bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-20. CANCER PREDISPOSITION SYNDROMES IN PEDIATRIC PATIENTS WITH HIGH-GRADE GLIOMAS
Authors: Baldo Giada Del , Cipri Selene , Boccuto Luigi , Agolini Emanuele , Novelli Antonio , Cacchione Antonella , Lodi Mariachiara , De Ioris Maria Antonietta , Barresi Sabina , Rossi Sabrina , Miele Evelina , Vinci Maria , Carai Andrea , Locatelli Franco , Mastronuzzi Angela 
Published: June 2024

Abstract
The association between pediatric high-grade gliomas (HGG) and cancer predisposition syndromes (CPS) remains inadequately elucidated in the existing literature, while next-generation sequencing (NGS) is increasingly utilized for diagnostic support. In this retrospective analysis, we evaluated a cohort of 95 consecutive pediatric patients with HGG reclassified according to the latest 2021 WHO classification, diagnosed and treated at the Bambino Gesù Children’s Hospital between 2011 and 2023. All patients underwent genetic germline testing with NGS technology to detect the presence of germline variants predisposing to cancer and were included in this study. Diagnosis of pHGG H3-IDH wild-type was performed in 23 patients (24.2%), diffuse midline glioma in 46 patients (48.4%), astrocytoma IDH-mutant in 7 patients (7.4%), anaplastic pleomorphic xanthoastrocytoma in 4 patients (4.2%), adult type HGG in 4 patients (4.2%), neuroepithelial tumor PATZ1 fusion-positive in 3 patients (3.2%), diffuse hemispheric glioma H3 G34-mutant in 2 patients (2.1%), infant-type hemisheric glioma in 2 patients (2.1%), other rare histologies in 4 patients (4.2%). Oncological family history was investigated up to the third generation for all patients and was positive in 43/95 (45.3%) cases. We identified a total of 65 variants in 95 patients, distributed as follows: 48 variants of uncertain significance (73.8%), 10 likely pathogenic (15.4%), and 7 pathogenic variants (10.8%). Notably, our findings reveal that pathogenic/likely pathogenic variants were detected in about 17% of the entire study population, higher than the 10% incidence reported in the existing literature. The high rate of mutations in CPS associated genes described in our work, leads to consider performing NGS even in the absence of clinical or anamnestic criteria suggestive of it. However, ethical and social issues are to be considered when we propose and investigate patients for CPS. Moreover, further research are needed to determine the role of variants of uncertain significance.
HGG-24. DIFFERENTIAL CELL SURFACE PROTEOMICS OF FLOTILLIN-1, HMGB1 AND AMINOPEPTIDASE N IN H3 MUTATED PAEDIATRIC HIGH-GRADE GLIOMAS
Authors: Fairley Hannah , Walugembe Chloe , Layfield Rob , Haque Farhana 
Published: June 2024

