bluuebunny/crossref_metadata_2025 huggingface dataset:
MBRS-23. SIGNIFICANCE OF mi-R33 IN GENERATION AND PROGRESSION OF MEDULLOBLASTOMA
Authors: Matsui Yasuzumi
Published: December 2020

Lipid metabolism has been shown to be associated with tumorigenicity in various malignancies. The purpose of this study was to investigate the association of miR-33, a key regulator of lipid metabolism, in tumorigenicity and progression of medulloblastoma. miR-33a is an only isotype of miR-33 in rodents although miR-33b is also detected in human. Incidence of medulloblastoma and histopathological findings were compared between ptch1+/- mice and ptch1+/- miR-33a-/- mice. Effect of miR-33b upregulation by cordycepin was tested in DAOY medulloblastoma cells both in vitro and in vivo. Knockout of miR-33a in ptch1+/- transgenic mouse model increased the incidence of spontaneous generation of medulloblastoma from 19.8% to 49.5% (p < 0.001) at 10 months. Cordycepin, which upregulates miR-33b, prevented tumor growth in DAOY human medulloblastoma cell line, but the effect was not evident in an orthotopic mouse medulloblastoma model. Although miR-33 seems to be an important regulator of medulloblastoma, treatment efficacy of cordycepin was not enough. Combination treatment with immunotherapy or cytotoxic treatment needs to be tested to show survival benefit in preclinical models.
MBRS-38. MOLECULAR CLASSIFICATION AND CLINICAL CHARACTERISTICS OF 236 MEDULLOBLASTOMAS IN JAPAN
Authors: Kanemura Yonehiro , Shofuda Tomoko , Yoshioka Ema , Kanematsu Daisuke , Ichimura Koichi , Sasaki Atsushi , Inoue Takeshi , Hirato Junko , Kodama Yoshinori , Mano Masayuki , Shibui Soichiro , Arai Hajime , Sakamoto Hiroaki , Date Isao , Nishikawa Ryo
Published: December 2020

Recent intensive genomic and molecular biological analyses have made a consensus that medulloblastomas (MBs) are at least classified into four core subgroups, and the new 2016 WHO brain tumor classification has introduced the classification of MBs genetically defined in addition to classical histopathological diagnosis. To establish a nationwide network of a molecular diagnosis system for pediatric brain tumors, the JPMNG co-organized by the Japan Society for Neuro-Oncology and the Japanese Society for Pediatric Neurosurgery have started the clinical researches in 2012, and we have summarized results of molecular analysis of Japanese MBs. Total 236 primary MBs have been subclassified by gene expression profile using the NanoString nCounter system or DNA methylation array, and their single nucleotide mutations and copy number aberrations have been also examined. Mean follow up time was 68.9 months. Proportion of four core subgroups were WNT (16.9%), SHH (25.4%), Group 3 (17.4%) and Group 4 (40.3%), respectively. In cases of less than 3 years old, no WNT have been found and 63.2% cases were SHH. In cases between 3 to 17 years old, Group 4 is the most (47%), and these trends is almost consistent with published references. TP53 mutations were identified in 23.3% of SHH, and they were significantly poor prognosis. Metastatic or MYC gain Group 3 MBs were poor prognosis, while Group 4 MBs with loss of chromosome 11 or whole chromosomal aberration were good prognosis. These findings reveal molecular properties of Japanese MBs and will contribute to develop new therapeutic strategies.
MBRS-51. MUTATIONS IN BRPF1 FOUND IN SHH MEDULLOBLASTOMA PREVENT INTERACTION WITH TP53 AND LEADS TO RADIORESISTANCE IN VITRO
Authors: Vouri Mikaela , Mercier Audrey , da Silva Patricia Benites Goncalves , Okonechnikov Konstantin , Forget Antoine , Yu Hua , Chivet Anais , Kool Marcel , Pfister Stefan , Ayrault Olivier , Kawauchi Daisuke
Published: December 2020

Medulloblastoma (MB) is one of the most common pediatric tumors in children. Among them, SHH subgroups of MB (MBSHH) is characterized by constitutive activation of SHH pathway. Somatic mutations in BRPF1, a chromatin modifier, is found in more than 5% of MBSHH and accounts for almost 20% of adult MBSHH but its potential role in MBSHH pathophysiology is still unknown. In this study, we first examined the function of Brpf1 on pro-tumorigenic features of MBSHH and evaluated molecular pathways regulated by Brpf1 using Brpf1floxed::Atoh1-Cre conditional knockout mice, in which Brpf1 is conditionally deleted in cerebellar granule neuron progenitors (GNPs). While RNA-seq analysis on GNPs from Brpf1 WT and KO mice showed significant differences in the pathways related with cell cycle and cell death, deletion of Brpf1 did not cause acceleration of tumorigenesis in the Ptch1 heterozygous tumor-prone. Background: Co-immunoprecipitation followed by mass spectrometry analysis identified interaction partners of BRPF1 including MOZ, MORF and ING5, known partners of BRPF1. Gene ontology analysis also depicted pathways important for cell cycle progression, cell death and response to DNA damage. Consistent with these observations, TP53 was identified as a novel co-factor of BRPF1. Of note, some of MBSHH-relevant BRPF1 mutations prevented interaction with TP53. According to the previous finding that cytosolic TP53 is required for apoptotic cell death, GNPs expressing the BRPF1-R600X mutant gene exhibited the resistance to irradiation-induced cell death. In conclusion, our data revealed that BRPF1 mutants found in MBSHH could prevent the complex formation with TP53, leading to enhanced resistance to cell apoptosis.
MBRS-53. CONTROL OF MEDULLOBLASTOMA VASCULATURE BY A REGULATOR OF NEUROGENESIS
Authors: Shaik Shavali , Maegawa Shinji , Haltom Amanda , Dobson Tara , Schadler Keri , Gopalakrishnan Vidya
Published: December 2020

