Pediatric Neuro-oncology Research Articles

EPCT-18. A TWO-PART, PHASE 1 STUDY OF RHENIUM-186 NANOLIPOSOME (186RNL) DELIVERED BY CONVECTION ENHANCED DELIVERY FOR RECURRENT, REFRACTORY, OR PROGRESSIVE EPENDYMOMA AND HIGH-GRADE GLIOMA (HGG) AND NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Ependymoma, HGG, and DIPG are gliomas that are often difficult to treat, frequently aggressive, and often carry an extremely poor prognosis. While external beam radiation therapy (EBRT) remains a central component of the management of pediatric gliomas, it is limited by tolerance of the surrounding normal brain tissue. Rhenium-186 NanoLiposome (186RNL) permits the selective delivery of beta-emitting radiation of high specific activity with excellent retention in the tumor. In a Phase 1 trial in adults with recurrent glioblastoma (NCT01906385), the mean absorbed dose to the tumor when coverage was 75% or greater (n=10) was 392 Gy (CI 306 – 478). Thus far, the therapy has been well tolerated, no dose-limiting toxicity has been observed, and no treatment-related serious adverse events have occurred despite markedly higher absorbed doses than typically delivered by EBRT (n=18).MethodsThis is a two-part, Phase 1 dose-finding study followed by an expansion cohort to explore efficacy. Part 1 will enroll up to 18 subjects to determine the maximum feasible dose (MFD) of 186RNL administered by convection enhanced delivery (CED). Tumor size will be limited to a diameter of 4 cm in the longest axis and a volume of 34 mL. The dose limiting toxicity period (DLT) is 28 days post infusion. Part 2 will independently evaluate 186RNL in 3 different cohorts: Cohort A: up to 12 subjects with a diagnosis of recurrent, refractory, or progressive ependymoma; Cohort B: up to 12 subjects with a diagnosis of recurrent, refractory, or progressive HGG; Cohort C: up to 15 subjects with newly diagnosed DIPG. The primary endpoint is overall response rate (ORR) by Radiographic Assessment in Pediatric Neuro-Oncology (RAPNO) criteria. Secondary endpoints are PFS-24 and OS-24 in Cohort A and PFS-12 and OS-12 in Cohorts B and C. Planned enrollment will begin in H2 2021.

EMBR-31. DEVELOPMENT OF INJECTABLE POLYSACCHARIDE HYDROGEL TO ENHANCE DRUG PENETRATION IN PEDIATRIC BRAIN TUMORS

Improving unacceptable low response rates and reducing acute and long-term morbidities remain significant challenges in pediatric neuro-oncology. Chemotherapy is an effective primary or adjuvant treatment for pediatric disease, but current administration approaches hinder the pharmacological activity exerted by chemotherapy treatments. Barriers in the route of drug administration and in the tumor microenvironment limit anticancer drugs from penetrating tissue efficiently and reaching all cancer cells. Strategies have been proposed to overcome these barriers with hope of leading to sustained and elongated drug exposure in solid tumors. However, few methods have been explored to design drug delivery systems to circumvent these barriers with potential to enhance drug penetration and reduce adverse systemic side effects in treating pediatric brain tumors. In this study, we validate an injectable polysaccharide hydrogel capable of releasing drugs locally at tumor site, sustaining drug concentration, and eliciting tumor response. We synthesized a hydrogel with dimethyl sulfoxide (DMSO) incorporating amylopectin, a polysaccharide found in starch, loaded with doxorubicin. We determined the structure of doxorubicin is not altered when released from the hydrogel through characterization of drug-loaded and unloaded hydrogels, suggesting drug is encapsulated in the hydrogel network and is able to maintain structure to induce mechanism of action. We tested sustained release of drug and therapeutic efficacy in vitro with DAOY, a medulloblastoma cell line. Our approach demonstrates that local drug delivery presents potential to enhance drug penetration in pediatric brain tumors by sustaining drug concentration at tumor site for an extended period of time. Local drug delivery systems have been investigated for decades but few have been investigated for treatment of pediatric brain tumors. For researchers, physicians, and clinicians, this research can lead to a greater effort to improve current outcomes of conventional drug treatment and provide an opportunity to address current challenges in pediatric oncology.

