Primary Pediatric Brain Tumors Research Articles

Abstract 6565: Improving survival of atypical teratoid/rhabdoid tumor orthotopic xenografts through the combination of PI3K inhibitor paxalisib and nucleoside analog gemcitabine

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are an aggressive infantile brain tumor with a dismal four-year event-free survival of 37%. We have previously identified high activation of mTORC1 and mTORC2 within AT/RT and shown that the highly brain penetrant PI3K inhibitor paxalisib is capable of simultaneously inhibiting mTORC1/2 by acting upstream of both complexes. In two orthotopic xenograft models, paxalisib slowed tumor growth and significantly extended survival (CHLA-06: 40 to 54 days, p=0.001; BT-12: 21 to 35 days, p=0.02). RNAseq analysis following mTOR inhibition in AT/RT cell lines showed an upregulation of genes involved in the activation of the integrated stress response (ISR) (ATF4, CHOP, PPP1R15A t-test p<0.05). Analysis of primary pediatric brain tumors through the Children’s Brain Tumor Network showed increased levels of ATF4 mRNA and eIF2α protein and mRNA in AT/RT compared to other indolent pediatric brain tumors. Increased expression of ISR components suggests this pathway may be a dependency in AT/RT. Activation of this pathway is known to be cytoprotective, however persistent over-activation drives cell death through induction of pro-apoptotic factors. Gemcitabine is a pyrimidine analog functioning to inhibit DNA synthesis and induce DNA damage; notably, recent literature has correlated DNA damage to activation of the ISR with downstream phosphorylation of eIF2α. We hypothesize that due to high baseline activation of ISR for AT/RT, paxalisib combined with gemcitabine will result in an over-activation of the ISR leading to AT/RT cell death. Western blot analysis of combination therapy compared to DMSO control showed induction of phospho-eIF2α, ATF4, and CHOP, denoting an activation of the ISR. Combination therapy in AT/RT cells induces cell death (Western blot analysis cPARP, MUSE Annexin V assay, SynergyFinder BLISS score [viability] CHLA-06: 21.50, CHLA-266: 22.60) and synergizes to decrease cell growth (SynergyFinder BLISS score [inhibition] CHLA-06: 16.80, BT-12: 14.30, CHLA-266: 13.90, BT-37: 11.40, CHLA-05: 10.40). Paxalisib/gemcitabine combination therapy in murine orthotopic xenograft models of AT/RT has slowed tumor growth (bioluminescent imaging) and led to significant extension of survival. Mice bearing BT-37 orthotopic xenografts and treated with vehicle control had a median survival of 56 days, while all of the paxalisib/gemcitabine treated mice were alive at 100 days of treatment (p<0.0001). In CHLA-06 orthotopic tumors combination therapy extended median survival from 22 days for control to 82.5 days (p<0.0001). Based on these findings, the Pacific Pediatric Neuro-Oncology Consortium (PNOC) is planning to include paxalisib/gemcitabine combination therapy in the next international clinical trial for patients with relapsed/recurrent AT/RT. Citation Format: Tyler Findlay, Kristen Malebranche, Anupa Geethadevi, Charles Eberhart, Jeffrey Rubens, Eric Raabe. Improving survival of atypical teratoid/rhabdoid tumor orthotopic xenografts through the combination of PI3K inhibitor paxalisib and nucleoside analog gemcitabine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6565.

Intraventricular Ependymoma in Pediatric Patients: A Systematic Review of Demographics, Clinical Characteristics, and Outcomes

