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Supplementary Table S3 from Bevacizumab Plus Irinotecan in Recurrent WHO Grade 3 Malignant Gliomas

Supplementary Figures S1 to S5

Purpose:Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials.Materials and Methods:Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3–21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles.Results:Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1–14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and 2 residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. SMARCB1 GLAs were not associated with PFS.Conclusions:Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.

Germline methodology

Purpose: Although patients with newly diagnosed WHO grade 3 malignant glioma have a more favorable prognosis than those with WHO grade 4 malignant glioma, salvage therapies following recurrence offer essentially palliative benefit. We did a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan for patients with recurrent grade 3 malignant glioma.Experimental Design: Upon documentation of adequate safety among an initial cohort of nine patients treated with bevacizumab (10 mg/kg) and irinotecan every 14 days, a second cohort (n = 24) was treated with bevacizumab (15 mg/kg) every 3 weeks with irinotecan on days 1, 8, 22, and 29 of each 42-day cycle. For both cohorts, the dose of irinotecan was 340 mg/m2 for patients on enzyme-inducing antiepileptic drugs (EIAED) and 125 mg/m2 for patients not on EIAEDs. After each 6-week cycle, patients were evaluated with a physical examination and magnetic resonance imaging.Results: The 6-month progression-free survival was 55% (95% confidence interval, 36-70%). The 6-month overall survival was 79% (95% confidence interval, 61-89%). Twenty patients (61%) had at least a partial response. Outcome did not differ between the two treatment cohorts. Significant adverse events were infrequent and included a central nervous system hemorrhage in one patient, and one patient who developed thrombotic thrombocytopenic purpura.Conclusion: Bevacizumab and irinotecan is an active regimen with acceptable toxicity for patients with recurrent WHO grade 3 malignant glioma.

Background Therapeutic options are limited in pediatric CNS malignancies. CheckMate 908 (NCT03130959) is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO + ipilimumab (IPI) in pediatric patients with high-grade CNS malignancies. Methods Patients (N = 166) in 5 cohorts received NIVO 3 mg/kg every 2 weeks (Q2W) or NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks (4 doses) followed by NIVO 3 mg/kg Q2W. Primary endpoints included overall survival (OS; newly diagnosed diffuse intrinsic pontine glioma [DIPG]) and progression-free survival (PFS; other recurrent/progressive or relapsed/resistant CNS cohorts). Secondary endpoints included other efficacy metrics and safety. Exploratory endpoints included pharmacokinetics and biomarker analyses. Results As of January 13, 2021, median OS (80% CI) was 11.7 (10.3–16.5) and 10.8 (9.1–15.8) months with NIVO and NIVO + IPI, respectively, in newly diagnosed DIPG. Median PFS (80% CI) with NIVO and NIVO + IPI was 1.7 (1.4–2.7) and 1.3 (1.2–1.5) months, respectively, in recurrent/progressive high-grade glioma; 1.4 (1.2–1.4) and 2.8 (1.5–4.5) months in relapsed/resistant medulloblastoma; and 1.4 (1.4–2.6) and 4.6 (1.4–5.4) months in relapsed/resistant ependymoma. In patients with other recurrent/progressive CNS tumors, median PFS (95% CI) was 1.2 (1.1–1.3) and 1.6 (1.3–3.5) months, respectively. Grade 3/4 treatment-related adverse-event rates were 14.1% (NIVO) and 27.2% (NIVO + IPI). NIVO and IPI first-dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor programmed death ligand 1 expression was not associated with survival. Conclusions NIVO ± IPI did not demonstrate clinical benefit relative to historical data. The overall safety profiles were manageable with no new safety signals.

Background Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. Methods Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, Results Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. Conclusions The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

BackgroundDiffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR).MethodsPatients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (ResultsAmong 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival.ConclusionPatients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.

We report disease control, survival outcomes, and treatment-related toxicity among adult medulloblastoma patients who received proton craniospinal irradiation (CSI) as part of multimodality therapy. We reviewed 20 adults with medulloblastoma (≥ 22 years old) who received postoperative proton CSI ± chemotherapy between 2008 and 2020. Patient, disease, and treatment details and prospectively obtained patient-reported acute CSI toxicities were collected. Acute hematologic data were analyzed. Median age at diagnosis was 27 years; 45% of patients had high-risk disease; 75% received chemotherapy, most (65%) after CSI. Eight (40%) patients received concurrent vincristine with radiotherapy. Median CSI dose was 36GyE with a median tumor bed boost of 54GyE. Median duration of radiotherapy was 44 days. No acute ≥ grade 3 gastrointestinal or hematologic toxicities attributable to CSI occurred. Grade 2 nausea and vomiting affected 25% and 5% of patients, respectively, while 36% developed acute grade 2 hematologic toxicity (36% grade 2 leukopenia and 7% grade 2 neutropenia). Those receiving concurrent chemotherapy with CSI had a 38% rate of grade 2 hematologic toxicity compared to 33% among those not receiving concurrent chemotherapy. Among patients receiving adjuvant chemotherapy (n = 13), 100% completed ≥ 4 cycles and 85% completed all planned cycles. With a median follow-up of 3.1 years, 4-year actuarial local control, disease-free survival, and overall survival rates were 90%, 90%, and 95%, respectively. Proton CSI in adult medulloblastoma patients is very well tolerated and shows promising disease control and survival outcomes. These data support the standard use of proton CSI for adult medulloblastoma.

