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PURPOSE Pediatric neuro-oncology resources are mostly unknown in Chile. We report the human and material resources available in Chilean hospitals 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] hospitals, 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 CNS tumors and chemotherapy-related toxicities were available in 100% and 67% of hospitals, respectively. CNS tumors were treated by pediatric oncologists in 92% of hospitals; none were formally trained in neuro-oncology. The most used treatment protocols were the national PINDA protocols. All WHO essential medicines for childhood cancer were available in more than 80% of the hospitals except for gemcitabine, oxaliplatin, paclitaxel, and procarbazine. The median number of pediatric neurosurgeons per hospital was two (range, 2-6). General neuroradiologists were available in 83% of the centers. Pathology specimens were sent to neuropathologists (58%), adult pathologists (25%), and pediatric pathologists (17%). Intensity-modulated radiotherapy, conformal radiotherapy, and cobalt radiotherapy were used by 67%, 58%, and 42% of hospitals, respectively. Only one private hospital performed autologous hematopoietic cell transplant for children with CNS tumors. CONCLUSION A wide range of up-to-date treatment modalities are available for children with CNS tumors. Our survey highlights future directions to improve the pediatric neuro-oncology services available in Chile such as the expansion of multidisciplinary clinics, palliative care services, long-term cancer survivorship programs, dedicated clinical research support teams, establishing standardized mechanism for sending pathologic specimen for second opinion to international specialized centers, and establishing specialized neuro-oncology training program.

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.

Wnt-activated medulloblastoma (MB) confers an excellent prognosis. However, specific treatment strategies for patients with relapsed Wnt-MB are unknown. We report two patients with recurrent beta-catenin nucleopositive Wnt-MB successfully treated by incorporating marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (HDCx/AuHPCR). We also present a review of the literature for previously reported cases of relapsed Wnt-MB. We propose that patients with recurrent Wnt-MB may be treated using a multi-disciplinary approach that includes HDCx/AuHPCR with or without re-irradiation.

Metastatic atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive central nervous system tumors that present during infancy and are associated with dismal outcomes. Patients receive multimodal treatment including surgical resection, systemic chemotherapy, and one or more of intrathecal chemotherapy (IT), marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and radiation therapy (XRT). While data regarding treatment modalities for AT/RT patients exist, no comprehensive data have been published regarding the metastatic patients.We performed a meta-analysis of 1578 articles published through September 2018, including 44 studies with a total of 123 subjects. In addition, seven patients were included through chart review of patients treated at Nationwide Children's Hospital.Analysis of 130 patients revealed a 3-year overall survival (OS) of 25%. Age at diagnosis had a significant effect on survival (P = 0.0355); 3-year OS for infants less than 18 months was 21%, 18 to 36 months was 26%, and greater than 36 months was 36%. Location of the primary tumor, metastatic stage, and extent of surgical resection did not have a significant impact on OS. On univariate analysis, XRT (P0.0001), IT (P = 0.01), and AuHCR (P0.0001) were found to significantly improve survival. The most substantial effect was noted in patients who received AuHCR (3-year OS of 60% vs 9% in those who did not). On multivariable analysis, XRT (P = 0.0006), IT (P = 0.0124), and AuHCR (P0.0001) were independently associated with reduced risk of death.Although more research is warranted to make generalizable conclusions, these results suggest that treatment regimens for patients with metastatic AT/RTs should include AuHCR, XRT, and IT.

The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have simultaneously developed with success treatment strategies with specific attention paid to long-term sequelae. Neurological sequelae may be reduced by establishing a diagnosis with an endoscopic biopsy and/or cerebrospinal fluid (CSF) and/or serum analysis, deferring the need to perform a radical surgery. Depending on markers and/or histological characteristics, patients are treated as either germinoma or non-germinomatous germ cell tumors (NGGCT). Metastatic disease is defined by a positive CSF cytology and/or distant drops in craniospinal MRI. The combination of surgery and/or chemotherapy and radiation therapy is tailored according to grouping and staging. With more than 90% 5-year event-free survival (EFS), localized germinomas can be managed without aggressive surgery, and benefit from chemotherapy followed by whole ventricular irradiation with local boost. Bifocal germinomas are treated as non-metastatic entities. Metastatic germinomas may be cured with craniospinal irradiation. With a 5-year EFS over 70%, NGGCT benefit from chemotherapy followed by delayed surgery in case of residual disease, and some form of radiotherapy. Future strategies will aim at decreasing long-term side effects while preserving high cure rates.

