bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGG-31. CHARACTERIZING TEMPORAL GENOMIC HETEROGENEITY IN PEDIATRIC LOW GRADE GLIOMAS: ANALYSIS OF AN EXPANDED MULTI-INSTITUTIONAL COHORT WITH 101 PAIRED TUMOR SAMPLES
Authors: Lazow Margot A , Schafer Austin , DeWire-Schottmiller Mariko D , Lane Adam , Boué Daniel R , Osorio Diana S , Finlay Jonathan L , Wright Erin , Rush Sarah , Hoffman Lindsey M , Reuss Jamie , Hummel Trent R , Salloum Ralph , de Blank Peter M , Smiley Natasha Pillay , Sutton Mary E , Asher Anthony , Stevenson Charles B , Drissi Rachid , Fouladi Maryam , Fuller Christine 
Published: December 2020

Abstract

INTRODUCTION
Recent discoveries have provided valuable insight into the genomic landscape of pediatric low grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence.

METHODS
Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and exome analyses were performed on paired tumor samples from primary diagnostic and subsequent surgeries.

RESULTS
101 tumor samples from 48 patients (43 with 2 specimens, 5 with 3 specimens) from 3 institutions underwent testing. BRAF fusion and BRAFV600E status were conserved in 100% and 97% of paired specimens, respectively. No loss or gain of IDH1 mutations or FGFR1, NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. CDKN2A deletions were acquired in 7 patients (including 3 who received chemotherapy [2 with temozolomide] and 1 who received radiation), and were associated with a trend toward shorter time to progression (median: 5.5 vs. 13.0 months [p=0.08]).

CONCLUSIONS
Most targetable genetic alterations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or radiation. However, CDKN2A deletion acquisition was demonstrated and may define a higher risk group. Given potential for targeted therapies for tumors acquiring CDKN2A deletions, performing a biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.
LGG-35. FUNCTIONAL GENOMIC APPROACHES TO IDENTIFY THERAPEUTIC TARGETS IN MYB AND MYBL1 EXPRESSING PEDIATRIC LOW-GRADE GLIOMAS
Authors: Condurat Alexandra-Larisa , Wefers Annika , Gonzalez Elizabeth , Doshi Jeyna , Khadka Prasidda , Jessa Selin , Tsai Jessica , Buchan Graham , Rouleau Cecile , Abid Tanaz , Goodale Amy , Persky Nicole , Beroukhim Rameen , Root David , Ligon Keith , Jabado Nada , Kleinman Clauda L , Piccioni Federica , Jones David T W , Bandopadhayay Pratiti 
Published: December 2020

Abstract

AIM
Recurrent structural variants involving MYB and MYBL1 transcription factors were recently identified in pediatric low-grade gliomas (pLGGs), such as the MYB-QKI rearrangement in Angiocentric Gliomas and truncations of MYBL1 (MYBL1tr) in Diffuse Astrocytomas. However, therapeutic dependencies induced by these alterations remain unexplored.

METHODOLOGY
We have generated in vitro pLGG mouse neural stem cell (NSCs) models engineered to harbor distinct MYB/MYBL1 genomic alterations. We used single cell RNA sequencing approaches to determine the transcriptional profile and dissect the central regulatory networks of our in vitro pLGG models over time. To identify specific genetic dependencies associated with MYB/MYBL1 mutations, we employed the Brie genome-wide mouse CRISPR lentiviral knockout pooled library, consisting of 78,637 single guide RNAs (sgRNAs) targeting 19,674 mouse genes.

RESULTS
MYB/MYBL1 expression in neural stem cells induced activation of cell-cycle related, glioma-related and senescence-related pathways that are involved in normal development, including activation of MAPK and mTOR signaling which are also activated in human pLGG samples. Genome-scale CRISPR-cas9 screens in isogenic NSCs expressing MYB-QKI or MYBL1tr identified differential genetic dependencies relative to GFP controls. These included regulators of cell-cycle progression and several modulators of the ubiquitin-proteasome degradation pathway. Analysis of RNA-sequencing data from human tumors revealed several of these dependencies identified in the cell line model to be differentially expressed in MYB-altered pLGG tumors relative to normal brain.

