bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-17. USE OF MRNA FOR SAFE AND EFFECTIVE GD2-DIRECTED CAR T CELLS TO TREAT DIFFUSE MIDLINE GLIOMAS
Authors: Foster Jessica , Griffin Crystal , Stern Allison , Brimley Cameron , Storm Phillip , Barrett David , Resnick Adam
Published: June 2021

Chimeric antigen receptor (CAR) T cells targeting the disialoganglioside GD2 have garnered interest as an effective therapeutic for treating diffuse midline glioma (DMG). However, prior studies raised significant concerns of neurotoxicity and fatality when using virally transduced CAR T cells against these midline tumors. Building upon our prior work optimizing mRNA for use in CAR T cells (Hum Gen Ther, 2019), we hypothesized transient GD2-directed mRNA CAR T cells could be successfully employed for safe and effective treatment of DMG. GD2-directed CAR T cells were created using mRNA encoding the 14G2a single chain variable fragment paired with 41BB and CD3-zeta co-stimulatory domains and transfected into human T cells. GD2-directed CAR T cells were tested against a panel of DMG cell lines and two murine xenograft models of DMG: 7316-6349 and SU-DIPG13P*. In all DMG cellular models, GD2-directed mRNA CAR T cells induced significant tumor cell death compared to CD19-directed mRNA CAR T cell controls. In vivo, mRNA CAR T cells were delivered locoregionally using an indwelling infusion catheter to allow for repeated dosing. Four intratumoral doses of 5 x 106 GD2-directed mRNA CAR T cells induced significant tumor regression measured by bioluminescence in DMG model 7316-6349 (p<0.0001). In addition, GD2-directed mRNA CAR T cells prolonged survival of mice harboring the aggressive DMG model SU-DIPG13P* by 61% (mean survival 29 days versus 18 days, p<0.01) following four intratumoral doses of 4 x 106 CAR T cells. No GD2-directed CAR T cell treatment-related deaths or toxicities were observed. These data highlight the utility of using mRNA to titrate CAR T cell therapy in the brain, and establish GD2-directed mRNA CAR T cells as a safe and effective method for treating DMG.
LGG-12. SAFETY AND EFFICACY OF DUAL THERAPY WITH DABRAFENIB AND TRAMETINIB IN AN INFANT WITH BRAF V600E MUTANT INOPERABLE LOW GRADE GLIOMA
Authors: Green Sage , Walter Andrew , Piatt Joseph , Kaur Gurcharanjeet
Published: June 2021

Objective

To describe safety and efficacy of dual targeted therapy with dabrafenib (BRAFi) and trametinib (MEKi) in an infant with inoperable low grade glioma with BRAF V600E mutation.

Introduction

Safety and efficacy of dual targeted therapy with BRAFi and MEKi for pediatric low grade glioma (pLGG) is currently being evaluated, however, infants are usually not included in these clinical trials.

Case

We report a case of a 2-month-old male infant who presented with involuntary movements and gaze deviation concerning for seizures. MRI brain revealed a tumor involving the medulla, T2/FLAIR dimensions: 2.5 x 2.2 x 2.7 cm and drop metastases to the cauda equina. An EEG ruled out seizure activity. Tumor biopsy was performed revealing Ganglioglioma, WHO grade I. IHC and somatic next generation sequencing revealed BRAF V600E point mutation. Germline testing was negative. Due to tumor progression on traditional chemotherapy, compassionate use of dual targeted therapy with dabrafenib (5.25mg/kg/day divided twice daily) and trametinib (0.032mg/kg daily) was initiated at 4.5 months of age. The patient has tolerated dual therapy for nearly 1 year without significant toxicity with exception of grade I skin rash. In terms of functional outcomes, previously noticed vocal cord paresis has resolved and our patient with global developmental delay continues to make developmental gains, albeit slowly. On recent neuroimaging, pLGG has continued to grow T2/FLAIR dimensions: 3.5 x 3.5 x 3.7 cm, however, combination therapy has halted the rate of growth of this tumor.

Conclusion

To our knowledge, our patient is the youngest to receive combination of BRAFi and MEKi. Tumor targeted therapy could be an important treatment option for infants with inoperable pLGG where aggressive surgery and radiation therapy are associated with significant morbidity. Multi-institutional clinical trials that include infants are needed to further comment on safety and efficacy of these agents.
LGG-14. PRESENTATION CHARACTERISTICS AND TREATMENT OUTCOMES FOR PEDIATRIC OPTIC PATHWAY GLIOMAS IN QATAR
Authors: Maaz Ata , Yousif Tayseer , Abdulmajeed Mohammed , Ederies Moegamad , Neri Pedro , Kamboh Abdul
Published: June 2021

Objectives

To review the presentation characteristics and treatment outcomes for pediatric optic pathway gliomas (OPG) in Qatar.

Methods

Retrospective review of data for children with OPG from January 2009 to February 2021. Presenting features, diagnostic imaging and indications for treatment were reviewed. Progression free survival (PFS) and overall survival(OS) were computed using standard statistical methods. Medical notes were also reviewed for visual outcomes.