Purpose: Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials. Materials and Methods: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3–21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles. Results: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1–14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and Conclusions: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.

BACKGROUND: Limited data exist regarding checkpoint inhibitor efficacy for pediatric CNS malignancies. METHODS: CheckMate 908 is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO + ipilimumab (IPI) in 5 cohorts of pediatric patients previously treated with standard-of-care (NCT03130959). Patients received NIVO-3mg/kg Q2W or NIVO-3mg/kg + IPI-1mg/kg Q3W (4 doses) followed by NIVO-3mg/kg Q2W. Primary endpoints included OS (newly diagnosed DIPG) and PFS (other CNS cohorts); secondary endpoints included other efficacy metrics/safety. Exploratory endpoints included pharmacokinetics/biomarker analyses. Comparisons between treatments/cohorts were not planned. RESULTS: At data cutoff (13-Jan-2021), 166 patients received NIVO (n=85) or NIVO+IPI (n=81) at median (m) ages of 10.0yrs (range, 1-21) and 11.0yrs (1-21), respectively. In newly diagnosed DIPG, mOS (80% CI) was 11.7mos (10.3-16.5) with NIVO (n=23) and 10.8mos (9.1-15.8) with NIVO+IPI (n=22). In recurrent/progressive HGG, mPFS (80% CI) was 1.7mos (1.4-2.7) with NIVO (n=16) and 1.3mos (1.2-1.5) with NIVO+IPI (n=15). In relapsed/resistant medulloblastoma, mPFS (80% CI) was 1.4mos (1.2-1.4) with NIVO (n=15) and 2.8mos (1.5-4.5) with NIVO+IPI (n=15). In relapsed/resistant ependymoma, mPFS (80% CI) was 1.4mos (1.4-2.6) with NIVO (n=12) and 4.6mos (1.4-5.4) with NIVO+IPI (n=10). In other recurrent/progressive CNS tumors, mPFS (95% CI) was 1.2mos (1.1-1.3) with NIVO (n=19) and 1.6mos (1.3-3.5) with NIVO+IPI (n=19). Median treatment duration was 2.1mos (range, 0-41.7+ [NIVO]/0-29.6+ [NIVO+IPI]). Grade 3/4 treatment-related AEs occurred in 14.1% (NIVO) and 27.2% (NIVO+IPI) of patients. NIVO and IPI first dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor PD-L1 expression was not associated with survival. Tumor mutational burden was high in 1 patient (NIVO+IPI) with HGG (OS=11.0mos). CONCLUSIONS: NIVO±IPI demonstrated no clinical benefit in pediatric patients with high-grade CNS malignancies, consistent with available historical data. The safety profiles were manageable.

Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations (CNVs) in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients decline with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma.

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.

BackgroundDisruption of cell-cycle regulators is a potential therapeutic target for brain tumors in children and adolescents. The aim of this study was to determine the maximum tolerated dose (MTD) and describe toxicities related to palbociclib, a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in pediatric patients with progressive/refractory brain tumors with intact retinoblastoma protein.MethodsPalbociclib was administered orally starting at 50mg/m2 daily for the first 21 days of a 28-day course. Dose escalation was according to the Rolling-6 statistical design in less heavily (stratum I) and heavily pretreated (stratum II) patients, and MTD was determined separately for each group. Pharmacokinetic studies were performed during the first course, and pharmacodynamic studies were conducted to evaluate relationships between drug levels and toxicities.ResultsA total of 21 patients were enrolled on stratum I and 14 patients on stratum II. The MTD for both strata was 75mg/m2 . Palbociclib absorption (mean Tmax between 4.9 and 6.6 h) and elimination (mean half-life between 11.3 and 19.5 h) were assessed. The most common toxicity was myelosuppression. Higher palbociclib exposure was associated with grade 3/4 neutropenia and leukopenia. Dose limiting toxicities included grade 4 neutropenia and grade 3 thrombocytopenia and dehydration. No patients had an objective response to palbociclib therapy.ConclusionsPalbociclib was safely administered to children and adolescents at a dosage of 75mg/m2 for 21 consecutive days followed by seven days of rest in both strata. Future studies will establish its optimal utilization in pediatric patients with brain tumors.

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.

© 2021 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/, Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

PURPOSE SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medulloblastoma trials.

Low-grade gliomas (LGGs) are the most common childhood brain tumor in the general population and in individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Surgical biopsy is rarely performed prior to treatment in the setting of NF1, resulting in a paucity of tumor genomic information. To define the molecular landscape of NF1-associated LGGs (NF1-LGG), we integrated clinical data, histological diagnoses, and multi-level genetic/genomic analyses on 70 individuals from 25 centers worldwide. Whereas, most tumors harbored bi-allelic NF1 inactivation as the only genetic abnormality, 11% had additional mutations. Moreover, tumors classified as non-pilocytic astrocytoma based on DNA methylation analysis were significantly more likely to harbor these additional mutations. The most common secondary alteration was FGFR1 mutation, which conferred an additional growth advantage in multiple complementary experimental murine Nf1 models. Taken together, this comprehensive characterization has important implications for the management of children with NF1-LGG, distinct from their sporadic counterparts.

