bluuebunny/crossref_metadata_2025 huggingface dataset:
DIPG-64. Feasibility and early results of radiotherapy, concomitant nimotuzumab and vinorelbine and re-irradiation at progression, for newly diagnosed childhood and adolescence diffuse midline glioma (DMG)
Authors: Schiavello Elisabetta , Biassoni Veronica , Barretta Francesco , Gattuso Giovanna , Pecori Emilia , Gandola Lorenza , Boschetti Luna , Mastronuzzi Angela , Cacchione Antonella , Quaglietta Lucia , Milanaccio Claudia , Simonetti Fabio , Buttarelli Francesca Romana , Antonelli Manila , Massimino Maura
Published: June 2022

BACKGROUND: The purposes of this trial were evaluating the feasibility, response and PFS/OS of patients receiving upfront radiotherapy and reirradiation at progression with concomitant nimotuzumab/vinorelbine chemotherapy as the standard arm of the ongoing protocol for DIPG. METHODS: Patients aged 2-21 years with not-pretreated DMG (evidence of H3.3K27M mutation at immunohistochemistry) received vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 weekly for 12 weeks; thereafter every other week until tumor progression or for up to 2 years. Focal photons irradiation was delivered within the 3rd week after first nimotuzumab+vinorelbine administration with a total dose of 54 Gy in 1.8 Gy daily fractions. For local progression re-irradiation was proposed at 19.8 Gy; in case of dissemination craniospinal-irradiation at 36 Gy was adopted. MRI were blindly centrally reviewed at diagnosis and every 12 weeks thereafter. RESULTS: Aggregated preliminary results are available for 20 patients from 4 Italian centers: 12 males, median age 11 years (range 3-17). Median time of observation was 12.5 months; 8 had thalamic/basal ganglia disease, in 5 pons was involved (2 pontobulbar, 3 pontomesencephalic), 6 spinal, 2 cerebellar. 13 patients had only biopsy, the others partial or near-total resection.14 relapsed: 5 locally, 4 with dissemination, 5 with both; 12 died, one was lost at follow-up. Two patients received reirradiation, one of them was irradiated three times without evidence of radionecrosis, still alive at 26 months from diagnosis. Median EFS/OS were 8.3/10.2 months, respectively; EFS/OS at 1 year were 25.8/36.7%. Survival curves between spinal and cerebral locations showed no difference. Patients after partial/near-total resection vs biopsied seemed to have earlier relapses (P 0.017) with EFS at 6 months of 34.3/75.0% respectively. CONCLUSIONS: This is one of the first series of DMG homogeneously and prospectively treated; treatment was feasible. A potential role of reirradiation emerge as in DIPGs.
DDEL-03. The use of programmable valves as a vehicle for intrathecal chemotherapy delivery in infants with CNS tumors and hydrocephalus.
Authors: Dvir Rina , Rosenberg Tom , Elhasid Ronit , Levin Dror , Constantini Shlomi , Roth Jonathan
Published: June 2022

INTRODUCTION: Current chemotherapy protocols for treatment of embryonal brain tumors in infants recommend administration of intrathecal chemotherapy either by a lumbar tap or via an Ommaya reservoir. Children with concurrent hydrocephalus and shunts may have sub-therapeutic levels of chemotherapy in the CSF due to constant CSF drainage to extra-CNS compartments. We present our experience in delivery of chemotherapy to young children via programmable valves. RESULTS: A retrospective analysis of infants with CNS malignancies and hydrocephalus treated with a shunt and a programmable valve (CERTAS™ Plus Programmable Valves - Integra Life Sciences) was conducted. Five infants 1.1-3 years of age (mean 2) were included. Pathologies included atypical teratoid rhabdoid tumor (ATRT N=2), medulloblastoma (N=2), and metastatic rhabdomyosarcoma(N=1). Intrathecal injections were conducted in an outpatient setting unless hospitalization was required for other reasons. Only one child required sedation due to noncompliance. A total of 61 chemotherapeutic administrations were performed directly through the valve while set on an extremely high opening pressure for several hours( 35 with hydrocortisone and cytarabine, 26 with topotecan). There were no infections, leaks or major complications. One child required a wound revision due to exposure of the proximal catheter related to extremely thin skin, one child developed somnolence and fever which were not related to a shunt malfunction or infection, and one child had clinical and radiological shunt over-drainage solved by increasing of valve settings. CONCLUSIONS: Programmable ventriculoperitoneal valves appear to a safe method for delivery of chemotherapy in infants with malignant CNS tumors .This technique may potentially have an added value for children with concurrent shunts, and may also obviate the need for an additional ventricular access device .
EPCT-09. ROVER: A phase 1/2 study of avapritinib in pediatric patients with solid tumors dependent on KIT or PDGFRA signaling
Authors: Chi Susan , Hsieh Antony , Foley Megan , Shi Hongliang , Swamy Preethi , Rodstrom Jill , Rudoltz Marc
Published: June 2022

