bluuebunny/crossref_metadata_2025 huggingface dataset:
BIOM-46. EXPLORING CLINICAL AND PATHOLOGIC CHARACTERISTICS IN GLIOBLASTOMA LONG -TERM SURVIVORS (LTS) VERSUS SHORT-TERM SURVIVORS (STS)
Authors: Briceno Nicole , Abdullaev Zied , Vera Elizabeth , Komlodi-Pasztor Edina , Choi Anna , Christ Alexa , Grajkowska Ewa , Leeper Heather , Levine Jason , Lindsley Matthew , Reyes Jennifer , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Penas-Prado Marta , Pillai Valentina , Theeler Brett , Kunst Tricia , Evans Karen , Mentges Kelly , Wu Jing , Polskin Lily , Papanicolau-Sengos Antonios , Quezado Martha , Aldape Kenneth , Gilbert Mark , Armstrong Terri
Published: November 2022

Glioblastoma (GBM) has a median survival of less than 18 months with infrequent long-term survival (LTS). Reports on LTS to date have not identified distinct molecular or clinical/imaging characteristic in long ( >3 years) versus short (< 3 year) survivors. We identified IDH wildtype GBM patients living ≥ 3 years post diagnosis (LTS, Nf25) and a control cohort (STS, Nf76) from our Natural History Study. Available tissue was analyzed with targeted panel sequencing (Nf25) and methylation analysis (Nf21) for classification, MGMT promoter (MGMTp) status and copy number changes. Median survival and age for LTS and STS was 54mo and 48yrs, and 16mo and 56yrs, respectively. LTS were more likely to be female (2.8x) or have a GTR (2.9x) but 83% less likely to be white. MGMTp was 10x more likely to be methylated in LTS tumors (95% CI [2.6, 39.6]), yet was unmethylated in 17%. LTS were 63% and 90% less likely to have TERTp or EGFR amplification (95% CI [0.14, 0.97] and [0.04, 0.29]). Core pathway review showed 21% of LTS had at least one alteration in p53, RB and RTK/PI3K with RTK/PI3K the most common (46%) . Methylation classifier identified 74% as GBM (STS=96%) with most the RTK II subtype (53%; STS=41%) and despite classic histologic features, indicated a non-GBM diagnosis in three cases (14%).Although uncommon, there are LTS with molecularly confirmed GBM. Remarkably, not all had MGMTp methylation, were young or had extensive tumor resection. Clinical estimates of outcome in GBM patients should consider the possibility of long-term survival even with established poor prognostic factors. Imaging characteristics in a subset of these cases are reported in a separate abstract. Additional interrogation of tumor from LTS may uncover additional determinants of response and outcomes.
BIOM-48. HOXD12 IS AN INDEPENDENTLY PROGNOSTIC AGE-ASSOCIATED INDICATOR FOR POOR SURVIVAL IN OLIGODENDROGLIOMA
Authors: Nuechterlein Nicholas , Cimino Sadie , Arora Sonali , Shapiro Linda , Holland Eric , Gilbert Mark , Cimino Patrick
Published: November 2022

BACKGROUND

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has variable outcomes that are strongly influenced by patient age. This study aimed to discover novel molecular biomarkers that may characterize an aggressive subgroup of oligodendroglioma that is associated with, but independently prognostic of patient age.

METHODS

Differential gene expression analysis, gene ontology analysis, and gene set enrichment analysis were conducted on TCGA RNA-seq data (N=169) to identify genes and pathways that differ significantly between older and younger patients. Genes whose expression was associated with age and survival in multivariate analyses were further studied using DNA methylation (N=171). The prognostic value of their expression and methylation profiles was then compared to known genomic biomarkers, radiographic features, and histopathologic features. RNA-seq and DNA methylation validation data were obtained from the CGGA (N=44) and a cohort published by Capper et al. (N=144), respectively.