CONCLUSION
Expression of MYB family alterations induces expression of key developmental and oncogenic pathways and genetic dependencies that represent potential therapeutic targets for MYB or MYBL1 rearranged pLGGs.
LGG-44. PROGNOSTIC SIGNIFICANCE OF IMAGING CHARACTERISTICS IN PEDIATRIC LOW GRADE GLIOMAS
Authors: Baig Muhammad , Chan Michael , Johnson Jason , Mohiuddin Sana , Lin Ruitao , Roth Michael , Sadighi Zsila , Slopis John , Khatua Soumen , Zaky Wafik 
Published: December 2020

Abstract
Pediatric low-grade gliomas (pLGG) account for one third of all central nervous system (CNS) tumors. MRI is the preferred imaging modality for diagnosis and response evaluation. This study aims to evaluate if radiographic characteristics of pLGG at diagnosis are prognostic. Medical records of 700 pLGG patients were reviewed who were seen between 1998- 2019 at our institution. Summary statistics were provided to describe patient demographic and clinical characteristics. 603 patients were not eligible because incomplete records, 97 patients were identified and eligible for the review. There were 45 females and 52 males with the mean age of 6.5 years at diagnosis. Patients were categorized based on contrast enhancement to 2 groups; none/mild versus moderate/high with 65 and 32 patients respectively. 31 patients had infiltrative glioma (32.3%) with more than one lobe involved at diagnosis. Fifteen patients (15.46%) had hydrocephalous at initial diagnosis. 32 patients (32.9%) did not have any treatment and remained stable while 65(67.0%) had either surgery, chemotherapy or radiation or combination. 21 patients had neurofibromatosis type-1(NF-1) with better outcome comparing to non-NF1 as previously reported. No statistically significant difference in outcome was found based on the imaging characteristics at diagnosis including contrast enhancement, hydrocephalus, tumor size, presence of cyst or infiltrative tumors. The 5 years PFS rate for the entire cohort was 47%. Our study results are limited by low patient number, hence collaborative multi-institutional studies are warranted to delineate consensus and investigate prognostic factors to improve the outcome of pLGG.
LGG-48. PROLIFIC GROWTH OF BRAF V600E MUTANT PILOCYTIC ASTROCYTOMA WHILE ON KETOGENIC DIET: CASE REPORT
Authors: Batchelder Patti , Nellan Anandani , Joshi Charuta , Green Adam , Handler Michael , Hankinson Todd C 
Published: December 2020

Abstract
Epilepsy is a common diagnosis among pediatric patients with supratentorial tumors, particularly infiltrating gliomas. The ketogenic diet can be a successful antiepileptic therapy for patients with medically intractable epilepsy. Acetoacetate, a main ketone released during ketosis, has been shown to increase BRAFV600E binding to MEK1 and MEK1 phosphorylation in BRAFV600E mutant melanoma cells, thereby promoting proliferation and tumor growth (Kang et al, 2015, Xia et al, 2017). BRAFV600E mutation is common in pediatric low-grade gliomas. Therefore, use of a ketogenic diet to manage coincident epilepsy could, in theory, promote tumor growth. However, this has not been previously reported in a human patient. We present a 3 year-old male with a non-NF1 optic pathway BRAFV600E mutant pilocytic astrocytoma and medically intractable epilepsy. He was treated with carboplatin and bevacizumab for 1 year, with good tumor response and vision recovery. He showed stable, non-progressive disease for several months. He was placed on a ketogenic diet 9 months into treatment and became seizure free. Tumor recurrence occurred at 8 months off therapy, at which time a biopsy demonstrated BRAFV600E mutation. The tumor progressed rapidly despite treatment with Trametinib and Dabrafenib, leading to salvage therapy with carboplatin, vinblastine, bevacizumab, and XRT, without tumor control. We discuss the potential effect of the ketogenic diet on this patient’s outcome.
LGG-49. SAFETY AND EFFICACY OF TRAMETINIB (T) MONOTHERAPY AND DABRAFENIB + TRAMETINIB (D+T) COMBINATION THERAPY IN PEDIATRIC PATIENTS WITH BRAF V600-MUTANT LOW-GRADE GLIOMA (LGG)
Authors: Bouffet Eric , Whitlock James A , Moertel Christopher , Geoerger Birgit , Aerts Isabelle , Hargrave Darren , Cohen Kenneth J , Kilburn Lindsay B , Upadhyaya Santhosh A , Wetmore Cynthia , Wright Karen D , Choi Jeea , Gasal Eduard , Russo Mark W , Fox Elizabeth 
Published: December 2020

