bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-90. NON-INVASIVE METABOLIC IMAGING OF DIFFUSE MIDLINE GLIOMAS AND THEIR RESPONSE TO THERAPY
Authors: Viswanath Pavithra , Taglang Celine , Batsios Georgios , Gillespie Anne Marie , Mueller Sabine 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline gliomas (DMGs) harboring histone H3K27M mutations are devastating pediatric brain tumors. ONC201 is the first drug in decades to extend survival in DMG patients and is likely to be widely used for treatment of DMGs. However, magnetic resonance imaging (MRI), the gold standard for patient management, does not provide a reliable readout of response to therapy. The Warburg effect describes the propensity of tumor cells to increase glucose uptake and conversion to lactate. Deuterium metabolic imaging of the Warburg effect using [6,6’-2H]-glucose provides the unparalleled opportunity to obtain a biologically meaningful readout of treatment response. Therefore, the goal of this study was to assess the utility of [6,6’-2H]-glucose for DMG imaging.

METHODS
We performed expression profiling and deuterium metabolic imaging in patient-derived and syngeneic DMG models.

RESULTS
Our studies indicate that DMG cells upregulate key components of the Warburg effect, including SLC2A1, SLC2A3, HK2, PFKFB3, PGK1, and LDHA relative to normal astrocytes. Silencing the H3K27M mutation in DMG cells reduced glycolytic gene expression. Spatially resolved 2D chemical shift imaging at 3T showed that lactate produced from [6,6’-2H]-glucose was localized to tumor vs. normal brain in mice bearing intracranial tumors. ONC201 downregulated glycolytic gene expression in DMG cells, an effect that was accompanied by reduced lactate production from [6,6’-2H]-glucose. Importantly, lactate production from [6,6’-2H]-glucose was reduced following treatment with ONC201 in mice bearing intracranial tumors at 3T, at an early timepoint independent of MRI-detectable volumetric alterations and predictive of extended survival.

CONCLUSIONS
Our studies mechanistically link the H3K27M mutation with the Warburg effect. Importantly, they identify [6,6’-2H]-glucose as a novel contrast agent for visualizing the metabolic lesion and imaging early response to therapy in DMGs. Since [6,6’-2H]-glucose is a safe, orally administered agent, our studies have the potential to be rapidly translated to the clinic, where they will provide physicians with a much-needed tool to determine whether DMG patients are responding to therapy.
ETMR-04. OPTIC NERVE SHEATH MENINGIOMAS IN CHILDREN-DIAGNOSTIC AND THERAPEUTIC CHALLENGES BASED ON A CASE SERIES
Authors: Ratnasingham Deysha , Lawson George , Hyare Harpreet , Soto Carmen , Gurney Sam , Apps John , Reekie Ian , Jorgensen Mette , Depani Sarita , Hargrave Darren , Szychot Elwira 
Published: June 2024

Abstract

BACKGROUND
Optic nerve sheath meningiomas (ONSM) are rare, comprising 1-2% of paediatric CNS meningiomas. Despite slow growth, ONSM often lead to vision loss in the affected eye. Diagnosis is challenging due to the tumour’s proximity to the optic nerve, complicating biopsy or complete removal.

METHODS
We searched our Neuro-Oncology MDT database for patients treated for ONSM between Jan 2018 and Dec 2023. We retrospectively reviewed clinical presentation and diagnostic workup that led to the diagnosis of ONSM.