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. METHODS: Retrospective review of 114 children (3-18 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 1.32 and the median age at diagnosis was 8.2 years. Headache (83%) and nausea/vomiting (78%) were the most common presenting symptoms. Overall survival (5y) was 59,1% and EFS (5y) was 58,4%. The OS for standard-risk patients was 69% and 53% for high-risk patients. Forty-five patients (35%) had metastatic disease at admission. Lower maternal education correlated with lower OS (71.3% versus 49% p=0.25). 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: The epidemiological characteristics of this series possibly explain the differences in survival that medulloblastoma patients have in Brazil. Issues related to limited health care resources, poverty, delayed diagnosis, treatment abandonment, and malnutrition are reflected in inferior survival outcomes when compared to high-income countries. Despite the difficulties encountered in an upper-middle income country, it was possible to deliver treatment with good results.

We aimed toidentify prognostic factors that may help better understand the behavior of relapsed central nervous system nongerminomatous germ cell tumors. We identified nine studies, including 101 patients; 33 patients (33%) were alive 12 months post-initial relapse. Sixty percent of patients with serum/cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) level ≤25 ng/mL at initial diagnosis were survivors compared with 28% among patients with serum/CSF AFP level >25 ng/mL (P = 0.01). Seventy-one percent of patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy at relapse were survivors compared with 7% among patients who had less than CR/CCR (P < 0.0001). Forty-eight percent of patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) following relapse were survivors compared with 12% among patients who did not receive HDCx/AuHCR (P = 0.0001). Local relapse site, gross total surgical resection, and radiotherapy at relapse were not associated with improved outcomes.

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of non-metastatic BGTGs, the 5- and 10-year event-free survival (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survival (OS) were 100%, and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980 to 2400 cGy/cGy[RBE]), WBI: 2340 (1800 to 3000 cGy/cGy[RBE]), WVI: 2340 cGy/cGy(RBE) (1800 to 2550 cGy/cGy[RBE]), focal: 3600 cGy (3060 to 5400 cGy). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p=0.84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p=0.0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

© The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

Germ cell tumors (GCT) in the central nervous system (CNS) are rare tumors that occur with highest frequency in males, Asian populations, and children less than age 20 years. Due to the rarity of these tumors, their patterns of incidence are not well-described. The aim of this study is to provide the most up-to-date data on incidence and survival patterns for CNS GCT by sex, race, and age at diagnosis. The Central Brain Tumor Registry of the United States (CBTRUS) is the largest aggregation of population-based incidence data on primary brain and other CNS tumors in the United States, containing incidence data from 51 central cancer registries and representing 100% of the US population. The current study used the CBTRUS analytic file to examine incidence (IR) of CNS GCT from 2006 to 2015, as well as registry data from the Surveillance, Epidemiology, and End Results (SEER) program to examine survival. Males had greater IR than females in all CNS GCT histologies examined. Asian and Pacific Islanders had a significantly greater IR of CNS GCT than the other race categories. We confirmed that CNS GCT IR was greatest for those age 10–14 years and male. Overall survival rates were high for malignant CNS GCT, germinoma, mixed GCT, and malignant teratoma. There is significant variation in CNS GCT incidence by sex, race, and age at diagnosis. Ascertaining accurate incidence and survival rates of CNS GCT provides vital information usable in real time for clinicians, public health planners, patients, and their families.

Background We report a patient with primary central nervous system mixed malignant germ cell tumor (GCT) who presented with recurrent malignant germinomatous infiltration of the retina. Case Description A 10-year-old girl initially presented with a large suprasellar mixed malignant GCT with a near-complete response after initial induction of chemotherapy and irradiation. Three and a half years after initial therapy, she presented with progressively worsening vision in her left eye. Magnetic resonance imaging showed infiltrative changes within the left optic nerve but no discrete mass. Serum and cerebrospinal fluid tumor markers were not elevated and cerebrospinal fluid cytology was negative. Left optic nerve biopsy confirmed the presence of mature teratoma and pure germinoma components. She was treated with gross-total resection of the left eye and optic nerve and chemotherapy. Histopathologic evaluation of the optic nerve showed only mature teratoma elements, but with pure germinoma cells infiltrating the inner layers of the retina. Conclusions Loco-regional extension of suprasellar GCT to the optic nerve is not uncommon; however, to the best of our knowledge, infiltration of the tumor into the retina is not reported in the literature. Early detection of optic pathway involvement and proper delineation of the irradiation field may prevent GCT infiltration of the retina with subsequent vision loss.