Medulloblastomas are characterized by poor neuronal lineage specification. Expression of the RE1 Silencing Transcription Factor (REST), a regulator of neurogenesis, is aberrantly elevated in human sonic hedgehog (SHH) medulloblastomas. Using a novel transgenic mouse (RESTTG) model, we demonstrated that REST is a driver of medulloblastoma genesis and promotes tumor progression in mice with loss of an allele of Ptch1 (Ptch+/−). Tumor formation in Ptch+/−/RESTTG mice occurred with 100% penetrance and a latency of 10–90 days in contrast to Ptch+/− mice, which developed tumors at a frequency of 15–20% at 6–9 months of age. Histopathological analyses showed leptomeningeal dissemination of tumors in Ptch+/−/RESTTG mice, in addition to a significant increase in tumor vasculature compared to tumors in Ptch+/− mice. These findings were recapitulated in xenografted tumors of isogenic low and high-REST medulloblastomas in mice. Proteome profiler human angiogenesis array analyses revealed a REST-dependent increase in vascular endothelial growth factor (VEGF) and placental growth factor (PLGF). Surprisingly, REST elevation also caused co-localization of tumor cells with tumor vasculature, specifically endothelial cells, and was associated with upregulated expression of a number of pro-angiogenic genes, including receptor VEGFR1 and the positive regulator of endothelial differentiation, E26 transformation specific-1 (ETS1), in tumor cells. In addition, expression of several anti-angiogenic molecules was downregulated. Knockdown of ETS1 reversed the above findings. Thus, our data demonstrate that REST elevation not only blocks neurogenesis in medulloblastoma cells, but also modulates the tumor microenvironment by mechanisms that likely involve vascular mimicry.
MBRS-54. POOR SURVIVAL IN REPLICATION REPAIR DEFICIENT HYPERMUTANT MEDULLOBLASTOMA AND CNS EMBRYONAL TUMORS: A REPORT FROM THE INTERNATIONAL RRD CONSORTIUM
Authors: Das Anirban , Bianchi Vanessa , Edwards Melissa , Varghese Nobish , Sudhaman Sumedha , Farah Roula , Dvir Rina , Reddy Alyssa , Raskin Salmo , Hansford Jordan , Hamid Syed Ahmer , Hsu Saunders , Yen Lee Yi , Quider Abed Abu , Ghalibafian Mithra , Koustenis Elisabeth , Al-Battashi Abeer , Mason Gary , Lee Joung , Bell Danille , Stearns Duncan , Ziegler David , Zapotocky Michal , Lasaletta Alvaro , Kulkarni Abhaya , Tsang Derek S , Laperriere Normand , Hawkins Cynthia , Bouffet Eric , Ramaswamy Vijay , Tabori Uri
Published: December 2020

BACKGROUND

Mutations in mismatch repair (MMR) and DNA-polymerase (POL) genes lead to DNA replication repair deficiency (RRD), resulting in a growing group of previously under-recognized childhood brain tumors. Medulloblastoma and embryonal tumors are rarely reported in RRD. Their biological and clinical significance is unknown.

METHODS

We analyzed the clinical and genomic data of embryonal tumors registered in the International RRD Consortium.

RESULTS

Twenty-six tumors were centrally reviewed to confirm medulloblastoma (n=18), embryonal-tumor, NOS (n=5), and three glioblastoma (excluded). Embryonal tumors were observed at a young age (median: 7-years, IQR: 5;11), and all but one exhibited clinical cues (café-au-lait macules/ family history) of germline RRD. Medulloblastomas with RRD exhibited high-risk features, including anaplastic histology (50%), and SHH-subgroup with TP53-mutation (50%). Importantly, 68% harbored POLE/POLD1 mutations, resulting in median tumor mutation burden of 164 mut/mb. POL-mutated tumors were significantly ultra-hypermutated (>100 mut/mb) than tumors with MMR-deficiency alone (p=0.015). Synchronous and metachronous tumors were observed in 40%. However 90% of the deaths were related to the diagnosis of embryonal CNS tumor. Median survival for the entire cohort was 17-months (95% CI: 10 to 23). Predicted 3-year survival was 37% for medulloblastoma, with no survivors among other embryonal tumors.

CONCLUSIONS

This is the largest cohort of replication repair deficient medulloblastoma reported till date. The tumors are hypermutated, harbor somatic mutations in TP53 and/or POLE/POLD1, and have very poor survival with current chemo-irradiation based approaches. These biologically unique tumors expand the spectrum of high-risk TP53-mutant SHH-medulloblastoma, and need novel strategies for treatment.
MBRS-56. RE-EVALUATION OF LEPTOMENINGEAL METASTASIS IN MEDULLOBLASTOMA WITH MAGNETIC RESONANCE IMAGING, RELATED SYMPTOMS AND CEREBROSPINAL FLUID METABOLOMIC PROFILES
Authors: Im Ji Hye , Yoo Byong Chul , Lee Jun Hwa , Kim Kyung-Hee , Kim Jong Heon , Park Hyeon Jin , Park Meerim , Kwon Ji Woong , Shin Sang Hoon , Yoo Heon , Choi Seung Ah , Yang Jae Yeol , Phi Ji Hoon , Kim Seung-Ki , Gwak Ho-Shin
Published: December 2020

BACKGROUND

Diagnosis of leptomeningeal metastasis (LM) in medulloblastoma is made by positive findings in either MRI or CSF cytology. We studied if CSF metabolomics profile can differentiate the discordant results between MRI and CSF cytology and reflect the sampling time related to treatment.

MATERIALS AND METHODS

We prospectively collected 83 CSF samples from 45 medulloblastoma patients. A total of 6,527 low-mass ions (LMIs) were detected using liquid chromatography tandem mass spectrometry (LC-MS/MS). Discriminative low-mass ions (LMIs) between four different MRI and cytology results groups were evaluated and representative LMIs were identified.