Abstract

BACKGROUND
Children with BRAF V600-mutant LGG have suboptimal response to standard chemotherapy. Previously, D (BRAF V600 inhibitor) monotherapy has demonstrated clinical benefit in this population. We report interim analysis results of pediatric patients with recurrent/refractory BRAF V600-mutant LGG treated with either T (MEK1/2 inhibitor) monotherapy or D+T combination therapy.

METHODS
This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772) in pediatric patients (&lt;18 y) with refractory/recurrent tumors. The dose-finding phase, including dose confirmation stratified by age, was followed by disease-specific cohorts at recommended dose levels. Efficacy was determined by both investigator and independent review using RANO criteria. Adverse events (AEs) were assessed per NCI-CTCAE v4.03.

RESULTS
Of 49 pediatric patients with BRAF V600-mutant LGG (T, n=13; D+T, n=36) enrolled, pooled efficacy data was available for both treatments while safety data was available for 30 patients (T, n=10; D+T, n=20). Most patients (n=8/10) receiving T monotherapy withdrew/discontinued the treatment in contrast to 3/20 in the D+T group. Pyrexia occurred in 50% of patients (n=5/10) in the monotherapy group and was a frequent AE in the combination group (75%; n=15/20). Objective response rate per independent review was 15% (95% CI, 2%–45%) with T monotherapy and 25% (95% CI, 12%–42%) with D+T combination therapy. Seven patients (54%) on monotherapy and 33 patients (92%) on combination therapy had stable disease or better.

CONCLUSION
In pediatric patients with previously treated BRAF V600-mutant LGG, T monotherapy and D+T combination therapy demonstrated clinical activity, with pyrexia being a common AE.
LGG-54. DETECTION OF THE KIAA1549-BRAF FUSION GENE IN CELLS FORMING MICROVASCULAR PROLIFERATIONS IN PILOCYTIC ASTROCYTOMA
Authors: Yamashita Shinji , Takeshima Hideo , Saito Kiyotaka , Watanabe Takashi , Ohta Hajime , Yokogami Kiyotaka 
Published: December 2020

