bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-44. EXTRINSIC ELECTRICAL MODULATION OF THE GLIOBLASTOMA TUMOR MICROENVIRONMENT
Authors: Castro Fernandes Gil Nuno , Palacin-Aliana Irina , Dussold Corey M , Tripathi Shashwat , Lesniak Maciej S , Heimberger Amy B , Sita Timothy L
Published: November 2024

BACKGROUND

Approximately 30 to 50% of patients with glioblastoma (GBM) present with glioma-related epilepsy (GRE). Despite morbidity associated with seizures, GRE constitutes an independent positive predictive predictor for survival in GBM. Our prior results showed that repeated seizure induction through extrinsic electrical modulation (EEM, a technique in which an electrical stimulus sufficient to produce a therapeutic seizure is applied) slows intracranial tumor growth and prolongs overall survival in immunocompetent CT-2A glioma-bearing mice. However, the overall survival advantage following EEM treatment was diminished in immunocompromised mice bearing human patient derived xenografts. We hypothesized that EEM induces immune-related tumor microenvironment (TME) changes that prolong survival in mice.

METHODS

C57BL/6J mice were orthotopically implanted with CT-2A xenografts and subjected to EEM of 2.0 millicoulombs or sham treatment. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed at 3 and 24 hours to determine mRNA level of inflammatory cytokines. Immunohistochemistry (IHC) and bulk RNA sequencing analysis were utilized to assess CD3+ T-cell infiltration and identify immune-related secreted genes, respectively. Flow cytometry at 3 and 96 hours was utilized to characterize tumor-infiltrating immune cell populations. Samples were subjected to Percoll gradient enrichment of immune cell populations and stained for extracellular (CD45, CD4, CD8, CD11b, F4/80, CD80, Ly6G, Ly6C, and CX3CR1) and intracellular (TNF-a, Il-1b, CCL2, and Arg1) antigens.

RESULTS

RT-qPCR showed an increase in pro-inflammatory cytokines TNF-α (P = 0.0087) and IL-1β (P = 0.000349). IHC analysis demonstrated an increase in intratumoral CD3+ T-cells in EEM-treated samples (P = 0.0171). From 1855 upregulated genes, 3 immune-related secreted genes (C1QTNF4, FAM19A4, and GREM2) were identified. Flow cytometric analysis showed a significant increase in CD11b+, CX3RC1+ microglia (P = 0.0306) and CD45+, CD11b+ tumor-associated myeloid cells (TAMCs) (P = 0.0192) at 3 hours post-EEM.

CONCLUSIONS

EEM treatment promotes an inflammatory TME with increased intratumoral microglia, TAMCs and T-cell infiltration. These inflammatory changes may prolong survival of CT-2A glioma-bearing mice.
IMMU-60. MYELOID POPULATIONS MODULATE GD2 CAR T CELL ACTIVITY IN DIFFUSE MIDLINE GLIOMA
Authors: Ramakrishna Sneha , Geraghty Anna , Good Zinaida , Desai Moksha , Mancusi Rebecca , Mahdi Jasia , Song Kun Wei , Ehlinger Zachary , Chen Yiyun , Hamilton Mark , Rietberg Skyler , Majzner Robbie , Schultz Liora , Richards Becky , Kamens Jennifer , Barsan Vali , Campen Cynthia , Partap Sonia , Moon Jennifer , Baggott Christina , Kunick Michael , Fujimoto Michelle , Li Amy , Jariwala Sneha , Mavroukakis Sharon , Egeler Emily , Jacobs Ashley , Erickson Courtney , Prabhu Snehit , Davis Kara , Feldman Steven , Sahaf Bita , Mackall Crystal , Monje Michelle
Published: November 2024

H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal cancers in children and young adults. Our team previously demonstrated efficacy of GD2-targeting chimeric antigen receptor T cells (GD2-CAR T-cells) in preclinical models of DMG of the pons (also called diffuse intrinsic pontine glioma (DIPG) and DMG of the spinal cord, and opened a Phase I clinical trial (NCT04196413) treating patients with first intravenous (IV) followed by repeated infusions of intracerebroventricular (ICV) GD2-CAR T-cells. We employed high-dimensional analyses to define immune states contributing to CAR-T activity in patients. Single cell RNA-sequencing (scRNAseq) was conducted on 555,406 single cells from 115 cerebrospinal fluid (CSF) samples of 13 patients before and after CAR-T treatment. This is the largest CSF CAR-T dataset in central nervous system (CNS) tumors and provides insights into the immune biology surrounding CAR-T treatment for CNS malignancies. Patient CSF samples were dominated by T cell and myeloid populations. After CAR-T infusion, patient CSF exhibited an increased fraction of regulatory T cells and myeloid populations from baseline. Myeloid cells in early timepoints after ICV administration demonstrated a unique pro-inflammatory signature, while CSF samples from IV and late ICV timepoints exhibited a suppressive signature. To further explore the immune biology of these myeloid contributors, we developed a patient-derived xenograft model of DMG relapse following low-dose ICV GD2 CAR-T treatment. Using a pharmacological CSF1R-inhibitor, we demonstrate that depletion of microglia/myeloid cells at a specific window following CAR-T administration enhances durability of tumor control. Together, these data display the power of in-depth correlative analyses to identify distinct immune populations that drive durability of response. Key findings from these data will allow for optimization of CAR-T therapies for H3K27M+ DMG patients, providing hope to shift the paradigm of this fatal disease.
IMMU-64. SEX-SPECIFIC ROLES OFYAP1 AND CD276/B7-H3 IN MEDULLOBLASTOMA IMMUNE SUPPRESSION
Authors: Abdelfattah Nourhan , Natarajan Sivaraman , Tran Han Nhat , Wong Thomas , Maldonado Jose , Borland Hannah , McMinimy Rachael , Chen Shu-hsia , Camargo Fernando , Olson James , George Joshy , Yun Kyuson
Published: November 2024