Background: Intraventricular neoplasms are rare occurrences observed in 5 – 7% of all primary pediatric brain tumors. Pediatric intraventricular ependymomas are a complex subset of these tumors, poorly discussed across the current literature. Although surgery is generally the accepted treatment of choice, information on clinical course and outcomes is limited to heterogeneous case reports and small case series focusing on specific histologic subtypes or ventricular locations. We conducted a systematic review on pediatric intraventricular ependymomas to survey the patient population, tumor characteristics, management strategies, and associated outcomes.
 Project Methods: PubMed, Scopus, Web-of-Science, and Cochrane were searched upon the PRISMA guidelines to include studies reporting pediatric patients with intraventricular ependymomas. Clinical characteristics, treatment protocols, and outcomes were analyzed.
 Results: A total of 9 studies with 70 patients were included. Most patients were male (54%), diagnosed at a mean age of 7 years (range, 0.2-17), and frequently exhibited nausea and vomiting (38%), headache (31%), and ataxia (25%). Tumors were predominantly located in the fourth ventricle (79%) and most tumors were WHO grade 2 (73%). Mean tumor volume was 3 cm3 (range, 0.1-13.2). Management included surgical resection (96%), radiotherapy (87%), and chemotherapy (38%). Gross total resection was achieved in 69% of cases. Cranial nerve deficit was the most common post-surgical complication (71%). Most common combination of treatment included surgical resection and radiotherapy (53%). Mean overall survival was 50 months in these patients.
 Conclusion/Impact: Pediatric intraventricular ependymomas are rare tumors with limited information on management strategies. The mainstay of treatment is complete surgical resection. Compared to ependymomas, intraventricular ependymomas appear to have a worse overall prognosis.

MDB-21. THE OTX2-REGULATED ALTERNATIVE SPLICING LANDSCAPE CONTROLS DIFFERENTIATION AND RECONSTITUTES THE DEVELOPMENTAL ORIGINS OF GROUP 3 MEDULLOBLASTOMA

Abstract Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor with Group 3 MB exhibiting the worst prognosis. Overexpression/amplification of OTX2 is a molecular hallmark of Group 3 MB and is primarily known to control tumor growth through regulation of cell cycle. Here, we utilized mass spectrometry and RNA-sequencing to report a non-canonical role for OTX2 in regulating alternative splicing. RNA-sequencing conducted on two OTX2-silenced Group 3 MB tumorsphere models identified 48 differentially spliced genes (DSG) associated with RNA processing, splicing and neurodevelopment that were common between both cell lines. Further interrogation of the OTX2-regulated DSGs revealed that 15 are also significantly correlated with OTX2 expression in a set of Group 3/Group 4 MB patient samples. Pseudotime mapping of the developmental trajectories of the DSGs onto the developing rhombic lip (RL) revealed significant overlap with RL lineages, including the majority of the 15 shared OTX2-regulated DSGs. We then functionally validated specific alternatively spliced exons of two DSGs, PPHLN1 and MADD which represent “early” and “late” RL developmental stages, respectively. PPHLN1 and MADD splice-blocking morpholinos were utilized to drive exon skipping and recapitulate splicing events identified in OTX2-silenced or OTX2-wildtype tumorspheres. Exon skipping altered tumorigenic properties of Group 3 MB cells in vitro, including tumorsphere size and number. Additionally, intracerebellar injections of Group 3 MB cells treated with PPHLN1 morpholino impaired tumor initiation and growth in vivo. Further breakdown of Group 3/Group 4 MBs by PPHLN1 and MADD percent spliced in (PSI) revealed that the PPHLN1 high/MADD low PSI signature observed in our OTX2 wildtype tumorspheres is associated with the most aggressive and primitive Group 3g subtype. Together, our findings reveal a previously unrecognized regulatory role for OTX2 in controlling Group 3 MB AS and offer fresh opportunities to exploit MB-specific AS events therapeutically to abrogate tumor progression.

Global trends, gaps, and future agenda in medulloblastoma research: a bibliometric analysis.

Medulloblastoma is the most common malignant primary pediatric brain tumor. Over the years, an increase in published research has been observed on this topic. However, there is a lack of analysis on the characteristics and trends and the socioeconomic indicators associated with medulloblastoma research productivity and impact. The Scopus database was used to search all articles from inception to 2020. Bibliometric information was obtained from Scopus, and bibliometrics diagrams were created using VOSviewer software. Statistical analysis was performed using the GraphPad Prism software version 7. A total of 4058 research articles on medulloblastoma research worldwide were included in this study. There has been an increase in published articles, with a steep increase observed in the last decade. The country with the most publications is the USA, with St. Jude Children's Research Hospital as the most productive institution in medulloblastoma research. The articles mainly focused on molecular biology, diagnosis, treatment, prognostic factors for medulloblastoma, and research on other pediatric tumors. The number of collaborations with other countries showed the strongest positive correlation with scientificproductivity. This analysis showed the trend and characteristics of published articles. The results of this study emphasized the need to increase funding for research, support for researchers and physicians, and promote more collaborations with countries and institutions engaged in medulloblastoma research.