RESULTS
6 children aged 3-15years (mean 9 years) were identified over 5 years. 3 children were treated at GOSH, 2 at UCLH and 1 at BCH. 3/6 patients were male. 2/6 underwent a biopsy. Presenting symptoms included headache, acute visual loss and eye pain. 2/6 patients presented with bilateral vision deterioration. The average time between onset of symptoms and presentation was 8 months (range 3–15 months). Identified causes of delayed diagnosis included delayed presentation related to COVID-19 pandemic (2 patients) and impaired quality of imaging due to dental braces (1 patient). Whilst awaiting diagnosis, 2 patients lost vision completely in their affected eye. Diagnostic workup included: optic disc examination (6 patients), lumbar puncture (2 patients), angiotensin-converting enzyme (sACE) (2 patients), MRI brain and spine (6 patients), CT scan (6 patients), PET-DOTATE scan (3 patients), NF2 genetic testing (4 patients). Two patients completed PBT therapy while 1 is undergoing radiotherapy. One patient underwent an enucleation, while the rest are under surveillance.

CONCLUSIONS
Paediatric ONSM diagnosis remains challenging despite advanced imaging. Our review highlights the added value of CT and PET-DOTATATE when a biopsy is high-risk. CT reveals calcification in 20-50% ONSM while the role of PET-DOTATATE is related to the expression of somatostatin receptor 2 in meningiomas. Despite optimal treatment, vision loss maybe unavoidable. Early multidisciplinary consultations are advised for enhanced outcomes.
ETMR-22. IDENTIFICATION OF 5-FLUROURACIL AS A SELECTIVE THERAPY IN A NOVEL EP300::BCOR FUSION GLIOMA TUMOR MODEL
Authors: Donson Andrew M , Amani Vladimir , Griesinger Andrea M , Calzadilla Annaliese , Grimaldo Enrique , Willard Nicholas , Foreman Nicholas K , Mulcahy-Levy Jean 
Published: June 2024

Abstract

INTRODUCTION
BCL6 corepressor gene (BCOR)-altered glioma brain tumors are a newly identified entity which include cases involving a gene fusion with histone acetyltransferase EP300. Treatment strategies for BCOR-fusion gliomas have not yet been established, largely due to their rarity. In this study we utilize a newly established EP300::BCOR fusion cell line to identify effective FDA-approved oncology compounds in vitro.

METHODS
EP300::BCOR fusion cell line MAF-1211, established from autopsy material, was molecularly defined to confirm the fusion and fidelity with patient samples. The treatment effect of FDA-approved oncology drugs (n=97) in MAF-1211 was compared to other pediatric brain tumor types to identify clinically available compounds with BCOR-fusion glioma selective potency.

RESULTS
RNAseq analysis of MAF-1211 cell line identified a fusion breakpoint between EP300 exon 31 and BCOR intron 6, which matched both patient presentation and autopsy samples. MAF-1211 also showed molecular fidelity with patient tumors, showing transcriptomic clustering with the patient tumor from which it was established, and matching most strongly with CNS BCOR-altered tumors by DNA methylation classifier analysis. FDA-approved oncology drug screening showed a relatively high sensitivity of MAF-1211 to fluorinated pyrimidines 5-fluorouracil (5-FU), carmofur, and floxuridine compared to other pediatric brain tumor cell lines (HGG, medulloblastoma, ependymoma, ATRT). Discussion: Identification of 5-FU and related drugs identified by our study have the potential to inform design of upcoming clinical studies in BCOR-fusion gliomas. Given the rarity of these tumors it may be more feasible to combine BCOR-fusion gliomas with a potential upcoming clinical trial of 5-FU in posterior fossa A ependymoma.
ETMR-30. CLINICAL AND MOLECULAR CHARACTERIZATION OFDICER-MUTANT CENTRAL NERVOUS SYSTEM SARCOMA
Authors: Dowiak* Alexis , Williamson* Lane , Povilaikaite* Julija , Cabrera Edgar , Aponte Nelson , Garcia Johnny , Quiroz Lina , Piña Martha , Martinez Cindy , Valencia Diana , Barragan Liliana , Reséndiz Alma Benito , Magelssen Henriette , Trujillo Ángela , Osorio Diana , Figueredo Oscar , Packer Roger , Sarmiento Isabel , Suarez Amaranto , Mushtaq Naureen , Abdullaev Zied , Poria Dipak , Bartels Ute , Bouffett Eric , Polo Barbara Rivera , Aldape Kenneth , Ramaswamy Vijay , Fonseca Adriana 
Published: June 2024

Abstract

BACKGROUND
Central nervous system (CNS) sarcomas are rare mesenchymal non-meningothelial tumors accounting for 0.2% of brain tumors. Due to their rarity, there is a lack of substantive clinical, histological and molecular data.