The molecular mechanism governing sex disparities in cancer prevalence, progression, and treatment outcomes represents an important yet understudied area of research with significant implications for cancer treatment. Medulloblastoma (MB), the most prevalent pediatric brain malignancy, exhibits a notable sex bias in incidence and survival rates. Males have a higher incidence rate across all age groups and have worse prognoses than their females for age groups over three years old. Here, we report an unanticipated sex-biased role of the oncogene Yap1 in SHH medulloblastoma. Our results reveal that Yap1 deletion significantly prolongs survival in male, but not female mice with SmoM2-driven SHH MB. Employing an integrated multi-omics approach, we demonstrate that YAP1 is required to maintain cancer stem cells simultaneously activating stemness genes (such as Sox2) and repressing differentiation genes (such as Neurod1 and Zic1/2) in both sexes. In contrast, Yap1 plays a more critical role in immune evasion in males than in females. Specifically, YAP1 regulates the expression of the immune checkpoint molecule Cd276/B7-H3, which suppresses cytotoxic T cell function. In males, CD276 blockade or Yap1 deletion in MB cells is enough to reverse T cell suppression effectively. In females, neither CD276 blockade nor Yap1 deletion alone in MB cells can reverse T cell suppression. Furthermore, YAP1’s direct transcriptional target gene signatures, including CD276, predict survival across multiple human cancers in male patients. These findings suggest broader implications of our findings beyond medulloblastoma and indicate a highly conserved mechanism across species. Our study provides compelling evidence for the male-biased efficacy of Yap1 or CD276 inhibitors and presents novel insights into sex-specific mechanisms of cancer immune evasion.
IMMU-66. PHYSIOLOGICALLY RELEVANT MURINE GLIOMA MODELS THAT REPRESENT GBM HETEROGENEITY AND ENABLE THE NEXT GENERATION OF DISCOVERY AND THERAPY EFFICACY STUDIES
Authors: Maldonado Jose , Wang Caiyi , Leu Jia-Shiun , Tran Han Nhat , Abdelfattah Nourhan , Yun Kyuson
Published: November 2024

To transform cancer drug development pipelines and gain a deeper mechanistic understanding of cancer: immune interactions, we desperately need better experimental models that faithfully recapitulate the cellular heterogeneity, complex and dynamic cell:cell interactions, and therapy responses in humans. To address this need, we developed and characterized a cohort of five new mouse glioma models in the C57BL6/j background. These transplantable tumorsphere models were derived from spontaneous gliomas that formed in genetically engineered mouse models with different oncogenic drivers, including EGFRviii, PDGFA, PTEN, p53, and NF1 mutations. They show a range of responses to standard of care (TMZ+IR) similar to GBM patients and all are resistant, to immune checkpoint inhibitors, anti-PD1+CTLA4, treatment, unlike the GL261 model and similar to GBM patients. We deeply characterized each model, including immune phenotyping and single-cell RNA-sequencing analyses. We also performed a cross-species comparison of human and mouse GBM and stromal cell phenotypes at the single-cell level. Our results show that new mouse models recapitulate the heterogeneity of glioma cell states observed in individual patients and, importantly, also the complex and immune suppressive TME. We demonstrate at the single-cell level that glioma-associated T and myeloid cell types are molecularly similar and conserved across species. Leveraging these data sets and experimental models, we are testing now novel immunotherapy targets for GBM.
IMMU-67. INTRACRANIAL IL12 SECRETING CAR-T CELLS OBVIATE THE NEED FOR LYMPHODEPLETION AND COMBAT HETEROGENEITY VIA MICROGLIAL INTERACTIONS
Authors: Mohan Aditya , Shen Steven , Moelker Eliese , Blandford Emily , Hardigan Andrew , Wilkinson Daniel , Fecci Peter , Sampson John , Patel Anoop
Published: November 2024

INTRODUCTION

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific antigen distinctively expressed in glioblastoma multiforme (GBM). However, its heterogeneous expression in GBM complicates its application as a target for Chimeric Antigen Receptor (CAR) T cells. Additionally, Interleukin-12 (IL12) has recently been identified as a potent cytokine in the treatment of solid tumors. In this study, we investigate the potential synergy between CAR-T cells and IL12 in targeting heterogeneous tumor antigens.

METHODS

To model tumor heterogeneity, mice were injected with a 50/50 mix of CT2A and CT2A EGFRvIII+ cells. EGFRvIII-specific third-generation CAR T cells, engineered with or without single-chain IL12, were cloned using an MSGV retrovirus backbone and transduced into murine T cells. The antitumor efficacy of CAR-T cells was evaluated through survival analysis. Additionally, the capability of CAR-T cells with or without IL12 to prolong survival and alter the tumor microenvironment was analyzed using single-cell sequencing.

RESULTS

EGFRvIII CARs alone were insufficient to cure mice with heterogeneous tumors, whereas EGFRvIII CARs co-expressing IL12 achieved a 60% cure rate. Interestingly, EGFRvIII CARs secreting IL12 demonstrated longer persistence in vivo compared to EGFRvIII CARs alone and did not require lymphodepletion before administration. We found that EGFRvIII CARs expressing IL12 promoted the elimination of EGFRvIII-negative tumor cells by recruiting endogenous CD8 T cells. Furthermore, among all Antigen Presenting Cell (APC) populations in the tumor microenvironment, we found that IL12 primarily acted on microglia to enhance antigen presentation pathways and support epitope spreading.