Prognosis for pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors is poor. KIT alterations are common in germ cell tumors and high-grade glioma (HGG); platelet-derived growth factor receptor alpha (PDGFRA) alterations are common in sarcoma and HGG. H3K27M-mutant gliomas are dependent on PDGFRA signaling. No KIT/PDGFRA targeted therapies are currently approved for pediatric patients with R/R solid or CNS tumors, or H3K27M-mutant gliomas. Selective KIT and PDGFRA inhibitor avapritinib demonstrated potent activity against KIT activation-loop (exon 17), juxtamembrane (exon 11), and extracellular-domain (exon 9) mutants (IC50<2 nM), and PDGFRA activation-loop (D842V) mutants (IC50=0.24 nM); cellular IC50 of PDGFRA wild-type was 95 nM. CNS penetration in preclinical models (steady-state brain-to-plasma ratios ranging from 0.74–1.00) has demonstrated potential for CNS antitumor activity. Avapritinib is approved in the USA to treat adults with unresectable/metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including D842V), and adults with advanced systemic mastocytosis. In the EU, avapritinib is approved for adults with unresectable/metastatic GIST harboring a PDGFRA D842V mutation. Objectives of ROVER 2-part phase 1/2, multicenter, open-label study (NCT04773782) are avapritinib safety, preliminary efficacy, and pharmacokinetics in pediatric patients aged 2 to <18 years with solid R/R tumors dependent on KIT or PDGFRA signaling, including H3K27M-mutant gliomas, and no alternative treatment options. Part 1 will enroll ≥12 patients; primary endpoint is confirmed age and body surface area physiologically based pharmacokinetic modeling predicted dose to provide equivalent exposure to the 300 mg adult avapritinib dose. Part 2 will enroll ≥25 patients at the recommended avapritinib dose from Part 1; the primary endpoint is objective response rate. Avapritinib once-daily will be administered in continuous 28-day cycles. Enrollment in this study is planned at 26 sites in 10 countries, including centers in North America, Europe, and Asia/Pacific.
EPEN-13. Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology
Authors: Gödicke Swenja , Ehlert Max , Obrecht Denise , Rutkowski Stefan , Schüller Ulrich
Published: June 2022

PFA ependymomas are aggressive posterior fossa tumors that mainly effect children and have a poor prognosis despite intensive therapy. Histopathology reveals glial neoplasms that usually show perivascular pseudorosettes throughout the tumor. Tumor cell density may vary within a tumor and sometimes shows well demarcated nodules of extremely densely packed tumor cells within surrounding loose glial tissue harboring diffusely distributed tumor cells. To determine potential molecular differences in such areas and to understand the clinical meaning, we analysed 70 clinically well-annotated PFA samples and 9 corresponding relapse samples. Areas of low and high cell density were digitally identified with a cut-off of 8,500 cells/mm². Global DNA methylation and copy-number profiling was performed in 52/79 cases for the entire tumor area of the sample and in 15/79 cases for the cell-dense and less cell-dense regions, separately. Fluorescence-in-situ-hybridization was performed for 20 cases, and scRNA-Seq data were analysed for 12 cases. The proportion of cell-dense areas proved to be highly variable on a continuum ranging from 0 % to 100 % of the tumor area. It was significantly higher in relapses in comparison to the respective primary tumors (p=0.036). Also, cell-dense areas displayed a significantly higher proportion of proliferating tumor cells (p<0.01). Global DNA methylation was similar, but not identical in different tumor areas. In 6/15 cases, the PFA subtype changed as determined by the current version of the brain tumor classfier (v12, www.molecularneuropathology.org). Chromosomal changes at 1q and 6q were only detectable in cell-dense areas in 5/12 and in 3/12 cases, respectively. Finally, scRNA-Seq data confirmed a widespread heterogeneity regarding 1q and 6q changes in PFA ependymoma cells. These data suggest that PFA ependymoma habor a previously unrecognized heterogeneity that has to be accounted for when selecting material for the analysis of clinically relevant DNA methylation profiles or copy number changes.
EPEN-14. A Phase 1, Safety and Dose Escalation Study of BXQ-350 in Patients with Advanced Solid Malignancies Demonstrates that BXQ-350 is Well Tolerated and Shows Signs of Potential Clinical Activity in Ependymoma Patients
Authors: Rixe Olivier , Morris John , Wesolowski Robert , Yilmaz Emrullah , Villano John , Muller Carolyn , Wise-Draper Trisha , Puduvalli Vinay , Curry III Richard , Takigiku Ray , Tapolsky Gilles
Published: June 2022

The significance of a dysregulated sphingolipid metabolism in cancer, including brain tumors, has been demonstrated and several enzymes involved in sphingolipid metabolism are being investigated as novel therapeutic targets for adult and pediatric brain cancers. Saposin C (Sphingolipid Activator PrO[S]etIN) is a human protein encoded by the Psap gene and is an allosteric activator of several enzymes involved in sphingolipid/ceramide metabolism. BXQ-350 is a nanovesicle of Saposin C that has broad anticancer activity, selectively inducing apoptosis of cancer cells by lowering Sphingosine-1-Phosphate and increasing ceramides concentrations and inducing an anti-tumoral immune response. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in cancer patients with advanced solid malignancies including brain tumors (NCT02859857). The primary objective of this single agent study was to describe the safety profile and to determine the maximum tolerated dose, or the biological effective dose, of BXQ-350 administered intravenously at escalating doses from 0.7 mg/kg up to 2.4 mg/kg. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetic parameters, efficacy profile and potential biomarkers. This trial was performed at four US sites. Results indicate that BXQ-350 was safe and well-tolerated as no DLT was observed and an MTD was not reached. RANO or RECIST 1.1 criteria were used to evaluate tumor response. Analysis of plasma samples suggests that BXQ-350 modulates sphingolipid metabolism and impacts the immune system positively. Furthermore, potential signs of single agent activity were observed across tumor types, including in two ependymomas for which results will be presented.
EPEN-18. Oncogenic 3D genome conformations identify novel therapeutic targets in ependymoma
Authors: Okonechnikov Konstantin , Camgöz Aylin , Park Donglim Esther , Chapman Owen , Hübner Jens-Martin , Jenseit Anne , Chakraborty Abhijit , Pagadala Meghana , Bump Rosalind , Chandran Sahaana , Kraft Katherina , Hidalgo Rocio Acuna , Reid Derek , Juarez Edwin F , Robinson James T , Pajtler Kristian W , Milde Till , Coufal Nicole , Levy Michael , Malicki Denise , Nahas Shareef , Snuderl Matija , Crawford John , Wechsler-Reya Robert , Mundlos Stefan , Schmitt Anthony , Carter Hannah , Michealraj Kulandaimanuvel Antony , Kumar Sachin A , Taylor Michael D , Rich Jeremy , Mesirov Jill , Pfister Stefan P , Ay Ferhat , Dixon Jesse , Kool Marcel , Chavez Lukas
Published: June 2022