RESULTS

Highly activated pathways in older oligodendrogliomas were linked to developmental transcription factors. Overexpression of HOXD12 was associated with patient age and survival in the TCGA (FDR< 0.01, FDR=1e-5) and the CGGA (p=0.03, p< 1e-3). Hypermethylation of HOXD12 was associated with age, tumor grade, and survival in the TCGA (p< 1e-5, p< 0.001, p< 1e-3) and with age and tumor grade in Capper et al. (p< 0.02, p=0.001). In the TCGA, HOXD12 hypermethylation and overexpression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, and MYC activation as well as mitotic figures, Ki-67 index, microvascular proliferation, and necrosis. HOXD12 overexpression was also independently prognostic of T1-post contrast enhancement, whole tumor volume, and peritumoral edema volume. We developed a risk-stratification nomogram predicting 5- and 10-year overall survival using patient age, HOXD12 methylation, and WHO grade.

CONCLUSIONS

HOXD12 overexpression and hypermethylation are associated with an aggressive subtype of oligodendroglioma and may serve as superior prognostic biomarkers than previously reported genomic, radiographic, and histopathologic features.
BIOM-52. DIAGNOSTIC POTENTIAL OF EXTRACELLULAR VESICLES IN MENINGIOMA PATIENTS
Authors: Ricklefs Franz , Maire Cecile , Wollmann Kathrin , Dührsen Lasse , Fita Krystian , Sahm Felix , Herold-Mende Christel , von Deimling Andreas , Fuh Marceline , Schlüter Hartmut , Westphal Manfred , Lamszus Katrin
Published: November 2022

Standard monitoring after meningioma resection relies on serial MRI examinations, which are time-consuming, expensive and provide no information on molecular alterations that may indicate progression towards a more aggressive tumor. Extracellular vesicles (EVs) secreted by tumor cells play an important role in cell-cell communication, and tumor-derived EVs circulating in patient blood can serve as biomarkers. We investigated the potential role of plasma EVs in meningioma patients for tumor detection and determined whether EVs secreted by meningioma cells reflect epigenetic, genomic and proteomic alterations of original tumors. EV concentrations were quantified in patient plasma (n = 46). Short-term meningioma cultures were established (n = 26) and secreted EVs were isolated. Methylation and copy number profiling was performed using 850k arrays, and mutations were identified by targeted gene panel sequencing. Differential quantitative mass spectrometry was employed for proteomic analysis. We found that the levels of circulating EVs were significantly elevated in meningioma patients compared to healthy individuals, and that plasma EV concentrations correlated with malignancy grade and extent of peritumoral edema. Postoperatively, EV counts dropped to normal levels, and the magnitude of the postoperative decrease was associated with extent of tumor resection (Simpson grade). Methylation profiling of EV-DNA allowed correct tumor classification as meningioma in all investigated cases, and accurate methylation subclass assignment in nearly all cases. Copy number variations present in tumors, as well as tumor-specific mutations were faithfully reflected in meningioma EV-DNA. Proteomic EV profiling did not permit original tumor identification but revealed tumor-associated proteins such as desmoplakin that could potentially be utilized to enrich meningioma EVs from biofluids. In conclusion, elevated EV levels in meningioma patient plasma may aid in tumor diagnosis and assessment of treatment response. Meningioma EV-DNA mirrors genetic and epigenetic tumor alterations and facilitates molecular tumor classification.
BIOM-54. ANALYTICAL VALIDATION OF A TARGETED GENE EXPRESSION BIOMARKER PREDICTING MENINGIOMA OUTCOMES AND RADIOTHERAPY RESPONSES
Authors: Chen William , Lucas Calixto-Hope , Choudhury Abrar , Vasudevan Harish , Magill Stephen , Raleigh David
Published: November 2022

BACKGROUND

Improvements in meningioma risk stratification are needed to guide postoperative management. We previously developed and externally validated a targeted gene expression biomarker predicting meningioma outcomes and radiotherapy response using fresh frozen meningiomas. Here, we present the analytical validity, test-retest and cross-platform reproducibility, intra-tumor heterogeneity, and formalin fixed paraffin embedded (FFPE) concordance for this biomarker.

METHODS

Matched FFPE and fresh frozen samples from 50 meningiomas underwent RNA extraction for concordance testing using a custom Nanostring gene expression panel comprised of 34 meningioma genes and 7 housekeeping genes. Matched Nanostring gene expression profiling and RNA-sequencing was available from 173 fresh frozen meningiomas. Nanostring batch, machine, and technician variability was tested on 10 FFPE meningiomas using 2 independent batches of biomarker reagents that were processed at 2 independent laboratories. To study intra-tumor heterogeneity, 68 spatially distinct meningioma biopsies obtained under stereotactic guidance from 13 tumors were analyzed using the Nanostring gene expression biomarker.