BACKGROUND Since 2013, pediatric oncologists from Central and South America discuss neuro-oncology cases with experts from North America and Europe in a web-based "Latin American Tumor Board" (LATB). Here, we evaluate the feasibility of recommendations rendered by the Board. METHODS An electronic questionnaire was distributed to physicians who had received recommendations between October 2017 and October 2018. Physicians were asked regarding the feasibility of each recommendation given during the LATB discussion. Baseline case characteristics of all presented cases were obtained from anonymized minutes. RESULTS Of the 142 patients discussed, data on 103 patients from 15 countries were available, corresponding to 283 recommendations. Physicians followed 60% of diagnostic procedural recommendations and 69% of therapeutic recommendations. The most difficult recommendations to follow were genetic and molecular testing, pathology review, chemotherapy, surgery, and molecular targeted therapies. Histological diagnoses changed in eight of 18 cases in which a pathology review was undertaken. Fifty-four percent of the recommendations that could not be implemented were considered not feasible in the specific context of the patient, while 31% were not implemented due to a decision of the medical staff or the parents (15% not specified). However, 96% of respondents considered the recommendations useful. CONCLUSION Recommendations were frequently perceived as useful, and were applicable in the participating institutions. Nevertheless, limitations in availability of diagnostic procedures and treatment modalities affected the feasibility of some recommendations. Tele-oncology tumor boards offer physicians from low- and middle-income countries access to real-time, high-level subspecialist expertise and provide a valuable platform for worldwide information exchange.

BACKGROUND Pediatric cancer cure rates differ among high-income countries (HIC) and upper middle-income countries (UMIC). We have compared individual capacities of two major referral pediatric centers from a HIC and an UMIC caring for children with central nervous system (CNS) cancer. METHODS A quantitative needs assessment questionnaire and key informant interviews, distributed in March of 2017, were used to evaluate the treatment of children with CNS cancer at Grupo de Apoio ao Adolescente e a Crianca com Câncer (GRAACC) children's cancer center in Sao Paulo, Brazil and Nationwide Children's Hospital (NCH) in Columbus, Ohio, United States of America (USA). RESULTS Both hospitals had 24-hour pediatric oncology, nursing and intensivist coverage. Supportive care available at both institutions included social workers, psychologists, child life specialists, and physical/occupational/speech therapists. Differences included two part-time neuroradiologists and one pathologist specializing in neuropathology at IOP/GRAACC/UNIFESP, whereas eight full-time neuroradiologists and two neuropathologists at NCH/OSU. There were four pediatric neurosurgeons on staff at each hospital; however, there were only 2 operative days per week at IOP/GRAACC/UNIFESP, compared with 7 days at NCH/OSU. Additionally, time to initiation of radiation therapy at IOP/GRAACC/UNIFESP extended 2-4 weeks compared with less than 1 week at NCH/OSU. CONCLUSIONS Center-specific differences in resources exist in highly specialized hospitals caring for children with CNS cancer in HIC and UMIC. This quantitative needs assessment may facilitate the development of targeted strategies for effective interventions to improve on the management of children with CNS cancers.

In this follow-up report, we present updated information regarding a previously reported pediatric patient with a World Health Organization grade I ganglioglioma harboring a BRAF p.T599dup mutation (Cold Spring Harb Mol Case Stud 4: a002618). This patient, based on our initial finding, is receiving combination targeted therapy with a selective BRAF inhibitor (dabrafenib) plus MEK inhibitor (trametinib). The combination therapy was started after the patient experienced progressive tumor growth and worsening neurological symptoms, including visual changes, headaches, and peripheral neuropathy, despite 9 months of treatment with adjuvant chemotherapy (vinblastine). The patient has been receiving dabrafenib plus trametinib for 15 months and continues to have stable disease as well as improved neurological symptoms. Although combinatorial therapy targeting BRAF and MEK using dabrafenib and trametinib, respectively, is indicated for tumors harboring a BRAF p.V600E/K mutation, our report demonstrates efficacy of this combination in a non-V600E BRAF-mutated tumor. The identification of BRAF alterations may assist clinicians in determining alternative targeted treatment strategies, especially considering the paucity of effective treatments for primary brain tumors and the poor prognosis associated with many central nervous system (CNS) diagnoses. Additional case studies or larger cohort reports will continue to clarify the efficacy of BRAF and/or MEK inhibitors in patients whose tumors harbor a BRAF alteration.

