bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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

Abstract
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

Abstract

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 (&gt;5 or &gt;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

Abstract
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 &gt;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&lt;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

Abstract
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

Abstract
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

Abstract
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

Abstract

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

Abstract
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.