RARE-01. ASSESSING THE SYMPTOM DIAGNOSTIC INTERVAL FOR CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMOURS

BackgroundDiagnostic delays in pediatric neuro-oncology is a subject of distress for families and providers. We aimed to evaluate the symptom diagnostic interval (SDI) and influencing variables for children with CNS tumors. MethodsThis retrospective study analyzed 210 patients diagnosed from 2001–2018 and managed at the tertiary care facility in Halifax, Canada. SDI was defined as time from first symptom until tissue diagnosis or, if not available, imaging diagnosis. Non-parametric tests were used to compare SDI between groups. ResultsMedian SDI was 12.4 weeks (IQR 4.3–30), longer than 7 other studies of 1308 children reporting medians of 4.5–10 weeks (p < 0.01). Most common tumors and their median SDI included low-grade glioma (LGG) (n=97, 46%; 17.9 weeks), medulloblastoma (n=31, 15%; 8.7 weeks), high-grade glioma (HGG) and DIPG (n=23, 11%; 5.6 weeks), and ependymoma (n=13, 6%; 13.6 weeks). The most common initial reported symptom included headache (n=63; 30%), nausea/vomiting (n=27, 18%), seizure (n=24, 12%), and visual impairment (n=13, 6.3%). Patients aged 0–3 years had a shorter SDI than patients 10 years and older (SDI 8.7 vs 14.6 weeks; p = 0.03). Tumor category showed longer SDI for LGG versus HGG (p = 0.003), DIPG (p = 0.02), medulloblastoma (p = 0.03) and other embryonal tumors (p = 0.03). Longer SDI was not associated with increased risk of disease progression for LGG (p = 0.93), medulloblastoma (p = 0.89), or ependymoma (p = 0.5). No difference in SDI was found with regard to diagnosis era, ethnicity, socioeconomic status, or distance to the tertiary care facility. ConclusionSDI at our centre is longer than previously reported studies. SDI is linked to tumor biology and its relevance within specific tumor groups deserves further investigation given it doesn’t appear to predict tumor progression/recurrence, yet families and providers feel distress when delays in diagnosis are perceived.

OMIC-14. OPENPBTA: AN OPEN PEDIATRIC BRAIN TUMOR ATLAS

Pediatric brain tumors comprise a heterogeneous molecular and histological landscape that challenges most current precision-medicine approaches. While recent large-scale efforts to molecularly characterize distinct histological entities have dramatically advanced the field’s capacity to classify and further define molecular subtypes, developing therapeutic and less toxic molecularly-defined clinical approaches remains a challenge. To define new approaches to meet these challenges and advance scalable, shared biospecimen- and data-resources for pediatric brain tumors, the Children’s Brain Tumor Network and Pacific Pediatric Neuro-Oncology Consortium, in partnership with the Alex’s Lemonade Stand Foundation Childhood Cancer Data Lab, launched OpenPBTA, a global open science Pediatric Brain Tumor Atlas initiative to comprehensively define the molecular landscape of pediatric brain tumors. The initiative contains multi-modal analyses of research- and clinical-trial based DNA and RNA sequences from nearly 1,000 subjects (with 1,256 tumors) along with their longitudinal clinical data. The OpenPBTA’s open science framework for analysis tests the capacity of crowd-sourced collaborative architectures to advance more rapid, iterative and integrated discovery of the underlying mechanisms of disease across pediatric brain and spinal cord tumors. Since the launch of the project, OpenPBTA has collaboratively created reproducible workflows for integrated consensus SNV, CNV, and fusion calling, enabled RNA-Seq-based classification of medulloblastoma subtypes, and more than 25 additional DNA- and RNA-based analyses. The open-science platform and associated datasets and processed results provide a continuously updated, global view of the integrated cross-disease molecular landscape of pediatric brain tumors. Such biospecimen- and clinically-linked scalable data resources provide unprecedented collaborative opportunities for precision-based, personalized therapeutic discovery and drug development with the upcoming further integration of proteomic sample data (N >300) and drug response datasets, additionally diversifying the multimodal discovery potential of crowd-sourced approaches for accelerated impact for children with brain tumors.

