bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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

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 (<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

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

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<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

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 < 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 >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

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

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

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.
LINC-40. VERY YOUNG PATIENTS AND CENTRAL NERVOUS SYSTEM TUMORS: A SINGLE-CENTER EXPERIENCE IN AN UPPER-MIDDLE-INCOME COUNTRY
Authors: Madrigal-Avila Claudia , Perez-Bañuelos Alfonso , Perez-Garcia Martin , Ruvalcaba-Sanchez Rafael , Vega-Vega Lourdes , Escamilla-Asiain Gabriela
Published: December 2020

Tumors of the central nervous system comprise nearly a quarter of all childhood cancers and are the most frequent solid tumor in the pediatric population. Primary central nervous system tumors (PCNST) are a rare and heterogeneous group of tumors responsible for high mortality and morbidity. Around 10% of primary CNS tumors occur during the first year of life with almost half of them during the first six months. About 18% of these tumors appear before the age of two years. Very young children differ from older children and adolescents regarding the incidence and location of different histological entities of CNS tumors. We aimed at providing descriptive epidemiological data and report the outcome in a tertiary center from December 2013 to January 2020 for all histological subtypes of primary central nervous system tumors in very young patients, defined as patients younger than three years. We collect data from 19 patients treated in an oncology exclusive tertiary center in Mexico between 2013 and 2020. This study aims to relate factors such as age, radiotherapy, surgery, chemotherapy with Lansky Performance Scale and determine the impact, not only in the overall survival but also in the quality of life.
LINC-42. EPIDEMIOLOGICAL OVERVIEW OF CHILDHOOD CNS TUMORS IN THE NEUROSURGICAL UNIT IN YEREVAN, ARMENIA
Authors: Karapetyan Nune , Danielyan Samvel , Tamamyan Gevorg , Tananyan Armen , Safaryan Liana , Martirosyan Margar , Saghatelyan Tatul , Bardakhchyan Samvel , Papyan Ruzanna , Arakelyan Jemma , Bedirian Karen , Harutyunyan Martin , Matevosyan Vahagn , Lalazaryan Nara , Asatryan Eduard
Published: December 2020

BACKGROUND

Central nervous system (CNS) tumors are the second most common malignant neoplasms among children worldwide. The current paper aims to analyze the situation in pediatric neuro-oncology in Armenia from the neurosurgical perspective.

METHODS

We have collected data of pediatric patients with CNS tumors treated in the Neurosurgery department of “Surb Astvasamayr” Medical Center from 01.01.2010 till 01.12.2019. Incidence by gender, age at diagnosis, and histopathology results were calculated. Survival rates were calculated based on the follow-up results performed until 30.12.2019.

RESULTS

Hospital-based data showed that during the previous 10 years 47 patients with CNS tumors received neurosurgical treatment in the unit, among them 66% were females. 38.3%, 31.9% and 29.8% of diagnosed patients were aged 0–4, 5–9, and 10–18 respectively. In 41 cases, the disease was not disseminated at diagnosis. The most common observed malignancies were low-grade gliomas (21.3%) and embryonal tumors (19.1%), followed by high-grade gliomas (14.9%) and ependymal tumors (8.5%). Follow-up information only for 33 patients is available. From them, 14 are dead and 19 alive. Survival rates in most common groups were 62.5%, 80%, 50%, and 50% respectively. The median follow-up time was 18 months (range 1–113 months).

CONCLUSION

Similar to the data reported in the literature, low-grade gliomas, and embryonal tumors are the most frequent pediatric CNS tumors in Armenia. On the other hand, the pediatric CNS tumor survival rates are lower compared to those reported in developed countries.
MBCL-02. ROLE OF PREOPERATIVE CHEMOTHERAPY IN METASTATIC MEDULLOBLASTOMA: A COMPARATIVE STUDY IN 92 CHILDREN
Authors: Guerrini-Rousseau Léa , Abbas Rachid , Huybrechts Sophie , Kieffer-Renaux Virginie , Puget Stéphanie , Andreiuolo Felipe , Beccaria Kevin , Blauwblomme Thomas , Bolle Stéphanie , Dhermain Frédéric , Longaud Audrey , Roujeau Thomas , Rose Christian Sainte , Tauziede-Esperiat Arnaud , Varlet Pascale , Zerah Michel , Valteau-Couanet Dominique , Dufour Christelle , Jacques Grill
Published: December 2020

BACKGROUND

Previous pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits and risks compared with initial surgery have not been assessed.

