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Background There are limited data available on incidence and survival of patients with choroid plexus tumors (CPT). This study provides the most current epidemiological analysis of choroid plexus tumors from 2004 to 2017 in the United States. Methods Data on 2013 patients with CPT were acquired from the Central Brain Tumor Registry of the United States in collaboration with the Centers for Disease Control and Prevention (CDC) and the National Cancer Institute, from 2004 to 2017. CPT cases were classified by the following pathological subtypes: choroid plexus papilloma (CPP), atypical choroid plexus papilloma (aCPP), and choroid plexus carcinoma (CPC). Frequencies and age-adjusted incidence rates (AAIR) per 100 000 and rate ratios per 100 000 (IRR) were reported for age, sex, race, and ethnicity for each pathological subtype with 95% confidence intervals (95% CI). Using CDC’s National Program of Cancer Registries survival database, survival curves and hazard ratios (HRs) evaluated overall survival from 2001 to 2016. Results CPP had the highest overall incidence (AAIR: 0.034, 95% CI: 0.033–0.036), followed by CPC (AAIR: 0.008, 95% CI: 0.008–0.009) and aCPP (AAIR: 0.005, 95% CI: 0.005–0.006). Incidence was highest among children less than one year old among all subtypes (CPP AAIR: 0.278; aCPP AAIR: 0.140; CPC AAIR: 0.195), reducing as patients aged. Overall survival was worse among patients with CPC, being five times more likely to die compared to patients with CPP (HR: 5.23, 95% CI: 4.05–7.54, P Conclusions This analysis is the most current and comprehensive study in the US on the incidence and survival for CPT. Population based statistics provide critical information in understanding disease characteristics, which impact patient care and prognosis.

Background The Head Start treatment protocols have focused on curing young children with brain tumors while avoiding or delaying radiotherapy through using a combination of high-dose, marrow-ablative chemotherapy and autologous hematopoietic cell transplantation (AuHCT). Late effects data from treatment on the Head Start II (HS II) protocol have previously been published for short-term follow-up (STF) at a mean of 39.7 months post-diagnosis. The current study examines long-term follow-up (LTF) outcomes from the same cohort. Methods Eighteen HS II patients diagnosed with malignant brain tumors Results There was no significant change in Full Scale IQ at LTF compared to baseline or STF. Similarly, most domains had no significant change from STF, including verbal IQ, performance IQ, academics, receptive language, learning/memory, visual-motor integration, and externalizing behaviors. Internalizing behaviors increased slightly at LTF. Clinically, most domains were within the average range, except for low average mathematics and receptive language. Additionally, performance did not significantly differ by age at diagnosis or time since diagnosis. Of note, children treated with high-dose methotrexate for disseminated disease or atypical teratoid/rhabdoid tumor displayed worse neurocognitive outcomes. Conclusions These results extend prior findings of relative stability in intellectual functioning for a LTF period. Ultimately, this study supports that treatment strategies for avoiding or delaying radiotherapy using high-dose, marrow-ablative chemotherapy and AuHCT may decrease the risk of neurocognitive and social-emotional declines in young pediatric brain tumor survivors.

INTRODUCTION: Primary central nervous system germ cell tumors (CNS GCT) are a heterogeneous group of malignancies that can be divided into germinomas and non-germinomatous GCT (NGGCT), accounting for 2-3% of brain tumors in children/adolescents in the Western hemisphere. The study aim is to report the ability to adequately treat Brazilian patients with CNSGCT through a consortium protocol, reporting their treatment, response and survival. Methods: Since 2013, 58 patients with histologic and/or tumor marker (TM) diagnosis of germinoma with/without HCGβ levels ≤200mIU/ml (n=43), five of them between 100-200mIU/ml, received carboplatin/ etoposide (4 cycles) and NGGCT (n=15), received carboplatin/etoposide/cyclophosphamide (6 cycles), all followed by 18Gy ventricular field irradiation and primary site(s) boost. Autologous hematopoietic cell transplant (AuHCT) was undertaken for NGGCT slow responders. Results: Mean age 13.2 years, 42 males. Diagnosis was made by TM (n=19), surgery (n=25) and both (n=12). Two bifocal cases with negative TM and inconclusive biopsy were treated as germinoma. Primary tumor location was pineal (n=30), suprasellar (n=16), bifocal (n=11) and basal ganglia/thalamus (n=1). Eighteen had ventricular/spinal spread. Second-look surgery occurred in seven patients. For the germinoma group, 36 achieved complete responses (CR) after chemotherapy, seven showed residual teratoma/scar. For the NGGCT after 4/6 cycles, six patients showed CR, two failure/progression and seven partial responses (five with negative TM). Two with positive TM underwent AuHCT. Radiotherapy was utilized as described, except in three patients. Four NGGCT patients died (two disease progression, two other causes with no disease). Toxicity was mostly grade 3/4 neutropenia/thrombocytopenia during chemotherapy. At a median follow-up of 40 months, event-free and overall survival was 100% for germinoma and 64.5% NGGCT. Conclusion: The proposed treatment was feasible to be performed in a developing country, with suitable survival even with VFI dose reduction to 18Gy.

BACKGROUND/RATIONAL: Following initial irradiation sparing therapy, many young children with relapsed medulloblastoma can be salvaged with craniospinal irradiation (CSI). However, the interval to relapse is short and neurocognitive sequelae remain a major concern. The contribution of molecular subgrouping may help refine indications and modalities of salvage strategies in this population. METHOD: From a cohort of 151 young children with molecularly characterized relapsed medulloblastoma, subset analysis of the SHH medulloblastoma was conducted to describe the practice of salvage radiotherapy and associated post-relapse survival (PRS). RESULTS: Sixty-seven SHH medulloblastoma patients (46 M0; 54 GTR; 11 non-ND/MBEN) received salvage therapy with curative intent. Before relapse, 54 (80.6%) received conventional chemotherapy (CC), 13 (19.4%) high-dose chemotherapy (HDC), while seven had additional focal radiotherapy (fRT). Median time to relapse was 11.1 months (range 3.8-41.0) and 43.3% were localized. Thirty patients (16 localized relapse) underwent surgery. Forty-seven (71.2%) received salvage radiotherapy (20 with CC; 10 with HDC; 15 alone, two unknown). CSI and fRT accounted for 82% and 18% respectively. CSI median dose was 36Gy (range 18-39Gy). Ten patients (eight with localized relapse) received CSI doses ≤23.4Gy. Nineteen patients (28.8%) did not receive any radiotherapy (nine HDC; 10 CC only). Radiotherapy was associated with better 3-year PRS (73.0% versus 36.1%; p=0.001). All patients treated with CSI ≤ 23.4Gy were alive at median follow-up of 69 months(24-142). Six of nine patients treated with HDC without irradiation were alive at last follow-up. Sixty-three percent of patients received reduced dose CSI(≤23.4Gy), fRT, or no radiotherapy, and their PRS did not significantly differ from those who received CSI ≥ 30.6Gy (p = 0.54). CONCLUSION: While salvage CSI provided PRS benefit in this SHH medulloblastoma cohort, we report the use of reduced salvage radiotherapy and irradiation avoidance in 63% of the patients, with 60% alive at last follow-up.

The Outcome for relapsed NGGCT is poor. Salvage therapy usually consist of reinduction platinum-based chemotherapy regimen followed by high-dose-chemotherapy and autologous-stem-cell-rescue (HDC/AuSCR) and re-irradiation with no consensus on optimal management and usually associated with remarkable toxicity. We present a 12-year-old boy diagnosed with a localized pineal Non-Germinaoteous Germ Cell Tumors NGGCTs of mixed origin with elevated AFP he had ETV and biopsy started on COG ACNS0122 protocol after receiving first cycle (carbo/Etoposide) he developed acute renal failure investigation showed small dysplastic kidney to avoid nephrotoxicity of platinum agents chemotherapy changed to VBE (Vinblastine, Bleomycin and Etoposide) post 3rd cycle MRI showed increase in size of the pineal mass with normal tumor markers representing Growing Teratoma Syndrome He had total surgical resection of the tumor Pathology showed predominant teratoma component He received radiation therapy CSI then another 3 cycles of VBE 4 months following treatment completion he presented with elevated AFB and new right anterior temporal lesion Spinal MRI and CSF were negative. He had 2 cycles of Salvage Non-nephrotoxic 4-drug regimens GEMPIV Gemcitabine 800 mg/m2 days 1 and 14. Paclitaxel 80 mg/m2 days 1 and14, Irinotecan 50 mg/m2 daily for 5 days Vinblastine 6 mg/m2 weekly days 1,8,14 MRI after 2 cycles showed remission with undetectable AFP then 2 consolidation cycles of etoposide and thiotepa (HDC/AuSCR) The 3rd consolidation cycles were cancelled due to hematological toxicity During treatment phases chemotherapy was well tolerated doses were adjusted according to his GFR with renal conservative and supportive therapy.post (HDC/AuSCR) he experienced delayed hematological recovery with persistent thrombocytopenia responded to Eltrombopag then he had focal Temporal lobe irradiation Currently patients in remission with chronic stage 3 renal Insufficiency Conclusions: this case showed that relapsed intracranial NGGCT can be successfully salvaged without platinum-based chemotherapy in patients with renal insufficiency.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. While survival has improved in high-income countries (HIC), the outcomes for patients in low-middle-income countries (LMIC) are unclear. Therefore, we sought to determine the survival of children with Medulloblastoma at the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 1997 and 2013 in Peru. METHODS: Between 1997-2013, data from 103 children older than three years with Medulloblastoma were analyzed. Fourteen patients were excluded. The patients were split into two distinct cohorts, 1997 – 2008 and 2009 – 2013, corresponding with chemotherapy regimen changes. Event-free (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method, while prognostic factors were determined by univariate analysis (log-rank test). RESULTS: Eighty-nine patients were included; median age was 8.1 years (range: 3-13.9 years). The five-year OS was 62% (95% CI: 53 – 74%) while EFS was 57% (95% CI: 48 – 69%). The variables adversely affecting survival were anaplastic histology [compared to desmoplastic; OS: HR=3.4, p=0.03], metastasis [OS: HR=3.5, p=0.01; EFS: HR=4.3, p=0.004], delay in radiation therapy of 31-60 days [compared to ≤30 days; EFS: HR=2.1, p=0.04], and treatment 2009 – 2013 cohort[OS: HR=2.2, p=0.02; EFS: HR=2.0; p=0.03]. CONCLUSIONS: Outcomes for Medulloblastoma at INEN were low compared with HIC. Anaplastic sub-type, metastasis at diagnosis, delay in radiation therapy, and treatment in the period 2009 - 2013 negatively affected the outcomes in our study. Multidisciplinary teamwork, timely delivery of treatment and partnerships with loco-regional groups and colleagues in HIC is likely beneficial.

