bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract

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

Abstract
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 &lt; 0.05) and are exquisitely sensitive to checkpoint anti-PD-1 blockade (p &lt; 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 &lt;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

Abstract
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 &lt; 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

Abstract

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

Abstract

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 &gt;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

Abstract
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

Abstract
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 &gt;1cm (N=15) and &lt;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

Abstract

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

Abstract

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.