tbuckley/cabot-search huggingface dataset:
NFS-21. DEMOGRAPHIC, CLINICAL AND IMAGING CHARACTERISTICS OF NEWLY DIAGNOSED OPTIC PATHWAY GLIOMAS ASSOCIATED WITH NF1: RESULTS FROM THE INTERNATIONAL MULTICENTER NF1-OPG NATURAL HISTORY STUDY
Authors: Michael J Fisher, Peter de Blank, Robert Listernick, Grant Liu, Rosalie Ferner, David Gutmann, Janice Lasky-Zeid, Nicole Ullrich, Gena Heidary, Miriam Bornhorst, Steven Stasheff, Teena Rosser, March Borcher, Simone Arden-Holmes, Maree Flaherty, Trent Hummel, Walker Motley, Kevin Bielamowicz, Paul Phillips, Eric Bouffet, Arun Reginald, David Wolf, Jason Peragallo, Mays El-Dairi, David Van Mater, Aimee Sato, Kristina Tarczy-Hornoch, Laura Klesse, Nick Hogan, Nicholas Foreman, Emily McCourt, Jeffrey Allen, Milan Ranka, Cynthia Campen, Shannon Beres, Christopher Moertel, Ray Areaux, Duncan Stearns, Faruk Orge, John Crawford, Henry O’Halloran, Julius Oattes, Alyssa Reddy, Michael Brodsky, Adam Esbenshade, Sean Donahue, Gary Cutter, Robert Avery
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Treatment and clinical management decisions for children with NF1-OPGs remain challenging as most existing data are retrospective and have not included standardized visual outcomes. In this study, we prospectively enrolled newly diagnosed NF1-OPGs and performed standardized neuro-oncology and ophthalmology assessments in order to develop evidence-based guidelines for monitoring and treatment. METHODS Children with NF1-OPG on MRI who were evaluated by both a study ophthalmologist and neuro-oncologist/NF1 expert within 1 month of radiologic diagnosis were eligible for enrollment. All subjects attempted quantitative visual acuity using Teller acuity cards (TAC) as well as ATS-HOTV testing. The neuro-oncologist/NF1 expert provided reasons for obtaining the MRI as well as initiating treatment, if applicable. Descriptive statistics calculated the success rate of acquiring TAC and reasons to obtain the MRI. RESULTS Two-hundred fifty subjects from 22 institutions were enrolled and had at least one visit beyond baseline (Median age 3.1 years, range 0.1–16.8; 53% female). TAC was successfully acquired in both eyes (N=195, 78%) and at least one eye in (N=206, 82%). ATS-HOTV was successfully acquired in both eyes (N=97, 39%) and at least one eye in (N=98, 39%). The two most common reasons to obtain an MRI were screening due to a diagnosis of NF1 (N=99, 39%) and ophthalmologic concern (N=81, 32%). At enrollment, continued observation occurred in a majority of subjects (N=221, 88%) while treatment with chemotherapy was initiated in only 11% (N=29). Twenty-nine (11%) subjects initially observed transitioned to treatment after enrollment (range: 2.5–25 months) thus far. DISCUSSION We present a prospective multicenter study of children with newly diagnosed NF1-OPGs. The ability to acquire quantitative visual acuity was higher than anticipated. The frequency of NF1-OPGs requiring treatment is lower than previously reported. Regression models of clinical and MRI features that prompted immediate treatment with chemotherapy versus observation will be discussed.