Children with brain tumors often carry germline mutations that have long been known to contribute to tumorigenesis and treatment response. However, less is known about how germline mutations may impact developmental and behavioral outcomes for children with tumors of the central nervous system (CNS). As the molecular mechanisms governing cancerous and normal tissue expand, we hypothesize that particular germline variants may impact baseline neurocognitive function and/or treatment-induced toxicities. In this preliminary study, 10 children on the Head Start 4 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 20 genes with alterations associated with lower scores with P-values less than 0.05, although none met FDR significance cutoffs. 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 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 suspect that follow-up studies with more patients will reveal alterations in cell-to-cell communication and signal transduction pathways, as these are common molecular perturbations in tumors that would likely impact regular CNS function. Future research with larger cohorts is essential to validate these findings and to improve our understanding of the functional impact of germline variants on both tumor and regular tissue biology, allowing for a more comprehensive view of the spectrum of neurodevelopmental impairment and novel strategies to circumvent these impairments. Funding: Thrasher Research Fund (JF, AC). R01CA108633, RC2CA148190, U10CA180850(NCI), and OSUCCC (AC).

BACKGROUND Central nervous system (CNS) tumors are the second most common malignancy of childhood, and published data on venous thromboembolism (VTE) rate and risk factors for these patients are outdated or incomplete. Here, we determine the cumulative incidence and risk factors for VTE in this population. PROCEDURE VTE diagnosis and associated clinical risk factors were abstracted and analyzed for two cohorts of children (0-21 years) diagnosed with CNS tumors between January 1, 2010 to September 30, 2018. The first study was a retrospective single institution cohort study. The initial observations were confirmed across multiple pediatric hospitals using the Pediatric Health Information System (PHIS) administrative database. RESULTS The single-institution cohort included 338 patients aged 3 days to 20.9 years (median age, 8.6 years); VTE developed in eight (2.4%) patients. The PHIS cohort included 17 634 patients aged from 0 to 21.9 years (median: 9.5 years); VTE developed in 354 (2.0%) patients. Univariate analysis for the single-institution cohort identified central venous catheter (CVC) placement as a risk factor for VTE (odds ratio [OR] 8.40, 95% confidence interval [CI] 1.43-49.41, P = .0186). Multivariable analysis of the PHIS dataset identified CVC placement (OR 1.97, 95% CI 1.57-2.46; P

Gliosarcoma is rare among pediatric patients and among individuals with Neurofibromatosis Type 1 (NF1). Here we compare 2 pediatric gliosarcoma patients, one of whom has NF1. We performed whole-exome sequencing, methylation, and copy number analysis on tumor and blood for both patients. Whole-exome sequencing showed higher mutational burden in the tumor of the patient without NF1. Copy number analysis showed differences in chromosomal losses/gains between the tumors. Neither tumor showed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The NF1 patient survived without progression while the other expired. This is the first reported case of gliosarcoma in a child with NF1.

Purpose Children with brain tumors experience cognitive late effects, often related to cranial radiation. We sought to determine differential effects of surgery and chemotherapy on brain structure and neuropsychological outcomes in children who did not receive cranial radiation therapy (CRT). Methods Twenty-eight children with a history of posterior fossa tumor (17 treated with surgery, 11 treated with surgery and chemotherapy) underwent neuroimaging and neuropsychological assessment a mean of 4.5 years (surgery group) to 9 years (surgery + chemotherapy group) posttreatment, along with 18 healthy sibling controls. Psychometric measures assessed IQ, language, executive functions, processing speed, memory, and social-emotional functioning. Group differences and correlations between diffusion tensor imaging findings and psychometric scores were examined. Results The z-score mapping demonstrated fractional anisotropy (FA) values were ≥2 standard deviations lower in white matter tracts, prefrontal cortex gray matter, hippocampus, thalamus, basal ganglia, and pons between patient groups, indicating microstructural damage associated with chemotherapy. Patients scored lower than controls on visuoconstructional reasoning and memory (P ≤ .02). Lower FA in the uncinate fasciculus (R = -0.82 to -0.91) and higher FA in the thalamus (R = 0.73-0.91) associated with higher IQ scores, and higher FA in the thalamus associated with higher scores on spatial working memory (R = 0.82). Conclusions Posterior fossa brain tumor treatment with surgery and chemotherapy affects brain microstructure and neuropsychological functioning years into survivorship, with spatial processes the most vulnerable. Biomarkers indicating cellular changes in the thalamus, hippocampus, pons, prefrontal cortex, and white matter tracts associate with lower psychometric scores.

Background “Head Start” III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma. Methods Following surgery, patients received 5 cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction. Results Between 2003 and 2009, 92 children Conclusion We report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy, with most patients surviving without irradiation.