RESULTS

Matched FFPE and fresh frozen meningioma samples (N=50) demonstrated high gene expression concordance (Pearson R=0.89, F-test P< 2.2e-16) and risk score concordance (R=0.78, F-test P< 1.8e-11, residual standard error 0.12). The biomarker achieved high performance on FFPE samples (local freedom from recurrence [LFFR] c-index 0.75±SEM 0.05, 5y LFFR AUC 0.84, 95% interval 0.67-0.96). Test-retest concordance on FFPE samples (N=10) across independent reagent batches, machines, and technicians was high (gene expression concordance: R=0.97; risk score concordance R=0.94). Transcript counts were concordant across Nanostring and RNA sequencing approaches (N=173 frozen samples, R=0.90). Stereotactic intra-operative sampling (N=68 samples from 13 patients) revealed low levels of intra-tumor heterogeneity (median inter-quartile risk score within tumor: 0.10±0.01).

CONCLUSIONS

We demonstrate analytical reproducibility and robustness of a gene expression biomarker predicting meningioma outcomes and radiotherapy responses in FFPE and frozen samples across multiple conditions and platforms.
BIOM-55. DE RITIS RATIO AS A NOVEL PROGNOSTIC BIOMARKER IN ATYPICAL MENINGIOMAS: A MULTI-INSTITUTIONAL STUDY
Authors: Chang Won Ick , Byun Hwa Kyung , Lee Joo Ho , Park Chul-Kee , Kim In Ah , Kim Chae-Yong , Chang Jong Hee , Kang Seok-Gu , Lee Sang Hyung , Kuranari Yuki , Tamura Ryota , Toda Masahiro , Yoon Hong In , Wee Chan Woo
Published: November 2022

PURPOSE

To investigate the impact of prognostic serum biomarkers in newly diagnosed surgically resected intracranial atypical meningiomas.

METHODS

This multi-institutional study included 523 grade 2 (according to the 4th edition of WHO Classification of Tumors of the Central Nervous System) patients who underwent resection between 1998–2018. The baseline characteristics and serum laboratory data within one week after surgery were obtained for analyses investigating the association with progression/recurrence (P/R) rate or progression-free survival (PFS). Optimal cut-offs were calculated for each serum marker using the maxstat package of R. Nomograms were developed based on the multivariate analyses of statistically significant prognosticators.

RESULTS

Among 523 patients, 454 patients were included in the multivariate analysis for P/R rate excluding patients with incomplete histopathologic or laboratory data. On multivariable analysis, tumor size >5 cm (HR, 2.18; 95% CI, 1.49–3.19) and subtotal resection (HR, 3.60; 95% CI, 2.37-5.47) were associated with higher P/R rate, whereas adjuvant radiotherapy (HR, 0.32; 95% CI, 0.20-0.53) and postoperative platelet >137 x 103/μL (HR, 0.58; 95% CI, 0.39-0.86) were associated with lower P/R rate. Interestingly, postoperative De Ritis Ratio (aspartate aminotransferase/alanine aminotransferase) >2 proved to be an adverse prognosticator (HR, 1.87; 95% CI, 1.15-3.05). Similarly, patients with De Ritis ratio >2 showed inferior PFS (HR, 1.87; 95% CI, 1.23-2.84). In the subgroup of patients who received adjuvant radiotherapy, tumor size >5 cm and postoperative neutrophil-to-lymphocyte ratio >21 were the only prognosticators and were associated with higher P/R rate. On the other hand, postoperative De Ritis ratio >2 remained to be an adverse prognosticator in patients who did not receive radiotherapy.