METHODS

Two therapeutic strategies were retrospectively compared in 92 patients with metastatic medulloblastoma treated at Gustave Roussy, France, between 2002 and 2015: surgery at diagnosis (n=54; group A) and surgery delayed after carboplatin and etoposide-based preoperative therapy (n=38; group B). Treatment strategies were similar in both groups.

RESULTS

The rate of complete tumor excision was significantly higher in group B than in group A (93.3% versus 57.4%, p=0.0013). Post-operative complications, chemotherapy-associated side effects and local progressions were not increased in group B. Preoperative chemotherapy led to a decrease in the primary tumor size in all patients, 4/38 patients experiencing meanwhile a distant progression. The histological review of 19 matched tumor pairs (before and after chemotherapy) showed that proliferation was reduced and histological diagnosis feasible and accurate even after preoperative chemotherapy. The 5-year progression-free and overall survival rates were comparable between groups. Comparison of the longitudinal neuropsychological data showed that intellectual outcome tended to be better in group B (the mean predicted intellectual quotient value was 6 points higher throughout the follow-up).

CONCLUSION

Preoperative chemotherapy is a safe and efficient strategy for metastatic medulloblastoma. It increases the rate of complete tumor excision and may improve the neuropsychological outcome without jeopardizing survival.
MBCL-08. INTEGRATIVE MOLECULAR ANALYSIS OF PATIENT-MATCHED DIAGNOSTIC AND RELAPSED MEDULLOBLASTOMAS
Authors: Kumar Rahul , Deng Maximilian , Smith Kyle , Liu Anthony , Dhall Girish , Kleese Laura , Bowers Daniel , Chintagumpala Murali , Leary Sarah , Nazarian Javad , Orr Brent , Onar-Thomas Arzu , Pfister Stefan , Korshunov Andrey , Robinson Giles , Gajjar Amar , Jones David , Ramaswamy Vijay , Northcott Paul
Published: December 2020

INTRODUCTION

The next generation of clinical trials for relapsed medulloblastoma demands a thorough understanding of the clinical behavior of relapsed tumors as well as the molecular relationship to their diagnostic counterparts.

METHODS

A multi-institutional molecular cohort of patient-matched (n=126 patients) diagnostic MBs and relapses/subsequent malignancies was profiled by DNA methylation array. Entity, subgroup classification, and genome-wide copy-number aberrations were assigned while parallel next-generation (whole-exome or targeted panel) sequencing on the majority of the cohort facilitated inference of somatic driver mutations.

RESULTS

Comprised of WNT (2%), SHH (41%), Group 3 (18%), Group 4 (39%), primary tumors retained subgroup affiliation at relapse with the notable exception of 10% of cases. The majority (8/13) of discrepant classifications were determined to be secondary glioblastomas. Additionally, rare (n=3) subgroup-switching events of Group 4 primary tumors to Group 3 relapses were identified coincident with MYC/MYCN pathway alterations. Amongst truly relapsing MBs, copy-number analyses suggest somatic clonal divergence between primary MBs and their respective relapses with Group 3 (55% of alterations shared) and Group 4 tumors (63% alterations shared) sharing a larger proportion of cytogenetic alterations compared to SHH tumors (42% alterations shared; Chi-square p-value < 0.001). Subgroup- and gene-specific patterns of conservation and divergence amongst putative driver genes were also observed.