Background United States studies documenting time interval from symptom onset to definitive diagnosis for childhood central nervous system (CNS) tumors are more than a quarter-century old. The purpose of this study is to establish an accurate and contemporary Ohio baseline of the diagnostic interval for children with newly diagnosed CNS tumors. Methods Medical records were retrospectively reviewed for 301 children with newly diagnosed CNS tumors from January 2004 to August 2015 at Nationwide Children’s Hospital. We obtained comprehensive data on 171 patients (56.8%). Records were reviewed for age, gender, tumor type, presenting symptoms, number of health care visits prior to diagnosis, time interval (in months) from onset of symptoms to definitive diagnosis, and any associated genetic syndromes. Results Of the 171 patients with newly diagnosed CNS tumors, 25 children (14.6%) had a known cancer predisposition syndrome (all with neurofibromatosis type 1). Among the remaining 146 children, the median and mean time intervals from symptom onset to definitive diagnosis were 42 days and 138 days (range < 1 to 2190 days), respectively. Conclusions We have documented and quantified the contemporary delays in diagnosis of childhood brain tumors in central Ohio to serve as a benchmark for our future planned interventions to reduce the time interval from symptom onset to diagnosis through adaptation of the United Kingdom HeadSmart program throughout the state of Ohio and ultimately throughout the United States.

Aims Survival has been poor in several multi-center/national trials since the 1980s, either delaying, avoiding or minimizing brain irradiation in young children with medulloblastoma. The introduction of German regimens supplementing “standard” chemotherapy with both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), have reported encouraging outcomes. We performed a comparative outcomes analysis of these differing strategies for young children with desmoplastic/extensive nodular medulloblastoma. Method Data from 12 trials reported between 2005 and 2020 for children Results The German HIT-SKK’92 and HIT-SKK’00 trials incorporating HD-MTX and IVENT-MTX reported 85+/-8% and 95+/-5% 5-10-year EFS respectively; a third trial (ACNS1221) incorporating HIT-SKK therapy but without IVENT-MTX reported only 49+/-10% EFS. Three trials (Head Start I and II combined and CCG-99703) employing induction chemotherapy without HD-MTX, followed by one or three HDCx+AuHCR cycles, reported 3-5-year EFS of 67+/-16% and 79+/-11%. Two trials employing HD-MTX-containing induction chemotherapy (Head Start III and ACNS0334), followed by one or three HDCx+AuHCR cycles, reported 3-5-year EFS of 89+/-6% and 100%, respectively. Finally, four trials utilizing neither IVENT-MTX nor HDCx+AuHCR (UK-CNS-9204, CCG-9921, COG-P9934 and SJYC07) reported 2-5 year EFS of 35+/-11%, 77+/-9%, 58+/-8% and 53+/-9% respectively. Conclusion A trend towards better EFS for young children with desmoplastic/extensive nodular medulloblastoma is observed in trials including eitherHD-MTX and IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.

BACKGROUND Patients with relapsed CNS NGGCTs experience poor outcomes. Our aim to explore prognostic factors that may guide future clinical trials. METHODS A review of clinical trials that included patients with relapsed CNS NGGCTs was performed. RESULTS Seventy-four patients were identified; only 14 patients (19%) were long-term survivors. Patients who relapsed >24 months after initial diagnosis had a survival rate of 47% compared with 15% of patients who relapsed in 25 ng/ml at relapse (p= 0.0015). Patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy had a survival rate of 59% compared with 3% among patients who had less than CR/CCR by the end of therapy (p= 0.0001). Patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) at relapse had a survival rate of 33% compared with 9% of patients who did not receive HDCx/AuHCR at relapse (p=0.056). The extent of surgical resection, receiving radiotherapy, and beta-human chorionic gonadotropin levels at relapse were not statistically associated with improved outcomes. CONCLUSION Timing of relapse (>24 months after initial diagnosis), serum/CSF AFP

BACKGROUND The optimal management for children with recurrent choroid plexus carcinoma (CPC), is not established. We report two children with germline TP53 mutations, whose CPC relapses were managed with marrow-ablative chemotherapy and oral biologically-targeted therapies. PATIENTS: Patient A: A 17 months old male presented with non-metastatic bilateral CPC. A de novo mosaic germline TP53 mutation was identified. After near-total resections, 16 months of standard chemotherapy were administered; 18 months later, localized tumor growth developed, again near-totally resected. Two cycles of re-induction chemotherapy were administered followed by three cycles of thiotepa/carboplatin with autologous hematopoietic cell rescue (AuHCR) and subsequently 21 months of sirolimus and thalidomide, continuing without residual or recurrent disease. Patient B: A 30 months old male presented with left lateral ventricular non-metastatic CPC. A de novo TP53 germline mutation was identified. Following sub-total resection, craniospinal irradiation with boost was administered followed by eight cycles of standard chemotherapy; 18 months later, localized recurrence developed; gross total resection was followed by 15 months of standard dose chemotherapies; four months thereafter, a second local recurrence developed, again gross totally resected. He then received one cycle of high-dose cyclophosphamide followed by three cycles of thiotepa/carboplatin with AuHCR. Subsequently he received sirolimus and thalidomide for 12 months, complicated by progressive pancytopenia. A small localized CPC recurrence was noted, gross totally resected, concomitant with myelodysplastic syndrome; he underwent an allogeneic matched unrelated donor marrow transplantation. CONCLUSIONS Marrow-ablative chemotherapy with post-transplant targeted biological therapy may afford durable survival for select children with recurrent CPC.

BACKGROUND Since 2013, pediatric oncologists from Latin America have discussed neuro-oncology cases with experts from North America and Europe in a web-based “Latin American Tumor Board” (LATB). This descriptive study evaluates the feasibility of the recommendations rendered during the Board. METHODS An electronic questionnaire was distributed to physicians who received recommendations between October 2017 and October 2018, two months after their case presentation on the LATB. Physicians were asked regarding the feasibility of each recommendation given during the Board. Baseline case characteristics of all presented cases were obtained from anonymized minutes prepared after the presentations. RESULTS 36 physicians from 15 countries answered 103 of 142 questionnaires (72.5%), containing 283 recommendations. Physicians followed 60% of diagnostic procedural recommendations and 70% of therapeutic recommendations. Overall, 96% of respondents considered the recommendations applicable and useful. The most difficult recommendations to follow were genetic and molecular testing, pathology review, locally adapted chemotherapy protocols administration, neurosurgical interventions and access to molecular targeted therapies. The most cited reasons for not implementing the recommendations were lack of resources, inapplicable recommendations to that low-to-middle income country (LMIC) setting, and lack of parental consent. CONCLUSION The recommendations given on the LATB are frequently applicable and helpful for physicians in LMIC. Nevertheless, limitations in availability of both diagnostic procedures and treatment modalities affected the feasibility of some recommendations. Virtual tumor boards offer physicians from LMIC access to real time, high-level subspecialist expertise and provide a valuable platform for information exchange among physicians worldwide.

INTRODUCTION Primary central nervous system (CNS) germ cell tumors (GCT) account for 2–3% brain tumors children/adolescents in Western hemisphere. The report aim is to present the results of a Brazilian CNSGCT consortium protocol. METHODS Since 2013, 45 patients with histologic and/or tumor marker (TM) diagnosis of germinoma with/without HCGβ levels≤200mIU/ml (n=33), four between 100-200mIU/ml and NGGCT (n=12), received carboplatin/etoposide/cyclophosphamide (4–6 cycles), followed by 18Gy ventricular field irradiation and primary site(s) boost. Autologous bone marrow transplant (ABMT) was conducted for NGGCT low responders. RESULTS Mean age 12.9 years (4.7-20y), 34 males. Diagnosis was made by TM (n=9), surgery (n=19), both (n=15). Two bifocal cases, (-)TM were treated as germinoma. Primary tumor location was pineal (n=20), suprasellar (n=13), bifocal (n=11) and basal ganglia/thalamus (n=1). Fourteen had ventricular/spinal spread. Second-look surgery occurred in 5 patients. For the germinoma group, 26 achieved complete response (CR) after chemotherapy, seven showed residual teratoma/scar. For the NGGCT after 2/4 cycles, four patients showed CR, 2 failure/progression and 6 partial response (4 (-)TM). Two were submitted to ABMT. Radiotherapy was performed as described, except in three. One recurrence to date. Two patients died (endocrinologic complications/progression). Toxicity was mostly grade ¾ neutropenia/thrombocytopenia during chemotherapy. At a median follow-up of 38 months, OS was 100% for Germinoma and 85% NGGCT. CONCLUSION The treatment is tolerable and VFI dose reduction to 18Gy seems to preserve efficacy. Further follow-up is warranted to assess the NG group and the slow-responder patients.