Results

Nineteen patients were diagnosed with OPG during the study period. There were 10 (52%) females. Median age was 29 months (range 6–186) months. Eleven (57%) tumors were related to neurofibromatosis Type 1 (NF-1). Nine (47%) of OPG were located in optic nerves, 5 (26%) were chiasmatic/suprasellar, while the remaining 5(26%) involved a combination of structures. Seven(36%) children presented with oculo-visual symptoms. Another 7 were diagnosed on screening imaging for NF-1. Seven(36%) children had debulking surgery/biopsy, while the remaining patients were diagnosed on neuro-imaging alone. Thirteen (68%) patients were treated with chemotherapy and 2 received additional radiotherapy. Indications for non-surgical treatment included visual impairment (46%) and large/progressive tumor (54%). Carboplatin based regimes were used as first line chemotherapy for 76 % of patients. Five (38%) patients required more than one lines of treatment. OS and PFS at 36 months were 100% and 48%. Baseline visual assessment showed 5 children each (26%) had unilateral and bilateral visual impairment, while 9 (48%) had normal vision. Of the 6 children receiving chemotherapy for visual impairment, 2 (33%) showed improvement. Of the 7 children treated for large/progressive tumors, 3 (42%) showed partial response, 2(28%) had progressive disease and 1 had stable disease after the first line therapy.

Conclusions

Our results are in-keeping with international data for optic pathway gliomas. Early referral and diagnosis may improve visual outcomes for this group of tumors.
LGG-16. TO BE PRECISE - KNOW YOUR TARGETS: INSTITUTIONAL EXPERIENCE WITH TUMOR TARGETED THERAPY FOR RECURRENT/PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA AND PLEXIFORM NEUROFIBROMA
Authors: Silverman Mackenzie , Piatt Joseph , Walter Andrew , Nikam Rahul , Kaur Gurcharanjeet
Published: June 2021

Introduction

The oncogenic drivers of pediatric CNS tumors are rapidly being identified with the implementation of high throughput genetic screening. Precision medicine approaches to treatment have shown promising results, but data remains limited in the community oncology setting. We aim to describe our institutional experience using targeted therapies for plexiform neurofibroma and recurrent/progressive pediatric low-grade glioma (pLGG).

Methods

We performed a retrospective chart review of all patients treated with tumor targeted therapies for recurrent/progressive pLGG and plexiform neurofibroma over the past 5 years.

Results

Ten patients treated with tumor targeted therapies were identified. Regimens included combination Dabrafenib and Trametinib (n=3), Trametinib monotherapy (n=2), Selumetinib (n=3), Vemurafenib (n=1), and Larotrectinib (n=1). Median age at therapy initiation was 11.5 years (range 1.1 - 18 years). Tumor molecular status included BRAFV600E mutation (n=4), NF1 mutation (n=2), KIAA1549-BRAF fusion (n=1), NACC-NTRK fusion (n=1), and FGFR1 mutation (n=1). Patients trialed an average of 2 treatment regimens prior to targeted therapy initiation (range 0–5). Mean duration of therapy was 14.5 months (range .5–33 months) with 8 patients remaining on treatment. Based on modified RANO criteria, responses included partial (n=1), stable disease (n=8), and progressive disease (n=1). Progressive disease was noted after 4 months of treatment with Dabrafenib and Trametinib combination therapy, but rate of tumor growth was decreased. Subjective functional improvement was seen in 50% of patients. The most common toxicities included rash (n=5) and pyrexia (n=2). Trametinib was discontinued in one patient due to intra-tumoral hemorrhage of unclear etiology.

Conclusion

Treatment of pediatric CNS tumors with targeted agents appears to be feasible and efficacious in the community oncology setting. Multi-institutional clinical trials are currently ongoing for each of these therapies. There remains a need for community oncology institutional data regarding their use.
TMOD-01. A PROGNOSTIC NOMOGRAM MODEL AND ONLINE SOFTWARE FOR PATIENTS WITH NEWLY DIAGNOSED LOWER-GRADE GLIOMAS
Authors: Han Mingzhi
Published: June 2021

The nomogram represents a statistical model that incorporates multiple risk factors to estimate individualized survival probabilities. In this study, we developed a nomogram which provides an important tool for individulized survival predicition for newly diagnosed low-grade gliomas (LGG). A total number of 582 newly diagnosed LGG patients were included; the median age was 39.93 years and 42% were female. Cox regression analysis showed that younger age at diagnosis, WHO grade II vs. III, the IDHmut-codel vs. the IDHwt, and the IDHmut-non-codel vs. the IDHwt were significantly associated with better prognosis. The adjuvant treatment following surgery showed a trend towards improved survival. Subsequently, the nomogram to estimate 60-, 90-, and 120-month survival probabilities was established. Our data showed that the age at diagnosis was the largest contributor to patient survival, followed by molecular subtype, WHO grade, treatment and gender. The calibration plot showed that the observed and the nomogram predicted OS curves were well-aligned. In addition, we also validated our nomogram for LGG patients who received postsurgical adjuvant therapy through cross-validation and the calibration plot. Finally, we developed a free online tool for this nomogram (softwarewebsite:https://rrlnnomogram.shinyapps.io/LGG_Nom_Asian/). Overall, this model should be a useful tool for counseling patients in clinical practice including treatment decisions, follow-up, and prognosis.
TMOD-05. GENOME-WIDE DNA METHYLATION PROFILE: A POWERFUL STRATEGY TO RECAPITULATE HETEROGENEITY OF PEDIATRIC BRAIN TUMORS IN PRIMARY CELL LINES
Authors: Pedace Lucia , Pizzi Simone , Vinci Maria , Pericoli Giulia , Catanzaro Giuseppina , Abballe Luana , Po Agnese , Del Bufalo Francesca , Rossi Sabrina , Camassei Francesca Diomedi , Giangaspero Felice , Tiberi Luca , Mastronuzzi Angela , Ferretti Elisabetta , Tartaglia Marco , Locatelli Franco , Ciolfi Andrea , Miele Evelina
Published: June 2021

Background

Development of in vitro models of pediatric brain tumors (pBT) is instrumental for both understanding the contributing oncogenic molecular mechanisms and identifying and testing new therapeutic strategies. Primary cell lines should be established and managed to prevent epigenetic and genetic alterations and thus recapitulating the original tumor. DNA methylation (DM) is a stable epigenetic modification, altered in cancer and recently used to classify tumors. We aim to apply DM and Copy Number Variation (CNV) profiling to characterize pBT primary cell lines and tumors.