CONCLUSION

Integrated molecular analysis of relapsed MB discloses potential mechanisms underlying treatment failure and disease recurrence while motivating rational implementation of relapse-specific therapies. The degree of genetic divergence between primary and relapsed MBs varied by subgroup but suggested considerably higher conservation than prior estimates.
MBCL-13. CORRELATION OF HISTOPATHOLOGY, CHROMOSOMAL MICROARRAY, AND NANOSTRING BASED 22-GENE ASSAY FOR MEDULLOBLASTOMA SUBGROUP ASSIGNMENT ON “HEAD START” 4 CLINICAL TRIAL
Authors: Dhall Girish , Patel Parth , Blue Megan , Biegel Jaclyn , Almiraz-Suarez Isabel , Hwang Eugene , Pierson Christopher , Boue Daniel , Finlay Jonathan
Published: December 2020

“Head Start” 4 (HS 4) is a prospective randomized clinical trial that tailors treatment based on medulloblastoma molecular subgroups and response to induction chemotherapy to compare efficacy of one versus three (tandem) cycles of myeloablative chemotherapy. Advances in RNA and DNA profiling have identified four molecular subgroups of medulloblastoma with prognostic significance: Sonic Hedgehog (SHH) subtype, WNT subtype, Group 3, and Group 4. In HS 4 trial, we utilize a combination of histopathology and immunohistochemistry (pathology/IHC), as well as chromosomal microarray analysis (CMA) utilizing OncoScanTM (Thermo Fisher) to classify medulloblastoma samples into either SHH, WNT, or non-WNT/non-SHH (Group 3/4) subgroups at the time of diagnosis. NanoString based 22-gene assay is performed retrospectively to test concordance. We have pathology/IHC, CMA, and NanoString data on 26 infants and young children with medulloblastoma enrolled on HS 4. Pathology/IHC was able to assign samples to SHH, WNT, and non-WNT/non-SHH subgroups in all but two cases: one case was classified as Group 3, and the second as SHH by both CMA and NanoString. CMA was indeterminate in six cases, of which, pathology/IHC was able to assign all six samples aforementioned three subgroups. NanoString was indeterminate in two cases: one case was classified as SHH by CMA and pathology/IHC, and the second case was indeterminate by CMA but was assigned as non-WNT/non-SHH on pathology/IHC. There is excellent correlation between NanoString and combination of histopathology and CMA for core medulloblastoma subgrouping on HS 4. Methylation studies are ongoing.
MBCL-24. CAN YOUNG CHILDREN WITH RELAPSED MEDULLOBLASTOMA BE SALVAGED AFTER INITIAL IRRADIATION-SPARING APPROACHES?
Authors: Erker Craig , Larouche Valérie , Margol Ashley , Cacciotti Chantel , Perreault Sébastien , Cohen Kenneth J , AbdelBaki Mohamed S , Hukin Juliette , Rassekh Shahrad Rod , Eisenstat David D , Wilson Beverly , Knipstein Jeffrey , Hoppmann Anna L , Sandler Eric S , Dorris Kathleen , Fay-McClymont Taryn B , Salloum Ralph , Harrod Virginia L , Crooks Bruce , Finlay Jonathan L , Bouffet Eric , Lafay-Cousin Lucie
Published: December 2020

INTRODUCTION

Irradiation-sparing approaches are used in young children with medulloblastoma (MB) given the vulnerability of the developing brain to neurocognitive impairment. Limited data are available following relapse for these patients. We aimed to describe the management and outcomes of young children with MB who relapsed after initial treatment without craniospinal irradiation (CSI).

METHODS

International retrospective study including patients with MB diagnosed between 1995–2017, ≤ 72 months old, initially treated without CSI, who subsequently relapsed.

RESULTS

Data are available for 52 patients (32 male). Median age at initial diagnosis was 27 months (range, 6–72) with 24 being metastatic. Initial therapy included conventional chemotherapy alone or high-dose chemotherapy (HDC) in 21 and 31 subjects, respectively. Three received upfront focal irradiation. Molecular subgrouping, available for 24 tumors, included 9 SHH and 15 non-WNT/non-SHH. Median time to relapse was 13 months (range, 3–63). Relapse was local, disseminated or combined in 20, 15, and 16, respectively. Salvage therapy with curative intent was given in 42/52 patients, including CSI in 28 subjects (median dose 36Gy, 18–41.4) or focal irradiation in 5 others. Three received HDC only. At a median follow-up time of 46 months (range, 4–255), 25 (48%) were alive, including 7/9 SHH and 7/15 non-WNT/non-SHH. The 2- and 5-year OS was 67% and 56% (SE, 7%), respectively. Two of 3 patients with SHH who did not receive salvage radiotherapy are survivors.