Immunotherapy for the treatment of pediatric brain tumors: a narrative review.

The goal of this narrative review is to report and summarize the completed pediatric immunotherapy clinical trials for primary CNS tumors. Pediatric central nervous system (CNS) tumors are the most common cause of pediatric solid cancer in children aged 0 to 14 years and the leading cause of cancer mortality. Survival rates for some pediatric brain tumors have improved, however, there remains a large portion of pediatric brain tumors with poor survival outcomes despite advances in treatment. Cancer immunotherapy is a growing field that has shown promise in the treatment of pediatric brain tumors that have historically shown a poor response to treatment. This narrative review provides a summary and discussion of the published literature focused on treating pediatric brain tumors with immunotherapy. MEDLINE via PubMed, Embase and Scopus via Elsevier were searched. The search utilized a combination of keywords and subject headings to include pediatrics, brain tumors, and immunotherapies. Manuscripts included in the analysis included completed clinical studies using any immunotherapy intervention with a patient population that consisted of at least half pediatric patients (<18 years) with primary CNS tumors. Conference abstracts were excluded as well as studies that did not include completed safety or primary outcome results. Search results returned 1,494 articles. Screening titles and abstracts resulted in 180 articles for full text review. Of the 180 articles, 18 were included for analysis. Another two articles were ultimately included after review of references and inclusion of newly published articles, for a total of 20 included articles. Immunotherapies included dendritic cell vaccines, oncolytic virotherapy/viral immunotherapy, chimeric antigen receptor (CAR) T-cell therapy, peptide vaccines, immunomodulatory agents, and others. In this review, 20 published articles were highlighted which use immunotherapy in the treatment of primary pediatric brain tumors. To date, most of the studies published utilizing immunotherapy were phase I and pilot studies focused primarily on establishing safety and maximum dose-tolerance and toxicity while monitoring survival endpoints. With established efficacy and toxicity profiles, future trials may progress to further understanding the overall survival and quality of life benefits to pediatric patients with primary brain tumors.

Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors

BackgroundPediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma...

Radiotherapy in the management of diffuse intrinsic pontine glioma- Three clinical cases with literature review

Diffuse intrinsic pontine glioma (DIPG) is an aggressive primary pediatric brain tumor. Typical DIPG was defined radiographically as a poorly defined tumor with mass effect occupying ≥75% of the pontine axial diameter that was hypointense on T1-weighted MR images and hyperintense on T2-weighted images. We present three children with DIPG after radiotherapy (RT) in order to expand the knowledge of this aggressive brain tumor and to emphasize the main role of the radiation method in its treatment. Our observations from the realized RT are that despite highly risky tumor localization, conventional and hypophractionated RT are well tolerated, without acute neurological toxicity and allow second irradiation /re-irradiation, due to local tumor progression. The atypical MRI image of the pontine tumors requires a stereotaxic biopsy or spectroscopic MRI. With a biopsy or MRI data on undifferential malignant tumor such as glioblastoma and meduloblastoma, radiation strategy is much more accurately assessed, as well as the need for craniospinal RT.

