Volume 22 | Supplement 3 | December 2020

Neuro-Oncology
Official Journal of the Society for Neuro-Oncology since 1997

Online ISSN: 1523-5866

Abstracts from the 19th International
Symposium on Pediatric
Neuro-Oncology (ISPNO 2020)

Print ISSN: 1522-8517

December 13 – 16, 2020
Karuizawa, Japan1
academic.oup.com/neuro-oncology

Neuro-Oncology Supplement Official Journalof the Society for Neuro-Oncology
Volume 22, 2020 Supplement 3

Abstracts from the 19th International Symposium on
Pediatric Neuro-Oncology (ISPNO 2020)

December 13–16, 2020
Karuizawa, Japan

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Neuro-Oncology
Volume 22 | Supplement 3

December 2020

Mission statement: The goal of Neuro-Oncology is to provide the international neuro-oncology community with high-quality,
rapid publication of information in all fields. The journal welcomes submissions from throughout the world and encourages theparticipation of neuro-oncologists in a wide array of subspecialities. Areas covered include, but are not limited to, biochemistry
and biophysics, clinical neuro-oncology, clincial therapy trials, epidemiology, imaging, immunology, medical neuro-oncology,
neuropathology, molecular genetics, pediatric neuro-oncology, preclinical experimental therapeutics, retrospective clinicalstudies, surgical neuro-oncology, and tumor biology. Published by Oxford University Press, Neuro-Oncology is the official
journal for the Society for Neuro-Oncology (SNO), the Japan Society for Neuro-Oncology, the European Association for­
Neuro-Oncology, and the World Federation of Neuro-Oncology Societies.

ATYPICAL TERATOID/RHABDOID TUMORSiii275
COVID-19 AND PEDIATRIC NEURO-ONCOLOGYiii282
DRUG DELIVERY/PHARMACOKINETICSiii283
DIFFUSE MIDLINE GLIOMA/DIPGiii287
EARLY PHASE CLINICAL TRIALSiii304
EPENDYMOMAiii307
EPIDEMIOLOGYiii319
ETMR AND OTHER EMBRYONAL TUMORSiii322
GERM CELL TUMORSiii328
HIGH GRADE GLIOMAiii344
IMAGINGiii354
IMMUNOTHERAPYiii359
PEDIATRIC NEURO-ONCOLOGY IN ASIA AND OTHER LOW/MIDDLE INCOME COUNTRIESiii378
MEDULLOBLASTOMA (CLINICAL)iii368
MEDULLOBLASTOMA (RESEARCH)iii399
PRECLINICAL MODELS/EXPERIMENTAL THERAPY/DRUG DISCOVERYiii411
NEUROFIBROMATOSISiii417
NURSING/PATIENT CAREiii421
OTHERS (NOT FITTING ANY OTHER CATEGORY)iii423
PATHOLOGY AND MOLECULAR DIAGNOSISiii424
NEUROPSYCHOLOGY/QUALITY OF LIFEiii431
CRANIOPHARYNGIOMA AND RARE TUMORSiii442
RADIATION ONCOLOGYiii456
NEUROSURGERYiii461
SOCIAL WORK/PATIENT SUPPORT/PALLIATIVE CAREiii465
TUMOR BIOLOGY (NOT FITTING A SPECIFIC DISEASE CATEGORY)iii467
VIRAL/GENE THERAPY AND OTHER NOVEL THERAPIESiii471
AUTHOR INDEX

iii474

Neuro-Oncology
Founded with a grant from The Pediatric Brain Tumor Foundation of the United States
Kenneth Aldape, Editor-in-Chief
Patrick Y. Wen, Executive Editor SNO
Riccardo Soffietti, Executive Editor EANO

Ryo Nishikawa, Executive Editor JSNO
Darell D. Bigner, Founding Editor

Associate Editors
Jill S. Barnholtz-Sloan
E. Antonio Chiocca
Howard Colman
Linda Dirven
Frank Furnari

Monika E. Hegi
Craig Horbinski
Annie A. Huang
Koichi Ichimura
Minesh P. Mehta

Hideho Okada
Whitney PopeDavid Schiff
Wolfgang Wick
Gelareh Zadeh

Editorial Board
Roger Abounader
Manmeet Ahluwalia
Brian Michael Alexander
Hidefumi Aoyama
Carmen Balana
Tracy T. Batchelor
Oren Becher
Martin Bendszus
Mitchel S. Berger
Rameen Beroukhim
Krishna Bhat
Rolf Bjerkvig
Eric Bouffet
Paul D. Brown
Jan C. Buckner
Nicholas Butowski
Daniel P. Cahill
Steven L. Carroll
Maria G. Castro
Arnab Chakravarti
Marc C. Chamberlain
Alain Charest
Zhong-Ping Chen
Shiyuan Cheng
Timothy F. Cloughesy
Joseph CostelloJohn de Groot
Lisa M. DeAngelis

Annick Desjardins
Hugues Duffau
Charles Eberhart
Jonathan L. Finlay
Gaetano Finocchiaro
Maryam Fouladi
Daniel W. Fults
Ama Gajjar
Isabelle Germano
Elizabeth R. Gerstner
Sourav GhoshMark R. Gilbert
Candelaria Gomez-Manzano
Stuart A. Grossman
David H. Gutmann
Christian Hartmann
Amy B. Heimberger
Raymond Huang
Jason T. Huse
C. David James
Robert B. Jenkins
Yonehiro Kanemura
Chunsheng Kang
Timothy J. Kaufmann
Mustafa Khasraw
Toshihiro Kumabe
Normand Laperriere
Andrew B. Lassman

John J. Laterra
Justin D. Lathia
Sean E. Lawler
Emilie Le Rhun
Keith Ligon
Zhimin Lu
Christine Marosi
Warren Mason
Joseph H. McCarty
Paul S. MischelMichelle Monje
Louis Burt Nabors
Motoo Nagane
Mitsutoshi Nakada
Yoko Nakasu
Do-Hyun Nam
Atsushi Natsume
Simone P. Niclou
Houtan Noushmehr
Andrea PaceDavid Peereboom
Heidi S. Phillips
Michael Platten
Michael D. Prados
Matthias Preusser
Vinay K. Puduvalli
Benjamin W. Purow
David A. Reardon

Managing Editor
Elizabeth A. Martinson, Neuro-Oncology Editorial Office, neuonc.editorialoffice@oup.com

Guido Reifenberger
Jeremy N. Rich
Roberta Rudà
James Rutka
John H. Sampson
Jann N. Sarkaria
Uwe Schlegel
Roy Strowd
Joachim Steinbach
Walter Stummer
Roger Stupp
Hideo Takeshima
Bakhos A. Tannous
Martin J.B. Taphoorn
Tomoki Todo
Joerg Tonn
Keisuke Ueki
Martin J. van den Bent
Roel G.W. Verhaak
Mariano ViapianoMichael A. Vogelbaum
Andreas von Deimling
Colin Watts
William Weiss
Michael Weller
Pieter Wesseling
Karen D. Wright
W.K. Alfred Yung

Neuro-Oncology 22:iii275–iii377, 2020.
doi:10.1093/neuonc/noaa222

NEURO-ON C O L O G Y

Taipei Medical University, Taipei, Taiwan, 6Pediatric Brain Tumor Program,Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

Abstracts

BACKGROUND: Atypical teratoid rhabdoid tumors (ATRTs) are among
the most malignant brain tumors in early childhood and remain incurable.
Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) wasapproved by the Food and Drug Administration as a primary treatment for
multiple myeloma. This study aimed to determine whether the upregulationof protein synthesis and proteasome degradation in Myc-ATRTs increases
tumor cell sensitivity to BTZ. METHODS: We performed differential gene
expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT.
The expressions of proteasome-encoding genes were compared among thispaired model as well as between the 24 human ATRT samples and normal
brain tissues. The antitumor effect of BTZ was evaluated in three human
Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12, andCHLA-266) and in the orthotopic xenograft models of Re1-P6 cell. RESULTS: Concomitant upregulation of the Myc pathway, protein synthesis,
and proteasome degradation were identified in recurrent ATRTs. In ATRTs,
the proteasome-encoding genes were highly expressed compared with innormal brain tissues, correlated with the malignancy of tumor cells, andwere essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in in vitro drug tests.
Furthermore, BTZ inhibited tumor growth and prolonged survival in MycATRT orthotopic xenograft mice. CONCLUSIONS: Our findings suggestthat BTZ may be a promising targeted therapy for Myc-ATRTs.

ABSTRACTS CATEGORY CODESATRT – ATYPICAL TERATOID/RHABDOID TUMORSCOVD - COVID-19 AND PEDIATRIC NEURO-ONCOLOGYDIPG - DIFFUSE MIDLINE GLIOMA/DIPG
DDEL - DRUG DELIVERY/PHARMACOKINETICS
EPCT - EARLY PHASE CLINICAL TRIALSEPEN - EPENDYMOMAEPID - EPIDEMIOLOGYETMR - ETMR AND OTHER EMBRYONAL TUMORS
GCT - GERM CELL TUMORSHGG - HIGH GRADE GLIOMA
IMG - IMAGINGIMMU – IMMUNOTHERAPY
LINC - 
PEDIATRIC NEURO-ONCOLOGY IN ASIA AND OTHER
LOW/MIDDLE INCOME COUNTRIESLGG - LOW GRADE GLIOMAMBCL - MEDULLOBLASTOMA (CLINICAL)MBRS - MEDULLOBLASTOMA (RESEARCH)
MODL - PRECLINICALMODELS/EXPERIMENTAL
DRUG DISCOVERYTHERAPY/

NFB - NEUROFIBROMATOSIS AND OTHER PREDISPOSITION SYNDROMES
NURS – NURSING/PATIENT CAREOTHR - OTHERS (NOT FITTING ANY OTHER CATEGORY)
PATH - PATHOLOGY/CLASSIFICATION
QOL - NEUROPSYCHOLOGY/QUALITY OF LIFE
RARE - CRANIOPHARYNGIOMA AND RARE TUMORSRONC - RADIATION ONCOLOGYSURG - NEUROSURGERY
SWK - SOCIAL WORK/PATIENT SUPPORT/PALLIATIVE CARE
TBIO - 
TUMOR BIOLOGY (NOT FITTING A SPECIFIC DISEASE
CATEGORY)
THER - VIRAL/GENE THERAPY AND OTHER NOVEL THERAPIESATRT-02. MEK/ERK SIGNALLING DEPENDENCY IN ATYPICALTERATOID RHABDOID TUMOURS
Hui (Claire) Shi1,2, Dhanya Sooraj2, Claire Sun2, Paul Daniel2,
Gabrielle Bradshaw2, Jason Cain2,1, and Ron Firestein2,1; 1Monash
University, Melbourne, Victoria, Australia, 2Hudson Institute of Medical
Research, Melbourne, Victoria, Australia
Atypical teratoid rhabdoid tumours (ATRTs) are high-grade malignant
paediatric brain tumours with a less than one-year survival rate after diagnosis. Current treatment for ATRT, which includes high-intensive radiotherapy
and chemotherapy, results in long-term side effects on ATRT patients. Hence,
there is an urgent need to discover targeted therapies that could be used totreat patients with ATRT. As part of the Hudson Monash Paediatric Precision
Medicine Program, we have collected 23 ATRT cell lines which we used toperformed high-throughput small molecule and genetic (CRISPR) screening to
identify new therapies and therapeutic targets. In parallel, we characterised the
ATRT cell lines based on transcriptomic (RNA-seq) and epigenetic (methylation) signatures. An integrative multi-omic approach was then used to uncoverdiscrete vulnerabilities in specific subsets of ATRT patients. Strikingly, theseinclude a number of druggable dependencies, such as MEK, CDK, HDAC, andTopoisomerase, that offer a promise of rapid clinical translation. In our study,
we focus on MEK dependency in a subtype of ATRT lines to further define
the underlying mechanisms and biomarkers. While future studies validating
the MEK/ERK signalling dependency in a wider cohort of patient models andin in vivo models are required, these data provide a framework for applying
an integrative multi-omic approach in paediatric cancer precision medicine.

ATYPICAL TERATOID/RHABDOID TUMORS (ATRT)ATRT-03. IDENTIFICATION OF MICRORNA-BASED PROGNOSTIC
BIOMARKERS AND CANDIDATE THERAPEUTIC AGENTS FORATYPICAL TERATOID/RHABDOID TUMOR
Yang Zhang, and Jianguo Xu; Department of Neurosurgery, West China
Hospital, Sichuan University, Chengdu, Sichuan, China

ATRT-01. UPREGULATION OF PROTEIN SYNTHESIS AND
PROTEASOME DEGRADATION CONFERS SENSITIVITY TO
PROTEASOME INHIBITOR BORTEZOMIB IN MYC-ATYPICALTERATOID/RHABDOID TUMORS
Minh-Huy Tran1,2, Kuo-Sheng Wu3, Che-Chang Chang4, and
Tai-Tong Wong5,6; 1International Master/Ph.D. Program in Medicine,College of Medicine, Taipei Medical University, Taipei, Taiwan,
2Department of Neurosurgery, University of Medicine and Pharmacy at Ho
Chi Minh City, Ho Chi Minh City, Vietnam, 3Institute of Clinical Medicine,College of Medicine, Taipei Medical University, Taipei, Taiwan, 4The Ph,D,
Program for Translational Medicine, Taipei Medical University, Taipei,
Taiwan, 5Department of Neurosurgery, Taipei Medical University Hospital,

BACKGROUND: MicroRNA (miRNA) has been found to be involved
in development of many malignant pediatric brain tumors, including atypical teratoid/rhabdoid tumor (AT/RT) that is highly aggressive and carries
a dismal prognosis. The current study investigated the potential value ofmiRNAs and pivotal genes associated with AT/RT using bioinformatics analysis, aiming to identify new prognostic biomarkers and candidate drugs
for AT/RT patients. METHODS: Differentially expressed miRNAs (DEMs)
and genes (DEGs) between AT/RT and normal control samples wereobtained from GEO database. The target genes of DEMs were predicted
via TargetScanHuman7.2 and miRDB, and then intersected with DEGs.
Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysesof overlapping genes were conducted, followed by construction of proteinprotein interaction network. Hub genes were determined by Cytoscape© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium,provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

iii275

Abstracts

software, and their prognostic values were evaluated using Kaplan-Meieranalysis. Connectivity Map database was used to identify latent therapeutic
agents. RESULTS: A total of 11 DEMs (hsa-miR-1224-5p, hsa-miR-128-3p,
hsa-miR-17-5p, hsa-miR-18b-5p, hsa-miR-29c-5p, hsa-miR-329-3p, hsamiR-379-5p, hsa-miR-433-3p, hsa-miR-488-5p, hsa-miR-656-3p and hsamiR-885-5p) were screened. By intersecting 3275 predicted target genes
and 925 DEGs, we finally identified 226 overlapping genes that were enriched in pathways in cancer and MAPK signaling pathway. Four hub genes(GRIA2, NRXN1, SLC6A1 and SYT1) were significantly associated withthe overall survival of AT/RT patients. Candidate drugs included histone
deacetylase inhibitor (givinostat), DNA synthesis inhibitor (floxuridine),
cyclin-dependent kinase inhibitor (purvalanol) and janus kinase inhibitor(lestaurtinib). CONCLUSION: In summary, this study systematically analyzed AT/RT-related miRNAs and pivotal genes to provide novel prognostic
biomarkers and potential therapeutic agents.
ATRT-04. INHERITED RHABDOID PREDISPOSITION SYNDROME:
A CASE OF CHOROID PLEXUS CARCINOMA AND ATYPICALTERATOID RHABDOID TUMOR IN SIBLINGS
Alexis Judd, Erin Wright, and Sarah Rush; Akron Children’s Hospital,
Akron, OH, USA
Choroid plexus carcinoma (CPC) and Atypical teratoid/rhabdoid tumor(ATRT) are aggressive, malignant brain cancers most commonly arising inchildren less than 3 years of age. These tumors often have genetic alterations in the tumor suppressor gene SMARCB1/INI1. Rhabdoid predisposition syndrome (RTPS) categorizes patients with germline mutations in
SMARCB1 or SMARCA4, leading to a markedly increased risk of developing
rhabdoid tumors. Both CPC and ATRT have been demonstrated in patientswith these rhabdoid predisposition syndromes. In general, these tumors tend
to have a poor prognosis. However, with the presence of a SMARCB1 mutation they may have improved overall survival. We present two interestingcases of siblings with maternally inherited SMARCB1 mutations: one a
21-month-old male who presented with an ATRT and another a 10 monthold female who presented with a CPC. The ATRT was treated as per theChildren’s Oncology Group study ACNS0333 with high dose chemotherapy
and stem cell rescue as well as cranial radiation. The CPC was treated as per
CPT-SIOP 2009 with etoposide, cyclophosphamide and vincristine. Unlike
other patients with these aggressive tumors, both of these patients are alive
without evidence of disease recurrence 8 and 7 years post therapy, respectively. Additional genomic testing on both tumors is currently pending inorder to potentially identify other mutations that may impact survival. These
cases further illustrate the similar profile of two very different tumors withimproved overall survival that may be secondary to mutations in SMARCB1
in RTPS.
ATRT-05. RESULTS OF MULTICENTER TRIAL CONCERNING
THE TREATMENT OF CHILDREN WITH ATYPICAL TERATOID/RHABDOID TUMORS (ATRT) OF THE CENTRAL NERVOUS
SYSTEM
Olga Zheludkova1, Lyudmila Olkhova2, Yuri Kushel’3, Armen Melikyan3,
Marina Ryzhova3, Alexey Kislyakov4, Evgeniy Shultz3, Irina Borodina5,
Svetlana Gorbatykh4, Vladimir Popov6, Marina Mushinskaya7,
Olga Polushkina1, Eugenia Inyushkina8, Natalya Yudina9,
Lyudmila Privalova10, Lyudmila Minkina11, Artem Zaichikov12,
Eugenia Matsekha13, Ivan Fisyun14, Daniil Sakun15, Nadezhda Dunaeva16,
Vladislav Mitrofanov17, Sergey Kovalenko18, Ekaterina Grishina19,
Eduard Chulkov20, Nadezhda Pishchaeva21, Asmik Gevorkyan22,
Evgeniy Nechesnyuk5, Elena Slobina23, Natalya Popova24,
Dmitriy Pogorelov25, Alexander Matitsyn26, Alexander Shapochnik27,
Valentina Timofeeva28, Andrey Korchunov29, and Nikolay Vorobiev30;
1St.Luka`s Clinical Research Center for Children, Moscow, RussianFederation, 2Russian Children’s Clinical Hospital, Moscow, RussianFederation, 3Federal State Autonomous Institution “N. N. Burdenko
National Medical Research Center of Neurosurgery” of the Ministryof Health of the Russian Federation, Moscow, Russian Federation,
4Morozov Children’s Clinical Hospital, Moscow, Russian Federation,
5Dmitry Rogachev National Medical Research Center Of PediatricHematology, Oncology and Immunology, Moscow, Russian Federation,
6Moscow Regional Research Clinical Institute named after M. F.
Vladimirsky, Moscow, Russian Federation, 7Perm Regional Hospital,
Perm, Russian Federation, 8Moscow Regional Oncology Center, Moscow,
Russian Federation, 9Voronezh Regional Clinical Hospital, Voronezh,
Russian Federation, 10Nizhny Novgorod Regional Clinical Hospital,
Nizhny Novgorod, Russian Federation, 11Regional Clinical Hospital,
Vladivostok, Russian Federation, 12Center for Pediatric Oncology and
Hematology, Ekaterinburg, Russian Federation, 13Regional Clinical
Hospital, Chita, Russian Federation, 14Regional Clinical Hospital, Orel,
Russian Federation, 15Regional Clinical Hospital, Simferopol, RussianFederation, 16Regional Clinical Hospital, Vologda, Russian Federation,
17Regional Clinical Hospital, Arkhangelsk, Russian Federation, 18Regional

iii276

N EU R O - O N C O L O G Y•

De c e mb e r 2 0 2 0

Clinical Hospital, Chelyabinsk, Russian Federation, 19Center for PediatricOncology and Hematology, Kazan, Russian Federation, 20Regional Clinical
Hospital, Krasnodar, Russian Federation, 21Regional Clinical Hospital,
Nizhnevartovsk, Russian Federation, 22Research Institute of PediatricOncology, Hematology and transplantation, R, M, Gorbacheva, SaintPetersburg, Russian Federation, 23Russian Scientific Center Of Radiology,
Moscow, Russian Federation, 24Regional Clinical Hospital, Volgograd,
Russian Federation, 25Regional Clinical Hospital, Lipetsk, RussianFederation, 26Regional Clinical Hospital, Tambov, Russian Federation,
27Regional Clinical Hospital, Orenburg, Russian Federation, 28Regional
Clinical Hospital, Ulyanovsk, Russian Federation, 29Heidelberg University
Hospital, Heidelberg, Germany, 30Medical Institute named after Sergei
Berezin, Saint Petersburg, Russian Federation
We analyzed 105 patients under 18 years. The median age was
21 months. There were 54 boys and 51 girls. The supratentorial tumors
were in 53 patients, infratentorial in 48, and in spinal cord in 4. 60 had
stage M0,29-М+and 16-Mx. All the patients got surgical treatment:total
tumor removal in 34,subtotal in 37,partial in 30,and biopsy in 4;75 patients got chemoradiotherapy to ATRT-2006;6-CWS;13-EU-RHAB;5-HITSKK;individual schemes in 6. RESULTS: 47 are alive,1 was LFU, and 57
died. PFS was 32%±0.05; the five-year OS 40%±0.05. The median survival-30 months, the median progression-free survival-12 months, and the
median of follow-up-23 months. PFS was significantly better in patients
more than 12 months compared to patients younger than 12 months:40 and12%;p=0.00161.After total resection PFS was higher compared to subtotal
resection, partial resection, and tumor biopsy:48,38,0,and 0%(p=0.025).
After chemoradiotherapy, PFS was higher compared to patients without
radiotherapy: 49and 0%(р=0.0000000).PFS for stage M0 was higher compared to stage M+and stage Mx:41,15,and 27%,respectively(р=0.00032).
PFS was better for the tumors in the spinal cord and infratentorial location compared to the supratentorial location:67,37,and 25%(p=0.0876).
The survival rate was higher among the patients who got treatment according to the ATRT-2006 protocol compared to EU-RHAB, individual regimens, CWS, and HIT-SKK:39,19,17,17,and 0% respectively;p=0.00159.
The survival was higher among the patients who got intraventricular/
intrathecal Methotrexate,Cytarabine, Prednisolone than among the patients who got only Methotrexate or none at all:40,0,and 5%, respectively;
p=0.00015. CONCLUSIONS: Survival was significantly better in patients more than 12month, without metastases, with total removal tumor,
chemotheradiotherapy by ATRT-2006 protocol with i/t, i/v Methotrexate/
Cytarabine/Prednisolone.
ATRT-06. SMARCB1 LOSS DRIVEN NON-CANONICAL PRC1ACTIVITY REGULATES DIFFERENTIATION IN ATYPICALTERATOID RHABDOID TUMORS (ATRT)
Irina Alimova1,2, Etienne Danis1, Marla Weetall3, Angela M Pierce1,2,
Dong Wang1, Natalie Serkova4, Ilango Balakrishnan1,
Krishna Madhavan1,2, Bridget Sanford1, Cole Michel5,
Nicholas K Foreman6,2, John Baird3, Sujatha Venkataraman1,2, andRajeev Vibhakar4,2; 1Department of Pediatrics, University of Colorado
Anschutz Medical Campus, Aurora, CO, USA, 2Morgan Adams Foundation
Pediatric Brain Tumor Research Program, Children’s Hospital, Aurora, CO,
USA, 3PTC Therapeutics, INC, South Plainfield, NJ, USA, 4Department ofRadiology, University of Colorado Anschutz Medical Campus, Aurora, CO,
USA, 5Department of Pharmaceutical Sciences Skaggs School of Pharmacy,
University of Colorado Anschutz Medical Campus, Aurora, CO, USA,
6Department of Pediatrics, Department of Neurosurgery University ofColorado Anschutz Medical Campus, Aurora, CO, USA
Loss of SMARCB1 is the hallmark genetic event that characterizes ATRT.
SMARCB1 is a member of the SWI/SNF chromatin remodeling complex
that is responsible for determining cellular pluripotency and lineage commitment. To identify co-operating epigenetic factors, we performed an unbiased
shRNA screen targeting 408 epigenetic/chromatin molecules in patientderived ATRT cell lines and identified BMI1, a component of the Polycomb
Repressive Complex 1 (PRC1), as essential for ATRT cell viability. Genetic
and Chemical inhibition of BMI1 inhibited clonogenic potential and induced apoptosis in vitro. In vivo PTC 596 significantly decreased growth of
intracranial orthotopic ATRT tumors as evaluated by T2 MRI imaging andsignificantly prolonged survival compared to control animals. Using RNAseq and ChIP-Seq our studies show that BMI1 co-operates with SMARCB1
loss to suppress transcription of pro-differentiation pathways and promote
self-renewal of tumor stem cells. We then used a doxycycline-inducible
SMARCB1 expression system and performed Immunoprecipitation for
BMI1, followed by and mass spectrometry analysis. In SMARCB1 deficient
cells BMI1 forms a partial PRC1 complex devoid of DNA binding components. Re-expression of SMARCB1 activates two PRC1 chromatin localizing
components CBX4 and CBX8. CBX4 is implicated DNA damage response,
tumor angiogenesis and self-renewal. CBX8 activates lineage-specific genes
during differentiation of ESC. Our data suggest that SMARCB1 deletion
results in reprograming of BMI1 chromatin occupancy away from lineage

Abstracts

specification by altering the components of the PRC1 complex. These studies
identify the mechanistic basis of BMI1 co-operation with SMARCB1 loss
in ATRT and establish BMI1 inhibition as a novel therapeutic approach in
ATRT.
ATRT-07. HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS
STEM CELL TRANSPLANTATION FOR AN ADULT PRESENTATION
OF THE ATYPICAL TERATOID-RHABDOID TUMOR (ATRT)
Maciej Mrugala1, Aditya Raghunathan2, and Jose Leis1; 1Mayo Clinic,
Phoenix, AZ, USA, 2Mayo Clinic, Rochester, MN, USA
BACKGROUND: ATRT is a rare primary CNS tumor occurring predominantly in children with the peak age of onset at less than 3 years old. Adult
presentations are exceedingly rare, associated with poor prognosis and no
standard therapies exist. METHODS: Case presentation. RESULTS: 61 y
old woman presented with headaches, sinus pressure, and cognitive decline.
She was found to have a pineal tumor causing obstructive hydrocephalus.
The patient underwent gross total resection of the tumor with pathology
reported as ATRT. Her CNS staging, including CSF, was negative. She subsequently received radiotherapy to the resection bed. There was no consensus
on what should be the next step in her therapy given lack of data in adults.
Ultimately, we adopted a pediatric regimen and treated the patient with a
combination of high-dose chemotherapy with cisplatin, cyclophosphamide,
and vincristine followed by autologous stem cell transplantation (ASCT).
This regimen called for up to 4 cycles of chemotherapy with ASCT and we
had collected enough cells to complete 3 cycles. The patient completed 2
cycles of therapy with moderate toxicity. Her CNS imaging remained stablewith no evidence of recurrence 14-months from the original diagnosis. CONCLUSIONS: ATRT continues to be an exceedingly rare diagnosis in adults.
No standard therapies exist and treatment decisions are challenging given
lack of data and lack of prospective clinical trials. Pediatric regimens can frequently be adopted for adults although high-dose chemotherapy with ASCT
can be challenging. Our case exemplifies the feasibility of treating ATRT in
an adult in the most aggressive fashion.
ATRT-08. A PHASE II STUDY OF CONTINUOUS LOW DOSEPANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANTRHABDOID TUMORS/ATYPICAL TERATOID RHABDOID TUMORSPaul Wood1,2, Jayesh Desai3,4, Kelly Waldeck3, Jason Cain5,
Nick Gottardo6, Robyn Strong7,8, Kathryn Kinross7,8, Michelle Carr7,8,
Janelle Jones7,8, Lily Wong9, David Ziegler10, Jordan Hansford11,12,
Michael Michael3, and David Ashley13; 1Monash Health, Melbourne,
VIC, Australia, 2Monash University, Melbourne, VIC, Australia, 3Peter
MacCallum Cancer Centre, Melbourne, VIC, Australia, 4Australia and
New Zealand Sarcoma Association, Melbourne, VIC, Australia, 5Hudson
Institute of Medical Research, Melbourne, VIC, Australia, 6Princess
Margaret Hospital for Children, Perth, WA, 7Australian and New ZealandChildren’s Haematology/Oncology Group, Melbourne, VIC, Australia,
8Australasian Children’s Cancer Trials, Melbourne, VIC, Australia, 9Kids
Oncology and Leukaemia Trials (KOALA), Sydney, NSW, Australia,
10Sydney Children’s Hospital, Sydney, NSW, Australia, 11Royal Children’s
Hospital, Melbourne, VVIC, Australia, 12University of Melbourne,
Melbourne, VIC, Australia, 13The Preston Robert Tisch Brain Tumor
Centre, Durham, NC, USA
BACKGROUND: Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid
rhabdoid tumors (ATRT) in pre-clinical models. This is an open label,phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose,
continuous panobinostat, its associated toxicities, the biological activityof low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in
fresh tumor tissue specimens. METHODS: Following cycles of induction
and consolidation chemotherapy and/or radiation treatment, patientswere enrolled and commenced on panobinostat as a continuous daily
oral dose starting at 10mg/m2 following a three-week wash out period
between therapies. Real-time acetylation status, measuring acetylated
H4 on PMNC, was performed to determine the pharmacodynamics of
panobinostat. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2. RESULTS: Six patientswith newly diagnosed ATRT/MRT and one patient with relapsed MRT
have been enrolled to date. The average age at enrollment was 2.5 years.
Currently, six patients (85.7%) remain on study with a mean treatment
duration of 170 days (range 44–327 days). One patient was removed
from study at day 44 due to disease progression. The main dose-limiting
toxicity observed to date has been myelosuppression. Panobinostat, at adose of 10mg/m2, caused significant acetylation of H4 in PMNC. CONCLUSIONS: Treatment with panobinostat appears to be well tolerated
in infants with MRT/ATRT, with successful real-time pharmacodynamic
assessment of H4 acetylation.

ATRT-09. IDENTIFICATION OF HUB GENES IN ATYPICALTERATOID/RHABDOID TUMORS BY MULTIPLE-MICROARRAYANALYSIS
Wei Liu1,2, Yi Chai1,2, Junhua Wang1,2, and Yuqi Zhang1,2; 1School ofClinical Medicine, Tsinghua University, Beijing, China, 2Department of
Neurosurgery, Yuquan Hospital, School of Clinical Medicine, Tsinghua
University, Beijing, China
BACKGROUND: Atypical teratoid/rhabdoid tumors (ATRT) are rare,highly malignant neoplasms arising in infants and young children. However,the biological basis of ATRTs remains poorly understood. In the present
study, we employed integrated bioinformatics to investigate the hub genes
and potential molecular mechanism in ATRT. METHODS: Three microarray datasets, GSE35943, GSE6635 and GSE86574, were downloaded
from Gene Expression Omnibus (GEO) which contained a total of 79 samples including 32 normal brain tissue samples and 47 ATRT samples. The
RobustRankAggreg method was employed to integrate the results of thesegene expression datasets to obtain differentially expressed genes (DEGs).
The GO function and KEGG pathway enrichment analysis were conductedat the Enrichr database. The hub genes were screened according to the degree using Cytoscape software. Finally, transcription factor (TF) of hub
genes were obtained by the NetworkAnalyst algorithm. RESULTS: A totalof 297 DEGs, consisting of 94 downregulated DEGs and 103 upregulated
DEGs were identified. Functional enrichment analysis revealed that thesegenes were associated with cell cycle, p53 signaling pathway and DNA
replication. Protein-protein interaction (PPI) network analysis revealed
that CDK1, CCNA2, BUB1B, CDC20, KIF11, KIF20A, KIF2C, NCAPG,NDC80, NUSAP1, PBK, RRM2, TPX2, TOP2A and TTK were hub genes
and these genes could be regulated by MYC, SOX2 and KDM5B according
to the results of TF analysis. CONCLUSIONS: Our study will improve theunderstanding of the molecular mechanisms and provide novel therapeutictargets for ATRT.
ATRT-10. ATYPICAL TERATOID/RHABDOID TUMOR OF THE
PINEAL REGION IN A PEDIATRIC PATIENTCarlos Almeida Jr1, Bruna Minniti Mançano1, Marcus Matsushita1,
Stephanie Previdelli2, Marina Lopes Lamim2, Fabio Costa Faustino1,
Fernanda Magalhaes Souza1, and Lucas Dias Lourenço1; 1Barretos´sChildren and Young Adults Cancer Hospital, Barretos, Sao Paulo, Brazil,
2School of Health and Science Dr Paulo Prata, Barretos, Sao Paulo, Brazil
BACKGROUND: Atypical teratoid/rhabdoid tumor (ATRT) is a malignant neoplasm of the central nervous system and corresponds to 1.5%of all intracranial tumors. Mainly affects children under three years of age
and shows aggressive behavior (most pediatric patients succumb to theirdisease within a year after the initial diagnosis, despite the treatment performed). Its place of occurrence in children is preferably in the posterior
fossa, and it is rare to appear in other regions. There are only seven patients with ATRT reported on literature; all of them are adults. We present
the case of a pediatric patient with a tumor in the pineal region diagnosed
as ATRT. CASE REPORT: Three-year-old female patient admitted with occipital headache, vomiting, and seizure. Magnetic resonance imaging (MRI)
showed obstructive hydrocephalus secondary to a solid-cystic lesion locatedat the pineal region that was 3.0 x 3.0 x 3.5 cm in size. Spine MRI did not reveal leptomeningeal spreading. We performed an occipital transtentorial approach to achieve the best safe resection possible, and a ventriculoperitoneal
shunt. Histological examination revealed ATRT. The patient received adjuvant treatment with radiotherapy and chemotherapy according to the “HeadStart” protocol. One year after the surgery, MRI did not identify any remaining lesion. CONCLUSION: ATRT is an aggressive and rare neoplasm
whose clinical picture depends on the location of the tumor; however, it
must be considered in the differential diagnosis of tumors of the pineal region in the pediatric population.
ATRT-11. PREVALENCE OF GERMLINE VARIANTS IN SMARCB1
INCLUDING SOMATIC MOSAICISM IN AT/RT AND OTHERRHABDOID TUMORS
Ryota Shirai1,2, Tomoo Osumi1,3, Keita Terashima3, Chikako Kiyotani3,
Meri Uchiyama1,3, Shinichi Tsujimoto1,3, Masanori Yoshida1,2,
Kaoru Yoshida1, Toru Uchiyama4, Daisuke Tomizawa3, Yoko Shioda3,
Masahiro Sekiguchi5, Kenichiro Watanabe6, Dai Keino7,
Hitomi Ueno-Yokohata1, Kentaro Ohki1, Junko Takita5, Shuichi Ito2,
Takao Deguchi3, Nobutaka Kiyokawa1, Hideki Ogiwara8,
Tomoro Hishiki9, Seishi Ogawa10, Hajime Okita11,12,
Kimikazu Matsumoto3, Takako Yoshioka11, and Motohiro Kato1,3;
1Department of Pediatric Hematology and Oncology Research, National
Research Institute for Child Health and Development, Tokyo, Japan,
2Department of Pediatrics, Yokohama City University, Yokohama,Japan, 3Children’s Cancer Center, National Center for Child Health andDevelopment, Tokyo, Japan, 4Department of Human Genetics, National
Research Institute for Child Health and Development, Tokyo, Japan,

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5Department of Pediatrics, University of Tokyo, Tokyo, Japan, 6Department
of Hematology and Oncology, Shizuoka Children’s Hospital, Shizuoka,
Japan, 7Department of Pediatrics, St. Marianna University School of
Medicine Hospital, Kawasaki, Japan, 8Division of Neurosurgery, National
Center for Child Health and Development, Tokyo, Japan, 9Division ofSurgery Oncology, Children’s Cancer Center, National Center for Child
Health and Development, Tokyo, Japan, 10Department of Pathology andTumor Biology, Graduate School of Medicine, Kyoto University, Kyoto,
Japan, 11Department of Pathology, National Center for Child Health andDevelopment, Tokyo, Japan, 12Department of Pathology, Keio University
School of Medicine, Tokyo, JapanBACKGROUND: Genetic hallmark of atypical teratoid/rhabdoid tumor(AT/RT) is loss-of-function variants or deletions in SMARCB1 gene on
22q11.2 chromosome, which is common to extracranial malignant rhabdoid
tumors (MRT). Previous studies demonstrated that approximately one-thirdsof AT/RT and extracranial MRT patients harbored germline SMARCB1
variants as the rhabdoid tumor predisposing syndrome. We studied herein
intensive analysis of the SMARCB1 gene in AT/RT and extracranial MRT
patients focusing on prevalence of germline genetic variants. PROCEDURE:
In total, 16 patients were included. Both tumor-derived DNA and germline
DNA were obtained from all patients. First, screening for SMARCB1 alterations in the tumor specimens was done by direct sequencing, ddPCR and
SNP array analysis. Then, analysis of germline DNA samples focusing on
the genomic abnormalities detected in the paired tumors in each case was
performed. RESULTS: In eight of 16 cases (50%), genomic alterations observed in the tumor-derived DNA were also detected in the germline DNA.
It is worth noting that three patients had germline mosaicism. Two of threepatients had mosaic deletion, including SMARCB1 region, and the average
copy number of the deleted region in the SMARCB1 gene in the germline
was 1.60 and 1.76. For another patient, the fraction of SMARCB1 variants in normal cells was as low as 1.7%. CONCLUSIONS: Approximately
half the MRT cases in this study had SMARCB1 germline alterations. Considering the presence of low-frequency mosaicisms which conventional
methods might overlook, inherited germline variants in predisposition genes
are more important than previously assumed for the pathogenesis of pediatric cancers.
ATRT-13. DIFFERENT CELLS OF ORIGIN PAVE THE WAY FOR
MOLECULAR HETEROGENEITY IN RHABDOID TUMORS
Monika Graf1, Marta Interlandi2,1, Natalia Moreno1, Dörthe Holdhof3,
Viktoria Melcher1, Dennis Kastrati1, Gerd Meyer zu Hörste4,
Martin Dugas2, Michael C. Frühwald5, Thomas K. Albert1,
Ulrich Schüller3,6, and Kornelius Kerl1; 1Department of PediatricHematology and Oncology, University Children’s Hospital Münster,
Münster, Germany, 2Institute of Medical Informatics, University of
Münster, Münster, Germany, 3Department of Pediatric Hematology andOncology, University Medical Center Hamburg-Eppendorf, Hamburg,
Germany, 4Department of Neurology with Institute of Translational
Neurology, University Hospital Münster, Münster, Germany, 5SwabianChildren’s Cancer Center, University Children’s Hospital Augsburg,
Augsburg, Germany, 6Research Institute Children’s Cancer Center, 20251
Hamburg, Hamburg, Germany
Rhabdoid tumors (RT) are rare but highly aggressive pediatric neoplasms.
These tumors carry homozygous loss-of-function alterations of SMARCB1
in almost all cases with an otherwise low mutational load. RT arise at different intracranial (ATRT) as well as extracranial (MRT) anatomical sites.
Three main molecular subgroups (ATRT-SHH, ATRT-TYR, ATRT-MYC)
have been characterized for ATRT which are epigenetically and clinicallydiverse, while MRT show remarkable similarities with ATRT-MYC distinct
from ATRT-SHH and ATRT-TYR. Even though there are hypotheses about
various cells of origin among RT subgroups, precursor cells of RT have notyet been identified. Previous studies on the temporal control of SMARCB1
knockout in genetically engineered mouse models have unveiled a tight vulnerable time frame during embryogenesis with regard to the susceptibility ofprecursor cells to result in RT. In this study, we employed single-cell RNA
sequencing to describe the intra- and intertumoral heterogeneity of murine
ATRT-SHH and -MYC as well as extracranial MYC tumor cells. We defined subgroup-specific tumor markers for all RT classes but also observed
a notable overlap of gene expression patterns in all MYC subgroups. By
comparing these single-cell transcriptomes with available single-cell maps ofearly embryogenesis, we gained first insights into the cellular origin of RT.
Finally, unsupervised clustering of published human RT methylation dataand healthy control tissues confirmed the existence of different cells of origin
for intracranial SHH tumors and MYC tumors independent of their anatomical localizations.

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ATRT-14. MACROPHAGE-TUMOR CELL INTERACTIONPROMOTES ATRT PROGRESSION AND CHEMORESISTANCE
Viktoria Melcher1, Monika Graf1, Marta Interlandi1,2, Natalia Moreno1,
Flavia W. de Faria1, Su Na Kim1, Dennis Kastrati1, Sonja Korbanka1,
Amelie Alfert1, Joachim Gerß3, Gerd Meyer zu Hörste4,
Wolfgang Hartmann5, Michael C. Frühwald6,7, Martin Dugas2,
Ulrich Schüller8,9, Martin Hasselblatt10, Thomas K. Albert1, andKornelius Kerl1; 1Department of Pediatric Hematology and Oncology,
University Children’s Hospital Münster, Münster, Germany, 2Institute ofMedical Informatics, University of Münster, Münster, Germany, 3Instituteof Biostatistics and Clinical Research, University of Münster, Münster,Germany, 4Department of Neurology with Institute of Translational
Neurology, Münster, Germany, 5Gerhard-Domagk-Institute of Pathology,
University of Münster, Münster, Germany, 6Swabian Children’s Cancer
Center, University Children’s Hospital Augsburg, Augsburg, Germany,
7EU-RHAB Registry Center, Augsburg, Germany, 8Department of PediatricHematology and Oncology, University Medical Center HamburgEppendorf, Hamburg, Germany, 9Research Institute Children’s Cancer
Center, Hamburg, Germany, 10Institute of Neuropathology, University
Hospital Münster, Münster, Germany
Atypical teratoid/rhabdoid tumors (ATRT) are pediatric brain neoplasmsthat are known for their heterogeneity concerning pathophysiology andoutcome. The three genetically rather uniform but epigenetically distinct
molecular subgroups of ATRT alone do not sufficiently explain the clinicalheterogeneity. Therefore, we examined the tumor microenvironment (TME)in the context of tumor diversity. By using multiplex-immunofluorescent
staining and single-cell RNA sequencing (scRNA-seq) we unveiled the panmacrophage marker CD68 as a subgroup-independent negative prognostic
marker for survival of ATRT patients. ScRNA-seq analysis of murine ATRTSHH, ATRT-MYC and extracranial RT (eRT) provide a delineation of theTME, which is predominantly infiltrated by myeloid cells: more specifically amicroglia-enriched niche in ATRT-SHH and a bone marrow-derived macrophage infiltration in ATRT-MYC and eRT. Exploring the cell-cell communication of tumor cells with tumor-associated immune cells, we found that
Cd68+ tumor-associated macrophages (TAMs) are central to intercellularcommunication with tumor cells. Moreover, we uncovered distinct tumor
phenotypes in murine ATRT-MYC that share genetic traits with TAMs.
These intermediary cells considerably increase the intratumoral heterogeneity of ATRT-MYC tumors. In vitro co-culture experiments recapitulated
the capability of ATRT-MYC cells to interchange cell material with macrophages extensively, in contrast to ATRT-SHH cells. We found that microglia
are less involved in the exchange of information with ATRT cells and that
direct contact is a prerequisite for incorporation. A relapse xenograft model
implied that intermediary cells are involved in the acquisition of chemotherapy resistance. We show evidence that TAM-tumor cell interaction is one
mechanism of chemotherapy resistance and relapse in ATRT.
ATRT-15. LY6D – A CANDIDATE FOR NANOPARTICLE-BASEDTARGETED THERAPIES OF ATRT
Lea Hagemeier1, Marthe Sönksen1, Natalia Moreno1, Romy Ettlinger2,
Hana Bunzen2, and Kornelius Kerl1; 1Department of Pediatric Hematology
and Oncology, University Children’s Hospital Münster, Münster, Germany,
2Institute of Physics, University Augsburg, Augsburg, Germany
Atypical Teratoid Rhabdoid Tumors (ATRT) are aggressive brain malignancies of the infant. Despite intensive multimodal therapy, the overallprognosis remains poor, making investigations on targeted therapies crucial.
Arsenic trioxide (ATO) is known to inhibit cell growth of ATRT in vitro
and in vivo but its efficacy in solid tumors is limited by its adverse effects.
We aimed to characterize whether a nanoparticle-based drug delivery could
overcome these limitations. Therefore metal-organic frameworks containing
ATO (MOF-ATO) were constructed. To improve drug specificity further,
we searched for unique proteins on the surface of ATRT, in order to create
antibody-drug-conjugates out of MOF-ATO and an ATRT-specific ligand.
ATRT are marked by a biallelic loss of SMARCB1, which results in an activation of the repressive histone methyltransferase EZH2. After chemical
inhibition of EZH2 with GSK126, a mass spectrometric based screening
for differentially expressed surface proteins was performed. Treatment with
ATO, as well as MOF-ATO and GSK126 each reduces the cell viability of
ATRT cell lines. It results in a cell cycle arrest and an induction in apoptosis, being analysed via MTT test and flow cytometry. GSK126 treatment
causes a significant upregulation of several cell surface proteins, upon themthe Lymphocyte antigen 6 family member D (LY6D). Being rarely expressedon other human cells, this protein is an interesting candidate. An antibodydrug-conjugate consisting of MOF-ATO and LY6D-ligands could be a
promising approach for future targeted therapies of ATRT.

Abstracts

ATRT-16. MODELLING ATRT THROUGH SWI/SNF COMPLEXDEFICIENCY IN GENETICALLY-ENGINEERED MOUSE MODELS
Andrew Bondoc1, Brian Golbourn2,3, Christian Smith1, Annie Huang1,4,
and James Rutka1,5; 1Labatt Brain Tumour Research Centre, The
Hospital for Sick Children, Toronto, ON, Canada, 2John G, Rangos Sr,
Research Center, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA,
3Department of Neurological Surgery, University of Pittsburgh Schoolof Medicine, Pittsburgh, PA, USA, 4Division of Hematology/Oncology,
The Hospital for Sick Children, Toronto, ON, Canada, 5Division of
Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada
Atypical Teratoid/Rhabdoid Tumours (ATRT) are highly malignant neoplasms arising primarily in the CNS of children. They are defined by lossof function mutations in smarcb1, a gene serving a vital role in neurogenesis and differentiation. In order to recapitulate ATRT in the mouse, weused a Cre-Lox recombination system to conditionally knockout smarcb1
in specific cell compartments. Loss of smarcb1 in BLBP-expressing cells of
the developing brain led to severe neurologic defects. Mice exhibited seizures, ataxia, and median 12-day survival. Histological analysis revealed
severe thinning of the cerebral cortex and cerebellum. Temporally-targeted
smarcb1 loss in BLBP/Nestin-expressing embryonic compartments did not
result in tumour formation. Similarly, BLBP-expressing, smarcb1-deficientneural stem/progenitor cells (NSC/NPCs) were isolated and allografted but
did not form tumours. These cells demonstrated decreased proliferation,higher apoptosis, and upregulation of p53, CDKN1A, and CDKN2A. In
contrast, ubiquitous smarcb1 loss at the earlier embryonic day 6.5 produced
widespread tumorigenicity in the forebrain, hindbrain, skullbase, and spine;each with unique phenotypes, survival, and morphology. We employed aclinically-relevant Nanostring gene-panel screen to stratify tumours into
genetically distinct subgroups. Our findings indicate that smarcb1 plays animportant role in CNS development. Loss of smarcb1 in NSC/NPCs is lethal, and its developmental context influences cell fate. Targeted smarcb1
loss likely plays a tumorigenic role at an earlier developmental stage thanpreviously determined, in a diverse array of primitive stem cells. These data
support the generation of a murine ATRT model capable of producing distinct tumour entities that recapitulate the human disease.
ATRT-17. TARGETING GLUTAMINE METABOLISM LOWERS
METHYLATION POTENCIALS IN AT/RT AND SYNERGIZE WITHTAZEMETOSTAT
Satoshi Nakata, Sabrina Wang, Jesse Alt, Barbara Slusher,
Charles Eberhart, Eric Raabe, and Jeffrey Rubens; Johns Hopkins
University, Baltimore, MD, USA
Atypical teratoid/rhabdoid tumors (AT/RT) have a single recurring genetic mutation in SMARCB1. This deletion leads to an abnormal SWI/SNF
chromatin remodeling complex and the constitutive activation of EZH2.
S-adenosyl-L-methionine (SAM) donates a methyl group to EZH2 whichthen methylates DNA and histones leading to the abnormal gene expression responsible for AT/RT’s aggressive phenotype. We have previously
shown that glutamine metabolic inhibition with 6-diazo-5-oxo-L-norleucine(DON) confers a survival advantage in AT/RT. In this study, we identified
with ultra-high performance liquid chromatography mass spectrometry that
DON treatment lowered the methylation potential in AT/RT (Decreased
SAM:SAH ratio, t-test in 5 AT/RT human-derived cell models comparing
DON treatment to DMSO control, p<0.05). AT/RT cell lines grown in glutamine deplete media compared to normal growth conditions also had areduced methylation potential (decreased SAM:SAH, t-test, p<0.05). DON
treatment over 5 days decreased histone methylation (as determined bywestern blot for H3K27me3). Tazemetostat is a small molecule inhibitorthat blocks the SAM methyl donor site on EZH2. We find that DON combines synergistically with Tazemetostat to slow AT/RT cell growth (MTS
assay, p<0.01 t-test; MUSE viability assay, p<0.01 ANOVA) and enhances
cytotoxicity (MUSE Annexin-V, p<0.01 by ANOVA). Synergies were especially pronounced at low concentrations of Tazemetostat which is significant
given that Tazemetostat’s efficacy in AT/RT has been limited by poor CNS
penetration. These studies identify a novel treatment strategy that has potential to improve survival in AT/RT.
ATRT-18. SHH-SUBTYPE ATYPICAL TERATOID/RHABDOIDTUMORS ARE SELECTIVELY SENSITIVE TO GEMCITABINETREATMENT
Dennis Metselaar1,2, Michaël Hananja Meel1, Joshua Goulding2,
Piotr Waranecki1,2, Mark de Gooijer3, Marjolein Breur2,
Sophie Veldhuizen van Zanten1, Marianna Bugiani2, Pieter Wesseling1,2,
Gertjan Kaspers1, and Esther Hulleman1; 1Princess Máxima Center for
Pediatric Oncology, Utrecht, Netherlands, 2Amsterdam University Medical
Centers, Amsterdam, Netherlands, 3The Netherlands Cancer Institute,
Amsterdam, Netherlands
Atypical Teratoid Rhabdoid Tumors (ATRT) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. ATRT

can be divided into three molecular subgroups of which the Sonic Hedgehog(SHH) subgroup is most prevalent. In this study, we developed and validated a novel patient-derived ATRT model, which we used along a panel ofother primary ATRT models for large scale drug discovery assays. We foundthat ATRTs are selectively sensitive to the nucleoside analogue gemcitabine,with SHH-subtype ATRTs being the most sensitive subgroup. Gene expression profiles and protein analysis indicated that gemcitabine treatment
causes degradation of Sirtuin 1 (SIRT1), which causes ATRT specific celldeath through NF-kB and p53 activation. Furthermore, we found that this
gemcitabine induced loss of SIRT1 results in a nucleus-to-cytoplasm shiftof the SHH signaling activator Gli, explaining the additional gemcitabinesensitivity in SHH-subtype ATRT. Treatment of SHH-subgroup ATRT
xenograft-bearing mice resulted in a >40% increase in median survival(p<0.01, log-rank test) and long-term survivors in two independent models.
To prepare translation of our findings to the clinic, we investigated potential gemcitabine induced resistance mechanisms by conducting kinome-wide
CRISPR/Cas9 knockout screens in primary ATRT cells. Through these experiments we found that low-dose gemcitabine treatment combined with
inhibition of protein kinase C zeta (PKCζ) prevents regrowth of resistant
ATRT subclones. Together, these findings show that ATRT are highly sensitive to gemcitabine treatment; and as such we suggest that gemcitabine
may be rapidly incorporated into future treatment regimens for SHH-ATRT.
ATRT-19. EPIGENETIC REPROGRAMMING LEADS TO INNATE
IMMUNE PATHWAY ACTIVATION IN AT/RT
Seethalakshmi Hariharan1,2, Cem Kilic1,2, Michelle Bowie1,2,
Zachary Reitman1,3, and David Ashley1,2; 1The Preston Robert TischBrain Tumor Center, Duke University Medical Center, Durham, NC, USA,
2Department of Neurosurgery, Duke University Medical Center, Durham,
NC, USA, 3Department of Radiation Oncology, Duke University Medical
Center, Durham, NC, USA
BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RT) are highly
aggressive brain tumors affecting early childhood and are characterized bybi-allelic inactivation of the SMARCB1 gene. Though patients benefit frommultimodal therapy, there is no improvement in overall survival necessitating
exploration of alternative approaches including innate-based immune
therapy and epigenetic therapy, which have shown promise in treating
adult brain tumors and other cancers. Though reconstitution of SMARCB1
in SMARCB1-deficient cells leads to activation of interferon-stimulated
genes, the role of innate immune signaling has not been investigated in AT/
RTs. METHODS: Our data from a panel of AT/RT cell lines indicates lossof expression of key innate signaling components, like RIG-I, MDA-5, cGAS
and STING that are required for sensing extracellular dsRNA and dsDNA.
These cell lines also do not respond to dsDNA-based or dsRNA-based innate agonists. However, co-treatment of the BT-16 cell line with two epigenetic drugs, panobinostat and 5-azacytidine leads to re-expression of STING
and RIG-I. Panobinostat/5-azacytidine co-treatment followed by either genomic DNA (dsDNA agonist) or poly(I:C) (dsRNA agonist) treatment results
in induction of innate responses, measured by STAT1 phosphorylation andproduction of ISG-15 and IFIT-1. CONCLUSION: Our data suggests that
AT/RT cell lines are unresponsive to innate agonists possibly due to the lossof expression of key innate immune components. However, these pathways
can be reactivated by epigenetic drugs and further potentiated by dsDNA/
dsRNA-based innate agonists. Combined epigenetic reprogramming andinnate pathway stimulation may serve as a potential therapy option fortreating AT/RT.
ATRT-20. CDK7 INHIBITION IN AT/RT
Andrew Morin1, Bethany Veo1, Susan Fosmire1, Michele Crespo1,
Shadi Zahedi1, Rajeev Vibhakar1,2, and Jean M Mulcahy Levy1,2;
1University of Colorado, Aurora, CO, USA, 2Childrens Hospital Colorado,
Aurora, CO, USA
Atypical teratoid/rhabdoid tumors (AT/RT) are characterized by lossof-function mutations in the SMARCB1 component (and less commonly
SMARCA4) of the SWI/SNF chromatin-remodeling complex. AT/RT demonstrate an overall silent genomic landscape with epigenetic dysregulationof the genome. CDK7 is a key transcriptional regulator that preferentiallyphosphorylates the Ser5 and Ser7 positions on RNA Polymerase C terminal
domain and is involved early in transcription. In tumor cells, CDK7 is enriched at super enhancers which preferentially regulate genes involved in celltransformation, and expressed at significantly higher levels in transformed
tissues than the surrounding normal brain. Our preliminary data showsthat CDK7 is expressed in a number of AT/RT tumor cell lines and patientderived tumor cultures, and that loss of CDK7 function though exposure
to the novel CDK7 inhibitor THZ2 results in lack of proliferation at lower
doses, and caspase-mediated apoptosis at higher concentrations. shRNAbased inhibition confirms that this effect is due specifically to loss of CDK7.
RNA sequencing of cells treated with lower doses of THZ2 show significant
alterations in transcript expression consistent with altered balance between
antagonistic SWI/SNF and PRC2 chromatin-modeling complex activities, as

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well as alterations in DNA damage response pathways, cell cycle checkpoints, miRNA transcription, and numerous proliferative factors. THZ2
penetrates the blood brain barrier (BBB), is well tolerated, and results inprolonged survival in murine xenograft models of AT/RT. CDK7 inhibition
also synergizes with a number of currently-approved oncology drugs, as wellas with ionizing radiation, in order to inhibit AT/RT growth and viability.
ATRT-21. RHABDOID PREDISPOSITION SYNDROME: REPORT
OF MOLECULAR PROFILES AND TREATMENT APPROACH IN
THREE CHILDREN WITH SYNCHRONOUS ATYPICAL TERATOID/RHABDOID TUMOR AND MALIGNANT RHABDOID TUMOR
Margaret Shatara1, Ajay Gupta1, Mohamed H. Abu Arja1,
Suzanne E. Conley1, Priyal Patel1, Daniel R. Boué2, Christopher R. Pierson2,
Diana L. Thomas2, Erin K. Meyer2, Summit H. Shah3, Jeremy Jones3,
Lisa Martin3, Aaron McAllister3, Kathleen M. Schieffer4,
Elizabeth A. Varga1, Kristen Leraas4, Tara Lichtenberg4,
Stephanie LaHaye4, Katherine E. Miller4, Vincent Magrini4,
Richard K. Wilson4, Catherine E. Cottrell4, Elaine R. Mardis4,
Jennifer H. Aldrink5, Jeffery J. Auletta1, Jonathan Pindrik6,
Jeffrey R. Leonard6, Diana S. Osorio1, Jonathan L. Finlay1, Mark Ranalli1,
and Mohamed S. AbdelBaki1; 1The Division of Hematology, Oncology,
Blood and Marrow Transplant, Nationwide Children’s Hospital and The
Ohio State University, Columbus, OH, USA, 2Department of Pathology
and Laboratory Medicine, Nationwide Children’s Hospital and The Ohio
State University, Columbus, OH, USA, 3The Department of Radiology,
Nationwide Children’s Hospital, Columbus, OH, USA, 4The Steve andCindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s
Hospital, Columbus, OH, USA, 5Department of Surgery, Division of
Pediatric Surgery, The Ohio State University College of Medicine,Nationwide Children’s Hospital, Columbus, OH, USA, 6The Division of
Pediatric Neurosurgery, Nationwide Children’s Hospital and The Ohio
State University, Columbus, OH, USA
BACKGROUND: Rhabdoid predisposition syndrome is characterized bygermline alterations in SMARCB1 or SMARCA4, leading to synchronous or
metachronous central nervous system (CNS) and extra-CNS rhabdoid tumors. Rare survivors have been reported to date. METHODS: We describe
the molecular profiling and treatment regimen of three patients with synchronous atypical teratoid/rhabdoid tumor (ATRT) and malignant rhabdoid
tumor of the kidney (MRT-K). All patients underwent radical nephrectomy of the kidney, and gross total resection of the primary CNS tumor
was achieved for two patients. An intensive chemotherapy regimen was
administered; an induction phase based on the modified Third Intergroup
Rhabdomyosarcoma Study (IRS-III) for ATRT followed by a consolidation
phase with three cycles of high-dose chemotherapy and autologous hematopoietic progenitor cell rescue, without irradiation. All three patients wereenrolled on an institutional comprehensive genomic profiling protocol. RESULTS: A germline focal 22q deletion, including SMARCB1, was detected
in two patients, while the third patient had a maternally-inherited heterozygous frameshift variant in SMARCB1. Somatic loss of heterozygosity of 22q
was identified in all patients, resulting in biallelic inactivation of SMARCB1.
Divergent tumor subgroups were described using DNA methylation. The
three MRT-K samples were classified as MYC subtype. One ATRT was classified as SHH while the other as TYR. One patient is currently three years
off-therapy without evidence of disease, while the other two patients havecompleted the consolidation phase without recurrent disease. CONCLUSION: Molecular profiling of CNS and extra-CNS rhabdoid tumors revealed different epigenetic subgroups. An intensive multimodal therapeutic
approach without irradiation may achieve prolonged survival.
ATRT-22. HIGH-THROUGHPUT DRUG SCREENING OF FDAAPPROVED CANCER DRUGS REVEALS POTENTIAL THERAPEUTICAPPROACHES FOR ATYPICAL TERATOID RHABDOID TUMOUR
Wai Chin Chong1,2, Nataliya Zhukova1,3, Paul Wood1,3, Peter A Downie3,4,
and Jason E Cain1,2; 1Centre for Cancer Research, Hudson Institute ofMedical Research, Clayton, VIC, Australia, 2Department of Molecular
and Translational Sciences, Monash University, Clayton, VIC, Australia,
3Children Cancer Centre, Monash Children Hospital/Monash Health,
Clayton, VIC, Australia, 4Department of Pediatrics, Monash University,
Clayton, VIC, Australia
Atypical teratoid/rhabdoid tumors (ATRT), are the most common brain tumor
in children under the age of 1 year with an overall survival of ~17%. Like extracranial rhabdoid tumors, ATRT is exclusively characterized by bi-allelic loss of
SMARCB1, a critical subunit of the SWI/SNF chromatin remodeling complex,
implicating epigenetic deregulation in the pathogenesis of disease. We have previously shown the ability of the histone deacetylase inhibitor, panobinostat, tomimic SMARCB1-mediated SWI/SNF functions in extracranial rhabdoid tumors to inhibit tumor growth by driving multi-lineage differentiation in vitro
and in vivo. Whether this also applies to ATRT is unknown. Using a panel ofhuman-derived ATRT cell lines, representing defined molecular subgroups, wehave shown that prolonged treatment with panobinostat at nanomolar concen-iii280N EU R O - O N C O L O G Y•

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trations results in markedly reduced clonogenicity, and increased senescence,
preceded by increased H3K27 acetylation, decreased H3K27 trimethylation and
EZH2 expression. To determine potentially synergistic therapies, we performed
high-throughput drug screening of 622 compounds already in advanced clinical
trials or FDA-approved for other indications, across our panel of ATRT models
and identified 30 common compounds, which decrease cell viability by >50%,
with no effect on neural stem cell controls and 12 compounds which demonstrated subgroup specificity, highlighting the necessity to consider therapies in
the molecular context. In addition to HDACi, consistent with our panobinostat
in vitro findings, inhibitors of CDK, survivin and PI3K were the top hits. In
vitro and in vivo validation of these compounds alone, and in combination withpanobinostat is ongoing.
ATRT-23. THE DUAL MTORC1/2 INHIBITOR SAPANISERTIBDISRUPTS THE NRF2-MEDIATED STRESS RESPONSE AND
COMBINES SYNERGISTICALLY WITH THE BH3 MIMETIC
OBATOCLAX TO EXTEND AT/RT SURVIVAL
Ashlyn Parkhurst, Sabrina Wang, Jesse Alt, Antje Arnold, Harpreet Kaur,
Barbara Slusher, Charles Eberhart, Eric Raabe, and Jeffrey Rubens; Johns
Hopkins University, Baltimore, MD, USA
Atypical teratoid/rhabdoid tumors are aggressive infantile tumors highly
resistant to intensive therapies. We aim to identify and target critical factors driving this therapy resistance to improve AT/RT survival. Analysis of
publically available RNASeq on 32 AT/RT identified elevated expression of
NRF2 (median expression 40.78, normal brain 18.81). NRF2 is a master
regulator of cell’s stress response whose expression is correlated with therapy
resistance and poor survival. NRF2 activation is sensitive to mTOR activity
and is a biomarker predicting response to the dual mTORC1/2 inhibitor,
Sapanisertib (TAK228, INK128). We performed RNASeq on 4 human-derived
AT/RT cell models after Sapanisertib treatment. Pathway analysis reveals disruption of the NRF2-mediated stress response (-log p value 0.39, Z-score1.0). As a result, Sapanisertib decreases ROS scavengers like glutathione (Metabolite analysis UHPLC-MS, t-test p<0.05) and induces a pro-death phenotype (decreased MCL-1 expression, western blot; gene-expression analysis,
RNASeq). The brain-penetrant BH3 mimetic Obatoclax increases ROS generation and induces apoptosis (MUSE oxidative stress and ANNEXIN V assays, t-test p<0.05). These complementary mechanisms of action synergize toinduce high rates of cell death (MUSE ANNEXIN V assay, ANOVA p<0.05,
C-PARP western blot, Compusyn Synergy analysis CI<1.0) and slow cell
growth (MUSE Cell viability, ANOVA p<0.05). Once-weekly treatments of
Sapanisertib combined with Obatoclax in orthotopic mouse models of AT/RT
are well tolerated, slow tumor growth (bioluminescence imaging) and significantly extend median survival from 35 to 55 days (Log-rank p<0.05). Thesefindings support a new clinical trial aimed at improving AT/RT survival.
ATRT-24. CELL SURFACE PROTEOME ANALYSIS OF ATRTIDENTIFIES TARGETS FOR IMMUNOTHERAPY
Allison Cole1, Eric Hoffmeyer1, Marco Zanini2, Rajeev Vibhakar1,
Anandani Nellan1, Olivier Ayrault2, and Siddhartha Mitra1; 1Children’s
Hospital Colorado, Aurora, CO, USA, 2Institut Curie, Paris, Paris, France
Atypical teratoid rhabdoid tumor (ATRT) is a rare and fast-growing childhood tumor of the brain and spinal cord. While the recent advances in DNA
and RNA sequencing have given deep insights into the biology of cancer,
about 90% of ATRTs harbor a single deletion which leads to uncontrolled
tumor growth. The lack of targetable genetic abnormalities in ATRT makes
it a tough target for therapy and hence radical new approaches are required
to develop a treatment. In many cases, the gene expression profile alone
DOES NOT represent the presence of the gene product on the surface andcannot detect post-translational modifications such as the addition of sugars
which are essential for the interaction of surface proteins with the tumor
microenvironment. The ability to escape from surveillance by the immune
system is regarded as one of the essential hallmarks of cancer cells. Here we
carried out a comprehensive unbiased large-scale surface receptor profilingusing high throughput multicolor flow cytometry on surgically resected
ATRT patient samples, primary ATRT cell lines, and patient-derived xenograft models. By multiplexing primary samples with antibodies for CD31,
CD45, CD11b, CCR2, Cx3cr1, and CD4, and CD8 we eliminated endothelial and immune cells from analysis while also identifying immune populations within the tumor. We identified increased surface expression of CD44,
CD146, CD59, CD151, and CD276. These were validated in our screeningof primary tumor samples. A combination of CAR-T cell and functionblocking monoclonal antibody approaches have been tested to verify theproof of principle of this approach.
ATRT-25. INTEGRATED QUANTITATIVE SWATH-MS PROTEOMICSANALYSIS OF ATRTS UNCOVERS NEW THERAPEUTICOPPORTUNITIESMartina Anna Finetti1, James Hacking1, Emma Lishman-Walker1,
Silvia A Synowsky2, Stephen Crosier1, Emmma Martin1, Jess Burns3,

Abstracts

Sally L Shirran2, Simon Bailey1, Steven C Clifford1, Paul Huang3, andDaniel Williamson1; 1Newcastle University, Newcastle Upon Tyne, Tyne
and Wear, United Kingdom, 2University of St. Andrews, St. Andrew, Fife,
United Kingdom, 3The Institute of Cancer Research, Sutton, London,
United Kingdom
The consequences of SMARCB1 loss in Atypical Teratoid Rhabdoid
Tumors (ATRTs) have been extensively characterized at the epigenetic/transcriptomic level. In this study we detail the functional effect of SMARCB1
mutation on the MRT proteome, its relationship with RNA deregulation or lack thereof. We performed unlabeled discovery proteomics using
MS-SWATH on MRT cells in which SMARCB1 was forcibly re-expressed (5cell lines, +/-SMARCB1); analyzing changes in protein abundance within 3
fractions (total, membrane, nuclear). We generated a custom spectral library,covering >8,000 proteins, for analysis of the ATRT proteome using a pH
fractionated pool of each cellular subfraction. This SMARCB1-dependent
ATRT spectral library constitutes a powerful tool for profiling proteins ofpotentially therapeutic relevance in both model systems and primary ATRT
samples. We show that whilst gene expression and protein abundance are
significantly related there are many instances whereby expression changes
do not reliably predict protein abundances. Several hundred proteins show
significantly increased abundance (p<0.01) with no concomitant change by
RNA-seq. SMARCB1 mutation is able to invoke critical changes in posttranscriptional/translational regulation as well as sub-cellular localization.
By integration with whole-genome CRISPR/cas9 screening we describe functionally essential SMARCB1 dependent pathway/membrane biomarkers,
evident at the protein but not the RNA level. We describe several which
are druggable and suggest certain therapeutic modalities e.g. specific combinations of RTKs, RNA-binding proteins/splicing factors (SpliceosomeA,
U4:U5:U6 tri-snRNP complexes). Our analysis links, for the first time in
ATRT, genome-wide transcriptomic and proteome aberrations and reveals
broad mechanisms underlying the effect of SMARCB1 mutation.
ATRT-26. META-ANALYSIS OF TREATMENT MODALITIES INMETASTATIC ATYPICAL TERATOID/RHABDOID TUMORS IN
CHILDREN
Reena M. Underiner1, Mostafa Eltobgy2, Joseph R. Stanek3,
Jonathan L. Finlay3, and Mohamed S. AbdelBaki3; 1The Ohio State
University College of Medicine, Columbus, OH, USA, 2Department ofMicrobial Infection and Immunity, The Ohio State University Wexner
Medical Center, Columbus, OH, USA, 3Division of Hematology, Oncology
and Bone Marrow Transplant, Nationwide Children’s Hospital, Columbus,
OH, USABACKGROUND: Metastatic atypical teratoid/rhabdoid tumors (AT/RT)
are aggressive central nervous system tumors that present during infancy
and are associated with dismal outcomes. Patients receive multimodal treatment including surgical resection, systemic chemotherapy and one or moreof intrathecal chemotherapy (IT), marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and radiation therapy (XRT).
While data regarding treatment modalities for AT/RT patients exist, nocomprehensive data have been published regarding the metastatic patient
population. METHODS: We performed a meta-analysis of 1,578 articles
published through September 2018, including 44 studies with a total of 123
subjects. Additionally, seven patients were incorporated through chart review of patients treated at Nationwide Children’s Hospital. RESULTS: Analysis of 130 patients revealed a 3-year overall survival (OS) of 25%. Age at
diagnosis had a significant impact on survival (p=0.0355); 3-year OS for
infants < 18 months was 21%; 18–36 months was 26%; and > 36 months
was 36%. Location of the primary tumor, metastatic stage and extent of surgical resection did not have significant impact on OS. On univariate analysis,
XRT (p<0.0001), IT (p=0.01) and AuHCR (p<0.0001) were found to significantly improve survival. The most substantial effect was noted in patients
who received AuHCR (3-year OS of 60% versus 9% in those who did not).
On multivariable analysis XRT (p=0.0006), IT (p=0.0124) and AuHCR(p<0.0001) were independently associated with reduced risk of death.
ATRT-27. COST-EFFECTIVE ASSAYS TO SUBGROUP ATRT IN THE
DAILY ROUTINE
María-Jesús Lobon-Iglesias1, Arnault Tauziede-Espariat2,
Mamy Andrianteranagna1, Zhiyan Han1, Julien Masliah-Planchon1, andFranck Bourdeaut1; 1Institut Curie, Paris, France, 2CHU Sainte-Anne, Paris,
FranceThree atypical teratoid rhabdoid tumors (ATRT) molecular subgroups
with different bio-clinical characteristics have been reported (TYR, SHH
and MYC). Molecular subgrouping relies on either methylation profiling(reference methods), or expression profiling. However, the cost-effectivenessof such pangenomic screening is questionable. This work aims to study thereliability of alternative techniques for subgroup classification in the daily
routine. Illumina EPIC-arrays were performed on 46 samples. Among thosecases, expression profiling were analysed by RNAseq (n=30). We designed
a 26-gene panel to assess expression profiling using the Nanostring technology; this was applied to 35 tumors. Immunohistochemistry (IHC) wasused for 20 samples; it relied on the expression of MITF, TYR, OTX2 and
MYC. We first assessed the concordance between DNA methylation andRNAseq based profilings; then, between RNAseq and Nanostring and, finally, between methylation profiling and Nanostring or IHC, the two
rapidest and cheapest tools. The concordance between the two expressionbased profiling was 19/21. EPIC-arrays and RNAseq or Nanostring wereconcordant in 26/30 and 30/35 samples, respectively. The concordance was
perfect for methylation-defined MYC subtype. Finally, 17/20 tumor samples
were classified in the same subgroup by EPIC-arrays and IHC; the 3/20 misclassified tumors were SHH by methylation but consistently MYC by IHC,
Nanostring and RNAseq. There was 90–100% of concordance for TYR
subgroup (all techniques). We have designed a gene panel-based expression
signature that shows promising concordance with RNAseq and methylation
profiling. Nanostring assay and IHC well predict ATRT subgroup classification for MYC and TYR subclass, but less so for methylation-defined SHH
ones.
ATRT-28. SINGLE NUCLEI SEQUENCING REVEALS THE
DIFFERENT PHENOTYPIC COMPOSITION OF THE ATRTSUBGROUPS
Pascal Johann1,2, Annette Büllesbach1, Kati Ernst3,
Konstantin Okonechnikov1, David T.W. Jones3, Stefan M. Pfister1,2,
Martin Hasselblatt4, and Marcel Kool5,1; 1Hopp Children’s Cancer Center
Heidelberg (KiTZ), Heidelberg, Germany, 2Department of PediatricOncology, Hematology, Immunology and Pulmonology, Heidelberg,
Germany, 3Pediatric Glioma Research Group, German Cancer ResearchCenter (DKFZ), Heidelberg, Germany, 4Institute for Neuropathology,
Muenster, Germany, 5Princess Máxima Center for Pediatric Oncology,
Heidelberg, Germany
Atypical teratoid/rhabdoid tumors (ATRT) represents a genomicallyhomogeneous disease characterized by loss of SMARCB1 protein in the vast
majority of cases. In recent years, it has become clear that these tumors
display a high degree of intertumoral heterogeneity with three molecularly
distinct subgroups. However, the degree of intratumoral heterogeneity andthe information on cellular subpopulations currently remains largely an unchartered territory. To explore the transcriptomic composition of ATRTs,
we performed single nuclei RNA sequencing for 16 ATRTs representing all
three molecular subgroups (5 ATRT-TYR, 7 ATRT-SHH, 4 ATRT-MYC).
By performing tSNE cluster analyses of all the single cell data (~50.000
cells have been sequenced), we were able to gain unprecedented insights
into the phenotypic composition of ATRTs and unravelled substantial differences between the three subgroups. Integrating transcriptomic information from non-neoplastic brain cells and the data derived from single nuclei
sequencing, we found an OPC like gene signature in ATRT-SHH. In contrast,
ATRT-TYR subpopulations overexpressed more markers of neuronal stem
cells suggesting a larger fraction of undifferentiated cells in this subgroup.
We also identified a subpopulation of cells with a clear overexpression of cell
cycle associated genes (CDK4, CDKN3), predominantly present in ATRTMYC samples, a finding which may harbour important consequences for atargeted therapy with e.g. CDK inhibitors. In summary, our analyses reveal
different cellular compartments in ATRT and provide important insights
into the cellular differentiation of the three ATRT-subgroups. Further analyses to achieve a specific mapping of ATRT to its physiological cell of origin
are currently being pursued.
ATRT-30. RETROSPECTIVE ANALYSIS OF CHILDREN WITH
ATYPICAL TERATOID RHABDOID TUMOR TREATED ACCORDING
TO ACNS0333
Lindsey Hoffman1, Ashley Margol2, Kelly Faulk3, Sara Hutchins4,
Gregory Friedman4, Alyssa Reddy5, and Girish Dhall4; 1Phoenix Children’s
Hospital, Phoenix, AZ, USA, 2Children’s Hospital of Los Angeles, Los
Angeles, CA, USA, 3University of Colorado, Aurora, CO, USA, 4Universityof Alabama, Birmingham, AL, USA, 5University of California San
Francisco, San Francisco, CA, USA
Atypical teratoid rhabdoid tumor (ATRT) is a central nervous system
tumor with poor outcome. ACNS0333, a Children’s Oncology Group phase
3 trial, enrolled 65 evaluable patients who received two cycles of induction chemotherapy, three cycles of consolidative high-dose chemotherapy(HDCT), and focal radiation therapy (RT) pre- or post-consolidation.
Craniospinal irradiation (CSI) was left to clinician discretion. We retrospectively analyzed medical records of 27 children treated at our institutions
according to ACNS0333. Median age at diagnosis was 14 months (range
4–165); 13 (48%) were male. M-stage was M0, M2, and M3 for 18 (66%), 5(19%), and 4 (15%), respectively. Tumor location was supratentorial (n=14,52%), infratentorial (n=12, 44%), or both (n=1, 4%). Complete resection
was achieved for 17 (63%). All but one completed induction. Of 13 (51%)

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with residual disease at diagnosis, 5 (36%) and 7 (50%), respectively, exhibited complete and partial response to induction. Three patients progressedon therapy, and six progressed after completion of therapy at a median of
9.7 months. In all, 18 patients completed RT (16 focal/4 CSI and 6 pre-/12
post-consolidation). Three died of therapy-related toxicity (two in primary
therapy and one in relapse therapy), and 8 died of disease. Sixteen patients(59%) are alive at a median follow up of 53 months (range 9–114). Of 17
with germline testing, eight (47%) had rhabdoid predisposition syndrome ofwhom three are alive. At the time of presentation, data for approximately 50
patients is expected, and we will compare outcomes to soon-to-be publisheddata from ACNS0333.
ATRT-31. SUCCESSFUL MULTIMODALITY MANAGEMENT OFATRT OF THE LOWER DORSAL SPINE WITH SPINAL DROPMETASTASIS
Ahitagni Biswas, Umesh Velu, Kalpana Kumari, Deepali Jain, andSameer Bakhshi; All India Institute of Medical Sciences, New Delhi, India
A 6 year old boy presented with low backache for the last 5 months. MRIof the spine showed a 1.5x1.5x4.7cm intradural mass extending from D10D12, causing compression of the conus medullaris. With a preoperative diagnosis of intradural ependymoma, a gross total resection (GTR) of tumour
was performed. Post-operative histopathology showed a markedly cellular,
malignant tumour with frequent mitotic figures. Cells were round to polygonal with vesicular nuclei, prominent nucleoli and were immunopositive
for CK,EMA,p53 and immunonegative for MIC2,desmin,SMA,GFAP,INI1(MIB1 labeling index-35–40%). The overall impression was spinal
atypical teratoid rhabdoid tumour(ATRT). Post-operative neuraxis MRI
revealed post-operative changes(D10-D12) with a 9 mm enhancing lesionat L5-S1 junction suggesting drop metastasis. There was no brain lesion.
CSF cytology did not show any malignant cell. The metastatic work-up was
normal. He was started on chemotherapy with ICE regimen (Ifosfamide-2g/
m 2IVD1–D3,Carboplatin-500mg/m 2IVD3,Etoposide-100mg/m 2IVD1–
D3q3weeks). Subsequently he received craniospinal irradiation (CSI)36Gray/20fractions/4weeks→ focal boost to primary tumour bed and spinal
drop metastasis-14.4Gray/8fractions/1.5 weeks. Thereafter he received 3
more cycles of ICE regimen. End-of-treatment MRI spine showed post-op
changes(D10-D12) and 38.9%reduction of the L5-S1 lesion suggesting
partial response. Six monthly spinal MRI showed serial reduction of themetastatic lesion leading to complete response (CR) 1 year after completionof treatment. On last follow-up (30 months from initial diagnosis), he wasneurologically intact and in CR. Multimodality management comprising
GTR,CSI followed by focal boost and multiagent chemotherapy(ICE) canlead to successful outcome in patients with this rare and aggressive spinal
tumour.
ATRT-32. GENOME-WIDE CRISPR AND SMALL-MOLECULE
SCREENS UNCOVER TARGETABLE DEPENDENCIES IN AT/RTS
Daniel Merk1, Sophie Hirsch1, Bianca Walter1, Lara Häusser1,
Nicole Persky2, David Root2, Ulrich Schüller3, and Ghazaleh Tabatabai1;
1Hertie Institute for Clinical Brain Research, Tübingen, Germany, 2The
Broad Institute of MIT and Harvard, Cambridge, MA, USA, 3University
Hospital Hamburg Eppendorf, Hamburg, Germany
Brain tumors are the leading cause of cancer-related deaths in children
and adolescents. Embryonal brain tumors are a group of high-grade neoplasms which primarily affect young patients, and atypical teratoid rhabdoid
tumors (AT/RTs) are the second most common type of tumor within thisgroup. In spite of intensive research efforts and the knowledge of molecularmechanisms driving subgroup-specific heterogeneity within ATRTs, survival
estimates stay relatively low as compared to other tumor entities with a median survival of around 17 months. More efficacious and durable therapies
are urgently needed to improve the situation of patients. We here used a combination of genome-wide CRISPR dependency screens and small-molecule
drug assays to identify genetic vulnerabilities and novel therapeutic targets
for this tumor entity. Here, we successfully generated a chemical library thatshows preferential activity in AT/RT cell lines, thereby validating our CRISPR
approach to identify tumor-specific vulnerabilities. Of note, none of the identified dependencies seemed to be subgroup-specific, suggesting that targets
identified here can be used as pan-AT/RT therapeutic avenues. Among others,
these include inhibition of EGF signaling and CDK4/6. Our data provide acomprehensive map of dependencies for AT/RTs which will serve as a starting
point in the development of targeted therapies for this tumor entity.
ATRT-33. ENABLING RAPID CLASSIFICATION OF ATRT WITH
NANOSTRING NCOUNTER PLATFORM
Ben Ho1,2, Anthony Arnoldo3, Yvonne Zhong4, Mei Lu5,2,Jonathon Torchia6, Fupan Yao2,7, Cynthia Hawkins2,4, and Annie Huang5,2;
1Department of Laboratory Medicine and Pathobiology, Faculty of
Medicine, University of Toronto, Toronto, ON, Canada, 2Arthur andSonia Labatt Brain Tumour Research Centre, The Hospital for Sickiii282

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De c e mb e r 2 0 2 0Children, Toronto, ON, Canada, 3Department of Laboratory Medicine
and Pathobiology, Faculty of Medicine, Toronto, ON, Canada, 4Divisionof Pathology, Department of Pediatric Laboratory Medicine, Hospital for
Sick Children, Toronto, ON, Canada, 5Division of Hematology/Oncology,
Dept, of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada,
6Genome Sequence Informatics, Ontario Institute for Cancer Research,
Toronto, ON, Canada, 7Department of Medical Biophysics, Faculty of
Medicine, University of Toronto, Toronto, ON, Canada
In recent years, using gene expression and methylation array platform,
multiple research groups have reported the presence of at least three major
Atypical Teratoid Rhabdoid Tumor (ATRT) subtypes that exhibit distinct
epigenetic, transcriptomic and clinical features. Yet, utilizing ATRT subtypes
in a clinical setting remains challenging due to a lack of suitable biologicalmarkers, limited sample quantities and relatively high cost of current assays.
To address this gap between research and clinical practice, we have designed
an assay that utilizes a custom 35 signature genes panel for the NanoStringnCounter System and have created a flexible machine learning classifier
package for ATRT tumour subtyping. We have analyzed 71 ATRT primary
tumours with matching gene expression data using the 35 genes panel. 60%of the data was used for models training (10 repeats of 10-fold cross validation with subgroup balanced sample splitting) resulting in overall 94.6%
training accuracy. The remaining 40% of the samples were used for model
validation and the assay was able to achieve 92–100% accuracy with no
subgroup bias. To demonstrate the flexibility of the workflow, we have tested
it against other transcriptome-based methods such as gene expression array
and RNASeq. We have also demonstrated its use in samples that were notclassifiable by methylation-based method. We are presenting here a rapid
and accurate ATRT subtyping assay for clinical usage that is compatible
with archived ATRT tissues.

COVID-19 AND PEDIATRIC NEURO-ONCOLOGY
COVD-01. VINBLASTINE MONOTHERAPY INDUCTION FOR
LOCALISED CNS GERMINOMA DURING THE COVID-19
PANDEMIC
Rafael Moleron1, Sara Stoneham2, Thankamma Ajithkumar3, Justin Cross3,
James Nicholson3, and Matthew Murray3,4; Aberdeen Royal Infirmary,
Aberdeen, United Kingdom, 2University College Hospital London, London,
United Kingdom, 3Cambridge University Hospitals NHS Foundation
Trust, Cambridge, United Kingdom, 4University of Cambridge, Cambridge,
United Kingdom
INTRODUCTION: Patients with localised CNS-germinoma have excellent
survival. More recently, intensive inpatient chemotherapy (carboPEI=carboplatin/
etoposide/ifosfamide in Europe) has been effectively employed to reduce radiotherapy fields and/or dose. Current research priorities focus on reducing treatment burden and long-term sequelae. Of note, outpatient-based single-agent
carboplatin chemotherapy is associated with excellent outcomes in metastatic
testicular seminoma (an identical pathology) [Alifrangis,EJC,2020]. Recently,
successful vinblastine monotherapy was reported in localised CNS-germinoma[Murray,Neurooncol-Adv,2020]. METHODS: Due to the COVID-19 pandemic, adapted UK guidelines for germ-cell-tumour management were distributed, including potential non-standard treatment options that would
reduce hospital visits/admissions. A 30-year-old patient presented with a
32mmx30mmx35mm diameter solid+multi-cystic localised pineal CNS lesion,consistent radiologically with a germ-cell-tumour with prominent teratoma
component. Investigation revealed negative AFP/HCG markers and biopsyproven pure germinoma. After appropriate consent, the patient commenced
12-week induction with weekly vinblastine monotherapy (low-grade-glioma
dosing [Lassaletta,JCO,2016]), with wk6&12 MRI re-assessment prior to definitive radiotherapy. RESULTS: Vinblastine was well-tolerated. After initial
4mg/m2 test-dosing (wk1), standard 6mg/m2 was delivered for wk2, but resulted in asymptomatic neutropenia (nadir 0.3x10^9/l) and missed dosing at
wk3. Subsequent doses were 4mg/m2, with no further neutropenia. As expected,
MRI showed moderate 40% tumour volume reduction by wk12. Surgical resection of the residual presumed teratoma component was undertaken prior toradiotherapy. CONCLUSION: Patients with CNS-germinoma have excellent
outcomes and reduction of treatment-effects remains a priority. The exquisite
chemosensitivity of germinoma, excellent results from monotherapy for metastatic testicular disease, and early promise of vinblastine monotherapy lend itself
to further exploration for CNS-germinoma.
COVD-02. COVID-19 AND CHILDHOOD CANCER CARE THEMATIC ANALYSIS OF PUBLISHED SCIENTIFIC AND CLINICAL
LITERATURE
Chris Barton; NHS, Liverpool, United Kingdom
INTRODUCTION: The SARS-CoV-2 pandemic has affected modern
medicine and healthcare provision profoundly. National and regional ex-Abstracts

periences with COVID-19 have been hugely variable across the globe, reflecting ethnic, governmental, cultural, economic and healthcare differences.
This thematic analysis was performed to identify scientific and clinical literature relating to the impact of COVID-19 on children with cancer andtreatment. METHODS: The NHS Evidence portal was used to conduct a
healthcare database advanced literature search. Duplicates were removed.
Remaining results were screened using clear inclusion and exclusion criteria. RESULTS: 172 results were identified and data extracted. Literature
was identified from all 5 continents, with lower and middle income countries well represented. Key themes identified included: 1: Impact on patientsalready diagnosed, including decreased treatment regimens, impact on outpatient clinics, COVID susceptibility and travel restrictions; 2: Delays inpresentation and diagnosis, and national screening programs; 3: The impact
of COVID on healthcare professionals; 4: Impact on current and future research; 5: Consequence of global economic crisis on childhood cancer care;
6: Impact on long-term survivorship, late effects and surveillance monitoring. CONCLUSION: COVID-19 has had a profound effect on healthcare, and the literature reflects the extent to which communities involved inchildhood cancer care have worked together to minimise the impact. It is inevitable that there have been consequences of the pandemic on the treatmentof existing patients, and the diagnosis of new ones, but evidence suggest
these effects in the short term are minimal. The greatest concerns are for
immediate and short-term research conduct.
COVD-03. IMPACT OF COVID-19 ON THERAPY PROVISION FOR
CHILDREN WITH CNS TUMOURS
Helen Hartley, Barry Pizer, Ram Kumar, Joanne Owen, Helen Paisley, andAmillie White; Alder Hey Children’s NHS Foundation Trust, Liverpool,
United Kingdom
INTRODUCTION: The COVID-19 pandemic has led to widespreadchange in the delivery of rehabilitation. The Teenage Cancer Trust reported that 69% of young people with cancer saw their physiotherapist
less than usual during the pandemic raising concerns about physiotherapy
input. METHODS: Retrospective analysis of all children’s therapy input
managed under the Neuro Oncology Rehabilitation Team (NORT) between 1st April and 30th July 2020. Descriptive analysis of change to physiotherapy provision during this time period by Tertiary and local community
services. RESULTS: 49 children were managed under the NORT Therapy
Team during this timeframe. 9 children were newly diagnosed with CNS tumours. There was no impact on inpatient therapy provision, 3 had delayed
local therapy provision on discharge requiring increased virtual input by
the Tertiary centre. 40 children were outpatients managed under the NORT
therapy team. 16 children were also receiving regular local physiotherapy
input prior to the COVID-19 pandemic. 13 of these children subsequently
had their local physiotherapy input suspended during this time period, 8
children were offered virtual input as an alternative by the Tertiary centre, 2
children received increased face to face appointments at the Tertiary centre.
14 of the 24 children managed solely under the Tertiary NORT Therapy
Team changed to virtual therapy reviews. DISCUSSION: There is a clear
change in therapy provision as a result of the COVID-19 pandemic. Future
research should consider the effectiveness of neurorehabilitation conductedvirtually and the impact on physical function of reduced local therapy provision in children with CNS tumours.
COVD-04. CHARACTERISTICS OF SARS-COV-2 IN 64 CHILDRENWITH CNS TUMORS: A REPORT FROM THE SIOP/ST. JUDECHILDREN’S RESEARCH HOSPITAL (SJCRH) GLOBAL COVID-19
CHILDHOOD CANCER REGISTRY
Daniel Moreira1, Eric Bouffet2, Nickhill Bhakta1, Guillermo Chantada3,
Yichen Chen1, Lane Faughnan1, Yuvanesh Vedaraju1,
Maghana Avula1, Maysam Homsi1, Paula Naidu1, Andrew Pappas1,
Radhikesh Ranadive1, Victor Santana1, Michael Sullivan4, Lorena Baroni3,
Miguela Caniza1, Meenakshi Devidas1, Kathy Pritchard-Jones5,
Carlos Rodriguez-Galindo1, and Sheena Mukkada1; 1St. Jude Children’s
Research Hospital, Memphis, TN, USA, 2The Hospital for Sick Children,
Toronto, ON, Canada, 3Hospital de Pediatría S.A.M.I.C. Prof Dr Juan P
Garrahan, Buenos Aires, Argentina, 5Royal Hospital for Sick Children,
Melbourne, Australia, 5UCL Great Ormond Street Institute of Child
Health, London, United Kingdom
BACKGROUND: The GCCCR is a collaboration between SIOP andSJCRH to describe the natural history of SARS-CoV-2 in children withcancer across the world. METHODS: The GCCCR is a deidentified registryof patients <19 years of age with cancer or recipients of a hematopoietic stem
cell transplant and laboratory-confirmed SARS-CoV-2 infection. Demographic data, cancer diagnosis, cancer-directed therapy, and clinical characteristics of SARS-CoV-2 infection were collected. Outcomes were collected
at 30-days and 60-days post infection. RESULTS: As of August 10th 2020,
the GCCCR included 730 cases from 35 countries, including 64 children
with CNS tumors (8.8%) from 17 countries. The most frequent diagnoses

were embryonal tumors (31.2%) and low-grade glioma (17.2%). Thirtynine (60.9%) children were asymptomatic from infection, while 19 (29.7%)
patients required hospital admission and 2 (6.3%) transferred to the intensive care unit. There was a significant association between infection severity
and ANC <500 (p=0.04). At the time of infection, 44 (68.8%) patientswere undergoing cancer-directed therapy. Thirty-two cases have follow-up
data. No modification in cancer-directed therapy occurred in 11 (34.4%)
patients, while chemotherapy was modified in 6 (18.8%), radiotherapy delayed in 2 (6.3%), and surgery postponed in 1 (3.1%). No patients diedfrom SARS-CoV-2 infection, although 2 died from non-COVID-19 relatedcauses. CONCLUSION: The frequency and severity of COVID infection
among children with CNS tumors appears to be proportionally lower compared to other children with cancer. Although this is the largest cohort ofpatients reported to date, additional insight is needed, including the effectsof treatment modifications on outcomes.

DRUG DELIVERY/PHARMACOKINETICS
DDEL-01. ENHANCING DRUG DELIVERY WITH MRGFUS FORDIFFUSE INTRINSIC PONTINE GLIOMA MODEL
Joji Ishida1, Saira Alli1, Andrew Bondoc1, Brian Golbourn1, Nesrin Sabha2,
Kristina Mikloska3, Dilakshan Srikanthan1, Amanda Luck1,
Christian Smith1, Kullervo Hynynen3, and James Rutka1; 1Division of
Neurosurgery, the Arthur and Sonia Labatt Brain Tumor Research Centre,
The Hospital For Sick Children, Toronto, ON, Canada, 2Genetics andGenome Biology, The Hospital for Sick Children, Toronto, ON, Canada,
3Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON,
CanadaDiffuse intrinsic pontine glioma (DIPG) is a surgically unresectableand devasting tumor in children. To date, there have been no effective
chemotherapeutics despite a myriad of clinical trials. The intact bloodbrain barrier (BBB) in part is responsible for the limited clinical responseto chemotherapy. MRI guided focused ultrasound (MRgFUS) is a promising non-invasive tissue ablative method for CNS tumors. Moreover,
MRgFUS allows for the temporary disruption of BBB. Our first objective
was to determine the feasibility and safety of temporary BBB disruption
within the brainstem using MRgFUS following intravenous (IV) administration of microbubbles in vivo. Our second objective was to select effective
chemotherapeutics against DIPG cell lines, and to examine their therapeutic
effects with MRgFUS in a mouse model of DIPG which exhibits an intact
BBB. The non-invasive opening of the BBB was determined in the brainstem of normal rodents using physiological monitoring and histologicalanalysis. Doxorubicin was selected from a drug screen consisting of conventional chemotherapeutics using SU-DIPG4 and SU-DIPG17 cell lines. We
established SU-DIPG17 xenografts which demonstrated diffusely infiltrative
tumor growth similar to human DIPG. By LC-MS/MS analysis, MRgFUS
led to a 4-fold increase in doxorubicin concentrations within the brainstem
tumors following IV administration when compared to IV administration
alone, We demonstrated feasibility and safety of MRgFUS in the rodent
brainstem and have shown that MRgFUS increases doxorubicin uptake
in the brainstem of a rodent model of DIPG. These preclinical data will
be helpful in designing clinical trials of BBB disruption using MRgFUS for
DIPG in children.
DDEL-02. DECREASED TOXICITY OF CONVENTIONAL DOSECHEMOTHERAPY UTILIZING BODY WEIGHT INSTEAD OF BODY
SURFACE AREA FOR DOSING IN YOUNG CHILDREN <6 YEARSOLD ENROLLED ON THE “HEAD START” 4 CLINICAL TRIAL
Girish Dhall1, Ziad Khatib2, Ossama Maher2, Megan Blue3,
Myeshia Harmon3, Parth Patel3, and Jonathan Finlay3; 1University of
Alabama at Birmingham, Birmingham, AL, USA, 2Nicklaus Children’s
Hospital, Miami, FL, USA, 3Nationwide Children’s Hospital, Columbus,
OH, USA
Metabolism of drugs in infants and young children is significantly different from older individuals due to differences in distribution, proteinbinding capacity, hepatic metabolism and renal excretion. To be consistent
with Children’s Oncology Group (COG) guidelines, body surface area (BSA)
was used to dose chemotherapeutics in children >3 years old enrolled on“Head Start” 4 clinical trial (HS 4). Four of 30 patients enrolled on HS 4
developed sinusoidal obstruction syndrome (SOS) while receiving induction
chemotherapy with cisplatin, etoposide, vincristine, cyclophosphamide andhigh-dose methotrexate using BSA for dosing (mg/m2). Patients #1 and #2
were both 2-years old at diagnosis, received and tolerated the first two cycles
with mg/kg dosing uneventfully, then turned 3-years old and received cycle#3 with mg/m2 dosing as per protocol guidelines, and developed SOS. Patient #3 was 3-years old at diagnosis, received induction chemotherapy with
mg/m2 dosing, and developed SOS during the very first cycle. Patient #4

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Abstracts

was 4-years old at diagnosis and received all 3 induction cycles with mg/m2
dosing, developed serious nephrotoxicity during cycle #1 followed by SOS
during cycle #3. The HS 4 trial was amended and reopened after external,
independent Data Safety Monitoring Board review to dose all chemotherapy
drugs in children <6 years old with mg/kg dosing instead of BSA. None of
75 patients enrolled since the amendment developed SOS during induction.
These data suggest using caution while dosing young children <6 years ofage with intensive induction chemotherapy by BSA.
DDEL-03. LONG-TERM INTRAVENTRICULAR THERAPY
ALTERNATING ETOPOSIDE AND LIPOSOMAL CYTARABINE:
EXPERIENCE IN 75 CHILDREN AND ADOLESCENTS WITH
MALIGNANT BRAIN TUMORS
Natalia Stepien1, Andreas Peyrl1, Amedeo Azizi1, Johannes Gojo1,
Lisa Mayr1, Dominik Reisinger1, Christine Haberler2, Thomas Czech3,
and Irene Slavc1; 1Medical University of Vienna, Department of Pediatrics
and Adolescent Medicine, Vienna, Austria, 2Medical University of Vienna,
Institute of Neurology, Vienna, Austria, 3Medical University of Vienna,
Department of Neurosurgery, Vienna, Austria
BACKGROUND: Malignant brain tumors of childhood carry a high risk
for leptomeningeal dissemination and tumor cells floating in the CSF areoften not amenable to systemic and/or antiangiogenic chemotherapy. We
report on our experience with an intraventricular therapy consisting of alternating cycles of liposomal cytarabine and etoposide. PATIENTS AND
METHODS: Between 2004 and 2017, 75 patients aged 0.6 to 22 years(median 11) with various malignant brain tumors received intraventricularetoposide 0.25mg (<1year) - 0.5mg on five consecutive days alternatingwith liposomal cytarabine at a dose of 25mg (<3 years) - 50mg via an
Ommaya reservoir. RESULTS: 5533 doses of etoposide (5–277/patient,median 141) corresponding to 1–56 five-day-cycles/patient alternating with
534 doses of liposomal cytarabine (1–21/patient, median 11) were administered. Treatment was given over a period of 1 – 146 months (median 73.5).
Toxicities did occur but were infrequent and mostly mild. Since all patients
received some sort of concurrent anti-cancer therapy, the efficacy of intrathecal therapy cannot be assessed independently. However, 29/75 patientsare still alive, and none of the patients had tumor cells in the CSF at theirlast evaluation. CONCLUSION: In conclusion, alternating intraventricularliposomal cytarabine and etoposide produced responses and proved to be
an important adjunct for patients receiving drugs with a low penetrance
into the CSF. Since production of liposomal cytarabine was discontinued in2017 it remains to be determined whether substitution of the slow releaseformulation by aqueous cytarabine on days 1, 4, 8, and 11 may produce
similar results.
DDEL-04. ENGINEERED NANOCARRIERS TO ENHANCE DRUG
DELIVERY ACROSS THE BLOOD-BRAIN BARRIER
Joelle P. Straehla1,2, Cynthia Hajal3, Hannah Safford2, Giovanni Offeddu4,
Jeffrey Wyckoff2, Roger D Kamm3,4, and Paula T Hammond2,5; 1DanaFarber/Boston Children’s Cancer and Blood Disorders Center, Boston,
MA, USA, 2Koch Institute for Integrative Cancer Research, Massachusetts
Institute of Technology, Cambridge, MA, USA, 3Mechanical Engineering,
Massachusetts Institute of Technology, Cambridge, MA, USA, 4Biologic
Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA,
5Chemical Engineering, Massachusetts Institute of Technology, Cambridge,
MA, USA
Pediatric central nervous system tumors are the leading cause of cancer
death in children. Promising therapeutics have been identified, but the ability
to deliver an effective concentration to the tumor without causing excessive
systemic toxicity remains a challenge. To address this, we leveraged a tunable
nanocarrier platform to design a brain-penetrant nanocarrier with preferential uptake into tumor cells over healthy brain cells. First, we used the layerby-layer technique to iteratively coat liposomes with nanometers-thick layersof oppositely charged polyelectrolytes. To investigate the influence of surface chemistry on cellular trafficking, a panel of layered liposomes was tested
for interactions with cancer cell lines, identifying poly-L-aspartic acid andhyaluronic acid as the highest-performing formulations across brain tumorlines. To facilitate nanocarrier transit across the blood-brain barrier (BBB),
we developed a click chemistry platform to functionalize the nanocarrier
with BBB shuttle ligands. To investigate trafficking in vitro, we utilized amicrofluidic brain microvascular model comprising endothelial cells, astrocytes, pericytes, and glioma cells that self-assemble into a perfusable vascular
network. We found that nanocarrier size influenced vascular transport, andthe addition of BBB shuttle ligands improved transport in the presence of aglioma spheroid. To investigate in vivo nanocarrier trafficking, we performed
intravital imaging through a cranial window in anesthetized mice. After intravenous administration, nanocarrier transit across intact brain capillaries was
visualized using two photon microscopy, and vessel permeability was quantified over time. Ongoing studies in mice bearing patient-derived xenograft
medulloblastoma and glioma tumors are being conducted to further characterize trafficking across tumor-associated vasculature.

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DDEL-05. BLOOD-BRAIN BARRIER DISRUPTION AND ENHANCEDRADIOSENSITIZERS EXTRAVASATION UPON FOCUSEDULTRASOUND FOR TREATMENT OF DIFFUSE INTRINSICPONTINE GLIOMA
Elvin ‘t Hart1, Marc Derieppe1, Maaike Bruin2, Helena Besse3,
Rianne Haumann4, Eelco Hoving1, Alwin Huitema3,2, Mario Ries3, andDannis van Vuurden1; 1Princess Máxima Center for Pediatric Oncology,
Utrecht, Netherlands, 2The Netherlands Cancer Institute, Amsterdam,
Netherlands, 3University Medical Center Utrecht, Utrecht, Netherlands,
4Amsterdam University Medical Center Location VU Medical Center,
Amsterdam, Netherlands
Poor prognosis of diffuse midline glioma, including diffuse intrinsic pontine glioma (DIPG), reflects the low efficacy of current treatment strategies,
mainly due to (1) a largely intact blood-brain barrier (BBB) and (2) the
proficiency of tumour tissues to upregulate multiple DNA repair genes, resulting into radio-resistance. In vitro studies showed therapeutic benefit bycombining radiotherapy and radiosensitizers, while pre-clinical and clinicalstudies evidenced safe and transient opening of the BBB using microbubble
mediated focused ultrasound (FUS). Previously, we demonstrated the enhanced extravasation of olaparib, a poly(ADP-ribose) polymerase (PARP)
inhibitor in the mouse pons. Local drug delivery was applied using an
in-house built X-ray image-guided FUS system with a 1 MHz mono-elementtransducer delivering a tone-burst pulse with a mechanical index of 0.4.
Tissue/blood drug concentrations were analysed by LC-MS/MS, 30 minutes after intraperitoneal injection of 10 mg/kg olaparib. The FUS systemallowed for precise treatment of the pons, proven by local extravasation ofEvans Blue-conjugated albumin. A significant 5.1 fold median increase wasobserved in absolute concentrations in the pons after FUS intervention compared to the control and a 4.9 fold increase of the median tissue-blood ratio(*p<0.05). No significant differences were detected in brain regions outside
the ultrasound focus and other organs, confirming the local intervention.
With this, the 299 nM equivalent olaparib concentration found in the pons
will facilitate PARP inhibition in future murine patient-derived xenograft
tumour models, thus leading to a greater therapeutic effect when in combination with radiotherapy treatment of DIPG.
DDEL-06. DRUG INTERACTION BETWEEN EVEROLIMUS AND
CANNABIDIOL IN PEDIATRIC PATIENTS WITH SUBEPENDYMAL
GIANT CELL ASTROCYTOMAS: A SINGLE INSTITUTION
EXPERIENCE
Ashley Sabus1, Shelby Winzent2,1, Molly Hemenway2,1,Jean Mulcahy Levy2,1, and Nicholas Foreman2,3; 1Children’s Hospital
Colorado, Aurora, CO, USA, 2University of Colorado, Denver, CO, USA,
3Children’s Hospital Colorado, Denver, CO, USA
Tuberous sclerosis complex (TSC) is an autosomal recessive genetic disorder associated with clinical manifestations including subependymal giant
cell astrocytomas (SEGA) and seizures. The combination of everolimus
and Epidiolex, a purified form of cannabidiol, has become an increasingly common treatment regimen in this population. Everolimus is primarily metabolized via CYP3A4, which may be inhibited by cannabidiol.
We seek to describe our institution’s experience with this drug interaction.
METHODS: Investigators conducted a retrospective review of neurooncology patients with TSC and SEGA who were treated concurrently witheverolimus and cannabidiol. Data collected included demographics, bodysurface area, everolimus dose, everolimus troughs, date of cannabidiol initiation, documented symptoms, liver and renal function tests, and reason
for discontinuing therapy. RESULTS: Three patients (ages 11–17 years) met
inclusion criteria. All patients were stable on everolimus doses ranging from
6.5 to 9.5 mg/m2/day and achieving trough goals of 5–10 ng/mL. Two tofour weeks after initiating cannabidiol, everolimus trough concentrations
rose 200–860% above goal. One patient reported new-onset involuntary
movements, but no other toxicities were noted. Cannabidiol was discontinued in all cases due to caregiver concerns regarding drug interactions.
All patients were able to achieve goal trough concentrations on previously
stable doses of everolimus after discontinuing cannabidiol. CONCLUSIONS: Cannabidiol appears to modulate everolimus metabolism leading tosignificantly elevated serum concentrations. Additional research is required
to determine the need for empiric dose adjustments upon cannabidiol initiation. Patient counseling, frequent trough monitoring, and surveillance foradverse effects are crucial for optimizing outcomes in patients prescribed
this regimen.
DDEL-07. A PHASE I STUDY EXAMINING THE FEASIBILITY OF
INTERMITTENT CONVECTION-ENHANCED DELIVERY (CED)OF MTX110 FOR THE TREATMENT OF CHILDREN WITH NEWLYDIAGNOSED DIFFUSE MIDLINE GLIOMAS
Stergios Zacharoulis1, Luca Szalontay1, Dominic Higgins1,
Zachary Englander1, ZhenZhen Jin1, James Garvin1,
Rebecca Zylber1, Eileen Stark1, Alexis Maddocks1,
Chankrit Sethi1, Peter Canoll1, Steve Dammnett2, Craig Cook2,

Abstracts

Neil Feldstein1, and Jeffrey Bruce1; 1Columbia University Medical Center,
New York, NY, USA, 2Midatech, Cardiff, United Kingdom
Convection-enhanced delivery (CED, the infusion of drugs under controlled pressure to the brain parenchyma via targeted micro-catheters, allows accurate anatomical targeting and delivery of higher (therapeutic)
drug concentrations through clinically relevant volumes of brain tissue ortumor. Histone deacetylase inhibitors have been found in vitro to be themost active agents against Diffuse Midline Gliomas (DMGs) Using a novel
device (implantable subcutaneous pump connected with catheter directly
implanted into the pons/thalamus) we are performing a Phase I safety studyof repeated infusions of MTX110 (MTX110, Midatech) in a dose escalation manner. Eligible patients include 3–18 years of age with newly diagnosed DMGs following radiation therapy without evidence of hemorrhage
or cysts with intact organ function. Patients undergo a tumor biopsy anda single catheter (Spetzler lumbar shunt catheter, Integra, Plainsboro, NJ)
is placed stereotactically into the geometric center of the tumor. A second
catheter is inserted subcutaneously with the distal tubing connected to theinfusion pump, (SynchroMed II (Medtronic)), also inserted subcutaneously.
The infusion pump is prefilled with MTX110 and administered using wireless N’Vison Clinical programmer into two 24-hour infusions, consisting of
20 hours of drug infusions at 0.2mL/hr. The pulse is completed 7 days later.
This is a dose escalation study with the infusate consisting of gadolinium
and MTX110 (30, 60, or 90 microM). The study describing the first use inchildren of this device for direct-to-tumor drug delivery is open to recruitment (January 2020) and the preliminary data will be available for presentation by June 2020.
DDEL-08. CONVECTION-ENHANCED DELIVERY OF NIMUSTINEHYDROCHLORIDE (ACNU) AGAINST PEDIATRIC DIFFUSE
INTRINSIC PONTINE GLIOMAS
Ryuta Saito, Masayuki Kanamori, and Teiji Tominaga; Department of
Neurosurgery, Tohoku University, Sendai, Miyagi, Japan
Diffuse intrinsic pontine gliomas (DIPGs) are amongst the most challenging tumors to treat. Surgery is not an option, the effects of radiation
therapy are temporary, and no chemotherapeutic agent has demonstrated
significant efficacy. Intracerebral infusion technique of convection-enhanced
delivery (CED) for patients with brain tumors could offer a novel approachfor effective chemotherapy. We have been working to develop an effective
chemotherapy using nimustine hydrochloride (ACNU) with this drug delivery method. After several studies targeting supratentorial recurrent malignant gliomas and recurrent gliomas affecting brainstem, we conducted
phase 1 study to evaluate the safety of combination of convection-enhanced
delivery of nimustine hydrochloride and systemic temozolomide againstrecurrent gliomas affecting brainstem. In this study, we demonstrated thesafety and feasibility of CED of ACNU as well as real time monitoring ofdrug distribution by mixing ACNU with contrast agent; Gd-DOTA. We also
defined the maximum tolerable concentration in this study and proceededto phase 2 trial against recurrent gliomas affecting brain stem. However,these trials revealed the difficulty of treating pediatric DIPG at the time ofrecurrence. Therefore, we decided to treat pediatric DIPG cases at their initial diagnosis in the subsequent study. Aiming at obtaining Shonin approval
both for intraparenchymal infusion catheter and drug to infuse into brain
parenchyma, we are now conducting Phase II physician-led trial against initially diagnosed pediatric DIPG cases.
DDEL-09. HIGH DOSE MTX110 (SOLUBLE PANOBINOSTAT)SAFELY ADMINISTERED INTO THE FOURTH VENTRICLE IN
A NON-HUMAN PRIMATE MODEL
Rachael W. Sirianni1, Natasha Kharas1, Bangning Yu1,
Christopher F. Janssen1, Amanda Trimble1, Leomar Y. Ballester1,
Rajan Patel1, Afroz S. Mohammad2, William F. Elmquist2, andDavid I. Sandberg1; 1University of Texas Health Science Center at Houston,
Houston, TX, USA, 2University of Minnesota, Minneapolis, MN, USA
OBJECTIVE: This study tested the safety and pharmacokinetics of shortterm and long-term administration of MTX110 (soluble panobinostat;
Midatech Pharma, UK) into the fourth ventricle of non-human primates. METHODS: Four rhesus macaque monkeys underwent posterior
fossa craniectomy and catheter insertion into the fourth ventricle. In GroupI (n=2), catheters were externalized and lumbar drain catheters were placed
simultaneously to assess cerebrospinal fluid (CSF) distribution after shortterm infusions. MTX110 (0.5 ml of 300 μM panobinostat solution) was
infused into the fourth ventricle daily for five consecutive days. Serial CSF
and serum panobinostat levels were measured. In Group II (n=2), fourth
ventricle catheters were connected to a subcutaneously-placed port for subsequent long-term infusions. Four cycles of MTX110, each consisting of 5
daily infusions (0.5 ml of 300 μM panobinostat solution), were administeredover 8 weeks. Animals underwent detailed neurological evaluations, MRI
scans, and post-mortem histological analysis. RESULTS: Neurological as-

sessments, MRI, and histology confirmed catheter placement and an absenceof neurotoxicity. Panobinostat was undetectable in serum collected two andfour hours after infusions in all samples in both groups. In Group I, mean
peak panobinostat level in fourth ventricle CSF (6242 ng/ml) was significantly higher than in lumbar CSF (9 ng/ml; p < 0.0001). In Group II, mean
peak CSF panobinostat level (11,042 ng/ml) was significantly higher than
mean trough CSF level (33 ng/ml; p<0.0001). CONCLUSION: MTX110
can be safely delivered via 4th ventricle at supra-therapeutic doses. These
results provide data for a pilot clinical trial in patients with recurrent
medulloblastoma.
DDEL-10. A NANOPARTICLE PLATFORM FOR INTRATHECALDELIVERY OF THE HISTONE DEACETYLASE INHIBITOR(HDACI) PANOBINOSTAT IN METASTATIC OR RECURRENTMEDULLOBLASTOMA
Sauradip Chaudhuri1, Afroz S. Mohammad2, Wenqui Zhang2,
Cassandra Baker1, Colton W. Broughton1, Martha J. Fowler1,
Sarah E. Stabenfeldt3, Robert J. Wechsler-Reya4, David I. Sandberg1,
William F. Elmquist2, and Rachael W. Sirianni1; 1University of Texas Health
Science Center at Houston, Houston, TX, USA, 2University of Minnesota,
Minneapolis, MN, USA, 3Arizona State University, Tempe, AZ, USA,
4Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
INTRODUCTION: Panobinostat is a histone deacetylase inhibitor (HDACi) that is a clinical candidate for treatment of pediatricmedulloblastoma and diffuse intrinsic pontine glioma. Panobinostat ispoorly water-soluble and experiences a number of barriers to effective
delivery. Here, we developed a novel drug delivery system consisting of
β-cyclodextrin-poly(β-amino ester). These cyclodextrin-networks (CDNs)
self-assemble into nanoparticles encapsulating a high quantity of HDACi
for slow release. We sought to test the hypothesis that panobinostat-loaded
CDNs would demonstrate a differentiated pharmacokinetic profile compared to free panobinostat in mice after direct administration to cerebrospinal fluid. METHODS: CDNs were synthesized via Michael addition andengineered to encapsulate a library of HDACi drugs. Nanoparticles werecharacterized for size, surface charge, loading, controlled release, and stability. CDNs or fluorescent surrogate nanoparticles were administered to thecisterna magna of mice. Tissues were collected for LC-MS/MS (pharmacokinetics [PK]: 1, 4, 8, 24, and 48 hrs) or microscopy (localization: 2, 6, 24,
and 48 hrs, 1 and 3 wks). RESULTS: Intravital and confocal microscopy
demonstrate that nanoparticles distribute rapidly in subarachnoid spaceand can localize with metastases, persisting for > 3 weeks. Nanoparticle
panobinostat is released over weeks and is better tolerated than free drug.
CDN-panobinostat delivery tended to be higher in the cerebellum and lower
in the spinal cord at both early and late time points compared to freely administered drug. CONCLUSIONS: We present a nanoparticle platform for
HDACi delivery with a differentiated PK profile in the CSF compared to free
drug. Additional PK and therapeutic studies are ongoing.
DDEL-11. CONVECTION-ENHANCED DELIVERY OF EZH2
INHIBITOR FOR THE TREATMENT OF DIFFUSE INTRINSICPONTINE GLIOMA
Takahiro Sasaki1, Hiroaki Katagi1, Stewart Goldman2, Oren Becher2,
and Rintaro Hashizume1; 1Department of Neurological Surgery, Feinberg
School of Medicine, Northwestern University, Chicago, IL, USA,
2Division of Hematology, Oncology and Stem Cell Transplantation in the
Department of Pediatrics, Feinberg School of Medicine, Northwestern
University, Chicago, IL, USA
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brain tumor and the majority of patients die within 2 years after initialdiagnosis. Factors that contribute to the dismal prognosis of these patients
include the infiltrative nature and anatomic location in an eloquent area ofthe brain, which precludes total surgical resection, and the presence of theblood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion
technique to deliver therapeutic agents into a target site in the brain and able
to deliver a high concentration drug to the infusion site without systemic
toxicities. OBJECTIVE: This study aims to assess the efficacy of enhancer ofzeste homolog-2 (EZH2) inhibitor by CED against human DIPG xenograftmodels. METHODS: The concentration of EZH2 inhibitor (EPZ-6438) inthe brainstem tumor was evaluated by liquid chromatography–mass spectrometry (LC/MS). We treated mice bearing human DIPG xenografts with
EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence image and thetherapeutic response was evaluated by animal survival. RESULTS: LC/
MS analysis showed that the concentration of EPZ-6438 in the brainstem
tumor was 3.74% of serum concentration after systemic administration.
CED of EPZ-6438 suppressed tumor growth and significantly extended
animal survival when compared to systemic administration of EPZ-6438(P=0.0475). CONCLUSION: Our results indicate that CED of an EZH2 in-

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hibitor is a promising strategy to bypass the BBB and to increase the efficacy
of an EZH2 inhibitor for the treatment of DIPG.
DDEL-12. NANOPARTICLE DELIVERY OF DOXORUBICIN FOR THE
TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Caitlin Ung1, Maria Tsoli1, Jie Liu1, Domenico Cassano1, Dannielle Upton1,
Anahid Ehteda1, Friederike Mansfield1,2, Tim Failes3, Maria Kavallaris1,2,
Greg Arndt3, Orazio Vittorio1,2, Valerio Voliani4, Giuseppe Cirilo5, andDavid S. Ziegler1,6; 1Children’s Cancer Institute, Lowy Cancer ResearchCentre, University of New South Wales, Sydney, NSW, Australia, 2ARC
Centre of Excellence in Bio-Nano Science and Technology Australian
Centre for NanoMedicine, UNSW, Sydney, NSW, Australia, 3ACRF Drug
Discovery Centre, Children’s Cancer Institute, Lowy Cancer ResearchCentre, University of New South Wales, Sydney, NSW, Australia, 4Centre
for Nanotechnology Innovation, Instituto Italiano di Technologia, Pisa,
Italy, 5Department of Pharmacy Health and Nutritional Science, Universityof Calabria, Calabria, Italy, 6Kids Cancer Centre, Sydney Children’s
Hospital, Randwick, NSW, Australia
DIPGs are the most aggressive pediatric brain tumors. Currently, the only
treatment is irradiation but due to its palliative nature patients die within
12 months. Effective delivery of chemotherapy across the blood-brain barrier (BBB) has been a key challenge for the eradication of this disease. We
have developed a novel gold nanoparticle functionalised with human serum
albumin (Au-NP, 98.8 ±19 nm) for the delivery of doxorubicin. In thisstudy, we evaluated the cytotoxic efficacy of doxorubicin delivered throughgold nanoparticles (Au-NP-Dox). We found that DIPG neurospheres wereequally sensitive to doxorubicin and Au-NP-Dox (at equimolar concentration) by alamar blue assay. Colony formation assays demonstrated a significantly more potent effect of Au-NP-Dox compared to doxorubicin alone,while the Au-NP had no effect. Furthermore, western blot analysis indicatedincreased apoptotic markers cleaved Parp, caspase 3/7 and phosphorylated
H2AX in Au-NP-Dox treated DIPG neurospheres. Live cell content andconfocal imaging demonstrated significantly higher uptake of Au-NP-Dox
compared to doxorubicin alone. Treatment of a DIPG orthotopic mousemodel with Au-NP-Dox showed no signs of toxicity with stable weights
being maintained during treatment. However, in contrast to the above in
vitro findings the in vivo study showed no anti-tumor effect possibly due topoor penetration of Au-NP-Dox into the brain. We are currently evaluating
whether efficacy can be improved using measures to open the BBB transiently. This study highlights the need for rigorous in vivo testing of newtreatment strategies before clinical translation to reduce the risk of administration of ineffective treatments.
DDEL-13. FOCUSED ULTRASOUND MEDIATED BLOOD BRAINBARRIER DISRUPTION IN A MURINE MODEL OF PONTINEGLIOMA: A SAFETY AND FEASIBILITY STUDY
Zachary Englander1, Hong-Jian Wei2, Antonios Pouliopoulos3,
Pavan Upadhyayula1, Chia-Ing Jan4, Eleonora Spinazzi1, Peter Canoll4,
Jeffrey Bruce1, Neil Feldstein1, Stergios Zacharoulis5, Elisa Konofagou3,
and Cheng-Chia Wu2; 1Department of Neurosurgery, Columbia University
Medical Center, New York, NY, USA, 2Department of Radiation Oncology,
Columbia University Medical Center, New York, NY, USA, 3Departmentof Biomedical Engineering, Columbia University, New York, NY, USA,
4Department of Pathology, Columbia University Medical Center, New
York, NY, USA, 5Department of Pediatrics, Columbia University Medical
Center, New York, NY, USA
BACKGROUND: Drug delivery remains a major obstacle in DIPG, as
the blood brain barrier (BBB) limits the penetration of systemic therapies
to the brainstem. Focused ultrasound (FUS) is an exciting new technology
that, when combined with microbubbles, can open the BBB permitting theentry of drugs across the cerebrovasculature. Given that the utility of FUS
in brainstem tumors remains unknown, the purpose of our study was todetermine the safety and feasibility of this technique in a murine pontine
glioma model. METHODS: A syngeneic orthotopic model was establishedby stereotactic injection of PDGF-B+PTEN-/-p53-/- murine glioma cells(10,000/1ul) into the pons of B6 albino mice. A single-element, sphericalsegment FUS transducer (center frequency=1.5MHz) driven by a function
generator through a power amplifier (acoustic pressure=0.7MPa) was usedwith concurrent intravenous microbubble injection (FUS+MB) to sonicate
the tumor on post-injection day 14. BBB opening was confirmed withgadolinium-enhanced MRI and Evans blue. Kondziela inverted screen (KIS)
testing was completed to measure motor function. Mice were either immediately sacrificed for histopathological assessment or serially monitored forsurvival. RESULTS: In mice treated with FUS (n=11), there was no measured deficit in KIS testing. Additionally, the degree of intra-tumoral hemorrhage and inflammation on H&E in control (n=5) and treated mice (n=5)
was similar. Lastly, there was no difference in survival between the groups(control, n=6, median=26 days; FUS, n=6, median=25 days, p>0.05). CONCLUSION: FUS+MB is a safe and feasible technique to open the BBB in a
preclinical pontine glioma model.

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DDEL-14. SAFETY OF INTERVENTRICULAR METHOTREXATEADMINISTRATION FOLLOWING RADIATION IN PEDIATRICPATIENTS WITH MALIGNANT BRAIN TUMORS
Kristofer Rosales, Ossama Maher, Maggie Fader, Natalie Gallegos,
Toba Niazi, John Ragheb, and Ziad Khatib; Nicklaus Children’s Hospital,
Miami, Fl, USA
BACKGROUND: Methotrexate has been used for intrathecal administration in leukemia as well as embryonal CNS tumors in children. Concerns
about neurologic side effects including leukoencephalopathy, demyelination,and seizures have limited the use of methotrexate following exposure to focalradiation. OBJECTIVE: To evaluate and determine safety of Intraventricularadministration of Methotrexate in pediatric patients with recurrent malignant
brain tumors along with systemic Topotecan and Cyclophosphamide after exposure to prior radiation therapy. DESIGN/METHOD: Patients with recurrent
cerebellar embryonal tumors after standard treatment that included radiation
were enrolled on this IRB approved phase 2 study. An Ommaya reservoir
was inserted in the lateral ventricle and used to administer 4 daily doses ofmethotrexate (2 mg/dose) along with (Topotecan [0.75mg/m2/day] and Cyclophosphamide [250 mg/m2/day]). A neurological evaluation was performed atbaseline and daily during the intraventricular administration of the Methotrexate, this evaluation was repeated prior to each subsequent cycle and at completion of the protocol. RESULTS: Three patients (age range 3–20) received
2–3 cycles of intra-Ommaya Methotrexate and Topotecan/Cyclophosphamide.
No MRI demyelination or white matter changes were seen after completion of
the intraventricular Methotrexate therapy. None of the patients enrolled on thistrial had adverse effects related to the therapy regimen received. Clinical neurological status was unchanged during the entire course of the treatment and uponcompletion of the scheduled therapy. CONCLUSION: Intraventricular administration of daily low dose Methotrexate is well tolerated in children with recurrent embryonal CNS tumors who had prior exposure to radiation.
DDEL-15. NANOTHERAPEUTIC TARGETING OF TUMORENDOTHELIUM FOR ENHANCING DRUG DELIVERY PAST THE
BLOOD-BRAIN BARRIER
Hiro Kiguchi1, Daniel Tylawsky1, Jake Vaynshteyn2, Jeffrey Gerwin2,
Mandana Manzari1, Janki Shah1, Na Li3, Yosi Shamay1,
Matthew Greenblatt3, Daniel Heller1, and Praveen Raju2,1; 1Memorial
Sloan Kettering Cancer Center, New York, NY, USA, 2Icahn School of
Medicine at Mount Sinai, New York, NY, USA, 3Weill Cornell Medicine,
New York, NY, USA
OBJECTIVE: The Sonic Hedgehog (SHH) medulloblastoma subgroupaccounts for ~25% of all cases and has an intermediate prognosis. Current
therapies result in devastating morbidities including intellectual disability
and secondary malignancies. Although molecularly targeted agents against
the SHH pathway have demonstrated efficacy, on-target bone toxicities suggest new therapeutic approaches are needed. METHODS: We investigatedthe SHH pathway inhibitor, vismodegib, packaged in a fucoidan-based
nanoparticle (Fi-Vis) that targets P-selectin expressed on endothelial cells andinduced by low-dose ionizing radiation (XRT) in a time- and dose-dependent
manner. This P-selectin targeting nanoparticle shows selectivity toward tumor
and not normal brain vasculature in a GEM SHH medulloblastoma model asassessed by ex vivo infrared imaging and molecular studies. RESULTS: Quantitative RT-PCR analysis of SHH medulloblastoma following single dose XRTand Fi-Vis treatment (10mg/kg) showed synergistic reduction of Gli1 expression (>90% target inhibition). We demonstrate that low-dose XRT (0.25Gy)
can induce P-selectin expression specifically on medulloblastoma tumor endothelium and synergize with low-dose Fi-Vis (10mg/kg) to significantly enhancemouse survival (p<0.01) compared to radiation or Fi-Vis alone. Assessment ofbone toxicity using micro-CT and histological analysis following Fi-Vis administration in postnatal (P10) mice shows no bone toxicity when comparedto free vismodegib. Finally, in vitro studies using bEnd.3 brain endothelial
cells and in vivo studies using Cav1 knockout mice suggest a caveolin-1 mediated transcytosis mechanism for nanoparticle entry across the blood-brain
barrier. CONCLUSIONS: These data suggest applicability of combined XRTand tumor vasculature-targeted nanotherapeutic dose de-escalation strategies
for SHH medulloblastoma with implications for other pediatric brain tumors.
DDEL-16. UNDERSTANDING OPTIMAL CONVECTIONENHANCED DELIVERY PHYSICO-CHEMICAL INFUSIONPARAMETERS: THE ROLE OF BBB EFFLUX PUMPS IN DRUG
DISTRIBUTION AND CLEARANCE
Erica Power1,2, Liang Zhang2, and David Daniels2,3; 1Mayo Clinic
Graduate School of Biomedical Sciences, Rochester, MN, USA, 2Mayo
Clinic Department of Neurologic Surgery, Rochester, MN, USA, 3Mayo
Clinic Department of Molecular Pharmacology and Experimental
Therapeutics, Rochester, MN, USA
BACKGROUND: Diffuse midline gliomas harboring the H3K27M mutation are aggressive and universally fatal brain tumors that primarily occur inchildren. The blood-brain barrier (BBB) prevents many drugs from reachingAbstracts

the tumor at cytotoxic concentrations and efflux pumps found on the epithelial cells of the BBB rapidly pump drugs out of the brain. Convection
enhanced delivery (CED) is a drug delivery technique that bypasses the BBB
by directly injecting the drug into the tumor site under a pressure gradient.
Further clinical implementation of CED requires understanding drug distribution, as optimal drug physico-chemical properties have never been
evaluated. METHODS: Sprague Dawley rats underwent a single injectionof drug by CED to the brainstem with and without an efflux pump inhibitor.
Animals were euthanized at 0, 2, 4, 8, 12 and 24 hours. Their brain drugconcentration/distribution was analyzed by MALDI-MSI and plasma drugconcentration was measured by LC-MS/MS. RESULTS: Drug distribution
and brainstem concentration were increased following BBB efflux pump inhibition compared to no pump inhibition controls. Additionally, efflux pumpinhibition resulted in slower drug clearance for those drugs that are known
pump substrates. CONCLUSIONS: BBB efflux pump inhibition resulted ina larger volume of distribution, increased drug concentration and slower
drug clearance following CED to the brainstem of known efflux substrates.
DDEL-17. TRIPLE INTRAVENTRICULAR CHEMOTHERAPY FOR
TREATMENT OF RELAPSED CHOROID PLEXUS CARCINOMA
Grace Lau1, Lisa Janson1, Julie Drummond1, and Nataliya Zhukova2,3;
1Monash Health, Clayton, VIC, Australia, 2Monash Children’s Hospital/
Monash Health, Clayton, VIC, Australia, 3Hudson Institute of Medical
Research, Clayton, VIC, Australia
Limited evidence for the optimal management of relapsed choroid plexus
carcinoma (CPC) exists, with a few case reports involving surgery, radiotherapy and intravenous chemotherapy. However, the safety and tolerability of intraventricular chemotherapy in this setting has not been widely
studied. We describe a case where triple intraventricular chemotherapy wasadministered to a child with relapsed metastatic CPC. A 7-year-old malewith a history of CPC presented with relapsed metastatic disease. At initialdiagnosis at 4 years of age, treatment involved gross total resection of an
intraventricular mass in the left temporal region followed by chemotherapy
and autologous stem cell transplantation (SCT) according to HEADSTART
II-D. One year after SCT, craniospinal radiation was delivered following
radiological relapse, achieving a partial response. Given previous treatmentlimiting myelosuppression, intraventricular chemotherapy via Ommaya®
reservoir with thiotepa 5mg, etoposide 0.5mg and topotecan 0.4mg twicea week (non-weight-based dosing) was commenced taking into consideration pharmaceutical formulation aspects for optimal intraventricular drugdelivery. After six cycles of intraventricular chemotherapy, palliative radiotherapy was administered due to radiological progression. Following completion, weekly triple intraventricular chemotherapy continued for 9 months.
The patient remained out of hospital with the main side effects being fatigue
and occasional nausea amenable to ondansetron. This case study demonstrates the safety and tolerability of a triple intraventricular chemotherapy
regimen used to delay disease progression and prolong quality of life in achild with relapsed CPC in the palliative setting. This could provide an alternative treatment regimen for patients with relapsed disease.

DIFFUSE MIDLINE GLIOMA/DIPG
DIPG-01. REIRRADIATION PRACTICES FOR DIFFUSE INTRINSICPONTINE GLIOMA
Chantel Cacciotti1, Kevin Liu2, Daphne Haas-Kogan2, andKatherine Warren1; 1Dana Farber/Boston Children’s Cancer and Blood
Disorder Center, Boston, MA, USA, 2Brigham and Women’s Hospital,
Boston, MA, USA
INTRODUCTION: Diffuse intrinsic pontine gliomas (DIPG) are aleading cause of brain tumor deaths in children. Current standard of careincludes focal radiation therapy (RT). Despite clinical improvement in the
majority of patients, the effect is temporary and median survival is lessthan one year. The use of reirradiation and possible benefit has been reported in progressive DIPG, yet standardized approaches are lacking.
We conducted an internet-based survey to assess physicians’ practices inpediatric DIPG. METHODS: A 14-question REDCap survey regarding
re-irradiation practices was emailed to 396 physicians identified throughan International Pediatric Neuro-Oncology and Radiation-Oncology database. RESULTS: Response rate was 35% overall (radiation-oncologists,
28%; pediatric oncologists, 57%). Two participants were excluded (didnot treat DIPG). Participants included radiation-oncologists (62%), pediatric oncologists (7%), and pediatric neuro-oncologists (29%). Most physicians (62%) treated 1–5 DIPG patients per year, with 10% treating >10/
year. Reirradiation was considered a treatment option in 88%. Progressive
disease or worsening clinical status were the most common reasons to consider reirradiation. The majority (84%) considered reirradiation a minimumof 6 months following initial RT. Doses varied, with median total dose 24Gy
(range 12–60); 2Gy/fraction (range 1–9). Concurrent use of systemic agentswith reirradiation was considered in 46%, mainly with targeted agents(37%), biologics (34%), or immunotherapy (25%). One-time reirradiation
was the most common practice (71%). Interestingly, 9% of respondents
would not consider reirradiation. CONCLUSION: Although, the vast majority of physicians agree with re-irradiation as a treatment option for DIPG
the total doses varied, and further clinical trials are needed.
DIPG-02. USEFULNESS OF BEVACIZUMAB IN MAINTAININGQUALITY OF LIFE AT THE TIME OF DIFFUSE INTRINSIC PONTINEGLIOMA RELAPSE
Akira Gomi1, Taku Uchiyama2, Hirofumi Oguma2, Takashi Yamaguchi2,
and Kensuke Kawai2; 1Jichi Children’s Medical Center Tochigi, Jichi
Medical University, Shimotsuke, Tochigi, Japan, 2Jichi Medical University,
Shimotsuke, Tochigi, JapanINTRODUCTION: Even in the age of molecular diagnosis, diffuse intrinsic pontine glioma (DIPG) is still a dismal disease. The usefulness of bevacizumab for DIPG relapse is reported. SUBJECTS AND
METHODS: The treatment and outcomes of 10 patients with DIPG whowere treated at our institute since 2001 were retrospectively reviewed. All
patients were diagnosed with DIPG by MRI imaging and underwent radiation therapy first. Three cases did not receive chemotherapy at the timeof relapse (Untreated Group). In 7 cases, chemotherapy was performed at
the time of relapse with ACNU/vincristine or interferon beta (Other Treatment Group), and 2 cases with bevacizumab (Bv Group). The change inthe Karnofsky Performance Status Scale (KPS) from the time of relapse wascompared. RESULTS: The average overall survival (OS) for all 10 cases was
10.0 months. No prolongation of OS by bevacizumab was observed. However, it was only in the Bv Group that the KPS increased from the time of
relapse. Comparison of the KPS at the time of relapse and the KPS after
4 months showed that the Bv Group remained unchanged or increased,
while the Untreated Group and the Other Treatment Group decreased. In
the Other Treatment Group, hospitalization was required for treatment, andside effects of bone marrow suppression were observed. However, in the Bv
Group, outpatient treatment was possible, there were no side effects, andall could be observed at home. CONCLUSION: From the above results,
bevacizumab appears useful for palliative treatment for maintaining qualityof life after DIPG relapse.
DIPG-03. THERAPEUTIC TARGETING OF TRANSCRIPTIONALELONGATION IN DIFFUSE INTRINSIC PONTINE GLIOMA
Hiroaki Katagi1,2, Nozomu Takata3, Yuki Aoi4, Yongzhan Zhang4,
Emily J. Rendleman4, Gavin T. Blyth5, Frank D. Eckerdt1,5,
Yusuke Tomita6,7, Takahiro Sasaki1, Amanda M. Saratsis1,4,5,8,
Akihide Kondo2, Stewart Goldman5,6,7, Oren J. Becher4,5,6,7,
Edwin Smith4,5, Lihua Zou4,5, Ali Shilatifard4,5 andRintaro Hashizume4,5,6,7; 1Department of Neurological Surgery,Northwestern University Feinberg School of Medicine, Chicago, IL, USA,
2Department of Neurological Surgery, Juntendo University, Tokyo, Japan,
3Center for Vascular and Developmental Biology, Feinberg Cardiovascular
and Renal Research Institute (FCVRRI), Northwestern University Feinberg
School of Medicine, Chicago, IL, USA, 4Department of Biochemistry
and Molecular Genetics, Northwestern University Feinberg School of
Medicine, Chicago, IL, USA, 5Robert H. Lurie Comprehensive Cancer
Center of Northwestern University, Chicago, IL, USA, 6Department ofPediatrics, Northwestern University Feinberg School of Medicine, Chicago,
IL, USA, 7Division of Hematology, Oncology, Neuro-Oncology and Stem
Cell Transplantation, Ann and Robert H. Lurie Children’s Hospital of
Chicago, Chicago, IL, USA, 8Department of Surgery, Division of Pediatric
Neurosurgery, Ann & Robert H. Lurie Children’s Hospital of Chicago,
Chicago, IL, USA
Diffuse intrinsic pontine glioma (DIPG) is highly aggressive brain stem
tumor and needed to develop novel therapeutic agents for the treatment.
The super elongation complex (SEC) is essential for transcription elongation
through release of RNA polymerase II (Pol II). We found that AFF4, a scaffold protein of the SEC, is required for the growth of H3K27M-mutant DIPG
cells. In addition, the small molecule SEC inhibitor, KL-1, increased promoterproximal pausing of Pol II, and reduced transcription elongation, resulting in
down-regulate cell cycle, transcription and DNA repair genes. KL-1 treatment decreased cell growth and increased apoptosis in H3K27M-mutant
DIPG cells, and prolonged animal survival in our human H3K27M-mutant
DIPG xenograft model. Our results demonstrate that the SEC disruption by
KL-1 is a novel therapeutic strategy for H3K27M-mutant DIPG.
DIPG-04. THERAPEUTIC STRATEGY FOR DIFFUSE MIDLINEGLIOMAS. A SINGLE CENTER EXPERIENCE
Takumi Yamanaka1, Yoshinobu Takahashi1, Tamaki Morisako1,
Toshiki Nagai1, Seisuke Tanigawa1, Daisuke Umebayashi1,
Hayato Takeuchi1, Kazunori Tatsuzawa1, Mitsuru Miyachi2,
Shigeki Yagyu2, Tomoko Iehara2, Hajime Hosoi2, and Naoya Hashimoto1;

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1Department of Neurosurgery, Kyoto Prefectural University of Medicine,
Graduate School of Medical Science, Kyoto, Japan, 2Department ofPediatrics, Kyoto Prefectural University of Medicine, Graduate School of
Medical Science, Kyoto, JapanINTRODUCTION: Diffuse midline gliomas have unfavorable prognoses
due to the difficulty of surgery and chemo-radiation resistances. The purpose of this study is to overview our surgical experiences and prognoses ofthis challenging neoplasm. MATERIALS AND METHODS: Five patientsof diffuse midline gliomas who were treated between 2016 and 2019 wereenrolled. Tumor locations, surgical procedures, molecular diagnoses, andprognoses were retrospectively reviewed. RESULTS: There were 3 maleand 2 female patients, and the median age was 15 years ranged from 7
to 21 years. Tumors were located at the basal ganglia in 1 patient, thalamus in 1, brain stem in 2, and cervical spine in 1. Mutations of H3 K27M
genes were detected in 4 surgically treated patients, except for 1 patient,
who were radiologically diagnosed as diffuse intrinsic pontine glioma(DIPG). Focal irradiation of ranged 35 to 54Gy were administered in allcases along with temozolomide in 2 cases and bevacizumab in 2 cases. The
median survival time was 13 months ranged from 4 to 18 months. DISCUSSION: Supratentorial tumors were maximumly resected, whereas just biopsies were performed in cases of exophytic brain stem and spinal tumors.
Diagnosis of DIPG was made without using surgical specimens. Therapeuticstrategies should be discussed with a concern to the patients’ qualities of life
for this tumor entity with dismal prognosis.
DIPG-05. HISTONE H3.3 K27M IMPAIRS SER31
PHOSPHORYLATION, RESULTING IN CHROMOSOMAL
INSTABILITY, LOSS OF CELL CYCLE CHECKPOINT CONTROL,AND TUMOR FORMATIONCharles Day1,2, Alyssa Langfald1, Florina Grigore1,
Sela Fadness1, Leslie Sepaniac3, Jason Stumpff3, Kevin Vaughan4,James Robinson1,5, and Edward Hinchcliffe1,5; 1Hormel Institute,
University of Minnesota, Austin, MN, USA, 2Mayo Clinic, Rochester, MN,
USA, 3University of Vermont, Burlington, VT, USA, 4University of Notre
Dame, Notre Dame, IN, USA, 5Masonic Cancer Center, University of
Minnesota, Minneapolis, MN, USA
Diffuse midline gliomas with the H3.3 K27M mutation are lethal brain
tumors in children. H3 K27M causes global loss of Lys27 triple methylation (Lys27me3), inducing epigenetic reprograming. Here we show that
H3.3 K27M also causes decreased H3.3 Ser31 phosphorylation on mitotic chromosomes. We show that H3.3 K27M DIPG cells have reduced
pericentromeric phospho-Ser31 and increased rates of chromosome
missegregation compared to normal, diploid human cells. CRISPR-editing
K27M to M27K restored phospho-Ser31 to WT levels and dramatically decreased the rate of chromosome missegregation. We confirm that Chk1 is
the H3.3 Ser31 kinase: K27M mutant H3.3 protein exhibits ~60% reduced
Chk1 phosphorylation of Ser31 in vitro. Chk1 knockdown completely abolishes phospho-Ser31 in cells and these have increased rates of chromosome
missegregation. In normal, diploid cells, expression of K27M or an S31A
non-phosphorylatable mutant increased chromosome missegregation; thisis suppressed by expressing a phosphomimetic double mutant (K27M/
S31E) that restores phospho-Ser31. WT cells arrest following chromosome missegregation. However, cells expressing H3.3 K27M or S31A failto arrest - despite having WT p53. Finally, we expressed H3F3AS31A and
PDGFb in an RCAS/TVA mouse model of DIPG and ~80% developed diffuse high-grade brain tumors and show significantly decreased survival.
Our results suggest that loss of phospho-Ser31 alone is oncogenic because
H3.3 S31A-expressing cells are WT for K27me3. Our results demonstratethat H3.3 K27M inhibits Ser31 phosphorylation both in vitro and in vivo,
leading to both chromosome missegregation and loss of subsequent G1 arrest – thus creating diffuse midline gliomas with both dynamic, complex
karyotypes and epigenetic reprogramming.
DIPG-07. HIGH THROUGHPUT DRUG SCREENING IDENTIFIESPOTENTIAL NEW THERAPIES FOR DIFFUSE INTRINSIC PONTINEGLIOMAS (DIPGS)
Dannielle Upton1, Santosh Valvi1, Jie Liu1, Nicole Yeung1, Sandra George1,
Caitlin Ung1, Aaminah Khan1, Laura Franshaw1, Anahid Ehteda1,
Han Shen1, Isabella Orienti2, Giovanna Farruggia2, Christa Nath3,
Patrick Reynolds4, Maria Tsoli1, and David Ziegler1,5; 1Children’s Cancer
Institute, Lowy Cancer Research Centre, University of New South Wales,
Sydney, NSW, Australia, 2Alma Mater Studiorum University of Bologna,
Department of Pharmacy and Biotechnology, Bologna, Italy, 3Departmentof Biochemistry, The Children’s Hospital at Westmead, Westmead, NSW,
Australia, 4Texas Tech University, Lubbock, TX, USA, 5Kid’s Cancer
Centre, Sydney Children’s Hospital, Randwick, NSW, Australia
DIPGs are the most devastating of all brain tumors. There are no effective treatments, hence almost all children will die of their tumor within

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12 months. There is an urgent need for novel effective therapies for thisaggressive tumor. We performed a high-throughput drug screen with over
3,500 biologically active, clinically approved compounds against a panelof neurosphere-forming DIPG cells. We identified 7 compounds- auranofin,fenretinide, ivermectin, lanatoside, parthenolide, SAHA and mefloquinethat 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 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 thePI3K/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 (LYM-X-Sorb andNanoMicelle) which were found to enhance survival. Fenretinide is clinically available with safety data in children. Validation of the activity ofFenretinide in PDGFRa-amplified or overexpressed DIPGs will lead to thedevelopment of a clinical trial, allowing the advancement of fenretinide as
potentially the first active therapy for DIPG.
DIPG-08. ELECTRONIC SEQUENCING PROVIDES OPTIMIZEDQUANTIFICATION OF SERIAL, MULTI-GENE MOLECULARRESPONSE IN THE CSF OF CHILDREN WITH HIGH-GRADE
GLIOMA
Amy Bruzek, Ashwath Muruganand, Karthik Ravi, Jack Wadden,
Clarissa Babila, Leo Tunkle, Kyle Wierzbicki, Stefanie Stallard,
Evan Cantor, Tingting Qin, Ian Wolfe, Rajen Mody, Karin Muraszko,
Andrea Franson, Patrica Robertson, Cormac Maher, Hugh Garton, andCarl Koschmann; University of Michigan, Ann Arbor, MI, USA
BACKGROUND: For pediatric high-grade glioma (pHGG), non-invasive
methods for diagnosis and surveillance are needed. Tumors release DNA(tDNA) into cerebrospinal fluid (CSF), allowing for detection of tumorassociated mutations by CSF sampling. We hypothesized that direct,
electronic analysis of tDNA with a novel, hand-held platform (Oxford
Nanopore MinION) could quantify patient-specific CSF tDNA variant allele fraction (VAF) with improved speed and limit of detection compared toestablished methods. METHODS: We integrated required multi-timepoint(0, 2, and 6 months) correlate lumbar punctures (LP) in two ongoing pHGG
clinical trials. Using Nanopore technology, we performed amplicon-based
PCR on CSF tDNA for recurrent mutations from patient samples (n=19) andnormal controls. VAF were determined via MinKNOW, Guppy, MiniMap2,
and Integrated Genome Browser. RESULTS: Nanopore CSF tDNA demonstrated improved sensitivity (91%) when compare to NGS sequencing(50%). Nanopore analysis of serially diluted CSF sample demonstrated
significantly lower limit of detection (attomolar) than typical NGS sample
requirement (nanomolar). H3K27M mutation was reliably detected with1,000x depth sequencing, which was achieved in less than 15 minutes ofsequencing after amplification. Multiplexed Nanopore analysis of H3F3A
and HIST1H3B was employed when H3 status was unknown. Serial CSF
tDNA analysis confirmed multi-gene (H3F3A K27M, PIK3CA, and TP53)
molecular remission in a 17-year-old with thalamic diffuse midline gliomathat correlated with sustained clinical response to ONC201 (14 months andongoing). CONCLUSIONS: Use of a hand-held, electronic DNA analysis
platform allows quantification of multi-gene molecular response with improved speed and limit of detection in the CSF of children with high-grade
glioma.
DIPG-10. OPTIMAL HDAC INHIBITION IN DIFFUSE INTRINSICPONTINE GLIOMA
Nicholas Vitanza1,2, Matt Biery1, Carrie Myers1, Eric Ferguson1,
Giulia Park1, Alyssa Noll1, Fiona Pakiam1, Emily Girard1, Shelli Morris1,
Bonnie Cole3,4, Mi-Youn Brusniak1, Andrew Mhyre1, and James Olson1,2;
1Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 2Division of
Pediatric Hematology/Oncology, Department of Pediatrics, University ofWashington, Seattle Children’s Hospital, Seattle, WA, USA, 3Department ofLaboratories, Seattle Children’s Hospital, Seattle, WA, USA, 4Departmentof Anatomic Pathology, University of Washington School of Medicine,
Seattle, WA, USA
As the majority of diffuse intrinsic pontine glioma (DIPG) have H3K27M
mutations, epigenetic-targeting agents have been studied, though evaluations
have been limited by their model systems, untranslatable drug concentrations, and/or evasive mechanisms of action. To develop a more translationalmodel, we used biopsy samples from newly diagnosed DIPG patients tocreate treatment-naïve in vitro and in vivo models (molecular aberrations inparentheses), including PBT-09FH (H3FA3, PI3KCA), PBT-22FH (H3F3A,

AbstractsTP53), PBT-24FH (PMS2), and PBT-27FH (HIST1H3B, TP53, NTRK2).
Models demonstrated radiation-resistance similar to the patient from whom
the culture was generated, supporting the models’ relevance (e.g. cell viability after 8 Gy was 36%, 81%, 71%, and 61% in PBT-09FH, -22FH,-24FH, and -27FH, respectively, compared to 7% in the medulloblastoma
model MED-411FH). We evaluated cell viability and apoptosis following
treatment with a panel of HDAC inhibitors, identifying the low nanomolar
IC50 of quisinostat (~50 nM) and romidepsin (~5 nM). While RNA expression changes induced by 100 nM panobinostat and quisinostat included
shared overexpression of the top 20/25 genes (e.g. FSTL5, ITIH5) andshared downregulation of the top 22/25 (e.g. GPR37L1, HEPACAM), only
9/25 were downregulated by panobinostat, quisinostat, and romidepsin(e.g. C21orf62, IFIT2), identifying these as potential vulnerabilities orbiomarkers of lethal HDAC inhibition. Mass-spectrometry (LC-MS) demonstrated panobinostat as the greatest acetylator of cortactin, potentiallyrelated to thrombocytopenia. While PBT-09 flank models demonstrated
quisinostat’s on-target acetylation and efficacy, orthotopic xenograft models
did not, supporting our model’s intact blood-brain barrier and emphasizing
the need for CNS penetrant versions of potentially efficacious agents.
DIPG-11. A PHASE I DOSE ESCALATION STUDY OF BXQ-350
IN CHILDREN AND YOUNG ADULTS WITH RELAPSED SOLID
TUMORS
Bhuvana Setty1, Timothy Cripe1, Mariko DeWire- Schottmiller2,
Richard Curry3, and Mohamed AdelBaki1; 1Nationwide Children’s
Hospital, Columbus, OH, USA, 2Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH, USA, 3Bexion Pharmaceuticals, Covington, KY,
USA
BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C (SapC) and dioleoyl- phosphatidylserine (DOPS).
BXQ-350 demonstrated antitumor effects in vitro and in vivo. Many tumors,
including diffuse intrinsic pontine glioma (DIPG), and cells of tumor vasculature have aberrantly-exposed PS-rich domains on the cell surface. BXQ-350 is
an anti-tumor agent in development from Bexion Pharmaceuticals, Inc. that
selectively targets tumor cell PS, particularly those translocated to the outerleaflet of the plasma membrane in tumor cells. BXQ-350 activates and participates in various cellular processes, including apoptosis and necrosis, andmay also exhibit novel mechanisms leading to cell death that require further
investigation. An adult Phase I trial with BXQ-350 completed enrollment in2019 having dosed 86 recurrent solid tumor patients, including glioblastoma,
with only one serious infusion-related reaction. The highest planned dose of
2.4 mg/kg was achieved and seven patients remain on study with multiple cases
demonstrating an objective response. A Phase I pediatric dose escalation trial
in recurrent solid tumors, including central nervous system (CNS) tumors, also
completed enrollment in 2019. The highest planned dose of 3.2 mg/kg wasachieved and there have been no BXQ-350 related serious adverse events. Eightpatients (7 CNS and 1 non-CNS) completed at least one cycle with one DIPG
patient completing cycle five. A pediatric Phase I trial in newly diagnosed DIPG
and diffuse midline glioma (DMG) is planned for 2nd quarter 2020.

1Centre for Cancer Research, Westmead Institute for Medical Research,
Westmead, NSW, Australia, 2Sydney Medical School, Faculty of Medicine
and Health, University of Sydney, Camperdown, NSW, Australia,
3Department of Radiation Oncology, Crown Princess Mary Cancer Centre,
Westmead Hospital, Westmead, NSW, Australia, 4Bill Walsh Translational
Cancer Research, Kolling Institute, St Leonards, NSW, Australia,
5Children’s Cancer Research Unit, Children’s Hospital at Westmead,
Westmead, NSW, Australia, 6Discipline of Child and Adolescent Health,
Faculty of Medicine and Health, University of Sydney, Camperdown, NSW,
Australia, 7The John Curtin School of Medical Research, The Australian
National University, Acton, ACT, Australia

DIPG is the leading cause of brain tumor-related death in children. Currently, radiation is the only treatment that offers transient benefit. Compared to normal brain tissue, DIPGs are hypoperfused with tumors being
exposed to hypoxia, a potent barrier to effective radiotherapy. Biguanides
are hypoglycemic agents that can reduce the oxygen consumption rate(OCR) in mitochondria, thereby reducing hypoxia. Our previous study has
shown that metformin significantly improves the radiosensitivity of DIPG
and extends survival in a patient-derived xenograft (PDX) model. In thepresent study, phenformin, a second biguanide derivative, demonstrated
even greater anti-DIPG activity and radiosensitising effect in vitro. As asingle agent, phenformin dose-dependently inhibited OCR and increased
extracellular acidification rate (ECAR). Low-dose phenformin reduced
mitoATP/glycoATP ratio, whereas high doses significantly suppressed net
ATP production. To attenuate the phenformin-induced ECAR, phenformin
was combined with dichloroacetate (DCA), a clinically relevant pyruvate
dehydrogenase kinase inhibitor that can suppress the elevated glycolytic
rate of cancers. This combination significantly blocked the phenformininduced ECAR and killed DIPG cells synergistically by inducing apoptosis,
DNA damage and metabolic catastrophe. Moreover, protein expression of
HIF-1α and c-Myc, two master regulators that collaboratively enhance themetabolic capacity of tumor cells through increased glycolysis thereby contributing to radioresistance, were also suppressed by phenformin-DCA treatment in vitro. This combination therapy upregulated genes inhibiting cellproliferation while downregulating genes for DNA repair. The triple combination of phenformin, DCA and irradiation demonstrated the most potent
efficacy in vitro and is currently being tested in our PDX cohort in vivo.
DIPG-14. TARGETING POLO-LIKE KINASE 1 IN COMBINATIONWITH KEY ONCOGENIC DRIVERS IN DIPG: FROM SINGLE AGENT
TO COMBINATION STRATEGIESLaura Franshaw1, Elisha Hayden1, Swapna Joshi1, Jie Liu1, Anahid Ehteda1,
Chi Nam Ignatius Pang2, Maria Tsoli1, and David S. Ziegler3; 1Children’s
Cancer Institute, Randwick, NSW, Australia, 2School of Biotechnology and
Biomolecular Sciences, University of New South Wales, Randwick, NSW,
Australia, 3Kids Cancer Centre, Sydney Children’s Hospital, Randwick,
NSW, Australia

DIPG is a universally fatal pediatric brainstem tumor with no effective therapy.
Recent work has shown that over 80% of DIPG cases harbor the H3K27M
mutation leading to global loss of the repressive H3K27 trimethylation mark,global DNA hypomethylation, and a distinct gene expression signature. We
sought to exploit epigenetic vulnerabilities in DIPG through the use of DNA
methyltransferase inhibitors and histone deacetylase (HDAC) inhibitors. We
find that treatment with low-dose 5-aza-2’-deoxycytidine (decitabine), alone
and in combination with HDAC inhibitors, elicits profound genome-wide
demethylation in DIPG patient-derived neurosphere cell lines, impairs proliferation, and induces apoptosis. We show that this treatment induces immune
activation, with induction of type I interferon signaling, increased expression ofmajor histocompatibility complexes, and expression of tumor antigens. These
results suggest that the immunogenicity of DIPG may be modulated by epigenetic therapies, suggesting the possibility of novel combination approaches toimmunotherapy of DIPG in the future.

Diffuse Intrinsic Pontine Glioma (DIPG) are devastating paediatric brainstem tumours. Loss of function mutations in DIPG decrease genetic stability
and impair DNA damage response pathways promoting tumourigenesis.
Polo-like Kinase 1 (PLK1) is a pivotal controller of cell growth, regulating
key intermediaries of DNA replication, homologous repair, the cell cycle andcell division. We have found DIPG cultures consistently overexpress PLK1
with inhibition resulting in decreased tumour cell growth, heightened cell
cycle arrest and apoptosis. Single agent treatment using PLK1 inhibitors
unprecedentedly doubled the median survival of animals harbouring DIPG
tumours. Through gene expression analysis, we’ve showed PLK1 inhibition
affected multiple pathways which control the cell cycle, cell death regulation, microtubule organization and regulation of cell migration. We foundthese pathways of differentially expressed genes were significantly enrichedfor known targets of both E2F1 and E2F4. Analysis of gene expression andproteomic studies also revealed PLK1 inhibition decreased the activationand expression of key tumour promoting mediators within multiple phasesof the cell cycle, decreased expression of tumour promoters including MYC
and the PI3K/mTOR pathway and reactivated tumour suppressors p53 andPTEN. Assessing these changes in the treated transcriptome and proteome,
we aim to develop multiple potentially translatable combination treatment
strategies for DIPG. We have performed mechanistic studies and identified
synergism with PLK1 inhibitors and the epigenetic regulator panobinostat,bet/bromodomain inhibitor JQ1, dual PI3K/mTOR inhibitor bimiralisib andPI3K inhibitor BKM120. Finally, we found PLK1 inhibitors act as potent
radiosensitizers, enhancing the therapeutic effects of radiotherapy in vitro
and in vivo.

DIPG-13. TARGETING HYPOXIA AND MITOCHONDRIA WITH
REPURPOSED METABOLIC DRUGS AS AN APPROACH TO
RADIOSENSITIZATION FOR DIFFUSE INTRINSIC PONTINEGLIOMAS (DIPG)
Han Shen1,2, Cecilia Chang1, Harriet Gee1,3, Kelly McKelvey4,2,Geraldine O’Neill5,6, Victoria Prior5,6, Anneke Blackburn7, and Eric Hau1,3;

DIPG-15. POLYAMINE PATHWAY INHIBITION IS A POTENTNOVEL THERAPEUTIC STRATEGY AGAINST DIFFUSE INTRINSICPONTINE GLIOMA
Aaminah Khan1, Laura Gamble1, Dannielle Upton1, Denise Yu1,
Anahid Ehteda1, Ruby Pandher1, Chelsea Mayoh1, Mark Burns2,
Murray Norris1,3, Michelle Haber1, Maria Tsoli1, and David Ziegler1,4;

DIPG-12. TARGETING EPIGENETIC MODIFIERS TO INDUCEIMMUNE SIGNALING IN DIPG
Ashley Tetens1, Allison Martin2, Antje Arnold1, Orlandi Novak1,
Charles Eberhart1, Andrew Feinberg1, Eric Raabe1, andMichael Koldobskiy1; 1Johns Hopkins University School of Medicine,
Baltimore, MD, USA, 2Albert Einstein College of Medicine, the Bronx, NY,USA

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iii289Abstracts

1Children’s Cancer Institute, University of New South Wales, Sydney, NSW,
Australia, 2Aminex Therapeutics, Kirkland, Washington, USA, 3Centre
for Childhood Cancer, University of New South Wales, Sydney, NSW,
Australia, 4Kids Cancer Centre, Sydney Children’s Hospital, Sydney, NSW,
Australia

DIPG is an aggressive paediatric brainstem tumour, with a median survival of less than 1 year. Polyamines are intracellular polycations that control important aspects of cell growth and are often upregulated in cancer.
Difluoromethylornithine (DFMO) is an FDA-approved inhibitor of the enzyme ornithine decarboxylase (ODC1) which is a key driver of polyaminesynthesis. We investigated the efficacy of polyamine pathway inhibitors as atherapeutic strategy against DIPG. We found high expression levels of synthetic enzymes in the polyamine pathway in primary patient samples andcultures. Using cytotoxicity and clonogenic assays, we found that DFMO
inhibited the proliferation of DIPG neurospheres. However, DIPG cells compensated for DFMO inhibition by increasing expression of the polyaminetransporter SLC3A2. Gene expression analysis showed that the polyaminetransporter, SLC3A2, was significantly overexpressed in DIPG comparedwith all other high-risk childhood cancers. Addition of polyamine transporter inhibitor AMXT 1501 to DFMO led to synergistic inhibition of
DIPG proliferation. Consistent with the in vitro results, the combination
treatment significantly prolonged the survival of mice bearing 3 different
DIPG orthografts with 2/3 of the animals surviving up to 160 days. Additionof irradiation further improved the survival of mice treated with DFMO andAMXT 1501. Our results suggest that DIPG tumours are exquisitely sensitive to polyamine inhibitors and that dual blockade of polyamine synthesis
and transport is a promising novel therapeutic strategy. AMXT 1501 is currently in clinical development for adult cancers (NCT03536728). A clinical
trial for DIPG patients is planned through the CONNECT consortium.
DIPG-16. COMBINATION OF ARGININE DEPLETION AND
POLYAMINE INHIBITION AS AN ANTICANCER STRATEGY FOR
DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Aaminah Khan1, Laura Gamble1, Ruby Pandher1, Mark R. Burns2,
Francis Mussai3, Murray Norris1, Michelle Haber1, Maria Tsoli1, andDavid S. Ziegler1,4; 1Children’s Cancer Institute, Sydney, NSW, Australia,
2Aminex Therapeutics Inc., Kirkland, WA, USA, 3Birmingham Children’s
Hospital and the University of Birmingham, Birmingham, United Kingdom,
4Kid’s Cancer Centre, Sydney Children’s Hospital, Sydney, NSW, Australia
DIPG is an aggressive pediatric brainstem tumor, with a median survival
below 12 months. Tumor cells are dependent upon arginine, a semi-essential
amino acid, metabolised by arginase enzymes into ornithine, a pivotal precursor to the polyamine pathway. Polyamines, frequently upregulated incancer, are intracellular polycations controlling key biological processes –the inhibition of which we have previously shown to be highly efficacious
in preclinical DIPG models. Pegylated arginase (BCT-100) has recently beenshown to significantly delay tumor development, prolonging survival ofneuroblastoma-prone Th-MYCN mice. This study investigated the effects
of arginine depletion therapy as a single agent and in combination withpolyamine pathway inhibitors in DIPG. We found that ARG2, the geneencoding for arginase II, is expressed significantly more highly in DIPG tumors compared to normal brain. Arginine depletion via BCT-100 reduced
DIPG cell proliferation and colony formation in patient-derived cell lines.
Using orthotopic patient-derived xenograft models of DIPG, we found thatfrequent dosing of BCT-100 (4x/week) significantly delayed tumor development and increased the survival of the mice (p<0.0001). DFMO is an
FDA-approved inhibitor of the enzyme ornithine decarboxylase, a key driverof polyamine synthesis. The combination of BCT-100 with DFMO led to significant enhancement in DIPG survival (p<0.005 compared to single agent
treatments). Triple combination therapy with addition of the polyaminetransport inhibitor AMXT-1501 led to a potent and profound improvementin survival. These data show that arginine depletion therapy using BCT-100
combined with dual polyamine inhibitory agents represents a potentially
exciting new approach for the treatment of DIPG.
DIPG-17. BIOPSY-PROVEN DIFFUSE MIDLINE GLIOMA IN
ADOLESCENTS AND YOUNG ADULTS
Shota Tanaka, Shunsaku Takayanagi, Yuki Shinya, Mariko Kawashima,
Masahiro Shin, Hirofumi Nakatomi, and Nobuhito Saito; The Universityof Tokyo, Tokyo, JapanINTRODUCTION: Diffuse midline glioma (DMG) mostly affects young
children. The newly-introduced disease entity DMG, H3K27M-mutant uniformly portends poor prognosis, and therefore that in the pons is usuallytreated based upon radiological diagnosis without histological confirmation.
DMG is rarer in adolescents and young adults (AYA), and remains poorly
characterized. In this study, we sought to investigate the clinical, pathological,
and molecular profiles of DMG in AYA generation. METHODS: Patientsof age between 16 and 39 undergoing biopsy at the University of Tokyoiii290N EU R O - O N C O L O G Y•

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Hospital between 2003 and 2019 were included in the study. Clinical dataand images were retrospectively reviewed. Genetic analyses were performedin cases with abundant tissues. RESULTS: Ten patients included 8 brainstem and 2 thalamic DMG. The median age was 25 years (range, 19–38).
Pathological diagnosis was DMG, H3K27M-mutant in 3 patients, glioblastoma, IDH-mutant in 1, anaplastic astrocytoma, IDH-wildtype in 4, diffuse astrocytoma, IDH-mutant in 1, and diffuse astrocytoma, IDH-wildtype
in 1. Genetic analyses detected H3F3A-K27M mutation in 2, HIST1H3BK27M mutation in 1, IDH1-R132H mutation in 1, and IDH1-R132S mutation in 1. With a median follow-up of 23 months (range, 2–61), only 3
patients died 29–61 months after diagnosis, and the remaining 7 patientssurvived for 2–59 months. Neither IDH1 mutation nor H3K27M mutation was associated with survival in this series. CONCLUSION: Survival of
AYA patients with DMG was seemingly variable with some long survivors.
H3K27M mutation was present in a subset of patients. A further study iswarranted to correlate molecular profile with clinical pictures including patient survival.
DIPG-18. IDENTIFICATION OF TARGETABLE PATHWAY
DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA
Sarah Parackal1, Wai Chin Chong1, Gabrielle Bradshaw1, Claire Sun1,Paul Daniel1, Enola Roussel2, Samantha Jayasekara1, Duncan Crombie1,
Ron Firestein1, and Jason Cain1; 1Centre for Cancer Research, Hudson
Institute of Medical Research, Department of Molecular Translational
Science, School of Clinical Sciences, Faculty of Medicine, Nursing and
Health Sciences, Monash University, Melbourne, VIC, Australia, 2Centre
for Cancer Research, Hudson Institute of Medical Research, Departmentof Genetics, School of Biological Sciences, Faculty of Science, Monash
University
Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive paediatricbrainstem tumour with a dismal prognosis. Recurrent heterozygous mutations (p.K27M) in Histone H3 variant genes have been identified in the majority of DIPG cases. While the exact mechanism of H3K27M’s function ispoorly understood, evidence suggests a role for epigenetic dysregulation indisease pathogenesis. This study aims to use functional genomics to identify
novel therapeutic dependencies in H3K27M DIPG. DIPG drug sensitivity
screening was carried out in twelve established and validated patient derived
cell lines (10 H3.3K27M and 2 Wt) using an FDA approved drug library
containing 1480 compounds. Highly prevalent targets identified from thisscreen include HDAC, microtubule, proteasome and CDK inhibitors. Additionally, a custom pooled CRISPR knockout library of druggable targets(300 genes, 1200 guide RNAs) was used to identify key DIPG cell survival
pathways. To date five DIPG cell lines (1 Wt; 1 H3.1; 3 H3.3) have undergone screening. Knockdown of known DIPG driver genes (TP53; PDGFRA;PIK3CA and PIK3CR1) resulted in reduced cell viability, consistent with
their proposed function and validating knockout screen utility. Preliminary
data demonstrates Wt and H3K27M DIPGs cluster independently based on
genes required for survival, suggesting differing tumorigenesis mechanisms
and the potential for therapeutically targeting genotype specific pathways.
Correlation of parallel drug screen and RNA-seq data will potentially reveal H3-dependent pathways for therapeutic exploitation. Collectively, weshow a functional genomics approach is able to identify genotype-specificpathway dependencies in DIPG, paving the way for molecularly informed
personalized therapies for patients.
DIPG-19. TARGETING ATM MUTATION IN METASTATIC DIFFUSE
MIDLINE GLIOMA – A CASE OF SUSTAINED RESPONSE USING
PARP INHIBITOR
Karen Tsui1,2, Andrew Law3, and Michael K Watson4; 1Department ofPaediatric Haematology/Oncology, Starship Children’s Hospital, Auckland,
New Zealand, 2Department of Paediatrics, The University of Auckland,
Auckland, New Zealand, 3Department of Neurosurgery, Auckland City
Hospital, Auckland, New Zealand, 4Department of Anatomical Pathology,
Auckland City Hospital, Auckland, New ZealandDiffuse midline glioma (DMG) with H3.3K27M mutation is associated with an extremely poor prognosis, with a median survival of 10 to
12 months. Radiation remains the standard of care however there is no established curative therapy available. We describe a patient diagnosed witha diffuse intrinsic pontine glioma at 5 years of age by clinical and radiological criteria. He was treated with focal radiation 59Gy which resulted
in reduction in size of the tumour, and partial improvement of T2 changes
on MRI. At 18 months post diagnosis, the patient developed metastatic
recurrence at the anterior fornix. This was biopsied and histopathology
demonstrated a high grade glioma. Next generation sequencing revealeda H3F3A K27M mutation, and an ATM R3008H mutation. He received
whole ventricular radiation 36Gy and boost to the lesion to 45Gy, followed by Olaparib 135mg/m2/day twice daily. He remains in radiologicalremission 20 months post metastatic relapse and has no organ toxicity
to Olaparib. CONCLUSION: H3.3K27M and ATM co-segregating muta-

Abstracts

tions are described in DMG. This is the first case report of targeting ATM
mutation with a PARP inhibitor which resulted in prolonged remission ofmetastatic DMG. Olaparib was well tolerated.
DIPG-20. DETERMINATION AND MANAGEMENT OF
HYDROCEPHALUS IN PATIENTS WITH DIPG, AN INSTITUTIONAL
EXPERIENCE
Adriana Fonseca1, Palma Solano-Paez2, Michal Zapotocky3, Ute Bartels1,
and Eric Bouffet1; 1The Hospital for Sick Children, Toronto, ON, Canada,
2Hospital Universitario Virgen del Rocio, Seville, Spain, 3University
Hospital Motol, Prague, Czech Republic
BACKGROUND: The is no consensus in best practices for the management of hydrocephalus in patients with Diffuse Intrinsic Pontine Glioma(DIPG). To date, the impact on survival of hydrocephalus and CerebroSpinal Fluid (CSF) diversion in this population remains to be elucidated.
Herein, we describe our institutional experience. METHODS: Patients witha clinical and radiological diagnosis of DIPG were identified at the Hospitalfor Sick Children between 2000–2019. Images at diagnosis and at diseaseprogression were assessed for hydrocephalus using the frontal-occipitalratio (FOR) method. Proportional hazard analyses were used to identify factors correlated with survival. RESULTS: Eighty-nine consecutive patientsdiagnosed with DIPGs were treated at our institution. At diagnosis, 29%(n=26) of patients presented with hydrocephalus, seven patients underwent
CSF diversion. Out of the remaining nineteen patients, n=6 had stable or
improved hydrocephalus in follow-up scans, n=6 had persistent hydro and
n=2 required CSF diversion at the time of disease progression. Seven did
not undergo a follow-up scan. Out of sixty-five patients with imaging at
the time of progression, fifty-five percent of patients (n=36) presented withhydrocephalus and ten of them required CSF diversion. On univariate analysis, the presence of hydrocephalus or CSF diversion at diagnosis and/or
did not correlate with a survival advantage. CONCLUSIONS: CSF diversion for the management of hydrocephalus in patients with DIPG does not
impact survival and in some cases resolves spontaneously after the initiationof radiotherapy and steroids. This observation needs to be validated in aprospective cohort.
DIPG-21. INDUCTION OF MITOTIC ABNORMALITIES AND BMI-1
MODULATION TO TREAT DIFFUSE INTRINSIC PONTINE GLIOMA
Shiva Senthil Kumar1, Satarupa Sengupta2, Xiaoting Zhu3,4,
Deepak Kumar Mishra1, Christine Fuller5, Maryam Fouladi1,6, andRachid Drissi1,6; 1Brain Tumor Center, Division of Oncology, Cincinnati
Children’s Hospital Medical Center, Cincinnati, OH, USA, 2Division of
Research, Department of Surgery, College of Medicine, University ofCincinnati, Cincinnati, OH, USA, 3Department of Electrical Engineeringand Computer Science, University of Cincinnati College of Engineering andApplied Science, Cincinnati, OH, USA, 4Division of Biomedical Informatics,
Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH, USA,
5Division of Pathology and Laboratory Medicine, Cincinnati Children’s
Hospital Medical Center, Cincinnati, OH, USA, 6Department of Pediatrics,
University of Cincinnati College of Medicine, Cincinnati, OH, USA
Diffuse intrinsic pontine glioma (DIPG) is a poor-prognosis pediatricbrain tumor with a median survival of less than one year. No effective
therapy is currently available, and no therapeutic advances have been
made in several decades. BMI-1 is a member of the multimeric protein
complex Polycomb repressor complex 1 (PRC1). It has been implicated inself-renewal of normal and cancer cells, and in DNA damage signaling. We
have previously identified BMI-1 as a potential therapeutic target in DIPG
and have shown that BMI-1 is highly expressed in DIPG tumors regardlessof histone 3 subtype. In the present study, we show that the modulationof BMI-1 leads to DNA damage, M phase cell cycle arrest, chromosome
abnormalities and cell death. Furthermore, modulation of BMI-1 sensitizes
DIPG patient-derived stem-like cells to ionizing radiation (IR). Treatmentof DIPG stem-like cells with PTC596, a BMI-1 modulator, and IR, impairs the kinetics of DNA damage response (DDR). Both DDR foci formation and resolution were delayed, resulting in further reduction in cell
viability compared with either treatment alone. In vivo, treatment of micebearing DIPG xenografts with PTC596 leads to decreased tumor volume
and growth kinetics, increased in-tumor apoptosis and sustained animal
survival benefit. Gene expression analysis indicates that BMI-1 expression
correlates positively with DIPG stemness and BMI-1 signature. Together
our findings indicate that BMI-1 modulation is associated with mitotic abnormalities, impaired DDR and cell death, supporting the combination of
BMI-1 modulation and radiation as a promising novel therapy to treat children with DIPG.
DIPG-22. DISSECTING THE ONCOGENIC ROLE OF FOXR2 IN
DIFFUSE INTRINSIC PONTINE GLIOMA
Jessica W. Tsai1, Smruti K. Patel2, Heather Bear2, Frank Dubois1,
Prasidda Khadka1, Sophie Lu1, Elizabeth Gonzalez1, Keith Ligon3,

Pratiti Bandopadhayay1, Timothy N. Phoenix2; 1Dana-Farber Cancer
Institute, Boston, MA, USA, 2University of Cincinnati, Cincinnati, OH,
USA, 3Brigham and Women’s Hospital, Neuropathology, Boston, MA, USA
BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) pose particular challenges for treatment. We recently completed a genomic analysisof close to 200 DIPGs and high-grade gliomas. We identified that nearly 10%of all DIPGs have increased expression of the fork head domain transcription factor FOXR2. We hypothesize that FOXR2 accelerates gliomagenesis
in histone mutant DIPGs and represents a previously unexplored therapeutictarget. METHODS: To determine whether FOXR2 is sufficient to mediate
gliomagenesis, we applied an integrative genomics approach using both invitro and in vivo DIPG models: mouse neural stem cell models expressing
FOXR2, in vivo mouse models using in utero brainstem electroporation,
patient-derived DIPG cell lines, and RNA sequencing analysis of human andmouse tumors expressing FOXR2. RESULTS: Our data shows that FOXR2
indeed is an oncogene that rapidly accelerates gliomagenesis using an in vivo
brainstem in utero electroporation model of DIPG. In human tumors, increased FOXR2 expression is mutually exclusive with MYC amplificationsuggesting functional redundancy. In vivo, FOXR2 results in large brainstem gliomas and rapid neurologic decline of animals. Transcriptional profiling of these tumors demonstrates activation of MYC signaling pathways.
In vitro, we have further identified patient-derived cell lines with increased
expression of FOXR2. CONCLUSION: FOXR2 is sufficient to enhance
gliomagenesis and represents a previously understudied therapeutic target
for patients with the devastating disease DIPG.
DIPG-23. SINGLE CASE REPORT OF LOW DOSE RADIOTHERAPYAND CHEMOTHERAPY IN THE TREATMENT OF DIPG
Chen Kan Tseng1, and I-Jun Chou2; 1Proton and Radiation Therapy Center,
Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan, 2Departmentof Pediatrics, Chang Gung Children’s Hospital, Taoyuan, Taiwan
A 3 year-old girl, was noted to have progressive gait problem since Nov.
2017 and brought to hospital for checkup. Brain MRI on Jan. 2018 showed
T2 hyperintensity infiltrative pontine lesion, favoring diffuse infiltrative pontine glioma and mild obstructive hydrocephalus, received VP-shunting on
Jan. 15, 2018. Due to the refusal of surgical biopsy for tissue proof, westarted the radiotherapy from Jan. 24, 2018, using Rapidarc technique with
6MV photon energy to treat the brain stem lesion, ended on Feb. 24, 2018with total dose of 25.5Gy in 17 fractions as our usual practice. Following
the completion of radiotherapy, we started the adjuvant chemotherapy using
1-week on, 1-week off regimen of temozolomide using dosage of 75 mg/
sq-m/day, and this patient’s general condition returned back to nearlynormal. Serial follow-up images of brain MRI on 04/30/2018, 08/01/2018,11/30/2018, 02/26/2019, 05/30/2019, 08/28/2019 showed slow progressionof the pontine lesion, without the development of contrast enhanced newlesion. She maintained the functional independent until Sep. 2019, she wasnoted to have symptoms of ataxic gait, esotropia and choking on drinking
liquid. We started the retreatment of radiotherapy from Oct.7, 2019, usingsame technique, ended on Nov. 5, 2019 with total dose of 30Gy in 20 fractions. The symptoms improved partially after the treatment, with residual
weakness over left extremity. We are still treating the patient with adjuvanttemozolomide, and she has survived most of time functionally independent
in these 2 years.
DIPG-25. KETOGENIC DIET IN DIFFUSE INTRINSIC PONTINEGLIOMA IN CHILDREN: A RETROSPECTIVE STUDYINVESTIGATING THE FEASIBILITY
Alexandre Perez1,2, Janak Nathan3, Moatasem El-Ayadi4,2, Christian Korff5,
Marc Ansari1,2, and André von Bueren1,2; 1Department of Pediatrics,
Obstetrics and Gynecology, Division of Pediatric Hematology andOncology, University Hospital of Geneva, Geneva, Switzerland,
2Department of Pediatrics, Obstetrics and Gynecology, CANSEARCH
Research Laboratory, Faculty of Medicine, University of Geneva, Geneva,
Switzerland, 3Department of Neurology, Shushrusha Hospital, Mumbai,
India, 4Department of Pediatric Oncology, National Cancer Institute,
Cairo University, Cairo, Egypt, 5Department of Pediatrics, Obstetrics andGynecology, Pediatric Neurology Unit, University Hospital of Geneva,
Geneva, Switzerland
PURPOSE: Diffuse Intrinsic Pontine Glioma (DIPG) is one of themost devastating diseases amongst children with cancer, thus novel strategies are urgently needed. We aimed to retrospectively evaluate thefeasibility of the carbohydrate restricted ketogenic diet (KD) in DIPG patients. METHODS: Searches of MEDLINE and Embase identified four publications meeting the inclusion criteria (diagnosis of DIPG and exposition
to a KD ≥ 3 months). One additional case was identified by contact withexperts. The minimal feasibility criteria were defined as the ability to use theKD for ≥ 3 months. Individual patient data were extracted from the publications or obtained from investigators. RESULTS: Five patients (males, n=3;
median age 4.4 years; range, 2.5–17 years) met the inclusion criteria (oneN E U R O -O N C O L O G Y•

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patient – identified and not included - was on KD < 3 months due to diseaseprogression). Further feasibility analyses showed a duration of the KD of≥ 3 months and less than 7 months (n=2), > 7 months and less than 1 year(n= 2), and two years (n=1), respectively. CONCLUSION: These results –based on a small patient population – suggest that the KD appears to be afeasible treatment option for children with DIPG. The potential duration of
the KD is limited by the aggressive clinical behavior of DIPG. The safety analysis is currently being retrospectively assessed. These data should encourage
further studies on a larger scale; ideally assessing the impact of the KD in
DIPG patients in a randomized controlled trial.
DIPG-26. THERAPEUTIC EFFECTS OF RADIOTHERAPY WITH
CONCOMITANT AND ADJUVANT TEMOZOLOMIDE VERSUSRADIOTHERAPY WITH CONCOMITANT TEMOZOLOMIDEALONE IN CHILDREN WITH DIPG: A SINGLE-CENTER
EXPERIENCE WITH 82 CASES
Mingyao Lai, Juan Li, Qingjun Hu, Jiangfen Zhou, Shaoqun Li,
Lei Wen, Zhaoming Zhou, Cheng Zhou, Lichao Wang, Changguo Shan,
Yangqiong Zhang, Rishun Luo, and Linbo Cai; Guangdong Sanjiu Brain
Hospital, Guangzhou, Guangdong, China
OBJECTIVE: To retrospectively analyze the therapeutic effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy
with concomitant temozolomide alone for pediatric diffuse intrinsic pontine
glioma (DIPG), and to evaluate the value of temozolomide in the treatmentof pediatric DIPG. METHODS: The clinical data of children with confirmed DIPG in Guangdong Sanjiu Brain Hospital between January 1, 2010
and December 30, 2019 were collected. The inclusive criteria included (1)receiving a total radiotherapy dose of 54 Gy in 27 fractions, (2) treated withconcomitant temozolomide chemotherapy, and (3) with or without adjuvanttemozolomide chemotherapy. RESULTS: A total of 82 pediatric patientswere eligible for the study, with a median age of 7 years (range 2–16 years).
The median follow-up was 8.6 months (range 2–28 months) and the median survival time was 9.4 months. The median survival time of 66 patientstreated with radiotherapy with concomitant and adjuvant temozolomide
was 9.8 months, longer than 7.5 months of the other 16 patients treatedwith radiotherapy with concomitant temozolomide alone, with statisticaldifferences (P=0.010). Moreover, bevacizumab and nimotuzumab didn’t
bring survival benefits to patients with disease recurrence or progression.
Hematological toxicity (Grade IV) was not found. CONCLUSION: Radiotherapy with concomitant and adjuvant temozolomide prolongs the survival
time of children with DIPG.
DIPG-27. TARGETING FACILITATES CHROMATIN
TRANSCRIPTION (FACT) AS A NOVEL STRATEGY FOR DIFFUSE
INTRINSIC PONTINE GLIOMA (DIPG) THAT ENHANCESRESPONSE TO HISTONE DEACETYLASE (HDAC) INHIBITION
Anahid Ehteda1, Laura Franshaw1, Jie Liu1, Swapna Joshi1, Sandy Simon1,
Chi Nam Ignatius Pang2, Federico Giorgi3, Ruby Pandher1, Caitlin Ung1,
Ornella Tolhurst1, Chelsea Mayoh1, Aaminah Khan1, Elisha Hayden1,
Anjana Gopalakrishnan1, Peter Trebilcock1, Dannielle Upton1,
Rebecca Lehmann1, Sandra George1, Orazio Vittorio1, Maria Tsoli1,
Katerina Gurova4, Andrei Gudkov Gudkov4, Murray D. Norris1,
Michelle Haber1, and David S. Ziegler1,5; 1Children’s Cancer Institute,
Sydney, NSW, Australia, 2School of Biotechnology and Biomolecular
Sciences, University of New South Wales, Sydney, NSW, Australia,
3Department of Pharmacy and Biotechnology, University of Bologna,
Bologna, Italy, 4Rosewell Park Cancer Institute, Buffalo, New York, USA,
5Kid’s Cancer Centre, Sydney Children’s Hospital, Randwick, NSW,
Australia
Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable
childhood brain tumour for which new treatments are needed. A highthroughput drug screen of 3500 pharmaceutical compounds identified anti-malarials, including quinacrine as having potent activity against
DIPG neurospheres. CBL0137, a compound modelled on quinacrine, is ananti-cancer compound which targets Facilitates Chromatin Transcription(FACT), a chromatin remodelling complex involved in transcription, replication, and DNA repair. CBL0137 effectively crosses the blood-brain barrier
and is currently in Phase I trials in adult cancer. CBL0137 induced apoptosis in DIPG neurospheres in vitro and had profound cytotoxic activity
against a panel of DIPG cultures. In a DIPG orthotopic model, treatment
with CBL0137 significantly improved survival. We found that treatment
with CBL0137 up-regulated TP53 and increased histone H3.3 acetylationand tri-methylation in DIPG cells. We therefore examined the interaction
between CBL0137 and the HDAC inhibitor, panobinostat. In vitro experiments showed that the two agents had profound synergistic activity
against DIPG neurospheres in clonogenic assays and enhanced apoptosis.
Transcriptomic analysis and immunoblotting indicated that combination
treatment activated signalling pathways controlled by Retinoblastoma (RB)/
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De c e mb e r 2 0 2 0enhancer of zeste homolog 2 (EZH2). Consistent with the in vitro results,
the combination of CBL0137 and panobinostat significantly prolonged
the survival of two orthotopic models of DIPG, while histological analysis
showed increased H3K27me3 and decreased Ki67 positive cells. Given thesepromising results, a paediatric trial of CBL0137 is planned to open throughthe Children’s Oncology Group with an expansion cohort for DIPG patients.
DIPG-28. REPEATED LOW DOSE RT FOR PEDIATRIC DIPG – LESSDISEASE BURDEN WITH COMPARABLE OUTCOMES
Yao Yu Wu, and Chen Kan Tseng; Chang Gung Children Hospital at
Linkou, Taoyuan, Taiwan
PURPOSE: Pediatric diffuse intrinsic pontine glioma (DIPG) is the mostdismal prognosis pediatric brain tumor. Six weeks radiation therapy (RT)remains the mainstay of treatment. The aim of the current study was tocompare the results of firstly reported repeated low dose RT (rLRT) withconventional RT (CRT). METHODS AND MATERIALS: This retrospective
review included 24 children with DIPG, aged 3 -18 years, underwent CRT(52- 60.0 Gy in 1.8- 2.0 Gy, n = 16) or rLRT (18 - 30 Gy in 1.5–2.0 Gy per
cycle for 1–3 cycles, n = 8). All children had typical symptoms and MRI
features of DIPG, or biopsy-proven DIPG. RESULTS: The median overall
survival (OS) was 12.6 months in rLRT group and 11.4 months in CRT
group (p =0.347), progression-free survival (PFS) was 3.6 months in rLRT
group and 6.5 months in CRT group (p = 0.821), no significant survival
difference was observed between two groups. Temporary discontinuation
or tapering of steroids rate was significantly higher in rLRT group (100%vs 60%, p = 0.028). Although not statistically significant, mean nonhospitalized days were longer in the rLRT group, 403 days versus 305 daysin the CRT group, as were mean cumulative progression-free days, 276 days
versus 163 days and 1-year free from CSF diversion rate was higher, 100%
versus 64.9%. CONCLUSIONS: For patients with newly diagnosed DIPG,
repeated low dose RT, given over 3 to 4 weeks per cycle for 1 to 3 cycles,
offers comparable survival outcome with less disease burden compared withconventional RT.
DIPG-29. PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE(PI3K) INHIBITION DRIVES PROTEIN KINASE C ACTIVATION (PKC)IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Ryan J. Duchatel1,2, Abdul Mannan1,2, Evangeline R. Jackson1,2,
Dilana Staudt1,2, David A. Skerrett-Byrne3, M. Fairuz B. Jamaluddin2,
Ameha S. Woldu1,2, Alicia Douglas1,2, Esther Hulleman4,
Angel M. Carcaboso5,6, Michelle Monje7, Frank Alvaro2,8, Maria Tsoli9,David S. Ziegler9,10, and Matthew D. Dun1,2; 1Cancer Signalling ResearchGroup, School of Biomedical Science and Pharmacy, Faculty of Health andMedicine, University of Newcastle, Callaghan, NSW, Australia, 2Priority
Research Centre for Cancer Research Innovation and Translation, Hunter
Medical Research Institute, Lambton, NSW, Australia, 3Priority ResearchCentre for Reproduction, Hunter Medical Research Institute, Lambton,
NSW, Australia, 4Princess Máxima Center for Pediatric Oncology, Utrecht,
Netherlands, 5Institute de Recerca Sant Joan de Deu, Barcelona, Spain,
6Department of Pediatric Hematology and Oncology, Hospital Sant Joande Deu, Barcelona, Spain, 77 Departments of Neurology, Neurosurgery,
Pediatrics, and Pathology, Stanford University School of Medicine,
Stanford, CA, USA, 8John Hunter Children’s Hospital, Lambton, NSW,
Australia, 9Childrens Cancer Institute, University of NSW, Randwick, NSW,
Australia, 10Kids Cancer Centre, Sydney Children’s Hospital, Randwick,
NSW, Australia
Recurring somatic mutations and gene amplifications to members of thephosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling axis are
overarching contributors to the aggressive growth and survival of diffuse intrinsic pontine gliomas (DIPG). However, targeting PI3K has thus far failed
to improve outcomes for patients in the clinic. To identify the mechanisms
underpinning PI3K/AKT/mTOR treatment failure in DIPG, we have employed high-resolution quantitative phosphoproteomic profiling in patientderived DIPG cell lines harboring H3K27M and PI3K mutations, +/- theblood-brain barrier permeable PI3K inhibitor, paxalisib (previously “GDC0084”, currently in Phase I trials - NCT03696355) and rapamycin. Paxalisib
was significantly more potent than rapamycin at inducing PI3K/AKT/mTOR
inhibition, however, both simultaneously activated protein kinase C signaling(pT500PKCβ +8.2 and +4.5 fold, respectively). PKC lies directly upstream of
myristoylated alanine-rich C-kinase substrate (MARCKs), which was phosphorylated at Ser170 by +9.4 and +4.7 fold, respectively; promoting actin
cytoskeletal remodeling and cellular migration. Indeed, activation of PKC
signaling using phorbol 12-myristate 13-acetate (PMA), increased DIPG
cell growth and migration by >3 fold. Targeting PKC using midostaurin(FDA-approved for acute myeloid leukemia), and enzastaurin (blood-brain
barrier penetrant inhibitor of PKCβ), in combination with paxalisib was
highly synergistic (CI=<0.9), reducing proliferation and driving apoptosis.
Mechanistically, compensatory activation of PKC signaling following PI3K
inhibition was regulated by the accumulation of Ca+2 ions, as chelation usingAbstracts

BAPTA-AM significantly reduced PKC activity following PI3K inhibition.
These data highlight the power of phosphoproteomic profiling for the rational design of drug combination strategies, which need to be tested in vivo
prior to clinical trials for DIPG.
DIPG-31. MOLECULAR MECHANISMS AND FUNCTIONAL IMPACT
OF ABERRANT SPLICING IN DIFFUSE MIDLINE GLIOMAS
Ammar Naqvi1,2, Krutika Gaonkar1,2, Yuankun Zhu1,2, Miguel Brown1,2,
Bo Zhang1,2, Brian Ennis1,2, Phillip Storm1,2, Adam Resnick1,2, andJo Lynne Rokita1,2; 1Children’s Hospital of Philadelphia, Philadelphia, PA,
USA, 2Center for Data-Driven Discovery in Biomedicine, Philadelphia, PA,
USA
Fewer than 1% of children diagnosed with diffuse-midline glioma (DMG)
survive for more than 5 years, because no effective therapies exist for thesepatients. Here, we sought to identify and characterize mechanisms of aberrant splicing (AS) in primary DMG tumors. We observed transcriptomewide AS (9,805 differential splicing variations in 4,734 genes), and identified
a DMG-specific splicing signature, that included known cancer genes. We
hypothesize that AS of cancer genes play a role in DMG tumor formation.
Assessing whether splicing factor dysregulation impacted known cancer
transcripts, we discovered several splicing factors, including SRRM4,
SRRM3 and RBFOX3 to be down-regulated in DMG. Additionally, we
found an enrichment of binding motifs for these proteins within flanking
regions of these mis-spliced exons. We also observed recurrent significant
exon inclusion in tumor suppressor SMARCA4, an integral member of the
SWI/SNF family of proteins involved in chromatin remodeling. Further, we
identified AS in 16 of the 27 members of the SWI/SNF complex, including
increased skipping of exon 7 in DPF2, representing a complete mRNA transcript switch in DMG. Since SRRM4, SRRM3 and RBFOX3 are known
regulators for neural-specific microexons, we focused on microexon splicing
changes, hypothesizing that these regulators may be driving microexon missplicing in these tumors. We identified 245 known microexons lost or gainedin DMG. Moreover, a quarter of which were observed in known cancer
genes, with the most frequent splice event causing gain of a clathrin-bindingsite in the tumor suppressor BIN1 with a concurrent loss of an out-of-frame
microexon in the oncogene BAK1, presumably activating it. Altogether,
our results suggest that aberrant splicing may be an alternative mechanism
driving DMG tumorigenesis and we are currently molecularly validating a
subset of these events with the overall goal of identifying novel therapeutictargets for DMG tumors.
DIPG-32. AKT SIGNALING DRIVES RESISTANCE TO ONC201 IN
DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Evangeline R. Jackson1,2, Ryan J. Duchatel1,2, Abdul Mannan1,2,
Esther Hulleman3, Angel M. Carcaboso4,5, Michelle Monje6,
Geoff B. McCowage7, Frank Alvaro2,8, and Matthew D. Dun1,2; 1Cancer
Signaling Research Group, School of Biomedical Sciences and Pharmacy,
Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW,
Australia, 2Priority Research Centre for Cancer Research Innovation andTranslation, Hunter Medical Research Institute, New Lambton Heights,
NSW, Australia, 3Princess Máxima Center for Pediatric Oncology, Utrecht,
Netherlands, 4Institute de Recerca Sant Joan de Deu, Barcelona, Spain,
5Department of Pediatric Hematology and Oncology, Hospital Sant Joande Deu, Barcelona, Spain, 6Departments of Neurology, Neurosurgery,
Pediatrics, and Pathology, Stanford University School of Medicine,
Stanford, CA, USA, 7Department of Oncology, The Children’s Hospitalat Westmead, Sydney, NSW, Australia, 8John Hunter Children’s Hospital,
New Lambton Heights, NSW, Australia
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive, childhood
brainstem cancer with a median overall survival of 10 months post diagnosis. Remarkably, 80–90% of patients harbor recurring point mutation inhistone H3, which induces a lysine for methionine substitution at aminoacid 27 (H3K27M) in either H3.1 (HIST1H3B ~25%) or H3.3 (H3F3A~65%) variants. Using the blood-brain barrier (BBB) permeable DRD2 antagonist, ONC201 (in clinical trials for DIPG and H3K27M-mutant gliomas– NCT03416530), we hypothesized that DRD2 antagonism would induce
TRAIL expression via indirect inhibition of AKT and ERK signaling, todrive apoptosis in both H3.1K27M and H3.3K27M patient-derived DIPG
cell lines alike. For the first time, we reveal that ONC201 shows efficacy
in 100% of WT-H3 and H3.1K27M mutant DIPG cell lines (n=5), compared to 50% of H3.3K27M mutant DIPGs (n=6). Investigations to identify the mechanisms of resistance to ONC201, revealed that cell lines withdecreased sensitivity upregulated the PI3K/AKT/MTOR signaling axis todrive phosphorylation of AKT and increase metabolic activity. Combined
administration of ONC201 and the BBB-permeable PI3K/AKT inhibitor,
paxalisib (previously GDC-0084, in clinical trials for newly diagnosed DIPG
– NCT03696355), showed synergistic cytotoxicity, reduced PI3K/AKT
signaling and metabolic reprogramming to drive apoptosis in all DIPG celllines tested. This combination was used to treat a 3-year-old DIPG patient,commencing 14 weeks post disease progression, completing 40 weeks oftherapy prior to her passing, December 2019. These studies highlight the potential of combined administration of two safe, BBB penetrant, oral targeted
therapies and supports testing under clinical trial conditions.
DIPG-33. CHARACTERIZING THE NEURO-VASCULAR UNIT IN
DIFFUSE INTRINSIC PONTINE GLIOMA
Fatma E. El-Khouly1,2, Rianne Haumann1,2, Marjolein Breur3,
Sophie E.M. Veldhuijzen van Zanten1,2, Gertjan J.L. Kaspers1,2,
N. Harry Hendrikse4,5, Esther Hulleman1,2, Dannis G. van Vuurden1,2,
Marianna Bugiani3; 1Emma Children’s Hospital, Amsterdam UMC,
Department of Pediatric Oncology/Hematology, Amsterdam, Netherlands,
2Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands,
3Amsterdam UMC, Department of Pathology, Amsterdam, Netherlands,
4Amsterdam UMC, Department of Clinical Pharmacology & Pharmacy,
Amsterdam, Netherlands, 5Amsterdam UMC, Department of Radiology &Nuclear Medicine, Amsterdam, Netherlands
Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor
with a median overall survival of eleven months. Lack of chemotherapy efficacy may be related to an intact blood-brain-barrier (BBB). In this study
we aim to compare the neuro-vascular unit (NVU) of DIPG to healthy
pons tissue. End-stage DIPG autopsy samples (n=5) and age-matchedhealthy pons samples (n=22), obtained from the NIH NeuroBioBank, were
immunohistochemically stained for tight-junction proteins claudin-5 andzonula occludens-1 (ZO-1), basement membrane component laminin, andpericyte marker PDGFRβ. Claudin-5 stains were also used to determine vascular density and diameters. In DIPG, expression of claudin-5 and ZO-1
was reduced, and claudin-5 was dislocated to the abluminal side of endothelial cells. Laminin expression at the glia limitans was reduced in bothpre-existent vessels and neovascular proliferation. In contrast to healthy
pons, no PDGFRβ expression was detected. The number of blood vessels
in DIPG was significantly reduced compared to healthy pons, 13.9±11.8/mm2 versus 26.3±14.2/mm2, respectively (P<0.01). Especially the number ofsmaller blood vessels (<10µm) was significantly lower (P<0.01). Distributionof larger blood vessels (≥10µm) did not differ between groups (P=0.223).
Mean vascular diameter was 9.3±9.9µm for DIPG versus 7.7±9.0µm in
healthy pons (P=0.016). Our study demonstrates evidence of structuralchanges in the NVU in end-stage DIPG. Chemotherapeutic inefficacy could
be the result of reduced vascular density. However, further research is needed
to determine meaning and extent of these changes and to determine whether
these observations are caused by the tumor or the result of treatment.
DIPG-34. SUPER ELONGATION COMPLEX AS A TARGETABLE
DEPENDENCY IN H3K27M+ DIFFUSE MIDLINE GLIOMA
Nathan Dahl, Etienne Danis, Ilango Balakrishnan, Dong Wang,
Angela Pierce, Faye Walker, Ahmed Gilani, Natalie Serkova,
Krishna Madhaven, Susan Fosmire, Adam Green, Nicholas Foreman,
Sujatha Venkataraman, and Rajeev Vibhakar; University of Colorado,
Aurora, CO, USA
Mutations in the histone 3 gene (H3K27M) are the eponymous driver in
diffuse intrinsic pontine gliomas (DIPGs) and other diffuse midline gliomas(DMGs), aggressive pediatric brain tumors for which no curative therapy
currently exists. To identify specific epigenetic dependencies within the context of the H3K27M mutation, we performed an shRNA screen targeting
408 genes classified as epigenetic/chromatin-associated molecules in patientderived DMG cultures. This identified AFF4, a component of the superelongation complex (SEC), as necessary for DMG cells to maintain growthand self-renewal. We hypothesized that aberrant SEC expression occurs as
a consequence of the H3K27M mutation and that this dysregulated SEC
signaling overcomes repressive transcriptional regulation in order to suppresses differentiation and promote self-renewal of DMG tumor stem cells.
We interrogated the role of AFF4 in DMG using an shRNA lentiviral approach. We demonstrate a significant decrease in in vitro clonogenicity andstem cell maintenance following AFF4 depletion. We employed RNA-seqbased gene set enrichment analysis to delineate differentiation programs
under SEC regulatory control. Finally, we sought to determine whether
CDK9, the catalytic subunit of the SEC, represents a therapeutic vulnerability in DMG. Using RNA polymerase II ChIP-seq, we demonstrate that
CDK9 pharmacologic inhibition restores regulatory Pol II pausing, promotes cellular differentiation, and leads to potent anti-tumor effect bothin vitro and in patient-derived xenograft models. These studies present a
biologic rationale for the translational exploration of CDK9 inhibition as apromising therapeutic approach.
DIPG-35. BIOLOGICAL MEDICINE FOR DIFFUSE INTRINSICPONTINE GLIOMA (DIPG) ERADICATION: RESULTS OF THE
THREE ARM BIOMARKER-DRIVEN RANDOMIZED BIOMEDE 1.0
TRIAL
Jacques Grill1, Gwenael Le Teuff1, Karsten Nysom2, Klas Blomgren3,
Darren Hargrave4, Geoff MacCowage5, Francisco Bautista6,

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Dannis Van Vuurden7, Volodia Dangouloff-Ros8, Stephanie Puget8,
Pascale Varlet9, Marie-Anne Debily1, Gilles Vassal1,
Marie-Cecile Le Deley10; 1Gustave Roussy, Villejuif, Paris-Saclay, France,
2Righospitalet, Copenhagen, Denmark, 3Karolinska Institutet, Stockholm,
Sweden, 4UCL, London, England, United Kingdom, 5Children’s Hospital,
Westmead, NSW, Australia, 6Hospital del Nino Jesus, Madrid, Castilla,
Spain, 7Princess Maxima Center, Utrecht, Netherlands, 8Necker Hospital,
Paris, France, 9Sainte-Anne Neuroscience GHU, Paris, France, 10Centre
Oscar Lambert, Lille, France
Despite 50 years of clinical trials, no improvement of survival has been
observed in DIPG and most children die within 2 years of diagnosis. Only
radiotherapy transiently controls disease progression. The study was conceived as a randomized multi-arm multi-stage program. It started with
an open-label phase-II trial comparing three drugs (everolimus, dasatinib,
erlotinib) combined with irradiation, allocated according to the presenceof their specific targets (PTEN-loss, EGFR-overexpression) defined with astereotactic biopsy after central confirmation of the diagnosis (presence ofhistone H3K27M mutation or loss of K27 trimethylation). Targeted therapies were started concomitantly with radiotherapy and were continued
until disease progression. No biopsy-related death was reported and diagnostic yield was excellent, with only 5 non-informative biopsies. Biopsy excluded the diagnosisof DIPG in 8% of the cases. At the 3rd interim analysis,
based on 193 randomized patients, the IDMC concluded that the study was
unlikely to show a difference of OS between the 3 drugs even if 250 patients would be randomized. The median OS from the time of diagnosis was
11.9, 10.5 and 10 months for everolimus, dasatinib and erlotinib. Treatment was discontinued due to toxicity in 2%, 13%, and 15%, respectively.
BIOMEDE shows the feasibility of biologically-driven treatment in DIPG
on a large international scale. Based on the better toxicity profile and theslightly better efficacy, although not statistically significant, the steering committee proposed that everolimus should be used as the control arm for the
next BIOMEDE 2.0 trial.
DIPG-37. PREDICTING OUTCOME IN CHILDHOOD DIFFUSE
MIDLINE GLIOMAS USING MAGNETIC RESONANCE IMAGING
BASED TEXTURE ANALYSIS
Elwira Szychot1,2, Adam Youssef3, Balaji Ganeshan2, Raymond Endozo2,
Harpreet Hyare2, Jenny Gains2, Ananth Shankar2, and Kshitij Mankad3;
1Royal Marsden Hospital, London, United Kingdom, 2University College
London Hospital, London, United Kingdom, 3Great Ormond Street
Hospital, London, United Kingdom
BACKGROUND: Diffuse midline gliomas (DMG) are aggressive brain
tumours with 10% overall survival (OS) at 18 months. Predicting OS will
help refine treatment strategy in this patient group. MRI based texture analysis (MRTA) is a novel technique that provides objective information about
spatial arrangement of MRI signal intensity and has potential as an imaging
biomarker. OBJECTIVES: To investigate MRTA in predicting OS in childhood DMG. METHODS: Retrospective study of patients diagnosed with
DMG, based on radiological features, treated at our institution 2007–2017.
MRIs were accomplished at diagnosis and 6 weeks after radiotherapy (54Gy
in 30 fractions). MRTA, performed using TexRAD software, on T2W sequence and Apparent Diffusion Coefficient (ADC) maps encapsulated tumour in the largest single axial plane. MRTA comprised filtration-histogram
technique using statistical and histogram metrics for quantification of texture. Kaplan-Meier analysis determined association of MRI texture parameters with OS. RESULTS: 32 children 2–14 years (median 7 years) were
included. MRTA was undertaken on T2W (n=32) and ADC (n=22). MRTA
on T2W was better at prognosticating than on ADC maps. Children withhomogenous tumour texture, at medium scale on baseline T2W MRI, hadworse prognosis (mean p=0.0098, SD p=0.0115, entropy p=0.0422, meanof positive pixels (MPP) p=0.0051, kurtosis p=0.0374). MPP was the mostsignificant texture parameter. Median survival in this group as identified by
MRTA (medium texture, MPP) was 7.5 months versus 17.5 months. CONCLUSIONS: DMG with more homogeneous texture on diagnostic MRI is
associated with worse prognosis. MPP texture parameter is the most predictive of OS in childhood DMG.
DIPG-38. ADDITION OF MULTIMODAL IMMUNOTHERAPY TO
COMBINATION TREATMENT STRATEGIES FOR CHILDREN WITH
DIPG: FINAL RESULTS OF A COHORT OF CHILDREN
Stefaan Van Gool1, Jennifer Makalowski1, Erin R. Bonner2,
Oliver Feyen3, Matthias Domogalla1, Lothar Prix4, Volker Schirrmacher1,
Javad Nazarian5, and Wilfried Stücker1; 1IOZK, Köln, Germany, 2Center
for Genetic Medicine, Children’s National Health System, Washington,
DC, USA, 3Zyagnum, Pfungstadt, Germany, 4Biofocus, Recklinghausen,
Germany, 5DIPG Research Institute, Zürich, Germany
The prognosis of children with Diffuse Intrinsic Pontine Glioma (DIPG)
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De c e mb e r 2 0 2 0molecular biology diagnostics. Immunotherapy is a powerful and promising
approach for improving the overall survival (OS). A retrospective analysis
for feasibility, immune responsiveness and OS was performed on 41 children treated in compassionate use with Newcastle Disease Virus, hyperthermia and autologous dendritic cell vaccines as part of an individualized
combined treatment approach for DIPG patients at diagnosis (n=28), or attime of progression (n=13). All except one patient had reduced values ofat least one immune test before starting immunotherapy. In all patients atleast one PanTum Detect test was outside the normal range. Ten patients
had PDL1 mRNA expression in circulating tumor cells at diagnosis. Multimodal immunotherapy was feasible as scheduled, until progression, in all
patients without major toxicity. When immunotherapy was part of primary
treatment, median PFS and OS were 8.4m and 14.4m respectively with a
2-year OS of 10.7%. When immunotherapy was given at the time of progression, median PFS and OS calculated from diagnosis were 6.5m and 9.1m
respectively. Th1 shift and rise in PanTum Detect test scores were linked
with longer OS. Multimodal immunotherapy is feasible without major toxicity, and its value as part of a combination treatment for primary diagnosed
DIPG should be elaborated in clinical trials.
DIPG-39. NOVEL PROTEOMIC ANALYSIS REVEALS EPIGENETIC
THERAPEUTIC TARGETS IN PEDIATRIC GLIOMA
Daphne Li1, Tina Huang2, Jeannie Camarillo2, Andrea Piunti2, Jin Qi2,
Shejuan An2, Javad Nazarian3,4, Paul Thomas2, and Amanda Saratsis2,5;
1Loyola University Medical Center, Chicago, IL, USA, 2Northwestern
University Feinberg School of Medicine, Chicago, IL, USA, 3Children’s
National Medical Center, Washington, DC, USA, 4George Washington
University, Washington, DC, USA, 5Ann & Robert H, Lurie Children’s
Hospital of Chicago, Chicago, IL, USA
INTRODUCTION: Diffuse midline glioma is a highly morbid pediatriccancer. Up to 80% harbor Histone H3K27M mutation, which alters Histone
H3 post-translational modifications (PTMs) and genomic enrichment patterns, affecting chromatin structure and transcription. We previously identified tumorigenic patterns of H3K27Ac/bromodomain co-enrichment andpre-clinical efficacy of bromodomain inhibition (JQ1) in DMG. Here, we
employ a novel proteomics approach developed at our institution to further
elucidate the impact of H3K27M mutation on glioma epigenetic signatures
and treatment response. METHODS: Epiproteomic analysis was performedon pediatric glioma cells (H3K27 WT n=2, H3K27M n=2) to characterize 95
distinct Histone H3 N-terminal tail modification states. Cells were treatedwith JQ1 or DMSO, and collected at 0h, 24h, 48h, Histones extracted
from isolated nuclei and immunopurified, then analyzed by LC-MS/MS.
Results were integrated with RNA-Seq and ChIP Seq (H3.3K27M, H3.3,
H3K27Ac, H3K27me3, H3K4me1, H3K4me3) from the same cell lines.
Pediatric glioma tissues (H3K27M WT n=3, H3K27M n= 9) were similarly
analyzed to validate cell line results. RESULTS: Cell PTM profiles clusterby H3 mutation status on unsupervised analysis. Significant differential
PTM abundance and genomic enrichment H3K27M, H3.3 WT, H3K27Me3
and H3K27Ac was observed between mutant and wild type cell lines with
epigenetic-targeted therapy, correlating with cell transcriptomes. CONCLUSIONS: Histone H3 tail analysis reveals the effects of H3K27M mutation
and bromodomain inhibition on the tumor epigenetic landscape, providing
insight into mechanisms of tumorigenesis and therapy response. Further investigation of the utility of these signatures as biomarkers for diagnosis andmonitoring treatment response are therefore underway.
DIPG-40. TARGETING MASTER REGULATOR DEPENDENCIES IN
DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Jovana Pavisic1, Chankrit Sethi1, Chris Jones2, Stergios Zacharoulis1, andAndrea Califano1; 1Columbia University Irving Medical Center, New York,NY, USA, 2Institute for Cancer Research, London, United Kingdom
Diffuse intrinsic pontine glioma (DIPG) remains a fatal disease with noeffective drugs to date. Mutation-based precision oncology approaches arelimited by lack of targetable mutations and genetic heterogeneity. We leveraged systems biology methodologies to discover common targetable disease
drivers—master regulator proteins (MRs)—in DIPG to expand treatment
options. Using the metaVIPER algorithm, we interrogated an integrated low
grade glioma and GBM gene regulatory network with 31 DIPG-gene expression signatures to identify tumor-specific MRs by differential expression of their transcriptional targets. Unsupervised clustering identified MR
signatures of upregulated activity in RRM2/TOP2A in 13 patients, CD3D
in 5 patients, and MMP7, TACSTD2, RAC2 and SLC15A1/SLC34A2 in individual patients, all of which can be targeted. Notably, intratumoral administration of etoposide by convection enhanced delivery was effective inmurine proneural gliomas in which TOP2 was identified as a MR while
RRM2—targetable by drugs such as cladribine—has been shown to be apositive regulator of glioma progression whose knock-down inhibits tumor
growth. We also prioritized drugs by their ability to reverse MR-activity
signatures using a large drug-perturbation database. Patients clustered by

Abstracts

predicted drug sensitivities with distinct groups of tumors predicted to respond to proteasome inhibitors, Thiotepa or Volasertib all of which haveearly evidence in treating gliomas. We will refine this analysis in a multiinstitutional study of >100 patient gene expression profiles to define MR
signatures driving known biological/molecular disease subtypes, use DIPG
cell lines recapitulating common MR architectures to optimize therapy prioritization, and validate our findings in vivo.
DIPG-41. DISSECTING THE MECHANISTIC BASIS FOR ACVR1 AND
PIK3CA MUTATION CO-OCCURRENCE IN DIFFUSE MIDLINEGLIOMAS USING GENETICALLY ENGINEERED MOUSE MODELS
Annette Wu, Tak Mak, and Jerome Fortin; Princess Margaret Cancer
Centre, University Health Network, Toronto, ON, Canada
Diffuse midline gliomas (DMGs) are aggressive childhood brain tumors
with a dismal prognosis. Most of these tumors carry K27M mutations in histone H3-encoding genes, particularly H3F3A and HIST1H3B. In addition,
activating mutations in ACVR1 and PIK3CA co-occur in a subset of DMGs. To
understand how these lesions drive the development of DMGs, we generated
genetically engineered mouse models in which Acvr1G328V, Hist1h3bK27M,
and Pik3caH1047R are targeted to the OLIG2-expressing cell lineage. Animals carrying Acvr1G328V and Pik3caH1047R, with (“AHPO”) or without(“APO”) Hist1h3bK27M, developed high-grade diffuse gliomas involving midline and forebrain regions. Neither Acvr1G328V nor Pik3caH1047R drove
tumorigenesis by themselves, but Acvr1G328V was sufficient to cause oligodendroglial differentiation arrest, pointing to a role in the earliest stages ofgliomas formation. Transcriptomic analyses of AHPO and APO tumors indicated a predominantly proneural and oligodendrocyte precursor-like gene expression signature, consistent with the corresponding human pathology. Genes
encoding transcription factors (TFs) with dual roles in controlling glial andneuronal differentiation were upregulated in tumors. Some of these genes weremildly induced by Acvr1G328V alone. Functional experiments using CRISPR/
Cas9-mediated gene editing in patient-derived cell lines confirmed a role forsome of these TFs in controlling DMG cell fitness. Overall, our results suggestthat Pik3caH1047R consolidates Acvr1G328V-induced glial differentiationarrest to drive DMG development and progression.
DIPG-42. TOWARD MULTIMODALITY THERAPY FOR DIPG/
DMG: DEVELOPMENT AND INVESTIGATION OF CRANIOSPINALIRRADIATION AND CONVECTION-ENHANCED DELIVERY PDXMODELS
Aaron J Knox1, Ahmed Gilani1, Benjamin van Court1, Ayman Oweida1,
Patrick Flannery1, John DeSisto1, Rakeb Lemma1, Hannah Chatwin1,
Fabia Gamboni1, Benjamin Brown1, Natalie Serkova1, Rajeev Vibhakar1,
Kathleen Dorris1, Michael Wempe2, Julie A Reisz1, Sana D Karam1, andAdam L Green1; 1The Morgan Adams Foundation Pediatric Brain Tumor
Research Program, University of Colorado School of Medicine/Children’s
Hospital Colorado, Aurora, CO, USA, 2University of Colorado School of
Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) and diffuse
midline glioma (DMG) are metastatic diseases, as demonstrated by early
convection-enhanced delivery (CED) clinical trials in which prolonged local
tumor control can sometimes be achieved, but fatal disseminated disease thendevelops. We hypothesize that improvements in treatment of both focal disease
and the entire neuraxis are necessary for long-term survival, and patient-derived
xenograft (PDX) models can help advance these efforts. METHODS: We useda BT245 murine orthotopic DIPG PDX model for this work. We developed aprotocol and specialized platform to deliver craniospinal irradiation (CSI) witha pontine boost. We separately compared intratumoral drug concentration by
CED and intraperitoneal delivery. In our CED model, mice receive gemcitabine
60 ug x1 in 15 ul at 0.5 ul/minute through a stepped catheter design with silica
tubing extending 2mm beyond a 27G needle. RESULTS: Mice receiving CSI(4 Gy x2d) plus boost (4 Gy x2d) showed minimal spinal and brain leptomeningeal metastatic disease by bioluminescence, MRI, and pathology compared to mice receiving radiation to the pons only (4 Gy x4d) or no radiation.
CED achieved an intratumoral gemcitabine concentration 50-fold greater thanintraperitoneal dosing when controlled for dose. CONCLUSIONS: In a DIPGPDX model, CSI+boost minimizes tumor dissemination compared to focal radiation, and CED achieves clinically significant improvements in intratumoral
chemotherapy concentration compared to systemic delivery. Adding these modalities to current treatment could improve both focal and metastatic tumor
control, leading to meaningful improvements in survival.
DIPG-43. CAN WE REPROGRAM DIFFUSE INTRINSIC PONTINEGLIOMA (DIPG)? EXPLORING THE ROLE OF DISTALLESS/DLXHOMEOBOX GENE REGULATION OF OLIGODENDROGLIAL
PROGENITOR CELLS (OPC) IN THE DEVELOPING VERTEBRATENERVOUS SYSTEM
Mikaela Nevin1, Janine Gallego1, Xiaohua Song1, Qiang Jiang1,
Alan Underhill1, Roseline Godbout1, Oren Becher2, and David Eisenstat1;

1University of Alberta, Edmonton, AB, Canada, 2Northwestern University,
Chicago, IL, USA

BACKGROUND: The identification of H3.3/H3.1K27M in most DIPG
has changed our understanding of this disease. H3K27M mutations usually demonstrate global loss of H3K27 trimethylation (me3) with gain of
H3K27 acetylation (ac). Single cell RNAseq has identified the putative cell oforigin as oligodendroglial progenitor cells (OPC). The distalless gene family
is necessary for the differentiation and tangential migration of committed
neural progenitors to become GABAergic interneurons. Dlx1/Dlx2 double
knockout (DKO) cells from the ganglionic eminences (GE) transplanted
into a wild-type environment become oligodendrocytes. RESULTS: We
identified DLX2 occupancy of early (Olig2, Nkx2.2) and late (Myt1, Plp1)
genes required for OPC differentiation in vivo and confirmed direct DLX2
protein-promoter DNA binding in vitro. Co-expression of Dlx2 with target
sequences reduced reporter gene expression in vitro. There was increased
expression of OLIG2, NKX2.2 and PLP-1 expression in vivo, consistent
with de-repression in the absence of Dlx1/Dlx2 function. Transient overexpression of a Dlx2-GFP construct into murine DIPG cells from a GEMM
that develops DIPG resulted in significant increases in expression of Gad
isoforms with concomitant decreases in Olig2 and Nkx2.2. Dlx2-transfected
mDIPG cells also demonstrated reduced migration, invasion and colony formation in vitro. Of significance, there was global restoration of H3K27me3
with corresponding loss of H3K27ac expression in transfected cells compared to controls. CONCLUSIONS: DLX2 promotes GABAergic differentiation and migration while concomitantly repressing OPC differentiation in
vivo. Developmental reprogramming of mDIPG cells by DLX2 demonstrates
the potential role for directed differentiation strategies towards improving
patient outcomes for this devastating pediatric cancer.
DIPG-44. A GAIN OF FUNCTION EZH2 MUTATION DELAYSDIFFUSE INTRINSIC PONTINE GLIOMA PROGRESSION
Swati Dhar1,2, Samantha Gadd1, Daniel Brat2, and Oren Becher1,2; 1Ann
& Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA,
2Northwestern University, Chicago, IL, USA
BACKGROUND: Diffuse Intrinsic Pontine Glioma (DIPG) remains an
incurable pediatric brain cancer. The oncohistone H3K27M implicated in
80% of the cases, is also predicted to target Enhancer of Zeste Homolog
2 (Ezh2), the catalytic component of the Polycomb Repressor Complex
2 (PRC2). There are no reported mutations of Ezh2 and its function in
DIPG is not fully determined. This work aims to address the role of Ezh2
in DIPG. METHODS: Brainstem tumors were established by intracranial
injections of Nestin;Tv-a; Ezh2Y641F/+ (NTv-a; Ezh2Y641F/+) neonatal pups
using Replication Competent Avian Sarcoma leucosis virus long terminal
repeat with splice acceptor (RCAS) viruses, expressing PDGF-B, p53 shRNA,
and RCAS-CRE/Y. Immunohistochemical staining for Ki-67 and H3K27me3
were performed on the Discovery ULTRA (Ventana). RESULTS: Ezh2
overexpression (Ezh2Y641F/+, RCAS CRE) conferred a survival advantage ofapproximately 10 days (n=20 mice/group, p<0.001). H3K27me3 levels weresignificantly upregulated in RCAS CRE group (50% vs 20% in RCAS Y,
n=4 tumors/group, p<0.03), with a concomitant lower Ki-67 staining (30%
vs. 55% in RCAS Y, n=3 tumors/group, p<0.05). Interestingly, pathologicalreview categorized more RCAS-CRE tumors as ‘atypical’. RNA-sequencing
of virus-infected neural precursor cells revealed a suppression of inflammatory/interferon gene signature in the Ezh2 overexpression group. CONCLUSIONS AND FUTURE DIRECTIONS: Enhanced Ezh2 activity appears todelay DIPG pathogenesis. Ongoing work aims to highlight the contributionof differentially expressed gene signatures that contribute to this phenotype.
DIPG-46. NON-DIPG PATIENTS ENROLLED IN THE
INTERNATIONAL DIPG REGISTRY: HISTOPATHOLOGICEVALUATION OF CENTRAL NEURO-IMAGING REVIEWMargot A. Lazow1, Christine Fuller1, Adam Lane1,
Mariko D. DeWire-Schottmiller1, Pratiti Bandopadhayay2, Ute Bartels3,
Eric Bouffet3, Sylvia Cheng4, Kenneth J. Cohen5, Tabitha M. Cooney6,
Scott L. Coven7, Hetal Dholaria8, Blanca Diez9, Kathleen Dorris10,
Motasem El-Ayadi11, Ayman El-Sheikh12, Paul G. Fisher13,
Mercedes Garcia Lombardi14, Robert J. Greiner15, Stewart Goldman16,
Nicholas Gottardo8, Sridharan Gururangan17, Jordan R. Hansford18,
Tim Hassall19, Cynthia Hawkins3, Lindsay Kilburn20, Carl J. Koschmann21,
Sarah E. Leary22, Jie Ma23, Jane E. Minturn24,
Michelle Monje-Deisseroth13, Roger J. Packer20, Yvan Samson25,
Eric S. Sandler26, Gustavo Sevlever9, Christopher Tinkle27, Karen Tsui28,
Lars M. Wagner29, Mohamed Zaghloul11, David S. Ziegler30,
Brooklyn Chaney1, Katie Black1, Anthony Asher1, Rachid Drissi1,
Maryam Fouladi1, Blaise V. Jones1, and James L. Leach1; 1Cincinnati
Children’s Hospital Medical Center, Cincinnati, OH, USA, 2BostonChildren’s Hospital, Boston, MA, USA, 3Hospital for Sick Children,
Toronto, ON, Canada, 4BC Children’s Hospital, Vancouver, BC, Canada,
5Johns Hopkins, Baltimore, MD, USA, 6UCSF Benioff Children’s Hospital
Oakland, Oakland, CA, USA, 7Riley Children’s Health, Indianapolis, IN,

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USA, 8Perth Children’s Hospital, Nedlands, WA, Australia, 9Fundacionpara Lucha contra las Enfermedes Neurologicas de Infantes, Buenos Aires,
Argentina, 10Children’s Hospital Colorado, Aurora, CO, USA, 11Children’s
Cancer Hospital Egypt, Cairo, Egypt, 12Dayton Children’s Hospital,
Dayton, OH, USA, 13Stanford Children’s Health, Palo Alto, CA, USA,
14Hospital de Ninos Ricardo Gutierrez, Gallo, Argentina, 15Penn State
Health Children’s Hospital, Hershey, PA, USA, 16Ann & Robert H, LurieChildren’s Hospital of Chicago, Chicago, IL, USA, 17University of Florida,
Gainesville, FL, USA, 18The Royal Children’s Hospital, Parkville, Australia,
19Queensland Children’s Hospital, South Brisbane, Australia, 20Children’s
National, Washington, DC, USA, 21University of Michigan, Ann Arbor, MI,
USA, 22Seattle Children’s, Seattle, WA, USA, 23Xinhua Hospital, Shanghai
Jiao Tong University School of Medicine, Shanghai, China, 24Children’s
Hospital of Philadelphia, Philadelphia, PA, USA, 25CHU Saint Justine,
Montreal, Canada, 26Nemous Children’s Health System, Jacksonville,
FL, USA, 27St, Jude Children’s Research Hospital, Memphis, TN, USA,
28Starship Children’s Health, Auckland, New Zealand, 29University of
Kentucky College of Medicine, Lexington, KY, USA, 30Sydney Children’s
Hospital, Sydney, Australia
INTRODUCTION: The role of diagnostic biopsy in diffuse intrinsic pontine glioma (DIPG) remains in question. Distinguishing radiographically between DIPG and other pontine tumors with more favorable prognosis anddifferent therapy is critically important. METHODS: Cases submitted to theInternational DIPG registry with histopathologic data were analyzed. Central imaging review was performed by two neuro-radiologists; all cases withimaging features or histopathology suggestive of alternative diagnoses werere-reviewed. Imaging features suggestive of alternative diagnoses included
non-pontine origin, <50% pontine involvement (without typical DIPG pattern on follow-up), focally exophytic morphology, sharply-defined margins,or marked diffusion restriction throughout. RESULTS: Among 297 patientswith pathology from biopsy and/or autopsy available, 27 (9%) had histologic
diagnoses not consistent with DIPG, commonly embryonal tumors (n=9) andpilocytic astrocytomas (n=11). 163 patients had diagnostic MRI available forcentral neuroimaging review. Among 81 patients classified as characteristicof DIPG, 80 (99%) had histopathology consistent with DIPG (diffuse midline glioma, H3K27M-mutant, glioblastoma, anaplastic astrocytoma, diffuse
astrocytoma). Among 63 patients classified as likely DIPG, but with unusual
imaging features, 59 (94%) had histopathology consistent with DIPG. 19 patients had imaging features suggestive of another diagnosis, including 13 with
non-pontine tumor origin; the remaining 6 all had histopathology not consistent with DIPG. Association between central imaging review and histopathology was significant (p<0.001). CONCLUSIONS: The important role andaccuracy of central neuroimaging review in diagnosing or excluding DIPG isdemonstrated. In patients with pontine tumors for which DIPG is felt unlikely
radiographically, biopsy may be considered to guide diagnosis and treatment.
DIPG-47. HISTONE MUTATIONS ENHANCE RAS MEDIATED ERK5GROWTH SIGNALING IN DIFFUSE MIDLINE GLIOMASAnn-Catherine Stanton1, Robert Koncar1, Brian Golbourn1, Brittany Dey1,
Nishant Agrawal1, Stephen Mack2, Ian Pollack1, and Sameer Agnihotri1;
1Department of Neurological Surgery, Children’s Hospital, University ofPittsburgh, Pittsburgh, PA, USA, 2Department of Pediatrics, Section of
Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA
Diffuse midline gliomas (DMGs) are incurable brain tumors with an aggressive
onset. Apart from irradiation, there are currently no effective therapies available
for patients with DMG, who have a median survival time of less than one year.
Most DMG cells harbor mutations in genes encoding histone H3 (H3K27M)
proteins, resulting in a global reduction of H3K27 trimethylation and activationof oncogenic signaling pathways. Here we show that the H3K27M mutations
contribute to RAS pathway signaling, which is augmented by additional RAS
activators including PDGFRA. H3K27M mutation led to increased expressionof receptor tyrosine kinases (RTK). A RAS pathway functional screen identified
ERK5, but not ERK1/2, as a RAS pathway effector important for DMG growth.
Suppression of ERK5 decreased DMG cell proliferation and induced apoptosis
in vitro and in vivo. In addition, depletion or inhibition of ERK5 significantly
increased survival of mice intracranially engrafted with DMG cells. Mechanistically, ERK5 directly stabilized the proto-oncogene MYC at the protein level. Additionally, persistent ERK5 depletion does not result in complete growth inhibition
and therefore we set out to determine potential adaptation or resistance mechanisms in response to ERK5 loss. Using RNA-sequencing and Immunoprecipitation(IP) mass spectrometry (IP-MS), we have identified several positive and negative
feedbacks involved in ERK5 that are also targetable. These findings identify the
H3K27M mutation as an enhancer of RAS activation in DMG with ERK5 and
ERK5 regulated networks immediately actionable pathways.
DIPG-49. BRAINSTEM AND PONTINE VOLUMETRIC ANALYSISAS A SURROGATE MEASURE OF LOCAL DISEASE CONTROL IN
CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Evan D. Bander1,2, Morgan E. Freret2, Eva Wembacher-Schroeder3,Suzanne L. Wolden2, and Mark M. Souweidane1; 1Weill Cornell Medical

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College/NY Presbyterian Hospital, New York, NY, USA, 2Memorial Sloan
Kettering Cancer Center, New York, NY, USA, 3Brainlab AG, Munich,Germany
INTRODUCTION: Response-assessment in pediatric neuro-oncology(RAPNO) criteria designed to describe treatment outcomes are poorly implemented in diffuse intrinsic pontine glioma (DIPG), due to inter-observer
variability in measurement of tumor volume, lack of tumor enhancement,
and undefined relationships between radiographic parameters and survival.
Given these issues, this study assessed whether anatomically defined brainstem and pontine volumes can serve as surrogate measures of local disease
burden and response to therapy in DIPG. METHODS: Thirty-two consecutive patients with newly diagnosed DIPG were treated with standard
definitive radiation therapy (RT) between 2010 and 2016 at a single institution. MRI brain scans throughout treatment course were analyzed using
iPlan® Flow software (Brainlab AG, Munich, Germany). Semi-automated
3D measurements of the brainstem and pons were calculated using a built-in
knowledge-based segmentation approach and manually adjusted. RESULTS: Mean age at diagnosis was 6.5+/-0.5 years (range 2–12 years). Median follow up time was 317 days. Average brainstem volume at diagnosis(Vdiag) was 52.7+/-2.1mL with subsequent decrease at first post-RT MRI to
41.4+/-2.0mL (p < 0.0001). By time of last follow up, brainstem volume increased to 51.9+/-3.3, no longer significantly different as compared to Vdiag(p=0.61). The same relationships were found for pontine volume. CONCLUSIONS: Volumetric changes in the brainstem and pons occur in response to treatment and correlate with local disease burden and responseto therapy. This surrogate may be a useful standardized measure in ongoingand future trials involving localized delivery of therapeutics in DIPG that
require evaluation of local-regional disease control in addition to survival.
DIPG-50. A NOVEL ORTHOTOPIC PATIENT-DERIVED XENOGRAFTMODEL OF RADIATION-INDUCED GLIOMA
Jacqueline Whitehouse1,2, Meegan Howlett1,2, Jason Stanley1,2, Hilary Hii1,
Santosh Valvi3, Christine White4, Chelsea Mayoh5,6, Marie Wong5,6,
Brooke Strowger1, Jason Dyke7, Mark Cowley5,6, Nicholas Gottardo1,3,
Raelene Endersby1,2; 1Telethon Kids Institute, Perth, WA, Australia,
2University of Western Australia, Perth, WA, Australia, 3Perth Children’s
Hospital, Perth, WA, Australia, 4Hudson Institute of Medical Research,
Melbourne, VIC, Australia, 5Children’s Cancer Institute, Sydney, NSW,
Australia, 6University of New South Wales, Sydney, NSW, Australia, 7Royal
Perth Hospital, Perth, WA, Australia
Diffuse midline glioma (DMG) can arise as a primary tumour but also
as a consequence of radiation therapy (RT) in survivors of other paediatric brain tumours. Radiation-associated gliomas are molecularly distinct
from primary gliomas and have poorer overall survival. We report a caseof radiation-associated DMG following treatment for medulloblastoma,
and the development of a matched patient-derived xenograft (PDX) model.
A four-year-old boy diagnosed with medulloblastoma was treated with surgical resection, RT and chemotherapy (COG:CCG-99701-Arm B). Elevenyears post-diagnosis, the patient relapsed with radiation-associated DMG,
participated in a Phase I clinical trial (COG:ACNS0927), and passed away
eight months later. Tumour tissue collected at autopsy was intracraniallyimplanted into immunodeficient mice and serially transplanted in vivo.
Immunohistochemistry demonstrated both the primary DMG and PDXs
expressed PDGFR-alpha and PTEN, were H3K27me3-positive, and had
undetectable levels of p53. Sequencing revealed an activating mutation in
PI3-kinase (H1047L) and variants of unknown significance in GRK4, FLG,
BAZ2A, and CRTC3. DNA methylation array of the PDX demonstrated 1p
loss, which is not typically associated with primary DMG, and broad deletion
within 9p including CDKN2A/B, MTAP and multiple interferon genes. The
methylation profile did not significantly classify with other tumours in the
Molecular Neuropathology database (molecularneuropathology.org/mnp).
We describe the first reported PDX model of radiation-associated DMG following medulloblastoma, which recapitulates the patient disease and is molecularly distinct from primary DMG. Interrogation of this model throughRNA and whole genome sequencing presents a valuable opportunity tobetter understand and identify novel therapeutic vulnerabilities against thiscurrently incurable disease.
DIPG-51. ACVR1 MUTATIONS PROMOTE TUMOR GROWTH IN
MODELS OF DIFFUSE INTRINSIC PONTINE GLIOMA
Jennifer Ocasio Adorno1, Laura Hover1, Chen He1, Xiaoyan Zhu1,
David Goldhamer2, Angel Carcaboso3,4, Sridevi Yadavilli5,
Javad Nazarian5,6, and Suzanne Baker1; 1St. Jude Children’s Research
Hospital, Memphis, TN, USA, 2University of Connecticut, Storrs, CT, USA,
3Institut de Recerca Sant Joan de Deu, Barcelona, Spain, 4Hospital Sant Joande Deu, Barcelona, Spain, 5Children’s National Health System, Washington
DC, USA, 6George Washington University, Washington DC, USA
Mutations in the gene encoding activin A receptor type 1 (ACVR1)
are found in approximately 25% of diffuse intrinsic pontine gliomas

Abstracts(DIPGs), a pediatric glioma with 2-year survival rate of less than 10%.
ACVR1mutations frequently coincide with activating PIK3CA or PIK3R1
mutations, indicating a potential cooperative effect of BMP and PI3K
signaling in gliomagenesis. We used genetically engineered mice with inducible knock-in of Acvr1R206H or Pik3caE545K alleles, such that cre-mediatedrecombination resulted in expression of the gain of function mutated genes
from their endogenous promoters at physiological levels. Cre-mediateddeletion in GFAP-CreER;Pik3caE545K/+;p53cKO mice (Pik3ca;p53) mediated Trp53 deletion and expression of Pik3caE545K in glial progenitors, and spontaneously induced high-grade glioma (HGG) in mice withcomplete penetrance. Heterozygous knock-in of the Acvr1R206H allele accelerated tumorigenesis and impaired survival in Pik3ca;p53 mice
(Acvr1;Pik3ca;p53). Transcriptomic analysis of Acvr1;Pik3ca;p53 tumors
compared to Pik3ca;p53 littermate controls, as in patient-derived tumors,
revealed broad molecular signatures associated with cell fate commitment
and chromosome maintenance. Pharmacologic inhibition of ACVR1 was
sufficient to impair growth in human patient-derived DIPG cell lines. Together, our studies show that ACVR1 activation promotes tumor growth inspontaneous mouse HGG and patient-derived DIPG cells, suggesting that
ACVR1 inhibition may produce a clinically significant therapeutic effect in
DIPG.
DIPG-52. PHASE I CLINICAL TRIAL OF ONC201 IN PEDIATRIC H3
K27M-MUTANT GLIOMA OR NEWLY DIAGNOSED DIPG
Sharon Gardner1, Rohinton Tarapore2, Jeffrey Allen1, Wafik Zaky3,
Yazmin Odia4, Matthew Hall4, Doured Daghistani4, Ziad Khatib5,
Carl Koschmann6, Dolly Aguilera7, Tobey MacDonald7, Maryam Fouladi8,
Susan McGovern3, Cassie Kline9, Nicholas Vitanza10, Guangrong Lu2,
Krystal Merdinger2, Wolfgang Oster2, Joshua Allen2, and Soumen Khatua3;
1NYU Langone Medical Center and School of Medicine, New York, NY,
USA, 2Oncoceutics, Inc, Philadelphia, PA, USA, 3The University of Texas
MD Anderson Cancer Center, Houston, TX, USA, 4Miami Cancer Institute,
Baptist Health South Florida, Miami, FL, USA, 5Nicklaus Children’s
Hospital, Miami, FL, USA, 6Michigan Medicine, University of Michigan
Medical School, Ann Arbor, MI, USA, 7Children’s Healthcare of Atlanta,
Emory University School of Medicine, Atlanta, GA, USA, 8Cincinnati
Children’s Hospital, Cincinnati, OH, USA, 9University of California San
Francisco, San Francisco, CA, USA, 10Seattle Children’s Hospital, Seattle,
WA, USAH3 K27M-mutant gliomas often manifest as midline gliomas, have adismal prognosis, and have no effective treatments. ONC201 efficacy
has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adults withrecurrent H3 K27M-mutant gliomas. These observations led to a Phase
I pediatric clinical trial of ONC201 dosed by body weight. This multicenter, open-label, 3 + 3 dose-escalation and dose-expansion clinical trial(NCT03416530) for H3 K27M-mutant glioma or non-biopsied DIPG has
6 arms: arms A and E determine the RP2D in pediatric post-radiation(recurrent or not-recurrent) H3 K27M-mutant glioma patients with
ONC201 administered as an oral capsule as well as a liquid formulation,
respectively. Both arms have completed accrual. The study is currently
enrolling newly diagnosed DIPG patients to determine the RP2D for
ONC201 in combination with radiation (arm B). Dedicated assessmentof intratumoral ONC201 concentrations in midline gliomas patients (armC) and the effects of ONC201 in H3K27M DNA levels in circulating
CSF (arm D) are currently enrolling patients. ONC201 as a single agent
in patients with progressive H3K27M mutant tumors following irradiation (excluding DIPG/spinal cord tumors) was recently opened (arm F).
Once the RP2D is confirmed, there is a dose-expansion cohort to confirm
the safety, radiographic efficacy and survival with ONC201. The primary
endpoints of arms A, B, and E have been established with the RP2D of625mg scaled by body weight as a capsule or liquid formulation administered alone or in combination with radiation without incidence of doselimiting toxicity.
DIPG-53. CHARACTERIZING THE ROLE OF PPM1D MUTATIONSIN THE PATHOGENESIS OF DIFFUSE INTRINSIC PONTINEGLIOMAS (DIPGS)
Prasidda Khadka1,2, Zachary Reitman3, Sophie Lu1, Graham Buchan1,
Rachel Hartley4,5, Heather Bear4,5, Yoahnna Georgis1, Spandana Jarmale1,
Kathleen Schoolcraft1,6, Peter Miller1, Elizabeth Gonzalez1,
Gabrielle Gionet1, Kenin Qian1, Randy Melanson7, Hasmik Keshishian7,
Diana Carvalho8, Alexandra Condurat1, Amy Goodale7, Tanaz Abid7,
Federica Piccioni7, Susan Chi1,9, Steven Carr7, Daphne Haas-Kogan1,9,Benjamin Ebert1,6, Mark Kieran1, Chris Jones8, Keith Ligon1,6,Rameen Beroukhim1,6, Timothy Phoenix4,5, and Pratiti Bandopadha
yay1,9; 1Dana-Farber Cancer Institute, Boston, MA, USA, 2Harvard
Medical School, Boston, MA, USA, 3Duke University, Durham, NC, USA,
4University of Cincinnati, Cincinnati, OH, USA, 5Cincinnati Children’s
Hospital Medical Center, Cincinnati, OH, USA, 6Brigham and Women’s

Hospital, Boston, MA, USA, 7Broad Institute of MIT and Harvard, Boston,
MA, USA, 8Institute of Cancer Research, London, United Kingdom,
9Boston Children’s Hospital, Boston, MA, USA
INTRODUCTION: We have previously found that up to 15% of all
DIPGs harbor mutations in PPM1D, resulting in the expression of an activated and truncated PPM1D (PPM1Dtr). Here we evaluate the mechanisms
through which PPM1Dtr enhances glioma formation and identify its associated therapeutic vulnerabilities. METHODS: We have developed multiple
in vitro and in vivo models of PPM1D-mutant DIPGs and applied quantitative proteomic and functional genomic approaches to identify pathways
altered by PPM1Dtr and associated dependencies. RESULTS: PPM1D
mutations are clonal events that are anti-correlated to TP53 mutations. We
find ectopic expression of PPM1Dtr to be sufficient to enhance glioma formation and to be necessary in PPM1D-mutant DIPG cells. In addition, endogenous truncation of PPM1D is sufficient to enhance glioma formationin the presence of mutant H3F3A and PDGFRA. PPM1Dtr overexpression
attenuates g-H2AX formation and suppresses apoptosis and cell-cycle arrest in response to radiation treatment. Deep scale phosphoproteomics analyses reveal DNA-damage and cell cycle pathways to be most significantly
associated with PPM1Dtr. Furthermore, preliminary analysis of genomewide loss-of-function CRISPR/Cas9 screens in isogenic GFP and PPM1Dtr
overexpressing mouse neural stem cells reveal differential dependency on
DNA-damage response genes in the PPM1Dtr overexpressing cells. Consistent with PPM1D’s role in stabilizing MDM2, PPM1D-mutant DIPG
models are sensitive to a panel of MDM2 inhibitors (Nutlin-3a, RG7388,
and AMG232). CONCLUSION: Our study shows that PPM1Dtr is bothan oncogene and a dependency in PPM1D- mutant DIPG, and there arenovel therapeutic vulnerabilities associated with PPM1D that may be exploited.
DIPG-54. A NON-INVASIVE PROGNOSTIC CIRCULATING MIRNASSIGNATURE IN DIFFUSE INTRINSIC PONTINE GLIOMASMaria Federica Iannò, Elisabetta Schiavello, Andrea Carenzo,
Andrea Anichini, Veronica Biassoni, Lorenza Gandola, Loris De Cecco,and Maura Massimino; Fondazione IRCCS Istituto Nazionale dei Tumori,
Milan, Italy
Diffuse intrinsic pontine gliomas (DIPG) are the most common brainstem tumors of childhood and represent one of the most challenging paediatric tumours to treat. A non-randomized, open label phase II pilot study
was conducted at Fondazione IRCCS Istituto Nazionale Tumori (Milan)
to assess the efficacy in terms of objective response rate according to the
RECIST criteria of combining nimotuzumab and vinorelbine with radiation in newly-diagnosed DIPG. Serum specimens were collected at baseline.
microRNA expression profiling was performed using Agilent platform andHuman miRNA SureSelect 8x60K containing 2006 miRNAs annotated on
miRBase19.0. Primary data analysis yielded a matrix containing 330 detectable miRNA. Association with PFS allowed us to disclose a signature of
10 miRNAs able to stratify high and low risk patients (HR=4.33, 95%CI
1.49–12.54; p=4.27E-05). To test the 10 ct-miRNA model performance,
we collected an independent cohort of the same sample size (n=24) and we
derived the index values and risk stratification. The distribution of index
values covers a range similar to the discovery cohort. Imposing the signaturethreshold patients were divided in high/low risk and Kaplan-Meier curvesconfirmed the different PFS time for the two groups with HR=3.5 (95%CI:
1.8–8.01, p-value=0.0002) for the high-risk patients, reaching AUC=0.833.
Our signature is a biomarker based on non-invasive procedures for prognosis able to enter into clinical practice. Further validation on multicenter
case series is warranted.
DIPG-55. PATTERNS OF CEREBROSPINAL FLUID DIVERSION ANDSURVIVAL IN CHILDREN WITH DIFFUSE INTRINSIC PONTINEGLIOMA: A REPORT FROM THE INTERNATIONAL DIPGREGISTRY
Tabitha Cooney1, Mariko DeWire-Schottmiller2, Adam Lane2,
Raya Saab3, Pratiti Bandopadhayay1, Kathleen Dorris4, Roger Packer5,
Lindsey Kilburn5, Jane Minturn6, Andrew Dodgshun7, Sara Parkin7,
Stewart Goldman8, Eric Sandler9, Robert Greiner10, Nicholas Gottardo11,
Hetal Dholaria11, Scott L. Coven12, Tim Hassall13, Jordan Hansford14,
Yvan Samson15, Sarah Leary16, Ute Bartels17, Eric Bouffet17,
Christopher Tinkle18, Michelle Monje19, Paul G. Fisher19, David Ziegler20,
Murali Chintagumpala21, Lars Wagner22, Carl Koschmann23,
Elisa Carrasquedo Benito2, James Leach2, Blaise Jones2, Brooklyn Chaney2,
Katie Black2, Anthony Asher2, Hailey Bond2, Maryam Fouladi2, andKatherine E. Warren1; 1Dana Farber Cancer Institute, Boston, MA,
USA, 2Cincinnati Children’s Hospital, Cincinnati, OH, USA, 3American
University of Beirut, Beirut, Lebanon, 4Children’s Hospital Colorado,
Denver, CO, USA, 5Children’s National Hospital, Washington D,C, USA,
6Children’s Hospital of Philadelphia, Philadelphia, PA, USA, 7Christchurch
Hospital, Canterbury, New Zealand, 8Lurie Children’s Hospital, Chicago,

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IL, USA, 9Nemours Children’s Hospital, Orlando, FL, USA, 10Penn StateChildren’s Hospital, Hershey, PA, USA, 11Perth Children’s Hospital,
Nedlands, Australia, 12Riley Hospital for Children, Indianapolis, IN, USA,
13Queensland Children’s Hospital, South Brisbane, Queensland, Australia,
14The Royal Children’s Hospital, Melbourne, Australia, 15CHU SainteJustine, Montreal, Quebec, Canada, 16Seattle Children’s Hospital, Seattle,
WA, USA, 17The Hospital for Sick Children, Toronto, Ontario, Canada,
18St. Jude Children’s Research Hospital, Memphis, TN, USA, 19Stanford
University, Stanford, CA, USA, 20Sydney Children’s Hospital, Randwick,Australia, 21Texas Children’s Hospital, Houston, TX, USA, 22University of
Kentucky, Lexington, Kentucky, USA, 23University of Michigan, Ann Arbor,
MI, USA
There is no standard of care for cerebrospinal (CSF) diversion in children
with diffuse intrinsic pontine glioma (DIPG), nor understanding of survival
impact. We evaluated CSF diversion characteristics in children with DIPG
to determine incidence, indications and potential impact on survival. Data
was extracted from subjects registered in the International DIPG registry(IDIPGR). IDIPGR team personnel obtained clinical and radiographic datafrom the registry database and when appropriate, abstracted additional datafrom individual medical records. Univariable analyses were performed using
the Fisher’s exact test or Wilcoxon rank sum test. Survival was estimatedusing the Kaplan-Meier method. Evaluable patients (n=457) met criteria for
DIPG diagnosis by central radiology review. Ninety-two patients (20%) had
permanent CSF diversion. Indications for permanent diversion were hydrocephalus (41%), hydrocephalus and clinical symptoms (35%), and clinicalsymptoms alone (3%). Those with permanent diversion were significantly
younger at diagnosis than those without diversion (median 5.3 years vs
6.9 years, p=0.0002), otherwise no significant differences in gender, race,or treatment were found. The progression-free and overall survival of thosewith permanent CSF diversion compared to those without permanent diversion was 4.5 and 10.9 months vs 6.9 and 11.2 months, respectively(p=0.001, p= 0.4). There was no significant difference in overall survival
in patients with or without permanent CSF diversion among a large cohortof DIPG patients. Patients without permanent diversion had significantly
prolonged progression free survival compared to those with permanent diversion. The qualitative risks and benefits of permanent CSF diversion need
to be further evaluated.
DIPG-56. EXPLORATION OF TUMOR/STROMA INTERACTIONSIN DIPG XENOGRAFT BY SPECIES-SPECIFIC RNA-SEQ
DECONVOLUTION INDICATES A ROLE OF MICROGLIA CELL IN
DIPG DEVELOPMENT
Jane Merlevede1, Alexandre Plessier2, Arthur Felix3, Cathy Philippe4,
Ludivine Le Dret3, David Hardy5, Kevin Beccaria6, Jacques Grill3,
David Castel3, Pascale Varlet7, and Marie-Anne Debily3; 1Institut Curie,
Paris, France, 2Paris University, Paris, France, 3Gustave Roussy, Villejuif,
France, 4CEA, Paris, France, 5Institut Pasteur, Paris, France, 6Necker
Hospital, Paris, France, 7Saint-Anne Hospital, Paris, France
Diffuse Intrinsic Pontine Glioma (DIPG) and more largely Diffuse Midline
Gliomas H3 K27M-mutant (DMG) harbor a unique property of infiltration. Our objective is to elucidate/describe the cellular and molecular determinants of micro-environmental modifications resulting from the tumour/stroma dialogue as it might provide pro-invasive conditions that favour
the development of the disease. To this end, we performed RNA-seq analyses to characterize exhaustively the bidirectional molecular modificationsof the stroma/tumour in DIPG xenograft models. Gene expression changes
in murine microenvironment compartment were investigated as continuousor semi-continuous traits of tumor load by measuring transcriptome inzone with high vs. low infiltration. We observed substantial modulations ingene expression in the microenvironment associated with increasing tumor
cell content, pointing to a modification of the macrophage/microglial infiltrate. The expression or overexpression of several modulated genes wasvalidated by IHC in the stroma of DMG primary tumors. Among them,overexpression of the cytokine CCL3 was confirmed, reflecting the activation status of microglial cells. Moreover, we observed in patients that thedensity of IBA-1 positive microglial cells increases according to the extent oftumor infiltration and that a significant part of them harbor a mitotic status,
supporting their interaction with DMG cells. The involvement of this interaction in DMG development needs further evaluation and might represent
opportunity to slow down DIPG extension.
DIPG-57. TRANSCRIPTOMIC AND PROTEOMIC ANALYSES OF DIPGRESPONSE TO ONC201
Sreepradha Sridharan1, Arif Harmanci2, Ajay Sharma1, Yanlai Lai1,
Bridget Kennis1, Tara Dobson1, Jyothishmathi Swaminathan1,
Amanda Haltom1, Soumen Khatua1, Rohinton Tarapore3,
Joshua Allen3, Donghang Cheng1, Wafik Zaky1, andVidya Gopalakrishnan1; 1Division of Pediatrics, University of Texas
MD Anderson Cancer Center, Houston, TX, USA, 2Center for Precisioniii298N EU R O - O N C O L O G Y•

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Health, University of Texas Health Science Center, Houston, TX, USA,
3Oncoceutics, Inc., Philadelphia, PA, USA
Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain
tumor. Current standard of care has shown no improvements in survival.
Here, we report our study of ONC201, a first-in-class small molecule developed by Oncoceutics, Inc., against a panel of DIPG cells in vitro and inmouse orthotopic models. ONC201 inhibits signaling through dopamine
receptor D2 (DRD2), a G protein-coupled receptor (GPCR). MTT assays
revealed a delayed but more robust response to ONC201, as measured
by IC50 values, in DIPGs with histone H3.3-K27M expression comparedto cells expressing wildtype (WT) or K27M mutant histone H3.1. Interestingly, transcriptomic profiling identified an association of this responsedelay with an elevation of genes controlling the cellular unfolded protein
response, lysosomal and vacuole organization, and a decline in nucleic acidbiosynthetic genes. These cells were also more committed to neuronal andoligodendrocytic lineage specification. By contrast, WT-H3 DIPGs that survived ONC201 treatment were stem-like and exhibited altered expressionof genes controlling cell proliferation and apoptosis induction, respectively.
Single cell proteomics validated the increase in anti-apoptotic proteins inthese cells. Intraperitoneal administration of ONC201 for 7-weeks in micebearing pontine xenografts of histone H3.1-K27M mutant DIPGs, caused
a complete blockade of tumor growth relative to untreated controls. However, identical treatment of animals with forebrain tumors resulted only ina partial reduction in tumor burden, suggesting that the tumor microenvironment may be involved in the differential effect. These data indicate thattumor intrinsic and extrinsic factors may contribute to the response of DIPG
tumors to ONC201.
DIPG-58. HISTONE H3 WILD-TYPE DIPG/DMG OVEREXPRESSING
EZHIP EXTEND THE SPECTRUM OF DIFFUSE MIDLINE GLIOMASWITH PRC2 INHIBITION BEYOND H3-K27M MUTATIONDavid Castel1, Thomas Kergrohen1, Arnault Tauziède-Espariat2,
Alan Mackay3, Samia Ghermaoui1, Emmanuèle Lechapt2, Stefan Pfister4,
Christof Kramm5, Nathalie Boddaert6, Thomas Blauwblomme6,
Stéphanie Puget6, Kévin Beccaria6, Chris Jones3, David Jones4,
Pascale Varlet2, Jacques Grill1, and Marie-Anne Debily1; 1Gustave Roussy,
Villejuif, France, 2GHU Paris Psychiatrie Neurosciences, Paris, France, 3The
Institute of Cancer Research, London, United Kingdom, 4German Cancer
Research Center (DKFZ), Heidelberg, Germany, 5University Medical
Center, Goettingen, Germany, 6Hôpital Necker-Enfants Malades, Paris,
FranceDiffuse midline gliomas (DMG) H3 K27M-mutant were introduced in
the 2016 WHO Classification unifying diffuse intrinsic pontine gliomas(DIPG) and gliomas from the thalamus and spinal cord harboring a histone H3-K27M mutation leading to Polycomb Repressor Complex 2(PRC2) inhibition. However, few cases of DMG tumors presenting a H3K27
trimethylation loss, but lacking an H3-K27M mutation were reported. To
address this question, we combined a retrospective cohort of 10 patientsbiopsied for a DIPG at the Necker Hospital or included in the BIOMEDE
trial (NCT02233049) and extended our analysis to H3-wildtype (WT)
diffuse gliomas from other midline locations presenting either H3K27
trimethylation loss or ACVR1 mutation from Necker, ICR, the HERBY trial,
the INFORM registry study and the St. Jude PCGP representing 9 additional
cases. Genomic profiling identified alterations frequently found in DMG,
but none could explain the observed loss of H3K27 trimethylation. Similar
observations were previously made in the PF-A subgroup of ependymoma,
where the H3K27me3 loss resulted from EZHIP/CXorf67 overexpression
rather than H3-K27M mutations. We thus analyzed EZHIP expression
and observed its overexpression in all but one H3-WT DMGs comparedto H3-K27M mutated tumors (EZHIP negative). Strikingly, based on
their DNA methylation profiles, all H3-WT DMG samples analyzed clustered close to H3-K27M DIPG, rather than EZHIP overexpressing PF-A
ependymomas. To conclude, we described a new subgroup of DMG lacking
H3-K27M mutation, defined by H3K27 trimethylation loss and EZHIP
overexpression that can be detected by IHC. We propose that these EZHIP/
H3-WT DMGs extend the spectrum of DMG with PRC2 inhibition beyond
H3-K27M mutation.
DIPG-59. UPREGULATION OF PRENATAL PONTINE ID1
SIGNALING IN DIPG
Micah K. Harris1, Viveka Nand Yadav1, Stefanie Stallard1,
Rinette Woo2, Robert Siddaway3, Tingting Qin4, Brendan Mullan1,
Zachary Miklja1, Ruby Siada1, Ramya Ravindran1, Xuhong Cao5,
Amy Pasternak6, Maria G. Castro7, Pedro R. Lowenstein7, Rajen Mody1,
Arul Chinnaiyan5, Cynthia Hawkins8, Pierre Desprez2, Sean McAllister2,
Sriram Venneti5, and Carl Koschmann1; 1Department of Pediatrics,
Division of Pediatric Hematology-Oncology, University of Michigan
Medical School, Ann Arbor, MI, USA, 2Cancer Research, California
Pacific Medical Center Research Institute, San Francisco, CA, USA,

Abstracts

3Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for
Sick Children, University of Toronto, Toronto, ON, Canada, 4Departmentof Computational Medicine and Bioinformatics, University of Michigan
Medical School, Ann Arbor, MI, USA, 5Department of Pathology,
University of Michigan Medical School, Ann Arbor, MI, USA, 6Departmentof Clinical Pharmacy, University of Michigan College of Pharmacy, Ann
Arbor, MI, USA, 7Departments of Cell and Developmental Biology and
Neurosurgery, Ann Arbor, MI, USA, 8Division of Pathology, The Hospitalfor Sick Children, Toronto, ON, Canada

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) are lethal
pediatric brain tumors with no curative therapies. Inhibitor of DNA binding(ID) proteins are key regulators of gene differentiation during embryogenesis. Previous work has shown that H3F3A and ACVR1 mutations increase
ID1 expression in cultured astrocytes, but this has not been validated inhuman DIPG, nor has the regulation and targetability of ID1 been exploredin DIPG. RESULTS: Analysis of post-mortem tissue and multiple humandatasets showed ID1 to be elevated in DIPG, and to correlate with reduced
survival. In a multi-focal autopsy of a DIPG case, we also found ID1 expression to be heterogeneous and to correlate with tumor invasion. Chromatin immunoprecipitation qPCR (ChIP-qPCR) revealed elevated H3K27ac
and low H3K27me3 at ID1 regulatory regions (enhancers/promoters) in
DIPG tissue compared to normal brain, regardless of H3 or ACVR1 mutation status. Analysis of publicly-available ISH and ChIP-sequencing dataof developing murine brains revealed H3K27ac at ID1 enhancers to be elevated in the prenatal hindbrain compared to prenatal forebrain and midbrain, and all postnatal brain regions. ID1 shRNA-mediated knockdown ofprimary human H3K27M DIPG cells (DIPG007) significantly reduced invasion and migration. We also treated DIPG007 cells with cannabidiol (CBD)and found reduced viability at clinically relevant dosing (IC50=2.4 uM) withdose-dependent reduction in ID1 protein. CONCLUSIONS: These findings indicate that a multifactorial (genetic and regionally-based) epigenetic
upregulation of ID1 drives DIPG invasiveness and is targetable with CBD.
ID1 knockdown and CBD treatment experiments in murine models of DIPG
are ongoing.
DIPG-60. PILOT STUDY OF CIRCULATING TUMOR CELLS IN
PEDIATRIC HIGH GRADE BRAIN TUMORS
Wafik Zaky, Long Dao, Dristhi Ragoonanan, Izhar Bath, Sofia Yi,
Jonathan Gill, Soumen Khatua, and Shulin Li; The University of Texas, MD
Anderson Cancer Center, Houston, TX, USA
BACKGROUND: Despite its increasing use, circulating tumor cells(CTCs) have not been studied in pediatric brain tumors. METHODS: Cellsurface vimentin (CSV) is a marker for CTC detection. We developed an
automated CSV-based CTC capture method for pediatric brain tumor using
the Abnova Cytoquest platform. PBMCs isolated from blood samples from52 brain tumor patients were processed to isolate CSV+ CTCs. Captured
cells were then stained for CSV and CD45 and scanned to determine thenumber of CTCs. DIPG samples were additionally examined for H3K27M
expression on CSV+ cells. Long term cancer survivors were used as a control
cohort. RESULTS: 86.4% of all the samples exhibited between 1–13 CSV+
CTCs, with a median of 2 CSV+ CTCs per sample. Using a value of ≥ 1 CTC
as a positive result, the sensitivity and specificity of this test was 83.05% and60.0% respectively. 19 DIPG samples were analyzed and 70% (13 samples)
were positive for 1–5 CTCs. Five of these 7 positive CSV+ CTCs DIPG samples were also positive for H3K27M mutations by immunohistochemistry(71%). Mean survival in days for the CTC positive and negative DIPG samples were 114 and 211 days, respectively (p= 0.13). CONCLUSION: Thisis the first study of CTCs in pediatric CNS tumors using an automated approach. Patients with brain tumors can exhibit CSV+ CTCs within peripheral blood. The use of specific molecular markers such as H3K27M can
improve the diagnostic capability of liquid biopsies and may enable future
disease assessment for personalized therapy.
DIPG-61. RESCUE REGIMENS AFTER BIOMEDE: POSSIBLE
INFLUENCE ON OS ASSESSMENT
Daniela Di Carlo1, Bertille Pommier1, Gwenael Le Teuff1, Samuel Abbou1,
Pablo Berlanga1, Birgit Geoerger1, Stephanie Puget2, Kevin Beccaria2,
Thomas Blauwblomme2, Marie-Anne Debily1, David Castel1,
Emmanuelle Lechapt3, Pascale Varlet3, Volodia Dangouloff-Ros2,
Nathalie Boddaert2, Gilles Vassal4, Marie-Cécile Le Deley5, andJacques Grill1; 1Gustave Roussy, Villejuif, Paris-Saclay, France, 2Necker
Hospital, Paris, Paris, France, 3Sainte-Anne Hospital, Paris, Paris, France,
4Gustave Roussy, Paris, Paris-Saclay, France, 5Centre Oscar Lambret, Lille,
Nord, France
BIOMEDE is a multicentric randomized phase II trial to evaluate in
DIPG the OS of patients treated with dasatinib, erlotinib or everolimus. The
OS is the result of the first line treatment but it could also be affected byre-irradiation and the second line treatment received after progression, es-

pecially in case of a possible crossover outside of the trial. This preliminary
analysis focuses on the first patients enrolled at Gustave Roussy (n=37). The
median age at diagnosis was 7 years, median interval from diagnosis to progression and median survival after progression were 7 (1–20) and 2 (0–13)
months respectively. Initial treatment was everolimus for 13, dasatinib for20, erlotinib for 4 patients. The most frequent targetable molecular alterations were mTOR pathway in 6, PDGRFA in 4, ACVR1 in 3 patients. Outof the 31 patients who relapsed and were evaluable, 18 and 13 had a mediansurvival < 3 and > 3 months respectively. At relapse patients have received
different types of therapies, in 6 cases matching the molecular profile ofthe tumour obtained by sequencing. At progression, seven patients switchedfrom dasatinib to mTOR inhibitors and 2 patients switched from everolimus
to dasatinib. Patients with OS after progression > 3 months had higher rateof reirradiation (77% vs 5%), steroid weaning (69% vs 33%) and Lansky/
Karnowsky > 50% (85 vs 67%). Extended results on the entire cohort will
be presented. It will be important to consider the distribution of reirradiation
to interpret the results of the randomisation on OS.
DIPG-62. PRECLINICAL EVALUATION OF IMIPRIDONE-BASEDCOMBINATION THERAPIES IN PEDIATRIC H3K27M MUTANTDIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Robyn Borsuk1, Lanlan Zhou2, Yiqun Zhang2, Varun Prabhua3,
Joshua Allen3, Wolfgang Oster3, Nikos Tapinos4, Rishi R. Lulla1, and
Wafik El-Deiry2; 1Department of Pediatrics, The Warren Alpert Medical
School of Brown University, Providence, RI, USA, 2Joint Program in
Cancer Biology, The Warren Alpert Medical School of Brown University,
Providence, RI, USA, 3Oncoceutics, Inc., Philadelphia, PA, USA,
4Department of Neurosurgery, The Warren Alpert Medical School ofBrown University, Providence, RI, USA
Imipridones induce apoptosis in cancer via p53 independent upregulationof TNF-related apoptosis inducing ligand (TRAIL) pathway and its
proapoptotic receptor DR5. ONC201, a first-in-class imipridone, is being
evaluated alone and with radiotherapy for children with H3K27M mutant
diffuse glioma. We sought to determine if ONC201 and its imipridone analogs(ONC206, ONC212) are synergistic with other chemotherapy agents.
Seven patient-derived DIPG cell lines, six H3.3K27M mutant (SU-DIPG-IV,
SU-DIPG-13, SU-DIPG-25, SU-DIPG-27, SU-DIPG-29, SF8628) and one
H3.1K27M mutant (SU-DIPG-36) were grown in culture and exposed to
ONC201, ONC206, and ONC212 alone and in combination with histonede-acetylase inhibitors (HDACi) or etoposide. A dose-dependent response
to ONC201, ONC206, and ONC212 was demonstrated in all cell lines,
with mean IC50 values of 1.46 µM, 0.11 µM, and 0.03 µM respectively.
ONC206 and ONC212 induced apoptosis measured by increased expression of cleaved PARP and ISR by increased expression ATF4. In two celllines, synergy studies revealed combination indices (CI) < 1 for ONC206 andetoposide, with a best CI of 0.62 in SU-DIPG-IV and 0.46 in SU-DIPG-25.
Synergy was also observed between ONC201 and etoposide (CI 0.46) and
ONC201 and panobinostat (CI 0.01). Imipridones and analogs were superior to panobinostat and etoposide in triggering apoptosis as measured by
sub-G1 phase content. Additional synergy and mechanistic analyses are ongoing and will be reported. Our results suggest that H3K27M mutant DIPG
cells demonstrate increased sensitivity to imipridone analogs (ONC206 andONC212) when compared to ONC201. Combinational strategies withetoposide or HDACi should be considered for clinical translation.
DIPG-63. LOSS OF THE H4 LYSINE METHYLTRANSFERASE KMT5B
DRIVES INVASION / MIGRATION BY DEPLETING H3K27ME3 AT
LOCI OTHERWISE RETAINED IN H3K27M MUTANT DIPG CELLS
Ketty Kessler1, Alan Mackay1, Valeria Molinari1, Haider Tari1,
Anna Burford1, Andrea Sottoriva1, Maria Vinci2, and Chris Jones1; 1The
Institute of Cancer Research, London, United Kingdom, 2Ospedale
Pediatrico Bambino Gesù, Rome, Italy
Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline glioma(DMG) are characterised by K27M mutations in histone H3 variants.
The major functional consequence is a global loss of the repressive markH3K27me3, causing a raft of transcriptional changes promoting tumorigenesis, although certain key loci retain trimethylation, such as CDKN2A/B.
We recently identified subclonal loss-of-function mutations in the H4 lysine methyltransferase KMT5B to be associated with an enhanced invasion/
migration, but the mechanism by which this occurred was unclear. Here
we show by ChIP-seq using patient-derived subclonal DIPG models and
CRISPR-Cas9 depletion that loss of KMT5B (or KMT5C) causes a paradoxical increase in global levels of H4K20me3 in promoters and regulatory
regions, only ablated by knocking out both enzymes. Loss of KMT5B alone
further causes loss of the majority of otherwise retained H3K27me3 loci in
DIPG cells, although CDKN2A/B itself was spared. De-repression occurredat bivalent loci marked by H3K4me3 and had elevated gene expression by
RNAseq; these were significantly enriched for genes involved in chromatin
remodelling and invasion/migration, the latter including MMP9/MMP24.

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Phenotypic assessment of the models in vitro by high-throughput imaging
demonstrated significantly increased invasion and migration in association
with either KMT5B or KMT5C loss, but not both. Quantitative proteomic assessment of the secretome identified factors by which a minority of
KMT5B-deficient cells may signal to promote motility of the neighbouring
populations. These data suggest a previously unrecognised trans-histone(H4/H3) interaction in DIPG cells with a potentially profound effect on theirdiffusely infiltrating phenotype.
DIPG-64. INTERNATIONAL PRECLINICAL DRUG DISCOVERYAND BIOMARKER PROGRAM INFORMING AN ADOPTIVECOMBINATORIAL TRIAL FOR DIFFUSE MIDLINE GLIOMAS
Justyna M Przystal*1, Sridevi Yadavilli*2, Christina Colman Abadi*3,
Viveka Nand Yadav4, Sandra Laternser1, Chiara Cianciolo Cosentino1,
Sebastian M Waszak5, Rodrigo Cartaxo4, Matt Biery6,
Carrie Myers6, Samantha Jayasekara7, James M Olson6, Mariella G Filbin8,
Nicholas A Vitanza6,9, Jason Cain7, Carl Koschmann#4, Sabine Müller#1,3,
Javad Nazarian#1,2; 1Oncology Department, University Children’s Hospital
Zurich, Zürich, Switzerland, 2Center for Genetic Medicine Research,
Children’s National Medical Center, Washington DC, USA, 3UCSF
Department of Neurology, Neurosurgery and Pediatrics, San Francisco,California, USA, 4Department of Pediatrics, Michigan Medicine, Ann
Arbor, MI, USA, 5European Molecular Biology Laboratory, Heidelberg,
Germany, 6Fred Hutchinson Cancer Research Center, Seattle, WA, USA,
7Developmental and Cancer Biology Centre for Cancer Research Hudson
Institute of Medical Research, Melbourne, Australia, 8Department ofPediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical
School, Broad Institute of Harvard and MIT, Cambridge, MA, USA,
9Division of Pediatric Hematology/Oncology, Department of Pediatrics,
University of Washington, Seattle Children’s Hospital, Seattle, WA, USA
INTRODUCTION: DMG-ACT (DMG- multi-arm Adaptive andCombinatorial Trial) aims to implement a highly innovative clinical trial
design of combinatorial arms for patients with diffuse midline gliomas(DMGs) at all disease stages that is adaptive to pre-clinical data generated in eight collaborating institutions. The goals of the team are to: i)rapidly identify and validate promising drugs for clinical use, and ii) predict biomarkers for promising drugs. METHODS: In vitro (n=15) and invivo (n=8) models of DMGs across seven institutions were used to assess
single and combination treatments with ONC201, ONC206, marizomib,
panobinostat, Val-083, and TAK228. In vivo pharmacokinetic assays using
clinically relevant dosing of ONC201, ONC206, and panobinostat were
performed. Predictive biomarkers for ONC201 and ONC206 were identified using extensive molecular assays including CRISPR, RNAseq, ELISA,
FACS, and IHC. RESULTS: Inhibitory concentrations (IC50) were established and validated across participating sites. In vivo validation of single
and combination drug assays confirmed drug efficacy as increased survival
for: ONC201 (p=0.01), ONC206 (p=0.01), ONC201+ONC206 (p=0.02),
and ONC201+panobinostat (p=0.01). Marizomib showed toxicity inmurine/zebrafish PDXs models. Murine pharmacokinetic analysis showed
peak brain levels of ONC201 and ONC206 above pre-clinical IC50. Molecular testing and analyses of existing drug screen across 537 cancer celllines validated mitochondrial stress and ATF4 as the main targets induced
by ONC201/6. CONCLUSION: Thorough preclinical testing in a multi-sitelaboratory setting is feasible and identified ONC201 in combination with
ONC206 as promising therapeutics for DMGs. Preclinical and correlativeclinical studies are ongoing.
DIPG-66. FEASIBILITY AND APPLICABILITY OF MOLECULARGUIDED THERAPY IN HIGH GRADE GLIOMA/DIFFUSE MIDLINEGLIOMA: RESULTS FROM BEAT CHILDHOOD CANCER NMTRC009 MOLECULAR GUIDED THERAPY STUDY
Virginia Harrod1, Abhinav Nagulapally2, Elizabeth Lewis2, andGiselle Sholler2; 1Dell Children’s Medical Center, Austin, TX, USA, 2Helen
DeVos Children’s Hospital, Grand Rapids, MI, USA
High grade gliomas/diffuse midline gliomas (HGG/DMG) historically have a poor prognosis with an overall survival of less than 20% at
5 years. The pathophysiology is under close investigation across the worldin efforts to understand this tumor type with aims of increasing effective
treatment options. We present our results on the feasibility and outcomesof patients treated on our Molecular Guided Therapy study. Tumor samples
were analyzed with whole exome (DNA) and RNA sequencing. Three drug
matching algorithms were utilized to generate a report that was reviewed ata multi-institutional tumor board meeting, culminating in a proposed treatment protocol. Eleven patients enrolled, but one did not complete cycle 1 oftherapy due to progression of disease, thus ten patients (6-HGG, 4-DMG)
were evaluable and received at least 2 cycles of therapy. Time to reports generated and tumor board assembly was (median) 18 and 24 days, respectively.
Secondary goals included evaluation of efficacy. Responses showed 50% of
patients with stable disease or better at 2 cycles of therapy, but these wereiii300N EU R O - O N C O L O G Y•

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temporary with median time to progression of 81 days. In conclusion, we
determined that it is feasible to collect individual biological DNA and RNA
sequencing information to offer patients individualized treatment plans forthis devastating group of diseases. Though data is not statistically significant,we show that there is a suggestion of efficacy in this approach to treatment
for patients, indicating a need to expand on this treatment approach withindividualized medicine.
DIPG-68. ALPHA-THALASSEMIA X-LINKED MENTAL
RETARDATION PROTEIN (ATRX) LOSS-OF-FUNCTION IN
A MOUSE MODEL OF DIFFUSE INTRINSIC PONTINE GLIOMA
Chen Shen1,2, David Picketts3, and Oren Becher1,2; 1Ann & Robert LurieChildren’s Hospital, Chicago, IL, USA, 2Northwestern University, Evanston,IL, USA, 3University of Ottawa, Ottawa, ON, Canada
Diffuse Intrinsic Potine Glioma (DIPG) is a rare pediatric brain tumor forwhich no cure or efficacious therapies exist. Previous discoveries have revealed that, DIPG harbors distinct genetic alterations, when compared withadult high-grade glioma (HGG) or even with non-DIPG pediatric HGGs.
ATRX alteration is found in 9% of clinical cases of DIPG, and significantly
overlaps with H3.3K27M mutation and p53 loss, the two most common
genetic changes in DIPG, found in 80% and 77% clinical cases, respectively. Here we developed genetically engineered mouse model of brainstem
glioma using the RCAS-Tv-a system by targeting PDGF-B overexpression,
p53 loss, H3.3K27M mutation and ATRX loss-of function to Nestinexpression brainstem progenitor cells of the neonatal mouse. Specifically, weused Nestin-Tv-a; p53 floxed; ATRX heterozygous female and Nestin-Tv-a;
p53 floxed; ATRX floxed male breeders, generated offsprings with ATRX
loss of function (n=18), ATRX heterozygous females (n=6), and ATRX WT(n=10). Median survial of the three groups are 65 days, 88 days and 51 days,
respectively. Also, ATRX null mice is lower in tumor incidence (44.4%),
compared with ATRX WT (80%). We evaluated the pathological features of
DIPG with or without ATRX alteration, RNA-seq is performed to identify
differentially expressed genes between ATRX WT and loss-of-function. In
conclution, this study generated the first genetically modified mouse model
studying ATRX loss-of-function in DIPG, and suggested that ATRX lossof-function in DIPG may slow down tumorigenesis and decrease tumor incidence.
DIPG-70. DISORDERED DNA METHYLATION IN DIPG UNDERLIESPHENOTYPIC PLASTICITY
Michael Koldobskiy1, Ashley Tetens1, Allison Martin2,
Charles Eberhart1, Eric Raabe1, John Goutsias1, and Andrew Feinberg1;
1Johns Hopkins University, Baltimore, MD, USA, 2Albert Einstein Collegeof Medicine, New York, NY, USA
Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem
tumor with a dismal prognosis and no effective treatment. Recent studies
point to a critical role for epigenetic dysregulation in this disease. Nearly
80% of DIPGs harbor mutations in histone H3 encoding replacement oflysine 27 with methionine (K27M), leading to global loss of the repressive histone H3K27 trimethylation mark, global DNA hypomethylation,
and a distinct gene expression profile. However, a static view of theepigenome fails to capture the plasticity of cancer cells and their gene
expression states. Recent studies across diverse cancers have highlighted
the role of epigenetic variability as a driving force in tumor evolution.
Epigenetic variability may underlie the heterogeneity and phenotypic
plasticity of DIPG cells and allow for the selection of cellular traits that
promote survival and resistance to therapy. We have recently formalized
a novel framework for analyzing variability of DNA methylation directly from whole-genome bisulfite sequencing data, allowing computation of DNA methylation entropy at precise genomic locations. Using
these methods, we have shown that DIPG exhibits a markedly disorderedepigenome, with increased stochasticity of DNA methylation localizing
to specific regulatory elements and genes. We evaluate the responsivenessof the DIPG epigenetic landscape to pharmacologic modulation in orderto modify proliferation, differentiation state, and immune signaling in
DIPG cells.
DIPG-71. SELECTIVE HDAC INHIBITOR RG2833 INDUCES DIPGCELL DEATH VIA DOWNREGULATION OF THE NFĸB PATHWAY
Katherine Barnett, Orlandi Novak, Charles Eberhart, and Eric Raabe;
Johns Hopkins, Baltimore, MD, USA
Histone deacetylase (HDAC) inhibitor panobinostat demonstrated activity against diffuse intrinsic pontine glioma (DIPG) in vitro, but its efficacy
in vivo was limited by toxicity and poor blood brain barrier penetration.
RG2833 (RGFP109) is a selective HDAC1/3 inhibitor that has establishedbrain penetration. In clinical trials, the Cmax (plasma) of RG2833 was
32uM. RG2833 demonstrated cytotoxicity against temozolomide-resistantAbstracts

glioblastoma and downregulated the NFĸB pathway. Because this pathway
is overexpressed in DIPG and may play a role in DIPG cell growth andsurvival, we hypothesized that RG2833 would kill DIPG cells. Treatmentof DIPG cell lines with RG2833 as a single agent suppresses cell proliferation in the 5–10μM range (MTS assay for HSJD007 p=0.0004 10μM vs
DMSO, JHH-DIPG1 p=0.001 10μM vs DMSO, SF-7761 p=0.04 10μM vs
DMSO, SU-DIPG13 p=0.01 10μM vs DMSO by t-test). RG2833 induces
apoptosis by 48 hours as measured by Western blot for cPARP and cleaved
caspase 3 immunofluorescence (HSJD007 p<0.003 8μM vs DMSO, JHHDIPG1 p=0.0026 10μM vs DMSO by t-test). RG2833 also slows cell proliferation as measured by Western blot for pRb and immunofluorescence for
BrdU (HSJD007 p=0.008 8μM vs DMSO, JHH-DIPG1 p=0.0002 10μM vsDMSO by t-test). Western blot confirmed a dose-dependent increase in histone 3 acetylation with RG2833 treatment at 5 hours. We detected increased
acetylated p65 and decreased expression of the NFĸB regulated pro-survival
genes BCL2, BCL-xL, and XIAP with RG2833 treatment. Together, this datashows that HDAC inhibitor RG2833 may be a promising therapeutic candidate for DIPG via downregulation of the NFĸB pathway.
DIPG-72. LONG-TERM SURVIVAL OF A CLASSIC DIFFUSE
INTRINSIC PONTINE GLIOMA TREATED WITH NIMOTUZUMAB
Sidnei Epelman1, Vijay Ramaswamy2, Ethel Gorender1, andLuis Henrique Sakamoto1; 1Santa Marcelina Hospital / Department ofPediatric Oncology, Sao Paulo, SP, Brazil, 2The Hospital for Sick Children,
Toronto, ON, Canada
BACKGROUND: Long-term survival in diffuse intrinsic pontine glioma
is rare, and typically associated with atypical imaging and/or atypical clinical course. Although most patients harbor hotspot mutations in H3.1/3K27M, a proportion of patients have alternate mutations, despite a typicalclinicoradiological course. Herein we describe a long-term survivor witha classical presentation, treated with nimotuzumab, highlighting the challenges associated with such cases. CASE REPORT: A 5 year old male, diagnose in 2012 with a 10 day history multiple cranial neuropathies and aright hemiparesis. Cranial MRI revealed a poorly delimited diffuse pontine
tumor and secondary hydrocephalus. Tumor biopsy was not performed dueto the classic clinical presentation, and he received 54Gy/30 of radiation
plus concomitant weekly nimotuzumab 150mg/m2. Initial tumor dimensions were 43x31x28mm. Nimotuzumab 150mg/m2 was continued every
2 weeks. Image assessment at week 12 of treatment revealed 16.9% volume
increase, 4 weeks after radiotherapy completion. Nevertheless, subsequentneuroimaging at 24th, 36th, 60th, 96th and 108th weeks of nimotuzumab
therapy showed a sustained and progressive tumor cytoreduction of 47.5%,
59%, 62.2%, 63.8% and 67%, respectively, when compared with postradiotherapy dimensions. Currently, the patient is 13y old, good school
performance, no neurologic disabilities. The last MRI at 394 weeks ofnimotuzumab revealed dimensions of 21x19x14mm which corresponds to
70% of reduction compared with initial volume. CONCLUSIONS: Ourcase of progressive cytoreduction over two years of a classic DIPG, diagnosed in the era prior to the discovery of the K27M mutation, highlights
the challenges associated with long-term survival of this devastating entity.
DIPG-73. SENESCENCE ASSOCIATED SECRETORY PHENOTYPE
AS A MECHANISM OF RESISTANCE AND THERAPEUTICVULNERABILITY IN BMI1 INHIBITOR TREATED DIPG
Ilango Balakrishnan1,2, Etienne Danis1,2, Angela Pierce1,2,
Krishna Madhavan1,2, Dong Wang1,2, Nathan Dahl1,2, Sanford Bridget1,
Diane K Birks1, Nate Davidson1, Dennis S. Metselaar3, Hans Neel3,
Andrew Donson1,2, Andrea Griesinger1,2, Hiroaki Katagi4,
Trinka Vijmasi1, Ismail Sola1, Irina Alimova1,2, Susan Fosmire1,
Esther Hulleman3, Natalie J. Serkova5, Rintaro Hashizume4,
Cynthia Hawkins6, Angel Montero Carcaboso7, Nalin Gupta8, Ken Jones1,
Nicholas Foreman1,2, Adam Green1,2, Rajeev Vibhakar1,2, andSujatha Venkataraman1,2; 1Department of Pediatrics and Section of
Pediatric Hematology/Oncology/BMT, University of Colorado Denver,Anschutz Medical Campus, Aurora, CO, USA, 2The Morgan Adams
Foundation Pediatric Brain Tumor Research Program, Children’s Hospital
Colorado, Aurora, CO, USA, 3Princess Maxima Center for PediatricOncology, Utrecht, the Netherlands and Department of Pediatric Oncology/
Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer
Center Amsterdam, Amsterdam, Netherlands, 4Department of Neurological
Surgery, Northwestern University Feinberg School of Medicine, Chicago,
IL, USA, 5Departments of Radiology, Radiation Oncology, Anesthesiology,
Colorado Animal Imaging Shared Resource (AISR), Aurora, CO, USA,
6Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospitalfor Sick Children, Toronto, ON, Canada, 7Institut de Recerca Sant Joande Deu, C/ Santa Rosa, Barcelona, Spain, 8Department of Neurological
Surgery, University of California San Francisco, San Francisco, CA, USA
BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) driven by
mutations in the histone 3 (H3) gene (H3K27M) are aggressive pediatricbrain tumors for which there is no curative therapy. METHODS: To identify novel therapeutic targets we performed a high throughput drug screen
combined with an epigenetically targeted RNAi screen using H3K27M andH3.3 WT DIPG cells. RESULTS: Chemical and genetic depletion of BMI1 in
vitro resulted in inhibition of clonogenicity and cell self-renewal consistent
with previous studies. We show for the first time that clinically relevant BMI1
inhibitors attenuates growth of orthotopic DIPG xenografts as measured by
MRI and prolong survival in vivo. We found that BMI1 inhibition drives
phenotypic cellular senescence and that the senescent cells were able reactivate to form new neurospheres in vitro and tumor growth in vivo. RNA-seq,
ChIP-Seq and immuno-proteomic analysis revealed that the senescent cells
induced the expression of the Senescence Associated Secretory Phenotype(SASP) cytokines by increasing occupancy of activated histone marks at SASP
factor promoters. The SASP results in increased expression of anti-apoptotic
BH3 proteins including BCLxl, and BCL2. Treatment of the PTC028 treatedsenescent DIPG cells with BH3 mimetics induces apoptosis and clears thesenescent cells. Combining BH3 mimetics with BMI1 inhibition attenuatestumor growth in vivo synergistically and significantly prolongs survivalof DIPG bearing mice compared to BMI1 inhibition alone. CONCLUSION: These data inform the current trial of BMI1 inhibition as a monotherapy and predict the need for adding BH3 mimetics to achieve efficacy.
DIPG-74. RE-IRRADIATION OF DIPG: DATA FROM THE
INTERNATIONAL DIPG REGISTRY
Lucie Lafay-Cousin1, Adam Lane2, Austin Schafer2, Raya Saab3,
Sylvia Cheng4, Pratiti Bandopadhayay5, Mohamed Zaghloul6,
Motasem El-Ayadi6, Kathleen Dorris7, Roger Packer8,
Lindsey Kilburn8, Jane Minturn9, Andrew Dodgshun10,
Sara Parkin10, Mercedes Garcia Lombardi11, Kenneth Cohen12,
David Gass13, Stewart Goldman14, Eric Sandler15, Katherine Warren16,
Robert Greiner17, Nicholas Gottardo18, Hetal Dholaria18, Tim Hassall19,
Scott Coven20, Jordan Hansford21, Yvan Samson22, Sarah Leary23,
Ute Bartels24, Eric Bouffet24, Jie Ma25, Christopher Tinkle26,
Michelle Monje-Deisseroth27, Paul Fisher27, Karen Tsui28, David Ziegler29,
Murali Chintagumpala30, Sridharan Gururangan31, Lars Wagner32,
Carl Koschmann33, Mariko DeWire-Schottmiller2, James Leach2,
Blaise Jones2, Christine Fuller2, Rachid Drissi2, Brooklyn Chaney2,
Katie Black2, Maryam Fouladi2, and Douglas Strother1; 1University ofCalgary, Calgary, AB, Canada, 2Cincinnati Children’s Hospital, Cincinnati,
OH, USA, 3American University of Beirut, Beirut, Lebanon, 4British
Columbia Children’s Hospital, Vancouver, BC, Canada, 5Boston Children’s
Hospital, Boston, MA, USA, 6Children’s Cancer Hospital Egypt, Cairo,
Egypt, 7Children’s Hospital Colorado, Denver, CO, USA, 8Children’s
National Hospital, Washington, DC, USA, 9Children’s Hospital ofPhiladelphia, Philadelphia, PA, USA, 10Christchurch Hospital, Christchurch,
New Zealand, 11Hospital de Ninos Ricardo Gutierrez, Buenos Aires,
Argentina, 12Johns Hopkins University, Baltimore, MD, USA, 13LevineChildren’s Hospital, Charlotte, NC, USA, 14Lurie Children’s Hospital,
Chicago, IL, USA, 15Nemour Children’s Hospital, Orlando, FL, USA,
16Dana-Farber Cancer Institute, Boston, MA, USA, 17Penn State Children’s
Hospital, Hershey, PA, USA, 18Perth Children’s Hospital, Perth, Australia,
19Queensland Children’s Hospital, Brisbane, Australia, 20Riley Children’s
Hospital, Indianapolis, IN, USA, 21Royal Children’s Hospital, Melbourne,
Australia, 22Sainte Justine, Montreal, QC, Canada, 23Seattle Children’s
Hospital, Seattle, WA, USA, 24SickKids Hospital, Toronto, ON, Canada,
25Shanghai Xinhua Hospital, Shanghai, China, 26St. Jude Children’s
Research Hospital, Memphis, TN, USA, 27Stanford Children’s Hospital,
Palo Alto, CA, USA, 28Starship Children’s Health, Auckland, New Zealand,
29Sydney Children’s Hospital, Sydney, Australia, 30Texas Children’s
Hospital, Houston, TX, USA, 31University of Florida, Gainesville, FL, USA,
32University of Kentucky, Lexington, KY, USA, 33University of Michigan,
Ann Arbor, MI, USA
PURPOSE: To review data from DIPG Registry patients recorded tohave received a second course of radiation therapy (rRT). METHODS: The
International DIPG Registry was searched for patients with DIPG who weretreated with a known dose of rRT. Doses of rRT, timing from initial diagnosis and primary radiation therapy (pRT), radiographic response to rRT
and survival from diagnosis (OS) were evaluated. RESULTS: Sixty (11.2%)of 535 Registry patients underwent rRT; dose was provided for 44 patients.
Median (range) data from those 44 revealed that rRT was given at 12 (2–65)
months from initial diagnosis of DIPG and at 9.6 (1–61) months from completion of pRT at a dose of 26.7 (1.8–74) Gy. After completion of rRT, MRI
showed response, progression, stable disease or was not available in 19, 8, 3
and 14 patients, respectively. Median PFS and OS were 11 and 18.1 months,
respectively. 475 Registry patients did not undergo rRT; their ages, durationof symptoms, and primary treatment with or without chemotherapy were
not significantly different from the rRT cohort. Median PFS and OS for thenon-rRT patients were 6.9 and 10 months, respectively. rRT patients weremore likely to have had radiographic evidence of tumor necrosis at diagnosis
than non-rRT patients. CONCLUSIONS: Administration of rRT to patientswith DIPG has been inconsistent with respect to timing and dose. Toxicity,

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response and quality of life data are incomplete, but survival appears to belengthened with rRT. Prospective clinical trials will elucidate benefits andrisks of rRT.
DIPG-75. PRECISION MEDICINE FOR PAEDIATRIC HIGH-GRADEDIFFUSE MIDLINE GLIOMAS - RESULTS FROM THE ZEROCHILDHOOD CANCER COMPREHENSIVE PRECISION MEDICINEPROGRAM
Dong-Anh Khuong-Quang1,2, Sumanth Nagabushan3,4,
Neevika Manoharan3,4, Greg Arndt3,5, Paulette Barahona3,
Mark J. Cowley3,6, Paul G. Ekert3,2, Tim Failes3,5,Noemi Fuentes Bolanos3,4, Maely Gauthier3, Andrew J. Gifford3,7,Michelle Haber3, Amit Kumar3,2, Richard B. Lock3, Glenn M. Marshall3,4,
Chelsea Mayoh3, Emily Mould3, Murray D. Norris3,
Anjana Gopalakrishnan3, Natacha Omer8, Peter Trebilcock3,
Toby N. Trahair3,4, Maria Tsoli3, Katherine Tucker7,9, Marie Wong3,
Vanessa Tyrrell3, Loretta Lau3,4, and David S, Ziegler3,4; 1Royal Children’s
Hospital, Melbourne, Victoria, Australia, 2Peter MacCallum Cancer Centre,
Melbourne, Victoria, Australia, 3Children’s Cancer Institute, Sydney, NewSouth Wales, Australia, 4Sydney Children’s Hospital, Sydney, New South
Wales, Australia, 5Lowy Cancer Research Centre, Sydney, New South
Wales, Australia, 6Garvan Institute, Sydney, New South Wales, Australia,
7Prince of Wales Hospital, Sydney, New South Wales, Australia, 8Children’s
Queensland Hospital, Brisbane, Queensland, Australia, 9University of New
South Wales, Sydney, New South Wales, Australia
The Australian Zero Childhood Cancer (ZERO) program aims to assess
the feasibility of a comprehensive precision medicine approach to improveoutcomes for patients with an expected survival <30%. ZERO combines
molecular profiling (whole genome sequencing, whole transcriptome
sequencing, DNA methylation profiling) with in vitro high-throughput drug
screening (HTS) and patient-derived xenograft drug efficacy testing. We
report on the cohort of patients with midline high-grade glioma (HGG),
including H3-K27M DMG, enrolled on the pilot study (TARGET) and on
the ongoing ZERO clinical trial (PRISM). We identified 48 patients withmidline HGG. Fresh or cryopreserved samples were submitted in 37 casesand cell culture was attempted in 30/37 cases with 45% success rate. The
most commonly mutated genes/pathways identified by molecular profilinginclude H3-K27M mutations, DNA repair pathway, and PI3K/mTOR
pathway. Two targetable fusions (NTRK and FGFR1) were reported. Five
patients with germline alterations were identified. Thirty-five (72%) patients
received a therapeutic recommendation from the ZERO molecular tumourboard and the main recommended therapies were mTOR inhibitors, PARP
inhibitors or tyrosine kinase inhibitors. HTS added evidence for the recommended therapy (n=3) or identified novel potential therapy (n=1). Out of the
35 patients, 16 received a recommended drug. Response to treatment wascomplete response for five months (n=1), partial response for nine months(n=1), stable disease (n=4), and progressive disease (n=10). These results
highlight the feasibility of the ZERO platform and the value of fresh biopsy,
necessary for pre-clinical drug testing. Targetable alterations were identified
leading to clinical benefit in six patients.
DIPG-76. HISTONE H3 PHOSPHORYLATION IN H3K27M MIDLINEGLIOMAS
Liang Zhang1, Charles Day2, Edward Hinchcliffe2, and David Daniels1;
1Mayo Clinic, Rochester, MN, USA, 2Hormel Institute, Austin, MN, USA
Diffuse midline gliomas (DMG) patients have a dire prognosis despiteradiation therapy and there is an urgent need to develop more effective
treatments. DMG are characterized by heterozygous mutations in selectH3 genes resulting in the replacement of lysine 27 by methionine (K27M)
that leads to global epigenetic reprogramming and drives tumorigenesis. We
previously reported that pharmacological inhibition of aurora kinase (AKI)
may represent a targeted approach for treating tumors with this mutation.
Our analysis with both published dataset and patient samples showed thatpatients with higher aurora kinase A (AKA) expression were associatedwith worse survival. AKA phosphorylates H3S10 and H3S28 during mitosis. Intriguingly, phosphorylation of the H3S28 (H3S28ph) by AKA blocks
PRC2 methyltransferase activity and decreases global H3K27me3 in certain stem cells. We propose that a similar mechanism occurs in H3K27M
DMG tumors, where there is a reciprocal relationship between H3S28phand H3K27me3. We found that AKI significantly decreases H3S28ph while
increasing H3K27me3 specifically in H3K27M tumors. To further evaluate
the link between the H3K27M mutation and H3 serine phosphorylation, weused CRISPR/Cas9-directed gene editing to silence H3S28ph by replacing
serine with alanine (H3S28A) in DIPG cell lines. Ectopic expression of histone H3S28A leads to a prominent epigenetic changes in H3K27M tumors
and is similar to AKA inhibition. Overall, this study highlights H3S28ph, oneof the targets of AK, is a key driver of epigenetic changes in H3K27M tumors through both direct and indirect changes to H3K27me3 and H3K27ac
across the genome.