PURPOSE Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02). CONCLUSION Use of BRAF inhibition results in robust and durable responses in BRAF V600E–mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

Pleomorphic xanthoastrocytoma (PXA) is a rare type of brain tumor that affects children and young adults. Molecular prognostic markers of PXAs remain poorly established. Similar to gangliogliomas, PXAs show prominent immune cell infiltrate, but its composition also remains unknown. In this study, we correlated DNA methylation and BRAF status with clinical outcome and explored the tumor microenvironment. We performed DNA methylation in 21 tumor samples from 18 subjects with a histological diagnosis of PXA. MethylCIBERSORT was used to deconvolute the PXA microenvironment by analyzing the associated immune cell-types. Median age at diagnosis was 16 years (range 7–32). At median follow-up of 30 months, 3-year and 5-year overall survival was 73% and 71%, respectively. Overall survival ranged from 1 to 139 months. Eleven out of 18 subjects (61%) showed disease progression. Progression-free survival ranged from 1 to 89 months. Trisomy 7 and CDKN2A/B (p16) homozygous deletion did not show any association with overall survival (p = 0.67 and p = 0.74, respectively). Decreased overall survival was observed for subjects with tumors lacking the BRAF V600E mutation (p = 0.02). PXAs had significantly increased CD8 T-cell epigenetic signatures compared with previously profiled gangliogliomas (p = 0.0019). The characterization of immune cell-types in PXAs may have implications for future development of immunotherapy.

Background Surgical resection is the treatment of choice for pleomorphic xanthoastrocytoma, while chemotherapy and radiation therapy are typically used in patients with anaplasia, metastasis, or sometimes in subtotally resected cases, especially upon recurrence. Extracranial dissemination has been only rarely reported. We describe a five year old boy with the rare occurrence multiply recurrent and extracranially disseminated anaplastic pleomorphic xanthoastrocytoma. A complete resolution of his tumor was achieved for greater than two years thus far after administering everolimus. Methods We performed a comprehensive literature review of all pleomorphic xanthoastrocytoma cases; 359 cases were described, and 132 of these individuals were less than 18 years of age. Results Gross total resection was achieved in only 132 (36.7%) cases, while additional therapy was administered in 186 patients. Only four patients in additon to our own have been documented with extracranial dissemination (four of five in the pediatric population); two patients who succumbed to their disease underwent subtotal resection of the primary tumor. Conclusions We report the first patient with extracranially disseminated anaplastic pleomorphic xanthoastrocytoma to be successfully maintained on everolimus as a single oral chemotherapy agent with complete resolution of the tumor. Pleomorphic xanthoastrocytoma can rarely disseminate extracranially in the pediatric population, hence pathologists and neuro-oncologists should be aware of this possibility.

The lack of a standard treatment approach has contributed to poor outcomes of patients with recurrent central nervous system (CNS) mixed malignant germ cell tumors (MMGCT). There are no data in the literature supporting optimal re-induction chemotherapy regimens that should be used for patients with recurrent CNS MMGCT. We conducted a literature review to explore the response rate of patients with recurrent CNS MMGCT to different re-induction chemotherapy regimens by searching PubMed from 1985 through November 2017. Tumors were classified according to Japanese, European, and North American prognostic group classifications determined at initial presentation. Forty-two responses to various re-induction chemotherapy regimens reported in 38 patients were included. Two patients were inevaluable and their responses to re-induction chemotherapy were excluded. Thirty-five responses to various re-induction chemotherapy regimens were evaluable in 33 patients following a first relapse. Six (17%) responses were reported as complete or continuous complete responses, seven (20%) partial responses, two (6%) were stable disease, two (6%) were mixed responses, and 18 (51%) were progressive disease. Five of ten patients treated without platinum-based chemotherapy experienced tumor progression. There was a trend towards a higher rate of tumor progression among histological poor prognostic group patients, and among patients relapsing within 24 months of initial diagnosis; however, it was not statistically significant. The histological prognostic group and time to relapse may affect the response to re-induction chemotherapy. However, further studies with larger sample size are needed to examine these associations and determine the optimal re-induction chemotherapy regimens for patients with recurrent MMGCT.

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.

Metastatic disease at initial presentation of intracranial ependymoma is an uncommon occurrence with only rare reports of survival and is reportedly more prevalent in the youngest of children. Clinical and molecular characteristics associated with metastatic presentation, their prognostic implications, as well as optimal treatment options for such patients, have not been identified. CASE REPORT: A seven months old child presented with posterior fossa anaplastic ependymoma; following sub-total resection of primary tumor, a spine MRI revealed leptomeningeal dissemination along the cervical spinal cord and nerve roots of the cauda equina. The patient was successfully treated with five cycles of intensive induction chemotherapy (as per Head Start with high-dose methotrexate) followed by three sequential cycles of marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHPCR) without irradiation; he is currently without evidence of the disease now 60 months following initial diagnosis. MOLECULAR/GENOMIC RESULTS: The patient was enrolled on a patient-centric comprehensive molecular profiling protocol, which included paired tumor-normal whole-exome sequencing, RNA sequencing of the disease-involved tissue, and DNA methylation classification. The genomic profile of the tumor was relatively unremarkable, revealing only a terminal gain of chromosome 3p and a terminal deletion of chromosome 22q, suggestive of an unbalanced translocation. Using RNA sequencing, we identified a novel SPECC1L-RAF1 gene fusion. The tumor harbors unique transcriptomic and DNA methylation profiles, failing to discretely classify with well-established ependymoma subgroups. CONCLUSION: Use of genomic profiling techniques provides meaningful information for disease characterization allowing for further expansion of the molecular spectrum associated with malignant disease.

