bluuebunny/crossref_metadata_2025_split huggingface dataset:
NIMG-76. INCORPORATING IMAGING FEATURES OF NORMAL BRAIN TO ENHANCE SPATIALLY DIFFERENTIATING TREATMENT-INDUCED EFFECTS FROM RECURRENT GLIOMA WITH AI
Authors: Ellison Jacob , Ngan Tiffany , Jakary Angela , Tran Nate , Phillips Joanna , Shai Anny , Molinaro Annette , Li Yan , Luks Tracy , Nair Devika , Villanueva-Meyer Javier , Berger Mitchel , Hervey-Jumper Shawn , Aghi Manish , Chang Susan , Lupo Janine 
Published: November 2024

Abstract

INTRODUCTION
Although AI-based approaches have been applied to discriminate between tumor recurrence (rTumor) and treatment-induced effects (TxE) from chemoradiotherapy in patients with recurrent glioma, these models typically either do not account for within-lesion mixtures of rTumor and TxE or generalize to independent test-sets with &gt;80% accuracy. We hypothesize that incorporating imaging features of normal-appearing brain (NAB) into existing AI-based models that leverage tissue-samples with known locations on MRI and physiological imaging will significantly improve performance for distinguishing regions of TxE from rTumor and allow for visualization of rTumor beyond the T2-lesion.

METHODS
Using 254 pathology-confirmed tissue-samples with coordinates on diffusion-weighted, perfusion-weighted, and anatomical MRI from 135 glioma suspected of progression, we modified previously-developed binary, AI-based prediction models to learn multi-class targets consisting of rTumor, TxE, and contralateral NAB-regions (3/patient) with imaging signatures of CSF, white-matter, and grey-matter (659 total 10mm-isotropic samples). The multi-class ensemble model was trained with 4 unique repeats of constrained-5-fold-cross-validation and evaluated on a held-out test set (30 patients). This process was repeated 20 times, and the performance was compared to corresponding binary AI-based models.

RESULTS
NAB was easiest to distinguish from individual and combined classes (AUC-ROCs&gt;0.98). Multi-class model performance for predicting TxE increased by 27% to 0.93±0.03 (p&lt;0.00001) when discriminating between NAB and rTumor as compared to just rTumor with the binary models. While TxE vs rTumor alone was most difficult to predict with the multi-class model (AUC-ROC=0.73) achieving equivalent performance to binary models, there was 67% less variance in test performance. This approach allowed for the quantification of whole-brain probability maps of rTumor, TxE, and NAB along with a combined 3-channel colormap, facilitating the visualization of rTumor predictions beyond the T2-lesion.

CONCLUSIONS
Including NAB imaging features improved performance of AI-based models of rTumor/TxE, while expanding the predicted area to produce more interpretable whole-brain probability maps. Current work is evaluating their utility in prospectively guiding sampling of rTumor tissue and predicting survival.
NIMG-77. MRI PHENOMENON OF PUNCTATE ENHANCING LESIONS IN PATIENTS TREATED WITH IDH INHIBITORS
Authors: Nisnboym Ziv Michal , Patel Mallika P , Minor Maria , Johnson Margaret O , Batich Kristen , Low Justin , Shoaf Madison L , Khasraw Mustafa , Desjardins Annick , Friedman Henry S , Ashley David M , Peters Katherine B 
Published: November 2024

Abstract

BACKGROUND
Magnetic Resonance Imaging (MRI) response assessment is essential in isocitrate dehydrogenase (IDH)-mutant gliomas and provides evidence of treatment efficacy. Ivosidenib, a mutant IDH1 inhibitor, and vorasidenib, a pan-mutant IDH inhibitor, may induce imaging stabilization or improvement. We describe an imaging phenomenon of punctate enhancing lesions in patients receiving ivosidenib or vorasidenib.

METHODS
From October 2020 to December 2023, we identified patients treated with IDH inhibitors who developed punctate enhancing lesions on imaging during their treatment course. We report their clinical and imaging characteristics.

RESULTS
In our cohort (n=5), patients age range was 29-47 years. Diagnoses included astrocytoma grades 2 (n=2) or 3 (n=1), and oligodendroglioma grades 2 (n=1) or 3 (n=1). Beside all having a prior resection, two had prior radiation therapy and temozolomide, one had prior temozolomide only and two were treatment-naïve. Before initiation of IDH inhibitor, all patients had some evidence of enhancement, albeit small (&lt;1 cm) for most. Four patients received ivosidenib (500mg daily) and one received vorasidenib (40mg daily). The median time to develop punctate lesions from treatment initiation was 16 months (range 1-28 months). All but one lesion was &lt; 1 cm and adjacent to the original tumor locations. Four had FLAIR correlation, and two had high DWI signal without associated restricted diffusion. Punctate lesions resolved on subsequent imaging, within 1-2 months, for all grade 2 tumors. Punctate lesions persisted in the grade 3 tumors, without further progression. Four patients remain on therapy. One discontinued treatment due to this enhancement, which resolved on subsequent imaging.