Methods

We investigated 34 pBT tissues from different histology paired to 52 their derived primary cultures in both 2D and 3D conditions, as stem-cells or in serum-supplemented medium, and both short and long-terms in culture. We studied 18 additional pBT-derived cell-lines, 9 organoids, 5 commercial cell-lines, and 122 pBT tissues from the same histological categories, as controls, for a total of 240 genome-wide DM profiles. We analyzed DM and CNV profiles by using Illumina EPIC-arrays. By means of a bump hunting strategy, we identified differentially methylated regions in faithful vs unfaithful cell lines, and performed a functional characterization using over-representation analysis. Results The 69% (25/36) of cells at early passages retained genetic alteration and the same DM patterns of the original tumors, with no differences related to 2D/3D methods or the presence of serum in media. The 70% (24/34) of primary cell lines analyzed at later passages (>5 or >14 days in culture) diverged from the primary tumor, the totality of those cultured with serum. All divergent cells clustered together acquiring common deregulated epigenetic signature induced by serum culture media, 2D methods and longer time in culture.

Conclusions

We have shown that global DM profiles, along with CNV analysis are useful tools to detect the recapitulation of pBT-derived primary cell-lines from the original tumor. Whatever subgroups tested, our results suggest that in vitro models should be passaged as little as possible to retain the epigenetic and genetic alterations of the tumors and thus to be considered relevant for basic and translational biology.
OMIC-09. MAPPING THE HISTONE MUTATIONAL LANDSCAPE ACROSS ADULT AND PEDIATRIC CANCER GENOMES UNCOVERS NOVEL SOMATIC MUTATIONS IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Bonner Erin , Gaonkar Krutika , Jain Payal , Zhu Yuankun , Laternser Sandra , Eze Augustine , Kambhampati Madhuri , Yadavilli Sridevi , Cain Jason , Mueller Sabine , Waszak Sebastian , Nazarian Javad
Published: June 2021

There is a growing role for mutations affecting histone linker and histone core-encoding genes across several adult and pediatric cancers. However, the extent to which somatic histone mutations may bridge across different cancers as common tumorigenic events – particularly in the context of pediatric CNS tumors – remains unclear. To address this knowledge gap, we set out to define a comprehensive pan-cancer landscape of somatic histone mutations. We first queried the ICGC PCAWG and TCGA Pan-Cancer Atlas representing >12,500 adult and pediatric cancer patients. We found lymphomas to be most enriched for histone mutations (50–75%) and, in particular, for mutations in linker histones (HIST1H1B-E), yet also in specific core histone genes (eg, HIST2H2BE). Moreover, we observed a significant enrichment of histone mutations in adult high-grade vs low-grade gliomas (10% vs 6%, P<0.05, n=922 patients). Interrogation of whole genome data from 800 pediatric CNS tumor genomes (PBTA/OpenDIPG), identified novel (non-H3K27/non-H3G34) somatic histone mutations in 5–10% of subjects, including pediatric high-grade gliomas (pHGGs) and diffuse midline gliomas (DMGs). We found an overlapping set of histone genes to be recurrently mutated in non-CNS cancers and pediatric CNS tumors alike (eg, HIST1H1B/C/E). Notably, the only pediatric primary CNS lymphoma patient also harbored a histone linker alteration (HIST1H1B), similar to adult non-CNS lymphoma patients. We validated novel somatic histone mutations in DMGs by Sanger sequencing. Ongoing studies include in vitro assessment of the impact of these mutations on cell proliferation, chromatin accessibility, histone spacing, and gene expression. In addition, we will further assess associations with clinical outcome, age, and tumor subtypes. Collectively, oncohistone vulnerabilities were identified and defined as histone gene families recurrently mutated across all cancer types. Our analyses of adult and pediatric cancer genomes have uncovered previously unknown mutations affecting histone linker and core proteins, which may play a yet-undefined role in tumor etiology.
OMIC-10. TRANSCRIPTOMIC ANALYSIS REVEALS SEX DIFFERENCES IN PEDIATRIC BRAIN MECHANISMS
Authors: Yang Wei , Lathia Justin D , Connor James R , Berens Michael E , Barnholtz-Sloan Jill S , Rubin Joshua B
Published: June 2021

A significant male overrepresentation exists in cancer incidence and in cancer-related deaths. This is true in all regions of the world and across the lifespan. We published an analysis of adult glioblastoma transcriptomes in which we identified sex-biased molecular features that distinguished the longest surviving male and female patients. Male GBM was characterized by decreased expression of positive regulators of the cell, while female GBM was characterized by decreased expression of intermediates in integrin signaling. To determine whether similar sex differences exist in pediatric brain tumors (pBTs), we accessed 860 pBT transcriptomes, representing all diagnostic categories and ages through the Children’s Brain Tumor Network. Unsupervised Bayesian nearest neighbor analysis of gene expression revealed distinct male and female expression patterns indicating fundamental differences exist in pBTs as a function of sex. Similar to our adult GBM analysis, male pBTs were distinguished from female pBTs by the involvement of cell cycle regulatory pathways. In contrast to adult GBM, female pBTs were characterized by involvement of metabolism and inflammatory/ immunity pathways. Interestingly, these sex differences were also evident in a parallel analysis of 209 of neuroblastoma cases. Focused analysis of the most common malignant pBTs (high-grade glioma, medulloblastoma, and ependymoma) revealed that each disease type exhibited significant sex differences in molecular profile, involving distinct pathways in each tumor type. Together, these data indicate that sex-based differences in molecular mechanisms exist in pBTs, and imply that sex-specific approaches to pBT treatment might yield improved outcomes for all patients.
OMIC-13. THE ROLE OF COPY NUMBER ALTERATIONS IN PREDICTING SURVIVAL AND INFLUENCING TREATMENT OF CHILDHOOD BRAIN TUMORS
Authors: Freshour Sharon , Fisk Bryan , Miller Christopher , Griffith Obi , Griffith Malachi , Rubin Joshua
Published: June 2021