CONCLUSION

Postoperative De Ritis Ratio was unrevealed as a novel serum prognosticator in newly diagnosed atypical meningiomas. Further studies are warranted to validate its clinical significance and biological background.
BIOM-58. ROLE OF CD79B Y196 MUTATION IN PCNSL AS A POTENT PREDICTIVE MARKER FOR FAVORABLE RESPONSE TO R-MPV TREATMENT AND DEVELOPMENT OF RAPID ALL-IN-ONE GENOTYPING SYSTEM FOR MOLECULAR MARKERS OF PCNSL
Authors: Yamaguchi Junya , Ohka Fumiharu , Lushun Chalise , Motomura Kazuya , Aoki Kosuke , Takeuchi Kazuhito , Nagata Yuichi , Ito Satoshi , Mizutani Nobuhiko , Ohno Masasuke , Suzaki Noriyuki , Takasu Syuntaro , Seki Yukio , Tanahashi Kuniaki , Hirano Masaki , Shimizu Hiroyuki , Kitano Yotaro , Maeda Sachi , Yamazaki Shintaro , Wakabayashi Toshihiko , Kondo Yutaka , Saito Ryuta
Published: November 2022

Although high-dose methotrexate (HD-MTX)-based chemotherapy, such as rituximab, HD-MTX, procarbazine and vincristine (R-MPV) regimen, has significantly prolonged the survival of patients with primary central nervous system lymphoma (PCNSL), predictive factors for response to R-MPV have not yet been investigated. Then, we investigated the correlation of MYD88 L265P and CD79B Y196 mutations, which are the most frequently found molecular alterations in PCNSL, with prognosis of patients with PCNSL treated with R-MPV. 47 and 21 patients with PCNSL treated with R-MPV and HD-MTX respectively were included, and correlation of their MYD88 and CD79B status with prognosis was analyzed. R-MPV achieved an excellent tumor control rate (61.6% and 69.9% of 5-year progression-free and overall survival rates, respectively). Among the 47 patients, 36 harbored MYD88 L265P or CD79B Y196 mutations. While the MYD88 L265P mutation had no significant effect on survival, patients with CD79B Y196 mutations exhibited prolonged survival (P < 0.05). However, the association of the CD79B Y196 mutation with a better prognosis was not observed in the HD-MTX cohort, which indicated that the CD79B Y196 mutation was a predictive marker for a favorable response to R-MPV. Furthermore, we established an all-in-one rapid genotyping system for these genetic mutations. This system enabled the detection of these genetic mutations in a small amount of biopsy samples within 90 min. In conclusion, we revealed that the CD79B Y196 mutation is associated with a good response to R-MPV, and the rapid and accurate genotyping system for MYD88 L265P and CD79B Y196 mutations that we developed in this study will enable reliable rapid molecular diagnosis and early prediction of response to R-MPV, which might help to determine the best treatment strategy for PCNSL.
BIOM-61. SYSTEMATIC REVIEW OF BIOLOGIC CORRELATES OF FRAILTY IN SOLID TUMORS: IMPLICATIONS FOR BRAIN TUMORS
Authors: Sass Dilorom (Delia) , Streck Brennan , Cooper Diane , Guida Jennifer , Armstrong Terri
Published: November 2022

BACKGROUND

Cancer and cancer treatments contribute to accelerated aging and frailty, which is present in over 50% of adult cancer survivors and increases vulnerability to poor outcomes. Biomarkers of frailty would allow for early identification and timely interventions. The purpose of this review is to synthesize the current literature examining biomarkers of frailty across solid tumor patients, including primary brain tumors (PBT).

METHODS

The systematic review was conducted using preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. PubMed, Web of Science, and Embase, were searched by the medical librarian (D.C.) of all reports from the inception to December 08, 2021. Inclusion criteria were: a) English language, b) biomarkers of aging hallmarks, c) association between biomarkers and frailty. Studies were limited to human solid tumors. Two reviewers (D.S. and B.P.S.) independently screened titles, abstracts, and full-text articles using Covidence platform with conflict resolution by the third researcher (T.S.A.). Included studies were independently evaluated for quality assessment using NIH tools for Observational Cohort, Cross-Sectional and Case-Control studies.

RESULTS

In total, 915 reports were screened and 15 full-text articles were included for the review. Studies were most commonly in breast tumors with no PBTs identified. Most were cross-sectional using small sample sizes. Fried, Balducci, and Leuven Oncogeriatric Frailty tools and cytokines (i.e. Interleukin-6 and C-reactive protein) were commonly used. Increased inflammatory response was the prevalent identified mechanism. Threats to internal validity of the studies were the use of unvalidated cut-off scores or modification of existing tools in about 50% of studies. Only six studies were rated as good using quality assessment ratings.