Ependymoma (EPN) is an aggressive pediatric tumor that occurs throughout the central nervous system. The two most aggressive molecular subgroups of EPN are the supratentorial ZFTA-fusion associated group (ST-EPN-ZFTA) and the posterior fossa group A (PF-EPN-A). Although the molecular characteristics underlying the tumorigenesis of these subgroups have been extensively studied, these tumors remain difficult to treat. Hence, innovative therapeutic approaches are urgently needed. Here, we used genome-wide chromosome conformation capture (Hi-C), complemented with CTCF (insulators) and H3K27ac (active enhancers) ChIP-seq, as well as gene expression and whole-genome DNA methylation profiling in primary and relapsed EPN tumors and cell lines, to identify chromosomal rearrangements and regulatory mechanisms underlying aberrant expression of genes that are essential for EPN tumorigenesis. By integrating these heterogenous data types, we have observed the formation of new topologically associated domains (‘neo-TADs’) caused by intra- and inter-chromosomal structural variants in both tumors. In addition, we observed 3D chromatin complexes of regulatory elements, and the replacement of CTCF insulators by DNA hyper-methylation in PF-EPN-A tumors. These tumor-specific 3D genome conformations can be associated with the transcriptional upregulation of nearby genes. Through inhibition experiments we validated that these newly identified genes, including RCOR2, ITGA6, LAMC1, and ARL4C, are highly essential for the survival of patient-derived EPN cell lines in a disease subgroup-specific manner. Thus, our study identifies novel potential therapeutic vulnerabilities in EPN and extends our ability to reveal tumor-dependency genes and pathways by oncogenic 3D genome conformations even in tumors that lack known genetic alterations.
EPEN-31. Developmental and Oncogenic Transcription Factor Circuits as Dependencies in Ependymoma
Authors: Mack Stephen
Published: June 2022

Brain tumors are the most common cause of cancer death in children. ZFTA-RELA gene fusion is one the most potent drivers of cancer and is sufficient to induce tumors when expressed during brain development. ZFTA-RELA (denoted ZRFUS) fusion is the most frequent events that occurs in an aggressive childhood brain tumor called ependymoma (> 70% of cases). ZFTA recruits RELA to novel DNA binding sites and is necessary to activate ependymoma oncogene transcription. There are currently no targetable treatments for ependymoma, thus studying the mechanisms that regulate ZRFUS oncogenic programs may yield opportunities to develop effective therapies. To study proteins that regulate gene expression programs in brain cancer, the Mack lab and others have comprehensively characterized the active chromatin landscapes of several adult and pediatric brain cancers. This genome-wide analysis has identified highly active TFs, termed core regulatory circuit (CRC) TFs that govern gene expression programs such as MYC, GLI2, SOX2, and OLIG1/2, previously described in brain tumors such as glioblastoma and medulloblastoma. Critically, a glial cell fate specification TF, SOX9, showed the highest levels of activity in ependymoma. A functional RNA interference screen of CRC TFs prioritized SOX9 as the top cancer dependency gene required for ZRFUS ependymoma cell proliferation. To study ZRFUS ependymoma, we developed one of the first genetic mouse models of the disease, and show in preliminary data, that SOX9 knockout abolishes tumor initiation. Surprisingly, SOX9 KO has no impact on tumor initiation in an aggressive glioma model, suggesting tumor-specific contributions of SOX9. This concept is supported by our data that shows SOX9 co-recruitment to a vast majority of ZRFUS binding sites in the genome. Our data supports that SOX9 regulates ZFTA-RELA target cistrome; presenting a potential pathway that may be explored for therapeutic benefit.
ETMR-03. Intra- and extra-cranial BCOR-ITD tumours are separate entities within the BCOR-rearranged family
Authors: Bouchoucha Yassine , Tauziède-Espariat Arnault , Gauthier Arnaud , Guillemot Delphine , Bochaton Dorian , Vibert Julien , Carton Matthieur , Watson Sarah , Grossetete Sandrine , Quignot Chloé , Orbach Daniel , Corradini Nadège , Schleiermacher Gudrun , Bourdeaut Franck , Simbozel Marie , Dufour Christelle , Minard Veronique , Brahmi Mehdi , Tirode Franck , Pissaloux Daniel , Karanian Marie , Machet Marie-Christine , Masliah-Planchon Julien , Delattre Olivier , Cardoen Liesbeth , Pierron Gaelle , Doz Francois
Published: June 2022

BCOR-ITD tumours form an emerging family of aggressive entities with an internal tandem duplication (ITD) in the last exon of the BCOR gene. The family includes cerebral tumours, termed central nervous system BCOR-ITD (CNS BCOR-ITD), and sarcomatous types described in the kidney as clear cell sarcoma of the kidney (CCSK), in the endometrium as high-grade endometrial stromal sarcoma (HG-ESS), in bone, and in soft tissue as undifferentiated round cell sarcoma (URCS) or primitive myxoid mesenchymal tumour of infancy (PMMTI). Based on a series of 33 retrospective cases, including 10 CNS BCOR-ITD and 23 BCOR-ITD sarcomas, we interrogated the homogeneity of the entity regarding clinical, radiological and histopathological findings, and molecular signatures. Whole transcriptomic sequencing and DNA methylation profiling were used for unsupervised clustering. Histopathological review revealed marked differences between CNS BCOR-ITD and BCOR-ITD sarcomas. These two groups were consistently segregated by unsupervised clustering of expression (n=22) and DNA methylation (n=21) data. Proximity between the two groups may result from common somatic changes within key pathways directly related to the novel activity of the ITD itself. Conversely, comparison of gene signatures with single-cell RNAseq atlases suggests that the distinction between BCOR-ITD sarcomas and CNS BCOR-ITD may result from differences in cells of origin.
ETMR-07. DNA methylation profiling of a series of rare CNS embryonal tumors in children: diagnostic and clinical impact
Authors: Dell’Anna Vito Andrea , Vallero Stefano Gabriele , Fagioli Franca , Peretta Paola , Cassoni Paola , Bertero Luca
Published: June 2022