Abstract
High-grade gliomas (HGG) are the deadliest central nervous system tumour in children. Despite this, treatment options remain elusive, leaving children with a dismal prognosis. Histone H3.3 mutations, K27M and G34V/R have been identified as the two most common recurrent somatic mutations in paediatric HGG (pHGG). These mutations are present in 50% of pHGG compared to only 1% in adult gliomas. Our previous proteomic research on cell membrane protein through protein MS data analyses have identified different signatures of differentially expressed cell membrane proteins in H3-G34R/V mutated pHGG cells, in comparison to H3 wild type tumour cells in culture. Among these proteins we have identified flotillin-1, HMGB1 (High mobility group box 1) and aminopeptidase N. Flotillin-1 is associated with numerous malignancies and HMGB1 also functions as an oncogene and aminopeptidase N is a cell surface metalloprotease involved in tumour progression. We have now verified the expression and localisation of these cell surface proteins in H3 mutated and wild type tumour cells, in order to validate as targets for developing novel therapeutics. Expression and localisation of flotillin-1, HMGB1 and aminopeptidase N in H3.3 mutated pHGG cell lines in comparison to H3 wildtype glioma and control cells was analysed, using different protein expression assays including immunofluorescence microscopy and western blotting. Experimental analyses showed statistically significant differential protein expression and localisation of these proteins. Flotillin-1 had increased cell membrane localization in H3 mutated cells.HMGB1 expression was increased, while aminopeptidase N expression was decreased in the H3 mutated cells in comparison to wildtype pHGG. This new knowledge of the cell membrane proteomics of H3 mutated pHGG may help us utilise Flotillin-1, HMGB1 and aminopeptidase N, as potential therapeutic targets for these unique H3 mutated children’s brain tumours.
HGG-30. TARGETED THERAPY OF PEDIATRIC HIGH GRADE GLIOMAS
Authors: Papusha Ludmila , Druy Alexander , Salnikova Ekaterina , Zaytseva Margarita , Panferova Agnesa , Vilesova Irina , Flegontov Andrey , Kasich Igor , Merishavyan Artur , Sysoev Andrey , Degtyarev Vitaly , Koldasheva Marina , Sanakoeva Agunda , Artemov Anton , Procvetkina Anastasia , Karachunskiy Alexander , Hwang Eugene , Packer Roger , Novichkova Galina 
Published: June 2024

Abstract

BACKGROUND
The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Recent advances in understanding tumor biology facilitate utilization of targeted therapies (TT) in pediatric neuro-oncology.

METHODS
We analyzed the efficacy of targeted therapy in patients with progressive pHGG treated with TT according to molecularly-identified actionable events. Molecular characterization of the tumor included DNA panel and transcriptomic RNA sequencing.

RESULTS
Eighteen patients were included (median age 3.7 years, range 0.1-17.7) with anaplastic pleomorphic xanthoastrocytoma (n=10), infant-type hemispheric glioma (n=4), and diffuse high-grade glioma (n=4). Metastatic disease was present in 3/18 patients. Molecular genetic alterations included BRAF V600E mutations (n=8), NTRK1/2/3 fusions (n=4), ROS1 fusions (n=4), MET fusion (n=1), KIT P627L mutation (n=1). Eight patients received an NTRK/ALK/ROS1 inhibitor (entrectinib), seven patients received combination therapy with BRAF and MEK inhibitors (dabrafenib and trametinib), and one patient anti-BRAF monotherapy (dabrafenib). Two patients were treated with a multi-tyrosine kinase inhibitor (cabozantinib). The median duration of targeted therapy was 10.6 months (1-42). Most patients tolerated treatment well with no grade 4-5 toxicities. The overall response rate was 66% (12/18), including 4 complete (22%) and 8 partial responses (44%). At 12 months, PFS was 86% with dabrafenib/trametinib and 42% with entrectinib; at 18 months PFS was 44 % with dabrafenib plus trametinib and 42% with entrectinib. Three out of four patients with ROS1 rearranged glioma experienced disease progression on entrectinib after an initial good response in all cases; two of them subsequently received lorlatinib with clinical benefit. All four patients with NTRK1/2/3 rearranged gliomas remain on entrectinib therapy without signs of progression. Cabozantinib therapy resulted in prolonged complete and partial responses in both cases.

CONCLUSIONS
TT for patients with progressive pHGG is feasible and provides unexpectedly good clinical efficacy.
HGG-31. GENOMIC CORRELATIONS WITH HEMORRHAGE RISK IN PEDIATRIC PATIENTS WITH DIFFUSE HEMISPHERIC GLIOMA
Authors: Joshi Nikhil , Bagheri Sina , Beaubien Ezra , Harvey Kyra , McManus Olivia , Wilson Cullen , Hajeebu Sreehita , Mishra Deepak , Nabavizadeh Ali , Madsen Peter , Foster Jessica 
Published: June 2024

Abstract

BACKGROUND
Pediatric diffuse hemispheric glioma (DHG) is a histone-mutated (H3.3G34R/V) high-grade glioma with poor prognosis. Clinical observation and previous reports have identified that a subset of patients present with tumor-associated hemorrhage. Here, we present our findings from radiological review of these patients and determine genomic risk factors predictive for hemorrhage risk in this cohort.