METHODS
Patients diagnosed with primary CNS sarcomas were identified through several international collaborations. DNA methylation profiles were generated using 850K microarray assays, followed by unsupervised hierarchical clustering and t-SNE analyses. Additionally, targeted DNA sequencing was employed to characterize the somatic landscape. Clinical data was collected and summarized using descriptive statistics, and survival estimates were calculated using the Kaplan-Meier method.

RESULTS
We analyzed DNA methylation data of 65 tumor samples. Clustering analyses demonstrated DICER-1 CNS sarcomas segregate into two distinct epigenetic subgroups. Copy number analysis demonstrated frequent CNV alterations and chromothripsis in 35% of the samples. DICER-1 mutations were present in 85% of cases and associated with frequent additional alterations in TP53 (65%) and KRAS (51%). The median age at diagnosis was 10.4 years (r: 0.4 - 71 y) and 52% (n=34) of subjects were male. Tumors were frequently (91%) located in the supratentorial compartment, frontal lobe involvement was noted in 62% of cases. Patients were treated with multimodal approaches including surgery, ICE chemotherapy, and focal radiation. At median follow-up time of 27.5 months, the 2-year progression-free and overall survival was 50.8% (r: 0.31-0.67) and 53.5% (r: 0.34-0.69) respectively.

CONCLUSIONS
DICER-1 CNS Sarcoma is an aggressive entity that segregates into two epigenetic subgroups, clinical and genotype correlations remain to be elucidated. Current multimodal approaches are only effective in a subset of patients. The identification of MAPK pathway alterations in most cases should be explored as a therapeutic avenue.
EPID-05. 60 YEARS OF CENTRAL NERVOUS SYSTEM TUMOURS IN THE WEST MIDLANDS, UK
Authors: Curry Helen , Adamski Jenny , English Martin , Hawkins Mike , Reulen Raoul , Gleeson Helena , Jenkinson Helen 
Published: June 2024

Abstract

BACKGROUND
The West Midlands Regional Children’s Tumour Registry is a specialist paediatric cancer registry in the West Midlands region of England, representing 9% of the national population. Our aim was to produce an historical, regional overview of central nervous system (CNS) tumour incidence and survival from 1957 onwards.

METHODS
Paediatric CNS tumour records included in the Registry from 01/01/57 to 31/12/16 were reviewed. There were 1945 cases: 1066 males and 879 females (M:F ratio 1.2:1) aged 0-14 years, resident in the West Midlands and diagnosed with a malignant, uncertain, or benign tumour. Patients were categorised according to the International Classification of Childhood Cancer, Third Edition (ICCC-3). Age and sex-specific incidence rates per million and directly age standardised incidence rates were calculated. Survival by decade of diagnosis was calculated using Kaplan-Meier survival analysis.

RESULTS
Incidence rates were broadly comparable to national data. Five-year survival for all CNS tumours combined increased from 38.0% [CI 32.2-43.8%] during 1957-1966 to 79.8% [CI 75.4-83.5] for diagnoses 2007-2016. Five-year survival for patients with ependymoma, astrocytoma and medulloblastoma diagnosed 2007-2016 was 95.7% [CI 72.9-99.4], 86.9% [CI 80.3-91.3] and 68.0% [CI 52.0-79.7] respectively: substantially above equivalent national figures. Five-year survival for groups including ‘Other Gliomas’ and Atypical teratoid/rhabdoid tumour (ATRT) had lower than nationally reported survival rates at 53.3% [CI 37.6-66.8] and 9.1% [0.5-33.3] however, small numbers and wide confidence intervals must be considered.