Brain and central nervous system tumors are the most common form of solid tumor cancers and the second most common cancer overall among children. While many advances have been made in understanding the genomics of childhood brain tumors in recent years, the role of copy number alterations (CNAs) has not been fully characterized. Although the genomes of childhood brain tumor patients are generally considered to be relatively stable diploid genomes, analysis of a subset of pretreatment diagnostic samples from a cohort of 84 deceased patients from Washington University revealed widespread alterations, suggesting CNAs may play a larger role in the progression and prognosis of childhood brain tumors than originally thought. Follow up analysis of the entire cohort, containing a variety of tumor types that had low-pass whole genome sequencing performed, similarly showed evidence of CNAs across samples. 75 out 84 patients showed the presence of CNAs with an average of 16% of the genome being altered per sample and a median of 7%. Preliminary results examining correlations between the percentage of the genome that was copy number altered and event free survival or overall survival indicated that CNA percentage may have some prognostic value. For example, ependymoma samples showed positive correlation between alteration percentage and overall survival, while glioblastoma samples showed negative correlation. To explore copy number alteration in a larger cohort and increase statistical power, similar analyses are being performed using an additional 950 samples from the Pediatric Brain Tumor Atlas curated by The Children’s Brain Tumor Network (CBTN) to determine if CNVs and CNV percentage or specific alterations can serve as prognostic markers and whether the biology of this genomic instability could inform therapeutic strategy.
RARE-08. POTENTIAL NEW THERAPIES FOR DIFFUSE INTRINSIC PONTINE GLIOMAS IDENTIFIED THROUGH HIGH THROUGHPUT DRUG SCREENING
Authors: Upton Dannielle , Valvi Santosh , Liu Jie , Yeung Nicole , George Sandra , Ung Caitlin , Khan Aaminah , Franshaw Laura , Ehteda Anahid , Shen Han , Orienti Isabella , Farruggia Giovanna , Reynolds Patrick , Tsoli Maria , Ziegler David
Published: June 2021

Diffuse Intrinsic Pontine Gliomas (DIPGs) are the most devastating of all brain tumors. There are no effective treatments, hence almost all children will die of their tumor within 12-months. There is an urgent need for novel effective therapies for this aggressive tumor. We performed a high-throughput drug screen with over 3,570 biologically active, clinically approved compounds against a panel of neurosphere-forming DIPG cells. We identified 7 compounds - auranofin, fenretinide, ivermectin, lanatoside, parthenolide, SAHA and mefloquine - that were confirmed to have potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells. Using cytotoxicity and clonogenic assays, we found that these drugs were able to inhibit DIPG-neurosphere proliferation and colony formation in vitro. To determine whether the in vitro efficacy could be replicated in vivo, we tested the activity of each of these compounds in an orthotopic DIPG model. Of the agents tested, fenretinide, auranofin and SAHA were the most active anti-tumor agents, significantly enhancing the survival of tumor bearing animals. Mechanistic studies showed fenretinide enhancing apoptotic cell death of DIPG cells via inhibition of PDGFRa transcription and downregulation of the PI3K/AKT/MTOR pathway. We therefore examined the therapeutic efficacy of fenretinide using a second orthotopic model with PDGFRa amplification. We used two different fenretinide formulations which were found to enhance survival. Fenretinide is clinically available with safety data in children. Validation of the activity of Fenretinide in PDGFRa-amplified or overexpressed DIPGs will lead to the development of a clinical trial, allowing the advancement of fenretinide as potentially the first active therapy for DIPG.
RARE-10. PRIMARY INTRACRANIAL EWING SARCOMA IN A 12 MONTH OLD MALE
Authors: Hoerig Clay , Goldberg Aaron , Pathare Jody , Dao Tuan , Amzajerdi Ali Nael , Loudon William , Plant-Fox Ashley , Olaya Joffre , Abongwa Chenue
Published: June 2021

Background

Ewing sarcoma (EWS) is a rare type of pediatric bone and soft tissue tumor that accounts for approximately 1% of all pediatric malignancies. It most commonly occurs in the long bones or axial skeleton, and rarely includes extraosseous sites or intracranial involvement. Reports of primary intracranial EWS are minimal. Pediatric intracranial EWS is even more rare with less than 15 cases reported.

Case Description

We describe the case of primary intracranial EWS in a 12 month old male. The patient’s initial MRI showed a large heterogeneous supratentorial cystic and solid mass centered in the right parietal region measuring 9.1cm x10.3cm x 7.6cm. No distant metastases were detected. The patient underwent surgical resection and pathology was consistent with a small round blue cell tumor. Further pathological evaluation revealed presence of EWSR1-FLI1 fusion and was negative for CD99, GFAP, synaptophysin, Olig2, desmin, and CAM5.2. Stains for INI1 and BRG1 were retained. The patient was treated with adjuvant chemotherapy and focal proton beam radiation (as per AEWS0031).