CONCLUSION

A substantial proportion of young children who relapse following irradiation-sparing strategies can be salvaged. Neurocognitive and ototoxicity outcomes are being evaluated.
MBCL-26. FACTORS ASSOCIATED WITH LONGER SURVIVAL AFTER FIRST RECURRENCE IN MEDULLOBLASTOMA BY MOLECULAR SUBGROUP AFTER RISK-BASED INITIAL THERAPY
Authors: Chintagumpala Murali , Terhune Colton , Tong Lin , Bouffet Eric , Bartels Ute , Fisher Michael , Hassall Tim , Gururangan Shridharan , Schroeder Kristin , Hansford Jordan , Quang Dong Anh Khuong , Cohn Richard , Kellie Stewart , McCowage Geoffrey , Smith Kyle , Northcott Paul , Robinson Giles , Gajjar Amar
Published: December 2020

OBJECTIVE

To evaluate differences in time to recurrence among molecular subgroups of medulloblastoma treated on a single protocol and to identify factors associated with survival after first recurrence.

METHODS

Time to recurrence following SJMB03 treatment was compared across methylation subgroups among relapsed patients. Therapies received subsequent to relapse were noted. Kaplan-Meier methods and log-rank tests were used for statistical analyses.

RESULTS

74 of 330 medulloblastoma patients developed recurrence after initial therapy. (38 Standard-Risk; 36 High-Risk). The 2- and 5-year survival after first recurrence was 30.4% and 14.6% respectively. DNA methylation-based subgroups from initial diagnosis were SHH (n=14), Group 3 (n=24), Group 4 (n=26), and unclassified (n=8). None of the pts with WNT MB had recurrent disease. Median time to first recurrence was 1.23, 0.91, and 3.09 years in SHH, Group3, and Group 4 respectively. Group 4 patients had longer post-recurrence survival than others (p-value=0.0169). Clinical risk at diagnosis (p-value=0.337), anaplasia (p-value=0.4032), TP53 (p-value=0.1969), MYC (p-value=0.8967), and MYCN (p value = 0.9404) abnormalities were not associated with post progression survival. Patients who received any therapeutic modality (chemotherapy, re-radiation and second surgery) had longer survival and those who had all three (n=10) had the best outcome (p-value<0.0001).

CONCLUSION

Outcome after recurrence in medulloblastoma is dismal, however, association with subgroups is still present. Group 4 patients had a longer time to recurrence and post progression survival. No other prognostic factor at initial diagnosis was associated with outcome after recurrence. Patients who received all 3 types of conventional therapy had better survival.
MBCL-30. NOVEL SMO MUTATION IN DESMOPLASTIC/NODULAR MEDULLOBLASTOMA: A CASE REPORT
Authors: Wright Avery , Aguilar-Bonilla Ana , Pickle Emily Owens , Smith Amy A
Published: December 2020