CONCLUSIONS
Punctate enhancing lesions may develop in patients on IDH inhibitors. We advocate for close interval imaging monitoring in these cases since they may not universally require treatment discontinuation. Future advanced imaging and tissue evaluations of punctate enhancement, to differentiate between inflammatory response and progression, would be of interest.
NIMG-80. IMPACT OF KETOGENIC DIET ON MOLECULAR METABOLIC IMAGING WITH [18F]FDG AND [18F]DASA-23 POSITRON EMISSION TOMOGRAPHY IN A PATIENT WITH GLIOBLASTOMA
Authors: Naya Lewis , Bilgin Seyma , Beinat Corinne , Khalaf Alexander , Recht Lawrence , Patel Chirag 
Published: November 2024

Abstract
The standard-of-care for neuroimaging in patients with glioblastoma is contrast-enhanced MRI, which does not provide tumor metabolism information. Although [18F]FDG PET is used to image tumor metabolism in many solid organ cancers, it has limited benefit in atients with brain tumors due to the high level of glucose uptake in normal brain cells. [18F]DASA-23 is a novel PET radiotracer that assesses the levels of pyruvate kinase M2 (PKM2), a protein highly expressed in cancer cells, which undergo aberrant glycolysis. Despite [18F]DASA-23 having a higher tumor-to-background ratio (TBR) of standardized uptake values (SUVs) in the brain compared to [18F]FDG, both may be susceptible to altered carbohydrate metabolism in the setting of a ketogenic diet (KD). We report the case of a patient with glioblastoma on a KD, whose [18F]FDG and [18F]DASA-23 PET brain scans were limited in identifying disease progression (PD). Background was defined as the white matter contralateral to the tumor, at the level of the centrum semiovale, for TBR of SUVmax. A 39-year-old man was diagnosed with right temporal glioblastoma after previous diagnoses of grade 2 gliofibrillary oligodendroglioma (age 20) and grade 3 anaplastic oligodendroglioma (age 22). He began a KD after the glioblastoma diagnosis. 21 months later, TBR on [18F]DASA-23 PET was 1.38. One month later, surveillance brain MRI showed PD. Ten days later, TBR on [18F]FDG PET was 1.03. The patient died 15 months later. Despite MRI-based PD, the TBR of each radiotracer was not markedly elevated, although the [18F]DASA-23 TBR 1-month pre-PD was 34% greater than the [18F]FDG PET TBR 10-days post-PD. This may suggest a limitation of metabolic imaging by PET in the setting of a KD, and provide an opportunity to develop novel PET radiotracers that are not susceptible to the patient’s diet.
NCOG-22. ELDER AGE INSTEAD OF LOW EDUCATION PREDICTS POOR LANGUAGE FUNCTION IN RECURRENT LEFT HEMISPHERIC DIFFUSE GLIOMA PATIENTS
Authors: Cheng Pi-Cheng , Wei Kuo-Chen , Chen Pin-Yuan , Chen Ko-Ting 
Published: November 2024

Abstract

PURPOSE
Language processing is multifactorial, requiring interactions between cognitive functions and connections of cerebral cortexes and subcortical fibers in dominant hemisphere. Previously, we identified distinct patient factors and tumor characters influencing language performance in treatment-naïve diffuse glioma. In this study, we aimed to investigate predictive factors between treatment-naïve and recurrent patients with diffuse glioma.

MATERIALS AND METHODS
Grade 2 to 4 diffuse glioma patients who underwent awake surgery with completed preoperative language assessment were included. The Chinese version of the short-form Boston Diagnostic Aphasia Examination (sfBDAE) was used for language testing. Patient age, sex, education level, tumor grade, language pathway involvement, T1 contrast enhanced (C+), and FLAIR (T2) volume were selected as variables. Univariate and multivariate logistic regression analysis were used on language function impairment. The statistical significance was defined as a p-value less than 0.05 by SPSS20.0.