BACKGROUND: CNS embryonal tumors are a clinically and biologically heterogeneous group of tumors, more frequently arising in very young children. In the last few years, tumor classification through DNA methylation profiling has been demonstrated to be a powerful diagnostic tool which could be especially informative in this setting. METHODS: We reviewed original diagnosis and molecular profile of childhood CNS embryonal tumors other than medulloblastoma or AT/RT from a retrospective single-center cohort. Sixteen FFPE tissue samples from 14 unique patients (diagnosed from 1996 to 2017) were analyzed using DNA methylation arrays and matched with the Heidelberg classifier. Then, cohort characteristics and outcome were re-evaluated according to the results of the array. RESULTS: Median age at diagnosis was 2.7 years; there was no statistically significant difference between ETMRs and CNS embryonal tumors, NOS. Male to female ratio was 4:3. Median OS was 17,5 months (IQR 10.2-103.3 months) and ETMRs presented the worst outcome. Methylation profiling matched with an adequate score in 50% of samples (8/16). DNA methylation profile was consistent with ETMR in two samples but only one showed amplification of C19MC. Seven CNS embryonal tumors, NOS were properly reclassified as supratentorial ependymoma and diffuse pediatric-type HGG (4 and 1) or better defined as CNS neuroblastoma, FOXR2-altered (2). Methylation profiling added a unique diagnostic contribution in 64.3% of all cases (9/14). After the integration of methylation array results, survival markedly differed according to the novel integrated diagnoses; supratentorial ependymomas presented the longest median OS while no patients refined as CNS neuroblastoma or HGG survived. CONCLUSIONS: Our study confirmed that DNA methylation profiling provides relevant information for the classification of rare neoplasms like CNS embryonal tumors. Especially for selected cases with ambiguous histology, implementation of this tool should be considered to improve diagnostic precision and tailor patients’ management.
ETMR-10. Retrospective molecular re-evaluation of CNS PNETs; a population-based study
Authors: Schepke Elizabeth , Löfgren Maja , Pietsch Torsten , Kling Teresia , Nordborg Claes , Bontell Thomas Olsson , Holm Stefan , Öberg Anders , Nyman Per , Eliasson-Hofvander Marie , Sabel Magnus , Lannering Birgitta , Carén Helena
Published: June 2022

BACKGROUND: The heterogeneous group of tumors, primitive neuro-ectodermal tumors of the central nervous system (CNS-PNETs), is a group of rare childhood embryonal tumors associated with a poor prognosis. In recent years, molecular analyzes have shown that CNS-PNETs consist of high-grade gliomas (HGG), ependymomas, different embryonal entities like atypical teratoid /rhabdoid tumors (AT/RT), CNS neuroblastoma FOXR2 and embryonal tumor with multi-layered rosettes (ETMR). Each of these tumor types is unusual and long-term clinical follow-up data are sparse. METHODS: We retrospectively re-evaluated all children (0-18 years old) diagnosed with a CNS-PNET in Sweden during 1984-2015. In total, 88 supratentorial CNS-PNETs were identified in the Swedish Childhood Cancer Registry and from these formalin-fixed paraffin-embedded tumor material was available for 69 patients. All tumors were reviewed histopathologically by an experienced neuropathologist and were analyzed using genome-wide DNA methylation profiling and classified by the MNP brain tumor classifier. RESULTS: The largest entities, after re-evaluation, were HGG (30%), CNS NB-FOXR2 (12%), AT/RT (10%) and ETMR (8%). Some tumors were difficult to classify and will be further evaluated molecularly. Some examples: Best treatment results were seen for patients with CNS-NB FOXR2 (5-year PFS: 100%) where all patients had received craniospinal radiotherapy (CSI). Patients with ETMR were all very young and survival data show early progression and poor survival (5-year OS 34%). CONCLUSIONS: Although the patient material is relatively small, it is population-based with long follow-up times. Our findings are in line with other studies and shows that CSI is important for cure for CNS-NB FOXR2 and that intensive multi-modal therapies needs to be evaluated in up-front studies for these rare embryonal tumors.
GCT-02. Imaging response assessment for Central Nervous System Germ Cell Tumours: consensus recommendations from the European Society for Paediatric Oncology Brain Tumour Group (SIOPE-BTG) and North American Children’s Oncology Group (COG)
Authors: Morana Giovanni , Shaw Dennis , MacDonald Shannon , Alapetite Claire , Ajithkumar Thankamma , Bhatia Aashim , Brisse Hervé , Jaimes Camilo , Czech Thomas , Dhall Girish , Fangusaro Jason , Faure-Conter Cecile , Fouladi Maryam , Hargrave Darren , Harreld Julie , Mitra Dipayan , Nicholson James , Souweidane Mark , Timmermann Beate , Calaminus Gabriele , Bartels Ute , Bison Brigitte , Murray Matthew
Published: June 2022