Abstract
Microvascular proliferation (MVP), an aberrant vascular structure is a histopathological hallmark of glioblastoma multiforme (GBM). Although MVP tends to be associated with high-grade glioma, it has also been detected in WHO grade I pilocytic astrocytoma (PA). However, little is known about the mechanism underlying its formation. Using TP53 point mutations as a marker for tumor-derived cells, we earlier reported that MVP was partially converted from tumor cells via mesenchymal transition. In the current study we used the KIAA1549-BRAF fusion gene as a marker to assess whether MVPs in PA contained tumor-derived cells and/or phenotypically distinct tumor cells expressing vascular markers. Samples from three PA patients harbored the KIAA1549 exon 15, BRAF exon 9 fusion gene. In two patient samples with abundant MVP, RT-PCR assay detected strong bands arising from the KIAA1549-BRAF fusion gene in both tumor cells and cellular components of MVP. Digital PCR showed that vis-à-vis tumor tissue, its relative expression in cellular components of MVP was 42% in one- and 76% in another sample. FISH revealed amplified signals in both tumor cells and cellular components of MVP indicative of tandem duplication. Our findings suggest that in patients with PA, some cellular components of MVP contained tumor derived cell and/or phenotypically distinct tumor cells expressing vascular markers.
LGG-55. OUTCOME OF BRAF V600E PEDIATRIC GLIOMAS TREATED WITH TARGETED BRAF INHIBITION
Authors: Nobre Liana , Zapotocky Michal , Ramaswamy Vijay , Ryall Scott , Bennet Julie , Alderete Daniel , Guill Julia Balaguer , Baroni Lorena , Bartels Ute , Bavle Abhishek , Bornhorst Miriam , Boue’ Daniel R , Canete Adela , Chintagumpala Murali , Coven Scott L , Cruz Ofelia , Dahiya Sonika , Dirks Peter , Dunkel Ira J , Eisenstat David , Conter Cecile Faure , Finch Elizabeth , Finlay Jonathan L , Frappaz Didier , Garre Maria Luisa , Gauvain Karen , Bechensteen Anne Grete , Hansford Jordan R , Harting Inga , Hauser Peter , Hazrati Lili-Naz , Huang Annie , Injac Sarah G , Iurilli Valentina , Karajannis Matthias , Kaur Gurcharanjeet , Kyncl Martin , Krskova Lenka , Laperriere Normad , Larouche Valerie , Lassaletta Alvaro , Leary Sarah , Lin Frank , Mascelli Samantha , McKeown Tara , Milde Till , Madrid Andres Morales La , Morana Giovanni , Morse Helena , Mushtaq Naureen , Osorio Diana S , Packer Roger , Pavelka Zdenek , Quiroga-Cantero Eduardo , Rutka James , Sabel Magnus , Salgado Duarte , Solano Palma , Sterba Jaroslav , Su Jack , Sumerauer David , Taylor Michael D , Toledano Helen , Tsang Derek S , Fernandes Mariana Valente , van Landeghem Frank , van Tilburg Cornelis M , Wilson Bev , Witt Olaf , Zamecbik Josef , Bouffet Eric , Hawkins Cynthia , Tabori Uri 
Published: December 2020

Abstract
Children with pediatric gliomas harboring BRAF V600E mutation have a poor outcome with current chemoradiation strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. We collected clinical, imaging, molecular and outcome information from BRAF V600E glioma patients treated with BRAFi across 29 centers from multiple countries. Sixty-seven patients were treated with BRAFi (56 pediatric low grade gliomas, PLGG and 11 pediatric high grade gliomas, PHGG) for up to 5.6 years. Objective responses were observed in 80% of PLGGs compared to 28% with conventional chemotherapy (p&lt;0.001). These responses were rapid (median, 4 months), and sustained in 86% of tumors up to 5 years while on therapy. PLGG which discontinued BRAFi, 76.5% (13/17) progressed rapidly after discontinuation (median 2.3 months). However, upon re-challenge with BRAFi therapy, 90% achieved an objective response. Poor prognostic factors to conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with a lack of response to BRAFi. In contrast, only 36% of PHGG responded to BRAFi with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95%CI, 35.3% to 69.5%) vs 29.8% (95% CI, 20% to 44.4%) for BRAFi vs chemotherapy respectively (p=0.02). The use of BRAFi results in robust and durable responses while on therapy in BRAF V600E PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAFi therapy in childhood gliomas.
LINC-03. MOLECULAR CLASSIFICATION OF PAEDIATRIC MEDULLOBLASTOMA FROM FOUR TERTIARY CENTRES IN MALAYSIA: DIAGNOSTIC DILEMMA WITH CONVENTIONAL METHODS
Authors: Rajagopal Revathi , Jawin Vida , Teng Ay Jiuan , Wong Oy Leng , Mun Kein Seong , Mahsin Hakimah , Rani Nor Haizura Abd , Gunasagaran Kogilavani , Yeoh Seoh Leng , Ong Gek Bee , Ariffin Hany , Jones David , Gottardo Nicholas G 
Published: December 2020

Abstract

OBJECTIVE
To determine the prognostic significance of the four molecular subgroups of medulloblastoma (MB) among children in Malaysia.