Metabolism of drugs in infants and young children is significantly different from older individuals due to differences in distribution, protein-binding capacity, hepatic metabolism and renal excretion. To be consistent with Children’s Oncology Group (COG) guidelines, body surface area (BSA) was used to dose chemotherapeutics in children >3 years old enrolled on “Head Start” 4 clinical trial (HS 4). Four of 30 patients enrolled on HS 4 developed sinusoidal obstruction syndrome (SOS) while receiving induction chemotherapy with cisplatin, etoposide, vincristine, cyclophosphamide and high-dose methotrexate using BSA for dosing (mg/m2). Patients #1 and #2 were both 2-years old at diagnosis, received and tolerated the first two cycles with mg/kg dosing uneventfully, then turned 3-years old and received cycle #3 with mg/m2 dosing as per protocol guidelines, and developed SOS. Patient #3 was 3-years old at diagnosis, received induction chemotherapy with mg/m2 dosing, and developed SOS during the very first cycle. Patient #4 was 4-years old at diagnosis and received all 3 induction cycles with mg/m2 dosing, developed serious nephrotoxicity during cycle #1 followed by SOS during cycle #3. The HS 4 trial was amended and reopened after external, independent Data Safety Monitoring Board review to dose all chemotherapy drugs in children

BACKGROUND We report the responses, toxicities and long-term outcomes of gemcitabine, paclitaxel and oxaliplatin (GemPOx) regimen administered, in responsive patients, prior to single cycle marrow-ablative chemotherapy (thiotepa, etoposide and carboplatin) with autologous hematopoietic progenitor cell rescue (HDCx+AuHPCR). METHODS Since December 2009, 11 recurrent/refractory patients (10 MMGCT, 1 germinoma; 10 males; mean age 16.5 years, range 7–46 years) have been treated with up to four cycles of gemcitabine (800mg/M2), paclitaxel (170mg/M2) and oxaliplatin (100mg/M2) administered on one day at 14 days intervals. RESULTS All 11 patients were enrolled on a prospective multi-center trial, which was closed in October 2019. Three patients achieved complete remissions (tumor marker and/or imaging studies), five achieved partial remissions, two developed disease progression (PD), and one was withdrawn after one cycle for severe paclitaxel neurotoxicity followed by rapid tumor progression and death. One patient with PD after one cycle had pathologically-confirmed metastatic transformation to pure embryonal rhabdomyosarcoma, and rapidly expired. A second patient, with pure pineal choriocarcinoma, progressed after the second GemPOx cycle, ultimately died of tumor progression. Eight of the 11 responsive patients subsequently underwent HDCx+AuHPCR; five of these received some form of radiotherapy. Seven patients (six MMGCT, one germinoma) are alive and disease-free without recurrence for a mean of 94 months (range 74–118 months) since completion of therapy. CONCLUSION GemPOx is an effective re-induction regimen for patient with recurrent CNS germ cell tumors, with acceptable toxicities; when followed by marrow-ablative chemotherapy and subsequent irradiation/re-irradiation, the regimen produces encouraging long-term disease-free survival.

BACKGROUND Medulloblastoma (MB), the most malignant brain tumor of childhood has survival outcomes exceeding 80% for standard risk and 60% for high risk patients in high-income countries (HIC). These results have not been replicated in low-to-middle income countries (LMIC), where 80% of children with cancer live. Brazil is an upper-middle income country according to World Bank, with features of LMIC and HIC. METHODS We conducted a retrospective review of 126 children (0–18 years) diagnosed with MB from 1997 to 2016 at INCA. Data on patients, disease characteristics and treatment information were retrieved from the charts and summarized descriptively; overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier Method. RESULTS The male/female ratio was 1.42 and the median age at diagnosis was 7.9 years. Headache (79%) and nausea/vomiting (75%) were the most common presenting symptoms. The median time from onset of symptoms to surgery was 50 days. The OS for standard-risk patients was 69% and 53% for high-risk patients. Patients initiating radiation therapy within 42 days after surgery (70.6% versus 59.6% p=0.016) experienced better OS. Forty-five patients (35%) had metastatic disease at admission. Lower maternal education correlated with lower OS (71.3% versus 49% p=0.025). Patients who lived >40km from INCA fared better (OS= 68.2% versus 51.1% p=0.032). Almost 20% of families lived below the Brazilian minimum wage. CONCLUSIONS These findings suggest that socioeconomic factors, education, early diagnosis and continuous data collection, besides oncological treatment must be adressed to improve the survival of children with MB.

“Head Start” 4 (HS 4) is a prospective randomized clinical trial that tailors treatment based on medulloblastoma molecular subgroups and response to induction chemotherapy to compare the efficacy of one versus three (tandem) cycles of myeloablative therapy. Advances in RNA and DNA profiling have identified four core molecular subgroups of medulloblastoma with prognostic significance: Sonic Hedgehog (SHH) subtype, WNT subtype, Group 3, and Group 4. In HS 4 trial, we utilize a combination of histopathology and immunohistochemistry (pathology/IHC), as well as chromosomal microarray analysis (CMA) utilizing OncoScanTM (Thermo Fisher) to classify medulloblastoma samples into either SHH, WNT, or non-WNT/non-SHH (Group 3/4) subgroups at the time of diagnosis. NanoString based 22-gene assay is performed retrospectively to test concordance. We have pathology/IHC, CMA, and NanoString data on 26 infants and young children with medulloblastoma enrolled on HS 4. Pathology/IHC was able to assign samples to SHH, WNT, and non-WNT/non-SHH subgroups in all but two cases: one case was classified as Group 3, and the second as SHH by both CMA and NanoString. CMA was indeterminate in six cases, of which, pathology/IHC was able to assign all six samples aforementioned three subgroups. NanoString was indeterminate in two cases: one case was classified as SHH by CMA and pathology/IHC, and the second case was indeterminate by CMA but was assigned as non-WNT/non-SHH on pathology/IHC. There is excellent correlation between NanoString and combination of histopathology and CMA for core medulloblastoma subgrouping on HS 4. Methylation studies are ongoing.

BACKGROUND Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. METHODS Fluorescence in situ hybridization, mutation-specific immunohistochemistry, exome analyses, and/or targeted sequencing were performed on paired tumor samples from diagnostic and subsequent surgeries. RESULTS Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status occurred in 10 patients (40%), with acquisition of CDKN2A deletion in seven (including three who received chemotherapy [two with temozolomide] and one who received radiation) and loss in three (including one who received targeted therapy and radiation). A trend toward shorter time to progression was observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration (median: 5.5 versus 14.0 months [p=0.078]). CONCLUSIONS Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or radiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.

INTRODUCTION Irradiation-sparing approaches are used in young children with medulloblastoma (MB) given the vulnerability of the developing brain to neurocognitive impairment. Limited data are available following relapse for these patients. We aimed to describe the management and outcomes of young children with MB who relapsed after initial treatment without craniospinal irradiation (CSI). METHODS International retrospective study including patients with MB diagnosed between 1995-2017, ≤ 72 months old, initially treated without CSI, who subsequently relapsed. RESULTS Data are available for 66 patients. The median age at initial diagnosis was 27 months (range, 6-72). At diagnosis, 27 patients had metastatic disease. Initial therapy included conventional chemotherapy or with high-dose chemotherapy (HDC) in 30 and 36 patients, respectively. Eight (12.1%) received upfront focal irradiation. Molecular subgrouping was available for 27 (41%) patients. Ten were SHH, five group 3, six group 4 and six others were non-WNT/non-SHH. The median time from initial diagnosis to relapse was 13 months (range, 3-63). Relapse was local, disseminated, or combined in 39%, 32%, and 29%, respectively. The median time to death from relapse was 18 months. Curative intent therapy was given in 53 patients with irradiation (81%), conventional chemotherapy without HDC (40%), and HDC (25%). For patients who received irradiation, 85% received CSI (median dose 33 Gy, 18-41.4) and 15% focal irradiation. Ten patients received chemotherapy without salvage irradiation. The median follow-up time was 44 months (range, 4-255), 33 (62%) patients who underwent curative-intent therapy were alive, including 8/10 SHH, 2/3 group 3, 2/6 group 4, and 4/5 non-WNT/non-SHH. Three of four patients with SHH and treated without salvage radiotherapy are survivors. The 5-year OS for curative intent was 70%. CONCLUSION A substantial proportion of young children who relapse following irradiation-sparing strategies can be salvaged. A proportion of children with SHH MB can be salvaged without salvage radiotherapy.