RESULTS
50.7% of all awake surgeries (112 of 221) in 171 patients had repeated operations in the retrospective cohort. Comparing to treatment-naïve patients, patients with recurrent tumor had higher academic year (p=0.016), more subventricular zone invasion (p=0.03), and more subcortical language pathway involvement (p=0.035), whereas showed no difference on language performance. In language function analysis, low education was the sole predictive factor for poor language function in treatment-naïve patients. In sharp contrast with low education, elder age factor was exclusively correlated with poor language function in recurrent patients. Furthermore, times of craniotomy was also an independent predictive factor in recurrent group.

CONCLUSIONS
Neurocognitive reserve is considered a protective factor against brain damage. Both age and education level are critical factors for cognitive reserve. Whether the phenomenon of a distinct and mutually exclusive patient factor affecting language function between treatment-naïve and recurrent diffuse glioma patients could be explained by the model of cognitive reserve necessitate more study.
NCOG-46. CHROMOSOMAL LOSSES CORRELATE WITH POOR OVERALL SURVIVAL IN H3K27M-ALTERED DIFFUSE MIDLINE GLIOMAS
Authors: Steven Leal-Ekman J , Nguyen Thien , Campen Cynthia , Ryan Katherine , Wheeler Joshua , Mahdi Jasia , Monje Michelle , Partap Sonia , Prolo Laura 
Published: November 2024

Abstract

BACKGROUND
H3K27M-altered diffuse midline gliomas (DMG) have poor outcomes with limited biomarkers to predict overall survival. Stratification based on chromosomal and molecular rearrangements represents a strategy to improve outcomes.

METHODS
We performed a retrospective analysis of 31 pediatric patients with biopsy-proven H3K27M-mutant DMG, who have undergone molecular next generation sequencing to define cytogenetics alterations that negatively impact overall survival. Median age at diagnosis in this cohort: 9.8 years (range 2.2-24.9 years). Among the cohort, 19 had H3F3A mutations confirmed by NGS, two had confirmed HIST1H3B mutations. Patients with intracranial masses received a standard fractionated radiation course with 54Gy or 59.4Gy XRT.

RESULTS
Pairwise comparisons demonstrate chromosomal losses and deletions are associated with poor overall survival (p=0.025, difference in Overall Survival [OS]: -19.9 months, 95%CI: -37.16 to -2.730) when compared to patients in the cohort without chromosomal deletions. Further subgroup analysis demonstrate worse outcomes in patients with deletions in chromosome 12 (p=0.003, difference in OS: -21.2 months, 95%CI: -34.74 to -7.702), deletions in chromosome 14 (p=0.007, difference in OS: -19.8 months, 95%CI: -33.72 to -5.892), or amplifications in chromosome 1 (p=0.003, difference in OS: -23.1 months, 95%CI: -37.53 to -8.613) relative to those without corresponding mutations. These data suggest that chromosomal alterations may serve as a potential biomarker to risk stratify patients. Likewise, genes within these deleted or amplified chromosomal segments may represent targets for therapeutic intervention.
EXTH-11. PEDIATRIC GLIOMA IMMUNE PROFILING IDENTIFIES TIM3 AS A THERAPEUTIC TARGET IN BRAF-FUSION PILOCYTIC ASTROCYTOMA
Authors: Tripathi Shashwat , Najem Hinda , Dussold Corey , Pacheco Sebastian , Du Ruochen , Sooreshjani Moloud , Chandler James , Stupp Roger , Sonabend Adam , Horbinski Craig , Lukas Rimas , Xiu Joanne , Nicolaides Theodore , Brown Valerie , Wadhwani Nitin , Lam Sandi , James Charles , Rao Ganesh , Castro Maria , Heimberger Amy , DeCuypere Michael 
Published: November 2024

