-cranial-NGGCT. We aim to determine the role of TM for relapse surveillance in children and adolescents with CNS-NGGCTs. Methods: European and North American data from germ cell tumor trials (SIOP GCT96, SFOP-TGM TC 90/92, COG-ACNS0122 and COG-ACNS1123) were pooled for analysis. Additionally, patients treated in the UK, Germany and France under strict protocol-guidelines were included. Details regarding imaging, pathology and TM elevation at diagnosis and relapse were collected. We report the proportion of relapses detectable by TM elevation. Results: Four-hundred and eighty-four patients enrolled in prospective cooperative group CNS-NGGCT trials from 1989 to 2016 were pooled for analysis. One-hundred and thirteen (23%) patients experienced a relapse/progression (SIOP GCT96: n = 57; SFOP TGM TC 90-92 n = 23, COG-ACNS0122 n = 16 & COG-ACNS1123 n = 17) and constitute the population of this report. Median age at diagnosis was 13 (range:1-30) years. The most common primary location was pineal in n = 60 (53%) patients. The site of relapse was available for 100 patients, 48 patients relapsed locally, 36 relapsed with distant disease, combined relapses were seen in 22 patients and 4 patients relapsed with TM elevation alone. TM in serum and/or CSF at diagnosis was available in 93(82%) patients, and in 90(80%) patients at the time of relapse. Eighty-four patients had TM available at both timepoints. At diagnosis 81 (96%) patients had TM elevation and 3 (4%) had negative TM. At relapse, 74(94%) patients with positive TM at diagnosis had TM elevation, while 7(6%) had TM negative. Conversely, 2/3 patients with negative TM at diagnosis, relapsed with elevated TM. Conclusions: Herein, we have assembled the largest prospective cohort to date of relapsed intracranial germ cell tumors. TM are highly sensitive detecting relapse/progression in CNS-NGGCT patients with elevated TM at diagnosis. The routine use of TM for relapse surveillance in patients with CNS-NGGCT can decrease the frequency of cross-sectional imaging, therefore, reducing lengthy hospital visits, sedation procedures and decreasing health-care costs.

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death., This project was funded by a Canadian Institutes of Health Research (CIHR) grant no. 137011 and b.r.a.i.n. child to A.H. T.S. is a CIHR Scholar.

PURPOSE OF REVIEW: Pediatric low-grade gliomas have been treated with similar therapies for the last 30 years. Recent biological insights have allowed a new generation of targeted therapies to be developed for these diverse tumors. At the same time, technological advances may redefine the late toxicities associated with radiation therapy. Understanding recent developments in pediatric low-grade glioma therapy is essential to the management of these common pediatric tumors. RECENT FINDINGS: It is now well understood that aberrations of the MAPK pathway are key to oncogenesis in low-grade gliomas. This understanding, along with the development of available targeted agents, have heralded a new era of understanding and treatment for these patients. Promising, sustained responses are now being seen in early phase trials among patients with multiply recurrent/progressive disease. Also, newer and highly conformal radiation approaches such as proton beam radiotherapy maintain efficacy of radiation but limit radiation-associated toxicities. SUMMARY: Novel therapies offer the potential for tumor control with greatly reduced toxicities. However, late effects of these therapies are just now being explored. Improved radiation approaches and targeted agents have the potential to redefine traditional therapy for pediatric low-grade glioma.

BACKGROUND: Pineoblastoma is a rare malignant pineal region tumor, the optimal management of which in young children remains unclear. METHODS: We report the outcomes of 23 children with pineoblastoma prospectively enrolled on three sequential Head Start (HS) trials between 1990 and 2009. The HS treatment strategy included maximal surgical resection followed by five cycles of intensive induction chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following recovery from consolidation was reserved for children over six years old or with residual tumor. RESULTS: Data on 23 children with pineoblastoma including two with trilateral retinoblastoma aged 0.44–5.72 (median 3.12) years were analyzed. Median overall survival (OS) was 12 months (95% CI: 7.6–29.7 months). The 3-year progression-free survival (PFS) and OS were 14.5% (95% CI: 5.1–41.2%) and 17.4% (95% CI: 7.1–42.4%), respectively. Three patients were long-term survivors beyond 5 years. Eight patients experienced progressive disease (PD) during induction chemotherapy, six following the fourth and fifth cycles. Ten patients proceeded to consolidation with HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation with boost(s) (median dose 20.7 (18–36) Gy), three patients as adjuvant therapy and four upon progression/recurrence. Favorable prognostic factors were administration of radiotherapy (hazard ratio (HR) for OS=0.30 (0.11–0.86), p