Conclusion

Primary intracranial Ewing Sarcoma is a rare pediatric brain tumor and, to our knowledge, this would be the youngest reported case to date. This case demonstrates the successful application of a sarcoma-based regimen to a primary intracranial EWS tumor with no evidence of residual tumor on MRI at 8 months into treatment. Future studies should be directed at understanding the biology of these rare tumors and optimizing treatment approaches.
RARE-11. PRIMARY INTRACRANIAL LEIOMYOSARCOMA IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1
Authors: Goldberg Aaron , Hoerig Clay , Xu Jordan , Pathare Jody , Abongwa Chenue , Olaya Joffre , Plant Ashley
Published: June 2021

Primary intracranial leiomyosarcoma (LMS) is very rare, with only a few reported cases. Only one prior case report of intracranial LMS in a patient with neurofibromatosis type 1 (NF1) was identified. We report a case of primary intracranial LMS in a patient with known history of NF1. Our patient is a 17-years-old female without history of immunocompromise presenting with severe headaches representative of right frontal hemorrhagic tumor found to be primary intracranial LMS. In prior reported cases, most primary intracranial LMS were treated with sarcoma-based chemotherapy and radiation therapy. Our patient underwent multiple resections, as well as focal radiation. Her chemotherapy initially included ifosfamide, carboplatin, and etoposide, but when she failed etoposide twice due to severe allergic reactions, she completed treatment successfully with the combination of ifosfamide and doxorubicin. She continues to be doing well with no evidence of disease at 41 months post-treatment.
RARE-15. THE MOLECULAR PROFILE OF SECONDARY MENINGIOMAS IN SURVIVORS OF CHILDHOOD NON-CENTRAL NERVOUS SYSTEM CANCERS
Authors: Corriveau-Bourque Catherine , Wong Derek , van Landeghem Frank , Snuderl Matija , Spavor Maria , Yip Stephen , Eisenstat David
Published: June 2021

Introduction

Cranial irradiation remains part of childhood cancer therapy and secondary meningiomas are a late effect. Secondary meningiomas are reported in patients who received low and high dose cranial irradiation and arise ~ 20 years post exposure. The molecular and genetic profile of primary meningiomas has been well studied; however, only a few studies describe these in radiation-induced meningiomas (RIM).

Methods

We identified patients followed at the Childhood Cancer Survivor Clinic, Stollery Children’s Hospital who had a history of non-central nervous system malignancies and received cranial irradiation who developed meningiomas between clinic inception in 1971 and June 2013. Whole exome sequencing (WES) as well as DNA methylation profiling were performed for patients where tumor and germline DNA were available.

Results

Of 96 patients who received cranial irradiation, 16 (16.7%) developed symptomatic meningiomas. This patient cohort is unique; all 16 patients received 2000–2400 cGy, suggesting a threshold dose. 9/16 (56%) had WHO Grade 2 meningiomas or greater and 7/16 (44%) were infiltrative. Post-surgical recurrences occurred in 43%. Patients experienced considerable morbidities directly attributable to the meningiomas or their treatment. 14 patients had samples suitable for further analysis. Preliminary results revealed that NF2 mutations were the most common (5). Other meningioma related genes with mutations identified in our patient cohort include TRAF7, AKT3, MSH4 (2), KMT2C (2), TET1 (2), KDM6A, and MLH3. Copy number alternations were noted with increased frequency on chromosomes 1p, 22q, 19q. 850k methylation analysis did not conclusively show any clustering. Ongoing studies include assessment of tumor mutation burden, RNAseq, and the mutational profile.

Conclusions

This study examined RIM in patients who received similar doses of radiation for their childhood cancer. To date, our findings are consistent with previously described primary and RIM mutations. Enhanced knowledge in secondary meningiomas is crucial for accurate patient counseling, prognostication, and treatment.
RARE-16. A PATIENT WITH MOSAIC POST-ZYGOTIC KRAS-G12D PATHOGENIC VARIANT PRESENTING WITH A SYMPTOMATIC SPINAL NEUROFIBROMA AND LARGE SEGMENTAL TRUNCAL CAFÉ AU LAIT SPOT
Authors: Demaliaj Dardan , Ji Jianglin , Deardorff Matthew , Chiarelli Peter , Tamrazi Benita , Hawes Debra , Biegel Jaclyn , Rosser Tena , Davidson Tom , Erdreich-Epstein Anat
Published: June 2021

An 11 year old boy presented with a three month history of progressive bilateral lower extremity weakness associated with recent intermittent incontinence. Spine MRI showed a right-sided T11-T12 paraspinal mass extending through the neural foramina into the epidural space and causing severe spinal cord compression. Skin showed a large macular lightly-hyperpigmented café au lait spot with irregular borders along the T10-T12 dermatome extending from the spine to approximately the anterior-axillary line. He was suspected to have segmental neurofibromatosis type 1 (NF1) as no additional clinical findings, radiographic features or family history of NF1 were identified. Patient underwent T10-12 laminectomy for resection of the epidural tumor component. Post-operative MRI showed resolution of the mass effect on the thecal sac and cord, with expected tumor residual lateral to the neural foramen. His residual spinal tumor and mild scoliosis remained stable over the two years of follow up to date. Pathological and molecular analysis of the resected tumor revealed a neurofibroma harboring an activating KRAS c.35G>A, p.Gly12Asp (KRAS-G12D) pathogenic variant at 27% variant allele frequency. Melanocytes cultured from two hyperpigmented skin biopsies showed the same KRAS-G12D pathogenic variant. This KRAS-G12D pathogenic variant was not found in leukocytes, indicating a post-zygotic origin. No NF1 pathogenic variant was identified in tumor tissue, melanocytes or leukocytes. The clinical findings were consistent with a mosaic KRASopathy due to a post zygotic KRAS-G12D pathogenic variant. The presence of the KRAS variant in the spinal neurofibroma and overlaying café au lait spot without an NF1 etiology in associated tissues demonstrates overlapping variability of presentations of RAS-MAPK pathway disorders. This case highlights the need for full clinical and genetic evaluation of patients presenting with segmental neurocutaneous disorders.
RARE-20. A RARE CASE OF A PRIMARY CENTRAL NERVOUS SYSTEM NEUROENDOCRINE CARCINOMA AND SUCCESSFULL THERAPY IN A FIVE-YEAR-OLD CHILD
Authors: Stepien Natalia , Haberler Christine , Schmook Maria-Theresa , Gojo Johannes , Azizi Amedeo A , Czech Thomas , Slavc Irene , Peyrl Andreas
Published: June 2021

