bluuebunny/crossref_metadata_2025 huggingface dataset:
HGG-21. DISTRIBUTION AND MUTATIONAL PATTERNS OF TP53 ALTERATIONS ACROSS SUBTYPES OF PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Blattner-Johnson Mirjam , Sturm Dominik , Hirsch Steffen , Jones Barbara , Schramm Kathrin , Balasubramanian Gnana Prakash , Sill Martin , Autry Robert , Previti Christopher , van Tilburg Cornelis M , Milde Till , Pajtler Kristian W , Sahm Felix , Kramm Christof M , Witt Olaf , Pfister Stefan M , Jones David T W
Published: June 2024

Inactivating alterations of tumor suppressor gene TP53 are a hallmark of tumor progression in various cancer entities. Unfortunately, TP53 inactivation has not yet provided an actionable vulnerability. To investigate distribution, mutational pattern and impact of TP53 alterations in pediatric high-grade gliomas (pedHGG), we investigated TP53 alterations in 407 pedHGG by analyzing genomic sequencing and survival data collected through the INFORM and MNP molecular diagnostic pipelines. Nearly half of pedHGG (47%) showed signs of genomic TP53 inactivation. A second hit suggesting complete loss of function was observed in 84% of tumors, with loss of heterozygosity as the most common mechanism (70%). The frequency of TP53 alterations ranged from 97% in H3 G34-mutated tumors, 70% in IDH-mutated tumors and 61% in H3 K27-mutated tumors down to 40% in H3-/IDH-wildtype subtypes and none in infant-type hemispheric gliomas. Alterations in TP53 were associated with significantly shorter mean overall survival of 11 vs. 15 months in patients diagnosed with H3 K27-mutated tumors. Previously described TP53 hotspot mutations, such as amino acid substitutions at position 17, 248, 273, 282 and 342 were also prominent in the studied cohort (NM_000546). Mutations at position 342 were enriched in H3 G34-mutated tumors, with one-third carrying a stopgain mutation at this position rarely seen in other pedHGG. G34-mutated tumors also showed an abundance of nonsense, splicing or frameshift mutations in contrast to the predominance of missense mutations in other subtypes. The functional impact of these differences is currently under investigation. Lastly, we observed potential evidence for a genotype-phenotype link with Li-Fraumeni syndrome (LFS)-associated (constitutional) TP53 mutations in pedHGG, including an absence of the R248 hotspot mutation in 15 LFS-associated tumors.
HGG-23. MAPPING GENETIC DEPENDENCIES IN PAEDIATRIC HIGH GRADE GLIOMAS AT GENOME-SCALE
Authors: Tsui Vanessa , Liang Yuqing , Lee Hanbyeol , Zhou Yichen , Sun Claire , Daniel Paul , Firestein Ron
Published: June 2024

BACKGROUND

Pediatric high-grade gliomas (HGGs) present a therapeutic challenge due to their aggressive behavior and limited treatment options. Traditional treatments often fall short in addressing the genetic complexity and aggressiveness of pediatric HGGs, urging the search for and validation of novel genetic dependencies as potential therapeutic targets.

METHODS

Loss of function CRISPR screens enable the systematic investigation of gene function by selectively disrupting gene expression, offering invaluable insights into the genetic dependencies fuelling tumor growth and survival. Herein, we conducted genome-scale, loss of function CRISPR/Cas12 screens across genetically-defined subtypes of pediatric HGG, including diffuse midline gliomas (n=30 cell lines).

RESULTS

Distinct genetic dependencies exclusive to pediatric high-grade gliomas (pHGG) are uncovered compared to their adult counterparts, particularly within druggable pathways. These dependencies are associated with specific pathways such as cellular metabolism, epigenetics, and tissue development. Notably, histone-altered subtypes of pHGG exhibit dependency on distinct gene sets for growth. Furthermore, machine learning techniques are applied to correlate various -omics features (RNA, DNA, epigenomics, proteomics) with genetic dependencies, facilitating the identification of biomarkers predictive of therapeutic response.

CONCLUSION

Our work provides a comprehensive genetic dependency map of pHGG. We expect this data to serve as a springboard for enriching our biological understanding of pHGG, ultimately improving clinical outcomes and quality of life.
HGG-37. CLINICAL AND MOLECULAR FEATURES OF BITHALAMIC GLIOMAS IN CHILDREN AND ADOLESCENTS: MULTICENTRIC STUDY AND META-ANALYSIS
Authors: Perez-Somarriba Marta , Cherungonath Anoop , Wasti Ajla , Pace Erika , Benjamin Philip , Villacampa Guillermo , Reisz Zita , Al-Sarraj Safa , Bridges Leslie , Jacques Thomas , Lavarino Cinzia , Gene Nagore , Pereira Rita , Grabovska Yura , Mackay Alan , Kessler Ketty , Clarke Matthew , Santa-Maria Vicente , Cruz Ofelia , La Madrid Andres Morales , Llort Anna , Lassaletta Alvaro , Vazquez-Gomez Felisa , Carceller Elena , Garrido Carmen , Solano-Paez Palma , Quiroga Eduardo , Zebian Bassel , Hettige Samantha , Cockle Julia , Mandeville Henry , Angelini Paola , Srivatsa Kavitha , Vaidya Sucheta , Marshall Lynley , Jones Chris , Carceller Fernando
Published: June 2024

BACKGROUND

Bithalamic gliomas (BTG) are rare brain tumors with dismal prognosis. Optimal management and role of novel therapies have not been established yet. This study aimed to improve our understanding of BTG to guide adapted treatments.

METHODS

Retrospective case series across 6 Pediatric Neuro-Oncology Units (United Kingdom, Spain) of ≤18-year-old patients with BTG between 2000-2022. Clinical, pathological, and molecular data were derived and reviewed. A systematic review of the literature, meta-analysis, and survival analysis were performed.