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DIPG-77. TREATMENT EXTENT AND THE EFFECT ON SURVIVALIN DIFFUSE INTRINSIC PONTINE GLIOMA
Joshua Baugh1, Niclas Colditz2, Geert Janssens3, Stefan Dietzsch4,
Darren Hargrave5, André von Bueren6, Rolf-Dieter Kortmann7,
Brigitte Bison8, Dannis van Vuurden1, Sophie Veldhuijzen van Zanten1,
and Christof Kramm2; 1Princess Máxima Center for Pediatric Oncology,
Utrecht, Netherlands, 2University of Göttingen, Göttingen, Germany,
3Department of Radiation Oncology, University Medical Center Utrecht,
Utrecht, Netherlands, 4Department of Radiation Oncology, University ofLeipzig, Leipzig, Germany, 5Great Ormond Street Hospital for Children
NHS Trust London, London, United Kingdom, 6Department of Pediatrics,
Obstetrics and Gynecology, Pediatric Neurology Unit, University Hospitalof Geneva, Geneva, Switzerland, 7Department of Radiooncology, Universityof Leipzig, Leipzig, Germany, 8Institute of Diagnostic and Interventional
Neuroradiology, University Hospital Wuerzberg, Wuerzberg, Germany
BACKGROUND: Front line radiotherapy for diffuse intrinsic pontine glioma (DIPG) remains the only standard of care. Is this still appropriate? PATIENTS AND METHODS: We examined survival outcomes
across six treatment modalities including I) no treatment (n=19), II) radiotherapy alone (n=38), III) radio-chemotherapy (n=101), IV) radiotherapy
and relapse chemotherapy (n=35), V) radio-chemotherapy and relapse
chemotherapy (n=163), and VI) radio-chemotherapy and relapse chemotherapy, plus reirradiation (n=54). Data were collected retrospectively
using the Society of Pediatric Oncology and Hematology (GPOH) and the
SIOPE DIPG Registry. 410 patients were included with radiologically centrally reviewed DIPG, mostly unbiopsied. Of note, the untreated patientsand radiotherapy only cohorts chose limited treatment voluntarily. RESULTS: Median overall survival (MOS) of the whole cohort was 11 months
and progression free survival (PFS) 7 months. PFS was not significantly
different between the treatment groups. OS and post-progression survival(PPS) were significantly different between cohorts. For the respective treatment groups, median OS was 3 months (I), 7 months (II), 8 months (III),
13 months (IV), 13 months (V), and 15 months (VI). For only front line
vs at least one second line therapy, MOS was 8 months vs 14 months and
PPS 2 months vs 5 months. CONCLUSIONS: Although subject to biases
to some extent, it seems that additional therapies beyond radiation therapy
are of benefit to extending survival in DIPG patients. This is at least partially caused by the introduction of reirradiation regimens. To what extent
other therapies contribute to survival and quality of life is subject to further
investigation.
DIPG-78. REVERTANCE OF THE H3K27M MUTATION RESCUESCHROMATIN MARKS NECESSARY FOR ONCOGENESIS IN DIFFUSE
MIDLINE GLIOMA
Cody Nesvick1, Charles Day2, Liang Zhang1, Edward Hinchcliffe2, andDavid Daniels1; 1Mayo Clinic, Rochester, MN, USA, 2Hormel Institute,
Austin, MN, USA
Diffuse midline glioma (DMG) is a lethal brain tumor that typicallyoccurs in children. Numerous studies have demonstrated the central roleof the H3K27M mutation and secondary loss of H3K27 trimethylation(H3K27me3) in DMG tumorigenesis. Understanding how the H3K27M
mutation alters the epigenetic landscape of the cell is necessary for revealing
molecular targets that are critical to tumorigenesis. To investigate the epigenetic effects of H3K27M mutation in DMG, we developed revertant
DMG cell lines with the mutant methionine residue reverted to wildtype(i.e., M27K). Revertant cells were analyzed for epigenetic changes andphenotypic differences in vitro and in vivo. H3M27K DMG cells grew inculture but displayed diminished proliferative capacity. H3M27K cells demonstrated total loss of H3K27M expression and restored trimethylation of
H3K27 and H3K4. Furthermore, consistent with the hypothesis that the
H3K27M mutation impacts H3 phosphorylation via expression of Aurora
Kinase during mitosis, H3M27K cells demonstrated reduced expression ofboth Aurora Kinase A and phosphorylation of H3 serine residues 10 and 28.
In line with the critical role of H3S10 phosphorylation in chromatin segregation, H3M27K cells also demonstrated restored chromosome segregation compared to H3K27M cells. In vivo data will be discussed. Revertanceof the H3K27M mutation reduces tumorigenesis in DMG tumors. Isogenic
H3M27K cells display reversal of key epigenetic changes associated with
oncogenesis in DMG. The revertant H3M27K DMG model is a useful
tool to investigate the downstream epigenetic reprogramming specific to
H3K27M mutation in these tumors.
DIPG-79. H3K27M INDUCES EPIGENETIC AND ONCOGENICCHANGES THAT ARE PARTIALLY REVERSED BY SMALL
MOLECULE AURORA KINASE B/C INHIBITION
Hannah Chatwin, Rakeb Lemma, John DeSisto, Aaron Knox,
Shelby Mestnik, Aidan Reid, Rajeev Vibhakar, Sujatha Venkataraman,and Adam Green; The Morgan Adams Foundation Pediatric Brain Tumor

Abstracts

Research Program, University of Colorado School of Medicine/Children’s
Hospital Colorado, Aurora, CO, USA
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor
with no curative treatments. Approximately 80% of DIPGs contain an
H3K27M mutation. The implications of the mutation and how they may
be targeted are not fully understood. We established an H3K27M effectisolating model by transducing H3K27-wildtype lines (HSJD-GBM-001,
normal human astrocytes) with lentiviral-packaged H3K27M. We characterized H3K27M-related changes through western blot, phenotypic assays,
and RNA-seq. Drug screening of H3K27-wildtype and matched H3K27Mtransduced lines was used to identify targets more effective with H3K27M
present. Patient-derived pediatric glioblastoma and DIPG lines (BT-245,
SU-DIPG-IV, HSJD-DIPG-007, SU-DIPG-XIII*, SF7761) were used for validation. We observed increased H3K27ac and decreased H3K27me3, as
well as increased proliferative and migratory abilities, with the addition of
H3K27M to H3K27-wildtype lines. RNA-seq showed downregulation ofcell cycle regulation and upregulation of epithelial-mesenchymal transition.
GSK1070916, an Aurora kinase B/C inhibitor, was isolated from a synthetic lethality screen with H3K27M. GSK1070916 showed strong efficacy
in native H3K27M lines (IC50s=60nM-1250nM), superior to the Aurora
kinase A inhibitor alisertib, to which all cell lines showed substantial resistance. Combination of both drugs was not synergistic. GSK1070916 treatment caused increased H3K27me3 and decreased H3S10ph and H3S28ph.
GSK1070916 induced apoptosis and S-phase stall. The H3K27M mutationinduces epigenetic, phenotypic, and cell cycle regulation changes resulting inrelaxation of transcriptional controls and more aggressive growth. Aurora
kinase B/C inhibition is a novel therapeutic modality for DIPG that appears
capable of reversing some H3K27M-related epigenetic changes, inducing
apoptosis, and repressing uncontrolled cellular division.
DIPG-80. CLINICAL AND RADIOGRAPHIC RESPONSE TO ONC201
IN A PEDIATRIC PATIENT WITH A THALAMIC H3K27M AND
BRAFV600E MUTANT DIFFUSE MIDLINE HIGH GRADE GLIOMA
Elizabeth Duke1, Jonathan Murnick1, Rohinton Tarapore2, Joshua Allen2,and Lindsay Kilburn1; 1Children’s National Hospital, Washington, DC,
USA, 2Oncoceutics, Inc, Philadelphia, PA, USA
Recent improved understanding of the molecular markers of high grade
glioma has shifted the approach to these aggressive CNS tumors to increasingly use molecularly guided targeted therapies. Treatment of patients with
BRAFV600E mutant high grade gliomas with BRAF inhibitors has shown
efficacy, however the impact of concomitant H3K27M mutation is unknown. ONC201 targets dopamine receptor D2 (DRD2), which is shown tobe broadly overexpressed in the thalamus as well as multiple tumor types; its
antagonism has demonstrated anti-tumor efficacy and immunomodulatory
properties in preclinical studies. ONC201 has also demonstrated clinical efficacy in patients with H3K27M mutant gliomas. We present the case of a
9-year-old male with a right thalamic H3.3K27M mutant diffuse midline
glioma with a concomitant BRAFV600E mutation with an ongoing partial response to ONC201 treatment. The patient was diagnosed in May
2018. He underwent biopsy, followed by standard focal proton radiation
therapy (54Gy) and subsequent treatment with dasatinib, bevacizumab andeverolimus over the course of five months. After continued radiographic progression on serial imaging, in April 2019 he started ONC201 375mg orally
once per week through an expanded access trial. He has tolerated the medication well with grade 1 nausea and fatigue. Over the next nine months, hedemonstrated clinical and radiographic improvement with modest increased
use of his left side and MRIs showing progressive decrease in size of the thalamic lesion with a 70 % decrease in the target lesion (measuring 53x62mm
prior to treatment, decreased to 38x26mm in January 2020).
DIPG-82. CLINICAL EXPERIENCE OF CONVECTION ENHANCED
DELIVERY (CED) OF CARBOPLATIN AND SODIUM VALPROATEINTO THE PONS FOR THE TREATMENT OF DIFFUSE INTRINSICPONTINE GLIOMA (DIPG) IN CHILDREN AND YOUNG ADULTS
AFTER RADIOTHERAPY
Elwira Szychot1,2, David Walker3,2, Peter Collins2, Harpreet Hyare4,2,Ananth Shankar4,2, Alison Bienemann5, Milo Hollingworth5, andSteven Gill5; 1The Royal Marsden Hospital, Sutton, United Kingdom,
2Harley Street Children’s Hospital, London, United Kingdom, 3Universityof Nottingham, Nottingham, United Kingdom, 4University College London
Hospitals NHS Foundation Trust, London, United Kingdom, 5University ofBristol, Bristol, United Kingdom
PURPOSE: Effective treatment of diffuse intrinsic pontine glioma (DIPG)
remains a formidable challenge due to inadequate penetration of the bloodbrain barrier (BBB) by systemically administered chemotherapies. The
BBB can be overcome by directly infusing drugs into pons using methodof convection-enhanced delivery (CED). We describe our clinical experienceand what we have learned about the safety and feasibility of treating DIPG

with intermittent CED of carboplatin and sodium valproate to the ponsthrough the Renishaw Drug Delivery System (RDDS). METHODS: Retrospective review (2017–2020) of children with DIPG, who following radiotherapy, received compassionate treatment commencing 3.3–10 months post
diagnosis (median 4.9 months). They received up to 7 cycles of 3–6 weekly
pontine infusions of carboplatin (0.12-0.18mg/ml) and sodium valproate(14.4- 28.8mg/ml). RESULTS: 13 children 3–19 years (mean 6.9 years) weretreated. There were no surgical complications. With the exception of infusion
channels blocking in one device there were no adverse device effects. Twopatients developed persistent 6th nerve palsies, which led to drug concentration reduction in the combination therapy. Subsequently infusion/ drug
related toxicities were transient. Tumour was controlled in pons in 11/13
patients. Median progression free survival (PFS) was 13.0 months, while
median overall survival (OS) was 15.3 months. CONCLUSIONS: Use of
the RDDS was safe and well tolerated in all 13 patients. Treatment improved
control of pontine disease resulting in longer PFS and OS than reported forconventional therapy and merits further evaluation in a clinical trial.
DIPG-83. USING COPPER CHELATING AGENTS TO TARGET
RECEPTOR TYROSINE KINASE SIGNALLING IN DIFFUSE
INTRINSIC PONTINE GLIOMA (DIPG)
Filip Michniewicz1,2, Federica Saletta1, Jourdin Rouen1,2, David Ziegler1,3,
and Orazio Vittorio1,2; 1Children’s Cancer Institute, Lowy Cancer ResearchCentre, Sydney, NSW, Australia, 2UNSW School of Women’s and Children’s
Health, Sydney, NSW, Australia, 3Sydney Children’s Hospital, Sydney,
NSW, Australia
DIPG is a universally fatal pediatric brain cancer. Receptor tyrosine
kinase (RTK) pathway alterations are among the defining characteristics inmany patients. Copper is a transition metal essential for cellular signaling,
known to impact PI3K/AKT and MAPK/ERK pathways. Copper chelating
agents are clinically approved for use in children with Wilson’s Disease,
documented to reduce brain copper levels and are cited as potential cancer
therapeutics. Due to copper’s wide cellular integration, we propose thattargeting copper in DIPG through use of copper chelators is a viable therapeutic strategy and are strong candidates for combination therapy. Cytotoxicity assays performed in a panel of DIPG cell lines using copper chelator
tetraethylenepentamine (TEPA) demonstrated a millimolar range of efficacy.
To identify copper integrated pathways, western blots were performed on
DIPG cell lines dosed with sub-lethal copper concentrations, which increased
phosphorylated expression of AKT, ERK1/2, ERK5 and STAT3. Conversely,
western blots performed after TEPA treatment demonstrated reduced phosphorylated expression of all these proteins compared to controls. Western
blots investigating TEPA in combination with Everolimus and Trametinibdemonstrated synergistic targeting of these proteins. Our results indicatethat adding copper in the culture media initiated two RTK-mediated downstream signal transductions, including AKT and ERK and additionally STAT
signaling. The use of copper chelator TEPA affected copper homeostasis andreduced DIPG cell proliferation. Our study proposes copper plays an important role in RTK-mediated signaling promoting DIPG proliferation. Thisimplies that reducing copper with clinically available chelation agents canrepresent a potential anti-cancer treatment for DIPG.
DIPG-84. COMPLEMENTARY AND ALTERNATIVE MEDICINE IN
DIFFUSE INTRINSIC PONTINE GLIOMA
Fatma El-Khouly1,2, Syed Adil1, Harry Hendrikse1, Gertjan Kaspers1,2,
Christof Kramm3, Sophie Veldhuijzen van Zanten1,2, andDannis van Vuurden2; 1Amsterdam UMC - location VUmc, Amsterdam,
Netherlands, 2Princess Maxima Center for Pediatric Oncology, Utrecht,
Netherlands, 3University medical center Goettingen, Goettingen, Germany
INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare
and aggressive childhood brainstem malignancy with a two-year survival
rate of ≤10%. In this international survey study we aim to evaluate the useof complementary and alternative medicine (CAM) in this patient population. METHODS: Parents of-, and physicians treating DIPG patientswere asked to participate in a retrospective online survey with questions
regarding CAM use during time of illness. RESULTS: 120 parents and 75
physicians contributed to the online survey between January and May 2020.
Physicians estimated that <50% of their patients used CAM, whereas 69%
of the parents reported to have used CAM to treat their child during timeof illness. Cannabis was the most widely used form of CAM, followed byvitamins and minerals, melatonin, curcumin and boswellic acid. CAM wasmainly used to actively treat the tumor. Other motivations were to treat side
effects of chemotherapy, or to comfort the child. Children diagnosed ≥2016
were more likely to use CAM (χ2=6.08, p=0.014). No significant difference
was found between CAM users and non-users based on ethnicity (χ2=4.18,
p=0.382) and country of residence (χ2=9.37, p=0.154). Almost 50% of
the physicians do not frequently ask their patients about possible CAM
use. CONCLUSION: This survey demonstrates that worldwide a considerable number of DIPG patients use CAM. Physicians should be more aware

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Abstractsof potential CAM use and more actively discuss the topic. More researchis needed to gain knowledge about possible anticancer effects of CAM andtheir interactions with conventional therapies.

pre-progression DIPG beginning at dose level 2, with 1 patient currently
enrolled. CONCLUSION: The CD40 agonistic antibody APX005M has
demonstrated preliminary safety in pediatric patients with recurrent/refractory primary malignant CNS tumors and has a likely RP2D of 0.6 mg/kg q3
weeks in this population. Preliminary efficacy data are pending.

EARLY PHASE CLINICAL TRIALSEPCT-01. PHASE I STUDY OF DAY101 (TAK580) IN CHILDREN AND
YOUNG ADULTS WITH RADIOGRAPHICALLY RECURRENT OR
PROGRESSIVE LOW-GRADE GLIOMA (LGG)
Karen Wright1, Emily Krzykwa1, Lianne Greenspan1, Susan Chi1,
Kee Kiat Yeo1, Sabine Mueller2, Michael Prados2, andDaphne Haas-Kogan1,3; 1Dana-Farber Cancer Institute/Boston Children’s
Hospital, Boston, MA, USA, 2UCSF Benioff Children’s Hospital, San
Francisco, CA, USA, 3Brigham and Woman’s Hospital, Boston, MA, USA
BACKGROUND: We report a phase I study examining pharmacokinetics, safety and recommended dosage of the type 2 RAF inhibitor DAY101
in children/young adults with radiographically recurrent/progressive LGGs
harboring MAPK pathway alterations. METHODS: Applying a 3 + 3 design, patients < 18 years of age with radiographically recurrent/progressive
LGG received oral DAY101 weekly for 4-week cycles up to a maximum of
2 years, if deriving clinical benefit. The starting DAY101 dosage was 280 mg/
m2. Dose limiting toxicities were determined after one cycle. RESULTS: We
treated nine eligible patients at 280, 350, and 420 mg/m2. Eight patients
had KIAA1549:BRAF fusions. One patient with NF1 did not have a biopsy. There were no DLTs. Weekly administration of DAY101 in children
resulted in dose-proportional increases in Cmax and AUC similar to that described in adults. A 2.2-fold mg/kg exposure difference was observed withrespect to weight-based dosing and suggested a correlation to best radiographic RANO responses of 2 complete responses, 2 partial responses, 3
stable disease, and 2 progressive disease (independently-reviewed). Mediantime to response was 10.5 weeks (range: 8–32 weeks). CONCLUSION: Thephase 1A data provide initial pharmacokinetic parameters to describe oral
weekly dosing of DAY101 in pediatric patients with radiographically recurrent/progressive LGG. Plasma exposures of DAY101 achieved in adults canbe reached in pediatric patients. Oral weekly DAY101 is well-tolerated andpossesses anti-tumor activity. The amended protocol will explore additionaldose levels and the potential for differential dosing to achieve similar responses across a variety of BSAs.
EPCT-02. PBTC-051: FIRST IN PEDIATRICS PHASE 1 STUDY OF
CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M IN
PEDIATRIC SUBJECTS WITH RECURRENT/REFRACTORY BRAIN
TUMORS
Holly Lindsay1, Arzu Onar-Thomas2, Mehmet Kocak3,
Tina Young Poussaint4, Girish Dhall5, Alberto Broniscer6, Anna Vinitsky7,
Tobey MacDonald8, Ovid Trifan9, Jason Fangusaro8, and Ira Dunkel10;
1Department of Pediatrics, Texas Children’s Hospital/Baylor Collegeof Medicine, Houston, TX, USA, 2Department of Biostatistics, St JudeChildren’s Hospital, Memphis, TN, USA, 3Department of Preventive
Medicine, University of Tennessee Health Science Center, Memphis, TN,
USA, 4Department of Radiology, Boston Children’s Hospital, Boston, MA,
USA, 5Division of Hematology and Oncology, Children’s of Alabama,
Birmingham, AL, USA, 6Children’s Hospital of Pittsburgh, Pittsburgh,
PA, USA, 7Division of Neuro-Oncology, St. Jude Children’s Research
Hospital, Memphis, TN, USA, 8Children’s Healthcare of Atlanta andEmory University, Atlanta, GA, USA, 9Apexigen, Inc., San Carlos, CA, USA,
10Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New
York, NY, USA
BACKGROUND: CD40 is a co-stimulatory molecule expressed on
antigen presenting cells (APCs). APX005M is a CD40 agonist monoclonal antibody which stimulates innate and adaptive anti-tumor immunity
through activation of APCs, macrophages, and antigen-specific CD8+T-cells.
Pediatric Brain Tumor Consortium study PBTC-051 is the first investigation of APX005M in pediatric patients and is evaluating the safety, recommended phase 2 dose (RP2D), pharmacokinetics, and preliminary efficacyof APX005M in children with central nervous system (CNS) tumors. RESULTS: Accrual of patients with recurrent/refractory primary malignant
CNS tumors (stratum 1) began in March 2018. 16 patients (2 ineligible)
have enrolled on this stratum; 14 were treated. Dose escalation through 3
planned dose levels of APX005M was completed without excessive or unanticipated toxicities. The highest dose level (0.6 mg/kg q3 weeks) is thepresumptive RP2D, and an expansion cohort is currently enrolling at thisdose. 2 patients at dose level 3 have received >12 cycles of therapy. Grade 3
or higher adverse events at least possibly attributable to APX005M include
11 lymphopenia, 5 neutropenia, 5 leukopenia, 3 ALT elevations, 1 AST elevation, 1 thrombocytopenia, and 1 hypoalbuminemia. PK data will be available March 2020. Stratum 2 is now enrolling patients with post-radiation/iii304

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EPCT-03. A PHASE I TRIAL OF 2-HYDROXYOLEIC ACID IN
PEDIATRIC PATIENTS WITH ADVANCED CENTRAL NERVOUS
SYSTEM TUMORS
Derek Hanson; Hackensack University Medical Center, Hackensack, NJ,
USA, Hackensack Meridian School of Medicine, Nutley, NJ, USA
2-hydroxyoleic acid (2-OHOA) is the first potential anti-cancer drug toact by modification of cell membrane lipid content. The agent is a derivative of oleic acid, a naturally occurring component of olive oil. Through its
unique mechanism of activating sphingomyelin synthase 1, 2-OHOA targets
the membrane lipid composition of cancer cells. These lipid changes alter
membrane-dependent signaling cascades, such as the Ras/MAPK pathway,that promote tumor cell proliferation. A comprehensive pre-clinical program has characterized the safety and effects of 2-OHOA across a host ofanimal models. A European phase I/IIa trial of 2-OHOA in adult patientshas shown initial promising results with five refractory high-grade glioma
patients demonstrating objective clinical benefit by RANO criteria for six
or more months. The drug has been very well-tolerated in adult patientswith minimal toxicity. This phase I study is the first pediatric investigationof 2-OHOA and focuses on the treatment of relapsed/refractory pediatriccentral nervous system (CNS) tumors. The trial consists of a dose-escalation
phase in up to 18 patients using a standard “3 + 3” design, followed by an
expanded safety cohort of up to 10 patients treated at the maximum tolerated dose to confirm the recommended phase II dose. Due to the promisingclinical results in adult neuro-oncology patients and the widespread involvement of the Ras/MAPK pathway and other membrane-dependent signalingcascades in the development of pediatric malignancies, we hypothesize that
2-OHOA may be a safe and effective treatment for pediatric patients withseveral types of advanced CNS tumors.
EPCT-05. A PHASE I TRIAL OF THE CDK 4/6 INHIBITOR
PALBOCICLIB IN PEDIATRIC PATIENTS WITH PROGRESSIVE
OR REFRACTORY CNS TUMORS: A PEDIATRIC BRAIN TUMORCONSORTIUM (PBTC) STUDYDavid Van Mater1, Sridharan Gururangan2, Sarah Leary3, Oren Becher4,
Joanna Phillips5, Jie Huang6, Olivia Campagne6, Tina Poussaint7,
Stewart Goldman4, Patricia Baxter8, Girish Dhall9, Giles Robinson6,
Mariko DeWire-Schottmiller10, Eugene Hwang11, Clinton Stewart6,
Arzu Onar-Thomas6, Ira Dunkel12, and Maryam Fouladi13; 1Duke
University Medical Center, Durham, NC, USA, 2University of Florida,
Gainesville, FL, USA, 3Seattle Children’s Hospital, Seattle, WA, USA, 4Ann
and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA,
5University of California San Francisco, San Francisco, CA, USA, 6St. JudeChildren’s Research Hospital, Memphis, TN, USA, 7Boston Children’s
Hospital, Boston, MA, USA, 8Texas Children’s Hospital, Houston,
TX, USA, 9Children’s of Alabama, Birmingham, AL, USA, 10Cincinnati
Children’s Hospital, Cincinnati, OH, USA, 11Children’s National Medical
Center, Washington, DC, USA, 12Memorial Sloan Kettering Cancer Center,
New York, NY, USA, 13Cincinnati Children’s Hospital, Cincinnati, OH,
USA
PBTC-042 was a phase I trial of palbociclib to determine the maximum
tolerated dose (MTD) and describe toxicities in children. Palbociclib isan oral, selective cyclin dependent kinase 4/6 inhibitor. METHODS: A
rolling-6 design was utilized. Eligible patients were children ≥4 and≤21 years-old with a progressive/refractory CNS tumor with intact retinoblastoma protein, measurable disease, and ability to swallow capsules.
Pharmacokinetic studies were performed during the first course. Here, wereport on the heavily pretreated stratum, which included patients who received >4 prior treatment regimens (either chemotherapy or biologic agent),
and/or craniospinal irradiation, and/or myeloablative chemotherapy plus
stem cell rescue. Palbociclib was initiated at 50 mg/m2/day for 21 consecutive days of a 28-day course. This was one dosage level below the MTD forthe less heavily pretreated stratum (75 mg/m2). RESULTS: Fourteen eligible
patients were enrolled (median age 12.8 years; male 79%). Eleven patients(79%) had either ependymoma or medulloblastoma. Four eligible andevaluable patients were enrolled at 50 mg/m2 with no DLTs. This prompted
a dosage increase to 75 mg/m2. Ten eligible subjects were enrolled and 7
were evaluable for DLT assessment. One of 7 evaluable patients experienced a DLT (grade 3 thrombocytopenia). This established 75 mg/m2 as
the MTD for more heavily pretreated patients. Mean ± SD palbociclib apparent oral clearance was 34.6 ± 18.4 L/h/m2. CONCLUSION: The MTD
for palbociclib on a 3 week on/1 week off schedule in children with brain
tumors is 75 mg/m2 and does not appear to be influenced by the degree ofprior therapy.

Abstracts

EPCT-06. A PHASE I STUDY OF MULTI-TARGETED THERAPYIN NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSICPONTINE GLIOMA
Muhammad Baig, Jason Johnson, Sumit Gupta, Zsila Sadighi, Wafik Zaky,
and Soumen Khatua; MD Anderson Cancer Center, Houston, TX, USA
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) constitutes
80% of pediatric brain stem tumors with a median survival of 12 months.
The PI3K/AKT/mTOR pathway is a key oncogenic driver of this tumor.
Targeting the chromatin dysregulation through HDAC inhibition, demonstrated benefit in vivo and vitro studies. We completed the first study
as a multi-targeted therapy using SAHA and temsirolimus in pediatric
DIPG. METHODS: After receiving institutional IRB approval, we enrolled
6 patients on this phase I study using a 3 + 3 statistical design. Patientswere divided into stratum 1 and stratum 2, based on newly diagnosed or relapsed DIPG respectively. Stratum I patients received radiation therapy concurrently with vorinostat, followed by maintenance therapy with vorinostat
and temsirolimus for 10 cycles (28 day cycle), while in stratum II patients
received vorinostat and temsirolimus for 12 cycles. Neuroimaging including
diffusion tensor imaging were evaluated where feasible. RESULTS: Threepatients were enrolled in each of the stratum. One patient in stratum 1 completed therapy, 2 other demonstrated progressive disease (PD) after 4th and1st cycle of maintenance therapy respectively. In stratum 2 all patients progressed 2 months after the start of therapy. However no dose-limiting toxicity (DLT) was noted. The patient in stratum 1 who completed therapy,
remained free of PD 21 months after diagnosis with continued improvements in the volume of enhancing and T2 hyperintense disease. CONCLUSION: Although no significant benefit was seen as compared to historicalcontrols during this study, no dose limiting toxicity was noticed with thistreatment.
EPCT-07. DEBIO1347, AN ORAL FGFR INHIBITOR: RESULTS FROMA SINGLE CENTER STUDY IN RECURRENT/REFRACTORY FGFRALTERED PEDIATRIC GLIOMASSameer Farouk Sait, Stephen Gilheeney, Ira Dunkel, andMatthias Karajannis; Memorial Sloan Kettering Cancer Center, New York,NY, USABACKGROUND: Oncogenic driver alterations in FGFR are present in a
subset of pediatric gliomas. Debio1347 is an orally available, highly selective
FGFR 1–3 inhibitor that had a favorable safety profile and encouraging
preliminary clinical activity in an adult phase 1 study. METHODS: Fivechildren with progressive/refractory CNS tumors harboring an FGFR genealteration following prior chemotherapy were treated with Debio1347 at
Memorial Sloan Kettering Cancer Center on single patient use protocols.
Patients were treated using the 20 mg tablet formulation at the adult recommended phase 2 dose (80 mg/1.73 m2 * BSA once daily). Toxicities were
graded using CTCAEv5.0 and imaging response assessments were performed
every 8–12 weeks. RESULTS: All AEs were grade 1–2. Most common
treatment-related adverse events were ALT increased, hypoalbuminemia
and hyperphosphatemia (4 patients). Two patients met criteria for partial response and two patients had stable disease. A 13 month-old patientwith a spinal cord high-grade glioma harboring two FGFR1 mutations(V592M, K687) had tumor reduction of 91.7% maintained for 12 months.
A 26-month-old patient with a pilomyxoid astrocytoma harboring an
FGFR1-TACC1 fusion had a tumor reduction of 74.5% maintained for9 months. Prolonged disease stabilization was noted in an eight year-old
patient with metastatic suprasellar pilomyxoid astrocytoma harboring an
FGFR1 mutation (9 months) and in a 14 year-old patient with posterior
fossa glioneuronal tumor harboring an FGFR3-TACC3 fusion (18 months
and ongoing). CONCLUSIONS: Debio1347 demonstrated tolerable toxicity and promising anti-tumor efficacy in pediatric patients with refractory
FGFR altered gliomas. Further studies in this population are warranted.
EPCT-08. ACTIVITY OF LAROTRECTINIB IN PEDIATRICTROPOMYOSIN RECEPTOR KINASE (TRK) FUSION CANCERPATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM (CNS)
TUMORS
Hiroaki Goto1, Birgit Geoerger2, Steven G. DuBois3,
Juneko E. Grilley-Olson4, Cornelis M. van Tilburg5, Johannes Schulte6,
Hyoung Jin Kang7, Makoto Tahara8, Valentina Boni9, Sebastien Perreault10,
Michael Capra11, John A. Reeves12, Nicoletta Brega12, Barrett H. Childs12,
Theodore W. Laetsch12, David S. Ziegler12, and François Doz12; 1Kanagawa
Children’s Medical Center, Yokohama, Japan, 2Gustave Roussy,
Department of Pediatric and Adolescent Oncology, Université Paris-Sud,
Université Paris-Saclay, Villejuif, France, 3Dana-Farber/Boston Children’s
Cancer and Blood Disorders Center, Boston, MA, USA, 4Lineberger Cancer
Center, University of North Carolina Hospitals, Chapel Hill, NC, USA,
5Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg University
Hospital and German Cancer Research Center (DKFZ), Heidelberg,
Germany, 6Charité – Universitätsmedizin Berlin, Berlin, Germany, 7Seoul
National University Hospital, Seoul, Republic of Korea, 8National Cancer

Center Hospital East, Kashiwa, Japan, 9START Madrid CIOCC, Madrid,
Spain, 10CHU Sainte Justine, Montreal, Canada, 11Our Lady Children’s
Hospital, Dublin, Ireland, 12Bayer HealthCare Pharmaceuticals, Whippany,
NJ, USABACKGROUND: TRK fusions are oncogenic drivers in a variety of tumors, many involving the CNS. Larotrectinib, a selective FDA- and EMAapproved TRK inhibitor, demonstrated a 79% objective response rate (ORR)
and a 35.2-month median duration of response (DoR) in adult and pediatricpatients with various non-CNS solid tumors harboring NTRK gene fusions.
We report the clinical activity of larotrectinib in pediatric patients with primary TRK fusion CNS tumors. METHODS: Patients aged <18 years withprimary CNS tumors harboring an NTRK gene fusion detected by local
molecular testing who were treated with larotrectinib in two clinical trials(NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity.
Disease status was investigator assessed (RANO). RESULTS: As of February 2019, 14 pediatric patients with primary TRK fusion CNS tumors
were identified. Gene fusions involved NTRK2 (n=10), NTRK1 (n=2), andNTRK3 (n=2). Median age was 7.0 years (range 1.3–16.7). ORR was 45%(95% CI 17–77%) among 11 evaluable patients. Two patients had complete
responses (pending confirmation), three had confirmed partial responses,
and six had stable disease. 24-week disease control rate was 73%. DoR
ranged from 2.6+ to 5.5+ months and progression-free survival ranged from
0.03+ to 13.9+ months. Duration of treatment ranged from 0.03+ to 16.6+
months. Treatment-emergent adverse events were mainly grade 1–2. CONCLUSIONS: Larotrectinib resulted in objective responses and durable
disease control in pediatric patients with primary TRK fusion CNS tumors.
These results support expanded testing for NTRK gene fusions in patientswith CNS tumors.
EPCT-09. CLR 131 IN PATIENTS WITH RELAPSED OR REFRACTORYPEDIATRIC MALIGNANCIES
Diane Puccetti1, Mario Otto1, Daniel Morgenstern2, Kenneth DeSantes1,
Steven Cho3,4, Lance Hall5, Kate Oliver6, and Jarrod Longcor6; 1Universityof Wisconsin American Family Children’s Hospital, Madison, WI,
USA, 2Hospital for Sick Children, Toronto, ON, Canada, 3Universityof Wisconsin-Madison Department of Radiology, Madison, WI, USA,
4University of Wisconsin Carbone Cancer Center, Madison, WI, USA,
5Emory University Department of Radiology and Imaging Sciences,Atlanta, GA, USA, 6Cellectar Biosciences, Florham Park, NJ, USA
BACKGROUND: CLR 131 is a novel targeted radiotherapeutic that exploits the selective uptake and retention of phospholipid ethers by malignant
cells. CLR 131 selectively delivers radiation to malignant tumor cells, thus
minimizing radiation exposure to normal tissues. OBJECTIVE: CLR 131 isbeing examined in a Phase 1 trial, CLOVER-2 (NCT03478462), to determine
the safety, tolerability, and initial efficacy of CLR 131 in children and adolescents with relapsed/refractory malignancies. METHODS: Eligibility criteria
include children with relapsed or refractory solid tumors or malignant brain
tumors for which there are no standard treatment options with curative potential. Subjects must be between ages 2 and 21 with no limit to the numberof prior therapies. CLR 131 is administered as a single infusion in escalating
doses beginning at 15 mCi/m2. Adverse events (AEs) are graded by NCICTCAE v5. RESULTS: As of 10Jan2020, four subjects with brain tumors
have received CLR 131; one at 15 mCi/m2 and three at 30 mCi/m2. Diagnoses
included DIPG (2), glioblastoma (1), and medulloblastoma (1). Median age is
13 years (range 10–15) and patients received a median of two prior therapies(range 1 to 8). There were no treatment emergent AEs at the 15 mCi/m2 doselevel attributed to CLR 131 by the investigator. Assessment of the 30 mCi/m2
dose level is ongoing. CONCLUSIONS: CLR 131 is a unique, first in classtargeted radiotherapeutic for pediatric malignancies. Preliminary data showsan acceptable and expected safety profile in this patient population. Dose escalation to determine the highest tolerated dose is ongoing.
EPCT-11. PHASE 1 STUDY OF FLUVASTATIN-CELECOXIBCOMBINATION IN CHILDREN WITH RELAPSING/REFRACTORY
OPTICO-CHIASMATIC LOW-GRADE GLIOMA OR HIGH-GRADE
GLIOMAS (FLUVABREX): FINAL RESULTS
Nicolas Andrew1, Arthur Sterin1, Caroline Solas1,
Marie-Cécile Le Deley2, Alicia Probst2, Isabelle Aerts3,
Cécile Faure-Conter4, Anne-Isabelle Bertozzi5, Pascal Chastagner6,
Natacha Entz-Werle7, Emilie De Carli8, Philippe Dory-Lautrec1,
Gauthier Bouche9, and Pierre Leblond2,4; 1CHU La Timone, Marseille,
France. 2Centre Oscar Lambret, Lille, France. 3Institut Curie, Paris, France.
4IHOPE, Lyon, France. 5CHU Purpan, Toulouse, France. 6CHU Brabois,
Nancy, France. 7CHU Hautepierre, Stasbourg, France. 8CHU Angers,
Angers, France. 9AntiCancer Fund, Strombeek-Bever, Belgium
BACKGROUND: Preclinical data support the activity of celecoxib andfluvastatin in high grade (HGG) and low grade gliomas (LGG). A Phase
I study was designed to evaluate this combination in children with re-

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fractory/relapsed glioma. AIM: To assess the safety, pharmacokinetics(PK), maximum tolerated dose, Recommended Dose for Phase II (RDP2).
METHOD: Multicenter phase I trial, including patients aged 6 to 21 year
old. Fluvastatin starting dose was 2 mg/kg/day, 14/28 days, with fixed doseof celecoxib (200–800 mg /day). Four dose levels of fluvastatin (2, 4, 6,
8 mg/kg/day) were evaluated. A Continual Reassessment Method was used
for dose escalation. Dose-limiting toxicities (DLT) were determined on the
1st cycle. PK samples were obtained at D1 and D14 of cycle 1, pre-dose ofcycle 2. RESULTS: 20 patients were enrolled with a median age of 12 years(5.9–19). They previously received a median of 3 (1–7) lines of treatment.
Ten patients were treated for LGG and 10 for HGG, receiving a median of
3.5 cycles (1–21). Patients with LGG received a median of 9 cycles (1–21).
Among the 17 patients evaluable for DLT, 2 DLTs were reported: 1 grade
3 maculo-papular rash (4 mg/kg), and 1 grade 4 increase of CPK (6 mg/
kg). The RP2D of fluvastatin is 6 mg/kg/day. CONCLUSION: In children
with refractory/relapsed glioma, the RDP2 of fluvastatin associated withcelecoxib is 6 mg/kg/day. This combination is well tolerated encouraging aphase 2 study in LGG.
EPCT-12. PNOC015: PHASE 1 STUDY OF MTX110 (AQUEOUS
PANOBINOSTAT) DELIVERED BY CONVECTION ENHANCED
DELIVERY (CED) IN CHILDREN WITH NEWLY DIAGNOSEDDIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PREVIOUSLY
TREATED WITH RADIATION THERAPY
Sabine Mueller1, Cassie Kline1, Javier Villanueva-Meyer1, Carly Hoffman1,
Shannon Raber1, Erin Bonner2, Javad Nazarian3, Shannon Lundy1,
Annette M. Molinaro1, Michael Prados1, Mariella Filbin4, andNalin Gupta1; 1University of California, San Francisco, San Francisco,
CA, USA, 2Children’s National Medical Center, Washington, DC, USA,
3Children’s Hospital Zurich - Eleonore Foundation, Zurich, Switzerland,
4Dana-Farber Cancer Institute, Boston, MA, USA
OBJECTIVE: To determine safety and distribution of MTX110 deliveredby CED in newly diagnosed DIPG patients. METHODS: DIPG patients(3–21 years) were enrolled after radiation. CED of MTX110 combinedwith gadoteridol was completed based on dose levels (DL) (30–90 µM withvolumes ranging from 3 cc (single dose) to 2 consecutive doses of 6 cc;
total number of DL=7). Catheter position was chosen to maximize tumor
coverage. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4–8 weeks if tolerated. Quality oflife (QOL) assessments using PedsQL Generic Core and Brain Tumor modules were obtained at baseline (n=5), 3-months (n=3), and end of therapy(n=2). Single-cell RNA sequencing and analysis of histone modifications was
performed to assess pharmacodynamic effects on DIPG cells. RESULTS: Between May 2018-Dec 2019, 6 patients were enrolled (median age 8 years,
range 5–21). Dose limiting toxicities included: grade 3 gait disturbance (DL7;cycle 1); grade 3 muscle weakness/vagus nerve disorder (DL5; cycle 4) andgrade 2 intolerable dysphagia (DL7; cycle 4). Twelve CED procedures werecompleted at DL7 and repeated cycles ranged from 2 to 7. Infusion to distribution volume ratio was approximately 1:3.5. There were no significant
changes in self-reported QOL. Parent ratings of patients’ worry (p = 0.04)
and overall QOL (p = 0.03) significantly decreased at 3-months. CONCLUSION: Repeat CED of MTX110 at the highest dose is tolerable. Tissue concentrations are likely to be substantially higher compared to oral dosing.
Pharmacodynamic effects will be presented.
EPCT-13. CMV PP65 RNA-PULSED DENDRITIC CELL VACCINESFOR PEDIATRIC GLIOBLASTOMA AND MEDULLOBLASTOMA:
PHASE I TRIAL RESULTS
Daniel Landi1,2, Gary Archer2, Timothy Driscoll1, Eric Lipp2,
Bridget Archambault1, Eric Thompson2,3, Charlene Flahiff2,
Denise Jaggers2, Kathleen Hahn2, Patrick Healy4, Luis Ramirez4,
James Herndon4, Kristin Schroeder1,2, John Sampson2, and David Ashley1,2;
1Department of Pediatrics, Duke University School of Medicine, Durham,
NC, USA, 2Preston Robert Tisch Brain Tumor Center, Duke University,
Durham, NC, USA, 3Department of Neurosurgery, Duke University,
Durham, NC, USA, 4Duke Cancer Institute Biostatistics, Duke University,
Durham, NC, USA
BACKGROUND: Recurrent medulloblastoma and malignant glioma
are lethal tumors that are virtually incurable. The cytomegalovirus (CMV)
antigen pp65 is ubiquitously expressed on medulloblastoma and malignant glioma but not on healthy brain. We evaluated autologous CMV pp65
RNA-pulsed dendritic cell (DC) vaccines in children and young adults ina phase I trial. METHODS: Circulating monocytes were harvested using
leukapheresis, differentiated into DCs, matured, and pulsed with pp65 RNA
using electroporation. DCs were packaged into vaccines (2x107DC/vaccine) and administered intradermally following tetanus-diphtheria toxoid
site preconditioning every 2 weeks x3, then monthly. The primary objectives of the study were to establish the feasibility of generating at least 3
vaccines and safety. An exploratory objective was to evaluate the ability ofiii306

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vaccination to create and enhance patient pp65-specific T cell responses. RESULTS: Eleven patients were enrolled with medulloblastoma (n=3) or glioblastoma (n=8). Ages ranged from 9–30 years old (mean 15.5y). Ten of 11
patients (91%) generated at least 3 vaccines (mean 6.2). Eight patients received at least 3 vaccines. To date, 4 patients have received all generated
vaccines without progression, 4 patients have progressed, and 2 patients arestill receiving vaccines. There have not been any severe adverse events probably or definitely related to vaccines. More mature data will be presented
at ISPNO. CONCLUSIONS: Leukapheresis and monocyte differentiation
is a feasible strategy for generating adequate DCs for active immunizationin children with malignant brain tumors. CMV pp65 RNA-pulsed DCs are
well-tolerated and immunogenic. Efficacy endpoints will be evaluated in a
subsequent phase II trial.
EPCT-15. THE REMIND TRIAL: MULTI-ANTIGEN TARGETED TCELLS FOR PEDIATRIC CNS TUMORS
Melanie Grant1, Maria Fernanda Fortiz1, Lu Wang1, Haili Lang1,
Anushree Datar1, Emily Reynolds1, Madeline Terpilowski1, Chris Lazarski1,
Jay Tanna1, Adriana Pitino1, Nan Zhang1, Fahmida Hoq1, Patrick Hanley1,
Lindsay Kilburn1, Roger Packer1,2, Brian Rood1, Catherine Bollard1,2, andEugene Hwang1; 1Children’s National Hospital, Washington, DC, USA,
2George Washington University, Washington, DC, USA
BACKGROUND: Patients with relapsed CNS malignancies or DIPG
face terrible prognoses. We hypothesized that T cells specific for 3 tumorassociated antigens (TAA), WT1, PRAME and survivin, would be safe andelicit anti-tumor immunity. METHODS: Patients (n=9) have received autologous tumor antigen-associated T cells (TAAT) (up to 4x107/m2) for
newly diagnosed DIPG (Group A) or recurrent CNS malignancies (GroupB) on a Phase I dose-escalation study (NCT03652545) and were monitored
for safety and response. RESULTS/DISCUSSION: 9/9 patients who received
TAAT completed the 45-day safety monitoring phase with no dose-limiting
toxicities. Infused cells were predominantly CD3+ T cells (median 96%;
range: 87–99%), with CD4+ and CD8+ comprising 16% (range: 5–87%)
and 40% (range: 4–67%) of the CD3+ cells, respectively. TAAT with specificity for 1–3 TAAs, at varying frequencies, was demonstrated in 8/9 TAAT
by anti-IFN-γ ELISPOT. Plasma cytokine profiles demonstrated infusionrelated immune cytokine responses. In summary, TAAT are safe and may
elicit anti-tumor responses in vivo. To confirm TAAT-driven effects, we are
evaluating plasma proteomic profiles for immune-response signatures andassessing unique T cell receptor rearrangements of infused TAAT. Response
assessment and dose escalation are ongoing.
EPCT-16. A PHASE IB STUDY OF PTC596 IN CHILDREN WITH
NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA AND
HIGH GRADE GLIOMA
Natasha Pillay Smiley1, Patricia Baxter2, Shiva Kumar1, Eugene Hwang3,
John Breneman4, Adam Lane1, Renee Doughman5, Michelle Deutsch1,
Charles Stevenson5, Clinton Stewart6, Jim Leach7, Xiao-Nan Li8,
Sonia Romero9, Pius Maliakal10, Lan Gao10, Maryam Fouladi5, andRachid Drissi5; 1Cincinnati Children’s Hospital Medical Center, Cincinnati,
Ohio, USA, 2Texas Children’s Hospital, Houston, TX, USA, 3Children’s
National Hospital, Washington, District of Columbia, USA, 4University ofCincinnati, Cincinnati, OH, USA, 5Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH, USA, 6St. Jude Children’s Hospital, Memphis, TN,
USA, 7Cincinnati Children’s Hospital Medical Center, Cincinnati, OH,
USA, 8Ann & Robert H, Lurie Children’s Hospital, Chicago, IL, USA, 9PTC
Therapeutics, South Plainfield, NJ, USA, 10PTC Therapeutics, Plainfield,
NJ, USABACKGROUND: BMI-1 is highly expressed in DIPG. Downregulation
leads to inhibition of cell proliferation, cell cycle signaling, self-renewal,
telomerase expression, activity, and suppression of DIPG cell migration.
Targeted inhibition of BMI-1 sensitizes DIPG cells to radiation and druginduced DNA damage. PTC596 (formulated by PTC Therapeutics, Inc.)is a novel, orally available drug that inhibits microtubule polymerization,
resulting in G2/M cell cycle arrest and post-translational modification of
BMI-1 protein and reduced BMI-1 protein levels. OBJECTIVES: To estimate
the maximum tolerated dose and describe dose limiting toxicities, pharmacokinetics and pharmacodynamics of PTC596 in children 3–21 years ofage with newly diagnosed diffuse intrinsic pontine glioma and high-grade
gliomas. METHODS: PTC596 is administered twice per week orally during
radiotherapy and as maintenance for up to two years. The starting dose of
PTC596 was 200 mg/m2, with a subsequent dose level of 260mg/m2/dose.
Pharmacokinetics are performed in Cycles 1 and 2. RESULTS: This study iscurrently ongoing. Nine patients (7 with DIPG, 2 with HGG), 8 evaluable,
have been enrolled. At dose level 1, 200 mg/m2, three evaluable patientswere enrolled and experienced no DLTs. At dose level 2, among 5 evaluable
patients, 2 experienced dose-limiting grade 4 neutropenia. PTC596 has beenotherwise well tolerated. Five patients remain in Cycles 2–11. CONCLUSION: This phase I trial is ongoing. PTC596 is tolerable at dose level 1. We

Abstracts

are amending the protocol to introduce tablets that can be dissolved in liquid to allow enrollment of younger patients and those unable to swallow
whole tablets.
EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIBAND EVEROLIMUS IN CHILDREN WITH RECURRENT OR
REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN
TUMOR CONSORTIUM INTERIM REPORTMariko DeWire1, Christine Fuller1, Olivia Campagne2, Tong Lin2,
Haitao Pan2, TIna Young-Pussaint3, Patricia Baxter4, Eugene Hwang5,
Andrew Bukowinski6, Kathleen Dorris7, Lindsey Hoffman8,
Angela Waanders9, Matthias Karajannis10, Clinton Steward2,
Arzu Onar-Thomas2, Ira Dunkel10, and Maryam Fouladi1; 1Cincinnati
Children’s Hospital, Cincinnati, OH, USA, 2St. Jude Children’s Research
Hospital, Memphis, TN, USA, 3Harvard Medical School, Boston, MA,
USA, 4Texas Children’s Cancer Center, Houston, TX, USA, 5Children’s
National Medical Center, Washington, DC, USA, 6Children’s Hospital of
Pittsburgh, Pittsburgh, PA, USA, 7Denver Children’s Hospital, Denver, CO,
USA, 8Phoenix Children’s, Phoenix, AZ, USA, 9Ann & Robert H LurieChildren’s Hospital, Chicago, IL, USA, 10Memorial Sloan Kettering Cancer
Center, New York, NY, USA
Genomic aberrations in the cell cycle and PI3K pathway are commonly
observed in recurrent childhood brain tumors. Dual inhibition of CDK4/6(ribociclib) and mTOR (everolimus) has strong biologic rationale, nonoverlapping single-agent toxicities, and adult clinical experience. The
maximum tolerated dosage (MTD) and/or recommended phase two dose
(RP2D) of ribociclib and everolimus was determined in the Phase I study
and ribociclib concentrations were characterized in plasma and tumor inchildren undergoing neurosurgical procedures. Following resection, eligible
patients were enrolled in the Phase I study according to a rolling 6 design
and received ribociclib and everolimus once daily for 21 days and 28 days,
respectively. Patients undergoing surgery received ribociclib at the pediatric
RP2D (350 mg/m2/day) for 7–10 days pre-operatively. Pharmacokinetic
samples were collected on both cohorts and analyzed in nine patients onphase I study. Sixteen eligible patients enrolled on phase I study (median age
10.3 years; range: 3.9–20.4) and 5 patients were enrolled on the surgicalcohort (median age 11.4 years; range: 7.2–17.1). Six patients enrolled atdose level 1 without dose limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4
ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. Everolimus concentrations following administrationof everolimus alone were lower than those following drug combination, suggesting an impact of ribociclib on everolimus pharmacokinetics. The MTD/
RP2D of ribociclib and everolimus in recurrent CNS tumors is 120 mg/m2
and 1.2 mg/ m2 daily for 21 days and 28 days, respectively.
EPCT-18. PHASE 0/I STUDY OF GM-CSF AND INTRATHECALTRASTUZUMAB IN CHILDREN WITH RECURRENT POSTERIORFOSSA EPENDYMOMA
Kathleen Dorris1,2, Melissa Widener1,2, Vladimir Amani2, Andrew Donson2,
Debra Schissel1, Jessica Carson1, Ashley Mettetal1, Dominique Ramirez3,
Daniel Gustafson3, Todd Hankinson1,2, Michael Handler1,2,
Margaret Macy1,2, and Nicholas Foreman1,2; 1Children’s Hospital
Colorado, Aurora, CO, USA, 2Morgan Adams Foundation Pediatric Brain
Tumor Research Program, Aurora, CO, USA, 3Flint Animal Cancer Center,
Colorado State University, Fort Collins, CO, USA
BACKGROUND: Posterior fossa ependymoma (PF EPN) is a pediatriccentral nervous system malignancy that has a poor outcome to standard
therapeutic approaches. The majority of PF EPN tumors have increased
HER2 expression. Trastuzumab is a monoclonal antibody that targets
HER2, and sargramostim (GM-CSF) stimulates hematopoietic progenitor
cell proliferation. The combination of trastuzumab and GM-CSF has beenshown to trigger antibody-dependent cell cytotoxicity in vitro in PF EPN
cell lines. METHODS: Children aged 1–21 years with relapsed PF EPN andno ventriculoperitoneal shunt or CSF obstruction are eligible for the Phase
0/I institutional trial at Children’s Hospital Colorado. Stratum 1 involves IT
trastuzumab and subcutaneous (subQ) GM-CSF prior to standard-of-caresurgical resection. Stratum 2 involves a 3 + 3 phase I design with serial IT
trastuzumab doses, each preceded by three days of GM-CSF, to establish the
MTD for IT trastuzumab. RESULTS: Trastuzumab was detected in a sufficient number of tumors after presurgical IT delivery in Stratum 1 to open
Stratum 2. Four patients (75% female) have been enrolled in Stratum 2 attrastuzumab Dose Level 1. Median age at enrollment is 9.8 years (range, 3.5–
20.2 years). Preliminary CSF pharmacokinetic analysis demonstrated detectable trastuzumab up to 14 days after IT doses. No dose-limiting toxicities
have occurred. Two patients progressed on therapy (median, 4 cycles). One
patient is progression-free at 18 months off therapy. One patient remains on
study therapy. CONCLUSIONS: IT trastuzumab penetrates PF EPN tumor
tissue. Stratum 2 remains open to accrual at Dose Level 2.

EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS
FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLYDIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG)AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)
Mariko DeWire1, James Leach1, Christine Fuller1, Peter de Blank1,
Trent Hummel1, Natasha Pillay-Smiley1, Ralph Salloum1,
Charles Stevenson1, Rachid Drissi1, Shiva Senthil Kumar1, Patricia Baxter2,
David Gass3, Stewart Goldman4, Sarah Leary5, Adam Lane1,
Olivia Campagne6, Clinton Stewart6, and Maryam Fouladi1; 1Cincinnati
Children’s Hospital Medical Center, Cincinnati, OH, USA, 2Texas
Children’s Cancer Center, Houston, TX, USA, 3Atrium Health LevineChildren’s Hospital, Charlotte, NC, USA, 4Ann & Robert H LurieChildren’s Hospital, Chicago, IL, USA, 5Seattle Children’s Hospital, Seattle,
WA, USA, 6St. Jude Children’s Research Hospital, Memphis, TN, USA
Genomic aberrations in the cell cycle and mTOR pathways have beenreported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG).
Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong
biologic rationale, non-overlapping single-agent toxicities, and adult clinicalexperience. The maximum tolerated dose (MTD) and/or recommended phasetwo dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as
a rolling 6 design. Ribociclib and everolimus were administered once dailyfor 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had
undergone biopsy were screened for RB protein by immunohistochemistry.
Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six
patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities(DLT). Currently, five patients are enrolled at dose level 3 expansion cohort.
The median number of cycles are 4.5 (range: 1–20+). Among the expansion
cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4
hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impactof ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib
and everolimus following radiotherapy in newly diagnosed DIPG and HGG
is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every
28 days which is equivalent to the adult RP2D.

EPENDYMOMAEPEN-01. MULTIDISCIPLINARY TREATMENT IN EPENDYMOMA
Daisuke Hirokawa; Kanagawa Children’s Medical Center, Yokohama,Japan
BACKGROUND: In intracranial ependymoma, the effectiveness of
chemotherapy and radiation therapy is unclear, and the degree of tumor
removal contributes to the improvement of life prognosis. METHODS: We
examined ependymoma cases treated in our institution from July 1998 to
March 2017. RESULTS: There were 18 boys and 7 girls. The average age at
the time of surgery is 5.3±3.6 years. The pathological diagnosis was Grade
II for 8 cases and Grade III for 17 cases. Genetic analysis was performed in
16/25 cases (64%). Of the infratentorial cases, 10/11 cases (90.1%) were
PFA and PFB were one case. Of the supratentorial cases, 3/5 cases (60%)
were positive for RELA fusion. As chemotherapy, 19 patients were VCR +VP-16 + CDDP + CPA. Irradiation was performed in all cases, local irradiation (50.4–55.8Gy) in 22 cases (88%), and craniospinal irradiationin 2 cases (8%). The 7-year OS was 74.6±9% and the 7-year PFS was
59.7±10.5%. Grade III showed a short OS (p = 0.053). GTR and NTR wereobtained in the first excision in 14 cases (56%), and OS and PFS were notsignificantly different from those in the STR group (p = 0.219, p = 0.248).
GTR and NTR including 2nd-look surgery were obtained in 18 cases (72%),
and significant improvement of OS was observed compared with STR group(p = 0.02). CONCLUSION: Even if it is not GTR or NTR at the first operation, improvement of OS is expected by total excision after chemotherapy.
EPEN-02. EVALUATION OF TREATMENT OUTCOMES AND
EXPRESSION OF EMT-RELATED TRANSCRIPTION FACTORS ASNOVEL THERAPEUTIC TARGETS IN PEDIATRIC EPENDYMOMA
Keishi Makino1,2, Jun-ichiro Kuroda2, Naoki Shinojima2, Kenji Fujimoto1,
Akira Takada1, and Akitake Mukasa2; 1Department of Neurosurgery,
Kumamoto City Hospital, Kumamoto, Japan, 2Department of
Neurosurgery, Kumamoto University, Kumamoto, JapanOBJECTIVE: Intracranial ependymomas are common brain tumorsin children. However, prognosis, especially in young children, remains
poor because of the chemo- and radioresistant properties of intracranial ependymomas. Furthermore, effective treatments for intracranial
ependymomas remain a challenge. The epithelial-to-mesenchymal transition

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Abstracts(EMT) is important for invasion and metastasis in many cancers. This study
aimed to evaluate and compare treatment outcomes with the expression of
EMT-related transcription factors in pediatric ependymomas. MATERIALAND METHODS: Medical and radio-imaging data of 22 (11 boys, 11
girls) patients aged <15 years with intracranial ependymomas were reviewed
from January 1983 to December 2018. Six cases were subdivided into
clinicopathological-molecular subgroups and immunohistochemically analyzed for Slug and ZEB. RESULTS: The median age at the start of treatment
was 5 years (range 8 months–15 years) (9 cases were aged <3 years). The
median progression-free survival (PFS) was 25.6 (range, 0.8–383.5) months;
the median overall survival (OS) was 81.9 (range, 2.9–383.5) months. Extent of resection and malignant histology were significant prognostic factors
for OS and PFS in multivariate analysis. There were 6 cases (2 cases of PFA,
2 of PFB, 1 of ST and 1 case of ST-RELA). Nuclear expression of ZEB1 wasfound in all tumors; however, that of Slug increased only in PFA and PFB
tumors, which were associated with a poor prognosis. CONCLUSION: Expression of EMT-related transcription factors was increased in pediatric
ependymomas. These data suggest that EMT is a novel therapeutic target
for treating pediatric intracranial ependymomas.
EPEN-03. LONG-TERM FOLLOW-UP OF AIEOP 2ND SERIES OF
CHILDREN AND ADOLESCENT WITH PRIMARY INTRACRANIAL(ST:SUPRATENTORIAL; PF: POSTERIOR FOSSA) EPENDYMOMAAND METHYLATION GROUPS RE-ANALYSES
Maura Massimino1, Francesca Romana Buttarelli2, Hendrik Witt3,4,
Pascal Johann3,4, Simone Minasi2, Stefan M. Pfister3,4, Kristian W. Pajtler3,4,
Manila Antonelli5, Francesco Barretta6, Piergiorgio Modena7,
Lorenza Gandola8, Maria Luisa Garrè9, Daniele Bertin10,
Angela Mastronuzzi11, Maurizio Mascarin12, Lucia Quaglietta13,
Elisabetta Viscardi14, Iacopo Sardi15, Antonio Ruggiero16, Bianca Pollo17,
Annamaria Buccoliero18, Luna Boschetti1, Veronica Biassoni1,
Elisabetta Schiavello1, Luisa Chiapparini19, Alessandra Erbetta19, andFelice Giangaspero5,20; 1Fondazione IRCCS Istituto Nazionale dei
Tumori, Pediatrics, Milano, Italy, 2Università La Sapienza, Human
Neurosciences, Roma, Italy, 3Hopp-Children’s Cancer Center Heidelberg
KiTZ, Heidelberg, Germany, 4German Cancer Research Center DKFZ,
German Cancer Consortium DKTK, Heidelberg, Germany, 5Università
La Sapienza, Radiological-Oncological and Anatomo-Pathological
Sciences, Roma, Italy, 6Fondazione IRCCS Istituto Nazionale dei Tumori,
Clinical Epidemiology and Trial Organization, Milano, Italy, 7A,S,S,T,
Lariana - Ospedale Sant’ Anna di Como, Genetic Laborator, Como, Italy,
8Fondazione IRCCS Istituto Nazionale dei Tumori, Pediatric Radiotherapy,
Milano, Italy, 9IRCCS Giannina Gaslini, Neuro-oncology, Genova, Italy,
10A,O,U, Città della Salute e della Scienza, Pediatric Oncology, Torino,
Italy, 11IRCCS Ospedale Pediatrico Bambino Gesù, Pediatric Hematology
and Oncology, Roma, Italy, 12Centro di Riferimento Oncologico CRO,
Radiotherapy, Aviano, Italy, 13Ospedale Santobono-Pausilipon, PediatricOncology, Napoli, Italy, 14Padova University, Pediatric Oncology, Padova,
Italy, 15Ospedale Pediatrico Meyer, Pediatric Oncology, Firenze, Italy,
16Fondazione Policlinico Universitario Agostino Gemelli, PediatricOncology, Roma, Italy, 17Fondazione IRCCS Istituto Neurologico Carlo
Besta, Pathology, Milano, Italy, 18Ospedale Pediatrico Meyer, Pathology,
Firenze, Italy, 19Fondazione IRCCS Istituto Neurologico Carlo Besta,nr,
Milano, Italy, 20IRCCS Neuromed, Pathology, Pozzilli, Italy
BACKGROUND: This 2002–2014 Italian prospective study stratified 160
patients by surgical resection (complete=NED/incomplete=ED) and centrallyreviewed grade. Grade2/NED patients received focal radiotherapy (RT) up
to 59.4Gy, Grade3/NED received 4 courses of VEC(vincristine,etoposide,cyclophosphamide) after RT.ED patients received 1–4 VEC courses, secondlook surgery, 59.4 Gy+8Gy boost on measurable residue. METHODS: We
re-analyzed data at 115 months follow-up including methylation profile onavailable samples. RESULTS: Global PFS/OS at 5/10 years were 66/59%
and 80/74%, respectively. Of the 64 relapsers at median 20 months, 53 diedat median 37/18 months after diagnosis/relapse, respectively.10/64 relapsed
after 5 years (66–126 months); 4 died, relapse was local in 8/10, metastatic
1, combined 1;5/10 patients were below age 3, 5 females, 8 PF tumors. Theirsurvival post-relapse was not longer than earlier relapsers’. At univariable
analysis, age over 3 years, female sex, complete surgery, grade 2, no shuntconfirmed better PFS/OS. 66/95 analyzed tumors received a score >0.80
through the DNA methylation-based central nervous system tumor classifier: 41/8 as PFA/PFB, respectively,14/17 ST as RELA-positive (3 scored forother molecular entities i.e. anaplastic PXA, LGG MYB, HGNET). Prognostic factors were equally distributed among PFA/PFB groups,1 only group
B patient relapsed locally at 96 months. CONCLUSIONS: Already published prognostic factors remained at long-term follow-up;6.2% patients
had late relapses. OS after relapse was not better in late relapsers. GroupB confirmed better prognosis but all patients had received «at least» adjuvant RT. Modern ependymoma trials need long follow-up to draw firm
conclusions.

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EPEN-04. ONCOGENIC 3D TUMOR GENOME ORGANIZATIONIDENTIFIES NEW THERAPEUTIC TARGETS IN EPENDYMOMA
Konstantin Okonechnikov1,2, Jens-Martin Hübner1,2, Owen Chapman3,
Abhijit Chakraborty4, Meghana Pagadala3, Rosalind Bump5,
Sahaana Chandran5, Katerina Kraft6, Rocio Acuna Hidalgo7,
Stefan Mundlos7, Robert Wechsler-Reya8, Edwin F. Juarez3, Nicole Coufal9,
Michael Levy10, John Crawford9,11, Kristian Pajtler1,2, Derek Reid12,
Anthony Schmitt12, Hannah Carter3, Ferhat Ay4, Jesse Dixon5,
Jill Mesirov3, Stefan M Pfister1,2, Marcel Kool1,2, and Lukas Chavez3;
1Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ),
Heidelberg, Germany, 2Division of Pediatric Neurooncology, German
Cancer Research Center (DKFZ), Heidelberg, Germany, 3Department ofMedicine, University of California San Diego (UCSD), San Diego, CA,
USA, 4Division of Vaccine Discovery, La Jolla Institute for Allergy and
Immunology, San Diego, CA, USA, 5Salk Institute for Biological Studies,
San Diego, CA, USA, 6Center for Personal Dynamic Regulomes, Stanford
University, Stanford, CA, USA, 7Max Planck Institute for Molecular
Genetics, Berlin, Germany, 8Tumor Initiation and Maintenance Program,
NCI-Designated Cancer Center, Sanford Burnham Prebys Medical
Research Discovery Institute, San Diego, USA, 9Department of Pediatrics,
University of California, San Diego, San Diego, CA, USA, 10Departmentof Neurosurgery, University of California San Diego – Rady Children’s
Hospital, San Diego, CA, USA, 11Department of Neurosciences, Universityof California San Diego – Rady Children’s Hospital, San Diego, CA, USA,
12Arima Genomics, Inc, San Diego, CA, USA
By profiling enhancers in primary ependymoma tumors, we have recently
identified putative oncogenes, molecular targets, and functional pathways.
Inhibition of selected targets diminished the proliferation of patient-derived
neurospheres and increased survival in mouse models of ependymoma.
While enhancers frequently regulate the nearest gene, identification of enhancer target genes remains to be a challenge in the absence of chromosome conformation information. Consequently, we have now used HiC to
map the 3-dimensional organization of tumor chromatin in the two mostcommon and aggressive ependymoma subgroups: posterior fossa group
A (PF-EPN-A) and supratentorial ependymomas with gene fusions involving
the NF-κB subunit gene RELA (ST-EPN-RELA). By an integrative analysisof enhancer and gene expression in the context of the newly derived HiC
data, we find that a large number of the predicted enhancer target genes areenriched for strong physical interactions. Importantly, we also identify many
new putative tumor-dependency genes activated by long-range promoterenhancer interactions and complex tumor-specific chromatin clusters of
regulatory elements. Complementary to the analysis of gene-enhancer interactions, we have also leveraged the HiC data for resolving structural rearrangements underlying copy number alterations. Copy number gains of
the 1q arm of chromosome 1 are especially associated with poor survival.
Our preliminary results in PFA relapse samples show complex structuralvariants underlying 1q gain that lead to inter-chromosomal rearrangements
and affect several genes that potentially contribute to poor survival. In ongoing work we are testing the relevance of the novel candidate genes fortumor cell growth and proliferation in-patient derived ependymoma models.
EPEN-05. CLINICAL AND GENETIC EVOLUTION OF
EPENDYMOMA EXPOSED FROM A MULTI-RECURRENCE GIRL
CASE
Zhong-ping Chen1, Jing Wang1, Shao-yan Xi1, Qi Zhao1, Yun-fei Xia1,
Cheng-cheng Guo1, Qun-ying Yang1, Zhao-jie Li2, Zhi Li2, Fu Han3,
Fang Wang4, Ke Sai1, Hai-ping Cai1, Xiang-heng Zhang1, Chao Ke1,
and Jian Wang1; 1Sun Yat-sen University Cancer Center, Guangzhou,
Guangdong, China, 2Guangdong Provincial Hospital, Guangzhou,
Guangdong, China, 3Chinese Traditional Medicine Hospital of Guangdong
Province, Guangzhou, Guangdong, China, 4Sun Yat-sen University Cancer
Center, Guangzhou, Guangdong, China
Ependymomas are glial brain tumors accounting for approximately 2~3%of all primary tumors of the central nervous system (CNS), and 12% of allpediatric intracranial tumors. To better understand the evolution processof ependymomas, we studied the clinical, pathological and genetic development of a rare girl case with repeatedly recurrent ependymoma. This girl was
diagnosed as ependymoma at age of 9 years old, and experienced 7 times
tumor relapse and received 9 times surgeries but finally ceased at 19 years
old with multiregional recurrences. The pathological characteristics, radiographic images and therapeutic strategies of the patient were all retrieved.
Molecular markers confirmed the diagnosis of anaplastic ependymoma
based on the updated WHO guideline for CNS tumors. Whole-genome
sequencing (WGS) was performed to elucidate the landscape of mutation
signatures and to identify potential driver mutations along the tumor progression. The seven tumor specimens showed a highly branched evolutionary pattern. There were six gene mutations found in 5 of the 7 specimens(PCDHA4, PCDHA8, SEC14L6, SETD2, RIOK2, and SLCO2A1) and threeAbstracts

in 6 of 7 the samples (RYR1, SNX25, DSC2). Strikingly, there was one gene,
ADGRL3, which was found to be consistently mutated in the entire diseaseprogression process. Our findings therefore suggest that ADGRL3 mightplay roles in the disease progression of ependymoma patient.
EPEN-06. CHEMOTHERAPY OF RECURRENT EPENDYMOMA:
LONG-TERM RESPONSE ONLY IN FEW CASES
Jonas Adolph1, Stephan Tippelt1, Ruth Mikasch1,
Stefan Pfister2,3, Kristian Pajtler4,3, Hendrik Witt4,3, Olaf Witt4,3,Brigitte Bison5, Monika Warmuth-Metz5, Rolf-Dieter Kortmann6,
Stefan Dietzsch6, Torsten Pietsch7, Beate Timmermann8, andGudrun Fleischhack1; 1University Hospital of Essen, Pediatrics III,
Pediatric Hematology and Oncology, Essen, Germany, 2University Hospital
Heidelberg & German Cancer Research Center (DKFZ), Heidelberg,
Germany, 3Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg,
Germany, 4University Hospital Heidelberg & German Cancer ResearchCenter (DKFZ), Heidelberg, Germany, 5University Hospital of Wuerzburg,
Institute for Diagnostik and Interventional Neuroradiology, Wuerzburg,
Germany, 6University of Leipzig, Radiooncology, Leipzig, Germany,
7University Hospital of Bonn, Institute of Neuropathology, Bonn, Germany,
8Department of Particle Therapy, University Hospital Essen, West German
Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ),
German Cancer Consortium (DKTK), Essen, Germany
INTRODUCTION: The efficacy of chemotherapy in recurrent
ependymoma is unclear. We present results from the German HIT-REZstudies. METHODS: 137 patients were analyzed regarding the treatment
with chemotherapy at first recurrence, the time from first relapse to progression (PFS) and to either time-point of death or last follow-up (OS). Tumor
response evaluation was based on MRI and clinically; molecular data wasavailable in 80. RESULTS: In our cohort, 96 patients (20 supratentorial, 73
infratentorial, 3 spinal) received chemotherapy during first recurrence: 49(51.0%) temozolomide (TMZ) monotherapy, 12 (12.5%) HIT-SKK regime,
9 (9.4%) carboplatin/etoposide (CE) and 26 (27.1%) other combinations. In
19.8% (26.5% in TMZ), chemotherapy was administered prior to surgery(neoadjuvant), which resulted in tumor progression in 78% (85% in TMZ).
Gross-total resection was achieved in 86% without neoadjuvant chemotherapy and in 74% (69% in TMZ) with neoadjuvant treatment. Switching
to trofosfamide/etoposide (TE) after surgery and unresponsiveness to TMZ
showed further progression in all cases of tumor-residuum after surgery.
Regarding 1-year-PFS, treatment with HIT-SKK (50.0%±14.4%) or CE(55.6%±16.6%) was advantageous over TMZ (30.2%±6.7%). However,
5-y-OS was lower in CE (19.0% ±16.8%) than in TMZ (39.8%±7.7%)
and HIT-SKK (42.9%±8.7%). Long-term control was seen in individual
cases of TMZ, HIT-SKK and CE, with TMZ providing longest responseof 72 months. CONCLUSION: Neoadjuvant TMZ has no significant advantage regarding PFS. However, in few cases chemotherapy prevented
progression after incomplete resection. Difficulties in response evaluationand variability in therapies hinder conclusions. Supported by the GermanChildren’s Cancer Foundation
EPEN-07. PATTERNS OF EXTRANEURAL METASTASES INPEDIATRIC SUPRATENTORIAL EPENDYMOMA: CASE SERIES AND
REVIEW OF THE LITERATURE
Priya P. Chan1, Nicholas S. Whipple1, Arie Perry2, David A. Solomon2,
Holly Zhou3, Luke L. Linscott4, John R. W. Kestle5, and Carol Bruggers1;
1Division of Pediatric Hematology-Oncology, Department of Pediatrics,
University of Utah, Salt Lake City, UT, USA, 2Department of Pathology,
University of California, San Francisco, San Francisco, CA, USA,
3Department of Pathology, University of Utah, Salt Lake City, UT, USA,
4Department of Radiology, Primary Children’s Hospital, Salt Lake City,
UT, USA, 5Department of Neurosurgery, University of Utah, Salt Lake City,
CA, USABACKGROUND: Ependymomas account for 10% of all malignant pediatric intracranial tumors. Standard therapy includes maximal safe surgicalresection followed by involved-field radiation. Up to 50% of localized pediatric ependymomas recur. Extraneural metastases at time of recurrence arerarely reported. OBJECTIVE: To describe extraneural metastases of pediatric ependymomas. METHODS: Retrospective review of patients’ medical records and literature review. RESULTS: Three patients with historyof locally recurrent, supratentorial ependymoma developed extraneural metastases: one in a cervical lymph node, one with a scalp nodule, and one
with a dural lesion. Each extraneural recurrence had similar histologic andmolecular features as the initial diagnosis. The cervical lymph node recurrence was treated with multimodal therapy; she is without disease four years
later. The isolated scalp nodule occurred at the exit site of a subgaleal drain
placed during prior resection. Following nodule resection, he developed additional scalp and lymph node disease and is receiving palliative care. The
isolated dural recurrence occurred at the exit site of a ventriculoperitoneal
shunt placed following a previous resection. She died of progressive disease
18 months after dural lesion resection. Reports of lymph node, scalp, anddural metastases of ependymomas are exceedingly rare, and outcomes arepoor. CONCLUSIONS: Extraneural manifestations of ependymoma are
rare. Regional seeding from prior surgical procedures may play a role inmetastatic spread. Extraneural metastases should be considered in children
previously treated for ependymoma who develop local findings even in theabsence of CNS relapse. Salvage therapy with curative intent should be considered using a multimodal approach.
EPEN-09. IMPACT OF MOLECULAR SUBGROUP ON OUTCOME
FOR INFANTS <12 MONTHS WITH INTRACRANIALEPENDYMOMA - GERMAN EXPERIENCE FROM HIT2000,
INTERIM-2000-REGISTRY AND I-HIT-MED REGISTRY
Denise Obrecht1, Martin Mynarek1, Katja von Hoff2, Hendrik Witt3,
Kristian W. Pajtler4,5, B.-Ole Juhnke1, Monika Warmuth-Metz6,
Brigitte Bison6, Rolf-Dieter Kortmann7, Beate Timmermann8,
Stefan M. Pfister4,5, Felix Sahm3,9, Dominik Sturm9,10,
Andreas von Deimling3, Ulrich Schüller11,12, Torsten Pietsch13,
Martin Benesch14, Nicolas U. Gerber15, and Stefan Rutkowski1; 1PediatricHematology and Oncology, University Hospital Hamburg-Eppendorf,
Hamburg, Germany, 2Charite – University Medical Center Berlin,
Berlin, Germany, 3Clinical Cooperation Unit Neuropathology, German
Consortium for Translational Cancer Research (DKTK), German Cancer
Research Center (DKFZ), Heidelberg, Germany, 4Hopp Children’s Cancer
Center Heidelberg (KiTZ) and Division of Pediatric Neurooncology,
German Cancer Research Center (DKFZ), Heidelberg, Germany,
5Department of Pediatric Oncology, Hematology and Immunology,
Heidelberg University Hospital, Heidelberg, Germany, 6Institute ofDiagnostic and Interventional Neuroradiology, University Hospital
Würzburg, Würzburg, Germany, 7Department for Radiation Therapy,
University Medical Center Leipzig, Leipzig, Germany, 8Department ofParticle Therapy, University Hospital Essen, West German Proton Therapy
Centre Essen (WPE), West German Cancer Center (WTZ), Germany,
German Cancer Consortium (DKTK), Essen, Germany, 9Hopp Children’s
Cancer Center Heidelberg (KiTZ), Heidelberg, Germany, 10Divisionof Pediatric Neurooncology, German Cancer Research Center (DKFZ)and German Consortium for Translational Cancer Research (DKTK),
Heidelberg, Germany, 11Department of Neuropathology, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany, 12ResearchInstitute Kinderkrebs-Zentrum Hamburg, Hamburg, Germany, 13Instituteof Neuropathology, Brain Tumor Reference Center of the German Society
for Neuropathology and Neuroanatomy (DGNN), University of Bonn,DZNE German Center for Neurodegenerative Diseases, Bonn, Germany,
14Division of Pediatric Hematology and Oncology, Department ofPediatrics and Adolescent Medicine, Medical University of Graz, Graz,
Austria, 15Department of Oncology, University Children’s Hospital, Zürich,
Switzerland
BACKGROUND: For infant ependymoma (EP), decision for radiotherapy during first-line therapy is a dilemma. We analyzed therapy outcomes of EP patients younger than 12 months at diagnosis according tomolecular subgroup. PATIENTS AND METHODS: Between 2001 and2017, 30 patients with histological diagnosis of intracranial EP <12 months
at diagnosis with DNA-methylation profiling available were registered in
HIT-MED-studies/-registries. RESULTS: In 3/30, DNA methylation-based
CNS tumor classification suggested a diagnosis other than EP or could
not be assigned to a reference class. Of the remaining 27 tumors, 16 wereclassified as PF-A, 8 as RELA-fusion positive and 3 as YAP-fusion positive. Median age at diagnosis was 0.73 (0.30–0.99) years. After a medianfollow-up time of 5.36 (0.20–12.90) years, 59.3% experienced progressive
disease (PD). 5y-PFS and -OS for the whole cohort were 38.2% and 73.1%.
RELA- and YAP-fusion positive EP had significantly better OS than PF-A
(5y-OS for PF-A: 55.9%; RELA 100%; YAP 100%; p=0.023). PFS was not
significantly different. All but one patient with relapsed PF-A died despite
multimodal salvage strategies. In contrast, patients with relapsing RELAand YAP-fusion positive EP (n=5), survived with a combination of re-surgery
and first or second local radiotherapy. CONCLUSION: In this cohort ofinfants <12 months, patients with PF-A had a significantly inferior OS compared to patients with RELA- and YAP-fusion positive EP. Salvage therapy
was ineffective for patients with PF-A, whereas patients with can RELAand YAP-fusion positive EP can be long-term survivors after PD. Therefore,
subgroups-specific therapy should be discussed.
EPEN-10. SPINAL MYXOPAPILLARY EPENDYMOMA AND
METHYLATION-PROFILING: THE MD ANDERSON CANCERCENTER (MDACC) EXPERIENCE
Sumit Gupta, Xiangjun Tian, Jing Wang, Jason Huse, Laurence Rhines,
Wafik Zaky, Claudio Tatsui, and Soumen Khatua; MD Anderson Cancer
Center, Houston, TX, USA
INTRODUCTION: Spinal myxopapillary ependymoma (MPE) is a rare
histological variant of ependymoma, classified as WHO grade I tumor.
Further interrogation of the molecular and clinical profile is warranted,

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iii309Abstracts

to better understand the biology and clinical phenotype. We summarize
our institutional experience with spinal MPE including methylationprofiling. METHODS: A retrospective analysis of charts during the periodof 2001 to 2019 of histologically proven MPE was done. We performed
methylation profiling for 12 patients by Infinium MethylationEPIC Kit. RESULTS: 26 patients with spinal MPE were identified, median age of diagnosis was 34.2 years with a range of 11 to 59.9 years. Ten patients were
below 30 years of age, lumbar spine location was commonest and 6 had
leptomeningeal spread at diagnosis. All the patients underwent surgery and
11 received radiation following surgery. Eight patients below the age of 30
received radiation due to residual disease or metastases. Methylation profiling revealed 11,752 CpGs differentially methylated between the younger
and older patients (p < 0.05), however only one CpG cg22496254 associated with gene NCAPG/DCAF16 (role in promoting mitosis) was detectablewith FDR < 0.25 that overly methylated in the younger age group. This is a
new finding in MPE. CONCLUSIONS: Spinal MPE is a rare spinal tumor.
Our study though limited by numbers, showed younger patients had aggressive phenotype, most requiring radiation. Methylation profiling reaffirmed
this finding and trend in the younger patients. Prospective studies in a larger
cohort of patients with methylation profiling are needed to identify prognostic variables and new targets for treatment.
EPEN-11. ONGOING RESPONSE IN A MULTIPLY RELAPSEDMETASTATIC POSTERIOR FOSSA EPENDYMOMA A AFTERVORINOSTAT AND CONCOMITANT IRRADIATION
Hamza S Gorsi1,2, Stephanie Toll1,2, and Maxim Yankelevich3; 1Children’s
Hospital of Michigan, Detroit, MI, USA, 2Central Michigan University,
Detroit, MI, USA, 3Rutgers Cancer Institute of New Jersey, New
Brunswick, NJ, USA
BACKGROUND: Among the nine molecular subgroups of ependymoma
identified, posterior fossa ependymoma A (PF-EPN-A) confers the worst
prognosis. These tumors often relapse despite aggressive resection and irradiation, resulting in limited therapeutic options. Although the genomic
profile of PF-EPN-A does not typically show any recurrent alterations; they
demonstrate distinct epigenetic changes which can be targeted with modulators such as histone deacetylase (HDAC) inhibitors. These inhibitors haveshown efficacy in pre-clinical studies in both their anticancer and radiosensitizing properties. CASE: We describe a male diagnosed with a posterior
fossa ependymoma at 3 years of age. After initial therapy with resection
and focal irradiation, he went on to have a number of recurrences requiring
multimodal therapy. Most recently, he developed diffuse intraventricularand leptomeningeal disease not amenable to surgical intervention. Genetic evaluation demonstrated a BCOR mutation and methylation profile
was consistent with PF-EPN-A. He received 23.4 Gray craniospinal irradiation with a 30.6 Gray boost to the nodular lesions. Vorinostat was given
concomitantly for radio-sensitization in 2 week intervals for a total of 6
weeks. Serial imaging after irradiation revealed decreased tumor burdenwith almost complete resolution of disease at 15 months. Unfortunately,
MRI at 18 months exhibited mild interval growth of 2 lesions. CONCLUSIONS: To our knowledge, this is the first report of a clinical response ina pediatric patient with PF-EPN-A following irradiation administered concomitantly with vorinostat therapy. This response highlights the importanceof further studies evaluating this combination therapy and its potential use
in this population.
EPEN-13. PRIMARY EXTRADURAL SACROCOCCYGEALSUBCUTANEOUS MYXOPAPILAR EPENDYMOMA MISDIAGNOSEDAS PILONIDAL CYST IN A 7 YEAR-OLD BOY: A CASE REPORTRegina M Navarro-Martin del Campo1,2, Geronimo M Tavares-Macias1,
Luis Ivan Pozos-Ochoa1, Ana L Orozco-Alvarado1,
Fernando Sanchez-Zubieta1, and Luis Angel Arredondo-Navarro3,2;
1Hospital Civil de Guadalajara “Dr. Juan I Menchaca”, Guadalajara,
Jalisco, Mexico, 2GAPNO, international, Mexico, 3Hospital Civil deGuadalajara “Fray Antonio Alcalde”, Guadalajara, Jalisco, Mexico
BACKGROUND: Ependymomas occur in the brain or spinal cord andrarely as an extraspinal variety at the sacrococcygeal region, separated fromthe spinal cord. This rare presentation is thought to originate from a groupof heterotopic ependymal cells called the coccygeal medullary vestige. There
are few reports of this occurrence in children. CLINICAL CASE: A 7-yearold male presented with a history of a soft mass arising in the sacrococcygeal
area 3 years earlier, diagnosed as pilonidal cyst at primary level and treatedwith surgery twice, as this mass recurred the boy was sent to our hospital,a 3rd surgery was performed, all tumoral tissue was removed, no attachment with dural space was founded, pathology revealed myxopapilar
ependymoma with positivity for PS100, EMA and Vimentin. After surgery a
Follow up MRI of cranium and spine showed absence of disease, no radiotherapy neither chemotherapy was implemented. He has been on surveillance from 3 years now without recurrence. CONCLUSION: This reporthighlights the fact that pediatric ependymoma can have an extradural pres-iii310N EU R O - O N C O L O G Y•

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entation and can be confounded with pilonidal cyst, total resection is needed
to control the disease. Potential for recurrence or metastatic disease can continue 20 years from the time of primary tumor, so prolonged surveillance isimportant.
EPEN-14. GENERATION OF A C11ORF95-RELA FUSIONTARGETING ANTIBODY AS A DIAGNOSTIC TOOL FOR
SUPRATENTORIAL EPENDYMOMA
Lisa Ruff1, Denice Y Chan2, Lesley Jenkinson2, Stuart Haynes2,
Mark Austin2, Sarah Holt2, Maria Groves2, and Richard J Gilbertson1;
1Cancer Research UK Cambridge Institute, Cambridge, United Kingdom,
2Cancer Research UK AstraZeneca Antibody Alliance Laboratory,
Cambridge, United Kingdom
Ependymomas account for 10% of paediatric brain tumours and arisein the ventricular walls of the central nervous system. Ependymomas werepreviously classified as one tumour type and all patients received similar
treatment. However, recent genomic studies have identified nine different
molecular subgroups of the disease, including one supratentorial subtype
characterized by a novel fusion gene C11ORF95-RELA. When introduced
into neural stem cells, this fusion is a potent driver of tumorigenesis and its
presence in patient samples has previously also been shown to negatively
correlate with overall survival. Accurate diagnosis of this subgroup is currently limited to sophisticated approaches such as break-apart FISH or RNA
sequencing. Here, we report the generation of a C11ORF95-RELA Fusionspecific antibody that can be used for routine immunohistochemistry (IHC).
Candidate antibodies were first selected using phage display and favourable
leads were subjected to affinity maturation using ribosome display after ascreening process involving immunoblotting and IHC. Further IHC-based
screening of affinity-matured candidates using fusion-positive and -negative
mouse tissue as well as human fusion-negative ependymoma tumour tissue
produced one lead antibody. The antibody detects fusion-specific nuclear
staining pattern on fusion-positive tissue and does not react with fusionnegative tissues. This candidate antibody is currently being tested on humanfusion-positive ependymoma tissue. This accurate diagnostic tool holds
great promise to transform the management of patients with supratentorial
ependymoma.
EPEN-16. TRANSCRIPTIONAL REGULATORY CIRCUITRIES AS
MOLECULAR TARGETS IN EPENDYMOMA
Kelsey Bertrand1,2, Stephen Mack1,2, and Donald W. Parsons1,2; 1Baylor
College of Medicine, Houston, TX, USA, 2Texas Children’s Hospital,
Houston, TX, USA
Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads.
Ependymomas comprise histologically similar tumor entities driven by
distinct molecular mechanisms, such as fusion oncoproteins, genome-wide
chromosomal instability, or disruption of DNA methylation patterns. Despite these differences, ependymomas resist chemotherapy and lack available targeted agents for clinical trial development. Based on our previous
findings, we hypothesized that mapping chromatin landscapes and superenhancers (SE) could uncover transcriptional dependencies as targets fortherapy (Mack, Pajtler, Chavez et al., Nature, 2018). To functionally test
the requirement of these SE genes for ependymoma cellular growth, we designed a pooled RNA interference screen against 267 SE associated genes.
Our screen was performed in one C11ORF95-RELA-fusion model and two
PF-EPN-A models as controls in biological triplicates. As an indication that
our screen was successful, positive controls scored among lead hits including
KIF11, BUB1B, PHF5A and MYC. Importantly, we identified many subtype specific dependencies in both C11ORF95-RELA-fusion and PF-EPN-A
models, thus revealing novel pathways that potentially govern subgroupspecific ependymoma cell growth. Further, several candidates detected acrossall ependymoma lines were also identified as pan-cancer dependencies or
glioma/glioblastoma specific essential genes from the DepMap Cancer Dependency Gene Resource. Our findings reveal novel targets and pathways
that are essential for ependymoma cell growth, which may provide new insight into therapeutic strategies against these aggressive brain tumors.
EPEN-17. FAVORABLE OUTCOME TO INTENSIVECHEMOTHERAPY WITHOUT IRRADIATION IN INFANTILEMETASTATIC EPENDYMOMA WITH A NOVEL MOLECULARPROFILE: A CASE REPORT
Flavia W. de Faria1, Kathleen M Schieffer2, Christopher Pierson3,
Daniel Boué3, Nicholas Zumberge4, Jerome Rusin4, Stephanie LaHaye2,
Katherine E. Miller2, Daniel C. Koboldt2, Tara Lichtenberg2,
Kristen Leraas2, Patrick Brennan2, Benjamin Kelly2, Peter White2,
Vincent Magrini2, Richard K. Wilson2, Elaine R. Mardis2,
Diana S. Osorio5, Jeffrey Leonard6, and Jonathan L. Finlay5; 1Department

Abstracts

of Pediatric Hematology and Oncology, Hospital da Criança de Brasilia,
Brasilia, DF, Brazil, 2The Steve and Cindy Rasmussen Institute for Genomic
Medicine, Columbus, OH, USA, 3Department of Pathology and Laboratory
Medicine, Nationwide Children’s Hospital, Columbus, OH, USA, 4The
Department of Radiology, Nationwide Children’s Hospital, Columbus,
OH, USA, 5The Division of Hematology, Oncology, Blood and Marrow
Transplant, Nationwide Children’s Hospital and The Ohio State University,
Columbus, OH, USA, 6The Division of Pediatric Neurosurgery, Nationwide
Children’s Hospital and The Ohio State University, Columbus, OH, USA
Metastatic disease at initial presentation of intracranial ependymoma
is an uncommon occurrence with only rare reports of survival and isreportedly more prevalent in the youngest of children. Clinical and molecular characteristics associated with metastatic presentation, their
prognostic implications, as well as optimal treatment options for suchpatients, have not been identified. CASE REPORT: A seven months oldchild presented with posterior fossa anaplastic ependymoma; following
sub-total resection of primary tumor, a spine MRI revealed leptomeningeal dissemination along the cervical spinal cord and nerve roots ofthe cauda equina. The patient was successfully treated with five cycles
of intensive induction chemotherapy (as per Head Start with high-dose
methotrexate) followed by three sequential cycles of marrow-ablative
chemotherapy and autologous hematopoietic progenitor cell rescue(AuHPCR) without irradiation; he is currently without evidence ofthe disease now 60 months following initial diagnosis. MOLECULAR/
GENOMIC RESULTS: The patient was enrolled on a patient-centriccomprehensive molecular profiling protocol, which included paired
tumor-normal whole-exome sequencing, RNA sequencing of the diseaseinvolved tissue, and DNA methylation classification. The genomic profileof the tumor was relatively unremarkable, revealing only a terminal gainof chromosome 3p and a terminal deletion of chromosome 22q, suggestive of an unbalanced translocation. Using RNA sequencing, we identified a novel SPECC1L-RAF1 gene fusion. The tumor harbors uniquetranscriptomic and DNA methylation profiles, failing to discretely classify with well-established ependymoma subgroups. CONCLUSION: Useof genomic profiling techniques provides meaningful information for
disease characterization allowing for further expansion of the molecular
spectrum associated with malignant disease.
EPEN-18. CROSS-SPECIES GENOMICS IDENTIFIES GLI2 AS AN
ONCOGENE OF C11ORF95 FUSION-POSITIVE SUPRATENTORIALEPENDYMOMA
Tuyu Zheng1, David R. Ghasemi1, Konstantin Okonechnikov1,
Andrey Korshunov2,3, Martin Sill1, Jens-Martin Hübner1,
Kendra K. Maaß1,4, Matija Snuderl5, Johannes Gojo6, Ulrich Schüller7,8,
Nicolas U. Gerber9, Pablo Hernáiz-Driever10, Till Milde11,4,
Dominik Sturm12,4, Rebecca Chapman13, Richard G. Grundy13,
Andreas von Deimling2,3, David T.W. Jones12, Marcel Kool1,
Stefan M. Pfister1,4, Felix Sahm14,3, Daisuke Kawauchi1,15, andKristian W. Pajtler1,4; 1Hopp Children’s Cancer Center Heidelberg (KiTZ)
and Division of Pediatric Neurooncology, German Cancer ResearchCenter (DKFZ), Heidelberg, Germany, 2Clinical Cooperation Unit
Neuropathology, German Cancer Research Center (DKFZ), German
Consortium for Translational Cancer Research (DKTK), Heidelberg,
Germany, 3Department of Neuropathology, Institute of Pathology,
Heidelberg University Hospital, Heidelberg, Germany, 4Department ofPediatric Oncology, Hematology, and Immunology, University Hospital
Heidelberg, Heidelberg, Germany, 5Division of Neuropathology,
Department of Pathology, NYU Langone Health, New York, NY, USA,
6Department of Pediatrics and Adolescent Medicine, Medical Universityof Vienna, Vienna, Austria, 7Research Institute, Children’s Cancer
Center Hamburg, Hamburg, Germany, 8Institute of Neuropathology,
University Medical Center Hamburg-Eppendorf, Hamburg, Germany,
9Department of Oncology, University Children’s Hospital, Zurich,
Switzerland, 10Department of Pediatric Oncology/Hematology, Charité
Universitätsmedizin, Corporate Member of Freie Universität Berlin,
Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin,
Germany, 11Hopp Children’s Cancer Center Heidelberg (KiTZ) and CCU
Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg,
Germany, 12Hopp Children’s Cancer Center Heidelberg (KiTZ) andPediatric Glioma Research Group, German Cancer Research Center(DKFZ), Heidelberg, Germany, 13Children’s Brain Tumour ResearchCentre, School of Medicine, University of Nottingham, Nottingham,
United Kingdom, 14Hopp Children’s Cancer Center Heidelberg (KiTZ)
and Clinical Cooperation Unit Neuropathology, German Cancer ResearchCenter (DKFZ), Heidelberg, Germany, 15Department of Bicochemistry andCelllar Biology, National Center of Neurology and Psychiatry (NCNP),
Tokyo, JapanThe majority of supratentorial ependymomas (ST-EPN) are driven by fusions between RELA and a zinc finger containing gene, C11orf95. Apartfrom fusions to the Hippo effector YAP1, which affects a small group of

infant patients, the oncogenic mechanism of remaining ST-EPNs is unclear.
Aiming at refining the molecular classification of ST-EPNs, we analyzed
methylation profiles, RNA and DNA sequencing results as well as clinical data in a cohort of 617 ST-EPNs. Unsupervised clustering analysis of
DNA methylation data revealed four distinct clusters that formed in addition to the known molecular groups ST-EPN-RELA and –YAP1. Tumors
within these additional clusters were characterized by fusions of C11orf95
to numerous fusion partners different from RELA, e.g. MAML2, MAML3,
NCOA2 and SS18, suggesting a general role of C11orf95 in tumorigenesisof ST-EPN. Transforming capacity of newly identified fusion genes was validated using an electroporation-based in vivo gene transfer technology. Allfusion genes were sufficient to drive malignant transformation in the cerebral cortex of mice and resulting tumors faithfully recapitulated molecularcharacteristics of their human counterparts. We found that both, the partner
gene and the zinc finger DNA binding domain of C11orf95, were essential to exert tumorigenesis. When exploring genes commonly upregulated in
C11orf95 fusion-expressing tumors of human and murine origin, the Sonic
Hedgehog effector gene Gli2 was identified as a promising downstream
target. Subsequent co-expression of C11orf95:RELA and a dominant negative form of Gli2 indeed hampered tumorigenesis. We thus propose GLI2
as a potential therapeutic downstream target of C11orf95 fusion-dependent
oncogenic signaling in ST-EPN.
EPEN-20. EZHIP/CATACOMB COOPERATES WITH PDGF-A AND
P53 LOSS TO GENERATE A GENETICALLY ENGINEERED MOUSE
MODEL FOR POSTERIOR FOSSA A EPENDYMOMA
Emily Kagan, Daniel Brat, Ali Shilatifard, Andrea Piunti, and Oren Becher;Northwestern University, Chicago, IL, USA
BACKGROUND: PFA ependymoma is a pediatric brain tumor with only
30% long-term survival. Recently a gene called CXORF67/EZHIP/CATACOMB (henceforward: CATACOMB) was found to be overexpressed in
PFA ependymoma. CATACOMB’s mechanism of action has been found to
be analogous to that of the H3K27M mutation as its expression reduces
H3K27me3 via inhibition of PRC2 catalytic activity. METHODS: We infected NESTIN- or GFAP-expressing neonatal hindbrain progenitors withwild-type CATACOMB or a loss of function (LOF) point mutant (M406K),
alone, with PDGFA, and with and without p53 deletion. RESULTS: CATACOMB overexpression alone or with p53 loss was insufficient to induce
tumorigenesis. CATACOMB overexpression with PDGFA and p53 loss was
sufficient to induce tumorigenesis using either the LOF mutant (M406K) or thewild-type CATACOMB in both cells-of-origin. The histology appeared more
ependymoma-like when CATACOMB was expressed in GFAP-expressing
progenitors. Median survival for the model initiated in NESTIN progenitors
was 99.5 days for the CATACOMB mutant (n=26) group and 61 days for the
CATACOMB wild-type (n=28; log-rank test p=0.0033). Median survival forthe model initiated in GFAP progenitors were 144 days for the CATACOMB
mutant (n=19) group and 65 days for the CATACOMB wild-type (n=21; logrank test is P<0.0013). Immunohistochemistry for H3K27me3 demonstrated
that CATACOMB wild-type tumors had reduced H3K27me3 compared to
CATACOMB mutant tumors. CONCLUSIONS: Disrupting CATACOMB
inhibitory activity toward PRC2 significantly increases survival in micein both models, suggesting this activity plays a critical role in acceleratingtumorigenesis. Ependymoma-like histology was more commonly observed in
the model initiated in the GFAP-expressing progenitors.
EPEN-21. IMPAIRED NEURONAL-GLIAL FATE SPECIFICATION IN
PEDIATRIC EPENDYMOMA REVEALED BY SINGLE-CELL RNA-SEQ
Bernhard Englinger1,2, Johannes Gojo1,3, Li Jiang1,2, Jens M Hübner4,5,
McKenzie L Shaw1,2, Olivia A Hack1,2, Sibylle Madlener3,
Dominik Kirchhofer3,6, Ilon Liu1,2, Jason Pyrdol7, Volker Hovestadt2,8,Emanuele Mazzola9, Nathan D Mathewson7, Maria Trissal1,2,Daniela Lötsch3,6, Walter Berger6, Christian Dorfer10, Christine Haberler11,
Angela Halfmann12, Lisa Mayr3, Andreas Peyrl3, Rene Geyeregger12,
Kristian W Pajtler4,5, Till Milde4,13, Jack E Geduldig14, Kristine Pelton14,
Thomas Czech10, Orr Ashenberg2, Kai W Wucherpfennig7,
Orit Rozenblatt-Rosen2, Sanda Alexandrescu15, Keith L Ligon2,16,
Stefan M Pfister4,5, Aviv Regev2,17, Irene Slavc3, Mario L Suva2,8,Marcel Kool4,5, and Mariella Filbin1,2; 1Department of Pediatric Oncology,
Dana-Farber Boston Children’s Cancer and Blood Disorders Center,
Boston, MA, USA, 2Broad Institute of Harvard and MIT, Cambridge,
MA, USA, 3Department of Pediatrics and Adolescent Medicine, Medical
University of Vienna, Vienna, Vienna, Austria, 4Hopp Children’s Cancer
Center Heidelberg (KiTZ), Heidelberg, BW, Germany, 5Division of
Pediatric Neurooncology, German Cancer Research Center (DKFZ) andGerman Cancer Consortium (DKTK), Heidelberg, BW, Germany, 6Instituteof Cancer Research, Department of Medicine I, Medical University of
Vienna, Vienna, Vienna, Austria, 7Department of Cancer Immunology andVirology, Department of Microbiology and Immunobiology, Departmentof Neurology, Dana-Farber Cancer Institute and Harvard Medical School,
Boston, MA, USA, 8Department of Pathology and Center for Cancer

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Research, Massachusetts General Hospital and Harvard Medical School,
Boston, MA, USA, 9Department of Biostatistics & Computational Biology,
Boston, MA, USA, 10Department of Neurosurgery, Medical Universityof Vienna, Vienna, Vienna, Austria, 11Division of Neuropathology and
Neurochemistry, Department of Neurology, Medical University of Vienna,
Vienna, Vienna, Austria, 12Clinical Cell Biology, Children’s Cancer
Research Institute (CCRI), St Anna Kinderkrebsforschung, Vienna,
Vienna, Austria, 13Department of Paediatric Haematology and Oncology,
Heidelberg University Hospital, Heidelberg, BW, Germany, 14Departmentof Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA,
15Department of Pathology, Boston Children’s Hospital, Boston, MA, USA,
16Department of Oncologic Pathology, Brigham and Women’s Hospital,
Boston Children’s Hospital, Dana-Farber Cancer Institute, Boston, MA,
USA, 17Howard Hughes Medical Institute and Koch Institute of Integrative
Cancer Research, Department of Biology, Massachusetts Institute ofTechnology, Cambridge, MA, USA
Ependymoma represents a heterogeneous disease affecting the entire neuraxis. Extensive molecular profiling efforts have identified molecular ependymoma subgroups based on DNA methylation. However, theintratumoral heterogeneity and developmental origins of these groups are
only partially understood, and effective treatments are still lacking for about
50% of patients with high-risk tumors. We interrogated the cellular architecture of ependymoma using single cell/nucleus RNA-sequencing to analyze 24
tumor specimens across major molecular subgroups and anatomic locations.
We additionally analyzed ten patient-derived ependymoma cell models andtwo patient-derived xenografts (PDXs). Interestingly, we identified an analogous cellular hierarchy across all ependymoma groups, originating fromundifferentiated neural stem cell-like populations towards different degrees
of impaired differentiation states comprising neuronal precursor-like, astroglial-like, and ependymal-like tumor cells. While prognostically favorable
ependymoma groups predominantly harbored differentiated cell populations, aggressive groups were enriched for undifferentiated subpopulations.
Projection of transcriptomic signatures onto an independent bulk RNAseq cohort stratified patient survival even within known molecular groups,
thus refining the prognostic power of DNA methylation-based profiling.
Furthermore, we identified novel potentially druggable targets including
IGF- and FGF-signaling within poorly prognostic transcriptional programs.
Ependymoma-derived cell models/PDXs widely recapitulated the transcriptional programs identified within fresh tumors and are leveraged to validate
identified target genes in functional follow-up analyses. Taken together,
our analyses reveal a developmental hierarchy and transcriptomic context
underlying the biologically and clinically distinct behavior of ependymoma
groups. The newly characterized cellular states and underlying regulatory
networks could serve as basis for future therapeutic target identification andreveal biomarkers for clinical trials.
EPEN-22. SINGLE-CELL RNA SEQUENCING IDENTIFIESUPREGULATION OF IKZF1 IN PFA2 MYELOID SUBPOPULATIONDRIVING AN ANTI-TUMOR PHENOTYPE
Andrea Griesinger1,2, Eric Prince1,3, Andrew Donson1,2, Kent Riemondy4,
Timothy Ritzman5, Faith Harris1,2, Vladimir Amani1,2, Michael Handler1,3,
Todd Hankinson1,3, Richard Grundy5, Andrew Jackson6, andNicholas Foreman1,2; 1The Morgan Adams Foundation Pediatric Brain
Tumor Research Program, Children’s Hospital Colorado, Aurora, CO,
USA, 2Department of Pediatrics-Hematology and Oncology, Universityof Colorado Anschutz, Aurora, CO, USA, 3Department of Neurosurgery,
University of Colorado Anschutz, Aurora, CO, USA, 4RNA Biosciences
Initiative, University of Colorado, Aurora, CO, USA, 5Children’s Brain
Tumor Research Centre, School of Medicine, University of Nottingham,
Nottingham, United Kingdom, 6Host-tumour interactions Group, Divisionof Cancer and Stem cells, School of Medicine, University of Nottingham,
Nottingham, United Kingdom
We have previously shown immune gene phenotype variations between
posterior fossa ependymoma subgroups. PFA1 tumors chronically secrete
IL-6, which pushes the infiltrating myeloid cells to an immune suppressivefunction. In contrast, PFA2 tumors have a more immune activated phenotype and have a better prognosis. The objective of this study was to use
single-cell(sc) RNAseq to descriptively characterize the infiltrating myeloid
cells. We analyzed approximately 8500 cells from 21 PFA patient samples
and used advanced machine learning techniques to identify distinct myeloid
and lymphoid subpopulations. The myeloid compartment was difficult tointerrupt as the data shows a continuum of gene expression profiles exist
within PFA1 and PFA2. Through lineage tracing, we were able to teaseout that PFA2 myeloid cells expressed more genes associated with an antiviral response (MHC II, TNF-a, interferon-gamma signaling); while PFA1
myeloid cells had genes associated with an immune suppressive phenotype(angiogenesis, wound healing, IL-10). Specifically, we found expression of
IKZF1 was upregulated in PFA2 myeloid cells. IKZF1 regulates differentiation of myeloid cells toward M1 or M2 phenotype through upregulationof either IRF5 or IRF4 respectively. IRF5 expression correlated with IKZF1,

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being predominately expressed in the PFA2 myeloid cell subset. IKZF1 isalso involved in T-cell activation. While we have not completed our characterization of the T-cell subpopulation, we did find significantly more T-cell
infiltration in PFA2 than PFA1. Moving forward these studies will provide
us with valuable information regarding the molecular switches involved in
the tumor-immune microenvironment and to better develop immunotherapy
for PFA ependymoma.
EPEN-23. A COMPUTATIONAL ANALYSIS OF THE TUMOUR
IMMUNE MICROENVIRONMENT IN PAEDIATRIC EPENDYMOMA
Timothy Ritzmann1, Anbarasu Lourdusamy1, Andrew Jackson2,
Lisa Storer1, Andrew Donson3,4, Andrea Griesinger3,4, Nicholas Foreman3,4,Hazel Rogers1, and Richard Grundy1; 1The Children’s Brain Tumour
Research Centre, Nottingham, United Kingdom, 2Host TumourInteractions Group, University of Nottingham, Nottingham, United
Kingdom, 3Children’s Hospital Colorado, Aurora, CO, USA, 4University ofColorado Anschutz Medical Campus, Aurora, CO, USA
Ependymoma is the third commonest childhood brain tumour. Relapse
is frequent, often fatal and current therapeutic strategies are inadequate.
Previous ependymoma research describes an immunosuppressive environment with T-cell exhaustion, indicating a lack of response to T-cell directed immunotherapy. Understanding the immune microenvironment istherefore critical. We present a computational analysis of ependymoma,
gene expression derived, immune profiles. Using 465 ependymoma samples from gene expression datasets (GSE64415, GSE50385, GSE100240)
and two RNA-seq databases from UK ependymomas, we applied bulk tumour deconvolution methods (CIBERSORT and xCell) to infer immune
cell populations. Additionally, we measured checkpoint blockade related
mRNAs and used immunohistochemistry to investigate cell populations in
ependymoma sections. CIBERSORT indicated high proportions of M2-likemacrophages and smaller proportions of activated natural killer (NK) cells,
T follicular helper cells, CD4+ memory T-cells and B-cells. xCell overlappedwith the M2-like macrophage and CD4+ memory T-cell signatures seen in
CIBERSORT. On immunohistochemistry, T and B cells were scarce, withsmall numbers of CD8+, CD4+ and CD20+ cells in the parenchyma but
greater numbers in surrounding regions. CD68 was more highly expressedin the parenchyma. Analysis of nine checkpoint ligands and receptors demonstrated only the TIM3/GAL9 combination was reliably detectable. GAL9
is implicated in tumour interactions with T-cells and macrophages elsewhere, possibly contributing to poorer outcomes. Our study supports thepresence of myeloid cells being leading contributors to the ependymoma immune microenvironment. Further work will delineate the extent of myeloid
contribution to immunosuppression across molecular subtypes. Modulationof tumour immunity may contribute to better clinical outcomes.
EPEN-24. SIOP EPENDYMOMA II: CENTRAL EPENDYMOMAMANAGEMENT ADVISORY GROUP – THE UK EXPERIENCE
Donald C. Macarthur1,5, Conor Mallucci2, Ian Kamaly-Asl3,John Goodden4, Lisa CD Storer6, Rebecca J. Chapman6, J-P Kilday3,
Martin English5 Tim Jaspan1, Arpita Chattopadhyay1, Rob A. Dineen1,5,
Shivaram Avula2, Stavros Stivaros3, and Richard Grundy1,5; 1Nottingham
University Hospitals, Nottingham, Nottinghamshire, United Kingdom,
2Alder Hey Children’s Hospital, Liverpool, Merseyside, United Kingdom,
3Royal Manchester Children’s Hospital, Manchester, Lancashire,
United Kingdom, 4Leeds Teaching Hospitals, Leeds, Yorkshire, United
Kingdom, 5Birmingham Children’s Hospital, Birmingham, West Midlands,
United Kingdom, 6School of Medicine, University of Nottingham,
Nottinghamshire, United Kingdom
Paediatric Ependymoma is the second most common malignant brain tumour of childhood with approximately 50% of cases recurring. It has been
described as a “surgical” disease since patients who have undergone a grosstotal surgical resection (GTR) have a better prognosis than those who havea subtotal resection (STR). Analysis of the UKCCSG/SIOP 1992 04 clinical
trial has shown that only 49% of cases had a GTR, with 5-year survival
rates for STR of 22–47% and GTR of 67–80%. As part of the SIOP II
Ependymoma trial the UK established a panel of experts in the treatment of
Ependymoma from Neuro-oncology, Neuro-radiology and Neuro-surgery.
Meeting weekly, cases are discussed to provide a consensus on radiologicalreview, ensuring central pathological review, trial stratification and whether
further surgery should be advocated on any particular case. Evaluation of
the first 68 UK patients has shown a GTR in 47/68 (69%) of patients and
STR in 21/68 (31%) of patients. Following discussion at EMAG it was feltthat 9/21 (43%) STR patients could be offered early second look surgery.
Following this 2nd look surgery the number of cases with a GTR increased
to 56/68 (82%). There has been a clear increase in the number of patientsfor whom a GTR has been achieved following discussion at EMAG andprior to them moving forwards with their oncological treatment. This canonly have beneficial effects in decreasing their risk of tumour recurrence or
CSF dissemination and also in reducing the target volume for radiotherapy.

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EPEN-25. EXCEPTIONAL CLINICAL AND IMAGING RESPONSE
TO TRK-INHIBITION IN A PATIENT WITH SUPRATENTORIALEPENDYMOMA HARBORING NTRK2 GENE FUSION
Ross Mangum1,2, Jacquelyn Reuther3,2, Adekunle Adesina3,2,
Marcia Kukreja4,2, Daniel Curry5,2, Fatema Malbari6,2,
Murali Chintagumpala1,2, Donna M. Muzny7,2, Kevin Fisher3,2,
Angshumoy Roy3,2, Kelsey C. Bertrand1,2, Stephen C. Mack1,2,
Sharon E. Plon7,2, D. Williams Parsons1,2, and Frank Y. Lin1,2; 1Texas
Children’s Hospital Cancer Center, Houston, TX, USA, 2Baylor College ofMedicine, Houston, TX, USA, 3Texas Children’s Hospital Department of
Pathology & Immunology, Houston, TX, USA, 4Texas Children’s Hospital
Department of Radiology, Houston, TX, USA, 5Texas Children’s Hospital
Department of Neurosurgery, Houston, TX, USA, 6Texas Children’s
Hospital Department of Neurology, Houston, TX, USA, 7Human Genome
Sequencing Center, Houston, TX, USA
BACKGROUND: Patients with metastatic pediatric ependymoma have
limited therapeutic options and poor outcomes. Approximately ¾ ofsupratentorial ependymomas are driven by C11ORF95-RELA fusions, andthe remaining by a heterogeneous group of fusion events. We present a six
year-old male diagnosed with supratentorial ependymoma with leptomeningeal carcinomatosis harboring an NTRK2-fusion. Local and distant multifocal, intracranial and intraspinal tumor recurrence occurred seven months
following gross total resection of the primary lesion and proton beam
craniospinal irradiation. METHODS: DNA and RNA from FFPE tumor
were used for targeted sequencing using an 81-gene fusion panel and 124gene mutation panel. Separately, capture transcriptome sequencing, exome
sequencing, and copy number array were performed as part of the Texas
KidsCanSeq study, an NHGRI/NCI-funded Clinical Sequencing EvidenceGenerating Research (CSER) consortium project. All sequencing was carriedout in CLIA-certified laboratories. RESULTS: An in-frame fusion between
5’ exons 1–3 of KANK1 and 3’ exons 16–21 of NTRK2, predicted to retain the kinase domain, was identified. At tumor recurrence, therapy was
initiated with Larotrectinib, an FDA-approved pan-TRK inhibitor. Clinicalimprovement in cognitive speed, motor strength, and coordination was observed at two weeks with significant tumor response on MRI at two andfour months. CONCLUSION: TRK gene fusions have not previously beenreported in ependymoma. Further tumor characterization by methylation
profiling is underway and will be of diagnostic interest given the apparent
discordance between tumor histology and molecular findings. This casehighlights the potential impact of clinical genomic analysis for children with
CNS tumors.
EPEN-26. NON-CANONICAL NF-ΚB SIGNALING DRIVESMESENCHYMAL EPENDYMAL CELL SUBPOPULATION IN PFAEPENDYMOMA
Andrea Griesinger1,2, Faith Harris1,2, Andrew Donson1,2, Austin Gillen3,
Kent Riemondy3, Sujatha Venkataraman1,2, Vladimir Amani1,2,
Michael Handler1,4, Todd Hankinson1,4, and Nicholas Foreman1,2; 1The
Morgan Adams Foundation Pediatric Brain Tumor Research Program,Children’s Hospital Colorado, Aurora, CO, USA, 2Department ofPediatrics-Hematology and Oncology, University of Colorado Anschutz,
Aurora, CO, USA, 3RNA Biosciences Initiative, University of Colorado,
Aurora, CO, USA, 4Department of Neurosurgery, University of Colorado
Anschutz, Aurora, CO, USA
NF-κB signaling is a hallmark of PFA1 ependymoma. Loss of
LDOC1, through epigenetic silencing, leads to constitutively active
NF-κB signaling and chronic IL-6 secretion. In this study, we investigate the loss of LDOC1 within the PFA tumor clusters. Using our PFA
scRNAseq database, in which there are 5 clusters within the tumor cellcompartment: mesenchymal (MEC), ciliated (CEC), transportive (TEC),
and undifferentiated (UEC). LDOC1 expression was significantly reduced and had an inverse correlation with genes defining the unfavorable MEC subpopulation, predominate in PFA1. This is consistent with
our findings that MEC was defined by an NF-κB2 signaling profile. In
contrast, LDOC1 expression was higher and positively correlated withgenes defining the favorable CEC subpopulation, mostly seen in PFA2.
RELA expression, which we studied as a target of LDOC1, was not localized to MEC and was wide-spread throughout the PFA compartment.
RELB, part of non-conical NF-κB signaling, was expressed only the MEC
subpopulation correlating with IL-6 gene expression found only in this
subpopulation. In MAF-811, a PFA cell line with more CEC-like gene
phenotype, RELB co-immunoprecipates with the active form of NF-κB2
in both the nucleus and cytoplasm. IL-6 gene expression is almost completely lost when NF-κB2 is knock-down using shRNA. Additionally, lossof LDOC1 leads to over 3 fold increase in NF-κB2 expression. Combinedwith our previous work, this would suggest that NF-κB2 drives IL-6 expression by binding with RELB in MEC subpopulation and targeting lossof LDOC1 may shift the MEC subpopulation toward the more favorable
CEC subpopulation.

EPEN-27. CDKN2A DELETION IN SUPRATENTORIALEPENDYMOMA WITH RELA ALTERATION INDICATES A DISMALPROGNOSIS – A RETROSPECTIVE ANALYSIS OF THE HITEPENDYMOMA TRIAL COHORTStephanie T. Jünger1, Felipe Andreiuolo1, Martin Mynarek2,
Evelyn Dörner1, Anja zur Mühlen1, Natalia Velez-Char1, Katja von Hoff2,
Stefan Rutkowski2, Monika Warmuth-Metz3, Rolf-Dieter Kortmann4,
Beate Timmermann5, Andre O. von Bueren2,6, and Torsten Pietsch1;
1Department of Neuropathology & DGNN Brain Tumor Reference Center,
University of Bonn, Bonn, Germany, 2Department of Pediatric Hematology
and Oncology, University Hospital Hamburg-Eppendorf, Hamburg,
Germany, 3Institute of Diagnostic and Interventional Neuroradiology,
University Hospital Würzburg, Würzburg, Germany, 4Department ofRadiation Oncology, University Hospital Leipzig, Leipzig, Leipzig,
Germany, 5Westdeutsches Protonentherapiezentrum, Essen, Germany,
6Department of Pediatrics, Obstetrics and Gynecology, Division of
Pediatric Hematology and Oncology, University Hospital Geneva, Geneva,
Switzerland
INTRODUCTION: Since
supratentorial
RELA-fusion
positive
ependymomas are considered a biologically distinct disease, we aimed to
identify histological and genetic predictors of outcome in a defined cohort ofpediatric patients. MATERIALS AND METHODS: We analyzed 54 RELA
ependymomas in pediatric patients treated according to HIT2000-E protocols. All cases underwent central neuropathological review. Genome-wide
copy number alterations were assessed by molecular inversion probe or SNP
array. RELA alterations were detected by RT-PCR, sequencing and assessment of nuclear p65-RelA protein. Copy number alteration of the CDKN2A(cyclin dependent kinase inhibitor 2A) locus and concordant p16 protein
expression were analyzed. RESULTS: Fifty-two tumors were classified as
WHO-grade III (96.3%) with high mitotic activity in 39 cases (72.2%),
vascular proliferation in 47 (87.0%), necrosis in 43 (79.6%) and clear cellmorphology in 19 (35.2%). All tumors harbored RELA alterations. Homoor heterozygous CDKN2A deletions were detected in 9 (16.7%) and 14(25.9%) cases, respectively. p16 protein expression was lost in all cases withhomozygous deletion. Median follow-up was 5.4 years with 5-years EFS
and OS of 74.1% and 92.6%. In Kaplan-Meier analysis high mitotic activity
was related to shorter EFS (p=0.016) and clear cell morphology to longer OS(p=0.039); CDKN2A deletion was associated with shorter OS (homozygous
deletion, p=0.009; homo-or heterozygous deletion, p=0.034). No correlation
between CDKN2A deletion and high mitotic activity was found but withhigher age at diagnosis (p=0.001). CONCLUSION: Deletion of CDKN2A
occurred in 42.6% of supratentorial ependymomas with RELA alteration
and represented a genetic predictor of worse overall outcome in pediatricpatients.
EPEN-28. NOVEL ONCOGENE AMPLIFICATION IN SPINALEPENDYMOMA INVOLVING THE MYC LOCUS (8Q24)
Margaret Shatara1, Daniel R. Boué2, Christopher R. Pierson2,
Diana L. Thomas2, Eric A. Sribnick3, Jeremy Jones4, Diana P. Rodriguez4,
Kathleen M. Schieffer5, Carol Deeg5, Elizabeth Hamelberg5,
Stephanie LaHaye5, Vincent Magrini5, Richard K. Wilson5,
Elaine R. Mardis5, Catherine E. Cottrell5, Elizabeth A. Varga1,
Mohamed S. AbdelBaki1, Jonathan L. Finlay1, and Diana S. Osorio1;
1The Division of Hematology, Oncology, Blood and Marrow Transplant,
Nationwide Children’s Hospital and The Ohio State University, Columbus,
OH, USA, 2Department of Pathology and Laboratory Medicine,Nationwide Children’s Hospital, Columbus, OH, USA, 3The Division of
Pediatric Neurosurgery, Nationwide Children’s Hospital and The Ohio
State University, Columbus, OH, USA, 4The Department of Radiology,
Nationwide Children’s Hospital, Columbus, OH, USA, 5The Steve andCindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s
Hospital, Columbus, OH, USA
BACKGROUND: We report a unique case of spinal ependymoma withclassic histology and aggressive clinical behavior which harbored a focal
MYC (8q24) amplification. CASE REPORT: A-12-year old male presented
with a three months history of back pain and acute onset weakness withataxia. A spine MRI revealed an avidly enhancing intradural, extramedullarymass occupying the dorsal spinal canal from C6 through T2. The tumor
demonstrated mild diffusion restriction and was associated with severe cord
compression and mild edema. He underwent gross total resection. Pathological diagnosis was classic grade II ependymoma. Eleven months later, he
re-presented with acute onset lower extremity paresthesia and left-handed
weakness. Spine MRI demonstrated tumor recurrence extending from C2through T1-T2 with resultant severe cord compression, again demonstrating
avid enhancement and restricted diffusion. He underwent subtotal resectionof the mass and focal proton beam irradiation. MOLECULAR CHARACTERISTICS: The patient was enrolled on an institutional comprehensive
genomic profiling protocol. The tumor’s copy number profile was complex,
including homozygous loss of 17p and notably, amplification of the MYC

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oncogene. Using fluorescence in situ hybridization, we identified >20 copies
of MYC in interphase cells, confirming the gene amplification, while twocopies of MYCN (2p24) were seen. DNA methylation further classified
this tumor as clustering near posterior fossa group A (score=0.6073) tumors. CONCLUSION: We report a unique case of an adolescent malewith aggressive spinal ependymoma harboring focal MYC amplification.
Testing for MYC amplification may be reasonable in newly-diagnosed spinal
ependymomas to aid in characterization.
EPEN-30. C11ORF95-RELA FUSION PROTEIN ENGAGES NOVELGENOMIC LOCI TO DRIVE MURINE EPENDYMOMA GROWTH
Amir Arabzade1, Yanhua Zhao2, Srinidhi Varadharajan2, Hsiao-Chi Chen2,
Austin Stuckert2, Bryan Rivas2, Sameer Agnihotri3, Courtney Hodges2,
Donald Parsons2, Susan Blaney2, Thomas Westbrook2, Charles Lin2,
Joanna Yi2, Benjamin Deneen2, Kelsey Bertrand2, and Stephen Mack2; 1Rice
University, Houston, TX, USA, 2Baylor College of Medicine, Houston, TX,
USA, 3University of Pittsburgh, Pittsburgh, PA, USA
RATIONALE: Over 70% of supratentorial (ST) ependymoma are characterized by an oncogenic fusion between C11ORF95 and RELA. C11ORF95RELA fusion is frequently the sole genetic driver detected in ST ependymoma,
thus ranking this genomic event as a lead target for therapeutic investigation. RELA is a transcription factor (TF) central to mediating NF-kB
pathway activation in processes such as inflammation, cellular metabolism,
and chemotaxis. HYPOTHESIS: We posited that C11ORF95-RELA acts as
an oncogenic TF that aberrantly shapes the tumor epigenome to drive aberrant transcription. Approach: To this end we developed an in utero electroporation (IUE) mouse model of ependymoma to express C11ORF95-RELA
during embryonic development. Our IUE approach allowed us to develop
C11ORF95-RELA driven tumor models and cell lines. We comprehensively
characterized the epigenome and transcriptome of C11ORF95-RELA fusion driven mouse cells by H3K27ac ChIP-seq, ATAC-seq, and RNA-seq.
RESULTS: This data revealed that: 1) C11ORF95-RELA directly engages‘open’ chromatin and is enriched at regions with known RELA TF bindingsites as well as novel genomic loci/motifs, 2) C11ORF95-RELA preferentiallybinds to both H3K27ac (active) enhancers and promoters, and 3) Bound
C11ORF95-RELA promoter loci are associated with increased transcriptionof genes shared with human ependymoma. CONCLUSION: Our findings
shed light on the transcriptional mechanisms of C11ORF95-RELA, and reveal downstream targets that may represent cancer dependency genes andmolecular targets.
EPEN-31. SINGLE-CELL RNASEQ OF CHILDHOOD EPENDYMOMAREVEALS DISTINCT NEOPLASTIC CELL SUBPOPULATIONSTHAT IMPACT ETIOLOGY, MOLECULAR CLASSIFICATION ANDOUTCOME
Andrew Donson1,2, Austin Gillen3, Riemondy Kent3, Ahmed Gilani4,
Sujatha Venkataraman1,2, Bridget Sanford2, Andrea Griesinger1,2,
Vladimir Amani1,2, Todd Hankinson5,1, Michael Handler5,1,
Jay Hesselberth3, Rajeev Vibhakar1,2, and Nicholas Foreman1,2; 1The
Morgan Adams Foundation Pediatric Brain Tumor Research Program,Children’s Hospital Colorado, Aurora, CO, USA, 2Department ofPediatrics-Hematology and Oncology, University of Colorado Anschutz
Medical Campus, Aurora, CO, USA, 3RNA Biosciences Initiative,
University of Colorado Anschutz Medical Campus, Aurora, CO, USA,
4Department of Pathology, University of Colorado Anschutz Medical
Campus, Aurora, CO, USA, 5Department of Neurosurgery, University ofColorado Anschutz Medical Campus, Aurora, CO, USA
Ependymoma (EPN) is a brain tumor commonly presenting in childhood that remains fatal in the majority of children. Intra-tumoral cellular
heterogeneity in bulk-tumor samples significantly confounds our understanding of EPN biology, impeding development of effective therapy. We
therefore used single-cell RNA sequencing to catalog cellular heterogeneityof 26 childhood EPN, predominantly from ST-RELA, PFA1 and PFA2 subgroups. ST-RELA and PFA subgroups clustered separately, with ST-RELA
clustering largely according to individual sample-of-origin. PFA1 and PFA2
subgroup EPNs cells were intermixed and revealed 4 major subpopulations– 2 with characteristics of ependymal differentiation (transporter and ciliated phenotype subpopulations), an undifferentiated subpopulation and amesenchymal phenotype. Pseudotime analysis showed the undifferentiatedprogenitor subpopulation either differentiating into ependymal differentiation subpopulations or transitioning into the mesenchymal subpopulation.
Histological analysis revealed that undifferentiated and mesenchymal
subpopulations cells colocalized to perinecrotic/perivascular zones, the putative ependymoma stem cell niche. Deconvolution of PFA bulk transcriptome data showed that undifferentiated and mesenchymal subpopulations
were associated with a poor prognosis; whereas the ciliated ependymal celldifferentiated subpopulation was associated with a good prognosis. In conflict with current distinct classification paradigms, the ratio of mesenchymal
and ciliated subpopulations determined bulk-tumor subgroups assignmentiii314

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to PFA1 and PFA2 respectively. This atlas of EPN cellular heterogeneity provides an important advance in our understanding of EPN biology, identifying
high-risk associated subpopulations for therapeutic targeting.
EPEN-33. PHARMACOGENOMICS REVEALS SYNERGISTICINHIBITION OF ERBB2 AND PI3K SIGNALING AS A THERAPEUTIC
STRATEGY FOR EPENDYMOMADavid Pauck1,2, Eunice Paisana3, Rita Cascão3,
Sevgi Sarikaya-Seiwert4,5, Viktoria Marquardt1,6, Daniel Picard1,2,
Jasmin Bartl1,2, Lena Blümel1,2, Mara Maue1,2, Christian Dimitriadis1,2,
Kübra Taban1,2, Ute Fischer2, Hans Jakob Steiger5, Cláudia Faria3,7,
Guido Reifenberger8, Arndt Borkhardt2, Thomas Beez5, andMarc Remke1,2; 1Division of Pediatric Neuro-Oncogenomics, German
Cancer Consortium and German Cancer Research Center, Partner
Site Essen/Düsseldorf, Düsseldorf, Germany, 2Department of PediatricOncology, Hematology and Clinical Immunology, Heinrich Heine
University Düsseldorf, Medical Faculty, Düsseldorf, Germany, 3Instituto de
Medicina Molecular, Faculdade de Medicina, da Universidade de Lisboa,
Lisbon, Portugal, 4Department of Neurosurgery, University of Bonn
Medical Center, Bonn, Germany, 5Department of Neurosurgery, Heinrich
Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany,
6Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine
University Düsseldorf, Düsseldorf, Germany, 7Department of Neurosurgery,
Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte,
Lisbon, Portugal, 8Institute of Neuropathology, Heinrich Heine University
Düsseldorf, Medical Faculty, Düsseldorf, Germany
Subgroups of ependymoma, especially RELA fusion-positive and posterior
fossa type A tumors, are associated with poor prognosis. Curative therapeutic strategies have not yet been identified. We set up a high-throughput
drug screening (HTS) pipeline to evaluate clinically established compounds(n=196) in primary ependymoma cultures (n=12). As culturing ependymoma
is challenging, assay miniaturization to 1536-well microplates emerged as a
key feature to process HTS despite smallest cell numbers. DNA methylation
profiling showed that entity and subgroup affiliation from primary diagnosis was maintained in primary cultures, as assessed through molecular
neuropathology 2.0 based classification (MNP 2.0, Capper, D. et al., Nature,2018). A comparison of HTS data of ependymoma and other pediatricbrain tumor models (n=48) revealed a remarkable chemoresistance in vitro.
However, we identified Neratinib, an irreversible ERBB2 inhibitor, as themost prominent candidate which was preferentially active in a subset of
the investigated ependymoma cultures (n=5). Combinatory treatment with
Copanlisib, a PI3K inhibitor, was able to overcome resistance to single agent
treatment using Neratinib in established cell lines of ependymoma (n=3) and
2/4 primary cultures for which combinatory treatment could be tested. Finally, we validated efficacy of Neratinib combined with Copanlisib in micebearing ependymoma xenografts which revealed significantly reduced tumor
size compared to vehicle-treated animals. In summary, our study demonstrates that HTS may reveal targeted therapies for pediatric brain tumors.
Specifically, we found a synergistic interaction of Neratinib and Copanlisib
for treatment of ependymoma, thereby providing a novel therapeutic approach in an otherwise largely chemoresistant entity.
EPEN-34. THE CRISPR-CAS9 SYSTEM-MEDIATED ENDOGENOUS
GENE REARRANGEMENT INDUCED C11ORF95-RELA FUSION
IN VITRO AND IN VIVO THAT LED TO THE DEVELOPMENT OF
EPENDYMOMA-LIKE TUMOR
Mutsumi Takadera1,2, Tatsuya Ozawa1, Kaishi Satomi1,3,
Tetsuya Yamamoto2, and Koichi Ichimura1; 1Division of Brain Tumor
Translational Research, National Cancer Center Research Institute,Chuo-ku, Tokyo, Japan, 2Department of Neurosurgery, Yokohama City
University, Yokohama, Kanagawa, Japan, 3Department of Diagnostic
Pathology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
Recent large-scale genomic studies of ependymal tumors have identified recurrent RELA and YAP1 fusion genes in supratentorial ependymomas. The
formation of the C11orf95-RELA fusion gene has been attributed to massive
genomic rearrangement involving chromosome 11q termed Chromothripsis
in many cases. However, the causal relationship has not been clarified experimentally. In this study, we developed a system to reproduce the oncogenic generearrangement using the CRISPR-Cas9 system and examined whether consequent endogenous ependymoma fusion genes are competent to form brain
tumors in mice. Initially, to investigate whether C11orf95-RELA fusion can beformed by inducing the relevant gene rearrangement in vitro, we designed multiple guide RNAs on the human and mouse genomic loci and introduced theminto cultured cells. RT-PCR and immunoblot analyses detected endogenous
C11orf95-RELA fusion transcript and protein in both human and mouse cultured cells. Subsequently, we lentivirally introduced the gRNAs into a mousebrain. Brain tumor formation was observed from around 2 months after thelentivirus injection, thus indicating successful gene rearrangement followed by
C11orf95-RELA fusion expression in vivo. Analysis of the tumor tissue con-

Abstracts

firmed the expression of the endogenous C11orf95-RELA fusion gene. These
results suggested that a gene rearrangement is a primary mechanism to form
the C11orf95-RELA fusion which is the direct driver of tumorigenesis. Our
system to simulate a genomic event will provide significant insights into theunderstanding of the tumorigenic mechanism in ependymomas.
EPEN-35. PERITONEAL CARCINOMATOSIS OF ANAPLASTICEPENDYMOMA: FIRST REPORTED CASE
Jonathan Schwartz, Dena Weinmann, Julia Guerin, Laurence Eckel,
Keating Gesina, and David Daniels; Mayo Clinic Childrens Center,
Rochester, MN, USA
Peritoneal Carcinomatosis of anaplastic ependymoma is not a previously
reported entity. The authors report on a child with multiple successfully
treated brain and spine disease occurrences who subsequently develops
carcinomatosis of the abdomen and no evidence of CNS recurrence.
Ependymoma accounts for up to 10% of childhood CNS tumors diagnosedin the United States with a median age of 51–71 months. Typical locations
are based on age. Disease is typically treated with surgical resection followedby radiation. The role of chemotherapy has not been proven but currently
being examined with open clinical trials. We will describe patient’s presentations, clinical treatment and recurrence with subsequent treatment andoutcome at time of meeting.
EPEN-36. THE TREATMENT OUTCOME OF PAEDIATRIC
SUPRATENTORIAL C11ORF95-RELA FUSED EPENDYMOMA:
A COMBINED REPORT FROM E-HIT SERIES AND AUSTRALIANNEW ZEALAND CHILDREN’S HAEMATOLOGY/ONCOLOGY
GROUP
Chia Huan Ng1, Denise Obrecht2, Molly Buntine3, Olivia Wells1,
Martin A Campbell1, Kanika Bhatia1, Michael Sullivan1, Molly Williams1,
Dong Anh Khuong Quang1, Kathryn Kinross3, Christine White3,4,
Elizabeth Algar3,4, Hendrik Witt5, Ulrich Schuller6, Martin Mynarek6,
Torsten Pietsch7, Nicolas U Gerber8, Martin Benesch9,
Monika Warmuth-Metz10, Rolf Kortmann10, Brigitte Bison11,
Michael D Taylor12,2, Vijay Ramaswamy12,2, Stefan Rutkowski6,
Stefan M Pfister13,14, David TW Jones15, Nicholas G Gottardo4,16,
Katja Von Hoff17, Kristian W Pajtler13,14, and Jordan R Hansford1,4;
1Children’s Cancer Centre, Royal Children’s Hospital, Murdoch Children’s
Research Institute, University of Melbourne, Melbourne, Australia,
2University of Toronto, Toronto, ON, Canada, 3Hudson Medical ResearchInstitute, Melbourne, Australia, 4Monash University, Melbourne,
Australia, 5German Cancer Research Centre DKFZ, Heidelberg, Germany,
6University Medical Centre Hamburg-Eppendorf, Heidelberg, Germany,
7University Bonn Medical Centre, Bonn, Germany, 8Children’s Hospitalof Zurich, Zurich, Switzerland, 9Medical University of Graz, Graz,
Austria, 10University Hospital Leipzig, Leipzig, Germany, 11Universityof Wuerzburg, Wurzburg, Germany, 12The Hospital for Sick Children,
Toronto, ON, Canada, 13Hopp Children’s Cancer Center Heidelberg(KiTZ) and Division of Pediatric Neurooncology, German Cancer ResearchCenter (DKFZ), Heidelberg, Germany, 14Department of Pediatric Oncology,
Hematology, and Immunology, University Hospital Heidelberg, Heidelberg,
Germany, 15Hopp Children’s Cancer Center Heidelberg (KiTZ), PediatricGlioma Research Group, German Cancer Research Center (DKFZ),
Heidelberg, Germany, 16Perth Children’s Hospital, Telethon Kid’s Institute,Western Australia, Australia, 17Charité Universitätsmedizin Berlin, Berlin,
Germany
AIM: Advances in molecular classification of paediatric ependymoma
have been pivotal in improving risk stratification and understanding of
this disease. C11orf95-RELA fused supratentorial ependymoma (ST-EPN)
have been reported to have a poor outcome, with 10-year overall survival (OS) of 49% and progression free survival (PFS) of 19%. A cohortof patients from multiple international institutions with molecularly confirmed C11orf95-RELA fused ST-EPN were reviewed to assess theirdisease behaviour. METHOD: We reviewed patients with molecularly determined C11orf95-RELA supratentorial ependymoma diagnosed between
1999 – 2019. Demographic information, extent of surgical resection, useof radiotherapy and/or chemotherapy, disease recurrence, treatment at recurrence and clinical outcome data was collected. PFS and OS of all patients were estimated using Kaplan-Meier method. RESULTS: A total of 76
ST-EPN patients with C11orf95-RELA fusion were identified (median age:
7 years3 months, range: 5 months – 18 years7 months). 58 patients (76.3%)
had complete surgical resection. 70 patients(92.1%) received radiotherapy.
55 patients(72.3%) received chemotherapy. The 10-year OS of C11orf95RELA fused ST-EPN was 72.4% and PFS was 63.8%. In contrast, ST-EPN
at a single institution with unconfirmed molecular status had an OS of
61.1% and PFS of 34.9%. CONCLUSION: Detailed molecular analysis
identified distinct subgroups of patients with ST-EPN. Patients from this cohort with C11orf95-RELA methylation profiles had a significantly higher
OS compared to previous reports and those with unconfirmed fusion status,
emphasising the critical importance of complete molecular profiling to as-sist in treatment decision making. Complete molecular analysis in future
prospective cohorts is essential for accurate risk stratification and treatment
selection.
EPEN-37. TREATMENT OUTCOME OF RECURRENTEPENDYMOMA IN CHILDREN IN NORTHERN EGYPT
Shady Fadel1, Zeyad Abdelaziz1, Amr Abdel Kerim2, Mahmoud Abbassy3,
Samer Samy3, and Basma Elsaba4; 1Peadiatric Oncology at Alexandria
University School of Medicine, Alexandria, Egypt, 2Radiology at
Alexandria University School of Medicine, Alexandria, Egypt,
3Neurosurgery at Alexandria University School of Medicine, Alexandria,
Egypt, 4Pathology at Alexandria University School of Medicine,
Alexandria, Egypt
INTRODUCTION: 1/3 of Ependymoma patients will develop recurrencewith only 25% are long term survivors. Treatment is usually between surgery, radiotherapy or combinations. PATIENTS AND METHODS: Retrospective review of children with recurrent Ependymoma in northwestof Egypt between 2005 and 2019 in Alexandria School of medicine records. RESULTS: 27 patients were identified 19 of them after 2010. The median age is 9.7 years (1.5–19), with 16 males and 11 females. Pathology
were 11 grade II Ependymoma and 16 anaplastic Ependymoma. 16 hadgross residual disease after 1st surgery and 22 received radiotherapy initiallyat median dose of 53.5 Gy, 4 patients received suboptimal radiotherapy.
The initial site was14 supratentorial tumors and 13 infratentorial. Mediantime to recurrence is 27.6 months(3–84), and recurrences were 17 local and9 CSF disseminated, and one patient had recurrence at the scar with lungmetastasis. At a median follow up of 56.6 months 14(51.8%) are still alive.
Treatment was surgery only in 6(4 alive) radiotherapy alone in 2(1alive),combined in 15(9 alive) and 4 patients received neither. The best outcome
were in patients with late local relapse treated with complete resection and
CSI after 2010. Radiotherapy dose was between 54 to 57.3 Gy and one patient developed reirradiation injury at brain stem. 5 of the 14 living patientsis having toxicity in form of hearing aids (4) and low TSH(1). CONCLUSION: Aggressive treatment of recurrent Ependymoma with surgery andradiotherapy is feasible and about half of the patients are salvageable.
EPEN-38. EZH2 INHIBITORY PROTEIN (EZHIP/CXORF67)
EXPRESSION IS HIGHLY CONCORDANT WITH H3K27ME3 LOSS
AND IS A PROMISING SURROGATE MARKER FOR POSTERIORFOSSA TYPE A EPENDYMOMAS
Aruna Nambirajan, Madhu Rajeshwari, Meher Boorgula,Ramesh Doddamani, Manmohan Singh, Ajay Garg, Vaishali Suri,
Chitra Sarkar, and Mehar Sharma; AIIMS, New Delhi, Delhi, India
BACKGROUND: Gene expression and DNA methylation have identified
2 distinct clinicopathological subgroups among the WHO Grade II/III posterior fossa (PF) ependymomas (EPN), of which the PF-A molecular subgroup associates with poor outcome. OBJECTIVE: To analyse the utilityof immunohistochemistry for H3K27me3, Tenascin C, EZHIP (Cxorf67),
EZH2 and fluorescence-in-situ-hybridisation for chromosome 1q21 locus
gain in the prognostic stratification of PF-EPNs. METHODS: All PF
Grade II/III tumors were retrieved (2009–2019). Immunohistochemistryfor H3K27me3, H3K27M-mutation-specific antibody, EZH2, EZHIP,
Tenascin-C and fluorescence in-situ hybridisation for 1q21 locus was performed and compared with outcome. RESULTS: 71 PF-EPNs were included.
H3K27me3 loss (PF-A) was seen in 65% (46/71) of cases, of which majority were positive for EZHIP (73%, 24/33) and Tenascin C (65%, 28/43).
Minority showed chromosome 1q gain (19%, 8/42). An EZHIP negative
PF-A tumor was immunopositive for H3K27M-mutant staining, while allothers were negative. PF-A EPNs occurred at a median age of 4.5 years(range 1–53), were predominantly grade III (Grade III:II – 1.6:1), and 50%(10/20) of patients on follow-up experienced tumor progression. EPNs withretained H3K27me3 (PF-B) did not show EZHIP expression (0/20) or 1q
gain; however, tenascin C expression was seen in 47% (8/25) of them. They
occurred predominantly in adults, showed Grade II preponderance and only
2/11 patients on follow-up experienced progression. EZH2 expression did
not correlate with H3K27me3 loss but positively correlated with EZHIP
expression (p=0.015). CONCLUSION: H3K27me3 is a reliable surrogate
for prognostic classification of PF-EPNs. EZHIP expression is highly concordant with H3K27me3 loss and is a valuable adjunct.
EPEN-39. CLINICAL STRATIFIED TREATMENT OF LOCALIZEDPEDIATRIC INTRACRANIAL EPENDYMOMA WITH COMBINEDLOCAL IRRADIATION AND CHEMOTHERAPY WITHIN THE
PROSPECTIVE, MULTICENTER E-HIT TRIAL – THE MOLECULAR
SUBGROUP MATTERS
Katja von Hoff1, Denise Obrecht2, Janna Wening2, Martin Mynarek2,
Nicolas U. Gerber3, Martin Benesch4, B.-Ole Juhnke2, Brigitte Bison5,
Monika Warmuth-Metz5, Beate Timmermann6, Andreas Faldum7,
Ulrich Schüller8,9, Stefan M. Pfister10,11, Marcel Kool10,12, Torsten Pietsch13,

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iii315

Abstracts

Rolf-D. Kortmann14, Robert Kwiecien15, Kristian W. Pajtler10,11,
Hendrik Witt10,11, and Stefan Rutkowski2; 1Department of PediatricOncology and Hematology, Charité – University Medicine, Berlin,
Germany, 2Department of Pediatric Hematology and Oncology, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany, 3Department of
Oncology, University Children’s Hospital, Zurich, Switzerland, 4Divisionof Pediatric Hematology and Oncology, Department of Pediatrics
and Adolescent Medicine, Medical University of Graz, Graz, Austria,
5Institute of Diagnostic and Interventional Neuroradiology, University
Hospital Würzburg, Würzburg, Germany, 6Klinik für Partikeltherapie,
Universitätsklinikum Essen, Westdeutsches Protonentherapiezentrum
Essen (WPE), Westdeutsches Tumorzentrum (WTZ), German Cancer
Consortium (DKTK), Essen, Germany, 7Institut für Biometrie und Klinische
Forschung, Universitätsklinikum Münster, Münster, Germany, 8Instituteof Neuropathology University Medical Center Hamburg-Eppendorf,
Hamburg, Germany, 9Research Institute Children’s Cancer Center,
Hamburg, Germany, 10Hopp Children’s Cancer Center Heidelberg (KiTZ)
and Division of Pediatric Neurooncology, German Cancer Research Center(DKFZ), Heidelberg, Germany, 11Department of Pediatric Oncology,
Hematology and Immunology, Heidelberg University Hospital, Heidelberg,
Germany, 12Princess Máxima Center for Pediatric Oncology, Utrecht,
Netherlands, 13Institute of Neuropathology, Brain Tumor Reference Centerof the German Society for Neuropathology and Neuroanatomy (DGNN),
University of Bonn, Bonn, Germany, 14Department of Radiation Oncology,
University of Leipzig, Leipzig, Germany, 15Institut für Biometrie undKlinische Forschung, Universitätsklinikum Münste, Münster, Germany
BACKGROUND: Pediatric ependymoma is a heterogenous disease.
Subgroup-specific clinical information on prospectively treated patients
will help to improve treatment stratification. METHODS: Within the
population based, prospective, multicenter E-HIT-trial (2001–2011) patients with localized ependymoma confirmed by neuropathological centralreview, received hyperfractionated local radiotherapy (68Gy, 2x1Gy/day)followed by chemotherapy (stratum-A), or chemotherapy followed by local
radiotherapy (54Gy, 1.8Gy/day) (children < 4years, stratum-B), or ageadapted radiotherapy with pre-/post-irradiation chemotherapy (residual
tumor, diagnosis after 2005, stratum-C). Retrospective classification of
DNA-methylation was available for n=164 E-HIT-trial participants, and
n=80 patients with comparable treatment and prospective registration in
the subsequent HIT-interim-registry (2012–2014). FINDINGS: For 291
E-HIT-trial patients, 5-year progression-free (PFS) and overall survival(OS) were 61±3%, and 81±2%. Five-year PFS/OS after complete resection were 71±4% and 87±3% in stratum-A (n=127), and 64±5% and86±4% in stratum-B (n=86). Outcome was poor after incomplete resection, irrespective of treatment-stratum (n=78, 5-year PFS/OS: 43±6%,68±5%). In the pooled trial- and registry-cohort, there were 152 patientswith PF-EPN-A (5-year PFS/OS: 44±4%, 77±4%), 40 of them with 1q-gain(5-year PFS/OS: 28±7%, 66±8%), 21 with PF-EPN-B (5-year PFS/OS:
90±7%, 100%), 59 with ST-EPN-RELA (5-year PFS/OS: 63±7%, 87±5%),
and 4 with ST-EPN-YAP1 (2 progression/relapse, no death). CONCLUSION: Outcome differed between molecular subgroups and insufficientsurvival rates were achieved for patients with PF-EPN-A with 1q-gain, despite combined radio- and chemotherapy treatment. Treatment reduction in
the context of a clinical trial may be considered for PF-EPN-B.
EPEN-41. C11ORF95-RELA FUSION REGULATES ABERRANT GENE
EXPRESSION THROUGH THE UNIQUE GENOMIC BINDING SITESFOR EPENDYMOMA FORMATION
Tatsuya Ozawa1, Syuzo Kaneko1, Mutsumi Takadera1, Eric Holland2,
Ryuji Hamamoto1, and Koichi Ichimura1; 1National Cancer Center
Research Institute, Chuo-ku, Tokyo, Japan, 2Fred Hutchinson Cancer
Research Center, Seattle, WA, USA
A majority of supratentorial ependymoma is associated with recurrent
C11orf95-RELA fusion (RELAFUS). The presence of RELA as one component of the RELAFUS leads to the suggestion that NF-kB activity is involvedin the ependymoma formation, thus being a viable therapeutic target inthese tumors. However, the oncogenic role of another C11orf95 component in the tumorigenesis is not still determined. In this study, to clarify
the molecular mechanism underlying tumorigenesis of RELAFUS, we performed RELAFUS-ChIP-Seq analysis in cultured cells expressing the RELAFUS
protein. Genomic profiling of RELAFUS binding sites pinpointed the transcriptional target genes directly regulated by RELAFUS. We then identified
a unique DNA binding motif of the RELAFUS different from the canonical
NF-kB motif in de novo motif discovery analysis. Significant responsivenessof RELAFUS but not RELA to the motif was confirmed in the reporter assay.
An N-terminal portion of C11orf95 was sufficient to localize in the nucleus
and recognizes the unique motif. Interestingly, the RELAFUS peaks concomitant with the unique motif were identified around the transcription startsite in the RELAFUS target genes as previously reported. These observations
suggested that C11orf95 might have served as a key determinant for the
DNA binding sites of RELAFUS, thereby induced aberrant gene expressioniii316

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De c e mb e r 2 0 2 0necessary for ependymoma formation. Our results will give insights into thedevelopment of new ependymoma therapy.
EPEN-42. MOLECULAR PROFILING REVEALS DISTINCTSUBGROUPS OF PEDIATRIC SPINAL EPENDYMOMA
Omar Ahmad1, Rebecca Chapman1, Lisa Storer1, Li Luo2, Linda Resar2,
Kenneth Cohen2, Richard Grundy1, and Anbarasu Lourdusamy1;
1University of Nottingham, Nottingham, United Kingdom, 2The John
Hopkins University School of Medicine, Baltimore, MD, USA
Paediatric spinal ependymomas are important, albeit uncommon, malignant central nervous system tumours. Unlike adults, children with thesetumours are likely to experience a more aggressive disease course, with ahigher rate of local failure and a higher rate of metastases. The clinical andmolecular factors underlying these differences remain poorly characterized.
We analyzed spinal ependymoma (SEPN) tumour samples from 27 paediatricpatients (female: 11, male: 15; age range: 4–18 years) using genome-wide
DNA methylation profiling, copy-number analysis, as well as transcriptome profiling. Using DNA methylation profiles, two distinct unsupervisedconsensus-clustering approaches, hierarchical clustering and non-negative
matrix factorization reliably identified two subgroups. These subgroups
were designated as Myxopapillary ependymomas (SP-MPE) and spinal
ependymomas (SP-EPN) based on the online Classifier tool (MNP2.0). The
genome-wide copy-number analysis showed differences in numbers and pattern of copy-number alterations between these groups. The gain of chromosome 20 (39%) followed by loss of chromosomes 6 (28%), 10 (28%), and
13 (28%) were detected in the SP-MPE group, whereas loss of chromosome 22 was frequent (60%) in the SP-EPN group. Transcriptomics analysis
showed that genes associated with oxidative phosphorylation, TCA cycle
components, electron transport, and Interferon-gamma production characterize the SP-MPE group whereas potassium ion import and regulation ofastrocyte differentiation characterize the SP-EPN group. Western blot analysis validated the increased protein expression of oxidative phosphorylation
complexes in SP-MPE. With this study, we provide a foundation for further
molecular characterization of pediatric SEPN subgroups. Our results suggestthat mitochondrial oxidative phosphorylation may drive the regulation ofenergy metabolism of SP-MPE tumours.
EPEN-43. TARGETING INTRA-TUMOUR HETEROGENEITY IN
PAEDIATRIC EPENDYMOMA: AN INTEGRATED OMICS STUDYTOWARDS PATIENT-TAILORED THERAPY
Alina Pandele1, Alison Woodward1, Donald MacArthur2,
Ian Kamaly-Asl3, David A. Barrett4, Richard G. Grundy1,
Dong-Hyun Kim4, and Ruman Rahman1; 1Children’s Brain Tumour
Research Centre, School of Medicine, The University of Nottingham,
Biodiscovery Institute, Nottingham, United Kingdom, 2Department of
Neurosurgery, Nottingham University Hospitals NHS Trust, Nottingham,
United Kingdom, 3Royal Manchester Children’s Hospital, Manchester,
United Kingdom, 4Centre for Analytical Bioscience, Advanced Materials
and Healthcare Technologies, School of Pharmacy, The University of
Nottingham, Nottingham, United Kingdom
Ependymoma (EPN) is the second most common malignant paediatricbrain tumour, which despite extensive genomic sequencing, no novel therapeutic options have been discovered. Multi-omics are anticipated to reveal dysregulated pathways that may be predictive of patient-specificbiomarkers. Given the close association between gene expression, active
biochemical signaling and metabolism, there is an unmet scientific challenge to determine whether EPN gene expression correlates with aberrant
metabolic pathways, thus presenting therapeutic vulnerabilities. We firstcompared two distinct subgroups of EPN, PF-A and ST-RELA, identifying
115 metabolites and 1580 upregulated genes between the two subgroups,
therefore validating previously reported genetic clustering of these two
subtypes. We next integrated transcriptomics and metabolomics, comparing 28 intra-tumour tissue regions from eight primary PF-A EPN patients. Polar metabolites and RNA were simultaneously extracted from thesame population of cells. RNAseq identified dysregulated genes and liquid
chromatography-mass spectrometry (LC-MS) detected 98 significantly altered metabolites between 18 multi-regions, the majority mapping onto thearginine and proline pathways. Integration of genes and metabolites using
pathway-based network analysis revealed 124 aberrant gene-metaboliteinteractions between intra-tumour regions, with large numbers occurringin the glucogenesis and glycine metabolic pathways in 6/8 patients. Thesemay represent ubiquitous and therapeutically relevant metabolic pathways critical for EPN survival. Additionally, patients presented at least
one unique intra-tumour genomic-metabolomic interaction, applicable forpatient-tailored therapy. This is the first exploration of EPN multi-omic integration and intra-tumour heterogeneity. Selected drug targets predicatedon aberrant gene-metabolite networks will be validated in multi-region
patient-derived cell lines and orthotopic models using repurposed therapeutics.

Abstracts

EPEN-44. EXTRACELLULAR VESICLES OF SUPRATENTORIALEPENDYMOMA RELA MEDIATE INTERACTIONS WITH CELLS OF
THE TUMOR MICROENVIRONMENT
Kendra K Maass1,2, Mieke Roosen1, Julia Benzel1, Tatjana Wedig1,2,
Britta Statz1, Torsten Mueller3, Mathias Kalxdorf3, Jeroen Krijgsveld3,
Stefan M Pfister1,2, and Kristian W Pajtler1,2; 1Hopp Children’s Cancer
Center Heidelberg (KiTZ) and Division of Pediatric Neurooncology,
German Cancer Consortium (DKTK), German Cancer Research Center(DKFZ), Heidelberg, Germany, 2Department of Pediatric Oncology,
Hematology and Immunology, University Hospital, Heidelberg, Germany,
3Division of Proteomics of Stem Cells and Cancer, German Cancer
Research Center (DKFZ), Heidelberg, Germany
Ependymal tumors (EPNs) account for ~10% of all pediatric brain tumors.
Supratentorial EPN characterized by RELA fusions (ST-EPN-RELA) and posterior
fossa EPN group A (PF-EPN-A) form the two most frequent molecular groups,
both of which are associated with poor prognosis and for which only limited therapeutic options are available. Since pediatric EPNs have a relatively low mutationalburden, identification and characterization of tumor-associated pathways and molecular processes is of critical importance to inform potential therapeutic targets.
Previous transcriptional studies implicated aberrant vesicular pathways in ST-EPNRELA, prompting further investigation into their putative role in EPN pathogenesis. To this aim, we isolated extracellular vesicles (EVs) of ST-EPN-RELA patientderived cell lines and performed protein mass spectrometry. The specific ST-EPNRELA EV protein content resembles the parental cells as well as primary tumors.
Promising candidates to be transferred by ST-EPN-RELA EVs but not control EVs
were associated with unfolded protein response and endoplasmic reticulum stress.
When uptaken by recipient cells of the tumor microenvironment, brain endothelial
cells or microglia, ST-EPN-RELA EVs induced proliferation and had a chemoattractant effect towards the tumor. ST-EPN-RELA EVs stimulated angiogenesis ofbrain endothelial cells potentially by the transfer of ER stress proteins. Uptake of
ST-EPN-RELA EVs by microglia changed their activation status indicating a tumor
promoting function through EV transfer. Therefore, we hypothesize that vesicularpathways play an important role in the pathogenesis of pediatric ST-EPN-RELAs
and that an improved understanding may promote new therapeutic opportunities.
EPEN-45. NORMALIZING AND FACILITATING GENOMIC TESTINGAT DIAGNOSIS IN PEDIATRIC EPENDYMOMA
Emily Owens Pickle, Ana Aguilar-Bonilla, and Amy Smith; Arnold Palmer
Hospital for Children, Orlando, FL, USA
The current consensus is that diagnosis and treatment of ependymoma
should be based upon clinical and molecular classification. As we move into
this paradigm, it is important all ependymoma cases undergo tumor collection, preservation, and molecular profiling at diagnosis. Our group of 6 sites
gathered data on a cohort of 72 ependymoma cases. Sites were asked toreport known molecular findings; 60/68 eligible cases (88%) did not include
genetic findings. The low number of cases with molecular findings was surprising and since cases were diagnosed from as early as 2004, we asked collaborators to share their current practice in profiling (e.g., how frequently;
in what setting were ependymomas sent for testing) to try and better understand current practice at sites. Since the publication of ependymoma molecular data, sites with a neuro-oncology program report sending almost
all newly diagnosed ependymomas for molecular testing, whereas current
practices at sites without dedicated neuro-oncology were less consistent.
Profiling in the setting of relapse was more frequently reported at all centers. The implementation of molecular testing at diagnosis may need support
at sites without dedicated neuro-oncology. Lead investigators for upcoming
ependymoma clinical trials will need to think carefully about the logistics ofprofiling at centers where this is not standard practice at diagnosis.
EPEN-46. DNA METHYLATION LANDSCAPE OF RECURRENTPEDIATRIC EPENDYMOMA IDENTIFIES KEY DRIVER EVENTS
Sibo Zhao1,2, Jia Li3, Huiyuan Zhang2, Lin Qi2,4, Yuchen Du2,4,Mari Kogiso2, Frank Braun2, Holly Lindsay2, Paola Genevini5,
Anne-Clemence Veillard5, Sol Schvartzman5, Miklos Laczik5,
Geoffrey Berguet5, Adekunle Adesina6, Clifford Stephan3,
Murali Chintagumpala2, Williams Parsons2, Laszlo Perlaky2,
Yongcheng Song7, Deqiang Sun3, and Xiao-Nan Li4,2; 1Hematology andOncology Center, Cook Children’s Medical Center, Fort Worth, TX, USA,
2Texas Children’s Cancer Center, Baylor College of Medicine, Houston,
TX, USA, 3Institute of Biosciences and Technology, Texas A&M University,
Houston, TX, USA, 4Ann & Robert H, Lurie Children’s Hospital of
Chicago; Department of Pediatrics, Northwestern University Feinberg
School of Medicine, Chicago, IL, USA, 5Diagenode Epigenetic Services,
Liege, Belgium, 6Department of Pathology, Texas Children’s Hospital,
Houston, TX, USA, 7Department of Pharmacology, Baylor College ofMedicine, Houston, TX, USA
Pediatric ependymoma has a propensity of developing late and multiple
relapses over many years. About 50% of patients will experience relapses

and eventually succumb to their disease. Our study is aimed to understand the mechanism of resistance and drivers associated with pediatric
ependymoma relapse. We developed 10 sets of patient-derived orthotopic
xenograft (PDOX) models of recurrent pediatric ependymoma from both
RELA and PFA tumors. Time from primary tumor to last recurrence ranges
from 2.75 – 13 years. Number of recurrences per patient ranges from 1 – 7times. We performed Reduced Representation Bisulfite Sequencing (RRBS)
and Whole Genome Bisulfite Sequencing (WGBS) to map the DNA methylation landscape of total of 30 samples of matched primary and recurrent tumors. Molecular subtypes and DNA methylation profiles were maintained,
and RELA/PFA signature genes showed similar expression pattern during
serial relapses. RELA- and PFA-specific Differentially Methylated CpGs
(DMCs) are identified from primary tumors. During the recurrent process,individual patients displayed consistent changes of DMCs and shared DMCs
among patients became convergent. We then identified shared common specific DMCs in recurrent RELA and PFA tumors that emerged as the driver
signatures. We found that these recurrent DNA methylation signatures
could be identified from primary tumors. Our analysis of the PDOX models
showed that they can mostly recapitulate humor tumors’ DNA methylation and we were able to identify shared recurrent specific DMCs associatedgenes in PDOX models. Our comprehensive data is the first of its kind aimed
to investigate the epigenetic mechanisms during pediatric ependymoma recurrence.
EPEN-47. PEDS: PEDIATRIC EPENDYMOMA DISCOVERY STUDY
Amy Smith1, Kristian Pajtler2, Koichi Ichimura3, Emily Owens Pickle1,
Gudrun Fleischhack4, Stephan Tippelt4, and Ana Aguilar-Bonilla1; 1Arnold
Palmer Hospital for Children, Orlando, FL, USA, 2German Cancer
Research Center (DKFZ), Heidelberg, Germany, 3National Cancer Center
Research Institute, Tokyo, Japan, 4University Hospital of Essen, Essen,
Germany
The prognosis for pediatric ependymoma remains unaffected by recent
discovery. Upfront therapy is maximal surgical resection followed by radiation and the utility of histologic diagnosis remains unreliable. Nine molecular subgroups and possible genetic drivers of ependymoma have been
identified, but the implementation of these findings into targeted therapy
and stratified clinical trials has not occurred. It is imperative that researchers work collaboratively to move discovery towards clinical testing.
Heterogeneity of ependymoma requires that we collect a large amountof data; progress in the field is dependent on deep analysis of this information. As we further subclassify ependymoma, it will be important tohave a large patient population for enrollment onto clinical trials, which
will maximize data collection and the amount of materials available forexperimentation and analysis. Researchers in the United States, Europe,
and Japan propose an international ependymoma research collaborative which aims to synthesize research across sites, foster drug discovery,
and prove strategies to integrate clinical and molecular diagnostics into
biology-based therapy. Our goal is to maximize information and materials
from existing bio and data repositories and not to ‘re-create the wheel’.
We envision PEDS as an open science platform and present this concept
at ISPNO to invite our colleagues to harmonize efforts towards pediatric
ependymoma discovery.
EPEN-49. RESPONSE OF RECURRENT EPENDYMOMATO MEMMAT BASED METRONOMIC ANTIANGIOGENICCOMBINATION THERAPY UTILIZING TAPERED BEVACIZUMAB
AND MAINTENANCE THERAPY WITH CELECOXIB AND
FENOFIBRATE
Eileen Gillan; Connecticut Children’s Medical Center, Hartford, CT, USA
Recurrent ependymomas have a dismal prognosis (2 year survival
rates 29% OS and 23% EFS) and are relatively resistant to conventional chemotherapy. We previously reported five relapsed ependymoma
patients treated with a MEMMAT based metronomic antiangiogenic
combination therapy. All patients are currently alive, including four patients who were multiply relapsed with at least three recurrences. Thesefour patients received between 44–52 weeks of therapy with minimal
toxicity. Three had recurrent disease within an average of 44 months(median 42 months) after discontinuation of therapy. One patient who
received the following tapering bevacizumab schedule: q3 weeks x 3,
q4 weeks x 4 and q5 weeks x 5 followed by maintenance therapy withfenofibrate and celecoxib is in complete remission 12 months post treatment. This regimen was well tolerated with good quality of life in thispatient population. Our results suggest that the chosen anti-angiogenic
drug combination prolonged the time to progression in these multiply
relapsed patients and thus may be particularly beneficial for patientswith recurrent ependymoma. Tapered bevacizumab and maintenancetherapy with celecoxib and fenofibrate may be modifications worth
further investigation for prolonged disease free survival in relapsed
ependymoma patients.

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EPEN-50. THE MANAGEMENT AND TREATMENT OFPEDIATRIC SPINAL CORD EPENDYMOMA: RESULTS FROMA COLLABORATIVE INTERNATIONAL MULTI-INSTITUTIONAL
REVIEW
John Lucas1, Ella Kumirova2, Derek Tsang3, Anna Vinitsky1, Jason Chiang1,
Lili-Naz Hazrati4, Shelby Lane5, Harold Agbahiwe6, Santhosh Upadhyay1,
Christopher Tinkle1, Dmitry Konovalov2, Moatasem El-Ayadi7,8,
Eslam Maher7, Victoria Emtsova2, Alexey Nechesnyuk2, Nasim Sarhan3,
Anna Loginova2, Chih-Yang Hsu1, Matthew Ladra9, Stephanie Terezakis10,
Frederick Boop1, Paul Klimo1, Soha Ahmed7,11, Normand Laperriere3,
Vijay Ramaswamy4, and Thomas Merchant1; 1St. Jude Children’s Research
Hospital, Memphis, TN, USA. 2Dmitry Rogachev National ResearchCenter, Moscow, Russian Federation, 3Princess Margaret Cancer Centre,
Toronto, Canada, 4Hospital for Sick Children, Toronto, Canada, 5Loma
Linda University Health, Loma Linda, CA, USA, 6Virginia Cancer
Specialists, Fairfax, VA, USA, 7Children’s Cancer Hospital, Cairo, Egypt,
8National Cancer Institute, Cairo University, Cairo, Egypt, 9Johns Hopkins
Kimmel Cancer Center, Bethesda, MD, USA, 10University of Minnesota,
Minneapolis, MN, USA, 11Aswan University, Aswan, Egypt
PURPOSE: Pediatric Spinal cord ependymoma (SCE) is rare, and the
management is often heterogeneous across centers. We evaluated the impact of clinical, pathologic, and treatment-related factors on outcomes ina multi-institutional, international cohort. METHODS: SCE patients age<21 years were reviewed across 5 institutions. We utilized nonparametricdescriptive statistics, survival, and recursive partitioning analysis (RPA)
to examine patient, tumor, histopathologic and treatment characteristics,
failure pattern, and cause of death. RESULTS: 125 patients were identified,
18 (14.4%) with metastases. Initial surgery was GTR, and STR in 44, 56%
of patients respectively. Histology was grade 1, 2, and 3 in 55, 17.7 and23.2% respectively. 55 patients with initial GTR were observed (52.7%)
or irradiated (43.6%); 60 patients had STR and were observed (40%) or
irradiated (60%). The 7-year event-free (EFS) and overall survival (OS) was
60% (95% CI 51.5–71.4) and 79% (95% CI 71.1–87.8) respectively. STR
and metastasis increased the hazard for death [HR 1.87, 95% CI 1.02–3.57,
p=0.05 (vs. GTR)] and [HR 2.28, 95% CI 1.1–5.2, p=0.048 (vs. localized)]
respectively. Across 43 failures, local failure predominated (48.8%). Distantand combined failure occurred in 30.2 and 13.9% respectively. Adjuvant
RT offered a 20% absolute improvement (vs. observation) in EFS at 5 years
regardless of extent of resection. RPA identified thoracic (vs. non-thoracic),
grade (1 & 3 vs. 2), STR (vs. GTR) and metastases as determinants of inferior EFS. CONCLUSIONS: Tumor and treatment-related factors are predictive of EFS. OS is favorable despite diverse schema and frequent distantfailures.
EPEN-51. CHILDHOOD INTRACRANIAL EPENDYMOMA: A MULTICENTER RETROSPECTIVE ANALYSIS
Emily Owens Pickle1, Ana Aguilar-Bonilla1, Bertha Ben Khallouq1,
Stacie Stapleton2, Eric Sandler3, Anne-Marie Langevin4, Jamie Libes5,
Iftikhar Hanif6, and Amy Smith1; 1Arnold Palmer Hospital for Children,
Orlando, FL, USA, 2John Hopkins All Children’s Hospital, St, Petersburg,
FL, USA, 3Nemours Children’s Health Systems, Jacksonville, FL, USA,
4University of Texas Health Science Center, San Antonio, TX, USA,
5University of Illinois College of Medicine, Peoria, IL, USA, 6Joe DiMaggio
Children’s Hospital, Hollywood, FL, USA
Ependymoma is a heterogeneous disease which is resistant to improvement. Current challenges are the unreliability of histologic classification,
the uncertain role of adjuvant chemotherapy, and a lack of clinical trials
integrating molecular and clinical diagnostics into risk-guided therapy.
Ependymoma can show surprising latency, reoccurring many years after theoriginal diagnosis. In this study, we performed a retrospective analysis ofependymoma cases treated at six centers over a period of 12 years. A totalof 73 cases were submitted from six sites; 68 cases were retained for review. Median age at diagnosis was 4.1 years and gender was reported as
male (50%) and female (50%). Histologic grade was reported as Grade II(49%) and Grade III (50%)(not reported: 1). Anatomic location reported
as supratentorial (27%) and infratentorial (73%). Metastatic disease wasreported in 9% of patients. At diagnosis, gross total resection was achievedin 59% of cases. Twenty-eight percent of patients have died, 59% of patients are alive (with and without disease), and 13% of patients are lost tofollow-up. Maximal safe surgical resection is currently the best predictor of
long-term survival but was achieved in only 60% of cases. Biology-based
therapy will be the next step towards improving the prognosis of pediatric
ependymoma.
EPEN-52. METABOLIC REGULATION OF THE EPIGENOME DRIVESLETHAL INFANTILE EPENDYMOMA
Sachin Kumar1,2, Antony Michealraj2, Leo Kim3, Jeremy Rich3, andMichael Taylor1,2; 1University of Toronto, Toronto, ON, Canada. 2Hospitaliii318N EU R O - O N C O L O G Y•

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for Sick Children, Toronto, ON, Canada. 3University of California San
Diego, La Jolla, CA, USA
PFA ependymomas are a lethal glial malignancy of the hindbrain found in
infants and toddlers. Lacking any highly recurrent somatic mutations, PFAs
have been proposed to be a largely epigenetically driven entity, defined byhypomethylation at the histone 3 lysine 27 residue. Unfortunately, an almost complete lack of model systems has limited the discovery of novel PFA
therapies. In this study, we have identified that the PFA hypoxic microenvironment controls the availability of specific metabolites, resulting in diminished H3K27 trimethylation and increased H3K27 acetylation in vitro andin vivo. Unique to PFA cells, transient exposure to ambient oxygen resultsin irreversible cellular toxicity. Furthermore, perturbation of key metabolic
pathways is sufficient to inhibit growth of PFA primary cultures in vitro.
Although PFA tumors exhibit a low basal level of H3K27me3, inhibitionof H3K27 methylation paradoxically demonstrates significant and specificactivity against PFA. Thus, we propose a “Goldilocks Model” of metabolicepigenetic regulation in PFA ependymoma, whereby increased or decreased
H3K27 trimethylation results in cell death. Mapping of PFA ependymoma
tumours suggests a cell of origin arising in the first trimester of human development where there is a known hypoxic microenvironment. Therefore,targeting metabolism and/or the epigenome presents a unique opportunity
for rational therapy for infants with PFA ependymoma.
EPEN-53. C11ORF95-RELA REPROGRAMS 3D EPIGENOME IN
SUPRATENTORIAL EPENDYMOMA
Jacqueline Jufen Zhu1, Nathaniel Jillette1, Xiao-Nan Li2,3, Albert Cheng1,4,
and Ching Lau1,5; 1The Jackson Laboratory for Genomic Medicine,
Farmington, CT, USA, 2Northwestern University, Chicago, IL, USA, 3Baylor
College of Medicine, Houston, TX, USA, 4University of Connecticut HealthCenter, Farmington, CT, USA, 5Connecticut Children’s Medical Center,
Hartford, CT, USA
Ependymoma is the third most common malignant brain tumor in children. However, there is no effective chemotherapy identified and treatment
is limited to surgery with or without adjuvant radiation therapy currently.
Thus, to develop targeted therapy based on the underlying biology is anurgent need. Since 2014, C11orf95-RELA fusion was found to be the mostrecurrent structural variation in approximately 70% of supratentorial
ependymomas (ST-EPN), but the molecular mechanisms of oncogenesis areunclear. Here we utilized HEK293T transgene models and a ST-EPN cellline to investigate the epigenomic changes and transcriptional regulations
by C11orf95-RELA fusion. By applying ChIP-seq and HiChIP approaches,
we found C11orf95-RELA is a novel transcription factor that recognizes a
specific DNA motif dictated by the C11orf95 component while the RELA
component is required for driving the expression of ependymoma-associatedgenes such as CCND1 and L1CAM. Moreover, C11orf95-RELA modulates
chromatin states and mediates chromatin interactions, leading to transcriptional reprogramming in ST-EPN cells. Multiple signaling pathways suchas Notch signaling and G-protein signaling are identified to be involved in
ST-EPN development. Our findings provide important characterization of
the molecular underpinning of C11orf95-RELA fusion and shed light on
potential therapeutic targets for C11orf95-RELA subtype ependymoma.
EPEN-54. ACNS0831, PHASE III RANDOMIZED TRIAL OF POSTRADIATION CHEMOTHERAPY IN PATIENTS WITH NEWLYDIAGNOSED EPENDYMOMA AGES 1 TO 21 YEARSAmy Smith1, Arzu Onar-Thomas2, David Ellison3, Emily Owens-Pickle1,
Shengjie Wu3, Sarah ES Leary4, Maryam Fouladi5, Thomas Merchant6,
Amar Gajjar3, and Nicholas Foreman7; 1Orlando Health-Arnold Palmer
Hospital for Children, Orlando, FL, USA, 2Department of Biostatistics, St.
Jude Children’s Research Hospital, Memphis, TN, USA, 3St. Jude Children’s
Research Hospital, Memphis, TN, USA, 4Seattle Children’s, Seattle, WA,
USA, 5Nationwide Children’s Hospital, Columbus, OH, USA, 6Departmentof Radiation Oncology, St. Jude Children’s Research Hospital, Memphis,
TN, USA, 7Children’s Hospital Colorado, Aurora, CO, USA
PURPOSE: The primary objective of this study is to determine the EFS
and OS of children with gross total and near totally resected ependymoma(EPN) treated with post-operative focal radiation therapy (RT) followedby randomization to either RT alone or RT + 4 cycles of maintenancechemotherapy with vincristine, cisplatin, cyclophosphamide and etoposide.
Secondary objectives include estimating the EFS and OS of children not randomized, evaluation of neurobehavioral and quality of life (QoL) endpoints,
and EPN biomarkers. RESULTS: 479 patients enrolled, 451 were eligible.
Of 325 eligible randomized patients, 161 were randomized to RT alone and
164 to RT + maintenance chemotherapy. Age range (1–21 years, median
4.9 years). The planned primary analysis was based on intent-to-treat, irrespective of actual treatment received. Based on the data available as of
12/31/2019, estimated 3-year EFS in the RT + maintenance chemotherapy

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vs. RT arms were 78% vs. 72%, respectively, which did not meet statistical criteria to establish the benefit of maintenance chemotherapy post RT(1-sided log-rank p-value=0.074). Due to significant noncompliance (30.5%
in the RT + maintenance vs 4.3% in the RT arm), a planned secondary “astreated” analysis was performed. With median follow-up of 42.6 months
among patients without events, the 3 year EFS estimates for patients who
received any chemotherapy (n=114) vs. those who received RT only (n=196)
were 80% vs. 71%, respectively (1-sided p-value = 0.0121). CONCLUSION: Early results in this randomized trial suggest that there may be some
EPN patients who benefit from maintenance chemotherapy. Genomic analyses are ongoing.

EPIDEMIOLOGY
EPID-01. TRENDS OF INCIDENCE IN PEDIATRIC BRAIN TUMORSIN KUMAMOTO PREFECTURE, JAPANTakashi Itoyama1, Naoki Shinojima1, Takahiro Yamamoto1,
Kenji Fujimoto2, Keishi Makino2, and Akitake Mukasa1; 1Kumamoto
University Hospital, Kumamoto, Japan, 2Kumamoto City Hospital,
Kumamoto, JapanBACKGROUND/PURPOSE: One of the most problematic issues Japan
has is a declining birthrate resulting in an aging society. There are some reports on the trends of incidence in brain tumors in the elderly, whereas few
reports on those in the children. The aim of this study is to investigate thetrends of incidence in childhood primary brain tumors. METHODS: The
population of children aged <15 years was available from Kumamoto
Prefecture’s annual census between 1990 and 2017. During the period 301
childhood primary brain tumors (124 gliomas, including astrocytic tumors and ependymomas, 35 embryonal tumors, 34 germ cell tumors, 22
craniopharyngioma, and 86 others) were registered with the Kumamoto
Brain Tumor Data Bank, and investigated. RESULTS: The average of theannual incidence rate per 100,000 child populations was 3.90 for total
brain tumors, 1.63 for gliomas, 0.44 for embryonal tumors, 0.42 for germ
cell tumors, 0.26 for craniopharyngioma, and 1.15 for others. Divided into
the first half from 1990 to 2003 and the second half from 2004 to 2017,
there was no significant difference in the incidence of brain tumors aged
<15 years between the two periods. However, the average of the annual incidence rate/100,000 child populations was 3.02 in the first half, while significantly increased in the second half of 4.78 (p=0.00075, t-test). DISCUSSION& CONCLUSIONS: The average number of children aged <15 years in
Kumamoto Prefecture was 31,2737.9 from 1990 to 2003, while decreased
remarkably to 251460.2 from 2004 to 2017. A decrease in the number ofchildren may affect increasing the incidence rate of pediatric brain tumors.
EPID-03. COMPARISON OF SURVIVAL IN ADULT AND PEDIATRICPATIENTS WITH MEDULLOBLASTOMA: A 2018 SEER BASEDANALYSIS
Hanna M Moisander-Joyce1, Anoushka Sinha1,
Shannon Fernandez-Ledon2, Davon T Lee3, Satoki Hatano4, Justine Kahn1,
James H Garvin1, Stergios Zacharoulis1, Robyn D Gartrell-Corrado1;
1Columbia University Irving Medical Center, Department of Pediatrics –Division of Pediatric Hematology/Oncology/Stem Cell Transplant, New
York, NY, USA, 2Vagelos College Physicians and Surgeons, Columbia
University, New York, NY, USA, 3City University of New York, HunterCollege, New York, NY, USA, 4Keio University School of Medicine, Tokyo,
Japan
Medulloblastoma (MB) is the most common high-grade primary brain
malignancy in children and accounts for 1% of adult brain tumors. Previous
studies have compared survival in pediatric and adult MB from the National Cancer Institute Surveillance Epidemiology and End Results (SEER)
database finding no difference. However, diagnostic subgroup analyses arelimited. We examined survival in children (age 0–19) and adults (20–79)
coded as MB in the 2018 SEER database (2000–2016), using Kaplan Meieranalysis, log-rank test and Cox proportional hazard ratios (HR) with 95%
confidence intervals (CI).). MB in SEER-18 is defined as ICD-O-3 histology
codes 9470–9474 (n=1,728). ICD 9473, supratentorial PNET (sPNET,
n=97) is biologically distinct so was analyzed separately. 5-year survival
for MB, excluding sPNET, was similar in children (n = 1,091, 75.3%) andadults (n= 488, 79.1%) (HR=0.97, CI: 0.79 – 1.17, p=0.50). Subtype analyses showed no survival difference comparing adults and children withdesmoplastic nodular MB (n=222, p=0.09), large cell MB (n=73, p=0.46), or
MB NOS (n=1330, p=0.10). In contrast, children with sPNET had improved
survival (n=65, 72.3%) compared to adults (n=29, 51.7%) (HR = 2.0, CI:
1.10 – 3.92; p=0.02,). In conclusion, 2018 SEER data for MB continue toshow no survival difference between adults and children, suggesting adultpatients could appropriately be entered on pediatric MB treatment protocols. Further analyses of the 2018 data are ongoing adjusting for sex, race,and treatment. Comparison of adults and children with MB and sPNET

will be re-evaluated using the new 2016 World Health Organization classification.
EPID-04. MORBIDITY IN PAEDIATRIC BRAIN TUMOURS: 17
YEARS’ EXPERIENCE IN A TERTIARY NEUROSURGICAL UNIT
Chun Peng Goh, Vincent Diong Weng Nga, and Cindy Wei Li Ho; National
University Hospital, Singapore, Singapore
The treatment of paediatric brain tumours has shown significant improvement over the last 2 decades. The aim of our study is to evaluate theprevalence of various effects among this population within our institution.
102 patients diagnosed with a brain tumour at the age of 0–18 years between 2002 and 2018 were identified within a single paediatric institution.
Data was collected retrospectively based on electronic medical records.
Medulloblastoma (20.6%) was the most common subtype followed bypilocytic astrocytoma (18.6%) and craniopharyngioma (11.8%). Overall,
the 5-years survival rate was approximately 77%. Endocrine dysfunction
was reported in 36% of the population, mainly due to tumour located insuprasellar region and irradiation causing progressive pituitary dysfunction. Neurological disorders such as epilepsy, weakness, cranial nerves palsy,
visual and hearing impairment were present in 46% of the population. Importantly, 20.4% of patients who received chemotherapy had some degreeof sensorineural hearing loss. 16% of the population suffered from impaired
neurocognition which is likely an underestimation as screening could not
be performed on all patients. Other significant complications are infections(12%) and ventriculoperitoneal shunt dysfunction (7%). Most of these effects can be attributed to direct injury to the developing brain caused by thetumour or related to its treatment during surgical excision and the long termside effects of chemotherapy and radiation therapy. Morbidities in various
domains can pose significant challenges to survivors of paediatric brain tumours. Active screening and surveillance of these effects can help improve
the health outcomes of survivors of paediatric brain tumours.
EPID-05. EVALUATION OF THE INCIDENCE OF CENTRALNERVOUS SYSTEM TUMORS IN A CHILDHOOD CANCER
TREATMENT CENTER AND THE CREATION OF A SPECIFIC
GROUP
Alessandra Azambuja1, Juliana Barreto1, Lilian Maria Cristofani1,
Felipe Sanders2, Helena Baraldi2, Eduardo Weltman2, Leandro Lucato2,
Vitor Paes2, Fernando Frassetto2, Carlo Petitto2, Sergio Rosemberg2,
Hamilton Matushita2, and Vicente Odone1; 1ITACI/FMUSP, Sao Paulo, SP,
Brazil, 2HCFMUSP, Sao Paulo, SP, Brazil
Central Nervous System Tumors (CNST) are the main solid neoplasm ofchildhood, representing 20% diagnosis. Based on this information, a search
was carried out at a reference treatment center for childhood cancer in thestate of Sao Paulo, belonging to University of Sao Paulo- ITACI/HCFMUSP,
and at between 2017 and 2019, 352 new patients, 116 of which were neoplasm of CNS (32.9%). Aiming at an incidence of new cases, in 2019, an
institutional group was created, with a team composed of Pediatric Oncologists, Neurosurgeons, Radiologists, Radiotherapists and Pathologists. In
this first year, 31,8% of the 132 new patients were diagnosed with CNS
tumor. According to WHO 2016, 15 patients were classified as a group that
includes Diffuse Astrocytomas, Oligodendrioglial Tumors and Other Astrocytic Tumors. Among the other patients, 14.2% were Medulloblastomas,
4.7% Embryonic Tumors and 2.3% ART / RT. Patients diagnosed with diffuse brainstem glioma accounted for 11.9% of the total. The institution had
a diagnosis of Angiocentric Glioma, Craniopharyngioma, Plexiform Neurofibroma and Anaplastic Ependymoma. Neuronal-glial tumors accounted for
9.5% of cases. Choroid plexus tumors represents 5%. Among them, 4.72%
had metastatic tumors: Neuroblastoma and Ewing’s Sarcoma. Of the totalof 42 patients, there were 5 deaths, 4 due to disease progression and one due
to clinical complications. With the group, the discussions were carried out,
allowing us to analyze that the presence of the Radiotherapy, Neurosurgery
and Pathology team from the first moment, optimized the beginning of treatment and increased the patients’ survival.
EPID-06. DIAGNOSTIC INTERVAL TIME OF PEDIATRIC CNS
TUMORS: A REPORT OF THE CANCER IN YOUNG PEOPLE IN
CANADA (CYP-C) DATABASE
Mohammad AlNajjar1, Divya Goel1, Valerie Larouche2, Craig Erker3,
Sylvia Cheng4, Randy Barber5, Douglas Strother1, Lillian Sung6, andLucie Lafay-Cousin1; 1Alberta Children’s Hospital, Calgary, AB, Canada,
2Centre Hospitalier Universitaire de Quebec, Quebec City, QC, Canada,
3IWK Health Centre, Halifax, Nova Scotia, Canada, 4BC Children ‘s
Hospital, Vancouver, BC, Canada, 5C17 Council, Edmonton, AB, Canada,
6Hospital for Sick Children, Toronto, ON, Canada
INTRODUCTION: CNS tumors are the second most common neoplasm
in children and have historically been associated with longer time to diagnosis. Data on the time-to-diagnosis for Canadian children with CNS tumors

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are limited and outdated. We aimed at evaluating the diagnostic intervaltime(DIT) for Canadian children, and identifying factors possibly associatedwith prolonged DIT. METHODS: Using the CYP-C database, we analyzed
data from children <15 years, diagnosed with CNS tumors between 2001–
2015. DIT was defined as time in weeks, elapsed from the first contact with ahealthcare provider to confirming diagnosis. We described DIT according topatient’s demographics, socioeconomic, geographic factors as well as tumorrelated criteria. RESULTS: Patients from all Canadian provinces, except
Ontario, had available timepoints to calculate DIT. The cohort included 842
patients. Mean DIT for all patients was 11.7 weeks(median 1.4). Gliomas
had the longest mean DIT and embryonal tumors had the shortest(14.6 and3.6 weeks p<0.01). ATRT and medulloblastoma had a mean DIT of 1.3
and 4.3 weeks respectively. DIT for HGG was shorter than for LGG (6.4
versus 16.1 weeks, p<0.01). Metastatic disease, infratentorial tumors, or age£36 months had significantly shorter DIT (5.6 vs 12.4 vs 18.4, 7.4 vs 13.1
and 8.6). Sex, annual income(QAIPPE), and distance from tertiary centerdid not influence DIT. CONCLUSION: The current diagnostic interval time
for pediatric CNS tumors in Canada is 11.7 weeks(median 1.4weeks). These
results only reflect the healthcare system’s contribution toward diagnosis
confirmation, but not the patient interval before seeking medical attention.
EPID-07. A GLOBAL PERSPECTIVE ON THE BURDEN OFPEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Daniel Moreira, Ibrahim Qaddoumi, Nickhill Bhakta, Amar Gajjar,
and Carlos Rodriguez-Galindo; St. Jude Children’s Research Hospital,
Memphis, TN, USA
Although approximately 90% of pediatric cancer cases exist in low- andmiddle-income countries, the magnitude of the global burden of pediatric central nervous system (CNS) tumors remains poorly quantified.
METHODS: Data from International Incidence of Childhood Cancer-3
and CONCORD-3, which include observed incidence and survival from
population-based cancer registries (PBCR), and from GLOBOCAN 2018
and Global Burden of Disease 2016, which produce burden estimates fromobserved and modelled data, were used to analyze epidemiologic characteristics and correlations for CNS tumors globally. Data from The WorldBank were used for national macroeconomic variables. RESULTS: The majority of countries are not covered by PBCR, with information on incidence
and survival available for 37% and 27% of countries, respectively. Survival
data is not available for any low-income country. The incidence of CNS
tumors varies markedly, from 0.4 to 49 x106 person-years, the greatest variability in pediatric cancer subgroups. Modelled data suggests that approximately 40,000 incident cases and 19,000 deaths occur from CNS tumors
worldwide. When country-level data are segregated based on World Bank
groups, a difference in incidence and survival exists (p<0.05). A higher national health expenditure correlates with both an increased incidence andsurvival of CNS tumors, while the inverse is true for under-5 mortality(p<0.05). CONCLUSIONS: Scarce facts are available, but this analysis establishes a link between national income and epidemiologic parameters for
CNS tumors. In this context, carefully designed initiatives, focusing on ahealth-systems approach are critical to meet the global challenge of pediatric CNS tumors.
EPID-08. FINDING THE NEEDLE IN THE HAY STACK –POPULATION-BASED STUDY OF PREDIAGNOSTIC SYMPTOMATIC
INTERVAL IN CHILDREN WITH CNS TUMORS
Clare Lambert1, Ran Goldman1, Douglas Cochrane2, Anita Dahiya1,
Heidi Mah1, Arsh Buttar1, and Sylvia Cheng3; 1The Pediatric Researchin Emergency Therapeutics (PRETx) Program, Department of Pediatrics,
University of British Columbia, BC Children’s Research Institute,
Vancouver, BC, Canada, 2Division of Pediatric Neurosurgery, Departmentof Surgery, University of British Columbia, BC Children’s ResearchInstitute, Vancouver, BC, Canada, 3Division of Hematology/Oncology/
BMT, Department of Pediatrics, University of British Columbia, BCChildren’s Research Institute, Vancouver, BC, Canada
PURPOSE: Delay in diagnosis of central nervous system (CNS) tumors inchildren is well documented. The aims of this study were to characterize thesymptomatology of CNS tumors and the time to diagnosis in a large pediatric hospital in Canada. METHODS: Retrospective chart review of children diagnosed with a CNS tumor between 2000 and 2016 in Vancouver,
British Columbia, Canada was performed. Data collected included demographics, symptomatology, tumor type, age at diagnosis, known visits tohealthcare professionals, neuroimaging, therapy and post treatment relapse
or progression. RESULTS: 148 children with complete medical records
were reviewed. The average age at diagnosis was 87.8 months (standard
deviation (SD) = 59.7; median = 72). 50.7% of patients had posterior
fossa tumors and 49.3% had supratentorial tumors. 30% of patients werediagnosed after a single visit to a health care provider. 7.7% of children
needed more than 4 visits. Median total time to diagnosis (PSI) was 62 days
(range = 0-2047 days). The longest prediagnostic interval was first symptom

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onset to first healthcare provider visit (PSI1, median 37 days). Patients withposterior fossa tumors, presence of metastases, and symptoms of ataxia andparesis were associated with shorter PSI. CONCLUSIONS: CNS tumors inchildren continue to pose a diagnostic challenge with significant variability
in time to diagnosis. Our population-based study found that median timefrom symptoms to seeking medical advice by parents was over a month. It isessential to uncover the reasons for delay and address them where possible.
EPID-09. THE INCIDENCE OF PRIMARY BRAIN TUMORS IN
CHILDREN IN JAPAN BASED ON 2016 NATIONAL CANCERREGISTRY IN JAPANYuko Watanabe1, Yoshitaka Narita2, and Takamasa Kayama3; 1Departmentof Pediatric Oncology, National Cancer Center, Tokyo, Japan, 2Departmentof Neurosurgery and Neuro-Oncology, National Cancer Center, Tokyo,
Japan, 3Department of Advanced Medicine Yamagata University School of
Medicine, Yamagata, JapanThe national cancer registries began in January 2016 and the actual
number of cancer patients in 2016 including primary brain tumors inJapan was released as a preliminary report in January 2019. According to
the report, 667 incidence of pediatric brain tumors were reported in aged
0–14 years (boy: 382; girl: 285), of them 537 patients underwent surgery,chemotherapy, or radiation therapy (diagnosis: 516, undiagnosed: 21), and
130 patients were followed up without any treatments. The breakdown oftumor types was 279 Neuroepithelial tumors, 73 Embryonal tumors (61Medulloblastomas), and 63 Germ Cell Tumors (GCTs). The crude rate per
100,000 population in 2016 was 4.23 for all pediatric brain tumors, 1.77
for Neuroepithelial tumor, 0.39 for Medulloblastoma, and 0.40 for GCTs. In
comparison, the United States CBTRUS2019 (2012–2016) reported that theage-adjusted incidence rates per 100,000 population in the United States was
5.74 for all pediatric brain tumors, 4.15 for Neuroepithelial tumors, 0.48 forMedulloblastoma, and 0.22 for GCTs. The age-adjusted incidence in Japan
based on the US population in 2000 was 4.21 for all pediatric brain tumors,
Neuroepithelial tumor 1.77, Medulloblastoma 0.39, and GCTs 0.39, suggesting that the incidence of Neuroepithelial tumor and Medulloblastoma
is lower whereas that of GCTs is approximately twice comparing to the US.
By taking advantage of the national cancer registry data, which was publicly
opened to researchers in 2019, we report the incidence of primary brain tumors and its comparison worldwide based on the re-classification criteria ofprimary brain tumors including benign tumor.
EPID-10. EPIDEMIOLOGY STUDY OF UNCOMMON CHILDHOOD
BRAIN TUMOURS IN ASIAN CHILDREN
Godfrey Chi-Fung Chan1,2, Anthony Pak-Yin Liu2,
Matthew Ming-Kong Shing1, Dennis Tak-Noi Ku3; 1Hong Kong Children’s
Hospital, Hong Kong, China, 2The University of Hong Kong, Hong Kong,
China, 3Hong Kong Children’s Hospital, Hong Kong, China
Our local registry identified 656 brain tumours from Jan 1999 to Dec 2018,(incidence: 29.8/yr/million). Other from Glioma, Medulloblastoma/PNET,
Germ Cell tumours, Ependymoma, the remaining rarer tumours accounted for
18% (n=118). The 7 more common groups are: craniopharyngioma(n=28);
ATRT(n=18); choroid plexus papilloma/CA(n=12); Ganglioglioma(n=11);
ETMR(n=7); DNET(n=7); meningioma(n=6). Their respective incidences are
1.27; 0.81; 0.55; 0.5; 0.32; 0.32 0.27/yr/million. For craniopharyngioma,
M:F=15:13 and median age was 7.4yrs (2mons-16.5yrs). 12/28 children had
surgery alone and 13/28 had focal RT post-surgery with better outcome.
3 underwent intra-cystic interferon-beta also stable. For ATRT, M:F=7:8
and median age was 2.3yrs (4mos-14.2yrs). 2 had metastatic disease and7/18 patients remained alive. For choroid plexus tumours, there were 7
papilloma, 2 atypia and 3 carcinoma. M:F=5:6 and median age was 1.5yrs(4mos-14yrs). All papilloma, 1/2 atypia and 1/3 carcinoma survived. For
ganglioglioma, M:F=7:4 with median age of 5.5yrs (5mos-13.2yrs). They
commonly presented with seizure and only one died (brainstem primary).
The ETMR includes ependymoblastoma and medulloepithelioma, they had
quite different clinical characteristics and outcome. 6/7 DNET had convulsion and M:F=6:1. Median age was 11.5yrs (2.66-14yrs). They all survived
even if incompletely resected. For meningioma, 1/6 had germline mutationof NF-2 gene. M:F=3:3 and onset was >8yrs except the NF-2 patient. All
survived but the NF-2 had multiple recurrences. 4 patients developed secondary meningioma due to irradiation but they were >18yrs so excluded. In
summary, rarer forms of childhood brain tumours only accounted for <20%of all brain tumours and they had diverse presenting features and outcome.
EPID-11. ESTABLISHING A BASELINE TIME-FRAME FOR SYMPTOM
ONSET TO DEFINITIVE DIAGNOSIS FOR CHILDREN WITH
NEWLY-DIAGNOSED CNS TUMORS: AN EXPANDED, MULTIINSTITUTIONAL COLLABORATIVE STUDY
Eamon Eccles1, Yan Han1, Hao Liu1, David Walker2, Sarah Rush3,
Jonathan Finlay4, and Scott Coven1,5; 1Indiana University School ofAbstracts

Medicine, Indianapolis, IN, USA, 2University of Nottingham, Nottingham,
United Kingdom, 3Akron Children’s Hospital, Akron, OH, USA,
4Nationwide Children’s Hospital, Columbus, OH, USA, 5Riley Hospital forChildren, Indianapolis, IN, USA
BACKGROUND: We have previously documented the presence of diagnostic delays in children with central nervous system (CNS) tumors in the
United States. This study serves to expand and validate the previously established baseline from symptom onset to definitive diagnosis in children with
newly-diagnosed CNS tumors. DESIGN: The medical records of children
with newly-diagnosed CNS tumors were retrospectively reviewed from January 2004 to December 2017 at Nationwide Children’s Hospital, Akron
Children’s Hospital and Riley Hospital for Children at IU Health. Records
were reviewed for age, gender, tumor type, presenting symptoms, number ofhealthcare visits prior to diagnosis, time interval (in months) from onset ofsymptoms to definitive diagnosis and any associated genetic syndromes. RESULTS: Of the 768 patients with newly-diagnosed CNS tumors, the median time interval from symptom onset to definitive diagnosis was 40.5 days
while the mean symptom interval was 144 days (range < 1 to 5,475 days).
The median age of diagnosis was 7 years, with a male predominance (57%).
This expanded cohort continues to reveal that pediatric brain tumor patients most often seek care at the primary care level, although many patientswere seen in various multiple subspecialty clinics prior to diagnosis. CONCLUSIONS: This multi-institutional cohort study updates our previously
documented single state time interval and provides a consistent Midwest“benchmark” to improve awareness for children with brain tumors throughthe adaptation of the UK ‘HeadSmart,’ now renamed ‘BrainFirst.’ Additionally, future work could include a prospective registry to better examine potential risk factors for delays in diagnosis.
EPID-12. TEMPORAL AND GLOBAL GEOGRAPHIC VARIATION IN
THE INCIDENCE OF PEDIATRIC CNS TUMORS, 1998–2012
Karina Ribeiro1,2, and Sidnei Epelman1; 1Santa Marcelina Hospital,
Department of Pediatric Oncology, Sao Paulo, SP, Brazil, 2Faculdade deCiencias Medicas da Santa Casa de Sao Paulo, Department of Collective
Health, Sao Paulo, SP, Brazil
AIMS: To describe the temporal and geographic variation in the incidence of pediatric CNS malignancies worldwide, presenting analyses
by sex, period, region, and histological subtype between 1998 and 2012.
METHODS: Data were extracted from volumes IX to XI of the Cancer
Incidence in 5 Continents, covering the periods 1998–2002 (1), 2003–2007(2), and 2008–2012 (3). We pooled data from 44 countries, classifying
them into 6 regions (Africa (AF), Asia (AS), Oceania (O), Europe (E), Central/South America (CSA), North America (NA)). Age-standardized incidence rates (ASIR per million, 0–19 years) were calculated and temporalvariation was evaluated using incidence rate ratios (IRR) (95% CI). RESULTS: The highest incidence (Period 3) was observed in NA (34.0 and
30.2 for males and females, respectively). Astrocytic tumors were predominant in all regions, with percentages ranging between 24.5% (E, females)
and 45.6% (NA, females). Increasing trends (Period 3 x 1) were observedin AS (IRR=1.15, 95% CI 1.06–1.25), CSA (IRR=1.25, 95% CI 1.01–1.55),
and NA (IRR=1.05, 95% CI 1.03–1.07), for males and in AS (IRR=1.15,
95% CI 1.05–1.26) and NA (IRR=1.08, 95% CI 1.06–1.11) for females.
Geographic discrepancies in time-trends were observed for astrocytomas,
ependymomas, medulloblastomas, other embryonal tumors, and other specified tumors. Reductions in the incidence of unspecified tumors from period
1 to 3 were noted in E, AS, and NA, ranging from -20% (E, females) to -66%
(AS, females). CONCLUSIONS: Heterogeneous trends and improvement in
the registration of histological types were noted. Geographic variation canhelp to raise hypotheses to investigate etiologic factors.
EPID-13. A POPULATION-BASED ANALYSIS OF CNS TUMORDIAGNOSES, TREATMENT, AND SURVIVAL IN CONGENITAL AND
INFANT AGE GROUPS
Muriel Hart1,2, Amy Mellies3, Alina Beltrami1,2, Ahmed Gilani1,4, andAdam Green3,5; 1Morgan Adams Foundation Pediatric Brain Tumor
Research Program, Aurora, CO, USA, 2Biomedical Sciences Program,
University of Denver, Denver, CO, USA, 3University of Colorado Cancer
Center, Aurora, CO, USA, 4Department of Pathology, University ofColorado School of Medicine and Children’s Hospital Colorado, Aurora,
CO, USA, 5Morgan Adams Foundation Pediatric Brain Tumor Research
Program, Department of Pediatrics, University of Colorado School of
Medicine and Children’s Hospital Colorado, Aurora, CO, USA
BACKGROUND: Congenital (<3 months) and infant (3 to 11 months)
brain tumors are biologically different from tumors in older children, but epidemiology of these tumors has not been studied comprehensively. Insight into
epidemiological differences could help tailor treatment recommendations by
age and increase overall survival (OS). METHODS: Population-based datafrom the SEER 18 registries was obtained for 14,493 0-19-year-olds diag-

nosed with CNS tumors between 1990 and 2015. Incidence, treatment, andsurvival were analyzed using Chi-square and Kaplan-Meier analyses. RESULTS: Between the <3 month, 3–5 month, 6–11 month, and 1–19 year age
groups, tumor type distribution differed significantly (p<0.001); high-grade
glioma (HGG) was most common in the <3-month-olds, while low-grade
glioma (LGG) was most common in the other groups. 5-year OS for all tumors was 36.7% (<3 months), 56.0% (<3–5 months), 63.8% (6–11 months),
and 74.7% (1–19 years) (log rank p<0.001). OS by tumor type was worst
for <3-month-olds with LGG, medulloblastoma, and other embryonal tumors; OS was worst for 3-5-month-olds with ependymoma, <1-year-olds
collectively with atypical teratoid-rhabdoid tumor, and 1-19-year-olds with
HGG (log rank p<0.02 for all tumor types). <3-month-olds were least likely
to receive any treatment for each tumor type and least likely to undergo
surgery for all except HGG. <1-year-olds were far less likely than 1-19-yearolds to undergo radiation for embryonal tumors, as expected, but were alsoless likely to undergo chemotherapy. CONCLUSIONS: Congenital/infant
CNS tumors differ pathologically, therapeutically, and prognostically fromthose in older children. Treatment changes could help address poorer outcomes for these young patients.
EPID-14. GABRIELLA MILLER KIDS FIRST DATA RESOURCECENTER: COLLABORATIVE PLATFORMS FOR ACCELERATINGRESEARCH IN PEDIATRIC CANCERS & STRUCTURAL BIRTH
DEFECTS
Allison P. Heath PhD1, Yuankun Zhu BS1, Michele Mattioni PhD2,
Bailey Farrow BS1, Jena Lilly MS1, Yiran Guo PhD1, Jo Lynne Rokita PhD1,
Phillip B. Storm MD1,3, Samuel L. Volchenboum MD, PhD4,5,
Javad Nazarian PhD6, Nicole Vasilevsky PhD7, Jack DiGiovanna PhD2,
Melissa Haendel PhD7,8, Robert L Grossman4,
Brandi Davis-Dusenbery PhD2, Deanne M. Taylor PhD1,9,
Vincent Ferretti PhD10,11, and Adam Resnick PhD1,3; 1Children’s Hospitalof Philadelphia, Philadelphia, PA, USA, 2Seven Bridges Genomics,
Cambridge, MA, USA, 3Department of Neurosurgery, Perelman Schoolof Medicine, University of Pennsylvania, Philadelphia, PA, USA, 4Center
for Research Informatics, The University of Chicago, Chicago, IL, USA,
5Department of Pediatrics, Biological Sciences Division, The Universityof Chicago, Chicago, IL, USA, 6Children’s National Medical Center,
Washington, DC, USA, 7Oregon Health & Science University, Portland,
OR, USA, 8Oregon State University, Corvallis, OR, USA, 9Departmentof Pediatrics, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA, USA, 10Ontario Institute of Cancer Research, Toronto,
ON, Canada, 11CHU Sainte-Justine Research Center, Montreal, QC,
CanadaSince launching to the public in September 2018, the Gabriella Miller
Kids First Data Resource Center (DRC) has made an increasing number ofpediatric genomic studies available to the research community. Currently,
1.3 PBs of genomic and clinical data drawn from 12,000 participants areavailable across a variety of pediatric cancer and structural birth defectstudies. The DRC has architected a secure, cloud-based platform with over
1,300 users that supports the ability of researchers to not only find, access,and reuse data, but also integrate, collaborate, and analyze data quickly at
scale. Users can use integrations with platforms such as Cavatica for bioinformatics workflows and PedcBioPortal for cancer genomic visualizations.
Additionally, a set of framework services, powered by Gen3, provide a foundation for interoperability with other large-scale data sources, platforms,
and a growing ecosystem of analysis and visualization applications. These
integrations allow users to search across both TARGET and Kids First clinical data in one location while allowing data governance to be maintainedby the original approvers. The new “explore data” feature allows users tosearch across all studies in order to identify virtual cohorts. Within the
portal, these cohorts can be saved and shared with collaborators for iterativerefinement and analysis. With appropriate approvals, the associated genomic
data can be accessed and analyzed seamlessly in Cavatica or other platforms
with interoperable framework services. Additionally, gene searching capabilities will be available in 2020. Data is free to download and cloud credits areavailable for analysis support.
EPID-15. THE INTERNATIONAL DIFFUSE INTRINSIC PONTINEGLIOMA (DIPG)/DIFFUSE MIDLINE GLIOMA (DMG) REGISTRYAND REPOSITORY (IDIPGR) EXPANSIONMarianne Torontali, Renee Doughman, Brooklyn Chaney, Katie Black,
Anthony Asher, Andrew Rupert, Christine Fuller, James Leach, Blaise Jones,
Maryam Fouladi, and Mariko DeWire; Cincinnati Children’s Hospital
Medical Center, Cincinnati, OH, USA
Established in April 2012, the mission of the IDIPGR is to provide secure integrated data sets including clinical, pathologic, radiologic and molecular genomics to the research community to promote hypothesis driven
research. Over 600 data points per patient are securely stored on a CCHMC
constructed web resource and domain using the open-source data mart

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development framework Harvest (PMID:24303304) (‘Links’). Genomic
data is stored in the cloud-enabled VIVA platform and accessed throughcross-platform integration and standardization algorithms for comparison
across datasets. Features include source identification, data wrangling, andstandardization of molecular and phenotypic data (2017), a web-enableddata mart that provides phenotype-genotype query/exploration, along with
raw and processed data file downloads to authorized investigators (Harvest, 2017), additional tools for filtering and analysis of genomic datasetsat the level of a phenotype, sample, gene, and variant (VIVA, 2017–2018),
and uploaded digitized slides (Aperio, 2019). The IDIPGR Repository stores
abstracted datasets for >1020 patients with DIPG/DMG, of whom 366
have tumor tissue available through biopsy and/or autopsy, and centrally reviewed and digitized specimens from 124 patients. The Repository contains>5000 radiology studies from >700 patients, with >550 patients centrally
reviewed, and genomics data from 80 patients. Currently 27 IDIPGR approved projects utilize these datasets. The DIPG/DMG Registry constructeda robust database platform and integration system that provides the infrastructure to promote highly collaborative, international, hypothesis-driven
research. Broadening collaboration among investigators for hypothesisdriven research studies will lead to better classification and more effective
treatment of patients with DIPG and DMG.
EPID-16. INTEGRATION OF EHR AND CANCER REGISTRYDATA TO CONSTRUCT A PEDIATRIC NEURO-ONCOLOGYSURVIVORSHIP COHORT AND IMPROVE LONG-TERM
FOLLOW-UP CAREDavid Noyd, Claire Howell, Kevin Oeffinger, Daniel Landi, andKristin Schroeder; Duke University Medical Center, Durham, NC, USA
BACKGROUND: Pediatric neuro-oncology (PNO) survivors suffer
long-term physical and neurocognitive morbidity. Comprehensive care addressing late effects of brain tumors and treatment in these patients is important. Clinical guidelines offer a framework for evaluating late effects,
yet lack of extended follow-up is a significant barrier. The electronic healthrecord (EHR) allows novel and impactful opportunities to construct, maintain, and leverage survivorship cohorts for health care delivery and as a platform for research. METHODS: This survivorship cohort includes all PNO
cases ≤18-years-old reported to the state-mandated cancer registry by our institution. Data mining of the EHR for exposures, demographic, and clinicaldata identified patients with lack of extended follow-up (>1000 days sincelast visit). Explanatory variables included age, race/ethnicity, and language.
Primary outcome included date of last clinic visit. RESULTS: Between January 1, 2013 and December 31, 2018, there were 324 PNO patients reported to our institutional registry with ongoing analysis to identify the
specific survivorship cohort. Thirty patients died with an overall mortality of
9.3%. Two-hundred-and-sixteen patients were seen in PNO clinic, of which
18.5%% (n=40) did not receive extended follow-up. Patients without extended follow-up were an average of 3.5 years older up (p<0.01); however,there was no significant difference in preferred language (p=0.97) or race/
ethnicity (p=0.57). CONCLUSION: Integration of EHR and cancer registrydata represents a feasible, timely, and novel approach to construct a PNO
survivorship cohort to identify and re-engage patients without extended
follow-up. Future applications include analysis of exposures and complications during therapy on late effects outcomes.
EPID-17. A SINGLE INSTITUTE EXPERIENCE IN THE
REGISTRATION STUDY OF PEDIATRIC SOLID TUMOR IN JAPANCHILDREN’S CANCER GROUP
Keiko Furukawa1, Yohei Mineharu2, and Yoshiki Arakawa3; 1Kyoto
University Hospital Cancer Center, Kyoto City, Kyoto Pref., Japan,
2Department of Neurosurgery, Kyoto University Graduate School of
Medicine, Kyoto City, Kyoto Pref, Japan, 3Department of Neurosurgery,
Kyoto University Graduate School of Medicine, Kyoto City, Kyoto Pref.,Japan
A larger scale prospective registration study has been conducted nationwide in Japan since 2011, called as “registration study in pediatric solid
tumor”, in Japan Children’s Cancer Group (JCCG). In this study, clinicaldata and surgical specimen are collected into the National Center for Child
Health. Kyoto University Hospital has participated in this study since IRB
approval in 2011. We reviewed our registered patients to the registration
study and assessed the current status. 40 patients with pediatric brain tumors participated in this study from 2011 to 2020. There were 13 intracranial germ cell tumors, 9 medulloblastomas, 6 gliomas in 4 diffuse midline
gliomas, 4 pilocytic astrocytoma, and 4 other types of tumor. The informed
consent was obtained from 36 patients by pediatricians and 3 patients byneurosurgeons. Twenty-five surgical specimens were collected for central review. The reasons of no surgical specimens were nonsurgical managementin 6 patients and no enough FFPE sample in 3 patients. There was no discrepancy between central review and institutional diagnosis. The status ofclinical data entry was complete in 13 patients and uncomplete in 9 patients.

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These registration data including pathological diagnosis, molecular diagnosis, treatment, clinical information in patients with pediatric brain tumor
are very important to realize current status. To conduct this study certainly,
the collaboration among pediatrician, neurosurgeon, and supporting staff
should be needed in collecting specimens and clinical data.
EPID-18. TRENDS IN INCIDENCE AND SURVIVAL OF MALIGNANT
PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS IN THE
NETHERLANDS
Raoull Hoogendijk1, Jasper van der Lugt1, Dannis van Vuurden1,
Eelco Hoving1, Leontien Kremer1,2, Pieter Wesseling1,3, andHenrike Karim-Kos1,4; 1Princess Máxima Center for Pediatric Oncology,
Utrecht, Netherlands, 2Amsterdam University Medical Centers/EmmaChildren’s Hospital/AMC, Amsterdam, Netherlands, 3Amsterdam
University Medical Centers/VUmc, Amsterdam, Netherlands, 4Netherlands
Comprehensive Cancer Organisation (IKNL), Utrecht, Netherlands
BACKGROUND: Variation in survival of pediatric central nervous
system (CNS) tumors is large between countries. Within Europe, the Netherlands had one of the worst reported survival rates of malignant CNS(mCNS) tumors during 2000–2007. METHODS: Using the Netherlands
Cancer Registry, we evaluated trends in incidence and survival of pediatricmCNS tumors (behavior /3, 5th digit in the morphology code) diagnosed
between 1990–2017. RESULTS: 839 newly-diagnosed mCNS tumor patients <18 years were registered between 1990–2017. Incidence of mCNS
tumors remained stable (average incidence rate, 21.6 per million personyears). However, an increased incidence of malignant gliomas, NOS was
found (Estimated Annual Percentage Change (EAPC) 11.6% p<0.001). Thisappears to be related to a registration shift between 1990–1999 and 2000–
2009 as brainstem tumors increased (+25%, n=79) for astrocytomas andother gliomas but decreased (-31%, n=32) for unspecified intracranial andintraspinal neoplasms. Overall, 5-year observed survival (5Y-OS) of mCNS
tumors increased from 51% in 1990–1999 to 61% in 2010–2017 (P-fortrend<0.001). This increase was not constant over time, as 5Y-OS for theperiod 2000–2009 was 47%. The only significant decrease in survival was
found for malignant astrocytomas and other gliomas with a 5Y-OS of 56%
in 1990–1999 decreasing to 48% in 2010–2017 (P-for-trend<0.001). CONCLUSION: Between 1990–2017 incidence of mCNS tumors in the Netherlands remained stable and survival increased. However, a decrease insurvival was seen for malignant astrocytomas and other gliomas, which ispartially explained by the registration shift of brainstem tumors. The impactof this shift on survival for all mCNS tumors is subject to further research.

ETMR AND OTHER EMBRYONAL TUMORSETMR-01. TREATMENT OUTCOME OF TWO CASES WITH HIGHGRADE NEUROEPITHELIAL TUMOR WITH BCOR ALTERATION
Ines Kristensen1, Louise Lindholt Hansen1, Torben Stamm Mikkelsen1,
Louise Tram Henriksen1, Benedicte Parm Uldhøi2, Gorm von Oettingen3,
Søren Cortnum3, and Yasmin Lassen-Ramshad4; 1Pediatric Department,
Aarhus University Hospital, Aarhus, Denmark, 2, Aarhus University
Hospital, Aarhus, Denmark, 3Department of Neurosurgery, Aarhus
University Hospital, Aarhus, Denmark, 4Danish Centre for Particle
Therapy, Aarhus, Denmark
INTRODUCTION: High grade neuroepithelial tumor with BCOR
exon 15 internal tandem duplication (HGNET BCOR) is a recently described tumor entity of the central nervous system (CNS) with a distinct
methylation profile and characteristic genetic alteration. We report the outcome of two cases after 1st line multimodality therapy. MATERIAL AND
METHOD: A 7 year old girl with a ventricular tumour and a 6 year old
boy with a tumour in the occipital region with infiltration of the transverseand sigmoid sinus were both diagnosed based on histology and methylation with HGNET-BCOR. No spinal or liquor dissemination were foundat diagnosis in both cases. Treatment consisted of radical resection of thetumour. In the case of the lesion with sinus infiltration residual tumourin the vessel could not be removed. Both children were postoperatively
treated with radiotherapy (craniospinal 36 Gy and boost to 54 Gy), concomitant Vincristin and adjuvant Cisplatin, Lomustine and Vincristine. RESULTS: The girl developed a local recurrence at the primary tumour site
18 months after diagnosis. Reoperation showed the same histology. Start of
2nd line chemotherapy with Temozolomid and Irinotecan is being discussed.
The boy with sinus infiltration developed seven months after diagnosis
multiple liver, lung and bone metastasis. Biopsy of a liver lesion showed
HGNET-BCOR. He was treated with Temozolomid, Irinotecan and diednine months after diagnosis. CONCLUSION: We report two cases with
failure after 1st line treatment for HGNET-BCOR. To our knowledge
HGNET-BCOR with development of hematological disease dissemination
is a rare finding.

Abstracts

ETMR-02. NOVEL CIC-LEUTX FUSION IN CNS EMBRYONALTUMOR: A CASE REPORT AND REVIEW OF THE LITERATURE
Wanming Hu1, Juan Wang1, Xing Zhang2,3, Yuhang Ji2,3, Chao Song2,3,
and Xiaofei Sun1; 1Sun Yat-sen University Cancer Center, Guangzhou,
Guangdong, China, 2Jiangsu Simcere Diagnostics Co, Ltd., Nanjing,
Jiangsu, China, 3Jiangsu Simcere Pharmaceutical Co, Ltd., The State Key
Laboratory of Translational Medicine and Innovative Drug Development,
Nanjing, Jiangsu, China
INTRODUCTION: Central nervous system (CNS) embryonal
tumor is a group of rare, poorly differentiated neuroepithelial malignant neoplasm predominantly occurs in pediatrics. Herein, we firstly
report a CNS embryonal tumor harboring pathogenic CIC-LEUTX fusion. METHODS: Immunohistochemistry (IHC), Fluorescence in Situ Hybridization (FISH) and Next Generation sequencing (NGS). RESULTS: A
2-year-old male was found to have solid and cystic mass in left temporallobe-basal ganglia and left parietal lobe (maximum diameter=75mm). The
pathological diagnosis was CNS embryonal tumor (NEC) after totally resection. The tumor was poorly differentiated embryonal neoplasms ofneuroectodermal origin that lacked the specific features and rosettes. IHC
showed Syn was strongly/diffusely positive and Ki67 proliferation index
was high (50%+), and copy number at the 19q13.42 C19MC locus showedno alterations. NGS showed pathogenic mutations including a brand new
CIC-LEUTX fusion, heterozygous germline NBN c.C127T mutation andsomatic TSC2 c.G2714A mutation. One month after operation, intracranial tumor recurred (maximum diameter=55mm) and spinal cord implantation metastasis occurred, and then the patient received chemotherapy(CTX+CBP+VCR/DDP+VP-16) and had significant improvement in symptoms and tumor shrinkage (maximum diameter=31mm). Literature review
revealed CIC fusion predominantly presented in sarcomas, such as CICNUTM1 fusion in rare CNS sarcoma, CIC-LEUTX fusion in epithelioid
angiosarcoma and CIC-DUX4 fusion in Ewing-like sarcoma. Hitherto, apartfrom this case, there were only two cases which had CIC-LEUTX fusion
in CNS, including a case of CNS angiosarcoma and a case of anaplastic
ganglioglioma. CONCLUSIONS: We firstly found a specific new type in
CNS embryonal tumor with distinct molecular-pathological characteristicsof CIC-LEUTX fusion.
ETMR-03. THE ROLE OF FOXR2 IN PEDIATRIC BRAIN CANCER
Felix Schmitt-Hoffner1,2, Sjoerd van Rijn1,2, Jens-Martin Hübner1,2,
Sander Lambo1,2, Monika Mauermann1,2, Norman Mack1,2,
Benjamin Schwalm1,2, Stefan Pfister1,2, and Marcel Kool1,2; 1HoppChildren’s Cancer Center Heidelberg (KiTZ), Heidelberg, BW, Germany,
2German Cancer Research Center (DKFZ), Heidelberg, BW, Germany
Forkhead Box R2 (FOXR2) is a transcription factor of the Forkhead Box
family that has been correlated with tumorigenesis, aberrant cell growthor tumor progression. Expression of FOXR2 in pediatric brain tumors is,
besides in subsets of medullo-, pineo- and glioblastoma, primarily present
in CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2), a
novel entity that we in 2016 identified from the former class of primitive
neuroectodermal tumors of the central nervous system (CNS-PNET). Analyzing CNS-NB-FOXR2 tumors we found that FOXR2 mRNA is expressedin an anti-correlative manner compared to the proto-oncogenes MYC and
MYCN. With immunoprecipitation analyses we show that FOXR2 binds to
MYC and MYCN and is thereby stabilizing these proteins. These observations on the interaction and the anti-correlative manner suggest that FOXR2
and MYC(N) may drive tumor formation in a molecularly similar fashion.
To investigate this further we stably expressed FOXR2, MYCN and MYC
and a combination of FOXR2 with MYC(N) in human neural stem cells(hNSC) and injected these in the striatum of NSG mice. We could show thathNSC itself do not from a tumor, whereas the expression of FOXR2 and/or
MYC(N) in hNSC results in tumorigenesis. Tumors expressing both, FOXR2
and MYC(N) were growing faster than tumors with FOXR2 alone. In addition, tumors are currently being analyzed by ChIP-sequencing for FOXR2,
MYC, and MYCN, to better understand the mechanisms how FOXR2 drives
tumor formation compared to its interaction partners MYC and MYCN.
ETMR-04. EMBRYONAL TUMOR WITH MULTILAYEREDROSETTES: THE MD ANDERSON CANCER CENTER EXPERIENCE
Sumit Gupta, Dristhi Ragoonanan, Nelda Itzep, David Sandberg,
Greg Fuller, Leena Ketonen, Heather Meador, Wafik Zaky, andSoumen Khatua; MD Anderson Cancer Center, Houston, TX, USA
BACKGROUND: Embryonal Tumor with Multilayered Rosettes(ETMR) are rare tumors that are molecularly diagnosed by C19MC amplification. Rarity of this tumor has precluded profiling uniform therapeuticstrategy. METHODS: Retrospective review after institutional approval,
identified 10 pediatric case of ETMR, treated at MD Anderson Cancer
Center during the period of 2005 to 2019. RESULTS: Median age of at diagnosis was 4.6 years. Tumor sites include frontal or parietal lobes (3), spine(3) and posterior fossa involving the brainstem (4). All patients received a
combination of chemotherapy and radiation. 4 patients had metastasis at
the presentation. 9 patients received focal radiation but only 6 of them received Craniospinal irradiation (CSI). Average dose of radiation was 50 Gy.
Surgical resection was performed in all cases except the brainstem tumors.
7 children had recurrence including all the patients with metastasis at diagnosis (median time: 9.4 months), 1 passed away secondary to hemorrhage
in brainstem and data was not available for 2 patients. 5/6 patients who received CSI had recurrence. CONCLUSIONS: To-date no well-defined treatment regimens exists for these neoplasms, resulting in poor overall survival.
Preclinical drug screen have shown the efficacy of topotecan, actinomycin D,
and volasertib as potential new therapeutic candidates, though this has nottranslated successfully into the clinical arena. Given the limited success withcurrent conventional therapeutic methods, molecular interrogation in addition to histopathological diagnosis are essential upfront, as it could provide
clues to targeted therapy. Defining molecularly-based treatment with lesstoxicities and increased survival are warranted.
ETMR-05. SINGLE-CELL RNA-SEQ OF ETMR REVEALS CELLPROGRAMS OF DEVELOPMENTAL HIERARCHY AND CELLULAR
DIVERSITY IN THE TUMOR MICROENVIRONMENT
Flavia W. de Faria1,2, Marta Interlandi2,3, Natalia Moreno2, Monika Graf2,
Viktoria Melcher2, Thomas K. Albert2, and Kornelius Kerl2; 1Departmentof Pediatric Hematology and Oncology, Hospital da Criança de Brasilia,
Brasilia, DF, Brazil, 2Department of Pediatric Hematology and Oncology,
University Children’s Hospital Münster, Münster, NW, Germany, 3Instituteof Medical Informatics, Westphalian Wilhelms-University Münster,
Münster, Germany
Embryonal tumors with multilayered rosettes (ETMR) are deadly brain
malignancies affecting young children. No standard treatment is available
and the median survival is less than 12 months. Molecularly, the disease
is characterized by the miRNA C19MC cluster amplification, with the expression of multiples miRNAs related to a stem cell program. The discoveries on the purely molecular mechanisms of the disease did not help tocreate a bridge for new treatment strategies so far and the cellular diversity of ETMR remains poorly understood. In this study, we used single-cell
RNA sequencing of murine and human tumors to describe ETMR cellular
heterogeneity. Our findings support that intra-tumoral heterogeneity ismainly characterized by 4 cellular programs defining a developmental hierarchy related to different metabolic states: 1) Early quiescent NSC-like cells
supported by fatty-acid oxidation 2) Late NSC and NP-like proliferative
cells fueled by glycolytic metabolism; 3) Post-mitotic neuroblast-like cells,
relying on oxidative-phosphorylation; 4) NSC-like proliferative cells, withmetabolic plasticity and capable of performing the three types of metabolism. Tumor-specific ligand-receptor interaction analysis revealed that
ETMR exchange with microglia and vascular mural cells (MC) signals related to extracellular matrix (ECM) organization (Cxcl12-CxCr4), stem cellsignaling (BMPs-BMP receptors), anti-apoptosis and survival (Ntf3-Ntrk),
not seen in the control brain. In addition, the vascular MC showed a cancerassociated fibroblast (CAF) phenotype, with potential prognostic implications, as previously demonstrated for other tumors. This study provides new
findings to build up a more robust understanding of ETMR biology andopens space for further studies in the field.
ETMR-06. DISSECTING THE MOLECULAR AND DEVELOPMENTAL
BASIS OF PINEOBLASTOMA THROUGH GENOMICS
Brian Gudenas1, Bernhard Englinger2, Anthony P. Y. Liu3,
Yiai Tong1, David Meredith4, Elke Pfaff5,6, Tong Lin7, Brent A. Orr8,Paul Klimo Jr.9,10, Laure Bihannic1, Leena Paul1, Rahul Kumar1,
Eric Bouffet11, Sridharan Gururangan12, John R. Crawford13,
Stewart J. Kellie14, Murali Chintagumpala15, Michael J. Fisher16,
Daniel C. Bowers17, Tim Hassall18, Daniel J. Indelicato19,
David W. Ellison8, Frederick A. Boop9,10, Thomas E. Merchant20,
Jason Chiang8, Giles W. Robinson3, Amar Gajjar3, Sanda Alexandrescu21,
David T. W. Jones5,6, Mariella G. Filbin2, and Paul A. Northcott1;
1Department of Developmental Neurobiology, St. Jude Children’s Research
Hospital, Memphis, TN, USA, 2Department of Pediatric Oncology,
Dana-Farber/Boston Children’s Cancer and Blood Disorder Center andHarvard Medical School, Boston, MA, USA, 3Department of Oncology, St.
Jude Children’s Research Hospital, Memphis, TN, USA, 4Department of
Pathology, Brigham and Women’s Hospital and Harvard Medical School,
Boston, MA, USA, 5Hopp Children’s Cancer Center Heidelberg (KiTZ),
Heidelberg, Germany, 6Pediatric Glioma Research Group (B360), German
Cancer Research Center (DKFZ), Heidelberg, Germany, 7Departmentof Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN,
USA, 8Department of Pathology, St. Jude Children’s Research Hospital,
Memphis, TN, USA, 9Department of Surgery, St. Jude Children’s Research
Hospital, Memphis, TN, USA, 10Department of Neurosurgery, Universityof Tennessee Health Science Center, Memphis, TN, USA, 11Pediatric Brain
Tumor Program, The Hospital for Sick Children, Toronto, ON, Canada,

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12Preston A, Wells Jr, Center of Brain Tumor Therapy, University of Florida,
Gainesville, FL, USA, 13University of California San Diego and Rady
Children’s Hospital, San Diego, CA, USA, 14Children’s Cancer Centre, The
Children’s Hospital at Westmead & University of Sydney, Sydney, Australia,
15Texas Children’s Cancer Center, Department of Pediatrics, Baylor Collegeof Medicine, Houston, TX, USA, 16Department of Pediatrics, Division of
Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA,
17Division of Pediatric Hematology and Oncology, University of Texas
Southwestern Medical Center, Dallas, TX, USA, 18Queensland Children’s
Hospital, Brisbane, QLD, Australia, 19Department of Radiation Oncology,
University of Florida, Jacksonville, FL, USA, 20Department of Radiation
Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA,
21Department of Pathology, Boston Children’s Hospital, Harvard Medical
School, Boston, MA, USA

Pineoblastoma (PB) is an aggressive embryonal brain tumor comprising
1% of pediatric CNS tumors. The clinico-molecular heterogeneity and developmental origins underlying PB are poorly understood; therefore, we haveassembled a molecular cohort of histologically defined PBs (n=43) with corresponding outcome data. Methylation profiling revealed four molecularly
and clinically distinct PB subgroups, including two novel entities. Mutational
and transcriptional analysis identified characteristic molecular features of eachsubgroup, such as mutations in the miRNA processing pathway or FOXR2
proto-oncogene overexpression. Furthermore, subgroups exhibited differences in propensity for metastasis, cytogenetics, and clinical outcomes. To
dissect PB developmental origins and resolve PB subgroup biology, we have
employed a combination of single-cell genomics and genetically engineeredmouse modeling. We created a single-cell transcriptional atlas of the developing
murine pineal gland across 11 timepoints and are currently integrating thesedata with single nuclei RNA-seq data of human PB (n=25). Single-cell analysis of the developing pineal gland revealed three distinct populations of
pinealocytes, referred to as early, mid and late pinealocytes, which segregate bydevelopmental stage yet lie along a single developmental trajectory. Preliminary
results implicate significant associations between PBs and the early pinealocyte
population as well as subgroup-specific differences in intratumoral heterogeneity. Furthermore, this knowledge has informed the downstream generation of
biologically faithful disease models, including a transgenic mouse model of the
PB-RB subgroup. Remarkably, this model shows up-regulation of key markers
of PB such as Crx, Asmt and Otx2 and substantiates early pinealocytes as theprobable cell-of-origin for this PB subgroup.
ETMR-07. ETANTR: A RARE TUMOR IN A RESOURCE-LIMITEDSETTING
Julieta Hoveyan1,2, Manushak Avagyan1,2, Anna Avagyan1,2,
Ruzanna Papyan1,2, Samvel Iskanyan1, Samvel Danielyan3,
Garik Hovhannisyan4, Parandzem Khachatryan5,2, Gevorg Tamamyan1,2,
and Samvel Bardakhchyan3,2; 1Pediatric Cancer and Blood Disorders
Center of Armenia, Hematology Center after Prof, R, Yeolyan, Yerevan,
Armenia, 2Yerevan State Medical University after Mkhitar Heratsi,
Yerevan, Armenia, 3Hematology Center after Prof, R, Yeolyan, Yerevan,
Armenia, 4Astghik Medical Center, Yerevan, Armenia, 5”Histogen”
Armenian-German Scientific-Practical Center of Pathology, Yerevan,
Armenia
INTRODUCTION: Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a rare aggressive brain tumor with low survival rates. There
are about 80 cases reported in literature since 2000 when it was first described.
There is no standard treatment scheme for ETANTR yet. CASE REPORT:
A 2 years old boy presented with a month-long of headache and inability tohold his head. CT scan and MRI revealed a large mass in the right frontal
lobe with midline shift. Subtotal tumor resection was done. Histological andimmunohistochemical analyses was consistent with ETANTR in one laboratory
and PNET in another. The second opinion suggested by the Center of PediatricOncology, Hematology and Immunology in Moscow the diagnosis ETANTR
was confirmed. Taking into account certain similarities with medulloblastoma
was decided to provide treatment according to HIT-2014 protocol. Control
MRI done after 2 cycles of Block SKK Carboplatin/Etoposide found tumor
progression and for that reason patient underwent second surgical resection.
Considering the age of the child radiation therapy was not expedient and thedecision was to continue treatment with HIT 2014 intensified regimen, which
includes Cisplatin, Vincristine, Etoposide, Cyclophosphamide and intravenous
High dose Methotrexate with intrathecal Methotrexate. Aiming to evaluate
the effectiveness of treatment we are planning to perform MRI after this 2nd
cycle of intensified regimen. DISCUSSION: There are difficulties in diagnosisof rare types of cancers in Armenia. Since there is no approved treatment for
ETANTR, there is a need for ongoing research to improve its prognosis.
ETMR-08. INTERNATIONAL CONSENSUS PROTOCOL FOREMBRYONAL TUMOR WITH MULTILAYER ROSETTES
Derek Hanson1,2, Nicolas Andre3, Susan Chi4,5, Mariella Filbin4,5,Michael Fisher6, Lindsey Hoffman7, Ziad Khatib8, Marcel Kool9,10,
Aru Narendran11, Barry Pizer12,13, Irene Slavc14, Timothy Vogel1,2,

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De c e mb e r 2 0 2 0David Ziegler15,16, and Mark Kieran6; 1Hackensack University Medical
Center, Hackensack, NJ, USA, 2Hackensack Meridian School of Medicine,
Nutley, NJ, USA, 3Service d’Hématologie et Oncologie Pédiatrique, Hôpitalpour Enfants de La Timone, AP-HM, Marseille, France, 4Dana-Farber
Cancer Institute, Boston, MA, USA, 5Harvard Medical School, Boston,
MA, USA, 6Division of Oncology, Children’s Hospital of Philadelphia,
Philadelphia, PA, USA, 7Phoenix Children’s Hospital, Center for Cancer
and Blood Disorders, Phoenix, AZ, USA, 8Nicklaus Children’s Hospital,
Miami, FL, USA, 9Hopp Children’s Cancer Center (KiTZ), Heidelberg,
Germany, 10German Cancer Research Center (DKFZ) and German
Cancer Consortium (DKTK), Heidelberg, Germany, 11Cumming Schoolof Medicine, University of Calgary, Calgary, AB, Canada, 12University ofLiverpool, Liverpool, United Kingdom, 13Alder Hey Children’s Hospital,
Liverpool, United Kingdom, 14Department of Pediatrics and Adolescent
Medicine, Medical University of Vienna, Vienna, Austria, 15Sydney
Children’s Hospital, Randwick, NSW, Australia, 16University of New South
Wales, Sydney, NSW, Australia
Embryonal tumors with multilayer rosettes (ETMR) are rare and highlyaggressive central nervous system (CNS) neoplasms which occur primarily
in young children and carry a dismal prognosis. To date, no large clinicalinvestigations have been conducted to determine the optimal therapy for
ETMR. Data from retrospective case series suggest that our most aggressive standard therapies are not sufficient for cure in the majority of cases.
New treatment approaches incorporating pre-clinical data and the known
biology of ETMR are therefore urgently needed. A German drug screen
using the patient-derived ETMR BT183 cell line and its xenograft revealed
anti-tumor activity of topotecan, doxorubicin, and actinomycin D; three
agents used infrequently for treating infant CNS tumors. Additional resultsfrom a small series of ETMR patients suggest that optimization of induction
chemotherapy using these active agents may improve response and survival
outcomes. In 2019, an international panel of pediatric neuro-oncology experts convened to advance therapy for ETMR. A consensus protocol wasdeveloped incorporating maximal safe surgical resection, induction chemotherapy with active pre-clinical agents, intrathecal chemotherapy, radiotherapy, and high-dose chemotherapy. This international consensus protocol
represents the first prospective clinical investigation specific to ETMR andwill be available through a treatment registry globally and as a clinical trial
at select centers. The study aims to improve survival by providing aggressive,
optimized therapy for ETMR and will serve as a platform to explore new
biologically-promising agents. The investigation will also provide valuable
prospective outcome data and correlative biological studies to serve as baseline comparators for future clinical trials.
ETMR-09. THE ROLE OF RADIATION FOR EMBRYONAL TUMOR
WITH MULTILAYERED ROSETTES
Akihide Kondo, Mario Suzuki, Junya Fujimura; Juntendo University,
Tokyo, JapanBACKGROUND: Embryonal tumor with multilayered rosettes (ETMR) is achallenging tumor. The prognosis of the patients suffering from this tumor isextremely poor. We have survival cases of more than 12 months. However, thestatus of illness is different. In order to clarify the cause of this difference, we
reviewed our treatments in this study. TREATMENT COURSE: We have twocases. Both have relapsed after the same chemotherapy after the same radiation
therapy. After the recurrence we used protocols that were included extended
resection, second radiation therapy with bevacizumab. METHODS: We compared molecular biological evaluations for the initial and recurrent tumors. The
resection rate at the time of second removal and the intensity of radiation therapy
intensity were compared. RESULTS: We succeeded to remove the tumors withthe confirmation of intraoperative MRI. No apparent differences could be seen
in molecular biological characters of tumors before and after treatment. There
was a difference between the period until radiation therapy and the irradiation
methods. CONCLUSIONS: This tumor is untreatable only by resection. We
need the second radiation therapy with bevacizumab. It was presumed thattumor should be irradiated quickly with appropriate irradiation field and dose.
ETMR-10. EARLY FOCAL RADIOTHERAPY AND TEMOZOLOMIDEFOLLOWING COMPLETE RESECTION APPEAR SUPERIOR TO
INTENSIVE CHEMOTHERAPY AND DELAYED RADIOTHERAPY IN
CHILDREN WITH EMBRYONAL TUMORS WITH MULTILAYEREDROSETTES (ETMR)
Lisa Mayr1, Johannes Gojo1, Andreas Peyrl1, Amedeo Azizi1,
Karin Dieckmann2, Christine Haberler3, Thomas Czech4, and Irene Slavc1;
1Medical University of Vienna, Department of Pediatrics and Adolescent
Medicine, Vienna, Austria, 2Medical University of Vienna, Department ofRadiotherapy, Vienna, Austria, 3Medical University of Vienna, Institute of
Neurology, Vienna, Austria, 4Medical University of Vienna, Department of
Neurosurgery, Vienna, Austria
BACKGROUND: Embryonal tumor with multilayered rosettes (ETMR)
is a rare, aggressive embryonal central nervous system tumor characterizedAbstracts

by LIN28A expression and alterations in the C19MC locus. ETMRs predominantly occur in young children, have a dismal prognosis, and no definitive treatment guidelines have been established. We report on our experiencein nine consecutive patients. METHODS: Between 2006 and 2017, ninepatients were diagnosed with ETMR. Median age was 25 months (5–38),
seven were treated for primary diagnosis, two referred with progressing tumors, seven diagnosed prospectively, two retrospectively, five were locatedsupratentorially, three pineal, one in the brainstem. RESULTS: Seven patients had a gross total resection, one a partial resection and one a biopsy at
initial diagnosis, followed by second resections at progression. Six patientswere treated with intensive chemotherapy regimens including high-dose
chemotherapy in three patients and all recurred after a median of 6 months(range 2–11) and all except one patient who died after high-dose chemotherapy, succumbed to their disease after a median of 13 months (range
7–28). Two patients were treated with gross total tumor resection, early focal
radiotherapy and concomitant temozolomide followed by temozolomide
and intrathecal therapy for one year and both are in continuous complete remission 51 and 46 months after diagnosis. CONCLUSION: Gross total resection followed by early focal radiotherapy, temozolomide, and intrathecal
chemotherapy seem to be superior to intensive chemotherapy including
high-dose chemotherapy. Steady progression was observed in both patientswith initial biopsy and PR only despite intensive therapy. Radiotherapy atrecurrence/progression was not successful.
ETMR-11. A CASE OF PRIMARY DIFFUSE LEPTOMENINGEALPRIMITIVE NEUROECTODERMAL TUMOR
Masahiro Sugawa1, Keita Terashima1, Yukihiro Matsukawa1,
Takanori Mizuno1, Kyohei Isshiki1, Shinichi Tsujimoto1, Meri Uchiyama1,
Kenichi Sakamoto1, Yoshihiro Gocho1, Tomoo Osumi1, Yoko Shioda1,
Chikako Kiyotani1, Motohiro Kato1, Daisuke Tomizawa1, Kenichi Usami2,
Hideki Ogiwara2, Yoshiaki Tsutsumi3, Masayuki Nakano4,
Takako Yoshioka4, and Kimikazu Matsumoto1; 1Children’s Cancer
Center, National Center for Child Health and Development, Tokyo,
Japan, 2Department of Neurosurgery, National Center for Child Healthand Development, Tokyo, Japan, 3Department of Radiology, National
Center for Child Health and Development, Tokyo, Japan, 4Department of
Pathology, National Center for Child Health and Development, Tokyo,
Japan
BACKGROUND: Primarydiffuseleptomeningeal
primitive
neuroectodermal tumor (PDL PNET) is a rare embryonal brain tumor
which arises primarily in the meninges without an intraparenchymal mass.
Few previous reports of this condition exist, and the clinical outcomes arepoor. We herein report a case of a child with PDL PNET and present a
cursory review of the literature. CASE: A 3-year-old female patient was seen
at a local clinic due to vomiting, headaches, and seizures. As a head MRI
revealed hydrocephalus but no mass, acute encephalopathy was initiallydiagnosed. She received steroid pulse therapy, but the symptoms progressed
to hallucination and lethargy. Another MRI at the 1-month follow-up revealed diffuse leptomeningeal enhancement. Thereafter she was transferredto our hospital. A spine MRI revealed spinal dissemination. She underwent
a dura mater biopsy, and the pathological analysis led to the diagnosis of
PDL PNET. She received chemotherapy consisting of vincristine, cyclophosphamide, etoposide, cisplatin, and intrathecal methotrexate injections twomonths after the initial presentation. The progressive hydrocephalus wasmanaged with external ventricular drainage. Two weeks after the first cycleof chemotherapy the hydrocephalus resolved, and the external ventriculardrainage was removed. A follow-up MRI showed that the leptomeningeal
enhancement decreased during the four cycles of chemotherapy without
radiotherapy. The patient is scheduled to receive high-dose chemotherapy as
consolidation therapy. CONCLUSION: PDL PNET is extremely rare, andits diagnosis is often delayed. Treatment of PDL PNET is very difficult due
to its aggressive course, and surgical resection is impossible. Early diagnosis
may help improve outcomes.
ETMR-12. EMBRYONAL TUMOR WITH MULTILAYEREDROSETTES: A SINGLE CENTER EXPERIENCE
Sodai Yoshimura1, Masahiro Sugawa2, Kohei Fukuoka2, Makiko Mori2,
Yuki Arakawa2, Masao Kobayashi3,4, Yutaka Tanami3, Atsuko Nakazawa5,
Katsuyoshi Koh2, and Jun Kurihara1; 1Department of Neurosurgery,
Saitama Children’s Medical Center, Saitama, Japan, 2Department of
Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan,
3Department of Radiology, Saitama Children’s Medical Center, Saitama,
Japan, 4Department of Radiology, Jikei University school of Medicine,Tokyo, Japan, 5Department of Clinical Research, Saitama Children’s
Medical Center, Saitama, JapanBACKGROUND: Embryonal tumor with multilayered rosettes (ETMR)
is a rare, highly malignant tumor of the central nervous system and is usuallydiagnosed in children aged <2 years. Currently, because no defined treatment strategy has been reported, treatment regimens are often extrapolated

from other embryonal tumors. Therefore, data collection of ETMR cases isimportant for further understanding EMTR. Here, we present our experience with four patients with ETMR. MATERIAL AND METHODS: Patients with a pathological diagnosis of ETMR from 1999 to 2016 at
Saitama Children’s Medical Center were included. Their clinical data wereretrospectively analyzed. RESULTS: This study included four cases of
ETMR (one male and three females). The mean age at diagnosis was 29.5
(range, 15–37) months. Presenting symptoms included seizure, hemiparesis,
vomiting, and headache. The mean maximal tumor diameter was 42.5 mm.
The tumor locations included frontal lobe, temporal lobe, occipital lobe,
cerebellum, and brainstem. Gross total resection was achieved in two cases.
Fluorescence in situ hybridization analysis demonstrated amplification of
19q13.42 chromosome region in all cases, and diffuse positive expression
was observed in the immunohistochemical staining for LIN28A. Systemic
postoperative chemotherapy was administered to all patients. Three patients
received intrathecal therapy and three were irradiated. The mean overall survival and progression-free survival were 45.3 and 42 months, respectively.
Two patients who underwent gross total resection are alive without recurrence. CONCLUSION: Complete surgical resection may be an important
prognostic factor in patients with ETMR. Further prospective studies areneeded to confirm these results.
ETMR-13. NFI GENES IN ETMR TUMORIGENESIS AND
NEURODEVELOPMENT
Jens Bunt1,2, Sander Lambo3,4, Jonathan Lim2, Monika Mauermann3,4,
Stefan Pfister3,4, Linda Richards2, Marcel Kool1,3; 1Princess Máxima Center
for Pediatric Oncology, Utrecht, Netherlands, 2Queensland Brain Institute,
University of Queensland, Brisbane, QLD, Australia, 3Hopp Children’s
Cancer Center (KiTZ), Heidelberg, Germany, 4Division of Pediatric
Neurooncology, German Cancer Research Center (DKFZ), Heidelberg,
Germany
Embryonal tumors with multilayered rosettes (ETMRs) are aggressive
pediatric embryonal brain tumors with a universally poor prognosis. Thesetumors are commonly characterized by amplification of C19MC, but other
miRNA-related aberrations, such as DICER mutations or MIR17HG amplifications, are also observed. Nevertheless, it remains unknown how theseaberrations are driving the tumorigenesis. We applied miRNA target prediction to investigate the downstream targets shared by these aberrations
affecting normal brain development and tumorigenesis. The nuclear factor
one (NFI) family of transcription factors were found to be top candidates
shared by both miRNA clusters. These genes are expressed at very low
levels in ETMRs, in contrast to other brain tumors. During normal brain
development these genes are expressed in radial glial progenitors and are
required for the transition of proliferation to differentiation. Since radial
glial progenitors are the potential cell-of-origin of ETMRs, we hypothesizethat downregulation of NFI is required for the proliferative, undifferentiated state of ETMRs. Indeed, mouse models with deletion of an Nfi family
member display sustained proliferation and delayed differentiation of radial glial progenitors during development. This leads into brain overgrowth,which has also been observed in humans with intellectual disabilities caused
by NFI haploinsufficiency. When multiple Nfi family members are simultaneously targeted in mice, the progenitors are retained and both neurogenesis
and gliogenesis are inhibited, resulting in a neuropathology similar to thatof human ETMR tumors. Hence, downregulation of NFI genes resulting
from miRNA aberrations could contribute to the developmental state andpossibly tumorigenesis of ETMRs.
ETMR-14. TREATMENT OF EMBRYONAL TUMOURS WITH
MULTILAYERED ROSETTES (ETMR) WITH CARBOPLATINETOPOSIDE INDUCTION AND TANDEM HIGH-DOSE
CHEMOTHERAPY WITHIN THE PROSPECTIVE HIT-TRIALS AND
REGISTRIES
Björn-Ole Juhnke1, Marco Gessi2, Nicolas Ulrich Gerber3,
Carsten Friedrich4, Christine Haberler5, Martin Mynarek1, Brigitte Bison6,
Rolf-Dieter Kortmann7, Monika Warmuth-Metz6, Ulrich Schüller8,
Stefan Michael Pfister9,10, Torsten Pietsch11, Marcel Kool9,10,
Stefan Rutkowski1, Katja von Hoff12
1Clinic for Paediatric Haematology and Oncology, University Medical
Centre Hamburg-Eppendorf, Hamburg, Germany, 2Neuropathology
Unit, Division of Pathology, Fondazione Policlinico Universitario “A
Gemelli” IRCCS, Catholic University, Rome, Italy, 3University Children’s
Hospital Zürich, Zürich, Switzerland, 4Children’s Clinic, University
Medical Centre Rostock, Rostock, Germany, 5Division of Neuropathology
and Neurochemistry, Department of Neurology, Medical Universityof Vienna, Wien, Austria, 6Institute for Diagnostic and Interventional
Neuroradiology, University Hospital Würzburg, Würzburg, Germany,
7Clinic for Radiotherapy, Leipzig University Medicine, Leipzig, Germany,
8Institute of Neuropathology, University Medical Centre HamburgEppendorf, Hamburg, Germany, 9Department of Pediatric Hematology andN E U R O -O N C O L O G Y•

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Oncology, Heidelberg University Hospital, Heidelberg, Germany, 10Divisionof Paediatric Neurooncology, German Cancer Research Centre (DKFZ)and German Consortium for Translational Cancer Research (DKTK),
Heidelberg, Germany, 11Institute of Neuropathology, DGNN Brain Tumour
Reference Centre, University Hospital Bonn, Bonn, Germany, 12Departmentof Paediatric Oncology and Haematology, Charité University Medicine,
Berlin, Germany
BACKGROUND: Embryonal tumours with multilayered rosettes(ETMR) are highly aggressive tumors, mostly occurring in infants. Published clinical data refer to retrospective cohorts of inhomogeneously treatedpatients. Here, we describe the outcome of patients, who were prospectively treated within the P-HIT2000-trial, the subsequent HIT2000-interimregistry and earlier HIT-trials. PATIENTS AND METHODS: Nineteen
patients from the P-HIT2000-trial (2001–2011), 12 patients from the subsequent HIT2000-interim-registry (2012–2014) and 4 patients from earlier
HIT-trials with centrally reviewed neuropathological and molecularlyconfirmed diagnosis of ETMR were included. Outcome of 18 patientstreated with carboplatin-etoposide-induction followed by tandem-high-dose
chemotherapy (“CARBO-ETO+HDCT”) with stage-stratified radiotherapy
administered in case of persistant disease, relapse or progression were compared to patients treated with HIT-SKK chemotherapy ± radiotherapy (n=9)
or other regimens (n=8). RESULTS: Median age at diagnosis was 2.9(1.0–
5.3) years. Metastases at diagnosis were detected in 9 patients (26%). For
the entire cohort of n=35, 5-year overall survival (OS) was 26.7%, andprogression-free survival (PFS) was 18.5%. Five-year OS for patients with
CARBO-ETO+HDCT, SKK chemotherapy or other regimens was 44.4%,
13.0% and 0%, respectively (p=0.006). Five-year PFS was 33.3%, 0%
and 0%, respectively (p=0.119). Of 10 survivors, n=8 were treated with
CARBO-ETO+HDCT; n=4 had craniospinal, n=2 local and n=4 no radiotherapy. Impact of initial gross-total-resection (p=0.231) and non-metastatic
disease (p=0.097) was limited. CONCLUSIONS: We show improved survival with carboplatin-etoposide-induction followed by tandem-high-dose
chemotherapy, indicating that a cure is possible for some patients. However,despite intensive treatment, outcome is unsatisfactory and innovative therapies urgently need to be included in an upfront setting.
ETMR-15. USE OF HIGH-DOSE CHEMOTHERAPY FOR TWO
CHILDREN WITH EMBRYONAL TUMOR WITH MULTILAYEREDROSETTES
Shimpei Kusano1, Junya Fujimura1, Megumi Fujiwara1, Akinori Yaguchi1,
Takeshi Ishibashi1, Osamu Tomita1, Hiroyuki Tamaichi1, Akihide Kondo2,
and Toshiaki Shimizu1; 1Department of Pediatrics, Juntendo University
Faculty of Medicine, Tokyo, Tokyo, Japan, 2Department of Neurosurgery,
Juntendo University Faculty of Medicine, Tokyo, Tokyo, Japan
Embryonal tumor with multilayered rosettes (ETMR) is new entity definedin the 4th revised edition of the WHO classification of tumors of the central
nervous system. Although radical resection, radiotherapy, and multiagent
chemotherapy are considered to be necessary for ETMR, the efficacy ofchemotherapy for ETMR in Japan has not been established. Here, we report
different clinical courses for two children with localized ETMR treated with
the St. Jude medulloblastoma-96 (SJMB96) regimen, which consists of fourcycles of high-dose chemotherapy with autologous peripheral blood stem
cell transplantation. For both children, the diagnosis of ETMR, C19MCaltered was confirmed after gross total tumor resection. Multiagent chemotherapy was administered following cranio-spinal irradiation with local
boost. One month after completion of the treatment, one patient experienced local recurrence but has been in remission for over 2 years after tumor
resection and stereotactic irradiation with a CyberKnife and treatment every
three weeks with bevacizumab. The other patient also experienced local recurrence after the third cycle of chemotherapy and several times thereafter.
Although she again underwent tumor resection and local irradiation, hertumor grew larger and invaded. Because her prognosis was very poor, herparents choose only palliative care. Based on our experience, we believe that
continuous chemotherapy at conventional doses is preferred over intensivedose chemotherapy such as SJMB96. However, the number of reports on
chemotherapy for ETMR is still small, and a prospective multicenter trial isneeded to establish effective chemotherapy for ETMR.
ETMR-17. SINGLE-CELL TRANSCRIPTOME ANALYSIS OF ETMRPATIENT SAMPLES
Volker Hovestadt1,2, McKenzie L. Shaw2,3, Alexander Beck3,4,
Sander Lambo5,6, Olivia A. Hack2,3, Johannes Gojo3,7, Sibylle Madlener7,
Lisa Mayr7, Christine Haberler8, Thomas Czech9, Derek R. Hanson10,
Carl Koschmann11, Nada Jabado12, Annie A. Huang13,14, Irene Slavc7,
Stefan M. Pfister5,6, Sanda Alexandrescu15, Bradley E. Bernstein1,2,Marcel Kool5,6, and Mariella G. Filbin2,3; 1Department of Pathology

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and Center for Cancer Research, Mass, General Hospital and Harvard
Medical School, Boston, MA, USA, 2Broad Institute of Harvard and MIT,
Cambridge, MA, USA, 3Department of Pediatric Oncology, Dana-Farber
Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA,
4Center for Neuropathology and Prion Research, Ludwig-MaximiliansUniversity, Munich, Germany, 5Hopp Children’s Cancer Center Heidelberg(KiTZ), Heidelberg, Germany, 6Division of Pediatric Neurooncology,
German Cancer Research Center, Heidelberg, Germany, 7Departmentof Pediatrics and Adolescent Medicine, Medical University of Vienna,
Vienna, Austria, 8Division of Neuropathology and Neurochemistry,
Department of Neurology, Medical University of Vienna, Vienna, Austria,
9Department of Neurosurgery, Medical University of Vienna, Vienna,
Austria, 10Hackensack University Medical Center, Hackensack, NJ, USA,
11Department of Pediatrics, University of Michigan Medical School, Ann
Arbor, MI, USA, 12Division of Hemato-Oncology, Department of Pediatrics,
McGill University Health Center, Montreal Children’s Hospital, Montreal,
QC, Canada, 13Division of Hematology/Oncology, Labatt Brain Tumour
Research Centre, The Hospital for Sick Children, Toronto, ON, Canada,
14Department of Pediatrics, Medical Biophysics, Laboratory Medicine andPathobiology, University of Toronto, Toronto, ON, Canada, 15Departmentof Pathology, Boston Children’s Hospital, Boston, MA, USA
Brain tumors are comprised of cells with heterogeneous genetic and transcriptional states, resulting in substantial phenotypic diversity. This diversity is particularly evident in embryonal tumor with multilayered rosettes(ETMR), which shows a striking bi-phasic pattern for which it is named.
A better understanding of its underlying molecular makeup is urgently
needed to develop more effective therapeutic strategies that eliminate all
malignant cell types underlying ETMR initiation, maintenance, progression,and relapse. Furthermore, the cellular origin of ETMR is currently poorly
understood. We used plate-based single-cell RNA sequencing to assess theintratumoral heterogeneity in 6 fresh and 4 snap-frozen surgical biopsies,
following a workflow that we have previously established to study pediatrichigh grade gliomas, medulloblastomas, and ependymomas. Computational
analyses conducted on >4,000 single cells identified cellular hierarchies ranging from a proliferative, undifferentiated cell population to more differentiated, predominantly neural-like progeny in all samples. Patient-derived cellline and xenograft models partially recapitulated this hierarchy. We further
integrated transcriptional programs identified in single cells with available
datasets of the developing normal brain, as well as with programs identified
in other pediatric brain tumor entities, to inform both putative cellular origins and ETMR-specific oncogenic pathways. These timely results provide
unparalleled insights into the molecular underpinnings of the phenotypic
heterogeneity observed in ETMR. Analyses aimed at further integrating
malignant cell type abundances with genetic alterations and clinical annotations, and therapeutical targeting of malignant cell populations using
in-vitro models are currently ongoing.
ETMR-18. TARGETING LIN28 IN ETMR WITH ODC1 INHIBITOR
DFMO
Austin Goodyke1, Shannon Kelly1, Joseph Zagorski1,
Elizabeth VanSickle1, Tyler Maser1, Caryl Sortwell2, Christopher Kemp2,
Abhinav Nagulapally1, Karl Dykema1, and Giselle Saulnier-Sholler1,2;
1Spectrum Health, Grand Rapids, MI, USA, 2Michigan State University,
Grand Rapids, MI, USA
Embryonal tumor with multilayered rosettes (ETMR), is an aggressive
brain tumor primarily occurring in young patients (<4 years of age) andcharacterized by C19MC amplification and Lin28 overexpression. These
genetic hallmarks have been shown to participate in driving ETMR ina C19MC-Lin28-MYCN circuit. Reducing Lin28 disrupts this circuit
and reduces cell viability in ETMR models. Investigation of therapeutic
agents targeting this pathway is required to provide new treatment options for this deadly disease. We present data showing the effect of DFMO
(α-difluoromethylornithine) in ETMR, an ODC1 inhibitor known to reduce
Lin28 in neuroblastoma. DFMO treatment of the ETMR cell line BT-183
resulted in a significant reduction of intracellular Lin28 protein levels(P<0.05) as indicated by flow cytometry. In concert with this reduction in
Lin28, there was a as significant reduction in viable cells (P<0.05), and thenumber of CD133+ cells were reduced 2-fold (P<0.05). High throughput
drug testing of BT-183 identified a number of additional therapeutic agentswith potential therapeutic efficacy for ETMR and combining these withcytostatic agent DFMO demonstrated the potential use of these drugs incombination. These in vitro data were complemented by testing of DFMOin an in vivo stereotaxic xenograft ETMR model, with inhibition of tumor
burden monitored by bioluminescent imaging of the tumors. Together thiswork shows that Lin28 targeting agents such as DFMO merit further examination and integrating these types of agents into treatment strategies for
ETMR may lead to better outcomes.

Abstracts

ETMR-19. SINGLE CELL ANALYSES OF ETMRS REVEAL THATC19MC+ POPULATION DRIVES CELL CYCLE PROGRESSION AND
STEM CELL MAINTENANCE
Iqra Mumal1,2, Liming Xu1, Fupan Yao1,2, Tannu Suwal1,2, Xiaolian Fan1,
Mei Lu1, and Annie Huang1,2; 1The Hospital for Sick Children, Toronto,
ON, Canada, 2University of Toronto, Toronto, ON, Canada
Embryonal tumors with multilayered rosettes (ETMRs) are highly fatal
diseases characterized by recurrent amplification of C19MC, an oncogenic
miRNA cluster. While C19MC was discovered as a major driver of ETMRs,
its direct role in ETMRs remains unknown. As ETMRs exhibit significant
heterogeneity in C19MC expression, we employed single cell transcriptomics
to investigate features of C19MC+ population. We conducted single-nuclei
RNAseq of 23,269 cells from 6 primary and 2 matched recurrent ETMRs.
We also conducted single-cell RNAseq of human neural stem cells (hNSC5miR) and ETMR cell line (A664-5miR) with stable expression of 5 C19MC
miRNAs. Bulk RNAseq (n=27), H3K27Ac ChiP-seq (n=5) and ATAC-seq(n=5) corroborated scRNAseq data and identified core transcription factors (TFs) of C19MC+ population. C19MC+ population (24%) mapped
to neuro-epithelial cells and exhibited signatures of cell cycle and stem cellmaintenance, consistent with bulk-RNAseq data. The C19MC+ population
overlaps with MKI67+ cycling (57%) and PROM1+ stem cell population(56%). Interestingly, interrogation of hNSC-5mir and A664-5miR showeda larger MKI67+/PROM1+ population compared to controls. Likewise,hNSC-5miR/A664-5miR in vitro and in vivo experiments showed increased
proliferation/stemness. C19MC+ population is characterized by SHH,
WNT, mTOR, Hippo and IGF-signalling and driven by MEIS1, SOX11,
ZNF521, RFX4 and NR2F2 TFs. Recurrent ETMRs exhibit a persistent but
smaller C19MC+ population. Intriguingly, recurrent tumors were more quiescent with a smaller proliferative population. C19MC is directly involvedin driving cell cycle and stemness in ETMRs. Cellular and molecular featuresof primary and recurrent ETMRs were remarkably different, suggesting thatC19MC plays a different role upon recurrence.
ETMR-20. IMPACT OF HIGH DOSE CHEMOTHERAPY WITH ANDWITHOUT METHOTREXATE (MTX) ON OUTCOME OF PATIENTSWITH EMBRYONAL TUMORS WITH MULTI-LAYERED ROSETTES(ETMRS): A REPORT FROM CHILDREN’S ONCOLOGY GROUPPHASE III TRIAL ACNS0334
Claire Mazewski1,2, Guolian Kang3, Stewart Kellie4, Jeffrey Gossett3,
Sarah Leary5, Bryan Li6,7, Paul Aridgides8, Laura Hayes9,
Alyssa Reddy10, Dennis Shaw11, Peter Burger12, Alexander Judkins13,
Jeffrey Russell Geyer14, Maryam Fouladi15, and Annie Huang16,17; 1Emory
University School of Medicine, Atlanta, Georgia, USA, 2Aflac Cancer andBlood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Georgia,
USA, 3Saint Jude Children’s Research Hospital, Department of Biostatistics,
Memphis, TN, USA, 4University of Sydney, Children’s Hospital atWestmead, Department of Oncology, Westmead, NSW, Australia, 5Seattle
Children’s Hospital, Department of Pediatric Hematology-Oncology,
Seattle, WA, USA, 6Hospital for Sick Children, Arthur and Sonia Labatt
Brain Tumour Research Centre, Pediatrics Department of Hematology
Oncology, Toronto, ON, Canada, 7University of Toronto, Toronto,
ON, Canada, 8SUNY Upstate Medical University, Syracuse, NY, USA,
9Nemours Children’s Hospital Department of Radiology, Orlando, FL,
USA, 10University of California San Francisco, Department of Neurology,
San Francisco, CA, USA, 11Seattle Children’s Hospital, Department ofRadiology, Seattle, WA, USA, 12Johns Hopkins University, Department of
Pathology, Neuropathology Division, Baltimore, MD, USA, 13Children’s
Hospital of Los Angeles, Keck School of Medicine, University of Southern
California, Pathology and Laboratory Medicine, Los Angeles, CA, USA,
14Seattle Children’s Hospital, Department of Pediatric Hematology
Oncology, Seattle, WA, USA, 15Cincinnati Children’s Hospital Medical
Center, Pediatric Hematology Oncology, Cincinnati, OH, USA, 16Hospitalfor Sick Children, Division of Hematology Oncology, Arthur and Sonia
Labatt Brain Tumour Research Centre, Pediatrics, Toronto, ON, Canada,
17University of Toronto, Laboratory Medicine and Pathology, Toronto, ON,
CanadaInfant embryonal brain tumors comprise a spectrum of histologic andmolecular entities including medulloblastoma (MB) and tumors collectively
called CNS PNET’s, including supratentorial PNET (sPNET), pineoblastoma
and other less common histologic entities. Non-MB embryonal tumors,
historically considered high risk disease, were included in ACNS0334,
A Children’s Oncology Group prospective phase III trial which comparedefficacy of an induction regimen with and without methotrexate combinedwith high dose chemotherapy and stem cell rescue; no radiation was mandated. Molecular testing performed after ACNS0334 closure identified 14
patients with embryonal tumors with multi-layered rosettes (ETMRs), a newmolecular entity previously classified under various diagnostic categories.
ETMR patients made up 20% of the molecularly analyzed ACNS0334 co-hort and were predominantly females. Tumors were largely non-metastatic(10/14 M0, 1 M1, 3 M2/M3) and originated in the cerebrum (8), cerebellum(3) and pineal gland (3). Gross total tumor resection was achieved in 5/11
patients with M0/M1 disease; 9/14 patients completed full treatment with
5 randomized to MTX induction and 9 to no-MTX. Five of 14 patients
progressed on treatment, one had a toxic death. Disease progression was primarily local (88 %). No difference by methotrexate randomization was observed. Four patients are alive without progression 5–10+ years off therapy,
none received radiation. No patients received radiation prior to progression.
Four were irradiated after progression and died from disease within 3 to
13 months. Our study, a first report on ETMRs prospectively treated on aclinical trial, suggests high dose chemotherapy benefits a portion of ETMR
patients.
ETMR-21. META-ANALYSIS OF PINEAL REGION TUMOURSDEMONSTRATES MOLECULAR SUBGROUPS WITH DISTINCT
CLINICO-PATHOLOGICAL FEATURES: A CONSENSUS STUDY
Bryan K Li1,2, Anthony PY Liu3, Elke Pfaff4,5, Brian Gudenas6,
Sivan Gershanov2, Christelle Dufour7, Christian Aichmüller8,
Martin Sill4,9, Tong Lin10, Arzu Onar-Thomas10, Brent A Orr11,
Cynthia Hawkins2,12, David W Ellison11, Matija Snuderl13,14,
Annie Laquierre15, Eugene Hwang16, Sri Gururangan17,
Matthias A Karajannis18, Giles W Robinson3, Eric Bouffet1,
Alexandre Vasiljevic19,20, Amar Gajjar3, Stefan M Pfister4,21,
Paul A Northcott6, David TW Jones4,5, and Annie Huang1,2; 1Division of
Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada,
2Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for
Sick Children, Toronto, ON, Canada, 3Department of Oncology, St. JudeChildren’s Research Hospital, Memphis, TN, USA, 4Hopp Children’s
Cancer Center Heidelberg (KiTZ), Heidelberg, Germany, 5Pediatric Glioma
Research Group, German Cancer Research Center (DKFZ), Heidelberg,
Germany, 6Department of Developmental Neurobiology, St. Jude Children’s
Research Hospital, Memphis, TN, USA, 7Département de Cancérologie del’Enfant et de l’Adolescent, Institut Gustave Roussy, Villejuif, Paris, France,
8Division of Molecular Genetics, German Cancer Research Center (DKFZ),
Heidelberg, Germany, 9Division of Pediatric Neurooncology, German
Cancer Research Center (DKFZ), Heidelberg, Germany, 10Departmentof Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN,
USA, 11Department of Pathology, St. Jude Children’s Research Hospital,
Memphis, TN, USA, 12Division of Pathology, The Hospital for Sick
Children, Toronto, ON, Canada, 13Division of Neuropathology, NYU
Langone Health, New York, NY, USA, 14Laura and Isaac Perlmutter
Cancer Center, NYU Langone Health, New York, NY, USA, 15Normandie
University, UNIROUEN, Inserm U1245, and Rouen University Hospital,
Department of Pathology, F76000, Normandy Center for Genomic
and Personalized Medicine, Rouen, France, 16Department of Oncology,
Children’s National Medical Center, Washington DC, USA, 17Preston A,
Wells Jr, Center for Brain Tumor Therapy and Department of Pediatrics,
UF Health Shands Hospital, University of Florida, Gainesville, FL, USA,
18Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New
York, NY, USA, 19Faculté de Médecine, Université de Lyon, Lyon, France,
20Service d’Anatomie et Cytologie Pathologiques, CHU de Lyon, Lyon,
France, 21Department of Pediatric Oncology, Hematology & Immunology,
Heidelberg University Hospital, Heidelberg, Germany
Pineoblastomas (PB) are rare, aggressive pineal gland tumours with poor
global OS of 50–70% and only 15–49% OS for patients <4 years, despite intensive treatments. Recently, three independent groups (German Cancer Research Centre, Rare Brain Tumour Consortium/SickKids, St. Jude Children’s
Research Hospital) collectively analyzed large tumour cohorts and revealed
molecular sub-groups of PB. To harmonize and better characterize clinicopathologic associations of these sub-groups, we undertook a meta-analysis
of molecular and clinical data of the combined cohorts. Unsupervised consensus cluster analyses of global methylation data from 227 unique cases
identified five robust molecular sub-groups of pineal region tumours: PB_
miRNA_1, PB_miRNA_2, PB_MYC/FOXR2, and PB_RB, mainly comprisedof pediatric WHO grade 4 PBs and PNETs; and a fifth group: named PPTID,
comprised of mainly pineal parenchymal tumours of intermediate differentiation, a WHO grade 2–3 tumour common in adults. PB_miRNA_1 and PB_
miRNA_2 tumours, primarily arising in children (median ages 7.7, 11.4y,
respectively), were characterized by alterations of miRNA biogenesis genes
DICER1, DROSHA, and DGCR8. PB_MYC/FOXR2 and PB_RB groups,
arising in infants/toddlers (median ages 1.4, 2.0y, respectively), were distinguished by recurrent MYC gain/amplification and RB1 loss, respectively.
The PPTID group affected mainly adults (median age 33y) and exhibited
limited CNAs. Higher rates of metastasis were observed with PB_miRNA_1(42%), PB_MYC/FOXR2 (38%), and PB_RB (75%) tumours, compared to
PB_miRNA_2 (20%) and PPTID (25%). Results from ongoing integrative
survival analyses of this large cohort will provide critical data for design offuture clinical trials.

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ETMR-22. TITLE: DEFINING THE CLINICAL AND PROGNOSTICLANDSCAPE OF EMBRYONAL TUMORS WITH MULTI-LAYEREDROSETTES (ETMRS), A RARE BRAIN TUMOR REGISTRY (RBTC)STUDYSara Khan1,2, Palma Solano-Paez,3,4, Tannu Suwal3,5, Salma Al-Karmi3,
Mei Lu1, Ben Ho1, Maryam Fouladi6, Sarah Leary7,
Jean M. Mulcahy Levy8, Alvaro Lassaletta9, Eloy Rivas10, Alyssa Reddy11,
G. Yancey Gillespie12, Nalin Gupta13, Michal Yalon-Oren14,
Laura Amariglio14, Hideo Nakamura15,
Kuo-Sheng Wu16, Tai-Tong Wong16, Young-Shin Ra17, Milena La Spina18,
Policlinico Vittorio Emanuele18, Luca Massimi19, Anna Maria Buccoliero20,
Jordan R Hansford21, Richard G Grundy22, Dariusz Adamek23,
Jason Fangusaro24, David Scharnhorst25, Donna Johnston26, Lucie LafayCousin27, Sandra Camelo-Piragua28, Nabil Kabbara29, Amar Gajjar30,
Mahjouba Boutarbouch31, Maria Joao Gil da Costa32, Derek Hanson33,34,
Paul Wood35, Maysa Al-Hussaini36, Nisreen Amayiri36, Yin Wang37,
Daniel Catchpoole38, Jean Michaud39, Anne E. Bendel40,
Benjamin Ellezam41, Nicholas Gerber42, Ashley Plant43, Rubens Jeffery44,
Christopher Dunham45, Christopher Moertel46, Andrew Walter47,
David Ziegler48, Andrew Dodgshun49, Nicholas Gottardo50,
Ahmet Demir51, Ramya Ramanujachar52, Eric Raabe53, Shago Mary54,
Peter Dirks54, Michael Taylor54, Hwang Eugene55, Holly Lindsey56,
Tarik Tihan57, Jorgensen Mette58, Christine Dahl58, Sharon Low59,
Amy Smith60, Lili-Naz Hazrati54, Jesse Kresak60, Somers Gino54,
Enrica Tan61, Andres Morales62, Vicente Santa-Maria62,
Cynthia Hawkins54, Ute Bartels63, Derek Stephens54, Sumihito Nobusawa64,
Christelle Dufour65, Franck Bourdeaut66, Nicolas Andre67, Eric Bouffet63,
and Annie Huang1,63; 1Arthur and Sonia Labatt Brain Tumor ResearchCentre, Toronto, Ontario, Canada, 2Hudson Institute of Medical Research,
Monash University, Melbourne, Victoria, Australia, 3Arthur and Sonia
Labatt Brain Tumor Research Centre, Division of Haematology/Oncology,
Hospital for Sick Children, Toronto, ON, Canada, 4Department ofPaediatric Oncology, Hospital Infantil Virgen del Rocio, Sevilla, Spain,
5Department of Laboratory Medicine and Pathobiology, Faculty of
Medicine, University of Toronto, Toronto, ON, Canada, 6Division of
Oncology, Cancer and Blood Diseases Institute, Cincinnati Children’s
Hospital Medical Center, Cincinnati, OH, USA, 7Cancer and Blood
Disorders Center, Seattle Children’s Hospital, Seattle, WA, USA,
8Department of Pediatrics, University of Colorado, Denver, Aurora, CO,
USA, 9Pediatric Hematology and Oncology Department, Hospital Infantil
Universitario Niño Jesús, Madrid, Spain, 10Hospital Universitario Virgendel Rocío, Sevilla, Spain, 11University of Alabama at Birmingham,
Birmingham, USA, 12Department of Neurosurgery, University of Alabama
at Birmingham, Birmingham, USA, 13Department of Neurological Surgery,
University of California, California, San Francisco, CA, USA, 14Departmentof Pediatric Neuro-Oncology, Sheba Medical Centre, Tel HaShomer, Ramat
Gan, Israel, 15Department of Neurosurgery, Kumamoto University,
Kumamoto, Japan, 16Taipei Medical Hospital, Taipei City, Taiwan,
17Department of Neurosurgery, Asan Medical Center, Seoul, Repulic ofKorea, 18Paediatric Haematology and Oncology Division, University of
Catania, Sicily, Italy, 19Department of Neurosurgery, Agostino Gemelli
University Hospital, Rome, Italy, 20Pathology Unit Meyer Children’s
Hospital, Florence, Italy, 21Children’s Cancer Centre, Royal Children’s
Hospital, Melbourne, VIC, Australia, 22Children’s Brain Tumor ResearchCentre, Queen’s Medical Centre University of Nottingham, Nottingham,
United Kingdom, 23Department of Pathomorphology, Jagiellonian
University Medical College, Krakow, Poland, 24Department of PediatricHematology and Oncology, Children’s Healthcare of Atlanta and theEmory University School of Medicine, Atlanta, GA, USA, 25Department of
Pathology, Valley Children’s Hospital, Madera, CA, USA, 26Department ofPediatrics Division of Hematology/Oncology, Children’s Hospital of
Eastern Ontario, Ottawa, ON, Canada, 27Department of PediatricOncology, Alberta Children’s Hospital, Calgary, AB, Canada, 28Departmentof Pathology, University of Michigan, Ann Arbor, MI, USA, 29Division of
Pediatric Hematology Oncology, Rafic Hariri University Hospital, Beirut,
Lebanon, 30Division of Neuro-Oncology, Department of Oncology, St. JudeChildren’s Research Hospital, Memphis, TN, USA, 31Department of
Neurosurgery, Mohamed Vth, University, School of Medicine, Hôpital desSpécialités, ONO CHU Ibn Sina, Rabat, Morocco, 32PediatricHemathology and Oncology Division, University Hospital S, João Alameda
Hernani Monteiro, Porto, Portugal, 33Division of Hematology-Oncology,
Steven and Alexandra Cohen Children’s Medical Center, Northwell Health,
New York, NY, USA, 34Children’s Hospital, Hackensack University
Medical Center, Hackensack, NJ, USA, 35Monash Children’s Hospital,
Melbourne, VIC, Australia, 36King Hussein Cancer Center, Al-Jubaiha
Amman, Jordan, 37Department of Neuropathology Huashan Hospital
Fudan University, Shanghai, China, 38The Tumour Bank, Children’s Cancer
Research Unit, Kids Research Institute, the Children’s Hospital atWestmead, NSW, Australia, 39Department of Pathology and Laboratory
Medicine, Children’s Hospital of Eastern Ontario, Ottawa, Canada,
40University of Minnesota Medical School Minneapolis, MN, USA,
41Department of Pathology, CHU Sainte-Justine Research Center,
Université de Montréal, Montreal, QC, Canada, 42Department ofiii328N EU R O - O N C O L O G Y•

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Oncology, University Children’s Hospital, Zurich, Switzerland, 43Divisionof Pediatric Oncology, Children’s Hospital of Orange County, Orange, CA,
USA, 44Department of Pediatrics, Johns Hopkins University School of
Medicine, Baltimore, MD, USA, 45Department of Pathology andLaboratory Medicine, University of British Columbia, Vancouver, BC,
Canada, 46Pediatric Hematology-Oncology, Department of Pediatrics,
University of Minnesota Masonic Children’s Hospital, Minneapolis, MN,
USA, 47Division of Pediatric Hematology/Oncology duPont Hospital forChildren, Wilmington, DE, USA, 48Children’s Cancer Institute, Universityof New South Wales, NSW, Australia, 49Department of Paediatrics,
University of Otago, Christchurch, New Zealand, 50Kids Cancer Centre,
Telethon Kids Institute, Subiaco, WA, Australia, 51Department of
Hematology, Trakya University Medical Faculty, Edirne, Turkey,
52Paediatric Haematology and Oncology, Southampton Children’s
Hospital, South Hampton, United Kingdom, 53Johns Hopkins School of
Medicine, Sidney Kimmel Comprehensive Cancer Center, Division of
Pediatric Oncology, Baltimore, MD, USA, 54The Hospital for Sick Children,
Toronto, ON, Canada, 55Department of Oncology, Children’s National
Medical Center, Washington, DC, USA, 56Center for Cancer and Blood
Disorders, Phoenix Children’s Hospital, Phoenix, AZ, USA, 57Departmentof Pathology, University of California, San Francisco (UCSF), San
Francisco, CA, USA, 58Great Ormond Street Hospital for Children NHSFoundation Trust, London, United Kingdom, 59Neurology Service,
Department of Pediatrics, KK Women’s and Children’s Hospital, Singapore,
Singapore, 60Orlando Regional Medical Center, Orlando, FL, USA,
61Paediatric Haematology/Oncology Service, KK Women’s and Children’s
Hospital, Singapore, Singapore, 62Neuro Oncology Unit Department ofPediatric Hematology, Oncology and Stem Cell Transplantation St Joan de
Déu Children´s Hospital, Barcelona, Spain, 63The Hospital for Sick
Children, Toronto, ON, Canada, 64Department of Human Pathology,
Gunma University, Gunma, Japan, 65Département de Cancérologie del’Enfant et de l’Adolescent, Institut Gustave Roussy, Villejuif, Paris, France,
66PSL Research University, Institut Curie Research Center, Paris, France,
67APHM La Timone Hospital, Saint-Pierre, France
ETMR, an aggressive disease characterised by C19MC alterations, werepreviously categorised as various histologic diagnoses. The clinical spectrum and impact of conventional multi-modal therapy on this new WHO
diagnostic category remains poorly understood as a majority of ~200 cases
reported to date lack molecular confirmation. We undertook comprehensive clinico-pathologic studies of a large molecularly confirmed cohort toimprove disease recognition and treatment approaches. Amongst 623 CNSPNETs patients enrolled in the RBTC registry, 159 primary ETMRs wereconfirmed based on a combination of FISH (125), methylation analysis (88),
SNP and RNAseq (32) analyses; 91% had C19MC amplification/gains/fusions, 9% lacked C19MC alterations but had global methylation featuresof ETMR NOS. ETMRs arose in young patients (median age 26 months)
predominantly as localized disease (M0-72%, M2-3 -18%) at multiple locations including cerebrum (60%) cerebellum (18%), midline structures(6%); notably 10% were brainstem primaries mimicking DIPG. Uni-and
multivariate analyses of clinical and treatment details of curative regimens
available for 110 patients identified metastatic disease (p=0.002), brainstem locations(p=0.005), extent of surgery, receipt of multi-modal therapy
including high dose chemotherapy and radiation (P<0.001) as significant
treatment prognosticators, while C19MC status, age and gender were nonsignificant risk factors. Analyses of events in all patients showed respective
EFS at 3 and 12 months of 84%(95%CI:77–91) and 37%(95%CI:20–41)
and 4yr OS of 27%(95%CI:18–37) indicating despite intensified therapies
ETMR is a rapidly progressive and fatal disease. Our comprehensive dataon the largest cohort of molecularly-confirmed ETMRs provides a criticalframework to guide current clinical management and development of clinical trials.