BackgroundETMRs are a newly recognized rare paediatric brain tumor with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and limited clinical data, disease features and determinants of outcome are poorly defined. We performed an integrated clinico-pathologic and molecular analyses of 159 primary ETMRs to define clinical phenotypes, identify predictors of survival and critical treatment modalities for this orphan disease.MethodsPrimary ETMR patients were identified from the Rare Brain Tumor Consortium (rarebraintumorconsortium.ca) global registry using histopathologic and molecular assays. Event-Free (EFS) and Overall Survival (OS) for 108 patients treated with curative multi-modal regimens were determined using Cox proportional hazard and log rank analyses.FindingsETMRs were predominantly non-metastatic (73%) tumors arising from multiple sites; 55% were cerebral tumors, 45% arose at sites characteristic of other brain tumors. Hallmark C19MC alterations were seen in 91%; 9% were ETMR-NOS. Survival and hazard analyses showed a 6 month median EFS and 2-4yr OS of 27-29% with metastatic disease (HR=0.44, 95% CI 0.26-0.74; p=0.002) and brainstem location (HR=0.40, 95% CI 0.021-0.75; p=0.005) correlating with adverse OS. Gross total resection (GTR: HR=0.38, 95% CI 0.21-0.68; p=0.001), high dose chemotherapy (HDC: HR=0.55, 95% CI 0.31-0.97; p=0.04) and radiation (RT: HR=0.32, 95% CI 0.16-0.60; p=InterpretationPrompt molecular diagnosis and post-surgical treatment with multi-modal therapy tailored to patient-specific risk features improves ETMR survival.FundingThis work was supported by the Canadian Institute of Health Research Grant No. 137011, Canada Research Chair Awards to AH. Funds from Miracle Marnie, Phoebe Rose Rocks, Tali’s Funds, Garron Cancer Centre, Grace’s Walk, Meagan’s Walk, Nelina’s Hope and Jean Martel Foundation are gratefully acknowledged. SK and PS were respectively supported by the Australian Lions Children’s Cancer Foundation and the Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía Project EF-0451-2017.

BACKGROUND Report disease control, survival outcomes, and acute radiotherapy related toxicity among young adult medulloblastoma patients who received proton craniospinal irradiation (CSI) as part of multimodality therapy. We reports the completion rates of planned adjuvant chemotherapy. METHODS All adult medulloblastoma patients (≥ 22 years old) who received postoperative proton CSI +/- chemotherapy at our institution between 2008 and 2020 were included. Patient, disease, and treatment details along with prospectively obtained patient-reported acute CSI toxicities were collected (CTCAE v3 or v4). Acute hematologic data were analyzed. RESULTS Twenty young adult medulloblastoma patients were included. The median age at diagnosis was 27 years (range, 22–30). 45% had high-risk disease. 75% received chemotherapy, most of whom (65%) received post-CSI chemotherapy. Eight patients (40%) received concurrent vincristine with CSI. The median CSI dose was 36 GyE (range, 23.4-36) with a median tumor bed boost of 54 GyE (54-55.8). The median duration of radiotherapy was 44 days (range, 40-49). There were no acute ≥ grade 3 gastrointestinal or hematologic toxicities attributable to CSI (during or within 4 weeks after completion of RT). Grade 2 nausea and vomiting affected 25% and 5% of patients, respectively. Acute grade 2 hematologic toxicity affected 36% of patients. Among patients planned to receive adjuvant chemotherapy (n=13), 100% completed at least 4 cycles and 85% completed all planned chemo cycles. With a median follow-up of 3.1 years, 4-year actuarial local control, DFS, and OS were 90% (95% CI 53-99), 90% (95% CI 53-99), and 95% (95% CI 72-99), respectively. Two patients had disease recurrence, both with local failures in the high dose boost volume in the tumor bed. CONCLUSIONS Proton radiotherapy for CSI in young adult medulloblastoma patients is well tolerated and shows promising disease control and survival outcomes. These data support the standard use of proton CSI for adult medulloblastoma.

Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations (CNVs) in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients decline with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma.

We evaluated circulating levels of immunosuppressive regulatory T cells (Tregs) and other lymphocyte subsets in patients with newly diagnosed medulloblastoma (MBL) undergoing surgery compared to a control cohort of patients undergo craniectomy for correction of Chiari malformation (CM) and further determined the impact of standard irradiation and chemotherapy on this cell population. Eligibility criteria for this biologic study included age 4–21 years, patients with CM undergoing craniectomy (as non-malignant surgical controls) and receiving dexamethasone for prevention of post-operative nausea, and those with newly diagnosed posterior fossa tumors (PFT) undergoing surgical resection and receiving dexamethasone as an anti-edema measure. Patients with confirmed MBL were also followed for longitudinal blood collection and analysis during radiotherapy and chemotherapy. A total of 54 subjects were enrolled on the study [22-CM, 18-MBL, and 14-PFT]. Absolute number and percentage Tregs (defined as CD4+CD25+FoxP3+CD127low/−) at baseline were decreased in MBL and PFT compared to CM [p = 0.0016 and 0.001, respectively). Patients with MBL and PFT had significantly reduced overall CD4+ T cell count (p = 0.0014 and 0.0054, respectively) compared to those with CM. Radiation and chemotherapy treatment in patients with MBL reduced overall lymphocyte counts; however, within the CD4+ T cell compartment, Tregs increased during treatment but gradually declined post therapy. Our results demonstrate that patients with MBL and PFT exhibit overall reduced CD4+ T cell counts at diagnosis but not an elevated proportion of Tregs. Standard treatment exacerbates lymphopenia in those with MBL while enriching for immunosuppressive Tregs over time.

