bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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 (&gt; 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.