CONCLUSION

EGFRvIII CARs engineered to secrete IL12 effectively treat antigen-heterogeneous tumors by modulating local APCs and recruiting endogenous T cells. IL12-secreting CARs demonstrate longer persistence without the need for lymphodepletion compared to traditional EGFRvIII CARs. Employing CAR-T cells that secrete IL12 is a promising strategy to address tumor heterogeneity, offering therapeutic potential against GBM in clinical settings.
IMMU-72. TYPE I INTERFERON SIGNALING WITHIN GLIOBLASTOMA CELLS PROMOTES T-CELL EXHAUSTION AND RESISTANCE TO CHECKPOINT INHIBITORS
Authors: Jackson Joshua , Fecci Peter
Published: November 2024

Glioblastoma (GBM) remains among the most fatal cancers with few treatment modalities and resistance to modern immunotherapeutic treatment paradigms including immune checkpoint inhibitors (ICI). ICIs neutralize the regulatory signals that disable T cells and have demonstrated remarkable efficacy against a variety of cancers, though not in GBM. The impotence of ICI in GBM has been linked to the tumor’s remarkable capacity to elicit T cell exhaustion, though the mechanism remains poorly understood. Chronic interferon (IFN) cytokine signaling is known to promote immunosuppression and Tex in several cancer types as well as resistance to ICI. However, the role of IFN in GBM has not been investigated despite evidence that IFN signatures exist within clinical samples of GBM. Syngeneic murine GBM cell lines CT2A and SB28 were utilized for in vivo and in vitro studies. Anti-mouse PD-1 and CD8 antibodies or PBS control were injected intraperitoneally. CRISPR editing was used to create validated knockouts (KO) of the type I IFN receptor (IFNAR1) in CT2A. Mice bearing IFNAR1 KO intracranial tumors have improved median survival (p < 0.05) and are exquisitely sensitive to checkpoint anti-PD-1 blockade (p < 0.05) with the majority of mice surviving. Furthermore, surviving mice reject the subsequent intracranial re-challenge with parental CT2A tumors compared to controls (p <0.05) suggesting central memory responses mediating rejection. We conclude that abrogation of Type I IFN signaling is sufficient to extend survival which is further enhanced by ICI. Work is ongoing to further elucidate the precise mechanism that mediates this response and to identify a therapeutic intervention that enables tumor-specific inhibition of the IFN pathway with preliminary work suggesting a CD8 T cell mediated response and reversal of the T cell exhaustion phenotype.
INNV-10. ULTRA-RAPID INTRAOPERATIVE GLIOMA TUMOR CELL QUANTIFICATION
Authors: Murphy Zacharmy , Bianchini Emilia , Smith Andrew , Koerner Lisa , Russell Teresa , Reinecke David , Wang Yuxiu , Snuderl Matija , Orringer Daniel , Evrony Gilad
Published: November 2024

The diagnosis and treatment of brain tumors often depends on molecular-genetic data. To date, however, there has been no intraoperative method to rapidly and iteratively utilize tumor-specific genetic alterations to guide brain tumor surgical resections, complicating intraoperative diagnosis and precluding measurement of tumor cell burdens at surgical margins. To address this gap, we developed Ultra-Rapid droplet digital PCR (UR-ddPCR), which can be completed in 15 minutes from tissue to result with an accuracy and sensitivity comparable to standard ddPCR. We demonstrate an UR-ddPCR assay for the IDH1 R132H clonal mutation that is present in many low-grade gliomas. We illustrate the clinical feasibility of UR-ddPCR by performing it intraoperatively for 49 samples from 13 glioma cases, achieving intraoperative quantification in an average of 14 minutes and 54 seconds spanning a wide dynamic range from 0.1% to 94% tumor cell percentages. We further combine UR-ddPCR measurements with UR-stimulated Raman histology intraoperatively to estimate tumor cell densities in addition to tumor cell percentages, across a wide range from < 1 to 1332 cells/mm2. We anticipate that UR-ddPCR, along with future refinements in assay instrumentation, will enable novel point-of-care diagnostics and the development of molecularly-guided brain tumor surgeries that improve clinical outcomes.
INNV-13. OPHTHALMOLOGICAL COMPLICATIONS IN NF-1 PATIENTS RECEIVING MEK INHIBITORS: MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Sadighi Zsila , Alqahtani Shaikha , Hummel Lena , Ameri May , Al-Zubidi Nagham
Published: November 2024

BACKGROUND

MEK inhibitors (MEKi) are a novel therapy for plexiform neurofibromas and optic gliomas in Neurofibromatosis type 1 (NF1). Potential ophthalmic complications are MEKi-induced retinopathy (MEKAR) requiring regular ophthalmologic assessments. We assess the importance of screening and ocular adverse events (OAE) in pediatric NF1 patients receiving MEKi.

METHODS

We reviewed 45 NF1 patients with baseline and follow-up examinations before and post MEKi treatment initiation. Evaluations included comprehensive eye examination, visual acuity, dilated fundoscopic examination, optical coherence tomography (OCT) of the macula and nerve fiber layer, and Humphrey visual field testing.

RESULTS

Twenty-six (62% male) of 45 patients were included. Median age at treatment was 15 (range 2-23) years. Plexiform neurofibromas were the most common indication for MEKi (n=22). Selumetinib was the most common MEKi (n=19, 77%), then trametinib (n=6, 23%), and mirdametinib (n=1, 4%). Only two patients had to switch to different MEKi. Patients were followed for a mean of 413-days after treatment initiation (range 103-1122 days) for an average of 3.85 ophthalmology exams per patient. No retinopathy was observed at each of the 3–6 month follow-ups. Around 15% of patients experienced dry eye symptoms with none requiring artificial tears for management. Seven patients had pre-existing optic neuropathy. No dose adjustments were needed due to OAEs. One patient’s visual acuity decreased temporarily but returned to baseline and the patient remains on MEKi.

