bluuebunny/crossref_metadata_2025 huggingface dataset:
DIPG-58. HISTONE H3 WILD-TYPE DIPG/DMG OVEREXPRESSING EZHIP EXTEND THE SPECTRUM OF DIFFUSE MIDLINE GLIOMAS WITH PRC2 INHIBITION BEYOND H3-K27M MUTATION
Authors: Castel David , Kergrohen Thomas , Tauziède-Espariat Arnault , Mackay Alan , Ghermaoui Samia , Lechapt Emmanuèle , Pfister Stefan , Kramm Christof , Boddaert Nathalie , Blauwblomme Thomas , Puget Stéphanie , Beccaria Kévin , Jones Chris , Jones David , Varlet Pascale , Grill Jacques , Debily Marie-Anne
Published: December 2020

Diffuse 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 patients biopsied 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 compared to 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-64. INTERNATIONAL PRECLINICAL DRUG DISCOVERY AND BIOMARKER PROGRAM INFORMING AN ADOPTIVE COMBINATORIAL TRIAL FOR DIFFUSE MIDLINE GLIOMAS
Authors: Przystal* Justyna M , Yadavilli* Sridevi , Abadi* Christina Colman , Yadav Viveka Nand , Laternser Sandra , Cosentino Chiara Cianciolo , Waszak Sebastian M , Cartaxo Rodrigo , Biery Matt , Myers Carrie , Jayasekara Samantha , Olson James M , Filbin Mariella G , Vitanza Nicholas A , Cain Jason , Koschmann# Carl , Müller# Sabine , Nazarian# Javad
Published: December 2020

INTRODUCTION

DMG-ACT (DMG- multi-arm Adaptive and Combinatorial 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 in vivo (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 in murine/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 cell lines validated mitochondrial stress and ATF4 as the main targets induced by ONC201/6.

CONCLUSION

Thorough preclinical testing in a multi-site laboratory setting is feasible and identified ONC201 in combination with ONC206 as promising therapeutics for DMGs. Preclinical and correlative-clinical studies are ongoing.
DIPG-79. H3K27M INDUCES EPIGENETIC AND ONCOGENIC CHANGES THAT ARE PARTIALLY REVERSED BY SMALL MOLECULE AURORA KINASE B/C INHIBITION
Authors: Chatwin Hannah , Lemma Rakeb , DeSisto John , Knox Aaron , Mestnik Shelby , Reid Aidan , Vibhakar Rajeev , Venkataraman Sujatha , Green Adam
Published: December 2020

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 effect-isolating 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 H3K27M-transduced 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 of cell 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 mutation induces epigenetic, phenotypic, and cell cycle regulation changes resulting in relaxation 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.
EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)
Authors: DeWire Mariko , Leach James , Fuller Christine , de Blank Peter , Hummel Trent , Pillay-Smiley Natasha , Salloum Ralph , Stevenson Charles , Drissi Rachid , Kumar Shiva Senthil , Baxter Patricia , Gass David , Goldman Stewart , Leary Sarah , Lane Adam , Campagne Olivia , Stewart Clinton , Fouladi Maryam
Published: December 2020

Genomic aberrations in the cell cycle and mTOR pathways have been reported 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 clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two 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 daily for 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 impact of 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.
EPEN-04. ONCOGENIC 3D TUMOR GENOME ORGANIZATION IDENTIFIES NEW THERAPEUTIC TARGETS IN EPENDYMOMA
Authors: Okonechnikov Konstantin , Hübner Jens-Martin , Chapman Owen , Chakraborty Abhijit , Pagadala Meghana , Bump Rosalind , Chandran Sahaana , Kraft Katerina , Hidalgo Rocio Acuna , Mundlos Stefan , Wechsler-Reya Robert , Juarez Edwin F , Coufal Nicole , Levy Michael , Crawford John , Pajtler Kristian , Reid Derek , Schmitt Anthony , Carter Hannah , Ay Ferhat , Dixon Jesse , Mesirov Jill , Pfister Stefan M , Kool Marcel , Chavez Lukas
Published: December 2020