EPCT-02. COMPARISON OF TARGETED AGENTS RECOMMENDED BY THE CNS-TAP TOOL TO THOSE SELECTED BY A TUMOR BOARD IN A MOLECULARLY-DRIVEN DIPG CLINICAL TRIAL

Recently, sequencing of diffuse intrinsic pontine glioma (DIPG) biopsy specimens has revealed genomic heterogeneity of these tumors, fueling an interest in individualized, targeted treatment options. The Pacific Pediatric Neuro-Oncology Consortium recently completed enrollment onto a feasibility study PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), in which a multidisciplinary tumor board recommended molecularly-targeted agents based on genomic and molecular profiling of each patient’s tumor. Separately, our group developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to allow for numeric scoring of targeted anticancer agents to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within CNS-TAP would overlap with the agents recommended by the tumor board in this study. For each PNOC003 participant, we utilized the genomic report to identify actionable alterations and input patient-specific data into CNS-TAP to identify the highest scoring agents. We compared high-scoring agents within CNS-TAP with recommendations from the PNOC003 tumor board for each of the enrolled 28 subjects. Overall, 93% (26/28) of patients had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% (37/95) of all agents recommended by the tumor board were also selected by CNS-TAP. Furthermore, we identified factors that likely contributed to the discordance between these two methods. Without clinician input, CNS-TAP is unable to account for drug-drug interactions, includes only designated anticancer agents, and cannot easily be updated in real time. However, CNS-TAP provides an objective evaluation of targeted therapies, whereas tumor boards are inherently subjective. Given the discordance identified between these methods and the strengths of each, a prospective study incorporating both CNS-TAP and a molecular tumor board for targeted therapy selection in DIPG patients is warranted.

FIREFLY-1: A phase 2 study of the pan-RAF inhibitor DAY101 in pediatric patients with low-grade glioma.

TPS10056 Background: The mitogen-activated protein kinase (MAPK) signaling pathway is an essential pathway that regulates key cell functions such as growth, survival, and differentiation. Genomic alterations and dysregulation of the MAPK pathway including BRAF fusions, point mutations (e.g. BRAF V600) and in-frame deletions have been described in many different types of malignancies, including pediatric low-grade glioma (pLGG) and other pediatric cancers. The identification of the KIAA1549:BRAF fusion in 2008 led to deeper understanding of the genomic events driving growth of pLGG (Jones, Cancer Res 2008). Despite the low-grade histology and excellent long-term survival, pLGGs are often associated with tumor- and treatment-associated morbidity and significant late-effects that persist throughout the lifespan of the patient. DAY101 is an oral, highly selective, CNS-penetrant small-molecule, Type II pan-RAF kinase inhibitor that is being developed for patients with pLGG harboring an activating BRAF-alteration. DAY101 has demonstrated tumor inhibition in preclinical models and has achieved clinically meaningful and durable responses in 7/8 patients with RAF-altered LGG in a pediatric phase 1 trial, including 2 complete responses, 3 partial responses, 2 stable disease and 1 progressive disease with a median time to response of 10.5 weeks. Patients have been treated for up to two years with no discontinuations due to toxicity or disease progression (Wright, SNO 2020). Methods: FIREFLY-1 is an open-label, multi-center, international Phase 2 study with DAY101 in pediatric and young adult patients between the ages of 6 months and 25 years with LGG harboring a documented BRAF-alteration as determined by local laboratory testing. DAY101 is administered orally once a week on a continuous 28-day schedule. Patients who respond will be treated for a minimum of two years after which they may at any point, opt to enter a “drug holiday” discontinuation period. Dosing is based on body surface area. DAY101 is available in a pediatric-friendly oral liquid formulation and tablets. The primary endpoint is objective response rate based on Response Assessment for Neuro-Oncology (RANO) as determined by an independent review committee. Secondary endpoints include objective response rate based on Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group criteria, duration of response and safety. Exploratory endpoints include quality-of-life measurements as well as functional outcomes. Molecular abnormalities will be characterized through the analysis of archival tissue. Enrollment began in February 2021 and is ongoing. Clinical trial information: NCT03429804.

Targeted agents recommended by the CNS TAP tool compared to those selected by a tumor board in a molecularly-driven clinical trial in children and young adults with DIPG.