CONCLUSIONS

Regular ophthalmologic assessments are crucial for NF1 patients undergoing MEKi treatment. Consensus guidelines on frequency of ophthalmologic screening during MEKi treatment are not well reported. In our cohort no patients had MEKAR at regular 3–6 month follow ups. In addition to baseline screening, future larger cohort studies are needed to confirm if decreasing the frequency of retinal exams is safe while on MEKi to inform future clinical screening guidelines for NF1 patients on MEKi.
INNV-19. MULTIMODAL THERAPY FOR BRAF V600E MUTANT MELANOMA BRAIN METASTASES: CHARACTERIZATION OF CHRONOLOGICAL TREATMENT STRATEGIES AND ASSOCIATIONS WITH OVERALL SURVIVAL
Authors: Rooney Michael , Erickson Lily , Alghodhaifi Hesham , Elliott Andrew , Green Hannah , Langshaw Holly , Panthi Bikash , Talpur Wasif , Thrower Sara , White Victoria , Chung Caroline
Published: November 2024

BACKGROUND

B-raf proto-oncogene (BRAF)-mutant melanoma brain metastases (BRAF MBM) are associated with poor prognosis. Amidst our large institutional experience treating patients with BRAF MBM with multimodality therapy, our aim was to identify disease and treatment-related prognostic features, accounting for longitudinal sequence of events, to inform clinical decision-making.

METHODS

We retrospectively reviewed electronic health records of 100 patients with primary cutaneous melanoma diagnosed with BRAF MBM. Demographic, disease, and clinical factors including treatment sequencing were tabulated. Descriptive statistics were used to summarize the study population and non-parametric tests were used to evaluate differences across groups. A multivariable Cox regression identified factors associated with overall survival (OS) following BRAF MBM diagnosis.

RESULTS

Median follow-up was 22 months and median OS was 33.5 months. Patients received an average [standard deviation (SD)] of 3.36 [1.06] unique therapies. After adjustment for covariates, greater number of brain metastases at initial diagnosis (hazard ratio (HR) 2.3 [1.14-4.62], p=0.01 for 3-10 metastases and HR 2.54 [1.01-6.36], p=0.04 for >10 metastases, respectively), receipt of combination IO and targeted therapy prior to BRAF MBM diagnosis (HR 2.91 [1.08-7.86], p=0.03), and receipt of no unique subsequent therapy after initial management strategy (HR 3.89 [1.48-10.16], p=0.005) were significantly associated with worse OS.

CONCLUSIONS

Despite heterogeneity in individual treatment sequences, patients with greater intracranial disease burden and those receiving combination targeted and immunotherapy prior to BRAF MBM diagnoses had the worst outcomes. Dynamic changes in therapy resistance may inform optimal treatment strategies for individuals with BRAF MBM.
INNV-28. CONNECTOMICS-GUIDED GLIOMA RESECTION: HOW CHANGES IN STRUCTURAL CONNECTIVITY CORRELATE WITH LANGUAGE FUNCTION
Authors: Clare Kevin , Nolan Bridget , Rickard Amy , McGee Erin , Zeller Sabrina , Spirollari Eris , Kancharla Aditya , Mureb Monica , Falo Cristina , Kitago Tomoko , Milligan Tracey , Gandhi Chirag , Wu Synphen , Hanft Simon
Published: November 2024

Postoperative aphasia is a risk inherent to resections of brain masses in language eloquent areas. Neurosurgical strategies to minimize damage of functional language structures include awake craniotomies combined with stimulation mapping and intra-operative speech and language pathology (SLP) testing. Until now, consideration of white matter tracts involved in language processing as measured by diffusion tensor imaging (DTI) has been minimally incorporated into resection planning. In addition, there is limited understanding as to the association between specific tracts and aphasia risk. Quicktome™ by Omniscient Neurotechnology is clinically-oriented connectomics software that uses DTI sequences from MRIs to model connectivity between geographically distinct brain regions. This model can then be integrated with intraoperative navigation to avoid language connections during resection. Here, we investigate how language tract changes affect clinical aphasia. Patients with language-eloquent gliomas with available pre- and post-operative DTI and SLP evaluations were included in this retrospective study. Structural networks were quantified using Quicktome™ and compared using Spearman correlation. Changes in language function were evaluated using the Boston Naming Test and the Western Aphasia Battery. Patients with postoperative auditory verbal deficits showed a moderate correlation in connectivity changes (ρ=0.42), whereas patients with postoperative naming deficits showed a weak correlation (ρ=0.19). The inferior frontal junction, anterior portion (IFJa), and the superior temporal sulcus, ventral posterior portion (STSvp), in the right hemisphere demonstrated the most associated structural connectivity changes. To our knowledge, this is the first study which uses Quicktome™ to directly associate postoperative connectivity with aphasia outcomes. Understanding the interplay between structural connectivity and neurological symptoms can elucidate neural pathways underlying cortical function with the potential to reduce neurosurgical postoperative morbidity.
INNV-31. THE USE OF IVOSIDENIB IN PATIENTS WITH ENHANCING IDH1 MUTANT GLIOMAS
Authors: Minor Maria , Ziv Michal Nisnboym , Patel Mallika , Johnson Margaret , Batich Kristen , Low Justin , Shoaf Madison , Khasraw Mustafa , Desjardins Annick , Friedman Henry , Ashley David , Peters Katherine
Published: November 2024

Ivosidenib offers a novel targeted therapy for non-enhancing IDH1 mutated gliomas following initial resection. Potential effects of IDH inhibitors on enhancing disease in clinical settings are not well established. This study characterizes a cohort of patients with IDH1 mutated gliomas with enhancing disease, who were initiated on monotherapy, off-label ivosidenib between October, 2020 to August, 2023. The cohort included 21 patients ages 29 to 73 years, 11 female and 10 male. Diagnoses represented were astrocytoma IDH1 mutant, grade 2-4 (N=9) and oligodendrogliomas IDH1 mutant, grade 2-3 (N=12). Prior treatment exposures included radiation therapy (N=11), temozolomide (N=15), bevacizumab (N=3), and treatment naïve (N=6). Time from diagnosis to ivosidenib initiation was 9.1±2.7 years. Although all patients had enhancing disease, ivosidenib was initiated due to non-enhancing disease progression (N=7), enhancing disease progression (N=13), and temozolomide intolerance (N=1). Size of enhancement by cross-section measured >1cm (N=15) and <1cm (N=6). Best radiographic responses per RANO criteria were partial response (N=3), stable disease (N=11), and progressive disease (N=7). At last contact, eleven patients were maintained on ivosidenib with no evidence of disease progression since initiation with an average treatment duration of 25.5±6.4 months and overall survival of 11.7±3.1 years. Ten patients had disease progression at median 5.2±3.1 months following ivosidenib initiation, three of whom died 16.7 (range 6.8-34.4) months after treatment initiation with an overall survival of 9.4 years (range 4.6-13.6). Adverse events from therapy included diarrhea (N=2), CK elevation (N=4), and QTc prolongation (N=2). No patients discontinued ivosidenib due to adverse events. No significant difference was detected between patients with and without disease progression due to size of enhancement (p=0.4) or prior treatment exposure (p=0.3). Future studies should include biopsies to understand the role of enhancing lesions in treatment response of IDH inhibitors.
PATH-04. THE PROGNOSTIC IMPACT OF CDKN2A/B HETEROZYGOUS DELETIONS IN MENINGIOMA- INSIGHTS OF A MULTICENTER ANALYSIS
Authors: Ippen Franziska Maria , Hielscher Thomas , Patel Areeba , Göbel Kirsten , Friedel Dennis , Maas Sybren L N , von Deimling Andreas , Wick Wolfgang , Suwala Abigail K , Sahm Felix
Published: November 2024