GERM CELL TUMORS
GCT-02. THE LONG-TERM OUTCOMES AND SEQUELAE ANALYSISOF INTRACRANIAL GERMINOMA FROM 187 PATIENTS IN THE
SINGLE INSTITUTE: NECESSITY FOR THE ADAPTATION OF
RADIOTHERAPY DOSE AND VOLUMEJoo Ho Lee1, Il Han Kim1, Keun-Yong Eom2, Seung Ki Kim1,
Kyu-Chang Wang1, Tae Min Kim1, Dae Seog Heo1, Hyoung Jin Kang1, andHee Young Shin1; 1Seoul National University Hospital, Seoul, Republic ofKorea, 2Seoul National University Bundang Hospital, Seongnam, Republicof Korea
PURPOSE: We aimed to refine the radiotherapy (RT) volume and dose
determinant for disease failures and long-term sequelae in the intracranial
germinoma. METHODS: The main treatment for intracranial germinoma
was craniospinal RT only (n=51) during 1981–1992 and RT with upfront
chemotherapy (CRT) (n=152) during 1992–2015 in Seoul National Uni-

Abstracts

versity Hospital. All 187 cases were confirmed histologically. RT fields included craniospinal, whole-ventricle (WV), whole-brain (WB), and focal
radiotherapy. RT dose was dependent on the M status and combinationof chemotherapy. The median follow-up duration was 115 months (range,
3–358). RESULTS: The 10-year overall and recurrence-free survival was
94.5% and 91.4%. The complete response rate after chemotherapy was
62.6%. For the patients with complete response, WV RT 16–20 Gy, andfocal boost of 25–36 Gy after upfront chemotherapy showed no in-field recurrence. The causes of death were progression (n=3), 2nd malignancy (n=6),treatment-related complications (n=7), and others (n=8). For non-sellar tumors, the rate of hormonal replacement treatment was significantly related
to WB RT and WB/WV RT dose ≥ 30 Gy (p=.030, and .026). After a latencyof the median 20 years, ten patients (5.3%) developed 2nd malignancy. WB
RT and WB/WV dose ≥ 30 Gy were significantly correlated with the 2nd malignancy (p=.024, and .004). The rate of severe neurocognitive dysfunction
was significantly associated with WB/WV dose ≥ 30 Gy (p=.027). CONCLUSION: CONCLUSION: RT with or without upfront chemotherapy
exhibits the excellent control rate of disease. However, the intensity andvolume of RT are critical for managing treatment toxicities. Adaptation andfurther de-intensification of RT should be followed.
GCT-03. TREATMENT OUTCOMES, PHYSICAL DEVELOPMENTAND QUALITY OF LIFE OF PATIENTS WITH BIFOCAL GERM CELLTUMOURS
Bo Li; Beijing Tiantan Hospital, Capital Medical University, Beijing, China
BACKGROUND: The optimal radiation field in patients with bifocal
germ cell tumours(GCTs) is controversial, especially in non-metastatic cases.
Accordingly, we analysed the survival, growth, and health-related quality oflife (HRQOL) data of patients with bifocal GCTs. METHODS: The dataof 87 patients diagnosed with bifocal GCTs at our hospital during the last
10 years were collected. The WHO AnthroPlus software—used to monitor
the growth of persons aged 5–19 years—was employed to calculate theZ-score of height (ZSOH) at diagnosis and the last follow-up. The absolutechange in the ZSOH was defined as |ZSOH last follow-up - ZSOH diagnosis|. The
Pediatric Quality of Life Inventory 4.0 was used to evaluate HRQOL. RESULTS: The median follow-up was 49 months (range,6–134 months).
Among 49 patients with non-metastatic germinoma, those receiving cranial spinal irradiation(CSI; n=12) or whole-brain radiotherapy (WBRT;n=34) had comparable disease-free survival (DFS;p=0.54), but better DFS
than those receiving focal radiotherapy(n=3;p=0.016). Furthermore, among
17 patients with non-metastatic non-germinomatous GCTs, DFS was not
significantly different between those treated with CSI(n=4) and those receiving WBRT(n=13;p=0.11). Twenty-nine patients had paired ZSOH data
at both diagnosis and the last follow-up. Patients receiving CSI(p=0.026)
or >40Gy(p=0.048) experienced a significant decline of absolute change in
the ZSOH. HRQOL analysis(n=35) did not reveal difference between patients receiving CSI and those not receiving CSI. CONCLUSIONS: Given
the comparable DFS and HRQOL but negative impact on growth, CSI could
be spared, especially in patients with non-metastatic bifocal germinoma.
GCT-06. DIAGNOSIS OF A RARE CASE OF RECURRENT GERM
CELL TUMOR BY CSF PLACENTAL ALKALINE PHOSPHATASEPRESENTING WITH DIFFUSE INTRAAXIAL ABNORMALITY IN
THE LOWER BRAINSTEM
Hiroki Yamada1, Tomohiro Abiko1, Hirokazu Fujiwara2,
Kazunari Yoshida1, and Hikaru Sasaki1; 1Department of Neurosurgery,
Keio University School of Medicine, Tokyo, Japan, 2Department of
Diagnostic Radiology, Keio University School of Medicine, Tokyo, JapanINTRODUCTION: Germ cell tumors in the central nervous system(CNS) typically arise either at suprasellar and/or pineal region, and occasionally at basal ganglia. We report a case of diagnostically challenging, recurrent germ cell tumor presented with diffuse intraaxial abnormality in andacross the lower brainstem, which was diagnosed by the elevated placental
alkaline phosphatase (PLAP) level in cerebrospinal fluid (CSF). CASE DESCRIPTION: A 28-year-old man had been treated by chemoradiotherapy
at the previous hospital for bifocal suprasellar and pineal lesions with theprovisional diagnosis of germinoma without histological confirmation.
Three years later, he presented with progressive weakness of bilateral extremities for weeks. Magnetic resonance imaging showed a diffuse, bilaterally symmetric high intensity lesion on T2-weighted image with slightcontrast enhancement across the ventral side of the medulla oblongata to
the upper cervical spinal cord. Serum and CSF hCG, hCG-β, and AFP were
all negative. Since the image findings were atypical for recurrent germ celltumor, some kind of myelitis was initially suspected. Therefore, steroid pulse
therapy was administered. However, the patient’s symptom was still gradually progressing. Then, the CSF PLAP turned out to be positive, indicating
the recurrence of germinoma. Accordingly, platinum-based chemotherapy
was administered, and the imaging findings, patient’s symptoms, and CSF
PLAP began to improve. The patient is to be treated with radiotherapy fol-lowing chemotherapy. CONCLUSION: We report a rare case of CNS germ
cell tumor that presented with diffuse intraaxial lesion in the lower brainstem in which examination of CSF PLAP was extremely useful.
GCT-08. PROTON BEAM RADIOTHERAPY FOR PEDIATRIC ANDYOUNG-ADULT PATIENTS WITH INTRACRANIAL GERM CELL
TUMOR
Minako Sugiyama1, Takayuki Hashimoto2, Takashi Mori2,
Kazuya Hara1, Yukayo Terashita1, Shinsuke Hirabayashi3, Yuko Cho1,
Akihiro Iguchi1, Michinari Okamoto4, Yukitomo Ishi4, Hiroaki Motegi4,
Shigeru Yamaguchi4, and Atsushi Manabe1; 1Department of Pediatrics,
Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido,
Japan, 2Department of Radiation Medicine, Faculty of Medicine, Hokkaido
University, Sapporo, Hokkaido, Japan, 3Department of Pediatrics,
Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido,
Jersey, 4Department of Neurosurgery, Faculty of Medicine, Hokkaido
University, Sapporo, Hokkaido, JapanBACKGROUND: To reduce treatment-related adverse events in pediatric and young-adult patients with brain tumors, proton beam radiotherapy (PBT) has recently been performed instead of conventional X-ray
radiotherapy. However, whether PBT is as effective as X-ray radiotherapy
has not been sufficiently investigated, especially in patients receiving
whole-ventricular irradiation. METHODS: We report a retrospective observation of 15 patients with intracranial germ cell tumors (GCT), whoreceived PBT at our institution from April 2014 to September 2019. We
evaluated their clinical course, short-term adverse events, and prognosis.
RESULTS/CONCLUSION: Fifteen patients (9 males and 6 females; medianage 13 years) who received PBT following induction chemotherapy wereanalyzed. Nine patients received 23.4–27.0 GyE of whole-ventricular irradiation due to GCT in the pituitary gland, pineal body, or hypothalamic area.
Three patients received 23.4 GyE of whole-brain irradiation: one of themhad boost irradiation for basal ganglia. Three patients received 30.6 GyEof craniospinal irradiation (CSI). Six of the 15 patients experienced nausea(grade 2, according to the CTCAE version 4.0). Four patients, including
two who received CSI, showed myelosuppression: decrease in white blood
cell count, lymphocyte cell count, and neutrophil count (grade 3). No othersevere short-term adverse events of >grade 2 was observed in any of the patients. At a median follow-up of 21 months (2‐62 months) after irradiation.
all patients are alive without recurrence. Our results may be encouraging
and further investigations with a larger scale is warranted.
GCT-09. HEALTH AND SOCIAL ISSUES IN THE LONG-TERM
GERM-CELL TUMOR SURVIVORS
Tomoo Matsutani1, Kentaro Horiguchi1, Shiro Ikegami1,
Seiichiro Hirono1, Hisayuki Murai2, Naokatsu Saeki3, and Yasuo Iwadate1;
1Chiba University Graduate School of Medicine, Chiba-shi, Chiba, Japan,
2Chibaken Saiseikai Narashino Hospital, Narashino-shi, Chiba, Japan,
3International University of Health and Welfare, Ichikawa Hospital,
Ichikawa-shi, Chiba, Japan
Germ cell tumor (GCT) is a rare juvenile CNS tumor that is more frequent in eastern Asia. Most survivors require continuous medical carefor hormone replacement, maintenance of shunting devices, and lateradiation-induced effects. In the present study, we retrospectively analyzed
medical records of long-term GCT survivors, and make the health andsocial issues clear. Ninety-two GCT patients were treated in our institutefrom 1982 to 2018, and 81 patients, of which medical records are available, are included. The median follow-up period is 12.2 years, and 47 patients (58.1%) are followed for more than ten years. The overall survival
rate is gradually decreasing more than ten years follow-up, such as 10-,15- and 25-years survival are 92.3, 87.7, and 73.3%, respectively. In thelong-term follow-up, eight subsequent malignancy and seven cerebrovascular events are recorded. These events occurred 20 years or more after thetreatments, and six CNS malignancies were observed in survivors irradiated with 50Gy or more. As social issues, forty-two of 50 adult survivors
had been employed after the treatments, but only thirty-four (70.8%) arestill working. Of note, only nine (18.8% of adults) survivors got married.
All four married women require any hormone replacement, while only oneof 4 men requires the replacement. Long-term follow-up of GCT survivors
revealed subsequent malignancy and social problems. A recent attempt todecrease the dose of irradiation might overcome some issues. As a conclusion, GCT survivors require a supporting program for not only health but
also social issues.
GCT-10. CAN HIGH LEVEL SERUM HCG-Β BE CONSIDERED
EQUIVALENT TO A DIAGNOSIS OF CHORIOCARCINOMA IN
PRIMARY CENTRAL NERVOUS SYSTEM GERM-CELL TUMOR?
Hiroaki Motegi, Shigeru Yamaguchi, Yukitomo Ishi, Michinari Okamoto,
Akihiro Iguchi, Yuko Cho, Minako Sugiyama, Atsushi Manabe, andN E U R O -O N C O L O G Y•

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Kiyohiro Houkin; Hokkaido University Hospital, Sapporo, Hokkaido,
Japan
BACKGROUND: Primarycentralnervoussystem(CNS)
choriocarcinoma(CC) is very rare and has the poorest prognosis among
germ cell tumor (GCT). CC usually has extremely high level (HL) of serumbeta-human chorionic gonadotropin (bhCG) over than 1,000 mIU/ml. Somestudies assign HL bhCG cases to poor prognosis group even without biopsy.
The purpose of this study was to find out if there was a good prognosis
subset in the HL bh group. MATERIALS AND METHODS: We analyzed
103 cases diagnosed with GCT from 1998 to 2019 in Hokkaido University Hospital and reviewed the literature of CNS CC and bhCG. Survival
was assessed using Kaplan-Meier method and log-rank statistics between
the group with CC component and that with no CC component but HL
bhCG. RESULTS: One out of 103 our cases was diagnosed as a mixed GCTwith CC component and did not respond to treatment and died 9 months
later. Two cases were treated as CC because of HL bhCG (1,226 and 2,739
mIU/ml) despite that the biopsy showed only germinomas and survived(105and 37 months), that is, no CC component. Combining our cases with 69
cases in the literature, all 7 cases with no CC component but HL bhCG
survived but the median survival of the other 65 cases with CC component
was 38.2 months (P=0.02). CONCLUSION: This study has a limitation of
selection bias, however, it suggests that patients with no CC component but
HL bhCG may have a better prognosis.
GCT-12. INTRACRANIAL GROWING TERATOMA SYNDROME:
CLINICAL IMPLICATION FROM SINGLE UNIVERSITY
EXPERIENCES
Chae-Yong Kim1,2, Ji-Yeon Kwon1, Kyeong-O Go1, Kihwan Hwang1,2,
Jung Ho Han1,2, Hyoung Soo Choi1,2, You Jung Kim1,2, Byung Se Choi1,2,
In Ah Kim1,2, Gheeyoung Choe1,2, Seung-Ki Kim3,2, Ji Hoon Phi3,2,
Kyu-Chang Wang3,2, and Byung-Kyu Cho4; 1Seoul National University
Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea,
2Seoul National University College of Medicine, Seoul, Republic ofKorea, 3Seoul National University Children’s Hospital, Seoul, Republicof Korea, 4Department of Neurosurgery, Armed Forces Capital Hospital,
Seongnam-si, Gyeonggi-do, Republic of Korea
In general, intracranial germ cell tumors (GCT) are sensitive to chemotherapy, radiation therapy, and have favorable outcomes. However, a rare
chemotherapeutic retro conversion phenomenon, known as intracranial
growing teratoma syndrome (iGTS), shown a poorer prognosis. We analyze the diagnostic characteristics and the result of treatment response forthe patients with iGTS treated in our institutes (SNUH and SNUBH, from1997 to 2019). The electronic medical records and PACS were used for reviewing the clinical information, follow-up MRI images, tumor markers(alpha-fetoprotein, human chorionic gonadotropin, in serum or cerebrospinal fluids), and pathological findings. Out of 328 intracranial GCT patients, seventeen were finally identified as iGTS. Sixteen out of 17 patientswere non-germinomatous GCTs, and 1 were germinomas. Initial pathology
was common in order of immature teratoma (26.7%), other than immature
teratoma (11.5%), and germinoma (0.5%). All of the tumors showed typical ‘honeycomb appearance’ in their follow-up MRI images. Sixteen out
of 17 tumors were surgically resected as 2nd look surgery. Among them, 13
tumors were gross totally resected. Twelve were alive without evidence ofrecurrences during follow-up periods, and the other was dead from the progression of the disease. Among the other than the gross total resection group(n=4), two patients were dead, one recurred the tumor, and the other is following up with stable disease after adjuvant radiation therapy. Early detection and total resection of the tumor as possible might be meaningful forfavor prognosis, especially in non-germinomatous GCTs patients.
GCT-13. THE TREATMENT OUTCOMES OF INTRACRANIALGERM CELL TUMORS WITH KSPNO PROTOCOL: SINGLE CENTER
RETROSPECTIVE ANALYSIS
Kyeong-O Go1, Soyoung Ji2, Kihwan Hwang3,4, Jung Ho Han3,4,Hyoung Soo Choi3,4, You Jung Kim3,4, Byung Se Choi3,4, In Ah Kim3,4,Gheeyoung Choe3,4, Jin-Myung Jung5,6, Yong-Kil Hong7,8, andChae-Yong Kim3,4; 1Department of Neurosurgery, Gyeongsang
National University Hospital, Jinju, Republic of Korea, 2Departmentof Neurosurgery, Seoul National University, Bundang Hospital, Seoul,
Republic of Korea, 3Seoul National University Bundang Hospital,
Seongnam-si, Gyeonggi-do, Republic of Korea, 4Seoul National
University College of Medicine, Seoul, Republic of Korea, 5Department of
Neurosurgery, Gyeongsang National University Hospital, Jingu, Republicof Korea, 6Department of Neurosurgery, Institute of Health Science,
College of Medicine, Gyeongsang National University, Jinju, Réunion,
7Seoul St, Mary’s Hospital, Seoul, Republic of Korea, 8College of Medicine,
The Catholic University of Korea, Seoul, Republic of Korea
Dho et al. (BTRT, 2017) reported that 1.1% (127/11,827) of primarybrain tumors are intracranial germ cell tumors (iGCT) in Korea. We analyzed

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the epidemiology and treatment results of germ cell tumors in our institution. From 2004 to 2019, among 6494 patients with intracranial neoplasms
the 61 (0.9%) patients with iGCTs were enrolled: histologically diagnosed
in 50 patients and clinically in 11 respectively. Pediatric patients underwent treatment according to the KSPNO protocol, and adult patients weretreated with bleomycin, etoposide, and cisplatin regimens. The median age
was 20 years (range: 1–42) and the follow-up period was 7.7 months (range:
10.0–203.4 months), respectively. The tumors arise most frequently in thepineal area (n=30, 49.2%). There were no significant differences in outcomes
between protocols, but in KSPNO protocol group showed lower tumor
recurrence rate (11.5% vs. 20%, p=0.494) and mortality (0% vs. 5.2%,
p=0.503). According to the pathological subtype, the outcomes showed statistically significant differences between germinoma and non-germinomatous
germ cell tumor (NGGCT) groups. The 10-year progression-free survival
was 93.2% and 67.1% in the germinoma and the NGGCT group, respectively (p=0.009). The NGGCT pathological type (p=0.021) was a significant
recurrence associated factor in multivariate analysis. Significant adverse
events (CTCAE version 5.0 grade≥3) were showed in 14 patients (7 patientsin both KSPNO and other treatment protocol groups). Pure germinoma
has a higher survival rate and a lower recurrence rate than NGGCT. And
KSPNO protocol might be safe and effective. For appropriate treatment for
iGTCs, a multidisciplinary approach might be needed.
GCT-14. SECOND-LOOK SURGERY FOR INTRACRANIAL GERM
CELL TUMORS
Hideki Ogiwara; National Center for Child Health and Development,
Tokyo, JapanOBJECTIVE: The authors present their experiences of second-look surgery in patients with intracranial GCTs who showed less than complete
response despite normalizing or decreasing tumor markers after chemotherapy. METHODS: Retrospective review of 14 patients who underwent
second-look surgery for an intracranial GCT was performed. RESULTS: Of
40 consecutive patients with newly diagnosed intracranial GCTs treated between August 2003 and 2019, 14 patients (35%) underwent second-looksurgery. The mean age was 9.2 years. The initial diagnoses were mixed germ
cell tumor in 6, immature teratoma in 4, yolk sac tumor in 2, and germinoma
2. Second-look surgery was performed after 1–3 courses of chemotherapy.
Magnetic resonance imaging (MRI) at the surgery demonstrated increasing
residual tumor in 8 and stable residual tumor in 6. Tumor markers werenormalized in 10 and nearly-normalized in 4. Gross total resection wasachieved in 12 patients and near-total resection in 2. Histopatholgy at
second-look surgery revealed mature teratoma in 6, immature teratoma in
3, fibrosis with atypical cells in 2, and fibrosis in 3. Eleven patients subsequently underwent additional chemo-radiation therapy according to theinitial diagnosis. All patients are alive with no evidence of recurrence with amean follow-up of 69 months. CONCLUSIONS: Second-look surgery plays
an important role in the treatment of intracranial GCTs. Surgery may be
encouraged at a relatively early phase after chemotherapy when the residual
tumor increases or does not change the size despite normalized or nearlynormalized tumor markers in order to achieve complete resection and improve the outcome.
GCT-15. INTEGRATED CLINICAL, HISTOPATHOLOGICAL, AND
MOLECULAR DATA ANALYSIS OF 190 CENTRAL NERVOUS
SYSTEM GERM CELL TUMORS FROM THE IGCT CONSORTIUM
Hirokazu Takami1,2, Koichi Ichimura1, Kohei Fukuoka3, Akitake Mukasa4,
Nobuhito Saito2, Yoshitaka Narita5, Soichiro Shibui5, Yoichi Nakazato6,
Ryo Nishikawa3, and Masao Matsutani3; 1National Cancer Center
Research Institute, Tokyo, Japan, 2The University of Tokyo, Tokyo, Japan,
3Saitama Medical University International Medical Center, Saitama, Japan,
4Kumamoto University, Kumamoto, Japan, 5National Cancer Center
Hospital, Tokyo, Japan, 6Hidaka Hospital, Gunma, JapanBACKGROUND: We integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights
into their management. METHODS: Data from the Intracranial Germ Cell
Tumor Genome Analysis Consortium were reviewed. A total of 190 cases
were classified as primary GCTs based on central pathological reviews. RESULTS: All but one of the cases that were bifocal (neurohypophysis andpineal glands) and cases with multiple lesions including neurohypophysis
or pineal gland were germinomas (34 of 35). Age was significantly higher
in patients with germinoma than other histologies. Comparison between
tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker-positive and 6.1% of
non-germinomatous GCTs were marker-negative, suggesting a limitation in
the utility of markers or histopathology alone using small specimens fordiagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly lessfrequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites(neurohypophysis or pineal gland) showed a better PFS than those at atyp-Abstracts

ical sites (p=0.03). A molecular-clinical association study revealed frequent
MAPK pathway mutations in males (51.4 vs 14.3 %, p=0.007), and PI3K/
mTOR pathway mutations in basal ganglia cases (p=0.004). Basal ganglia
cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance. CONCLUSIONS: These in-depth findings of this study regarding
the clinical and molecular heterogeneity will increase our understanding of
the pathogenesis of this enigmatic tumor.
GCT-16. LONG-TERM CLINICAL OUTCOMES OF GERM CELL
TUMORS
Kenichiro Matsuda, Kaori Sakurada, Takamasa Kayama, andYukihiko Sonoda; Department of Neurosurgery, Faculty of Medicine,
Yamagata University, Yamagata, JapanBACKGROUND: Intracranial germ cell tumors (GCT) are mainly arisingin adolescent term and treated with chemotherapy concomitant with radiation therapy. There is accumulating evidence that the progress of treatment. Besides, long-term outcome and adverse effects are major problem
in treatment. So, we must grasp the influence of these outcomes on dailyand social life. Then we investigated in clinical outcome in cases of GCTtreated in our institution. METHOD: We reviewed the clinical featuresand outcomes of 52 cases of intracranial GCT in 1975 to 2019. Ages on
diagnosis are 5–35 years old (median 14 years old), consisted with 44 malecases. The pathological distributions are these: pure germinoma: 40 cases,
non-germinomatous germ cell tumor (NGGCT): 10 cases (mature teratoma:
4, mixed germ cell tumors: 3, and one cases of choriocarcinoma, embryonal carcinoma, yolk sac tumor), unidentified pathology: 2 cases. Almost allcases have biopsied and treated by chemotherapy and radiation therapy. RESULTS: Chemotherapy with ICE regimen (ifosphamide, cisplatin, etoposide)or CARE regimen (carboplatin, etoposide) concomitant with radiation
therapy (mainly, extended local irradiation) have done in almost cases by
the era. Clinical outcomes are relatively well in our cases, but 10 cases experienced recurrence. 3 cases have dead. Some cases with suprasellar involvement have need hormone replacement in long term. There are 10 cases
at work. CONCLUSION: Almost cases have gained better outcome and
ADL. But there is slightly lower rate in work or marriage. Serial evaluationin outcome, and higher brain functions should be performed in follow up.
GCT-17. WHAT IS THE CLINICAL OUTCOME OF PROTON BEAM
THERAPY FOR PATIENTS WITH INTRACRANIAL GERM CELL
TUMOR IN KOREA?
Sang Hee Youn, and Joo-Young Kim; National Cancer Center, Goyang-si,
Republic of Korea
PURPOSE: To evaluate the clinical outcome of patients with intracranial germ cell tumor treated with proton beam therapy (PBT). MATERIALS AND METHODS: Fifty-seven patients with intracranial germ celltumor treated with PBT between 2009 and 2016 were retrospectively analyzed. RESULTS: Median follow-up duration was 63.7 months (range, 5.6–
204.5). Thirty-seven patients (64.9%) were pure germinoma and 20 patients(35.1%) were non-germinomatous germ cell tumor (NGGCT). All patients
except 2 patients received chemotherapy before PBT. Twenty-one patients(36.8%) of localized germinoma were treated with whole ventricle irradiation (WVI), while 36 (63.2%) patients who were diagnosed as disseminated germinoma or NGGCT received cranio-spinal irradiation (CSI). Twopatients with pure germinoma in basal ganglia showed disease relapse at 3.0
and 6.9 years after PBT at the primary site and pituitary gland, respectively.
There was one patient with NGGCT who died of chemotherapy-related
mortality at 4.7 years after PBT while her disease was complete remission.
The 7-year progression-free survival and overall survival were 70.8% and100% for focal germinoma, 100% and 100% for disseminated germinoma,
100% and 100% for focal NGGCTs, and 100% and 80.0% for disseminated NGGCTs, respectively. CONCLUSIONS: PBT of pure germinoma
resulted in comparable clinical outcomes to that with photon radiotherapy.
Our result for NGGCT is also excellent compared to other reports. Failure
patterns of germ cell tumors originating in basal ganglia needs to be assessedin large pooled data.
GCT-18. CLINICAL FEATURES OF GERM CELL TUMORS IN
CHILDREN
Nayuta Higa; Kagoshima University, Kagoshima, JapanINTRODUCTION: Here, we discuss the presentation, histology, therapy,
and outcome of germ cell tumors in children. METHODS: Treatment outcome and management was assessed for children diagnosed with germ celltumors from 2007 to 2017 at Kagoshima University. RESULTS: Twenty-six
patients (20 boys, 6 girls) with a mean age of 11.5 ± 4.9 years were includedin this study. Patient tumor types included: germinoma (n = 19); immature
teratoma (n = 3); yolk sac tumor (n = 3); choriocarcinoma (n = 1); embryonalcarcinoma (n = 1). The most common patient clinical features were headache and vomiting associated with hydrocephalus. The median follow-up
period was 96.5 months. Tumor location was pineal (n=9), bifocal (n=6),
suprasellar (n = 5), basal ganglia (n=2), frontal lobe (n=2), and cerebellum(n=2). Surgical procedures included stereotactic biopsy (n=13), endoscopic
third ventriculostomy and biopsy (n=8), and tumor decompression (n=5).
All patients with germ cell tumors underwent adjuvant chemotherapy andradiation therapy; patients with germinoma or immature teratoma were still
alive, while patients with embryonal carcinoma, yolk sac tumor, or choriocarcinoma had poor prognosis with a median survival of 16 months. CONCLUSIONS: Patients with germinoma had a relatively good prognosis, whilepatients with embryonal carcinoma, yolk sac tumor, or choriocarcinoma had
a poor prognosis. A multidisciplinary approach including surgical strategy
based on location, appropriate radiation planning, and chemotherapy isneeded for effective treatment and improved outcomes.
GCT-19. MODELING GERM CELL TUMORS WITH KIT MUTANTHIPSCS
Sakura Kuzuoka1, Yoji Kojima2, Koichi Ichimura3, and Mitinori Saitou1,2;
1Kyoto University Institute for Advanced Study, Kyoto, Kyoto, Japan,
2Kyoto University CiRA, Kyoto, Kyoto, Japan. 3National Cancer Center,
Chuo-ku, Tokyo, Japan
Central Nervous System Germ Cell Tumor (CNS GCT) is the second mostcommon pediatric brain tumor in Japan, and within CNS GCT, germinoma
is the most common subtype, accounting for 62.3%. Recent reports of transcriptome and methylome analysis suggested that germinoma highly resemble the state of gonocytes, the germ cells at around 5th to 7th week ofhuman embryo development. It is also identified that 60% of germinoma
harbored somatic mutations in KIT/RAS pathway. As the protocol to derive gonocytes from human iPSCs have been reported, we aimed to recapitulate tumorigenesis by generating human iPSCs bearing common genetic
mutations and derive gonocytes from them. We first introduced the mostcommon mutation KITD816V to human iPSCs using CRISPR/Cas9, andconfirmed in iPSCs that mutated KIT was phosphorylated in the absenceof ligand stimulation, and also found that KIT activation contribute to thephosphorylation of AKT but not of ERK. Upon differentiation towards
primordial germ cell -like cells (PGCLCs), KIT mutant lines were efficiently
induced into PGCLCs, however, by comparing conditions with or without
KIT ligand (SCF), mutant lines exhibited less dependency to SCF comparedto wildtype cells. Mutant cells were further differentiated to gonocytes following published protocol and the cells were collected for transcriptome
analysis. By comparing with the transcriptome of germinoma, we confirmedthat germinoma samples express germ cell genes similar to gonocytes. We
are attempting to identify the molecular mechanism of tumorigenesis in relation to KIT activation using this system.
GCT-20. EVALUATION OF NEURORADIOLOGICAL RESPONSE TO
INDUCTION CHEMOTHERAPY FOR PATIENTS WITH LOCALISEDGERMINOMA IN THE SIOP CNS GCT II TRIAL
Brigitte Bison1, Giovanni Morana2, Dipayan Mitra3, Herve Brisse4,
Cecile Faure-Conter5, Thankamma Ajithkumar6, Claire Alapetite7,
Beate Timmermann8, James Nicholson9, Gabriele Calaminus10, andMatthew Murray9; 1Department of Neuroradiology, University ofWuersburg, Wuersburg, Germany, 2Department of Neuroradiology,
Gaslini Hospital, Genoa, Italy, 3Department of Neuroradiology, RoyalVictoria Infirmary, Newcastle, United Kingdom, 4Imaging Department,
Curie Institute, Paris, France, 5Department of Paediatric Haematology
and Oncology, Institute of Paediatric Haematology and Oncology, Lyon,
France, 6Department of Radiation Oncology, Cambridge University
Hospitals NHS Foundation Trust, Cambridge, United Kingdom,
7Department of Radiation Oncology, Curie Institute, Paris, France,
8Department of Particle Therapy, University Hospital Essen, West German
Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ),
Essen, Germany, 9Department of Paediatric Haematology and Oncology,
Cambridge University Hospitals NHS Foundation Trust, Cambridge,
United Kingdom, 10Department of Paediatric Haematology and Oncology,
University Hospital, Bonn, Germany
INTRODUCTION: The SIOP-CNS-GCT-96 trial demonstrated excellent survival for patients with germinoma. Localised patients received
either craniospinal irradiation (CSI) 24Gy plus tumour-bed-boost 16 Gy
or 2xcarboPEI chemotherapy (carboplatin/etoposide alternating withetoposide/ifosfamide) and focal-radiotherapy 40 Gy. Following trial
closure, whole-ventricular-irradiation (WVI) was delivered with focalradiotherapy to avoid ventricular relapse. Accordingly, current research priorities focus on reducing treatment burden and long-term neurocognitive
sequelae. METHODS: SIOP-CNS-GCT-II employed national central
radiological review to assess whether dropping the 16Gy boost was safe
for localized germinoma in complete-remission (CR) following 2xcarboPEI:
i.e. no disease on clinical/marker/radiological assessment. Any abnormal

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thickening/enhancement after chemotherapy was to be classified as partialremission (PR). Patients with less than CR after chemotherapy received aboost. RESULTS: Shortly before trial closure (2018), it was noted that national CR rates were discrepant across the largest recruiting countries. For
German patients, CR rates were ~80%, compared with ~30–40% for UK
and France. A formal neuroradiology review was therefore convened. A totalof 59 cases were randomly selected (UK, n=32; France, n=14 and Germany,n=13), including those deemed to be in CR and PR. Cases included thosewith disease at pituitary, pineal and bifocal sites. Both diagnostic scan andscan after induction chemotherapy were used for assessment. Detailed analysis is ongoing and will be presented. CONCLUSION: Residual changes
at both pituitary and pineal sites of uncertain significance may remain after
chemotherapy. This process should facilitate consensus to define the best response criteria allowing treatment reduction for CNS germinoma for future
clinical trials.
GCT-21. CENTRAL NERVOUS SYSTEM GERMINOMA PONDERING THE NEXT STEPSMohamed S. AbdelBaki1, and Ute Bartels2; 1The Division of Hematology,
Oncology and Bone Marrow Transplant, Nationwide Children’s Hospital,
Columbus, OH, USA, 2The Pediatric Brain Tumour Program, Hospital for
Sick Children, Toronto, ON, Canada
Central nervous system germinoma (CNS) represents one successful
example where the introduction of chemotherapy into the treatment allowed significant and meaningful reductions in the volume and dose ofradiation therapy while maintaining excellent outcomes. However, thelong-term toxicities and morbidities of the current therapies, in addition
to their substantial negative impact on the social wellbeing of germinoma
patients, should clearly indicate that the current achievements are notenough. While stepwise cutback of the radiation therapy needs to becommended, real progress must be achieved in the exploration and investigation of biological and molecular markers. Furthermore, the differences that still exist between the several working groups around theglobe in determining the tumor marker cut-offs that help diagnose thesetumors illustrate their shortcomings, and therefore the need for newer
and more reliable methods. Additionally, efforts should focus on the inclusion of metastatic and basal ganglia/thalamic germinomas in future
prospective clinical trials given the lack of evidence on the best treatment
strategy for these patients. A comprehensive review of all major CNS
germinoma clinical trials will be presented aiming to lay a foundation forresearchers and clinicians alike who are currently working on designinginnovative approaches for this group of patients. This review also details
the current issues of debate, and provides suggestions which may assist
in the design of future prospective clinical trials for children with CNS
germinomas.
GCT-22. PROTEIN DEUBIQUITINATION PATHWAY IS A NOVELTHERAPEUTIC TARGET AGAINST MALIGNANT NONGERMINOMATOUS CNS GERM CELL TUMORS
Arata Tomiyama1,2, Eita Uchida1,3, Kojiro Wada2, and Koichi Ichimura1;
1National Cancer Center Research Institute, Tokyo, Japa,. 2National
Defense Medical College, Saitama, Japan, 3Saitama Medical University
International Medical Center, Saitama, Japan
Central nervous system germ cell tumors (CNSGCTs) are rare intracranial neoplasm usually developed in adolescents and young adults. However, in East Asia including Japan, incidence of CNSGCTs is considerably
higher compare with other regions of the world. Whereas germinomas
generally respond to chemo-radiotherapy well, malignant subtypes of nongerminomatous germ cell tumors (NGGCT) are refractory, and development of novel therapy against NGGCTs is urgently needed. To develop a
new therapeutic strategy against aggressive NGGCTs, we have investigatednovel molecular targets for NGGCT treatment. We screened a total of 120
CNSGCT tumor tissues (including 55 NGGCT), which were registered
to the Intracranial Germ Cell Tumor Consortium (iGCT), and discovered
multiple mutations of a molecule that regulates protein ubiquitination anddegradation specifically in NGGCT cases (5 of 55 cases; 1 immature teratoma, 3 mixed gem cell tumors, and 1 embryonal carcinoma). An in vitro
ubiquitination assay revealed the mutations of this molecule discoveredin NGGCT cases were loss of function mutations. Reduced expression ofthis molecule by knockdown in an established human seminoma cell line
Tcam2 or a human yolk sac tumor cell line YST1, which was recently
established in our institute, resulted in enhanced proliferation as well as
upregulation of MEK-ERK activation. Importantly, treatment of these two
GCT cell lines with reduced expression of this molecule by MEK inhibitor
trametinib suppressed augmented proliferation of these cells. Taken together, these results suggest that protein ubiquitination-related pathways
as well as MEK-ERK cascade may serve as a novel therapeutic target
against NGGCTs.

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GCT-23. MULTI-INSTITUTIONAL ANALYSIS OF TREATMENT
MODALITIES IN BASAL GANGLIA AND THALAMIC GERMINOMA
Richard T. Graham1, Mohammad H. Abu-Arja2, Joseph Stanek3,
Ute Bartels4, Andrea Cappellano5, Susan Chi6, Tabitha Cooney6,
Girish Dhall7, Jonathan L. Finlay8, Michael J. Fisher9, Gregory Friedman7,
Amar Gajjar1, Karen Gauvain10, Lindsey M. Hoffmann11, Juliette Hukin12,
Ashley Margol13, Sabine Mueller14, Pournima Navalkele15,
Rebecca Ronsley12, Stephanie Villeneuve4, Kee Kiat Yeo6, Jack M. Su16,
Nicholas G. Gottardo17, Jeffrey Allen18, Roger Packer19, andMohamed AbdelBaki8; 1Department of Oncology, St. Jude Children’s
Research Hospital, Memphis, TN, USA, 2The Department of Pediatrics,
New York-Presbyterian Brooklyn Methodist Hospital, Weill-Cornell
College of Medicine, Brooklyn, NY, USA, 3Division of Hematology,
Oncology and Bone Marrow Transplant, Nationwide Children’s Hospital,
Columbus, OH, USA, 4Division of Hematology/Oncology, Hospital for
Sick Children, Toronto, ON, Canada, 5Instituto de Oncologia Pediátrica
GRAACC/UNIFESP, Division of Neuroncology, Sao Paulo, Brazil,
6Dana Farber Cancer Institute, Pediatric Neuro-Oncology, Boston, MA,
USA, 7Division of Pediatric Hematology and Oncology, Departmentof Pediatrics University of Alabama at Birmingham, Birmingham, AL,
USA, 8Division of Hematology, Oncology and Bone Marrow Transplant,
Nationwide Children’s Hospital and The Ohio State University, Columbus,
OH, USA, 9Division of Oncology, Children’s Hospital of Philadelphia,
Philadelphia, PA, USA, 10Washington University Medical Center & St,
Louis Children’s Hospital, St. Louis, MO, USA, 11Division of Hematology/
Oncology, Phoenix Children’s Hospital, Phoenix, AZ, USA, 12Division of
Hematology and Oncology, Children’s and Women’s Health Centre of
BC, University of British Columbia, Vancouver, BC, Canada, 13Cancer andBlood Disease Institute and Division of Hematology-Oncology, Children’s
Hospital Los Angeles, Keck School of Medicine, University of Southern
California, Los Angeles, CA, USA, 14Departments of Pediatrics, Neurology,
and Neurological Surgery, University of California San Francisco, San
Francisco, San Francisco, CA, USA, 15Department of Pediatrics, SSM
Cardinal Glennon Children’s Hospital, Saint Louis University, St. Louis,
MO, USA, 16Texas Children’s Cancer Center, Texas Children’s Hospital,
Baylor College of Medicine, Houston, TX, USA, 17Perth Children’s
Hospital, Perth, Western Australia, Australia, 18Department of Pediatrics,
NYU Langone Health, New York, NY, USA, 19Center for Neuroscience andBehavioral Medicine, Brain Tumor Institute Children’s National Health
System, Washington, DC, USA
BACKGROUND: Central nervous system (CNS) germinomas are radiotherapy (RT)-sensitive tumors with excellent survival. Current treatment
strategies combine chemotherapy with RT to reduce the field and dose of
RT. There is no standard treatment for germinomas originating in the basal
ganglia/thalami (BGTG) given their rarity and poorly-defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI),
and focal RT have been previously utilized; however, the optimal strategy
remains unclear. METHODS: Retrospective multi-institutional analysis was
conducted across 18 institutions in four countries. RESULTS: For 46 caseswith non-metastatic BGTG, the event-free survival (EFS) was 86.9% at both
5 and 10 years, while overall survival (OS) was 100%, and 95.7% respectively at 5 and 10 years. Median RT dose and range for the various treatment volumes were as follows: CSI (n=10): 2340 cGy (1980–3060 cGy),
WBI (n=8): 2340 (1800–3000 cGy), WVI (n=14): 2340 cGy (1800–2550
cGy), focal (n=9): 3600 cGy (3060–5400 cGy). There was no statistically significant difference in the EFS based on RT modality (p=0.57), but
EFS for subjects with CSI and WBI were both 100%. The three subjects
who received chemotherapy alone had significantly lower EFS than those
who received chemotherapy and RT (p=0.001), but were salvageable with
RT. CONCLUSION: In the largest study to date for BGTG, there were no
significant differences in outcomes between patients who received CSI, WBI,WVI or focal RT. This group of patients should be included in future prospective clinical trials, and a more limited RT field may be considered.
GCT-24. RELAPSE PATTERN AND QUALITY OF LIFE IN PATIENTSWITH LOCALIZED GERMINOMA ORIGINATING FROM BASALGANGLIA REGION
Bo Li; Beijing Tiantan Hospital, Beijing, China
BACKGROUND: The optimal radiation field in localized basal ganglia(BG) germinoma was not well defined, mostly due to unknown relapse patterns. In our institute, both focal radiotherapy (FR) and craniospinal irradiation (CSI) plus boost were considered in this population until whole-brain
radiotherapy (WBRT) plus boost became an option in 2008. Thus, a retrospective study was conducted to address the issue. Furthermore, the healthrelated quality of life (HRQOL) was also evaluated. METHODS: Patients
who were diagnosed as localized BG germinoma between 2000 and 2017
were studied. HRQOL was evaluated by PedsQL 4.0 (≤15 years) andSF-36 (>15 years) questionnaires based on the age at last follow-up. RESULTS: Among 161 patients included, 35 patients received FR, 109 patients

Abstracts

received WBRT plus boost, and 17 patients received CSI plus boost. After amedian follow-up of 83 months (range, 13 to 214 months), 15 patients relapsed in FR group, 4 in WBRT group and 0 in CSI group. The 5-year DFS
was 74.3%, 97.2%, and 100%, respectively (p<0.001). Among 15 patients
who relapsed after FR, 14 had positive radiological findings, in which 6(42.8%) had lesions documented at the periventricular area, and 7 (50.0%)
in the frontal lobe. HRQOL data were available in 69 patients, which generally scored low. In 38 patients evaluated by SF-36, those receiving CSI had
significantly lower mental component scores than those receiving WBRT
(p=0.027) or FR (p=0.011). CONCLUSIONS: Patients with localized BG
germinoma present a unique relapse pattern. WBRT, which covers at-riskareas, showed both better disease control and HRQOL.
GCT-25. INNOVATIVE, INTENSIVE IRRADIATION-AVOIDING/MINIMIZING CHEMOTHERAPY FOR HIGH-RISK PRIMARYCENTRAL NERVOUS SYSTEM (CNS) MIXED MALIGNANT GERM
CELL TUMORS (HR-MMGCT): A PILOT STUDY AND PROPOSEDMULTI-NATIONAL PROSPECTIVE TRIAL
Jonathan L. Finlay1,2, Mohammad H. Abu-Arja3,4, Rolla Abu-Arja1,2,
Jeffery Auletta1,2, Mohamed S. AbdelBaki1,2, Diana S. Osorio1,2,
Suzanne Conley1, Margaret Shatara1, Daniel R. Boué1,2,
Christopher R. Pierson1,2, Jerome Rusin1,2, Lisa Martin1,2, Jeremy Jones1,2,
Joshua D. Palmer1,2, Ralph Vatner5,6, Annie Drapeau1,2, Eric Sribnick1,2,
and Jeffrey R. Leonard1,2; 1Nationwide Children’s Hospital, Columbus,
OH, USA, 2The Ohio State University, Columbus, OH, USA, 3New YorkPresbyterian Brooklyn Methodist Hospital, Brooklyn, NY, USA, 4WeillCornell College of Medicine, New York, NY, USA, 5Cincinnati Children’s
Hospital, Cincinnati, OH, USA, 6University of Cincinnati, Cincinnati, OH,USA
BACKGROUND: About one-third of children with primary CNS
MMGCT experience incomplete responses to initial induction chemotherapy prior to irradiation, many of whom will subsequently relapse. Suchhigh-risk patients are variably defined as having initial alpha-fetoprotein(AFP) elevations exceeding 1,000ng/mL, predominant histopathologies ofmalignant non-germinomatous GCT and incomplete responses to induction chemotherapy. Drugs targeting GCT-specific molecular markers havebeen identified for non-germinomatous GCT elements but have yet to beincorporated into prospective clinical trials. Four children with clearly identified HR-MMGCT characteristics have been treated on an innovative pilot
regimen incorporating intensified chemotherapy and molecularly targeted
agents, with avoidance or minimization of irradiation. METHODS: Fourchildren (two with pure suprasellar embryonal carcinoma (EC) - onewith Down syndrome and the other with pre-diagnosis cognitive dysfunction; one with initial serum AFP exceeding 7,000ng/mL and yolk sactumor (YST)+EC+Teratoma pathology; one with initial serum AFP exceeding 1,000ng/mL) were treated with 3 cycles of “standard” induction
chemotherapy (ACNS1123), followed by 1–3 transplant cycles (thiotepa/
carboplatin) each with complete radiographic and tumor marker responses.
Two children with pure EC subsequently received six cycles of brentuximabvedotin without irradiation and remain disease-free off therapy for 2–4 years.
One child with YST+EC+Teratoma has subsequently received reduced dose
craniospinal irradiation and pineal region boost, and will receive oral
everolimus, erlotinib, palbocyclib and intravenous brentuximab-vedotin.
The fourth child with YST+MT will commence everolimus, erlotinib andpalbocyclib without irradiation. CONCLUSION: This treatment strategy
for HR-MMGCT patients provides preliminary tolerance and response data
justifying extension to a multi-center trial.
GCT-26. PROGNOSTIC FACTORS IN PATIENTS WITH BASALGANGLIA GERM-CELL TUMORS: A RETROSPECTIVE ANALYSIS OF
THE SINGLE CHINESE INSTITUTE EXPERIENCE FROM 2009 TO
2019
Qingjun Hu, Juan Li, Mingyao Lai, Cheng Zhou, Zhaoming Zhou,
Changguo Shan, Weiping Hong, Yangqiong Zhang, Lichao Wang, andLinbo Cai; Guangdong Sanjiu Brain Hospital, Guangzhou, Guangdong,
China
OBJECTIVE: To evaluate the clinical factors related to the prognosis ofbasal ganglia germ cell tumors. METHODS: A retrospective analysis of 52
cases of the basal ganglia germ cell tumors treated from January 2009 to
January 2019 in the department of oncology of Guangdong Sanjiu Brain
Hospital. The median age: 12 years (range: 5–32), The median course of
disease: 11.7 months (range: 1–54). Thirteen cases were diagnosed by biopsy and 39 cases were diagnosed by elevated tumor markers. There were
31 patients (59.6%) diagnosed with germinomas and 21 patients (40.4%)
with non-germ germ cell tumors. Univariate and multivariate survival analysis was performed. RESULTS: To October 15, 2019, the median follow-up
time was 30.4 months (range 2–124 months). The 5-year survival rate was
85%, and the 5-year progression-free survival rate was 84%. Multivariate
analysis found whether serum AFP was greater than 100mIU / ml, (with HR:

11.441,95% CI: 2.09–47.66, P = 0.005),the degree of surgical resection(withHR 5.323 (1.19–23.812), P = 0.029), PD as the effect of radiotherapy (HR:16.53, (1.19–23.81), P = 0.001) were independent prognostic factor affecting survival. CONCLUSION: The pathological type, degree of surgicalresection, and response to initial treatment can all affect survival.
GCT-27. CLINICAL FEATURES AND PROGNOSTIC FACTORSOF NONGERMINOMATOUS GERM CELL TUMORS IN 111
CONSECUTIVE PATIENTS IN A SINGLE INSTITUTION: IMPACT OF
IRRADIATION AND CHEMOTHERAPY CYCLES ON SURVIVAL
Lei Wen, Juan Li, Qingjun Hu, Mingyao Lai, Cheng Zhou, Junjie Zhen,
Changguo Shan, Weiping Hong, Rishun Luo, Yangqiong Zhang,
Xing Zhang, Lichao Wang, and Linbo Cai; Guangdong Sanjiu Brain
Hospital, Guangzhou, Guangdong, China
BACKGROUND: Limiteddata
isavailableinintracranial
nongerminomatous germ cell tumors (NGGCTs) in Chinese population. Here
we aimed to retrospectively assess the clinical-pathological and prognostic
factors of NGGCTs in a single large institution in China. METHODS: From
June 2003 to December 2018, 111 consecutive NGGCTs were treated in
Guangdong Sanjiu Brain Hospital, China. RESULTS: The median follow-up
was 36.2 months (range, 1.2 to 131.2 months). Three-year EFS and OS for
111 NGGCTs patients were 78.5%±4.5% and 82.8%±4.0%, respectively.
98 patients received CSI plus boost yielded better survival than those who
received reduced-volume radiotherapy or no radiotherapy (3y OS, 86.7%
vs. 51.4%, p=0.007). Patients had at least four cycles of chemotherapy werestrongly associated with improved 3-year OS, compared to those received
less than 4 cycles (94.1% vs. 63.6%, p＜0.001). There was no significant
difference in survival of patients stratified by age, surgery, hydrocephalus,
as well as tumor diameter. Multivariate analysis identified chemotherapy
cycles less than 4 was the only prognostic factor that conferring a worse
OS (p=0.003). Patients both received CSI and at least 4 courses of chemotherapy were correlated with lower incidence of relapse (p=0.044). CONCLUSIONS: Multimodal approach including CSI and enough courses ofchemotherapy was effective and should be recommended for the treatmentof newly diagnosed NGGCTs in Chinese population.
GCT-28. RECURRENCE PATTERN AND SURVIVAL FOR RELAPSEDINTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMORS:A SINGLE-INSTITUTION EXPERIENCE
Lei Wen, Zhaoming Zhou, Qingjun Hu, Juan Li, Mingyao Lai,
Cheng Zhou, Changguo Shan, Junjie Zhen, Weiping Hong, Xing Zhang,Yangqiong Zhang, Rishun Luo, Lichao Wang, and Linbo Cai; Guangdong
Sanjiu Brain Hospital, Guangzhou, Guangdong, China
PURPOSE: Intracranial non-germinomatous germ cell tumors (NGGCTs)
have lower overall survival than germinoma because relatively higher recurrence usually occurs after first line therapy. METHODS: Between January
2003 and December 2018, 111 consecutive patients diagnosed with NGGCTs
reviewed. Those who progressed after first line therapy were included in thisstudy. Data of first line treatment, salvage treatment, clinicopathological features and survival were collected and analyzed. RESULTS: Totally, thirtypatients (30/111, 27.0%) relapsed in our cohort, including 19 patients withaccurate relapse information detail, and 11 patients who died of diseaseprogression during follow up but without exact time and site of relapse. The
median OS from diagnosis of the disease was 49.2 months (95% CI: 14.1
to 84.3 months) and 3-year OS was 54.3%. Patients who received both CSI
and chemotherapy relapsed less than those who received reduced volumeof radiotherapy or only CSI or only chemotherapy (22.5% vs. 45.5%,
p=0.034). Of 19 patients who had detail information of recurrence time andsite, the median time from diagnosis of disease to relapse was 9.5 months(2.2 to 72.1 months). Regarding to recurrence site, most patients relapsedin primary site (10/19, 52.6%) or distant intracranial (6/19, 31.6%). The
recurrence site of other 3 patients were spinal (n=1), ventricular (n=1) andperitoneal (n=1). CONCLUSION: Protracted follow-up is recommended
because late recurrence is not uncommon. Primary tumor site and distantintracranial are the most prevalent relapsed location. Patients who relapsed
could benefited from both CSI and salvage chemotherapy.
GCT-29. DOES TUMOUR MARKER DECLINE PREDICT OUTCOME
IN INTRACRANIAL NON-GERMINOMATOUS GERM CELLTUMOURS (NGGCTS)?
Cecile Faure Conter1, Audrey Lardy-Cleaud2, Matthew Murray3,
James Nicholson3, Lea Guerrini-Rousseau4, Gilles Palenzuela5,
Claire Alapetite6, Maria Louise Garre7, Rolf Kortmann8, Frank Saran9,
Thankamma Ajithkumar3, Torsten Pietsch10, Alexandre Vasiljevic11,
Umberto Ricardi12, Beate Timmermann13, Jans Enno Muller14, andGabriele Calaminus14; 1IHOPE, Lyon, France, 2CLB, Lyon, France,
3Cambridge University Hospitals NHS foundation Trust, Cambridge,
United Kingdom, 4IGR, Villejuif, France, 5Hopital Arnaud de Villeneuve,

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Montpellier, France, 6Institut Curie, Paris, France, 7Gaslini Children’s
hospital, Genova, Italy, 8Universitatsklinikum, Leipzig, Germany, 9Royal
Marsden NHS Foundation Trust, Sutton, United Kingdom, 10Universityof Bonn Medical Center, Bonn, Germany, 11Institut de Pathologie
Multisite, Bron, France, 12University of Torino, Torino, Italy, 13Klinik fur
Partikeltherapie, Essen, Germany, 14University Hospital of Bonn, Bonn,
Germany
INTRODUCTION: The prognostic impact of tumour marker (TM)decline rate has been demonstrated for extracranial poor prognostic nonseminomatous/germinomatous germ cell tumours (NGGCT). The current
series aimed to assess if this finding can be applied to intracranial primaries. METHODS: Patients were retrieved from the SIOP-CNS-GCT-96
database. They were selected if they had i/assessable values of serum alphafetoprotein (AFP) and/or human chorionic gonadotropin (HCG) before and
18 to 28 days after the first course of chemotherapy and ii/ available datafor outcome. Decline rate was calculated using a logarithmic transformationand expressed as time to normalization (TTN) as published by Fizazi (JCO
2004). TTN≤ 9 weeks for AFP and ≤ 6 weeks for HCG were considered as
favourable decline rate. Prognostic impact of TTN on outcomes was assessed using the log-rank test. RESULTS: Out of 149 patients with NGGCT,59 were evaluable for both HCG and AFP TTN of whom 44 (74%) had afavourable decline rate. After a median follow-up of 88 months (2–251), 20
relapses and 15 deaths occurred. The 5-year PFS rates were 72% and 60%
in patients who had a favourable and an unfavourable TTN, respectively(p=0.15). The 5-year OS rates were 77 % and 69%, respectively (p=0.66).
Separate analysis of TTN based only on AFP or only on HCG gave similar
results. CONCLUSION: Despite the use of a methodology similar to thatused in extracranial NGGCT, no significant impact of serum TM decline on
prognosis was observed, but insufficient statistical power cannot be ruledout.
GCT-30. TREATMENT OF PRIMARY INTRACRANIAL GERM CELL
TUMORS: SINGLE INSTITUTION EXPERIENCE OF 74 CASESWITHOUT HISTOLOGICAL CONFIRMATION
Chengcheng Guo, Qunying Yang, Jian Wang, Yonggao Mou, andZhongping Chen; Sun Yat-Sen University Cancer Center, Guangzhou,
Guangdong, China
BACKGROUND AND OBJECTIVE: Primary intracranial germ cell tumors (PIGCTs) are a group of heterogeneous tumors. It is very difficult totreat those patients without pathological diagnosis. This study retrospectively analyzed the clinical data and outcomes of patients with clinicallydiagnosed (without histologically confirmed) PIGCTs in SunYat-sen University Cancer Center. METHODS: Patients who were clinically diagnosed as
PIGCTs without histological diagnosis through surgical resection or biopsy
were included in this study. Patients were analyzed for clinical characteristics, treatment patterns, outcomes and adverse effects. RESULTS: FromMay 2002 to July 2014, 74 patients clinically diagnosed with PIGCTs received chemotherapy and/or radiotherapy at the Sun Yat-sen University
Cancer Center. The median age was 16.5 years old (4–45 years old, majority was teenagers). The most of tumors were found in male, and locatedin the pineal and suprasellar regions. When the patients were grouped into
diagnostic chemotherapy group (57 cases), diagnostic radiotherapy group(5 cases) and gamma knife radiosurgery group (12 cases) based on their initial anti-tumor therapy. The 5-year survival rates were 84.3%, 75.0% and75.0%, respectively. There was a trend that the chemotherapy group got abetter survival. Patients were allocated to secretory tumor group (49 cases)
and non-secretory tumor group (25 cases) based on their levels of tumor
makers (α-FP and β-hCG). The 5- year survival rates were 80% and 77.8%(P value = 0.966), respectively. CONCLUSION: Clinical diagnosed PIGCT(without histological confirmation) patients may obtain good responses
when receiving comprehensive treatments of chemotherapy combined withradiotherapy.
GCT-31. DIAGNOSTIC CAPABILITY OF CSF-PLAP ON
INTRACRANIAL GERM CELL TUMOR
Michinari Okamoto1, Shigeru Yamaguchi1, Yukitomo Ishi1,
Hiroaki Motegi1, Yukayo Terashita2, Shinsuke Hirabayashi2,
Minako Sugiyama2, Yuko Cho2, Akihiro Iguchi2, Atushi Manabe2, andKiyohiro Houkin1; 1Department of Neurosurgery, Hokkaido University
Graduate School of Medicine, Sapporo, Hokkaido, Japan, 2Department ofPediatrics, Hokkaido University Graduate School of Medicine, Sapporo,
Hokkaido, JapanBACKGROUND: Since the majority of intracranial germ cell tumor(GCT)
is sensitive for chemoradiation, biopsy specimens are usually tiny and notenough for accurate pathological diagnosis. To supply complementary diagnostic information, a-fetoprotein or human chorionic gonadotropin-b areimportant biomarkers. Recently CSF-placental alkaline-phosphatase(PLAP)is also reported as an additional biomarker in intracranial GCT. This study’s
purpose is to evaluate the significance of CSF-PLAP. METHODS: CSF-PLAP

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was obtained from the patients with the intraventricular and periventriculartumor before any adjuvant therapy. Definitive diagnoses were made by histopathological information and/or their clinical courses; GCT(germinoma or
non-germinomatous GCT(NGGCT)) or other tumors. In GCT, the relationship between CSF-PLAP and tumor reduction volume was evaluated.
Tumor volumes were calculated on gadolinium-enhanced T1-weighted magnetic resonance imaging before and after initial chemoradiotherapy. RESULTS: Between 2005 and 2019, 42 patients were studied: 24 with GCT
and 18 with others. CSF-PLAP value in patients with GCT was significantly
higher than those with others: the Specificity was 88% and the sensitivity
was 95% at the cutoff value of 8.0 pg/ml. For GCT patients, CSF-PLAP
value tended to be higher in germinoma(n=12, mean 4756 pg/ml), comparedto the value in NGGCT(n=7, mean 332 pg/ml), although there was no statistical difference. There was a significant positive correlation between initial
CSF-PLAP value and tumor reduction volume. CONCLUSION: CSF-PLAP
is a useful tumor marker for GCT differentiating from the other tumors
located in intraventricular and periventricular region and CSF-PLAP value
might correlate with the volume of germinomatous component of the tumor.
GCT-33. A PHASE 2 TRIAL OF RESPONSE-BASED RADIATIONTHERAPY FOR PATIENTS WITH LOCALIZED CENTRALNERVOUS SYSTEM GERM CELL TUMORS: A CHILDREN’SONCOLOGY GROUP (COG) STUDY. IMPACT OF RAPID CENTRALRADIOTHERAPY REVIEW ON RADIOTHERAPY QUALITY ANDPATTERN OF FAILURE FOR NON-GERMINOMATOUS GERM CELL
TUMORS
Erin S Murphy1, Girish Dhall2, Jason Fangusaro3, Ute Bartels4,
Maryam Fouladi5, Dennis Shaw6, Soumen Khatua7, Ashok Panigraphy8,
Mark Souweidane9, Amar Gajjar10, Chris Williams-Hughes11, Arzu Onar10,
Shengjie Wu10, Daphne Haas-Kogan12, and Shannon MacDonald13;
1Cleveland Clinic, Cleveland, OH, USA, 2Children’s of Alabama,
Birmingham, AL, USA, 3Emory University, Atlanta, GA, USA, 4The
Hospital for Sick Children, Toronto, ON, Canada, 5Cincinatti Children’s
Hospital Medical Center, Cincinnati, OH, USA, 6Seattle Children’s
Hospital, Seattle, WA, USA, 7MD Anderson Cancer Center, Houston, TX,
USA, 8Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA,
9Weill Cornell Medical College and Memorial Sloan-Kettering Cancer
Center, NY, NY, USA, 10St. Jude Children’s Research Hospital, Memphis,
TN, USA, 11Children’s Oncology Group, Monrovia, CA, USA, 12BostonChildren’s Hospital, Boston, MA, USA, 13Massachusetts General Hospital,
Boston, MA, USA
BACKGROUND: COG ACNS 1123 tested reduced radiotherapy (RT) for
non-metastatic, non-germinomatous germ cell tumor (NGGCT) patients. The
impact of central review on quality of RT and pattern of failure for NGGCT
patients is evaluated. METHODS: Patients who achieved a complete response (CR) or partial response (PR) to induction chemotherapy were eligible
for reduced dose and field RT of 30.6 Gy whole ventricular field (WVI) and
54 Gy tumor-bed total dose. An online contouring atlas was available. Within
three days of RT start, WVI plans were submitted for rapid central review.
Within one week of RT completion, the complete RT record was submitted.
Brain and spine MRIs of relapsed patients were centrally reviewed. RESULTS: Between 5/2012–9/2016, 107 eligible patients were accrued and 70
met reduced RT criteria. Rapid RT review was performed for 49 (70%) of 70
patients. Forty-four (89.8%) required no modification. All modifications werecompleted and plans became compliant. Final central review was performedfor 66 evaluable patients: 62 (94%) were per protocol; there were 2 major (1dose and 1 target) and 2 minor deviations. Eight patients progressed; none had
deviations. Median time to progression was 3.54 months (range: 1.7–19.1)
from RT start. All failures had a spine component; two also had cranial component: one local progression (within the RT boost volume) and one leptomeningeal disease. CONCLUSION: Providing an online contouring atlas andperforming a rapid central review lead to high quality radiotherapy on thisprospective trial. The deviations did not contribute to the pattern of failure.
GCT-34. ELUCIDATION OF THE MECHANISMS OF
TUMORIGENESIS IN INTRACRANIAL GERM CELL TUMOR BY
WHOLE GENOME SEQUENCE
Yuki Yamagishi1, Hirokazu Takami1, Daichi Narushima2,
Yuko Matsushita1, Eiji Sugihara3, Ryo Nishikawa4, Mamoru Kato2,
Koichi Ichimura1, and Intracranial Germ Cell Tumor Genetic Analysis
Consortium5; 1Division of Brain Tumor Translational Research, National
Cancer Center Research Institute, Tokyo, Japan, 2Department of
Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan,
3Department of Medical Genomics, Research and Development Center for
Precision Medicine University of Tsukuba, Tsukuba, Japan, 4Department of
Neurosurgery/Neuro-Oncology, Saitama Medical University International
Medical Center, Hidaka, Japan, 5IGCTGAC, Japan
Intracranial germ cell tumors (iGCT) are heterogenous group of primarybrain tumors that consist of various subtype, and driver genetic alterationsin iGCTs remain largely unknown. We have previously reported in a study

Abstractsof whole exome sequence that iGCTs frequently harbored mutations in the
KIT gene and its downstream MAPK/PI3K pathway, regardless of tumor
subtype. However, no mutations were detected in about one-quarter ofgerminomas and half of non-germinomatous germ cell tumors. A genomewide methylation profiling revealed that only germinomas exhibited extreme
DNA hypomethylation among iGCTs. Moreover, in mixed iGCT tumors
which contained more than one tumor subtypes, each component exhibited
distinct methylation status depending on the subtype, while they shared thesame mutations. These data suggested that not only mutations in the coding
region as previously reported, but also genetic alterations in regulatory regions including promoters and enhancers as well as non-coding RNA genes
may be involved in the tumorigenesis of iGCTs. In order to comprehensively
search for driver gene alterations, we performed whole genome sequencein 18 paired tumor blood samples from iGCT tumors (16germinomas andtwo yolk sac tumors (YST)) registered in the Intracranial Germ Cell Tumor
Genome Analysis Consortium. In a preliminary analysis of four cases, YSTs
harbored a significantly higher number of structural abnormalities, compared with germinomas. Of note, 62 structural abnormalities were clustered
within the small genomic region of 95Mb at 1q21-44 in one YST case, suggesting a possibility of chromothripsis. A full analysis of somatic alterations
is underway and will be reported.
GCT-35. SALVAGE CRANIOSPINAL IRRADIATION FOR
RECURRENT GERMINOMAS
Masayuki Kanamori1, Ryuta Saito1, Yukihiko Sonoda2, Toshihiro Kumabe3,
and Teiji Tominaga1; 1Department of Neurosurgery, Tohoku University
Graduate School of Medicine, Sendai, Japan, 2Department of
Neurosurgery, Yamagata University School of Medicine, Yamagata, Japan,
3Department of Neurosurgery, Kitasato University School of Medicine,
Sagamihara, JapanBACKGROUND: The treatment strategies for recurrence has notbeen established. PURPOSE: To clarify the tumor control and complications of salvage craniospinal irradiation (CSI) for recurrent
germinoma. METHODS: We retrospectively reviewed the medical record.
Among 153 germinomas treated in Tohoku University Hospital since 1983,
22 had recurrence of germinoma. At first recurrence, 7 cases received CSI,
whereas 15 cases did chemotherapy and/or radiation therapy other thancraniospinal field (non- CSI). CSI was performed at 24 Gy/ 12 fractions
or 30 Gy/ 25 fractions. RESULTS: CSI had statistically significant betterrecurrence-free survival rate after recurrence than non-CSI (100% vs 33%,
p<0.001: log-rank test). In addition, tumor control was obtained in all offour cases with the failure after non- CSI treatments for recurrence. The latecomplications of these 11 cases were examined. The local dose before CSI
was 24- 50 Gy, and the median interval from last irradiation to CSI was
33 months. Median follow- up period after CSI was 126 months. Threepatients developed newly developed visual or cognitive deficits. These patients received high-dose irradiation at initial treatment or multiple treatment before CSI. There were no late complications in the cases which hadprior chemotherapy and 24 Gy of irradiation to whole ventricle only before
CSI. CONCLUSION: Low dose CSI for the first recurrence of germinoma iseffective and safe in the cases treated by chemotherapy and low dose irradiation to whole ventricle only.
GCT-36. TREATMENT RESULTS AND RADIATION-INDUCEDTUMORS IN CASES OF CENTRAL NERVOUS SYSTEM GERM CELL
TUMOR: A LONG-TERM FOLLOW-UP STUDY IN KUMAMOTO
PREFECTURE
Takahiro Yamamoto1, Keishi Makino2, Hideo Nakamura3,
Jun-ichiro Kuroda1, Takashi Itoyama1, Tatsuya Takezaki1, Kazutaka Ota1,
Naoki Shinojima1, and Akitake Mukasa1; 1Department of Neurosurgery,
Kumamoto University Medical School, Kumamoto, Japan, 2Department of
Neurosurgery, Kumamoto City Hospital, Kumamoto, Japan, 3Departmentof Neurosurgery, Kurume University Medical School, Kurume, JapanINTRODUCTION: Central nervous system germ cell tumor (GCT) is
one of the pediatric brain tumors. Although there have been epidemiologicalstudies in the past, long-term prognosis and the late effects remained unclear. In this study, we examined GCT over the past 41 years in Kumamoto
prefecture. METHODS: Epidemiological features and complications withradiation-induced tumors were searched in patients diagnosed with GCT in
the 41-year period from 1977 to 2018. RESULTS: There were 93 patientsdiagnosed with GCT. These cases were divided into 14-year periods before
and after incorporation of chemotherapy into the treatment, and the results
for germinomas were compared. An improvement in the 10-year survival
rate from 12 of 23 cases (52.2%) between 1977 and 1991 to 19 of 28 cases(67.9%) between 1992 and 2006 was observed. The 10-year survival rate
for germinoma cases that received medical treatment during a more recent
5-year period between 2004 and 2009 increased to over 90%. However,
10.3% of all long-term survivors of GCT developed radiation-induced glioblastoma. The examination results showed that regardless of the tumor type,patients who received a high dose of radiation during their initial treatment
developed the complication of radiation-induced glioblastoma within 10 to
25 years after their initial treatment. CONCLUSION: This study suggeststhat the long-term survival rates for GCT are improving but the rate ofradiation-induced glioblastoma in these cases are too high to be ignored.
Long-term follow-up of at least 10 years is essential to effectively evaluate
the details of treatment for pediatric brain tumors.
GCT-37. PREVALENCE OF AUTISM SPECTRUM DISORDER AND
OTHER NEURODEVELOPMENTAL DISORDERS IN PEDIATRICPATIENTS WITH INTRACRANIAL GERM CELL TUMORS
Kevin X. Liu1, Roshan V. Sethi1, Margaret B. Pulsifer2, Alissa M. D’Gama3,
Beverly Lavally2, Nancy J. Tarbell2, Torunn I. Yock2, andShannon M. MacDonald2; 1Harvard Radiation Oncology Program, Boston,
MA, USA, 2Massachusetts General Hospital, Boston, MA, USA, 3BostonChildren’s Hospital, Boston, MA, USA
PURPOSE/OBJECTIVE(s): Intracranial germ cell tumors (IGCTs) are raretumors of the central nervous system with peak incidence around puberty.
Due to the developmental origins of IGCTs, we investigated the prevalenceof neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), in our retrospective institutional cohort of patients diagnosed
with IGCTs. MATERIALS/METHODS: A retrospective review of medical
records was conducted for 105 patients who were diagnosed with IGCTs
and treated at Massachusetts General Hospital between 1998 and 2016. All
patients with ASD had thorough neuropsychological assessment at the timeof radiotherapy that confirmed their diagnoses. RESULTS: Median age at
diagnosis was 12.8 years (range: 4.3–21.6) and median follow-up time was
4.7 years (range: 0.4–15.8). Seventeen patients with IGCTs were diagnosed
with NDDs prior to cancer diagnoses, including five patients with ASD, andthree patients with chromosomal abnormalities, including one patient with
Down syndrome. Interestingly, four of five patients with ASD developed
pure germinomas, giving an ASD prevalence rate of 6.5% and 2.3% in thepure germinoma and NGGCT cohorts, respectively. All other patients had
no known diagnoses of NDDs. CONCLUSIONS: Our study found 17 patients with IGCTs were diagnosed with NDDs prior to their cancer diagnoses. An ASD prevalence of 6.5% in the pure germinoma cohort is morethan three-fold greater than the national prevalence, suggesting there may
be an association between ASD and pure germinomas. Future prospective
studies with larger cohorts are still needed to examine associations between
NDDs and ASD and IGCTs.
GCT-38. RELAPSE PATTERNS OF INTRACRANIAL GERMINOMASBEFORE AND AFTER ENDOSCOPIC ERA
Takao Tsurubuchi1, Shingo Takano1, Ai Muroi1, Kei Hara1,
Masahide Matsuda1, Hiroyoshi Akutsu1, Masashi Mizumoto2,
Hiroko Fukushima3, Ryoko Suzuki3, Yuni Yamaki3, Eiichi Ishikawa1,
Akira Matsumura1; 1Department of Neurosurgery, Faculty of Medicine,
University of Tsukuba, Tsukuba, Japan, 2Proton Medical ResearchCenter, University of Tsukuba, Tsukuba, Tsukuba, Japan, 3Department ofPediatrics, Faculty of Medicine, University of Tsukuba, Tsukuba, JapanPURPOSE: We evaluated the relapse patterns of CNS germinomas before
and after introducing neuroendoscopic biopsy in 2000. METHODS: We
retrospectively assessed the relapse patterns of 57 patients treated as puregerminoma or germinoma with STGC between 1980 and 2019 at Universityof Tsukuba, partially containing the patients of the previous report (Takano
S et al., World Neurosurg, 2015). Median age was 15 y.o.(7y.o.~38y.o.), andmen was 80.7%. Tumor locations were pineal 35, sellar 19, basal ganglia
3, others 11. Group A;1980~1999 was 20, and group B;2000~2019 was
37. From 1980 to 1994, whole brain irradiation(WB) 30.6 Gy plus whole
ventricle irradiation(WV) 19.8 Gy. From 1995 to 1999, WV 26~30.6 Gy
with Chemotherapy(Chem) or Chem alone. Since 2000, Chem for 3 kurr
with WV 24~30.6 Gy, and 6–19.8 Gy as local boost to residual lesion. RESULTS: Follow up periods were median 121 M(4.5M~386M; group A),
and median 89 M(4 M~231 M; group B). Six patients(30%) recurred in thegroup A, as ex field 4(1;brain and extramedullary, 1;brain and paranasal
sinus, 1;LV & third ventricle, 1;extramedullary), in field 1(LV). Chem
only 1(LV & third ventricle). Two patients(5.4%) recurred in the groupB, as ex field 2(1;intramedullary, 1;extramedullary). The group A showed
CR;18, PR;1, Dead;1(Dissemination), and the group B showed CR;35,
PR;1 Dead;1(Encephalopathy). CONCLUSION: WV and Chem prevented
extrafield recurrence keeping good quality of life. Neuroendscopy biopsy
with ETV did not increase CSF seeding.
GCT-40. PROGNOSTIC FACTORS FOR PATIENTS WITH RELAPSEDCENTRAL NERVOUS SYSTEM (CNS) NON-GERMINOMATOUS
GERM CELL TUMORS (NGGCTS)
Mohammad H. Abu-Arja1, Diana S. Osorio2, Joseph R. Stanek2,
Jonathan L. Finlay2, and Mohamed S. AbdelBaki2; 1New York-Presbyterian

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Brooklyn Methodist Hospital, Brooklyn, NY, USA, 2Nationwide Children’s
Hospital, Columbus, OH, USA
BACKGROUND: Patients with relapsed CNS NGGCTs experience pooroutcomes. Our aim to explore prognostic factors that may guide future clinical trials. METHODS: A review of clinical trials that included patients withrelapsed CNS NGGCTs was performed. RESULTS: Seventy-four patientswere identified; only 14 patients (19%) were long-term survivors. Patients
who relapsed >24 months after initial diagnosis had a survival rate of 47%
compared with 15% of patients who relapsed in <24 months after initialdiagnosis (p= 0.015). Patient with serum/cerebrospinal fluid (CSF) alphafetoprotein (AFP) level <25 ng/ml at relapse had a survival rate of 40%
compared with 0% among patients with serum/CSF AFP level >25 ng/ml
at relapse (p= 0.0015). Patients who achieved complete response/continued
complete response (CR/CCR) by the end of therapy had a survival rate of
59% compared with 3% among patients who had less than CR/CCR by theend of therapy (p= 0.0001). Patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR)
at relapse had a survival rate of 33% compared with 9% of patients who did
not receive HDCx/AuHCR at relapse (p=0.056). The extent of surgical resection, receiving radiotherapy, and beta-human chorionic gonadotropin levels
at relapse were not statistically associated with improved outcomes. CONCLUSION: Timing of relapse (>24 months after initial diagnosis), serum/
CSF AFP <25 ng/ml at relapse, achieving CR/CCR after treatment were associated with a positive impact on survival. Receiving HDCx/AuHCR at
relapse was associated with an improved outcome trend among the patients.
GCT-41. RESPONSE-BASED RADIATION THERAPY IN PATIENTSWITH NEWLY DIAGNOSED CENTRAL NERVOUS SYSTEMLOCALIZED GERMINOMA: A CHILDREN’S ONCOLOGY GROUP(COG) PROSPECTIVE PHASE 2 CLINICAL TRIAL
Ute Bartels1, Jason Fangusaro2, Dennis Shaw3, Aashim Bhatia4,
Arzu Omar-Thomas5, Shengjie Wu5, Shannon MacDonald6,
Erin Murphy7, Mark Souweidane8, Maryam Fouladi9, Amar Gajjar5,
Girish Dhall10, and Soumen Khatua11; 1The Hospital for Sick Children,
Toronto, ON, Canada, 2Aflac Cancer Center, Emory University andChildren’s Healthcare of Atlanta, Atlanta, GA, USA, 3Seattle Children’s
Hospital, Seattle, WA, USA, 4Children’s Hospital of Pittsburgh of UPMC,
Pittsburgh, PA, USA, 5St. Jude Children’s Research Hospital, Memphis,
TN, USA, 6Massachusetts General Hospital, Boston, MA, USA, 7Taussig
Cancer Institute, Cleveland Clinic, Cleveland, OH, USA, 8Weill Cornell
Medical College and Memorial Sloan-Kettering Cancer Center, New York,NY, USA, 9Cincinnati Children’s Hospital Medical Center, Cincinnati, OH,
USA, 10The Alabama Center for Childhood Cancer and Blood Disorders at
Children’s of Alabama, Alabama, AL, USA, 11MD Anderson Cancer Center,
Houston, TX, USA
BACKGROUND: The objective of stratum 2 of COG ACNS1123 wasto evaluate children and young adults (3–21 years) with localized central
nervous system (CNS) germinoma and investigate whether simplified preirradiation chemotherapy followed by response based dose-reduced whole
ventricular irradiation (WVI) would maintain a high progression-free survival (PFS) while reducing long term treatment burden. METHODS: Preirradiation chemotherapy consisted of 4 cycles of carboplatin and etoposideevery 21 days followed by response-based irradiation (XRT). Patients witha complete response (CR) to pre-XRT chemotherapy received 18Gy WVI+ 12Gy boost to the tumor bed. Patients with partial response (PR) but
less than 1.5 cm residual proceeded to 24Gy WVI + 12Gy boost. All patients were also enrolled on COG ALTE07C1 to prospectively evaluate andlongitudinally model the cognitive, social and behavioral functioning. RESULTS: During a total accrual time of 45.5 months from 05/2012 to
06/2018, 137 eligible patients were enrolled. Median age was 14.09 years(4.95–21.46), 73% were male, and 45.26% had elevated βhCG in serum
and/or cerebrospinal fluid. Twenty-nine patients (21.17%) did not havetissue biopsy. Eleven patients underwent second-look surgery; 7 had mature teratoma and 4 had non-viable tumor. Eighty-one patients (59.13%)
had a CR. There were 4 relapses in patients receiving 18Gy WVI + boost,but no deaths. No unexpected treatment-related events were observed. The
estimated 3-year PFS was 94.4 ±2.7% among 74 evaluable subjects. CONCLUSION: This study shows promise in XRT reduction for patients withlocalized CNS germinoma and CR. Long-term survival outcomes and
ALTE07C1 data are being evaluated.
GCT-42. CLINICAL CHARACTERISTICS OF LOCALIZED CENTRALNERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL
TUMORS (NGGCT) PATIENTS ENROLLED ON ACNS1123 WITHRELAPSE: A CHILDREN’S ONCOLOGY GROUP (COG) STUDY
Girish Dhall1, Shengjie Wu2, Arzu Onar-Thomas2, Dennis Shaw3,
Shannon MacDonald4, Erin Murphy5, Soumen Khatua6, Ute Bartels7, andJason Fangusaro8; 1University of Alabama at Birmingham, Birmingham,
AL, USA, 2St. Jude Children’s Research Hospital, Memphis, TN, USA,iii336

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3Seattle Children’s Hospital, Seattle, WA, USA, 4Massachusetts General
Hospital, Boston, MA, USA, 5Cleveland Clinic, Cleveland, OH, USA, 6M,D,
Anderson Cancer Center, Houston, TX, USA, 7Hospital for Sick Children,
Toronto, ON, Canada, 8Emory University, Atlanta, GA, USA

ACNS1123 was a Children’s Oncology Group Phase 2 study that wasundertaken to determine whether irradiation could be safely reduced
without impacting survival in a subgroup of NGGCT patients. Between May
2012-Jan 2017, 107 eligible patients were accrued to Stratum 1 (NGGCT
stratum). Sixty-six (61.7%) patients achieved a complete/partial response(CR/PR) to induction chemotherapy and received 30.6Gy whole ventricularfield irradiation followed by 54Gy tumor-bed boost achieving a 2-year
progression-free survival rate of 89% (95% CI:81%-97%) and overall survival rate of 92% (95% CI:86%- 99%). Eight patients progressed; 6 had aspinal relapse and 2 patients had a local plus spinal relapse. Seven of eightpatients had marker elevation at relapse and data was not available in one
patient. At diagnosis, location was pineal in six cases, suprasellar in one,and bifocal in one case. Four patients had beta HCGβ and AFP elevationand two each had HCGβ and AFP elevation alone at diagnosis. Only twopatients had HCGβ or AFP >1000 (HCGβ 3550 in one patient and AFP of
1340 in another). All eight patients were CR by markers; four had radiographic CR and four had a PR. Five patients had surgery at diagnosis: two
had embryonal carcinoma, one germinoma, and two mixed germ cell tumor
with malignant elements on histology. A consistent significant risk factor
could not be identified to explain excess of spinal failures seen in our cohort.
GCT-43. GAIN OF SHORT ARM OF CHROMOSOME 12 IS
A MOLECULAR MARKER TO PREDICT PROGNOSIS AND
REPRESENTS AN EARLY EVENT IN TUMORIGENESIS IN
INTRACRANIAL GERM CELL TUMORS
Kaishi Satomi1,2, Hirokazu Takami2,3, Shintaro Fukushima2,
Yoichi Nakazato4, Shota Tanaka3, Nobuhito Saito3, Masayuki Kanamori5,
Toshihiro Kumabe5, Keiichi Kobayashi6, Motoo Nagane6,
Toshihiko Iuchi7, Koji Yoshimoto8, Masahiro Mizoguchi8, Kaoru Tamura9,
Taketoshi Maehara9, Keiichi Sakai10, Kazuhiko Sugiyama11,
Kiyotaka Yokogami12, Hideo Takeshima12, Masahiro Nonaka13,
Akio Asai13, Ryo Nishikawa14, Masao Matsutani15, and Koichi Ichimura2;
1Department of Diagnostic Pathology, National Cancer Centre Hospital,
Chuo, Tokyo, Japan, 2Division of Brain Tumour Translational Research,
National Cancer Center Research Institute, Chuo, Tokyo, Japan,
3Department of Neurosurgery, Faculty of Medicine, The Universityof Tokyo, Bunkyo, Tokyo, Japan, 4Department of Pathology, Hidaka
Hospital, Takasaki, Gumma, Japan, 5Department of Neurosurgery,
Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan,
6Department of Neurosurgery, Kyorin University Faculty of Medicine,
Mitaka, Tokyo, Japan, 7Department of Neurosurgery, Chiba Cancer
Center, Chiba, Chiba, Japan, 8Department of Neurosurgery, Graduate
School of Medical Sciences Kyusyu University, Fukuoka, Fukuoka,
Japan, 9Department of Functional Neurosurgery, Tokyo Medical and
Dental University, Bunkyo, Tokyo, Japan, 10Department of Neurosurgery,
Shinshu Ueda Medical Center, Ueda, Nagano, Japan, 11Department ofClinical Oncology and Neuro-oncology Program, Cancer Treatment
Center, Hiroshima University Hospital, Hiroshima, Hiroshima, Japan,
12Department of Neurosurgery, Faculty of Medicine, University ofMiyazaki, Miyazaki, Miyazaki, Japan, 13Department of Neurosurgery,
Kansai Medical University Hospital, Hirakata, Osaka, Japan, 14Departmentof Neuro-Oncology/Neurosurgery, Saitama Medical University
International Medical Center, Hidaka, Saitama, Japan, 15Gotanda
Rehabilitation Hospital, Shinagawa, Tokyo, Japan
Gain of short arm of chromosome 12 (12p) is commonly observed in
testicular germ cell tumors (tGCTs) and also seen in intracranial GCTs
(iGCTs). However, little is known about the clinical significance of 12p gainin iGCTs. We have collected over 200 fresh frozen tissue samples of iGCTs
through the Intracranial Germ Cell Tumor Genome Analysis Consortium inJapan. Firstly, we analyzed DNA methylation profile in 83 iGCTs, 3 tGCTs(seminomas) and 6 normal control samples using Infinium Human Methylation 450K BeadChip array (Illumina, CA, USA) in order to determine 12p
gain status. Then, fluorescence in situ hybridization (FISH) study was carried out on 3 mixed iGCT cases using 12p/CEP12 probe (Abbott Molecular,
Abbott park, IL, USA). Lastly, 58 iGCTs with clinicopathological information were analyzed for progression-free survival (PFS) and overall survival(OS). Gain of 12p was observed in 100% (3/3) of seminoma, 14% (3/22)
of germinoma, 17% (1/6) of mature teratoma, 25% (1/4) of immature teratoma, 55% (11/20) of mixed germ cell tumor, 100% (4/4) of yolk sac tumor,
100% (1/1) of embryonal carcinoma, and 100% (1/1) of choriocarcinoma.
In total, 45% (37/83) of iGCT showed 12p gain. Different histological components in each mixed GCT shared the same 12p copy number status withineach mixed GCT case. Both PFS and OS were significantly worse in iGCTswith 12p gain (PFS: P=0.027, OS: P=0.0012). Gain of 12p can be a molecular marker to predict prognosis and represents an early event in tumorigenesis prior to histological differentiation in iGCTs.

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GCT-44. A CASE OF INTRACRANIAL GERMINOMA WHICH
RECURRED IN THE SPINAL CORD 13 YEARS AFTER THE INITIALTREATMENT
Yasuhiro Murota, Juri Kiyokawa, Mariko Ishikawa, Hiroto Yamaoka,
Satoshi Kaneko, Masataka Yoshimura, Shin Hirota, and Shinji Yamamoto;
Tsuchiura Kyodo General Hospital, Tsuchiura, Ibaraki, JapanBACKGROUND: Central nervous system germinoma occurs most often
in early teens, accounting for 15% of childhood brain tumors. Here, wereport a case of germinoma which recurred in the spinal cord 13 years
after complete remission. CASE DESCRIPTION: A 15-year-old boy presented with diabetes insipidus (DI). MRI showed a pineal gland tumor andventriculomegaly. Biopsy was performed and the histological examinations
revealed PLAP and c-kit positive pure germinoma. Ki67 LI was 64.4%.
Gamma knife radiosurgery and 3 courses of ICE chemotherapy brought disappearance of the tumor. However, it recurred in lateral ventricles. FortyGray whole brain radiation resulted in complete remission of the tumor. For
the sake of DI treatment and MRI examinations, he kept periodical visit toour hospital. Thirteen years later, when he was 28y/o, he complained paresthesia in the right upper extremity. MRI demonstrated gadolinium-enhance
mass lesion in the cervical spinal cord. Recurrence of the tumor and multiple sclerosis were the principal differential diagnosis. Pulse steroid therapy
did not make any change, and radiation therapy to the cervical spinal cord
led to tumor disappearance. Nevertheless, the tumor recurred on the dorsal
medulla oblongata one and a half years later. Biopsy of the tumor clarified that the tumor was germinoma. ICE chemotherapy which was limited
to three courses due to severe bone marrow suppression was carried out.
MRI proved no enhanced mass lesion in the central nervous system. DISCUSSION: Germinoma may recur even after long period of remission,
demonstrating that long-term follow-up is indispensable.
GCT-45. YOLK SAC TUMOR IN THE CEREBELLAR VERMIS A CASE REPORT
Saori Otake1, Tomoo Matsutani1, Yousuke Watanabe1, Osamu Numata2,
Ryo Ando2, Hidemasa Ochiai3, Ikeda Junichiro4, and Yasuo Iwadate1;
1Department of Neurological Surgery, Chiba University Graduate Schoolof Medicine, Chiba, Japan. 2Department of Neurosurgery, Chiba Child
Hospital, Chiba, Japan. 3Department of Hematology and Oncology, Chiba
Child Hospital, Chiba, Japan. 4Department of Pathology, Chiba University
Graduate School ofMmedicine, Chiba, Japan
Yolk sac tumor (YST) is a non-germinomatous malignant germ cell tumor
in a young child. It usually arises along a midline axis, mostly pineal region or suprasellar compartment, and it is exceedingly rare to locate in a
cerebellar vermis. In the present report, we describe a case of a pure YST
located in the cerebellar vermis and review the previous literature. A threeyear-old boy visited a local clinic for gait disturbance and frequent vomiting.
Gadolinium-enhanced magnetic resonance imaging (MRI) showed ahomogeneously-enhanced mass with a cystic component in his cerebellar
vermis, and it resulted in hydrocephalus. By its location and his age, our preoperative diagnosis was a medulloblastoma, and we performed a total resection of the tumor with ventricular drainage. Unexpectedly, the histologicalinvestigation revealed it to be a YST. We confirmed that the serum levels of
α-fetoprotein (AFP) had elevated at 3176.4 ng/ml in his preserved sample,
obtained before the surgery, and it was consistent with the pathological diagnosis. He is receiving chemotherapy consisting of ifosfamide, cisplatin, andetoposide, followed by radiation therapy. In this case, pre-operative MRI revealed that the tumor did not grow into the IVth ventricle in spite of midline
location, which was not typical for medulloblastoma. Of note, serum AFPlevels had increased, and they might contribute to a precise pre-operative
diagnosis and be able to propose an alternative treatment plan, such as
neoadjuvant chemotherapy to reduce surgical risk. As a conclusion, a YST
should be considered even if it locates in a cerebellar vermis.

we screened small molecule inhibitors of kinases specifically targeting cell
membrane receptors, such as receptor tyrosine kinases, and their related
molecular signaling, which could effectively exert antitumor effects against
NGGCT cells. As the NGGCT model cells, the Tcam2 cell, a mixed germ celltumor cell line composed of germinoma and embryonal carcinoma components, and the YST1 cell, a novel yolk sac tumor cell line established in our
institute, were used. As a result, effective induction of cell death in both celllines was confirmed only by treatment with two multi-kinase inhibitors. Immunoblotting revealed these multi-kinase inhibitors suppressed activation ofvarious kinases concurrently. Furthermore, these multi-kinase inhibitors also
triggered cell death in the Tcam2 cell stably expressing mutant KIT, the mostcommon oncogenic driver genes of CNS GCTs, suggesting that these inhibitors would be also effective against CNS GCTs harboring activated KITmutants. In vivo studies of these multi-kinase inhibitors using CNS GCT
xenografts are currently on going.
GCT-47. TREATMENT STRATEGIES FOR GIANT IMMATURETERATOMAS IN INFANTS
Tomoru Miwa1, Maya Kono1, Haruko Shima2, Hiroyuki Shimada2, andKazunari Yoshida1; 1Department of Neurosurgery, Keio University Schoolof Medicine, Tokyo, Japan. 2Department of Pediatrics, Keio University
School of Medicine, Tokyo, JapanINTRODUCTION: Immature teratomas are the most frequent fetal
brain tumors and show a poor prognosis. At onset, the tumor is often already giant with deep origins such as suprasellar or pineal region, and easy
bleeding is also considered to be a cause of poor prognosis. On the other
hand, it is also known that the prognosis is improved in total removal
cases. METHODS: We investigated the best treatment strategy based on
two cases of total removal of giant immature teratomas in infants. RESULTS: 1.5 month after birth at onset (median), maximum diameter of
75 mm (median). A giant tumor centered around the third ventricle withhydrocephalus. First, biopsy (+septostomy) was performed using an endoscope. The tumor showed easily bleeding. In addition, external ventriculardrainage was taken out of the lower abdomen subcutaneously by long tract.
After chemotherapy (carboplatin and etoposide), tumor removal was performed by using drainage tract. Both cases showed not easily bleeding atthat time and the tumor was safely removed. Regarding the deep blind spot,using a flexible endoscope was effective. They showed no recurrence after
total removal (median 50 months). DISCUSSION: There have been reportsof cases in which chemotherapy for immature teratomas suppressed tumor
growth and reduced bleeding and safely removed totally. In infants giant
immature teratomas, chemotherapy before tumor removal can be expected
to reduce bleeding, and further increase body weight during that period. In
addition, long-term placement of ventricular drainage by long tract during
the chemotherapy can prevent brain development delay due to hydrocephalus.

GCT-46. MULTI-KINASE INHIBITORS AS NOVEL THERAPEUTICAGENTS AGAINST INTRACRANIAL NON-GERMINOMATOUS
GERM CELL TUMORS
Eita Uchida1,2, Tatsuya Ozawa1, Masamichi Takahashi3, Ryo Nishikawa2,
Koichi Ichimura1, and Arata Tomiyama1,4; 1National Cancer Center
Research Institute, Chuo-Ku, Tokyo, Japan, 2Saitama Medical University
International Medical Center, Hidaka, Saitama, Japan, 3National Cancer
Center Hospital, Chuo-Ku, Tokyo, Japan, 4National Defense Medical
College, Tokorozawa, Saitama, Japan

GCT-48. OUTCOME OF CNS MALIGNANT NONGERMINOMATOUS GERM CELL TUMORS (GCT) WITH AFP >1000 NG/ML AT DIAGNOSIS TREATED ACCORDING TO SIOP CNS
GCT 96
Gabriele Calaminus1, Didier Frappaz2, Rolf-Dieter Kortmann3, 4Thankamma Ajithkumar4, Torsten Pietsch5, Alexandre Vasiljevic6,
Umberto Ricardi7, Cecile Faure-Conter8, Beate Timmermann9,Claire Alapetite10, Matthew J Murray11, Maria Luisa Garre12, andJames C Nicholson11; 1Department of Paediatric Haematology andOncology University Hospital, Bonn, Germany, 2Department of Paediatric
Haematology and Oncology, Institute of Paediatric Haematology andOncology (IHOPe), Lyon, France, 3Department of Radiotherapy andRadiooncology, University Hospital, Leipzig, Germany, 4Department ofRadiotherapy and Radiooncology, University Hospital, Cambridge, United
Kingdom, 5, Institute of Neuropathology, University of Bonn Medical
Center, Bonn, Germany, 6Department of Biopathology, Institut Multisite
de Pathologie, Hospices Civiles, Lyon, France, 7Department of Oncology,
University of Turin, Turin, Italy, 8Department of Paediatric Haematology
and Oncology, Institute of Paediatric Haematology and Oncology(IHOPe), Lyon, France, 9Department of Radiation Oncology, Clinic ofProton Therapy, Essen, Germany, 10Department of Radiation Oncology,
Curie Institute, Paris, France, 11Department of Paediatric Haematology
and Oncology, Cambridge University Hospitals NHS Foundation Trust,Cambridge, United Kingdom, 12Department of Paediatric Haematology
and Oncology, Gaslini Childrens Hospital, Genova, Italy

Central nervous system germ cell tumors (CNS GCTs) are rare intracranial
malignancies developing in adolescents and young adults which relatively
frequently occur in East Asia region of the world including Japan. However, among CNS GCTs, non-germinomatous germ cell tumors (NGGCTs)
are highly resistant to the current chemoradiotherapies, and the prognosisof CNS NGGCTs is still extremely poor. Therefore, development of novel
therapeutic strategy against CNS NGGCTs is urgently needed. In this study,

Analysis of CNS MMGCT with AFP >1000 ng/ml (serum and/or CSF) at
diagnosis, treated on trial in SIOP-CNS-GCT-96, revealed an inferior prognosis (32% 5-year progression-free survival) compared with AFP <1000 ng/
ml (76%). As this patient group is small, to evaluate a bigger cohort, werevisited all patients treated according to SIOP-CNS-GCT-96, who were registered in the database until July 2015. Between October 1996 and July
2015, 373 patients with CNS MMGCT were registered. 48 patients (13%)

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presented with an AFP >1000 ng/ml at diagnosis. 41 patients were evaluablewith a median observation time of 2.4 years; 6/41 received chemotherapy
alone. Primary site, histological components (if available), metastatic status
and outcome were evaluated. Primary site was pineal in 29/41, suprasellar
in 6/41, bifocal 1/41 and other in 5/41 patients. 10/41 patients were metastatic at diagnosis. Four to five courses of standard PEI and radiotherapy(RT) or 2 standard and two intensified PEI (as for SIOP CNS GCT II) wereadministered in 32 patients. Two received less then 4x PEI and RT, 6 patients<6 years were treated with PEI (either standard or intensified) alone. 16/34
patients with PEI and RT are alive in CR; 2/6 patients without RT survived.
Overall, 18/40 (45%) survived. 10–15% of CNS MGGCT are high-risk patients by diagnostic AFP, with the pineal as the main tumour site. Outcomeof <50% survival is unsatisfactory. Further research, international cooperation and common data analysis is needed to identify additional risk factors
and develop alternative treatment strategies.
GCT-49. EVALUATION OF THE PERIOPERATIVE AND
POSTOPERATIVE COURSE OF SURGERY OF PINEAL GERMINOMAACCORDING TO THE SIOP CNS GCT 96 TRIAL
Ehab Shabo1, Thomas Czech2, James C Nicholoson3, Conor Mallucci4,
Sevgi Sarikaya-Seiwert1, Lea Guerini-Rousseau5, Gianluca Piatelli6,
Matthew C Murray3, Cecile Faure-Conter7, and Gabriele Calaminus8;
1Department of Neurosurgery, University Hospital, Bonn, Germany,
2Department of Neurosurgery, University Hospital, Vienna, Austria,
3Department of Paediatric Haematology and Oncology, Cambridge
University Hospitals NHS Foundation Trust, Cambridge, Cambridge,
United Kingdom, 4Alder Hey Children’s Hospital, Eaton Road, Liverpool,
United Kingdom, 5Department of Pediatric and Adolescents Oncology,
Institut Gustave Roussy Cancer Center, Paris-Saclay University, Villejuif,
France, 6Neuro-Oncology Unit, Department of Pediatric Hematology
and Oncology, G, Gaslini Children’s Hospital, Genova, Genova, Italy,
7Department of Paediatric Haematology and Oncology, Instituteof Paediatric Haematology and Oncology (IHOPe), Lyon, France,
8Department of Paediatric Haematology and Oncology University
Hospital, Bonn, Germany
INTRODUCTION: CNS germinoma, being marker-negative, are diagnosed by surgical biopsy. Here we evaluate the perioperative status andpostoperative complications of patients with pineal germinoma who underwent a primary biopsy or resection, treated according to SIOP CNS GCT
96. METHODS: 235 patients with histologically conﬁrmed germinoma
were registered, of which 113 were pineal: 55 were biopsied and 58 underwent primary resection. Initial symptoms, tumour size, complications
and neurological status were assessed. 111 patients were evaluable. RESULTS: Pure germinoma was present in 101 patients; 10 had additional
teratoma components. The main clinical symptoms at diagnosis were
headache (n=98), hydrocephalus (n=93), double vision (n=62), Parinaud
syndrome (n=57) and papilloedema (n=44). Tumour size was documented in
81 patients (<2cm, n=14; 2-3cm, n=35; ≥3cm, n=32). 17 patients underwent
primary total resection, 14 subtotal resection >50%, 26 subtotal resection<50%, 39 stereotactic biopsy, 11 endoscopic biopsy, 2 open biopsy and 2
not documented. The postoperative neurological status after resection was
improved in 23 patients, unchanged in 27, deteriorated in 6 and not documented in one. Clinical status after biopsy improved in 26 patients, was unchanged in 15, deteriorated in 2 and not documented in 11. Postoperatively,
16/57 patients after resection and 5/54 after biopsy developed complications (Parinaud syndrome, double vision and hydrocephalus). CONCLUSION: Although surgical techniques have improved within recent decades,
these results support the practice of biopsy over resection for histologicalconfirmation of germinoma arising at the pineal site. Supported in part byGerman Cancer Aid.
GCT-50. LONG-TERM OUTCOMES OF INTRACRANIALGERMINOMA IN A SINGLE INSTITUTION
Etsuko Yamamoto1, Yoshiki Arakawa1, Katsutsugu Umeda2,
Youhei Mineharu1, Megumi Uto3, Junko Takita2, Takashi Mizowaki3,and Susumu Miyamoto1; 1Department of Neurosurgery, Kyoto University
Graduate School of Medicine, Kyoto, Japan, 2Department of Pediatrics,
Kyoto University Graduate School of Medicine, Kyoto, Japan, 3Departmentof Radiation Oncology and Image-applied Therapy, Kyoto University
Graduate School of Medicine, Kyoto, JapanThe treatment for intracranial germinoma has been well-established.
Complete removal is not necessary, but radiation therapy is important. As
the prognosis of patients with germinoma has become better, side effect ofradiotherapy and chemotherapy must be well considered. The aim of thisstudy was to evaluate the outcome of intracranial germinomas at Kyoto
University Hospital from 1979 to 2019. 64 patients were diagnosed as intracranial germinoma. Patients with hCG > 100 IU/l and/or AFP > 10 ng/ml
were excluded. Patients, who were histologically diagnosed as germinoma
without information of hCG and AFP, were included. Follow-up time wasiii338N EU R O - O N C O L O G Y•

De c e mb e r 2 0 2 0from 2 to 486 months (median 136 months). Recently, germinoma patientswere diagnosed with biopsy and received low dose whole-ventricle irradiation with intensity modulated radiation therapy (IMRT) (total 24-30Gy)
and chemotherapy dominated by platinating agent. 10-year PFS was
80.21% (high dose radiation alone), 86.36% (high dose radiation withchemotherapy) and 100% (low dose radiation with chemotherapy). Many
recurrent sites were out of irradiation areas. Late cognitive dysfunction was
identified in 6 patients, and 5 of them were treated with high dose radiation.
Patients with intracranial germinoma can obtain long-term survival. It is
important to prevent recurrence without increasing late iatrogenic complications. Low dose radiotherapy and chemotherapy is highly effective, and it
potentially reduces late adverse effects.
GCT-51. IMMUNE CHECKPOINT MOLECULES AND
TUMOR INFILTRATING LEUKOCYTES IN THE TUMORMICROENVIRONMENT ARE ASSOCIATED WITH THE GROWTH
OF INTRACRANIAL GERMINOMAS
Masaaki Nishimoto1, Kentaro Ohara2, Dai Kamamoto1, Ryota Tamura1,
Tomoru Miwa1, Kazunari Yoshida1, and Hikaru Sasaki1; 1Department of
Neurosurgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan,
2Department of Pathology, Keio University School of Medicine, Shinjuku,
Tokyo, JapanThe role of immune checkpoint molecules and the tumor immune microenvironment in the development of intracranial germ cell tumors remains
unclear. In the present study, we investigated the expression of immune
checkpoint molecules, as well as the number of tumor-infiltrating lymphocytes (TILs), in intracranial germinomas to determine whether there were
any correlations between the statuses of these immune-related molecules/
cells and clinical manifestations in patients with germinoma. The 8 patients were categorized based on the duration between symptom onset andpathological diagnosis into the long-term onset (LTO) group (> 1 year of
symptoms, 3 patients) and the short-term onset (STO) group (< 1 year of
symptoms, 5 patients). Compared with STO tumors, LTO tumors were significantly associated with a lower ratio of programed cell death ligand-1(PD-L1)–positive tumor cells (p = 0.012), higher number of infiltrating
CD3- and CD8-positive lymphocytes (p = 0.016, 0.003, respectively), andlower ratio of programed cell death-1 (PD-1)–positive cells per CD8–positive lymphocytes (p = 0.047). LTO germinomas were significantly smaller
in size than STO tumors and tended to be present in patients with atypical tumor location. Our data suggest that the tumor immune microenvironment, including PD-1/PD-L1 signaling, is associated with the growth of
intracranial germinomas. Immune checkpoint inhibitors might be a reasonable treatment option for recurrent germinomas or as replacement for radiotherapy in patients with intracranial germinomas.
GCT-52. TRANSCRIPTOME OF CENTRAL NERVOUS SYSTEMGERM CELL TUMOR REVEALS ITS PATHOGENESIS AND
CONTRASTS WITH TESTICULAR COUNTERPARTS IN
INTEGRATED OMICS ANALYSIS
Hirokazu Takami1,2, Asmaa Elzawahry1, Mamoru Kato1, Kohei Fukuoka1,
Yasin Mamatjan3, Tomonari Suzuki4, Takaaki Yanagisawa4,
Yuko Matsushita1, Taishi Nakamura1,5, Kai Yamasaki1,6,
Akitake Mukasa7,2, Nobuhito Saito2, Masayuki Kanamori8,
Toshihiro Kumabe9,8, Teiji Tominaga8, Keiichi Kobayashi10,Motoo Nagane10, Toshihiko Iuchi11, Kaoru Tamura12,
Taketoshi Maehara12, Kazuhiko Sugiyama13, Mitsutoshi Nakada14,
Yonehiro Kanemura15, Masahiro Nonaka16, Akio Asai16,
Kiyotaka Yokogami17, Hideo Takeshima17, Yoshitaka Narita18,
Soichiro Shibui18, Yoichi Nakazato19, Yasushi Totoki1, Tatsuhiro Shibata1,
Ryo Nishikawa4, Masao Matsutani4, and Koichi Ichimura1; 1National
Cancer Center Research Institute, Tokyo, Japan, 2The University ofTokyo, Tokyo, Japan, 3Princess, Margaret Cancer Center, Toronto, ON,
Canada, 4Saitama Medical University International Medical Center,
Saitama, Japan, 5Yokohama City University, Kanagawa, Japan, 6Osaka
City General Hospital, Osaka, Japan, 7Kumamoto University, Kumamoto,Japan, 8Tohoku University School of Medicine, Miyagi, Japan, 9Kitasato
University, Kanagawa, Japan, 10Kyorin University Faculty of Medicine,Tokyo, Japan, 11Chiba Cancer Center, Chiba, Japan, 12Tokyo Medical
and Dental University, Tokyo, Japan, 13Hiroshima University Faculty of
Medicine, Hiroshima, Japan, 14Kanazawa University, Ishikawa, Japan,
15Osaka National Hospital, Osaka, Japan, 16Kansai Medical University
Hospital, Osaka, Japan, 17University of Miyazaki Faculty of Medicine,
Miyazaki, Japan, 18National Cancer Center Hospital, Tokyo, Japan,
19Hidaka Hospital, Gunma, Japan
Germ cell tumors (GCTs) are unique neoplasms in that they arise from themigrated cells which were supposed to be directed to gonads. They occur inthe central nervous system (CNS), as well as gonadal organs such as testisand ovary. Our genomic analysis revealed that they are characterized by mutations in MAPK and PI3K pathways, chromosomal instability and global

Abstracts

hypomethylation in germinoma. However, there were plenty of cases which
lacked driver alterations and their pathogenesis is yet to be fully unraveled.
Here we aimed to uncover CNSGCT’s pathogenesis from a transcriptomic
perspective. Genome-wide transcriptional analysis was performed for 58
CNS and 3 testicular GCTs. This demonstrated that germinoma had a transcriptional profile characteristic to primordial germ cells (PGCs) at early
embryogenesis, whereas non-germinomatous germ cell tumors (NGGCTs)
showed that with differentiation into various tissues. Integration of transcriptome and methylome corroborated the above finding that pluripotency/
meiosis-genes were unmethylated and highly expressed in germinoma compared with NGGCT. Co-analysis with transcriptome of various developmental stages of embryonic cells revealed germinoma and NGGCT had
similarities in expression to PGC and embryonic stem cells, respectively.
Multi-omics analysis with testicular GCTs (n=134) from TCGA showedshared genomic backgrounds between germinoma-seminoma and NGGCTnonseminomatous GCT (NSGCT) in mutation and methylation profiles,
and contrast in the chromosomal instability, which was more highlighted in
testicular GCTs. These new insights into molecular profiles of GCTs lead toa better understanding of the complex pathogenesis of GCTs, and will hopefully provide a clue to future development of new treatments.
GCT-53. CASE OF INTRACRANIAL GROWING TERATOMASYNDROME WITH DIFFICULTY IN TIMING OF RESECTION
Hidenobu Yoshitake1,2, Hideo Nakamura1, Yuta Hamamoto1,
Yusuke Otsu2, Jin Kikuchi1, Motohisa Koga1, Soushou Kajiwara1,
Yui Nagata2, Yoshihisa Matsumoto2, Takuro Hashikawa2,
Hideki Sakai2, Satoru Komaki1, Nobuyuki Takeshige1, Naohisa Miyagi1,
Setsuko Nakagawa2, Kenji Takahashi2, Yasuo Sugita3, andMotohiro Morioka1; 1Department of Neurosurgery, Kurume University
School of Medicine, Kurume, Fukuoka, Japan, 2Department of
Neurosurgery, St. Mary’s Hospital, Kurume, Fukuoka, Japan, 3Neurology
Center Neuropathology, St. Mary’s Hospital, Kurume, Fukuoka, JapanBACKGROUND: Intracranial Growing teratoma syndrome(iGTS) is aphenomenon in which a tumor with a teratoma component grows during
treatment, and its pathological tissue is often a mature teratoma. Here we
report a case of iGTS in which the timing of surgery was determined bytumor markers and changes in tumor size on MRI images. CASE-REPORT:
11-year-old boy with a short stature. He developed a headache and we
found a pineal gland tumor on MRI. Due to obstructive hydrocephalus, anendoscopic third ventriculostomy and biopsy were performed. The pathological diagnosis was mature teratoma, but AFP was elevated at 104.2 ng/
mL. Considering NGGCT, we started chemoradiation immediately. Despite
the declining AFP, it gradually increased, at which point we suspected iGTS.
Resection was considered, but at some point tumor growth had stopped, so
radiation therapy and a second course of ICE therapy preceded the resection. Thereafter, the tumor was completely removed, and a third course of
ICE therapy was performed. DISCUSSION: The onset mechanism of iGTS
has not been elucidated, and its prediction is difficult. Early resection of thetumor is required, but discontinuation of radiation therapy and side effects
of chemotherapy also need to be considered. In our case, resection was performed after normalization of AFP and recovery of myelosuppression. The
patient followed an uneventful course, but the timing of resection was controversial. CONCLUSION: We experienced a case of iGTS in NGGCT, amixed tumor with mature teratoma. The optimal timing of the resection was
discussed and literature was reviewed.
GCT-55. INTRACRANIAL GERMINOMA ORIGINATING FROMATYPICAL LOCATION WITH SUBCLINICAL ADH INSUFFICIENCY
Yuki Kuranari, Tomoru Miwa, Maya Kono, Tokunori Kanazawa, andKazunari Yoshida; Keio University School of Medicine, Shinjuku, Tokyo,
Japan
INTRODUCTION: Intracranial germinomas are rare tumors whichusually develop in the midline structures and affect in 90% of cases thepineal gland and suprasellar regions. Sometimes they involve basal ganglia,
septum pellucidum, and other regions. We report a very unusual presentation of an intracranial germinoma originating from the lateral ventricle. METHODS: A 10-year-old boy presented with a 1-year history ofpolydipsia and polyuria. During the hypertonic saline test, a low ADH wasdetected and established the diagnosis of subclinical ADH insufficiency.
MRI showed a heterogeneously enhancing periventricular lesion in thelateral ventricle, but no other abnormal findings, including hypophyseal
stalk. Initially, the correlation of imaging findings and clinical symptoms
were not clear. With suspected subependymoma, tumor removal was performed by small craniotomy. Since the intra-operative pathological diagnosis was germinoma, we performed only partial removal of the tumor.
After establishing the histological diagnosis of germinoma, the patient
received chemotherapy using carboplatin and etoposide, followed by radiation therapy. MRI showed no recurrence for five years after treatment.
RESULTS/CONCLUSION: Our case presents two atypical features. First,

intracranial germinoma originating from the lateral ventricle is quite rare.
Though the cases with intracranial germinoma originating from septum
pellucidum and corpus callosum have been reported, this case is even different. Second, imaging findings did not match clinical symptoms. The causeof subclinical ADH deficiency may be the occult hypophyseal germinoma. In
conclusion, we report a 10-year-old case with a very unusual presentation of
an intracranial germinoma originating from the lateral ventricle.
GCT-56. ACUTE MYELOID LEUKEMIA FOLLOWINGCHEMORADIOTHERAPY FOR INTRACRANIAL GERMINOMA:A CASE REPORT
Masato Nakaya1, Yuya Koda2, Kentaro Yamaguchi2, Kazunari Yoshida1,
and Hikaru Sasaki1; 1Department of Neurosurgery, Keio University Schoolof Medicine, Shinjyuku-ku, Tokyo, Japan, 2Department of Hematology,
Keio University School of Medicine, Shinjyuku-ku, Tokyo, JapanINTRODUCTION: Therapy-related acute myeloid leukemia (t-AML) is
known as possible complication of chemotherapy, especially topoisomerase Ⅱ inhibitor, alkylating agents, and platinum agents. Although
there are many reports of therapy-related leukemia associated with gonadal germ cell tumor, few cases have been reported on central nervous
system (CNS) germ cell tumor. CASE REPORT: A 35-year old gentleman
presented with diplopia. CT and MR imaging showed enhancing nodules
on his right hypothalamus and around fourth ventricle, and differential
diagnoses included sarcoidosis and germinoma. Biopsy for fourth ventricle
lesion was performed via transvermian approach, and histopathologicaldiagnosis was germinoma. He was treated by 3 cycles of CARE chemotherapy (carboplatin and etoposide) followed by craniospinal irradiation(CSI, 24Gy). After completion of chemoradiotherapy, he was followed up
every half year by MRI, and there had been no evidence of tumor recurrence. Two years after chemoradiotherapy, however, the patient presented
with bleeding tendency, which led to the diagnosis of AML. Based on the history of chemoradiotherapy and the presence of t(16;21)(q24; q22), t-AML
was diagnosed. Complete remission was successfully achieved by chemotherapy consisting of idarubicin and cytarabine. DISCUSSION: t-AML was
diagnosed after chemoradiotherapy in a patient with CNS germinoma probably due to the administration of topoisomerase II inhibitor, etoposide.
The prognosis of t-AML is known to be poorer as compared with de novo
AML. Therefore, intensive therapy such as allogeneic stem cell transplantation should be considered in younger patients. CONCLUSION: A possibility of t-AML should be kept in mind following chemotherapy for CNS
germ cell tumors.
GCT-57. ARE MELATONIN LEVELS A RELIABLE MARKER FOR
INTRACRANIAL GERM CELL TUMORS POST TREATMENT
DEFICIENCY?
Andréa M Cappellano1, Alex M M Fujita2, Nasjla S Silva1,
Daniela B Almeida1, and Fernanda G Amaral2; 1IOP/GRAACC/UNIFESP,São Paulo, São Paulo, Brazil, 2Department of Physiology/UNIFESP, SãoPaulo, São Paulo, Brazil
BACKGROUND: Pineal is the melatonin-producing gland, with thishormone importantly acting as a central and peripheral chronobiotic, antioxidant and in energy metabolism. The urinary dosage of 6-sulfatoxymelatonin(aMT6s), a melatonin metabolite, is an indirect marker to estimate the total
melatonin nocturnal production, ranging in clinically normal individuals from
10–50 micrograms(ug). The purpose of this study was to evaluate aMT6s
in patients with diagnosis of intracranial germ cell tumors (iGCT) treatedat IOP/GRAACC/UNIFESP. METHODS: After an interview to collect data
about therapies employed and medications, night urine samples (from 8:00pm
to first void in the morning) were collected and analyzed by ELISA. RESULTS: Twenty patients between 5–42 years old (mean 20.9 years), allmale, were analyzed. Thirteen patients had diagnosis of Germinoma, 1 with
Imature Teratoma, 5 NGGCT and 2 Mature Teratoma. The first site waspineal (N=15) and bifocal (N=5). The treatment was surgery/biopsy/2º looksurgery in 17 patients associated with chemotherapy/ radiotherapy, except
in 2 (pure teratoma-surgery only) and 1 (chemo only). Three patients haddiagnosis by tumor markers treated with chemo only (N=1) and chemotherapy/radiotherapy (N=2). The levels of aMT6s were between 0.2–3.2ug
in all participants, except in one (14.8ug-biopsy, chemo and RT). CONCLUSION: aMT6s levels found in most patients are below the expected for thegeneral population suggesting that this is an appropriate marker for pineal
tumors with melatonin deficiency. It may contribute to support future studies
in this area and adoption of follow-up protocols, with eventual hormone supplementation and consequently improved quality of life.
GCT-58. BRAZILIAN CENTRAL NERVOUS SYSTEM GERM CELL
TUMOR CONSORTIUM PROTOCOL
Andréa M Cappellano1, Nasjla S Silva1, Bruna Mançano2,
Daniela B Almeida1, Sergio Cavalheiro1, Patricia A Dastoli1,

N E U R O -O N C O L O G Y•

D e ce mb e r 2 0 20

iii339Abstracts

Frederico A Silva1, Sidnei Epelman3, Simone S Aguiar3, andJonathan L Finlay4; 1IOP/GRAACC/UNIFESP, São Paulo, São Paulo, Brazil,
2Hospital do Amor, Barretos, São Paulo, Brazil, 3Hospital Santa Marcelina/
TUCCA, São Paulo, São Paulo, Brazil, 4Nationwide Children’s Hospital,
Columbus, OH, USA
INTRODUCTION: Primary central nervous system (CNS) germ cell tumors (GCT) account for 2–3% brain tumors children/adolescents in Western
hemisphere. The report aim is to present the results of a Brazilian CNSGCT
consortium protocol. METHODS: Since 2013, 45 patients with histologic
and/or tumor marker (TM) diagnosis of germinoma with/without HCGβlevels≤200mIU/ml (n=33), four between 100-200mIU/ml and NGGCT(n=12), received carboplatin/etoposide/cyclophosphamide (4–6 cycles), followed by 18Gy ventricular field irradiation and primary site(s) boost. Autologous bone marrow transplant (ABMT) was conducted for NGGCT low
responders. RESULTS: Mean age 12.9 years (4.7-20y), 34 males. Diagnosis
was made by TM (n=9), surgery (n=19), both (n=15). Two bifocal cases,(-)TM were treated as germinoma. Primary tumor location was pineal(n=20), suprasellar (n=13), bifocal (n=11) and basal ganglia/thalamus (n=1).
Fourteen had ventricular/spinal spread. Second-look surgery occurred in 5
patients. For the germinoma group, 26 achieved complete response (CR)after chemotherapy, seven showed residual teratoma/scar. For the NGGCT
after 2/4 cycles, four patients showed CR, 2 failure/progression and 6 partial response (4 (-)TM). Two were submitted to ABMT. Radiotherapy was
performed as described, except in three. One recurrence to date. Two patients died (endocrinologic complications/progression). Toxicity was mostly
grade ¾ neutropenia/thrombocytopenia during chemotherapy. At a median follow-up of 38 months, OS was 100% for Germinoma and 85%
NGGCT. CONCLUSION: The treatment is tolerable and VFI dose reduction to 18Gy seems to preserve efficacy. Further follow-up is warranted toassess the NG group and the slow-responder patients.
GCT-59. EPIDEMIOLOGY OF PEDIATRIC INTRA-CRANIAL GERM
CELL TUMORS: COMPARING THE INCIDENCE OF INTRACRANIAL GERM CELL TUMORS IN THE NATIVE JAPANESEPOPULATION AND IMMIGRANT JAPANESE POPULATIONSABROAD
Ashley Plant1, Tomonari Suzuki2, Rosdaili Diaz Coronado3,
Sidnei Epelman4, Luis Sakamoto4, Sylvia Cheng5, Takaaki Yanagisawa2,6,
Bernard Rosner7, Susan Chi8, and Mark Kieran8; 1Children’s Hospital
Orange County, Orange, CA, USA, 2Saitama Medical University
International Medical Centre, Saitama-ken, Japan, 3Instituto Nacional deEnfermedades Neoplasicas Clinica Delgado, Lima, Peru, 4Hospital Santa
Marcelina, San Paolo, Brazil, 5British Columbia Children’s Hospital,
Vancouver, Canada, 6Jikei University School of Medicine, Tokyo, Japan,
7Harvard T,H, Chan School of Public Health, Boston, MA, USA, 8Dana
Farber Cancer Institute, Boston, MA, USA
Pediatric intra-cranial germ cell tumors (iGCTs) occur at an incidence of
0.6–1.2 cases/million/year in Western countries. The incidence is reported
up to 5 times higher in the Japan. It is unknown whether this increased incidence is due to tumor biology or environment. The incidence of iGCTs inchildren ages 0–19 years was evaluated from 12/1/96-12/1/2016 in stable
Japanese immigrant populations living abroad compared to current native
Japanese registry data. Medulloblastoma incidence was used as a control toaccount for assumptions in the data. A review of the Brain Tumor Registryof Japan from 1984–2004 revealed an incidence of 2.5 cases/million/year
and a lower incidence of medulloblastoma at 1.1 cases/million/year. Sites
outside of Japan included Vancouver, Canada, Lima, Peru, and San Paolo,
Brazil and together included a population of 853,174 Japanese persons.
Within this population, 0 cases of iGCT were identified over a 20-years. The
ratio of medulloblastoma to iGCT cases in Japan was identified as 1:2 while
the ratio was 2:1, 6.5:1, and 5:1, respectively, in the other three locations.
The data suggests increased incidence in the native Japan may not translate
to higher incidence in immigrant Japanese populations abroad and a clear
genetic component was not found in this preliminary data set. A more precise and comprehensive study is needed to determine the cause of this difference in incidence. This study also emphasizes the importance of nationaland state registries and is a call to collaborate on state and country levelepidemiology studies.
GCT-60. DEVELOPMENT OF MICROBLEEDING AFTER PROTON
THERAPY FOR PATIENTS WITH GERM CELL TUMOR
Hidehiro Kohzuki1, Ai Muroi1, Masashi Mizumoto2, Hideaki Sakurai3,
Eiichi Ishikawa1, and Akira Matsumura1; 1Department of Neurosurgery,
University of Tsukuba, Tsukuba, Ibaraki, Japan, 2Department of Radiology,
University of Tsukuba, Tsukuba, Ibaraki, Japan. 3Department of Radiology,
University of Tsukuba, Tsukuba, Ibaraki, JapanBACKGROUND: Proton therapy has been increasingly used to treat
pediatric brain tumor. However, there were few reports about radiation-iii340N EU R O - O N C O L O G Y•

De c e mb e r 2 0 2 0

induced cerebral microbleeds(CMBs) and cavernous malformation among
these patients. Here we evaluate the incidence and risk factor of CMBs with
MR imaging. MATERIAL AND METHOD: We retrospectively identified
patients with germ cell tumor treated with whole ventricle irradiation of
30.6 Gy using proton therapy at the Tsukuba University Hospital between
2004 and 2017. CMBs were characterized by examination of MR imaging
scan including susceptibility-weighted imaging and T2* weighed gradientrecalled echo sequence. RESULT: The mean age at the time of proton
therapy was 14.5 years. The median follow-up duration was 62.3 months.
Three patients were treated by local boost in addition to whole ventricle irradiation. CMBs were found in 78% at 5 years, and 88% at 10 years from
irradiation. Over 80% of CMBs occurred in area of the brain exposed to
30 Gy. CONCLUSION: This study indicated over 30 Gy irradiation may
become a risk factor for development of CMBs. Although the correlation between development of CMBs and cognitive function, proton therapy might
have an advantage to reduce late sequelae with decreasing irradiating doseto surrounding normal brain tissue.
GCT-61. CORRELATION OF PATTERNS OF DISEASE RECURRENCEWITH RADIOTHERAPY TECHNIQUES AND DOSE IN
INTRACRANIAL GERM CELL TUMOURS (ICGCT): LESSONS FROMTHE UK COHORT OF SIOP GCT96 STUDY
Thankamma Ajithkumar1, Henry Mandeville2, Fernando Carceller2,
Milind Ronghe3, Tina Foord4, Stephen Lowis5, Michelle Kwok-Williams6,
Gabriele Calaminus7, Matthew Murray1, and James Nicholson1;
1Cambridge University Hospital, Cambridge, United Kingdom, 2The Royal
Marsden NHS foundation trust, Sutton, United Kingdom, 3NHS Greater
Glasgow and Clyde, Glasgow, United Kingdom, 4Churchill Hospital,
Oxford, United Kingdom, 5University Hospital Bristol NHS Foundation
Trust, Bristol, United Kingdom, 6Leeds Teaching Hospitals NHS Trust,Leeds, United Kingdom, 7Universitätsklinikum Bonn, Bonn, Germany
BACKGROUND: There are global variations in radiotherapy approaches for icGCT. An understanding of patterns of disease recurrence
correlated with radiation techniques and doses is important in standardising and improving the quality of radiotherapy using high-precision techniques. METHODS AND RESULTS: Data from 20 patients with tumour
recurrence after treatment within the SIOP GCT96 study in the UK wereanalysed. Seven (35%) patients had germinoma and 13 (65%) had nongerminoma. Twelve patients had local recurrence, 5 had metastatic and 3
had local and metastatic disease. Radiotherapy details were retrieved inonly 8 patients (40%). Six patients had received focal radiotherapy and two
craniospinal radiotherapy. Of the patients who received focal radiotherapy,
4 had recurrence within the radiation portal, one had periventricular recurrence and one had marker-positive recurrence with no radiological lesions.
Both patients who received CSI recurred within the CSF space. The main
reasons for poor retrieval of treatment details were difficulty in retrievingarchived information and that the study was conducted during a period before PACS or electronic radiotherapy records. CONCLUSION: This study
highlights the importance prospective data collection and analysis to understand the patterns of recurrence in icGCT. Even within a prospective study,
radiotherapy techniques varied between centres. There is therefore an urgent need for centralised radiological review and prospective radiotherapy
quality assurance measures in future clinical trials.
GCT-62. DISSECTING INTRATUMORAL HETEROGENEITY OF
CENTRAL NERVOUS SYSTEM GERM CELL TUMORS BY SINGLECELL RNA-SEQUENCING
Tomoyuki Nakano1,2, Yuko Matsushita1,3, Ritsuko Onuki4,
Daisuke Shiokawa5, Kiyomi Imamura6, Terumi Horiuchi6, Eita Uchida7,8,
Yui Kimura1,9, Satoshi Ihara10, Tomonari Suzuki8, Takao Tsurubuchi11,
Eiichi Ishikawa11, Taishi Nakamura12, Makiko Yoshida13,
Atsufumi Kawamura14, Kohei Fukuoka15, Kurihara Jun16, Yasuji Miyakita3,
Yoshitaka Narita3, Keiichi Kobayashi17, Motoo Nagane17,
Hirokazu Takami18, Ryo Nishikawa8, Mamoru Kato4, Yutaka Suzuki6,
and Koichi Ichimura1; 1Division of Brain Tumor Translational Research,
National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan,
2Department of Neurosurgery, Tokyo Medical and Dental University,
Bunkyo-ku, Tokyo, Japan, 3Department of Neurosurgery and NeuroOncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan,
4Department of Bioinformatics, National Cancer Center Research Institute,Chuo-ku, Tokyo, Japan, 5Division of Cancer Differentiation, National
Cancer Center Research Institute, Chuo-ku, Tokyo, Japan, 6Department ofComputational Biology and Medical Sciences, Graduate School of Frontier
Sciences, The University of Tokyo, Kashiwa, Chiba, Japan, 7Division ofBrain Tumor Translational Research, National Cancer Center ResearchInstitute, Tokyo, Japan, 8Department of Neuro-Oncology/Neurosurgery,
Saitama Medical University International Medical Center, Hidaka, Saitama,
Japan, 9Children’s Cancer Center, National Center for Child Health andDevelopment, Setagaya-ku, Tokyo, Japan, 10Division of Neurosurgery,Tokyo Metropolitan Children’s Medical Center, Fuchu, Tokyo, Japan,

Abstracts

11Department of Neurosurgery, Faculty of Medicine, University of Tsukuba,
Tsukuba, Ibaraki, Japan, 12Department of Neurosurgery, Graduate
School of Medicine, Yokohama City University, Yokohama, Kanagawa,Japan, 13Department of Pathology, Hyogo Prefectural Kobe Children’s
Hospital, Kobe, Hyogo, Japan, 14Department of Neurosurgery, Hyogo
Prefectural Kobe Children’s Hospital, Kobe, Hyogo, Japan, 15Department
of Hematology/Oncology, Saitama Children’s Medical Center, Saitama,
Japan, 16Department of Neurosurgery, Saitama Children’s Medical Center,
Saitama, Japan, 17Department of Neurosurgery, Kyorin University Facultyof Medicine, Mitaka, Tokyo, Japan, 18Department of Neurosurgery, Facultyof Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, JapanBACKGROUND: Central nervous system germ cell tumor (CNSGCT) isa rare pediatric brain tumor. However, they are found at a relatively highincidence in East Asia. Germinoma is sensitive toward radiotherapy andchemotherapy; however, non-germinoma GCTs (NGGCT) often show poor
response. Some cases are a mixture of germinoma and NGGCT (mixed
GCT), and they sometimes change histological subtypes at recurrence.
Previous report demonstrated that a germinoma and NGGCT component
within the same mixed GCT tissue shared the same gene mutation, whereas
the genome-wide methylation profiles were distinct from each other. The
methylation profiles of germinoma was similar to the primordial germ
cells (PGC) at the migration phase, supporting a model that PGC is thecell of origin for CNSGCT. However, tumor heterogeneity hinder information of the mixed bulk RNA-sequence data, causing difficulty in elucidating
the mechanism of tumor development. The purpose of this study was toinvestigate the tumor cells subpopulations at the resolution of individual
cells by single-cell RNA-seq. RESULTS: Fresh surgical tumor tissue wasimmediately dissociated mechanically and enzymatically. Tumor cells are
separated from CD45-labelled lymphocytes by FACS, and libraries weregenerated by Chromium Single cell 3’ Reagent Kit. Total of 11 tumor samples were collected and sequenced. Unsupervised Clustering showed individual clusters. One of the clusters had high expression of Oct-4, which isa marker of germinoma. The other clusters showed different subtypes ofcells representing the heterogeneity of CNSGCT. Further analysis including
a pseudo-time course analysis is underway to identify the lineage of tumor
cell development.
GCT-63. STEREOTACTIC RADIOSURGERY FOR RESIDUAL LESIONSOF PINEAL NON-GERMINOMATOUS GERM CELL TUMORS AFTERCONVENTIONAL RADIOTHERAPY: A RETROSPECTIVE STUDY
Mingyao Lai, Juan Li, Qingjun Hu, Zhaoming Zhou, Lei Wen,
Cheng Zhou, Changguo Shan, and Linbo Cai; Guangdong Sanjiu Brain
Hospital, Guangzhou, Guangdong, China
OBJECTIVE: To explore the efficacy and safety of SRS for residual lesions of NGGCTs after conventional RT. METHODS: The clinical data ofpatients with iGCT who were admitted to Department of Oncology, Guangdong Sanjiu Brain Hospital between January 1, 2008 and December 30,
2019 were gathered. Those who were pathologically or clinically diagnosed
with NGGCTs, with lesions located at pineal region, limited stage and residual lesions (with a maximum diameter>10mm) of pineal NGGCTs after
RT with a total dose of 50-54Gy/25-30f, were eligible for the study. Several
indexes such as local control rate, PFS, OS and treatment-related toxicity
were analyzed. RESULTS: A total of 27 patients were included; all weremale, with a median age of 16 years (range 8–31 years). The patients were
followed-up to December 30, 2019, but there were 2 cases lost to follow-up.
The median follow-up time was 34 months (range 8–142 months). Aftera month of treatment with SRS, the ORR and DCR were 71.4% and95.2%, respectively. During follow-up, 5 cases had radiographic progressions, including 3 cases combined with increased AFP which were diagnosed
with local recurrence and 2 cases diagnosed with GTS；The 3y-PFS and OS
were 85.2% and 88.0%.no acute radiation response was found after treatment with SRS, and only one patient had brain neurotoxicity. CONCLUSION: SRS for residual lesions of NGGCTs after RT is proved to be safeand feasible, with well tolerance, which is beneficial for the improvement oflocal control and the prolongation of survival.
GCT-64. TREATMENT RESULTS IN CHILDREN WITH LOCALIZEDCNS NGGCT
Irina Vilesova1, Ekaterina Tarasova2, Andge Valiakhmetova3,
Ekaterina Salnikova1, Alexey Pshonkin1, Galina Novichkova1,
Alexander Karachunsky1, and Ludmila Papusha1; 1Dmitry Rogachev
National Medical Research Center Of Pediatric Hematology, Oncology and
Immunology, Moscow, Russian Federation, 2Russian Children’s Clinical
Hospital, Moscow, Russian Federation, 3N. N. Burdenko National Medical
Research Center of Neurosurgery, Moscow, Russian Federation
BACKGROUND/OBJECTIVES: Treatment of children with CNS
NGGCT remains challenge: 5y OS is 60 – 80%; relapses are very aggressive. DESIGN/METHODS: Between 2003 and 2019, 14 children (medianage 10.5, range 4 – 16 years) with localized intracranial NGGCT weretreated with RT after induction chemotherapy (focal – 4, WVI+boost – 6,
WBI+boost – 3, CSI+boost – 1). Tumor markers were elevated in 13 patients: 6 – AFP, 5 – HCG, 2 – both. One patient with level of HCG 72049
IU/l in serum and 121451 IU/l in CSF received 4 cycles of PEI + CSI 30
Gy with boost 54Gy. RESULTS: At a median follow-up of 4,7 years (range
1 – 16,25 years), 12 patients are alive. 5-year PFS and OS are 77,1% and85,7%, respectively. Two patients (both AFP and HCG) progressed during
RT (1 – focal, 1 – WBI+boost), both died. Two patients with high level of
HCG recurred after therapy (WVI+boost – 1, focal – 1), both are alive. The
first of them at recurrence (mts of lateral ventricle) received 4 cycles of PEI
and RT (WBI+boost). The second patient had level of HCG 620IU/l and initially received focal irradiation 54Gy. At recurrence with distant spinal mts
he received HD-CHT with auto-SCT, surgical resection of residual tumor
and CSI with boost. CONCLUSIONS: Good results of treatment of localized CNS NGGCT with CSI, WBI or WVI in compare with focal RT show
advantages of extended irradiation field. CSI should be considered for patients with extremely high levels of tumor markers and respectively poor
prognostic histology.
GCT-65. INCIDENCE AND OUTCOME OF INTRACRANIAL
MALIGNANT GERM CELL TUMOURS DIAGNOSED IN WESTERN
DENMARK IN THE LAST DECADE
Yasmin Lassen-Ramshad1, Torben Stamm Mikkelsen2, Steen Rosthoej3,
Louise Tram Henriksen2, Ruta Tuckuvienne3, Ines Ackerl Kristensen2,
Gorm von Oettingen4, Soeren Cortnum4, Anne-Birgitte Als5,
Akmal Safwat1,5, and Mads Agerbaek5; 1Danish Centre For Particle
Therapy, Aarhus University Hospital, Aarhus, Denmark, 2PediatricDepartment, Aarhus University Hospital, Aarhus, Denmark, 3PediatricDepartment, Aalborg University Hospital, Aalborg, Denmark, 4Departmentof Neurosurgery, Aarhus University Hospital, Aarhus, Denmark,5Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
INTRODUCTION: Intracranial malignant germ cell tumours (iGCT)
are rare brain tumours mainly diagnosed in children and younger
adults. MATERIAL AND METHODS: A retrospective analysis was performed by chart review of patients treated for iGCT in the northern andcentral region of Denmark. Teratoma only patients were not includedin the study. RESULTS: 20 patients with iGCT were diagnosed from2008–2019 in Western Denmark. The cumulative incidence was 1.05 per
100.000. The yearly incidence was 0.1 per 100.000. Mean age at diagnosis was 18 years (range 8–36 years), 17 were males and 3 were females. 13 patients presented with germinoma and 7 patients with non
germinomateous germ cell tumours (NGGCT). Three patients had disseminated disease, two with germinoma and one with NGGCT. All patients
had received radiotherapy and 18 patients were treated with multidrug
chemotherapy including platinum and etoposide before irradiation. Twopatients experienced recurrent disease, both non disseminated at diagnosis, one patient with germinoma and one patient with NGGCT. Both received salvage treatment including high dose chemotherapy with stem celltransplantation and reirradiation. Two NGGCT patients died, one patient
after development of an anaplastic astrocytoma in the radiation field five
years after radiotherapy and one patient after intracranial hemorraghe
18 months after salvage treatment for recurrent disease. Overall survival
was 90%, 100% for GCT and 71% for NGGCT. CONCLUSION: The
outcome of patients with iGCT in Western Denmark was comparable tothe literature. A nationwide study of epidemiology and outcome of iGCTin Denmark is planned.
GCT-66. FINAL REPORT OF THE PROSPECTIVE NEXT/CNS-GCT-4
CONSORTIUM TRIAL (GEMPOX FOLLOWED BY MARROWABLATIVE CHEMOTHERAPY) IN PATIENTS WITH REFRACTORY/RECURRENT CNS GERM CELL TUMORS
Margaret Shatara1, Megan Blue1, Joseph R. Stanek1,
Allison Y. Liu2, Diana S. Osorio1, Mohamed S. AbdelBaki1,
Daniel Prevedello3, Vinay Puduvalli3, Pierre Giglio3, Sharon Gardner4,
Jeffrey Allen4, Kenneth E. Wong5, Girish Dhall6,7, and Jonathan L Finlay1;
1The Division of Hematology, Oncology, Blood and Marrow Transplant,
Nationwide Children’s Hospital and The Ohio State University, Columbus,
OH, USA, 2University of California-Davis Health, Sacramento, CA, USA,
3The Ohio State University, Columbus, OH, USA, 4New York University
School of Medicine, New York, New York, USA, 5Children’s Hospitalof Los Angeles, Sacramento, CA, USA, 6The University of Alabama at
Birmingham, Birmingham, AL, USA, 7Children’s Hospital of Alabama,
Birmingham, AL, USA
BACKGROUND: We report the responses, toxicities and long-term
outcomes of gemcitabine, paclitaxel and oxaliplatin (GemPOx) regimen
administered, in responsive patients, prior to single cycle marrow-ablative
chemotherapy (thiotepa, etoposide and carboplatin) with autologous hematopoietic progenitor cell rescue (HDCx+AuHPCR). METHODS: Since De-N E U R O -O N C O L O G Y•

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cember 2009, 11 recurrent/refractory patients (10 MMGCT, 1 germinoma;
10 males; mean age 16.5 years, range 7–46 years) have been treated withup to four cycles of gemcitabine (800mg/M2), paclitaxel (170mg/M2)
and oxaliplatin (100mg/M2) administered on one day at 14 days intervals. RESULTS: All 11 patients were enrolled on a prospective multicenter trial, which was closed in October 2019. Three patients achieved
complete remissions (tumor marker and/or imaging studies), five achieved
partial remissions, two developed disease progression (PD), and one waswithdrawn after one cycle for severe paclitaxel neurotoxicity followed by
rapid tumor progression and death. One patient with PD after one cycle
had pathologically-confirmed metastatic transformation to pure embryonal
rhabdomyosarcoma, and rapidly expired. A second patient, with pure pineal
choriocarcinoma, progressed after the second GemPOx cycle, ultimately
died of tumor progression. Eight of the 11 responsive patients subsequently
underwent HDCx+AuHPCR; five of these received some form of radiotherapy. Seven patients (six MMGCT, one germinoma) are alive and diseasefree without recurrence for a mean of 94 months (range 74–118 months)
since completion of therapy. CONCLUSION: GemPOx is an effective
re-induction regimen for patient with recurrent CNS germ cell tumors, withacceptable toxicities; when followed by marrow-ablative chemotherapy andsubsequent irradiation/re-irradiation, the regimen produces encouraging
long-term disease-free survival.
GCT-67. CENTRAL NERVOUS SYSTEM GERMINOMA IN TWOCAUCASIAN AMERICAN SIBLINGS WITH AUTISM SPECTRUM
DISORDER
Stephanie Toll1,2, and Hamza Gorsi1,2; 1Children’s Hospital of Michigan,
Detroit, MI, USA, 2Central Michigan University, Mount Pleasant, MI, USA
BACKGROUND: Central nervous system germ cell tumors (CNS-GCT)
account for approximately 5% of all pediatric brain tumors. These tumors
are pathologically heterogeneous, but have recurrent somatic mutations in
KIT and rare germline variants in a Japanese cohort. Chromosomal abnormalities, specifically Klinefelter Syndrome, are associated with increased
tumor development and familial cases have been reported, but no germline
tumor syndromes are known. We describe a pair of siblings, both with autism
spectrum disorder (ASD) that developed CNS-GCT, which previously has
not been described outside of Japan. CASES: We report two siblings with
ASD who developed CNS germinomas within two months of each other.
The older brother, with basal ganglia and hypothalamic tumors, underwent
surgical resection followed by treatment per ACNS0232 with chemotherapy
and whole-ventricular irradiation (WVI). The younger sibling, with a midbrain tumor, also received ACNS0232, but due to poor response required
additional chemotherapy and WVI. Both siblings are without evidence ofdisease 7 years after end of therapy. Genetic testing, including chromosomal
microarray, karyotyping, and whole genome sequencing did not elucidate
any variant identified as causative at that time. CONCLUSIONS: CNSGCT are rare tumors, diverse in both histopathologic diagnosis and clinical outcomes. Currently there are known somatic alterations and germline
chromosomal disorders associated with increased tumor development, but
no known inheritable causes. Despite this, familial CNS-GCT have been reported in patients of Japanese descent. The description of two CaucasianAmerican siblings with ASD and CNS-GCT is novel, refuting that familial
CNS-GCT are limited to the Japanese population.
GCT-69. VOLUMETRIC CHANGE BEFORE CHEMORADIOTHERAPYAND INFLUENCE OF DIAGNOSTIC RADIATION EXPOSURE IN
INTRACRANIAL GERMINOMAS
Naoki Kagawa1, Ryuichi Hirayama1, Chisato Yokota1,2, Yasuyoshi Chiba3,
Yasunori Fujimoto4, Tomoyoshi Nakagawa1, Toru Umehara1,
Noriyuki Kijima1, Manabu Kinoshita1, and Haruhiko Kishima1;
1Department of Neurosurgery, Osaka University Graduate School of
Medicine, Osaka, Japan, 2Department of Neurosurgery, Suita Municipal
Hospital, Osaka, Japan, 3Department of Neurosurgery, Osaka Women’sand Children’s Hospital, Osaka, Japan, 4Department of Neurosurgery,
Osaka Rosai Hospital, Osaka, JapanBACKGROUND: Spontaneous regression in intracranial germ cell tumors has been reported in some literatures, but the mechanism has notbeen well known. We retrospectively measured the tumor volume before
chemoradiotherapy and analyzed factors that influence reduction of tumor
volume. PATIENTS AND METHODS: Plural MRI scans were done before
the first course of chemotherapy regimen in 27 patients with primary intracranial germinomas. Their age ranged from 8 to 31 years. 35 lesions fromthem were enrolled and included 13 pineal, 4 neurohypophyseal, 4 basal
ganglia, 4 bifocal type, and 2 multiple lesions. All regions were verified as
pure germinoma or HCG-producing germinoma by histopathological examination. Tumor volume of 35 lesions was analyzed by volumetric assessment
based on MRI. Ratio of volumetric change between the first MRI and thescan immediately before chemotherapy was defined as shrinking rate (%).
Period between disease onset and the first chemotherapy was 20 to 47 days.
Diagnostic radiation dose was calculated in each case. RESULTS: Ini-

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De c e mb e r 2 0 2 0tial tumor volume ranged from 0.962 to 72.356 cubic centimeters (mean:
8.27). Diagnostic radiation dose: 40.5 to 910.1 mGy. Shrinking rate ranged
from -57.8 to 85.4% (mean: 30.8). In 10 regions, shrinking rate was within
30%. Shrinking rate was significant positively influenced by diagnostic radiation dose (p<0.05) and negatively influenced by initial volume (p<0.05).
But, other factors such as age, sex, histopathological parameters did not
influence tumor shrinkage. CONCLUSION: This study shows that thevolume of intracranial germ cell tumors is changing dynamically before
chemoradiotherapy in many cases. Diagnostic exposure to low-dose radiation influences tumor shrinkage of intracranial germinomas.
GCT-70. INTRACRANIAL GROWING TERATOMA SYNDROME IN
CHILDREN
Maria Carter Febres1, Carol S. Bruggers1, Holly Zhou1, Arie Perry2,
John Kestle1, and Nicholas Whipple1; 1University of Utah, Salt Lake City,
Utah, USA, 2University of San Francisco, San Francisco, California, USA
Germ cell tumors account for less than 5% of all intracranial malignancies
in children. Intracranial growing teratoma syndrome (GTS) is a rare pathophysiologic process characterized by growth of mature teratoma elementsof a non-germinomatous germ cell tumor (NGGCT) during or following
treatment with chemotherapy, in addition to normalization of or declining
AFP/βHCG of the cerebral spinal fluid (CSF)/serum. A 13-year-old male presented with headache, emesis, and diplopia. MRI of the brain/spine revealed
a localized 3.1 x 3.1 x 3.2 cm pineal tumor. Biopsy confirmed NGGCT(germinoma, immature and mature teratoma). Serum AFP (227ng/ul) andβHCG (12 IU/L) and CSF AFP (21ng/ul) and βHCG (31 IU/L) were elevated.
Prior to cycle two of chemotherapy, he developed unstable gait and moderatehearing loss. Repeat MRI brain demonstrated tumor enlargement (4.4 x
5.2 x 5.1 cm) and obstructive hydrocephalus, although serum AFP/βHCG
had normalized. Gross total resection of tumor confirmed GTS, without
residual immature/malignant elements. Following six cycles of multiagent
chemotherapy (carboplatin, etoposide, ifosfamide) and proton beam
craniospinal irradiation (36 Gy with 18 Gy boost), he remains free of diseaseat eleven months since diagnosis. The pathogenesis of GTS remains unclear.
Care must be taken to avoid misdiagnosing GTS as progressive NGGCT,
as treatment and prognosis differ significantly. Second-look surgery, with agoal of complete resection, should be considered in cases of NGGCT whenresidual tumor grows during or following therapy, as this may represent
GTS. Although histologically benign, GTS can be fatal. In patients with GTS,
complete resection is usually curative.
GCT-71. SIOP STRATEGY TREATMENT FOR CENTRAL NERVOUS
SYSTEM GERM CELL TUMORS IN A MIDDLE INCOME COUNTRY
Agustina Oller, Claudia Sampor, Lorena Baroni, Candela Freytes,
Nicolas Fernandez Ponce, Gabriela Villanueva, and Daniel Alderete;
Garrahan Hospital, Buenos Aires, Buenos Aires, Argentina
BACKGROUND/OBJECTIVES: Central nervous system (CNS) germ
cell tumors (GCTs) represent 3% of primary paediatric brain tumours in
occident. They can be divided into major groups including germinomas
and nongerminomatous GCTs (NGGCTs). The aim is to describe demographic characteristics, Event Free Survival (EFS) and Overall Survival(OS) in patients with GCTs treated at Oncology Unit of Garrahan Hospital(HG). DESIGN/METHODS: Retrospective analysis of patients with GCTs
admitted between September 1st,2000 to September 1st,2019. Variables analysed: age, localization, treatment, relapse and death. Patients were treatedper SIOP-CNSGCTs protocol. For statically analysis SPSS (IBM), for EFS/
OS Kaplan-Meyer, Long-rank for significance. RESULTS: Fifty-seven patients were included, comprising 38 Germinomas and 19 NGGCTS. Medianage was 146 months (range 11–228). Primary site in localized Germinomas
were pineal (16p), suprasellar (7p) and bifocal (7p). Five-year EFS and
OS of 100% and 88.5%, respectively. Four patients presented metastatic
disease, with an EFS and OS of 60.9% and 66.6%. Tumor site in localized
NGGCT were pineal(8p) and suprasellar(5p). Five-year EFS was 81.8% andOS was 80.2%. No patients presented metastatic disease. All patients withhigh-risk tumor markers at diagnosis relapsed. No significative differenceswere found in OS neither EFS between groups (Germinomas OS5y 90%
vs NGGCTs 74.6%p=0.19[CI95%0.0786–1.689]), (Germinomas EFS5y
78.9% vs NGGCTs5y 81.8%p=0.85[CI95%0.3046–4.230). Global OS andEFS5y was 83% and 72.9%. CONCLUSION: OS of our cohort is lower
than what has been shown in current literature. This result may be related
to the lack of resources and lower social economic status in our population.
GCT-72. ANALYSIS OF MICRORNA EXPRESSION PROFILE OFINTRACRANIAL GERM CELL TUMORS: A PROMISING TOOL FOR
DIFFERENTIAL DIAGNOSIS
Yoshiko Nakano1, Kaishi Satomi2,1, Hirokazu Takami1,3, Ryo Nishikawa4,
Fumiyuki Yamasaki5, Maehara Taketoshi6, Nobuhito Saito3,
Yonehiro Kanemura7, Hiroaki Sakamoto8, Takahiro Ochiya9,10, andKoichi Ichimura1; 1Division of Brain Tumor Translational Research,

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National Cancer Center Research Institute, Tokyo, Japan, 2Department
of Diagnostic Pathology National Cancer Centre Hospital, Tokyo,
Japan, 3Department of Neurosurgery, Graduate School of Medicine, The
University of Tokyo, Tokyo, Japan, 4Department of Neuro-Oncology and
Neurosurgery, Saitama Medical University, Saitama, Japan, 5Departmentof Neurosurgery, Graduate School of Biomedical and Health Sciences,
Hiroshima University, Hiroshima, Japan, 6Department of Neurosurgery,Tokyo Medical and Dental University, Tokyo, Japan, 7Department of
Biomedical Research and Innovation, Institute for Clinical Research,
National Hospital Organization Osaka National Hospital, Osaka, Japan,
8Department of Pediatric Neurosurgery, Osaka City General Hospital,
Osaka, Osaka, Japan, 9Division of Molecular and Cellular Medicine,National Cancer Center Research Institute, Tokyo, Japan, 10Departmentof Molecular and Cellular Medicine, Institute of Medical Science, Tokyo
Medical University, Tokyo, JapanINTRODUCTION: One of the major limitations of pathologicaldiagnosis for intracranial germ cell tumors (iGCTs) is tumor heterogeneity, which cannot be evaluated using limited amount of tumor tissues. In this study, we performed comprehensive analysis of microRNA(miRNA) of iGCTs to identify miRNAs profile to help determine tumor
diagnosis. METHODS: RNA was extracted from frozen samples of 16
germinoma and 14 NGGCTs. Five non-iGCT pediatric brain tumor tissues
were used as control. miRNA expression analysis was performed using a
3D-Gene Human miRNA Oligo Chip ver.22 (Toray Industries, Inc) which
was designed to detect 2565 miRNAs. The miRNA expression profile wasanalyzed using t-SNE dimensionality reduction and weighted average difference method (WAD). RESULTS: Different histological subtypes of theiGCTs and control samples were clustered into distinct classes. Furthermore, we found that the germinoma, NGGCTs and control samples may bereadily distinguished by expression patterns of miR-200 and miR-371a-3p:
a high expression of miR-200 was observed in the NGGCTs, whereas ahigh expression of miR-371a-3p was observed in all cases of germinoma
and some of NGGCTs. Neither of miR-200 nor miR371-3p was highly
expressed in control samples. CONCLUSION: Our data indicated thatgerm cell tumor and other pediatric brain tumors, and also germinoma andNGGCT can be distinguished by expression patterns of 2 micro RNA, miR200 and miR-371a-3p. These 2 microRNA may serve as a useful tool for
supporting the pathological diagnosis of iGCTs.
GCT-73. EXPRESSION PROFILING OF INTRACRANIAL GERM CELL
TUMORS REVEALS UPREGULATION OF RAS THROUGH MRNAMICRORNA SIGNALING PATHWAY
Aaron M. Taylor1,2, Jianhe Shen1,3, Lingzhao Ren4, Keita Terashima5,
Lei Huang6, Elizabeth M. Snyder7, Adekunle Adesina1,3, Jack Su1,3,
Ryo Nishikawa8, Hideo Nakamura9, Ho-Keung Ng10, Stephen T.C. Wong6,
Robert E. Braun7, Tsz-Kwong Man1,3, and Ching C. Lau2,11; 1Baylor
College of Medicine, Houston, Texas, USA, 2The Jackson Laboratory for
Genomic Medicine, Farmington, Connecticut, USA, 3Texas Children’s
Hospital, Houston, Texas, USA, 4Rice University, Houston, Texas, USA,
5National Center for Child Health and Development, Tokyo, Japan,
6Houston Methodist, Houston, Texas, USA, 7The Jackson Laboratory, Bar
Harbor, Maine, USA, 8Saitama International Medical Center, Saitama,
Japan, 9Kurume University, Fukuoka, Japan, 10The Chinese University ofHong Kong, Shatin, Hong Kong, 11Connecticut Children’s Medical Center,
Hartford, Connecticut, USA
Intracranial germ cell tumors (IGCTs) account for 3% of CNS tumorsin children in the U.S. and 11% in Japan and East Asian countries. IGCTs
are separated into two distinct subtypes based on histology: germinomas
and non-germinomatous germ cell tumors (NGGCTs). The deep central location of IGCTs makes surgical resection and therefore molecular subtypeclassification difficult, and previous gene expression studies are limited.
We performed mRNA expression profiling (Human Genome U133 Plus
2.0) and microRNA expression profiling (ABI TaqMan) with 36 and 49
IGCTs, respectively. Sample stratification using non-negative matrix factorization clustering of gene expression revealed two distinct subgroups
that delineated germinomas from NGGCTs. Employing stepwise modelbuilding in each data set separately, we were able to separate these groups
using only mRNA probes for the LIN28B and L1TD1 genes, and two
microRNA, microRNA-26a and microRNA-373. MicroRNA26a suppresses the LIN28B gene and is down-regulated in germinoma. LIN28B
directly binds and suppresses the let-7 microRNA family, which suppress
the KRAS oncogene, previously found to be mutated in ~19% of IGCTs.
L1TD1 is required for human stem cell renewal and directly interacts
with LIN28B for its RNA binding function. LIN28B and L1TD1 are both
known to be upregulated in other systemic germ cell tumors, but thishas not yet been documented in IGCTs. In conclusion, these results showthat intracranial germinomas have similar gene expression compared tosystemic seminoma, and suggest a mechanism by which activation of
LIN28B and L1TD1 downregulates the let-7 microRNA and subsequently
upregulates KRAS.

GCT-74. RETROSPECTIVE LITERATURE REVIEW OF CENTRALNERVOUS SYSTEM (CNS) GERM CELL TUMORS (GCTS) IN
PATIENTS WITH DOWN SYNDROME (DS)Micah K. Harris1,2, Margaret Lamb1, Joseph R. Stanek1,
Jonathan L. Finlay1, and Mohamed S. AbdelBaki1; 1The Division of
Hematology, Oncology, Blood and Marrow Transplant, Nationwide
Children’s Hospital and The Ohio State University, Columbus, OH, USA,
2The Ohio State University College of Medicine, Columbus, OH, USA
BACKGROUND: A standard-of-care has not been established forthe management of DS patients who develop primary CNS GCTs –the most common CNS neoplasm in DS – despite being more susceptible to treatment-related adverse events. METHODS: A review of the
English-language medical literature between 1960 and 2020 was conducted. RESULTS: Thirty-one cases of CNS GCTs in DS patients (mediannine-years-old; 21 males) were reported; the majority (23/31) originatedfrom East Asia. Twelve had germinomas (39%), 12 had non-germinomatous
germ cell tumors (NGGCTs) (39%), and seven had teratomas (22%). Fourpatients (13%) died from tumor progression (one germinoma versus threeteratoma). Seven patients (23%) died from treatment-related complications(four germinoma versus three NGGCT). Of the germinoma patients, twodied from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, and one from Moyamoya following radiation-therapy (RT)
only. Of the NGGCT patients, one died from chemotherapy-related sepsis,
one from post-surgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival (OS) was 58.1% for all
patients, 52.5% for germinoma, 64.8% for NGGCT, and 60% for teratoma. Three-year OS for patients who received RT or chemotherapy was
63.6% and 59.6% respectively. Twenty patients (65%) remain alive (seven
germinoma versus nine NGCCT versus four teratoma). Ten patients (32%)
experienced serious treatment-related complications (five germinoma versus
five NGGCT). CONCLUSIONS: Patients with DS and CNS GCTs are at
an increased risk of treatment-related complications. Therefore, a different
therapeutic approach may need to be considered for this patient population in order to mitigate the treatment-related complications and long-term
neurocognitive sequelae.
GCT-75. ISOLATED PITUITARY STALK THICKENING
Julie Bennett, Liana Nobre, Eric Bouffet, Oussama Abla,
Jonathan Wasserman, Birgit Ertl-Wagner, and Ute Bartels; The Hospital for
Sick Children, Toronto, ON, Canada
OBJECTIVES: Only few studies have examined the predictive factors
and outcome of isolated pituitary stalk thickening (PST) in children. We
aim to describe our institutional cohort to determine predictors of future
malignancy. METHODS: A search of the radiology, endocrinology andneuro-oncology databases was performed to identify patients with isolated
PST diagnosed between January 2000 and June 2019. Clinical data wascollected. A detailed radiology review of baseline and follow up magnetic
resonance imaging (MRI) was undertaken in a blinded fashion by two
examiners. RESULTS: Forty-four patients were identified, with 37 meeting
criteria for isolated PST and adequate imaging. Median age of baseline MRI
was 9.9 years (range 0.9–17.5). Twenty-three were female (62%). Medianfollow up time was 5 (0.31–18.6) years. Indication for MRI was symptoms
of diabetes insipidus (DI) in 28 patients with the remainder having otherconcerns for endocrine disturbance (7), headache (1) or visual impairment(1). Thirty-five subjects had pituitary dysfunction (95%), including 30 withdiabetes insipidus (81%). Nine patients developed a malignancy (24%),with germinoma (5), Langerhans cell histiocytosis (3) and lymphoma (1) ata median of 0.36 years, 0.63 years and 1.1 years respectively. Elevated whiteblood cell count (>5 x 106/L) in initial cerebrospinal fluid analysis was predictive of future diagnosis of germinoma or lymphoma (p=0.027). CONCLUSION: In this cohort 24% of children with PST were eventuallydiagnosed with a neoplasia after a median of 0.63 years. Pleocytosis ininitial CSF samples was predictive for future development of germinoma
or lymphoma.
GCT-76. 24GY WHOLE VENTRICULAR RADIOTHERAPYALONE IS SUFFICIENT FOR DISEASE CONTROL IN LOCALISEDGERMINOMA IN CR AFTER INITIAL CHEMOTHERAPY – EARLYRESULTS OF THE SIOP CNS GCT II STUDY
Gabriele Calaminus1, Brigitte Bison2, Cecile Faure-Conter3,
Didier Frappaz3, Andreas Peyrl4, Nicolas Gerber5, Jans-Enno Müller1,
Ajithkumar Thankamma6, Dipayan Mitra7, Justin Cross8, Torsten Pietsch9,
Colin Smith10, Kristin Solem11, Irene Devenney12, Maria Luisa Garre13,
Herve Brisse14, Martin Zimmermann15, Rolf-Dieter Kortmann16,
Claire Alapetite17, and James Nicholson18; 1University Children’s
Hospital Bonn, Dep, of Paediatric Haematology and Oncology, Bonn,
Germany, 2Institute for Diagnostic and Interventional Neuroradiology,
University Hospital Würzburg, Würzburg, Germany, 3Institut d’Hémato‐
oncologie Pédiatrique, Lyon, France, 4Department of Pediatrics, Medical

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University of Vienna, Vienna, Austria, 5The Center for Oncology at the
University Children’s Hospital Zurich, Department of Oncology, Zurich,
Switzerland, 6Department of Clinical Oncology, Cambridge University
Hospitals, Cambridge, United Kingdom, 7Department of Radiology,
University of Newcastle, Newcastle, United Kingdom, 8Department ofRadiology, Cambridge University Hospitals, Cambridge, United Kingdom,
9Department of Neuropathology, DGNN Brain Tumor Reference Center,
University of Bonn, Bonn, Germany, 10Academic Neuropathology,
University of Edinburgh, Edinburgh, United Kingdom, 11Dept for Children
and Adolescents, St, Olav University Hospital of Trondheim, Trondheim,
Norway, 12Dept, Pediatric Oncology, BOND Linköping University
Hospital, Linköping, Sweden, 13Unit of Neurooncology, Department of
Haemato-Oncology Gaslini Children’s Hospital, Genova, Italy, 14Imaging
Department, Institut Curie, Paris, France, 15Department of PediatricHematology/Oncology, Hannover Medical School, Hannover, Germany,
16Department of Radiation Oncology, Leipzig, Germany, 17Radiation
Oncology Department Institut Curie, Paris & Proton Centre, Orsay, Paris,
France, 18Department of Paediatric Oncology, Cambridge University
Hospitals, Cambridge, United Kingdom
SIOP CNS GCT II aimed to establish if 24Gy Whole Ventricular Radiotherapy (WVRT) in localised germinoma is sufficient for tumour control.
After central review of radiological response after ‘CarboPEI’ chemotherapy,
patients in complete remission (CR) were consolidated with 24Gy WVRT.
Between 2/2012 and 7/2018, 182 patients from 8 European countries withhistologically-confirmed fully-staged localised germinoma were registered.
70 patients were in CR after chemotherapy, 98 in partial remission (PR),seven had stable disease, two progressive disease, and in five no response
data were documented. Of the 70 patients in CR, 58 received 24Gy WVRT
alone; two of these relapsed, one local and one disseminated, two and six
years after diagnosis. Of the 98 patients in PR after chemotherapy, 86 received 24Gy WVRT and 16Gy boost, of which five relapsed (three local,
two distant) 12–24 months from diagnosis. Twelve patients in each of the
CR/PR groups received non-protocol or undocumented radiotherapy fields/
doses. Median follow-up was 3.7 years. Event-free survival (EFS) for patients in CR and with WVRT only (n=58) was 98% at 4 years. 4-years EFSof patients with PR and WVRT 24Gy and 16Gy tumor boost (n=86) was
95%. Localised germinoma in CR after chemotherapy had an excellent outcome with 24Gy WVRT alone; 24GY WVRT can therefore be considered
standard consolidation treatment in this group. International consensus onradiological response criteria is of utmost importance to avoid over- andundertreatment of such patients and to pave the way for further treatment
reduction in this group of patients.

HIGH GRADE GLIOMA
HGG-01. ENTRECTINIB IN RECURRENT OR REFRACTORY SOLID
TUMORS INCLUDING PRIMARY CNS TUMORS: UPDATED DATA
IN CHILDREN AND ADOLESCENTS
Giles Robinson1, Ami Desai2, Ellen Basu3, Jennifer Foster4, Karen Gauvain5,
Amit Sabnis6, Suzanne Shusterman7, Margaret Macy8, Luke Mease9,
Janet Yoon10, Thomas Cash11, Mohamed Abdelbaki12, Kellie Nazemi13,
Christine Pratilas14, Brian Weiss15, Saibah Chohan16, Alison Cardenas17,
Katherine Hutchinson17, Guillaume Bergthold18, and Amar Gajjar1; 1St.
Jude Children’s Research Hospital, Memphis, TN, USA, 2University of
Chicago Medical Center, Chicago, IL, USA, 3Memorial Sloan Kettering
Cancer Center, New York, NY, USA, 4Texas Children’s Hospital, Houston,
TX, USA, 5Washington University School of Medicine, St, Louis, MO,
USA, 6University of California San Francisco, Benioff Children’s Hospital,
San Francisco, CA, USA, 7Dana Farber Cancer Institute, Boston Children’s
Cancer and Blood Disorders Center, Boston, MA, USA, 8Children’s
Hospital Colorado, Department of Hematology- Oncology & Bone
Marrow Transplantation, Aurora, CO, USA, 9University of Utah/Huntsman
Cancer Institute, Primary Children’s Hospital, Salt Lake City, UT, USA,
10Rady Children’s Hospital, San Diego, CA, USA, 11Aflac Cancer & Blood
Disorders Center, Children’s Healthcare of Atlanta, Emory University
School of Medicine, Atlanta, GA, USA, 12Nationwide Children’s Hospital,
Columbus, OH, USA, 13Oregon Health & Science University, Doernbecher
Children’s Hospital, Portland, OR, USA, 14Sidney Kimmel Comprehensive
Cancer Center, Johns Hopkins University School of Medicine, Baltimore,
MD, USA, 15Cincinnati Children’s Hospital Medical Center, Cincinnati,
OH, USA, 16F. Hoffmann-La Roche Limited, Mississauga, ON, Canada,
17Genentech, South San Francisco, CA, USA, 18F. Hoffmann-La Roche,
Basel, Switzerland
STARTRK-NG (phase 1/2) is evaluating entrectinib, a CNS-penetrant
oral, TRK/ROS1/ALK tyrosine kinase inhibitor, in patients <21 years withrecurrent/refractory solid tumors, including primary CNS tumors. After
determining the recommended dose, 550mg/m2/day, in all-comers, expansion
cohorts with gene-fusion-positive CNS/solid tumors (NTRK1/2/3, ROS1)

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are being enrolled. As of 5Nov2019 (data cut-off), 39 patients (4.9m–20y;median 7y) have been evaluated for response, classified as complete (CR) or
partial response (PR), stable (SD) or progressive disease (PD) using RANO
(CNS), RECIST (solid tumors), or Curie score (neuroblastoma). Responses
in patients with fusion-positive tumors were Investigator-assessed (BICR assessments are ongoing) and occurred at doses ≥400mg/m2. Best responses
in fusion-positive CNS tumors (n=14) were: 4 CR (GKAP1-NTRK2,
ETV6-NTRK3 [n=2], EML1-NTRK2); 5 PR (KANK1-NTRK2, GOPCROS1, ETV6-NTRK3, TPR-NTRK1, EEF1G-ROS1); 3 SD (BCR-NTRK2,
ARHGEF2-NTRK1, KIF21B-NTRK1); 2 PD (PARP6-NTRK3, EML4ALK); and in fusion-positive solid tumors (n=8) were: 3 CR (ETV6-NTRK3[n=2], DCTN1-ALK); 5 PR (EML4-NTRK3, TFG-ROS1 [n=3], KIF5BALK). Responses (Investigator-assessed) in non-fusion tumors (n=17) were:
1 CR (ALK F1174L mutation), 3 SD, 10 PD, 3 no data/unevaluable. The objective response rate (CR+PR/total) in patients with fusion-positive tumors
was 77% (17/22) versus 6% (1/17) in those with non-fusion tumors. All 39
patients experienced ≥1 adverse event (AE); the most frequent AEs included
weight gain and anemia (both 48.7%); increased ALT, increased AST, coughand pyrexia (all 46.2%); increased creatinine and vomiting (both 43.6%);and bone fractures (n=10, in 9 patients). Entrectinib has produced striking,rapid, and durable responses in solid tumors with target gene fusions, especially high-grade CNS neoplasms.
HGG-02. ADOLESCENT AND YOUNG ADULT (AYA) GLIOMA WITH
BRAF V600E-MUTANTATION
Yui Kimura1,2, Yukitomo Ishi3, Yuko Watanabe4, Yoshiko Nakano1,
Shigeru Yamaguchi3, Yoshitaka Narita5, and Koichi Ichimura1; 1Divisionof Brain Tumor Translational Research, National Cancer Center ResearchInstitute, Chuo, Tokyo, Japan, 2Unit of Comprehensive Oncology, Nagasaki
University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki,
Japan, 3Department of Neurosurgery, Hokkaido University Graduate
School of Medicine, Sapporo, Hokkaido, Japan, 4Department of PediatricOncology, National Cancer Center, Chuo, Tokyo, Japan, 5Department of
Neurosurgery, National Cancer Center, Chuo, Tokyo, JapanBACKGROUND: Biological features of pediatric glioma differ significantly from those of adult glioma, and limited data are available on thoseof AYA patients. Here, we focused on AYA patients with glioma, especiallythose harboring BRAF V600E mutation, and investigated their clinical andgenetic features. METHOD: We retrospectively analyzed AYA patients withbrain tumors harboring BRAF V600E, who were treated in two hospitals
in Japan. RESULTS: Clinical information was available for 14 patients.
The median age at diagnosis was 25 years (range: 15–38). Five patientswere diagnosed with glioblastoma (GBM), including one epithelioid type.
These patients were over 25. Although one patient with GBM died of thedisease 6.9 years after initial diagnosis, the remaining patients were alive.
Two patients were alive without recurrence at 38 and 51 months after thetreatment. The patient with epithelioid glioblastoma experienced early recurrence. The remaining nine patients (64%) were diagnosed with low-grade
glioma, including ganglioglioma, pilocytic astrocytoma, diffuse astrocytoma,
oligodendroglioma, pleomorphic xanthoastrocytoma, and polymorphous
low-grade neuroepithelial tumor of the young. No patients died of thedisease, and four patients are alive without recurrence after initial operation
without adjuvant treatment. Two patients are (epithelioid glioblastoma andganglioglioma) currently undergoing treatment with a BRAF inhibitor forrecurrent tumors. DISCUSSION: Although the number of this study islimited, our study suggested that the prognosis of AYA patients with BRAFV600E positive GBM may not be as dismal as that of children or adults.
HGG-04. ZINC ENHANCES TEMOZOLOMIDE CYTOTOXICITY IN
PEDIATRIC GLIOBLASTOMA MULTIFORME MODEL SYSTEM
Amos Toren, Michal Yalon, Aner Dafni, and Ruty Mehrian-Shai; Sheba
Medical Center, Ramat Gan, Israel
BACKGROUND: Temozolomide (TMZ) is an alkylating agent that has
become the mainstay treatment of the most malignant brain cancer, glioblastoma multiforme (GBM). Unfortunately only a limited number of patients respond to it positively. We have shown that zinc metal reestablishes
chemosensitivity in adult GBM in vitro and also in vivo but this effect has
not been tested with pediatric GBM. METHODS: Using Human pediatricglioblastoma cell lines- KNS42 (mutant p53/ MGMT [+]) and SF188 (mutant p53/ MGMT [-]), we investigated whether addition of zinc to TMZ
enhances its cytotoxicity against GBM. RESULTS: In vitro cell viability
analysis showed that the cytotoxic activity of TMZ was substantially increased with addition of zinc and this response was accompanied by an elevation of p21, PUMA, BAX and a decrease in growth fraction as manifested
by low ki67. Beta gal analysis showed that most of the remaining cells after
the combination therapy are in senescence state. In order to eliminate thesenescent population created as a result of the combined treatment of TMZ
and Zinc, we decided to use a senolytic agent Navitoclax (ABT-263) thatwas demonstrated to be effective in reducing senescent cells by specific in-Abstracts

hibition of Bcl-2, Bcl-XL and Bcl-w. Following the addition of Navitoclax
to the combined treatment, SF188 cells, but not KNS42, show a significancereduction in viability compare to the combination treatment. CONCLUSIONS: Our results suggest that zinc may serve as a potentiator of TMZ
therapy in pediatric GBM patients and using a second hit with senolytic drugin some cases may be even more beneficial.
HGG-05. REGRESSION OF RECURRENT GLIOBLASTOMAAFTER BORON NEUTRON CAPTURE THERAPY AND CHIMERICANTIGEN RECEPTOR T-CELL THERAPY IN A CHILD
Hsin-Hung Chen1,2, and Yi-Wei Chen1,2; 1Taipei Veterans General Hospital,
Taipei, Taiwan, Taiwan, 2National Yang-Ming University, Taipei, Taiwan,
TaiwanA 6 y/o girl with recurrent multifocal glioblastoma received 3 times ofboron neutron capture therapy (BNCT) and chimeric antigen receptor(CAR)–engineered T cells targeting the tumor-associated antigen HER2.
Multiple infusions of CAR T cells were administered over 30 days throughintraventricular delivery routes. It was not associated with any toxic effects
of grade 3 or higher. After BNCT and CAR T-cell treatment, regression of
all existing intracranial lesions were observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid, but
new lesions recurred soon after the treatment. This clinical response continued for 14 months after the initiation of first recurrence.
HGG-06. REMARKABLE RESPONSE TO BRAF INHIBITOR IN AN
INFANT WITH DISSEMINATED DIFFUSE LEPTOMENINGEALGLIONEURONAL TUMOR (DLGNT)Le Le Aung; Parkway Cancer Centre, Singapore, Singapore
INTRODUCTION: Diffuse Leptomeningeal Glioneuronal Tumor(DLGNT) are rare CNS tumors and in infants, they can be lethal. There
are several anecdotal reports in infants with low grade gliomas (LGG) withtreated with BRAF inhibitors. METHODS: A six-month old baby girl presented with a 2-week history of absent visual contact and vomiting. Imaging
revealed a large 4.7 X 4.2 X 2.8 cm suprasellar charismatic region massand multiple small extra-axial plaques in spinal canal. The child developed
significant ascites post VP shunt requiring shunt externalization, extensive
protein infusion support and hospitalization for six weeks. Immunohistochemical staining revealed Olig-2 and S-100, GFAP and synaptophysin
positive. EMA showed patchy cytroplasmic reactivity in stromal cells andCD99 showed diffuse reactivity in stromal and lesional cells. INI-1, IDH-1,
and CD117 were negative. Ki-67 proliferation index was 8–10%. PCR for
BRAF V600E/E2/D was detected and KIAA1549-BRAF fusion as negative.
This was confirmed by Genome Wide Next Generation Sequencing. While
waiting for GNS testing results, the baby received one dose of Vinblastine.
However, within seven days of initiating Debrafenib, significant clinical andradiological responses were observed. CONCLUSION: The baby continues
safely on Debrafenib with continued dramatic radiological response. Thissuggest that there may be a role in early initiation of targeted therapy suchas BRAF inhibitors rather than giving standard chemotherapy such as Vinblastine or Carboplatin-Vincristine in extremely ill infants with low grade
gliomas.
HGG-07. CYCLIN-DEPENDENT KINASES AS TARGET STRUCTURESFOR CANCER THERAPY – A COMPARATIVE IN VITRO ANALYSISON PATIENT-DERIVED GLIOBLASTOMA CELL CULTURE MODELS
Christin Riess, Carl Friedrich Classen, and Claudia Maletzki; University
Medicine, Rostock, Mecklenburg-Vorpommern, Germany
INTRODUCTION: Current therapeutic approaches have limited clinicalsuccess for Glioblastoma patients, making novel strategies urgent. Cyclindependent kinases (CDK) are crucial in cell cycle, oncogenic transcription,
DNA repair, and stem-cell renewal. Glioma cells frequently show genomic
alterations in CDKs. Here, we evaluated the antitumoral activity of selective
CDK inhibitors (CDKI) abemaciclib (CDK4/6), palbociclib (CDK4/6), anddinaciclib (CDK1/2/5/9) alone and in combination with chemo-/radiotherapy. MATERIALS/METHODS: Low passage glioblastoma cell lines(N=5) with different molecular characteristics were cultured in 2D and 3D(neurospheroids (NSPs), glioma stem-cells (GSCs). The impact of CDKI
alone or in combination with TMZ and radiation (2Gy) was examined. Viability was measured using Calcein-AM and 3D-Glo assays; DNA doublestrand breaks by γ-H2AX immunofluorescence. Functional analyses were
performed from a 2D culture (72h treatment). RESULTS: Dinaciclib significantly affected viability of GBM cell lines even shortly after low-dose treatment. CDK 4/6 inhibitors were less effective. Abemaciclib and dinaciclib
acted radio-sensitizing. Dinaciclib combined with different substances (72h,dose: IC20), synergistically potentiated antitumoral effects. In a scratch assay,
abemaciclib decelerated wound healing; dinaciclib even induced cell death.
Microarray analysis revealed altered gene expression: Genes mediating celladhesion, division, DNA-binding, apoptosis (Casp3,Casp8), senescence(ASF1A,CENPA,FBXO31), and autophagy (ATG4D,ATG2A,SOGA1)
were upregulated. Chemotaxis-mediating (CXCL8,CCL20) and protooncogenes like JUNB and FOS were strongly down-regulated. Long-term
treatment induced dinaciclib resistance in 1/5 cases, and none abemaciclibtreated cells. This was reversed when dinaciclib was combined with
TMZ. CONCLUSION: Our results demonstrate strong anti-GBM activityof dinaciclib and abemaciclib, with additive effects of chemotherapy andradiosensitization, encouraging to move forward this strategy.
HGG-09. FIRST LINE THERAPY OF PEDIATRIC GLIOBLASTOMAWITH LAROTRECTINIB
Musa Alharbi1, Nahla Ali Mobark1, Ali Abdullah O. Balbaid2,
Fatmah A. Alanazi3, wael abdel Rahman Aljabarat1, Eman A.K. Bakhsh4,
Murad Turkistani5, and Malak Abedalthagafi6; 1Department of PaediatricOncology Comprehensive Cancer Centre, King Fahad Medical, Riyadh,
Saudi Arabia, 2Radiation Oncology Department Comprehensive Cancer
Centre, King Fahad Medical City, Riyadh, Saudi Arabia, 3Departmentof Clinical Pharmacy, King Fahad Medical City, Riyadh, Saudi Arabia,
4Radiology Department King Fahad Medical CITY, Riyadh, Saudi Arabia,
5Department of Pathology, King Abdulaziz University Hospital, Jeddah,
Saudi Arabia, 6Genomics Research Department, Saudi Human Genome
Project, King Fahad Medical City and King Abdulaziz City for Science andTechnology, Riyadh, Saudi Arabia
PURPOSE: In this case report, we document new recommendations for thetreatment of pediatric glioblastoma based on a genetic understanding of thedisease. PATIENTS AND METHODS: A Saudi girl aged 18 months presented
with a history of right sided weakness and partial seizures. MRI revealed thepresence of large complex left frontal tumor. Craniotomy and gross total resection were performed. post-operatively The patient showed excellent recovery
with no neurological deficits. Pathology reports confirmed glioblastoma (GBM).
Due to the expected poor survival, the patient’s family declined standard therapy,
including chemotherapy and/or radiation therapy. RESULTS: Molecular analysis showed positive fusion mutations for ETV6-NTRK3 making the patientan ideal candidate for larotrectinib, an oral tyrosine kinase (TRK) inhibitor.
Unfortunately, follow-up MRI showed local tumor recurrence at 3-months
post-surgery. The family agreed to the initiation of oral larotrectinib as a lessinvasive therapy. The patient tolerated Larotrectinib very well with no reportedside effects. Follow up MRI was performed 8-weeks post-larotrectinib treatment and showed significant tumor regression, indicating an excellent treatment
response. CONCLUSION: This case highlights how TRK-inhibitors can be integrated as a first-line therapy for pediatric high grade GBMs harboring TRKfusions. We also highlight the need for the integration of genomic profiling andmolecular analysis into the routine histopathologic analyses of pediatric patientswith malignant primary intracranial tumors, to detect any genetic mutations
that can be targeted with available therapies to avoid the morbidity associatedwith non-precision conventional therapies.
HGG-11. HIGH-GRADE GLIOMAS IN ADOLESCENTS AND YOUNG
ADULTS HIGHLIGHT HISTOMOLECULAR DIFFERENCES WITH
THEIR ADULT AND PAEDIATRIC COUNTERPARTS
Alexandre Roux1,2, Johan Pallud1,2, Raphaël Saffroy3,
Myriam Edjlali-Goujon4,2, Marie-Anne Debily5, Nathalie Boddaert6,
Marc Sanson7,8, Stéphanie Puget9, Steven Knafo10, Clovis Adam11,
Thierry Faillot12, Dominique Cazals-Hatem13, Emmanuel Mandonnet14,
Marc Polivka15, Georges Dorfmüller16, Aurélie Dauta17,
Mathilde Desplanques18, Albane Gareton18, Mélanie Pages18,2,
Arnault Tauziède-Espariat18,2, Jacques Grill19,5, Franck Bourdeaut20,
François Doz20, Frédéric Dhermain21, Karima Mokhtari22,7,
Fabrice Chrétien18, Dominique Figarella-Branger23, and Pascale Varlet18;
1Department of Neurosurgery, GHU Paris, Sainte-Anne Hospital,
University of Paris, Paris, France, 2INSERM UMR 1266, IMA-Brain,
Institute of Psychiatry and Neurosciences of Paris, Paris, France,
3Department of Biochemistry, Paul-Brousse Hospital, AP-HP, Villejuif,
France, 4Department of Neuroradiology, GHU Paris, Sainte-Anne Hospital,
University of Paris, Paris, France, 5INSERM U981, «Biomarqueurs and
New Therapeutic Targets in Oncology», Team «Genomics and Oncogenesisof Brain Tumors”, Paris-Sud University, Paris-Saclay University, Villejuif,
France, 6Department of Neuroradiology, Necker Enfants-Malades Hospital,
AP-HP, University of Paris, Paris, France, 7Brain and Spine Institute (ICM),
Experimental Neuro-Oncology Department, Inserm U1127, CNRS UMR
7225, Sorbonne University, UPMC University Paris 06, Paris, France,
8Department of Neurology 2, Mazarin Unit, Pitié-Salpêtrière Hospital,
AP-HP, Paris, France, 9Department of Neurosurgery, Necker EnfantsMalades Hospital, AP-HP, University of Paris, Paris, France, 10Departmentof Neurosurgery, Bicêtre Hospital, AP-HP, Paris-Sud University, KremlinBicêtre, France, 11Department of Pathology, Bicêtre Hospital, AP-HP, ParisSud University, Kremlin-Bicêtre, France, 12Department of Neurosurgery,Beaujon Hospital, AP-HP, Clichy, France, 13Department of Pathology,
Beaujon Hospital, AP-HP, Clichy, France, 14Department of Neurosurgery,N E U R O -O N C O L O G Y•

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Lariboisière Hospital, AP-HP, Paris, France; Paris 7 University, Paris,
France, 15Department of Pathology, Lariboisière Hospital, AP-HP, Paris,
France, 16Department of Paediatric Neurosurgery, Rothschild Foundation
Hospital, Paris, France, 17Department of Neurosurgery, Henri-Mordor
Hospital, AP-HP, Créteil, France, 18Department of Neuropathology,
GHU Paris – Sainte-Anne Hospital, University of Paris, Paris, France,
19Department of Paediatric Oncology, Gustave-Roussy University Hospital,
Paris-Sud University, Paris-Saclay University, Villejuif, France, 20SIREDO
Oncology Center (Care, Innovation and research for children and AYA
with cancer), Institut Curie, University of Paris, Paris, France, 21Departmentof Radiotherapy, Gustave Roussy University Hospital, Villejuif, France,
22Department of Neuropathology, Pitié-Salpêtrière Hospital, AP-HP, Paris,
France, 23Department of Pathology and Neuropathology, La Timone
Hospital, AP-HM, Marseille, France
BACKGROUND: Considering that paediatric high-grade gliomas(HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescentsand young adults (AYAs). METHODS: We performed a multicentric
retrospective study of 112 AYAs from adult and paediatric Ile-deFrance neurosurgical units, treated between 1998 and 2013 to analyse
their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25-years, histopathological HGG diagnosis, available clinical data, pre-operative and follow-up MRI. MRI
and tumoral samples were centrally reviewed. Immunohistochemistry
and complementary molecular techniques such as targeted/next generation sequencing, whole exome sequencing and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the2016 WHO classification. RESULTS: Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and moleculargroups, with a predominant representation of paediatric-subtypes (Histone H3-mutants, 40%) but also adult-subtypes (IDH-mutants, 28%)
characterized by the rarity of oligodendrogliomas, IDH-mutant and1p/19q co-deleted and the relative high frequency of “rare adult IDH
mutations” (20%). H3G34-mutants (14%) represent the most specificsubgroup in AYAs. In the H3K27-mutant subgroup, the non-brainstem
diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic
pontine gliomas (23.8%), contrary to children. We found that WHO
grade has no prognostic value, but molecular subgrouping has major
prognostic importance. CONCLUSIONS: HGGs in AYAs could benefit
from a more personalized neuro-oncological management, driven by molecular subtyping rather than age group. Collaborative efforts are neededfrom paediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs.
HGG-12. A CASE OF PEDIATRIC SPINAL HIGH-GRADE GLIOMAWITH NTRK1 GENE FUSION
Tamaki Morisako1, Daisuke Umebayashi1, Kazuaki Kamata1,
Hiroyuki Yamamoto1, Takumi Yamanaka1, Hayato Takeuchi1,
Yoshinobu Takahashi1, Kazunori Tatsuzawa1, Mitsuru Miyachi2,
Shigeki Yagyu2, Tomoko Iehara2, Hajime Hosoi2, and Naoya Hashimoto2;
1Department of Neurosurgery, Kyoto Prefectural University of Medicine,
Graduate School of Medical Science, Kyoto, Japan, 2Department ofPediatrics, Kyoto Prefectural University of Medicine, Graduate School of
Medical Science, Kyoto, JapanINTRODUCTION: Tumors arising from the spinal cord are uncommon, especially high-grade tumors in pediatric patients. We reporta case of high-grade glioma in the spinal cord harboring NTRK1 genefusion, who received effective entrectinib therapy. CASE REPORT:
A 5-year-old boy presented right hemiparesis and MR imaging revealed
an intramedullary enhancing mass at the vertebral body level between
C3 and Th1. He underwent microsurgical partial resection and thehistological diagnosis was low-grade astrocytoma. After the first-line
chemotherapy with vincristine and carboplatin, his right hemiparesis
deteriorated and recurrent MR imaging showed growth of the tumor.
He underwent microsurgical partial resection again and the histologicalexamination was high-grade glioma with endothelial proliferation andnecrosis. The chemoradiotherapy with temozolomide and focal irradiation of 50.4 Gy were given, and his neurological symptom slightly
improved. One month later, he presented respiratory disturbance andrequired assisted ventilation with tracheostomy. MR imaging showedtumor progression invading upward to medulla oblongata. NTRK1
gene fusion was detected in the previous surgical specimen by a genepanel testing, and he received entrectinib, a potent inhibitor of tropomyosin receptor kinase (TRK). Since then, no tumor progression has been
demonstrated for several months by MRI and he has been stable neurologically. CONCLUSION: High-grade spinal cord tumors are rare andeffective treatment strategies have not been addressed. Although the frequency of the gene fusion is very low in pediatric gliomas, identificationof the driver gene aberration like in this case by a gene panel can provide
potential targeted therapies for selected patients.

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HGG-14. TREATMENT AND PROGNOSTIC FACTORS FOR
PEDIATRIC GLIOBLASTOMAS--THE 10 YEARS EXPERIENCE FROMONE SINGLE CENTER
Juan Li, Mingyao Lai, Qingjun Hu, Cheng Zhou, Zhaoming Zhou,
Changguo Shan, Weiping Hong, Xing Zhang, Yangqiong Zhang,
Rishun Luo, Lichao Wang, Ming Lu, and Linbo Cai; Guangdong Sanjiu
Brain Hospital, Guangzhou, Guangdong, China
OBJECTIVE: We retrospectively analyzed the clinical features of pediatricglioblastoma patients in our center in the past 10 years. METHODS: From
November 2009 to December 2018, patients with glioblastoma under
18 years were admitted to Guangdong Sanjiu Brain Hospital. Clinical andpathological features were summarized, and the curative effect was evaluated. RESULTS: A total of 31 pediatric patients were enrolled. The medianage is 13.8 years (range 0.8–18), including 19 males and 12 females. To
Sep, 2019, the median follow-up time was 18 months(Range 4–80 months).
Among them,2 were lost to follow-up,13 died, 16 still survived, and thelongest survivor survived for 80 months. The median survival time was
16.4 months, the 2-year survival rate was 38%. In the prognostic factor analysis, the median survival time of patients with surgical resection ≥90% was
18 months (95% CI 15.9–20 months), and for children with resection 90%
was 11 months (95% CI 9.9–12 months), P=0.027, with significantly statistically difference. Multivariate analysis showed that tumor resection rate
was an independent prognostic factor for survival. CONCLUSION: The
prognosis of pediatric glioblastoma is still dismal. This study demonstrates
that prognosis of such patients with GTR or near GTR is better.
HGG-16. EXOSOME-MEDIATED INTER-CLONAL INTERACTIONSIN PEDIATRIC GBM AND DIPG
Giulia Pericoli1, Angela Galardi1, Stefania Petrini2, Ezio Giorda3,
Lucia Lisa Petrilli1, Alessandro Paolini4, Marta Colletti5,
Emmanuel De Billy1, Luisa Pascucci6, Hector Peinado7,
Will Court8, Chris Jones9, Andrea Carai10, Angela Mastronuzzi11,
Andrea Masotti4, Franco Locatelli1, Angela Di Giannatale1, andMaria Vinci1; 1Department of Onco-hematology, Cell and Gene Therapy,
Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy, 2Microscopy
service, Research Laboratories, Bambino Gesù Children’s HospitalIRCCS, Rome, Italy, 3Core Facilities research laboratories, BambinoGesù Children’s Hospital-IRCCS, Rome, Italy, 4Multifactorial andComplex Phenotype research Area, Bambino Gesù Children’s HospitalIRCCS, Rome, Italy, 5Department of Onco-hematology, Cell and Gene
Therapy, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy, Italy,
6Department of Veterinary Medicine, University of Perugia, Perugia,
Italy, 7Microenvironment & Metastasis Group, Molecular Oncology
Program, Spanish National Cancer Research Centre (CNIO), Madrid,
Italy, 8Department of Cancer Therapeutics, The Institute of Cancer
Research, Sutton, United Kingdom, 9Department of Molecular Pathology,
The Institute of Cancer Research, Sutton, United Kingdom, 10Oncological
Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation,
Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy, 11Neuro-oncology
Unit, Department of Onco-hematology, Cell and Gene Therapy, BambinoGesù Children’s Hospital-IRCCS, Rome, Italy
Pediatric Glioblastoma (pGBM) and Diffuse Intrinsic Pontine Glioma(DIPG) are highly heterogeneous brain tumors which we demonstrated
are comprised by distinct sub-clones interacting in a functional network.
Exosomes are known to mediate the crosstalk between tumor and its microenvironment. Based on this, we aimed to investigate the role of exosomes inmediating pGBM and DIPG inter-clonal communication. By using opticalbarcoding for single cell-tracking, we generated two bulk multicolor patientderived-cell lines (one DIPG H3.3K27M and one pGBM histone WT) fromwhich we obtained two and five single cell-derived clones respectively. The
sub-clones demonstrated significantly phenotypic differences in terms ofmorphology, growth, adhesion, migration and invasion properties. In particular, co-culture experiments, with the two most different clones for bothcell-lines, confirmed the cell-cell interaction key role in driving their moreaggressive phenotype. Furthermore, we found that pGBM and DIPG subclones release exosomes which are actively and differentially up-taken byindividual clones. Analysis of the exosomal microRNAs showed a different
profile between the two selected clones in each cell-line. In particular, wefound a pool of five upregulated microRNAs in 1C5 clone (DIPG cell-line)
strongly associated to Wnt-signaling and PI3K-AKT pathway. Similarly, apool of five upregulated microRNAs for 5E2 clone (pGBM cell-line) were
found associated with focal adhesion and PI3K-AKT pathway. Our study
may provide novel therapeutic strategies by interfering with the exosomemediated inter-clonal communication in pGBM and DIPG.
HGG-17. HIGH-GRADE GLIOMA IN VERY YOUNG CHILDREN;
A SINGLE-CENTER 11-YEAR-EXPERIENCE
Moatasem El-ayadi1,2, Omar Shawky1,2, Eman Naguib1,2, Eslam Maher2,
Amal Abdelaziz2, Soha Ahmed3, Amal Refaat1,2, André O. von Bueren4,

Abstracts

Hala Taha1,2, Shahenda El-naggar2, and Mohamed El-beltagy5,2; 1National
Cancer Institute, Cairo University, Cairo, Egypt, 2Children Cancer
Hospital- Egypt (CCHE-57357), Cairo, Egypt, 3Faculty of Medicine,
Aswan University, Aswan, Egypt, 4University Hospital of Geneva, Geneva,
Switzerland, 5Kasr El-Ainy School of medicine, Cairo University, Cairo,
Egypt
BACKGROUND: Data about high-grade glioma (HGG) in very young
children (≤3 years old at diagnosis) is scarce. METHODS: 180 pediatric HGG patients were treated at the Children Cancer Hospital - Egypt(CCHE-57357) between July 2007 and June 2018, with 17 patients aged
≤3 years at diagnosis. Medical records were retrospectively reviewed forclinical, radiological and histopathological data, treatment received andsurvival outcome. RESULTS: Median age was 29.2 months (range: 2.4 –35.8 months; males = 9). Most frequent pathological diagnosis was Glioblastoma, WHO grade-IV (n = 11, 64.7%) and one patient had H3-mutant
diffuse midline glioma. All patients underwent surgery (gross-total resection, n = 6, 35.3%; subtotal-resection, n = 5, 29.4%; biopsy, n = 6, 35.3%).
One patient (age = 7 months) progressed and died before starting adjuvant
therapy. All patients ≤1 year of age (n = 5) received adjuvant chemotherapy(CT) only, older children (n = 11) received adjuvant radiotherapy (RT)(total dose range: 54 – 60 Gy) and CT (CCG-945 protocol). The 1-year
overall survival (OS) rate was 47.1%; and event-free survival (EFS) rate
was 35.3%. EFS differed between those who received RT and those who
did not (1-year EFS 54.5% and 0% respectively, p = 0.001). Compared toolder children, anatomical distribution of tumors was significantly different
with non-midline locations being the commonest in patients ≤3 years old(88.2% vs 46.4%, p=0.01). CONCLUSIONS: HGG in very young children arise predominantly in non-midline locations and usually lack theH3-mutation. RT seems crucial in the management of pHGG regardlessof age subgroup.
HGG-18. CLINICAL EFFICACY OF ONC201 IN THALAMIC H3
K27M-MUTANT GLIOMA
Abed Rahman Kawakibi1, Rohinton S. Tarapore2, Sharon Gardner3,
Andrew Chi3, Sylvia Kurz3, Patrick Y. Wen4, Isabel Arrillaga-Romany5,
Tracy T. Batchelor6, Nicholas A. Butowski7, Ashley Sumrall8,
Nicole Shonka9, Rebecca Harrison10, John DeGroot10, Minesh Mehta11,
Yazmin Odia11, Matthew D. Hall11, Doured Daghistani11,
Timothy F. Cloughesy12, Benjamin M. Ellingson12, Yoshie Umemura1,
Jonathan Schwartz13, Vivekanand Yadav1, Rodrigo Cartaxo1, Ruby Siada1,
Zachary Miklja1, Amy Bruzek1, Evan Cantor1, Kyle Wierzbicki1,
Alyssa Paul1, Ian Wolfe1, Marcia Leaoard1, Hugh Garton1, Rajen Mody1,
Patricia L. Robertson1, Guangrong Lu2, Krystal Merdinger2,
Sriram Venneti1, Wolfgang Oster2, Joshua E. Allen2, and Carl Koschmann1;
1University of Michigan, Ann Arbor, MI, USA, 2Oncoceutics Inc.,
Philadelphia, PA, USA, 3NYU Langone Health, New York, NY, USA,
4Dana-Farber Cancer Institute, Boston, MA, USA, 5Massachusetts General
Hospital, Boston, MA, USA, 6Brigham and Women’s Hospital, Boston, MA,
USA, 7University of California San Francisco, San Francisco, CA, USA,
8Levine Cancer Institute, Charlotte, NC, USA, 9University of Nebraska
Medical Center, Omaha, NE, USA, 10University of Texas MD Anderson
Cancer Center, Houston, TX, USA, 11Miami Cancer Institute, Miami,
FL, USA, 12University of California Los Angeles, Los Angeles, CA, USA,
13Mayo Clinic, Rochester, MN, USA
ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has
shown encouraging efficacy in H3 K27M-mutant glioma. Given that thethalamus has the highest extra-striatal expression of DRD2, we performed
an integrated preclinical and clinical analysis of ONC201 in thalamic H3
K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro
IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02,n=14). We analyzed thalamic H3 K27M-mutant glioma patients treated with
ONC201 on active clinical trials as of 5/22/19 enrollment (n=19 recurrent
and 10 post-radiation, non-recurrent; 5–70 years old). As of 12/18/2019,
PFS6 and OS12 are 26.3% and 36.8%, respectively, in the recurrent group.
For non-recurrent patients, with median follow up of 21.9 months (8.6–
26.6) from diagnosis, median PFS or OS have not been reached. This surpasses historical OS of 13.5 months. Best response by RANO includes 1
CR, 3 PR, 4 SD, 8 PD for recurrent patients and 2 PR, 4 SD, 1 PD for nonrecurrent patients (4 on-trial patients experienced regressions that are yet
unconfirmed responses). Median duration of response for recurrent patientsis 14.0 months (2.0–33.1). Furthermore, H3 K27M cell-free tumor DNA in
plasma and CSF correlated with MRI response. In summary, single agent
ONC201 administered at recurrence, or adjuvantly following radiation,
demonstrates promising clinical efficacy in thalamic H3 K27M-mutant
glioma patients who currently have no effective treatments following radiation. Investigations are ongoing to assess whether micro-environmental
DRD2 expression explains the early exceptional responses in thalamic H3
K27M-mutant glioma.

HGG-19. IDENTIFICATION OF NOVEL SUBGROUP-SPECIFICMIRNA EXOSOMAL BIOMARKERS IN PEDIATRIC HIGH-GRADE
GLIOMAS
Lucia Lisa Petrilli1, Alessandro Paolini2, Angela Galardi1, Giulia Pericoli1,
Marta Colletti1, Roberta Ferretti1, Virginia Di Paolo1, Luisa Pascucci3,
Hector Peinado4, Chris Jones5, Antonella Cacchione1, Luca De Palma6,
Marta Alonso7, Andrew Moore8, Angel Montero Carcaboso9,
Andrea Carai10, Angela Mastronuzzi11, Franco Locatelli1, Andrea Masotti2,
Angela Di Giannatale1, and Maria Vinci1; 1Department of Oncohematology, Cell and Gene Therapy, Bambino Gesù Children’s
Hospital-IRCCS, Rome, Italy, 2Multifactorial and Complex Phenotypes
Research Area, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy,
3Department of Veterinary Medicine, University of Perugia, Perugia, Italy,
4Microenvironment & Metastasis Group, Molecular Oncology Program,
Spanish National Cancer Research Centre (CNIO), Madrid, Spain,
5Department of Molecular Pathology, The Institute of Cancer Research,
Sutton, United Kingdom, 6Rare and Complex Epilepsy Unit, Departmentof Neuroscience, Bambino Gesù’ Children’s Hospital, IRCCS, Rome, Italy,
7Department of Pediatrics, University Hospital of Navarra, Pamplona,
Spain, 8The University of Queensland Diamantina Institute, Translational
Research Institute, Brisbane, Australia, 9Developmental Tumor Biology
Laboratory, Hospital Sant Joan de Déu, Barcelona, Spain, 10Departmentof Neuroscience and Neuro-rehabilitation, Neurosurgery Unit, BambinoGesù Children’s Hospital-IRCCS, Rome, Italy, 11Neuro-oncology Unit,
Department of Onco-hematology, Cell and Gene Therapy, Bambino GesùChildren’s Hospital-IRCCS, Rome, Italy
Pediatric high-grade gliomas (pHGG) are heterogeneous brain tumors
for which new specific diagnostic/prognostic biomarkers are needed. In thisstudy, we aimed to identify new pHGG subgroup specific biomarkers by
exploiting exosomes, known vehicles of oncogenic signals. We used plasma
from 23 patients (including 6 controls) and conditioned medium from 12
patient-derived cell-lines, representing all locational and molecular subgroups. Upon exosome isolation, total RNA was extracted and miRNAs
were assessed using a PCR Panel. Analysis of plasma miRNome showedthat tumor exosomal samples were largely clustered together, independently
from their locational and/or molecular subgroup. We identified 20 significantly upregulated and 25 downregulated miRNAs compared to controls.
Interestingly, 27 miRNAs were expressed only in tumors. Furthermore,
the unsupervised clustering showed a clear separation based on locational(hemispheric vs pontine) and mutational (WT vs H3.3G34R or H3.3G34R
vs H3K27M) subgroup comparisons, with the identification of distinct
miRNomes underlying the key role of location and mutations in defining the
pHGG exosomal miRNA profile. This was further confirmed analyzing themiRNOme from cell-line derived exosomes. Moreover, we identified a poolof significantly differentially regulated miRNAs in diagnose vs relapse andbiopsy vs autopsy cell-lines. Most importantly, when comparing hemisphericvs pontine and H3.3G34R vs H3.3K27M, we identified respectively fourand three miRNas equally dysregulated and in common between plasmaand cell-lines. Those were strongly associated mainly to transcriptional regulation and targeting TTC9, linked to cancer invasion and metastasis. Basedon this, we suggest exosomal miRNAs as a powerful new pHGG diagnostic/
prognostic tool.
HGG-20. DIAGNOSTIC AND BIOLOGICAL ROLE OF
METHYLATION PATTERNS IN REPLICATION REPAIR DEFICIENT
HIGH GRADE GLIOMASAndrew Dodgshun1,2, Kohei Fukuoka3, Melissa Edwards4,
Vanessa Bianchi4, Alexandra Sexton-Oates5, Valerie Larouche6,
Vanan Magimairajan7, Scott Lindhorst8, Michal Yalon9, Gary Mason10,
Bruce Crooks11, Shlomi Constantini12, Maura Massimino13,
Stefano Chiaravalli13, Jagadeesh Ramdas14, Warren Mason15,
Ashraf Shamvil16, Roula Farah17, An Van Damme18, Enrico Opocher19,
Syed Ahmer Hamid20, David Ziegler21, David Samuel22, Kristina A Cole23,
Patrick Tomboc24, Duncan Stearns25, Gregory Thomas26,
Alexander Lossos27, Michael Sullivan28, Jordan R Hansford28,
David Jones29, Alan Mackay30, Chris Jones30, Vijay Ramaswamy4,
Cynthia Hawkins4, Eric Bouffet4, and Uri Tabori4; 1Canterbury District
Health Board, Christchurch, New Zealand, 2University of Otago,
Christchurch, New Zealand, 3Jichi Medical University, Shimotsuke, Japan,
4The Hospital for Sick Children, Toronto, Canada, 5International Agency
for Research on Cancer, Lyon, France, 6Universite Laval, Quebec, Canada,
7University of Manitoba, Winnipeg, Canada, 8Medical University of South
Carolina, Charleston, SC, USA, 9Sheba Medical Center, Tel Hashomer,
Israel, 10University of Pittsburgh, Pittsburgh, PA, USA, 11Dalhousie
University, Halifax, Canada, 12Tel Aviv Sourasky Medical Center, TelAviv, Israel, 13Istituto Nazionale dei Tumori, Milan, Italy, 14Geisinger
Medical Center, Danville, PA, USA, 15Princess Margaret Cancer Centre,
Toronto, Canada, 16Children’s Cancer Hospital, Karachi, Pakistan, 17SaintGeorge Hospital University Medical Center, Beirut, Lebanon, 18Universite
Catholique de Louvain, Brussels, Belgium, 19University of Padova, Padova,

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Italy, 20The Indus Hospital, Karachi, Pakistan, 21University of New South
Wales, Sydney, Australia, 22Valley Children’s Hospital, Madera, CA, USA,
23Children’s Hospital of Philadelphia, Philadelphia, PA, USA, 24Ruby
Memorial Hospital, Morgantown, WV, USA, 25University Hospitals
Cleveland, Cleveland, OH, USA, 26Oregon Health and Science University,
Portland, OR, USA, 27Hadassah Medical Center, Jerusalem, Israel, 28RoyalChildren’s Hospital, Melbourne, Australia, 29Hopp Children’s Cancer
Center, Heidelberg, Germany, 30The Institute of Cancer Research, London,
United Kingdom
Replication repair deficiency (RRD) is an important driving mechanism ofpediatric high grade glioma (pHGG) occurring predominantly in the context
of germline mutations in RRD-associated genes. Although pHGG present
specific patterns of DNA methylation corresponding to driving oncogenic
processes, methylation patterns have not been well studied in RRD tumors.
We analyzed 52 RRD pHGG using either 450k or 850k methylation arrays. These arrays were compared with 234 PHGG driven by other genetic
or epigenetic mechanisms and 10 additional pHGG samples known to be
hypermutant. RRD pHGG displayed a methylation pattern corresponding to
specific secondary mutations such as IDH1 and H3K27M. Strikingly, RRD
pHGG lacking these known secondary mutations largely clustered together
with a poorly described group previously labelled Wild type-C. Most of thehypermutant tumors clustered in a similar location suggesting undiagnosed
RRD may be a driving force for tumors clustering in this location. Analysis of methylation patterns revealed that RRD pHGG displayed a unique
CpG Island Demethylator Phenotype in contrast to the Methylator Phenotype described in other cancers. This effect was most concentrated at genepromotors. Prominent demethylation was observed in genes and pathways
critical to cellular survival including cell cycle, gene expression, cellular metabolism and cellular organization. These data suggest that methylation profiles may provide diagnostic information for the detection of RRD pHGG.
Furthermore, our findings highlight the unique natural selection pressures inthese highly dysregulated, hypermutant cancers and provide novel impact ofhypermutation and RRD on the cancer epigenome.
HGG-21. GERMLINE MUTATIONS IN MSH2 GENE IN PEDIATRICPATIENTS WITH CONGENITAL AND SPORADIC GLIOBLASTOMAMaria Ejmont, Małgorzata Rydzanicz, Wiesława Grajkowska,
Marta Perek-Polnik, Agnieszka Sowińska, Magdalena Kozłowska,
Maria Łastowska, Maciej Pronicki, Rafał Płoski,Bożenna Dembowska-Bagińska, and Joanna Trubicka; The Children’sMemorial Health Institute, Warsaw, Poland
INTRODUCTION: Glioblastoma (GBM) remains one of the biggest
therapeutic challenges in neuro-oncology. In spite of multimodal treatment
approaches the prognosis of GBM is extremely poor, median survival is estimated about 12–16 months. Although GBM is one of the most common
and malignant primary brain tumors, pediatric glioblastoma, including congenital is a very rare tumor, with an incidence of about 1.1–3.4 per million
live births. Moreover, the mode of presentation, behavior, response to therapy
and molecular background of pediatric glioblastomas differs from adulttype of GBM. Until now, about ten patients with congenital glioblastoma
have been described and in none of them germline markers were examined.
Here we report two patients with GBM, one with congenital tumor with
germline mutations in MSH2 gene. METHODS: Targeted Next-Generation
Sequencing (NGS) of the probands DNA extracted from leucocytes was
performed using the TruSight One sequencing panel on an Illumina HiSeq
1500. Applied gene panel investigated the coding sequence and splice sites of
4813 genes associated with known disease phenotypes. The NGS data wereanalyzed using an in-house procedure. Identified variants were validatedby Sanger sequencing. RESULTS: NGS analysis of patients constitutional
DNA revealed know, pathogenic variants c.940C>T and c.942 + 3A>T in
MSH2 gene (NM_000251.3) associated with MMR-dependent hereditarycancer syndromes. CONCLUSION: Molecular analysis are heavily needed
for better understanding of pediatric GBM etiology and new treatment modality implementation. Identification of this oncogenic driver may provide
insight into the pathogenesis of GBM, including congenital cases. Fundedby National Science Centre, Poland (2016/23/B/NZ2/03064 and 2016/21/B/
NZ2/01785).
HGG-24. HIGH-GRADE GLIOMA WITH A NOVEL FUSION GENE OF
VCL-ALK
Shunsuke Yamamoto1, Yuhki Koga1, Hiroaki Ono1,
Hiroshi Asai1, Kyutaro Ono2, Ryusuke Hatae2, Nobuhiro Hata2,
Masahiro Mizoguchi2, Hidetaka Yamamoto3, Satoshi O. Suzuki4,
Toru Iwaki4, and Shouichi Ohga5; 1Department of Pediatrics, Graduate
School of Medical Sciences, Kyushu University, Fukuoka, Japan,
2Department of Neurosurgery, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, Japan, 3Department of Anatomic Pathology,
Graduate of School of Medical Sciences, Kyushu University, Fukuoka,
Japan, 4Department of Neuropathology, Graduate School of Medical

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Sciences, Kyushu University, Fukuoka, Japan, 5Department of Pediatrics,
Graduate School of Medical Sciences, Kyushu University, Fukuoka, JapanA previously healthy 2-year-old boy presented with status epilepticus following intermittent vomiting. Computed tomography scan showed a 7 cm
mass on the left occipital lobe with midline shift, inferior cerebellar herniation, and diffuse cerebral edema. The extensive dissemination to bilateral cerebral hemispheres, brain stem, and optic nerve was also observed.
He underwent brain biopsy from the lesion on his left occipital lobe. The
histopathological diagnosis determined the diffuse or epithelial proliferation of astrocytic tumor cells with high mitotic rate, positive for p53 andglial fibrillary acidic protein positive staining consistent with high-grade
glioma. The progressive tumor led to communicating hydrocephalus, thatwas favorably controlled by cerebrospinal fluid shunting. The data fromthe FoundationOne CDx cancer genome profile disclosed a novel VCLanaplastic lymphoma kinase (ALK) fusion in the tumor cells of the patient.
ALK rearrangement was determined to be positive for the tumor cells assessed by fluorescence in situ hybridization. Only 4 pediatric cases of glioma
with ALK-rearrangement have ever been reported. All of them received subtotal or gross total resections and then survived with or without chemotherapy. This is the first case of glioma harboring VCL as a novel partner of
ALK fusion gene. After the favorable response to the first-line chemotherapy,
subsequent irradiation therapy has now been scheduled. The molecular classification of high-grade glioma may help to expand the targeted therapy forunresectable advanced brain tumor.
HGG-26. H3G34V MUTATION AFFECTS GENOMIC H3K36
METHYLATION IN PEDIATRIC GLIOMA
Tina Huang1, Andrea Piunti1, Elizabeth Bartom1, Jin Qi1,
Rintaro Hashizume1, Ali Shilatifard1, and Amanda Saratsis1,2;
1Northwestern University Feinberg School of Medicine, Chicago, IL, USA,
2Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
BACKGROUND: Histone H3.3 mutation (H3F3A) occurs in 50% ofcortical pediatric high-grade gliomas. This mutation replaces glycine 34 witharginine or valine (G34R/V), impairing SETD2 activity (H3K36-specifictrimethyltransferase), resulting in reduced H3K36me on H3G34V nucleosomes relative to wild-type. This contributes to genomic instability anddrives distinct gene expressions associated with tumorigenesis. However, it
is not known if this differential H3K36me3 enrichment is due to H3G34V
mutant protein alone. Therefore, we set to elucidate the effect of H3G34V
on genomic H3K36me3 enrichment in vitro. METHODS: Doxycyclineinducible short hairpin RNA (shRNA) against H3F3A was delivered via
lentivirus to established H3G34V mutant pediatric glioma cell line KNS42,
and H3G34V introduced into H3.3 wild type normal human astrocytes(NHA). Transfections were confirmed by western blot, fluorescent imaging,and flow cytometry, with resulting H3.3WT and H3K36me3 expression
determined by western blot. H3.3WT, H3K36me3, and H3G34V ChIPSeq was performed to evaluate genomic enrichment. RESULTS: Complete
knockdown of H3G34V was achieved with DOX-induced shRNA, with nochange in total H3.3, suggesting disproportionate allelic frequency of genes
encoding H3.3 (H3F3A and H3F3B). Modest increase in H3K36me3 occurred after H3F3A-knockdown from KNS42, suggesting H3G34V alone
impacts observed H3K36me3 levels. Distinct H3K36me3 genomic enrichment was observed with H3G34V knock-in. CONCLUSIONS: We demonstrate that DOX-inducible knockdown of H3F3A in an H3G34V mutant
pediatric glioma cells and H3G34V mutation transduction in wild-type
astrocytes affects H3K36me3 expression. Further evaluation by ChIP-Seq
analysis for restoration of wild-type genomic H3K36me3 enrichment patterns with H3G34V knockdown, and mutant H3K36me3 patterns with
H3G34V transduction, is currently underway.
HGG-27. ANTI-CANCER POTENTIAL OF ARGINASE FOR HIGHGRADE GLIOMA IN VITRO & IN-VIVO
MKL Fung1, S Chan1, S Sun2, PD Zhang2, GKK Leung2, and GCF Chan1;
1Department of Paediatrics & Adolescent Medicine, University of Hong
Kong, Hong Kong, Hong Kong, 2Department of Surgery, University ofHong Kong, Hong Kong, Hong KongBACKGROUND: High-grade glioma is currently incurable. It was reported that glioma may be auxotrophic to arginine due to the lack of urea
cycle genes expressions, suggesting arginase may be a potential agent forhigh grade glioma. AIM: We investigated the efficacy of pegylated arginase
I (pegArg-I) or in combination with other anti-cancer drugs for high-grade
glioma in vitro and in vivo. METHODS: 4 high-grade glioma cell lines(U87, U373, U138, D54) were treated with pegArg-I in vitro. The molecularmechanism of pegArg-I-induced cytotoxicity was tested in U87. The ultramorphological changes of pegArg-I-treated U87 was investigated by bothscanning and transmission electron microscopy. Orthotopic glioma xenograft model with luciferase-transfected U87 cell line was tested for anticancer efficacy of peg-Arg I in vivo. RESULTS: We showed that pegArg-I

Abstracts

induced significant cell death in all 4 cell lines in vitro. Temozolomide,
difluoromethyornithine and chloroquine (CQ) were then tested together
with pegArg-I in U87 in vitro. We found that only CQ showed additive effectwith pegArg-I against glioma in vitro. Such additive cytotoxic effect may be
associated with enhanced autophagy and necrosis as shown in transmission
electron microscopy and autophagy markers’ expression by Western blotting. PegArg-I prolonged the survival of glioma mice, suggesting its possible
anti-glioma efficacy. However, CQ+pegArg-I didn’t show further significant anti-cancer efficacy in vivo. CONCLUSION: PegArg-I may be usefulin slowing the progression of glioma, but additional drug candidate whichworks synergistically with pegArg-I remains to be explored.
HGG-29. A CASE OF CIRCUMSCRIBED HIGH-GRADEASTROCYTOMA WITH ATRX AND CDKN2A/B ALTERNATIONS
WHO WAS INITIALLY DIAGNOSED AS GLIOBLASTOMA AND HAS
20 YEARS SURVIVAL
Yusuke Kobayashi, Yosuke Sato, Takashi Kon, Daisuke Tanioka,
Katsuyoshi Shimizu, and Tohru Mizutani; Department of Neurosurgery.
Showa University School of Medicine, Sinagawa-ku, Tokyo, Japan
Pediatric high-grade gliomas are rare and often hard to classify, which growlocally and show longer survival than diffuse high-grade gliomas in adults.
We report a case of circumscribed high-grade astrocytoma who was initiallydiagnosed as glioblastoma and has 20 years survival. A 7-year-old girl suffered from epileptic seizure due to a left occipital lobe tumor. The tumor was
resected in another hospital and diagnosed as glioblastoma. The tumor disappeared after extended local irradiation and chemotherapy using nimustinehydrochloride (ACNU) and cisplatin (CDDP). Eighteen years after initialonset, first recurrence was confirmed as the intra-tumoral hemorrhage. The
tumor was resected and diagnosed as anaplastic oligoastrocytoma. After 6
courses of temozolomide (TMZ), the tumor disappeared. Twenty years after
initial onset, the second local recurrence was confirmed. Although gamma
knife and TMZ was performed, the tumor did not disappear. The tumor was
surgically resected. Histopathology showed localized growth with some infiltration and mitosis but lacked pseudopallisading and microvascular proliferation. The tumor was diagnosed as circumscribed high-grade astrocytoma.
Immunostaining revealed ATRX nuclear loss and CDKN2A / B homozygous
deletion. After 10 courses of TMZ, the third local recurrence was confirmed.
The tumor was completely removed and has not occurred recurrence morethan 3 months after the last operation. Circumscribed high-grade glioma is
expected to survive longer than invasive glioma. Pediatric gliomas should
differ from adult gliomas in the genes of tumorigenesis. Care should betaken for its diagnosis and treatments. We also need a new classification
based on histology and gene profile. HGG-30, ANALYSIS OF PEDIATRIC
GLIOMAS IN OUR INSTITUTE Kaoru Tamura, Mai Fujioka, Masae
Kuroha, Motoki Inaji, Yoji Tanaka, Tadashi Nariai, and Taketoshi Maehara;
Tokyo Medical and Dental University, Tokyo, Japan. PURPOSE: Recent advances in genetic interrogation of pediatric glioma increase the importanceof molecular diagnosis using surgical specimen. However, surgical resection
may be avoided to preserve quality of life, especially in brain stem glioma
cases. We retrospectively examined diagnosis and treatment of pediatricgliomas in our hospital. METHODS: This study includes 14 consecutive
glioma patients under the age of 18 who underwent initial treatment at our
hospital from 2000 to 2019. Histopathological diagnosis, clinical course
and molecular status such as IDH, H3F3A and BRAF were analyzed. RESULTS: 5 patients (1 pilocytic astrocytoma (PA), 3 diffuse astrocytomas,
1 oligodendroglioma were treated only by surgical resection (group A). 7
patients (1 PA, 1 anaplastic oligodendroglioma, 2 diffuse midline gliomasand 3 glioblastomas (GBM)) received radiation and/or chemotherapy after
surgical resection (group B). 2 diffuse intrinsic pontine gliomas (DIPG) received radiation and chemotherapy without surgical resection (Group C).
No IDH mutation was observed in all pathological specimen obtained cases.
BRAF alteration was observed in all PA cases. 1 case of GBM had BRAF
V600Emutation and the other had H3K27M mutation. During a medianof 7.7 years of follow-up, group A patients have no recurrence. Group B
includes various diagnosis and prognosis. 2 group C patients diagnosed
DIPG by MRI showed different clinical courses. CONCLUSION: Pediatricgliomas include diverse biological subgroups and show broad range of clinical behavior. Since pediatric glioma has a low incidence and a wide varietyof genetic mutations, multicenter study is important to improve the treatment of pediatric glioma.
HGG-31. UNIQUE BIOLOGICAL CHARACTERISTICS OF
RADIATION-INDUCED GLIOMASKateřina Váňová1,2, Aleš Vícha1,2, Lenka Krsková3, Josef Zámečník3,Běla Malinová3, David Sumerauer1,2, Adéla Mišove4,2, Petr Libý5, andMichal Zápotocký1,2; 1Prague Brain Tumor Research Group, Second
Faculty of Medicine, Charles University and University Hospital Motol,
Prague, Czech Republic, 2Department of Pediatric Haematology andOncology, Second Faculty of Medicine, Charles University and University
Hospital Motol, Prague, Czech Republic, 3Department of Pathology andMolecular Medicine, Second Faculty of Medicine, Charles University
and University Hospital Motol, Prague, Czech Republic, 4Prague Brain
Tumor Research Group, Second Faculty of Medicine, Charles University
and University Hospital Motol, Prague, Czech Republic, 5Departmentof Neurosurgery, Second Faculty of Medicine, Charles University andUniversity Hospital Motol, Prague, Czech RepublicRadiation-induced gliomas (RIGs) are the most common secondary
solid tumours with very unfavourable prognosis. We aimed to describe different clinical and molecular biological characteristic of RIGs from primary
gliomas. We reviewed clinical data of ten patients with RIGs. In patientswith available samples, we used the whole genome methylation array andperformed targeted sequencing for specific mutations. Between 2000–2018,
we diagnosed RIG in 10 patients (M/F 2/8) aged 5–12 years at primary diagnosis of different solid tumours and acute leukaemia. These patients developed RIG with a median 9.5 years (ranging 3–31) after primary diagnosis.
Eight patients died within 1 year after diagnosis of RIG and 2 patients arestill alive more than 4 years from this diagnosis. According to Heidelberg
DNA methylation-based classification, most RIGs belong to the IDH-wild
type glioblastoma subclass midline which biologically corresponds to diffuse midline glioma (DMG). However, compared to primary DMGs they
do not carry the characteristic H3K27M mutation. One patient developed
anaplastic ganglioglioma with BRAF-V600E mutation and methylation
profile identical to pleomorphic xanthoastrocytoma (alive for 4 years after
diagnosis of RIG). In half of the patients from the group DMGs IDH wild
type, examined by methylation array, PDGFRA amplification was found.
Our data shows that most RIGs are midline IDH-wild type glioblastomas
with poor prognosis that are biologically different from primary DMGs.
PDGFRA amplifications are potentially targetable by kinase inhibitors inorder to order to prognosis of these patients.
HGG-32. UNCOVERING THERAPEUTIC VULNERABILITIES INMISMATCH REPAIR-DEFICIENT GLIOMASAdam Boynton1, Sangita Pal1, Mehdi Touat1, Naomi Currimjee1,
Kenin Qian1, Charlotte Bellamy1, Patricia Ho1, Jim Berstler2, Keith Ligon1,
Rameen Beroukhim1, and Pratiti Bandopadhayay1; 1Dana-Farber Cancer
Institute, Boston, MA, USA, 2Broad Institute, Boston, MA, USA
INTRODUCTION: We have observed that approximately 26% of recurrent gliomas acquire hypermutation following treatment with temozolomide(TMZ). Intriguingly, 91% of these tumors harbor mutations in mismatch repair (MMR) genes. Strategies to target MMR-deficient gliomas thus stand to
impact a large number of patients. METHODS: We ablated the MMR genes
MSH2, MSH6, MLH1, and PMS2 using an all-in-one sgRNA-CRISPR/Cas9
expression vector to generate panels of isogenic MMR knockouts in patientderived glioma cell lines. We have characterized the phenotype of these
MMR-deficient glioma cells, and leveraged high-throughput drug screens to
identify therapeutic vulnerabilities induced by loss of MMR. RESULTS: We
demonstrate that sgRNA-CRISPR/Cas9 targeting of either MSH2 or MLH1 –the two obligatory components of the MutSα and MutLα complexes, respectively – also results in loss of protein expression of their respective
binding partner MSH6 or PMS2. Moreover, we show that loss of each
MMR component confers resistance to TMZ while maintaining sensitivity
to the alkylating nitrosourea CCNU. Furthermore, we show that long-term
TMZ treatment of MSH2 and MSH6 knockouts in an MGMT-methylatedline induces hypermutation with enrichment of C > T mutations but not in
MMR wild-type controls. Lastly, loss of MSH2 or MLH1 confers differential dependencies to small molecule inhibitors. CONCLUSIONS: CRISPR/
Cas9 knockout of individual MMR pathway members allows us to systematically study the response of MMR-deficient cells to alkylating agents in an
isogenic context. MMR deficiencies in glioma confer dependencies to small
molecule treatment, which may inform future therapies for MMR-deficienttumors.
HGG-34. DETECTION OF ONCOGENIC FUSION EVENTS IN
SUPRATENTORIAL GLIOBLASTOMAS OF YOUNG CHILDREN
Torsten Pietsch1, Christian Vokuhl2, Gerrit H. Gielen1,
Andre O. von Bueren3, Everlyn Dörner1, Glen Kristiansen2,
Andreas Waha1, and Christof Kramm4; 1Department of Neuropathology& DGNN Brain Tumor Reference Center, University of Bonn, Bonn,
Germany, 2Department of Pathology, University of Bonn, Bonn, Germany,
3Department of Pediatrics, Obstetrics and Gynecology, Division of PediatricHematology and Oncology, University Hospital of Geneva, Geneva,
Switzerland, 4Department of Pediatric Hematology / Oncology, University
of Göttingen, Göttingen, Germany
INTRODUCTION: Glioblastoma in infancy and early childhood ischaracterized by a more favorable outcome compared to older children, astable genome, and the occurrence of tyrosine kinase gene fusions that may
represent therapeutic targets. METHODS: 50 glioblastomas (GBM) withsupratentorial location occurring in children younger than four years were

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retrieved from the archives of the Brain Tumor Reference Center, Institute of
Neuropathology, University of Bonn. DNA and RNA were extracted fromFFPE tumor samples. Gene fusions were identified by FISH using breakapart probes for ALK, NTRK1, -2, -3, ROS1 and MET, Molecular Inversion
Probe (MIP) methodology, and targeted RNA sequencing. RESULTS: 37
supratentorial GBM occurred in the first year of life, 13 GBM between one
and four years. 18 cases showed fusions of ALK to different fusion partners; all occurred in the first year of life (18/37 cases, 48.6%). Fusions of
ROS1 were found in 5, MET in 3, NTRK1, -2, -3 in 10 cases. 12 cases
showed no and two novel fusions. The different methods led to comparable
results; targeted RNA sequencing was not successful in a fraction of cases.
Break-apart FISH led to reliable results on the next day, MIP technology
represented the most sensitive method for analysis of FFPE samples. CONCLUSIONS: Gene fusions involving the tyrosine kinase genes ALK, MET,ROS1 and NTRK1, -2, -3 occurred in 72% of glioblastomas of children
younger than four years; the most frequent were ALK fusions occurring ininfant GBM. DNA based MIP technology represented the most robust andsensitive assay.
HGG-35. PEDIATRIC PLEOMORPHIC XANTHOASTROCYTOMAWITH ANAPLASIA TREATED WITH SURGERY AND ADJUVANTCHEMOTHERAPY: A CASE SERIES OF 3 LONG-TERM SURVIVORS
Rebecca Ronsley1, Christopher Dunham1, Stephen Yip2, Juliette Hukin1,
and Sylvia Cheng1; 1British Columbia Children’s Hospital, Vancouver, BC,
Canada, 2British Columbia Cancer Agency, Vancouver, BC, Canada
OBJECTIVE: Pleomorphic xanthoastrocytoma (PXA) with anaplasia
is a rare histological subtype of central nervous system astrocytoma andgenerally treated as high grade gliomas. The optimal extent of therapy
required is unknown. Here we report on 3 pediatric cases of PXA
with anaplasia. We also describe molecular features and methylation
profile of PXA with anaplasia compared to age-matched PXA without
anaplasia. METHODS: Our institutional database was queried for casesof PXA since 1998 and 3 cases with anaplasia were identified and records
reviewed. RESULTS: 2/3 patients were male and all were aged 12 at diagnosis. All underwent a gross total resection (GTR), where the diagnosis of
PXA with anaplasia was made. Immunohistochemistry demonstrated that
two cases were BRAF V600E positive and two were CD34 positive. Methylation profiling revealed unique pattern of CpG methylation/unmethylation.
All patients underwent 5400cGy radiation to the surgical bed. 2/3 patients
received concurrent temozolamide with radiation followed by maintenancechemotherapy with temozolamide and lomustine for 6 cycles as per theChildren’s Oncology Group Protocol ACNS0423. These two patients had
a continued complete response. The third patient received temozolamide
following radiation and subsequently had recurrent disease at the end oftreatment and went on to have a re-resection GTR and achieved complete
response after 6 cycles of lomustine, vincristine and procarbazine. All are
alive with no evidence of disease at more than 2 years post treatment completion (OS=100%,EFS=67%). CONCLUSIONS: This rare pediatric tumor
is not well understood. The genetic landscape may be informative for optimizing treatment and prognosis.
HGG-36. HIF-2: A NEW DRUG TARGET IN PEDIATRIC HIGHGRADE GLIOMA WITH PROMISING PRECLINICAL RESULTS
Quentin Fuchs1, Marina Pierrevelcin1, Christophe Papin2,
Monique Dontenwill1, and Natacha Entz-Werlé1,3; 1UMR CNRS 7021,
Strasbourg, France, 2IGBMC, Strasbourg, France.,3University Hospital ofStrasbourg, Strasbourg, France
Pediatric high-grade gliomas (pHGGs) have a very dismal prognosis andneed new innovative strategy for treatment. Despite the past discovery ofhistone H3 driver mutations, we are not able for instance to stop this induced epigenetic remodulation. Therefore, proactive translational studies
wish to go further discovering new targetable proteins in pHGG. In ourpast clinical work, we were able to link significantly HIF-2alpha to a worse
pHGG outcome and to their treatment resistance. We designed this newwork to determine in several patient-derived cell lines (6 PDCLs) with orwithout H3.3 mutation the variation of HIF-2alpha, its role, its induction
in normoxic and hypoxic microenvironment and its transcriptional targets
using RNAseq, metabolomics and ChipSeq analyses. Complementary functional analyses were performed using siRNA strategy during cultures andmigration assays. Finally, preclinical drug testing involving commercialized
and non-commercialized HIF-2alpha specific inhibitors in the same PDCLs
were evaluating their antiproliferative and pro-apoptotic effect. Our results
confirmed the central role of HIF-2alpha in cell resistance to treatment, in
pHGG stemness features and its direct link with metabolism adaptationand histone interaction. After the confirmation of its frequent presence inmultiple PDCLs initiated from thalamic pHGGs and DIPG, we were using
inhibitors in a single and combinatorial strategy targeting HIF-2alpha plus
another hypoxia biomarker (mTor). This preclinical targeting was highly
effective to favor cell arrest, apoptosis and to stop cell migration. In con-iii350N EU R O - O N C O L O G Y•

De c e mb e r 2 0 2 0clusion, HIF-2alpha seem to be a major biomarker in pHGGs that might betargeted giving a useful new opportunity for pHGG treatments.
HGG-37. PAEDIATRIC GLIOBLASTOMA CELLS SHOW CRITICAL
DEPENDENCIES ON EPIGENOMIC AND EPITRANSCRIPTOMICCONTROL OF GENE EXPRESSION BY H3.3G34R/V MUTATIONS
Lynn Bjerke1, Alan Mackay1, Rebecca Rogers1, Yura Grabovska1,
Valeria Molinari1, Sara Temelso1, Kristina Cole2, Angela Waanders3,
Angel Montero Carcaboso4, Maria Vinci5, and Chris Jones1; 1The Instituteof Cancer Research, London, United Kingdom, 2Children’s Hospital ofPhiladelphia, Philadelphia, PA, USA, 3Ann & Robert H Lurie Children’s
Hospital, Chicago, IL, USA, 4Hospital Sant Joan de Deu, Barcelona, Spain,
5The Bambino Gesù Children’s Hospital, Rome, Italy
H3.3G34R/V mutations are restricted to glioblastomas of the cerebral
hemispheres, and occur predominantly in adolescents and young adults. We
had previously shown these mutations to result in a global re-organisation of
the activating mark H3K36me3 to drive transcription of key developmental
transcription factors and oncogenes such as MYCN, however the precise
mechanism was unclear. Using multiple H3G34R/V samples and ChIP-seq
with antibodies specific to both wild-type and mutant histone H3.3, we showa high degree of incorporation of mutant histone into nucleosomes, with only
a minority (<15%) remaining wild-type only. Heterogenous G34-mutant nucleosomes displayed significantly elevated H3K36me3 binding, the majority
apparently in trans to the mutation on the wild-type H3.3, and expression
signatures associated with chromatin modification, cell cycle progression,
DNA repair and gene transcription. Super-enhancer analysis by H3K27ac
ChIP-Seq highlighted lineage-dependent transcription factors and previously identified targets MYCN and NOTCH1 (both stabilised by FBXW7,
down-regulated by loss of chromosome 4q), as well as specific H3K36 lysine
demethylases and splicing factors. Whole-genome CRISPR-Cas9 screeningof patient-derived H3.3G34R/V cells identified critical dependencies onthese latter targets, in addition to a general essentiality for genes involved in
RNA processing. Assessment of RNA methylation by MeRIP-seq revealeda strong concordance of m6A-modified RNA and H3K36me3 binding,with differentially modified transcripts in mutant cellsassociated with the
3’-UTR but also the promoter and gene bodies. These data highlight thecritical nature of the epitranscriptome in H3.3G34R/V-mutant paediatricglioblastoma, and highlight novel targets for therapeutic intervention.
HGG-38. A COMPARATIVE PROTEOMIC-ANALYSIS OF THE CELLMEMBRANE FRACTIONS OF HISTONE 3 MUTATED BRAINTUMOURS TO IDENTIFY NOVEL THERAPEUTICSJames Pickering, Ruman Rahman, Richard Grundy, Robert Layfield, andFarhana Haque; University of Nottingham, Nottingham, United Kingdom
Improvements in the treatments for childhood and adolescent brain tumours, High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), have not advanced much and they continue to carry avery poor prognosis. These brain tumours are now defined by mutations
affecting histone 3 proteins, indeed 80% of DIPGs harbour histone H3.1
and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3
G34R or G34V mutations. We hypothesized that the histone 3 mutant tumours will have distinct mutation specific surfactome. We therefore analysed
the cell surface proteomics of pHGG and DIPG, in order to identify novel
targets for therapy. We have at first isolated the cell membrane fractions
from a range of patient cells carrying different histone 3 mutations (G34R,
G34V, K27M), relative to wild type histone 3. A comparative quantitative
mass-spectrometry analyses of these cell surface membrane fractions is thenperformed to identify specific targetable factors, which can be then be used
for tumour specific precision-therapy. Results of these experiments will bepresented.
HGG-39. CLINICAL CHARACTERISTICS AND OUTCOME OF
PATIENTS WITH RADIATION-INDUCED GLIOMA
Makoto Ohno1, Yasuji Miyakita1, Masamichi Takahashi1,
Takaki Ohmura1, Natsuko Satomi1, Yukie Tamura1, Yuko Matsushita1,
Koichi Ichimura2, and Yoshitaka Narita1; 1National Cancer Center
Hospital, Chuo-ku, Tokyo, Japan, 2National Cancer Center ResearchInstitute, Chuo-ku, Tokyo, JapanThe development of gliomas subsequent to therapeutic cranial irradiation
is a rare but serious complication. The purpose of this study is to understandthe clinical characteristics and outcome of patients with radiation-induced
glioma (RIG). Between 2001 and 2018, we identified 10 patients with RIG,
which satisfied the Cahan’s criteria in our data base. There was no sex predominance (M: 5, F: 5), and the median age of the primary diseased was
13.5 years (range: 1–39). The primary diseases included 2 germinoma, 2acute lymphoblastic lymphoma, 2 medulloblastoma, 1 diffuse astrocytoma,
1 pilocytic astrocytoma, 1 pituitary adenoma and 1 metastatic tumor from

Abstracts

lung cancer. All the patients received cranial radiation (range: 12–60 Gy).
The median latency time between primary disease and RIG was 16 years(range: 9–30 years), which was not correlated with age at the time of primary disease (r2= 0.014, p=0.74). Radiation-induced gliomas included 8
glioblastoma and 2 grade III glioma based on histological diagnosis. After
surgical removal or biopsy of the RIG, 4 patients underwent chemotherapy
alone (nimustine, temozolomide (TMZ), carboplatin and etoposide), and6 received chemotherapy (nimustine, TMZ, bevacizumab) combined withradiotherapy (range: 40-66Gy). The median progression free survival andsurvival time from RIG were 10.1 and 27.5 months, respectively. In summary, RIG may occur many years after successful initial treatment using
radiotherapy, and the outcome of our patients with RIG supports the use ofradiotherapy and/or chemotherapy after surgical resection.

intermediate or simple signature activities. These associated with distinct
combinations of known driver oncogenes. Our statistical analysis revealed
recurring SVs in the topologically associating domains of MYCN, MYC,
EGFR, PDGFRA & MET. These correlated with increased mRNA expression and amplification of H3K27ac peaks. Complex recurring amplifications
showed characteristics of extrachromosomal amplicons and were enrichedin coding SVs splitting protein regulatory from effector domains. Integrative analysis of all SCNAs, SNVs & SVs revealed patterns of characteristic
combinations between potential drivers and signatures. This included two
distinct groups of H3K27M DMGs with either complex or simple signaturesand different combinations of associated variants. CONCLUSION: Recurrent SVs associate with signatures shaped by an underlying process, which
can lead to distinct mechanisms to activate the same oncogene.

HGG-40. EXCEPTIONAL SYNCHRONOUS OCCURENCE OF A BRAF
V600E MUTANT GLIOBLASTOMA AND A H3.3K27M MUTANTDIFFUSE INTRINSIC PONTINE GLIOMA: A CASE REPORT
Emilie De Carli1, Blandine Boisselier2,3, Luc Le Fournier4,
Stéphane Supiot5,6, Coralie Mallebranche1, Stéphanie Proust-Houdemont1,
Mylène Duplan1, Isabelle Pellier1,7, and Audrey Rousseau2,3; 1PediatricImmuno-Hemato-Oncology Unit, University Hospital, Angers, France,
2Department of Cellular and Tissue Pathology, University Hospital,
Angers, France, 3Center for Research in Cancerology and Immunology
Nantes/Angers, INSERM, University of Nantes, University of Angers,
Angers, France, 4Department of Pediatric Neurosurgery, University
Hospital, Angers, France, 5Department of Radiation Oncology, Institut deCancérologie de l’Ouest, Nantes, St-Herblain, France, 6Center for Researchin Cancerology and Immunology Nantes/Angers, INSERM U1232, CNRSERL 6001, University of Nantes, Nantes, France, 7Center for Research inCancerology and Immunology Nantes/Angers, team 7, INSERM U1232,
University of Angers, Angers, France

HGG-42. CLINICAL FEATURES AND TREATMENT OUTCOME OF
MALIGNANT GLIOMAS IN CHILDREN AND ADOLESCENTS
Hajime Yonezawa, Hiroyuki Uchida, Nayuta Higa, Tatsuki Oyoshi, andKoji Yoshimoto; Department of Neurosurgery, Graduate School of Medical
and Dental Sciences, Kagoshima University, Kagoshima, Japan

We report herein the case of a 17-year-old female who presented withintracranial hypertension and diplopia. Magnetic resonance imaging
showed a large left cystic and solid temporoparietal lesion, associated withan infiltrating lesion of the brainstem, hypointense in T1 and hyperintensein FLAIR sequences, without enhancement after injection of gadolinium.
Complete resection of the parietal mass and biopsy of the brainstem lesion
were performed. Histopathological analysis of the parietal mass showedglioblastoma (WHO grade IV) with no IDH1/2 or H3.3/H3.1 gene mutation detected by Sanger sequencing. Immunohistochemistry found the expression of the proteins of mismatch repair system. Whole exome and RNA
sequencing identified a BRAF-V600E mutation. The brainstem lesion was adiffuse midline glioma, H3K27M-mutant (grade IV) according to the 2016
WHO classification. Pan-genomic SNP arrays of the 2 tumors showed distinct genetic alterations. The parietal glioblastoma displayed complex genomic alterations whereas the brainstem glioma harbored chromosome 7q
gain, chromosome 9p and 10 losses, and RB, TP53 and CDKN2A homozygous deletions. The patient was treated by concomitant radiochemotherapy(according to Stupp protocol). After 12 cycles of temozolomide, there wascomplete remission persistant in the parietal lobe. The brainstem tumor
was stable but progressed after 3 months of temozolomide discontinuation.
Treatment with mTOR inhibitors was initiated. At 21-month follow-up, thepatient remains with few symptoms. No predisposition syndrome was identified in the patient or her family. Concurrent glioblastomas with distinct
driver gene mutations are exceptional.
HGG-41. STRUCTURAL VARIANT DRIVERS IN PEDIATRIC HIGHGRADE GLIOMAFrank Dubois1,2, Ofer Shapira1,2, Noah Greenwald1,2, Travis Zack1,2,
Jessica W Tsai1,2, Ashot S. Harutyunyan3, Kiran Kumar2,1, Claire Sinai1,
Hayley Malkin1, Robert Jones1, Patricia Ho1, Ryan O’Rourke1,
Kyung S Kang1,2, Nada Jabado3, Mark W Kieran4, Keith Ligon1,2,Rameen Beroukhim1,2, and Pratiti Bandopadhayay1,2; 1Dana-Farber Cancer
Institute, Boston, MA, USA, 2Broad Institute, Cambridge, MA, USA,
3McGill University, Montreal, QC, Canada, 4Bristol-Myers Squibb, New
York, NY, USA
BACKGROUND: Driver single nucleotide variants (SNV) and somatic
copy number aberrations (SCNA) of pediatric high-grade glioma (pHGGs),
including Diffuse Midline Gliomas (DMGs) are characterized. However,structural variants (SVs) in pHGGs and the mechanisms through which
they contribute to glioma formation have not been systematically analyzed
genome-wide. METHODS: Using SvABA for SVs as well as the latest pipelines for SCNAs and SNVs we analyzed whole-genome sequencing from 174
patients. This includes 60 previously unpublished samples, 43 of which are
DMGs. Signature analysis allowed us to define pHGG groups with shared
SV characteristics. Significantly recurring SV breakpoints and juxtapositions
were identified with algorithms we recently developed and the findings
were correlated with RNAseq and H3K27ac ChIPseq. RESULTS: The SV
characteristics in pHGG showed three groups defined by either complex,

INTRODUCTION: Malignant gliomas in children and adolescents are
rare. They are difficult to treat and are associated with an extremely poor
prognosis. SUBJECTS AND METHODS: The treatment and outcomes of
WHO grade IV -gliomas and diffuse intrinsic pontine gliomas (DIPG) in
children and adolescents (Age 4–39, median 28) treated at our institute since2001 were retrospectively reviewed. Thirty-five cases were included in thisstudy. Nine cases were located in their brain stem and 2 of them were diagnosed as DIPG clinically without biopsy. Three (brain stem -2, thalamus1) cases were diffuse midline glioma H3 K27 M mutant. Remaining 30
cases were diagnosed histologically as glioblastoma. Expect for 2 cases, allwere irradiated. Twenty-four cases were treated with temozolomide (TMZ).
Bevacizumab (BEV) was administrated as an initial therapy in 10 cases (concomitant with TMZ in 9 cases) and was administrated at the time of relapse
in 9 cases. In summary, 19 cases were treated with BEV. RESULTS: Mediansurvival time (MST) of all cases was 16.8 (4.4 -152.3) months. In total, BEV
did not prolonged overall survival (OS), MST 16.02 vs 14.44, (p=0.498).
Among adolescents (age 15–39), patients treated with BEV had a trend of
longer OS but did not reached statistical significance, MST 19.64 vs 10.76(p=0.167). An extent of resection and KPS =>70 at discharge from hospitalwere beneficial factors associated with prolonged OS. CONCLUSION: As
well as in elderly cases, multidisciplinary treatment including resection, radiation and chemotherapy including BEV improves outcomes.
HGG-43. CONGENITAL GLIOBLASTOMA MULTIFORME: A CASEREPORT OF A RARE PEDIATRIC BRAIN TUMOR, MOLECULARANALYSIS, AND REVIEW OF THE LITERATURE
Christina Amend1, James Stadler1, Shahriar Salamat1, Erik Dedekam1,
Angela Waanders2, and Nitin Wadhwani2; 1University of Wisconsin,
Madison, WI, USA, 2Northwestern University, Chicago, IL, USA
Congenital brain tumors are rare, accounting for less than 4% of all pediatric brain tumors. Congenital glioblastoma multiforme (GBM) is rarer still,
accounting for 3–15% of congenital brain tumors. There is literature to suggest that these tumors differ from pediatric and adult GBM clinically andmolecularly, and as such should be treated as their own distinct entity. Ourcase is a 4 week old male who initially presented to his pediatrician forenlarging head circumference and upward gaze palsy. An MRI was obtained
revealing a right parietal mass. He underwent gross total resection the following day with pathology revealing glioblastoma, WHO grade IV. Further
analysis revealed ATRX retained, p53 immunoreactivity in 15–20% of nuclei, IDH1 and IDH2 wildtype, MGMT promoter not methylated, H3K27M
wildtype, no 1p and/or 19q deletion/codeletion. Interestingly, RNA analysis
of his tumor detected the PPP1CB-ALK fusion transcript as well as amplification of the ALK gene. Co-occurrence of these mutations has been reported
in a small number of pediatric glioblastoma patients and PPP1CB-ALK fusions are one of the most common receptor tyrosine kinase fusions in infantile gliomas. ALK rearrangements and amplifications suggest a potential
therapeutic target with tyrosine kinase inhibitors in glioblastoma. This patient serves as an example of a rare congenital glioblastoma with unique molecular features that may suggest novel treatment opportunities. We present
his clinical course along with a pertinent review of the literature.
HGG-44. DEFECTS OF MISMATCH REPAIR PROTEINS INPEDIATRIC HIGH GRADE GLIOMAS
Christine Haberler1, Philippe Muller2, Leonhard Müllauer3,
Andreas Peyrl4, Thomas Czech5, Katharina Wimmer6, and Irene Slavc4;
1Division of Neuropathology and Neurochemistry, Department of
Neurology, Medical University of Vienna, Vienna, Austria, 2Medical
University of Vienna, Division of Neuropathology and Neurochemistry,
Department of Neurology, Vienna, Austria, 3Clinical Institute of Pathology,

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Abstracts

Medical University Vienna, Vienna, Austria, 4Department of Pediatrics
and Adolescent Medicine, Medical University of Vienna, Vienna, Austria,
5Department of Neurosurgery, Medical University of Vienna, Vienna,
Austria, 6Division of Human Genetics, Medical University of Innsbruck,
Innsbruck, Austria
Hetero- and homozygous germline mutations of the mismatch repair
genes MLH1, PMS2, MSH2 and MSH6 cause Lynch and constitutional
mismatch repair (CMMRD) cancer predisposition syndrome, respectively.
Affected CMMRD individuals are at risk to develop a variety of neoplasms
including CNS tumors, particularly high grade gliomas (HGG), during childhood. Currently, few data exist on the prevalence of CMMRD in children
with pediatric HGG. We screened a consecutive series of 79 supratentorial
HGGs. Tumor tissue was available in 42 patients, 5 were reclassified as
non-HGGs. Immunohistochemistry with antibodies against MLH1, PMS2,
MSH2 and MSH6 was performed in 37 tumors. Four patients (3 families)
with known CMMRD were included. The evaluation of the slides was
performed blinded to the CMMRD status. All four patients with known
CMMRD (3 patients with PMS2, one with MSH6 mutation) were identified, showing loss of PMS2 and MSH2/MSH6, respectively. Additionally, we identified 6 patients with loss of MSH2/MSH6 staining in tumor
cells, but retained staining in preexisting cells, indicating a pattern like in
Lynch syndrome. NGS sequencing of these tumor tissues revealed in 2 patients MSH2 mutations and in one patient a hypermutator phenotype with
MSH2 and MSH6 mutations. In 3/6 patients no mutations in the MMR
genes were detectable. In summary, we found a low prevalence of CMMRD
among HGGs, but identified also 2 patients with probable Lynch syndrome.
Immunhistochemistry is an effective tool to screen for patients with MMR
defects and should be performed in HGGs to optimize treatment and offer
affected families genetic counseling.
HGG-45. PROTEOMIC ANALYSIS OF PEDIATRIC DIFFUSEASTROCYTOMAS YIELDS PATHWAYS ASSOCIATED WITH BOTH
PROGRESSION-FREE AND OVERALL SURVIVAL
Blake Sells1, Jessica Fleming1, Richard Graham2, Joseph McElroy1,
Jahar Haque1, Daniel Boué3, Aline Becker1, Erica Bell1, Jonathan Finlay3,
and Arnab Chakravarti1; 1The Ohio State University, Columbus, OH, USA,
2St. Jude Children’s Research Hospital, Memphis, TN, USA, 3Nationwide
Children’s Hospital, Columbus, OH, USA
Brain tumors are now responsible for more deaths each year than any
other childhood cancer. Current studies aim to discover key moleculardrivers that can explain prognosis and serve as targets for new therapeutic
approaches, reducing morbidity. In this study, we performed LC-MS/MS
proteomics on a cohort of 28 primary diffuse astrocytoma formalin-fixedparaffin embedded samples (WHO Grades II-IV) from patients at Nationwide Children’s Hospital with a median follow-up time of 2.3 (0.6–20.2)
years. Ingenuity Pathway Analysis was used to analyze the proteomic
data after using both age and grade as covariates and only including
proteins with p-values less than 0.05. The upregulation of a well-known
oncogenic pathway, the Protein Kinase A signaling pathway, was significantly associated with greater risk of progression and death (P=5.5E-07
and P=4.6E-04). Integrin signaling, a pathway commonly suppressed incancer, was similarly downregulated in those with greater risk of progression and death (P=3.3E-04 and P=1.7E-07). A global upstream analysisof the proteomic data also predicted activation of the oncogene MYCN
in those who performed poorly, supporting previous studies. When comparing grade II (n=10) to grade III (n=8) and IV (n=10) primary tumors,
the pathway most upregulated in higher histopathological grades was
EIF2 Signaling (P=4.9E-49). This pathway has previously been associatedwith resistance in adult glioblastoma. These pathways, and the proteinsdetected within, may provide novel means by which to better understandand treat pediatric diffuse gliomas. Ongoing studies are in progress tounderstand how these pathways drive aggressiveness and differ fromadult astrocytomas.
HGG-47. DECREASED GROWTH VELOCITY WITH LONG TERMUSE OF BRAFV600E AND MEK INHIBITION IN A PATIENT WITH
ANAPLASTIC GANGLIOGLIOMA
Hung Tran, and Robert Cooper; Kaiser Permanente, Los Angeles, CA, USA
PURPOSE: To describe decreased growth velocity with long term
use of BRAFV600e and MEK inhibition in a patient with anaplastic
ganglioglioma. RESULTS: 4-year-old patient was found to have a 6 x 4.6 x
5 cm mass in the hypothalamus. Pathology consistent with anaplastic
ganglioglioma and chromosomal microarray revealed a BRAFV600e mutation. Patient started on dabrafenib and trametinib and tumor decreased
85% after 3 months. She is stable without significant toxicities 39 months
on therapy, and is now 8 years old. Patient had been growing at the 25% forweight and 12% for height but is now 65% for weight and 0.5% for height.

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It is difficult to tease out the relationship between the tumor, the location of
the tumor, and the BRAF and MEK inhibitors and their effect on growth.
Discussions with the family and endocrinology are ongoing but being <1%
for height will lead to decrease in quality of life. CONCLUSIONS: Further
follow-up study is needed to determine if this is truly a long-term toxicity,or if this may just be a direct result of the location of the tumor. Would
supplementation with growth hormone in this patient lead to losing control
of a high grade tumor, or would it simply replace a hormone that is notproduced?
HGG-48. ROS1 INHIBITOR ENTRECTINIB USE IN RELAPSE/REFRACTORY INFANTILE GLIOBLASTOMA WITH POSITIVE ROS1FUSION - A CASE REPORT WITH PROMISING RESPONSE
Dennis Tak-Loi Ku1, Matthew Ming-Kong Shing1,
Godfrey Chi-Fung Chan1,2, Eric Fu1, Ping-Wa Yau1, Chung-Wing Luk1,
King-Fai Cheng1, Wilson Wai-Shing Ho1, Ho-Keung Ng3, Yin-Chung Po4,
and Alvin Siu-Cheung Ling4; 1Hong Kong Children’s Hospital, Hong Kong,
Hong Kong, 2The University of Hong Kong, Hong Kong, Hong Kong,
3Chinese University of Hong Kong, Hong Kong, Hong Kong, 4Princess
Margaret Hospital, Hong Kong, Hong Kong
INTRODUCTION: Infantile glioblastoma is rare with poor prognosis.
Recent molecular study for infantile hemispheric high grade glioma found
its association with ALK/ROS1/NTRK/MET pathway. This suggested thepotential use of targeted therapy for refractory / relapse patients. CASE:
A newborn presented with apnea, CT brain showed intracranial haemorrhage. MRI then showed a left parietal tumour with bleeding and masseffect. Craniotomy achieved subtotal resection. Chemotherapy VCR/CPM
alternating with CDDP/VP-16 was given for one year. Patient was stablewith static residual tumour during chemotherapy. However patient developed status epilepticus two weeks after off treatment. MRI showed significant tumour progression which required 2nd & 3rd debulking surgery.
Molecular assay by nanostring panel showed BRAF-KIAA1549 fusion.
MEK inhibitor Trametinib was tried for 3 months and stopped as diseaseprogression. Further molecular assay by RNASeq showed presence of ROS1
fusion (ZCCHC8-ROS1) while absent of BRAF fusion. Patient underwent
4th debulking surgery as impending herniation while waiting for the targeted therapy. It was complicated with right hemiplegia and facial nerve
palsy postoperatively. Finally, ROS1 inhibitor Entrectinib was started 2
weeks later. It was well tolerated without significant adverse reaction. Patient made dramatic neurological recovery including improved facial nerve
palsy, able to walk unaided and self feed. MRI brain 1 and 3 months after
Entrectinib showed interval reduction in residual tumour. Patient is currently progression-free for 6 months. CONCLUSION: Early molecularstudy for infantile glioblastoma is useful to guide novel therapy. Molecular
result may varies between different panels or change over time, to be interpreted with caution.
HGG-49. A PEDIATRIC THALAMIC HIGH-GRADE GLIOMA WITH
H3F3A K27M AND BRAF V600E DOUBLE MUTATIONS
Keita Terashima1, Masahiro Sugawa1, Kenichi Sakamoto2,
Chikako Kiyotani1, Tomoo Osumi1, Yoko Shioda1, Takao Deguchi1,Motohiro Kato1, Daisuke Tomizawa1, Kenichi Usami2, Hideki Ogiwara2,
Yoshiyuki Tsutsumi3, Hiroshi Fuji4, Noriyuki Nakano5, Takako Yoshioka5,
Yoshiko Nakano6, Koichi Ichimura6, and Kimikazu Matsumoto1;
1Children’s Cancer Center, National Center for Child Health andDevelopment, Tokyo, Japan, 2Department of Neurosurgery, National
Center for Child Health and Development, Tokyo, Japan, 3Department of
Diagnostic Radiology, National Center for Child Health and Development,
Tokyo, Japan, 4Department of Radiation Oncology, National Center forChild Health and Development, Tokyo, Japan, 5Department of Pathology,
National Center for Child Health and Development, Tokyo, Japan,
6Division of Brain Tumor Translational Research, National Cancer Center
Research Institute, Tokyo, Japan
CASE: A 18-month-old boy presented with approximately 2 months history of progressive left hemiparesis and left exotropia. MRI study showed a
3–4 cm T1-iso, T2-high tumor at right thalamus to midbrain with little contrast enhancement. The patient underwent endoscopic biopsy of the tumor,
which showed relatively dense proliferation of small cells with round nuclei,
mitosis of the tumor cell, but no necrosis. Immunohistochemical showed
positive stain of GFAP and Olig2. Ki-67 was 34%. The histopathologicaldiagnosis was compatible with high grade glioma. Chemotherapy with vincristine, cyclophosphamide, cisplatin and etoposide was initiated. Molecular
testing of the tumor revealed H3F3A K27M and BRAF V600E double mutations in DNA from frozen tumor tissue. DISCUSSION: The concurrent
mutation of H3F3A K27M and BRAF V600E in pediatric glioma is very
rare, but there are several cases previously reported in literature. Interestingly those cases are heterogenous in age, location, histopathological subtypes and clinical outcome.

Abstracts

HGG-50. TWO CASES OF H3 K27M-MUTANT DIFFUSE MIDLINEGLIOMA OF CERVICAL SPINAL CORD
Masae Kuroha1, Kaoru Tamura1, Motoki Inaji1, Satoka Hashimoto1,
Daisuke Kobayashi2, Yoji Tanaka1, Tadashi Nariai1, andTaketoshi Maehara1; 1Department of Neurosurgery, Tokyo Medical and
Dental University, Tokyo, Japan, 2Department of Pathology, Tokyo Medical
and Dental University, Tokyo, JapanBACKGROUND: “Diffuse midline glioma, H3 K27M-mutant’ wasnewly categorized as a separate pathological entity in the 2016 WHO classification, based on recently discovered mutation. Spinal cord glioma with H3
K27M-mutant is rare, so we reported the clinical course of two cases. CASE
1: A 17-year-old male presented with posterior headache and right limbs
paralysis. MRI showed cervical spinal cord with expansion, T2-weighted
high intensity and a part of enhancement. The biopsy revealed a diffuse midline glioma, H3 K27M-mutant. He received bevacizumab plus radiotherapytemozolomide. In a few months, he had quadriplegia and cranial nerve
paralysis and needed respirator. There was not expansion of mass, but intracranial dissemination. CASE 2: A 16-year-old male presented with posteriorneck pain and right limbs paralysis. On brain stem and cervical spine, MRI
findings were same to case 1. The biopsy was undergone and revealed H3
K27M mutation. He received bevacizumab in addition to radiotherapytemozolomide. Although he also had quadriplegia, the progression of tumor
has stopped. He has received chemotherapy with respirator at home. DISCUSSION: It was previously reported that the prognostic factors for diffuse
midline glioma were tumor location, H3 K27M-mutation and age, but there
are few relevant studies. The consensus on the treatment is also not clearly
determined. Because the cervical spinal cord gliomas are rapidly advanced
miserably, we added bevacizumab to standard radiotherapy-temozolomide
for initial treatment. In addition, whole brain and spine radiation may beconsidered to avoid dissemination. Multicenter study is important to collectinformation and improve treatment of H3 K27M-mutant glioma.
HGG-51. PAIRED EPITHELIOID GLIOBLASTOMA PATIENTDERIVED XENOGRAFT MODELS WITH/WITHOUT MOLECULARTARGET THERAPYJo Sasame, Kensuke Tateishi, Naoki Ikegaya, Yohei Miyake,
Shigeta Miyake, Taishi Nakamura, and Tetsuya Yamamoto; Department of
Neurosurgery Yokohama City University, Yokohama, Kanagawa, Japan
Epithelioid glioblastoma (E-GBM) predominantly arises at younger age
and promotes dismal prognosis. Because of its rare etiology, pathologicaland genetical characterization of E-GBM remains elusive. Herein, we report 2 patient-derived E-GBM xenograft (PDX) models from young adultpatients (YMG62 and YMG89) with BRAFV600E and TERT promoter
mutation. The YMG62 patient received dabrafenib with trametinib, while
YMG89 patient received dabrafenib monotherapy after recurrence with
Stupp regimen. These molecular target therapies were initially responded,
but gradually became resistant (YMG62R and YMG89R) and resulted inlethal. Treatment resistant cells were collected from CSF. These primary cells
were propagated at multiple passage in vitro. Paired PDX models were established from initial and recurrent cells. All PDX tumors were preferentiallydisseminated and negative expression of GFAP, which were recapitulated tothe patient characteristics. BRAF and MEK inhibitor moderately suppressed
cell viability of YMG62 and YMG89 in vitro. However, BRAF and MEK
inhibitor became resistant at recurrence in vitro. Western blotting indicatedretained phospho-MEK expression after BRAF/MEK inhibitor treatment
in recurrent cells, which implies crucial role of MEK activation for tumor
maintenance in BRAFV600E mutant E-GBM. Together, paired E-GBM PDX
models with/without molecular target therapy recapitulate patient characteristics, which may contribute to elucidate tumor biology and establish
novel therapeutic target in E-GBM.
HGG-52. SUSTAINED RESPONSE TO CRIZOTINIB MONOTHERAPYIN AN INFANT WITH GOPC-ROS1 FUSED CONGENITALHEMISPHERIC GLIOMA
Rishi Lulla1, Konstantina Svokos2, Kristine Pelton3, Douglas Anthony4,
Mehdi Touat3, and Keith L. Ligon3; 1Department of Pediatrics, The Warren
Alpert School of Medicine at Brown University, Providence, RI, USA,
2Department of Neurosurgery, The Warren Alpert School of Medicine
at Brown University, Providence, RI, USA, 3Department of Oncologic
Pathology, Dana-Farber Cancer Institute, Boston, MA, USA, 4Departmentof Pathology, The Warren Alpert School of Medicine at Brown University,
Providence, RI, USA
Recent studies identified the presence of ALK/ROS/NTRK/MET alterations in a subset of infantile hemispheric gliomas. We report a case of
GOPC-ROS1 fused congenital hemispheric glioma with a sustained responseto crizotinib. An infant born at 28 weeks gestation was diagnosed with alarge hemispheric mass at 2 weeks of life. The tumor was partially resected at
7 weeks of life. Histological evaluation confirmed a neoplasm with a spindlecell growth pattern, hypercellularity, nuclear pleomorphism, endothelial
proliferation and necrosis consistent with glioblastoma. Fresh tissue wassubmitted for targeted panel sequencing (Oncopanel) which identified thepresence of a GOPC-ROS1 fusion (exon 36:intron 4). This was confirmed
by copy number analysis which showed a focal intragenic deletion with abreakpoint in ROS1 on 6q22. Given the lack of preclinical native models for
ROS1 and other congenital kinase-driven gliomas, live cells were utilized toattempt to establish a patient derived cell line (organoid/neurosphere model)
and intracranial patient derived xenograft model, the results of which are
pending and will be reported. The GOPC-ROS1 rearrangement was structurally predicted to respond to kinase inhibitors with activity against ROS1
and crizotinib was started at 280 mg/m2/dose twice daily at 6 months oflife with progressive tumor noted on imaging. Three months after initiating
therapy, a 56% reduction in the tumor size and subsequent imaging revealed
additional response. Our report is the first to demonstrate clinical responseto crizotinib in a GPOC-ROS1 fused congenital glioblastoma and describe
the development of a renewable resources for future analysis.
HGG-53. PROJECT HOPE: “PEDIATRIC AND AYA HIGH-GRADE
GLIOMA OMICS PROJECT”- A LONGITUDINAL MOLECULARLANDSCAPE OF HIGH-GRADE GLIOMAS RESOLVED AT SINGLECELL LEVEL
Olivia A. Hack1,2, Husam Babikir3, Li Jiang1,2, Karin Shamardani3,
Ilon Liu1,2, McKenzie Shaw1,2, Kennedy Cunliffe-Koehler4, Adam Resnick5,
Michael Prados3, Michelle Monje4,6, Aaron Diaz3, and Mariella G. Filbin1,2;
1Department of Pediatric Oncology, Dana-Farber Boston Children’s
Cancer and Blood Disorders Center, Boston, MA, USA, 2Broad Instituteof Harvard and MIT, Cambridge, MA, USA, 3Department of Neurological
Surgery, University of California, San Francisco, San Francisco, CA, USA,
4Department of Neurology, Stanford University, Stanford, CA, USA,
5Center for Data Driven Discovery in Biomedicine, Children’s Hospitalof Philadelphia, Philadelphia, PA, USA, 6Department of Neurosurgery,
Stanford University, Stanford, CA, USA
High-grade gliomas (HGG) are among the most prevalent and fatal cancers
in pediatric, adolescent, and young adult (AYA) patients. Especially understudied are older children and young adults, aged 16–39 years. Previously,
we profiled primary pediatric HGGs through single-cell transcriptomics andidentified the genetic, epigenetic and developmental programs that drive
their malignant progression. However, the questions of how these programs
compare to those in older HGG patients, what the mechanisms are by whichthese tumors ultimately evolve to drive recurrence and treatment resistance,and how distinct tumor cell subpopulations bidirectionally communicate
with their microenvironment remain to be elucidated. Here, we use singlenucleus RNA sequencing to compare 11 paired, matched high-grade gliomas
at diagnosis and recurrence and 15 additional H3K27M primary and recurrent DMG samples in pediatric and AYA patients. In all tumors, we findboth undifferentiated and differentiated tumor cells recapitulating distinct
glial lineages, as well as diverse microenvironmental cell populations. Whenlongitudinally comparing this tumor architecture within matched pairs, wefind substantial differences in transcriptional program expressions. Diagnostic samples include more differentiated, astrocyte-like tumor cells, whilecells from recurrent samples more highly express ribosomal and heat-shockprotein genes, suggesting tumor progression- and treatment-related shifts.
Ongoing sequencing and analysis will allow for unprecedented insight into
the evolutionary dynamics of pediatric and AYA high-grade gliomas as well
as delineate differences in the biology of DMGs occurring in different age
groups. This multi-institutional project was funded by the National Instituteof Health.
HGG-54. HISTOLOGICAL AND MOLECULAR
CHARACTERIZATION OF HIGH-GRADE BRAIN TUMORSSECONDARY TO TOTAL BODY IRRADIATION FORHEMATOLOGICAL MALIGNANCIES
Evelina Miele, Daria Pagliara, Lucia Pedace, Francesca Diomedi Camassei,
Antonella Cacchione, Giovanna Stefania Colafati, Andrea Carai,
Franco Locatelli, and Angela Mastronuzzi; Bambino Gesù Children’s
Hospital, Rome, Italy
INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) is
increasingly used in the treatment of acute leukemias (AL), non-Hodgkin
lymphomas and other primary malignancies. However, a growing number ofneoplasms secondary to HSCT are reported. The combination of total body
irradiation (TBI) and high dose chemotherapy (HD-CT) as conditioning
regimen is considered a risk factor. We present four children who survived
AL, treated with HSCT and conditioning regimens including TBI/HD-CT.
These patients developed a high-grade-brain tumor. We analyzed histologicaland molecular characteristics of neoplasms. METHODS: Histologically, tumors were assessed for: presence of mitosis, necrosis and vascular proliferation; expression of ki67; expression of neuronal and glial markers, p53
and therapeutic targets. We analyzed the DNA methylation profile (DMP)N E U R O -O N C O L O G Y•

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Abstractsof all tumors using IlluminaEPICarrays and compared it to the brain tumor
classifier which allowed to generate the CNVs. RESULTS: Morphologically
two cases were defined as anaplastic astrocytoma, two cases as glioblastoma.
Based on the DMP, all cases were found to belong to the methylation class“glioblastoma, IDH wildtype, subclass midline”, hypermutants, with gainof chromosome 1q and loss of 1p. Two cases showed PDGFRA amplification. All patients were treated with Temozolomide combination therapy+/- Bevacizumab and radiation therapy. At progression three patients weretreated with checkpoint inhibitors. CONCLUSIONS: The improvement of
the precision medicine is fundamental in the therapeutic decision of brain tumors and even more in neoplasms secondary to antiblastic treatments. DMP
and CNV have proven to be useful tools to complement the histologicalcharacterization of the reported cases.
HGG-56. EXTENSIVE MOLECULAR HETEROGENEITY WITHIN
H3-/IDH-WILDTYPE PEDIATRIC GLIOBLASTOMA
Mirjam Blattner-Johnson1, Felix Sahm2, Martin Sill3, Dominik Sturm1,4,
Christof M. Kramm5, Stefan M. Pfister3,4, and David Jones1; 1Hopp
Children’s Cancer Center Heidelberg (KiTZ), Pediatric Glioma ResearchGroup, German Cancer Research Center (DKFZ), Heidelberg, Germany,
2Department of Neuropathology, Institute of Pathology, Heidelberg
University Hospital, Heidelberg, Germany, and CCU Neuropathology,
German Consortium for Translational Cancer Research (DKTK), German
Cancer Research Center (DKFZ), and Hopp Children’s Cancer Center
Heidelberg (KiTZ), Heidelberg, Germany, 3Hopp Children’s Cancer Center
Heidelberg (KiTZ), Division of Pediatric Neurooncology, German Cancer
Research Center (DKFZ) and German Cancer Consortium (DKTK),
Heidelberg, Germany, 4Hopp Children’s Cancer Center Heidelberg (KiTZ),
Department of Pediatric Hematology and Oncology, Heidelberg University
Hospital, Heidelberg, Germany, 5Division of Pediatric Hematology andOncology, University Medical Center Göttingen, Göttingen, Germany
About half of all pediatric high-grade gliomas (HGG) harbor mutations
in histone 3 or IDH genes. The remaining HGG are currently broadly classified as H3-/IDH-wild-type. Since the introduction of a uniform approach
to DNA methylation-based classification of CNS tumors in 2018, DNA
methylation data from over 45,000 CNS tumor samples have been generated. From this large cohort, a number of smaller yet distinct subgroups
start to emerge within H3-/IDH-wild-type HGG. Three such subgroups areenriched for focal gene amplifications and have been provisionally termed
pedGBM_MYCN, pedGBM_RTK1 and pedGBM_RTK2. Since a significant
subset of samples in each subgroup is lacking characteristic alterations, we
further investigated the molecular and transcriptional composition of H3-/
IDH-wild-type HGG. We evaluated DNA methylation and copy-number
profiles in >1000 tumors classified as H3-/IDH-wild-type HGG. Tumorsclassified pedGBM_MYCN showed a focal MYCN amplification in 25%,
with a similar fraction showing amplification of EGFR (8% of samples
harbored both alterations) compared to 4% and 4% in pedGBM_RTK1
and 14% and 22% in pedGBM_RTK2. Deletion of CDKN2A/B was much
more prevalent in the pedGBM_RTK2 subgroup (~50% compared to 27%
in pedGBM_RTK1 and <10% in the pedGBM_MYCN group). We defined a pedGBM_MYCN transcriptional signature, which will be helpful
in identifying subgroup-defining mechanisms and alterations. Initial results
suggest an involvement of the sonic hedgehog pathway and genes controlling stem-cell pluripotency. Patient-derived xenograft models and murine
neural stem cells are now being used for functional characterization andpre-clinical testing of potential drug targets in these molecularly defined subgroups.
HGG-57. WHOLE-GENOME SEQUENCING, METHYLATIONANALYSIS, AND SINGLE-CELL RNA-SEQ DEFINE UNIQUE
CHARACTERISTICS OF PEDIATRIC TREATMENT-INDUCED HIGHGRADE GLIOMA AND SUGGEST ONCOGENIC MECHANISMSJohn Lucas1, John DeSisto2, Ke Xu1, Andrew Donson2, Tong Lin1,
Bridget Sanford2, Gang Wu1, Quynh Tran1, Dale Hedges1,
Chih-Yang Hsu1, Gregory Armstrong1,3, Michael Arnold4, Smita Bhatia5,3,Patrick Flannery3, Rakeb Lemma3, Lakotah Hardie3, Ulrich Schuller6,
Lindsey Hoffman3, Kathleen Dorris3, Jean Levy3, Todd Hankinson3,
Michael Handler3, Arthur Liu3, Nicholas Foreman3, Rajeev Vibhakar3,
Kenneth Jones3, Sariah Allen2, Jinghui Zhang1, Suzanne Baker2,
Thomas Merchant2, Brent Orr1, and Adam Green3; 1St. Jude Children’s
Research Hospital, Memphis, TN, USA, 2University of Colorado School of
Medicine, Aurora, CO, USA, 3Childhood Cancer Survivor Study, Memphis,
TN, USA, 4Nationwide Children’s Hospital, Columbus, OH, USA,
5University of Alabama, Birmingham, AL, USA, 6Children’s Cancer Center,
Hamburg, Germany
BACKGROUND: Pediatric treatment-induced high-grade glioma(TIHGG) is among the most severe late effects observed in childhood cancer
survivors and is uniformly fatal. We previously showed that TIHGG are divergent from de novo pediatric high-grade glioma (pHGG) and cluster into
two gene expression subgroups, one stemlike and the other inflammatory.

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N EU R O - O N C O L O G Y•

De c e mb e r 2 0 2 0Here we systematically compared TIHGG molecular profiles to pHGG andevaluated expression and single cell sequencing profiles in order to identify
oncogenic mechanisms and the cellular basis for the observed TIHGG gene
expression subgroups. MATERIALS/METHODS: 450/850K methylationand mutational signature analysis was conducted in 36 TIHGG samples.
Resultant data were analyzed for the presence of chromothripsis, distinct
molecular alterations, and mutational signatures in a subset of 10 samples
with whole genome sequencing data. Five TIHGGs underwent single-cell
RNA-Seq analysis (scRNAseq). RESULTS: 26/36 TIHGG clustered withthe pedRTK1 methylation class. TIHGG were characterized by an increased
frequency of chromothripsis relative to pHGG (67% vs. 31%, p=0.036).
FISH and WGS revealed frequent PDGFRA amplification secondary to enrichment in ecDNA. TIHGG were enriched for COSMIC mutational signatures 5 and 19 (p=0.0003) relative to pHGG. scRNAseq data showed thatTIHGG tumors are composed of stem-like, neuronal, and inflammatory cell
populations which may contribute to the previously described dominant expression profiles. CONCLUSIONS: TIHGG represents a distinct molecularsubtype of pHGG. Chromothripsis, leading to enriched expression of genes
in extrachromosomal DNA, likely contribute to TIHGG oncogenesis. The
dominant cell type (stem-like vs. inflammatory) may define the expression
subgroup derived from bulk RNA-seq in heterogeneous tumors.