2048 Background: Genetic sequencing of diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) biopsy specimens has revealed genomic heterogeneity, fueling an interest in individualized, targeted treatment options. The Pacific Pediatric Neuro-Oncology Consortium recently completed a feasibility study PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), in which a multidisciplinary tumor board recommended targeted agents based on the molecular and genetic profiling of each patient’s tumor. Separately, our group developed a numeric scoring tool of targeted anticancer agents, the Central Nervous System Targeted Agent Prediction (CNS TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to generate a numeric score for each agent to objectively evaluate these targeted therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within the CNS-TAP tool would overlap, at least in part, with the agents recommended by the molecular tumor board in PNOC003. Methods: For each study participant (n=28), a retrospective analysis was completed, utilizing the genomic report to identify actionable genetic alterations and to input patient-specific data into CNS TAP to identify the highest scoring agents. We compared high-scoring agents within the CNS TAP tool with recommendations from the PNOC003 tumor board for each of the enrolled 28 patients. Results: Overall, 93% (26/28) of patients had at least one agent recommended by both the tumor board and CNS TAP. Additionally, 39% (37/95) of all agents recommended by the tumor board were also selected by CNS TAP, with additional analysis ongoing. Conclusions: There was significant overlap between the highest-scoring and selected agents via CNS TAP compared with those chose by the molecular tumor board. Through this work, we also identified factors that likely contributed to the discordance in choice of targeted therapies. Without clinician input, the CNS TAP tool is unable to account for drug-drug interactions, includes only designated anticancer agents, and cannot easily be updated in real time, requiring extensive manual literature review for each included agent. However, CNS TAP provides an objective evaluation of targeted therapies, in contrast to inherently subjective recommendations of a tumor board. Given the discordance identified between these methods and the strengths of each, a prospective study incorporating both CNS TAP and a molecular tumor board for targeted therapy selection in patients with high grade glioma is warranted.

World Cancer Day 2021 - Perspectives in Pediatric and Adult Neuro-Oncology.

Significant advances in our understanding of the molecular genetics of pediatric and adult brain tumors and the resulting rapid expansion of clinical molecular neuropathology have led to improvements in diagnostic accuracy and identified new targets for therapy. Moreover, there have been major improvements in all facets of clinical care, including imaging, surgery, radiation and supportive care. In selected cohorts of patients, targeted and immunotherapies have resulted in improved patient outcomes. Furthermore, adaptations to clinical trial design have facilitated our study of new agents and other therapeutic innovations. However, considerable work remains to be done towards extending survival for all patients with primary brain tumors, especially children and adults with diffuse midline gliomas harboring Histone H3 K27 mutations and adults with isocitrate dehydrogenase (IDH) wild-type, O6 guanine DNA-methyltransferase gene (MGMT) promoter unmethylated high grade gliomas. In addition to improvements in therapy and care, access to the advances in technology, such as particle radiation or biologic therapy, neuroimaging and molecular diagnostics in both developing and developed countries is needed to improve the outcome of patients with brain tumors.

A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value.

Simple SummaryPediatric high-grade gliomas are incurable brain tumors for which there is a critical need for new therapeutic strategies as well as treatment-predictive biomarkers. This study examined the expression of DNA repair and cell cycle genes in pediatric high-grade gliomas with distinct driving mutations. The aim is to propose a novel classification of these tumors based on sub-groups exposing therapeutic vulnerabilities. Several DNA repair factors were identified that might become new diagnostic markers.Background: Pediatric high-grade gliomas (pHGGs) are the leading cause of mortality in pediatric neuro-oncology, displaying frequent resistance to standard therapies. Profiling DNA repair and cell cycle gene expression has recently been proposed as a strategy to classify adult glioblastomas. To improve our understanding of the DNA damage response pathways that operate in pHGGs and the vulnerabilities that these pathways might expose, we sought to identify and characterize a specific DNA repair and cell-cycle gene expression signature of pHGGs. Methods: Transcriptomic analyses were performed to identify a DNA repair and cell-cycle gene expression signature able to discriminate pHGGs (n = 6) from low-grade gliomas (n = 10). This signature was compared to related signatures already established. We used the pHGG signature to explore already transcriptomic datasets of DIPGs and sus-tentorial pHGGs. Finally, we examined the expression of key proteins of the pHGG signature in 21 pHGG diagnostic samples and nine paired relapses. Functional inhibition of one DNA repair factor was carried out in four patients who derived H3.3 K27M mutant cell lines. Results: We identified a 28-gene expression signature of DNA repair and cell cycle that clustered pHGGs cohorts, in particular sus-tentorial locations, in two groups. Differential protein expression levels of PARP1 and XRCC1 were associated to TP53 mutations and TOP2A amplification and linked significantly to the more radioresistant pHGGs displaying the worst outcome. Using patient-derived cell lines, we showed that the PARP-1/XRCC1 expression balance might be correlated with resistance to PARP1 inhibition. Conclusion: We provide evidence that PARP1 overexpression, associated to XRCC1 expression, TP53 mutations, and TOP2A amplification, is a new theranostic and potential therapeutic target.