INTRODUCTION The role of diagnostic biopsy in diffuse intrinsic pontine glioma (DIPG) remains in question. Distinguishing radiographically between DIPG and other pontine tumors with more favorable prognosis and different therapy is critically important. METHODS Cases submitted to the International DIPG registry with histopathologic data were analyzed. Central imaging review was performed by two neuro-radiologists; all cases with imaging features or histopathology suggestive of alternative diagnoses were re-reviewed. Imaging features suggestive of alternative diagnoses included non-pontine origin, RESULTS Among 297 patients with pathology from biopsy and/or autopsy available, 27 (9%) had histologic diagnoses not consistent with DIPG, commonly embryonal tumors (n=9) and pilocytic astrocytomas (n=11). 163 patients had diagnostic MRI available for central neuroimaging review. Among 81 patients classified as characteristic of DIPG, 80 (99%) had histopathology consistent with DIPG (diffuse midline glioma, H3K27M-mutant, glioblastoma, anaplastic astrocytoma, diffuse astrocytoma). Among 63 patients classified as likely DIPG, but with unusual imaging features, 59 (94%) had histopathology consistent with DIPG. 19 patients had imaging features suggestive of another diagnosis, including 13 with non-pontine tumor origin; the remaining 6 all had histopathology not consistent with DIPG. Association between central imaging review and histopathology was significant (p CONCLUSIONS The important role and accuracy of central neuroimaging review in diagnosing or excluding DIPG is demonstrated. In patients with pontine tumors for which DIPG is felt unlikely radiographically, biopsy may be considered to guide diagnosis and treatment.

PURPOSE To review data from DIPG Registry patients recorded to have received a second course of radiation therapy (rRT). METHODS The International DIPG Registry was searched for patients with DIPG who were treated with a known dose of rRT. Doses of rRT, timing from initial diagnosis and primary radiation therapy (pRT), radiographic response to rRT and survival from diagnosis (OS) were evaluated. RESULTS Sixty (11.2%) of 535 Registry patients underwent rRT; dose was provided for 44 patients. Median (range) data from those 44 revealed that rRT was given at 12 (2–65) months from initial diagnosis of DIPG and at 9.6 (1–61) months from completion of pRT at a dose of 26.7 (1.8–74) Gy. After completion of rRT, MRI showed response, progression, stable disease or was not available in 19, 8, 3 and 14 patients, respectively. Median PFS and OS were 11 and 18.1 months, respectively. 475 Registry patients did not undergo rRT; their ages, duration of symptoms, and primary treatment with or without chemotherapy were not significantly different from the rRT cohort. Median PFS and OS for the non-rRT patients were 6.9 and 10 months, respectively. rRT patients were more likely to have had radiographic evidence of tumor necrosis at diagnosis than non-rRT patients. CONCLUSIONS Administration of rRT to patients with DIPG has been inconsistent with respect to timing and dose. Toxicity, response and quality of life data are incomplete, but survival appears to be lengthened with rRT. Prospective clinical trials will elucidate benefits and risks of rRT.

Pineoblastoma (PB) is an aggressive embryonal brain tumor comprising 1% of pediatric CNS tumors. The clinico-molecular heterogeneity and developmental origins underlying PB are poorly understood; therefore, we have assembled a molecular cohort of histologically defined PBs (n=43) with corresponding outcome data. Methylation profiling revealed four molecularly and clinically distinct PB subgroups, including two novel entities. Mutational and transcriptional analysis identified characteristic molecular features of each subgroup, such as mutations in the miRNA processing pathway or FOXR2 proto-oncogene overexpression. Furthermore, subgroups exhibited differences in propensity for metastasis, cytogenetics, and clinical outcomes. To dissect PB developmental origins and resolve PB subgroup biology, we have employed a combination of single-cell genomics and genetically engineered mouse modeling. We created a single-cell transcriptional atlas of the developing murine pineal gland across 11 timepoints and are currently integrating these data with single nuclei RNA-seq data of human PB (n=25). Single-cell analysis of the developing pineal gland revealed three distinct populations of pinealocytes, referred to as early, mid and late pinealocytes, which segregate by developmental stage yet lie along a single developmental trajectory. Preliminary results implicate significant associations between PBs and the early pinealocyte population as well as subgroup-specific differences in intratumoral heterogeneity. Furthermore, this knowledge has informed the downstream generation of biologically faithful disease models, including a transgenic mouse model of the PB-RB subgroup. Remarkably, this model shows up-regulation of key markers of PB such as Crx, Asmt and Otx2 and substantiates early pinealocytes as the probable cell-of-origin for this PB subgroup.

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: Pediatric brain tumors are poorly immunogenic preventing current immunotherapies (i.e. checkpoint blockers) from having significant activity. Unlocking immunotherapy against these malignancies is predicated on reprogramming their immunogenicity. OBJECTIVE/METHODS: We developed a novel treatment platform, which leverages the use of clinically translatable lipid-nanoparticles (NPs) combined with tumor derived mRNA that simultaneously function as both vaccines and immunomodulating agents to reprogram the systemic/local microenvironments of pediatric brain cancers. RESULTS: Systemic tumor mRNA-NPs localize to lymphoid organs (i.e. liver, spleen lymph nodes) and to the intratumoral milieu, activating the immunologic microenvironment therein through release of type I interferon from plasmacytoid dendritic cells. This culminates in a CD4 and CD8 central memory T cell response against H3.1K27M murine gliomas. In immunologically resistant murine tumor models, RNA-NPs induce robust anti-tumor efficacy and mediate synergistic activity in settings where immune checkpoint inhibitors (i.e. anti-PD-L1 therapy) do not confer therapeutic benefit. We demonstrate safety of RNA-NPs in acute/chronic murine toxicity studies and in a client-owned canine (pet dog) diagnosed with a malignant glioma. In our first canine subject, RNA-NPs elicited activation of dendritic cells, release of type I interferon and activation of CD8+ T cells. CONCLUSION: RNA-NPs bypass MHC restriction and can be made readily available for all patients (and not only HLA specific haplotypes); they also provide a renewable antigen resource that can be used to continuously vaccinate patients for months/years after diagnosis. Through partnership with the Pacific Pediatric Neuro-Oncology Consortium (PNOC), we are in the final stages of FDA-IND submission before first-in-human trials.