RESULTS

Overall, 148 BTG cases were evaluated (study=25; literature=123). Of those, 97/148 (65%) had individual survival data. Median overall survival (mOS) (95%CI/range) was 13.2 months (12-16.8/0.6-262.2). mOS stratified by histological grading: 21.0 months (low-grade, n=32) versus 12.0 months (high-grade, n=55); hazard ratio (HR) 0.37 (95%CI 0.20-0.68), p-value=0.001. Molecular analyses (n=70) showed EGFR alterations (56%), TP53 mutations (30%), and H3K27M mutations (23%). mOS of EGFR-altered BTG based on targeted therapy was 13.2 months (no EGFR-inhibitors, n=26) versus 21.6 months (EGFR-inhibitors, n=9); HR 0.36 (95CI% 0.11-1.22). Methylation array data was generated for 4 patients and combined with 10 previously available profiles. Integrated MNP12.8 and mutation information classified 57% as DMG_EGFR and 21% as pedHGG_RTK2B. The remaining cases were classified as DMG_K27M (2/14) or pedHGG_A (1/14). Work is underway to establish a patient-derived EGFR-mutated BTG cell culture and further studies.

CONCLUSIONS

BTG have distinct radiological, and molecular features. EGFR alterations are seen in approximately half of BTG and H3K27M mutations are less frequent than in other midline high-grade gliomas (HGG). Low-grade histology is associated with a survival advantage, although still poor compared to pediatric low-grade gliomas. Therefore, treatment as per HGG guidelines should be considered for all BTG regardless of histological grading. EGFR-altered BTG patients can derive survival benefit from EGFR inhibitors, indicating that these should be considered as part of future treatment protocols.
HGG-40. UNRAVELING THE IMMUNOLOGIC VULNERABILITIES OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Galvin Robert T , Sadeghipour Negar , Xiu Joanne , Ashley David M , Ahluwalia Manmeet S , Aulakh Sonikpreet , Huang R Stephanie , Largaespada David A
Published: June 2024

BACKGROUND

Insights into the pathogenesis of diffuse hemispheric glioma, H3 G34-mutant (DHG-G34), an incurable high-grade glioma, have opened new therapeutic possibilities. The DHG-G34 oncohistone mutation impairs the epigenetic regulator SETD2, which normally orchestrates DNA-mismatch-repair and negatively regulates Polycomb Repressive Complex 2 (PRC2). In DHG-G34, a mismatch-repair-deficiency phenotype is predicted, but an anti-tumor immune response is notably absent, which we hypothesize is linked to the aberrant transcriptional repression by PRC2. Here, we investigate DHG-G34 immunosuppression mechanisms in a real-world multi-omics cohort and cell line model.

METHODS

Clinical, molecular, and immunologic characteristics of a DHG-G34 cohort, sequenced at Caris Life Sciences, are contrasted against diffuse midline glioma (DMG) and pediatric low-grade glioma (LGG). KNS-42 DHG-G34 cell line was exposed to valemetostat (a EZH1/2 inhibitor) or DMSO in-vitro. Flow cytometry and RNA-sequencing were utilized to determine differential immunologic characteristics.

RESULTS

29 DHG-G34, 51 DMG, and 52 LGG were identified. DHG-G34 median OS was 15.4 mo., like DMG (HR=1.1, p=0.686). Common DHG-G34 alterations were TP53 (93.1%), ATRX (69.0%), PDGFRA (31.0%). Tumor mutational burden (TMB) was high, >=10mt/MB, in 10% of DHG-G34, with 0 DMG or LGG events (p<0.01, q>0.05), but innate and adaptive immune fractions and antigen-presenting genes were decreased (fold-change: 0.19–0.83, q<0.05). In KNS-42, PRC2 inhibition upregulated MHC class 1 (p<0.001). Of 402 missense variants, 43 were upregulated following EHZ2 inhibition, and 4 were downregulated (q<0.05). Among immunostimulatory genes, P2RX7, which engages T-cells, was downregulated in patient samples (q<0.001) and upregulated in EZH2 inhibited KNS-42 (q<0.001).

CONCLUSIONS

DHG-G34 has a propensity for high TMB but remains immunologically cold. Our pilot experiment suggests inhibiting PRC2’s unique role in DHG-G34 may sensitize DHG-G34 to an immune response by inducing MHC class 1 expression and transcriptional read-through of mutated transcripts. Understanding whether treatment induces TMB in DHG-G34 may affect timing of an immunotherapeutic intervention.
HGG-42. COMBINED PRECLINICAL AND CLINICAL INVESTIGATION OF WHICH PEDIATRIC HIGH-GRADE GLIOMA SUBTYPES BENEFIT FROM CCNU/TEMOZOLOMIDE
Authors: Haase Rebecca D , Kilburn Lindsay , Filbin Mariella , Green Adam L
Published: June 2024

BACKGROUND

The only chemotherapy regimen that has shown a clear survival benefit in pediatric high-grade glioma (pHGG) is combining temozolomide (TMZ) and lomustine (CCNU) with RT per COG ACNS0423. However, which pHGG subgroups benefit from this treatment is unknown.

METHODS

Through the Children’s Brain Tumor Network (CBTN) database, we found 20 pHGG patients treated with RT-TMZ-CCNU, along with 95 control patients who received other treatment. We compared overall (OS) and event-free survival (EFS) using the Log-rank test for the respective pHGG subtype. We used a patient-derived xenograft (PDX) model, representing newly diagnosed hemispheric pHGG (diffuse hemispheric glioma, G34R-mutant (DHG), to test the effects of combining TMZ-CCNU.