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 most common 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 analysis of 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 are enriched for strong physical interactions. Importantly, we also identify many new putative tumor-dependency genes activated by long-range promoter-enhancer 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 structural variants 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 for tumor cell growth and proliferation in-patient derived ependymoma models.
EPEN-53. C11orf95-RELA REPROGRAMS 3D EPIGENOME IN SUPRATENTORIAL EPENDYMOMA
Authors: Zhu Jacqueline Jufen , Jillette Nathaniel , Li Xiao-Nan , Cheng Albert , Lau Ching
Published: December 2020

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 an urgent need. Since 2014, C11orf95-RELA fusion was found to be the most recurrent structural variation in approximately 70% of supratentorial ependymomas (ST-EPN), but the molecular mechanisms of oncogenesis are unclear. Here we utilized HEK293T transgene models and a ST-EPN cell line 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-associated genes 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 such as 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.
ETMR-01. TREATMENT OUTCOME OF TWO CASES WITH HIGH-GRADE NEUROEPITHELIAL TUMOR WITH BCOR ALTERATION
Authors: Kristensen Ines , Hansen Louise Lindholt , Mikkelsen Torben Stamm , Henriksen Louise Tram , Parm Uldhøi Benedicte , von Oettingen Gorm , Cortnum Søren , Lassen-Ramshad Yasmin
Published: December 2020

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 transverse and sigmoid sinus were both diagnosed based on histology and methylation with HGNET-BCOR. No spinal or liquor dissemination were found at diagnosis in both cases. Treatment consisted of radical resection of the tumour. In the case of the lesion with sinus infiltration residual tumour in 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 died nine 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.
ETMR-02. NOVEL CIC-LEUTX FUSION IN CNS EMBRYONAL TUMOR: A CASE REPORT AND REVIEW OF THE LITERATURE
Authors: Hu Wanming , Wang Juan , Zhang Xing , Ji Yuhang , Song Chao , Sun Xiaofei
Published: December 2020

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 temporal lobe-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 of neuroectodermal 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 showed no alterations. NGS showed pathogenic mutations including a brand new CIC-LEUTX fusion, heterozygous germline NBN c.C127T mutation and somatic 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 CIC-NUTM1 fusion in rare CNS sarcoma, CIC-LEUTX fusion in epithelioid angiosarcoma and CIC-DUX4 fusion in Ewing-like sarcoma. Hitherto, apart from 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 characteristics of CIC-LEUTX fusion.
ETMR-14. TREATMENT OF EMBRYONAL TUMOURS WITH MULTILAYERED ROSETTES (ETMR) WITH CARBOPLATIN-ETOPOSIDE INDUCTION AND TANDEM HIGH-DOSE CHEMOTHERAPY WITHIN THE PROSPECTIVE HIT-TRIALS AND REGISTRIES
Authors: Juhnke Björn-Ole , Gessi Marco , Gerber Nicolas Ulrich , Friedrich Carsten , Haberler Christine , Mynarek Martin , Bison Brigitte , Kortmann Rolf-Dieter , Warmuth-Metz Monika , Schüller Ulrich , Pfister Stefan Michael , Pietsch Torsten , Kool Marcel , Rutkowski Stefan , von Hoff Katja
Published: December 2020

BACKGROUND

Embryonal tumours with multilayered rosettes (ETMR) are highly aggressive tumors, mostly occurring in infants. Published clinical data refer to retrospective cohorts of inhomogeneously treated patients. Here, we describe the outcome of patients, who were prospectively treated within the P-HIT2000-trial, the subsequent HIT2000-interim-registry 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 molecularly-confirmed diagnosis of ETMR were included. Outcome of 18 patients treated 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%, and progression-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-21. META-ANALYSIS OF PINEAL REGION TUMOURS DEMONSTRATES MOLECULAR SUBGROUPS WITH DISTINCT CLINICO-PATHOLOGICAL FEATURES: A CONSENSUS STUDY
Authors: Li Bryan K , Liu Anthony P Y , Pfaff Elke , Gudenas Brian , Gershanov Sivan , Dufour Christelle , Aichmüller Christian , Sill Martin , Lin Tong , Onar-Thomas Arzu , Orr Brent A , Hawkins Cynthia , Ellison David W , Snuderl Matija , Laquierre Annie , Hwang Eugene , Gururangan Sri , Karajannis Matthias A , Robinson Giles W , Bouffet Eric , Vasiljevic Alexandre , Gajjar Amar , Pfister Stefan M , Northcott Paul A , Jones David T W , Huang Annie
Published: December 2020