Vincristine (VCR), a microtubule inhibitor that arrests the cell cycle by blocking metaphase of mitosis, is unique among the vinca alkaloids for causing polyneuropathy. Patients with increased risk of VCR neurotoxicity include the elderly and those with prior history of neuropathy-prone medical conditions. Identifying such risk factors prior to the development of neurotoxicity should be a goal prior to VCR administration. Clinicians should obtain a thorough medical and family history of neuropathies in any child scheduled to receive neurotoxic medications to avoid exacerbating an underlying disorder. We report a case of a young child with newly diagnosed medulloblastoma who started treatment on a VCR-containing chemotherapy regimen following surgery and craniospinal radiation. She subsequently developed severe peripheral polyneuropathy and new enhancement of the cranial and nerve roots following a relatively low cumulative dose of VCR and was diagnosed with previously unidentified Charcot–Marie–Tooth disease (CMTD) Type 1A. This case highlights that an evaluation of risk factors should be completed prior to initiation of neurotoxic chemotherapies and advocates for testing for inherited neuropathies such as CMTD even in asymptomatic patients when hereditary neuropathy is suspected.

PBTC-042 was a phase I trial of palbociclib to determine the maximum tolerated dose (MTD) and describe toxicities in children. Palbociclib is an oral, selective cyclin dependent kinase 4/6 inhibitor. METHODS: A rolling-6 design was utilized. Eligible patients were children ≥4 and ≤21 years-old with a progressive/refractory CNS tumor with intact retinoblastoma protein, measurable disease, and ability to swallow capsules. Pharmacokinetic studies were performed during the first course. Here, we report on the heavily pretreated stratum, which included patients who received >4 prior treatment regimens (either chemotherapy or biologic agent), and/or craniospinal irradiation, and/or myeloablative chemotherapy plus stem cell rescue. Palbociclib was initiated at 50 mg/m2/day for 21 consecutive days of a 28-day course. This was one dosage level below the MTD for the less heavily pretreated stratum (75 mg/m2). RESULTS: Fourteen eligible patients were enrolled (median age 12.8 years; male 79%). Eleven patients (79%) had either ependymoma or medulloblastoma. Four eligible and evaluable patients were enrolled at 50 mg/m2 with no DLTs. This prompted a dosage increase to 75 mg/m2. Ten eligible subjects were enrolled and 7 were evaluable for DLT assessment. One of 7 evaluable patients experienced a DLT (grade 3 thrombocytopenia). This established 75 mg/m2 as the MTD for more heavily pretreated patients. Mean ± SD palbociclib apparent oral clearance was 34.6 ± 18.4 L/h/m2. CONCLUSION: The MTD for palbociclib on a 3 week on/1 week off schedule in children with brain tumors is 75 mg/m2 and does not appear to be influenced by the degree of prior therapy.

Pineoblastomas (PB) are rare, aggressive pineal gland tumours with poor global OS of 50–70% and only 15–49% OS for patients

Immune checkpoint inhibitors that target programmed death receptor-1 (PD-1) have recently been shown to be a promising option for the management of recurrent mismatch repair (MMR) deficient GBM following radiotherapy. We report a case of a 9-year-old boy who presented with a 6 week history of frontal headaches and was found to have a left frontal lobe mass. Pathology obtained from a gross total resection (GTR) was consistent with classic GBM, WHO Grade IV. Neuroimaging four weeks following initial resection was remarkable for local recurrence. The patient underwent another GTR of the tumor at our center. While pathology again confirmed GBM, GlioSequencing of tumor tissue from second resection showed MSI-H, NF2 mutation p.R338H, NF1 mutations p.R2450* and pI193Yfs*11, TP53 mutations p.R213* and p.R273C, EGFR mutation, and multiple variants of uncertain significance. Germline testing was negative for MMR deficiency or other deleterious mutations. Parents opted to defer radiotherapy and consented to monotherapy treatment with Nivolumab (Opdivo, BMS pharmaceuticals, USA), a PD-1 inhibitor, at a dose of 3 mg/kg administered every two weeks. Our patient is now 22 months post-second resection and continues to receive Nivolumab without evidence of recurrent disease or adverse autoimmune effects from PD-1 blockade. He has remained in school with good academic performance and has exhibited no regression of functional status during the entirety of his treatment course. This case provides evidence of possible efficacy of PD-1 blockade without focal radiotherapy in this child with GBM and somatic MSI instability.