RESULTS

From our clinical (CBTN) data, we found that median OS for the RT-TMZ-CCNU group was significantly greater compared to the control cohort (990 days (d) vs. 427d, p=0.011), as was EFS (510 vs. 215d, p=0.0041). For patients with hemispheric tumors, median OS and EFS were significantly increased for the RT-TMZ-CCNU group (n=8) vs. controls (n=47) (OS 5,274 vs. 496d, p=0.018; EFS 903 vs. 271d, p=0.018). For patients with midline pHGG, median OS and EFS were not significantly different between the RT-TMZ-CCNU group (n=11) and controls (n=43). In our PDX model, we found that TMZ-CCNU led to long-term survival compared to vehicle control and single-agent treatment (p<0.001). DISCUSSION: Patients with hemispheric pHGG had a significant survival benefit from RT-TMZ-CCNU treatment, while those with midline pHGG did not. Hemispheric pHGG, which are enriched for H3G34 and IDH mutations, may be more likely to respond to RT-TMZ-CCNU. These findings are supported by preclinical data showing that mice with DHG, G34R-mutant were cured after TMZ-CCNU treatment. Given our results and those from ACNS0423, RT-TMZ-CCNU should be strongly considered for treatment of patients with hemispheric pHGG and as a backbone for future clinical trials in this population.
HGG-46. PEDIATRIC RADIATION-INDUCED GLIOMA PATIENT SAMPLES AND NOVEL PATIENT-DERIVED MODELS REVEAL TRANSLATIONALLY RELEVANT TREATMENT SUSCEPTIBILITIES AND POTENTIAL GERMLINE RISK FACTORS
Authors: DeSisto John , Knox Aaron , Slade Mathew , Link Gabrielle , Zhuang Yonghua , Donson Andrew , Miller Kristen , Barsh Elinor , Arnold Michael , Armstrong Gregory T , Bhatia Smita , Karam Sana D , Serkova Natalie , Vibhakar Rajeev , Foreman Nicholas , Green Adam L
Published: June 2024

BACKGROUND

Pediatric radiation-induced glioma (RIG) is an incurable secondary high-grade glioma (HGG) afflicting up to 4% of children who previously received cranial radiotherapy (RT) for other malignancies. RIG accounts for up to 10% of pediatric brain tumor deaths. It has no known genetic risk factors nor effective treatment and is uniformly fatal, partly due to extremely limited available models. Our recent molecular characterization of patient samples showed that while RIG and primary pediatric HGG share histological similarities, their genetic alterations and gene expression profiles differ.

METHODS

We obtained germline DNA sequencing from 28 RIG patients and 112 matched controls who received RT but did not develop RIG. In addition, we developed cell culture and murine orthotopic patient-derived xenograft (PDX) models from four RIGs. We conducted single-cell RNA-seq (scRNA-seq), drug screening/validation, and CRISPR functional screening on our novel models.

RESULTS

Germline mutations in TP53, PARP10, POLI, DCLRE1A, and MLH3 were more common in RIG patients than controls (p<0.002). Our matched cell culture and PDX models of RIG represent the genetic diversity of the disease. The PDX models form tumors in 30-120 days and closely recapitulate human RIG by histology and scRNA-seq. They show susceptibility across models to DNA-damaging treatments (etoposide, irinotecan, radiation), as well as MEK, PARP, and proteasome inhibition, with orthogonal supporting findings via CRISPR screening. Several two-treatment combinations also show efficacy and synergy across models, including radiation and trametinib in vivo (logrank p=0.029). Discussion: RIG is an understudied but major cause of pediatric CNS tumor mortality that differs genetically from primary pediatric HGG. Our findings suggest specific germline alterations in DNA repair pathways may put some patients at higher risk of developing RIG after cranial RT. We also introduce the first set of patient-derived RIG models in order to advance translational RIG research, with characterization of translationally relevant treatment susceptibilities.
HGG-51. INTRANASAL DELIVERY OF PDGFRA-IMMUNOLIPOSOMAL SN-38 FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Kaur Savneet , Watanabe Jun , Uchida Eita , Zhang Peng , Hashizume Rintaro
Published: June 2024

INTRODUCTION

pHGGs are the most common cause of cancer-related death in children, of which the most malignant and devastating tumors include diffuse midline glioma (DMG). Its anatomical location in the braistem, infiltrative nature, and blood-brain barrier (BBB) limit surgical resection and the distribution of systemically administered drugs. Intranasal delivery (IND) is a noninvasive method that bypasses the BBB, by leveraging the unique anatomic connections of the olfactory and trigeminal nerve pathways with the nasal cavity. We previously demonstrated the efficacy of IND of liposomal (LS) formulation of the active metabolite of the DNA topoisomerase I inhibitor, irinotecan, LS-SN-38, in orthotopic human brainstem xenograft models. The specificity of liposomes can be enhanced by using immunoliposome (iLS) formulation, which are coated with antibodies specific to the tumor cells leading to targeted drug delivery and reduced toxicity to normal cells. Platelet-derived growth factor receptor alpha (PDGFRA) plays a role in DMG oncogenesis and is expressed in as much as 70% of DMG by immunohistochemistry. In this study, we evaluated the specificity of anti-PDGFRA monoclonal antibody conjugated immunoliposome (PDGFRA-iLS) in pHGG cell lines.

METHODS

PDGFRA signals were assessed in pHGG cells using western blotting. Cells with high and low expression of PDGFRA were treated with rhodamine (Rho) labeled PDGFRA-iLS and imaged with fluorescent microscope.

RESULTS

DIPG007, SF7761 and KNS42 expressed high levels of PDGFRA, while SF8628 and DIPG36 cells showed low expression. Fluorescence microscopy revealed high PDGFRA-rhodamine (Rho)-iLS expression in DIPG007 cells (PDGFRA high), relative to SF8628 and DIPG36 cells (PDGFRA low).

CONCLUSION

PDGFRA-Rho-iLS shows increase cellular uptake in DIPG cells. Work is underway to determine the biodistribution, host toxicity, and anti-tumor activity of IND of PDGFRA-iLS-SN- 38 alone and in combination with radiation therapy in pHGG xenograft models.
IMG-06. IMAGING-BASED, TEMPORALIS MUSCLE THICKNESS AS A BIOMARKER IN CHILDREN WITH GLIOMAS
Authors: Zapaishchykova Anna , Tak Divyanshu , Ye Zezhong , Vajapeyam Sridhar , Smith Ceilidh , Liu Kevin X , Aerts Hugo J W L , Chi Susan N , Haas-Kogan Daphne A , Nabavizadeh Ali , Familiar Ariana , Mueller Sabine , Poussaint Tina Y , Kann Benjamin H
Published: June 2024

BACKGROUND

Sarcopenia, or lean muscle loss, causes morbidity and early mortality in pediatric cancer patients and survivors. Sarcopenic patients who are also obese have a particularly morbid metabolic condition that cannot be identified by body mass index (BMI) alone. Temporalis muscle thickness (TMT) on T1-weighted MRI provides a direct assessment of lean muscle mass. In this study, we determined how TMT was associated with nutritional and survival outcomes in children with gliomas using an automated deep-learning pipeline that calculates TMT on MRI and provides age-and sex-specific TMT percentiles (iTMT).