DIPG-21. PRECLINICAL ASSESSMENT OF A MULTIMODAL TREATMENT APPROACH WITH GIVINOSTAT, PAXALISIB, AND RADIOTHERAPY FOR DIFFUSE MIDLINE GLIOMA (DMG)
Authors: Aimée du Chatinier, Michaël H Meel, Piotr Waranecki, Dennis S Metselaar, Esther Hulleman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite an extensive body of clinical research conducted, the prognosis for patients with Diffuse Midline Glioma (DMG) has remained stagnant for the past five decades. Years of investigations underscore the robust resistance of DMG tumors to treatment, rendering monotherapy an improbable route to a cure. Recognizing the need for a multimodal approach, this study evaluated a treatment strategy incorporating radiotherapy and two brain-penetrable compounds with potential immunomodulatory effects, Givinostat and Paxalisib. METHODS We selected Givinostat, a pan-HDAC inhibitor undergoing clinical studies in children with Duchenne muscular dystrophy, by comprehensive screening of a panel of HDAC inhibitors for their efficacy in DMG neurosphere cultures, ability to penetrate the blood-brain barrier, and clinical utility. in addition, we selected the PI3K/mTOR inhibitor Paxalisib based on a phase II clinical trial currently undergoing in DMG patients (PNOC DMG Adaptive Combination Trial, PNOC022). The anti-tumor, radio-sensitizing, and immunomodulatory effects of both compounds were assessed in vitro and in immunocompetent mice, using various cytotoxicity and proteomic assays and (single-cell) sequencing techniques. RESULTS Our investigations revealed that the combination of Givinostat and Paxalisib exerts a profound cytostatic and cytotoxic effect on DMG cells, by reducing cell viability, enhancing DNA damage, and inducing apoptosis. Moreover, this combination therapy sensitized DMG cells to ionizing radiation, potentially by diminishing DNA repair mechanisms and elevating oxidative stress. Additionally, the combination of Givinostat and Paxalisib considerably reduced tumor growth in vivo and transformed the immune-cold microenvironment of DMG tumors into a pro-inflammatory phenotype. CONCLUSIONS This study positions Givinostat as a potential addition to the backbone of Paxalisib in forthcoming clinical trials, either as a radio/chemotherapy combination or as a foundation for immunotherapy.
IMG-20. IDENTIFICATION OF PRE-OPERATIVE IMAGING FEATURES ASSOCIATED WITH COGNITIVE IMPAIRMENT IN CHILDREN WITH BRAIN TUMOURS USING A LANGUAGE MODELLING SYSTEM COMBINED WITH MACHINE LEARNING ANALYSIS
Authors: Simon Dockrell, Anna Maria Tsakiroglou, Kate Vaughan, Lesley Albutt, John-Paul Kilday, Ian Kamaly-Asl, Martin McCabe, Martin Fergie, Stavros Stivaros
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cognitive impairments caused by paediatric brain tumours negatively impact future quality-of-life. Impairments of processing speed and working memory are important contributors to challenges these children encounter in education. Inconsistent image acquisition and poor imaging quality can restrict advanced radiomic analysis in historical datasets. We developed and refined a language modelling human image-analysis support system, passing data to specific machine learning techniques that can utilise datasets with many data points in a limited population. METHODS Medical records of children treated for brain tumours with surgery and radiotherapy in Manchester between 2000-2020 were reviewed with imaging accessible from 2006-2020. Pre-operative MRI scans were reviewed for 52 patients along with their most recent processing speed and/or working memory test scores. 274 radiological variables analysing tumour features and damage to brain structures were reported per patient using a standardised reporting tool. Univariate analysis was performed using Linear Regression with time-to-test analysed as a covariate. Multivariate analysis used Elastic Net Regression. RESULTS Univariate analysis revealed risk factors for slower processing speed included midline shift, tumour in the corpus callosum, right temporal periventricular white matter oedema, diffusion changes in the left frontal lobe or amygdala and FLAIR changes in the left caudate nucleus (p&amp;lt;0.005). Risk factors for impaired working memory included midline shift, cortical tumour location, left periventricular white matter oedema and diffusion or FLAIR changes in the left frontal lobe (p&amp;lt;0.005). Despite the limited population size and review of only pre-operative features, multivariate analysis produced multiple predictive models able to outperform chance when predicting processing speed and working memory outcomes. CONCLUSIONS This study provides evidence that a radiological language modelling approach can be utilised for outcome prediction. It identified imaging features predictive of cognitive impairments prior to surgery and radiotherapy. Further work is needed to assess inter-observer variability and validate these findings.
