bluuebunny/crossref_metadata_2025 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

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

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

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

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

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

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

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

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 <6 years and/or serum/CSF AFP >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

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.
GCT-14. TREATMENT APPROACH FOR METASTATIC INTRACRANIAL GERMINOMA: A MULTI-INSTITUTIONAL EXPERIENCE
Authors: Power^ Phoebe C , Liu^ Kevin X , Chi Susan N , Wright Karen D , Marcus Karen J , Haas-Kogan Daphne A , Ebb David , Yock Torunn I , MacDonald* Shannon M , Yeo* Kee Kiat
Published: June 2024

BACKGROUND

Germinoma is the most common CNS germ cell tumor in children. Treatment with 24Gy craniospinal irradiation (CSI) with boost to 40Gy alone results in excellent survival irrespective of disease stage. For localized germinoma, recent studies have demonstrated the efficacy of neoadjuvant chemotherapy in decreasing the field/dose of radiation therapy (RT) needed for cure. For metastatic germinoma however, the optimal RT approach when combined with chemotherapy is unclear. Herein, we present our experience in treating patients with metastatic germinoma.

METHODS

We performed a retrospective, IRB-approved study of patients with metastatic germinoma diagnosed between 2001-2023 at Boston Children’s Hospital, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Mass General Hospital. Clinical features, treatment plan, and outcomes were collected and analyzed using the Kaplan-Meier method and Fisher’s exact test.

RESULTS

Twenty-eight patients with metastatic germinoma were identified. Median age at diagnosis was 15.9 years (range:6.2-25.9). Metastasis was intracranial in 20, craniospinal in three and CSF-only in five patients. Six patients received CSI only. Twenty-two patients received neoadjuvant chemotherapy and CSI. Median number of chemotherapy cycles was 4 (range:3-6). Seventeen patients had complete response, four patients had partial response, and one patient had progressive disease with chemotherapy. All patients went on to receive CSI, with median dose of 21Gy (range:18-36Gy) with median IF boost to 36Gy (range:30-51.6Gy). Median duration of follow-up was 11 years (range:0.3-25.3). There were no recurrences or deaths within the cohort. Analysis of long-term outcomes data revealed no significant differences in frequency of endocrinopathies, CNS vasculopathies, or memory loss between the doses of RT.

CONCLUSIONS

Our data show that neoadjuvant chemotherapy followed by CSI is associated with excellent overall survival in patients with metastatic germinoma. Importantly, our experience suggests that in combination with neoadjuvant chemotherapy, 21Gy CSI may be sufficient as a curative dose in this patient population.
GCT-24. ISOLATED PITUITARY STALK THICKENING
Authors: Bennett Julie , Nobre Liana , Bouffet Eric , Maguire Bryan , Amirabadi Afsaneh , Hawkins Cynthia , Abla Oussama , Wasserman Jonathan , Ertl-Wagner Birgit , Bartels Ute
Published: June 2024

BACKGROUND

Few studies have examined predictive factors and outcome of isolated pituitary stalk thickening (iPST) in children. We aim to describe our institutional cohort to determine predictors of future proliferative disease.

METHODS

A search of the radiology, endocrinology and neuro-oncology databases was performed to identify patients with iPST diagnosed between January 2000 and June 2019. Clinical data was collected along with detailed radiology review of MRIs in a blinded fashion.

RESULTS

Forty-seven patients were identified, with 40 meeting criteria for inclusion. Median age of baseline MRI was 9.6 years (range 0.9-17.5). Twenty-five (63%) were female. Median follow up time was 5.2 years (range 0.3-18.6). Indication for MRI was symptoms of diabetes insipidus (DI) in 29 patients followed by concerns for anterior endocrine disturbance (6), headache (1) or visual impairment (1). Thirty-four (85%) subjects had pituitary dysfunction, including 31 with DI however DI was not predictive of future development of proliferative disease (69% with presumed hypophysitis vs 93% with proliferative disease, p=0.12). Fourteen (35%) patients developed proliferative disease, with germinoma (8), Langerhans cell histiocytosis (5) and lymphoma (1) at median of 1.3 years (range 0.3-4.0), 2.2 years (range 0.3-9.4) and 1.1 years after initial MRI respectively. Lumbar puncture was performed in 24 patients with elevated white blood cell count (>5 x 106/L) found in 6 (75%) patients with germinoma, 1 (100%) patient with lymphoma, 0 patients with LCH and 3 of 11 (27%) patients with presumed hypophysitis (p=0.015). Thickening of the entire stalk at time of diagnosis and radiographic progression were more likely to be seen in those that developed proliferative disease.