BACKGROUND: Central nervous system (CNS) germ cell tumours (GCT) comprise a heterogeneous and relatively rare group of neoplasms. Improving the ability to conduct international clinical trials for CNS GCT requires use of homogeneous, common objective disease assessments and standardised response criteria. Currently, different criteria are employed between European and North American protocols for assessing radiological disease response. METHODS: An international working group of the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group (BTG) and North American Children’s Oncology Group (COG) was therefore established to develop consensus recommendations for imaging response assessment for CNS GCT. The working group first reviewed existing literature and current practices and identified major challenges regarding imaging assessment. RESULTS: New clinical imaging standards were defined for the most common sites of intracranial GCT disease (suprasellar/pineal/bifocal), as well as for definition of loco-regional extension. In particular, clear standards were highlighted for definition of partial response (PR) and complete response (CR) to induction chemotherapy at different sites. Furthermore, growing teratoma syndrome (GTS) was clearly defined [apparent radiological increase in non-germinomatous GCT (NGGCT) size during induction chemotherapy despite normalising/normalised AFP/HCG markers – requiring surgery], to avoid such potential cases being classified as progressive disease (PD). CONCLUSION: This consensus will allow more consistent prospective neuroradiological evaluation of response to therapy for patients with CNS GCT and facilitate direct comparison of treatment outcomes across international studies. Ultimately, it may allow international trials to be developed and undertaken across a larger group of collaborating nations, which will be essential to answer many of the remaining questions for this rare but diverse group of tumours.
GCT-04. Pattern of Treatment Failures in Central Nervous System Non-Germinomatous Germ Cell Tumors (CNS-NGGCT): A Pooled Analysis of Clinical Trials
Authors: Fonseca Adriana , Faure-Conter Cecile , Murray Matthew , Fangusaro Jason , Bailey Shivani , Goldman Stewart , Khatua Soumen , Frapaz Didier , Calaminus Gabriele , Dhall Girish , Nicholson James , Bouffet Eric , Bartels Ute
Published: June 2022

BACKGROUND: Central Nervous System- Non-Germinomatous Germ Cell Tumors (CNS-NGGCT) are rare but curable tumors. Due to their rarity, treatment failures remain a poorly characterized disease with unfavorable outcomes. In this study, we sought to characterize the treatment failures in a large cohort of prospectively treated patients. METHODS: European and North American clinical trials for patients with CNS-NGGCT (SIOP-GCT96, SFOP-TGM TC 90/92, COG-ACNS0122 and COG-ACNS1123) were pooled for analysis. Additionally, patients included and treated in the UK and France national registries under strict protocol-guidelines were included as an independent, non-overlapping cohort. RESULTS: A total of 118 patients experienced a treatment failure. Twenty-four patients had progressive disease during therapy and additional eleven patients were diagnosed with growing teratoma syndrome (GTS). Patients with GTS are significantly younger and present with local failures and negative tumor markers. Eighty-three individuals experienced disease relapses after treatment ended. Patients’ metastatic relapses presented significantly earlier than local relapses and were associated with tumor marker elevation (OR: 4.39; p=0.026). In our analysis, focal or whole ventricular (WVI) radiation therapy was not associated with an increased risk of metastatic relapses. CONCLUSIONS: Herein, we present the largest pooled dataset of prospectively treated patients with relapsed CNS-NGGCT. Our study identified younger age and negative tumor markers to be characteristic of GTS. Additionally, we elucidated that metastatic relapses occur earlier than local relapses, are associated with elevated tumor markers, and are not associated with the field of radiation therapy. These findings are of utmost importance for the planning of future clinical trials and the implementation of surveillance strategies in these patients.
GCT-08. Patients with Metastatic Central Nervous System Germinoma Involving the Basal Ganglia and Thalami, a Case Series
Authors: Abu-Arja Mohammad , Graham Richard , Cappellano Andrea , Finlay Jonathan , Gajjar Ammar , Lucas John , Tinkle Christopher , Allen Jeffrey , Abdelbaki Mohamed
Published: June 2022

BACKGROUND: Central nervous system (CNS) germinomas are commonly located in the suprasellar and/or pineal regions. Current treatment strategies include irradiation (RT) alone or chemotherapy with RT to reduce the dose and field of RT. However, given their rarity and poorly defined imaging characteristics, germinomas originating in the basal ganglia/thalami (BGTG) have proven challenging to treat. We present a case series of six patients with metastatic BGTG, given the paucity of published research on patients with metastatic CNS BGTG. METHODS: A retrospective multi-institutional review was performed across four institutions in two countries. RESULTS: Two patients were females, and four were males. The median age at presentation was 14.9 years. Biopsies were performed in all patients except for one patient who underwent subtotal surgical resection of her primary tumor. Three patients received RT only, while the remaining three received chemotherapy with RT. Carboplatin and etoposide were used in all three patients who received chemotherapy. All six patients received craniospinal irradiation (CSI). For patients who received RT only, the CSI dose ranged between (24 – 27.2 Gy) with a total dose to the primary site ranging between (36 – 40 Gy). For patients who received chemotherapy, one patient received 36 Gy with a total dose of 54 Gy to the primary site. The second patient received 24 Gy with a total dose of 40 Gy to the primary site. The CSI dose was not available for the third patient. All patients remain alive with a median event-free survival (EFS) and overall survival (OS) of 49 months (range: 14.3 – 168 months). CONCLUSION: In our series, patients with metastatic CNS BGTG treated with CSI with or without chemotherapy had excellent outcomes. Future larger studies are needed to compare the outcomes between CSI only and chemotherapy with low-dose CSI among patients with metastatic CNS BGTG.
GCT-16. Management of Patients with Metastatic Central Nervous System (CNS) Germinoma; A Literature Review
Authors: Abu-Arja Mohammad , Shatara Margaret , Abdelbaki Mohamed
Published: June 2022