EPID-07. Outcome disparities in children, adolescents and young adults with medulloblastoma: A population-based analysis

Abstract Medulloblastoma (MB) is the most common high-grade primary pediatric brain tumor. Recent registry-based studies in children with central nervous system (CNS) tumors have demonstrated that survival outcomes differ by race/ethnicity in multivariable analyses, with Hispanic patients having highest hazard of death overall. To investigate this finding in MB patients, we examined survival in children (0-14 years) and adolescent/young adults (15-39 years) with MB from 2007-2016 in the 2018 Surveillance Epidemiology and End Results Program database, using Kaplan Meier analysis, log-rank test and Cox proportional hazard ratios (HR) with 95% confidence intervals (CI). Race and ethnicity were categorized according to the U.S. Census, with Hispanic ethnicity (yes/no) analyzed separately from race (Black, White, Asian, Other). Among 1612 patients, 81% were White, 9% were Black, 8% were Asian or Pacific Islander, and 2% were from “other” or unknown racial groups. 28% of the cohort was of Hispanic ethnicity. Univariate analysis found that Black patients had a significantly higher hazard of death than White patients (HR=1.55, CI: 1.16 – 2.08, p=0.003). In contrast, Hispanic ethnicity was not significantly associated with outcome (HR=0.98, CI: 0.79-1.21, p=0.8). Medicaid or no insurance (vs. private) were each significantly associated with higher risk of death; Medicaid (HR =1.23, CI = 1.01 - 1.51, p=0.041); Uninsured (HR=2.07, CI=1.41-3.02, p=&amp;lt;0.001). Of the treatment modalities analyzed, patients who received neither chemotherapy nor radiation experienced higher hazard of death than patients who received both treatments (HR=3.63, CI 2.78-4.76, p=&amp;lt;0.001). Consistent with observations in other cancers, racial disparities are observed in patients with MB, with Black race conferring increased risk of death. Public insurance was also significantly associated with death, as was not receiving combined-modality therapy. Further work is needed to understand the multilevel factors impacting diagnosis, treatment and outcome among children and AYAs with MB and prospective studies are warranted.

GCT-20. Multi-Institutional Analysis of Pediatric Relapsed/Refractory Central Nervous System Germ Cell Tumors

Central nervous system (CNS) germ cell tumors (GCTs) constitute ~ 4% of primary pediatric brain tumors in the United States. While multimodality therapy approaches have ensured >80% survival benefit, these patients still experience relapses, with no established standard of care. Their rarity limits knowledge of their outcomes and associations with location, metastatic status, impact of surgery, serum, and cerebrospinal fluid (CSF) biomarkers, to only a few smaller trials and case series.This international multi-institutional retrospective study for relapsed/refractory germinomas and NGGCTs, will evaluate the association between different treatment modalities and 5-year OS and EFS; patterns of relapse, including along biopsy tracts; and potentially identify predictors of recurrence. De-identified patient data at primary and relapse time points will be collected focusing on treatment approaches such as surgery, conventional/high dose chemotherapy, photon/proton radiation therapy; timing and site of relapse; imaging characteristics and serum/CSF biomarkers (BHCG/AFP). Our collaborators include multiple sites across North America, Australia, Europe, Africa, South America, the Middle east, India, Singapore, and Malaysia. 6 recurrent intracranial germinomas on the CBTN (Children’s Brain Tumor Consortium) database were assessed, demonstrating a male gender preponderance (4) and recurring in the suprasellar region (3), frontal lobe (2) and spinal cord (1). 2 underwent gross total resection while 1 had biopsy only. Conventional or high-dose chemotherapy was administered in 5, while 2 received craniospinal and 1 proton radiation. 4 patients are alive. Median OS was 738 days and EFS 1093 days. However, biomarker (AFP/BHCG) data was unavailable. Updated results will be presented at the conference. With global partnership and contribution, we anticipate this study to help bridge existing gaps in our knowledge of this rare patient cohort and establish a consensus standard of care, through prospective clinical trials in the future. We acknowledge the CBTN for kindly providing data access.