METHODS
We assembled MB samples of children &lt; 18 years between January 1999 and July 2017 in University Malaya Medical Centre, Penang General Hospital, Sarawak General Hospital and Sabah Woman and Children’s Hospital. MB was sub-grouped using 850k DNA methylation profiling.

RESULTS
Fifty-one tumour samples were retrieved. Histopathological subtypes were classic (n=12), MB extensive nodularity/desmoplastic (n=9) and 30 MB results without subtypes. Thirteen patients were M1-M4. Fourteen patients were stratified as standard-risk (SR,27.4%), 22 as high-risk (HR,43.2%) and 15 as high-risk children ≤ 3 years old (iHR,29.4%). Molecular subgrouping revealed 16 Group4, 11 SHH, 10 Group3 and 4 Wnt. In 8 patients, DNA methylation profiling identified a diagnosis other than MB and in 2 samples the DNA was inadequate. For patients &gt;3 years old, the 5-year event-free survival (EFS) was 35.7%±13% in HR and 39.7%±20% in SR. The 5-year overall survival (OS) in these two groups was 43.4%±14% and 41.7±30% respectively. iHR had 5-year EFS and OS of 48.0%±16% and 60.0%±16% respectively. WNT tumours had the best 5y-OS of 66.7±22% of the cohort, albeit significantly lower than other reports, followed by SHH (56.8±17%), Group4 (44.3±17.6%) and Group3 (41.7±18%). Treatment abandonment rate was 20%.

CONCLUSION
The discrepancy in the histological diagnoses highlights the importance of DNA methylation profiling technique for accurate diagnosis. We observed poor OS across all the subgroups, in part due to treatment abandonment.
LINC-06. OBSERVATION ONLY IN A PATIENT WITH SUSPECTED LOW GRADE GLIOMA. SHOULD NEUROSURGERY ALWAYS BE THE FIRST STEP IN LOW AND MIDDLE INCOME COUNTRIES?
Authors: Leal - Cavazos Carlos , Arenas-Ruiz Jose , Vidal-Gutierrez Oscar 
Published: December 2020

Abstract

BACKGROUND
Low grade gliomas (LGGs) are the most frequent pediatric brain tumor and they comprise a variety of histologies. Complete surgery is curative but sometimes its location makes it difficult. Recent publications highlight the excellent long-term outcomes of patients with LGGs with complete and incomplete resected tumors. Current strategies are focused on reducing risks of treatment related sequelae.

METHOD
We describe a patient with a suspected LGG managed by close observation. We describe the case of a 6 year old female with 5 months history of focal onset seizures. During this time a brain MRI was requested and tumor was evidenced. After “tumor diagnosis” was made family visited a handful of private neurosurgeons with a uniformly dismal prognosis and high risk morbidity from procedures offered. When first seen at our Hospital, the clinical history seemed compatible with a LGG and seizures well controlled with antiepileptic drugs. Neurological examination was completely normal. MRI showed a large tumor (7x5x5 cm) hypointense on T1, hyperintense on T2, without contrast enhancement, involving the right temporal lobe white matter, insula, internal capsule, hipoccampus, thalamus and mesencephalus with middle cerebral artery encasement. Interval imaging was proposed and after 4.5 years since diagnosis the tumor has been stable and patient clinically excellent.

CONCLUSION
Overall survival in pediatric LGGs is excellent and risk of sequelae should always be part of multidisciplinary team considerations. In centers with significant neurosurgical morbidity, biopsy of large tumors that are compatible with LGG may not be required in selected cases.
LINC-09. TREATMENT AND OUTCOME IN CHILDREN WITH LOW-GRADE GLIOMAS IN WESTERN MEXICO: EXPERIENCE AT HOSPITAL CIVIL DE GUADALAJARA
Authors: del Campo Regina M Navarro-Martin , Casillas-Toral Erika , Orozco-Alvarado Ana L , Sanchez-Zubieta Fernando , Arredondo-Navarro Luis A , Gutierrez-Oliva Lorelai 
Published: December 2020

Abstract

BACKGROUND
Brain tumors are the most common solid tumors in childhood, 35% of them being low-grade gliomas (LGGs). Few data is available regard LGGs in low-and-middle-income countries. This study evaluates LGGs in a tertiary center in Mexico. DESIGN: A retrospective review of clinical files of 105 children diagnosed with LGG other than optic nerve glioma from 2007 to 2019 was done.