BACKGROUND

Meningiomas are one of the most common primary brain tumors. Homozygous deletions of CDKN2A/B have reliably been shown to confer an increased risk of progression. However, the role of heterozygous CDKN2A/B deletions remains less clear.

MATERIAL AND METHODS

DNA methylation data, copy-number information and mutation data were generated on a multicenter cohort of meningiomas for a total of 970 samples. The CDKN2A/B locus was determined manually for each individual case in relation to whole chromosomal or larger segmental losses and gains in the chromosomal profile. Survival probabilities were assessed using the Kaplan–Meier method.

RESULTS

A total of 970 meningioma cases were identified with 30 homozygous and 114 heterozygous CDKN2A/B deletion cases, 826 cases had balanced CDKN2A/B. Heterozygous CDKN2A/B deletions in general did not confer an increased risk of progression compared to CDKN2A/B balanced cases (p= 0.074). However, segmental heterozygous losses of 9p, encompassing CDKN2A/B, yielded a significantly worse prognosis when compared to meningiomas CDKN2A/B-balanced (p= 0.002) and in contrast to focal heterozygous deletions (p= 0.523). Segmental heterozygous 9p deletions encompassing CDKN2A/B were significantly more frequently associated with a higher amount of copy number variations (CNVs) than focal losses.

CONCLUSION

Segmental heterozygous CDKN2A/B deletions do confer an increased risk of progression, but focal heterozygous CDKN2A/B deletions do not. The signal for segmental deletions may not be locus-specific but just one representation of the generally instable genome of aggressive meningiomas.
PATH-12. CLINICAL AND NEUROPATHOLOGICAL MARKERS FOR DISTINGUISHING BETWEEN IDH-MUTANT ASTROCYTOMAS OF WHO GRADE 2 AND 3
Authors: Blobner Jens , Harter Patrick N , Weller Jonathan , Teske Nico , Ruf Viktoria , Schoenecker Stephan , Forbrig Robert , Albert Nathalie L , von Baumgarten Louisa , Tonn Joerg-Christian , Thon Niklas , Karschnia Philipp
Published: November 2024

BACKGROUND

The neuropathological criteria of anaplasia to distinguish between IDH-mutant astrocytomas of WHO grade 2 and 3 are ill-defined by the WHO 2021 classification. Following the positive phase III trial results and the expected approval of Vorasidenib for grade 2 astrocytomas, identifying prognostic markers distinguishing grade 2 and 3 tumors remains crucial.

METHODS

We retrospectively searched our institutional database for patients meeting the diagnostic criteria for IDH-mutant astrocytomas per the WHO 2021 classification. Clinical, neuropathological, and molecular data were collected, and outcomes compared using log-rank analysis. Centralized slide review is ongoing to exclude inter-rater variability due to the study’s retrospective nature.

RESULTS

We identified 99 patients with IDH-mutant astrocytomas in which detailed neuropathological and clinical information were available for review, including 63 tumors (63.6%) which were assigned to WHO grade 2 and 36 tumors (36.4%) assigned to WHO grade 3. At a median follow-up of 7.5 years, median progression-free survival was 5.7 years for WHO grade 2 tumors and 4.4 years for WHO grade 3 tumors. Median overall survival for WHO grade 2 and WHO grade 3 tumors was not reached. On univariate analysis, higher WHO grade, an increased number of mitoses, elevated Ki67 indices and the presence of contrast-enhancement on pre-operative imaging were associated with less favourable outcome. However, only the presence of contrast-enhancement retained its prognostic significance when forwarded into a multivariate model (p = 0.034 for overall survival, p = 0.012 for progression-free survival). The findings on the association between contrast-enhancement and outcome were confirmed in treatment-based subgroups, including individuals treated with a watch-and-scan approach (n = 30), radiotherapy (n = 25), or chemotherapy (n = 33).

CONCLUSION

While our findings await confirmation in larger prospective cohorts, neuropathological criteria for anaplasia might need to be accompanied by clinical information including contrast enhancement to prognostically distinguish grade 2 from grade 3 tumors particularly in patients undergoing biopsy given the risk for undersampling.
PATH-21. SINGEL CELL TRANSCRIPTOMICS OF SPINAL EPENDYMOMA SUBTYPES IDENTIFIES INTRATUMORAL HETEROGENEITY
Authors: Hack Karoline , Jauch-Speer Saskia-Larissa , Schüller Ulrich
Published: November 2024

