bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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 (&lt;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&lt;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&lt;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&lt;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

Abstract

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

Abstract

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

Abstract

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&gt;G and C.1573A&gt;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

Abstract

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

Abstract
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

Abstract

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

Abstract

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 &lt;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.