Clinical Observations after Radiotherapy with Re-Irradiation of Diffuse Intrinsic Pontine Glioma in Childhood - Clinical Case with Literature Review

Diffuse intrinsic pontine glioma (DIPG) is an aggressive primary pediatric brain tumor. Despite the application of various curative methods, including radiotherapy (RT) with or without chemotherapy (Ch), targeted agents and immunological approaches, there is no achievement of clear improvement in median overall or progression-free survival (PFS). We present a 6-year-old girl with DIPG after a 3 D conformal radiotherapy (3D CRT) in the brain stem tumor with a 1.5 cm insurance zone, by three fractions gradually rising daily doses (DD) 1,6 Gy -1,8 Gy -2.2 Gy, followed by 11 fractions hypofractionated RT with DD 3 Gy up to total dose (TD) 33 Gy. The sum of total tumor dose is 38.6 Gy, corresponding to a biological equivalent dose to 2 Gy/ equieffective dose (EQD2) 46.71 Gy. After 8 months, due to local tumor progression, local tumor re-irradiation up to TD 20 Gy with DD 2 Gy was performed. In children with rapidly enhancing neurological symptoms and worsened forecast, it is appropriate to carry out hypophractionated RT up to 45 Gy with DD 3 Gy in 15 fractions, which achieves PFS similar to conventional fractionated RT. Our observations from the realized RT are that despite highly risky tumor localization, hypophractionated RT is well tolerated, without acute neurological toxicity and allows second irradiation / re-irradiation, due to local tumor progression.

Synthetic extracellular matrices and astrocytes provide a supportive microenvironment for the cultivation and investigation of primary pediatric gliomas.

Pediatric gliomas comprise a diverse set of brain tumor entities that have substantial long-term ramifications for patient survival and quality of life. However, the study of these tumors is currently limited due to a lack of authentic models. Additionally, many aspects of pediatric brain tumor biology, such as tumor cell invasiveness, have been difficult to study with currently available tools. To address these issues, we developed a synthetic extracellular matrix (sECM)-based culture system to grow and study primary pediatric brain tumor cells. We developed a brain-like sECM material as a supportive scaffold for the culture of primary, patient-derived pediatric glioma cells and established patient-derived cell lines. Primary juvenile brainstem-derived murine astrocytes were used as a feeder layer to support the growth of primary human tumor cells. We found that our culture system facilitated the proliferation of various primary pediatric brain tumors, including low-grade gliomas, and enabled ex vivo testing of investigational therapeutics. Additionally, we found that tuning this sECM material allowed us to assess high-grade pediatric glioma cell invasion and evaluate therapeutic interventions targeting invasive behavior. Our sECM culture platform provides a multipurpose tool for pediatric brain tumor researchers that enables both a wide breadth of biological assays and the cultivation of diverse tumor types.

The epidemiology of primary and metastatic brain tumors in infancy through childhood.

To evaluate the epidemiology of primary and metastatic pediatric brain tumors in the United States according to the WHO CNS 4th and 5th editions classifications. Pediatric patients (age ≤ 14) presenting between 2004 and2017 with a brain tumor were identified in the National Cancer Database and categorized by NICHD age stages. Patients' age, sex, race/ethnicity, overall survival, and tumor characteristics were evaluated according to WHO CNS 4th and 5th editions. 23,978 pediatric brain tumor patients were identified. Overall, other (i.e. circumscribed) astrocytic gliomas (21%), diffuse astrocytic/oligodendroglial gliomas (21%; 64% of which were midline), and embryonal tumors (16%) predominated. A minority of brain tumors were of ependymal (6%), glioneuronal & neuronal (6%), germ cell tumor (GCT; 4%), mesenchymal non-meningothelial (2%), cranial nerve (2%), choroid plexus (2%), meningioma (2%), pineal (1%), and hematolymphoid (0.4%) types. GCTs were more likely in patients of Asian/Pacific Islander race/ethnicity. Brain metastases were exceedingly rare, accounting for 1.4% overall, with the most common primary tumor being neuroblastoma (61%) and non-CNS sarcoma (16%). Brain metastatic, choroid plexus, and embryonal tumors peaked during infancy and toddlerhood; whereas diffuse gliomas peaked in middle-late childhood. GCTs and glioneuronal & neuronal tumors uniquely displayed bimodal distributions, with elevated prevalence in both infancy and middle-to-late childhood. We systematically described the epidemiology of pediatric brain tumors in the context of contemporary classification schema, thereby validating our current understanding and providing key insights.

Palliative endoscopic third ventriculostomy for pediatric primary brain tumors: a single-institution case series.