CONCLUSIONS

Varied use of frailty measures and nonspecific blood biomarkers limited conclusions for mechanisms of frailty in cancer survivors. There are missed opportunities in neuro-oncology; inclusion of frailty assessment and biomarkers is instrumental to advancing science in PBTs.
BIOM-66. MULTIPARAMETRIC QUALITIES OF PLASMA EXTRACELLULAR VESICLES AS NOVEL DIAGNOSTIC BIOMARKERS FOR GLIOBLASTOMA
Authors: Aibaidula Abudumijiti(Zack) , Fain Cori , Garcia Luz Cumba , Jung Miyeon , Johnson Aaron , Parney Ian
Published: November 2022

INTRODUCTION: Plasma extracellular vesicles (EVs) have been shown as a promising source for biomarker identification in glioblastoma (GBM) and could help differential diagnosis, treatment evaluation and tumor progression monitoring. These EVs are enriched in molecular signatures indicative of their cell origins, giving an indication of the key players in this pathology. In this project, we aimed to identify diagnostic biomarkers for GBM plasma EVs and their cells of origin. METHODS: Plasma EV samples were prepared following the MIFlowCyt-EV guideline of the International Society for Extracellular Vesicles, then stained for EV markers (CD9/CD63/CD81) and markers indicative of cell origins (CD31/CD45/CD41a/CD11b). Actin phalloidin was used as a negative marker. Stained plasma samples were analyzed using a Cytek Aurora flow cytometer. Percentages of different EV subpopulations were analyzed and compared between GBM and normal donor (ND) plasma EVs (reference group). Further clustering analysis was performed on EV events by t-distributed stochastic neighbor embedding (t-SNE) and self-organizing maps on flow cytometry data (FlowSOM) analysis. The predictive value of multiparametric qualities derived from the reference group was tested in blinded test group samples. RESULTS: Percentages of CD9, CD81, and CD11b positive EVs were higher in GBM patient plasma, while ND plasma had more CD41a positive EVs. GBM plasma EVs had unique multiparametric signatures compared to ND plasma EVs based on t-SNE and FlowSOM analysis. Our analysis also identified 15 distinct EV subpopulations which differed in size and various surface marker expression levels. Eight of these subpopulations were enriched for GBM EVs, while three were enriched for ND EVs. Our method of multiparametric analysis demonstrates high sensitivity and specificity in predicting disease status in human samples. CONCLUSIONS: GBM plasma EVs have a unique surface marker expression profile and distinct EV subpopulations compared to ND plasma EVs. Multiparametric signatures show promise as potential diagnostic markers of GBM.
CNSC-02. BREAST TO BRAIN METASTASIS IS EXACERBATED WITH CHEMOTHERAPY THROUGH BLOOD-CEREBRAL SPINAL FLUID-BARRIER AND INDUCES ALZHEIMER’S-LIKE PATHOLOGY
Authors: Neman Josh , Saatian Behnaz , Deshpande Krutika , Martisorian Vahan , LaViolette Peter , Boire Adrienne , Chow Frances , Hurth Kyle , Fecci Peter , Shiroishi Mark , Eisenbarth Rachel
Published: November 2022

Control of breast to brain metastasis remains an urgent unmet clinical need. While chemotherapies are essential in reducing systemic tumor burden, they have also shown to promote non-brain metastatic invasiveness and drug-driven neurocognitive deficits through formation of neurofibrillary tangles (NFT) independently. Now, in this study we investigated the effect of chemotherapy on brain metastatic progression and promoting tumor-mediated NFT. Results show chemotherapies promote increased brain-barrier permeability and facilitate enhanced tumor infiltration, particularly through the blood-cerebrospinal fluid-barrier (BCSFB). This is attributed to increased expression of matrix metalloproteinase 9 (MMP9) which, in turn, mediates loss of Claudin-6 within the choroid plexus cells of the BCSFB. Importantly, increased MMP9 activity in the choroid epithelium following chemotherapy results in cleavage of Tau released from breast cancer cells. This cleaved Tau forms tumor-derived NFT that further destabilize the BCSFB. Our results underline for the first time the importance of the BCSFB as a vulnerable point of entry for brain-seeking tumor cells post-chemotherapy and indicate that tumor cells themselves contribute to Alzheimer’s-like tauopathy.
CNSC-06. TEMOZOLOMIDE-INDUCED GUANINE MUTATIONS CREATE EXPLOITABLE VULNERABILITIES OF GUANINE-RICH DNA AND RNA REGIONS IN DRUG-RESISTANT GLIOMAS
Authors: Tiek Deanna , Cheng Shi-Yuan , Song Xiao , Goenka Anshika , Iglesia Rebeca , Hu Bo , Riggins Rebecca
Published: November 2022