METHODS

We analyzed a cohort of 343 patients and 1,673 scans (244 low-grade gliomas(LGG) and 99 high-grade gliomas (HGG)) diagnosed between 2000-2023 at Boston Children’s Hospital/Dana-Farber Cancer Institute, who had linked longitudinal MRI and clinical data available. We calculated and compared age-adjusted iTMT, BMI, weight percentiles, and serum albumin. Sarcopenic obesity in glioma survivors was defined as sarcopenic iTMT (<5th %tile) and obese BMI (>95th %tile).

RESULTS

iTMT was significantly correlated with BMI (N=1,574 scans, Spearman r=0.34, p=4e-45) and weight (N=1,574 scans, r=0.21, p=1e-17), but not serum albumin (N=84 scans, r=-0.04, p=0.66) at any given time point. Of all patients, 113(36.4%) had sarcopenic obesity during at least one time point. For HGG patients, those with less than the median survival time (550 days) had significantly lower baseline iTMT (median: 6th %tile vs. 33rd %tile, p=0.01). For LGG patients, symptoms of malnutrition at diagnosis were associated with a trend toward lower iTMT (N=244, 19th %tile vs.28th %tile, p=0.07).

CONCLUSION

Our study demonstrates that iTMT is an independent biomarker for malnutrition and survival for pediatric gliomas and can identify patients with sarcopenic obesity. iTMT assessment on routine clinical MRI could be a practical way to monitor muscle status and guide supportive interventions in children with brain tumors.
IMG-11. RADIOGENOMIC ANALYSIS INFORMS ON IMMUNOLOGICAL PROFILES, PROGNOSIS, AND TREATMENT RESPONSE IN PEDIATRIC LOW-GRADE GLIOMA
Authors: Kazerooni Anahita Fathi , Kraya Adam , Rathi Komal S , Kim Meen Chul , Vossough Arastoo , Kesherwani Varun , Khalili Nastaran , Familiar Ariana , Gandhi Deep , Khalili Neda , Anderson Hannah , Koptyra Mateusz , Storm Phillip B , Ware Jeffrey B , Foster Jessica , Mueller Sabine , Fisher Michael J , Resnick Adam C , Nabavizadeh Ali
Published: June 2024

BACKGROUND

Pediatric low-grade gliomas (pLGGs) have variable prognosis and treatment responses. Complete resection cannot be achieved for all tumors, especially for highly infiltrative or deep-seated tumors, necessitating additional therapy, from chemotherapy to targeted inhibitors. We integrated imaging-derived phenotypes with genotypic traits from transcriptional analysis, offering an in-depth characterization of pLGG immune microenvironment, progression risk, and likelihood of multiple treatments.

METHODS

Analyzing 549 treatment-naïve pLGGs with multiparametric MRI and RNA sequencing, we identified distinct immunological groups using XCell scores based on immune cell infiltration. We developed a radiomic signature using conventional MRI and machine learning techniques (support vector machines with a linear kernel and nested cross-validation) to distinguish the ‘immune-hot’ group, and incorporated diffusion MRI to improve signature accuracy. Additionally, a clinicoradiomic model predicting tumor progression risk and treatment response was trained, integrating clinical and radiomic data. Transcriptomic analysis was conducted to identify pathways correlated with clinicoradiomic risk, predictive of pLGG progression.

RESULTS

Three immunological groups were revealed, the ‘immune-hot’ group characterized by poor prognosis due to a high concentration of pro-tumorigenic M2-polarized macrophages, despite a higher preponderance of T-lymphocytes. The radiomic signature effectively distinguished the ‘immune-hot’ group with balanced accuracies of 76.8%/86.0% in discovery/replication sets, improved by diffusion MRI to 81.5%/84.4%. The clinicoradiomic model showed concordance indices of 0.71 (discovery) and 0.77 (replication), predicting patient progression risk. Significant differences (p=0.0010) were found in clinicoradiomic risk scores between patients undergoing one versus multiple treatments post-diagnosis, linking higher scores to a likelihood of multiple treatments. Transcriptomic pathways associated with higher clinicoradiomic risk highlighted the importance of fatty acid oxidation, a tumor-promoting mechanism that drives adaptive resistance to cytolytic immune cell effectors.

CONCLUSIONS

This first large-scale radiogenomic analysis in pLGGs aids in prognostication, assessing progression risk, predicting treatment response to standard-of-care therapies, and stratification of patients to identify potential candidates for novel therapies targeting aberrantly regulated pathways.
IMG-18. DIFFERENTIAL DIAGNOSIS OF POSTERIOR FOSSA TUMORS USING RADIOMICS; A FIRST-LINE DIAGNOSTIC STEP REQUIRED FOR DOWNSTREAM ANALYSES
Authors: Kazerooni Anahita Fathi , Khalili Neda , Gandhi Deep , Jain Paarth , Familiar Ariana , Kim Meen Chul , Khalili Nastaran , Haldar Debanjan , Storm Phillip B , Kline Cassie , Vossough Arastoo , Resnick Adam , Nabavizadeh Ali
Published: June 2024

BACKGROUND

Accurate radiographic diagnosis of pediatric brain tumors (PBTs) that originate in the brainstem and posterior fossa, including medulloblastoma (MB), pilocytic astrocytoma (PA), ependymoma (EPN), atypical teratoid/rhabdoid tumor (ATRT), and diffuse intrinsic pontine glioma (DIPG), is crucial for optimizing surgical approaches and enhancing neoadjuvant therapies. Existing research on the radiographic differential diagnosis of posterior fossa tumors has limitations, including small sample sizes, lack of inclusion of certain histologies especially rarer tumors such as ATRTs, and incomplete analysis of the whole tumor, including peritumoral edema. In this study, we aimed to perform a comprehensive analysis using radiomics and machine learning to differentiate among the common posterior fossa and brainstem tumors.