Children with nonoperative brain tumors, such as diffuse intrinsic pontine gliomas (DIPGs), often have life-threatening hydrocephalus. Palliative shunting is common in such cases but can be complicated by hardware infection and mechanical failure. Endoscopic third ventriculostomy (ETV) is a minimally invasive alternative to treat hydrocephalus without implanted hardware. Herein, the authors report their institutional experience with palliative ETV for primary pediatric brain tumors. The authors conducted a retrospective review of consecutive patients who had undergone palliative ETV for hydrocephalus secondary to nonresectable primary brain tumors over a 10-year period at Rady Children's Hospital. Collected variables included age, sex, tumor type, tumor location, presence of leptomeningeal spread, use of a robot for ETV, complications, ETV Success Score (ETVSS), functional status, length of survival, and follow-up time. A successful outcome was defined as an ETV performed without clinically significant perioperative complications or secondary requirement for a new shunt. Fifteen patients met the study inclusion criteria (11 males, 4 females; average age 7.9 years, range 0.8-21 years). Thirteen patients underwent manual ETV, and 2 patients underwent robotic ETV. Preoperative symptoms included gaze palsy, nausea/vomiting, headache, lethargy, hemiparesis, and seizures. Tumor types included DIPG (3), intraventricular/thalamic glioblastoma (2), and leptomeningeal spread of medulloblastoma (2), anaplastic oligo-/astrocytoma (2), rhabdoid tumor (2), primitive neuroectodermal tumor (1), ganglioglioma (1), pineoblastoma (1), and embryonal carcinoma (1). The mean preoperative ETVSS was 79 ± 8.8. There was 1 perioperative complication, a wound breakdown consistent with refractory hydrocephalus. The mean follow-up was 4.9 ± 5.5 months overall, and mean survival for the patients who died was 3.2 ± 3.6 months. Two patients remained alive at a mean follow-up of 15.7 months. Palliative ETV was successful in 7 patients (47%) and unsuccessful in 8 (53%). While patients with successful ETV were significantly older (11.9 ± 5.6 vs 4.4 ± 4.1 years, p = 0.010), there were no significant differences in preoperative ETVSS (p = 0.796) or postoperative survival (p = 0.476) between the successful and unsuccessful groups. Overall, functional outcomes were similar between the two groups; there was no significant difference in posttreatment Karnofsky Performance Status scores (68.6 ± 19.5 vs 61.3 ± 16.3, p = 0.454), suggesting that including ETV in the treatment algorithm did not worsen outcomes. Palliative ETV is a safe and potentially efficacious treatment option in selected pediatric patients with hydrocephalus from nonoperative brain tumors. Close follow-up, especially in younger children, is required to ensure that patients with refractory symptoms receive appropriate secondary CSF diversion.

Epidemiologic profile and outcome of primary pediatric brain tumors in Iran: retrospective study and literature review.

Primary pediatric tumors are the most common solid tumors in children. There are limited reports on the management and outcome of these tumors in the developing countries. In recent years, advances have been done in the diagnosis, treatment, and outcome of these tumors. The aim of this study was to evaluate the histopathology, characteristics, and outcome of primary pediatric tumors in Iran. This retrospective study examines primary brain tumors in children below 14years of age who have undergone surgery. Histopathological characteristics according to WHO 2017 classification, age, sex, tumor resection rate, and patient outcome were extracted and studied. The results of the study were compared with the results of similar reports from neighboring countries and other parts of the world. In this study, 199 primary pediatric tumors were examined. Out of 199 cases, 114 cases were males, and 85 cases were females, and the male/female ratio was 1.34. The most common tumor group in this study was astrocytic tumors (68.3%) and the most common tumor was pilocytic astrocytoma (22.1%). In terms of malignancy, 50.7% of tumors were benign, and 49.3% were malignant. Total resection was done in 46% and subtotal resection in 35%. The mortality rate was found 19.2%. َAmong the remaining cases during follow-up, 76.6% had a good outcome without neurological deficits or mild disability and 23.4% had moderate to severe disability. The results of the study in terms of pathology and demographic characteristics were mainly similar to other reports. The mean age of patients was lower, and the patients' outcome was better than the other countries in the region.