Neuroendocrine tumors (NETs) are rare neoplasms predominantly arising in the GI-tract or the lungs of adults. To date, only ten cases of primary CNS NETs have been reported with just three of them describing a neuroendocrine carcinoma (NEC) in patients aged 34–77 years and none occurring in a child. We report on a previously healthy 5-year-old boy, who presented with headaches, nausea and vomiting and was diagnosed with a left cerebellar solid mass with a cystic component, radiologically suggestive of a pilocytic astrocytoma. After gross-total resection, histological analysis revealed an epithelial tumor growing in a nest-like pattern with a very high mitotic frequency, staining positive for CK8, CK18 and CK19. Chromogranin A and synaptophysin expression indicated a neuroendocrine differentiation. Molecular analysis of the tumor tissue revealed a KRAS- splice-site mutation (c451-3C>T). After extensive search for an extracranial primary, including Ga-68 DOTANOC-PET-CT, the diagnosis of a primary CNS NEC was made, and proton irradiation was performed. However, the patient developed an in-field recurrence just five weeks after the end of radiotherapy. The tumor was re-resected en-bloc, showing vital tumor tissue, demonstrating its aggressiveness. Chemotherapy consisting of etoposide, cisplatin and ifosfamide was initiated. After two cycles chemotherapy was continued with etoposide and carboplatin for another four cycles. The patient remains disease free one year after the end of relapse-treatment, supporting the beneficial effect of platinum- and etoposide-based chemotherapy for this tumor entity. Physical exam revealed a sagittal synostosis with a mild dolichocephaly. Interestingly, the KRAS-mutation was discovered to be a maternal germline mutation, previously described as likely benign. However, alterations of the RAS/MAPK pathway have been described in NECs and in craniosynostosis cases. It remains to be elucidated whether the KRAS-mutation is merely a variant of uncertain significance or might have been implicated in the development of this exceptional tumor.
RARE-24. IDENTIFYING INDIVIDUALS WITH PRIMARY CENTRAL NERVOUS SYSTEM TUMORS AT RISK FOR HEREDITARY CANCER SYNDROMES USING THE UTAH POPULATION DATABASE
Authors: Whipple Nicholas , Kohlmann Wendy , Cheshier Samuel , Yu Zhe , Curtin Karen , Schiffman Joshua
Published: June 2021

Background

CNS tumors are the most common solid tumors and the deadliest cancers in children. Approximately 10% of children with a CNS tumor harbor a hereditary cancer syndrome (HCS), but many will not be tested for a HCS. The Utah Population Database (UPDB) contains comprehensive cancer registry data for Utah families and can determine multigenerational cancer pedigrees across an archive of 5.8 million individuals. We hypothesize that the UPDB can identify children and families with HCSs not previously identified.

Methods

We queried the UPDB for individuals ages 0–39 diagnosed with a primary CNS tumor (malignant and benign) between 1966–2017 and generated cancer pedigrees of 3 generations or more for probands, extending to at least third-degree relatives. Specialized software calculated a familial standardized incidence ratio (FSIR) to determine families with excess clustering of CNS tumors. Clinical cancer genetics experts reviewed pedigrees to confirm patterns of HCS.

Results

We identified 4,634 CNS tumors in 4,550 individuals, of whom 2,233 (49%) reside in high-quality pedigrees containing ≥2 grandparents, at least 1 from both maternal and paternal sides. To identify families with excess clustering of CNS tumors, we selected pedigrees with an FSIR P<0.05 and ≥2 affected patients, resulting in 161 high-risk families with a mean of 170 (median 96) relatives per pedigree of 3–6 generations. Among these 161 families, there were 2,017 unique relatives (first-third degree) of CNS probands with 2,355 tumors (any site), for a per pedigree average of 14.7 tumors in 12.5 relatives. Review of the 10 highest risk pedigrees indicated that 4 meet HCS criteria, including Li-Fraumeni (n=2), von Hippel-Lindau (n=1), and rhabdoid tumor predisposition (n=1).

Conclusion

The UPDB can produce multigenerational cancer pedigrees that identify individuals and families at risk of harboring a HCS who warrant germline testing. These findings should encourage clinicians to perform thorough family history screening.
EPCT-03. SERIAL PLASMA AND CSF CELL-FREE TUMOR DNA (CF-TDNA) TRACKING IN DIFFUSE MIDLINE GLIOMA PATIENTS UNDERGOING TREATMENT WITH ONC201
Authors: Cantor Evan , Wierzbicki Kyle , Tarapore Rohinton S , Thomas Chase , Cartaxo Rodrigo , Yadav Viveka Nand , Ravindran Ramya , Bruzek Amy K , Wadden Jack , Babilla Clarissa May , Kawakibi Abed Rhaman , Ji Sunjong , Ramos Johanna , Paul Alyssa , Wolfe Ian , Leonard Marcia , Robertson Partricia , Franson Andrea , Mody Rajen , Garton Hugh , Odia Yazmin , Kline Cassie , Vitanza Nicholas A , Khatua Soumen , Mueller Sabine , Allen Joshua E , Gardner Sharon , Koschmann Carl
Published: June 2021