METHODS

We employed 927 radiomic features extracted from whole tumor regions within treatment-naïve, standard multiparametric MRI sequences (pre-/post-contrast T1-weighted, T2-weighted, FLAIR) of 264 patients (106 MBs, 78 PAs, 28 EPNs, 27 ATRTs, and 25 DIPGs), collected from the Children’s Brain Tumor Network (CBTN). We adopted a one-versus-rest classification strategy, employing Support Vector Machines combined with the Least Absolute Shrinkage and Selection Operator (LASSO) for feature selection, and implementing nested cross-validation for robustness.

RESULTS

The performances of the classifiers were evaluated using the Area Under the Receiver Operating Characteristic Curve, yielding values of 0.84 for MBs, 0.84 for PAs, 0.70 for EPNs, 0.75 for ATRTs, and 0.71 for DIPGs.

CONCLUSIONS

Our method effectively differentiates between various tumor types in the posterior fossa and brainstem, paving the path towards the development of comprehensive diagnostic and prognostic AI tools for pre-treatment histological diagnosis of these tumors. These AI tools can lead to more tailored, risk-adjusted treatments for PBTs, reducing morbidities and improving patient outcomes. Based on our promising initial results, we will expand our dataset to include more samples and incorporate rarer tumor types, as well as piloting in different molecular subclassifications.
IMG-30. DIFFUSE MIDLINE GLIOMA MAP TO A COMMON FUNCTIONAL NETWORK ASSOCIATED WITH TUMOUR PROGRESSION AND OVERALL SURVIVAL
Authors: Sidpra Jai , Massey Flavia , Biswas Asthik , Sudhakar Sniya , Peres Bruno S , Sepulveda Francisco , Opipari Raffaella Scotto , Akram Harith , Aquilina Kristian , Mankad Kshitij , Jacques Thomas S , Hargrave Darren R
Published: June 2024

BACKGROUND

Gliomas form bidirectional, functional synapses with otherwise healthy neurons: increasing neuronal excitability and driving tumour growth. The prognostic significance of this phenomenon does, however, remain unknown.

METHODS

This study used tumour location and tumour network mapping to identify brain networks associated with tumour progression and overall survival (OS) in 90 children with diffuse midline glioma, H3K27-altered (DMG). Tumours were segmented on volumetric magnetic resonance imaging and mapped to a standard template. Brain networks functionally connected to each tumour were computed using normative paediatric resting-state functional magnetic resonance imaging (n=525).

RESULTS

Median OS in the discovery cohort was 9.5 months (interquartile range 7.0-14.5 months). Comparison of tumour location in short-term (<18 months; n=75) and long-term (≥18 months; n=15) survivors of DMG identified an area of maximal anatomic overlap associated with short-term survival in the mid-pontine tegmentum and corticospinal tracts (89%; P<0.05). Tumour location was, however, not associated with OS (P=0.347). We, therefore, seeded tumour-to-brain resting-state functional connectivity maps from this a priori tegmental region-of-interest, identifying a specific brain network associated with short-term survival defined by functional connectivity to the medial prefrontal cortex, thalami, and cerebellum (P<0.0005). High and low tumour connectivity to this network was associated with short-term and long-term OS, respectively, using both univariate (P=0.013) and multivariate models controlling for treatment and tumour volume (P=0.016). Final, subset analysis of longitudinal neuroimaging in children within one month of death (n=21) showed tumour progression mapped to this same functional network and exhibited a dominant (left) hemispheric predominance (P<0.05), underpinned by increased tumour connectivity to the right (P=0.0270) rather than left (P=0.1802) corticospinal tract, and associated with OS (P=0.02).

DISCUSSION

We map DMG to a unified and prognostically important functional network, further establishing DMG as a circuit disorder. Interventions aiming to modulate this network may inform future treatment strategies for affected children.
IMMU-14. MULTI-INSTITUTION ANALYSIS OF TREATMENT MATCHING STATUS AND OUTCOMES IN PEDIATRIC CNS TUMOR PATIENTS
Authors: Horowitz Emma J , Parisi Rose , Rood Gavrielle , Bowden Acacia , Byrwa David , Patel Roshal , Turco George , Korones David , Andolina Jeffrey , Comito Melanie , Barth Matthew , Weintraub Lauren
Published: June 2024

BACKGROUND

With the advent of immunotherapies and targeted therapies, research is needed to assess how pediatric brain tumor genomic biomarkers may impact treatment modality choice and outcomes.

METHODS

We conducted a retrospective analysis of 160 pediatric patients (78 male, 82 female) with a median age of 9 years (2 months-26 years) diagnosed with a primary CNS tumor at four academic institutions from 2008-2023. Tumor mutational burden (TMB), treatment type, outcomes, and matching status were analyzed. Matching status refers to the presence of tumor genomic markers that matched with the pharmacologic target.

RESULTS

Low-grade glioma (N=68, 42.5%) and high-grade glioma (N=36, 22.5%) were the most common tumors. Other tumors included medulloblastoma (N=17, 10.6%), atypical teratoid rhabdoid tumor (N=4, 2.5%), ependymoma (N=8, 5%), ganglioglioma (N=7, 4.4%), other embryonal tumors (N=5, 3.1%), and choroid plexus tumors (N=5, 3.1%). Of the patients who received targeted or immunotherapy (N=30), most patients had matched (N=19) versus unmatched therapy (N=11) and similar survival rates (p=0.44). Although not statistically significant (p=0.065), patients who received standard therapy had higher overall survival rates (N=103/130) compared to those receiving targeted or immunotherapy (N=19/30). When comparing only patients with high TMB tumors (≥3 mutations/megabase), patients were significantly more likely to survive when receiving standard therapy only (N=20/33) versus targeted or immunotherapy (N=1/7) (p=0.026). Notably, targeted and immunotherapy were not used upfront in these cases. Among patients who had progressed or recurrent disease specifically, there was a non-statistically significant trend towards better survival rates for those who received targeted or immunotherapy (p=0.46).