Robot assisted laser-interstitial thermal therapy with iSYS1 and Visualase: how I do it.

Laser-interstitial thermal therapy (LITT) is an ablative treatment based on a surgically implanted laser-emitting catheter to induce a focal ablation of the pathological tissue. The main indications in neurosurgery are primary brain tumors, metastases, radiation necrosis, and pediatric brain tumors. Several approaches have been proposed to implant the laser-emitting catheter, both in frameless and frame-based conditions. We report our approach for Robot assisted laser-interstitial thermal therapy of brain lesions with iSYS1 and Visualase (Medtronic). iSYS1 represents a significant adjunct to LITT procedures and may be safely implemented in routine laser-catheter positioning.

Phase 2 Study of Pomalidomide (CC-4047) Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors.

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

RARE-25. DISSECTING THE CONTEMPORARY EPIDEMIOLOGY OF PRIMARY AND SECONDARY BRAIN TUMORS IN INFANCY THROUGH CHILDHOOD

IntroductionHerein we utilize national registry data to evaluate the epidemiology of primary and secondary pediatric brain tumors according to the WHO2016 classification. MethodsPediatric patients (age≤14) presenting between 2004–2017 with a brain tumor were identified by ICD-O-3 and brain metastasis (2010–2017) coding from the National Cancer Database (comprising >70% of newly-diagnosed cancers in the U.S.), and categorized by NICHD age stages: infant (<1yr; n=1,686), toddler (1-2yrs; n=1,732), early- (2-5yrs; n=6,712), middle- (6-11yrs; n=9,175), and late- (12-14yrs; n=5,042) childhood. Patients’ age, sex, race/ethnicity, and overall survival, and tumor location and size were evaluated by WHO2016 tumor type. Results24,347 pediatric brain tumor patients were identified. Overall, other astrocytic tumors (24% of females, 20% of males), diffuse astrocytic/oligodendroglial gliomas (23% of females, 21% of males – 64% of which were midline), embryonal (13% of females, 19% of males), and sellar region tumors (12% of females, 8% of males) predominated. Embryonal tumors prevailed in infancy (24%) and toddlerhood (24%), declining to 9% in late childhood; only 40% were female. Ependymal tumors peaked at 15% in toddlerhood (6% overall), whereas choroid plexus tumors peaked at 11% in infancy (1.9% overall). A minority of brain tumors were of neuronal & mixed neuronal-glial (6.1%), germ cell (3.8%), cranial nerve (3.2%), mesenchymal non-meningothelial (2.4%), meningioma (1.6%), pineal (1.1%), hematological/histiocytic (0.5%), and other glioma (0.2%) types. Brain metastases were rare (1.5% overall; from 4.0% in infancy to 0.8% in late childhood; and only 41% were female) – 61% came from adrenal neuroblastoma, 16% from sarcomas, and 6% from malignant rhabdoid tumors/extracranial AT/RT. ConclusionsPediatric brain metastases overwhelmingly originate from adrenal neuroblastoma. Although, overall, diffuse astrocytic/oligodendroglial, other astrocytic, embryonal, and sellar region tumors predominate among pediatric brain tumors, together they only comprise 70% of cases and their distribution varies substantially by patients’ age and sex.

Imaging of brain tumors in children: the basics-a narrative review.

Primary pediatric brain tumors comprise a broad group of neoplasm subtypes that can be categorized based on their histological and molecular features according to the 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors. The majority of the pediatric brain tumors demonstrate a singular preference for this age group and have a unique molecular profile. The separation of certain tumor entities, including different types of embryonal tumors, low-grade gliomas, and high-grade gliomas, may have a significant impact by guiding appropriate treatment for these children and potentially changing their outcomes. Currently, the focus of the imaging diagnostic studies is to follow the molecular updates, searching for potential imaging patterns that translate this information in molecular profile results, therefore helping the final diagnosis. Due to the high impact of accurate diagnosis in this context, the scientific community has presented extensive research on imaging pediatric tumors in recent years. This article summarizes the key characteristics of the imaging features of the most common primary childhood brain tumors, categorizing them according to the recent WHO classification update, which is based on each of their molecular profiles. The purpose of this review article is to familiarize radiologists with their key imaging features and thereby improve diagnostic accuracy.