RESULTS

CSF cytology and MRI finding were both positive for LM in 8 samples and both negative for 47 samples. Tests were cytology (-) and MRI (+) in 20 samples, whereas cytology (+) and MRI (-) status were in the remaining 8 samples. The diagnostic accuracy by area under the curve (AUC) was 0.722 for cytology and 0.888 for MRI each. Based on the exclusiveness of LMI between groups, we verified 27 discriminative LMIs in MRI (+)/ cytology (+), 9 LMIs in MRI (+)/ cytology (-), and 12 LMIs in MRI (-) and cytology (+) group, separately. Metabolic pathways involved in MRI (+)/ cytology (+) group were linoleic acid, phenylalanine, TCA cycle, retinol, arginine-ornithine, nicotinate-nicotinamide, etc. Low-mass-ion discriminant equation (LOME), which could differentiate both different MRI and cytology results and the sampling time or presence of LM-related symptoms was found.

CONCLUSION

Non-targeted MSanalysis CSF metabolite in medulloblastomas revealed significantly different profiles, and these results suggest LMI profiles might have a higher sensitivity for LM diagnosis than either MRI or cytology.
MBRS-64. STUDY OF ARGININE METHYL TRANSFERASES IN MEDULLOBLASTOMA
Authors: Cheng Donghang , Taylor Pete , Gireud Monica , Maegawa Shinji , Yang Yanwen , Majumder Sadhan , Gopalakrishnan Vidya
Published: December 2020

Medulloblastoma is the most common malignant pediatric cancer and a leading cause of childhood cancer-related mortality. There is dire need for new therapies. Molecular sub-classification of medulloblastomas has identified chromatin modifiers as potential drivers of tumorigenesis. Expression of the RE1 Silencing Transcription Factor (REST), a hub for assembly of repressive chromatin remodelers and a known regulator of neurogenesis, is elevated in a subset of human sonic hedgehog (SHH) subgroup medulloblastomas, and is associated with poor prognosis. Using a novel transgenic mouse model, we showed REST to be a driver of medulloblastoma development. Surprisingly, our studies also revealed a role for REST in promoting proliferation of granule cell progenitors (GCPs), the cells of origin of SHH-driven medulloblastoma, and a concomitant loss of telomeres and increased genomic instability. We performed a gain of function screen using a library of chromatin modifiers to understand the mechanism by which proliferative potential was maintained, despite the loss of telomeres. This screen identified the Protein Arginine Methyltransferase 6 (PRMT6) as a high confidence hit. PRMT6 upregulation caused a reduction in CDKN2A, an important regulator of replicative senescence. Evasion of senescence is frequently implicated in tumor progression. Using a chemical screen, we also identified a novel, selective, reversible and competitive inhibitor of PRMT6. The consequence of genetic and pharmacological inhibition of PRMT6 on cell proliferation and senescence will be reported. Thus, our studies are the first to demonstrate a role for arginine methyl transferase family of chromatin modifiers in medulloblastoma genesis.
MBRS-69. METABOLITE PROFILING OF SHH MEDULLOBLASTOMA IDENTIFIES A SUBSET OF CHILDHOOD TUMOURS ENRICHED FOR HIGH-RISK MOLECULAR BIOMARKERS AND CLINICAL FEATURES
Authors: Bennett Christopher , Kohe Sarah , Burte Florence , Rose Heather , Hicks Debbie , Schwalbe Ed , Crosier Stephen , Storer Lisa , Lourdusamy Anbarasu , Wilson Martin , Avula Shivaram , Mitra Dipayan , Dineen Robert , Bailey Simon , Williamson Daniel , Grundy Richard , Clifford Steven , Peet Andrew
Published: December 2020

SHH medulloblastoma patients have a variable prognosis. Infants (<3–5 years at diagnosis) are associated with a good prognosis, while disease-course in childhood is associated with specific prognostic biomarkers (MYCN amplification, TP53 mutation, LCA histology; all high-risk). There is an unmet need to identify prognostic subgroups of SHH tumours rapidly in the clinical setting, to aid in real-time risk stratification and disease management. Metabolite profiling is a powerful technique for characterising tumours. High resolution magic angle spinning NMR spectroscopy (HR-MAS) can be performed on frozen tissue samples and provides high quality metabolite information. We therefore assessed whether metabolite profiles could identify subsets of SHH tumours with prognostic potential. Metabolite concentrations of 22 SHH tumours were acquired by HR-MAS and analysed using unsupervised hierarchical clustering. Methylation profiling assigned the infant and childhood SHH subtypes, and clinical and molecular features were compared between clusters. Two clusters were observed. A significantly higher concentration of lipids was observed in Cluster 1 (t-test, p=0.012). Cluster 1 consisted entirely of childhood-SHH whilst Cluster 2 included both childhood-SHH and infant-SHH subtypes. Cluster 1 was enriched for high-risk markers - LCA histology (3/7 v. 0/5), MYCN amplification (2/7 v. 0/5), TP53 mutations (3/7 v. 1/5) and metastatic disease - whilst having a lower proportion of TERT mutations (0/7 v. 2/5) than Cluster 2. These pilot results suggest that (i) it is possible to identify childhood-SHH patients linked to high-risk clinical and molecular biomarkers using metabolite profiles and (ii) these may be detected non-invasively in vivo using magnetic-resonance spectroscopy.
MODL-08. OPTIMIZATION OF A NOVEL LOCAL DELIVERY SYSTEM FOR THE TREATMENTS OF SUPRATENTORIAL EPENDYMOMA
Authors: Ruff Lisa , Parkins Chris , Terranova Sabrina , Nathan Erica , Kasapidou Paraskevi , Lang Renata , Scherman Oren , Gilbertson Richard J
Published: December 2020