METHODS
Data was abstracted through the Children’s Brain Tumor Network (CBTN) and EGAS00001004301. Transcriptomic and genomic analyses were completed in R 4.3.1 using edgeR, msigdbr, and xCell. Presence of blood products was determined on preoperative MRI by a board certified pediatric neuroradiologist.

RESULTS
48 samples were available across cohorts with transcriptomic or genomic data. 10 samples (21%) had pre-operative imaging and transcriptomic data available. Initial analysis determined that 6 samples (60%) had acute/chronic hemorrhage based on radiological review. Samples with hemorrhage had increased levels of VEGFA (LFC: 3.45, p=2E-07) and CA9 (LFC: 5.97, p=8E-05) expression on the transcriptomic level suggesting that patients with high expression of these markers (AngioHi) had increased risk of hemorrhage compared to patients with low expression of these markers (AngioLo). AngioHi patients had notably higher levels of IL8 (LFC: 3.56, p=0.01) and increased macrophage populations. Genomic information was available for 15 samples (31%, 7 AngioHi, 8 AngioLo). PTEN alterations (n=4, 57%), FBXW7 alterations (n= 2, 29%), or PDGFRa driver alterations (n= 3, 43%) were found in the AngioHi cohort while none of these alterations were identified in the AngioLo cohort. Notably, at least one of these mutations was seen in all cases in the AngioHi cohort.

CONCLUSIONS
These findings identify potential mutational alterations predictive for tumor-associated hemorrhage in pediatric DHG. Current work is being completed to further characterize how these mutations impact vascular remodeling for patients with DHG and may offer targeted therapeutic opportunities.
HGG-44. BRAINSTEM HIGH-GRADE ASTROCYTOMA WITH PILOID FEATURES (HGAP) WITH AN NTRK FUSION: A HISTOLOGICAL MIMICKER AND RARE PEDIATRIC BRAIN TUMOR
Authors: Balikani Lame , Yilmaz Yasin , Mattera Emily , Leonard Jeffrey R , Leung Marco , Tsuchiya Karen , Schieffer Kathleen M , Akkari Yassmine , McEnroe Allison , McAllister Aaron , Cottrell Catherine , Mardis Elaine , Fouladi Maryam , Khan Sara , Boue Daniel R 
Published: June 2024

Abstract

BACKGROUND
HGAP is a recently defined rare glial neoplasm, whose classification requires pathognomonic epigenetic signatures. HGAP can arise anywhere within the central nervous system but most have been reported in the cerebellum (74%). Rarely seen in children, the diagnosis of HGAP can be challenging due to morphologic overlap with other glial neoplasms, especially pilocytic astrocytoma (PA).

CASE
We present an 11-year male with history of poor weight gain and bilateral sensorineural hearing loss detected on routine screening. Examination showed ataxia, with nystagmus on lateral gaze. MRI brain showed a solid/cystic, dorsally exophytic, cervicomedullary tumor with extension into the 4th ventricle, and hydrocephalus. The tumor showed heterogeneous enhancement with no restricted diffusion, nor intracranial or spinal metastases. Histologic sections from the biopsy suggested classic biphasic PA, with abundant Rosenthal fibers, vascular sclerosis, and no obvious mitoses. Ki67 index was low (&lt;5%; hotspots up to 5-10%+). ATRX mostly retained, even within the most atypical nuclei. The histological impression was classic PA. Comprehensive molecular analysis with DNA methylation showed a high confidence match (0.9883) for HGAP. Paired exome sequencing revealed CDKN2A/2B biallelic loss, missense variant and copy number loss involving NF1, loss of function splice variant in ATRX with no germline alterations detected. Interestingly, fusion panel revealed a BCR::NTRK2 fusion. He received focal photon radiation (54Gy) and adjuvant therapy with Larotrectinib. He remains well with stable disease (EFS 7months).