A phase II study was performed to assess vaccine-related toxicities and efficacy of x-ALT+tt-RNA DC following MAC +PBSC (group A) or NMAC +PBSC (group B) in pts with r-PNET. METHODS: Eligible pts underwent biopsy to confirm r-PNET and obtain tumor for vaccine preparation. Pts with local (group A) or metastatic (group B) disease received cytoreductive induction chemotherapy prior to either MAC (carboplatin+ thiotepa+ etoposide) or NMAC (cyclophosphamide + fludarabine) respectively and then received one dose of x-ALT (3 x 107cells/kg), PBSC, and 3 doses of bi-weekly intradermal tt-RNA DCs (107cells each). Patients were followed for survival and vaccine-related toxicities. Correlative studies included TCR RNA sequencing and measurement of serum cytokines. RESULTS: 20 evaluable pts (75% males) [Medulloblastoma 17, PNET 3; unifocal 40%] were treated on protocol (group A 7, group B 13). There were no significant vaccine-related toxicities. At a median follow-up of 8.5 months, 5 patients (all with medulloblastoma) are alive following vaccine therapy; 2 pts with SD (3.5+ and 6.5+ months) and 3 pts with PD that stabilized with salvage therapies (26+, 31+, and 46+ months respectively). One patient with medulloblastoma and bone marrow involvement who had PD despite MAC, had an almost complete response one month following x-ALT + tt-RNA DCs and TCR RNA sequencing demonstrated massive clonal expansion of T cells. Correlative studies are ongoing. CONCLUSIONS: x-ALT+tt-RNA DC following either MAC or NMAC is safe and shows signs of biologic and possible clinical activity in some pts with r-PNET.

Background We conducted an integrated analysis of clinical data to describe long-term effects of bevacizumab on growth and bone development in pediatric and adolescent patients with solid tumors. Procedure Clinical data were pooled from five phase I/II trials of bevacizumab versus chemotherapy: BERNIE, HERBY, and AVF4117s enrolled newly diagnosed patients, AVF3842s and AVF2771s enrolled patients with relapsed/refractory disease. Height, weight, body mass index (BMI), and bone-age data were pooled by treatment group. Growth charts were used to track and monitor growth in relation to a reference population of healthy children. Bone age was measured based on X-ray of the left hand and wrist. Analyses were exploratory/descriptive. Results Overall, 268 patients received bevacizumab ± chemotherapy and 135 received chemotherapy alone. Baseline characteristics were generally balanced. Median duration of long-term follow-up was 41.8 months (range, 2.4-75.1) with bevacizumab and 22.9 months (range, 2.8-69.2) with chemotherapy alone. Patients had age-appropriate baseline height and weight. Mean height and weight percentiles decreased over time in both treatment groups, but remained within the normal range (height: mean standard deviation score [SDS] range -2 to +3; weight: mean SDS range -2 to +1). Similar trends were seen in BMI. A tendency for reduced growth velocity relative to the reference population was observed at 6 months and 1 year in both groups, but there was no additional decrease for patients receiving bevacizumab. Conclusion Bevacizumab did not appear to have additional negative effects on growth or development of pediatric and adolescent patients with solid tumors.

Extensive clonal T cell expansion is associated with response to immunotherapy., In both human and murine systems, we have developed an adoptive cellular therapy platform against medulloblastoma and glioblastoma that uses dendritic cells pulsed with a tumor RNA transcriptome to expand polyclonal tumor-reactive T cells against a plurality of antigens within heterogeneous brain tumors. We demonstrate that peripheral TCR Vβ repertoire analysis after adoptive cellular therapy reveals that effective response to adoptive cellular therapy is concordant with massive in vivo expansion and persistence of tumor-specific T cell clones within the peripheral blood. In preclinical models of medulloblastoma and glioblastoma, and in a patient with relapsed medulloblastoma receiving adoptive cellular therapy, an early and massive expansion of tumor-reactive lymphocytes, coupled with prolonged persistence in the peripheral blood, is observed during effective therapeutic response to immunotherapy treatment.

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.

We performed a phase I study to assess feasibility, safety, and efficacy of ALT+DCV following HDC +ASCR (group A) or NMAC (group B) in pts with r-PNET. METHODS: Eligible pts underwent surgery to confirm diagnosis and obtain tumor for vaccine preparation. Pts with local (group A) or metastatic (group B) recurrence received 4 cycles of cytoreductive chemotherapy prior to either MAC (carboplatin + thiotepa + etoposide) (group A) or NMAC (cyclophosphamide + Fludarabine) (group B). Two dose levels of ALT were evaluated [3 x 10(6) or 3 x 10(7) cells/kg] with 3 intradermal biweekly DCVs (10(7)cells each). Safety evaluation for DLT assessment was 2 weeks past third DCV with monthly vaccines thereafter as available. Correlative studies for immune response included TCR sequencing and measurement of serum cytokines RESULTS: Ten pts (M5; F5) were treated on protocol (group A 1, group B 9). Nine evaluable pts received immunotherapy; DCV [median 3 doses (3-9)] + ALT [3 x10(6)/kg (n=4) or 3 x 10(7)/kg (n=5)]. There were no DLTs observed. At median of 21 months follow-up, 3 pts are alive with (n=2) or without (n=1) disease 33-42 months following treatment. TCR RNA sequencing demonstrates massive clonal expansion of T cells following ALT+DCV and positive correlation with clinical outcomes. Persistence of tumor-reactive (IFN-gamma secreting) T cell clones in the peripheral blood was observed 4 months after treatment in a patient with long-term disease control. CONCLUSIONS: ALT+DCV is feasible, safe, and shows signs of biologic and clinical activity in some pts with r-PNET.