Diffuse midline glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2, 6 months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. CSF collection was feasible in this cohort, with no procedural complications. We collected 96 plasma samples and 53 CSF samples from 29 patients, including those with H3F3A (H3.3) (n=13), HIST13HB (H3.1) (n= 4), and unknown H3 status/not biopsied (n=12) [range of 0–8 CSF samples and 0–10 plasma samples]. We performed digital droplet polymerase chain reaction (ddPCR) analysis and/or amplicon-based electronic sequencing (Oxford Nanopore) of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Preliminary analysis of samples demonstrates a correlation between changes in tumor size and H3K27M cf-tDNA VAF, when removing samples with concurrent bevacizumab. In multiple cases, early reduction in CSF cf-tDNA predicts long-term clinical response (>1 year) to ONC201, and does not increase in cases of later-defined pseudo-progression (radiation necrosis). For example, a now 9-year old patient with thalamic H3K27M-mutant DMG underwent treatment with ONC201 after initial radiation and developed increase in tumor size at 4 months post-radiation (124% baseline) of unclear etiology at the time. Meanwhile, her ddPCR declined from baseline 6.76% VAF to <1%, which has persisted, with now near complete response (15% tumor reduction) at 30 months on treatment from diagnosis. In summary, we present the feasibility and utility of serial CSF/plasma monitoring of a promising experimental therapy for DMG.
EPCT-04. RESULTS OF A PHASE 1 STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 WITH RADIOTHERAPY FOR NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Garcia-Moure Marc , Pérez-Larraya Jaime Gállego , Patiño Ana , Gonzalez-Huarriz Marisol , Jones Chris , MacKay Alan , Van der Lugt Jasper , Hulleman Esther , de Andrea Carlos , Astigarraga Itziar , García-Ariza Miguel , Lopez-Ibor Blanca , Villalba Maria , Lang Frederick F , Fueyo Juan , Gomez-Manzano Candelaria , Dobbs Jessica , Diez-Valle Ricardo , Alonso Marta M , Tejada Sonia
Published: June 2021

Background

A Phase 1, single center study is ongoing to evaluate the conditionally replicative oncolytic adenovirus, DNX-2401 (tasadenoturev), followed by radiotherapy (RT) in pediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

Methods

Patients 1–18 years with newly diagnosed DIPG with no prior treatment, Lansky/Karnofsky performance score ≥ 70, and adequate organ function were enrolled. A tumor biopsy was performed followed by a single intratumoral injection of 1e10-5e10 virus particles (vp) DNX-2401. Conventional radiotherapy was initiated within 1 month of DNX-2401 administration.

Results

Enrolled subjects (n=12) had a median age of 9 (range 3–18) and performance scores of 90–100 (n=4; 33%) or 70–80 (n=8; 67%). As part of a dose escalation design, subjects were treated with 1e10 vp (n=4) or 5e10 vp DNX-2401 (n=8), which was then followed by standard RT in 11 of 12 subjects (92%). No dose-limiting toxicities were observed and the treatment regimen was well-tolerated. Adverse events (AEs) have been primarily mild to moderate and consistent with underlying disease. The most commonly reported AEs (≥ 5 subjects), regardless of study drug relationship, include headache, asthenia, vomiting, anemia, leukocytosis, and fever. Two SAEs have been reported including grade 3 lymphopenia and grade 3 abdominal pain. Tumor reductions have been observed and efficacy evaluations are ongoing. As of 09Dec2020, 12-month survival (OS-12) was 71% and 4 of 12 patients had survived > 20 months. Four subjects continue to be followed for survival. Correlative analysis of tumor biopsy and peripheral samples is ongoing.

Conclusions

DNX-2401 followed by RT can be safely administered to pediatric subjects with newly diagnosed DIPG; clinical activity and preliminary survival are encouraging.
EPCT-07. ID1 IS A KEY TRANSCRIPTIONAL REGULATOR OF DIPG INVASION AND IS TARGETABLE WITH CANNABIDIOL
Authors: Nand Yadav Viveka , Harris Micah K , Thomas Chase , Stallard Stefanie , Woo Rinette , Siddaway Robert , Qin Tingting , Cummings Jessica R , Mullan Brendan , Siada Ruby , Ravindran Ramya , Niculcea Michael , Cao Xuhong , Castro Maria G , Lowenstein Pedro R , Mody Rajen , Chinnaiyan Arul , Hawkins Cynthia , Desprez Pierre , McAllister Sean , Venneti Sriram , Koschmann Carl
Published: June 2021

Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with no effective therapies beyond radiation. The highly invasive nature of DIPG is key to its aggressive phenotype, but the factors and mechanisms contributing to this aggressive invasion are unknown. Inhibitor of DNA binding (ID) proteins, key regulators of lineage commitment during embryogenesis, are implicated in tumorigenesis in multiple human solid tumors. Prior work showed that recurrent H3F3A and ACVR1 mutations increase ID1 expression in cultured astrocytes. However, the impact and targetability of ID1 have not been explored in human DIPG. Exome and transcriptome sequencing analyses of multi-focal DIPG tumors and normal brain tissue from autopsy (n=52) revealed that ID1 expression is significantly elevated in DIPG samples. Higher ID1 expression correlates with reduced survival in DIPG patients and increased regional invasion in multi-focal autopsy samples. Analyses of developing mouse brain RNA/ChIP-Seq data revealed high ID1 expression and H3K27ac promoter binding in prenatal hindbrain compared to all other prenatal and postnatal brain regions. ChIP-qPCR for H3K27ac and H3K27me3 revealed that ID1 gene regulatory regions are epigenetically poised for upregulation in DIPG tissues compared to normal brain, regardless of H3/ACVR1 mutational status. These data support that the developing pons is regionally poised for ID1 activation. Genetic (shRNA) ID1 knockdown of primary human H3.3K27M-DIPG cells (DIPG007) resulted in significantly reduced invasion/migration and significantly improved survival of K27M-DIPG mice. Knockdown of ID1 in DIPG cells also resulted in down-regulation of the WNK1-NKCC1 pathway, which regulates tumor cell electrolyte homeostasis and migration. Finally, treatment of DIPG007 cells with cannabidiol (CBD) reduced ID1 levels, viability of DIPG cells and significantly improved survival of K27M-DIPG mice. In summary, our findings indicate that multifactorial (genetic and regional) epigenetic upregulation of ID1 drives DIPG invasiveness; and that targeting ID1 with CBD could potentially be an effective therapy for DIPG.
EPCT-11. RURALITY INDEX SCORE AND PEDIATRIC NEURO-ONCOLOGICAL OUTCOME IN ONTARIO
Authors: Kameda-Smith Michelle , Pond Gregory , Farrokhyar Forough , Seow Hsien
Published: June 2021