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 clinico-pathologic 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 comprised of 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 of future clinical trials.
GCT-19. MODELING GERM CELL TUMORS WITH KIT MUTANT hiPSCs
Authors: Kuzuoka Sakura , Kojima Yoji , Ichimura Koichi , Saitou Mitinori
Published: December 2020

Central Nervous System Germ Cell Tumor (CNS GCT) is the second most common 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 of human 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 most common mutation KITD816V to human iPSCs using CRISPR/Cas9, and confirmed in iPSCs that mutated KIT was phosphorylated in the absence of ligand stimulation, and also found that KIT activation contribute to the phosphorylation 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 compared to 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 confirmed that 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-25. INNOVATIVE, INTENSIVE IRRADIATION-AVOIDING/MINIMIZING CHEMOTHERAPY FOR HIGH-RISK PRIMARY CENTRAL NERVOUS SYSTEM (CNS) MIXED MALIGNANT GERM CELL TUMORS (HR-MMGCT): A PILOT STUDY AND PROPOSED MULTI-NATIONAL PROSPECTIVE TRIAL
Authors: Finlay Jonathan L , Abu-Arja Mohammad H , Abu-Arja Rolla , Auletta Jeffery , AbdelBaki Mohamed S , Osorio Diana S , Conley Suzanne , Shatara Margaret , Boué Daniel R , Pierson Christopher R , Rusin Jerome , Martin Lisa , Jones Jeremy , Palmer Joshua D , Vatner Ralph , Drapeau Annie , Sribnick Eric , Leonard Jeffrey R
Published: December 2020

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. Such high-risk patients are variably defined as having initial alpha-fetoprotein (AFP) elevations exceeding 1,000ng/mL, predominant histopathologies of malignant non-germinomatous GCT and incomplete responses to induction chemotherapy. Drugs targeting GCT-specific molecular markers have been identified for non-germinomatous GCT elements but have yet to be incorporated 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

Four children (two with pure suprasellar embryonal carcinoma (EC) - one with Down syndrome and the other with pre-diagnosis cognitive dysfunction; one with initial serum AFP exceeding 7,000ng/mL and yolk sac tumor (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 brentuximab-vedotin 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 and palbocyclib without irradiation.

CONCLUSION

This treatment strategy for HR-MMGCT patients provides preliminary tolerance and response data justifying extension to a multi-center trial.
GCT-27. CLINICAL FEATURES AND PROGNOSTIC FACTORS OF NONGERMINOMATOUS GERM CELL TUMORS IN 111 CONSECUTIVE PATIENTS IN A SINGLE INSTITUTION: IMPACT OF IRRADIATION AND CHEMOTHERAPY CYCLES ON SURVIVAL
Authors: Wen Lei , Li Juan , Hu Qingjun , Lai Mingyao , Zhou Cheng , Zhen Junjie , Shan Changguo , Hong Weiping , Luo Rishun , Zhang Yangqiong , Zhang Xing , Wang Lichao , Cai Linbo
Published: December 2020

BACKGROUND

Limited data is available in intracranial 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 were strongly 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 of chemotherapy was effective and should be recommended for the treatment of newly diagnosed NGGCTs in Chinese population.
GCT-28. RECURRENCE PATTERN AND SURVIVAL FOR RELAPSED INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMORS: A SINGLE-INSTITUTION EXPERIENCE
Authors: Wen Lei , Zhou Zhaoming , Hu Qingjun , Li Juan , Lai Mingyao , Zhou Cheng , Shan Changguo , Zhen Junjie , Hong Weiping , Zhang Xing , Zhang Yangqiong , Luo Rishun , Wang Lichao , Cai Linbo
Published: December 2020

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 this study. Data of first line treatment, salvage treatment, clinicopathological features and survival were collected and analyzed.