CONCLUSION
A comprehensive 2023 review of literature revealed only 14 pediatric cases (range 4-18yo) out of 144 reported cases. Including our patient, 9 were male; 8 posterior fossa, 4 supratentorial, 1 spinal cord, and 2 of unknown location. Molecular analysis of the previously reported 14 pediatric cases showed only one case with a different NTRK fusion. We herein present a unique pediatric HGAP, with entirely classic biphasic and benign PA-like features, brainstem location, and targetable NTRK2 fusion.
HGG-50. LOW GRADE GLIOMA CAUGHT IN TRANSFORMATION: UTILITY OF COMPREHENSIVE GENOMIC PROFILING IN PEDIATRIC LI FRAUMENI SYNDROME ASSOCIATED HIGH-GRADE GLIOMA
Authors: Nagabushan Sumanth , Fuentes-Bolanos Noemi , Lau Loretta M S , Rumford Megan , Warby Meera , Courtney Eliza , Grant Andrew , Rodriguez Michael , Solinas Annalisa , Ziegler David S , Kellie Stewart J , Heath John , Ballinger Mandy , Tucker Katherine 
Published: June 2024

Abstract

BACKGROUND
Diffuse paediatric-type high-grade glioma (HGG), H3-wildtype (WT) and IDH-WT have been recognised as a distinct subgroup in the 5th edition of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) (2021).

METHODS
We describe two patients with LFS with conflict between histological and molecular findings. They underwent integrated multi-omics to guide personalised therapy.

RESULTS
The first patient is a 10-year-old female with a left thalamic diffuse astrocytoma, histologically at least CNS WHO grade 2, with H3K27M, BRAFV600E and IDH1R132H negativity by immunohistochemistry (IHC) and retained H3K27me3, prompting initial management as a low-grade glioma. ZERO2 multi-omics profiling demonstrated no DNA methylation match, (v11b4 and 12.5), but loss of TP53 function (heterozygous germline mutation with tumour whole copy chromosome 17 loss); single copy chromosome X loss with BCOR mutation, and NF1 and FGFR1 mutations. However, tumor aneuploidy, IDH-WT status, co-segregated NF1 alteration and LFS suggested malignant transformation, leading to HGG treatment. The second patient is a 6-year-old boy with LFS, detected on cascade testing, after his brother’s diagnosis of bithalamic diffuse paediatric-type HGG MYCN, following cancer surveillance through Surveillance Study in Multi-organ Cancer Prone Syndrome (SMOC-Junior). Baseline whole-body MRI identified an asymptomatic bithalamic glioma, histopathologically compatible with low-grade astrocytoma except for mosaic loss of H3K27me3. DNA methylation matched (0.99) to diffuse pediatric-type HGG MYCN-subtype, with multiple copy number aberrations, EGFR amplification/overexpression, NF1 mutations and TP53 loss of heterozygosity, without MYCN-alteration or increased expression. He received HGG-specific radiation therapy and is on an NF1-targeted maintenance therapy with trametinib, a MEK inhibitor. In both cases, molecular features suggested early transformation.

CONCLUSIONS
These patients highlight that integrated multi-omic diagnostic approaches can identify transformation in TP53-altered low grade gliomas and inform development of personalised management guidelines for patients and families with Li Fraumeni syndrome.
IMG-08. SYNTHESIZING MISSING MRI SEQUENCES IN PEDIATRIC BRAIN TUMORS USING GENERATIVE ADVERSARIAL NETWORKS; TOWARDS IMPROVED VOLUMETRIC TUMOR ASSESSMENT
Authors: Chrysochoou Dimosthenis , Familiar Ariana , Gandhi Deep , Storm Phillip B , Vossough Arastoo , Resnick Adam C , Davatzikos Christos , Nabavizadeh Ali , Kazerooni Anahita Fathi 
Published: June 2024

Abstract

BACKGROUND
Standard MRI sequences, such as pre- and post-contrast T1w, T2w, and FLAIR images, are essential for optimizing segmentation of tumor subregions and evaluating treatment responses in pediatric brain tumors (PBTs). However, MRI sets are often incomplete due to imaging artifacts or inconsistent acquisition protocols across various centers. Generative Adversarial Networks (GANs) have been effectively utilized to generate missing MRI sequences for adult brain tumors. This study applies image-to-image translation models using GANs to synthesize missing FLAIR images from T2w images in PBTs.