IMAGING
IMG-01. DWI RATIO OF HISTOLOGICAL MOLECULAR SUBTYPESOF PAEDIATRIC MEDULLOBLASTOMAS
Phua Hwee Tang, Sharon Low, Enrica Tan, and Kenneth Chang; KK
Women’s and Children’s Hospital, Singapore, Singapore
AIM: To evaluate if diffusion weighted imaging (DWI) ratio on MRI is
able to distinguish between the histological molecular subtypes of paediatric medulloblastomas. MATERIALS AND METHODS: From 2002 to
2017, 38 cases of medulloblastoma with preoperative MRI available hadhistological subtyping performed with NanoString nCounter technology.
The medulloblastomas were classified into 4 subtypes. There were 3 Sonic
Hedgehog (SHH), 9 Wingless (WNT), 12 Group 3 and 14 Group 4 subtypes.
Single operator manually outlined solid non-haemorrhagic component of thetumour on DWI images with largest axial tumour cross sectional diameter,
correlating with the other MRI images (T1 pre and post contrast, SWI/GRE,
FLAIR) to identify areas of haemorrhage. The same operator also drew region of interest to identify normal cerebellar tissue on the same axial images
on which the tumour was outlined. All MRI images were obtained from thedepartment’s Radiological Information System Picture Archiving and Communicating System (RIS PACS). DWI ratio for each case was obtained by
dividing the values obtained from tumour by normal cerebellar tissue seenon the same axial image. RESULTS: DWI ratio of all medullloblastomas
is 1.34 +/- 0.18. DWI ratio of SHH subtype is 1.43 +/- 0.07. DWI ratio of
WNT subtype is 1.40 +/- 0.07. DWI ratio of Group 3 subtype is 1.31 +/0.25. DWI ratio of Group 4 subtype is 1.30 +/- 0.17. There is no significant
statistical differences in the DWI ratio between the various subtypes. CONCLUSION: DWI ratio of medulloblastoma is unable to distinguish between
the 4 medulloblastoma subtypes.
IMG-02. USEFUL DIAGNOSIS OF PEDIATRIC CYSTIC BRAIN
TUMORS USING MULTIPLE POSITRON EMISSION TOMOGRAPHYSTUDIES
Keisuke Miyake, Takeshi Fujimori, Yasunori Toyota, Daisuke Ogawa,
Tetsuhiro Hatakeyama, Masanobu Okauchi, Masahiko Kawanishi, andTakashi Tamiya; Department of Neurological Surgery, Kagawa University
Faculty of Medicine, Kita-gun Kagawa, JapanOBJECTIVE: Pediatric brain tumors are primarily diagnosed using MRI
or CT examination; however, determining the correct diagnosis using only
morphological MRI can sometimes be challenging. Positron emission tomography (PET) uses radiotracers for metabolic and molecular imaging. We
examined the accumulation of multiple PET (FDG, MET, FLT, and FMISO)
studies for diagnosing pediatric cystic brain tumors. METHODS: We performed PET scans for eight pediatric patients (five pilocytic astrocytoma,
one pleomorphic xanthoastrocytoma, one diffuse astrocytoma with IDH1
mutation, one ganglioglioma) from April 2010 to December 2019. The resulting studies were compared by measuring the tumor-to-normal lesion(T/N) ratio of FDG, MET, and FLT and the tumor-to-blood value (T/B)
ratio of FMISO between each pediatric cystic brain tumor. RESULTS: All
pediatric brain tumors showed tumor uptake of FDG, MET, and FLT. We
could not examine FMISO PET for one diffuse astrocytoma with IDH1
mutation. The T/N ratios of FDG, MET, and FLT and the T/B ratio of
FMISO were 1.07, 2.76, 4.6, and 1.12 for pilocytic astrocytoma; 0.65, 4.6,
7.67, and 1.38 for pleomorphic xanthoastrocytoma; 0.61, 2.14, and 3.82
for diffuse astrocytoma with IDH1 mutation; and 0.79, 1.78, 5, and 1.49
for ganglioglioma, respectively. The T/N ratios of MET and FLT for pleo-

Abstracts

morphic xanthoastrocytoma were high, but the Ki-67 labeling index was
1%. In the ganglioglioma, the T/N ratio of FLT was high, but the T/N ratioof MET was low. CONCLUSION: Specialized multiple PET accumulation
patterns for tumors are useful for discriminating each tumor.
IMG-03. RESPONSE ASSESSMENT IN PEDIATRIC LOW-GRADE
GLIOMA: RECOMMENDATIONS FROM THE RESPONSEASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY (RAPNO)
WORKING GROUP
Jason Fangusaro1, Olas Witt2, Pablo Hernaiz Driever3,
Asim Bag4, Peter de Blank5, Nadja Kadom6, Lindsay Kilburn7,
Robert Lober8, Nathan Robison9, Michael Fisher10, Roger Packer11,
Tina Young Poussaint12, Ludmila Papusha13, Shivaram Avula14,
Alba Brandes15, Eric Bouffet16, Daniel Bowers17, Anton Artemov18,
Murali Chintagumpala19, David Zurakowski20, Martin van den Bent21,
Brigitte Bison22, Kristen Yeom23, Walter Taal24, and Katherine Warren25;
1Emory University and Children’s Healthcare of Atlanta, Atlanta, GA,
USA, 2Hopp Children’s Cancer Center (KiTZ), University Hospitaland German Cancer Research Center (DKFZ), Heidelberg, Germany,
3Charité-Universitätsmedizin Berlin, Freie Universität Berlin, HumboldtUniversität zu Berlin, and Berlin Institute of Health, Berlin, Germany, 4St.
Jude Children’s Research Hospital, Memphis, TN, USA, 5University ofCincinnati and Cincinnati Children’s Hospital Medical Center, Cincinnati,
OH, USA, 6Emory University and the Children’s Healthcare of Atlanta,
Atlanta, GA, USA, 7National Medical Center, Washington, DC, USA,
8Dayton Children’s Hospital and Wright State University Boonshoft
School of Medicine, Dayton, OH, USA, 9Children’s Hospital Los Angeles,
University of Southern California Keck School of Medicine, Los Angeles,
CA, USA, 10The Children’s Hospital of Philadelphia, Perelman Schoolof Medicine at the University of Pennsylvania, Philadelphia, PA, USA,
11Children’s National Hospital, Washington, DC, USA, 12Boston Children’s
Hospital, Boston, MA, USA, 13Dmitry Rogachev National Medical
Research Center of Pediatric Hematology, Moscow, Russian Federation,
14Alder Hey Children’s NHS Foundation Trust, Liverpool, United
Kingdom, 15AUSL-IRCCS Scienze Neurologiche, Bologna, Italy, 16The
Hospital for Sick Children, Toronto, ON, Canada, 17UT Southwestern,
Dallas, TX, USA, 18Dmitry Rogachev National Medical Research Centerof Pediatric Hematology, Oncology and Immunology, Moscow, RussianFederation, 19Texas Children’s Cancer Center, Baylor College of Medicine,
Houston, TX, USA, 20Boston Children’s Hospital and Harvard Medical
School, Boston, MA, USA, 21Erasmus MC Cancer Institute, Rotterdam,
Netherlands, 22Universitatsklinikum Wurzburg, Wurzburg, Germany,
23Lucile Packard Children’s Hospital, Stanford University, Palo Alto, CA,
USA, 24Erasmus University MC Cancer Institute, Rotterdam, Netherlands,
25Dana Farber Cancer Institute/Boston Children’s Cancer and Blood
Disorders Center, Boston, MA, USA
INTRODUCTION: Pediatric low-grade gliomas (pLGG) show clinical and biological features that are distinct from their adult counterparts.
Consequently, additional considerations are needed for response assessment in children compared to the established adult Response Assessment
in Neuro-Oncology (RANO) criteria. Standardized response criteria inpediatric clinical trials are lacking, complicating comparisons of responses
across studies. We therefore established an international committee of theRadiologic Assessment in Pediatric Neuro-Oncology (RAPNO) working
group to develop consensus recommendations for response assessment in
pLGG. METHODS: The committee consisted of 25 international experts
in the areas of Pediatric Neuro-Oncology, Neuroradiology and Neurosurgery. The committee first developed a set of agreed upon topics they deemednecessary to understand the controversies of imaging utilization and assessment in pLGG. These topics were divided up among the committee members who presented all available literature to the entire RAPNO committee
via web teleconference. Once presented, the group discussed these data anddeveloped consensus statements and recommendations based on available
literature, committee expertise and clinical experience. Each topic was discussed until a consensus was reached. RESULTS: Final consensus included
recommendations about the following topics: specific imaging sequences,advanced imaging techniques, NF1-associated pLGG, molecular and histologic classification, assessment of cysts, vision and other functional outcomesas well as overall radiologic response assessment. CONCLUSIONS: The
RAPNO pLGG consensus establishes systemic recommendations that represent an initial effort to uniformly collect and assess response in pLGG. These
recommendations should now be evaluated internationally and prospectively in an effort to assess clinical utility, validate and modify as appropriate.
IMG-04. RESPONSE ASSESSMENT IN PEDIATRIC HIGH-GRADE
GLIOMA: RECOMMENDATIONS FROM THE RESPONSEASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY WORKING
GROUP
Craig Erker1,2, Benita Tamrazi3,4, Tina Y. Poussaint5,6, Sabine Mueller7,8,
Daddy Mata-Mbemba1,2, Enrico Franceschi9,10, Alba A. Brandes9,11,
Arvind Rao12, Kellie B. Haworth13, Patrick Y. Wen5,14,

Stewart Goldman15,16, Gilbert Vezina17,18, Tobey J. Macdonald19,20,
Ira J. Dunkel21,22, Paul S. Morgan23,24, Tim Jaspan23,24, Michael D. Prados7,
and Katherine E. Warren25; 1Dalhousie University, Halifax, NS, Canada,
2IWK Health Centre, Halifax, NS, Canada, 3Keck School of Medicine
University of Southern California, Los Angeles, CA, USA, 4Children’s
Hospital of Los Angeles, Los Angeles, CA, USA, 5Harvard Medical
School, Boston, MA, USA, 6Boston Children’s Hospital, Boston, MA,
USA, 7University of California San Francisco, San Francisco, CA, USA,
8UCSF Benioff Children’s Hospital, San Francisco, CA, USA, 9Azienda
Unità Sanitaria Locale– Istituto di Ricovero e Cura a Carattere Scientifico
Istituto delle Scienze Neurologiche, Bologna, Italy, 10Bellaria-Maggiore
Hospital, Bologna, Italy, 11Bellaria-Maggiore Hospital, AUSL Bologna,
Bologna, Italy, 12University of Michigan, Ann Arbor, MI, USA, 13St. JudeChildren’s Research Hospital, Memphis, TN, USA, 14Dana-Farber Cancer
Institute, Boston, MA, USA, 15Northwestern University Feinberg School of
Medicine, Chicago, IL, USA, 16Ann & Robert H, Lurie Children’s Hospitalof Chicago, Chicago, IL, USA, 17George Washington University Schoolof Medicine and Health Sciences, Washington, DC, USA, 18Children’s
National Medical Center, Washington, DC, USA, 19Emory University
School of Medicine, Atlanta, GA, USA, 20Children’s Healthcare of Atlanta,
Atlanta, GA, USA, 21Weill Cornell Medical College, New York, NY, USA,
22Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical
College, New York, NY, USA, 23Nottingham University Hospitals National
Health Service Trust, Nottingham, United Kingdom, 24Queen’s Medical
Centre, Nottingham, United Kingdom, 25Dana-Farber/Boston Children’s
Cancer and Blood Disorders Center, Boston, MA, USA
INTRODUCTION: Response criteria for pediatric high-grade gliomas(pHGG) have varied historically and across clinical trials. Compared toadult HGG, pHGG response assessment has unique challenges. An international Response Assessment in Pediatric Neuro-Oncology (RAPNO)
working group was established to develop pHGG response assessment criteria. METHODS: Pediatric and adult neuro-oncologists, neuro-radiologists
and experts in imaging informatics developed a consensus statement and established a unified response assessment for biopsy-proven pHGG, excluding
DIPG. This was achieved by identifying major challenges, reviewing existing
literature and current practices, and finally developing recommendations
through an iterative process. RESULTS: Categories for response assessment
include complete response, partial response, minor response, stable disease
and progressive disease. Refractory disease is excluded. Criteria used to determine response assessment include quantitative evaluation of measurable
disease, qualitative assessment of diffusion imaging, presence or absence of
new lesions, clinical status using performance score, and vascular endothelial growth factor inhibitor and/or corticosteroid use. Response is determined over 2-time points ≥ 8 weeks apart, and when progressive disease
is unclear, guidance for repeat MRI imaging and/or utility of repeat biopsy
is described. A number of recommendations are also given to standardize
response assessment across clinical trials including MRI protocol sequence
recommendations for brain and spine, definitions for measurable and nonmeasurable disease, and imaging time points with post-operative considerations. In addition, guidance is given for differentiating vasogenic edema
versus tumor invasion in non-enhancing disease. CONCLUSION: Consensus recommendations and response definitions have been establishedand, similar to other RAPNO recommendations, prospective validation inclinical trials is warranted.
IMG-05. INITIAL RADIOGRAPHIC ASSESSMENT OF DWI AND ADC
VALUES IN CHILDREN AND YOUNG ADULTS TREATED WITH
DAY101 (TAK-580) FOR RECURRENT LOW-GRADE GLIOMAS (LGG)
HARBORING MAPK ALTERATIONS
Emily Krzykwa1, Ronald L. Korn2, Samuel C. Blackman3, andKaren D. Wright1; 1Dana Farber Cancer Institute, Boston, MA, USA,
2Imaging Endpoints, Scottsdale, AZ, USA, 3Day One Biopharmaceuticals,
Seattle, WA, USA
BACKGROUND: Apparent diffusion coefficient (ADC) is a quantitative measure reflecting observed net movement of water calculated froma diffusion-weighted image (DWI), correlating with tumor cellularity. The
higher cellularity of high-grade gliomas results in diffusion restriction andreduced ADC values, whereas the lower cellularity of low-grade gliomas(LGGs) gives higher ADC values. Here we examine changes in ADC values
in patients with LGGs treated with the type 2 RAF inhibitor DAY101 (formerly TAK580). METHODS: Historical, baseline, and on-treatment brain
MRIs for 9 patients enrolled on a phase 1 study of DAY101 in children andyoung adults with radiographically recurrent or progressive LGG harboring
MAPK pathway alterations were obtained, de-identified and independently
evaluated for ADC changes. Time points included baseline, first follow-up,
and best response. Data processing of ADC estimates was performed using
pmod molecular image software package. ADC changes were displayed asa histogram with mean values. Results were based upon a single read paradigm. RESULTS: There was a clear shift to lower ADC values for the solid
component of tumors, reflecting changes in cellularity and tissue organization, while necrosis correlated with a shift toward higher ADC values. DWIN E U R O -O N C O L O G Y•

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reveals reduced ADCs in responding tumors, with the percent change in
ADC from baseline correlating with deeper RANO responses. CONCLUSION: DWI analysis reveals reductions in ADC values that correlates withtreatment response and a shift toward more normal cellularity in tumors
treated with DAY101. Changes in ADC may represent a novel imaging biomarker, reflecting biological response to DAY101 treatment.
IMG-06. PREDICTING SURVIVAL FROM PERFUSION AND
DIFFUSION MRI BY MACHINE LEARNINGJames T. Grist1, Stephanie Withey2,3, Christopher Bennett4, Heather Rose5,
Lesley MacPherson6, Adam Oates6, Stephen Powell1, Jan Novak7,
Laurence Abernethy8, Barry Pizer9, Simon Bailey10, Dipayan Mitra11,
Theodoros N. Arvanitis12, Dorothee P. Auer13, Shivaram Avula14,
Richard Grundy15, and Andrew C. Peet5; 1University of Birmingham,
Birmingham, WM, United Kingdom, 2University of Birmingham,
Birmingham, WM, United Kingdom, 3Oncology - Birmingham Women’sand Children’s NHS Foundation Trust, Birmingham, United Kingdom,
4Institute of Cancer and Genomic Sciences - University of Birmingham,
Birmingham, WM, United Kingdom, 5Institute of Cancer and Genomic
Sciences - University of Birmingham, Birmingham, WM, United Kingdom,
6Radiology - Birmingham Women’s and Children’s NHS Foundation
Trust, Birmingham, United Kingdom, 7Neurosciences - Aston University,
Birmingham, United Kingdom, 8Radiology - Alder Hey Children’s NHSFoundation Trust, Liverpool, United Kingdom, 9Oncology - Alder Hey
Children’s NHS Foundation Trust, Liverpool, United Kingdom, 10Sir James
Spence Institute of Child Health, Royal Victoria Infirmary, Newcastle,
United Kingdom, 11Neuroradiology, Royal Victoria Infirmary, Newcastle,
United Kingdom, 12Institute of Digital Healthcare, WMG, University of
Warwick, Warwick, United Kingdom, 13Sir Peter Mansfield Imaging Centre,
University of Nottingham Biomedical Research Centre, Nottingham,
United Kingdom, 14Radiology, Alder Hey Children’s NHS Foundation
Trust, Liverpool, United Kingdom, 15The Children’s Brain Tumour
Research Centre, University of Nottingham, Nottingham, United Kingdom
INTRODUCTION: Magnetic Resonance Imaging (MRI) is routinely
used in the assessment of children’s brain tumours. Reduced diffusion andincreased perfusion on MRI are commonly associated with higher grade
but there is a lack of quantitative data linking these parameters to survival.
Machine learning is increasingly being used to develop diagnostic tools but
its use in survival analysis is rare. In this study we combine quantitative
parameters from diffusion and perfusion MRI with machine learning todevelop a model of survival for paediatric brain tumours. METHOD: 69
children from 4 centres (Birmingham, Liverpool, Nottingham, Newcastle)
underwent MRI with diffusion and perfusion (dynamic susceptibility contrast) at diagnosis. Images were processed to form ADC, cerebral blood
volume (CBV) and vessel leakage correction (K2) parameter maps. Parameter mean, standard deviation and heterogeneity measures (skewness andkurtosis) were calculated from tumour and whole brain and used in iterative
Bayesian survival analysis. The features selected were used for k-means clustering and differences in survival between clusters assessed by Kaplan-Meierand Cox-regression. RESULTS: Bayesian analysis revealed the 5 top features determining survival to be tumour volume, ADC kurtosis, CBV mean,
K2 mean and whole brain CBV mean. K-means clustering using these features showed two distinct clusters (high- and low-risk) which bore significantly different survival characteristics (Hazard Ratio = 5.6). DISCUSSION
AND CONCLUSION: Diffusion and perfusion MRI can be used to aid theprediction of survival in children’s brain tumours. Tumour perfusion playeda particularly important role in predicting survival despite being less routinely measured than diffusion.
IMG-07. GADOLINIUM IS NOT NECESSARY FOR SURVEILLANCE
MR IMAGING IN CHILDREN WITH CHIASMATICHYPOTHALAMIC LOW GRADE GLIOMA
Fatema Malbari1,2, Murali Chintagumpala1,2, Jack Su1,2, Mehmet Okcu1,2,Frank Lin1,2, Holly Lindsay1,2, Surya Rednam1,2, Patricia Baxter1,2,
Guillermo Aldave1,2, William Whitehead1,2, Robert Dauser1, andStephen Kralik1,2; 1Texas Children’s Hospital, Houston, TX, USA, 2Baylor
College of Medicine, Houston, TX, USA
BACKGROUND: Patients with chiasmatic-hypothalamic low grade
glioma (CHLGG) have frequent MRIs with gadolinium based contrast
agents (GBCA) for disease monitoring. Cumulative gadolinium deposition in children is a potential concern. The purpose of this research is toestablish whether MRI with GBCA is necessary for determining tumor
progression in children with CHLGG. METHODS: Children with progressive CHLGG were identified from Texas Children’s Cancer Center between 2005–2019. Pre- and post-contrast MRI sequences were separately
reviewed by one neuroradiologist who was blinded to the clinical course.
Three dimensional measurements and tumor characteristics were collected.
Radiographic progression was defined as a 25% increase in size (product of
two largest dimensions) compared to baseline or best response after initi-

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ation of therapy. RESULTS: A total of 28 patients with progressive CHLGG
including 683 MRIs with GBCA (mean 24 MRIs/patient; range: 10–43
MRIs) were reviewed. No patients had a diagnosis of NF1. Progression wasobserved 92 times, 91 (98.9%) on noncontrast and 90 (97.8%) on contrast
imaging. Sixty-seven radiographic and/or clinical progressions necessitating
management changes were identified in all (100%) noncontrast sequences
and 66 (98.5%) contrast sequences. Tumor growth >2 mm in any dimension
was identified in 184/187(98.4%) on noncontrast and 181/187(96.8%) with
contrast imaging. Non primary metastatic disease was seen in seven patients(25%), which were better visualized on contrast imaging in 4 (57%). CONCLUSION: MRI without GBCA effectively identifies patients with progressive disease. One should consider eliminating contrast in imaging of children
with CHLGG with GBCA reserved for monitoring those with metastatic
disease.
IMG-08. UNUSUAL IMAGING FINDINGS IN TWO CASES OF
PAEDIATRIC LOW GRADE GLIOMA
Vickyanne Carruthers1, Kathryn Siddle1, Gail Halliday1, Simon Bailey1,2,
and Rebecca Hill1; 1Newcastle Upon Tyne Hospitals Trust, Newcastle
Upon Tyne, United Kingdom, 2Sir James Spence Institute of Child Health,
Newcastle Upon Tyne, United Kingdom
Low grade gliomas (LGG), including pilocytic astrocytoma (PCA), arethe commonest paediatric brain tumours and their behaviour is well understood, typically following a benign course. BRAF fusion is common, particularly in PCA of the cerebellum and optic pathway. Here we present twopatients whose LGG behaved in an unusual fashion. The first patient who
was treated 6 years previously on LGG2 with vincristine and carboplatin
for a tectal plate lesion was identified on routine imaging to have local tumour progression and underwent completion staging. This showed a newenhancing soft tissue abnormality within the spinal cord at the level of L2.
Due to radiological dubiety both lesions were biopsied for histological andmolecular analysis, confirming LGG of the tectal plate and finding the spinal
lesion to be a myxopapillary ependymoma. The second patient presented
with acute hydrocephalus following a 2 year history of neurocognitive impairments. He was found to have a large, complex tumour centred in andexpanding the bodies of both lateral ventricles with significant mass effect.
Radiologically this was most in keeping with a central neurocytoma but
histological analysis confirmed it to be a PCA with KIAA1549-BRAF fusion.
The first case demonstrates the utility of molecular analysis in confirming
two distinct tumour types in one patient, in a situation where metastasis
would not be expected and would significantly alter treatment and prognosis. The second is an example of how imaging can be misleading in a
KIAA1549-BRAF fused PCA presenting as an intraventricular mass.
IMG-09. RESPONSE ASSESSMENT IN DIFFUSE INTRINSIC PONTINEGLIOMA (DIPG): RECOMMENDATIONS FROM THE RESPONSEASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY COMMITTEE
Tabitha Cooney1, Kenneth J. Cohen2, Carolina V. Guimaraes3,
Girish Dhall4, James Leach5, Maura Massimino6, Alessandra Erbetta7,
Luisa Chiapparini7, Fatema Malbari8, Kim Kramer9, Ian F. Pollack10,
Patricia Baxter8, Suzanne Laughlin11, Zoltan Patay12,
Tina Young Poussaint13, and Katherine E. Warren1; 1Dana Farber Cancer
Institute, Boston, MA, USA, 2Johns Hopkins University, Baltimore,
MD, USA, 3Stanford University, Stanford, CA, USA, 4University of
Alabama at Birmingham, Birmingham, AL, USA, 5Cincinnati Children’s
Hospital Medical Center, Cincinnati, OH, USA, 6Fondazione IRCCS
Istituto Nazionale dei Tumori, Milan, Italy, 7Fondazione IRCCS Istituto
Neurologico Carlo Besta, Milan, Italy, 8Texas Children’s Hospital,
Houston, TX, USA, 9Memorial Sloan Kettering Cancer Center, New York,NY, USA, 10UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA,
USA, 11The Hospital for Sick Children, Toronto, ON, Canada, 12St. JudeChildren’s Research Hospital, Memphis, TN, USA, 13Boston Children’s
Hospital, Boston, MA, USA
Optimizing the conduct of clinical trials for diffuse intrinsic pontine
glioma (DIPG) involves use of consistent, objective disease assessments andstandardized response criteria. The Response Assessment in Pediatric NeuroOncology (RAPNO) committee, an international panel of pediatric and adultneuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address unique challenges in assessing response
in children with CNS tumors. A subcommittee of RAPNO was formed to
specifically address response assessment in children and young adults with
DIPG and to develop a consensus on recommendations for response assessment. Distinct issues related to the response assessment of DIPG include its
definition and recent molecular classifications, dearth of imaging response
data, the phenomena of pseudoprogression, and measuring response in theera of focal drug delivery. The committee has recommended response be
assessed using magnetic resonance imaging (MRI) of brain and spine, neurologic examination, and use of supportive medication, i.e. steroids and antiangiogenic agents. Clinical imaging standards and imaging quality control

Abstracts

are defined. Unique recommendations for DIPG response include an eightweek response duration, a twenty-five percent decrease for partial response,
and the distinction of pontine and extra-pontine response for trials that use
focal drug delivery. The recommendations presented here represent an initialeffort to uniformly collect and evaluate response assessment criteria; theserecommendations can now be incorporated into clinical trials to assess feasibility and corroboration with patient outcomes.

(2 clones:25/28days, control:14days). These models have the advantage ofan intact immune system and short latency for initial efficacy studies. Primary pGBM cells yield tumours that are more representative of the spectrumof clinical disease; variable hyperintensity on T2w-MRI corresponding tocellular density, with diffusely infiltrative disease less clearly definable, a paucity of oedema and a range of contrast-enhancement. Pathological features
including giant multinucleated cells, and mitotic figures were also evident.

IMG-10. MRI-BASED RADIOMIC PROGNOSTIC MARKERS OF
DIFFUSE MIDLINE GLIOMA
Lydia Tam1, Michelle Han1, Jason Wright2, Sebastien Toescu3,
Andrew Campion1, Katie Shpanskaya1, Kshitij Mankad3, Chang Ho4,
Robert Lober5, Samuel Cheshier6, Darren Hargrave3, Tom Jacques3,
Kristian Aquilina3, Michelle Monje1, Gerald Grant1, Sarah Mattonen7,
Nick Vitanza2, and Kristen Yeom1; 1Stanford University, Stanford, CA,
USA, 2Seattle Children’s Hospital, Seattle, WA, USA, 3Great OrmondStreet Hospital, London, United Kingdom, 4Indiana University School of
Medicine, Indianapolis, IN, USA, 5Dayton Children’s Hospital, Dayton,
OH, USA, 6University of Utah, Salt Lake City, UT, USA, 7Western
University, Ontario, Canada

IMG-13. MRI-BASED RADIOMICS PROGNOSTIC MARKERS OF
POSTERIOR FOSSA EPENDYMOMA
Lydia Tam1, Derek Yecies1, Michelle Han1, Sebastien Toescu2,
Jason Wright3, Kshitij Mankad2, Chang Ho4, Robert Lober5,
Samuel Cheshier6, Nick Vitanza3, Paul Fisher1, Darren Hargrave2,
Tom Jacques2, Kristian Aquilina2, Gerald Grant1, Michael Taylor7,
Sarah Mattonen8, Vijay Ramaswamy7, and Kristen Yeom1; 1Stanford
University, Stanford, CA, USA, 2Great Ormond Street Hospital, London,
United Kingdom, 3Seattle Children’s Hospital, Seattle, WA, USA, 4Indiana
University School of Medicine, Indianapolis, IN, USA, 5Dayton Children’s
Hospital, Dayton, OH, USA, 6University of Utah, Salt Lake City, UT, USA,
7Hospital for Sick Children, Toronto, ON, Canada, 8Western University,
Ontario, Canada

BACKGROUND: Diffuse midline gliomas (DMG) are lethal pediatricbrain tumors with dismal prognoses. Presently, MRI is the mainstay of
disease diagnosis and surveillance. We aimed to identify prognostic imagebased radiomics markers of DMG and compare its performance to clinical variables at presentation. METHODS: 104 treatment-naïve DMG
MRIs from five centers were used (median age=6.5yrs; 18 males, median
OS=11mos). We isolated tumor volumes of T1-post-contrast (T1gad) andT2-weighted (T2) MRI for PyRadiomics high-dimensional feature extraction. 900 features were extracted on each image, including first order statistics, 2D/3D Shape, Gray Level Co-occurrence Matrix, Gray Level Run
Length Matrix, Gray Level Size Zone Matrix, Neighboring Gray tone
Difference Matrix, and Gray Level Dependence Matrix, as defined by Imaging Biomarker Standardization Initiative. Overall survival (OS) served as
outcome. 10-fold cross-validation of LASSO Cox regression was used to
predict OS. We analyzed model performance using clinical variable (age at
diagnosis and sex) only, radiomics only, and radiomics plus clinical variable.
Concordance metric was used to assess the Cox model. RESULTS: Nine
radiomic features were selected from T1gad (2 texture wavelet) and T2 (5first-order features (1 original, 4 wavelet), 2 texture features (1 wavelet, 1log-sigma). This model demonstrated significantly higher performance thana clinical model alone (C: 0.68 vs 0.59, p<0.001). Adding clinical featuresto radiomic features slightly improved prediction, but was not significant(C=0.70, p=0.06). CONCLUSION: Our pilot study shows a potential rolefor MRI-based radiomics and machine learning for DMG risk stratification
and as image-based biomarkers for clinical therapy trials.
IMG-12. CHARACTERISATION OF MODELS OF H3F3A_G34R/V
MUTANT PAEDIATRIC GLIOBLASTOMA IN VIVO USINGMAGNETIC RESONANCE IMAGING
Jessica Boult1, Lynn Bjerke1, Mariama Fofana1, Maria Vinci2,
Valeria Molinari1, Alan Mackay1, Sara Temelso1, Gary Box1,
Suzanne Eccles1, Angel Carcaboso3, Maria Castro4, Angela Waanders5,
Kristina Cole6, Chris Jones1, and Simon Robinson1; 1The Institute ofCancer Research, London, United Kingdom, 2Bambino Gesù Ospedale
Pediatrico - IRCSS, Rome, Italy, 3Institut de Recerca Sant Joan de Deu,
Barcelona, Spain, 4University of Michigan Medical School, Ann Arbor,
USA, 5Ann & Robert H Lurie Children’s Hospital, Chicago, USA, 6The
Children’s Hospital of Philadelphia, Philadelphia, USA
Approximately 15% of paediatric/young adult cerebral hemispheric glioblastomas (pGBM) harbour G34R/V mutations in H3F3A, encoding the histone H3.3 variant. Development of novel therapeutic interventions demands
models that accurately recapitulate this subset of disease and sensitive imaging methods with which to study tumours in situ. Three H3F3A_G34R
primary-patient-derived cultures, alongside established cell-line KNS42(H3F3A_G34V), were implanted orthotopically in immunocompromised
mice. KNS42 (TP53_R342*) tumours were clearly detectable using T2weighted (T2w)-MRI, enhanced following contrast agent administration,
indicating impaired blood-brain barrier (BBB) integrity, and demonstrated
minimal invasion. OPBG_GBM_001 cells (TP53_89-90X,ATRX_II21332144X) formed infiltrative tumours that were hyperintense on T2w-MRI
and demonstrated contrast-enhancement suggestive of heterogeneous BBB
integrity. HSJD_GBM_002 cells (TP53_P278T,ATRX_R666*) spread diffusely throughout the brain with their full extent typically not discernible by
T2w-MRI, the BBB also remaining intact. No evidence of CHOP_GBM_001
tumour was detected by MRI 11months post-implantation. Immunocompetent syngeneic models using tumour cells induced by mutations modelling
hemispheric pGBM (NRAS/shP53/shATRX±H3.3G34R) are being explored.
Fast growing heterogeneous lesions with variable contrast-enhancement
were identified; the H3.3G34R mutation conferred longer median survival

PURPOSE: Posterior fossa ependymomas (PFE) are common pediatricbrain tumors often assessed with MRI before surgery. Advanced radiomic
analysis show promise in stratifying risk and outcome in other pediatricbrain tumors. Here, we extracted high-dimensional MRI features to identify
prognostic, image-based, radiomics markers of PFE and compared its performance to clinical variables. METHODS: 93 children from five centers(median age=3.3yrs; 59 males; mean PFS=50mos) were included. Tumor volumes were manually contoured on T1-post contrast and T2-weighted MRI
for PyRadiomics feature extraction. Features include first-order statistics,
size, shape, and texture metrics calculated on the original, log-sigma, andwavelet transformed images. Progression free survival (PFS) served as outcome. 10-fold cross-validation of a LASSO Cox regression was used to predict PFS. Model performance was analyzed and concordance metric (C) was
determined using clinical variable (age at diagnosis and sex) only, radiomics
only, and radiomics plus clinical variable. RESULTS: Six radiomic features
were selected (all T1): 1 first-order kurtosis (log-sigma) and 5 texture features (3 wavelet, 2 original). This model demonstrated significantly higher
performance than a clinical model alone (C: 0.69 vs 0.58, p<0.001). Adding
clinical features to the radiomic features didn’t improve prediction (p=0.67).
For patients with molecular subtyping (n=48), adding this feature to the clinical plus radiomics models significantly improved performance over clinicalfeatures alone (C = 0.79 vs. 0.66, p=0.02). Further validation and modelrefinement with additional datasets are ongoing. CONCLUSION: Our pilot
study shows potential role for MRI-based radiomics and machine learning
for PFE risk stratification and as radiographic biomarkers.
IMG-14. DEVELOPING A PREDICTIVE GRADING MODEL FOR
CHILDREN WITH GLIOMAS BASED ON DIFFUSION KURTOSISIMAGING METRICS: ACCURACY AND CLINICAL CORRELATIONSWITH SURVIVAL
Ioan Paul Voicu, Antonio Napolitano, Alessia Carboni, Lorenzo Lattavo,
Andrea Carai, Maria Vinci, Francesca Diomedi-Camassei,
Antonella Cacchione, Giada Del Baldo, Paolo Tomà, Angela Mastronuzzi,
and Giovanna Stefania Colafati; Bambino Gesù Children’s Hospital, Rome,
Italy
PURPOSE: To develop a predictive grading model based on diffusion
kurtosis imaging (DKI) metrics in children affected by gliomas, and to investigate the clinical impact of the model via correlations with overall survival and progression-free survival. MATERIALS AND METHODS: We
retrospectively studied 59 children (33M, 26F, median age 7.2 years) affected by gliomas on a 3T magnet. Patients with tumor locations other thaninfratentorial midline were included. Conventional and DKI sequences wereobtained. Mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), fractional anisotropy (FA) and apparent diffusion coefficient (ADC) maps wereobtained. Whole tumor volumes (VOIs) were segmented semiautomatically.
Mean DKI values were calculated for each metric. The quantitative values
from DKI-derived metrics were used to develop a predictive grading modelwith penalized logistic regression (glmnet package, R). Elasticnet regularization was used to avoid model overfitting. Fitted model coefficients from each
metric were used to develop a probability prediction of a high-grade glioma(HGG). Grading accuracy of the resulting probabilities was tested with ROC
analysis. Finally, model predictions were correlated to progression-free survival (PFS) with a Kaplan-Meier analysis. RESULTS: The cohort included
46 patients with low-grade gliomas (LGG) and 13 patients with HGG. The
developed model predictions yielded an AUC of 0.946 (95%CI: 0.890–1).
Model predictions were significantly correlated with PFS (23.1 months for
HGG vs 34.7 months for LGG, p<0.004). CONCLUSION: In our cohort,a DKI-based predictive model was highly accurate for pediatric glioma

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grading. DKI-based model predictions were significantly correlated with
progression-free survival.

Sujatha Venkataraman, Adam Green, Nathan Dahl, Nicholas Foreman,and Rajeev Vibhakar; University of Colorado Anschutz Medical Campus,
Aurora, CO, USA

IMG-15. PEDIATRIC GLIOBLASTOMAS CONTRAST
ENHANCEMENT PATTERN IS PREDICTIVE OF SURVIVAL
Zsila Sadighi, Halyna Pokhylevych, Maria Gule-Monroe, Melissa Chen,
Greg Fuller, Stephen Gruschkus, David Sandberg, Susan McGovern,
Mary Frances McAleer, Wafik Zaky, Soumen Khatua, and Jason Johnson;
The University of Texas MD Anderson Cancer Center, Houston, TX, USA

BACKGROUND: Previously, we have reported on the development ofadvanced magnetic resonance imaging (MRI) protocols for mouse brain
tumors. The goal of this follow-up pre-clinical study was to develop amachine-learning MRI classifier (radiomics) for four subtypes of childhood
brain tumor in patient-derived xenograft (PDX) mice. METHODS: MRI
scans on orthotopic medulloblastoma, ependymoma, ATRT and DIPGPDX (each n=12 animals) were performed on the animal 9.4 Tesla scannerwith an in-plane resolution of 47 microns. Image segmentation, as well as
shape and texture based radiomics descriptors were modeled using a modified COLIAGE software for tumor classification and to characterize tumor
habitat of each tumor subtype. RESULTS: The mean tumor volumes were11.2 mm3. Each MRI scan was segmented into three regions: (i) well defined tumor (including distant metastases); (ii) peritumoral edema; (iii)tumor necrosis. 360 radiomics features (capturing co-occurrence, grey-level
dependence and directional gradients) were obtained for each region. The
model classified four subtypes with high accuracy while achieving sufficientsegmentation accuracy despite the small lesion size. A subset of fourteen
tumoral, six peritumoral and five distant MRI radiomics features were
found to be predictive of the tumor sub-type (p=0.0017) independently oftumor anatomical location. CONCLUSIONS: MRI protocols followed byradiomics feature analysis discriminated among specific radiological features for four distinct orthotopic PDX models: medulloblastomas exhibit
low ADC values, high angiogenesis and cortical metastases as compared to
ependymomas (high levels of edema and olfactory bulb metastases), ATRT(the highest level of necrosis) and DIPG (highest T2 signal intensities andspinal metastases).

BACKGROUND: Pediatric GBMs are rare, accounting for 3% of allpediatric CNS tumors. Despite advances in treatment, the outcomes forpediatric glioblastomas (GBM) have not significantly improved. Researchsuggests a link between enhancement patterns and survival in adult patientswith glial tumors. We sought to study this relationship in a cohort of pediatric GBMs. METHODS: A radiology database was searched for cases <22 years, pathology proven brain glioblastoma, and pre-surgical MR imaging available for review. Based on pre-treatment, T1-contrast enhanced
MR images, size, and contrast enhancement patterns were characterized as
focal, diffuse, or ring-like. The extent of resection was assessed by comparing
pre- and post-surgery T2 hyperintensity and contrast enhancement. RESULTS: 64 eligible patients (age 2-21y, 14.6 + 5.4) were identified. The
majority of lesions demonstrated enhancement on gadolinium-enhanced T1
imaging. (n=58/64; 90%). The lesions were categorized into six (9.4%) caseswith focal enhancement, 37 (57.8%) cases with diffuse enhancement, and 15(23.4%) with ring-like enhancement. Patients who received GTR/subtotal
resection (STR) and had focal-enhanced GBMs had a significantly longer
progression-free survival (PFS) – 14.1 months (p = 0.0308), comparing todiffuse and ring-like enhancing glioblastomas which had respectively 13.9
and 5.5 months of PFS. DISCUSSION: Our data suggests that the contrast
enhancement pattern is a significant prognostic factor for survival in pediatric GBM. Patients with GTR/STR who had focal-enhancing GBMs had asignificantly longer progression-free survival (p=0.03) comparing to otherenhancement patterns.
IMG-16. WHOLE TUMOR DIFFUSION KURTOSIS IMAGINGANALYSIS FOR DISCRIMINATING PEDIATRIC POSTERIOR FOSSATUMORS: ACCURACY AND REPEATABILITY
Ioan Paul Voicu1, Antonio Napolitano1, Alessia Carboni1,
Massimo Caulo2, Andrea Carai1, Maria Vinci1, Evelina Miele1,
Sabrina Rossi1, Antonella Cacchione1, Sabina Vennarini3,
Elisabetta Ferretti4, Angela Mastronuzzi1, Paolo Tomà1, andGiovanna Stefania Colafati1; 1Bambino Gesù Children’s Hospital, Rome,
Italy, 2Institute for Advanced Biomedical Technologies-ITAB, Chieti, Italy,
3Santa Chiara Hospital, Trento, Italy. 4University “La Sapienza”, Rome,
Italy
PURPOSE: Diffusion kurtosis imaging (DKI) has not yet been tested
for pediatric brain tumors. Estimating diffusion values from whole-tumor
based (VOI) segmentations may improve diffusion measurement repeatability compared to conventional region-of-interest (ROI) approaches.
Our purpose was to compare repeatability between ROI and VOI DKIderived diffusion measurements and to assess VOI-based DKI accuracy indiscriminating among pediatric posterior fossa tumors. MATERIALS AND
METHODS: We retrospectively analyzed 34 children (19 M, 15F, meanage 7.48 years) with posterior fossa tumors who underwent preoperative
3T MRI including DKI. For each patient, two neuroradiologists independently segmented the whole solid tumor (VOI), the area of maximum tumor
diameter and a smallROI.Inter-observer variability was assessed with coefficient of variation (COV) and Bland-Altman plots. VOI-based DKI metrics
accuracy in discriminating among tumor histology and for tumor gradingwere assessed with MANOVA and ROC analyses respectively. Correlation
between grading accuracy and inter-observer variability was assessed with
Spearman’s rho. RESULTS: Tumor histology included medulloblastoma(15), pilocytic astrocytoma (14) and ependymoma (5). VOI-based measurements presented lower variability than ROI-based measurements acrossall DKI metrics. DKI-derived metrics could accurately discriminate between tumor subtypes (Pillai’s trace: p<0.001) and were accurate for tumor
grading (AUCs of 0.919, 0.986, 0.996, 0.842 and 0.926 for RK, MK, AK,
FA and MD respectively). VOI-based COV was significantly correlated to
AUC values (R=-0.900, p<0.037). CONCLUSIONS: DKI-derived metrics
are useful for pediatric posterior fossa tumor discrimination and grading.
VOI-based diffusion measurements present improved repeatability compared to ROI-based measurements and are significantly correlated to diagnostic accuracy.
IMG-17. RADIOMICS CHARACTERIZATION OF FOUR PEDIATRICBRAIN TUMOR SUBTYPES IN PDX MOUSE MODELSNatalie Serkova, Marina Stukova, Samuel Henehan, Jenna Steiner,
Angela Pierce, Andrea Griesinger, Bethany Veo, Irina Alimova,

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IMG-18. ASSESSMENT OF SUSPECTED DISEASE PROGRESSIONUSING MULTIPARAMETRIC 18F-CHOLINE PET/MRI IN
CHILDHOOD AND TEENAGE-YOUNG ADULT GLIOMAS
Valentina Ferrazzoli, Ananth Shankar, Julia Cockle, Christine Tang,
Ahmed Al-khayfawee, Benjamin Thomas, Anna Barnes, Jamshed Bomanji,
Francesco Fraioli, and Harpreet Hyare; UCLH, London, United Kingdom
OBJECTIVES: Evaluation of post-treatment glioma burden remains a significant challenge in children, teenagers and young adults (TYA). The aim of
this study was to evaluate the utility of ChoPET/MRI for evaluation of suspected disease progression in childhood and TYA gliomas. METHODS: 27
patients (mean age 14 years, range 6–21 years) with suspected glioma
disease progression were evaluated with ChoPET/MRI (n=59). Relative
cerebral blood volume (rCBV), apparent diffusion coefficient (ADC) andmaximum standardised uptake values (SUVmax) in enhancing (enh) andnon-enhancing (ne) tumour and normal-appearing white matter (wm) were
calculated (rCBVenh, rCBVne, rCBVwm, ADCenh, ADCne, ADCwm, SUVenh,
SUVne, SUVwm). 2 blinded radiologists scored tumour probability (1 = unlikely; 5 = definitely). Sensitivity and specificity calculated with gold standard
histopathology or clinical follow-up. RESULTS: Accuracy for the detectionof residual/recurrent tumour on conventional MRI was 96.3% (91.7%≤14 years, 100% ≥15 years) and ChoPET was 73.1% (66.7% ≤14 years,
80.0% ≥15 years). Lack of agreement was observed in 9/27 patients, with
ChoPET superior to MRI in 1 case of a posterior fossa tumour. Tumour
component analysis demonstrated significantly higher SUVenh and SUVne
than SUVwm (SUVenh: p<0.001; SUVne: p=0.004, equivalent to results wereobserved for ADV and rCBV (ADCenh, ADCne: p<0.001 vs ADCwm; rCBVenh,
rCBVne: p<0.001 vs rCBVwm). CONCLUSIONS: MRI is more sensitive
than ChoPET in the evaluation of suspected disease progression in TYA
gliomas. However, quanititative ChoPET is able to detect enhancing andnon-enhancing tumour and may be helpful in evaluating posterior fossa
disease where MRI is equivocal.
IMG-19. RADIOMICS AND SUPERVISED DEEP LEARNING TO
PREDICT MOLECULAR SUBGROUPS IN MEDULLOBLASTOMABASED ON WHOLE TUMOR VOLUME LABELING: A SINGLECENTER MULTIPARAMETRIC MR ANALYSIS
Ioan Paul Voicu1, Piero Chiacchiaretta2, Massimo Caulo2,
Evelina Miele1, Alessia Carboni1, Andrea Carai1,
Francesca Diomedi-Camassei1, Sabrina Rossi1, Antonella Cacchione1,
Giada Del Baldo1, Elisabetta Ferretti3, Angela Mastronuzzi1, Paolo Tomà1,
and Giovanna Stefania Colafati1; 1Bambino Gesù Children’s Hospital,
Rome, Italy, 2Institute for Advanced Biomedical Technologies-ITAB, Chieti,
Italy, 3University “La Sapienza”, Rome, Italy
PURPOSE: Medulloblastoma (MB) is a complex pathology. Four molecular subgroups have been unveiled (Wingless-WNT, Sonic HedgehogSHH, Group 3-G3 and Group 4-G4), characterized by significant differencesin patient clinical outcome. We investigated the utility of a radiomic analysis to predict molecular subgroups in patients with MB. MATERIALSAbstracts

AND METHODS: We retrospectively evaluated 42 patients with histological diagnosis of MB, known molecular subgroup, and diagnostic MRI
scan performed in our Institution on a 3 Tesla magnet. For each patient,
FLAIR, ADC, T2 and contrast-enhanced MPRAGE sequences were analysed. Solid tumor volumes were segmented semiautomatically. 107 features were extracted for each sequence (Pyradiomics, Python). Features
were tested for stability against labelling variations, selecting those presenting Intraclass Correlation Coefficient (ICC)>0.9 across all labellingvariations and all sequences. Among the remaining features, relevant features were selected with an all-relevant wrapper algorithm (Boruta, R).
Remaining features were used to predict MB subgroup with a Random
Forest algorithm(R). The most relevant features were ranked based on Gini
index (R). RESULTS: 83/107 features presented ICC >0.9 for all sequences.
Boruta selected 10 features. Classification analysis yielded an out-of-bag(OOB) error rate of 0.6%, (99.4% accuracy). The most relevant features
for classification were “simple” first-order features such as volume, major
axis or shape. CONCLUSION: This radiomic study yielded robust features,
which showed high accuracy in predicting the molecular MB subgroups.
Random forest algorithms are ideal for multiclass classification (eg. MB subgroups) and are intrinsically suited against overfitting. The most relevant formolecular classification were first-order features.
IMG-20. RADIOMIC FEATURES IMPROVE PROGNOSTICATIONOVER CONVENTIONAL MR DERIVED QUALITATIVEDESCRIPTORS IN PEDIATRIC SUPRATENTORIAL HIGH GRADE
GLIOMA: COMPARISON OF MACHINE LEARNING TECHNIQUESJohn Lucas1, Chih-Yang Hsu1, Jared Becksfort1, Scott Hwang1,
Zhaohua Lu1, Yichuan Wang2, Jason Chiang1, Christopher Tinkle1,
Amar Gajjar1, Thomas Merchant1, and Zoltan Patay2; 1St. Jude Children’s
Research Hospital, Memphis, TN, USA, 2Yale School of Public Health,
New Haven, CT, USA
PURPOSE/OBJECTIVES: Pediatric supratentorial high-grade glioma(stHGG) is a biologically heterogeneous disease defined by unique mutations, natural history and prognosis. Prior work by our group outlined a rolefor qualitative imaging features in aiding prognostication. We build on thatwork by evaluating the prognostic utility of radiomic features (RM) when
paired with clinical factors. MATERIALS/METHODS: Ninety-one patientsage < 21 years with stHGG treated between 1980–2007 were retrospectively reviewed. Prognostic clinical, qualitative imaging (Visually AcceSAble
Rembrandt Images, VASARI), and treatment characteristics were evaluatedin concert with manual and automatically segmented (DeepMedic), tumorderived semi-quantitative radiomic features (Pyradiomics) extracted fromMR images. Prognostic RM were limited to stable imaging features whichwere subsequently selected using bootstrapped least absolute shrinkage
and selection operator (LASSO). Nonparametric descriptive statistics andprognostication model evaluation, incorporating RM and clinical variables,
were developed using random forest (RF), Cox proportional hazards (CPH),and deep learning (deepsurv) algorithms and assessed for goodness of fit
using (c-index). RESULTS: A subset (N=80) of 386 intensity, shape, andtexture derived RM were stable between pre-treatment MR. 28 RM features
were independently predictive of survival when compared to models utilizing combinations of clinical, VASARI and had comparable model fit statistics. CPH, RF and deepsurv showed comparable utility in modelling RM
features. Combined modelling of clinical, VASARI and RM features using
CPH, RF, and deepsurv resulted in c-indices of 0.68, 0.67, 0.68, respectively. CONCLUSION: RM features are stable and independently prognostic. Combined modelling of clinical, VASARI, and RM features improves
prognostication in stHGG.
IMG-21. PROSPECTIVE PREOPERATIVE DETERMINATION OF
ISOCITRATE DEHYDROGENASE MUTATION IN GLIOMAS USING
SPECTRAL EDITING MAGNETIC RESONANCE SPECTROSCOPY
Thanh Nguyen1, Gerd Melkus1, Michael Taccone2,3, Diana Ghinda1,
Carlos Torres1, Nader Zakhari1, John Woulfe1, Gerrard Jansen1,
Ian Cameron1, Ioana Moldovan1, and Fahad Alkherayf1; 1The Ottawa
Hospital, Ottawa, ON, Canada, 2Division of Neurosurgery, Departmentof Surgery, University of Ottawa, Ottawa, ON, Canada, 3Arthur & Sonia
Labatt Brain Tumour Research Centre, The Hospital for Sick Children,
Toronto, ON, Canada
BACKGROUND: Gliomas are the most common malignant brain tumors in children and adults. A subset of these tumors harbour mutationsin the enzyme isocitrate dehydrogenase (IDH) which produces the novel
oncometabolite 2-hydroxyglutarate (2HG). In general, patients with an
IDH mutant glioma have a longer survival—often necessitating more
re-treatment sessions over the span of a patient’s life and surveillance monitoring for tumor recurrence. The need to non-invasively detect early evidence of tumor recurrence is therefore heightened in this unique subset ofpatients with extended survival. As magnetic resonance spectroscopy (MRS)
has been demonstrated to measure biochemical components of intracranialtumors using MRI, we conducted a study in 58 pre-operative adult patientsto determine if a diagnosis of IDH mutant glioma could be made confidently using imaging data. METHODS: Patients underwent neuroimaging
for diagnosis or preoperative planning on a 3 tesla MR scanner. A MEGAPRESS spectral editing technique was employed. Imaging findings weredirectly compared to post-operative histopathologic diagnosis. RESUTLS:
For all patients with gliomas from grade II to IV, detection of 2-HG with
MEGA-PRESS sequence had a sensitivity between 48% and 81%, specificity
between 60% and 100%, PPV between 53% and 100% and NPV between
77% and 85% depending on the CRLB threshold. Among the different metabolite ratios, a 2-HG/NAA ratio >0.034 had the highest sensitivity andspecificity, 86% and 73% respectively. DISCUSSION: Magnetic resonancespectroscopy (MRS) is an underused advanced MR technique that deservesconsideration in pediatric neuro-oncology given its utility in non-invasively
detecting malignant gliomas.
IMG-22. A DEEP LEARNING MODEL FOR AUTOMATIC POSTERIORFOSSA PEDIATRIC BRAIN TUMOR SEGMENTATION: A MULTIINSTITUTIONAL STUDY
Lydia Tam1, Edward Lee1, Michelle Han1, Jason Wright2, Leo Chen1,
Jenn Quon1, Robert Lober3, Tina Poussaint4, Gerald Grant1,
Michael Taylor5, Vijay Ramaswamy5, Chang Ho6, Samuel Cheshier7,
Mourad Said8, Nick Vitanza2, Michael Edwards1, and Kristen Yeom1;
1Stanford University, Stanford, CA, USA, 2Seattle Children’s Hospital,
Seattle, WA, USA, 3Dayton Children’s Hospital, Dayton, OH, USA,
4Boston Children’s Hospital, Boston, MA, USA, 5Hospital for Sick
Children, Toronto, ON, Canada, 6Indiana University School of Medicine,
Indianapolis, IN, USA, 7University of Utah, Salt Lake City, UT, USA,
8Centre International Carthage Médicale, Monastir, Tunisia
BACKGROUND: Brain tumors are the most common solid malignancies
in childhood, many of which develop in the posterior fossa (PF). Manual
tumor measurements are frequently required to optimize registration into
surgical navigation systems or for surveillance of nonresectable tumors after
therapy. With recent advances in artificial intelligence (AI), automated MRIbased tumor segmentation is now feasible without requiring manual measurements. Our goal was to create a deep learning model for automated PF
tumor segmentation that can register into navigation systems and provide
volume output. METHODS: 720 pre-surgical MRI scans from five pediatriccenters were divided into training, validation, and testing datasets. The study
cohort comprised of four PF tumor types: medulloblastoma, diffuse midline
glioma, ependymoma, and brainstem or cerebellar pilocytic astrocytoma.
Manual segmentation of the tumors by an attending neuroradiologist served
as “ground truth” labels for model training and evaluation. We used 2D
Unet, an encoder-decoder convolutional neural network architecture, with apre-trained ResNet50 encoder. We assessed ventricle segmentation accuracy
on a held-out test set using Dice similarity coefficient (0–1) and comparedventricular volume calculation between manual and model-derived segmentations using linear regression. RESULTS: Compared to the ground truth
expert human segmentation, overall Dice score for model performanceaccuracy was 0.83 for automatic delineation of the 4 tumor types. CONCLUSIONS: In this multi-institutional study, we present a deep learningalgorithm that automatically delineates PF tumors and outputs volumetric
information. Our results demonstrate applied AI that is clinically applicable,potentially augmenting radiologists, neuro-oncologists, and neurosurgeons
for tumor evaluation, surveillance, and surgical planning.

IMMUNOTHERAPY
IMMU-01. IMMUNE CHECKPOINT INHIBITION FOR PEDIATRICCNS TUMORS: A SINGLE INSTITUTION EXPERIENCE
Chantel Cacciotti1, Jungwhan Choi2, Mary Ann Zimmerman1,
Elise Tierney1, Christine Chordas1, Jessica Clymer1, Susan Chi1, and
Kee Kiat Yeo1; 1Dana Farber / Boston Children’s Cancer and Blood
Disorder Center, Boston, MA, USA, 2Boston Children’s Hospital, Boston,
MA, USAINTRODUCTION: Immune checkpoint inhibition through PD-1 andCTLA-4 blockade has shown efficacy in some adult malignancies and isbeing investigated in pediatrics. We describe our institutional experience withimmune checkpoint inhibition in pediatric CNS tumors. METHODS: We
performed a retrospective chart review of patients with recurrent, progressive, or refractory pediatric CNS tumors treated with immunotherapy
at Dana-Farber/Boston Children’s Hospital between 2018–2019. RESULTS: Eleven patients were identified, with median age of 11 years(range:3–9). Diagnoses included DIPG (n=3), HGG (n=4), ependymoma(n=1), craniopharyngioma (n=1), HGNET (n=1) and NGGCT (n=1). Eightpatients had recurrent disease (5 local; 3 disseminated); three had refractory disease (non-recurrent). Nine patients were treated with combination

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iii359Abstracts

therapy (ipilimumab/nivolumab); two patients received monotherapy witheither nivolumab or pembrolizumab. Median time from initial diagnosisto-treatment was 8 months (range 0.8–156). Ten patients received radiation
therapy (RT) prior to immunotherapy, with one receiving concurrent RT.
Median duration of treatment was 6.1 months (range:1–19). Therapy was
discontinued in nine patients: seven due to disease progression and two due
to adverse events (colitis, transaminitis). Other pertinent toxicities included
type 1 diabetes, hypothyroidism and skin toxicity. Based on iRANO criteria,
best responses included partial (n=4), stable (n=6) and progressive disease(n=1). Durable response (>12months) was noted in two patients (HGG andprogressive NGGCT). CONCLUSION: Immune checkpoint inhibition appears to have clinical benefit and is relatively well tolerated in this cohort ofpatients. Results from recently completed prospective clinical trials will be
critical to inform clinical decisions.
IMMU-02. CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL
NEUROTOXICITY CORRELATES WITH PRETREATMENT AND
ACUTE CSF NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS
Juliane Gust1, Ashley Wilson2, Olivia Finney3, Kendra Jae Hartsuyker2,
Prabha Narayanaswamy4, Vicky Wu5, Gwenn Garden6, Colleen Annesley1,
and Rebecca Gardner1; 1Seattle Children’s, Seattle, WA, USA, 2Seattle
Children’s Research Institute, Seattle, WA, USA, 3Bluebird Bio, Boston, MA,
USA, 4Seattle Children’s Immunotherapy Integration Hub, Seattle, WA,
USA, 5Fred Hutch Cancer Research Center, Seattle, WA, USA, 6Universityof North Carolina, Chapel Hill, NC, USA
OBJECTIVE: Immunotherapy for hematologic malignancies with CD19directed CAR T cells is complicated by neurotoxicity in approximately 40%
of patients. We have previously reported evidence of glial injury in pediatric patients with CAR T neurotoxicity by elevated CSF levels of GFAPand S100b. We now hypothesize that NFL is also a useful biomarker ofneuronal injury related to abnormal blood-brain-barrier and glial function. METHODS: We used the Mesoscale Discovery platform to measure
CSF and serum NFL levels in a consecutive cohort of 43 pediatric patientswith B cell ALL who received CD19-directed CAR T cells. In addition, we
will present expansion cohort measurements of NFL and GFAP (N=95). RESULTS: CSF NFL levels prior to CAR T cell infusion positively correlatedwith the risk of subsequently developing severe neurotoxicity (no neurotoxicity, median 275pg/mL, mild 378pg/mL, severe 951pg/mL, P=0.0182 forsevere vs none, P=0.0458 for severe vs mild). During neurotoxicity, mean
CSF NFL levels increased to 1179pg/mL (mild neurotoxicity, P=0.0338)
and 1345 pg/mL (severe neurotoxicity, P=0.0148), respectively. In serum,
pretreatment NFL levels were highly abnormal in many patients (median 368pg/mL, range 10–56,321pg/mL; healthy control median 4pg/mL,
range 1–7.5pg/mL). However, there was no correlation with neurotoxicity,history of CNS radiation, peripheral neuropathy, stem cell transplant, or
number of prior chemotherapies. Day 7 serum NFL levels did not change
significantly (median 439pg/mL, range 5–17,439pg/mL, P=0.3254). CONCLUSION: We conclude that CSF NFL is promising biomarker of CAR T
neurotoxicity risk and severity. The abnormal baseline serum NFL concentrations remain unexplained and require further study.
IMMU-03. UPDATES ON BRAINCHILD-01, -02, AND -03: PHASE 1
LOCOREGIONAL CAR T CELL TRIALS TARGETING HER2, EGFR,AND B7-H3 FOR CHILDREN WITH RECURRENT CNS TUMORSAND DIPG
Nicholas Vitanza1,2, Juliane Gust3,4, Ashley Wilson5, Wenjun Huang5,
Francisco Perez6, Jason Wright6, Sarah Leary1,2, Bonnie Cole7,
Catherine Albert8,2, Navin Pinto1,2, Rimas Orentas1,9, Michael Jensen1, andJulie Park1,2; 1Division of Pediatric Hematology/Oncology, Departmentof Pediatrics, University of Washington, Seattle Children’s Hospital,
Seattle, WA, USA, 2Center for Clinical and Translational Research, Seattle
Children’s Research Institute, Seattle, WA, USA, 3Division of Pediatric
Neurology, Department of Neurology, University of Washington, Seattle,
WA, USA, 4Center for Integrative Brain Research, Seattle Children’s
Research Institute, Seattle, WA, USA, 5Therapeutics Innovation Core,
Immunotherapy Integration Hub, Seattle Children’s Research Institute,
Seattle, WA, USA, 6Division of Radiology, Department of Pediatrics,
Seattle Children’s Hospital, University of Washington, Seattle, WA, USA,
7Department of Laboratories, Seattle Children’s Hospital; Department of
Pathology, Seattle, WA, USA, 8Division of Pediatric Hematology/Oncology,
Department of Pediatrics, University of Washington, Seattle, WA, USA,
9Ben Towne Center for Childhood Cancer Research, Seattle Children’s
Research Institute, Seattle, WA, USA
We report preliminary results of three Phase 1 trials of repetitively dosed
locoregional CAR T cells for children with recurrent/refractory CNS tumors, targeting HER2 (BrainChild-01), EGFR (BrainChild-02), and B7-H3(BrainChild-03). Cells are delivered into the tumor cavity (Arm A) or ventricular system (Arm B and BrainChild-03’s DIPG-specific Arm C). Primary
endpoints are feasibility and safety. Successful CAR T cell manufacture oc-

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curred in 2/2 subjects (BrainChild-01) and 2/3 (BrainChild-02). All subjects
tolerated intra-patient dose escalation from 1x107 to 2.5x107 cells/dose
without DLTs. Two subjects were evaluable on BrainChild-01 (S-001: glioblastoma, Arm A, survival 173 days post-first infusion, received 6 infusions;S-002: ependymoma, Arm B, survival 111 days, 9 infusions). One subject
was evaluable on BrainChild-02 (glioblastoma, Arm A, withdrew from trial
at 49 days, 5 infusions). One enrolled patient on BrainChild-03 has not
begun treatment. None of the subjects developed new neurologic toxicities,
although transient worsening of baseline tumor-related signs and symptoms were seen. Secondary endpoints are efficacy and disease response. No
objective radiographic responses have been observed. Both BrainChild-01
subjects had transient systemic CRP elevations following infusions (S-001:
peak of 3.9 post Course 1 Week 1; S-002: peak of 2.3 post Course 2 Week1), possibly indicating an inflammatory response. Both subjects had postinfusion CSF cytokine elevations (CXCL10, GCSF, GM-CSF, IFNa2, IFNg,
IL-10, IL12-p40, IL12-p70, IL-15, IL-1a, IL-3, IL-6, IL-7, TNFa, VEGF)
without concurrent systemic changes. In summary, we provide preliminary
evidence of safety and feasibility of intracranial delivery of CAR T cells forpediatric CNS tumors.
IMMU-05. B7-H3-SPECIFIC CAR T CELLS HAVE POTENT ANTITUMOR ACTIVITY IN THE GL261 IMMUNE-COMPETENT
MURINE BRAIN TUMOR MODEL
Dalia Haydar, Zhongzhen Yi, Chris DeRenzo, Stephen Gottschalk, andGiedre Krenciute; St. Jude Children’s Research Hospital, Memphis, TN,USA
BACKGROUND: We and others have identified B7-H3 (CD276) as apromising target for CAR-based immunotherapies for pediatric brain tumors. So far, B7-H3-CAR T cells have only been studied in xenograft models
for brain tumors, which do not recapitulate the immunosuppressive tumor
microenvironment (TME). To overcome this obstacle, we decided to adapt
the immune-competent GL261 murine glioma model which mimics humandisease and host immune barriers. METHODS: To evaluate the safety andefficacy of antigen-specific CAR T cells, murine B7-H3-CAR T cells weregenerated using retroviral particles encoding 2nd generation B7-H3-specificCD28.z CAR. Expansion, persistence, and anti-tumor activity were evaluated in vitro and in vivo. Components of the brain TME were then evaluated using flow cytometry and immunostaining. RESULTS: B7-H3-CAR T
cells only killed B7-H3+ tumor cells, secreted significant levels of IFNγ and
IL-2 in an antigen-dependent manner and expanded an average of 33-foldin repeat stimulation assay with B7-H3+ tumor cells in contrast to control
CAR T cells. In vivo, intratumoral injection of B7-H3-CAR T cells into
orthotopic GL261 glioma induced complete regression in 60% of treatedmice. Preliminary studies show numerous infiltration of suppressive tumorassociated macrophages within the tumor and its periphery. CONCLUSIONS: In summary, we successfully generated murine B7-H3-CAR T cells
and have demonstrated that these cells have potent anti-tumor activity inthe immune-competent GL261 glioma model. However, it is likely that thetumor-associated macrophages are mediating immunosuppressive effects on
B7-H3-CAR T cells. Therefore, studies focusing on TME/CAR T cell interactions are in progress.
IMMU-06. T-CELL IMMUNOTHERAPY FOR PEDIATRIC BRAIN
TUMORS: DIVERSITY IN CELL SURFACE ANTIGEN AND HLAEXPRESSION NECESSITATES A MULTI-PRONGED APPROACH
Haley Houke, Xiaoyan Zhu, Kimberly S. Mercer, Jennifer L. Stripay,
Jason Chiang, Suzanne J. Baker, Martine F. Roussel, Stephen Gottschalk,
and Giedre Krenciute; St. Jude Children’s Research Hospital, Memphis,
TN, USA
Cell surface or intracellular antigens expressed in pediatric brain tumors arepotential targets for chimeric antigen receptor (CAR) or ab (T-cell receptor)
TCR T-cell immunotherapy. At present it remains unknown what cell surface
antigens are suitable CAR targets for pediatric brain tumors; in addition, cellsurface expression of HLA class I, a molecule critical for ab TCR T-cell recognition, has not been systemically studied in these tumors. Therefore, we
set out to assess expression of five CAR targets (IL13Ra2, HER2, EphA2,
B7-H3, GD2) and HLA class I. We established and validated a flow cytometrybased method to profile CAR targets and HLA class I expression from pediatric patient-derived xenograft (PDX) samples. To date, we profiled 53 PDX
samples, including medulloblastoma, HGG, DIPG, ATRT, and ependymoma.
We found that antigen expression has high intra- and inter-PDX sample variability with B7-H3 and IL13Ra2 being most consistently expressed. We confirmed these findings using conventional IHC for B7-H3 with PDX samples
and patient tissue microarrays. HLA class I was present on the cell surface of
HGGs and DIPGs, however significantly down-regulated in 26 out of 36 otherbrain tumor types. Finally, matched fresh tissue and PDX sample analysis revealed that cells derived from PDX models are indeed representative of fresh
tissue. Our results indicate that more than one antigen needs to be targetedto achieve a more complete tumor clearance. In addition, variable expression

Abstractsof HLA class I suggests that pediatric brain tumors have developed immune
evasion strategies to prevent recognition by conventional T cells.
IMMU-07. IMMUNE EFFECTOR CELL ASSOCIATED
NEUROTOXICITY (ICANS) AMONG PEDIATRIC AND AYA
PATIENTS: MD ANDERSON CANCER CENTER EXPERIENCE
Brandon Brown, Paolo Tambaro, Kris Mahadeo, Sajad Khazal,
Priti Tewari, Demetrios Petropoulos, John Slopis, and Zsila Sadighi; The
University of Texas at MD Anderson Cancer Center, Houston, TX, USA
INTRODUCTION: Immune effector cell associated neurotoxicity(ICANS) and cytokine release syndrome (CRS) are potentially life-threatening
complications associated with immune effector cell (IEC) therapies. We characterize ICANS in pediatric and adult young adolescent (AYA) patients receiving IEC therapy at our institution. METHODS: We reviewed clinicalcharacteristics and severity (based on ASTCT Consensus Criteria) in pediatric and AYA patients with IEC products from 2018–2019 at MDACC. RESULTS: Nine patients, median age 15.5 (range: 3–25) years received chimericantigen receptor (CART) IEC therapy. Four (44%) developed ICANS within
median of 8 (range: 3–27) days of CAR T cell infusion and median 6 (range:
2–7) days after CRS. Primary diagnoses were pre-B cell acute lymphoblastic
leukemia (8) and mediastinal large B-cell lymphoma (1). Median CRS andICANS severity grade was 2 (range 1–4). Symptoms included altered mental
status (AMS) (5), seizure (1), aphasia (2), impaired ability to write a standard
sentence (4). Neuroimaging did not correlate to ICANS symptoms or severity. EEG was performed in 3 and 1 had background slowing correlatingwith aphasia. CSF was obtained in two revealing lymphocytosis. All received
prophylactic anti-epileptic medication and tocilizumab for concomitant CRS.
Three received steroids. CONCLUSION: ICANS may present in almost halfof pediatric patients within one week of receiving CART products associatedwith CRS. CAR-T trafficking into the CSF may explain pleocytosis in the CSF.
Prospective studies may clarify. Impaired ability to write a standard sentence
and the Cornell Assessment of Pediatric Delirium (CAPD) may be early indicators of ICANS in pediatric/AYA patients.
IMMU-08. REMATCH PROTOCOL: PHASE II STUDY OF EX-VIVO
EXPANDED AUTOLOGOUS TUMOR SPECIFIC LYMPHOCYTE
TRANSFER (X-ALT) + TOTAL TUMOR RNA DC VACCINE(TT-RNA DC) DURING RECOVERY FROM MYELOABLATIVECHEMOTHERAPY (MAC) AND PERIPHERAL BLOOD STEM CELL(PBSC) RESCUE OR NON-MYELOABLATIVE CHEMOTHERAPY(NMAC) AND PBSC IN PATIENTS (PTS) WITH RECURRENT PNET
(R-PNET)
Sridharan Gururangan1,2, Eugene Hwang3, Girish Dhall4, Oleg Yegorov1,5,
Lance Governale6,2, Jason Blatt6,2, Biljana Horn7,2, and Duane Mitchell1,5;
1Preston A, Wells Center Jr. Center for Brain Tumor Therapy, Gainesville,
FL, USA, 2UF Health Shands Hospital, Gainesville, FL, USA, 3Children’s
National Medical Center, Washington, DC, USA, 4Children’s Hospital of
Alabama, Birmingham, AL, USA, 5University of Florida, Gainesville, FL,
USA, 6Department of Neurosurgery, Gainesville, FL, USA, 7Department ofPediatric Hematology-Oncology, Gainesville, FL, USA
A phase II study was performed to assess vaccine-related toxicities andefficacy of x-ALT+tt-RNA DC following MAC +PBSC (group A) or NMAC+PBSC (group B) in pts with r-PNET. METHODS: Eligible pts underwent
biopsy to confirm r-PNET and obtain tumor for vaccine preparation. Pts
with local (group A) or metastatic (group B) disease received cytoreductive
induction chemotherapy prior to either MAC (carboplatin+ thiotepa+
etoposide) or NMAC (cyclophosphamide + fludarabine) respectively andthen received one dose of x-ALT (3 x 107cells/kg), PBSC, and 3 doses ofbi-weekly intradermal tt-RNA DCs (107cells each). Patients were followed
for survival and vaccine-related toxicities. Correlative studies included
TCR RNA sequencing and measurement of serum cytokines RESULTS: 20
evaluable pts (75% males) [Medulloblastoma 17, PNET 3; unifocal 40%]
were treated on protocol (group A 7, group B 13). There were no significant vaccine-related toxicities. At a median follow-up of 8.5 months, 5 patients (all with medulloblastoma) are alive following vaccine therapy; 2 pts
with SD (3.5+ and 6.5+ months) and 3 pts with PD that stabilized withsalvage therapies (26+, 31+, and 46+ months respectively). One patient withmedulloblastoma and bone marrow involvement who had PD despite MAC,
had an almost complete response one month following x-ALT + tt-RNA
DCs and TCR RNA sequencing demonstrated massive clonal expansion of
T cells. Correlative studies are ongoing CONCLUSIONS: x-ALT+tt-RNA
DC following either MAC or NMAC is safe and shows signs of biologic andpossible clinical activity in some pts with r-PNET.
IMMU-09. NIVOLUMAB THERAPY FOR A PEDIATRIC-ONSETPRIMARY INTRACRANIAL MELANOMA
Utako Oba1, Yuhki Koga1, Riichiro Kawaguchi1, Kentaro Nakashima1,
Yojiro Akagi2, Nobuhiro Hata2, Nanae Yamamoto3, Kenichi Kohashi4,

Satohiro Masuda3, Koji Iihara2, Yoshinao Oda4, and Shouichi Ohga1;
1Department of Pediatrics, Graduate School of Medical Sciences, Kyushu
University, Fukuoka, Japan, 2Department of Neurosurgery, Graduate
School of Medical Sciences, Kyushu University, Fukuoka, Japan,
3Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan,
4Department of Anatomic Pathology, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, Japan
Primary intracranial malignant melanoma (PIMM) is an uncommon
cancer in childhood, that accounts for approximately 1% of melanoma,
and 0.07% of brain tumors even in all age group. Because extracranial malignant melanoma usually occurs as a cutaneous lesion, affected patients
have a chance to receive the early diagnosis and curable resection of theisolated tumor. However, unresectable metastatic cases have a poor prognosis with a median overall survival of 8 months. We report a 12-year-old
girl with PIMM who received nivolumab therapy after an administrationof dacarbazine. The tumor harbored no BRAF mutation. After the intravenous administration of nivolumab, cerebrospinal fluid 5-S-cysteinyldopa
levels declined and circulating CD8+HLA-DR+T cells increased, indicating
the initial effect of nivolumab on PIMM. However, multiple lesions progressed for two month-immunotherapy, during which cerebrospinal fluid
nivolumab concentrations attained to 1.2% of serum ones. The present casedemonstrated the safety and modest effect of nivolumab for CNS melanoma.
Nivolumab is a tolerable first-line therapy for diffuse PIMM, but pediatricpatients need a more intensified CNS-specific immunotherapy.
IMMU-10. INTERIM ANALYSIS OF THE HIT-HGG REZ IMMUNVACSTUDY - DENDRITIC CELL VACCINATION WITH PARTIAL TREG
DEPLETION IN CHILDREN, ADOLESCENTS, AND ADULTS WITHRELAPSED HIGH-GRADE GLIOMASMatthias Eyrich1, Jürgen Krauss2, Johannes Rachor1, Camelia Monoranu3,
Brigitte Bison4, Mario Löhr2, Stefan Rückriegel2, Matthias Wölfl1,
Elisabeth Miller1, Paul G Schlegel1, and Christof Kramm5; 1University
Children’s Hospital, Würzburg, Germany, 2Dep. Neurosurgery,
Würzburg, Germany, 3Dep. Neuropathology, Würzburg, Germany, 4Dep.
Neuroradiology, Würzburg, Germany, 5University Children’s Hospital,
Göttingen, Germany
Efficacy of therapeutic dendritic cell vaccines (DCV) can be limited byimmunosuppressive mechanisms in the micromilieu of high-grade gliomas.
In the HIT-HGG-Rez Immunovac trial (Eudra-CT 2013-000419-26), we
investigate whether a reduction of Treg with metronomic cyclophosphamide (metrCyc) might be a feasible option to improve vaccine efficacy. 10
pediatric (mean age 11.4±4.2y) and 5 adult patients (mean age 39.5±19.9y)with relapsed glioblastoma were treated according to the HIT-HGG-Rez
Immunovac protocol so far. 2 children were treated within the trial, the other13 in the pilot phase. Patients received upfront oral metrCyc for 2–4 weeks.
After reoperation and monocyte-apheresis, patients received 4 weekly intradermal doses of autologous, TNFa/IL-1ß matured DCs pulsed with tumor
lysate in imiquimod-prepared skin. Thereafter, tumor lysate boosts were
given. All patients received at least 5 vaccines (4xDCs, 1xlysate boosts).
MetrCyc was well tolerated and led to a reduction in Treg-frequency of
35.6±17.8% followed by a rebound after cessation of metrCyc. Importantly,
13/14 analyzed patients showed a positive IFNg-T-cell response against
autologous tumor lysate with a tendency to decrease over time. 6-monthoverall survival was 100%, compared to 65% in a historical control. MeanPFS and OS were 5.7 and 21.1 months with no difference between adults
and children. We conclude that DCV in combination with partial Treg depletion is feasible, safe, and related with a high rate of tumor-specific IFNgresponses. As the clinically and immunologically beneficial effects seem todiminish over time, we aim to combine our approach with checkpoint inhibition in the next amendment.
IMMU-11. LOCOREGIONAL DELIVERY OF TRANSIENT GD2 CAR TCELLS FOR SAFE AND EFFECTIVE TREATMENT OF DIPG
Jessica Foster, Crystal Griffin, Allison Stern, Cameron Brimley,
Tiffany Smith, Phillip Storm, and Adam Resnick; Children’s Hospital ofPhiladelphia, Philadelphia, PA, USA
Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain
tumor with a median survival of one year. Recently Mount et al (Nat Med2018) discovered the disialoganglioside GD2 is present at high levels on thesurface of DIPG and can be targeted using GD2-directed CAR T cells. However, permanently expressed CAR T cells created by lentiviral transduction resulted in a significant number of deaths from tumor swelling with uncontrolled
T cell proliferation. We hypothesized that using mRNA to create transient
GD2-directed CAR T cells delivered locally with repeated dosing would resultin a safer yet equally effective way to treat DIPG using CAR T cell therapy. In
vitro studies using mRNA GD2-directed CAR T cells resulted in robust tumor
cytotoxicity and T cell degranulation across a panel of six DIPG cell lines.
Using an orthotopic murine model of SU-DIPGXIIIP*, an extremely aggres-

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sive model, we delivered of a single dose of two million mRNA GD2-directed
CAR T cells locoregionally to the pons via stereotactic injection. The mRNA
GD2-directed CAR T cells resulted in no toxic deaths of the mice. In addition,a single dose of mRNA CAR T cells targeting GD2 prolonged survival of themice by a median of six days (p<0.05). Ongoing studies using an indwelling
catheter for repeated dosing of mRNA CAR T cells are currently underway andresults expected at the time of presentation. This work will form of the basis of
an mRNA CAR T cell trial targeting GD2 for patients with DIPG.
IMMU-12. PHASE I/II TRIAL OF IMMUNOTHERAPY WITHFUSIONS OF DENDRITIC CELLS AND TUMOR CELLS FORRELAPSED OR REFRACTORY BRAIN TUMORS IN CHILDREN AND
YOUNG ADULTS
Masayoshi Yamaoka1, Yasuharu Akasaki2, Jun Takei2,
Masaharu Akiyama1, Tetsunori Tasaki3, Toya Ohashi4, Hiroyuki Ida1, andTakaaki Yanagisawa2; 1Jikei University School of Medicine, Pediatrics,
Tokyo, Japan, 2Jikei University School of Medicine, Neurosurgery, Tokyo,
Japan, 3Jikei University School of Medicine, Blood transfusion and celltherapy, Tokyo, Japan, 4Jikei University School of Medicine, Gene therapy,
Tokyo, JapanBACKGROUND/OBJECTIVES: Relapsed or refractory brain tumors inchildhood continue to have a dismal prognosis in spite of intensive multidisciplinary treatment. Cancer immunotherapy is newly developed to
be expected as next promising treatment for highly aggressive pediatriccancer. This trial was designed to evaluate the safety and effectiveness ofan immunotherapy with fusions of dendritic cells (DCs) and tumor cells
in patients with malignant brain tumors. METHODS: Patients with histopathologically confirmed malignant and recurrent/refractory brain tumor
were eligible for this immunotherapy trial. Autologous cultured tumor cells
obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in thecervical region and repeated 3–10 times in each 28–84 days cycle. Treatmentrelated toxicity, progression-free survival (PFS), and overall survival (OS) were
evaluated. RESULTS: Six patients were enrolled, three with high grade glioma
and three with ependymoma. Median age at first course of immunotherapy
was 10 years (range 8–25 years) and median follow-up time from the firstcourse of immunotherapy was 13.5 months (range 3–33 months). All patientswith immunotherapy were well tolerated to this treatment with no adverse
events except local erythema in injected site. Median progression free survival
and overall survival were 18 months and 18.5 months, respectively. CONCLUSIONS: FC immunotherapy with autologous DCs and tumor cells forbrain tumor in children and young adults were extremely well tolerated andshowed encouraging responses in this series. Further phase II study of FC
immunotherapy is planned to improve survival and reduce treatment related
morbidity.
IMMU-13. DUAL IGF1R/IR INHIBITOR IN COMBINATION WITH
GD2-CAR T-CELLS AS A POTENT THERAPEUTIC STRATEGY FOR
H3K27M-MUTANT DIFFUSE MIDLINE GLIOMASEmmanuel de Billy1, Marsha pellegrino1, Biagio De Angelis1,
Pietro Businaro1, Domenico Orlando1, Giulia Pericoli1, Lucia Lisa Petrilli1,
Sabrina Rossi2, Roberta Ferretti1, Nicola Maestro1, Luca Massimi3,
Marco Pezzullo4, Cristiano De Stefanis4, Rossella Rota1,
Francesco Ferrari5,6, Elisa Salviato5, Andrea Carai7, Ignazio Caruana1,
Franco Locatelli1,8, Angela Mastronuzzi9, Concetta Quintarelli1, andMaria Vinci1; 1Department of Paediatric Haematology and Oncology,
Cellular and Gene Therapy, Bambino Gesù Children’s Hospital-IRCCS,
Rome, Italy, 2Department of Laboratories, Pathology Unit, BambinoGesù Children’s Hospital-IRCCS, Rome, Italy, 3Pediatric Neurosurgery,
Department of Neurosurgery, Fondazione Policlinico Gemelli-IRCCS,
Rome, Italy, 4Research Laboratories, Bambino Gesù Children’s HospitalIRCCS, Rome, Italy, 5IFOM, the FIRC Institute of Molecular Oncology,
Milano, Italy, 6CNR Institute of Molecular Genetics “Luigi Luca CavalliSforza”, Pavia, Italy, 7Oncological Neurosurgery Unit, Departmentof Neuroscience and Neurorehabilitation, Bambino Gesù Children’s
Hospital-IRCCS, Rome, Italy, 8Department of Gynaecology/Obstetrics andPaediatrics, Sapienza University of Rome, Rome, Italy, 9Neuro-oncology
Unit, Department of Paediatric Haematology and Oncology, Cellular andGene Therapy, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
Diffuse midline gliomas (DMG) are aggressive paediatric brain tumors
for which there is no effective treatment. Recent pre-clinical studies suggestthat adoptive transfer of chimeric antigen receptor (CAR) T-cells targetingthe disialoganglioside antigen GD2 (GD2-CAR) has a significant therapeuticpotential for H3K27M-mutant DMG. Still, some tumor cells resist to treatment suggesting that a multimodal approach may be necessary to treat more
efficiently the disease. Our aim was to identify chemical compounds that,in combination with CAR T-cells, would enhance anti-tumor efficacy. After
having confirmed the GD2 expression in tissue samples and patient-derived
H3K27M-mutant DMG cells, we developed a high throughput cell-based
assay to screen 40 kinase inhibitors in combination with T-cells expressing

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the GD2-CAR.CD28.4-1BB.z construct. The screening led to the identification of the dual IGF1R/IR antagonists, BMS-754807 and linsitinib, which,in combination with GD2-CAR T-cells, improved antitumor activity by
25% (p<0.0001) and 20% (p<0.0001) respectively, compared to GD2-CAR
T-cells alone. The two compounds inhibited tumor cell proliferation throughIGF1R/IR dependent mechanisms at a concentration which did not affectCAR T-cell expansion. Linsitinib, but not BMS-754807, decreased GD2CAR T-cells exhaustion and increased their memory profile. Furthermore,
linsitinib attenuated the expression of 10 out of 71 DMG genes involved
in immunomodulation (e.g. IL33, VEGFC, STAT5A) and regulated upontumor/CAR T-cells co-culture. Finally, we confirmed the anti-tumor activityof the new linsitinib/GD2-CAR T-cells combination strategy in a DMG
H3K27M-mutant 3D culture model. Our work supports the developmentof IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for
H3K27M-mutant DMG therapy.
IMMU-14. IMMUNE CHECKPOINT INHIBITOR THERAPY FOR
TREATMENT OF SYNCHRONOUS CANCERS IN PAEDIATRICPATIENTS WITH CONSTITUTIONAL MISMATCH REPAIR
DEFICIENCY
Jacob Henderson1, Daniel Morgenstern2, Melissa Edwards2,
Sumedha Sudhaman2, David Kram3, Michael Osborn4, Yoon-Jae Cho5,and Uri Tabori2; 1Mary Bridge Children’s Hospital, Tacoma, WA, USA,
2Hospital for Sick Children, Toronto, ON, Canada, 3Wake Forest School of
Medicine, Winston Salem, NC, USA, 4Royal Adelaide Hospital, Adelaide,
Australia, 5Oregon Health and Science University, Portland, OR, USA
Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessive condition in which affected patients carry biallelic germline mutationsin the MMR genes. This highly penetrant syndrome results in nearly universal development of malignant neoplasms at a young age, most commonly
pediatric brain tumors. Importantly, in addition to brain tumors, patientsfrequently develop multiple metachronous or even synchronous tumors
making it impossible to treat these cancers with current chemotherapeutic
approaches due to the complexity of different chemoradiation regimens required, resulting in excess toxicity and lack of efficacy. We first, assessed
the metachronous (defined here as serial tumors diagnosed >1 year apart orafter completion of definitive treatment for the initial tumor) or synchronous
cancers (defined here as tumors diagnosed within a year of each other or
during the definitive treatment for the initial tumor) in all patients within the
consortium. Strikingly, 47% developed synchronous and/or metachronous
cancers leading to patient demise. Molecular analysis revealed that all synchronous tumors (n=26) harbored a hypermutational burden accompanied
by high genomic microsatellite instability and the relevant signatures. We
therefore treated two patients with glioblastomas who had synchronous
solid tumors with checkpoint inhibitors. In both patients, objective tumor
response was associated with clinical benefit and prolonged survival. Biomarker analysis revealed increased tumor mutational burden, microsatellite
instability and immune cell infiltration. These cases highlight the role of universal, mechanism based and tumor-agnostic approach to treat patients withbrain tumors with additional synchronous cancers in the setting of cancer
predisposition.
IMMU-15. PROTEOGENOMIC DISCOVERY OF NOVEL TUMORPEPTIDES AS NEOANTIGENS FOR PERSONALIZED T CELLIMMUNOTHERAPY IN MEDULLOBLASTOMA
Samuel Rivero-Hinojosa, Melanie Grant, Aswini Panigrahi,
Huizhen Zhang, Veronika Caisova, Catherine Bollard, and Brian Rood;Children’s National Research Institute, Washington, DC, USA
T cell immunotherapies are promising new tools to combat high-risk subgroups of medulloblastoma without increasing the late effects burden. The
ideal target antigen of an effective antitumor T-cell response is abundantly
expressed by tumor cells but not by normal tissues, in order to limit offtarget effects. Tumors translate a host of highly novel transcripts that are
the result of aberrations in tumor DNA and the unmasking of alternative
or novel exons. We developed a novel proteogenomic approach to identify
tumor-restricted peptides and used them to select and expand T cells capableof mounting a tumor-specific cytotoxic immune response. Using RNA-seq
and WGS data, we created personalized custom searchable databases containing predicted novel proteins from somatic mutations, novel junctions
and fusion transcripts from 56 medulloblastoma tumors. By searching these
databases with raw mass spectrometry data from paired medulloblastoma
tumors, we identified tens of neoantigen peptides arising from the translation of tumor-specific transcripts; novel isoforms being the predominantsource. We tested these peptides for their ability to select and expand autologous polyclonal populations of T cells and tested the immunogenicity
of each individual peptide. Flow cytometry revealed populations of CD4+
and CD8+ cells with an activation profile marked by IFN-γ and TNF-α. Immunosuppressive marker profiles were also characterized. Using cytotoxicity
assays, we demonstrated that tumor specific T cells can eliminate neoantigen
bearing tumor cells. Thus, proteogenomics can identify immunogenic tumorAbstracts

specific peptides that can be used to create a personalized, targeted T celltherapy for children with high risk medulloblastoma.
IMMU-16. INTRA-TUMOURAL IL-12 DELIVERY ENABLES CAR
T-CELL IMMUNOTHERAPY FOR HIGH-GRADE GLIOMA
Giulia Agliardi1, Anna Rita Liuzzi2, Alastair Hotblack1, Donatella De Feo2,
Nicolás Núñez2, Ekaterina Friebel2, Francesco Nannini1, Thomas Roberts3,
Rajiv Ramasawmy3, Cassandra Stowe1, Iwan Williams1, Bernard Siow3,4,Mark Lythgoe3, Tammy Kalber3, Sergio Quezada1, Martin Pule1,
Sonia Tugues2, Burkhard Becher2, and Karin Straathof5,1; 1UCL Cancer
Institute, London, GB, United Kingdom, 2Institute of Experimental
Immunology, University of Zurich, Zurich, CH, Switzerland, 3UCL Centre
for Advanced Biomedical Imaging, London, GB, United Kingdom, 4Francis
Crick Institute, London, GB, United Kingdom, 5UCL Great Ormond Street
Institute of Child Health, London, GB, United Kingdom
Treatment with T-cells redirected to tumour specificity with a chimericantigen receptor (CAR) may be well suited to treat intracranial tumours dueto the ability of T-cells to access the central nervous system and migrate toinfiltrative sites of disease. In adult glioblastoma, a case report of local anddistant eradication of intracranial and spinal tumour deposits following
intraventricular infusion of IL13Ra2-CAR T-cells indicates the potential ofthis approach. However, in contrast to the sustained complete remissions
observed in haematological malignancies, in the majority of patients withglioblastoma CAR T-cell therapy has not resulted in clinical benefit. Tumour
heterogeneity and the highly immune inhibitory tumour microenvironment(TME) are likely key barriers to achieving durable anti-tumour immunity.
Here use intra-tumoural administration of IL-12 to enable CAR T-cell
immunity. We employed CAR-T cells targeting the tumour-specific epidermal
growth factor variant III (EGFRvIII). In an immunocompetent orthotopic
mouse model of high-grade glioma, we show that CAR-T cells alone failed
to control fully established tumour, but when combined with a single, locallydelivered dose of IL-12, durable antitumor responses were achieved. IL-12 not
only boosted cytotoxicity of CAR T-cells, but also reshaped the TME driving
increased infiltration of proinflammatory CD4+ T-cells, decreased numbers of
regulatory T-cells (Tregs) and activation of the myeloid compartment. Critically, immunotherapy enabling benefits of IL-12 were achieved with minimal
systemic effects. Our findings show that local delivery of IL-12 is an effective
adjuvant for CAR-T cell therapy for high-grade glioma. Assessment of application in high-risk childhood brain tumours is ongoing.
IMMU-17. CAR T CELLS TARGETING THE INTEGRINALPHAVBETA3 EXHIBIT ROBUST ANTI-TUMOR RESPONSESAGAINST DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND
GLIOBLASTOMA (GBM)
Dustin Cobb, Jacopo de Rossi, Lixia Liu, Erin An, and Daniel Lee;
University of Virginia, Charlottesville, VA, USA
Effective therapies for DIPG and GBM are lacking. CD19 chimeric antigen
receptor (CAR) T cells are highly effective in patients with refractory B-cellmalignancies. We aim to develop novel CARs for high-grade gliomas. The
integrin complex alphavbeta3 was selected as a CAR-T cell target due to its
expression on gliomas and their vasculature, yet with minimal expression
throughout normal tissues, vessels and organs. Indeed, a majority of DIPG
and GBM cell lines express surface αvβ 3. Second-generation CAR-T cells expressing an anti-α vβ 3 scFv and either a CD28 or 4-1BB co-stimulatory domain
and CD3zeta were constructed. Transduced healthy, donor-derived T cells
exhibited high level CAR expression, efficient expansion, and representative
populations of memory subsets including central, effector, and stem cell-likememory CAR-T cells. α vβ 3.28z and α vβ 3.BBz CAR-T cells exhibited antigenspecific in vitro cytotoxicity and cytokine production against DIPG and
GBM cell lines. Both CARs mediated rapid and robust anti-tumor responses
in NSG mice bearing orthotopic DIPG or GBM tumors. 5/13 α vβ 3.28z and
0/14 α vβ 3.BBz treated animals died without detectable disease within 2 weeks
of infusion suggesting different toxicity profiles and is consistent with faster
CAR-T cell expansion in CD28-versus 4-1BB-containing CD19 CAR-T cells
seen clinically. Our results demonstrate that α vβ 3.BBz CAR-T cell therapy
may be both highly effective and safe in DIPG and GBM patients. Due to therestricted nature of α vβ 3 expression in normal tissues, the robust responses
seen in tumor-bearing mice, and the slower kinetics of α vβ 3.BBz CAR-T cell
expansion, a first-in-human clinical trial is being planned.
IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR
DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNECHECKPOINT INHIBITION: AN INTERNATIONAL RRD
CONSORTIUM REGISTRY STUDY
Eric Bouffet1, Sumedha Sudhaman1, Jiil Chung1, Jacalyn Kelly1,
Ailish Coblentz1, Melissa Edwards1, Tatiana Lipman1,

Cindy Zhang1, Ayse Bahar Ercan1, Lauren Sambira1, Anne Bendel2,
Stefan Bielack3, Elisabeth Koustenis3, Deborah Blumenthal4,
Daniel Bowers5, Alberto Broniscer6, Annika Bronsema7, Sara Carroll8,
Stefano Chiaravalli9, Kristina Cole10, Shlomi Constantini4,
Rebecca Loret De Mola11, Gavin Dunn12, Charlotta Fröjd13,
David Gass14, Karen Gauvain12, Ben George15, Nobuko Hijiya16,
Lindsey Hoffman17, Jeffrey Knipstein15, Ted Laetsch5, Valérie Larouche18,
Alvaro Lassaletta19, Scott Lindhorst20, Alexander Lossos21,
Sandra Luna-Fineman17, Vanan Magimairajan22, Gary Mason23,
Warren Mason24, Maura Massimino9, Oz Mordechai25, Enrico Opocher26,
Michal Oren27, Michael Osborn28, Alyssa Reddy29, Mark Remke30,
Sumita Roy31, Magnus Sabel32, David Samuel33, Kami Schneider17,
Santanu Sen34, Duncan Stearns35, David Sumerauer36, Gregory Thomas11,
Patrick Tomboc37, An Van Damme38, Margaret Wierman39,
Ira Winer40, Lee Yi Yen41, Michal Zapotocky36, David Ziegler42,
Stefanie Zimmermann43, Rina Dvir4, Gidi Rechavi27, Carol Durno1,
Melyssa Aronson44, Michael Taylor1, Peter Dirks1, Trevor Pugh45,
Adam Shlien1, Cynthia Hawkins1, Daniel Morgenstern1, and Uri Tabori1;
1The Hospital for Sick Children, Toronto, ON, Canada, 2Children’s
Minnesota Minneapolis Hospital, Minneapolis, MN, USA, 3Klinikum
Stuttgart-Olgahospital, Stuttgart, Germany, 4Tel-Aviv Sourasky Medical
Center, Tel-Aviv, Israel, 5UT Southwestern Medical Centre, Dallas, TX,
USA, 6St. Jude’s Children’s Research Hospital, Memphis, TN, USA,
7University Medical Centre of Hamburg-Eppendorf, Hamburg, Germany,
8Cleveland Clinic Florida, Weston, FL, USA, 9Fondazione IRCCS Istituto
Nazionale dei Tumori, Milan, Italy, 10Children’s Hospital of Philadelphia,
Philadelphia, PA, USA, 11Oregon Health & Science University, Portland,
OR, USA, 12Washington University School of Medicine, St, Louis, MO,
USA, 13Västra Götalandsregionen, Vänersborg, Sweden, 14Carolinas
Healthcare System, Charlotte, NC, USA, 15Medical College of Wisconsin,
Milwaukee, WI, USA, 16Ann and Robert H, Lurie Children’s Hospital of
Chicago, Chicago, IL, USA, 17Children’s Hospital of Colorado, Aurora,
CO, USA, 18Centre Mère-Enfant Soleil du CHU de Québec, Sante-Foy,
QC, Canada, 19Hospital Infantil Universitario Niño Jesús, Madrid, Spain,
20Medical University of South Carolina, Charleston, SC, USA, 21Hadassah
Medical Organization, Jerusalem, Israel, 22Cancer Care Manitoba,
Winnipeg, MB, Canada, 23Children’s Hospital of Pittsburg of UPMC,
Pittsburgh, PA, USA, 24Princess Margaret Hospital, Toronto, ON, Canada,
25Rambam Academic Hospital, Haifa, Israel, 26Università Degli Studi diMilano, Milan, Italy, 27The Chaim Sheba Medical Center, Tel HaShomer,
Israel, 28Women’s and Children’s Hospital, North Adelaide, Australia,
29UCSF Benioff Children’s Hospital, San Francisco, CA, USA, 30University
Hospital Düsseldorf, Dusseldorf, Germany, 31Children’s Hospital of
Michigan, Detroit, MI, USA, 32Queen Silvia Children’s Hospital, Göteborg,
Sweden, 33Valley Children’s Hospital, Madera, USA, 34Kokilaben
Dhirubhai Ambani Hospital, Mumbai, India, 35Rainbow Babies andChildren’s Hospital, Cleveland, OH, USA, 36FN Motol, Prague, Czech
Republic, 37West Virginia University Children’s Hospital, Morgantown,
WV, USA, 38Saint Luc UCL, Brussels, Belgium, 39University of Colorado(UCHealth), Aurora, CO, USA, 40Wayne State University, Detroit, MI, USA,
41Taipei Veterans General Hospital, Taipei City, Taiwan, 42Kids Cancer
Centre, Randwick, Australia, 43Universitätsklinikum Frankfurt, Frankfurt,
Germany, 44Mount Sinai Hospital, Toronto, ON, Canada, 45Princess
Margaret Cancer Centre, Toronto, ON, Canada
Pediatric brain tumors with replication repair deficiency (RRD) are
hypermutant and may respond to immune checkpoint inhibition (ICI).
We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinallyon all patients. Biomarkers included tumor mutational burden (TMB),
neoantigens and genetic signatures obtained from whole genome andexome sequencing. Immune inference was obtained by RNAseq and T
cell rearrangement was collected in the tumor and in blood throughout
treatment. Of the 46 tumors on the study, 32 were brain tumors withglioblastoma in 96%. Rapid, objective responses (>50%) were observedin 50% of glioblastomas. Three year overall survival for the whole cohort was 48+/-8% which compares favorably with historical controls.
Brain tumors fared worse with OS of 39+/-10% and late recurrences
observed even after 2 years of therapy (p=0.02). Tumor size and acute“flare” constitute poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens correlatedwith response to ICI (p=0.02). Specific signatures extracted from SNVs
and total mutations predicted response to ICI and favorable outcome(p=0.005). RNA inference and TCR reveal that the FLARE phenotype
is mostly acute nonspecific immune response and not true progression.
Finally, glioblastomas (n=8) which failed single agent ICI had favorable
responses to combinational immunotherapies with prolonged survivalof 65%+/-8% at one year after failure vs 0 for other patients (p=0.01).
RRD glioblastomas exhibit favorable outcome and responses to ICI.
Combinational therapies based on tumor and immune signatures ofthese cancers are necessary.

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IMMU-19. HDAC INHIBITORS SENSITIZE MYC-AMPLIFIEDMEDULLOBLASTOMA TO IMMUNOTHERAPY BY ACTIVATINGTHE NF-KB PATHWAYS
Viktoria Marquardt1, Johanna Theruvath2, David Pauck1, Daniel Picard1,
Guido Reifenberger1, Arndt Borkhardt3, Samuel Cheshier4, Thomas Kurz1,
Marc Remke1, and Siddhartha Mitra5; 1Heinrich Heine University,
Dusseldorf, Germany, 2Stanford University, Stanford, CA, USA, 3Heinrich
Heine University Düsseldorf, Dusseldorf, Germany, 4Huntsman Cancer
Institute, Salt Lake City, UT, USA, 5University of Colorado School of
Medicine, Denver, CO, USA
Medulloblastoma is the most common malignant brain tumor in childhood and comprises four distinct molecular subgroups with further layersof intertumoral heterogeneity. Amplification of the oncogene MYC drives
tumorigenesis and constitutes a hallmark feature underlying Group 3 biology.
Employing our in-house drug screening pipeline, we evaluated a library of
epigenetic inhibitors (n=78) in various brain tumor cell lines followed by a secondary HDACi library (n=20) screen, we identified the clinically established,class I selective HDACi CI-994 as the compound with the most preferential
antitumoral effect in MYC-driven medulloblastoma. We confirmed that the
inhibitor response was in part MYC-dependent as our lentiviral-based MYCoverexpression model showed higher sensitivity towards CI-994 treatment
as compared to the isogenic control with low endogenous MYC expression.
CI-994 showed significant antitumoral effects at the primary site and at themetastatic compartment in two orthotopic mouse models of MYC-driven
medulloblastoma. RNA sequencing profiling of tumor cells treated with
CI-994 at IC50 revealed an up-regulation of multiple innate inflammatory
pathways like NFκB, TLR4, Interferon-gamma, and TGFbeta. Flow cytometry
analysis revealed an increased surface expression of MHC-I. We combined
CI-994 with an anti-body against the innate checkpoint CD47 which acts as
a “don’t eat me” signal previously shown by us to have significant anti-tumor
activity against MYC-driven MB. Combining CI-994 with anti-CD47 shows asignificant increase in macrophage-mediated phagocytosis of tumor cells anda significant increase in the survival of tumor-bearing mice.
IMMU-20. EVALUATION OF CAR T CELLS IN EPENDYMOMA
Anandani Nellan, Andrew Donson, Jacob Calhoun, Andrea Griesinger,
Terry Fry, and Nicholas Foreman; University of Colorado, Denver, CO,USA
BACKGROUND: Ependymoma is the third most common pediatricbrain tumor and current treatment still results in a 10-year relapse rateof over 70% in the highest risk groups. The treatment refractory natureof ependymoma to standard therapies strongly supports the developmentof novel interventions. Ependymoma tumor cells express HER2 and there
are active clinical trials treating children with ependymoma using local delivery of second-generation HER2 CAR T cells. METHODS: Two high-riskpatient-derived ependymoma cell lines, MAF811 and MAF928, that display
HER2 surface expression are used for testing. We tested second-generation
HER2-BBz CAR T cells in vitro and in vivo. RESULTS: HER2 CAR T cells
effectively kill ependymoma tumor cells in culture, but this strategy cannot
eradicate the same tumor cells in mice when implanted in the fourth ventricle of the brain. HER2 CAR T cells proliferate and traffic into the tumor,
but this causes a dramatic influx of immune cells, tumor swelling and lethal
toxicity in a subset of mice. Mice that survive this initial tumor swelling,
display significant tumor shrinkage but all tumors eventually start growing
again. Ependymoma tumor cells release high amounts of inflammatory
chemokines that strongly attract neutrophils and monocytes to the tumor,
compared to other brain tumors, and can downregulate HER2 expression toescape recognition by CAR T cells. CONCLUSION: The immunosuppressive microenvironment as well as tumor heterogeneity make HER2 CAR T
cells ineffective in ependymoma. Studying these two hurdles in CAR T celltherapy is critical to effectively treat brain tumors with CAR T cells.
IMMU-21. INVESTIGATION OF WHITE BLOOD CELL
CHARACTERISTICS IN CSF SAMPLES AT PEDIATRIC BRAIN
TUMOR DIAGNOSIS
Hunter Greer1, Kristen Campbell2, Sadaf Samay3, and Adam Green1; 1The
Morgan Adams Foundation Pediatric Brain Tumor Research Program,
University of Colorado School of Medicine/Children’s Hospital Colorado,
Aurora, CO, USA, 2Department of Pediatrics, School of Medicine
University of Colorado, Aurora, CO, USA, 3Research Informatics,
Children’s Hospital Colorado, Aurora, CO, USA
BACKGROUND: There has been a recent surge in investigation of
immunity and immunotherapy, but their role in pediatric brain tumors is
incompletely defined. We hypothesized that investigating an understudied
dataset, WBC and differential results in CSF drawn at the time of pediatricbrain tumor diagnosis to look for microscopic metastases, would provide insight into the role of immunology and potential for immunotherapy in these
diseases and correlate with prognosis and/or metastasis. METHODS: We
conducted a retrospective comparison analysis of CSF values in 349 pa-

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De c e mb e r 2 0 2 0tients at our institution from samples drawn within 60 days of initial CNS
tumor diagnosis from 1998–2018. We examined total nucleated cell count,absolute counts and percentages for WBC subtypes. We compared CSF
values by tumor cell presence, patient vital status, and disease group: atypical teratoid rhabdoid tumor, ependymoma, germinoma, high-grade glioma(HGG), low-grade glioma (LGG), medulloblastoma, non-germinomatous
germ cell tumor, and other embryonal tumors (OET). We used Wilcoxon andKruskal-Wallis tests for comparisons. RESULTS: Overall, higher lymphocyte percentage (p=0.002) and lower monocyte percentage (p=0.007) wereassociated with survival. WBC characteristics did not differ significantly
based on tumor cell presence. Compared to medulloblastoma, ependymoma
showed a more active CSF immune response, while LGG, HGG, and OET
showed a less active response, based on total WBC and/or absolute neutrophil count (p=0.001–0.007). CONCLUSIONS: Higher lymphocyte andlower monocyte percentages in CSF correlated with better prognosis overall;causality requires further investigation. Tumor subtypes varied in their immune stimulation, offering potential insight into which will be amenable toimmunotherapy.
IMMU-22. PHASE IB IMMUNOTHERAPY CLINICAL TRIAL WITH
THE USE OF AUTOLOGOUS DENDRITIC CELLS PULSED WITH AN
ALLOGENIC TUMORAL CELL LINES LYSATE IN PATIENTS WITH
NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA(DIPG)
Andres Morales La Madrid1, Jaume Mora1, Ofelia Cruz2,
Vicente Santa-Maria Lopez2, Sara Perez-Jaume2, Antonio Guillen2,
Sonia Paco2, Angel M Carcaboso2, Patricia Puerta2, Noelia Salvador2,
Manuel Juan3, Daniel Benitez-Ribas4, Raquel Cabezon4,
Georgina Flórez-Grau4, and Mari Carmen Molero2; 1Hospital Sant
Joan de Deu, Barcelona, Barcelona, Spain, 2Hospital Sant Joan de Deu,
Barcelona, Spain, 3Hospital Sant Joan de Déu-Clinic, Barcelona, Spain,
4Hospital Clinic, Barcelona, Spain
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a lethal
condition, and therefore novel approaches are needed. Monocyte-derived
dendritic cells (mDCs) pulsed with tumor antigens, as professional antigenpresenting cells, are a promising strategy for immunotherapy of invasive
brain tumors. METHODS: Our Ib pilot study explored the use of immunotherapy with mDCs for the treatment of newly diagnosed DIPG. Patient´s
mDCs were extracted after irradiation and were primed with an allogenic
tumor lysate from five patients with K27M-mutated DIPGs. The principal
goal of this study was to establish the feasibility and safety of the intradermic
administration of these mDC vaccines in patients with DIPG. In the absenceof progression, patients received maintenance boosts of tumor lysate. Additionally, we evaluated the non-specific and antitumoral immune response
generated in peripheral blood mononuclear cells (PBMC) and in cerebrospinal fluid (CSF) cells. RESULTS: Nine patients were included in the study(2016–2018). Vaccines fabrication was feasible and administered in all cases
without grade 3 or 4 toxicities. KLH (9/9 patients) and antitumor (8/9 patients) specific responses were identified in PBMC. Immunological responses
were also confirmed in T-lymphocytes from the CSF of two patients. Twentyfour month overall survival and progression free survival was 33.3% (95 %CI 13.2% to 84.0 %) and zero, respectively. DISCUSSION: These results
demonstrate that mDC vaccination is feasible, safe, and generates a DIPGspecific immune response detected in PBMC and CSF. There was a trend in
improved OS when compared to historic controls. This strategy shows apromising immunotherapy backbone for future combination schemas.
IMMU-23. A NOVEL MASS CYTOMETRY-BASED MULTIPARAMETER CHARACTERIZATION OF NEOANTIGEN-REACTIVE
CD8+ T-CELLS IN PATIENTS PARTICIPATING IN PNOC007
H3.3K27M PEPTIDE VACCINE CLINICAL TRIAL
Jared Taitt1, Takahide Nejo1, Payal Watchmaker1, Neil Almeida1,
Kaori Okada1, Maryam Shahin1, Ryan Gilbert1, Annette Molinaro1,
Michael Prados1, Sabine Mueller1,2, and Hideho Okada1,3; 1University ofCalifornia, San Francisco, San Francisco, CA, USA, 2University Children’s
Hospital, Zurich, Switzerland, 3Parker Institute for Cancer Immunotherapy,
San Francisco, CA, USA
BACKGROUND: We have identified an HLA-A*02:01-restricted
neoantigen epitope encompassing the H3.3K27M mutation and implemented a multi-center clinical trial of the peptide vaccine through the Pacific
Pediatric Neuro-Oncology Consortium (PNOC007) for patients with diffuse
midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG).
We sought to characterize vaccine-reactive CD8+T-cells subpopulations
using their precise activation and developmental status to find their associations with clinical outcomes. METHODS: Mass cytometry (CyTOF)
analysis was performed on patient-derived peripheral blood mononuclear
cells collected at baseline as well as pre-specified time points throughout
the study. Each cell subtype was characterized via tSNE-clustering based on
their expression profiles and quantified as a fraction of total CD45+cells.
H3.3K27M-reactive CD8+T-cells were evaluated using an H3.3K27M-

Abstracts

HLA-A2 dextramer along with a panel of T-cell and myeloid markers. RESULTS: Among all 29 patients enrolled, we analyzed samples from all 19
DIPG and 9 of 10 non-brainstem DMG cases, of which 18 had longitudinalsamples available (range: 2–5). Utilizing a novel CyTOF-based immunomonitoring platform, the expansion of H3.3K27M-reactive CD8+T-cells,
defined as a 25% increase at any time-point relative to baseline, was observed in 7 of these 18 patients. Survival analyses indicated that the expansion of H3.3K27M-reactive CD8+T-cells, particularly the effector-memory
phenotype, positively correlated with longer overall survival (OS) (median:
16.1 vs 9.7 months, p=0.03), whereas an abundance of early and monocytic
myeloid-derived suppressor cells at baseline correlated with shorter OSamong DIPG patients (9.5 vs 14.3 months, p=0.002). CONCLUSION: Ournovel immuno-monitoring approach offers insight into how vaccine-induced
immune responses impact clinical outcomes.
IMMU-26. DISEASE CONTROL IN A PEDIATRIC PATIENT WITH
NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) AND
SOMATIC HIGH MICROSATELLITE INSTABILITY (MSI-H) WITH
PD-1 INHIBITOR NIVOLUMAB (NIVO) ONLY AND NO FOCALRADIOTHERAPY (RT)
Trisha Larkin1, Jason Blatt2, and Sridharan Gururangan2; 1University of
Florida, Gainesville, FL, USA, 2Preston A. Wells Center for Brain Tumor
Therapy, UF Health Shands Hospital, Gainesville, FL, USA
Immune checkpoint inhibitors that target programmed death receptor-1(PD-1) have recently been shown to be a promising option for the management of recurrent mismatch repair (MMR) deficient GBM following radiotherapy. We report a case of a 9-year-old boy who presented with a 6 weekhistory of frontal headaches and was found to have a left frontal lobe mass.
Pathology obtained from a gross total resection (GTR) was consistent withclassic GBM, WHO Grade IV. Neuroimaging four weeks following initialresection was remarkable for local recurrence. The patient underwent another GTR of the tumor at our center. While pathology again confirmed
GBM, GlioSequencing of tumor tissue from second resection showed MSIH, NF2 mutation p.R338H, NF1 mutations p.R2450* and pI193Yfs*11,
TP53 mutations p.R213* and p.R273C, EGFR mutation, and multiple variants of uncertain significance. Germline testing was negative for MMR deficiency or other deleterious mutations. Parents opted to defer radiotherapy
and consented to monotherapy treatment with Nivolumab (Opdivo, BMS
pharmaceuticals, USA), a PD-1 inhibitor, at a dose of 3 mg/kg administered
every two weeks. Our patient is now 22 months post-second resection andcontinues to receive Nivolumab without evidence of recurrent disease or
adverse autoimmune effects from PD-1 blockade. He has remained in schoolwith good academic performance and has exhibited no regression of functional status during the entirety of his treatment course. This case provides
evidence of possible efficacy of PD-1 blockade without focal radiotherapy inthis child with GBM and somatic MSI instability.
IMMU-27. ANALYSIS OF IMMUNE SIGNATURES IN PEDIATRICGLIOBLASTOMAS FOR PATIENT STRATIFICATION TO
IMMUNOTHERAPY
Vidyalakshmi Chandramohan1,2, Tyler Evangelous3, Eric S. Lipp1,
Bhavna Hora3, Darell D. Bigner1,2, Roger E. McLendon1,4, andDavid M. Ashley1,2; 1The Preston Robert Tisch Brain Tumor Center,
Duke University Medical Center, Durham, NC, USA, 2Department of
Neurosurgery, Duke University Medical Center, Durham, NC, USA,
3Department of Medicine and Duke Human Vaccine Institute, Duke
University Medical Center, Durham, NC, USA, 4Department of Pathology,
Duke University Medical Center, Durham, NC, USA
BACKGROUND: Pediatric glioblastoma (pGBM), despite being relatively rare (incidence rate: 0.5/100,000), are a leading cause of cancer deathsin children with a median overall survival of 9–15 months. In recent years,
immunotherapy has emerged as one of the more promising advances in oncology, with impressive response rates reported in several malignancies. Effective application of immunotherapy in brain tumors depends upon a better
understanding of the immune cell phenotype and mechanisms of immunosuppression in these tumors. This understanding will allow for the selectionof patient population who are most likely to benefit from immunotherapeutic
approaches. MATERIAL AND METHODS: In order to determine the frequency, distribution, and phenotype of tumor-infiltrating immune cells in
pGBMs, we undertook an immunohistochemical survey on 19 recurrent
pGBMs for CD3, CD8, CD4, CD163, PD-1, PD-L1, and FoxP3; RNA-Seq
was also performed on a subset of 9 cases. Distribution of lymphocytes(LYMPHS) was recorded as intratumoral (IT) or perivascular (PV). RESULTS: The analysis indicates intratumoral CD3+ LYMPHS are commonly<5% of tumor cell mass; however, approximately half (10/19) of these recurrent pGBM have infiltrates that range from 5 to 30% CD3+ LYMPHS. Of
these, 4/10 CD3+ tumors exhibit brisk CD8+ infiltrates that are associatedwith PD-L1+ tumor cells. These tumors with brisk CD3+/CD8+ LYMPHS
and PD-L1+ tumor cells were associated with longer survivals. The data

were confirmed by RNA-seq analysis. CONCLUSION: PD-L1+ pGBMs associated with CD3+/CD8+ LYMPH infiltrates deserve further investigationas candidates for immunotherapy.
IMMU-28. IMMUNOGENOMIC ANALYSIS REVEALS LGALS1CONTRIBUTES TO THE IMMUNE HETEROGENEITY AND
IMMUNOSUPPRESSION IN GLIOMA
Qun Chen1, Jinquan Cai2, Bo Han3, and Xiangqi Meng2; 1Department of
Neurosurgery, The First Affiliated Hospital, College of Medicine, Zhejiang
University, Hangzhou, China, 2Department of Neurosurgery, the Second
Affiliated Hospital of Harbin Medical University, Harbin, China, 3Beijing
Neurosurgical Institute Department of Neurosurgery Beijing Tiantan
Hospital Capital Medical University, Beijing, China
Mutualistic and dynamic communication between tumour cells andthe surrounding microenvironment accelerates the initiation, progression,
chemoresistance and immune evasion of glioblastoma (GBM). However,
the immunosuppressive mechanisms of GBM has not been thoroughly elucidated to date. We enrolled six microenvironmental signatures to identify
glioma microenvironmental genes. The functional enrichment analysis suchas ssGSEA, ESTIMATE algorithm, Gene Ontology, Pathway analysis is conducted to discover the potential function of microenvironmental genes. In
vivo and in vitro experiments are used to verify the immunologic function of
LGALS1 in GBM. We screen eight glioma microenvironmental genes fromglioma databases, and discover a key immunosuppressive gene (LGALS1
encoding Galectin-1) exhibiting obviously prognostic significance among
glioma microenvironmental genes. Gliomas with different LGALS1 expression have specific genomic variation spectrums. Immunosuppression isa predominate characteristic in GBMs with high expression of LGALS1.
Knockdown of LGALS1 remodels the GBM immunosuppressive microenvironment by down regulating M2 macrophages and myeloid-derived
suppressor cells (MDSCs), and inhibiting immunosuppressive cytokines.
Our results thus implied an important role of microenvironmental regulation in glioma malignancy and provided evidences of LGALS1 contributing
to immunosuppressive environment in glioma and that targeting LGALS1
could remodel immunosuppressive microenvironment of glioma.
IMMU-29. AIF1 IS A PROGNOSTIC BIOMARKER AND
CORRELATED WITH IMMUNE INFILTRATES IN GLIOMASYi Chai, Wei Liu, Junhua Wang, Libo Hu, and Yuqi Zhang; Departmentof Neurosurgery, Yuquan Hospital, School of Clinical Medicine, Tsinghua
University, Beijing, China
Gliomas remain highly variable clinical behaviors, leading to emerging
studies to identify prognostic factors. AIF1 (Allograft Inflammatory Factor
1) is critical for promoting both macrophage- and dendritic cells (DCs)mediated inflammatory response and growth of vascular smooth muscle
cells and T-lymphocytes. Through comparative analyses of primary LGG patients from The Cancer Genome Atlas (TCGA) dataset and Chinese Glioma
Genome Atlas(CGGA) dataset, we reported that the expression level andmethylation level of AIF1 gene vary among glioma patients and AIF1 expression or gene body methylation is significantly associated with glioma patient
survival. Cox regression results confirmed that AIF1 played an independent
predictor of survival in lower-grade glioma(LGG), with a cox coefficient of0.251 indicating a worse prognosis. Moreover, AIF1 expression was positively correlated with infiltrating levels of CD4+ T and B cells, macrophages,
neutrophils, and DCs in LGG and glioblastoma(GBM). AIF1 expression also
showed strong correlations with specific immune cell markers in LGG and
GBM. In addition, AIF1 expression potentially contributed to the regulationof glioma-associated macrophages and microglia. In conclusion, our findings
suggested that AIF1 was correlated with prognosis and immune infiltratinglevels, and it can be used as a prognostic factor in gliomas.
IMMU-30. UPREGULATED T CELL AND INTERFERON-Γ-RELATEDGENE EXPRESSION IS ASSOCIATED WITH INCREASED SURVIVALIN RECURRENT PEDIATRIC HIGH-GRADE GLIOMATom Davidson1,2, Willy Hugo3, Anthony Wang4, Jiyoon Kim5,6, Gang Li7,8,
and Robert Prins9,4; 1Cancer and Blood Disease Institute and Division of
Hematology-Oncology, Children’s Hospital Los Angeles, Los Angeles, CA,
USA, 2Keck School of Medicine, University of Southern California, Los
Angeles, CA, USA, 3Division of Dermatology, Department of Medicine,David Geffen School of Medicine, University of California, Los Angeles,
Los Angeles, CA, USA, 4Department of Neurosurgery, David Geffen Schoolof Medicine, University of California, Los Angeles, Los Angeles, CA, USA,
5Jonsson Comprehensive Cancer Center, University of California, Los
Angeles, Los Angeles, CA, USA, 6Department of Biostatistics, Fielding
School of Public Health, University of California, Los Angeles, Los Angeles,
CA, USA, 7Jonsson Comprehensive Cancer Center, University of California,
Los Angeles, Los Angeles, California, USA, 8Department of Biostatistics,
Fielding School of Public Health, University of California, Los Angeles,

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Los Angeles, California, USA, 9Department of Medical and Molecular
Pharmacology, David Geffen School of Medicine, University of California,
Los Angeles, Los Angeles, CA, USA
Recurrent pediatric high-grade glioma (pHGG) is the leading cause ofcancer-related mortality in children. Immunotherapy is a successful treatment approach for a growing number of cancers and is being investigatedas a treatment strategy for pHGG. Immunotherapy has shown the mostbenefit in tumors with increased infiltrating T cells at baseline. Our recently published results revealed that neoadjuvant checkpoint inhibition inrecurrent adult glioblastoma was associated with upregulation of a T celland interferon-γ-related gene expression signature (Tcell-IFNγGES) andwas correlated with a significantly extended overall survival (OS). In thisstudy, we examined the immune landscape in recurrent pHGG and the association of Tcell-IFNγGES in the tumor with survival. We analyzed tumor
RNAseq data collected at time of recurrence from a historical cohort of 42
pHGG patients from the Children’s Brain Tumor Tissue Consortium. We
found a significant transcriptional enrichment of Tcell-IFNγGES in 54%
of the tumors. The survival of patients with high Tcell-IFNγGES was observed to be significantly higher than patients with low Tcell-IFNγGES,(log-rank p=0.05). The 3-year OS for patients with low versus high TcellIFNγGE was 28.5% (95%, CI:13.7%-59.5%) compared to 50.2% (95%,
CI:33.1%-76.1%). When patients were stratified by age, gender and race,
low Tcell-IFNγGES was found to be a poor OS prognostic factor (hazard
ratio=2.4 (1.14–5.14), p=0.02). This indicates a strong relationship ofdecreased Tcell-IFNγGES and increased risk of death. Future investigations are necessary to validate these findings, and to explore the value of
Tcell-IFNγGES as a predictive biomarker for response to immunotherapy
in pHGG.
IMMU-31. PNOC007: H3.3K27M SPECIFIC PEPTIDE VACCINECOMBINED WITH POLY-ICLC FOR THE TREATMENT OF NEWLYDIAGNOSED HLA-A2+ H3.3K27M DIFFUSE MIDLINE GLIOMAS(DMG)
Sabine Mueller1, Jared Taitt1, Erin Bonner2, Rishi Lulla3,
Stewart Goldman4, Anu Banerjee1, Susan Chi5,
Nicholas S. Whipple6, John Crawford7, Karen Gauvain8, Kellie Nazemi9,Payal Watchmaker1, Takahide Nejo1, Kaori Okada1, Lisa H. Butterfield1,
Javad Nazarian10, Javier Villaneuva-Meyer1, Annette M. Molinaro1,
Michael Prados1, and Hideho Okada1; 1University of California, San
Francisco, San Francisco, CA, USA, 2Children’s National, Washington, DC,
USA, 3Hasbro Children’s Hospital, Providence, RI, USA, 4Ann & Robert
H, Lurie Children’s Hospital of Chicago, Chicago, IL, USA, 5Dana-Farber
Cancer Institute, Boston, MA, USA, 6University of Utah, Salt Lake City,
UT, USA, 7University of California, San Diego, San Diego, CA, USA,
8Washington University School of Medicine, St, Louis, MO, USA, 9Oregon
Health & Science University, Portland, OR, USA, 10Children’s Hospital
Zurich - Eleonore Foundation, Zurich, Switzerland
OBJECTIVE: To assess safety and efficacy within a multi-center trial
the H3.3K27M specific peptide vaccine with poly-ICLC in HLA-A02.01+
patients diagnosed with H3.3K27M+ DMGs. METHODS: After focalradiation therapy, participants 3–21 years of age were enrolled into
two strata. Stratum A: newly diagnosed diffuse intrinsic pontine glioma(DIPG); Stratum B: other DMGs. H3.3K27M vaccine was administeredwith poly-ICLC IM every 3 weeks for 8 doses followed by every 6 weeks
for a total of 96 weeks. Immuno-monitoring of peripheral blood mononuclear cell (PBMC) and imaging occurred every 3 months. Modified
iRANO criteria were applied. PBMC samples were evaluated by mass
cytometry. RESULTS: From November 2016 until March 2019, 19 eligible patients (median age 11, range 5–17 yrs; 53 % female) were enrolledin Stratum A and 10 eligible patients (median age 13, range 7–18 yrs; 60% female) in Stratum B. Treatment was well tolerated (7 grade 3; 0 grade
4 related toxicities). Median number of vaccines per participant was 6(range 1–11). Overall survival at 12 months was 40% (95% CI 22–73%)
for Stratum A and 39% (95% CI 16–93%) for Stratum B. Among the 19
subjects with longitudinal immune cell assessments, 7 exhibited an expansion of K27M-reactive CD8+ effector memory T-cells correlating withprolonged survival (p=0.028). CONCLUSION: H3.3K27M specific vaccine in combination with poly-ICLC is well tolerated. CyTOF-based immune monitoring of PBMCs facilitates sensitive high-throughput analysis.
Further investigation is warranted to determine if this may be predictiveof clinical outcomes.

LOW GRADE GLIOMA
LGG-01. CLINICAL MANAGEMENT AND GENOMIC PROFILING OFPEDIATRIC LOW-GRADE GLIOMAS IN SAUDI ARABIA
Nahla A. Mobark1, Musa Alharbi1, Ali Abdullah O. Balbaid2,
Lamees Al-Habeeb3, Latifa AlMubarak3, Rasha Alaljelaify3,

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De c e mb e r 2 0 2 0Mariam AlSaeed3, Amal Almutairi3, Fatmah A Alanazi4, Yara Bashawri5,
Maqsood Ahmad6, Ayman Al-Banyan6, Fahad E. Alotabi6, Duna Barakeh7,
Malak AlZahrani7, Hisham Al-Khalidi7, Abdulrazag Ajlan7,
Lori A. Ramkissoon8, Shakti H. Ramkissoon9, and Malak Abedalthagafi3;
1Department of Paediatric Oncology Comprehensive Cancer Centre,
King Fahad Medical City, Riyadh, Saudi Arabia, 2Radiation oncology
department Comprehensive Cancer Centre, King Fahad Medical City,
Riyadh, Saudi Arabia, 3Genomics Research Department, Saudi Human
Genome Project, King Fahad Medical City and King Abdulaziz City for
Science and Technology, Riyadh, Saudi Arabia, 4Department of ClinicalPharmacy, King Fahad Medical City, Riyadh, Saudi Arabia, 5Departmentof Biostatistics, Research Centre, King Fahad Medical City, Riyadh, Saudi
Arabia, 6Department of Neurosurgery, King Fahad Medical City, Riyadh,
Saudi Arabia, 7Department of Pathology, King Khalid Hospital, King Saud
University, Riyadh, Saudi Arabia, 8Department of Neurosurgery, Universityof North Carolina School of Medicine, Chapel Hill, NC, USA, 9Wake
Forest Comprehensive Cancer Center and Department of Pathology, Wake
Forest School of Medicine, Winston-Salem, NC, USA
Pediatric Low Grade Gliomas (PLGGs) display heterogeneity regarding
morphology, genomic drivers and clinical outcomes. The treatment modality
dictates the outcome and optimizing patient management can be challenging. In this study, we profiled a targeted panel of cancer-related genes in 37
Saudi Arabian patients with pLGGs to identify genetic abnormalities that
can inform prognostic and therapeutic decision-making. We detected genetic
alterations (GAs) in 97% (36/37) of cases, averaging 2.51 single nucleotide variations (SNVs) and 0.91 gene fusions per patient. The KIAA1549BRAF fusion was the most common alteration (21/37 patients) followed by
AFAP1-NTRK2 (2/37) and TBLXR-PI3KCA (2/37) fusions that were observed at much lower frequencies. The most frequently mutated) genes were
NOTCH1 3 (7/37), ATM (4/37), RAD51C (3/37), RNF43 (3/37), SLX4
(3/37) and NF1 (3/37). BRAF V600E mutations were observed in only 2/37
patients, while H3F3A (K27M) histone mutations were not detected. Interestingly, we identified a GOPC-ROS1 fusion in an 8-year-old patient whose
tumor lacked BRAF alterations and histologically classified as low grade
glioma. The patient underwent gross total resection (GTR) currently he isdisease free. To our knowledge this is the first report of GOPC-ROS1 fusionin PLGG which may represent a genomically-distinct subgroup of pLGGs
that could be targeted with oral target therapy crizotinib. Taken together, we
reveal the genetic characteristics of pLGG Saudi patients can enhance diagnostics and therapeutic decisions. In addition, we identified a GOPC-ROS1
fusion that may be a biomarker for pLGG. Our study proves the possibilityof using genetic profiling to guide optimal treatment strategies for pLGG in
Saudi population
LGG-02. A BRAIN TUMOR DIAGNOSED AFTER TRANSITION TO
THE DEPARTMENT OF ADULT NEUROSURGERY FROM THE
DEPARTMENT OF PEDIATRICS
Yasushi Shibata; University of Tsukuba, Mito, Ibaraki, Japan
The patient was a 17-year-old boy with a history of 4 non-febrile convulsions at 15 and 16 years of age. He visited the Department of Pediatrics at a pediatric hospital. An electroencephalogram showed right frontal
spike discharge. MRI was performed and judged to show no abnormality.
The pediatric doctor diagnosed him with epilepsy. At 17 years old, he wasreferred to our Department of Adult Neurosurgery for transition. Physical and neurological examinations showed no abnormalities. Brain MRI
showed right frontal cortical small tumor, with T1 low, T2 high, diffusionweighted imaging low, and partial contrast enhancement. We diagnosed him
with a brain tumor and symptomatic epilepsy. We surgically removed a rightfrontal cortical tumor. A pathological examination finalized the diagnosis ofdysembryoplastic neuroepithelial tumor. MRI confirmed the total removalof the tumor. Anticonvulsant was started before surgery. No epileptic seizure
was observed, so the anticonvulsant medication was gradually tapered andstopped at two years after the surgery. No epilepsy nor recurrence has been
observed thus far. The problem with the initial management of this case at
the Department of Pediatrics in the pediatric hospital was that the brain
tumor was missed despite an MRI examination. Had the transition nothappened, this brain tumor might not have been diagnosed. A brain tumor
is a rare disease, and epilepsy is a common disease. However, in cases of
non-febrile convulsion, a brain tumor should be considered. Collaboration
within a single department, hospital and local area should be established.
LGG-03. INCIDENCE AND OUTCOME OF PEDIATRIC IDHMUTANT GLIOMA
Kee Kiat Yeo, Sanda Alexandrescu, Chantel Cacciotti, Emily Krzykwa,
Jessica Clymer, Christine Chordas, Mary Ann Zimmerman, Susan Chi,
Katherine Warren, and Karen Wright; Dana Farber / Boston Children’s
Cancer and Blood Disorder Center, Boston, MA, USA
INTRODUCTION: The incidence of IDH mutations in pediatric glioma
is unclear. Recent publications suggest rates ranging between 0–20%.

Abstracts

Therapy poses challenges as it is unclear if the biology and prognosis ofpediatric IDH-mutant gliomas are identical to adults. METHODS: We performed an IRB approved, systematic retrospective search for IDH-mutant
gliomas in the Dana-Farber Cancer Institute/Boston Children’s Hospital
database between 2009–2018, analyzing incidence, demographics, histology, co-occurring genetic alterations and outcome. RESULTS: We
identified 575 patients with glioma, ages 0–21 years. Of these, 394 underwent biopsy/resection (0–9 years:n=204; 10–21 years:n=190), with 294
genetic testing. Fifteen of 294 tumors (5%) were IDH1-mutant. Among
patients 0–9 years and 10–21 years, 1/156 (0.6%) and 14/138 (10%)
had IDH1-mutant tumors, respectively. Among patients 10–21 year old,
13/115 low-grade gliomas were IDH1-mutant (11%). High-grade gliomas
accounted for the remaining 23, with one IDH1-mutant glioma (4%).
Most common co-occurring genetic alterations for diffuse astrocytoma(n=12) were TP53 (n=9) and ATRX (n=2). Three patients with IDH1mutant oligodendrogliomas had 1p/19q deletion. Eleven IDH1-mutant
patients were evaluable for outcomes with median follow-up of five years.
Five-year radiation-free, progression-free and overall survival for patientswith low-grade histology were 76% and 100%, respectively. One patientwith high-grade glioma recurred 1.2 years after upfront chemo-radiationand died soon after recurrence. CONCLUSION: IDH-mutant gliomas
comprise a small proportion of pediatric gliomas. Incidence rate is higher
in the second decade of life. Comparative analyses between pediatricIDH-mutant gliomas and adult historical cohorts are currently underway,
evaluating outcomes, radiation therapy and frequency of malignant transformation.
LGG-04. A PHASE II RE-TREATMENT STUDY OF SELUMETINIBFOR RECURRENT OR PROGRESSIVE PEDIATRIC LOW-GRADE
GLIOMA (PLGG): A PEDIATRIC BRAIN TUMOR CONSORTIUM(PBTC) STUDY
Jason Fangusaro1, Arzu Onar-Thomas2, Shengjie Wu2,
Tina Young Poussaint3, Roger Packer4, Lindsay Kilburn4,
Ibrahim Qaddoumi2, Girish Dhall5, Ian F Pollack6, Alicia Lenzen7,
Sonia Partap8, Maryam Fouladi9, and Ira Dunkel10; 1Emory University andChildren’s Healthcare of Atlanta, Atlanta, GA, USA, 2St. Jude Children’s
Research Hospital, Memphis, TN, USA, 3Boston Children’s Hospital,
Boston, MA, USA, 4Children’s National Hospital, Washington, DC,
USA, 5University of Alabama at Birmingham, Birmingham, AL, USA,
6Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA, 7Lurie Children’s
Hospital, Chicago, IL, USA, 8Stanford University & Lucile PackardChildren’s Hospital, Palo Alto, CA, USA, 9Cincinnati Children’s Hospital,
Cincinnati, OH, USA, 10Memorial Sloan Kettering Cancer Center,
New York, NY, USA
The PBTC conducted a re-treatment study (NCT01089101) evaluating
selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children
with recurrent/progressive pLGG. Eligible patients must have previously
enrolled on PBTC-029 or PBTC-029B and progressed after coming offtreatment with selumetinib. Patients must have maintained stable disease(SD) for ≥12 courses or had a sustained radiographic response (partial orcomplete) during their first exposure to selumetinib. Thirty-five eligible patients (median age: 13.11 years [range 7.96–25.33]) were enrolled, 57%
of whom had optic pathway or hypothalamic target lesions. At the timeof submission, median duration of treatment was 18 courses (range 2–48)
and 21 subjects remained on therapy. Best responses reported to date are
6/35 (17%) partial response, 22/35 (63%) SD and 7/35 (20%) progressive
disease with a 2-year progression-free survival of 75.7 + 8.3%, which met
the design parameters for success. The most common attributable toxicities
were grade 1 diarrhea, elevated AST, hypoalbuminemia, elevated CPK,
maculo-papular rash, fatigue, paronychia, ALT elevation, acneiform rashand grade 2 CPK elevation. Rare grade 3 toxicities included CPK elevation (3), lymphopenia (2), paronychia (2) and ALT elevation (2). There wasonly one grade 4 CPK elevation. Five patients (14%) required dose reductions due to toxicity. There does not appear to be a notable difference intoxicities observed during initial selumetinib therapy versus re-treatment. In
pLGG that has recurred/progressed following treatment with selumetinib,
re-treatment with selumetinib appears to be effective with 80% of patients
again achieving response or prolonged stable disease. Long-term follow-up
is ongoing.
LGG-05. MOLECULAR GUIDED THERAPY FOR A PEDIATRIC LOWGRADE GLIOMA: A CASE REPORT
Jayne VonBergen, Beth Armstrong, and Morgan Schmitt; Riley Hospital forChildren, Indianapolis, IN, USA
Low grade gliomas are the most common type of central nervous system
tumors among children. Despite the fact that they are not typically life
threatening, low grade gliomas remain a significant clinical challenge. Case
Study: Patient is a 4-year-old male who presented at 20 months of age withseveral weeks of ataxia, emesis, and head tilt. Imaging revealed a right tem-poral lobe lesion; he was subsequently taken to surgery, where a gross total
resection was achieved. Imaging 9 months post resection revealed recurrent
disease within the right temporal region with leptomeningeal involvement.
Four months later imaging revealed progression of multifocal disease andnew growth within the sella. At this time the patient started standard treatment, Carboplatin and Vincristine, per CCG 9952A. Persistent slow progression was observed despite receiving standard therapy. The patient developed
a grade 3 reaction to carboplatin, worsening with each subsequent dose. At
this time, he was referred to our Precision Genomics Neuro Oncology program for tumor molecular characterization. Somatic tumor testing revealed
an ETV6-NTRK3 fusion, at which time standard treatment was stopped,
and patient began targeted therapy, Larotrectinib. Imaging was preformed
2 months post start of targeted therapy and revealed interval decrease in sizeof previously enhancing nodular lesions; findings consistent with treatment
response. Disease burden continues to decrease with therapy. This case illustrates a clear benefit of using molecular guided therapy in low grade gliomas.
LGG-06. LONG-TERM OUTCOME OF NEWLY DIAGNOSED LOW
GRADE GLIOMA
Nongnuch Sirachainan1, Attaporn Boongerd2, Samart Pakakasama1,
Usanarat Anurathapan1, Ake Hansasuta2, Duantida Songdej1,
Pongpak Pongpicha1, Mantana Dhanachai3, and Suradej Hongeng1;
1Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital,
Bangkok, Thailand. 2Department of Surgery, Faculty of Medicine
Ramathibodi Hospital, Bangkok, Thailand. 3Department of Radiology,
Faculty of Medicine Ramathibodi Hospital, Bangkok, Thailand
INTRODUCTION: Low grade glioma (LGG) is the most common central
nervous system (CNS) tumor in children accounted for 30–50%. Regarding
benign characteristic of disease, surgical management remains the mainstayof treatment. However, surgical approach is limited in some conditions suchas location at brainstem or infiltrative tumor. Chemotherapy and radiation
treatments have been included in order to control tumor progression. The
5-years survival rate is approach 90% especially in patients who receive
complete resection. However, the outcome of children with LGG in low to
middle income is limited. Therefore, the aim of the study was to determine
long-term outcome of children with newly diagnosed LGG. METHODS: A
retrospective study enrolled children aged <18 years who were newly diagnosed LGG during January 2006- December 2019. Diagnosis of LGG was
confirmed by histological findings of grade I and II according to WHO criteria. RESULTS: A total of 40 patients, female to male ratio was 1:1.35
and mean (SD) for age was 6.7 (4.0) years. The most common location was
optic chiasmatic pathway (42.5%), followed by suprasellar region (25.0%).
Sixty percent of patients received at least partial tumor removal. Chemotherapy and radiation had been used in 70% and 10.0% respectively. The
10-year progression free survival was 74.1±11.4% and overall survival was
96.2±3.8%. SUMMARY: Treatment of Pediatric LGG mainly required surgical management, however, chemotherapy and radiation had been used inprogressive disease. The outcome was excellent.
LGG-09. CORRELATING GENETIC SIGNATURE OF PILOMYXOIDASTROCYTOMAS AND PILOCYTIC ASTROCYTOMASWITH QUALITATIVE AND QUANTITATIVE MR IMAGING
CHARACTERISTICS
Sandra Abi Fadel, Zeynep Erson Omay, Armine Darbinyan,
Richard Bronen, Robert Fulbright, Amit Mahajan, and Mariam Aboian;
Yale University, New Haven, CT, USA
PURPOSE: Pilomyxoid astrocytomas are predominantly located insupra-chiasmatic region and are more clinically aggressive than pilocytic
astrocytomas, although recent WHO 2016 classification placed them into
the grade I/II category. In our study, we describe imaging correlation of PMA
to their genetic signature. MATERIALS AND METHODS: We identified
12 pediatric patients with pathologically proven PMA, PA, and PA withmyxoid features in an IRB approved study. Three of the tumors had wholeexome somatic and germline sequencing. Qualitative MRI characteristics oflocation, size, enhancement, edema, T2 and T1 intensity, and multifocality
were assessed. RESULTS: Among the PMA, 3 cases were found to have
KIAA1549-BRAF fusion, 1 case BRAF V600E mutation, and 2 cases had
wildtype BRAF. The BRAF wildtype tumors had atypical imaging featureswith intraventricular extension of tumor, involvement of frontal lobe parenchyma and one tumor demonstrating increase in size and development ofenhancement at 5 years. Whole exome sequencing of BRAF wildtype tumors
identified somatic truncation mutations in NF1 R1534X and R1513X withwildtype germline NF1 and missense mutations in KMT2C and GLTSCR1.
Among PAM, one was BRAF wildtype with mutations i PTCH1 M956V and
PTPN1 (A72V) and demonstrated atypical features of intratumoral hemorrhage on presentation. Among PA, one was positive for KIAA1549-BRAF,
one was BRAF wildtype. CONCLUSIONS: BRAF wildtype PMA and PA
demonstrate atypical tumor localization and are associated with atypicalgenetic mutations on whole exome sequencing. On the contrary, presence

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Abstractsof KIAA1549-BRAF fusion or BRAF V600E mutation within PMA and PA
correlates with classic qualitative imaging characteristics.
LGG-11. INSTITUTIONAL EXPERIENCE OF BRAF TARGETING
THERAPY
Gino Bardi Lola and Mariko Sato; Stead Family Children’s Hospital,
University of Iowa, Iowa City, IA, USA
BACKGROUND: The use of BRAF inhibitors is widely accepted in adultoncology as treatment for BRAF mutated cancers. BRAF alterations are frequently found in both pediatric low grade and high-grade gliomas, which
has opened a new door to targeted therapies for pediatric gliomas. Targeted
therapy drugs are associated with predictable patterns of adverse events.
However treating in children may potentiate unique challenges. We present
our institutional experience of targeted therapy with a focus on adverse
events. METHODS: We conducted a retrospective chart review of patientstreated with BRAF and/or MEK inhibitors between 2015–2019. RESULTS: There are nine patients treated with either MEK inhibitor(n=) orthe combination therapy(n=). The most common diagnosis was Pilocytic
astrocytoma. Targeted therapy was chosen as salvage therapy in all patients.
The most common side effect was a pruritic erythematous rash, observed in
8 out of 9 patients. Cardiac toxicity (Grade 2, n=1) and GI toxicity (Grade 3,n=1) were found in patients treated with MEK inhibitor. Both cases resulted
in cessation of therapy or significant decreased dose respectively. While twopatients died due to progression of disease and two other continued to progress, 5 patients have demonstrated stable disease while on therapy. CONCLUSIONS: Our study revealed the incidence of severe adverse events in
two patients with BRAF targeted therapy. Due to the potential life-long useof targeted therapy, it is important to follow guidelines of adverse event
monitoring and to develop a prevention and management strategy for severe
adverse events.
LGG-12. TRAMETINIB FOR PEDIATRIC LOW GRADE GLIOMAS:A SINGLE INSTITUTION EXPERIENCE
Mustafa Barbour1,2 and Michael Angelo Huang1,2; 1University ofLouisville, Louisville, KY, USA. 2Norton Children’s Cancer Institute,Louisville, KY, USA
INTRODUCTION: Low grade gliomas (LGG) are the most common
pediatric brain tumors. Tumors not amenable to resection can recur or progress despite treatment with chemotherapy and/or radiation. Recent discovery of the activation of the mitogen-activated-protein-kinase (MAPK)
pathway as the primary oncogenic driver for this group of tumors has led toa shift towards the use of BRAF and MEK inhibitors. METHODS: Herein
we performed a chart review of seven pediatric LGG treated with trametinib,a MEK inhibitor. While most were treated in the relapse setting, one patient
was treated for de novo LGG as a result of experiencing multiple severe
adverse effects to conventional agents. RESULTS: Median age was 14 years
old (range: 5 to 17 years). Six of seven patients had tissue for molecularcharacterization. The 2 patients with Neurofibromatosis Type 1 (NF-1) carried no other molecular aberrations. Two had the BRAF V600e mutation (1had a concurrent PTPN11 mutation) and 2 were positive for the KIAA1549BRAF fusion. Average duration on treatment was 8 months (range: 3 to
31 months). Disease control was achieved in 6 of 7 subjects, with one PRas best response. One patient with concurrent BRAF V600e and PTPN11
mutations progressed on trametinib and was switched to dual BRAF and
MEK inhibitor therapy. Most common toxicities were acne (57.1%), oral
mucositis (42.9%), skin rash, and paronychia (both 28.6%). Three patientsrequired dose reduction and/or intermittent dose interruption. CONCLUSION: Our data supports the use of trametinib for both upfront and relapsed/refractory pediatric LGG.
LGG-13. THE CLINICAL AND MOLECULAR LANDSCAPE OF
GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS
Julie Bennett1, Karen Fang1, Javal Sheth1, Scott Ryall1, Komosa Martin1,
Nuno Nunes1, Liana Nobre1, James Perry2, Arjun Sahgal2, Warren Mason3,
Sunit Das4, Andrew Gao3, Derek Tsang3, Lananh Nguyen4,
Normand Laperriere3, Julia Keith2, David Munoz4, Uri Tabori1, andCynthia Hawkins1; 1The Hospital for Sick Children, Toronto, ON, Canada.
2Sunnybrook Health Sciences Center, Toronto, ON, Canada. 3University
Health Network, Toronto, ON, Canada. 4St. Michael’s Hospital, Toronto,
ON, Canada
OBJECTIVE: Pediatric low grade gliomas are typically driven by MAPK
upregulation with excellent long-term survival. In contrast, adult lower
grade gliomas commonly harbor IDH-1 mutations and undergo malignant
transformation. Gliomas in adolescents and young adults (AYA) are an orphan group of tumors that have been poorly described. We aim to determine
the clinical and molecular landscape of AYA gliomas. METHODS: A multiinstitutional population based cohort of 839 patients diagnosed with gliomaiii368N EU R O - O N C O L O G Y•

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between 15–40 years has been identified. Complete molecular analysis, longterm outcome and therapeutic data are being collected. RESULTS: Of 364
AYA gliomas analyzed, the prevalence of WHO grade I tumors was highest
in those <21 years (54%), while the prevalence of higher grade tumors increased with age. Interestingly, only 38% harbor IDH-1 mutations while
23% harbor pediatric mutations, including 8% with BRAF p.V600E, and
4% with KIAA1549:BRAF fusion. The median age for IDH-1 mutation is
32 years, with highest frequency in WHO grade II and III tumors. In contrast, BRAF alterations were most frequently observed in WHO grade I andII tumors and enriched in those less than 20 years. Five-year progressionfree survival for BRAF fusion, p.V600E and IDH-1 p.R132H were 81%,78% and 26% respectively. No survivors were observed in H3 p.K27M and
p.G34R gliomas (p<0.0001). CONCLUSIONS: Gliomas in AYA overlap
pediatric and adult classification and exhibit enrichment for pediatric alterations. As the latter are associated with improved PFS and are amenable totargeted therapies, this should be considered in the work up of these tumors.
LGG-14. MULTI-OMIC ANALYSIS OF MAPK ACTIVATION IN
PEDIATRIC PILOCYTIC ASTROCYTOMA
Romain Sigaud1,2, Florian Selt1,2, Thomas Hielscher3, Nina Overbeck4,
Diren Usta1,2, Marc Remke5,6, Daniel Picard5,6, Stephan M. Pfister1,7,David T.W. Jones1,8, Tilman Brummer9, Olaf Witt1,2, and Till Milde1,2;
1Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany,
2Clinical Cooperation Unit Pediatric Oncology, German Cancer ResearchCenter (DKFZ) and German Consortium for Translational Cancer
Research (DKTK), Heidelberg, Germany, 3Division of Biostatistics,
German Cancer Research Center (DKFZ) and German Consortium forTranslational Cancer Research (DKTK), Heidelberg, Germany, 4MolecularProteomics Laboratory (MPL), Biological-Medical Research Center(BMFZ), Heinrich-Heine University Düsseldorf, Düsseldorf, Germany,
5Department of Pediatric Neuro-Oncogenomics, German Cancer ResearchCenter (DKFZ), Heidelberg, Germany, and German Consortium forTranslational Cancer Research (DKTK), partner site Essen/Düsseldorf,
Düsseldorf, Germany, 6Department of Pediatric Oncology, Hematology,
and Clinical Immunology, Medical Faculty, University Hospital
Düsseldorf, Düsseldorf, Germany, 7Division of Pediatric Neurooncology,
German Cancer Research Center (DKFZ) and German Consortium forTranslational Cancer Research (DKTK), Heidelberg, Germany, 8PediatricGlioma Research Group, German Cancer Research Center (DKFZ)and German Consortium for Translational Cancer Research (DKTK),
Heidelberg, Germany, 9Institute of Molecular Medicine and Cell Research(IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany,
Centre for Biological Signalling Studies BIOSS, University of Freiburg andGerman Consortium for Translational Cancer Research (DKTK), Freiburg,
Germany
Pilocytic astrocytomas (PA) are low-grade gliomas (pLGG) and are themost frequent childhood brain tumors. They are characterized by oncogeneinduced senescence (OIS) initiated and sustained by senescence-associatedsecretory phenotype (SASP) factors. OIS and SASP in PA are thought tobe driven by aberrations of the mitogen-activated protein kinase (MAPK)
pathway (e.g. KIAA1549:BRAF fusion, BRAFV600E mutation, for the mostcommon MAPK alterations occuring in PA), leading to its sustained activation. The MAPK pathway cascade is activated in a sequential manner:
1) ERK activation, which phosphorylates downstream partners in both cytoplasm and nucleus. 2) ERK-mediated induction of immediate early genes
encoding transcription factors. 3) Induction of MAPK target genes expression. 4) Activation of downstream pathways. Our aim is to unravel themolecular partners involved at each level of the sustained MAPK pathway
activation in pLGG with different genetic backgrounds (KIAA1549:BRAF
fusion and BRAFV600E mutation), and leading to the induction of OIS and
SASP factors expression. pLGG cell lines DKFZ-BT66 (KIAA1549:BRAF)
and BT-40 (BRAFV600E) were treated with the MEK inhibitor trametinib
at key time points, and gene expression profile analysis was performed,
allowing transcriptome analysis at each step of the MAPK cascade. This
will be combined with a whole proteomic and phospho-proteomic analysis.
Combination of the transcriptome and proteome data layers will allow theidentification of a) downstream targetable partners activated by the MAPK
pathway involved in PA senescence, b) new putative targets that might bring
benefit in combination with MAPK inhibitors.
LGG-15. PEDIATRIC LOW-GRADE GLIOMAS IN SAUDI ARABIA:RETROSPECTIVE ANALYSIS OF CHILDREN WITH LOW-GRADE
GLIOMAS TREATED IN KING FAHAD MEDICAL CITY KFMCSINGLE INSTITUTIONAL EXPERIENCE
Fahad Alammar1, Musa Alharpi1, Maqsood Ahmad2, Ayman Al-Banyan2,
Fahad E. Alotaibi2, Wafa Al Shakweer3, Malak Abedalthagafi4, andNahla Ali Mobark1; 1Department of Pediatric Oncology Comprehensive
Cancer Centre, King Fahad Medical City, Riyadh, Saudi Arabia, 2Pediatric
Neurosurgical Department, King Fahad Medical City, Riyadh, Saudi
Arabia, 3Pathology Department, King Fahad Medical City, Riyadh, Saudi

Abstracts

Arabia, 4Genomics Research Department, Saudi Human Genome Project,
King Fahad Medical City and King Abdulaziz City for Science andTechnology, Riyadh, Saudi Arabia
Pediatric Low-grade gliomas (PLGGs) are extremely heterogeneous tumors and account for approximately 35% of childhood brain tumors.
This retrospective study on 55 newly diagnosed children (<14 ys) withpathologically confirmed LGG from 2006 to 2016 aimed to review
demographic data, clinical and therapeutic aspects and treatment outcome of PLGGs in children in Saudi Arabia. RESULTS: 33 (60.0%)
males,22 (40.0%) females, median age at diagnosis 68 months. Pilocytic
astrocytoma was the most common pathological diagnosis 42 (76.4%)
location of tumor was Infratentorial in 30 patients (54.0%) andSupratentorial in 24 patients (43.2%), 19 patients (34.6%) had total
surgical excision, 10 (18.2%) subtotal resection, 20 (36.4%) partial excision and 6 (10.9%) had biopsy only; After initial Surgery 30 patients(54.5%) required adjuvant chemotherapy of whom 14 patients (46.7%)
experienced a treatment failure event, 25 patients (45.5%) who were initially observed post surgery 6 patients (24%) of them had relapse /progression and required further therapy. Only 2 patients (3.6%) received
radiotherapy due to uncontrolled progression first line chemotherapy
carboplatin and vincristine (CV) regimen was tolerated, Carboplatin allergic reactions developed in 21.1% of patients. Median follow-up of
6.49 years, the median time of relapse/ progression was 2.85 years The
5-year overall survival (OS) rates and progression free survival for all
patients were 92.2 %, and 63.3% respectively. This study was to document the outcome of pediatric LGG in Saudi Arabia and to serve as a
guideline for the future management with incorporation of molecularstudies on pediatric LGGs which may help improve the outcome for
Saudi children with LGG.
LGG-16. PILOMYXOID ASTROCYTOMA OF THE CERVICAL SPINAL
CORD IN A 7-YEAR-OLD ARMENIAN BOY: A CASE REPORT
Anna Avagyan1,2, Lilit Sargsyan2,1, Julia Hoveyan1, Samvel Iskanyan2,
Samvel Bardakhchyan1,3, Samvel Danielyan3, and Gevorg Tamamyan1,2;
1Yerevan State Medical University after Mkhitar Heratsi, Yerevan,
Armenia, 2Pediatric Cancer and Blood Disorders Center of Armenia,
Hematology Center after Prof. R. Yeolyan, Yerevan, Armenia, 3Hematology
Center after Prof. R. Yeolyan, Yerevan, Armenia
BACKGROUND: Pilomyxoid astrocytoma (PMA) is a glial tumor that
occurs predominantly in the hypothalamic-chiasmatic region and rarelyin spinal cord. It has similar features as pilocytic astrocytomas, with somedistinct histological characteristics and worse prognosis. The 2007 WHO
recognized PMA as a Grade II glioma due to its aggressive behavior anddissemination tendency, but according to 2016 version grading of thepilomyxoid variant is under research. Here we report a case with a rare
location, aggressive behavior and rapid progression. CASE PRESENTATION: A 7-year-old boy presented with headache, nausea, vomiting. Imaging revealed an intramedullary tumor extending from C2 to C6 withhydrocephalus. A ventriculo-peritoneal shunt and complete surgical resection were performed with significant improvement in the patient’s
condition. Histopathological findings were consistent with pilomyxoid
variant of pilocytic astrocytoma, with negative BRAF V600E and MGMT.
Three months later, the follow-up imaging revealed disease recurrencewith leptomeningeal metastases, for which the patient received standarddose craniospinal irradiation 35.2 Gy with boosts to tumor bed andmetastatic sites 49.6 Gy and 54 Gy respectively. 11 months later tumor
progression was revealed with new metastatic lesions in the bones. Patient received 6 cycles of chemotherapy with TMZ and Avastin, but continued to suffer disease progression on therapy and he succumbed to his
disease at 24 months from diagnosis. CONCLUSION: Given the rarityof documented patients with spinal pilomyxoid astrocytoma with rapid
progression, as well as the lack of certain WHO classification and treatment guidelines, this case report might be useful for development of more
efficient treatment strategies.
LGG-17. SYNERGISTIC ACTIVITY OF MAPK INHIBITOR CLASSESREVEALED BY A NOVEL CELL-BASED MAPK ACTIVITY PEDIATRICLOW-GRADE GLIOMA ASSAY
Diren Usta1,2, Romain Sigaud1,2, Juliane L. Buhl1,2, Florian Selt1,2,
Viktoria Marquardt3,4, David Pauck3,4, Stefan Pusch5,6, Jonas Ecker1,2,
Thomas Hielscher7, Johanna Vollmer1,2, Alexander C. Sommerkamp1,8,
Tobias Rubner9, Darren Hargrave10, Cornelis M. van Tilburg1,2,
Stefan M. Pfister1,11, David T.W. Jones1,8, Marc Remke3,4,
Tilman Brummer12,13, Olaf Witt1,2, and Till Milde1,2; 1Hopp Children’s
Cancer Center Heidelberg (KiTZ), Heidelberg, Germany, 2ClinicalCooperation Unit Pediatric Oncology, German Cancer Research Center(DKFZ), Heidelberg, Germany, 3Department of Pediatric Oncology,
Hematology, and Clinical Immunology, Medical Faculty, University
Hospital, Düsseldorf, Germany, 4Department of Pediatric Neuro-

Oncogenomics, German Cancer Consortium (DKTK), Düsseldorf,
Germany, 5Department of Neuropathology, Heidelberg University Hospital,
Heidelberg, Germany, 6Clinical Cooperation Unit Neuropathology,
German Cancer Research Center (DKFZ), Heidelberg, Germany, 7Divisionof Biostatistics, German Cancer Research Center (DKFZ), Heidelberg,
Germany, 8Pediatric Glioma Research Group, German Cancer ResearchCenter (DKFZ), Heidelberg, Germany, 9Flow Cytometry Unit, German
Cancer Research Center (DKFZ), Heidelberg, Germany, 10Neurooncology
and Experimental Therapeutics, Great Ormond Street Hospital forChildren, London, United Kingdom, 11Division of Pediatric Neurooncology,
German Cancer Research Center (DKFZ), Heidelberg, Germany, 12Instituteof Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine,
University of Freiburg, Freiburg, Germany, 13German Consortium forTranslational Cancer Research (DKTK), Freiburg, Germany
Pilocytic astrocytomas (PAs) and other pediatric low-grade gliomas(pLGGs) exhibit aberrant activation of the MAPK signaling pathway caused
by genetic alterations, most commonly KIAA1549:BRAF fusions, BRAF
V600E and NF1 mutations. In such a single-pathway disease, novel drugs
targeting the MAPK pathway (MAPKi) are prime candidates for treatment.
We developed an assay suitable for pre-clinical testing of MAPKi in pLGGs,
aiming at the identification of novel MAPK pathway suppressing synergistic
drug combinations. We generated a reporter plasmid (pDIPZ) expressing
destabilized firefly luciferase driven by a MAPK-responsive ELK-1-binding
element, packaged in a lentiviral vector system. We stably transfected pediatric glioma cell lines with a BRAF fusion (DKFZ-BT66) and a BRAFV600E
mutation (BT-40) background, respectively. Measurement of MAPK
pathway activity was performed using the luciferase reporter. pERK protein
levels were detected for validation. We performed a screen of a MAPKi library and calculated Combination Indices of selected combinations. The
MAPKi library screen revealed MEK inhibitors as the class inhibiting thepathway with the lowest IC50s, followed by ERK and second generation
RAF inhibitors. Synergistic effects in both BRAF-fusion and BRAFV600E
mutation backgrounds were observed following combination treatmentswith different MAPKi classes (RAFi/MEKi, > RAFi/ERKi > MEKi/ERKi).
We have generated a novel reporter assay for medium- to high-throughput
pre-clinical drug testing of MAPKi in pLGG cell lines. MEK, ERK andnext-generation RAF inhibitors were confirmed as potential treatment approaches for KIAA1549:BRAF and BRAFV600E mutated pLGGs. Synergistic suppression of MAPK pathway activity upon combination treatments
was revealed using our assay in addition.
LGG-18. EVEROLIMUS TREATMENT IN PEDIATRIC PATIENTSAFFECTED BY LOW-GRADE GLIOMAS (PLGG) NON-TSC, BRAF
V600-WT
Antonella Cacchione, Evelina Miele, Maria Chiara Lodi, Andrea Carai,
Giovanna Stefania Colafati, Francesca Diomedi Camassei, Franco Locatelli,and Angela Mastronuzzi; Bambino Gesu’ Children Hospital, Rome, Italy
BACKGROUND: MAPK pathway is the hallmark of pediatric low
grade gliomas (pLGGs); hyperactivation of mTOR (mammalian target of
rapamycin) might be a suitable biomarker for therapeutic response. We investigated the feasibility of Everolimus, mTOR inhibitor, in patients affectedby pLGGs. METHODS: Patients 1 to 18 years old, diagnosed with pLGG,
with a positive tumor biopsy for mTOR/phospho-mTOR and radiologicaland / or clinical disease progression, treated at Bambino Gesù Children’s
Hospital in Rome were evaluated. Tumor DNA methylation analysis was
performed in 10 cases. Exclusion criteria included: Tuberous Sclerosis patients, Sub Ependymal Giant Astrocytoma. Everolimus was administered orally at a dose of 2.5 mg or 5 mg daily based on body weight. Patients were
evaluated with brain MRI every 4, 8 and 12 months after treatment start andevery six months thereafter. RESULTS: 16 patients were enrolled from September 2014 and 2019. The median age was 7.5 years old. All patients had
at least one adverse event. Events rated as severe (grade 3/4) were reported
in 6 patients. Stomatitis was the most frequent adverse event. One patient
discontinued treatment due to grade 4 toxicity (ulcerative stomatitis andfatigue). The median duration of treatment was 21 months (4–57 months).
Brain MRI evaluations have showed disease stability in 11 patients, partial response in 2 patients and disease progression in 3 patients. CONCLUSIONS: Everolimus has proven to be well tolerated and effective treatment
in terms of disease stability in patients with pLGGs. It’s also an excellent
example of chemo-free personalized approach.
LGG-19. SPINAL LOW-GRADE GLIOMAS IN CANADIAN CHILDREN:A MULTI-CENTRE RETROSPECTIVE REVIEWHallie Coltin1,2, Savvy Benipal3, S. Rod Rassekh4, Liana Figueiredo Nobre2,
Julie Bennett2, Uri Tabori2, Bev Wilson5, Vivek Mehta5, Wendy Beaudoin5,
Shayna Zelcer6, Sylvia Cheng4, Juliette Hukin4, Cynthia Hawkins2,
Eric Bouffet2, and Donna Johnston1; 1CHEO, Ottawa, Canada, 2Hospitalfor Sick Children, Toronto, ON, Canada, 3Royal College of Surgeons in
Ireland, Dublin, Ireland, 4BC Children’s Hospital, Vancouver, BC, Canada,

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5Stollery Children’s Hospital, Edmonton, AB, Canada, 6London Health
Sciences Centre, London, ON, Canada

PURPOSE: Primary spinal low-grade gliomas (LGGs) are rare, can be difficult to treat, and can result in significant morbidity. The management of pediatric spinal LGGs remains controversial. METHODS: A national multi-centre
retrospective review of spinal LGGs diagnosed in children less than 18 yearsof age between 1990–2015 was undertaken to examine the clinical features,
pathological subtypes, and treatment outcomes. RESULTS: Forty-three patients from five institutions were included. The median age of diagnosis was
5.2 years. All patients were symptomatic at diagnosis. Forty-four percent ofpatients were diagnosed at least 6 months after symptoms developed. Twopatients had metastatic disease at diagnosis. The most common histology was
pilocytic astrocytoma (48.8%). Molecular information was available for 15/43
patients: 6 patients had BRAF fusions and 4 patients had BRAF V600E mutations. Gross-total resection was achievable in only 6 patients. Twenty-seven patients were treated with surgery-only and the others received chemotherapy and/or focal radiation. Eleven patients were irradiated. No patients were registeredin clinical trials for first-line therapy. Twenty-three patients experienced relapse
or progression. Patients were followed for a median of 8.3 years (range, 0.5–
20.4 years). Five-year progression-free survival (PFS) and overall survival (OS)rates were 48.3% (95% CI, 32.3% to 62.5%) and 89.7% (95% CI, 74.6%
to 96.1%) respectively. CONCLUSION: There is significant heterogeneity insurgical outcomes and treatment modalities of pediatric spinal LGGs. The PFS
and OS rates remain suboptimal, likely due to tumor location. The low clinical
trial enrollment rate highlights the paucity of available trials for spinal LGGs.
LGG-20. CLINICAL FEATURES AND TREATMENT RESULTS FOR
PEDIATRIC OPTICO-HYPOTHALAMIC ASTROCYTOMA
Koji Yoshimoto1, Nobuhiro Hata2, Nayuta Higa1, Hajime Yonezawa1,
Hiroyuki Uchida1, Tatsuki Oyoshi1, and Masahiro Mizoguchi2;
1Department of Neurosurgery, Graduate School of Medical and Dental
Sciences, Kagoshima University, Kagoshima, Japan, 2Department of
Neurosurgery, Graduate School of Medical Sciences, Kyushu University,
Fukuoka, Japan
Current consensus for the treatment of optico-hypothalamic astrocytoma(OHA) is a chemotherapy-first policy, limiting the role of surgery for histopathological diagnosis and partial decompression. However, a subgroup of
OHA patients show resistance to chemotherapy and have a worse prognosis.
In this study, we retrospectively analyzed our clinical experiences of the treatment of patients with OHA in two university hospitals. We have extracted andanalyzed the medical charts of 15 pediatric OHA patients treated in two university hospitals since 1990. NF-1-associated OHA patients were excluded. Patientages ranged from 10 months to 21 years (median 7 years). Out of 15 cases, 12
patients had a tumor larger than 3 cm and classified as Dodge 3. The final histopathological diagnosis was pilocytic astrocytoma in 13 cases. Three patientswith tumors classified as Dodge 1 or 2 show good prognosis only by biopsy or
partial resection. However, regarding Dodge 3 tumor, patient prognosis is worse
regardless of chemotherapy and radiotherapy. After the initial surgery, chemotherapy was administered in 11 cases and radiotherapy in 5 cases. Multiple
surgeries are needed for tumor control in 7 patients. Four patients died of tumor
progression or treatment-associated complications. When the initial tumor islarge enough to cause neurological deterioration, a chemotherapeutic tumor
suppressive effect might be limited in a subset of large OHA cases. Therefore, it
is important to consider the proper timing of safe surgical decompression in theearly phase when a large tumor does not respond to chemotherapy.
LGG-21. MR-GUIDED LASER INTERSTITIAL THERMAL THERAPYFOR UNRESECTABLE AND SYMPTOMATIC PEDIATRIC LOWGRADE GLIOMADavid Kram, Jessica Benjamin-Eze, Roy Strowd, and Stephen Tatter; Wake
Forest School of Medicine, Winston-Salem, NC, USA
BACKGROUND: Pediatric low-grade gliomas (LGG) not amenable to resection, while often indolent, represent a significant source of cancer-related
morbidity and an unmet therapeutic need. Standardly, these patients aretreated with sequential lines of chemotherapy, while delaying as long as possible radiation. Magnetic resonance-guided laser interstitial therapy (LITT)
is a minimally invasive procedure that utilizes real-time MR thermography
to ablate brain lesions. METHODS: A 15-year-old girl was diagnosed witha suprasellar, hypothalamic LGG, BRAF V600E mutation positive. The
tumor was unresectable, and due to progressive vision loss and headaches,the patient underwent treatment. Despite sequential trials of thioguanine/
procarbazine/lomustine/vincristine, carboplatin/vincristine, dabrafenib,
and combination dabrafenib/trametinib, the patient continued to experience debilitating headaches, malnutrition, school absenteeism, and overall
poor quality-of-life. Using real-time, sequential MRI-thermometry and the
Neuroblate cooled directional laser catheter, the bulk of the enhancing
tumor was heated to a killing temperature. RESULTS: At 1-year post LITT,
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proved headaches, malnutrition, school absenteeism, and overall quality oflife. LITT was generally well tolerated, though the patient had slight progressive left homonymous hemianopia, thought secondary to LITT impact
on the optic tracts. The tumor progressively shrank over the year post-LITT
to a peak of 42% volume reduction. CONCLUSION: We report a case ofa pediatric patient with an unresectable low grade glioma who underwent
LITT with excellent clinical and radiographic effects. LITT should be considered for children with unresectable and morbid LGGs that fail to respondto more conventional therapies.
LGG-22. EVALUATION OF IMMUNE AND GENOMIC
CHARACTERISTICS IN PEDIATRIC OPTIC NERVE GLIOMA (ONG)
Ashley A. Campbell1,2, Andrew M. Silverman3,
Hanna Moisander-Joyce3, Cheng-Chia Wu4, Mahesh Mansukhani5,
George Zanazzi5, Andrew Turk5, Peter D. Canoll5,
James H. Garvin3, Michael Kazim2, and Robyn D. Gartrell-Corrado3;
1Wilmer Eye Institute, Johns Hopkins University School of Medicine,
Baltimore, MD, USA, 2Columbia University Irving Medical Center,
Department of Ophthalmology, New York, NY, USA, 3Columbia University
Irving Medical Center, Department of Pediatrics, New York, NY, USA,
4Columbia University Irving Medical Center, Department of Radiation,
New York, NY, USA, 5Columbia University Irving Medical Center,
Department of Pathology, New York, NY, USA
Pediatric optic nerve glioma (ONG) is a rare, sight-threatening tumor.
We previously reported clinical, radiologic, histopathologic, and molecularcharacteristics of pediatric ONG patients treated at Columbia University
Medical Center between 2000–2017. Here we evaluate this cohort and one
additional patient using quantitative multiple immunofluorescence (qmIF)
and next generation sequencing (NGS) using the Columbia Combined
Cancer Panel (CCCP). For qmIF, 4 micron immuno-blank slides were stained
for CD3, CD8, CD68, CD163, HLA-DR, and Olig2. QmIF images were analyzed and data were processed in R studio and compared based on tumor
mutation and treatment history. QmIF failed in 1 case and CCCP failed in
2 cases. CCCP confirmed KIAA1549:BRAF fusions in 2 patients, identified
NF1 in 2 patients, and demonstrated both a KIAA1549:BRAF fusion and
SETD2 mutation in the added case. Qualitative analysis showed immune
infiltrate across cases included macrophages (CD68+, 1.6–6.5% of all cells)
and T cells (CD3+, 0.4% to 1.5%). Non-cytotoxic T cells (CD3+CD8-) comprised 60.7–100% of the T cell compartment. There was no difference whencomparing mutation groups. However, patients who previously received
radiation had increased CD3+, specifically CD3+CD8- cells compared to
non-irradiated patients (p=0.01 and p<0.01, respectively) while CD3+CD8+
and CD68+ cells were not different between groups (p=0.49 and p=0.27,
respectively). In summary, qmIF analysis showed increased tumor infiltration by non-cytotoxic T cells in previously irradiated pediatric ONG patients compared to non-irradiated patients, while there was no differencein macrophages of cytotoxic T cells. This type of analysis may be useful indesigning immunotherapeutic strategies for pediatric ONG.
LGG-23. EXCELLENT CLINICAL / RADIOLOGICAL RESPONSE
TO BRAF INHIBITION IN A YOUNG CHILD WITH IN-OPERABLE
SUPRA-SELLAR PILOCYTIC ASTROCYTOMA
Stacy Chapman1, Demitre Serletis2, Colin Kazina2, Mubeen Rafay3,
Sherry Krawitz4, Katya Rozovsky5, and Magimairajan Issai Vanan1;
1Cancer Care Manitoba / University of Manitoba, Winnipeg, MB,
Canada, 2Neurosurgery, University of Manitoba, Winnipeg, MB, Canada,
3Neurology, University of Manitoba, Winnipeg, MB, Canada, 4Neuropathology, University of Manitoba, Winnipeg, MB, Canada, 5Radiology,
University of Manitoba, Winnipeg, MB, Canada
In-operable low grade gliomas (LGG) in the pediatric population continue
to present a treatment dilemma. Due to the low-grade nature of these tumors,and variable response to chemotherapy / radiation, the choice of adjuvant treatment is difficult. Overall survival is directly related to the degree of surgical resection, adding complexity to these inoperable tumors. Current chemotherapeutic
regimen for these inoperable tumors includes vincristine (VCR) and carboplatin(Carbo). With advancements in the molecular characterization of gliomas, therole of targeted therapy has come into question. We present a 2-year-old female
with biopsy proven Pilocytic Astrocytoma (positive BRAF-V600E mutation)
involving the hypothalamic/optic chiasm region. She presented with ataxic gait,bi-temporal hemianopia, obstructive hydrocephalus and central hypothyroidism,
which progressed to altered consciousness, and right hemiparesis due to location/
mass effect of the tumor. She was initially treated with chemotherapy (VCR/
Carbo) but her tumor progressed at 6 weeks of treatment. As her tumor was positive for BRAF-V600E mutation, she was started on Dabrafenib monotherapy,
resulting in dramatic improvement in her clinical symptoms (able to stand, improved vision), and a 60% reduction in tumor size at 3-months. At 6-months,
follow up MRI showed slight increase in the solid portion of the tumor, with noclinical symptoms. We plan to add MEK inhibitor (Trametinib) and continue
with Dabrafenib. Our experience and literature review suggests that LGG with

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BRAF-V600E mutations may benefit from upfront targeted therapy. Prospective
clinical trials comparing the efficacy of BRAF inhibitors versus standard chemotherapy in LGG with BRAF mutations are urgently needed.
LGG-24. CARBOPLATIN-INDUCED HEMATURIA IN A PEDIATRICPATIENT WITH LOW-GRADE GLIOMA AND REVIEW OF
LITERATURE
Alex Hoover and Mariko Sato; University of Iowa, Iowa City, IA, USA
OBJECTIVE: In this case report, we present a pediatric patient with grosshematuria and hydroureteronephrosis associated with high dose carboplatin.
Given the paucity of literature on the subject, we also conduct and present
a review of cases. CASE PRESENTATION: A 6-year-old Caucasian female
with history of Type 1 neurofibromatosis was undergoing treatment for a
low-grade glioma with monthly high dose carboplatin (560 mg/m2). After
8th dose out of 13, the patient developed severe nausea and vomiting andwas admitted for dehydration. She was noted to have microscopic hematuria.
After 9th dose, the patient again developed severe nausea, vomiting and grosshematuria with clots. She was admitted and treated with IV hydration. Renal
ultrasound showed newly developed bilateral hydroureteronephrosis. Coagulation studies were normal. Multiple cultures and viral studies were negative.
Hematuria cleared spontaneously after 4 days of aggressive hydration. RESULTS: Subsequent carboplatin was given with aggressive hydration andminimized nausea/vomiting and no hematuria was observed. Literature review
revealed only 4 reported cases of carboplatin-induced hematuria, including
only one pediatric case that occurred in a patient with concurrent thrombocytopenia. Carboplatin may exhibit toxicity to the transitional epithelial cellsof the urogenital tract causing hemorrhage from the renal pelvis and ureters.
If untreated, this may lead to urinary outflow obstruction and subsequent
obstructive nephropathy. CONCLUSION: We present a rare toxicity, grosshematuria caused by high-dose carboplatin treatment. Providers should beaware of this rare toxicity and provide timely hydration and supportive care
to prevent development of obstructive kidney injury and/or renal failure.
LGG-25. A PHASE 2 STUDY OF TRAMETINIB FOR PATIENTS WITHPEDIATRIC GLIOMA WITH ACTIVATION OF THE MAPK/ERK
PATHWAY. TRAM-01
Sébastien Perreault1, Valérie Larouche2, Uri Tabori3, Cynthia Hawkins4,
Sarah Lippé5, Benjamin Ellezam6, Jean-Claude Décarie7, Yves Théoret8,
Marie-Élaine Métras8, Serge Sultan5, Édith Cantin9, Marie-Ève Routhier9,
Maxime Caru5, Geneviève Legault10, Eric Bouffet3, Lucie Lafay-Cousin11,
Juliette Hukin12, Craig Erker13, and Nada Jabado14; 1Division of Child
Neurology, Department of Pediatrics, CHU Sainte-Justine, Universitéde Montréal, Montréal, QC, Canada, 2Division of Hemato-Oncology,
Department of Pediatrics, Centre Hospitalier Universitaire de QuébecUniversité Laval, Québec City, QC, Canada, 3Division of HematoOncology, Department of Pediatrics, Hospital for Sick Children, Toronto,
ON, Canada, 4Department of Pathology, Hospital for Sick Children,
Toronto, ON, Canada, 5CHU Sainte-Justine Research Center, CHU SainteJustine, Université de Montréal, Montréal, QC, Canada, 6Department of
Pathology, CHU Sainte-Justine, Université de Montréal, Montréal, QC,
Canada, 7Department of Radiology, CHU Sainte-Justine, Université deMontréal, Montréal, QC, Canada, 8Department of Pharmacology, CHU
Sainte-Justine, Université de Montréal, Montréal, QC, Canada, 9Divisionof Neuropsychology, Centre Hospitalier Universitaire de Québec-Université
Laval, Québec City, QC, Canada, 10Division of Neurology, Department ofPediatrics, McGill University Health Center, Montreal Children’s Hospital,
Montréal, QC, Canada, 11Departments of Oncology and Pediatrics; Alberta
Children’s Hospital, University of Calgary, Cumming School of Medicine,
Calgary, AB, Canada, 12Division of Child Neurology and Oncology, BCChildren’s Hospital, University of British Columbia, BC, Vancouver, BC,
Canada, 13Division of Hemato-Oncology, Department of Pediatrics, IWK
Health Centre, Dalhousie University, Halifax, NS, Canada, 14Division of
Hemato-Oncology, Department of Pediatrics, McGill University HealthCenter, Montreal Children’s Hospital, Montréal, QC, Canada
BACKGROUND: Pediatric low-grade gliomas (PLGG) are the mostfrequent brain tumors in children. It is now known that the majority of
PLGG have activation of the MAPK/ERK pathway. We hypothesize that
we will observe responses in recurrent/refractory PLGG treated withtrametinib. METHODS: This is a multicenter phase II including three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion
patients and patients with other activation of the MAPK/ERK pathway(excluding V600E). Patients will receive daily oral trametinib for a total of
18 cycles of 28 days. A total of 104 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progressionfree survival, tolerability of trametinib, serum levels of trametinib andevaluation of quality of life during treatment. RESULTS: As of January 7
2020, 28 patients have been enrolled (NF1: 6 patients, KIAA1549-BRAF
fusion: 17, other: 5 including 3 patients FGFR1 alteration). Median age is

8.5 years (range 2.5–25.4 years). Median follow-up is currently 4.6 months(range 0.16–14.7 months). Twenty patients are currently evaluable. Best
response includes: 1 complete response (5%), 3 partial response (15%), 4
minor response (20%), 8 stable disease (40%), 4 progressive disease (20%).
8 patients (28,5%) discontinued treatment: 4 for progressive disease, 3
adverse event (alanine aminotransferase increase), 1 withdrew. CONCLUSION: Trametinib is potential effective targeted therapy for patients withrecurrent/refractory PLGG. Overall treatment is well tolerated. This ongoingtrial will continue to gather data on response rate, duration of response andsafety of trametinib for PLGG.
LGG-26. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR(DLGNT) IN CHILDREN: DIFFERENT CLINICAL PRESENTATIONSAND OUTCOMES
Andge Valiakhmetova1,2, Ludmila Papusha2, Ludmila Yasko2,
Alexander Druy2, Alexander Karachunsky2, Galina Novichkova2,
Eugene I. Hwang3, and Roger J. Packer3; 1N.N. Burdenko National
Medical Research Center of Neurosurgery, Moscow, Russian Federation,
2D. Rogachev NMRC of Pediatric Hematology, Oncology and Immunology,
Moscow, Russian Federation, 3Center for Neuroscience and Behavioral
Medicine, Brain Tumor Institute, Children’s National Health System,
Washington, DC, USA
Diffuse leptomeningeal glioneuronal tumor (DLGNT) is an extremely raredisease, newly recognized in the 2016 WHO classification of tumors of the
CNS. Most DLGNTs are low-grade neuroepithelial tumors with variable
elements of neuronal/neurocytic and glial differentiation, have diffuse leptomeningeal enhancement on MRI, and typically harbor KIAA1549-BRAF
fusions. Other alterations, such as the BRAF V600E substitution, are lesscommon. Here, we present three cases of DLGNT with different presentations and outcomes. The first patient is a 2yr-old male with KIAA1549BRAF fusion, and was treated with Carbo/VCR chemotherapy after abiopsy, with resultant ongoing stable disease for 3.5 years. The second patient, an 8yr-old male had the BRAF V600E point mutation and was treatedwith conventional chemotherapy (VCR/carboplatin). On progression, he
received the BRAF inhibitor vemurafenib, achieving a complete response
which last 14 month. The third patient, a 27 month old male, harbored a
KIAA1549-BRAF fusion and was treated at diagnosis with the MEK inhibitor trametinib. The tumor has been radiographically stable in the context of clinical improvement for 21 months since the treatment initiation,
ongoing 24 month. In summary, we present further evidence of MAPK
pathway alterations in children with DLGNT. We describe a range of molecular presentations and clinical outcomes, including one patient treatedwith conventional chemotherapy with further stabilization of disease during
3.5 years and two patients who were successfully treated with targeted
therapy.
LGG-27. TARGETED THERAPY FOR PEDIATRIC LOW-GRADE
GLIOMAS AND PLEXIFORM NEUROFIBROMAS WITH
TRAMETINIB
Tiffany Nguyen1, Kathleen McMahon2, Molly Hemenway2,3,Jean Mulcahy Levy2,3, Nicholas Foreman2,3, and Kathleen Dorris2,3;
1University of Colorado School of Medicine, Aurora, CO, USA, 2Children’s
Hospital Colorado, Aurora, CO, USA, 3Morgan Adams Foundation
Pediatric Brain Tumor Research Program, Aurora, CO, USA
BACKGROUND: Targeted therapy aimed at modulating the RAS/
RAF/MEK/ERK pathway is of increasing interest for patients with plexiform neurofibromas and low-grade gliomas. Trametinib is an FDAapproved MEK inhibitor that has little published pediatric experience todate. METHODS: A retrospective chart review of patients treated withtrametinib for low-grade gliomas (LGG) and/or plexiform neurofibromas(PN) between 2015–2018 was conducted at Children’s Hospital Colorado.
Data collected included patient demographics, lesion location, Neurofibromatosis type 1 (NF1) status, best response of PN/LGG to trametinib,
duration of trametinib therapy, and reported toxicities at least possibly attributed to trametinib. RESULTS: Thirty (57% male; 73% NF1) patientswere identified. Sixteen (53%) patients had PN only, 12 (40%) had LGG
only, and two (7%) patients had both PN and LGG. The most common LGG
location was the optic pathway/hypothalamus (72%). The most common
location of PN was the face (63%). Two-thirds (8/12) of patients with
LGG had a BRAF alteration or NF1 mutation. The median age at start oftrametinib therapy was 9.9 years (range, 2.0 – 18.8 years). The median duration of trametinib therapy was 0.8 years (range 0.1 – 2.9 years). The mostcommonly reported adverse event was rash. No patients developed retinal
toxicity or cardiotoxicity. Only two (7%) patients discontinued for toxicity
and one (3%) for progressive disease. CONCLUSIONS: Trametinib can beadministered without significant toxicity to children with PN or LGG. Clinical benefit is noted in this cohort; however, prospective clinical trials arenecessary to characterize efficacy formally.

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LGG-28. NOVEL BRAF INTRAGENIC DELETION IN A GLIOMA:A CASE REPORT OF A PEDIATRIC PATIENT
Valerie Cruz Flores, Maxine Sutcliffe, Thomas Geller,
Ignacio Gonzalez Gomez, Stephanie Smith, and Stacie Stapleton; Johns
Hopkins All Children’s Hospital, St. Petersburg, FL, USA
BACKGROUND: Numerous variant BRAF genetic alterations havebeen associated with malignancies. BRAF activating fusions/mutations are
frequently present in low grade gliomas. BRAF intragenic deletions havebeen reported in melanoma, but have not previously been reported ingliomas. OBJECTIVE: To report a BRAF intragenic deletion in a pediatricpatient with recurrent low-grade glioma. RESULTS: A 3-year-old female
underwent a complete resection of a posterior fossa pilocytic astrocytoma.
She had recurrences at age 4, and then at age 9; pathology was consistent
with pilocytic astrocytoma. Microarray analysis on sample from the first recurrence showed one region of loss encompassing 86 Kbp within the BRAF
gene. The deletion breakpoints are within intron 1 and 9, resulting in lossof exons 2 through 9, inclusive. This has been previously described melanoma, but appears to be a novel finding in glioma. It is hypothesized that,since the loss retains the kinase and ATP binding pocket domains but deletes the N-terminal conserved region 1 and 2 (CR1, CR2) of the BRAF
gene, it is likely functionally similar to the loss and activation resulting fromthe more usually described KIAA1549 and BRAF gene fusion. CONCLUSION: This is the first BRAF intragenic deletion involving exons 2–9 reported in a glioma. Although 86kbp is small using whole genome microarray
technology, it is large using sequencing strategies, and a targeted sequencing
approach to investigate the BRAF gene would not readily identify this deletion. It is speculated that the deletion may be under ascertained in thepediatric population.
LGG-29. TREATMENT FOR RECURRENT OPTIC PATHWAYPILOCYTIC ASTROCYTOMA
Masahiro Nonaka, Mayuko Miyata, Natsumi Yamamura, and Akio Asai;
Kansai Medical University, Hirakata, Osaka, Japan
Chemotherapy after biopsy or partial resection of the tumor is widely
accepted as first-line therapy for optic pathway pilocytic astrocytoma. However, there is no standard of care for recurred tumors. We investigated ourcases which showed recurrence after initial therapy. Retrospective analysis offour recurrent optic pathway pilocytic astrocytoma cases was performed. All
patients underwent partial resection or biopsy of the tumor, and all received
carboplatin and etoposide- based chemotherapy as initial treatment. Meanage at first therapy was 2.3 years old, and mean time from initial therapy
to recurrence of the tumor was 5.6 years. Two patients were totally blind at
the time of recurrence, and other two had partial visual field losses. One patient underwent total resection of the tumor, and other three patients underwent partial resection followed by chemotherapy. Visual function in patientswith visual acuity did not deteriorate after removal of the recurrent tumor.
There was no recurrence of the tumor who underwent total resection. Allof the three patients who had partial resection followed by chemotherapy recurred. Mean time from first recurrence to second recurrence was 1.8 years.
After second recurrence, all patients underwent radiation therapy. One patient died due to malignant transformation of the tumor. For recurrent optic
pathway pilocytic astrocytoma, prognosis may be better if total resection of
the tumor without deteriorating the vision is possible.
LGG-30. TRAMETINIB-ASSOCIATED HYPONATREMIA IN
A CHILD WITH LOW GRADE GLIOMA IS NOT SEEN FOLLOWINGTREATMENT WITH ALTERNATIVE MEK INHIBITOR
Margot A. Lazow, Sarah A. Lawson, Ralph Salloum, Trent R. Hummel,
Natasha Pillay Smiley, Mariko D. DeWire-Schottmiller, Maryam Fouladi,
and Peter M. de Blank; Cincinnati Children’s Hospital Medical Center,
Cincinnati, OH, USA
Molecularly targeted therapy with MEK inhibitors is increasingly being
incorporated into the treatment of pediatric low-grade gliomas (LGGs).
Trametinib is an orally available MEK1/2 inhibitor that has demonstrated
tumor control in LGGs with BRAF alterations. Safe expansion of MEK inhibitor therapy within the pediatric patient population demands adequate
understanding of and surveillance for potential MEK-inhibitor specifictoxicities, especially among young children. Hyponatremia has been reported
in adult patients receiving BRAF/MEK inhibitor combination treatment aswell as in two pediatric patients with known diabetes insipidus treated withtrametinib monotherapy. To our knowledge, single-agent trametinib has
not previously been reported to be associated with hyponatremia in children in the absence of an underlying endocrinopathy. We present a case ofhyponatremia associated with trametinib use in an infant with progressive
LGG without known endocrine dysfunction, which recurred after significant
dose reduction. Therapy with an alternative MEK1/2 inhibitor, binimetinib,

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provided excellent tumor response without hyponatremia. Hyponatremia isa rare but serious side effect of trametinib, even without underlying pituitary
dysfunction. Infants and patients lacking the ability to quickly regulate fluid
intake in response to osmolality changes are at particular risk of suffering
severe consequences from hyponatremia and should be monitored closelywith initiation of trametinib. Switching to a different drug within the sameclass may offer an alternative to significant dose reduction or discontinuation due to this toxicity.
LGG-31. CHARACTERIZING TEMPORAL GENOMIC
HETEROGENEITY IN PEDIATRIC LOW GRADE GLIOMAS:ANALYSIS OF AN EXPANDED MULTI-INSTITUTIONAL COHORTWITH 101 PAIRED TUMOR SAMPLES
Margot A. Lazow1, Austin Schafer1, Mariko D. DeWire-Schottmiller1,
Adam Lane1, Daniel R. Boué2, Diana S. Osorio2, Jonathan L. Finlay2,Erin Wright3, Sarah Rush3, Lindsey M. Hoffman4, Jamie Reuss1,
Trent R. Hummel1, Ralph Salloum1, Peter M. de Blank1,
Natasha Pillay Smiley1, Mary E. Sutton1, Anthony Asher1,
Charles B. Stevenson1, Rachid Drissi1, Maryam Fouladi1, andChristine Fuller1; 1Cincininati Children’s Hospital Medical Center,
Cincinnati, OH, USA, 2Nationwide Children’s Hospital, Columbus, OH,
USA, 3Akron Children’s Hospital, Akron, OH, USA, 4Phoenix Children’s
Hospital, Phoenix, AZ, USA
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, andexome analyses were performed on paired tumor samples from primary
diagnostic and subsequent surgeries. RESULTS: 101 tumor samples from48 patients (43 with 2 specimens, 5 with 3 specimens) from 3 institutions
underwent testing. BRAF fusion and BRAFV600E status were conservedin 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 whoreceived 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 andmay 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-32. CLINICAL OUTCOME OF PEDIATRIC GLIOMAS IN SINGLEINSTITUTION
Hiroyuki Uchida, Nayuta Higa, Hajime Yonezawa, Tatsuki Oyoshi, andKoji Yoshimoto; Kagoshima University Hospital, Kagoshima, Japan
Gliomas in children are rarer than in adult, then treatment strategies
might vary from facility to facility. We report clinical features and outcomeof pediatric glioma in our institution. Twenty-nine patients diagnosed withglioma, exclude ependymoma, 14 boys and 15 girls, among 98 pediatricbrain tumor patients treated at Kagoshima University Hospital since 2006
were reviewed histopathology, extent of resection, adjuvant therapy and outcome, etc. Mean age at surgery was 10.4 (S.D. 5.6) years. Median follow-up
period was 19.1 months. Histopathological diagnosis comprised 8 pilocytic
astrocytoma, 3 ganglioglioma, 2 subependymal giant cell astrocytoma,
5 WHO grade Ⅱ astrocytoma, 8 glioblastoma, and desmoplastic infantile
astrocytoma, anaplastic astrocytoma and astroblastoma were one case each.
Tumor resection was performed in 24 cases, and 5 cases underwent biopsy.
Chemotherapy was performed in 15 cases and irradiation was performed
in 9 cases. Out of 5 WHO grade Ⅱ astrocytoma cases, 2 cases underwent
biopsy following chemotherapy, 1 case underwent biopsy only and other1 case underwent total resection. The four cases show long survival ranged
from 71 to 136 months without irradiation. All of eight glioblastoma cases
show poor prognosis ranged from 8.6 to 26.7 months regardless of chemoradiotherapy. In management for pediatric brain tumor patients, irradiation
is often laid over until recurrence. In WHO grade Ⅱ astrocytoma, the treatment strategy might be reasonable using appropriate chemotherapy eventhough biopsy cases.

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LGG-33. ISOMORPHIC DIFFUSE GLIOMA HAS RECURRENT GENEFUSIONS OF MYBL1 OR MYB AND CAN BE DISTINGUISHED FROMOTHER MYB/MYBL1 ALTERED GLIOMAS BASED ON A DISTINCT
MORPHOLOGY AND DNA METHYLATION PROFILE
Annika K. Wefers1,2, Damian Stichel1,2, Daniel Schrimpf1,2, Felix Sahm1,2,
Andreas von Deimling1,2, Ingmar Blumcke3, David T.W. Jones4,5, andDavid Capper6; 1Institute of Pathology, Department of Neuropathology,
University Hospital Heidelberg, Heidelberg, Germany, 2German Cancer
Consortium (DKTK), German Cancer Research Center (DKFZ), ClinicalCooperation Unit Neuropathology, Heidelberg, Germany, 3Departmentof Neuropathology, University Hospital Erlangen, Erlangen, Germany,
4Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany,
5German Cancer Research Center (DKFZ), Pediatric Glioma ResearchGroup, Heidelberg, Germany, 6Charité - Universitätsmedizin Berlin,
corporate member of Freie Universität Berlin, Humboldt-Universität zu
Berlin, and Berlin Institute of Health, Department of Neuropathology,
Berlin, Germany
Isomorphic diffuse glioma (IDG) was first described in 2004 as an
epilepsy-associated supratentorial diffuse glioma with low cellularity,
low proliferation and very monomorphic tumour cells. Most patients
had seizures since childhood but were operated on as adults. To study the
position of these lesions among brain tumours we histologically, molecularly and clinically analysed 26 histologically typical IDGs. Tumour cells
were GFAP-positive, MAP2-, OLIG2- and CD34-negative and the nuclear
ATRX-expression was retained. Proliferation was very low. Sequencing of
24 cases revealed an IDH-wildtype status. Cluster analyses of DNA methylation data showed that IDG has a DNA methylation profile distinct fromthose of different glial/glio-neuronal brain tumours and normal hemispheric tissue. About half of IDGs had copy number alterations of MYBL1or MYB (13/25) and half of the cases analysed by RNA-sequencing had
gene fusions of MYBL1 or MYB with various gene partners (11/22),
often associated with an increased RNA-expression of the respective
MYB-family gene. Integrating all data available, 77% of IDGs had either
MYBL1 (54%) or MYB (23%) alterations. All patients had a good outcome and most were seizure-free after surgery. In summary, we show thatisomorphic diffuse glioma is a distinct benign tumour in the family of
MYB/MYBL1-altered gliomas. DNA methylation analysis is very helpful
for their identification. More recent analyses of a large cohort of MYB/
MYBL1-altered brain tumours suggest the presence of a third methylationgroup that primarily contains paediatric cases and seems to be distinct
from IDG and angiocentric gliomas. Further histological, molecular andclinical analyses are ongoing.
LGG-34. CLINICAL AND MOLECULAR CHARACTERIZATION OF
A MULTI-INSTITUTIONAL COHORT OF PEDIATRIC SPINAL CORD
LOW-GRADE GLIOMAS
Sydney Grob1,2, Lianna Nobre3, Kurtis Davies1, Scott Ryall3, Dara Aisner1,
Lindsey Hoffman4, Shadi Zahedi1,2, Andrew Morin1,2, Anandani Nellan1,2,
Adam Green1,2, Nicholas Foreman1,2, Rajeev Vibhakar1,2,
Todd Hankinson1,2, Michael Handler1,2, Cynthia Hawkins3, Uri Tabori3,
BK Kleinschmidt-DeMasters1, and Jean Mulcahy Levy1,2; 1University ofColorado Denver, Aurora, CO, USA, 2Morgan Adams Foundation PediatricBrain Tumor Program, Aurora, CO, USA, 3Hospital for Sick Children,
Toronto, ON, Canada, 4Phoenix Children’s Hospital, Phoenix, AZ, USA
BACKGROUND: The MAPK/ERK pathway is involved in cell growthand proliferation, and mutations in the BRAF paralog of this pathway
have made it an oncogene of interest in pediatric cancer. Previous studies
have identified that BRAF mutations as well as BRAF-KIAA1549 fusions
are common in intracranial low-grade gliomas (LGGs). Fewer studies
have tested for the presence of these genetic aberrations in spinal LGGs.
The aim of this study was to better understand the prevalence of BRAF
and other genetic aberrations in spinal LGG. METHODS: We analyzed
46 spinal LGGs from children age 1–25 years from two institutions,Children’s Hospital Colorado (CHCO) and The Hospital for Sick Children (Sick Kids) for the presence of BRAF fusions or mutations. Data
was correlated with clinical information. A 67 gene panel additionally
screened for other possible genetic abnormalities of interest in the patient cohort from CHCO. In the Sick Kids cohort, BRAFV600E was tested
for by ddPCR and IHC while BRAF fusions where detected by FISH,
RT-PCR or Nanostring platform. RESULTS: Of the 31 patient samples who underwent fusion analysis, 13 (42%) harbored the BRAFKIAA1549 fusion. Overall survival (OS) for patients confirmed positive
for BRAF-KIAA1549 was 100% compared to 76% for fusion negative
patients. Other mutations of interest were also identified in this patient
cohort including BRAFV600E, STK11, PTPN11, H3F3A, APC, TP53,
PIK3CA (polymorphism), FGFR1, and CDKN2A deletion. CONCLUSION: BRAF-KIAA1549 was seen in higher frequency than BRAFV600E
or other genetic aberrations in pediatric spinal LGGs and trends towards
longer OS although not statistically significant.

LGG-35. FUNCTIONAL GENOMIC APPROACHES TO IDENTIFY
THERAPEUTIC TARGETS IN MYB AND MYBL1 EXPRESSINGPEDIATRIC LOW-GRADE GLIOMASAlexandra-Larisa Condurat1,2, Annika Wefers3,4, Elizabeth Gonzalez1,2,
Jeyna Doshi1, Prasidda Khadka1,2, Selin Jessa5,6, Jessica Tsai1,2,
Graham Buchan1,2, Cecile Rouleau7, Tanaz Abid2, Amy Goodale2,
Nicole Persky2, Rameen Beroukhim7,2, David Root2, Keith Ligon8,
Nada Jabado9,10, Clauda L. Kleinman6,9, Federica Piccioni2,
David T.W. Jones4,11, and Pratiti Bandopadhayay1,2; 1Department ofPediatric Oncology, Dana-Farber Boston Children’s Cancer and Blood
Disorders Center, Boston, MA, USA, 2Broad Institute of MIT and Harvard,
Cambridge, MA, USA, 3Department of Neuropathology, Institute of
Pathology, University Hospital Heidelberg, Heidelberg, Germany, 4Hopp
Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany,
5Quantitative Life Sciences, McGill University, Montreal, Canada, 6Lady
Davis Institute for Medical Research, Jewish General Hospital, Montreal,Montreal, Canada, 7Department of Cancer Biology, Dana-Farber Cancer
Institute, Boston, MA, USA, 8Department of Oncologic Pathology,
Dana-Farber Cancer Institute, Boston, MA, USA, 9Department of Human
Genetics, McGill University, Montreal, Canada, 10The Research Institute of
the McGill University Health Center, Montreal, Canada, 11Pediatric Glioma
Research Group, German Cancer Research Center (DKFZ), Heidelberg,
Germany
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 activatedin 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 differentiallyexpressed 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-36. DESMOPLASTIC INFANTILE GANGLIOGLIOMA (DIG)
WITH A PPP1CB-ALK FUSION IN A 6-YEAR-OLD GIRL
William McDonald1, Mahmoud Nagib2, Robert Jenkins3, Cristiane Ida3,
Kevin Halling3, Mary Skrypek2, and Anne Bendel2; 1Abbott Northwestern,
Minneapolis, MN, USA, 2Children’s Minnesota, Minneapolis, MN, USA,
3Mayo Clinic, Rochester, MN, USA
Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile
ganglioglioma (DIG) are benign glioneuronal tumors that typically occur ininfants, involve the superficial cerebral cortex, and have an excellent prognosis. DIA/DIG are a distinct molecular entity based on DNA methylation
profiling. BRAF600 mutations are frequently reported in DIG/DIA. A recent
comprehensive genetic analysis of infantile hemispheric gliomas identified 2
unique groups: group 1 harbored alterations in the receptor tyrosine kinase(RTK) genes ALK, ROS1, NTRK, and MET and group 2 harbored alterations in the RAS/MAPK pathway. We report a case of a 6.5-year-old girlwho presented with seizures and right homonymous hemianopia. MRI of
her brain demonstrated a large cystic/solid left hemispheric mass with remodelling of the overlying skull, consistent with a long-standing process.
She underwent a gross total resection (GTR) and pathology demonstrateda DIG with a PPP1CB-ALK gene fusion (exon 5 to exon 20) identified by
RNA sequencing. She remains disease free 12 months following GTR. A literature review identified 4 reported cases of pediatric brain tumors with
PPP1CB-ALK gene fusions including: a 3-month-old with a hemispherichigh-grade glioma which recurred 4 years later and pathology showed mature ganglioglioma, with both tumors showing the identical PPP1CB-ALK
gene fusion; a 10-month-old infant with a hemispheric low-grade glioma;
an infant with a “congenital” hemispheric high-grade glioma; and a childwith an astrocytoma with no further clinical data. PPP1CB-ALK gene fusion
appears to be a rare oncogenic driver in gliomas of infancy, including DIG.

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LGG-38. GENETIC ANALYSIS OF NEUROEPITHELIAL TUMORS IN
THE PEDIATRIC AND ADOLESCENT AND YOUNG ADULT AGE IN
A SINGLE INSTITUTE
Yasuhide Makino1,2, Takeshi Kawauchi1,3, Yoshiki Arakawa1,
Tomoko Shofuda2, Ema Yoshioka2, Masahiro Tanji1, Yohei Mineharu1,
Yonehiro Kanemura2, and Susumu Miyamoto1; 1Department of
Neurosurgery, Kyoto University, Kyoto, Japan, 2Department of ClinicalResearch, Osaka National Hospital, Osaka, Japan, 3Department ofClinical, Osaka, Japan
Molecular diagnosis in brain tumors has been widely spread after the publication of WHO 2016 classification. But it become a major problem that
there are some tumors not to be classified on its criteria, especially in pediatricneuroepithelial tumors. To clarify the characteristics of gliomas in pediatricand adolescent and young adult age (AYA), we picked up 131 neuroepithelial tumors under 30-year-old at Kyoto University and analyze their molecular profiles. Hot spot mutations in IDH1/2, H3F3A, HIST1H3B, TERT
promoter, and BRAF were analyzed by Sanger sequencing, and 1p/19q
codeletion was examined by FISH or MLPA. With the pathohistologicaldiagnosis and genetic information, all tumors were classified based on WHO
2016 classification. The terms “not otherwise specified” (NOS) and “not elsewhere classified” (NEC) were used based on cIMPACT-NOW. There were 25
glioblastomas and 34 pilocytic astrocytomas, which accounted for a larger
percentage than in adult tumors. IDH-wild type gliomas accounted for 55%
in diffuse astrocytomas and 69% in anaplastic astrocytomas. The percentages of gliomas with NEC were 50% of oligodendrogliomas and 20% in
anaplastic oligodendrogliomas, respectively. Most pilocytic astrocytomas
were under 20-year-old (27 patients) and located in infratentorial area (21patients). Based on WHO 2016 classification, not a few neuroepithelial tumors in pediatric and AYA ages could be classified clearly. These tumors had
more different genetic abnormalities than those in adult. Therefore, it may
be important to evaluate these tumors with comprehensive genetic analysis.
LGG-40. NATURAL COURSE AND MANAGEMENT OF SMALLASYMPTOMATIC LESION SUSPECTED OF LOW-GRADE GLIOMA
IN CHILDREN
Ai Muroi1, Takao Tsurubuchi1, Hidehiro Kohzuki1, Ryoko Suzuki2,
Hiroko Fukushima2, Yuni Yamaki2, Eiichi Ishikawa1, andAkira Matsumura1; 1Department of Neurosurgery, Faculty of Medicine,
University of Tsukuba, Tsukuba, Japan, 2Department of Pediatrics, Facultyof Medicine, University of Tsukuba, Tsukuba, JapanOBJECTIVE: The natural course of incidentally discovered small intracranial lesions has not been well discussed. Surgical intervention, including
resection and biopsy, could be achieved if the lesion is growing. We present
13 cases with incidentally found, small non-enhancing lesions without related symptoms. METHODS: We retrospectively reviewed a series of 13
children with T1 hypointense and T2 hyperintense intracranial lesions lessthan 20 mm in diameter without enhancement. We excluded the patientswith NF-1 or Tuberous sclerosis. RESULTS: Most patients underwent MRI
for headache unrelated to the lesions. All cases were located supratentorially.
The median age of the patients at the initial examination was 8.9 years(range, 2.2–14.6). Of these children, 2 patients (15.3%) underwent surgery
because of progression on follow-up MR images. The pathological diagnosis
was compatible with diffuse astrocytoma. Patients were followed for a median of 55 months (range, 11–87) and the overall survival rate was 100%.
No patient experienced increase in size after 3 years of follow-up. CONCLUSIONS: In most patients with small intracranial lesions, the lesions remained stable and conservative management was appropriate. However, ina few cases, the lesions changed in size or quality and surgical intervention
was necessary. Long-term follow-up at least 3 years is mandatory.
LGG-42. BEVACIZUMAB-ASSOCIATED SECONDARYAMENORRHEA AND PREMATURE OVARIAN FAILURE IN
ADOLESCENT FEMALE PATIENTS WITH LOW-GRADE CNSDISEASE
Nataliya Zhukova1,2, Kiri Chan3, Kathryne Walshe1, Peter A Downie1,4,
and Paul Wood1,2; 1Children Cancer Centre, Monash Children Hospital/
Monash Health, Clayton, VIC, Australia, 2Centre for Cancer Research,
Hudson Institute of Medical Research, Clayton, VIC, Australia,
3Department of Adolescent Gynaecology, Monash Children Hospital/
Monash Health, Clayton, VIC, Australia, 4Department of Pediatrics,
Monash University, Clayton, VIC, Australia
Compelling body of evidence exists to use bevacizumab, a humanized monoclonal anti-VEGF antibody, in selected paediatric patients with
low-grade CNS tumours. Common toxicities of bevacizumab, hypertension,
proteinuria, epistaxis, mucosal perforation, decreased wound healing are
well reported. However, the effect of bevacizumab on female ovarian func-

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De c e mb e r 2 0 2 0tion and long-term fertility is still being documented. Current evidence forbevacizumab-associated decline in ovarian function is largely from breastand colon cancer cohorts where exposure to multimodal chemotherapy confounds causative relationships. Fertility counseling and oocyte cryopreservation is currently offered as standard of care to post-pubertal females athigh risk of infertility due to high-dose radiation and chemotherapy. Adolescent females with low-grade CNS tumours on bevacizumab represent aunique population which could potentially be at high risk for infertility.
We report 2 cases of adolescent girls treated with bevacizumab as a single
agent and in combination with vinblastine for NF2-associated vestibular
schwannomas and brainstem glioma respectively. Both patients were postpubertal with established menstrual cycles and normal baseline FSH/LH/
oestradiol/AMH values prior to commencement of therapy. They became
amenorrhoeic shortly after starting of therapy with levels of FSH/LH/oestradiol suggestive of premature ovarian failure. One patient has remained
asymptomatic, whereas the other has developed profound post-menopausal
symptoms interfering with quality of life which necessitated commencementof hormone-replacement therapy. Appropriate pretreatment fertility investigation and consultation should be offered to all post-pubertal females
starting on bevacizumab. Further research into the long-term effects of gonadal toxicity in both females and males with drugs inhibiting angiogenesis
is needed.
LGG-44. PROGNOSTIC SIGNIFICANCE OF IMAGING
CHARACTERISTICS IN PEDIATRIC LOW GRADE GLIOMAS
Muhammad Baig, Michael Chan, Jason Johnson, Sana Mohiuddin,
Ruitao Lin, Michael Roth, Zsila Sadighi, John Slopis, Soumen Khatua, and
Wafik Zaky; MD Anderson Cancer Center, Houston, TX, USA
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 recordsof 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-45. A REPORT OF IDH-MUTANT BRAINSTEMASTROCYTOMAS IN YOUNG ADULTS
Ellen Chang, Benita Tamrazi, Jennifer Cotter, and Ashley Margol;Children’s Hospital Los Angeles, Los Angeles, CA, USA
IDH-mutant astrocytomas are well-recognized in the adult population
and while increasingly identified, are rare in children and young adults.
These tumors typically arise in cortical locations, however cases of these tumors occurring in the brainstem have been reported in the adult literature.
Here we present two cases of young adults with IDH-mutant astrocytomasof the brainstem. Patient 1 was initially diagnosed with an infiltrative low
grade glioma (LGG) of the brainstem at 19 years of age based on conventional magnetic resonance imaging and magnetic resonance spectroscopy
characteristics. She was treated with LGG therapy and had stable disease forover three years. At the time of disease progression she underwent biopsy andpathology was consistent with an anaplastic astrocytoma, IDH1 R132S mutant. Despite treatment she experienced rapid disease progression and diedsix months later. Patient 2 is a 17-year-old male who underwent up-front biopsy of an infiltrating brainstem lesion; pathology was consistent with diffuse
astrocytoma, IDH1 R132H mutant. He was treated with focal irradiationand chemotherapy and continues to have stable disease 26 months post diagnosis. To our knowledge, this is the first report of IDH-mutant astrocytomas
occurring the brainstem in young adult patients. Both patients’ tumors harbored accompanying TP53 mutations, but not ATRX mutations. These twocases reveal the importance of obtaining biopsies for brainstem tumors to perform molecular characterization and appropriate prognostication.

Abstracts

LGG-46. MOLECULAR CHARACTERIZATION OF HEMISPHERIC
LOW-GRADE GLIOMAS IN CHILDREN
Adéla Mišove, Lenka Krsková, David Sumerauer, Josef Zámečník,Kateřina Váňová, Jan Starý, Ivana Perníková, Aleš Vícha, Petr Libý,Michal Tichý, Jakub Táborský, Martin Kynčl, and Michal Zápotocký;University Hospital Motol, Second Faculty of Medicine, Charles University,
Prague, Czech Republic
BACKGROUND: Heterogeneous pathology in hemispheric low-grade
gliomas (hemLGG) stress the importance of molecular testing in terms ofprognosis prediction and targeted therapy options. METHODS: Demographic data was collected and targeted genomic approach was employedin the single institutional study. RT-PCR was used to screen for KIAA1549BRAF fusion and FGFR1 tyrosine-kinase domain duplication (FGFR1-ITD).
Direct sequencing evaluated point mutations (BRAF ex15 and ex11, FGFR1
ex12 and ex14). Samples with no detected alteration were subjected to panel
RNA-sequencing (FusionPlex Archer Diagnostics). RESULTS: Within 2000–
2019 were diagnosed 76 patients with hemLGG (median age 11.1y, range
0.0y–18.5y) comprising predominantly of ganglioglioma, dysembryoplastic
neuroepithelial tumors, and diffuse astrocytoma. 40 % of hemLGG werecharacterized by BRAF alterations with over 2/3 of those cases harboring
BRAF point mutations (two BRAFex11, 12 BRAFV600E). Notably, BRAF
fusions were uncommon and detected only in six patients (two KIAA-BRAF
fusion, two minor oncogenic BRAF variants, two non-KIAA BRAF fusion). 25% of alterations were found in genes for receptor tyrosine kinases, consistingof seven patients with FGFR1-ITD, three FGFR2/3 fusions, two FGFR1 mutations, two ALK fusions, and one ROS fusion. Out of MAP kinase pathway,
the most frequent alteration was IDH1 mutations (n=9). Two angiocentric
gliomas were characterized by MYB-QKI fusion. CONCLUSION: Targeted
sequencing combined with RNA-sequencing is feasible to establish moleculardiagnosis in majority of cases and reveal new and rare alterations. Significant
prevalence of non-BRAF alterations explains heterogeneity among hemLGG.
LGG-47. SYSTEMIC THERAPY OF ROSETTE-FORMINGGLIONEURONAL TUMOR OF THE FOURTH VENTRICLE INAN
ADOLESCENT
Rene McNall-Knapp1, Naina Gross1, Wafik Zaky2, Benjamin Cornwell1,
Theresa Gavula1, and Abhishek Bavle1; 1University of Oklahoma Collegeof Medicine, Oklahoma City, OK, USA, 2MD Anderson Cancer Center,
Houston, TX, USA
An 11 y.o. female presented to a GI specialist with complaints of morning
vomiting and periumbilical abdominal pain for several months. Had progressing symptoms with GI work-up for ~1 year. She developed diplopia
and worsening headaches. Imaging revealed a T2/FLAIR hyperintense massin the 4th ventricle with heterogeneous enhancement and obstructive hydrocephalus. Three T2 bright, non-enhancing, subcentimeter masses identified
in the right cerebellum. Due to poor differentiation between tumor andnormal tissue at brainstem, only partial resection (PR) was feasible. Pathology initially called pilocytic astrocytoma (PA). All symptoms resolved
after PR. Slow progression in the tumor and “satellite” lesions noted over
two years. Second opinion and molecular typing reclassified the tumor as
rosette-forming glioneuronal tumor (RFGNT) with a mutation in PIK3CA.
Therapy started with vinblastine and carboplatin with stable disease x
7 months, discontinued due to allergic reaction to carboplatin. Initiatedtherapy with everolimus, an mTOR inhibitor. The tumor’s characteristics on
imaging changed with initial growth and increase in peripheral enhancement
in one satellite and the primary tumor. Nevertheless, we persevered. When
comparing pre-treatment MRI to most recent 7 months later, there has been
an overall decrease in volume of expansile heterogenous tumor along themargins of the fourth ventricle. The degree of peripheral enhancement associated with the mass has increased. RFGNT is a rare tumor included in
WHO classification since 2007. Ellezam et al identified recurrent PIK3CA
mutations. To our knowledge, this is the only report of treatment targetingthe mutation. We report a radiographic response despite initial growth.

present a 3 year-old male with a non-NF1 optic pathway BRAFV600E mutant
pilocytic astrocytoma and medically intractable epilepsy. He was treatedwith carboplatin and bevacizumab for 1 year, with good tumor responseand vision recovery. He showed stable, non-progressive disease for several
months. He was placed on a ketogenic diet 9 months into treatment andbecame 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 dieton 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)
Eric Bouffet1, James A. Whitlock1, Christopher Moertel2, Birgit Geoerger3,
Isabelle Aerts4, Darren Hargrave5, Kenneth J. Cohen6, Lindsay B. Kilburn7,
Santhosh A. Upadhyaya8, Cynthia Wetmore9, Karen D. Wright10,
Jeea Choi11, Eduard Gasal11, Mark W. Russo11, and Elizabeth Fox8,12;
1Hospital for Sick Children, University of Toronto, Toronto, Ontario,
Canada, 2University of Minnesota Masonic Children’s Hospital,
Minneapolis, Minnesota, USA, 3Department of Pediatric and Adolescent
Oncology, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif,
France, 4Institut Curie, PSL Research University, Oncology Center
SIREDO, Paris, France, 5UCL Great Ormond Street Institute of Child
Health, London, United Kingdom, 6The Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins, Baltimore, Maryland, USA, 7Children’s
National Medical Center, Washington, DC, USA, 8St, Jude Children’s
Research Hospital, Memphis, Tennessee, USA, 9Phoenix Children’s
Hospital, Phoenix, Arizona, USA, 10Dana-Farber Cancer Institute, BostonChildren’s Cancer and Blood Disorders Center, Boston, Massachusetts,
USA, 11Novartis Pharmaceuticals Corporation, East Hanover, New Jersey,
USA, 12Children’s Hospital of Philadelphia, Philadelphia, USA
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, openlabel, 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 V600mutant 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 occurredin 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 stabledisease 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-48. PROLIFIC GROWTH OF BRAF V600E MUTANT PILOCYTICASTROCYTOMA WHILE ON KETOGENIC DIET: CASE REPORT
Patti Batchelder1,2, Anandani Nellan1,2, Charuta Joshi1,2, Adam Green1,2,Michael Handler1,2, and Todd C Hankinson1,2; 1Childrens Hospital
Colorado, Aurora, CO, USA, 2University of Colorado, Aurora, CO, USA

LGG-50. INTEGRATED MOLECULAR AND CLINICAL ANALYSIS
OF 1,000 PEDIATRIC LOW-GRADE GLIOMAS UNCOVERS NOVELSUBGROUPS FOR CLINICAL RISK STRATIFICATION
Uri Tabori1,2, Scott Ryall1,2, Michal Zapotocky1,3, Julie Bennett1,
Liana Nobre1, David Ellison4, Mariarita Santi5, Matthias Karajannis6,
Cynthia Hawkins1,2; 1Hospital for Sick Children, Toronto, ON, Canada,
2University of Toronto, Toronto, ON, Canada, 3Charles University andUniversity Hospital Motol, Prague, Czech Republic, 4St. Jude Children’s
Research Hospital, Memphis, TN, USA, 5Children’s Hospital ofPhiladelphia, Philadelphia, PA, USA, 6Memorial Sloan Kettering Cancer
Center, New York, NY, USA

Epilepsy is a common diagnosis among pediatric patients withsupratentorial tumors, particularly infiltrating gliomas. The ketogenic dietcan be a successful antiepileptic therapy for patients with medically intractable epilepsy. Acetoacetate, a main ketone released during ketosis, has beenshown to increase BRAFV600E binding to MEK1 and MEK1 phosphorylationin BRAFV600E mutant melanoma cells, thereby promoting proliferation andtumor growth (Kang et al, 2015, Xia et al, 2017). BRAFV600E mutation iscommon in pediatric low-grade gliomas. Therefore, use of a ketogenic dietto manage coincident epilepsy could, in theory, promote tumor growth.
However, this has not been previously reported in a human patient. We

Pediatric low-grade gliomas (pLGG) are primarily driven by genetic alterations in the RAS/MAPK pathway, most commonly involving BRAF of
NF1. Despite their molecular convergence, pLGG often show unexplained
variability in their clinical outcome. To address this, we molecularly characterized a cohort of >1,000 clinically annotated pLGG. 84% of cases harboreda detectable driver mutation. The remaining 16% of patients nonethelessshowed RAS/MAPK pathway up-regulation at the RNA level. The clinicalpresentation and outcome of pLGG appeared highly variable and linked
to the alteration type: re-arrangement or SNV. Re-arrangement-driven tumors were diagnosed at a younger age (6.6 versus 10.9 years, p<0.0001),

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enriched for WHO grade I histology (88% versus 66%, p<0.0001), infrequently progressed (27% versus 46%, p<0.0001), and rarely resulted indeath (3 versus 13%, p<0.0001) as compared to SNV-driven tumors. These
included the rarest molecular drivers of pLGG, for which we now havethe clinicopathologic features of including MYB, MYBL1, FGFR2 fusions,
FGFR1-TACC1, FGFR1 SNVs, IDH1 p.R132H, and H3.3 p.K27M. Utilizing
this information, we suggest novel risk categories of pLGG that effectively
predicted patient outcome. Low-risk tumors progressed infrequently andrarely succumbed to their disease (10-year PFS of 71% and OS of 98%).
Intermediate-risk pLGG had a 10-year PFS and OS of 35% and 90%, respectively. High risk pLGG almost invariably progressed (10-year PFS of 0%)
and these patients often succumbed to their disease (10-year OS of 41%).
These data highlight the biological and clinical differences between pLGG
subtypes and offers molecular based risk stratification to these cancers.
LGG-51. BRAF ALTERATIONS IN PEDIATRIC LOW-GRADE
GLIOMAS: RESULTS FROM A BRAZILIAN COHORT
Felipe Restine1, Luis Henrique Sakamoto2,3, Juliana Monte Real3,
Gregorio Pereira3, Jennifer Marx Fernandes3, Simone dos Santos Aguiar2,
and Sidnei Epelman2,3; 1Santa Marcelina Faculty / Department of Medine,
Sao Paolo, SP, Brazil, 2Santa Marcelina Hospital / Department of PediatricOncology, Sao Paolo, SP, Brazil, 3Nucleo Avancado de Pesquisa em
Oncologia / Santa Marcelina Faculty, Sao Paolo, SP, Brazil
BACKGROUND: Pediatric low grade gliomas (PLGG) are the mostcommon central nervous system neoplasms in children. These are driven almost exclusively by alterations in the RAS/MAPK pathway. Specifically, alterations in the BRAF gene have emerged as an important target for therapy. This
study aimed to identify the frequency of BRAF alterations in a Brazilian cohortof PLGGs. RESULTS: Forty-one patients diagnosed between 2001 and 2017
had enough FFPE tissue available for analysis. Real-time PCR test (n=35) wasused to assess for BRAFV600E mutations, while BRAF fusions were detectedby break-apart fluorescence in situ hybridization (n=30). The histologic distribution was as follows: 73% pilocytic astrocytoma, 12% ganglioglioma,
3% diffuse astrocytoma, 5% pleomorphic xanthoastrocytomas (PXA) and
7% NOS (n = 41). BRAF fusions were present in 21 patients (51%): 17
pilocytic astrocytomas, 2 xanthoastrocytoma, 1 pilomyxoid astrocytoma
and 1 diffuse astrocytoma. BRAFV600E was detected in 4 cases (10%): 2
pilocytic astrocytomas, 1 ganglioglioma and 1 PXA. As expected, BRAF
translocations were more frequent in pilocytic astrocytomas (p<0.001). From
22 patients treated in our institution, 59% were male with a mean age of
9.7 years, 50% occurred in the posterior fossa and 77% treated by surgery
only. One patient relapsed and died from disease (BRAF V600E positive)(follow-up median=44.7 months). These are the first results using a CLIA
method showing the frequency of BRAF abnormalities in a Brazilian population. Although preliminary, BRAF alterations are present in 61% of thecases emphasizing the importance of incorporating this analysis in the current work-up guidelines.
LGG-52. BINIMETINIB IN CHILDREN WITH PROGRESSIVE OR
RECURRENT LOW-GRADE GLIOMA NOT ASSOCIATED WITH
NEUROFIBROMATOSIS TYPE 1: INITIAL RESULTS FROM A MULTIINSTITUTIONAL PHASE II STUDYNathan Robison1,2, Jasmine Pauly1, Jemily Malvar1, Sharon Gardner3,
Jeffrey Allen3, Tobey MacDonald4, Dolly Aguilera4, Patricia Baxter5,
Anne Bendel6, Lindsay Kilburn7, Sarah Leary8, Daniel Bowers9,
Kathleen Dorris10, Karen Gauvain11, Elizabeth Alva12, Kenneth Cohen13,
Kellie Nazemi14, Yi Juin Tan1, Ashley Margol1,2, Girish Dhall12,
Tena Rosser1,2, Tom Davidson1,2, Ashley Plant15, Nicole Ullrich16,17,
Pratiti Bandopadhayay17,16, Nathalie Agar17, Keith Ligon17,16,
Richard Sposto2, Karen Wright17,16, and Mark Kieran17; 1Children’s
Hospital Los Angeles, Los Angeles, CA, USA, 2University of Southern
California Keck School of Medicine, Los Angeles, CA, USA, 3New York
University School of Medicine, New York, NY, USA, 4Emory University,
Atlanta, GA, USA, 5Texas Children’s Hospital, Houston, TX, USA,
6Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, USA,
7Children’s National Hospital, Washington, DC, USA, 8Seattle Children’s
Hospital, Seattle, WA, USA, 9University of Texas Southwestern Medical
Center, Dallas, TX, USA, 10Children’s Hospital Colorado, Aurora, CO,
USA, 11Washington University School of Medicine, St Louis, MO, USA,
12University of Alabama, Birmingham, AL, USA, 13Johns Hopkins
University, Baltimore, MD, USA, 14Oregon Health and Science University,
Portland, OR, USA, 15CHOC Children’s, Orange, CA, USA, 16BostonChildren’s Hospital, Boston, MA, USA, 17Dana-Farber Cancer Institute,
Boston, MA, USA
BACKGROUND: RAS/RAF/MEK/ERK pathway activation is the primary driver for most pediatric low-grade gliomas (LGG). Binimetinib isan orally bioavailable MEK1/2 inhibitor found to have significant central
nervous system penetration in a preclinical model. OBJECTIVE: The pri-iii376

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De c e mb e r 2 0 2 0mary objective of this multi-institutional open-label phase II study was toassess preliminary efficacy of binimetinib in progressive pediatric LGG.
The study included strata for both neurofibromatosis type I (NF1) andnon-NF1 associated tumors, as well as a target validation (surgical) stratum.
NF1 and surgical strata remain open to enrollment and will be reported
separately. METHODS: Children aged 1–18 years with previously treatedrecurrent or progressive LGG were eligible. The dose of binimetinib was
32 mg/m2/dose twice daily. Partial and minor responses were defined, respectively, as 50% and 25% decrease in maximal two-dimensional measurements. RESULTS: Fifty-seven eligible patients without NF1, median age
8 years, were enrolled and began treatment; 26 were female; 28 had documented KIAA1549-BRAF fusion. Eleven patients discontinued drug in thefirst year due to toxicity, and an additional 27 required dose reduction. The
most common drug-attributable grade 3 toxicities included creatine kinase
elevation (n=9 patients), rash (n=8), and truncal weakness (n=8). Truncal
weakness improved or resolved with dose reduction or cessation. Grade 4
toxicities included creatine kinase elevation (n=2) and transient colitis (n=1).
Of 44 patients with preliminary response data available, 22 (50%) showeda minor (n=7) or partial (n=15) response. CONCLUSION: Binimetinib isactive, with manageable toxicities, in children without NF1 with progressive LGG.
LGG-53. PNOC001 (NCT01734512): A PHASE II STUDY OF
EVEROLIMUS FOR RECURRENT OR PROGRESSIVE PEDIATRICLOW-GRADE GLIOMAS (PLGG)
Sabine Mueller1, Mariam Aboian2, Kellie Nazemi3, Karen Gauvain4,
Janet Yoon5, Jane Minturn6, Sarah Leary7, Mohamed S. AbdelBaki8,
Stewart Goldman9, Jennifer Elster5, Adam Resnick6, Annette M. Molinaro1,
Joanna Phillips1, Michael Prados1, and Daphne Haas-Kogan10; 1Universityof California, San Francisco, San Francisco, CA, USA, 2Yale University,
New Haven, CT, USA, 3Oregon Health & Science University, Portland,
OR, USA, 4Washington University School of Medicine, St, Louis, MO,
USA, 5University of California, San Diego, San Diego, CA, USA, 6Children’s
Hospital of Philadelphia, Philadelphia, PA, USA, 7University of Washington,
Seattle Children’s, Seattle, WA, USA, 8Nationwide Children’s Hospital,
Columbus, OH, USA, 9Ann & Robert H. Lurie Children’s Hospital of
Chicago, Chicago, IL, USA, 10Dana-Farber Cancer Institute, Boston, MA,
USA
OBJECTIVE: To estimate the 6-month Progression Free Survival(PFS6) associated with everolimus for progressive/recurrent pLGGs andto determine if activated PI3K/Akt/mTOR pathway as measured by positive phosphorylated-ribosomal protein S6 (p-RPS6) status was associatedwith response. METHOD: Patients 3–21 years of age with recurrent or
progressive pLGG were enrolled. Everolimus was administered orally at
5 mg/m2 daily. Tissue availability for molecular analysis was mandatory.
Immunohistochemistry (IHC) for p-RPS6 was performed centrally. An adaptive Simon two-stage design was employed based on p-RPS6 status. Basedon results of the first stage, enrollment in the second stage was either limited
to pathway activated patients or open to all subjects. RESULTS: From December 2012 to July 2019 a total of 65 subjects enrolled [median age 9 years(range 3–19); 43% female]. As of December 15, 2019 median number oftreatment cycle is 8 (range 1–24); 7 patients remain on treatment. Toxicity
profile is similar to published reports with rash and elevated lipid profiles
as most common adverse events. PFS6 for the entire cohort is 63%; PFS6
is 64% for the activated and 61% for the non-activated patients. Central
imaging review (n=52) revealed 1 partial response, 1 complete response, 33
stable disease, and 17 progressive disease at the end of study treatment. Initial molecular analysis identified BRAF alterations in 35/65 patients. CONCLUSION: Everolimus is well tolerated and active in a subset of pLGGs.
Ongoing analyses will assess predictive biomarkers of response and will bereported at the meeting.
LGG-54. DETECTION OF THE KIAA1549-BRAF FUSION GENE
IN CELLS FORMING MICROVASCULAR PROLIFERATIONS INPILOCYTIC ASTROCYTOMA
Shinji Yamashita, Hideo Takeshima, Kiyotaka Saito, Takashi Watanabe,Hajime Ohta, and Kiyotaka Yokogami; Division of Neurosurgery,
Department of Clinical Neuroscience, Faculty of Medicine, University ofMiyazaki, Miyazaki, Japan
Microvascular proliferation (MVP), an aberrant vascular structure is ahistopathological 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Abstracts

distinct tumor cells expressing vascular markers. Samples from three PA patients harbored the KIAA1549 exon 15, BRAF exon 9 fusion gene. In twopatient 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. Ourfindings 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 GLIOMASTREATED WITH TARGETED BRAF INHIBITION
Liana Nobre1, Michal Zapotocky2, Vijay Ramaswamy1, Scott Ryall1,
Julie Bennet1, Daniel Alderete3, Julia Balaguer Guill4, Lorena Baroni3,
Ute Bartels1, Abhishek Bavle5, Miriam Bornhorst6, Daniel R. Boue’7,
Adela Canete4, Murali Chintagumpala8, Scott L. Coven9,
Ofelia Cruz10, Sonika Dahiya11, Peter Dirks1, Ira J. Dunkel12,David Eisenstat13, Cecile Faure Conter14, Elizabeth Finch15,
Jonathan L. Finlay7, Didier Frappaz16, Maria Luisa Garre17,
Karen Gauvain18, Anne Grete Bechensteen19, Jordan R. Hansford20,
Inga Harting21, Peter Hauser22, Lili-Naz Hazrati1, Annie Huang1,
Sarah G. Injac8, Valentina Iurilli17, Matthias Karajannis12,
Gurcharanjeet Kaur12, Martin Kyncl2, Lenka Krskova2,
Normad Laperriere1, Valerie Larouche23, Alvaro Lassaletta24,
Sarah Leary25, Frank Lin8, Samantha Mascelli17, Tara McKeown1,
Till Milde21, Andres Morales La Madrid26, Giovanni Morana17,
Helena Morse27, Naureen Mushtaq28, Diana S. Osorio7, Roger Packer6,
Zdenek Pavelka29, Eduardo Quiroga-Cantero30, James Rutka1,
Magnus Sabel31, Duarte Salgado32, Palma Solano30, Jaroslav Sterba29,
Jack Su8, David Sumerauer2, Michael D Taylor1, Helen Toledano33,
Derek S Tsang1, Mariana Valente Fernandes32, Frank van Landeghem13,
Cornelis M van Tilburg21, Bev Wilson13, Olaf Witt21, Josef Zamecbik2,
Eric Bouffet1, Cynthia Hawkins1, and Uri Tabori1; 1The Hospital For Sick
Children, Toronto, ON, Canada, 2University Hospital Motol, Prague,
Czech Republic, 3Hospital of Pediatrics S,A,M,I,C, Prof, Dr, Juan P,
Garrahan, Buenos Aires, Argentina, 4Hospital Universitario y Politécnico
La Fe, Valencia, Spain, 5Oklahoma Health Sciences Center, Oklahoma City,
OK, USA, 6Children’s National Health System, Washington, DC, USA,
7Nationwide Children’s Hospital, Columbus, OH, USA, 8Texas Children’s
Cancer Center, Houston, TX, USA, 9Indiana University, Indianapolis,
IN, USA, 104Hospital Sant Joan de Déu, Barcelona, Spain, 11Washington
University School of Medicine, St Louis, MO, USA, 12Memorial Sloan
Kettering Cancer Center, New York, NY, USA, 13Stollery Children’s
Hospital, Edmonton, AB, Canada, 14Institute d’Hémato-Oncologie
Pédiatrique, Lyon, Canada, 15University of North Carolina, Chapel Hill,
NC, USA, 16Institute d’Hémato-Oncologie Pédiatrique, Lyon, France,
17G,Gaslini Children’s Hospital, Genoa, Italy, 18Washington University,
St Louis, MO, USA, 19Oslo University Hospital, Oslo, Norway, 20The
Royal Children’s Hospital, Melbourne, Australia, 21Hopp Children’s
Cancer Center, Heidelberg, Germany, 22Semmelweis, Budapest, Hungary,
23Ubiversite Laval, Quebec City, Canada, 24Hospital Infantil Universitario
Nino Jesus, Madrid, Spain, 25Seattle Children’s Hospital, Seattle, WA, USA,
26Hospital Sant Joan de Déu, Barcelona, Spain, 27Lund University, Lund,
Sweden, 28Aga Khan University Hospital, Karachi, Pakistan, 29University
Hospital Brno, Brno, Czech Republic, 30Hospital Infantil Virgen delRocío, Sevilla, Spain, 31University of Gothenburg, Gothenburg, Sweden,
32Portuguese Cancer Institute, Lisbon, Portugal, 33Schneiders Children’s
Medical Center Of Israel, Petah Tikva, IsraelChildren with pediatric gliomas harboring BRAF V600E mutation havea poor outcome with current chemoradiation strategies. Our aim was tostudy the role of targeted BRAF inhibition in these tumors. We collectedclinical, 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 comparedto 28% with conventional chemotherapy (p<0.001). These responses wererapid (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, uponre-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%) vs29.8% (95% CI, 20% to 44.4%) for BRAFi vs chemotherapy respectively(p=0.02). The use of BRAFi results in robust and durable responses whileon therapy in BRAF V600E PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAFi therapy inchildhood gliomas.
LGG-56. INFANTILE HEMISPHERIC BRAIN TUMOR WITH A GOPCROS1 FUSION GENE: A CASE REPORT
Rieko Taniguchi1, Atsushi Natsume2, Nozomu Kawashima1,
Shinji Tanioka3, Hideki Muramatsu1, Motoharu Hamada1,
Daisuke Ichikawa1, Masayuki Imaya1, Kotaro Narita1,
Michihiro Kurimoto1,2, Yoshiki Shiba2, Kosuke Aoki2, Fumiharu Ohka2,Junko Hirato4,5, Toshihiko Wakabayashi2, and Yoshiyuki Takahashi1;
1Department of Pediatrics, Nagoya University Graduate School of
Medicine, Nagoya, Japan, 2Department of Neurosurgery, Nagoya
University Graduate School of Medicine, Nagoya, Japan, 3Department ofPediatrics, Nagasaki University Hospital, Nagasaki, Japan, 4Department of
Pathology, Gunma University Hospital, Maebashi, Japan, 5Department of
Pathology, Public Tomioka General Hospital, Tomioka, JapanINTRODUCTION: Infantile hemispheric gliomas with ROS1 fusion
genes have been reported to have a relatively poor prognosis. Treatmentusing a ROS1 inhibitor is expected to generate less toxicity and effective
for brain tumors with ROS1 fusion genes. CASE PRESENTATION: A onemonth-old female presented with a seizure, and a large hypervascular massin the right hemisphere was found on MRI. The tumor was not biopsied
over concerns of an increased risk for bleeding. The mass was clinicallydiagnosed as an atypical teratoid rhabdoid tumor. She received neoadjuvant
chemotherapy using the modified EU-RHAB protocol. The tumor gradually
decreased to 70% of its original size with a reduction of vascularity. A neartotal resection (> 95%) was performed at eight months of age. Pathologicalexamination revealed the unusual histology with immunostaining positive for INI-1, GFAP, synaptophysin, neurofilament, and slightly positive
for NeuN. MIB-1 labeling index was 6%. The pathological diagnosis wasa glioneuronal tumor with desmoplastic infantile ganglioglioma-like features, suggestive of low grade. She received adjuvant chemotherapy withcarboplatin and vincristine, which is the standard treatment for low-grade
gliomas, and achieved a partial response. The GOPC-ROS1 fusion gene was
detected in the tumor by FoundationOneⓇ CDx. CONCLUSION: Chemotherapy may effectively reduce the size of an infant’s brain tumor which is
initially considered to be inoperable. A gene profile should be performed assoon as possible in order to direct appropriate management.
LGG-57. SIGNALLING MECHANISMS IN PAEDIATRIC LOW-GRADE
GLIOMA
Ankit Patel1, Tania Jones1, Lewis Woodward1, Arran Dokal2,
Vinothini Rajeeve2, Pedro Cutillas2, Thomas Stone3,4, Thomas Jacques3,4,and Denise Sheer1; 1Barts and the London School of Medicine andDentistry, London, United Kingdom. 2Barts Cancer Institute, London,
United Kingdom. 3UCL Great Ormond Street Institute of Child Health,London, United Kingdom. 4Great Ormond Street Hospital for Children
NHS Foundation Trust, London, United Kingdom
Paediatric low-grade gliomas (pLGGs) constitute the largest group ofchildhood CNS tumours. They often cause significant disability and morbidity, despite their indolent growth and the good survival rate of patients.
The most common genetic alterations in these tumours, KIAA1549:BRAF
fusion and BRAFV600E mutation, lead to abnormal activation of MAPK
signalling. The central role of this pathway in pLGG development is emphasized by the occasional presence of other MAPK-activating alterations
such as RTK mutations. It is not known how these different aberrations can
induce the variety of clinical phenotypes seen in pLGG. Here, we comparedpilocytic astrocytomas (PAs) containing the KIAA1549:BRAF fusion withglioneuronal tumours (GNTs) containing the BRAFV600E mutation, toidentify differentially activated downstream targets of the MAPK pathway.
Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used
as a multi-proteomic approach. Kinase Set Enrichment Analysis (KSEA)
using PhosphositePlus and NetworkIN was used to determine relative enrichment of kinase activity in the tumours compared to healthy control brain
tissue. Significant similarities and differences were found in the two tumour
types. For example, more robust MAPK activation was found in the GNTs
than in PAs. However, while PI3K/AKT1/mTOR signalling was active inboth PAs and GNTs, there was statistically higher activation in the PAs. In
both tumour types, there was significant reduction in casein kinase 2 activity,
which likely affects nuclear translocation of ERK and, in turn, alters therange of its phosphorylated substrates. We will present these data together
with transcriptomics to further characterise the downstream targets of thesegenetic alterations.

N E U R O -O N C O L O G Y•

D e ce mb e r 2 0 20

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Abstracts

PEDIATRIC NEURO-ONCOLOGY IN ASIA AND OTHER LOW/
MIDDLE INCOME COUNTRIESLINC-01. COMPLIANCE TO FOLLOW UP IN PEDIATRIC PATIENTSWHO HAVE RECEIVED CRANIOSPINAL IRRADIATION
Khin Pyone1, Thwe Tun1, Yin Win1, Aye Thinn1, Khin Win1, Tint Hnin2,
and Aye Khaing2; 1Yangon General Hospital, Yangon, Yangon, Myanmar.
2Yangon Children Hospital, Yangon, Yangon, Myanmar
OBJECTIVE: Attendance to follow-up after completion of cancer treatment is understudied area. Pediatric cancer patients have sequelae of illness
or treatment. Many have no symptom immediately after completion oftreatment. Long term follow-up is important to access disease control, early
diagnosis of recurrence, second cancer and treatment-related morbidities.
Purpose of this study was to evaluate the compliance to follow-up in pediatric patients treated with craniospinal irradiation (CSI). METHODS: Thiswas retrospective review of follow-up in pediatric neuro-oncology patients
who received (CSI) from January 2017 to June 2018 in the Radiotherapy
Department of Yangon General Hospital, Myanmar. RESULT: Twenty-threepatients received CSI; majority (43%) were medulloblastoma. Median age
was 7.5 years (3–17 years). Only seven patients (30.4%) were attended tofollow-up more than 6 months after completion of treatment. More than
two-thirds of patients (n=16,69.6%) were lost to follow-up. Patients in active follow-up were diagnosed and treated at earlier age below 10years(n=5,21.7%). Demographically, 5 patients (22%) were living in the region
around tertiary hospital. Sixteen patients (69.6%) from rural area had limited
transportation and difficulty for accommodation in which they were treated.
In socioeconomic points, 18 parents (78.2%) had poor education and financial status, lack of understanding about disease, treatment, long-term effects
and follow-up. CONCLUSION: Although this was limited data in CSI patients only, loss to follow-up after 6 months was high. We need to evaluate
in all pediatric cancer patients and collaborate to provide financial support,childcare centres for lodging, transportation and health education to promotecompliance to follow-up.
LINC-02. IMPLEMENTATION OF AN INTEGRATED NEUROONCOLOGY SERVICE: CLINICIANS’ PERSPECTIVE ON CONDUCTOF NEURO-ONCOLOGY MULTIDISCIPLINARY TEAM MEETINGFROM A SINGLE-INSTITUTION IN MALAYSIA
Jen Chun Foo, Jawin Vida, Ariffin Hany, Pei Yuin Loh,
Sockalingam Sutharsan, Ganesan Dharmendra,
Thambinayagam Hari Chandran, and Rajagopal Revathi; University
Malaya Medical Centre, Kuala Lumpur, Federal Territory, Malaysia
INTRODUCTION: Multidisciplinary Team (MDT) meetings are essential in the management of complex cancer cases. There are limited data
regarding clinicians’ perception on conduct of neuro-oncology MDT meetings and its impact on clinical management. In University Malaya Medical
Centre (UMMC), weekly neuro-oncology MDT meeting was established since2013 to discuss adult and paediatric complex central nervous system tumour
cases. OBJECTIVE: To determine clinicians’ perception and level of satisfaction of neuro-oncology MDT meeting. METHODOLOGY: Web-based questionnaire was distributed via e-mail to all neuro-oncology MDT clinicians at
UMMC in April 2019. RESULT: Eighteen out of 20 clinicians responded tothe survey. Respondents were: neurosurgeons (n=5), adult oncologists (n=4),
paediatric oncologists (n=3), radiologists (n=2), radiation oncologists (n=2)
and pathologists (n=2). Majority of clinicians (65%) agreed at current weekly
MDT meeting with maximum length of one hour duration and 75% of themsuggested to discuss 5 to 10 cases during each meeting. Almost all of them
(94.4%) preferred e-mail as method of communication to disseminate information before and after the meetings. MDT members expected 100% attendance from neurosurgeons. Fourteen (70%) clinicians agreed that patients/
parents/ carers do not receive copy of MDT meeting plans and only seven(35%) clinicians document MDT meeting plans in patients’ medical record.
Overall, all clinicians felt that MDT meeting improved decision-making process, enhanced continuity of coordinated care and promoted good communication among team members. CONCLUSION: The structure and logistics ofneuro-oncology MDT meeting in UMMC are generally agreed upon. However, documentation of post-meeting plan and notification to patients need
uniformity.
LINC-03. MOLECULAR CLASSIFICATION OF PAEDIATRICMEDULLOBLASTOMA FROM FOUR TERTIARY CENTRES IN
MALAYSIA: DIAGNOSTIC DILEMMA WITH CONVENTIONALMETHODS
Revathi Rajagopal1, Vida Jawin1, Ay Jiuan Teng2, Oy Leng Wong2,
Kein Seong Mun1, Hakimah Mahsin3, Nor Haizura Abd Rani4,
Kogilavani Gunasagaran4, Seoh Leng Yeoh3, Gek Bee Ong2, Hany Ariffin1,

iii378N EU R O - O N C O L O G Y•

De c e mb e r 2 0 2 0David Jones5, and Nicholas G Gottardo6,7; 1University Malaya Medical
Centre, Kuala Lumpur, Kuala Lumpur, Malaysia, 2Sarawak General
Hospital, Kuching, Sarawak, Malaysia, 3Penang General Hospital, Penang,
Penang, Malaysia, 4Sabah Woman and Children’s Hospital, Likas, Sabah,
Malaysia, 5Brain Tumour Research Centre, Heidelberg, Heidelberg,
Germany, 6Perth Children’s Hospital, Perth, WA, Australia, 7Brain Tumour
Research Programme, Telethon Kids Institute, Nedlands, WA, Australia
OBJECTIVE: To determine the prognostic significance of the fourmolecular 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 otherreports, followed by SHH (56.8±17%), Group4 (44.3±17.6%) andGroup3 (41.7±18%). Treatment abandonment rate was 20%. CONCLUSION: The discrepancy in the histological diagnoses highlights theimportance of DNA methylation profiling technique for accurate diagnosis. We observed poor OS across all the subgroups, in part due totreatment abandonment.
LINC-04. POSSIBLE ROLE OF NEOADJUVANT CHEMOTHERAPY IN
METASTATIC PURE GERMINOMA IN LOW AND MIDDLE INCOME
COUNTRIES. A PRO POS OF A CASE
Carlos Leal-Cavazos, Paola Escamilla-Luna, Marissa Fernandez-De Luna,
and Oscar Vidal-Gutierrez; Hospital Universitario “Dr.Jose Eleutetrio
Gonzalez”, Monterrey, NL, Mexico
BACKGROUND: CNS germ cell tumors represent about 3–5 % ofpediatric brain tumors, 60% are pure germinomas. Germinomas arevery sensitive to chemotherapy which has helped to reduce volume anddose of radiotherapy in localized disease while maintaining excellent
survival. In metastatic disease the SIOP GCT-96 trial showed no benefit
with addition of chemotherapy to craniospinal irradiation alone. Radiotherapy maybe not readily available in Low/Middle Income Countries(LMIC). METHOD: We describe a patient in which the use of neoadjuvant
chemotherapy helped to rescue vision. The patient is a 9 year old female
with a 3 months history of morning headaches and vomits. Visual decline
was noticed a month before admission when the child had completely loss
vision of the right eye and left eye was partially affected. MRI showeda large suprasellar mass with ventricular nodules. Beta-hGC in CSF was
mildly elevated. Patient received 2 cycles of carboplatin/etoposide. After
first cycle there was a complete vision recovery in both eyes. After thesecond course the MRI showed complete response in primary and metastatic disease. Patient received CSI (24Gy + 16 Gy Boost) after 2 cycles ofchemotherapy. Chemotherapy was very well tolerated without side effects.
Patient vision is 20/20 in both eyes without deficit in visual fields. CONCLUSION: Although the addition of chemotherapy in metastatic
germinoma has no clear role in reducing radiotherapy it could possible
help selected patients in attempt to rescue vision when radiotherapy is notreadily available.
LINC-05. PRIMARY CENTRAL NERVOUS SYSTEM EWINGSARCOMA IN PEDIATRIC AND AYA PATIENTS: 2 INSTITUTIONSEXPERIENCE IN BUENOS AIRES ARGENTINA
Roberto Nicolas Palomar1,2, Florencia Yorio2, Lucas Alessandro2,
Naomi Arakaki2, Alejandro Muggeri2, Mercedes Garcia Lombardi1,
and Blanca Diez2; 1Hospital Gutiérrez, CABA, Buenos Aires, Argentina,
2FLENI, CABA, Buenos Aires, Argentina
INTRODUCTION: Ewing Sarcoma (ES) is defined by molecular markers,
being t(11;22)(q24;q12) the most frequent. Intracranial ES usually shows asmetastases from extracranial sites. Primary central nervous system (CNS)
lesions are extremely rare. MATERIAL AND METHODS: Retrospective
review of clinical records from patients with primary CNS ES, assessed at 2

Abstracts

institutions in Argentina between 2007–2019. Translocation was evidenced
in all cases through molecular testing. Clinical characteristics, imaging,histopathology, and treatment response were evaluated. Extracranial andosseous lesions were excluded. RESULTS: 15 patients. Median age at beginning of symptoms: 8 yo (2–20). Most patients had intracranial hypertension
syndrome (14/15). In brain MRI, 5/15 supratentorial lesions, 4/15 posterior
fosa, 1/15 medullary, 2/15 supra and infratentorial, and 3/15 lesions diffuse
leptomeningeal infiltration. Histopathologic findings showed diffuse patternwith small round blue cells in most cases, other patterns were also described.
CD99 marked positive in all cases. Misdiagnosis with glial tumors (4/15),
medulloblastoma (6/15) and infectious diseases (3/15); led to median delay
to accurate diagnosis of 3 months (range 0–67). After correct diagnosis patients were treated with standard ES treatment (6 VIDE cycles plus radiotherapy) in 14/15 patients. Vincristine, irinotecan and temozolamide wasused as second line treatment in all relapse cases whenever possible. EFS was
22 months (2- 65). OS at 5 years of follow-up was 46,67% (mean OS 31mo). CONCLUSION: Even though molecular assessment led to accurate
diagnosis in all cases, treatment response and outcome showed two different
groups of patients with long and very short survival. Adaptative therapy
should be considered.
LINC-06. OBSERVATION ONLY IN A PATIENT WITH SUSPECTEDLOW GRADE GLIOMA. SHOULD NEUROSURGERY ALWAYS BE THE
FIRST STEP IN LOW AND MIDDLE INCOME COUNTRIES?
Carlos Leal - Cavazos, Jose Arenas-Ruiz, and Oscar Vidal-Gutierrez;
Hospital Universitario “Dr.Jose Eleuterio Gonzalez”, Monterrey, NL,
MexicoBACKGROUND: 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 ofprivate neurosurgeons with a uniformly dismal prognosis and high risk morbidity from procedures offered. When first seen at our Hospital, the clinicalhistory 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 whitematter, insula, internal capsule, hipoccampus, thalamus and mesencephalus
with middle cerebral artery encasement. Interval imaging was proposed andafter 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 teamconsiderations. In centers with significant neurosurgical morbidity, biopsy oflarge tumors that are compatible with LGG may not be required in selectedcases.
LINC-07. PREVALENCE AND SPECTRUM OF EARLY ENDOCRINEDISORDERS IN SURVIVORS OF PEDIATRIC EMBRYONAL BRAIN
TUMORS (PEBT): EXPERIENCE FROM INDIA
Maya Prasad1, Kalasekhar Vijayasekharan Nair1, Rahul Krishnatry1,
Girish Chinnaswamy1, Tejpal Gupta1, and Sudha Rao2; 1Tata Memorial
Centre, Mumbai, India. 2BJ Wadia Childrens Hospital, Mumbai, India
BACKGROUND: Survivors of pediatric brain tumors are at high risk ofdeveloping endocrine disorders, potentially impacting growth,development
and quality of life. METHODS: etrospective audit of 2-year survivorsof PEBT(3-18years at diagnosis)viz. medulloblastoma(MB),Central nervous system Primitive neuro-ectodermal tumors(CNS-PNET) and atypicalteratoid/rhabdoid tumor(ATRT) treated January 2006-December 2017 at
Tata Memorial Centre,Mumbai, with surgery, cranio-spinal irradiation(CSI;
35Gy in high-risk MB,CNS-PNET,ATRT and 23.4Gy in average-risk MB
with tumor boost 19.8Gy)and six cycles of adjuvant chemotherapy(cycloph
osphamide,cisplatin and vincristine).Patients were followed up by a paediatric endocrinology team specialized in management of PEBT. RESULTS: Of
249 PEBT treated during this period,88 are alive in remission >2 years (69MB, 15-CNS PNET,4-ATRT),median age at diagnosis 6 years. At a medianfollow-up of 5.6 years (range 3- 12.5years),63 patients(72%) had at least one
endocrine disorder,26(29.%)≥2 hormonal deficiencies. The most common
endocrine disorders were central hypothyroidism(57%),growth hormone
deficiency(40%), central hypogonadism(5%)and central hypoadrenalism(3.5%).The median time to develop hypothyroidism was 2.8 years(range
5months to 8.5 years) from CSI. Growth hormone replacement therapy
began after a median period of 4.2 years(range-1.5 to 11.5years) from
CSI. Higher dose of CSI was associated with development of endocrine

disorder (odds ratio [OR] 2.71; 95% CI, 1.03 to 7.04,p-0.04). CONCLUSIONS: The high incidence of endocrine deficits in survivors of PEBT necessitates early and lifelong monitoring. Early and appropriate management is
crucial to achieve full growth potential.
LINC-08. INCREASED TREATMENT TOXICITIES AND INFERIOROUTCOMES IN UNDERNOURISHED CHILDREN WITH BRAINTUMOURSMaya Prasad, Ekta Chheda, Girish Chinnaswamy, Tejpal Gupta,
Rahul Krishnatry, Tushar Vora, and Jayant Godashastri; Tata Memorial
Centre, Mumbai, India
BACKGROUND: Children on treatment for brain tumours are known to
be at high risk of undernutrition, the impact on outcome and toxicity is notwell understood. METHODS: Retrospective audit of children(<18 years)
diagnosed January 2017-December 2018 with embryonal brain tumours(medulloblastoma, primitive neuro-ectodermal tumors, pinealoblastoma,atypical teratoid/rhabdoid tumour) and treated at our centre. Data wasretrieved from case records and electronic medical records. Nutritional
status(NS) was defined as per World Health Organization (WHO) into
severe malnutrition (SAM),moderate malnutrition (MAM),well nourished (WN) and overweight. Undernutrition(UN) was defined as SAM/
MAM.Toxicity was documented till end of treatment,defined as treatment
delay>1week,significant infection or toxic death. RESULTS: Of 124 eligible patients who received entire chemotherapy at our centre, NS data
was available in 73 at diagnosis and 58 at follow-up. At diagnosis-29,16,26
and 2 and at follow-up-20,16,22 and 0 were SAM,MAM,WN and overweight. During treatment, weight gain was documented in 26%, stableweight in 55% and weight loss in 19%. Those UN at diagnosis had worse
outcomes at follow-up with 70% alive in remission compared to 88% ofWN(p-0.14). There was increased toxicity in UN group(50%) compared to
WN(24%),p-0.04.All 3 toxic deaths were in UN. Those who lost weight
during treatment had higher toxicities(70%) compared to those with stableweight (30%)or weight gain(20%),p-0.02. CONCLUSIONS: In spite ofnutritional intervention, children on treatment for brain tumours tend tolose weight. Increased treatment toxicities and inferior outcomes in undernourished children with brain tumours necessitates proactive and aggressive
nutritional monitoring and intervention.
LINC-09. TREATMENT AND OUTCOME IN CHILDREN WITH
LOW-GRADE GLIOMAS IN WESTERN MEXICO: EXPERIENCE AT
HOSPITAL CIVIL DE GUADALAJARA
Regina M Navarro-Martin del Campo1,2, Erika Casillas -Toral1,
Ana L Orozco-Alvarado3, Fernando Sanchez-Zubieta1,
Luis A Arredondo-Navarro4,2, and Lorelai Gutierrez-Oliva4; 1Hospital
Civil de Guadalajara “Dr. Juan I Menchaca”, Guadalajara, Jalisco, Mexico,
2Gapno, International, Mexico, 3Hospital Civil de Guadalajara “Dr. Juan
I Menchaca”, Guadalajara, Jalisco, Mexico, 4Hospital Civil de Guadalajara“Fray Antonio Alcalde”, Guadalajara, Jalisco, Mexico
BACKGROUND: Brain tumors are the most common solid tumors inchildhood, 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 ofclinical 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 byobservation 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 grosstotal resection, 44% subtotal resection and 16% only biopsy. One or morerecurrences were found in 20 % of patients. The 5 and 10-year overall survival (OS) was 83% and 73% respectively. The 5 and 10-year progressionfree 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-10. SIOP PODC ADAPTED TREATMENT GUIDELINESFOR CRANIOPHARYNGIOMA IN LOW- AND MIDDLE-INCOMESETTINGS
Nisreen amayiri1, Ariane Spitaels2, Mohamed Zaghloul3, Anthony Figaji4,
Sergio Cavalheiro5, Hermann L. Muller6, Moawia Elhassan7,
Jeannette Parkes8, Naureen Mushtaq9, Mohamed El Beltagy10,

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Yacoub Yousef11, Natia Esiashvili12, Michael Sullivan13,
Marcos Devanir da Costa14, Patricia Dastoli14, Fatima Mubarak15,
Ute Bartels16, Omar Chamdine17, Alan Davidson18, Awni Musharbash19,
Patricia Alcasabas20, Eric Bouffet16, and Simon Bailey21; 1PediatricOncology Department, King Hussein Cancer Center, Amman, Jordan,
2Division of Endocrinology, Department of Pediatric Medicine, Facultyof Health Sciences, UCT, Cape Town, South Africa, 3Radiation Oncology
Department, National Cancer Institute, Cairo University & Children’s
Cancer Hospital, Cairo, Egypt, 4Department of Neurosurgery, Red Cross
War Memorial Children’s Hospital and University of Cape Town, CapeTown, South Africa, 5Division of Neurosurgery, Pediatric Oncology
Institute/GRAACC, Universidade Federal de São Paulo, São Paulo, Brazil,
6Department of Pediatrics and Pediatric Hematology/Oncology, University
Children’s Hospital, Klinikum Oldenburg AöR, Oldenburg, Germany,
7Clinical Oncology department, National Cancer Institute, Universityof Gezira, Gezira State, Sudan, 8Department of Radiation Oncology,
University of Cape Town and Groote Schuur Hospital, Cape Town, South
Africa, 9Department of Pediatric Hematology and Oncology, Aga Khan
University Hospital, Karachi, Pakistan, 10Department of Neurosurgery,
Kasr Al-Ainy School of Medicine, Children’s Cancer Hospital Egypt, Cairo,
Egypt, 11Opthalmology division/ Surgery department, King Hussein Cancer
Center, Amman, Jordan, 12Radiation Oncology Department, Winship
Cancer Institute, Emory University, Atlanta, GA, USA, 13Department ofPediatric Hematology and Oncology, Royal Hospital for Sick Children,
Melbourne, Australia, 14Division of Neurosurgery, Pediatric Oncology
Institute/GRAACC, Universidade Federal de São Paulo, Sao Paulo,
Brazil, 15Radiology Department, Aga Khan University, Karachi, Pakistan,
16Division of Hematology/Oncology, Hospital for Sick Children, Toronto,
ON, Canada, 17Department of Pediatric Hematology Oncology and stem
cell transplantation, King Fahad Specialist Hospital, Dammam, Saudi
Arabia, 18Hematology-Oncology Service, Red Cross Children’s Hospital,
Department of Pediatrics and Child Health, University of Cape Town, capetown, South Africa, 19Neurosurgery division/Surgery department, King
Hussein Cancer Center, Amman, Jordan, 20University of the PhilippinesPhilippine General Hospital, Manila, Philippines, 21Department of PediatricOncology, Great North Children’s Hospital, Newcastle, United Kingdom
Pediatric craniopharyngioma is a rare tumor with excellent survival but
significant long-term morbidities due to the loco-regional tumor growth orsecondary to its treatment. Visual impairment, panhypopituitarism, hypothalamic damage and behavioral changes are amongst the main challenges.
This tumor should be managed under the care of a multidisciplinary team
to determine the optimum treatment within the available resources. Thisis particularly important for low middle-income countries (LMICs) where
resources are variable. We provide a risk-stratified management guideline
for children diagnosed with craniopharyngioma in a resource limited setting
based on the service levels describing the facilities and personnel required for
management as previously specified by the Pediatric Oncology in Developing
Countries (PODC) committee of The International Society of Pediatric Oncology (SIOP). A multi-disciplinary group of neurosurgeons, radiation andpediatric oncologists, radiologists, pediatric endocrinologists and an ophthalmologist with experience in managing children with craniopharyngioma
in LMIC setting was formed and carried online meetings to form a consensus guideline. The clinical characteristics (including the visual and endocrine presentations), suggestive radiological features as well as potential
treatment options including surgery, radiotherapy and intra-cystic therapies
were discussed in depth and in relation to available resources. In addition,
hormonal management, pre- and post-operative PICU care and expected
future complications related to craniopharyngioma and to follow up thesechildren were discussed and documented in the guideline. We believe thisguideline is a useful reference for health care providers in LMIC.
LINC-11. NEUROPATHOLOGY REVIEW OF LATIN AMERICANCHILDHOOD AND ADOLESCENT BRAIN TUMOR PATIENTS:
A MULTI-NATIONAL, MULTI-DISCIPLINARY PEDIATRIC NEUROONCOLOGY TELECONFERENCE EXPERIENCE
Diana S. Osorio1, Christopher R. Pierson2, Alvaro Lassaletta3,
Andres Morales la Madrid4, Ibrahim Qaddoumi5, Ute Bartels6,
Daniel R. Boue’2, and Jonathan L. Finlay1; 1The Division of Hematology,
Oncology, Blood and Marrow Transplant, Nationwide Children’s Hospitaland the Ohio State University, Columbus, OH, USA, 2Department of
Pathology and Laboratory Medicine, Nationwide Children’s Hospitaland The Ohio State University, Columbus, OH, USA, 3Hospital Infantil
Universitario Niño Jesús, Madrid, Spain, 4Pediatric Hematology/Oncology,
Hospital St Joan de Déu, Barcelona, Spain, 5Global Pediatric Medicine,
Oncology Department, St. Jude Children’s Research Hospital, Memphis,
TN, USA, 6Brain Tumour Program, Division of Hematology/Oncology
Hospital for Sick Children, Toronto, ON, Canada
BACKGROUND: Pediatric brain tumor classification has undergone significant evolution over the last decade requiring a high-level of expertise anddiagnostic techniques. Such advances have created challenges for patholo-iii380N EU R O - O N C O L O G Y•

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gists particularly in low-to-middle income countries (LMIC). We conduct
weekly pediatric neuro-oncology teleconferences linking global pediatricneuro-oncologists from high-income countries (HIC) to review patients withpediatric subspecialists from Latin America. METHODS: Three to five patients are discussed weekly and second neuropathology review is offered
when a high-level of suspicion emerges of a questionable diagnosis basedon clinical and radiographical information. Nationwide Children’s Hospital(NCH) provides second neuropathology review at no cost to institutionsin Latin America that fulfill these criteria. RESULTS: From July 2015 to
December 2019 NCH reviewed 54 pathology samples from eleven Latin
American countries. Of these, 33 (61.1%) cases resulted in diagnostic
changes, of which 28 (51.8%) were significant, impacting treatment plansand overall patient outcomes. The remaining 21 (38.9%) confirmed institutional diagnosis; however, in eight of these 21 cases additional molecular
information and/or further tumor subtyping unavailable in their homecountry at the time (eg: BRAF, RELA-fusion, medulloblastoma subtyping)
was provided. CONCLUSIONS: This study highlights the importance ofcentralized pathology review by institutions with the proper equipment, infrastructure and expertise in pediatric neuropathology. Furthermore, thisdocuments the beneficial impact of teleconferencing for subspecialists in
LMIC who must treat a wide variety of pediatric cancers with few resources
and support. Additionally, our findings underscore the need for pediatricsubspecialty training in LMIC.
LINC-12. COMBINED ADULT AND PAEDIATRIC NEUROONCOLOGY LONG-TERM SURVIVOR CLINIC EXPERIENCE FROMA TERTIARY CANCER CENTRE IN A LOW-MIDDLE-INCOME
COUNTRY
Rahul Krishnatry1,2, Maya Prasad1,2, Girish Chinnaswamy1,2,Abhisheik Chaterjee1,2, Jayant Goda1,2, Epari Sridhar1,2,
Aliasgar Moiyadi1,2, Prakash Shetty1,2, Arushi Saha1,2, Vikas Singh1,2,
Nayana Golambade1,2, and Tejpal Gupta1,2; 1Tata Memorial Center,
Mumbai, Maharashtra, India. 2HBNI University, Mumbai, Maharashtra,
India
NeuroOncology survivor clinics (NOS) is uncommon in low-middleincome countries. We started combined (paediatric and adult) NOS clinic
in our tertiary a cancer centre (Jan-2017) and review here the demographic,clinical-pathological and treatment spectrum for our paediatric (0-18years)
and adult (>18years) survivors (>5years since their initial diagnosis) tilldate. Of total 312 patients registered, 198 (63.5%) were adults while 114(36.5%) were paediatric at-diagnosis with median age (IQR) at presentation: 34 (23–41) and 9(6 – 13) years respectively. In both groups, only 33%
were females. The median (IQR) time since diagnosis was 9 (9–14) and 8(6–12) years respectively with 60% of paediatric turning into adult survivors. The commonest paediatric tumours were glioma (52, 45.6%), embryonal (34, 29.8%), and ependymoma (12, 10.5%) versus gliomas (114,
57.6%) and benign tumours (42, 21.2%) in adults. The low-grade-glioma
comprised 90.4% of all pediatric gliomas and intermediate-grade (90%) in
adults. The primary treatment consisted of radiotherapy and chemotherapy
in 95% and 43% versus 99% and 36% in adults versus paediatric patients
respectively. Temozolomide and multi-drug combinations were the commonest chemotherapy used in adults and paediatrics respectively. Relapse
and retreatments were seen in 16.6 and 14% of adults and paediatric patients. There were two deaths each in each group since registration (median
12 months). Although the baseline diagnosis/treatment characteristics aredifferent, survivors of both group had a similar number of retreatments anddeaths. Combined survivor clinics may present an interesting and unique opportunity to learn and provide challenging service in this part of the world.
LINC-13. THE STATE OF PEDIATRIC NEURO-ONCOLOGY IN
ARMENIA
Samvel Bardakhchyan1,2, Armen Tananyan2, Samvel Danielyan1,
Jemma Arakelyan1,2, Sergo Mkhitaryan3, Karen Bedirian4, Liana Safaryan1,
Mikayel Arustamyan5, and Gevorg Tamamyan1,2; 1Haematology Center
after Prof. Yeolyan, Yerevan, Armenia, 2Yerevan State Medical University,
Yerevan, Armenia, 3Berd Military Hospital, Berd, Armenia, 4City of Smile
Charitable Foundation, Yerevan, Armenia, 5Ira Medical Group, Yerevan,
Armenia
BACKGROUND: Every year in Armenia we have approximately 80–90
new pediatric cancer cases from which 10–15 are brain tumors (PBT). Here
we try to summarize the current state of pediatric neuro-oncology in Armenia. DISCUSSION: In Armenia pediatric neuro-oncology is still in its firststeps. Surgical treatment of PBTs is performed only in one medical center– “Sourb Astvatsamayr” Medical Center, with 7 practicing pediatric neurosurgeons. Radiation therapy service with two linear accelerators is locatedat the “National Oncology Center”, however there are no dedicated pediatric radiation neuro-oncologists, and 2 specialists are treating pediatrictumors. Chemotherapy for all pediatric cancers currently is performed at
the Pediatric Cancer and Blood Disorders Center of Armenia, established inAbstracts

February 2019 as a result of merging of all pediatric oncology units in the
country. Among the 11 practicing pediatric hematologist/oncologists no one
is dedicated specifically to PBTs. Since September 2017 we have started discussing all PBT cases (up to now 18 cases) through the telemedicine with St.
Jude Children’s Research Hospital (SJCRH). In Sept 2019 neuro-oncology
multidisciplinary team was created with the involvement of local and foreign
specialists. On a weekly basis the multidisciplinary team discusses all new
and problematic cases. The team also concentrates on adaptation of diagnostic and treatment guidelines for pediatric CNS tumors, creation of educational materials for different stakeholders, and identification of current
problems and their possible solutions. CONCLUSION: To the best of ourknowledge this is the first report summarizing the current state of pediatricneuro-oncology in Armenia.
LINC-14. TREATMENT OF PEDIATRIC CNS TUMORS IN ARMENIA.
10 YEARS OF EXPERIENCE IN A 29 YEARS OLD RESOURCELIMITED SETTING
Martin Harutyunyan1,2, Lilit Sargsyan3, Samvel Iskanyan3,
Lusine Hakobyan3, Ruzanna Papyan3, Gevorg Tamamyan3,1,
Karen Bedirian2, Samvel Danielyan3, Armen Tananyan1,
Manushak Avagyan1, Nune Karapetyan1, and Samvel Bardakhchyan3,1;
1Yerevan State Medical University, Yerevan, Armenia, 2City of Smile
Charitable Foundation, Yerevan, Armenia, 3Hematology Center after Prof.
R. Yeolyan, Yerevan, Armenia
BACKGROUND: Pediatric CNS tumors are the most common solid
childhood malignancies with many challenges facing optimal outcome due tomultimodality complex therapies, abandonment, and long-term morbidity.
In our three-decades young, country the field of neuro-oncology is in its
infancy. MATERIALS: The aim of our study is to assess incidence, epidemiology and treatment outcomes of children diagnosed and treated with CNS
tumors within the last 10 years (2009–2019) in the Chemotherapy Clinicof “Muratsan” Hospital Complex of Yerevan State Medical University. RESULTS: During these periods 20 patients with CNS tumors were treated inour clinic. 13 patients (65%) were diagnosed with medulloblastoma (2 patients were infants), two patients (10%) with optic pathway glioma, and 5
patients each with pilocytic astrocytoma, ATRT, ETANTR, DIPG, and glioblastoma. Five patients (3 patients with medulloblastoma, 1 patient withpilocytic astrocytoma, 1 patient with ATRT) had metastatic disease at thetime of diagnosis. Seventeen patients (80%) had undergone surgery, 8 patients with medulloblastoma received chemo-RT with vincristine. Medianfollow up time was 15.5 months (range 5–94). Twelve patients (60%) arealive without evidence of disease. 5 patients had disease progression andthree patients relapsed. From them, 3 patients died. Long-term survivors
are mainly standard risk medulloblastoma patients. All medulloblastoma
patients were treated according to HIT-MED guidelines. CONCLUSION: Here we report about the pediatric brain tumors of one of the main
pediatric oncology units in Armenia for a period of 10 years. The numbers
are quite small for firm conclusions, but it shows the emerging need forfurther research.
LINC-15. OUTCOME OF CHINESE CHILDREN WITH
MEDULLOBLASTOMA: A MULTI-CENTER EXPERIENCE WITH
RISK-ADAPTED THERAPY
Xiaofei Sun1, Anthony Pak-Yin Liu2, Qunying Yang1, Jian Wang1,
Shaoxiong Wu1, Zijun Zhen1, Jingsheng Wang3, Haixia Guo4, Lian Jiang5,
Xiaoli Ma6, Wenjun Weng7, Lihua Yang8, Libin Huang9, Juan Li10,
and Godfrey Chi-Fung Chan2; 1Sun Yat-sen University Cancer Center,
Guangzhou, China, 2Hong Kong Children’s Hospital, Hong Kong SAR,
China, 3Shenzhen Children’s Hospital, Shenzhen, China, 4Southern
Medical University Nanfang Hospital, Guangzhou, China, 5Hebei Medical
University the Fourth Hospital, Hebei, China, 6Beijing Children’s Hospital,
Beijing, China, 7Sun Yat-sen University Memorial Hospital, Guangzhou,
China, 8Southern Medical University Zhujiang Hospital, Guangzhou,
China, 9Sun Yat-sen University the First Affiliated Hospital, Guangzhou,
China, 10Guangdong 999 Brain Hospital, Guangzhou, China
BACKGROUND: Medulloblastoma is the commonest brain tumor inyoung children but literature on Chinese is scarce. We hereby present the outcome of children with medulloblastoma managed according to a risk- andage-stratified guideline from ten institutions across China. METHODS: Patients <18 years of age diagnosed with medulloblastoma between January
2016 and April 2019 were reviewed. Patients ≥3 years, stratified into averagerisk (≤1.5cm2 residual tumor, non-metastatic, non-anaplastic histology) andhigh-risk (others) groups, were treated with risk-adapted craniospinal irradiation (average-risk: 23.4Gy, high-risk: 36Gy), tumor boost, and chemotherapy (lomustine/cisplatin/vincristine). Patients <3 years (consideredhigh-risk, other than patients with localized and desmoplastic/nodular histology) received chemotherapy (cyclophosphamide/vincristine, high-dose
methotrexate, carboplatin/etoposide) with/without delayed irradiation. RESULTS: 112 patients were included with a median age at diagnosis of
6.5 years (range: 0.5–16.7). 16 patients (14.3%) had residual tumor >1.5cm2

and 36 (32%) had metastasis. Available data on histological subtype (n=87)
were classic in 56 (64%), desmoplastic/nodular or extensive nodularity
in 23 (26%), and large cell/anaplastic in 8 (9%). Molecular subgrouping(n=55) assigned tumors as WNT-activated (n=8, 15%), SHH-activated(n=17, 31%), Group 3 (n=12, 22%) and Group 4 (n=18, 33%). Respective
2-year EFS/OS for patients ≥3 and <3 years were 86.0±4.0%/96.4±2.1%
and 57.8±12.6%/81.4±9.8% (EFS/OS p<0.001/p=0.009). Significant difference in outcome was also observed between patients with average-riskand high-risk disease (EFS/OS p=0.006/p=0.018). CONCLUSION: We
demonstrated feasibility in protocolizing the inter-disciplinary treatment for
medulloblastoma in China. This will serve as a prototype for the standardization of pediatric neuro-oncology care in the country.
LINC-16. MEDULLOBLASTOMA IN A BOY WITH RUBINSTEINTAYBI SYNDROME: A CASE REPORTRegina M Navarro-Martin del Campo1,2, Juan Luis Soto-Mancilla3,
Luis A Arredondo-Navarro3,2, Ana L Orozco-Alvarado1, andFernando A Sanchez-Zubieta1; 1Hospital Civil de Guadalajara Dr Juan
I Menchaca”, Guadalajara, Jalisco, Mexico, 2GAPNO, International
Group, Mexico, 3Hospital Civil de Guadalajara “Fray Antonio Alcalde”,
Guadalajara, Jalisco, Mexico
BACKGROUND: Rubinstein–Taybi syndrome (RTS) is characterized bymultiple congenital anomalies and associated with mutations in CREBBP(70%) and EP300 (5–10%). Previous reports have suggested an increased incidence of benign and possibly also malignant tumors, but the correlation remains
unclear. Here we present a case of a patient with RTS and medulloblastoma.
CLINICAL CASE: A 5-year-old male presented with increased intracranialpressure. An MRI revealed a 4.2 x 4.7 cm mass in the midline of cerebellum
arising from the floor of 4th ventricle. The patient underwent a complete resection and pathology revealed medulloblastoma, classic histology. Staging established no disseminated disease. At diagnosis, a peculiar phenotype consisting inmild mental retardation, microcephaly, down-slanting palpebral fissures, broad
nasal bridge, highly arched palate, mild micrognathia, screwdriver incisors andwide thumbs and toes was noted. Clinical genetics evaluation was consistent
with RTS. Karyotype was performed and normal. Further genetics testing was
not done. Treatment consisted in 8 cycles of chemotherapy and craniospinal
radiation (2300 cGy to spine, 5500 cGy Total). At the end of treatment, there
was no evidence of disease. He was under surveillance for 33 months free of
disease, but relapsed with a supratentorial meningeal disease that ultimately resulted in death. CONCLUSION: This report highlights the fact that pediatricmedulloblastoma can be associated to RTS, in this case associated to classicalhistology and recurrent disease.
LINC-17. SIROLIMUS AS AN ALTERNATIVE TO SURGICALRESECTION OF PEDIATRIC TUBEROUS SCLEROSIS COMPLEXASSOCIATED BILATERAL SUBEPENDYMAL GIANT CELLASTROCYTOMAS: AN AFFORDABLE OPTION FOR PATIENTSFROM LOW-MIDDLE INCOME COUNTRIESPatricia Orduña; UP-Philippine General Hospital, Manila, Philippines
Subependymal giant cell astrocytomas (SEGA) may lead to significant neurological morbidity in children diagnosed with tuberous sclerosis complex (TSC).
Surgical resection is warranted for SEGAs demonstrating continuous growth,causing hydrocephalus and increased intracranial pressure. mTOR inhibitors(sirolimus and everolimus) are alternatives to surgery and have shown efficacy
in stabilizing and shrinking SEGAs. Everolimus showed stronger evidence inefficacy, but its cost poses a limitation for this treatment among patients fromlow-middle income countries. We explored sirolimus as a potentially morecost-effective alternative in our setting. We present a 10-year-old Filipino childwith TSC admitted due to headache, vomiting, and increased sleeping time.
Neuroimaging revealed large bilateral SEGAs involving the frontal horns andforamina of Monro, causing moderate obstructive hydrocephalus. Surgical excision was offered, but parents opted for medical treatment. Bilateral posteriorparietal ventriculoperitoneal shunts were inserted to decrease intracranial pressure. Due to the cost of everolimus, the patient was started on sirolimus at
1mg/m2/day. Imaging done 6 months after initiating therapy demonstrated significant decrease in size of both SEGAs (right: 82.5%, left: 64.1%). Sirolimus
levels were maintained at 15.7ng/ml and minimal elevations on cholesterol andtriglyceride levels were observed and treated with simvastatin. Results of thiscase and review of related data suggest that sirolimus can be used as a conservative approach in inducing regression of large bilateral SEGAs, and an affordable alternative to everolimus for pediatric TSC patients from low-middle
income countries. Prospective studies and clinical trials are needed to further
establish its efficacy, safety and cost-effectiveness in our setting.
LINC-18. FOLLOW-UP EVALUATION OF A WEB-BASED PEDIATRICBRAIN TUMOR BOARD IN LATIN AMERICA
Mariel Rosabal Obando1, Diana S. Osorio2, Alvaro Lassaletta3,
Andrés Morales La Madrid4, Ute Bartels5, Jonathan L. Finlay2,
Ibrahim Qaddoumi6, Stefan Rutkowski1, and Martin Mynarek1;

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Abstracts

1University Medical Center Hamburg-Eppendorf, Hamburg, Germany,

2Nationwide Children´s Hospital and the Ohio State University, Columbus,

Ohio, USA, 3Hospital Infantil Universitario Niño Jesús, Madrid, Spain,
4Hospital Sant Joan de Déu, Barcelona, Spain, 5Hospital for Sick Children,
Toronto, Canada, 6St. Jude Children´s Research Hospital, Memphis,
Tennessee, USA

BACKGROUND: Since 2013, pediatric oncologists from Latin America
have discussed neuro-oncology cases with experts from North America andEurope in a web-based “Latin American Tumor Board” (LATB). This descriptive study evaluates the feasibility of the recommendations renderedduring the Board. METHODS: An electronic questionnaire was distributed
to physicians who received recommendations between October 2017 andOctober 2018, two months after their case presentation on the LATB. Physicians were asked regarding the feasibility of each recommendation given
during the Board. Baseline case characteristics of all presented cases wereobtained from anonymized minutes prepared after the presentations. RESULTS: 36 physicians from 15 countries answered 103 of 142 questionnaires (72.5%), containing 283 recommendations. Physicians followed 60%
of diagnostic procedural recommendations and 70% of therapeutic recommendations. Overall, 96% of respondents considered the recommendations
applicable and useful. The most difficult recommendations to follow were
genetic and molecular testing, pathology review, locally adapted chemotherapy protocols administration, neurosurgical interventions and access tomolecular targeted therapies. The most cited reasons for not implementing
the recommendations were lack of resources, inapplicable recommendations
to that low-to-middle income country (LMIC) setting, and lack of parental
consent. CONCLUSION: The recommendations given on the LATB are frequently applicable and helpful for physicians in LMIC. Nevertheless, limitations in availability of both diagnostic procedures and treatment modalities
affected the feasibility of some recommendations. Virtual tumor boards offer
physicians from LMIC access to real time, high-level subspecialist expertiseand provide a valuable platform for information exchange among physicians worldwide.
LINC-19. CURRENT SITUATION OF PEDIATRIC TUMORS OF
CENTRAL NERVOUS SYSTEM IN CHINA - THE FIRST CNOG
NATIONAL WIDE REPORT
Jie Ma1, CNOG (Children’s Neuro-Oncology Group) in China2;
1Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to
Shanghai Jiaotong University School of Medicine, Shanghai, China,
2CNOG (Children’s Neuro-Oncology Group) in China, Shanghai, China
Tumors of Central Nervous System (CNS) are most seen solid tumor inchildhood. Accounting approximate 25–30% of pediatric neoplasms, treatments on these tumors are complicated as they occur in different age ranges,
have various types according to classification system and contain different
characteristic molecular profiles. There are huge gaps of medical services forchildren with CNS tumors in different regions in China, which is blamed tolimited medical resources and lack of epidemiology data for Chinese population. After the establishment of CNOG (Children’s Neuro-Oncology Group)in China in 2017, national wide registry (CNOG-MC001) was conductedto collect data on the basic information about pediatric tumors of CNS. Results of 4059 cases from 37 centers providing medical services for pediatric
CNS tumors in 25 provinces from 6 greater administrative areas in China
showed distinct tumor ratio, compared to worldwide data by WHO classification. The mean of age was 8.01 ± 4.73, with a male vs. female ratio
as 1.48 to 1. Embryonal tumor, astrocytic & oligodendroglial tumors, andother astrocytic tumors were three most common tumor types in CNS ofchildren. The lost follow-up rate was surprisingly high as 53.07%. In all,this is the first national wide registry for pediatric CNS tumor in China andthe results attracted public and government’s attentions for further epidemic
investigations.
LINC-20. INFANT BRAIN TUMOURS IN HONG KONG
Matthew MK Shing1,2, Dennis TL Ku1,3, Godfrey CF Chan1,4, CW Luk1,5,
Jeffrey PW Yau1,5, Eric Fu1,5, Carol LS Yan1,2, and Alvin SC Ling6; 1HongKong Children’s Hospital, Hong Kong, Hong Kong, 2Prince of Wales
Hospital, the Chinese University of Hong Kong, Hong Kong, Hong Kong,
3Tuen Mun Hospital, Hong Kong, Hong Kong, 4Queen Mary Hospital,
the University of Hong Kong, Hong Kong, Hong Kong, 5Queen Elizabeth
Hospital, Hong Kong, Hong Kong, 6Princess Margret Hospital, Hong
Kong, Hong Kong
OBJECTIVES: To review the clinical features, pathology and survivalsof infants with brain tumours. METHODS: A retrospective review of theclinical findings, pathology, treatment and survival outcome in infants withbrain tumours. RESULTS: From 1999 to 2018, there were 507 children(<18 years) who were diagnosed to have brain tumours in Hong Kong. The
patients were treated in five public hospitals. The clinical data were collectedby the Hong Kong Paediatric Haematology and Oncology Study Group,
and were cross-checked with the data of the Hong Kong Cancer Registry. In

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this group of patients, there were 36 infants (birth to 365 days of age) i.e.
7.1% of the whole group. Both benign and malignant brain tumours were
included, while non-neoplastic lesions were excluded. On average, there was
1.89 cases per year. The pathology of the tumours were astrocytoma (n= 8),
medulloblastoma (n=6), germ cell tumour (n=6), PNET (n=5), ATRT (n=4),choroid plexus tumours (n=3), ependymoma (n=2), craniopharyngioma (n=1) and ganglioglioma (n= 1). These infants were treated according to theirclinical conditions and prognosis, with operation, chemotherapy or both.
Radiotherapy was withheld or postponed to older age. Some patients only
received palliative care due to the poor neurological status or prognosis.
The overall survivals of children younger than 18 years old vs infants were
67.3% (±2.3) vs 50.5%(±9.2) respectively, while the event free survivals
were 64.4% (±2.4) and 43.5% (±8.8) at 10-years respectively. CONCLUSION: Infants with brain tumours have different pathology and inferior
outcome.
LINC-21. SURVEY ON THE RESOURCES AVAILABLE FORPEDIATRIC NEURO-ONCOLOGY IN CHILE, SOUTH AMERICA
Mohammad H. Abu-Arja1, Nicolás Rojas del Río2,
Andres Morales La Madrid3, Alvaro Lassaletta4, Rosita Moreno5,
Miguel Valero6, Veronica Perez7, Felipe Espinoza8,9, Eduardo Fernandez10,
José Díaz10, José Santander11, Juan Tordecilla12, Veronica Oyarce13,
Katherine Kopp14, Ute Bartels15, Ibrahim Qaddoumi16,
Jonathan L. Finlay17, Adrián Cáceres18, Ximena Espinoza19, andDiana S. Osorio17; 1New York Presbyterian Brooklyn Methodist Hospital,
Brooklyn, NY, USA, 2Pontificia Universidad Católica de Chile, Santiago,
Chile, 3Hospital Sant Joan de Déu, Barcelona, Spain, 4Hospital Infantil
Universitario Niño Jesús, Madrid, Spain, 5Pediatría Hospital Dr, Sótero
del Río, Puente Alto, Chile, 6Hospital Carlos van Buren, Valparaíso, Chile,
7Hospital San Juan de Dios, Santiago, Chile, 8San Borje Arriaran Clinic
Hospital, Santiago, Chile, 9Clínica Bicentenario, Santiago, Chile, 10Hospital
Clínico Regional Dr, Guillermo Grant Benavente de Concepción,
Concepción, Chile, 11Clinica Davila, Recoleta, Chile, 12Clinica Santa
Maria, Providencia, Chile, 13Dr, Exequiel González Cortés Hospital, San
Miguel, Chile, 14Dr, Luis Calvo Mackenna Hospital, Santiago, Chile,
15Hospital for Sick Children, Toronto, ON, Canada, 16St. Jude Children’s
Research Hospital, Memphis, TN, USA, 17Nationwide Children’s Hospital,
Columbus, OH, USA, 18Hospital Nacional de Niños Carlos Sáenz Herrera,
San José, Costa Rica, 19Hospital de Niños Dr, Roberto del Río, Santiago,
Chile
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). Pediatricneuro-oncology services were mainly provided within general hospitals(67%). Registries for pediatric central nervous system (CNS) tumors andchemotherapy-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 morethan 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 wereavailable 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 neurooncology services available in Chile. A wide range of up-to-date treatment
modalities is available for children with CNS tumors in Chile. Establishingformal pediatric neuro-oncology training may be beneficial.
LINC-23. PRE-OPERATIVE AND POST-OPERATIVEINTERVENTIONS REDUCE RATES OF VENTRICULITIS IN
PEDIATRIC BRAIN TUMOR PATIENTS: A PILOT STUDY
Laura Melissa Stephanie Diamante - San1, Marciel Pedro1,
Ana Patricia Alcasabas1, Marissa Lukban1, Kathleen Khu1,
Gerardo Legaspi1, Ibrahim Qaddoumi2, and Daniel Moreira2; 1Philippine
General Hospital, Manila, Philippines, 2St. Jude Childrens Research
Hospital, Memphis, TN, USA
BACKGROUND: The Philippine General Hospital, a public nationalreferral center, sees 60–80 pediatric brain tumor cases per year. Historically, the rate of post-operative ventriculitis has been high, resulting inAbstracts

treatment delays and poor outcomes. Starting in July 2019, as a means todecrease infections, patients were provided standardized bathing and woundcare kits and caregivers were trained to follow a bathing and wound care
protocol. METHODS: This quality improvement study included patients
younger than 18 years who underwent craniotomy at PGH were enrolled.
The type of surgery, length of surgery, existence of post-operative CNS infection, length of stay and total cost of care was collected. The outcomeof these interventions are analyzed 6 months after implementation. RESULTS: Thirty-two 32 patients were included, with mean age of 7 years(1–16). The surgeries performed were: tumor resection (n=20), ventriculoperitoneal shunt insertion (VPS) (n=3), endoscopic third ventriculostomy(n=3), resection with tube ventriculostomy (n=3), Ommaya reservoir placement (n=2), and resection with shunt (n=1). Median surgery time was 4hours (1–10). Three patients (9.4%) developed ventriculitis. No surgicalsite infections occurred. Compared to historical controls, a lower rate of
infections was noted (9.4% vs. 15.5%, runchart analysis). Patients without
post-operative infections had a shorter length of stay (median 14 vs48 days, p<0.05) and a lower cost of care (median $1098 vs. $2425 USD,
p<0.05). CONCLUSION: Implementation of simple hygiene interventions
effectively lowered post-operative CNS infections and hospital costs in a
public hospital setting. Incorporation of these into standard clinical practices is urgently needed.
LINC-24. CHARACTERISTICS OF PEDIATRIC BRAIN TUMORSAT DEPARTMENT OF CHILD HEALTH FACULTY OF MEDICINEUNIVERSITAS INDONESIA-DR. CIPTO MANGUNKUSUMOTERTIARY GENERAL HOSPITAL, JAKARTA, INDONESIA
Dwi Putro Widodo, Irawan Mangunatmadja, Marsintauli Siregar,
Hardiono Pusponegoro, Setyo Handryastuti, Amanda Soebadi, andAchmad Rafli; Neurology Division Department of Child Health Faculty of
Medicine Universitas Indonesia-Dr. Cipto Mangunkusumo Tertiary General
Hospital, Jakarta, Indonesia, Jakarta, DKI Jakarta, Indonesia
Brain tumors are still the second leading cause of death among cancers
in children. Based on data from National Brain Tumor Society (2019), in
United States, there are 28.000 children living with brain tumor with varied
clinical, radiological, and histopathological features. The most prevalentchildren’s brain tumor types in US are gliomas (ependymal tumors, pilocytic
astrocytomas) and embroyonal tumors, including medulloblastoma. From
1993–1994 at Department of Child Health Faculty of Medicine Universitas Indonesia-Dr. Cipto Mangunkusumo Tertiary General Hospital, Jakarta, Indonesia, there are 19 patients with brain tumors hospitalized withmost of patients with astrocytoma 8 patients (42%), 4 patients (21%)
medulloblastoma, 2 patients (11%) neuroblastoma, 2 patients (11%)
ependymoma, 2 patients (11%) craniopharyngioma, and one patient (4%)
meningioma. Retrospective cohort study (2010–2015) with subjects 100
children revealed that based on the radiographs, the brain tumors were located mostly in the cerebellum (24%) and the suprasellar region (10%);based on the histopathology, the most common types of brain tumor wereastrocytomas (18%), medulloblastoma (21%), and gliomas (17%). The
most common symptom of brain tumors was headache and impaired vision. Survival patients with brain tumors for 5 years in the age group aged
3 years and above was better than that in children aged under 3 years (60%
vs 55% and 17% vs 14%). This report can serve as one of basic data for
profile children’s brain tumors in Indonesia. Keywords: brain; tumor; children; survival; Indonesia
LINC-25. BRAF ABERRATIONS IN PEDIATRIC PILOCYTICASTROCYTOMAS (PCAS): PREVALENCE AND IMPACT ON
CLINICAL OUTCOME
Subramaniam Ramanathan1, Maya Prasad1, Tushar Vora1, Mamta Gurav2,
Ayushi Sahay3, Arpita Sahu4, Aliasgar Moiyadi5, Prakash Shetty5,
Jayant Sastri Goda6, Rahul Krishnatry6, Tejpal Gupta6, Sridhar Epari3,2,and Girish Chinnaswamy1; 1Pediatric Oncology, Tata Memorial Centre,
Mumbai, Maharashtra, India, 2Molecular Pathology, Tata Memorial
Centre, Mumbai, Maharashtra, India, 3Pathology, Tata Memorial Centre,
Mumbai, Maharashtra, India, 4Radiodiagnosis, Tata Memorial Centre,
Mumbai, Maharashtra, India, 5Neurosurgery, Tata Memorial Centre,
Mumbai, Maharashtra, India, 6Radiation Oncology, Tata Memorial Centre,
Mumbai, Maharashtra, India
BACKGROUND: Increasing knowledge on pilocytic astrocytoma (PCA)
biology now points towards an aberration in BRAF/MAPK/ERK pathway
which has both diagnostic and therapeutic implications. This study wasdone to note the impact of BRAF aberrations on clinical outcome in childhood PCA. METHODS: FFPE tissues of all childhood PCA diagnosed
during 2011–2017 were evaluated for BRAFV600E mutation by Sanger
sequencing and KIAA1549 fusion transcripts (16–9;15–9;16-11) by reverse
transcriptase polymerase chain reaction. Children undergoing gross tumor
resection received no adjuvant treatment. Unresectable tumors (only bi-opsy) and NF-1 associated PCAs, were treated if clinically indicated. Only
patients with documented therapy details/followup were included for analysis. STUDY RESULTS: Ninety-eight patients (median age-7.7yrs; boy:girlratio-1.4) were included. Major sites were: Cerebellum-37(38%), 3rd Ventricle-26(27%), Cerebrum-15(15%). While BRAFV600E mutation wasnoted in 7/89(8%) specimens, BRAF-fusions were found in 34/85(40%).
Following surgery/biopsy, 23(24%) and 21(22%) received adjuvant chemotherapy and radiotherapy respectively. The 1-year/3-year/5-year-EFS of theoverall cohort was 90.7%/81.3%/67.4% respectively. Cerebellar tumors
did better vis-à-vis other sites(5yr-EFS:74.3% v/s 66.4%;p=0.403). The
5yr-EFS of BRAF-fusion positive tumors (34), tumors without any BRAF
aberration (40) and BRAFV600E mutant tumors (7) was 84.8%/ 69.6%/
42.9% (p=0.215). CONCLUSIONS: BRAF-fusion and BRAFV600E mutation were associated with good and poor outcomes respectively. Lack ofstatistical significance could be attributed to use of radiation as planned
therapy in patients from earlier years. Data on BRAF aberrations in PCAs
aids decision making regarding adjuvant therapy and choosing appropriate
salvage-therapy especially in relapsed/refractory PCAs.
LINC-26. ORAL VINORELBINE IN PROGRESSIVE UNRESECTABLE
LOW-GRADE GLIOMA
Andréa M Cappellano, Milena RS Oliveira, Sergio Cavalheiro,
Patricia Dastoli, Daniela B Almeida, Frederico A Silva,
Maria Teresa S Alves, and Nasjla S Silva; IOP/GRAACC/UNIFESP, SãoPaulo, São Paulo, Brazil
BACKGROUND: The management of progressive unresectable low-grade
glioma (PULGG) remains controversial. Some series suggests that chemotherapy may delay or even avoid radiotherapy and/or surgery in a groupof patients. Within this context, we performed at IOP/GRAACC/UNIFESP
an institutional protocol with IV vinorelbine, a semi-synthetic vinca alkaloid that showed activity against PULGG. The objective of this study wasto evaluate the response as long as the tolerability of oral vinorelbine in
PULGG. PATIENTS AND METHODS: From April 2013 to Aug 2017, 17
patients with recurrent (n=5) and newly-diagnosed (n=12) optic-pathway
glioma (OPG) were treated with oral vinorelbine in a dose of 90 mg/m² days
0, 8 and 22 for 18 cycles. Response criteria used a combination of magnetic
resonance imaging, physical and visual evaluation. RESULTS: Mean age
8.6 years (4.8–17.9y). Three children with neurofibromatosis type 1. Elevenpatients had neurosurgical intervention revealing grade I (n=8) and grade
II astrocytoma (n=3). Twelve patients were assessable after 8 cycles ofvinorelbine with 2 objective response (OR), 8 stable disease (SD) and 2 progressive disease (PD), one died after surgery and 1 alive in different protocol.
After 18 cycles, eight patients were assessable to date for response with 1
OR, 7 SD. The most important toxicity was gastrointestinal observed in 12
patients- six of them switched to IV vinorelbine (3OR, 3SD). None of thepatients showed neurotoxicity. CONCLUSION: These results suggest thatoral vinorelbine, as the IV formulation, may show some activity in OPG.
However, gastrointestinal toxicity should be considered.
LINC-27. PAEDIATRIC SUPRASELLAR TUMOURS: CLINICALEXPERIENCE FROM A SINGLE TERTIARY CENTRE IN KUALALUMPUR, MALAYSIA
Hamidah Alias, and C-Khai Loh; Department of Paediatrics, UKM Medical
Centre, Jalan Yaacob Latif, Cheras, Kuala Lumpur, Malaysia
INTRODUCTION: The outcome of suprasellar tumours in children
varies with the diagnosis and morbidity is significant. We herein report
the clinical features of children with suprasellar tumours treated at ourcentre. METHODS: Clinical data were collected by retrospective review
from January 2000 to December 2019. The patients were identified from thepaediatric haematology and oncology unit registry. RESULTS: There was a
total of 103 children with brain tumour and suprasellar tumours comprise of
14.6% (n=15). Median age at presentation was 7 years old. Male to female
ratio was 3:2. Majority of cases was low grade glioma, 40% (n=6) and germ
cell tumour(GCT) 33.3% (n=5) followed by craniopharyngioma, 13.3%(n=2) and Rathke cleft cyst, 6.7% (n=1). All patients had tissue diagnosis
except one with secreting GCT and one with unsatisfactory tissue sample.
Mean duration of follow up was 7.4 years. One patient with germinoma
was lost to follow-up after radiotherapy. Three out of 13 (23%) patients
died; 2 with GCT from disease progression; 1 craniopharyngioma after
11 years of unknown cause. All survivors have significant morbidity; 70%
have moderate to severe visual impairment, 90% have at least two pituitaryhormones deficiency, 20% have neurological deficit and 1 was surgically related. Two boys have precocious puberty not related to disease progression.
Two with GCT with diabetes insipidus had history of thromboembolism(stroke and pulmonary embolism). CONCLUSIONS: Suprasellar tumours
in children at our centre pose a significant long-term complications andmultidisciplinary team management and follow up is required to improvethe morbidity.