Ependymomas are the third most common paediatric brain tumour, incurable in up to 40% of cases. Until recently, ependymomas were regarded as a single disease group with all patients receiving combinations of maximal surgical resection and radiotherapy. Use of chemotherapy has been limited by the resistant nature of the tumour and poor access to tumours behind the blood brain barrier (BBB). It is now known that ependymoma comprises up to nine different molecular subgroups. One subgroup is characterized by a novel fusion protein, C11orf95-RELA, which acts as a potent driver of oncogenesis resulting in a poor prognosis. Here, we present the optimization of a novel drug delivery system that uses biodegradable hydrogels to deliver drugs with potent anti-ependymoma properties into post-resection cavity of supratentorial ependymoma. Our previous high-throughput in-vivo drug screens identified candidate ependymoma therapies with poor BBB penetrance properties. Using in-vitro delivery assays, we have confirmed and monitored the release of these compounds from the hydrogel. Additionally, we have implemented this delivery system in our preclinical mouse hospital in which mice receive standard-of-care surgery and radiotherapy. The efficacy of hydrogel-based delivery of these compounds is now being tested preclinically, in combination with radiotherapy. Treatment for ependymoma patients have not changed in the last 30 years and therefore an effective chemotherapy could add a great survival benefit to in the clinic.
MODL-13. GENETICALLY ENGINEERED PIG MODEL OF RHABDOID TUMOR PREDISPOSITION SYNDROME-1
Authors: Na Brian , Rubinstein C Dustin , Meudt Jennifer J , Biegel Jaclyn A , Judkins Alexander R , Lehman Brent P , Reichert Jamie L , Vitte Jeremie , Shanmuganayagam Dhanansayan , Giovannini Marco
Published: December 2020

Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/RT demonstrate genomic alterations in the SMARCB1 gene. There are two major hurdles in the development of safe and effective treatments for AT/RT: first, the mouse models do not fully recapitulate the disease seen in patients and their predictivity of clinical efficacy is still unproven. Second, due to a small patient population, the ability to recruit enough patients for clinical trials is challenging. Genetic studies have demonstrated that germline deletion of SMARCB1 exons 4 and 5 predisposes to AT/RT at an early age. Comparison of human, swine, and mouse SMARCB1 genes show similarities in gene and protein structure, with 100% amino acid identity between swine and human SMARCB1 isoforms. Thus, we hypothesized that germline deletion of exons 4 and 5 will predispose heterozygote swine to AT/RT development. SMARCB1+/- founder pigs are obtained using a CRISPR/Cas9 mediated gene-editing of conventional crossbred swine embryos, followed by embryo transfer into female swine surrogates. They are evaluated for clinical criteria used to diagnose AT/RT and by MRI at 6, 12, and 24 months of age, followed by histopathology and molecular analysis of the tumors as they are detected. Generating a large animal model of AT/RT would represent a breakthrough in the field from a genomic, pathophysiologic, pre-clinical and therapeutic perspective.
MODL-29. EVALUATING TUMOR-IMMUNE INTERACTIONS IN MOUSE MODELS OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Furnish Robin , Bear Heather , Wei Xin , Phoenix Timothy
Published: December 2020

BACKGROUND

While adult gliomas show some level of immune cell infiltration, diffuse intrinsic pontine glioma (DIPG) is characterized as having an “immune cold” state. We have developed new immunocompetent mouse models of DIPG. These models faithfully recapitulate the pathological hallmarks of DIPG and provides a unique platform to investigate immune modulatory therapies and potential therapeutic benefits of check point inhibitor combination therapies.

METHODS

To evaluate the effects of CDK4/6 inhibition (CDK4/6i) on cell proliferation and immune interactions we performed a series of in vitro and in vivo studies using DIPG mouse models. In vitro assays included dose response curves, transcriptional profiling, and MHC1 expression. In vivo preclinical studies treated mouse models with CDK4/6i with or without immune check-point inhibitors (ICI). We also examined other candidate immune modulatory therapies in vitro.

RESULTS

CDK4/6i (Abemeciclib) reduced proliferation of DIPG cells derived from mouse models, and displayed a modest increase in immune activation by MHC1 expression and transcriptome. Pilot in vivo preclinical studies did not show any significant changes in DIPG proliferation or immune changes with CDK4/6i treatment, ICI treatment, or the combination of CDK4/6i + ICI. In vitro testing of other immune-modulatory drugs identified additional candidates that can be tested in vivo.

CONCLUSION

CDK4/6i displayed in vitro action, but lacked efficacy in DIPG mouse models in vivo. Further use of spontaneous DIPG mouse models will provide a rapid preclinical platform to evaluate in vivo tumor-immune interactions, drug efficacy, and mechanisms of resistance.
MODL-31. RADIATION-DERIVED TREATMENT-RESISTANT PDX AND CELL CULTURE MODELS RECAPITULATE THE CHARACTERISTICS OF MATCHED PRIMARY/RECURRENT PEDIATRIC HIGH-GRADE GLIOMA
Authors: Knox Aaron J , Flannery Patrick , Zukosky Anjali , DeSisto John , Sanford Bridget , van Court Benjamin , Donson Andrew , Lemma Rakeb , Chatwin Hannah , Karam Sana D , Vibhakar Rajeev , Jones Ken , Green Adam L
Published: December 2020

BACKGROUND

Pediatric high-grade glioma (pHGG) is the most common cause of childhood cancer death. Recurrence after therapy is a major challenge, since recurrent pHGG proliferates aggressively and resists therapy. We developed and validated preclinical models of matched primary and recurrent tumors, providing a method to study recurrence and potential therapies.

METHODS

We irradiated H3K27M thalamic pHGG cells (BT245) (8 Gy/week,2Gy fractions x3 weeks) and propagated the surviving cells (BT245R). We developed a murine recurrence model by orthotopically implanting BT245 cells, irradiating the resultant tumors (4 Gy/day x2d) and propagating irradiated (BT245RM) or control (BT245CM) tumor cells at endpoint. We performed phenotypic analyses, RNA-Seq, and drug testing.

RESULTS

BT245R cells were more stemlike than BT245, with an 8-fold greater rate of neurosphere formation (p<0.03). Geneset enrichment analysis showed similar molecular changes in BT245RM cells and primary/recurrent H3K27M pHGG patient sample pair, including relaxation of the G2/M cell cycle checkpoint (Hallmark_G2M_Checkpoint: BT245RM NES=-5.95, FDR=0.0; patient NES=-5.86, FDR=0.0), downregulation of MYC targets (Hallmark_MYC_Targets_V1: BT245RM NES=-7.43, FDR=0.0; patient NES=-5.86, FDR=0.0), and decreased differentiation (Go_Regulation_of_Stem_Cell_Differentiation: BT245RM NES=-3.35, FDR=0.0; patient NES=-3.15, FDR=0.0). Enrichment of the protein_kinase_C_signaling in BT245RM (NES=2.18,FDR=0.03) suggested response to MAPK pathway inhibition. BT245R cells were twice as sensitive as BT245 cells to the MEK inhibitor trametinib (p<0.05).