RESULTS
Median age at diagnosis was 7.2 years (from 5 months to 18 years). Male to female ratio was 0.75:1. WHO Grade I represented 68% of the cases. Anatomic sites were: posterior fossa (41%), supratentorial (43.5 %), spinal (8.5%), subependymal (6 %) and pineal (1%). Ten percent of patients had a diagnosed phacomatosis. Treatment was observation without surgery in 3.8%, surgery followed by observation in 49.5%, only chemotherapy in 2.8%, only radiotherapy in 6.7%, and surgery combined with chemotherapy or radiotherapy in 37.2% of cases. Among patients who had surgical intervention, 40% achieved gross total resection, 44% subtotal resection and 16% only biopsy. One or more recurrences were found in 20 % of patients. The 5 and 10-year overall survival (OS) was 83% and 73% respectively. The 5 and 10-year progression-free survival (PFS) was 66 % and 44 % respectively.

CONCLUSIONS
In this series the OS were lower compared with countries with high income, reflecting the need to improve surgery, since only 40% achieved complete resection that is a determining factor for the prognosis. We observed a decrease in OS until 10-year follow and the PFS was even lower due to recurrence/progression.
LINC-21. SURVEY ON THE RESOURCES AVAILABLE FOR PEDIATRIC NEURO-ONCOLOGY IN CHILE, SOUTH AMERICA
Authors: Abu-Arja Mohammad H , del Río Nicolás Rojas , Madrid Andres Morales La , Lassaletta Alvaro , Moreno Rosita , Valero Miguel , Perez Veronica , Espinoza Felipe , Fernandez Eduardo , Díaz José , Santander José , Tordecilla Juan , Oyarce Veronica , Kopp Katherine , Bartels Ute , Qaddoumi Ibrahim , Finlay Jonathan L , Cáceres Adrián , Espinoza Ximena , Osorio Diana S 
Published: December 2020

Abstract

BACKGROUND
We report the human and material resources available in Chilean institutions providing pediatric neuro-oncology services.

METHODS
A cross-sectional survey was distributed to 17 hospitals providing pediatric neuro-oncology services (Programa Infantil Nacional de Drogas Antineoplásicas (PINDA) centers=11, Private=6).

RESULTS
Response rate was 71% (PINDA=8; Private=4). Pediatric neuro-oncology services were mainly provided within general hospitals (67%). Registries for pediatric central nervous system (CNS) tumors and chemotherapy-related toxicities were available in 100% and 67% of centers, respectively. Children with CNS tumors were treated by pediatric oncologists in 92% of institutions; none were formally trained in neuro-oncology. The most utilized treatment protocols were the national PINDA protocols followed by the Children’s Oncology Group protocols. All World Health Organization essential medicines for childhood cancer were available in more than 80% of participating institutions except for gemcitabine, oxaliplatin, paclitaxel, and procarbazine. The median number of pediatric neurosurgeons per institution was two (range,0–8). General neuro-radiologists were available in 83% of institutions. Pathology specimens were sent to pediatric neuropathologists (33%), neuropathologists (25%), adult pathologists (25%), and pediatric pathologists (16.7%). In-house pediatric radiation oncologists were available in 25% of centers. Intensity-modulated radiotherapy, conformal radiotherapy and cobalt radiotherapy were utilized by 67%, 58% and 42% of hospitals, respectively. Only one center performed autologous hematopoietic cell transplant for pediatric CNS tumors.

CONCLUSIONS
These results provide a glimpse into the pediatric neuro-oncology services available in Chile. A wide range of up-to-date treatment modalities is available for children with CNS tumors in Chile. Establishing formal pediatric neuro-oncology training may be beneficial.