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LINC-28. EPIDEMIOLOGICAL CHARACTERISTICS AND SURVIVALOUTCOMES OF CHILDREN WITH MEDULLOBLASTOMATREATED AT THE NATIONAL CANCER INSTITUTE (INCA) IN RIO
DE JANEIRO, BRAZIL
Gabriela Oigman1, Diana Osorio2, Joseph Stanek2, Jonathan Finlay3,
Denizar Vianna4, and Sima Ferman1; 1INCA, Rio de Janeiro, RJ, Brazil,
2The Division of Hematology, Oncology, Blood and Marrow Transplant,
Nationwide Children´s Hospital, Columbus, OH, USA, 3Nationwide
Children´s Hospital, Columbus, OH, USA, 4UERJ, Rio de Janeiro, RJ,
BrazilBACKGROUND: Medulloblastoma (MB), the most malignant brain tumorof childhood has survival outcomes exceeding 80% for standard risk and 60%
for high risk patients in high-income countries (HIC). These results have notbeen replicated in low-to-middle income countries (LMIC), where 80% of children with cancer live. Brazil is an upper-middle income country according toWorld Bank, with features of LMIC and HIC. METHODS: We conducted aretrospective review of 126 children (0–18 years) diagnosed with MB from1997 to 2016 at INCA. Data on patients, disease characteristics and treatment
information were retrieved from the charts and summarized descriptively;
overall survival (OS) and event-free survival (EFS) were calculated using the
Kaplan-Meier Method. RESULTS: The male/female ratio was 1.42 and the
median age at diagnosis was 7.9 years. Headache (79%) and nausea/vomiting(75%) were the most common presenting symptoms. The median time fromonset of symptoms to surgery was 50 days. The OS for standard-risk patientswas 69% and 53% for high-risk patients. Patients initiating radiation therapy
within 42 days after surgery (70.6% versus 59.6% p=0.016) experienced better
OS. Forty-five patients (35%) had metastatic disease at admission. Lower maternal education correlated with lower OS (71.3% versus 49% p=0.025). Patients who lived >40km from INCA fared better (OS= 68.2% versus 51.1%
p=0.032). Almost 20% of families lived below the Brazilian minimum
wage. CONCLUSIONS: These findings suggest that socioeconomic factors,
education, early diagnosis and continuous data collection, besides oncologicaltreatment must be adressed to improve the survival of children with MB.
LINC-29. IMPACT OF RELA FUSION ON OUTCOMES OF
CHILDHOOD SUPRATENTORIAL EPENDYMOMAS (ST-EPEN)
Girish Chinnaswamy1, Subramaniam Ramanathan1, Maya Prasad1,
Tushar Vora1, Ayushi Sahay2, Mamta Gurav3, Arpita Sahu4,
Aliasgar Moiyadi5, Prakash Shetty5, Jayant Sastri Goda6,
Rahul Krishnatry6, Tejpal Gupta6, and Sridhar Epari3,2; 1PediatricOncology, Tata Memorial Centre, Mumbai, Maharahstra, India,
2Pathology, Tata Memorial Centre, Mumbai, Maharashtra, India,
3Moelcular Pathology, Tata Memorial Centre, Mumbai, Maharashtra,
India, 4Radiodiagnosis, Tata Memorial Centre, Mumbai, Maharashtra,
India, 5Neurosurgery, Tata Memorial Centre, Mumbai, Maharashtra, India,
6Radiation Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
BACKGROUND: Ependymomas are heterogenous group of tumours
with variable clinical course and diverse molecular features. RELA fusion
status has been reported to have prognostic impact in ST-EPEN. Our retrospective study analysed the prevalence and clinical impact of RELA fusion inchildhood ST-EPEN at our centre. STUDY METHODS: FFPE tissues of allchildhood ST-EPEN diagnosed during 2011–2017 were evaluated for RELA
fusion 1/2 by RT-PCR. Children were treated as per guidelines by the Neurooncology multidisciplinary team. Outcomes were correlated with RELA fusion, histological features and immunohistochemical parameters(L1CAM
expression and Mib-1 index). Only patients with therapy details were included. RESULTS: A total of 37 patients(0–50 years) with ST-EPEN were
included(median age-10.2 years; boy:girl ratio-1.4:1)for analysis. Histological grade II, II/III and III was seen in 4(11%),2(5%) and 31(84%) patients
respectively. Mib-1 index was assessable in 33 patients of which, 9 patients(24%) had a Mib-1 index >20%. RELA fusion was detected in 13(35%)tumors. The 3-year and 5-year EFS/OS of the overall cohort was 64.2%/83.6%
and 60.1%/73.1% respectively. The 3-year/5-year EFS of RELA-positive
tumors was inferior compared to RELA-negative tumours (53.8%/36%
v/s 62.6%/53.6%; p=0.391). The 3-year/5-year EFS of tumors expressing
L1CAM versus negative-expression was comparable (61.1%/55%v/
s59.8%/47.9%;p=0.44). Presence of Mib-1>20% correlated with inferior
survival (5-year EFS:81.1%vs22.2%; p<0.01). CONCLUSIONS: ST-EPEN
with RELA fusion had trend towards increased relapse/progression. HighMib-1 correlated with poor survival. RELA fusion status needs to be studied
in a larger cohort prospectively to confirm its clinical impact.
LINC-30. A CLINICOPATHOLOGICAL STUDY OF
IMMUNOGENICITY AND IMMUNE EVASION MECHANISMSAMONG MOLECULAR SUBGROUPS OF MEDULLOBLASTOMA
Kavneet Kaur, Vaishali Suri, Mehar C Sharma, Ashish Suri, andChitra Sarkar; All India Institute of Medical Sciences, New Delhi, India
INTRODUCTION: Medulloblastomas have been well characterised
in terms of genomics, epigenomics, transcriptomics and recently prote-iii384

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De c e mb e r 2 0 2 0omics. However, there is limited knowledge regarding immunogenicity,
immune-microenvironment and immune evasion mechanisms in different
molecular subgroups of medulloblastoma. It is important to analyze theseparameters to understand tumor progression, prognostic stratification as
well as treatment response to available immunotherapeutic drugs. MATERIALS AND METHODS: Molecular subgrouping performed byimmunohistochemistry(IHC), Nanostring and 850k-methylation array.
Immune profile by IHC for CD3, 20, CD8 [tumor infiltrating lymphocytes(TILs)], CD163 [tumor-associated macrophages (TAMs)], and PD-L1 andCTLA-4 [immune checkpoint proteins]. RESULTS: A total of 35 cases wereanalyzed with age-range from 1 to 54 years (77% pediatric and 23% adult).
82% cases were located in midline, while rest in cerebellar hemispheres.
On molecular subgrouping, MBs were subdivided into 8 WNT, 10 SHH, 8Group 3 and 9 Group 4. Twenty four cases had follow up, 12 with no evidence of disease while 12 with progressive disease or death. PD-L1 expression ranged from 0% to 20% and included 5SHH, 2WNT and 1Group 3.
CTLA4 positive lymphocytes ranged from 0 to 33 in 4 cases: 1WNT, 3 SHH,
1Group4. TILs ranged from 0–220/mm2 with a median of 3. TAMs ranged
from 0–60/mm2 with a median of 18. Both TILs and TAMs were significantly
higher in SHH subgroup. CONCLUSION: PD-L1 positivity and number ofTILs and TAMs were significantly more in SHH-subgroup tumors followed
by WNT tumors. CTLA-4 expression did not correlate with subgroups. All
parameters showed a positive trend with increasing age.
LINC-31. TREATMENT OUTCOME IN CHILDREN WITH
MEDULLOBLASTOMA IN MEDIUM-INCOME COUNTRY: AN
EXPERIENCE FROM A SINGLE TERTIARY CENTRE IN KUALALUMPUR, MALAYSIA
C-Khai Loh, Hamidah Alias, and Doris Lau; Universiti Kebangsaan
Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia
INTRODUCTION: Medulloblastoma is the most common malignant brain tumour in children. The overall outcome has improved however, this was not translated to developing nations. METHOD: This wasa retrospective review of patients from January 2000 to December 2017.
Treatment was given using modified SIOP PNET 4 protocol: cranio spinal
irradiation (CSI), a total of 54G with vincristine followed by 8 cycles of adjuvant chemotherapy. Prior to year 2007, patients had CSI with or without
adjuvant chemotherapy. Those <3 years old received modified UKCCSG/
SIOP CNS protocol with 2 weekly chemotherapy for a duration of 392 days
followed by CSI when required. All patients had MRI brain and spine,
and tissue histopathological examination but without molecular subtype. RESULTS: Medulloblastoma comprised of 30% (n=31) out of total
103 brain tumour cases. Mean age at presentation was 7.6 years old (SD4.4) with male to female ratio of 2:1. Average time of symptoms was 4.8
weeks. Majority, 77.4% was high risk and 19.4% was standard risk. There
was high treatment abandonment rate (35.5%, n=11). Three patients returned and completed treatment after multiple surgeries in an average of
9 months. Three years OS and EF were 69.6% and 74.8%, respectively.
Six patients aged < 3years; half had advance disease on palliative care post
surgery. Other survivors had severe learning difficulty and two had second
malignancy (meningioma and thyroid carcinoma) at average 15.5 years after
diagnosis. CONCLUSION: Strategy to reduce treatment abandonment is
crucial. Moreover, multidisciplinary management and molecular stratification are important in improving the outcome.
LINC-32. REPORT OF AN INITIAL SITE VISIT TO DETERMINEFEASIBILITY AND IMPLEMENTATION OF A COMPREHENSIVENEURO-ONCOLOGY PROGRAM IN KENYA
Beth Armstrong1, Mark Mbiro2, Michael Magoha2,3, Minda Okemwa3,
Nimrod Mwang’ombe3, and Scott Coven1,4; 1Riley Hospital for Children,
Indianapolis, IN, USA, 2Kenyatta National Hospital, Nairobi, Kenya,
3University of Nairobi, Nairobi, Kenya, 4Indiana University School of
Medicine, Indianapolis, IN, USA
BACKGROUND: Pediatric central nervous system (CNS) tumors are theleading solid tumors in the United States, but vastly under-reported in the
African population. There’s limited data on childhood brain tumors as wellas the histopathological distribution in Kenya. This report surveys as an initial site visit to determine the feasibility of a comprehensive neuro-oncology
program at Kenyatta National Hospital (KNH) in Nairobi, Kenya. DESIGN:This collaboration began with a visit from the director of neuropathology at
KNH to our neuro-Oncology program at Riley Hospital for Children at Indiana University Health in May 2019. This report includes recommendations
from the May 2019 trip, as well as a reciprocal site visit to Kenya in January
2020. RESULTS: Building off the May 2019 trip, a brain tumor registry has
been initiated and maintained. Additionally, the KNH program has many necessary components to forming a comprehensive neuro-oncology program,including capable neurosurgeons with a neurosurgical training program,radiology, intensive care unit, oncology ward, rehab, skilled nursing, and radiation oncology services. Currently, neurosurgery, radiology, and pathology
meet weekly to review challenging cases. CONCLUSION: Kenyatta National

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Hospital has the expertise to build a comprehensive neuro-oncology program.
The program currently lacks a dedicated nurse coordinator and “specialist”
in neuro-oncology. Ongoing discussions with local stakeholders are aimed
to galvanize national support to improve awareness for children with brain
tumors and to plan a multidisciplinary neuro-oncology symposium in 2021.
In the meantime, telemedicine efforts can support nursing education and reiterate the multidisciplinary needs for children with brain tumors.
LINC-33. MULTIMODALITY MANAGEMENT OF PAEDIATRICPRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA- UPDATEDEXPERIENCE FROM A REGIONAL CANCER CENTRE IN NORTH
INDIA
Ahitagni Biswas, Swarnaditya Roy, Yousra KN, Sameer Bakhshi,
Vaishali Suri, Mehar Sharma, and Pramod Julka; All India Institute ofMedical Sciences, New Delhi, Delhi, India
Paediatric primary central nervous system lymphoma(PCNSL) constitutes 1% of all PCNSLs. Data pertaining to paediatric PCNSL (2016–19)
was abstracted by retrospective chart review. We identified 7 paediatric patients with PCNSL. None had congenital or acquired immunodeficiency. The
median age at presentation was 13 years. The male to female ratio was 4:3.
The median ECOG performance status was 2. On neuro-imaging, 3 patients
had solitary and 4 patients had multiple lesions. CSF cytology showed atypical cells in 1 patient. None had ocular involvement. Systemic lymphoma
work-up was negative in all. Biopsy and resection of tumour were done in
4 patients each. Histopathology revealed DLBCL in 6 and B-cell NHL
in 1 patient. All patients underwent induction chemotherapy (median-5
cycles)- modified DeAngelis protocol (IV Methotrexate-2.5g/m2,IT Methotrexate-12 mg,Vincristine,Procarbazine and Rituximab-375mg/m2 every 2
weeks) in 6 and single agent Methotrexate -3.5g/m2 every 3 weeks in 1 patient.
Severe haematological toxicities included grade 3 neutropenia, leucopenia andfebrile neutropenia in 2,1 and 1 patient respectively. Radiotherapy(RT) was
administered in all-whole brain RT(36-45Gy/20-25fractions/4-5weeks) in 6
patients and craniospinal RT(36Gy/18fractions/3.5weeks) followed by wholebrain RT(9Gy/5fractions/1week) in 1 patient(with positive CSF cytology). Subsequently consolidation chemotherapy with 2 cycles of Cytarabine(3g/m2 IV
D1-2 every 3 weeks) was administered in 5 patients. After a median follow-up of
14 months(mean-18.2 months), all patients are in complete radiological remission. Paediatric PCNSL is a rare tumour entity and multimodality managementwith high dose Methotrexate and Rituximab based chemo-immunotherapy
and cranial radiotherapy leads to excellent early clinical outcome.
LINC-34. OPTIC NERVE INFILTRATION: RARE MANIFESTATION
OF CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA IN
REMISSION
Ludi Dhyani Rahmartani; Department of Child Health, Universitas
Indonesia - Cipto Mangunkusumo National Hospital, Jakarta, Indonesia
BACKGROUND: Optic nerve infiltration in acute lymphoblastic leukemia
is a rare manifestation. This infiltration may appear months in advance as an
isolated sign of extramedullary relapse and considered as one of the significant clinical findings of central nervous system leukemia. AIM: To describe acase of rapidly progressive optic nerve infiltration in a girl with ALL in remission. CASE: A 13-year-old girl in full remission following treatment for B-cell
acute lymphoblastic leukemia presented with decreased vision and proptosison the left eye. She completed the chemotherapy course two years before. On
physical examination, we found the optic disc swelling in her left eyes. There
were no signs of relapse from the hematological, cerebrospinal fluid analysis,
and bone marrow aspiration. The orbital CT found a mass on the left retrobulbar (size 29x48x32 mm), suspected of optic nerve glioma. The mass hasgrown rapidly in a month, and she lost her left sight. The involved eye wasexenterated (60x55x40 mm). The histopathology and immunohistochemistry
showed the B-cell acute lymphoblastic lymphoma. Unfortunately, the patient
could not come for further follow up due to the COVID-19 large-scale social
distancing. Two months later, she came with pallor and pain in all of her body.
The bone marrow aspiration showed leukemic relapse and she is undergoing
chemotherapy. CONCLUSION: Optic nerve infiltration by leukemia requires
both diagnostic certainty and urgent management. A routine ophthalmic assessment is recommended in patients with a history of acute lymphoblastic
leukemia to diagnose optic nerve involvement due to leukemic infiltration.
LINC-35. THE ST. JUDE GLOBAL ACADEMY NEURO-ONCOLOGYTRAINING SEMINAR: A MULTIDISCIPLINARY, INTERNATIONALEDUCATION PROGRAM
Daniel Moreira, Zoltan Patay, Frederick Boop, Jason Chiang,
Thomas Merchant, Teresa Santiago, Amar Gajjar,
Carlos Rodriguez-Galindo, and Ibrahim Qaddoumi; St. Jude Children’s
Research Hospital, Memphis, TN, USA
The success of the treatment of children with central nervous system(CNS) tumors relies on an effective multidisciplinary team, with up-to-dateand broad knowledge and skills. The St. Jude Global Academy NeuroOncology Training Seminar was launched as course in globally applicable
content in pediatric neuro-oncology with a focus on multidisciplinary
teams in low- and middle-income countries (LMICs). To identify the content that is most relevant for the learners, a needs assessment survey that
included evaluation of team dynamics, treatment capacity, existing knowledge, and educational goals was designed. Survey questions in 11 domains
were answered by 24 sites in LMICs across the world. This information wasused to create the course that consists of two components: a 9-week online course and a 10-day workshop at the St. Jude campus. 72 participantsfrom 11 institutions enrolled in the online portion and 20 participants wereselected based on grades to attend the workshop. A retrospective post-test
evaluation established that learners improved their understanding of thebarriers to care, possible solutions to improve care, understanding of diagnosis and treatment, and methodology to implement projects (p<0.01). All
participating teams developed projects that are locally implemented. Thosepresent at the workshop formed a multidisciplinary, international collaborative group (Global Alliance in Pediatric Neuro-Oncology). This experienceestablishes that educational programs with systematically created curricula
can not only improved knowledge but be a mechanism to share experiences
and create collaborative networks. Ultimately, patient outcomes will be
tracked to monitor the true impact of the course.
LINC-36. TRILATERAL RETINOBLASTOMA: A REPORT OF FOUR
CASES
Ludi Dhyani Rahmartani; Department of Child Health, Universitas
Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia
Retinoblastoma is the most common primary malignant intraocularcancer that usually develops in early childhood. About 5% of those patientsare at risk of developing trilateral retinoblastoma (TRB). In developing
countries, most of them came in the late stage; therefore, ocular and patient survival rates are lower than in developed countries. From 2015–2019,
we found four cases of trilateral retinoblastoma. Two of them had bilateralretinoblastoma, and two had unilateral retinoblastoma. They all presented
with leukocoria and had no family history of retinoblastoma. The mean
age was 13.8 months (range 9–24 months of age). The diagnosis of trilateral retinoblastoma was made from initial head CT/MRI. They were treatedconservatively with high dose VEC chemotherapy, and three of them havedied during treatment. Trilateral retinoblastoma is usually fatal and needs
multidisciplinary treatment care. In developing countries, it is important toevaluate distant metastasis. Head CT or MRI from the initial diagnosis to
exclude the trilateral retinoblastoma.
LINC-38. 500 CONSECUTIVE SURGICAL CASES FROM
THE PEDIATRIC ONCOLOGY NEUROSURGERY GROUP:UNDERSTANDING THE PERSPECTIVE OF A TERTIARY CENTER
IN BRAZIL
Felipe Hada Sanders, Hamilton Matushita, and Manoel Jacobsen Teixeira;
USP, Sao Paulo, SP, Brazil
With this presentation we aim to present cases submitted to surgery by
the same group of surgeons since 2010, presenting the physical structure,
medical assistance, scientific production and the challenges that we need toovercome in the second decade of the twenty-first century, in a developing
country.
LINC-39. PERFORMANCE STATUS OF PEDIATRIC PATIENTS WITH
CENTRAL NERVOUS SYSTEM TUMORS TREATED IN MEXICO,A SINGLE-CENTER EXPERIENCEClaudia Madrigal-Avila, Alfonso Perez-Bañuelos,
Rafael Ruvalcaba-Sanchez, Lourdes Vega-Vega, andGabriela Escamilla-Asiain; Teleton Pediatric Oncology Hospital,
Queretaro, Queretaro, Mexico
BACKGROUND: Central nervous system (CNS) tumors are the mostcommon solid neoplasms in the pediatric age, they comprise about a quarterof all cancers at this age. Little is known about the specific epidemiologyof this group in Mexico and there are no reports of results focused on the
Performance Status of patients who are treated in a multidisciplinary setting. OBJECTIVE: To describe the Performance Status of CNS pediatricpatients after being treated with a multidisciplinary approach in a tertiary
center. METHODS: We report a retrospective chart review of all pediatricpatients who presented to the Neuro-Oncology Clinic at Teleton PediatricOncology Hospital in Queretaro, Mexico, from December 2014 to January
2020. We analyzed age, gender, the extent of surgical resection and histopathology. Performance Status was assessed using ECOG and Karnofsky/
Lansky scores during every patient’s last follow-up visit. RESULTS: A totalof 56 patients were treated, epidemiology and histopathology variants are
similar to those described in the international literature. With a medianfollow-up of 33 months, 35 patients are alive (62.5%), 28 of them (74.2%)

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have an excellent Performance Status (ECOG score 0 or Lansky/Karnofsky≥ 90), 5 (14.2%) scored ECOG 1–2 and only 4 (11.4%) scored ECOG
3–4. CONCLUSIONS: A multidisciplinary approach with a focus on Performance Status and the potential for neurological recovery is essential in
the management of pediatric patients with CNS tumors. Efforts should beaimed at reducing post-surgical morbidity and early rehabilitation to reintegrate patients into society in the long term.
LINC-40. VERY YOUNG PATIENTS AND CENTRAL NERVOUS
SYSTEM TUMORS: A SINGLE-CENTER EXPERIENCE IN AN UPPERMIDDLE-INCOME COUNTRY
Claudia Madrigal-Avila, Alfonso Perez-Bañuelos, Martin Perez-Garcia,
Rafael Ruvalcaba-Sanchez, Lourdes Vega-Vega, andGabriela Escamilla-Asiain; Teleton Pediatric Oncology Hospital,
Queretaro, Queretaro, Mexico
Tumors of the central nervous system comprise nearly a quarter of allchildhood cancers and are the most frequent solid tumor in the pediatricpopulation. Primary central nervous system tumors (PCNST) are a rare andheterogeneous group of tumors responsible for high mortality and morbidity. Around 10% of primary CNS tumors occur during the first year oflife with almost half of them during the first six months. About 18% of thesetumors appear before the age of two years. Very young children differ fromolder 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 torelate 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-41. TREATMENT OF RECURRENT MEDULLOBLASTOMA IN
CHILDREN IN LOW INCOME SETTINGS
Roman Kizyma, Khrystyna Zapotochna, Bogdan Romanyshyn,
Zoryana Kizyma, and Roman Sobko; Western Ukrainian Specialized
Pediatric Medical Centre, Lviv, Ukraine
INTRODUCTION: Children with recurrent medulloblastoma after initial
therapy have very poor prognosis due to limited second line treatment options
and significant treatment-related morbidity. METHODS: A retrospective
chart review of 18 children with recurrent or progressive medulloblastoma,treated initially with risk-adapted therapy in Western Ukrainian Specialized
Pediatric Medical Centre from 2012 to 2019, was performed. RESULTS: Allpatients received first line multimodal treatment: surgery, distant beam radiotherapy and chemotherapy. Recurrent disease in 11 patients presented withmetastatic dissemination and in 7 patients as local relapse. The median time
to recurrence was 10 months. The median follow-up after diagnosis of recurrent disease diagnosed was 2 years and 2 months. Second line therapy included re-surgery (5 cases), radiation therapy (10 cases) and various cytostatic
agents as monotherapy or combination - carboplatin, cisplatin, cyclophosphamide, etoposide, methotrexate, temozolomide, lomustine. Patients treatedwith radiotherapy for salvage had prolonged local control compared to thosethat received chemotherapy only. On follow-up 8 children are currently
alive. CONCLUSION: Recurrent and progressive medulloblastoma had apoor prognosis with a 2-year overall survival (OS) of 28% on different salvage therapy. The variety in the treatment of all patients experiencing recurrence was observed due to low income country settings. The factors that
influenced higher survival after recurrence of medulloblastoma were longer
time to relapse, and local pattern of relapse/progression.
LINC-42. EPIDEMIOLOGICAL OVERVIEW OF CHILDHOOD CNS
TUMORS IN THE NEUROSURGICAL UNIT IN YEREVAN, ARMENIA
Nune Karapetyan1, Samvel Danielyan2,3, Gevorg Tamamyan4,1,
Armen Tananyan1, Liana Safaryan2,1, Margar Martirosyan5,
Tatul Saghatelyan6,1, Samvel Bardakhchyan2,1, Ruzanna Papyan4,1,Jemma Arakelyan2,1, Karen Bedirian7, Martin Harutyunyan1,
Vahagn Matevosyan5, Nara Lalazaryan5, and Eduard Asatryan5; 1Yerevan
State Medical University after Mkhitar Heratsi, Yerevan, Armenia,
2Hematology Center after Prof. R. Yeolyan, Yerevan, Armenia, 3Yerevan
State Medical University after Mkhitar Heratsi, Yerevan, Armenia,
4Pediatric Cancer and Blood Disorders Center of Armenia, Hematology
Center after Prof. R. Yeolyan, Yerevan, Armenia, 5Surb Astvatsamayr
Medical Center, Yerevan, Armenia, 6National Center of Oncology
named after V.A, Fanarjian, Yerevan, Armenia, 7City of Smile Charitable
Foundation, Yerevan, Armenia
BACKGROUND: Central nervous system (CNS) tumors are the second
most common malignant neoplasms among children worldwide. The cur-iii386

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De c e mb e r 2 0 2 0rent 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, and10–18 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 inmost 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, andembryonal 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.
LINC-43. FACTORS LEADING TO DIAGNOSTIC DELAY FORCHILDREN WITH PRIMARY TUMORS OF CENTRAL NERVOUS
SYSTEM (CNS) IN QATAR
Tayseer Yousif, Ayman Saleh, and Ata Maaz; Sidra Medicine, Doha, Qatar
INTRODUCTION: Median time to diagnosis for primary CNS tumors
for children in Qatar has been reported to be 28 days. However, a wide
variation in diagnostic times is seen. This study was undertaken to analyze
the factors leading to delay in diagnosis. METHODS: Data were retrospectively analyzed for children who had diagnostic delay (more than 28 days)
from September 2006 to February 2020. Presenting symptoms, number andtype of healthcare contacts and presenting symptom interval (PSI) werereviewed. Parental delay (PSI-1) was defined as the date of onset of firstsymptom to the date of first healthcare contact. Healthcare delay (PSI-2) was
defined as date of first healthcare contact to the date of diagnostic scan. RESULTS: Twenty-four patients were identified with diagnostic delay. Medianage at diagnosis was 48.2 (range 5.4–171.6) months with an equal sex distribution. Fifteen (62.5%) patients were older than 3 years, 13(54%) patients
had low grade glioma, 16 (66.7%) had supratentorial tumors and 12 (50%)
presented with raised intracranial pressure. Diagnosis was made after a median 3 (range 1–8) healthcare contacts. Nineteen (79%) patients presented
to primary care. Median PSI was 132 (31–783) days. Parental delay (PSI-1)
was 35 (0–496) days, while healthcare delay (PSI-2) was 41 (0–562) days.
Endocrine (241 days) and oculo-visual (184 days) symptoms were associated with the longest PSI. CONCLUSIONS: There was no significant difference between parental and healthcare delay. Endocrine and oculo-visual
symptoms were associated with longest PSI. Increased awareness is required
for early recognition of signs suggestive of CNS tumors.

MEDULLOBLASTOMA (CLINICAL)
MBCL-01. METHYLATION PROFILING OF PEDIATRICMEDULLOBLASTOMA IN SAUDI ARABIA IN A CLINICAL SETTINGPERMITS SUB-CLASSIFICATION AND REVEALS NEW OUTCOME
PREDICTIONS
Musa Alharbi1, Nahla Mobark1, Ali Abdullah O. Balbaid2, Yara Bashawri3,
Leen Abu Safieh4, Albandary Alowayn4, Rasha Alaljelaify4,
Mariam AlSaeed4, Amal Almutairi4, Fatmah Alqubaishi4, Ebtehal Alsolm4,
Maqsood Ahmad5, Ayman Al-Banyan5, Fahad E. Alotabi5, Matija Snuderl6,
and Malak Abedalthagafi4; 1Department of Paediatric Oncology
Comprehensive Cancer Centre, King Fahad Medical, Riyadh, Saudi Arabia,
2Radiation Oncology Department Comprehensive Cancer Centre, King
Fahad Medical City, Riyadh, Saudi Arabia, 3Department of Biostatistics,
Research Centre, King Fahad Medical City, Riyadh, Saudi Arabia,
4Genomics Research Department, Saudi Human Genome Project, King
Fahad Medical City and King Abdulaziz City for Science and Technology,
Riyadh, Saudi Arabia, 5Department of Neuroscience, King Fahad Medical
City, Riyadh, Saudi Arabia, 6Department of Pathology, NYU Langone
Medical Center, New York, NY, USA
Medulloblastoma (MB) is the most common childhood malignant brain
tumor. DNA methylation profiling has rapidly advanced our understandingof MB pathogenesis at the molecular level, MBs can be sub-grouped according to methylation patterns from FPPE samples into Wingless(WNT-MB), Sonic Hedgehog (SHH-MB), Group 3 (G3) and Group 4 (G4)WNT-MB and SHH-MB subgroups are characterized by gain-of function
mutations that activate oncogenic cell signalling whilst G3/G4 tumors
show recurrent chromosomal alterations. each subgroup has distinct clin-Abstracts

ical outcomes, the ability to subgroup SA-FPPE samples holds significant
prognostic and therapeutic value. We performed the first assessment of
MB-DNA methylation patterns in Saudi Arabian SA cohort using archival
biopsy materials (FPPE n=49). Of the 41 materials available for methylation assessments, 39 could be classified into the major DNA methylation subgroups (SHH, WNT, G3 and G4). Methylation analysis was able
to reclassify tumors that could not be sub-grouped through NGS testing,highlighting its improved accuracy for MB molecular classifications. Independent assessments demonstrate clinical relationships of the subgroups,
exemplified by the high survival rates observed for WNT tumors. Surprisingly, the G4 subgroup did not conform to previously identified phenotypes,
with a high prevalence in females, high metastatic rates and a large numberof tumor-associated deaths. DNA methylation profiling enables the robust
sub-classification of four disease sub-groups in SA-MB patients. Moreover,the incorporation of DNA methylation biomarkers can significantly improve current disease-risk stratification schemes, particularly concerning
the identification of aggressive G4 tumors. These findings have important
implications for future clinical disease management in MB cases across the
Arab world.
MBCL-02. ROLE OF PREOPERATIVE CHEMOTHERAPY IN
METASTATIC MEDULLOBLASTOMA: A COMPARATIVE STUDY IN
92 CHILDREN
Léa Guerrini-Rousseau1, Rachid Abbas1, Sophie Huybrechts2,
Virginie Kieffer-Renaux1, Stéphanie Puget3, Felipe Andreiuolo4,
Kevin Beccaria3, Thomas Blauwblomme3, Stéphanie Bolle1,
Frédéric Dhermain1, Audrey Longaud1, Thomas Roujeau5,
Christian Sainte Rose3, Arnaud Tauziede-Esperiat4, Pascale Varlet4,Michel Zerah3, Dominique Valteau-Couanet1, Christelle Dufour1, andGrill Jacques1; 1Gustave Roussy, Villejuif, France, 2Luxembourg Hospital,
Luxembourg, Luxembourg, 3APHP Necker, Paris, France, 4Sainte Anne
Hospital, Paris, France, 5Guy de Chauliac Hospital, Montpellier, France
BACKGROUND: Previous pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits andrisks compared with initial surgery have not been assessed. METHODS: Twotherapeutic strategies were retrospectively compared in 92 patients withmetastatic 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; groupB). Treatment strategies were similar in both groups. RESULTS: The rateof complete tumor excision was significantly higher in group B than ingroup 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 meanwhilea distant progression. The histological review of 19 matched tumor pairs(before and after chemotherapy) showed that proliferation was reduced andhistological 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 (themean predicted intellectual quotient value was 6 points higher throughout
the follow-up). CONCLUSION: Preoperative chemotherapy is a safe andefficient strategy for metastatic medulloblastoma. It increases the rate ofcomplete tumor excision and may improve the neuropsychological outcome
without jeopardizing survival.
MBCL-03. RESULTS OF HIGH-DOSE THIOTEPA, CARBOPLATIN
AND ETOPOSIDE WITH AUTOLOGOUS HEMATOPOIETIC STEMCELL TRANSPLANTATION FOR PATIENTS WITH RECURRENTMEDULLOBLASTOMA
Asmik Gevorgian1, Polina Tolkunova1, Ilya Kazantsev1, Tatiana Iukhta1,
Andrew Kozlov1, Darya Zvyagintseva1, Elena Morozova1,
Ludmila Zubarovskaya1, Boris Afanasiev1, Olga Zheludkova2, andYury Punanov1; 1Gorbacheva Memorial Institute of Children Oncology,
Hematology and Transplantation, Pavlov First Saint Petersburg State
Medical University, Saint Petersburg, Saint Petersburg, Russian Federation,
2Practical Scientific center of specialized medical care for children named
after V,F, War-Yasenetsky, Moscow, Moscow, Russian Federation
AIM: Medulloblastoma is a highly lethal disease when it recurs. Very few
patients survive with second line conventional treatment after relapse. This
study evaluated the use of high-dose thiotepa, carboplatin and etoposidewith autologous hematopoietic stem-cell transplantation (HSCT) in patientswith recurrent medulloblastoma. METHODS: From 2010 to 2019, 60 patients at the age 4–32 years (median, 12) with recurrent medulloblastoma
were received high-dose chemotherapy (HDCT) with auto-HSCT after induction second line chemotherapy. HDCT included thiotepa 150 mg/m2#4; carboplatin 500 mg/m2 #4; etoposide 250 mg/m2 #4 and +/- etoposide
1 mg intraventricular on days #5 if patient had Ommaya reservoir; followed

by HSCT. At the moment of HDCT 24 patients were in complete response(CR), 31 patients were in partial response (PR) and 5 patients had stabledisease (SD) after second line conventional chemotherapy. RESULTS: The
median follow-up is 65 months (range, 24–227). The median time to engraftment after auto-HSCT was day +11 (range, 8–39). Five-year overall
survival (OS) was 58% and disease free survival (DFS) was 46%. DFS wassignificantly better among patients in CR or PR 50% in compared to children in SD 20% at the moment of HDCT (p=0,002). Transplant related
mortality were 12%, there were 7 patients died because of severe complications within 14 days after transplantation. CONCLUSIONS: HDCT with
auto-HSCT in pediatric patients with recurrent medulloblastoma may be afeasible option for cases who had CR or PR after induction chemotherapy. It
is ineffective as a salvage therapy in refractory patients.
MBCL-04. 5 – AZACYTIDINE IN TREATMENT OF CHILDREN WITH
DE NOVO AND RELAPSED METASTATIC MEDULLOBLASTOMA:RESULTS OF INTERCENTER PILOT STUDY
Andrey Levashov1, Dmitry Khochenkov1, Anna Stroganova1,
Marina Ryzhova2, Sergey Gorelyshev2, Shavkat Kadirov2,
Svetlana Zagidullina1, Stepan Babelyan1, Natalya Subbotina1,
Georgy Mentkevich1, Dmitry Sidelnikov3, Vidmante Daylidite1, andVasily Grigorenko1; 1N.N. Blokhin National Medical Research Centerof Oncology, Moscow, Russian Federation, 2N.N. Burdenko National
Medical Research Center of Neurosurgery, Moscow, Russian Federation,
3I.M. Sechenov First Moscow State Medical University, Moscow, RussianFederation
The aim of this study was to estimate treatment toxicity and event-freesurvival (EFS) according to therapeutic program, MYC/MYC-N gene amplification and MGMT/DNMT (1, 3a, 3b) proteins expression in tumor cells.
From 2016 to 2018 twenty four patients were included in trial. Children
underwent adjuvant therapy: craniospinal radiation (CSI) or local radiation
therapy (RT) to the relapsed site up to 23.4Gy with 5-azacytidine, 2 cycles
methotrexate/5-azacytidine/cisplatin/etoposide, 3 cycles 5-azacytidine/temozolomide - for relapsed group (arm A, n = 5); for patients with de novo
medulloblastoma: arm B, n = 11 – vincristine/cyclophosphamide/cisplatin/
etoposide (OPEC) - based induction, CSI 36Gy + local RT to the tumor bed
up to 54Gy with 5-azacytidine, 1 cycle OPEC and 2 cycles thiophosphamide/carboplatin with auto stem cell transplantation (auto-SCT); arm C, n = 8 –cyclophosphamide/cisplatin - based induction, CSI 23.4 Gy followed by 2
cycles 5-azacytidine/thiophosphamide/carboplatin with auto-SCT, local
RT with 5-azacytidine. The combination of 5-azacytidine with local RT or
temozolomide was safety and tolerability. Arm C was discontinued due tosevere gastrointestinal grade 3/4 toxicity, hemorrhagic syndrome after combination of 5-azacytidine with thiophosphamide/carboplatin. EFS was 0%
in arm A, 53.0 ± 15.5%, 50.0 ± 17.7% in arms B and C, a median follow-up
8.8 ± 1.1 months (arm A), 18.8 ± 2.5 months (arm B), 25.0 ± 4.4 months(arm C). Addition of 5-azacytidine to RT or chemotherapy did not improve
EFS of patients with MYC/MYC-N gene amplification positive tumor. There
was not determined any prognostic significance of MGMT/DNMT (1, 3a,3b) proteins expression in this cohort.
MBCL-05. TREATMENT OF CHILDREN WITH
MEDULLOBLASTOMA WITHOUT METASTATIC INVOLVEMENT
IN THE AGE GROUP OLDER THAN 3 YEARS: RESULTS OF
INTERCENTER TRIAL
Andrey Levashov1, Anna Stroganova1, Dmitry Khochenkov1,
Svetlana Zagidullina1, Stepan Babelyan1, Marina Ryzhova2,
Sergey Gorelyshev2, Shavkat Kadirov2, Natalya Subbotina1,
Vidmante Daylidite1, Dmitry Sidelnikov3, Georgy Mentkevich1, andVasily Grigorenko1; 1N.N. Blokhin National Medical Research Centerof Oncology, Moscow, Russian Federation, 2N.N. Burdenko National
Medical Research Center of Neurosurgery, Moscow, Russian Federation,
3I.M. Sechenov First Moscow State Medical University, Moscow, RussianFederation
The aim of this study was to identify a group of patients aged 3 to 7 years
for whom there is the possibility for reducing of craniospinal radiationdose (CSI). From 2008 to 2018 fifty one pediatric patients with primary
diagnosed medulloblastoma in the age group 3 - 18 years were included intrial, 38 in standard risk group, 13 in high risk group. Treatment program
consisted of surgical removal of the primary tumor site with subsequent
radiation therapy (with CSI of 23,4 Gy or 36 Gy, depending on the risk
group) and high-dose chemotherapy (with high-dose cyclophosphamide
or thiophosphamide). As a result of this study, sufficiently high rates ofoverall survival and progression/relapse - free survival (PFS) were achievedin standard and high-risk groups patients, which amounted to 76,0 ± 8,8%
and 83,3 ± 10,8% with median follow-up 62,9 ± 6,2 months and 52,2 ±7,8 months, respectively. There was revealed patients group in the age 3 7 years with 100% PFS and median follow-up 66,9 ± 8,9 months. Morphological and molecular biological factors of an unfavorable outcome of the

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disease (large cell - anaplastic histology, MYC/MYC-N gene amplification,
Iso17q and TP53 gene mutation) were absent in this tumor samples. We
have also achieved 100% PFS in patients with desmoplastic tumor histology
and in patients, who were treated with thiphosphamide - based chemotherapy regimen. Molecular - biological characteristics analysis of tumor
cells showed a negative effect on PFS of DNMT - positive status (Score 4and>, by 3 markers) and presence of MYC-N gene amplification (SHH molecular subgroup).
MBCL-06. RISK STRATIFICATION IMPROVEMENT OF THE
HIT2000 AND I-HIT-MED COHORTS USING MOLECULARSUBTYPES I-VIII OF GROUP 3/4 MEDULLOBLASTOMAS
Martin Mynarek1, Denise Obrecht1, Martin Sill2,3, Florian Selt2,4,
Katja von Hoff5, David Jones2,3, Dominic Sturm2,3, B.-Ole Juhnke6,
Jonas Ecker2,4, Torsten Pietsch7, Andreas von Deimling8,9, Felix Sahm8,9,Stefan M. Pfister2,3, Olaf Witt2,4, Michael Ludwig Bockmayr1,
Ulrich Schüller1,10, Stefan Rutkowski1, and Till Milde2,4; 1PediatricHematology and Oncology, University Medical Center HamburgEppendorf, Hamburg, Germany, 2Hopp Children’s Cancer Center
Heidelberg (KiTZ), Heidelberg, Germany, 3Division of Pediatric
Neurooncology, German Cancer Research Center (DKFZ) and German
Consortium for Translational Cancer Research (DKTK), Heidelberg,
Germany, 4KiTZ Clinical Trial Unit (ZIPO), Department of PediatricHematology and Oncology, Heidelberg University Hospital, Heidelberg,
Germany, 5Charite – University Medical Center Berlin, Berlin, Germany,
6University Medical Center Hamburg-Eppendorf, Hamburg, Germany,
7Institute of Neuropathology, Brain Tumor Reference Center of theGerman Society for Neuropathology and Neuroanatomy (DGNN),
University of Bonn, DZNE German Center for Neurodegenerative
Diseases, Bonn, Germany, 8Department of Neuropathology, Institute of
Pathology, University Hospital Heidelberg, Heidelberg, Germany, 9ClinicalCooperation Unit Neuropathology, German Consortium for Translational
Cancer Research (DKTK), German Cancer Research Center (DKFZ),
Heidelberg, Germany, 10Department of Neuropathology, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany
OBJECTIVE: Molecular subtypes of Group 3/4 medulloblastoma havebeen identified by unsupervised clustering methods in different studies. We
hypothesized that risk stratification using these subtypes I-VIII improves
outcome prediction. PATIENTS AND METHODS: n=340 patients withGroup 3 or Group 4 medulloblastoma defined by DNA methylation array
profiling enrolled into the HIT2000 study and HIT-MED registries were
subtyped by the Heidelberg Medulloblastoma Classifier. The discovery cohort consisted of n=162 previously published samples, the validation cohort of n=178 newly analyzed samples. RESULTS AND DISCUSSION:
n=300/340 (88%) MBs could be assigned to one of the subtypes with confidence (score >0.8; Heidelberg Medulloblastoma classifier). Subtype II,III andV showed a poor PFS and OS and were classified as HR (discovery:5y-PFS
45%[95%-CI:33–62], 5y-OS 50%[37–67]; validation:5y-PFS 32%[20–50],
5y-OS 40%[27–61]). Subtypes I, IV, VI-VIII fared better (discovery:5y-PFS
67%[58–77], 5y_OS 84%[77–91]; Validation:5y-PFS 70%[58–83], 5y-OS
89%[81–99]). Survival prediction by subtype-based risk assessment was improved compared to Group 3 versus 4 differentiation in both cohorts inunivariate and multivariable Cox regression models (PFS:Hazard ratio HR
versus LR 2.474, p<0.001; Group 3 versus Group 4 1.842, p=0.003; adjustment for anaplasia, age and metastatic disease). Patients older than 4 with
subtype IV tumors (mainly Group 3) treated with radiotherapy achieved
a 100% PFS, while subtype V patients (mainly Group 4) had poor survival. CONCLUSION: We showed that molecular subtypes I-VIII improved
risk stratification of Group 3/4 medulloblastomas. Group 3 subtype IV MB
treated with RT had very high cure rates.
MBCL-07. NON-METASTATIC MEDULLOBLASTOMA OF EARLY
CHILDHOOD: RESULTS FROM THE PROSPECTIVE CLINICAL
TRIAL HIT-2000 AND AN EXTENDED VALIDATION COHORT
Martin Mynarek1, Katja von Hoff1,2, Torsten Pietsch3,
Holger Ottensmeier4, Monika Warmuth-Metz5, Brigitte Bison6,
Stefan Pfister7,8, Andrey Korshunov9,10, Tanvi Sharma7,11, Natalie Jaeger7,12,
Marina Ryzhova13, Olga Zheludkova14, Andrey Golanov15,
Elisabeth Jane Rushing16, Martin Hasselblatt17, Arend Koch18,
Ulrich Schüller1,19, Andreas von Deimling9,20, Felix Sahm7,20, Martin Sill7,12,
Markus J. Riemenschneider21, Hildegard Dohmen22,
Camelia-Maria Monoranu23,24, Clemens Sommer25,
Ori Staszewski26,27, Christian Mawrin28, Jens Schittenhelm29,
Wolfgang Brück30, Katharina Filipski31,32, Christian Hartmann33,
Matthias Meinhardt34, Klaus Pietschmann35, Christine Haberler36,
Irene Slavc37, Nicolas U. Gerber38,39, Michael Grotzer38,39,
Martin Benesch40, Paul-Gerhardt Schlegel4, Frank Deinlein4,
André O. von Bueren41,42, Carsten Friedrich43, Denise Obrecht1,
Gudrun Fleischhack44, Robert Kwiecien45, Andreas Faldum45,
Rolf-Dieter Kortmann46, Marcel Kool7,12, and Stefan Rutkowski1;

iii388N EU R O - O N C O L O G Y•

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1Department of Pediatric Hematology and Oncology, University
Medical Center Hamburg Eppendorf, Hamburg, Germany, 2Departmentof Pediatric Oncology, Hematology and Stem Cell Transplantation,
Charite – University Medical Center Berlin, Berlin, Germany, 3Institute of
Neuropathology, Brain Tumor Reference Center of the German Society
for Neuropathology and Neuroanatomy (DGNN), University of Bonn,DZNE German Center for Neurodegenerative Disease, Bonn, Germany,
4Department of Pediatric Hematology and Oncology, University Children’s
Hospital Wuerzburg, Wuerzburg, Germany, 5Institute of Diagnostic andInterventional Neuroradiology, University Hospital Wuerzburg, Wuerzburg,
Germany, 6Institute of Diagnostic and Interventional Neuroradiology,
University Hospital Wuerzburg, Wuerzburg, Germany, 7Hopp Children’s
Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany,
8Department of Pediatric Hematology and Oncology, Heidelberg
University Hospital, Heidelberg, Germany, 9Clinical Cooperation Unit
Neuropathology (B300), German Cancer Research Center (DKFZ),
Heidelberg, Germany, 10Department of Neuropathology, Heidelberg
University Hospital, Heidelberg, Germany, 11Faculty of Biosciences,
Heidelberg University, Heidelberg, Germany, 12Division of Pediatric
Neurooncology (B062), German Cancer Research Center (DKFZ) andGerman Cancer Consortium (DKTK), Heidelberg, Germany, 13Departmentof Neuropathology, N.N. Burdenko Neurosurgical Institute, Moscow,
Russian Federation, 14Department of Pediatric Oncology, Russian
Scientific Center of Roentgenoradiology, Moscow, Russian Federation,
15Department of Stereotactic Radiotherapy and Radiosurgery National
Medical Research Center of Neurosurgery named after N.N. Burdenko,
Moscow, Germany, 16Institute of Neuropathology, University Medical
Center Zurich, Zurich, Germany, 17Institute of Neuropathology, University
Hospital Muenster, Muenster, Germany, 18Department of Neuropathology,
Charite – University Medical Center Berlin, corporate member of Freie
Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of
Health, Berlin, Germany, 19Department of Neuropathology, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany, 20Departmentof Neuropathology, Heidelberg University Hospital, Heidelberg, Germany,
21Department of Neuropathology, Regensburg University Hospital,
Regensburg, Germany, 22Institute for Neuropathology, University
Hospital Gießen and Marburg, Gießen, Germany, 23Institute of Pathology,
Department of Neuropathology, University of Wuerzburg, Wuerzburg,
Germany, 24Comprehensive Cancer Center (CCC) Mainfranken,
Wuerzburg, Germany, 25Institute for Neuropathology, University Medical
Center of the Johannes Gutenberg University Mainz, Mainz, Germany,
26Institute of Neuropathology, Faculty of Medicine, University of Freiburg,
Freiburg, Germany, 27Berta-Ottenstein-Programme for Advanced Clinician
Scientists, Faculty of Medicine, University of Freiburg, Freiburg, Germany,
28Institute for Neuropathology, University of Magdeburg, Magdeburg,
Germany, 29Department of Neuropathology, Institute for Pathology
and Neuropathology, University Medical Center Tuebingen, Tuebingen,Germany, 30Institute for Neuropathology, University Medical Center
Goettingen, Goettingen, Germany, 31Institute of Neurology (Edinger
Institute), University Hospital, Frankfurt Am Main, Germany, 32German
Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Heidelberg,
Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany,
33Department of Neuropathology, Institute for Pathology, Hannover
Medical Schoo, Hannover, Germany, 34Institute for Pathology, University
Medical Center Carl Gustav Carus, Technical University Dresden, Dresden,
Germany, 35Department for Radiotherapy, Poliklinik Chemnitz, Chemnitz,
Germany, 36Institute of Neurology, and Comprehensive Cancer Center,
Medical University of Vienna, Vienna, Austria, 37epartment of Pediatrics
and Adolescent Medicine, Medical University of Vienna, Vienna, Austria,
38Department of Oncology, University Children’s Hospital, Zurich,
Switzerland, 39Children’s Research Centre, University Children’s Hospital,
Zurich, Switzerland, 40Division of Pediatric Hematology and Oncology,
Department of Pediatrics and Adolescent Medicine, Medical Universityof Graz, Graz, Austria, 41Department of Pediatrics, Obstetrics andGynecology, Division of Pediatric Hematology and Oncology, University
Hospital of Geneva, Geneva, Switzerland, 42Department of Pediatrics,
CANSEARCH Research Laboratory, Faculty of Medicine, Universityof Geneva, Geneva, Switzerland, 43Division of Pediatric Oncology and
Hematology, University Children’s Hospital Rostock, Rostock, Germany,
44Paediatric Haematology and Oncology, Paediatrics III, University
Hospital of Essen, Essen, Germany, 45Institute of Biostatistics and ClinicalResearch, University of Muenster, Muenster, Germany, 46Department ofRadiation Oncology, University of Leipzig, Leipzig, Germany

OBJECTIVE: To avoid craniospinal irradiation (CSI) in children younger
than four years with non-metastatic medulloblastoma by chemotherapy,
intraventricular methotrexate and risk-adapted local radiotherapy. PATIENTSAND METHODS: Eighty-seven patients received systemic chemotherapy andintraventricular methotrexate. Until 2006, CSI was reserved for non-response orprogression. After 2006, local radiotherapy was introduced for non-responders
or classic (CMB), anaplastic or large-cell medulloblastoma (LCA). Infantile
SHH-activated medulloblastomas (SHH_INF) were subdivided by DNAmethylation profiling. Survival in SHH_INF subtypes were also assessed in a val-

Abstracts

idation cohort (n=71). RESULTS: Patients with desmoplastic medulloblastoma(DMB) or medulloblastoma with extensive nodularity (MBEN) (n=42) had
93% 5-year PFS, 100% 5-year OS and 93% 5-year CSI-free survival. Patientswith CMB/LCA (n=45) had 37% 5y-PFS, 62% 5y-OS and 39% 5y-CSI-freesurvival. Local radiotherapy did not improve survival in CMB/LCA patients.
All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH_
INF subgroup. Group 3 patients (5y-PFS 36% [n=14]) relapsed more frequently
than SHH_INF (5y-PFS 93% [n=28]) or Group 4 patients (5y-PFS 83% [n=6],
p<0.001). SHH_INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4
and the validation cohort, without prognostic impact (5y-PFS: iSHH-I 73% vs.
iSHH-II 83%, p=0.25, n=99). Mean IQ was 90 (radiotherapy-free survivors) vs.
74 (patients that received CSI) [p=0.012]. CONCLUSION: Systemic chemotherapy and intraventricular methotrexate led to favorable survival in bothiSHH-subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity.
Survival in non-WNT/non-SHH CMB/LCA patients was not improved by local
radiotherapy. Survival was more favorable in patients with Group 4 than in patients with Group 3 medulloblastoma.
MBCL-08. INTEGRATIVE MOLECULAR ANALYSIS OF PATIENTMATCHED DIAGNOSTIC AND RELAPSED MEDULLOBLASTOMAS
Rahul Kumar1, Maximilian Deng2, Kyle Smith1, Anthony Liu1,
Girish Dhall3, Laura Kleese4, Daniel Bowers4, Murali Chintagumpala5,Sarah Leary6, Javad Nazarian7, Brent Orr1, Arzu Onar-Thomas1,
Stefan Pfister2, Andrey Korshunov2, Giles Robinson1, Amar Gajjar1,
David Jones2, Vijay Ramaswamy8, and Paul Northcott1; 1St. JudeChildren’s Research Hospital, Memphis, TN, USA, 2German Cancer
Research Center (DKFZ), Heidelberg, Germany, 3Children’s Hospital of
Los Angeles, Los Angeles, CA, USA, 4University of Texas Southwestern
Medical Center, Dallas, TX, USA, 5Texas Children’s Hospital, Houston,
TX, USA, 6Seattle Children’s Hospital, Seattle, WA, USA, 7Children’s
National Hospital, Washington, DC, USA, 8Hospital for Sick Children,
Toronto, ON, Canada
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 ofpatient-matched (n=126 patients) diagnostic MBs and relapses/subsequentmalignancies 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). Subgroupand gene-specific patterns of conservation and divergence amongst putative
driver genes were also observed. CONCLUSION: Integrated molecularanalysis 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-09. ISOLATED M1 METASTASES IN PEDIATRICMEDULLOBLASTOMA: IS POSTOPERATIVE RADIOTHERAPYFOLLOWED BY MAINTENANCE CHEMOTHERAPY SUPERIORTO POSTOPERATIVE SANDWICH-CHEMOTHERAPY AND
RADIOTHERAPY?
Denise Obrecht1, Martin Mynarek1, Christian Hagel2, Robert Kwiecien3,
Michael Spohn2,4, Michael L. Bockmayr1,4, Brigitte Bison5,
Monika Warmuth-Metz5, Stefan M. Pfister6,7, David T.W. Jones6,8,
Dominik Sturm6,7, Andreas von Deimling9, Felix Sahm9,6,
Katja von Hoff10, B.-Ole Juhnke1, Martin Benesch11, Nicolas U. Gerber12,
André O. von Bueren13, Carsten Friedrich14, Rolf-Dieter Kortmann15,
Rudolf Schwarz16, Torsten Pietsch17, and Stefan Rutkowski1; 1PediatricHematology and Oncology, University Hospital Hamburg-Eppendorf,
Hamburg, Germany, 2Department of Neuropathology, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany, 3Instituteof Biostatistics and Clinical Research, University of Münster, Münster,Germany, 4Research Institute Kinderkrebs-Zentrum Hamburg, Hamburg,
Germany, 5Institute of Diagnostic and Interventional Neuroradiology,
University Hospital Würzburg, Würzburg, Germany, 6Hopp Children’s
Cancer Center Heidelberg (KiTZ), Heidelberg, Germany, 7Division of

Pediatric Neurooncology, German Cancer Research Center (DKFZ)and German Consortium for Translational Cancer Research (DKTK),
Heidelberg, Germany, 8Pediatric Glioma Research Group, German Cancer
Research Center (DKFZ), Heidelberg, Germany, 9Clinical Cooperation
Unit Neuropathology, German Consortium for Translational Cancer
Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg,
Germany, 10Charite – University Medical Center Berlin, Berlin, Germany,
11Division of Pediatric Hematology and Oncology, Department ofPediatrics and Adolescent Medicine, Medical University of Graz, Graz,
Austria, 12Department of Oncology, University Children’s Hospital, Zürich,
Switzerland, 13Department of Pediatrics, Obstetrics and Gynecology,
Division of Pediatric Hematology and Oncology, University Hospitalof Geneva, Geneva, Switzerland, 14Division of Pediatric Oncology and
Hematology, University Children’s Hospital Rostock, Rostock, Germany,
15Department for Radiation Therapy, University Medical Center
Leipzig, Leipzig, Germany, 16Department for Radiotherapy, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany, 17Institute of
Neuropathology, Brain Tumor Reference Center of the German Society for
Neuropathology and Neuroanatomy (DGNN), University of Bonn, DZNE
German Center for Neurodegenerative Diseases, Bonn, Germany
BACKGROUND: Impact of isolated spread into the cerebrospinal fluid(CSF) is still not investigated comprehensively for childhood medulloblastoma
and the best therapeutic strategy is currently unclear. MATERIALAND METHODS: Sixty-six patients with isolated M1-MB registered to the
HIT-MED-database from 2000–2018 were identified. CSF and MRI were centrally reviewed for all patients. Patients were stratified by age and either treatedwith upfront craniospinal irradiation (CSI) followed by maintenance chemotherapy (CT) or with postoperative CT and delayed CSI. RESULTS: Fortynine patients were non-infants ≥4 years and seventeen were infants <4 years.
Median age was 7.3y (1.1–18.0). 83.3% were histologically classified as
CMB, 12.1% as LCA-MB and 4.6% as DMB. Molecular subgroup was Gr.3
in 25.8%, Gr.4 in 28.8%, SHH in 4.5%, WNT in 1.5% and not evaluatedfor 39.4%. Lumbar puncture was performed on median postoperative day 19(range: 14–77). Median follow-up for survivors was 7.6y (range: 1.2–15.9).
The whole cohort showed a 3y- and 5y-PFS of 68.0(±6.0) and 60.0(±6.5)%,
while OS was 79.1(±5.2) and 72.9(± 5.9)%. 10y-OS was 54.4(±7.5). Patientswith upfront CSI had more favourable outcomes (5y-PFS 66.1 vs. 55.8%[p=0.119]; 5y-OS 90.6 vs. 64.5% [p=0.035]). The trend towards improved
survival in patients with postoperative CSI was retained when only noninfants were considered (pPFS=0.176, pOS=0.055). M1-persistence occurredexclusively in patients with postoperative CT. CONCLUSION: Isolated
M1-MB is rare. Patients without contraindication for CSI appear to benefit
from treatment by upfront CSI followed by maintenance CT, while cumulative
CT-doses would be reduced compared to sandwich strategies.
MBCL-10. LOCAL RECURRENCE AND SURVIVAL OUTCOMESOF MEDULLOBLASTOMA (MB) IN ADOLESCENT AND YOUNG
ADULT PATIENTS (AYA)
Warissara Rongthong, Teeradon Treechairusame, Nan Suntornpong,and Kullathorn Thephamongkhol; Faculty of Medicine Siriraj Hospital,
Bangkok, Thailand
OBJECTIVE: The aim of this study is to evaluate the local recurrencefree survival (LRFS) and overall survival (OS) of MB in AYA patients at our
institute. METHOD: Patients 15–39 years old with MB who was sent for
post-operative radiation therapy (RT) in 2007 - 2017 at our institute were included. Kaplan-Meier statistics were used to estimate the LRFS and OS. RESULTS: Seven patients were included. The median age at RT was 18.3 years(16.7–28.6 years). Male was more common than female, 5 males vs. 2 females.
NTR or GTR was achieved in 71.4% (5 in 7 patients). Only one patient had
metastatic disease (M1) and received combined chemotherapy-RT. The rest
6 patients were received RT alone, all were M0. The median craniospinal
irradiation (CSI) dose and total RT dose were 36Gy (23.4-46Gy) and 54Gy
(54-56Gy), respectively. Five patients had available follow-up MRI brain.
Local recurrence (LR) was found in one patient at 4.3 years after finished
RT. Her initial treatment was subtotal resection (STR) followed by RT alone;
CSI 36 Gy and posterior fossa boost to 55.8Gy. The 2-years and 5-years
LRFS were 100% and 66.7%, respectively. Both 2-years and 5-years OS were100%. The median follow-up time was 7.6 years (0.4–11.5 years). CONCLUSION: Our study shows high 2-years LRFS and OS of post-operative
RT alone in AYA MB. Combined chemotherapy-RT should be considered in
STR or M1. More number of patients and molecular histopathology subtype
reports are still needed to confirm this report.
MBCL-11. TIME TO RADIOTHERAPY IMPACTS SURVIVALIN PEDIATRIC AND ADOLESCENT NON-METASTATICMEDULLOBLASTOMA TREATED BY UPFRONT RADIOTHERAPY –A REPORT FROM THE HIT 2000 TRIAL
Stefan Dietzsch1, Felix Placzek1, Klaus Pietschmann2,1,
André O. von Bueren3, Christiane Matuschek4, Albrecht Glück5,N E U R O -O N C O L O G Y•

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iii389Abstracts

Matthias Guckenberger6, Volker Budach7, Jutta Welzel8,
Christoph Pöttgen9, Heinz Schmidberger10, Frank Heinzelmann11,Frank Paulsen11, Montserrat Pazos12, Rudolf Schwarz13,
Dagmar Hornung13, Carmen Martini14, Anca Ligia Grosu14,
Frank Michael Meyer15, Karolina Jablonska16, Juergen Dunst17,
Karin S. Kapp18, Karin Dieckmann19, Beate Timmermann20,
Torsten Pietsch21, Monika Warmuth-Metz22, Robert Kwiecien23,
Martin Benesch24, Nicolas U. Gerber25, Stefan M. Pfister26,
Steven C. Clifford27, Katja von Hoff28, Sabine Klagges1,
Stefan Rutkowski29, Rolf-Dieter Kortmann1, and Martin Mynarek29;
1Department for Radiation Oncology, University of Leipzig Medical
Center, Leipzig, Germany, 2Department of Radiation Oncology, Chemnitz
Municipal Hospital, Chemnitz, Germany, 3Department of PediatricHematology and Oncology, University Hospital Geneva, Geneva,
Switzerland, 4Department of Radiation Oncology, Medical Faculty,
Heinrich Heine University of Düsseldorf, Düsseldorf, Germany, 5Radiation
Oncology, Munich-Schwabing Municipal Hospital, Munich, Germany,
6Department of Radiation Oncology, University of Zurich Medical Center,
Zurich, Germany, 7Department for Radiation Oncology, Charité School of
Medicine and University Hospital Berlin, Berlin, Germany, 8Departmentof Radiation Oncology, Pius Hospital Oldenburg, Oldenburg, Germany,
9Department of Radiotherapy, West German Cancer Center, University ofDuisburg-Essen, Essen, Germany, 10Department for Radiation Oncology,
University of Mainz Medical Center, Mainz, Germany, 11Department for
Radiation Oncology, University of Tuebingen Medical Center, Tuebingen,Germany, 12Department of Radiotherapy and Radiation Oncology, Ludwig
Maximilian University Munich, Munich, Germany, 13Department ofRadiation Oncology, University Medical Center Eppendorf, Hamburg,
Germany, 14Department of Radiation Oncology, University Medical Center
Freiburg, Freiburg, Germany, 15Radiation Oncology, MVZ medical carecenter, Hospital Augsburg, Augsburg, Germany, 16Department of Radiation
Oncology, University Medical Center Cologne, Cologne, Germany,
17Department of Radiation Oncology, University Hospital SchleswigHolstein, Kiel, Germany, 18Department of Therapeutic Radiology andOncology, Medical University of Graz, Graz, Austria, 19Department ofRadiotherapy, Medical University of Vienna, Vienna, Austria, 20Clinic
for Particle Therapy, West German Proton Therapy Centre, University of
Essen, Essen, Germany, 21Department of Neuropathology, University ofBonn, Bonn, Germany, 22Department of Neuroradiology, University ofWuerzburg, Wuerzburg, Germany, 23Institute of Biometry and ClinicalResearch, University of Muenster, Muenster, Germany, 24Division of
Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent
Medicine, Medical University of Graz, Graz, Austria, 25Children´sHospital, University of Zurich, Zurich, Switzerland, 26Hopp Children´sCancer Center Heidelberg (KiTZ), Division of Pediatric Neurooncology,
German Cancer Research Center (DKFZ) and German Cancer Consortium(DKTK), Department of Pediatric Oncology, Hematology and Immunology,
Heidelberg University Hospital, Heidelberg, Germany, 27Wolfson
Childhood Cancer Research Centre, Newcastle University Centre forCancer, Newcastle upon Tyne, United Kingdom, 28Department of PaediatricOncology and Hematology, Charité University Medicine Berlin, Berlin,
Germany, 29Department of Pediatric Hematology and Oncology, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany
PURPOSE: To evaluate prognostic factors and impact of participation in arandomized trial in non-metastatic medulloblastoma. METHODS AND PATIENTS: 382 patients with non-metastatic medulloblastoma aged 4–21 years
with primary neurosurgical resections between 2001 and 2011 were enrolled
into the HIT 2000 trial and centrally reviewed. Between 2001 and 2006, 176of these patients participated in the randomized trial HIT-SIOP PNET 4. Threedifferent radiotherapy protocols were applied. Molecular subgroup was available
for 157 patients. RESULTS: Median follow-up was 6.35 [0.09–13.86] years. The
5-year progression-free (PFS) and overall survival (OS) rates were 80.3 % ± 2.1% and 86.5 % ± 1.8 %, respectively. On univariate analysis, there was no difference in PFS and OS according to radiotherapy protocols or in patients who
participated in the HIT-SIOP PNET 4 trial or not, while histology, molecular subgroup and postoperative residual tumor influenced PFS significantly. Time interval
between surgery and irradiation (≤48 days vs. ≥49 days) failed the significancelevel (p=0.052). On multivariate analyses, molecular subgroup (WNT activatedvs. Group3 HR 5.49; p=0.014) and time interval between surgery and irradiation (HR 2.2; p=0.018) were confirmed as independent risk factors. CONCLUSION: Using a centralized review system, multiprofessional and multiinstitutional
collaboration as established for pediatric brain tumor patients in Germany, andrisk-stratified therapy, outcome for non-metastatic medulloblastoma treatedwithin HIT-SIOP PNET4 could be maintained outside the randomized trial. Prolonged time to radiotherapy negatively influenced survival.
MBCL-12. MOLECULAR SIGNATURES AND TUMORINFILTRATING IMMUNOLOGICAL CELLS ASSOCIATED WITH
ASIAN MEDULLOBLASTOMA PATIENT SURVIVAL
Kung-Hao Liang1, Kuo-Sheng Wu2, Yi-Yen Lee1, Muh-Lii Liang1,
Jun-Jeng Fen1, and Tai-Tong Wong3; 1Taipei Veterans General Hospital,iii390N EU R O - O N C O L O G Y•

De c e mb e r 2 0 2 0

Taipei, Taiwan, 2Taipei Medical University, Taipei, Taiwan, 3Taipei Medical
University Hospital, Taipei, Taiwan
BACKGROUND: Medulloblastoma is an aggressive pediatric brain
tumor with surgery and post-resection radiotherapy plus chemotherapy
as the major type of treatment currently. METHODS: A cohort of 52
medulloblastoma patients were treated in Taipei Medical University Hospitaland Taipei Veterans General Hospital. Among them, 28 (53.85%) are male.
The average age at presentation is 7.21 ± 4.15. Genome-wide RNA profilingwere performed on fresh-frozen surgical samples. Tumor infiltrating immune
cell percentages were inferred by the cibersort immune deconvolution algorithm. RESULTS: A total of 13 leading genes, including DLL1, ASIC2,
SLC22A17, TRPM3, RPS2P5 and KCNC3, were found to be significantly
associated with overall survival (All P < 0.001). A risk score was constructed,
which is indicative of overall survival (Hazard Ratio [HR] = 2.720, 95%
confidence interval [CI] = 1.798 ~ 4.112, P < 0.001) and recurrence-freesurvival (HR = 1.645, CI = 1.337 ~ 2.025, P < 0.001). After adjustmentof clinical factors, the score remained significantly associated with overall
survival (HR = 2.781, CI = 1.762 ~ 4.390, P < 0.001) and recurrence-freesurvival (HR = 1.604, CI = 1.292 ~ 1.992, P < 0.001). The percentage of
Natural Killer and T follicular helper (Tfh) cells were higher in patients with
better overall survival (P = 0.046 and 0.001, respectively). Furthermore, theTfh percentage is also positively associated with mutation burdens in the expressed exonic regions (P < 0.001). CONCLUSION: Higher mutation burdens are correlated with higher levels of tumor infiltrating Tfh cells, which isindicative of better post-surgery prognosis.
MBCL-13. CORRELATION OF HISTOPATHOLOGY,
CHROMOSOMAL MICROARRAY, AND NANOSTRING BASED
22-GENE ASSAY FOR MEDULLOBLASTOMA SUBGROUPASSIGNMENT ON “HEAD START” 4 CLINICAL TRIAL
Girish Dhall1, Parth Patel2, Megan Blue2, Jaclyn Biegel3,
Isabel Almiraz-Suarez4, Eugene Hwang4, Christopher Pierson2,
Daniel Boue2, and Jonathan Finlay2; 1University of Alabama at
Birmingham, Birmingham, AL, USA, 2Nationwide Children’s Hospital,
Columbus, OH, USA, 3Children’s Hospital Los Angeles, Los Angeles, CA,
USA, 4Children’s National Medical Center, Washington DC, USA“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 withprognostic 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 havepathology/IHC, CMA, and NanoString data on 26 infants and young children with medulloblastoma enrolled on HS 4. Pathology/IHC was able toassign 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, ofwhich, pathology/IHC was able to assign all six samples aforementioned
three subgroups. NanoString was indeterminate in two cases: one case wasclassified as SHH by CMA and pathology/IHC, and the second case wasindeterminate 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-14. A STUDY OF LOW-DOSE CRANIOSPINAL RADIATIONTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED AVERAGE-RISK
MEDULLOBLASTOMA
Aaron Mochizuki1, Anna Janss2, Sonia Partap1, Paul Fisher1, Yimei Li3,
Michael Fisher3, and Jane Minturn3; 1Lucile Packard Children’s Hospital at
Stanford University, Palo Alto, CA, USA, 2Children’s Healthcare of Atlanta,
Atlanta, GA, USA, 3Children’s Hospital of Philadelphia, Philadelphia, PA,
USA
INTRODUCTION: Medulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (nonmetastatic, completely resected) medulloblastoma includes craniospinal
radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival ofthese patients, exposing the long-term morbidities associated with radiation
therapy. METHODS: We performed a single-arm, multi-institution study,
seeking to reduce the late effects of treatment in patients with average-risk
medulloblastoma prior to advances in molecular subgrouping. To do so, weAbstracts

reduced the dose of craniospinal irradiation by 25% to 18 gray with thegoal of maintaining the therapeutic efficacy as described in CCG 9892 withmaintenance chemotherapy. RESULTS: 28 patients aged 3–30 years wereenrolled across three institutions between April 2001 and December 2010.
Median age at enrollment was 9 years with a median follow-up time of
11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were
78.6% (95% CI 58.4% to 89.8%) and 92.9% (95% CI 74.4% to 98.2%),
respectively. The 5-year RFS and OS were 71.4% (95% CI 50.1% to 84.6%)
and 85.7% (95% CI 66.3% to 94.4%), respectively. Toxicities were similar
to those seen in other studies; there were no grade 5 toxicities. CONCLUSIONS: Given the known neurocognitive adverse effects associated withcranial radiation therapy, studies to evaluate the feasibility of dose reduction
are needed. In this study, we demonstrate that select patients with averagerisk medulloblastoma may benefit from reduced craniospinal radiation doseof 18 gray without impacting relapse-free or overall survival.
MBCL-15. IMPACT OF MOLECULAR SUBGROUPS ON OUTCOMESFOLLOWING RADIATION TREATMENT RANDOMIZATIONS FOR
AVERAGE RISK MEDULLOBLASTOMA: A PLANNED ANALYSIS OF
CHILDREN’S ONCOLOGY GROUP (COG) ACNS0331
Jeff Michalski1, Paul Northcott2, Yimei Li2, Catherine Billups2, Kyle Smith2,
Peter Burger3, Thomas Merchant2, Amar Gajjar2, TJ Fitzgerald4,
Gilbert Vezina5, Maryam Fouladi6, Roger Packer5, Nancy Tarbell7, andAnna Janss8; 1Washington University School of Medicine, St. Louis, MO,
USA, 2St. Jude’s Research Hospital, Memphis, TN, USA, 3Johns Hopkins
Hospital, Baltimore, MD, USA, 4UMass Memorial Medical Center,
Worcester, MA, USA, 5Children’s National Medical Center, Washington,
DC, USA, 6Cincinnati Children’s Medical Center, Cincinnati, OH,
USA, 7Massachusetts General Hospital, Boston, MA, USA, 8Children’s
Healthcare of Atlanta, Atlanta, GA, USA
The COG conducted a randomized trial for average-risk medulloblastoma(AR-MB). Patients age 3–21 years were randomized to a radiation boost to
the whole posterior fossa (PFRT) or an involved field volume (IFRT) after
receiving CSI. Patients age 3–7 years were also randomized to standard dose
CSI (23.4Gy, SDCSI) or low dose CSI (18Gy, LDCSI). 464 evaluable patientswere available to compare PFRT vs. IFRT and 226 for SDCSI vs. LDCSI.
380 cases had sufficient tissue for DNA methylation-based molecular classification: 362 confirmed medulloblastoma; 6 non-medulloblastoma; 12 inconclusive. Molecular subgrouping confirmed the following representation
amongst the evaluable cohort: 156 Group 4 (43.1%), 76 Group 3 (21.0%),
66 SHH (18.2%), 64 WNT (17.7%). Five-year event-free survival (EFS) estimates were 82.5±2.7% and 80.5±2.7% for IFRT and PFRT, respectively(p=0.44). Five-year EFS estimates were 71.4±4.4% and 82.9±3.7% for
LDCSI and SDCSI, respectively (p=0.028). EFS distributions differed significantly by subgroup (p<0.0001). Group 3 had the worst outcome, while
WNT had the best outcome. There was a significant difference in EFS by RTgroup among SHH patients; SHH patients receiving IFRT arm had better
EFS compared to PFRT (p=0.018). There was a significant difference in EFS
distributions by CSI group in Group 4 patients; young Group 4 patientstreated with SDCSI had better EFS compared to LDCSI (p=0.047). As previously reported, IFRT is noninferior to PFRT in all patients with AR-MB
but LDCSI is worse than SDCSI in younger children. Significant differencesin outcome by study randomization and molecular subgroup are observed.
MBCL-16. EFFICACY OF CARBOPLATIN GIVEN CONCOMITANTLYWITH RADIATION AND ISOTRETINOIN AS A PRO-APOPTOTICAGENT IN MAINTENANCE THERAPY IN HIGH-RISK
MEDULLOBLASTOMA: A REPORT FROM THE CHILDREN’SONCOLOGY GROUP
Sarah Leary1,2, Roger Packer3, Alok Jaju4, Linda Heier5, Peter Burger6,7,
Kyle Smith8, Jeff Michalski9, Yimei Li8, Catherine Billups8, Eugene Hwang3,
Amar Gajjar8, Ian Pollack10, Maryam Fouladi11, Paul Northcott8, andJames Olson12,1; 1Seattle Children’s, Seattle, WA, USA, 2University ofWashington, Seattle, WA, USA, 3Children’s National Medical Center,
Washington, DC, USA, 4Ann and Robert H Lurie Children’s Hospital,
Chicago, IL, USA, 5NYP/Weill Cornell Medical Center, New York, NY,
USA, 6Johns Hopkins University, Baltimore, MD, USA, 7Sidney Kimmel
Cancer Center, Baltimore, MD, USA, 8St. Jude Children’s Research
Hospital, Memphis, TN, USA, 9Washington University School of Medicine,
St. Louis, MO, USA, 10Children’s Hospital of Pittsburgh of UPMC,
Pittsburgh, PA, USA, 11Cincinnati Children’s Hospital Medical Center,
Cincinnati, OH, USA, 12Fred Hutchinson Cancer Research Center, Seattle,
WA, USABACKGROUND: Metastasis, residual disease, and diffuse anaplasia are
high-risk features in medulloblastoma. METHODS: This was a randomized
phase 3 study. Patients age 3–21 years with high-risk medulloblastoma received (+/-) daily carboplatin with 36Gy craniospinal radiation and weekly
Vincristine followed by six cycles of maintenance chemotherapy with Cisplatin, Cyclophosphamide and Vincristine (+/) 12 cycles of isotretinoin

during and following maintenance. The primary endpoint was event-freesurvival, with exact log-rank test to compare arms. Retrospective molecularanalysis included DNA methylation and exome sequencing. RESULTS: Of
294 medulloblastoma patients enrolled, 261 were eligible by central review
of radiology and pathology, median age 8.6 years (range 3.3–21.2), 70%
male, 189 (72%) with metastatic disease, 58 (22%) with diffuse anaplasia,
14 (5%) with >1.5cm2 residual disease. The 5-year EFS and OS for all
subjects was 63%+4 and 73%+3, respectively. Isotretinoin randomization
was closed due to futility. 5-year EFS was 66 + 5 with carboplatin versus
59 + 5 without (p=0.11), with effect exclusively observed in Group 3 subtype: 73%+8 with carboplatin versus 54%+9 without (p<0.05). Overall
survival differed by molecular subgroup (p=0.006): WNT 100%, SHH
54%+11, Group 3 74%+6, Group 4 77%+5 at 5 years. MYC amplification
or isochromosome 17 were unfavorable in Group 3 (p=0.029). Chromosome 11 loss or chromosome 17 gain were favorable in group 4 (p<0.001).
No survival difference was observed with TP53 mutation in SHH subtype
in this high-risk cohort. CONCLUSIONS: Therapy intensification withcarboplatin improved survival for high-risk group 3 medulloblastoma.
These findings further support an integrated clinical and molecular risk
stratification for medulloblastoma.
MBCL-17. METASTATIC MEDULLOBLASTOMA CAN BE CUREDWITHOUT EXCISION OF THE PRIMARY TUMOR: A SINGLECENTER EXPERIENCE
Rina Dvir1,2, Shlomi Constantini3,4, Jonathan Roth3,4,
Hila Rosenfeld-Keidar1, Inna Ospovat5, and Ronit Elhasid1,2; 1PediatricHemato-Oncology Department, Tel-Aviv Sourasky Medical Center, TelAviv, Israel, 2Sackler Medical School, Tel-Aviv University, Tel-Aviv, Israel,
3Pediatric Neurosurgery Department, Tel-Aviv Sourasky Medical Center,
Tel-Aviv, Israel, 4Sackler Medical School, Tel-Aviv University, Tel-Aviv,
Israel, 5Radiotherapy Department, Tel-Aviv Sourasky Medical Center, Telaviv, Israel
INTRODUCTION: Metastatic medulloblastoma is a challenging disease
The current clinical approach advocates removal of the primary tumor in
the posterior fossa despite evidence of metastatic disease and administer
oncologic treatment within several weeks: Infants of 3–4 years are treatedby tandem high dose chemotherapy with stem cell support (ACNS0334
protocol), while older children are given radiotherapy and tandem highdose chemotherapy with stem cell support (SJMB03 protocol). We postulatethat a resection of the primary tumor is not obligatory, and a biopsy may
suffice in order to enable prompt oncological treatment without affecting
the long-term survival. PATIENTS AND METHODS: Between 2010-2019
7 patients with metastatic medulloblastoma (median age 4.5, age 1–10) weretreated with biopsy only, five spinal and two from the primary tumor. Six
children had a concurrent VP shunt. Four presented with cord compression,and two with neurological deterioration. Four needed emergency radiotherapy. Two infants received protocol ACNS0334, five patients received
protocol SJMB03. RESULTS: Six patients (85%) survived; .3 patients arelong term survivors (> 5 years), 2 patients are in remission for 2–3 years,
one patient is on active therapy. Only 1 patient died after a late (4 years)
metastatic relapse not in the posterior fossa. CONCLUSIONS: Metastatic
medulloblastoma can be cured without excision of the primary tumor andwithout mutilating surgery. Long term prognosis is probably more attributable to disease subtype and prompt oncologic treatment. This approach
merits further studies and may have implications on treatment of nonmetastatic tumors.
MBCL-18. ANALYSIS OF DNA METHYLATION PROFILES OFPEDIATRIC MEDULLOBLASTOMAS: EXPERIENCE AT THE
BAMBINO GESÙ CHILDREN’S HOSPITAL
Evelina Miele, Giuseppe Petruzzellis, Lucia Pedace, Antonella Cacchione,
Andrea Carai, Giovanna Stefania Colafati, Francesca Diomedi Camassei,
Sabrina Rossi, Franco Locatelli, and Angela Mastronuzzi; Bambino GesùChildren’s Hospital, Rome, Italy
BACKGROUND: Medulloblastoma is the most frequent malignant brain
tumor in children, still resulting fatal in about one third of affected patients. An
accurate diagnosis is essential for correct therapeutic stratification. The DNA
methylation profile (DMP) is a combination of changes in DNA methylationand genetic features that reflect the cell of tumor origin. DMP contributed
to classify Medulloblastoma into four subgroups: WNT, SHH, Group 3/4(the latter recently further subdivided into 8 subclasses). Each Methylation
is associated with different genetic, demographic and clinical characteristics.
We report our experience on Medulloblastoma molecular classification basedon DMP. MATERIALS AND METHODS: 54 Medulloblastoma patients(28 males, 26 females) were selected. The DMP analysis was carried out via
IlluminaEPICarrays. The results were obtained using the brain tumor classifier (Capper, 2018). RESULTS: In all cases the DMP allowed to classify theneoplasm, with an optimal score, in a defined methylation class. 10 WNTs,
15 SHHs, 10 Group 3, 19 Group 4 were found. Groups 3/4 were further re-

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fined based on the new consensus (Sharma 2019) in group I (n = 1); group II(n = 5); group III (n = 2); group IV (n = 4); group V (n = 3); group VI (n = 2);
group VII (n = 6); group VIII (n = 7). CONCLUSIONS: This study carriedout the first classification of Medulloblastomas diagnosed in Italy through
DMP, demonstrating its high reproducibility, precision and accuracy. The
molecular classification improves diagnostic accuracy and provides further
information that can guide personalized treatment.
MBCL-19. CHEMOTHERAPY STRATEGIES FOR YOUNG
CHILDREN NEWLY DIAGNOSED WITH DESMOPLASTIC/EXTENSIVE NODULAR MEDULLOBLASTOMA UP TO THE ERA
OF MOLECULAR PROFILING – A COMPARATIVE OUTCOMESANALYSIS OF PROSPECTIVE MULTI-CENTER EUROPEAN ANDNORTH AMERICAN TRIALS
Jonathan L Finlay1,2, Martin Mynarek3, Girish Dhall4,5,Lucie Lafay-Cousin6,7, Claire Mazewski8,9, David Ashley10,11,
Sarah Leary12,13, Bruce H Cohen14, Giles Robinson15, J Russell Geyer12,13,
Diana Tait16, Joseph Stanek1, Amar Gajjar15,17, and Stefan Rutkowski3;
1Nationwide Children’s Hospital, Columbus, Ohio, USA, 2The Ohio State
University, Columbus, Ohio, USA, 3University Medical Center HamburgEppendorf, Hamburg, Germany, 4Children’s Hospital of Alabama,
Birmingham, Alabama, USA, 5University of Alabama at Birmingham,
Birmingham, Alabama, USA, 6Alberta Children’s Hospital, Calgary,Alberta, USA, 7University of Calgary, Calgary, Alberta, USA, 8Aflac Cancer
and Blood Disorders Institute-Children’s Healthcare of Atlanta, Atlanta,
Georgia, USA, 9Emory University School of Medicine-Winship Cancer
Institute, Atlanta, Georgia, USA, 10Duke University School of Medicine,
Durham, North Carolina, USA, 11Preston Robert Tisch Brain Tumor
Institute, Durham, North Carolina, USA, 12Seattle Children’s Hospital,
Seattle, Washington, USA, 13University of Washington School of Medicine,
Seattle, Washington, USA, 14Akron Children’s Hospital, Akron, Ohio,
USA, 15St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.
16The Royal Marsden Hospital, London, United Kingdom, 17University ofTennessee Health Science Center, Memphis, Tennessee, USA
BACKGROUND/OBJECTIVE: Survival has been poor in several multicenter/national trials since the 1980s, either delaying, avoiding or minimizing
brain irradiation in young children with medulloblastoma. The introductionof German regimens incorporating both intravenous high-dose (HD-MTX)
and intraventricular (IVENT-MTX) methotrexate, and North American regimens utilizing marrow-ablative chemotherapy with autologous hematopoietic
cell rescue (HDCx+AuHCR), have reported encouraging outcomes. We performed a comparative outcomes analysis of these strategies for young children
with desmoplastic/extensive nodular medulloblastoma (D/ENMB). DESIGN/METHODS: Data from 12 trials reported between 2005 and 2019 for children<six-years-old with D/ENMB were reviewed; event-free (EFS) with standard
errors were compared. RESULTS: The German HIT-SKK’92 and HIT-SKK’00
trials incorporating HD-MTX and IVENT-MTX reported 85+/-8% and 95+/5% 5-10-year EFS respectively; a third trial (ACNS1221) incorporating HITSKK therapy but without IVENT-MTX reported 49+/-10% EFS. Three trials(Head Start I/II combined and CCG-99703) employing induction chemotherapy
without HD-MTX, followed by 1/3 HDCx+AuHCR cycles, reported 3-5-year
EFS of 67+/-16% and 79+/-11%. Two trials employing HD-MTX-containing
induction chemotherapy (Head Start III and ACNS0334), followed by 1/3
HDCx+AuHCR cycles, reported 3-5-year EFS of 89+/-6% and 100%, respectively. Finally, four trials utilizing neither IVENT-MTX nor HDCx+AuHCR(UK-CNS-9204, CCG-9921, COG-P9934 and SJYC07) reported 2-5-year EFS
of 35+/-11%, 77+/-9%, 58+/-8% and 53+/-9%. CONCLUSIONS: A trend
towards better EFS for young children with D/ENMB is observed in trials
including either HD-MTX as well as IVENT-MTX or including HD-MTXcontaining induction chemotherapy and HDCx+AuHCR. Trials excluding
HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.
MBCL-20. DETECTION OF SOMATIC MUTATIONS BY USING
RNA-SEQ DATA IN CHILDHOOD MEDULLOBLASTOMA AND ITSPOTENTIAL CLINICAL APPLICATION: A COHORT SERIES OF 52
CASES STUDY IN TAIWAN
Tai-Tong Wong1, Kuo-Sheng Wu2, Donald Ming-Tak Ho3, Shih-Chieh Lin4,
Wen-Chang Huang5, Muh-Lii Laing6, and Hsin-Hung Chen6; 1Pediatric
Neurosurgery, Department of Neurosurgery, Taipei Medical University
Hospital and Taipei Neurological Institute, Taipei Medical University,
Taipei, Taiwan, 2Institute of Clinical Medicine, College of Medicine,
Taipei Medical University, Taipei, Taiwan, 3Department of Pathology
and Laboratory Medicine, Cheng Hsin General Hospital, Taipei, Taiwan,
4Department of Pathology and Laboratory Medicine, Taipei, Taiwan,
5Department of Pathology, Wan Fang Hospital and College of Medicine,
Taipei, Taiwan, 6Division of Pediatric Neurosurgery, Neurological Institute,
Taipei Veterans General Hospital and School of Medicine, National YangMing University, Taipei, Taiwan
BACKGROUND: In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). Part of our aim wasiii392

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to explore the clinical application for drug target identification and finding
clues to genetic predisposition. METHODS: In total, 52 frozen tumor tissues of childhood MBs were collected. RNA-Seq and DNA methylation arraydata were generated. Molecular subgrouping was performed. We selected 51
clinically relevant genes for somatic variant calling using RNA-Seq data.
Correlated clinical findings to genetic predisposition were defined. Potential drug targets and genetic predispositions were explored. RESULTS: Fourcore molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Potential drug targets were detected in the pathways of DNA damage
response. Five patients with relevant clinical findings to genetic predisposition clustered in SHH MBs. The corresponding somatic driver mutations
involved TP53, MSH6, PTEN, PTCH1, and TERT promoter (suspicious).
For validation, whole exome sequencing (WES) of blood and tumor tissue
was used in 10 patients with SHH MBs in the cohort series. This study included the five patients with potential genetic predispositions. Four patients
exhibited relevant germline mutations named as TP53, MSH6, PTEN, andSUFU. CONCLUSION: The findings of this study provide valuable information for personalized care of childhood MB in our cohort series and in
Taiwan.
MBCL-21. GERMLINE ELONGATOR MUTATIONS IN SONICHEDGEHOG MEDULLOBLASTOMA
Giles W. Robinson1, Sebastian M. Waszak2, Brian L. Gudenas1,
Kyle S. Smith1, Antoine Forget3, Marija Kojic4, Garcia-Lopez Jesus1,
Jennifer Hadley1, Kayla V. Hamilton5, Emilie Indersie3, Ivo Buchhalter6,
Natalie Jager7, Tanvi Sharma7, Tobias Rausch2, Marcel Kool7,8,Dominic Sturm7, David T. W. Jones7, Ruth Tatevossian1,
Berangere Lombard9, Damarys Loew9, Daniel Bowers10, Anne Bendel11,
Sonia Partap12, Murali Chintagumpala13, John Crawford14,
Nicholas G. Gottardo15, Amy Smith16, Christelle Dufour17,
Stefan Rutkowski18, Michael Grotzer19, Mark Remke20,
Stephanie Puget21, Kristian W. Pajtler7, Till Milde7, Olaf Witt7,
Marina Ryzhova22, Andrey Korshunov6, Brent A. Orr1, David W. Ellison1,
Laurence Brugieres17, Peter Lichter23, Kim E. Nichols1, Amar Gajjar1,
Brandon J. Wainwright4, Olivier Ayrault3, Jan O. Korbel2,
Paul A. Northcott1, and Stefan M. Pfister7; 1St. Jude Children’s Research
Hospital (SJCRH), Memphis, TN, USA, 2European Molecular Biology
Laboratory (EMBL), Heidelberg, Germany, 3Institut Curie, PSL Research
University, Orsay, France, 4Institute for Molecular Bioscience, Universityof Queensland, Brisbane, Australia, 5Dana Farber Cancer Institute,
Boston, MA, USA, 6German Cancer Research Center (DKFZ), Heidelberg,
Germany, 7Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg,
Germany, 8Princess Maxima Center for Pediatric Oncology, Utrecht,
Netherlands, 9Institut Curie, PSL Research University, Paris, France,
10University of Texas Southwestern Medical School, Dallas, TX, USA,
11Children’s Minnesota, Minneapolis, MN, USA, 12Stanford University,
Stanford, CA, USA, 13Texas Children’s Cancer Center, Baylor College ofMedicine, Houston, TX, USA, 14Rady Children’s Hospital, University ofCalifornia San Diego, San Diego, CA, USA, 15Perth Children’s Hospital,
Perth, Australia, 16Arnold Palmer Hospital Center for Children’s Cancer,
Orlando, FL, USA, 17Gustave Roussy Cancer Campus, Villejuif, France,
18University Medical Center Hamburg-Eppendorf, Hamburg, Germany,
19University Children’s Hospital Zurich, University of Zurich, Zurich,
Switzerland, 20University Hospital Dusseldorf, Dusseldorf, Germany,
21Necker Hospital, Paris, France, 22Burdenko Neurosurgical Institute,
Moscow, Russian Federation, 23German Consortium for Translational
Cancer Research (DKTK), Heidelberg, Germany
BACKGROUND: Our previous analysis of established cancer predisposition genes in medulloblastoma (MB) identified pathogenic germline variantsin ~5% of all patients. Here, we extended our analysis to include all proteincoding genes. METHODS: Case-control analysis performed on 795 MB
patients against >118,000 cancer-free children and adults was performed
to identify an association between rare germline variants and MB. RESULTS: Germline loss-of-function variants of Elongator Complex Protein
1 (ELP1; 9q31.3) were strongly associated with SHH subgroup (MBSHH).
ELP1-associated-MBs accounted for ~15% (29/202) of pediatric MBSHH
cases and were restricted to the SHHα subtype. ELP1-associated-MBs
demonstrated biallelic inactivation of ELP1 due to somatic chromosome
9q loss and most tumors exhibited co-occurring somatic PTCH1 (9q22.32)
alterations. Inheritance was verified by parent-offspring sequencing (n=3)
and pedigree analysis identified two families with a history of pediatric MB. ELP1-associated-MBSHH were characterized by desmoplastic/
nodular histology (76%; 13/17) and demonstrated a favorable clinical outcome when compared to TP53-associated-MBSHH (5-yr OS 92% vs 20%;
p-value=1.3e-6) despite both belonging to the SHHα subtype. ELP1 is a
subunit of the Elongator complex, that promotes efficient translational
elongation through tRNA modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed ELP1-associatedMBs exhibit destabilization of the core Elongator complex, loss of tRNA
wobble modifications, codon-dependent translational reprogramming, andinduction of the unfolded protein response. CONCLUSIONS: We identified
ELP1 as the most common MB predisposition gene, increasing the total gen-

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etic predisposition for pediatric MBSHH to 40%. These results mark MBSHH
as an overwhelmingly genetically-predisposed disease and implicate disruption of protein homeostasis in MBSHH development.
MBCL-22. EFFICACY OF DOUBLE-CONDITIONING REGIMENCOMPRISING THIOTEPA AND MELPHALAN FOR RELAPSEDMEDULLOBLASTOMA – A SINGLE INSTITUTION EXPERIENCEKai Yamasaki1, Kazuki Tanimura1, Yuki Okuhiro1, Kota Hira1,
Chika Nitani1, Keiko Okada1, Hiroyuki Fujisaki1, Noritsugu Kunihiro2,
Yasuhiro Matsusaka2, Hiroaki Sakamoto2, and Junichi Hara1; 1Departmentof Pediatric Hematology and Oncology, Osaka City General Hospital,
Osaka, Japan, 2Department of Pediatric Neurosurgery, Osaka City General
Hospital, Osaka, JapanBACKGROUND: The prognosis of relapsed medulloblastoma wasdismal. Recently, we published the promising outcome of metastatic
medulloblastomas treated with a double-conditioning regimen comprisinghigh-dose thiotepa and melphalan (HD-TM). Here, we report a singlecenter study of HD-TM for relapsed medulloblastomas. MATERIALSAND METHODS: From April 2006 to January 2019, 17 consecutive
medulloblastoma patients with the first relapse were identified, and of which
10 received HD-TM were retrospectively reviewed. RESULTS: The medianage at first relapse was 11.9 years (range 1.8–31.7). The median follow-up
period was 23.5 months after 1st relapse. Four localized relapses at the posterior fossa and 6 metastatic relapses including 3 with multiple sites wereobserved. Surgical resection and re-irradiation were administered in 5 and9 patients, respectively. Two-year PFS and OS after relapse were 21±18.1%
and 60±21.9%, respectively, and significantly better than in patients who
did not receive HD-TM. Among 7 evaluable patients, tumor shrinkage wasobserved in 6 after HD-TM administration including 3 patients who wereresistant to prior chemotherapy. At the present time, 5 patients are alive withno evidence of disease (NED). The last 5 patients received re-irradiation
including 12 Gy craniospinal irradiation (CSI), and 4 are alive with NED.
In multivariate analysis for all patients, both HD-TM and re-irradiation
were associated with improved OS and PFS, but disseminated relapse had
no prognostic value (p=0.56). CONCLUSION: HD-TM contributes to prolonged survival when combined with re-irradiation. HD-TM might becomea curative approach for relapsed medulloblastoma, especially when combined with CSI.
MBCL-23. PRELIMINARY ANALYSIS OF TREATMENT-RELATEDTOXICITIES DURING INDUCTION CHEMOTHERAPY FORPATIENTS ON THE HEAD START 4 TRIAL
Vibhuti Agarwal1, Joseph Stanek2, Megan Jaeger2, Girish Dhall3, andJonathan Finlay2; 1Nemours Children’s Hospital, Orlando, FL, USA,
2Nationwide Children’s Hospital, Columbus, OH, USA, 3Children’s
Hospital of Alabama, Birmingham, AL, USA
The currently active, prospective multi-center Head Start 4 (HS4) trial for
CNS embryonal tumors differs from prior HS I-III trials by utilizing absolutephagocyte count (APC) as a measure of myeloid recovery instead of absolute
neutrophil count. The aim of this study was to determine if utilization of
APC resulted in unanticipated treatment-related toxicities during induction
chemotherapy for patients enrolled on HS4. Review of the RedCap database
was conducted for treatment-related CTCAE grade 3 and 4 toxicities. Data
were summarized descriptively. Nonparametric statistical methods wereused for comparisons. At the time of this most recent analysis, a total of
180 induction cycles were completed for the 57 patients enrolled. Of the 57
patients, nine voluntarily discontinued therapy after completing a median ofthree cycles each. These patients had a higher number of documented infections (59% versus 24%, p=0.0004). Veno-occlusive disease (VOD) occurredin five patients, three of whom voluntarily discontinued therapy. Since theprotocol amendment utilizing milligram per kilogram dosing for patients
less than six years of age, there have been no documented episodes of VOD.
The overall toxicities for this cohort were comparable to those reported for
induction chemotherapy in HS I-II trials. The toxic death rate is lower forHS4 compared to HS I-II (0.018% versus 4.7–6%) (Chi et al 2004). Other
than the high rate of infection, possibly associated with shorter duration of
the immediately prior cycles, the use of APC as part of a dose-compression
strategy in HS4 does not appear associated with more significant toxicities.
MBCL-24. CAN YOUNG CHILDREN WITH RELAPSEDMEDULLOBLASTOMA BE SALVAGED AFTER INITIALIRRADIATION-SPARING APPROACHES?
Craig Erker1,2, Valérie Larouche3, Ashley Margol4,5, Chantel Cacciotti6,
Sébastien Perreault7,8, Kenneth J. Cohen9,10, Mohamed S. AbdelBaki11,12,
Juliette Hukin13,14, Shahrad Rod Rassekh13,14, David D. Eisenstat15,16,
Beverly Wilson15,16, Jeffrey Knipstein17,18, Anna L. Hoppmann19,
Eric S. Sandler20,21, Kathleen Dorris22,23, Taryn B. Fay-McClymont24,25,
Ralph Salloum26,27, Virginia L. Harrod28,29, Bruce Crooks1,2,Jonathan L. Finlay11,12, Eric Bouffet30,31, and Lucie Lafay-Cousin24,25;
1Dalhousie University, Halifax, Nova Scotia, Canada, 2IWK HealthCentre, Halifax, Nova Scotia, Canada, 3CHU de Québec-Université Laval,
Québec City, Québec, Canada, 4Keck School of Medicine of University ofSouthern California, Los Angeles, California, USA, 5Children’s Hospitalof Los Angeles, Los Angeles, California, USA, 6Dana-Farber/ BostonChildren’s Cancer and Blood Disorders Center, Boston, Massachusetts,
USA, 7Université de Montréal, Montreal, Québec, Canada, 8CHU SainteJustine, Montreal, Québec, Canada, 9The Sidney Kimmel Comprehensive
Cancer Center, Baltimore, Maryland, USA, 10Johns Hopkins University
School of Medicine, Baltimore, Maryland, USA, 11Ohio State University,
Columbus, Ohio, USA, 12Nationwide Children’s Hospital, Columbus,
Ohio, USA, 13University of British Columbia, Vancouver, British Columbia,
Canada, 14BC Children’s Hospital, Vancouver, British Columbia, Canada,
15University of Alberta, Edmonton, Alberta, Canada, 16Stollery Children’s
Hospital, Edmonton, Alberta, Canada, 17Medical College of Wisconsin,
Milwaukee, Wisconsin, USA, 18Children’s Hospital of Wisconsin,
Milwaukee, Wisconsin, USA, 19University of Alabama at Birmingham,
Birmingham, Alabama, USA, 20Nemours Children’s Specialty Care,
Jacksonville, Florida, USA, 21Wolfson Children’s Hospital, Jacksonville,
Florida, USA, 22University of Colorado School of Medicine, Aurora,
Colorado, USA, 23Children’s Hospital Colorado, Aurora, Colorado, USA,
24University of Calgary, Calgary, Alberta, Canada, 25Alberta Children’s
Hospital, Calgary, Alberta, Canada, 26University of Cincinnati, Cincinnati,
Ohio, USA, 27Cincinnati Children’s Hospital Medical Center, Cincinnati,
Ohio, USA, 28University of Texas, Dell Medical School, Austin, Texas, USA,
29Dell Children’s Medical Center of Central Texas, Austin, Texas, USA,
30University of Toronto, Toronto, Ontario, Canada, 31The Hospital for Sick
Children, Toronto, Ontario, Canada
INTRODUCTION: Irradiation-sparing approaches are used in young
children with medulloblastoma (MB) given the vulnerability of thedeveloping 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 combinedin 20, 15, and 16, respectively. Salvage therapy with curative intent wasgiven 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 amedian 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 irradiationsparing strategies can be salvaged. Neurocognitive and ototoxicity outcomesare being evaluated.
MBCL-25. PILOT STUDY OF A SURGERY AND CHEMOTHERAPYONLY APPROACH IN THE UPFRONT THERAPY OF CHILDRENWITH WNT-POSITIVE STANDARD RISK MEDULLOBLASTOMA:UPDATED OUTCOMES
Kenneth Cohen1, Susan Chi2, Cynthia Hawkins3, Fausto Rodriguez4,
Wendy London2, Robert Craig Castellino5, Dolly Aguilera5,
Stacie Stapleton6, David Ashley7, Daniel Landi7, andPratiti Bandopadhayay2; 1Johns Hopkins Sidney Kimmel Comprehensive
Cancer Center, Baltimore, MD, USA, 2Dana-Farber Cancer Institute,
Boston, MA, USA, 3Hospital for Sick Children, Toronto, Ontario, Canada,
4Johns Hopkins University School of Medicine, Baltimore, MD, USA,
5Children’s Healthcare of Atlanta, Atlanta, GA, USA, 6Johns Hopkins All
Children’s Hospital, St. Petersburg, FL, USA, 7Duke University Medical
Center, Durham, NC, USA
BACKGROUND: Wnt+ medulloblastoma (WPM) is a favorable subtype
with EFS > 90% when treating postoperatively with craniospinal irradiationand posterior fossa boost (CSI/XRT) followed by adjuvant chemotherapy.
This pilot study explored the safety of omitting radiation in standard-risk
WPM. METHODS: Subjects had to meet standard-risk criteria (< 1.5 cm2
residual tumor, no metastatic spread, no anaplasia) and have a WPM.
Subjects received chemotherapy following the COGACNS0331 AAB-AABAAB (A=cisplatin/CCNU/VCR; B=cyclophosphamide/vincristine) backbone. RESULTS: Six children were enrolled on study treatment prior toearly study closure. Subject #1 completed planned protocol therapy but relapsed 3 months following the completion of therapy. Subject #2 completed

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planned protocol therapy but relapsed 6 months following the completionof therapy. In both cases, relapse was local and disseminated. Further accrualwas halted. Both subjects were salvaged with CSI/XRT followed by adjuvant chemotherapy. Of the remaining 4 subjects, two had recently completed
planned protocol therapy at the time of study closure and received CSI/XRT
while in remission and remain in remission approximately one year fromthe completion of treatment. One subject aborted protocol therapy andtransitioned to a Head Start regimen and remains in remission 10 months
from completion of therapy. The final subject had just completed protocol
therapy and had new areas of restricted diffusion concerning for early relapse. Went on to receive CSI/XRT but subsequently relapsed and is now receiving salvage chemotherapy. CONCLUSIONS: Chemotherapy following
ACNS0331, omitting CSI/XRT, appears to be insufficient for the treatmentof non-metastatic WPM.
MBCL-26. FACTORS ASSOCIATED WITH LONGER SURVIVALAFTER FIRST RECURRENCE IN MEDULLOBLASTOMA BY
MOLECULAR SUBGROUP AFTER RISK-BASED INITIAL THERAPY
Murali Chintagumpala1, Colton Terhune2, Lin Tong3, Eric Bouffet4,
Ute Bartels4, Michael Fisher5, Tim Hassall6, Shridharan Gururangan7,
Kristin Schroeder8, Jordan Hansford9, Dong Anh Khuong Quang9,
Richard Cohn10, Stewart Kellie11, Geoffrey McCowage12, Kyle Smith3,
Paul Northcott3, Giles Robinson3, and Amar Gajjar3; 1Texas Children’s
Hospital, Houston, TX, USA, 2University of South Hampton, South
Hampton, United Kingdom, 3St. Jude Children’s Research Hospital,
Memphis, TN, USA, 4Hospital for Sick Children, Toronto, Ontario,
Canada, 5Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania,
USA, 6Children’s Health Queensland, Brisbane, Queensland, Australia,
7University of Florida, Gainsville, FL, USA, 8Duke University, Durham, NC,
USA, 9Royal Children’s Hospital, Melbourne, Victoria, Australia, 10Sydney
Childre, Sydney, New South Wales, Australia, 11Westmead Children’s,
Sydney, New South Wales, Australia, 12Westmead Children’s, Sydney, NSW,
Australia
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: Timeto recurrence following SJMB03 treatment was compared across methylation subgroups among relapsed patients. Therapies received subsequent torelapse were noted. Kaplan-Meier methods and log-rank tests were used forstatistical 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 ofthe 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-27. ASSOCIATION OF MEDULLOBLASTOMA WITH
CHARCOT-MARIE-TOOTH DISEASE
Kenichiro Watanabe1, Kazuyuki Komatsu1, Koji Kawaguchi1,
Risa Makino1, Takayuki Takachi1, Taemi Ogura1, Yasuo Horikoshi1,
Ryuji Ishizaki2, Hideto Iwafuchi3, and Yuzuru Tashiro2; 1Department of
Hematology and Oncology, Shizuoka Children’s Hospital, Shizuoka, Japan,
2Department of Neurosurgery, Shizuoka Children’s Hospital, Shizuoka,
Japan, 3Department of Pathology, Shizuoka Children’s Hospital, Shizuoka,
Japan
Charcot-Marie-Tooth disease (CMT) is one of the most common hereditary neurological disorders and damages peripheral nerves that resultsin motor and sensory disturbance. Association of medulloblastoma (MBL)
with CMT has been rarely reported. A one-year-old male was referred toour hospital because of cerebellar mass. He had partial resection of thetumor, and was pathologically diagnosed as having desmoplastic nodular
medulloblastoma. He received chemotherapy according to the HIT protocol,
however, developed severe peripheral neurotoxicity in the initial stage ofthe treatment. Reinvestigation of family history revealed his mother, grandmother, and aunt had muscle weakness. We suspected he had an inherited
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vincristine. Fluorescence in situ hybridization analysis detected duplicationof PMP22 gene located on 17p11.2, confirming the diagnosis of CMT1A.
He completed the rest of chemotherapy without vincristine, and remainedin complete remission for four years from the end of treatment. In the literature, there are reports of patients with CMT who developed MBL andwere complicated with severe peripheral neurotoxicity due to the use ofvincristine. The present case, along with previous reports, suggests that
medulloblastoma can develop in patients with CMT and reminds the importance of recalling the possibility of CMT when patients develop severe
chemotherapy-induced peripheral neurotoxicity upon use of vincristine.
Desmoplastic nodular medulloblastoma may be successfully treated bychemotherapy without vincristine.
MBCL-28. LONG-TERM FOLLOW-UP RESULTS OF REDUCEDDOSE CRANIOSPINAL RADIOTHERAPY AND TANDEM HIGHDOSE CHEMOTHERAPY IN PATIENTS WITH HIGH-RISK
MEDULLOBLASTOMAJi Won Lee1, Do Hoon Lim2, Meong Hi Son1, Ki Woong Sung1,
Hee Won Cho1, Hee Young Ju1, Ju Kyung Hyun1, Keon Hee Yoo1,
Hye Lim Jung3, Hong Hoe Koo1, Yeon-Lim Suh4, Yoo Sook Joung5, andHyung Jin Shin6; 1Department of Pediatrics, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Republic ofKorea, 2Department of Radiation Oncology, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul,Republic of Korea,
3Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan
University School of Medicine, Seoul, Republic of Korea, 4Department of
Pathology, Samsung Medical Center, Sungkyunkwan University School of
Medicine, Seoul, Republic of Korea, 5Department of Psychiatry, Samsung
Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Republic of Korea, 6Department of Neurosurgery, Samsung Medical
Center, Sungkyunkwan University School of Medicine, Seoul, Republic ofKorea
BACKGROUND: In this study, we report the follow-up results ofreduced-dose of craniospinal radiotherapy (CSRT) followed by tandem highdose chemotherapy (HDCT) in patients with high-risk medulloblastoma(MB). METHODS: Newly diagnosed high-risk MB patients (metastatic
disease, postoperative residual tumor > 1.5 cm2 or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre-RT
chemotherapy, RT including reduced-dose CSRT (23.4 or 30.6 Gy), 4 cycles
of post-RT chemotherapy and tandem HDCT were given. NanoString andDNA sequencing were done with archival tissues. RESULTS: Forty patientswere enrolled, and molecular subgrouping was possible in 21 patients (2WNT, 3 SHH, 8 Group 3 and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy
underwent HDCT. Relapse/progression occurred only in four patients (10year cumulative incidence 10.4 ± 0.3%). However, six patients died fromtreatment-related mortality (TRM) (4 acute TRMs and 2 late TRMs) resulting in 18.5 ± 0.5% of 10-year cumulative incidence. Taken together,
the 10-year event-free survival and overall survival were 71.1 ± 8.0% and68.9 ± 8.5%, respectively. Late effects were evaluated in 25 patients andhigh-tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common. CONCLUSIONS: Strategy using tandem HDCT
following reduced-dose CSRT showed promising results in terms of low relapse/progression rate, however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can have benefit
from HDCT will be needed in the future study.
MBCL-29. PHASE I/II STUDY OF SEQUENTIAL HIGH-DOSE
CHEMOTHERAPY WITH STEM CELL SUPPORT IN CHILDREN
YOUNGER THAN 5 YEARS OF AGE WITH HIGH-RISK
MEDULLOBLASTOMA
Christelle Dufour1, Julien Masliah-Planchon2, Marie-Bernadette Delisle3,
Anne Geoffray4, Rachid Abbas1, Franck Bourdeaut2,
Anne-Isabelle Bertozzi3, Cecile Faure-Conter5, Celine Chappe6,
Emilie De Carli7, Natacha Entz-Werle8, Fanny Fouyssac9, Nicolas Andre10,
Christine Soler11, Claire Pluchart12, Gilles Palenzuela13, Pierre Leblond14,
and Jacques Grill1; 1Gustave Roussy, Villejuif, France, 2Curie Institute,
Paris, France, 3Toulouse University Hospital, Toulouse, France, 4Fondation
Lenval Children’s Hospital, Nice, France, 5Institut d’Hématologie etd’Oncologie pédiatrique, Lyon, France, 6Rennes University Hospital,
Rennes, France, 7University Hospital, Angers, France, 8CHU of Strasbourg,
Strasbourg, France, 9Children’s Hospital, Nancy, France, 10CHU Timone,
Marseille, France, 11CHU of Nice, Nice, France, 12CHU of Reims, Reims,
France, 13CHU of Montpellier, Montpellier, France, 14Oscar Lambret, Lille,
FrancePURPOSE: To assess the 3-year EFS rate of children younger than 5 yearsof age with high-risk medulloblastoma (MB) treated according to the prospective multicenter trial HR MB-5. PATIENTS AND METHODS: After
surgery, all children received 2 cycles of Etoposide- Carboplatine. If par-

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tial (PR) or complete response (CR) was achieved after induction chemotherapy, children received 2 courses of thiotepa (600mg/m²) with stem cell
rescue. For patients in CR after high-dose chemotherapy, they received one
course of Cyclophosphamide – Busilvex with stem cell rescue (Phase I part).
The others patients (not in PR after induction or in CR after thiotepa) weretreated with 2 cycles of Temozolomide-Irinotecan followed by age-adapted
craniospinal irradiation and maintenance treatment. RESULTS: 28 children(2 to 4 years; median: 3.0 years) were enrolled. Group 3 MB were mostcommon (57%). The response rate to Etoposide-Carboplatine was 60.7%.
Among 20 patients treated with Thiotepa, 13 children were in CR and received Cyclophosphamide – Busilvex without radiotherapy. Out of them,
9 patients (45%) are alive in CR without craniospinal irradiation (medianfollow-up 5 years). Among 15 patients treated with radiotherapy, 8 patientsare alive (median follow-up 3.8 years). The study was prematurely stopped
for an excess of events. The median follow-up was 4 years (range 1.5 - 6.1).
The 3-year EFS and OS were 42.3% [25.9 - 60.6] and 71.3% [52.7 - 84.7],
respectively. CONCLUSIONS: This risk-adapted strategy did not improve
EFS in young children with high-risk MB. However, the study shows that
good responders to chemotherapy can be cured without recourse to irradiation.
MBCL-30. NOVEL SMO MUTATION IN DESMOPLASTIC/NODULARMEDULLOBLASTOMA: A CASE REPORT
Avery Wright, Ana Aguilar-Bonilla, Emily Owens Pickle, and Amy A Smith;Arnold Palmer Hospital for Children, Orlando, Florida, USA
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 havemutations within the SHH signaling pathway, often in PTCH1, SUFU, andSMO. We present a case of desmoplastic/nodular medulloblastoma with themutation 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 effectof 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-31. TREATMENT RESULTS AMONG 106 PATIENTS WITH
MEDULLOBLASTOMA OF MOLECULAR SUBGROUP 3
Olga Zheludkova1, Lyudmila Olkhova2, Yuri Kushel’3, Armen Melikyan3,
Marina Ryzhova3, Lyudmila Shishkina3, Andrey Golanov3,
Alexey Kislyakov4, Evgeny Shultz3, Irina Borodina5, Svetlana Gorbatykh4,
Vladimir Popov6, Marina Mushinskaya7, Olga Polushkina1,
Еugenia Inyushkina8, Natalia Yudina9, Lyudmila Privalova10,
Lyudmila Minkina11, Artem Zaichikov12, Evgeny Matsekha13,
Ivan Fisyun14, Daniil Sakun15, Nadezhda Dunaeva16, Svetlana Avanesyan17,
Vladislav Mitrofanov18, Sergey Kovalenko19, Ekaterina Grishina20,
Oleg Chulkov21, Nadezhda Pishchaeva22, Nikolay Vorob’ev23,
Alexey Nechesnyuk5, Natalia Popova24, Dmitriy Pogorelov25,
Alexander Matitsyn26, Alexander Shapochnik27, Valentina Timofeeva28,
Andrey Korchunov29,30, and Elena Slobina31; 1St.Luka`s Clinical ResearchCenter for Children, Moscow, Russian Federation, 2Russian Children
Clinical Hospital, Moscow, Russian Federation, 3Burdenko Neurosurgical
Institute, Moscow, Russian Federation, 4Morozov Children’s Clinical
Hospital, Moscow, Russian Federation, 5Dmitry Rogachev National
Medical Research Center of Pediatric Hematology, Oncology and
Immunology, Moscow, Russian Federation, 6SBHI of MA MRRCI n.a. M.F.
Vladimirskiy, Moscow, Russian Federation. 7Regional Oncology Center,
Perm’, Russian Federation, 8Regional Oncology Center, Moscow, RussianFederation, 9Regional Oncology Center, Voronezh, Russian Federation,
10Regional Oncology Center, Nizhny Novgorod, Russian Federation,
11Regional Oncology Center, Vladivostok, Russian Federation, 12Regional
Oncology Center, Ekaterinburg, Russian Federation, 13Regional Oncology
Center, Chita, Russian Federation, 14Regional Oncology Center, Orel,
Russian Federation, 15Regional Oncology Center, Simpheropol, RussianFederation, 16Regional Oncology Center, Vologda, Russian Federation,
17Regional Oncology Center, Irkutsk, Russian Federation, 18Regional
Oncology Center, Arkhangelsk, Russian Federation, 19Regional Oncology
Center, Chelyabinsk, Russian Federation, 20Regional Oncology Center,
Kazan, Russian Federation, 21Regional Oncology Center, Krasnodar,
Russian Federation, 22Regional Oncology Center, Nizhnevartovsk, RussianFederation, 23Proton Therapy Center, Saint Petersburg, Russian Federation,

24Regional Oncology Center, Volgograd, Russian Federation, 25Regional

Oncology Center, Lipetsk, Russian Federation, 26Regional Oncology
Center, Tambov, Russian Federation, 27Regional Oncology Center,
Orenburg, Russian Federation, 28Regional Oncology Center, Ulyanovsk,
Russian Federation, 29Clinical Cooperation Unit Neuropathology (G380),
German Cancer Research Center, Heidelberg, Germany, 30Heidelberg
University Hospital, Heidelberg, Germany, 31Russian Scientific Center ofRoentgeno-Radiology, Moscow, Russian Federation
OBJECTIVE: To evaluate the treatment results among 106 patientsof molecular subgroup 3 and to determine the factors affecting the prognosis. PATIENTS AND METHODS: In all the patients, initial removal of
the tumor was performed. All the patients got chemoradiotherapy according
to the HIT protocol. There were 34girls and 72boys. Most patients wereover 3 years:74 compared to 32 younger than 3. The majority of the patients had stage M+: 65; in 38 stage M0 was determined; in 3patients, stage
was not specified, Mx.MYC amplification was found in 20 patients; MYCN
amplification, in 4 patients. Classic medulloblastoma was predominant: 65,
and 41 patients had anaplastic/large cell medulloblastoma. RESULTS: The
five-year progression-free survival was 0.51±0.05, the five-year overall survival was 0.52±0.04.The median survival was 82months,and the medianprogression-free survival was 37 months. There were no significant variations of PFS depending on the sex and age. The treatment results depended
on the histological subtype: for classic medulloblastoma, the five-year PFS
was 0.57; for the anaplastic/largecell,0.38(р = 0.02030). The presence ofmetastases significantly affected the survival: PFS for stage M0 was 0.77; forstage М+,0.35(р = 0.00062). Patients with MYC amplification had a significantly worse survival compared to MYCN patients and those without MYC
amplification: 0.1, 0.75, and 0.58, respectively (р = 0.00002). Three patientswith MYC amplification are alive: two patients had MGMT methylation
detected. CONCLUSIONS: The results of treatment among the patientswith molecular subgroup 3 depended on the tumor subtype, presence ofmetastases, MYC amplification and MGMT methylation. In the absence ofunfavorable factors, the survival was the same as in molecular subgroup 4.
MBCL-32. HIGH-DOSE CHEMOTHERAPY WITH STEM CELLRESCUE FOR RECURRENT PREVIOUSLY IRRADIATED
MEDULLOBLASTOMA
Ekaterina Salnikova, Irina Vilesova, Artur Merishavyan, Alexander Druy,
Ludmila Yasko, Andrey Sysoev, Alexey Nechesnyuk, Irina Borodina,
Alexander Karachunsky, Galina Novichkova, and Ludmila Papusha;
Dmitry Rogachev National Medical Research Center of PediatricHematology, Oncology and Immunology, Moscow, Russian Federation
BACKGROUND/OBJECTIVES: Relapse of medulloblastoma (MB) is
highly lethal in previously irradiated patients. As one of therapeutic options for recurrence MB, high-dose chemotherapy with stem cell rescue(HDSCR) is suggested. The aim of our work was to evaluate the effectiveness of this therapy. DESIGN/METHODS: We retrospectively analyzed
the data of 8 pts with previously irradiated relapse MB using HDSCR.
Initially, M0-stage was verified in 4 cases. Histological diagnoses were
desmoplastic (2 pts), classic (2 pts), anaplastic (2 pts) and MB NOS (2 pts).
Molecular genetic analyses was performed in 6 cases: Group 3 was verified in 2 cases (1-classic, 1-anaplastic), Group 4 – in 3 cases (1-classic,
1-anaplastic, 1-desmoplastic). Time to first PD was from 15 to 86 months(median=29,4 months). Local relapse was revealed in 1 pt, metastatic – in
5 pts, mixed – in 2 pts. RESULTS: All pts were treated according HIT-REZ
2005 (3–5 cycles without/with intraventricular etoposide), with CR achievedin 3 pts and PR in 5 pts. HDCT regimens consisted of carboplatin, etoposide,
thiotepa and temozolomide. 2 pts received re-irradiation – focal RT (1) andCSI (1). 7/8 patients died, 1 pt alive with PD. Time from HDCT to death was
5–15 months (median=9,6 months). CONCLUSIONS: HDSCR for recurrent previously irradiated MB is ineffective. Use of other methods should beconsidered in these cases.
MBCL-33. RARE PULMONARY TOXICITY IN THREEMEDULLOBLASTOMA PATIENTS UNDERGOINGANTIANGIOGENIC METRONOMIC COMBINATION THERAPY
Alicia Lenzen1,2, Daniel Gryzlo2, Irene McKenzie1, Stewart Goldman1,2,
and Natasha Pillay-Smiley3,4; 1Ann & Robert H. Lurie Children’s Hospitalof Chicago, Chicago, IL, USA, 2Northwestern University Feinberg Schoolof Medicine, Chicago, IL, USA, 3Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH, USA, 4University of Cincinnati College ofMedicine, Cincinnati, OH, USA
BACKGROUND: Metronomic and targeted anti-angiogenesis therapy(MEMMAT) has emerged as a promising treatment for recurrent/progressive medulloblastoma. This treatment includes bevacizumab, oral
agents (thalidomide, celecoxib, fenofibrate, etoposide & cyclophosphamide) and intrathecal chemotherapy (etoposide & cytarabine). Common
toxicities include myelosuppression, nausea, and infection. Mild respira-N E U R O -O N C O L O G Y•

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tory toxicities can occur. We report three cases with significant respiratory
toxicity. METHODS: An IRB approved chart review was performed ofthree children with recurrent medulloblastoma on MEMMAT treatment
and meaningful pulmonary toxicity. Literature review found no reports ofsimilar findings. RESULTS: Patient ages ranged from 3 to 11 years old. Patients completed a mean of 6.33 months on treatment. There was no history of chronic respiratory disease prior to starting MEMMAT. Patient #1
developed chronic cough requiring multiple respiratory and anti-infective
treatments; CT scan demonstrated airspace opacities concerning for chronic
inflammatory change. Each new viral infection led to significant respiratory
distress. He eventually died from respiratory failure with large cystic lesions
noted on CT. Patient #2 developed a chronic cough not responsive to antibiotics or respiratory treatments. Images reported airspace disease, bronchiectasis, and chronic inflammatory state. Patient #3 developed chronic coughwithout improvement despite antibiotics and inhaled respiratory treatments;
images were suggestive of small airway disease. All three patients required
numerous hospitalizations and additional treatment. CONCLUSION: WithMEMMAT, many side effects are expected though respiratory symptoms
have rarely been reported. Our cases highlight the possible important correlation of pulmonary toxicity while being treated on MEMMAT, and its
impact on patients’ overall health and quality of life.
MBCL-34. EFFICACY OF METHOTREXATE (MTX) ACCORDING
TO MOLECULAR SUB-TYPE IN YOUNG CHILDREN WITH
MEDULLOBLASTOMA (MB): A REPORT FROM CHILDREN’SONCOLOGY GROUP PHASE III TRIAL ACNS0334
Claire Mazewski1,2, Guolian Kang3, Stewart Kellie4, Jeffrey Gossett3,
Sarah Leary5, Bryan Li6, Paul Aridgides7, Laura Hayes8, Alyssa Reddy9,
Dennis Shaw10, Peter Burger11, Alexander Judkins12, Jeffrey Russell Geyer5,
Maryam Fouladi13, and Annie Huang14,15; 1Emory University School of
Medicine, Department of Pediatrics, Division of Pediatric Hematology
Oncology, Atlanta, GA, USA, 2Aflac Cancer & Blood Disorders Center,Children’s Healthcare of Atlanta, Atlanta, GA, USA, 3Saint Jude Children’s
Research Hospital, Department of Biostatistics, Memphis, TN, USA,
4University of Sydney, Children’s Hospital at Westmead, Departmentof Oncology, Westmead, NSW, Australia, 5Seattle Children’s Hospital,
Department of Pediatric Hematology-Oncology, Seattle, WA, USA,
6Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumour
Research Centre, Pediatrics, Toronto, ON, Canada, 7SUNY Upstate
Medical University, Syracuse, NY, USA, 8Nemours Children’s Hospital,
Pediatric Neuro-radiology, Orlando, Fla, USA, 9University of California
San Francisco, Department of Neurology, San Francisco, CA, USA, 10Seattle
Children’s Hospital, Department of Radiology-Oncology, Seattle, WA,
USA, 11Johns Hopkins University, Department of Pathology, Division of
Neuropathology, Baltimore, MD, USA, 12Children’s Hospital Los Angeles,
Keck School of Medicine, University of Southern California, Pathology
and Laboratory Medicine, Los Angeles, CA, USA, 13Cincinnati Children’s
Hospital Medical Center, Pediatrics, Cincinnati, OH, USA, 14Hospitalfor Sick Children, Division of Hematology Oncology Arthur and Sonia
Labatt Brain Tumour Research Centre, Pediatrics, Toronto, ON, Canada,
15University of Toronto, Laboratory Medicine and Pathology, Toronto, ON,
CanadaACNS0334, a Phase 3 trial, compared outcomes of children <36 months
treated with intensive chemotherapy +/-high-dose methotrexate. Nodulardesmoplastic M0-stage MB were excluded. Treatment included 3 induction
cycles (cyclophosphamide/etoposide/vincristine/cisplatin+/-mtx) and 3 consolidation cycles (carboplatin/thiotepa with stem cell rescue). Radiation (RT)
was at physician discretion. Molecular sub-typing was by DNA-methylation.
Log-rank testing was used to compare survival differences. Molecular subtyping of 38 MB identified 11 Sonic Hedgehog (SHH), 25 Group 3 (GP3), 2
Group 4 (GP4). Five-year survival (OS) was 100% for 5 SHH with MTX and4 SHH without MTX; 80% for 10 GP3 with MTX, 40% for 15 GP3 without
MTX (p=0.025). Only 6/14 survivors received RT: 4 for residual following
therapy (1 SHH and 3 GP3) and 2 GP3 salvaged after progression. Two GP3deaths were associated with toxicity; all others were due to disease. Histology
among SHH was nodular-desmoplastic (8) or classic (3); GP3 histology wasclassic (17) or anaplastic (7). Whole-exome sequencing identified 6 somatic
PTCH1 and 1 germline SUFU alteration(s) among 9 SHH. Among GP3, nop53 mutations were found; copy-number analysis identified 5/25 with mycamplification, 5/25 iso17q, 11/25 with 8 loss, 14/25 with loss of 11. Among
GP3, 14/19 had no significant germline mutation. ACNS0334 achieved 100%survival for metastatic SHH. Benefit of methotrexate was observed in GP3
MB supporting incorporation of methotrexate into standard therapy for GP3.
Upfront central pathology review and molecular sub-typing are critical for future clinical trial risk stratification of young children with embryonal tumors.
MBCL-35. SALVAGE RADIATION THERAPY FOR PROGRESSIVE
AND/OR RELAPSED PEDIATRIC MEDULLOBLASTOMA
Muhammad Baig1, Mary McAleer1, David Grosshans1, Arnold Paulino1,
Patricia Baxter2, Murali Chintagumpala2, Wafik Zaky1, andiii396

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Susan McGovern1; 1MD Anderson Cancer Center, Houston, TX, USA,
2Texas Children’s Hospital, Houston, TX, USA
Medulloblastoma (MB) has a dismal prognosis after progression or relapse, and there is no standard of care for salvage therapy. Medical recordsof pediatric patients with progressive/relapsed MB were reviewed for clinicalcharacteristics. We identified 23 patients with recurrent MB with medianage at diagnosis of 3.8 years, 14 males (60%). At diagnosis, 16 patients
had gross total resection, 1 near total, 5 subtotal, and 1 had biopsy alone.
Fifteen patients (66%) had metastatic disease. Tumor histology was classic/
nodular in 10, 4 desmoplastic, 8 anaplastic and 1 myogenic. Ten patients(43%) ages < 3 years, were treated with induction chemotherapy followedby high dose chemo and stem cell rescue. Other 13 patients were treatedwith chemoradiation (11 craniospinal and 2 posterior fossa radiation).
Progression free survival after initial treatment was 11 months (range,
3–58 months); 8 patients (34%) had local recurrence, 10 patients (43%) had
distant metastasis, 4 patients (17%) had local and distant, and one patient
had CSF only recurrence. Salvage therapy was surgery followed by radiationin 12 patients (52%), radiation alone in 3 patients (13%), chemoradiationin 7 patients (30%), and chemotherapy alone in 1 patient. Thirteen patients(56%) received CSI, 6 (26%) received focal and 2 received spinal radiation
only. Five year progression free survival and overall survival from the timeof relapse were 25% and 45%, respectively. Multidisciplinary care is essential for patients with relapsed MB. Salvage radiation that accounts for thepatient’s initial treatment volumes should be considered for these patients.
MBCL-36. HOW TO INCREASE SURVIVAL IN 7 TO 10% OF
PATIENTS WITH AVERAGE-RISK MEDULLOBLASTOMA WITHOUTNEW THERAPIES: EARLY PROSPECTIVE NEURORADIOLOGYSCREENING EXPERIENCE FROM THE CHILDREN’S ONCOLOGY
GROUP
Nicholas Gottardo1,2, Sarah Leary3, Guolian Kang4, Jeffrey Gossett4,
Maryam Fouladi5, Sandy Kessel6, Noah Sabin4, Alok Jaju7,8, andJulie Harreld4; 1Perth Children’s Hospital, Perth, WA, Australia, 2Telethon
Kids Institute, Perth, WA, Australia, 3Seattle Children’s, Seattle, WA, USA,
4St. Jude Children’s Research Hospital, Memphis, TN, USA, 5Cincinnati
Children’s Hospital Medical Center, Cincinnati, OH, USA, 6IROC,
Quality Assurance Review Center, Lincoln, RI, USA, 7Ann and Robert H,
Lurie Children’s Hospital of Chicago, Chicago, IL, USA, 8Northwestern
University Feinberg School of Medicine, Chicago, IL, USA
BACKGROUND: Previous Children’s Oncology Group (COG) averagerisk medulloblastoma studies retrospectively identified that 7 to 10% of patients were wrongly staged; either due to the presence of unequivocal residual
disease greater than 1.5cm2 or metastatic disease. Notably, these patients
had an inferior survival. The current COG front-line average-risk study for
WNT-driven medulloblastoma patients, ACNS1422, is a reduced-intensity
therapeutic protocol. Given the potentially devastating consequences ofdose reduction in a wrongly staged patient, ACNS1422 is utilizing optimized MRI sequences, including thin slices with no gap and post contrast
T2 FLAIR sequences, combined with a rapid central neuroradiology review. RESULTS: The study opened on October 2 2017. As of 31 December
2019, a total of 34 patients have undergone central neuroradiology review.
In 27/34 (79%) repeat scans were requested due to technically inadequate
sequences (majority due to missing post contrast T2 FLAIR, slice thickness and gap issues). Of 19 repeat scans received, four patients (12%) were
wrongly staged as average-risk; three patients were identified with residual
disease >1.5cm2 (in 2 residual disease was confirmed at second resection)and one patient had widespread spinal metastases previously obscured bymotion. In addition, metastatic disease was excluded in another patient,
reported as having metastatic disease. CONCLUSION: Our data is consistent with previous reports revealing that approximately 10% of patientsare wrongly staged as average-risk. The early experience of ACNS1422
reveals that the optimized MRI sequences combined with a rapid central
neuroradiology review are very valuable in a cooperative group setting tomore accurately stage patients.
MBCL-37. CHEMOTHERAPY STRATEGIES FOR YOUNG CHILDRENNEWLY DIAGNOSED WITH CLASSIC (CLMB) OR ANAPLASTIC/LARGE CELL (A/LCMB) MEDULLOBLASTOMA UP TO THE ERA
OF MOLECULAR PROFILING – A COMPARATIVE OUTCOMESANALYSIS
Jonathan Finlay1,2, Martin Mynarek3, Girish Dhall4,5, Claire Mazewski6,7,
Richard Grundy8, Bruce H. Cohen9, Giles Robinson10, David Ashley11,
Joseph R. Stanek1, Amar Gajjar10, and Stefan Rutkowski3; 1Nationwide
Children’s Hospital, Columbus, OH, USA, 2The Ohio State University,
Columbus, OH, USA, 3University Medical Center Hamburg-Eppendorf,
Hamburg, Germany, 4Children’s Hospital of Alabama, Birmingham,
AL, USA, 5The University of Alabama at Birmingham, Birmingham, AL,
USA, 6Aflac Cancer and Blood Disorders Center - Children’s Healthcareof Atlanta, Atlanta, GA, USA, 7Emory University School of Medicine -Abstracts

Winship Cancer Institute, Atlanta, GA, USA, 8University of Nottingham
School of Medicine, Nottingham, United Kingdom, 9Akron Children’s
Hospital, Akron, OH, USA, 10St, Jude Children’s Research Hospital,
Memphis, TN, USA, 11Duke University School of Medicine, Durham, NC,
USA
BACKGROUND/OBJECTIVE: The introduction of German regimens,
supplementing “standard” chemotherapy with both intravenous highdose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, andNorth American regimens incorporating marrow-ablative chemotherapy
with autologous hematopoietic cell rescue (HDCx+AuHCR), reportencouraging outcomes for young children with medulloblastoma. We performed a comparative outcomes analysis of treatment strategies for young
children with ClMB or A/LCMB. DESIGN/METHODS: Data from 12
prospective multi-center trials published between 2005 and 2019 for children <six-years-old with ClMB or A/LCMB were reviewed; survivals werecompared. RESULTS: COG-9921, UKCCSG-CNS9204, COG-P9934 andSJYCO7 employing standard chemotherapy with either no or risk-based
irradiation, reported 3-5-year event-free survival (EFS) of 17+/-5%, 33+/28% (ClMB), 14+/-7% and 13.8+/-9% (ClMB) respectively, with reported
EFS of 0% for A/LCMB in UKCCSG-CNS9204 and SJYCO7. HIT-SKK’87,
HIT-SKK’92 and HIT-SKK’00 incorporating HD-MTX and IVENT-MTX
reported 2-10-year EFS of 30–34+/-10–11% for ClMB and 33+/-27% (HITSSK’00) for A/LCMB. Head Start HS-I-II combined, CCG-99703 and HS-III
employing induction chemotherapy, with or without HD-MTX, followedby single or tandem HDCx+AuHCR reported 3-5-year EFS of 42+/-14%,
50+/-11% and 27+/-6% for ClMB, with EFS for A/LCMB of 38+/-13%(HS-III). Finally, 5-year overall survivals for ACNS0334, without or withinduction HD-MTX, are 39% and 69% respectively for ClMB and A/LCMB
combined. CONCLUSIONS: A trend towards better outcomes for young
children with ClMB and A/LCMB is observed in trials including either
HD-MTX and IVENT-MTX or including HD-MTX-containing induction
chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENTMTX and HDCx+AuHCR have poorer outcomes.
MBCL-38. UNUSUAL EXTRANEURAL METASTASIS OF PEDIATRICEMBRYONAL TUMORS: TWO CASE REPORTS
Aaron Goldberg1,2, Chenue Abongwa1, Jody Pathare1, Clay Hoerig1,2,
Michael Muhonen1, Joffre Olaya1, Amar Gajjar3, Krista Warren4,
Ramesh Patel4, Hollie Lai1, William Loudon1, and Ashley Plant1,2;
1Children’s Hospital Orange County, Orange, CA, USA, 2University ofCalifornia, Irvine, Irvine, CA, USA, 3St. Jude Children’s Research Hospital,
Memphis, TN, USA, 4Miller Children’s Hospital, Long Beach, CA, USA
We report two cases of unusual extraneural metastasis in patients withembryonal tumors without central nervous system disease progression andprolonged 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 thetemporal lobe three years post treatment. He had multiple recurrences in thebrain 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 fromrecurrent 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-41. LYMPHOHEMATOPOIETIC TOXICITY IDENTIFIEDIN PATIENTS WITH MEDULLOBLASTOMA RECEIVINGCRANIOSPINAL IRRADIATION
Atsuko Watanabe, Yuuki Shimizu, Atsuhiko Ohta, Takashi Fukushima,
Tomonari Suzuki, Ryo Nishikawa, and Ryuhei Tanaka; Saitama Medical
University International Medical Center, Hidaka-shi, Saitama, JapanBACKGROUND: Medulloblastoma (MB) is the most common malignant brain tumor of childhood. MB easily disseminates through the spinal
fluid. Surgery followed by radiotherapy, applied to the entire craniospinal
axis (CSI), and adjuvant chemotherapy, represent the treatment of choicefor patients aged ≥3 years. Since the bone marrow of the skull and ver-tebral column are the major hematopoietic organs, we investigated the
myelosuppressive effect of irradiation treatment in patients with MB retrospectively. METHODS: Medical records of newly diagnosed MB patientstreated at our hospital from 2007–2019 were analyzed. Children <3 years
old were excluded because they did not receive CSI to avoid potential neurotoxicity. RESULTS: Medical records of 18 patients (11 males and 7 females,
aged 6–26, median 11 years) were reviewed. Eight patients were stratified
as high-risk disease and 10 patients with standard risk. All patients received
CSI (dosage range 23.4–39.6 Gy based on disease risk) and posterior fossa
boost. All patients developed lymphocytopenia (<0.5×109/L) during irradiation, and for 11 of 18 patients, lymphocytopenia (<0.2×109/L) was severe.
Although 13 patients recovered from the lymphocytopenia before the initiation of chemotherapy, five patients underwent chemotherapy without recovery. Conversely, only six patients developed neutropenia (<1.0×109/L),
and five of the six patients were <10 years old. CONCLUSION: Althoughinfectious episode associated with lymphocytopenia was not observed in thisstudy, CSI treatment in children and adolescents may induce immunodeficient condition particularly in the lymphocytic system. Pediatric oncologists
should pay attention to the impaired immunity of patients with MB who
receive CSI.
MBCL-43. RECURRENT MEDULLOBLASTOMA – LONG-TERM
SURVIVAL WITH A “MEMMAT” BASED ANTIANGIOGENICAPPROACH
Irene Slavc1, Andreas Peyrl1, Johannes Gojo1, Stefan Holm2,
Klas Blomgren2, Astrid M Sehested3, Pierre Leblond4, and Thomas Czech5;
1Medical University of Vienna, Department of Pediatrics and Adolescent
Medicine, Vienna, Austria, 2Karolinska Institute, Department of Women’sand Children’s Health, Stockholm, Sweden, 3Rigshospitalet, Departmentof Pediatrics and Adolescent Medicine, Copenhagen, Denmark, 4Oscar
Lambert Cancer Center, Lille, France, 5Medical University of Vienna,
Department of Neurosurgery, Vienna, Austria
INTRODUCTION: Patients with recurrent medulloblastoma have a poor
prognosis with only around 8% of patients surviving at 5 years irrespectiveof 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 werediagnosed 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 wasgroup 3 or 4 in all except two (one WNT, one SHH-infant). For their current
relapse patients received an antiangiogenic combination therapy consistingof 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 suggestthat 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 MARROWABLATIVE THIOTEPA AND CARBOPLATIN CHEMOTHERAPY(HDCX) AND AUTOLOGOUS HEMATOPOIETIC PROGENITOR
CELL RESCUE (AUHPCR): A DUAL REPORTMicah K. Harris1,2, Zachary N. Funk1,2, Daniel R. Boué3,
Christopher R. Pierson3, Jeremy Jones4, Jeffrey Leonard5, Rolla Abu-Arja1,
Jeffrey Auletta1, Diana S. Osorio1, Margaret Shatara1, Stephan R. Paul6,
Jonathan L. Finlay1, and Mohamed S. AbdelBaki1; 1The Division of
Hematology, Oncology, Blood and Marrow Transplant, Nationwide
Children’s Hospital and The Ohio State University, Columbus, OH, USA,
2The Ohio State University College of Medicine, Columbus, OH, USA,
3Department of Pathology, Nationwide Children’s Hospital and The Ohio
State University, Columbus, OH, USA, 4The Department of Radiology,
Nationwide Children’s Hospital, Columbus, OH, USA, 5The Division of
Pediatric Neurosurgery, Nationwide Children’s Hospital and The Ohio
State University, Columbus, OH, USA, 6Section of Pediatric Hematology/
Oncology, West Virginia University Healthcare Children’s Hospital,
Morgantown, WV, USA
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

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Abstracts

recurrent beta-catenin nucleopositive Wnt-MBs treated with an irradiationsparing strategy, incorporating HDCx/AuHPCR. PATIENT 1: A nine-yearold female experienced local recurrence of a non-metastatic Wnt-MB ninemonths 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 concomitantweekly vincristine, followed by a maintenance regimen that included ninealternating 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. MRIof the brain showed no residual tumor one month post-treatment. He currently awaits follow-up stereotactic radiosurgery. CONCLUSION: Patientswith recurrent Wnt-MB may be treated with curative intent using a multidisciplinary approach that includes HDCx/AuHPCR, and minimization or
avoidance of re-irradiation.
MBCL-48. OUTCOMES OF TREATMENT BASED ON THE ST. JUDEMEDULLOBLASTOMA-96 REGIMEN FOR JAPANESE CHILDRENWITH MEDULLOBLASTOMA
Junya Fujimura1, Tomonari Suzuki2, Yuko Watanabe3, Hidetaka Niizuma3,
Ryuta Saito4, Masayuki Kanamori4, Yukihiko Sonoda5,
Atsuko Watanabe6, Ryuhei Tanaka6, Megumi Fujiwara1, Akinori Yaguchi1,
Takeshi Ishibashi1, Osamu Tomita1, Akihide Kondo7, Toshiaki Shimizu1,
Takaaki Yanagisawa2,8, Teiji Tominaga4, Ryo NIshikawa2, andHajime Arai7; 1Department of Pediatrics, Juntendo University Faculty of
Medicine, Bunkyo-ku, Tokyo, Japan, 2Department of Neuro-Oncology/
Neurosurgery, Saitama Medical University International Medical Center,
Hidaka, Saitama, Japan, 3Department of Pediatrics, Tohoku University
Graduate School of Medicine, Sendai, Miyagi, Japan, 4Department of
Neurosurgery, Tohoku University Graduate School of Medicine, Sendai,
Miyagi, Japan, 5Department of Neurosurgery, Yamagata University Facultyof Medicine, Yamagata, Yamagata, Japan, 6Department of PediatricOncology/Hematology, Saitama Medical University International Medical
Center, Hidaka, Saitama, Japan, 7Department of Neurosurgery, Juntendo
University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan, 8Departmentof Neurosurgery, Jikei University School of Medicine, Minato-ku, Tokyo,
Japan
Medulloblastoma is a type of malignant embryonal tumor in childhoodthat is considered to require multiagent chemotherapy followed by radical resection and craniospinal irradiation (CSI). However, the outcomes of chemotherapy for this tumor in Japan are unclear. Here, we performed a multicenter
retrospective study to determine the prognosis of pediatric medulloblastoma
patients in Japan treated with the St. Jude medulloblastoma-96 (SJMB96)
regimen. Thirty patients with newly diagnosed medulloblastoma received
treatment with the SJMB96 regimen at Juntendo University Hospital inTokyo (n=10), Saitama Medical University International Medical Centerin Saitama (n=10), and Tohoku University Hospital in Miyagi (n=10) from2011 to 2018. All patients underwent tumor resection and CSI, with radiation doses of 23.4Gy for standard-risk patients (n=11) and 39.6Gy forhigh-risk patients (n=19). Six weeks after radiation therapy, patients received
four cycles of high-dose chemotherapy with autologous peripheral blood
stem cell transplantation according to the SJMB96 regimen. We found that5-year overall survival was 80.8% among standard-risk patients and 74.2%
among high-risk patients. No treatment-related deaths occurred. Eight patients who experienced recurrence died within 80 months of diagnosis. As
these treatment outcomes are comparable to those previously reported outside of Japan, our findings indicate that this regimen is a therapeutic option
for medulloblastoma patients in Japan.
MBCL-50. DISMAL OUTCOME OF HIGH RISKMEDULLOBLASTOMA TREATED WITH CHEMOTHERAPY FIRSTAPPROACH IN MALAYSIA
Shiao Wei Quah, EJ Abdul Rahman, H Mohd Ibrahim, Z Muda,
IS Othman, MN Mohamed Unni, K Gunasagaran, MP Ang, CB Goh,and KH Teh; Paediatric Haematology & Oncology Unit, PaediatricDepartment, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
INTRODUCTION: Patients with high risk medulloblastoma are treatedeither with high dose chemotherapy or hyperfractionated radiotherapy.
Both approaches are not feasible in resource-limited countries. POG9031
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standard chemotherapy and radiotherapy only. Hence, we have adopted theprotocol using chemotherapy first approach due to logistical reasons. OBJECTIVE: To review the outcome of children diagnosed with high risk
medulloblastoma in Hospital Kuala Lumpur. METHODS: Patients diagnosed with high risk medulloblastoma between January 2015 and June 2018
treated using the chemotherapy first approach as per POG9031 protocol
were identified. Data was then extracted and analysed. RESULTS: Nine patients were identified, 3 boys and 9 girls. Median age was 9.3 years (range
2.6 – 15.9 years). Median follow up for survivors are 3.6 years. Five patients(55.6%) had macroscopic metastatic disease at diagnosis. All patients had
significant residual disease post-op. Only 3 patients are disease free till last
follow up, giving a 3 years event free survival of 16%. Of the 6 patients who
had relapsed, 4 have died, giving a 3 years overall survival of 46%. Patientswith no metastasis at diagnosis (M0) fared better with 3 years event free survival of 38%, but 3 years event free survival for patients with macroscopic
metastatic disease (M+) was 0%. CONCLUSION: Outcome of children
with high risk medulloblastoma treated with chemotherapy first approach
was dismal.
MBCL-51. POST-AUTOLOGOUS HEMATOPOIETIC CELL
TRANSPLANTATION (AUHCT) PRACTICES FOR YOUNG
CHILDREN WITH MALIGNANT BRAIN TUMORS
Mahvish Rahim1,2, Jeffrey Auletta3,4, Girish Dhall5,6, Jonathan Finlay3,4,
and Scott Coven1,2; 1Indiana University School of Medicine, Indianapolis,
IN, USA, 2Riley Hospital for Children, Indianapolis, IN, USA, 3Nationwide
Children’s Hospital, Columbus, OH, USA, 4The Ohio State University,
Columbus, OH, USA, 5Children’s of Alabama, Birmingham, AL, USA,
6University of Alabama at Birmingham, Birmingham, AL, USA
BACKGROUND: “Head Start” protocols have used autologous hematopoietic stem cell transplant (AuHSCT) for infants and young children
with malignant brain tumors in order to avoid cranial irradiation. The
post-AuHSCT practice for children with a brain tumor diagnosis varies
greatly. The goal of this research study is to explore practices and attitudes
about post-AuHSCT care for children with brain tumors. DESIGN: An anonymous REDCap survey link was provided to all site primary investigators
and additional support personnel at “Head Start” institutions. The survey
questions defined the role of the medical provider completing the form andexplored the various practices relating to transition, management, communication and overall satisfaction. RESULTS: Twenty-one individual replies
have been received so far. The majority report that prophylactic medicines
were discontinued upon WBC recovery; however, management of discontinuation was split evenly between the neuro-oncology and stem-cell transplant teams. Nearly half of responders follow T-cell recovery following
transplant without immunology guidance. Post-AuHCT vaccination practices are highly variable, with no clear consensus. Lastly, most responders
reported adequate ease of transition and communication between the neurooncology and transplant teams. CONCLUSIONS: This work underscores
the need for both multidisciplinary communication for children with brain
tumors in the post-AuHCT period and for the development of standardized
vaccination and other prophylaxis practices.
MBCL-52. ENDOCRINE PROFILE AFTER MEDULLOBLASTOMATREATMENT
Miriam Pavon-Mengual1, Helen Curry1, Vrinda Saraff1,
Zainaba Mohamed1, Helen Benghiat2, Daniel Ford2, Andrew Peet1,
Jenny Adamski1, and Martin English1; 1Birmingham Women’s andChildren’s NHS Foundation Trust, Birmingham, United Kingdom,
2University Hospitals Birmingham NHS Foundation Trust, Birmingham,
United Kingdom
BACKGROUND: Treatment of medulloblastoma has evolved substantially with more chemotherapy, risk-adapted dosing of radiotherapy (RT)and new RT techniques. We present the endocrine profile for our patientstreated over a 20-year period. METHODS: The charts of patients treatedfor medulloblastoma between 1/1/00 and 31/12/19 were reviewed. 105 wereavailable. Group 1 received chemotherapy alone, Group 2 received 23.4 Gywhole CNS RT with a posterior fossa (PF) boost to 54 Gy, Group 3 received > 35 Gy whole CNS RT with PF boost to 54–59 Gy, Group 4 received PF RT to 54 Gy. All received chemotherapy according to nationalguidelines or clinical trials relevant at the time. RESULTS: Group 1 (M:F
11:6, 7 survivors mean age 2 years range 1–7) had no endocrinopathies. At
5 years from diagnosis Group 2 (M:F 15:13) and Group 3 (M:F 35:14) had
the following % RESULTS: Survival 77:61; Growth Hormone deficiency
92:100; Thyroid deficiency 75:81; ACTH deficiency 42:33. Girls were more
likely to need sex hormone replacement than boys. Group 4 (M:F 7:5 mean
age 2) were all treated in the first decade. 3 survivors, one GH deficiency,
one thyroxine deficiency, one both. CONCLUSIONS: There is a trend toearlier endocrinopathies in the group 3 vs group 2 patients, but it does notreach statistical significance. Girls are more likely to need sex hormone replacement than boys. This investigation provides a contemporary profile ofAbstracts

endocrinopathy after treatment for medulloblastoma that can be used for
future comparisons.

MEDULLOBLASTOMA (RESEARCH)
MBRS-01. DISSECTING REGULATORS OF THE ABERRANT POSTTRANSCRIPTIONAL LANDSCAPE IN MYC-AMPLIFIED GROUP 3
MEDULLOBLASTOMA
Michelle Kameda-Smith1, Helen Zhu2, EnChing Luo3, Chitra Venugopal1,
Agata Xella4, Kevin Brown5, Raymond Fox3, Brian Yee3,
Sansi Xing6, Frederick Tan7, David Bakhshinyan6, Ashley Adile6,
Minomi Subapanditha6, Daniel Picard8, Jason Moffat5, Adam Fleming6,
Kristin Hope6, Provias John6, Marc Remke8, Yu Lu6, Tannishitha Reya9,
Juri Reimand5, Robert Wechsler-Reya10, Gene Yeo9, and Sheila Singh6;
1McMaster, Hamilton, ON, Canada, 2University of Toronto, Toronto,
Ontario, Canada, 3UCSD, San Diego, CA, USA, 4Sanford Burnham Prebys
Medical Discovery Institute, San Diego, CA, USA, 5University of Toronto,
Toronto, ON, Canada, 6McMaster, Hamilton, ON, Canada, 7UCSD,San Diego, ON, Canada, 8University Hospital Dusseldorf, Dusseldorf,
Germany, 9UCSD, San Diego, CA, Canada, 10Sanford Burnham Prebys
Medical Discovery Institute, San Diego, CA, Canada
Medulloblastoma (MB) is the most common solid malignant pediatricbrain neoplasm, with Group 3 (G3) MB representing the most aggressive
subgroup. MYC amplification is an independent poor prognostic factor in
G3 MB, however, therapeutic targeting of the MYC pathway remains limited
and alternative therapies for G3 MB are urgently needed. Here we show thatan RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3
MB in both MYC-overexpressing mouse models and patient-derived xenografts. Unbiased integrative multi-omics analysis of MSI1 function in human
G3 MB suggests a paradigm shift beyond traditional gene-based profilingof oncogenes. Here we identify MSI1 as an oncogene in G3 MB driving
stem cell self-renewal through stabilization of HIPK1 mRNA, a downstream
context-specific therapeutic target for drug discovery.
MBRS-02. BET BROMODOMAIN PROTEIN-KINASE
INHIBITOR COMBINATIONS FOR THE TREATMENT OFMEDULLOBLASTOMA
Nagi Ayad1, Robert Suter1, David Robbins1, and Martine Roussel2;
1University of Miami, Miami, FL, USA, 2St. Jude Children’s Research
Hospital, Memphis, TN, USA
Recent sequencing studies have implicated many epigenetic regulators in
medulloblastoma. The epigenetic reader protein Brd4 has been implicatedin various cancers including medulloblastoma. Brd4 controls expression of
the medulloblastoma essential genes MYC in G3 medulloblastomas, whichhave 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 thatpredicts 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 beutilized to inform patient selection for clinical trials utilizing Brd4 inhibitors
in medulloblastoma and other brain tumors.
MBRS-03. SINGLE NUCLEUS TRANSCRIPTOME PROFILES FROMHUMAN DEVELOPING CEREBELLUM REVEAL POTENTIALCELLULAR ORIGINS OF MEDULLOBLASTOMA BRAIN TUMORS
Konstantin Okonechnikov1,2, Mari Sepp3, Kevin Leiss3, Lena Kutscher1,2,
Kati Ernst1,2, David Jones1,2, Natalie Jäger1,2, Kristian W. Pajtler1,2,
Henrik Kaessmann3, and Stefan M. Pfister1,2; 1Hopp-Children’s Cancer
Center Heidelberg (KiTZ), Heidelberg, Germany, 2German Cancer
Research Center (DKFZ), Heidelberg, Germany, 3Center for Molecular
Biology of Heidelberg University (ZMBH), Heidelberg, Germany
Medulloblastoma (MB) is a highly malignant pediatric brain tumor
originating from the cerebellum and brainstem. Identification of molecularsubgroups forming this heterogeneous tumor entity was initially achieved
from transcriptome characterization and further strengthened using DNA
methylation profiling. While subgroup classification improved clinical diagnosis and treatment options, the lack of knowledge of the cell-of-origin forsome of the subgroups hinders further treatment improvements. In addition

identification of the precise cells of origin for each subgroup could help tounderstand tumor cell biology. Single cell sequencing is the optimal way tosolve this task; recently, there were attempts to uncover putative MB cellof-origin by using such information obtained from mouse embryonic cerebellum. However, such a comparative strategy can miss important results
due to the differences between mouse and human. To solve this issue, we
performed global single nucleus sequencing on human cerebellum pre- andpostnatal materials across several developmental time points and generated
transcriptome profiles from ~200k single cells. We identified known cell
types forming the human cerebellum and performed detailed comparison of
normal cells to RNA-seq bulk data from MB brain tumors across all subgroups. By selecting an optimal analysis strategy, we verified granule neuron
precursors as cells of origin for the SHH MB subgroup. Additionally, we
also found other cell types in conjunction with the remaining MB subgroups,
suggesting new potential targets for investigation. Notably, this strategy canbe further applied to the examination of other brain tumors and has perspectives in medical application.
MBRS-04. MEDULLOBLASTOMA DETECTION BY BLOOD TEST
Michal Yalon1, Amos Toren1, Shany Freedman1, Marc Remke2, andRuty Meharian-Shai1; 1Sheba Medical Center, Ramat Gan, Israel, 2German
Cancer Research Center, Dusseldorf, Germany
INTRODUCTION: Long non coding RNAs (lincRNAs) are functionallydefined 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 ona 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 inpatients 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 agood target for therapy.
MBRS-06. GLI3 INDUCES NEURONAL DIFFERENTIATION IN WNTAND SHH- ACTIVATED MEDULLOBLASTOMAManabu Natsumeda1, Hiroaki Miyahara2, Junichi Yoshimura1,
Yoshihiro Tsukamoto1, Makoto Oishi1, Takafumi Wataya3,
Charles Eberhart4, Akiyoshi Kakita5, and Yukihiko Fujii1; 1Department of
Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan,
2Department of Neuropathology, Institute for Medical Science of Aging,
Aichi Medical University, Nagakute, Japan, 3Department of Neurosurgery,Shizuoka Children‘s Hospital, Shizuoka, Japan, 4Department of Pathology,
Johns Hopkins University School of Medicine, Baltimore, MD, USA,
5Department of Pathology, Brain Research Institute, Niigata University,
Niigata, JapanBACKGROUND: We have previously investigated the expression of Gli3,a downstream target of the Sonic Hedgehog pathway, which main function is to suppress Gli1/2 in medulloblastomas. We found that Gli3 is associated with neuronal and glial differentiation in desmoplastic / nodular(D/N) type medulloblastomas (Miyahara et al., Neuropathology, 2013). In
the present study, we investigated the expression of Gli3 in molecular subgroups. METHOD: Thirty-one medulloblastomas treated at Niigata University between 1982 and 2013 were studied. Molecular classification into
4 subgroups (WNT-activated, SHH-activated, Group 3 and Group 4) using
Nanostring and immunohistochemistry was performed. Furthermore, Gli3
and Gli1 expression in molecular subgroups was assessed using public databases. RESULTS: Nanostring was considered reliable (confidence > 0.9)
in 28 cases. Four cases were classified as WNT-, 5 cases as SHH-activated,
4 cases as Group 3 and 16 cases as Group 4. Gli3 was positive in 7 outof 9 (78%) WNT-/SHH- cases, but positive in only 8 out of 19 (42.1%)
non-WNT-/SHH- subgroup cases (p = 0.1145, Fisher’s exact test). R2 database analysis confirmed that Gli3 was significantly elevated in WNT- andSHH-activated medulloblastoma. Gli1 was elevated in SHH-activated cases
but suppressed in WNT-activated cases. IHC analysis revealed that Gli3
was elevated inside nodules showing neuronal differentiation in D/N type

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medulloblastoma. Results of single cell RNA analyses were consistent withthose of IHC, Nanostring and R2. CONCLUSION: These results suggestthat Gli3 is elevated inside the nodules of SHH-activated medulloblastoma,
whereas in WNT-activated cases, Gli3 diffusely suppresses HH signaling.
MBRS-08. SONIC HEDGEHOG SIGNALING PRIMES CEREBELLARGRANULE NEURON PROGENITORS, THE CELL OF ORIGIN FOR
MEDULLOBLASTOMA, FOR APOPTOSIS BY INDUCING PRO
APOPTOTIC BIM
Abigail Cleveland, and Timothy Gershon; University of North Carolina at
Chapel Hill, Chapel Hill, NC, USA
Medulloblastomas, unlike other malignant brain tumors, are typicallysensitive to radiation therapy, but the mechanisms that mediate this sensitivity are unclear. Cerebellar granule neuron progenitors (CGNPs), the cellof origin for SHH-subgroup medulloblastoma, are also highly sensitive toradiation. In early life, CGNPs proliferate in response to Sonic Hedgehog(SHH) signaling, and hyperactivation of SHH signaling in CGNPs can leadto the development of SHH-subgroup medulloblastoma. We propose that
SHH activation induces radiation sensitivity along with tumorigenesis. We
have previously shown that the proapoptotic protein BAX is required forradiation sensitivity of both SHH-driven medulloblastomas and CGNPs in
mice, and that BCL-xL supplies critical regulation of BAX, preventing spontaneous cell death. Here, we show that SHH signaling increases the radiation
sensitivity of CGNPs by inducing the proapoptotic protein BIM. We foundthat BIM expression depends on SHH activity, and that genetic deletion of
Bim decreases the radiation-sensitivity of CGNPs. Mechanistically, we showthat BIM binds to anti-apoptotic proteins BCL-xL and MCL-1, where it
may alter the balance of BAX and BCL-xL interactions. Consistent with ourmechanistic model, human medulloblastoma patients with high BIM expression show a better prognosis. Based on these observations, we propose that
SHH-induced BIM mediates the typical radiation sensitivity of SHH-driven
medulloblastoma. Finding ways to enhance BIM activity may open new opportunities for targeted medulloblastoma therapy.
MBRS-10. QUIESCENT SOX9-POSITIVE CELLS BEHIND MYC
DRIVEN MEDULLOBLASTOMA RECURRENCE
Sara Bolin1, Vasil Savov1, Anna Borgenvik1, Gabriela Rosén1,
Karl Holmberg Olausson1, Miao Zhao1, Alexandra Garancher2,
Aldwin Suryo Rahmanto3, Sonja Hutter1, Oliver Mainwaring1,
Jessica Rusert2, Anders Sundstrom1, Stacey Richardson4,
Grammatiki Fotaki1, Rebecca M. Hill4, Adrian M. Dubuc5,
Antonia Kalushkova1, Marc Remke5, Matko Čančer1,
Helena Jernberg-Wiklund1, Vijay Ramaswamy5, Xingqi Chen1,
Michael D. Taylor5, Olle Sangfelt3, Ulrich Schüller6, Steve C. Clifford5,
Robert J. Wechsler-Reya2, Holger Weishaupt1, and Fredrik J. Swartling1;
1Uppsala University, Uppsala, Sweden, 2Sanford Burnham Prebys Medical
Discovery Institute, La Jolla, CA, USA, 3Karolinska Institutet, Stockholm,
Sweden, 4Newcastle University, Newcastle upon Tyne, United Kingdom,
5The Hospital for Sick Children, Toronto, ON, Canada, 6University
Medical Center Hamburg-Eppendorf, Hamburg, Germany
Tumor recurrence is the leading cause of death in medulloblastoma, themost frequent malignant pediatric brain tumor. Recurrence occurs whensubpopulations of cancer cells evade standard therapy by acquiring features of immune escape, metastatic spread, and treatment resistance. The
transcription factor SOX9 correlated with treatment resistance and dissemination in aggressive Group 3 medulloblastoma. By studying paired primaryrecurrent medulloblastoma samples and patient-derived xenograft models,
we identified rare SOX9-positive slow-cycling, therapy-resistant tumor cells
that accumulate in relapses and in metastases. In an inducible transgenic
Group 3 tumor model, doxycycline treatment kills all tumor cells by turning
MYC off. However, when MYC expression was redirected to the SOX9 promoter, recurrences from rare, dormant SOX9-positive cells developed with
100% penetrance. Expression profiling revealed that recurrences were more
inflammatory, metastatic, and showed elevated MGMT methyltransferase
levels which depleted recurrent cells when selectively inhibited. Our model
explains how recurrences develop from SOX9-induced quiescence in MYCdriven brain cancer.
MBRS-12. A TRANSPOSON MUTAGENESIS SCREEN IDENTIFIESRREB1 AS A DRIVER FOR GROUP 3 MEDULLOBLASTOMA
Meher Beigi Masihi, Catherine Lee, Grace A Furnari, Alexandra Garancher,and Robert J. Wechsler-Reya; Sanford Burnham Prebys Medical Discovery
Institute, La Jolla, CA, USA
Medulloblastoma (MB) is the most common malignant childhood brain
tumor. MB can be divided into four major subgroups – WNT, Sonic hedgehog(SHH), Group 3 (G3), and Group 4 (G4) – that exhibit distinct genetic alterations, gene expression profiles, and clinical outcomes. Patients with G3-MB

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have the worst prognosis, and a deeper understanding of this disease is critical for development of new therapies. Most G3-MBs express high levelsof the MYC oncogene, suggesting that MYC plays an important role intumorigenesis. To identify genes that cooperate with MYC to promote formation of G3-MB, we performed an in vivo mutagenesis screen using miceexpressing the Sleeping Beauty (SB) transposon. Cerebellar stem cells fromtransposon/transposase-expressing mice were infected with viruses encoding
Myc, and transplanted into the cerebellum of adult hosts. The resulting tumors were sequenced to identify transposon-targeted genes, and these genes
were functionally analyzed to determine whether they could cooperate with
Myc to drive G3-MB. These studies identified the transcription factor Rasresponsive element binding protein 1 (Rreb1) as a potent Myc-cooperating
gene. Tumors driven by Myc and Rreb1 resemble G3-MB at a histologicaland molecular level. Moreover, RREB1 is overexpressed in human G3-MB,
and knockdown of RREB1 impairs growth of G3-MB cell lines and patientderived xenografts. Ongoing studies are aimed at identifying the mechanisms by which Rreb1 contributes to tumor growth. Our studies demonstrate
an important role for RREB1 in G3-MB, and provide a new model that canbe used to identify therapeutic targets and develop more effective therapies
for medulloblastoma.
MBRS-13. MIR-1253 POTENTIATES CISPLATIN RESPONSE IN
PEDIATRIC MEDULLOBLASTOMA BY REGULATING FERROPTOSIS
Ranjana K. Kanchan1, Naveenkumar Perumal1, Pranita Atri1,
Ramakanth Chirravuri Venkata1, Ishwor Thapa2, Mohd. Wasim Nasser1,
Surinder K. Batra1, and Sidharth Mahapatra1,3; 1Department ofBiochemistry, University of Nebraska Medical Center, Omaha, NE, USA,
2School of Interdisciplinary Informatics, University of Omaha, Omaha, NE,
USA, 3Children’s Hospital and Medical Center, Omaha, NE, USA
Despite improvements in targeted therapies, few group 3 medulloblastoma
patients survive long-term. Haploinsufficiency of 17p13.3 is a hallmark ofthese high-risk tumors; included within this locus is miR-1253, which hastumor suppressive properties in medulloblastoma. Therapeutic strategies
capitalizing on the anti-neoplastic properties of miRNAs can provide promising adjuncts to chemotherapy. In this study, we explored the potentiation of
miR-1253 on cisplatin cytotoxicity in group 3 MB. Overexpression of miR1253 sensitized group 3 MB cell lines to cisplatin, leading to a pronounced
downregulation in cell viability and induction of apoptosis. Cisplatin isreported as an inducer of both apoptosis and ferroptosis-mediated cancer
cell death. In silico analysis revealed an upregulation of several ABC transporters in high-risk MB tumors. When compared to cell lines overexpressing
miR-1253, the ABC transporter ABCB7, which regulates both apoptosis andferroptosis, was revealed as a putative target of miR-1253 with poor survivalthat may facilitate its chemosensitizing effects by modulating mitochondrial
ROS and HIF1α-driven NFκB signaling. We observed high expression of
ABCB7 and GPX4, ferroptosis regulators, in MB patients with poor overall
survival. MiR-1253 negatively regulated the expression of ABCB7 in Group
3 MB cell lines and induced cytoplasmic ROS and mitochondrial O2-,
suggesting ROS-mediated induction of ferroptosis through regulation of
ABCB7 and GPX4. Treatment with ROS and ferroptosis inhibitors rescued
miR-1253 transfected cells treated with cisplatin. We conclude that miR1253 induced ROS and potentiated the ferroptotic effects of cisplatin via
targeting miR-1253/ABCB7/GPX4/mtROS axis.
MBRS-14. INTEGRATING CLINICAL AND GENOMIC
CHARACTERISTICS IN PEDIATRIC MEDULLOBLASTOMASUBTYPES IN A SINGLE COHORT IN TAIWAN
Kuo-Sheng Wu1, and Tai-Tong Wong2; 1Institute of Clinical Medicine,College of Medicine, Taipei Medical University, Taipei, Taipei, Taiwan,
2Division of Pediatric Neurosurgery, Department of Neurosurgery, Taipei
Medical University Hospital and Institute of Clinical Medicine, Taipei
Medical University, Taipei, Taipei, Taiwan
BACKGROUND: Medulloblastoma (MB) was classified to 4 molecularsubgroups: 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 methylationarray. 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 wereclassified into 11 subtypes by SNF cluster analysis. WNT tumors shown nometastasis 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Abstracts

highest metastatic rate, however G4 γ showed the worst survival. CONCLUSION: We identified molecular subgroups and subtypes of MBs basedon 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 andchildren.

MBRS-18. TUMOR SUPPRESSOR P53 DEFINES THE THERAPEUTICRESPONSES IN TREATMENT OF MEDULLOBLASTOMA
Avinash L. Mohan1, Anubhav G. Amin1, Michael E. Tobias1,
Mohan K. Das1, Raphael SS de Medeiros2, Nelci Zanon2,
Chirag D. Gandhi1, Sidnei Epelman2, and Meena Jhanwar-Uniyal1; 1NewYork Medical College/Westchester Medical Center, Valhalla, NY, USA,
2Hospital Santa Marcelina, São Paolo, Brazil

MBRS-16. MYC REGULATED LONG NONCODING RNA
LNC-HLX-2–7 IS A PUTATIVE MOLECULAR MARKER AND
A THERAPEUTIC TARGET FOR GROUP 3 MEDULLOBLASTOMASIN CHILDREN
Keisuke Katsushima1, Piyush Joshi2, Stacie Stapleton2,
Alexandra Garancher3, Rajeev Vibhakar4, Eric Raabe5, Charles Eberhart5,
Robert Wechsler-Reya3, George Jallo2, and Ranjan Perera1; 1Johns Hopkins
University, St. Petersburg, FL, USA, 2JHACH, St. Petersburg, FL, USA,
3Sanford Burnham, La-Jolla, CA, USA, 4University of Colorado, Boulder,
CO, USA, 5Johns Hopkins University, Baltimore, MD, USA

Medulloblastoma (MB) is the most common primary pediatric malignant
brain tumor. Current molecular analysis classifies MB into 4 groups, classic(WNT), sonic hedgehog (Shh), group 3, and group 4. Furthermore, atypical p53 signaling is associated with disease progression and confers poor
prognosis. This study investigated the correlation of mutational status ofp53 and iSO17q with disease progression and metastatic potential. In addition, we used small molecule inhibitors of PI3K (Buparlisib; BKM120) andHDAC (LBH-589) on a p53-mutant MB cell line to find novel therapeutictargets. Efficacy of these drugs were assessed using functional assays (cellproliferation, migration, cell cycle and drug resistance). MB tumors (n=53)
were evaluated for GLI-1, GAB-1, NPR, KV1, YAP expression and mutant
p53 via immunohistochemistry and correlated to patient outcomes. Results
demonstrated that: 1) high expression of GAB-1 and YAP were found in the
Shh group, while KV1 expression was present in all subtypes; 2) mutant p53
expression was present in various subsets of MB with no apparent correlation with metastasis or disease progression; 3) patients displaying iSO17q(determined by fluorescence in situ hybridization (FISH) technique) exhibited metastatic disease; 4) LBH-589 and BKM120 caused both time anddose-dependent inhibition of MB cell proliferation and migration; 5) combined treatment of BKM120 and LBH-589 had a synergistic effect; 6) MBcells demonstrated drug-resistance to BKM120. In conclusion, these findings
underscore use of Buparlisib and LBH-589 in treatment of MB. Further, therole of mutant p53 in disease progression remains elusive, whereas presenceof iSO17q defines metastatic potential.

Medulloblastoma (MB), a central nervous system tumor that predominantly affects children, requires aggressive therapy. Recent advances in
the noncoding RNA genome could contribute to the sub-classification of
medulloblastoma. The focus of this study is to identify novel long noncoding
RNAs (lncRNAs) as molecular markers and potential therapeutic targets
within each subgroup of MBs, in particular within Group 3. We analyzed
publicly available 175 RNA-seq datasets to identify a group of putative
lncRNA signatures that may be able to differentiate medulloblastoma
subgroups accurately. Among those, lncRNA lnc-HLX-2–7 was highly
upregulated in Group 3 MB cell lines, patient-derived xenografts, FFPE samples compared to other groups. CRISPR/Cas9 deletion of the lnc-HLX-2–7
followed by the fluorescence-activated sorting and generating monoclonalGroup 3 MB cells significantly reduced the cell growth and 3-D colony
formation together with the induction of apoptosis. Intracranial injection
to mouse cerebellum using lnc-HLX-2–7 deleted cells resulted in reduced
tumor growth compared to parental cells, and tumors were further characterized by single-cell sequencing. We identified that oncogene MYC regulateslnc-HLX-2–7 and its expression can be controlled by the small molecule
JQ1, a BET-bromodomain (BRD4) inhibitor that disrupts interactions with
MYC. RNA-FISH analysis using FFPE, PDX, and tissue microarrays revealed that lnc-HLX-2–7 expression is specific to Group 3 MB compared toother groups. We present supporting evidence that lnc-HLX-2–7 is a novel
molecular marker and a potential therapeutic target for Group 3 MBs inchildren.
MBRS-17. EXAMINING THE ROLE OF LHX9 IN GROUP 3
MEDULLOBLASTOMA
Sarah Injac1,2, L. Frank Huang3, Stephen Mack1,2, Frank Braun2,1,
Yuchen Du4, Mari Kogiso1,2, Holly Lindsay1,2, D. William Parsons1,2,
Hong Zhao5, Ching C. Lau6, Stephen T.C. Wong5, and Xiao-nan Li1,4;
1Baylor College of Medicine, Houston, TX, USA, 2Texas Children’s Cancerand Hematology Centers, Houston, TX, USA, 3Experimental Hematology
and Cancer Biology, Brain Tumor Center, Cincinnati Children’s Hospital,
Cincinnati, OH, USA, 4Department of Pediatrics, Northwestern University,
Chicago, IL, USA, 5Department of Systems Medicine and Bioengineering,
Houston Methodist Research Institute and Cancer Center, Weill Cornell
School of Medicine, Houston, TX, USA, 6Connecticut Children’s Medical
Center, The University of Connecticut School of Medicine, Hartford, CT,
USA
Medulloblastoma (MB) is the most common malignant brain tumor ofchildhood. Despite major advances in our understanding of the biology ofMB, novel treatments remain urgently needed. Using a chemical-genomics
driven drug repositioning strategy, we identified the cardiac glycoside familyof compounds as potential treatments for Group 3 MB. We subsequently
demonstrated that single-agent treatment with digoxin prolongs survival
in a patient-derived xenograft model (PDOX) of Group 3 MB to a degreecomparable to radiation therapy, a mainstay in the treatment of MB. Finally,
we examined the mechanism of digoxin-mediated cell killing using RNAseq. This work identified LHX9, a member of the LIM homeobox familyof transcription factors, as the gene most significantly down-regulated following treatment (Huang and Injac et al, Sci Trans Medicine, 2018). Homologs of LHX9 play key roles in cerebellar development via spatially andtemporally restricted expression and LHX9 has been proposed as a coretranscription factor (TF) in the regulatory circuitry of Group 3 tumors.
Loss of function of other core TFs has been shown to impact MB growth.
The role of LHX9 in MB, however, has not been previously experimentally
evaluated. We now report that knockdown of LHX9 in MB-derived celllines results in marked growth inhibition raising the possibility that loss of
LHX9 plays a major role in digoxin-mediated cell killing and that LHX9
represents a key dependency required for the growth of Group 3 MB. Clinical targeting of core TFs would represent a novel approach to targeting
this devastating disease.

MBRS-19. SYNERGISM OF HDAC AND PARP INHIBITORS IN MYCDRIVEN GROUP 3 MEDULLOBLASTOMA CELLS
Johanna Vollmer1,2, Jonas Ecker1,2, Thomas Hielscher3,
Gintvile Valinciute1,2, Sina Oppermann1,2, Heike Peterziel1,2, Ina Oehme1,2,Olaf Witt1,2, and Till Milde1; 1Hopp Children’s Cancer Center Heidelberg(KiTZ), Heidelberg, Germany, 2Clinical Cooperation Unit PediatricOncology, German Cancer Research Center (DKFZ), Heidelberg, Germany,
3Division of Biostatistics, German Cancer Research Center (DKFZ),
Heidelberg, Germany
Patients with MYC-driven Group 3 medulloblastoma (MB) show particularly poor outcome. It was previously shown that MYC-driven MBs
are highly sensitive to class I histone deacetylase inhibition (HDACi). We
studied the molecular effects of the class I HDACi entinostat in MYC-driven
MB cells to identify potentially synergistic drug combinations, prioritizing
drug clinical availability to enable clinical translation. Gene expression profiles of the MYC-amplified group 3 MB cell line HD-MB03 treated withentinostat were analyzed using bioinformatic approaches, identifying 29
altered biomechanisms. Overlay with a translational drug library of n=76
compounds resulted in 44 compounds targeting 9 biomechanisms. Filteringfor publications supporting each drug´s role in MYC-driven entities, or functional interaction with HDACs, without publication of this combination inMBs, resulted in 5 compounds (olaparib, idasanutlin, ribociclib, selinexor,
vinblastine). Synergism testing identified olaparib as the drug with thestrongest synergism. Validation of the combination olaparib and entinostat
by p.H2AX and PI staining as well as trypan blue exclusion showed increased double strand breaks (DSBs), increased cell death, loss of viability
and cell numbers. Selectivity of MYC-amplified MB cells was shown by comparison to MYC-non amplified cell lines, which showed higher IC50s, andreacted with cell cycle arrest as opposed to cell death to the combination
treatment. The role of HDACis in DNA damage repair was confirmed byincreased DSBs when entinostat was added to the combination of olaparibwith doxorubicin. Our study identified olaparib as a potential combination
partner with entinostat for the treatment of MYC-driven Group 3 MB.
MBRS-20. CSF-DERIVED CIRCULATING TUMOR DNA AS
A BIOMARKER FOR DISEASE PROGRESSION AND TUMOREVOLUTION IN MEDULLOBLASTOMA
Anthony Pak-Yin Liu1, Rahul Kumar2,3, Smith Kyle2, Leena Paul2,
Murali Chintagumpala4, Eric Bouffet5, Michael J Fisher6, Tim Hassall7,
Sri Gururangan8, Jordan Hansford9, Richard Cohn10, David W. Ellison11,
Richard J. Gilbertson12, Amar Gajjar1, Giles W. Robinson1, andPaul A. Northcott2; 1Division of Neuro-Oncology, Department of
Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA,
2Division of Brain Tumor Research, Department of Developmental
Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA,
3St. Jude Graduate School of Biomedical Sciences, Memphis, TN, USA,
4Department of Pediatrics, Texas Children’s Cancer Center, Baylor College

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Abstractsof Medicine, Houston, Texas, USA, 5Division of Hematology-Oncology,
The Hospital for Sick Children, Toronto, ON, Canada, 6Division of
Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia,
Philadelphia, PA, USA, 7Queensland Children’s Hospital, Brisbane, QLD,
Australia, 8Preston A, Wells Jr, Center for Brain Tumor Therapy, UF
Health Shands Hospital, Gainesville, FL, USA, 9The Royal Children’s
Hospital, Melbourne, VIC, Australia, 10Centre for Children’s Cancer andBlood Disorders, Sydney Children’s Hospital, Randwick, NSW, Australia,
11Department of Pathology, St Jude Children’s Research Hospital,
Memphis, TN, USA, 12Cancer Research UK Cambridge Centre, CRUK
Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom
BACKGROUND: Cell-free DNA (cfDNA) profiling has been shownto carry utility as a clinically relevant biomarker in a variety of cancers,
but studies in pediatric brain tumors, including medulloblastoma, arescarce. We hereby evaluated the actionability of profiling cfDNA from
cerebrospinal fluid (CSF) based on a multi-institutional cohort of children with medulloblastoma. METHODS: 103 children aged ≥ 3 years
with medulloblastoma harboring chromosomal aneuploidy enrolled on
two prospective therapeutic trials were included. cfDNA was extracted
from CSF obtained longitudinally, and profiled by low-coverage wholegenome sequencing (lcWGS) for annotating copy-number variants(CNVs). cfDNA-derived CNVs were compared against patient-matchedprimary tumor-derived CNVs and correlated with outcome. cfDNA
profiles at diagnosis and relapse were compared to evaluate tumor evolution. RESULTS: Tumor-derived somatic CNVs were detected in 72%
of baseline cfDNA samples, with higher detection rate in samples frompatients with metastatic disease than those without (90% versus 50%,
chi-square p=0.001). Longitudinal profiling of cfDNA revealed correlation
between CNV detectability and clinical course, with detection of tumorderived CNVs in cfDNA samples predating radiographic progression for≥ 3 months in 62% of relapsing patients. Presence of cfDNA-derived
CNVs in CSF collected during chemotherapy and at the end of therapy
was significantly associated with inferior PFS (log-rank p<0.0001 for bothtime-points). Comparison of CNV profiles from cfDNA at baseline andrelapse revealed molecular divergence in a subset of patients. CONCLUSION: These results carry major implications and supports the incorporation of cfDNA profiling in upcoming medulloblastoma protocols formore sensitive and accurate disease monitoring and personalization oftreatment.
MBRS-21. CLINICAL AGGRESSIVENESS OF TP53-WILD TYPE SONICHEDGEHOG MEDULLOBLASTOMA WITH MYCN AMPLIFICATION
Yuichi Mitani1, Kohei Fukuoka1, Yuko Matsushita2, Yuko Hibiya2,
Satoko Honda3, Makiko Mori1, Yuki Arakawa1, Koichi Ichimura2,
Masao Kobayashi4,5, Yutaka Tanami4, Atsuko Nakazawa3, Jun Kurihara6,
and Katsuyoshi Koh1; 1Department of Hematology/Oncology, Saitama
Children’s Medical Center, Saitama, Saitama, Japan, 2Division of Brain
Tumor Translational Research, National Cancer Center Research Institute,Chuo, Tokyo, Japan, 3Department of Clinical Research, Saitama Children’s
Medical Center, Saitama, Saitama, Japan, 4Department of Radiology,
Saitama Children’s Medical Center, Saitama, Saitama, Japan, 5Departmentof Radiology, Jikei University school of Medicine, Minato, Tokyo, Japan,
6Department of Neurosurgery, Saitama Children’s Medical Center, Saitama,
Saitama, Japan
Clinical implication of MYCN amplification in sonic hedgehog(SHH) medulloblastoma may still be controversial due to the frequentco-occurrence with TP53 mutation, which is one of the poorest prognostic
factors among the subgroup. We described two cases of TP53-wild type SHH
medulloblastoma with MYCN amplification, showing dismal clinical coursewith rapid disseminated relapse just after the end of treatment. CASE 1:
A 7-year-old boy developed a non-metastatic cerebellar tumor. Pathology of
the tumor was consistent with classic medulloblastoma. The patient received
treatment that involved reduced-dose (18 Gy) craniospinal irradiation (CSI),
local irradiation, and chemotherapy. However, sudden respiratory arrest
developed due to massive intracranial disseminated relapse 9 months after
the initial surgery. CASE 2: A 6-year-old boy presented a large mass in his
4th ventricle without dissemination. He diagnosed with large cell/anaplastic
medulloblastoma and underwent radiation therapy (24 Gy of CSI and local
irradiation) and chemotherapy, followed by high-dose chemotherapy. However, dissemination through neuroaxis occurred 9 months after the diagnosis. Methylation data of the cases was entered into a recently publishedclassifier and both tumors were classified as “medulloblastoma, subclassSHH A (children and adult)”. Copy number analysis demonstrated MYCN
amplification in both cases. TP53 mutation analysis from exon 2 to 10 indicated wild type in one case. Additionally, p53 immunochemistry in bothcases also indicated wild type. The cases remind us of the clinical aggressiveness of SHH medulloblastoma with MYCN amplification, even if there is noTP53 mutation. The tumor should still be treated with the most intensified
treatment.

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MBRS-22. SIGNIFICANCE OF RNF213 IN TUMORGENICITY OF
MEDULLOBLASTOMA
Yohei Mineharu1, Yuki Oichi1, Takahiko Kamata1, Yasuzumi Matsui1,
Takaaki Morimoto1,2, Masahiro Tanji1, Hatasu Kobayashi1,3,
Hiroko Okuda1, Kouji H Harada1, Akio Koizumi1,4, Yoshiki Arakawa1,and Susumu Miyamoto1; 1Kyoto University, Kyoto, Japan, 2Hyogo
Prefectural Amagasaki General Medical Center, Amagasaki, Japan, 3Mie
University, Tsu, Japan, 4Kyoto Hokenkai Social Health Medicine Welfare
Laboratory, Kyoto, Japan
RNF213 gene, initially identified as a disease-causing gene for moyamoya
cerebrovascular disease, has recently been recognized as a tumor regulator.
The gene is known to be associated with WNT signaling, lipid metabolism,
angiogenesis and genomic instability. The purpose of this study was to investigate the association of RNF213 in tumorgenicity of medulloblastoma.
Incidence of medulloblastoma and histopathological findings were compared among ptch1+/-, ptch1+/- rnf213+/-, and ptch1+/- rnf213-/- mice.
Knockout of rnf213 in ptch1+/- transgenic mouse model increased theincidence of spontaneous generation of medulloblastoma from 19.8%(ptch1+/-) to 76.5% (rnf213+/- ptch1+/-) at 9 months (p < 0.001). Heterozygous knockout was equivalent to homozygous knockout. Haploinsufficiency
of rnf213 seems to be associated with tumorgenicity in medulloblastoma.
Molecular mechanism of medulloblastoma generation needs to be further
investigated.
MBRS-23. SIGNIFICANCE OF MI-R33 IN GENERATION AND
PROGRESSION OF MEDULLOBLASTOMA
Yasuzumi Matsui; Department of Neurosurgery, Kyoto, Kyoto, Japan
Lipid metabolism has been shown to be associated with tumorigenicity
in various malignancies. The purpose of this study was to investigate theassociation of miR-33, a key regulator of lipid metabolism, in tumorigenicity and progression of medulloblastoma. miR-33a is an only isotype ofmiR-33 in rodents although miR-33b is also detected in human. Incidenceof medulloblastoma and histopathological findings were compared between
ptch1+/- mice and ptch1+/- miR-33a-/- mice. Effect of miR-33b upregulationby cordycepin was tested in DAOY medulloblastoma cells both in vitro andin vivo. Knockout of miR-33a in ptch1+/- transgenic mouse model increased
the incidence of spontaneous generation of medulloblastoma from 19.8% to49.5% (p < 0.001) at 10 months. Cordycepin, which upregulates miR-33b,
prevented tumor growth in DAOY human medulloblastoma cell line, but
the effect was not evident in an orthotopic mouse medulloblastoma model.
Although miR-33 seems to be an important regulator of medulloblastoma,treatment efficacy of cordycepin was not enough. Combination treatment
with immunotherapy or cytotoxic treatment needs to be tested to show survival benefit in preclinical models.
MBRS-24. FUNCTIONAL CHARACTERIZATION OF IKBKAP/ELP1
AS A NOVEL SHH MEDULLOBLASTOMA PREDISPOSITION GENE
Jesus Garcia Lopez1, Lena Kutscher2, Marija Kojic3, Brian Gudenas1,
Kyle Smith1, Jennifer Hadley1, Amar Gajjar4, Giles W. Robinson4,
Stefan M. Pfister2,5, Brandon J. Wainwright3, Daisuke Kawauchi2,6, andPaul A. Northcott1; 1Department of Developmental Neurobiology, St.
Jude Children’s Research Hospital, Memphis, TN, USA, 2Hopp Children´sCancer Center Heidelberg (KiTZ), Division of Pediatric Neurooncology,
German Cancer Research Center (DKFZ), Heidelberg, Germany, 3Institutefor Molecular Bioscience, University of Queensland, Queensland,
Australia. 4Department of Oncology, St. Jude Children’s Research Hospital,
Memphis, TN, USA, 5Heidelberg University Hospital, Department ofPediatric Hematology and Oncology, Heidelberg, Germany, 6National
Center of Neurology and Psychiatry (NCNP), Department of Degenerative
Neurological Diseases, Tokyo, Japan
Medulloblastoma (MB), a common malignant pediatric brain tumor, comprises at least four distinct molecular entities: WNT, SHH, Group 3, andGroup 4. SHH-MB is driven by aberrant activation of the Sonic hedgehog(SHH) pathway in granule neuron progenitors (GNPs) and is associatedwith hereditary cancer predisposition syndromes including Li Fraumeni
and Gorlin. We recently identified germline loss of function (LoF) mutations affecting IKBKAP/ELP1, the primary scaffolding subunit of theElongator complex in a subset of SHH-MB patients. Germline ELP1 mutations account for ~15% of all pediatric SHH-MBs and position ELP1 as
the most prevalent hereditary predisposition gene in MB. We genetically engineered Elp1 LoF in mouse GNPs to determine Elp1 function in cerebellar
development and SHH-MB. Results of both mechanistic and phenotypicexperiments demonstrate that GNPs harboring Elp1 loss exhibit ribosome pausing and protein aggregation, reinforcing the critical role of Elp1
in translational elongation and protein homeostasis. Further, we generated
new transgenic mouse models mimicking germline ELP1 LoF mutations observed in SHH-MB patients. Elp1+/- transgenic mice exhibit purkinje cell

Abstracts

degeneration and an increased DNA damage response. These mice are currently being evaluated for their capacity to recapitulate ELP1-associated
SHH-MB. Additional analyses carried out on SHH-MB patient-derived
xenografts showed that ELP1-mutant tumor cells specifically exhibit defects in tRNA biogenesis. Therefore, the function of ELP1 as a translational
regulator is severely impaired in ELP1-mutant SHH-MBs. Our ongoing molecular and functional studies will provide important insights into the mostcommon MB predisposition gene and will lay the foundation for future preclinical studies.
MBRS-26. CDK7 MEDIATED TRANSCRIPTIONAL PROCESSIVITY
OF DNA REPAIR NETWORKS REGULATES SENSITIVITY TO
RADIATION IN MYC DRIVEN MEDULLOBLASTOMA
Bethany Veo1,2, Etienne Danis1,2, Susan Fosmire1,2, Dong Wang1,2,
Angela Pierce1,2, Nathan Dahl1,3, Sana Karam1,3, Natalie Serkova1,
Sujatha Venkataraman1,2, and Rajeev Vibhakar1,3; 1University of Colorado
Anschutz Medical Campus, Aurora, CO, USA, 2The Morgan Adams
Pediatric Brain Tumor Foundation, Aurora, CO, USA, 3Children’s Hospital
Colorado, Aurora, CO, USA
Myc-driven Medulloblastoma remains a major therapeutic challenge due
to frequent metastasis and a poor 5-year survival rate. Myc overexpression
results in transcriptional dysregulation, proliferation, and survival of malignant cells. To identify therapeutic targets in Myc-amplified medulloblastoma
we performed a CRISPR-Cas9 essentiality screen targeting 1140 genes
annotated as the druggable genome. The cyclin-dependent kinase, CDK7,
was identified as a top candidate. CDK7 phosphorylates the c-terminal domain of RNA Pol II facilitating transcriptional initiation and elongation.
We subjected Myc-amplified cells treated with CDK7 inhibitors to wholetranscriptomic analysis. The resultant data revealed gene networks mediating
DNA repair were functionally repressed. Consistent with this data, ChIPsequencing showed the most significant reduction in RNA Pol II and Myc
promoter occupancy within a subset of DNA repair genes including BRCA2and RAD51 but not across the whole genome. These data suggest that inhibition of CDK7 mechanistically limits Myc driven transcriptional processivityof DNA repair networks. Further, evaluation of genes mediating DNA repair show a muted response to DNA damage and increased cell death with
CDK7 inhibition. We next evaluated Myc-amplified MB cell response toionizing radiation in vitro and in vivo with CDK7 inhibition. Inhibition of
CDK7 enhanced radiation sensitivity of Myc MB cells by potentiating DNA
damage. Further, cotreatment produced decreased MRI T2 tumor volumes
and enhanced survival benefit in orthotopic PDX xenografted mice compared to radiation alone. Our studies establish a mechanism for selective
inhibition of Myc-driven MB by CDK7 inhibition combined with radiation
as a viable therapeutic strategy for Myc-amplified medulloblastoma.
MBRS-27. EXOSOMES CARRY DISTINCT MIRNAS THAT DRIVEMEDULLOBLASTOMA PROGRESSION
Hannah K Jackson1, Franziska Linke1, Ian Kerr2, and Beth Coyle1;
1Children’s Brain Tumour Research Centre, School of Medicine,
University of Nottingham Biodiscovery Institute, Nottingham, United
Kingdom, 2School of Life Sciences, Queen’s Medical Centre, University of
Nottingham, Nottingham, United Kingdom
INTRODUCTION: Extracellular vesicles (EVs) represent an ideal
source of functional biomarkers due to their role in intercellular communication and their ability to protect cargo, including RNA, from degradation. The most investigated EV’s are exosomes, nanovesicles secreted by
all cell types and able to cross the blood-brain-barrier. Here we characterised the RNA of exosomes isolated from medulloblastoma cell lines,
with the aim of investigating exosomal RNA cargo as potential functional
biomarkers for medulloblastoma. METHODS: Exosomes derived from apanel of matched (original tumour and metastasis) medulloblastoma celllines were isolated and characterised by NanoSight, electron microscopy,
western blotting and Nanoscale flow cytometry. Exosomal miRNA andmRNA from our matched cell lines and foetal neuronal stem cells, whichwere used as a normal control, were analysed by RNA-sequencing technology. RESULTS: Based on hierarchical clustering, malignant derived
exosomes were distinctly separated from normal control exosomes. miRNAprofiling revealed several established oncomiRs identified in our malignant
derived exosomes compared to control samples. Using interaction pathway
analysis, we identified that our malignant exosomes carry numerous
miRNAs implicated in migration, proliferation, cellular adhesion and tumour growth. Several previously identified oncomiRs were also identified
to be present at higher levels in metastatic exosomes compared to primaryand normal, including hsa-miR-455-3p and hsa-miR-92a-3p. CONCLUSION: This study shows that exosomes from MB cells carry a distinct
miRNA cargo which could enhance medulloblastoma progression. The useof circulating exosomes as markers of metastatic disease could be an innovative and powerful non-invasive tool.

MBRS-28. EXOSOMES DRIVE MEDULLOBLASTOMA METASTASISIN A MMP2 AND EMMPRIN DEPENDENT MANNER
Hannah K Jackson1, Franziska Linke1, Ian Kerr2, and Beth Coyle1;
1Children’s Brain Tumour Research Centre, School of Medicine,
University of Nottingham Biodiscovery Institute, Nottingham, United
Kingdom. 2School of Life Sciences, Queen’s Medical Centre, University of
Nottingham, Nottingham, United Kingdom
INTRODUCTION: Recurrent/metastatic medulloblastoma (MB) is adevastating disease with an abysmal prognosis of less than 10% 5-year survival. The secretion of extracellular vesicles (EVs) has emerged as a pivotal mediator for communication in the tumour microenvironment duringmetastasis. The most investigated EV’s are exosomes, nanovesicles secreted by all cell types and able to cross the blood-brain-barrier. Matrix
metalloproteinases (MMPs) are enzymes secreted by tumour cells that canpotentiate their dissemination by modification of the extracellular matrix.
We hypothesise that exosomal MMP2 and its inducer EMMPRIN could
enhance metastasis of MB. METHODS: Proliferation, invasion and migration assays were used to evaluate the phenotypic behaviour of primarycell lines pre-treated with metastatic tumour cell-derived exosomes. Gelatin
zymography and western blotting were performed to confirm MMP2 functional activity in cell lines and exosomes. Nanoscale flow cytometry wasused to measure surface exosomal EMMPRIN levels. Exosomal MMP2
and EMMPRIN were modulated at the RNA level. RESULTS: Number of
exosomes is directly related to the migratory behaviour of parental MB celllines (p<0.01). Notably, functional exosomal MMP2 and EMMPRIN levels
also correlate with this. Furthermore, exosomes from metastatic cell lines
conferred enhanced migration and invasion on their matched isogenic primary (non-metastatic) cell line pair by ~3.8-fold (p<0.01). Exosomes frommetastatic cell lines also conferred increased migration on poorly migratory
foetal neuronal stem cells. CONCLUSION: Together this data suggests that
exosomal MMP2 and EMMPRIN may promote medulloblastoma metastasis and supports analysis of exosomal MMP2 and EMMPRIN levels inpatient cerebral spinal fluid samples.
MBRS-29. PROSPECTIVE MOLECULAR PROFILING IN PEDIATRICMEDULLOBLASTOMA PATIENTS ENROLLED ON THE “HEAD
START 4” PROTOCOL
Jessica Fleming1, Erica Bell1, Richard Graham2, Amy Webb1,
Joseph McElroy1, Cynthia Timmers3, Aline Becker1, Yingshi Guo1,
Girish Dhall4, Jonathan Finlay5, and Arnab Chakravarti1; 1The Ohio State
University, Columbus, OH, USA, 2St. Jude Children’s Research Hospital,
Memphis, TN, USA, 3Medical University of South Carolina, Charleston,SC, USA, 4Children’s of Alabama, Birmingham, AL, USA, 5Nationwide
Children’s Hospital, Columbus, OH, USA
Medulloblastoma is the most common malignant embryonal brain tumor
in children with only modest improvements in outcomes achieved over thelast 20 years. The implementation of irradiation-avoiding strategies, including
trials by the “Head Start” consortium, have demonstrated improved curerates along with enhanced quality of life. Simultaneously, the classificationof medulloblastomas has undergone a dramatic shift as molecular testing has
made it possible to divide these tumors into distinctive subtypes. Currently,
the WHO recognizes four medulloblastoma molecular subgroups; however
it remains unclear how patients within these subgroups respond to modern
irradiation-avoiding therapies. This study aims to demonstrate the feasibilityof prospective molecular profiling in medulloblastoma patients enrolled on
the “Head Start 4” trial. Whole-exome sequencing (SureSelect Human All
Exon V6+COSMIC) and DNA methylation (Illumina EPIC Array) profilingwere performed on 10 paired tumor/blood samples and 4 tumor samples, respectively. High-quality mutational and copy number data were produced foreach of the 10 subjects demonstrating well-described gene mutations (SUFU)
and chromosomal losses (9q and 10q). Four subjects had methylation profiling which successfully separated them into the WHO subgroups (two SHH
and two Group 3). These data showed the feasibility of prospective highdimensional mutational and DNA methylation analysis using “Head Start 4”
patients. Future work will focus on finalizing these profiling efforts, enabling
the development of models that predict response to irradiation-avoiding
treatment and, in general, a better understanding of the molecular mechanisms underlying treatment resistance and tumor progression, leading to more
personalized approaches to treating children with medulloblastoma.
MBRS-31. COMBINING IRRADIATION AND ANTI-CD47 TO
ENHANCE THE TREATMENT OF GROUP 3 MEDULLOBLASTOMA
Osama Youssef, Jeff Turner, Gongping He, Jingye Yang, andSamuel Cheshier; Huntsman Cancer Institute, University of Utah, Salt Lake
City, UT, USA
Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor. The Group 3 molecular subgroup of Medulloblastoma

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Abstracts(Group 3 MB) is the deadliest with only 30% long term survival. Irradiation for Group 3 Medulloblastoma is required for long term survival ofchildren. Methods to enhance the effect of irradiation against Group 3 MB
are an active area of investigation. Immunotherapy using the anti-CD47
treatment has shown promise in treating Group 3 MB. We recently demonstrated that irradiation significantly enhanced anti-CD47-mediated phagocytosis of high-grade glioma cells in vitro. Furthermore, mice engrafted withhuman high-grade glioma that received anti-CD47 combined with irradiation showed a significant increase in the survival rate and a significant decrease in tumor growth than those that received a single treatment. We have
now extended these studies to demonstrate the enhancement of anti-CD47dependent phagocytosis of human Group 3 MB with irradiation. We also
analyzed normal human neural stem cells exposed to the same treatments
to assess for the potential toxicity that uniquely exists with this treatment
combination.
MBRS-32. TOPOISOMERASE II Β INDUCES NEURONAL, BUT NOTGLIAL, DIFFERENTIATION IN MEDULLOBLASTOMA
Hiroaki Miyahara1, Manabu Natsumeda2, Junichi Yoshimura2,
Yukihiko Fujii2, Akiyoshi Kakita3, Yasushi Iwasaki1, and Mari Yoshida1;
1Department of Neuropathology, Institute for Medical Science of Aging,
Aichi Medical University, Nagakute, Aichi, Japan, 2Departments of
Neurosurgery, Brain Research Institute, University of Niigata, Niigata,
Niigata, Japan, 3Departments of Pathology, Brain Research Institute,
University of Niigata, Niigata, Niigata, JapanBACKGROUND: We previously reported that Gli3, which was a downstream molecule of Sonic Hedgehog signal, induced neuronal and/or glial
differentiation in some types of medulloblastoma (desmoplastic/nodular
medulloblastoma and medulloblastoma with extensive nodularity), andpatients of medulloblastoma with neuronal differentiation showed favorable prognosis, but those with glial differentiation tended to show miserable prognosis (Miyahara H, Neuropathology, 2013). This time, we
focused on Topoisomerase II β (Top2β), which was reported to induce
neuronal differentiation and inhibit glial differentiation, and examined theexpression of Top2β in medulloblastomas with neuronal and glial differentiations. METHODS: We assessed the expression of Top2β, NeuN, and
GFAP using triple fluorescent immunostaining method in medulloblastoma
samples with both neuronal and glial differentiations. Furthermore, the expression of Top2β, H3K4me2, and H3K27me3 were also assessed, because
Top2βwas positively or negatively regulated by H3K4me2 and H3K27me3,
respectively. RESULTS: Many large nuclei in the nodules, in which differentiated cells were seen, was visualized by Top2β. The Top2β signals wereseen in NeuN+ cells but not GFAP+ cells. H3K4me2 signals were visualizedin Top2β+ large nuclei, but H3K27me3 and NeuN+ large nuclei were distributed independently. CONCLUSIONS: These results indicate that Top2β
may be a molecule associated with neuronal, but not glial, differentiationof medulloblastoma cells. Drugs targeting histone modification enzymes
such as EZH2 inhibitors are possible therapeutic targets as a differentiationinducing therapy for medulloblastoma.
MBRS-33. TEMPORARY RESTORATION OF P53 ACTIVITY
DURING FRACTIONATED RADIOTHERAPY IN A GROUP3
MEDULLOBLASTOMA GEMM REPRESENTS A POWERFUL TOOLFOR RADIOBIOLOGY STUDIES
Alaide Morcavallo1, Henry Mandeville2, Karen Barker1,
Stacey Richardson3, Janet Lindsey3, Nikita Lockett1, Jessica K.R. Boult4,
Simon P. Robinson4, Uwe Oelfke2, Daniel Williamson3, Steven C. Clifford3,
and Louis Chesler1; 1Division of Clinical Studies, The Institute of Cancer
Research, and The Royal Marsden NHS Trust, Sutton, Surrey, United
Kingdom, 2Division of Radiotherapy and Imaging, The Institute of Cancer
Research, and The Royal Marsden NHS Trust, Sutton, Surrey, United
Kingdom, 3Wolfson Childhood Cancer Research Centre, Newcastle
University Centre for Cancer, Newcastle upon Tyne, United Kingdom,
4Division of Radiotherapy and Imaging, The Institute of Cancer Research,
Sutton, Surrey, United Kingdom
TP53 pathway alterations are well-described events in medulloblastoma(MB) and are predictive of poor clinical outcome. Alterations are rare at
diagnosis in Group3 (Gr3) and Group4, but enriched in Sonic Hedgehog
and WNT subgroups. However, TP53 mutations are observed in all subgroups at relapse. Radiation therapy, along with surgery and chemotherapy,
represents the standard of care treatment for MB. Loss of p53 function correlates with increased resistance to radiation in several cancers conferring
poor survival for patients. In this study, we exposed the MYCN-driven/
Trp53kiki (with tamoxifen-inducible p53 activation) Gr3 MB GEMM to aclinically relevant fractionated radiation therapy (RT) regime, to assess therole of p53 in Gr3 radio-resistance and relapse. Mice exhibiting tumour progression (bioluminescence (BLI) signal >109 photons/second) were randomized to treatment groups. A small animal radiation research platform wasused to deliver CT-guided cranio-spinal irradiation (CSI) and a cranial boost

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De c e mb e r 2 0 2 0(CB). Mice were followed for survival and tumour burden tracked using
BLI. Bodyweight was monitored to evaluate treatment tolerability. Full doseradiation therapy (54Gy CB, 36Gy CSI, α/β=10) or dose modulation (12Gy
CB, 8Gy CSI) was performed. The results showed comparable primary tumour regression in response to RT in p53 inactive and active backgrounds,
followed by imminent relapse or prolonged remission respectively. No significant acute toxicity was observed. Temporary activation of p53 during
RT improved tumour-free survival and decreased the incidence of relapse.
In conclusion, we developed a new model which will help improve understanding of the radiobiology of high-risk MB and future preclinical trials.
MBRS-37. RECURRENT ACTIVATING MUTATIONS OF AKT GENES
IN WNT-ACTIVATED MEDULLOBLASTOMAS
Julien Masliah-Planchon1, Emmanuelle Lechapt-Zalcman2,
Jean-Baptiste Aillaud1, Olivier Ayrault3, Célio Pouponnot4,
Francois Doz5, Olivier Delattre5, and Franck Bourdeaut5,6; 1Unité deGénétique Somatique, Institut Curie, Paris, France, 2Neuropathology,
Centre Hospitalier Sainte-Anne, Paris, France, 3PSL Research University,
CNRS UMR, INSERM, Orsay, France, 4INSERM U1021, Orsay, France,
5SIREDO Center, Institut Curie, Paris, France, 6RTOP Unit, Institut Curie,
Paris, France
Medulloblastoma (MB) can be classified into four distinct molecular subgroups (WNT group, SHH group, group 3, and group 4). Medulloblastomaof the WNT subgroup (WNT-MB) are commonly associated with favorable prognosis. Prospective molecular analysis based on a combinationof CGH-array, targeted NGS and Nanostring-based subgrouping on 272
MB was conducted. Our custom targeted NGS panel of 75 genes includes
genes recurrently affected in MB together with actionable genes with therapeutic purpose including some involved in the PIK3/AKT signaling pathway.
Among the 272 MB analyzed, 26 cases (9.6%) belonged to the WNT subgroup based on CTNNB1 mutations, monosomy of chromosome 6 andNanostring-based molecular subgrouping. Our targeted NGS revealed three
hotspot activating mutations in AKT3 in WNT-MB and only one cases inanother MB subgroup (in a group 4 MB; among the 33 cases of confirmed
group 4 MB in our cohort). We subsequently performed Sanger sequencingof the hotspot Glu17 codon of AKT1, AKT2, and AKT3 in 42 additional
WNT-MB. This analysis revealed six additional activating mutations of
AKT genes (four AKT3 and two AKT1 hotspots mutations) in WNT-MB.
Altogether, we report 9/68 (13.2%) cases of WNT-MB with AKT genes mutations (two mutations in AKT1 and seven mutations in AKT3). Our molecular analysis revealed AKT hotspot mutations that presumably activate
the PIK3/AKT signaling pathway in WNT-MB. Even though WNT-MB is
the subgroup of MB with the most favorable prognosis, this result emphasizes a possibility of targeted therapy that need to be further explored invitro and in vivo.
MBRS-38. MOLECULAR CLASSIFICATION AND CLINICAL
CHARACTERISTICS OF 236 MEDULLOBLASTOMAS IN JAPAN
Yonehiro Kanemura1,2, Tomoko Shofuda1,2, Ema Yoshioka1,2,
Daisuke Kanematsu1,2, Koichi Ichimura3,2, Atsushi Sasaki4,2,
Takeshi Inoue5,2, Junko Hirato6,2, Yoshinori Kodama7,2, Masayuki Mano8,2,Soichiro Shibui9,2, Hajime Arai10,2, Hiroaki Sakamoto11,2, Isao Date12,2, and
Ryo Nishikawa13,2; 1Department of Biomedical Research and Innovation,
Institute for Clinical Research, National Hospital Organization Osaka
National Hospital, Osaka, Japan, 2Japanese Pediatric Molecular Neurooncology Group, Tokyo, Japan, 3Division of Brain Tumor Translational
Research, National Cancer Center Research Institute, Tokyo, Japan,
4Department of Pathology Saitama Medical University, Moroyama, Jersey,
5Department of Pathology, Osaka City General Hospital, Osaka, Jersey,
6Department of Pathology, Public Tomioka General Hospital, Tomioka,
Japan, 7Division of Pathology Network, Kobe University Graduate Schoolof Medicine, Kobe, Japan, 8Department of Central Laboratory and Surgical
Pathology, National Hospital Organization Osaka National Hospital,
Osaka, Japan, 9Department of Neurosurgery, Teikyo University Hospital,
Mizonokuchi, Kanagawa, Japan, 10Department of Neurosurgery, Juntendo
University, Tokyo, Japan, 11Department of Pediatric Neurosurgery, Osaka
City General Hospital, Osaka, Japan, 12Department of Neurological
Surgery, Okayama University Graduate School of Medicine, Dentistry
and Pharmaceutical Sciences, Okayama, Japan, 13Department of NeuroOncology/Neurosurgery, International Medical Center, Saitama Medical
University, Hidaka, Japan
Recent intensive genomic and molecular biological analyses have madea consensus that medulloblastomas (MBs) are at least classified into four
core subgroups, and the new 2016 WHO brain tumor classification has
introduced the classification of MBs genetically defined in addition toclassical histopathological diagnosis. To establish a nationwide networkof a molecular diagnosis system for pediatric brain tumors, the JPMNG
co-organized by the Japan Society for Neuro-Oncology and the JapaneseSociety for Pediatric Neurosurgery have started the clinical researches inAbstracts

2012, and we have summarized results of molecular analysis of JapaneseMBs. Total 236 primary MBs have been subclassified by gene expression
profile using the NanoString nCounter system or DNA methylation array,and their single nucleotide mutations and copy number aberrations havebeen also examined. Mean follow up time was 68.9 months. Proportion offour core subgroups were WNT (16.9%), SHH (25.4%), Group 3 (17.4%)
and Group 4 (40.3%), respectively. In cases of less than 3 years old, no WNT
have been found and 63.2% cases were SHH. In cases between 3 to 17 years
old, Group 4 is the most (47%), and these trends is almost consistent withpublished references. TP53 mutations were identified in 23.3% of SHH, andthey were significantly poor prognosis. Metastatic or MYC gain Group 3
MBs were poor prognosis, while Group 4 MBs with loss of chromosome
11 or whole chromosomal aberration were good prognosis. These findings
reveal molecular properties of Japanese MBs and will contribute to develop
new therapeutic strategies.
MBRS-39. MAP4K4 CONTROLS PRO-INVASIVE SIGNALING IN
MEDULLOBLASTOMA CELLS
Jessica Migliavacca, Charles Capdeville, Buket Seçkin, Michael Grotzer,
and Martin Baumgartner; University Children’s Hospital Zurich, Zurich,
Switzerland
The molecular mechanisms contributing to distant dissemination andlocal recurrence of medulloblastoma, the most common malignant brain
tumor in childhood, are poorly understood and no targeted anti-invasion
therapies exist till date. We explored regulators and effectors of MAP4K4,
a pro-invasive kinase overexpressed in MB and associated with metastatic
progression in different solid malignancies. MAP4K4 is upregulated both atmRNA and protein levels in primary pediatric brain tumors compared tonormal cerebellum. MAP4K4 is required for growth factor- and irradiationinduced migration and invasion of medulloblastoma cells. It furthermore
promotes turnover and activation of the receptor tyrosine kinase c-Met andof the ß1 integrin adhesion receptor 1. To characterize these clinically relevant consequences and to identify druggable targets of MAP4K4 function,
we profiled the interactome of MAP4K4 in starved and growth factor stimulated medulloblastoma cells. To systematically address MAP4K4 impact on
receptor expression and turnover, we determined the MAP4K4-dependent
surface proteome in medulloblastoma cells. We found that MAP4K4 ispart of the striatin-interacting phosphatase and kinase (STRIPAK) complex
and that STRIPAK component striatin 4 is controlling cell motility andinvasiveness in medulloblastoma cells. Invasiveness of medulloblastoma
cells is abrogated by a truncation mutant of MAP4K4 lacking the striatin 4
interaction domain. We furthermore found that MAP4K4 mediates growth
factor-induced surface expression of solute carriers and immunomodulatory
proteins involved in chemoresistance and immune evasion. Thus, our study
identified MAP4K4 as a missing link between pro-tumorigenic growth factor
signaling and tumor cell functions relevant for disease progression. It may
help identifying druggable vulnerabilities in medulloblastoma cells to restrict
tumor growth and dissemination. 1. Tripolitsioti, D. et al., Oncotarget 9,23220–23236 (2018).
MBRS-42. YB-1 - A NOVEL THERAPEUTIC TARGET IN HIGH-RISK
MEDULLOBLASTOMA?
Louisa Taylor1, Ian Kerr2, and Beth Coyle1; 1Children’s Brain Tumour
Research Centre, School of Medicine, University of Nottingham
Biodiscovery Institute, Nottingham, United Kingdom, 2School of Life
Sciences, University of Nottingham, Nottingham, United Kingdom
Medulloblastoma relapse occurs in 30–40% of patients and is typicallyfatal. The emergence of therapy resistant sub-clones likely plays a major rolein a large proportion of recurrent medulloblastoma. Y-box binding protein
1 (YB-1) is a multifunctional transcription/translation factor and known
onco-protein. Overexpression has been described in numerous cancers,
where elevated expression and nuclear accumulation correlates with diseaseprogression, metastasis and drug resistance. Genomic analysis of a large
medulloblastoma cohort revealed YB-1 up-regulation across all subgroupsof medulloblastoma, where elevated expression correlated with poor survival. Immunohistochemical staining of patient tissue microarrays displayed
significant YB-1 expression, with a high proportion (83%) of patients exhibiting nuclear accumulation. High YB-1 expression was also observed at bothprotein and RNA level across medulloblastoma cell lines, with expression
highest in Group 3 and 4. Hence, we hypothesised that YB-1 plays a role inmedulloblastoma chemoresistance and progression. Treatment of Group 3(HDMB-03 and D283MED) and SHH (DAOY) cell lines with vincristineand cisplatin and analysis of cellular localisation by nuclear/cytoplasmic
fractionation and immunofluorescence demonstrated that YB-1 undergoes nuclear translocation in response to these standard medulloblastoma
chemotherapy agents. Chromatin immunoprecipitation (ChIP) analysis ofuntreated Group 3 cell lines (D283MED and HDMB-03) demonstrated considerable YB-1 interaction with an inverted CCAAT box in the ATP-binding
cassette subfamily B member 1 (ABCB1) promoter. RT-PCR analysis of

ABCB1 following vincristine and cisplatin treatment revealed differencesin transcript expression, indicative of different YB-1 promoter interactions
dependent on chemotherapeutic treatment. Our results highlight YB-1 as anovel candidate chemoresistance driver in medulloblastoma.
MBRS-43. ELUCIDATING HOW NOVEL EXTRACELLULAR
MATRIX SUBTYPES DIFFERENTIALLY IMPACT THE SURVIVAL OF
MEDULLOBLASTOMA SUBGROUPSJames Johnson1, Franziska Linke1, Catherine L. R. Merry2, andBeth Coyle1; 1Children’s Brain Tumour Research Centre, School of
Medicine, University of Nottingham Biodiscovery Institute, Nottingham,
United Kingdom, 2Division of Cancer and Stem Cells, University of
Nottingham Biodiscovery Institute, Nottingham, United Kingdom
Medulloblastoma (MB) is the most common malignant paediatric brain
tumour and frequently exhibits metastasis and chemoresistance. MBs are
categorised into four molecular subgroups (WNT, Sonic hedgehog, Group 3
and Group 4), each associated with different demographics and clinical features. We have shown that the expression of specific extracellular matrix
proteins in the brain tumour microenvironment differ between subgroups.
A prime example is laminin (an ECM glycoprotein) the expression of whichcorrelates with good overall survival in the SHH subgroup and poor overall
survival in Group 4. Our aim is to determine the cause of this differencein survival. Candidate laminin-responsive-genes (LRGs) were identified
using the Cavalli data set and RNA-Seq analysis of MB cells grown on 3Dhydrogels with and without laminin. The role of laminin in the regulationof MMPs and the other LRG candidates was investigated by qRT-PCR,
western blotting and zymography in 2D and long-term 3D-hydrogel assays.
Thus far we have shown that in CHLA-01-R (metastatic Group 4 cell line)
three of our LRGs are upregulated in response to laminin in 2D, as well asin preliminary 3D studies. Additionally, we have observed a unique MMP9
secretion profile of SHH cells grown in 3D compared to 2D, suggesting thatour 3D assay allows us to observe relevant phenotypes absent in 2D culture.
We are now in the process of identifying which of these LRG candidates are
involved in metastasis and chemoresistance. This will enable the elucidation of novel therapeutic targets and crucially increase our understanding of
MB-microenvironment interactions.
MBRS-44. TIME, PATTERN AND OUTCOME OF
MEDULLOBLASTOMA RELAPSE ARE ASSOCIATED WITHTUMOUR BIOLOGY AT DIAGNOSIS AND UPFRONT THERAPY:
A COHORT STUDY
Rebecca Hill1, Stacey Richardson1, Edward Schwalbe1,2, Debbie Hicks1,
Janet Lindsey1, Stephen Crosier1, Gholamreza Rafiee1, Yura Grabovska1,
Stephen Wharton3, Thomas Jacques4, Anthony Michalski5, Abhijit Joshi6,
Barry Pizer7, Daniel Williamson1, Simon Bailey1, and Steven Clifford1;
1Newcastle University Centre for Cancer, Newcastle upon Tyne, United
Kingdom, 2Northumbria University, Newcastle upon Tyne, United
Kingdom, 3Sheffield Institute of Translational Neuroscience, Sheffield,
United Kingdom, 4UCL Great Ormond Street Institute for Child Health,London, United Kingdom, 5Great Ormond Street Hospital for Children,
London, United Kingdom, 6Royal Victoria Infirmary, Newcastle upon
Tyne, United Kingdom, 7Alder Hey Children’s Hospital, Liverpool, United
Kingdom
Disease relapse occurs in ~30% of children with medulloblastoma, andis fatal in the majority. We sought to establish whether clinico-molecularcharacteristics at diagnosis are associated with the nature of relapse, subsequent disease-course, and whether these associations could inform clinicalmanagement. We surveyed the clinical features of medulloblastoma relapse(time-to-relapse, pattern-of-relapse, time-to-death and overall outcome) in
247 centrally-reviewed patients who relapsed following standard-upfronttherapies. We related these to clinico-molecular features at diagnosis,
prognostic factors, and first-line/relapse treatment. Patients who received
upfront craniospinal irradiation (CSI-treated) displayed prolonged timeto-relapse compared to CSI naïve patients (p<0.001). Similarly, in CSInaïve patients, CSI at relapse, alongside re-resection and desmoplastic/
nodular histology, were associated with long-term survival. In CSI-treatedpatients, the nature of relapse was subgroup-dependent. Local-nodular relapse patterns were enriched in relapsed-MBSHH patients (p<0.001), but anotable proportion (65%) also acquired distant-diffuse disease (p=0.010).
MBGroup3 relapsed quickly (median 1.3 years), MBGroup4 slowly (median
2.1 years). Distant-disease was prevalent in MBGroup3 and MBGroup4 relapses (90%) but, in contrast to relapsed-MBSHH, nodular and diffuse patterns of distant-disease were observed. Furthermore, nodular disease wasassociated with a prolonged time-to-death post-relapse (p=0.006). Investigation of second-generation MBGroup3/4 subtypes refined our understandingof heterogeneous relapse characteristics. Subtype VIII had prolonged timeto-relapse; subtype II a rapid time-to-death. Subtypes II/III/VIII developed
a significantly higher incidence of distant-disease at relapse, whereas subtypes V/VII did not. The nature of medulloblastoma relapse are biology

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and therapy-dependent, providing immediate translational opportunities
for improved disease management through biology-directed surveillance,
post-relapse prognostication and risk-stratified selection of second-line
treatment.
MBRS-45. TWIST1 AND ABCB1 ARE FUNCTIONAL
DETERMINANTS OF METASTASIS IN MEDULLOBLASTOMA
Alice Cardall1, Franziska Linke1, Ian Kerr2, and Beth Coyle1; 1Children’s
Brain Tumour Research Centre, School of Medicine, University of
Nottingham Biodiscovery Institute, Nottingham, United Kingdom, 2Schoolof Life Sciences, University of Nottingham, Nottingham, United Kingdom
Paediatric medulloblastomas (MB) are frequently metastatic, resulting ina poor prognosis for the patient. Of the four MB subgroups, group 3 patients present with the highest rates of metastasis and worst outcomes. The
mechanisms behind the metastatic process are poorly understood, limiting
our ability to develop novel therapeutic treatments. We hypothesised thatthe epithelial-mesenchymal transition (EMT) transcription factor TWIST1
and the multidrug efflux pump ABCB1 (ATP-binding cassette subfamily B
member 1) synergistically drive MB metastasis. TWIST1 protein expression
was analysed in patient tissue microarrays by immunohistochemistry. HighTWIST1 expression was associated with metastatic patients (p=0.041).
Physical and functional interactions between TWIST1 and ABCB1 were
investigated using chromatin immunoprecipitation (ChIP) and a 3D migration and invasion model. ChIP analysis confirmed TWIST1 binding
to the ABCB1 promoter in SHH (ONS-76) and group 3 (D283MED and
HD-MB03) metastatic cell lines. TWIST1 and ABCB1 were inhibited in
HDMB03 cells with harmine and vardenafil respectively, resulting in attenuated cell migration in the 3D model. Western blot and qRT-PCR analysis ofharmine treated cells confirmed a reduction in ABCB1 protein and gene expression. Overall our data reveals TWIST1 and ABCB1 to be key targets for
MB metastatic disease. Using bioinformatics analysis and ChIP sequencing,
additional TWIST1 downstream targets are now being identified and compared across the metastatic cell lines (ONS-76, D283MED and HD-MB03).
This data will provide a deeper insight into the pathways associated with
MB metastases, enabling personalised treatment approaches for patientswith metastatic disease.
MBRS-46. CHARTING NEOPLASTIC AND IMMUNE CELL
HETEROGENEITY IN HUMAN AND GEM MODELS OF
MEDULLOBLASTOMA USING SCRNASEQ
Andrew Donson1,2, Kent Riemondy3, Sujatha Venkataraman1,2,Ahmed Gilani4, Bridget Sanford2, Andrea Griesinger1,2, Vladimir Amani1,2,
Todd Hankinson5,1, Michael Handler5,1, Jay Hesselberth3,
Timothy Gershon6, Robert Wechsler-Reya7, Nicholas Foreman1,2, andRajeev Vibhakar1,2; 1The Morgan Adams Foundation Pediatric Brain
Tumor Research Program, Children’s Hospital Colorado, Aurora, CO,
USA, 2Department of Pediatrics-Hematology and Oncology, University ofColorado Anschutz Medical Campus, Aurora, CO, USA, 3RNA Biosciences
Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO,
USA, 4Department of Pathology, University of Colorado Anschutz Medical
Campus, Aurora, CO, USA, 5Department of Neurosurgery, University ofColorado Anschutz Medical Campus, Aurora, CO, USA, 6Department of
Neurology, University of North Carolina, Chapel Hill, NC, USA, 7Sanford
Burnham Prebys Medical Discovery Inst., La Jolla, CA, USA
We explored cellular heterogeneity in medulloblastoma using single-cell
RNA sequencing (scRNAseq), immunohistochemistry and deconvolutionof bulk transcriptomic data. Over 45,000 cells from 31 patients from all
main subgroups of medulloblastoma (2 WNT, 10 SHH, 9 GP3, 11 GP4 and1 GP3/4) were clustered using Harmony alignment to identify conserved
subpopulations. Each subgroup contained subpopulations exhibiting mitotic, undifferentiated and neuronal differentiated transcript profiles, corroborating other recent medulloblastoma scRNAseq studies. The magnitude ofour present study builds on the findings of existing studies, providing further
characterization of conserved neoplastic subpopulations, including identification of a photoreceptor-differentiated subpopulation that was predominantly, but not exclusively, found in GP3 medulloblastoma. Deconvolution of
MAGIC transcriptomic cohort data showed that neoplastic subpopulations
are associated with major and minor subgroup subdivisions, for example,
photoreceptor subpopulation cells are more abundant in GP3-alpha. In both
GP3 and GP4, higher proportions of undifferentiated subpopulations is associated with shorter survival and conversely, differentiated subpopulation
is associated with longer survival. This scRNAseq dataset also afforded
unique insights into the immune landscape of medulloblastoma, and revealed an M2-polarized myeloid subpopulation that was restricted to
SHH medulloblastoma. Additionally, we performed scRNAseq on 16,000
cells from genetically engineered mouse (GEM) models of GP3 and SHH
medulloblastoma. These models showed a level of fidelity with corresponding human subgroup-specific neoplastic and immune subpopulations.

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Collectively, our findings advance our understanding of the neoplastic andimmune landscape of the main medulloblastoma subgroups in both humans
and GEM models.
MBRS-47. RAPID MOLECULAR SUBGROUPING OF
MEDULLOBLASTOMA BASED ON DNA METHYLATION BY
NANOPORE SEQUENCING
Julien Masliah-Planchon1, Elodie Girard2, Philipp Euskirchen3,
Christine Bourneix1, Delphine Lequin1, Maud Blanluet1,
Jean-Baptiste Aillaud1, Francois Doz4, Franck Bourdeaut5,6, andOlivier Delattre5,1; 1Unité de Génétique Somatique, Institut Curie, Paris,
France, 2U900, Institut Curie, Paris, France, 3Department of Neurology,
Charité - Universitätsmedizin Berlin, Berlin, Germany, 4SIREDO Center,
France, France, 5SIREDO Center, Paris, France, 6RTOP Department, Paris,
FranceMedulloblastoma (MB) can be classified into four molecular subgroups(WNT group, SHH group, group 3, and group 4). The gold standard ofassignment of molecular subgroup through DNA methylation profilinguses Illumina EPIC array. However, this tool has some limitation in termsof cost and timing, in order to get the results soon enough for clinical use.
We present an alternative DNA methylation assay based on nanopore
sequencing efficient for rapid, cheaper, and reliable subgrouping of clinical MB samples. Low-depth whole genome with long-read single-molecule
nanopore sequencing was used to simultaneously assess copy number profile
and MB subgrouping based on DNA methylation. The DNA methylation
data generated by Nanopore sequencing were compared to a publicly available reference cohort comprising over 2,800 brain tumors including the four
subgroups of MB (Capper et al. Nature; 2018) to generate a score that estimates a confidence with a tumor group assignment. Among the 24 MB
analyzed with nanopore sequencing (six WNT, nine SHH, five group 3, andfour group 4), all of them were classified in the appropriate subgroup established by expression-based Nanostring subgrouping. In addition to thesubgrouping, we also examine the genomic profile. Furthermore, all previously identified clinically relevant genomic rearrangements (mostly MYC
and MYCN amplifications) were also detected with our assay. In conclusion,
we are confirming the full reliability of nanopore sequencing as a novel rapid
and cheap assay for methylation-based MB subgrouping. We now plan toimplement this technology to other embryonal tumors of the central nervous system.
MBRS-48. IDENTIFICATION OF NOVEL THERAPEUTICAPPROACHES FOR MYC-DRIVEN MEDULLOBLASTOMA
Kübra Taban1,2, David Pauck1,2, Mara Maue1,2, Viktoria Marquardt1,2,
Hua Yu3, Olivier Ayrault3, Daniel Picard1,2, Jasmin Bartl1,2, Nan Qin1,2,
Arndt Borkhardt2, Guido Reifenberger4, and Marc Remke1,2; 1Division of
Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ)and German Cancer Consortium (DKTK), partner site University Hospital
Düsseldorf, Düsseldorf, Germany, 2Department of Pediatric Oncology,
Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine
University Düsseldorf, Düsseldorf, Germany, 3Institut Curie, PSL Research
University, CNRS UMR, INSERM, 91405, Orsay, France, 4Institute of
Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf,
Düsseldorf, Germany
Medulloblastoma (MB) is the most common malignant brain tumor inchildren and is frequently metastatic at diagnosis. Treatment with surgery,radiation and multi-agent chemotherapy may leave survivors of these brain
tumors with long-term deficits as a consequence. One of the four consensus
molecular subgroups of MB is the MYC-driven group 3 MB, which is themost malignant type and has a poor prognosis under current therapy. Thus,
it is important to discover more effective targeted therapeutic approaches.
We conducted a high-throughput drug screening to identify novel compounds showing efficiency in group 3 MB using both clinically establishedinhibitors (n=196) and clinically-applicable compounds (n=464). More than
20 compounds demonstrated a significantly higher anti-tumoral effect in
MYChigh (n=7) compared to MYClow (n=4) MB cell models. Among thesecompounds, Navitoclax and Clofarabine showed the strongest effect ininducing cell cycle arrest and apoptosis in MYChigh MB models. Furthermore, we show that Navitoclax, an orally bioavailable and blood-brain barrier passing anti-cancer drug, inhibits specifically Bcl-xL proteins. In line,
we found a significant correlation between BCL-xL and MYC mRNA levels
in 763 primary MB patient samples (Data source: “R2 https://hgserver1.
amc.nl”). In addition, Navitoclax and Clofarabine have been tested in cells
obtained from MB patient-derived-xenografts, which confirmed their specific efficacy in MYChigh versus MYClow MB. In summary, our approach
has identified promising new drugs that significantly reduce cell viability in
MYChigh compared to MYClow MB cell models. Our findings point to novel
therapeutic vulnerabilities for MB that need to be further validated in vitro
and in vivo.

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MBRS-51. MUTATIONS IN BRPF1 FOUND IN SHHMEDULLOBLASTOMA PREVENT INTERACTION WITH TP53 AND
LEADS TO RADIORESISTANCE IN VITRO
Mikaela Vouri1, Audrey Mercier2, Patricia Benites Goncalves da Silva1,
Konstantin Okonechnikov1, Antoine Forget2, Hua Yu2,
Anais Chivet2, Marcel Kool1, Stefan Pfister1, Olivier Ayrault2, andDaisuke Kawauchi1,3; 1Hopp-Children’s Cancer Center at the NCT
Heidelberg (KiTZ), German Cancer Research Center, Heidelberg, Germany,
2Institut Curie, INSERM, Orsay, France, 3National Center of Neurology
and Psychiatry, Tokyo, Japan
Medulloblastoma (MB) is one of the most common pediatric tumors in children. Among them, SHH subgroups of MB (MBSHH) is characterized by constitutive activation of SHH pathway. Somatic mutations in BRPF1, a chromatin
modifier, is found in more than 5% of MBSHH and accounts for almost 20% of
adult MBSHH but its potential role in MBSHH pathophysiology is still unknown.
In this study, we first examined the function of Brpf1 on pro-tumorigenic features of MBSHH and evaluated molecular pathways regulated by Brpf1 using
Brpf1floxed::Atoh1-Cre conditional knockout mice, in which Brpf1 is conditionally deleted in cerebellar granule neuron progenitors (GNPs). While RNA-seq
analysis on GNPs from Brpf1 WT and KO mice showed significant differencesin the pathways related with cell cycle and cell death, deletion of Brpf1 did notcause acceleration of tumorigenesis in the Ptch1 heterozygous tumor-prone
BACKGROUND: Co-immunoprecipitation followed by mass spectrometry
analysis identified interaction partners of BRPF1 including MOZ, MORF
and ING5, known partners of BRPF1. Gene ontology analysis also depicted
pathways important for cell cycle progression, cell death and response to
DNA damage. Consistent with these observations, TP53 was identified asa novel co-factor of BRPF1. Of note, some of MBSHH-relevant BRPF1 mutations prevented interaction with TP53. According to the previous findingthat cytosolic TP53 is required for apoptotic cell death, GNPs expressing the
BRPF1-R600X mutant gene exhibited the resistance to irradiation-induced
cell death. In conclusion, our data revealed that BRPF1 mutants found in
MBSHH could prevent the complex formation with TP53, leading to enhanced resistance to cell apoptosis.
MBRS-53. CONTROL OF MEDULLOBLASTOMA VASCULATURE BY
A REGULATOR OF NEUROGENESIS
Shavali Shaik1, Shinji Maegawa1, Amanda Haltom1, Tara Dobson1,
Keri Schadler1, and Vidya Gopalakrishnan1,2; 1Department of Pediatrics,
University of Texas, MD Anderson Cancer Center, Houston, TX, USA,
2Department of Molecular and Cellular Oncology, University of Texas, MD
Anderson Cancer Center, Houston, TX, USA
Medulloblastomas are characterized by poor neuronal lineage specification. Expression of the RE1 Silencing Transcription Factor (REST), a regulator of neurogenesis, is aberrantly elevated in human sonic hedgehog (SHH)
medulloblastomas. Using a novel transgenic mouse (RESTTG) model, we
demonstrated that REST is a driver of medulloblastoma genesis and promotes tumor progression in mice with loss of an allele of Ptch1 (Ptch+/−).
Tumor formation in Ptch+/−/RESTTG mice occurred with 100% penetrance
and a latency of 10–90 days in contrast to Ptch+/− mice, which developed
tumors at a frequency of 15–20% at 6–9 months of age. Histopathologicalanalyses showed leptomeningeal dissemination of tumors in Ptch+/−/RESTTG mice, in addition to a significant increase in tumor vasculaturecompared to tumors in Ptch+/− mice. These findings were recapitulated
in xenografted tumors of isogenic low and high-REST medulloblastomas
in mice. Proteome profiler human angiogenesis array analyses revealed a
REST-dependent increase in vascular endothelial growth factor (VEGF) andplacental growth factor (PLGF). Surprisingly, REST elevation also caused
co-localization of tumor cells with tumor vasculature, specifically endothelial cells, and was associated with upregulated expression of a number of
pro-angiogenic genes, including receptor VEGFR1 and the positive regulator of endothelial differentiation, E26 transformation specific-1 (ETS1),
in tumor cells. In addition, expression of several anti-angiogenic molecules
was downregulated. Knockdown of ETS1 reversed the above findings. Thus,
our data demonstrate that REST elevation not only blocks neurogenesis in
medulloblastoma cells, but also modulates the tumor microenvironment bymechanisms that likely involve vascular mimicry.
MBRS-54. POOR SURVIVAL IN REPLICATION REPAIR DEFICIENT
HYPERMUTANT MEDULLOBLASTOMA AND CNS EMBRYONALTUMORS: A REPORT FROM THE INTERNATIONAL RRD
CONSORTIUM
Anirban Das1, Vanessa Bianchi1, Melissa Edwards1, Nobish Varghese1,
Sumedha Sudhaman1, Roula Farah2, Rina Dvir3, Alyssa Reddy4,
Salmo Raskin5, Jordan Hansford6, Syed Ahmer Hamid7,
Saunders Hsu8, Lee Yi Yen9, Abed Abu Quider10, Mithra Ghalibafian11,
Elisabeth Koustenis12, Abeer Al-Battashi13, Gary Mason14,
Joung Lee15, Danille Bell16, Duncan Stearns17, David Ziegler18,
Michal Zapotocky19, Alvaro Lasaletta20, Abhaya Kulkarni1,

Derek S. Tsang21, Normand Laperriere21, Cynthia Hawkins1, Eric Bouffet1,
Vijay Ramaswamy1, and Uri Tabori1; 1The Hospital for Sick Children,
Toronto, Canada, 2Saint George Hospital University Medical Center,
Beirut, Lebanon, 3Tel Aviv Medical Center, Tel-Aviv, Israel, 4Children’s
Hospital of Alabama, University of Alabama, Birmingham, Alabama, USA,
5Genetika, Curitiba, Brazil, 6Children’s Cancer Centre, Royal Children’s
Hospital, University of Melbourne, Melbourne, Australia, 7Indus Hospital,
Karachi, Pakistan, 8Sutter Health, California, USA, 9Taipei Veterans
General Hospital, Taipei, Taiwan, 10Soroka University Medical Center, Beer
Sheva, Israel, 11MAHAK Pediatric Cancer Treatment and Research Center,
Tehran, Iran, Islamic Republic of, 12Stuttgart Cancer Center, Stuttgart,
Germany, 13Ministry of Health, Muscat, Oman, 14Children’s Hospital of
Pittsburg, Pittsburg, USA, 15Cleveland Clinic, Florida, USA, 16Ascension,
St Louis, USA, 17Rainbow Babies and Children’s Hospital, Cleveland, USA,
18Sydney Children’s Hospital, Sydney, Australia, 19University Hospital
Motol, Prague, Czech Republic, 20Hospital Infantil Universitario Niño
Jesús, Madrid, Spain, 21Princess Margaret Hospital, Toronto, Canada
BACKGROUND: Mutations in mismatch repair (MMR) and DNApolymerase (POL) genes lead to DNA replication repair deficiency (RRD),
resulting in a growing group of previously under-recognized childhood brain
tumors. Medulloblastoma and embryonal tumors are rarely reported in
RRD. Their biological and clinical significance is unknown. METHODS: We
analyzed the clinical and genomic data of embryonal tumors registered in
the International RRD Consortium. RESULTS: Twenty-six tumors were
centrally reviewed to confirm medulloblastoma (n=18), embryonal-tumor,
NOS (n=5), and three glioblastoma (excluded). Embryonal tumors wereobserved at a young age (median: 7-years, IQR: 5;11), and all but one
exhibited clinical cues (café-au-lait macules/ family history) of germline
RRD. Medulloblastomas with RRD exhibited high-risk features, including
anaplastic histology (50%), and SHH-subgroup with TP53-mutation(50%). Importantly, 68% harbored POLE/POLD1 mutations, resulting
in median tumor mutation burden of 164 mut/mb. POL-mutated tumors
were significantly ultra-hypermutated (>100 mut/mb) than tumors with
MMR-deficiency alone (p=0.015). Synchronous and metachronous tumors were observed in 40%. However 90% of the deaths were related
to the diagnosis of embryonal CNS tumor. Median survival for the entire
cohort was 17-months (95% CI: 10 to 23). Predicted 3-year survival was
37% for medulloblastoma, with no survivors among other embryonal tumors. CONCLUSIONS: This is the largest cohort of replication repair deficient medulloblastoma reported till date. The tumors are hypermutated,
harbor somatic mutations in TP53 and/or POLE/POLD1, and have very
poor survival with current chemo-irradiation based approaches. These biologically unique tumors expand the spectrum of high-risk TP53-mutant
SHH-medulloblastoma, and need novel strategies for treatment.
MBRS-56. RE-EVALUATION OF LEPTOMENINGEAL METASTASISIN MEDULLOBLASTOMA WITH MAGNETIC RESONANCEIMAGING, RELATED SYMPTOMS AND CEREBROSPINAL FLUIDMETABOLOMIC PROFILESJi Hye Im1, Byong Chul Yoo1, Jun Hwa Lee1, Kyung-Hee Kim1,
Jong Heon Kim1, Hyeon Jin Park1, Meerim Park1, Ji Woong Kwon1,
Sang Hoon Shin1, Heon Yoo1, Seung Ah Choi2, Jae Yeol Yang2,
Ji Hoon Phi2, Seung-Ki Kim2, Ho-Shin Gwak1; 1National Cancer Center,
Goyang, Republic of Korea, 2Seoul National University College ofMedicine, Seoul, Republic of Korea
BACKGROUND: Diagnosis of leptomeningeal metastasis (LM) in
medulloblastoma is made by positive findings in either MRI or CSF cytology.
We studied if CSF metabolomics profile can differentiate the discordant results between MRI and CSF cytology and reflect the sampling time related
to treatment. MATERIALS AND METHODS: We prospectively collected
83 CSF samples from 45 medulloblastoma patients. A total of 6,527 lowmass ions (LMIs) were detected using liquid chromatography tandem mass
spectrometry (LC-MS/MS). Discriminative low-mass ions (LMIs) between
four different MRI and cytology results groups were evaluated and representative LMIs were identified. RESULTS: CSF cytology and MRI finding
were both positive for LM in 8 samples and both negative for 47 samples.
Tests were cytology (-) and MRI (+) in 20 samples, whereas cytology (+) andMRI (-) status were in the remaining 8 samples. The diagnostic accuracy
by area under the curve (AUC) was 0.722 for cytology and 0.888 for MRI
each. Based on the exclusiveness of LMI between groups, we verified 27
discriminative LMIs in MRI (+)/ cytology (+), 9 LMIs in MRI (+)/ cytology(-), and 12 LMIs in MRI (-) and cytology (+) group, separately. Metabolic
pathways involved in MRI (+)/ cytology (+) group were linoleic acid, phenylalanine, TCA cycle, retinol, arginine-ornithine, nicotinate-nicotinamide, etc.
Low-mass-ion discriminant equation (LOME), which could differentiate
both different MRI and cytology results and the sampling time or presence of LM-related symptoms was found. CONCLUSION: Non-targeted
MSanalysis CSF metabolite in medulloblastomas revealed significantly different profiles, and these results suggest LMI profiles might have a higher
sensitivity for LM diagnosis than either MRI or cytology.

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MBRS-57. IDENTIFICATION OF MYC-DEPENDENTTHERAPEUTIC VULNERABILITIES FOR TARGETING GROUP 3
MEDULLOBLASTOMA
Gemma Llargués-Sistac1, Janet Lindsey1, Shanel Swartz1, Matthew Selby1,
Alaide Morcavallo2, Simon Bailey1, Louis Chesler2, Christopher J. Lord3,
Daniel Williamson1, and Steven C. Clifford1; 1Wolfson Childhood Cancer
Research Centre, Newcastle University Centre for Cancer, Newcastle
Upon Tyne, United Kingdom, 2Paediatric and Solid Tumour Biology andTherapeutics Group, The Institute of Cancer Research London, London,
United Kingdom, 3The Breast Cancer Now Toby Robins Breast Cancer
Research Centre and CRUK Gene Function Laboratory, The Institute ofCancer Research London, London, United Kingdom
Group 3 medulloblastoma (MBGroup3) is a highly aggressive tumour characterised by MYC amplification and elevated expression (17% of MBGroup3).
MYC amplification in MBGroup3 confers a dismal prognosis using standard
therapies, and there is an urgent unmet need for novel therapeutic approaches.
The identification and targeting of MYC’s biological dependencies thus represents a promising strategy to treat MYC-MBGroup3 tumours. Three independentisogenic MYC-regulable MBGroup3 human cell-based models, in which elevated
MYC expression can be directly down-regulated by doxycycline-inducible
shRNAs, were developed and used initially to establish MYC-dependent
growth of each model. Our novel models were then used to investigate MYCdependent drug sensitivity, by characterising responses to a panel of candidate
cancer therapeutics and small molecule inhibitors, including a high-throughput
compound screen of >500 established/clinically-relevant small molecule inhibitors. This approach identified several specific, consistently observed,
druggable MYC-dependencies (e.g. cell cycle regulators, DNA-damage response controllers, mitotic control machinery) with potential for the development of treatments against MYC-MBGroup3 tumours. PLK1, CHK1 and AURK
were identified as prime candidate targets with consistent MYC-dependent
response profiles. Subsequent validation of each candidate, by genetic andpharmacological target inhibition, confirmed their MYC-dependent effects,
associated with downregulation of MYC and established target-dependent
pharmacodynamic biomarkers/pathways. Results were consistent across all of
our MBGroup3 models. In summary, our novel models reveal druggable MYCassociated dependencies as a feature of MBGroup3. Our findings support the development of PLK1, CHK1 and AURK inhibition as therapeutic approaches
against MYC-dependent MBGroup3. Future work is now essential to validate ourfindings in vivo, to support the design of future clinical trials.
MBRS-59. SINGLE-CELL WHOLE-GENOME SEQUENCING DISSECTSINTRA-TUMOURAL GENOMIC HETEROGENEITY AND CLONALEVOLUTION IN CHILDHOOD MEDULLOBLASTOMAMarina Danilenko1, Masood Zaka2, Claire Keeling1, Stephen Crosier1,
Rafiqul Hussain3, Edward Schwalbe4, Dan Williamson1,
Jonathan Coxhead3, Vikki Rand2, Simon Bailey1, and Steven Clifford1;
1Wolfson Childhood Cancer Research Centre, Translational & ClinicalResearch Institute, Newcastle University Centre for Cancer, Newcastle
upon Tyne, United Kingdom, 2National Horizons Centre, Darlington,
United Kingdom, 3Genomics Core Facility, Biosciences Institute, Newcastle
University, Newcastle upon Tyne, United Kingdom, 4Department ofApplied Sciences, Northumbria University, Newcastle upon Tyne, United
Kingdom
Medulloblastomas harbor clinically-significant intra-tumoral heterogeneity for key biomarkers (e.g. MYC/MYCN, β-catenin). Recent studies havecharacterized transcriptional heterogeneity at the single-cell level, however the underlying genomic copy number and mutational architecture remains to be resolved. We therefore sought to establish the intra-tumouralgenomic heterogeneity of medulloblastoma at single-cell resolution. Copy
number patterns were dissected by whole-genome sequencing in 1024 single
cells isolated from multiple distinct tumour regions within 16 snap-frozen
medulloblastomas, representing the major molecular subgroups (WNT,
SHH, Group3, Group4) and genotypes (i.e. MYC amplification, TP53 mutation). Common copy number driver and subclonal events were identified,providing clear evidence of copy number evolution in medulloblastoma development. Moreover, subclonal whole-arm and focal copy number alterations covering important genomic loci (e.g. on chr10 of SHH patients) weredetected in single tumour cells, yet undetectable at the bulk-tumor level. Spatial copy number heterogeneity was also common, with differences between
clonal and subclonal events detected in distinct regions of individual tumours.
Mutational analysis of the cells allowed dissection of spatial and clonal heterogeneity patterns for key medulloblastoma mutations (e.g. CTNNB1,
TP53, SMARCA4, PTCH1) within our cohort. Integrated copy number andmutational analysis is underway to establish their inter-relationships andrelative contributions to clonal evolution during tumourigenesis. In summary, single-cell analysis has enabled the resolution of common mutationaland copy number drivers, alongside sub-clonal events and distinct patternsof clonal and spatial evolution, in medulloblastoma development. We anticipate these findings will provide a critical foundation for future improved
biomarker selection, and the development of targeted therapies.

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MBRS-60. THE ACTIONABLE GENOMIC LANDSCAPE OF
RELAPSED MEDULLOBLASTOMA IS DEFINED BY MAINTENANCE
AND ACQUISITION OF DRIVER EVENTS
Stacey Richardson1, Rebecca M Hill1, Christopher Kui1,
Janet C Lindsey1, Yura Grabovska1, Edward C Schwalbe1,2, Debbie Hicks1,
Daniel Williamson1, Stephen Crosier1, Abjhit Joshi3, Stephen B Wharton4,
Jordan Hansford5, Barry Pizer6, Maria Vinci7, Angela Mastronuzzi7,
Andrea Carai7, Anthony Michalski8, Thomas S Jacques9, Simon Bailey1,and Steven C Clifford1; 1Newcastle University Centre for Cancer,
Newcastle upon Tyne, United Kingdom, 2Department of Applied Sciences,
Northumbria University, Newcastle upon Tyne, United Kingdom,
3Department of Neuropathology, Royal Victoria Infirmary, Newcastle
upon Tyne, United Kingdom, 4Sheffield Institute for Translational
Neuroscience, University of Sheffield, Sheffield, United Kingdom, 5The
Royal Children’s Hospital Melbourne, Melbourne, Australia, 6Instituteof Translational Research, University of Liverpool, Liverpool, United
Kingdom, 7Department of Pediatric Onco-Hematology and Transfusion
Medicine, Ospedale Pediatrico Bambino Gesu, Rome, Italy, 8Department of
Haemotology and Oncology, Great Ormond Street Hospital for Children
NHS Foundation Trust, London, United Kingdom, 9Neural Development
Unit, UCL Institute of Child Health, London, United Kingdom
Medulloblastoma relapse (rMB) occurs in 30–40% of patients and is almost universally fatal. Understanding the genomic landscape of rMB, andits relationship to disease characteristics at diagnosis, will be essential tounderpin the development of improved therapeutic strategies, delivered atboth diagnosis and relapse. Utilising NGS and Illumina DNA methylationarrays, we interrogated the molecular landscape of >100 rMBs, alongsidematched diagnostic samples (n>80), encompassing molecular subgroup,novel subtypes, copy number (CNV) and mutational variants. Molecularsubgroup and novel subtypes were stable over disease-course. The majorityof genomic aberrations were also maintained (total arm-level CNVs at relapse, 60% maintained/40% acquired; deleterious/driver mutations, 75%
maintained/25% acquired). Importantly, however, the landscape of alterations differed markedly at relapse, through both selective maintenanceand acquisition of specific gene and pathway aberrations. For instance,
we observed significant enrichment of subgroup-specific events at relapse,
including focal CDK6/CDK14 amplifications (4/26 (15%) of MBGroup4) and
CDKN2A/CDKN2B deletions (3/48 (6%) of MBSHH). In contrast, mutations in DNA damage response pathways were commonly enriched acrossall molecular subgroups, most significantly in MBSHH (~40% of rMBSHH;
TP53, 9/36 (25%); ATM, 5/36 (14%)). Driver events in rMB are characterised by both selective maintenance and acquisition across disease-course,
and together combine to define its actionable genetic landscape. Evaluationof their clinical and biological significance will be essential to establish theirpotential (i) as biomarkers to direct disease management and (ii) as a basis
for therapeutic strategies targeted against medulloblastoma relapse.
MBRS-61. MOLECULAR SUB-GROUPING OF PEDIATRICMEDULLOBLASTOMA: CORRELATION WITH CLINICAL AND
HISTOLOGICAL FEATURES, A SINGLE INSTITUTIONAL STUDY
Gauri Deshpande, Mamta Gurav, Omshree Shetty, Vinayak Kadam,
Vishal Chaubey, Tejpal Gupta, Aliasgar Moiyadi, Girish Chinnaswamy, andSridhar Epari; Tata Memorial Centre, Mumbai, Maharashtra, India
INTRODUCTION: Molecular subgroups of pediatric medulloblastomas
are distinctive in infantile and non-infantile age-groups. METHODS: Realtime quantitative PCR based GEP of customized 12 protein-coding genes
was performed on 206 FFPE childhood medulloblastoma samples. FISH
for MYC amplification, monosomy 6 and sequencing for CTNNB1 exon
3 mutation were done in relevant cases. H&E and reticulin-stained slides
were used for histological subtyping. p53-protein immunoreactivity pattern
was noted. RESULTS: Infantile (n=33) comprised 57.6% SHH-activated(desmoplastic: 73.7%; MBEN: 15.8% and classic: 10.5%), 21.2% group 3(large cell/anaplastic [LCA]: 28.6% and none were desmoplastic) and 12%group 4. 40% of group 3 patients died of disease and 21% of the SHHactivated (all desmoplastic) had subsequent local recurrence. Non-infantile(n=173) comprised 19.4% WNT-activated, 12.9% SHH-activated (15%classic, 30% desmoplastic, 10% paucinodular), 19.4% group 3 (63.3%
classic & 26.7% LCA), 48.4% group 4 (73.3% classic, 5.3% desmoplastic,
10.7% paucinodular & 1.4% LCA), and non-WNT/non-SHH (NWNS),NOS (n=14,9%) and unclassified (n=4,2.6%). None of WNT-activated were
desmoplastic/LCA histology. Non-infantile WNT-activated and group 3
MBs showed 90% monosomy 6 & CTNNB1 mutation, and 16.7% MYCamplification respectively. 17.4% (13% spinal, 4.4% local) WNT-activated,
31% (12.5% local, 18.5% distant [spinal: 12.5%, intracranial:6%]) SHHactivated, 27% (18% both spinal and local, 9% spinal) group 3 and 31.5%(7.4% local, 5.5% intracranial, 11.2% spinal, 7.4% both spinal and local)
group 4 showed metastases during follow up. CONCLUSIONS: SHHactivated and group 3 are the common infantile subgroups but group 4 is
not non-existent in infantile age. No desmoplastic (including paucinodular)
histological subtype is of WNT- activated and group 3.

Abstracts

MBRS-62. CURAXIN CBL0137 INHIBITS THE VIABILITY OF
CANCEROUS CELLS IN PRE-CLINIC MODELS OF MYC-AMPLIFIEDMEDULLOBLASTOMA
Jiajia Wang, Baocheng Wang, Yang Zhao, and Jie Ma; XinHua Hospital
Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai,
China
Medulloblastoma is a malignant brain tumour that mostly occurs inchildren, and MYC-amplified medulloblastoma is characterized by pronounced invasiveness and dismal prognosis. There is no effective treatment
for Medulloblastoma and its precise pathological mechanism remains obscure. Previous studies indicated that the altered epigenetic machinery manifested in the neoplastic transformation of MYC-amplified MB has become
increasingly evident. It is hypothesized that epigenetic genes dependencies
associated with small molecule inhibitors that have been approved or are
in advanced development may help identify the potential therapeutic targets. By integrating mRNA expression profiles and the corresponding clinicpathologic information of patients suffering from medulloblastoma, andanalysing prior CRISPR screening results, we demonstrated that SSRP1 isa negative prognostic factor that functions to stimulate the viability of MB
cells. SSRP1 is a subunit of the FACT complex, an important histone chaperone required for transcriptional regulation, DNA replication and damage
repair. Its biological effect on tumour proliferation was assessed by using
RNA interference and administering CBL0137, a small molecular inhibitorof FACT. Gene expression analysis also demonstrated that CBL0137 selectively downregulated the expression of MYC and NEUROD1. Furthermore,
the administration of CBL0137 suppressed tumour growth in mouse xenograft models. This pharmacological method to selectively target MYC transcription was demonstrated in our study, and therefore can be applied as apromising treatment strategy for MYC-amplified medulloblastoma. In Conclusion, we identified an attractive strategy of selectively downregulating
MYC transcription by applying inhibitor CBL0137, thereby revealing thepotential clinical utility of CBL0137 to improve the prognosis of MYCamplified medulloblastoma patients.
MBRS-63. THE ROLE OF THE SWI/SNF COMPLEX SUBUNITSMARCD3 IN MEDULLOBLASTOMA
Brad Poore1,2, Han Zou1,2, Vaibhav Sharma2, Ian Pollack1,2, andBaoli Hu1,2; 1University of Pittsburgh School of Medicine, Pittsburgh, PA,
USA, 2UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
Medulloblastoma is the most common malignant brain tumor in children, with the Group 3 (G3) having the worst prognosis of the subgroups(WNT, SHH, and Group 4). We aimed to determine the underlying differences between G3 and the other subgroups, with an emphasis on genes that
control the epigenome for developing effective treatments for patients withthis disease. To this end, we found that G3 has elevated expression of the
SWI/SNF subcomponent, SMARCD3 (P<0.001), which serves to guide the
SWI/SNF complex to different genomic regions through interactions withvarious transcription factors. However, little is known about function of
SMARCD3 in cancer, particularly in medulloblastoma. Clinically, elevated
SMARCD3 mRNA resulted in a poorer prognosis in medulloblastoma
patients (P<0.0001), which was further validated in 63 patient tumors byimmunohistochemical staining for SMARCD3. Interestingly, tumors that
had metastasized often had elevated expression of SMARCD3, in all subgroups of medulloblastomas (P<0.0001) and G3 only (P<0.01) based on
analyzing multiple published databases. An orthotopic mouse model further
supported that SMARCD3 is highly expressed in metastatic tumors compared to primary tumors. Importantly, CRISPR-CAS9-mediated SMARCD3
deletion decreased cell migration in medulloblastoma cell lines. Mechanistically, SMARCD3 deletion led to decreased H3K27me3, suggesting that
SMARCD3 may cooperate with PRC2 in regulation of gene expression. Together, our results indicate that SMARCD3 plays a significant role in the development of metastatic dissemination in medulloblastoma, especially in theG3 subgroup. Thus, targeting the SMARCD3-containing SWI/SNF Complex
may effectively prevent tumor dissemination and improve clinical outcomesin children with medulloblastoma.
MBRS-64. STUDY OF ARGININE METHYL TRANSFERASES IN
MEDULLOBLASTOMA
Donghang Cheng1, Pete Taylor1, Monica Gireud1, Shinji Maegawa1,
Yanwen Yang1, Sadhan Majumder2, and Vidya Gopalakrishnan1,3;
1Department of Pediatrics, University of Texas, MD Anderson Cancer
Center, Houston, TX, USA, 2Department of Genetics, University ofTexas, MD Anderson Cancer Center, Houston, TX, USA, 3Departmentof Molecular and Cellular Oncology, University of Texas, MD Anderson
Cancer Center, Houston, TX, USA
Medulloblastoma is the most common malignant pediatric cancer and aleading cause of childhood cancer-related mortality. There is dire need for
new therapies. Molecular sub-classification of medulloblastomas has iden-tified chromatin modifiers as potential drivers of tumorigenesis. Expressionof the RE1 Silencing Transcription Factor (REST), a hub for assembly ofrepressive chromatin remodelers and a known regulator of neurogenesis, is elevated in a subset of human sonic hedgehog (SHH) subgroupmedulloblastomas, and is associated with poor prognosis. Using a noveltransgenic mouse model, we showed REST to be a driver of medulloblastoma
development. Surprisingly, our studies also revealed a role for REST in promoting proliferation of granule cell progenitors (GCPs), the cells of originof SHH-driven medulloblastoma, and a concomitant loss of telomeres andincreased genomic instability. We performed a gain of function screen using
a library of chromatin modifiers to understand the mechanism by which
proliferative potential was maintained, despite the loss of telomeres. This
screen identified the Protein Arginine Methyltransferase 6 (PRMT6) as ahigh confidence hit. PRMT6 upregulation caused a reduction in CDKN2A,
an important regulator of replicative senescence. Evasion of senescence isfrequently implicated in tumor progression. Using a chemical screen, we also
identified a novel, selective, reversible and competitive inhibitor of PRMT6.
The consequence of genetic and pharmacological inhibition of PRMT6 on
cell proliferation and senescence will be reported. Thus, our studies are thefirst to demonstrate a role for arginine methyl transferase family of chromatin modifiers in medulloblastoma genesis.
MBRS-65. FBXW7 ACTS A TUMOR SUPPRESSOR IN MYC-DRIVENMEDULLOBLASTOMA BY CONTROLLING A FEED-FORWARD
REGULATORY LOOP OF PLK1 AND MYC
Dong Wang1, Angela Pierce1, Bethany Veo1, Susan Fosmire1,
Krishna Madhavan1, Ilango Balakrishnan1, Sujatha Venkataraman1,2, andRajeev Vibhakar1,2; 1University of Colorado School of Medicine, Aurora,
CO, USA, 2Morgan Adams Pediatric Brain Tumor Research Program,
Aurora, CO, USAGroup 3 medulloblastoma (MB) is often accompanied by MYC amplification and has a higher rate of metastatic disease. So, it is critical to have more
effective therapies for high MYC expressing sub-groups. Here we reportthat FBXW7, a substrate recognition component of the SKP1-CUL1-Fbox(SCF) E3 ligase, interacts with and targets c-MYC for polyubiquitinationand proteasomal degradation. FBXW7 shows lower expression level in
MYC-driven MB compared with other MB subgroups suggesting activity as
a tumor suppressor. Genomic deletion or mutation of Fbxw7 has frequently
been identified in many human cancers but not in MB. We demonstratethat overexpression of Fbxw7 in MB cells induces apoptosis and suppresses
proliferation in vitro and in vivo. Both phospho-deficient (T205A) andphosphomimetic aspartic acid (T205D) mutants deactivate its tumor suppressor function suggesting a conformational change of its protein structure. Mechanistically, PLK1 kinase specifically phosphorylates FBXW7 andpromotes its auto-polyubiquitination and proteasomal degradation, counteracting FBXW7-mediated degradation of oncogene substrates, including
c-MYC and PLK1. Chip-Seq results show stabilized c-MYC in turn directly
activates PLK1 and FBXW7 transcription, constituting a feedforward regulatory loop. Co-immunoprecipitation demonstrates that FBXW7 directly
binds to PLK1 and c-MYC, facilitating their protein degradation by promoting the ubiquitination of both proteins. Furthermore, we show thatFBXW7 protein can be stabilized by various kinase inhibitors, proposing amechanism of kinase-targeted agents to treat MYC-driven MB. These results
collectively demonstrate how kinase inhibition stabilizes the tumor suppressor FBXW7 in MYC-driven MB, thus revealing an important functionof FBXW7 in suppressing MB progression.
MBRS-66. COST-EFFECTIVE METHOD TO INCORPORATE
MOLECULAR CLASSIFICATION OF MEDULLOBLASTOMA INTOA LATIN-AMERICAN CLINICAL TRIAL
Sidnei Epelman1,2, Luis Henrique Sakamoto1,2, Juliana Monte Real2,
Vijay Ramaswamy3, Gregorio Pereira2, Simone dos Santos Aguiar4, andFlavia Caldeira Queiroz2; 1Santa Marcelina Hospital / Department ofPediatric Oncology, Sao Paulo, SP, Brazil, 2Nucleo Avancado de Pesquisa
em Oncologia / Santa Marcelina Faculty, Sao Paulo, SP, Brazil, 3The
Hospital for Sick Children, Toronto, ON, Canada, 4Santa Marcelina
Hospital, Sao Paulo, SP, Brazil
BACKGROUND: It is now widely accepted that medulloblastoma actually comprises four distinct molecular subgroups, requiring specifictreatment strategies. Implementing routine subgrouping in a time andcost effective manner is a major challenge in Latin America, particularly
the development of molecular informed clinical trials. Herein we describe
the feasibility of reliable and rapid molecular stratification using a qPCR
method integrated with immunohistochemistry (IHC) and fluorescentin situ hybridization (FISH – c-myc, monosomy 6) from heterogeneously
fixed, low-quality FFPE samples across Latin America. RESULTS: Fiftyfour FFPE samples were classified according to histologic and molecular
criteria. Classic medulloblastoma was found in 53.7%, desmoplastic/extensive nodularity in 24.1%, NOS in 16,7% and anaplastic in 5,6%. IHC

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markers classified patients in three groups (WNT, SHH and non-WNT/nonSHH) in 98% of cases. PCR-based method confirmed results from IHC in
81,5%. Additionally, we were able to detect WNT activation in 2 patients,
previously classified as SHH. For both cases, the presence of monosomy
6 further confirmed WNT subgroup. Integration of these three techniques
resulted in the following frequencies: WNT (13.0%), SHH (38.9%), group
3 (9.3%), group 4 (20.3%) and non-WNT/non-SHH (18.5%). From 40 patients with clinical information available, 3-year overall survival (n=40) for
low, intermediate and high-risk groups were 100%, 60% and 20%, respectively (p<0.05), based only in molecular criteria, which confirmed the prognostic importance of this method. CONCLUSIONS: At an estimated cost of$220 per patient, we are able to implement central molecular diagnosis forthe incorporation into a prospective clinical trial protocol in Latin America.

activity differed revealing actively cycling embryonic stem (ES) cell-like andmore differentiated neuronal-like cell types. In addition, distinct histologicalcomponents of these tumours were subjected to bulk RNA sequencing following microdissection. This approach was repeated for DNA methylation
profiling in an independent paraffin embedded MBEN cohort. However,these analyses did not reveal significant transcriptomic differences or differential methylation patterns between the two histological components. In
summary, snRNA-seq identified a strongly proliferating, ES-like subset ofcells in MBEN, which might represent the driving cell population in thesemalignancies, while direct analyses of nodular and inter-nodular regions did
not reveal any significant differences. These findings suggest that both components originate from the same cell of origin but represent different cellulardevelopmental stages.

MBRS-67. ROLE OF CYCLIN DEPENDENT KINASE-9 IN MYCENHANCED MEDULLOBLASTOMA
Krishna Madhavan1, Bethany Veo1, Etienne Danis1, Ilango Balakrishnan1,
Angela Pierce1, Dong Wang1, Ahmed Abdel-Hafiz1, Natalie Serkova2,
Nathan Dahl1,3, Sujatha Venkataraman1, and Rajeev Vibhakar1,3; 1Morgan
Adams Foundation Pediatric Brain Tumor Research Program, Universityof Colorado Denver Anschutz Medical Campus, Aurora, CO, USA,
2University of Colorado Denver Anschutz Medical Campus, Aurora, CO,
USA, 3The Children’s Hospital of Colorado, Aurora, CO, USA

MBRS-69. METABOLITE PROFILING OF SHHMEDULLOBLASTOMA IDENTIFIES A SUBSET OF CHILDHOOD
TUMOURS ENRICHED FOR HIGH-RISK MOLECULAR
BIOMARKERS AND CLINICAL FEATURES
Christopher Bennett1,2, Sarah Kohe1,2, Florence Burte3, Heather Rose1,2,
Debbie Hicks3, Ed Schwalbe4, Stephen Crosier3, Lisa Storer5,
Anbarasu Lourdusamy5, Martin Wilson1, Shivaram Avula6,
Dipayan Mitra7, Robert Dineen5, Simon Bailey3,8, Daniel Williamson3,
Richard Grundy5, Steven Clifford3, and Andrew Peet1,2; 1University ofBirmingham, Birmingham, United Kingdom, 2Birmingham Children’s
Hospital, Birmingham, United Kingdom, 3Newcastle University Centre forCancer, Newcastle upon Tyne, United Kingdom, 4Northumbria University,
Newcastle upon Tyne, United Kingdom, 5University of Nottingham,
Nottingham, United Kingdom, 6Alder Hey Children’s Hospital, Liverpool,
United Kingdom, 7Newcastle Hospitals NHS Foundation Trust, Newcastle
upon Tyne, United Kingdom, 8Great North Children’s Hospital, Newcastle
upon Tyne, United Kingdom

Myc is highly expressed in group 3 medulloblastoma (Myc-MB) and influences cell growth, proliferation and oncogenesis by directly promoting theactivity of RNA polymerases (RNA Pol). Myc driven RNA Pol II activity is
mediated by Positive Transcription Elongation Factor b (pTEFb). pTEFb’s
catalytic core consists of cyclin dependent kinase-9 (CDK9) and Cyclin T,that phosphorylate and release RNA Pol II into active elongation. CDK9 isover expressed in group 3 MB suggesting that MB may be vulnerable to inhibition of CDK9 (CDK9i). The exact mechanism is not completely knownin MB. Genetic depletion of CDK9 suppressed Myc-MB cell clonogenicity invitro and tumor growth in vivo. CDK9i by two clinically relevant inhibitors,
Atuveciclib and AZD4573, suppressed clonogenicity and cell self-renewalof Myc-MB cell lines. CDK9i in Myc-MB cell lines downregulated Myc
and RNA Pol II phosphorylation at Ser2 and Ser5, and, upregulated P21.
Further, mice with orthotopic xenografts treated with CDK9 inhibitors survived significantly longer than control mice. RNA-Seq-based gene set enrichment analysis showed that CDK9i decreased c-Myc driven transcriptomic
programs and enhanced differentiation networks. ChIP-Seq for Pol2 andMyc, demonstrated that the Myc-driven aberrant transcriptional input canbe reversed via CDK9i. These findings highlight the role of CDK9 in Mycdriven pathogenesis and that its inhibition is critical to the treatment of
Myc-MB.
MBRS-68. SINGLE NUCLEUS RNA-SEQUENCING DECIPHERSINTRATUMORAL HETEROGENEITY IN MEDULLOBLASTOMAWITH EXTENSIVE NODULARITY (MBEN)
David N. Ghasemi1, Konstantin Okonechnikov1, Jan-Philipp Malm2,3,
Kati Lappalainen4, Katharina Bauer2, Michelle S. Liberio2,
Laura Giese2, Kendra K. Maass1, Marcel Kool1,5, David T.W. Jones4,
Andreas von Deimling6,7, Stefan M. Pfister1,8, Andrey Korshunov6,7, andKristian W. Pajtler1,8; 1Hopp-Children’s Cancer Center Heidelberg (KiTZ)
and Division of Pediatric Neurooncology, German Cancer Research Center(DKFZ), Heidelberg, Germany, 2Single-cell Open Lab, German Cancer
Research Center (DKFZ), Heidelberg, Germany, 3Division of Chromatin
Networks, German Cancer Research Center (DKFZ) and BioQuant,Heidelberg, Germany, 4Hopp-Children’s Cancer Center Heidelberg (KiTZ)
and Pediatric Glioma Research Group, German Cancer Research Center(DKFZ), Heidelberg, Germany, 5Princess Máxima Center for PediatricOncology, Utrecht, Netherlands, 6Department of Neuropathology, Instituteof Pathology, Heidelberg University Hospital, Heidelberg, Germany,
7Clinical Cooperation Unit Neuropathology, German Cancer ResearchCenter (DKFZ), Heidelberg, Germany, 8Department of Pediatric Oncology,
Hematology, and Immunology, University Hospital Heidelberg, Heidelberg,
Germany
Medulloblastoma (MB) with extensive nodularity (MBEN) represent a rare subtype of cerebellar tumors of infancy which comprise two
histologically distinct components, nodular reticulin-free zones and internodular reticulin-rich regions. We applied single nucleus RNA-sequencing(snRNA-seq) using the 10X Genomics and the SMARTseq V2 protocols, bulk
RNA-sequencing, DNA-methylation profiling and DNA-panel sequencing
to ten histologically confirmed MBEN specimens. All tumors were classified
as sonic hedgehog (SHH) MB based on DNA methylation. Somatic mutations within the SHH-pathway were detected in seven samples (3x SUFU,
2x PTCH1, 2x SMO) by DNA panel sequencing. The combined snRNAseq
approach resulted in data on ~30.000 single cells. Several non-malignant
cell types were identified, e.g. endothelial cells, astrocytes, and microglia.
Amongst malignant cell populations SHH-pathway activation and mitotic

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SHH medulloblastoma patients have a variable prognosis. Infants(<3–5 years at diagnosis) are associated with a good prognosis, while
disease-course in childhood is associated with specific prognostic biomarkers(MYCN amplification, TP53 mutation, LCA histology; all high-risk). Thereis an unmet need to identify prognostic subgroups of SHH tumours rapidly
in the clinical setting, to aid in real-time risk stratification and disease management. Metabolite profiling is a powerful technique for characterising tumours. High resolution magic angle spinning NMR spectroscopy (HR-MAS)
can be performed on frozen tissue samples and provides high quality metabolite information. We therefore assessed whether metabolite profiles could
identify subsets of SHH tumours with prognostic potential. Metabolite concentrations of 22 SHH tumours were acquired by HR-MAS and analysedusing unsupervised hierarchical clustering. Methylation profiling assigned
the infant and childhood SHH subtypes, and clinical and molecular features
were compared between clusters. Two clusters were observed. A significantly
higher concentration of lipids was observed in Cluster 1 (t-test, p=0.012).
Cluster 1 consisted entirely of childhood-SHH whilst Cluster 2 included
both childhood-SHH and infant-SHH subtypes. Cluster 1 was enriched forhigh-risk markers - LCA histology (3/7 v. 0/5), MYCN amplification (2/7
v. 0/5), TP53 mutations (3/7 v. 1/5) and metastatic disease - whilst having
a lower proportion of TERT mutations (0/7 v. 2/5) than Cluster 2. Thesepilot results suggest that (i) it is possible to identify childhood-SHH patients
linked to high-risk clinical and molecular biomarkers using metabolite profiles and (ii) these may be detected non-invasively in vivo using magneticresonance spectroscopy.
MBRS-70. FUNCTIONAL DEPENDENCY BETWEEN REST AND
DNMT1 IN MEDULLOBLASTOMA
Shinji Maegawa1, Tara Dobson1, Yue Lu2, Marcos Estecio2,3,
Arif Harmanci4, and Vidya Gopalakrishnan1,5; 1Department of Pediatrics,
University of Texas, MD Anderson Cancer Center, Houston, TX, USA,
2Department of Epigenetics and Molecular Carcinogenesis, University ofTexas, MD Anderson Cancer Center, Houston, TX, USA, 3Department of
Leukemia, University of Texas, MD Anderson Cancer Center, Houston,
TX, USA, 4School of Biomedical Informatics, Center for Precision
Health, University of Texas Health Science Center, Houston, TX, USA,
5Department of Molecular and Cellular Oncology, University of Texas, MD
Anderson Cancer Center, Houston, TX, USA
Medulloblastomas exhibit poor neuronal lineage specification. Expression of RE1 Silencing Transcription Factor (REST), a repressor ofneurogenesis, is aberrantly elevated in human sonic hedgehog (SHH)
medulloblastomas. Constitutive REST expression in mice (RESTTG) drives
medulloblastoma genesis and promotes tumor progression in the context of
Ptch1 haploinsufficiency (Ptch+/−), implicating it as a driver of tumorigenesis. Tumor formation in Ptch+/−/RESTTG mice showed significantly decreased latency and increased penetrance compared to that in Ptch+/− mice.
Since REST silences gene expression by chromatin remodeling, we sought
to identify cooperating epigenetic events that contributed to its oncogenic

Abstracts

activity. To this end, we performed a loss of function screen employing abar-coded library of short hairpin RNAs against epigenes, to identify candidates whose loss could create a proliferative vulnerability in the context of
REST-elevation. This screen identified DNA methyltransferase 1 (DNMT1)
as a high-priority epigenetic modifier. DNMT1 and the Ubiquitin like with
PHD and Ring finger domain 1 (UHRF1) proteins are essential for methylation of hemi-methylated DNA at the replication fork during S-phase. Their
expression is downregulated during neuronal differentiation. In human
SHH-medulloblastoma tumors, REST and UHRF1 expression are positively correlated with higher levels of both genes noted specifically in theSHH-beta subtype, and is associated with poor prognosis. The requirementfor DNMT1/UHRF1 in the context of REST elevation, was established by
RNA-Seq and Reduced Representation Bisulfite Sequencing (RRBS), which
revealed hypermethylation and downregulated expression of REST-target
genes needed for neurogenesis. Thus, DNMT1/UHRF1 is a functional andpotential therapeutic vulnerability in REST-elevated SHH medulloblastomas.
MBRS-71. ATAXIA TELANGIECTASIA AND RAD3-RELATEDPROTEIN ATTENUATES DNA DAMAGE AND IS A THERAPEUTICTARGET IN MYC-DRIVEN MEDULLOBLASTOMA
Ahmed Abdel-Hafiz1, Krishna Madhavan1, Ilango Balakrishnan1,
Angela Pierce1, Dong Wang1, Etienne Danis1, Natalie Serkova2,
Sujatha Venkataraman1, and Rajeev Vibhakar1,3; 1Morgan Adams
Foundation Pediatrics Brain Tumor Research Program, Universityof Colorado Denver Anschutz Medical Campus, Aurora, CO, USA,
2University of Colorado Denver Anschutz Medical Campus, Aurora, CO,
USA, 3The Children’s Hospital of Colorado, Aurora, CO, USAGroup 3 medulloblastoma tumors (Myc-MB), and particularly the 3γ
subtype, have the worst prognosis and show a 5-year overall survival ofless than 40%. Group 3 tumors are often accompanied by Myc amplification and have a higher rate of metastatic disease and relapse. Unfortunately, therapeutic strategies to target Mychave remained elusive. Further,
the relapse of the MB has been linked to DNA replication stress. Ataxia telangiectasia and Rad3-related protein (ATR) senses persistent DNA damage,which arises due to replication stress, and activates damage checkpoints,
thereby leading to increased cell survival. ATR is highly expressed in MB andis thought to contribute to undisturbed DNA replication to protect genomic
integrity. Yet, the exact underlying mechanisms involving ATR are still unclear in MB. Inhibition of ATR (ATRi) using the ATR inhibitor, AZD6738,
suppressed clonogenicity and cell self-renewal in Myc-MB. ATRi in Myc-MB
cell lines downregulated Chk1 and upregulated P21. ATRi also induced cell
cycle arrest and increased apoptosis in Myc-MB cell lines. Further, micewith orthotopic xenografts treated with ATR inhibitor survived significantly
longer than control mice. High-throughput drug screening showed ATRi
to be synergistic with chemotherapeutic agents including gemcitabine, cisplatin and topotecan. The treatment of Myc-MB cells with ATR inhibitorin combination with gemcitabine and with radiation increased in expression of DNA damage markers. These findings emphasize the role of ATR
in alleviating DNA replication stress and that its inhibition is critical to thetreatment of Myc-MB.
MBRS-72. MIR-212 FUNCTIONS AS A TUMOR SUPPRESSOR GENE
IN GROUP 3 MEDULLOBLASTOMA VIA TARGETING NUCLEAR
FACTOR I/B (NFIB)
Naveenkumar Perumal1, Ranjana Kanchan1, Pranita Atri1,
Ramakanth Venkata1, Ishwor Thapa1, Mohd Nasser1, Surinder Batra1, andSidharth Mahapatra1,2; 1University of Nebraska Medical Center, Omaha,
NE, USA, 2Children’s Hospital and Medical Center, Omaha, NE, USA
Medulloblastoma (MB), the most frequent malignant pediatric brain
tumor is divided into four primary subgroups, i.e. wingless-type (WNT),
sonic hedgehog (SHH), group 3, and group 4. Haploinsufficiency of chromosome 17p13.3 and c-myc amplification distinguish high-risk group 3 tumors
and are associated with rapid recurrence and early mortality. We sought
to identify the role of miR-212, which resides on chromosome 17p13.3, inthe pathophysiology of group 3 medulloblastoma. RNA expression analyses revealed dramatically reduced levels of miR-212 in group 3 tumorsand cell lines mainly through epigenetic silencing via histone modification(deacetylation). Restoring in vitro expression reduced tumor cell proliferation with decreased p-AKT and p-ERK levels, colony formation, migration and invasion in group 3 MB. Interestingly, a shift in differential c-myc
phosphorylation (from serine-62 to threonine-58) was noted, resulting in
reduced total c-myc levels, concurrent with elevated cellular apoptosis. Inturn, pro-apoptotic binding partners of c-myc, i.e. Bin-1 and P19ARF, wereupregulated in these cells. A dual luciferase assay confirmed direct targetingof miR-212 to NFIB, a nuclear transcription factor implicated in metastasis
and recurrence. Concurrently, increased expression of NFIB was confirmed
in group 3 MB tumors with poor survival in high NFIB-expressing patients.
Transient NFIB silencing in vitro reduced tumor cell proliferation, migration and invasion, and medullosphere formation along with a reduction instem cell markers (Nanog, Oct4, Sox2, CD133) and the multi-drug resistance maker, ABCG2. Taken together, these results substantiate the tumor
suppressive role of miR-212 in group 3 medulloblastomas and provide a
potential new therapeutic target, NFIB.
MBRS-73. AN EXPLORATORY ANALYSIS LOOKING AT THE
ASSOCIATION OF GERMLINE CODING MUTATIONS WITH
IMPAIRED DEVELOPMENT AND ADAPTIVE BEHAVIOR FUNCTION
IN PEDIATRIC MEDULLOBLASTOMA PATIENTS TREATED ON
HEAD START 4
Jessica L. Fleming1, Blake E. Sells1, Erica H. Bell1, Joseph P. McElroy1,
Amy Webb1, Yue Zhao1, Richard T. Graham2, Yingshi Guo1, Tom Liu1,
Cynthia Timmers3, Girish Dhall4, Stephen Sands5, Jonathan Finlay1, andArnab Chakravarti1; 1The Ohio State University, Columbus, OH, USA,
2St. Jude Children’s Research Hospital, Memphis, TN, USA, 3Medical
University of South Carolina, Charleston, SC, USA, 4Children’s Hospitalof Alabama, Birmingham, AL, USA, 5Memorial Sloan Kettering Cancer
Center, New York, NY, USA
Children with brain tumors often carry germline mutations known to contribute to tumorigenesis and treatment response; however, little is known
about how these mutations impact developmental and behavioral outcomes.
As the molecular mechanisms governing cancerous and normal tissues expand, we hypothesize that specific germline variants may impact baseline
neurocognitive function and/or treatment-induced toxicities. In this pilot
study, ten children on the Head Start 4 (HS4) clinical trial diagnosed withmedulloblastoma were assessed for baseline adaptive functioning using
the Adaptive Behavior Assessment System Third Edition (ABAS-III) andgermline whole-exome sequencing was performed. After filtering for highimpact variants, Welch’s T-tests were used to identify mutations associatedwith lower ABAS-III General Adaptive Composite (GAC) scores, reflecting
developmental and adaptive behavior delays compared with peers their age.
We found twenty genes with alterations associated with lower scores withp-values less than 0.05. Genes found to be significant included LAMC1(p=0.04) and KRTAP1-1 (p=0.045), which encode members of the laminin
and keratin family respectively and are involved in extracellular matrix adhesion. Mutations in PITX1, a known suppressor of RAS, were also associated with lower ABAS-III GAC scores (p=0.007). We hypothesize that
additional analyses of HS4 patients will reveal alterations in cell-to-cell communication and signal transduction pathways, common molecular perturbations in tumors that would likely impact central nervous system function.
Validation studies are essential to improve our understanding of the functional impact of germline variants on both tumor and regular tissue biology,
allowing for novel strategies to circumvent these delays.