METHODS
This retrospective study developed two GAN models, pix2pix in both 2D and 3D, trained and validated on T2w and FLAIR image pairs from 79 and 19 patients, respectively, with pediatric-type diffuse high-grade gliomas (diffuse midline glioma (DMG) including diffuse intrinsic pontine glioma (DIPG)), collected from the Children’s Brain Tumor Network (CBTN). The 2D pix2pix model processes each T2w MRI volume slice-by-slice, generating corresponding FLAIR slices to reconstruct the complete image volume. The 3D pix2pix model allows translation of 3D FLAIR volumes directly from T2w volumes without the need for individual slice processing and reconstruction. The quality of the generated FLAIR volumes was evaluated using Structural Similarity Index (SSI; best closer to 1) and Mean Squared Error (MSE; best near 0) on the validation set.

RESULTS
The 2D and 3D models achieved robust performance with median SSI, MSE of 0.88, 0.004, and 0.92, 0.002, respectively.

CONCLUSIONS
The GAN models developed in this study effectively generate missing FLAIR MRI volumes from corresponding T2w images in PBTs. The 3D model, outperforming 2D, speeds the overall processing pipeline by eliminating volume slicing and reconstruction. Future work includes assessing the impact of these synthesized images on the accuracy of our pretrained autosegmentation models in differentiating tumor subregions and measuring tumor volumes in longitudinal MRIs.
IMG-23. AN MRI-BASED RADIOMIC SIGNATURE TO PREDICT LONG-TERM SURVIVAL IN PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Frouin Frédérique , Khalid Fahad , Frouin Vincent , Dangouloff-Ros Volodia , Boddaert Nathalie , Grill Jacques 
Published: June 2024

Abstract

BACKGROUND
Diffuse intrinsic pontine gliomas are characterized by a short life expectancy after diagnosis, with a mean overall survival of less than 12 months. To stratify patients and possibly better adapt therapy, we are proposing a radiomic signature that predicts, at the time of diagnosis, which patients might survive beyond 2 years.

METHODS
A retrospective database comprising 80 patients who had undergone 3D multimodal MRI at the time of diagnosis was compiled. All images were acquired at a single center, and the protocol included T1-weighted images acquired before and after contrast injection, T2-weighted and FLAIR images. Depending on the patient, some modalities were missing (around 10% per modality). After manual tumor delineation, a dedicated radiomic pipeline extracted 79 features (first-order statistics and texture parameters) per imaging modality. In addition, gender, age and 14 tumor shape features were collected without missing data. After feature selection (maximum of 4 features per model), five logistic regression models were defined, one per modality and another for clinical and shape variables. Each patient was eligible for 2 to 5 models, with an average score calculated over these models.

RESULTS
Based on a leave-one-out approach, the multi-model was able to define patients who survive more than 2 years correctly, (sensitivity=100%, specificity =79%). A prediction could be made for each patient despite missing MR modalities. Defining a radiomic signature based on the multi-model score (cut-off=0.5), Kaplan-Meier analysis shows a good separation of the two groups (p-value&lt;0.001). This result is superior to that obtained with the TP53 mutation (available for 61 patients, with p-value&lt;0.01).