CONCLUSION

In this cohort 35% of children with PST were eventually diagnosed with a proliferative disease. Importantly, central DI was not associated with risk of proliferative disease. Several radiographic features and elevated CSF WBC were predictive of this outcome.
HGG-08. DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT: A MULTI-INSTITUTIONAL EXPERIENCE
Authors: Tlais Dana , Roach Jordan T , Tinkle Christopher L , Zhang Qunyu , Li Xiaoyu , Lin Tong , McNall-Knapp Rene Y , Rush Sarah Z , Le Brian H , Sinno Sara , Agarwal Apeksha , Ginn Kevin F , Green Richard M , Onar-Thomas Arzu , Bag Asim K , Chiang Jason
Published: June 2024

BACKGROUND

Diffuse hemispheric glioma (DHG), H3 G34-mutant, is a rare, aggressive brain tumor molecularly defined by mutations in the H3-3A gene. Our study explored the association between patient outcomes and key molecular findings, resection extent, and temozolomide (TMZ) use.

METHODS

Multi-institutional chart and molecular analysis of 32 patients with H3 G34-mutant DHG.

RESULTS

The median patient age was 14 (10-28 years), with a M/F ratio of 1.4. The 1-year, 2-year, and 5-year PFS were 40.4% (23.7%, 57.1%), 22.1% (9.0%, 38.7%), and 11.0% (1.9%, 33.7%), respectively. The 1-year, 2-year, and 5-year OS were 82.5% (63.2%, 92.3%), 49.3% (28.7%, 66.3%), and 29.6% (9.1%, 50.6%), respectively. Patients who underwent a gross total resection (GTR) had improved PFS (p=0.0105) and OS (p=0.0184) compared to non-GTR patients. 22 patients (68.8%) received concurrent and/or adjuvant TMZ and had improved PFS (p=0.0278) compared to patients who did not receive front-line TMZ. Disease recurrence in relation to the radiation therapy (RT) field was analyzed in 17 patients; 5 recurred locally within the high-dose RT field, 5 recurred distantly, and 7 had both local and distant recurrences. There was no significant association between MGMT promoter methylation status (18 evaluable cases), PDGFRA amplification (N=6), and CDKN2A homozygous deletion (N=10) and survival outcomes. MGMT promoter methylation was not associated with increased TMZ efficacy (N=8 with MGMT silencing, N=4 without).

CONCLUSIONS

In our cohort, MGMT promoter methylation was not a favorable prognostic factor, in distinction from prior reports in adult and pediatric high-grade gliomas. Resection extent and the use of TMZ were associated with improved survival outcomes. As most treatment failures occurred within the high-dose RT field, extended fields do not appear warranted. Our findings may guide prognostic and therapeutic decisions in patients with H3 G34-mutant DHG and support the need for prospective efforts to improve outcomes in this patient population.
HGG-22. LINKS BETWEEN M6A RNA METHYLATION, R-LOOPS AND DNA DAMAGE IN PAEDIATRIC HIGH-GRADE GLIOMAS
Authors: Walker Lauryn , Radhi Masar , Knight Helen , Smith Stuart
Published: June 2024

BACKGROUND

Paediatric high-grade gliomas (pHGG) are aggressive malignant tumours of the central nervous system that unfortunately carry poor prognoses. R-loops, which are DNA:RNA hybrids, are a known source of genomic instability in eukaryotic cells. The RNA strand of R-loops can be m6A methylated at double-strand break sites in order to facilitate DNA repair. Therefore, we investigated whether dysregulation of m6A methylation and R-loop homeostasis at DNA damage sites deregulates DNA repair pathways in pHGG.

METHODS

Immunocytochemistry was performed to assess global m6A, R-loop, γH2AX and several DNA repair protein levels in pHGG cell lines compared to human astrocytes. Colocalisation between m6A and R-loops, R-loops and γH2AX, m6A and γH2AX, R-loops and 53BP1, R-loops and PARP1, R-loops and total ATM, and R-loops and phosphorylated ATM was assessed in pHGG cell lines and human astrocytes.