Reporting morbidity associated with pediatric brain tumor surgery: are the available scoring systems sufficient?

Complications in pediatric neurooncology surgery are seldom and inconsistently reported. This study quantifies surgical morbidity after pediatric brain tumor surgery from the last decade in a single center, using existing morbidity and outcome measures. The authors identified all pediatric patients undergoing surgery for an intracranial tumor in a single tertiary pediatric neurosurgery center between January 2008 and December 2018. Complications between postoperative days 0 and 30 that had been recorded prospectively were graded using appropriate existing morbidity scales, i.e., the Clavien-Dindo (CD), Landriel, and Drake scales. The result of surgery with respect to the predetermined surgical aim was also recorded. There were 477 cases (364 craniotomies and 113 biopsies) performed on 335 patients (188 males, median age 9 years). The overall 30-day mortality rate was 1.26% (n = 6), and no deaths were a direct result of surgical complication. Morbidity on the CD scale was 0 in 55.14%, 1 in 10.69%, 2 in 18.66%, 3A in 1.47%, 3B in 11.74%, and 4 in 1.05% of cases. Morbidity using the Drake classification was observed in 139 cases (29.14%). Neurological deficit that remained at 30 days was noted in 8.39%; 78% of the returns to the operative theater were for CSF diversion. To the authors' knowledge, this is the largest series presenting outcomes and morbidity from pediatric brain tumor surgery. The mortality rate and morbidity on the Drake classification were comparable to those of published series. An improved tool to quantify morbidity from pediatric neurooncology surgery is necessary.

Targeted therapy for pediatric low-grade glioma.

Pediatric low-grade gliomas are the most frequent brain tumors in children. The standard approach for symptomatic unresectable tumors is chemotherapy. Recently, key molecular alterations/pathways have been identified and targeted drugs developed and tested in clinical trials. We describe our institutional experience with MAPK pathway targeted therapy. We retrospectively reviewed the medical reports of 23 patients diagnosed with PLGG and treated with either trametinib or dabrafenib at Hospital Sant Joan de Dèu (Barcelona, Spain). Patients with neurofibromatosis were excluded. Objective response rate (ORR) and disease control rate (DCR) were determined using the Response Assessment in Pediatric Neuro-Oncology criteria in low-grade glioma. ORR was defined as the proportion of patients with the best overall response including complete remission (CR) or partial remission (PR). DCR was the sum of the CR, PR, and stable disease (SD) rates. ORR with trametinib was 0% (95% CI, 0%-23.2%) and DCR was 78.6% (95% CI, 49.2%-95.3%). Eleven patients had SD and three patients presented PD. ORR with dabrafenib was 41.7% (95% CI, 16.5%-71.4%), including four CR and one patient with PR. DCR with dabrafenib was 100% (95% CI, 73.5%-100%); there were seven SD and none PD. Treatment was well tolerated. Only three patients, on trametinib, presented grade 3 adverse effects: leukocytoclastic vasculitis, cheilitis, and bone infection. Our experience adds to the growing data about the efficacy and tolerability of targeted therapy in patients with PLGG. When present, toxicity is mainly mild-moderate and transient. Ongoing prospective clinical trials are trying to address if its use should be advanced to first-line therapy.

Evofosfamide Is Effective against Pediatric Aggressive Glioma Cell Lines in Hypoxic Conditions and Potentiates the Effect of Cytotoxic Chemotherapy and Ionizing Radiations.