Abstract
Despite being the leading cause of childhood mortality, pediatric gliomas have been relatively understudied. Repurposing of adult brain tumor immunotherapies in pediatric patients has not been successful, highlighting the need for pediatric-specific immunotherapies. Pilocytic astrocytomas (PA) are the most common pediatric glioma. While surgical resection of PA is the first-line treatment, the ten-year progression-free survival rate for patients with residual tumors is &lt;50%. Notably, some PAs undergo spontaneous regression after partial resection, suggesting potential baseline tumor immunoreactivity. Whole transcriptome sequencing performed on a commercial platform of pediatric gliomas (n=250) showed that MAPK-driven gliomas have higher interferon signatures compared to other molecular subgroups. Single-cell sequencing identified a unique activated and cytotoxic microglia population designated MG-Act in BRAF-fused MAPK-activated PA (n=13; p &lt; 0.05), but not in pediatric high-grade gliomas (n=5) or normal brain (n=3). TIM3 was expressed on the luminal side of endothelial cells and MG-Act, but not in the surrounding normal brain based on sequential multiplex imaging. Flow cytometry showed that TIM3 intensity is upregulated on immune cells in the PA tumor microenvironment (TME) relative to matched peripheral blood immune cells (n=6; p &lt; 0.01). Anti-TIM3 reprogrammed fresh ex vivo immune cells from the TME of human PAs (n=3) to a pro-inflammatory cytotoxic phenotype. In a genetically engineered murine model of MAPK-driven low-grade gliomas, median survival (MS) was 252 days in mice treated with anti-TIM3 (n=21; p&lt;0.01) relative to IgG control (MS: 110 days; n=20) or anti-PD-1 (MS: 134 days; n=20). The therapeutic activity of anti-TIM3 was abrogated in the CX3CR1 microglia knockout background. ScRNA sequencing data during the therapeutic window of anti-TIM3 in wild-type mice demonstrated enrichment of the MG-Act population within low-grade gliomas at two different longitudinal time points but not in IgG-treated controls. Together, these data indicate that anti-TIM3 should be considered for clinical trials in pediatric low-grade MAPK-driven gliomas.
EXTH-21. WINNING THE TUG OF WAR BETWEEN VIRUS AND TUMOR IMMUNODOMINANCE IN GLIOMAS TREATED WITH ONCOLYTIC ADENOVIRUSES USING TOLEROGENIC STRATEGIES
Authors: Ho Shin Dong , Ozpolat Bulent , Gillard Andrew , Garcia-Moure Marc , Jiang Hong , Lopez-Rivas Andres , Parthasarathy Akhila , Fan Xuejun , Alemany Ramon , Alonso Marta , He Jiasen , Ene Chibawanye , Al-Atrash Gheath , Lang Frederick , Gomez-Manzano Candelaria , Fueyo Juan 
Published: November 2024

Abstract
Phase 1 and 2 clinical trials of our oncolytic adenovirus Delta-24-RGD for patients with recurrent malignant gliomas have demonstrated its safety and efficacy, and showed that 20% of the patients experienced long-term tumor remissions often associated with inflammatory responses and tumor infiltration of lymphocytes. Based on our preliminary data, we expected that the most frequent tumor-infiltrating CD8+ T cell clones will target adenoviral hexon, with a single virus-specific clone representing up to 5% of the total population. Competition between T cells for resources may limit the expansion of subdominant clones recognizing tumor antigens. We hypothesized that mitigating virus-specific immunity allows the expansion of tumor-specific T cells and results in better therapeutic efficacy. In mice, intravenously injected nanoparticles encapsulating adenoviral antigens preferentially accumulated in the liver (P&lt;0.0001), where self-reactive immune cells are deleted through peripheral tolerance. RNA-sequencing of antigen-specific T cells isolated after nanoparticle injection revealed enriched expression of gene sets involved in immune tolerance through clonal deletion and T cell anergy, including increased expression of immune checkpoint molecules (P&lt;0.001). In glioma-bearing mice treated with virotherapy in combination with nanoparticle administration, tumor infiltrating lymphocytes exhibited decreased IFNγ secretion against viral antigens and increased secretion against tumor antigens, suggesting a redirection of the immunity from anti-viral to anti-tumoral (P&lt;0.05). Importantly, virotherapy with nanoparticles increased the overall survival of tumor-bearing mice compared to virus treatment alone (P&lt;0.001). To further characterize the roles of virus- and tumor-specific immune cells during virotherapy we are analyzing the T cell receptor repertoire of surgical specimens from nine glioma patients treated with Delta-24-RGD in a phase 1 clinical trial. In summary, our data provide the basis for a future clinical trial using tolerogenic strategies to redirect immunodominance of the viral to the glioma antigens, and represent a novel strategy to enhance anti-tumor immunity during virotherapy of brain tumors.
EXTH-25. OPTIMIZATION OF NEW CHEMOTHERAPEUTIC AGENTS BY INTRA-ARTERIAL INFUSION IN GLIOBLASTOMAS
Authors: Latulippe Juliette , Roy Laurent-Olivier , Charest Gabriel , Gobeil Fernand Jr , Fortin David 
Published: November 2024