RESULTS

Immunocytochemistry analysis revealed that levels of global m6A, R-loop, γH2AX and several DNA repair proteins were generally higher in pHGG cell lines, thereby indicating that cellular homeostasis is dysregulated. Furthermore, a high degree of colocalisation between m6A and R-loops was observed. R-loops were found to colocalise with γH2AX, and m6A was found to colocalise with γH2AX, thereby corroborating the notion that m6A methylated R-loops are likely present at DNA damage sites. Finally, R-loops were also found to colocalise with a variety of DNA repair proteins, including 53BP1, PARP1, total ATM, and phosphorylated ATM, where different Pearson’s correlation coefficient values were obtained, thereby suggesting that R-loops associate with DNA repair proteins to different extents.

CONCLUSIONS

The link between m6A methylation, R-loops and DNA damage in relation to the pathogenesis of pHGG is currently being investigated. Experiments are also being performed where we are investigating m6A readers to see whether their aberrant expression contributes to disease pathogenesis via deregulating DNA repair pathways.
HGG-35. SIGNIFICANT RESPONSE TO LAROTRECTINIB AS FIRST LINE THERAPY IN INFANT WITH INFANT-TYPE HEMISPHERIC GLIOMA
Authors: Rocco Abbey , Brossier Nicole M , Shatara Margaret , Abdelbaki Mohamed , Strahle Jennifer , Cluster Andrew S
Published: June 2024

BACKGROUND

Infant-type hemispheric gliomas represent a recent WHO classification of high grade pediatric brain tumors that are often characterized by NTRK, ROS1, MET or ALK fusions. Novel agents may target their driver mutations but are not yet considered front line therapy.

METHODS

Patient data was reviewed retrospectively through chart review.

RESULTS

A 7 day old male infant who presented with vomiting, shaking and a full fontanelle was found to have a 8.7 x 7.2 x 9.3 cm solid and cystic mass with internal hemorrhage in the right parietal and occipital lobes associated with significant mass effect and midline shift. He underwent VP shunt placement and tumor biopsy, but later developed seizures and declining mental status. Cyst decompression was used as stabilizing measure. Due to his very small size and tenuous clinical status full tumor resection was not feasible at that time. Pathology revealed an infant-type hemispheric glioma with ETV6-NTRK3 fusion. Although cytogenetic testing for NTRK alterations was negative, the fusion was confirmed by NGS. Given his age and the risks for electrolyte imbalances and cytopenias in a patient with recent hemorrhage, we elected to treat with Larotrectinib instead of traditional cytotoxic chemotherapy. He had notable disease response within 8 weeks and remains on drug 18 months later with continued response. His tumor now measures 2 x 1.5 x 1.6 cm. He has had one grade 3 toxicity with neutropenia, which was likely impacted by viral bone marrow suppression. He is currently meeting most developmental milestones but does have orthotics and sees speech therapy.

CONCLUSIONS

Targeted agents may represent a viable front line therapy to decrease tumor mass and temporize very young patients until they can undergo definitive resection and therapy. Future clinical trials will need to compare efficacy to current standards of care.
IMG-02. USING MRI RADIOMICS AND MACHINE LEARNING TO PREDICT OVERALL SURVIVAL FOR PEDIATRIC DIFFUSE MIDLINE GLIOMAS
Authors: Liu Xinyang , Jiang Zhifan , Roth Holger R , Anwar Syed M , Bonner Erin R , Packer Roger J , Kazerooni Anahita F , Bornhorst Miriam , Linguraru Marius George
Published: June 2024

BACKGROUND

Pediatric diffuse midline gliomas (DMG) are aggressive central nervous system tumors with a median overall survival (OS) of less than one year from diagnosis. There is no curative therapy for DMG, and radiation therapy (RT) is the standard treatment. Magnetic resonance imaging (MRI) is the common noninvasive tool for DMG diagnosis and monitoring of tumor response to therapy. We developed an automatic pipeline to segment subregions of DMG and select MRI features that predict patient OS.