INTRODUCTION: Focal radiation therapy has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing radiation therapy (RT). Since chemotherapy does not provide significant outcome improvement, it is crucial to find a suitable radiosensitizer. Our research has shown that the JMJD3 demethylase inhibitor, GSK-J4, exerts potent anti-tumor activity on DIPG cells while restoring methylation. Our aim is to We hypothesized that GSK-J4 may inhibit radiation-induced DNA repair, making it a potential radiosensitizer. METHODS: RNA sequencing (RNA-Seq) was used to analyze gene expression changes by GSK-J4 in DIPG cells. ATAC-seq was conducted to determine chromatin accessibility in DIPG cells treated with GSK-J4. We evaluated DNA damage repair using DNA repair assay and immunocytochemistry of DSB markers γH2AX and 53BP1. Western blotting and quantitative PCR (qPCR) were conducted to evaluate differential expression of mRNA and proteins involved in DNA DSB repair. In vivo response to radiation monotherapy and combination of RT + GSK-J4 were measured by animal survival studies. RESULTS: RNA-Seq and qPCR show that GSK-J4 significantly reduces DNA DSB repair genes in DIPG cells. ATAC-seq results reveal that GSK-J4 modifies DNA accessibility to regulate expression of DNA repair genes. Immunocytochemistry results support that GSK- J4 sustains high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair. DNA repair assay demonstrate that GSK-J4 inhibits DNA damage repair via the homologous recombination pathway. Western blotting revealed that GSK-J4 causes a sustained level of phosphorylated Rad50 and gH2AX in irradiated DIPG cells. In vivo studies revealed increased survival of animals treated with combination therapy compared to monotherapy. These results highlight GSK-J4 as a potential radiosensitizer in DIPG treatment.

Background Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets. Methods Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG. Surgical biopsies were performed after enrollment and prior to definitive treatment. All subjects were treated with conventional external beam radiotherapy with bevacizumab, and then stratified to receive bevacizumab with erlotinib or temozolomide, both agents, or neither agent, based on O6-methylguanine-DNA methyltransferase status and epidermal growth factor receptor expression. Whole-genome sequencing and RNA sequencing were performed but not used for treatment assignment. Results Fifty-three patients were enrolled at 23 institutions, and 50 underwent biopsy. The median age was 6.4 years, with 24 male and 29 female subjects. Surgical biopsies were performed with a specified technique and no deaths were attributed to the procedure. Two subjects experienced grade 3 toxicities during the procedure (apnea, n = 1; hypertension, n = 1). One subject experienced a neurologic deficit (left hemiparesis) that did not fully recover. Of the 50 tumors biopsied, 46 provided sufficient tissue to perform the study assays (92%, two-stage exact binomial 90% CI: 83%–97%). Conclusions Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions.

Pineoblastoma (PB) is a rare but aggressive pediatric brain tumour arising from the pineal gland. Outcomes remain dismal with long-term survival rates between 10–40% despite intensive treatment regimens. Although germline RB1 and DICER1 alterations have been reported in a small proportion of PB, the clinical significance of such alterations and the biology of sporadic cases remains unknown. We undertook global methylation profiling of 75 PB cases, and discovered that PBs comprise four molecular sub-types, designated groups 1 to 4 with characteristic copy number alterations and mutational patterns. Molecular sub-groups of PB also exhibited distinct clinical features and survival outcomes. While PBs group 1–3 arose in older children (median ages 5.2–12.6 years), group 4 PB was restricted to much younger children (median age 1.4 years). Group 4 PB exhibited the highest incidence of metastases (53%) and had the worst 5-year event-free survival (EFS) and overall survival (OS), respectively 7.7% and 16.7%. In contrast, group 2 patients had a 5-year EFS and OS of 100%, while group 1 and 3 had intermediate outcomes (68.1%, 53.3% respectively). These findings demonstrate significant clinical and molecular heterogeneity in PB and underscore the critical need to define mechanisms underlying PB, so that precise patient stratification and selection of biology-informed therapies can be undertaken in future clinical trials.

The PBTC is conducting a phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata. We present the updated data on Stratum 2 and 5. Also, data on subsequent progression after treatment completion in patients enrolled on Stratum 1 and 3 will be discussed. Finally, we present details on the re-treatment study (PBTC-029C). Both stratum 2 (pilocytic astrocytoma [PA] without common BRAF aberrations) and Stratum 5 (non-pilocytic LGG with BRAF aberrations) met response criteria for expansion (> 2 objective responses in 16 patients), and accrual to a total of 25 patients on each stratum is ongoing. Among 50 patients treated on Stratum 1 (PA with BRAF aberrations) or Stratum 3 (NF-associated LGG), 21 have progressed. Thirteen of 21 have progressed after stopping therapy. The median time to progression for these 13 patients is 119 days (10–928). The re-treatment study has enrolled 25 patients who received a median of 12 re-treatment courses (2–36). The most common attributable toxicities after re-treatment were grade 1 CPK elevation (44%), diarrhea (44%), hypoalbuminemia (40%), elevated AST (36%), rash (36%) and fatigue (32%). The most common grade 3/4 attributable toxicities were grade 3 paronychia (8%), CPK elevation (4%), AST elevation (4%), decreased ejection fraction (4%), neutropenia (4%), elevated triglycerides (4%), peripheral neuropathy (4%) and grade 4 CPK elevation (4%). There is not a significant difference between the toxicities observed during original therapy versus re-treatment. The most current response and patient demographic data will be presented.