Smoothened (SMO) is a transmembrane protein which is regulated by SHH (Sonic hedgehog) protein binding to PTCH1. SMO activation controls GLI which then translocates into the nucleus and activates target genes. The SHH subtype of medulloblastoma has been extensively studied to have mutations within the SHH signaling pathway, often in PTCH1, SUFU, and SMO. We present a case of desmoplastic/nodular medulloblastoma with the mutation SMO c.1810G>A. The patient presented at 11 years old with a two-week history of headaches and morning vomiting. His neuroimaging revealed a T2 hyperintense, enhancing mass centered at the fourth ventricle. He underwent gross total resection and had no metastatic spread. There were no alterations in PTCH1, SUFU, Tp53, GLI2, MYC/MYCN, CTNNB1, or the WNT pathway. The SMO c.1810G>A alteration has not been previously identified as a somatic mutation in a CNS tumor. The functional effect of this mutation has not been studied. It is known that desmoplastic/nodular histology in medulloblastoma is associated with the SHH subtype and given the fact that SMO is regulated by SHH signaling, this patient was ultimately diagnosed with SHH subtype medulloblastoma. Findings of novel somatic mutations in patients raises the question of whether the mutation is in fact the driver of neoplasia.
MBCL-38. UNUSUAL EXTRANEURAL METASTASIS OF PEDIATRIC EMBRYONAL TUMORS: TWO CASE REPORTS
Authors: Goldberg Aaron , Abongwa Chenue , Pathare Jody , Hoerig Clay , Muhonen Michael , Olaya Joffre , Gajjar Amar , Warren Krista , Patel Ramesh , Lai Hollie , Loudon William , Plant Ashley
Published: December 2020

We report two cases of unusual extraneural metastasis in patients with embryonal tumors without central nervous system disease progression and prolonged survival. The first patient presented at 16 years of age with atypical teratoid rhabdoid tumor of the cervical spine. The tumor was confirmed to have loss of INI1, SMARCB1 deletion of exons 1–3, and heterozygous deletion of 22q11.2. The patient received treatment initially per ACNS0333 with high dose chemotherapy and tandem autologous transplants. The patient developed a biopsy-confirmed liver metastasis six months from diagnosis and, subsequently, had disease progression including liver metastases, bony lesions, muscle involvement, and lung nodules. Two and a half years from diagnosis the patient has still not had a relapse in the CNS. The second patient presented with medulloblastoma isolated to the posterior fossa at 11 years of age and was treated on SJMB03 protocol with craniospinal irradiation and high dose chemotherapy. He had his first recurrence in the temporal lobe three years post treatment. He had multiple recurrences in the brain over the next five years treated with re-resections, adjuvant chemotherapy, and gamma knife radiotherapy. He then developed cervical lymphadenopathy, bony lesions, liver lesions, and lung nodules. Cervical lymph node biopsy confirmed medulloblastoma. Next generation sequencing from recurrent tumor showed somatic mutations in p53, KDM6A, and PPP2R1A. Fourteen years from treatment, he has now developed a temporal lobe lesion. These cases are notable for prolonged survival despite widely metastatic disease and genomics predicting poor prognosis as well as metastatic disease disproportionate to CNS disease.
MBCL-43. RECURRENT MEDULLOBLASTOMA – LONG-TERM SURVIVAL WITH A “MEMMAT” BASED ANTIANGIOGENIC APPROACH
Authors: Slavc Irene , Peyrl Andreas , Gojo Johannes , Holm Stefan , Blomgren Klas , Sehested Astrid M , Leblond Pierre , Czech Thomas
Published: December 2020

INTRODUCTION

Patients with recurrent medulloblastoma have a poor prognosis with only around 8% of patients surviving at 5 years irrespective of salvage therapy used. We report on 29 patients from four institutions treated with a “MEMMAT” based antiangiogenic combination therapy.

PATIENTS AND METHODS

From 11/2006 to 06/2016, 29 patients were diagnosed with a recurrent medulloblastoma (19 first, 10 multiple recurrences). Median age at start of antiangiogenic therapy was 10 years (range 1–27). Subgroup of medulloblastoma was available in 18 patients and was group 3 or 4 in all except two (one WNT, one SHH-infant). For their current relapse patients received an antiangiogenic combination therapy consisting of bevacizumab, thalidomide, celecoxib, fenofibrate, and etoposide, alternating with cyclophosphamide and augmented with intraventricular therapy (etoposide and liposomal cytarabine).

RESULTS

As of 01/2020, 8/29 patients are alive at a median of 44 months after recurrence. 6/8 surviving patients are currently in CCR between 66 and 134 months after recurrence that prompted MEMMAT therapy. Two patients are again in remission after intercurrent relapses 105 and 102 months after first starting MEMMAT therapy. Five patients died of another cause (accident, leukemia, septicemia). OS (median 44 months) was 44±10% at 5 years and 39±10% at 10 years, PFS was 33±10% at 5 years and 28 ±9% at 10 years. Therapy was well tolerated and toxicities were manageable.