CONCLUSIONS

Patients with high TMB tumors who received targeted or immunotherapy have worse outcomes than patients with low TMB, or with high TMB receiving standard therapy. High TMB tumors often require therapy for relapsed/refractory disease. These findings are critical for identifying patient subsets in need of alternative treatment options.
IMMU-21. B7-H3 NANOBODY CAR-T CELL THERAPY IN PEDIATRIC GLIOBLASTOMA
Authors: Fanuzzi Mia , Singh Mohit Pratap , Puebla Mariela , Cole Allison , Li Dan , Ho Mitchell , Nellan Anandani
Published: June 2024

BACKGROUND

Immunotherapy is a developing but challenging field of research for the treatment of central nervous system malignancies. Chimeric antigen receptor (CAR)-T cell therapy has been effective in treating hematologic malignancies, but that success has not been clinically translated to solid tumors in children. B7-H3 has been identified as a promising immunotherapy target as it is highly expressed in pediatric glioblastoma and correlates with tumor progression and poor prognosis. We aim to evaluate a nanobody-based CAR-T cell therapy that binds B7-H3 with high affinity and hypothesize that anti-B7-H3 nanobody CAR-T cells can effectively kill B7-H3-expressing tumor cells.

METHODS

B7-H3 nanobodies were isolated from camel phage libraries and cloned into lentiviral CAR-T cell constructs. Human T cells were transduced by lentivirus to express CAR on the surface. Nanobody CAR-T cell functionality was evaluated by an impedance-based cytotoxicity assay and cytokine release was measured by ELISA. CAR-T avidity was quantified by the Lumicks z-Movi assay. In vivo studies are evaluating the efficacy of B7-H3 CAR-T cells in an orthotopic glioblastoma model in immunodeficient mice. Mice were treated with B7-H3 CAR-T cells by intracerebroventricular or intravenous delivery.

RESULTS

We confirmed high expression of B7-H3 on the surface of three pediatric glioblastoma cell lines by flow cytometry and Quantibrite staining. We confirmed effective killing of B7-H3-expressing tumor cells and the release of high levels of cytokines. B7-H3 nanobody CAR-T cells were observed to have high avidity compared to control CAR-T cells. In vivo studies are currently ongoing and treatment response will be evaluated by luminescence imaging and endpoint histologic analysis.

CONCLUSION

We have shown that B7-H3 nanobody CAR-T cells demonstrate significant preclinical efficacy. It is critical to study CAR-T cell therapy in immunocompetent in vivo models for further development and clinical application.
LGG-08. DIFFUSE ASTROCYTOMA IN A PATIENT WITH POSSIBLE MBD4-ASSOCIATED NEOPLASIA SYNDROME (MANS)- EXPANDING THE SPECTRUM OF MANS-ASSOCIATED NEOPLASM
Authors: Gorsi Hamza , Finlay Jonathan , Yankelevich Maxim
Published: June 2024

BACKGROUND

MBD4-associated neoplasia syndrome (MANS) is a recently identified genetic syndrome characterized by the development of colorectal polyps, acute myeloid leukemia, and uveal melanoma, with an elevated mutation burden. MANS is attributed to bi-allelic germline variations in the MBD4 gene.

METHOD

We present a case of a pediatric patient with diffuse astrocytoma WHO-grade II and bi-allelic germline variations in the MBD4 gene.

CASE REPORT

A previously healthy 10-year-old female with a significant family history of high-grade IDH wild type-glioma in the deceased older brother presented with vague symptoms and was found to have abnormal brain MRI with multiple foci of subcortical FLAIR/T2 hyperintensity involving the right frontotemporal lobe, left frontal lobe, and left thalamus. She had intact neurologic exam findings and was followed with serial brain MRIs. Over the next 2 years, she continued to be asymptomatic, but her MRI showed an increase in the size of her brain lesions. Following a stereotactic biopsy of the right temporal lesion, a diagnosis of diffuse astrocytoma (WHO-grade II) was confirmed. Molecular analysis showed point mutations in IDH1, TP53, and PTEN genes, along with LOH at 17p (including TP53 gene), and outline gene expressions for NTRK2, OLIG2, GRM3, FGF1, SOX8, MBP, MGMT genes. Given the low grade of the tumor and the absence of tumor-related symptoms, a decision was made to continue monitoring with serial MRIs. Whole exome sequencing identified germline bi-allelic missense variations in the MBD4 gene, specifically C.1405A>G and C.1573A>C. Both parents were found to be heterozygous for one of these mutations.

CONCLUSION

The significance of MBD4 mutation remains unknown in our patient, but bi-allelic variations coupled with the presence of a brain tumor and positive family history raise concerns about MANS in our patient. Additional studies are needed to elucidate the potential association between brain tumors and MANS.
LGG-22. INVESTIGATING THE EFFICACY OF BELVARAFENIB, A TYPE II PAN-RAF INHIBITOR, AS A POTENTIAL THERAPEUTIC AGENT TO TREAT PEDIATRIC LOW-GRADE GLIOMAS HARBORINGBRAF FUSIONS
Authors: Lebert Brittany M , Gonzalez-Vega Maxine , Jafrani Ryan , Aguilar-Bonilla Ana , Smith Amy A
Published: June 2024

BACKGROUND

Low-grade gliomas (LGGs) are the most common central nervous system (CNS) tumor found in children, comprising nearly one-third of all diagnoses. Fifteen to twenty percent of pediatric LGGs arise due to mutations in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway, most commonly at the B-Raf proto-oncogene (BRAF) gene. Modern advances in personalized medicine have led to widespread use of targeted therapies to treat pediatric LGGs, specifically pan-RAF inhibitors that target BRAF V600E missense mutations and KIAA1549:BRAF fusions. However, to date, very few RAF inhibitors have been approved for use in children.