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 Wnt-MB infers an excellent prognosis, and metastatic disease is rare. However, specific treatment strategies and patterns of failure for patients with recurrent Wnt-MB are unknown. We report two cases of recurrent beta-catenin nucleopositive Wnt-MBs treated with an irradiation-sparing strategy, incorporating HDCx/AuHPCR. PATIENT 1: A nine-year-old female experienced local recurrence of a non-metastatic Wnt-MB nine months after gross total resection (GTR) followed by 18Gy craniospinal irradiation (CSI) with primary site boost to 54Gy, accompanied by weekly vincristine, followed by a maintenance regimen of nine cycles of cisplatin/lomustine/vincristine alternating with cyclophosphamide/vincristine every third cycle. GTR of the relapsed tumor was followed by three cycles of HDCx/AuHPCR. She is disease-free for over three years following relapse treatment. PATIENT 2: A 17-year-old male initially underwent GTR, followed by 23.4Gy CSI with 54Gy posterior fossa boost with concomitant weekly vincristine, followed by a maintenance regimen that included nine alternating cycles of vincristine/lomustine/cisplatin and cyclophosphamide/vincristine. Isolated right frontal horn metastatic recurrence developed 19 months post-treatment; three cycles of irinotecan/temozolomide/bevacizumab and gamma-knife radiosurgery produced complete response. A second isolated metastatic recurrence within the left frontal horn occurred 13 months post-treatment, which was treated with two cycles of cyclophosphamide/etoposide followed by two cycles of HDCx/AuHPCR. MRI of the brain showed no residual tumor one month post-treatment. He currently awaits follow-up stereotactic radiosurgery. CONCLUSION Patients with recurrent Wnt-MB may be treated with curative intent using a multi-disciplinary approach that includes HDCx/AuHPCR, and minimization or avoidance of re-irradiation.

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.

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

“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.

// Kellie B. Haworth 1, 2 , Michael A. Arnold 3, 4 , Christopher R. Pierson 3, 4, 5 , Kwangmin Choi 6 , Nicholas D. Yeager 1 , Nancy Ratner 6 , Ryan D. Roberts 1, 2 , Jonathan L. Finlay 1 and Timothy P. Cripe 1, 2 1 Division of Hematology, Oncology, Blood and Marrow Transplant, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio, USA 2 Center for Childhood Cancer and Blood Diseases, The Research Institute, Nationwide Children’s Hospital, Columbus, Ohio, USA 3 Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio, USA 4 Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio, USA 5 Division of Anatomy, Department of Biomedical Education and Anatomy, The Ohio State University College of Medicine, Columbus, Ohio, USA 6 Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA Correspondence to: Kellie B. Haworth, email: kellie.haworth@nationwidechildrens.org Keywords: NF1, MPNST, neurofibromas, immunotherapy, immunophenotype Received: December 14, 2016 Accepted: April 16, 2017 Published: May 30, 2017 ABSTRACT Successful treatment of neurofibromatosis type 1 (NF1)-associated tumors poses a significant clinical challenge. While the primary underlying genetic defect driving RAS signaling is well described, recent evidence suggests immune dysfunction contributes to tumor pathogenesis and malignant transformation. As immunologic characterizations, prognostic and predictive of immunotherapeutic clinical response in other cancers, are not fully described for benign and malignant NF1-related tumors, we sought to define their immunologic profiles. We determined the expression of human leukocyte antigen (HLA)-A/-B/-C, β-2-microglobulin (B2M), and T cell inhibitory ligands PD-L1 and CTLA-4 by microarray gene analysis and flow cytometry. We examined HLA-A/-B/-C, B2M, and PD-L1 expression on thirty-six NF1-associated tumor samples by immunohistochemistry, and correlated these with tumoral CD4 + , CD8 + , FOXP3 + , CD56 + , and CD45RO + lymphocytic infiltrates. We evaluated several tumors from a single patient, observing trends of increasing immunogenicity over time, even with disease progression. We observed similarly immunogenic profiles for malignant peripheral nerve sheath tumors (MPNST) and nodular and plexiform neurofibromas, contrasting with diffuse neurofibromas. These studies suggest that while immunotherapies may offer some benefit for MPNST and nodular and plexiform neurofibromas, tumor heterogeneity might pose a significant clinical challenge to this novel therapeutic approach.