RADT-03. IDENTIFYING BRAIN STRUCTURES LINKED TO RADIATION-INDUCED ENDOCRINE AND COGNITIVE SEQUELAE: A MULTI-CENTRE VOXEL-BASED ANALYSIS
Authors: Angela Davey, Lydia J Wilson, Eliana Vasquez Osorio, Andrew Green, Kate Vaughan, Peter Clayton, Lesley Albutt, Marcel van Herk, Thomas E Merchant, Martin G McCabe, Marianne C Aznar
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Radiotherapy (RT) is a common treatment for paediatric brain tumours. Despite advancements in techniques to mitigate RT-induced toxicity, almost two-thirds of patients develop long-lasting endocrine and cognitive sequalae. Image-based data mining (IBDM) is a voxel-based analysis tool that can identify dose-sensitive regions, supporting development of tailored radiation treatments for future patients that avoids these regions. We present the first IBDM study localising endocrine and cognitive effects in paediatric brain tumour patients. METHODS Imaging (MRI and CT) and clinical data were available for 261 children (146 medulloblastoma patients in centre A, 115 patients with mixed diagnoses in centre B). Outcomes were reported as Growth Hormone Deficiency (GHD, presence/absence, both centres) and processing speed (PS, continuous slope derived from a linear mixed-effects model, centre A). IBDM evaluated where dose was associated with outcome (p-value&amp;lt;0.01). Mean dose to this region was included in multivariable analysis adjusting for age, risk status, hydrocephalus status/management, and chemotherapy. RESULTS GHD was associated with dose to a region overlapping the pituitary and brainstem. In centre A, multivariable analysis revealed a 13(2-27)% average increase in GHD odds per 1Gy increase in dose, with an inverse effect for age. Center B showed a 8(4-13)% average increase for every 1Gy, with no other predictors. For PS, a central frontal region from the medial frontal lobes to the hypothalamus was identified (139 patients in centre A). Every 1Gy increase led to a -0.08(-0.20 – 0.04) PS change, with age and hydrocephalus management as contributing factors. CONCLUSION We identified a region (encompassing the pituitary and brainstem) associated with increased risk of GHD, that was consistent in two independent cohort analyses. Furthermore, PS decline was linked to dose to a frontal region. Minimising dose to these regions for future patients could reduce the risk of cognitive and endocrine sequelae.
RADT-02. PROTON THERAPY IN PEDIATRIC ONCOLOGY IN SLOVAKIA: A COMPREHENSIVE ANALYSIS
Authors: Estera Bublakova, Stanislava Hederova, Alexandra Kolenova, Miroslava Makohusova
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Radiotherapy has been a cornerstone in pediatric oncology for decades. Recognizing the potential to mitigate side effects, proton therapy (PT) has gained prominence, becoming part of treatment in pediatric oncology in Slovakia since 2014. METHODOLOGY This retrospective analysis investigates a cohort of patients with CNS tumors treated at the National Institute of Children’s Diseases in Bratislava, who underwent PT at the Proton Center in Prague between 2014 and 2022. RESULTS Among 47 patients, embryonal tumors constituted the largest group (40%), followed by germ cell tumors (21%), ependymal tumors (19%), less common CNS tumors (10%), and glial tumors (8%). Acute complications included skin toxicity (38%), CNS toxicity (23%), GIT toxicity (14%), and blood count changes (8%). Notably, 22 patients experienced no acute toxicity. Late reactions, predominantly endocrine dysfunction (65%), featured central hypothyroidism (45%), ACTH deficiency (22%), GH deficiency (16%), and gonadotropin deficiency (10%). Ocular complications affected 55%, while tensive cephalea and post-radiation necrosis-related epileptic seizures were observed in limited cases. Disease recurrence was absent in 89% of patients, with 10% exiting due to disease progression. CONCLUSION This pioneering analysis highlights the unique experiences of Slovak pediatric patients undergoing PT at the Proton Center in Prague. The study emphasizes the dual impact of PT, enhancing survival rates while reducing adverse effects, thereby significantly contributing to a better quality of life for pediatric cancer patients.