METHODS

The present study utilized patient-derived pediatric LGG cell lines to investigate the efficacy of Belvarafenib (0.5nM to 5nM), a type II pan-RAF inhibitor, as a potential therapeutic agent to treat BRAF-altered pediatric LGGs. A recent study demonstrated Belvarafenib’s ability to cross the blood-brain barrier, leading to an interest in its potential use in BRAF-mutated pediatric brain tumors. Belvarafenib has already shown promise in treating BRAF V600E-mutated melanomas and other solid tumors in adults, although its ability to effectively target BRAF fusions is unclear. Hence, three pediatric patient-derived cell lines with BRAF fusions will help elucidate any effect from Belvarafenib.

RESULTS

When treated with Belvarafenib, the cell lines harboring BRAF fusions demonstrated the compound’s inability to significantly decrease tumor cell viability.

CONCLUSIONS

This preliminary data highlights the possible limitations associated with using Belvarafenib as a single agent to treat pediatric LGGs with BRAF fusions.
LGG-26. A ROLE FOR BRAF FUSION PARTNERS IN ONCOGENIC SIGNALING
Authors: Misek Sean , Borgenvik Anna , Fekade Ruth , Zhang Alexander , Ragnoni Timothy , Fultineer Aaron , Zhou Kevin , Bondeson Daniel , Novikov Dana , Bahadur Sher , Choi Seung Hyun , Goodale Amy , Condurat Alexandra-Larisa , Cordero Carolina , Persky Nicole , Kiessling Laura , Root David , Eck Michael , Boehm Jesse , Jones David , Beroukhim Rameen , Bandopadhayay Pratiti
Published: June 2024

t was originally hypothesized that loss of BRAF N-terminal negative regulatory domains, which are deleted in the KIAA1549:BRAF rearrangement, results in constitutive activation of the BRAF kinase. This model suggests that BRAF fusion partners are dispensable for BRAF oncogenic signaling. Paradoxically, our data suggest expression of truncated BRAF is insufficient for transformation and identify specific domains in KIAA1549 that are necessary for transformation. These domains are critical for regulating subcellular localization of the fusion protein and highlight an aberrant pattern of cellular localization that is not observed with wildtype BRAF. Altered subcellular localization results in proteolytic cleavage of KIAA1549:BRAF, and we identify the protease responsible for this cleavage event. This protease is therapeutically tractable and clinically relevant inhibitors have been developed, presenting a MAPK-independent mechanism to target the fusion. We also highlight an unexpected role for rare fusion partners, including FAM131B, in BRAF activation. In total, these data suggest that BRAF fusion partners are not indispensable for transformation as was previously thought, presenting unexplored opportunities to therapeutically target pLGG tumors with BRAF rearrangements. We are currently working on the IP measures required to disclose the specific enzyme(s) at ISPNO.
LGG-27. LOWER GRADE GLIOMA (LGG) IN INFANTS. ANALYSIS OF 25 NON-NF1 PATIENTS
Authors: Perek-Polnik Marta , Drogosiewicz Monika , Filipek Iwona , Swieszkowska Ewa , Tarasinska Magdalena , Trubicka Joanna , Grajkowska Wieslawa , Kowalczyk Pawel , Ciolkowski Maciej , Jurkiewicz Elzbieta , Dembowska-Baginska Bozenna
Published: June 2024

INTRODUCTION

Infants constitute approximately 5% of all pediatric LGG. This group is identified as having aggressive course and worse prognosis as compared to older children. No specific therapeutic guidelines are yet available for this specific age group. AIM: Retrospective analysis of infants diagnosed and treated for LGG. METHODOLOGY: 25 patients treated between 2001-2023 were analyzed for: sex, age, tumor location, pathology, treatment and outcome. NF1 patients were excluded.

RESULTS

There were 13 boys and 12 girls, aged 3 months-11 months, median 6 months. 12 had optic chiasm tumors, 6 of visual pathway, 3 had tumors of posterior fossa, 2 of pineal region and 1 spinal tumor. Pathology was available for 16 children revealing Pilocytic astrocytoma in 9, Pilomyxoid astrocytoma in 6, ganglioglioma in 1. Resection as first line treatment was performed in posterior fossa and spinal locations, in 4 cases of visual tracts tumors. All patients were treated with chemotherapy with a maximum of 6 subsequent episodes in a patient with visual pathway tumor. MEK inhibitors were given to 3 pts (in 2 discontinued due to cardiotoxicity). Radiotherapy was applied in 5 (older than 4 years). Twenty two patients are alive, from 4 months to 22 years 4 months (median 8 years 11 months) from diagnosis. Three patients died (midline tumors) 2 from electrolyte disorders and 1 from radiation related cerebral bleeding with observation time of 3, 10, 9 years. Among children with visual tract tumors 5 are blind, 3 have impaired vision. Five patients with very good response to first line treatment have excellent quality of life. Ten patients are disabled, requiring help in everyday life.

CONCLUSIONS

The risk of disability or death is highest in infants of all LGG patients, those who respond the first line treatment have very good quality of life.
LGG-39. REAL-LIFE STUDY OF THE EFFICACY AND TOLERANCE OF TRAMETINIB IN THE TREATMENT OF LOW-GRADE GLIOMAS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1
Authors: BIBOLLET Amandine , KHOURI Celine , ABBOU Samuel , FAURE-CONTER Cécile , AMINI-ADLE Mona , DARNIS Sophie , PHILIPPE Michael , NEUMANN Florent , LEBLOND Pierre
Published: June 2024

BACKGROUND

Low grade gliomas (LGG) are the most common brain tumors in children. Targeted therapies such as the MEK-inhibitor trametinib have revolutionized the management of pediatric LGGs. NF1 mutations generate misregulations in the RAS/MAP kinase pathway, but data on trametinib in type 1 neurofibromatosis (NF1)-related LGG are scarce. Efficacy and safety of trametinib in NF1 patients with LGG need to be further investigated.

METHODS

This retrospective study included patients with NF1 <18 years from two French centers having received trametinib for a relapsing/progressive LGG between March 2020 and July 2022. Treatment efficacy was assessed according to RAPNO criteria, and toxicities and therapeutic exposure were assessed using real-life data collected retrospectively up to July 2023.