CONCLUSIONS
Huge improvements in survival, nationally and in the West Midlands, over the past 60 years are attributable to a greater understanding of tumour biology, intensification of multi-agent chemotherapy and new treatments. Despite these gains, certain diagnoses - most prominently ATRT - remain resistant to cure with five-year survival below 10%. Certain diagnoses showed a notable rise in late mortality, demonstrating the importance of long-term follow-up for detecting late effects and subsequent malignancies.
METB-05. CSF LIQUID BIOPSY: PAVING THE WAY FOR MINIMALLY INVASIVE BRAIN TUMOR SURVEILLANCE USING LOW-PASS WHOLE GENOME SEQUENCING
Authors: Tam Lydia T , Rossi Grace , Stevens Jeff , Ronsley Rebecca , Vitanza Nicholas A , Cole Bonnie L , Paulson Vera A , Lockwood Christina M , Leary Sarah E S , Crotty Erin E 
Published: June 2024

Abstract

OBJECTIVE
We describe a clinical liquid biopsy platform for disease detection and surveillance in pediatric patients with primary central nervous system (CNS) tumors using low-pass whole genome sequencing (LP-WGS) on cell-free DNA (cfDNA) isolated from cerebrospinal fluid (CSF).

METHODS
CSF samples were collected during routine clinical procedures. cfDNA was extracted and LP-WGS performed using a validated Illumina NextSeq sequencing with a 37 bp paired-end read configuration. Sequencing results were compared to tumor molecular profiling performed by UW-Oncoplex™, a targeted DNA-based next-generation sequencing panel.

RESULTS
Sixty-one CSF specimens were collected from 29 individual patients with primary brain tumors across 7 institutions, with samples obtained at initial diagnosis or staging (n=17), during treatment (n=29), at therapy completion (n=4), or at disease recurrence (n=11). Patients with medulloblastoma (n=13), ATRT (n=3), high-grade glioma (n=3), low-grade glioma (n=6), ependymoma (n=1), and high-grade neuroepithelial tumor/ embryonal tumors (n=3) were included. Copy number variants consistent with tumor were detected in 24 samples from a median CSF volume of 2.5 mL (range: 1-8 mL) and 54.6 pg/ul of cfDNA (median, range: 1.3-5,220). 31/61 samples yielded enough DNA for LP-WGS while 30 were insufficient due to absence of tumor DNA (true negatives) or low DNA quantity (technical insufficiency). Among the 10 diagnostic samples collected from patients with MRI evidence of disease at initial staging, LP-WGS was positive in 8/10 (80%), compared to 2/10 (20%) positive by cytologic analysis for malignant cells. All 4 staging samples from patients with leptomeningeal metastasis were positive by LP-WGS. At recurrence, LP-WGS was positive for tumor in 6/8 (75%) of MRI-positive patients.

CONCLUSIONS
LP-WGS of CSF-derived cfDNA can identify clinically relevant somatic copy number variants, offering a minimally invasive liquid biopsy option for ongoing surveillance in pediatric CNS tumors. Further prospective analysis is needed to mitigate interpretation error and refine clinical applications.
METB-14. INTEGRATED GERMLINE AND SOMATIC PROFILING OF PEDIATRIC BRAIN TUMORS REVEALS INCIDENTAL FINDINGS AND NOVEL TUMOR BIOLOGY
Authors: Corbett Ryan J , Kaufman Rebecca , McQuaid Shelly W , Vaksman Zalman , Phul Saksham , Brown Miguel A , Mason Jennifer L , Desai Heena , Hausler Ryan , Naqvi Ammar S , Chroni Antonia , Geng Zhuangzhuang , Zhang Bo , Zhong Chuwei , Zhu Yuankun , Heath Allison P , Li Marilyn , Storm Phillip B , Resnick Adam C , Maxwell Kara N , Bornhorst Miriam , Cole Kristina A , Waanders Angela J , MacFarland Suzanne P , Rokita Jo Lynne , Diskin Sharon J 
Published: June 2024

Abstract

BACKGROUND
The contribution of rare pathogenic germline variation to central nervous system (CNS) tumor formation in pediatric patients without a family history of cancer remains unclear.

