tbuckley/cabot-search huggingface dataset:
IMG-22. ASL PERFUSION LIGHTBULB SIGN: A POTENTIAL PATHOGNOMONIC FEATURE OF PEDIATRIC POSTERIOR FOSSA HEMANGIOBLASTOMA
Authors: Onur Simsek, Nakul Sheth, Amirreza Manteghinejad, Mix Wannasarnmetha, Aashim Bhatia
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Hemangioblastoma is a rare vascular tumor which occurs within the central nervous system in children. Differentiating hemangioblastoma from other posterior fossa tumors can be challenging on imaging and preoperative diagnosis can change neurosurgical approach. We hypothesize a ‘lightbulb sign’ (diffuse homogenous intense hyperperfusion within solid component of tumor) will help differentiate hemangioblastoma from other posterior fossa tumors. METHODS In this retrospective case-control study, we only included pathology-proven cases of hemangioblastoma, while the control group consisted of other randomly selected pathology-proven posterior fossa tumors from January 2022 to January 2024. Two blinded neuroradiologists analyzed all applicable MRI sequences. Their perfusion analysis also included the “lightbulb sign” as an extra criterion. Disagreements between the radiologists were confirmed by a third pediatric neuroradiologist. Chi-square and Fisher’s exact test were used to analyze the data. RESULTS 95 patients were enrolled in the study, 57(60%) were male. The median age at diagnosis was 8 (IQR: 3-14). Out of the enrolled patients, 8 had hemangioblastoma, and 87 had other posterior fossa tumors, including medulloblastoma (n=31), pilocytic astrocytoma (n=23), posterior fossa ependymoma type A (n=16), and other tumors (n=17). The comparison of hemangioblastoma vs non-hemangioblastoma showed that peripheral edema (p=0.020, OR=1.8) and T2 flow void (p=0.021, OR=1.7) favors hemangioblastoma, whereas reduced diffusion (low ADC) (p=0.002, OR=2.3) and ventricular system extension (p=0.001, OR=2.4) favors non-hemangioblastoma tumors. 42 cases also had perfusion studies. While high perfusion favors hemangioblastoma (p=0.021, OR=2.9), the lightbulb sign shows a complete distinction since all the ASL series of hemangioblastoma cases (n=4) showed the lightbulb sign, whereas none of the non-hemangioblastoma cases (n=38) showed the sign (p&amp;lt;0.001). CONCLUSION Lightbulb-like intense and homogenous hyperperfusion pattern on ASL allows differentiation of hemangioblastoma from other posterior fossa tumors in children.
DIPG-29. PHENOTYPIC SCREENS IDENTIFY GENETIC REGULATORS OF NANOPARTICLE DELIVERY IN DIFFUSE MIDLINE GLIOMAS
Authors: Jessica W Tsai, Marissa Coppola, Julianna Kenny-Serrano, John G Doench, Paula T Hammond, Pratiti Bandopadhayay, Joelle P Straehla
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline gliomas (DMGs) are a universally fatal pediatric brain tumor with a median survival of 12 months. There is a dire need to develop novel treatment strategies for these patients. Nanomedicine harbors great potential to encapsulate cargoes across tissue barriers and selectively target cells of interest. To effectively utilize existing nanomedicines and develop design criteria for novel formulations, an improved understanding of nano-bio interactions within the context of disease and development is required. METHODS We harnessed a lentiviral all-in-one CRISPR/Cas9 knock-out library paired with fluorescence-activated cell sorting to probe the functional impact of 700 genes on the delivery of lipid-based nanoparticles to DMGs. Layer-by-layer electrostatic assembly was utilized to synthesize a library of liposomal nanoparticles with polymer surface coatings. RESULTS Two patient-derived neurosphere models of DMG were transduced with the pooled, barcoded all-in-one CRISPR/Cas9 library. Following selection, cells were incubated with nanoparticles for 1, 4, or 24 hours and dynamically sorted into populations based on nanoparticle affinity. Genomic DNA was isolated from sorted cells and subjected to next generation sequencing for barcode identification. The relative enrichment of each single guide RNA in each population was determined relative to matched controls. We found strong agreement between biologic replicates and both cell lines, and our phenotypic screens revealed strong genetic regulators of nanoparticle uptake. We identified formulation-dependent and independent regulators, as well as regulators that were time-dependent. The top target genes are currently being validated in DMG and human neural stem cell models. CONCLUSIONS In ongoing work, we are leveraging genetic and chemical inhibition to sensitize DMG cells to nanoparticle therapeutics. We plan to leverage our screening technique to develop novel combination therapy approaches that could be implemented across multiple administration routes to enhance the use of nanomedicine for DMG and other pediatric brain tumors.