PRECLINICAL MODELS/EXPERIMENTAL THERAPY/DRUG DISCOVERY
MODL-01. SAFETY IN CONCOMITANT USE OF MEK AND BRAF
INHIBITORS WITH BEVACIZUMAB
Shelby Winzent, Ashley Sabus, Molly Hemenway, Anandani Nellan, andJean Mulcahy-Levy; Univ of CO, SOM, Children’s Hospital Colorado,
Aurora, CO, USA
BACKGROUND: MEK and BRAF inhibitors are increasingly common
treatments for pediatric nervous system tumors. While effective in blocking
Ras/Raf/MEK/ERK pathway activation driving tumor progression, the side
effect profile differs from traditional cytotoxic chemotherapies. Little data
exists on overlapping toxicities with other targeted agents like bevacizumab
despite their potential combined therapeutic benefit. METHODS: A retrospective review of patients treated with MEK +/- BRAF inhibitors andbevacizumab from 2015–2019 was conducted. Data collected included
demographics, tumor type, neurofibromatosis status, treatment duration,
reason for concurrent treatment, and toxicities. RESULTS: Fifteen patients
aged 3–24 years old (median age 14 years) were identified. Diagnoses included five high-grade gliomas, four low-grade gliomas, four benign nerve
sheath tumors, and one ependymoma. Nearly half (46.7%) were positive
for neurofibromatosis type 1. Three patients were treated with a BRAF +MEK inhibitor and twelve were treated with a MEK inhibitor combinedwith bevacizumab. Duration of treatment ranged from 16–420 days (median 119 days). Reasons for concomitant therapy included progressive
disease with neurologic decline (46.7%), painful benign nerve sheath tumors(26.7%), and visual loss with optic pathway gliomas (26.7%). Toxicities
while on concurrent therapy included one episode of grade 1 left ventricular
dysfunction, one grade 1 bleeding episode, and one grade 2 wound complication. There were no episodes of hypertension, thrombosis, GI perforations,or cytopenias. CONCLUSIONS: Our preliminary experience suggests
bevacizumab in combination with MEK and BRAF inhibitors can be used

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safely across a variety of pediatric nervous tumors. Larger studies are needed
to confirm these findings.
MODL-02. TARGETING REPLICATION STRESS IN PEDIATRICBRAIN TUMORS
Sonja Krausert1,2, Sander Lambo1,2, Norman Mack1,2,
Benjamin Schwalm1,2, Stefan Pfister1,2, and Marcel Kool1,2; 1HoppChildren’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany,
2German Cancer Research Center (DKFZ), Heidelberg, Germany
Pediatric brain tumors harboring amplifications or high overexpressionof MYC-/MYCN are often associated with poor outcome. High MYC(N)
expression in these tumors leads to increased transcription, which can be inconflict with DNA replication and subsequently can cause replication stress,
R-loops and DNA damage. We hypothesize that high MYC(N) expression
makes them vulnerable to DNA damage response inhibitors (DDRi) andeven more vulnerable to combinations of DDRi and chemotherapeutics. To
test this hypothesis we performed in vitro drug experiments using Group 3
medulloblastoma (MB) and ETMR cell lines. IC50-values were evaluatedof topoisomerase inhibitor Irinotecan (SN-38) and Pamiparib (BGB-290),a brain-penetrant PARP-inhibitor, in monotherapy. All cell lines were sensitive for SN-38 and showed IC50-values in the low nM-range but PARPinhibitors were ineffective. However, a significant decrease in IC50 can beobserved when SN-38 and Pamiparib are used in combination. For in vivo
treatments, we injected NSG mice with luciferase labelled patient-derived
xenograft- (PDX-) cells of various models (MB Group 3, MB SHH, ETMR,RELA EPN), monitored tumor growth via IVIS and randomized the mice
into four groups (vehicle, BGB-290, Irinotecan and Irinotecan+Pamiparib)
when a predefined threshold of tumor growth was reached. Mice weretreated with Irinotecan (or vehicle) once per day i.p. and Pamiparib (orvehicle) twice per day per oral gavage. Treatment with Pamiparib did notshow any survival benefit, but mice treated with Irinotecan or the combination showed a clear survival benefit. Treatments are ongoing and more results will be presented at the conference.
MODL-03. ADAPTING PALBOCICLIB FOR MEDULLOBLASTOMATHERAPY BY IMPROVING DRUG DELIVERY AND ADDRESSINGRESISTANCE
Taylor Dismuke, and Timothy Gershon; University of North Carolina at
Chapel Hill, Chapel Hill, North Carolina, USA
CDK4/6 inhibition may be a promising therapy for medulloblastoma.
All medulloblastoma subgroups show D-cyclin/CDK4/RB pathway activity,
suggesting broad potential for efficacy. To address drug delivery and systemic toxicity limitations, we developed a nanoparticle formulation of CDK
4/6 inhibitor, palbociclib, in poly (2-oxazoline) micelles (POx-palbo). POxpalbo showed reduced systemic toxicity in transgenic mice engineered todevelop medulloblastoma, allowing for higher dosing. Pharmacodynamic
studies showed POx-palbo suppressed RB phosphorylation acutely and after
24hrs, the effect diminished. This inhibition produced a longer lasting suppression of SHH pathway activity, demonstrated by Gli-luc reporter tumor
mice. Importantly, POx-palbo therapy, administered daily, reduced tumor
growth and improved the survival of mice with medulloblastoma. While
POx-palbo was clearly effective as a single agent, all mice treated with POxpalbo eventually developed progressive disease, as resistant populations oftumors cells emerged. To understand the mechanisms of resistance, we compared tumors early and late in the course of therapy. We found that after
5 days of treatment, palbociclib altered cell cycle progression to produce
an extended period of S-phase and that the fractions of cell expressing thestem cell marker Olig2 were markedly increased. Based on these data, we
propose that tumors respond to the initial suppressive effect of palbociclib
by increasing the pool of Olig2+ stem cells, that these cells show discernably
different cell cycle kinetics and are resistant to CDK4/6 inhibition. Combining POx-palbo with additional therapies that target Olig2+ stem cells,
by disrupting their prolonged S-phase, or by disrupting Olig2 function, may
lead to newly effective medulloblastoma treatment.
MODL-04. MODELING CNS HGNET-BCOR PATHOGENESIS USINGNEURAL STEM CELLSSatoshi Nakata, Ming Yuan, Eric Raabe, and Charles Eberhart; Johns
Hopkins University, Baltimore, MD, USA
Central nervous system high-grade neuroepithelial tumor with BCL6corepressor alteration (CNS HGNET-BCOR) is a recently identified entity
characterized by internal tandem duplication (ITD) of BCOR, a core component of polycomb repressive complex (PRC) 1.1. BCOR-ITD exclusively
occurs within an essential binding domain, suggesting aberrant epigenetic
activities as a possible mechanism of gliomagenesis; however, the effect of
this alteration on the transcriptome and DNA methylation are poorly under-iii412

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stood. We have generated new CNS HGNET-BCOR models by lentiviraltransduction of the BCOR-ITD into human and murine neural stem cells.
In the human model, qRT-PCR and subsequent RNA-seq identified a transient derepression of PRC2-target genes comparing to an isogenic modelwith overexpression of wildtype-BCOR. A similar effect was found in clinical specimens from previous studies. In the murine-cell model, we confirmed
increased clonogenicity in soft-agar assays, and tumors developed in miceflanks. Global DNA methylation levels evaluated by ELISA were significantly lower than those of parent cells, and 177 genes were differentiallyexpressed on RNA-seq analysis comparing to BCOR-overexpressing control cells, including upregulation of known oncogenes. These results suggestthat BCOR-ITD and associated alterations in the function of PRC1.1 affectmethylation patterns in neural stem cells, driving transcriptional changes
and oncogenic transformation into CNS HGNET-BCOR. More detailed
analyses, including methylation arrays comparisons with clinical samples
and in-silico drug sensitivity testing, are being performed.
MODL-06. PRECLINICAL EFFICACY OF THE IMIPRIDONE ONC-206
AGAINST MEDULLOBLASTOMA
Anshu Malhotra1, Jingbo Liu1, Hongying Zhang1, Minhui Ma2,Jose Velazquez Vega2, Matthew Schniederjan2, Varun Prabhu3,
Joshua Allen3, and Tobey MacDonald1; 1Emory University, Atlanta, GA,
USA, 2Children’s Healthcare of Atlanta, Atlanta, GA, USA, 3Oncoceutics,
Inc, Philadelphia, PA, USA
Treatment for medulloblastoma (MB) is typically ineffective for MYC
amplified or metastatic SHH, Group 3 and 4 subgroups. Promising preclinical and clinical results have been obtained in brain cancers treated with
ONC-201, a selective antagonist of DRD2, a G-protein coupled receptor
that regulates prosurvival pathways. Herein, we report the activity of ONC201 and ONC-206, which has increased non-competitive antagonism of
DRD2, against MB. We treated three different MB cell types representativeof SHH- and Group 3-like cells, with varied levels of DRD2 expression,and consistently observed increased cell death in a dose-dependent mannerat lower doses of ONC-206 compared to ONC-201. We also evaluatedClpP as an additional drug target in MB. ClpP is a mitochondrial proteasethat has been shown to directly bind and be activated by ONC 201, and ishighly expressed at the protein level across pediatric MB, malignant glioma
and ATRT, but not normal brain. We observed that similar to ONC-201,
ONC-206 treatment of MB cells induces the restoration of mitochondrial
membrane potential to the non-proliferative state, degradation of the mitochondrial substrate SDHB, reduction in survivin and elevation in ATF4
(integrated stress response). Importantly, ONC-206 treatment induced
significant cell death of patient-derived SHH, WNT, and Group 3 tumors
ex vivo and Group 4 cells in vitro, while having no observable toxicity innormal brain. Efficacy studies of ONC-206 against MB in vivo will be reported in preparation for a planned Phase I study of ONC-206 in children
with malignant brain tumors.
MODL-08. OPTIMIZATION OF A NOVEL LOCAL DELIVERYSYSTEM FOR THE TREATMENTS OF SUPRATENTORIALEPENDYMOMA
Lisa Ruff1, Chris Parkins2, Sabrina Terranova1, Erica Nathan1,
Paraskevi Kasapidou2, Renata Lang2, Oren Scherman2, andRichard J Gilbertson1; 1Cancer Research UK Cambridge Institute,Cambridge, United Kingdom, 2Melville Laboratory, Department ofChemistry, Cambridge, United Kingdom
Ependymomas are the third most common paediatric brain tumour, incurable in up to 40% of cases. Until recently, ependymomas were regarded
as a single disease group with all patients receiving combinations of maximal surgical resection and radiotherapy. Use of chemotherapy has been
limited by the resistant nature of the tumour and poor access to tumours
behind the blood brain barrier (BBB). It is now known that ependymoma
comprises up to nine different molecular subgroups. One subgroup is characterized by a novel fusion protein, C11orf95-RELA, which acts as a potent driver of oncogenesis resulting in a poor prognosis. Here, we present
the optimization of a novel drug delivery system that uses biodegradablehydrogels to deliver drugs with potent anti-ependymoma properties into
post-resection cavity of supratentorial ependymoma. Our previous highthroughput in-vivo drug screens identified candidate ependymoma therapies with poor BBB penetrance properties. Using in-vitro delivery assays,
we have confirmed and monitored the release of these compounds fromthe hydrogel. Additionally, we have implemented this delivery system inour preclinical mouse hospital in which mice receive standard-of-care surgery and radiotherapy. The efficacy of hydrogel-based delivery of thesecompounds is now being tested preclinically, in combination with radiotherapy. Treatment for ependymoma patients have not changed in the last
30 years and therefore an effective chemotherapy could add a great survival benefit to in the clinic.

Abstracts

MODL-09. FEASIBILITY OF ACUTE SLICE CULTURE-SINGLE
CELL SEQUENCING DRUG SCREENING AS A TOOL TO SELECTTHERAPY FOR CHILDREN WITH RELAPSED BRAIN TUMORS
Bradley Gampel1, Luca Szalontay2, Wenting Zhao3, James Garvin1,
Chankrit Sethi1, Eileen Stark1, Peter Sims3, Peter Canoll1, andStergios Zacharoulis1; 1New York-Presbyterian/Columbia, New York,NY, USA, 2Memorial Sloan Kettering, New York, NY, USA, 3Columbia
University Medical Center, New York, NY, USA
Children with relapsed brain tumors are less responsive to treatment.
These children often receive therapies without having any robust predictive
method of potential benefit. Acute slice culturing(ASC) is a methodology
permitting freshly operated tumor to undergo a culturing process preserving
the tumor’s micro-environment. With the current study, we investigated thefeasibility of obtaining therapeutically meaningful data in a timely manner(3–5 days), performing direct drug testing and single cell sequencing using
ASC. Previously, we have combined ex vivo slices of intact, patient-derived
Glioblastoma tissue with single-cell RNA-seq for small-scale drug screening
and assessment of patient and cell type-specific drug responses. We generated slices from preclinical mouse glioma models and surgical specimensfrom adult Glioblastoma patients, as well as from children with relapsed
Ependymomas, Medulloblastomas, and Gliomas. We demonstrated thatthese acute slices preserved both the tumor heterogeneity and tumor microenvironment observed in single-cell RNA-seq of cells directly isolated fromtumor tissue. Testing drug responses, we then treated tissue slices from the
Glioblastoma mouse models and different patients with multiple drugs andcombinations. This technique allowed us to identify drug-induced transcriptional responses in specific subpopulations of tumor cells, patient-specificdrug sensitivities, and drug effects conserved in both mouse and human tumors. Preliminary data suggests that we can apply this procedure within
5–7 days and provide real-time drug screening/single cell sequencing ASC
results to Recurrent/ Progressive pediatric Low-Grade Gliomas, High Grade
Gliomas, Ependymomas and Medulloblastomas.
MODL-11. COMPARISON OF HUMAN & MURINE PA/PXA
CHARACTERISTICS
Alexander C. Sommerkamp1,2, Pengbo Sun1,3, Annika K. Wefers4,5,Britta Ismer1,2, Kathrin Schramm6, Andrea Wittmann1,2, Jan Gronych6,
Andrey Korshunov4,5, Andreas von Deimling4,5, Natalie Jäger1,3,
Stefan M. Pfister1,3, and David T. W. Jones1,2; 1Hopp Children’s Cancer
Center Heidelberg (KiTZ), Heidelberg, Germany, 2Pediatric Glioma
Research Group, German Cancer Consortium (DKTK), German Cancer
Research Center (DKFZ), Heidelberg, Germany, 3Division of Pediatric
Neurooncology, German Cancer Consortium (DKTK), German Cancer
Research Center (DKFZ), Heidelberg, Germany, 4Department of
Neuropathology, University Hospital Heidelberg, Heidelberg, Germany,
5Clinical Cooperation Unit Neuropathology, German Cancer Consortium(DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany,
6Division of Molecular Genetics, German Cancer Consortium (DKTK),
German Cancer Research Center (DKFZ), Heidelberg, Germany
Pediatric low-grade gliomas (pLGGs) are the most common brain tumors in children. Despite recent advances in the molecular characterization of this heterogeneous set of tumors, the separation of specific tumor
types is still not fully established. Pilocytic astrocytoma (PA; WHO grade I)
and pleomorphic xanthoastrocytoma (PXA; WHO grade II) are two pLGG
types that can be difficult to distinguish based on histology alone. Even
though their clinical course is different, they are often grouped as ‘pLGG’in clinical trials (and therefore treated similarly). Based on a cohort of 89
human pediatric tumor samples, we show that PAs and PXAs have clearly
distinct methylation and transcriptome profiles. The difference in gene expression is mainly caused by cell cycle- and development-associated genes,suggesting a key difference in the regulatory circuits involved in tumor
growth. In addition to BRAF V600E, we found NTRK fusions and a previously unknown EGFR:BRAF fusion as mutually exclusive driving events in
PXAs. Both tumor types show marked signs of immune cell infiltration, butwith significant qualitative differences, which might represent therapeutic
vulnerabilities. To pave the way for further research on PA and PXA, we developed corresponding mouse models using the virus-based RCAS system,
which allows introduction of an oncogenic driver into immunocompetentmice for molecular and preclinical research. The murine tumors do not only
histologically resemble their human counterparts but also show a similar
growth behavior. Expression analysis revealed that the murine PXAs havea stronger gene signature of proliferation and immune cell infiltration compared to PAs.
MODL-12. DEVELOPMENT OF A NOVEL IMMUNOCOMPETENT
MOUSE MODEL FOR DIFFUSE INTRINSIC PONTINE GLIOMA
Maggie Seblani1, Markella Zannikou2, Katarzyna Pituch2, Liliana Ilut2,
Oren Becher1, Irina Balyasnikova2 1Ann and Robert H. Lurie Children’s

Hospital, Chicago, IL, USA, 2Northwestern University Department of
Neurological Surgery, Chicago, IL, USA
Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor
affecting young children. Immunotherapies hold promise however thelack of immunocompetent models recreating a faithful tumor microenvironment (TME) remains a challenge for development of targeted
immunotherapeutics. We propose to generate an immunocompetent DIPG
mouse model through induced overexpression of interleukin 13 receptoralpha 2 (IL13Rα2), a tumor-associated antigen overexpressed by glioma
cells. A model with an intact TME permits comprehensive preclinical assessment of IL13Rα2-targeted immunotherapeutics. Our novel model uses theretroviral avian leucosis and sarcoma virus (RCAS) for in vivo gene delivery
leading to IL13Rα2 expression in proliferating progenitor cells. Transfected
cells expressing IL13Rα2 and PDGFB, a ligand for platelet derived growth
factor receptor, alongside induced p53 loss via the Cre-Lox system are injected in the fourth ventricle in postnatal pups. We validated the expressionof PDGFB and IL13Rα2 transgenes in vitro and in vivo and will characterize the TME through evaluation of the peripheral and tumor immunologic compartments using immunohistochemistry and flow cytometry. We
confirmed expression of transgenes via flow cytometry and western blotting. Comparison of survival dynamics in mice inoculated with PDGFB
alone with PDGFB+IL13Rα2 demonstrated that co-expression of IL13Rα2
did not significantly affect mice survival compared to the PDGFB model.
At time of application, we initiated experiments to characterize the TME.
Preliminary data demonstrate establishment of tumors within and adjacentto the brainstem and expression of target transgenes. Preclinical findings ina model recapitulating the TME may provide better insight into outcomesupon translation to clinical application.
MODL-13. GENETICALLY ENGINEERED PIG MODEL OFRHABDOID TUMOR PREDISPOSITION SYNDROME-1
Brian Na1,2, C. Dustin Rubinstein3, Jennifer J. Meudt4, Jaclyn A. Biegel5,
Alexander R. Judkins5, Brent P. Lehman3, Jamie L. Reichert4,
Jeremie Vitte1, Dhanansayan Shanmuganayagam4, and Marco Giovannini1;
1Department of Head and Neck Surgery, David Geffen School of Medicine
at UCLA and Jonsson Comprehensive Cancer Center (JCCC), University ofCalifornia Los Angeles, Los Angeles, CA, USA, 2Department of Pediatrics,
Division of Pediatric Hematology/Oncology, David Geffen School of
Medicine at UCLA, Los Angeles, CA, USA, 3Biotechnology Center,
University of Wisconsin-Madison, Madison, WI, USA, 4Biomedical &Genomic Research Group, University of Wisconsin-Madison, Madison,
WI, USA, 5Department of Pathology and Laboratory Medicine, Children’s
Hospital of Los Angeles, and Keck School of Medicine, University ofSouthern California, Los Angeles, CA, USA
Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/
RT demonstrate genomic alterations in the SMARCB1 gene. There are two
major hurdles in the development of safe and effective treatments for AT/RT:
first, the mouse models do not fully recapitulate the disease seen in patientsand their predictivity of clinical efficacy is still unproven. Second, due to asmall patient population, the ability to recruit enough patients for clinical
trials is challenging. Genetic studies have demonstrated that germline deletion of SMARCB1 exons 4 and 5 predisposes to AT/RT at an early age.
Comparison of human, swine, and mouse SMARCB1 genes show similarities in gene and protein structure, with 100% amino acid identity between
swine and human SMARCB1 isoforms. Thus, we hypothesized that germline
deletion of exons 4 and 5 will predispose heterozygote swine to AT/RT development. SMARCB1+/- founder pigs are obtained using a CRISPR/Cas9
mediated gene-editing of conventional crossbred swine embryos, followedby embryo transfer into female swine surrogates. They are evaluated forclinical criteria used to diagnose AT/RT and by MRI at 6, 12, and 24 monthsof age, followed by histopathology and molecular analysis of the tumors as
they are detected. Generating a large animal model of AT/RT would represent a breakthrough in the field from a genomic, pathophysiologic, preclinical and therapeutic perspective.
MODL-14. SMALL MOLECULE TARGETING OF ONCOGENIC FGF2FGFR SIGNALING IN BRAIN TUMORS
Karthiga Santhana Kumar1, Cyrill Brunner2, Matthias Schuster3,
Oliver Zerbe3, Michael Grotzer1, Gisbert Schneider2, andMartin Baumgartner1; 1University Children’s Hospital Zurich, Zurich,
Switzerland, 2ETH Zurich, Zurich, Switzerland, 3University of Zurich,
Zurich, Switzerland
FGF2, the ligand of FGF receptors (FGFRs), is expressed in the developing
and adult brain. FGF2-FGFR1 signaling causes the induction and maintenanceof cancer stem cells through ERK-dependent up-regulation of ZEB1 and Olig2
in glioblastoma. In SHH medulloblastoma, Olig2 triggers tumor initiation

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from GCPs, maintains quiescent stem-like cells during the disease and contributes to tumor outgrowth at recurrence. We found that FGF2-FGFR signaling
causes increased growth and tissue invasion through the FGFR adaptor protein
FRS2 in SHH and group-3 medulloblastoma 1. Thus, targeting of FGFRFRS2 signaling could abrogate brain tumor growth and spread by repressing
tumor-promoting functions that are induced by microenvironmental FGF2.
Using virtual screening combined with functional validation, we identified
protein-protein interaction inhibitors (F2i) that bind FRS2 and abrogate FGFR
signaling to the MAP-ERK pathway. Consistent with the requirement of FRS2
for pro-invasive signaling downstream of FGFR1 in medulloblastoma, F2i also
efficiently block FGF2-induced migration and invasion in medulloblastomaderived cells. Selected F2i display excellent binding kinetics with a similar Kd
as the natural ligand domain of FGFR and cause steric alterations in the targeted protein domain. On-target activity was confirmed by thermal proteome
profiling. Neither in silico screening nor empirical testing revealed significant
off-target activity of the compounds. No toxicity of F2i was observed in cellbased models with confirmed functional activity on invasion and MAPK activation. Thus, we identified novel, low molecular weight pharmacologicalprotein-protein interaction inhibitors with an excellent potential to specifically block FGFR functions relevant for brain tumor progression. 1. Santhana
Kumar et al., CellReports 23, 3798–3812.e8 (2018).
MODL-15. THE COMBINATION TREATMENT OF PARP INHIBITOR
AND TMZ, OR DAG WILL BE PROMISING TREATMENT IN SF8628
Shigeo Ohba, and Yuichi Hirose; Fujita Health University, Toyoake, Japan
Diffuse midline glioma, H3 K27M-mutant (DMG) is a newly defined
entity. The prognosis of DMG is poor. Because surgical resection is often
incomplete for DMG, radiotherapy and chemotherapy are important.
Temozolomide (TMZ) is an alkylating agent that adds a methyl group to
DNA (O6-guanine, N7-guanine, and N3-adenine). TMZ-induced cytotoxicity is mainly derived from O6-methylguanine, which is repaired by
O6-methylguanine DNA methyltransferase (MGMT). It has been reported
that most of DMG lacked MGMT promoter hypermethylation, which isthought to contribute to less effectiveness of TMZ to DMG. The purposeof the study is to explore the way to inhibit the proliferation of DMG.
A DMG cell line, SF8628, was used for the experiments. SF8628 had theexpression of MGMT and was revealed to be resistant to TMZ. Because
N7-methylguanine and N3-methyladenine are repaired via base excision
repair, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor
combined with TMZ was considered to be effective to suppress the proliferation of SF8628. As expected, PARP inhibitor enhanced TMZ-induced
cytotoxicity in SF8628. Dianhydrogalactiol (DAG) is a bifunctional DNAtargeting agent forming N7-alkylguanine and inter-strand DNA crosslinks.
DAG reduced the clonogenicity of SF8628. Moreover, inhibition of homologous recombination enhanced the DAG-induced cytotoxicity in SF8629. The
combination treatment of PARP inhibitor and TMZ, or DAG were revealed
to be promising treatments in SF8628.
MODL-16. ABEMACICLIB, A SELECTIVE CDK4/6 INHIBITOR,RESTRICTS GROWTH OF PEDIATRIC GLIAL-LINEAGE TUMORS IN
VITRO AND IN VIVO
Muh-Lii Liang1, Tsung-Han Hsieh2, and Tai-Tong Wong3; 1Department of
Neurosurgery, Mackay Memorial Hospital, Taipei, Taiwan, 2Joint Biobank,
Office of Human Research, Taipei Medical University, Taipei, Taiwan,
3Department of Neurosurgery, Taipei Medical University Hospital, Taipei,
TaiwanBACKGROUND: Glial-lineage tumors constitute a heterogeneous groupof neoplasms, comprising gliomas, oligodendrogliomas, and ependymomas,
which account for 40%–50% of all pediatric central nervous system tumors. Advances in modern neuro-oncological therapeutics are aimed at
improving neoadjuvant chemotherapy and deferring radiotherapy becauseradiation exposure may cause long-term side effects on the developing
brain in young children. Despite aggressive treatment, more than half thehigh-grade gliomas (pHGGs) and one-third of ependymomas exhibit recurrence within 2 years of initial treatment. METHODS: By using integrated bioinformatics and through experimental validation, we found thatat least one gene among CCND1, CDK4, and CDK6 was overexpressed in
pHGGs and ependymomas. RESULTS: The use of abemaciclib, a highly selective CDK4/6 inhibitor, effectively inhibited cell proliferation and reduced
the expression of cell cycle–related and DNA repair–related gene expression, which was determined through RNA-seq analysis. The efficiency of
abemaciclib was validated in vitro in pHGGs and ependymoma cells andin vivo by using subcutaneously implanted ependymoma cells from patientderived xenograft (PDX) in mouse models. Abemaciclib demonstrated the
suppression of RB phosphorylation, downstream target genes of E2F, G2M
checkpoint, and DNA repair, resulting in tumor suppression. CONCLUSION: Abemaciclib showed encouraging results in preclinical pediatricglial-lineage tumors models and represented a potential therapeutic strategy
for treating challenging tumors in children.

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MODL-17. SHP2 INHIBITORS SHOW ACTIVITY AGAINSTNF1-DEFICIENT GLIOMAS AND ENHANCE MAPK PATHWAYINHIBITION IN BRAF-V600E MUTANT GLIOMAS
Daniel Muldoon1, Guisheng Zhao1, Carly Batt1, Mallika Singh2, andTheodore Nicolaides1; 1New York University Langone Health, New York,NY, USA, 2Revolution Medicines, Inc., Redwood City, CA, USA
INTRODUCTION: Activation of the RAS-MAPK signaling cascade is common in pediatric gliomas. Based on the role of SHP2 in RAS
pathway signaling, we hypothesized that NF1-deficient pediatric glioma
models would respond to SHP2 inhibitor monotherapy whereas BRAFV600E gliomas would not. However, we postulated that the latter would
exhibit increased sensitivity to a BRAF inhibitor (BRAFi) in combination
with SHP2i. Here we demonstrate that the SHP2 inhibitors SHP099 and
RMC-4550 (SHP2i) show significant single-agent activity in vitro against
NF1-deficient glioma cells and that the combination of RMC-4550 with
BRAFi shows increased activity in BRAF-V600E glioma cells relative tothe single-agents. METHODS: Using a panel of NF1 mutant/deficient and
BRAF-V600E mutant glioma cell lines we examined effects on cell viability
and protein expression levels of total and phosphorylated MEK, ERK, andAKT. RESULTS: LN229 and U87 NF1-deficient glioma cells are sensitive
to SHP2i alone but not A375 cells (melanoma, BRAF-V600E). Additionally,
we show that in multiple BRAF-V600E glioma cell lines BRAFi sensitivity
increases when combined with a SHP2i. Immunoblots show decreased expression of pERK and pMEK in LN229 cells following SHP2i exposure,while A375 cells maintain MAPK pathway signaling. A sustained decreasein the expression of pERK after 24 hours was observed in BRAF-V600E
glioma cells with BRAFi in combination with SHP2i, consistent with reliefof feedback inhibition. In vivo studies using orthotopic xenograft models
are underway. CONCLUSION: SHP2i shows preclinical activity in vitro
against NF1-deficient pediatric glioma cell lines as a single-agent and against
BRAF-V600E gliomas in combination with BRAFi.
MODL-19. DIPG HARBOUR ALTERATIONS TARGETABLE BY
MEK INHIBITORS, WITH ACQUIRED RESISTANCE MECHANISMSOVERCOME BY COMBINATORIAL UP- OR DOWN-STREAMINHIBITION
Elisa Izquierdo1, Diana Carvalho1, Alan Mackay1, Sara Temelso1,
Jessica KR Boult1, Valeria Molinari1, Mark Stubbs1, Sarita Depani2,
Patricia O’Hare2, Simon P Robinson1, Michael Hubank3,
Darren Hargrave2, and Chris Jones1; 1The Institute of Cancer Research,
London, United Kingdom, 2Great Ormond Street Hospital, London, United
Kingdom, 3The Royal Marsden Hospital, London, United Kingdom
The survival of children with DIPG remains dismal, with new treatments desperately needed. In the era of precision medicine, targeted therapies represent an exciting treatment opportunity, yet resistance can rapidly
emerge, playing an important role in treatment failure. In a prospective
biopsy-stratified clinical trial (BIOMEDE), we combined detailed molecularprofiling (methylation BeadArray, exome, RNAseq, phospho-proteomics)
linked to drug screening in newly-established patient-derived models of
DIPG in vitro and in vivo. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib (GI50 16-50nM) in samples whichharboured genetic alterations targeting the MAPK pathway, including thenon-canonical BRAF_G469V mutation, and those affecting PIK3R1. Treatment of PDX models and the patient with trametinib at relapse, however,failed to elicit a significant response. We generated trametinib-resistantclones (62-188-fold, GI50 2.4–5.2µM) in the BRAF_G469V model throughcontinuous drug exposure, and identified acquired mutations in MEK1/2(MEK1_K57N, MEK1_I141S and MEK2_I115N) with sustained pathway
up-regulation. These cells showed the hallmarks of mesenchymal transition, with overexpression of key proteins involved in invasion/migration,such as collagen-family proteins, integrins, MMPs and AHNAK2, amongst
others. Resistant clones were conversely sensitive to the upstream receptor
tyrosine kinase inhibitor dasatinib (GI50 36-93nM), and combinations oftrametinib with dasatinib and the downstream ERK inhibitor ulixertinib
showed synergistic effects in vitro. These data highlight the MAPK pathway
as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatments likely to be required
for meaningful clinical translation.
MODL-20. A BIOBANK OF ~100 PATIENT-DERIVED MODELSREPRESENTING BIOLOGICAL HETEROGENEITY AND DISTINCTTHERAPEUTIC DEPENDENCIES IN PAEDIATRIC HIGH GRADE
GLIOMA AND DIPG
Diana Carvalho1, Alan Mackay1, Sara Temelso1, Elisa Izquierdo1,
Elisabet Potente Fernandez1, Rebecca Rogers1, Jessica Boult1,
Janat Fazal Salom1, Natalie Simon1, Matthew Clarke1,
Valeria Molinari1, Ketty Kessler1, Anna Burford1, Lynn Bjerke1,
Mariama Fofana1, Michael Hubank1,2, Jane Pears3, Andrew Moore4,
Angel Montero Carcaboso5, Lynley Marshall2, Fernando Carceller2,

Abstracts

Simon Robinson1, Darren Hargrave6, Maria Vinci7, and Chris Jones1;
1Institute of Cancer Research, London, United Kingdom, 2Royal Marsden
Hospital, London, United Kingdom, 3Our Lady’s Children’s Hospital,
Dublin, Ireland, 4The University of Queensland, Brisbane, Australia,
5Institut de Recerca Sant Joan de Deu, Barcelona, Spain, 6Great OrmondStreet Hospital, London, United Kingdom, 7Bambino Gesù Children’s
Hospital, Rome, Italy
Paediatric high-grade glioma comprise multiple biological and clinicalsubgroups, the majority of which urgently require novel therapies. Patientderived models represent useful tools for mechanistic and preclinical investigations based upon their retention of key genetic/epigenetic features andtheir amenability to high-throughput approaches. We have collected ~100in vitro models representing multiple subtypes (H3.3/H3.2/H3.1K27M,
H3.3G34R/V, BRAF, MYCN_amp, NTRK_fusion, hypermutator, others)
established under 2D (laminin) and/or 3D (neurosphere) conditions, credentialed by phenotypic (growth, invasion/migration) and molecular (methylation array, DNA sequencing, RNAseq) comparison to the original tumour
sample. These were derived from patients at our local hospitals (n=29), aspart of national co-clinical trials (n=19), from international collaborating
centres (n=11), or shared directly by research groups worldwide (n=45).
These have variously been subjected to pharmacological (approved/experimental drug libraries) and/or genetic screening (whole-genome CRISPR)
to identify specific biological dependencies. Many have been established asorthotopic xenografts in vivo (PDX), with detailed pathological and radiological correlations with the clinical disease, and with tumorigenic latencies
ranging from 48–435 days. This resource has allowed us to identify genotypespecific synthetic lethalities and responses to targeted inhibitors, including
olaparib (PARP) with ATRX, nutlin-3 (MDM2) with PPM1D, AZD1775(WEE1) with TP53, and CYC065 (CDK9) with MYCN-amplification. Combinatorial screening highlighted synergies in ACVR1-mutant DIPG between
novel ALK2 inhibitors and ONC201 (DRD2). Rapid screening allows for
feedback of drug sensitivities to treating clinicians at relapse, whilst mechanistic underpinning of these interactions and use of the models to identify
specific mediators of resistance will allow for rational future trial design.
MODL-21. INTEGRATIVE APPROACHES IN FUNCTIONALGENOMICS TO IDENTIFY GENETIC DEPENDENCIES INPEDIATRIC BRAIN CANCER
Claire Sun, Caroline Drinkwater, Dhanya Sooraj, Gabrielle Bradshaw,
Claire Shi, Dasun Fernando, Sarah Parackal, Daniel Gough, Jason Cain,and Ron Firestein; Hudson Institute of Medical Research, Clayton, VIC,
Australia
The precise decoding of human genomes facilitated by the advancements
in next-generation sequencing has led to a better understanding of genetic underpinnings of pediatric brain cancers. Indeed, it is now evident
that tumours of the same type harbour distinct driving mutations and molecular aberrations that can result in different prognosis and treatment
outcomes. The profounder insight into the the identity, amount and typesof molecular aberrations has paved the way for the advent of targeted
therapies in precision medicine. Nevertheless, less than 10% of pediatriccancer patients harbour actionable mutations. Strictly limited therapeutic
options that are firstly available for brain cancers and secondly acceptable for children’s development further impede the breakthrough in thesurvival rate in pediatric brain cancers. This underscores a desperate needto delve beyond genomic sequencing to identify biomarker coupled therapies that not only featured with treatment efficacy in the central nervous
system but also acceptable side effects for children. The Hudson-Monash
Paediatric Precision Medicine (HMPPM) Program focuses on utilising
genetic profiles of patients’ tumour models to identify new therapeutictargets and repurpose existing ones using high-throughput functional genomics screens (2220 drugs and CRISPR screen of 300 oncogenic genes).
Using a large compendium of over sixty patient derived paediatric brain
cancer models, we provide proof-of-concept data that shows an integrative pipeline for functional genomics with multi-omics datasets to performgenotype-phenotype correlations and, therefore, identify genetic dependencies. Herein, using several examples in ATRT, DIPG and HGG, we show
how functional interrogations can better define molecular subclassificationof tumours and identify unique vulnerabilities.
MODL-22. DEVELOPING A REAL-TIME PERSONALIZED DRUGTESTING PLATFORM FOR PEDIATRIC CNS CANCERS
Sandra Laternser1, Chiara Cianciolo Cosentino2, Justyna M Przystal1,
Susanne Dettwiler3, Elisabeth Jane Rushing3, Nicolas U Gerber4,
Ana Guerreiro Stücklin4, Rachna Prasad2, Michael Grotzer4,
Niklaus Krayenbühl4, Sabine Müller2,4, and Javad Nazarian2,4; 1University
Children’s Hospital Zurich, DRIz, Oncology Department, Zurich, ZH,
Switzerland, 2University Children’s Hospital Zurich, DRIz, Oncology
Department, Zurich, ZH, Switzerland, 3University Hospital Zurich,Institute of Pathology and Molecular Pathology, Zurich, ZH, Switzerland,
4University Children’s Hospital Zurich, Zurich, ZH, Switzerland
INTRODUCTION: The relatively small size of biopsied CNS tumors haspresented a historical challenge for real-time drug screens. Moreover, in vivo
assessment of drug response does not often benefit patients with aggressive
gliomas given the relatively long time (>8 months) of tumor engraftment in
the classic mouse PDX models. Here, we aimed to develop an innovative
real-time in vivo and in vitro drug screening platform capable of analyzing
a minimal number (<1E6) of cells obtained at biopsy. METHODS: Existing
primary cells were used to test 6 different culture platforms. The top platform was selected and used to expand tumor cells obtained of DMG biopsy.
Tumor cells were validated using the minION sequencing platform. Single
and combination drug (n=7) screens were performed. Effective drugs were
further evaluated in zebrafish PDX and non-tumor bearing models to assess efficacy and toxicity, respectively. RESULTS: A total of 8 biopsies wereobtained. Successful cell expansion was achieved in 6/8 (75%) and a limited
drug screen in 3/6 (50%) of cases. Single and combination drug (n=7) assays identified responder and non-responders to candidate drugs. Systemic
toxicity of effective drugs was tested in non-tumor bearing zebrafish. Tumor
cells were engrafted in zebrafish providing the opportunity for an in vivo
screen. The entire process was completed within 21 days on average. CONCLUSIONS: A novel platform was developed for rapid in vitro and in vivo
drug screens of tumor cells obtained at biopsy. This platform will provide
the opportunity to establish personalized therapy for heterogeneous cancers
including DMGs.
MODL-23. DNA METHYLATION AND COPY NUMBER VARIATIONPROFILE FOR CHARACTERIZATION OF PEDIATRIC BRAIN
TUMOR PRIMARY CELL LINES
Lucia Pedace1, Maria Vinci1, Simone Pizzi1, Giulia Pericoli1,
Giuseppina Catanzaro2, Luana Abballe2, Francesca Del Bufalo1,
Ignazio Caruana1, Francesca Diomedi Camassei1, Sabrina Rossi1,
Felice Giangaspero2, Elisabetta Ferretti2, Andrea Ciolfi1, Marco Tartaglia1,
Franco Locatelli1, Angela Mastronuzzi1, and Evelina Miele1; 1BambinoGesù Children’s Hospital, Rome, Italy, 2University of Rome Sapienza,
Rome, Italy
BACKGROUND: In vitro models of pediatric brain tumors (pBT) are
instrumental for both understanding the oncogenic molecular mechanisms and identifying/testing new therapeutic strategies. DNA methylation(DM) is a stable epigenetic modification 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 included 36
pBT tissues from different histology (13 LGG, 9 DIPG, 9 HGG, 3 MB, and2 Ependymomas), paired to their derived primary cultures. Cultures were
established in two-dimensional (2D) or three-dimensional (3D) condition, as
stem-cell or in serum-supplemented medium. For 9 cultures, both early (P2P3) and long-term passages (>P4) were considered. Samples were analyzed
for DM and CNV profiles using Illumina EPIC arrays and data comparedwith those of the brain tumor classifier. RESULTS: At early passages all cells
retained the same DM and genetic patterns of original tumors, with no differences related to 2D/3D methods or presence of serum in media. Primarycell lines analyzed at > P4 and cultured in serum diverged from the primarytumor. CONCLUSIONS: DM profiles and CNV are useful tools to detect
the recapitulation of pBT-derived primary cell-lines from the original tumor.
Whatever subgroups tested, results suggest that in vitro models should be
passaged as little as possible to retain the epigenetic and genetic alterationsof the tumors and thus to be considered relevant for basic and translational
biology. Ongoing experiments are aimed to determine how stable DM and
CNV are in other conditions/tumor subgroups.
MODL-24. AN ORGANOTYPIC CHUNK CULTURE TECHNIQUETO STUDY DISEASE MECHANISM AND DEVELOP TARGETEDTHERAPEUTICS FOR PEDIATRIC ADAMANTINOMATOUS
CRANIOPHARYNGIOMA
Trinka Vijmasi1, Eric Prince1, Astrid Hengartner1, Susan Staulcup2,
Andrea Griesinger3, Andrew Donson3, Ahmed Gilani4, Nicholas Foreman3,
and Todd Hankinson2; 1Department of Neurosurgery, University ofColorado Anschutz Medical Campus, Aurora, CO, USA, 2Departmentof Neurosurgery, Children’s Hospital Colorado, Aurora, CO, USA,
3Deparment of Pediatrics, Children’s Hospital Colorado, Aurora, CO, USA,
4Department of Pathology, Children’s Hospital Colorado, Aurora, CO, USA
BACKGROUND: Advances in the treatment of Adamantinomatous
Craniopharyngioma (ACP) face challenges with translation to clinical study
due to the absence of robust culture models of the disease. We developed atechnique for culturing human ACP tissue in an organotypic chunk culture
format that retains the tumor microenvironment for a duration sufficientto evaluate potential targeted therapeutics. METHODS: Intraoperatively

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collected tumor tissue from pediatric ACP was cut into volumes of approximately 3 mm3 and rested over a semi-permeable insert placed in the wellsof a 6-well plate. Specimens were cultured in (1) Control media, media containing (2) Tocilizumab, (3) Trametinib, and (4) combination of Tocilizumab
and Trametinib, for 24 and 96 hours. Specimens were harvested for paraffin embedding, protein and gene expression assays. Supernatants werecollected to assay secreted components. Paraffin embedded specimens weresectioned and stained for H&E, Pan-CK, Beta-Catenin, cleaved Caspase-3,
Ki-67, and Phospho-ERK. RESULTS: H&E staining revealed characteristic
histologic features of ACP with epithelial cells with palisading nuclei, wet
keratin and ghost cells. Tumor sections were markedly positive for epithelial
cell markers, Pan-CK and Beta-Catenin. Ki-67 and cleaved Caspase-3 wererestricted to a small fraction of cells, indicating low index of proliferation
and apoptosis under the culture conditions. The response to drug treatments shall be determined using gene expression assays and evaluation of
the secreted components. CONCLUSION: The organotypic chunk culture
technique appears to maintain the viability and integrity of ACP tumors forseveral days and may serve as an appropriate model for pre-clinical studies
to develop targeted therapeutics for pediatric ACP.
MODL-25. REPLICATION REPAIR DEFICIENT MOUSE MODELSPROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS,MECHANISMS OF IMMUNE EVASION, AND COMBINATORIALIMMUNOTHERAPY
Melissa Galati1, Li Li1, Sumedha Sudhaman1, Tatiana Lipman1,
Lucie Stengs1, Dana Elshaer1, Taylor Bridge1, Dar’ya Semenova1,
Melissa Edwards1, Karl Hodel2, Victoria J. Forster1, Nuno M. Nunes1,
Alberto Martin3, Eric Bouffet4, Zachary Pursell2, Cynthia Hawkins1,
and Uri Tabori1,4; 1The Arthur and Sonia Labatt Brain Tumour
Research Centre, The Hospital for Sick Children, Toronto, ON, Canada,
2Department of Biochemistry, Tulane University, New Orleans, LA, USA,
3Department of Immunology, University of Toronto, Toronto, ON, Canada,
4Division of Hematology and Oncology, The Hospital for Sick Children,
Toronto, ON, Canada
Replication repair deficiency (RRD) is the leading cause of hypermutant
brain tumours in children. RRD is caused by defects in one of four mismatch
repair (MMR) genes and mutations in POLE or POLD1. Such tumours
are resistant to common therapeutic agents and animal models are needed
to study RRD in vivo and test novel therapies like immune checkpoint inhibitors (ICIs). To model RRD brain tumours specifically, we engineered a
Pole mutant mouse model harbouring the S459F mutation (PoleS459F). We
combined PoleS459F mice with conditional Msh2 knockout (Msh2LoxP)and Nestin-cre mice. All Nestin-cre+Msh2LoxP/LoxPPoleS459F/+ mice
rapidly succumbed to posterior fossa brain tumours between 8.6 and 12.4
weeks. Importantly, tumours exhibited hallmark “ultrahypermutation”(~350 mutations/Mb) and the corresponding signatures characteristic of
human combined MMR and POLE-proofreading glioblastoma. Interestingly, Nestin-cre+Msh2LoxP/LoxPPoleS459F/S459F mice failed toestablish normal cerebella, suggesting such mutational loads may not support normal brain development. Furthermore, OLIG2-cre+Msh2LoxP/
LoxPPoleS459F/+ mice failed to develop tumors. Tumors transplanted intosyngeneic vs immunocompromised animals egrafted well orthotopically inthe mouse hindbrain but significantly less efficiently when engrafted subcutaneously. Furthermore, immunocompromised and subcutaneous tumors
revealed striking differences in mutational burden and clonal architecture,suggestive of nonautonomous immunoediting. Finally, anti-PD1 was sufficient to treat subcutaneously engrafted tumors in immunocompetent animals. This first mouse model of immunocompetent, hypermutant brain
tumors can be used to uncover unique characteristics of RRD tumour evolution and allow for immune based therapeutic preclinical testing. Experiments to assess combinational ICIs and other therapeutic interventions inorthotopically transplanted tumors will also be presented.
MODL-26. CHILDREN’S BRAIN TUMOR NETWORK:ACCELERATING RESEARCH THROUGH COLLABORATION AND
OPEN-SCIENCE
Jena Lilly1, Jennifer Mason1, Elizabeth Appert1, Allison Heath1,
Yuankun Zhu1, Bo Zhang1, Mateusz Koptyra1, Mariarita Santi1,
Ian Pollack2, Stewart Goldman3, Sarah Leary4, Anna Buccoliero5,
Mirko Scagnet5, David Haussler6, Derek Hanson7, Jiangguo Zhang8,
Weiqing Wan9, Chunde Li9, Ron Firestein10, Jason Cain10,
Joanna Phillips11, Nalin Gupta11, Sabine Mueller11, Gerald Grant12,
Michelle Monje-Deisseroth12, Sonia Partap12, Jeffrey Greenfield13,
Brian Rood14, Javad Nazarian14, Eric Raabe15, Eric Jackson15,
Stacie Stapleton16, Robert Lober17, David Kram18, Phillip Storm1,
Rishi Lulla19, Michael Prados11, Adam Resnick1, and Angela Waanders3;
1Children’s Hospital of Philadelphia, Philadelphia, PA, USA, 2UPMC
Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA, 3Ann and Robertiii416

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H Lurie Children’s Hospital, Chicago, IL, USA, 4Seattle Children’s
Hospital, Seattle, WA, USA, 5Meyer Children’s Hospital, Florence, Italy,
6Genomic Institute, UCSC, Santa Cruz, CA, USA, 7Joseph M, SanzariChildren’s Hospital at Hackensack University Medical, Hackensack, NJ,
USA, 8Genebank, Beijing Genomics Institute, Shenzhen, China, 9Beijing
Tiantan Hospital Neurosurgery Center, Beijing, China, 10Hudson Instituteof Medical Research, Melbourne, Australia, 11University of California San
Francisco Benioff Children’s Hospital, San Francisco, CA, USA, 12Stanford
University/Lucile Packard Children’s Hospital, Palo Alto, CA, USA,
13Pediatric Brain and Spine Center, Weill Cornell Medicine, New York, NY,
USA, 14Children’s National Health System, Washington DC, USA, 15Johns
Hopkins, Baltimore, MD, USA, 16Johns Hopkins All Children’s Hospital,
St Petersburg, FL, USA, 17Dayton Children’s Hospital, Dayton, OH, USA,
18Wake Forest Baptist Health- Brenner Children’s Hospital, Winston-Salem,
NC, USA, 19Hasbro Children’s Hospital, Providence, RI, USA
The Children’s Brain Tumor Network (formerly known as Children’s
Brain Tumor Consortium- CBTTC) is a global organization pioneering amodel of open-science medical research to improve treatment and discovercures. Started in 2011, our objective was to utilize a regulatory, agreement,
and governance architecture to remove existing research barriers that slowed
down the pace of research and collaboration. Our network now includes 17
institutions working together to empower research. As of December 2019,
over 3,600 subjects have been enrolled resulting in collection of over 45,000
specimens. Clinical data collection is longitudinal and includes medical
history, diagnosis, treatment, pathology slides and reports, radiology imaging and reports, and outcome data. The tissue is collected flash-frozen, infreezing media, and fresh for the generation of pre-clinical models including
cell lines. Blood is collected from the subject, with blood or saliva collectedfrom the parents for germline comparison. Additionally, the Children’s Brain
Tumor Network- Pediatric Brain Tumor Atlas has generated 952 WGS andRNAseq, 221 proteomics, with annotated clinical data. All of this data, bothgenerated raw and processed data, has been made available broadly to thescientific community via cloud-based platforms, including the Gabriella
Miller Kids First Data Resource Portal, Cavatica, and PedCbioportal. As ofJanuary 2020, we have 45 approved biospecimen requests and 80 genomic/
molecular data requests. In summary, the Children’s Brain Tumor Network’s
goal is to accelerate the pace of discovery by providing resources and expanding the network of scientists working towards a cure.
MODL-27. MEK INHIBITION WITH TRAMETINIB SLOWSPROGRESSION OF MEDULLOBLASTOMA AND ATYPICALTERATOID RHABDOID TUMOR IN ORTHOTOPIC XENOGRAFTMURINE MODEL
Sujata Mushrif1, Long Hung2, Sakunthala Muthugounder2, andShahab Asgharzadeh2; 1SRCC Children’s Hospital-Managed by Narayana
Health, Mumbai, Maharashtra, India, 2Children’s Hospital of Los Angeles,
Los Angeles, CA, USA
BACKGROUND: Combination of surgery, chemotherapy, autologoustransplantation, irradiation constitutes treatment of CNS embryonal-celltumors (Medulloblastoma-MBL, atypical teratoid rhabdoid tumor-AT/RT).
Targeted agents to improve survival and decrease side effects are necessary.
We hypothesize that inhibiting MAPK pathway in MBL and AT/RT may
be beneficial. METHODS: IHC(pERK) was performed on clinical tumors.
Trametinib(MEK inhibitor) was tested on MBL(UW228, D283, DAOY);
AT/RT(CHLA06, BT12) cell-lines. Luminescent cell-viability assay wasdone(72 hrs) and with crystal violet assay(10 days). Orthotopic, xenograftsof MBL and AT/RT were made in NOD-Scid gamma mice. Mice were given
Trametinib daily by gavage for 6 weeks(0.6mg/kg b.w). Western blot was
performed on protein from cell lines and tumor xenografts incubated with
Trametinib. H&E staining was done on murine tumors. RESULTS: AT/
RT(48%) and MBL(57%); Anaplastic(50%), Desmoplastic(40%),Classic(38%); Group 4(66%), Group 3(20%), SHH(55%), WNT(0%)
showed presence of pERK(clinical samples). In-vitro, Trametinib completely
abrogated the phosphorylation of ERK at 125nM in AT/RT and 50nM in
MBL. The IC50 after 10 days exposure was 10nM for AT/RT and 35nM for
MBL. Trametinib treated mice showed delay in tumor growth and significant survival advantage in both AT/RT (p=0.00336) and MBL (p=0.0069).
Murine tumors showed decreased proliferation (H&E). CONCLUSION: Trametinib decreased cell proliferation, increased survival in our
murine model in both MBL and AT/RT. Pre-clinical results indicate benefits
in subgroups of AT/RT and MBL with active MAPK pathway.
MODL-28. IMMUNE PRIMING WITH INTERFERON-Γ COMBINEDWITH EPIGENETIC MODULATION IN PEDIATRIC BRAIN TUMORS
Erin Crotty1,2, Shelli Morris2, Ken Brasel2, Emily Girard2, Alyssa Noll2,3,Andrew Mhyre2, and James Olson1,2; 1Division of Pediatric Hematology/
Oncology, Department of Pediatrics, University of Washington, Seattle

Abstracts

Children’s Hospital, Seattle, WA, USA, 2Fred Hutchinson Cancer ResearchCenter, Seattle, WA, USA, 3University of Washington, Seattle, WA, USA
Systemic interferon-γ (IFNγ) has been shown to induce major histocompatibility complex class I (MHC-I) and T cell infiltration in solid tumorsin adult patients, demonstrating a potential strategy to abrogate tumorintrinsic mechanisms of immune escape. Pediatric brain tumors (PBT)
may be particularly sensitive to this approach but have a paucity of immunogenic tumor antigens for presentation on MHC-I. Decitabine andother DNA methyltransferase (DNMT) inhibitors promote expression of
oncofetal antigens and endogenous immune responses through epigenetic
alterations. We tested the convergence of these immune priming mechanisms using a novel combination of IFNγ and decitabine across a spectrumof PBT. Primary human cell lines (Med-411FH, PBT-05FH, GBM-511FH,
CCHMC-GBM-1, CCHMC-GBM-4, ATRT-310FH) and murine transgenic
models were treated with IFNγ alone or in combination with decitabineand evaluated expression of cell surface MHC-I and PD-L1, interferon
response genes (ISGs), and oncofetal antigens. PBT showed exquisite sensitivity to IFNγ, increasing expression of MHC-1/PD-L1 along with ISGs
(TAP1, MX1, IRF1). Decitabine enhanced IFNγ-induced gene expression of
oncofetal antigens NY-ESO-1 and MAGE-A1. In a medulloblastoma flanktumor model, MHC-I was increased by 40-fold following intraperitoneal
IFNγ treatment (p=0.01), with a 3-fold increase in PD-L1 (p=0.005) compared to untreated controls. Effect on CD8+ T cell killing and validationin humanized models is ongoing. Immune priming of PBT with IFNγ is
feasible and results in more substantial MHC-I upregulation compared tohypomethylating agents alone. These results provide a strong rationale forpriming prior to checkpoint inhibition as a compelling therapeutic strategy
in immunologically-quiescent PBT.
MODL-29. EVALUATING TUMOR-IMMUNE INTERACTIONS IN
MOUSE MODELS OF DIFFUSE INTRINSIC PONTINE GLIOMA
Robin Furnish1, Heather Bear1, Xin Wei1, and Timothy Phoenix1,2;
1University Of Cincinnati, Cincinnati, OH, USA, 2Cincinnati Children’s
Medical Center, Cincinnati, OH, USA
BACKGROUND: While adult gliomas show some level of immune cell
infiltration, diffuse intrinsic pontine glioma (DIPG) is characterized ashaving an “immune cold” state. We have developed new immunocompetent mouse models of DIPG. These models faithfully recapitulate the pathological hallmarks of DIPG and provides a unique platform to investigate
immune modulatory therapies and potential therapeutic benefits of checkpoint inhibitor combination therapies. METHODS: To evaluate the effectsof CDK4/6 inhibition (CDK4/6i) on cell proliferation and immune interactions we performed a series of in vitro and in vivo studies using DIPG
mouse models. In vitro assays included dose response curves, transcriptional profiling, and MHC1 expression. In vivo preclinical studies treatedmouse models with CDK4/6i with or without immune check-point inhibitors (ICI). We also examined other candidate immune modulatory therapies
in vitro. RESULTS: CDK4/6i (Abemeciclib) reduced proliferation of DIPG
cells derived from mouse models, and displayed a modest increase in immune activation by MHC1 expression and transcriptome. Pilot in vivo preclinical studies did not show any significant changes in DIPG proliferation
or immune changes with CDK4/6i treatment, ICI treatment, or the combination of CDK4/6i + ICI. In vitro testing of other immune-modulatory
drugs identified additional candidates that can be tested in vivo. CONCLUSION: CDK4/6i displayed in vitro action, but lacked efficacy in DIPG
mouse models in vivo. Further use of spontaneous DIPG mouse models will
provide a rapid preclinical platform to evaluate in vivo tumor-immune interactions, drug efficacy, and mechanisms of resistance.
MODL-30. DISSECTING THE ROLE OF MULTI-CILIOGENESISNETWORK IN CHOROID PLEXUS TUMOR
Haotian Zhao, and Tasneem Zahran; New York Institute of Technology,
Old Westbury, New York, USA
The choroid plexus (CP) in brain ventricles consists of a fibro-vascularcore encapsulated by epithelial cells that possess clusters of primary cilia oncell surface. CP tumors are rare primary brain neoplasms that most commonly occur in young children. Compared to the benign CP papilloma,
choroid plexus carcinoma (CPC) is poorly understood and highly lethal
with few treatments available. Molecular, cytogenetics and genomics studies
uncovered complex alterations in CPC including frequent chromosomal loss
and recurrent focal aberrations, whereas abnormal NOTCH signaling is observed in many CP tumors. We showed that activation of both NOTCH and
Sonic Hedgehog (SHH) signaling in mice drives the formation of aggressive CP tumor. Molecular and histology analyses demonstrated that thesemurine CP tumors closely resemble their human counterparts, which also
display aberrant SHH and NOTCH signaling, suggesting they may represent potential therapeutic avenues. Indeed, treatment with vismodegib, an
FDA-approved SHH pathway inhibitor, suppresses CP tumor growth. Un-

like multi-ciliated CP epithelial cells, tumor cells in these animal models arecharacterized by a solitary primary cilium. Though key genes of the multiciliogenesis circuit driven by Geminin coiled-coil domain-containing protein
1 (GEMC1) are expressed in CP epithelium, GEMC1-dependent transcriptional program is suppressed in NOTCH-driven CP tumors. Importantly,
CPCs in humans consist of tumor cells with a solitary primary cilium andexhibit profound defects multi-ciliogenesis program. Together, these results
indicate that a solitary primary cilium is crucial for CPC development,
whereas multi-ciliogenesis circuit possesses tumor suppressive functions andmay represent a novel therapeutic target in CPC.
MODL-31. RADIATION-DERIVED TREATMENT-RESISTANTPDX AND CELL CULTURE MODELS RECAPITULATE THE
CHARACTERISTICS OF MATCHED PRIMARY/RECURRENTPEDIATRIC HIGH-GRADE GLIOMA
Aaron J Knox, Patrick Flannery, Anjali Zukosky, John DeSisto,
Bridget Sanford, Benjamin van Court, Andrew Donson, Rakeb Lemma,
Hannah Chatwin, Sana D Karam, Rajeev Vibhakar, Ken Jones, andAdam L Green; The Morgan Adams Foundation Pediatric Brain Tumor
Research Program, University of Colorado School of Medicine/Children’s
Hospital Colorado, Aurora, CO, USA
BACKGROUND: Pediatric high-grade glioma (pHGG) is the mostcommon cause of childhood cancer death. Recurrence after therapy is amajor challenge, since recurrent pHGG proliferates aggressively and resists
therapy. We developed and validated preclinical models of matched primaryand recurrent tumors, providing a method to study recurrence and potential therapies. METHODS: We irradiated H3K27M thalamic pHGG cells(BT245) (8 Gy/week,2Gy fractions x3 weeks) and propagated the surviving
cells (BT245R). We developed a murine recurrence model by orthotopicallyimplanting BT245 cells, irradiating the resultant tumors (4 Gy/day x2d)
and propagating irradiated (BT245RM) or control (BT245CM) tumor
cells at endpoint. We performed phenotypic analyses, RNA-Seq, and drug
testing. RESULTS: BT245R cells were more stemlike than BT245, with an
8-fold greater rate of neurosphere formation (p<0.03). Geneset enrichment
analysis showed similar molecular changes in BT245RM cells and primary/recurrent H3K27M pHGG patient sample pair, including relaxation of theG2/M cell cycle checkpoint (Hallmark_G2M_Checkpoint: BT245RM NES=5.95, FDR=0.0; patient NES=-5.86, FDR=0.0), downregulation of MYC
targets (Hallmark_MYC_Targets_V1: BT245RM NES=-7.43, FDR=0.0;
patient NES=-5.86, FDR=0.0), and decreased differentiation (Go_Regulation_of_Stem_Cell_Differentiation: BT245RM NES=-3.35, FDR=0.0; patient NES=-3.15, FDR=0.0). Enrichment of the protein_kinase_C_signalingin BT245RM (NES=2.18,FDR=0.03) suggested response to MAPK pathway
inhibition. BT245R cells were twice as sensitive as BT245 cells to the MEK
inhibitor trametinib (p<0.05). CONCLUSIONS: Our neurosphere andmurine orthotopic patient-derived xenograft models recapitulate gene expression changes of matched primary/recurrent pHGG. RNA-Seq analysis
validated the model against patient samples and identified trametinib as potentially effective in recurrent pHGG.

NEUROFIBROMATOSISNFB-01. FUNCTIONAL CHARACTERIZATION OF ATRX LOSS IN
NF1-ASSOCIATED GLIOMA AND MPNSTMing Yuan1, Karlyne Reilly2, Christine Pratilas1, Christopher Heaphy3,
and Fausto Rodriguez1; 1Johns Hopkins University School of Medicine,
Baltimore, MD, USA, 2National Cancer Institute, Bethesda, MD, USA,
3Boston University School of Medicine, Boston, MA, USA
To identify the biologic relevance of ATRX loss in NF1-associatedgliomagenesis, we studied the effects of Atrx loss using four previously characterized Nf1+/-Trp53+/- murine glioma lines. Lines 130G#3 and 158D#8(corresponding to grade IV and III gliomas, respectively) displayed preserved ATRX protein expression compared to NIH-3T3 cells. We studied
the effects of Atrx knockdown in these two lines in the presence and absenceof the TERT inhibitor, BIRBR1532. Using a telomere-specific FISH assay,
we identified increased signal intensity after Atrx knockdown, only in thepresence of the TERT inhibitor. These features are reminiscent of ALT, although there were no significant alterations in cell growth. Next, we studied
the effect of ATRX loss in MPNST lines ST88-14, NF90-8, STS-26T. Thesecell lines all expressed ATRX and DAXX. However, STS-26T contained a
TERT promoter mutation and ST88-14 had a known SNP in the TERT
promoter, while NF90-8 had no alterations. ATRX siRNA knockdown
showed no significant effects in cell proliferation or apoptosis. However,
ATRX knockdown resulted in rare ultra-bright foci, indicative of ALT. Next,
we studied the in vitro effect of the ATR inhibitor VE-821 in MPNST celllines. Only NF90-8 (lacking TERT alterations) demonstrated a decrease in
growth after ATRX knockdown and VE-821 treatment. However, ATRXN E U R O -O N C O L O G Y•

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knockdown alone did not affect sensitivity to carboplatin. Our findings
further support a role for ATRX loss with subsequent ALT activation ina biologic subset of NF1-associated malignancies, thereby opening an opportunity for therapeutic targeting of these aggressive tumors using specificclasses of drugs.
NFB-02. TREATMENT OF PAIN AND TUMOR GROWTH IN NF2
Molly Hemenway, Anan Nellan, Kate McMahon, Nicholas Foreman,
Kartik Reddy, Anan Nellan, and Alexandra Suttman; Univ of CO,
Children’s Hospital Colorado, Aurora, CO, USA
BACKGROUND: Neurofibromatosis Type 2 (NF2) is an autosomal dominant disorder characterized by multiple nervous system tumors. Chronic
pain affects the majority of patients with NF2 and is the primary factor
that contributes to decreased quality of life. There are limited therapies that
effectively reduce pain in NF2, but intravenous (IV) bevacizumab has beenreported to provide significant relief to patients suffering from debilitating
pain. CASE STUDY: James is a 24-year-old who initially presented withmanifestations of NF2 at age 10, and by 15 years old had developed daily
pain affecting his neck, back, and lower extremity. He has multiple CNS
schwannomas, meningiomas, neurofibromas, and meets clinical NF2 criteria. While genetic testing did not reveal a mutation in his gDNA, low levelskipping of exon 4 via RNA supports (likely mosaic) NF2. James’s pain was
poorly controlled with multiple oral medications, including opioids. Jamesstarted IV bevacizumab at age 16 that improved his pain. He was critically dependent on bevacizumab for pain control and required continuous
IV pain medication when bevacizumab was held for a surgical procedure.
Following five years of bevacizumab he developed worsening toxicities
including hypertension, proteinuria, and elevated hemoglobin. James transitioned to therapy with trametinib, a MEK inhibitor, and was able to wean
off bevacizumab six months later. Treatment of NF2 related pain withtrametinib instead of bevacizumab has improved his QOL with decreased
medical visits, improved pain management, and decreased side effects. FUTURE IMPLICATIONS: Treatment of NF2 tumor related pain can be managed with MEK inhibitors.
NFB-03. TRAMETINIB FOR ORBITAL PLEXIFORMNEUROFIBROMAS IN YOUNG CHILDREN WITH NF1Helen Toledano1,2, Gad Dotan1,2, Rivka Friedland1,2, Rony Cohen1,2,
Iftach Yassur3, Hagit Toledano4,2, Shlomi Constantini4,2, andMika Shapira Rootman1,2; 1Schneider Children’s Medical Center, Petach
Tikva, Israel, 2Tel Aviv University, Tel Aviv, Israel, 3Rabin Medical Center,
Petach Tikva, Israel, 4Sourasky Medical Center, Tel Aviv, Israel
Plexiform neurofibromas (PN) in NF1 are diagnosed in early childhood
and may grow rapidly during this period. In 10% of patients they involve theorbital-periorbital area and may cause visual problems including glaucoma
and visual loss from amblyopia (deprivational, strabismic, or refractive),
optic nerve compression or keratopathy. Ptosis, proptosis and facial disfigurement lead to social problems and decreased self-esteem. Complete surgical removal is usually impossible and there is a tendency for regrowth
after debulking. Recently inhibitors of the RAS/MAPK pathway have been
investigated for their activity in PN. We describe 5 young children with NF1and PN of the orbital area treated with the MEK inhibitor trametinib followed clinically and by volumetric MRI. Treatment was initiated at mean
age 26.8 months (SD ±12.8) and continued for median 25 months (range
17– 48). Reasons for initiating treatment were visual compromise and progressive tumor growth. Doses were as recommended. One child reported
decreased orbital pain after one week and another, with involvement of themasseters, had increased ability to chew food. Toxicities were mostly to skinand nails grades 1–2 as expected. Additionally, 60% had debulking surgery
of preseptal eyelid tumor in first year of medical treatment. Volumetric MRI
measurements showed reduction of 8–26% at 1 year from baseline with amaximal reduction of 45% in two patients at 22 & 45 months. No change
in visual function was recorded following treatment initiation. In conclusion, trametinib may decrease tumor size in young children with orbital PN
and may prevent progressive disfigurement.
NFB-04. EXAMINING DIFFUSION, ARTERIAL SPIN-LABELEDPERFUSION, AND VOLUMETRIC CHANGES IN THE
NEUROFIBROMATOSIS TYPE 1 BRAIN USING AN ATLAS-BASED,
MULTI-PARAMETRIC APPROACH
Lydia Tam1, Nathan Ng1, Peter Moon1, Jimmy Zheng1, Emily McKenna1,
Nils Forkert2, Cynthia Campen1, and Kristen Yeom1; 1Stanford University,
Stanford, CA, USA, 2University of Calgary, Calgary, AB, Canada
BACKGROUND: Neurofibromatosis Type 1 (NF1) is a multisystem disorder with wide ranging clinical implications. Patients may present withmacrocephaly, stroke, and cognitive deficits, all of which may impede
normal neural development. We applied atlas-based, multi-parametric MRI

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analysis of regional brain to evaluate diffusion, arterial spin-labeled (ASL)
perfusion, and volumetric changes in children with NF1. METHODS: Children evaluated for NF1 from 2009 to 2018 at Stanford University (n=78)
were retrospectively reviewed and compared to healthy controls (n=100). All
patients underwent diffusion-weighted (DWI) magnetic resonance imaging
at 3T, and children with brain tumors were excluded. Using atlas-based DWI
analyses, we assessed volume, median apparent diffusion coefficient (ADC),
and cerebral blood flow in the cerebral cortex, thalamus, caudate, putamen,
globus pallidus, hippocampus, amygdala, nucleus accumbens, brain stem,
and cerebral white matter. We also measured volume of the lateral ventricles. Multivariate analysis of covariance was used to test for differences
between controls and NF1 patients, controlling for gender and age at timeof imaging. RESULTS: Comparing NF1 to controls, we detected increased
volume and decreased ASL cerebral blood flow in white matter and all subcortical and cortical structures except for brainstem volume. Median ADC
was also increased in the thalamus, pallidum, hippocampus, and brainstem. CONCLUSIONS: Using a multi-parametric approach, we demonstrate quantitative measures of microstructural and physiologic changes of
the NF1 brain. Atlas-based, quantitative MRI brain signatures may serveas biomarkers of neural development and further provide insight into associated cognitive dysfunction or risks for vasculopathy-related strokes inchildren with NF1.
NFB-05. AN UNUSUAL PRESENTATION OF RECURRENT
LANGERHANS CELL HISTIOCYTOSIS OF THE CRANIOFACIAL
BONES IN A PATIENT WITH NEUROFIBROMATOSIS TYPE I
Blake Chaffee1, Alexis Judd2, Sarah Rush2, and Erin Wright2; 1Ohio
University Heritage College of Osteopathic Medicine, Cleveland, OH, USA,
2Akron Children’s Hospital, Akron, OH, USA
Neurofibromatosis type 1 (NF1), predisposes patients to benign and malignant tumors due to lack of suppression of the mitogen activated protein
kinase (MAPK) signaling pathway. Langerhans cell histiocytosis (LCH)
manifests in numerous ways, from localized lesions to multisystem organ
involvement secondary to a constitutively active MAPK signaling cascade
often driven by BRAF mutations. While both LCH and NF1 are characterized by overactive MAPK signaling, there are few reports of the two diseases occurring simultaneously. We report a novel case of a patient with
underlying NF1 and recurrent LCH without a BRAFV600E mutation. She
initially presented at 2 years of age with an aggressive appearing mass of
the left temporal bone found on surveillance imaging. Pathology was consistent with Langerhans histiocytosis and she was treated with the LCH-III
protocol for patients with high-risk LCH due to the location of her lesion.
Five years after completion of therapy, MRI demonstrated development ofa calvarial mass consistent with relapsed LCH in a new risk site. Lesional
curettage was performed and pathology confirmed recurrence of LCH withjuvenile xanthogranulomatous features. BRAF testing of blood and the lesion were negative for any BRAF alterations. Further genomic evaluation of
the tumor is in progress at this time to evaluate for other known mutations
associated with LCH. The patient is currently receiving monthly cytarabine
treatment which she has tolerated to date. Our patient represents a uniquepresentation of recurrent LCH in a patient with NF1 and further molecularevaluation may help identify other drivers of LCH activation.
NFB-06. TREATMENT CHALLENGES IN PEDIATRICGLIOBLASTOMA MULTIFORME WITH CONCURRENT SOMATIC
AND GERMLINE NF1 MUTATIONS WITH GERMLINE MISMATCH
REPAIR MUTATIONS: TWO UNIQUE CASES
Muhammed Baig, Maureen Mork, Soumen Khatua, John Slopis,
Wafik Zaky, Racheal Bingham, Sumit Gupta, Greg Fuller, andZsila Sadighi; University of Texas MD Anderson Cancer Center, Houston,
TX, USAINTRODUCTION: We report the first known cases of pediatric glioblastoma (GBM) with prior clinical NF1 diagnoses, one with concurrent germline Lynch syndrome (LS) and NF1, and the other with somatic
NF1 mutation and germline constitutional mismatch repair deficiency(CMMRD). METHODS: Two pediatric GBM cases with prior NF1 clinicaldiagnoses based on neurocutaneous criteria were reviewed. Next generation
sequencing and immunohistochemical staining were used for somatic andgermline NF1 and MMR gene mutation detection, and for MMR protein
expression, respectively. RESULTS: Sixteen year old male with prior NF1
clinical diagnosis had resection of right frontal GBM revealing somatic mutations of POLE and PMS2, but not NF1. His father had confirmed LS with
MSH2 mutation and no neurocutaneous stigmata. Patient’s germline testing
revealed both pathogenic MSH2 plus NF1 mutations confirming LS and
NF1. Treatment consisted of chemoradiation with temozolomide followedby adjuvant temozolomide with stable disease at 8 cycles. Nineteen year old
male with former NF1 clinical diagnosis had 2 GBMs, first in left midbrain
biopsied revealing somatic PMS2 and NF1 mutations underwent radiation
then 7 cycles of temozolomide, then new left frontal GBM underwent re-Abstracts

section followed by radiation and 5 cycles of pembrolizumab stable at 5th
cycle. CONCLUSION: Children with NF1 stigmata and GBM can haveconcurrent NF1 and LS, or CMMRD with NF1 somatic mutations. Ourpatients tolerated alkylating agents, despite risk for secondary malignancies
as upfront therapy and at recurrence checkpoint inhibitors. Upfront therapy
in GBM with mismatch repair syndrome with checkpoint inhibitors should
be studied.
NFB-07. USE OF PEGYLATED INTERFERON Α- 2B IN PEDIATRICPATIENTS AFFECTED BY UNRESECTABLE PLEXIFORMNEUROFIBROMAS: MONOCENTRIC EXPERIENCE
Antonella Cacchione, Maria Chiara Lodi, Giada Del Baldo, Andrea Carai,
Giovanna Stefania Colafati, Francesca Diomedi Camassei, Franco Locatelli,and Angela Mastronuzzi; Bambino Gesù Children Hospital, Rome, Italy
BACKGROUND: Neurofibromatosis type 1 (NF1) is autosomal dominant neurogenetic disorder characterized by progressive cutaneous, neurologic, skeletal, and neoplastic manifestations. Plexiform neurofibromas (PN)
are one of the different types of neurofibromas that occur in these patients.
Complete surgical resection is difficult due to the tumor infiltrative behavior.
We evaluated pegylated interferon- α-2b (PI) in patients with unresectable
progressive or symptomatic PN. METHODS: Pediatric patients (1–21 years
old) affected by unresectable PN, followed at Bambino Gesù Hospital, weretreated with PI. We administered PI as a weekly subcutaneous injection at a
beginning dose of 1.0 mcg/kg/wk, increased to 3.0 mcg/kg/wk if well tolerated. Paracetamol (15mg/kg) was given 30 minutes prior the dose of PI andthen every 4–6 hours as needed. Patients were evaluated with Magnetic Resonance Imaging (MRI) every 12 months after treatment start in case of stabledisease. RESULTS: 10 patients (3 females, 7 males) were enrolled. Medianage was 12 years old. The median duration of treatment was 12,6 months.
Grade 3 neutropenia (30%) and increased liver transaminases level (20%)
were the most common toxicity. 6/10 patients experienced an improvement
about pain. 7/10 patients showed clinical response. 1/10 patient had a radiological response at MRI, 1/10 experienced progression disease and 8/10
showed a stable disease at MRI evaluation. CONCLUSIONS: Our study
demonstrated that PI could be a suitable treatment for unresectable PN in
terms of stabilization of the tumour size due to its antitumor activity although clinical response does not correlate with radiographic changes.
NFB-08. PHASE II STUDY OF AXITINIB IN PATIENTS WITH
NEUROFIBROMATOSIS TYPE 2 AND PROGRESSIVE VESTIBULARSCHWANNOMAS
Sheetal Phadnis1, Mari Hagiwara1, Anna Yaffe1, Carole Mitchell1,
Theodore Nicolaides1, Srivandana Akshintala2, Tsivia Hochman1,
Judith Goldberg1, Jeffrey Allen1, and Matthias Karajannis3; 1NYU Langone
Hospital, New York, NY, USA, 2National Institute of Health, Bethesda,
MD, USA, 3Memorial Sloan Kettering Cancer Center, New York, NY, USA
INTRODUCTION: Vascular endothelial growth factor receptor (VEGFR),
platelet derived growth factor receptor (PDGFR), and c-KIT represent clinically
and/or preclinically validated molecular targets in vestibular schwannomas.
We conducted a single institution, prospective, open-label, two-stage phase II
study (ClinicalTrials.gov identifier NCT02129647) to estimate the response
rate to axitinib, an oral multi-receptor tyrosine kinase inhibitor targeting
VEGFR, PDGFR and c-KIT, in neurofibromatosis type 2 (NF2) patients with
progressive vestibular schwannomas (VS). METHODS: NF2 patients older
than 5 years with at least one volumetrically measurable, progressive VS were
eligible. The primary endpoint was to estimate the objective volumetric response rates to axitinib. Axitinib was given continuously in 28-day cycles for
up to of 12 cycles. Response was assessed every 3 months with MRI using
3-D volumetric tumor analysis and audiograms. Volumetric response and progression were defined as ≥20% decrease or increase in VS volume, respectively. RESULTS: Twelve eligible patients (ages: 14–56 years) were enrolled on
this study. Seven of twelve patients completed 12 cycles (range: 2 to 12 cycles).
We observed two imaging and three hearing responses. Best volumetric response was -53.9% after nine months on axitinib. All patients experienced
drug-related toxicities, the most common adverse events were diarrhea, hematuria and skin toxicity, not exceeding grade 2 and hypertension, not exceeding
grade 3. CONCLUSIONS: While axitinib has modest anti-tumor activity in
NF2 patients, it is more toxic and appears to be less effective compared tobevacizumab. Based on these findings, further clinical development of axitinib
for this indication does not appear warranted.
NFB-09. ENROLLMENT AND CLINICAL CHARACTERISTICS OF
NEWLY DIAGNOSED, NEUROFIBROMATOSIS TYPE 1 ASSOCIATED
OPTIC PATHWAY GLIOMA (NF1-OPG): PRELIMINARY RESULTS
FROM AN INTERNATIONAL MULTI-CENTER NATURAL HISTORY
STUDY
Michael J. Fisher1, Grant T. Liu1, Rosalie E. Ferner2, David H. Gutmann3,
Robert Listernick4, Peter de Blank5, Janice Zeid4, Nicole J. Ullrich6,

Gena Heidary6, Miriam Bornhorst7, Steven F. Stasheff7, Tena Rosser8,
Mark Borchert8, Simone Ardern-Holmes9, Maree Flaherty9,
Trent R. Hummel5, W. Walker Motley5, Kevin Bielamowicz10,
Paul H. Phillips10, Eric Bouffet11, Arun Reginald11, David S. Wolf12,
Jason Peragallo12, David Van Mater13, Mays El-Dairi13, Aimee Sato14,
Kristina Tarczy-Hornoch14, Laura Klesse15, Nick Hogan15,
Nick Foreman16, Emily McCourt16, Jeffrey Allen17, Milan Ranka17,
Cynthia Campen18, Shannon Beres18, Christopher Moertel19, Ray Areaux19,
Duncan Stearns20, Faruk Orge20, John Crawford21, Henry O’Halloran21,
Michael Brodsky22, Adam J. Esbenshade23, Sean Donahue23, Gary Cutter24,
and Robert A. Avery1; 1The Children’s Hospital of Philadelphia,
Philadelphia, PA, USA, 2Guy’s and St, Thomas’ Hospitals NHS Foundation
Trust, London, England, United Kingdom, 3Washington University Schoolof Medicine, St. Louis, MO, USA, 4Ann & Robert H. Lurie Children’s
Hospital of Chicago, Chicago, IL, USA, 5Cincinnati Children’s Hospital
Medical Center, Cincinnati, OH, USA, 6Boston Children’s Hospital,
Boston, MA, USA, 7Children’s National Hospital, Washington, DC, USA,
8Children’s Hospital Los Angeles, Los Angeles, CA, USA, 9The Children’s
Hospital at Westmead, Sydney, NSW, Australia, 10Arkansas Children’s
Hospital, Little Rock, AR, USA, 11The Hospital for Sick Children, Toronto,
ON, Canada, 12Children’s Healthcare of Atlanta, Atlanta, GA, USA, 13Duke
University Medical Center, Durham, NC, USA, 14Seattle Children’s, Seattle,
WA, USA, 15University of Texas Southwestern Medical Center, Dallas,
TX, USA, 16Children’s Hospital Colorado, Aurora, CO, USA, 17New York
University Langone Health, New York, NY, USA, 18Stanford University,
Palo Alto, CA, USA, 19University of Minnesota Masonic Children’s
Hospital, Minneapolis, MN, USA, 20University Hospital Cleveland Medical
Center, Cleveland, OH, USA, 21Rady Children’s Hospital, University ofCalifornia San Diego, San Diego, CA, USA, 22Mayo Clinic, Rochester,
MN, USA, 23Vanderbilt University Medical Center, Nashville, TN, USA,
24University of Alabama at Birmingham, Birmingham, AL, USA
INTRODUCTION: Because treatment and clinical management decisions for children with NF1-OPG remain challenging, we sought to establish
evidence-based guidelines. We prospectively enrolled children with newlydiagnosed NF1-OPGs, and gathered standardized clinical neuro-oncology
and ophthalmology assessments. METHODS: Only children with NF1 andnewly diagnosed OPGs, confirmed by central review, were eligible. Indications for obtaining the initial MRI, as well as factors associated with thedecision to treat with chemotherapy or observe without treatment, wereobtained. Quantitative visual acuity (VA), other ophthalmic features, andimaging were captured at standard time points. Goal enrollment is 250
subjects. RESULTS: One-hundred thirty-three children (52% female) from
20 institutions met inclusion criteria, and were included in this preliminary
analysis. Eighty-six percent of subjects were able to perform quantitative
VA testing at enrollment. The most common reasons for the diagnostic MRI
included screening related to NF1 diagnosis (36.8%), ophthalmologic concerns (29.3%), and non-ophthalmologic concerns (24.8%), such as headache. To date, twenty subjects have initiated treatment with chemotherapy,
twelve (9%) at the time of the initial OPG diagnosis. Median age at OPG
diagnosis was 3.1 years. Age and sex distribution were similar in subjects
immediately entering the observation and treatment arms (median age
3.0 versus 3.5 years, respectively). CONCLUSION: Most children with
NF1-OPGs are observed at time of their initial OPG diagnosis, rather thantreated. Importantly, a large proportion of children are able to completequantitative VA testing at enrollment. Once enrollment is complete, thesedata will help to establish evidence-based guidelines for clinical managementof NF1-OPGs.
NFB-11. WHITE MATTER DIFFERENCES IN CHILDREN WITH NF1COMPARED TO CONTROLS
Lisa Bruckert, Katie Travis, Emily McKenna, Kristen Yeom, andCynthia Campen; Stanford, Palo Alto, CA, USA
INTRODUCTION: Neurofibromatosis type 1 (NF1) is a genetic condition in which children develop learning challenges and glioma. White matter
tracts (WMT) are implicated in these cognitive functions, while oligodendroglial precursor cells are implicated in both gliomagenesis and whitematter development. Specific WMTs have not been well characterized in
NF1. METHODS: Twenty NF1 patients aged 1.4–17.6 years (M = 9.5 years,
24 male) and 20 age-and-sex-matched controls underwent dMRI at 3T (25directions, b=1000 s/mm2). Automated segmentation of WMTs extracted
fractional anisotropy (FA) and mean diffusivity (MD) of 18 major WMTs.
Covariance analysis examined the effect of group (NF1/controls) on FA/MD
after controlling for intracranial volume. Regression analyses for WMTs determined the interaction of FA/MD with age for NF1 patients compared tocontrols. Significance was set at p<0.05 after correcting for multiple comparisons using false discovery rate. RESULTS: Compared to controls, children with NF1 had significantly decreased FA in 8 and increased MD in
12/18 tracts. Differences held after controlling for intracranial volume. Theinteraction between group and age accounted for a significant proportionof the variance in FA in 9 and in MD in 16/18 tracts. FA and MD differ-

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iii419Abstracts

ences between children with NF1 and controls were greater at younger thanolder ages. CONCLUSION: Microstructural differences were observed in
WMTs in children with NF1 compared to controls. These differences were
not explained by intracranial volume and were most pronounced in younger
children with NF1 compared to controls. These findings have implications
for understanding neurocognitive deficits and gliomagenesis observed inchildren with NF1.

were identified in 9 of 10 tumors tested (5 BRAF fusion, 1 BRAFV600E, 1
FGFR1+NF1, 1 FGFR1+PTPN11, 1 NF1). Radiology review of response
will be presented. CONCLUSIONS: This real-world pediatric cohort supports efficacy and tolerability of MEK inhibitor therapy for short-term control of plexiform neurofibroma and low-grade glioma with and without
NF1. Further studies are warranted to evaluate comparative efficacy, combination therapy and duration of therapy.

NFB-12. TRAMETINIB THERAPY FOR PEDIATRIC PATIENTSWITH REFRACTORY LOW GRADE GLIOMA OR EXTENSIVESYMPTOMATIC PLEXIFORM NEUROFIBROMA
Celine D. Hounjet2, Rebecca Ronsley1, Sylvia Cheng1, S. Rod Rassekh1,
Walter J. Duncan3, Christopher Dunham4, Jane Gardiner5,
Arvindera Ghag6, Jeffrey P, Ludemann7, David Wensley8,
Wingfield Rehmus9, Michael A. Sargent10, Naomi Evans2, Vesna Popovska2,and Juliette Hukin1,11; 1Division of Hematology, Oncology & BMT,
Department of Pediatrics, University of British Columbia, Vancouver, BC,
Canada, 2Faculty of Medicine, University of British Columbia, Vancouver,
BC, Canada, 3Division of Pediatric Cardiology, Department of Pediatrics,
University of British Columbia, Vancouver, BC, Canada, 4Division of
Anatomic Pathology, Department of Pathology, University of British
Columbia, Vancouver, BC, Canada, 5Division of Pediatric Ophthalmology,
Department of Surgery, University of British Columbia, Vancouver, BC,
Canada, 6Division of Pediatric Orthopedic Surgery, Department of Surgery,
University of British Columbia, Vancouver, BC, Canada, 7Division of
Pediatric Otolaryngology, Department of Surgery, University of British
Columbia, Vancouver, BC, Canada, 8Division of Pediatric Respiratory
Medicine, Department of Pediatrics, University of British Columbia,
Vancouver, BC, Canada, 9Division of Dermatology, Department ofPediatrics, University of British Columbia, Vancouver, BC, Canada,
10Division of Pediatric Neuro-Radiology, Department of Radiology,
University of British Columbia, Vancouver, BC, Canada, 11Division of
Pediatric Neurology, Department of Pediatrics, University of British
Columbia, Vancouver, BC, Canada

NFB-14. PSYCHOSOCIAL OUTCOMES IN CHILDRENWITH NEUROFIBROMATOSIS TYPE 1 AND PLEXIFORMNEUROFIBROMAS
Sudarshawn Damodharan, Paige Mission, and Diane Puccetti; University of
Wisconsin Hospital and Clinics, Madison, WI, USA

OBJECTIVE: Refractory symptomatic plexiform neurofibromas (PNF)
and inoperable refractory low grade gliomas (LGG) pose a clinical challengethat may be life threatening. Phase 1 and 2 clinical trials of MEK inhibition
with selumetinib in inoperable PNF and LGG have demonstrated promising
results in pediatrics, however access has been limited to enrollment on clinical trial. Phase 1 clinical trial for trametinib a MEK 1 and 2 inhibitor has
been completed, publication is pending. Thus we have treated a series ofchildren on a compassionate basis with extensive PN or LGG refractorydisease with trametinib, as this is available in Canada. METHODS: We
have treated children with trametinib on a compassionate basis in our province since 2017. Review of the clinical data regarding this therapy has been
IRB approved. RESULTS: Two young patients were treated for indication oflife threatening extensive PNF and have had tumor shrinkage and improvement of clinical status. Treatment has been complicated by paronychiae,eczema exacerbation, chondrodermatitis nodularis helicis, RSV and influenza B infection and CTCAE grade 2 pneumonia. In spite of the side effects
these two patients remain on treatment due to clear benefit from therapy
including: improved respiratory compromise, hearing and dysphagia. We
will present the data of additional patients treated with trametinib. CONCLUSION: Trametinib is an effective therapy for life threatening PNF bychanging the natural history of tumor growth in young children. Further
data is required in terms of tolerance, efficacy and durability of response insuch patients in the setting of clinical trials.
NFB-13. TRAMETINIB FOR PLEXIFORM NEUROFIBROMA AND
RECURRENT LOW-GRADE GLIOMA
Aimee Sato, Nathan Millard, Francisco Perez, Nicholas Vitanza, andSarah Leary; Seattle Children’s, Seattle, WA, USA
BACKGROUND: Based on early clinical efficacy data, Seattle Children’s
established a standard clinical practice for MEK inhibitor therapy for children with plexiform neurofibroma (PN) or recurrent low-grade glioma(LGG). METHODS: Data were collected under an IRB-approved retrospective chart review. Trametinib was prescribed off-label at 0.025 mg/kg
daily for up to two years. Physical exam and laboratory monitoring weremonthly for 3 months, then every 3 months. Retinal examination, ECHO/ECG were every 3 months. Tumor response was evaluated by MRI every
3 months for LGG; imaging for PN was dependent on tumor location. RESULTS: 30 patients received trametinib; 17 LGG, 16 PN (3 both); 22 with
Neurofibromatosis, Type-1 (NF1); 16 female/15 male; median age 11 (range
4.1–22.6). Most common tumor location was optic pathway (n=11) andface/neck (n=10). Most common adverse events (AE) were dermatologic andgastrointestinal. Ten had dose interruption/reduction, only one discontinued
therapy for AE. Six received dermatology specialty care for AE. With medianfollow-up of 12 months, only 3 patients had progression, one with NF1.
One-year EFS was 100% for PN and 88%+7 for LGG. Driver mutationsiii420N EU R O - O N C O L O G Y•

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OBJECTIVE: This case series seeks to examine neurocognitive outcomes, social-emotional functioning, and family burden in young children
diagnosed with Neurofibromatosis, type 1 (NF1) with early growing plexiform neurofibromas (PNFs). BACKGROUND: Neurofibromatosis, type1 (NF1) is a common predisposing chronic disease arising in early childhood, with an incidence of approximately 1:3000. Though NF1 displays awide range of phenotypic variability, the primary feature of the disease isperipheral nerve sheath tumors called neurofibromas. Less is well known
regarding the broader neurocognitive and social-emotional profile in presentations with more complex tumor growths, namely PNFs, which arepresent in at least half of the NF1-affected population. METHODS: Participants with NF1 and PNFs (n=2) aged 6-7years completed comprehensive
neuropsychological evaluations and parents completed measures of qualityof life, social-emotional/behavioral functioning of child, parental stress,
family adaptability, and family cohesion. RESULTS: Outcomes suggest
broad neurocognitive dysfunction (e.g., executive functioning deficits, attention problems, visual-motor delays, and poor motor coordination), socialemotional challenges (e.g., symptoms of anxiety and depression, and poorsocial skills), and familial distress. CONCLUSIONS: Findings indicate thevalue of early and frequent monitoring of children with PNFs in medical systems and multi-disciplinary teams, and the importance of early intervention
for both children and families.
NFB-16. MTOROPATHIES AND SUBEPENDYMAL GIANT CELLASTROCYTOMAS: PREDICTIVE VALUE OF GERMINAL TSC1/2
MUTATIONS SCREENING IN FAMILIAL CASES
Nouha Bouayed Abdelmoula, Walid Smaoui, Balkiss Abdelmoula,Samir Aloulou, Imen Masmoudi, Imen Bouaziz, Ines Lamloum,
Hadil Chaari, Asma Yaich, Rafik Dhouib, Sonia Sellami, Mariem Keskes,
Sourour Fellah, Khawla Khlifi, Amir Medhioub,and Nabil Mhiri;
UR17ES36 Genomics of Signalopathies at the Service of Medicine, Medical
University of Sfax, Sfax, Tunisia
mTOR controls several important aspects of cell function particularlyin the nervous system. Its hyperactivation has been involved in tuberous
sclerosis complex (TSC) and other mTORopathies as well as drug-resistant
epilepsy. Mutations in TSC1 and TSC2 genes cause loss of normal inhibition of mTORC1 complex, leading to cell overgrowth and disruptions insynaptogenesis. Many children and adults with TSC harbour neurologic
defects especially subependymal giant cell astrocytomas (SEGAs) in thebrain. Here, we have performed mutational analysis followed by a genetic
counselling for a Tunisian family from Sfax town harboring epileptic seizures associated to a neurocutaneous disorder. Index cases were referred forrenal angiolipomas (RAL) associated to seizures crisis and were diagnosed
as having TSC. The first 26-year-old patient complained of epilepsy since theage of 22 with left temporal crisis related to cortical tubers near the Heschl’s
gyrus. His brother, a 36-year-old man presented more severe epileptic crisis(since 15 years-old), multiples RAL, subependymal nodules, and a rapid
evolution of his mTORopathy with tumoral progression of his renal andcentral nerve lesions: renal cell carcinoma and SEGAs. TSC1 gene mutation
screening showed heterozygous two bp deletion at codons 213 and 214 ofexon 5. SEGAs are rare, low-grade glioneuronal brain tumors that occur almost exclusively in TSC patients but can lead to nervous complications. We
showed through this report, the predictive value of germinal TSC mutations
screening in familial cases, because early recognition of the molecular defectmay lead to appropriate management of the tumoral progression.
NFB-17. MEK INHIBITOR BINIMETINIB SHOWS CLINICALACTIVITY IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1ASSOCIATED PLEXIFORM NEUROFIBROMAS: A REPORT FROMPNOC AND THE NF CLINICAL TRIALS CONSORTIUM
Sabine Mueller1,2, Alyssa T. Reddy1, Eva Dombi3, Jeffrey Allen4,
Roger Packer5, Wade Clapp6, Stewart Goldman7, Elizabeth Schorry8,
James Tonsgard9, Jaishri Blakeley10, Nicole J. Ullrich11, Andrea Gross3,
Karin Walsh5, Coretta Thomas12, Lloyd Edwards12, Michael Prados1,
Bruce Korf12, and Michael J. Fisher13; 1University of California, SanAbstracts

Francisco, San Francisco, CA, USA, 2Children’s Hospital Zurich, Zurich,
Switzerland, 3National Cancer Institute, Center for Cancer Research,
Bethesda, MD, USA, 4NYU Langone Health, New York, NY, USA,
5Children’s National, Washington, DC, USA, 6Indiana University, Schoolof Medicine, Indianapolis, IN, USA, 7Ann & Robert H, Lurie Children’s
Hospital of Chicago, Chicago, IL, USA, 8Cincinnati Children’s, Cincinnati,
OH, USA, 9The University of Chicago, Dept, of Pediatrics, Chicago, IL,
USA, 10John Hopkins University, School of Medicine, Baltimore, MD,
USA, 11Dana-Farber / Harvard Cancer Center, Boston, MA, USA, 12The
University of Alabama, School of Public Health, Birmingham, AL, USA,
13Children’s Hospital of Philadelphia, Philadelphia, PA, USA
BACKGROUND: Plexiform neurofibromas (PNs) can cause significant morbidity. In this phase 2 study, we assessed imaging and functional
outcomes to the MEK-inhibitor Binimetinib in pediatric patients with
PNs. METHODS: Children (age 1–17 years) with PN that were progressiveor causing significant morbidity were eligible. Binimetinib is dosed twicedaily (starting dose of 32mg/m2) for maximum of 24 four-week courses.
Participants with partial response (PR; >20% decrease in PN volume on
central MRI review) at cycle 12 may stay on therapy. Participants undergo
MRI and functional assessments at baseline and after courses 4, 8, 12, 18
and 24. Functional assessments are based on PN location. RESULTS: Here
we present 1-year response data. Twenty participants (55% male) with median age 12 years (range 2–16 years) enrolled; 19 are evaluable for response.
Median baseline tumor volume was 326 ml (range, 8-6661 ml). Fourteen
participants (74%) met criteria for PR, with 11 achieving PR by course
5. Median maximal PN volume reduction was 25.5% (range, 9–54%). As of
August 2020, 14 participants received at least 12 cycles of Binimetinib; 10
remain on therapy. Off study reasons include treatment associated toxicities(n=2), subject withdrawal (n=2), non-compliance (n=2), prolonged treatment delay (n=1), and lack of response (n=3). Thirteen participants underwent dose reduction. Institution-reported related grade 3 toxicities included
dry skin, weight gain, muscle weakness, rash, paronychia, cellulitis, diarrhea, gastric hemorrhage and CPK increase. CONCLUSIONS: Binimetinib
appears reasonably well-tolerated and shows promising activity in children
with NF1-associated PNs. Outcomes on functional improvement will be reported at the meeting.

and choroid plexus carcinomas. It is also used for relapsed or recurrent tumors. Giving IT chemotherapy via an ICV device instead of via an LP can bepreferable as it requires no deep sedation and allows for more uniform drug
distribution. Drugs given IT include methotrexate, cytarabine, hydrocortisone, etoposide, and topotecan. ICV devices can be placed in patients withadequate CSF flow and a flow study can be done if needed to confirm. Accessing the ICV device for administration of chemotherapy is typically done
by a physician or nurse practitioner using sterile technique. Our institution
has had success using music therapy and child life specialists for assistancewith coping during the procedure as patients are awake. The procedure has
few complications the most common being infection usually with skin flora.
It can also cause nausea and headache. There are few long term risks.
NURS-02. CLINICAL MANAGEMENT OF PATIENTS RECEIVINGCAR T CELL THERAPY FOR CNS TUMORS
Susan Holtzclaw, and Corrine Hoeppner; Seattle Children’s Hospital,
Seattle, WA, USA
Chimeric antigen receptor (CAR) T cells are an innovative new therapy
with proven efficacy in some pediatric cancers such as leukemia andlymphoma, but much less experience in solid tumors, especially tumors of
the central nervous system (CNS). Seattle Children’s has three open Phase
1 CAR T cell studies (BrainChild-01, -02, and -03 targeting HER2, EGFR,
and B7-H3, respectively) for recurrent/refractory CNS tumors and DIPG
(BrainChild-03 only). As of December 2019, four patients have been treatedat Seattle Children’s Hospital with CAR T cells infused on a weekly schedulethrough indwelling catheters into the tumor resection cavity or ventricularsystem. Given the scrutiny of clinical care needed for Phase 1 studies, we are
now able to report detailed clinical information that we have learned during
the treatment of these patients. Clinical care includes the judicious use ofsteroids, the clinical support of patient’s symptoms pre- and post-infusion,and the management of peritumoral edema. We will also discuss the psychosocial support needed for families who travel long distances to receive thistherapy compounded by the many emotional components of being enrolled
on any Phase 1 trial. Case studies and experience from a Nurse Practitioner
role will be provided and discussed.

NFB-18. IMMUNE FUNCTION IN CHILDREN TREATED WITH
TRAMETINIB
Perla Moukhaiber, Anna Samolej, Palita Somsri, and Geoffrey McCowage;
Children’s Hospital at Westmead, Sydney, NSW, Australia

NURS-03. DEVELOPMENT OF A PATIENT-HELD TREATMENT
SUMMARY FOR PAEDIATRIC CNS TUMOUR PATIENTSRachel McAndrew, Bernadine Wilkie, Mark Brougham, and Jo Phillips;
NHS Lothian, Edinburgh, Scotland, United Kingdom

BACKGROUND: Trametinib (Tr) has been applied in the treatmentof children with various tumor types, often for prolonged periods. Little
is known regarding immune function (IF) following prolonged Tr in thisage group. OBJECTIVE: Describe laboratory measures of IF in children
on Tr. METHOD: Patients receiving Tr had low grade glioma with BRAF
anomalies (6), or neurofibromatosis-1 (16) with glioma or plexiform neurofibroma. IF was evaluated using leukocyte/lymphocyte counts, immunoglobulin levels, and antibody titres. RESULTS: 22 patients received Tr. 2
also received Dabrafenib. Median age at Tr initiation of Tr was 7.75 years.
As of June 2020, 7 patients have had IFT; results are pending on 15. Median duration of Tr therapy at time of IF was 3.5 years (0.8 – 4). In these 7
patients, median white cell count was 6.9 x 10^9/L (4.1 – 12.6), neutrophils
4.2 x 10^9/L (1.8 – 6.8) and lymphocytes 3.2 x 10^9/L (1.4 – 7). IgG levels,
B cells and CD8 cytotoxic T cells were normal across 7/7 patients:medians
9.47 g/L (8.62 – 17), 0.51 x 10^9/L (0.2 – 1.26) and 0.58 x 10^9/L (0.25 –2.03) respectively. CD3 and CD4 T cells: median 2.08 x 10^9/L (0.67 – 4.62)
and 1.34 x 10^9/L (0.35 – 2.31), borderline low in 1 heavily pre-treated patient. An adequate immune response was present in all 4 vaccine antigens
tested in 5/5 patients. CONCLUSION: IF appears relatively intact, relevant
for immunisation and infection precautions in children on Tr. Data on thecomplete cohort will be presented.

BACKGROUND: Following the Scottish Government Cancer Plan 2012–15(1) ‘End of Treatment’ summaries for paediatric oncology patients treatedin SE Scotland have been successfully implemented. However, it became evident that the particular needs of patients with CNS tumours were not adequately captured on the standardised documentation. METHODS: In viewof these difficulties an alternative document was prepared specifically forthis patient cohort by the multi-disciplinary team, including Nurse Specialists, Paediatric Neuro-oncology and Neuro-psychology. This was designed
to be a flexible, fluid summary to be used for all such patients regardlessof tumour grade or treatment modality and included those undergoing surveillance only. OUTCOMES: The document is primarily completed by the
Neuro-Oncology Nurse Specialist alongside the patient and family, usuallyfollowing initial treatment and is used alongside their holistic needs assessment. The document is circulated to all involved professionals, includingPrimary Care, and a copy is retained by the patient. This then provides aconcise source of information detailing diagnosis and treatment, any specific ongoing sequelae and details of red flag symptoms to alert patients andhealth professionals to the potential of relapse or other associated significant
health problems. These treatment summaries are currently being piloted andhave been well received thus far. They will be formally audited in due coursewith the aim to use nationally throughout Scotland in future.

NURSING/PATIENT CARE
NURS-01. INTRACEREBROVENTRICULAR DRUG
ADMINISTRATION FOR TREATMENT OF PEDIATRIC BRAIN
TUMORS
Caroline Fitzgerald, and Kathryn Matson; Boston Children’s Hospital,
Boston, MA, USA
Intrathecal (IT) chemotherapy, given via lumbar puncture (LP) or an
intracerebroventricular (ICV) device has become a safe and effective way
to deliver chemotherapy into the cerebrospinal fluid (CSF) space. The blood
brain barrier makes treating tumors with CSF dissemination difficult withsystemic chemotherapy alone. IT chemotherapy is often necessary for tumors which disseminate into the CSF space including embryonal tumors

NURS-04. COMBINATION OF NEURO-ONCOLOGY AND
DERMATOLOGY CLINICS IMPROVE THE MANAGEMENT AND
KNOWLEDGE OF SKIN-RELATED TOXICITIES WITH MEK AND
BRAF TARGETED THERAPY
Tara McKeown, Irene Lara-Corrales, and Andrea Cote; Hospital for Sick
Children, Toronto, ON, Canada
BACKGROUND: The recent advancement in treating pediatric low grade
glioma has led to upfront use of MEK and BRAF (MAPK) inhibitor therapy.
At the Hospital for Sick Children we are the National leaders in treating
pediatric oncology diagnosis with MAPK therapies. DESIGN: After treating
several patients on MAPK inhibitors with various degrees of skin toxicity,
we found we had poor and inconsistent access to dermatology services
and as oncology practitioners had limited front-line knowledge about skinmanagement. It was determined that a more formalized expertise and timewith dermatology was needed. In 2018, in combination with the derma-

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tology team, our new agents and innovative therapy and the nursing team
we collaborated to develop a combined oncology and dermatology clinic.
This clinic occurs twice a month to give our families and oncology teams
better front-line access to dermatology knowledge and care. RESULTS: The
dermatology and oncology team have collaborated to provide information
sessions for the oncology medical team about current research, skin gradingand education. This combined approach has allowed us to ensure that each
new family starting MAPK inhibitor therapy undergoes a baseline skinassessment, education on prophylactic skin measures and easier access todermatology within their oncology clinic. We are also developing guidelines
to consistently treat common skin related toxicities. CONCLUSION: The
early involvement of the dermatology clinic and increase knowledge with
the nursing and medical team has allowed our families to gain confidence inmanaging skin related complication and reducing the need to hold targeted
therapies as a result of dermatological toxicity.
NURS-06. NURSING PROFESSIONALS AND THEIR AID IN
RESEARCH BIOBANKING
Lauren Hancock, and Madhuri Kambhampati; Children’s National
Hospital, Washington, DC, USA
Nursing teams play an integral role in the care of patients with brain tumors; however nurses do not often see themselves as essential contributors
to translational research. Recent development of nurse-researcher relationships and involvement of the multidisciplinary team have led to successful
biobanking strategies. Though there are challenges associated with fostering
these relationships, their vital role has significantly enhanced participant
recruitment and sample collection at one large urban Children’s Hospital.
Researchers at the institution have established a biobank to collect samples from pediatric brain tumor patients at diagnosis, during therapy, andpost mortem using conventional methods. However, a collaborative environment between nursing and research teams greatly enhanced the growthof the biobank. We have increased patient recruitment by more than 50%
in the past four years and supported different types of specimen collection.
Our success entails: 1) development of nurse-researcher relationships, 2) anefficient consent process, 3) streamlined sample collection, and 4) appreciation of the vital role of the nursing team in clinical data collection pertinent to molecular analysis. Additionally, the support of nursing is valuable
during post mortem consents and provides emotional support to the family
to fulfil their wish to donate. Nurses play a major role in coordination of
the post-mortem donation process, and assist in the formation of partnerships within the community to promote this opportunity to families. As
biobanking continues to be an important part of bench research, all institutions should recognize and support the vital role that nurses can have inenhancing this endeavor.
NURS-07. STAFF EDUCATION THROUGH NURSING AND
PHARMACY COLLABORATION
Lauren Hancock1, and Whitney Pittman2; 1Children’s National Hospital,
Washington, DC, USA, 2Children’s Hospital at OU Medical Center,
Oklahoma City, OK, USA
Even within the focused field of pediatric oncology, there are healthcare
providers who lack education regarding the specialized population of children
with brain tumors. In order to improve staff knowledge of pediatric neurooncology, nursing and pharmacy developed a collaborative Lunch and Learn
program to provide additional education. An eight week brain tumor curriculum was developed, and informal sessions grouped by diagnosis were held
over lunch between the neuro-oncology nursing team (nurse practitioners andnurse coordinator) and a clinical pharmacy resident. A nurse practitioner provided academic literature and the pharmacy resident did further research anddeveloped an outline for discussion. During these sessions, nursing was able tocontribute academic knowledge and clinical experience, while pharmacy presented an overview of each tumor and provided education about medications.
After each session, the pharmacy resident presented the information from theLunch and Learn to all staff oncology pharmacists, which then increased theirworking knowledge of neuro-oncology as a whole, helping them feel better
able to manage this population within their scope of practice. Because thisinnovative collaboration was so successful in heightening knowledge andawareness of the care and management of pediatric neuro-oncology patientsfor all those involved, the team now has future plans to utilize a similar model
to provide neuro-oncology education to clinic and inpatient RNs.
NURS-08. A CASE REPORT OF RARE AND PROFOUNDANTEROGRADE AMNESIA IN A PAEDIATRIC SURVIVOR OF
A BIFOCAL NON GERMINOMATOUS GERM CELL TUMOUR AND
DIABETES INSIPIDUS
Elizabeth Bland; Sydney Children’s Hospital, Sydney, NSW, Australia
We present the case of a 12yo female who presented to the emergency
department with increasing agitation, confusion, fluctuating GCS, hydro-iii422

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cephalus, and deranged electrolytes. MRI revealed tumour in pineal region
and filling the third ventricle. Biopsy and tumour markers confirmed the
diagnosis of bifocal Non Germinomatous Germ Cell Tumour (NGGCT).
The diagnosis was complicated with the secondary diagnoses of diabetes insipidus and profound permanent anterograde amnesia. Whilst DI is common
in NGGT in pineal region, anterograde amnesia is a very rare condition in
paediatrics. Thus there is paucity of literature available to the clinicians toknow how much improvement to expect or how to target rehabilitationwhilst undergoing curative therapy, chemotherapy and craniospinal irradiation; however the importance of a consistent and coordinated nursing andallied health team approach with structure and errorless learning must be
initiated from the beginning if independence is to be achieved.
NURS-09. INTRODUCTION OF A WELLNESS PROGRAM FOR
PEDIATRIC NEURO-ONCOLOGY PROVIDERS
Kaaren Waters1, Helene Morgan2, Kasey Rangan1, Kim Bira1,
Tom Davidson1,3, Nathan Robison1,3, and Ashley Margol1,3; 1Cancer andBlood Disease Institute and Division of Hematology-Oncology, Children’s
Hospital Los Angeles, Los Angeles, CA, USA, 2Office of Academic Affairs,
Children’s Hospital Los Angeles, Los Angeles, CA, USA, 3Keck School of
Medicine, University of Southern California, Los Angeles, CA, USA
INTRODUCTION: Pediatric oncology providers have unique and rewarding careers. The medical and psychosocial complexity of caring
for pediatric oncology patients and their family units is simultaneously
inspiring and challenging. In addition, the complex demands of thehealthcare system can lead to chronic stress, burnout, and disruption to thehealthcare professional’s individual well-being. Time constraints, lack of resources, and limited access to wellness interventions serve as barriers forproviders to address adaptive coping within themselves. Identifying gaps toachieving wellness and implementing interventions may lead to improved
equanimity for pediatric oncology providers in their personal lives as wellas their medical practice. METHODS: An interdisciplinary team of nurse
practitioners and physicians in a large pediatric neuro-oncology programat an academic institution completed anonymized wellness self-assessments
regarding the areas of emotional, environmental, intellectual, occupational,
physical, social, spiritual, coping, and professional role wellness. The results
were analyzed and barriers to provider health and well-being were identified. Tailored and regularly scheduled wellness interventions were implemented for the study participants addressing the identified wellness barriers.
Participants will each complete post-intervention wellness self-assessments
to evaluate the effectiveness of the program. CONCLUSION: The introduction of a provider wellness program exemplifies a feasible approach toidentify barriers and evaluate efficacy of wellness interventions in achieving
multi-factorial provider wellness. Secondary aims include dissemination offindings, with the intention of cultivating improvement in provider qualityof life throughout the healthcare profession, and the ultimate goal of
improving care to patients and families.
NURS-10. IMPROVEMENTS IN A BEHAVIORAL TRAINING AND
PHARMACOLOGICAL ANXIOLYSIS ALGORITHM FOR INCREASEDCOMPLIANCE IN PEDIATRIC PATIENTS IN PREPARATION FORRADIATION THERAPY: A RETROSPECTIVE ANALYSIS
Judy Tran1, Jennifer Holt1, Danielle Crump2, Anita Shea2, Lin Whetzel3,
Andrea Lattimore1, Rebecca Carson4, and Roberta Anderson2; 1Sibley
Memorial Hospital, Washington, DC, USA, 2Johns Hopkins Medical
Institute, Baltimore, MD, USA, 3Childrens National Hospital System,
Washington, DC, USA, 4Cincinnati Children’s Hospital, Cincinnati, OH,USA
BACKGROUND: In the pediatric population, the probability of compliance with radiation involves multifactorial elements. Younger pediatric patients often require anesthesia to ensure accurate delivery of radiotherapy.
The purpose of this analysis was to refine our algorithm in pediatric patients to better identify children who would benefit from behavioral training
and/or anxiolyxis intervention with the goal of minimizing anesthesia
use. METHOD: Retrospective data was collected from electronic medical
records from 150 pediatric oncology patients <18 years old, treated withphoton and proton radiation at our center from August 2016 to December
2019. We identified potential socio-developmental treatment factors thought
to impact behavioral compliance and categorized risk factors based on analgorithm to determine risk for noncompliance with radiotherapy. RESULTS: Six categories demonstrated statistical significance (p<0.05) in theirinfluence on behavioral compliance during radiotherapy: age category (specifically age <7: Odds ratio [OR] 3.0, 95% Confidence Interval [CI] 1.0, 9.1),
need for sedation with prior imaging studies (p<0.001), parental premonition of requiring anesthesia for successful treatment (p<0.001), durationof treatment, primary language (p<0.001), and use of total body irradiation(OR 3.1, 95% CI 1.1, 9.3). CONCLUSION: Identification of pre-radiation
risk factors allowed for better recognition of patients at risk for treatment
non-compliance and for requiring daily sedation. Future studies should
focus on implementing the algorithm prospectively in an effort to identify

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and direct early intervention with behavioral training and/or anxiolytics tominimize the need for sedation.
NURS-11. MARIJUANA, HEMP, AND THE CHILD WITH CANCER:
PATIENT, PARENT, AND CLINICIAN EDUCATION
Molly Hemenway; Univ of Colorado, Children’s Hospital Colorado,
Aurora, CO, USA
Many pediatric oncology patients report medical marijuana (MMJ) andhemp-based CBD use. Eleven states and Washington, DC have legalized marijuana for recreational use for adults greater than 21. Medical marijuanais legalized in 33 states. Additionally, due to the bipartisan Farm Bill passed
in December of 2018, hemp is federally legal. Marijuana has medical legalization in 23 countries worldwide. Clinical trials in adults have examined
MMJ for cancer-related symptoms. New research is emerging on MMJ in
anticancer therapy, MMJ receptors on tumor cells, and the potential role for
MMJ as an immunomodulator. Few pediatric oncology studies have evaluated MMJ. We describe the initial findings of a prospective observational
study of MMJ on the quality of life (QOL) in pediatric brain tumor patients. Specific aims included (1) MMJ’s association with symptoms (nausea,
anxiety, pain, fatigue, and cognitive problems) and (2) MMJ’s impact onfamily dynamics. The legality of hemp plus the increasing use of MMJ raises
concerns with pharmacological interactions with CBD and the medications
routinely administered to children with cancer. Nurses are the frontline fordiscussions with patients about MMJ and must be aware of the emerging
field of MMJ in pediatric cancer. Additionally, nurses can influence patientcare protocols and processes for alternative therapy administration enablingan open dialogue between providers, parents, and patients regarding treatments, symptoms, adverse effects, and drug interactions. Education about
how to have conversations about important facets to cover and consider iscrucial to patient safety and increased quality of life.
NURS-12. MAKING SURVIVORS HEALTHIER:A MULTIDISCIPLINARY APPROACH TO HYPOTHALAMIC OBESITY
Molly Hemenway, Kathleen Dorris, Amy Rydin, Thomas Inge,
Megan Kelsey, Todd Hankinson, Suzanne Paul, Matthew Haemer, andJaime Moore; Univ of Colorado SOM, Children’s Hospital Colorado,
Aurora, CO, USA
BACKGROUND: Pediatric survivors of hypothalamic/suprasellar tumors
have significant morbidities that greatly impact their quality of life. Management of hypothalamic obesity has traditionally fallen between multiple
subspecialties without a timely and comprehensive approach. METHODS: A
multidisciplinary group of key players from neuro-oncology, endocrinology,
nutrition, neurosurgery, and bariatric surgery were identified. Through thiscollaboration, a clinical algorithm for early identification of and intervention for hypothalamic obesity was developed. The goal of the quality improvement process is to increase the number of encounters with a registereddietitian (RD) with earlier and more consistent referrals to a specialized,
multidisciplinary weight management program [Lifestyle Medicine; (LM)]for counseling and pharmacologic interventions. Indications for referral
to LM were BMI >95th percentile, crossing >2 BMI percentiles on growth
curve and/or hyperphagia symptoms. A retrospective review of pediatricpatients who have suprasellar/ hypothalamic tumors was also conducted.
Data collected included demographics, tumor type, BMI, RD visit, and LM
clinic referral/visit. RESULTS: Fifty patients were identified for analysis six
months following clinical algorithm institution. Thirty-three (66%) patients
had craniopharyngioma, 15 (30%) had low-grade gliomas, and two (4%)
had germ cell tumors. Thirty-three (66%) patients were noted to be obese(defined as BMI >95th percentile) at review. The median BMI of the entire
cohort was 93rd (range, 1st-137th) percentile. Thirty-four (68%) patients had
been seen by an RD. Twenty-seven (82%) of the obese patients had beenreferred to LM. CONCLUSIONS: The development and implementation of
the process for hypothalamic obesity prevention and intervention will be
discussed.

OTHER (NOT FITTING ANY OTHER CATEGORY)OTHR-02. MULTIMODALITY TREATMENT FOR CHILDREN WITH
CENTRAL NERVOUS SYSTEM (CNS) TUMOR IN OUR INSTITUTE
Mari Sasano1, Koichiro Sumi1, Nobuhiro Moro1, Hideki Oshima1,
Maiko Hirai2, Hiroshi Yagasaki2, and Atsuo Yoshino1; 1Department of
Neurological surgery, Nihon University School of Medicine, Tokyo, Japan,
2Department of Pediatrics and Child Health, Nihon University School of
Medicine, Tokyo, JapanBACKGROUND: The brain tumor has a highest mortality rate amongchildhood malignant tumors. Development of peripheral blood stem celltransplant combined chemotherapy and radiation therapy improved thesurvival rate of patients with pediatric brain tumor drastically late years.
Because of its complicated treatment plan, neurosurgeons cannot readily
manage these aggressive therapies which require minute whole body control
including prevention of lethal infection due to bone marrow suppression.
Even if such treatment is effective and patient survives, the aftereffects may
reduce patient’s QOL. PURPOSE: We report outcomes of the patients with
CNS tumor after multimodality treatment. In addition, we introduce theactivity contents by the in-hospital children brain tumor multi-disciplinary
medical treatment team organized in March 2016. METHODS: We retrospectively reviewed 29 patients (under 15 years old) diagnosed as CNS
tumors with total of 43 tumor surgeries between January 2001 and December 2019. RESULTS: The histopathological diagnoses were 7 germ
cell tumor, 7 astrocytic tumor, 4 ependymal tumor, 4 medulloblastoma, 2craniopharyngioma, 2 AT/RT and 3 others. The mean age at first surgery
was 7.4 y.o. (range: 0.3–14.8). Both chemotherapy and radiation therapy
were performed in 22 cases out of 29. There were 15 survivors (11 ambulant, 3 W/C, 1 bedridden), 12 deaths, 2 lost follow-ups. Mean follow-up
period was 66 months (range: 1–206). CONCLUSION: To improve outcomes, we hold on a regular basis of team meeting, discuss treatment plan,and share information. Recently, we also care issues of the patients, such as
fertility and palliative medicine.
OTHR-07. CHRONIC ENCEPHALOPATHY DUE TO
METHOTREXATE NEUROTOXICITY AS A RARE COMPLICATIONIN A CHILD WITH LEUKEMIA: A CASE REPORT
Achmad Rafli, Srisadono Fauzi Adiprabowo, Ludi Dhyani Rahmartani,and Setyo Handryastuti; Department of Child Health Faculty of Medicine
Universitas Indonesia Dr.Cipto Mangunkusumo Tertiary National
Hospital, Jakarta, Indonesia, Jakarta, DKI Jakarta, Indonesia
Methotrexate (MTX) is an essential component of chemotherapy forchildhood acute lymphoblastic leukemia (ALL). Both intravenous (IV) andmost commonly intrathecal (IT) routes of MTX have been complicated inacute, subacute, and chronic neurotoxicity syndromes. A 9-year-old girl had
been diagnosed with standard risk ALL since 2011 with first chemotherapy
protocol was Indonesian protocol standard risk ALL 2006 and remission in
2012. On July 2015, patient was diagnosed as relapse ALL and underwent
Indonesian protocol high risk ALL 2013. The last chemotherapy protocolof patient was Indonesian protocol high risk ALL 2013 maintenance phase89th weeks with total dosage of MTX was 336 mg (IT), 6000 mg/m2 (IV),and 2500 mg/m2 orally. Her presenting symptom was progressive decreaseof consciousness since 3 months before hospital admission. First brain computed tomography (CT-Scan) and magnetic resonance imaging (MRI) revealed brain atrophy. One month later she had abnormality in behavior andfunctional ability with second brain CT-Scan revealed brain atrophy andlacunar infarct in left pons. This case can be in accordance with chronic encephalopathy due to MTX. It is important to recognize early complications
taking the form of subclinical or symptomatic CNS damage (e.g. headache,dizziness, tremor, ataxia, aphasia, dysarthria, emotional instabilities, seizures, hemiparesis, encephalopathy) that can occur in the course of chemotherapy especially MTX. Determination of the cause of encephalopathy is
associated with considerable difficulty despite the use of various diagnostic
methods and also treatment of MTX neurotoxicity is mainly supportive andrecovery is usually complete. Keywords: imaging, methotrexate, neurotoxicity, leukemia
OTHR-09. CENTRAL DIABETES INSIPIDUS: A RARE UNREPORTEDSIDE EFFECT OF TEMOZOLOMIDE IN PEDIATRICS
Christopher Kuo1, Kaaren Waters2, Clement Cheung3, andAshley Margol4,2; 1Department of Pediatrics, Children’s Hospital Los
Angeles, Los Angeles, CA, USA, 2Cancer and Blood Disease Institute andDivision of Hematology-Oncology, Children’s Hospital Los Angeles,
Los Angeles, CA, USA, 3The Center for Endocrinology, Diabetes, andMetabolism Children’s Hospital Los Angeles, Los Angeles, CA, USA, 4Keck
School of Medicine, University of Southern California, Los Angeles, CA,USA
Temozolomide is a chemotherapeutic agent commonly used in the treatment of central nervous system tumors. While there are case reports oftemozolomide associated central diabetes insipidus (CDI) in adults, this has
not been reported in children. We describe the first case of temozolomide
associated CDI in a pediatric patient. The patient was a previously healthy
12yr old male diagnosed with anaplastic astroblastoma. He underwent grosstotal resection of the lesion and was subsequently treated with focal radiation therapy and concurrent temozolomide. On day 21 of therapy he developed thrombocytopenia, severe polyuria and polydipsia. Temozolomide washeld and he underwent a preliminary evaluation for CDI. Initial laboratory
findings were concerning for CDI, and he was admitted for further work-up
and to assess the need for desmopressin. Additional laboratory tests demonstrated normal anterior pituitary function and his serum sodium normalized

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when allowed to drink to thirst, mitigating the need for desmopressin.
Temozolomide was not restarted and the symptoms of polyuria and polydipsia resolved and did not recur. Upon review, the tumor did not involve
the pituitary or hypothalamus. Additionally, these areas were not involvedin the irradiation field. CDI is a rare but clinically significant side effect oftemozolomide, reported in adults. Given this is the first report of CDI secondary to temozolomide in a pediatric patient, we speculate that this is likely
under-recognized in children. Prompt recognition and treatment is necessary
to prevent severe sequelae of hypernatremia.
OTHR-12. ANEURYSMAL BONE CYST RESEMBLING A POSTERIORFOSSA TUMOR
Luis Angel Arredondo Navarro1,2,
Regina Malinali Navarro Martin Del Campo1,2,
Gutierrez Oliva Lorelay Livier1, Valeria Estefania Aguilar Mercado1,
Juan Luis and Soto Mancilla1; 1Hospital Civil de Guadalaja, Guadalajara,
Jalisco, Mexico, 2GAP-NO, International, Mexico
We presented the case of a 6-year-old boy who was seen in the emergency room because of signs of intracranial hypertension and left cerebellar
syndrome. The CT scan revealed a heterogeneous lesion within the left
hemisphere displacing the fourth ventricle and eroding the occipital bone.
The MRI showed the same heterogeneous lesion majorly cystic, involving
the bone and displacing the left cerebellar hemisphere. A minor hydrocephalus was evident in both studies. A suboccipital craniectomy was done anda cystic epidural tumor remodeling and eroding the bone was noted. The
histopathological diagnosis corresponded to an aneurysmal bone cyst. Aneurysmal bone cyst is a rare benign tumor accounting for 3–6 % of tumorsof the cranial base. We discuss the unusual location of the lesion.
OTHR-14. DIENCEPHALIC SYNDROME SECONDARY TO
PITUITARY STALK THICKENING
Carlos Almeida Jr, Bruna Minniti Mançano, Gilda D’Agostino Eugui,
Marcus Matsushita, Gabrielle Alvarenga, and Lucas Dias Lourenço;
Barretos´s Children and Young Adults Cancer Hospital, Barretos, Sao
Paulo, Brazil
BACKGROUND: Diencephalic syndrome (DS) is a rare condition associated with neoplastic lesions of the sellar-suprasellar region, whose
pathophysiological mechanisms are still unclear. DS occurs in <10% of hypothalamic gliomas and has also been described in suprasellar germinomas,
craniopharyngiomas, epidermoid cysts, rarely with non-suprasellar lesions
such as brainstem gliomas. DS has not been associated with isolated pituitary stalk thickening. Isolated pituitary stalk thickening (IPST) presents adiagnostic challenge, ranging from benign (craniopharyngioma) to malignant lesions (germinoma, metastasis, histiocytoses of the Langerhans group).
The coexistence of diabetes insipidus (DI) with anterior pituitary dysfunction
and IPST implies more risk to harbor neoplasia. CASE REPORT: A 6-year
old girl presented with DI and inadequate weight gain (despite regular caloric intake) and preservation of linear growth. Neurological examination
showed no abnormalities. However, physical examination revealed a malnourished patient (both weight-for-age value and body-mass-index below
the third percentile). Blood tests and negative IgA anti-endomysial antibodies excluded malabsorption as a cause of her malnutrition; endocrine
work-up excluded thyroid dysfunction, growth hormone deficiency, andadrenal insufficiency. Magnetic resonance imaging (MRI) showed thickening of the pituitary stalk with a transverse diameter of 7 mm. The patientunderwent a biopsy through a supraorbital eyebrow approach. Histopathological examination revealed lymphocytic hypophysitis, with tissue markers
all negative for germinoma. The girl is currently under follow up with serial
MRI every three months. CONCLUSION: DS should be considered as adifferential diagnosis in any child with failure to thrive, and imaging studies
should be performed even if there are no additional neurological symptoms.
OTHR-16. CONCURRENT USE OF APREPITANT AND IFOSFAMIDE
IN PEDIATRIC CANCER PATIENTS
Shelby Winzent, Nathan Dahl, Molly Hemenway, Rachel Lovria, andKathleen Dorris; Univ of CO, SOM, Children’s Hospital Colorado, Aurora,
CO, USABACKGROUND: Aprepitant, a selective neurokinin-1 receptor antagonist, is commonly used for prevention of chemotherapy-induced
nausea and vomiting. Its use with ifosfamide is controversial due to theputative risk of potentiating neurotoxicity via inhibition of cytochrome
P450 3A4 (CYP3A4). The current literature examining this interaction
is inconclusive, and little data exists in pediatrics. We seek to describe asingle-institution experience with concurrent aprepitant and ifosfamide administration. METHODS: A retrospective review of patients treated with
ifosfamide and aprepitant from 2009–2018 was conducted. Data collected
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dosing, and documented of neurotoxicity. RESULTS: Twenty patients aged
7–21 years (median 17 years) were identified. Diagnoses included thirteen
sarcomas and seven CNS tumors (6 germ cell tumors; 1 intracranial sarcoma).
Five patients received high dose ifosfamide (>2,000mg/m2/day). The numberof concurrent ifosfamide and aprepitant doses ranged from 2–18 (median,8.5). Only one patient (5%) developed ifosfamide-induced neurotoxicity: a
7-year-old female with a nongerminomatous germ cell tumor who presented
with seizures and somnolence. She received methylene blue and returned toher neurologic baseline. She completed her ifosfamide course without incident. She was the only patient to require weight-based aprepitant dosing
and to receive the liquid formulation. CONCLUSIONS: Aprepitant should
be used with caution when administered concurrently with ifosfamide dueto the risk of neurotoxicity. However, the incidence of neurotoxicity in thisretrospective pediatric cohort was low. This interaction may be more significant in younger patients due to age-related differences in hepatic metabolism, but further study is required.

PATHOLOGY AND MOLECULAR DIAGNOSISPATH-01. MOLECULAR PROFILING OF PAEDIATRIC CENTRALNERVOUS SYSTEM TUMOURS IN AUSTRALASIA – AN UPDATE ON
THE AIM BRAIN AND MNP2.0 PROJECTSElizabeth Algar1,2, White Christine1, Kathryn Kinross3, Molly Buntine1,
David Jones4, Stefan Pfister4, Robyn Strong3, Nicholas Gottardo5,6, andJordan Hansford7,8; 1Hudson Institute of Medical Research, Melbourne,
Victoria, Australia, 2Monash University, Melbourne, Victoria, Australia,
3Australian and New Zealand Children’s Oncology Group, Melbourne,
Victoria, Australia, 4Hopp Children’s Cancer Center, Heidelberg, Germany,
5Perth Children’s Hospital, Perth, Western Australia, Australia, 6Telethon
Kids Institute, Perth, Western Australia, Australia, 7Royal Children’s
Hospital, Melbourne, Victoria, Australia, 8University of Melbourne,
Melbourne, Victoria, Australia
The Access to Innovative Molecular Profiling for Paediatric Brain Cancers(AIM BRAIN) project is a trial testing the feasibility of clinical implementation of diagnostic methylation and molecular profiling for central nervous
system (CNS) tumours in Australia and New Zealand. AIM BRAIN builds
on an existing study, MNP2.0, and allows cross-validation of results derived
from identical samples in separate laboratories in Melbourne, Australia, and
DKFZ, Heidelberg, Germany. Parallel methylation profiling (Illumina 850K
EPIC array) from co-enrolled cases has revealed excellent concordance between laboratories with 50/51 cases (98%) yielding identical classification
using the DKFZ Molecular Neuropathology 2.0 Classifier v11b4. 77/91(85%) of AIM BRAIN cases classified concordantly by methylation array
when compared to their diagnostic histopathology. Of these 77 cases, 16 hadclassifications below a threshold of 0.90, however still classified correctly.
In 14 discordant cases either the histopathology was not well defined, notrepresented on the classifier, or a very low classification score was obtained.
Molecular profiling through MNP2.0 identified 49/167 (29.3%) tumours
with gene fusions including BRAF-KIAA1549 (n=29), RELA-C1lorf95(n=5) and 15 rare or novel fusions. BRAF-KIAA1549 was almost exclusively
associated with pilocytic astrocytoma (28/29) and RELA-C1lorf95 withependymoma. Six pathogenic germline mutations were identified in TP53(n=2), BRCA1, NF1, LZTR1 and ATM. The incidence of germline predisposition was low (4%) and sex biased towards females (5F:1M), (p<0.08).
Our findings confirm methylation profiling as a robust platform for classifying CNS tumours with potential to reveal new CNS tumour entities whencombined with molecular profiling.
PATH-03. HIGH-GRADE NEUROEPITHELIAL TUMOR SHOWINGBCOR IMMUNOPOSITIVITY WITHOUT EXON 15 INTERNALTANDEM DUPLICATIONS IN A FIVE-YEAR-OLD BOY: A CASEREPORT
Shogo Wakita1, Tomoo Matsutani1, Yosuke Watanabe1, Seiichiro Hirono1,
Yoshinori Higuchi1, Yasuo Iwadate1, Zyunichiro Ikeda2, andHideaki Yokoo3; 1Department of Neurological Surgery, Chiba University
Graduate School of Medicine, Chiba, Japan, 2Department of Diagnostic
Pathology, Chiba University Graduate School of Medicine, Chiba,
Japan, 3Department of Pathology, Gunma University Graduate School of
Medicine, Gunma, Japan
Recent DNA methylation profiling clarified several rare entities of pediatric CNS tumors from institutionally-diagnosed primitive neuroectodermal
tumors (PNETs). One of which is CNS high-grade neuroepithelial tumor
with BCOR alteration (CNS HGNET-BCOR), and it carries in-frame internal tandem duplications (ITD) of the BCL6 corepressor (BCOR) in exon
15. In the report, we describe a case of immunohistologically-diagnosed CNS
HGNET-BCOR, which lacks exon 15 ITD of BCOR. A five-year-old boy
visited a local hospital complaining uncontrolled vomiting for two months,

Abstracts

and magnetic resonance imaging (MRI) showed a large well-circumscribed
mass in his left cerebellum with ventricular dilatation. He referred to our
hospital, and an additional MRI revealed diffuse and weak enhancementof gadolinium and low ADC values in mass. Immediately, he underwent
total removal of the tumor and ventricular drainage, and his consciousness
recovered soon after surgery. The tumor presented high BCOR expression
by IHC, but target PCR did not identify exon 15 ITD of BCOR. As thepreviously-reported clinical and imaging features of CNS HGNET-BCOR
resembled our case, we clinically diagnosed it as a similar phenotype of CNS
HGNET-BCOR without exon 15 ITD. He received 60 Gy of extended-local
irradiation with concomitant temozolomide and discharged without any
neurological deficits. Since BCOR alterations, including ITD, gene fusions,and mutations, play an oncogenic role in several cancers, the present casemight harbor another gene aberration of BCOR.
PATH-04. AN ENHANCED AI-DRIVEN PLATFORM FOR PRECISION
MOLECULAR BRAIN TUMOR DIANOSTICS
Martin Sill1,2, Felix Sahm3,4, Daniel Schrimpf3,4, David Capper5,
Stefan M. Pfister1,2, Andreas von Deimling3,4, and David T.W. Jones6,7;
1Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ),
Heidelberg, Germany, 2Division of Pediatric Neurooncology, German
Cancer Research Center (DKFZ), Heidelberg, Germany, 3ClinicalCooperation Unit Neuropathology, German Cancer Research Center(DKFZ), Heidelberg, Germany, 4Department of Neuropathology, Instituteof Pathology, Heidelberg University Hospital, Heidelberg, Germany,
5Charité — Universitätsmedizin Berlin, corporate member of Freie
Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Instituteof Health, Department of Neuropathology, Berlin, Germany, 6Hopp
Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg,
Germany, 7Pediatric Glioma Research Group, German Cancer ResearchCenter (DKFZ), Heidelberg, Germany
Tumors of the CNS represent one of the most complex groups of humancancer, with a vast number of different entities occurring across a spectrumof ages and anatomic locations. This heterogeneity makes accurate diagnosis challenging, with the current gold standard relying on multiple subjective elements. We recently proposed a classification algorithm based ontumor DNA methylation profiling as an objective way to assign samples
to over 80 distinct molecular classes. Here we present a substantial update
to our machine learning-based algorithm, with more than 170 molecularclasses now being represented amongst the 5,915 samples in our reference
cohort. These new classes include further subclassification of known groups
such as medulloblastoma and ependymoma, as well as multiple new molecular entities described here for the first time. A further improvement is theintroduction of a more rationally layered output, making use of ‘families’of closely-related molecular classes to improve the compatibility with thecurrent WHO classification of CNS tumors. This approach is designed toincrease the clinical relevance of the primary output, while also retaining
the full information content from the random forest-driven classification.
Benchmarking our new algorithm by cross-validation and on an independent validation cohort indicates a retention of the excellent accuracy of
diagnosis (error-rate < 4%), with a significant improvement in the proportion of confidently classifiable tumors compared with our previous tool. We
believe that this approach, freely accessible through an online web portal,
has the potential to enhance diagnostic precision and thereby support clinical care for brain tumor patients.
PATH-05. A CASE OF PILOCYTIC ASTROCYTOMA HARBORING
THE FGFR1 GENE MUTATION WITH A PREDOMINANT
OLIGODENDROGLIOMA-LIKE COMPONENT
Nobuyoshi Sasaki1,2, Tomohiro Chiba3, Kuniaki Saito1, Keiichi Kobayashi1,
Yoshiaki Shiokawa1, Junji Shibahara3, and Motoo Nagane1; 1Departmentof Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan,
2Department of Brain Tumor Translational Research, National Cancer
Center Research Institute, Tokyo, Japan, 3Department of Pathology, Kyorin
University Faculty of Medicine, Tokyo, Japan
Pilocytic astrocytomas rarely present with oligodendroglioma-like morphological features, which gives rise to a diagnostic challenge. In this report
we present a case of pilocytic astrocytoma harboring the FGFR1 mutation,accompanied with a predominant oligodendroglioma-like component, thus
initially diagnosed as oligodendroglioma. A 14-year-old female presented
with syncope and simple partial seizure involving her right upper limb.
Contrast-enhanced MRI revealed an enhancing lesion with substantial cystic
portion and perifocal edema in the left parietal lobe. Open surgery was performed and a gross total resection of the tumor was achieved. On initialhistopathological diagnosis, tumor cells with monotonous round nuclei
and perinuclear halo predominated with branching capillaries, which werestrongly suggestive for oligodendroglioma. Immunohistochemically, IDH1
R132H was negative, and Ki-67 index was around 5%. The patient was thus
initially diagnosed as oligodendroglioma, WHO grade II, based on the 2007

WHO classification criteria. However, histopathological re-review revealed
a minor astrocytic component with Rosenthal fibers and rare eosinophilic
granular bodies, thus the diagnosis was changed as pilocytic astrocytoma.
FGFR1 K654E mutation was confirmed by Sanger sequencing. Although
she postoperatively developed mild sensory disturbance in her right hands,
finger agnosia, and left-right disorientation, her symptoms had gradually
improved, and she was discharged on day 17 with a Karnofsky performancestatus (KPS) of 90 and no cognitive decline. Without any adjuvant therapies, she has remained recurrence-free for 85 months. While the diagnosisof pilocytic astrocytoma with predominant oligodendroglioma-like component can be challenging, analysis of IDH1 and FGFR1 mutations can bebeneficial in certain cases.
PATH-06. IMAGE-BASED MACHINE LEARNING CLASSIFIER FOR
PEDIATRIC POSTERIOR FOSSA TUMOR HISTOPATHOLOGY
Lydia Tam, Wasif Bala, Jonathan Lavezo, Seth Lummus, Hannes Vogel, andKristen Yeom; Stanford University, Stanford, CA, USA
BACKGROUND: Pediatric posterior fossa (PF) tumors can include
astrocytomas, ependymomas, and medulloblastomas, all of which demonstrate unique histopathology. Whole slide image analyses can be time
consuming and difficult. Therefore, we used machine learning to create ascreenshot-based histopathology image classifier that can distinguish between types of pediatric PF tumors. METHODS: We took 179 histopathology slides from Stanford University, dated from 2008–2019: 87
astrocytomas, 42 ependymomas, and 50 medulloblastomas, per pathology
report. Each slide was viewed under a microscope at 20x. Then, a screenshot
was taken of the region of interest representative of principal slide pathology, confirmed by a trained neuropathologist. These screenshots were used
to train Resnet-18 models pre-trained on the ImageNet dataset and modified to predict three classes. Various models with different hyperparameters
were trained using a random hyperparameter search method. Trainedmodels were evaluated using 5-fold cross-validation, assigning 20% of thedataset for validation with each evaluation. Qualitative analysis of model
performance was assessed by creating Class Activation Map (CAM) representations of image predictions. RESULTS: The top performing Resnet-18
model achieved a cross-validation F1 of 0.967 on categorizing screenshotsof tumor pathology into three types. Qualitative analysis using CAMs indicated the model was able to identify salient distinguishing features of eachtumor type. CONCLUSIONS: We present a PF lesion classifier capable ofdistinguishing between astrocytomas, ependymomas, and medulloblastomas
based on a histopathology screenshot. Given its ease of use, this tool has
potential as an educational tool in an academic setting.
PATH-07. QUALITY ASSURANCE IN CEREBROSPINAL FLUIDCYTOLOGY ASSESSMENT FOR MEDULLOBLASTOMA STAGINGLEADS TO POTENTIAL IMPROVED RISK-GROUP ASSESSMENT IN
THE PROSPECTIVE MULTICENTER HIT-2000 TRIAL
Christian Hagel1, Veronika Sloman2, Martin Mynarek2,
Katharina Petrasch2, Denise Obrecht2, Frank Deinlein3, Renate Schmid3,
André O. von Bueren4, Carsten Friedrich5, B. Ole Juhnke2,
Nicolas U. Gerber6, Robert Kwiecien7, Hermann Girschick8,
Alexandra Höller9, Antonia Zapf9, Katja von Hoff10, andStefan Rutkowski2; 1Institute of Neuropathology, University Medical
Center, Hamburg-Eppendorf, Hamburg, Germany, 2Department ofPediatric Oncology, University Medical Center, Hamburg-Eppendorf,
Hamburg, Germany, 3Department of Pediatric Hematology and Oncology,
University Children’s Hospital Wuerzburg, Wuerzburg, Germany,
4Department of Pediatrics, Obstetrics and Gynecology, Division of PediatricHematology and Oncology, University Hospital of Geneva, Geneva,
Switzerland, 5Division of Pediatric Oncology and Hematology, University
Children’s Hospital Rostock, Rostock, Germany, 6Department of Oncology,
University Children’s Hospital Zurich, Zurich, Switzerland, 7Institut
für Biometrie und Klinische Forschung, Universitätsklinikum Münster,
Münster, Germany, 8Kinder- und Jugendmedizin, Vivantes-Klinikum,
Berlin Friedrichshain, Berlin, Germany, 9Institute of Medical Biometry andEpidemiology, University Medical Center, Hamburg-Eppendorf, Hamburg,
Germany, 10Department of Pediatric Oncology/Hematology, CharitéUniversitätsmedizin Berlin, Berlin, Germany
BACKGROUND: Cerebrospinal
fluid
(CSF)
disseminationofmedulloblastoma (M1 stage) is a high-risk prognostic factor. However, because diagnostic criteria for M1 staging are missing we specified processrelated and cytomorphological parameters influencing the predictive valueof the CSF status. PATIENTS AND METHODS: CSF samples and cytology
reports from 405 medulloblastoma patients of the prospective multicenter
trial HIT-2000 were reviewed and related to 5-year progression free survival(5y-PFS). RESULTS: Tumor cells were detected in 237/1073 CSF cytospins.
M1-patients and M2/3 patients with radiologically detected metastases
showed a worse 5y-PFS than M0 patients (54% and 52% vs. 76%; p=0.01
and p<0.001). Lumbar sampling was more sensitive than ventricular sam-N E U R O -O N C O L O G Y•

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iii425

Abstracts

pling. M0 diagnosed specimens containing >50% lytic cells and/or less than
10 nucleated cells showed a decreased 5y-PFS (61%). Further investigationof cytological parameters revealed a poor outcome for cases harboring > 3
tumor cell clusters and individual tumor cells (5y-PFS 33%) vs. cases with ≥2 individual tumor cells but no clusters (5y-PFS 61%). In bi-variable Coxregression, ≥ 2 vs. 0 or 1 tumor cells were associated with a Hazard Ratio(HR) of 0.52 (95%-Confidence Interval (CI): 0.12, 2.30; p=0.39), whereas> 3 vs. no tumor cell clusters were associated with a HR of 8.94 (95%-CI:
1.66, 48.22; p=0.01). CONCLUSIONS: CSF staging in medulloblastoma
should comprise lumbar specimens with <50% lytic cells and a minimumof 10 nucleated cells. The predictive value of CSF cytology in M1 cases may
predominantly depend on tumor cell clusters. The latter finding needs to be
confirmed in prospective trials.
PATH-08. THE IMPORTANCE OF RE-DIAGNOSIS OF TUMORSPREVIOUSLY CLASSIFIED AS CENTRAL NERVOUS SYSTEMPRIMITIVE NEUROECTODERMAL TUMORS
Naohide Fujita, Osamu Akiyama, and Akihide Kondo; Department of
Neurosurgery, Juntendo University Faculty of Medicine, Tokyo, JapanBACKGROUND: The recent molecular analyses have revealed that central nervous system primitive neuroectodermal tumors (CNS PNETs) thosehaving clusters of small round tumor cells are genetically different tumors.
However, the concepts of CNS PNET are complicated, and it is difficult todiagnose them appropriately in clinical field. To overcome this difficulty, we
reviewed previous studies associated with CNS PNETs, and carried out several approaches, those are relatively easy access to use in clinics, for our 8
samples of embryonal brain tumors diagnosed CNS PNETs in our institution,
initially. METHODS: We used in combination with immunohistochemistry(IHC), Sanger sequence, Pyrosequence, polymerase chain reaction (PCR),
real time PCR and copy number analysis referring recent reports. RESULTS: In terms of the diagnosis three out of 8 cases were changed basedon the results in this study from previous diagnoses. CONCLUSION: In thisreview, it seemed that either the histopathological evaluation or molecularanalyses would be not enough to make accurate diagnosis of CNS embryonal brain tumors, and it is essential to combine both of them including
recent comprehensive analysis methods.
PATH-09. SJMB12 CLINICAL TRIAL: DISCREPANCY BETWEENLOCAL AND CENTRAL PATHOLOGY IN ASSESSING ANAPLASTICMEDULLOBLASTOMA – REPORT FROM A SINGLE SITE
EXPERIENCE
Dong-Anh Khuong-Quang1,2, Karli Williamson1, Duncan MacGregor1,
Brent A. Orr3, Amar Gajjar3, Giles W. Robinson3, Michael J. Sullivan1,4,
and Jordan R. Hansford1,4; 1Royal Children’s Hospital, Melbourne, VIC,
Australia, 2Peter MacCallum Cancer Centre, Melbourne, VIC, Australia,
3St. Jude Children’s Research Hospital, Memphis, TN, USA, 4University of
Melbourne, Melbourne, VIC, Australia
INTRODUCTION: SJMB12 is a phase 2 clinical trial led by the St.
Jude Children’s Research Hospital (St. Jude) that enrolls patients withmedulloblastoma based on their biological subgroup. The large cell/
anaplastic (LCA) histologic variant has been identified as an important independent risk factor associated with poor outcome. However, the histologic
criteria for LCA is subjective, making the distinction between anaplastic andnon-anaplastic medulloblastoma difficult in some cases. METHODS: Pathological central review was performed at St. Jude. For all patients enrolled in
the study to date, concordance was assessed between the initial and central
review diagnosis and histologic variant calls made at the Royal Children’s
Hospital Melbourne (RCH) and at St. Jude, respectively. RESULTS: Since
the SJMB12 clinical trial opened locally in 2014, 34 patients were enrolled,and 31 were eligible for this retrospective study. A total of 12 (39%) caseswith discordance were identified. The most frequent disagreement was between the designation of LCA (10 cases, 32%). In five cases the tumour was
not designated as LCA variant locally. In five cases the initial designation of
LCA was refuted centrally. Overall, this led to a change of treatment stratum
for four patients (13%). CONCLUSION: A high discordance rate exists between neuropathologists in the designation of LCA variant. Differences ininterpretation of the subjective histologic criteria and inconsistencies in thematerial submitted for central review contributed to the discordance. Incorporation of more objective histologic criteria and implementation of unbiased
diagnostic tools may improve the generalisability of future risk stratification.
PATH-10. PROGNOSTIC RELEVANT IMMUNOPHENOTYPES OFPEDIATRIC HIGH-GRADE NON-BRAINSTEM GLIOMAS
Taisiya Mikhaleuskaya, Natalya Konoplya, and Alena Valochnik;
Belorussian Research Center for Pediatric Oncology, Hematology and
Immunology, Minsk, Belarus
Pediatric diffuse astrocytomas comprise a wide range of malignancies
with variable prognosis. The 4th grading system used now not always cor-iii426

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rectly characterizes the biological behavior of these tumors. We collected 24
pediatric supratentorial non-brainstem high grade glioma cases. Patient age
ranged from 1 to 18 years old (median 11y). Main tumor locations wereas follows: parietal lobe 8 cases; temporal lobe, 10 cases; frontal lobe, 3cases; occipital lobe 3 cases. Eight of them were totally removed. All patients were treated with standard CT and RT. The main objective was toassess the prognostic impact of histopathological and molecular criteria on
progression‐free(PFS) and overall survival (OS) of high grade gliomas. The
following criteria were analyzed: IDH1 R132H, BRAF V600E expression,
ALT-phenotype, CDKN2A deletion, 1p/19q co-deletion, glial and neuronalmarkers expression. RESULTS: IDHR132H mutation was identified in 3
cases. 4 cases carried BRAFV600E mutation with CDKN2A deletion anddisplayed PXA phenotype. 5 cases showed undifferentiated glial morphology and ALT–phenotype. Also there was a group of tumors without any of
the above mentioned genetic changes. Interestingly 3 of them were post radiation tumors. Statistical analysis showed that low OS correlated with ALTphenotype(p-0.015), absence of neuronal markers expression and absence ofmolecular changes (p-0.03). Mutation of IDH1R132H was a favorable prognostic factor as in the adult population. PFS was affected only by the presenceof neuronal expression (p-0.015). Employing immunohistochemical analysis
with surrogate molecular markers in complex with FISH can provide additional prognostic information in case of pediatric high grade gliomas.
PATH-11. PROSPECTIVE (EPI-)GENETIC CLASSIFICATION OF >1,000 PEDIATRIC CNS TUMORS—THE MNP 2.0 STUDY
Dominik Sturm1,2, Felix Sahm1,3, Felipe Andreiuolo4, David Capper5,
Marco Gessi4, Agata Rode1,2, Brigitte Bison6, Steffen Hirsch1,7,Nicolas U. Gerber8, Nicholas G. Gottardo9, Christof M. Kramm10,
Stefan Rutkowski11, Andreas von Deimling3, Torsten Pietsch4,
Stefan M. Pfister1,12, and David T.W. Jones1,2; 1Hopp Children’s Cancer
Center Heidelberg (KiTZ), Heidelberg, Germany, 2Pediatric Glioma
Research, German Cancer Research Center (DKFZ) and German
Cancer Consortium (DKTK), Heidelberg, Germany, 3Department of
Neuropathology, Heidelberg University Hospital, Heidelberg, Germany,
4Department of Neuropathology, DGNN Brain Tumor Reference Center,
University of Bonn, Bonn, Germany, 5Department of Neuropathology,
Charité – Universitätsmedizin Berlin, Berlin, Germany, 6Department of
Diagnostic and Interventional Neuroradiology, University Hospital of
Würzburg, Würzburg, Germany, 7Institute of Human Genetics, Heidelberg
University Hospital, Heidelberg, Germany, 8Department of Oncology,
University Children’s Hospital Zürich, Zürich, Switzerland, 9Departmentof Oncology and Haematology, Perth Children’s Hospital, Perth, Australia,
10Division of Pediatric Hematology and Oncology, Department of Childand Adolescent Health, University Medical Center Göttingen, Göttingen,Germany, 11Department of Paediatric Haematology and Oncology,
University Medical Center Hamburg-Eppendorf, Hamburg, Germany,
12Division of Pediatric Neurooncology, German Cancer Research Center(DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
The large variety of CNS tumor entities affecting children and adolescents, some of which are exceedingly rare, results in very diverging patient
outcomes and renders accurate diagnosis challenging. To assess the diagnostic utility of routine DNA methylation-based CNS tumor classification and gene panel sequencing, the Molecular Neuropathology 2.0 study
prospectively integrated these (epi-)genetic analyses with reference neuropathological diagnostics as an international trial for newly-diagnosed
pediatric patients. In a four-year period, 1,215 patients with sufficienttissue were enrolled from 65 centers, receiving a reference neuropathological diagnosis according to the WHO classification in >97%. Using
10 FFPE sections as input, DNA methylation analysis was successfully
performed in 95% of cases, of which 78% with sufficient tumor cell content were assigned to a distinct epigenetic tumor class. The remaining
22% did not match any of 82 represented classes, indicating novel raretumor entities. Targeted gene panel sequencing of >130 genes performedfor 96% of patients with matched blood samples detected diagnostically,
prognostically, or therapeutically relevant somatic alterations in 48%.
Germline DNA sequencing data indicated potential predisposition syndromes in ~10% of patients. Discrepant results by neuropathological andepigenetic classification (29%) were enriched in histological high-grade
gliomas and implicated clinical relevance in 5% of all cases. Clinicalfollow-up suggests improved survival for some patients with high-grade
glioma histology and lower-grade molecular profiles. Routine (epi-)genetic profiling at the time of primary diagnosis adds a valuable layer of
information to neuropathological diagnostics and will improve clinicalmanagement of CNS tumors.
PATH-13. PLEOMORPHIC XANTHOASTROCYTOMA INTEGRATEDGENOMIC CHARACTERIZATION - WHAT HAVE WE LEARNED?
Rachael Vaubel1, Valentina Zschernack2, Alissa Caron1,
Dragana Milosevic1, Robert Jenkins1, Benjamin Kipp1, Fausto Rodriguez3,
Quynh Tran4, Brent Orr4, Torsten Pietsch2, and Caterina Giannini1,5;
1Mayo Clinic, Rochester, MN, USA, 2Neuropathology - University of Bonn,Abstracts

Bonn, Germany, 3Johns Hopkins, Baltimore, MD, USA, 4St. Jude Children’s
Research Hospital, Memphis, TN, USA, 5Alma Mater Studiorum University of Bologna, Bologna, Italy
Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma occurring
predominantly in children and young adults. It is characterized histologicallyby large pleomorphic, spindled and lipidized cells with frequent eosinophilic
granular bodies and pericellular reticulin deposition. BRAF p.V600E mutation and CKDN2A/B deletion are the most common genetic alterations.
We report the integrated genomic characterization of a cohort of 67 patients (37 F, 30 M; median age 20.3 years (interquartile 13.4–32.9) withhistologically defined PXA (52, 78%) or anaplastic PXA (A-PXA) (15,22%), using genome-wide cytogenetic (ThermoFisher Oncoscan, n=67),
methylation profiling (Illumina EPIC array, n=43), and targeted next generation sequencing (n=32). BRAF p.V600E mutation (n=51, 76.1%) and
CDKN2A/B deletion (n=63; 94%) were the most frequent alterations. Of
16 BRAF p.V600E negative cases, 7 showed an alternative BRAF activating
mutation (n=2), NF1 (n=3) mutation or ATG7-RAF1 fusion (n=2). Targeted
TERT analysis found promoter mutations in 3 (of 58) cases, but TERT
amplification was absent. Supervised and unsupervised methylation profiling against a comprehensive reference cohort demonstrated consensus
grouping with the PXA class in 36 of 43 cases; while the minority groupedwith a ganglioglioma class (n=3), with reactive brain or had no resolvable
subgroup (n=4). Follow-up was available in 61 patients (91.0%) (median
63 months). Overall survival was significantly different between PXA and
A-PXA (5-year:80.4% vs. 55.1%; p=0.001), but not progression-free survival (5-year:61.7% vs. 39.8%; p=0.128). Our data confirm the high frequency of MAP-K abnormalities and CDKN2A/B deletion in PXA. WHO
grade remains a strong predictor of patient overall survival.
PATH-14. GENETIC SUSCEPTIBILITY AND OUTCOMES OFPEDIATRIC, ADOLESCENT AND YOUNG ADULT IDH-MUTANTASTROCYTOMAS
Miriam Bornhorst1, Liana Nobre2, Michal Zapotocky3, Hayk Barseghyan4,
Jeremy Goecks5, Daniel Boue6, Uri Tabori2, Cynthia Hawkins2,
Eric Bouffet2, Tobey MacDonald7, Matthew Schniederjan7,
Alberto Bronischer8, Brent Orr9, David Solomon10, Sabine Mueller10,11,
Enrico Opocher12,13, Alexander Vortmeyer14, Asher Marks14,
Carl Koschmann15, Denise Leung Leung16, Rajen Mody17, Eugene Hwang4,
Surajit Bhattacharya4, Eric Vilain4, Joyce Turner4, Lindsay Kilburn4,
Brian Rood4, Roger Packer1, Javad Nazarian11, and Cheng-Ying Ho18;
1Children’s National Hospital, Washington, DC, USA, 2Hospital for Sick
Children, Toronto, ON, Canada, 3University Hospital Motol, Prague,
Czech Republic, 4Children’s National Hospital, Washington, DC, USA,
5Oregon Health and Science University, Portland, OR, USA, 6Nationwide
Children’s Hospital, Columbus, OH, USA, 7Children’s Healthcare ofAtlanta, Atlanta, GA, USA, 8UPMC Children’s Hospital of Pittsburgh,
Pittsburgh, PA, USA, 9St. Jude Children’s Research Hospital, Memphis,
TN, USA, 10University of California San Francisco, San Francisco, CA,
USA, 11Children’s Hospital of Zurich, Zurich, Switzerland, 12Great
Ormond Street Hospital for Children, London, United Kingdom, 13Azienda
Ospedaliera di Padova, Padova, Italy, 14Yale University, New Haven, CT,
USA, 15University of Michigan Mott Children’s Hospital, Ann Arbor,
MI, USA, 16University of Michigan, Ann Arbor, MI, USA, 17University ofMichigan Mott Children’s Hospital, Ann Arbor, MI, USA, 18University of
Maryland, Baltimore, MD, USA
INTRODUCTION: Previously thought to be rare, recent case series
have shown that IDH mutations in young patients are more common thanpreviously described. In this study, we analyzed IDH-mutant tumors todetermine clinical significance of these mutations in children, adolescentsand young adults. METHODS: Through this multi-institution study (10institutions), we collected 64 IDH1/2-mutant infiltrating astrocytoma specimens from 58 patients aged 4–26 (M:F, 0.4:0.6). Specimens included
46 low-grade (LGG) and 18 high-grade (HGG) astrocytomas. Tumor
sequencing data (n=45), germline sequencing data (n=37) and outcome
data (n=40) was analyzed. RESULTS: Similar to adults, most sequenced
tumors had a co-mutation in the TP53 gene, while ATRX mutations wereless common and primarily seen in HGGs. Approximately 60% (n=21)
of patients with germline data available had a mutation in a cancer predisposition gene. Mismatch repair (MMR) mutations were most common(n=12; MSH6 n=9), followed by TP53mutations (n=7). All patients with
MMR gene mutations had HGGs and poor progression free (PFS=10% at
2 years, mean TTP=9 months) and overall (OS <30% at 2 years) survival.
Despite an OS of 90% at 5 years, many LGG patients had tumor progression/recurrence requiring additional treatment (PFS= 80% at 2 yrs, 40% at
5 yrs, mean TTP=3.5 years). Four LGG tumors (2 with TP53+ATRXloss,
2 with TP53 loss+1p19q co-deletion) underwent malignant transformation. CONCLUSION: IDH-mutant tumors in pediatric patients arestrongly associated with cancer predisposition and increased risk for progression/recurrence or malignant transformation. Routine screening for
IDH1/2 mutations in children with grade 2–4 astrocytomas could greatly
impact patient management.

PATH-15. PROTEOMIC SIGNATURES PREDICT GRADE IN
PEDIATRIC AND YOUNG ADULT INFILTRATIVE ASTROCYTOMAS
Richard T Graham1, Blake E Sells2, Jessica Fleming2, Joseph P McElroy3,
Erica H Bell2, S Jaharul Haque2, Aline P Becker2, Daniel R Boué4,
Jonathan L Finlay5, and Arnab Chakravarti2; 1St. Jude Children’s Research
Hospital, Memphis, TN, USA, 2Department of Radiation Oncology, The
Ohio State University Comprehensive Cancer Center – Arthur G, James
Cancer Hospital and Richard J, Solove Research Institute, Columbus, OH,
USA, 3Center for Biostatistics, Department of Biomedical Informatics, The
Ohio State University, Columbus, OH, USA, 4Department of Pathology andLaboratory Medicine, Nationwide Children’s Hospital, Columbus, OH,
USA, 5Division of Hematology/Oncology/BMT, Nationwide Children’s
Hospital, Columbus, OH, USA
BACKGROUND: Infiltrative astrocytomas in children and young adults
pose a treatment challenge due to the difficulty of achieving gross total resection and tumor resistance to irradiation and chemotherapy. Histopathologic
grade is an essential part of determining prognosis and treatment, but it issubjective and provides limited understanding of the molecular mechanisms
underlying tumor development and progression. METHODS: We performed
liquid chromatography/mass spectrometry (LC/MS-MS) on 28 FFPE samples
of primary infiltrative astrocytomas (10 grade II, 8 grade III and 10 grade IV –WHO classification) from Nationwide Children’s Hospital (NCH). Initial unsupervised clustering was performed. Lasso regression yielded a protein signature separating low- and high-grade tumors which was validated using asimilar cohort of pediatric and young adult infiltrative astrocytomas from theProteomic Data Commons (PDC) (n=28) of the National Cancer Institute. RESULTS: Unsupervised clustering of NCH samples essentially recapitulated
grade and lasso regression yielded a 10-protein signature that distinguishedgrade II from grade III/IV tumors. This 10-protein signature when applied to
the PDC validation dataset, accurately predicted grade for 89.3% of the tumors (p=0.00014). CONCLUSIONS: We identified a quantitative protein signature that can reliably distinguish between low- and high-grade infiltrative
astrocytomas from FFPE tissue. Further validation will enable the development
an objective prognostic proteomic clinical test that complements and may outperform current histopathological strategies. Additionally, proteomic profilingof tumors will clarify the molecular mechanisms contributing to treatment resistance and tumor progression and help identify novel treatment targets. Independent functional validation and characterization of proteins is ongoing.
PATH-16. CORRELATION OF PATHOLOGICAL AND
RADIOGRAPHICAL DIAGNOSES FOR CHILDREN WITH BRAIN
TUMORS AT TWO MAJOR HOSPITAL IN KENYA
Dr Minda Okemwa1, Dr Simon Omouk2, Prof Nimrod Mwangombe2,
and Dr Benson Macharia3; 1University of Nairobi, Nairobi, Kenya, Kenya,
2University of Nairobi, Nairobi, Nairobi, Kenya, 3Moi Teaching andReferral Hospital, Eldoret, Kenya, Kenya
BACKGROUND: Central nervous system (CNS) tumors are the leading
solid tumors in the childhood population but vastly underreported in the African population. There’s limited data on childhood brain tumors as well as
the histopathological distribution in Kenya. Our study aimed at assessing thespectrum as well as the level of correlation with imaging in diagnosis of brain
tumors within two major hospital settings. DESIGN: This was a cross-sectional
retrospective descriptive study conducted at the two major hospitals in Kenya:
Kenyatta National Hospital (KNH) and Moi Teaching and Referral Hospital(MTRH). Children who underwent treatment for brain tumors between 2015
and 2017 and whose tissue biopsies were available at the laboratory archives
were included. RESULTS: 87 cases were available for review, and the majority of the affected population were of ages 5–9 years. The most affected site
was infratentorial compartment (48.3%) with gliomas and medulloblastoma
being equally distributed. Majority of the gliomas were low grade (69%) withpilocytic astrocytoma being the most common subtype (42.9%). The overallsensitivity for the diagnosis of brain tumors through radiology was 69.4%.
The level of correlation of histopathological to radiological diagnosis was statistically insignificant with P and kappa values of 0.814 and -0.024 respectively. CONCLUSION: Gliomas and medulloblastomas were the commonest
tumors at both centers. Histopathological diagnoses have a high concordanceof agreement among various morphologists. The level of correlation between
histopathological and radiological diagnosis was high. Next steps include
standardizing clinical, radiological and pathological details within Kenya.
PATH-17. INTRAGENIC COPY NUMBER BREAKPOINT ANALYSIS
OF METHYLATION DATA FROM CNS TUMOURS IDENTIFIESNOVEL SUBGROUP-SPECIFIC CANDIDATE FUSION GENE
ENRICHMENTS
Alan Mackay, Yura Grabovska, Matthew Clarke, Diana Carvalho,
Sara Temelso, and Chris Jones; Institute of Cancer Research, London,
United Kingdom
Methylation array-based molecular profiling has redefined the classification of brain tumours and now forms an important part of their integrated

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diagnosis, providing both subgroup assignment and genome wide DNA copy
number profiles. These latter data can be used to identify intragenic breakpoints
which are frequently associated with structural variations resulting in therapeutically targetable oncogenic fusion genes. To systematically assess the landscape of these alterations, we combined publicly available methylation datasets
resulting in a total of 5660 CNS tumours, around half paediatric, and including>1000 high grade glioma and DIPG. These were analysed by standard methodology (MNP, conumee), and intragenic breakpoint enrichment was comparedwithin methylation subgroups, superfamilies, and tumours with no highscoring classification. Benchmarking included sequence-verified cases such as
infant hemispheric gliomas (IHG) with ALK(15%) and ROS1(7%) fusions,and pathognomic alterations associated with specific entities such as RELAEPN, MYB-LGG and HGNET-MN1. We identified previously unreported enrichments of well-recognised fusion targets such as NTRK2in GBM_MID andNTRK3in DMG_K27 (both 5%), METin A_IDH / A_IDH_HG (3–5%), andFGFR1/3in GBM_G34 (8–9%). Novel recurrent kinase gene candidates to beverified and explored further include IGF1Rin 2–12% cases spanning glioma
subgroups, and TIE1in poorly classified tumours. This latter ‘NOS’ group werealso enriched in various transcription factor targets of breakpoints, including
TCF4and PLAGL2. Despite limitations due to sample quality, resolution orbalanced translocations, breakpoint analysis of methylation copy number profiles provides simple screening for structural rearrangements which may directly influence targeted therapy in paediatric CNS tumours.
PATH-18. HIGH-GRADE NEUROEPITHELIAL TUMOR (HGNET) IN
A PEDIATRIC CASE-SERIES
Felipe Hada Sanders, Alessandra Azambuja, Fernando Frasseto,
Sergio Rosemberg, and Hamilton Matushita; USP, Sao Paulo, SP, Brazil
The central nervous system (CNS) high-grade neuroepithelial tumor is a
recently described molecular entity. We report 2 new CNS HGNET cases
sharing common clinical presentation and pathologic features. In summary,
CNS HGNET represents a rare tumor occurring in young patients withdismal prognosis. We think it is important to report these cases to spread theexperience and raise the knowledge of the medical community.
PATH-19. MOLECULAR CLASSIFICATION BASED ON THE DNA
METHYLATION PROFILE OF CENTRAL NERVOUS SYSTEM (CNS)
TUMORS IN CHILDREN: TWO-YEARS EXPERIENCE AT THE
BAMBINO GESÙ HOSPITAL
Evelina Miele1, Sabrina Rossi1, Lucia Pedace1,
Francesca Diomedi Camassei1, Manila Antonelli2, Antonella Cacchione1,
Giovanna Stefania Colafati1, Andrea Carai1, Francesca Gianno2,
Hiba Alzoubi2, Marco Gessi3, Marco Tartaglia1, Felice Giangaspero2,
Franco Locatelli1, and Angela Mastronuzzi1; 1Bambino Geù Children’s
Hospital, Rome, Italy, 2University of Rome Sapienza, Rome, Italy,
3University of Rome Catholic, Rome, Italy
INTRODUCTION: Pediatric brain tumors (PBT) represent the second
most common pediatric cancer, with the highest mortality rate among childhood malignancies. Improvement of PBT diagnostic accuracy is fundamental
to optimize treatment strategy. OBJECTIVES: We aimed to explore theimpact of DNA methylation arrays implementation in PBT clinical practice. METHODS: 214 PBT were analyzed by Illumina 850KEPICmethylationarray. Low score and discordant cases were collegially reviewed. RESULTS: Calibrated score was 0.8 or higher in 159 cases (74.3%), withpathological diagnosis confirmation in 132 cases and molecular subgroupdefinition in 47 of them, including cases of medulloblastoma, CNS neuroblastoma FOXR2, HGNET MN1; methylation profiling amended diagnosis
in 10 cases, e.g. HGNET BCOR and anaplastic PXA, was non-contributoryin 4 and misleading in 12 cases, including glioneural tumors and tumors
arising in syndromic contexts. Calibrated score ranged between 0.8 and 0.3
in 37 cases (17.3%) and was below 0,3 (no match) in 18 cases (8.4%). Calibrated score below 0,8 was more frequently assigned to low grade gliomas
and low grade glioneural tumors (p <0.0006). Challenging/very rare cases, e.g.
intracranial AFH with EWSR1:CREM fusion and nonRELA supratentorial
ependymomas, were assigned to “no match subgroup”; in syndromic patientsthe score tended to be lower (p=0.07); no correlation between score and age <3-years was found (p=0.1). CONCLUSION: Methylation profiling refine on
diagnostic accuracy in PBT classification. Improvements are needed in classifying low grade glioma/glioneuronal tumors and challenging/very rare PBT. In
syndromic cases, there is a high rate of misleading profiles and/or low scores.
PATH-20. METHYLATION ARRAY PROFILING OF PEDIATRICBRAIN TUMORS; SINGLE CENTRE EXPERIENCE
Michal Zapotocky1, Ales Vicha1, Lenka Krskova2, Josef Zamecnik2,
Lucie Stolova1, Adela Misove1, Katerina Vanova1, Miroslav Koblizek2,
Vijay Ramaswamy3, David Jones4, and David Sumerauer1; 1Departmentof Paediatric Haematology and Oncology, Second Faculty of Medicine,Charles University, Prague, Czech Republic, 2Department of Pathology
and Molecular Medicine, Second Faculty of Medicine, Charles University,iii428N EU R O - O N C O L O G Y•

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Prague, Czech Republic, 3Division of Pediatric Hematology/Oncology,
Hospital for Sick Children, Toronto, ON, Canada, 4Hopp Children’s
Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
BACKGROUND: Significant heterogeneity of pediatric brain tumors
poses major challenge on diagnostics. Therefore, we aimed to evaluate feasibility of methylation array in the diagnostic process. METHODS: Methylation array (Infinium MethylationEPIC, Illumina) was performed on DNA
extracted from fresh frozen tissue from prospective newly diagnosed andselected retrospective patients. Results from Heidelberg classifier (www.
molecularneuropathology.org) were compared to the histological diagnosis
and further genetic testing was performed to establish integrated morphological/molecular diagnosis. RESULTS: Within years 2018–2019, we performed methylation array profiling of 102 samples consisting mainly ofependymoma, medulloblastoma high-grade and low-grade glioma. Highcalibrated score (>0.9) was achieved in 62 patients (61%). In 46 cases (74%)
with score >0.9, the histological diagnosis matched the methylation class(MC). In the remaining cases (16) that were classified by histopathology
mainly as ependymomas, the methylation profiles were classified as novel
molecular entities (HGNET_BCOR, HGNET_MN1, etc.) or different tumor
type. In 40 cases (39%) with the score <0.9, six were found to have highnormal tissue content. Nine cases had no match in the classifier and 25 wereassigned MC with score 0.3 to 0.89. In 20 out of 34 cases with low score,
the molecular diagnosis could be confirmed based on copy number variants
inferred from the methylation array or using additional testing for gene fusions and mutations. CONCLUSIONS: Our experience on the first 100+
cases demonstrated that methylation array could be integral part of diagnostic process in order to establish integrated morphological and moleculardiagnosis of pediatric brain tumors.
PATH-21. TELOMERE LENGTH ANALYSIS OF CNS TUMORS IN
THE PEDIATRIC BRAIN TUMOR ATLAS
Jo Lynn Rokita1, Krutika Gaonkar1, Heba Ijaz2, Daniel Miller1,
Tasso Karras2, Mariarita Santi3, Daniel Martinez3, Mateusz Koptyra1,4,
Thomas De Raedt2, Jennifer Mason4, Elizabeth Appert4, Jena Lilly1,
Yakun Zhu1, Angela Waanders5,4, Adam Resnick1,6, Jay Storm7, andKristina Cole2; 1The Center for Data Driven Discovery in Biomedicine(D³b), Children’s Hospital of Philadelphia, Philadelphia, PA, USA, 2Divisionof Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia,
Philadelphia, PA, USA, 3Department of Pathology, Children’s Hospital ofPhiladelphia, Philadelphia, PA, USA, 4The Children’s Brain Tumor Tissue
Consortium (CBTTC), Operations Center at the Children’s Hospital ofPhiladelphia, Philadelphia, PA, USA, 5Lurie Children’s Hospital of Chicago,
Chicago, IL, USA, 6The Children’s Brain Tumor Tissue Consortium(CBTTC), Operations Center at the Children’s Hospital of Philadelphia,
Philadelphia, USA, 7Division of Neurosurgery, Children’s Hospital ofPhiladelphia, Philadelphia, PA, USA
Subsets of pediatric cancers, including high grade glioma (pHGG), havehigh rates of uniquely long telomeres, associated with ATRX gene mutations and alternative lengthening of telomeres (ALT). Ultimately, these cancers may benefit from a therapy stratification approach. In order to identify
and further characterize pediatric brain tumors with telomere lengthening(TL), we determined the intratelomeric content in silico from paired WGS of
918 tumors from CBTTC Pediatric Brain Tumor Atlas (PBTA). The results
were highly concordant with experimental assays to determine ALT in a
subset of 45 pHGG tumors from the set. Overall, 13% of the PBTA cohort had telomere lengthening. We confirmed the highest rate of TL (37%)
in the pHGG cohort (37/100 tumors; 30/82 patients). There was no statistical difference in age, gender or survival in subset analysis. As expected, thepatient pHGG tumors with telomere lengthening were enriched for ATRX
mutations (60%, q= 1.76e-3). However, 6 tumors without ATRX mutation also had normal protein expression, suggesting a different mechanismof inactivation or TL. The pHGG tumors with telomere lengthening had
increased mutational burden (q=8.98e-3) and included all known pHGG
cases (n=6) in the cohort with replication repair deficiencies. Of interest,
the second highest rate of telomere lengthening was 9 subjects (24%) in
the craniopharyngioma cohort. None of the craniopharyngioma tumors
had ATRX mutations or low ATRX expression, and 55% of those with
TL had CTNNB1 mutations. Finally, lower rates of telomere lengthening
were found in medulloblastoma (10%), ependymoma (10%), low grade
astrocytoma (8%) and ganglioglioma (7/47, 15%).
PATH-22. COMPARISON OF SUPERVISED CLASSIFICATIONMETHODS FOR CENTRAL NERVOUS SYSTEM TUMORS BASEDON DNA-METHYLATION
Brent Orr, Alex Breuer, Tong Lin, Quynh Tran, Edward Suh, andStanley Pounds; St. Jude Children’s Research Hospital, Memphis, TN, USA
Classification of brain tumors using methylation profiling is an importantdiagnostic advance, reducing subjectivity and improving interpretability ofclinical outcome data. Despite the recognized value of methylation profilingAbstracts

in the clinical laboratory, the performance characteristics of different supervised classification models has not been directly compared. We developed 3
methods using methylation profiles to classify CNS tumors: an exact bootstrap k-nearest neighbor (kNN), a multi-layer perceptron neural net (NN),and a random forest classifier (RF). We trained these methods on the publicly available CNS tumor reference cohort (GSE90496) with 2,801 profiles
and 91 classes. We evaluated the performance of these methods by leaveout-25% cross-validation. The relative performance of these methods were
evaluated in terms of accuracy, precision, and recall for class or class family.
The kNN, RF, and NN classifier had an estimate error rate of 10.74%,
4.01%, and 1.89%, respectively for class prediction and an error rate forfamily prediction of 5.97%, 0.90%, and 0.6%, respectively. At perfect recall for class assignment, the RF and kNN had a precision of 0.96 and 0.89
while the NN reached 0.98. For family assignment, the precision for thethree classifiers was almost 1.0 with recall of nearly 0.8. At the recall rateof 1.0, the precision dropped to 0.94, 0.991 and 0.994 for kNN, RF, andNN, respectively. Overall, the NN showed improved performance metrics
compared to the kNN and RF in CNS tumor classification for both classand class family assignment.
PATH-23. ADULT SPINAL CORD ASTROBLASTOMA WITH EWSR1BEND2 FUSION
Takeyoshi Tsutsui1, Yoshiki Arakawa1, Yasuhide Makino1,
Hiroharu Kataoka1, Sachiko Minamiguti2, Takanori Hirose3,
Sumihito Nobusawa4, Yoshiko Nakano5, Koichi Ichimura5, andSusumu Miyamoto1; 1Department of Neurosurgery, Kyoto University
Hospital, Kyoto, Kyoto, Japan, 2Department of Pathology, Kyoto
University Hospital, Kyoto, Kyoto, Japan, 3Department of Pathology,
Hyogo Cancer Center, Akashi, Hyogo, Japan, 4Graduate School of
Medicine, Gunma University Pathology and Pathology, Maebashi, Gunma,
Japan, 5Division of Brain Tumor Translational Research, National Cancer
Center Research Institute, Chuo-ku, Tokyo, JapanThe most recurrent fusion of CNS high-grade neuroepithelial tumor
with MN1alteration(HGNET-MN1) is MN1- BEN Domain Containing
2(BEND2) fusion. Recently, there was a report of a 3-month-old boy withspinal astroblastoma, classified as CNS HGNET-MN1 by DKFZ methylation classification but positive for EWSR1-BEND2 fusion(Yamasaki, 2019).
Here, we report a 36-year old man with a spinal cord astroblastoma with
EWSR1 alternation. The patient presented with back pain, gait disorder anddysesthesia in lower extremities and trunk was referred to our hospital. MRI
showed intramedullary tumor in Th3-5 level, displaying low-intensity on T1
weighted image, high-intensity on T2 weighted image, and homogeneous
gadolinium enhancement. Partial removal was performed with the laminectomy. The tumor extended to extramedullary and its boundary was unclear.
Histological examinations showed the epithelium-like tumor cells with eosinophilic cytoplasm with high cellularity palisade, intracellar fibrosis, andmitosis. Immunohistochemical staining showed positive for Olig2, GFAP,
EMA, SSTR2, S-100, but negative for p53, PgRAE1/AE3. The tumor wasdiagnosed as astroblastoma, and was classified as HGNET-MN1 by the
DKFZ methylation classifier. However, the MN1 alternation was not detected by fluorescence in situ hybridization, instead EWSR1 and BEND2alternations which suggested EWSR1-BEND2 fusion were detected. Afterradiation therapy of 54Gy/30fr with bevacizumab and temozolomide, theresidual tumor reduced the size and his symptoms improved. This case provides evidence that EWSR1-BEND2 fusion is recurrent in HGNET-MN1
and, as previously reported, suggests the importance of BEND2 in this entity.
These two cases suggested that it may be the BEND2 alteration that biologically defines the HGNET-MN1 subclass rather than MN1.
PATH-24. MOLECULAR CLASSIFICATION OF HIGH RISK INFANTEMBRYONAL BRAIN TUMORS ENROLLED IN THE ACNS0334
TRIAL: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP
Bryan K Li1,2, Peter Burger3, Alexander R Judkins4, Ben LB Ho2,5,Guolian Kang6, Jeffrey Gossett6, Sarah Leary7, Ian Pollack8, Amar Gajjar9,
Maryam Fouladi10, Stewart J Kellie11, Claire Mazewski12, andAnnie Huang1,2; 1Division of Hematology/Oncology, Hospital for Sick
Children, Toronto, ON, Canada, 2Arthur and Sonia Labatt Brain Tumour
Research Centre, Hospital for Sick Children, Toronto, ON, Canada,
3Neuropathology Division, The Johns Hopkins Hospital, Baltimore,
MD, USA, 4Department of Pathology and Laboratory Medicine,Children’s Hospital Los Angeles, Keck School of Medicine Universityof Southern California, Los Angeles, CA, USA, 5Laboratory Medicine
and Pathobiology, Faculty of Medicine, University of Toronto, Toronto,
ON, Canada, 6Department of Biostatistics, St. Jude Children’s Research
Hospital, Memphis, TN, USA, 7Department of Pediatric HematologyOncology, Seattle Children’s Hospital, Seattle, WA, USA, 8Department of
Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh
School of Medicine, Pittsburgh, PA, USA, 9Department of Oncology,
Division of Neuro-Oncology, St, Jude Children’s Research Hospital,
Memphis, TN, USA, 10Division of Oncology, Cincinnati Children’s

Hospital Medical Center, Cincinnati, OH, USA, 11Department of Oncology,
University of Sydney, Children’s Hospital at Westmead, Westmead, NSW,
Australia, 12Department of Pediatrics, Emory University, Children’s
Healthcare of Atlanta, Atlanta, GA, USA
Young children with embryonal brain tumors including medulloblastoma(MB), supratentorial primitive neuro-ectodermal tumor, or pineoblastoma
have historically been considered high-risk patients with poor outcomes
despite the use of intensive radiation-sparing treatment. In the ACNS0334
phase III trial, 91 consented children <36 months old with the above
diagnoses were randomized to intensive induction chemotherapy with orwithout methotrexate followed by consolidation with stem cell rescue.
Here we present the results of a centralized integrated molecular analysis
including global methylation profiling (65/91), and whole exome sequencing
of tumor (46/91) and germline (35/91) DNA. Unsupervised clustering analyses of methylation profiles using multiple orthogonal methods against areference dataset of 1200 pediatric brain tumors, revealed known and newmolecular entities. For tumors diagnosed as MB on central pathology review,
7.3% (3/41) had a non-MB molecular diagnosis (2 embryonal tumor withmultiple rosettes/ETMR, 1 group MYC pineoblastoma), with the remainder
as MB Group SHH (11/41), Group3 (25/41), and Group4 (2/41). Amonghistologic non-MBs, 3/24 (12.5%) were molecular entities not intended
for trial inclusion (1 each for ATRT, pleomorphic xanthoastrocytoma, andhigh-grade glioma). ETMR, historically considered a rare entity, was molecularly identified in a significant proportion (14/65; 21.5%) of samples.
Among MB-SHH, we detected deleterious PTCH1 mutations in 6/9 tumors
but none among 5 germline samples tested; a germline SUFU frameshift mutation with tumor LOH was also observed in MB-SHH. Correlation of theseand other molecular features to the parallel clinical analysis will yield important markers of risk stratification and predictors of treatment response.
PATH-25. GENOME-WIDE METHYLATION ANALYSIS CANSEGREGATE RADIATION-INDUCED GLIOBLASTOMA FROM LATE
RECURRENCE OF MEDULLOBLATOMAS
Takamasa Hiraki1, Kohei Fukuoka1, Yuko Matsushita2, Yuko Hibiya2,
Satoko Honda3, Makiko Mori1, Yuki Arakawa1, Koichi Ichimura2,
Masao Kobayashi4,5, Yutaka Tanami4, Atsuko Nakazawa3, Jun Kurihara6,
and Katsuyoshi Koh1; 1Department of Hematology/Oncology, Saitama
Children’s Medical Center, Saitama, Saitama, Japan, 2Division of Brain
Tumor Translational Research, National Cancer Research Institute, Tokyo,
Tokyo, Japan, 3Department of Clinical Research, Saitama Children’s
Medical Center, Saitama, Saitama, Japan, 4Department of Radiology,
Saitama Children’s Medical Center, Saitama, Saitama, Japan, 5Departmentof Radiology, Jikei University School of Medicine, Tokyo, Tokyo, Japan,
6Department of Neurosurgery, Saitama Children’s Medical Center, Saitama,
Saitama, Japan
It could be difficult to diagnose recurrent medulloblastoma with conventional diagnostic tools because other lesions mimic relapse of the tumor
from both a morphological and radiological standpoint, particularly when
it happens late. We report two medulloblastoma cases, both of which
seemed to develop late-recurrence more than 5 years from the initial surgery. Genome-wide methylation analysis revealed that one of the recurrent
tumors was in fact a radiation-induced glioblastoma. The first patient was
a 6-year-old female patient who developed a posterior fossa tumor. The
pathological diagnosis was medulloblastoma with focal desmoplasia. She
was in complete remission for 9 years after the treatment but developed an
intradural lesion in her thoracic spine. The lesion was biopsied and pathologically confirmed as recurrence of the tumor. The second patient was afemale patient who developed non-metastatic medulloblastoma at the ageof 10. She suffered local recurrence 5 years after the diagnosis. Biopsy was
performed, and the pathological diagnosis was relapse of the tumor. We performed unsupervised hierarchical clustering of the methylation data fromour cases and reference data. In contrast to consistency of methylation profiling and copy number abnormalities between primary and recurrent tumors of case 1, the analysis revealed that the recurrent tumor of case 2
was distinct from medulloblastomas and clustered with “IDH-wild typeglioblastomas”, which suggested that the recurrent tumor was radiationinduced glioblastoma. This report highlights the clinical utility of molecular
genetic/epigenetic approach to confirm diagnosis of brain tumor recurrence.
PATH-26. RNA SEQUENCING OF FORMALIN-FIXED PARAFFINEMBEDDED SPECIMENS IN DIAGNOSTIC ROUTINE IDENTIFIESCLINICALLY RELEVANT GENE FUSIONS
Damian Stichel1,2, Daniel Schrimpf2,1, Jochen Meyer2,1, Annika Wefers2,1,
Philipp Sievers2,1, Stefan M. Pfister3,1, Wolfgang Wick4,1,
David T. W. Jones3,1, Andreas von Deimling2,1, and Felix Sahm2,1; 1German
Cancer Research Center (DKFZ), Heidelberg, Germany, 2Department of
Neuropathology, Institute of Pathology, University Hospital Heidelberg,
Heidelberg, Germany, 3Hopp Children’s Cancer Center (KiTZ), Heidelberg,
Germany, 4Department of Neurology and Neurooncology Program,

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National Center for Tumor Diseases, Heidelberg University Hospital,
Heidelberg, Germany
Pediatric brain tumor entities harbor a variety of gene fusions. Whilst
other molecular parameters like somatic mutations and copy number alterations have become pivotal for brain tumor diagnostics, gene fusions
are only less well covered by routinely applied methylation arrays or targeted next-generation sequencing of DNA. In a routine diagnostic setting
we established and optimized a workflow for investigation of gene fusions
in formalin-fixed paraffin-embedded (FFPE) tumor tissues by using RNA
sequencing. Assessing different tools for calling fusions from raw data, wefound relevant fusions in 66 out of 101 (65%) analyzed cases in a prospective cohort collected over 26 months. In 43 (43%) cases the fusions
were of decisive diagnostic relevance and in 40 (40%) cases the fusion genes
rendered a druggable target. Besides the relevance of pathognomonic fusions
for diagnostics, especially the detection of druggable gene fusions yields
direct benefit to the patients. This approach allows for an unbiased search
for fusion events in the tested samples. Besides rare variants of establishedfusions which were not detected by prior targeted analyses, we identified
previously unreported fusion events. Exemplified on KIAA1549:BRAF fusion, we in addition provide an overview of the detection accuracy of different methods, including breakpoint detection in DNA methylation arraydata and fusion gene detection in DNA panel sequencing data. Our data
show that RNA sequencing has great diagnostic as well as therapeutic value
by clinically detecting relevant alterations.
PATH-27. MUTATION DETECTION USING PLASMA CELL-FREE
DNA IN CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMORS
Ross Mangum1,2, Jacquelyn Reuther3,2, Koel Sen Baksi1,2,
Ryan C. Zabriskie1,2, Ilavarasi Gandhi1,2, Alva Recinos1,2,
Samara L. Potter1,2, Frank Y. Lin1,2, Murali Chintagumpala1,2,
Donna M. Muzny4,2, Kevin Fisher3,2, Sharon E. Plon4,2, Angshumoy Roy3,2,and D. Williams Parsons1,2; 1Texas Children’s Hospital Cancer Center,
Houston, Texas, USA, 2Baylor College of Medicine, Houston, Texas, USA,
3Texas Children’s Hospital Department of Pathology & Immunology,
Houston, Texas, USA, 4Human Genome Sequencing Center, Houston,
Texas, USA
BACKGROUND: The role of plasma cell-free DNA (cfDNA) as acancer biomarker for tracking treatment response and detecting early relapse has been well described for solid tumors outside the central nervous
system (CNS). However, the presence of a blood-brain barrier complicatesthe application of plasma cfDNA analysis for patients with CNS malignancies. METHODS: cfDNA was extracted from plasma of pediatric patientswith CNS tumors utilizing a QIAmp® MinElute® kit and quantitated with
Qubit 2.0 Fluorometer. Extensive genomic testing, including targeted DNA
and RNA solid tumor panels, exome and transcriptome sequencing, as wellas copy number array, was performed on matched tumor samples as partof the Texas KidsCanSeq study. An Archer® Reveal ctDNA28 NGS kit wasthen used for assaying the sensitivity of detecting tumor-specific mutationsin the plasma of these patients. RESULTS: A median of 10.7ng cfDNA/mL
plasma (Interquartile range: 6.4 – 15.3) was extracted from 78 patients attime of study enrollment. Longitudinal samples from 24 patients exhibited a
median yield of 7.7ng cfDNA/mL plasma (IQR: 5.9 – 9.1). An initial cohortof 6 patients was identified with 7 somatic variants covered by the Archer®
Reveal kit. Four of seven mutations identified in matched tumor specimens
were detected in patient plasma at variant allele frequencies ranging from
0.2–1%. CONCLUSIONS: While challenging, detection of cfDNA in theplasma of pediatric patients with CNS tumors is possible and is being explored in a larger patient cohort along with pilot studies investigating cerebrospinal fluid as an additional source for tumor-specific cfDNA.
PATH-28. MOLECULAR DIAGNOSIS FOR CENTRAL DIAGNOSISOF BRAIN TUMORS FROM 2016 TO 2019— A REPORT FROM THE
JAPAN CHILDREN’S CANCER GROUP (JCCG)
Yoshiko Nakano1, Junko Hirato2,3, Takako Yoshioka4,
Sumihito Nobusawa5, Tomoko Shoufuda6, Mai Kitahara1,
Kohei Fukuoka1,7, Kai Yamasaki1,8, Hiroaki Sakamoto9, Ryo Nishikawa10,
Junichi Hara8, Yonehiro Kanemura6, and Koichi Ichimura1; 1Division ofBrain Tumor Translational Research, National Cancer Center ResearchInstitute, Tokyo, Japan, 2Department of Pathology, Gunma University
Hospital, Gunma, Japan, 3Department of Pathology, Republic Tomioka
General Hospital, Gunma, Japan, 4Department of Pathology, National
Center for Child Health and Development, Tokyo, Japan, 5Departmentof Human Pathology, Gunma University Graduate School of Medicine,Gunma, Japan, 6Department of Biomedical Research and Innovation,
Institute for Clinical Research, National Hospital Organization Osaka
National Hospital, Osaka, Japan, 7Department of Hematology/Oncology,
Saitama Children’s Medical Center, Saitama, Japan, 8Department ofPediatric Hematology and Oncology, Osaka City General Hospital,

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Osaka, Japan, 9Department of Pediatric Neurosurgery, Osaka City
General Hospital, Osaka, Japan, 10Department of Neuro-Oncology and
Neurosurgery, Saitama Medical University, Saitama, JapanINTRODUCTION: Since 2016, the Japan Children’s Cancer Group(JCCG) has established a nationwide network that prospectively provides
pathological review and molecular analysis. METHODS: Patients who
were diagnosed with brain tumors between ages 0 and 29 were eligible.
The central office at National Center for Child Health and Development
served as a hub for the hospitals involved and institutions conducting
pathological and molecular analysis, and managed the patients’ clinicalinformation and tumor samples. Histopathology of all cases were centrally
reviewed. Routine non-NGS based analyses were conducted based on
histological diagnosis and included pyrosequencing for glioma-associated
hot spot mutations and PFA/PFB classification for ependymoma, RT-PCR
for RELA fusion and BRAF fusion, and nanostring for subgrouping
medulloblastoma. In selected cases, methylation analysis, RNA sequencing
and exon sequencing of 93 genes were performed in selected cases. RESULTS: In total, 985 cases were registered to this study in four years.
Frozen samples were collected from approximately 80% of cases. The
number increased from 152 in 2016 to 326 in 2019. They includes glioma(n=268), medulloblastoma (n=161), ependymoma (n=103), germ celltumor (n=93), ATRT (n=29) and others. In 55 % of the glioma cases, atleast one abnormality was detected by the routine analysis. The detailed
analysis for atypical cases identified targetable alternations. DISCUSSION:
This nationwide central diagnostic system has now been well established.
Current issues and future prospective of the system will be discussed.
PATH-29. HIGH FREQUENCY OF CLINICALLY-RELEVANT TUMORVARIANTS DETECTED BY MOLECULAR TESTING OF HIGH-RISKPEDIATRIC CNS TUMORS – PRELIMINARY FINDINGS FROM THE
TEXAS KIDSCANSEQ STUDYFrank Y Lin1, Ross Mangum1, Jacquelyn Reuther2, Samara L Potter1,
Dolores H López-Terrada2, Adekunle M Adesina2, Carrie A Mohila2,
Guillermo Aldave3, Murali M Chintagumpala1, Donna M Muzny4,
Juan Carlos Bernini5, Jonathan Gill6, Timothy Griffin7, Gail Tomlinson8,
Kelly Vallance9, Kevin E Fisher2, Angshumoy Roy2, Sharon E Plon4, andD Williams Parsons1; 1Texas Children’s Cancer Center, Baylor College ofMedicine, Houston, TX, USA, 2Dept of Pathology & Immunology, Baylor
College of Medicine, Houston, TX, USA, 3Div of Pediatric Neurosurgery,
Baylor College of Medicine, Houston, TX, USA, 4Dept Molecular andHuman Genetics, Baylor College of Medicine, Houston, TX, USA, 5Vannie
Cook Children’s Clinic, Baylor College of Medicine, McAllen, TX, USA,
6Division of Pediatrics, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA, 7Children’s Hospital of San Antonio, Baylor
College of Medicine, San Antonio, TX, USA, 8Pediatric Blood & Cancer
Center, UT Health Sciences Center at San Antonio, San Antonio, TX, USA,
9Department of Hematology/Oncology, Cook Children’s Medical Center,
Fort Worth, TX, USA
BACKGROUND: DNA and RNA-based tumor sequencing tests
have the potential to guide the clinical management of children with
CNS tumors. However, data describing the utility of these tests arelimited. METHODS: Children with high-risk or recurrent CNS tumors
are included in the diverse cohort of patients enrolling in the KidsCanSeq
study from six Texas sites. DNA and RNA from FFPE tumor is subjected to targeted sequencing using a 124-gene mutation panel and an
81-gene fusion panel. Tumor capture transcriptome sequencing, exome
sequencing, and copy number array (as well as germline panel and exome
testing) are also performed. Tumor variants are classified using AMP/
ASCO/CAP consensus guidelines. RESULTS: A total of 74 children withhigh-risk/recurrent CNS tumors enrolled as of 1/28/20. Targeted tumor
DNA and RNA panel testing was completed for 57 patients with varieddiagnoses. At least one tumor variant with strong or potential clinicalsignificance was identified in 43 of 57 (75%) tumors, with therapeuticsignificance in 20 of 57 (35%) tumors. The 38 therapeutically-relevant
variants most frequently affected MAPK signaling (BRAF x9, EGFR x3,
FGFR2, FGFR3, KRAS, NF1, NTRK2) and the AKT/mTOR pathway(PIK3CA x3, PTEN x2, mTOR, TSC1, PIK3R1). Most had not been
detected by prior targeted diagnostic testing (27/38, 71%). CONCLUSION: Integrated DNA and RNA-based panel testing identified variants with potential to impact clinical decision-making in a majority ofchildren with high-risk/recurrent CNS tumors. The comparative yieldof panel testing vs. exome/transcriptome/array will be evaluated in the
KidsCanSeq study cohort.
PATH-30. EXOSOMES AS A SOURCE OF PLASMA CTDNA TO
IDENTIFY POINT MUTATIONS IN PEDIATRIC GLIOMA PATIENTS
Liana Nobre1,2, Isabel Porto Carreiro3, Aline Helen da Silva Camacho3,
Rafaela Reis3, Leila Chimelli3, Ilana Zalcberg3, Sima Ferman3,

Abstracts

Sima Ferman3, and Barbara Monte Mor3; 1Instituto Nacional de Cancer,
Rio de Janeiro, Brazil, 2The Hospital for Sick Children, Toronto, ON,
Canada, 3Instituto Nacional de Cancer, Rio de Janeiro, Brazil

Toronto, ON, Canada, 6Princess Margaret Cancer Centre, Toronto, ON,
Canada, 7Mayo Clinic, Rochester, MN, USA, 8St. Jude Children’s Research
Hospital, Memphis, TN, USA

Surgery consists in the mainstay of treatment in most gliomas, but inmany cases, a resection is not feasible. Liquid biopsy is an ideal tool providing a minimally invasive method through plasma or CSF sampling toassess cell-free tumor DNA (ctDNA). Here we explore the feasibility ofdetecting DNA in plasma exosomes (exoDNA) extracted from glioma patients and further investigate its use in identifying molecular alterations.
Exosomes were isolated from 2ml of plasma from 24 patients (13 LGG,
8 HGG, 3 DIPG) and fully characterized by nanoparticle tracking analysis
and transmission electron microscopy. DNA was extracted from 13 samples (exoDNA) so far. Five patients had confirmed point mutations in the
primary tumor (3BRAFV600E; 1FGFR1N546K; 1H3.3), additionally, 3
samples were collected from clinically diagnosed DIPG patients to inquire
H3K27M mutations. DNA was extracted successfully from all exosome
samples; a pre-amplification step was needed and direct sequencing was
carried out for BRAFV600E. FGFR1N546K and H3K27M mutations weresought in patients with positive tumors. Wildtype BRAF fragment was identified in 12/13samples (1 patient failed sequencing). However, none of thefive tumor positive patients nor the DIPG patients had mutations detected
at the exo-DNA level. There is growing evidence that CSF may be the ideal
source of ctDNA in brain tumor patients, therefore although we could notdetect mutations in plasma DNA we are currently analyzing CSF exoDNA
and cell-free DNA to evaluate if this proves a successful strategy and weather exoDNA is more representative of the tumor content.

PURPOSE: By reducing dose to normal brain tissue, proton radiotherapy (PRT) may lessen neurocognitive risk traditionally associated withphoton radiotherapy (XRT). We examined change in neurocognitive scores
over time in pediatric medulloblastoma patients treated with PRT versus
XRT. METHODS: Neurocognitive scores from 79 patients (37 PRT, 42
XRT) were examined. Patients were treated between 2007–2018 on thesame treatment protocols that differed only by craniospinal modality (PRT
versus XRT). Change in scores over time since diagnosis were compared
between groups. RESULTS: Groups were similar on most demographic/clinical variables: sex (67.1% male), age at diagnosis (mean 8.6 years), CSI
dose (median 23.4 Gy), length of follow-up (mean 4.3 years), and parental
education (mean 14.3 years). Boost dose (p<0.001) and margin (p=0.001)
differed between groups. Adjusting for covariates, the PRT group exhibitedsuperior outcomes in global IQ, perceptual reasoning, and working memory
versus the XRT group (all p<0.05). The XRT group exhibited significant decline in global IQ, working memory, and processing speed (all p<0.05). The
PRT group exhibited stable scores in all domains except processing speed(p=0.003). Posterior fossa syndrome imparted risk independent of modality. CONCLUSION: This is the first study comparing neurocognitive trajectories between pediatric patients treated for medulloblastoma with PRT
versus XRT on comparable, contemporary protocols. PRT was associatedwith more favorable neurocognitive outcomes in most domains compared to
XRT, although processing speed emerged as vulnerable in both groups. Thisis the strongest evidence to date of an intellectual sparing advantage with
PRT in the treatment of pediatric medulloblastoma.

PATH-31. THE IMPACT OF MOLECULAR PROFILING OFPEDIATRIC CNS TUMORS ON TUMOR DIAGNOSIS AND
MANAGEMENT - A SINGLE CENTER EXPERIENCE
Kazuhiro Sabet1, Marike Zwienenberg1, Mirna Lechpammer1,
Lee-Way Jin1, David Solomon2, and Cassie Kline2, Reuben Antony1;
1University of California Davis, Sacramento, CA, USA, 2University ofCalifornia San Francisco, San Francisco, CA, USA
BACKGROUND: Next generation sequencing (NGS) plays a role inneuro-oncology research and in clinical diagnosis and management. Here,
we describe how NGS for pediatric CNS tumors impacted clinical diagnosis
and therapy at a single institution. METHODS: NGS was performed using
the UCSF 500 Gene Panel (targeted sequencing platform covering about 500
cancer associated genes). Patients were selected for NGS based on tumor
pathology /need to identify therapeutic targets. We collected data on patient
demographics, tumor histology/pathway alterations/therapeutic targets/therapy and used descriptive statistics for data analysis. RESULTS: Between January 2016 and July 2019, about one-third of patients with CNS
tumors seen at our institution (N=29) were interrogated. NGS revealed
pathway alterations in 20/29 patients. Treatment recommendations/modifications based on pathway alterations/therapeutic targets impacted thetherapy of 18 patients. Patient groups: Medulloblastoma (N=6), alterations
in WNT, SHH, and TP53 pathways (Vismodegib recommended for SHH
pathway alteration but not used). High-grade glioma (N=4), alterations(with treatment changes) included, NF1(Trametinib, Everolimus); MSH2/
MLH1(Nivolumab); CDKN2A/CDKN2B/CDKN2C(Abemaciclib); EGFR
(Osimertinib, Afatinib); H3K27M (Panobinostat/ONC201); BRAFV600(Dabrafenib, Trametinib); ATRT (N=1) SMARCB1; Low Grade Glioma(N=10), BRAFV600(Vemurafenib) /BRAFKIAA1549 fusion (Trametinib)/
PIK3CA; DIPG (N=5), H3K27M/BCOR/ P53/ACVR/PIK3CA (LY3023414,
Everolimus)/PDGFR(Dasatinib); Ependymoma (N=3), PFA/PFB/RELA
Fusion. Seven patients were treated with targeted therapy + conventional
therapy. In 8 patients targeted therapy remains an option but not yet
needed. CONCLUSIONS: NGS of pediatric brain tumors is widely available and contributes to the diagnosis/therapy of pediatric CNS tumors. Optimal chemotherapy/targeted therapy combinations are areas of study.

NEUROPSYCHOLOGY/QUALITY OF LIFE
QOL-01. LONGITUDINAL COMPARISON OF NEUROCOGNITIVETRAJECTORIES IN PEDIATRIC MEDULLOBLASTOMA PATIENTSTREATED WITH PROTON VERSUS PHOTON RADIOTHERAPY
Lisa Kahalley1,2, Rachel Peterson3, M. Douglas Ris1,2, Laura Janzen3,
M. Fatih Okcu1,2, David Grosshans4, Vijay Ramaswamy3,5,Arnold Paulino4, David Hodgson6, Anita Mahajan7, Derek Tsang6,
Normand Laperriere6, William Whitehead1,2, Robert Dauser1,
Michael Taylor3,5, Heather Conklin8, Eric Bouffet3,5,
Murali Chintagumpala1,2, and Donald Mabbott3,5; 1Baylor College ofMedicine, Houston, TX, USA, 2Texas Children’s Hospital, Houston,
TX, USA, 3The Hospital for Sick Children, Toronto, ON, Canada, 4MD
Anderson Cancer Center, Houston, TX, USA, 5The University of Toronto,

QOL-02. PERCEPTIONS OF LATE EFFECTS CARE NEEDS AMONGSURVIVORS OF PEDIATRIC BRAIN TUMOURS
Chantel Cacciotti1,2, Adam Fleming1, Hanna Tseitlin1, JoAnn Duckworth1,
and Stacey Marjerrison1; 1McMaster University, Hamilton, ON, Canada,
2Dana Farber / Boston Children’s Cancer and Blood Disorder Center,
Boston, MA, USA
OBJECTIVES: Pediatric brain tumour survivors are at risk of long-term
consequences of therapy. Comprehensive late effects care may mitigate theserisks, but the best care model is unclear. We sought to describe the care experience and quality of life (QOL) of pediatric brain tumour survivors at theMcMaster Children’s Hospital joint adult/pediatric Neuro-Oncology clinic.
METHODS: Cross-sectional survey data were collected. Care needs wereassessed with the Cancer Care Experience Questionnaire (CCEQ), Cancer
Worry Scale (CWS), and Self-Management Skills Scale (SMSS). Quality oflife was measured utilizing the PedsQL Brain Tumor Module. Data were analyzed descriptively. RESULTS: Thirty-two childhood brain tumor survivors
and/or their parents participated. Their malignancies included embryonal
tumors (medulloblastoma/ATRT) (62%), ependymoma (22%), and germ
cell tumours (16%). Among 77%, therapy included chemotherapy, surgery
and radiation. Most respondents reported high quality cancer care, althoughsome could not recall discussions of late effects risks and health promotion. Mean cancer worry scores were low (71.8 (± 28.4)). Survivors reported
limited self-management skills (58.5 (±18.2)), with support required inclinic visits, arranging medical appointments, filling prescriptions and tasksof daily living. Overall median QOL scores were in the ‘good’ range (parental report 72.3 (±17.7), survivor 68.2 (±16.6)). CONCLUSION: In comparison to other childhood cancer survivor cohorts, this group of long-term
brain tumour survivors appear to have similar QOL, fewer cancer worries,
and increased need for aid with self-management. Given this, along with thepositive care experience reported, this clinic model of care appears to meetthe needs of this population.
QOL-04. INFLUENCE OF FAMILY, SCHOOL, AND HOSPITALSYSTEMS IN SUPPORTING SURVIVORS OF PEDIATRIC BRAIN
TUMORS WITH NEUROCOGNITIVE LATE EFFECTS
Emily Moscato1,2, Lisa Gies1,2, Aimee Miley2, Ralph Salloum3,4, andShari Wade1,2; 1University of Cincinnati, Cincinnati, OH, USA, 2Division of
Pediatric Rehabilitation Medicine, Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH, USA, 3Cancer and Blood Diseases Institute, Brain
Tumor Center, Cincinnati Children’s Hospital Medical Center, Cincinnati,
OH, USA, 4University of Cincinnati School of Medicine, Cincinnati, OH,USAOBJECTIVE: Pediatric brain tumor survivors (PBTS) are at risk fordeveloping neurocognitive late effects that may interfere with academic
and adaptive functioning. To mitigate the potential impact, some PBTS may
implement strategies independently, while others may rely on system-levelsupport from family, school, or hospital systems. Given the limited knowledge on survivor and family perspectives of these supports, we conducteda mixed-methods study involving PBTS and their caregivers to examine the

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Abstracts

influence of family, educational, and hospital supports, and identify areasof unmet need. PARTICIPANTS AND METHODS: PBTS (N=56,Mage=1
8.12,range=10–25) completed questionnaires on academic accommodations. Medical chart reviews provided diagnosis and treatment information.
A subset of families, who did not significantly differ from the larger sample
on demographics, completed qualitative interviews (N=25). Three coders
identified themes separately for parents and survivors and reached consensus(kappa’s > .78) using thematic content analysis. RESULTS: Families emphasized the role of family support, including providing individualized help,
setting up a structured learning environment, and suggesting metacognitive
strategies. Parents also emphasized how they have adjusted their expectations. At school, 53% reported an individualized education plan. Formal
accommodations (e.g., modified coursework, small group instruction, extratime) were helpful, yet some noted barriers, including embarrassment andlack of follow-through. Survivors emphasized the value of informal accommodations. Families described unmet needs related to connecting with othersurvivors, navigating community and educational resources, and transitioning to adulthood. CONCLUSIONS: PBTS seem to rely on systems-levelsupports to mitigate neurocognitive effects. Future work should strengthencommunication between systems and adult transition services.
QOL-05. TUMOR LOCATION IS LESS LIKELY INFLUENCE ON
COGNITIVE DYSFUNCTION IN CHILDREN
Riho Nakajima1, Masashi Kinoshita2, Shingo Tanaka2, andMitsutoshi Nakada2; 1Department of Occupational therapy, Kanazawa
University, Kanazawa, Japan, 2Department of Neurosurgery, Kanazawa
University, Kanazawa, JapanINTRODUCTION: Though several factors are known to influenceon long-term cognitive function in children with brain tumor, the impactof tumor localization to specific cognitive function was not well known.
Here we investigated the influence of local brain resection by surgery on
postoperative cognitive outcome in school-aged children. METHODS: Participants were seven pediatric patients who underwent craniotomy for tumor
resection in our hospital (mean age, 13.9 years). Their diagnosis were WHO
grade 1 or 2 glioma (n=6) and hemangioma (n=1). Tumor were mainly located in following regions; frontal, n=2; parietal, n=2; temporal, n=3 (Theselesions included hippocampus or were located very close to it). Temporal
assessments for cognitive function of several functional domains were performed according to tumor location until post-op 1 year. Based on MRI,
we estimated cognitive dysfunctions and compared them to observational
symptoms. RESULTS: Preoperative cognitive function was normal in all
patients. Cognitive dysfunctions estimated from resected area were as follows (cumulative total number); memory or working memory disorder, n=4;
visuospatial cognitive disorder, n=3; disorder of processing speed, n=2; facial
or topographical agnosia, n=2; Gerstman syndrome, n=1. Just after surgery,
cognitive function was declined in two functional domains of two patients,
which were only 16.7% of estimated deficit from resected region. They recovered completely until 3 months postoperatively, and returned to school
without any deficits. CONCLUSIONS: In pediatric lower-grade tumor,
focal cognitive symptom was unlikely to be induced by local resection.
QOL-06. QUALITY OF LIFE IN MEDULLOBLASTOMA SURVIVORSIN WESTERN MEXICO
Regina M Navarro-Martin del Campo1,2, Jorge L Macias-Toscano1,
Erika Toral-Casillas1, Fernando Sánchez-Zubieta1, andAna L Orozco-Alvarado1; 1Hospital Civil de Guadalajara “Dr. Juan
I Menchaca”, Guadalajara, Jalisco, Mexico, 2GAPNO, International,
MexicoBACKGROUND: Treatment of children with medulloblastoma (MB)can lead survivors to lidiate with long term sequelae and affect their
quality of life (QoL). This study evaluates QoL in long term MB survivors.
DESIGN/METHODS: Clinical files of MB survivors from 1997 to 2016
were retrospectively analyzed. QoL was defined by Schipper Criteria in a fivedimensional evaluation: clinical data, physic effects of treatment, academic
develop, functional state and self welfare report. RESULTS: Clinical data:
Twenty eight survivors were identified, mean age at review was 18 years,
median follow up was 106 months. Functional state: Last visit Karfnosky/
lansky were 90 to 80% in 25% of patients. Physic effects of treatment: Cerebellar Mutism or ataxia were present in 25% of cases. Two patients required external dispositives. Audiometry detected an auditive tonal decreasein 25% of cases. An endocrine disfunction was present in 46% of cases, 32%
required hormone replacement and 28% having short size. Renal damage
without dialysis was detected in 7% and 10% had a transient tubulopaty.
One case had bilateral amaurosis and 14% uses glasses. Three patients had
a life partner. One female has offspring and two males had azoospermia.
Academic development: While 90% attends to school, 35.7% complainedof learning difficulties and 18% needed special education. Self welfare report: Difficulties in social environment were described in 21% and 14% still
feeling sick during years. CONCLUSIONS: Survivors of MB had adverse

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De c e mb e r 2 0 2 0physical effects, followed by academic development, functional state and self
welfare report and all this has a negative impact in their QoL.
QOL-07. CORTICAL VOLUME AND THICKNESS IN ADULTSURVIVORS OF CHILDHOOD POSTERIOR FOSSA TUMORSCharlotte Sleurs1, Jurgen Lemiere2, Jeroen Blommaert1, Sabine Deprez1,
Karen Van Beek2, Anne Uyttebroeck2, and Sandra Jacobs2; 1KU Leuven,
Leuven, Belgium, 2UZ Leuven, Leuven, Belgium
PURPOSE: A brain tumor treatment including cranial radiotherapy has previously been associated with long-term neurocognitive
sequelae. Since underlying neurological mechanisms remain inconclusive, we investigated cortical features in childhood posterior
fossa tumor survivors. METHODS: T1-weighted MRI (MPRAGE,
resolution=.98x.98x1.2mm) was acquired to investigate the cortical structure in adult survivors of childhood infratentorial tumors (n=19, 15males)(16.4–34.8 years old, >2years after treatment). These scans were comparedto age- and gender- matched controls. Supratentorial cortical volume andthickness were investigated using voxel-based morphometry (VBM) andsurface-based morphometry (SBM), respectively. We compared patients andcontrols, irradiated (n=13) versus non-irradiated patients, and investigated
the age at radiotherapy (peak level: p<.001). RESULTS: Lower GM volumes were encountered in multiple brain areas of patients compared to controls, with the largest clusters in the right and left occipital fusiform gyri.
Irradiated patients showed lower GM volumes then non-irradiated patientsin the superior and middle frontal gyri, the right supramarginal gyrus andprecuneus. Age at radiotherapy was associated with GM volume in the inferior frontal gyrus. SBM yielded larger cortical thickness in patients in theleft precuneus, inferior temporal and fusiform gyrus. The opposite effectwas only marginally significant, in the left temporal lingual gyrus. Age atradiotherapy was not associated with cortical thickness, but radiotherapy
was associated with lower thickness of the left pars opercularis. CONCLUSION: Widespread differences in cortical volumes and thickness wereobserved in posterior fossa tumor survivors. Both radiotherapy and age atradiotherapy could be suggested as risk factors for long-term cortical development.
QOL-09. WHOLE-BRAIN WHITE MATTER NETWORKCONNECTIVITY IS DISRUPTED BY PEDIATRIC BRAIN TUMOR
TREATMENT
Adeoye Oyefiade, Kiran Beera, Iska Moxon-Emre, Jovanka Skocic,
Ute Bartels, Suzanne Laughlin, Vijay Ramaswamy, and Donald Mabbott;
The Hospital for Sick Children, Toronto, ON, Canada
INTRODUCTION: Treatments for pediatric brain tumors (PBT) areneurotoxic and lead to long-term deficits that are driven by the perturbationof underlying white matter (WM). It is unclear if and how treatment may
impair WM connectivity across the entire brain. METHODS: Magnetic resonance images from 41 PBT survivors (mean age: 13.19 years, 53% M)
and 41 typically developing (TD) children (mean age: 13.32 years, 51% M)
were analyzed. Image reconstruction, segmentation, and node parcellation
were completed in FreeSurfer. DTI maps and probabilistic streamline generation were completed in MRtrix3. Connectivity matrices were based on thenumber of streamlines connecting two nodes and the mean DTI (FA) index
across streamlines. We used graph theoretical analyses to define structuraldifferences between groups, and random forest (RF) analyses to identify
hubs that reliably classify PBT and TD children. RESULTS: For survivors
treated with radiation, betweeness centrality was greater in the left insular (p < 0.000) but smaller in the right pallidum (p < 0.05). For survivors
treated without radiation (surgery-only), betweeness centrality was smallerin the right interparietal sulcus (p < 0.05). RF analyses showed that differences in WM connectivity from the right pallidum to other parts of thebrain reliably classified PBT survivors from TD children (classification accuracy = 77%). CONCLUSIONS: The left insular, right pallidum, and rightinter-parietal sulcus are structurally perturbed hubs in PBT survivors. WM
connectivity from the right pallidum is vulnerable to the long-term effectsof treatment for PBT.
QOL-11. COMPARISON OF TREATMENT BURDEN RATINGSCALES ON NEUROCOGNITIVE OUTCOMES IN A MIXED SAMPLE
OF PEDIATRIC BRAIN TUMOR SURVIVORS
Muhammad Baig1, Ineke Olsthoorn2, Grace Yang1, Wafik Zaky1, andPeter Stavinoha1; 1MD Anderson Cancer Center, Houston, TX, USA,
2Fielding Graduate University, Santa Barbara, CA, USA
BACKGROUND: Predicting neurocognitive outcomes in pediatric brain
tumor (PBT) patients is challenging. Rarity of PBT makes inclusion of detailed risk factors (e.g., treatment modality, intensity, individual complications) difficult when sample sizes are small. The Neurological Predictor
Scale (NPS) summarizes complications and treatment factors associatedAbstracts

with neurocognitive risks and has modest validation. Recently, the Pediatric
Neuro-Oncology Rating of Treatment Intensity (PNORTI) was developed
to evaluate the impact of treatment intensity on psychosocial outcomes but
has not been compared to neurocognitive outcomes. This study compared
the NPS and PNORTI in terms of relationship to neurocognitive outcomes
known to be at risk in PBT survivors. METHODS: 88 PBT survivors’
neuropsychological outcomes were retrospectively analyzed in relation to
the NPS and PNORTI. Variables of interest included IQ, working memory,and processing speed. RESULTS: NPS associated with lower IQ (rs=-.476,
p=.001), lower working memory (rs=-.323, p=.010), and lower processing
speed (rs=-.389, p=.007) in patients diagnosed at a younger age, but only
processing speed for children diagnosed after age 7 years (rs=-.262, p=.036).
PNORTI was not correlated with neurocognitive variables for eithergroup. CONCLUSION: NPS has value in predicting neurocognitive outcomes, though much more in a younger age at diagnosis group compared toolder patients. The PNORTI did not demonstrate predictive value for theseneurocognitive domains in our sample. Given the potential clinical and research value of a summary rating of treatment burden relating to long-term
outcome, future research should include relationship to psychosocial outcomes and quality of life.
QOL-12. CLINICAL SIGNIFICANCE OF RADIATION-INDUCEDCEREBROVASULAR DISEASE IN CHILDHOOD BRAIN TUMORSURVIVORS
Tiina Remes1,2, Maria Suo-Palosaari3, Niina Ritari1,
Riina Puosi1, Päivi Koskenkorva4, Anna Sutela4,
Sanna-Maria Toiviainen-Salo1, Pekka Arikoski4, Mikko Arola5,
Emma Hovén6, Päivi Lähteenmäki7, Tuula Lönnqvist1, Pekka Riikonen4,
Kirsti Sirkiä1, Heikki Rantala3, Marika Harila2, Marja Ojaniemi3, andArja Harila-Saari8; 1Helsinki University Hospital, Helsinki, Finland, 2Oulu
University, Oulu, Finland, 3Oulu University Hospital, Oulu, Finland,
4Kuopio University Hospital, Kuopio, Finland, 5Tampere University
Hospital, Tampere, Finland, 6Karolinska Institutet, Stockholm, Sweden,
7Turku University Hospital, Turku, Finland, 8Uppsala University, Uppsala,SwedenBACKGROUND: Childhood brain tumor survivors have a high risk ofearly cerebrovascular disease, but currently its clinical significance is unknown. METHODS: In a nation-wide study, we investigated 68 childhood
brain tumor survivors treated with radiotherapy by using magnetic resonance imaging (MRI) and neuropsychological examination after medianfollow-up time of 20.6 years (range 5.0 – 33.1 years) since radiotherapy.
Associations between imaging markers of cerebrovascular disease, whitematter hyperintensities and the results of neuropsychological examination
were investigated. RESULTS: Majority (65 %) of the survivors was diagnosed with cerebrovascular disease at median age of 27.1 years (range16.2 –43.8 years). The presence of imaging markers of cerebrovascular disease orwhite matter hyperintensities was associated with poorer performance inverbal (VIQ) and performance (PIQ) intelligent quotient, working and semantic memory, executive functions, visuospatial ability, and immediate andgeneral auditive memory (P < 0.05). Survivors with microbleeds performed
worse in PIQ, processing speed, executive functions, and visuospatial ability(P <0.05). Lacunar infarcts were associated with difficulties in visuospatial
ability (P <0.05). Survivors with white matter hyperintensities in MRI had
higher impairment of working and semantic memory, visuospatial ability,and general auditive memory (P < 0.05). Cerebrovascular and small-vessel
disease burden associated with poorer neurocognitive performance. CONCLUSION: The imaging markers of cerebrovascular disease and whitematter hyperintensities were related to poorer cognitive performance inradiation-treated long-term survivors of childhood brain tumor. Longitudinal studies are urgently needed to investigate how cerebrovascular disease
and related cognitive impairment progress in the survivors.
QOL-13. NEUROCOGNITIVE OUTCOMES ACCORDING TO RISKADAPTED TREATMENT REGIMENS FOR CHILDREN OLDER
THAN 4 WITH MEDULLOBLASTOMA AND POSTERIOR FOSSAEPENDYMOMA – RESULTS OF THE HIT2000 TRIAL
Martin Mynarek1, Anne Neumann-Holbeck1, Anika Resch2,
Holger Ottensmeier3, Katja von Hoff4,1, Thomas Traunwieser5, RolfDieter Kortmann6, Denise Obrecht1,
Monika Warmuth-Metz7, Brigitte Bison7, Torsten Pietsch8,
Stefan M. Pfister9,10, Martin Sill9,11, Marcel Kool9,11, Dominik Sturm11,
David Jones11, Andreas von Deimling12,13, Felix Sahm9,13, Tanja Tischler1,
and Stefan Rutkowski1; 1Department of Pediatric Hematology andOncology, University Medical Center Hamburg Eppendorf, Hamburg,
Germany, 2Department of Pediatrics, University Hospital Rostock, Rostock,Germany, 3Department of Pediatric Hematology and Oncology, University
Children’s Hospital Wuerzburg, Wuerzburg, Germany, 4Department ofPediatric Hematology and Oncology, Charite – University Medicine,
Berlin, Germany, 5Swabian Children’s Cancer Center, University Hospital
Augsburg, Augsburg, Germany, 6Department of Radiation Oncology,

University of Leipzig, Leipzig, Germany, 7Institute of Diagnostic andInterventional Neuroradiology, University Hospital Wuerzburg, Wuerzburg,
Germany, 8Institute of Neuropathology, Brain Tumor Reference Center of
the German Society for Neuropathology and Neuroanatomy (DGNN),
University of Bonn, DZNE German Center for Neurodegenerative
Diseases, Bonn, Germany, 9Hopp Children’s Cancer Center Heidelberg(KiTZ), Heidelberg, Germany, 10Department of Pediatric Hematology
and Oncology, Heidelberg University Hospital, Heidelberg, Germany,
11Division of Pediatric Neurooncology (B062), German Cancer ResearchCenter (DKFZ) and German Cancer Consortium (DKTK), Heidelberg,
Germany, 12Clinical Cooperation Unit Neuropathology (B300), German
Cancer Research Center (DKFZ), Heidelberg, Germany, 13Department of
Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
OBJECTIVES: Reduced neuropsychological outcomes are a major
concern in pediatric patients with malignant brain tumors. We aimed
to estimate decline in cognitive function according to treatment regimens. METHODS: Cross-sectional analysis of cognitive functions
tested with the Neuropsychological Basic Diagnostic tool (NBD) in 279
patients >4 years at diagnosis (median: 8.66; range: 4.01–18.98) withmedulloblastoma (n=110, 23.7–25.0Gy CSI; n=131, >30Gy CSI) or posterior fossa ependymoma (n=38 local radiotherapy) who participatedin the HIT-2000 trial. Multivariable regression analysis was conductedto adjust for postoperative cerebellar mutism syndrome, preoperativehydrocephalus, postoperative shunt placement, the interval between
diagnosis and assessment, sex and age. RESULTS: Mean time fromdiagnosis to assessment was 5.1 years. Increasing CSI-dose was significantly associated with a deterioration in performance of most subtests,
particularly in areas of fluid intelligence (mean z-values per test for no
CSI/23.4Gy/>30Gy respectively: matrix reasoning:-0.40/-0.52/-0.98,
p<.001), short-term memory (number recall: -0.07/-0.58/-0.64, p=.002),
visuo-spatial skills (visual-motor integration:-0.49/-0.68/-1.12, p<.001)
and fine motor skills (dominant-hand:-1.09/-1.80/-2.12, p=.008;
non-dominant-hand:-1.47/-2.59/-2.82, p=.003; bimanual coordination:-1.33/-2.68/-2.76, p=.001). These differences were retained after
adjustment for confounding variables. Within medulloblastoma patientstreated with >30Gy CSI, selective attention, but no other function was reduced in patients treated with pre-radiotherapy chemotherapy including
intraventricular MTX (selective attention (with chemotherapy/without
chemotherapy mean z-values: -0.66/0.00, p=.006)). Patients with SHHactivated medulloblastoma did significantly better than WNT or Group3/
Group4 medulloblastoma patients in fluid intelligence and fine motor
skills. CONCLUSION: CSI dose among other highly relevant factors
had significant effects on neuropsychological outcome. Pre-radiotherapy
intraventricular MTX had only minor effects. Patients with SHH-activatedmedulloblastomas showed a more favorable outcome when compared topatients in the other subgroups.
QOL-14. A BIOPSYCHOSOCIAL APPROACH TO BRAIN
INJURY REHABILITATION FOLLOWING TREATMENT FOR
PAEDIATRIC BRAIN TUMOURS: CAN PHARMACOTHERAPY AIDNEUROPSYCHOLOGICAL OUTCOME?
Jo Phillips and Mark Brougham; Royal Hospital for Sick Children,
Edinburgh, Lothian, United Kingdom
Long term survival following paediatric brain tumours has vastly improved in recent decades. Consequently there is a drive towards improved
quality of survivorship. Brain tumours, surgical resection and adjuvant therapies represent mechanisms for brain injury and can therefore negatively
impact a child’s neuropsychological trajectory; affecting cognition, behaviour, emotional and adaptive functioning and educational/occupational outcomes. A biopsychosocial approach to rehabilitation should target each ofthese domains through supported remediation, environmental modificationand psychoeducation for young people and the key systems around them(e.g. families, education). There is a growing evidence base for the role ofconcordant psychopharmacologies to improve neuropsychological outcome.
Since 2015 children treated at RHSC Edinburgh for brain tumours havebeen offered pharmacotherapy alongside usual rehabilitation approaches
if they demonstrate significant difficulties with Attention, Processing Speed
and/or Executive Function on formal neuropsychological assessment. Patients are referred to a Consultant Psychiatrist or Paediatrician (as per local
protocol) for medication selection, titration and monitoring. A short caseseries (N=14) is presented outlining brain tumour pathologies, treatment
modalities, neuropsychological profile and rationale for recommending
pharmacotherapy. Approximately 50% of patients took up the offer. The
treatment/s offered and self or parents reported outcomes is summarised.
Pharmacotherapy was broadly effective; “it’s been like night and day”, although for one case (N=1) the side effects outweighed any benefit; “she became even more emotional”. Findings indicate that pharmacotherapy should
be considered alongside conventional neurorehabilitation techniques for
CYP with specific cognitive difficulties following treatment for paediatricbrain tumours.

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QOL-15. NEURAL NETWORK INTEGRITY FOR FACIAL AFFECTRECOGNITION IN SURVIVORS OF MEDULLOBLASTOMATara Brinkman, Kevin Krull, Matthew Scoggins, Zhenghong Li, John Glass,
Ping Zou, Kirsten Ness, Noah Sabin, Amar Gajjar, Gregory Armstrong,
Leslie Robison, Melissa Hudson, and Wilburn Reddick; St. Jude Children’s
Research Hospital, Memphis, TN, USA
BACKGROUND: Medulloblastoma survivors are at risk for social
deficits, yet underlying mechanisms are poorly understood. METHODS: Facial affect recognition was assessed in 50 medulloblastoma survivors
treated with craniospinal radiation (median[range] 21.4[12.5–30.9] years
old, 11.0[5.7–22.6] years since diagnosis) and 56 non-cancer age-, sex-,
and race-matched controls. Brain activation and connectivity in core regions/nodes of the face perception network (fusiform gyri, occipital gyri,
superior temporal sulcus) were examined using structural and functional
neuroimaging. Structural networks were constructed from diffusion tensor
imaging (DTI) data and individual node strength and efficiency were assessed. Functional MRI (fMRI) was conducted using a 1-back facial affectrecognition task with assessment of regional differences in task-related
cerebral blood flow (BOLD). Standardized neurocognitive testing wascompleted with 24 hours of brain imaging. RESULTS: Medulloblastoma
survivors performed worse on a behavioral measure of facial affect recognition (P=0.003) compared to matched controls. During the facial affectrecognition task, controls demonstrated greater BOLD activation of theleft and right fusiform gyri and the left and right middle occipital gyricompared to survivors (P’s<0.05, corrected for multiple comparisons).
DTI indicated weaker core node strength in survivors in the right lateral occipital gyri (P=0.02) and efficiency was lower in the left (P=0.01)
and right (P=0.03) occipital gyri compared to controls. CONCLUSIONS: Medulloblastoma survivors have deficits in facial affect recognition and reduced activation and efficiency in brain regions comprising
the face perception network compared to matched controls. Interventions
targeting this specific skill and neural network may improve social functioning in survivors.
QOL-17. BIOLOGICAL CORRELATES OF QUALITY OF SURVIVAL
AND NEUROCOGNITIVE OUTCOMES IN MEDULLOBLASTOMA;A META-ANALYSIS OF THE SIOP-UKCCSG-PNET3 AND HIT-SIOPPNET4 TRIALS
Mathilde Chevignard1, Kim Bull2, James Holt3, Marie-Amelie Heng4,
Colin Kennedy2, Francois Doz5, Birgitta Lannering6, Stefan Rutkowski7,
Maura Massimino8, Steven Clifford3, and Debbie Hicks3; 1Saint
Maurice Hospitals, Saint Maurice, France, 2University of Southampton,
Southampton, United Kingdom, 3Newcastle University Centre for Cancer,
Newcastle upon Tyne, United Kingdom, 4Institut Curie, Paris, France,
5Institut Curie, Paris, United Kingdom, 6University of Gothenburg,
Gothenburg, Sweden, 7University Medical Center Hamburg-Eppendorf,
Hamburg, Germany, 8Fondazione IRCCS Istituto Nazionale dei Tumori,
Milan, Italy
Relationships between biological factors (genetic, tumour molecularsubgroup) and neurocognitive/Quality of Survival (QoS) outcomes inmedulloblastoma survivors are emerging, based on studies of limited
retrospective cohorts. Integrated investigations of the medulloblastoma
late-effects pathway (considering biological, clinical and treatment factors), using larger clinically-controlled cohorts, are now essential todetermine their independent significance and potential for clinical application. In a combined cohort of SIOP-UKCCSG-PNET3 and HIT-SIOPPNET4 patients (n=150), molecular subgroup (MBWNT, MBSHH, MBGrp3,
MBGrp4) was assessed against QoS measures [health status: HUI3; emotional and behavioural difficulties: SDQ; Health-related Quality of Life
(HrQoL): PedsQL]. Additionally, in DNA remaining from HIT-SIOPPNET4 (n=74), 39 candidate SNPs (involved in metabolism, DNA maintenance/repair, neural growth/repair and oxidative stress/inflammation)
were genotyped by multiplexed MALDI-TOF MassArray and assessedagainst Wechsler Intelligence Scale (WISC) scores. Molecular subgroupwas significantly associated with HrQoL and health status in univariate
analyses; MBGrp4 predicted significantly worse outcomes than MBSHH
and MBGrp3 (p<0.05), but not in multivariate analyses taking into consideration other significant and reported QoS predictors (e.g. treatment,
gender, age). In contrast, 6 SNPs were significantly associated with ≥1
WISC domain; 4/6 showed associations across domains. 3 SNPs wereindependently prognostic in multivariate analyses, and further significant associations were apparent at the gene (BDNF, APOE) and pathway(folate) level. This cross-discipline, international study encompassing
two medulloblastoma trials has identified relationships between molecular subgroup, genotype and survivorship outcomes. These findings
now require assessment in larger series, to inform our understanding of
medulloblastoma survivorship outcomes and impact future disease management strategies.

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QOL-18. A LONGITUDINAL STUDY OF NEUROCOGNITION IN
CHILDREN TREATED FOR A BRAIN TUMOR
Jurgen Lemiere, Linde Van den Wyngaert, Josefien Vandereydt,
Karen Vandenabeele, Trui Vercruysse, Charlotte Sleurs, and Sandra Jacobs;
University Hospital Leuven, Leuven, Belgium
It is well known that neurocognition in children treated for a brain tumor
can be affected. However, studies on the trajectory of these neurocognitive
problems are scarce. In the present study we investigated the evolution ofneurocognition between timepoints of diagnosis, 2, 4 and 6 years later.
A total of 53 children diagnosed with a brain tumor were recruited inthis study, of which all completed a comprehensive neuropsychologicaltest battery at three successive timepoints and 30 at 4 timepoints. The
first assessment was conducted as soon as possible after diagnosis and before initiation of chemo- and/or radiotherapy. Mean age at diagnosis was
8.06 years. The most common diagnoses were pilocytic astrocytoma (n=28)
and medulloblastoma (n=10). 24.5% and 18.9% of these patient groups
received focal or craniospinal irradiation, respectively. A repeated measures analysis with cranial irradiation (no, focal, craniospinal) as betweensubjects factor demonstrated a significant interaction effect between time
and type of irradiation for overall intelligence (p=0.02) for children withthree assessments. The same interaction effect was found for overall intelligence and processing speed for children with four assessments (p=.005 and
p=.002, respectively). The group who received craniospinal irradiation demonstrated the most pronounced decline. Interestingly, no main time effect orinteraction effect was found for general memory functioning. Our results
demonstrate that not all neurocognitive functions in children treated for abrain tumor decline after treatment. Overall IQ and processing speed are themost vulnerable outcomes in our cohort, especially for the children treatedwith craniospinal irradiation.
QOL-19. PARENT-REPORTED COGNITIVE PROBLEMS AND
DIRECT ASSESSMENT OF COGNITION IN CHILDREN TREATED
FOR A BRAIN TUMOR
Jurgen Lemiere1, Charlotte Sleurs2, Linde Van den Wyngaert1,
Karen Vandenabeele1, Josefien Vandereydt1, Trui Vercruysse1, andSandra Jacobs1; 1University Hospital Leuven, Leuven, Belgium, 2KULeuven,
Leuven, Belgium
The Pediatric Perceived Cognitive Function (PedsPCF) item bank is a
short parent and self-reported cognitive screening questionnaire developedin the context of pediatric oncology. The PedsPCF demonstrated satisfactory
psychometric properties and the scores of the PedsPCF are found to be associated with clinical outcomes. Today little research is available to evaluate
whether the PedsPCF is correlated with direct assessments of neurocognitive
domains. The aim of the current study is to investigate whether importantcognitive domains, such as different aspects of intelligence, memory, visuomotor integration can predict the PedsPCF score. We obtained 100 PedsPCF
filled in by parents from children treated for a brain tumor. All these children
completed a comprehensive neuropsychological battery. Mean age at diagnosis was 7.47 years and mean age at completion of PedsPCF and testing
13.84. The most common diagnoses were pilocytic astrocytoma (n=43) andmedulloblastoma (n=14). A linear regression model with verbal comprehension, perceptual reasoning, processing speed, visuomotor integration as predictors for overall PedsPCF score was significant (p.005), but the overallmodel fit was limited (adjusted R2: 14%). Visuomotor integration andprocessing speed were significant predictors (beta = 0.56 and -0.29). Our
results are in line with the overall finding that the correlation between questionnaires assessing quality of survival and direct assessments of cognition
are low. For clinical practice these results are important as the PedsPCF can’t
be used to replace direct cognitive assessments or vice versa.
QOL-20. IMPACT OF RADIATION DOSE AND VOLUMEON MEMORY FUNCTIONING IN CHILDREN WITH
MEDULLOBLASTOMA: A REPORT FROM CHILDREN’SONCOLOGY GROUP (COG) ACNS0331
Leanne Embry1, Paul Colte2, Patsy Cullen3, Jeff Michalski4, Yimei Li5,
Yuanyuan Han5, and Kristina Hardy6; 1University of Texas Health Science
Center, San Antonio, TX, USA, 2Primary Children’s Hospital, Salt Lake
City, UT, USA, 3Regis University, Denver, CO, USA, 4Washington University
School of Medicine, St, Louis, MO, USA, 5St. Jude Children’s Research
Hospital, Memphis, TN, USA, 6Children’s National Medical Center,
Washington, DC, USA
BACKGROUND/OBJECTIVES: We examined longitudinal verbal andvisual memory functioning in children treated for medulloblastoma on COG
protocol ACNS0331. METHODS: Children with medulloblastoma participated in neuropsychological testing at three timepoints over a 6-year period.
Children aged 3–7 years were randomized to receive craniospinal irradi-Abstracts

ation (CSI) of either 23.4Gy (standard dose; SDCSI) or 18Gy (lower dose;
LDCSI). Children aged 8+ received SDCSI. All children were also randomized to receive either a reduced radiation boost to the involved field (IFRT)
or a standard boost to the whole posterior fossa (PFRT). Memory functioning was evaluated an average of 0.67(T1), 2.95(T2), and 4.90(T3) years
post-diagnosis. RESULTS: Of 464 eligible patients enrolled on ACNS0331,
354 (76%; 65.3% male, 83.1% white) completed some neuropsychologicaltesting. Mean age at diagnosis was 9.1 years (range=3–19). Verbal and visual
short-term memory and learning were broadly within the average range forthe overall sample at all three timepoints. However, a large percentage ofchildren exhibited scores ≥1SD below the mean on tasks of verbal learning
both immediately (43.4%) and after a delay (40.7%) at T3. In addition,
58.6% of children randomized to SDCSI exhibited impairment in verbal
learning after a delay compared to 34.8% of children randomized to LDSCI,and 35.0% of those aged ≥8 at diagnosis receiving SDCSI. CONCLUSIONS: Younger children receiving SDCSI have particularly high rates ofmemory impairment five years after diagnosis of medulloblastoma. Limiting
CSI dose and/or volume in young children treated for this diagnosis may
improve outcomes for memory functioning.
QOL-21. DEVELOPMENT AND UTILISATION OF A NEUROONCOLOGY REHABILITATION TEAM: 2018–2019 UPDATE
Helen Paisley, Helen Hartley, Anna Kearney, Alex Hagan, Joanne Owen,
Barry Pizer, Natalie Holman, and Ram Kumar; Alder Hey Childrens NHSFoundation Trust, Liverpool, United Kingdom
INTRODUCTION: A multi-disciplinary Neuro-Oncology Rehabilitation Team (NORT) was established at our institution in 2014. We reviewed NORT inputs, processes and outputs in 2018 to 2019 comparedto our previously presented data from 2015, soon after service inception. METHODS: Retrospective analysis of patients who received NORT
input June 2018 - May 2019 compared to 2015 data. Descriptive analysisof changes to NORT operational processes and structure. Complexity ofrehabilitation needs was measured using the Rehabilitation Complexity
Scale-Extended V13 (RCS). RESULTS: 54 children received NORT input
in 2018–2019 (10 children in 2015) with total of 129 outputs. NORT input
was highest in children with high grade glioma (median reviews: 3; median
RCS: 5) and ependymoma (median reviews: 3; median RCS: 5). Pilocytic
astrocytoma formed the largest tumour group (n = 11; median reviews: 2;
median RCS: 7). 11% patients were referred to neurologist (9% alreadyknown); 17% referred to community services (44% already known); 31%
referred to neuropsychology. In 2015, outputs were predominantly referralto occupational therapy and physiotherapy. 6 patients (11% of 54) weredischarged in 2018–2019 (40% of 10 patients in 2015). 4 patients died.
Between 2015 and 2019, developments included: clarifying referral and discharge pathways, use of screening measures, neuropsychology integration,therapy-led drop-in clinics, use of RCS-E. DISCUSSION: There has been aclear increase in utilisation and scope of work of NORT over last 4 years.
The strength of this team is multidisciplinary working and expertise. Further
developments planned: multidisciplinary rehabilitation interventions andNORT outcome tools.
QOL-22. MACHINE-LEARNING INFERENCE MAY PREDICTQUALITY OF LIFE SUBGROUPS OF ADAMANTINOMATOUS
CRANIOPHARYNGIOMA
Astrid C. Hengartner1,2, Eric Prince1,2, Susan Staulcup1,2, Trinka Vijmasi1,2,
Mark Souweidane3,4, Eric M. Jackson5, James M. Johnston6,
Richard C. E. Anderson7, Robert P. Naftel8, Gerald Grant9,
Toba N. Niazi10, Roy Dudley11, David D. Limbrick12,13, Kevin Ginn14,
Amy Smith15, Lindsay Kilburn16,17, George Jallo18, Greta Wilkening19,20,
and Todd Hankinson1,2; 1Children’s Hospital Colorado, Division of
Pediatric Neurosurgery, Aurora, CO, USA, 2University of Colorado Schoolof Medicine, Department of Neurosurgery, Aurora, CO, USA, 3Memorial
Sloan Kettering Cancer Center, Department of Neurosurgery, New York,NY, USA, 4Weill Cornell Medical College, Department of Neurological
Surgery, New York, NY, USA, 5Johns Hopkins University School of
Medicine, Department of Neurosurgery, Baltimore, MD, USA, 6Universityof Alabama at Birmingham, Department of Neurosurgery, Division of
Pediatric Neurosurgery, Birmingham, AL, USA, 7Columbia University,
Morgan Stanley Children’s Hospital of NewYork-Presbyterian, Departmentof Neurosurgery, New York, NY, USA, 8Vanderbilt University Medical
Center, Monroe Carell Jr, Children’s Hospital at Vanderbilt, Departmentof Neurological Surgery, Nashville, TN, USA, 9Lucile Packard Children’s
Hospital at Stanford University, Department of Pediatric Neurosurgery,
Palo Alto, CA, USA, 10Nicklaus Children’s Hospital, Department ofPediatric Neurosurgery, Miami, FL, USA, 11McGill University, Departmentof Neurosurgery, Montreal, QC, Canada, 12Washington University Schoolof Medicine, Department of Pediatrics, St, Louis, MO, USA, 13Washington
University School of Medicine, Department of Neurosurgery, St, Louis,
MO, USA, 14Children’s Mercy Hospital, The Division of PediatricHematology and Oncology, the Department of Pediatrics, Kansas

City, MO, USA, 15Arnold Palmer Hospital, Department of PediatricHematology‐Oncology, Orlando, FL, USA, 16Children’s National Health
System, Center for Cancer and Blood Disorders, Washington DC, USA,
17Children’s National Health System, Brain Tumor Institute, Washington
DC, USA, 18Johns Hopkins All Children’s Hospital, Institute of Brain
Protection Sciences, St, Petersburg, FL, USA, 19Children’s Hospital
Colorado, Department of Pediatric Neuropsychology, Aurora, CO, USA,
20University of Colorado School of Medicine, Department of PediatricsNeurology, Aurora, CO, USA
BACKGROUND: Due to disease and/or treatment-related injury, such as
hypothalamic, visual, and endocrine damage, quality of life (QoL) scores
after childhood-onset Adamantinomatous Craniopharyngioma (ACP) areamong the lowest of all pediatric brain tumors. Decision-making regarding
management would be aided by more complete understanding of a patients
likely QoL trajectory following intervention. METHODS We retrospectively analyzed caregiver and patient-reported QoL-instruments from thefirst 50 patients (ages 1–17 years at diagnosis) enrolled in the international
Advancing Treatment for Pediatric Craniopharyngioma (ATPC) consortium.
Surveys included 205 pediatric-relevant questions and were completed at
diagnosis, and 1- and 12-months following diagnosis. Using Multiple Correspondence Analysis (MCA), these categorical QoL surveys were interrogated to identify time-dependent patient subgroups. Additionally, custom
deep learning classifiers were developed using Google’s TensorFlow framework. RESULTS By representing QoL data in the reduced dimensionalityof MCA-space, we identified QoL subgroups that either improved or declined over time. We assessed differential trends in QoL responses to identify variables that were subgroup specific (Kolmogorov-Smirnov p-value< 0.1; n=20). Additionally, our optimized deep learning classifier achieveda mean 5-fold cross-validation area under precision-recall curve score >0.99 when classifying QoL subgroups at 12 month follow-up, using only
baseline data. CONCLUSIONS: This work demonstrates the existence oftime-dependent QoL-based ACP subgroups that can be inferred at time-ofdiagnosis via machine learning analyses of baseline survey responses. The
ability to predict an ACP patient’s QoL trajectory affords caregivers valuable
information that can be leveraged to maximize that patient’s psychosocial
state and therefore improve overall therapy.
QOL-23. ASSESSING THE IMPACT OF METHYLPHENIDATE ON
LATE COGNITIVE EFFECTS IN PAEDIATRIC BRAIN TUMOURSURVIVORS: A SERVICE-BASED EVALUATION
Sarah Verity1,2, Rebecca Hill1,2, Gail Halliday1, Jade Ryles1, andSimon Bailey1,2; 1Newcastle Upon Tyne Hospitals NHS Foundation Trust,
Newcastle Upon Tyne, United Kingdom, 2Northern Institute of Cancer
Research, Newcastle University, Newcastle Upon Tyne, United Kingdom
OBJECTIVE: One of the most disabling side effects of treatment in survivors of brain tumours is the resultant reduction in level of processing
speed and attention. This study aimed to evaluate intellectual and psychological benefit of short-acting methylphenidate to survivors of brain tumour. METHODS: Paediatric BT patients attending a UK specialist treatment
centre received assessment of cognitive performance. All patients identified
with attentional difficulties were screened for contraindications to methylphenidate. Participants (N=23), mean age 11.09 years, completed a 6-monthtrial of methylphenidate. Measures of attention (Test of Everyday Attention
for Children 2; SNAP-IV), side-effects (Stimulant Side-Effects Rating Scale),
Health-Related Quality of Life (PEDS-QL), and experience of methylphenidate questionnaire (purpose-developed semi-structured questionnaire) wereadministered prior to medication and after six months. RESULTS: Participants showed improvement in selective attention (t(18)=-5.4, p=<.001, d=.93)
and processing speed (t(16)=-3.0, p=.01) at follow up. Family ratings of attention were significant (t(17)=14.46, p<.001, d=-1.19). Change in subjective
measures of Health-Related Quality of Life (HRQoL) was also statisticallysignificant as reported by children (t(16)=3.91, p=.001, d=-.99), and on aparental-report measure of child HRQoL (t(15)=-8.19, p<.001, d=-1.09).
HRQoL measures show improvement to physical, academic, and emotional
domains as reported by participants. CONCLUSIONS: Paediatric BT survivors showed benefit from provision of methylphenidate in terms of reduced
attentional and processing deficit, and in terms of emotional wellbeing. Treatment was well tolerated. Continued follow-up of the current participants in alongitudinal study aims to evidence longer-term benefit to participants.
QOL-24. DIFFERENTIAL IMPACT OF TUMOR LOCATION, LOCALAND CRANIOSPINAL IRRADIATION ON NEUROPSYCHOLOGICALLONG-TERM OUTCOME IN CHILDREN WITH
MEDULLOBLASTOMA, EPENDYMOMA AND SUPRATENTORIALPNET: A LONGITUDINAL MULTICENTER OUTCOMEASSESSMENT OF CHILDREN FROM THE HIT-2000 AND HIT-REZ
TRIALS
Holger Ottensmeier1, Paul G Schlegel1, Matthias Eyrich1,
Bernhard Zimolong2, Martin Mynarek3, Katja von Hoff4,

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Stefanie Frahsek1, Rene Schmidt5, Andreas Faldum5, Johannes Wolff6,
Gudrun Fleischhack7, Monika Warmuth-Metz8, Jürgen Krauss9,
Rolf-Dieter Kortmann10, Niels Galley11, Joachim Kühl1, andStefan Rutkowski3; 1University Children’s Hospital, Würzburg, Germany,
2Department of Psychology, University of Bochum, Bochum, Germany,
3Department for Pediatric Hematology and Oncology, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany, 4Department
for Pediatric Oncology, Charité University-Medicine, Berlin, Germany,
5Institute of Biometry, University of Münster, Münster, Germany, 6Abbview,
Oncology Development, Chicago, IL, USA, 7Pediatrics III, University
Children’s Hospital, Essen, Germany, 8Department of Neuroradiology,
University Medical Center Würzburg, Würzburg, Germany, 9Department of
Neurosurgery, University Medical Center Würzburg, Würzburg, Germany,
10Department of Radiotherapy, University of Leipzig, Leipzig, Germany,
11Institute of Psychology University of Cologne, Cologne, Germany

QOL-26. I’VE GOT FRIENDS NOW: PAEDIATRIC PATIENTS’
EXPERIENCES OF METHYLPHENIDATE TREATMENT FOR
NEUROCOGNITIVE LATE-EFFECTS ASSOCIATED WITH BRAINTUMOUR
Sarah Verity1,2, Rebecca Hill1,2, Gail Halliday1, Jade Ryles1, andSimon Bailey1,2; 1Newcastle Upon Tyne Hospitals NHS Foundation Trust,
Newcastle Upon Tyne, United Kingdom, 2Northern Institute of Cancer
Research, Newcastle University, Newcastle Upon Tyne, United Kingdom

Neurocognitive deficits are frequent in childhood brain tumor survivors
and affect mental intelligence, psychomotor and executive abilities. The differential impact of factors such as disease (location, histology) or treatment(local (LI) vs. craniospinal irradiation (CSI)) on these parameters is not fully
understood. Between 2007–2011 and 2013–2017 300 testings were performed on-site by one neuropsychologist. Of these, 274 tests from n=208
children with medulloblastoma (MB), ependymoma (EP) and supratentorial
embryonal tumors (SET) <4 years at diagnosis are currently included into
the analysis. Applied tests included the Bayley II, WUEP-KD, K-ABC, tapping speed (TS), CPT_Hits/CPT_DT, and, as a new score, CPT_Power which
integrates the latter. Treatment consisted of surgery and chemotherapy ± LI/
CSI. All children receiving CSI and MB children with LI showed substantial
deficits in general intelligence scores. In contrast, children with MB or SET
without CSI/LI and those with EP receiving LI performed surprisingly wellafter 2 and 5 years follow-up. Motor function (TS) was reduced in all children except those with SET without irradiation. Of note, mental processing
speed (as measured in CPT_Power) was not essentially reduced in MB andEP patients, indicating that mental processing is less affected than motor
speed (TS) in children with infratentorial tumors. In conclusion, our data
show that besides the established detrimental effects of CSI on general intelligence, infratentorial tumor location is a main risk factor for motor dysfunction irrespective of irradiation. Appropriate sensitive testing tools are
warranted to assess cognitive function without the interfering influence of
motor dysfunction.

BACKGROUND: Whilst rates of survival following paediatric brain
tumour have increased, quality of survival continues to present a significant challenge to children and their families. The neurocognitive impact of
cranial radiotherapy (CRT) in childhood upon future intellectual development is well established. Both CRT and chemotherapy are associated withmedium-term slowed speed of cognitive processing, attention, and memory
impairment, and with longer-term failure to achieve pre-morbid intellectual
potential and low Health-Related Quality of Life (HRQoL).Methylphenidate is a psychostimulant drug shown to be effective in alleviating some of
the neurocognitive symptoms of cancer treatment, however the subjective
experience of paediatric participants is not reported. AIM: The current study
aimed to explore the subjective experience of HRQoL in paediatric neurooncology patients currently receiving methylphenidate. METHODS: A
retrospective audit was conducted on 12 paediatric neuro-oncology patientsin receipt of methylphenidate. Both standardised and novel measures wereused to assess aspects of HRQoL, specifically; social life, perceived independence, mood, confidence, school life, self-esteem, interpersonal relationships and fatigue levels. Data collected were analysed using Thematic
Analysis. RESULTS: Five key themes were identified; physical, emotional,social, academic and neuropsychological impact. CONCLUSION: The current findings evidence the perception of patients that methylphenidate supported them to regain previously lost functionality. Methylphenidate has thepotential to increase HRQoL in this population and to provide children withthe opportunity to regain a sense of normality in their lives.

QOL-25. MICROSTRUCTURAL BRAIN CHANGES ASSOCIATED
WITH NEUROCOGNITIVE AND FUNCTIONAL OUTCOMESOF INTRACRANIAL GERM CELL TUMUOR SURVIVORS –A DIFFUSIONAL KURTOSIS IMAGING STUDY
Wan-Yee Winnie Tso1, Sai Kam Hui2, Tatia Mei Chun Lee3,
Anthony Pak Yin Liu1, Patrick Ip1, Kevin Cheng4, Daniel Fong5,
Dorita Chang3, Frederick KW Ho6, Ka Man Yip1, Dennis Ku7,
Daniel KL Cheuk7, Chung Wing Luk7, Ming Kong Shing7, LK Leung1,
Pek Lan Khong2, and Godfrey Chi Fung Chan1; 1Department of Paediatrics& Adolescent Medicine, LKS Faculty of Medicine, University of Hong
Kong, Hong Kong, Hong Kong, 2Department of Diagnostic Radiology, LKS
Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong,
3State Key Laboratory of Brain and Cognitive Sciences, The Universityof Hong Kong, Hong Kong, Hong Kong, 4Department of Neurosurgery,
Queen Mary Hospital, Hong Kong, Hong Kong, 5Department of Nursing,
LKS Faculty of Medicine, University of Hong Kong, Hong Kong, Hong
Kong, 6Institute of Health and Wellbeing, University of Glasgow, Glasgow,
United Kingdom, 7Hong Kong Children’s Hospital, Hong Kong,
Hong Kong

QOL-27. SWALLOWING ASSESSMENT IN PEDIATRIC PATIENTSWITH BRAIN TUMOR
Natalia Oliveira Machado, Ana Paula Duarte, Aline Azevedo dos Santos,
Bruna Minniti Mançano, and Carlos Almeida Jr; Barretos´s Children andYoung Adults Cancer Hospital, Barretos, Sao Paulo, Brazil

BACKGROUND: Childhood intracranial germ cell tumour (iGCT) survivors are prone to radiotherapy-related neurotoxicity which can lead toneurocognitive dysfunction. Diffusion kurtosis imaging (DKI) is a MRI technique that quantifies microstructural changes in the grey and white matter ofthe brain. This study aims to investigate the associations between MR-DKI
metrics, the cognitive and functional outcomes of childhood iGCT survivors. METHOD: 20 childhood iGCT survivors who had received cranialradiotherapy were recruited. DKI parameters were determined for iGCT survivors and 18 control subjects. Neurocognitive assessment using the Hong
Kong Wechsler Intelligence Scales for Children (HKWISC)/ Wechsler Adult
Intelligence Scale – Revised (WAIS-R) and functional assessment using
the Lansky/ Karnofsky performance scales were performed for GCT survivors. RESULTS: There were significant negative correlation between the
IQ scores and the mean diffusivity (MD) in multiple white matter regions of
iGCT survivors including: anterior limb of internal capsule, superior frontooccipital fasciculus, anterior corona radiata, uncinate fasciculus, cingulum
and hippocampus. Mean kurtosis (MK) values of the superior fronto-occipitalfasciculus were positively correlated with IQ scores. For grey matter, theMD of the olfactory, insula, caudate, heschl gyrus, parahippocampal gyrus,
hippocampus, anterior cingulum, frontal inferior operculum, middle and superior temporal gyrus, middle and superior frontal orbital gyri, cuneus andiii436

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precentral gyrus were negatively correlated with IQ scores. Most of the microstructural changes with associated functional impairment were white matterregions. CONCLUSION: Our study identified vulnerable brain regions withsignificant white and grey matter microstructural changes that were associatedwith impaired cognitive function or deficits in physical functioning.

BACKGROUND: Neurosurgical intervention is the initial modality oftreatment for the vast majority of pediatric brain tumors. However, studies
on the swallowing process in pediatric patients with brain tumors are scarce,
especially comparing changes that can be identified before and after surgery.
In clinical practice, it is possible to observe that these patients may present
modifications in the swallowing phases both before and after surgery. Therefore, we conducted a longitudinal study with a cohort of 20 patients ranging
in age from 0 to 17 years, in order to characterize the swallowing disorders. RESULTS: 30% of the patients presented some change in orofacial
motricity in the organs related to initiation, coordination, and maintenanceof swallowing at the time of hospital admission, and 65% of the patients
exhibited these changes after surgery. Due to worsening in swallowing after
surgery, 40% of the patients required modification of the consistence oforal diet or required the use of an alternative route of feeding. CONCLUSIONS: There is a high prevalence of swallowing disorders in pediatric patients with brain tumors, mainly regarding the proper functioning of organs
related to initiation, coordination, and maintenance of swallowing even
before the surgical intervention, and these changes increase after surgery especially in patients with posterior fossa tumors. The role of the speech/
language pathologist is of paramount importance, given their role in theassessment and adequacy of the feeding route, identifying patients at riskof pulmonary aspirations, minimizing swallowing complications, and also
facilitating communication with patients and their families.
QOL-28. NEUROCOGNITIVE PROFILE OF PEDIATRICMEDULLOBLASTOMA PATIENTS PRIOR TO RADIATIONTHERAPY
Muhammad Baig, Ineke Osthoorn, Susan McGovern, David Grosshans,
Mary McAleer, Kristina Woodhouse, Arnold Paulino, Grace Yang,Peter Stavinoha, and Wafik Zaky; MD Anderson Cancer Center, Houston,
TX, USA
Neurocognitive late effects are unfortunately common following treatment for pediatric medulloblastoma. While radiation therapy is an essen-

Abstracts

tial component of treatment for most pediatric medulloblastoma patients,
it is associated with neurocognitive compromise. Effects include deficits incognitive speed and performance efficiency, aspects of attention, as well asworking memory. Yet long after treatment it is difficult to tease apart relative contributions of other risk factors to neurocognitive functioning beyond
radiation. We examined neurocognitive functioning in a sample of pediatricmedulloblastoma patients prior to radiation therapy, including investigationof neurocognitive risk factors such as hydrocephalus, presence of posterior
fossa syndrome, and duration of neurological symptoms prior to diagnosis.
Results indicated that the sample functioned in the average range in termsof overall IQ (n=34, X̅=103). Patients also functioned in the normal range
in terms of language-based ability (X̅=106), nonverbal ability (X̅=104), andworking memory (X̅=103). However, the sample performed statistically significantly lower than the general population in terms of cognitive speed andefficiency (z=-2.026, p=.043). The sample was also rated by parents as exhibiting more attention problems relative to the general population (z=1.988,
p=.047). There was no specific association with hydrocephalus, durationof symptoms, or history of posterior fossa syndrome. Results suggest
weaknesses in attention and processing speed may exist in some pediatricmedulloblastoma patients prior to radiation therapy secondary to tumor
and related complications. Implications for future research are presented,
along with difficulties inherent to “baseline” assessment with pediatric brain
tumor survivors.
QOL-31. USE OF PATIENT-REPORTED OUTCOMES TO IDENTIFYYOUTH AT RISK FOR IMPAIRED OVERALL HEALTH
Lisa Ingerski1,2, Rebecca Williamson Lewis2, Ann Mertens1,2, andTobey MacDonald1,2; 1Emory University School of Medicine, Atlanta, GA,
USA, 2Aflac Cancer & Blood Disorders Center, Children’s Healthcare ofAtlanta, Atlanta, GA, USA
Pediatric brain tumor survivors often experience persistent and clinically significant late-effects following treatment. Critical to understanding
morbidity is utilization of patient-reported outcomes (PROs). The current
study evaluated PROs of individuals previously diagnosed with a pediatric brain tumor and identified risk factors for less optimal overall health.
Participants included 127 youth 10.59±4.81 (M±SD) years old at survey
completion and 4.45±3.82 years from diagnosis of a brain tumor (34.6%
Pilocytic Astrocytoma, 9.4% Medulloblastoma, 9.4% Ependymoma, 7.9%
Craniopharyngioma, 38.6% Other). Outcomes were assessed via PatientReported Outcomes Measurement Information System (PROMIS) parentproxy measures. Overall health was assessed via PROMIS Global Health(i.e., a measure of general, physical, mental, and social health). Univariate
and logistic regression analyses examined potential demographic, medical,
and psychosocial factors (e.g., age, race, diagnosis, treatment) related topoor global health. Initial descriptive analyses suggested that most youth
experienced anxiety symptoms (T-score M±SD=50.71±11.54), depressive
symptoms (47.96±10.34), cognitive functioning (46.52±9.10), and fatigue (55.14±10.62) similar to their peers. However, 31.0% of youth experienced impaired global health (T-score<40). After adjusting for otherpotential covariates, the final model suggested that youth with significant anxiety (OR=6.20, CI=1.56–24.65), youth with significant fatigue(OR=3.96, CI=1.26–12.41), and youth who did not undergo a gross total
resection (OR=0.25, CI=0.07–0.96) were at risk for impaired global health.
Identifying those at-risk for impaired health is essential to reducing survivor
morbidity and optimizing overall quality of life following treatment. Current data suggest potentially modifiable factors that may improve long-term
outcomes for survivors of pediatric brain tumors.
QOL-32. THE PROMOTE STUDY: HEALTH-RELATEDQUALITY OF LIFE COMMUNICATION NEEDS OF CHILDREN,
ADOLESCENTS, AND THEIR FAMILIES ATTENDING OUTPATIENTCONSULTATIONS AFTER TREATMENT FOR A BRAIN TUMOUR
Shelly Stubley1, Anita Freeman2, Christina Liossi3,
Anne-Sophie Darlington3, Martha Grootenhuis4, Darren Hargrave5,
Christopher Morris6, David Walker1, Colin Kennedy3, and Kim Bull3;
1University of Nottingham, Nottingham, United Kingdom, 2St. Mary’s
Hospital, London, United Kingdom, 3University of Southampton,
Southampton, United Kingdom, 4Princess Máxima Centre for PaediatricOncology, Utrecht, Netherlands, 5UCL Great Ormond Street Institute ofChild Health, London, United Kingdom, 6University of Exeter, Exeter,
United Kingdom
BACKGROUND: Childhood brain tumours and their treatment can
reduce health-related quality of life (HRQoL) and cause anxiety and depression, withdrawal, and social isolation. Improved communication within
outpatient consultations may allow early identification and treatment ofthese issues. We explored family communication needs in survivors of childhood brain tumours receiving six-monthly follow-up outpatient review
within the English NHS. METHODS: Semi-structured interviews were conducted with 18 families whose child aged 8–17 years had finished treat-ment for a brain tumour within the preceding five years. Thematic analysis
used the Framework Method. RESULTS: Adjusting to change and findinga “new normal” was the overarching theme to emerge. HRQoL issues included fatigue, coping with physical changes, challenges at school, isolation,
and adjusting to changes in abilities. Survivors described a need for greater
knowledge about and more support with changes in cognitive functioning.
Parents spoke about the impact on the wider family and their changed rolein supporting the child’s HRQoL. Communication barriers included shortterm memory loss, shyness, and the need to suppress or regulate emotions
evoked by these issues. Communication needs included more information
regarding recovery and rehabilitation and/or help managing anxiety or emotional health. CONCLUSION: The above communication needs and barriers should be addressed. Having a digital record to document and monitor
this information systematically could improve service planning and provide
patients and their families with the resources to reach their full potential andexperience a better HRQoL.
QOL-33. THE PROMOTE STUDY: DEVELOPMENT AND TESTINGOF KLIK-UK, AN ONLINE PLATFORM, TO ENHANCE OUTPATIENTCOMMUNICATION ABOUT HEALTH-RELATED QUALITY OF
LIFE (HRQOL) AT THREE UK CHILDREN’S BRAIN TUMOUR
TREATMENT CENTRES (CBTTCS)
Kim Bull1, Shelly Stubley2, Natalia Kouzoupi3, Anne-Sophie Darlington1,
Martha Grootenhuis4, Darren Hargrave5, Christina Liossi1,
Christopher Morris6, David Walker2, and Colin Kennedy1; 1University ofSouthampton, Southampton, United Kingdom, 2University of Nottingham,
Nottingham, United Kingdom, 3Great Ormond Street Hospital forChildren, London, United Kingdom, 4Princess Máxima Centre for
Paediatric Oncology, Utrecht, Netherlands, 5UCL Great Ormond Street
Institute of Child Health, London, United Kingdom, 6University of Exeter,
Exeter, United Kingdom
BACKGROUND: The HRQoL of survivors of childhood brain tumour
is significantly reduced into adulthood but is not systematically assessed. In
the UK, referral for appropriate support is often reactive rather than proactive. We developed KLIK, the online Dutch platform, for use to enable
the systematic assessment of HRQoL in the UK NHS using patient-reported
outcomes measures (PROMs) which could be fed back to clinicians during
outpatient review appointments. METHODS: PARTICIPANTS: Children
aged 5–17.9 years, receiving outpatient care >6 monthly for a brain tumour diagnosed within preceding 5 years and their parents and clinicians.
SETTING: Three UK CBTTCs – UHS, Southampton; GOSH, London; andQMC, Nottingham. PROCEDURE: KLIK-UK was developed throughout
the study and barriers and opportunities for its use logged. A. Development phase: relevant PROMs were identified through systematic literature
review1 and families’ views regarding choice of PROMs, communicationneeds within consultations, and KLIK-UK were obtained by interview. B:
Feasibility phase: KLIK-UK was tested in outpatient review appointments
followed by interviews with the family and clinician. RESULTS: 57 families
and 10 clinicians participated. The PedsQL-Core module was preferred byfamilies. Communication needs and barriers were identified. All clinicians
reported that they could see the potential value of using KLIK-UK but views
differed as to whether they could use it within their current timetable. Analysis of interviews from the feasibility phase will be reported. CONCLUSION: KLIK-UK is ready for use in the UK but will need to be adapted
according to local resources, needs, and preferences. 1Bull et al. 2019 https://doi.org/10.1093/nop/npz064
QOL-34. CAREER FAIR AND RESOURCE EXPO: ADVOCATING FOR
THE LONG TERM SUCCESS OF BRAIN TUMOR SURVIVORS
Clay Hoerig1,2, Karlie Allen1, Kara Noskoff1, Jamie Frediani1,
Jody Pathare1, Casey Koerner1, Veronica DeRosa1, Nina Madrid1,
Kristin Miller3, Grace Mucci1, Chenue Abongwa1, and Ashley Plant1,2;
1Children’s Hospital Orange County, Orange, CA, USA, 2University ofCalifornia, Irvine, Irvine, CA, USA, 3Children’s Hospital Orange County,
Orange, Ca, USA
Pediatric cancer survivors have increased unemployment and lower educational attainment rates. This is most significant in brain tumor survivors
who show five-fold relative odds increase in unemployment over other pediatric cancer survivors. The long-term effects of brain tumor treatment potentiate the difficulty with work and school reintegration seen in the broader
Adolescent and Young Adult (AYA) population. To address this, our teamdesigned an annual job fair for AYA Neuro-Oncology survivors. Vendors
were invited representing disability advocacy groups, legal services, scholarship organizations, and employers with strong disability services, several
who offered on-site interviews. Additionally, brain tumor survivors served as
inspirational speakers for the event. Between thirty to forty survivors haveattended each event. Pre- and post-surveys, as well as 3- and 6- month follow
up was obtained. Universally, the day was engaging and motivating, both forsurvivors and staff, and stimulated conversation for pursuing career or aca-

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Abstracts

demic success within families and the care team. While all the patients took
applications, none of the patients completed the on-site interviews, finding
them overwhelming. Even at the 3- and 6-month follow-ups following thefirst event, the survivors continued to be at varying levels of application
completion; no one who was previously unemployed attained new employment. This improved after pre-event meetings were held with survivors toparticipate in resume building and interview preparation. Currently, twosurvivors obtained employment and are still employed at 1 year and fivesurvivors were able to advocate for their disabilities services in college withhelp of a non-profit legal assistant.
QOL-36. USE OF CANNABINOIDS IN THE PEDIATRIC CENTRALNERVOUS SYSTEM TUMOR POPULATION
Kathleen Dorris1,2, Jessica Channell1, Ashley Mettetal1,
Molly Hemenway1,2, Natalie Briones3, Alexander Tran3,
Andrea Griesinger2, Andrew Donson2, Rajeev Vibhakar1,2, Adam Green1,2,
Anandani Nellan1,2, Jean Mulcahy Levy1,2, Daniel Ambruso1,3, andNicholas Foreman1,2; 1Children’s Hospital Colorado, Aurora, CO, USA,
2Morgan Adams Foundation Pediatric Brain Tumor Research Program,
Aurora, CO, USA, 3University of Colorado Anschutz, Aurora, CO, USA
BACKGROUND: Cannabinoids, including cannabidiol (CBD) and tetrahydrocannabinol (THC), are a class of compounds found in marijuana. Numerous studies in adults have examined cannabinoid use in management ofcancer-related symptoms such as nausea, anorexia, and pain. Less is known
about the use in the pediatric oncology population. METHODS: A prospective observational study has been ongoing since 2016 at Children’s Hospital Colorado to evaluate cannabinoids’ impact using PedsQL™ modules
on quality of life of pediatric patients with central nervous system (CNS)
tumors who are 2–18 years old. Laboratory assessments of T-cell activity
and pharmacokinetics of CBD, THC and associated metabolites are in process. Diaries with exploratory information on cannabinoid use patterns arebeing collected. RESULTS: Thirty-three patients (14:19; male:female) havebeen enrolled with a median age of 6.4 years (range, 2.9–17.7 years). The
most common tumor type in enrolled patients is embryonal tumors (13/33;39%). Nine (27%) patients have low-grade glial/glioneuronal tumors, andeight (24%) had high-grade/diffuse midline gliomas. The remaining patients
had ependymoma or craniopharyngioma. The median time on cannabinoids
is 9 months. Most (n=20) patients have used oral products with CBD and
THC. One patient continues on cannabinoid therapy in follow up. Preliminary immune function analyses identified impaired neutrophil superoxideanion production and chemotaxis in patients taking cannabinoids at earlytime points on therapy. CONCLUSIONS: Families of children with various
CNS tumors are pursuing cannabinoid therapy for both antitumor and supportive care purposes. Analysis of the impact of cannabinoids on patients’quality of life is ongoing.
QOL-37. USE OF COMPUTERIZED NEUROPSYCHOLOGICALMEASURES TO ASSESS COGNITIVE MORBIDITY IN CHILDRENUNDERGOING ACTIVE RADIATION THERAPY
Lorri Kais1,2, Kellie Roesser3, Michelle Kleman1, Greta Wilkening1,2,
Arthur Liu4,5, Todd Hankinson1,2, Nicholas Foreman1,2, andChrista Hutaff-Lee1,2; 1Children’s Hospital Colorado, Aurora, CO, USA,
2University of Colorado Anschutz Medical Campus, Aurora, CO, USA,
3Children’s Hospital Colorado, Aurora, CO, USA, 4UCHealth, Fort Collins,
CO, USA, 5University of Colorado, Aurora, CO, USA
Cognitive late effects of brain tumors and related treatments are wellestablished; however, limited information regarding changes in cognition
during radiation therapy (RT) is available. Recent advances in computerizedneuropsychological assessments for monitoring of acute and late treatment
effects have been developed, though the feasibility of using these tools in a
population undergoing active RT has limited empirical evidence. This study
investigated performance of pediatric patients with brain tumors actively
undergoing RT on the NIH Toolbox (N = 10; M age = 11.29 ± 3.35 years;
86% Caucasian; 86% female). Given significant individual variability, onesample proportion tests were calculated to assess whether the proportionof patients with performances >1 standard deviation below the mean significantly differed from normative expectations. Of the 12 participants thatwere enrolled in the study, 10 completed the NIH Toolbox during active RT.
Compared to normative expectations, a greater proportion of participants
undergoing active RT exhibited deficits on measures of processing speed,
working memory, and response inhibition (p=<.01). Differences between
participants and normative expectations were not seen on measures of visualmemory and vocabulary (p=>.05). Seventy-seven percent of recruited participants completed computerized assessment during active RT, suggestingreasonable feasibility within the small cohort recruited. Consistent with theliterature regarding late effects of RT, performance on computerized measures of cognitive functioning mediated by processing speed and aspects ofexecutive functioning were lower for patients undergoing active RT. Further
investigation will focus on clarifying the trajectory of deficits across treat-iii438N EU R O - O N C O L O G Y•

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QOL-38. USE OF COMPUTERIZED NEUROPSYCHOLOGICALMEASURES TO ASSESS COGNITIVE MORBIDITY IN SURVIVORS OF
CHILDHOOD BRAIN TUMORS
Duncan Dickson1, Jessica Channell1, Ashley Mettetal1, Elizabeth Chick1,
Greta Wilkening1,2, Arthur Liu3,2, Todd Hankinson1,2, Nicholas Foreman1,2,
and Christa Hutaff-Lee1,2; 1Children’s Hospital Colorado, Aurora, CO,
USA, 2University of Colorado Anschutz Medical Campus, Aurora, CO,
USA, 3UCHealth, Fort Collins, CO, USA
Treatment of central nervous system (CNS) tumors in pediatric populations is associated with significant cognitive morbidity. Documentationof neuropsychological deficits is vital to treatment and educational planning. We investigated the feasibility and utility of a computerized neuropsychological measure (NIH Toolbox Cognitive Battery) in differentiating
individuals who received tumor treatment from healthy controls. Participants included pediatric CNS tumor survivors (N = 85; Mean Age = 13.47;
SD = 4.76) at least 1-year post-completion of treatment and healthy sibling controls (N = 20; Mean Age = 10.2; SD = 3.21) who completed the
NIH Toolbox. Ninety-eight percent of the participants enrolled completed the computerized tasks. The overall logistical regression model,
with NIH Toolbox tests as predictors, was statistically significant [χ2 (7,N = 105) = 26.176; p < .001] and improved correct group classification from
81% to 82.9%. Picture Sequencing (β = -0.059; Wald = 6.942; p = .008) and
Flanker (β = -0.083; Wald = 7.473; p = .006) were both statistically significant and negatively predictive of membership in the treatment group. For
each 1 unit increase in standard score on measures of working memory andinhibition, odds of membership in the treatment group decreased by 6.2%
and 8.7%, respectively. Consistent with the literature, worse performance on
computerized measures of cognitive functioning mediated by executive functioning was correlated with a history of brain tumor treatment. Further investigation will focus on comparing computerized neuropsychological tools
to traditional comprehensive neuropsychological evaluations and clarifying
the trajectory of these deficits across recovery.
QOL-40. THE IMPACT OF TASK COMPLEXITY ON INFORMATIONPROCESSING SPEED AND NEURAL COMMUNICATION IN
PAEDIATRIC BRAIN TUMOUR SURVIVORS
Elizabeth Cox1,2, Juanita Atton2, Julie Tseng1, Sonya Bells1,
Cynthia de Medeiros1, Suzanne Laughlin1,2, Eric Bouffet1,2, andDonald J. Mabbott1,2; 1Hospital for Sick Children, Toronto, ON, Canada,
2University of Toronto, Toronto, ON, Canada
Paediatric brain tumour survivors (PBTS) experience slower information
processing speed (IPS) that contributes to difficulty performing tasks of minimal(MC) and greater complexity (GC), and is related to aberrant neural communication. It is still unknown whether deficient IPS exists during increasing complexity.
We aim to determine if PBTS experience deficient IPS and neural communication
relative to typically developing children (TDC) during an increasingly complex
visual-motor reaction time (RT) task. During magnetoencephalography recording, participants (n=58, 12.69 ±3.24 years) pressed a button with their leftor right thumb after an arrow pointing in the corresponding direction appearedon a screen. During two MC conditions, the arrow pointed in a single direction. During a GC condition, the arrow alternated direction randomly. Mean
RT >3SD and signal artifacts were removed prior to analyses. The phase lag
index (PLI) estimated neural communication between 90 cortical sources. Linear
regression and Network Based Statistics assessed group differences in mean RT
and the PLI. PBTS demonstrated increased RT relative to TDC during the GC
condition (p=0.04, MPBTS=354.00s, MTDC=326.00s). Group differences in mean
RT during MC conditions and the PLI during all conditions were not detected(p>0.05). These results suggest PBTS experience slower IPS during GC. Reduced
IPS is thought to contribute to difficulty recruiting cognitive resources needed
to perform more complex tasks. Subtle deficits in neural communication may
underlie slower IPS. The weighted PLI is superior to the PLI when estimatingsmall differences in neural communication. We will now use the weighted PLI toassess task-related neural communication.
QOL-41. CARDIAC DYSFUNCTION IN MEDULLOBLASTOMASURVIVORS TREATED WITH PHOTON IRRADIATION
Chantel Cacciotti1, Christine Chordas1, Kate Valentino2, Rudy Allen2,Peter Manley1, and Natasha Pillay-Smiley3; 1Dana Farber / BostonChildren’s Cancer and Blood Disorder Center, Boston, MA, USA, 2LurieChildren’s Hospital/Northwestern University, Chicago, IL, USA, 3Cincinnati
Children’s Hospital Medical Center/ University of Cincinnati, Cincinnati,
OH, USABACKGROUND: Medulloblastoma is an aggressive central nervous
system (CNS) tumor that occurs mostly in the pediatric population. Treat-Abstracts

ment includes surgical resection, craniospinal radiation (CSI) and chemotherapy. Children who receive standard photon radiation (RT) are at risk for
cardiac toxicities. Potential late effects include coronary artery disease, left
ventricular scarring and dysfunction, valvular damage and atherosclerosis.
Current survivorship guidelines recommend routine ECHO surveillance forthese patients but this comes at significant health care costs over a lifetime.
We describe the experience of cardiac dysfunction in medulloblastoma survivors in a multi-institution study. METHODS: A retrospective chart review
of medulloblastoma patients treated between 1980 and 2010 with radiation
at Lurie Children’s Hospital and Dana-Farber/ Boston Children’s Hospital
who had an echocardiogram done following completion of therapy. RESULTS: 168 patients were treated for medulloblastoma during the study
time. Of whom, 80 patients had echocardiogram follow up and 76 received
photon irradiation. The latter were included in the study. The mean age at
CSI was 8.6 years (range 2.9- 20), and mean number of years post RT at
echocardiogram 7.4 years (range 2–16). Mean ejection fraction (EF) was
60.03% and shortening fraction (SF) 33.8%. Four patients (5%) had abnormal results, all of which had EF<50%. CONCLUSION: Patients who
received craniospinal irradiation for medulloblastoma therapy have relatively normal echocardiograms post treatment. Although RT may result in
cardiac risks, echocardiograms may not be the most cost effective or efficacious mode to evaluate the risk in these survivors long term.
QOL-43. ENDOCRINE AND METABOLIC CHANGES IN CHILDREN
TREATED FOR MEDULLOBLASTOMA
Alexey Kalinin1, Natalia Strebkova2, and Olga Zheludkova3;
1Endocrinology Research Centre, Moscow, Russian Federation,
2Endocrinology Research Centre, Moscow, Saint-Barthélemy, 3Russian
Scientific Center of Roentgenoradiology, Moscow, Russian Federation
We examined 63 patients (40 males/23 females) after complex treatmentof medulloblastoma. Patients had a median age (range) of 11.3 (5.5 ÷ 17.9)
years. The median time after the end of treatment was 3.7 (1.5 ÷ 11.6)
years. Endocrine disorders were detected with the following frequency:
growth hormone deficiency - 98.41% (62 of 63 patients), thyroid hormone
deficiency – 69.8% (44/63), adrenal hormone deficiency - 17.4% (11/63).
Three cases (4.7%) of premature sexual development were also detected.
Lipids levels, beta-cell function and insulin resistance (IR) during 2-horal glucose tolerance test were evaluated. A mono frequent bioelectrical
impedanciometer was used to measure body composition. Overweight (SDS
BMI> 1) was observed only in 16 patients (3 girls and 13 boys), obesity (SDS
BMI> 2) in 1 boy. Dyslipidemia was found in 34 patients (54%). All patients
underwent oral glucose tolerance test. Insulin resistance (ISI Matsuda <2.5
and/or HOMA-IR> 3.2) was detected in 7 patients (11/1%), impaired glucose tolerance (120 min glucose ≥7.8 mmol / l) was observed in 2 patientswith IR and in 2 patients without IR. At the same time, IR and impaired
glucose tolerance were encountered in only 5 children with overweight andno one with obesity. All patients with impaired glucose tolerance had normal
values of fasting glucose (4.3 ÷ 5.04 mmol / l) and HbA1c (4.8 ÷ 5.8%).
A bioelectrical impedanciometer was used to measure body composition in
49 cases, the percentage of adipose tissue was increased in 14 patients (28%)
with normal BMI.
QOL-44. ASSESSMENT OF NEUROCOGNITIVE FUNCTION
AND MRI PARAMETERS IN LONG-TERM SURVIVORS WITH
POSTERIOR FOSSA TUMORS: A COMPARISON BETWEENMEDULLOBLASTOMAS TREATED BY REDUCED-DOSE
CRANIOSPINAL IRRADIATION AND OTHER TUMORS
Naoki Kagawa1, Takako Miyamura2, Ryuichi Hirayama1,
Chisato Yokota1,3, Tomoyoshi Nakagawa1, Noriyuki Kijima1,
Manabu Kinoshita1, Yoshiko Hashii2,4, Keiko Okada5, Jyunichi Hara5,and Haruhiko Kishima1; 1Department of Neurosurgery, Osaka
University Graduate School of Medicine, Osaka, Japan, 2Department ofPediatrics, Osaka University Graduate School of Medicine, Osaka, Japan,
3Department of Neurosurgery, Suita Municipal Hospital, Osaka, Japan,
Osaka, Japan, 4Department of Cancer Immunotherapy, Osaka University
Graduate School of Medicine, Osaka, Japan, 5Department of PediatricHematology/Oncology, Osaka City General Hospital, Osaka, JapanBACKGROUND: Children with medulloblastoma cannot avoid
chemoradiotherapy including craniospinal radiation, although prognosisof medulloblastoma has improved and previous studies have reported asignificant risk of intellectual disturbance by these treatments. We retrospectively analysed neurocognitive functions, clinical MRI parameters ofpatients with posterior fossa tumors, especially medulloblastomas. MATERIALS AND METHODS: Twenty-two patients (12 medulloblastomas,
5 ependymomas, 5 astrocytomas) treated in our institution were enrolled inthis study. Mean age was 7.8 years and 6.5 years, percentage of hydrocephalus at onset was 66.7% and 60%, respectively in medulloblastoma groupand in other tumor group (ependymoma and astrocytoma). Postoperative
chemoradiotherapy including reduced-dose craniospinal irradiation (18Gy)

was done for medulloblastoma group and local radiation or operation only
was done for other group. Version 3 or 4 of Wechsler Intelligent Scale forChildren (WISC) was used by neurocognitive function analysis. Ventricularsize, white matter volume and other parameters were also was estimatedbased on MRI. Follow-up duration was 6–17 years (mean: 10.5 years). RESULTS: Evaluations of neurocognitive functions based on WISC pointed
out lower performance IQ than verbal IQ in long term survivor of bothgroup, especially working memory (P=0.05). Both hydrocephalus and cranial nerve complications was influenced lower scores of WISC, but age
at onset did not influence WISC scores. Comparison between both group
showed there was no significant difference about cognitive function andwhite matter volume. SUMMARY: Chemoradiotherapy including reduceddose craniospinal irradiation and for medulloblastomas did not have significant risk increasing neurocognitive disfunction. But long-term follow-up
and assessment of health-related quality of life are further needed.
QOL-46. LATE EFFECTS CARE FOR CHILDHOOD BRAIN TUMOURSURVIVORS: A QUALITY IMPROVEMENT PROJECT
Chantel Cacciotti1,2, Adam Fleming1, JoAnn Duckworth1, Hanna Tseitlin1,
Loretta Anderson1, and Stacey Marjerrison1; 1McMaster University,
Hamilton, ON, Canada, 2Dana Farber / Boston Children’s Cancer andBlood Disorder Center, Boston, MA, USA
BACKGROUND: Childhood and adolescent brain tumor survivors are
at risk for considerable late morbidity and mortality from their disease andthe treatment they receive. Surgery, chemotherapy, radiation therapy andtumor location all have the potential to impact the physical, psychological,
functional and social health of these survivors. Comprehensive late effects
care may mitigate these risks, but the necessary elements of this care modelis unclear. We describe a quality-improvement initiative to improve thelong-term follow-up (LTFU) care provided to brain tumour survivors at theMcMaster Children’s Hospital. METHODS: An anonymous needs assessment circulated to health providers was used to evaluate the LTFU practices.
Utilizing this feedback as well as the LTFU guidelines from the Children’s
Oncology Group a care plan was made for these survivors. RESULTS: 17
of 33 (52%) health care staff responded to the survey, this included 70%
physicians or nurse practitioners, and 30% nurses and allied health staff.
Improvements suggested included consistent inclusion of additional careproviders (i.e. social work, dietitians, endocrinology) reported by 76%, as
well as a need for improved patient education and surveillance for late effects of therapy. CONCLUSION: Treatment summaries with surveillancecare plans and LTFU resources were created for all survivors of childhood
brain tumours at risk of treatment-related complications. Late effects counselling with distribution of these materials is ongoing as part of this quality
improvement initiative. To provide comprehensive management, a neurooncology specific late effects programs with multi-disciplinary support isessential for the care of brain tumour survivors.
QOL-48. INTERDISCIPLINARY SPIRITUAL CARE TRAINING IN
PEDIATRIC NEURO-ONCOLOGYAlex Lion1,2, Saneta Maiko3, Csaba Szilagyi4, James Slaven5, andChristina Puchalski6,7; 1Indiana University School of Medicine,
Indianapolis, IN, USA, 2The Evans Center for Spiritual and Religious
Values in Healthcare at IU Health, Indianapolis, IN, USA, 3Indiana
University, Indianapolis, IN, USA, 4Johns Hopkins Medicine, Baltimore,
MD, USA, 5Indiana University School of Medicine, Indianapolis, IN, USA,
6George Washington Institute for Spirituality and Health, Washington
DC, USA, 7George Washington University School of Medicine and Health
Sciences, Washington DC, USA
INTRODUCTION: Pediatric neuro-oncology requires attention to not
only cancer biology and therapeutics, but also to the suffering of the patient. In addressing patient suffering, consensus guidelines direct attention
to the spiritual distress and resources of patients and families. A lack oftraining has been a key barrier to integrating this aspect of health into patient care. METHODS: A neuro-oncologist and a chaplain participated ina train the trainer for the Interprofessional Spiritual Care Education Curriculum (ISPEC) through the George Washington University’s Institute for
Spirituality and Health. After the train the trainer, the online curriculum
was offered to interdepartmental team members, combined with in-person
discussion groups, which met weekly for six sessions. A survey was given
before and after the training, and Likert scores were analyzed using the
Wilcoxon rank-sum non-parametric test. OUTCOMES: 17 interdisciplinary members participated in the training. These members included neurooncologists, neuro-surgeons, rehabilitation physicians, nurse practitioners,
nurses, physical therapists, music therapists, a child life specialist, a school
liaison, and a patient experience specialist. The training resulted in multiple improvements, including increased ability to identify spiritual issues(p=.0278) and increased ability to respond to these issues (p=.0056). CONCLUSION: ISPEC addressed a key barrier to providing generalist spiritualcare to patients with pediatric brain tumors. Diverse disciplines were repre-

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sented during the training. With implementation of interdisciplinary spiritual care, outcomes that may be measured in the future include improved
quality of life, patient satisfaction, and the resilience of both patients andteam members.
QOL-49. THE IMPACT OF OTOTOXICITY AND VISUALIMPAIRMENT ON EDUCATION IN CHILDREN TREATED FOR CNS
TUMOURS
Harriet Dulson1, Rachel McAndrew2, and Mark Brougham2; 1University of
Edinburgh Medical School, Edinburgh, United Kingdom, 2Royal Hospitalfor Sick Children, Edinburgh, United Kingdom
INTRODUCTION: Children treated for CNS tumours experience avery high burden of adverse effects. Platinum-based chemotherapy and cranial radiotherapy can cause ototoxicity, which may be particularly problematic in patients who have impaired vision and cognition as a result of
their tumour and associated treatment. This study assessed the prevalenceof impaired hearing and vision and how this may impact upon education. METHODS: 53 patients diagnosed with solid tumours in Edinburgh,
UK between August 2013–2018 were included in the study. Patients weresplit into three groups according to treatment received: Group 1 – cisplatinbased chemotherapy and cranial radiotherapy; Group 2 - platinum-based
chemotherapy, no cranial radiotherapy; Group 3 – benign brain tumours
treated with surgery only. Data was collected retrospectively from patient
notes. RESULTS: Overall 69.5% of those treated with platinum-based
chemotherapy experienced ototoxicity as assessed by Brock grading and5.9% of patients had reduced visual acuity. Patients in Group 1 had thehighest prevalence of both. 44.4% of patients in Group 1 needed increased
educational support following treatment, either with extra support in theclassroom or being unable to continue in mainstream school. 12.5% ofGroup 2 patients required such support and 31.3% in Group 3. CONCLUSIONS: Children with CNS tumours frequently require support for future
education but those treated with both platinum-based chemotherapy andcranial radiotherapy are at particular risk, which may be compounded byco-existent ototoxicity and visual impairment. It is essential to provide appropriate support for this patient cohort in order to maximise their educational potential.
QOL-51. LISTENING BEFORE WE SPEAK: A PATIENT-CENTEREDAPPROACH TO DEVELOPING RESOURCES FOR PEDIATRIC BRAIN
TUMOR SURVIVORS AND THEIR FAMILIES
Kathy Riley; Pediatric Brain Tumor Foundation, Asheville, NC, USA
In the United States, more than 28,000 children and teenagers live withthe diagnosis of a primary brain tumor (Porter, McCarthy, Freels, Kim, &Davis, 2010). In 2017, an estimated 4,820 new cases of childhood primarybrain and other central nervous system tumors were expected to be diagnosed in children ages 0 – 19 in the United States (Central Brain Tumor
Registry of the United States, 2017). Survivors suffer from lifelong side effects caused by their illness or by various treatments. Commonly identified
late effects of treatment include a decline in intellectual functioning andprocessing speed, performance IQ deficits, memory deficits, psychologicaldifficulties, deficits in adaptive functioning (daily life skills), and an overall
decrease in health-related quality of life (Castellino, Ullrich, Whelen, &Lange, 2014). To address the ongoing challenges these survivors and theirfamilies face, the Pediatric Brain Tumor Foundation (PBTF) met extensively
with working groups comprised of survivors and caregivers to develop theoutline for a comprehensive Survivorship Resource Guidebook. In 2019,
the PBTF published the guidebook which categorizes survivor and caregiverneeds into three primary areas: physical and mental health, quality of life,
and working the system. Expert authors included survivors and caregivers
themselves in addition to medical and mental health professionals. Key outcomes discovered during the creation and production of this resource highlight how caregivers, survivors and professionals can collaborate to provide
needed information and practical help to one segment of the pediatric cancer
population who experience profound morbidities as a result of their diagnosis and treatment.
QOL-53. GENOME ASSOCIATIONS WITH NEUROCOGNITIVEOUTCOMES, CEREBRAL MICROBLEEDS (CMBS), AND BRAIN
VOLUME AND WHITE MATTER (WM) CHANGES IN PEDIATRICBRAIN TUMOR SURVIVORS
Cassie Kline1, Schuyler Stoller1, Lennox Byer1, Caleb Edwards1,
Rachna Prasad1, Joseph Torkildson2,3, Karen Gauvain4, David Samuel5,
Janine Lupo1, Melanie Morrison1, Elizabeth Tong6, Solomiia Savchuk6,
Christian Rodrigo Ugaz Valencia6, Andreas Rauschecker1, Jeffrey Rudie1,
Thomas Hoffman1, Dena Dubal1, Heather Fullerton1, andSabine Mueller1,7; 1University of California, San Francisco, San Francisco,
CA, USA, 2University of California, San Francisco-Oakland, Oakland, CA,
USA, 3Banner Health, Mesa, AZ, USA, 4Washington University in Saintiii440N EU R O - O N C O L O G Y•

De c e mb e r 2 0 2 0Louis, St Louis, MO, USA, 5Valley Children’s Hospital, Madera, CA, USA,
6Stanford University, Stanford, CA, USA, 7Universitäts-Kinderspital Zürich,
Zurich, Switzerland
OBJECTIVE: To identify genetic predictors of neurocognition,
CMBs, brain volume, and WM changes in pediatric brain tumor survivors. METHODS: Patients were selected from an existing cohort(RadART) if they had: 1) at least one neurocognitive evaluation using
computer-based CogState; 2) available DNA; 3) standard imaging. Candidate gene or genome-wide genotyping was performed on all patients. CMBs
were identified using a semi-automated algorithm developed in MATLAB.
Volume of T2/FLAIR WM signal abnormality was measured using a semiautomated method based on a convolutional neural network. Brain volume
and cortical thickness were measured using FreeSurfer volumetric analysis.
Logistic and linear regression were done to compare phenotypes with candidate genotypes. Genome-wide efficient mixed-model analysis was done
to compare neurocognition and CMBs. Gene set analysis was done using
https://fuma.ctglab.nl/. RESULTS: APOE4 was a candidate variant associated with non-lobar, larger volume CMBs (p<0.05). At the GWAS-level(n=225), specific genes trended with visual memory, psychomotor function,
and CMB count (p<5x10-8). Using gene set analyses, there were gene set
trends seen with CMB count and psychomotor function. Small sample sizeand low mutant allele frequency limited reliability of these findings. Preliminary volumetric analysis show reduced volume within the right parietal,
medial occipital and inferior temporal lobes with increased cortical thickness in the left occipital and medial parietal lobe in patients carrying theApoE4 allele. WM signal assessments are ongoing. CONCLUSION: Genetic markers may be associated with neurocognition, CMBs, brain volume
and WM changes in pediatric brain tumor survivors; however, larger cohorts
are needed to confirm specific gene relevance.
QOL-54. HEIGHT, WEIGHT AND CARDIOVASCULAR EFFECTS OFSTIMULANTS ON CHILDREN WITH BRAIN TUMOR
Raja Khan1, Maha Bano2, Igal Mirman2, Fang Wang1, Pan Haitao1,
Jessica Smith1, Simmons Andrea1, William Greene1, Anthony Christensen1,
and Zsila Sadighi3; 1St. Jude Children’s Research Hospital, Memphis, TN,
USA, 2University of Tennessee, Memphis, TN, USA, 3MD Anderson Cancer
Center, Houston, TX, USA
INTRODUCTION: Children with brain tumors may develop inattention, slow processing, and hypersomnia. Stimulant medications improvethese problems but their effect on growth, heart rate, and blood pressure
are inadequately explored. METHODS: We retrospectively studied children
with brain tumors treated at our institution that had data available for oneyear pre and two year post stimulant treatment. Tumor location, gender,
radiation treatment (RT), age at RT, drug type, and hormone therapy werevariables of interest. RESULTS: We identified 65 children (35 males) that
fulfilled eligibility criteria. Focal RT was utilized in 58; 11 additionally received whole brain RT. Thirty were treated for hypersomnia and inattention,
8 for hypersomnia alone, and rest for inattention. Modafinil was the first
drug in 18 (27.7%) and methylphenidate in the others. Forty-seven (72.3%),
40 (61.5%) and 49 (75.4%) were on thyroxine, cortisone and growth
hormone respectively. There was no difference in pre and post stimulant
BMI, heart rate, and blood pressure. There was also no difference between
modafinil and methylphenidate groups. Rate of increase in height slowed
on stimulants (p=0.0096). Thyroxine treatment correlated with increase in
BMI after stimulants (p=0.0434). Younger age (p=0.0003) and higher BMI(p=0.0063) pre stimulants correlated with increased heart rate on stimulants, while higher age at RT (0.0159) correlated with elevated systolic BP
on stimulants. No association of studied variables was found with heightand diastolic BP. CONCLUSION: Stimulants are well tolerated by children
with brain tumors that are appropriately managed for endocrine deficiencies
but may reduce the trajectory of height attainment.
QOL-55. INTEGRATED MULTI-SCALE MODEL FOR PEDIATRICBRAIN TUMOR SURVIVAL PREDICTION
Yeping Lina Qiu, Amaury Sabran, Hong Zheng, Olivier Gevaert; Stanford
University, Stanford, CA, USA
Brain tumors are the most common solid tumors affecting children, and its
prognosis has been a great challenge for physicians and researchers. With theadvances in high-throughput sequencing technology and digital pathology,
more quantitative data is now becoming available and more information may
potentially be discovered in whole slide images (WSIs) and molecular tumor
characteristics to determine survival and treatment. Imaging and genomic data,
though very different in nature, both may contain different aspects of diseasecharacteristics that are important for survival prediction. Hence our work aims
to build a framework to integrate two data modules, whole-slide histopathology
image data, and RNA sequencing data, for a unified model to improve pediatricbrain tumor survival outcome prediction. The imaging data and genomic data
are both of high dimensions and on different scales. We use two independent

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modules, each of which consists of a deep neural network, to extract lower dimensional features from imaging and genomic data respectively. We concatenate
the extracted features and use a third neural network to train a Cox regression
model using the merged feature as input. Each module is first pre-trained with
TCGA adult brain tumor data, and subsequently fine-tuned with pediatric brain
tumor data. The entire pipeline is tested on the holdout pediatric brain tumor
dataset. Preliminary results suggest that the integrated framework achieves improved prediction performance than using each single data module alone. The
concordance index (C-index) of integrated model is 0.68, compared to 0.62
with imaging data only, and 0.66 with genomic data only.
QOL-56. THE RELAPSED AND OR PROGRESSED BRAIN TUMOURSIN CHILDREN: RHC, GLASGOW EXPERIENCE
Jairam Sastry, Paul Van Siang Liang Mang, Dermot Murpy, Milind Ronghe,
and Diana McIntosh; Royal Hospital for Children, Glasgow, United
Kingdom
INTRODUCTION: The outcome for children with relapsed or progressed brain tumours is poor. The aim of this project was to identify total
number of children who have relapsed or progressed with Brain tumour
and to determine the types of tumours, treatment offered and assess outcome. METHODS: This is a retrospective study of all patients treated forrelapsed or progressed brain tumours between 2007 and 2017 at the Royal
Hospital for children. Patients were identified using the unit database. Clinical data included demographics, histologic diagnosis, treatment characteristics and outcome which was obtained from electronic records. RESULTS: 46
children were included (22M:24F). The median age of diagnosis was 5 years.
There were 16 histological subtypes of brain tumours: pilocytic astrocytoma(n=12, 26%), optic pathway glioma (n=4,7%), medulloblastoma (n=8, 17%),
ependymoma (n=4, 9%), high grade glioma (n=3, 7%, DIPG (n=2, 4%) andothers 13(32.2%). 28(61%) had relapsed at a median time of 18 months.
Tumour progression occurred in 18(31%) at a median time of 21.5 months.
Post-relapse or progression therapy included surgery (14, 30%), chemotherapy (17, 40%) and radiotherapy (5, 10.9%). 50% of the patients remain
alive with 17(37%) being stable and 6(13%) with progression of disease.
50% had died of disease progression. CONCLUSIONS: The relapse and or
progression was seen 61% of patients. The commonest tumours in this cohort were pilocytic astrocytoma and medulloblastoma. Chemotherapy was
the most used regimen followed by surgery and radiotherapy. Primary dissemination at the time of diagnosis was associated with poor prognosis.
QOL-57. SOUTHERN CALIFORNIA KAISER PERMANENTEPEDIATRIC NEURO-ONCOLOGY PROGRAM DEVELOPMENT
Hung Tran; Kaiser Permanente, Los Angeles, Ca, USA
KEY MESSAGE: Standardization of care for subspecialty patients require centralization and support across multi-disciplinary groups within
the Kaiser Permanente medical group, which is a large health maintenanceorganization (HMO) in the United States. BACKGROUND: Prior to thedevelopment of a Pediatric Neuro-Oncology program, Southern California
Kaiser Permanente pediatric neuro-oncology patients were routinely referred
to respective regional academic centers for consultation. The process was notstandard across the region, resulting in additional costs and differences intreatment recommendations, potentially affecting outcomes. METHODS: A
Pediatric Neuro-Oncology program was established, July 2017, based at
the Kaiser Permanente Los Angeles Medical Center (LAMC), consisting ofpediatric neuro-oncology, pediatric neurosurgery, pediatric neuro-radiology,
pediatric radiation oncology, and pediatric neuro-oncology case management. RESULTS: A Pediatric Neuro-Oncology tumor board was established
to meet on a bi-monthly basis. Pediatric neuro-oncology patients across theSouthern California now have their magnetic resonance imaging (MRI) reviewed by the same pediatric neuro radiologists. Neuropathology is standardized and sent to Children’s Hospital Los Angeles and reviewed at themolecular neuropathology tumor board attended by the pediatric neurooncologist. Cases discussions regarding the patients include the regional
pediatric neurosurgeons, the pediatric radiation oncologists, and the pediatric neuro-oncologist, and treatment plans are recommended and recordedby the case manager. CONCLUSIONS: Centralization of care has allowed
for more consistent and standard care across the Southern California Region,
but requires support from multi-disciplinary groups.
QOL-58. ASSESSING FATIGUE EXPERIENCED BY PEDIATRICPATIENTS WITH INTRACRANIAL NEOPLASMS
Eamon Eccles1, Yan Han1, Hao Liu1, Jordan Holmes1, and Scott Coven1,2;
1Indiana University School of Medicine, Indianapolis, IN, USA, 2Riley
Hospital for Children, Indianapolis, IN, USA
BACKGROUND: Indiana University possessed one of the earliest clinical proton facilities in the United States. The purpose of this study was toassess fatigue and nausea/vomiting in children with central nervous system(CNS) tumors undergoing radiation therapy as part of their treatment
regimen, and to understand what factors influence fatigue. DESIGN: The
study was approved by the institutional review board at Indiana University
and consent and/or assent from eligible participants was obtained prior toenrollment. The validated Fatigue Scale is scored on a 5-point Likert scale.
Surveys were completed 1) prior to radiation therapy, 2) week three of radiation therapy, and 3) week six of radiation therapy. A score of 41 or higher
for the Fatigue Scale-Parent (< 7 years), 12 or higher for the Fatigue ScaleChild (8–12 years), and 17 or higher for the Fatigue Scale-Adolescent (13–18 years), indicates significant cancer-related fatigue. RESULTS: The study
aimed to recruit a total of 50 patients during the eligible period; however,data on 31 individual participants were available for analysis. 25 patients
underwent proton radiation therapy, while 6 patients underwent conventional photon therapy. The mean age of children was 8.8 years. Of the 31
patients, 22 recorded scores indicating significant cancer-related fatigue atsome point during radiation therapy. CONCLUSIONS: Cancer related fatigue continues to be a challenge, with limited understanding of factors thatmight predict clinically relevant fatigue This work demonstrates the feasibility of conducting symptom research for children undergoing radiation
therapy; further research is needed to characterize predictors of fatigue.
QOL-59. CEREBELLAR MUTISM SYNDROME AND THE SURGICALRISK FACTORS: A PROSPECTIVE MULTICENTRE STUDY OF 500
PATIENTS UNDERGOING TUMOUR SURGERY IN THE POSTERIOR
FOSSA
Jonathan Kjær Grønbæk1,2, Morten Wibroe1,2, Sebastian Toescu3,4,Pernilla Grillner5, Conor Mallucci6, Emanuela Molinari7, Kristin Solem8,
Mia Westerholm-Ormio9, Rosita Kiudeliene10, Katalin Mudra11,
Peter Hauser12, Kirsten van Baarsen13, Eelco Hoving13, Julian Zipfel14,
Karsten Nysom2, Kjeld Schmiegelow2,15, Astrid Sehested2,
Marianne Juhler1,16, and René Mathiasen2; 1Department of Neurosurgery,
The University Hospital Rigshospitalet, Copenhagen, Denmark,2Department of Paediatrics and Adolescent Medicine, The University
Hospital Rigshospitalet, Copenhagen, Denmark, 3Developmental
Imaging and Biophysics Section, UCL-GOS Institute of Child Health,London, UK, 4Department of Neurosurgery, Great Ormond Street
Hospital for Children, London, UK, 5Pediatric Oncology, Karolinska
University Hospital, Stockholm, Sweden, 6Department of Paediatric
Neurosurgery, Alder Hey Children’s NHS Foundation Trust, Liverpool,UK, 7Department of Neurology, The Queen Elizabeth University Hospital,
University of Glasgow, Glasgow, UK, 8Department of Pediatrics, St Olavs
Hospital, Trondheim, Norway, 9Hospital for Children and Adolescents,
University of Helsinki, Finland, 10Center of Pediatric Oncology and
Hematology at Pediatric Department and Hospital of Kauno Klinikos,
Lithuanian University of Health Sciences, Kaunas, Lithuania, 112nd Dept.
of Pediatrics, Semmelweis University, Budapest, Hungary, 12PediatricOncology and Transplantation Unit, Velkey László Child’s Health Center,
Borsod-Abaúj-Zemplén County University Teaching Hospital, Miskolc,
Hungary, 13Princess Máxima Center for Pediatric Oncology, Utrecht, The
Netherlands, 14Department of Neurosurgery, Pediatric Neurosurgery,
University Hospital Tuebingen, Tuebingen, Germany, 15Institute of Clinical
Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen,Denmark, 16Department of Neurosurgery, Aarhus University Hospital,
Aarhus, Denmark
OBJECTIVE: Cerebellar mutism syndrome (CMS) is a severe neurological complication of tumour surgery in the posterior fossa in childhood. The incidence is reported between 8 and 39%, where CMS sets inwithin days of surgery and resolves within months, yet long-term sequelae
are seen in most patients. This prospective cohort study investigates thecourse of CMS and the surgical cause of the syndrome. POPULATION
AND METHODS: We included 500 children with a tumour in the posterior fossa with planned surgery or open biopsy. Enrolment was conducted between 2014 and 2020 in 26 centres in ten European countries.
Speech, neurological symptoms and surgical procedure were registered inpredefined standardized forms pre-operatively and at three post-operative
follow-ups within one year. PRELIMINARY RESULTS: A total of 426
children underwent primary surgery and were eligible for analyses. CMS
occurred in 56 patients (13.1%) one day (median; IQR: 0–2 days) after surgery and resolved within 38 days (median; IQR: 4–52 days). Another 58 patients (13.6%) had less severe speech impairment. Mutism was associatedwith lower age (OR: 0.91 [95%CI: 0.85;0.98, p=0.014]), medulloblastoma(OR: 2.5 [95%CI: 1.4;4.7, p=0.0036]) and ATRT (OR: 12.9 [95%CI:
3.4;51.9, p=0.00018]) and tumour location in the fourth ventricle (OR: 4.0[95%CI: 2.3;7.2, p<0.0001]). Preliminary multivariate analyses revealed
no significant association between mutism and surgical access. CONCLUSION: CMS is a common complication predominantly seen in younger
children after tumour surgery for a medulloblastoma or ATRT in the fourth
ventricle. The incidence is not related to the surgical access in this study
population.