METHODS

We acquired diagnostic and post-RT multisequence MRI (T1, T1ce, T2, T2 FLAIR) and manual segmentations of pediatric DMG patients from two centers: 53 from Children’s National Hospital (internal) and 16 from Children’s Hospital of Philadelphia (external). We pretrained a deep learning model on a public adult brain tumor dataset, and finetuned the model to segment tumor core (TC) and whole tumor (WT) of DMG. We used PyRadiomics and sequential feature selection to select discriminative features based on the segmented volumes. Two machine learning models were trained on our internal cohort to predict patient 1-year survival from diagnosis. One model used only diagnostic tumor features and the other used both diagnostic and post-RT features.

RESULTS

For segmentation, Dice score (mean [median]±SD) was 0.91 (0.94)±0.12 and 0.74 (0.83)±0.32 for TC, and 0.88 (0.91)±0.07 and 0.86 (0.89)±0.06 for WT for internal and external cohorts, respectively. For OS prediction, accuracy was 77% and 81% at time of diagnosis, and 85% and 78% post-RT for internal and external cohorts, respectively. Heterogeneous WT intensity in baseline T2 FLAIR and smaller post-RT TC/WT volume ratio indicate longer OS.

CONCLUSIONS

Our method accurately predict OS for DMG patients and can be extended to other rare pediatric brain tumors. With automated and standardized analysis, early prognostication of OS can guide patient risk stratification and clinical decisions.
IMG-13. PREDICTION OF PEDIATRIC MEDULLOBLASTOMA SUBGROUPS USING CLINICO-RADIOMIC ANALYSIS
Authors: Familiar Ariana M , Kazerooni Anahita Fathi , Kraya Adam , Rathi Komal , Khalili Nastaran , Gandhi Deep , Anderson Hannah , Mahtabfar Aria , Ware Jeffrey B , Vossough Arastoo , Storm Phillip B , Resnick Adam C , Nabavizadeh Ali
Published: June 2024

BACKGROUND

Pediatric medulloblastoma is an aggressive brain tumor and tailored treatment has the potential to lead to better patient outcomes. The WHO 2021 classification of medulloblastoma involves an integrated diagnosis that incorporates genetically defined characteristics, including molecular subgroups (WNT-activated, SHH-activated TP53 wildtype, SHH-activated TP53-mutant, and non-WNT/non-SHH). Clinically acquired radiology (MRI) imaging characteristics could provide a non-invasive, pre-treatment biomarker for such subgroups faster than standard methylation-based turn-around times, and for use in countries where methylation is not available.

METHODS

Herein, we utilize a multi-institutional dataset of multi-parametric, clinical MRIs of pediatric medulloblastoma patients from the Children’s Brain Tumor Network (median age = 8.9 years) to assess the predictive value of patient-level radiomic and clinical factors. 89 subjects with treatment-naïve T1w/T1w contrast-enhanced/T2w/FLAIR images and molecular subgroups (derived from methylation profiling or RNA sequencing) were included (SHH=18, WNT=10, non-SHH/WNT=61). Radiomic features were extracted from a radiologist-defined volumetric (3D) segmentation for each subject separately (including solid tumor, cystic, and peritumoral edema regions). Clinical variables included sex, age at diagnosis, and metastatic disease. 20 top performing features were selected based on an ANOVA between features/classes and subsequently used to train and evaluate three separate classification models based on radiomic, clinical, or clinico-radiomic features (Linear SVM; leave-one-subject-out cross-validation).

RESULTS

The combined clinico-radiomic model had the top performance (AUC=0.83) followed by radiomic (0.78) and clinical (0.5) for predicting SHH/WNT vs. non-SHH/WNT groups. Predictive radiomic features included intensity-based statistics (T1w, T2w, T1w-CE), texture (T2w), and morphological shape characteristics.

CONCLUSIONS

Our findings show potential for early prediction of molecular subgroups using baseline imaging that could lend to faster decision-making in patient treatment planning. Future work aims to evaluate the inclusion of histological characteristics for a full integrated diagnostic approach as well as assessment of prognostic value of the combined multi-omic features.
IMG-15. A STRATEGIC FLOWCHART FOR PREOPERATIVE IMAGING IN PEDIATRIC POSTERIOR FOSSA TUMORS
Authors: Gonçalves Fabrício G , Marecha Mario , Cerron-Vela Carmen , Yildiz Harun , Dias Tassiana Cristhina S , Bathia Aashim
Published: June 2024

BACKGROUND

This comprehensive study delves into pediatric posterior fossa tumors (PFTs), focusing on both common and rare types, including pseudoneoplasms. The aim is to understand the diagnostic challenges of these less typical tumors, enhancing knowledge beyond usual pathologies. A detailed flow chart has been created to aid in accurate preoperative diagnoses.