INTRODUCTION Recent discoveries have provided valuable insight into the genomic landscape of pediatric low grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. METHODS Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and exome analyses were performed on paired tumor samples from primary diagnostic and subsequent surgeries. RESULTS 101 tumor samples from 48 patients (43 with 2 specimens, 5 with 3 specimens) from 3 institutions underwent testing. BRAF fusion and BRAFV600E status were conserved in 100% and 97% of paired specimens, respectively. No loss or gain of IDH1 mutations or FGFR1, NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. CDKN2A deletions were acquired in 7 patients (including 3 who received chemotherapy [2 with temozolomide] and 1 who received radiation), and were associated with a trend toward shorter time to progression (median: 5.5 vs. 13.0 months [p=0.08]). CONCLUSIONS Most targetable genetic alterations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or radiation. However, CDKN2A deletion acquisition was demonstrated and may define a higher risk group. Given potential for targeted therapies for tumors acquiring CDKN2A deletions, performing a biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.

BACKGROUND “Head Start” protocols have used autologous hematopoietic stem cell transplant (AuHSCT) for infants and young children with malignant brain tumors in order to avoid cranial irradiation. The post-AuHSCT practice for children with a brain tumor diagnosis varies greatly. The goal of this research study is to explore practices and attitudes about post-AuHSCT care for children with brain tumors. DESIGN: An anonymous REDCap survey link was provided to all site primary investigators and additional support personnel at “Head Start” institutions. The survey questions defined the role of the medical provider completing the form and explored the various practices relating to transition, management, communication and overall satisfaction. RESULTS Twenty-one individual replies have been received so far. The majority report that prophylactic medicines were discontinued upon WBC recovery; however, management of discontinuation was split evenly between the neuro-oncology and stem-cell transplant teams. Nearly half of responders follow T-cell recovery following transplant without immunology guidance. Post-AuHCT vaccination practices are highly variable, with no clear consensus. Lastly, most responders reported adequate ease of transition and communication between the neuro-oncology and transplant teams. CONCLUSIONS This work underscores the need for both multidisciplinary communication for children with brain tumors in the post-AuHCT period and for the development of standardized vaccination and other prophylaxis practices.

BACKGROUND Central nervous system (CNS) germinomas are radiotherapy (RT)-sensitive tumors with excellent survival. Current treatment strategies combine chemotherapy with RT to reduce the field and dose of RT. There is no standard treatment for germinomas originating in the basal ganglia/thalami (BGTG) given their rarity and poorly-defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have been previously utilized; however, the optimal strategy remains unclear. METHODS Retrospective multi-institutional analysis was conducted across 18 institutions in four countries. RESULTS For 46 cases with non-metastatic BGTG, the event-free survival (EFS) was 86.9% at both 5 and 10 years, while overall survival (OS) was 100%, and 95.7% respectively at 5 and 10 years. Median RT dose and range for the various treatment volumes were as follows: CSI (n=10): 2340 cGy (1980–3060 cGy), WBI (n=8): 2340 (1800–3000 cGy), WVI (n=14): 2340 cGy (1800–2550 cGy), focal (n=9): 3600 cGy (3060–5400 cGy). There was no statistically significant difference in the EFS based on RT modality (p=0.57), but EFS for subjects with CSI and WBI were both 100%. The three subjects who received chemotherapy alone had significantly lower EFS than those who received chemotherapy and RT (p=0.001), but were salvageable with RT. CONCLUSION In the largest study to date for BGTG, there were no significant differences in outcomes between patients who received CSI, WBI, WVI or focal RT. This group of patients should be included in future prospective clinical trials, and a more limited RT field may be considered.

BACKGROUND A standard-of-care has not been established for the management of DS patients who develop primary CNS GCTs – the most common CNS neoplasm in DS – despite being more susceptible to treatment-related adverse events. METHODS A review of the English-language medical literature between 1960 and 2020 was conducted. RESULTS Thirty-one cases of CNS GCTs in DS patients (median nine-years-old; 21 males) were reported; the majority (23/31) originated from East Asia. Twelve had germinomas (39%), 12 had non-germinomatous germ cell tumors (NGGCTs) (39%), and seven had teratomas (22%). Four patients (13%) died from tumor progression (one germinoma versus three teratoma). Seven patients (23%) died from treatment-related complications (four germinoma versus three NGGCT). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, and one from Moyamoya following radiation-therapy (RT) only. Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival (OS) was 58.1% for all patients, 52.5% for germinoma, 64.8% for NGGCT, and 60% for teratoma. Three-year OS for patients who received RT or chemotherapy was 63.6% and 59.6% respectively. Twenty patients (65%) remain alive (seven germinoma versus nine NGCCT versus four teratoma). Ten patients (32%) experienced serious treatment-related complications (five germinoma versus five NGGCT). CONCLUSIONS Patients with DS and CNS GCTs are at an increased risk of treatment-related complications. Therefore, a different therapeutic approach may need to be considered for this patient population in order to mitigate the treatment-related complications and long-term neurocognitive sequelae.

Brain tumors are now responsible for more deaths each year than any other childhood cancer. Current studies aim to discover key molecular drivers that can explain prognosis and serve as targets for new therapeutic approaches, reducing morbidity. In this study, we performed LC-MS/MS proteomics on a cohort of 28 primary diffuse astrocytoma formalin-fixed paraffin embedded samples (WHO Grades II-IV) from patients at Nationwide Children’s Hospital with a median follow-up time of 2.3 (0.6–20.2) years. Ingenuity Pathway Analysis was used to analyze the proteomic data after using both age and grade as covariates and only including proteins with p-values less than 0.05. The upregulation of a well-known oncogenic pathway, the Protein Kinase A signaling pathway, was significantly associated with greater risk of progression and death (P=5.5E-07 and P=4.6E-04). Integrin signaling, a pathway commonly suppressed in cancer, was similarly downregulated in those with greater risk of progression and death (P=3.3E-04 and P=1.7E-07). A global upstream analysis of the proteomic data also predicted activation of the oncogene MYCN in those who performed poorly, supporting previous studies. When comparing grade II (n=10) to grade III (n=8) and IV (n=10) primary tumors, the pathway most upregulated in higher histopathological grades was EIF2 Signaling (P=4.9E-49). This pathway has previously been associated with resistance in adult glioblastoma. These pathways, and the proteins detected within, may provide novel means by which to better understand and treat pediatric diffuse gliomas. Ongoing studies are in progress to understand how these pathways drive aggressiveness and differ from adult astrocytomas.

BACKGROUND About one-third of children with primary CNS MMGCT experience incomplete responses to initial induction chemotherapy prior to irradiation, many of whom will subsequently relapse. Such high-risk patients are variably defined as having initial alpha-fetoprotein (AFP) elevations exceeding 1,000ng/mL, predominant histopathologies of malignant non-germinomatous GCT and incomplete responses to induction chemotherapy. Drugs targeting GCT-specific molecular markers have been identified for non-germinomatous GCT elements but have yet to be incorporated into prospective clinical trials. Four children with clearly identified HR-MMGCT characteristics have been treated on an innovative pilot regimen incorporating intensified chemotherapy and molecularly targeted agents, with avoidance or minimization of irradiation. METHODS Four children (two with pure suprasellar embryonal carcinoma (EC) - one with Down syndrome and the other with pre-diagnosis cognitive dysfunction; one with initial serum AFP exceeding 7,000ng/mL and yolk sac tumor (YST)+EC+Teratoma pathology; one with initial serum AFP exceeding 1,000ng/mL) were treated with 3 cycles of “standard” induction chemotherapy (ACNS1123), followed by 1–3 transplant cycles (thiotepa/carboplatin) each with complete radiographic and tumor marker responses. Two children with pure EC subsequently received six cycles of brentuximab-vedotin without irradiation and remain disease-free off therapy for 2–4 years. One child with YST+EC+Teratoma has subsequently received reduced dose craniospinal irradiation and pineal region boost, and will receive oral everolimus, erlotinib, palbocyclib and intravenous brentuximab-vedotin. The fourth child with YST+MT will commence everolimus, erlotinib and palbocyclib without irradiation. CONCLUSION This treatment strategy for HR-MMGCT patients provides preliminary tolerance and response data justifying extension to a multi-center trial.

BACKGROUND Infiltrative astrocytomas in children and young adults pose a treatment challenge due to the difficulty of achieving gross total resection and tumor resistance to irradiation and chemotherapy. Histopathologic grade is an essential part of determining prognosis and treatment, but it is subjective and provides limited understanding of the molecular mechanisms underlying tumor development and progression. METHODS We performed liquid chromatography/mass spectrometry (LC/MS-MS) on 28 FFPE samples of primary infiltrative astrocytomas (10 grade II, 8 grade III and 10 grade IV – WHO classification) from Nationwide Children’s Hospital (NCH). Initial unsupervised clustering was performed. Lasso regression yielded a protein signature separating low- and high-grade tumors which was validated using a similar cohort of pediatric and young adult infiltrative astrocytomas from the Proteomic Data Commons (PDC) (n=28) of the National Cancer Institute. RESULTS Unsupervised clustering of NCH samples essentially recapitulated grade and lasso regression yielded a 10-protein signature that distinguished grade II from grade III/IV tumors. This 10-protein signature when applied to the PDC validation dataset, accurately predicted grade for 89.3% of the tumors (p=0.00014). CONCLUSIONS We identified a quantitative protein signature that can reliably distinguish between low- and high-grade infiltrative astrocytomas from FFPE tissue. Further validation will enable the development an objective prognostic proteomic clinical test that complements and may outperform current histopathological strategies. Additionally, proteomic profiling of tumors will clarify the molecular mechanisms contributing to treatment resistance and tumor progression and help identify novel treatment targets. Independent functional validation and characterization of proteins is ongoing.