ETMR-25. UNRAVELING THE ROLE OF SHH SIGNALING PATHWAY IN RETINOBLASTOMA
Authors: Xiao Liu, Jiao Zhang, Zhenhua Xu, Andrzej Dlugosz, Stephan Frank, Peter Meyer, Hiromichi Suzuki, Taakuma Nakashima, Yanxin Pei
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Retinoblastoma (RB) is a pediatric cancer affecting the retina, often requiring surgical removal of one or both eyes due to the limited effectiveness of current treatments. There is an urgent need for advanced therapeutic strategies capable of effectively eliminating tumors, thereby obviating the need for surgical removal of eyes in affected children. Achieving this goal requires a deeper understanding of the cellular and molecular mechanisms governing RB initiation and progression. METHODS Using a transgenic mouse model, we identified the crucial role of the Shh signaling pathway in Rb1 mutation-induced tumorigenesis, highlighting its potential as a novel therapeutic target for RB treatment. RESULTS We have observed frequent overexpression of Shh signaling proteins (SHH, GLI1, and GLI2) in human RB, correlating with aggressive clinicopathological features. GLI2 overexpression is necessary for Rb1 deletion-induced RB tumor initiation in mouse retinal progenitor cells (RPCs). These mouse intraocular tumors accurately replicate human RB at both cellular and molecular levels. Additionally, Shh pathway activation extends to normal retinal cells adjacent to human RB tumors, suggesting the involvement of Shh signaling in RB-microenvironment interactions. Importantly, our studies have identified a novel small molecular inhibitor targeting the Shh pathway, effectively inhibiting RB growth in vitro and in vivo by targeting both tumor cells and the tumor microenvironment (TME). CONCLUSIONS The proposed research aims to provide unprecedented insights into the role of SHH signaling pathway in RB initiation and progression and the supporting communication network between RB tumors and TME. These outcomes have the potential to treat RB effectively while improving the well-being of young individuals with RB and those at risk of RB.
IMG-18. DIFFERENTIAL DIAGNOSIS OF POSTERIOR FOSSA TUMORS USING RADIOMICS; A FIRST-LINE DIAGNOSTIC STEP REQUIRED FOR DOWNSTREAM ANALYSES
Authors: Anahita Fathi Kazerooni, Neda Khalili, Deep Gandhi, Paarth Jain, Ariana Familiar, Meen Chul Kim, Nastaran Khalili, Debanjan Haldar, Phillip B Storm, Cassie Kline, Arastoo Vossough, Adam Resnick, Ali Nabavizadeh
Journal: Neuro-Oncology (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.
DIPG-44. DIFFUSE MIDLINE GLIOMA, H3K27-ALTERED: A COMPREHENSIVE CLINICAL AND BIOMOLECULAR LANDSCAPE OF THE NON-PONTINE TUMORS
Authors: Cassandra Mariet, Arnault Tauziède-Espariat, Lucie Auffret, Yassine Ajlil, Alexandre Roux, Johan Pallud, Stéphane Palfi, Alice Métais, Kevin Beccaria, Thomas Blauwblomme, Stéphanie Puget, Marc Sanson, Marie Peloux, Juliette Richard, Julian Thalhammer, Alice Carvalho, Chloé Puiseux, Victor Pereira, Emilie de Carli, Thomas Lesieur, Jeremie Rouger, Philipe Page, François Doz, Franck Bourdeaut, Christelle Dufour, Samuel Abou, Léa Guerrini-Rousseau, Frédéric Dhermain, Stéphanie Bolle, Pascale Varlet, Jacques Grill, David Castel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Since 2016, the WHO classification of CNS tumors groups all midline gliomas with H3K27me3 loss under the term diffuse midline glioma (DMG), H3K27-altered. Molecular characteristics enable their sub-classification based on driver mutations, co-driver mutations and epigenetic alterations. Predominantly studied in the pons (Diffuse Intrinsic Pontine Glioma, DIPG), where these are mainly pediatric tumors with a median overall survival (OS) of one year, fewer studies have been conducted on non-pontine DMG (npDMG), prompting this study to clinically and biologically characterize these gliomas and compare them with DIPG. METHODS Retrospective monocentric study from 1994 to 2022, including pediatric and adult patients diagnosed with