RESULTS

Totally, thirty patients (30/111, 27.0%) relapsed in our cohort, including 19 patients with accurate relapse information detail, and 11 patients who died of disease progression 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 volume of 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 and site, 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 relapsed in 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) and peritoneal (n=1).

CONCLUSION

Protracted follow-up is recommended because late recurrence is not uncommon. Primary tumor site and distant intracranial are the most prevalent relapsed location. Patients who relapsed could benefited from both CSI and salvage chemotherapy.
GCT-37. PREVALENCE OF AUTISM SPECTRUM DISORDER AND OTHER NEURODEVELOPMENTAL DISORDERS IN PEDIATRIC PATIENTS WITH INTRACRANIAL GERM CELL TUMORS
Authors: Liu Kevin X , Sethi Roshan V , Pulsifer Margaret B , D’Gama Alissa M , Lavally Beverly , Tarbell Nancy J , Yock Torunn I , MacDonald Shannon M
Published: December 2020

PURPOSE/OBJECTIVE(s)

Intracranial germ cell tumors (IGCTs) are rare tumors of the central nervous system with peak incidence around puberty. Due to the developmental origins of IGCTs, we investigated the prevalence of 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 time of 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, and three 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 the pure 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 more than 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-60. DEVELOPMENT OF MICROBLEEDING AFTER PROTON THERAPY FOR PATIENTS WITH GERM CELL TUMOR
Authors: Kohzuki Hidehiro , Muroi Ai , Mizumoto Masashi , Sakurai Hideaki , Ishikawa Eiichi , Matsumura Akira
Published: December 2020

BACKGROUND

Proton therapy has been increasingly used to treat pediatric brain tumor. However, there were few reports about radiation-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 gradient-recalled 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 dose to surrounding normal brain tissue.
GCT-63. STEREOTACTIC RADIOSURGERY FOR RESIDUAL LESIONS OF PINEAL NON-GERMINOMATOUS GERM CELL TUMORS AFTER CONVENTIONAL RADIOTHERAPY: A RETROSPECTIVE STUDY
Authors: Lai Mingyao , Li Juan , Hu Qingjun , Zhou Zhaoming , Wen Lei , Zhou Cheng , Shan Changguo , Cai Linbo
Published: December 2020

OBJECTIVE

To explore the efficacy and safety of SRS for residual lesions of NGGCTs after conventional RT.

METHODS

The clinical data of patients 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 were male, 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). After a month of treatment with SRS, the ORR and DCR were 71.4% and 95.2%, 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 safe and feasible, with well tolerance, which is beneficial for the improvement of local control and the prolongation of survival.
GCT-64. TREATMENT RESULTS IN CHILDREN WITH LOCALIZED CNS NGGCT
Authors: Vilesova Irina , Tarasova Ekaterina , Valiakhmetova Andge , Salnikova Ekaterina , Pshonkin Alexey , Novichkova Galina , Karachunsky Alexander , Papusha Ludmila
Published: December 2020

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 (median age 10.5, range 4 – 16 years) with localized intracranial NGGCT were treated 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% and 85,7%, 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-74. RETROSPECTIVE LITERATURE REVIEW OF CENTRAL NERVOUS SYSTEM (CNS) GERM CELL TUMORS (GCTs) IN PATIENTS WITH DOWN SYNDROME (DS)
Authors: Harris Micah K , Lamb Margaret , Stanek Joseph R , Finlay Jonathan L , AbdelBaki Mohamed S
Published: December 2020