Vincristine-induced neuropathy has been well described in the literature. However, few cases of underlying hereditary neuropathy revealed after vincristine therapy in pediatrics have been reported. We present a case of a 6 year old female with medulloblastoma. Patient presented with two weeks of headaches, gait instability, and vomiting. Pathology from tumor resection was consistent with SHH medulloblastoma. She started treatment per the SJMB12 study and received CSI+ focal boost for average risk disease followed by chemotherapy with vincristine, cisplatin, and cyclophosphamide. Ten days after Cycle 2, she developed lower extremity weakness that ascended to her upper extremities. Magnetic resonance imaging of the brain and spine noted thickening and enhancement of lower cranial nerves and the anterior and posterior spinal nerve roots. A presumptive diagnosis of Guillain-Barre syndrome was made and she received IVIG 1 mg/kg daily for three consecutive days. Vincristine was removed from her treatment regime given its known association with peripheral neuropathy. Further evaluation of patient noted presence of deep tendon reflexes and persistent foot drop, leading to consideration of hereditary neuropathy. Subsequent genetic testing revealed previously asymptomatic and undiagnosed CMT1A. Decision was made to exclude Cisplatin from her regime due to reported exacerbations of underlying peripheral neuropathy. At the time of this report, our patient is without disease three months post-treatment. She has returned to school and shown significant improvements with physical therapy. This case highlights the importance of early recognition of acute vincristine neurotoxicity as it may raise a suspicion of an underlying hereditary neuropathy.

Adoptive cellular therapy (ACT) using transfer of tumor-specific lymphocytes has emerged as a potent strategy for treatment of advanced and refractory malignancies. We have employed deep TCR repertoire sequencing approach to explore dynamics of T-cell immunity in the nine patients with recurrent medulloblastoma and PNETs undergoing adoptive cellular therapy (Re-MATCH protocol, FDA IND BB-14058). Total RNA was isolated from patient PBMC samples collected prior to adoptive cellular therapy and weekly for one month and then monthly following immunotherapy treatment. cDNA was generated with addition of a common adapter at 5’ end of cDNA using RACE technology. Raw sequencing data were preprocessed using MiXCR software. Further TCR repertoire analysis was performed using tcR R-package and VDJtools software. We observed remarkable dynamic changes in the TCR repertoire in peripheral blood following ACT in all patients. The blood samples collected after adoptive cellular therapy revealed that certain T-cells were clonally expanded after ACT, with an increasing number of “hyper-expanded” TCR clones (comprising >1% of all TCR beta or alpha sequences). Hyper-expanded TCR clones and increased TCR diversity following ACT was associated with radiographic response to ACT and prolonged progression-free and overall survival. Limited TCR expansion and diversity following ACT was observed in patients with short overall and progression-free survival. These findings support further study of the use of TCR sequencing to monitor responses to adoptive cellular therapy and suggest that TCR clonal expansion and increasing TCR diversity following treatment may be associated with positive clinical responses.

BACKGROUND Complex multi-modality treatment for children with brain tumors can cause major distress for patients and caregivers. Active coordination of medical and psychosocial services can improve QoL for affected patients and their caregivers. Few studies have evaluated manifestations of psychosocial distress in pediatric neuro-oncology patients and their caregivers. OBJECTIVE We aim to describe symptoms of psychosocial impairment in children with brain tumors and their caregivers in order to identify possible actionable determinants of psychological wellness. METHODS Children older than 3 years of age diagnosed with a malignant brain tumor receiving care at a large tertiary center and their caregivers underwent psychosocial assessment using the Kessler-10 and the Pediatric Symptoms Checklist. Questionnaires were voluntarily completed at routine visits. Rates of primary outcomes, patient and caregiver distress as defined by the respective scoring scales, were calculated for both groups. Correlation between patient and caregiver distress was evaluated with a Spearman’s Rho calculation. RESULTS A total of 30 patient-caregiver dyads consented to participation and 60 total questionnaires were analyzed. Median patient age was 10 years. 80% of caregivers (N= 24/30) scored high for symptoms of psychological illness on Kessler-10 assessments. Patients exhibited substantial psychosocial impairment in physical (N= 22/30), emotional (N= 18/30), cognitive (N= 12/30), and social (N= 26/30) subdomains of the PSC. There was a significant correlation between clinical manifestations of patient and caregiver psychosocial distress, specifically with regards to symptoms of anxiety (p < 0.05) and depression (p < 0.05). CONCLUSIONS Pediatric neuro-oncology patients and caregivers report considerable levels of psychosocial impairment, particularly in physical, cognitive, emotional, and social function, as well as fatigue and insomnia. The majority of patients and caregivers exhibited coinciding symptoms, suggesting that family-based intervention may improve psychosocial stressors. This hypothesis requires future study to determine optimal timing and methods for intervention.

Introduction: Medulloblastoma is the most common malignant brain tumor in children. Standard of care treatment for children ≥ 3 years has resulted in a cure rate of approximately 70 – 75%. However, treatment-related toxicity often has a major impact on long-term quality of survival.Areas covered: This article summarizes the epidemiology, clinical presentation, radiologic features, pathology, prognosis, risk stratification, molecular genetics and current and future treatment strategies of medulloblastoma.Expert opinion: Treatment of children with newly diagnosed medulloblastoma includes maximal surgical resection, risk-adapted craniospinal radiotherapy plus a focal boost to the tumor bed, and dose-intensive chemotherapy consisting of cisplatin, vincristine and cyclophosphamide and lomustine. Recent studies using next-generation sequencing have identified the complex molecular heterogeneity of this malignant tumor allowing a more precise identification of prognostic factors and specific oncogenic targets fo...