npDMG, H327-altered with neuropathological confirmation at Sainte Anne Hospital in Paris, France. Comparative literature review of cases of npDMG and series of DIPG. RESULTS 108 patients were included (54.7% male, median age 13.05-years [2.4-59.3]). The most frequent location was monothalamic (62.9%), followed by bithalamic, spinal, cerebellar, bulbo-medullar and other. H3K27M mutation was found in 85.2% of cases, EZHIP overexpression in 14.8% and EGFR alteration (mutation and/or amplification) in 16.7%. EZHIP-overexpressing patients were younger than H3K27M-mutated patients, as were EGFR-altered patients compared to those without EGFR alteration. Along with data from the literature, npDMG are older at diagnosis and have a slightly longer median OS (15 months [0.1-247.2]) than DIPG. Positive prognosis factors upon univariate analysis included longer time from symptom onset until diagnosis, treatment with ONC201, re-irradiation upon relapse, microcalcifications, proliferative index &amp;gt;10%, MAP kinase alteration and absence of TP53 mutation and EGFR amplification. However, surgery quality did not impact OS. CONCLUSIONS npDMG is a heterogeneous group of gliomas, affecting all ages, which can develop in diverse locations, with an overall poor prognosis. Despite shared clinical, immuno-histochemical and molecular properties with DIPG, recent molecular biology advancements reveal distinct subtypes within DMG, with varying prognoses, challenging the unified classification.
NFS-28. CLINICAL CHARACTERISTICS AND THERAPEUTIC INTERVENTIONS IN A CASE SERIES OF PEDIATRIC PATIENTS WITH VESTIBULAR SCHWANNOMAS AND NEUROFIBROMATOSIS TYPE 2
Authors: Lea M Stitzlein, Yusha Y Sun, Faryal Munir, Ian E McCutcheon, John M Slopis, Wafik Zaky
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric neurofibromatosis type 2 (NF2) is an understudied genetic disorder with high incidence of tumors including vestibular schwannomas (VS) and meningiomas. Although predominately recognized as an adult disease, there is a shortage of comprehensive studies in pediatric NF2. This case series describes a large cohort of pediatric NF2 patients with VS and their disease management. METHODS Our study included 24 patients with initial symptoms of NF2 before age 19. The patients were treated at the Neurofibromatosis Clinic of The University of Texas MD Anderson Cancer Center between 1/1/2005-12/31/2023. Our analysis incorporated data from clinic notes, surgical reports, audiology reports, electromyography reports, pathology reports, and imaging studies. RESULTS Patients presented with NF2 at an age range from 18 months to 18 years (mean age 8.1 ± 5.2 years). Among the patients, 67% underwent surgical interventions, including auditory brainstem implants, cochlear implants, ventriculoperitoneal shunts, and/or craniotomies for tumor resection. Additionally, treatment in 21% of cases involved radiotherapy, employing stereotactic radiosurgery, intensity-modulated radiotherapy, and proton beam irradiation. Targeted therapies, including bevacizumab, lapatinib, everolimus, temsirolimus, brigatinib, or a combination thereof, were administered to eleven patients. The best exhibited response by most patients was stable disease for a median duration of 10 months, and clinical improvement/stabilization of the hearing loss. Most reported toxicities related to bevacizumab or temsirolimus. Overall, limited clinical improvement was observed within this cohort after interventions. CONCLUSION This study discusses the clinical presentation of pediatric NF2 with VS and highlights the need for effective therapeutic options to manage tumors and symptoms in this patient population. A notable research gap exists in pediatric NF2, compounded by the lack of preclinical models to study the disease. The absence of approved drugs underscores the necessity for more comprehensive studies to guide therapeutic strategies. Combination therapies may advance treatment approaches and achieve improved outcomes.