CONCLUSIONS

Our neurosphere and murine orthotopic patient-derived xenograft models recapitulate gene expression changes of matched primary/recurrent pHGG. RNA-Seq analysis validated the model against patient samples and identified trametinib as potentially effective in recurrent pHGG.
NFB-02. TREATMENT OF PAIN AND TUMOR GROWTH IN NF2
Authors: Hemenway Molly , Nellan Anan , McMahon Kate , Foreman Nicholas , Reddy Kartik , Nellan Anan , Suttman Alexandra
Published: December 2020

BACKGROUND

Neurofibromatosis Type 2 (NF2) is an autosomal dominant disorder characterized by multiple nervous system tumors. Chronic pain affects the majority of patients with NF2 and is the primary factor that contributes to decreased quality of life. There are limited therapies that effectively reduce pain in NF2, but intravenous (IV) bevacizumab has been reported to provide significant relief to patients suffering from debilitating pain.

CASE STUDY

James is a 24-year-old who initially presented with manifestations of NF2 at age 10, and by 15 years old had developed daily pain affecting his neck, back, and lower extremity. He has multiple CNS schwannomas, meningiomas, neurofibromas, and meets clinical NF2 criteria. While genetic testing did not reveal a mutation in his gDNA, low level skipping of exon 4 via RNA supports (likely mosaic) NF2. James’s pain was poorly controlled with multiple oral medications, including opioids. James started IV bevacizumab at age 16 that improved his pain. He was critically dependent on bevacizumab for pain control and required continuous IV pain medication when bevacizumab was held for a surgical procedure. Following five years of bevacizumab he developed worsening toxicities including hypertension, proteinuria, and elevated hemoglobin. James transitioned to therapy with trametinib, a MEK inhibitor, and was able to wean off bevacizumab six months later. Treatment of NF2 related pain with trametinib instead of bevacizumab has improved his QOL with decreased medical visits, improved pain management, and decreased side effects. FUTURE IMPLICATIONS: Treatment of NF2 tumor related pain can be managed with MEK inhibitors.
NFB-09. ENROLLMENT AND CLINICAL CHARACTERISTICS OF NEWLY DIAGNOSED, NEUROFIBROMATOSIS TYPE 1 ASSOCIATED OPTIC PATHWAY GLIOMA (NF1-OPG): PRELIMINARY RESULTS FROM AN INTERNATIONAL MULTI-CENTER NATURAL HISTORY STUDY
Authors: Fisher Michael J , Liu Grant T , Ferner Rosalie E , Gutmann David H , Listernick Robert , de Blank Peter , Zeid Janice , Ullrich Nicole J , Heidary Gena , Bornhorst Miriam , Stasheff Steven F , Rosser Tena , Borchert Mark , Ardern-Holmes Simone , Flaherty Maree , Hummel Trent R , Motley W Walker , Bielamowicz Kevin , Phillips Paul H , Bouffet Eric , Reginald Arun , Wolf David S , Peragallo Jason , Van Mater David , El-Dairi Mays , Sato Aimee , Tarczy-Hornoch Kristina , Klesse Laura , Hogan Nick , Foreman Nick , McCourt Emily , Allen Jeffrey , Ranka Milan , Campen Cynthia , Beres Shannon , Moertel Christopher , Areaux Ray , Stearns Duncan , Orge Faruk , Crawford John , O’Halloran Henry , Brodsky Michael , Esbenshade Adam J , Donahue Sean , Cutter Gary , Avery Robert A
Published: December 2020

INTRODUCTION

Because treatment and clinical management decisions for children with NF1-OPG remain challenging, we sought to establish evidence-based guidelines. We prospectively enrolled children with newly-diagnosed NF1-OPGs, and gathered standardized clinical neuro-oncology and ophthalmology assessments.

METHODS

Only children with NF1 and newly diagnosed OPGs, confirmed by central review, were eligible. Indications for obtaining the initial MRI, as well as factors associated with the decision to treat with chemotherapy or observe without treatment, were obtained. Quantitative visual acuity (VA), other ophthalmic features, and imaging were captured at standard time points. Goal enrollment is 250 subjects.

RESULTS

One-hundred thirty-three children (52% female) from 20 institutions met inclusion criteria, and were included in this preliminary analysis. Eighty-six percent of subjects were able to perform quantitative VA testing at enrollment. The most common reasons for the diagnostic MRI included screening related to NF1 diagnosis (36.8%), ophthalmologic concerns (29.3%), and non-ophthalmologic concerns (24.8%), such as headache. To date, twenty subjects have initiated treatment with chemotherapy, twelve (9%) at the time of the initial OPG diagnosis. Median age at OPG diagnosis was 3.1 years. Age and sex distribution were similar in subjects immediately entering the observation and treatment arms (median age 3.0 versus 3.5 years, respectively).

CONCLUSION

Most children with NF1-OPGs are observed at time of their initial OPG diagnosis, rather than treated. Importantly, a large proportion of children are able to complete quantitative VA testing at enrollment. Once enrollment is complete, these data will help to establish evidence-based guidelines for clinical management of NF1-OPGs.
NURS-04. COMBINATION OF NEURO-ONCOLOGY AND DERMATOLOGY CLINICS IMPROVE THE MANAGEMENT AND KNOWLEDGE OF SKIN-RELATED TOXICITIES WITH MEK AND BRAF TARGETED THERAPY
Authors: McKeown Tara , Lara-Corrales Irene , Cote Andrea
Published: December 2020

BACKGROUND

The recent advancement in treating pediatric low grade glioma has led to upfront use of MEK and BRAF (MAPK) inhibitor therapy. At the Hospital for Sick Children we are the National leaders in treating pediatric oncology diagnosis with MAPK therapies. DESIGN: After treating several patients on MAPK inhibitors with various degrees of skin toxicity, we found we had poor and inconsistent access to dermatology services and as oncology practitioners had limited front-line knowledge about skin management. It was determined that a more formalized expertise and time with dermatology was needed. In 2018, in combination with the dermatology team, our new agents and innovative therapy and the nursing team we collaborated to develop a combined oncology and dermatology clinic. This clinic occurs twice a month to give our families and oncology teams better front-line access to dermatology knowledge and care.