BACKGROUND We report the human and material resources available in Chilean institutions providing pediatric neuro-oncology services. METHODS A cross-sectional survey was distributed to 17 hospitals providing pediatric neuro-oncology services (Programa Infantil Nacional de Drogas Antineoplásicas (PINDA) centers=11, Private=6). RESULTS Response rate was 71% (PINDA=8; Private=4). Pediatric neuro-oncology services were mainly provided within general hospitals (67%). Registries for pediatric central nervous system (CNS) tumors and chemotherapy-related toxicities were available in 100% and 67% of centers, respectively. Children with CNS tumors were treated by pediatric oncologists in 92% of institutions; none were formally trained in neuro-oncology. The most utilized treatment protocols were the national PINDA protocols followed by the Children’s Oncology Group protocols. All World Health Organization essential medicines for childhood cancer were available in more than 80% of participating institutions except for gemcitabine, oxaliplatin, paclitaxel, and procarbazine. The median number of pediatric neurosurgeons per institution was two (range,0–8). General neuro-radiologists were available in 83% of institutions. Pathology specimens were sent to pediatric neuropathologists (33%), neuropathologists (25%), adult pathologists (25%), and pediatric pathologists (16.7%). In-house pediatric radiation oncologists were available in 25% of centers. Intensity-modulated radiotherapy, conformal radiotherapy and cobalt radiotherapy were utilized by 67%, 58% and 42% of hospitals, respectively. Only one center performed autologous hematopoietic cell transplant for pediatric CNS tumors. CONCLUSIONS These results provide a glimpse into the pediatric neuro-oncology services available in Chile. A wide range of up-to-date treatment modalities is available for children with CNS tumors in Chile. Establishing formal pediatric neuro-oncology training may be beneficial.

BACKGROUND Rhabdoid predisposition syndrome is characterized by germline alterations in SMARCB1 or SMARCA4, leading to synchronous or metachronous central nervous system (CNS) and extra-CNS rhabdoid tumors. Rare survivors have been reported to date. METHODS We describe the molecular profiling and treatment regimen of three patients with synchronous atypical teratoid/rhabdoid tumor (ATRT) and malignant rhabdoid tumor of the kidney (MRT-K). All patients underwent radical nephrectomy of the kidney, and gross total resection of the primary CNS tumor was achieved for two patients. An intensive chemotherapy regimen was administered; an induction phase based on the modified Third Intergroup Rhabdomyosarcoma Study (IRS-III) for ATRT followed by a consolidation phase with three cycles of high-dose chemotherapy and autologous hematopoietic progenitor cell rescue, without irradiation. All three patients were enrolled on an institutional comprehensive genomic profiling protocol. RESULTS A germline focal 22q deletion, including SMARCB1, was detected in two patients, while the third patient had a maternally-inherited heterozygous frameshift variant in SMARCB1. Somatic loss of heterozygosity of 22q was identified in all patients, resulting in biallelic inactivation of SMARCB1. Divergent tumor subgroups were described using DNA methylation. The three MRT-K samples were classified as MYC subtype. One ATRT was classified as SHH while the other as TYR. One patient is currently three years off-therapy without evidence of disease, while the other two patients have completed the consolidation phase without recurrent disease. CONCLUSION Molecular profiling of CNS and extra-CNS rhabdoid tumors revealed different epigenetic subgroups. An intensive multimodal therapeutic approach without irradiation may achieve prolonged survival.

Children with brain tumors often carry germline mutations known to contribute to tumorigenesis and treatment response; however, little is known about how these mutations impact developmental and behavioral outcomes. As the molecular mechanisms governing cancerous and normal tissues expand, we hypothesize that specific germline variants may impact baseline neurocognitive function and/or treatment-induced toxicities. In this pilot study, ten children on the Head Start 4 (HS4) clinical trial diagnosed with medulloblastoma were assessed for baseline adaptive functioning using the Adaptive Behavior Assessment System Third Edition (ABAS-III) and germline whole-exome sequencing was performed. After filtering for high impact variants, Welch’s T-tests were used to identify mutations associated with lower ABAS-III General Adaptive Composite (GAC) scores, reflecting developmental and adaptive behavior delays compared with peers their age. We found twenty genes with alterations associated with lower scores with p-values less than 0.05. Genes found to be significant included LAMC1 (p=0.04) and KRTAP1-1 (p=0.045), which encode members of the laminin and keratin family respectively and are involved in extracellular matrix adhesion. Mutations in PITX1, a known suppressor of RAS, were also associated with lower ABAS-III GAC scores (p=0.007). We hypothesize that additional analyses of HS4 patients will reveal alterations in cell-to-cell communication and signal transduction pathways, common molecular perturbations in tumors that would likely impact central nervous system function. Validation studies are essential to improve our understanding of the functional impact of germline variants on both tumor and regular tissue biology, allowing for novel strategies to circumvent these delays.

Brain and central nervous system (CNS) tumors found in adolescents and young adults (AYA) are a distinct group of tumors that pose challenges not only to treatment but also to reporting. Overall, cancer that occurs in this age group is biologically distinct from those that occur in both younger and older age groups1,2 posing significant challenges for clinicians. The most commonly diagnosed histologies in AYA vary from those in both children age (0-14 years), and older adults (40+ years).3,4 Prognosis and expected survival also varies between younger and older adults, with those who are diagnosed with brain and CNS tumors at younger ages having significantly longer survival. Despite this survival advantage, recent analyses have reported that while cancer survival has been improving overall, AYA have not experienced these same increases in survival and in some cases may have worse survival than those cancers diagnosed in persons over age 40 years.5 This report provides an in depth analyses of the epidemiology of brain and CNS tumors in adolescents and young adults in the United States (US), and is the first report to provide histology-specific statistics in this population for both malignant and non-malignant brain and other CNS tumors. In 2006, the National Institutes of Health, the National Cancer Institute (NCI) and the LiveStrong Young Adult Alliance conducted a Progress Review Group to investigate AYA Oncology entitled Research and care imperatives for adolescents and young adults with cancer: A Report of the Adolescent and Young Adult Oncology Progress Review Group. This group established the standard age range for the AYA group as 15-39 years. This is the age range used by the Surveillance Epidemiology and End Results (SEER) program of the NCI, as well as in the 2015 CBTRUS Statistical Report.3,6 Brain tumors and other CNS tumors are less common in AYA than in older adults, but they have a higher incidence than brain tumors in children (age 0-14 years).3 Non-malignant tumors are significantly more common in AYA than children (Average annual age adjusted incidence in age 15-39 years: 6.17 per 100,000; age 0-14 years: 0.79 per 100,000), while malignant tumors are slightly more common in those age 0-14 years (Average annual age adjusted incidence in 15-39 years old: 3.26 per 100,000; 0-14 years old: 3.73 per 100,000). While a rare cancer overall, brain and CNS tumors are among the most common cancers occurring in this age group (4.4% of all cancers in those age 15-39 years as compared to 32.4% in children age 0-14 years, and 2.2% of cancers in adults age 40+ years).3,4,7 Malignant brain and CNS tumors are the 11th most common cancer and the 3rd most common cause of cancer death7,8 in the AYA population. Incidence rates of brain tumors overall as well as specific histologies vary significantly by age. It is, therefore, important to provide an accurate statistical assessment of brain and other CNS tumors in the adolescent and young adult population to better understand their impact on the US population and to serve as a reference for afflicted individuals, for researchers investigating new therapies and for clinicians treating patients.

BACKGROUND Few neuroimaging studies of children with brain tumors treated with chemotherapy without radiation exist, and the neuropsychological effects of chemotherapy remain unclear. We aimed to differentiate the effects of surgery and chemotherapy on brain microstructure and cognition. METHODS Twenty-eight children with a history of posterior fossa tumor (17 treated with surgery alone; 11 treated with surgery + chemotherapy), and 21 sibling controls (n= 49) underwent diffusion tensor imaging (DTI) and neuropsychological assessment a mean of 4.5 (surgery group) to 9 years (surgery + chemotherapy group) after treatment. Psychometric measures focused on general intelligence, executive functions, processing speed, learning and memory, and social-emotional functioning. Age at diagnosis and time since diagnosis were covariates in the analyses. Group differences in DTI findings and psychometric scores, and correlations between psychometric scores and DTI results were examined. RESULTS Mean fractional anisotropy (FA) in the prefrontal cortex, white matter tracts, hippocampus, putamen, globus pallidus, thalamus, and pons were significantly (z≥ 2SD) lower in children treated with surgery + chemotherapy compared to those treated with surgery alone. In neuropsychological evaluation, the patient groups differed only in receptive vocabulary (p= 0.05), with children treated with surgery + chemotherapy scoring lower. Both patient groups scored lower than healthy sibling controls on measures of visuoconstructional reasoning (p= 0.02) and delayed visual (p= 0.02) and spatial memory (p= 0.01). Lower FA in the uncinate fasciculus and higher FA in the right thalamus associated with higher scores on general intelligence (p= 0.003, p= 0.002), and higher FA in the right thalamus associated with higher scores on spatial learning (p= 0.01) and memory (p= 0.01) in children treated with surgery + chemotherapy. CONCLUSIONS Chemotherapy is associated with injury to the microstructure of white and gray matter and neuropsychological deficits not seen in children with posterior fossa tumors treated with surgery alone.