METHODS

The study examines neuroimaging data, primarily from MRI and CT scans, collected from various clinical studies and case reports. It concentrates on identifying unique imaging characteristics of rare PFTs and pseudoneoplasms. The flow chart considers lesion location in various anatomical areas of the posterior fossa and factors such as lesion localization, MRI details (including DWI), and patient age. It also emphasizes the identification of cells in the posterior fossa that can lead to tumors, including osseous tissue cells, dura mater cells, arachnoid cells, pia mater cells, various glial cells, neurons, and choroid plexus cells.

RESULTS

The study reveals distinct imaging features of less common PFTs and pseudoneoplasms, critical for differentiating them from more common tumors. Advanced imaging techniques are highlighted as essential for improving diagnostic accuracy, impacting clinical management and treatment decisions. The review also discusses the varied presentation of tumors and the challenges this poses to standard diagnostic methods.

CONCLUSIONS

Understanding the imaging characteristics of rare PFTs and pseudoneoplasms, especially in children, is vital. This thorough analysis enhances diagnostic accuracy and influences treatment approaches, potentially improving patient outcomes. The study underscores the necessity of combining clinical observations with advanced imaging for precise diagnoses in atypical cases. This approach is crucial for healthcare professionals managing pediatric PFTs, leading to better clinical decisions and advancing pediatric neuro-oncology.
IMG-25. PREDICTING ANATOMICAL TUMOR GROWTH IN PEDIATRIC HIGH-GRADE GLIOMAS VIA DENOISING DIFFUSION MODELS
Authors: Laslo Daria , Monzon Maria , Ramakrishnan Divya , von Reppert Marc , Stoller Schuyler , Stücklin Ana Sofia Guerreiro , Gerber Nicolas U , Rauschecker Andreas , Nazarian Javad , Mueller Sabine , Jutzeler Catherine R , Brüningk Sarah C
Published: June 2024

BACKGROUND

Pediatric diffuse midline glioma (DMG) has a poor prognosis with radiotherapy as the standard of palliative care. Radiation strategies using individual geometric doseshaping have the potential to maximize patient benefit. This study aimed to establish a proof-of-principle to generate clinically relevant anatomical representations of the progression of pediatric DMG magnetic resonance image (MRI) slices through denoising diffusion implicit models (DDIM).

METHODS

Based on the BraTS23 data, we analyzed the generation of MRIs with enlarged tumor sizes starting from a baseline scan. Models were pre-trained on adult glioblastoma (GBM) prior to transfer learning on pediatric high-grade glioma. Test set performance was evaluated using the Frechet Inception Distance (FID), and Structural Similarity Index (SSIM). Qualitative evaluation involved visual classification of real vs generated images by two independent radiology trainees. The optimized network was tested to forecast anatomical tumor growth in five DMG patients from an independent dataset comprising longitudinal T2-FLAIR images.

RESULTS

We obtain high-fidelity generated images, supported by an FID of 12.4 and 0.8 SSIM on the adult test set. Despite the smaller pediatric BraTS dataset yielding a 34.8 FID and 0.84 SSIM, human observers failed to distinguish generated from real MRIs (mean recall and precision of 0.51). The generated anatomical predictions also closely resemble the observed longitudinal tumor progression in the pediatric DMG subset. Notably, the direction and extent of tumor growth align while the surrounding brain anatomy is preserved. Quantitatively, the mean DICE score between segmentations of generated and real tumors was 0.8.

CONCLUSIONS

Our model produces high-quality images that conform to growth patterns of pediatric DMGs. Further quantitative validation on larger longitudinal datasets is required, to ensure the method’s robustness. The proposed method enables a personalized approach for defining target regions in radiation therapy which could translate to improved clinical outcomes.
IMG-28. AUTOMATIC BRAIN TUMOR VOLUMETRIC ANALYSIS IN MAGNETIC RESONANCE IMAGING GENERALIZABLE TO PEDIATRIC NEURO-ONCOLOGY
Authors: Jiang Zhifan , Capellán-Martín Daniel , Parida Abhijeet , Liu Xinyang , Van Lam  , Nisar Hareem , Tapp Austin , Ledesma-Carbayo María J , Anwar Syed Muhammad , Linguraru Marius George
Published: June 2024

BACKGROUND

The prognosis of brain tumors is variable in clinical practice if it only relies on human interpretation of magnetic resonance imaging (MRI). The automatic segmentation of brain tumors in MRI enables quantitative analysis in support of clinical trials and personalized patient care. We developed benchmarked deep learning-based tools that are generalizable to the volumetric quantification of various tumor types across diverse populations.