Simple SummaryDespite many therapeutic approaches attempted over the last years, the prognosis of children with high-grade glioma or diffuse intrinsic pontine glioma remains dismal. Hypoxia-activated prodrugs (HAPs) were developed to target hypoxic areas within solid tumors as gliomas. Evofosfamide (Evo) is a 2nd generation HAP exhibiting significant preclinical and clinical activities against adult glioblastoma. We thus investigated the potential of Evo in six pediatric glioma cell lines. Interestingly, we showed that the growth of all cell lines was inhibited by Evo, mainly under hypoxia as expected. We also evidenced a significant synergism between Evo and three drugs widely used in pediatric oncology. Finally, Evo appeared able to potentiate the effect of ionizing radiations. Since these tumors are highly hypoxic and Evo appears effective in hypoxic glioma cells as a single drug and in combination with radio- and chemotherapy, hypoxia-activated prodrugs could represent a promising therapeutic option for children with brain tumors.Hypoxia is a hallmark of many solid tumors and is associated with resistance to anticancer treatments. Hypoxia-activated prodrugs (HAPs) were developed to target the hypoxic regions of these tumors. Among 2nd generation HAPs, Evofosfamide (Evo, also known as TH-302) exhibits preclinical and clinical activities against adult glioblastoma. In this study, we evaluated its potential in the field of pediatric neuro-oncology. We assessed the efficacy of Evo in vitro as a single drug, or in combination with SN38, doxorubicin, and etoposide, against three pediatric high-grade glioma (pHGG) and three diffuse intrinsic pontine glioma (DIPG) cell lines under hypoxic conditions. We also investigated radio-sensitizing effects using clonogenic assays. Evo inhibited the growth of all cell lines, mainly under hypoxia. We also highlighted a significant synergism between Evo and doxorubicin, SN38, or etoposide. Finally, Evo radio-sensitized the pHGG cell line tested, both with fractionated and single-dose irradiation schedules. Altogether, we report here the first preclinical proof of evidence about Evofosfamide efficiency against hypoxic pHGG and DIPG cells. Since such tumors are highly hypoxic, and Evo potentiates the effect of ionizing radiation and chemotherapy, it appears as a promising therapeutic strategy for children with brain tumors.

Evaluation of the Pediatric Neuro-Oncology Resources Available in Chile.

PURPOSEPediatric neuro-oncology resources are mostly unknown in Chile. We report the human and material resources available in Chilean hospitals providing pediatric neuro-oncology services.METHODSA cross-sectional survey was distributed to 17 hospitals providing pediatric neuro-oncology services (Programa Infantil Nacional de Drogas Antineoplásicas [PINDA] hospitals, 11; private, 6).RESULTSResponse 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.CONCLUSIONA 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.

Integration of cancer registry and electronic health record data to construct a childhood cancer survivorship cohort, facilitate risk stratification for late effects, and assess appropriate follow-up care.

This retrospective study harnessed an institutional cancer registry to construct a childhood cancer survivorship cohort, integrate electronic health record (EHR) and geospatial data to stratify survivors based on late-effect risk, analyze follow-up care patterns, and determine factors associated with suboptimal follow-up care. The survivorship cohort included patients ≤18years of age reported to the institutional cancer registry between January 1, 1994 and November 30, 2012. International Classification of Diseases for Oncology, third revision (ICD-O-3) coding and treatment exposures facilitated risk stratification of survivors. The EHR was linked to the cancer registry based on medical record number (MRN) to extract clinic visits. Five hundred and ninety pediatric hematology-oncology (PHO) and 275 pediatric neuro-oncology (PNO) survivors were included in the final analytic cohort. Two hundred and eight-two survivors (32.6%) were not seen in any oncology-related subspecialty clinic at Duke 5-7years after initial diagnosis. Factors associated with follow-up included age (p=.008), diagnosis (p<.001), race/ethnicity (p=.010), late-effect risk strata (p=.001), distance to treatment center (p<.0001), and area deprivation index (ADI) (p=.011). Multivariable logistic modeling attenuated the association for high-risk (OR 1.72; 95% CI 0.805, 3.66) and intermediate-risk (OR 1.23, 95% CI 0.644, 2.36) survivors compared to survivors at low risk of late effects among the PHO cohort. PNO survivors at high risk for late effects were more likely to follow up (adjusted OR 3.66; 95% CI 1.76, 7.61). Nearly a third of survivors received suboptimal follow-up care. This study provides a reproducible model to integrate cancer registry and EHR data to construct risk-stratified survivorship cohorts to assess follow-up care.