The treatment of children with embryonal brain tumors (EBT) includes craniospinal irradiation (CSI). There are limited data regarding the effect of CSI on pulmonary function.Protocol SJMB03 enrolled patients 3 to 21 years of age with EBT. Pulmonary function tests (PFTs) (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC] by spirometry, total lung capacity [TLC] by nitrogen washout or plethysmography, and diffusing capacity of the lung for carbon monoxide corrected for hemoglobin [DLCO(corr)]) were obtained. Differences between PFTs obtained immediately after the completion of CSI and 24 or 60 months after the completion of treatment (ACT) were compared using exact Wilcoxon signed-rank tests and repeated-measures models.Between June 24, 2003, and March 1, 2010, 303 eligible patients (spine dose: ≤ 2345 cGy, 201;2345 cGy, 102; proton beam, 20) were enrolled, 260 of whom had at least 1 PFT. The median age at diagnosis was 8.9 years (range, 3.1-20.4 years). The median thoracic spinal radiation dose was 23.4 Gy (interquartile range [IQR], 23.4-36.0 Gy). The median cyclophosphamide dose was 16.0 g/m(2) (IQR, 15.7-16.0 g/m(2)). At 24 and 60 months ACT, DLCO(corr) was75% predicted in 23% (27/118) and 25% (21/84) of patients, FEV1 was80% predicted in 20% (34/170) and 29% (32/109) of patients, FVC was80% predicted in 27% (46/172) and 28% (30/108) of patients, and TLC was75% predicted in 9% (13/138) and 11% (10/92) of patients. DLCO(corr) was significantly decreased 24 months ACT (median difference [MD] in % predicted, 3.00%; P = .028) and 60 months ACT (MD in % predicted, 6.00%; P = .033) compared with the end of radiation therapy. These significant decreases in DLCO(corr) were also observed in repeated-measures models (P = .011 and P = .032 at 24 and 60 months ACT, respectively).A significant minority of EBT survivors experience PFT deficits after CSI. Continued monitoring of this cohort is planned.

Purpose Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB). Patients and Methods Adult patients enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available. Results A total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH–MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS, and diffuse staining of P53 was associated with reduced PFS. Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses. Conclusion Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH–MB. Inadequate accrual of pediatric patients precluded conclusions in this population. Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor. Such inhibitors should be advanced in SHH-MB studies; however, molecular and genomic work remains imperative to identify target populations that will truly benefit.

We present three cases of genetically confirmed Gorlin syndrome with desmoplastic medulloblastoma (DMB) in whom tumor recurred despite standard therapy. One patient was found to have a novel germline missense PTCH1 mutation. Molecular analysis of recurrent tumor using fluorescent in situ hybridization (FISH) revealed PTEN and/ or PTCH1 loss in 2 patients. Whole exome sequencing (WES) of tumor in one patient revealed loss of heterozygosity of PTCH1 and a mutation of GNAS gene in its non-coding 3' -untranslated region (UTR) with corresponding decreased protein expression. While one patient died despite high-dose chemotherapy (HDC) plus stem cell rescue (ASCR) and palliative radiotherapy, two patients are currently alive for 18+ and 120+ months respectively following retrieval therapy that did not include irradiation. Infants with DMB and GS should be treated aggressively with chemotherapy at diagnosis to prevent relapse but radiotherapy should be avoided. The use of molecular prognostic markers for DMB should be routinely used to identify the subset of tumors that might have an aggressive course.

For decades, intracerebroventricular (ICV), or intraventricular, devices have been used in the treatment of a broad range of pediatric and adult central nervous system (CNS) disorders. Due to the limited permeability of the blood brain barrier, diseases with CNS involvement may require direct administration of drugs into the brain to achieve full therapeutic effect. A recent comprehensive literature review on the clinical use and complications of ICV drug delivery revealed that device-associated complication rates are variable, and may be as high as 33% for non-infectious complications and 27% for infectious complications. The variability in reported safety outcomes may be driven by a lack of consensus on best practices of device use. Numerous studies have demonstrated that employing strict aseptic techniques and following stringent protocols can dramatically reduce complications. Key practices to be considered in facilitating the safe, long-term use of these devices are presented.

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.

Background Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. Methods Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization. Results Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%. Conclusion Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) remains a devastating and incurable disease. The DIPG-BATs clinical trial incorporates diagnostic biopsy with molecularly determined treatment stratification. Here we present the initial genomic analysis of the DIPG-BATs cohort. METHODS: Children enrolled on the DIPG-BATs clinical trial underwent upfront diagnostic biopsies prior to commencement of therapy. RNA and DNA were extracted from single core biopsies and subjected to whole-genome sequencing (WGS) and RNA-sequencing. Tumor samples were also collected at autopsy if there was parental consent. RESULTS: Fifty-three patients were enrolled on study, of whom 50 underwent biopsy. There were no biopsy-related deaths. A mean of 5ug of RNA and 10ug of DNA were extracted from single frozen cores. WGS on 41 DIPG samples (including eight autopsy samples) revealed a mean mutation rate of 0.753 mutations per Mb. We confirmed TP53, PIK3CA, H3F3A, ACVR1, PPM1D, and HIST1H3B to be recurrently mutated in DIPG. Additional mutations were found in epigenetic modifiers including ASXL1. Copy-number analysis revealed PDGFRA to meet statistical significance as a recurrent amplification peak in DIPG (q