MBRS-18. TUMOR SUPPRESSOR p53 DEFINES THE THERAPEUTIC RESPONSES IN TREATMENT OF MEDULLOBLASTOMA

Medulloblastoma (MB) is the most common primary pediatric malignant brain tumor. Current molecular analysis classifies MB into 4 groups, classic (WNT), sonic hedgehog (Shh), group 3, and group 4. Furthermore, atypical p53 signaling is associated with disease progression and confers poor prognosis. This study investigated the correlation of mutational status of p53 and iSO17q with disease progression and metastatic potential. In addition, we used small molecule inhibitors of PI3K (Buparlisib; BKM120) and HDAC (LBH-589) on a p53-mutant MB cell line to find novel therapeutic targets. Efficacy of these drugs were assessed using functional assays (cell proliferation, migration, cell cycle and drug resistance). MB tumors (n=53) were evaluated for GLI-1, GAB-1, NPR, KV1, YAP expression and mutant p53 via immunohistochemistry and correlated to patient outcomes. Results demonstrated that: 1) high expression of GAB-1 and YAP were found in the Shh group, while KV1 expression was present in all subtypes; 2) mutant p53 expression was present in various subsets of MB with no apparent correlation with metastasis or disease progression; 3) patients displaying iSO17q (determined by fluorescence in situ hybridization (FISH) technique) exhibited metastatic disease; 4) LBH-589 and BKM120 caused both time and dose-dependent inhibition of MB cell proliferation and migration; 5) combined treatment of BKM120 and LBH-589 had a synergistic effect; 6) MB cells demonstrated drug-resistance to BKM120. In conclusion, these findings underscore use of Buparlisib and LBH-589 in treatment of MB. Further, the role of mutant p53 in disease progression remains elusive, whereas presence of iSO17q defines metastatic potential.

MBRS-39. MAP4K4 CONTROLS PRO-INVASIVE SIGNALING IN MEDULLOBLASTOMA CELLS

The molecular mechanisms contributing to distant dissemination and local recurrence of medulloblastoma, the most common malignant brain tumor in childhood, are poorly understood and no targeted anti-invasion therapies exist till date. We explored regulators and effectors of MAP4K4, a pro-invasive kinase overexpressed in MB and associated with metastatic progression in different solid malignancies. MAP4K4 is upregulated both at mRNA and protein levels in primary pediatric brain tumors compared to normal cerebellum. MAP4K4 is required for growth factor- and irradiation-induced migration and invasion of medulloblastoma cells. It furthermore promotes turnover and activation of the receptor tyrosine kinase c-Met and of the ß1 integrin adhesion receptor 1. To characterize these clinically relevant consequences and to identify druggable targets of MAP4K4 function, we profiled the interactome of MAP4K4 in starved and growth factor stimulated medulloblastoma cells. To systematically address MAP4K4 impact on receptor expression and turnover, we determined the MAP4K4-dependent surface proteome in medulloblastoma cells. We found that MAP4K4 is part of the striatin-interacting phosphatase and kinase (STRIPAK) complex and that STRIPAK component striatin 4 is controlling cell motility and invasiveness in medulloblastoma cells. Invasiveness of medulloblastoma cells is abrogated by a truncation mutant of MAP4K4 lacking the striatin 4 interaction domain. We furthermore found that MAP4K4 mediates growth factor-induced surface expression of solute carriers and immunomodulatory proteins involved in chemoresistance and immune evasion. Thus, our study identified MAP4K4 as a missing link between pro-tumorigenic growth factor signaling and tumor cell functions relevant for disease progression. It may help identifying druggable vulnerabilities in medulloblastoma cells to restrict tumor growth and dissemination. 1. Tripolitsioti, D. et al., Oncotarget9, 23220–23236 (2018).