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CRANIOPHARYNGIOMA AND RARE TUMORS
RARE-01. MANAGEMENT AND OUTCOMES OF PAEDIATRICCRANIOPHARYNGIOMA: A 15-YEAR EXPERIENCE IN SINGAPORE
Mervyn Jun Rui Lim1,2, Sherry Jiani Liu3, Cindy Wei Li Ho1, Kejia Teo1,
Sein Lwin1, Ning Chou1, Tseng Tsai Yeo1, Miriam Kimpo1, andVincent Diong Weng Nga1; 1National University Hospital, Singapore,
Singapore, 2Saw Swee Hock School of Public Health, Singapore, Singapore,
3Ministry of Health Holdings, Singapore, Singapore
BACKGROUND: Craniopharyngiomas are rare embryonic malformations of the sellar region with high survival rates but high morbidity due
to long-term sequelae caused by the location of the tumour. We summarise
our institution’s experience on the management and outcomes of paediatriccraniopharyngiomas in Singapore. METHODS: This was a retrospective review of all paediatric patients (18 years and below) with histologically diagnosed craniopharyngioma managed by the National University Hospital,
Singapore from January 2002 to June 2017. Data on clinical presentation,
imaging, treatments, and outcomes were extracted from the electronic medical records using a standardized data collection form. Data analysis was
conducted using RStudio (Version 1.2.5033). Institutional ethics approval
was obtained for the study. RESULTS: We identified 12 cases of paediatriccraniopharyngiomas. The majority of cases were male (8, 66.7%) and the
median age at presentation was 6.0 (IQR 3.8 – 9.5). Initial surgical management was tumour excision (11, 91.7%) or insertion of a reservoir into
the cyst cavity (1, 8.3%). All cases had diabetes insipidus, 10 (83.3%) had
endocrine dysfunction, and 8 (66.7%) had visual impairment on long term
follow up. 7 (58.3%) cases had recurrence, and 3 (25.0%) had demised.
Cox-regression showed that females (HR=33.9, p=0.049), and Chinese race
(HR=13.3, p=0.034) were at higher risk for recurrence, but age at diagnosis
and residual tumor on post-operative MRI was not significant. CONCLUSION: The management of craniopharyngioma is complex as it is complicated by high recurrence rates and significant long-term morbidity. Further
research on treatment strategies focusing on maintaining quality of life isimportant.
RARE-02.RE-IRRADIATION FOR RECURRENTCRANIOPHARYNGIOMA
Sarah Foran1, Normand Laperriere1, Kim Edelstein1, Laura Janzen2,
Vijay Ramaswamy2, David Shultz1, Fred Gentili3, Eric Bouffet2,
and Derek Tsang1; 1Princess Margaret Cancer Centre, Toronto, ON,
Canada, 2Hospital for Sick Children, Toronto, ON, Canada, 3Toronto
Western Hospital, Toronto, ON, Canada
PURPOSE: Patients with recurrent craniopharyngioma after radiotherapy(RT) have few treatment options. At our institution, re-irradiation has beenoffered to selected individuals with recurrent craniopharyngioma not suitablefor further surgery, intracystic therapy or targeted agents. METHODS: A
retrospective study was performed of patients with craniopharyngioma
treated with two courses of fractionated RT. First RT (RT1) prescriptions
ranged from 50–54 Gy in 25–30 fractions; re-irradiation (RT2) prescriptions were 54 Gy in 30 fractions with full, in-field overlap of dose. The maximum dose to organs-at-risk (brainstem, optic structures) were maintainedat or below the prescription dose. There was no cumulative dose limit to
any structure. RESULTS: We identified four patients. Median RT1-to-RT2
interval was 5.8 years (range, 4.7–20.4). Cumulative maximum doses to
optic chiasma and nerves were >100 Gy in all four patients. With a median follow-up of 33 months after RT2, three patients had disease control
and are alive at 9, 23 and 42 months from RT2; one patient developed
progressive disease and died 33 months after RT2. In three evaluable patients, vision remained stable or improved after RT2; the remaining one
patient had no light perception prior to re-irradiation. Two patients had
neuropsychological testing before and after RT2; neurocognitive domains
were generally stable in one patient but working memory declined in thesecond patient. CONCLUSIONS: Despite exceeding usual tolerances for
optic chiasm and nerves, visual outcomes were stable in all living patients.
Re-irradiation should be discussed as a treatment option for patients withrecurrent craniopharyngioma but without other therapeutic options.
RARE-03. AGGRESSIVE RESECTION FOR PEDIATRICCRANIOPHARYNGIOMAS VIA ENDOSCOPIC ENDONASAL
APPROACH
Hiroki Morisako, Takeo Goto, Hiroki Ohata, Hiroaki Sakamoto, andKenji Ohata; Osaka City University Graduate School of Medicine, Osaka,Japan
OBJECTIVE: In recent years, the endoscopic endonasal approach (EEA)
has been increasingly used for pediatric craniopharyngiomas. We here
present our experience and the outcomes of the EEA resection of pediatric craniopharyngiomas. MATERIALS AND METHODS: Between

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April 2014 and December 2019, 16 cases of pediatric craniopharyngiomas
were operated at the Osaka city university (OCU) hospital. Eight patientswere diagnosed with primary craniopharyngiomas while 8 had a recurrent
tumor. There were 5 males and 11 females, with a mean age of 10.7 years(3–17 years). EEA was selected in all patients and a case of large mutilobulated tumor was resected by combination of microscopic transcranial
approach. RESULTS: Gross total resection was achieved in 14 patientsand near total resection in other 2. Post-op CSF leak occurred in 3 patients, which was treated with re-exploration. Pituitary stalk was preserved
intraoperatively in 4 cases, and 15 patients developed diabetes insipidus
and anterior hormonal replacement therapy was required in 15 patients atlast follow-up. Visual improvement was noted in 4 patients while vision remained unchanged in the rest. Neuropsychological function status was preserved in all patients, and there was no new-onset obesity postoperatively.
The mean follow-up duration was 35.1 months (2 – 69 months) and 4 of 8
recurrent cases had re-recurrence during this period, however there was norecurrent in 8 primary cases. CONCLUSIONS: EEA should be the surgicalmodality of choice for treating pediatric craniopharyngiomas. It results inbetter visual and cognitive outcomes with a significantly increased extent
of resection.
RARE-04. INTELLECTUAL DEVELOPMENT IN CHILDREN WITHPEDIATRIC CRANIOPHARYNGIOMA AFTER TUMOR REMOVAL
Tatsuki Oyoshi, Shingo Fujio, Nayuta Higa, Hajime Yonezawa, andKoji Yoshimoto; Department of Neurosurgery, Graduate school of Medical
and Dental Sciences, Kagoshima University, Kagoshima, Kagoshima, JapanINTRODUCTION: Intellectual
assessment
inchildrenwithcraniopharyngioma after tumor removal is still unknown. We assessed intellectual development in children who underwent microsurgical resection in
our institute over the last twelve years. MATERIALS AND METHODS: Tenchildren among 41 patients with craniopharyngioma treated and followed at
Kagoshima University Hospital between 2007 and 2019 were reviewed. We
also assessed intellectual development in 10 years or younger children withcraniopharyngioma one year after tumor removal. Intelligence was assessedusing the Wechsler Intelligence Scale for Children-Fourth Edition (WISCⅣ). RESULTS: Ten children underwent microsurgical tumor removal. The
mean age at surgery was 5.8 (range 1–10) years. Transcranial approach was
performed in 8 children, transsphenoidal approach in two children. The
mean follow up period was 110 months. Gamma knife surgery (GKS) was
performed in 6 children less than 6 months after first surgery. Regional recurrences occurred in 5 children, and additional GKS was performed in fourchildren, second microsurgical removal in one child. Severe obesity with atransient electrolyte imbalance occurred in one child. Eight children withGH deficiency underwent GH replacement therapy. Eight children were assessed working memory index (WMI), processing speed index (PSI), Perceptual reasoning index (PRI), and verbal comprehension index (VCI) using
WISC 4. Each mean value of WMI, PSI, and PRI was lower than VCI, except for 2 children with normal full scale intelligence quotient. CONCLUSION: WMI, PSI and PRI in children with intellectual disabilities werelower tendency than VCI after surgical removal of craniopharyngiomas in
the present study.
RARE-06. OPTIMIZATION OF PROTON RADIATION THERAPYFOR GIANT CRANIOPHARYNGIOMAS
Valerie Cruz Flores1, Stacie Stapleton1, Gerald Tuite1, andNaren Ramakrishna2; 1Johns Hopkins All Children’s Hospital, St
Petersburg, FL, USA, 2Orlando Health UF Health Cancer Center, Orlando,
FL, USA
Craniopharyngiomas are benign intracranial tumors located in the sellar
and suprasellar region. Their size and extent of invasion into surrounding
structures vary considerably. While the majority of craniopharyngiomas
on presentation are between 1–3 cm without hypothalamic invasion, a significant proportion of patients present with ‘giant’ craniopharyngiomas of>4cm in dimension with large cystic extension through the 3rd ventricle.
These tumors pose a challenge both for surgical resection as well as forradiation therapy. Proton beam therapy (PBT) has become the preferredstandard of care after subtotal resection of pediatric craniopharyngiomas. In
the setting of giant craniopharyngioma, the use of proton therapy allows areduction of dose to surrounding normal brain, but changes in cyst volume
can result in either under-coverage of tumor or excess dose to surrounding
brain, an effect further magnified by the sharp gradients associated with
proton dose distributions. In this case report we describe the proton treatment planning and intra-treatment monitoring of two patients with giant
craniopharyngiomas with largest pre-operative of dimension 6cm, and 9cm,
respectively, and 6cm and 5.5cm, respectively, pre-radiation. Both patients
had drains inserted to Ommaya reservoirs. We performed surveillance imaging during RT utilizing spiral computer tomography (CT) on a weekly
basis and reconstructed the treatment dose on the surveillance CTs to ensure
target coverage and normal tissue sparing. We compared the dosimetry inAbstracts

these cases for PBT versus intensity-modulated radiation therapy, characterized the cyst evolution during treatment in 3 dimensions, and define an
optimized protocol for treatment planning and intra-treatment monitoring.
RARE-07. THE LANDSCAPE OF GENOMIC ALTERATIONS IN
ADAMANTINOMATOUS CRANIOPHARYNGIOMASPrasidda Khadka1,2, Eric Prince3, Sophie Lu1, Sandro Santagata4,1,
Keith Ligon1,4, Peter Manley1, Rameen Beroukhim1,4, Todd Hankinson3,
and Pratiti Bandopadhayay1,5; 1Dana-Farber Cancer Institute, Boston, MA,
USA, 2Harvard Medical School, Boston, MA, USA, 3University of Colorado
Anschutz Medical Campus, Aurora, CO, USA, 4Brigham and Women’s
Hospital, Boston, MA, USA, 5Boston Children’s Hospital, Boston, MA,
USA
INTRODUCTION: Adamantinomatous craniopharyngiomas (ACPs) arecharacterized by activating mutations in the CTNNB1 gene. Here we perform a comprehensive genomic analysis of 23 ACPs to define the landscapeof genomic alterations in this disease. METHODS: We performed wholegenome sequencing of 24 ACPs and their matched normal tissues. We used
Mutect 2.0 to detect mutations and indels in these samples and MutSig2CV
to identify significant mutations. Copy numbers were called using theGATK4 pipeline and GISTIC 2.0 was applied to identify significant alterations. Finally, SvABA was applied to identify genome-wide structural variants and rearrangements. RESULTS: 18/24 (75%) of the sequenced ACPs
harbored activating mutations in exon 3 of CTNNB1 gene with an averagevariant allele fraction (VAF) of 0.4±0.1. These mutations have previously
been shown to activate the WNT signaling pathway in these tumors. No
other significantly recurrent mutations were detected in our samples. The
ACPs were quiet with regard to copy number alterations and no recurrent
amplifications or deletions were detected. 528 structural variations and rearrangements were detected in total in all 24 samples with an average of 22
variants per sample. Gene-Set Enrichment Analysis (GSEA) of the RNAseq
data revealed upregulation of WNT/B-catenin (FDR q-value <0.25) in the
CTNNB1 mutant samples compared to CTNNB1 WT samples. CONCLUSION: Our study identified previously described activating CTNNB1
mutations in the majority of ACPs. In addition, we identified several rearrangements and structural variations in these tumors that could play animportant role in the pathogenesis of the disease.
RARE-08. CYST FLUID CYTOKINES MAY PROMOTEEPITHELIAL-TO-MESENCHYMAL TRANSITION IN PEDIATRICADAMANTINOMATOUS CRANIOPHARYNGIOMA
Trinka Vijmasi1, Eric Prince1, Astrid Hengartner1, Chibueze Agwu2,
Susan Staulcup3, Maryna Pavlova4, Andrea Griesinger5, Andrew Donson5,
Kathleen Dorris5, Michael Handler3, and Todd Hankinson3; 1Departmentof Neurosurgery, University of Colorado Anschutz Medical Campus,
Aurora, CO, USA, 2School of Medicine, Washington University Saint Louis,
St. Louis, MO, USA, 3Department of Neurosurgery, Children’s Hospital
Colorado, Aurora, CO, USA, 4Charles C. Gates Center for Regenerative
Medicine and Stem Cell Biology, University of Colorado Anschutz Medical
Campus, Aurora, CO, USA, 5Department of Pediatrics, Children’s Hospital
Colorado, Aurora, CO, USA
BACKGROUND: Despite poor clinical outcomes, no targeted therapies havebeen established for the treatment of Adamantinomatous Craniopharyngioma(ACP). The only known genetic aberration is a mutation in CTNNB1 that
results in the nuclear accumulation of beta-catenin. Nuclear beta-catenin is anestablished inducer of Epithelial-to-Mesenchymal Transition (EMT). ACP cyst
fluid is enriched with pro-inflammatory and SASP cytokines, many of which
are also directly implicated in EMT. We sought to investigate the role of EMT
in ACP pathology. METHODS: Normal human epithelial cells were cultured
and treated with ACP cyst fluid (10%) for 1, 2, 4 and 8 days. Cell morphology
was monitored by live cell brightfield microscopy. The expression of EMT associated genes, ZEB1, ZEB2, SNAI-1, SLUG, TWIST, E-Cadherin, Beta-Catenin
and Vimentin was determined by RT-qPCR. RESULTS: ACP cyst fluid treatedepithelial cells were markedly transformed into long, spindle-shaped cells.
ACP cyst fluid treatment resulted in the progressive up-regulation of ZEB2
over 8 days (RQ=12.0; P<0.01), the progressive up-regulation of SNAI-1 over
4 days (RQ=5.1; P<0.05) and up-regulation of Vimentin (RQ=2.2; p<0.01),
identified only on Day 8. CONCLUSION: ACP cyst fluid can induce EMT-likechanges in normal human epithelial cells. In conjunction with the frequency ofbeta-catenin mutation in ACP, it is possible that EMT plays a crucial role in thepathology of ACP. Understanding ACP pathology in the context of the EMT
paradigm may aid the development of new targeted therapeutics.
RARE-09. PRESERVATION OF ENDOCRINE FUNCTION AFTEROMMAYA RESERVOIR INSERTION IN CHILDREN WITH CYSTICCRANIOPHARYNGIOMA
Laura-Nanna Lohkamp1, Abhaya Kulkarni1, James Drake1,
James T Rutka1, Peter Dirks1, Michael Taylor1, George Ibrahim1,

Lorena Baroni2, Jill Hamilton3, and Ute Katharina Bartels2; 1The Hospitalfor Sick Children, Division of Neurosurgery, Toronto, ON, Canada, 2The
Hospital for Sick Children, Division of Haematology/Oncology, Toronto,
ON, Canada, 3The Hospital for Sick Children, Division of Endocrinology,
Toronto, ON, Canada
INTRODUCTION: Children with craniopharyngiomas (CP) can be subjected to significant morbidities caused by radical surgery and/or radiation
with severe long-term consequences. Ommaya reservoir Insertion (ORI) into
cystic CP represents a minimally invasive procedure that aims to preserve
endocrine, hypothalamic and neurocognitive function. The purpose of thisstudy was to determine the relevance of upfront ORI (+/- intracystic treatment) for preservation of endocrine function. METHODS: A retrospective
chart review of children with CP treated at the Hospital for Sick Children
between 01/01/2000 and 15/01/2020 was undertaken. Endocrine function
was reviewed at the time of initial ORI or surgical resection and throughout
the course of follow-up. Event free survival (EFS) was defined as the time
to additional surgical resection or irradiation. RESULTS: Fifty-five patientswith sufficient endocrine follow-up data were included. The median age ofdiagnosis was 8.3 years (range 2.1–18.0 years), 31 were males. ORI was performed as upfront treatment in 30 patients, gross total or partial resectionin 24 patients and radiation in 1 patient, respectively. Endocrine function
remained stable after ORI with a median EFS of 19.2 (0 – 105.3) months
while the majority of patients who underwent surgical resection had documented worsened endocrine function postoperatively (median of 0; range
0 – 29.4 months) (p< 0.001). The event most commonly related to secondary
endocrine deterioration was initial or delayed surgical resection. CONCLUSIONS: Endocrine function was preserved in patients with upfront ORI (+/intracystic treatment). Further studies will elucidate the implications of ORI
with respect to ophthalmological, vascular and neurocognitive long-term
outcome.
RARE-10. ADAMANTINOMATOUS CRANIOPHARYNGIOMARESIDES OUTSIDE THE BLOOD BRAIN BARRIER
Eric Prince1, Trinka Vijmasi1, Jennifer McWilliams2,
Astrid Hengartner1, Susan Staulcup1, Nicholas Foreman1,
Kimberly Jordan2, Kathleen Dorris1, Lindsey Hoffman3, andTodd Hankinson1; 1Children’s Hospital Colorado, Aurora, CO, USA,
2University of Colorado Anschutz Medical Campus, Aurora, CO, USA,
3Phoenix Children’s Hospital, Phoenix, AZ, USA
BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is adevastating skull-base tumor believed to derive from epithelial remnants ofthe primordial craniopharyngeal duct (Rathke’s pouch), which gives rise to
the anterior pituitary gland. Genetically engineered mouse models of ACP
demonstrate that perturbation of the fetal anterior pituitary can generate
tumors analogous to ACP. Clinical and preclinical data indicate that IL-6
blockade may contribute to ACP tumor control, with the most common
agent being the humanized monoclonal antibody, tocilizumab. This agent
demonstrated poor blood-brain barrier (BBB) penetration in primates.
We present findings from two children enrolled on a phase 0 clinical trial(NCT03970226) of a single dose of preoperative intravenous tocilizumab
prior to resection of newly diagnosed ACP. METHODS: Blood samples
were obtained at multiple timepoints. Serum was isolated via ficoll separation. Tumor tissue and cyst fluid were obtained 4–6 hours following thesingle IV dose of tocilizumab. Tissue was snap-frozen. Tumor was homogenized in RIPA buffer. Free tocilizumab in serum, cyst fluid, and tumor tissue
was measured using enzyme-linked immunosorbent assay (ELISA) against a
standard curve. RESULTS: Both patients in this trial demonstrated clinically
relevant levels of tocilizumab (≥ 4µg/mL) in serum, cyst fluid, and tumor
tissue, compared to undetectable levels in control samples. CONCLUSION: ACP resides outside BBB protection. In addition to demonstrating
the feasibility of systemic delivery of tocilizumab, these findings indicate that
other large molecules, including those known to have poor BBB penetration,
may be systemically delivered as part of an antitumor regimen in the treatment of ACP.
RARE-11. QUANTITATIVE MR IMAGING FEATURES ASSOCIATED
WITH UNIQUE TRANSCRIPTIONAL CHARACTERISTICS IN
PEDIATRIC ADAMANTINOMATOUS CRANIOPHARYNGIOMA:A POTENTIAL GUIDE FOR THERAPYDavid Mirsky1, Eric Prince1, Susan Staulcup1, Astrid Hengartner1,
Trinka Vijmasi1, James Johnston2, Luca Massimi3, Richard Anderson4,Mark Souweidane5, Robert Naftel6, David Limbrick7, Gerald Grant8,
Toba Niazi9, Roy Dudley10, Lindsay Kilburn11, Eric Jackson12,
George Jallo13, Kevin Ginn14, Amy Smith15, Joshua Chern16,
Amy Lee17, Annie Drapeau18, Mark Krieger19, Michael Handler1, andTodd Hankinson1; 1Children’s Hospital Colorado, Aurora, CO, USA,
2University of Alabama at Birmingham, Birmingham, AL, USA, 3Università
Cattolica del Sacro Cuore, Rome, Italy, 4Columbia University, New York
City, NY, USA, 5Memorial Sloan Kettering Cancer Center, New York City,N E U R O -O N C O L O G Y•

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iii443

Abstracts

NY, USA, 6Vanderbilt University Medical Center, Nashville, TN, USA,
7Washington University School of Medicine, St. Louis, MO, USA, 8Lucile
Packard Children’s Hospital at Stanford University, Palo Alto, CA, USA,
9Nicklaus Children’s Hospital, Miami, FL, USA, 10McGill University,
Montreal, Canada, 11Children’s National Health System, Washington DC,
USA, 12Johns Hopkins University School of Medicine, Baltimore, MD,
USA, 13Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA,
14Children’s Mercy Hospital, Kansas City, MO, USA, 15Arnold Palmer
Hospital, Orlando, FL, USA, 16Emory University School of Medicine,Atlanta, GA, USA, 17Seattle Children’s Hospital, Seattle, WA, USA,
18Nationwide Children’s Hospital, Columbus, OH, USA, 19Children’s
Hospital Los Angeles, Los Angeles, CA, USA
METHODS: Through the Advancing Treatment for Pediatric
Craniopharyngioma (ATPC) consortium we accumulated preoperative
MRIs and tumor RNA for 50 unique ACP patients. MRIs were assessed
quantitatively for 28 different features and analyzed using Multiple Factor
Analysis (MFA) and optimal clustering was determined via maximizationof Bayesian Information Criterion (BIC). Following bulk RNAseq, differential expression and pathway enrichment were performed using standard
methodologies (i.e., DESeq2 and GSEA). RESULTS: MRI features were well
represented in the first 3 dimensions of MFA (variance explained=67.32%);
specifically tumor/cyst size, ventricular size, and cyst fluid diffusivity. Using
this three-way axis, we identified 3 patient subgroups. Transcriptional differences between these subgroups indicated one group was enriched for
DNA damage response and MYC related pathways, one group enriched for
SHH, and one group enriched for WNT/β-catenin and EMT-related pathways. CONCLUSION: This preliminary work suggests that there may beunique gene expression variants within ACP, which may be identified preoperatively using easily quantifiable MRI parameters. These radiogenomic
signatures could provide prognostic information and/or guidance in the selection of antitumor therapies for children with ACP.
RARE-12. VASCULOPATHY IN PEDIATRIC CRANIOPHARYNGIOMAPATIENTS TREATED WITH SURGERY AND RADIOTHERAPYJohn Lucas1, David LeVine2, Yousef Ismael1, Chi-Yang Hsu2,
Kaleb Darrow2, Austin Faught2, Vadim Moskvin2, Fakhriddin Pilepesov2,
Noah Sabin2, Frederick Boop2, Paul Klimo1, Lucas Elijovich2, andThomas Merchant2; 1St. Jude Children’s Research Hospital, Memphis, TN,
USA, 2University of TN Health Sciences Center, Memphis, TN, USA
PURPOSE: As much as 40% of pediatric brain tumor patients will experience varied levels of Vasculopathy (VS), however few predictive factors
have been described. Here we describe the type and timing of VS and explore
the relationship between treatment modality and the timing, location, anddistribution of VS. METHODS: 94 pediatric Craniopharyngioma patients
underwent surgery and proton radiotherapy. Pre- and post-treatment imaging, cumulative physical and biological proton dose maps, clinical characteristics, and measures of dyslipidemia were evaluated. MR and MRAs were
evaluated for pre- and post-radiotherapy VS (type, workup, location, andseverity). VS events were segmented and described according to their normal
brain region, and vascular territory. RESULTS: 47 patients were found tohave 154 confirmed VS of varying severity with a median time to event of
3.41 years 95% CI 3.08–3.88. 22% (N=21) of patients had ≥1 pre-existing
instances of VS and 26.6% (N=25) had a dyslipidemia at diagnosis. Forty-six(48.9%) patients had evidence of VS post-RT with 9.5% (N=9) being clinically significant. Aspirin was recommended in 10.6% (N=10) patients. Only
4 (4.2%) patients required revascularization. Clinical characteristics were
not predictive of VS. An increased frequency of VS were observed along theoperative corridor and high-dose radiotherapy field. CONCLUSIONS: VS
often precedes radiotherapy necessitating appropriate baseline imaging. Surgery type and extent are interrelated to the risk for radiotherapy-induced VS.
While the spatial radiotherapy dose distribution approximated most vascular injury events, it was not all-inclusive. Spatial modeling of biologicaland physical dose may offer insights into therapy related vascular injury.
RARE-13. INFLAMMATORY MYOFIBROBLASTIC TUMORMIMICKING DESMOPLASTIC INFANTILE GANGLIOGLIOMA (DIG)
OF THE TEMPORAL LOBE
Ibrahim Abukhiran1, Gino Bardi Lora2, Patricia Kirby1, Julia Shelton2,
Joel Shilyanski2, Saul Wilson1, Aaron Bossler1, Yutaka Sato2,
Amani Bashir1, and Mariko Sato2; 1University of Iowa, Iowa City, Iowa,
USA, 2Stead Family Children’s Hospital University of Iowa, Iowa City,
Iowa, USA
Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm
composed of fascicles of myofibroblastic spindle cells in a background ofprominent inflammatory infiltrate. It is categorized as ‘intermediate, rarely
metastasizing’ in the World Health Organization classification of tumors ofsoft tissue and bone. We present a novel case of concurrent brain and lungtumor with diagnosis of TFG-ROS1-rearranged IMT in a 14 year old femaleiii444

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patient, in which targeted next-generation sequencing became a powerfultool for detection of genomic alterations in both lung and brain tumors. At
age 9, the patient’s lung mass was incidentally found and investigated forvarious infectious diseases with negative result. At age 14, she presented withseizure and was noted to have a stable size lung mass and a left temporal
lobe tumor. The left temporal lobe tumor showed a desmoplastic spindlecell neoplasm involving the meninges and cerebral cortex and Desmoplastic
Infantile Ganglioglioma (DIG) was considered one of differentials. Subsequently, her right lung mass was resected and showed a similar spindlecell neoplasm with a background of dense fibrosis and chronic inflammation, consistent with Inflammatory Myofibroblastic Tumor. Molecular
microdissection revealed that both tumors shares TFG-ROS1 fusion whichis associated with (t(3;6) (q12;q22)), thus it is strongly suggestive that two
tumors arose from the same origin. No predisposition syndrome was identified.
RARE-14. DEVELOPMENT OF ANAPLASTIC ASTROCYTOMAAS A THIRD MALIGNANCY IN A PEDIATRIC PATIENT WITHCONSTITUTIONAL MISMATCH REPAIR DEFICIENCY (CMMRD):A CASE REPORT AND EVALUATION OF TUMOR GENOMICSIDENTIFYING BIALLELIC MSH6 MUTATIONSErin Wright, Alexis Judd, Jennifer Stanke, Sarah Rush, and Daniel Pettee;
Akron Children’s Hospital, Akron, OH, USA
Congenital mismatch repair deficiency (CMMRD) is a pediatric cancer
predisposition syndrome secondary to biallelic mutations in mismatch repair
genes including MLH1, MSH2, MSH6, and PMS2. Due to the resulting lackof repair mechanisms, these patients develop a high intracellular mutationalburden and have a high risk of development of multiple malignancies ata young age. Similar to patients with Lynch Syndrome (monoallelic mutations in MMR genes), these patients are at risk for development of central nervous system (CNS) tumors including high grade gliomas. Forty-eightpercent of patients with CMMRD are diagnosed with a CNS malignancy.
In this interesting case, a patient developed three metachronous malignancies prior to the age of 13, including Burkitt lymphoma, T-Cell lymphoma
and anaplastic astrocytoma. Genomic analysis revealed a high mutationalburden in his initial tumors, with multiple oncogenic mutations, as well as apreviously unreported germline compound heterozygous MSH6 E744fs*12
and R248fs*8 alteration. He received a gross total resection of the tumor
which in previous studies has been shown to have the highest impact onsurvival. Surgery was followed by radiation and ongoing treatment with an
immune checkpoint inhibitor with stable disease at 6 months. The purposeof this case report is to describe the interesting presentation of CMMRD anddiscuss the previously unreported biallelic MSH6 mutations.
RARE-15. EARLY PSEUDOPROGRESSION POST-RADIATIONIN PAEDIATRIC HIGH-GRADE GLIOMA PATIENTS WITHCONSTITUTIONAL MISMATCH REPAIR DEFICIENCY: TWO CASEREPORTS FROM A SINGLE CENTRE
Ay-Jiuan Teng1,2, Breege Gilmartin3, Marty Campbell1, Kanika Bhatia1,
Greg Wheeler4, Michael Sullivan1,5, Jordan Hansford1,5, andDong-Anh Khuong-Quang1,6; 1Children’s Cancer Centre, The RoyalChildren’s Hospital, Parkville, Melbourne, VIC, Australia, 2Sarawak
General Hospital, Kuching, Sarawak, Malaysia, 3Medical Imaging,
The Royal Children’s Hospital, Parkville, Melbourne, VIC, Australia,
4Radiation Therapy Centre, Peter MacCallum Cancer Centre, Melbourne,
VIC, Australia, 5Department of Paediatrics, University of Melbourne,
Melbourne, VIC, Australia, 6Cancer Research, Peter MacCallum Cancer
Centre, Parkville, Melbourne, VIC, Australia
BACKGROUND: Constitutional Mismatch Repair Deficiency (CMMRD)
is a cancer predisposition syndrome caused by biallelic mutations in the mismatch repair pathway, and high-grade glioma (HGG) constitute the mostprevalent brain tumours. Pseudoprogression alludes to radiological changes
that mimic tumour progression, but are in fact due to other causes such as
therapy related inflammation. It can occur as early as three months post
treatment. To our knowledge, its characteristics in CMMRD patients has
not been reported. METHODS: We retrospectively identified seven patientswith CMMRD and history of HGG at The Royal Children’s Hospital, Melbourne from 2005 to 2019. Our objective was to review the characteristics ofpseudoprogression in this cohort. RESULTS: Out of the seven patients, twowith constitutional loss of PMS2 demonstrated evidence of pseudoprogression.
Patient 1 presented at 16 years old with a cerebellar anaplastic astrocytoma.
She developed clinical and radiological progression within two weeks ofstarting radiotherapy, persisting up to four months after completion. However,six months post radiation she improved without intervention and the tumour
remains stable five years post therapy. Patient 2 presented at 17 years old with a
midbrain anaplastic astrocytoma, and showed signs of progression four weeks
after completion of radiotherapy. She was then treated with Bevacizumab,
an anti-VEGFA antibody with remarkable response. She subsequently received Nivolumab, a checkpoint inhibitor with ongoing stable disease for fourAbstracts

months. CONCLUSION: Our findings showed that pseudoprogression canoccur early in the treatment course in CMMRD patients. Identification of thisentity is important for appropriate clinical management.
RARE-16. SEVEN CASES OF RETINOBLASTOMA WITH CNSINVOLVEMENTS
Chikako Kiyotani, Masahiro Sugawa, Yukihiro Matsukawa,
Yoshihiro Gocho, Kenichi Sakamoto, Noriyuki Azuma, Takako Yoshioka,
Yoshiyuki Tsutsumi, Hiroshi Fuji, Kenichi Usami, Hideki Ogiwara,
Keita Terashima, and Kimikazu Matsumoto; National Center for Child
Health and Development, Tokyo, Japan
Treatment strategy for trilateral retinoblastoma (TRb: very rare RB withbrain tumor) or retinoblastoma with central nervous system (CNS) involvement is not established yet. We retrospectively reviewed our seven cases ofthese rare almost fatal tumors. Their ages at diagnosis are 0y3m-1y10m(median 1y3m) (Male 4, Female 3). Only one had RB family history. Theiraffected eyes were bilateral 3, unilateral 3 and no 1. Their CNS involvements were suprasellar tumor 4, pineal tumor 1 and cerebrospinal fluid(CSF) cytology positive 2. Three of the suprasellar tumor patients had spinal
metastasis. Four of the seven patients were TRb and one were geneticallyclassified suprasellar retinoblastoma. All of them were treated with chemotherapy and four received high-dose chemotherapy. Three brain tumors offour TRb almost disappeared with chemotherapy. Two of them also received
radiotherapy but relapsed. Although one radiation-free long-term TRb survivor developed secondary osteosarcoma, he got remission again and live
5 more years. One CSF positive Rb patient with chiasm invasion died of
disease 11 months later. The other patient had no chiasm invasion nor CSF
involvement at diagnosis, but his CSF cytology turned to positive after his
second cycle of chemotherapy. He got remission with radiotherapy and highdose chemotherapy, and alive without disease for 4 years. 2-year RFS and
2-year OS of all patients were 40% and 60%. Although our TRb patients
responded to chemotherapy, it was difficult to avoid radiotherapy except
one. Data accumulation is necessary for better treatment of these cancerpredisposed patients.
RARE-17. SURVIVAL BENEFIT FOR INDIVIDUALS WITHCONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME
AND BRAIN TUMORS WHO UNDERGO SURVEILLANCEPROTOCOL. A REPORT FROM THE INTERNATIONALREPLICATION REPAIR CONSORTIUM
Ayse Bahar Ercan1, Carol Durno2, Vanessa J. Bianchi1, Melissa Edwards1,
Melyssa Aronson3, Eric Bouffet4, Abeer Al-Battashi5, Musa Alharbi6,
Donald Basel7, Raymond Bedgood8, Anne Bendel9,
Deborah T. Blumenthal10, Miriam Bornhorst11, Annika Bronsema12,
Elizabeth Cairney13, Sara Carroll14, Aghiad Chamdin15,
Stefano Chiaravalli16, Shlomi Constantini17, Anirban Das18, Rina Dvir19,
Roula Farah20, William Foulkes21, Zehavit Frenkel22, Sharon Gardner23,
Mithra Ghalibafian24, Cathy Gilpin25, Catherine Goudie26,
Syed Ahmer Hamid27, Jordan Hansford28, Craig Harlos29,
Nobuko Hijiya30, Saunders Hsu31, Junne Kamihara32, Jeffrey Knipstein33,
Carl Koschmann34, Valerie Larouche35, Alvaro Lassaletta36,
Scott Lindhorst37, Simon Ling38, Michael Link39, Rebecca Loret De Mola40,
Rebecca Luiten41, Michal Lurye22, Jamie Maciaszek42,
Vanan Magimairajan43, Ossama Maher44, Maura Massimino16,
Naureen Mushtaq45, Monica Newmark46, Garth Nicholas47,
Kim Nichols42, Theodore Nicolaides23, Enrico Opocher48,
Michael Osborn49, Benjamin Oshrine50, Rachel Pearlman51, Daniel Pettee52,
Jan Rapp53, Mohsin Rashid54, Alyssa Reddy55, Lara Reichman56,
Marc Remke57, Gabriel Robbins23, Magnus Sabel58, David Samuel59,
Isabelle Scheers60, Santanu Sen61, Duncan Stearns62, David Sumerauer63,
Carol Swallow64, Leslie Taylor65, Helen Toledano66, Patrick Tomboc67,
An Van Damme68, Ira Winer69, Michal Yalon70, Lee Yi Yen71,
Michal Zapotocky72, Vahid Fallah Azad24, Shayna Zelcer73,
David Ziegler74, Stefanie Zimmerman75, and Uri Tabori76; 1The Arthur andSonia Labatt Brain Tumour Research Centre, The Hospital for Sick
Children, Toronto, ON, Canada, 2Division of Gastroenterology,
Hepatology & Nutrition, The Hospital for Sick Children, University ofToronto, Toronto, ON, Canada, 3The Familial Gastrointestinal Cancer
Registry at the Zane Cohen Centre for Digestive Disease, Mount Sinai
Hospital, Toronto, ON, Canada, 4Division of Hematology and Oncology,
The Hospital for Sick Children, University of Toronto, Toronto, ON,
Canada, 5Child Health Specialist, Ministry of Health, Muscat, Oman,
6Pediatric Hematology Oncology, King Fahad Medical City, Riyahd, ON,
Saudi Arabia, 7Division of Genetics, Department of Pediatrics, Medical
College of Wisconsin, Milwaukee, WI, USA, 8Coliseum Medical Centers
and Coliseum Northside Hospital, GA, USA, 9Department of PediatricHematology-Oncology, Children’s Hospitals and Clinics of Minnesota,
MN, USA, 10Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv,
Israel, 11Brain Tumor Institute, Children’s National Medical Center,

Washington, DC, USA, 12Department of Pediatric Hematology andOncology, University Medical Center Hamburg-Eppendorf, Hamburg,
Germany, 13Department of Paediatrics, Western University and London
Health Sciences Centre, London, ON, Canada, 14Department of
Hematology and Oncology, Cleveland Clinic, Cleveland, OH, USA,
15College of Human Medicine, Center for Bleeding and Clotting Disorders,Michigan State University, MI, USA, 16Pediatric Unit, Fondazione IRCCS
Istituto Nazionale dei Tumori, Milano, Italy, 17Department of Pediatric
Neurosurgery, Dana Children’s Hospital, Tel-Aviv, Israel, 18Division of
Hematology and Oncology, The Hospital for Sick Children, Toronto, ON,
Canada, 19Department of Pediatric Hemato-Oncology, Tel Aviv Medical
Center, Tel-Aviv, Israel, 20Saint George Hospital University Medical Center,
Beirut, Lebanon, 21Division of Medical Genetics, Department of Medicine,
McGill University Health Centre, Montreal, QC, Canada, 22Sheba - Tel Ha
Shomer Hospital, Ruhama, Israel, 23Pediatric Hematology-Oncology, NYU
Langone Health, New York, NY, USA, 24MAHAK Pediatric Cancer
Treatment and Research Center (MPCTRC), Tehran, Iran, Islamic Republicof, 25The Children’s Hospital of Eastern Ontario, Ottawa, Canada,
26McGill University, Division of Experimental Medicine, Montreal, QC,
Canada, 27The Indus Hospital, Karachi, Pakistan, 28Children’s Cancer
Centre, Royal Children’s Hospital, University of Melbourne, Melbourne,
Australia, 29Department of Medical Oncology and Hematology,
CancerCare Manitoba, Manitoba, Canada, 30Division of Hematology,
Oncology, and Stem Cell Transplantation, Ann & Robert H, LurieChildren’s Hospital/Northwest, University of Chicago, Chicago, IL, USA,
31Pediatric Hematology-Oncology, Sutter Health, California, USA,
32Dana-Farber Cancer Institute and Boston Childrens Hospital, Boston,
MA, USA, 33Pediatric Neurology, Medical College of Wisconsin,
Milwaukee, WI, USA, 34Division of Pediatric Hematology-Oncology,
Department of Pediatrics, University of Michigan School of Medicine,Michigan, USA, 35Hematology/Oncology Centre Hospitalier Universitairede Quebec, Quebec, Canada, 36CNIO-HNJ Clinical Research Unit,
Pediatric Oncology, Hematology and Stem Cell Transplant Department,
Hospital Infantil Universitario Niño Jesús, Madrid, Spain, 37NeuroOncology, Department of Neurosurgery, and Department of Medicine,
Division of Hematology/Medical Oncology, Medical University of South
Carolina, Charleston, SC, 38Division of Gastroenterology, Hepatology andNutrition, The Hospital for Sick Children, University of Toronto, Toronto,
ON, Canada, 39Standford Medicine, The Stanford Cancer Center,
California, USA, 40Oregon Health and Science University, Portland, OR,
USA, 41Clinical Cancer Genetics Banner MD Anderson Cancer Center,
Gilbert, AZ, USA, 42St Jude Children’s Research Hospital, Memphis, TN,
USA, 43Department of Pediatric Hematology-Oncology, Cancer Care
Manitoba; Research Institute in Oncology and Hematology, University of
Manitoba, Winnipeg, Canada, 44Nicklaus Children’s Hospital, PediatricHematology and Oncology, Florida, USA, 45Agha Khan Hospital, Karachi,
Pakistan, 46Lurie Children’s Hospital of Chicago, Chicago, IL, USA,
47University of Ottawa Division of Medical Oncology, Ottawa, Canada,
48Pediatric Hematology/Oncology Unit, Department of Pediatrics,
University of Padua, Padua, Italy, 49Women’s and Children’s Hospital,
North Adelaide, Australia, 50Cancer and Blood Disorders Institute, Johns
Hopkins All Children’s Hospital, St. Petersburg, FL, USA, 51Department ofInternal Medicine, Division of Human Genetics, The Ohio State University
Comprehensive Cancer Center, Ohio, USA, 52Akron Childrens Hospital,
Akron, OH, USA, 53West Virginia University, WVU Cancer Institute,
Virginia, USA, 54IWK Health Center, Halifax, Canada, 55Children’s
Hospital of Alabama, University of Alabama at Birmingham, Birmingham,
AL, USA, 56McGill University Health Centre, Research Institute(RI-MUHC), Montreal, Canada, 57University Hospital Düsseldorf,
Dusseldorf, Germany, 58Department of Pediatrics, Institute of Clinical
Sciences, Sahlgrenska Academy, University of Gothenburg & Queen Silvia,
Gothenburg, Sweden, 59Department of Pediatrics, Valley Childrens
Hospital, California, USA, 60Pediatric Gastroenterology, Hepatology andNutrition Unit, Cliniques Universitaires St Luc, Brussels, Belgium,
61Department of Pediatrics, Kokilaben Dhirubhai Ambani Hospital &Research Centre, Mumbai, India, 62Department of Pediatric HematologyOncology, Rainbow Babies and Children’s Hospital, Cleveland, OH, USA,
63Department of Pediatric Hematology and Oncology, 2nd Faculty of
Medicine, University Hospital Motol, Charles University, Prague, Czech
Republic, 64Department of Surgery, Mount Sinai Hospital and Departmentof Surgery, University of Toronto, Toronto, ON, Canada, 65St. Jude’sChildren’s Research Hospital, Memphis, TN, USA, 66Pediatric Hematology
Oncology, Schneider Children’s Medical Center of Israel, Petah Tikya,
Israel, 67Department of Pediatrics, Ruby Memorial Hospital, West Virginia
University, West Virginia, USA, 68Department of Pediatric Hematology andOncology, Cliniques Universitaires Saint-Luc, Université Catholique deLouvain, Louvain, Belgium, 69Wayne State University, Detroit, MI, USA,
70Sheba Medical Center, Ramat Gan, Israel, 71Department of Neurosurgery,
Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan,
72University Hospital Motol, Prague, Czech Republic, 73Childrens Hospital,
London Health Science Center, London, ON, Canada, 74Sydney Children’s
Hospital, New South Wales, Australia, 75University Hospital Frankfurt,

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Paediatric Haematology and Oncology, Frankfurt, Germany, 76Division of
Hematology and Oncology, The Hospital for Sick Children, University ofToronto, Toronto, ON, Canada
BACKGROUND: Constitutional mismatch repair deficiency syndrome(CMMRD) is a severe cancer predisposition syndrome resulting in early
onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. METHODS: We surveyed all confirmed CMMRD
patients in the International Replication Repair Deficiency Consortium.
A surveillance protocol consisting of frequent biochemical, endoscopic andimaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS: Surveillancedata were collected from 105 CMMRD individuals from 41 countries.
Of the 193 malignant tumors, CNS malignancies were the most common(44%). The surveillance protocol uncovered 49 asymptomatic tumors
including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p<0.004). Similarly, 5-year survival was 82+/-11% and24+/-6% for surveillance and non-surveillance of brain tumors (p=0.005).
Yearly total body and q6 month brain MRI detected asymptomatic cancers
in all but 3 symptomatic CNS gliomas. These were tumors uncovered whentime between scans was >6 months as per protocol. Finally, of the low grade
tumors identified asymptomatically, 5 were low grade gliomas. All of the low
grade gliomas, which were not resected transformed to high grade tumors at
a median of 1.6 ± 0.9 years. CONCLUSION: These data support a survival
benefit in CMMRD patients undergoing a surveillance protocol. Adherence
to protocol and resection of lower grade lesions may improve survival forpatients with CNS tumors.
RARE-18. GENETIC EVALUATION IN PATIENTS WITH CHOROID
PLEXUS TUMORS
Milena Oliveira, Nasjla Silva, Andrea Cappellano, Daniela Almeida,
Sergio Cavalheiro, Patrícia Dastoli, Frederico Silva, and Fernanda Lima;
IOP/GRAACC/UNIFESP, São Paulo, São Paulo, Brazil
INTRODUCTION: Choroid plexus tumors (CPT) are rare
intraventricular neoplasms of epithelial origin. They usually occur in the 2ndyear of life, corresponding to 0.4–0.6% of intracranial tumors in this age
group. They are sub classified, according to WHO 2016, in choroid plexus
carcinoma (CPC), atypical choroid plexus papilloma (ACPP) and choroid
plexus papilloma (CPP). Li-Fraumeni syndrome (LFS) is present in 50% of
patients with CPC. In Brazil, the TP53 p.R337H mutation affects 0.3% of
the population in the South/Southeast. OBJECTIVE: Evaluate the incidenceof genetic mutations in patients with choroid plexus tumors and therefore
the importance of genetic evaluation. PATIENTS AND METHODS: Between 1992–2019, 38 patients were diagnosed with CPT in our institution,
23 with CPC. From 2012, 21 patients were referred for genetic evaluation,
16 of which had CPC (2 had previously CPP). Positive family history forneoplasms was present in 87.5%; 37.5% compatible with LFS, 50% ofthem with mutations. All the patients with positive, but unspecific, family
history of neoplasms, had pathogenic mutation. The molecular investigation of the TP53 gene in patients with CPC was performed and positivein 56.2%: R337H (5 patients), R110C, R158H, H179R, R196* (1 patienteach). Of those with R337H, p53 protein immunohistochemistry resulted in
90–100% positivity. One of the patients with CPP that evolved to CCP had
the H179R mutation. Clinical course was similar among them, and withthose without mutations. CONCLUSION: These results confirm the needfor genetic evaluation in patients with choroid plexus tumors for adequate
therapeutic management and long-term follow-up.
RARE-19. PEDIATRIC HIGH GRADE GLIOMA WITH DNA REPAIR
PATHWAY ABERRATIONS, CLINICAL CHARACTERISTICS ANDOUTCOME
Muhammad Baig, David McCall, Tyler Moss, David Sandberg,
Gregory Fuller, Susan McGovern, Arnold Paulino, Amer Najjar,
Joya Chandra, Soumen Khatua, and Wafik Zaky; MD Anderson Cancer
Center, Houston, TX, USA
DNA mismatch repair machinery is an integral part of the human genome
and its defect has been involved in tumorigenesis and treatment resistance.
Heterozygous monoallelic germline loss of function in MLH-1, MSH-2,
MSH-6 or PMS-2 is involved in Lynch syndrome, whereas biallelic mutations cause constitutional mismatch repair deficiency (CMMRD) which is
associated with hematologic malignancies and glioblastoma. We report here
the clinical characterization and molecular analyses of 7 patients who presented with gliomas and MMR machinery aberrations. Two patients hada clinical diagnosis of NF-1 with dermatologic stigmata, of whom one patient has CMMRD and the other has Lynch syndrome. Two patients had aknown family history of Lynch syndrome upon their diagnosis of glioma.
Three patients with high-grade glioma and negative family history, 2 hadiii446

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germline mutations in MMR genes, and one had numerous mutations
including MMR genes with microsatellite instability. Patients were initiallytreated with chemotherapy and radiation for high-grade gliomas (HGG);
5/7 had progression. Median time to progression was 12 months (range:5–52), and median time from progression to death was 7 months (range:2–25). One patient had low-grade glioma initially but progressed to HGG
and is currently on therapy. Another patient treated with temozolomide andradiation is currently receiving maintenance therapy without any disease
recurrence. Although the literature data on brain tumors with MMR deficiency is limited, these consistently show that MMRD-associated gliomas
are treatment-resistant and have a dismal outcome. Collaborative efforts areneeded to better understand this subgroup of pediatric HGG and to define
optimal treatment strategy.
RARE-20. MALIGNANT PERIPHERAL NERVE SHEATH TUMOR OF
A CRANIAL NERVE IN AN INFANT WITH NEUROCUTANEOUS
MELANOSIS
Lacey Carter, Naina Gross, Rene McNall-Knapp,and Jo Elle Peterson;
University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
At one month of age, a female presented with a giant congenital nevus
along lower back and thighs and hydrocephalus. A ventriculoperitoneal
shunt was placed. An MRI was done at six months, initially reported as
normal. At eleven months of age, five months after original MRI, patientpresented with dysconjugate gaze and lethargy. MRI showed new 3.8 x 3.7 x
3.4 cm right cerebellopontine angle mass extending into Meckel’s cave andforamen ovale along with leptomeningeal disease extending from the mass
along the entire length of the spinal cord. Retrospective review of prior MRI
revealed subtle leptomeningeal enhancement concerning for neurocutaneous
melanosis (NCM). Given the leptomeningeal disease, family elected for open
biopsy and debulking of lesion instead of aggressive resection. Histologically,
the mass showed hypercellular spindle cell neoplasm with mitotic activity
and necrosis mixed with remnants of normal cranial nerve. GFAP was negative, excluding a glioma. HMB-45, MITF, panmelanoma, and Melan-A
were negative, excluding melanoma. A negative myogenin stain ruled out
ectomesenchymoma. S-100 protein and SOX-10 positivity with variable lossof staining for trimethylation of histone H3 K27 were indicative of malignant peripheral nerve sheath tumor (MPNST). Given the course of themass, trigeminal nerve MPNST was presumed. Given the poor prognosis
of intracranial MPNST and NCM, family elected to forgo treatment andwas discharged with hospice. She died 25 days after surgery. Cranial nerve
MPNST is rare. MPNST in patients with NCM has not previously been reported to our knowledge.
RARE-21. CANCER SPECTRUM IN GERMLINE SUFU MUTATIONCARRIERS: A COLLABORATIVE PROJECT OF THE SIOPE HOST
GENOME WORKING GROUP
Léa Guerrini-Rousseau1, Sebastian Waszak2, Franck Bourdeaut3,
Olivier Delattre3, Nicola Dikow4, Christelle Dufour1, Amar Gajjar5,
Jacques Grill1, Steffen Hirsch4, Saskia Hopman6, David Jones7,
Majoline Jongmans6, Andrey Korshunov4, Christian Kratz8,
Lucie Lafay-Cousin9, Julien Masliah3, Till Milde10,
Paul Northcott5, Kristian Pajtler7, Stefan Pfister7, Stéphanie Puget11,Marie Agnès Rame Collonge12, Giles Robinson13, Eric Sariban14,
Nicolas Sevenet15, Miriam Smith16, Dominik Sturm10, Hélène Zattara17,
Pascale Varlet18, Gareth Evans19, and Laurence Brugières1; 1Gustave
Roussy, Villejuif, France, 2EMBL, Heidelberg, Germany, 3Institut Curie,
Paris, France, 4Medicine University, Heidelberg, Germany, 5St. Jude,
Memphis, TN, USA, 6UMC, Utrecht, Netherlands, 7KiTZ, Heidelberg,
Germany, 8MH, Hannovre, Germany, 9Alberta Children Hospital, Calgary,
AB, Canada, 10DKFZ, Heidelberg, Germany, 11APHP Necker, Paris, France,
12CHU, Besançon, France, 13St. Jude, Memphis, TN, USA, 14Hôpital
Universitaire des Enfants Reine Fabiola, Bruxelles, Belgium, 15Institut
Bergonié, Bordeaux, France, 16University, Manchester, United Kingdom,
17APHM, Marseille, France, 18St. Anne Hospital, Paris, France, 19St. Mary’s
Hospital, Manchester, United Kingdom
BACKGROUND: Little is known about cancer risk associated withpathogenic germline SUFU variants. METHODS: Data of all previously
published and 25 still unpublished patients with a pathogenic germline
SUFU mutation were compiled. RESULTS: 124 patients in 67 families were identified, most of them ascertained after the occurrence of a
medulloblastoma (MB) or as part of Gorlin syndrome cohorts. Overall, 30
patients were healthy carriers and 94 patients developed a total of 129 tumors (up to 4 tumors/patient): 68 MBs, always as first tumor (median age
at diagnosis: 1.5yr [0.1–5]), 22 patients with at least 1 basal cell carcinoma(BCC) (median 10/patient) (median age at first BCC: 43yr, [17–52]), 15
meningiomas (median age 43yr, [13–72]), 7 ovarian stromal/fibrous tumors(median age 12yr [5–34]), and 17 other tumors including 5 sarcomas (median age: 50yr [7–79]). Median age at last follow-up was 30yr. Nineteen
patients died, including 11 from MB. Second malignancies were diagnosed

Abstracts

in 21 patients including 13 in MB survivors. Mutations were inherited in
58/66 (88%) of cases in which inheritance could be tested and de novo in
8. In 6/67 families (9%), >2 children were diagnosed with a MB. CONCLUSION: In this large cohort of germline SUFU mutation carriers, MB
in infants is the most frequent tumor but the spectrum also includes typical
Gorlin syndrome tumors (BCC, meningiomas, and ovarian stromal/fibroustumors) either as first tumors or as second malignancies. This broad tumor
spectrum and the high risk of second malignancies justify the implementation of specific cancer surveillance programs.
RARE-22. GERMLINE PATHOGENIC VARIANT C.1552G>A;P.E518K
IN DGCR8 CONFERS SUSCEPTIBILITY FOR SCHWANNOMATOSISAND THYROID TUMORS
Anne-Sophie Chong1, Javad Nadaf2, Elia Grau3, Maria Apellaniz-Ruiz1,2,
Somayyeh Fahiminiya1, Avi Saskin1,4, HyeRim Han5,6, Robert Turcotte1,4,Karl Muchantef1,4, Christian Thomas7, Rabea Wagener8,
Angelia Bassenden1, Ozgur Mete9,10, Marc Pusztaszeri2, Werner Paulus7,
Albert Berghuis1, Reiner Siebert8, Steffen Albrecht1, Martin Hasselblatt7,
Conxi Lazaro3, Alexander Teule3, Marc Fabian2,1, Joan Brunet3,
William Foulkes1,2, and Barbara Rivera5,1; 1McGill University, Montreal,
QC, Canada, 2Jewish General Hospital, Montreal, QC, Canada, 3Catalan
Institute of Oncology, Barcelona, Spain, 4McGill University Health Centre,
Montreal, QC, Canada, 5Bellvitge Biomedical Research Institute, IDIBELL,
Barcelona, Spain, 6University of Barcelona, Barcelona, Spain, 7University
Hospital Münster, Münster, Germany, 8University of Ulm and University of
Ulm Medical Center, Ulm, Germany, 9University of Toronto, Toronto, ON,
Canada, 10University Health Network, Toronto, ON, Canada
Germline mutations in DICER1 cause a pleiotropic susceptibility
syndrome characterized by the development of pediatric or early-onset tumors including pleuropulmonary blastoma, Wilms tumors, pineoblastomas,
multinodular goiter (MNG) and thyroid cancers. Somatic mutations in theother two microprocessors DROSHA and DGCR8 have been found inWilms Tumors and pineoblastomas. We present here two families with peripheral schwannomatosis and thyroid tumors carrying a germline variantc.1552G>A;p.E518K in DGCR8. Family one had six affected memberswith early-onset MNG and five of them developed schwannomatosis. Allfive members were heterozygous for the variant. One of the carriers had
also been diagnosed with a choroid plexus papilloma at 7 years old. The
common second event in all tumors tested was the loss of chromosome 22
at the somatic level. In family two, a 35-year-old male was diagnosed with aperipheral schwannoma at the age of 12. Since then, he has developed seven
extra peripheral schwannomas (one of which was an ancient schwannoma)
and papillary thyroid cancer. DGCR8 lies on chromosome 22q, adjacent to
the three schwannoma genes: LZTR1, SMARCB1 and NF2. The variant,c.1552G>A;p.E518K localizes to the first RNA-binding domain of DGCR8and structural modelling predicts that it abolishes proper binding of RNA.
It is also a hotspot somatic mutation in Wilms tumors. Using miRNA profiling, we show that this variant disrupts global microRNA production and
DGCR8 mutated tumors show a specific miRNA profile different fromDGCR8 wild type tumors. These findings reinforce DGCR8 as a novel susceptibility gene for schwannomatosis and thyroid tumors.
RARE-23. NOVEL NF1 MUTATIONS IN TWO OCCURRENCES
OF GLIOBLASTOMA MULTIFORM IN A PATIENT WITHCONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME
Kaylyn Utley1, Jens Reuter2, Lei Li2, Devon Evans1, Jeffrey Florman1, andStanley Chaleff1; 1Maine Medical Center, Portland, ME, USA, 2JacksonLaboratory, Bar Harbor, ME, USA
Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare
cancer predisposition syndrome in children. Its main associated tumor types
include brain and CNS tumors, hematologic malignancies, intestinal polyps
and colorectal tumors, and other malignancies. Tumor genesis within thispopulation is highly complex and poorly understood. We describe a caseof a patient with two occurrences of glioblastoma multiforme (GBM), eachwith unique NF1 mutations. The patient is a female with CMMRD who
was first diagnosed with GBM of the right frontal lobe in 2015. She subsequently underwent gross total resection, radiation to the field and concomitant and maintenance therapy with Temozolomide and Everolimus,
due to high suspicion for NF-1. Genetic studies didn’t show NF-1, instead
revealing a diagnosis of CMMRD. Molecular testing of the GBM showeda high mutational burden and an NF1 mutation. Later, screening revealed
stage IV colon cancer, for which she underwent subtotal colectomy, partial
liver resection and chemotherapy. Molecular testing from the colon cancer
found a hypermutant malignancy without mutations in NF1. Surveillance
imaging detected a mass at the original site of her GBM, for which she hada resection. Notably, the genetic profile of the second tumor substantiallydifferent from the original tumor and the colon cancer sample, but had new
mutations in NF-1. These findings highlight the significant variability in thegenetic profiles of tumors in the context of CMMRD. It is also worth consid-

ering that NF1 is one of the first in a cascade of mutations leading to GBM
in these patients.
RARE-24. LARGE CONGENITAL MELANOCYTIC NEVI AND
NEUROCUTANEOUS MELANOCYTOSIS: A RETROSPECTIVE CASESERIES
Ugur Sener1, Elsie Ennin1, Stephanie Suser1, Ashfaq Marghoob1,
Sofia Haque1, and Yasmin Khakoo1,2; 1Memorial Sloan Kettering Cancer
Center, New York, NY, USA, 2Weill Medical College of Cornell University,
New York, NY, USA
Neurocutaneous melanocytosis (NCM) is a rare disease characterized
by excessive proliferation and deposition of melanocytes in the leptomeninges and brain parenchyma, occurring in children with large congenitalmelanocytic nevi (LCMN). Manifestations of NCM range from asymptomatic CNS melanin deposition to cranial neuropathies, seizures, andhydrocephalus. Patients with NCM are at risk for malignant melanoma. We
conducted a retrospective, single-institution study of patients with LCMN
evaluated at Memorial Sloan Kettering Cancer Center from June 2000 to
January 2020. Of 55 patients studied, 15 had no radiographic NCM, and 40
had radiographic NCM at initial evaluation. MRI findings included: focal
melanocytosis (33), diffuse leptomeningeal disease (4), solid melanoma (3).
Malformations were identified in 13, including arachnoid cyst (4), congenitalhydrocephalus (4), Dandy-Walker malformation (3), and tethered cord (1).
Twenty-one patients completed imaging once and were followed clinically.
Seventeen with serial imaging (10 with focal melanocytosis, 7 with normal
MRI) remained stable over a median 24-month follow up (range: 1–124).
Six had suspected radiographic progression of NCM without melanoma.
Malignant melanoma developed in 11 patients, 5 with focal melanocytosis
on initial imaging. Median time from focal melanocytosis identification tomelanoma diagnosis was 80 months (range: 18–200). Median age at melanoma diagnosis was 9.9 years (range: 1.1–25.3). Median survival from melanoma diagnosis was 9.1 months (range: 1–60.4). Focal NCM on neuroaxis
imaging does not predict time to transformation to malignant melanoma.
Serial imaging is not indicated in absence of disease-modifying treatment.
Clinical follow up of at-risk individuals is essential in early identificationof complications.
RARE-25. RETINAL ASTROCYTOMA MTOR INHIBITOR THERAPYIN TUBEROUS SCLEROSIS MOSAICISM
Naomi Evans1, Katherine Paton2, Harinder Kaur Gill3, and Juliette Hukin1;
1Children’s and Women’s Health Centre of British Columbia, Vancouver,
BC, Canada, 2Vancouver General Hospital, Vancouver, BC, Canada,
3University of British Columbia, Vancouver, BC, Canada
INTRODUCTION: Everolimus is an inhibitor of mTORC1 (mammaliantarget of rapamycin complex 1), it is Health Canada and FDA approved
for SEGA and renal angiomyolipoma in the setting of tuberous sclerosis
complex (TSC). There is little data available in regards to this treatment of
TSC associated retinal astrocytoma (RA). Although the behaviour of RA
is often indolent or slowly progressive, aggressive behaviour with retinal
detachment and neovascular glaucoma requiring enucleation has been reported in several patients. Definite TSC diagnosis is established when either
two major features or one major and two minor features are present. Probable TSC diagnosis is established when one major plus one minor feature
is present. METHODS: We report a child with probable TSC mosaicism,with negative serum NGS for TSC but RA and retinal achromic patch on
the left. A left retinal peripapillary astrocytoma around optic nerve and very
close to fovea was noted. There was concern that if it grew or there were
to be any leakage it would cause visual impairment. This lead to therapy
with everolimus 4.5 mg/m2/d aiming for level between 5 and 10 mcg/L. RESULTS: This boy has had a gradual reduction of the RA over the last
29 months, with healthy retina in the region no longer occupied by the lesion
and preserved vision. He has tolerated therapy well with occasional mouth
ulcers. CONCLUSION: mTORC1 inhibition is effective therapy to preserve
vision in the setting of retinal astrocytoma and tuberous sclerosis mosaicism.
RARE-26. RETROSPECTIVE ANALYSIS OF PEDIATRIC CHOROID
PLEXUS TUMORS
Yoshiko Nakano1, Atsufumi Kawamura2, Yuko Watanabe3, Ryuta Saito4,
Masayuki Kanemori3, Chikako Kiyotani5, Fumiyuki Yamasaki6,
Naoki Nakagawa7, Akira Gomi8, Taishi Nakamura9, Noritsugu Kunihiro10,
Keiko Okada11, Hiroaki Sakamoto10, Mai Kitahara12, Yuko Hibiya12,
Sumihito Nobusawa13, and Koichi Ichimura12; 1Division of Brain Tumor
Translational Research, National Cancer Center Research Institute, Tokyo,
Jersey, 2Department of Neurosurgery, Hyogo Prefectural Kobe Children’s
Hospital, Kobe, Japan, 3Department of Pediatrics, Tohoku University
School of Medicine, Miyagi, Japan, 4Department of Neurosurgery,Miyagi, Japan, 5Division of Leukemia and Lymphoma, Children’s Cancer
Center, National Center for Child Health and Development, Tokyo,

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Japan, 6Department of Neurosurgery, Graduate School of Biomedical and
Health Sciences, Hiroshima, Japan, 7Department of Neurosurgery, Osaka
University Graduate School of Medicine, Osaka, Japan, 8Departmentof Pediatric Neurosurgery, Jichi Children’s Medical Center Tochigi,
Jichi Medical University, Tochigi, Japan, 9Department of Neurosurgery,
Graduate School of Medicine, Yokohama City University, Yokohama,Japan, 10Department of Pediatric Neurosurgery, Osaka City General
Hospital, Osaka, Japan, 11Department of Pediatric Hematology andOncology, Osaka City General Hospital, Osaka, Japan, 12Division of Brain
Tumor Translational Research, National Cancer Center Research Institute,Tokyo, Japan, 13Department of Human Pathology, Gunma University
Graduate School of Medicine, Gunma, JapanBACKGROUND: Choroid plexus tumors (CPT) include choroid
plexus papilloma (CPP), atypical choroid plexus papilloma (aCPP), andchoroid plexus carcinoma (CPC). Because of their rarity, limited data are
available on the current status of treatment and outcomes for pediatric
CPTs. METHOD: We retrospectively reviewed clinical information on
patients with CPT patients aged between 0 and 30 years at diagnosis andwere treated in 8 institutions in Japan. RESULTS: Of forty-two cases initially diagnosed as CPT, 18 cases were reviewed by central pathologists. As
a result, the diagnosis of CPC or aCPP in five cases were changed to othertumors including AT/RT and astroblastoma. The remaining 37 cases were
subjected to analysis. Median age at diagnosis was two years (0 to 25) andthe mean follow-up period was seven years. All 26 patients with CPP (n=20)
or aCPP (n=6) underwent gross-total resection without adjuvant therapy.
Of them 24 patients are alive without recurrence. Four patients of patientswith CPC (n=11) died of cancer. Five patients including three patients experienced local relapse, achieved complete remission after resection of tumor
plus chemoradiotherapy. All three patients with dissemination of CPC at
diagnosis or relapse died of the disease. At least three patients were diagnosed with Li-Fraumeni syndrome: one died of medulloblastoma and one
patient developed osteosarcoma. CONCLUSION: Compared with the excellent prognosis of CPP, the survival rates for CPC, especially disseminated
CPC are unsatisfactory. Our results also underline the importance of considering genetic testing of TP53 for patients with CPC.
RARE-27. DOUBLE MUTATIONS: DIFFERENT GERMLINE AND
TUMOR MUTATIONS LEAD TO POOR OUTCOMES
Molly Hemenway, Anan Nellan, Nicholas Foreman, Alexandra Suttman,
and Kami Schneider; Univ of Colorado, SOM, Children’s Hospital
Colorado, Aurora, CO, USA
BACKGROUND: As genetic testing for both germline and tumor
mutations has increased in completeness, complexity, and availability,
more mutations and their impact on patient outcomes have been identified. METHODS: A retrospective review of pediatric patients who haveidentified germline mutations and a different tumor mutation was conducted. Data collected included demographics, tumor type, germline
mutation status, tumor mutation status, relapse status, and patient outcome. RESULTS: Six patients aged 8–13 years old (median age 10 years)
were identified for analysis. Four patients had pilocytic astrocytoma and two
had pilomyxoid astrocytoma. One of the patients with pilocytic astrocytoma
also had MPNST diagnosed very early at age 9. The combination of
germline/tumor mutations is as follows: Neurofibromatosis Type I (NF1)/
BRAF v600e, NF1, CHEK2/MYB-QKI, NF1, Klinefelter, ATM, MUTYH,
GPC3/BRAF-KIAA fusion, NF1/BRAF-KIAA (2 patients), and Marfan’s/
BRAF-KIAA. The number of relapses per patient following initial diagnosis
range from 3–7 with an average of 3.3. Four of the patients are alive and on
therapy, which two are deceased. The two deceased patients both had NF1/
BRAF-KIAA fusions and pilocytic astrocytomas. CONCLUSIONS: Patientswith differing and compounded germline and tumor molecular genetic mutations have worse outcomes. These patients have more relapses and deathwhen compared to those patients with one mutation, either germline ortumor. Broad molecular testing and germline testing for mutations is crucial
in determining patient risk for poor outcomes.
RARE-29. PRIMARY CENTRAL NERVOUS SYSTEM NON-HODGKINLYMPHOMA IN AN 11-YEAR-OLD BOY: A CASE REPORT
Jorge Luis Ramírez-Melo1, Regina M Navarro-Martin del Campo2,3,
Manuel D Martinez-Albarran1, Fernando Sánchez-Zubieta4,
Ana L Orozco-Alvarado2, Luis A Arredondo-Navarro5,3, andLorelai Gutierrez-Oliva5; 1Hospital Civil de Guadalajara “Dr. Juan
I Menchaca”, Guadalajara, Jalisco, Mexico, 2Hospital Civil de Guadalajara“Dr. Juan I Menchaca”, Guadalajara, Jalisco, Mexico, 3GAPNO,
INTERNATIONAL, Mexico, 4Hospital Civil de Guadalara “Dr, Juan
I Menchaca”, Guadalajara, Jalisco, Mexico, 5Hospital Civil de Guadalajara“Fray Antonio Alcalde”, Guadalajara, Jalisco, Mexico
BACKGROUND: Primary central nervous system lymphoma (PCNSL)
are very rare in children. CLINICAL CASE: An 11-year-old male presented

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De c e mb e r 2 0 2 0with a 2 months history with myoclonic movements in the upper right limb,
and a sudden frontal headache, gait disturbance due to right hemiparesis
and an ipsilateral convulsive episode. Upon admission he had critical condition, with hypertensive skull syndrome, Glasgow of 12, Karnofsky 40%,right hemiparesis, swallowing disorder, facial paralysis, and loss of photomotor reflex and unilateral amaurosis. A CT and MRI showed a hugetumor mass in the left tempo-parietal region, infiltrating the white matterand shifting the midline. A Tumor biopsy was done, and reported diffuse
small cell non-Hodgkin lymphoma of high-grade, Burkitt type. Systemic
lymphoma workup was negative. He received six cycles of chemotherapy
based on high dose methotrexate, rituximab and triple intrathecal.After thesecond cycle an ophthalmologic evaluation was done, and found infiltration
to the right retina, for which 6 cycles of intra vitreous chemotherapy withmethotrexate were applied, he showed an excellent response, and recovered
all his neurological functions except that right hemianopia persist. Control
MRI showed partial response at 2nd cycle and complete response after the 4th
cycle. No Radiation was performed. CONCLUSION: This report highlights
the fact that pediatric PCNSL may be effectively treated by a combination of
HDMTX and rituximab-based chemoimmunotherapy without irradiation.
Lack of awareness of this rare entity may lead to extense resections of brain,
and potential permanent secuelae that were avoided in this illustrative case.
RARE-30. A RARE CASE OF PRIMARY EWING’S SARCOMA OF THE
CERVICAL SPINE
Amandeep Kalra1,2, Jayson Neil2, Sarah Mann3, and Pierre Giglio4; 1Sarah
Cannon Cancer Institute, Kansas City, MO, USA, 2HCA, Kansas City, MO,
USA, 3UC Davis, Sacramento, CA, USA, 4Ohio State University, Columbus,
OH, USA
Ewing sarcoma family of tumors predominantly affect the pediatric population in the long bones of the extremities or the pelvis, and only 8% ofcases arise within the spine. Primary Ewing’s sarcoma of the cervical spine
is extremely rare and less than 30 cases have been reported in the literaturethus far. Here we present a case of primary Ewing’s sarcoma of the cervicalspine in a 28-year-old female who presented with a three-month history ofneck pain and right arm radiculopathy. MRI revealed a homogeneously contrast enhancing, eccentric mass with dural tail at C2-C7. After undergoing ahemilaminectomy, histopathology confirmed extraosseous Ewing’s sarcoma
with CD99 positivity. A comprehensive systemic and neuraxis work-up
ruled out overt metastasis. We extrapolated data from children’s cooperative
group studies and IESS-II clinical trial to formulate a three phase treatment
protocol as described below. To date, patient is in remission with no evidence of any residual disease in the cervical spine. In conclusion, although
Primary Ewing’s sarcoma of the cervical spine is extremely rare it should beconsidered a differential diagnosis in patients with neck pain and a spinal
mass under the age of thirty. Less than 25% of EFT’s present with overt
metastasis and almost all have subclinical metastatic disease at the timeof diagnosis, therefore, a comprehensive evaluation and systemic chemotherapy is recommended. We recommend a multidisciplinary approach ofsurgical decompression to preserve neurological functions, followed by compressed chemotherapy regimens, reevaluation for local treatment, and adjuvant chemotherapy.
RARE-31. RECURRENT CHOROID PLEXUS CARCINOMA IN
THE SETTING OF LI-FRAUMENI SYNDROME: REPORT OF TWO
CHILDREN MANAGED WITH INTENSIVE RE-INDUCTION AND
MARROW-ABLATIVE CONSOLIDATION CHEMOTHERAPYWITHOUT IRRADIATION FOLLOWED BY MOLECULARLYTARGETED BIOLOGICAL THERAPY
Margaret Shatara1, Iwona Filipek2, Maciej Ciołkowski3,Paweł Kowalczyk3, Diana S. Osorio1, Mohamed S. AbdelBaki1,
Elizabeth A. Varga1, Rolla Abu-Arja1, Claire Heinerich1,4, Daniel R. Boué5,
Christopher R. Pierson5, Jeremy Jones6, Catherine E. Cottrell7,
Elaine R. Mardis7, Richard K. Wilson7, Jeffrey R. Leonard8, andJonathan L. Finlay1; 1The Division of Hematology, Oncology, Blood andMarrow Transplant, Nationwide Children’s Hospital and The Ohio State
University, Columbus, OH, USA, 2Department of Oncology, Children’sMemorial Health Institute, Warsaw, Poland, 3Department of Neurosurgery,Children’s Memorial Health Institute, Warsaw, Poland, 4Universidade de
Uberaba Medical School, Uberaba, Brazil, 5Department of Pathology andLaboratory Medicine, Nationwide Children’s Hospital, Columbus, OH,
USA, 6The Department of Radiology, Nationwide Children’s Hospital,
Columbus, OH, USA, 7The Steve and Cindy Rasmussen Institute for
Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USA,
8The Division of Pediatric Neurosurgery, Nationwide Children’s Hospitaland The Ohio State University, Columbus, OH, USA
BACKGROUND: The optimal management for children with recurrent
choroid plexus carcinoma (CPC), is not established. We report two children
with germline TP53 mutations, whose CPC relapses were managed withmarrow-ablative chemotherapy and oral biologically-targeted therapies. PA-

Abstracts

TIENTS: Patient A: A 17 months old male presented with non-metastatic
bilateral CPC. A de novo mosaic germline TP53 mutation was identified.
After near-total resections, 16 months of standard chemotherapy were administered; 18 months later, localized tumor growth developed, again neartotally resected. Two cycles of re-induction chemotherapy were administeredfollowed by three cycles of thiotepa/carboplatin with autologous hematopoietic cell rescue (AuHCR) and subsequently 21 months of sirolimus andthalidomide, continuing without residual or recurrent disease. Patient B:
A 30 months old male presented with left lateral ventricular non-metastatic
CPC. A de novo TP53 germline mutation was identified. Following subtotal resection, craniospinal irradiation with boost was administered followed by eight cycles of standard chemotherapy; 18 months later, localized
recurrence developed; gross total resection was followed by 15 months ofstandard dose chemotherapies; four months thereafter, a second local recurrence developed, again gross totally resected. He then received one
cycle of high-dose cyclophosphamide followed by three cycles of thiotepa/
carboplatin with AuHCR. Subsequently he received sirolimus and thalidomide for 12 months, complicated by progressive pancytopenia. A small localized CPC recurrence was noted, gross totally resected, concomitant withmyelodysplastic syndrome; he underwent an allogeneic matched unrelateddonor marrow transplantation. CONCLUSIONS: Marrow-ablative chemotherapy with post-transplant targeted biological therapy may afford durable
survival for select children with recurrent CPC.
RARE-32. PEDIATRIC METASTATIC SKULL BASE CHORDOMA
WITH TP53 MUTATION – A CASE REPORT AND REVIEW OF THE
LITERATURE
Akira Shimada1, Kazuhiko Kurozumi1, Kiichiro Kanamitsu1,
Hisashi Ishida Ishida1, Kaori Fujiwara1, Kana Washio Washio1,
Tadashi Kumamoto2, Chitose Ogawa2, and Masahiro Shin3; 1Okayama
University Hospital, Okayama, Japan, 2National Cancer Center, Tokyo,
Japan, 3Tokyo University, Tokyo, Japan
Chordoma is an uncommon bone tumor arising from notochordal remnant, which accounts for 1–4% of all bone malignancies. It commonly occurs along the cranial-spinal axis, and skull base is one of most frequentsites, representing 35–49% of all chordoma cases. Surgical resection is
widely accepted as the first choice of treatment. There are only limited
number of reports about pediatric chordoma cases, and its biological behavior including genetic backgrounds were largely unknown. Here, we
present a 5 year-old girl with a large aggressive skull base chordoma of 6 cm
in maximum diameter, which eventually had multiple systemic metastasis.
We initially tried chemotherapy based on the protocol for the osteosarcoma,
but in vain. Because the tumor was highly vascularized on angiography,
after embolization of the feeding arteries and bilateral internal maxillaryarteries, endoscopic endonasal surgery was performed. The tumor was sufficiently removed, achieving effective mass reduction, and the residual tumors
involving the lower cranial nerves and craniocervial junction were additionally treated with Gamma Knife radiosurgery. However, one month later, it
showed systemic metastasis to bilateral cervical lymph nodes and lung. We
tried chemotherapy with nivolmab and imatinib for this patient, whereas
they showed the partial effect. The genetic analysis revealed somatic TP53
c.569C>T, (p.P190L) mutation in chordoma specimen. In the past literature,
we found only one study of the adult chordoma cases, in which majorityof the patients had somatic TP53 mutation (p.P72R). Further investigation
with large number of the cases is essential to clarify the molecular biologyof pediatric chordomas.
RARE-33. GIANT CELL TUMOR OF THE SKULL BASE WITH
A HISTORY OF A SUCCESSFUL RESPONSE TO DENOSUMAB AND
LATER DEVELOPING A SECOND TUMOR
Manushak Avagyan1,2, Gevorg Tamamyan1, Samvel Danielyan1,
Martin Harutyunyan2, Nune Karapetyan3, Nerses Karamyan4,Hovhannes Vardevanyan5, Armen Mkhitaryan6, andSamvel Bardakhchyan1; 1Hematology Center After Prof. Yeolyan, Yerevan,
Armenia, 2Yerevan State Medical University, Yerevan, Armenia, 3Yerevan,
Yerevan, Armenia, 4”IRA Medical Group” Radiotherapy Center, Yerevan,
Armenia, 5Armenian-American wellness center, Yerevan, Armenia,
6”Histogen” Armenian-German Scientific Practical Center of Pathology,
Yerevan, Armenia
BACKGROUND: Giant cell tumor of bone(GCTB) is a rare neoplasm
with unpredictable behavior, possible malignant transformations, and/orlung metastases. Surgery is usually the treatment of choice. In unresectableor metastatic cases, treatment with denosumab is a new treatment option.
CASE PRESENTATION: A 14-years-old female presented with cachexia,
dysphagia, diplopia, discoordination, strabismus, and multiple cranial nerve
palsies in 10.2015. MRI revealed intra-extracranial mass arising from C2
vertebrae, compressing the medulla oblongata and the left cerebellar hemisphere, invading to the sphenoid bone and nasopharynges. Biopsy showeda GCTB. Surgical resection was done, which was incomplete because oftumor location (cranial nerve and vertebral artery involvement). Then local
radiation therapy was performed 50.4Gy. During RT patient’s condition
declined and MRI showed disease progression. Treatment with denosumab
120mg q4w was initiated in 03.2016, which yielded successful results.
Disease was under control for three years until 03.2019. Then she returned
with clinical symptoms of diplopia and severe headache. MRI showed local
tumor progression. Repeated biopsy revealed undifferentiated pleomorphic
sarcoma, which could be either a malignant transformation of GCTB or a
new tumor. The patient later underwent two cycles of chemotherapy with
Ifosfamide/Doxorubicin. MRI after 2nd cycle showed marked tumor progression. The patient didn’t receive any further treatment because of cachexia and died due to disease progression in 12.2019. CONCLUSION: To
our knowledge, this is the youngest patient ever reported with a skull basetumor with such a clinical development, successful and long-time remission
with denosumab and with such a chemotherapy-resistant malignant transformation or second cancer.
RARE-34. UK CHILDREN’S CANCER AND LEUKAEMIA GROUP(CCLG): GUIDELINES FOR THE MANAGEMENT OF MENINGIOMA
IN CHILDREN, TEENAGERS AND YOUNG ADULTS
Elwira Szychot1,2, John Goodden3, Whitfield Gillian4, and Sarah Curry5,6;
1Royal Marsden Hospital, London, United Kingdom, 2Institute of Cancer
Research, London, United Kingdom, 3Leeds General Infirmary, Leeds,
United Kingdom, 4Christie Hospital, Manchester, United Kingdom,
5Southampton Children’s Hospital, Southampton, United Kingdom, 6Our
Lady’s Children’s Hospital, Crumlin, Ireland
Primary tumours of the meninges are rare accounting for only 0.4–4.6%of all paediatric tumours of the central nervous system. Due to the rarity ofthese tumours in children, and the consequent absence of collaborative prospective trials, there is no clear consensus on how the unique characteristics
of paediatric meningiomas impact clinical status, management approach,and survival. Much of the evidence and treatment recommendations for
paediatric meningiomas are extrapolated from adult data. Translating andadapting adult treatment recommendations into paediatric practice can bechallenging and might inadvertently lead to inappropriate management. In
2009 Traunecker et al. published guidelines for the management of intracranial meningioma in children and young people on behalf of UK Children’s
Cancer and Leukaemia Group (CCLG). Ten years later we have developed
the updated guidelines following a comprehensive appraisal of the literature. Complete surgical resection is the treatment of choice for symptomatic meningiomas, while radiotherapy remains the only available adjuvant
therapy and may be necessary for those tumours that cannot be completely
removed. However, significant advances have been made in the identificationof the genetic and molecular alterations of meningioma, which has not only
a potential value in development of therapeutic agents but in surveillanceof childhood meningioma survivors. This guideline builds upon the CCLG
2009 guideline. We summarise recommendations for the diagnosis, treatment, surveillance and long-term follow up of children and adolescents withmeningioma.
RARE-35. PINEOBLASTOMA IN CHILDREN SIX YEARS OF AGE
OR LESS: FINAL REPORT OF THE HEAD START I, II AND III
EXPERIENCE
Mohamed S. AbdelBaki1, Mohammad H. Abu-Arja2, Tom B. Davidson3,
Jason R. Fangusaro4, Joseph R. Stanek1, Ira J. Dunkel5, Girish Dhall6,
Sharon L. Gardner7, and Jonathan L. Finlay1; 1Nationwide Children’s
Hospital, Columbus, Ohio, USA, 2New York-Presbyterian Brooklyn
Methodist Hospital, Brooklyn, Y, USA, 3Children’s Hospital Los Angeles,
Los Angeles, CA, USA, 4Children’s Healthcare of Atlanta, Atlanta, GA,
USA, 5Memorial Sloan Kettering Cancer Center, New York, NY, USA,
6The University of Alabama at Birmingham, Birmingham, AL, USA, 7The
Stephen D, Hassenfeld Children’s Center for Cancer & Blood Disorders,
New York, NY, USA
BACKGROUND: We report the outcomes of patients with pineoblastoma
enrolled on the Head Start I-III trials. METHODS: Twenty-three children
were enrolled between 1991–2009. Treatment included maximal surgicalresection followed by five cycles of intensive-chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell
rescue (HDCx/AuHCR). Irradiation following consolidation was reserved
for children over six years of age or those with residual tumor at the endof induction. RESULTS: The median age was 3.12 years (range:0.44–5.72).
Three patients withdrew from the protocols and two patients experienced
chemotherapy-related mortality. Eight patients experienced progressive
disease (PD) during induction chemotherapy. Ten patients received HDCx/
AuHCR; eight experienced PD post-consolidation. Seven patients received
craniospinal irradiation (CSI) with a median dose of 20.7 Gy (range:18–36
Gy) with boost(s) (median dose 27 Gy, range:18–36 Gy); three received CSI
as adjuvant therapy (2 post-HDCx/AuHCR) and four upon progression/recurrence. The 5-year progression-free survival (PFS) and overall survival

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iii449Abstracts(OS) were 9.7% (95%,CI:2.6–36.0%) and 13% (95%,CI:4.5–37.5%), respectively. Three patients survived beyond five years. Nineteen patients
relapsed in the following sites: local site (n=4), distal site (n=6), local anddistal sites (n=9). Favorable OS prognostic factors were CSI (hazard ratio(HR)=0.30 (0.11–0.86), p=0.025), and HDCx/AuHCR (HR=0.40 (0.16–0.99), p=0.047). CONCLUSION: CSI and HDCx/AuHCR were statisticallyassociated with improved survival. The overall poor outcomes and high PD
rate during later induction cycles and following consolidation chemotherapy
warrants consideration of fewer induction cycles before consolidation andthe intensification of consolidation with multiple cycles of marrow-ablative
chemotherapy.
RARE-36. DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS:A REVIEW OF CLINICAL AND MOLECULAR CHARACTERISTICS,
AND OUTCOME IN A PEDIATRIC POPULATION AT A SINGLECENTER
Valerie Cruz Flores, Thomas Geller, Ignacio Gonzalez Gomez,
Luis Rodriguez, Javier Quintana, and Stacie Stapleton; Johns Hopkins All
Children’s Hospital, St. Petersburg, FL, USA
BACKGROUND: Neuronal and mixed neuro-glial tumors of the central
nervous system (CNS) are relatively rare. Dysembryoplastic neuroepithelial
tumor (DNET) is a benign, rare, slow-growing tumor, but in many cases is
associated with intractable epilepsy. OBJECTIVE: To report the experience
with DNET at a single free-standing children’s institution. METHODS: A
retrospective chart review of 24 patients with confirmed DNET between
2001 and 2019 was performed. Data was collected on clinical characteristics, tumor location, surgical management, histopathological and molecularfindings, and outcomes. RESULTS: Mean age at diagnosis was 10 years(range 2 to 19 years), with female predominance (54.2%). Most common
presenting symptoms were seizures (79.2%) and headaches (12.5%). Location of the tumor was temporal (29.2%), frontal (25.0%), parietal (16.7%),
cerebellar (12.5%) and occipital (4.2%). A gross total resection was achieved
in half the cases. Recurrence occurred in 4 patients (16.7%), all of whom
had subtotal resections. The average follow up since diagnosis was 4.6 years(range 0.3 to 14 years). Nineteen patients presented with seizures, of which
63.2% were seizure free after surgery. The samples with molecular genetic
testing (microarrays or FISH), were all normal except one patient positive
for BRAF V600E mutation. CONCLUSIONS: This is the first and largest
review of pediatric DNETs in the last 10 years. Despite majority of patients
having a favorable outcome after surgery, a subset of patients remains symptomatic. As molecular mechanisms in DNET remain unknown, future aim
is to describe the molecular characteristics of our DNET population, andcorrelate with outcomes.
RARE-37. NOONAN SYNDROME AND GLIONEURONAL TUMORS:A CENTRAL NERVOUS SYSTEM CANCER PREDISPOSITIONASSOCIATION?
Margaret Shatara1, Elizabeth A. Varga1, Daniel R. Boué2, Lisa Martin3,
Jerome A. Rusin3, Diana P. Rodriguez3, Jeremy Jones3, Aaron McAllister3,
Jeffrey R. Leonard4, Jonathan Pindrik4, Kathleen M. Schieffer5,
Kristen M. Leraas5, Tara M. Lichtenberg5, Elaine R. Mardis5,Catherine E. Cottrell5, Diana S. Osorio1, Mohamed S. AbdelBaki1, andJonathan L. Finlay1; 1The Division of Hematology, Oncology, Bloodand Marrow Transplant, Nationwide Children’s Hospital and The Ohio
State University, Columbus, OH, USA, 2Department of Pathology andLaboratory Medicine, Nationwide Children’s Hospital, Columbus, OH,
USA, 3The Department of Radiology, Nationwide Children’s Hospital,
Columbus, OH, USA, 4The Division of Pediatric Neurosurgery, Nationwide
Children’s Hospital and The Ohio State University, Columbus, OH,
USA, 5The Steve and Cindy Rasmussen Institute for Genomic Medicine,Nationwide Children’s Hospital, Columbus, OH, USA
BACKGROUND: Noonan syndrome (NS) is associated with germline
Ras signaling pathway mutations, RAS overactivation and increased tumorigenesis risk. Rosette-forming glioneuronal tumors (RFGT) are rare indolent tumors. We report the molecular profiling of two patients with NS and
RFGT. PATIENT 1: A 22-year-old male with NS was diagnosed with RFGT
after partial tumor resection followed by focal irradiation. He was enrolled
on a comprehensive genomic profiling study involving paired tumor-normal
whole exome sequencing and RNA sequencing of the disease-involved
tissue, revealing a germline PTPN11 alteration (p.Gly60Ala) consistent
with NS, and a somatic deletion (p.Ile442_Thr454del) in PIK3R1 and asomatic variant (p.Lys656Glu) in FGFR1 with concomitant increased expression of PIK3R1 and FGFR1 by RNA-sequencing. The patient remains
without tumor progression now nine months since irradiation. PATIENT 2:
A 19-year-old male with persistent headaches, underwent a brain MRI demonstrated multiple abnormal signals in the pineal region and midbrain. He
had a stereotactic biopsy revealing RFGT. He was enrolled on the genomic
study revealing a germline PTPN11 alteration (p.Asn308Asp) resulting in
a new diagnosis of NS. Several family members were subsequently iden-

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tified with clinical features of NS, including his mother and two siblings,
enabling appropriate counseling. Two somatic variants were found in transin PIK3R1 (p.Thr454_Phe456del and p.Glu451_Asn453delinsAsp), and asomatic variant (p.Val695Met) in FGFR1, with resultant overexpressionof PIK3R1. The patient is monitored with surveillance imaging. CONCLUSION: We report the molecular profiling of two patients with NS and
RFGT; strongly suggesting their connection to RASopathies through theoveractivation of the MAPK and PI3K/AKT/mTOR signaling pathways.
RARE-38. CLINICAL PRESENTATION OF MGA-NUTM1 FUSION
TRANSCRIPT SARCOMA
Pongpak Pongphitcha1, Nongnuch Sirachainan1, Artit Jinawat2,
Atthaporn Boonkird3, Putipun Puataweepong4, Chaiyos KhongKhatithum1,
Samart Pakakasama1, Usanarat Anurathapan1, Duantida Songdej1,
Eric Bouffet5, and Suradej Hongeng1; 1Department of Pediatrics,
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand,
2Department of Pathology, Ramathibodi Hospital, Mahidol University,
Bangkok, Thailand, 3Department of Surgery, Ramathibodi Hospital,
Mahidol University, Bangkok, Thailand, 4Department of Radiology,
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 5Divisionof Hematology/Oncology, Pediatric Brain Tumor Program, The Hospitalfor Sick Children, Toronto, ON, Canada
BACKGROUND: MGA-NUTM1 fusion gene tumor are recently described as new subtype of NUTM1-rearranged tumors. Regarding its rarity,
standard treatment has not been reported. Here we described clinical presentation, radiologic finding, immunohistological profile, and treatment of aboy with MGA-NUTM1 fusion gene tumor. CASE REPORT: A 13-year-old
boy with 2-month history of progressive right hemiparesis and headache.
Magnetic resonance imaging (MRI) revealed 7.8 x10.6 x 8.0 cm well defined heterogeneous enhancing mass at left fronto-parietal lobe. CT chest
and abdomen, bone scan, MRI spine, and CSF studies were unremarkable.
He underwent craniotomy with total tumor removal. Pathology demonstrated high grade spindle cell sarcoma. The immunohistological profile
was positive for BCOR, NUT1, and TEL1, but negative for CD34, STAT6,
desmin, SMA, actin sarcomeric, EMA, PR, S100, SOX10, BCL 6, and
SABT2. The INI-1 showed nuclear expression and Ki-67 was positive in
50% of tumor nuclei. Molecular test for MGA-NUTM1 fusion transcript
was positive, while SYT-SSX1, SYT-SSX2, and SYT-SSX4 fusion transcripts
were negative. Four months after operation, MRI showed newly-seen two
small enhancing foci at lateral and inferior aspects of the surgical cavity. He
underwent re-surgery. Then focal radiation (54Gy and boost up to 60Gy atrecurrent area) to the resection cavity was decided. Post-radiation chemotherapy including ifosfamide 3 g/m2 and etoposide 150 mg/m2 on Day 1–2,
and carboplatin 500 mg/m2 on Day 3, every 21–28 days was started. He
has completed the first course of chemotherapy without any complication. CONCLUSION: MGA-NUTM1 fusion CNS sarcoma is rare. Treatment may require surgery, radiation and chemotherapy.
RARE-39. MOLECULARLY CONFIRMED ATYPICAL CHOROID
PLEXUS PAPILLOMA WITH INTRACRANIAL DISSEMINATION
Masato Yanagi1, Kohei Fukuoka1, Yuko Matsushita2, Yuko Hibiya2,
Satoko Honda3, Makiko Mori1, Yuki Arakawa1, Koichi Ichimura2,
Yutaka Tanami4, Atsuko Nakazawa3, Jun Kurihara5, and Katsuyoshi Ko1;
1Department of Hematology/Oncology, Saitama Children’s Medical Center,
Saitama, Saitama, Japan, 2Division of Brain Tumor Translational Research,
National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan,
3Department of Clinical Research, Saitama Children’s Medical Center,
Saitama, Saitama, Japan, 4Department of Radiology, Saitama Children’s
Medical Center, Saitama, Saitama, Japan, 5Department of Neurosurgery,
Saitama Children’s Medical Center, Saitama, Saitama, JapanINTRODUCTION: Among choroid plexus tumors (CPTs), metastasis occurs more frequently as pathological grading increases. There could be anunderestimation of pathological diagnosis if disseminated CPTs are diagnosed
with lower grade tumors such as choroid plexus papilloma (CPP) or atypicalchoroid plexus papilloma (aCPP). Thus, molecular diagnosis using genomewide DNA methylation profiling may be useful to clarify malignant potential
among thetumor entity. Here, we report about a case of aCPP with intracranial
dissemination that was molecularly diagnosed by methylation profiling. CASE
DESCRIPTION: A 2-year-old girl presented with a history of vomiting. Brainmagnetic resonance imaging showed a large tumor mass in the right lateral
ventricle and diffuse enhancement surrounding her brainstem, which suggested
dissemination. Gross total resection of the mass was performed. Intraoperative
findings revealed multiple spot metastatic lesions on the inner wall of lateral
ventricle. The pathological diagnosis was aCPP owing to the presence of a glandular structure with a papillary pattern suggesting a neoplasm of epithelial
origin, increased cellularity, several necrotic areas, and an intermediate numberof mitoses. The CPT-SIOP-2000 treatment protocol was followed without
radiation therapy, and the disseminated lesion was disappeared during thechemotherapy. Methylation data of the current case was entered into a recently

Abstracts

published classifier, and the tumor was classified as methylation class “plexus
tumor, subclass pediatric A” with high confidence (calibrated score 0.96), which
includes cases diagnosed as CPP and aCPPs. CONCLUSION: Our case indicates the clinical significance of molecular confirmation of diagnosis among
CPTs, particularly lower grade tumors with dissemination.
RARE-40. CASE REPORT: LONG-TERM SURVIVOR OF A RARE,PEDIATRIC PRIMARY HISTIOCYTIC SARCOMA (HS) OF
THE CENTRAL NERVOUS SYSTEM (CNS) FOLLOWINGCOMPLETE RESECTION, CHEMOTHERAPY AND ALLOGENEIC
HEMATOPOIETIC CELL TRANSPLANTATION (ALLO-HCT)
Diana S Osorio1, Rolla Abu-Arja1, Mohamed S. Abdel-Baki1,
Jeffrey R. Leonard2, Eric A. Sribnick2, Jonathan L. Finlay1,
David W. Ellison3, Jennifer Picarsic4, Samir Kahwash5, andDaniel R. Boue’5; 1The Division of Hematology, Oncology, Blood andMarrow Transplant, Nationwide Children’s Hospital and The Ohio State
University, Columbus, OH, USA, 2Department of Pediatric Neurosurgery,
Nationwide Children’s Hospital and The Ohio State University, Columbus,
OH, USA, 3Department of Pathology, St. Jude Children’s Research
Hospital, Memphis, TN, USA, 4Department of Pathology, Cincinnati
Children’s Hospital, Cincinnati, OH, USA, 5Department of Pathology andLaboratory Medicine, Nationwide Children’s Hospital and The Ohio State
University, Columbus, OH, USA
We report an unusual case of a patient with primary CNS-HS a very rare
neoplasm of histiocytic lineage with usually poor prognosis. An 8 year old boy
presented with a one month history of headaches, nausea and vomiting. Physical examination revealed nystagmus and dysmetria. Brain MRI revealed a
localized 2.4 cm posterior fossa (cerebellar) mass with restricted diffusion. The
patient underwent a gross total resection of the mass. Initial post-operative
lumbar puncture was positive for rare malignant cells. Pathology showed afocally necrotic neoplasm, composed of nests and cords of large relatively uniform cells with abundant eosinophilic cytoplasm, moderately pleomorphic
nuclei and numerous mitotic figures, consistent with CNS-HS with juvenile
xanthogranuloma phenotype, as supported by positive IHC expression of
CD163, CD68, CD14, fascin, and Factor XIIIa, while negative for CD1a,
Lymphoid and Myeloid markers, and BRAFv600e mutation. He was treatedwith two cycles of clofarabine and cytarabine and triple intrathecal (IT)chemotherapy. He developed generalized seizures and MRI showed demyelination consistent with IT methotrexate toxicity; MTX was then discontinued.
He was then given two additional cycles of cladribine and weekly intrathecal
therapy prior to consolidation with an Allo-HCT using a 10/10 HLA allelicmatched unrelated donor. His conditioning regimen included total body irradiation and cyclophosphamide. He did well post-transplant with peripheral
blood chimerism at 1 year showing > 95% donor cells. He remains diseasefree with an excellent quality of life since August 2016. We report one of the
few known survivors of this unusual and highly malignant entity.
RARE-41. SECOND MALIGNANCIES FOLLOWING TREATMENT
FOR PRIMARY CENTRAL NERVOUS SYSTEM TUMORSIN PEDIATRIC PATIENTS: A SINGLE-INSTITUTIONALRETROSPECTIVE REVIEW
Nicholas Pytel, Erik Dedekam, M. Shahriar Salamat, and Diane Puccetti;
University of Wisconsin, Madison, WI, USA
Second malignant neoplasms following treatment for primary central nervous system (CNS) tumors in children are rare occurrences but may often havedire consequences, particularly, if thought to be induced by prior therapies.
The authors retrospectively reviewed pediatric patients with primary CNS
malignancies from the University of Wisconsin over the last 25 years (1994 –2019) with any secondary malignant neoplasm and determined seven patientsmet criteria. Treatment modalities were reviewed with all patients receiving
surgery, chemotherapy, and radiotherapy for treatment of their first malignancy. The second neoplasms found included 4 high-grade gliomas, 1 meningioma, 1 thyroid carcinoma, and 1 myelodysplastic syndrome. The medianlatency time between diagnoses was 9 years (range 4 -17 years). The outcomesvaried according to histopathology of the second neoplasm with the high-grade
glioma patients all deceased from progressive disease. The high-grade gliomas
were thought to have been induced by prior radiation in most cases. The remaining patients are still alive, at the time of this writing, and in follow up after
treatment for their second neoplasm. Thus, long-term follow up is essential
for children treated for a primary CNS tumor given the variety of second neoplasms that could arise with differential consequences. In addition to our single
institutional outcomes, we will also present an updated review of the literatureof pediatric patients with primary CNS tumors and second malignancies.
RARE-42. PRIMARY INTRACRANIAL SARCOMA WITH DICER1MUTATION - TREATMENT RESULTS OF A NEW MOLECULAR
ENTITY
Rosdali Diaz1,2, Martin Mynarek3, Sandro Casavilca4,
Antonio Wachtel Aptomizer5, Pamela Mora6, Christian Koelsche7,8,Andreas Von Deimling9,8, Ulrich Schüller10,11, Raymundo Sernaque12,
Gustavo Sarria13,14, Tatiana Negreiros13, Luis Ojeda15,
Pamela Garcia-Corrochano15, Danny Campos16, Jimena Ponce17,
Stefan Rutkowski3, and Juan Garcia1,17; 1Instituto Nacional deEnfermedades Neoplasicas, Pediatric Oncology Department, LIMA, Peru,
2Global Alliance for Pediatric Neuro Oncology GAP-NO, International,
Peru, 3University Medical Center Hamburg-Eppendorf, Department ofPediatric Hematology and Oncology, Hamburg, Germany, Hamburg,
Germany, 4Instituto Naciconal de Enfermedades Neoplasicas, Pathology
Deaprtment, LIMA, Peru, 5Clinica Angloamericana, Lima, Peru,
6Instituto Nacional de Enfermedades Neoplasicas, Genetics Department,
Lima, Peru, 7Institute of Pathology, Heidelberg University Hospital,
Department of Neuropathology, Heidelberg, Germany, 8ClinicalCooperation Unit Neuropathology, German Cancer Research Center(DKFZ), Heidelberg, Germany, 9Institute of Pathology, Heidelberg
University Hospital, Department of Neuropathology, Heidelberg,
Germany, 10University Medical Center Hamburg-Eppendorf, Departmentof Pediatric Hematology and Oncology, Hamburg, Germany, 11Instituteof Neuropathology, University Medical Center Hamburg Eppendorf,
Hamburg, Germany, 12Instituto Nacional de Enfermedades Neoplasicas,
Radiology Department, Lima, Peru, 13Instituto Nacional de Enfermedades
Neoplasicas, Radiotherapy Department, Lima, Peru, 14Clinica Delgado,
Oncosalud, Lima, Peru, 15Instituto Nacional de Enfermedades Neoplasicas,
Neurosurgery Department, Lima, Peru, 16Clinica Angloamericana,
Neurosurgery Department, Lima, Peru, 17Clinica Angloamericana, PediatricOncology Department, Lima, PeruOBJECTIVE: An unexpectedly high incidence of sarcomas of the Central
Nervous System (SCNS) was recently observed in Peru. We describe clinicaland biological characteristics of the disease. METHODS: Seventy pediatricpatients with primary SCNS diagnosed between January 2005 and June2018 were analyzed. DNA methylation profiling and gene panel sequencing
was available from 28 and 27 tumors, respectively. RESULTS: Medianage was 6 years (range 2–17.5), 66/70 patients had supratentorial tumors,
56 patients intratumoral hemorrhage at diagnosis. Three patients fulfilled
clinical criteria of NF1; 35 had café-au-lait spots and/or freckling. DNAmethylation profiling classified 28/28 as “intracranial spindle cell sarcoma with rhabdomyosarcoma-like features and DICER1 mutations”.
DICER1 mutations were found in 26/27, TP53 mutations in 22/27, andRAS-pathway gene mutations (NF1, KRAS, NRAS) in 19/27 tumors, all ofwhich were somatic (germline control available in n=19 cases). Survival was
analyzed in 57 patients with non-metastatic disease who received adjuvant
therapy. Two patients had metastatic disease, eleven did not receive or abandoned treatment. Two-year OS was 66.3% (95%-CI: 54–81%), 2-year PFS
51% (38–67%). PFS was highest in patients treated with postoperative ICE
chemotherapy followed by radiotherapy and ICE (2y-EFS 79% [59–100%],n=18) and worse after upfront radiotherapy followed by ICE (40% [19–85%]; n=10) or VAC (50% [28–88%], n=12) and radiotherapy only (21%
[6–71%], n=11; p=0.008). CONCLUSION: Primary SCNS with DICER1
mutation have an aggressive clinical course. A combination of chemotherapy and radiotherapy seems beneficial. A link to a cancer predisposition
syndrome could not be established so far.
RARE-43. FAVORABLE OUTCOME OF A YOUNG GIRL WITH
RECURRENT METASTATIC PINEOBLASTOMA ASSOCIATED WITH
A DICER1 MUTATION
Adam Rossi1, Gregory Verona2, Ann Ritter3, Hope Richard4, India Sisler1,
and Zhihong Wang1; 1Pediatric Hematology Oncology, CHoR at VCU,
Richmond, VA, USA, 2Department of Pediatric Radiology, CHoR at VCU,
Richmond, VA, USA, 3Department of Neurosurgery, VCU, Richmond, VA,
USA, 4Department of Pathology, VCU, Richmond, VA, USA
Pineoblastomas have been thought to portend a poor prognosis, especially in younger children or those with metastases. Long term survivors
after relapse, especially for those with metastatic disease are rare. We report a young girl with a DICER1 mutation who survived recurrent metastatic pineoblastoma. She was initially diagnosed at the age of 3 with alocalized pineoblastoma, underwent gross total surgical resection, and received high dose chemotherapy with autologous stem cell transplant per
COG ACNS0334 without radiation therapy. 16 months after completionof treatment, she relapsed at primary site with widespread spinal metastasis. She then received cranial spinal radiation of 3600Gy with protonbeam, with boost to primary to 5580Gy, followed by chemotherapy withTemozolomide, Irinotecan and Avastin per COG ACNS0821. She is now
3 years and 3 months from completion of treatment, is doing well clinicallywith stable imaging findings. No particular alteration was identified fromthe tumor molecular testing of her initial pineoblastoma. Of note, she wasdiagnosed with pleuropulmonary blastoma soon after her initial diagnosisof pineoblastoma, and was found to have a DICER1 mutation (c.2062C>T;
pR688*) thought to be a nonsense mutation. While radiation therapy following recurrence is known to improve the outcome, more recent studies
suggest that tumors lacking the molecular features of high grade glioma also
has a positive impact on prognosis. In addition, we speculate that DICER1N E U R O -O N C O L O G Y•

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mutations might increase sensitivity of cancer cells to some chemotherapy
through modulating gene expression and /or interfering with DNA repair
mechanisms, therefore, affecting treatment outcome.
RARE-44. CLINICAL CHARACTERIZATION AND OUTCOME;
OUR EXPERIENCE OF CHORDOMAS IN PEDIATRIC AND YOUNG
ADULTS
Amber Gibson, Muhammad Baig, Shaan Raza, David Grosshans, and
Wafik Zaky; MD Anderson Cancer Center, Houston, TX, USA
Pediatric chordomas are exceedingly rare and there are limited data to
guide treatment decisions. We report a retrospective analysis of 19 patientswith chordomas who received treatment at our institution from 2001–2020.
Of the 19 patients, 15 had clival (79%), 3 cervical and 1 sacral chordoma.
There were 9 males (47%). Median age at diagnosis of 10.6 years. Eight patients had gross total (42%) and 11 (58%) had sub-total resection. As frontline therapy 15 patients (79%) underwent surgery followed by radiation(1 photon and 14 proton), 3 patients (16%) received surgery and chemotherapy (anaplastic histology) and 1 patient received only surgery. For patients treated with radiation therapy the average prescribed dose was 70 Gy(range: 52–74). Post-surgery and radiation, 14 of 15 patients remained inremission. Five (26%) patients had progressive disease (PD) with mediantime to progression of 13 months of whom 3 died of disease at median of
18 months. Treatment of PD consisted of chemotherapy and radiation for 3,
re-resection with radiation for 1 and chemotherapy alone for 1 patient. The
patients with metastatic and anaplastic disease mean survival is 21 monthversus 45 for the rest of the cohort. In summary, post-operative adjuvant
radiation provided an overall good outcome in majority of patients. Patientswith anaplastic pathology and metastasis at diagnosis had worse outcome.
Those who relapsed, subsequent treatment was palliative at best with shortsurvival. Molecular analysis is warranted in future for better disease stratification.
RARE-45. SARCOMAS INVOLVING THE CENTRAL NERVOUS
SYSTEM AT INITIAL PRESENTATION IN CHILDREN AND YOUNG
ADULTS: A CASE SERIES
Yen-Lin Liu1,2, Shu-Mei Chen2, Hsin-Lun Lee2,3, Jia-Hui Huang2, ShuHuey Chen1,4, Yu-Chien Kao1,4, Hsi Chang2, Min-Lan Tsai2,
Sung-Hui Tseng2, Kevin L.C. Hsieh2, Chia-Yau Chang2, Jinn-Li Wang1,5,James S. Miser1,6, and Tai-Tong Wong2; 1Taipei Medical University, Taipei,
Taiwan, 2Taipei Medical University Hospital, Taipei, Taiwan, 3Taipei
Cancer Center, Taipei, Taiwan, 4Shuang Ho Hospital, New Taipei, Taiwan,
5Taipei Municipal Wan Fang Hospital, Taipei, Taiwan, 6City of Hope,
Duarte, CA, USA
Sarcomas of bone, soft tissue, or neural origin may occasionally invade
the central nervous system (CNS), causing diagnostic and therapeutic challenges. We aim to investigate the clinical features of sarcomas involving the
CNS at initial presentation. During 2015/01–2019/12, nine consecutive patients (4 Males and 5 Females) younger than 30 years of age treated at a
University Healthcare System in Northern Taiwan were included. The median age was 8.7 years (range, 2–24 years); diagnoses were Ewing Sarcoma
with EWSR1 rearrangements (n=4), CIC-NUTM1 Sarcoma (n=1), Osteosarcoma (n=2), Malignant Peripheral Nerve Sheath Tumor (MPNST; n=1),
and extramedullary myeloid sarcoma (n=1). The tumors originated from theskull (n=1), dura (n=1), vertebra (n=4), spinal canal (n=1), or extra-CNS sites(n=2). Four patients had metastases (1 Ewing sarcoma, 2 osteosarcoma, and 1
extramedullary myeloid sarcoma). The main symptom at diagnosis was facial/
eye pain (n=2), back pain (n=3), arm weakness (n=1), or gait disturbance (n=3).
Upfront neurosurgical decompression (n=7) or urgent radiotherapy (n=1) was
performed in most patients. At a median follow-up duration of 20.1 months,
the overall survival rate was 70%. All patients with Ewing sarcoma (n=4)
and CIC-NUTM1 sarcoma (n=1) achieved Complete Response after surgery, interval-compressed chemotherapy, radiotherapy, and adjuvant chemotherapy. Patients with stage IV osteosarcoma (n=2) had Partial Response; thepatients with MPNST and extraskeletal myeloid sarcoma died of Progressive
Disease at 18 and 3 months after diagnosis, respectively. We conclude thattimely decompression, early diagnosis, and histology-driven multimodality
treatment are effective strategies in managing sarcomas involving the CNS.
RARE-46. A THIRTEEN YEAR PATIENT JOURNEY OF INFANTGIANT CLIVAL CHORDOMA: CASE REPORT AND LITERATURE
REVIEW
John Apps1,2, Eloise Neumann1, Fardad Afshari1, Guirish Solanki1,
and Martin English1; 1Birmingham Women’s and Children’s Hospital,
Birmingham, United Kingdom, 2Cancer Research UK Clinical Trials Unit,
University of Birmingham, Birmingham, United Kingdom
In 2006 we reported the youngest case of a large clival chordoma, a15-week old baby, the second case to present without skull base involve-iii452

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This unusually rare case (surgically un-resect able) underwent endoscopic
skull-base diagnostic biopsy and a novel chemotherapy regime that aimed
to control his disease[i]. Initial tumour control was achieved with chemotherapy (Ifosfamide, doxorubicin with dexrazonane, intrathecal hydrocortisone, methotrexate, cytarabine). Carboplatin and etoposide were later
given for a further year. Following this, Sirolimus and imatinib were used
for another twelve months due to primary tumour regrowth and three newskull-vault lesions. Sirolimus alone was continued for an additional year, but
stopped due to optic neuritis. Imatinib was given until further progression
two years later, leading to a change to everolimus. Surgery for the ventral
foramen magnum was performed a year later. The patient received further
surgery and radiotherapy for tumour recurrence. Sadly the tumour metastasised and he succumbed at age 13. Chordomas are aggressive and recur frequently. Complete primary resection followed by radiotherapy/proton beam
therapy offers the best chance of cure but is not an option in infants withgiant lesions, as in our case. We inform on alternative targeted treatment
strategies and review the literature on these rare lesions. [i] Kambogiorgas D,
St George EJ, Chapman S, English M, Solanki G: Infantile Clivus chordoma
without clivus involvement: Case report and review of the literature, Childs
Nerv System (2006) 22:1369–1374
RARE-47. DIFFUSE LEPTOMENINGEAL DISSEMINATED
GLIONEURONAL TUMOR: CASE-SERIES
Felipe Hada Sanders, Hamilton Matushita, Alessandra Azambuja,
Fernando Frasseto, Sergio Rosemberg, Vicente Odone, andManoel Jacobsen Teixeira; USP, Sao Paulo, SP, Brazil
Diffuse leptomeningeal disseminated glioneuronal tumor (DL-GNT) is arare brain tumor that presents as a plaque-like subarachnoid tumor, commonly involving the basal cisterns and interhemispheric fissure of children
but lacking intraparenchymal tumor. Here we report two cases focusing on
clinicopathologic features. In all patients, radiography revealed characteristic leptomeningeal thickening and enhancement with minor superficial parenchymal lesions. The broadcast of the knowledge about this type of disease
is important to increase awareness on this subject.
RARE-48. CHARACTERISTICS AND OUTCOME OF DIFFUSELEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT): A SINGLEINSTITUTION EXPERIENCE
Emily Owens Pickle, Ana Aguilar-Bonilla, and Amy Smith; Arnold Palmer
Hospital for Children, Orlando, FL, USA
Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare with an
unknown etiology and unestablished incidence. Most frequently reported
genetic alteration is KIAA1549-BRAF fusion. We present four DLGNT
cases diagnosed between 2005–2018. Patient 1 is a female who presented
with a 2-year history of back pain subsequently diagnosed with pilocytic
astrocytoma. Re-imaging 3 months post-resection revealed a low grade
glioneuronal tumor with BRAF duplication. Patient 2 is a female who presented with recurrent vomiting, dizziness, and hydrocephalus. The patientunderwent biopsy which was consistent with oligodendrogliomatosis; nogenetic analysis was done. Patient 3 is a male who presented with worsening
headaches and intermittent vomiting. Approximately 5 months after resection, imaging showed leptomeningeal disease and further testing revealed
KIAA1549-BRAF fusion and 1p deletion. Patient 4 is a male who presented with hydrocephalus. Imaging showed disseminated leptomeningeal
enhancement without a dominant mass lesion; biopsy and clinical history
confirmed the diagnosis. All four patients received chemotherapy, Patients 1
and 3 underwent radiation therapy, and Patient 3 received a MEK-inhibitor
to which he had a great response. However, the patient was non-compliant
and had PD which continued despite re-starting therapy. Patients 1, 2, and 3
have died of progressive disease; survival was Patient 1, 276 days, Patient 2,
approximately 7 years and 8 months, and Patient 3, 2 years and 11 months.
Patient 4 remains alive with disease 4.5 years from diagnosis. There is muchto be learned about this rare, poorly understood disease but hope for improvement through therapeutic targeting of the MAPK pathway.
RARE-49. CHOROID PLEXUS ADENOMA WITHOUT ASSOCIATED
HYDROCEPHALUS PRESENTING AS PRECOCIOUS PUBERTY
Kaylyn Utley, Michael Dedekian, James Wilson, and Stanley Chaleff;
Maine Medical Center, Portland, ME, USA
Precocious puberty (PP) is a rare presentation of intracranial pathology
unrelated to the pituitary. PP in this setting is considered a paraneoplastic
phenomenon, achieved through synthesis of sex-hormones by the tumor itself or via alterations in the release of gonadotrophins from the pituitary.
The latter has been described with masses adjacent to the pituitary or withthose which cause hydrocephalus. We describe a case of a choroid plexus
papilloma (CPP) without hydrocephalus presenting as precocious puberty.

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An 18 month-old female presented with 4-months of weight loss, bilateralgalactorrhea and constipation. Her weight decreased from the 15th to below
the 1st percentile. CBC, celiac and thyroid studies were normal. Prolactin
was at the upper limit of normal (25.8;ref 3.3–26.3). Breast ultrasound demonstrated symmetric breast tissue development. She was referred to pediatricgastroenterology for constipation and failure to thrive. Caloric supplementation, bowel regimen and barium enema were recommended. One week later,
she was admitted with dehydration, painful constipation and further weightloss in the setting of an acute febrile illness. MRI revealed a normal pituitary and an intraventricular mass without hydrocephalus. She underwent
gross total resection of the mass, later determined to be a choroid plexus
papilloma. The patient’s galactorrhea resolved abruptly following resection.
Because of her galactorrhea, our patient underwent neuroimaging revealing
an incidental mass without associated hydrocephalus. To our knowledge,
precocious puberty and hyperprolactinemia have not been described in neoplasms distant from the pituitary. Thus, these lesions should be recognized asa potential etiology of precocious puberty and hyperprolactinemia.
RARE-50. TREATMENT RESPONSE OF CNS HIGH-GRADENEUROEPITHELIAL TUMORS WITH MN1 ALTERATION
Lorena V. Baroni1, Carlos Rugilo2, Fabiana Lubieniecki3,
Claudia Sampor1, Candela Freytes1, Liana Nobre4, Jordan R. Hansford5,6,
Vajiranee S. Malalasekera5, Michal Zapotocky7, Andrew Dodgshun8,
Vijay Ramaswamy4,9, and Daniel Alderete1; 1Service of Hematology/
Oncology, Hospital JP Garrahan, Buenos Aires, Argentina, 2Service ofDiagnostic Imaging, Hospital JP Garrahan, Buenos Aires, Argentina,
3Service of Pathology, Hospital JP Garrahan, Buenos Aires, Argentina,
4Division of Haematology/Oncology, Hospital for Sick Children, Toronto,
ON, Canada, 5Children`s Cancer Centre, Royal Children`s Hospital,
Melbourne, Australia, 6Division of Cancer, Murdoch Children’s ResearchInstitute, Melbourne, Australia, 7Department of Paediatric Haematology
and Oncology, Second Medical School, Charles University and University
Hospital Motol, Prague, Czech Republic, 8Children’s Haematology/
Oncoloy Centre, Christchurch Hospital, Christchurch, New Zealand,
9Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick
Children, Toronto, ON, Canada
BACKGROUND: CNS high-grade neuroepithelial tumor with MN1alteration (CNS HGNET-MN1) are a rare entity recently described as ahigh-grade tumor containing a mixture of solid and pseudopapillary patterns with MN1 rearrangement. METHODS: CNS HGNET-MN1 patientswere identified using genome wide methylation arrays across 5 institutions(the Hospital JP Garrahan, Hospital for Sick Children, the University Hospital Motol, Royal Children`s Hospital and Christchurch Hospital) and wascorrelated with treatment and outcome. Central imaging review with radiological features analysis was performed. RESULTS: We identified 9 patients
harboring CNS HGNET-MN1 tumors through application of the Heidelberg brain tumor classifier. Seven tumors were T supratentorial and two in
the spinal cord. Median age was 5 (range 3.6–14.6). All patients had surgery(6 GTR and 3 STR) as initial management followed by radiotherapy (focal
5/CSI 1) and systemic chemotherapy in 2 patients. Four of the 9 patients
relapsed by 3 years post diagnosis, with 2 local and 2 metastatic failures
despite complete surgical resections and radiotherapy. Three patients died
due to tumor relapse after 24 months despite upfront radiotherapy. Seven of
9 patients had an initial diagnosis of ependymoma. CONCLUSION: Treatment of CNS HGNET-MN1 remains a major challenge with multiple
failures, despite aggressive surgical resections and upfront involved fieldradiotherapy. Further multicenter, international prospective studies are required to determine the optimal treatment strategy for this group of tumors.
RARE-51. MOLECULAR INSIGHTS INTO MALIGNANT
PROGRESSION OF CHOROID PLEXUS PAPILLOMA (CPP)
Maxim Yankelevich1, Jonathan L. Finlay2, Hamza Gorsi3,
William Kupsky4, Daniel R. Boue5, Carl J. Koschmann6,7,
Chandan Kumar8,7, and Rajen Mody6,7; 1Rutgers Cancer Institute of New
Jersey, New Brunswick, NJ, USA, 2Division of Hematology, Oncology,
and BMT, Nationwide Children’s Hospital and The Ohio State University,
College of Medicine, Columbus, OH, USA, 3Division of PediatricHematology/Oncology, Children’s Hospital of Michigan and Wayne
State University School of Medicine, Detroit, MI, USA, 4Department of
Pathology, Wayne State University School of Medicine, Detroit, MI, USA,
5Department of Pathology, Nationwide Children’s Hospital and The Ohio
State University, College of Medicine, Columbus, OH, USA, 6Departmentof Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI,
USA, 7Rogel Cancer Center, Michigan Medicine, University of Michigan,
Ann Arbor, MI, USA, 8Michigan Center for Translational Pathology,
Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
Malignant transformation of CPP is rare and the mechanisms remain elusive. We report a case of progression of papilloma into carcinoma where
we performed molecular sequencing of both samples. A boy was found tohave a brain mass soon after birth. The gross total resection (GTR) was
diagnostic of CPP. Six years later he developed a recurrent mass that demonstrated progression to a choroid plexus carcinoma (CPC). The patient received chemotherapy according to a “HeadStartII” protocol. He is 2.5 years
off therapy and disease-free. A sequencing study consisting of 1700 genes
and tumor transcriptome was done. The analysis of both samples revealed
a germline variant of TP53(R248W) with LOH and an allele frequency of
39% in the germline sample, suggesting a mosaicism. Analysis of both samples identified extensive aneuploidy and similar pattern of gains in chromosomes 7/8/12/20/21/X. Copy number aberrations newly acquired in the
carcinoma included copy gain of chromosomes 5q/12/15q/20, and copy lossof chromosomes 5q/13/22. The papilloma was found to harbor 3 somatic
mutations with 4% to 21% allelic fractions, all lost in the carcinoma. Thesemutations were of unknown significance and with too low allelic fractions to
be responsible for the transformation. More pertinently, chromosomal aneuploidy was significant with additional losses in the carcinoma. This resulted
in the losses of two critical tumor suppressor genes, RB and BRCA2, playing
a possible role in the observed transformation. The “HeadStart” experiencesuggested that the prognosis of TP53 mutant CPC may be improved in theabsence of radiation therapy.
RARE-52. RB1 GENE DELETIONS ARE THE NOVEL MECHANISM
OF CHOROID PLEXUS TUMORS (CPT) ONCOGENESIS
Alexander Druy1,2, Liudmila Yasko1, Andge Valiakhmetova1,
Galina Novichkova1, and Liudmila Papusha1; 1D. Rogachev National
Medical Research Center, Moscow, Russian Federation, 2Research Instituteof Medical Cell Technologies, Yekaterinburg, Russian Federation
BACKGROUND: CPTs are known to be rare TP53-dependent neoplasms, while major molecular alterations underlying tumor progression,
especially in TP53-wild type cases, are still unclear. METHODS: 18 primary CPT, including 16 choroid plexus carcinomas (CPC) and two atypicalchoroid plexus papillomas (CPP), were evaluated for copy number status of
87 major oncogenes and tumor suppressor genes by nCounter Cancer CNV
assay by Nanostring and TP53 and RB1 by MLPA. Germline TP53 nucleotide substitutions were analyzed by Sanger sequencing. RESULTS: Pathogenic germline TP53 variants were present in 4 cases confirming Li-Fraumeni
syndrome (LFS). Two patients have somatic TP53 substitutions. Only one
patient with LFS harbored somatic TP53 deletion. In 7 patients, heterozygous deletions of RB1 involving from 3 exons to the whole coding sequence
detected by MLPA were discovered. All these findings were validated bynCounter CNV assay. Additionally, four patients have WT1 deletions, twopatients – BRCA2, and in 1 case - NF1, concomitant with RB1 deletionsin 3 cases. Interestingly, in one patient who faced a progression of CPP to
CPC germline, RB1 deletion was detected, and in both subsequent tumors,
the length of the deleted region progressively increased. Notably, that RB1
deletions are mostly mutually exclusive to TP53 substitutions. 3 of 4 patients with RB1 deletions having follow-up period >1 year faced with tumorrelated adverse events. CONCLUSIONS: Somatic or uncommon germline
RB1 heterozygous deletions have been unraveled as a novel mechanism of
aggressive CPT and could be implemented in prognosis definition schemes.
RARE-53. PINEAL PARENCHYMAL TUMOR OF INTERMEDIATE
DIFFERENTIATION (PPTID) AND DICER1 SYNDROME: A CASEREPORT
Stephanie Toll1,2, Avanti Gupte1, Sandeep Sood3, William Kupsky3,
Deniz Altinok1,3, Steven Miller3, and Kanta Bhambhani4,3; 1Children’s
Hospital of Michigan, Detroit, MI, USA, 2Central Michigan University,
Mount Peasant, MI, USA, 3Wayne State University, Detroit, MI, USA,
4Children’s Hospital of Michigan, Detroit, USA
BACKGROUND: DICER1 syndrome is a rare inherited tumor predisposition syndrome linked to an increased risk of several malignancies. Affectedindividuals most commonly develop pleuropulmonary blastoma (PPB) andovarian sex cord-stromal tumors. Brain tumors in these patients are rare,
however; the increased frequency of pineoblastoma in this population has
been established. Traditionally, pineal parenchymal tumors of intermediate
differentiation (PPTIDs) have not been associated with DICER1 syndrome,with research suggesting alternative mutations driving tumorigenesis. Thesetumors are pathologically and clinically diverse, with long-term surveillance
based on therapeutic interventions. Here we describe a case of a germline
DICER1 mutation in a patient with a PPTID, suggesting that this mutation
is not limited to pineoblastoma as previously reported. CASE: We describe
a 19 year-old female with a WHO grade III PPTID treated with multimodal
therapy including surgery, craniospinal irradiation (CSI) and chemotherapy.
She was noted to have a thyroid mass at diagnosis and was subsequently
diagnosed with a benign thyroid nodule, followed most recently by a cataract with pathology concerning for medulloepithelioma of the ciliary body.
Due to the known association between medulloepithelioma and DICER1
syndrome, targeted germline sequencing was obtained and confirmed apathogenic heterozygous mutation. CONCLUSION: To our knowledge thisN E U R O -O N C O L O G Y•

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is the first report of a PPTID in a patient with DICER1 syndrome. This association highlights the clinical implications of molecular evaluation in pediatric brain tumors, for both immediate therapeutic decisions and long-term
surveillance.
RARE-54. MOLECULAR ANALYSIS OF ROSETTE-FORMINGGLIONEURONAL TUMOR AT MIDBRAIN; REPORT OF TWO CASES
Hajime Handa; Kitasato University, Sagamihara, Kanagawa, Japan
Rosette-forming glioneuronal tumor (RGNT) is a tumor that primarily
arises at posterior fossa. We experienced two rare cases of RGNT located at
midbrain and investigated their molecular features. Case 1 is a 23-year-old
female, and Case 2 is an 18-year-old male. Both cases were surgically removedby the occipital transtentorial approach. Histological analysis demonstrated abiphasic pattern of neurocytic and glial components. The former consisted ofneurocytic rosettes and perivascular pseudorosettes, and the latter was GFAP
positive, corresponding to the diagnosis of RGNT. Both cases have an excellent clinical course without receiving chemotherapy or radiation therapy.
Small residual tumors of both cases shrunk and maintained for 27 and12 months, respectively. Case 1 underwent DNA methylation array and a subsequent DNA methylation-based classifier, indicating that the case matched
RGNT with a 0.99 calibrated score. Also, we identified FGFR1 K656 mutation. Pyrosequence analysis of other genes such as IDH1 R132, IDH2 R172,
BRAF T599, BRAF V600, H3F3A K27, H3F3A G34, HIST1H3B K27, TERT
C228, FGFR1 N546 had no mutations. RT-PCR of KIAA1549-BRAF fusion
was not detected. DNA methylation status of Case 2 is under investigation.
Pyorosequence analysis identified TERT C228 mutation but did not identify
other mutations such as FGFR1 N546 and K656. Midbrain RGNT corresponds to the histological and molecular features of RGNT. RGNT needs to bedifferentially diagnosed in the case of a midbrain tumor.
RARE-55. CHALLENGES AND SPECIFIC STRATEGIES FORCONSTITUTIONAL MISMATCH REPAIR DEFICIENCYSYNDROME IN LOW RESOURCE SETTINGS. ON BEHALF OF
THE INTERNATIONAL RRD CONSORTIUM IN LOW RESOURCESETTINGS PANEL
Rejin Kebudi1, Nisreen Amayiri N2, Malak Abedalthagafi3,
Asim Noor Rana4, Slman Kirmani5, Naureen Musthaq6, Zakiya Al Lamki7,
Jamilla El Houdzi8, Hulya Yazıcı9, S El-Naggar10, Melissa Edwards11,
Vanessa Bianchi11, Carol Durno12, Uri Tabori11, and Eric Bouffet11;
1Istanbul University Oncology Institute, Istanbul, Turkey, 2King Hussein
Cancer Center, Department of Pediatrics, Hematology/Oncology, Amman,
Jordan, 3King Fahad Medical City, King Abdulaziz City for Science andTechnology, Riyad, Saudi Arabia, 4Department of Pediatrics, Divisionof Hematology-Oncology, Dubai, UAE, 5Aga Khan University, Karachi,
Pakistan, 6Department of Pharmaceutical Sciences, MM College of
Pharmacy, MM University, Mullana, Hryana, India, 7Sultan Qaboos
University, Muscat, Oman, 8Mohammed VI University Hospital, Marakesh,
Morocco, 9Istanbul University, Oncology Institute, Cancer Genetics,
Istanbul, Turkey, 10Children’s Cancer Hospital in Egypt 57357, Cairo,
Egypt, 11Department of Pediatrics, Division of Hematology-Oncology,
The Hospital for Sick Children, Toronto, ON, Canada, 12Department ofPediatrics, Division of Gastroenterology, Hepatology and Nutrition, The
Hospital for Sick Children, Toronto, ON, Canada
Germline biallelic mutations in one of the mismatch repair genes (MSH2/
MSH6/MLH1/PMS2 results in constitutional mismatch repair deficiency(CMMRD), a condition associated with multiple tumors arising from multiple organs during childhood, and these individuals rarely reach adulthood.
The paucity of information with respect to these conditions leads to mismanagement and may be a factor in the high mortality of patients with CMMRD.
Two international consortia, the European CARE4CMMRD, and the international replication repair deficiency (RRD) consortium, are addressing themany challenges associated with this condition. To address specific issues
surrounding the management of CMMRD in low and middle income countries (LMIC), a multidisciplinary taskforce of 11 specialists from nine countries was formed. Preliminary conclusions are: 1) Immunohistochemistry for
CMMRD should be considered for all patients with suggestive clinical features. In countries where CMMRD is common, malignant gliomas, coloncancers and T cell lymphomas should be stained routinely as the prevalence of
CMMRD in these tumors can exceed 40%. 2) Temozolomide should not be
used in the management of malignant glioma. By contrast, preclinical studies
have suggested increased sensitivity to nitrosoureas. For the management of
CMMRD related lymphoma and leukemia, mercaptopurines should not be
avoided or discontinued as a part of the standard of care before more data
are collected. 3) Management with checkpoint inhibitors should be limited tocenters with intensive care units and expertise in complex supportive care to
manage side effects of immune therapy. 4) Surveillance protocols have demonstrated long term survival benefits and should be implemented in LMIC.

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RARE-56. PERITONEAL SEEDING OF A DIFFUSELEPTOMENINGEAL GLIONEURONAL TUMOR IN A CHILD
Julie Messiaen1,2, Anne Uyttebroeck1,3, Bart Depreitere4,5,Isabelle Vanden Bempt6,7, Raf Sciot2,8, and Sandra A. Jacobs1,3;
1Department of Pediatric Hematology and Oncology, University Hospitals
Leuven, Leuven, Belgium, 2Translational Cell and Tissue Research,
Department of Imaging and Pathology, KU Leuven, Leuven, Belgium,
3Department of Oncology, KU Leuven, Leuven, Belgium, 4Department of
Neurosurgery, University Hospitals Leuven, Leuven, Belgium, 5Departmentof Neurosciences, KU Leuven, Leuven, Belgium, 6Department of Human
Genetics, University Hospitals Leuven, Leuven, Belgium, 7Department of
Human Genetics, KU Leuven, Leuven, Belgium, 8Department of Pathology,
University Hospitals Leuven, Leuven, Belgium
Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare neoplasms of the central nervous system and have been included in the 2016
update of the WHO classification. This is the first description of a DLGNT
disseminating to the peritoneal cavity via a ventriculoperitoneal shunt(VPS) in a child. We describe an 11-year old girl who received a VPS fora Dandy-Walker malformation at the age of seven, and was diagnosed
with a spinal pilocytic astrocytoma with leptomeningeal metastases six
months later. She received chemotherapy (SIOP-LGG protocol) with partial response, and had progressive disease eight months after therapy cessation. Following a novel biopsy, the diagnosis was revised to a DLGNT,with a KIAA1549-BRAF fusion and loss of 1p. She received vinblastine,
but was clinically progressive and craniospinal radiotherapy was initiated.
13 months later, she suddenly presented with ascites. The inferior vena cava
was compressed due to the ascites, and an abdominal drain was placed,with massive fluid release. Abdominal MRI indicated an omental cake andperitoneal contrast enhancement. Bone metastases were suspected in theiliac and femoral bones. Anatomopathological examination of the ascites
showed an atypical cell population, with irregular, hyperchromatic andenlarged nuclei resembling the primary tumor. The cells were positive forsynaptophysin, MAP2 and weakly positive for S100. Pan-NTRK staining
was negative. The diagnosis of a metastatic localization of the DLGNT
was made, due to seeding of tumoral cells via the VPS. Treatment with a
MEK-inhibitor was initiated, but was stopped due to progressive disease
and she died 3 weeks later.
RARE-57. PEDIATRIC CHORDOMA: WHOLE EXOME SEQUENCING
OF 11 PEDIATRIC CHORDOMA SAMPLES
Katrina O’Halloran1, Moiz Bootwalla2, Daria Merkurjev2,
Kristiyana Kaneva3, Alex Ryutov2, Jennifer Cotter2, Jianling Ji2,
Dejerianne Ostrow2, Jaclyn A. Biegel4, and Xiaowu Gai2; 1Division of
Hematology, Oncology and Blood & Marrow Transplantation, Children’s
Hospital Los Angeles, Los Angeles, CA, USA, 2Department of Pathology,
Children’s Hospital Los Angeles, Los Angeles, CA, USA, 3Division of
Hematology-Oncology, Neuro-Oncology & Stem Cell Transplantation,
Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA,
4Department of Pathology, Children’s Hospital Los Angeles, Los Angeles,
California, USA
Chordoma is a rare tumor and while SMARCB1 alterations have been
observed in poorly differentiated chordomas, conventional chordomas
are not well understood. We interrogated nuclear and mitochondrial genomes of 11 chordoma samples from 7 children. Frozen tumor
tissue DNA was extracted and whole exome libraries generated using
Agilent SureSelect Human All Exon V6 kit plus mtDNA genome capture kit. Libraries were sequenced using Illumina Nextseq 500. MuTect2,
VarDict and LUBA variant callers were used with allele frequency
cutoff 2%. Potential germline variants were filtered bioinformatically.
In total, 656±74 high-confidence somatic variants, including 368±43
nonsynonymous variants per sample were detected. Of 2,607 combined
unique nonsynonymous variants, 95% were missense. Remaining highimpact variants were frameshift (37%), stop gain (39%), splice acceptor/
donor (22%), start and stop loss (2%). Of the unique nonsynonymous
variants, 137 fall within Cosmic Cancer Census Genes, including highimpact variants in SETD2, MLLT4. No previously reported TBXT,CDKN2A, PI3K, LYST mutations identified. Tumor Mutation Burden/
Megabase was 10±1. The mitochondrial analysis revealed heteroplasmic
m.11727C>T MT-ND4 missense variants in three tumors resected at
different time points from the same patient, and another heteroplasmic
m.1023C>T rRNA mutation from the primary and recurrent tumors ofanother patient. Intriguingly, two Children’s Brain Tumor Tissue Consortium patients with chordoma had identical heteroplasmic m.10971G>AMT-ND4 nonsense mutations. Pediatric chordomas appear to lacksomatic nuclear mutations. Observing recurrent mitochondrial mutations across multiple tumors from the same and/or different patients is
striking, suggesting they may be implicated in tumorigenesis and be potential diagnostic markers.

Abstracts

RARE-58. CONGENITAL METASTATIC CHORDOMA OF THE
CLIVUS
Wieslawa Grajowska, Maria Stepaniuk, Joanna Trubicka,
Katarzyna Wójcicka-Kowalczyk, Piotr Krych,
Bozenna Dembowska-Baginska, and Marta Perek-Polnik; Children’sMemorial Health Institute, Warsaw, Poland
Chordomas are rare midline axial skeletal neoplasms that typically present
in adults. They are infrequent in childhood with typical localization in thespheno-occipital skull base. They are derived from remnants of the embryonic notochord. We present the case of 4 months old girl, who was born with„blueberry muffin” syndrome and was first negatively diagnosed for neuroblastoma and leukemia (two negative skin biopsies were performed) was
admitted with axial laxity. In imaging testes there was a tumor of the scullbase, metastases in the lungs and kidneys (that were not seen at previous assessments) and a small lesion in the heart. The third biopsy of skin lesion was
performed and pathological examination revealed a neoplasm composedof cords, clusters, and chains of multivacuolated cells embedded within a
myxoid matrix and separated by fibrous septa. No atypical and dedifferentiated features were present. Mitotic activity was not observed. Neoplastic
cells showed the typical cytoplasmic immunostaining for EMA, S100 andcytokeratin AE1/AE3, strong nuclear brachyury expression, and retentionof nuclear INI-1 expression. The diagnosis of chordoma was established.
Neoplastic tissue and blood samples were obtained for molecular analysis
using next generation sequencing, including germline mutations assessment(are ongoing). Chemotherapy as for soft tissue sarcomas was undertaken.
Currently a patient is on treatment with improvement of neurological status.
RARE-59. CARDIAC REMODELING IN PATIENTS WITH
CHILDHOOD-ONSET CRANIOPHARYNGIOMA – RESULTS OF HITENDO AND KRANIOPHARYNGEOM 2000/2007
Panjarat Sowithayasakul1,2, Leona Katharin Buschmann2,
Svenja Boekhoff2, and Hermann L. Müller2; 1Department of Pediatrics,
Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand,
2Department of Pediatrics and Pediatric Hematology/Oncology, University
Children’s Hospital, Carl von Ossietzky University, Klinikum Oldenburg
AöR, Oldenburg, Lower Saxony, Germany
BACKGROUND: Hypothalamic obesity caused by childhood–onset
craniopharyngioma results in long–term cardiovascular morbidity. Knowledge about clinical markers and risk factors is rare. PATIENTS AND
METHODS: A cross–sectional study on transthoracic echocardiographic
parameters was performed to determine the associations with clinicaland anthropometric parameters in 36 patients with childhood-onset
adamantinomatous craniopharyngioma. RESULTS: Body mass index(BMI) correlated with the thickness of interventricular septum in diastole(IVSd) (r=0.604, p<0.001) and left ventricular diastolic posterior wall indiastole (LVPWd) (r=0.460, p=0.011). Due to wide range of disease duration, 17 pediatric and 19 adult patients were analyzed separately. In theadult subgroup (age at study ≥18 years), BMI correlated with IVSd (r=0.707,
p=0.003), LVPWd (r=0.592, p=0.020) and left ventricular internal diameterin diastole (LVIDd) (r=0.571, p=0.026). In the pediatric subgroup (age atstudy <18 years), no correlation between cardiac parameters and BMI wasobserved. Only LVIDd correlated with disease duration (r=0.645, p<0.001).
All cardiac functions were within the normal range, indicating no association
with severe functional impairments. CONCLUSIONS: Cardiac remodelingin patients with childhood-onset craniopharyngioma correlates with the degree of hypothalamic obesity and disease duration. However, echocardiography has limited sensitivity in craniopharyngioma patients with obesity,
so cardiac magnetic resonance imaging (MRI) should be considered as analternative diagnostic approach for patients with craniopharyngioma andhypothalamic obesity.
RARE-60. PREGNANCIES AFTER CHILDHOODCRANIOPHARYNGIOMA – RESULTS OF KRANIOPHARYNGEOM
2000/2007
Panjarat Sowithayasakul1,2, Svenja Boekhoff1, Brigitte Bison3, andHermann L. Müller1; 1Department of Pediatrics and PediatricHematology/Oncology, University Children’s Hospital, Klinikum
Oldenburg AöR, Oldenburg, Lower Saxony, Germany, 2Department ofPediatrics, Faculty of Medicine, Srinakharinwirot University, Bangkok,
Thailand, 3Department of Neuroradiology, University Hospital, Würzburg,
Bavaria, Germany
BACKGROUND: Data on female fertility, pregnancy, and outcome ofoffspring after childhood-onset craniopharyngioma (CP) are rare. STUDYDESIGN: Observational study on pregnancy rate and offspring outcome in female CP patients recruited in KRANIOPHARYNGEOM
2000/2007. RESULTS: A total of 451 CP patients (223 female) have been
recruited, and 269 (133 female) were postpubertal at study. Six of 133
female CP patients (4.5%) with median age of 14.9 years at CP diagnosis

had 9 pregnancies, giving birth to 10 newborns. Three patients achieved
complete surgical resections. No patient underwent postoperative irradiation. Five natural pregnancies occurred in 3 CP patients without pituitary
deficiencies. Four pregnancies in 3 CP patients with hypopituitarism wereachieved under assisted reproductive techniques (ART) (median 4.5 cycles,
range: 3–6 cycles). Median maternal age at pregnancy was 30 years (range:
22–41 years). Six babies (60%) were delivered by caesarean section. Median gestational age at delivery was 38 weeks (range: 34–43 weeks); median birth weight was 2,920 g (range: 2,270– 3,520 g), the rate of preterm
delivery was 33%. Enlargements of CP cysts occurred in 2 women during
pregnancy. Other complications during pregnancy, delivery, and postnatal
period were not observed. CONCLUSIONS: Pregnancies after CP are rare
and were only achieved after ART in patients with hypopituitarism. Close
monitoring by an experienced reproductive physician is necessary. Due toa potentially increased risk for cystic enlargement, clinical, ophthalmological, and MRI monitoring are recommended in patients at risk. Perinatal complications, birth defects, and morbidity of mothers and offspringwere not observed.
RARE-61. BODY COMPOSITION AND NUCHAL SKINFOLDTHICKNESS IN PEDIATRIC BRAIN TUMOR PATIENTS
Junxiang Peng1,2, Svenja Boekhoff1, Maria Eveslage3, Brigitte Bison4,
Panjarat Sowithayasakul1,5, and Hermann L. Müller1; 1University
Children’s Hospital, Department of Pediatrics and Pediatric Hematology/
Oncology, Klinikum Oldenburg AöR, Oldenburg, Lower Saxony, Germany,
2Department of Neurosurgery, Nanfang Hospital, Southern Medical
University, Guangzhou, China, 3Institute of Biostatistics and ClinicalResearch, University of Münster, Münster, Germany, 4Department of
Neuroradiology, University Hospital, Würzburg, Bavaria, Germany,
5Department of Pediatrics, Faculty of Medicine, Srinakharinwirot
University, Bangkok, Thailand
BACKGROUND: Obesity, cardiovascular disease (CVD), and relapse/
progression have major impact on prognosis in pediatric brain tumor(BT) patients. Cranial MRI is part of routine follow-up. METHODS: In across-sectional study, we analyzed nuchal skinfold thickness (NST) on MRI
performed for BT follow-up monitoring as a novel parameter for body composition (BC) and CVD in 177 BT patients (40 WHO grade 1–2 BT; 31 grade
3–4 BT; 106 craniopharyngioma (CP)), and 53 healthy controls (HC). Associations of NST with body mass index (BMI), waist-to-height ratio (WHtR),
caliper-measured skinfold thickness (cSFT), and blood pressure (BP) wereanalysed in BT and HC. RESULTS: CP patients showed higher BMI, WHtR,
NST and cSFT when compared with BT and HC, whereas these differenceswere not detectable between BT and HC. However, WHO grade 1–2 BT
patients were observed with higher BMI, waist circumference and triceps
cSFT when compared to WHO grade 3–4 BT patients. NST showed highcorrelations with BMI, WHtR, and cSFT. NST, BMI and WHtR had predictive value for CVD in terms of increased BP, and in multivariate analysis, only BMI was selected for the final model resulting in an odds ratio of
1.25 (1.14–1.379). In CP patients with hypothalamic involvement/lesion or
gross-total resection, rate and degree of obesity were increased. CONCLUSIONS: As monitoring of MRI and BC play an important role in follow-up
after BT, NST could serve as a novel useful parameter for assessment of BC
and CVD risk in BT patients.
RARE-62. VISUAL FUNCTION IN CHILDREN WITH
CRANIOPHARYNGIOMA AT DIAGNOSIS: A SYSTEMATIC REVIEW
Myrthe Nuijts1, Nienke Veldhuis2, Inge Stegeman1, Hanneke van Santen1,
Giorgio Porro1, Saskia Imhof1, and Antoinette Schouten - van Meeteren3;
1University Medical Center Utrecht, Utrecht, Netherlands, 2Utrecht
University, Utrecht, Netherlands, 3Princess Máxima Center for PediatricOncology, Utrecht, Netherlands
Childhood craniopharyngioma is a rare and slow growing brain tumour,often located in the sellar and suprasellar region. It commonly manifests
with visual impairment, increased intracranial pressure and hypothalamic
and/or pituitary deficiencies. Visual impairment in childhood adversely affects a child’s daily functioning and quality of life. We systematically reviewed the literature to provide an extensive overview of the visual function
in children with craniopharyngioma at diagnosis in order to estimate the diversity, magnitude and relevance of the problem of visual impairment. Of the543 potentially relevant articles, 84 studies met our inclusion criteria. Visual
impairment at diagnosis was reported in 1041 of 2071 children (50.3%),
decreased visual acuity was reported in 546 of 1321 children (41.3%)
and visual field defects were reported in 426 of 1111 children (38.3%).
Other ophthalmological findings described were fundoscopic (32.5%) andorthoptic abnormalities (12.5%). Variations in ophthalmological testing
methods and ophthalmological definitions precluded a meta-analysis. The
results of this review confirm the importance of ophthalmological examination in children with craniopharyngioma at diagnosis in order to detect
visual impairment and provide adequate support. Future studies should

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Abstracts

focus on long-term visual follow-up of childhood craniopharyngioma in response to different treatment strategies to provide insight in risks and ways
to prevent further loss of vision.
RARE-63. CYST WALL OF ADAMANTINOMATOUS
CRANIOPHARYNGIOMA CONTAINS TUMOR CELLS THAT
COULD LEAD TO RECURRENCE AFTER SURGERY
Chuan Zhao1, Ye Wang1, Hongxing Liu1, Xueling Qi1, Zhongqing Zhou1,
Ching Lau2,3, and Zhixiong Lin1; 1Sanbo Brain Hospital, Capital Medical
University, Beijing, China, 2Connecticut Children’s Medical Center,
Hartford, CT, USA, 3The Jackson Laboratory for Genomic Medicine,
Farmington, CT, USA
BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is theprimary subtype of craniopharyngioma in children, frequently with mutations
in exon 3 of the CTNNB1 gene. Most ACP consists of both a solid tumor andone or more cysts. Despite surgical resection of the solid tumor followed byradiation, recurrence involving the cystic component is common, suggestingthat the cyst wall contains tumor cells. We present here conclusive molecularpathology evidence of the presence of tumor cells in the cyst wall similar to
those in the solid tumor. METHODS: We used standard H&E staining andimmunohistochemistry (IHC) to compare the histopathology characteristics
between the matched cyst wall and solid tumor of 11 cases of ACP as well as
their CTNNB1 expression and exon 3 mutation. RESULTS: Samples of thecyst wall and solid tumor were collected separately during the operation of
11 cases of ACP through careful dissection. The cyst wall showed the nested
cell clusters and peripheral palisading epithelium which are identical to thosein the solid tumor. The cyst wall and solid tumor both showed Ki67 andnuclear β-catenin expression by IHC. There is no difference in the transcription level of CTNNB1 between the cyst wall and the solid tumor, both being
significantly higher than that in normal brain tissue. Exon 3 mutations of
the CTNNB1 gene of the cyst wall and the solid tumor are identical in eachcase. CONCLUSION: Follow-up of clinical cases suggests that tumor cells inresidual cyst wall may be the cause of recurrence after surgery.

RADIATION ONCOLOGYRONC-01. PROTON BEAM THERAPY IN THE MULTIDISCIPLINARYTHERAPY FOR PEDIATRIC BRAIN AND SPINAL TUMOR AT KOBE
CHILDREN’S HOSPITAL WITH KOBE PROTON CENTER
Atsufumi Kawamura1, Junji Koyama1, Nobuyuki Akutsu1, Yuske Demizu2,
Nobuyoshi Fukumitsu2, Toshinori Soejima2, and Yoshiyuki Kosaka3;
1Department of Neurosurgery Hyogo Prefectural Kobe Children’s
Hospital, Kobe, Hyogo, Japan, 2Department of Radiation Oncology Hyogo
Prefectural Ion Beam Medical Center Kobe Proton, Kobe, Hyogo, Japan,
3Department of Hemato-oncology Hyogo Prefectural Kobe Children’s
Hospital, Kobe, Hyogo, Japan
It could be remarked that Radiotherapy (RT) has the important role
for the multidisciplinary therapy to Malignant Pediatric Central Nervous
System tumor. And recently among RT, Proton Beam Therapy (PBT) is expected to be effective and decrease serious late effects after RT in malignant
pediatric tumor. PBT could be controlled precisely the dose and depth andspare the normal structures outside the target. Thus, PBT becomes applicable for pediatric solid tumor to insurance in April, 2016 in Japan. We haveworked in closer cooperation with Hyogo Prefectural Ion Beam Medical
Center and started PBT from April 2015. And from December 2017, our PBT
has transferred to adjacent new medical center (Kobe Proton Center) which
has the only institute that equipped the exclusive gantry for children in ourcountry. The treated cases are 28 boys and 35 girls (age average 8.2 yearsoid). They are 15 Germ cell tumor, 14 Ependymoma, 13 Medulloblastoma, 4Chordoma, 4 Atypical teratoid/rhabdoid tumor, 2 Craniopharyngioma andothers. We have simulated the applications of not only broad beam but alsoscanned beam to limit the dose distribution and prepare for the cranio-spinal
irradiation. All cases underwent magnetic resonance imaging to evaluate theresults at out clinic and also the complications are assessed after treatments.
The effect of PBT in this series is similar to our experience of traditional RT.
There are a few controllable complications such as conventional RT. Farther
more follow up is necessary to evaluate the advantage of PBT which could
reduce delayed complications of RT.
RONC-02. MEASURING THE EFFECT OF CLINICALLY-RELEVANT
RADIOTHERAPY PROTOCOLS ON THE JUVENILE MOUSE BRAIN
Jessica Buck1,2, Kale Somers1, Jacqueline Whitehouse1,2,Meegan Howlett1,2, Hilary Hii1, Brooke Strowger1, Martin Ebert2,3,
Andrew Mehnert2, Nick Gottardo1,4, and Raelene Endersby1,2; 1Telethon
Kids Institute, Perth, Australia, 2University of Western Australia, Perth,iii456

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De c e mb e r 2 0 2 0Australia, 3Sir Charles Gairdner Hospital, Perth, Australia, 4PerthChildren’s Hospital, Perth, Australia
Treatment for medulloblastoma involves craniospinal irradiation whichis associated with devastating late effects. Clinical trials that simply reduceradiotherapy dosage have resulted in inferior survival rates, whereas new
chemo/radiotherapy combinations that improve survival have been identified using preclinical models. However, the potential late effects of novel
treatments are currently understudied and the assessment of radiationinduced late effects in mice remains challenging. Here, we aimed to measure
the effect of multifractionated radiotherapy on the juvenile mouse brain asa baseline measure for future studies. NOD/Rag1-/- mice received either
8Gy whole-brain radiotherapy (WBRT) using an X-RAD SmART preclinical platform, 18Gy fractionated WBRT (9x2Gy doses), single, or multiple
sham treatments beginning at postnatal day (P)16. Mice were aged to adulthood (>P63), then high resolution anatomical brain scans were obtained ona Bruker 9.4T MRI to measure the effects of WBRT on whole brain andspecific regional area volumes. A single 8Gy dose (n=10) markedly reduced
brain volume by 8.5% compared to single-sham controls (n=11, p<0.0001),
whereas fractionated 18Gy treatment (n=7) did not cause significant differences in brain volume compared to multi-sham controls (n=4, p>0.99). Current analyses are focused on measuring treatment effects on specific areasof the brain, as well as other anatomical differences using a range of MRItechniques. These results will serve as a valuable tool to measure potential
treatment-associated effects caused by novel chemo/radiotherapy combinations on the developing brain. This will enable future studies to assess thepotential safety of novel treatment to inform clinical decision making.
RONC-03. NEUROCOGNITIVE CHANGES AFTER RADIATION FOR
PEDIATRIC BRAIN TUMOURS: WHICH BRAIN SUBSTRUCTURES
ARE MOST IMPORTANT?
Derek S. Tsang1, Laurence Kim1, Donald Mabbott2,
Mohammad Khandwala1, Zhihui Amy Liu1, Normand Laperriere1,
Lauran Janzen2, Hitesh Dama1, Vijay Ramaswamy2, Dana Keilty1,
Eric Bouffet2, and David C. Hodgson1; 1Princess Margaret Cancer Centre,
Toronto, ON, Canada, 2Hospital for Sick Children, Toronto, ON, Canada
INTRODUCTION: The contribution of different intracranial structures
on neurocognitive decline after radiation therapy (RT) in children is unclear. METHODS: This was a retrospective study of children with brain tumours treated from 2005 to 2017. Patients with longitudinal neurocognitive
assessments and photon dosimetric data (if RT given) were included. Fullscale intelligence quotient (FSIQ) was the primary endpoint; sub-indicesof neurocognition were modelled separately (perceptual reasoning [PRI],
processing speed [PSI], verbal comprehension [VCI] and working memory[WMI]). Multivariable linear mixed effects models were used to model
endpoints, with age at diagnosis & dose to different brain regions as fixed effects and patient-specific random intercepts. RESULTS: Sixty-nine patientswere included; ten patients did not receive any RT (i.e. low-grade glioma).
Median neurocognitive follow-up was 3.2 years. Right hippocampus meandose was a strong predictor of declines in FSIQ (p < .001), VCI (p = 0.002)
and PRI (p = 0.049). Dose to 50% of the supratentorial brain (D50) was
the strongest predictor for WMI (p < .001) and PSI (p < .001). Each gray increase in mean right hippocampus dose resulted in a decrease of 0.038 FSIQ
points/year. After adjusting for dose to brain substructures, younger age &presence of a ventriculoperitoneal shunt were also associated with decreased
FSIQ. CONCLUSIONS: Mean dose to the right hippocampus was associated with declines in FSIQ, VCI and PRI, while supratentorial brain D50 was
associated with WMI and PSI. Efforts should be made to reduce unnecessary
dose to these brain structures.
RONC-04. RE-IRRADIATION AFTER TREATMENT OFMEDULLOBLASTOMA; RELAPSED CASES AND SECOND CANCER
CASES
Toshinori Soejima1, Nobutoshi Fukumitsu1, Yusuke Demizu1,
Masayuki Mima1, Takeshi Suzuki1, Atsufumi Kawamura2, andYoshiyuki Kosaka2; 1Kobe Proton Center, Kobe, Japan, 2Kobe Children’s
Hospital, Kobe, JapanPURPOSE: Late complications such as brainstem necrosis are great
concern of re-irradiation for brain tumor. Proton beam therapy can reduce radiation dose of organs at risk such as brainstem, so is expected toreduce late complications. PATIENTS AND METHODS: Patients withmedulloblastoma treated with re-irradiation from January 2015 to February
2019 at the Kobe Children’s Hospital and the Kobe Proton Center were reviewed. There were three cases of relapsed medulloblastoma and three casesof second cancer (glioblastomas). RESULTS: In relapsed cases, all threecases treated with 12 Gy in 8 fractions cranio-spinal irradiation followed
by gamma knife radiosurgery (one) or 28.8 Gy (RBE) in 16 fractions ofproton beam therapy (two). Follow-up periods were 8 to 19 months (medianAbstracts

12 months) and all three cases survived without relapse. In second cancer
cases, all three cases were treated with 40.05 Gy per 15 fractions of radiation therapy (2 cases were treated with photon and one case with proton).
However, all cases relapsed and two cases died of disease. CONCLUSION: Twelve Gy in 8 fractions cranio-spinal irradiation followed by 28.8
Gy (RBE) in 16 fractions of proton beam therapy is thought to be useful forthe relapsed case. Re-irradiation for second cancer was disappointing andfurther study is warranted.
RONC-05. PRESERVING VISION IN OPTIC PATHWAY GLIOMAAMONG PATIENTS WITHOUT NEUROFIBROMATOSIS TYPE 1
Alexander Hanania1, Arnold Paulino2, Ethan Ludmir2, Veeral Shah3,
Susan McGovern2, David Grosshans2, Fatih Okcu4, Patricia Baxter4,
Jack Su4, and Murali Chintagumpala4; 1Department of Radiation
Oncology, Baylor College of Medicine, Houston, Texas, USA, 2Departmentof Radiation Oncology, University of Texas M D Anderson Cancer Center,
Houston, Texas, USA, 3Department of Ophthalmology, Texas Children’s
Hospital, Baylor College of Medicine, Houston, Texas, USA, 4Texas
Children’s Cancer Center, Baylor College of Medicine, Houston, Texas,
USA
PURPOSE: Sporadic optic pathway/hypothalamic gliomas (OP/HGs)represent a unique entity within pediatric low-grade glioma. Despite favorable survival, the location makes treatment difficult and local progression debilitating. We conducted longitudinal assessment of visual acuity(VA) among patients treated in the modern era with chemotherapy (CT)or early radiotherapy (RT). METHODS: Clinical characteristics wereabstracted for patients treated over a 15-year period (2000–2015) at asingle institution. Comprehensive ophthalmologic data taken at three
to six-month intervals was examined with age-appropriate VA metrics converted to LogMAR scale. Kaplan-Meir “blindness-free survival”(BFS) curves were calculated as time to bilateral functional blindness(i.e. LogMAR ≥ 0.8 in both eyes), stratified by treatment and comparedusing log-rank test. RESULTS: Thirty-six patients with median follow-up
of 7.6 years (range: 2–17) were identified. Median age at diagnosis was
2.5 years (IQR: <1–5). Early RT was administered as initial therapy (n=6)
or first-line salvage (n=5) in a total of eleven patients (31%) at a mean ageof 12 years (range: 6–17). Twenty-five patients (69%) were maintained
primarily on CT with a mean age at initiation of 2.4 years (range <1–8).
Of these, five patients received RT after ≥2 systemic therapy regimens.
In terms of visual preservation, five/eight-year BFS rates were 84%/59%
and 100%/100%, for CT and early RT, respectively (p=0.046). CONCLUSIONS: In a contemporary cohort, early RT, defined as initial or
1st line salvage therapy for OP/HGs manifested in superior VA. Children
undergoing CT are at highest risk of functional blindness following five
years of treatment.
RONC-06. VOLUMETRIC-MODULATED ARC WHOLE-BRAIN
RADIOTHERAPY FOR THE PREVENTION OF PERMANENTALOPECIA IN PEDIATRIC PATIENTS
Megumi Uto, Katsutsugu Umeda, Yoshiki Arakawa, Keiichi Takehana,
Tatsuya Kamitori, Atsushi Iwai, Itaru Kato, Satoshi Saida,
Hidefumi Hiramatsu, Yohei Mineharu, Masahiro Tanji, Junko Takita,
Takashi Mizowaki; Kyoto University Graduate School of Medicine, Kyoto,
Japan
Permanent alopecia is a grave late complication of multi-drug chemotherapy (CTx) plus cranial irradiation, reducing both patient self-esteem
and quality of life in pediatric patients. We started to use craniospinal
irradiation (CSI) using the volumetric-modulated arc whole-brain radiotherapy (VMAT-WBRT) in order to prevent permanent alopecia. We
treated 5 pediatric patients with CSI using VMAT-WBRT, and report theinitial clinical outcome. Five consecutive patients (4–11 years old) who
received CSI using VMAT-WBRT from June 2015 to November 2018
were included into this study. One patient with embryonic carcinoma
received radiotherapy (RT) with concurrent CTx; four patients withmedulloblastoma (two patients with standard risk, and two patients withhigh risk) received RT followed by CTx. The prescribed doses of CSI were23.4–35.2 Gy in 13–22 fractions, respectively. Optimization for VMATWBRT was performed to reduce doses to the hair follicles with keeping
the dose coverage to the planning target volume. Although all patients
experienced temporary alopecia, their hair fully recovered over the whole
scalp within 8 months after finishing RT. One patient had disease progression after 6 months after completing CTx; this patient who was diagnosed
as Group 3 subtype had diffuse meningeal dissemination confirmed with
contrast enhanced spinal MRI before RT. The other four patients had noevidence of recurrence. Although CSI with VMAT-WBRT might be one ofconsiderable options, more cases are needed to verify the efficacy to prevent permanent alopecia for pediatric patients who receive multi-drug CTx
and cranial irradiation.

RONC-08. SURVIVAL IMPACT OF POSTOPERATIVERADIOTHERAPY TIMING IN PEDIATRIC AND YOUNG ADULTEPENDYMOMA
Sunny Shah1, Chase Mallory1, Kevin Gates1, Muni Rubens1,
Ossama Maher2, Toba Niazi2, Ziad Khatib2, Haley Appel1,
Rupesh Kotecha1, Minesh Mehta1, Matthew Hall1,2; 1Miami Cancer
Institute, Miami, FL, USA, 2Nicklaus Children’s Hospital, Miami, FL, USA
INTRODUCTION: Postoperative radiotherapy is commonly given for
WHO Grade 2–3 intracranial ependymoma. Clinicians generally aim tobegin radiotherapy ≤5 weeks following surgery, but the optimal timing remains uncertain. METHODS: The National Cancer Database was queried
for patients (age ≤39 years) with localized WHO Grade 2–3 intracranial ependymoma treated with surgery and postoperative radiotherapy.
Multivariable logistic regression was used to identify factors associatedwith delayed postoperative radiotherapy, defined as starting >8 weeks after
surgery. Overall survival (OS) curves were plotted based on radiotherapy
timing (≤5 weeks, 5–8 weeks, and >8 weeks after surgery) and comparedby log-rank test. Multivariate analysis (MVA) was used to identify factors
associated with OS. RESULTS: In the final analytic set of 1,043 patients,age ≥21 years (OR 2.07, 95% CI 1.56–2.74) and WHO Grade 2 tumors(OR 1.41, 95% CI 1.08–1.85) were significantly associated with delayed
time to adjuvant radiotherapy. No difference in 3-year OS was observedin patients who initiated radiotherapy ≤5 weeks, 5–8 weeks, and >8 weeks
after surgery (89.8% vs. 89.1% vs. 88.4%; p= 0.796). On MVA, anaplastic
histology (HR 2.414, 95% CI 1.784–3.268, p<0.001) and subtotal resection(HR 2.398, 95% CI 1.519–3.788, p<0.001) were significantly associatedwith reduced OS. Timing of radiotherapy, total radiotherapy dose, age, insurance status, and other factors were not significant. CONCLUSION: Delayed postoperative radiotherapy was not associated with inferior survival
in patients with intracranial ependymoma, suggesting delayed radiotherapy
initiation may be considered in patients requiring longer postoperative recovery or referral to an appropriate radiotherapy center.
RONC-09. PSEUDOPROGRESSION AFTER PROTON THERAPYOF PEDIATRIC SPINAL PILOCYTIC ASTROCYTOMA ANDMYXOPAPILLARY EPENDYMOMA
Susan McGovern1, Jason Johnson1, Stephen Kralik2, David Grosshans1,
Mary Frances McAleer1, Wafik Zaky1, Patricia Baxter2, Frank Lin2,
Murali Chintagumpala2, and Arnold Paulino1; 1MD Anderson Cancer
Center, Houston, TX, USA, 2Texas Children’s Hospital, Houston, TX, USA
BACKGROUND: Pseudoprogression after proton therapy of CNS tumors is a challenging clinical situation. The rate of pseudoprogression after
proton therapy of pediatric spinal tumors is unknown. METHODS: Records of pediatric patients with spinal pilocytic astrocytoma (sPA; n = 9) or
myxopapillary ependymoma (MPE; n = 6) with gross disease treated with
proton therapy with at least 6 months of follow up from completion of
proton therapy were retrospectively reviewed for demographics, treatment
characteristics, and occurrence of pseudoprogression. Pseudoprogression
was defined as a post-radiation increase in tumor size with subsequent decrease in size without additional tumor-directed therapy. RESULTS: The
median age at radiation for sPA patients was 10.1y (range, 7.0 – 16.2y)and 12.7y (range, 7.9 – 14.4y) for MPE patients. The median prescribed
dose was 45 GyRBE (range, 39.6 – 50.4 GyRBE) for sPA patients and 50.4
GyRBE (range, 45 – 54 GyRBE) for MPE patients. One sPA patient received concurrent vincristine. Median follow up after proton therapy was
44 months (range, 9 – 99 months). Six of nine sPA patients (67%) had
pseudoprogression occurring at a median of 81 days (range, 34 – 136 days)
after proton therapy; no MPE patients developed pseudoprogression (0%;p < 0.03). Two sPA patients with pseudoprogression were symptomatic andimproved with medical therapy. CONCLUSION: Preliminary analysis suggests that pseudoprogression occurs frequently within 6 months after proton
therapy for sPA and infrequently after proton therapy for MPE.
RONC-12. TREATMENT AGE AND NEUROCOGNITIVEOUTCOMES FOLLOWING PROTON BEAM RADIOTHERAPY FORPEDIATRIC LOW GRADE GLIOMA
Andrew Heitzer1,2, Lisa Kahalley1,2, David Grosshans3, M. Fatih Okcu1,2,
Kimberly Raghubar1,2, Marsha Gragert1,2, Mark McCurdy1,2,
Emily Warren1,2, M. Douglas Ris1, Arnold Paulino3, andMurali Chintagumpala1,2; 1Baylor College of Medicine, Houston, TX, USA,
2Texas Children’s Hospital, Houston, TX, USA, 3M.D. Anderson Cancer
Center, Houston, TX, USA
INTRODUCTION: Younger age at radiotherapy increases cognitive riskfor patients with pediatric low grade glioma (LGG). We examined the impact of age at treatment on cognitive trajectories in LGG patients treatedwith proton radiotherapy (PRT) compared to patients treated without
radiotherapy (surgery only; SO). METHODS: We examined cognitive

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scores of 48 LGG patients on a prospective, longitudinal study. Generallinear mixed models evaluated change in cognitive scores over time. RESULTS: The sample included 16 patients treated with PRT and 32 with SO(median follow-up=3.1 years, range 0.9–6.1). Median age of PRT patientswas 8.2 years at diagnosis (range 1.0–14.4) and 9.4 years at PRT (range
4.2–16.7). 13 PRT patients also received surgery: 53.8% biopsy, 30.8% subtotal resection, 15.4% gross total resection. Tumor sites included: 31.2%
hypothalamic/suprasellar, 25.0% optic pathway, 18.8% temporal, 25.0%
other. Median age of SO patients was 8.2 years at diagnosis (range 2.9–18.6). Surgical outcomes were: 75.0% gross total resection, 21.9% biopsy/
other. There were no group differences in diagnosis age, tumor volume, or
shunt history (all p>0.05). Both PRT and SO groups displayed stable cognitive functioning over time (all p>0.1). Slopes (i.e., change in scores overtime) did not differ between groups (all p>0.1). Age at treatment was not
associated with slope or performance at last follow-up in either group (allp>0.05). CONCLUSIONS: We observed stable cognitive functioning, independent of age at treatment, following PRT for LGG. Outcomes were similar
to patients receiving surgery only. Further examination in a larger sample iswarranted.
RONC-13. RADIATION INDUCED BRAIN STEM GLIOMA AFTERRADIATION THERAPY FOR MIXED GERM CELL TUMOR
Natsumi Yamamura, Masahiro Nonaka, and Akio Asai; Kansai Medical
University, Osaka, Japan
We report a case of radiation-induced glioma in the pons after radiation
therapy for germ cell tumor. A 17-year-old man was diagnosed as HCG
and AFP secreting germ cell tumor at the age of 9. The tumor was locatedin the suprasellar region, which filled up most part of the third ventricle.
Five courses of chemotherapy with cisplatin, etoposide, and cyclophosphamide, and whole ventricle plus local radiation therapy (total 51.2 Gy / 32Fr)
were performed. After the treatment, most part of the tumor was regressed,
and only small enhanced lesion remained. Six years after the treatment, hestarted to be ataxic, and worsened. An MRI revealed an enhanced lesion in
the pons. Lesion biopsy was performed via the right cerebellar peduncle.
Histopathological diagnosis confirmed the lesion was high grade glioma. He
underwent extended local radiation therapy (50.4 Gy / 28 Fr) and administered temozolomide. Later, bevacizumab was added, and 3 months after
treatment started, the size of the tumor was reduced and his symptoms were
improving. There is no established treatment for radiation induced glioma.
However, additional radiation therapy, temozolomide and bevacizumab appears to be useful to reduce tumor size and resolve the symptoms, even if
it is transient.
RONC-15. OUTCOMES OF BRAIN AND SKULL-BASE TUMOURSIN ADOLESCENTS AND YOUNG ADULTS TREATED WITH PENCIL
BEAM SCANNING PROTON THERAPYPei Shuen Lim1,2, Sébastien Tran3, Stephanie GC Kroeze4, Alessia Pica2,
Jan Hrbacek2, Barbara Bachtiary2, Marc Walser2, Anthony J Lomax2,5, andDamien C Weber2,6; 1University College London Hospitals, London, United
Kingdom, 2Centre for Proton Therapy, Paul Scherrer Institute, Villigen,
Switzerland, 3Geneva University Hospital, Geneva, Switzerland, 4University
Hospital Zürich, Zürich, Switzerland, 5ETH, Department of Physics,
Zürich, Switzerland, 6University of Zürich, Zürich, Switzerland
BACKGROUND: The use of highly conformal proton therapy in adolescents and young adults (AYAs) for management of brain/skull-basetumours is becoming increasingly common. This study aims to assess thelong-term clinical outcomes, prognostic factors and employment statusof AYAs (15–39 years) treated with pencil-beam-scanning proton-therapy(PT). METHODS: Between 1997–2018, 176 AYAs were treated with PT
at the Paul Scherrer Institute. Median age was 30 years (range, 15–39)
and the male/female ratio was 0.8. RESULTS: After a median follow-up
of 66 months (range, 12–236), 24 (13.6%) local failures and 1 (0.6%) distant failure were observed between 6 and 152 months after PT. The mostcommon histologies treated were chordomas/chondrosarcomas (61.4%),
followed by meningiomas (14.2%) and gliomas (15.3%). The 6-year localcontrol (LC), distant-progression-free survival and overall-survival (OS)rate was 83.2%, 97.4% and 90.2% respectively. On univariate analysis,age ≥24 years was a negative prognostic factor for LC. Recurrent disease,infratentorial tumours and low-grade-glioma histology were poor prognostic factors for both LC and OS. The 6-year ≥G3 PT-related late toxicityfree survival was 88.5%. The moderate-high grade late toxicity crude rates
were 37.8% G2, 12.2% G3, 0.6% G4 and 0.6% G5. No secondary malignancies were observed. The unemployment rate was 7.3% at PT, rising to
25.3% at survivorship. High-grade(≥G3) toxicity rate in the unemployedvs employed group was 21% vs 8.5%. CONCLUSION: PT is an effective
treatment for AYAs with brain/skull-base tumours with good tumour control and acceptable long-term toxicity. Despite having satisfactory clinicaloutcomes, around 1 in 4 AYAs surviving brain/skull base tumours are unemployed.

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RONC-16. PROTON BEAM THERAPY FOR PATIENTS WITH
INTRACRANIAL EPENDYMOMA UNDER 3 YEARS OLD: INITIAL
CLINICAL OUTCOMES
Takayuki Hashimoto1, Shigeru Yamaguchi2, Takashi Mori3,4,
Akihiro Iguchi5, Yukitomo Ishi2, Hiroaki Motegi2,
Rikiya Onimaru4, Atsushi Manabe5, Shinichi Shimizu1, andHidefumi Aoyama4; 1Department of Radiation Medical Science andEngineering, Faculty of Medicine, Hokkaido University, Sapporo,
Japan, 2Department of Neurosurgery, Faculty of Medicine, Hokkaido
University, Sapporo, Japan, 3Department of Oral Radiology, Faculty of
Dental Medicine, Hokkaido University, Sapporo, Japan, 4Departmentof Therapeutic Radiology, Faculty of Medicine, Hokkaido University,
Sapporo, Japan, 5Department of Pediatrics, Hokkaido University Graduate
School of Medicine, Sapporo, JapanBACKGROUND: Proton beam therapy (PBT) provides dosimetric benefits in sparing normal tissue when treating pediatric patients with brain tumors. We report the preliminary clinical outcomes of surgery and adjuvant
PBT for patients under 3 years old diagnosed as intracranial ependymoma
at our institute. METHODS: This is a retrospective review of the medical
records for 3 children with ependymoma in the fourth ventricle, diagnosed
between March 2013 and September 2019. PBT was performed after tumor
resection in all the patients. RESULTS: Gross total resection was achievedin 2 males and 1 female patients with fourth ventricle WHO grade II to
III ependymoma at 15, 18, and 37 months old. All the patients received
adjuvant PBT (54.0 GyE/30 fractions) to the postoperative tumor bed
under general anesthesia or sedation. PBT was acutely well tolerated, withmostly mild alopecia and skin reactions at the irradiated sites. At a medianfollow-up of 54 months (4–59 months) after irradiation, all the patients arealive without recurrence. No serious late adverse events were observed inany of the patients. CONCLUSION: The number of patients in this study
remains small for drawing any definite conclusion, however our preliminary
results are still encouraging. Further studies of a large number of pediatricpatients with long term follow-up are needed to more fully assess tumor
control and late adverse events.
RONC-17. STEREOTACTIC RADIOSURGERY FOR SPINEMETASTASES IN PEDIATRIC MALIGNANCIES
Kristina Woodhouse1, Victor Albornoz Alvarez1,2, David Boyce1,
Jing Li1, Debra Yeboa1, David Grosshans1, Tina Briere1, Claudio Tatsui1,
Laurence Rhines1, Amini Behrang1, Susan McGovern1, Arnold Paulino1,
Mary Frances McAleer1, and Amol Ghia1; 1MD Anderson Cancer Center,
University of Texas, Houston, TX, USA, 2Baylor College of Medicine,
Houston, TX, USA
BACKGROUND: Spine stereotactic radiosurgery (SSRS) is a
non-invasive technique that delivers ablative radiotherapy for optimal control of bony disease. While SSRS is known to provide excellent local control(LC) and minimal toxicity in adults, the role of SSRS in pediatrics is lessclear. PURPOSE: To evaluate SSRS in pediatric patients with spinal metastases. METHODS: A retrospective review of patients (<18 yrs) treatedwith SSRS at MDACC was performed after IRB approval. Descriptive statistics were utilized for analysis. RESULTS: From 2011–2019, 12 metastatic
osseous sites (3 cervical, 4 thoracic, 5 lumbar-sacral) in 9 patients weretreated. Median follow-up was 9 months (range 2–41). Six males (67%)
and 3 females (33%) all KPS ≥70, received radiation to ≤3 contiguous vertebral bodies. Median age was 16 yrs (range 8–18). No patients required sedation. Histologies included 7 osteosarcomas, one rhabdomyosarcoma andone Ewing’s sarcoma. Metastatic epidural spinal cord compression scores
ranged from 0 (6), 1b (3) and 3 (3). No sites had surgery prior to SSRS andone site received prior conventional radiation. SSRS doses included 24 Gy
in 1 fraction (7), 24–27 Gy in 3 fractions (4) and 50 Gy in 5 fractions (1).
Six-month LC was 83% with one local failure following 27 Gy. OS at 6 and12 mo were 55% and 23%. There was no grade ≥3 acute toxicity, no radiation myelopathy or vertebral compression fractures. CONCLUSION: In
this initial report, SSRS represents a promising modality that is well tolerated and provides excellent LC. However, further follow-up is warranted in
the pediatric setting.
RONC-18. ANALYSIS OF BRAIN TUMOR INDUCED BY
IRRADIATION IN CHILDHOOD - A SINGLE INSTITUTIONALANALYSIS
Takashi Sano, Kaoru Tamura, Masae Kuroha, Kazutaka Sumita,
Yukika Arai, Takashi Sugawara, Motoki Inaji, Yoji Tanaka, Tadashi Nariai,
and Taketoshi Maehara; Department of Neurosurgery, Tokyo Medical and
Dental University, Bunkyo, Tokyo, JapanBACKGROUND: Radiation-induced brain tumors are rare tumors thatappear during long-term follow-up after radiation therapy. Children are at
greater risk for radiation -induced brain tumors than adults. The clinicalcharacteristics of radiation-induced brain tumor treated at our hospitalAbstracts

were retrospectively examined. PATIENTS AND METHODS: Clinicalcharacteristics of seven radiation-induced brain tumors that developedin 6 patients irradiated in their childhood at our hospital were analyzed.
The background disease, age at irradiation, irradiation dose, period from
irradiation to onset, pathological diagnosis, and treatment for radiationinduced brain tumor were examined. RESULTS: Background diseases forirradiation were leukemia in 3 patients, germinoma in 2, medulloblastoma
in 1, and the average cranial irradiation dose was 23.2 Gy. The patientstended to be young at irradiation (2–17 yeays; median:4 years old). The
time between irradiation and the onset of radiation-induced brain tumors
ranged from 9.5 to 39.1 years (median:28 years). Radiation-induced brain
tumors comprised 6 meningioma（grade I:5, grade II:1）and 1 high-grade
gliomas. All patients underwent surgical removal of the radiation-induced
brain tumors and 2 received additional irradiation. During a median of
5.3 years of follow-up after the diagnosis of radiation-induced brain tumors, 2 underwent second surgery, while the remaining 4 have no recurrence. DISCUSSION: In most cases, radiation-induced brain tumors occur
for a long time after irradiation in childhood. Monitoring of radiationinduced brain tumors as well as primary tumor recurrence was considered
important.
RONC-19. TWO CASES OF RE-IRRADIATION FOR LATE
RECURRENT OR RADIATION-INDUCED TUMOR AFTERRADIATION THERAPY FOR PEDIATRIC BRAIN TUMORS
Takashi Mori1,2, Shigeru Yamaguchi3, Rikiya Onimaru4,
Takayuki Hashimoto4, and Hidefumi Aoyama4; 1Department of Radiation
Oncology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan,
2Department of Oral Radiology, Hokkaido University Hospital, Sapporo,
Hokkaido, Japan, 3Department of Neurosurgery, Faculty of Medicine,
Hokkaido University, Sapporo, Hokkaido, Japan, 4Department ofRadiation Oncology, Faculty of Medicine, Hokkaido University, Sapporo,
Hokkaido, JapanBACKGROUND: As the outcome of pediatric brain tumors improves,late recurrence and radiation-induced tumor cases are more likely tooccur, and the number of cases requiring re-irradiation is expected toincrease. Here we report two cases performed intracranial re-irradiation
after radiotherapy for pediatric brain tumors. CASE 1: 21-year-old
male. He was diagnosed with craniopharyngioma at eight years old andunderwent a tumor resection. At 10 years old, the local recurrence ofsuprasellar region was treated with 50.4 Gy/28 fr of stereotactic radiotherapy (SRT). After that, other recurrent lesions appeared in the left
cerebellopontine angle, and he received surgery three times. The tumor
was gross totally resected and re-irradiation with 40 Gy/20 fr of SRT
was performed. We have found no recurrence or late effects during the
one year follow-up. CASE 2: 15-year-old female. At three years old,she received 18 Gy/10 fr of craniospinal irradiation and 36 Gy/20 fr ofboost to the posterior fossa as postoperative irradiation for anaplastic
ependymoma and cured. However, a anaplastic meningioma appearedon the left side of the skull base at the age of 15, and 50 Gy/25 fr ofpostoperative intensity-modulated radiation therapy was performed.
Two years later, another meningioma developed in the right cerebellar
tent, and 54 Gy/27 fr of SRT was performed. Thirty-three months after
re-irradiation, MRI showed a slight increase of the lesion, but no late
toxicities are observed. CONCLUSION: The follow-up periods areshort, however intracranial re-irradiation after radiotherapy for pediatricbrain tumors were feasible and effective.
RONC-20. RECURRENT HIGH-GRADE ASTROBLASTOMATREATED WITH STEREOTACTIC RADIOTHERAPY
Shota Nishimoto, Yu Kawanishi, Shohei Fujita, Toshio Yawata, andTetsuya Ueba; Kochi Medical School, Nankoku, Kochi, JapanINTRODUCTION: Astroblastoma is a rare, mostly supratentorial
glial tumor, occurring predominantly in children and young adults.
However, treatment strategies have not yet been established for this raredisease. CASE PRESENTATION: A 6-year-old male presented with headache and nausea. CT and MR imaging revealed a left frontal mass lesion
with slight edema and macrocalcifications. Gross tumor resection was performed. Histological examination found neoplastic cells with astroblastic
characteristics, and a striking perivascular array of pseudorosettes. The
final diagnosis was high-grade astroblastoma. MR imaging 13 months
after surgery suggested local recurrence and enlargement was found
3 months later. Stereotactic radiotherapy (SRT) was performed. MR imaging after SRT showed enhanced cyst formation around the tumor bed,suggesting tumor recurrence. However, 11C-methionine PET revealed radiation necrosis. The last follow-up MR imaging 15 months after SRT
showed no further recurrence. CONCLUSION: Astroblastoma is rare, so
no optimal management is known. SRT may be effective to treat recurrent
astroblastomas. 11C-methionine PET/CT is useful for the differentiationfrom radiation necrosis.

RONC-21. IDENTIFICATION OF EPIGENETIC DRUGS AS
RADIOSENSITIZERS IN PEDIATRIC HIGH-GRADE GLIOMAS
Dennis Metselaar1,2, Giovanna ter Huizen2, Michaël Hananja Meel1,
Joshua Goulding2, Piotr Waranecki1,2, Angel Montero Carcaboso3,
Gertjan Kaspers1, and Esther Hulleman1; 1Princess Máxima Center for
Pediatric Oncology, Utrecht, Netherlands, 2Amsterdam University Medical
Centers, Amsterdam, Netherlands, 3Hospital Sant Joan de Deu, Barcelona,
Spain
Pediatric high-grade gliomas (pHGG) are malignant brain tumors with ahigh mortality rate. Radiotherapy (RT) is one of the cornerstones of current
pHGG treatment, while the efficacy of chemotherapeutics remains inferior.
The use of chemotherapeutics that specifically sensitize tumor cells to irradiation are poorly understood, but may help to increase the effect of RT
in pHGG treatment. Since recent studies revealed pHGG to be epigenetically dysregulated, we tested 148 epigenetic drugs on eight primary pHGG
models in the presence and absence of RT, to assess their radiosensitizing
potential. Based on synergy scores, we found 22 compounds that resulted inenhanced cytotoxicity in the presence of RT. The effect of these compounds
on pHGG was further investigated by tracking spheroid growth microscopically for 30 days, identifying four molecules that stopped spheroidexpansion solely in combination with RT (p=<0.001, multilevel regression).
Parallel cell-viability assays reported identical results. Furthermore, tumor
migration in 3D matrigel growth assays, using non-toxic doses of the four
identified compounds, revealed that two compounds (the selective HDACinhibitors; chidamide and entinostat) stop the infiltrative growth characteristics of pHGG cells, exclusively in combination with RT. RNA-Seq data
showed that entinostat and chidamide inhibit DNA-repair pathways likethe Fanconi anemia cascade and homologous recombination. Since we anticipate that entinostat- or chidamide-induced radiosensitization can beenhanced by blocking kinase-driven escape mechanisms, we are currently
conducting a kinome-wide CRISPR/Cas9 knockout screen in three primary
pHGG models to develop combinational therapies. These results highlightentinostat and chidamide as potential radiosensitizers in pHGG treatment.
RONC-22. SECOND TUMORS IN PEDIATRIC PATIENTS TREATED
WITH PROTON THERAPY TO THE CENTRAL NERVOUS SYSTEM
Daniel J Indelicato, James Bates, Raymond Mailhot-Vega,
Christopher Morris, Eric Sandler, Phillip Aldana, and Julie Bradley;
University of Florida, Jacksonville, FL, USA
BACKGROUND: Previous institutional data suggests the 10-year cumulative incidence of second tumors is 3% in children treated with photon
radiation for central nervous system (CNS) malignancy, with 90% of thesetumors occurring in areas receiving ≤36 Gy. Comparative figures for children treated with proton therapy (PT) does not exist. METHODS: 1056
consecutive pediatric patients with a median follow-up of 5.0 years weretreated between 2006–2019 with double-scattered PT to a site within the
craniospinal axis. 230 patients were ≤3 years old and 14 had neurofibromatosis. A second tumor was defined as any solid neoplasm with histologic features different from the original tumor that had arisen within the irradiatedvolume. RESULTS: Five patients developed second tumors resulting in a
5- and 10-year cumulative incidence of 0.2% (95% CI: 0–1.2%) and 1.6%
(95% CI: 0.6%-3.9%), respectively. Of those who developed second tumors,
median age at radiation was 4.3 years old (range, 2.1 to 5.1 years old) anddiagnoses consisted of medulloblastoma (n=2), ependymoma (n=2), andcraniopharyngioma (n=1). The second tumors included high grade gliomas(n=3) and high grade sarcoma (n=1) that occurred in regions receiving atleast 54 Gy. One patient with neurofibromatosis developed both a low-grade
glioma and choroidal melanoma in craniospinal irradiation regions receiving 36 Gy. Four of five patients with second tumors are alive. CONCLUSION: The reduction in moderate-to-low dose radiation exposure fromproton therapy may be associated with a decreased incidence of second tumors in children treated for CNS neoplasms. More follow-up is needed toconfirm these findings.
RONC-23. NOVEL APPROACH TO REDUCE ACUTE ESOPHAGEALTOXICITY IN CRANIO-SPINAL IRRADIATION USING INTENSITYMODULATED PROTON THERAPY
Vineet Nakra, Srinivas Chilukuri, Utpal Gaikwad, Noufal MP,
Kartikeshwar Patro, Rajesh T, Dayananda Shamurailatpam, Sham Sunder,
Nagarjuna Burela, Rishan T, Raees Tonse, Muthiah K, Rakesh Jalali,
Manikandan A, and Ganapathy Krishnan; Apollo Proton Cancer Centre,
Chennai, Tamil Nadu, India
INTRODUCTION: We present our experience of a novel approach using
intensity modulated proton therapy(IMPT) for cranio-spinal irradiation(CSI)
leading to reduced acute esophageal toxicity and reduced treatment interruptions. MATERIAL AND METHODS: Seven children younger than
12 years old treated consecutively with CSI using IMPT were included in thisstudy. Three among 7 children received concurrent chemotherapy(CCT). En-

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tire vertebral body(VB) was part of target volume in all patients. The IMPT
plan was generated using 3 fields with single field optimisation technique.
Last 5 patients were treated using dose gradient(DG) (98-93%) deliberately
created in anterior most 3-5mm of VB. Initial 2 patients were treated withintention of covering entire VB with 98% isodose. Monte Carlo algorithm
was used for dose calculations and optimisation, and robustness assessed for
3mm setup and 3.5% range uncertainty. RESULTS: The CSI dose ranged
from 21.6GyE to 35GyE. In patients without DG, maximum and meandose to esophagus(36.67GyE vs. 25.45GyE, 31.53GyE vs. 20.41GyE), midline mucosa(28.95GyE vs. 25.31GyE, 21.8GyE vs. 14.61GyE) and bowelbag(32.9GyE vs. 24.27GyE, 3.59GyE vs. 3.21GyE) were higher comparedto patients with DG. Both patients where DG was not created, developed
grade 2 esophageal toxicities requiring supportive care and treatment interruptions(4 and 2days). All 5 patients with DG did not develop significant
esophageal toxicity and had no interruptions. CONCLUSION: Creating adose gradient over anterior VB using IMPT reduces dose to esophagus andmidline mucosa leading to lower acute esophageal toxicity which potentiallyavoids treatment interruptions during CSI.
RONC-24. PROTON THERAPY FOR PEDIATRIC EPENDYMOMA:
MATURE OUTCOMES FROM THE UNIVERSITY OF FLORIDA AND
MASSACHUSETTS GENERAL HOSPITAL
Daniel J Indelicato1, Myrsini Ioakeim-Ioannidou2, Julie Bradley1,
Raymond Mailhot-Vega1, Christopher Morris1, Nancy Tarbell2,
Torunn Yock2, and Shannon MacDonald2; 1University of Florida,
Jacksonville, FL, USA, 2Massachusetts General Hospital, Boston, MA, USA
OBJECTIVE: Report long-term efficacy and toxicity of proton therapy
for pediatric ependymoma. MATERIALS AND METHODS: Between
2000–2017, 318 children with nonmetastatic grade II/III intracranial
ependymoma received proton therapy at Massachusetts General Hospital and the University of Florida. Median age was 3.5 years (range, 0.7–
21.3 years); 56% were male. Most (69%) tumors were in the posterior fossa
and classified as WHO grade III (64%). Eighty-four percent had a grosstotal or near total tumor resection before radiotherapy and 30% received
chemotherapy. Median radiation dose was 55.8 CGE (range, 50.4–59.4
CGE). RESULTS: Median follow-up was 6 years (range, 0.6–19.2 years).
Seven-year local control, progression-free survival, and overall survival rates
were 77.1% (95% CI 71.7–81.7%), 64.4% (95% CI 58.6–69.8%), and
82% (76.9–86.2%), respectively. Subtotal resection was associated with inferior local control (60% vs 80%; p<0.01), progression-free survival (49%vs 67%; p<0.01), and overall survival (69% vs 84%; p<0.05). Male gender
was associated with inferior progression-free (59% vs 71%; p<0.01) andoverall survival (77% vs 89%; p<0.05). Twenty patients (6.2%) require
hearing aids; of these, 12/20 received cisplatin. Grade 3+ brainstem toxicity rate was 1.6% and more common in patients who received >54 CGE.
The rate of second malignancy was 0.9%. CONCLUSION: Proton therapy
offers commensurate disease control to modern photon therapy without
unexpected toxicity. The high rate of long-term survival justifies efforts to
reduce radiation exposure in this young population with brain tumors. Independent of modality, this large series confirms extent of resection as the mostimportant modifiable factor for survival.
RONC-25. A CASE OF PEDIATRIC PONTINE GLIOMA TREATED
WITH GAMMA KNIFE SURGERY
Satoshi Kaneko1, Juri Kiyokawa1, Shin Hirota1, Yasuhiro Murota1,
Mariko Ishikawa1, Hiroto Yamaoka1, Masataka Yoshimura1,
Masaaki Yamamoto2, and Shinji Yamamoto1; 1Tsuchiura Kyodo General
Hospital, Tsuchiura, Ibaraki, Japan, 2Mito Gamma House, Hitachinaka,Ibaraki, JapanBACKGROUND: Pediatric brainstem gliomas rarely occur and are aheterogeneous group of diseases, which increases the difficulty of treatment strategy. Here, we present a case of pediatric pontine glioma treatedwith Gamma Knife surgery (GKS) after open biopsy. CASE DESCRIPTION: An 11-year-old boy presented with diplopia due to the left MLF
syndrome. MRI showed a well-circumscribed, protruding tumor withpartial gadolinium enhancement in the dorsal pons. An open biopsy was
performed via the suprafacial triangle following midline suboccipital approach. Histological examinations revealed high cellularity and mild atypia.
Immunohistochemistry demonstrated positive stain for GFAP and Olig2
antibodies, and negative for p53 protein. The Ki67-labeling index was
6.8%. Pyrosequence analysis indicated IDH1/2 wild type (wt), BRAF V600
wt, H3F3A K27 wt, FGFR1 wt, and TERT wt. The final diagnosis was pediatric diffuse astrocytoma, WHO grade II, pons. GKS was performed one
month after the biopsy. After transient worsening of the symptom, it disappeared gradually. The tumor is stable for three years with mild shrinkage ofthe size. DISCUSSION: Gross total resection (GTR) of pediatric low-grade,brainstem gliomas may result in a good prognosis. However, unlike pilocytic
astrocytoma, diffuse astrocytoma is not easy to perform GTR without any
complications. There are some reports regarding GKS for brainstem gliomas,

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regression is achieved in our case, but tumor growth is well-controlled sofar. CONCLUSION: GKS after biopsy can be a useful treatment option for
pediatric low-grade brainstem gliomas.
RONC-26. A CASE OF RADIATION NECROSIS OF THE
CEREBELLUM 16 YEARS AFTER CHEMORADIOTHERAPY FORMEDULLOBLASTOMAMayuko Miyata, Masahiro Nonaka, and Akio Asai; Department of
Neurosurgery, Kansai Medical University, Hirakata City, Osaka, JapanBACKGROUND: If new lesions are observed during follow-up of themalignant tumor after treatment, it is difficult to distinguish whether thetumor is a recurrent lesion, secondary cancer, or radiation necrosis of thebrain. We have encountered a patient with symptomatic radiation necrosisof the cerebellum 16 years after treatment of medulloblastoma. CASE PRESENTATION: A 24-year-old man who had received a tumor resection andchemoradiotherapy for cerebellar medulloblastoma at the age of 8 presented
with dizziness. For the past 16 years, there was no recurrence of the tumor.
He subsequently underwent MRI scan, and T1-Gd image showed enhanced
lesion in the right cerebellar peduncle. Cerebrospinal fluid cytology analysis
was negative for tumor. We suspected tumor reccurence or secondary cancer,
and performed lesion biopsy. The result of the pathological examination wasradiation necrosis of the cerebellum. DISCUSSION: The interval of radiation necrosis of the brain and radiotherapy can vary from months to morethan 10 years. So, whenever a new lesion is identified, radiation brain necrosis must be envisioned. According to guidelines in Japan, there is no absolute examination for discriminating tumor recurrence from radiation brain
necrosis and diagnosis by biopsy may be required. CONCLUSION: We
experienced a case of symptomatic radiation necrosis of the cerebellum
16 years after treatment. In patients showing new lesion after long periodsof time, the possibility of radiation necrosis to be considered.
RONC-27. PROTON THERAPY REDUCES DOSE TO
CRITICAL CENTRAL NERVOUS SYSTEM STRUCTURES IN
MEDULLOBLASTOMA: A DOSIMETRIC ANALYSIS OF CHILDREN’SONCOLOGY GROUP (COG) ACNS0331
Matthew Deek1, Matthew Ladra1, Lan Lin1, Yimei Li2, Yuanyuan Han2,
Kristina Hardy3, and Jeff Michalski4; 1Johns Hopkins Hospital, Baltimore,
MD, USA, 2St. Jude Children Hospital, Memphis, TN, USA. 3Childrens
National, Washington DC, USA.,4Washington University in St. Louis,
St. Louis, MO, USA
BACKGROUND: Recently published data demonstrated proton
therapy (PRT) significantly reduced cognitive decline relative to photons
for pediatric medulloblastoma. These findings imply that reductions indose to critical CNS structures during the boost phase may account for
better outcomes over time. Here, we examine differences in dosimetricdata for medulloblastoma patients treated on ACNS0331 with photon(Intensity Modulated Radiation Therapy, 3D-Conformal Radiation
Therapy) vs PRT to identify potential structures responsible for cognitive
benefit. METHODS: COG ACNS0331 was a randomized trial examining
the impact of reduced craniospinal irradiation (CSI) dose (standard vs low
dose, in patients aged 3–7) and volume (whole posterior fossa vs involved
field) in pediatric medulloblastoma patients. We identified 136 patients(IMRT=95, 3DCRT=28, Proton=13) enrolled on ACNS0331 with complete
radiation and imaging data and re-contoured 10 critical brain structures
to calculate dose. RESULTS: Proton therapy significantly reduced the doseto critical structures. For example, temporal lobe mean dose and V30 were
30Gy/38% (PRT), 40Gy/89% (IMRT), 41Gy/84% (3DCRT)), hippocampi
mean dose were 51 Gy (IMRT), 52 Gy (3DCRT), and 44Gy (PRT) and cochlear mean dose were 43 Gy (IMRT), 49 Gy (3DCRT), and 31Gy (PRT). Doseto several other critical structures were also significantly reduced including
the whole brain, supratentorium, cerebellum, and pituitary. CONCLUSIONS: Proton therapy greatly reduces dose to critical CNS structures whencompared to IMRT or 3DCRT. Further studies are needed to correlate dose
reductions in these structures with improved cognitive outcomes.
RONC-31. ADVANCED ECHOCARDIOGRAPHY WITH
MYOCARDIAL-STRAIN-ANALYSIS DESCRIBES SUBCLINICALCARDIAC DYSFUNCTION AFTER CRANIOSPINAL IRRADIATION(CSI) IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH
CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Hugo Martinez, Ralph Salloum, Erin Wright, Philip Khoury, Justin Tretter,
and Thomas Ryan; Cincinnati Children’s Hospital Medical Center,
Cincinnati, Ohio, USA
CSI is part of the treatment of CNS tumors and is associated with cardiovascular disease; data in pediatric/young-adult patients are limited.
Myocardial-strain-analysis can reveal subclinical dysfunction. Retrospective,

Abstracts

single-center study in CNS tumor patients managed with CSI from 1986–
2018. Clinical details, and echocardiography including myocardial-strainanalysis were collected at T1=first echocardiogram after CSI, and T2=mostrecent echocardiogram. Data are mean±standard deviation. Echocardiograms were available in 44 patients (36%female, 14±8.0years) at T1 and39 patients (38%female, 21.0±11.3years) at T2. Standard echocardiography
was normal for all subjects. At T1, global longitudinal peak systolic strain(GLS) was -16.3%±3.7% in CSI vs. -21.6%±3.5% in controls (p<0.0001);
global radial peak systolic strain (GRS) was 21.5%±10.1% in CSI vs.
26.5%±7.4% in controls, and global circumferential peak systolic strain(GCS) was -19.5%±6.0% in CSI vs. -21.4%±3.4% in controls (p<0.05,
both comparisons). At T2, GLS was -15.8%±5.2% in CSI vs. -21.9±3.5% incontrols (p<0.0001); GRS was 22.6%±10.4% in CSI vs. 27.1±8.2% in controls (p<0.05); GCS was -20.5%±6.9% in CSI vs. -21.8±3.5% in controls(p=0.10). For 17 patients with myocardial-strain-analysis available for bothtime points: difference in GLS was 0.06±7.2% (p>0.95); GRS was 5.5±9.5%(p<0.05); GCS was -3.4±4.9% (p<0.05). Subclinical dysfunction is present
at first echocardiogram after CSI. Myocardial impairment may recover withtime, however further analysis is needed to identify risk factors and trends.
These results argue for inclusion of baseline cardiovascular assessment andlongitudinal follow-up in CNS tumor patients post CSI.
RONC-32. LOCAL CONTROL FOLLOWING PROTON THERAPYFOR PEDIATRIC CHORDOMA
Daniel Indelicato1, Ronny Rotondo2, Raymond Vega1, Adam Holtzman1,
Wen Shen Looi1, Christopher Morris1, Eric Sandler3, Philipp Aldana1, andJulie Bradley1; 1University of Florida, Jacksonville, FL, USA, 2Universityof Kansas, Kansas City, KS, USA, 3Nemours Children’s Specialty Clinic,
Jacksonville, FL, USA
BACKGROUND: Due to the location and high dose required for disease
control, pediatric chordomas are theoretically well-suited for treatment with
proton therapy, but their low incidence limits the clinical outcome data available in the literature. METHODS AND MATERIALS: Between 2008 and2019, 29 patients with a median age of 14.8 years (range, 3.8–21.8) received
proton therapy for non-metastatic chordoma at a single institution. Twentyfour tumors arose in the clivus/cervical spine region and 5 in the lumbosacral
spine. Twenty-six tumors demonstrated well-differentiated histology and 3
were dedifferentiated or not otherwise specified (NOS). Approximately halfof the tumors underwent specialized testing: 14 were brachyury-positive and
10 retained INI-1. Seventeen patients had gross disease at the time of radiation. The median radiation dose was 73.8 GyRBE. RESULTS: With a
median follow-up of 4.3 years (range, 1.0–10.7), the 5-year estimates of
local control, progression-free survival, and overall survival rates were85%, 82%, and 86%, respectively. Excluding 3 patients with dedifferentiated/NOS chordoma, the 5-year local control, progression-free survival,and overall survival rates were 92%, 92%, and 91%, respectively. Serious
toxicities included 3 patients with hardware failure or related infection requiring revision surgery, 2 patients with hormone deficiency, and 2 patientswith Eustachian tube dysfunction causing chronic otitis media. CONCLUSION: In pediatric patients with chordoma, proton therapy is associatedwith a low risk of serious toxicity and high efficacy, particularly in welldifferentiated tumors. Complete resection may be unnecessary for local control and destabilizing operations requiring instrumentation may result in
additional complications following therapy.

NEUROSURGERY
SURG-02. INITIAL MANAGEMENT OF HYDROCEPHALUS IN
THE PEDIATRIC AND YOUNG-ADULT PATIENTS WITH BRAIN
TUMORS; THE EFFICACY OF LONG-TERM INDWELLING
EXTERNAL VENTRICULAR DRAINAGE
Shigeru Yamaguchi1, Hiroaki Motegi1, Yukitomo Ishi1,
Michinari Okamoto1, Akihiro Iguchi2, Yuko Cho2, Minako Sugiyama2,
Atushi Manabe2, and Kiyohiro Houkin1; 1Department of Neurosurgery,
Hokkaido University Hospital, Sapporo, Japan, 2Department of Pediatrics,
Hokkaido University Hospital, Sapporo, JapanBACKGROUND: Pediatric and Young-Adult (AYA) brain tumors often
present with hydrocephalus. As temporary cerebrospinal fluid (CSF) diversion procedure, we perform long-term indwelling external ventriculardrainage (EVD) in the case of the management of CSF diversion more than
two weeks presumably. The aim of this study is to investigate the initialmanagement for hydrocephalus in pediatric /AYA patients with brain tumor,
especially about long-term EVD. MATERIALS AND METHODS: The patients less than 30 years of age diagnosed with brain tumor between 2005
and 2019 were retrospectively analyzed. Procedures of long-term EVD
were similar to that of ventriculoperitoneal shunt (VPS) operation. Usingflow-control VPS system, peritoneal catheter passed out of the body at theanterior chest, and distal end of the catheter was connected to standard
EVD system. RESULTS: In total of 345 patients with brain tumor, 109
had hydrocephalus at presentation. Among them, 25 patients (23%) underwent long-term EVD. The main reasons for selecting long-term EVD wereto avoid intraperitoneal dissemination (n=13), and to maintain longer
period of CSF diversion for the treatment of tumor (n=12). The median oflong-term EVD was 38 days (range: 12 – 222 days). Although one case suffered from drainage tube occlusion at 59 days, there were no other complications such as infection or accidental evulsion. Eventually, 3 cases required
permanent VPS for persistent hydrocephalus. CONCLUSION: Long-term
EVD is safe and effective option for CSF diversion. This procedure should
be taken into consideration if patients have a risk of dissemination and may
elude permanent VPS.
SURG-03. IMMERSIVE VIRTUAL REALITY APPLICATIONS IN
NEUROSURGICAL ONCOLOGY
Andrea Carai1, Angela Mastronuzzi1, Giovanna Stefania Colafati1,
Paul Voicu1, Nicola Onorini1, Alessia Carboni1, Giada Del Baldo1,
Aalap Jamadagni Herur-Raman2, Alessandro De Benedictis1, andCarlo Efisio Marras1; 1Bambino Gesù Children’s Hospital, Rome, Italy,
2Surgical Theatre Inc., Cleveland, OH, USA
Tridimensional (3D) rendering of volumetric neuroimaging is increasingly
been used to assist surgical management of brain tumors. New technologies allowing immersive virtual reality (VR) visualization of obtained models
offer the opportunity to appreciate neuroanatomical details and spatial relationship between the tumor and normal neuroanatomical structures to alevel never seen before. We present our preliminary experience with the Surgical Theatre, a commercially available 3D VR system, in 60 consecutive
neurosurgical oncology cases. 3D models were developed from volumetric
CT scans and MR standard and advanced sequences. The system allows theloading of 6 different layers at the same time, with the possibility to modulate opacity and threshold in real time. Use of the 3D VR was used during
preoperative planning allowing a better definition of surgical strategy.
A tailored craniotomy and brain dissection can be simulated in advanced
and precisely performed in the OR, connecting the system to intraoperative
neuronavigation. Smaller blood vessels are generally not included in the 3D
rendering, however, real-time intraoperative threshold modulation of the
3D model assisted in their identification improving surgical confidence andsafety during the procedure. VR was also used offline, both before and after
surgery, in the setting of case discussion within the neurosurgical team andduring MDT discussion. Finally, 3D VR was used during informed consent,
improving communication with families and young patients. 3D VR allows
to tailor surgical strategies to the single patient, contributing to procedural
safety and efficacy and to the global improvement of neurosurgical oncology
care.
SURG-04. THE APPLICATION OF EN BLOC RESECTION IN THE
OPERATION OF PEDIATRIC POSTERIOR FOSSA TUMOR
Ma Jie, Weiwei Mao, Shuaiwei Tian, Baocheng Wang, and Yang Zhao;
Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to
Shanghai Jiaotong University School of Medicine, Shanghai, China
OBJECTIVE: To explore the efficacy and safety of en bloc resection
therapy on posterior fossa tumor in children. METHODS: A retrospective
analysis was conducted on the clinical data of 94 patients with posterior
fossa tumor admitted to Department of Pediatric Neurosurgery, Xinhua
Hospital Affiliated to Shanghai Jiaotong University School Of Medicine fromJanuary 2018 to December 2019. Among them, 35 cases were treated withtraditional resection (control group) and 59 cases with en bloc resection (observation group). We counted the amount of blood loss and the time during
tumor resection, We compare the symptoms and signs between the twogroups and determine a extent of tumor resection based on microscopic observation and preoperative and postoperative imaging comparison. RESULT:The total tumor resection rate of the observation group (88.1%, 52 / 59)
was significantly higher than that of the control group (62.85%, 22 / 35,
P < 0.05). The average bleeding volume of 90.8ml in the observation groupwas significantly smaller than that of the control group (113.3ml, P < 0.05),
and the average operation time of 38.6min in the observation group was
shorter than that of the control group (57.4min, P < 0.05) only for tumor
resection procedure. CONCLUSION: En bloc resection technique can effectively accelerate the resection time, reduce intraoperative bleeding andimprove the total resection rate of tumors in children’s posterior cranial
fossa.
SURG-05. AN AWAKE SURGERY FOR A CHILD SUFFERING FROMEPILEPSY DUE TO DYSEMBRYPLASTIC NEUROEPITHELIALTUMOR LOCATED IN THE LEFT PARIETAL LOBE
Juri Kiyokawa1, Shinji Yamamoto1, Yasuhiro Murota1, Mariko Ishikawa1,
Hiroto Yamaoka1, Satoshi Kaneko1, Masataka Yoshimura1, Shin Hirota1,

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Motoki Inaji2, and Taketoshi Maehara2; 1Tsuchiura Kyodo General
Hospital, Tsuchiura, Ibaraki, Japan, 2Tokyo Medical and Dental University,
Bunkyo-ku, Tokyo, JapanBACKGROUND: An awake surgery is a useful measure to remove tumors
located close to eloquent areas of the brain to reduce surgical complications
and maximize the resection. However, it has some disadvantages comparedto surgeries under general anesthesia. Generally speaking, applying it to achild under 15 years-old (y/o) is hesitating because of anxiety, poor tolerance, failure to cooperate in tasks and so forth. Here, we present a caseof a 13y/o girl who underwent an awake surgery due to dysembryplastic
neuroepithelial tumor (DNT) located in the left parietal lobe. CASE PRESENTATION: She consulted our hospital for epileptic seizures. MRI showeda multilocular mass lesion in the left parietal lobe. The tumor was locatedin or close to eloquent areas. The epilepsy was refractory even with multiple antiepileptic drugs (AEDs). A Wada examination revealed that her
speech area is on the left hemisphere. The operations were performed in twostages. Prior to the operations, we had several thought-out simulations in
the operating room and ICU with her, her parents, and our staff including
nurses and lab technicians. The first operation was to perform tumor biopsy
and place intracranial electrodes. The histological diagnosis was DNT. Video
electroencephalogram showed that the epileptogenic lesion was around thetumor. The second operation resulted in total tumor resection and reductionof paroxysmal epileptic spikes without major complications. She is seizure
free for more than three years with two AEDs. CONCLUSION: Careful
preparations may enable an awake surgery even for a child under 15y/o.
SURG-06. AWAKE CRANIOTOMY FOR BRAIN TUMOR IN
PEDIATRIC PATIENTSCarlos Almeida Jr, Alessandra Levy Antoniazzi, Bruna Minniti Mançano,Marcus Matsushita, Rachel Eggers Bacci, Danielli Basso, andLucas Dias Lourenço; Barretos´s Children and Young Adults Cancer
Hospital, Barretos, Sao Paulo, Brazil
BACKGROUND: The challenge of surgery in neurooncology is to achieve
the maximum extent of resection while preserving eloquent functions. Intraoperative cortical mapping during resection of a brain tumor allows direct
stimulation in eloquent areas with a reduction in postoperative deficits. This
procedure has been performed in adults and children down to the age of
11 years. There are only two cases reported on the literature of an 8-year-old
and 9-year-old child submitted to an awake craniotomy for brain tumor resection. Pediatric patients are prone to more risks than adults because they
become easily agitated after pain sensation. Extensive preparation for the procedure is essential for pediatric patients in order to avoid a lack of cooperation. CASE PRESENTATION: Two patients, with 9-year-old presented withseizures due to a tumor in the left temporoparietal region. In order to identify
language and motor–controlling areas during resection, we proposed an awake
craniotomy. Because of their ages, they were prepared by a multidisciplinary
team. The children’s cooperation during the mapping procedure and tumor
resection were exceptional. Postoperative cranial MRI confirmed partial resection of the lesion, whose remnant was located in the left motor area. No
seizures occurred during the postoperative period, and both were discharged
without a neurological disability on the fifth day after the surgery. Histology
revealed a dysembryoplastic neuroepithelial tumor (WHO grade I). CONCLUSION: Brain mapping during resection of a tumor in an awake pediatric patient is feasible and can be safely performed even in patients under 11-year-old.
SURG-07. CEREBELLAR PEDUNCLE TUMORS IN PEDIATRICNEUROSURGERY: FEW CITATIONS FOR BEING RARE OR FORLACK OF AWARENESS
Felipe Hada Sanders, and Hamilton Matushita; USP, Sao Paulo, SP, Brazil
We present a case-series of 6 pediatric patients, with a follow-up for aminimum of 1 year, with a diagnostic, therapeutic and prognostic description. This type of disease was first mentioned by Professor Tomita in 1986,
in a case-series with 4 patients, with few citations in literature, no other caseseries cited at the literatures. and in our oncology center of excellence it isan entity that draws attention for diverging from intrinsic tumors of thecerebellum, fourth ventricle and trunk. In this way, we created an algorithm
approaching these patients and would like to present this associated to honouring the esteemed professor in neurosurgery.
SURG-08. SUPRASELLAR DERMOID CYST IN A PEDIATRICPATIENT
Carlos Almeida Jr, Bruna Minniti Mançano, Gisele Caravina Almeida,
Gilda D’Agostino Eugui, and Carlos Bezerra Cavalcante; Barretos´sChildren and Young Adults Cancer Hospital, Barretos, Sao Paulo, Brazil
BACKGROUND: Intracranial dermoid cysts (DC) are rare congenital
non-neoplastic lesions that account for 0.04 – 0.6% of all intracranial tu-

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De c e mb e r 2 0 2 0mors. They are formed by a fibrous capsule composed of epidermal anddermal derivatives (hair follicles, sebaceous and sweat glands), enclosing aviscous fluid. Intradural DC often arise in the midline and are more common
in infratentorial locations. CASE REPORT: A 14-year-old male patientpresented with headache, partial motor seizures and behavioral changes.
Neurological examination and endocrine workup revealed no abnormalities. Brain magnetic resonance imaging showed a lesion that was 4.4cm x
2.2cm x 4.4cm in size, located at supraselar region, and extended superiorly
to the left lateral ventricle and anterolaterally to the left orbitofrontal lobe,
associated with hyperintense fat droplets in the right lateral ventricle. We
performed a left transventricular microsurgical approach. The tumor capsule was coagulated and opened and a subtotal resection with peacemeal
removal of the the lesion was obtained: it had gelatinous consistency, composed of droplets of fat and hair and keratinized scamous epihelium content.
A total removal of the DC capsule was not possible due to its firm adherence
to optic chiasm and to hypothalamus. Histological examination revealed
dermoid cyst. CONCLUSION: Surgery is the only effective treatment, andits goal should be the radical resection of the lesion to avoid recurrence.
Whenever radical resection is not possible, because of the adhesions of thecyst capsule to surrounding tissues, a subtotal resection with piecemeal removal may be a satisfactory option in such cases to avoid high morbidity.
SURG-09. REACTIVATION OF HERPES SIMPLEX VIRUS AFTERNEUROLOGIC SURGERY
Carlos Almeida Jr, Bruna Minniti Mançano, Seila Israel Prado,
Gisele Caravina Almeida, Fernanda Magalhães Souza, andLucas Dias Lourenço; Barretos´s Children and Young Adults Cancer
Hospital, Barretos, Sao Paulo, Brazil
BACKGROUND: Herpes simplex virus encephalitis (HSVE) is a rarecomplication after neurosurgery, and its clinical picture mimics features ofother most frequent infectious complications of bacterial origin. Probable
triggering factors are manipulation and surgical stress, since most cases
occur due to reactivation rather than primary infection. The main symptoms include fever and altered consciousness. DNA identification of HSV
by PCR has accuracy. Even with adequate treatment, HSVE is associatedwith a mortality of 30%, and potential neurologic sequelae such as cognitiveand motor. CASE REPORT: An 18-year-old male patient presented with lossof vision due to cystic craniopharyngioma. We inserted an Omaya catheterand drained the cyst. On the third day, he presented with fever, seizures,and decreased consciousness. Magnetic resonance imaging (MRI) showed
high signal intensity on T2-weighted and FLAIR images in the left frontal
and temporal lobe, cingulate gyrus, and corpus callosum, with mass effect.
He was submitted to decompressive craniectomy and empirical antibiotic
therapy. CSF and blood cultures were negative. Due to inexpressive clinical improvement after 48 hours, CSF was collected for polymerase chain
reaction (PCR), and we performed a brain biopsy and started intravenous
acyclovir. Histology and PCR confirmed HSVE type 1 and 2. He received
antiviral for two weeks and was discharged after CSF PCR negative. CONCLUSION: Clinical suspicion, CSF PCR, and imaging are of paramountimportance for early diagnosis of HSVE, which should be considered in the
differential diagnosis of recent postoperative neurologic surgery in cases of
unexplained postoperative fever with altered consciousness.
SURG-10. SPECTROSCOPIC MEASUREMENT OF 5-ALA-INDUCEDINTRACELLULAR PROTOPORPHYRIN IX IN PEDIATRIC BRAIN
TUMORS
Michael Schwake1, Sadahiro Kaneko2,1, Eric Suero Morina1, andWalter Stummer1; 1Department of Neurosurgery, University Hospital
Münster, Münster, Germany, 2Department of Neurosurgery National
Hospital Organization Hokkaido Medical Center, Sapporo, Hokkaido,
Japan
OBJECTIVE: 5-ALA guided resection of glioma in adults enables betterdelineation between tumor and normal brain, allowing improved resection and improved patients’ outcome. Recently, several reports were published regarding 5-ALA for resection of pediatric brain tumors. The aimof the study was to determine the intracellular fluorescence of PPIX in
pediatric brain tumors by hyperspectral imaging and to compare it withvisually observed intraoperative fluorescence. METHODS: 5-ALA was administered orally four hours prior to surgery. During tumor resection thesurgeon assessed the fluorescence signal to be strong, weak or absent. Subsequently, fluorescence intensity of samples was measured via spectroscopy.
In addition, clinical data, imaging and laboratory data were analyzed. RESULTS: Eleven children (1–16 years) were operated. Tumor entities included:
three medulloblastomas, two pilocytic astrocytomas (PA), two anaplastic
ependymomas and one diffuse astrocytoma, anaplastic astrocytoma,
pilomyxoid astrocytoma and anaplastic pleomorphic xanthoastrocytoma.
Strong fluorescence was visible in all anaplastic tumors and one PA; one
PA demonstrated weak fluorescence. Visible fluorescence was strongly
associated with intracellular fluorescence intensity and PPIX concen-

Abstracts

tration (P<0.05). Within all tumors with visible fluorescence the intracellular PPIX concentration was greater than 4 µg/ml. Except for moderate
and transient elevation of liver enzymes, no 5-ALA related adverse eventswere reported. CONCLUSION: We demonstrate a strong association between intraoperative observations and spectrometric measurements of PPIX
fluorescence in tumor tissue. As in former studies, fluorescence signal was
more commonly observed in malignant glial tumors. Further prospective
controlled trials should be conducted to investigate the feasibility of 5-ALA
guided resection of pediatric brain tumors.
SURG-12. PAEDIATRIC BRAIN TUMOUR SURGERY: HOW CANWE REPORT OUR SURGICAL OUTCOMES AND OPERATIVE
MORBIDITY?
Mitchell Foster1, Dawn Hennigan1, Rebecca Greystone1,
Kirsten van Baarsen1, Geraint Sunderland1, Christopher Millward1,
Harishchandra Srinivasan1, Deborah Ferguson1, Teddy Totimeh2,
Barry Pizer1, and Conor Mallucci1; 1Alder Hey Children’s Hospital,
Liverpool, Merseyside, United Kingdom, 2Korle Bu Teaching Hospital,
Korle Bu, Ghana
OBJECTIVE: Our objective was to quantify resection outcomes and operative morbidity in paediatric brain tumour surgery using existing scales,
assessing their applicability. METHODS: We investigated morbidity using
the Clavien-Dindo (CD) scale and the Drake classification. All paediatric patients receiving a biopsy or craniotomy for an intracranial tumour in a single
tertiary paediatric neurosurgery centre between January 2008 and December
2018 were studied. Complications up to day 30 post op were graded. RESULTS: There were 459 operations: 92 biopsies and 367 craniotomies comprising 166 infratentorial and 292 supratentorial tumours. Median age was
9 years (56% male). The surgical goal was achieved or exceeded in 94% ofcases. Thirty-day mortality was 1.31% with all deaths related to disease andnone to surgical complications. The overall CD score was 1 in 10.9% ofcases, 2 in 18.9%, 3A in 1.7%, 3B in 11.8%, and 4 in 1.1%. There was nooperative morbidity in 54% of cases. Using the Drake classification, meningitis was seen in 3.92% of cases, seizures in 3.92%, neurological deficit(that persisted at 30 days) in 8.5%, CSF leak in 5.01%, wound infection
in 1.96%, haemorrhage 1.75 %, shunt infection in 1.53%, shunt block in
0.65%, medical complications in 2.4%, and others in 3.05%. CONCLUSIONS: This is the largest series presenting morbidity from paediatric brain
tumour surgery, and the first to validate the CD scale. Our morbidity on the
Drake scale was comparable with other series. There is a need to develop
improved tools to quantify morbidity in this high-risk specialty.
SURG-14. ENDOSCOPIC SURGERY FOR PEDIATRICINTRAVENTRICULAR TUMOR WITHOUT HYDROCEPHALUS:
INDICATION, SURGICAL TECHNIQUE, AVOIDANCE OFCOMPLICATION, AND ITS PROSPECT
Shunsaku Takayanagi, Hirokazu Takami, Shota Tanaka, Masahiro Shin,and Nobuhito Saito; The University of Tokyo Hospital, Tokyo, JapanINTRODUCTION: Neuroendoscopic surgery is useful for intraventriculartumors accompanied by ventriculomegaly. However, it is often challenging
for cases with small ventricles. Our institution is actively performing surgeries
for pediatric intraventricular tumors without frank ventriculomegaly. METH
ODS: Seven cases of intraventricular tumors without ventriculomegaly (5cases of subependymal giant cell astrocytoma (SEGA) and 2 cases of germ
cell tumors (GCTs)) were analyzed. The age ranged between 3 and 14 years(median 5 years). The sizes of SEGA were between 10-27mm, and all the tumors showed an enlargement around the foramen of Monro, which was theindication for surgery. Biopsy and third ventriculostomy were performed for
GCTs. For resection, after making a small craniotomy of 2 x 3 cm, ellipsecone-like sheath with a diameter of 12mm or 17mm was inserted throughit to the lateral ventricle, which enabled a wide surgical view. Under a rigid
endoscope of 4mm diameter, 2 types of surgical instruments were employed,
making the microsurgical procedure like under a microscope, with a wider
view, possible. For the cases of tumor resection, septostomy and placement ofa drain in the ventricle were performed at the end of surgery. RESULTS: Thelesions were safely approached in all the cases. For resection, endoscopic
microsurgery was possible, and tumor was totally removed in all the cases.
No postoperative complication was observed in any of them. CONCLUSIONS: Our experience shows that tumor resection can be safely achieved
with the aid of endoscope even for cases without ventriculomegaly.
SURG-15. THE SURGERY OF THALAMIC LESIONS IN PEDIATRICBRAIN TUMORS
Yuzaburo Shimizu, Osamu Akiyama, and Akihide Kondo; Juntendo
University, Tokyo, JapanBACKGROUND: Pediatric brain tumors are occurred in the center ofcentral nervous system. Since mid-line glioma has defined in the new clas-

sification, thalamus has attracted attention as a site that requires surgicalintervention. However, the surgery for thalamus is a challenging procedure
for neurosurgeons. In this study, we studied our surgical cases of patients
suffering from pediatric brain tumors in thalamus and/or thalamic regions toevaluate the safety of surgeries and the consideration of appropriate surgicalapproaches. METHODS: We reviewed neuroradiological images, medical
record, and, surgical videos for the assessment of surgical fields in patients
under the age of 15 who had surgical treatments at our institution. RESULTS: We had six cases that could be analyzed. The lesions in the posterior parts of the thalamus had been operated by the occipital transtentorial
approach. The lesions in the superior parts of thalamus were treated withtranscortical transventricle approach. It was possible to achieve sufficient
removal of tumors and have good surgical view. The monitoring of motor
function and visual function was used in all cases. After removal, we could
have a nice view of the important structures around thalamus. CONCLUSIONS: The surgeries for thalamus and thalamic regions were safety withenough considerations for neurological examinations and radiological imaging. The intra operative monitoring for motor and visual function should
be used.
SURG-16. SURGICAL TECHNIQUES TO AVOID COMPLICATIONSDURING REPEAT RESECTIONS FOR PEDIATRIC BRAIN TUMORS
Ichiyo Shibahara; Kitasato University, Sagamihara, Kanagawa, Japan
Complications due to repeat resection for recurrent pediatric brain tumors remain unclear. The present study focused on surgical techniques toavoid surgical morbidities during repeat resections for pediatric brain tumors. This study included 57 consecutive repeat resections for 28 pediatric patients under the age of 15 with recurrent brain tumors. Resections
were performed 2–14 times for each patient by the senior author (TK).
Reviewed factors were wound-related complications, bleeding/ischemic
complications, and Eastern Cooperative Oncology Group performancestatus (PS) before and after surgery. No patients presented any complications to decrease PS, postoperatively. No wound-related complications
were worthy of special mention. Surgical techniques to prevent woundrelated complications are as follows: 1) shaving the hair around the previous skin incision just before the surgery; 2) washing and disinfecting
around the skin incision using chlorhexidine soap and an alcohol swab,
followed by Povidone-Iodine solution; 3) after craniotomy, removing
all granulation tissues, residual titanium plates, and screws; 4) brushingall surgical fields and a bone flap before opening the dura mater using
Povidone-Iodine solution followed by normal saline; 5) maintaining abone flap in normal saline with antibiotics; 6) changing all the surgicalinstrument and gloves; 8) closing the dura mater completely to prevent
CSF leakage, and 8) using postoperative antibiotics for six days. Meticulous dissecting postsurgical adhesion of brain and dura mater, arteries andnerves; usage of neuronavigation system and neuromonitoring to understand the anatomy radiologically and functionally; applying papaverinehydrochloride for spastic arteries, are important to avoid complications
during the intracranial procedure.
SURG-17. CLINICAL CHARACTERISTICS AND OUTCOMES OF
EPILEPSY-RELATED BRAIN TUMOR IN CHILDREN
Kenichi Usami1, Keita Terashima2, Yuichi Abe3, Chikako Kiyotani2,and Hideki Ogiwara4; 1Division of Neurosurgery, National Center forChild Health and Development, Tokyo, Japan, 2Division of NeuroOncology, National Center for Child Health and Development, Tokyo,
Japan, 3Division of Neurology, National Center for Child Health andDevelopment, Tokyo, Japan, 4Division of Neurosurgery National Centerfor Child Health and Development, Tokyo, JapanOBJECTIVE: Epilepsy is one of the earliest symptoms in pediatric brain
tumor. Gross total resection (GTR) of the tumor does not necessarily achieve
seizure free, therefore it is controversial whether surrounding epileptic focishould be resected at the initial surgery. The aims of this study are to report clinical characteristics and outcome of pediatric epilepsy-related brain
tumor (ERBT) and to discuss treatment strategy. METHODS: Subjects
were children less than 18 years old who underwent surgery for ERBT.
Patients in whom epilepsy had been controlled before surgery were excluded. Data were collected from medical record and retrospectively
reviewed. RESULTS: Twenty-one children (8 boys and 13 girls) were analyzed in this study. The mean age at surgery was 6.8 years. Tumor was
astrocytic tumor in 10, gangliogioma in 4 and dysembryoplastic neuroepithelial tumor in 3. Intracranial subdural electrodes were placed prior totumor resection in 5 cases. GTR was achieved in 14 (67%). Seizure free wasachieved in 15 (71.4%). GTR was significantly associated with seizure free(p=0.002). CONCLUSION: In most of ERBT, seizure free can be achievedby lesionectomy alone. However, the resection of surrounding epileptic fociis required in some cases. Detailed examinations to detect the epileptic focishould be performed in ERBT, particularly in case of drug-resistant intractable epilepsy.

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SURG-19. COMPLETE RESOLUTION OF ADHD AFTER GROSSTOTAL RESECTION OF DYSEMBRYIOPLASTIC NEUROEPITHELIALTUMORLuis Angel Arredondo Navarro1,2,
Regina Malinali Navarro Martín del Campo1,2,
Lorelay Livier Gutiérrez Oliva1, Juan Luis Soto Mancilla1,
Maria De Lourdes De La Mora Carnalla1, Daniel Perez-Rulfo Ibarra1, andFernando Sánchez Zubieta1; 1Hospital Civil de Guadalajara, Guadalajara,
Jalisco, Mexico, 2GAP-NO, International, Mexico
A 3-year-old boy with a history of attention-deficit/hyperactivity disorder(ADHD) presented a single focal tonic seizure. A thorough physical examination revealed no neurological deficit. A contrast enhanced MRI showed
an isointense lesion in the anterior part of the cingulate gyrus extending
through the left frontal lobe. After initial evaluation, the parents refused surgical treatment and a close follow up was then considered. At the age of five,the ADHD become more evident and the patient was started on methylphenidate. Poor clinical response was seen with the initiation of stimulant. The
boy presented a second generalized seizure and the parents agreed surgicalmanagement. An interhemispheric approach was then performed and a grosstotal resection was achieved. The histopathological diagnosis corresponded toa dysembryoplastic neuroepithelial tumor (DNET). Four years after the resection, the patient is seizure free and the ADHD has also resolved without theneed of medication. The disappearance of seizures is common after surgical resection of DNET tumors, but this case establishes an association with ADHD.
SURG-20. DIENCEPHALIC SYNDROME IN PEDIATRICNEUROSURGERY
Felipe Hada Sanders, Hamilton Matushita, Alessandra Azambuja, andFernando Frasseto; USP, Sao Paulo, SP, Brazil
This report details the histories of twelve patients with clinical diencephalic syndrome who collectively demonstrate the variability found in the
syndrome with respect to: (1) clinical course, (2) site of the tumor, and (3)ease of obtaining radiologic confirmation of the presence of a tumor. Timely
diagnosis of diencephalic syndrome is not often the case for patients presenting with failure to thrive (FTT) because of its rarity and lack of specificsymptoms. These cases illustrate the importance of cranial imaging and consideration of diencephalic syndrome for children presenting with FTT despite normal or increased caloric intake.
SURG-21. ENDO- AND EXOSCOPIC SURGERY FOR PEDIATRICNEUROSURGICAL OPERATION
Kazuhiko Kurozumi, Masahiro Kameda, Kentarou Fujii, Yosuke Shimazu,
Takao Yasuhara, and Isao Date; Department of Neurological Surgery,Okayama University Graduate School of Medicine, Dentistry, andPharmaceutical Sciences, Okayama, JapanINTRODUCTION: Recently endo- and exoscopic surgeries have been gradually performed in neurosurgery. To improve the accuracy and safety of ourendoscopic procedures, we are currently trialing 4K or 8K systems. Here we report our experience of endo- and exoscopic procedures for pediatric neurosurgery. METHODS: We retrospectively identified 22 patients (15 males, 7 females;mean age, 9.2 years) who underwent surgery for sellar lesions and intraventricular
or intraparenchymal lesions with an endo- or exoscopic procedure at our institute between 2010 and 2020. We used a full HD endoscope system (Storz) andan organic electroluminescence (EL) monitor (Sony), and a 4K system (Sony andOlympus). VITOM 3D (Storz) was used as the exoscope. Videoscope (Olympus)
was used as a flexible scope for intraventricular tumors. RESULTS: We performed surgical procedures as 11 biopsies, 6 third ventriculostomies, 5 resections,and 3 fenestrations. The full HD system with organic EL monitor presented highcolor contrast. We could easily distinguish between tumor microstructure and thenormal structure with the 4K system comparing to full HD. Moreover, electronic
zoom function enabled us to discriminate tumor boundaries without having tomove the endoscope closer. As a result, we could delineate the surgical working
space. VITOM 3D was simple to sharpen the focus on the wider surgical field,
similar to the application of an operating microscope. CONCLUSION: In pediatric neurosurgery, an endo- or exoscope enables clear visual recognition of aboundary between tumor and normal area.
SURG-22. CERVICAL SPINE ANEURYSMAL BONE CYST OF
A PEDIATRIC PATIENTCarlos Almeida Jr1, Luis Marcelo Ventura1, Stephanie Previdelli2,
Marina Lopes Lamim2, Bruna Minniti Mançano1,
Carlos Bezerra Cavalcante1, and Lucas Dias Lourenço1; 1Barretos´sChildren and Young Adults Cancer Hospital, Barretos, Sao Paulo, Brazil,
2School of Health Sciences, Barretos, Sao Paulo, Brazil
BACKGROUND: Aneurysmal bone cysts (ABCs) are benign, expanding
lesions that represent 15% of all primary spine tumors, and only 2% haveiii464

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been found at the cervical level. There are different therapeutic options; themost successful is complete surgical resection. Although not always possible,
due to high blood loss that occurs during the procedure, a combination ofsurgery with other treatment modalities was used in 40% of the cases reported so far. We describe a pediatric patient that we managed with embolization plus surgery. CASE REPORT: A 5-year-old girl presented withpainful torticollis associated with a left posterior cervical mass, without
neurological impairment. Magnetic resonance imaging of the cervical spine
showed a multiseptated bony lesion with multiple fluid levels, involving theposterior elements of C2, associated with diffuse soft tissue enhancement of
the left paravertebral muscles. We proposed a multi-staged treatment withpre-operative arterial embolization followed by the posterior surgical approach. Super selective embolization of the left ascending cervical artery
was performed. The right ascending cervical artery also contributed to thetumor blush, but due to its connection to the right vertebral artery and,
therefore, associated with a high risk of neurological injury, we prefer not
to embolize it. Two days later, we performed a posterior surgical approach,with a gross total resection of the tumor. Histological examination revealed
an ABC. CONCLUSION: An aneurysmal bone cyst is a rare cervical spine
lesion that demands a multidisciplinary approach due to its locally aggressive behavior and the excessive blood loss related to surgery.
SURG-24. NOVEL MALLEABLE FORCIPES FOR ENDOSCOPICASSISTED TECHNIQUE IN PEDIATRIC BRAIN TUMORS
Yukiko Nakahara, Hiroshi Ito, Fumitaka Yoshioka, Kohei Inoue,
Atsushi Ogata, Jun Masuoka, and Tatsuya Abe; Department of
Neurosurgery, Faculty of Medicine, Saga University, Saga, Japan
Recent advances in optical devices and surgical instruments have been
applied to neurosurgery. Even with modifications, one of the most serious risks is injury of neuronal and vascular structure caused by operationof surgical instruments in a narrow surgical field. Fixed instruments are
not practical for pediatric brain tumor surgeries because the length of thecurved or angled tip portion is limited because of the narrow entrance.
We developed a novel malleable forceps to resolve the difficulties related
to microsurgical procedures. The malleable forceps has two shafts with asharp cup at the tip. The entire forceps was made of stainless steel, with asilver and nickel alloy inserted between 10 and 40 mm from the tip. In thealloy part, the surgeon can flex the forceps freely using a special cylinder.
The special cylinder is useful to prevent from slipping of the cups of tip.
The maximum angle that can be bent is 70 degrees vertically. We also developed a monoshaft malleable forceps. We used these flexible forcipes in
the case of various pediatric brain tumors including craniopharyngioma.
We performed tumor resection by anterior interhemispheric trans-lamina
terminalis approach. After procedure of tumor resection using microscope,endoscope inserted around the pituitary stalk. The piece of calcified tumor
could be easily removed without any complications. These forcipes can be
deformed to an appropriate angle and can be applied to various cases, especially pediatric brain tumors.
SURG-29. A SINGLE CENTRE EXPERIENCE OF USING INTRAOPERATIVE MRI IN MANAGING PEDIATRIC CRANIAL NEUROONCOLOGY CASES
Dharmendra Ganesan1,2, Nor Faizal Ahmad Bahuri1,2,
Revathi Rajagopal1,2, Jasmine Loh PY1,2, Kein Seong Mun1,2, andRaja Rizal Azman Raja Aman1,2; 1University of Malaya Medical Centre,
Kuala Lumpur, Malaysia, 2GAPNO, International Group, Malaysia
The University of Malaya Medical Centre, Kuala Lumpur had acquired a intraoperative MRI (iMRI) brain suite via a public private
initiative in September 2015. The MRI brain suite has a SIEMENS
1.5T system with NORAS coil system and NORAS head clamps in a
two room solution. We would like to retrospectively review the cranial
paediatric neuro-oncology cases that had surgery in this facility from
September 2015 till December 2019. We would like to discuss our experience with regard to the clear benefits and the challenges in using
such technology to aid in the surgery. The challenges include the physical setting up the paediatric case preoperatively, the preparation andperforming the intraoperative scan, the interpretation of intraoperative
images and making a decision and the utilisation of the new MRI data
set to assist in the navigation to locate the residue safely. Also discuss the utility of the intraoperative images in the decision of subsequent adjuvant management. The use of iMRI also has other technicalchallenges such as ensuring the perimeter around the patient is free offerromagnetic material, the process of transfer of the patient to thescanner and as a consequence increased duration of the surgery. CONCLUSION: Many elements in the use of iMRI has a learning curve and it
improves with exposure and experience. In some areas only a high level ofvigilance and SOP (Standard operating procedure) is required to minimize
mishaps. Currently, the iMRI gives the best means of determining extent
of resection before concluding the surgery.

Abstracts

SOCIAL WORK/PATIENT SUPPORT/PALLIATIVECARE
SWK-02. WEAVING COMFORT AND SUPPORT FOR CHILDRENWITH BRAIN TUMORS AND THEIR FAMILIES IN AN OUTPATIENT
CLINICRia Hawks1, Jane Bloom1, Maurine Packard1, Sonia Lugo2,
Nadine Ulysses2, and Stergios Zacharoulis3; 1Saori Arts NYC, NY, NY,
USA, 2New York Presbyterian, NY, NY, USA, 3Columbia University
Medical Center, NY, NY, USA
Parents of children diagnosed with brain tumors report high levels of stressat diagnosis and feelings of “being lost” on transition to outpatient follow-up
care (Jackson AC, et al, 2007). Ssori is a Japanese form of free-style weavingthat encourages people facing life-limiting challenges to discover innerstrengths. We report our experience with Saori weaving with brain tumor patients and their families in a pediatric oncology outpatient clinic at a major
university medical center. During 2019, we offered weaving sessions twice aweek. We had a total of 151 encounters with hematology/oncology patients(age 5–18 years), siblings, or parents. Among these patients there were 20
with primary brain tumor diagnoses. Weaving was offered in the art therapy
area of the clinic. After creating a fabric, the weavers had the opportunity tohave their work sewn into functional objects, such as pillows, bags, purses, or
healing pouches filled with beans that can be heated or cooled for comfort.
Brain tumor patients readily engaged in weaving, despite various degrees ofneurologic disability including hemiparesis or low vision. In the words of an 8
y/o weaver. “This is so cool. Daddy, can we always come when the weavers are
here, so I can weave?” And from a mother: “This is great. She’s focused andbusy!” Case studies, including a presentation of Legacy work, will be reported.
In conclusion, Saori weaving can be an impactful intervention for childhood
brain tumor patients and their families in an outpatient clinic setting.
SWK-03. CAREGIVER EXPERIENCES FOR PEDIATRIC BRAIN
TUMOR PATIENTS AND THEIR FAMILIES AT A DEDICATEDMEDICAL SPECIALTY CAMP
Ryan Brownfield1, Barb Galantowicz1, Claire Russell2, Jennifer Chabot3,
and Scott Coven4,5 1Flying Horse Farms, Mt, Gilead, OH, USA,
2Nationwide Children’s Hospital, Columbus, OH, USA, 3Ohio University,
Athens, OH, USA, 4Indiana University School of Medicine, Indianapolis,
IN, USA, 5Riley Hospital for Children, Indianapolis, IN, USA
BACKGROUND: Medical specialty camps have provided children withunique psychosocial experiences; however, dedicated pediatric brain tumor
camps are rare in the United States, except in limited locations. This study
aimed to glean caregiver perceptions from a dedicated family brain tumor
camp, and to learn about the family experience with navigating a neurooncology diagnosis. DESIGN: Flying Horse Farms is a non-profit organization located in Mt. Gilead, Ohio and a member of the SeriousFun Children’s
Network, a global community of camps and programs serving children withserious illnesses and their families, at no cost. The institutional review board
at Ohio University approved this project at Flying Horse Farms in September
2017. Consent from caregivers was obtained prior to participation in the
study, which provided the opportunity to complete three separate phases:
a pre-camp survey, attend a semi-structured interview during the weekend,
and complete a post-camp survey. RESULTS: 11 families were present for
the weekend, and 10 families consented to participate in all three phases. For
6 families, this was their first experience at Flying Horse Farms. For 9 of the
10 families, the camp met their expectations. Additionally, 9 out of 10 families
reported they would be interested in attending a diagnosis specific camp again
in the future. CONCLUSIONS: This work demonstrates the feasibility of
conducting research at a medical specialty camp without restricting the camp
experience. Better understanding of the attendee’s attitudes toward camp may
enhance the experience and the neuro-oncology journey in the future.
SWK-04. A MOBILE AUGMENTED REALITY APP FOR SURGICALPREPARATION FOR CHILDREN WITH BRAIN TUMORS
Sharon Granville1, Jessica Spat-Lemus1, Blakely Rice1, Allison Pzena1,
Phil Stieg1, Jeffrey Greenfield1,2, and Mark Souweidane1,2; 1New
York-Presbyterian /Weill Cornell Medical Center, New York, NY, USA,
2Memorial Sloan Kettering Cancer Center, New York, NY, USA
BACKGROUND: Children with brain tumors experience significant anxiety secondary to diagnosis and interventions such as surgical management.
Preoperative anxiety is known to adversely affect operative outcomes andoverall quality of life. Programs that utilize “child-friendly” approaches
have been shown to ease anxiety, decrease analgesic requirements, shorten
hospital stay, and contribute toward better outcomes. Implementation ofthese programs is limited due to time, cost, and staffing constraints as well
as sociodemographic factors (i.e., language barriers). Therefore, an effective
and cost-efficient method could be advantageous. We sought to develop auniversally available APP that can assist with these goals and address thecurrent barriers. METHODS: In conjunction with a philanthropic resource(Brain Tumor Foundation, New York, NY, USA) a developer was tasked
with creating an App for children with brain tumors. The developer integrated published clinical research, multi-specialty input, and patient andfamily testimonials for possible integration into the tool. RESULTS: A mobile App was developed that is modifiable for patient-specific features (age,language, and ethnicity). Initial evaluations of the prototype by healthcare
providers, appropriately aged children, and their parents have demonstrated
positive engagement, appeal, and ease of use. CONCLUSIONS: The mobile
App provides a rapid, affordable, and modifiable platform for assisting children with brain tumors cope with their diagnosis and intervention options.
Validation with measurable outcomes is planned. The App is currently being
evaluated for purposes of psycho-social clinical research tool.
SWK-05. EDUCATIONAL APPROACH TO GRIEF MANAGEMENT
Veronica DeRosa, and Nina Madrid; CHOC Children’s Hospital, Orange,
CA, USA
Pediatric neuro-oncology has a high mortality rate compared to otherchildhood cancers. This project sought to bring Awareness to the Grief andTrauma that families undergo during treatment through end of life. It alsosought to create a pool of parent partners to support families receiving palliative care and to mend the healthcare relationship that is severed whena child passes away. The educational series included Grief Workshops for
Bereaved Parents using the ATTEND model, a mindfulness-based bereavement model and seminars with traumatic grief experts for providers. This
provided a better understanding on how healthcare workers are influential
in the “death story” of a child and how this can dictate the family’s lifelong grief journey. Grief workshops consisted of 2 English and 1 Spanish
speaking cohort each with 10–12 bereaved parents. The curriculum provided psychoeducation with the goal of creating a safe space to validate,clarify, and understand the events that happened in their child’s life; support
for the parent as they explore emotional awareness; relief of emotional tension; support as the parent expresses their perspective of their new world toothers that are in their life; and support as the parent finds meaning in theirchild’s life and untimely death. At the end of each group surveys showed thatparents found that the group provided a safe community, a place to say theirchild’s name, a place to share their story, and a need to advocate for futureoncology parents who undergo this journey.
SWK-06. ANSWERING 900 VOICES: A NATIONAL NONPROFITORGANIZATION RESPONDS TO A NATIONWIDE COMMUNITYHEALTH NEEDS ASSESSMENT THAT ELUCIDATED KEY
CHALLENGES FACED BY PEDIATRIC BRAIN TUMOR FAMILIES
Kathy Riley; Pediatric Brain Tumor Foundation, Asheville, NC, USA
The five-year relative survival rate for childhood primary brain and other central nervous system tumors is nearly 75 percent (Central Brain Tumor Registryof the United States, 2017). Nevertheless, childhood brain tumor survivors often
suffer from lifelong side effects caused by their illness or treatments such as surgery, radiation and chemotherapy. To define the nature and extent of problems
survivors and their families face, the Pediatric Brain Tumor Foundation (PBTF),
the world’s largest nonprofit solely dedicated to children and teens with brain
tumors, conducted a 2017 national community health needs assessment in collaboration with the Sol Price Center for Social Innovation at the University ofSouthern California. The assessment found that pediatric brain tumor patientsand their families face key challenges in four general areas: 1) interpersonal andemotional support, 2) logistical and financial support, 3) information and medical education gathering, and 4) educational and vocational anxieties. In 2020,
the PBTF’s response to the 900 assessment participants who represent the thousands living with the effects of this disease includes the launch of a national Peer
to Peer Mentoring program to meet the ongoing challenges families face; thedisbursement of emergency financial assistance to hundreds of families in thethroes of treatment; and the distribution of a resource notebook for newly diagnosed families and a comprehensive guidebook for survivors and their families.
The results of the needs assessment suggest additional clear, actionable areas
for impact not only by the PBTF but by medical professionals, other nonprofit
organizations and governmental agencies.
SWK-07. A MULTINATIONAL SURVEY OF PAEDIATRIC NEUROONCOLOGY SERVICES: A EUROPEAN RESEARCH NETWORK(ERN) PAEDCAN PROJECT
Katherine Cooper1, Barry Pizer1, Steven Lane2, and Stefan Rutkowski3;
1Alder Hey Childrens Hospital, Liverpool, United Kingdom, 2Universityof Liverpool, Liverpool, United Kingdom, 3University Medical Centre
Hamburg - Eppendorf, Hamburg, Germany
BACKGROUND: Brain tumours are clinically and biologically highly diverse and account for 25% of paediatric neoplasms. They carry the highest
mortality and morbidity of tumour groups. Their management presents

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significant challenges with performing modern diagnostic assessments, applying multimodal treatment and establishing interdisciplinary cooperation.
Outcomes across Europe differ significantly with varying 5year survival
reports of 42–79%. This SIOP-Europe PaedCan survey assessed the structures and facilities for individual states and highlight areas for cooperationand support. DESIGN: An online questionnaire was sent to SIOP-Europe
Brain Tumour Group members. This had 55 questions assessing pathology,
staging, surgery, radiotherapy and paediatric oncology infrastructure. For
analysis of the data we divided countries into lower and higher economic
status according to GDP (World Bank 2019) with a cut off of $30,100. RESULTS: There were 388 respondents from 44 countries in 181 different institutions. In the lower GDP group we noted decreased access to biologicalcharacterisation of tumours and interdisciplinary tumour boards. In thisgroup of nations, patients were less likely to have treatment by a paediatricspecialist neurosurgeon, paediatric neuro-oncologist, neuroradiologist, andpaediatric radiation oncologist. There was also less availability to perform
early MRI (ventilated) and less access to proton beam therapy. This study
supports the aim of the ERN to produce a roadmap document with specificstandards and publish guidelines for all relevant diagnostic and therapeutic
components of care. The ERN also aims to identify a network of institutions
to provide patient advice and training to equalise treatment and outcomesfor all children across Europe.
SWK-08. DELAYED DIAGNOSIS OF CENTRAL NERVOUS SYSTEM(CNS) TUMORS IN CHILDREN: PERSPECTIVE FROM THE
FRONTLINE
Manisha Jogendran1, Rebecca Ronsley1,2, Ran D. Goldman3, andSylvia Cheng1,2; 1University of British Columbia, Vancouver, BC,
Canada, 2Division of Hematology/Oncology/BMT, Department ofPediatrics, Vancouver, BC, Canada, 3The Pediatric Research in Emergency
Therapeutics (PRETx) Program, Department of Pediatrics, Vancouver, BC,
CanadaDelayed diagnosis of CNS tumors in children is well documented, partially due to challenges in recognizing rare diagnoses. Our objective was todescribe Canadian family physicians’ attitudes and confidence in diagnosing
and managing pediatric CNS tumors. A standardized questionnaire wasadministered at a Canadian national family physicians’ conference. Items
were based on observations from our institutional study of prediagnostic
symptomatic interval in pediatric CNS tumors. 449 surveys were completed. 302/443 (68%) physicians practice in cities. 153/447 (34%) reportencountering parents that inquire about their children having brain tumors.
261/449 (58%) have not managed a pediatric brain tumor. 153/447 (34%)
report they are not confident, 255/447 (57%) somewhat confident and39/447 (9%) confident in managing a suspected brain tumor in a stablechild. 259/447 (58%) would refer directly to a hospital/specialist. The reported median time for suspicion of a brain tumor was 8–14 days for children with vomiting and/or headache and 1 day for children with seizure and/or ataxia. 410/447 (97%) report not knowing any guidelines to help withmanagement. 235/447 (53%) suggested barriers they experience to include
52/235 (22%) wait times for imaging/specialists, 37/235 (16%) geographicallocation of the child, 27/235 (12%) knowledge, 25/235 (11%) access to imaging/specialist, and 15/235 (6%) patient-related factors or system barriers,and 8/235 (3%) specialist attitudes. 68/235 (29%) identified no barriers intheir practice. This study provides insight into family physicians’ perceived
challenges and barriers in diagnosing and managing new suspected pediatric
CNS tumors. Educational effort and overcoming systemic perceived barriers
may increase physicians’ confidence.
SWK-09. SELF-CARE OUTCOMES AND INTERVENTIONS FOR
CHILDREN WHO HAVE HAD A BRAIN TUMOUR: EVIDENCE AND
HYPOTHESES. WHAT SHOULD SELF-CARE INTERVENTIONS FOR
CHILDREN WITH PAST OR PRESENT BRAIN TUMOUR BE?
Elizabeth Rowen1,2, Niina Kolehmainen2, and Simon Bailey1,2; 1Newcastle
upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United
Kingdom, 2Newcastle University, Newcastle upon Tyne, United Kingdom
OBJECTIVE: To determine the evidence with regards to self-care outcomes and interventions for children who have been treated for a brain tumour and identify when best to intervene. METHODS: A scoping review ofthe literature with regards to self-care interventions, outcomes and mechanisms was undertaken. The information from these themes were populated
onto a logic model alongside the clinical expertise of the team. The logic
model was used to develop hypotheses to inform subsequent research; andidentified areas for further patient and public involvement. RESULTS: Of
27 papers found, 13 were deemed relevant. The literature suggested the diagnosis of a brain tumour can have a long-term negative impact on self-careoutcomes whilst evidence with regards to interventions to promote self-careis scarce. The child’s physical and cognitive functions were identified as hypothesised factors influencing self-care, while health related quality of lifeand participation in other life domains were secondary consequences of selfcare. The team expertise was further used to hypothesise that parent factors

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De c e mb e r 2 0 2 0(emotions, identity, actions), the child’s emotional functions and personal
factors as well as peer relationships and norms may influence children’s selfcare. These factors were not covered in the existing literature. CONCLUSIONS: Subsequent research will investigate the hypotheses developed tofurther specify factors that self-care interventions for children and young
people with a brain tumour should target. This will involve specifying when,
how and to whom interventions should be targeted.
SWK-10. TELEHEALTH IN OUTPATIENT PEDIATRIC NEUROONCOLOGY CARE
Shannon Raber1, Carly Hoffman1, Carol Yarbrough2, Linda Branagan2,
Neela Penumarthy3, Jami Manning1, Alyssa Reddy2, Anuradha Banerjee2,
Cassie Kline2, and Sabine Mueller2,4; 1University of California San
Francisco - Benioff Children’s Hospital, San Francisco, CA, USA,
2University of California San Francisco, San Francisco, CA, USA,
3University of Washington, Seattle, WA, USA, 4Zurich Children’s Hospital,
Zurich, Switzerland
BACKGROUND: Telehealth is an emerging modality that can include patient evaluation, review of test results, and clinical decision-making. Accessto care and quality of life are challenges for patients with pediatric brain
tumors and their families. Herein we describe the introduction of video visits
within our outpatient services led by nurse practitioners and nurse coordinators. METHODS: The pediatric neuro-oncology program at University ofCalifornia, San Francisco - Benioff Children’s Hospital (UCSF) established arobust telehealth practice to improve access to care for children and young
adults with brain and spine tumors. Our nursing team identifies appropriate time points to offer video visits in lieu of in-person visits. Families are
guided to connect through secure video conferencing. Data was collected
retrospectively through electronic medical record schedules, billing records,
and UCSF patient satisfaction surveys. RESULTS: Since 2015 we have utilized telehealth for over 400 encounters. The service was limited to patientslocated in California. Introduction of telehealth resulted in savings of 2300
hours of travel by car, over $22,000 in gas, and over 127,000 miles traveled. Surveys indicate patient satisfaction is equal to or better than in-person
experiences. Anecdotally, this service allows for face-to-face contact withpatients who have significant barriers to travel. Challenges have included
technology platforms, native language, provider and patient acceptance, andbilling. CONCLUSION: Overall, telehealth is feasible as a tool to deliver
outpatient care in pediatric neuro-oncology. Implementation of video visits
in clinical practice increases access to neuro-oncologic care and improves
quality of life for patients and families.
SWK-11. ASSESSMENT OF THE INDIRECT COSTS ASSOCIATED
WITH PROTON THERAPY TREATMENT FOR ALBERTA PATIENTSREFERRED OUT OF COUNTRY
Karina Black1, Jackie Middleton2, Sunita Ghosh2, David Eisenstat2, andSamor Patel3; 1Stollery Children’s Hospital, Edmonton, AB, Canada,
2University of Alberta, Edmonton, AB, Canada. 3Cross Cancer Institute,
Edmonton, AB, Canada
BACKGROUND: Proton therapy for benign and malignant tumors has
dosimetric and clinical advantages over photon therapy. Patients in Alberta,
Canada are referred to the United States for proton treatment. The Alberta
Heath Care Insurance Plan (AHCIP) pays for the proton treatment andthe cost of flights to and from the United States (direct costs). This study
aimed to determine the out-of-pocket expenses incurred by patients or theirfamilies (indirect costs). METHODS: Invitation letters linked to an electronic survey were mailed to patients treated with protons between 2008
and 2018. Expenses for flights for other family members, accommodations,transportation, food, passports, insurance, and opportunity costs including
lost wages and productivity were measured. RESULTS: Fifty-nine invitation letters were mailed. Seventeen surveys were completed (28.8% responserate). One paper survey was mailed at participant request. Nine respondents
were from parent/guardian, 8 from patients. All patients were accompanied
to the US by a family member/friend. Considerable variability in costs andreimbursements were reported. Many of the accompanying family/friends
had to miss work; only 3 patients themselves reported missed work. Timeaway from work varied, and varied as to whether it was paid or unpaid
time off. CONCLUSIONS: Respondents incurred indirect monetary andopportunity costs which were not covered by AHCIP when traveling out ofcountry for proton therapy. Prospective studies could help provide current
data minimizing recall bias. These data may be helpful for administrators inassessing the societal cost of out-of-country referral of patients for proton
therapy.
SWK-12. PEDIATRIC NEURO-ONCOLOGY PARENT PERSPECTIVE
ON ASPECTS OF SOCIAL AND EMOTIONAL SUPPORT FOR
ONLINE APPLICATION
Kendra Koch1,2, Tatum Fettig3, and Meghan Slining4; 1The University ofTexas Dell Medical School, Austin, TX, USA, 2The University of Texas

Abstracts

Steve Hicks School of Social Work, Austin, TX, USA, 3Sweet Tea Cancer
Connections, Seattle, WA, USA, 4Furman University, Greenville, SC, USA
Addressing family needs for social/emotional support is part of the duty of
oncology care teams. This research presents a (2020) scoping review and a(2019) focus group initiated to explore pediatric neuro-oncology parent experience of social/emotional support in conjunction with developing an online
peer application to address family needs. Currently, the value of online support is in the forefront of clinical conversation. The focus group queried eightparents whose children were under neuro-oncology treatment in the Northwest USA. Thematic findings include—parents want supportive peers who
have (1) a personal and deep understanding of parenting a child with serious
illness (they “get it”); (2) particular characteristics and skills that promote andsustain relationships, including—(a) good social skills, (b) ability to engage
in “balanced” (cancer/non-cancer) conversations, (c) individual similarities(beliefs, age of children, cancer diagnosis/treatment), (d) logistic commonalities (location, availability), (e) pro-social personal characteristics (i.e. sense ofhumor, emotional/social flexibility), and an (f) ability to navigate and maintain social/emotional boundaries. Parents also initiated discussion about “theburden of supportive relationships” and supporting families doing “normal”
activities without worrying about treatment side effects and contagions. The
literature review supports finding (1) above; reveals the paucity of evidencebased supports available to this population; underscores the critical need forpractitioners and researchers to develop more evidence-based supports andinterventions for families of children experiencing cancer; and supports practitioners’ consistently assessing parent and sibling social and emotional needs
and then consistently referring or intervening when needs are identified.