Transitioning to molecular diagnostics in pediatric high-grade glioma: experiences with the 2016 WHO classification of CNS tumors.

BackgroundPediatric neuro-oncology was profoundly changed in the wake of the 2016 revision of the WHO Classification of Tumors of the Central Nervous System. Practitioners were challenged to quickly adapt to a system of tumor classification redefined by molecular diagnostics.MethodsWe designed a 22-question survey studying the impact of the revised WHO classification on pediatric high-grade glioma. The survey collected basic demographics, general attitudes, issues encountered, and opinions on pediatric subtypes. Participant answers were analyzed along socioeconomic lines utilizing the human development index (HDI) of the United Nations and membership in the group of seven (G7) world economic forum.ResultsFour hundred and sixty-five participants from 53 countries were included, 187 pediatric neurooncologists (40%), 160 neuropathologists (34%), and 118 other experts (26%). When asked about pediatric high-grade glioma entities, participants from very high development countries preferred treating a patient based on genetic findings. Participants from high and medium development countries indicated using traditional histology and tumor location as mainstays for therapeutic decisions. Non-G7 countries tended to regard the introduction of molecularly characterized tumor entities as a problem for daily routine due to lack of resources.ConclusionsOur findings demonstrate an overall greater reliance and favorability to molecular diagnostics among very high development countries. A disparity in resources and access to molecular diagnostics has left some centers unable to classify pediatric high-grade glioma per the WHO classification. The forthcoming edition should strain to abate disparities in molecular diagnostic availability and work toward universal adaptation.

The Treatment Outcomes in Children with Medulloblastoma

Background: Medulloblastoma is the most common central nervous system tumor in childhood. This study aims to evaluate the clinical features, treatments, and outcomes of pediatric patients diagnosed with medulloblastoma Materials and Method:Between 2006 and 2019, the medical records of children with medulloblastoma were reviewed retrospectively. Patients who died after surgery, before chemotherapy or radiotherapy were not included in the survival analysis Results: During the study period, 38 children were diagnosed with medulloblastoma. Twenty-one of the patients were male (55.3%) and 17 were female (44.7%). The ages of the children ranged from 3 months to 17 years (median age 8 years). The ages of five patients were under 3 years (13.1%). The most common complaints were headache (n: 26, 68.4%), imbalance (n: 21, 55.3%), and vomiting (n: 20, 52.6%). The mass sizes ranged between 3 and 6 cm in 32 patients (84.2%). At the time of diagnosis, 5 patients had seeding metastasis (13.1%). The most commonlyused chemotherapy protocol included vincristine, cisplatin, etoposide (60.5%). Five patients died after surgery without any chemotherapy or radiotherapy. Of the 33 patients included in the life analysis, 12 died (36.4%). Follow-up times ranged from 2 months to 14 years (median, 44 months). The overall survival rate was 59.1%. Eight patients had relapsed (24.2%). Late relapse was detected in 3 of the relapsed patients (relapse times were the 91st, 69th, and 72nd months). Conclusions: It is possible to achieve satisfactory treatment results in children with medulloblastoma using international treatment guidelines and recommendations, with an experienced professional team dedicated to pediatric neurooncology.

Canadian Pediatric Neuro-Oncology Standards of Practice.

Primary CNS tumors are the leading cause of cancer-related death in pediatrics. It is essential to understand treatment trends to interpret national survival data. In Canada, children with CNS tumors are treated at one of 16 tertiary care centers. We surveyed pediatric neuro-oncologists to create a national standard of practice to be used in the absence of a clinical trial for seven of the most prevalent brain tumors in children. This allowed description of practice across the country, along with a consensus. This had a multitude of benefits, including understanding practice patterns, allowing for a basis to compare in future research and informing Health Canada of the current management of patients. This also allows all children in Canada to receive equivalent care, regardless of location.