Spinal ependymomas comprise glial neoplasms that are classified by histological and molecular features. Two of the respective types, myxopapillary ependymomas (MPE) and spinal ependymomas (SP-EPN) are largely understudied. For each of these, our group identified clinically relevant subtypes with poorer (MPE-A; SP-EPN-A) and more favorable progression-free survival (MPE-B; SP-EPN-B) employing global methylation and transcriptomic profiling. As cellular origin and pathogenesis of these tumors are largely unknown, therapeutic options for patients with unfavorable subtypes are unavailable. We performed single cell transcriptomic sequencing of 12 formalin-fixed and paraffin-embedded spinal ependymomas including all MPE and SP-EPN subtypes and obtained a median of 10,091 cells per tumor after quality control. Uniform Manifold Approximation and Projection (UMAP) analysis revealed intertumoral heterogeneity as most samples formed separate clusters with tumors of the same subtype located in proximity. The expression of literature-defined neoplastic consensus cell states was examined for each cell of the data set and revealed intratumoral heterogeneity. Tumors expressed predominantly two programs, being a ciliated (ependymal-like) cell state (61% of all neoplastic cells) and the astrocytic state (31 % of all neoplastic cells). Interestingly, third and fourth most abundant states (mesenchymal and hypoxia) were almost exclusively expressed in MPE-A and SP-EPN-A. Furthermore, distinct clones of chromosomal copy number variations were identified across all tumors. These clones can be distinguished in UMAP representation of MPE single cell transcriptomes and to a lesser extend in SP-EPN. Next, we sought to characterize the resemblance of integrated tumor subtypes to normal spinal cord cell populations and observed a high similarity to human spinal cord ependymal cells. All spinal ependymoma subtypes display intratumoral heterogeneity with respect to the transcriptomic cell state resemblance of the neoplastic cells. Together with the transcriptomic similarity to ependymal and astrocytic cells, our data suggest the tumor origin within the astro-ependymal lineage.
PATH-41. PRIMARY BRAIN SARCOMA WITH DROP METASTASES AND LEPTOMENINGEAL DISEASE
Authors: Farooq Shama , Correia Carlos Eduardo Silva
Published: November 2024

INTRODUCTION

Primary brain sarcoma is extremely rare and has a very poor prognosis. Sarcomas are a highly diverse group, with over 100 different subtypes identified in the recent WHO classification. Case: In this case, we describe a 51-year-old man diagnosed with primary right frontal poorly differentiated sarcoma. He experienced cognitive changes for weeks. Brain MRI revealed a lobulated mass with peripheral enhancement measuring 67 mm by 61 mm by 52 mm. He underwent gross total resection, and pathology indicated high-grade poorly differentiated sarcomatous lesions. Further analysis at Memorial Sloan Kettering and NIH failed to match any DNA methylation class. Next generation sequence (NGS) testing revealed mutation of NF2, CDKN2A, COL3A1, CD33, and PIK3CA genes, increased PD-L1 mRNA, and PD-L1 expression, greater than 50%. The conclusive diagnosis was a PD-L1 high poorly differentiated sarcoma, not otherwise specified. Since no primary site was found elsewhere, planned to treat it as a primary brain sarcoma. Patient underwent focal radiation therapy with a plan to start immunotherapy combination of anti-CTLA4 and anti-PD1 therapy. In addition, an anti-VEGF therapy with pazopanib because of the efficacy of pazopanib in the setting of soft tissue sarcomas. The patient completed IMRT on 07/13/2023 and presented with a new onset of left leg weakness and urinary incontinence on 07/25/2024, further neuraxis imaging with MRI showed local and distant intracranial recurrence with drop metastasis at C1, C5-C6, and S2. The patient was started on IMRT to address drop metastasis, however further clinical decline led to treatment discontinuation.

DISCUSSION

There is no consensus on treatment guidelines on primary brain sarcomas given that they are exceedingly rare. DNA methylation and NGS provided very valuable information. We were unable to find any reported cases of primary brain sarcoma with drop metastases and leptomeningeal disease in the literature.
NIMG-08. IMAGING FINDINGS AND PROGNOSTIC FACTORS IN DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Kegoya Yasuhito , Otani Yoshihiro , Ikemachi Ryosuke , Omae Ryo , Nishigaki Shohei , Inoue Yohei , Umeda Tsuyoshi , Hokama Madoka , Mizuta Ryo , Imoto Ryoji , Kemmotsu Naoya , Suruga Yasuki , Hirano Shuichiro , Higaki Fumiyo , Washio Kana , Yamamoto Norio , Koizumi Shinichiro , Kurozumi Kazuhiko , Ishida Joji , Tanaka Yoshihiro , Tanaka Shota
Published: November 2024

INTRODUCTION

Diffuse hemispheric glioma, H3 G34-mutant (DHGs), are a newly categorized tumor in pediatric-type diffuse high-grade gliomas in the 2021 World Health Organization classification, with a poor prognosis. DHGs has been reported to occur in less than 1% of all gliomas, but prognostic factors have not been fully investigated in previous studies due to small sample sizes. In this study, we investigated the relationship between clinical factors, including imaging findings, and prognosis in patients with DHGs.

METHODS

We searched Medline through the PubMed database using two search terms: “G34” and “glioma”, between 1 April 2012 and 1 July 2023. We retrieved articles that described imaging findings and overall survival (OS), and added one DHG case from our institution. We defined midline invasion (MI) as invasion to the contralateral cerebrum, brainstem, corpus callosum, thalamus, and basal ganglia on magnetic resonance imaging. The primary outcome was 12-month survival, estimated using Kaplan–Meier curves and logistic regression.

RESULTS

A total of 96 patients were included in this study. The median age was 22 years, and the proportion of male patients was 48.4%. Lesions were most frequently located in the frontal lobe (52.6%). MI was positive in 39.6% of all patients. The median OS of all cases was 14.4 months. Univariate logistic regression analysis with 12-month OS as the outcome showed that the MI-positive group had a significantly higher mortality than that in the MI-negative group, and the gross total resection achieved group had a significantly lower mortality than that in the group that underwent biopsy alone. Multivariate logistic regression analysis revealed that MI was an independent prognostic factor in DHGs.