CONCLUSION

Our results suggest that antiangiogenic metronomic chemotherapy has clinical activity in recurrent medulloblastoma. Further investigation with an international phase II study is ongoing (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290).
MBCL-46. TREATMENT OF RECURRENT WINGLESS-ACTIVATED MEDULLOBLASTOMA (Wnt-MB) INCORPORATING MARROW-ABLATIVE THIOTEPA AND CARBOPLATIN CHEMOTHERAPY (HDCx) AND AUTOLOGOUS HEMATOPOIETIC PROGENITOR CELL RESCUE (AuHPCR): A DUAL REPORT
Authors: Harris Micah K , Funk Zachary N , Boué Daniel R , Pierson Christopher R , Jones Jeremy , Leonard Jeffrey , Abu-Arja Rolla , Auletta Jeffrey , Osorio Diana S , Shatara Margaret , Paul Stephan R , Finlay Jonathan L , AbdelBaki Mohamed S
Published: December 2020

BACKGROUND

Wnt-MB infers an excellent prognosis, and metastatic disease is rare. However, specific treatment strategies and patterns of failure for patients with recurrent Wnt-MB are unknown. We report two cases of recurrent beta-catenin nucleopositive Wnt-MBs treated with an irradiation-sparing strategy, incorporating HDCx/AuHPCR. PATIENT 1: A nine-year-old female experienced local recurrence of a non-metastatic Wnt-MB nine months after gross total resection (GTR) followed by 18Gy craniospinal irradiation (CSI) with primary site boost to 54Gy, accompanied by weekly vincristine, followed by a maintenance regimen of nine cycles of cisplatin/lomustine/vincristine alternating with cyclophosphamide/vincristine every third cycle. GTR of the relapsed tumor was followed by three cycles of HDCx/AuHPCR. She is disease-free for over three years following relapse treatment. PATIENT 2: A 17-year-old male initially underwent GTR, followed by 23.4Gy CSI with 54Gy posterior fossa boost with concomitant weekly vincristine, followed by a maintenance regimen that included nine alternating cycles of vincristine/lomustine/cisplatin and cyclophosphamide/vincristine. Isolated right frontal horn metastatic recurrence developed 19 months post-treatment; three cycles of irinotecan/temozolomide/bevacizumab and gamma-knife radiosurgery produced complete response. A second isolated metastatic recurrence within the left frontal horn occurred 13 months post-treatment, which was treated with two cycles of cyclophosphamide/etoposide followed by two cycles of HDCx/AuHPCR. MRI of the brain showed no residual tumor one month post-treatment. He currently awaits follow-up stereotactic radiosurgery.

CONCLUSION

Patients with recurrent Wnt-MB may be treated with curative intent using a multi-disciplinary approach that includes HDCx/AuHPCR, and minimization or avoidance of re-irradiation.
MBRS-02. BET BROMODOMAIN PROTEIN-KINASE INHIBITOR COMBINATIONS FOR THE TREATMENT OF MEDULLOBLASTOMA
Authors: Ayad Nagi , Suter Robert , Robbins David , Roussel Martine
Published: December 2020