TUMOR BIOLOGY (NOT FITTING A SPECIFICDISEASE CATEGORY)
TBIO-01. SEX DIFFERENCES IN REDOX STATE UNDERLIEGLUTAMINE DEPENDENCY IN MALE GLIOBLASTOMA
Jasmin Sponagel1, Shanshan Zhang1, Prakash Chinnaiyan2, Joshua Rubin1,
and Joseph Ippolito1; 1Washington University School of Medicine, St.
Louis, MO, USA, 2Oakland University William Beaumont School of
Medicine, Royal Oak, MI, USA
Glioblastoma (GBM) is an aggressive brain tumor in children and adults.
It occurs more commonly in males, but female patients survive significantly
longer. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. In this regard, we foundthat male and female GBM patient samples differ in their metabolite abundance and that males exhibit a significantly higher abundance of aminoacid metabolites. We confirmed those findings in a murine model of GBM,
which has previously yielded important insights into sexual dimorphism in
GBM. Furthermore, we found that male GBM cell cultures are significantly
more sensitive to amino acid deprivation, which was almost entirely driven
by amino acids involved in the synthesis of the antioxidant glutathione.
Glutaminase 1 (GLS1) mediates the conversion from glutamine to glutamate,a crucial component of glutathione. We found that male GBM cells exhibited
higher levels of GLS1, suggesting they are more dependent on glutamate. Indeed, we found that male GBM cells are more sensitive to pharmacological
GLS1 inhibition with the clinical inhibitor CB-839. This correlated withsignificantly increased reactive oxygen species (ROS) in males compared tofemales. We further confirmed sex differences in redox state through pharmacological depletion of glutathione that resulted in a significant increase in
ROS and cell death in male GBM. Together, these data indicate that male
GBM cells are more dependent on glutamine to regulate ROS levels. Thisreveals novel sex-specific metabolic targets for GBM and underlines the importance of considering sex in metabolic targeting approaches.
TBIO-02. IMMUNE PROFILING OF RARE EMBRYONALBRAIN TUMORS REVEAL EVIDENCE OF DYSREGULATEDINTERFERON SIGNALLING AS A POTENTIAL DETERMINANT OFIMMUNOLOGICAL HETEROGENEITY
Dean Popovski1, Fupan Yao1, Andrew Bondoc1, Salma Al-Karmi1, Ben Ho1,
Holly Lindsay2, Xiao-Nan Li2,3, James Rutka1,4, and Annie Huang1,4;
1Arthur and Sonia Labatt Brain Tumour Centre, Division of Haematology/
Oncology, The Hospital for Sick Children, Toronto, ON, Canada,
2Department of Pediatrics, Division of Hematology and Oncology, Baylor
College of Medicine, Texas Children’s Hospital, Houston, TX, USA,
3Department of Pediatrics, Feinberg School of Medicine, Northwestern
University, Chicago, IL, USA, 4Department of Laboratory Medicine andPathobiology, Faculty of Medicine, University of Toronto, Toronto, ON,
CanadaEmbryonal brain tumors (EBTs) remain the most common malignant
pediatric brain tumors. Despite recent advances and improved under-

standing of the molecular biology of EBTs, clinical outcomes remain poor
for rare EBTs. Previous large-scale genomic studies of rare EBTs have shedlight on distinct genomic, transcriptomic and epigenomic profiles. Interestingly, these studies have revealed prominent tumor heterogeneity that provides opportunity to develop novel treatment strategies to improve patient
outcomes. To examine the tumor microenvironment and identify tumor- specific biological dependencies, we performed deconvolution analysis of bulk
gene expression (171 RNA-seq, 236 microarrays) and 586 methylation arrays, which revealed significant intra and inter-tumoral heterogeneity andimplicated interferon (IFN)-mediated signalling as a determinant of a distinct immunological profile in rare EBTs. To further elucidate the importanceof IFN signalling, we performed scRNA-seq on 20 primary samples, which
provided evidence of a spectrum of IFN-immunological responses that varyfrom immunosuppressive to immunologically exhaustive that occur in a hostdependent manner. To further validate our findings, we utilised a geneticallyengineered murine model of Atypical Teratoid Rhabdoid Tumor and primary xenografts in humanised mice to corroborate our in-silico profiles invivo. Through amalgamation of our in-silico data with our in vivo data, wehave identified evidence that dysregulated IFN responses represent a coreelement of the immunological heterogeneity present within subsets of rare
EBTs. An improved understanding of the immune milieu in rare EBTs will
provide avenues to develop specific onco-immune targets to address thisclinical need.
TBIO-03. THE GIFT FROM A CHILD PROGRAM IS EMPOWERING
POST-MORTEM TISSUE DONATION ACROSS THE UNITED STATESAngela Waanders1,2, Melissa Williams1, Nitin Wadwhani1,2, Xiao-Nan Li1,
Stewart Goldman1,2, Kella Tran-Du3,2, Jane Minturn3,2, Jennifer Mason3,2,Mariarita Santi3,2, Angela Viaene3,2, Mateusz Koptyra3,2,Michelle Monje-Deisseroth4,2, Javad Nazarian5,2, Madhuri Kambhampati5,
Augustine Eze5, Mark Souweidane6, Nicole Lyons7, Ginny McLean7,
Patti Gustafson7, and Allen Gustafson7; 1Ann & Robert H. LurieChildren’s Hospital, Chicago, IL, USA, 2Children’s Brain Tumor Network(CBTN,org), Philadelphia, PA, USA, 3Children’s Hospital of Philadelphia,
Philadelphia, PA, USA, 4Stanford University/Lucile Packard Children’s
Hospital, Palo Alto, CA, USA, 5Children’s National Health System,
Washington DC, USA, 6Pediatric Brain and Spine Center, Weill Cornell
Medicine, New York, NY, USA, 7On behalf of Swifty Foundation and Giftfrom a Child (giftfromachild.org), Chicago, IL, USA
The Gift from a Child (GFAC) program was inspired by the dream of
one child to donate his brain for research, recognizing the need to study
tumor tissue collected at diagnosis, recurrence, and at the time of death.
Founded by the Swifty Foundation in 2016, GFAC currently is comprisedof five “Centers of Excellence” at institutions with expertise in pediatricneuro-oncology. Partnering with the Children’s Brain Tumor Network, theprogram’s mandate is twofold: make it possible for families to donate no
matter where they live in the United States and make tissue available toscientists globally to empower discovery. In order to overcome barriers thathave stifled postmortem collection in the past, GFAC has invested in Tissue
Navigators - individuals at each center who coordinate all aspects of donation and communicate with families, medical providers, and laboratory
scientists. In 2019 alone, GFAC coordinated 55 autopsy collections frommultiple diagnosis. A key metric of the program is also capturing the global
sharing and usage of each tissue sample, ensuring that tissue isn’t simply“banked” but is actively being actively used to help unravel tumor biology.
To date, tissue has been used for genomic and molecular data generation,
preclinical model development including cell lines and PDX models, and fornovel drug screening. Together with Children’s Brain Tumor Network, theGift from a Child program is helping to ensure the most precious gift that afamily can make is used to accelerate the path to cures.
TBIO-05. GENOME-SCALE NUCLEOTIDE-SPECIFIC
CHARACTERIZATION OF 5-HYDROXYMETHYLCYTOSINE IN
PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Nasim Azizgolshani1, Curtis L. Petersen1, Lucas Salas1,
Youdinghuan Chen1, Laurent Perreard1, Lananh N. Nguyen2,3, andBrock C. Christensen1; 1Dartmouth College, Hanover, NH, USA,
2Dartmouth Hitchcock Medical Center, Lebanon, NH, USA, 3University
Health Network, Toronto General Hospital, Toronto, Ontario, Canada
Though aberrant cytosine modifications are prevalent in cancer, nucleotidespecific 5-hydroxymethylcytosine (5hmC) modifications remain understudied, including in pediatric CNS tumors. Brain 5-hydroxymethylation
is linked with development and differentiation. We measured genome-scale
nucleotide-specific 5hmC in patients with diagnoses of glioma, ependymoma,
and embryonal tumors under age 18 (n=36), and in non-tumor pediatricbrain tissues (n=3). DNA was processed with tandem oxidative (OxBS) andbisulfite (BS) treatments followed by hybridization to the Illumina Methylation EPIC Array that interrogates over 860,000 CpG sites. We used the
OxyBS R package to determine levels of 5hmC and 5mC. Mean 5hmC levels
were lower in tumors (gliomas 4.1%, ependymomas 3.9%, and embryonal

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tumors 3.4%) compared to nontumor tissues (5.3%). We subset to the CpGs
with the 5% highest 5hmC content for downstream analyses (37,173 CpGs).
These sites were enriched among regulatory elements, including TFBS (Odds
Ratio 1.14 p-value 3.57E-20) and super-enhancers (OR 1.93, p-value 1.14E126). Linear mixed-effects models adjusted for age, sex, and cell type proportions tested the CpG-specific differences in 5hmC between tumor andnontumor samples, as well as between tumor subtypes. 5hmC levels weredepleted across tumors compared with nontumor brain tissues, including
at CpG islands. Model-based clustering (RPMM) results indicated that patients with low 5hmC patterns have poorer overall survival and increased
risk of recurrence. Our results indicate that 5hmC localizes to sites in the
DNA critical to gene regulation and is associated with patient outcomes.
This study offers an opportunity to potentially contribute to classification
markers for childhood brain tumors.
TBIO-06. BDNF-TRKB SIGNALING REGULATES NEURON-GLIOMASYNAPTOGENESIS AND PROMOTES TUMOR PROGRESSION
Kathryn Taylor, Helena Zhang, Alexa Hui, Shawn Gillespie, andMichelle Monje; Stanford, Stanford, CA, USA
Pediatric high-grade gliomas (pHGG) are a devastating group of diseases
that urgently require novel therapeutic options. We have previously demonstrated that pHGGs hijack mechanisms of brain development and plasticity
to their advantage. Here, we investigated the role of microenvironmental
BDNF on pediatric gliomas, independent of the NTRK fusion events commonly identified in infant HGG. Genetic deletion or pharmacologicalblockade of NTRK2 (TrkB), in patient-derived pediatric glioma increases
survival in multiple DIPG and pGBM patient-derived orthotopic xenograft models. Unlike the paracrine BDNF-TrkB signaling observed between
subpopulations of adult HGG malignant cells, pediatric glioma express
TrkB, but not BDNF ligand. BDNF is secreted by normal brain cells in response to neuronal activity and conditioned medium experiments from cortical slices of mice indicates the brain microenvironment as the chief sourceof BDNF ligand. Addition of recombinant BDNF protein increases pediatricglioma cell proliferation and activates the canonical downstream MAPK
signaling pathway, an effect that is blocked by genetic or pharmacological
TrkB inhibition in pHGG. However, the glioma growth-promoting effects of
BDNF in vivo cannot be explained by stimulation of MAPK signaling alone.
We therefore examined the effects of BDNF signaling on neuron-to-glioma
synapse formation, a newly recognized microenvironmental interaction important for pediatric glioma progression. We find that BDNF-TrkB signaling
promotes neuron-to-glioma synaptogenesis in neuron-glioma co-culture. We
are presently exploring the role for BDNF-TrkB signaling in glioma synaptic
plasticity and function. Funding: Abbie’s Army Foundation
TBIO-07. SINGLE-CELL TRANSCRIPTOMIC PROFILE REVEALS
MACROPHAGE HETEROGENEITY IN SONIC-HEDGEHOGMEDULLOBLASTOMA AND THEIR DISTINCT RESPONSES TO
DIFFERENT TREATMENT MODALITIESMai Dang1, and Malay Haldar2; 1Children’s Hospital of Philadelphia,
Philadelphia, PA, USA, 2University of Pennsylvania, Philadelphia, PA, USA
Tumor-associated macrophages (TAMs) are an important component of thetumor microenvironment. Pro-inflammatory macrophages can suppress whileanti-inflammatory macrophages can promote tumor growth. Despite their abundance in many tumors, the origins and diversity of TAMs are not well understood, especially in pediatric brain tumors. Using single-cell RNA sequencing
in a genetically engineered mouse model (Ptch+/-:p53-/-) of SHH-MB, we
identified the dual microglia and monocytic origin of macrophage and theirtranscriptomic heterogeneity. We demonstrate differential recruitment and function of macrophages under distinct modalities of tumor therapy of molecular targeted hedgehog inhibition versus radiation. We additionally identify a monocytic
macrophage population recruited post-radiation that is immune suppressive,
suggesting a mechanism for radiation treatment failure. These insights uncoverpotential strategies for immunomodulation as adjunctive therapy for radiation.
TBIO-08. BASE-RESOLUTION METHYLOMES OF GLIOMASBEARING HISTONE H3.3 MUTATIONS REVEAL A G34 MUTANTSPECIFIC SIGNATURE SHARED WITH BONE TUMORS
Yuhei Sangatsuda1, Fumihito Miura2, Hiromitsu Araki2,
Masahiro Mizuguchi1, Nobuhiro Hata1, Daisuke Kuga1, Ryusuke Hatae1,
Yojiro Akagi1, Takeo Amemiya1, Yutaka Fujioka1, Yasuhito Arai3,
Tatsuhiro Shibata3, Koji Yoshimoto4, Takashi Ito2, and Koji Iihara1;
1Department of Neurosurgery, Kyushu University, Fukuoka, Japan,
2Department of Biochemistry, Kyushu University, Fukuoka, Japan,
3Division of Cancer Genomics, National Cancer Center Research Institute,Tokyo, Japan, 4Department of Neurosurgery, Kagoshima University,
Kagoshima, JapanBACKGROUND: Two recurrent mutations, K27M and G34R/V, in
H3F3A, encoding non-canonical histone H3.3, are reported in pediatric andiii468N EU R O - O N C O L O G Y•

De c e mb e r 2 0 2 0young adult gliomas, whereas G34W mutation was prevalent in bone tumors. In contrast to K27 mutation, it remains elusive how G34 mutations affect the epigenome. Here we performed whole-genome bisulfite sequencing
of four G34R-mutated gliomas and the G34V-mutated glioma cell line
KNS-42. Similarly, we analyzed seven and three gliomas harboring K27M
and no mutations in H3F3A, respectively. These data were compared withthose on bone tumors. RESULTS: G34R-mutated gliomas exhibited lower
global methylation levels, similar CpG island (CGI) methylation levels,and compromised hypermethylation of telomere-proximal CGIs comparedwith those bearing K27M and no mutations. Hypermethylated regions specific to G34R-mutated gliomas were enriched for CGIs, including those of
OLIG1, OLIG2, and canonical histone genes in the HIST1 cluster. These
CGIs were hypermethylated in osteosarcomas with, but not without, theG34W mutation. In KNS-42 cells, CGIs with G34V-mutated histone H3.3
exhibited higher methylation levels than those with wild-type histone H3.3.
This effect was also observed in the G34R-mutated glioma samples. CONCLUSIONS: Gliomas bearing G34R/V mutations display characteristic
methylomic alterations, some of which are shared by osteosarcomas with
the G34W mutation. Deposition of G34 variants may lead to elevatedmethylation of otherwise hypomethylated, histone H3.3-bearing CGIs.
TBIO-09. IN SILICO ANALYSIS IDENTIFIES A PUTATIVE CELL-OFORIGIN FOR BRAF FUSION-POSITIVE CEREBELLAR PILOCYTICASTROCYTOMA
Subhi Talal Younes; University of Mississippi Medical Center, Jackson, MS,
USA
Childhood cancers are increasingly recognized as disorders of cellulardevelopment. This study sought to identify the cellular and developmental
origins of cerebellar pilocytic astrocytoma, the most common brain tumorof childhood. By leveraging publicly available gene expression data fromsuch tumors and controlling for driver mutations, a set of eight known
neuro-developmental genes were identified as being upregulated in cerebellar pilocytic astrocytoma. Mapping those genes onto mouse neurodevelopmental atlases identified significant overlap in their expression
within the ventricular zone of the cerebellar anlage. Further analysis witha single cell RNA-sequencing atlas of the developing mouse cerebellum defined this overlap as occurring in ventricular zone progenitor cells at thedivision point between GABA-ergic neuronal and glial lineages, a developmental trajectory which closely mirrors that previously described to occur
within pilocytic astrocytoma cells. Furthermore, ventricular zone progenitor
cells and their progeny exhibited evidence of MAPK pathway activation, theparadigmatic oncogenic cascade known to be active in cerebellar pilocytic
astrocytoma. Gene expression from developing human brain atlases recapitulated the same anatomic localizations and developmental trajectories
as those found in mice. Taken together, these data suggest this populationof ventricular zone progenitor cells as the cell-of-origin for BRAF fusionpositive cerebellar pilocytic astrocytoma.
TBIO-11. DEEP LEARNING-BASED SINGLE-CELL RNA
SEQUENCING DIFFERENTIATION IDENTIFIES SIMPLE
AND COMPLEX TRANSCRIPTIONAL NETWORKS FORSUBPOPULATION CLASSIFICATION
Eric Prince, and Todd Hankinson; Children’s Hospital Colorado, Aurora,
CO, USABACKGROUND: Genomic assays capable of cellular resolution (i.e.
scRNA-seq) are becoming ubiquitous in biomedical research. Machinelearning, and the subtype known as Deep Learning, have broad application within scRNA-seq analytics. However, methods to facilitate theclassification of cell populations are lacking. We present the novel computational framework HD Spot, which generates interpretable and robust
Deep Learning classifiers that enable unbiased interrogation of linear andnon-linear genomic signatures. METHODS: HD Spot is written in python
and relies on Google’s TensorFlow2 deep learning framework. Four datasetsof immune cells were obtained from the publicly available Seurat repository, generated using the 10X chromium platform. Data preprocessing used
standard Seurat methodology. HD Spot generated optimized classifiers via
a custom platform. Network interpretability was achieved using Shapley
values. Ontology analysis was performed using Metascape. RESULTS: HD
Spot identified meaningful ontologic signatures across all tested datasets.
In the binary case of control versus IFN-B stimulated CD4+ T cells, gene
ontologies reflected Th0 and Th2 T cell populations, congruent with T cell
activation. In the 9-class case of PBMCs, HD Spot identified meaningfulgene networks characteristic of the ground-truth populations using raw feature counts alone. When feature counts are processed into expression values,
HD Spot demonstrates increased specificity of top genes and respective
ontologies between subpopulations. CONCLUSION: This work introducesa broadly applicable computational tool for the advanced bioinformatician
to decipher complex cellular heterogeneity (e.g., tumors) in an unbiased way.
Additionally, HD Spot lowers the barrier for novice bioinformaticists to derive actionable insights from their data.

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TBIO-12. THE SPECTRUM OF MITOCHONDRIAL DNA (MTDNA)
MUTATIONS IN PEDIATRIC CENTRAL NERVOUS SYSTEM (CNS)
TUMORS
Kristiyana Kaneva1, Petr Triska2, Daria Merkurjev3, Moiz Bootwalla3,
Jennifer Cotter3, Dejerianne Ostrow3, Katrina O’Halloran3, Jaclyn Biegel3,
and Xiaowu Gai3; 1Ann & Robert H. Lurie Children’s Hospital of
Chicago, Chicago, IL, USA, 2Charles University, Prague, Czech Republic,
3Children’s Hospital Los Angeles, Los Angeles, California, USA
To explore the role of mitochondrial DNA mutations in pediatric CNS
tumors, we analyzed 749 tumor-normal paired whole genome sequencing
data sets from the Children’s Brain Tumor Tissue Consortium (CBTTC). We
detected 307 somatic mtDNA mutations in 222 CNS tumors (29.6%). Most
frequently observed were missense mutations (38.1%). We also detected 34
loss-of-function mutations. Different pediatric CNS tumor subtypes havedistinct mtDNA mutation profiles. For categorical comparisons, we analyzed subtypes with at least 15 samples. The highest number of mtDNA
mutations per tumor sample was in meningiomas (0.85), while atypicalteratoid rhabdoid tumors (ATRTs) had the lowest number per sample(0.18). High-grade gliomas had a higher number of mtDNA mutations per
sample than low-grade gliomas (0.56 vs. 0.31) (p = 0.0011), with almost
twice as many missense mtDNA mutations per sample (0.22 vs. 0.13) (p <0.001), and higher average heteroplasmy levels (11% vs. 9%). The average
heteroplasmy was 10.1%, ranging from 15.6% in medulloblastoma to
6.36% in schwannoma suggesting that these are clonal alterations and not
artifacts. Intriguingly, the two chordoma patients in the CBTTC database
had an identical heteroplasmic m.10971G>A MT-ND4 nonsense mutation. Similarly, our patient with recurrent gliofibroma harbored the same
somatic MT-ND4 synonymous variant (m.10700A>G) detected at 53%
heteroplasmy in the initial tumor, 79% in the first recurrence, and 97% in
the second recurrence. Although the functional consequences of these alterations are not yet understood, our findings suggest that sequencing the
mtDNA genome may be used to characterize CNS tumors at diagnosis andmonitor disease progression.
TBIO-13. USE OF NEXT GENERATION SEQUENCING TO IDENTIFY
MOVE DRIVERS OF CRYPTIC, CLINICALLY AGGRESSIVE BRAIN
TUMORS
Subhi Talal Younes, Amanda Boudreaux, Kristin Weaver, Cynthia Karlson,
and Betty Herrington; University of Mississippi Medical Center, Jackson,
MS, USAINTRODUCTION: Next generation sequencing (NGS) is an emerging
technology which allows for in-depth analysis of pediatric brain tumors.
NGS has particular use in the context of ambiguous or aggressive neoplasms,
where it can be leveraged to discover novel drivers, inform pathologic classification, and direct targeted therapies. OBJECTIVE: The objective of thiscase series was to utilize NGS technology to illuminate the biology of aggressive brain tumors with ambiguous pathologic features and clinically aggressive behavior. METHODS: FFPE tumor tissue and matched germline DNA
were subjected to whole exome sequencing (WES). Data were analyzed according to the GATK pipeline. RESULTS: The first case is a 6-year-old male
who presented with innumerable foci of leptomeningeal nodules throughout
the neuroaxis. Original pathology was CNS embryonal tumor. WES identified loss of chromosome 1p and 16q with gain of 1q and amplificationof MYC and OTX2 loci (cytogenetic aberrations characteristic of group 3
medulloblastoma) and a deleterious mutation in BCL7B, a known tumor
suppressor gene. The second case is a 2-year-old female who presented witha parietal lobe mass diagnosed as high grade neuroepithelial tumor with
C11orf95 translocation, but no RELA fusion. WES revealed loss of small
region of chromosome 2p and mutations in IDH3G, TRAF2, and JMJD1C,
suggesting novel targets for further study. CONCLUSIONS: In both cases,
NGS studies were able to shed light on the underlying tumor biology and/or
refine the pathologic diagnosis. These data underscore the utility of applying
NGS technology to study the biology of pediatric brain tumors.
TBIO-14. CHARACTERISATION OF THE ARGININE PATHWAYENZYMES IN PAEDIATRIC BRAIN TUMOURS TO DETERMINESUSCEPTIBILITY TO THERAPEUTIC ARGININE DEPLETION
Eleanor Bishop, Monika Dimitrova, Lisa Storer, Richard Grundy, andMadhumita Dandapani; University of Nottingham, Nottingham, United
Kingdom
INTRODUCTION: Extracellular arginine dependency (auxotrophy) is
increasingly being recognised in several tumours. This is due to the inabilityof cancer cells to recycle or synthesise intracellular arginine through theurea cycle pathway compared to normal cells. Whilst adult glioblastoma
is known to exhibit this, the expression of the arginine pathway enzymes
has not been delineated in paediatric brain tumours. METHODS: We
used immunohistochemical methods to stain for arginine pathway en-

zymes in Paediatric High grade glioma (pHGG), low grade glioma (pLGG)
and medulloblastoma (MB) tumour tissue microarrays (TMAs). The antibodies detected protein expression of the metaboliser Arginase (Arg2),
recycling enzymes ornithine transcarbamoylase (OTC), Arginosuccinate
synthetase (ASS1) and arginosuccinate lyase (ASL) as well as the transporter SLC7A1. RESULTS: Deficiency of OTC, ASS1 and ASL were seen in
92%, 98% and 93% of pHGG samples (n=156) respectively, with deficiency
defined as low (<20%) or negative antibody expression. Identical results
were seen in pLGG (n=98) - 83%, 97% and 95% were deficient in OTC,ASS1 and ASL. Both pHGG and pLGG highly expressed SLC7A1 and Arg2,
demonstrating that they could transport and utilise arginine. In MB (n=82),
this auxotrophic signature was again seen in 90% of TMAs with absent or
low expression of OTC, ASS1 and ASL and high Arg2 and SLC7A1 expression. CONCLUSIONS: These results show that pHGG, pLGG and MB arearginine auxotrophs. Pegylated arginase (BCT-100) is currently in Phase I/II
trials in relapsed pHGG. Our results suggest that therapeutic arginine depletion may also be useful in MB and pLGG.
TBIO-15. MODELING DEVELOPMENTAL GENE EXPRESSIONDYNAMICS AT CELLULAR RESOLUTION TO INTERPRETPEDIATRIC BRAIN TUMOR TRANSCRIPTIONAL PROGRAMS
Selin Jessa1,2, Nisha Kabir1,2, Maria Vladoiu3, Steven Hébert2,
Michael D. Taylor3, Nada Jabado1,4, and Claudia L. Kleinman1,2; 1McGill
University, Montreal, QC, Canada, 2Lady Davis Institute for Medical
Research, Montreal, QC, Canada, 3The Hospital for Sick Children,
Toronto, ON, Canada, 4The Research Institute of the McGill University
Health Centre, Montreal, QC, Canada
A central challenge in understanding the biology of pediatric brain tumors
is defining the cellular and molecular context where oncogenesis occurs. We
hypothesize that spatiotemporally restricted cell types are uniquely susceptible to specific genetic alterations, which alter normal neurodevelopmental
programs and ultimately lead to oncogenesis. The resulting tumors retainsome transcriptomic features of their lineage of origin. To delineate these
origins, we assembled a densely sampled developmental time course of themouse forebrain and pons, doubling our recently published single-cell atlas.
This dataset comprises >100,000 cells at 9 timepoints from E10-P6. However, while single cell transcriptomics reveal rich gene dynamics during celldifferentiation, interpretation of individual genes can be challenging due
to data sparsity. Leveraging this time-series, we present strategies to modeland visualize the expression of a given gene across differentiation of distinct lineages. We demonstrate an interactive web app to interrogate the expression of genes or gene sets during brain development, extract temporally
correlated genes, and search active transcription factor regulatory modules.
Finally, we profile the expression of core transcriptional programs of several pediatric brain tumor entities during development. Our analyses reveal
genes with restricted expression patterns that elucidate tumor etiology. More
broadly, these resources harness single cell data to enable exploration ofneurodevelopmental gene programs with great relevance to pediatric brain
tumor oncogenesis.
TBIO-16. NOTCH1 PATHWAY AS TARGET FOR DRUG
INTERVENTION FOR HISTONE 3 G34R MUTATED PHGG
Katie Foot1, Anbarasu Lourdusamy2, Sofia Christou2, Ruman Rahman2,
Robert Layfield2, Richard Grundy2, and Farhana Haque2; 1University ofBirmingham, Birmingham, United Kingdom, 2University of Nottingham,
Nottingham, United Kingdom
There have been no significant improvements in the treatments for childhood High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), which continue to have a very poor prognosis. Thesecancers harbor mutations affecting histone 3 (H3) proteins; 80% of DIPGs
with histone H3 K27M somatic mutations whilst 30% of pHGGs exhibit
H3.3 G34R or G34V mutations. We have generated and validated a histone 3.3 G34R mutant-specific antibody and investigated the downstream
effects of H3.3 G34R mutations in pHGG. In order to identify the genesthat may be deregulated by G34R mutant histone expression, we have
performed chromatin immunoprecipitation (ChIP) assays with our H3.3
G34R and wild type H3 antibodies, using pHGG H3 G34R mutant andwild-type cell lines. Initial analyses of ChIP data have implicated deregulation of cell-signaling pathways including Notch1, Hedgehog, PPAR-1,
PLC-beta and Androgen, in H3 G34R mutated pHGG. We are currently
determining the effects of altered expression of Notch1 pathway components on tumorigenesis of H3 G34R mutated pHGG, through gene andprotein expression and inhibition assays. Specifically we find that the
Notch1 pathway component HES1 shows increased expression in G34R
mutant cells compared to controls, directing our evaluation of the utilityof gamma-secretase inhibitors as potential therapeutics. These analyses
may underpin development of novel treatment strategies for H3 mutated
pHGG.

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TBIO-17. INTEGRATIVE ANALYSES OF BRAFV600E MUTATEDGLIOMAS: FROM MOLECULAR BIOLOGY TO RADIOLOGY AND
TREATMENTS
Benoit Lhermitte1,2, Eric Guerin1, Elisa Ruhland1, Consuelo Sebastia1,
Agathe Chammas1, Quentin Fuchs2, Caroline Bund1, Izzie Jacques Namer1,
Monique Dontenwill2, and Natacha Entz-Werle1,2; 1University Hospital ofStrasbourg, Strasbourg, France, 2UMR CNRS 7021, Strasbourg, France
BRAFv600e mutation is encountered mostly in low-grade pediatric gliomas(LGG) and epileptogenic glioneuronal tumors, such as gangliogliomas(GG). Less frequently this mutation is present in high-grade glial (HGG) or
glioneuronal tumors. Recent publications were highlighting BRAF mutation
and CDKN2A deletion, as independent prognostic factors linked to a worst
outcome in LGGs. We studied retrospectively a monocentric cohort of 12
LGGs (9 GG and 3 pilocytic astrocytomas) and 9 HGG (5 “de novo” tumors and 4 with a long past of LGG evolution) with BRAFv600e positivity.
The patients were aged from 1 to 47 years. LGGs were under 20 years andonly 3 patients with HGGs had less than 18 years. We focused on extended
tumors’ biology assessment by DNA single-cell analyses, RNAsequencing,
NGS, metabolomics, radiology (MRI, PET-scanning and spectroscopy)
and correlated them to tumor’s data. One LGG had a CDKN2A deletion.
Six had a complete surgical resection, 2 had a minimal residue and 4 had
chemotherapies after partial surgery and relapsed. All HGGs had a surgical resection followed by chemotherapy and radiotherapy and additional
CDKN2A deletion. Two pediatric HGGs relapsed rapidly. Only one benefited positively from targeted therapy. Specific radiological and spectroscopic
signs were linked to the BRAF mutation itself and those different groups(LGGs, HGGs and LGGs with long term evolution of HGG), where specificmolecular pathways and metabolomic profiles are associated. Currently, weare going further in the correlations to be able to predict in LGG their potential long-term evolution, where MAPK pathway modulations might beinvolved.
TBIO-18. ESTABLISHING A PIPELINE FOR INDIVIDUALIZEDTREATMENT OPTIONS FOR PEDIATRIC BRAIN CANCER
Luna Djirackor1, Skarphedinn Halldorsson1, Cecilie Sandberg1,
Philipp Euskirchen2, Erlend Skaga1, Evgeny Kulesskiy3,
Krister Wennerberg3, Iver Langmoen1, and Einar Vik-Mo1; 1Oslo
University Hospital, Oslo, Norway, 2Charité – Universitätsmedizin Berlin,
Berlin, Germany, 3Institute for Molecular Medicine Finland, Helsinki,
FinlandINTRODUCTION: Despite being able to characterize pediatric brain
tumors such as medulloblastoma and high-grade gliomas using detailed
molecular analysis tools, this knowledge hasn’t been translated to better
treatment methods. In this project, we aim to create a biobank of pediatric brain tumors (PBTs), characterize samples using next generation molecular diagnostics and identify patient specific drug-treatment options using
high-throughput drug screening (HTDS). METHODS: To establish tumor
spheres from biopsies, we mechanically dissociated the tissue and digested
it in trypsin. The cells isolated were cultured in serum free DMEM medium.
Immunocytochemistry analysis was done to compare the spheres and original tumor. After the second passage, DNA was extracted and subjected to
low-pass whole genome nanopore sequencing. HTDS with a library of FDA/
EMA-approved anticancer drugs and investigational compounds was also
performed. RESULTS: We’ve established tumor sphere cultures that grew
to passage two and onwards from five juvenile pilocytic astrocytomas, twogangliogliomas and two midline gliomas. The spheres expressed markers
of stem cells (Nestin), neurons (β3-tubulin) and glial (GFAP), similar to theoriginal tumor. Copy number profiling and methylation-based classificationof the spheres showed the same alterations and classification as the biopsy.
HTDS revealed significant differences in drug sensitivity including patientspecific vulnerabilities to anticancer drugs. CONCLUSION: We’ve createda protocol to generate tumor spheres from PBTs. We are also building abiobank comprising high and low grade PBTs. Our tumor spheres maintainthe characteristics of the original tumor and can be used for further downstream analysis including drug screening.
TBIO-19. INTEGRATED GENOMIC, PROTEOMIC ANDPHOSPHOPROTEOMIC ANALYSIS OF SEVEN TYPES OF PEDIATRICBRAIN CANCER
Francesca Petralia1, Nicole Tignor1, Dmitri Rykunov1, Boris Revas1,
Shrabanti Chowdhury1, Azra Krek1, Pichae Raman2, Jiayi Ji1,
Yuankun Zhu2, Weiping Ma1, Xiaoyu Song1, David Fenyo3, Steven Gygi4,Richard Ivey5, Antonio Iavarone3, Jeffrey Whiteaker5, Antonio Colaprico6,
Alexey Nesvizhskii7, Henry Rodriguez8, Amanda Paulovich5, Tara Hiltke8,
Adam Resnick2, Pei Wang1, and Brian Rood9; 1Icahn School of Medicine
at Mount Sinai, New York, NY, USA, 2Children’s Hospital of Philadelphia,
Philadelphia, PA, USA, 3New York University, New York, NY, USA,
4Harvard University, Cambridge, MA, USA, 5Fred Hutchinson Cancer
Center, Seattle, WA, USA, 6University of Miami, Miami, FL, USA,iii470N EU R O - O N C O L O G Y•

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7University of Michigan, Ann Arbor, MI, USA, 8National Cancer Institute,
Bethesda, MD, USA, 9Children’s National Research Institute, Washington,
DC, USAWe performed a comprehensive proteogenomic analysis across sevenchildhood brain tumors for a deeper understanding of their functional
biology. Whole genome sequencing, RNAseq, quantitative proteomic profiling and phosphoproteomics were performed on 219 fresh frozen tumor
samples representing the histologic diagnoses of: low grade astrocytoma(93), ependymoma (32), high grade astrocytoma (26), medulloblastoma(22), ganglioglioma (18), craniopharyngioma (16) and atypical teratoid
rhabdoid tumor (12). Unsupervised clustering analysis based on proteomics
data reveals eight clusters with distinct protein profiles and pathway activities. While some clusters coincide with histologic diagnoses, a couple ofclusters appear to be a mixture of different diagnoses, including one cluster
consisting of “aggressive” tumors characterized by poor survival and highstemness scores. By integrating proteomic data with RNAseq and WGS data,
we characterize the impact of mutations (H3K27M, BRAFV600E, BRAF
fusion) and CNVs upon the proteome across various diagnoses. Multiomics
based kinase-substrate association analysis and co-expression network analysis reveal targetable active kinase networks within these tumors. Proteomic
data reveals unique biology associated with H3K27M mutation status in
HGG and BRAF aberrations in LGG. Characterization of the tumor microenvironment through deconvolution analyses based on multi-omics data
reveals 5 distinct tumor clusters associated with different populations ofinfiltrating immune cells and the relative activity of the immune system based
upon the expression of pro-inflammation or immunosuppressive markers.
This study reports the first large-scale deep comprehensive proteogenomic
analysis crossing traditional histologic boundaries to uncover foundational
pediatric brain tumor biology including functional insight that helps drive
translational efforts.
TBIO-21. LNC-TALC PROMOTES O6-METHYLGUANINE-DNA
METHYLTRANSFERASE EXPRESSION VIA REGULATING THE
C-MET PATHWAY BY COMPETITIVELY BINDING WITH MIR20B-3P
Pengfei Wu1, Jinquan Cai1, and Qun Chen2; 1Department of Urology, The
Second Affiliated Hospital of Harbin Medical University, Harbin, China,
2Department of Urology, The Second Affiliated Hospital of Harbin Medical
University Department of Neurosurgery, The First Affiliated Hospital,
College of Medicine, Zhejiang University, Hangzhou, China
Long noncoding RNAs (lncRNAs) have emerged as new regulatory
molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediatedtemozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ
resistant GBM cells, perform a lncRNA microarray of the parental and
TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC(temozolomide-associated lncRNA in glioblastoma recurrence), correlatedwith TMZ resistance via competitively binding miR-20b-3p to facilitate
c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC
expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased
MGMT expression by mediating the acetylation of H3K9, H3K27 andH3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In
clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutictarget to overcome TMZ resistance, enhancing the clinical benefits of TMZ
chemotherapy.
TBIO-24. USING MOLECULAR GUIDED THERAPY IN PEDIATRICNEURO ONCOLOGY PATIENTS: THE SUCCESS AND BARRIERS
Beth Armstrong, Morgan Schmitt, and Jayne VonBergen; Riley Children’s
Health, Indianapolis, IN, USA
Remarkable advances have been made in pediatric brain tumor treatments, however many of these children suffer significant side effects fromstandard chemotherapy-based treatment. Recent advances in precision
medicine offer great hope to pediatric patients in terms of improved
therapeutic precision, safety, and efficacy. However, there are barriers to
implementing precision medicine that are best approached from a multidisciplinary perspective. The goals of the Riley Hospital for Children at
Indiana University Health Precision Genomics Neuro Oncology program
are to optimize the treatment of children by assessing children’s cancers
for actionable molecular targets and finding available, affordable therapies that treat those actionable targets. Children are referred to the Riley
Precision Genomics Neuro Oncology program at the time of diagnosis
or with relapse. Tumor tissue is tested for somatic and germline findings.
Riley’s Precision Genomics Neuro Oncology program has received 55
patient referrals. Of these 55 patients, 46 (84%) had molecular analysis
completed, and the results of 40 (87%) patients indicated actionable tar-

Abstracts

gets. Of the 40 patients with results, 23 (58%) patients went on to receive
genomics guided therapy. Limited availability of tissue has accounted for
6 (13%) patients’ lack of results. Many guided therapy options are oral
medications, which positively impact patient’s quality of life. The learner
will increase their knowledge of how molecular guided therapy is now
innovatively being used to treat children with cancer, and the challenges
involved.
TBIO-26. NON-CANONICAL OPEN READING FRAMES ENCODE
FUNCTIONAL PROTEINS ESSENTIAL FOR CANCER CELLSURVIVALJohn Prensner1,2, Oana Enache2, Victor Luria3, Karsten Krug2,
Karl Clauser2, Joshua Dempster2, Amir Karger3, Li Wang2,
Karolina Stumbraite2, Vickie Wang2, Ginevra Botta2, Nicholas Lyons2,
Amy Goodale2, Zohra Kalani2, Briana Fritchman2, Adam Brown2,
Douglas Alan2, Thomas Green2, Xiaoping Yang2, Jacob Jaffe2,
Jennifer Roth2, Federica Piccioni2, Marc Kirschner3, Zhe Ji4, David Root2,
and Todd Golub1,2; 1Boston Children’s Hospital/Dana-Farber Cancer
Institute, Boston, MA, USA, 2Broad Institute, Cambridge, MA, USA,
3Harvard Medical School, Boston, MA, USA, 4Harvard Medical School,
Cambridge, MA, USA
The brain is the foremost non-gonadal tissue for expression of
non-coding RNAs of unclear function. Yet, whether such transcripts are
truly non-coding or rather the source of non-canonical protein translation is unknown. Here, we used functional genomic screens to establish the cellular bioactivity of non-canonical proteins located in putative
non-coding RNAs or untranslated regions of protein-coding genes. We
experimentally interrogated 553 open reading frames (ORFs) identified
by ribosome profiling for three major phenotypes: 257 (46%) demonstrated protein translation when ectopically expressed in HEK293T cells,
401 (73%) induced gene expression changes following ectopic expression across 4 cancer cell types, and 57 (10%) induced a viability defectwhen the endogenous ORF was knocked out using CRISPR/Cas9 in 8
human cancer cell lines. CRISPR tiling and start codon mutagenesis indicated that the biological impact of these non-canonical ORFs required
their translation as opposed to RNA-mediated effects. We functionallycharacterized one of these ORFs, G029442—renamed GREP1 (GlycineRich Extracellular Protein-1)—as a cancer-implicated gene with highexpression in multiple cancer types, such as gliomas. GREP1 knockoutin >200 cancer cell lines reduced cell viability in multiple cancer types,
including glioblastoma, in a cell-autonomous manner and produced cell
cycle arrest via single-cell RNA sequencing. Analysis of the secretome of
GREP1-expressing cells showed increased abundance of the oncogenic
cytokine GDF15, and GDF15 supplementation mitigated the growth inhibitory effect of GREP1 knock-out. Taken together, these experimentssuggest that the non-canonical ORFeome is surprisingly rich in biologically active proteins and potential cancer therapeutic targets deserving offurther study.
TBIO-27. RASOPATHIES AND BRAIN TUMOROGENESIS: ARE SOS1
MUTATIONS ARE CONCERNED?
Nouha Bouayed Abdelmoula, Rim Louati, Balkiss Abdelmoula, andSamir Aloulou; UR17ES36 Genomic of Signalopathies at the service ofMedicine, Medical University of Sfax, Sfax, Tunisia
Germ line gain-of-function mutations in several members of the RAS/MAPK pathway, including PTPN11 are associated with signalopathies
named Rasopathies and known as Noonan syndrome and closely related conditions. Patients harboring Rasopathies are at increased risk of
myeloproliferative diseases and solid tumors, such as neuroblastoma. Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor
for Ras, represent the second most frequent genetic defect in Rasopathies.
However, SOS1 mutations are rare in human malignancies and patientswith germline SOS1 mutations may not be at increased risk of developing
cancer. Here, we report a SOS1 variant found to segregate in a Tunisianpedigree with many members affected by brain tumors as well as epileptic disorder. During our genetic counselling for congenital heart diseases, a 9-year-old female born at Sfax from a consanguineous couple andhaving pulmonic valvular stenosis, has been investigated at the molecularlevel. Screening of mutations in the entire coding sequence of PTPN11,
Braf and SOS1, was conducted using HRM analysis and bidirectionalsequencing. Heterozygous single nucleotide substitution of SOS1 gene:c.1655 G>A was confirmed. This mutation affected the PH‐REM linker
domain with substitution of residue Arg552 to Lys: p.Arg552Lys. Thismutation accounts for one‐third of all mutations reported in SOS1 during
Rasopathies. Although no other molecular exploration was done, family
history revealed other affected children by neurodevelopmental and epileptic conditions as well as recurrent brain malignancies in the paternalfamily. Two aunts developed blindness and then died subsequently totumor progression.

VIRAL/GENE THERAPY AND OTHER NOVELTHERAPIES
THER-01. AWAKING THE IMMUNE SYSTEM WITH AN IMMUNOONCOLYTIC VIRUS AS A THERAPEUTIC STRATEGY FOR DIPGS
Virginia Laspidea1, Montse Puigdelloses1, Iker Ausejo-Mauleon1,
Dolores Hambardzumyan2, Zhihong Chen2, Naiara Martinez-Velez1,
Marta Zalacain1, Jaime Gallego Perez de Larraya1, Oren Becher3,
Juan Fueyo4, Candelaria Gomez-Manzano4, and Marta M Alonso1;
1Clinica Universidad de Navarra, Pamplona, Spain, 2Mount Sinai, New
York, USA, 3Northwestern University, Chicago, USA, 4MD Anderson
Cancer Center, Houston, USA
Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumour,
being the leading cause of paediatric death caused by cancer. Despite all
the advances made regarding effective therapies, the survival is dismal.
Our lab has engineered the oncolytic virus Delta-24-ACT armed with thecostimulatory ligand 41BBL in order to increase the antitumoral effect of the
adenovirus. 41BB is a costimulatory receptor which promotes the expansionof activated T cells and the generation and maintenance of CD8 T memory
cells. Therefore, we propose the use of Delta-24-ACT as a therapeutic approach for DIPG tumours. We observed that Delta-24-ACT is able to infectand replicate in NP53 and PDGFB-driven, two DIPG murine cell lines. Furthermore, 41BBL is expressed in the membranes of the infected cells andresults with immunogenic cell death as shown by the different DAMPs. Injection of Delta-24-ACT in DIPG model was safe, showed no sign of toxicity
and led to a significantly increase in the median overall survival, generating
anti-glioma memory in long-term survivors. Mechanistic experiments,
showed an increase of T cell infiltration (mainly CD8), decrease of proliferating cells and a reduction of the number of vessels in FFPE brain samples
in the treated mice. We are currently performing nanostring analyses to assess the changes in the transcriptional immune phenotype of treated versus
control mice. In summary, our data suggest that Delta-24-ACT is safe andinduces a potent antitumor immune response in DIPG models mainly basedin the activation of CD8 lymphocytes recruited by the viral activity.
THER-02. EVALUATION OF THE ONCOLYTIC VIRUS DELTA24RGD AS AN ANTI-TUMOR AGENT IN PRECLINICAL MODELS OF
LOCALIZED AND DISSEMINATED AT/RT
Marc Garcia-Moure1,2, Marisol González-Huarriz1,2,Daniel de la Nava3,2, Lucía Marrodán1,2, Cande Gomez-Manzano4,
Juan Fueyo4, Ana Patiño-García1,2, and Marta M Alonso1,2; 1University
Clinic of Navarra, Pamplona, Spain, 2Health Research Institute of Navarra(IDISNA), Pamplona, Spain, 3University of Navarra, Pamplona, Spain,
4MD Anderson Cancer Center, Houston, Texas, USA
Current therapies for atypical teratoid/rhabdoid tumors (AT/RTs) are suboptimal, resulting in a 2-year OS below 20% and the development of severeside effects. Therefore, we need to explore alternative therapeutic approaches
for this disease. Since the virus Delta24-RGD has already demonstrated its
efficacy and safety as a therapeutic agent for brain tumors, including pediatricpatients, here we propose to evaluate the anti-tumor effect of Delta24-RGD
in AT/RT. In vitro, Delta24-RGD infects and replicates in AT/RT cultures followed by oncolysis, obtaining IC50 values below 1 PFU/cell. In vivo, a single
local injection of Delta-24-RGD in three infratentorial AT/RT models (BT12, CHLA-06 and CHLA-266) extended significantly the median OS (50 to
78 days BT-12; 21 to 31 days CHLA-06; 64 to 110 days CHLA-266). Delta24-RGD also increased the survival of mice bearing supratentorial CHLA-266
tumors (from 93 to 132 days). Next, we evaluated the efficacy of Delta24RGD in a model mimicking metastatic disease through intraventricular injection of BT-12-luciferase cells. Administration of Delta24-RGD inhibitedtumor growth and development of metastases, leading to an increased OS andnearly 70% of long-term survivors. The interaction between Delta24-RGD
and the immune system was evaluated in humanized mice models bearing
CHLA-06. In this model, Delta24-RGD treatment extended OS (from 23 to
34 days) and we characterized the anti-tumor immune landscape in control
and Delta24-RGD treated mice by transcriptional and functional analyses.
These results underscore the potential of Delta24-RGD as a promising therapeutic choice for patients affected by AT/RT.
THER-03. IN VITRO EVALUATION OF THE EFFECT OF
CANNABIDIOL ON PAEDIATRIC BRAIN TUMOUR CELL LINES
USING A PULSED TREATMENT REGIME
Sophie Faulkes, George Lockwood, Saoirse E O’Sullivan,
Richard G Grundy, and Lisa C D Storer; University of Nottingham,
Nottingham, Nottinghamshire, United Kingdom
Paediatric brain tumours are the second most common cancer after haematological malignancies. Intermittent dosing regimens are typical for chemo-

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therapy drugs in order to avoid excessive damage to organs and avoid theonset of late effects. Cannabidiol (CBD) has been shown to have cytotoxic
properties on paediatric brain tumour cell lines. Although CBD is far lesstoxic and damaging than the classical chemotherapy options which are currently available to children suffering with brain tumours, there are somepossible side effects. Given that the half-life of the drug is 24 hours, it was
important to establish the nature of the effect of cumulative dosing on top of
the remaining drug in the system. The pHGG cell line, SF188 was cultured
in different concentrations of CBD with either 1, 2 or 3 doses being given on
consecutive days. 24 hours after the last dose the cells were analysed using
the resazurin assay. It was observed that the amount of drug required for
an EC50 to be obtained decreased; 17.6µM (1 dose), 8µM (2 doses), 5µM (3doses) and that cell survival was reduced to nearly 0% in those cells which
received multiple does of CBD at 17.6µM. In order to mimic the intermittent
dosing regime, the cells were returned to the incubator for 4 days before theresazurin assay was repeated. The decrease in viability was maintained overthe extended culture period meaning that the ability of even the apparent“healthy” cells to proliferate had been permanently affected.
THER-04. IS THERE A ROLE FOR CANNABIDIOL IN THE
TREATMENT OF CHILDHOOD BRAIN TUMOURS?
George Lockwood, Amelia Hatfield, Mohamed Mabrouk,
Saoirse E O’Sullivan, Richard G Grundy, and Lisa C D Storer; University of
Nottingham, Nottingham, Nottinghamshire, United Kingdom
Brain tumours are the leading cause of cancer related death in children
with limited treatment options and high recurrence rates. Recent evidence
suggests there may be anti-tumoral properties of cannabinoids, and of
cannabidiol (CBD) in particular. We evaluated the effect of CBD on paediatric brain tumour cell lines in 2D and 3D spheroids; pHGG (SF188),
ependymoma (BxD-1425EPN) and human astrocytes. At the CBD EC50 concentration, astrocytic cell death was insignificant. 3D spheroids decreased insize by approximately 20% when cultured in CBD compared to cells only
after 5-day exposure. Cell death increased with time after a single dose of
CBD. Western Blot showed an increase in Lc3b expression (autophagy) after
24 hours incubation (early cell death) with CBD in both BxD-1425EPN
and SF188 with PARP expression (apoptosis) increased after 5 days incubation (late cell death). Cell cycle analysis showed a decrease of cells in
G1 and no change in G2 indicating cell cycle arrest. In hypoxia, SF188 andBxD-1425EPN cells showed decreased cell death after 24 hours and 5 days
when compared to normoxia and an EC50 within acceptable limits could not
be achieved. SF188 cells pre-treated with receptor antagonists indicate that
CBD was not acting through CB1, CB2, GPR18, PPARα or PPARγ receptors
but may act as a partial agonist of the TRPV1 and 5-HT1A receptors and afull agonist of the GPR55 receptor (resazurin assay). This provides evidence
that CBD is effective at killing paediatric brain tumour cells and does nothave a significant effect on normal astrocytes.
THER-05. GENETICALLY STABLE POLIOVIRUS VECTORCARRYING H3.3K27M ANTIGEN FOR TREATMENT OF DIFFUSE
MIDLINE GLIOMA BY INTRAMUSCULAR INJECTION
Mubeen Mosaheb1, Daniel Landi2,3, Elena Dobrikova2, Michael Brown2,
Yuanfan Yang4, Jana Cable1, Hideho Okada5,6, Smita Nair2,7,Darell Bigner2, David Ashley2, and Matthias Gromeier1,2; 1Department of
Molecular Genetics and Microbiology, Duke University Medical School,
Durham, NC, USA, 2Department of Neurosurgery, Duke University
Medical School, Durham, NC, USA, 3Department of Pediatrics, Duke
University Medical School, Durham, NC, USA, 4Department of Pathology,
Duke University Medical School, Durham, NC, USA, 5Department of
Neurological Surgery, University of California at San Francisco, San
Francisco, CA, USA, 6Parker Institute for Cancer Immunotherapy,
University of California at San Francisco, San Francisco, CA, USA,
7Department of Surgery, Duke University Medical School, Durham, NC,
USA
BACKGROUND: H3 K27M-mutant diffuse midline glioma (DMG) isinvariably lethal. Viruses naturally engage innate immunity, induce antigen
presentation, and mediate CD8 T cell priming against foreign antigens.
Polioviruses, in particular, are uniquely tropic for dendritic cells (DC) andpotently activate DC, inducing Th1-dominant cytokine profiles, CD8 T cell
immunity, and enhanced epitope presentation. Thus, poliovirus is ideallysuited for vectored delivery of signature tumor neoantigens, e.g. the H3
K27M feature of DMG. However, poliovirus vector design is inherently
limited by genetic instability and the underlying neuropathogenicity ofpoliovirus. METHODS: We created a genetically stable, polio:rhinovirus
chimera vector devoid of neuropathogenicity and modified for stable expression of the HLA-A2 restricted H3.3 K27M antigen (RIPO (H3.3)). RESULTS: RIPO(H3.3) infects, activates, and induces H3.3K27M antigen
presentation in DCs in vitro. Given intramuscularly in vivo, RIPO(H3.3)
recruits and activates DCs with Th1-dominant cytokine profiles, efficiently

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primes H3.3K27M-specific CD8 T cells, induces antigen-specific CD8
T cell migration to the tumor site, delays tumor growth, and enhances
survival in murine tumor models. CONCLUSION: This novel approachleverages the unique ability of polioviruses to activate DCs while simultaneously introducing the H3.3 K27M antigen. In this way, DCs are activated optimally in situ, while being simultaneously infected to express/
present tumor antigen. RIPO(H3.3), given by intramuscular injection, will
be evaluated in a clinical trial for children with H3 K27M-mutant diffuse
midline glioma.
THER-06. THERAPEUTIC EFFICACY OF RRV-MEDIATED
PRODRUG ACTIVATOR GENE THERAPY IN CLINICAL TRIALSOF RECURRENT HIGH-GRADE GLIOMA AND IN MURINE
ORTHOTOPIC MODELS OF INTRACEREBRAL GLIOMA AND
INTRACEREBELLAR MEDULLOBLASTOMAAngela Richardson1,2, Sara Collins3, Akihito Inagaki3, Valerie Armstrong4,
David Robbins5, Nagi Ayad6, Harry Gruber7, Douglas Jolly7,
Timothy Cloughesy8, and Noriyuki Kasahara9; 1Department of
Neurosurgery, University of Miami, Miami, FL, USA, 2Jackson Health
System, Miami, FL, USA, 3Department of Neurological Surgery, Universityof California, San Francisco (UCSF), San Francisco, CA, USA, 4Miller
School of Medicine, University of Miami, Miami, FL, USA, 5Departmentsof Surgery and Biochemistry, University of Miami, Miami, FL, USA,
6Department of Psychiatry and Behavioral Sciences, Miami, FL, USA,
7Tocagen Inc., San Diego, CA, USA, 8Department of Neurology, Universityof California, Los Angeles (UCLA), Los Angeles, CA, USA, 9Departmentsof Neurological Surgery and Radiation Oncology, University of California,
San Francisco (UCSF), San Francisco, CA, USA
Toca 511, a clinical-stage tumor-selective retroviral replicating vector(RRV), encodes optimized yeast cytosine deaminase (CD), which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil(5-FU) within infected cancer cells. In preclinical models of intracerebral
glioblastoma, 5-FU generated locally by Toca 511 (RRV-CD) prodrug
activator gene therapy has also been shown to kill immunosuppressive
myeloid cells in the tumor microenvironment, leading to anti-cancer immune activation and long-term survival. Early-phase clinical trials ofToca 511 in recurrent high-grade glioma showed highly promising evidence of therapeutic benefit, leading to a Phase III trial completed in late2019 (n=400 patients, randomized 1:1 vs. standard chemotherapy), whichappeared to show negative results overall. However, additional analysis
showed possible efficacy in prespecified subgroups, and further clinicalinvestigation is being pursued. In preclinical studies, we have also evaluated RRV for use in medulloblastoma, the most common malignant tumorof the pediatric nervous system. Both established and primary human
medulloblastoma cell lines supported efficient RRV replication in vitro,with spread to >90% of cells by day 10 post-inoculation, and RRV-CDtransduced medulloblastoma cells showed significant dose-dependent reduction of viability upon exposure to 5-FC, compared to controls. In an
intracerebellar HDMB03 medulloblastoma model, RRV-CD-treated mice
exhibited long-term survival while on sequential cycles of 5-FC prodrug,
until prodrug treatment was stopped, after which 25% long-term survival
was observed (median survival 110 days) as compared to controls (median survival 28 days, 100% lethality) (p=0.00007). These results support
further evaluation of RRV-mediated prodrug activator gene therapy forpediatric brain tumors.
THER-07. INHIBITION OF THE RAS SIGNALING ENHANCES VIRALONCOLYSIS IN MALIGNANT GLIOMAS
Yoshiki Arakawa, Makoto Yamaguchi, Masahiro Tanji, Yohei Mineharu,
and Susumu Miyamoto; Department of Neurosurgery, Kyoto University
Graduate School of Medicine, Kyoto, Japan
Pediatric malignant glioma indicates rapid proliferation, widely infiltrative
properties and resistance to various therapies, and carries a very poor prognosis. There are methods of using virus within novel therapies under development against malignant neoplasms, which have been studied for many
years already. We examined the treatment with sunitinib or GW5074 to ourexperimental model of vaccinia virus therapy for malignant glioma, andthen evaluated changes in the tumoricidal activity, the viral infectivity, andthe impact on the Ras signaling pathway. Glioma cells (U251MG, LN229,
LN18, rat C6) infected with vaccinia virus was fatal, in its course of death,
apoptosis and autophagy were induced. The activity of Ras signaling invaccinia-infected cells heightened in the early stage and declined in the latestage Inhibition of the Ras signaling pathway at the early stage of viral infection prevented vaccinia virus replication, while viral oncolysis was not inhibited when the pathway was blocked after sufficient viral spread. Glioma
cells infected with vaccinia virus are led to cell death. Vaccinia virus regulates Ras or other survival signaling pathways in the infected cells. It enhances the signaling in the early stage (viral replicative period), however

Abstracts

suppresses in the later stage (virus-releasing stage). Inhibition of the Ras
signaling pathway at the early stage of viral infection prevents vaccinia virus
from replicating, while viral oncolysis appears to be accelerated when thepathway was blocked after sufficient viral reproduction.
THER-08. SGT53 – A NOVEL P53 NANOMEDICINE INDUCESSIGNIFICANT RESPONSES IN CHILDREN WITH RECURRENTMEDULLOBLASTOMA AND CHOROID PLEXUS CARCINOMA:A REPORT OF TWO CASES
Eugene Hwang1, Lindsay Kilburn1, Lauren Hancock1, Kathleen Pirollo2,
Chris Leung2, Roger Packer1, and Esther Chang3; 1Children’s National
Hospital, Washington, DC, USA, 2Synergene Therapeutics, Bethesda, MD,
USA, 3Georgetown University, Washington, D, USA
BACKGROUND: Abnormal p53 function commonly defines high-risk
CNS tumors, but functional restoration has eluded investigators. SGT53 is a targeted nanomedicine encapsulating a plasmid DNA encoding
wild-type human p53 with a transferrin receptor-targeting scFv on the
nanocomplex surface resulting in efficient delivery across the BBB androbust tumor binding/uptake. Data generated by collaborators demonstrated synergy with irradiation and chemotherapy. REPORT: Two children with recurrent CNS malignancies have been treated with SGT-53,
each receiving greater than 50 infusions in combination with irradiation and chemotherapy with no grade 3/4 AEs positively attributed
to SGT-53. The first was an 11yo male with recurrent disseminatedp53+ SHH medulloblastoma, with bulky intracranial/thoracolumbar
disease. He received irradiation followed by biweekly doses of SGT-53
and temozolomide, bevacizumab and irinotecan given one week out offour. This patient exhibited a complete response of all disease on his first
follow-up scan 8 weeks after therapy initiation and remained in remission
for 8 months. The second patient was a 3yo male with disseminated recurrent choroid plexus carcinoma. He received CSI with SGT-53, followed
by SGT-53, temozolomide and irinotecan as described above, again withno related grade 3/4 AEs. He experienced a partial response to all sites of
disease and completed therapy after six months, progressing 7.8 months
after initiating treatment. CONCLUSIONS: SGT-53 was well tolerated
in two heavily-pretreated patients despite aggressive combinatorial strategies. The majority of the AEs experienced were mild and manageable.
Each patient had significant responses, suggesting that SGT-53 should be
evaluated in a clinical trial for similar patients.

THER-09. ONCOLYTIC ADENOVIRUS, DNX-2401, FOR NAIVE
DIFFUSE INTRINSIC PONTINE GLIOMAS: A PHASE I CLINICAL
TRIAL
Ignacio Iñigo-Marco1, Marisol Gonzalez-Huarriz1, Marc García-Moure2,
Ibon Tamayo3, Sandra Hervas3, Ruben Hernandez3, Maria Buñales3,
Carlos DeAndrea1, Maria Villalba2, Chris Jones4, Alan MacKay4,
Esther Hulleman5, Jasper Van der Lugt5, Guillermo Aldave6,
Blanca Lopez-Ibor7, Ana Patiño-Garcia2, Ricardo Diez-Valle8, Juan Fueyo9,
Candelaria Gomez-Manzano9, Jaime Gallego Perez de Larraya2,
Sonia Tejada8, and Marta M Alonso2; 1Clinica Universidad de Navarra,
Pamplona, Navarra, Spain, 2Clinica Universidad de Navarra, Pamplona,
Spain, 3CIMA, Pamplona, Spain, 4Institute of Cancer Research, London,
United Kingdom, 5Princess Maxima Centera, Utrech, Netherlands, 6Texas
Children´s-Baylor, Houston, USA, 7Hospital Monteprincipe, Madrid, Spain,
8Fundación Jimenez-Diaz, Madrid, Spain, 9MD Anderson Cancer Center,
Houston, USA
The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in newly diagnosed DIPG patients (NCT03178032)
followed by radiotherapy. Secondary endpoints are overall survival at
12 months, percentage of responses and induced immune response against
tumor. Tumor biopsy was performed through the cerebellar peduncle, followed by intratumoral injection of DNX-2401 (N=12). Three patientswere treated with 1x1010vp and given the lack of toxicity we escalated to
5x1010vp. The procedure was well tolerated and reduced tumor volume
was demonstrated in all patients after combined treatment (virus + radiotherapy). We performed molecular studies (RNAseq and the OncomineChildhood Research Panel from Thermo Fisher). The immune cell composition of the biopsies pre-virus injection was assessed using multiplexed quantitative immunofluorescence. T cells were hardly detectable in these tumors
while macrophages were abundant. Using a multiplexed TCR-sequencing
mRNA-based assay to analyze 18 available paired pre- and post-treatment
samples from the trial, we detected increased clonal T cell diversity following
treatment with the virus. We also measured pre and post treatment neutralizing antibodies and their relationship with survival. Finally, we performed
functional studies using 2 cell lines isolated from patients included in thistrial to assess the response to the virus (infectivity, viability, T-cell recognition). In summary, the virus has shown safety and efficacy in some patients.
The information obtained in this clinical study would aid understanding the
response of DIPG patients to viral therapies and, therefore, to better tailor
this strategy to improve the survival of these patients.

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Neuro-Oncology 22:iii474–iii506, 2020.
doi:10.1093/neuonc/noaa223

N E U R O - O NCOLOGY

Author Index  AA, M: RONC-23
Abballe, L: MODL-23
Abbas, R: MBCL-02, MBCL-29
Abbassy, M: EPEN-37
Abbou, S: DIPG-61
Abd Rani, N: LINC-03
Abdel Kerim, A: EPEN-37
Abdelaziz, A: HGG-17
Abdelaziz, Z: EPEN-37
AbdelBaki, M: ATRT-21, ATRT-26,
EPEN-28, GCT-21, GCT-23, GCT-25,
GCT-40, GCT-66, GCT-74, HGG-01,
LGG-53, MBCL-24, MBCL-46, RARE31, RARE-35, RARE-37, RARE-40
Abdel-Hafiz, A: MBRS-67, MBRS-71
Abdelmoula, B: NFB-16, TBIO-27
Abdul Rahman, E: MBCL-50
Abe, T: SURG-24
Abe, Y: SURG-17
Abedalthagafi, M: HGG-09, LGG-01,
LGG-15, MBCL-01, RARE-55
Abernethy, L: IMG-06
Abi Fadel, S: LGG-09
Abid, T: DIPG-53, LGG-35
Abiko, T: GCT-06
Abla, O: GCT-75
Aboian, M: LGG-09, LGG-53
Abongwa, C: MBCL-38, QOL-34
Abu Quider, A: MBRS-54
Abu Safieh, L: MBCL-01
Abu-Arja, M: ATRT-21, GCT-23, GCT25, GCT-40, LINC-21, RARE-35
Abu-Arja, R: GCT-25, MBCL-46,
RARE-31, RARE-40
Abukhiran, I: RARE-13
Ackerl Kristensen, I: GCT-65
Acuna Hidalgo, R: EPEN-04
Adam, C: HGG-11
Adamek, D: ETMR-22
Adamski, J: MBCL-52
AdelBaki, M: DIPG-11
Adesina, A: EPEN-25, EPEN-46,
GCT-73, PATH-29
Adil, S: DIPG-84
Adile, A: MBRS-01
Adiprabowo, S: OTHR-07

Adolph, J: EPEN-06
Aerts, I: EPCT-11, LGG-49
Afanasiev, B: MBCL-03
Afshari, F: RARE-46
Agar, N: LGG-52
Agarwal, V: MBCL-23
Agbahiwe, H: EPEN-50
Agerbaek, M: GCT-65
Agliardi, G: IMMU-16
Agnihotri, S: DIPG-47, EPEN-30
Agrawal, N: DIPG-47
Aguiar, S: GCT-58
Aguilar Mercado, V: OTHR-12
Aguilar-Bonilla, A: EPEN-45, EPEN-47,
EPEN-51, MBCL-30, RARE-48
Aguilera, D: DIPG-52, LGG-52,
MBCL-25
Agwu, C: RARE-08
Ahmad, M: LGG-01, LGG-15, MBCL-01
Ahmad, O: EPEN-42
Ahmad Bahuri, N: SURG-29
Ahmed, S: EPEN-50, HGG-17
Ahmer Hamid, S: HGG-20
Aichmüller, C: ETMR-21
Aillaud, J: MBRS-37, MBRS-47
Aisner, D: LGG-34
Ajithkumar, T: COVD-01, GCT-20, GCT29, GCT-48, GCT-61
Ajlan, A: LGG-01
Akagi, Y: IMMU-09, TBIO-08
Akasaki, Y: IMMU-12
Akiyama, M: IMMU-12
Akiyama, O: PATH-08, SURG-15
Akshintala, S: NFB-08
Akutsu, H: GCT-38
Akutsu, N: RONC-01
Al Lamki, Z: RARE-55
Al Shakweer, W: LGG-15
Alaljelaify, R: LGG-01, MBCL-01
Alammar, F: LGG-15
Alan, D: TBIO-26
Alanazi, F: LGG-01, HGG-09
Alapetite, C: GCT-20, GCT-29,
GCT-48, GCT-76
Al-Banyan, A: LGG-01,
LGG-15, MBCL-01
Al-Battashi, A: MBRS-54, RARE-17
Albert, C: IMMU-03

Albert, T: ATRT-13, ATRT-14, ETMR-05
Albornoz Alvarez, V: RONC-17
Albrecht, S: RARE-22
Alcasabas, A: LINC-23
Alcasabas, P: LINC-10
Aldana, P: RONC-22, RONC-32
Aldave, G: IMG-07, PATH-29, THER-09
Alderete, D: GCT-71, LGG-55,
RARE-50Aldrink, J: ATRT-21
Alessandro, L: LINC-05
Alexandrescu, S: EPEN-21, ETMR-06,
ETMR-17, LGG-03
Alfert, A: ATRT-14
Algar, E: EPEN-36, PATH-01
Al-Habeeb, L: LGG-01
Alharbi, M: HGG-09, LGG-01, LGG-15,
MBCL-01, RARE-17
Al-Hussaini, M: ETMR-22
Alias, H: LINC-27, LINC-31
Alimova, I: ATRT-06, DIPT-73, IMG-17
Aljabarat, w: HGG-09
Al-Karmi, S: ETMR-22, TBIO-02
Al-Khalidi, H: LGG-01
Al-khayfawee, A: IMG-18
Alkherayf, F: IMG-21
Allen, Jeffrey: DIPG-52, GCT-23, GCT66, LGG-52, NFB-08, NFB-09, NFB-17
Allen, Joshua: DIPG-52, DIPG-57,
DIPG-62, DIPG-80, HGG-18, MODL-06
Allen, K: QOL-34
Allen, R: QOL-41
Allen, S: HGG-57
Alli, S: DDEL-01
Almeida, D: GCT-57, GCT-58,
LINC-26, RARE-18
Almeida, G: SURG-08, SURG-09
Almeida, N: IMMU-23
Almeida Jr, C: ATRT-10, OTHR14, QOL-27, SURG-06, SURG-08,
SURG-09, SURG-22
Almiraz-Suarez, I: MBCL-13
AlMubarak, L: LGG-01
Almutairi, A: LGG-01, MBCL-01
AlNajjar, M: EPID-06
Alonso, M: HGG-19, THER-01,
THER-02, THER-09
Alotabi, F: LGG-01, LGG-15, MBCL-01© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial
License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, andreproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
journals.permissions@oup.com

iii474

Author Index

Aloulou, S: NFB-16, TBIO-27
Alowayn, A: MBCL-01
Alqubaishi, F: MBCL-01
Als, A: GCT-65
AlSaeed, M: LGG-01, MBCL-01
Alsolm, E: MBCL-01
Alt, J: ATRT-17, ATRT-23
Altinok, D: RARE-53
Alva, E: LGG-52
Alvarenga, G: OTHR-14
Alvaro, F: DIPG-29, DIPG-32
Alves, M: LINC-26
AlZahrani, M: LGG-01
Alzoubi, H: PATH-19
Amani, V: EPCT-18, EPEN-22, EPEN26, EPEN-31, MBRS-46
Amaral, F: GCT-57
Amariglio, L: ETMR-22
Amayiri, N: ETMR-22,
LINC-10, RARE-55
Ambruso, D: QOL-36
Amemiya, T: TBIO-08
Amend, C: HGG-43
Amin, A: MBRS-18
An, E: IMMU-17
An, S: DIPG-39
Anderson, L: QOL-46
Anderson, Richard:
QOL-22, RARE-11
Anderson, Roberta: NURS-10
Ando, R: GCT-45
Andre, N: ETMR-08,
ETMR-22, MBCL-29
Andrea, S: QOL-54
Andreiuolo, F: EPEN-27,
MBCL-02, PATH-11
Andrew, N: EPCT-11
Andrianteranagna, M: ATRT-27
Ang, M: MBCL-50
Anichini, A: DIPG-54
Annesley, C: IMMU-02
Ansari, M: DIPG-25
Anthony, D: HGG-52
Antonelli, M: EPEN-03, PATH-19
Antoniazzi, A: SURG-06
Antony, R: PATH-31
Anurathapan, U: RARE-38
Aoi, Y: DIPG-03
Aoki, K: LGG-56
Aoyama, H: RONC-16, RONC-19
Apellaniz-Ruiz, M: RARE-22
Appel, H: RONC-08
Appert, E: MODL-26, PATH-21
Apps, J: RARE-46
Aquilina, K: IMG-10, IMG-13
Arabzade, A: EPEN-30
Arai, H: MBCL-48, MBRS-38
Arai, Yasuhito: TBIO-08
Arai, Yukika: RONC-18
Arakaki, N: LINC-05

Arakawa, Yoshiki: EPID-17, GCT50, LGG-38, MBRS-22, PATH-23,
RONC-06, THER-07
Arakawa, Yuki: ETMR-12, MBRS-21,
PATH-25, RARE-39
Arakelyan, J: LINC-13, LINC-42
Araki, H: TBIO-08
Archambault, B: EPCT-13
Archer, G: EPCT-13
Ardern-Holmes, S: NFB-09
Areaux, R: NFB-09
Arenas-Ruiz, J: LINC-06
Aridgides, P: ETMR-20, MBCL-34
Ariffin, H: LINC-03
Arikoski, P: QOL-12
Armstrong, B: LGG-05,
LINC-32, TBIO-24
Armstrong, G: HGG-57, QOL-15
Armstrong, V: THER-06
Arndt, G: DDEL-12, DIPG-75
Arnold, A: ATRT-23, DIPG-12
Arnold, M: HGG-57
Arnoldo, A: ATRT-33
Arola, M: QOL-12
Aronson, M: IMMU-18, RARE-17
Arredondo Navarro, L: EPEN-13,
LINC-09, LINC-16, OTHER-12,
RARE-29, SURG-19
Arrillaga-Romany, I: HGG-18
Artemov, A: IMG-03
Arustamyan, M: LINC-13
Arvanitis, T: IMG-06
Asai, A: GCT-43, GCT-52, LGG-29,
RONC-13, RONC-26
Asai, H: HGG-24
Asatryan, E: LINC-42
Asgharzadeh, S: MODL-27
Ashenberg, O: EPEN-21
Asher, A: DIPG-46, DIPG-55,
EPID-15, LGG-31
Ashley, D: ATRT-08, ATRT-19, EPCT13, IMMU-27, MBCL-19, MBCL-25,
MBCL-37, THER-05
Atri, P: MBRS-13, MBRS-72
Atton, J: QOL-40
Auer, D: IMG-06
Auletta, J: ATRT-21, GCT-25,
MBCL-46, MBCL-51
Aung, L: HGG-06
Ausejo-Mauleon, I: THER-01
Austin, M: EPEN-14
Avagyan, A: ETMR-07, LGG-16
Avagyan, M: ETMR-07,
LINC-14, RARE-33
Avanesyan, S: MBCL-31
Avery, R: NFB-09
Avula, M: COVD-04
Avula, S: EPEN-24, IMG-03,
IMG-06, MBRS-69
Ay, F: EPEN-04

Ayad, N: MBRS-02, THER-06
Ayrault, O: ATRT-24, MBCL-21, MBRS37, MBRS-48, MBRS-51
Azambuja, A: EPID-05, PATH-18,
RARE-47, SURG-20
Azizgolshani, N: TBIO-05
Azizi, A: DDEL-03
Azizi, A: ETMR-10
Azuma, N: RARE-16

B
Babelyan, S: MBCL-04, MBCL-05
Babikir, H: HGG-53
Babila, C: DIPG-08
Bacci, R: SURG-06
Bachtiary, B: RONC-15
Bag, A: IMG-03
Bahar Ercan, A: RARE-17
Baig, M: EPCT-06, LGG-44, MBCL35, NFB-06, QOL-11, QOL-28,
RARE-19, RARE-44
Bailey, C: DIPG-06, HGG-08
Bailey, S: ATRT-25, IMG-06, IMG-08,
LINC-10, MBRS-44, MBRS-57, MBRS59, MBRS-60, MBRS-69, QOL-23,
QOL-26, SWK-09
Baird, J: ATRT-06
Baker, C: DDEL-10
Baker, S: DIPG-51, HGG-57,
HGG-22, IMMU-06
Bakhsh, E: HGG-09
Bakhshi, S: ATRT-31, LINC-33
Bakhshinyan, D: MBRS-01
Baksi, K: PATH-27
Bala, W: PATH-06
Balaguer Guill, J: LGG-55
Balakrishnan, I: ATRT-06,
DIPG-34, DIPG-73, MBRS-65,
MBRS-67, MBRS-71
Balbaid, A: HGG-09,
LGG-01, MBCL-01
Ballester, L: DDEL-09
Balyasnikova, I: MODL-12
Bander, E: DIPG-49
Bandopadhayay, P: DIPG-22, DIPG46, DIPG-53, DIPG-55, DIPG-74,
HGG-32, HGG-41, LGG-35, LGG-52,
MBCL-25, RARE-07
Banerjee, Anu: IMMU-31
Banerjee, Anuradha: SWK-10
Bano, M: QOL-54
Barahona, P: DIPG-75
Barakeh, D: LGG-01
Baraldi, H: EPID-05
Barber, R: EPID-06
Barbour, M: LGG-12
Bardakhchyan, S: ETMR-07, LGG-16,
LINC-13, LINC-14, LINC-42, RARE-33

NEURO-ONCOLOGY•DECEMBER 2020

iii475

Author Index

Bellamy, C: HGG-32
Bells, S: QOL-40
Beltrami, A: EPID-13
Bendel, A: ETMR-22, IMMU-18, LGG36, LGG-52, MBCL-21, RARE-17
Benesch, M: EPEN-09, EPEN36, EPEN-39, MBCL-07,
MBCL-09, MBCL-11
Benghiat, H: MBCL-52
Benipal, S: LGG-19
Benites Goncalves da Silva,
P: MBRS-51
Benitez-Ribas, D: IMMU-22
Benjamin-Eze, J: LGG-21
Bennet, J: LGG-55
Bennett, C: IMG-06, MBRS-69
Bennett, J: GCT-75, LGG-13,
LGG-19, LGG-50
Benzel, J: EPEN-44
Beres, S: NFB-09
Berger, W: EPEN-21
Berghuis, A: RARE-22
Bergthold, G: HGG-01
Berguet, G: EPEN-46
Berlanga, P: DIPG-61
Bernini, J: PATH-29
Bernstein, B: ETMR-17
Beroukhim, R: DIPG-53, HGG-32,
HGG-41, LGG-35, RARE-07
Berstler, J: HGG-32
Bertin, D: EPEN-03
Bertozzi, A: EPCT-11, MBCL-29
Bertrand, K: EPEN-16,
EPEN-25, EPEN-30
Besse, H: DDEL-05
Bezerra Cavalcante,
C: SURG-08
Bhakta, N: COVD-04, EPID-07
Bhambhani, K: RARE-53
Bhatia, A: GCT-41
Bhatia, K: EPEN-36, RARE-15
Bhatia, S: HGG-57
Bhattacharya, S: PATH-14
Bianchi, V: HGG-20, MBRS-54,
RARE-17, RARE-55
Bianski, B: HGG-22
Biassoni, V: DIPG-54, EPEN-03
Biegel, J: MBCL-13, MODL-13,
RARE-57, TBIO-12
Bielack, S: IMMU-18
Bielamowicz, K: NFB-09
Bienemann, A: DIPG-82
Biery, M: DIPG-10, DIPG-64
Bigner, D: IMMU-27, THER-05
Bihannic, L: ETMR-06
Billups, C: MBCL-15, MBCL-16
Bingham, R: NFB-06
Bira, K: NURS-09
Birks, D: DIPG-73
Bishop, E: TBIO-14

Bardi Lola, G: LGG-11, RARE-13
Barker, K: MBRS-33
Barnes, A: IMG-18
Barnett, K: DIPG-71
Baroni, L: COVD-04, GCT-71, LGG-55,
RARE-09, RARE-50
Barreto, J: EPID-05
Barrett, D: EPEN-43
Barretta, F: EPEN-03
Barseghyan, H: PATH-14
Bartels, U: DIPG-20, DIPG-46, DIPG55, DIPG-74, ETMR-22, GCT-21, GCT23, GCT-33, GCT-41, GCT-42, GCT-75,
LGG-55, LINC-10, LINC-11, LINC-18,
LINC-21, MBCL-26, QOL-09, RARE-09
Bartl, J: EPEN-33, MBRS-48
Bartom, E: HGG-26
Barton, C: COVD-02
Basel, D: RARE-17
Bashawri, Y: LGG-01, MBCL-01
Bashir, A: RARE-13
Bassenden, A: RARE-22
Basso, D: SURG-06
Basu, E: HGG-01
Batchelder, P: LGG-48
Batchelor, T: HGG-18
Bates, J: RONC-22
Bath, I: DIPG-60
Batra, S: MBRS-13, MBRS-72
Batt, C: MODL-17
Bauer, K: MBRS-68
Baugh, J: DIPG-77
Baumgartner, M: MBRS-39, MODL-14
Bautista, F: DIPG-35
Bavle, A: LGG-47, LGG-55
Baxter, P: EPCT-05, EPCT-16, EPCT-17,
EPCT-19, IMG-07, IMG-09, LGG-52,
MBCL-35, RONC-05, RONC-09
Bear, H: DIPG-22, DIPG-53, MODL-29
Beaudoin, W: LGG-19
Beccaria, K: DIPG-56, DIPG-58,
DIPG-61, MBCL-02
Bechensteen, A: LGG-55
Becher, B: IMMU-16
Becher, O: DDEL-11, DIPG-03, DIPG06, DIPG-43, DIPG-44, DIPG-68, EPCT05, EPEN-20, MODL-12,THER-01
Beck, A: ETMR-17
Becker, A: HGG-45,
MBRS-29, PATH-15
Becksfort, J: IMG-20
Bedgood, R: RARE-17
Bedirian, K: LINC-13,
LINC-14, LINC-42
Beera, K: QOL-09
Beez, T: EPEN-33
Behrang, A: RONC-17
Bell, D: MBRS-54
Bell, E: HGG-45, MBRS-29,
MBRS-73, PATH-15

vi476

NEURO-ONCOLOGY•

DE C E M B E R 2 0 2 0

Bison, B: DIPG-77, EPEN-06, EPEN09, EPEN-36, EPEN-39, ETMR-14,
GCT-20, GCT-76, IMG-03, IMMU-10,
MBCL-07, MBCL-09, PATH-11, QOL-13,
RARE-60, RARE-61
Biswas, A: ATRT-31, LINC-33
Bjerke, L: HGG-37, IMG-12, MODL-20
Black, Karina: SWK-11
Black, Katie: DIPG-46, DIPG-55,
DIPG-74, EPID-15
Blackburn, A: DIPG-13
Blackman, S: IMG-05
Blakeley, J: NFB-17
Bland, E: NURS-08
Blaney, S: EPEN-30
Blanluet, M: MBRS-47
Blatt, J: IMMU-08, IMMU-26
Blattner-Johnson, M: HGG-56
Blauwblomme, T: DIPG-58,
DIPG-61, MBCL-02
Blomgren, K: DIPG-35, MBCL-43
Blommaert, J: QOL-07
Bloom, J: SWK-02
Blue, M: DDEL-02, GCT-66, MBCL-13
Blumcke, I: LGG-33
Blümel, L: EPEN-33
Blumenthal, D: IMMU-18, RARE-17
Blyth, G: DIPG-03
Bockmayr, M: MBCL-06, MBCL-09
Boddaert, N: DIPG-58,
DIPG-61, HGG-11
Boekhoff, S: RARE-59,
RARE-60, RARE-61
Boisselier, B: HGG-40
Bolin, S: MBRS-10
Bollard, C: EPCT-15, IMMU-15
Bolle, S: MBCL-02
Bomanji, J: IMG-18
Bond, H: DIPG-55
Bondoc, A: ATRT-16,
DDEL-01, TBIO-02
Boni, V: EPCT-08
Bonner, E: DIPG-38,
EPCT-12, IMMU-31
Boonkird, A: RARE-38
Boop, F: EPEN-50, ETMR-06,
LINC-35, RARE-12
Boorgula, M: EPEN-38
Bootwalla, M: RARE-57, TBIO-12
Borchert, M: NFB-09
Borgenvik, A: MBRS-10
Borkhardt, A: EPEN-33,
IMMU-19, MBRS-48
Bornhorst, M: LGG-55, NFB-09,
PATH-14, RARE-17
Borodina, I: ATRT-05,
MBCL-31, MBCL-32
Borsuk, R: DIPG-62
Boschetti, L: EPEN-03
Bossler, A: RARE-13

Author Index

Botta, G: TBIO-26
Bouayed Abdelmoula, N:
NFB-16, TBIO-27
Bouaziz, I: NFB-16
Bouche, G: EPCT-11
Boudreaux, A: TBIO-13
Boué, D: ATRT-21, EPEN-17, EPEN-28,
GCT-25, HGG-45, LGG-31, LGG-55,
LINC-11, MBCL-13, MBCL-46,
PATH-14, PATH-15, RARE-31,
RARE-37, RARE-40, RARE-51
Bouffet, E: COVD-04, DIPG-20, DIPG46, DIPG-55, DIPG-74, ETMR-06,
ETMR-21, ETMR-22, GCT-75, HGG-20,
IMG-03, IMMU-18, LGG-19, LGG-25,
LGG-49, LGG-55, LINC-10, MBCL24, MBCL-26, MBRS-20, MBRS-54,
MODL-25, NFB-09, PATH-14, QOL-01,
QOL-40, RARE-02, RARE-17, RARE-38,
RARE-55, RONC-03
Boult, J: IMG-12, MBRS-33, MODL-20
Bourdeaut, F: ATRT-27, ETMR22, HGG-11, MBCL-29, MBRS-37,
MBRS-47, RARE-21
Bourneix, C: MBRS-47
Boutarbouch, M: ETMR-22
Bowers, D: ETMR-06, IMG-03, IMMU18, LGG-52, MBCL-08, MBCL-21
Bowie, M: ATRT-19
Box, G: IMG-12
Boyce, D: RONC-17
Boynton, A: HGG-32
Bradley, J: RONC-22,
RONC-24, RONC-32
Bradshaw, G: ATRT-02, MODL-21
Branagan, L: SWK-10
Brandes, A: IMG-03, IMG-04
Brasel, K: MODL-28
Brat, D: DIPG-44, EPEN-20
Braun, F: EPEN-46, MBRS-17
Braun, R: GCT-73
Brega, N: EPCT-08
Breneman, J: EPCT-16
Brennan, P: EPEN-17
Breuer, A: PATH-22
Breur, M: ATRT-18, DIPG-33
Bridge, T: MODL-25
Bridget, S: DIPG-73
Briere, T: RONC-17
Brimley, C: IMMU-11
Brinkman, T: QOL-15
Briones, N: QOL-36
Brisse, H: GCT-20, GCT-76
Brodsky, M: NFB-09
Bronen, R: LGG-09
Broniscer, A: EPCT-02, IMMU-18
Bronischer, A: PATH-14
Bronsema, A: IMMU-18, RARE-17
Brougham, M: NURS-03,
QOL-14, QOL-49

Broughton, C: DDEL-10
Brown, A: TBIO-26
Brown, Benjamin: DIPG-42
Brown, Brandon: IMMU-07
Brown, K: MBRS-01
Brown, Michael: THER-05
Brown, Miguel: DIPG-31
Brownfield, R: SWK-03
Bruce, J: DDEL-07, DDEL-13
Brück, W: MBCL-07
Bruckert, L: NFB-11
Bruggers, C: EPEN-07, GCT-70
Brugieres, L: MBCL-21, RARE-21
Bruin, M: DDEL-05
Brummer, T: LGG-14, LGG-17
Brunet, J: RARE-22
Brunner, C: MODL-14
Brusniak, M: DIPG-10
Bruzek, A: DIPG-08, HGG-18
Buccoliero, A: EPEN-03,
ETMR-22, MODL-26
Buchan, G: DIPG-53, LGG-35
Buchhalter, I: MBCL-21
Buck, J: RONC-02
Budach, V: MBCL-11
Bugiani, M: ATRT-18, DIPG-33
Buhl, J: LGG-17
Bukowinski, A: EPCT-17
Bull, K: QOL-17, QOL-32, QOL-33
Büllesbach, A: ATRT-28
Bump, R: EPEN-04
Buñales, M: THER-09
Bund, C: TBIO-17
Bunt, J: ETMR-13
Buntine, M: EPEN-36, PATH-01
Bunzen, H: ATRT-15
Burela, N: RONC-23
Burford, A: DIPG-63, MODL-20
Burger, P: ETMR-20, MBCL-15, MBCL16, MBCL-34, PATH-24
Burns, J: ATRT-25
Burns, M: DIPG-15, DIPG-16
Burte, F: MBRS-69
Buschmann, L: RARE-59
Businaro, P: IMMU-13
Butowski, N: HGG-18
Buttar, A: EPID-08
Buttarelli, F: EPEN-03
Butterfield, L: IMMU-31
Byer, L: QOL-53

C
Cabezon, R: IMMU-22
Cable, J: THER-05
Cacchione, A: HGG-19, HGG-54, IMG14, IMG-16, IMG-19, LGG-18, MBCL18, NFB-07, PATH-19

Cacciotti, C: DIPG-01, IMMU-01, LGG03, MBCL-24, QOL-02, QOL-41, QOL-46
Cáceres, A: LINC-21
Cai, H: EPEN-05
Cai, J: IMMU-28, TBIO-21
Cai, L: DIPG-26, GCT-26, GCT-27, GCT28, GCT-63, HGG-14
Cain, J: ATRT-02, ATRT-08,
ATRT-22, DIPG-18, DIPG-64,
MODL-21, MODL-26
Cairney, E: RARE-17
Caisova, V: IMMU-15
Calaminus, G: GCT-20, GCT-29, GCT48, GCT-49, GCT-61, GCT-76
Caldeira Queiroz, F: MBRS-66
Calhoun, J: IMMU-20
Califano, A: DIPG-40
Camarillo, J: DIPG-39
Camelo-Piragua, S: ETMR-22
Cameron, I: IMG-21
Campagne, O: EPCT-05,
EPCT-17, EPCT-19
Campbell, A: LGG-22
Campbell, K: IMMU-21
Campbell, M: EPEN-36, RARE-15
Campen, C: NFB-04, NFB-09, NFB-11
Campion, A: IMG-10
Campos, D: RARE-42
Čančer, M: MBRS-10
Canete, A: LGG-55
Caniza, M: COVD-04
Canoll, P: DDEL-07, DDEL-13,
LGG-22, MODL-09
Cantin, E: LGG-25
Cantor, E: DIPG-08, HGG-18
Cao, X: DIPG-59
Capdeville, C: MBRS-39
Cappellano, A: GCT-23, GCT-57, GCT58, LINC-26, RARE-18
Capper, D: LGG-33, PATH-04, PATH-11
Capra, M: EPCT-08
Carai, A: HGG-16, HGG-19, HGG-54,
IMG-14, IMG-16, IMG-19, IMMU-13,
LGG-18, MBCL-18, MBRS-60, NFB-07,
PATH-19, SURG-03
Carboni, A: IMG-14, IMG-16,
IMG-19, SURG-03
Carcaboso, A: DIPG-29, DIPG-32,
DIPG-51, IMG-12, IMMU-22
Carceller, F: GCT-61, MODL-20
Cardall, A: MBRS-45
Cardenas, A: HGG-01
Carenzo, A: DIPG-54
Caron, A: PATH-13
Carr, M: ATRT-08
Carr, S: DIPG-53
Carrasquedo Benito, E: DIPG-55
Carroll, S: IMMU-18, RARE-17
Carruthers, V: IMG-08
Carson, J: EPCT-18

NEURO-ONCOLOGY•DECEMBER 2020

iii477

Author Index

Chapman, R: EPEN-18,
EPEN-24, EPEN-42
Chapman, S: LGG-23
Chappe, C: MBCL-29
Chastagner, P: EPCT-11
Chaterjee, A: LINC-12
Chattopadhyay, A: EPEN-24
Chatwin, H: DIPG-42,
DIPG-79, MODL-31
Chaubey, V: MBRS-61
Chaudhuri, S: DDEL-10
Chavez, L: EPEN-04
Chen, Hsiao-Chi: EPEN-30
Chen, Hsin-Hung: HGG-05, MBCL-20
Chen, L: IMG-22
Chen, M: IMG-15
Chen, Q: IMMU-28, TBIO-21
Chen, Shu-Huey: RARE-45
Chen, Shu-Mei: RARE-45
Chen, X: MBRS-10
Chen, Yichen: COVD-04
Chen, Yii-Wei: HGG-05
Chen, Youdinghuan: TBIO-05
Chen, Zhihong: THER-01
Chen, Zhongping: EPEN-05, GCT-30
Cheng, A: EPEN-53
Cheng, D: DIPG-57, MBRS-64
Cheng, Kevin: QOL-25
Cheng, King-Fai: HGG-48
Cheng, S: DIPG-46, DIPG-74, EPID-06,
EPID-08, GCT-59, HGG-35, LGG-19,
NFB-12, SWK-08
Chern, J: RARE-11
Cheshier, S: IMG-10, IMG-13, IMG-22,
IMMU-19, MBRS-31
Chesler, L: MBRS-33, MBRS-57
Cheuk, D: QOL-25
Cheung, C: OTHR-09
Chevignard, M: QOL-17
Chheda, E: LINC-08
Chi, A: HGG-18
Chi, S: DIPG-53, EPCT-01, ETMR-08,
GCT-23, GCT-59, IMMU-01, IMMU-31,
LGG-03, MBCL-25
Chiacchiaretta, P: IMG-19
Chiang, J: EPEN-50, ETMR-06, IMG20, IMMU-06, LINC-35
Chiapparini, L: EPEN-03, IMG-09
Chiaravalli, S: HGG-20,
IMMU-18, RARE-17
Chiba, T: PATH-05
Chiba, Y: GCT-69
Chick, E: QOL-38
Childs, B: EPCT-08
Chilukuri, S: RONC-23
Chimelli, L: PATH-30
Chinnaiyan, A: DIPG-59
Chinnaiyan, P: TBIO-01
Chinnaswamy, G: LINC-07, LINC-08,
LINC-12, LINC-25, LINC-29, MBRS-61

Carson, R: NURS-10
Cartaxo, R: DIPG-64, HGG-18
Carter, H: EPEN-04
Carter, L: RARE-20
Carter, T: HGG-08
Carter Febres, M: GCT-70
Caru, M: LGG-25
Caruana, I: IMMU-13, MODL-23
Carvalho, D: DIPG-53, MODL-19,
MODL-20, PATH-17
Casavilca, S: RARE-42
Cascão, R: EPEN-33
Cash, T: HGG-01
Casillas -Toral, E: LINC-09
Cassano, D: DDEL-12
Castel, D: DIPG-56, DIPG-58, DIPG-61
Castellino, R: MBCL-25
Castro, M: DIPG-59, IMG-12
Catanzaro, G: MODL-23
Catchpoole, D: ETMR-22
Caulo, M: IMG-16, IMG-19
Cavalcante, C: SURG-22
Cavalheiro, S: GCT-58, LINC-10,
LINC-26, RARE-18
Cazals-Hatem, D: HGG-11
Chaari, H: NFB-16
Chabot, J: SWK-03
Chaffee, B: NFB-05
Chai, Y: ATRT-09, IMMU-29
Chakraborty, A: EPEN-04
Chakravarti, A: HGG-45, MBRS-29,
MBRS-73, PATH-15
Chaleff, S: RARE-23, RARE-49
Chamdin, A: RARE-17
Chamdine, O: LINC-10
Chammas, A: TBIO-17
Chan, D: EPEN-14
Chan, G: EPID-10, HGG-27, HGG-48,
LINC-15, LINC-20, QOL-25
Chan, K: LGG-42
Chan, M: LGG-44
Chan, P: EPEN-07
Chan, S: HGG-27
Chandra, J: DIPG-06,
HGG-08, RARE-19
Chandramohan, V: IMMU-27
Chandran, S: EPEN-04
Chaney, B: DIPG-46, DIPG-55,
DIPG-74, EPID-15
Chang, Cecilia: DIPG-13
Chang, Che-Chang: ATRT-01
Chang, Chia-Yau: RARE-45
Chang, D: QOL-25
Chang, Ellen: LGG-45
Chang, Esther: THER-08
Chang, H: RARE-45
Chang, K: IMG-01
Channell, J: QOL-36, QOL-38
Chantada, G: COVD-04
Chapman, O: EPEN-04

vi478

NEURO-ONCOLOGY•

DE C E M B E R 2 0 2 0

Chintagumpala, M: DIPG-55, DIPG74, EPEN-25, EPEN-46, ETMR-06,
IMG-03, IMG-07, LGG-55, MBCL-08,
MBCL-21, MBCL-26, MBCL-35, MBRS20, PATH-27, PATH-29, QOL-01, RONC05, RONC-09, RONC-12
Chivet, A: MBRS-51
Cho, B: GCT-12
Cho, H: MBCL-28
Cho, S: EPCT-09
Cho, Yoon-Jae: IMMU-14
Cho, Yuko: GCT-08, GCT-10,
GCT-31, SURG-02
Choe, G: GCT-12, GCT-13
Chohan, S: HGG-01
Choi, B: GCT-12, GCT-13
Choi, H: GCT-12, GCT-13
Choi, Jeea: LGG-49
Choi, Jungwhan: IMMU-01
Choi, S: MBRS-56
Chong, A: RARE-22
Chong, W: ATRT-22, DIPG-18
Chordas, C: IMMU-01,
LGG-03, QOL-41
Chou, I: DIPG-23
Chou, N: RARE-01
Chowdhury, S: TBIO-19
Chrétien, F: HGG-11
Christensen, A: QOL-54
Christensen, B: TBIO-05
Christine, W: PATH-01
Christou, S: TBIO-16
Chulkov, E: ATRT-05
Chulkov, O: MBCL-31
Chung, J: IMMU-18
Chung, S: EPEN-15
Cianciolo Cosentino, C:
DIPG-64, MODL-22
Ciolfi, A: MODL-23
Ciołkowski, M: RARE-31
Cirilo, G: DDEL-12
Clapp, W: NFB-17
Clarke, M: MODL-20, PATH-17
Classen, C: HGG-07
Clauser, K: TBIO-26
Cleveland, A: MBRS-08
Clifford, S: ATRT-25, MBCL-11,
MBRS-10, MBRS-33, MBRS-44,
MBRS-57, MBRS-59, MBRS-60,
MBRS-69, QOL-17
Cloughesy, T: HGG-18, THER-06
Clymer, J: IMMU-01, LGG-03
Cobb, D: IMMU-17
Coblentz, A: IMMU-18
Cochrane, D: EPID-08
Cockle, J: IMG-18
Cohen, B: MBCL-19, MBCL-37
Cohen, K: DIPG-46, DIPG-74, EPEN42, IMG-09, LGG-49, LGG-52,
MBCL-24, MBCL-25

Author Index

Cohen, R: NFB-03
Cohn, R: MBCL-26, MBRS-20
Colafati, G: HGG-54, IMG-14, IMG-16,
IMG-19, LGG-18, MBCL-18, NFB-07,
PATH-19, SURG-03
Colaprico, A: TBIO-19
Colditz, N: DIPG-77
Cole, A: ATRT-24
Cole, B: DIPG-10, IMMU-03
Cole, K: HGG-20, HGG-37, IMG-12,
IMMU-18, PATH-21
Colletti, M: HGG-16, HGG-19
Collier, T: DIPG-06
Collins, P: DIPG-82
Collins, S: THER-06
Colman Abadi, C: DIPG-64
Colte, P: QOL-20
Coltin, H: LGG-19
Condurat, A: DIPG-53, LGG-35
Conklin, H: QOL-01
Conley, S: ATRT-21, GCT-25
Constantini, S: HGG-20, IMMU-18,
MBCL-17, NFB-03, RARE-17
Cook, C: DDEL-07
Cooney, T: DIPG-46, DIPG-55,
GCT-23, IMG-09
Cooper, K: SWK-07
Cooper, R: HGG-47
Cornwell, B: LGG-47
Cortnum, S: ETMR-01, GCT-65
Cote, A: NURS-04
Cotter, J: LGG-45, RARE-57, TBIO-12
Cottrell, C: ATRT-21, EPEN-28,
RARE-31, RARE-37
Coufal, N: EPEN-04
Court, W: HGG-16
Coven, S: DIPG-46, DIPG-55, DIPG-74,
EPID-11, LGG-55, LINC-32, MBCL-51,
QOL-58, SWK-03
Cowley, M: DIPG-50, DIPG-75
Cox, E: QOL-40
Coxhead, J: MBRS-59
Coyle, B: MBRS-27, MBRS-28, MBRS42, MBRS-43, MBRS-45
Crawford, J: EPEN-04, ETMR-06,
IMMU-31, MBCL-21, NFB-09
Crespo, M: ATRT-20
Cripe, MD, PhD, T: DIPG-11
Cristofani, L: EPID-05
Crombie, D: DIPG-18
Crooks, B: HGG-20, MBCL-24
Crosier, S: ATRT-25, MBRS-44, MBRS59, MBRS-60, MBRS-69
Cross, J: COVD-01, GCT-76
Crotty, E: MODL-28
Crump, D: NURS-10
Cruz, O: IMMU-22, LGG-55
Cruz Flores, V: LGG-28,
RARE-06, RARE-36
Cullen, P: QOL-20

Cunliffe-Koehler, K: HGG-53
Currimjee, N: HGG-32
Curry, D: EPEN-25
Curry, H: MBCL-52
Curry, R: DIPG-11
Curry, S: RARE-34
Cutillas, P: LGG-57
Cutter, G: NFB-09
Czech, T: DDEL-03, EPEN-21, ETMR10, ETMR-17, GCT-49, HGG-44,
MBCL-43

D
da Silva Camacho, A: PATH-30
Dafni, A: HGG-04
Daghistani, D: DIPG-52, HGG-18
Dahiya, A: EPID-08
Dahiya, S: LGG-55
Dahl, C: ETMR-22
Dahl, N: DIPG-34, DIPG-73, IMG-17,
MBRS-26, MBRS-67, OTHR-16
Dama, H: RONC-03
Dammnett, S: DDEL-07
Damodharan, S: NFB-14
Dandapani, M: TBIO-14
Dang, M: TBIO-07
Dangouloff-Ros, V: DIPG-35, DIPG-61
Daniel, P: ATRT-02, DDEL-16, DIPG-76,
DIPG-78, EPEN-35
Danielyan, S: ETMR-07, LGG-16,
LINC-13, LINC-14, LINC-42, RARE-33
Danilenko, M: MBRS-59
Danis, E: ATRT-06, DIPG-34, DIPG-73,
MBRS-26, MBRS-67, MBRS-71
Dao, L: DIPG-60
Darbinyan, A: LGG-09
Darlington, A: QOL-32, QOL-33
Darrow, K: RARE-12
Das, A: MBRS-54, RARE-17
Das, M: MBRS-18
Das, S: LGG-13
Dastoli, P: GCT-58, LINC-10,
LINC-26, RARE-18
Datar, A: EPCT-15
Date, I: MBRS-38, SURG-21
Dauser, R: IMG-07, QOL-01
Dauta, A: HGG-11
Davidson, A: LINC-10Davidson, N: DIPG-73
Davidson, T: IMMU-30, LGG-52,
NURS-09, RARE-35
Davies, K: LGG-34
Davis-Dusenbery, B: EPID-14
Day, C: DIPG-05, DIPG-76, DIPG-78
Daylidite, V: MBCL-04, MBCL-05
De Angelis, B: IMMU-13
De Benedictis, A: SURG-03

De Billy, E: HGG-16, IMMU-13
de Blank, P: EPCT-19, IMG-03, LGG30, LGG-31, NFB-09
De Carli, E: EPCT-11,
HGG-40, MBCL-29
De Cecco, L: DIPG-54
de Faria, F: ATRT-14,
EPEN-17, ETMR-05
De Feo, D: IMMU-16
de Gooijer, M: ATRT-18
de la Mora Carnalla, M: SURG-19
de la Nava, D: THER-02
de Medeiros, C: QOL-40
de Medeiros, R: MBRS-18
De Mola, R: IMMU-18
De Palma, L: HGG-19
De Raedt, T: PATH-21
de Rossi, J: IMMU-17
De Stefanis, C: IMMU-13
DeAndrea, C: THER-09
Debily, M: DIPG-35, DIPG-56, DIPG58, DIPG-61, HGG-11
Décarie, J: LGG-25
Dedekam, E: HGG-43, RARE-41
Dedekian, M: RARE-49
Deeg, C: EPEN-28
Deek, M: RONC-27
DeGroot, J: HGG-18
Deguchi, T: ATRT-11, HGG-49
Deinlein, F: MBCL-07, PATH-07
Del Baldo, G: IMG-14, IMG-19,
NFB-07, SURG-03
Del Bufalo, F: MODL-23
Delattre, O: MBRS-37,
MBRS-47, RARE-21
Delisle, M: MBCL-29
Delorenzo, M: PATH-12
Dembowska-Baginska, B:
HGG-21, RARE-58
Demir, A: ETMR-22
Demizu, Y: RONC-01, RONC-04
Dempster, J: TBIO-26
Deneen, B: EPEN-30
Deng, M: MBCL-08
Depani, S: MODL-19
Depreitere, B: RARE-56
Deprez, S: QOL-07
DeRenzo, C: IMMU-05
Derieppe, M: DDEL-05
DeRosa, V: QOL-34, SWK-05
Desai, A: HGG-01
Desai, J: ATRT-08
DeSantes, K: EPCT-09
Deshpande, G: MBRS-61
DeSisto, J: DIPG-42, DIPG-79,
HGG-57, MODL-31
Desplanques, M: HGG-11
Desprez, P: DIPG-59
Dettwiler, S: MODL-22
Deutsch, M: EPCT-16

NEURO-ONCOLOGY•DECEMBER 2020

iii479

Author Index

Donson, A: DIPG-73, EPCT-18, EPEN22, EPEN-23, EPEN-26, EPEN-31,
HGG-57, IMMU-20, MBRS-46, MODL24, MODL-31, QOL-36, RARE-08
Dontenwill, M: HGG-36, TBIO-17
Dorfer, C: EPEN-21
Dorfmüller, G: HGG-11
Dörner, E: EPEN-27, HGG-34
Dorris, K: DIPG-42, DIPG-46, DIPG-55,
DIPG-74, EPCT-17, EPCT-18, HGG-57,
LGG-27, LGG-52, MBCL-24, NURS-12,
OTHR-16, QOL-36, RARE-08, RARE-10
Dory-Lautrec, P: EPCT-11
dos Santos, A: QOL-27
dos Santos Aguiar, S:
LGG-51, MBRS-66
Doshi, J: LGG-35
Dotan, G: NFB-03
Doughman, R: EPCT-16, EPID-15
Douglas, A: DIPG-29
Downie, P: ATRT-22, LGG-42
Doz, F: EPCT-08, HGG-11, MBRS-37,
MBRS-47, QOL-17
Drake, J: RARE-09
Drapeau, A: GCT-25, RARE-11
Drinkwater, C: MODL-21
Driscoll, T: EPCT-13
Drissi, R: DIPG-21, DIPG-46, DIPG-74,
EPCT-16, EPCT-19, LGG-31
Drummond, J: DDEL-17
Druy, A: LGG-26, MBCL-32, RARE-52
Du, Y: EPEN-46, MBRS-17
Duarte, A: QOL-27
Dubal, D: QOL-53
Dubois, F: DIPG-22, HGG-41
DuBois, S: EPCT-08
Dubuc, A: MBRS-10
Duchatel, R: DIPG-29, DIPG-32
Duckworth, J: QOL-02, QOL-46
Dudley, R: QOL-22, RARE-11
Dufour, C: ETMR-21, ETMR-22, MBCL02, MBCL-21, MBCL-29, RARE-21
Dugas, M: ATRT-13, ATRT-14
Duke, E: DIPG-80
Dulson, H: QOL-49
Dun, M: DIPG-29, DIPG-32
Dunaeva, N: ATRT-05, MBCL-31
Duncan, W: NFB-12
Dunham, C: ETMR-22,
HGG-35, NFB-12
Dunkel, I: EPCT-02, EPCT-05, EPCT07, EPCT-17, IMG-04, LGG-04,
LGG-55, RARE-35
Dunn, G: IMMU-18
Dunst, J: MBCL-11
Duplan, M: HGG-40
Durno, C: IMMU-18,
RARE-17, RARE-55
Dvir, R: IMMU-18, MBCL-17,
MBRS-54, RARE-17

Devanir da Costa, M: LINC-10
Devenney, I: GCT-76
Devidas, M: COVD-04
DeWire, M: EPCT-17, EPCT-19, EPID-15
DeWire- Schottmiller, MD, M: DIPG11, DIPG-46, DIPG-55, DIPG-74, EPCT05, LGG-30, LGG-31
Dey, B: DIPG-47
D’Gama, A: GCT-37
Dhall, G: ATRT-30, DDEL-02, EPCT-02,
EPCT-05, GCT-23, GCT-33, GCT-41,
GCT-42, GCT-66, IMG-09, IMMU-08,
LGG-04, LGG-52, MBCL-08, MBCL-13,
MBCL-19, MBCL-23, MBCL-37, MBCL51, MBRS-29, MBRS-73, RARE-35
Dhar, S: DIPG-44
Dharmendra, G: LINC-02
Dhermain, F: HGG-11, MBCL-02
Dholaria, H: DIPG-46,
DIPG-55, DIPG-74
Dhouib, R: NFB-16
Dhyani Rahmartani, L: OTHR-07
Di Carlo, D: DIPG-61
Di Giannatale, A: HGG-16, HGG-19
Di Paolo, V: HGG-19
Diamante - San, L: LINC-23
Diaz, A: HGG-53
Diaz, J: LINC-21
Diaz, R: RARE-42
Diaz Coronado, R: GCT-59
Dickson, D: QOL-38
Dieckmann, K: ETMR-10, MBCL-11
Dietzsch, S: DIPG-77,
EPEN-06, MBCL-11
Diez, B: DIPG-46, LINC-05
Diez-Valle, R: THER-09
DiGiovanna PhD, J: EPID-14
Dikow, N: RARE-21
Dimitriadis, C: EPEN-33
Dimitrova, M: TBIO-14
Dineen, R: EPEN-24, MBRS-69
Diomedi Camassei, F: HGG-54, IMG14, IMG-19, LGG-18, MBCL-18, MODL23, NFB-07, PATH-19
Dirks, P: ETMR-22, IMMU-18,
LGG-55, RARE-09
Dismuke, T: MODL-03
Dixon, J: EPEN-04
Djirackor, L: TBIO-18
Dobrikova, E: THER-05
Dobson, T: DIPG-57,
MBRS-53, MBRS-70
Doddamani, R: EPEN-38
Dodgshun, A: DIPG-55, DIPG-74,
ETMR-22, HGG-20, RARE-50
Dohmen, H: MBCL-07
Dokal, A: LGG-57
Dombi, E: NFB-17
Domogalla, M: DIPG-38
Donahue, S: NFB-09

vi480

NEURO-ONCOLOGY•

DE C E M B E R 2 0 2 0

Dyke, J: DIPG-50
Dykema, K: ETMR-18

E
Eberhart, C: ATRT-17, ATRT-23, DIPG12, DIPG-70, DIPG-71, MBRS-06,
MBRS-16, MODL-04
Ebert, B: DIPG-53
Ebert, M: RONC-02
Eccles, E: EPID-11, QOL-58, IMG-12
Eckel, L: EPEN-35
Ecker, J: LGG-17, MBCL-06, MBRS-19
Eckerdt, F: DIPG-03
Edelstein, K: RARE-02
Edjlali-Goujon, M: HGG-11
Edwards, C: QOL-53
Edwards, L: NFB-17
Edwards, Melissa: HGG-20, IMMU14, IMMU-18, MBRS-54, MODL-25,
RARE-17, RARE-55
Edwards, Michael: IMG-22
Ehteda, A: DDEL-12, DIPG-07, DIPG14, DIPG-15, DIPG-27
Eisenstat, D: DIPG-43, LGG-55,
MBCL-24, SWK-11
Ejmont, M: HGG-21
Ekert, P: DIPG-75
El Beltagy, M: LINC-10
El Houdzi, J: RARE-55
El-Ayadi, M: DIPG-25, DIPG-46, DIPG74, EPEN-50, HGG-17
El-beltagy, M: HGG-17
El-Dairi, M: NFB-09
El-Deiry, W: DIPG-62
Elhasid, R: MBCL-17
Elhassan, M: LINC-10
Elijovich, L: RARE-12
El-Khouly, F: DIPG-33, DIPG-84
Ellezam, B: ETMR-22
Ellezam, B: LGG-25
Ellingson, B: HGG-18
Ellison, D: EPEN-54, ETMR-06,
ETMR-21, LGG-50, MBCL-21,
MBRS-20, RARE-40
Elmquist, W: DDEL-09, DDEL-10
El-Naggar, S: HGG-17, RARE-55
Elsaba, B: EPEN-37
Elshaer, D: MODL-25
El-Sheikh, A: DIPG-46
Elster, J: LGG-53
Eltobgy, M: ATRT-26
Elzawahry, A: GCT-52
Emanuele, P: ETMR-22
Embry, L: QOL-20
Emtsova, V: EPEN-50
Enache, O: TBIO-26
Endersby, R: DIPG-50, RONC-02
Endozo, R: DIPG-37

Author Index

Englander, Z: DDEL-07, DDEL-13
Englinger, B: EPEN-21, ETMR-06
English, M: EPEN-24,
MBCL-52, RARE-46
Ennin, E: RARE-24
Ennis, B: DIPG-31
Entz-Werle, N: EPCT-11, HGG-36,
MBCL-29, TBIO-17
Eom, K: GCT-02
Epari, S: LINC-25, LINC-29, MBRS-61
Epelman, S: DIPG-72, EPID12, GCT-58, GCT-59, LGG-51,
MBRS-18, MBRS-66
Erbetta, A: EPEN-03, IMG-09
Ercan, A: IMMU-18
Erker, C: EPID-06, IMG-04,
LGG-25, MBCL-24
Ernst, K: ATRT-28, HGG-22, MBRS-03
Erson Omay, Z: LGG-09
Ertl-Wagner, B: GCT-75
Esbenshade, A: NFB-09
Escamilla-Asiain, G:
LINC-39, LINC-40
Escamilla-Luna, P: LINC-04
Esiashvili, N: LINC-10
Espejo, A: HGG-08
Espinoza, F: LINC-21
Espinoza, X: LINC-21
Estecio, M: MBRS-70
Ettlinger, R: ATRT-15
Eugene, H: ETMR-22
Eugui, G: OTHR-14, SURG-08
Euskirchen, P: MBRS-47, TBIO-18
Evangelous, T: IMMU-27
Evans, D: RARE-23
Evans, G: RARE-21
Evans, N: NFB-12, RARE-25
Eveslage, M: RARE-61
Eyrich, M: IMMU-10, QOL-24
Eze, A: TBIO-03

F
Fabian, M: RARE-22
Fadel, S: EPEN-37
Fader, M: DDEL-14
Fadness, S: DIPG-05
Fahiminiya, S: RARE-22
Failes, T: DDEL-12, DIPG-75
Faillot, T: HGG-11
Faldum, A: EPEN-39,
MBCL-07, QOL-24
Fallah Azad, V: RARE-17
Fan, X: ETMR-19
Fang, K: LGG-13
Fangusaro, J: EPCT-02, ETMR-22,
GCT-33, GCT-41, GCT-42, IMG-03,
LGG-04, RARE-35

Farah, R: HGG-20,
MBRS-54, RARE-17
Faria, C: EPEN-33
Farouk Sait, S: EPCT-07
Farrow, B: EPID-14
Farruggia, G: DIPG-07
Faughnan, L: COVD-04
Faught, A: RARE-12
Faulk, K: ATRT-30
Faulkes, S: THER-03
Faure Conter, C: EPCT-11, GCT-20,
GCT-29, GCT-48, GCT-49, GCT-76,
LGG-55, MBCL-29
Faustino, F: ATRT-10
Fay-McClymont, T: MBCL-24
Fazal Salom, J: MODL-20
Feinberg, A: DIPG-12, DIPG-70
Feldstein, N: DDEL-07, DDEL-13
Felix, A: DIPG-56
Fellah, S: NFB-16
Fen, J: MBCL-12
Fenyo, D: TBIO-19
Ferguson, D: SURG-12
Ferguson, E: DIPG-10
Ferman, S: LINC-28, PATH-30
Fernandez, E: LINC-21
Fernandez Ponce, N: GCT-71
Fernandez-De Luna, M: LINC-04
Fernandez-Ledon, S: EPID-03
Fernando, D: MODL-21
Ferner, R: NFB-09
Ferrari, F: IMMU-13
Ferrazzoli, V: IMG-18
Ferretti, E: IMG-16, IMG-19, MODL-23
Ferretti, R: HGG-19, IMMU-13
Ferretti, V: EPID-14
Fettig, T: SWK-12
Feyen, O: DIPG-38
Figaji, A: LINC-10
Figarella-Branger, D: HGG-11
Figueiredo Nobre, L: LGG-19
Figueroa, M: DIPG-06
Filbin, M: DIPG-64, EPCT-12,
EPEN-21, ETMR-06, ETMR-08,
ETMR-17, HGG-53
Filipek, I: RARE-31
Filipski, K: MBCL-07
Finch, E: LGG-55
Finetti, M: ATRT-25
Finlay, J: ATRT-21, ATRT-26, DDEL-02,
EPEN-17, EPEN-28, EPID-11, GCT-23,
GCT-25, GCT-40, GCT-58, GCT-66,
GCT-74, HGG-45, LGG-31, LGG-55,
LINC-11, LINC-18, LINC-21, LINC-28,
MBCL-13, MBCL-19, MBCL-23, MBCL24, MBCL-37, MBCL-46, MBCL-51,
MBRS-29, MBRS-73, PATH-12, PATH15, RARE-31, RARE-35, RARE-37,
RARE-40, RARE-51
Finney, O: IMMU-02

Firestein, R: ATRT-02, DIPG-18,
MODL-21, MODL-26
Fischer, U: EPEN-33
Fisher, K: EPEN-25, PATH-27, PATH-29
Fisher, M: ETMR-06, ETMR-08,
GCT-23, IMG-03, MBCL-14, MBCL-26,
MBRS-20, NFB-09, NFB-17
Fisher, P: DIPG-46, DIPG-55, DIPG-74,
IMG-13, MBCL-14
Fisyun, I: ATRT-05, MBCL-31
Fitzgerald, C: NURS-01
Fitzgerald, T: MBCL-15
Flaherty, M: NFB-09
Flahiff, C: EPCT-13
Flannery, P: DIPG-42,
HGG-57, MODL-31
Fleischhack, G: EPEN-06, EPEN-47,
MBCL-07, QOL-24
Fleming, A: QOL-02, QOL-46,
HGG-45, MBRS-01, MBRS-29,
MBRS-73, PATH-15
Flórez-Grau, G: IMMU-22
Florman, J: RARE-23
Fofana, M: IMG-12, MODL-20
Fong, D: QOL-25
Fonseca, A: DIPG-20
Foo, J: LINC-02
Foord, T: GCT-61
Foot, K: TBIO-16
Foran, S: RARE-02
Ford, D: MBCL-52
Foreman, N: ATRT-06, DDEL-06,
DIPG-34, DIPG-73, EPCT-18, EPEN22, EPEN-23, EPEN-26, EPEN-31,
EPEN-54, HGG-57, IMG-17, IMMU-20,
LGG-27, LGG-34, MBRS-46, MODL24, NFB-02, NFB-09, QOL-36, QOL-37,
QOL-38, RARE-10, RARE-27
Forget, A: MBCL-21, MBRS-51
Forkert, N: NFB-04
Forster, V: MODL-25
Fortin, J: DIPG-41
Fortiz, M: EPCT-15
Fosmire, S: ATRT-20, DIPG-34, DIPG73, MBRS-26, MBRS-65
Foster, Jennifer: HGG-01
Foster, Jessica: IMMU-11
Foster, M: SURG-12
Fotaki, G: MBRS-10
Fouladi, M: DIPG-21, DIPG-46, DIPG52, DIPG-55, DIPG-74, EPEN-54,
EPCT-05, EPCT-16, EPCT-17, EPCT-19,
EPID-15, ETMR-20, ETMR-22, GCT-33,
GCT-41, LGG-04, LGG-30, LGG31, MBCL-15, MBCL-16, MBCL-34,
MBCL-36, PATH-24
Foulkes, W: RARE-17, RARE-22
Fouyssac, F: MBCL-29
Fowler, M: DDEL-10
Fox, E: LGG-49

NEURO-ONCOLOGY•DECEMBER 2020

iii481

Author Index

Fuller, G: ETMR-04, IMG-15,
NFB-06, RARE-19
Fullerton, H: QOL-53
Fung, M: HGG-27
Funk, Z: MBCL-46
Furnari, G: MBRS-12
Furnish, R: MODL-29
Furukawa, K: EPID-17

Fox, R: MBRS-01
Frahsek, S: QOL-24
Fraioli, F: IMG-18
Franceschi, E: IMG-04
Franshaw, L: DIPG-07,
DIPG-14, DIPG-27
Franson, A: DIPG-08
Frappaz, D: GCT-48, GCT-76, LGG-55
Frasseto, F: EPID-05, PATH-18,
RARE-47, SURG-20
Frediani, J: QOL-34
Freedman, S: MBRS-04
Freeman, A: QOL-32
Freeman, B: HGG-22
Frenkel, Z: RARE-17
Freret, M: DIPG-49
Freytes, C: GCT-71, RARE-50
Friebel, E: IMMU-16
Friedland, R: NFB-03
Friedman, G: ATRT-30, GCT-23
Friedrich, C: ETMR-14, MBCL-07,
MBCL-09, PATH-07
Fritchman, B: TBIO-26
Fröjd, C: IMMU-18
Frühwald, M: ATRT-13, ATRT-14
Fry, T: IMMU-20
Fu, E: HGG-48, LINC-20
Fuchs, Q: HGG-36, TBIO-17
Fuentes Bolanos, N: DIPG-75
Fueyo, J: THER-01,
THER-02, THER-09
Fuji, H: HGG-49, RARE-16
Fujii, K: SURG-21
Fujii, Y: MBRS-06, MBRS-32
Fujimori, T: IMG-02
Fujimoto, K: EPEN-02, EPID-01
Fujimoto, Y: GCT-69
Fujimura, J: ETMR-09,
ETMR-15, MBCL-48
Fujio, S: RARE-04
Fujioka, M: HGG-30
Fujioka, Y: TBIO-08
Fujisaki, H: MBCL-22
Fujita, A: GCT-57
Fujita, N: PATH-08
Fujita, S: RONC-20
Fujiwara, H: GCT-06
Fujiwara, K: RARE-32
Fujiwara, M: ETMR-15, MBCL-48
Fukumitsu, Nobutoshi: RONC-04
Fukumitsu, Nobuyoshi: RONC-01
Fukuoka, K: ETMR-12, GCT-15, GCT52, GCT-62, HGG-20, MBRS-21, PATH25, PATH-28, RARE-39
Fukushima, H: GCT-38M, LGG-40
Fukushima, S: GCT-43
Fukushima, T: MBCL-41
Fulbright, R: LGG-09
Fuller, C: DIPG-21, DIPG-46, DIPG-74,
EPCT-17, EPCT-19, EPID-15, LGG-31

vi482

NEURO-ONCOLOGY

G
Gadd, S: DIPG-44
Gai, X: RARE-57, TBIO-12
Gaikwad, U: RONC-23
Gains, J: DIPG-37
Gajjar, A: EPEN-54, EPID-07, ETMR06, ETMR-21, ETMR-22, GCT-23,
GCT-33, GCT-41, HGG-01, IMG-20,
LINC-35, MBCL-08, MBCL-15, MBCL16, MBCL-19, MBCL-21, MBCL-26,
MBCL-37, MBCL-38, MBRS-20,
MBRS-24, PATH-09, PATH-24,
QOL-15, RARE-21
Galantowicz, B: SWK-03
Galardi, A: HGG-16, HGG-19
Galati, M: MODL-25
Gallego, J: DIPG-43
Gallego Perez de Larraya, J:
THER-01, THER-09
Gallegos, N: DDEL-14
Galley, N: QOL-24
Gamble, L: DIPG-15, DIPG-16
Gamboni, F: DIPG-42
Gampel, B: MODL-09
Gandhi, C: MBRS-18
Gandhi, I: PATH-27
Gandola, L: DIPG-54, EPEN-03
Ganesan, D: SURG-29
Ganeshan, B: DIPG-37
Gangadharan, A: DIPG-06, HGG-08
Gao, A: LGG-13
Gao, L: EPCT-16
Gaonkar, K: DIPG-31, PATH-21
Garancher, A: MBRS-10,
MBRS-12, MBRS-16
Garcia, J: RARE-42
Garcia Lombardi, M: DIPG-46,
DIPG-74, LINC-05
Garcia Lopez, J: MBRS-24
Garcia-Corrochano, P: RARE-42
Garcia-Moure, M: THER-02, THER-09
Garden, G: IMMU-02
Gardiner, J: NFB-12
Gardner, R: IMMU-02
Gardner, S: DIPG-52, GCT-66,
HGG-18, LGG-52, PATH-12,
RARE-17, RARE-35
Gareton, A: HGG-11•

DE C E M B E R 2 0 2 0Garg, A: EPEN-38
Garre, M: EPEN-03, GCT-29, GCT-48,
GCT-76, LGG-55
Garton, H: DIPG-08, HGG-18
Gartrell-Corrado, R: EPID-03, LGG-22
Garvin, J: DDEL-07, EPID-03,
LGG-22, MODL-09
Gasal, E: LGG-49
Gass, D: DIPG-74, EPCT-19, IMMU-18
Gates, K: RONC-08
Gauthier, M: DIPG-75
Gauvain, K: GCT-23, HGG-01, IMMU18, IMMU-31, LGG-52, LGG-53,
LGG-55, QOL-53
Gavula, T: LGG-47
Geduldig, J: EPEN-21
Gee, H: DIPG-13
Geller, T: LGG-28, RARE-36
Genevini, P: EPEN-46
Gentili, F: RARE-02
Geoerger, B: DIPG-61,
EPCT-08, LGG-49
Geoffray, A: MBCL-29
George, B: IMMU-18
George, S: DIPG-07, DIPG-27
Georgis, Y: DIPG-53
Gerß, J: ATRT-14
Gerber, N: EPEN-09, EPEN-18, EPEN36, EPEN-39, ETMR-14, ETMR-22,
GCT-76, MBCL-07, MBCL-09, MBCL-11,
MODL-22, PATH-07, PATH-11
Gershanov, S: ETMR-21
Gershon, T: MBRS-08,
MBRS-46, MODL-03
Gerwin, J: DDEL-15
Gesina, K: EPEN-35
Gessi, M: ETMR-14,
PATH-11, PATH-19
Gevaert, O: QOL-55
Gevorgian, A: MBCL-03
Gevorkyan, A: ATRT-05
Geyer, J: ETMR-20,
MBCL-19, MBCL-34
Geyeregger, R: EPEN-21
Ghag, A: NFB-12
Ghalibafian, M: MBRS-54, RARE-17
Ghasemi, David N: MBRS-68
Ghasemi, David R: EPEN-18
Ghermaoui, S: DIPG-58
Ghia, A: RONC-17
Ghinda, D: IMG-21
Ghosh, S: SWK-11
Giangaspero, F: EPEN-03,
MODL-23, PATH-19
Giannini, C: PATH-13
Gianno, F: PATH-19
Gibson, A: RARE-44
Gielen, G: HGG-34
Gies, L: QOL-04
Giese, L: MBRS-68

Author Index

Gifford, A: DIPG-75
Giglio, P: GCT-66, RARE-30
Gilani, A: DIPG-34, DIPG-42, EPEN31, EPID-13, MBRS-46, MODL-24
Gilbert, R: IMMU-23
Gilbertson, R: EPEN-14,
MODL-08, MBRS-20
Gilheeney, S: EPCT-07
Gill, H: RARE-25
Gill, J: DIPG-60, PATH-29
Gill, S: DIPG-82
Gillan, E: EPEN-49
Gillen, A: EPEN-26, EPEN-31
Gillespie, G: ETMR-22
Gillespie, S: TBIO-06
Gillian, W: RARE-34
Gilmartin, B: RARE-15
Gilpin, C: RARE-17
Ginn, K: QOL-22, RARE-11
Gino, S: ETMR-22
Gionet, G: DIPG-53
Giorda, E: HGG-16
Giorgi, F: DIPG-27
Giovannini, M: MODL-13
Girard, Elodie: MBRS-47
Girard, Emily: DIPG-10
Girard, E: MODL-28, MBRS-64
Girschick, H: PATH-07
Glass, J: QOL-15
Glück, A: MBCL-11
Go, K: GCT-12, GCT-13
Gocho, Y: ETMR-11, RARE-16
Goda, J: LINC-12, LINC-25, LINC-29
Godashastri, J: LINC-08
Godbout, R: DIPG-43
Goecks, J: PATH-14
Goel, D: EPID-06
Goh, CB: MBCL-50
Goh, Chun Peng: EPID-04
Gojo, J: DDEL-03, EPEN-18, EPEN-21,
ETMR-10, ETMR-17, MBCL-43
Golambade, N: LINC-12
Golanov, A: MBCL-07, MBCL-31
Golbourn, B: ATRT-16,
DDEL-01, DIPG-47
Goldberg, A: MBCL-38
Goldberg, J: NFB-08
Goldhamer, D: DIPG-51
Goldman, R: EPID-08, SWK-08
Goldman, S: DDEL-11, DIPG-03,
DIPG-46, DIPG-55, DIPG-74, EPCT-05,
EPCT-19, IMG-04, IMMU-31, LGG-53,
MBCL-33, MODL-26, NFB-17, TBIO-03
Golub, T: TBIO-26
Gomez-Manzano, C: THERE-01,
THER-02, THER-09
Gomi, A: DIPG-02, RAER-26
Gonzalez, E: DIPG-22,
DIPG-53, LGG-35
Gonzalez Gomez, I: LGG-28, RARE-36

Gonzalez-Huarriz, M:
THERE-02, THER-09
Goodale, A: DIPG-53,
LGG-35, TBIO-26
Goodden, J: EPEN-24, RARE-34
Goodyke, A: ETMR-18
Gopalakrishnan, A: DIPG-27, DIPG-75
Gopalakrishnan, V: DIPG-06, DIPG-57,
MBRS-53, MBRS-64, MBRS-70
Gorbatykh, S: ATRT-05, MBCL-31
Gorelyshev, S: MBCL-04, MBCL-05
Gorender, E: DIPG-72
Gorsi, H: EPEN-11, GCT-67, RARE-51
Gossett, J: ETMR-20, MBCL-34,
MBCL-36, PATH-24
Goto, H: EPCT-08
Goto, T: RARE-03
Gottardo, N: ATRT-08, DIPG-46,
DIPG-50, DIPG-55, DIPG-74, EPEN36, ETMR-22, GCT-23, LINC-03,
MBCL-21, MBCL-36, PATH-01,
PATH-11, RONC-02
Gottschalk, S: IMMU-05, IMMU-06
Goudie, C: RARE-17
Gough, D: MODL-21
Goulding, J: ATRT-18, RONC-21
Goutsias, J: DIPG-70
Governale, L: IMMU-08
Grabovska, Y: HGG-37, MBRS-44,
MBRS-60, PATH-17
Graf, M: ATRT-13, ATRT-14, ETMR-05
Gragert, M: RONC-12
Graham, R: GCT-23, HGG-45, MBRS29, MBRS-73, PATH-15,
Grajkowska, W: HGG-21, RARE-58
Grant, G: IMG-10, IMG-13, IMG-22,
MODL-26, QOL-22, RARE-11
Grant, M: EPCT-15, IMMU-15
Granville, S: SWK-04
Grau, E: RARE-22
Green, A: DIPG-34, DIPG-42, DIPG73, DIPG-79, EPID-13, HGG-57,
IMG-17, IMMU-21, LGG-34, LGG-48,
MODL-31, QOL-36
Green, T: TBIO-26
Greenblatt, M: DDEL-15
Greene, W: QOL-54
Greenfield, J: MODL-26, SWK-04
Greenspan, L: EPCT-01
Greenwald, N: HGG-41
Greer, H: IMMU-21
Greiner, R: DIPG-46,
DIPG-55, DIPG-74
Greystone, R: SURG-12
Griesinger, A: DIPG-73, EPEN-22,
EPEN-23, EPEN-26, EPEN-31, IMG17, IMMU-20, MBRS-46, MODL-24,
QOL-36, RARE-08
Griffin, C: IMMU-11
Griffin, T: PATH-29

Grigore, F: DIPG-05
Grigorenko, V: MBCL-04, MBCL-05
Grill, J: DIPG-35, DIPG-56, DIPG-58,
DIPG-61, HGG-11, MBCL-29, RARE-21
Grilley-Olson, J: EPCT-08
Grillner, P: QOL-59
Grishina, E: ATRT-05, MBCL-31
Grist, J: IMG-06
Grob, S: LGG-34
Gromeier, M: THER-05
Grønbæk, J: QOL-59
Gronych, J: MODL-11
Grootenhuis, M: QOL-32, QOL-33
Gross, A: NFB-17, LGG-47, RARE-20
Grosshans, D: MBCL-35, QOL-01,
QOL-28, RARE-44, RONC-05, RONC09, RONC-12, RONC-17
Grossman, R: EPID-14
Grosu, A: MBCL-11
Grotzer, M: MBCL-07, MBCL-21,
MBRS-39, MODL-14, MODL-22
Groves, M: EPEN-14
Gruber, H: THER-06
Grundy, R: EPEN-18, EPEN-22, EPEN23, EPEN-24, EPEN-42, EPEN-43,
ETMR-22, HGG-38, IMG-06, MBCL37, MBRS-69, TBIO-14, TBIO-16,
THER-03, THER-04
Gruschkus, S: IMG-15
Gryzlo, D: MBCL-33
Guckenberger, M: MBCL-11
Gudenas, B: ETMR-06, ETMR-21,
MBCL-21, MBRS-24
Gudkov, A: DIPG-27
Guerin, E: TBIO-17
Guerin, J: EPEN-35
Guerini-Rousseau, L: GCT-29, GCT-49,
MBCL-02, RARE-21
Guerreiro Stücklin, A: MODL-22
Guillen, A: IMMU-22
Guimaraes, C: IMG-09
Gule-Monroe, M: IMG-15
Gunasagaran, K: LINC-03, MBCL-50
Guo, C: EPEN-05, GCT-30
Guo, H: LINC-15
Guo, Yingshi: MBRS-29, MBRS-73
Guo, Yiran: EPID-14
Gupta, A: ATRT-21
Gupta, N: DIPG-73, EPCT-12,
ETMR-22, MODL-26
Gupta, S: EPCT-06, EPEN-10,
ETMR-04, NFB-06
Gupta, T: LINC-07, LINC-08, LINC-12,
LINC-25, LINC-29, MBRS-61
Gupte, A: RARE-53
Gurav, M: LINC-25,
LINC-29, MBRS-61
Gurova, K: DIPG-27
Gururangan, S: DIPG-46,
DIPG-74, EPCT-05, ETMR-06,

NEURO-ONCOLOGY•DECEMBER 2020

iii483

Author IndexHan, Z: ATRT-27
Hanania, A: RONC-05
Hancock, L: NURS-06,
NURS-07, THER-08
Handa, H: EPCT-18, EPEN-22, EPEN26, EPEN-31, HGG-57, LGG-34, LGG48, MBRS-46, RARE-08, RARE-11
Handryastuti, S: LINC-24, OTHR-07
Hanif, I: EPEN-51
Hankinson, T: EPCT-18, EPEN-22,
EPEN-26, EPEN-31, HGG-57, LGG-34,
LGG-48, MBRS-46, MODL-24, NURS12, QOL-22, QOL-37, QOL-38, RARE-07,
RARE-08, RARE-10, RARE-11, TBIO-11
Hanley, P: EPCT-15
Hansen, L: ETMR-01
Hansford, J: ATRT-08, DIPG-46,
DIPG-55, DIPG-74, EPCT-08, EPEN-36,
ETMR-22, HGG-20, LGG-55, MBCL26, MBRS-20, MBRS-54, MBRS60, PATH-01, PATH-09, RARE-15,
RARE-17, RARE-50
Hanson, D: EPCT-03, ETMR-08,
ETMR-17, ETMR-22, MODL-26
Hany, A: LINC-02
Haque, F: HGG-38, TBIO-16
Haque, J: HGG-45, PATH-15
Haque, S: RARE-24
Hara, J: MBCL-22, PATH-28, QOL-44
Hara, Kazuya: GCT-08
Hara, Kei: GCT-38
Harada, K: MBRS-22
Hardie, L: HGG-57
Hardy, D: DIPG-56
Hardy, K: QOL-20, RONC-27
Hargrave, D: DIPG-35, DIPG-77, IMG10, IMG-13, LGG-17, LGG-49, MODL19, MODL-20, QOL-32, QOL-33
Hari Chandran, T: LINC-02
Hariharan, S: ATRT-19
Harila, M: QOL-12
Harila-Saari, A: QOL-12
Harlos, C: RARE-17
Harmanci, A: DIPG-57, MBRS-70
Harmon, M: DDEL-02
Harreld, J: MBCL-36
Harris, F: EPEN-22, EPEN-26
Harris, M: DIPG-59, GCT-74, MBCL-46
Harrison, R: HGG-18
Harrod, V: DIPG-66, MBCL-24
Hart, M: EPID-13
Harting, I: LGG-55
Hartley, H: COVD-03, QOL-21
Hartley, R: DIPG-53
Hartmann, C: MBCL-07
Hartmann, W: ATRT-14
Hartsuyker, K: IMMU-02
Harutyunyan, A: HGG-41
Harutyunyan, M: LINC-14,
LINC-42, RARE-33

ETMR-21, IMMU-08, IMMU-26,
MBCL-26, MBRS-20
Gust, J: IMMU-02, IMMU-03
Gustafson, A: TBIO-03
Gustafson, D: EPCT-18
Gustafson, P: TBIO-03
Gutierrez-Oliva, L: LINC-09,
RARE-29, SURG-19
Gutmann, D: NFB-09
Gwak, H: MBRS-56
Gygi, S: TBIO-19

H
Haas-Kogan, D: DIPG-01, DIPG-53,
EPCT-01, GCT-33, LGG-53
Haber, M: DIPG-15, DIPG-16, DIPG27, DIPG-75, DDEL-03, EPEN-21,
ETMR-10, ETMR-14, ETMR-17,
HGG-44, MBCL-07
Hack, O: EPEN-21, ETMR-17, HGG-53
Hacking, J: ATRT-25
Hadley, J: MBCL-21, MBRS-24
Haemer, M: NURS-12
Haendel, M: EPID-14
Hagan, A: QOL-21
Hagel, C: MBCL-09, PATH-07
Hagemeier, L: ATRT-15
Hagiwara, M: NFB-08
Hahn, K: EPCT-13
Haitao, P: QOL-54
Hajal, C: DDEL-04
Hakobyan, L: LINC-14
Haldar, M: TBIO-07
Halfmann, A: EPEN-21
Hall, L: EPCT-09
Hall, M: DIPG-52, HGG-18, RONC-08
Halldorsson, S: TBIO-18
Halliday, G: IMG-08, QOL-23, QOL-26
Halling, K: LGG-36
Haltom, A: DIPG-57, MBR-53
Hamada, M: LGG-56
Hamamoto, R: EPEN-41
Hamamoto, Y: GCT-53
Hambardzumyan, D: THER-01
Hamelberg, E: EPEN-28
Hamid, S: MBRS-54, RARE-17
Hamilton, J: RARE-09
Hamilton, K: MBCL-21
Hammond, P: DDEL-04
Han, B: IMMU-28
Han, F: EPEN-05
Han, H: RARE-22
Han, Jung Ho: GCT-12, GCT-13
Han, Jung Woo: EPEN-15
Han, M: IMG-10, IMG-13, IMG-22
Han, Yan: EPID-11, QOL-58
Han, Yuanyuan: QOL-20, RONC-27

vi484

NEURO-ONCOLOGY•

DE C E M B E R 2 0 2 0

Hashii, Y: QOL-44
Hashikawa, T: GCT-53
Hashimoto, N: DIPG-04, HGG-12
Hashimoto, S: HGG-50
Hashimoto, T: GCT-08,
RONC-16, RONC-19
Hashizume, R: DDEL-11, DIPG-03,
DIPG-73, HGG-26
Hassall, T: DIPG-46, DIPG-55, DIPG74, ETMR-06, MBCL-26, MBRS-20
Hasselblatt, M: ATRT-14, ATRT-28,
MBCL-07, RARE-22
Hata, N: HGG-24, IMMU-09,
LGG-20, TBIO-08
Hatae, R: HGG-24, TBIO-08
Hatakeyama, T: IMG-02
Hatano, S: EPID-03
Hatfield, A: THER-04
Hau, E: DIPG-13
Haumann, R: DDEL-05, DIPG-33
Hauser, P: LGG-55. QOL-59
Häusser, L: ATRT-32
Haussler, D: MODL-26
Hawkins, C: ATRT-33, DIPG-46,
DIPG-59, DIPG-73, ETMR-21, ETMR22, HGG-20, IMMU-18, LGG-13,
LGG-19, LGG-25, LGG-34, LGG50, LGG-55, MBCL-25, MBRS-54,
MODL-25, PATH-14
Hawks, R: SWK-02
Haworth, K: IMG-04
Haydar, D: IMMU-05
Hayden, E: DIPG-14, DIPG-27
Hayes, L: ETMR-20, MBCL-34
Haynes, S: EPEN-14
Hazrati, L: EPEN-50,
ETMR-22, LGG-55
He, C: DIPG-51, HGG-22
He, G: MBRS-31
Healy, P: EPCT-13
Heaphy, C: NFB-01
Heath, A: EPID-14, MODL-26
Hébert, S: TBIO-15
Hedges, D: HGG-57
Heidary, G: NFB-09
Heier, L: MBCL-16
Heinerich, C: RARE-31
Heinzelmann, F: MBCL-11
Heitzer, A: RONC-12
Heller, D: DDEL-15
Hemenway, M: DDEL-06, LGG-27,
MODL-01, NFB-02, NURS-11, NURS12, OTHR-16, QOL-36, RARE-27
Henderson, J: IMMU-14
Hendrikse, H: DIPG-33, DIPG-84
Henehan, S: IMG-17
Heng, M: QOL-17
Hengartner, A: MODL-24, QOL-22,
RARE-08, RARE-10, RARE-11
Hennigan, D: SURG-12

Author Index

Henriksen, L: ETMR-01
Henry, V: DIPG-06
Heo, D: GCT-02
Hernaiz Driever, P: EPEN-18, IMG-03
Hernandez, R: THER-09
Herndon, J: EPCT-13
Herrington, B: TBIO-13
Herur-Raman, A: SURG-03
Hervas, S: THER-09
Hesselberth, J: EPEN-31, MBRS-46
Hibiya, Y: MBRS-21, PATH-25,
RARE-26, RARE-39
Hicks, D: MBRS-44, MBRS-60,
MBRS-69, QOL-17
Hielscher, T: LGG-14,
LGG-17, MBRS-19
Higa, N: GCT-18, HGG-42, LGG-20,
LGG-32, RARE-04
Higgins, D: DDEL-07
Higuchi, Y: PATH-03
Hii, H: DIPG-50, RONC-02
Hijiya, N: IMMU-18, RARE-17
Hill, R: IMG-08, MBRS-10, MBRS-44,
MBRS-60, QOL-23, QOL-26
Hiltke, T: TBIO-19
Hinchcliffe, E: DIPG-05,
DIPG-76, DIPG-78
Hira, K: MBCL-22
Hirabayashi, S: GCT-08, GCT-31
Hirai, M: OTHR-02
Hiraki, T: PATH-25
Hiramatsu, H: RONC-06
Hirato, J: LGG-56, MBRS-38, PATH-28
Hirayama, R: GCT-69, QOL-44
Hirokawa, D: EPEN-01
Hirono, S: GCT-09, PATH-03
Hirose, T: PATH-23
Hirose, Y: MODL-15
Hirota, S: GCT-44,
RONC-25, SURG-05
Hirsch, Sophie: ATRT-32
Hirsch, Steffen: PATH-11, RARE-21
Hishiki, T: ATRT-11
Hnin, T: LINC-01
Ho, B: ATRT-33, ETMR-22,
PATH-24, TBIO-02
Ho, Chang: IMG-10, IMG-13, IMG-22
Ho, Cheng-Ying: PATH-14
Ho, Cindy Wei Li: EPID-04, RARE-01
Ho, D: MBCL-20
Ho, F: QOL-25
Ho, P: HGG-32, HGG-41
Ho, W: HGG-48
Hochman, T: NFB-08
Hodel, K: MODL-25
Hodges, C: EPEN-30
Hodgson, D: QOL-01, RONC-03
Hoeppner, C: NURS-02
Hoerig, C: MBCL-38, QOL-34
Hoffman, C: EPCT-12, SWK-10

Hoffman, L: ATRT-30, EPCT-17, ETMR08, HGG-57, IMMU-18, LGG-31,
LGG-34, RARE-10
Hoffman, T: QOL-53
Hoffmann, L: GCT-23
Hoffmeyer, E: ATRT-24
Hogan, N: NFB-09
Holdhof, D: ATRT-13
Holland, E: EPEN-41
Höller, A: PATH-07
Hollingworth, M: DIPG-82
Holm, S: MBCL-43
Holman, N: QOL-21
Holmberg Olausson, K: MBRS-10
Holmes, J: QOL-58
Holt, James: QOL-17
Holt, Jennifer: NURS-10
Holt, S: EPEN-14
Holtzclaw, S: NURS-02
Holtzman, A: RONC-32
Homsi, M: COVD-04
Honda, S: MBRS-21,
PATH-25, RARE-39
Hong, W: GCT-26, GCT-27,
GCT-28, HGG-14
Hong, Y: GCT-13
Hongeng, S: RARE-38
Hoogendijk, R: EPID-18
Hoover, A: LGG-24
Hope, K: MBRS-01
Hopman, S: RARE-21
Hoppmann, A: MBCL-24
Hoq, F: EPCT-15
Hora, B: IMMU-27
Horiguchi, K: GCT-09
Horikoshi, Y: MBCL-27
Horiuchi, T: GCT-62
Horn, B: IMMU-08
Hornung, D: MBCL-11
Hosoi, H: DIPG-04, HGG-12
Hotblack, A: IMMU-16
Houke, H: IMMU-06
Houkin, K: GCT-10, GCT-31, SURG-02
Hounjet, C: NFB-12
Hovén, E: QOL-12
Hover, L: DIPG-51
Hovestadt, V: EPEN-21, ETMR-17
Hoveyan, Julia: LGG-16
Hoveyan, Julieta: ETMR-07
Hovhannisyan, G: ETMR-07
Hoving, E: DDEL-05, EPID-18, QOL-59
Howell, C: EPID-16
Howlett, M: DIPG-50, RONC-02
Hrbacek, J: RONC-15
Hsieh, K: RARE-45
Hsieh, T: MODL-16
Hsu, C: EPEN-50, HGG-57,
IMG-20, RARE-12
Hsu, S: MBRS-54, RARE-17
Hu, B: MBRS-63

Hu, L: IMMU-29
Hu, Q: DIPG-26, GCT-26, GCT-27, GCT28, GCT-63, HGG-14
Hu, W: ETMR-02
Huang, Annie: ATRT-16, ATRT-33,
ETMR-17, ETMR-19, ETMR-20, ETMR21, ETMR-22, LGG-55, MBCL-34,
PATH-24, TBIO-02
Huang, F: MBRS-17
Huang, Jia-Hui: RARE-45
Huang, Jie: EPCT-05
Huang, Lei: GCT-73
Huang, Libin: LINC-15
Huang, M: LGG-12
Huang, P: ATRT-25
Huang, T: DIPG-39, HGG-26
Huang, Wen-Chang: MBCL-20
Huang, Wenjun: IMMU-03
Hubank, M: MODL-19, MODL-20
Hübner, J: EPEN-04, EPEN-18,
EPEN-21, ETMR-03
Hudson, M: QOL-15
Hugo, W: IMMU-30
Hui, A: TBIO-06
Hui, S: QOL-25
Huitema, A: DDEL-05
Hukin, J: GCT-23, HGG-35, LGG-19,
LGG-25, MBCL-24, NFB-12, RARE-25
Hulleman, E: ATRT-18, DIPG29, DIPG-32, DIPG-33, DIPG-73,
RONC-21, THER-09
Hummel, T: EPCT-19, LGG-30,
LGG-31, NFB-09
Hung, L: MODL-27
Huse, J: EPEN-10
Hussain, R: MBRS-59
Hutaff-Lee, C: QOL-37, QOL-38
Hutchins, S: ATRT-30
Hutchinson, K: HGG-01
Hutter, S: MBRS-10
Huybrechts, S: MBCL-02
Hwang, E: EPCT-05, EPCT-15,
EPCT-16, EPCT-17, ETMR-21, IMMU08, LGG-26, MBCL-13, MBCL-16,
PATH-14, THER-08
Hwang, K: GCT-12, GCT-13
Hwang, S: IMG-20
Hyare, H: DIPG-37, DIPG-82, IMG-18
Hynynen, K: DDEL-01
Hyun, J: MBCL-28

IIannò, M: DIPG-54
Iavarone, A: TBIO-19
Ibrahim, G: RARE-09
Ichikawa, D: LGG-56
Ichimura, K: EPEN-34, EPEN-41,
EPEN-47, GCT-15, GCT-19, GCT-22,

NEURO-ONCOLOGY•DECEMBER 2020

iii485

Author Index

Iukhta, T: MBCL-03
Iurilli, V: LGG-55
Ivey, R: TBIO-19
Iwadate, Y: GCT-09, GCT-45, PATH-03
Iwafuchi, H: MBCL-27
Iwai, A: RONC-06
Iwaki, T: HGG-24
Iwasaki, Y: MBRS-32
Izquierdo, E: MODL-19, MODL-20

GCT-34, GCT-43, GCT-46, GCT-52,
GCT-62, GCT-72, HGG-02, HGG39, HGG-49, MBRS-21, MBRS38, PATH-23, PATH-25, PATH-28,
RARE-26, RARE-39
Ida, C: LGG-36
Ida, H: IMMU-12
Iehara, T: DIPG-04, HGG-12
Iguchi, A: GCT-08, GCT-10, GCT-31,
RONC-16, SURG-02
Ihara, S: GCT-62
Iihara, K: IMMU-09, TBIO-08
Ijaz, H: PATH-21
Ikeda, Z: PATH-03
Ikegami, S: GCT-09
Ikegaya, N: HGG-513
Ilut, L: MODL-12
Im, J: MBRS-56
Imamura, K: GCT-62
Imaya, M: LGG-56
Imhof, S: RARE-62
Inagaki, A: THER-06
Inaji, M: HGG-30, HGG-50,
RONC-18, SURG-05
Indelicato, D: ETMR-06, RONC-22,
RONC-24, RONC-32
Indersie, E: MBCL-21
Inge, T: NURS-12
Ingerski, L: QOL-31
Iñigo-Marco, I: THER-09
Injac, S: LGG-55, MBRS-17
Inoue, K: SURG-24
Inoue, T: MBRS-38
Interlandi, M: ATRT-13,
ATRT-14, ETMR-05
Inyushkina, E: ATRT-05, MBCL-31
Ioakeim-Ioannidou, M: RONC-24
Ip, P: QOL-25
Ippolito, J: TBIO-01
Ishi, Y: GCT-08, GCT-10, GCT-31, HGG02, RONC-16, SURG-02
Ishibashi, T: ETMR-15, MBCL-48
Ishida, H: RARE-32
Ishida, J: DDEL-01
Ishikawa, E: GCT-38, GCT-60,
GCT-62, LGG-40
Ishikawa, M: GCT-44,
RONC-25, SURG-05
Ishizaki, R: MBCL-27
Iskanyan, S: ETMR-07,
LGG-16, LINC-14
Ismael, Y: RARE-12
Ismer, B: MODL-11
Isshiki, K: ETMR-11
Ito, H: SURG-24
Ito, S: ATRT-11
Ito, T: TBIO-08
Itoyama, T: EPID-01, GCT-36
Itzep, N: ETMR-04
Iuchi, T: GCT-43, GCT-52

vi486

NEURO-ONCOLOGYJJabado, N: ETMR-17, HGG-41, LGG25, LGG-35, TBIO-15
Jablonska, K: MBCL-11
Jackson, A: EPEN-22, EPEN-23
Jackson, Eric: MODL-26,
QOL-22, RARE-11
Jackson, Evangeline:
DIPG-29, DIPG-32
Jackson, H: MBRS-27, MBRS-28
Jacobs, S: QOL-07, QOL-18,
QOL-19, RARE-56
Jacques, G: MBCL-02
Jacques, T: IMG-10, IMG-13, LGG-57,
MBRS-44, MBRS-60
Jaeger, M: MBCL-23
Jaeger, N: MBCL-07
Jaffe, J: TBIO-26
Jäger, N: MBRC-21,
MBRS-03, MODL-11
Jaggers, D: EPCT-13
Jain, D: ATRT-31
Jaju, A: MBCL-16, MBCL-36
Jalali, R: RONC-23
Jallo, G: MRBS-16, QOL-22, RARE-11
Jamaluddin, M: DIPG-29
Jan, C: DDEL-13
Jansen, G: IMG-21
Janson, L: DDEL-17
Janss, A: MBCL-14, MBCL-15
Janssen, C: DDEL-09
Janssens, G: DIPG-77
Janzen, L: QOL-01,
RARE-02, RONC-03
Jarmale, S: DIPG-53
Jaspan, T: EPEN-24, IMG-04
Jawin, V: LINC-03
Jayasekara, S: DIPG-18, DIPG-64
Jeffery, R: ETMR-22
Jenkins, R: LGG-36, PATH-13
Jenkinson, L: EPEN-14
Jensen, M: IMMU-03
Jernberg-Wiklund, H: MBRS-10
Jessa, S: LGG-35, TBIO-15
Jesus, G: MBCL-21
Jhanwar-Uniyal, M: MBRS-18
Ji, Jianling: RARE-57
Ji, Jiayi: TBIO-19•

DE C E M B E R 2 0 2 0

Ji, S: GCT-13
Ji, Y: ETMR-02
Ji, Z: TBIO-26
Jiang, Li: EPEN-21, HGG-53
Jiang, Lian: LINC-15
Jiang, Q: DIPG-43
Jie, M: SURG-04
Jillette, N: EPEN-53
Jin, L: PATH-31
Jin, Z: DDEL-07
Jinawat, A: RARE-38
Joao Gil da Costa, M: ETMR-22
Jogendran, M: SWK-08
Johann, P: ATRT-28, EPEN-03
John, P: MBRS-01
Johnson, James: MBRS-43
Johnson, Jason: EPCT-06, IMG-15,
LGG-44, RONC-09
Johnston, D: ETMR-22, LGG-19
Johnston, J: QOL-22, RARE-11
Jolly, D: THER-06
Jones, B: DIPG-46, DIPG-55,
DIPG-74, EPID-15
Jones, C: DIPG-40, DIPG-53, DIPG-58,
DIPG-63, HGG-16, HGG-19, HGG-20,
HGG-37, IMG-12, MODL-19, MODL-20,
PATH-17, THER-09
Jones, David: DIPG-58, HGG-20,
HGG-56, LINC-03, MBCL-06, MBCL08, MBRS-03, PATH-01, PATH-20,
QOL-13, RARE-21
Jones, David TW: ATRT-28, EPEN18, EPEN-36, ETMR-06, ETMR-21,
HGG-22, LGG-14,
LGG-17, LGG-33, LGG-35, MBCL-09,
MBCL-21, MBRS-68, MODL-11, PATH04, PATH-11, PATH-26
Jones, Janelle: ATRT-08
Jones, Jeremy: ATRT-21, EPEN-28,
GCT-25, MBCL-46, RARE-31, RARE-37
Jones, K: DIPG-73, HGG-57, MODL-31
Jones, R: HGG-41
Jones, T: LGG-57
Jongmans, M: RARE-21
Jordan, K: RARE-10
Joshi, A: MBRS-44, MBRS-60
Joshi, C: LGG-48
Joshi, P: MBRS-16
Joshi, S: DIPG-14, DIPG-27
Joung, Y: MBCL-28
Ju, H: MBCL-28
Juan, M: IMMU-22
Juarez, E: EPEN-04
Judd, A: ATRT-04, NFB-05, RARE-14
Judkins, A: ETMR-20, MBCL-34,
MODL-13, PATH-24
Juhler, M: QOL-57
Juhnke, B: EPEN-09, EPEN-39, ETMR14, MBCL-06, MBCL-09, PATH-07
Julka, P: LINC-33

Author IndexJun, K: GCT-62
Jung, H: MBCL-28
Jung, Jin-Myung: GCT-13
Jünger, S: EPEN-27
Junichiro, I: GCT-45

K
K, M: RONC-23
Kabbara, N: ETMR-22
Kabir, N: TBIO-15
Kadam, V: MBRS-61
Kadirov, S: MBCL-04, MBLC-05
Kadom, N: IMG-03
Kaessmann, H: MBRS-03
Kagan, E: EPEN-20
Kagawa, N: GCT-69, QOL-44
Kahalley, L: QOL-01, RONC-12
Kahn, J: EPID-03
Kahwash, S: RARE-40
Kais, L: QOL-37
Kajiwara, S: GCT-53
Kakita, A: MBRS-06, MBRS-32
Kalani, Z: TBIO-26
Kalber, T: IMMU-16
Kalinin, A: QOL-43
Kalra, A: RARE-30
Kalushkova, A: MBRS-10
Kalxdorf, M: EPEN-44
Kamaly-Asl, I: EPEN-24, EPEN-43
Kamamoto, D: GCT-51
Kamata, K: HGG-12
Kamata, T: MBRS-22
Kambhampati, M: NURS-06, TBIO-03
Kameda, M: SURG-21
Kameda-Smith, M: MBRS-01
Kamihara, J: RARE-17
Kamitori, T: RONC-06
Kamm, R: DDEL-04
Kanamitsu, K: RARE-32
Kanamori, M: DDEL-08, GCT-35, GCT43, GCT-52, MBCL-48
Kanazawa, T: GCT-55
Kanchan, R: MBRS-13, MBRS-72
Kaneko, Sadehiro: SURG-10
Kaneko, Satoshi: GCT-44,
RONC-25, SURG-05
Kaneko, Syuzo: EPEN-41
Kanematsu, D: MBRS-38
Kanemori, M: RARE-26
Kanemura, Y: GCT-52, GCT-72, LGG38, MBRS-38, PATH-28
Kaneva, K: RARE-57, TBIO-12
Kang, G: ETMR-20, MBCL-34,
MBCL-36, PATH-24
Kang, H: EPCT-08, GCT-02
Kang, K: HGG-41
Kao, Y: RARE-45

Kapp, K: MBCL-11
Karachunsky, A: GCT-64,
LGG-26, MBCL-32
Karajannis, M: EPCT-07, EPCT-17,
ETMR-21, LGG-50, LGG-55, NFB-08
Karam, S: DIPG-42,
MBRS-26, M0DL-31
Karamyan, N: RARE-33
Karapetyan, N: LINC-14,
LINC-42, RARE-33
Karger, A: TBIO-26
Karim-Kos, H: EPID-18
Karlson, C: TBIO-13
Karras, T: PATH-21
Kasahara, N: THER-06
Kasapidou, P: MODL-08
Kaspers, G: ATRT-18, DIPG-33,
DIPG-84, RONC-21
Kastrati, D: ATRT-13, ATRT-14
Katagi, H: DDEL-11, DIPG-03, DIPG-73
Kataoka, H: PATH-23
Kato, I: RONC-06
Kato, Mamoru: GCT-34,
GCT-52, GCT-62
Kato, Motohiro: ATRT-11,
ETMR-11, HGG-49
Katsushima, K: MBRS-16
Kaur, G: LGG-55
Kaur, H: ATRT-23
Kaur, K: LINC-30
Kavallaris, M: DDEL-12
Kawaguchi, K: MBCL-27
Kawaguchi, R: IMMU-09
Kawai, K: DIPG-02
Kawakibi, A: HGG-18
Kawamura, A: GCT-62, RARE-26,
RONC-01, RONC-04
Kawanishi, M: IMG-02
Kawanishi, Y: RONC-20
Kawashima, M: DIPG-17
Kawashima, N: LGG-56
Kawauchi, D: EPEN-18,
MBRS-24, MBRS-51
Kawauchi, T: LGG-38
Kayama, T: EPID-09, GCT-16
Kazantsev, I: MBCL-03
Kazim, M: LGG-22
Kazina, C: LGG-23
Ke, C: EPEN-05
Kearney, A: QOL-21
Kebudi, R: RARE-55
Keeling, C: MBRS-59
Keilty, D: RONC-03
Keino, D: ATRT-11
Keith, J: LGG-13
Kellie, S: ETMR-06, ETMR-20, MBCL26, MBCL-34, PATH-24
Kelly, B: EPEN-17
Kelly, J: IMMU-18
Kelly, S: ETMR-18

Kelsey, M: NURS-12
Kemp, C: ETMR-18
Kennedy, C: QOL-17, QOL-32, QOL-33
Kennis, B: DIPG-06, DIPG-57
Kent, R: EPEN-31
Kergrohen, T: DIPG-58
Kerl, K: ATRT-13, ATRT-14,
ATRT-15, ETMR-05
Kerr, I: MBRS-27, MBRS-28,
MBRS-42, MBRS-45
Keshishian, H: DIPG-53
Keskes, M: NFB-16
Kessel, S: MBCL-36
Kessler, K: DIPG-63, MODL-20
Kestle, J: EPEN-07, GCT-70
Ketonen, L: ETMR-04
Khachatryan, P: ETMR-07
Khadka, P: DIPG-22, DIPG-53,
LGG-35, RARE-07
Khaing, A: LINC-01
Khakoo, Y: RARE-24
Khallouq, B: EPEN-51
Khan, A: DIPG-07, DIPG-15,
DIPG-16, DIPG-27
Khan, R: QOL-54
Khan, S: ETMR-22
Khandwala, M: RONC-03
Kharas, N: DDEL-09
Khatib, Z: DDEL-02, DDEL-14, DIPG52, ETMR-08, RONC-08
Khatua, S: DIPG-52, DIPG-57, DIPG60, EPCT-06, EPEN-10, ETMR-04, GCT33, GCT-41, GCT-42, IMG-15, LGG-44,
NFB-06, RARE-19
Khazal, S: IMMU-07
Khlifi, K: NFB-16
Khochenkov, D: MBCL-04, MBCL-05
Khong, P: QOL-25
KhongKhatithum, C: RARE-38
Khoury, P: RONC-31
Khu, K: LINC-23
Khuong Quang, D: DIPG-75, EPEN36, MBCL-26, PATH-09, RARE-15
Kieffer-Renaux, V: MBCL-02
Kieran, M: DIPG-53, ETMR-08, GCT59, LGG-52, HGG-41
Kiguchi, H: DDEL-15
Kijima, N: GCT-69, QOL-44
Kikuchi, J: GCT-53
Kilburn, L: DIPG-46, DIPG-55,
DIPG-74, DIPG-80, EPCT-15, IMG-03,
LGG-04, LGG-49, LGG-52, PATH-14,
QOL-22, RARE-11, THER-08
Kilday, J: EPEN-24
Kilic, C: ATRT-19
Kim, C: GCT-12, GCT-13
Kim, Dong-Hyun: EPEN-43
Kim, Dong-Seok: EPEN-15
Kim, Il Han: GCT-02
Kim, In Ah: GCT-12, GCT-13

NEURO-ONCOLOGY•DECEMBER 2020

iii487

Author IndexKoch, K: SWK-12
Koda, Y: GCT-56
Kodama, Y: MBRS-38
Koelsche, C: RARE-42
Koerner, C: QOL-34
Koga, M: GCT-53
Koga, Y: HGG-24, IMMU-09
Kogiso, M: EPEN-46, MBRS-17
Koh, K: ETMR-12, MBRS-21, PATH-25
Kohashi, K: IMMU-09
Kohe, S: MBRS-69
Kohzuki, H: GCT-60, LGG-40
Koizumi, A: MBRS-22
Kojic, M: MBCL-21, MBRS-24
Kojima, Y: GCT-19
Koldobskiy, M: DIPG-12, DIPG-70
Kolehmainen, N: SWK-09
Komaki, S: GCT-53
Komatsu, K: MBCL-27
Kon, T: HGG-29
Koncar, R: DIPG-47
Kondo, A: DIPG-03, ETMR-09, ETMR15, MBCL-48, PATH-08, SURG-15
Kono, M: GCT-47, GCT-55
Konofagou, E: DDEL-13
Konoplya, N: PATH-10
Konovalov, D: EPEN-50
Koo, H: MBCL-28
Kool, M: ATRT-28, EPEN-04, EPEN-18,
EPEN-21, EPEN-39, ETMR-03, ETMR08, ETMR-13, ETMR-14, ETMR-17,
MBCL-07,
MBCL-21, MBRS-51, MBRS-68,
MODL-02, QOL-13
Kopp, K: LINC-21
Koptyra, M: MODL-26,
PATH-21,TBIO-03
Korbanka, S: ATRT-14
Korbel, J: MBCL-21
Korchunov, A: ATRT-05, MBCL-31
Korf, B: NFB-17
Korff, C: DIPG-25
Korn, R: IMG-05
Korshunov, A: EPEN-18, MBCL07, MBCL-08, MBCL-21, MBRS-68,
MODL-11, RARE-21
Kortmann, R: DIPG-77, EPEN06, EPEN-09, EPEN-27, EPEN-36,
EPEN-39, ETMR-14, GCT-29, GCT48, GCT-76, MBCL-07, MBCL-09,
MBCL-11, QOL-13,
Kosaka, Y: RONC-01, RONC-0
Kosaka, Y: RONC-04
Koschmann, C: DIPG-08, DIPG-46,
DIPG-52, DIPG-55, DIPG-59, DIPG-64,
DIPG-74, ETMR-17, HGG-18, PATH-14,
RARE-17, RARE-51
Koskenkorva, P: QOL-12
Kotecha, R: RONC-08
Koustenis, E: IMMU-18, MBRS-54

Kim, Jiyoon: IMMU-30
Kim, Jong Heon: MBRS-56
Kim, Joo-Young: GCT-17
Kim, K: MBRS-56
Kim, Laurence: RONC-03
Kim, Leo: EPEN-52
Kim, Seung Ki: GCT-02,
GCT-12, MBRS-56
Kim, Su Na: ATRT-14
Kim, T: GCT-02
Kim, Y: GCT-12, GCT-13
Kimpo, M: RARE-01
Kimura, Y: GCT-62, HGG-02
Kinoshita, Manabu: GCT-69, QOL-44
Kinoshita, Masashi: QOL-05
Kinross, K: ATRT-08,
EPEN-36, PATH-01
Kipp, B: PATH-13
Kirby, P: RARE-13
Kirchhofer, D: EPEN-21
Kirmani, S: RARE-55
Kirschner, M: TBIO-26
Kishima, H: GCT-69, QOL-44
Kislyakov, A: ATRT-05, MBCL-31
Kitahara, M: PATH-28, RARE-26
Kiudeliene, R: QOL-59
Kiyokawa, J: GCT-44,
RONC-25, SURG-05
Kiyokawa, N: ATRT-11
Kiyotani, C: ATRT-11, ETMR-11, HGG49, RARE-16, RARE-26, SURG-17
Kizyma, R: LINC-41
Kizyma, Z: LINC-41
Klagges, S: MBCL-11
Kleese, L: MBCL-08
Kleinman, C: LGG-35, TBIO-15
Kleinschmidt-DeMasters, B: LGG-34
Kleman, M: QOL-37
Klesse, L: NFB-09
Klimo, P: EPEN-50, RARE-12
Klimo Jr., P: ETMR-06
Kline, C: DIPG-52, EPTCT-12, PATH31, QOL-53, SWK-10
KN, Y: LINC-33
Knafo, S: HGG-11
Knipstein, J: IMMU-18,
MBCL-24, RARE-17
Knox, A: DIPG-42, DIPG-79, MODL-31
Ko, K: RARE-39
Kobayashi, D: HGG-50
Kobayashi, H: MBRS-22
Kobayashi, K: GCT-43, GCT-52,
GCT-62, PATH-05
Kobayashi, M: ETMR-12,
MBRS-21, PATH-25
Kobayashi, Y: HGG-29
Koblizek, M: PATH-20
Koboldt, D: EPEN-17
Kocak, M: EPCT-02
Koch, A: MBCL-07

vi488

NEURO-ONCOLOGY•

DE C E M B E R 2 0 2 0

Kouzoupi, N: QOL-33
Kovalenko, S: ATRT-05, MBCL-31
Kowalczyk, P: RARE-31
Koyama, J: RONC-01
Kozłowska, M: HGG-21
Kozlov, A: MBCL-03
KR Boult, J: MODL-19
Kraft, K: EPEN-04
Kralik, S: IMG-07, RONC-09
Kram, D: IMMU-14, LGG-21, MODL-26
Kramer, K: IMG-09
Kramm, C: DIPG-58, DIPG-77,
DIPG-84, HGG-34, HGG-56,
IMMU-10, PATH-11
Kratz, C: RARE-21
Krausert, S: MODL-02
Krauss, J: IMMU-10, QOL-24
Krawitz, S: LGG-23
Krayenbühl, N: MODL-22
Krek, A: TBIO-19
Kremer, L: EPID-18
Krenciute, G: IMMU-05, IMMU-06
Kresak, J: ETMR-22
Krieger, M: RARE-11
Krijgsveld, J: EPEN-44
Krishnan, G: RONC-23
Krishnatry, R: LINC-07, LINC-08, LINC12, LINC-25, LINC-29
Kristensen, I: ETMR-01
Kristiansen, G: HGG-34
Kroeze, S: RONC-15
Krskova, L: HGG-31, LGG-46,
LGG-55, PATH-20
Krug, K: TBIO-26
Krull, K: QOL-15
Krych, P: RARE-58
Krzykwa, E: EPCT-01, IMG-05, LGG-03
Ku, D: EPID-10, HGG-48,
LINC-20, QOL-25
Kuga, D: TBIO-08
Kühl, J: QOL-24
Kui, C: MBRS-60
Kukreja, M: EPEN-25
Kulesskiy, E: TBIO-18
Kulkarni, A: MBRS-54, RARE-09
Kumabe, T: GCT-35, GCT-43, GCT-52
Kumamoto, T: RARE-32
Kumar, A: DIPG-75
Kumar, C: RARE-51
Kumar, K: HGG-41
Kumar, Rahul: ETMR-06,
MBCL-08, MBRS-20
Kumar, Ram: COVD-03, QOL-21
Kumar, Sachin: EPEN-52
Kumar, Shiva: DIPG-21, EPCT-16
Kumari, K: ATRT-31
Kumirova, E: EPEN-50
Kunihiro, N: MBCL-22, RARE-26
Kuo, C: OTHR-09
Kupsky, W: RARE-51, RARE-53

Author Index

Kuranari, Y: GCT-55
Kurihara, J: ETMR-12, MBRS-21,
PATH-25, RARE-39
Kurimoto, M: LGG-56
Kurland, D: PATH-12
Kuroda, J: EPEN-02, GCT-36
Kuroha, M: HGG-30,
HGG-50, RONC-18
Kurozumi, K: RARE-32, SURG-21
Kurz, S: HGG-18
Kurz, T: IMMU-19
Kusano, S: ETMR-15
Kushel’, Y: ATRT-05, MBCL-31
Kutscher, L: MBRS-03, MBRS-24
Kuzuoka, S: GCT-19
Kwiecien, R: EPEN-39, MBCL-07,
MBCL-09, MBCL-11, PATH-07
Kwok-Williams, M: GCT-61
Kwon, Ji Woong: MBRS-56
Kwon, Ji-Yeon: GCT-12
Kyle, S: MBRS-20
Kynčl, M: LGG-46, LGG-55

L
La Spina, M: ETMR-22
Lötsch, D: EPEN-21
Laczik, M: EPEN-46
Ladra, M: EPEN-50, RONC-27
Laetsch, T: EPCT-08, IMMU-18
Lafay-Cousin, L: DIPG-74, EPID06, ETMR-22, LGG-25, MBCL-19,
MBCL-24, RARE-21
LaHaye, S: ATRT-21,
EPEN-17, EPEN-28
Lähteenmäki, P: QOL-12
Lai, H: MBCL-38
Lai, M: DIPG-26, GCT-26, GCT-27, GCT28, GCT-63, HGG-14
Lai, Y: DIPG-57
Laing, M: MBCL-20
Lalazaryan, N: LINC-42
Lamb, M: GCT-74
Lambert, C: EPID-08
Lambo, S: ETMR-03, ETMR-13,
ETMR-17, MODL-02
Lamim, M: ATRT-10, SURG-22
Lamloum, I: NFB-16
Landi, D: EPCT-13, EPID-16,
MBCL-25, THER-05
Lane, A: DIPG-46, DIPG-55, DIPG-74,
EPCT-16, EPCT-19, LGG-31
Lane, S: EPEN-50, SWK-07
Lang, H: EPCT-15
Lang, R: MODL-08
Langevin, A: EPEN-51
Langfald, A: DIPG-05
Langmoen, I: TBIO-18

Lannering, B: QOL-17
Laperriere, N: EPEN-50, LGG13, LGG-55. MBRS-54, QOL-01,
RARE-02, RONC-03
Lappalainen, K: MBRS-68
Laquierre, A: ETMR-21
Lara-Corrales, I: NURS-04
Lardy-Cleaud, A: GCT-29
Larkin, T: IMMU-26
Larouche, V: EPID-06, HGG-20,
IMMU-18, LGG-25, LGG-55,
MBCL-24, RARE-17
Lasaletta, A: MBRS-54
Laspidea, V: THER-01
Lassaletta, A: ETMR-22, IMMU18, LGG-15, LINC-11, LINC-18,
LINC-21, RARE-17
Lassen-Ramshad, Y: ETMR-01, GCT-65
Łastowska, M: HGG-21
Laternser, S: DIPG-64
Laternser, S: MODL-22
Lattavo, L: IMG-14
Lattimore, A: NURS-10
Lau, C: EPEN-53, GCT-73,
MBRS-17, RARE-63
Lau, D: LINC-31
Lau, G: DDEL-17
Lau, L: DIPG-75
Laughlin, S: IMG-09. QOL-09, QOL-40
Lavally, B: GCT-37
Lavezo, J: PATH-06
Law, A: DIPG-19
Lawson, S: LGG-30
Layfield, R: HGG-38, TBIO-16
Lazaro, C: RARE-22
Lazarski, C: EPCT-15
Lazow, M: DIPG-46, LGG-30, LGG-31
Le Deley, M: DIPG-61,
EPCT-11, DIPG-35
Le Dret, L: DIPG-56
Le Fournier, L: HGG-40
Le Teuff, G: DIPG-35, DIPG-61
Leach, J: DIPG-46, DIPG-55, DIPG-74,
EPCT-16, EPCT-19, EPID-15, IMG-09
Leal-Cavazos, C: LINC-04, LINC-06
Leaoard, M: HGG-18
Leary, S: DIPG-46, DIPG-74, EPCT-05,
EPCT-19, EPEN-54, ETMR-20, ETMR22, IMMU-03, LGG-52, LGG-53,
LGG-55, MBCL-08, MBCL-16, MBCL19, MBCL-34, MBCL-36, MODL-26,
NFB-13, PATH-24
Leblond, P: EPCT-11,
MBCL-29, MBCL-43
Lechapt, E: DIPG-58, DIPG-61
Lechapt-Zalcman, E: MBRS-37
Lechpammer, M: PATH-31
Lee, A: RARE-11
Lee, C: MBRS-12
Lee, Daniel: IMMU-17

Lee, Davon: EPID-03
Lee, Dean: DIPG-06
Lee, E: IMG-22
Lee, H: RARE-45
Lee, Ji Won: MBCL-28
Lee, Joo Ho: GCT-02
Lee, Joongyo: EPEN-15
Lee, Joung: MBRS-54
Lee, Jun Hwa: MBRS-56
Lee, T: QOL-25
Lee, Y: MBCL-12
Legaspi, G: LINC-23
Legault, G: LGG-25
Lehman, B: MODL-13
Lehmann, R: DIPG-27
Leis, J: ATRT-07
Leiss, K: MBRS-03
Lemiere, J: QOL-07, QOL-18, QOL-19
Lemma, R: DIPG-42, DIPG-79,
HGG-57, MODL-31
Lenzen, A: LGG-04, MBLC-33
Leonard, J: ATRT-21, EPEN-17,
GCT-25, MBCL-46, RARE-31,
RARE-37, RARE-40
Lequin, D: MBRS-47
Leraas, K: ATRT-21,
EPEN-17, RARE-37
Leung, C: THER-08
Leung, D: PATH-14
Leung, G: HGG-27
Leung, L: QOL-25
Levashov, A: MBCL-04, MBCL-05
LeVine, D: RARE-12
Levy, J: HGG-57
Levy, M: EPEN-04
Lewis, E: DIPG-66
Lhermitte, B: TBIO-17
Li, Bo: GCT-03, GCT-24
Li, Bryan: ETMR-20, ETMR-21, MBCL34, MODL-26, PATH-24
Li, D: DIPG-39
Li, G: IMMU-30
Li, Jia: EPEN-46
Li, Jing: RONC-17
Li, Juan: DIPG-26, GCT-26, GCT-27,
GCT-28, GCT-63, HGG-14, LINC-15
Li, Lei: RARE-23
Li, Li: MODL-25
Li, N: DDEL-15
Li, Shaoqun: DIPG-26
Li, Shulin: DIPG-60
Li, X: EPCT-16, EPEN-46, EPEN-53,
MBRS-17, TBIO-02, TBIO-03
Li, Yimei: MBCL-14, MBCL-15, MBCL16, QOL-20, RONC-27
Li, Zhao-jie: EPEN-05
Li, Zhenghong: QOL-15
Li, Zhi: EPEN-05
Liang, K: MBCL-12
Liang, M: MBCL-12, MODL-16

NEURO-ONCOLOGY•DECEMBER 2020

iii489

Author Index

Liu, W: ATRT-09, IMMU-29
Liu, Y: RARE-45
Liu, Z: RONC-03
Liuzzi, A: IMMU-16
Llargués-Sistac, G: MBRS-57
Lober, R: IMG-03, IMG-10, IMG-13,
IMG-22, MODL-26
Lobon-Iglesias, M: ATRT-27
Locatelli, F: HGG-16, HGG-19, HGG54, IMMU-13, LGG-18, MBCL-18,
MODL-23, NFB-07, PATH-19
Lock, R: DIPG-75
Lockett, N: MBRS-33
Lockwood, G: THER-03, THER-04
Lodi, M: LGG-18, NFB-07
Loew, D: MBCL-21
Loginova, A: EPEN-50
Loh, C: LINC-27, LINC-31
Loh, J: SURG-29
Loh, P: LINC-02
Lohkamp, L: RARE-09
Löhr, M: IMMU-10
Lomax, A: RONC-15
Lombard, B: MBCL-21
London, W: MBCL-25
Longaud, A: MBCL-02
Longcor, J: EPCT-09
Lönnqvist, T: QOL-12
Looi, W: RONC-32
Lopez-Ibor, B: THER-09
López-Terrada, D: PATH-29
Lord, C: MBRS-57
Lorelay Livier, G: OTHR-12
Loret De Mola, R: RARE-17
Lossos, A: HGG-20, IMMU-18
Lötsch, D: EPEN-21
Louati, R: TBIO-27
Loudon, W: MBCL-38
Lourdusamy, A: EPEN-23, EPEN-42,
MBRS-69, TBIO-16
Lourenço, L: ATRT-10, OTHR-14,
SURG-06, SURG-09, SURG-22
Lovria, R: OTHR-16
Low, S: ETMR-22, IMG-01
Lowenstein, P: DIPG-59
Lowis, S: GCT-61
Lu, G: DIPG-52, HGG-18
Lu, Mei: ATRT-33, ETMR-19, ETMR-22
Lu, Ming: HGG-14
Lu, S: DIPG-22, DIPG-53, RARE-07
Lu, Yu: MBRS-01
Lu, Yue: MBRS-70
Lu, Z: IMG-20
Lubieniecki, F: RARE-50
Lucas, J: EPEN-50, HGG-57,
IMG-20, RARE-12
Lucato, L: EPID-05
Luck, A: DDEL-01
Ludemann, J: NFB-12
Ludmir, E: RONC-05

Liberio, M: MBRS-68
Libes, J: EPEN-51
Libý, P: HGG-31, LGG-46
Lichtenberg, T: ATRT-21,
EPEN-17, RARE-37
Lichter, P: MBCL-21
Ligon, K: DIPG-22, DIPG-53, EPEN-21,
HGG-32, HGG-41, HGG-52, LGG-35,
LGG-52, RARE-07
Lilly, J: EPID-14, MODL-26. PATH-21
Lim, D: MBCL-28
Lim, J: ETMR-13
Lim, M: RARE-01
Lim, P: RONC-15
Lima, F: RARE-18
Limbrick, D: QOL-22, RARE-11
Lin, C: EPEN-30
Lin, F: EPEN-25, IMG-07, LGG-55,
PATH-27, PATH-29, RONC-09
Lin, L: RONC-27
Lin, R: LGG-44
Lin, S: MBCL-20
Lin, T: EPCT-17, ETMR-06, ETMR-21,
HGG-57, PATH-22
Lin, Z: RARE-63
Lindhorst, S: HGG-20,
IMMU-18, RARE-17
Lindsay, H: EPCT-02, EPEN-46, ETMR22, IMG-07, MBRS-17, TBIO-02
Lindsey, J: MBRS-33, MBRS-44,
MBRS-57, MBRS-60
Ling, A: HGG-48, LINC-20
Ling, S: RARE-17
Link, M: RARE-17
Linke, F: MBRS-27, MBRS-28,
MBRS-43, MBRS-45
Linscott, L: EPEN-07
Lion, A: QOL-48
Liossi, C: QOL-32, QOL-33
Lipman, T: IMMU-18, MODL-25
Lipp, E: EPCT-13, IMMU-27
Lippé, S: LGG-25
Lishman-Walker, E: ATRT-25
Listernick, R: NFB-09
Liu, Allison: GCT-66
Liu, Anthony: EPID-10, ETMR06, ETMR-21, LINC-15, MBCL-08,
MBRS-20, QOL-25
Liu, Arthur: HGG-57, QOL-37, QOL-38
Liu, G: NFB-09
Liu, Hao: EPID-11, QOL-58
Liu, Hongxing: RARE-63
Liu, I: EPEN-21, HGG-53
Liu, Jie: DDEL-12, DIPG-07,
DIPG-14, DIPG-27
Liu, Jingbo: MODL-06
Liu, K: DIPG-01, GCT-37
Liu, L: IMMU-17
Liu, S: RARE-01
Liu, T: MBRS-73

vi490

NEURO-ONCOLOGY•

DE C E M B E R 2 0 2 0Lugo, S: SWK-02
Luiten, R: RARE-17
Luk, C: HGG-48, LINC-20, QOL-25
Lukban, M: LINC-23
Lulla, R: DIPG-62, HGG-52,
IMMU-31, MODL-26
Lummus, S: PATH-06
Luna-Fineman, S: IMMU-18
Lundy, S: EPCT-12
Luo, E: MBRS-01
Luo, L: EPEN-42
Luo, R: DIPG-26, GCT-27,
GCT-28, HGG-14
Lupo, J: QOL-53
Luria, V: TBIO-26
Lurye, M: RARE-17
Lwin, S: RARE-01
Lyons, N: TBIO-26, TBIO-03
Lythgoe, M: IMMU-16

M
Ma, J: DIPG-46, DIPG-74,
LINC-19, MBRS-62
Ma, M: MODL-06
Ma, W: TBIO-19
Ma, X: LINC-15
Maass, K: EPEN-18,
EPEN-44, MBRS-68
Maaz, A: LINC-43
Mabbott, D: QOL-01, QOL-09,
QOL-40, RONC-03
Mabrouk, M: THER-04
MacArthur, D: EPEN-24, EPEN-43
MacCowage, G: DIPG-35
MacDonald, S: GCT-33, GCT-37, GCT41, GCT-42, RONC-24
MacDonald, T: DIPG-52, EPCT02, IMG-04, LGG-52, MODL-06,
PATH-14, QOL-31
MacGregor, D: PATH-09
Machado, N: QOL-27
Macharia, D: PATH-16
Macias-Toscano, J: QOL-06
Maciaszek, J: RARE-17
Mack, N: ETMR-03, MODL-02
Mack, S: EPEN-16, EPEN-25,
EPEN-30, MBRS-17
Mackay, A: DIPG-58, DIPG-63, HGG20, HGG-37, IMG-12, MODL-19, MOD20, PATH-17, THER-09
MacPherson, L: IMG-06
Macy, M: EPC-10, EPCT-18, HGG-01
Maddocks, A: DDEL-07
Madhavan, K: ATRT-06,
DIPG-34, DIPG-73, MBRS-65,
MBRS-67, MBRS-71
Madlener, S: EPEN-21, ETMR-17

Author Index

Madrid, N: QOL-34, SWK-05
Madrigal-Avila, C: LINC-39, LINC-40
Maegawa, S: MBRS-53,
MBRS-64, MBRS-70
Maehara, T: GCT-43, GCT-52, HGG-30,
HGG-50, RONC-18, SURG-05
Maestro, N: IMMU-13
Magimairajan, V: HGG-20,
IMMU-18, RARE-17
Magoha, M: LINC-32
Magrini, V: ATRT-21,
EPEN-17, EPEN-28
Mah, H: EPID-08
Mahadeo, K: IMMU-07
Mahajan, A: LGG-09, QOL-01
Mahapatra, S: MBRS-13, MBRS-72
Maher, C: DIPG-08, EPEN-50, HGG-17
Maher, O: DDEL-02, DDEL-14,
RARE-17, RONC-08
Mahsin, H: LINC-03
Maiko, S: QOL-48
Mailhot-Vega, R: RONC-22, RONC-24
Mainwaring, O: MBRS-10
Majumder, S: MBRS-64
Mak, T: DIPG-41
Makalowski, J: DIPG-38
Makino, K: EPEN-02, EPID-01, GCT-36
Makino, R: MBCL-27
Makino, Y: LGG-38, PATH-23
Malalasekera, V: RARE-50
Malbari, F: EPEN-25, IMG-07, IMG-09
Maletzki, C: HGG-07
Malhotra, A: MODL-06
Maliakal, P: EPCT-16
Malinová, B: HGG-31
Malkin, H: HGG-41
Mallebranche, C: HGG-40
Mallory, C: RONC-08
Mallucci, C: EPEN-24, GCT-49,
QOL-59, SURG-12
Malm, J: MBRS-68
Malvar, J: LGG-52
Mamatjan, Y: GCT-52
Man, T: GCT-73
Mançano, B: ATRT-10, GCT-58, OTHR14, QOL-27, SURG-06, SURG-08,
SURG-09, SURG-22
Manabe, Atsushi: GCT-08,
GCT-10, RONC-16
Manabe, Atushi: GCT-31, SURG-02
Mandeville, H: GCT-61, MBRS-33
Mandonnet, E: HGG-11
Mang, P: QOL-56
Mangum, R: EPEN-25,
PATH-27, PATH-29
Mangunatmadja, I: LINC-24
Mankad, K: DIPG-37, IMG-10, IMG-13
Manley, P: QOL-41, RARE-07
Mann, S: RARE-30
Mannan, A: DIPG-29, DIPG-32

Manning, J: SWK-10
Mano, M: MBRS-38
Manoharan, N: DIPG-75
Mansfield, F: DDEL-12
Mansukhani, M: LGG-22
Manzari, M: DDEL-15
Mao, W: SURG-04
Mardis, E: ATRT-21, EPEN-17, EPEN28, RARE-31, RARE-37
Marghoob, A: RARE-24
Margol, A: ATRT-30, GCT-23,
LGG-45, LGG-52, MBCL-24,
NURS-09, OTHR-09
Marjerrison, S: QOL-02, QOL-46
Marks, A: PATH-14
Marquardt, V: EPEN-33, IMMU-19,
LGG-17, MBRS-48
Marras, C: SURG-03
Marrodán, L: THER-02
Marshall, G: DIPG-75
Marshall, L: MODL-20
Martin, Alberto: MODL-25
Martin, Allison: DIPG-12, DIPG-70
Martin, E: ATRT-25
Martin, K: LGG-13
Martin, L: ATRT-21, GCT-25, RARE-37
Martinez, D: PATH-21
Martinez, H: RONC-31
Martinez-Albarran, M: RARE-29
Martinez-Velez, N: THER-01
Martini, C: MBCL-11
Martirosyan, M: LINC-42
Marx Fernandes, J: LGG-51
Mary, S: ETMR-22
Mascarin, M: EPEN-03
Mascelli, S: LGG-55
Maser, T: ETMR-18
Masihi, M: MBRS-12
Masliah, J: RARE-21
Masliah-Planchon, J: ATRT-27, MBCL29, MBRS-37, MBRS-47
Masmoudi, I: NFB-16
Mason, G: HGG-20,
IMMU-18, MBRS-54
Mason, J: MODL-26,
PATH-21, TBIO-03
Mason, W: HGG-20,
IMMU-19, LGG-13
Masotti, A: HGG-16, HGG-19
Massimi, L: ETMR-22,
IMMU-13, RARE-11
Massimino, M: DIPG-54, EPEN03, HGG-20, IMG-09, IMMU-18,
QOL-17, RARE-17
Mastronuzzi, A: EPEN-03, HGG-16,
HGG-19, HGG-54, IMG-14, IMG-16,
IMG-19, IMMU-13, LGG-18, MBCL18, MBRS-60, MODL-23, NFB-07,
PATH-19, SURG-03
Masuda, S: IMMU-09

Masuoka, J: SURG-24
Mata-Mbemba, D: IMG-04
Matevosyan, V: LINC-42
Mathewson, N: EPEN-21
Mathiasen, R: QOL-59
Matitsyn, A: ATRT-05, MBCL-31
Matsekha, E: ATRT-05, MBCL-31
Matson, K: NURS-01
Matsuda, M: GCT-38
Matsui, Y: MBRS-22, MBRS-23
Matsukawa, Y: ETMR-11, RARE-16
Matsumoto, K: ATRT-11, ETMR-11,
HGG-49, RARE-16
Matsumoto, Y: GCT-53
Matsumura, A: GCT-39,
GCT-60, LGG-40
Matsusaka, Y: MBCL-22
Matsushita, M: ATRT-10,
OTHR-14, SURG-06
Matsushita, Y: GCT-34, GCT-52,
GCT-62, HGG-39, MBRS-21,
PATH-25, RARE-39
Matsutani, M: GCT-15,
GCT-43, GCT-52
Matsutani, T: GCT-09,
GCT-45, PATH-03
Mattioni, M: EPID-14
Mattonen, S: IMG-10, IMG-13
Matuschek, C: MBCL-11
Matushita, H: EPID-05,
LINC-38, PATH-18, RARE-47,
SURG-07, SURG-20
Maue, M: EPEN-33, MBRS-48
Mauermann, M: ETMR-03, ETMR-13
Mawrin, C: MBCL-07
Mayoh, C: DIPG-15, DIPG-27,
DIPG-50, DIPG-75
Mayr, L: DDEL-03, EPEN-21,
ETMR-10, ETMR-17
Mazewski, C: ETMR-20, MBCL-19,
MBCL-34, MBCL-37, PATH-24
Mazzola, E: EPEN-21
Mbiro, M: LINC-32
McAleer, M: IMG-15, MBCL-35, QOL28, RONC-09, RONC-17
McAllister, A: ATRT-21, RARE-37
McAllister, S: DIPG-59
McAndrew, R: NURS-03, QOL-49
McCall, D: RARE-19
McCourt, E: NFB-09
McCowage, G: DIPG-32,
MBCL-26, NFB-18
McCurdy, M: RONC-12
McDonald, W: LGG-36
McElroy, J: HGG-45, MBRS-29,
MBRS-73, PATH-15
McGovern, S: DIPG-52, IMG-15,
MBCL-35, QOL-28, RARE-19, RONC05, RONC-09, RONC-17
McIntosh, D: QOL-56

NEURO-ONCOLOGY•DECEMBER 2020

iii491

Author Index

Michalski, J: MBCL-15, MBCL-16,
QOL-20, RONC-27
Michaud, J: ETMR-22
Michealraj, A: EPEN-52
Michel, C: ATRT-06
Michniewicz, F: DIPG-83
Middleton, J: SWK-11
Miele, E: HGG-54, IMG-16, IMG-19,
LGG-18, MBCL-18, MODL-23, PATH-19
Migliavacca, J: MBRS-39
Mikasch, R: EPEN-06
Mikhaleuskaya, T: PATH-10
Mikkelsen, T: ETMR-01
Miklja, Z: DIPG-59, HGG-18
Mikloska, K: DDEL-01
Milde, T: EPEN-18, EPEN-21, LGG-14,
LGG-17, LGG-55, MBCL-06, MBCL-21,
MBRS-19, RARE-21
Miley, A: QOL-04
Millard, N: NFB-13
Miller, D: PATH-21
Miller, E: IMMU-10
Miller, Katherine: ATRT-21, EPEN-17
Miller, Kristin: QOL-34
Miller, P: DIPG-53
Miller, S: RARE-53
Millward, C: SURG-12
Milosevic, D: PATH-13
Mima, M: RONC-04
Minamiguti, S: PATH-23
Minasi, S: EPEN-03
Mineharu, Yohei: EPID-17, LGG-38,
MBRS-22, RONC-06, THER-07
Mineharu, Youhei: GCT-50
Minkina, L: ATRT-05, MBCL-31
Minturn, J: DIPG-46, DIPG-55, DIPG74, LGG-53, MBCL-14, TBIO-03
Mirman, I: QOL-54
Mirsky, D: RARE-11
Miser, J: RARE-45
Mishra, D: DIPG-21
Mišove, A: HGG-31,
LGG-46, PATH-20
Mission, P: NFB-14
Mitani, Y: MBRS-21
Mitchell, C: NFB-08
Mitchell, D: IMMU-08
Mitra, D: GCT-20, GCT-76,
IMG-06, MBRS-69
Mitra, S: ATRT-24, IMMU-19
Mitrofanov, V: ATRT-05, MBCL-31
Miura, F: TBIO-08
Miwa, T: GCT-47, GCT-51, GCT-55
Miyachi, M: DIPG-04, HGG-12
Miyagi, N: GCT-53
Miyahara, H: MBRS-06, MBRS-32
Miyake, K: IMG-02
Miyake, S: HGG-51
Miyake, Y: HGG-51
Miyakita, Y: GCT-62, HGG-39

McKelvey, K: DIPG-13
McKenna, E: NFB-04, NFB-11
McKenzie, I: MBCL-33
McKeown, T: LGG-55, NURS-04
McLean, G: TBIO-03
McLendon, R: IMMU-27
McMahon, K: LGG-27, NFB-02
McNall-Knapp, R: LGG-47, RARE-20
McWilliams, J: RARE-10
Meador, H: ETMR-04
Mease, L: HGG-01
Medhioub, A: NFB-16
Meel, M: ATRT-18, RONC-21
Meharian-Shai, R: MBRS-04
Mehnert, A: RONC-02
Mehrian-Shai, R: HGG-04
Mehta, M: HGG-18, RONC-08
Mehta, V: LGG-19
Meinhardt, M: MBCL-07
Melanson, R: DIPG-53
Melcher, V: ATRT-13,
ATRT-14, ETMR-05
Melikyan, A: ATRT-05, MBCL-31
Melkus, G: IMG-21
Mellies, A: EPID-13
Meng, X: IMMU-28
Mentkevich, G: MBCL-04, MBCL-05
Mercer, K: IMMU-06
Merchant, T: EPEN-50, EPEN-54,
ETMR-06, HGG-57, IMG-20, LINC-35,
MBCL-15, RARE-12
Mercier, A: MBRS-51
Merdinger, K: DIPG-52, HGG-18
Meredith, D: ETMR-06
Merishavyan, A: MBCL-32
Merk, D: ATRT-32
Merkurjev, D: RARE-57, TBIO-12
Merlevede, J: DIPG-56
Merry, C: MBRS-43
Mertens, A: QOL-31
Mesirov, J: EPEN-04
Messiaen, J: RARE-56
Mestnik, S: DIPG-79
Mete, O: RARE-22
Métras, M: LGG-25
Metselaar, D: ATRT-18,
DIPG-73, RONC-21
Mette, J: ETMR-22
Mettetal, A: EPCT-18,
QOL-36, QOL-38
Meudt, J: MODL-13
Meyer, E: ATRT-21
Meyer, F: MBCL-11
Meyer, J: PATH-26
Meyer zu Hörste, G: ATRT-13, ATRT-14
Mhiri, N: NFB-16
Mhyre, A: DIPG-10, MODL-28
Michael, M: ATRT-08
Michalski, A: MBRS-44, MBRS-60

vi492

NEURO-ONCOLOGY•

DE C E M B E R 2 0 2 0

Miyamoto, S: GCT-50, LGG-38,
MBRS-22, PATH-23, THER-07
Miyamura, T: QOL-44
Miyata, M: LGG-29, RONC-26
Mizoguchi, M: GCT-43,
HGG-24, LGG-20
Mizowaki, T: GCT-50, RONC-06
Mizuguchi, M: TBIO-08
Mizumoto, M: GCT-38, GCT-60
Mizuno, T: ETMR-11
Mizutani, T: HGG-29
Mkhitaryan, A: RARE-33
Mkhitaryan, S: LINC-13
Mobark, N: HGG-09, LGG-01,
LGG-15, MBCL-01
Mochizuki, A: MBCL-14
Modena, P: EPEN-03
Mody, R: DIPG-08, DIPG-59, HGG-18,
PATH-14, RARE-51
Moertel, C: ETMR-22,
LGG-49, NFB-09
Moffat, J: MBRS-01
Mohamed, Z: MBCL-52
Mohamed Unni, M: MBCL-50
Mohammad, A: DDEL-09, DDEL-10
Mohan, A: MBRS-18
Mohd Ibrahim, H: MBCL-50
Mohila, C: PATH-29
Mohiuddin, S: LGG-44
Moisander-Joyce, H:
EPID-03, LGG-22
Moiyadi, A: LINC-12, LINC-25,
LINC-29, MBRS-61
Mokhtari, K: HGG-11
Moldovan, I: IMG-21
Molero, M: IMMU-22
Moleron, R: COVD-01
Molinari, E: QOL-59
Molinari, V: DIPG-63, HGG-37, IMG12, MODL-19, MODL-20
Molinaro, A: EPCT-12, IMMU-23,
IMMU-31, LGG-53
Monje, M: DIPG-06, DIPG-29,
DIPG-32, DIPG-55, HGG-53,
IMG-10, TBIO-06
Monje-Deisseroth, M: DIPG-46, DIPG74, MODL-26, TBIO-03
Monoranu, C: IMMU-10, MBCL-07
Monte Mor, B: PATH-30
Monte Real, J: LGG-51, MBRS-66
Montero Carcaboso, A: DIPG-73,
HGG-19, HGG-37, MODL-20, MODL-21
Moon, P: NFB-04
Moore, A: HGG-19, MODL-20
Moore, J: NURS-12
Mora, J: IMMU-22
Mora, P: RARE-42
Morales, A: ETRM-22
Morales La Madrid, A: IMMU-22,
LGG-55, LINC-11, LINC-18, LINC-21

Author Index

Morana, G: GCT-20, LGG-55
Morcavallo, A: MBRS-33, MBRS-57
Mordechai, O: IMMU-18
Moreira, D: COVD-04, EPID-07,
LINC-23, LINC-35
Moreno, N: ATRT-13, ATRT-14,
ATRT-15, ETMR-05
Moreno, R: LINC-21
Morgan, H: NURS-09
Morgan, P: IMG-04
Morgenstern, D: EPCT-09,
IMMU-14, IMMU-18
Mori, M: ETMR-12, MBRS-21,
PATH-25, RARE-39
Mori, T: GCT-08, RONC-16, RONC-19
Morimoto, T: MBRS-22
Morin, A: ATRT-20, LGG-34
Morioka, M: GCT-53
Morisako, H: RARE-03
Morisako, T: DIPG-04, HGG-12
Mork, M: NFB-06
Moro, N: OTHR-02
Morozova, E: MBCL-03
Morris, C: QOL-32, QOL-33, RONC-22,
RONC-24, RONC-32
Morris, S: DIPG-10, MODL-28
Morrison, M: QOL-53
Morse, H: LGG-55
Mosaheb, M: THER-05
Moscato, E: QOL-04
Moskvin, V: RARE-12
Moss, T: RARE-19
Motegi, H: GCT-08, GCT-10, GCT-31,
RONC-16, SURG-02
Motley, W: NFB-09
Mou, Y: GCT-30
Moukhaiber, P: NFB-18
Mould, E: DIPG-75
Moxon-Emre, I: QOL-09
MP, N: RONC-23
Mrugala, M: ATRT-07
Mubarak, F: LINC-10
Mucci, G: QOL-34
Muchantef, K: RARE-22
Muda, Z: MBCL-50
Mudra, K: QOL-59
Mueller, S: EPCT-01, EPCT-12, GCT23, IMG-04, IMMU-23, IMMU-31,
LGG-53, MODL-26, NFB-17, PATH-14,
QOL-53, SWK-10
Mueller, T: EPEN-44
Muggeri, A: LINC-05
Muhonen, M: MBCL-38
Mukasa, A: EPEN-02, EPID-01, GCT15, GCT-36, GCT-52
Mukkada, S: COVD-04
Mulcahy Levy, J: ATRT-20, DDEL06, ETMR-22, LGG-27, LGG-34,
QOL-36, MODL-01
Muldoon, D: MODL-17

Mullan, B: DIPG-59
Müllauer, L: HGG-44
Müller, H: RARE-59,
RARE-60, RARE-61
Muller, H: LINC-10
Müller, J: GCT-76
Müller,S: DIPG-64, MODL-22
Muller, J: GCT-29
Muller, P: HGG-44
Mumal, I: ETMR-19
Mun, K: LINC-03, SURG-29
Mundlos, S: EPEN-04
Munoz, D: LGG-13
Murai, H: GCT-09
Muramatsu, H: LGG-56
Muraszko, K: DIPG-08
Murnick, J: DIPG-80
Muroi, A: GCT-38, GCT-60, LGG-40
Murota, Y: GCT-44,
RONC-25, SURG-05
Murphy, E: GCT-33, GCT-41, GCT-42
Murpy, D: QOL-56
Murray, M: COVD-01, GCT-20, GCT29, GCT-48, GCT-49, GCT-61
Muruganand, A: DIPG-08
Musharbash, A: LINC-10
Mushinskaya, M: ATRT-05, MBCL-31
Mushrif, S: MODL-27
Mushtaq, N: LGG-55,
LINC-10, RARE-17
Mussai, F: DIPG-16
Musthaq, N: RARE-55
Muthugounder, S: MODL-27
Muzny, D: EPEN-25, PATH-27,
PATH-29,
Mwangombe, P: PATH-16
Mwang’ombe, N: LINC-32
Myers, C: DIPG-10, DIPG-64
Mynarek, M: EPEN-09, EPEN-27,
EPEN-36, EPEN-39, ETMR-14, LINC18, MBCL-06, MBCL-07, MBCL-09,
MBCL-11, MBCL-19, MBCL-37, PATH07, QOL-13, QOL-24, RARE-42

N
Na, B: MODL-13
Nadaf, J: RARE-22
Naftel, R: QOL-22, RARE-11
Nagabushan, S: DIPG-75
Nagai, T: DIPG-04
Nagane, M: GCT-43, GCT-52,
GCT-62, PATH-05
Nagata, Y: GCT-53
Nagib, M: LGG-36
Naguib, E: HGG-17
Nagulapally, A: DIPG-66, ETMR-18
Naidu, P: COVD-04

Nair, S: THER-05
Najjar, A: RARE-19
Nakada, M: GCT-52, QOL-05
Nakagawa, N: RARE-26
Nakagawa, S: GCT-53
Nakagawa, T: GCT-69, QOL-44
Nakahara, Y: SURG-24
Nakajima, R: QOL-05
Nakamura, H: ETMR-22, GCT-36,
GCT-53, GCT-73
Nakamura, T: GCT-52, GCT-62,
HGG-51, RARE-26
Nakano, M: ETMR-11
Nakano, N: HGG-49
Nakano, T: GCT-62
Nakano, Y: GCT-72, HGG-02, HGG-49,
PATH-23, PATH-28, RARE-26
Nakashima, K: IMMU-09
Nakata, S: ATRT-17, MODL-04
Nakatomi, H: DIPG-17
Nakaya, M: GCT-56
Nakazato, Y: GCT-15, GCT-43, GCT-52
Nakazawa, A: ETMR-12, MBRS-21,
PATH-25, RARE-39
Nakra, V: RONC-23
Nambirajan, A: EPEN-38
Namer, I: TBIO-17
Nannini, F: IMMU-16
Napolitano, A: IMG-14, IMG-16
Naqvi, A: DIPG-31
Narayanaswamy, P: IMMU-02
Narendran, A: ETMR-08
Nariai, T: HGG-30, HGG-50, RONC-18
Narita, K: LGG-56
Narita, Y: EPID-09, GCT-15, GCT-52,
GCT-62, HGG-02, HGG-39
Narushima, D: GCT-34
Nasser, M: MBRS-72
Nasser, W: MBRS-13
Nath, C: DIPG-07
Nathan, E: MODL-08
Nathan, J: DIPG-25
Natsume, A: LGG-56
Natsumeda, M: MBRS-06, MBRS-32
Navalkele, P: GCT-23
Navarro-Martin del Campo, R: EPEN13, LINC-09, LINC-16, OTHR-12, QOL06, RARE-29, SURG-19
Nazarian, J: DIPG-06, DIPG-38, DIPG39, DIPG-51, DIPG-64, EPCT-12, EPID14, IMMU-31, MBCL-08, MODL-22,
MODL-26, PATH-14, TBIO-03
Nazemi, K: HGG-01, IMMU-31,
LGG-52, LGG-53
Nechesnyuk, A: EPEN-50,
MBCL-31, MBCL-32
Nechesnyuk, E: ATRT-05
Neel, H: DIPG-73
Negoto, T: GCT-53
Negreiros, T: RARE-42

NEURO-ONCOLOGY•DECEMBER 2020

iii493

Author Index

Núñez, N: IMMU-16
Nysom, K: DIPG-35, QOL-59

Neil, J: RARE-30
Nejo, T: IMMU-23, IMMU-31
Nellan, A: ATRT-24, IMMU-20,
LGG-34, LGG-48, MODL-01, NFB-02,
QOL-36, RARE-27
Ness, K: QOL-15
Nesvick, C: DIPG-78
Nesvizhskii, A: TBIO-19
Neumann, E: RARE-46
Neumann-Holbeck, A: QOL-13
Nevin, M: DIPG-43
Newmark, M: RARE-17
Ng, C: EPEN-36
Ng, H: GCT-73, HGG-48
Ng, N: NFB-04
Nga, V: EPID-04, RARE-01
Nguyen, L: LGG-13, TBIO-05
Nguyen, Thanh: IMG-21
Nguyen, Tiffany: LGG-27
Niazi, T: DDEL-14, QOL-22,
RARE-11, RONC-08
Nicholas, G: RARE-17
Nicholoson, J: GCT-49
Nichols, K: MBCL-21, RARE-17
Nicholson, J: COVD-01, GCT-20, GCT29, GCT-48, GCT-61, GCT-76
Nicolaides, T: MODL-17, NFB-08,
PATH-12, RARE-17
Niizuma, H: MBCL-48
Nishikawa, R: GCT-15, GCT-34,
GCT-43, GCT-46, GCT-52, GCT-62,
GCT-72, GCT-73, MBCL-41, MBCL-48,
MBRS-38, PATH-28
Nishimoto, M: GCT-51
Nishimoto, S: RONC-20
Nitani, C: MBCL-22
Nobre, L: GCT-75, LGG-13, LGG34, LGG-50, LGG-55, PATH-14,
PATH-30, RARE-50
Nobusawa, S: ETMR-22, PATH-23,
PATH-29, RARE-26
Noll, A: DIPG-10, MODL-28
Nonaka, M: GCT-43, GCT-52, LGG-29,
RONC-13, RONC-26
Noor Rana, A: RARE-55
Norris, M: DIPG-15, DIPG-16,
DIPG-27, DIPG-75
Northcott, P: ETMR-06, ETMR21, MBCL-08, MBCL-15, MBCL-16,
MBCL-21, MBCL-26, MBRS-20,
MBRS-24, RARE-21
Noskoff, K: QOL-34
Novak, J: IMG-06
Novak, O: DIPG-12, DIPG-71
Novichkova, G: GCT-64, LGG-26,
MBCL-32, RARE-52
Noyd, D: EPID-16
Nuijts, M: RARE-62
Numata, O: GCT-45
Nunes, N: LGG-13, MODL-25

vi494

NEURO-ONCOLOGYOOates, A: IMG-06
Oba, U: IMMU-09
Obrecht, D: EPEN-09, EPEN-36,
EPEN-39, MBCL-06, MBCL-07, MBCL09, PATH-07, QOL-13
Ocasio Adorno, J: DIPG-51
Ochiai, H: GCT-45
Ochiya, T: GCT-72
Oda, Y: IMMU-09
Odia, Y: DIPG-52, HGG-18
Odone, V: EPID-05, RARE-47
Oeffinger, K: EPID-16
Oehme, I: MBRS-19
Oelfke, U: MBRS-33
Offeddu, G: DDEL-04
Ogata, A: SURG-24
Ogawa, C: RARE-32
Ogawa, D: IMG-02
Ogawa, S: ATRT-11
Ogiwara, H: ATRT-11, ETMR-11, GCT14, HGG-49, RARE-16, SURG-17
Oguma, H: DIPG-02
Ogura, T: MBCL-27
O’Halloran, H: NFB-09, RARE-57
O’Halloran, K: TBIO-12
Ohara, K: GCT-51
O’Hare, P: MODL-19
Ohashi, T: IMMU-12
Ohata, H: RARE-03
Ohata, K: RARE-03
Ohba, S: MODL-15
Ohga, S: HGG-24, IMMU-09
Ohka, F: LGG-56
Ohki, K: ATRT-11
Ohmura, T: HGG-39
Ohno, M: HGG-39
Ohta, A: MBCL-41
Ohta, H: LGG-54
Oichi, Y: MBRS-22
Oigman, G: LINC-28
Oishi, M: MBRS-06
Ojaniemi, M: QOL-12
Ojeda, L: RARE-42
Okada, H: IMMU-23,
IMMU-31, THER-05
Okada, Kaori: IMMU-23, IMMU-31
Okada, Keiko: MBCL-22,
QOL-44, RARE-26
Okamoto, M: GCT-08, GCT-10,
GCT-31, SURG-02
Okauchi, M: IMG-02
Okcu, F: QOL-01, RONC-05, RONC-12
Okcu, M: IMG-07•

DE C E M B E R 2 0 2 0

Okemwa, M: LINC-32, PATH-16
Okita, H: ATRT-11
Okonechnikov, K: ATRT-28,
EPEN-04, EPEN-18, MBRS-03,
MBRS-51, MBRS-68
Okuda, H: MBRS-22
Okuhiro, Y: MBCL-22
Olaya, J: MBCL-38
Oliveira, M: LINC-26, RARE-18
Oliver, K: EPCT-09
Olkhova, L: ATRT-05, MBCL-31
Oller, A: GCT-71
Olson, J: DIPG-10, DIPG-64,
MBCL-16, MODL-28
Olsthoorn, I: QOL-11
Omar-Thomas, A: GCT-41
Omer, N: DIPG-75
Omouk, D: PATH-16
Onar-Thomas, A: EPCT-02, EPCT-05,
EPCT-17, EPEN-54, ETMR-21, GCT-33,
GCT-42, HGG-22, LGG-04, MBCL-08
O’Neill, G: DIPG-13
Ong, G: LINC-03
Onimaru, R: RONC-16, RONC-19
Ono, H: HGG-24
Ono, K: HGG-24
Onorini, N: SURG-03
Onuki, R: GCT-62
Opocher, E: HGG-20, IMMU-18,
PATH-14, RARE-17
Oppermann, S: MBRS-19
Orduña, P: LINC-17
Oren, M: IMMU-18
Orentas, R: IMMU-03
Orge, F: NFB-09
Orienti, I: DIPG-07
Orlando, D: IMMU-13
O’Rourke, R: HGG-41
Orozco-Alvarado, A: EPEN-13, LINC09, LINC-16, QOL-06, RARE-29
Orr, B: ETMR-06, ETMR-21, HGG-57,
MBCL-08, MBCL-21, PATH-09, PATH13, PATH-14, PATH-22
Osborn, M: IMMU-14,
IMMU-18, RARE-17
Oshima, H: OTHR-02
Oshrine, B: RARE-17
Osorio, D: ATRT-21, EPEN-17, EPEN28, GCT-25, GCT-40, GCT-66, LGG-31,
LGG-55, LINC-11, LINC-18, LINC-21,
LINC-28, MBCL-46, PATH-12, RARE31, RARE-37, RARE-40
Ospovat, I: MBCL-17
Oster, W: DIPG-52, DIPG-62, HGG-18
Osthoorn, I: QOL-28
Ostrow, D: RARE-57, TBIO-12
O’Sullivan, S: THER-03, THER-04
Osumi, T: ATRT-11, ETMR-11, HGG-49
Ota, K: GCT-36
Otake, S: GCT-45

Author Index

Othman, I: MBCL-50
Otsu, Y: GCT-53
Ottensmeier, H: MBCL-07,
QOL-13, QOL-24
Otto, M: EPCT-09
Overbeck, N: LGG-14
Oweida, A: DIPG-42
Owen, J: COVD-03, QOL-21
Owens Pickle, E: EPEN-45, EPEN-51,
EPEN-54, MBCL-30, RARE-48
Oyarce, V: LINC-21
Oyefiade, A: QOL-09
Oyoshi, T: HGG-42, LGG-20,
LGG-32, RARE-04
Ozawa, T: EPEN-34, EPEN-41, GCT-46

P
Packard, M: SWK-02
Packer, R: DIPG-46, DIPG-55, DIPG-74,
EPCT-15, GCT-23, IMG-03, LGG-04,
LGG-26, LGG-55, MBCL-15, MBCL-16,
NFB-17, PATH-14, THER-08
Paco, S: IMMU-22
Paes, V: EPID-05
Pagadala, M: EPEN-04
Pages, M: HGG-11
Pagliara, D: HGG-54
Paisana, E: EPEN-33
Paisley, H: COVD-03, QOL-21
Pajtler, K: EPEN-03, EPEN-04,
EPEN-06, EPEN-09, EPEN-18, EPEN21, EPEN-36, EPEN-39, EPEN-44,
EPEN-47, MBCL-21, MBRS-03,
MBRS-68, RARE-21
Pakakasama, S: RARE-38
Pakiam, F: DIPG-10
Pal, S: HGG-32
Palenzuela, G: GCT-29, MBCL-29
Pallud, J: HGG-11
Palmer, J: GCT-25
Palomar, R: LINC-05
Pan, H: EPCT-17
Pandele, A: EPEN-43
Pandher, R: DIPG-15,
DIPG-16, DIPG-27
Pang, C: DIPG-14, DIPG-27
Panigrahi, A: IMMU-15
Panigraphy, A: GCT-33
Paolini, A: HGG-16, HGG-19
Papin, C: HGG-36
Pappas, A: COVD-04
Papusha, L: GCT-64, IMG-03, LGG-26,
MBCL-32, RARE-52
Papyan, R: ETMR-07,
LINC-14, LINC-42
Parackal, S: DIPG-18, MODL-21
Park, G: DIPG-10

Park, H: MBRS-56
Park, J: IMMU-03
Park, M: MBRS-56
Parkes, J: LINC-10
Parkhurst, A: ATRT-23
Parkin, S: DIPG-55, DIPG-74
Parkins, C: MODL-08
Parsons, D: EPEN-16, EPEN-25,
EPEN-30, EPEN-46, MBRS-17,
PATH-27, PATH-29
Partap, S: LGG-04, MBCL-14,
MBCL-21, MODL-26
Pascucci, L: HGG-16, HGG-19
Pasternak, A: DIPG-59
Patay, Z: IMG-09, IMG-20, LINC-35
Patel, A: LGG-57
Patel, Parth: DDEL-02, MBCL-13
Patel, Priyal: ATRT-21
Patel, Rajan: DDEL-09
Patel, Ramesh: MBCL-38
Patel, Samor: SWK-11
Patel, Smruti: DIPG-22
Pathare, J: MBCL-38, QOL-34
Patiño-García, A: THER-02, THER-09
Paton, K: RARE-25
Patro, K: RONC-23
Pauck, D: EPEN-33, IMMU-19,
LGG-17, MBRS-48
Paul, A: HGG-18
Paul, L: ETMR-06, MBRS-20
Paul, Stephan: MBCL-46
Paul, Suzanne: NURS-12
Paulino, A: MBCL-35, QOL-01, QOL28, RARE-19, RONC-05, RONC-09,
RONC-12, RONC-17
Paulovich, A: TBIO-19
Paulsen, F: MBCL-11
Paulus, W: RARE-22
Pauly, J: LGG-52
Pavelka, Z: LGG-55
Pavisic, J: DIPG-40
Pavlova, M: RARE-08
Pavon-Mengual, M: MBCL-52
Pazos, M: MBCL-11
Pearlman, R: RARE-17
Pears, J: MODL-20
Pedace, L: HGG-54, MBCL-18,
MODL-23, PATH-19
Pedro, M: LINC-23
Peet, A: IMG-06, MBCL-52, MBRS-69
Peinado, H: HGG-16, HGG-19
Pellegrino, M: IMMU-13
Pellier, I: HGG-40
Pelton, K: EPEN-21, HGG-52
Peng, J: RARE-61
Penumarthy, N: SWK-10
Peragallo, J: NFB-09
Pereira, G: LGG-51, MBRS-66
Perek-Polnik, M: HGG-21, RARE-58
Perera, R: MBRS-16

Perez, A: DIPG-25
Perez, F: IMMU-03, NFB-13
Perez, V: LINC-21
Perez-Bañuelos, A: LINC-39, LINC-40
Perez-Garcia, M: LINC-40
Perez-Jaume, S: IMMU-22
Perez-Rulfo Ibarra, D: SURG-19
Pericoli, G: HGG-16, HGG-19,
IMMU-13, MODL-23
Perlaky, L: EPEN-46
Perníková, I: LGG-46
Perreard, L: TBIO-05
Perreault, S: EPCT-08,
LGG-25, MBCL-24
Perry, A: EPEN-07, GCT-70
Perry, J: LGG-13
Persky, N: ATRT-32, LGG-35
Perumal, N: MBRS-13, MBRS-72
Petersen, C: TBIO-05
Peterson, J: RARE-20
Peterson, R: QOL-01
Peterziel, H: MBRS-19
Petitto, C: EPID-05
Petralia, F: TBIO-19
Petrasch, K: PATH-07
Petrilli, L: HGG-16, HGG-19, IMMU-13
Petrini, S: HGG-16
Petropoulos, D: IMMU-07
Petruzzellis, G: MBCL-18
Pettee, D: RARE-14, RARE-17
Peyrl, A: DDEL-03, EPEN-21, ETMR10, GCT-76, HGG-44, MBCL-43
Pezzullo, M: IMMU-13
Pfaff, E: ETMR-06, ETMR-21
Pfister, S: ATRT-28, DIPG-58, EPEN03, EPEN-04, EPEN-06, EPEN-09,
EPEN-18, EPEN-21, EPEN-36, EPEN39, EPEN-44, ETMR-03, ETMR-13,
ETMR-14, ETMR-17, ETMR-21,
HGG-22, HGG-56, LGG-14, LGG-17,
MBCL-06, MBCL-07, MBCL-08, MBCL09, MBCL-11, MBCL-21, MBRS-03,
MBRS-24, MBRS-51,
MBRS-68, MODL-02, MODL-11,
PATH-01, PATH-04, PATH-11, PATH-26,
QOL-13, RARE-21
Phadnis, S: NFB-08
Phi, J: GCT-12, MBRS-56
Philippe, C: DIPG-56
Phillips, J: EPCT-05, LGG-53, MODL26, NURS-03, QOL-14
Phillips, P: NFB-09
Phoenix, T: DIPG-22,
DIPG-53, MODL-29
Piatelli, G: GCT-49
Pica, A: RONC-15
Picard, D: EPEN-33, IMMU-19, LGG14, MBRS-01, MBRS-48
Picarsic, J: RARE-40
Piccioni, F: DIPG-53, LGG-35, TBIO-26

NEURO-ONCOLOGY•DECEMBER 2020

iii495

Author Index

Pouponnot, C: MBRS-37
Poussaint, T: EPCT-05, IMG-04,
IMG-09, IMG-22
Powell, S: IMG-06
Power, E: DDEL-16
Pozos-Ochoa, L: EPEN-13
Prabhu, V: MODL-06
Prabhua, V: DIPG-62
Prado, S: SURG-09
Prados, M: EPCT-01, EPCT-12, HGG53, IMG-04, IMMU-23, IMMU-31,
LGG-53, MODL-26, NFB-17
Prasad, M: LINC-07, LINC-08, LINC-12,
LINC-25, LINC-29
Prasad, R: MODL-22, QOL-53
Pratilas, C: HGG-01, NFB-01
Prensner, J: TBIO-26
Prevedello, D: GCT-66
Previdelli, S: ATRT-10, SURG-22
Prince, E: EPEN-22, MODL-24, QOL22, RARE-07, RARE-08, RARE-10,
RARE-11, TBIO-11
Prins, R: IMMU-30
Prior, V: DIPG-13
Pritchard-Jones, K: COVD-04
Privalova, L: ATRT-05, MBCL-31
Prix, L: DIPG-38
Probst, A: EPCT-11
Pronicki, M: HGG-21
Proust-Houdemont, S: HGG-40
Przystal, J: DIPG-64, MODL-22
Pshonkin, A: GCT-64
Puataweepong, P: RARE-38
Puccetti, D: EPCT-09,
MFB-14, RARE-41
Puchalski, C: QOL-48
Puduvalli, V: GCT-66
Puerta, P: IMMU-22
Puget, S: DIPG-35, DIPG-58, DIPG-61,
HGG-11, MBCL-02, MBCL-21, RARE-21
Pugh, T: IMMU-18
Puigdelloses, M: THER-01
Pule, M: IMMU-16
Pulsifer, M: GCT-37
Punanov, Y: MBCL-03
Puosi, R: QOL-12
Pursell, Z: MODL-25
Pusch, S: LGG-17
Pusponegoro, H: LINC-24
Pusztaszeri, M: RARE-22
Pyone, K: LINC-01
Pyrdol, J: EPEN-21
Pytel, N: RARE-41
Pzena, A: SWK-04

Pickering, J: HGG-38
Picketts, D: DIPG-68
Pierce, A: ATRT-06, DIPG-34, DIPG73, IMG-17, MBRS-26, MBRS-65,
MBRS-67, MBRS-71
Pierrevelcin, M: HGG-36
Pierson, C: ATRT-21, EPEN-17,
EPEN-28, GCT-25, LINC-11, BCL-13,
MBCL-46, RARE-31
Pietsch, T: EPEN-06, EPEN-09, EPEN27, EPEN-36, EPEN-39, ETMR-14,
GCT-29, GCT-48, GCT-76, HGG-34,
MBCL-06, MBCL-07, MBCL-09, MBCL11, PATH-11, PATH-13, QOL-13
Pietschmann, K: MBCL-07, MBCL-11
Pilepesov, F: RARE-12
Pillay Smiley, N: EPCT-16, EPCT-19,
LGG-30, LGG-31, MBCL-33, QOL-41
Pindrik, J: ATRT-21, RARE-37
Pinto, N: IMMU-03
Pirollo, K: THER-08
Pishchaeva, N: ATRT-05, MBCL-31
Pitino, A: EPCT-15
Pittman, W: NURS-07
Pituch, K: MODL-12
Piunti, A: DIPG-39, EPEN-20, HGG-26
Pizer, B: COVD-03, ETMR-08, IMG06, MBRS-44, MBRS-60, QOL-21,
SURG-12, SWK-07
Pizzi, S: MODL-23
Placzek, F: MBCL-11
Plant, A: ETMR-22, GCT-59, LGG-52,
MBCL-38, QOL-34
Plessier, A: DIPG-56
Plon, S: EPEN-25, PATH-27, PATH-29
Płoski, R: HGG-21
Pluchart, C: MBCL-29
Po, Y: HGG-48
Pogorelov, D: ATRT-05, MBCL-31
Pokhylevych, H: IMG-15
Polivka, M: HGG-11
Pollack, I: DIPG-47, IMG-09,
LGG-04, MBCL-16, MBRS-63,
MODL-26, PATH-24
Pollo, B: EPEN-03
Polushkina, O: ATRT-05, MBCL-31
Pommier, B: DIPG-61
Ponce, J: RARE-42
Pongphitcha, P: RARE-38
Poore, B: MBRS-63
Popov, V: ATRT-05, MBCL-31
Popova, N: ATRT-05, MBCL-31
Popovska, V: NFB-12
Popovski, D: TBIO-02
Porro, G: RARE-62
Porto Carreiro, I: PATH-30
Potente Fernandez, E: MODL-20
Potter, S: PATH-27, PATH-29
Pöttgen, C: MBCL-11
Pouliopoulos, A: DDEL-13
Pounds, S: PATH-22

vi496

NEURO-ONCOLOGY

Q
Qaddoumi, I: EPID-07, LGG04, LINC-11, LINC-18, LINC-21,
LINC-23, LINC-35•

DE C E M B E R 2 0 2 0

Qi, J: DIPG-39, HGG-26
Qi, L: EPEN-46
Qi, X: RARE-63
Qian, K: DIPG-53, HGG-32
Qin, N: MBRS-48
Qin, T: DIPG-08, DIPG-59
Qiu, Y: QOL-55
Quaglietta, L: EPEN-03
Quah, S: MBCL-50
Quezada, S: IMMU-16
Quintana, J: RARE-36
Quintarelli, C: IMMU-13
Quiroga-Cantero, E: LGG-55
Quon, J: IMG-22

R
Ra, Y: ETMR-22
Raabe, E: ATRT-17, ATRT-23, DIPG-12,
DIPG-70, DIPG-71, ETMR-22, MBRS16, MODL-04, MODL-26
Raber, S: EPCT-12, SWK-10
Rachor, J: IMMU-10
Radmanesh, A: PATH-12
Rafay, M: LGG-23
Rafiee, G: MBRS-44
Rafli, A: LINC-24, OTHR-07
Ragheb, J: DDEL-14
Raghubar, K: RONC-12
Raghunathan, A: ATRT-07
Ragoonanan, D: DIPG-60, ETMR-04
Rahim, M: MBCL-51
Rahman, R: EPEN-43,
HGG-38, TBIO-16
Rahmanto, A: MBRS-10
Rahmartani, L: LINC-34, LINC-36
Raja Aman, R: SURG-29
Rajagopal, R: LINC-03, SURG-29
Rajeeve, V: LGG-57
Rajeshwari, M: EPEN-38
Raju, P: DDEL-15
Ramakrishna, N: RARE-06
Raman, P: TBIO-19
Ramanathan, S: LINC-25, LINC-29
Ramanujachar, R: ETMR-22
Ramasawmy, R: IMMU-16
Ramaswamy, V: DIPG-72, EPEN-36,
EPEN-50, HGG-20, IMG-13, IMG-22,
LGG-55, MBCL-08, MBRS-10, MBRS54, MBRS-66, PATH-20, QOL-01, QOL09, RARE-02, RARE-50, RONC-03
Ramdas, J: HGG-20
Rame Collonge, M: RARE-21
Ramirez, D: EPCT-18
Ramirez, L: EPCT-13
Ramírez-Melo, J: RARE-29
Ramkissoon, L: LGG-01
Ramkissoon, S: LGG-01
Ranadive, R: COVD-04
Ranalli, M: ATRT-21

Author Index

Rand, V: MBRS-59
Rangan, K: NURS-09
Ranka, M: NFB-09
Rankovic, Z: HGG-22
Rantala, H: QOL-12
Rao, A: IMG-04
Rao, S: LINC-07
Rapp, J: RARE-17
Rashid, M: RARE-17
Raskin, S: MBRS-54
Rassekh, S: LGG-19,
NFB-12, MBCL-24
Rausch, T: MBCL-21
Rauschecker, A: QOL-53
Ravi, K: DIPG-08
Ravindran, R: DIPG-59
Raza, S: RARE-44
Rechavi, G: IMMU-18
Recinos, A: PATH-27
Reddick, W: QOL-15
Reddy, A: ATRT-30, ETMR-20, ETMR22, IMMU-18, MBCL-34, MBRS-54,
NFB-17, RARE-17, SWK-10
Reddy, K: NFB-02
Rednam, S: IMG-07
Reeves, J: EPCT-08
Refaat, A: HGG-17
Regev, A: EPEN-21
Reginald, A: NFB-09
Rehmus, W: NFB-12
Reichert, J: MODL-13
Reichman, L: RARE-17
Reid, A: DIPG-79
Reid, D: EPEN-04
Reifenberger, G: EPEN-33,
IMMU-19, MBRS-48
Reilly, K: NFB-01
Reimand, J: MBRS-01
Reis, R: PATH-30
Reisinger, D: DDEL-03
Reisz, J: DIPG-42
Reitman, Z: ATRT-19, DIPG-53
Remes, T: QOL-12
Remke, M: EPEN-33, IMMU-19,
LGG-14, LGG-17, MBRS-01, MBRS04, MBRS-10, MBRS-48, RARE-17,
IMMU-18, MBCL-21
Ren, L: GCT-73
Rendleman, E: DIPG-03
Resar, L: EPEN-42
Resch, A: QOL-13
Resnick, A: DIPG-31, EPID-14, HGG53, IMMU-11, LGG-53, MODL-26,
PATH-21, TBIO-19
Restine, F: LGG-51
Reuss, J: LGG-31
Reuter, J: RARE-23
Reuther, J: EPEN-25,
PATH-27, PATH-29
Revas, B: TBIO-19

Revathi, R: LINC-02
Reya, T: MBRS-01
Reynolds, E: EPCT-15
Reynolds, P: DIPG-07
Rhines, L: EPEN-10, RONC-17
Ribeiro, K: EPID-12
Ricardi, U: GCT-29, GCT-48
Rice, B: SWK-04
Rich, J: EPEN-52
Richard, H: RARE-43
Richards, L: ETMR-13
Richardson, A: THER-06
Richardson, S: MBRS-10, MBRS-33,
MBRS-44, MBRS-60
Riemenschneider, M: MBCL-07
Riemondy, K: EPEN-22,
EPEN-26, MBRS-46
Ries, M: DDEL-05
Riess, C: HGG-07
Riikonen, P: QOL-12
Riley, K: QOL-51, SWK-06
Ris, M: QOL-01, RONC-12
Ritari, N: QOL-12
Ritter, A: RARE-43
Ritzmann, T: EPEN-22, EPEN-23
Rivas, B: EPEN-30
Rivas, E: ETMR-22
Rivera, B: RARE-22
Rivero-Hinojosa, S: IMMU-15
Robbins, D: MBRS-02, THER-06
Robbins, G: RARE-17
Roberts, T: IMMU-16
Robertson, P: DIPG-08, HGG-18
Robinson, G: EPCT-05, ETMR06, ETMR-21, HGG-01, MBCL-08,
MBCL-19, MBCL-21, MBCL-26,
MBCL-37, MBRS-20, MBRS-24,
PATH-09, RARE-21
Robinson, J: DIPG-05
Robinson, S: IMG-12, MBRS-33,
MODL-19, MODL-20
Robison, L: QOL-15
Robison, N: IMG-03,
LGG-52, NURS-09
Rode, A: PATH-11
Rodrigo Ugaz Valencia, C: QOL-53
Rodriguez, D: EPEN-28, RARE-37
Rodriguez, F: MBCL-25,
NFB-01, PATH-13
Rodriguez, H: TBIO-19
Rodriguez, L: RARE-36
Rodriguez-Galindo, C: COVD-04,
EPID-07, LINC-35
Roesser, K: QOL-37
Rogers, H: EPEN-23
Rogers, R: HGG-37, MODL-20
Rojas del Río, N: LINC-21
Rokita, J: DIPG-31, EPID-14, PATH-21
Romanyshyn, B: LINC-41
Romero, M: DIPG-06

Romero, S: EPCT-16
Ronghe, M: GCT-61, QOL-56
Rongthong, W: MBCL-10
Ronsley, R: GCT-23,
HGG-35, SWK-08
Rood, B: EPCT-15, IMMU-15, MODL26, PATH-14, TBIO-19
Roosen, M: EPEN-44
Root, D: ATRT-32, LGG-35, TBIO-26
Rosabal Obando, M: LINC-18
Rosales, K: DDEL-14
Rose, H: IMG-06, MBRS-69
Rosemberg, S: EPID-05,
PATH-18, RARE-47
Rosén, G: MBRS-10
Rosenfeld-Keidar, H: MBCL-17
Rosner, B: GCT-59
Rosser, T: LGG-52, NFB-09
Rossi, A: RARE-43
Rossi, S: IMG-16, IMG-19, IMMU-13,
MBCL-18, MODL-23, PATH-19
Rosthoej, S: GCT-65
Rota, R: IMMU-13
Roth, Jennifer: TBIO-26
Roth, Jonathan: MBCL-17
Roth, M: LGG-44
Rotondo, R: RONC-32
Rouen, J: DIPG-83
Roujeau, T: MBCL-02
Rouleau, C: LGG-35
Rousseau, A: HGG-40
Roussel, E: DIPG-18
Roussel, M: IMMU-06, MBRS-02
Routhier, M: LGG-25
Roux, A: HGG-11
Rowen, E: SWK-09
Roy, A: EPEN-25, PATH-27, PATH-29
Roy, Sumita: IMMU-18
Roy, Swarnaditya: LINC-33
Rozenblatt-Rosen, O: EPEN-21
Rozovsky, K: LGG-23
Rubens, J: ATRT-17, ATRT-23
Rubens, M: RONC-08
Rubin, J: TBIO-01
Rubinstein, C: MODL-13
Rubner, T: LGG-17
Rückriegel, S: IMMU-10
Rudie, J: QOL-53
Ruff, L: EPEN-14, MODL-08
Ruggiero, A: EPEN-03
Rugilo, C: RARE-50
Ruhland, E: TBIO-17
Rupert, A: EPID-15
Rusert, J: MBRS-10
Rush, S: ATRT-04, EPID-11, LGG-31,
NFB-05, RARE-14
Rushing, E: MBCL-07, MODL-22
Rusin, J: EPEN-17, GCT-25, RARE-37
Russell, C: SWK-03
Russo, M: LGG-49

NEURO-ONCOLOGY•DECEMBER 2020

iii497

Author Index

Saito, R: DDEL-08, GCT-35,
MBCL-48, RARE-26
Saitou, M: GCT-19
Sakai, H: GCT-53
Sakai, K: GCT-43
Sakamoto, H: GCT-72, MBCL22, MBRS-38, PATH-28,
RAER-03, RARE-26
Sakamoto, K: ETMR-11,
HGG-49, RARE-16
Sakamoto, L: DIPG-72, GCT-59,
LGG-51, MBRS-66
Sakun, D: ATRT-05, MBCL-31
Sakurada, K: GCT-16
Sakurai, H: GCT-60
Salamat, M: RARE-41
Salamat, S: HGG-43
Salas, L: TBIO-05
Saleh, A: LINC-43
Saletta, F: DIPG-83
Salgado, D: LGG-55
Salloum, R: EPCT-19, LGG-30, LGG31, MBCL-24, QOL-04, RONC-31
Salnikova, E: GCT-64, MBCL-32
Salvador, N: IMMU-22
Salviato, E: IMMU-13
Samay, S: IMMU-21
Sambira, L: IMMU-18
Samolej, A: NFB-18
Sampor, C: GCT-71, RARE-50
Sampson, J: EPCT-13
Samson, Y: DIPG-46,
DIPG-55, DIPG-74
Samuel, D: HGG-20, IMMU-18,
QOL-53, RARE-17
Samy, S: EPEN-37
Sánchez-Zubieta, F: EPEN13, LINC-09, LINC-16, QOL-06,
RARE-29, SURG-19
Sandberg, C: TBIO-18
Sandberg, D: DDEL-09, DDEL-10,
ETMR-04, IMG-15, RARE-19
Sanders, F: EPID-05, LINC-38, PATH18, RARE-47, SURG-07, SURG-20
Sandler, E: DIPG-46, DIPG-55,
DIPG-74, EPEN-51, MBCL-24,
RONC-22, RONC-32
Sands, S: MBRS-73
Sanford, B: ATRT-06, EPEN-31, HGG57, MBRS-46, MODL-31
Sangatsuda, Y: TBIO-08
Sangfelt, O: MBRS-10
Sano, K: HGG-23
Sano, T: RONC-18
Sanson, M: HGG-11
Santagata, S: RARE-07
Santa-Maria, V: ETMR-22
Santa-Maria Lopez, V: IMMU-22
Santana, V: COVD-04
Santander, J: LINC-21

Rutka, J: ATRT-16, DDEL-01, LGG-55,
RARE-09, TBIO-02
Rutkowski, S: EPEN-09, EPEN27, EPEN-36, EPEN-39, ETMR-14,
LINC-18, MBCL-06, MBCL-07, MBCL09, MBCL-11, MBCL-19, MBCL-21,
MBCL-37, MBRS-25, PATH-07,
PATH-11, QOL-13, QOL-17, QOL-24,
RARE-42, SWK-07
Ruvalcaba-Sanchez, R:
LINC-39, LINC-40
Ryall, S: LGG-13, LGG-34,
LGG-50, LGG-55
Ryan, T: RONC-31
Rydin, A: NURS-12
Rydzanicz, M: HGG-21
Rykunov, D: TBIO-19
Ryles, J: QOL-23, QOL-26
Ryutov, A: RARE-57
Ryzhova, M: ATRT-05, MBCL-04,
MBCL-05, MBCL-07, MBCL-21,
MBCL-31

S
Saab, R: DIPG-55, DIPG-74
Sabel, M: IMMU-18,
LGG-55, RARE-17
Sabet, K: PATH-31
Sabha, N: DDEL-01
Sabin, N: MBCL-36, QOL-15, RARE-12
Sabnis, A: HGG-01
Sabran, A: QOL-55
Sabus, A: DDEL-06, MODL-01
Sadighi, Z: EPCT-06, IMG-15, IMU-07,
LGG-44, NFB-06, QOL-54
Saeki, N: GCT-09
Safaryan, L: LINC-13, LINC-42
Safford, H: DDEL-04
Saffroy, R: HGG-11
Safwat, A: GCT-65
Saghatelyan, T: LINC-42
Saha, A: LINC-12
Sahay, A: LINC-25, LINC-29
Sahgal, A: LGG-13
Sahm, F: EPEN-09, EPEN-18,
HGG-56, LGG-33, MBCL-06, MBCL07, MBCL-09, PATH-04, PATH-11,
PATH-26, QOL-13
Sahu, A: LINC-25, LINC-29
Sai, K: EPEN-05
Said, M: IMG-22
Saida, S: RONC-06
Sainte Rose, C: MBCL-02
Saito, Kiyotaka: LGG-54
Saito, Kuniaki: PATH-05
Saito, N: DIPG-17, GCT-15, GCT-43,
GCT-52, GCT-72, SURG-14

vi498

NEURO-ONCOLOGY•

DE C E M B E R 2 0 2 0Santhana Kumar, K: MODL-14
Santi, M: LGG-50, MODL-26,
PATH-21, TBIO-03
Santiago, T: LINC-35
Saraff, V: MBCL-52
Saran, F: GCT-29
Saratsis, A: DIPG-03,
DIPG-39, HGG-26
Sardi, I: EPEN-03
Sargent, M: NFB-12
Sargsyan, L: LGG-16, LINC-14
Sarhan, N: EPEN-50
Sariban, E: RARE-21
Sarikaya-Seiwert, S:
EPEN-33, GCT-49
Sarkar, C: EPEN-38, HGG-13, LINC-30
Sarria, G: RARE-42
Sasaki, A: MBRS-38
Sasaki, H: GCT-06, GCT-51, GCT-56
Sasaki, N: PATH-05
Sasaki, T: DDEL-11, DIPG-03
Sasame, J: HGG-51
Sasano, M: OTHR-02
Saskin, A: RARE-22
Sastry, J: QOL-56
Sato, A: NFB-09, NFB-13
Sato, M: LGG-11, LGG-24, RARE-13
Sato, Yosuke: HGG-29
Sato, Yutaka: RARE-13
Satomi, K: EPEN-34, GCT-43, GCT-72
Satomi, N: HGG-39
Saulnier-Sholler, G: ETMR-18
Savchuk, S: QOL-53
Savov, V: MBRS-10
Scagnet, M: MODL-26
Schadler, K: MBRS-53
Schafer, A: DIPG-74, LGG-31
Scharnhorst, D: ETMR-22
Scheers, I: RARE-17
Scherman, O: MODL-08
Schiavello, E: DIPG-54, EPEN-03
Schieffer, K: ATRT-21, EPEN-17,
EPEN-28, RARE-37
Schirrmacher, V: DIPG-38
Schissel, D: EPCT-18
Schittenhelm, J: MBCL-07
Schlegel, P: IMMU-10,
MBCL-07, QOL-24
Schmid, R: PATH-07
Schmidberger, H: MBCL-11
Schmidt, R: QOL-24
Schmiegelow, K: QOL-59
Schmitt, A: EPEN-04
Schmitt, M: LGG-05, TBIO-24
Schmitt-Hoffner, F: ETMR-03
Schneider, G: MODL-14
Schneider, K: IMMU-18, RARE-27
Schniederjan, M: MODL-06, PATH-14
Schoolcraft, K: DIPG-53
Schorry, E: NFB-17

Author Index

Schouten - van Meeteren,
A: RARE-62
Schramm, K: MODL-11
Schrimpf, D: LGG-33,
PATH-04, PATH-26
Schroeder, K: EPCT-13,
EPID-16, MBCL-26
Schüller, U: ATRT-13, ATRT-14,
ATRT-32, EPEN-09, EPEN-18, EPEN36, EPEN-39, ETMR-14, HGG-57,
MBCL-06, MBCL-07, MBRS-10,
MBRS-25, RARE-42
Schulte, J: EPCT-08
Schuster, M: MODL-14
Schvartzman, S: EPEN-46
Schwake, M: SURG-10
Schwalbe, E: MBRS-44, MBRS-59,
MBRS-60, MBRS-69
Schwalm, B: ETMR-03, MODL-02
Schwartz, J: EPEN-35, HGG-18
Schwarz, R: MBCL-09, MBCL-11
Sciot, R: RARE-56
Scoggins, M: QOL-15
Sebastia, C: TBIO-17
Seblani, M: MODL-12
Sebolt-Leopold, J: HGG-08
Seçkin, B: MBRS-39
Sehested, A: MBCL-43. QOL-59
Sekiguchi, M: ATRT-11
Selby, M: MBRS-57
Sellami, S: NFB-16
Sells, B: HGG-45, MBRS-73, PATH-15
Selt, F: LGG-14, LGG-17, MBCL-06
Semenova, D: MODL-25
Sen, S: IMMU-18, RARE-17
Sener, U: RARE-24
Sengupta, S: DIPG-21
Senthil Kumar, S: EPCT-19
Sepaniac, L: DIPG-05
Sepp, M: MBRS-03
Serkova, N: ATRT-06, DIPG-34,
DIPG-42, DIPG-73, IMG-17, MBRS-26,
MBRS-67, MBRS-71
Serletis, D: LGG-23
Sernaque, R: RARE-42
Serrano, J: PATH-12
Sethi, C: DDEL-07, DIPG-40, MODL-09
Sethi, R: GCT-37
Setty, B: DIPG-11
Sevenet, N: RARE-21
Sevlever, G: DIPG-46
Sexton-Oates, A: HGG-20
Shabo, E: GCT-49
Shah, J: DDEL-15
Shah, Summit: ATRT-21
Shah, Sunny: RONC-08
Shah, V: RONC-05
Shahin, M: IMMU-23
Shaik, S: MBRS-53
Shamardani, K: HGG-53

Shamay, Y: DDEL-15
Shamurailatpam, D: RONC-23
Shamvil, A: HGG-20
Shan, C: DIPG-26, GCT-26, GCT-27,
GCT-28, GCT-63, HGG-14
Shankar, A: DIPG-37, DIPG-82, IMG-37
Shanmuganayagam, D: MODL-13
Shapira, O: HGG-41
Shapira Rootman, M: NFB-03
Shapochnik, A: ATRT-05, MBCL-31
Sharma, Ajay: DIPG-57
Sharma, Anjali: EPEN-38,
LINC-30, LINC-33
Sharma, T: MBCL-07, MBCL-21
Sharma, V: MBRS-63
Shatara, M: ATRT-21, EPEN28, GCT-25, GCT-66, MBCL-46,
RARE-31, RARE-37
Shaw, D: ETMR-20, GCT-33, GCT-41,
GCT-42, MBCL-34
Shaw, M: EPEN-21, ETMR-17, HGG-53
Shawky, O: HGG-17
Shea, A: NURS-10
Sheer, D: LGG-57
Shelton, J: RARE-13
Shen, C: DIPG-68
Shen, H: DIPG-07, DIPG-13
Shen, J: GCT-73
Sheth, J: LGG-13
Shetty, O: MBRS-61
Shetty, P: LINC-12, LINC-25, LINC-29
Shi, C: MODL-21
Shi, H: ATRT-02
Shiba, Y: LGG-56
Shibahara, I: SURG-16
Shibahara, J: PATH-05
Shibata, T: GCT-52, TBIO-08
Shibata, Y: LGG-02
Shibui, S: GCT-15, GCT-52, MBRS-38
Shilatifard, A: DIPG-03,
EPEN-20, HGG-26
Shilyanski, J: RARE-13
Shima, H: GCT-47
Shimada, A: RARE-32
Shimada, H: GCT-47
Shimazu, Y: SURG-21
Shimizu, K: HGG-29
Shimizu, S: RONC-16
Shimizu, T: ETMR-15, MBCL-48
Shimizu, Yuzuki: MBCL-41
Shimizu, Yuzaburo: SURG-15
Shin, Hee Young: GCT-02
Shin, Hyung Jin: MBCL-28
Shin, M: DIPG-17, RARE-32, SURG-14
Shin, S: MBRS-56
Shing, M: EPID-10, HGG-48,
LINC-20, QOL-25
Shinojima, N: EPEN-02,
EPID-01, GCT-36
Shinya, Y: DIPG-17

Shioda, Y: ATRT-11,
ETMR-11, HGG-49
Shiokawa, D: GCT-62
Shiokawa, Y: PATH-05
Shirai, R: ATRT-11
Shirran, S: ATRT-25
Shishkina, L: MBCL-31
Shlien, A: IMMU-18
Shofuda, T: LGG-38, MBRS-38
Sholler, G: DIPG-66
Shonka, N: HGG-18
Shoufuda, T: PATH-28
Shpanskaya, K: IMG-10
Shultz, D: RARE-02
Shultz, E: ATRT-05, MBCL-31
Shusterman, S: HGG-01
Siada, R: DIPG-59, HGG-18
Siddaway, R: DIPG-59
Siddle, K: IMG-08
Sidelnikov, D: MBCL-04, MBCL-05
Siebert, R: RARE-22
Sievers, P: PATH-26
Sigaud, R: LGG-14, LGG-17
Sill, M: EPEN-18, ETMR-21, HGG-56,
MBCL-06, MBCL-07, PATH-04, QOL-13
Silva, A: LGG-35
Silva, F: GCT-58, LINC-26, RARE-18
Silva, N: GCT-57, GCT-58,
LINC-26, RARE-18
Silverman, A: LGG-22
Simon, N: MODL-20
Simon, S: DIPG-27
Sims, P: MODL-09
Sinai, C: HGG-41
Singh, Mallika: MODL-17
Singh, Manmohan: EPEN-38
Singh, S: MBRS-01
Singh, V: LINC-12
Sinha, A: EPID-03
Siow, B: IMMU-16
Sirachainan, N: RARE-38
Siregar, M: LINC-24
Sirianni, R: DDEL-09, DDEL-10
Sirkiä, K: QOL-12
Sisler, I: RARE-43
Skaga, E: TBIO-18
Skerrett-Byrne, D: DIPG-29
Skocic, J: QOL-09
Skrypek, M: LGG-36
Slavc, I: DDEL-03, EPEN-21, ETMR08, ETMR-10, ETMR-17, HGG-44,
MBCL-07, MBCL-43
Slaven, J: QOL-48
Sleurs, C: QOL-07, QOL-19, QOL-19
Slining, M: SWK-12
Slobina, E: ATRT-05, MBCL-31
Sloman, V: PATH-07
Slopis, J: IMMU-07, LGG-44, NFB-06
Slusher, B: ATRT-17, ATRT-23
Smaoui, W: NFB-16

NEURO-ONCOLOGY•DECEMBER 2020

iii499

Author Index

Sposto, R: LGG-52
Sribnick, E: EPEN-28,
GCT-25, RARE-40
Sridhar, E: LINC-12
Sridharan, S: DIPG-57
Srikanthan, D: DDEL-01
Srinivasan, H: SURG-12
Stabenfeldt, S: DDEL-10
Stadler, J: HGG-43
Stallard, S: DIPG-08, DIPG-59
Stamm Mikkelsen, T: GCT-65
Stanek, J: ATRT-26, GCT-23, GCT-40,
GCT-66, GCT-74, LINC-28, MBCL-19,
MBCL-23, MBCL-37, RARE-35
Stanke, J: RARE-14
Stanley, J: DIPG-50
Stanton, A: DIPG-47
Stapleton, S: EPEN-51
Stapleton, S: LGG-28
Stapleton, S: MBCL-25, MBRS-16,
MODL-26, RARE-06, RARE-36
Stark, E: DDEL-07, MODL-09
Starý, J: LGG-46
Stasheff, S: NFB-09
Staszewski, O: MBCL-07
Statz, B: EPEN-44
Staudt, D: DIPG-29
Staulcup, S: MODL-24, QOL-22,
RARE-08, RARE-10, RARE-11
Stavinoha, P: QOL-11, QOL-28
Stearns, D: HGG-20, IMMU-18,
MBRS-54, NFB-09, RARE-17
Stegeman, I: RARE-62
Steiger, H: EPEN-33
Steiner, J: IMG-17
Stengs, L: MODL-25
Stepaniuk, M: RARE-58
Stephan, C: EPEN-46
Stephens, D: ETMR-22
Stepien, N: DDEL-03
Sterba, J: LGG-55
Sterin, A: EPCT-11
Stern, A: IMMU-11
Stevenson, C: EPCT-16,
EPCT-19, LGG-31
Steward, C: EPCT-17
Stewart, C: EPCT-05,
EPCT-16, EPCT-19
Stichel, D: LGG-33
Stichel, D: PATH-26
Stieg, P: SWK-04
Stivaros, S: EPEN-24
Stoller, S: QOL-53
Stolova, L: PATH-20
Stone, T: LGG-57
Stoneham, S: COVD-01
Storer, L: EPEN-23, EPEN-24,
EPEN-42, MBRS-69, TBIO-14,
THER-03, THER-04
Storm, J: PATH-21

Smith, E: EPEN-45, EPEN-47,
EPEN-51, EPEN-54, ETMR-22,
MBCL-21, MBCL-30, QOL-22,
RARE-11, RARE-48
Smith, Christian: ATRT-16, DDEL-01
Smith, Colin: GCT-76
Smith, E: DIPG-03
Smith, J: QOL-54
Smith, K: MBCL-08, MBCL-15, MBCL16, MBCL-21, MBCL-26, MBRS-24
Smith, M: RARE-21
Smith, S: LGG-28
Smith, T: IMMU-11
Snuderl, M: EPEN-18, ETMR-21,
MBCL-01, PATH-12
Snyder, E: GCT-73
Sobko, R: LINC-41
Soebadi, A: LINC-24
Soejima, T: RONC-01, RONC-04
Sola, I: DIPG-73
Solanki, G: RARE-46
Solano, P: LGG-55
Solano-Paez, P: DIPG-20, ETMR-22
Solas, C: EPCT-11
Solem, K: GCT-76, GCT-59
Soler, C: MBCL-29
Solomon, D: EPEN-07,
PATH-14, PATH-31
Somers, K: RONC-02
Sommer, C: MBCL-07
Sommerkamp, A: LGG-17,
MODL-11
Somsri, P: NFB-18
Son, M: MBCL-28
Song, C: ETMR-02
Song, Xiaohua: DIPG-43
Song, Xiaoyu: TBIO-19
Song, Y: EPEN-46
Songdej, D: RARE-38
Sönksen, M: ATRT-15
Sonoda, Y: GCT-16, GCT-35,
HGG-23, MBCL-48
Sood, S: RARE-53
Sooraj, D: ATRT-02, MODL-21
Sortwell, C: ETMR-18
Soto Mancilla, J: LINC-16,
OTHR-12, SURG-19
Sottoriva, A: DIPG-49, DIPG-63,
GCT-33, GCT-41, QOL-22, RARE-11,
SWK-04, TBIO-03
Souza, F: ATRT-10, SURG-09
Sowińska, A: HGG-21
Sowithayasakul, P: RARE-59,
RARE-60, RARE-61
Spat-Lemus, J: SWK-04
Spinazzi, E: DDEL-13
Spino, M: PATH-12
Spitaels, A: LINC-10
Spohn, M: MBCL-09
Sponagel, J: TBIO-01

vi500

NEURO-ONCOLOGY•

DE C E M B E R 2 0 2 0

Storm, P: DIPG-31, EPID-14,
IMMU-11, MODL-26
Stowe, C: IMMU-16
Straathof, K: IMMU-16
Straehla, J: DDEL-04
Strebkova, N: QOL-43
Stripay, J: IMMU-06
Stroganova, A: MBCL-04, MBCL-05
Strong, R: ATRT-08, PATH-01
Strother, D: DIPG-74, EPID-06
Strowd, R: LGG-21
Strowger, B: DIPG-50, RONC-02
Stubbs, M: MODL-19
Stubley, S: QOL-32, QOL-33
Stücker, W: DIPG-38
Stuckert, A: EPEN-30
Stukova, M: IMG-17
Stumbraite, K: TBIO-26
Stummer, W: SURG-10
Stumpff, J: DIPG-05
Sturm, D: EPEN-09, EPEN-18, HGG56, MBCL-06, MBCL-09, MBCL-21,
PATH-11, QOL-13, RARE-21
Su, J: GCT-23, GCT-73, IMG-07,
LGG-55, RONC-05
Subapanditha, M: MBRS-01
Subbotina, N: MBCL-04, MBCL-05
Sudhaman, S: IMMU-14, IMMU-18,
MBRS-54, MODL-25
Suero Morina, E: SURG-10
Sugawa, M: ETMR-11, ETMR-12,
HGG-49, RARE-16
Sugawara, T: RONC-18
Sugihara, E: GCT-34
Sugita, Y: GCT-53
Sugiyama, K: GCT-43, GCT-52
Sugiyama, M: GCT-08, GCT-10,
GCT-31, SURG-02
Suh, C: EPEN-15
Suh, E: PATH-22
Suh, Y: MBCL-28
Sullivan, M: COVD-04, EPEN-36,
HGG-20, LINC-10, PATH-09, RARE-15
Sultan, S: LGG-25
Sumerauer, D: HGG-31, IMMU-18,
LGG-46, LGG-55, PATH-20, RARE-17
Sumi, K: OTHR-02
Sumita, K: RONC-18
Sumrall, A: HGG-18
Sun, C: ATRT-02, MODL-21
Sun, D: EPEN-46
Sun, P: MODL-11
Sun, S: HGG-27
Sun, Xiaofei: ETMR-02, LINC-15
Sun, Y: HGG-08
Sunder, S: RONC-23
Sunderland, G: SURG-12
Sundstrom, A: MBRS-10
Sung, K: MBCL-28
Sung, L: EPID-06

Author Index

Suntornpong, N: MBCL-10
Suo-Palosaari, M: QOL-12
Supiot, S: HGG-40
Suri, A: LINC-30
Suri, V: EPEN-38, LINC-30,
LINC-33
Suser, S: RARE-24
Sutcliffe, M: LGG-28
Sutela, A: QOL-12
Suter, R: MBRS-02
Sutharsan, S: LINC-02
Suttman, A: NFB-02, RARE-27
Sutton, M: LGG-31
Suva, M: EPEN-21
Suwal, T: ETMR-19, ETMR-22
Suzuki, M: ETMR-09
Suzuki, R: GCT-38, LGG-40
Suzuki, S: HGG-24
Suzuki, Takeshi: RONC-04
Suzuki, Tomonari: GCT-52, GCT-59,
GCT-62, MBCL-41, MBCL-48
Suzuki, Y: GCT-62
Svokos, K: HGG-52
Swallow, C: RARE-17
Swaminathan, J: DIPG-57
Swartling, F: MBRS-10
Swartz, S: MBRS-57
Synowsky, S: ATRT-25
Sysoev, A: MBCL-32
Szalontay, L: DDEL-07, MODL-09
Szilagyi, C: QOL-48
Szychot, E: DIPG-37, DIPG-82,
RARE-34

T
T, Rajesh: RONC-23
T, Rishan: RONC-23‘t Hart, E: DDEL-05
Taal, W: IMG-03
Taban, K: EPEN-33, MBR-58
Tabatabai, G: ATRT-32
Tabori, U: HGG-20, IMMU-14,
IMMU-18, LGG-13, LGG-19, LGG25, LGG-34, LGG-50, LGG-55,
MBRS-54, MODL-25, PATH-14,
RARE-17, RARE-55
Táborský, J: LGG-46
Taccone, M: IMG-21
Taha, H: HGG-17
Tahara, M: EPCT-08
Tait, D: MBCL-19
Taitt, J: IMMU-23, IMMU-31
Takachi, T: MBCL-27
Takada, A: EPEN-02
Takadera, M: EPEN-34, EPEN-41
Takahashi, K: GCT-53
Takahashi, M: GCT-46, HGG-39

Takahashi, Yoshinobu:
DIPG-04, HGG-12
Takahashi, Yoshiyuki: LGG-56
Takami, H: GCT-15, GCT-34, GCT-43,
GCT-52, GCT-62, GCT-72, SURG-14
Takano, S: GCT-38
Takata, N: DIPG-03
Takayanagi, S: DIPG-17, SURG-14
Takehana, K: RONC-06
Takei, J: IMMU-12
Takeshige, N: GCT-53
Takeshima, H: GCT-43,
GCT-52, LGG-54
Taketoshi, M: GCT-72
Takeuchi, H: DIPG-04, HGG-12
Takezaki, T: GCT-36
Takita, J: ATRT-11, GCT-50, RONC-06
Tam, L: IMG-10, IMG-13, IMG-22,
NFB-04, PATH-06
Tamaichi, H: ETMR-15
Tamamyan, G: ETMR-07, LGG-16,
LINC-13, LINC-14, LINC-42, RARE-33
Tamayo, I: THER-09
Tambaro, P: IMMU-07
Tamiya, T: IMG-02
Tamrazi, B: IMG-04, LGG-45
Tamura, K: GCT-43, GCT-52, HGG-30,
HGG-50, RONC-18
Tamura, R: GCT-51
Tamura, Y: HGG-39
Tan, E: ETMR-22, IMG-01
Tan, F: MBRS-01
Tan, Y: LGG-52
Tanaka, R: MBCL-41, MBCL-48
Tanaka, Shingo: QOL-05
Tanaka, Shota: DIPG-17,
GCT-43, SURG-14
Tanaka, Y: HGG-30, HGG-50, RONC-18
Tanami, Y: ETMR-12, MBR-21,
PATH-25, RARE-39
Tananyan, A: LINC-13,
LINC-14, LINC-42
Tang, C: IMG-18
Tang, K: PATH-12
Tang, P: IMG-01
Tanigawa, S: DIPG-04
Taniguchi, R: LGG-56
Tanimura, K: MBCL-22
Tanioka, D: HGG-29
Tanioka, S: LGG-56
Tanji, M: LGG-38, MBRS-22,
RONC-06, THER-07
Tanna, J: EPCT-15
Tapinos, N: DIPG-62
Tarapore, R: DIPG-52, DIPG-57,
DIPG-80, HGG-18
Tarasova, E: GCT-64
Tarbell, N: GCT-37,
MBCL-15, RONC-24
Tarczy-Hornoch, K: NFB-09

Tari, H: DIPG-63
Tartaglia, M: MODL-23, PATH-19
Tasaki, T: IMMU-12
Tashiro, Y: MBCL-27
Tateishi, K: HGG-51
Tatevossian, R: MBCL-21
Tatsui, C: EPEN-10, RONC-17
Tatsuzawa, K: DIPG-04, HGG-12
Tatter, S: LGG-21
Tauziède-Espariat, A: ATRT-27, DIPG58, HGG-11, MBCL-02
Tavares-Macias, G: EPEN-13
Taylor, A: GCT-73
Taylor D: EPID-14
Taylor, K: TBIO-06
Taylor, Leslie: RARE-17
Taylor, Louisa: MBRS-42
Taylor, M: EPEN-36, EPEN-52,
ETMR-22, IMG-13, IMG-22, IMMU18, LGG-55, MBRS-10, QOL-01,
RARE-09, TBIO-15
Taylor, P: MBRS-64
Teh, K: MBCL-50
Teixeira, M: LINC-38, RARE-47
Tejada, S: THER-09
Temelso, S: HGG-37, IMG-12, MODL19, MOD-20, PATH-17
Teng, A: LINC-03, RARE-15
Teo, K: RARE-01
ter Huizen, G: RONC-21
Terashima, K: ATRT-11, ETMR-11,
GCT-73, HGG-49, RARE-16, SURG-17
Terashita, Y: GCT-08, GCT-31
Terezakis, S: EPEN-50
Terhune, C: MBCL-26
Terpilowski, M: EPCT-15
Terranova, S: MODL-08
Tetens, A: DIPG-12, DIPG-70
Teule, A: RARE-22
Tewari, P: IMMU-07
Thankamma, A: GCT-76
Thapa, I: MBRS-13, MBRS-72
Théoret, Y: LGG-25
Thephamongkhol, K: MBCL-10
Theruvath, J: IMMU-19
Thinn, A: LINC-01
Thomas, B: IMG-18
Thomas, Cheddhi: PATH-12
Thomas, Christian: RARE-22
Thomas, Coretta: NFB-17
Thomas, D: ATRT-21, EPEN-28
Thomas, G: HGG-20, IMMU-18
Thomas, P: DIPG-39
Thompson, E: EPCT-13
Tian, S: SURG-04
Tian, X: EPEN-10
Tichý, M: LGG-46
Tierney, E: IMMU-01
Tignor, N: TBIO-19
Tihan, T: ETMR-22

NEURO-ONCOLOGY•DECEMBER 2020

iii501

Author Index

Trifan, O: EPCT-02
Trimble, A: DDEL-09
Triska, P: TBIO-12
Trissal, M: EPEN-21
Trubicka, J: HGG-21, RARE-58
Tsai, J: DIPG-22, HGG-41, LGG-35
Tsai, M: RARE-45
Tsang, D: EPEN-50, LGG-13,
LGG-55, MBRS-54, QOL-01,
RARE-02, RONC-03
Tseitlin, H: QOL-02, QOL-46
Tseng, C: DIPG-23, DIPG-28
Tseng, J: QOL-40
Tseng, S: RARE-45
Tso, W: QOL-25
Tsoli, M: DDEL-12, DIPG-07, DIPG14, DIPG-15, DIPG-16, DIPG-27,
DIPG-29, DIPG-75
Tsui, K: DIPG-19, DIPG-46, DIPG-74
Tsujimoto, S: ATRT-11, ETMR-11
Tsukamoto, Y: MBRS-06
Tsurubuchi, T: GCT-38,
GCT-62, LGG-40
Tsutsui, T: PATH-23
Tsutsumi, Yoshiaki: ETMR-11
Tsutsumi, Yoshiyuki:
HGG-49, RARE-16
Tucker, K: DIPG-75
Tuckuvienne, R: GCT-65
Tugues, S: IMMU-16
Tuite, G: RARE-06
Tun, T: LINC-01
Tunkle, L: DIPG-08
Turcotte, R: RARE-22
Turk, A: LGG-22
Turkistani, M: HGG-09
Turner, Jeff: MBRS-31
Turner, Joyce: PATH-14
Tylawsky, D: DDEL-15
Tyrrell, V: DIPG-75

Timmermann, B: EPEN-06, EPEN-09,
EPEN-27, EPEN-39, GCT-20, GCT-29,
GCT-48, MBCL-11
Timmers, C: MBRS-29, MBRS-73
Timofeeva, V: ATRT-05, MBCL-31
Tinkle, C: DIPG-46, DIPG-55, DIPG-74,
EPEN-50, HGG-22, IMG-20
Tippelt, S: EPEN-06, EPEN-47
Tischler, T: QOL-13
Tobias, M: MBRS-18
Toescu, S: IMG-10, IMG-13. QOL-59
Toiviainen-Salo, S: QOL-12
Toledano, Hagit: NFB-03
Toledano, Helen: LGG-55,
NFB-03, RARE-17
Tolhurst, O: DIPG-27
Tolkunova, P: MBCL-03
Toll, S: EPEN-11, GCT-67, RARE-53
Tomà, P: IMG-14, IMG-16, IMG-19
Tomboc, P: HGG-20,
IMMU-19, RARE-17
Tominaga, T: DDEL-08, GCT-35,
GCT-52, MBCL-48
Tomita, O: ETMR-15, MBCL-48
Tomita, Y: DIPG-03
Tomiyama, A: GCT-22, GCT-46
Tomizawa, D: ATRT-11,
ETMR-11, HGG-49
Tomlinson, G: PATH-29
Tong, E: QOL-53
Tong, L: MBCL-26
Tong, Y: ETMR-06
Tonse, R: RONC-23
Tonsgard, J: NFB-17
Toral-Casillas, E: QOL-06
Torchia, J: ATRT-33
Tordecilla, J: LINC-21
Toren, A: HGG-04, MBRS-04
Torkildson, J: QOL-53
Torontali, M: EPID-15
Torres, C: IMG-21
Totimeh, T: SURG-12
Totoki, Y: GCT-52
Touat, M: HGG-32, HGG-52
Toyota, Y: IMG-02
Trahair, T: DIPG-75
Tram Henriksen, L: GCT-65
Tran, A: QOL-36
Tran, H: HGG-47, QOL-57
Tran, J: NURS-10
Tran, M: ATRT-01
Tran, Q: HGG-57, PATH-13,
PATH-22
Tran, S: RONC-15
Tran-Du, K: TBIO-03
Traunwieser, T: QOL-13
Travis, K: NFB-11
Trebilcock, P: DIPG-27, DIPG-75
Treechairusame, T: MBCL-10
Tretter, J: RONC-31

vi502

NEURO-ONCOLOGYUUchida, E: GCT-22, GCT-46, GCT-62
Uchida, H: HGG-42, LGG-20, LGG-32
Uchiyama, M: ATRT-11, ETMR-11
Uchiyama, Taku: DIPG-02
Uchiyama, Toru: ATRT-11
Ueba, T: RONC-20
Ueno-Yokohata, H: ATRT-11
Uldhøii, B: ETMR-01
Ullrich, N: LGG-52, NFB-09. NFB-17
Ulysses, N: SWK-02
Umebayashi, D: DIPG-04, HGG-12
Umeda, K: GCT-50, RONC-06
Umehara, T: GCT-69
Umemura, Y: HGG-18
Underhill, A: DIPG-43
Underiner, R: ATRT-26•

DE C E M B E R 2 0 2 0Ung, C: DDEL-12, DIPG-07, DIPG-27
Upadhyay, S: EPEN-50, LGG-49
Upadhyayula, P: DDEL-13
Upton, D: DDEL-12, DIPG-07,
DIPG-15, DIPG-27
Usami, K: ETMR-11, HGG-49,
RARE-16, SURG-17
Usta, D: LGG-14, LGG-17
Utley, K: RARE-23, RARE-49
Uto, M: GCT-50, RONC-06
Uyttebroeck, A: QOL-07, RARE-56

V
Valente Fernandes, M: LGG-55
Valentino, K: QOL-41
Valero, M: LINC-21
Valiakhmetova, A: GCT-64,
LGG-26, RARE-52
Valinciute, G: MBRS-19
Vallance, K: PATH-29
Valochnik, A: PATH-10
Valteau-Couanet, D: MBCL-02
Valvi, S: DIPG-07, DIPG-50
van Baarsen, K: QOL-59, SURG-12
Van Beek, K: QOL-07
van Court, B: DIPG-42, MODL-31
Van Damme, A: HGG-20,
IMMU-18, RARE-17
van den Bent, M: IMG-03
Van den Wyngaert, L: QOL-18, QOL-19
van der Lugt, J: EPID-18, THER-09
Van Gool, S: DIPG-38
van Landeghem, F: LGG-55
Van Mater, D: EPCT-05, NFB-09
van Rijn, S: ETMR-03
van Santen, H: RARE-62
van Tilburg, C: EPCT-08,
LGG-17, LGG-55
van Vuurden, D: DDEL-05, DIPG-33,
DIPG-35, DIPG-77, DIPG-84, EPID-18
Vanan, M: LGG-23
Vanden Bempt, I: RARE-56
Vandenabeele, K: QOL-18, QOL-19
Vandereydt, J: QOL-18, QOL-19
Váňová, K: HGG-31, LGG-46, PATH-20
VanSickle, E: ETMR-18
Varadharajan, S: EPEN-30
Vardevanyan, H: RARE-33
Varga, E: ATRT-21, EPEN-28,
RARE-31, RARE-37
Varghese, N: MBRS-54
Varlet, P: DIPG-35, DIPG-56, DIPG-58,
DIPG-61, HGG-11, MBCL-02, RARE-21
Vasilevsky PhD, N: EPID-14
Vasiljevic, A: ETMR-21,
GCT-29, GCT-48
Vassal, G: DIPG-35, DIPG-61
Vasudevaraja, V: PATH-12

Author Index

Vatner, R: GCT-25
Vaubel, R: PATH-13
Vaughan, K: DIPG-05
Vaynshteyn, J: DDEL-15
Vedaraju, Y: COVD-04
Vega, R: RONC-32
Vega-Vega, L: LINC-39, LINC-40
Veillard, A: EPEN-46
Velazquez Vega, J: MODL-06
Veldhuijzen, S: ATRT-18
Veldhuijzen van Zanten, S: DIPG-77,
DIPG-84, DIPG-33
Veldhuis, N: RARE-62
Velez-Char, N: EPEN-27
Velu, U: ATRT-31
Venkata, R: MBRS-13, MBRS-72
Venkataraman, S: ATRT-06, DIPG-34,
DIPG-73, DIPG-79, EPEN-26, EPEN31, IMG-17, MBRS-26, MBRS-46,
MBRS-65, MBRS-67, MBRS-71
Vennarini, S: IMG-16
Venneti, S: DIPG-59, HGG-18
Ventura, L: SURG-22
Venugopal, C: MBRS-01
Veo, B: ATRT-20, IMG-17, MBRS-26,
MBRS-65, MBRS-67
Vercruysse, T: QOL-18, QOL-19
Verity, S: QOL-23, QOL-26
Verona, G: RARE-43
Vezina, G: IMG-04, MBCL-15
Viaene, A: TBIO-03
Vianna, D: LINC-28
Vibhakar, R: ATRT-06, ATRT-20,
ATRT-24, DIPG-34, DIPG-42, DIPG-73,
DIPG-79, EPEN-31, HGG-57, IMG-17,
LGG-34, MBRS-16, MBRS-26, MBRS46, MBRS-65, MBRS-67, MBRS-71,
MODL-31, QOL-36
Vícha, A: HGG-31, LGG-46, PATH-20
Vida, J: LINC-02
Vidal-Gutierrez, O: LINC-04, LINC-06
Vijayasekharan Nair, K: LINC-07
Vijmasi, T: DIPG-73, MODL-24, QOL22, RARE-08, RARE-10, RARE-11
Vik-Mo, E: TBIO-18
Vilain, E: PATH-14
Vilesova, I: GCT-64, MBCL-32
Villalba, M: THER-09
Villanueva, G: GCT-71PCT-12,
Villaneuva-Meyer, J: EIMMU-31
Villeneuve, S: GCT-23
Vinci, M: DIPG-63, HGG-16, HGG19, HGG-37, IMG-12, IMG-14,
IMG-16, IMMU-13, MBRS-60,
MODL-20, MODL-23
Vinitsky, A: EPCT-02, EPEN-50
Viscardi, E: EPEN-03
Vitanza, N: DIPG-10, DIPG-52,
DIPG-64, IMG-10, IMG-13, IMG-22,
IMMU-03, NFB-13

Vitte, J: MODL-13
Vittorio, O: DDEL-12,
DIPG-27, DIPG-83
Vladoiu, M: TBIO-15
Vogel, H: PATH-06
Vogel, T: ETMR-08
Voicu, I: IMG-14, IMG-16, IMG-19
Voicu, P: SURG-03
Vokuhl, C: HGG-34
Volchenboum MD, PhD, S: EPID-14
Voliani, V: DDEL-12
Vollmer, J: LGG-17, MBRS-19
von Bueren, A: DIPG-25, DIPG-77,
EPEN-27, HGG-17, HGG-34, MBCL-07,
MBCL-09, MBCL-11, PATH-07
von Deimling, A: EPEN-09, EPEN-18,
LGG-33, MBCL-06, MBCL-07, MBCL09, MBRS-68, MODL-11, PATH-04,
PATH-11, PATH-26, QOL-13, RARE-42
von Hoff, K: EPEN-09, EPEN-27,
EPEN-36, EPEN-39, ETMR-14, MBCL06, MBCL-07, MBCL-09, MBCL-11,
PATH-07, QOL-13, QOL-24
von Oettingen, G: ETMR-01, GCT-65
VonBergen, J: LGG-05, TBIO-24
Vora, T: LINC-08, LINC-25, LINC-29
Vorobiev, N: ATRT-05, MBCL-31
Vortmeyer, A: PATH-14
Vouri, M: MBRS-51

W
Waanders, A: EPCT-17, HGG37, HGG-43, IMG-12, MODL-26,
PATH-21, TBIO-03
Wachtel Aptomizer, A: RARE-42
Wada, K: GCT-22
Wadden, J: DIPG-08
Wade, S: QOL-04
Wadhwani, N: HGG-43, TBIO-03
Wagener, R: RARE-22
Wagner, L: DIPG-55, DIPG-74
Waha, A: HGG-34
Wainwright, B: MBCL-21, MBRS-24
Wakabayashi, T: LGG-56
Wakita, S: PATH-03
Waldeck, K: ATRT-08
Walker, D: DIPG-82, EPID-11,
QOL-32, QOL-33
Walker, F: DIPG-34
Walser, M: RONC-15
Walsh, K: NFB-17
Walshe, K: LGG-42
Walter, A: ETMR-22
Walter, B: ATRT-32
Wan, W: MODL-26
Wang, A: IMMU-30
Wang, B: MBRS-62, SURG-04

Wang, D: ATRT-06, DIPG-34,
DIPG-73, MBRS-26, MBRS-65,
MBRS-67, MBRS-71
Wang, F: EPEN-05, QOL-54
Wang, Jiajia: MBRS-62
Wang, Jian: EPEN-05,
GCT-30, LINC-15
Wang, Jing: EPEN-05, EPEN-10
Wang, Jingsheng: LINC-15
Wang, Jinn-Li: RARE-45
Wang, Juan: ETMR-02
Wang, Junhua: ATRT-09, IMMU-29
Wang, K: GCT-02, GCT-12
Wang, Li: TBIO-26
Wang, Lichao: DIPG-26, GCT-26, GCT27, GCT-28, HGG-14
Wang, Linghua: DIPG-06
Wang, Lu: EPCT-15
Wang, P: TBIO-19
Wang, S: ATRT-17, ATRT-23
Wang, V: TBIO-26
Wang, Ye: RARE-63
Wang, Yichuan: IMG-20
Wang, Yin: ETMR-22
Wang, Yingzhe: HGG-22
Wang, Z: RARE-43
Waranecki, P: ATRT-18, RONC-21
Warmuth-Metz, M: EPEN-06, EPEN09, EPEN-27, EPEN-36, EPEN-39,
ETMR-14, MBCL-07, MBCL-09, MBCL11, QOL-13, QOL-24
Warren, E: RONC-12
Warren, Katherine: DIPG-01, DIPG74, IMG-03, LGG-03, DIPG-55,
IMG-04, IMG-09
Warren, Krista: MBCL-38
Washio, K: RARE-32
Wasserman, J: GCT-75
Waszak, S: DIPG-64,
MBCL-21, RARE-21
Watanabe, A: MBCL-41, MBCL-48
Watanabe, K: ATRT-11, MBCL-27
Watanabe, T: LGG-54
Watanabe, Yosuke: PATH-03
Watanabe, Yousuke: GCT-45
Watanabe, Yuko: EPID-09, HGG-02,
MBCL-48, RARE-26
Wataya, T: MBRS-06
Watchmaker, P: IMMU-23,
IMMU-31
Waters, K: NURS-09, OTHR-09
Watson, M: DIPG-19
Weaver, K: TBIO-13
Webb, A: MBRS-29, MBRS-73
Weber, D: RONC-15
Wechsler-Reya, R: DDEL-10, EPEN04, MBRS-01, MBRS-10, MBRS-12,
MBRS-16, MBRS-46
Wedig, T: EPEN-44
Weetall, M: ATRT-06

NEURO-ONCOLOGY•DECEMBER 2020

iii503

Author Index

Win, K: LINC-01
Win, Y: LINC-01
Winer, I: IMMU-18, RARE-17
Winzent, S: DDEL-06,
MODL-01, OTHR-16
Withey, S: IMG-06
Witt, H: EPEN-03, EPEN-06, EPEN-09,
EPEN-36, EPEN-39
Witt, Olaf: EPEN-06, LGG-14, LGG-17,
LGG-55, MBCL-06, MBC-21, MBRS-19
Witt, Olas: IMG-03
Wittmann, A: MODL-11
Wójcicka-Kowalczyk, K: RARE-58
Wolden, S: DIPG-49
Woldu, A: DIPG-29
Wolf, D: NFB-09
Wolfe, I: DIPG-08, HGG-18
Wolff, J: QOL-24
Wölfl, M: IMMU-10
Wong, K: GCT-66
Wong, L: ATRT-08
Wong, M: DIPG-50, DIPG-75
Wong, O: LINC-03
Wong, S: GCT-73, MBRS-17
Wong, T: ATRT-01, ETMR-22,
MBCL-12, MBCL-20, MBRS-14,
MODL-16, RARE-45
Woo, R: DIPG-59
Wood, P: ATRT-08, ATRT-22,
ETMR-22, LGG-42
Woodhouse, K: QOL-28, RONC-17
Woodward, A: EPEN-43
Woodward, L: LGG-57
Woulfe, J: IMG-21
Wright, A: MBCL-30
Wright, E: ATRT-04, LGG-31, NFB-05,
RARE-14, RONC-31
Wright, J: IMG-10, IMG-13,
IMG-22, IMMU-03
Wright, K: EPCT-01, IMG-05, LGG-03,
LGG-49, LGG-52
Wu, A: DIPG-41
Wu, C: DDEL-13, LGG-22
Wu, G: HGG-57
Wu, K: ATRT-01, ETMR-22, MBCL-12,
MBCL-20, MBRS-14
Wu, P: TBIO-21
Wu, Shaoxiong: LINC-15
Wu, Shengjie: EPEN-54, GCT-33, GCT41, GCT-42, LGG-04
Wu, V: IMMU-02
Wu, Y: DIPG-28
Wucherpfennig, K: EPEN-21
Wyckoff, J: DDEL-04

Wefers, A: LGG-35, LGG-33,
MODL-11, PATH-26
Wei, H: DDEL-13
Wei, X: MODL-29
Weinmann, D: EPEN-35
Weishaupt, H: MBRS-10
Weiss, B: HGG-01
Wells, O: EPEN-36
Weltman, E: EPID-05
Welzel, J: MBCL-11
Wembacher-Schroeder, E: DIPG-49
Wempe, M: DIPG-42
Wen, L: DIPG-26, GCT-27,
GCT-28, GCT-63
Wen, P: HGG-18, IMG-04
Weng, W: LINC-15
Wening, J: EPEN-39
Wennerberg, K: TBIO-18
Wesseling, P: ATRT-18, EPID-18
Westbrook, T: EPEN-30
Westerholm-Ormio, M: QOL-59
Wetmore, C: LGG-49
Wharton, S: MBRS-44, MBRS-60
Wheeler, G: RARE-15
Whetzel, L: NURS-10
Whipple, N: EPEN-07,
GCT-70, IMMU-31
White, A: COVD-03
White, C: DIPG-50, EPEN-36
White, P: EPEN-17
Whiteaker, J: TBIO-19
Whitehead, C: HGG-08
Whitehead, W: IMG-07, QOL-01
Whitehouse, J: DIPG-50, RONC-02
Whitlock, J: LGG-49
Wibroe, M: QOL-59
Wick, W: PATH-26
Widener, M: EPCT-18
Widodo, D: LINC-24
Wierman, M: IMMU-18
Wierzbicki, K: DIPG-08, IMG-18
Wilkening, G: QOL-22,
QOL-37, QOL-38
Wilkie, B: NURS-03
Williams, I: IMMU-16
Williams, Melissa: TBIO-03
Williams, Molly: EPEN-36
Williams-Hughes, C: GCT-33
Williamson, D: ATRT-25, MBRS33, MBRS-44, MBRS-57, MBRS-59,
MBRS-60, MBRS-69
Williamson, K: PATH-09
Williamson Lewis, R: QOL-31
Wilson, A: IMMU-02, IMMU-03
Wilson, B: LGG-19, LGG-55, MBCL-24
Wilson, J: RARE-49
Wilson, M: MBRS-69
Wilson, R: ATRT-21, EPEN-17,
EPEN-28, RARE-31
Wilson, S: RARE-13
Wimmer, K: HGG-44

vi504

NEURO-ONCOLOGY

X
Xella, A: MBRS-01
Xi, S: EPEN-05•

DE C E M B E R 2 0 2 0Xia, Y: EPEN-05
Xing, S: MBRS-01
Xu, J: ATRT-03
Xu, K: HGG-57
Xu, L: ETMR-19

Y
Yadav, V: DIPG-18, DIPG-59, DIPG-64
Yadavalli, S: DIPG-06,
DIPG-51, DIPG-64
Yaffe, A: NFB-08
Yagasaki, H: OTHR-02
Yaguchi, A: ETMR-15, MBCL-48
Yagyu, S: DIPG-04, HGG-12
Yaich, A: NFB-16
Yalon, M: HGG-04, HGG-20,
MBRS-04, RARE-17
Yalon-Oren, M: ETMR-22
Yamada, H: GCT-06
Yamagishi, Y: GCT-34
Yamaguchi, K: GCT-56
Yamaguchi, M: THER-07
Yamaguchi, S: GCT-08, GCT10, GCT-31, HG-02, RONC-16,
RONC-19, SURG-02
Yamaguchi, T: DIPG-02
Yamaki, Y: GCT-38, LGG-40
Yamamoto, E: GCT-50
Yamamoto, Hidtaka: HGG-24
Yamamoto, Hiroyuki: HGG-12
Yamamoto, M: RONC-25
Yamamoto, N: IMMU-09
Yamamoto, Shinji: GCT-44,
RONC-25, SURG-05
Yamamoto, Shunsuke: HGG-24
Yamamoto, Takahiro: EPID-01, GCT-36
Yamamoto, Tetsuya:
EPEN-34, HGG-51
Yamamura, N: LGG-29, RONC-13
Yamanaka, T: DIPG-04, HGG-12
Yamaoka, H: GCT-44,
RONC-25, SURG-05
Yamaoka, M: IMMU-12
Yamasaki, F: GCT-72, RARE-26
Yamasaki, K: GCT-52,
MBCL-22, PATH-28
Yamashita, S: LGG-54
Yan, C: LINC-20
Yanagi, M: RARE-39
Yanagisawa, T: GCT-52, GCT-59,
IMMU-12, MBCL-48
Yang, G: QOL-11, QOL-28
Yang, Jae Yeol: MBRS-56
Yang, Jingye: MBRS-31
Yang, L: LINC-15
Yang, Q: EPEN-05, GCT-30, LINC-15
Yang, X: TBIO-26
Yang, Yanwen: MBRS-64

Author Index

Yang, Yuanfan: THER-05
Yankelevich, M: EPEN-11, RARE-51
Yao, F: ATRT-33, ETRM-19, TBIO-02
Yarbrough, C: SWK-10
Yasko, L: LGG-26, MBCL-32, RARE-52
Yassur, I: NFB-03
Yasuhara, T: SURG-21
Yau, J: LINC-20
Yau, P: HGG-48
Yawata, T: RONC-20
Yazıcı, H: RARE-55
Yeboa, D: RONC-17
Yecies, D: IMG-13
Yee, B: MBRS-01
Yegorov, O: IMMU-08
Yen, L: IMMU-18, MBRS-54, RARE-17
Yeo, G: MBRS-01
Yeo, K: EPCT-01, GCT-23,
IMMU-01, LGG-03
Yeo, T: RARE-01
Yeoh, S: LINC-03
Yeom, K: IMG-03, IMG-10, IMG-13,
IMG-22, NFB-04, NFB-11, PATH-06
Yeung, N: DIPG-07
Yi, J: EPEN-30
Yi, S: DIPG-60
Yi, Z: IMMU-05
Yip, K: QOL-25
Yip, S: HGG-35
Yock, T: GCT-37, RONC-24
Yokogami, K: GCT-43,
GCT-52, LGG-54
Yokoo, H: PATH-03
Yokota, C: GCT-69, QOL-44
Yonezawa, H: HGG-42, LGG-20,
LGG-32, RARE-04
Yoo, B: MBRS-56
Yoo, H: MBRS-56
Yoo, K: MBCL-28
Yoon, H: EPEN-15
Yoon, J: HGG-01, LGG-53
Yorio, F: LINC-05
Yoshida, Kaoru: ATRT-11
Yoshida, Kazunari: GCT-06, GCT-47,
GCT-51, GCT-55, GCT-56
Yoshida, Makiko: GCT-62
Yoshida, Mari: MBRS-32
Yoshida, Masanori: ATRT-11
Yoshimoto, K: GCT-43, HGG-42, LGG32, RARE-04, TBIO-08
Yoshimura, J: MBRS-06, MBRS-32
Yoshimura, M: GCT-44,
RONC-25, SURG-05
Yoshimura, S: ETMR-12
Yoshimoto, K: LGG-20
Yoshino, A: OTHR-02
Yoshioka, E: LGG-38, MBRS-39
Yoshioka, F: SURG-24
Yoshioka, T: ATRT-11, ETMR-11, HGG49, PATH-28, RARE-16

Yoshitake, H: GCT-53
Youn, S: GCT-17
Younes, S: TBIO-09, TBIO-13
Young Poussaint, T: EPCT-02, EPCT-17,
IMG-03, LGG-04
Yousef, Y: LINC-10
Yousif, T: LINC-43
Youssef, A: DIPG-37
Youssef, O: MBRS-31
Yu, B: DDEL-09
Yu, D: DIPG-15
Yu, H: MBRS-48, MBRS-51
Yuan, M: MODL-04, NFB-01
Yudina, N: ATRT-05, MBCL-31

Z
Zabriskie, R: PATH-27
Zacharoulis, S: DDEL-07, DDEL-13,
DIPG-40, EPID-03, MODL-09, SWK-02
Zack, T: HGG-41
Zaghloul, M: DIPG-46,
DIPG-74, LINC-10
Zagidullina, S: MBCL-04, MBCL-05
Zagorski, J: ETMR-18
Zahedi, S: ATRT-20, LGG-34
Zahran, T: MODL-30
Zaichikov, A: ATRT-05, LGG-34
Zaka, M: MBRS-59
Zakhari, N: IMG-21
Zaky, W: DIPG-06, DIPG-52, DIPG57, DIPG-60, EPCT-06, EPEN-10,
ETMR-04, IMG-15, LGG-44, LGG-47,
MBCL-35, NFB-06, QOL-11, QOL-28,
RARE-19, RARE-44, RONC-09
Zalacain, M: THER-01
Zalcberg, I: PATH-30
Zamecbik, J: LGG-55
Zámečník, J: HGG-31,
LGG-46, PATH-20
Zanazzi, G: LGG-22
Zanini, M: ATRT-24
Zannikou, M: MODL-12
Zanon, N: MBRS-18
Zapf, A: PATH-07
Zapotochna, K: LINC-41
Zapotocky, M: DIPG-20, HGG-31,
IMMU-18, LGG-46, LGG-50, LGG55, MBRS-54, PATH-14, PATH-20,
RARE-17, RARE-50
Zattara, H: RARE-21
Zeid, J: NFB-09
Zelcer, S: LGG-19, RARE-17
Zerah, M: MBCL-02
Zerbe, O: MODL-14
Zhang, B: DIPG-31, MODL-26
Zhang, C: IMMU-18
Zhang, Helena: TBIO-06

Zhang, Hongying: MODL-06
Zhang, Huiyuan: EPEN-46
Zhang, Huizhen: IMMU-15
Zhang, Jiangguo: MODL-26
Zhang, Jinghui: HGG-57
Zhang, L: DDEL-16, DIPG-76,
DIPG-78
Zhang, N: EPCT-15
Zhang, P: HGG-27
Zhang, S: TBIO-01
Zhang, W: DDEL-10
Zhang, Xiang-heng: EPEN-05
Zhang, Xing: ETMR-02, GCT-27,
GCT-28, HGG-14
Zhang, Yang: ATRT-03, DIPG-26
Zhang, Yangqiong: GCT-26, GCT-27,
GCT-28, HGG-14
Zhang, Yiqun: DIPG-62
Zhang, Yuqi: ATRT-09, IMMU-29
Zhang, Yongzhan: DIPG-03
Zhao, C: RARE-63
Zhao, G: MODL-17
Zhao, Haotian: MODL-30
Zhao, Hong: MBRS-17
Zhao, M: MBRS-10
Zhao, Q: EPEN-05
Zhao, S: EPEN-46
Zhao, W: MODL-09
Zhao, Yang: MBRS-62, SURG-04
Zhao, Yanhua: EPEN-30
Zhao, Yue: MBRS-73
Zheludkova, O: ATRT-05, MBCL-03,
MBCL-07, MBCL-31, QOL-43
Zhen, J: GCT-27, GCT-27
Zhen, Z: LINC-15
Zheng, H: QOL-55
Zheng, J: NFB-04
Zheng, T: EPEN-18
Zhong, Y: ATRT-33
Zhou, C: DIPG-26, GCT-26, GCT-27,
GCT-28, GCT-63, HGG-14
Zhou, H: EPEN-07, GCT-70
Zhou, J: DIPG-26
Zhou, L: DIPG-62
Zhou, Zhaoming: DIPG-26, GCT-26,
GCT-28, GCT-63, HGG-14
Zhou, Zhongping: RARE-63
Zhu, H: MBRS-01
Zhu, J: EPEN-53
Zhu, Xiaoting: DIPG-21
Zhu, Xiaoyan: DIPG-51,
HGG-22, IMMU-06
Zhu, Yuankun: DIPG-31, EPID-14,
MODL-26, TBIO-19
Zhukova, N: ATRT-22,
DDEL-17, LGG-42
Ziegler, D: ATRT-08, DDEL-12, DIPG07, DIPG-14, DIPG-15, DIPG-16,
DIPG-27, DIPG-29, DIPG-46, DIPG-55,
DIPG-74, DIPG-75, DIPG-83, EPCT-08,

NEURO-ONCOLOGY•DECEMBER 2020

iii505

Author Index

Zipfel, J: QOL-59
Zou, H: MBRS-63
Zou, L: DIPG-03
Zou, P: QOL-15
Zschernack, V: PATH-13
Zubarovskaya, L: MBCL-03
Zuckermann, M: HGG-22

ETMR-08, ETMR-22, HGG-20, IMMU18, MBRS-54, RARE-17
Zimmerman, M: IMMU-01, LGG-03
Zimmerman, S: RARE-17
Zimmermann, M: GCT-76
Zimmermann, S: IMMU-18
Zimolong, B: QOL-24

vi506

NEURO-ONCOLOGY•

DE C E M B E R 2 0 2 0

Zukosky, A: MODL-31
Zumberge, N: EPEN-17
zur Mühlen, A: EPEN-27
Zurakowski, D: IMG-03
Zvyagintseva, D: MBCL-03
Zwienenberg, M: PATH-31
Zylber, R: DDEL-07