CONCLUSIONS

Similar to glioblastomas, DHGs have a poor prognosis if they invade deep structures or the contralateral cerebrum; however, safe and maximal tumor resection may prolong survival.
NIMG-52. ARTIFICIAL INTELLIGENCE-BASED VOLUMETRIC KINETICS FOR EVALUATING TREATMENT RESPONSE IN IDH-MUTANT GLIOMA TREATED WITH IMMUNOTHERAPY
Authors: Sergi Zach , Belue Mason , Fernandez Kelly , Kim Olga , Li Qi , Lu Peng , Turkbey Baris , Harmon Stephanie , Wu Jing
Published: November 2024

BACKGROUND

Interpretating radiographic findings of glioma patients receiving immunotherapy is challenging. Repeated imaging is often required for clinical decisions, potentially delaying next line of treatment. Here we assess a glioma segmentation AI model to evaluate treatment response in IDH-mutant glioma patients receiving nivolumab.

METHODS

Clinical magnetic resonance imaging (MRI)s from twenty-nine patients enrolled in a clinical trial (NCT03718767) were retrospectively analyzed. All patients had at least two sequential MRIs, including baseline study. T2, T1 (pre/post-contrast), and T2 FLAIR MRI sequences were pre-processed using publicly available AI-based whole-brain segmentation models. Lesion contours were derived from a validated 4-class brain tumor segmentation AI model, distinguishing healthy brain parenchyma, peri-lesional edema, non-contrast enhancing volume (NEV), and contrast-enhancing volume (CEV). Total lesion burden volume (TLBV=NEV + CEV + Edema) was also calculated. Growth rates between responders (R) and non-responders (NR), defined as progression-free survival ≥ or < 6months, respectively, were compared using a Wilcoxon Rank Sum Test.

RESULTS

The R group displayed significantly lower median rates of change for CEV (R -35% vs. NR +142% p = 4.31e-04) and TLBV (R +6% vs NR +43% p = 1.55e-03), compared to NR from baseline to post-cycle 1-2. Additionally, similar trends persisted at post-cycle 3-4 for CEV (R -41% vs. NR +367% p = 3.03e-03) and TLBV (R +12% vs. NR +40% p = 7.74e-03). Although NR showed a higher average baseline TLBV, there was no discernible correlation detected between baseline TLBV and the rate of change during treatment.

CONCLUSIONS

AI-based volumetric analysis offers an objective response assessment, showing promise in tracking disease progression in IDH-mutant glioma patients on nivolumab, potentially enabling earlier identification of progressive disease and allowing for timely treatment adjustments. A larger prospective study is warranted to refine volumetric pattern analysis for early clinical decisions in immunotherapy.
NIMG-54. AUTOMATED IMAGING RESPONSE EVALUATION SYSTEM (AIRES) FOR NEURO-ONCOLOGY: PROTOTYPE SOFTWARE TOOL FOR DETERMINING STANDARDIZED RADIOGRAPHIC RESPONSE ASSESSMENT FOR GLIOBLASTOMA CLINICAL TRIALS
Authors: Teraishi Ashley , Sanvito Francesco , Cho Nicholas , Raymond Catalina , Lai Albert , Nghiemphu Phioanh , Salamon Noriko , Cloughesy Timothy , Ellingson Benjamin
Published: November 2024

Standardized radiographic response assessment criteria like Modified Response Assessment in Neuro-Oncology (mRANO) and now the RANO 2.0 are utilized for evaluating progression-free survival and objective response rate during glioblastoma clinical trials. After measuring tumor size with either bidimensional diameters or volumetric segmentations, the crucial and final time-consuming step of categorizing progression, stable disease, and response based on multiple criteria and numerical thresholds (e.g. ≥40% volumetric growth = progressive disease) is currently done manually. We developed an application prototype, Automated Imaging Response Evaluation System (AIRES) for Neuro-Oncology, that uses the mRANO criteria to label each timepoint as treatment response, stable disease, or disease progression based on either bidimensional or volumetric measurements as well as optional inputs of clinical status and corticosteroid dosage. These inputs may be uploaded via CSV files, which can integrate with automated tumor segmentation volumetry workflows, or entered in the AIRES graphical user interface (GUI). The AIRES GUI displays a patient report consisting of a table and graph that contain the lesion size, percent change from baseline, percent change from nadir, and the mRANO response category for each timepoint. To test AIRES in a real-world application, tumor size measurements from 367 scans across 41 patients from NUTMEG, a phase II multicenter clinical trial, were used to perform mRANO reads and calculate progression-free survival and time to response. AIRES-assisted reads performed by reader 1 were significantly quicker than fully manual reads performed by reader 2 (37.1±8.6 vs 107.7±58.6 seconds, P<0.0001). These results show that the AIRES app can make the reads quicker and potentially feasible for non-trained personnel, while reducing the amount of error-prone manual steps. Additionally, the underlying logic of AIRES is easily adaptable to integrate other response criteria including but not limited to RANO 2.0 and other future response assessment updates.
NIMG-64. SURVIVAL IMPLICATIONS OF POSTOPERATIVE RESTRICTED DIFFUSION IN HIGH-GRADE GLIOMA AND LIMITATIONS OF INTRAOPERATIVE MRI DETECTION
Authors: Aaronson Daniel , Laing Brandon , Singhal Ishan , Boerger Timothy , Beck Ryan , Schmainda Kathleen , Meuller Wade , Krucoff Max
Published: November 2024

AIMS

In glioma surgery, surgically induced cerebral ischemia may poorly affect overall survival. While intraoperative MRI (iMRI) is an established tool used to maximize extent of resection, its ability to detect cerebral ischemia during surgery has not been studied. Here we evaluate both the association of post-surgical cerebral ischemia on survival independent of new functional deficits and the sensitivity of iMRI in detecting cerebral ischemia.

METHODS

We retrospectively reviewed 361 cranial surgeries that used a 3 Tesla iMRI. 165 patients met all inclusion criteria and were included in the final analysis. Diffusion weighted imaging (DWI) obtained during iMRI was compared to postoperative DWI obtained within 7 days of the operation in cases where no further resection occurred after the iMRI.