Recent sequencing studies have implicated many epigenetic regulators in medulloblastoma. The epigenetic reader protein Brd4 has been implicated in various cancers including medulloblastoma. Brd4 controls expression of the medulloblastoma essential genes MYC in G3 medulloblastomas, which have poor prognosis as well as GLI1 and GLI2 levels in Sonic hedgehog (SHH) driven medulloblastomas, which have intermediate prognosis. Highly selective Brd4 inhibitors have been developed that reduce MYC, GLI1 and GLI2 levels. These inhibitors have gone into clinical trials for multiple cancer indications including medulloblastoma. However, resistance is common for Brd4 inhibitors warranting combination therapies for improved clinical outcome. We have developed a computational pipeline termed SynergySeq that predicts patient specific combinations of Brd4 inhibitors along with kinase inhibitors. We demonstrate that Brd4-kinase inhibitors robustly reduce proliferation of Shh and MYC driven medulloblastoma cells. Improved efficacy is related to dampening the adaptive kinome reprogramming response that occurs after Brd4 inhibition. Our findings suggest that SynergySeq can be utilized to inform patient selection for clinical trials utilizing Brd4 inhibitors in medulloblastoma and other brain tumors.
MBRS-04. MEDULLOBLASTOMA DETECTION BY BLOOD TEST
Authors: Yalon Michal , Toren Amos , Freedman Shany , Remke Marc , Meharian-Shai Ruty
Published: December 2020

INTRODUCTION

Long non coding RNAs (lincRNAs) are functionally defined as transcripts longer than 200 nucleotides in length with no protein coding potential. lincRNA involvement in human cancers etiology is being increasingly proved. Cancer-secreted long non-coding RNAs (lncRNAs) in exosomes are emerging mediators of cancer-host cross talk communication in tumor microenvironments. The ability to monitor and detect tumor markers in real time enables access to tumor biology and may allow highly personalized treatment for each patient. METHODS AND

RESULTS

We analyzed RNA sequencing of 64 Medulloblastoma samples and quantified the genome wide long non coding RNAs (lincRNA) expression levels. We identified a lincRNA that is distinctively highly expressed in group 4 (MB4). MB4 expression was further examined in microarray analysis on a larger cohort of medulloblastoma patient samples and a large cohort (n=1405) of patient samples that include normal brain and different brain tumor samples. MB4 proved to be specific and highly expressed in group 4 Medulloblastoma. MB4 was detected in the plasma of medulloblastoma patients with active disease, or subtotal resection. MB4 was not detected in patients that their tumors were resected. MB4 expression is not detected in the serum of medulloblastoma type SHH, penioblastoma, ewing sarcoma and neuroblastoma patients.

CONCLUSIONS

We have found that MB4 lncRNA is a highly specific medulloblastoma tumor biomarker and is sensitive and noninvasive biomarker that can be quantified from a blood test. MB4 can be a good diagnostic marker, and in future both may also be a good target for therapy.
MBRS-14. INTEGRATING CLINICAL AND GENOMIC CHARACTERISTICS IN PEDIATRIC MEDULLOBLASTOMA SUBTYPES IN A SINGLE COHORT IN TAIWAN
Authors: Wu Kuo-Sheng , Wong Tai-Tong
Published: December 2020

BACKGROUND

Medulloblastoma (MB) was classified to 4 molecular subgroups: WNT, SHH, group 3 (G3), and group 4 (G4) with the demographic and clinical differences. In 2017, The heterogeneity within MB was proposed, and 12 subtypes with distinct molecular and clinical characteristics.

PATIENTS AND METHODS: PATIENTS AND METHODS

We retrieved 52 MBs in children to perform RNA-Seq and DNA methylation array. Subtype cluster analysis performed by similarity network fusion (SNF) method. With clinical results and molecular profiles, the characteristics including age, gender, histological variants, tumor location, metastasis status, survival, cytogenetic and genetic aberrations among MB subtypes were identified.

RESULTS

In this cohort series, 52 childhood MBs were classified into 11 subtypes by SNF cluster analysis. WNT tumors shown no metastasis and 100% survival rate. All WNT tumors located on midline in 4th ventricle. Monosomy 6 presented in WNT α, but not in β subtype. SHH α and β occurred in children, while SHH γ in infant. Among SHH tumors, α subtype showed the worst outcome. G3 γ showed the highest metastatic rate and worst survival associated with MYC amplification. G4 α has the highest metastatic rate, however G4 γ showed the worst survival.

CONCLUSION

We identified molecular subgroups and subtypes of MBs based on gene expression and DNA methylation profile in children in our cohort series. The results may contribute to the establishment of nation-wide correlated optimal diagnosis and treatment strategies for MBs in infant and children.