RESULTS

The dermatology and oncology team have collaborated to provide information sessions for the oncology medical team about current research, skin grading and education. This combined approach has allowed us to ensure that each new family starting MAPK inhibitor therapy undergoes a baseline skin assessment, education on prophylactic skin measures and easier access to dermatology within their oncology clinic. We are also developing guidelines to consistently treat common skin related toxicities.

CONCLUSION

The early involvement of the dermatology clinic and increase knowledge with the nursing and medical team has allowed our families to gain confidence in managing skin related complication and reducing the need to hold targeted therapies as a result of dermatological toxicity.
NURS-06. NURSING PROFESSIONALS AND THEIR AID IN RESEARCH BIOBANKING
Authors: Hancock Lauren , Kambhampati Madhuri
Published: December 2020

Nursing teams play an integral role in the care of patients with brain tumors; however nurses do not often see themselves as essential contributors to translational research. Recent development of nurse-researcher relationships and involvement of the multidisciplinary team have led to successful biobanking strategies. Though there are challenges associated with fostering these relationships, their vital role has significantly enhanced participant recruitment and sample collection at one large urban Children’s Hospital. Researchers at the institution have established a biobank to collect samples from pediatric brain tumor patients at diagnosis, during therapy, and post mortem using conventional methods. However, a collaborative environment between nursing and research teams greatly enhanced the growth of the biobank. We have increased patient recruitment by more than 50% in the past four years and supported different types of specimen collection. Our success entails: 1) development of nurse-researcher relationships, 2) an efficient consent process, 3) streamlined sample collection, and 4) appreciation of the vital role of the nursing team in clinical data collection pertinent to molecular analysis. Additionally, the support of nursing is valuable during post mortem consents and provides emotional support to the family to fulfil their wish to donate. Nurses play a major role in coordination of the post-mortem donation process, and assist in the formation of partnerships within the community to promote this opportunity to families. As biobanking continues to be an important part of bench research, all institutions should recognize and support the vital role that nurses can have in enhancing this endeavor.
NURS-12. MAKING SURVIVORS HEALTHIER: A MULTIDISCIPLINARY APPROACH TO HYPOTHALAMIC OBESITY
Authors: Hemenway Molly , Dorris Kathleen , Rydin Amy , Inge Thomas , Kelsey Megan , Hankinson Todd , Paul Suzanne , Haemer Matthew , Moore Jaime
Published: December 2020

BACKGROUND

Pediatric survivors of hypothalamic/suprasellar tumors have significant morbidities that greatly impact their quality of life. Management of hypothalamic obesity has traditionally fallen between multiple subspecialties without a timely and comprehensive approach.

METHODS

A multidisciplinary group of key players from neuro-oncology, endocrinology, nutrition, neurosurgery, and bariatric surgery were identified. Through this collaboration, a clinical algorithm for early identification of and intervention for hypothalamic obesity was developed. The goal of the quality improvement process is to increase the number of encounters with a registered dietitian (RD) with earlier and more consistent referrals to a specialized, multidisciplinary weight management program [Lifestyle Medicine; (LM)] for counseling and pharmacologic interventions. Indications for referral to LM were BMI >95th percentile, crossing >2 BMI percentiles on growth curve and/or hyperphagia symptoms. A retrospective review of pediatric patients who have suprasellar/ hypothalamic tumors was also conducted. Data collected included demographics, tumor type, BMI, RD visit, and LM clinic referral/visit.

RESULTS

Fifty patients were identified for analysis six months following clinical algorithm institution. Thirty-three (66%) patients had craniopharyngioma, 15 (30%) had low-grade gliomas, and two (4%) had germ cell tumors. Thirty-three (66%) patients were noted to be obese (defined as BMI >95th percentile) at review. The median BMI of the entire cohort was 93rd (range, 1st-137th) percentile. Thirty-four (68%) patients had been seen by an RD. Twenty-seven (82%) of the obese patients had been referred to LM.

CONCLUSIONS

The development and implementation of the process for hypothalamic obesity prevention and intervention will be discussed.
OTHR-12. ANEURYSMAL BONE CYST RESEMBLING A POSTERIOR FOSSA TUMOR
Authors: Navarro Luis Angel Arredondo , Campo Regina Malinali Navarro Martin Del , Livier Gutierrez Oliva Lorelay , Mercado Valeria Estefania Aguilar , Luis Juan , Mancilla Soto
Published: December 2020

We presented the case of a 6-year-old boy who was seen in the emergency room because of signs of intracranial hypertension and left cerebellar syndrome. The CT scan revealed a heterogeneous lesion within the left hemisphere displacing the fourth ventricle and eroding the occipital bone. The MRI showed the same heterogeneous lesion majorly cystic, involving the bone and displacing the left cerebellar hemisphere. A minor hydrocephalus was evident in both studies. A suboccipital craniectomy was done and a cystic epidural tumor remodeling and eroding the bone was noted. The histopathological diagnosis corresponded to an aneurysmal bone cyst. Aneurysmal bone cyst is a rare benign tumor accounting for 3–6 % of tumors of the cranial base. We discuss the unusual location of the lesion.
PATH-05. A CASE OF PILOCYTIC ASTROCYTOMA HARBORING THE FGFR1 GENE MUTATION WITH A PREDOMINANT OLIGODENDROGLIOMA-LIKE COMPONENT
Authors: Sasaki Nobuyoshi , Chiba Tomohiro , Saito Kuniaki , Kobayashi Keiichi , Shiokawa Yoshiaki , Shibahara Junji , Nagane Motoo
Published: December 2020