DIPG-36. DRD2 ANTAGONISM RESCUES IMMUNE-TUMOR SURVEILLANCE, WARMING THE TUMOR IMMUNE MICROENVIRONMENT OF DIFFUSE MIDLINE GLIOMA MODELS
Authors: Mika L Persson, Evangeline R Jackson, Ryan J Duchatel, Daniel de la Nava, Bryce C Thomas, Clara Savary, Holly P McEwen, Tyrone S Beitaki, Padraic S Kearney, Izac J Findlay, Alicia M Douglas, Martin R Larsen, Pouya Faridi, Jeff Holst, Jemma Mayall, Hubert Hondermarck, Jay Horvat, Brett Nixon, Rodrigo T Cartaxo, Javad Nazarian, Esther Hulleman, Sabine Mueller, Nicholas A Vitanza, Carl Koshmann, Marta M Alonso, Tiago Carvalheiro, Jasper van der Lugt, Matthew D Dun
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Less than 10% of patients with diffuse midline glioma (DMG) survive 2-years post-diagnosis, with no approved treatments other than palliative radiotherapy. Immune-checkpoint inhibition has failed in the clinic, likely due to a lack of tumor infiltrating lymphocytes (TILs) and limited/no expression of immune checkpoint proteins or proinflammatory cytokines in the tumor immune microenvironment (TIME). Similarly, glioblastoma patients suffer from a ‘cold’ TIME, linked to the sequestration of T cells in the bone marrow (BM) through β-arrestin-induced internalization of S1PR1. β-arrestin is activated by Dopamine receptors (DRD2); therefore, we hypothesized that systemic DRD2 antagonism using the antagonist ONC201, might reverse lymphopenia, increasing TIL populations. METHODS Flow cytometry analysis was performed on bloods from DMG patients at diagnosis. Circulating immune cells and BM from the immunocompetent PPK model +/-ONC201 and tumor-naïve mice were analyzed by a hematology analyzer and flow cytometry. Immunocompromised SU-DIPG-VI and HSJD-DIPG-007 and immunocompetent XFM murine models were treated +/-ONC201 and tumors analyzed by immunoblotting, immunohistochemistry, and flow cytometry. scRNAseq and scATACseq analysis was performed on tumors from immunocompetent PPK models +/-ONC201. RESULTS DMG patients displayed low levels of total lymphocytes, including CD4+, CD8+ and NK subsets (n=9). Similarly, DMG-bearing mice displayed lower levels of lymphocytes (CD45+, CD4+, CD8+ subsets, n=3) compared to sham-engrafted mice. ONC201 treated mice showed lymphocyte levels comparative to sham-engrafted mice, reversing tumor-induced lymphopenia. A significant increase of T cells expressing S1PR1+ was seen in the BM following ONC201. Tumor immune cell infiltration following ONC201 was confirmed in both immunocompromised and immunocompetent models. Multiomics analysis identified ONC201 to promote pro-inflammatory polarization of microglia/macrophages (MHC II and CD86) and increase expression of immune checkpoints (VISTA and PD-L1). CONCLUSIONS DMG patients suffer from low peripheral lymphocytes, likely contributing to cold TIME. ONC201 reversed tumor-induced lymphopenia, promoting TIL recruitment within the tumor, warming the TIME.