CONCLUSIONS
We have demonstrated the value of multimodal 3D MRI in predicting which DIPG patients might survive beyond 2 years. The robustness of this radiomic signature has yet to be tested using multicentric images.
IMG-32. USER EVALUATION OF AN AI-POWERED WEB APPLICATION TO SUPPORT RADIOGRAPHIC INTERPRETATION OF PATIENTS WITH ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Prince Eric W , Mirsky David M , Görg Carsten , Hankinson Todd C 
Published: June 2024

Abstract

BACKGROUND
In neuro-oncology, accurately interpreting radiographic images, especially for diagnosing central nervous system (CNS) tumors like Adamantinomatous Craniopharyngioma (ACP), presents formidable challenges. Even with advanced imaging technologies such as Magnetic Resonance Imaging (MRI) and Computed Tomography (CT), pinpointing features related to ACP invasiveness remains daunting.

METHODS
We introduced an interactive web application that utilizes a custom AI model to analyze preoperative MRI and CT images of 50 patients with ACP. This application can predict a 12-point radiographic feature profile and rank patients based on similarity, aiming to support clinicians in making more precise diagnoses. We deployed our application on a hospital-grade radiographic reading terminal. Our application’s utility and user-friendliness were evaluated through a user study involving four neurosurgeons and two neuroradiologists, who constructed 12-point radiographic feature profiles for ten patients within a 30-minute timeframe given patient MRI and CT images.

RESULTS
Our study subjects reported high self-assessed numeracy (SNS scores ranging from 4 to 5.25) despite varied preferences in engaging with numerical data. Subjects could efficiently learn to navigate our software interface, with an average task completion time of approximately 3 minutes and 25 seconds per patient. Introducing AI into the task workflow resulted in a slight, statistically non-significant increase in completion time, indicating that while AI modifies interaction dynamics, it does not significantly hinder efficiency in task performance. We observed distinct agreement patterns between clinicians and AI prediction, utilizing Fleiss’ Kappa for categorization. AI assistance subtly boosted clinicians’ confidence and slightly lessened the perceived difficulty of interpreting radiographic images. However, these benefits were not statistically significant.

CONCLUSIONS
Our study highlights the promise of AI in improving neuro-oncology diagnostics, showing that clinicians quickly adapted to an AI-enhanced application, which subtly influenced their radiographic interpretation. This finding underscores the potential for AI to enhance decision-making accuracy in challenging cases like ACP.
IMG-33. EXPLORING RARE CASES OF SUBEPENDYMAL GIANT CELL ASTROCYTOMA (SEGA) IN PATIENTS WITH AND WITHOUT TUBEROUS SCLEROSIS COMPLEX (TSC): EXPERIENCE FROM INDONESIA
Authors: Amal Mohamad Yanuar , Rahmartani Ludi Dhyani , Susanto Eka 
Published: June 2024

Abstract

INTRODUCTION
Subependymal giant cell astrocytoma (SEGA) represents a rare type of brain tumor that predominantly manifests in individuals with tuberous sclerosis complex (TSC), a genetic disorder characterized by the growth of benign tumors in various organs. In radiology, SEGA exhibits distinct imaging characteristics in various modalities such as magnetic resonance imaging (MRI) and computed tomography (CT). Radiological features include well-defined intraventricular masses with variable enhancement patterns and associated hydrocephalus. Moreover, SEGA typically demonstrates signal characteristics consistent with glial tumors on MRI, aiding in differentiation from other intraventricular lesions. In TSC patients, SEGA often arises in association with other typical manifestations such as cortical tubers and subependymal nodules, facilitating diagnosis through multimodal imaging approaches. In contrast, SEGA occurring in non-TSC individuals presents challenges in diagnosis due to its rarity and lack of associated clinical features.

CASE PRESENTATION
Two patients with tuberous sclerosis complex exhibit intraventricular masses suggestive of SEGA, confirmed by histopathological results. Another patient, one patient with an intraventricular mass was suspected to have choroid plexus papilloma based on MRI findings; however, additional features correlated with SEGA. Histopathological examination subsequently confirmed the diagnosis of SEGA.

CONCLUSION
Radiological evaluation plays a crucial role in the assessment of SEGA, guiding treatment decisions and prognostic considerations. This abstract provides an overview of the radiological findings of SEGA in the context of TSC and non-TSC populations, highlighting the importance of imaging in managing this uncommon brain tumor.