METHODS

We participated in the well-established international brain tumor segmentation challenge (BraTS 2023) and benchmarking competition. The challenge made available 4,500 multi-national brain tumor cases with multi-sequence MRIs, including pediatric high-grade gliomas (PED), i.e., high-grade astrocytoma and diffuse midline glioma, and adult gliomas, brain metastases (MET) and intracranial meningiomas (MEN). Each case comprises four MRI volumes: T1, contrast-enhanced T1, T2, and T2-FLAIR. Manual segmentations were provided to establish ground truth for enhancing tumor (ET), tumor core (TC), and whole tumor (WT). Our framework used a model ensemble strategy based on two state-of-the-art deep learning models: a convolutional neural network (nnU-Net) and a vision transformer (Swin UNETR) and was tested for broader applicability across multiple tumor types. The framework was trained on 99, 1,000, and 165 cases and validated on 45, 141, and 31 unseen cases for PED, MEN, and MET, respectively. Automatic segmentations were evaluated by lesion-wise volume overlap (Dice similarity score, DSC) and Hausdorff distance (HD).

RESULTS

In the evaluation on independent unseen test datasets, our automatic tool was ranked first for PED, third for MEN, and fourth for MET volumetric analysis. Our method resulted in PED lesion-wise DSC of 0.733, 0.782, 0.817 and HD (mm) of 75.93, 25.54, 24.18 for ET, TC, and WT, respectively.

CONCLUSIONS

These brain tumor volumetric analysis tools are readily available to be efficiently tested on diverse datasets. Automatic MRI analysis provides consistent quantitative data for multi-institutional protocols and clinical trials.
IMG-29. IMPLICATIONS OF IMAGE HARMONIZATION FOR BRAIN TUMOR CLINICAL TRIALS
Authors: Parida Abhijeet , Jiang Zhifan , Anwar Syed Muhammad , Stence Nicholas , Foreman Nicholas , Packer Roger J , Fisher Michael J , Avery Robert A , Linguraru Marius George
Published: June 2024

BACKGROUND

Clinical trials for rare pediatric conditions like optic pathway gliomas associated with NF1 (NF1-OPGs) require numerous sites that utilize different MRI scanners and protocols. These MRIs must be harmonized for reliable comparison using machine learning tools. We propose a deep-learning based MRI harmonization that enables reproducible data analysis across multiple sites and MRI platforms.

METHODS

One-hundred eighty clinical T1-weighted-MRIs of pediatric NF1-OPG subjects were acquired from three sites [Children’s National Hospital (site A, N=60), Children’s Hospital Colorado (site B, N=60), and Children’s Hospital of Philadelphia (site C, N=60)] using different MR scanners (GE, Phillips, and Siemens, respectively). MRIs from A and B were used to train a branched neural network and C were used for testing. Using unsupervised learning, the neural network identified differences in imaging protocols and harmonized data to a chosen protocol, e.g., that of site A, while preserving the patient anatomy. The harmonization was evaluated using Wasserstein distance (nWD), which measured similarity between two gray scale appearances of MRI intensity histograms. Anatomy preservation metric (AP) measured relative volume changes in gray matter (GM) segmented using Freesurfer, before and after harmonization. For both metrics, 100% means the best possible harmonization was achieved.

RESULTS

Before harmonization, nWD between grayscale appearance of MRIs from sites A and B was 27.3±3.1%. After harmonization, the similarity became 94.2±2.0% with a GM volume error of 3.11±0.56ml which corresponded to AP of 93.1±4.7%. For the test data, nWD similarity post harmonization improved from 38.2±3.9% to 93.4±2.2% with GM volume error of 4.12±0.47ml which corresponded to AP of 90.3±3.5%.

CONCLUSIONS

Our approach enables MRI harmonization while preserving anatomy for precise analysis using machine learning tools. It scales to new sites to support multisite clinical trials that utilize imaging outcomes for brain tumors and other rare diseases.