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.

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

Background Histological grading of choroid plexus tumors (CPTs) remains the best prognostic tool to distinguish between aggressive choroid plexus carcinoma (CPC) and the more benign choroid plexus papilloma (CPP) or atypical choroid plexus papilloma (aCPP); however, these distinctions can be challenging. Standard treatment of CPC is very aggressive and often leads to severe damage to the young child’s brain. Therefore, it is crucial to distinguish between CPC and less aggressive entities (CPP or aCPP) to avoid unnecessary exposure of the young patient to neurotoxic therapy. To better stratify CPTs, we utilized DNA methylation (DNAm) to identify prognostic epigenetic biomarkers for CPCs. Methods We obtained DNA methylation profiles of 34 CPTs using the HumanMethylation450 BeadChip from Illumina, and the data was analyzed using the Illumina Genome Studio analysis software. Validation of differentially methylated CpG sites chosen as biomarkers was performed using pyrosequencing analysis on additional 22 CPTs. Sensitivity testing of the CPC DNAm signature was performed on a replication cohort of 61 CPT tumors obtained from Neuropathology, University Hospital Münster, Germany. Results Generated genome-wide DNAm profiles of CPTs showed significant differences in DNAm between CPCs and the CPPs or aCPPs. The prediction of clinical outcome could be improved by combining the DNAm profile with the mutational status of TP53. CPCs with homozygous TP53 mutations clustered as a group separate from those carrying a heterozygous TP53 mutation or CPCs with wild type TP53 (TP53-wt) and showed the worst survival outcome. Specific DNAm signatures for CPCs revealed AK1, PER2, and PLSCR4 as potential biomarkers for CPC that can be used to improve molecular stratification for diagnosis and treatment. Conclusions We demonstrate that combining specific DNAm signature for CPCs with histological approaches better differentiate aggressive tumors from those that are not life threatening. These findings have important implications for future prognostic risk prediction in clinical disease management. Electronic supplementary material The online version of this article (10.1186/s13148-019-0708-z) contains supplementary material, which is available to authorized users.

BACKGROUND Germ cell tumors (GCT) arising from non-midline structures (basal ganglia, thalamus, and posterior fossa) are rare. Although patients with midline (pineal and suprasellar) germinoma have excellent survival with chemotherapy and whole ventricular irradiation (WVI), germinoma in non-midline locations have traditionally been treated with craniospinal irradiation (CSI) or whole brain irradiation (WBI) to achieve similar outcomes. However, CSI and WBI are associated with significant long-term neuropsychological sequelae. METHODS We describe the clinical and neuropsychological outcomes of patients with non-midline germinoma treated at the Children's Hospital Los Angeles between 1990 and 2015. RESULTS Nine patients had basal ganglia/thalamic germinoma and one patient had a cerebellar primary. Eight patients received chemotherapy followed by reduced dose/volume irradiation, whereas two patients received chemotherapy alone as upfront therapy. One patient in the chemotherapy alone group relapsed after 4.3 years and was salvaged with CSI plus boost. The overall survival for the entire cohort was 100% at a median follow-up of 8.5 years. Neuropsychological data were available for six patients at a median of five months (baseline) and 4.2 years (follow-up) post-diagnosis. At four-year follow-up, data available revealed intact overall cognitive ability, verbal memory, and executive functioning, but persistent deficits in fine motor function. Comparison of baseline to follow-up suggests a downward trend in working memory, planning/problem-solving, verbal memory, and visuospatial integration. CONCLUSION Chemotherapy followed by reduced dose/volume of irradiation is an effective strategy resulting in long-term survival in patients with non-midline germinoma. Neuropsychological data suggest relatively minimal morbidity over time.