BACKGROUND Children with pediatric low grade glioma’s (PLGG) harboring BRAF V600E mutation have poor outcome due to relative resistance to chemo-radiation and higher risk of malignant transformation. However, the role of targeted BRAF inhibition in these tumors is poorly defined. METHODS We assembled an international cohort of children with BRAF V600E mutant gliomas treated with BRAF inhibition, from 29 centers participating in the PLGG taskforce, and collected response, survival and molecular parameters. RESULTS Sixty-seven patients were treated with BRAFi (56 PLGG and 11 high grade gliomas) for a median time of 17.4 months (6 – 61 months), with 13 PLGG treated upfront. Objective responses was observed in 80% of PLGG patients compared to 28% with conventional chemotherapy (p< 0.001). Rapid responses were observed in most PLGG patients (median of 4 months), sustained in 86% of tumors up to 5 years while on therapy. In contrast, only 36% of PHGG responded to BRAFi with all but one tumor progressing within 18 months. Seventeen patients with PLGG discontinued BRAFi and 76.5% (13/17) progressed rapidly after discontinuation (median time 2.3 months). However, upon re-challenge with BRAFi therapy, 90% achieved an objective response. Poor prognostic factors to conventional therapies such as concomitant homozygous deletion of CDKN2A or H3K27M mutation were not associated with lack of response to BRAFi. Overall these responses translated to 2-year progression-free survival of 0.636 (95%CI 0.505–0.802) and 0.43 (95% CI 0.32–0.57) for BRAFi and chemotherapy treated BRAF V600E PLGG respectively (p=0.003). CONCLUSION The use of BRAFi results in objective, robust and durable responses in BRAF V600E PLGG and is associated with favorable survival. Larger prospective studies will be required to determine appropriate regiments, and long-term functional outcomes with BRAFi therapy in childhood gliomas.

BACKGROUND/OBJECTIVE Survival had been poor in several multi-center/national studies since the 1980s attempting to delay, avoid or minimize brain irradiation in young children with medulloblastoma. The introduction of regimens in Germany incorporating both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, as well as regimens in North America incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), have reported encouraging outcomes. The objective of this report is to perform a comparative outcomes analysis of these differing strategies. METHODS Data from 17 prospective multi-center trials published between 1990 and 2018 for children under six years old with medulloblastoma were reviewed; event-free (EFS) and overall survivals (OS) were compared. RESULTS Two trials using full-dose cranio-spinal irradiation with or without chemotherapy reported 5-year survivals of 32–38%. Three trials using standard chemotherapy with delayed irradiation reported 2-4-year EFS and OS of 23–34% and 31–46%. Two trials employing standard chemotherapy without irradiation reported 3-5-year EFS and OS of 22–33% and 34–43%. Four trials incorporating HD-MTX with or without IVENT-MTX reported 5-10-year EFS and OS of 56–59% and 67–80%, and 31% and 59% respectively; one trial with HD-MTX without IVENT-MTX for localized desmoplastic/nodular medulloblastoma (DN-MB) reported 2-year EFS and OS of 52% and 92%. Finally, five trials employing induction chemotherapy, with or without HD-MTX, followed by single or tandem HDCx+AuHCR have reported 3-5-year EFS and OS of 45–60% and 60–70%. CONCLUSIONS The best survivals are observed in trials including HD-MTX and IVENT-MTX or including HD-MTX during induction followed by HDCx+AuHCR. Because histology/biology (classic and large cell/anaplastic versus DN-MB; SHH versus non-SHH subtypes) have crucial prognostic roles, EFS and irradiation-free survival advantages require analysis in these settings. The benefit of these trials appears true for all young children with medulloblastoma. Risk-adapted treatment stratification for young children may be improved by molecular profiling of SHH- and non-SHH medulloblastoma.

The CBTRUS Statistical Report: Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007–2011 comprehensively describes the current population-based incidence of primary malignant and non-malignant brain and CNS tumors in children ages 0–14 years, collected and reported by central cancer registries covering approximately 99.8% of the United States population (for 2011 only, data were available for 50 out of 51 registries). Overall, brain and CNS tumors are the most common solid tumor, the most common cancer, and the most common cause of cancer death in infants and children 0–14 years. This report aims to serve as a useful resource for researchers, clinicians, patients, and families.

BACKGROUND: The safety of intra-ventricular or intrathecal monotherapy with topotecan, thiotepa and etoposide has previously been demonstrated in several publications. To our knowledge, the utility of the combination topotecan, thiotepa and etoposide through an intraventricular reservoir as a treatment strategy has never been documented. DESIGN: We describe 8 patients who underwent multi-agent intra-ventricular chemotherapy at Nationwide Children’s Hospital with topotecan, thiotepa and etoposide. The pathological diagnoses included 3 children with medulloblastoma, 2 with ependymoma (1 child, 1 adult), 1 child with AT/RT (atypical teratoid/rhabdoid tumor) and 2 children with atypical malignant tumors with neuraxis dissemination. All intra-ventricular chemotherapy was administered in the setting of relapsed disease concomitant with other forms of systemic chemotherapy. RESULTS: Patients received intra-ventricular chemotherapy from 2 to 84 weeks (median: 8.5 weeks). Four patients died of progressive disease. Of the 4 living patients, one continues on therapy nearly two years from initiation (ependymoma), one has progressive disease (fibromyxoid sarcoma), one has stable disease (primitive neuroepithelial tumor) and one (medulloblastoma) is proceeding to transplant in a minimal disease state. Although we do report several children with myelosuppression, this was in the setting of heavily pre-treated and concurrently-treated patients. Furthermore, we report no headaches, seizures, other neurological toxicities, bleeding or infections from this treatment strategy. CONCLUSIONS: We have documented the safety and tolerability of multi-agent intra-ventricular chemotherapy, which can be performed quickly and effectively in the ambulatory clinic. The utilization of multi-agent intra-ventricular chemotherapy could provide an alternative treatment regimen, in combination, for patients with relapsed disease.

Leptomeningeal metastasis remains a difficult clinical challenge. Some success has been achieved by direct administration of therapeutics into the cerebrospinal fluid (CSF) circumventing limitations imposed by the blood brain barrier. Here we investigated continuous infusion versus bolus injection of therapy into the CSF in a preclinical model of human Group 3 medulloblastoma, the molecular subgroup with the highest incidence of leptomeningeal disease. Initial tests of selected Group 3 human medulloblastoma cell lines in culture showed that D283 Med and D425 Med were resistant to cytosine arabinoside and methotrexate. D283 Med cells were also resistant to topotecan, whereas 1 µM topotecan killed over 99% of D425 Med cells. We therefore introduced D425 Med cells, modified to express firefly luciferase, into the CSF of immunodeficient mice. Mice were then treated with topotecan or saline in five groups: continuous intraventricular (IVT) topotecan via osmotic pump (5.28 µg/day), daily bolus IVT topotecan injections with a similar daily dose (6 µg/day), systemic intraperitoneal injections of a higher daily dose of topotecan (15 µg/day), daily IVT pumped saline and daily intraperitoneal injections of saline. Bioluminescence analyses revealed that both IVT topotecan treatments effectively slowed leptomeningeal tumor growth in the brains. Histological analysis showed that they were associated with localized brain necrosis, possibly due to backtracking of topotecan around the catheter. In the spines, bolus IVT topotecan showed a trend towards slower tumor growth compared to continuous (pump) IVT topotecan, as measured by bioluminescence. Both continuous and bolus topotecan IVT showed longer survival compared to other groups. Thus, both direct IVT topotecan CSF delivery methods produced better anti-medulloblastoma effect compared to systemic therapy at the dosages used here.

The BRAF-V600E mutation is found in 15–20% of pediatric low grade gliomas (PLGG) and result in worse outcome and higher risk of transformation to high grade gliomas (PHGG). Although ongoing trials are assessing the role of BRAF inhibitors (BRAFi) in these children, data are still limited. We aimed to report overall response rates and predictors of outcome in childhood BRAF-V600E gliomas. We collected clinical, imaging and molecular information of patients treated with BRAFi outside trials from centers participating in the PLGG taskforce. Response was calculated by RANO criteria and follow up data were collected for all patients. Sixty-six patients were treated with BRAFi (55 PLGG and 11 PHGG); median follow-up time was 1.5 years (0.1-5y). In PLGG, objective response (tumor reduction of >25%) was observed in 77% compared to 15% in a cohort treated with conventional chemotherapy (pCDKN2A deletion was not associated with lack of response, while specific enhancing patterns correlated strongly with response to BRAFi. Two-year PFS for the BRAF-V600E PLGG was 74% vs 47% for BRAFi vs chemotherapy, respectively (p=0.02). Our data reveal rapid, dramatic and sustained response of BRAF-V600E PLGG to BRAFi. These are in contrast to BRAF-V600E PHGG and non-enhancing PLGG. Additional molecular analyses are being performed to identify poor responders and emerging mechanisms of resistance in these tumors.

Background. Cure rates among children with brain tumors differ between low-income and high-income countries. To evaluate causes of these differences, we an- alyzed aspects of care provided to pediatric neuro-oncol- ogy patients in a low middle-income South American country. Methods. Three methods were used to evaluate treat- ment of children with brain tumors in Paraguay: (1) a quantitative needs assessment questionnaire for local treating physicians, (2) site visits to assess 3 tertiary care centers in Asuncion and a satellite clinic in an un- derdeveloped area, and (3) interviews with health care workers from relevant disciplines to determine their per- ceptions of available resources. Treatment failure was defined as abandonment of therapy, relapse, or death. Results. All 3 tertiary care facilities have access to che- motherapy and pediatric oncologists but lack training and tools for neuropathology and optimal neurosurgery. The 2 public hospitals also lack access to appropriate ra- diological tests and timely radiotherapy. These results demonstrate disparities in Paraguay, with rates of treat- ment failure ranging from 37% to 83% among the 3 facilities. Conclusions. National and center-specific deficiencies in resources to manage pediatric brain tumors contribute to poor outcomes in Paraguay and suggest that both national and center-specific interventions are warranted to improve care. Disparities in Paraguay reflect different levels of governmental and philanthropic support, program development, and socio-economic status of pa- tients and families, which must be considered when de- veloping targeted strategies to improve management. Effective targeted interventions can serve as a model to develop pediatric brain tumor programs in other low- and middle-income countries.