BACKGROUND: Outcomes of patients with primary metastatic CNS Germinoma are excellent. There is no global consensus over the optimal irradiation doses and fields to reduce long-term radiotherapy side effects. Our literature review explores the different treatment modalities utilized for patients with metastatic CNS germinoma. METHODS: A literature review of studies that included patients with primary metastatic CNS germinoma via PubMed database. RESULTS: Sixty-eight patients (male: 48, female: 13, not specified: 7) were identified. At presentation, the median age was 14.4 years (range: 1.5–47 years). Primary tumor location included the following: pineal (n=15), suprasellar (n=11), bifocal (suprasellar and pineal) (n=21), other (n=9), not specified (n=12). Metastasis sites included the following: multifocal intracranial with/without ventricular metastasis (n=18), ventricular metastasis only (n=21), spinal metastasis only (n=8), CSF cytology dissemination only (n=3), and not specified (n=18). Seventeen patients received radiotherapy only, and 51 received radio-chemotherapy. Radiotherapy modalities included the following: craniospinal irradiation (n=36) with a mean whole-brain dose of 23.3 Gy (range:10.8-40.5 Gy) and spinal dose of 21.6 Gy (range: 10.8 – 30.6 Gy), whole-brain irradiation (n=13) with a mean dose of 24.2 Gy (range: 18 - 40 Gy), whole ventricular irradiation (n=16) with a mean dose of 24.7 Gy (range: 23.4 – 30 Gy), Focal irradiation only (n=1) with a dose of 40 Gy, and not specified (n=2). Four patients died of disease progression or relapse. Two patients were alive with relapse/residual disease. Sixty-two patients were alive with no evidence of disease with a mean follow of 77 months (range: 10.3 – 256 months). Further analysis is underway and will be presented at the meeting. CONCLUSION: The role of neoadjuvant chemotherapy in reducing the dose and field of radiation therapy remains unclear. Further analysis is pending which may highlight the role of neoadjuvant chemotherapy in managing patients with metastatic germinoma.
GCT-18. Endoscopic third ventriculostomy (ETV) and tumor biopsy are not associated with relapse rate or patterns in primary central nervous system (CNS) germ cell tumor (GCT)
Authors: Yan Rachel , Lin Tong , MacDonald Shannon , Carnevale Joseph , Bhatia Aashim , Shaw Dennis , Murphy Erin , Leary Sarah , Bartels Ute , Khatua Soumen , Fouladi Maryam , Gajjar Amar , Dhall Girish , Fangusaro Jason , Onar-Thomas Arzu , Souweidane Mark
Published: June 2022

BACKGROUND: ETV and tumor biopsy are central to the surgical management of children with primary CNS GCT. An ETV creates a communication between the intraventricular compartment and the subarachnoid spaces and decompartmentalizes the ventricular system. “Tumor spill” or shedding may result from surgical interventions, such as biopsy. ETV with simultaneous biopsy may impart a greater tendency for dissemination and possible distant relapse. This is a concern in CNS GCT given the attempts of irradiation field and dose reduction following chemotherapy. METHODS: We performed a retrospective review of the prospective database for the Children’s Oncology Group (COG) ACNS1123 study. Possible associations were explored among ETV, endoscopic biopsy, and combined ETV+biopsy with relapse, distant relapse, progression free survival (PFS), and time to distant relapse. RESULTS: Among 244 eligible patients, 97 ETV+/-biopsies were performed, and 30 relapses occurred. There were no associations among ETV and/or biopsy with relapse (Cochran-Mantel-Haenszel [CMH] test, with histology (germinoma vs. nongerminomatous germ cell tumor (NGGCT)) as stratification variable: ETV: p=0.3167, biopsy: p=0.3375, combined: p=0.3066), distant relapse (CMH test, ETV: p=0.4631, ETV+biopsy: p=0.6795), PFS (log-rank test, ETV: NGGCT p=0.1632, germinoma p=0.9288; biopsy: NGGCT p=0.1682, germinoma p=0.9701; ETV+Biopsy: NGGCT p=0.1306, germinoma p=0.7758), or time to distant relapse with death/local relapse as competing risk (Gray’s test, ETV: NGGCT p=0.5694, germinoma p=0.2327; biopsy: NGGCT p=0.3505, germinoma p=0.5747; ETV+Biopsy: NGGCT p=0.3988, germinoma p=0.6839). CONCLUSIONS: Based on a secondary analysis of prospective data from the ACNS1123 trial, ETV and biopsy did not impart a greater likelihood of relapse in children with primary CNS GCT treated with combined chemotherapy and irradiation. However, three tract recurrences did occur (all germinoma), suggesting that they may affect pattern of relapse. Current and future prospective trials should continue to explore associations among these variables and relapse, including patterns of relapse.
HGG-04. Intramedullary spinal high grade glioma with ALK fusion and excellent response to targeted treatment with alectinib: case report
Authors: Dvir Rina , Ringel Amit , Elhasid Ronit , Constantini Shlomi , Roth Jonathan
Published: June 2022

INTRODUCTION: Intramedullary spinal cord high grade gliomas are rare pediatric tumors , with a grim prognosis. Current therapeutical strategies include a surgical resection if feasible, and radiotherapy. Additional treatments with various chemotherapy agents have had a minor effect and did not change the course of the disease. New molecular targets are a source of hope. Recent molecular evidence regarding high grade infantile hemispheric gliomas describe specific tyrosine kinase receptor fusions or mutations in ALK, ROS, NTRK and MET domains which may lead to therapeutical targets. There is no data regarding these molecular changes in infantile intramedullary high grade gliomas. We present a two year old girl with a cervical high grade glioma with an ALK mutation which received targeted therapy. CASE REPORT: A two year old girl presented with progressive torticollis and hemiparesis. An intramedullary cervical tumor with ill -defined borders was diagnosed. A limited partial excision was performed and the pathological diagnosis was high grade glioma. Within weeks she developed progressive clinical and radiological deterioration. Molecular studies (Oncomine) revealed an ALK fusion (KIF5B) which was confirmed by immunohistochemistry. Treatment with ALK inhibitor alectinib at 150mg daily was initiated. Torticollis resolved within a week, and MRI after 3 months showed outstanding tumor shrinkage with a small residual mass. There were no adverse events to treatment. DISCUSSION: ALK fusion positive high grade glioma has recently been recognized in infants with hemispheric tumors, and a preliminary recent case report demonstrated excellent response to ALK inhibitors. Intramedullary spinal cord high grade gliomas are rare and harbor poor prognosis. This is the first case of ALK fusion glioma of the spine with excellent preliminary response to alectinib. The duration of treatment and long term prognosis is unknown. Molecular investigations can change the approach to pediatric rare CNS tumors.
HGG-08. Lorlatinib for the treatment of ALK fusion positive infant high grade glioma
Authors: Greenwell Alyssa , Altinok Deniz , Marupudi Neena , Kupsky William , Gorsi Hamza
Published: June 2022