LMIC-07. OUTCOMES OF NEUROFIBROMATOSIS TYPE 1-ASSOCIATED OPTIC PATHWAY GLIOMAS AT A SINGLE TERTIARY PEDIATRIC ONCOLOGY CENTER IN EGYPT: BORG EL ARAB UNIVERSITY HOSPITAL (BAUH) EXPERIENCE
Authors: Nuha Omran, Nourelhoda S Bahaie, Shady Fadel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neurofibromatosis type 1 (NF-1) is a multisystem disease inherited in an autosomal dominant fashion. About 15% of the pediatric cases have associated brain tumors, among which the optic pathway gliomas (OPG) remain the most common. Due to their location, OPG can cause visual impairment, and endocrinal dysfunction, hence requiring therapeutic interventions, more commonly in sporadic non-NF-1 cases. METHODS NF-1 children with associated OPG followed at a single tertiary pediatric oncology center since its establishment from 2018 to 2023 were retrospectively evaluated. RESULTS Forty patients were identified either as firstly diagnosed NF-1 cases in our center or referred to us for follow up. Twenty-three of them who had associated OPG (mean age at diagnosis 83.7 months) were included in our study. The commonest clinical presentation was the bilateral initial visual affection occurring in 13 patients. Six had hormonal imbalance and four presented with seizures. Biopsy was taken only in 30%, with histopathology being mainly pilocytic astrocytoma. In terms of treatment, 10 cases received only one line of chemotherapy, six patients were kept on follow up, and the rest received more than one line of therapy. Overall survival (OS) was 100% throughout the study period, and progression-free survival was 64.1% at 1.5 years, and 46.8% at 5 years. Visual assessment at the end of treatment was stable in 71%, better in 22%, and worse in 7% of cases. Same pattern was observed in MRI assessment post therapy showing 57% stable disease, 39% regression, and 4% progression. CONCLUSIONS Survival of children with OPG is different in every center of the world as decisions regarding their management being challenging. Therefore, NF-1 multidisciplinary clinics are important to be established, with a high emphasis on early detection and referral of patients, standardization of symptoms grading and indications to start treatment.
DIPG-30. ELUCIDATING DOWNSTREAM MEDIATORS OF ONCOGENESIS IN<i>FOXR2</i>-EXPRESSING DIFFUSE MIDLINE GLIOMAS
Authors: Jessica W Tsai, Marissa Coppola, Phonepasong Arounleut, Jared B Collins, Patrick Hart, Hasmik Keshishian, David T W Jones, Pratiti Bandopadhayay, Timothy N Phoenix
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline gliomas (DMGs) are universally fatal pediatric tumors with a median survival of less than one year. Forkhead Box R2 (FOXR2) is a forkhead family TF that we have found to be aberrantly expressed in DMGs. FOXR2 expression is sufficient to enhance glioma formation, and we have shown that regulation of FOXR2 occurs through a previously unrecognized epigenetic mechanism. FOXR2 is necessary for proliferation in FOXR2-expressing DMGs. It is also a potent oncogene, sufficient to enhance cell proliferation and in vivo tumor formation. However, the downstream mediators of FOXR2-mediated gliomagenesis are poorly understood. METHODS We applied an integrative approach using proteomics, transcriptomics, in vitro cancer models, and in vivo in utero electroporation mouse models to systematically evaluate how FOXR2 mediates gliomagenesis. RESULTS We have found that FOXR2 is aberrantly activated in DMGs. FOXR2 enhances MYC protein stability, even in the presence of cycloheximide. However, FOXR2 also exerts its oncogenic effects through MYC independent functions. FOXR2 is highly enriched at E26-transformation (ETS) motifs and specifically activates ETS transcriptional gene sets. To identify FOXR2 protein-protein interactions, we performed immunoprecipitation and mass spectrometry to identify FOXR2 protein interactors. Moreover, we have performed both proteomic and phospho-proteomic analyses of FOXR2-expressing human neural stem cells. These proteomic studies have allowed us to identify proteins, phospho-sites, and signaling pathways that are highly enriched in FOXR2-expressing cells. These pathways could be potential therapeutic targets in FOXR2-expressing DMGs. CONCLUSIONS Taken together, this study elucidates how FOXR2 protein interactors mediate oncogenesis in FOXR2-expressing diffuse midline gliomas.