Pilocytic astrocytomas rarely present with oligodendroglioma-like morphological features, which gives rise to a diagnostic challenge. In this report we present a case of pilocytic astrocytoma harboring the FGFR1 mutation, accompanied with a predominant oligodendroglioma-like component, thus initially diagnosed as oligodendroglioma. A 14-year-old female presented with syncope and simple partial seizure involving her right upper limb. Contrast-enhanced MRI revealed an enhancing lesion with substantial cystic portion and perifocal edema in the left parietal lobe. Open surgery was performed and a gross total resection of the tumor was achieved. On initial histopathological diagnosis, tumor cells with monotonous round nuclei and perinuclear halo predominated with branching capillaries, which were strongly suggestive for oligodendroglioma. Immunohistochemically, IDH1 R132H was negative, and Ki-67 index was around 5%. The patient was thus initially diagnosed as oligodendroglioma, WHO grade II, based on the 2007 WHO classification criteria. However, histopathological re-review revealed a minor astrocytic component with Rosenthal fibers and rare eosinophilic granular bodies, thus the diagnosis was changed as pilocytic astrocytoma. FGFR1 K654E mutation was confirmed by Sanger sequencing. Although she postoperatively developed mild sensory disturbance in her right hands, finger agnosia, and left-right disorientation, her symptoms had gradually improved, and she was discharged on day 17 with a Karnofsky performance status (KPS) of 90 and no cognitive decline. Without any adjuvant therapies, she has remained recurrence-free for 85 months. While the diagnosis of pilocytic astrocytoma with predominant oligodendroglioma-like component can be challenging, analysis of IDH1 and FGFR1 mutations can be beneficial in certain cases.
PATH-10. PROGNOSTIC RELEVANT IMMUNOPHENOTYPES OF PEDIATRIC HIGH-GRADE NON-BRAINSTEM GLIOMAS
Authors: Mikhaleuskaya Taisiya , Konoplya Natalya , Valochnik Alena
Published: December 2020

Pediatric diffuse astrocytomas comprise a wide range of malignancies with variable prognosis. The 4th grading system used now not always correctly characterizes the biological behavior of these tumors. We collected 24 pediatric supratentorial non-brainstem high grade glioma cases. Patient age ranged from 1 to 18 years old (median 11y). Main tumor locations were as follows: parietal lobe 8 cases; temporal lobe, 10 cases; frontal lobe, 3 cases; occipital lobe 3 cases. Eight of them were totally removed. All patients were treated with standard CT and RT. The main objective was to assess the prognostic impact of histopathological and molecular criteria on progression-free(PFS) and overall survival (OS) of high grade gliomas. The following criteria were analyzed: IDH1 R132H, BRAF V600E expression, ALT-phenotype, CDKN2A deletion, 1p/19q co-deletion, glial and neuronal markers expression. RESULTS: IDHR132H mutation was identified in 3 cases. 4 cases carried BRAFV600E mutation with CDKN2A deletion and displayed PXA phenotype. 5 cases showed undifferentiated glial morphology and ALT–phenotype. Also there was a group of tumors without any of the above mentioned genetic changes. Interestingly 3 of them were post radiation tumors. Statistical analysis showed that low OS correlated with ALT-phenotype(p-0.015), absence of neuronal markers expression and absence of molecular changes (p-0.03). Mutation of IDH1R132H was a favorable prognostic factor as in the adult population. PFS was affected only by the presence of neuronal expression (p-0.015). Employing immunohistochemical analysis with surrogate molecular markers in complex with FISH can provide additional prognostic information in case of pediatric high grade gliomas.
PATH-24. MOLECULAR CLASSIFICATION OF HIGH RISK INFANT EMBRYONAL BRAIN TUMORS ENROLLED IN THE ACNS0334 TRIAL: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP
Authors: Li Bryan K , Burger Peter , Judkins Alexander R , Ho Ben L B , Kang Guolian , Gossett Jeffrey , Leary Sarah , Pollack Ian , Gajjar Amar , Fouladi Maryam , Kellie Stewart J , Mazewski Claire , Huang Annie
Published: December 2020

Young children with embryonal brain tumors including medulloblastoma (MB), supratentorial primitive neuro-ectodermal tumor, or pineoblastoma have historically been considered high-risk patients with poor outcomes despite the use of intensive radiation-sparing treatment. In the ACNS0334 phase III trial, 91 consented children <36 months old with the above diagnoses were randomized to intensive induction chemotherapy with or without methotrexate followed by consolidation with stem cell rescue. Here we present the results of a centralized integrated molecular analysis including global methylation profiling (65/91), and whole exome sequencing of tumor (46/91) and germline (35/91) DNA. Unsupervised clustering analyses of methylation profiles using multiple orthogonal methods against a reference dataset of 1200 pediatric brain tumors, revealed known and new molecular entities. For tumors diagnosed as MB on central pathology review, 7.3% (3/41) had a non-MB molecular diagnosis (2 embryonal tumor with multiple rosettes/ETMR, 1 group MYC pineoblastoma), with the remainder as MB Group SHH (11/41), Group3 (25/41), and Group4 (2/41). Among histologic non-MBs, 3/24 (12.5%) were molecular entities not intended for trial inclusion (1 each for ATRT, pleomorphic xanthoastrocytoma, and high-grade glioma). ETMR, historically considered a rare entity, was molecularly identified in a significant proportion (14/65; 21.5%) of samples. Among MB-SHH, we detected deleterious PTCH1 mutations in 6/9 tumors but none among 5 germline samples tested; a germline SUFU frameshift mutation with tumor LOH was also observed in MB-SHH. Correlation of these and other molecular features to the parallel clinical analysis will yield important markers of risk stratification and predictors of treatment response.
PATH-31. THE IMPACT OF MOLECULAR PROFILING OF PEDIATRIC CNS TUMORS ON TUMOR DIAGNOSIS AND MANAGEMENT - A SINGLE CENTER EXPERIENCE
Authors: Sabet Kazuhiro , Zwienenberg Marike , Lechpammer Mirna , Jin Lee-Way , Solomon David , Kline Cassie , Antony Reuben
Published: December 2020

BACKGROUND

Next generation sequencing (NGS) plays a role in neuro-oncology research and in clinical diagnosis and management. Here, we describe how NGS for pediatric CNS tumors impacted clinical diagnosis and therapy at a single institution.