BACKGROUND: High grade gliomas (HGG) are very rare in the infant age group with approximately 800 cases diagnosed in the USA and Europe each year. Histologically, HGG in infants resemble HGG in older children and adults but have distinct molecular features like ALK, NTRK, MET and ROS1 fusions. HGG in infants have superior outcomes compared to older age groups (5-year overall survival >50%) when treated with a radiation sparing regimen. Here we present the unique treatment course for an infant with ALK fusion positive HGG, including molecularly targeted therapy. CASE DESCRIPTION: A 3-month-old African-American female presented with acute onset vomiting, right facial droop and focal seizures. MRI of the brain revealed a right frontal intraparenchymal mass. Upfront gross total resection (GTR) was performed and histologic diagnosis of epithelioid glioblastoma was made. The molecular analysis of the tumor showed ZNF397-ALK fusion. The patient was treated with a radiation sparing regimen consisting of Carboplatin 8 mg/kg x 2 days and Etoposide 3 mg/kg x 3 days for 6 cycles. The patient tolerated the chemotherapy and had no evidence of disease recurrence at the completion of chemotherapy. However, 8 months after completion of therapy, she had a localized relapse and underwent a second GTR. Repeat molecular analysis confirmed the presence of ZNF 397-ALK fusion. She was started on Lorlatinib at 95 mg/m2/day once a day. She continued on the medication for 15 months and had no evidence of disease at the end of 15 months. During the course of her treatment, she had excessive weight gain (CTCAE grade-3) despite dose reduction. CONCLUSION: Infant high grade gliomas have a high prevalence of gene fusions including ALK fusions. This case shows that these fusions may be amenable to molecularly targeted treatments and should be studied in prospective clinical trials.
HGG-16. Final analysis of the HIT-HGG-2007 trial (ISRCTN19852453): Significant survival benefit for pontine and non-pontine pediatric high-grade gliomas in comparison to previous HIT-GBM-C/-D trials.
Authors: von Bueren Andrè O , Kwiecien Robert , Gielen Gerrit H , Benesch Martin , Perwein Thomas , Nussbaumer Gunther , Sturm Dominik , Jones David T W , Pfister Stefan M , Eyrich Matthias , Rutkowski Stefan , Fleischhack Gudrun , von Buiren Miriam , Karremann Michael , Kortmann Rolf-Dieter , Hagel Christian , Calaminus Gabriele , Faldum Andreas , Bison Brigitte , Pietsch Torsten , Hoffmann Marion , Kramm Christof M
Published: June 2022

The aim of the HIT-HGG-2007 trial (ISRCTN19852453) was to demonstrate therapeutic non-inferiority of temozolomide radiochemotherapy for pediatric patients (3-18 years) with high-grade gliomas (pedHGG) in comparison to the cisplatinum-based radiochemotherapy of the two previous clinical trials HIT-GBM-C/-D. Between 06/2009 and 12/2016, 456 patients were enrolled at 79 centers in Germany, Austria, and Switzerland (n=18 dropouts, remaining patients for confirmatory analysis: n=438). 438 patients from HIT-GBM-C/-D served as historical control. All pedHGG diagnoses had been confirmed by central neuroradiological and neuropathological review. Primary objective was achieved since non-inferiority of HIT-HGG-2007 in comparison to HIT-GBM-C/-D as indicated by 6 months event-free survival (EFS) was statistically confirmed (p=0.0125). Statistical survival analyses even revealed a better overall survival (OS) and EFS for HIT-HGG-2007 patients in comparison to their HIT-GBM-C/-D counterparts (EFS: p<0.0001; OS: p=0.0328). While EFS subgroup analyses for pontine and non-pontine pedHGG also showed a better survival of HIT-HGG-2007 patients (median EFS pontine pedHGG: 8.2 (n=152; confidence interval (CI): 7.6-9.4) versus 6.2 (n=170; CI: 5.5-6.9) months, p=0.0079; median EFS non-pontine pedHGG: 10.7 (n=276; CI: 9.6-12.4) versus 7.4 (n=267; CI: 6.4-9.2) months, p<0.0001), OS was only improved in HIT-HGG-2007 patients with non-pontine pedHGG (median OS non-pontine pedHGG: 19.3 (CI: 16.8-23.3) versus 16.2 (CI: 14.2-19.1) months; p=0.0181) but not with pontine pedHGG (median OS pontine pedHGG: 11.4 months versus 11.3 months, p=0.4021) Toxicity profile of HIT-HGG-2007 seemed very favorable with most CTCAE (common toxicity criteria adverse event) ≥ grade 3 as hematological toxicity, hepatotoxicity, and neurotoxicity. Less toxicity was observed during concomitant radiochemotherapy in comparison to HIT-GBM-C/-D. Further subgroup survival analyses as well as the assessment of the impact of MGMT promoter methylation are ongoing. In conclusion, our data show non-inferiority of the HIT-HGG-2007 trial with increased survival and less toxicity when compared with previous trials HIT-GBM-C/-D.
HGG-30. H3.3 G34R/V mutations disrupt H3.3 mitotic phosphorylation leading to high-grade glioma formation through the induction of chromosomal instability
Authors: Day Charles , Grigore Florina , Hakkim Faruck , Langfald Alyssa , Hinchcliffe Edward , Robinson James
Published: June 2022