CNSC-05. THE GABAERGIC INTERNEURONAL AND NEURAL PROGENITOR LINEAGE OF THE DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT, SHOW CALCIUM EVENTS IN THE FORM OF INTERCELLULAR WAVES AND SPONTANEOUS ELECTRICAL ACTIVITY
Authors: Gustavo Alencastro Veiga Cruzeiro, Costanza Lo Cascio, Sina Neyazi, Carlos Alberto Oliveira Biagi Junior, Rebecca Haase, Andrezza Nascimento, Stephen Charles Frederico, Katharina Sarnow, Varun Venkataramani, Ilon Liu, Kun Huang, Xin Tang, Rosalind Segal, Michelle Monje, Mariella Filbin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade gliomas are one of the deadliest pediatric brain cancers. A diffuse subtype of hemispheric high-grade gliomas in adolescents and young adults is assigned as DHGH3G34-mutant. Notably, DHGH3G34-mutant gliomas distinctively contain cancer cell types resembling progenitors and GABAergic interneurons (eIN-like). Normal GABAergic interneurons influence neural network dynamics in the brain by communicating with other cells through the transmission of calcium and electrical signals. Our goal is to investigate the spatial organization of eIN-like glioma cells and evaluate whether they form networks and exert electrical activity relevant to tumor progression. METHODS Calcium Imaging: We used the Genetically encoded calcium indicator GCAMP7s with hDCX tdTomato promoter reporter construct. Voltage Imaging: We used the voltage indicator ASAP3 for detecting changes in membrane potential. Light microscopy: The whole fixed DHGH3G34-mutant PDX brain was mounted and imaged using the Zeiss Lightsheet 7 Microscope. RESULTS Using single-cell RNA sequencing and immunocytochemistry on DHGH3G34-mutant primary samples, we found that eIN-like cells express DCX (doublecortin) and form structures observed in ganglionic eminences. Calcium imaging revealed that DHGH3G34-mutant cells exhibit intercellular calcium waves. To track eIN-like cells, we developed a tdTomato fluorescent reporter for the DCX gene promoter activity (hDCX). Combining hDCX with GCAMP7s, we conducted calcium imaging and observed rhythmic calcium events in eIN-like cells at a frequency of 62.5mHz. Additionally, voltage imaging demonstrate that DHGH3G34-mutant cells show spontaneous action potential bursts. Furthermore, using light sheet microscopy on DHGH3G34-mutant PDX models, we observed glioma cells spreading into the contralateral hemisphere of the brain parenchyma. CONCLUSION DHGH3G34-mutant tumors represent highly invasive gliomas distinguished by the presence of progenitors and cells of the GABAergic interneuron lineage, exhibiting calcium waves and spontaneous action potential bursts. We are currently delving into the biological implications of these distinctive traits to gain insights into novel therapeutic strategies for the unique biology of DHGH3G34-mutant gliomas.
DIPG-09. PROGNOSTIC FACTORS IN REIRRADIATED DIFFUSE INTRINSIC PONTINE GLIOMA: CLINICAL AND RADIOMIC ANALYSIS
Authors: Dominik Wawrzuta, Marzanna Chojnacka, Monika Drogosiewicz, Katarzyna Pędziwiatr, Bożenna Dembowska-Bagińska
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain tumor. Radiation therapy (RT) is the standard treatment, with reirradiation considered at progression. However, the prognostic factors for reirradiation remain unclear. This study aims to investigate the outcomes of patients with DIPG undergoing reirradiation and to identify radiomic prognostic factors. METHODS We analyzed patients with histopathologically proven DIPG who underwent reirradiation at our institution. We delineated pre-reirradiation tumors using 3D Slicer software and extracted radiomic features from FLAIR MRI sequences using the Python package PyRadiomics. Finally, we used the least absolute shrinkage and selection operator (Lasso) for Cox’s proportional hazard model with leave-one-out cross-validation to select optimal prognostic factors for survival after reirradiation. We have also compared the reirradiated group with our cohort of 22 non-reirradiated DIPG patients eligible for reirradiation but whose parents chose only supportive care at progression. RESULTS The study included 15 patients who received reirradiation at the first progression, with a total dose of 20 Gy or 24 Gy in 2 Gy fractions. Reirradiation was well tolerated, without grade &amp;gt;2 toxicity. Neurological improvement was observed in 80% of patients. Median survival from the end of the first RT was significantly (p = 0.01) longer in the reirradiated group (68 weeks) compared to the non-reirradiated group (25 weeks). The Cox model demonstrated a concordance of 0.88 (95% CI: 0.83–0.92), revealing that tumor sphericity and structural gray-level heterogeneity in FLAIR MRI images were associated with more prolonged survival in reirradiated patients. CONCLUSIONS Reirradiation is a safe and effective approach for patients with DIPG. MRI-based radiomic models could help predict survival after treatment. Our results revealed that tumors with low sphericity and high homogeneity of gray levels are associated with a worse prognosis after reirradiation.