BACKGROUND: We report two cases of infantile tectal gliomas initially concerning on biopsy for high-grade features, but which are proving over time to have indolent clinical courses. Case I. A three-months-old female presented with hydrocephalus and a small tectal mass; she underwent an endoscopic third ventriculostomy (ETV). The first follow-up MRI performed 5 months later showed relief of hydrocephalus but marked increase (three- to four-fold) in mass size, likely due to decompression post-alleviation of hydrocephalus. A biopsy yielded a tiny fragment of diffuse low-grade glioma, low Ki-67; IHC for H3.3 K27M was initially reported as mutant, but on more recent review as indeterminate, in view of the tiny tumor fragment and high background staining. Therapeutic recommendations included proton-beam irradiation, marrow-ablative chemotherapy, conventional-dose chemotherapy - and observation only. The parents elected careful follow-up. Now 16 months following biopsy, the child is developing well and the MRI is stable, with advanced imaging characteristics of a low-grade glial lesion. Case 2. A male was diagnosed in utero with hydrocephalus, a post-natal MRI confirming this and revealing a small tectal mass. An ETV and biopsy were performed, yielding a tiny tumor fragment; pathology was consistent with a diffuse glial tumor, with rare mitoses; IDH1 and ATRX intact, P53 negative, GFAP positive and Ki67 20–30%. The tumor was deemed a high-grade glioma. Insufficient tissue for sequencing was available. The infant has been followed with close follow-up MRI scans with advanced imaging, which remain consistent with a low-grade glioma, and continues stable at 3 months since birth; a repeat biopsy is planned concomitant with shunt revision. CONCLUSION: Infants with tectal gliomas are rare, and anecdotally never undergo progression to high-grade. In the absence of definitive sequencing data, extreme caution should be exercised in offering treatment recommendations.

Background: High-dose chemotherapy with autologous hematopoietic cell rescue (AuHCR) is a potentially curative approach used in the management young children with medulloblastoma), with the additional benefit of avoiding the late effects of craniospinal irradiation (CSI). We report the outcome of infants and young children with classic and large cell/anaplastic (LCA) medulloblastoma treated on “Head Start (HS)” III, a prospective, multi-national clinical trial. Methods: Between April 2003 and December 2009, 92 children with newly-diagnosed medulloblastoma were enrolled amongst 29 participating institutions. All children were to receive 5 induction cycles (vincristine, cisplatin, cyclophosphamide, etoposide, high dose methotrexate - cycles 1, 3, 5), and vincristine, cyclophosphamide, oral VP-16 and temozolomide (cycles 2, 4), followed by 1 consolidation cycle of myeloablative chemotherapy (thiotepa, carboplatin, etoposide) and AuHCR. Only children between 6-10 years old or with residual tumor pre-consolidation, were to receive irradiation after consolidation. Results: Of 92 children with medulloblastoma enrolled on HSIII, 52 patients had classic and 13 had LCA medulloblastoma. Eighteen patients with classic and 6 with LCA medulloblastoma had localized disease (M0) whereas 33 patients with classic and 7 patients with LCA medulloblastoma had evidence of dissemination (M+). The 2-year event-free (EFS) and overall survival (OS) rates (+/- SE) for patients with classic medulloblastoma (primary objective of the study) were 37 ± 7% and 62 ± 7%, and for patients with LCA medulloblastoma were 54 ± 14% and 62 ± 13%, respectively. The 5-year EFS and OS rates were 26 ± 6% and 53 ± 7% for classic medulloblastoma and 38 ± 13% and 46 ± 14% for LCA medulloblastoma patients, respectively. For patients with M0 medulloblastoma, the 5-year EFS and OS rates were 38 ± 12% and 66 ± 11% for patients with classic histology and 50 ± 20% and 67 ± 19% for patients with LCA histology. Similarly, for patients with M+ medulloblastoma, the 5-year EFS and OS rates were 21 ± 7% and 48 ± 9% for patients with classic histology and 29 ± 17% and 29 ± 17% for patients with LCA histology. In multivariate Cox regression analyses, no significant difference in EFS was found between classic and LCA tumors. 5-year irradiation free-EFS for non-nodular/desmoplastic patients was 29 +/- 6%. Conclusion: Encouraging survival figures are reported for patients with classic medulloblastoma, similar to other contemporary infant protocols, whereas patients with LCA medulloblastoma had equivalent survival when compared to patients with classic medulloblastoma when treated with high-dose chemotherapy with AuHCR. These are among the best survival data published so far on infants and young children with LCA medulloblastoma. Approximately third of the survivors were able to avoid irradiation.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant condition caused by mutation in the NF1 tumor-suppressor gene which encodes neurofibrin, a regulator of cell proliferation through the RAS/MAPK pathway. NF1 patients frequently develop central nervous system low-grade gliomas (LGGs), but are also at increased risk for developing malignant tumors such as neuroblastoma which combined are associated with worse prognosis. The association between NF1 and neuroblastoma has been well established, though rarely reported, and its molecular basis still requires further investigation. Additionally, MEK inhibition via disruption of the RAS/MAPK pathway has been shown to be effective in neuroblastoma models in vitro, and is currently being tested in several LGG clinical trials. Co-occurrence of both tumors in a patient with NF1 is exceedingly rare and has been reported only once thus far. Here, we report on the first case in the literature for the use of a MEK inhibitor in a seven years old NF1 patient with high-risk metastatic neuroblastoma and optic pathway glioma without BRAF mutation or fusion. The patient is currently maintained on MEK inhibitor monotherapy for over a year with minimal dermatological side effects. Significant radiographic improvement in the optic pathway glioma as well as stability in the metastatic neuroblastoma has been demonstrated. Comprehensive clinical molecular testing of both tumors is currently pending.

BACKGROUND: The optimal management of young children with newly-diagnosed supratentorial ependymomas remains poorly-defined. We report outcomes of young children under 7 years old at diagnosis prospectively treated on three sequential multi-center trials of intensive chemotherapy with intent of avoiding irradiation. METHODS: Between 1991 and 2009, 14 children (median/mean ages of 34 months, range 3–74 months) were enrolled on “Head Start” (HS) trials (3 on HS-I, 3 on HS-II and 8 on HS-III). Induction chemotherapy was identical on HS-I and HS-II; on HS-III, this regimen was supplemented with high-dose systemic methotrexate in each cycle. Consolidation was uniform with a single cycle of marrow-ablative thiotepa/etoposide/carboplatin followed by autologous hematopoietic cell rescue. Irradiation was reserved for children >72 months old or with residual disease following Induction. Tumor pathology underwent central review. RESULTS: Ten children achieved initial gross total resections (GTRx) of tumor and 4 subtotal resections 2 of whom achieved GTRx following chemotherapy. Pathology revealed cellular ependymoma in 6 and anaplastic ependymoma in 8. There was 1 toxic death in Induction, on HS-I. Four children relapsed (3 on HS-II, 1 on HS-III), all locally, 3 expiring of disease despite focal irradiation, 20–72 months from initial diagnosis; the fourth continues recurrence-free after GTRx and focal irradiation. Seven patients survive without irradiation. CONCLUSIONS: Young children with supratentorial ependymomas have a good survival outcome when treated with irradiation-avoiding chemotherapy incorporating high-dose systemic methotrexate. However, it remains unclear if similar results could have been achieved with GTRx alone. The prognostic significance of molecular subtype is under evaluation.

Metabolism of drugs in infants and young children is significantly different from older individuals due to differences in distribution, protein-binding capacity, hepatic metabolism and renal excretion. Body surface area (BSA) is used to dose chemotherapeutics in older children; however, this is inappropriate for infants and young children since it does not take into account the differences in extracellular water distribution. We describe four cases of sinusoidal obstruction syndrome (SOS) that occurred in young children while receiving induction chemotherapy with cisplatin, etoposide, vincristine, cyclophosphamide and high-dose methotrexate on the “Head Start (HS)” 4 clinical trial using BSA for dosing (mg/m2). Patients #1 and #2 were both 2-years old at diagnosis, received and tolerated the first two cycles with mg/kg dosing uneventfully, then turned 3-years old and received cycle #3 with mg/m2 dosing as per protocol guidelines, and developed SOS. Patient #3 was 3-years old at diagnosis, received induction chemotherapy with mg/m2 dosing, and developed SOS during the very first cycle. Patient #4 was 4-years old at diagnosis and received all 3 induction cycles with mg/m2 dosing, developed serious nephrotoxicity during cycle #1 followed by SOS during cycle #3. In contrast, none of the 40 patients treated on HS II protocol with identical chemotherapy regimen, but with mg/kg dosing, developed SOS. Caution should be exercised when dosing young children between 3-6 years of age by BSA. The HS 4 trial was amended and reopened after external, independent DSMB review to dose all chemotherapy drugs in children