Abstract
Being the most aggressive malignant primary brain tumor, glioblastoma (GBM) is a difficult disease to treat. The first line treatment is well established, but most patients will relapse before or during the treatments. The overall survival is only 14,6 months while the progression-free survival is 6,9 months. In Sherbrooke, Dr Fortin prioritize the intra-arterial (IA) administration of chemotherapeutic agents (CTA) as a second line treatment. Unfortunately, certain patients will not respond or will even develop chemoresistance to the agents. Therefore, there is a strong need for bringing more CTAs onto clinical care. The maximal tolerable dosage (MTD) of every agent was first determined. Every CTAs were then administered IA by retrograde infusion in the external carotid but also intravenously (IV) by the caudal vein. We used the Fischer-F98 glioma rat model in our studies. For the efficacy study, we implanted 10 000 F98 cells into their brain. After 10 days, they received the treatment associated to their group. The animals were followed every day and were euthanized when their condition was too deteriorated. The dosages found in the MTD study for topotecan and cytarabine was 4 mg/kg and 8,75 mg/kg respectively while paclitaxel was too toxic. As for the efficacy study, the IA group of topotecan showed a promising outcome with a higher survival rate (29 days) compared to the IV one (23,5 days). As for the cytarabine, the opposite was observed (IA: 22 days, IV: 26,5 days). While topotecan and cytarabine could be given intra-arterially, only topotecan showed conclusive results. More animals will be added to this group to confirm this outcome. Cytarabine is not a good option since the IV group survived a longer time than the IA group. As for the paclitaxel, the intra-tumoral infusion will be tested to see if we can get positive results.
EXTH-27. POLYCOMB OVERACTIVITY DRIVES TUMORIGENESIS IN AGGRESSIVE CUSHING’S DISEASE
Authors: Asuzu David , Mullaney Dustin , Bhatt Shyama , Mandal Debjani , Maric Dragan , Elkahloun Abdel , Chittiboina Prashant 
Published: November 2024

Abstract

INTRODUCTION
Aggressive Cushing’s disease (CD) tumors (Ki67 &gt; 3%) exhibit rapid growth, poor postsurgical outcomes, and resistance to conventional therapies. Polycomb group (PcG) proteins are canonical epigenetic silencers that can drive tumor aggressiveness. We asked if PcG underlies rare but fatal pituitary tumor progression.

METHODS
We performed paired multiome analysis (single nucleus RNAseq and ATACseq) in 5 aggressive CD adenomas, and adjacent normal gland. We verified protein expression with multiplexed immunohistochemistry (mIHC) and PcG activity by H3K27me3 ChIPseq. Aggressive murine pituitary tumor cells ATT20 were treated using PcG inhibitors (DZNep, tazemetostat), HDAC inhibitor (vorinostat), or siRNA (Ezh2, Suz12). PcG binding to the POMC promoter was assessed by reverse chromatin immunoprecipitation (rChIP). We treated one patient off-label with oral vorinostat 400mg daily for 6 days prior to radiation.

RESULTS
PcG loci (EZH2 and EED) were more accessible in aggressive CD adenoma versus normal gland corticotrophs, and EZH2, SUZ12 and EED mRNA was robustly overexpressed. mIHC confirmed SUZ12, EZH2 and H3K27me3 overexpression, and ChIPseq confirmed polycomb overactivity in aggressive CD adenomas. Polycomb inhibition by DZNep, vorinostat, or siRNAs led to proliferative arrest and Pomc suppression in ATT20 cells (P &lt; 0.05 versus controls). Vorinostat enriched Suz12 at the Pomc promoter (P &lt; 0.01), confirming direct silencing. In a patient with aggressive CD and hypercortisolemia despite two prior surgeries, a single course of vorinostat decreased cortisol (24mcg/dL to 7.5mcg/dL) and ACTH (63.7pg/mL to 44.9pg/mL) prior to radiation therapy initiation.

CONCLUSIONS
PcG hyperactivity is associated with a more aggressive CD phenotype. We report here the therapeutic potential of HDAC inhibition against aggressive CD adenomas in a first-in-human application.
EXTH-30. GENETIC ALTERATIONS THAT DEREGULATE RB AND PDGFRA SIGNALING PATHWAYS DRIVE TUMOR PROGRESSION IN IDH2-MUTANT ASTROCYTOMA
Authors: Tateishi Kensuke , Miyake Yohei , Nakamura Taishi , Fujii Satoshi , Yamamoto Tetsuya , Cahill Daniel , Wakimoto Hiroaki 
Published: November 2024

Abstract
In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain unclear. In this presentation, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2R172K and TP53R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recur- rent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2R172K and TP53R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astro- cytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. On the other hand, in accord with our previous study that IDH1 inhibitor was not sufficient to induce anti-tumor effects in IDH1-mutant high-grade gliomas (Tateishi K et al. Cancer Cell. 2015), we did not find decreased cell viability nor histone methylation status changes after mutation specific IDH2 inhibitor treatment of recurrent cells. These findings underlie that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.