RESULTS

The study enrolled 11 patients, the median age at LGG diagnosis was 3 (1-9) years. All patients previously received a median number of 2 (1-4) lines of chemotherapy. Median age at treatment initiation was 9 (4-13) years. Median duration of trametinib treatment was 9.3 (5.8-24) months. Progression-free survival was 91% at 6 months and 61% at 2 years. Median time to best response was 2.7 (1.1-9) months, including 5 stable diseases, 4 minor responses, and 2 partial responses. Median duration of response was 8.6 (3.7-36.2) months. Adverse events (AEs) occurred in all patients, and 64% of the patient had grade 3 AEs. Skin toxicities and paronychia were the most frequent AEs. Treatment interruption occurred in 55% of the patients, and 3 patients permanently discontinued trametinib due to treatment-related toxicities. Real therapeutic exposure was significantly shorter than theoretically expected (19.6% treatment reduction).

CONCLUSION

Trametinib showed promising efficacy in NF1 children with relapsing/progressive LGG. Trametinib toxicity remains challenging. Further prospective clinical trials stratified according to molecular alterations are needed to support these preliminary results.
LGG-41. DECIPHERING PEDIATRIC LOW-GRADE GLIOMA TRAJECTORIES: DEEP LEARNING-BASED VOLUMETRICS FOR PATIENTS UNDER SURVEILLANCE
Authors: Pardo Juan Carlos Climent , Zapaishchykova Anna , Boyd Aidan , Tak Divyanshu , Mahootiha Maryamalsadat , Ye Zezhong , Vajapeyam Sridhar , Bandopadhayay Pratiti , Nabavizadeh Ali , Familiar Ariana , Poussaint Tina Young , Aerts Hugo , Haas-Kogan Daphne A , Kann Benjamin H
Published: June 2024

BACKGROUND

Pediatric low-grade gliomas (pLGGs) have heterogeneous clinical presentations and prognoses. Given the morbidity of treatment, suspected pLGGs are surveilled without treatment, though the natural histories of these tumors have yet to be systematically studied.

METHODS

We conducted a pooled, retrospective study of pLGG patients diagnosed between 1992 and 2020 from two sources (Dana-Farber Cancer Institute/Boston Children’s Hospital and the Children’s Brain Tumor Network), who were surveilled untreated for at least one-year post-diagnosis and who had linked clinical data and longitudinal MRI available. We applied a validated pLGG deep learning segmentation algorithm to longitudinal T2-weighted MRIs and calculated the 3-dimensional volumes at each timepoint. We evaluated individual tumor trajectories, treatment initiation, and clinical risk factors for radiographic progression and regression (defined as volumetric change >=25% and <=-25% respectively) with univariable and multivariable logistic regression. Unsupervised time-series K-means and density-based spatial clustering with dynamic time wrapping were conducted to uncover volumetric phenotypes and a statistical time-series algorithm with auto-regressive integrated moving average was evaluated to predict future volumetric changes.

RESULTS

Of 1774 scans from 129 patients (median follow-up of 4.0 years), baseline tumor median volume was 5.8cm3 (range: 0.01-108.1), with 33 cortical (25.5%), 21 brainstem (16.2%), and 21 (16.2%) cerebellar locations. At the last follow-up, 33.8% of tumors progressed, 35.8% were stable, and 30.2% had regressed. Treatment was initiated for 46.5% of the tumors, of which 70.4% underwent surgery. Risk factors such as adolescent age, larger baseline volume size, cortical location and symptomatic presentation were most associated with progression (p<0.05 for each). Clustering revealed three distinct volumetric phenotypes with diverging natural histories, corresponding to progression, stability or regression. The forecasting showed average root-mean-squared error values of >1cm3 at testing.

CONCLUSIONS

Deep learning auto-segmentation enables longitudinal, volumetric tracking of pLGG, yielding novel insights into the clinical trajectories of untreated tumors on surveillance.
LGG-44. CLINICAL AND MOLECULAR TUMOR CHARACTERISTICS OF ‘HIGHER RISK’ PEDIATRIC LOW-GRADE GLIOMAS
Authors: Rijsdijk Tiago , Lammers Julie A S , Hoving Eelco W , Wesseling Pieter , Tops Bastiaan B J , Kester Lennart , Meijer Lisethe , van Meeteren Netteke A Y Schouten- , Kersbergen Karina J , van der Lugt Jasper , Hoogendijk Raoll , Kranendonk Mariette E G
Published: June 2024

BACKGROUND

CNS WHO grade 1 pediatric low-grade gliomas (pLGGs) have an overall excellent survival. A small but relevant proportion of these patients, however, suffer from severe disease burden reflected in recurrent progression, metastasis or even death. To unravel clinicomolecular tumor characteristics that identify these ‘pLGG-higher risk’ patients we retrospectively analyzed clinical and molecular data of 223 patients from our center.

METHODS

All tumors were classified using histology, DNA methylation profiling and whole transcriptome analysis (RNA sequencing), with whole exome or panel DNA sequencing in a subset of cases, revealing a driver alteration in 100% of cases. Progression of disease was defined as continuous tumor growth upon treatment or need for multiple treatments. The effect of clinical and molecular variables on progression free survival was analyzed with the univariate and multivariate cox proportional hazard model.

RESULTS

The median follow-up of the entire cohort was 3,4 years. In univariate analyses the risk of progression significantly decreased with age (in years) at diagnosis (HR 0.92,p<0.001). For tumor location using hemispheric tumors as reference, chiasm/suprasellar LGGs showed a significantly higher risk of progression (HR 2.96,p<0.001). Type of molecular driver and sex was not associated with progression. In a multivariable model including age, location and driver, there was no longer a significant effect on progression for age but the effect of chiasm/suprasellar location remained intact. Furthermore, NF1 (HR 0.37,p0.02), and posterior fossa LGG (HR 0.24,p0.03) were both significantly associated with a lower risk of progression.

CONCLUSIONS

Our multivariate results show that the ‘pLGG-higher risk’ patients were characterized by a tumor in the chiasm/suprasellar location, while molecular driver (at least so far) did not affect risk of progression. Future work will focus on extending the cohort and integrating other multiomic data enabling to compose a prediction model for higher risk pLGG.