Medulloblastoma (MB) is a malignant pediatric brain tumor characterized by poor neuronal differentiation. The RE1 Silencing Transcription Factor (REST), which negatively regulates neurogenesis by promoting repressive chromatin remodeling via epigenetic modifications, is overexpressed in human MBs. Analyses of a publically available gene expression array data set revealed association of elevated REST expression in patients with Sonic Hedgehog (SHH) medulloblastoma with poor prognosis. Upon closer evaluation, we identified a subset of highly undifferentiated SHHα tumors with elevated REST expression and activity as determined by expression of REST target genes. These patients had an overall survival rate of 50% at 5 years. To understand the underlying mechanisms, we generated a novel mouse model expressing human REST transgene in a conditional manner in granule neural progenitors (GNPs), the cells of origin of SHH driven MB. Mice with constitutive activation of Shh signaling and REST elevation (Ptch(+/-)/REST(TG)) in their GNPs developed tumors with a significant decrease in latency and increase in penetrance. We observed that 100% of Ptch(+/-)/REST(TG) animals developed heterogeneously proliferative and undifferentiated tumors compared to tumor-bearing Ptch(+/-) animals. Mechanistic studies revealed deregulation of the Shh signaling pathway by REST-dependent G9a activity, accompanied by loss of Ptch1 heterozygosity in Ptch(+/-)/REST(TG) tumors. Thus, our studies suggest that REST contributes to mis-regulation of SHH activity and drives an aggressive disease course by deregulating proliferation and differentiation. Ours is also the first study to implicate G9a, a repressive chromatin remodeler, in medulloblastoma pathogenesis and as a potential therapeutic target.

The management of intracranial germ-cell tumours is complex because of varied clinical presentations, tumour sites, treatments and outcomes, and the need for multidisciplinary input. Participants of the 2013 Third International CNS Germ Cell Tumour Symposium (Cambridge, UK) agreed to undertake a multidisciplinary Delphi process to identify consensus in the clinical management of intracranial germ-cell tumours. 77 delegates from the symposium were selected as suitable experts in the field and were invited to participate in the Delphi survey, of which 64 (83%) responded to the invitation. Invited participants represented multiple disciplines from Asia, Australasia, Europe, and the Americas. 38 consensus statements encompassing aspects of intracranial germ-cell tumour work-up, staging, treatment, and follow-up were prepared. To achieve consensus, statements required at least 70% agreement from at least 60% of respondents. Overall, 34 (89%) of 38 statements met consensus criteria. This international Delphi approach has defined key areas of consensus that will help guide and streamline clinical management of patients with intracranial germ-cell tumours. Additionally, the Delphi approach identified areas of different understanding and clinical practice internationally in the management of these tumours, areas which should be the focus of future collaborative studies. Such efforts should translate into improved patient outcomes.

We present a unique case of radiation necrosis in a child with brain stem low-grade glioma (LGG) presenting with trigeminal neuralgia. Despite extensive therapies, severe pain persisted. She received proton beam radiation with significant improvement. However, she developed radiation necrosis and hydrocephalus. Despite surgical correction of hydrocephalus, the patient remained critically ill. She was treated with dexamethasone and bevacizumab with rapid clinical improvement. Subsequent MRIs revealed almost complete resolution of the necrosis. This case illustrates the successful treatment of trigeminal neuralgia with radiation and a rare case of radiation necrosis in an LGG successfully treated with bevacizumab and dexamethasone.

Despite the fact that they are not typically life-threatening, low-grade gliomas (LGGs) remain a significant clinical challenge in pediatric neuro-oncology due to comorbidities associated with these tumors and/or their treatments, and their propensity to multiply recurs. LGGs, in total the most common brain tumors arising in childhood, can often become a chronic problem requiring decades of management. The Second International Consensus Conference on Pediatric Low-Grade Gliomas held in Padua, Italy in 2016 was convened in an attempt to advance the pace of translating biological discoveries on LGGs into meaningful clinical benefit. Topics discussed included: the implications of our growing biological understanding of the genomics underlying these tumors; the assessment of the model systems available; the implications of the molecular and histopathologic differences between adult and pediatric diffuse gliomas; and steps needed to expedite targeted therapy into late-stage clinical trials for newly diagnosed cases. Methods for the diagnostic assessment of alterations in the Ras/mitogen-activated protein kinase pathway, typical for these tumors, were also considered. While the overall tone was positive, with a consensus that progress is being and will continue to be made, the scale of the challenge presented by this complex group of tumors was also acknowledged. The conclusions and recommendations of the meeting panel are provided here as an outline of current thinking and a basis for further discussion.