METHODS
We characterized the prevalence of pathogenic germline variants in 214 cancer predisposition genes (CPGs) in 837 patients profiled in the Pediatric Brain Tumor Atlas by whole genome or exome sequencing (n=820 and n=17, respectively). Rare SNVs and small INDELs were annotated as pathogenic (P) or likely pathogenic (LP) consistent with American College of Medical Genetics criteria using AutoGVP, our open-source automated pathogenicity assessment tool. We classified pathogenicity of germline structural variants (SVs) using ClassifyCNV and AnnotSV. Somatic alterations and mutational signatures from matched tumor sequencing were integrated to identify functional consequences associated with germline pathogenic variation.

RESULTS
We observed 206 germline P/LP SNVs/small INDELs and 18 SVs (16 deletions, 2 duplications) within 78 unique CPGs in 195 patients (23.3%). We detected syndrome-associated P/LP variants in 45/58 patients with a clinically-reported cancer predisposition syndrome and incidentally in 41 patients. Ninety-five (42%) germline P/LP variants co-occurred with at least one somatic alteration in the same gene in matched tumors: n=6 oncogenic SNVs, n=28 CNVs, n=54 loss of heterozygosity (LOH), n=26 differential gene or protein expression, and n=18 alternative splicing. NF1, TSC1, and TSC2 germline P/LP carriers exhibited significantly higher tumor LOH scores and lower gene expression in tumors relative to non-P/LP carriers. Patients with germline splice region P/LP variants exhibited significantly increased skipping of most the proximal exon in matched tumor relative to patients with non-splice region P/LP variants (W=401, p=1.1E-04).

CONCLUSION
We have identified rare germline P/LP variants associated with cancer predisposition syndromes and diverse functional consequences in pediatric CNS tumor patients. Efforts are underway to extend this work to include 1,801 additional probands and 1,105 parents to further characterize the prevalence and heritability of germline pathogenic variation in children diagnosed with CNS tumors.
GCT-08. THE PURSUIT OF OPTIMUM TREATMENT FOR NONGERMINOMATOUS GERM CELL TUMOURS (NGGCT) OF THE CNS – A PROGRESS REPORT FROM THE EUROPEAN GROUP (SIOP CNS GCT II)
Authors: Nicholson James C , Alapetite Claire , Timmerman Beate , Conter Cecile Faure , Schönberger Stefan , Murray Matthew J , Gerber Nicolas , Peyrl Andreas , Zimmermann Martin , Lassen-Ramshad Yasmin , Frappaz Didier , Kortmann Rolf-Dieter , Ajithkumar Thankamma , Calaminus Gabriele 
Published: June 2024

Abstract

BACKGROUND
Controversy surrounds the optimum treatment for localised nongerminomatous germ-cell-tumours (NGGCT). The European group has employed more dose-intense chemotherapy followed by 54 Gy focal radiotherapy (fRT), whilst others additionally apply whole-ventricular or craniospinal radiotherapy (CSI). Historically, these approaches have led to comparable outcomes.

PATIENTS/METHODS
SIOP-CNS-GCT-II aimed to improve event free survival (EFS) for NGGCT by standardising the surgical approach for residual disease and by chemotherapy dose escalation in patients identified as high-risk (age &lt;6 years and/or serum/CSF AFP &gt;1000 ng/ml). Standard treatment with four courses of cisplatin, etoposide and ifosfamide (PEI) followed by 54 Gy fRT with 30 Gy CSI for metastatic disease, was retained from the SIOP-CNS-GCT-96 trial for patients not defined as high-risk. Radiotherapy technique (protons or photons) was not dictated in the trial, but the number of cases receiving proton beam therapy has increased over time. Between 02/2012 and 07/2018, 112 patients with NGGCT from eight European countries were treated according to the SIOP-CNS-GCT-II protocol; 89 were standard-risk, and 14 of these were metastatic. This compared with 149 NGGCT patients treated overall in SIOP-CNS-GCT-96, of which 33 were metastatic.