Pediatric high-grade gliomas (pHGG) are among the most lethal of all human cancers. Histone H3.3 G34R/V mutations are an early event in these tumors and show reduced H3.3 K36 trimethylation; implicating epigenetic dysregulation in tumorigenesis. Here we present evidence that H3.3 G34R/V mutations promote tumor formation via the induction of chromosomal instability (CIN). Pericentromeric H3.3 is phosphorylated at S31 by Chk1 during mitosis. We observed that the H3.3 G34R mutation reduced Chk1 phosphorylation of H3.3 S31 by >90% in vitro. Furthermore, H3.3 G34 mutant cells have reduced pericentromeric H3.3 S31 phosphorylation in mitosis compared to WT H3.3 cell lines. H3.3 G34 mutant pHGG cells also have significantly elevated rates of CIN as compared to H3.3 WT cells. Overexpression of H3.3 G34R, G34V or non-phosphorylatable S31A in H3.3 WT, diploid cells caused a significant increase in CIN, but H3.3 K36M overexpression had no effect on chromosome segregation. These studies demonstrate that H3.3 G34R/V mutations are sufficient to induce CIN in normal, diploid cells. To determine if this process contributes to tumorigenesis, we used RCAS Nestin-TVA mice to overexpress H3.3 WT, G34R, or S31A – P2A-linked to PDGFB in glial precursor cells of newborn mice. Over 100 days, S31A and G34R mice had drastically reduced survival (averaging 77, 81, and 100 days for S31A, G34R, and WT). Furthermore, most G34R and S31A mice developed HGG, while H3.3 WT mice remained tumor-free. Our work implicates CIN as a driver of H3.3 G34 mutant pHGG formation.
HGG-33. Prognostic factors of H3K27M histone-mutant diffuse midline gliomas in patients ≤18yrs
Authors: Hu Qingjun , Lai Mingyao , Li Juan , Cai Linbo
Published: June 2022

OBJECTIVE：Diffuse midline gliomas associated with high malignancy and poor prognosis. The primary treatment modalities include surgery, radiotherapy and chemotherapy. The purpose of this study was to investigate the prognostic factors of diffuse intracranial midline glioma. METHODS: A retrospective analysis was performed on 44 cases younger than 18 yrs of H3K27M histone-mutant diffuse midline gliomas diagnosed in Guangdong Sanjiu Brain Hospital from November 2017 to November 2021. The median age was 9 years (range:3-18), including 24 males and 20 females, lesions located in thalamus were 9, while in brain stem were 35. Treatment methods: 35 cases received radiotherapy, 9 cases did not. Among the patients who received RT, 26 cases with concurrent chemoradiotherapy + adjuvant chemotherapy, 8 cases with concurrent chemoradiotherapy only, and 1 case only with radiotherapy. Kaplan-meier method was used to calculate overall survival (OS), and log-rank test was used to test. P < 0.05 was considered statistically significant. RESULTS: By January 27, 2022, 13 cases survived, 25 cases died, and 6 cases were lost to follow-up. The median survival time of 44 patients was 6.95 months (range：1-23.5 months). The median survival was 8.4 months in the radiotherapy group vs 3.7 months in the non-radiotherapy group (P＜0.001); The median survival time of radiotherapy without adjuvant chemotherapy vs radiotherapy with adjuvant chemotherapy was 6.2 months vs 9.35 months (P=0.479). CONCLUSION: Radiotherapy can prolong the survival time of diffuse midline glioma in children with H3K27M histone mutant but no survival benefit was observed in patients with concurrent chemotherapy.
HGG-35. Radiation Induced High Grade Gliomas: A Single Center Experience
Authors: Joshirao Mrinal , Sait Sameer Farouk , Bouvier Nancy , Hill Katherine , Khakoo Yasmin , Kramer Kim , Gilheeney Stephen , Wolden Suzanne , Nolan Craig , Schaff Lauren , Rosenblum Marc , Bale Tejus A , Yang Jonathan T , Lin Andrew , Dunkel Ira J , Karajannis Matthias
Published: June 2022

INTRODUCTION: Patients receiving cranial radiotherapy (RT) are at risk for a subsequent radiation-induced glioma (RIG). RIGs are rare, generally develop with a latency of 2 years to several decades, display high-grade histology and an aggressive clinical course with poor prognosis. METHODS: We retrospectively analyzed patients with a diagnosis of RIG seen at our institution from 2001-2021, analyzing clinical, histological, molecular, and genetic characteristics. RESULTS: Twenty-one patients (n=15 male) with a history of ALL (n=6), medulloblastoma (n=5), germ cell tumors (n=4), or other (n=6) diagnosed at a median age of 8.3 years (range 1.6 to 36.4) were identified. Median age at RIG diagnosis was 18 years (range 7.8 to 66.9). Prior RT was focal+craniospinal (n=7), whole brain (n=5), total body (n=3), focal (n=1), or unknown (n=5). Median radiation dose received was 2,340 cGy (range 1,200 to 5,400). The median time from RT to RIG diagnosis was 7.7 years (range 1.6 to 23.8). All RIGs were histologically high grade (WHO Grade III or IV). Immunohistochemistry did not reveal IDH(R132H) (n=9) or H3K27M (n=8) in any tumor. Some tumors demonstrated loss of expression of ATRX (1/9) and/or H3K27me3 (3/6), and/or strong diffuse expression of p53 (0/3). Targeted panel sequencing (n=10) revealed recurrent somatic alterations including CDKN2A/B, PDGFRa/KIT/KDR, TEK, MTAP, ATM and NF1. Germline alterations were detected in 4/12 patients (pathogenetic variants in ATM, CHEK2, HOXB13 and NF1). With median follow-up of 4.5 years, two-year PFS and OS for the cohort (n=20) were 10% and 44% respectively. Two patients (with anaplastic oligodendroglioma and anaplastic astrocytoma) are alive without progression 5.4 and 13.6 years after diagnosis following surgery, RT and chemotherapy. CONCLUSION: Although RIGs are associated with a poor prognosis, they are not always fatal. Our findings suggest aggressive therapy should be considered for these patients.