Paediatric posterior fossa tumour resection rates in a small volume centre: the past decade’s experience

Background Paediatric brain tumour resection rates have been shown to correlate with outcome and, it is argued, are linked to operator volume and caseload. The British paediatric neurosurgery community has previously debated centralisation of paediatric neuro-oncology. At the 2018 British Paediatric Neurosurgery Group (BPNG) meeting, a commitment was made to prospectively collect tumour resection data at each Neurosurgical Unit (NSU). Here we review our prospectively-collected 10-year database of the three commonest paediatric posterior fossa tumours – astrocytomas, medulloblastomas and ependymomas. Materials and methods Our primary outcome was extent of resection (EOR) on post-operative MRI scans reviewed by neuro-radiologists. Secondary outcomes comprised neurosurgical morbidity including infection, need for cerebrospinal fluid (CSF) diversion and the occurrence of posterior fossa syndrome (PFS). Results 55 children had 62 operations, where our complete resection rates for pilocytic astrocytomas, medulloblastomas and ependymomas were 77%, 79% and 63%, respectively. Both our primary and secondary outcomes were in keeping with the published literature and we discuss here some of the factors which may contribute towards favourable outcomes in a small volume centre. Conclusion Our results suggest that small volume centres can expect equivalent results to larger volume NSUs with regards to paediatric brain tumour surgery. Continuing efforts nationally for data collection on resection rates and operative outcomes is a key step towards optimising management in these children.

QOL-57. SOUTHERN CALIFORNIA KAISER PERMANENTE PEDIATRIC NEURO-ONCOLOGY PROGRAM DEVELOPMENT

KEY MESSAGEStandardization of care for subspecialty patients require centralization and support across multi-disciplinary groups within the Kaiser Permanente medical group, which is a large health maintenance organization (HMO) in the United States.BACKGROUNDPrior to the development of a Pediatric Neuro-Oncology program, Southern California Kaiser Permanente pediatric neuro-oncology patients were routinely referred to respective regional academic centers for consultation. The process was not standard across the region, resulting in additional costs and differences in treatment recommendations, potentially affecting outcomes.METHODSA Pediatric Neuro-Oncology program was established, July 2017, based at the Kaiser Permanente Los Angeles Medical Center (LAMC), consisting of pediatric neuro-oncology, pediatric neurosurgery, pediatric neuro-radiology, pediatric radiation oncology, and pediatric neuro-oncology case management.RESULTSA Pediatric Neuro-Oncology tumor board was established to meet on a bi-monthly basis. Pediatric neuro-oncology patients across the Southern California now have their magnetic resonance imaging (MRI) reviewed by the same pediatric neuro radiologists. Neuropathology is standardized and sent to Children’s Hospital Los Angeles and reviewed at the molecular neuropathology tumor board attended by the pediatric neuro-oncologist. Cases discussions regarding the patients include the regional pediatric neurosurgeons, the pediatric radiation oncologists, and the pediatric neuro-oncologist, and treatment plans are recommended and recorded by the case manager.CONCLUSIONSCentralization of care has allowed for more consistent and standard care across the Southern California Region, but requires support from multi-disciplinary groups.

LINC-35. THE ST. JUDE GLOBAL ACADEMY NEURO-ONCOLOGY TRAINING SEMINAR: A MULTIDISCIPLINARY, INTERNATIONAL EDUCATION PROGRAM

The success of the treatment of children with central nervous system (CNS) tumors relies on an effective multidisciplinary team, with up-to-date and broad knowledge and skills. The St. Jude Global Academy Neuro-Oncology Training Seminar was launched as course in globally applicable content in pediatric neuro-oncology with a focus on multidisciplinary teams in low- and middle-income countries (LMICs). To identify the content that is most relevant for the learners, a needs assessment survey that included evaluation of team dynamics, treatment capacity, existing knowledge, and educational goals was designed. Survey questions in 11 domains were answered by 24 sites in LMICs across the world. This information was used to create the course that consists of two components: a 9-week online course and a 10-day workshop at the St. Jude campus. 72 participants from 11 institutions enrolled in the online portion and 20 participants were selected based on grades to attend the workshop. A retrospective post-test evaluation established that learners improved their understanding of the barriers to care, possible solutions to improve care, understanding of diagnosis and treatment, and methodology to implement projects (p<0.01). All participating teams developed projects that are locally implemented. Those present at the workshop formed a multidisciplinary, international collaborative group (Global Alliance in Pediatric Neuro-Oncology). This experience establishes that educational programs with systematically created curricula can not only improved knowledge but be a mechanism to share experiences and create collaborative networks. Ultimately, patient outcomes will be tracked to monitor the true impact of the course.