Introduction

Rapid access to neurosurgical decisions and definitive management are vital for the outcome of neurocritical patients. There are increased challenges of providing services and to maintain critical infrastructure for rural citizens. The relationship between rurality, marginalization and health outcomes has been identified as associated with higher mortality rates and higher rates of many diseases[G1].

Methods

Employing linked administrative databases, we retrospectively analyzed a population based cohort of patients diagnosed with a pediatric brain tumour between 1996 to 2017 in Ontario, Canada. The Ontario Marginalization Index was employed as a surrogate for rurality providing an overall Rurality Index for Ontario (RIO) in addition to the 2016 Ontario Marginalization Index (ON-MARG).

Results

Of 1457 patients included, 54.0% were male, 277 of whom were diagnosed in infancy (i.e., < 3 years of age). Income quintile was evenly distributed with 11.5% classified as living in a rural area of Ontario. The median[G2] distance to the nearest pediatric neurosurgical hospital was 59.6km. The rurality index score (RIO) was 0 in 38.8% of children with the majority of patients with a RIO score of <39. The ON-MARG identified 51.9% of patients living in communities with low concentration of individuals without income from employment. A higher RIO score was not a significant factor (Continuous p=0.092/Ordinal p=0.20) associated with length[G3] of follow up, indicating rurality was not a significant factor for determining compliance to[G4] clinical follow-up. However, a trend towards reduced follow-up compliance in the higher RIO score cohort was identified.

Conclusion

Rurality and social determinants of health of the region pediatric neuro-oncological patients reside were not associated with patient outcome but a trend towards lower follow-up compliance was identified when children were from regions with RIO>39. Implementation of telehealth follow-up for these patients may overcome barrier to clinical follow-up.[G5]
EPCT-19. DRUG RESISTANCE IN MEDULLOBLASTOMA ADDRESSED WITH OLIG2 INHIBITOR, CT-179
Authors: Dismuke Taylor , Lim Chaemin , Gershon Timothy
Published: June 2021

Patients with medulloblastoma, the most common malignant pediatric brain tumor. need improved treatment options. Conventional medulloblastoma treatment, with resection, chemotherapy, and radiation, leaves survivors at risk of neurocognitive injury, growth defects, and psychosocial impairment. Moreover, there is no effective therapy for recurrent medulloblastoma. We seek to identify novel treatments that will address systemic toxicity and tumor recurrence. We tested a nanoparticle formulation of the CDK4/6 inhibitor, palbociclib (POx-palbo) in mice genetically-engineered to develop medulloblastoma (G-Smo mice) and found a significant anti-tumor effect that was consistently limited by the recurrence of OLIG2+ medulloblastoma stem cells. We then tested the hypothesis that directly targeting OLIG2 function would improve the efficacy of palbociclib and forestall resistance. We therefore examined the potential efficacy of CT-179, a first-in-class OLIG2 inhibitor, in G-Smo mice engineered to express luciferase as an SHH reporter. These studies showed that CT-179 decreased SHH signaling and prolonged event-free survival. Pharmacodynamic studies of G-Smo mice during treatment showed that CT-179 alters cell-cycle progression and promotes a shift towards cell-cycle arrest. Mechanistically, CT-179 decreased the Olig2 phosphorylation. The combination of CT-179 and POx-palbo increased event-free survival of G-Smo mice compared to either agent administered alone. Our studies show both the potential of the palbociclib CT-179 combination, and the potential for CT-179 to improve the efficacy of therapies limited by OLIG2+ stem cell recurrence. As OLIG2+ stem cells have been shown to drive recurrence to conventional therapy and OLIG2 phosphorylation disables p53-driven apoptosis, CT-179 may be a versatile agent to enhance both targeted and cytotoxic treatments.
EPCT-20. TECHNICAL FEASIBILITY SODIUM (23NA) MRI OF PEDIATRIC GLIOMAS
Authors: Bhatia Aashim
Published: June 2021

Pediatric glioma response to novel targeted therapy can be heterogeneous on conventional proton (1H) MRI. Sodium concentration, as measured with 23Na MRI in adult brain tumors can provide complementary assessment of tumor proliferation to conventional MRI. However, 23Na MRI pediatric brain tumor studies are lacking. Determine the technical feasibility of performing sodium23Na MRI on pediatric glioma patients. Prospective study of an immunotherapy trial for newly diagnosed and recurrent gliomas (high-grade gliomas, low-grade gliomas, brainstem gliomas) in which participants were imaged with 23Na MRI at 3.0 Tesla. The participants (n=26, 14 males) with median age of 11 years (range = 4–23 years of age) were prospectively evaluated with sodium. 23Na MRI is technically feasible in the pediatric population and can distinguish different types of pediatric gliomas at baseline.