BACKGROUND

A standard-of-care has not been established for the 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 (median nine-years-old; 21 males) were reported; the majority (23/31) originated from East Asia. Twelve had germinomas (39%), 12 had non-germinomatous germ cell tumors (NGGCTs) (39%), and seven had teratomas (22%). Four patients (13%) died from tumor progression (one germinoma versus three teratoma). Seven patients (23%) died from treatment-related complications (four germinoma versus three NGGCT). Of the germinoma patients, two died 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-76. 24Gy WHOLE VENTRICULAR RADIOTHERAPY ALONE IS SUFFICIENT FOR DISEASE CONTROL IN LOCALISED GERMINOMA IN CR AFTER INITIAL CHEMOTHERAPY – EARLY RESULTS OF THE SIOP CNS GCT II STUDY
Authors: Calaminus Gabriele , Bison Brigitte , Faure-Conter Cecile , Frappaz Didier , Peyrl Andreas , Gerber Nicolas , Müller Jans-Enno , Thankamma Ajithkumar , Mitra Dipayan , Cross Justin , Pietsch Torsten , Smith Colin , Solem Kristin , Devenney Irene , Garre Maria Luisa , Brisse Herve , Zimmermann Martin , Kortmann Rolf-Dieter , Alapetite Claire , Nicholson James
Published: December 2020

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 with histologically-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 EFS of 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 on radiological response criteria is of utmost importance to avoid over- and undertreatment of such patients and to pave the way for further treatment reduction in this group of patients.
HGG-01. ENTRECTINIB IN RECURRENT OR REFRACTORY SOLID TUMORS INCLUDING PRIMARY CNS TUMORS: UPDATED DATA IN CHILDREN AND ADOLESCENTS
Authors: Robinson Giles , Desai Ami , Basu Ellen , Foster Jennifer , Gauvain Karen , Sabnis Amit , Shusterman Suzanne , Macy Margaret , Mease Luke , Yoon Janet , Cash Thomas , Abdelbaki Mohamed , Nazemi Kellie , Pratilas Christine , Weiss Brian , Chohan Saibah , Cardenas Alison , Hutchinson Katherine , Bergthold Guillaume , Gajjar Amar
Published: December 2020

STARTRK-NG (phase 1/2) is evaluating entrectinib, a CNS-penetrant oral, TRK/ROS1/ALK tyrosine kinase inhibitor, in patients <21 years with recurrent/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) 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, GOPC-ROS1, ETV6-NTRK3, TPR-NTRK1, EEF1G-ROS1); 3 SD (BCR-NTRK2, ARHGEF2-NTRK1, KIF21B-NTRK1); 2 PD (PARP6-NTRK3, EML4-ALK); 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], KIF5B-ALK). 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, cough and 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-11. HIGH-GRADE GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS HIGHLIGHT HISTOMOLECULAR DIFFERENCES WITH THEIR ADULT AND PAEDIATRIC COUNTERPARTS
Authors: Roux Alexandre , Pallud Johan , Saffroy Raphaël , Edjlali-Goujon Myriam , Debily Marie-Anne , Boddaert Nathalie , Sanson Marc , Puget Stéphanie , Knafo Steven , Adam Clovis , Faillot Thierry , Cazals-Hatem Dominique , Mandonnet Emmanuel , Polivka Marc , Dorfmüller Georges , Dauta Aurélie , Desplanques Mathilde , Gareton Albane , Pages Mélanie , Tauziède-Espariat Arnault , Grill Jacques , Bourdeaut Franck , Doz François , Dhermain Frédéric , Mokhtari Karima , Chrétien Fabrice , Figarella-Branger Dominique , Varlet Pascale
Published: December 2020

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 adolescents and young adults (AYAs).

METHODS

We performed a multicentric retrospective study of 112 AYAs from adult and paediatric Ile-de-France 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 the 2016 WHO classification.

RESULTS

Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, 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 and 1p/19q co-deleted and the relative high frequency of “rare adult IDH mutations” (20%). H3G34-mutants (14%) represent the most specific subgroup 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 needed from paediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs.
HGG-17. HIGH-GRADE GLIOMA IN VERY YOUNG CHILDREN; A SINGLE-CENTER 11-YEAR-EXPERIENCE
Authors: El-ayadi Moatasem , Shawky Omar , Naguib Eman , Maher Eslam , Abdelaziz Amal , Ahmed Soha , Refaat Amal , von Bueren André O , Taha Hala , El-naggar Shahenda , El-beltagy Mohamed
Published: December 2020

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 for clinical, radiological and histopathological data, treatment received and survival 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 to older 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 the H3-mutation. RT seems crucial in the management of pHGG regardless of age subgroup.