DIPG-62. REPURPOSING OF ANTIPSYCHOTIC TRIFLUOPERAZINE FOR INHIBITING MITOCHONDRIAL FUNCTION IN DIFFUSE MIDLINE GLIOMA
Authors: Antonela Petrovic, Kamil Wojnicki, Sandra Laternser, Ana Kitanovic, Tatjana Kleele, Michael Grotzer, Sabine Müller, Javad Nazarian
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse Midline Gliomas (DMGs) present formidable challenges in neuro-oncology, prompting the exploration of innovative therapeutic strategies. Repurposing approved drugs, particularly those exhibiting multifaceted effects, holds promise for addressing these challenges efficiently. In this study, we investigate the potential of trifluoperazine (TFP), an antipsychotic medication, with a specific focus on its mitochondrial-targeted actions in DMGs. METHODS TFP, a phenothiazine derivative, displayed robust in vitro anticancer activity against DMGs. Our investigation explored the molecular mechanisms underlying TFP’s interaction with mitochondria, emphasizing its influence on mitochondrial function, membrane potential, and reactive oxygen species (ROS) production. TFP is well known to induce irreversible Ca2+ release from intracellular stores by directly interacting with calmodulin 2 (CaM2) at the inositol triphosphate receptor (IP3R), leading to IP3R opening. In DMGs, intracellular Ca2+ plays a pivotal role in gene expression, cell motility, differentiation, and survival. TFP disrupts calcium homeostasis by elevating intracellular Ca2+ concentration, thereby inhibiting DMG invasion and growth. DMG cell lines, exhibiting heightened CaM2 expression compared to control healthy astrocyte cells, display increased sensitivity to TFP. RESULTS Remarkably, mitochondrial homeostasis was seriously affected by TFP, and a loss of mitochondrial membrane potential, ROS overproduction and fragmentation of mitochondrial network was observed. This mitochondrial stress, coupled with ER stress, activated the integrated stress response. We demonstrated that TFP induces cell death triggered by a poor ATP content, observed in TFP-treated cells as a consequence of a dramatic decrease in OXPHOS metabolism due to mitochondrial stress. CONCLUSIONS Our findings underscore TFP’s potential as a targeted therapeutic agent against DMGs, offering a better understanding of its impact on mitochondrial and intracellular signaling pathways. As the mitochondrial landscape remains critical in DMG biology, the observed mitochondrial damage-induced oxidative stress provides valuable insights for future investigations into the clinical application of TFP in neuro-oncology.
DIPG-60. OPERATIVE PERFORMANCE OF RAPNO DIPG CRITERIA FOR IMAGING REVIEW- A STUDY FROM THE INTERNATIONAL DIPG/DMG REGISTRY (IDIPGR)
Authors: Hamza S Gorsi, Melike Guryildirim, Michael Kuwabara, Jovan Dhatt, Lindsey M Hoffman, Kenneth J Cohen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group for diffuse intrinsic pontine glioma (DIPG) recently published its recommendations. Response criteria incorporate radiologic findings, neurologic status, and use of concurrent steroids and antiangiogenic drugs to define response. To test the operative performance of the imaging component, we retrospectively applied RAPNO DIPG recommendations to a convenience sample of 46 patients enrolled in the International DIPG/DMG Registry(IDIPGR). METHODS MRIs were independently reviewed by 2 pediatric neuro-radiologists. These measurements were analyzed utilizing RAPNO DIPG imaging criteria to categorize the response as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). For PR evaluation, each MRI was compared to the baseline MRI, and for PD evaluation, each MRI was compared to the MRI with the smallest cross-sectional measurement. The response category for each MRI was compared between 2 neuro-radiologists and was classified as concordant if they agreed, minor discordant if one reported SD and the other reported PR or PD, and major discordant if one reported PR and the other reported PD. RESULTS A total of 276 paired MRIs were analyzed. Sixty-seven percent of the time, the analyzed response assessment was concordant. In 33% discordant reads, 26% were minor discordant, and 7% were major discordant. There were no CRs reported. Further analysis of minor discordant cases showed that 62% of these cases were within 10% of the boundary for PR or PD. The median difference between 2 neuro-radiologists’ long axis measurements was 2 mm (range 0-27mm) and short axis measurements was 2mm (range 0-29mm). These small differences in measurements account for all discordant response categories between 2 neuro-oncologists. CONCLUSION This study demonstrated that RAPNO DIPG imaging criteria can be successfully applied with high concordance between readers. When discordant, measurements were largely at the boundaries of response type.