RESULTS

42 of 165 patients (25%) showed evidence of restricted diffusion on postoperative (poMRI); 37 of these 42 (88%) lacked evidence of restricted diffusion on iMRI (false-negative rate of 88%, sensitivity of 12%). In high-grade gliomas, poMRI restricted diffusion volume was predictive of overall survival independent of new functional deficit (p = 0.011).

CONCLUSION

Here we present the largest case series to date analyzing the sensitivity of iMRI in detecting ischemia. In high-grade gliomas, increased volume of ischemia correlated with worsening median overall survival (OS) irrespective of postoperative neurologic deficits. Future work will focus on improving intraoperative detection of ischemia during the hyperacute phase when interventions such as blood pressure modulation or direct application of vasodilator agents may be effective.
NIMG-82. DEVELOPMENT AND VALIDATION OF AN MRI-BASED DEEP LEARNING MODEL TO DIFFERENTIATEIDH-WILDTYPE GLIOBLASTOMA AND TUMEFACTIVE MULTIPLE SCLEROSIS
Authors: Marco Conte Gian , Moassefi Mana , Decker Paul , Kosel Matthew , McCarthy Christina , Fereidan Mah , Nikanpour Yalda , Pump Heather , Jenkins Robert , Lachance Daniel , Erickson Bradley , Tobin W Oliver , Eckel-Passow Jeanette
Published: November 2024

Clinical management of IDH wildtype glioblastoma (GBM) and tumefactive multiple sclerosis (tMS) is drastically different. GBM requires maximal safe resection followed by chemoradiation, while tMS outcome is worsened by surgery and radiotherapy. Noninvasive methods are needed to help with accurate diagnosis of tumor and non-tumor etiologies. To develop an MRI-based classification model, tMS subjects diagnosed prior to January 1, 2020, were matched to tMS by age at diagnosis, sex, index MRI date, and 2D/3D acquisition. Inclusion criteria included one cm minimal lesion size and pre-operative post-contrast T1 and T2 images available for analysis. A 3D-DenseNet121 was used to develop a classification model using prespecified parameters: 650 epochs, batch size 16, learning rate 10-3, cross-entropy loss, and AdamW optimizer. The stopping rule was defined as three sequential differences in epoch cross-entropy loss <0.02. Models were developed using both T1gd and T2, as well as from only T1gd and only T2. Training included 220 subjects (110 GBM, 110 tMS). A 2-stage validation design was used, which included both retrospective and prospective cohorts. Stage 1 consisted of 272 retrospective GBM (diagnosed prior to January 1, 2020). Stage 2 consisted of 69 and 34 prospective (diagnosed after January 1, 2020) GBM and tMS, respectively. External validation on the 272 retrospective GBM demonstrated accuracy of 91%, 84%, and 78% for T1gd+T2, T1gd only, and T2 only, respectively. External validation on the 69 prospective GBM demonstrated an accuracy of 87%, 64%, and 67% for T1gd+T2, T1gd only, and T2 only, respectively. The 34 prospective tMS demonstrated accuracy of 76%, 76%, and 82% for T1gd+T2, T1gd only, and T2 only, respectively. This shows the feasibility of deep learning to aid in differential diagnosis of brain lesions. Future work entails the integration of germline variants into the classification model, including variants associated with the risk of glioma or MS.
NCMP-01. EARLY RECURRENCE OF GLIOBLASTOMA MULTIFORM INVOLVING MULTIPLE BRAIN REGIONS ASSOCIATED WITH MUTATIONS IN EXON 4 OF ISOCITRATE DEHYDROGENASE 1 COMPLICATED BY GADOLINIUM-INDUCED ACUTE KIDNEY FAILURE: A CASE REPORT
Authors: Kamabu Larrey Kasereka , Ronald Oboth , Paul Okiror , Tansya Doddie , Ibula Serge , Muka Alain , Polepole Marius Kizito , Ruhambya Sem Mushagalusa , Kataka Louange Maha , Valimungighe Moise Muhindo , Lekuya Hervé Monka , Kangitsi Charles Kahindo
Published: November 2024

BACKGROUND

Glioblastoma multiform (GBM) remains one of the most aggressive primary brain tumors with high recurrence rates. Case presentation We present a case of a 43-year-old female, Yira, diagnosed with early recurrence of GBM involving multiple brain regions, accompanied by mutations in exon 4 of isocitrate dehydrogenase 1 (IDH1), a marker associated with poor prognosis. Additionally, this case was complicated by gadolinium-induced acute kidney failure on postoperative day 3. The patient initially presented with progressive neurological symptoms, including headache and cognitive decline. Multiplanar multiecho MRI of the brain was performed with IV contrast in orthogonal plane and revealed a moderate sized multilobulated heterogeneously and predominantly peripherally enhancing mass lesion with irregular margins and central non enhancing areas of necrosis arising from the right corona radiata, insular cortex, external capsule, lentiform nucleus, temporal, and frontal white matter with blood products. Perilesional edema was seen. Effacement of sulcal spaces. Right sylvian fissure, compression over right ventricle and midline shift of 8mm toward left side. There was dilatation of the left lateral ventricle with periventricular cerebrospinal fluid ooze. Uncal herniation was right side. On MR spectroscopy large choline, creatinine levels were seen in the lesion with reduced N-acetyl aspartate levels as compared to the normal parenchyma. Findings were suggestive of neoplastic lesion mostly high-grade glioma. Polymerase chain reaction sequencing confirmed missense mutation R132H in exon 4 of isocitrate dehydrogenase 1 gene. Despite maximal safe surgical resection, the patient developed recurrent GBM within three months, with gadolinium-based contrast agent exposure leading to acute kidney injury.

CONCLUSION

The combination of aggressive tumor behavior and complications from contrast agent administration highlights the challenges in managing recurrent GBM. This case underscores the importance of vigilant monitoring for complications in GBM patients, particularly those with IDH1 mutations, and the need for further research into novel therapeutic strategies.