RESULTS
In SIOP-CNS-GCT-96, 3-year EFS for localised NGGCT receiving PEI chemotherapy and 54 Gy fRT was 0.72, and for metastatic cases, receiving PEI and 30 Gy CSI with boost, 0.68. In SIOP-CNS-GCT-II, 3-year EFS for metastatic cases receiving similar treatment was excellent at 0.94 (p=0.087 compared with SIOP-CNS-GCT-96) but for localised cases, only 0.63 (p=0.032).

CONCLUSION
To understand the impact of radiotherapy volumes on EFS and guide future trials, a detailed dosimetric study on the patterns of relapses is in progress. In the meantime, based on our current understanding, most participating countries are recommending addition of whole ventricular radiotherapy to fRT for localised NGGCT.
GCT-13. OUTCOMES OF INTRACRANIAL GERMINOMA TREATED AT A SINGLE UK PROTON CENTRE ACCORDING TO UK CHILDREN’S CANCER AND LEUKAEMIA GROUP (CCLG) GUIDELINES
Authors: Goyal Love , France Anna , Gaito Simona , Colaco Rovel J , Pan Shermaine , Saunders Daniel , Thorp Nicola , Whitfield Gillian A 
Published: June 2024

Abstract

BACKGROUND
After SIOP-CNS-GCT II closed in 2018, the CCLG recommended, with caveats, following the standard trial arms: 4 cycles of chemotherapy (Etoposide-Carboplatin alternating with Etoposide-Ifosfamide) followed by whole ventricular radiotherapy (WVRT) (24Gy/15fractions) and boost (16Gy/10fr) to the primary site(s) for localised germinoma and craniospinal irradiation (CSI) (24Gy/15fr) followed by boost (16Gy/10fr) to primary and metastatic sites for metastatic disease. Since 04/2021, the CCLG formally recommended omitting the boost for localised unifocal germinoma in complete radiological response after chemotherapy. From autumn 2022, we also omitted boosts to completely responded primary sites for localised bifocal germinoma.

METHODS
Retrospective reviewed of all patients referred to our proton centre 12/2018–06/2023. We collected patient, tumour and treatment factors, acute toxicities (CTCAE grade≥3), and event-free survival(EFS) from radiotherapy until 09/2023.

RESULTS
Forty-two patients (36M:6F) were included, 23 localised and 19 (including 3 incompletely staged) treated as metastatic. Primary sites: 21 pineal, 8 pituitary/suprasellar, 10 bifocal and 3 atypical (optic nerve, periventricular, thalamic). Diagnosis was by histopathology in 40 and bifocal disease with negative CSF and serum markers in 2. Median age was 15 years (IQR 13-16), median follow-up 13 months (IQR 6-15). Patients were treated according to CCLG guidance, apart from three patients with metastatic pure germinoma, of whom one received 2 cycles Cisplatin-Etoposide, and two received 5 and 3 cycles of Vinblastine before CSI, and one patient with metastatic germinoma plus teratoma who received 2 cycles of Cisplatin-Etoposide and non-germinoma radiotherapy doses (30Gy/20fr CSI, 24Gy/15fr cranial boosts). No patient had subsequent surgery. All remained progression free at last follow-up. Eight patients developed acute grade 3 toxicities: 3 vomiting (2 CSI, 1 WVRT), and 5 lymphopenia (all CSI).

CONCLUSIONS
Disease control was excellent, with no relapses to date. Proton therapy was well tolerated with low rates of acute high grade toxicities.