METHODS

NGS was performed using the UCSF 500 Gene Panel (targeted sequencing platform covering about 500 cancer associated genes). Patients were selected for NGS based on tumor pathology /need to identify therapeutic targets. We collected data on patient demographics, tumor histology/pathway alterations/therapeutic targets/therapy and used descriptive statistics for data analysis.

RESULTS

Between January 2016 and July 2019, about one-third of patients with CNS tumors seen at our institution (N=29) were interrogated. NGS revealed pathway alterations in 20/29 patients. Treatment recommendations/modifications based on pathway alterations/therapeutic targets impacted the therapy of 18 patients. Patient groups: Medulloblastoma (N=6), alterations in WNT, SHH, and TP53 pathways (Vismodegib recommended for SHH pathway alteration but not used). High-grade glioma (N=4), alterations (with treatment changes) included, NF1(Trametinib, Everolimus); MSH2/MLH1(Nivolumab); CDKN2A/CDKN2B/CDKN2C(Abemaciclib); EGFR (Osimertinib, Afatinib); H3K27M (Panobinostat/ONC201); BRAFV600 (Dabrafenib, Trametinib); ATRT (N=1) SMARCB1; Low Grade Glioma (N=10), BRAFV600(Vemurafenib) /BRAFKIAA1549 fusion (Trametinib)/ PIK3CA; DIPG (N=5), H3K27M/BCOR/ P53/ACVR/PIK3CA (LY3023414, Everolimus)/PDGFR(Dasatinib); Ependymoma (N=3), PFA/PFB/RELA Fusion. Seven patients were treated with targeted therapy + conventional therapy. In 8 patients targeted therapy remains an option but not yet needed.

CONCLUSIONS

NGS of pediatric brain tumors is widely available and contributes to the diagnosis/therapy of pediatric CNS tumors. Optimal chemotherapy/targeted therapy combinations are areas of study.
QOL-19. PARENT-REPORTED COGNITIVE PROBLEMS AND DIRECT ASSESSMENT OF COGNITION IN CHILDREN TREATED FOR A BRAIN TUMOR
Authors: Lemiere Jurgen , Sleurs Charlotte , Van den Wyngaert Linde , Vandenabeele Karen , Vandereydt Josefien , Vercruysse Trui , Jacobs Sandra
Published: December 2020

The Pediatric Perceived Cognitive Function (PedsPCF) item bank is a short parent and self-reported cognitive screening questionnaire developed in the context of pediatric oncology. The PedsPCF demonstrated satisfactory psychometric properties and the scores of the PedsPCF are found to be associated with clinical outcomes. Today little research is available to evaluate whether the PedsPCF is correlated with direct assessments of neurocognitive domains. The aim of the current study is to investigate whether important cognitive domains, such as different aspects of intelligence, memory, visuomotor integration can predict the PedsPCF score. We obtained 100 PedsPCF filled in by parents from children treated for a brain tumor. All these children completed a comprehensive neuropsychological battery. Mean age at diagnosis was 7.47 years and mean age at completion of PedsPCF and testing 13.84. The most common diagnoses were pilocytic astrocytoma (n=43) and medulloblastoma (n=14). A linear regression model with verbal comprehension, perceptual reasoning, processing speed, visuomotor integration as predictors for overall PedsPCF score was significant (p.005), but the overall model fit was limited (adjusted R2: 14%). Visuomotor integration and processing speed were significant predictors (beta = 0.56 and -0.29). Our results are in line with the overall finding that the correlation between questionnaires assessing quality of survival and direct assessments of cognition are low. For clinical practice these results are important as the PedsPCF can’t be used to replace direct cognitive assessments or vice versa.
QOL-20. IMPACT OF RADIATION DOSE AND VOLUME ON MEMORY FUNCTIONING IN CHILDREN WITH MEDULLOBLASTOMA: A REPORT FROM CHILDREN’S ONCOLOGY GROUP (COG) ACNS0331
Authors: Embry Leanne , Colte Paul , Cullen Patsy , Michalski Jeff , Li Yimei , Han Yuanyuan , Hardy Kristina
Published: December 2020

BACKGROUND/OBJECTIVES

We examined longitudinal verbal and visual memory functioning in children treated for medulloblastoma on COG protocol ACNS0331.

METHODS

Children with medulloblastoma participated in neuropsychological testing at three timepoints over a 6-year period. Children aged 3–7 years were randomized to receive craniospinal irradiation (CSI) of either 23.4Gy (standard dose; SDCSI) or 18Gy (lower dose; LDCSI). Children aged 8+ received SDCSI. All children were also randomized to receive either a reduced radiation boost to the involved field (IFRT) or a standard boost to the whole posterior fossa (PFRT). Memory functioning was evaluated an average of 0.67(T1), 2.95(T2), and 4.90(T3) years post-diagnosis.

RESULTS

Of 464 eligible patients enrolled on ACNS0331, 354 (76%; 65.3% male, 83.1% white) completed some neuropsychological testing. Mean age at diagnosis was 9.1 years (range=3–19). Verbal and visual short-term memory and learning were broadly within the average range for the overall sample at all three timepoints. However, a large percentage of children exhibited scores ≥1SD below the mean on tasks of verbal learning both immediately (43.4%) and after a delay (40.7%) at T3. In addition, 58.6% of children randomized to SDCSI exhibited impairment in verbal learning after a delay compared to 34.8% of children randomized to LDSCI, and 35.0% of those aged ≥8 at diagnosis receiving SDCSI.

CONCLUSIONS

Younger children receiving SDCSI have particularly high rates of memory impairment five years after diagnosis of medulloblastoma. Limiting CSI dose and/or volume in young children treated for this diagnosis may improve outcomes for memory functioning.