BACKGROUND: Primary CNS embryonal carcinoma confers a poor prognosis despite conventional chemotherapy and radiotherapy. We report upon a novel treatment approach to CNS embryonal carcinoma using intensive, including marrow-ablative, chemotherapy followed by maintenance therapy with brentuximab-vedotin without irradiation. Brentuximab-vedotin is an anti-CD30 antibody conjugated to an anti-tubulin synthetic analog. METHODS: Retrospective review of two patients’ medical records treated since 2015 at Nationwide Children’s Hospital. RESULTS: We report upon the management of two patients with suprasellar pure, CD30-positive embryonal carcinoma. A 17-years-old female with Down syndrome compounded by autism and a 9-years-old male with documented cognitive dysfunction received two cycles of carboplatin/etoposide interspersed with one cycle of cyclophosphamide/etoposide for induction, followed by three cycles of marrow-ablative thiotepa/carboplatin with autologous hematopoietic cell rescue. The first patient achieved complete radiographic and tumor marker response to induction and marrow-ablative chemotherapy, and has completed six cycles of intravenous brentuximab-vedotin, continuing now disease-free 28 months since diagnosis without adverse effects. The second patient had a complete serum and cerebrospinal fluid tumor marker response and a dramatic radiographic response with a small residual abnormality at the end of marrow-ablative chemotherapy that was found at surgery to be composed of predominately reactive changes. Currently, the patient has received the first of six proposed cycles of intravenous brentuximab-vedotin. CONCLUSION: Intensive, including marrow-ablative chemotherapy followed by maintenance with an anti-CD30 antibody-drug conjugate may provide selective and safe alternative to radiotherapy in the management of patients with CNS embryonal carcinoma especially for patients at high risk of developing irradiation-related complications.

BACKGROUND: Pediatric cancer cure rates differ among high-income countries (HIC) and low-to-middle income (LMIC) countries. The World Health Organization reports 20% of LMIC have the necessary data and resources to significantly decrease the rate of mortality in their patients. We compared individual capacities of two major pediatric institutions from a HIC and LMIC caring for children with CNS cancer, the second most common type of cancer of childhood. METHODS: A quantitative-needs assessment questionnaire and key informant interviews were used to evaluate the treatment of children with CNS cancer at IOP/GRAACC/UNIFESP children’s cancer center in São Paulo, Brazil and Nationwide Children’s Hospital/The Ohio State University (NCH/OSU) in Columbus, OH; United States. RESULTS: Both hospitals have 24-hour pediatric oncology, nursing and pediatric intensivist coverage. Supportive care including social workers, psychologists, child life specialists, and physical/occupational/speech therapists are available at both centers. Differences included 2 part-time neuro-radiologists and 2 pathologists at IOP/GRAACC/UNIFESP, whereas 8 full-time neuro-radiologists and 12 pathologists (with 2 specially trained in neuro-pathology) at NCH/OSU. There are 4 pediatric neurosurgeons on staff at each hospital, however, 2 surgical days at IOP/GRAACC/UNIFESP, compared to 7 days/week at NCH/OSU. Additionally, delays in initiation of radiation treatment at IOP/GRAACC/UNIFESP extended 2–4 weeks compared to less than 1 week at NCH/OSU. CONCLUSION: Center-specific differences in resources exist in highly-specialized hospitals caring for children with CNS cancer in LMIC and HIC. This quantitative-needs assessment can develop targeted strategies for effective interventions to improve on the management of children with CNS cancers.

INTRODUCTION: Pediatric low-grade gliomas (pLGG) represent the most common brain tumors in children. Though malignant transformation is rare, these tumors pose a formidable therapeutic challenge due to anatomy-limiting surgical options and local recurrence. The temporal and therapy-driven genomic evolution in pLGG is largely unknown. METHODS: To characterize the temporal genomic heterogeneity of pLGG, we performed fluorescence in situ hybridization, mutation-specific immunohistochemistry, and exome analyses on paired tumor samples from primary diagnostic and subsequent surgeries of 27 pLGG patients. RESULTS: 59 tumor samples were available for review and included pilocytic / pilomyxoid astrocytoma (PA) (67%), low grade astrocytoma (19%), ganglioglioma (11%), and pleomorphic xanthoastrocytoma (3%). BRAF duplication/rearrangement was detected in 56% of tested samples, limited to PA in all but one patient (ganglioglioma). 58% of samples harbored CDKN2A deletion, which was demonstrable across various histologies. BRAF duplication/rearrangement was found consistently conserved across primary and subsequent surgical samples, whereas CDKN2A status changed in 60% of tested temporal pairs, with deletion acquisition the most frequent finding (40%) at second surgery. Likewise, BRAF V600E mutation in one PA was lost at second surgery. Although CDKN2A status changes were seen following surgery alone, the addition of chemo-and/or radiation therapy was associated with a higher rate of temporal CDKN2A deletion acquisition (50%, versus 33% with surgery alone). CONCLUSION: Temporal genomic heterogeneity may be encountered in a significant proportion of pLGG, with some alterations potentially facilitated by therapy. Recurrence biopsy may provide improved guidance, particularly if targeted therapeutics are being considered.

PURPOSE: The LATB is a weekly teleconference operating over 3.5 years connecting pediatric neuro-oncologists from high-income countries with pediatric subspecialists from 20 Latin-American countries. This survey explored the participants’ experience utilizing this resource. METHODS: A web-based questionnaire was distributed to 159 participants through email and www.Cure4Kids.org. RESULTS: Ninety-five respondents (60%) from all the 20 participating countries completed the survey. Sixty-one reported frequent-attendance (≥ 1 per month), 23 reported infrequent-attendance (< 1 per month), and 11 never participated. The main barriers to attendance were the subspecialist’s respective workload (64%), the timing of the teleconference (38%), and internet connectivity problems (29%). Subspecialist’s workload amount was more commonly reported as a barrier compared with other barriers, in both the frequent and infrequent-attendance groups (p

BACKGROUND/OBJECTIVE: Gliosarcoma is a WHO grade IV histologic variant of glioblastoma that occurs very rarely among pediatric patients, even more so amongst Neurofibromatosis Type 1 (NF1) individuals. Patients with NF1-associated high-grade gliomas (HGGs) reportedly have better clinical outcomes than others despite their germline tumor-suppressor mutation. Since molecular data to explain this are lacking, we compared tumor exomes from two pediatric gliosarcoma patients, one with NF1 (P1) and one without (P2). PATIENTS/METHODS: Two patients with gliosarcoma (ages 12 and 11 years), were treated with resection (gross total for P1 and near-total for P2), bevacizumab, temozolomide and irradiation. We performed whole-exome sequencing (WES, Agilent SureSelect V6 + Cosmic) on tumor and blood to determine both germline and somatic mutations. Tumor mutations were filtered based on predicted deleterious effects and a list of genes was compared to online pediatric tumor databases (PeCan and PedcBioPortal). RESULTS: P1 is alive without progression after 5.8 years. P2 developed tumor recurrence after 2 years, expiring 4.6 years from diagnosis. Tumor DNA revealed a lower mutational burden in P1 (NF1) than in P2 including some genes which have been previously reported in pediatric HGGs (e.g. IKBKB in P2). However, there was no overlap in specific gene mutations. CONCLUSIONS: This is the first report of WES in pediatric gliosarcoma. The differences in mutational burden between these patients might explain improved survival outcomes for HGG patients with NF1 as well as shedding light on the different mutational processes leading to their tumors. Further molecular analyses including methylation profiling are ongoing.

Activation of the MAPK pathway represents a hallmark of pediatric low-grade glioma (pLGG) and is frequently caused by BRAF alterations. BRAF-V600E represent an aggressive type of pLGG with less than optimal response to conventional chemo-radiation approaches. While clinical trials using BRAF-V600E inhibitors are ongoing, these data are not yet available. We have assembled an international cohort of BRAF-V600E glioma patients treated off-label with BRAF inhibitors as a monotherapy. Complete molecular, clinical and imaging data is being collected and compared to previous chemo-radiation therapies. Ongoing data form the taskforce on 40 BRAF-V600E gliomas from 25 international institutions is summarized below. The most prevalent histologies were ganglioglioma, pilocytic astrocytoma and pleomorphic xanthoastrocytoma, located mainly in the chiasm, brainstem and temporal lobes. Strikingly, 66% of BRAF V600E pLGG patients achieved partial response (PR) to targeted inhibitors versus only 6.6% response to conventional chemotherapy (p

We previously reported a phase 2 trial of 69 patients with newly diagnosed anaplastic or aggressive oligodendroglioma who were treated with intensive procarbazine, CCNU (lomustine), and vincristine (PCV) followed by high-dose thiotepa with autologous stem cell rescue. This report summarizes the long-term follow-up of the cohort of 39 patients who received high-dose thiotepa with autologous stem cell support. Thirty-nine patients with a median age of 43 (range, 18–67) and a median KPS of 100 (range, 70–100) were treated. Surviving patients now have a median follow-up of 80.5 months (range, 44–142). The median progression-free survival is 78 months, and median overall survival has not been reached. Eighteen patients (46%) have relapsed. Neither histology nor prior low-grade oligodendroglioma correlated with risk of relapse. Persistent nonenhancing tumor at transplant was identified in our initial report as a significant risk factor for relapse; however, long-term follow-up has not confirmed this finding. Long-term neurotoxicity has developed only in those patients whose disease relapsed and required additional therapy; no patient in continuous remission has developed a delayed neurologic injury. This treatment strategy affords long-term disease control to a subset of patients with newly diagnosed anaplastic oligodendroglioma without evidence of delayed neurotoxicity or myelodysplasia.