Klippel-Feil syndrome (KFS) is an exceerlingly rare constitutional disorder in which a paucity of knowledge exists about the disease and its associated morbidity and mortality. We present a 4-year-old male with KFS, who notably was also diagnosed with large-cell anaplastic medulloblastoma. We evaluated the genetic basis of co-occurring KFS and medulloblastoma and the role of MYO18B as related to medulloblastoma. Constitutional and somatic variant and copy number analyses were performed from DNA-based exome studies, along with RNA-sequencing of tumor tissue, to elucidate the genetic etiology of the co-existing disease states. We identified novel constitiitional compound heterozygous frameshift variants (NM_032608.5: p.Leu2257SerfsTerl6 and p.Arg2220SerfsTer74) each encoding a premature stop of translation in MYO18B, consistent with a diagnosis of KFS. We did not identify any somatic variants of known relevance or disease-relevant therapeutic targets in the tumor. The somatic copy number profile was suggestive of Group 3γ medulloblastoma. Relative to pediatric brain tremors, medulloblastoma, particularly, Group 3, had increased gene expression of MYO18B. In summary, coexisting constitutional and somatic diagnoses in this patient enabled the elucidation of the genetic etiology of KFS and provided support for the role of MYO18B in tumor suppression.

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.

Pediatric oligodendroglioma is a low-grade glioma that remains relatively rare when compared to adults. Retrospective studies have clearly defined the most common presenting symptoms and tumor locations. Delays in diagnosis are likely to occur given the nature of pediatric oligodendroglioma. Prospective studies are required to better understand the “time-clock” with respect to progression of symptoms requiring further intervention.

Central nervous system (CNS) hemangioblastomas are the most common primary posterior fossa neoplasm in adults. These pathologically benign, vascular tumors occur sporadically in approximately two-thirds of cases and arise in the context of the familial neoplasia syndrome, von Hippel-Lindau disease (VHL), in the remainder of cases. Whether they occur sporadically or in association with VHL, 99% of hemangioblastomas occur below the tentorium. Ninety-five percent of VHL patients with a hemangioblastoma will have multiple hemangioblastomas. Due to a germline mutation of the VHL tumor suppressor gene, located on the short arm of chromosome 3, VHL is typically transmitted in an autosomal dominant manner. Nonetheless, germline mutations of the VHL gene can arise de novo in approximately 5% of patients. In addition to CNS hemangioblastomas, VHL patients are also predisposed to endolymphatic sac tumors, renal cell carcinoma, pheochromocytoma, and pancreatic neuroendocrine tumors.

BACKGROUND Pediatric brain tumor classification has undergone significant evolution over the last decade requiring a high-level of expertise and diagnostic techniques. Such advances have created challenges for pathologists particularly in low-to-middle income countries (LMIC). We conduct weekly pediatric neuro-oncology teleconferences linking global pediatric neuro-oncologists from high-income countries (HIC) to review patients with pediatric subspecialists from Latin America. METHODS Three to five patients are discussed weekly and second neuropathology review is offered when a high-level of suspicion emerges of a questionable diagnosis based on clinical and radiographical information. Nationwide Children’s Hospital (NCH) provides second neuropathology review at no cost to institutions in Latin America that fulfill these criteria. RESULTS From July 2015 to December 2019 NCH reviewed 54 pathology samples from eleven Latin American countries. Of these, 33 (61.1%) cases resulted in diagnostic changes, of which 28 (51.8%) were significant, impacting treatment plans and overall patient outcomes. The remaining 21 (38.9%) confirmed institutional diagnosis; however, in eight of these 21 cases additional molecular information and/or further tumor subtyping unavailable in their home country at the time (eg: BRAF, RELA-fusion, medulloblastoma subtyping) was provided. CONCLUSIONS This study highlights the importance of centralized pathology review by institutions with the proper equipment, infrastructure and expertise in pediatric neuropathology. Furthermore, this documents the beneficial impact of teleconferencing for subspecialists in LMIC who must treat a wide variety of pediatric cancers with few resources and support. Additionally, our findings underscore the need for pediatric subspecialty training in LMIC.

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 Metastatic atypical teratoid/rhabdoid tumors (AT/RT) are aggressive central nervous system tumors that present during infancy and are associated with dismal outcomes. Patients receive multimodal treatment including surgical resection, systemic chemotherapy and one or more of intrathecal chemotherapy (IT), marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and radiation therapy (XRT). While data regarding treatment modalities for AT/RT patients exist, no comprehensive data have been published regarding the metastatic patient population. METHODS We performed a meta-analysis of 1,578 articles published through September 2018, including 44 studies with a total of 123 subjects. Additionally, seven patients were incorporated through chart review of patients treated at Nationwide Children’s Hospital. RESULTS Analysis of 130 patients revealed a 3-year overall survival (OS) of 25%. Age at diagnosis had a significant impact on survival (p=0.0355); 3-year OS for infants < 18 months was 21%; 18–36 months was 26%; and > 36 months was 36%. Location of the primary tumor, metastatic stage and extent of surgical resection did not have significant impact on OS. On univariate analysis, XRT (p

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.