Temozolomide (TMZ) is a chemotherapeutic agent that has been the first-line standard of care for the aggressive braincancer glioblastoma (GBM) since 2005. Although initially beneficial, TMZ resistance is universal and second-lineinterventions are an unmet clinical need. Here, we took advantage of the known mechanism of action of TMZ to targetguanines (G) and investigated G-rich G-quadruplex (G4) and splice site changes that occur upon TMZ resistance. We reportthat TMZ-resistant GBM has guanine mutations that disrupt the G-rich DNA G4s and splice sites that lead to deregulatedalternative splicing. These alterations create vulnerabilities, which are selectively targeted by either the G4-stabilizingdrug TMPyP4 or a novel splicing kinase inhibitor of cdc2-like kinase. Lastly, we show that the G4 and RNA binding proteinEWSR1, member of the FUS, EWSR1, and TAF15 family, aggregates in the cytoplasm in TMZ-resistant GBM cells and patient samples. Together, our findings provide insight into targetable vulnerabilities of TMZ-resistant GBM and present cytoplasmic EWSR1 as a putative biomarker.
CNSC-11. T-TYPE CALCIUM CHANNELS DRIVE GLIOBLASTOMA GROWTH BY PROMOTING NEURONAL INTERACTIONS
Authors: Dube Collin , Zhang Ying , Saha Shekhar , Lai Michelle , Gibert Myron , Escalante Miguel , Mulcahy Elizabeth , Ottolini Matteo , Hudson Kadie , Yener Ulas , Bednarek Sylwia , Hanif Farina , Xu Esther , Sorot Aditya , Sonkusare Swapnil , Sontheimer Harald , Abounader Roger
Published: November 2022

Glioblastoma (GBM) is the most common primary malignant brain tumor with a dismal median survival of 15 months. Calcium signaling regulates a plethora of cellular processes making it an ideal target for therapeutic intervention. T-type calcium channels (TTCCs) are low voltage gated calcium channels expressed in various types of neurons throughout the brain regulating glutamatergic synaptic transmission. Our group identified T-type calcium channels as upregulated in GBM cells, stem cells and human tumors. Utilizing an FDA repurposed TTCC blocker mibefradil we demonstrated that inhibition of TTCCs decreases GBM malignancy parameters. To further elucidate the mechanisms of action of TTCC, we treated glioma stem cells (GSCs) with mibefradil followed by RNA-sequencing. Analysis of the transcriptome revealed that mibefradil downregulated genes associated with neuronal processes including synapse organization, postsynaptic density and glutamatergic synapses. The effects of TTCC inhibition on neuronal processes led us to examine the role of neuronal TTCC in promoting GBM growth. Genetic loss of TTCC, Cav3.2 via knockout (KO) in the microenvironment of mice xenografted with syngeneic cell lines exhibited delayed tumor progression. Cav3.2 KO mice exhibited a 5.5-fold reduction in tumor volume as measured by MRI and an increase in survival compared to WT mice. Cav3.2 KO tumors exhibited a decrease in proliferation measured by Ki67+ cells compared to WT mice. Cav3.2KO tumors exhibit fewer connections between tumor cells and neurons as measured by immunofluorescence. To further test the roles of neuronal Cav3.2 in GBM, we isolated WT and Cav3.2KO neurons for neuron-GBM co-cultures. Cav3.2KO neuron-GBM co-cultures exhibited a significant decrease in proliferation compared to WT neuron-GBM co-cultures. Additionally, Cav3.2KO neuron-GBM co-cultures exhibited a decrease in synaptic connections and a decrease in neuronal projections to GBM cells compared to WT neuron-GBM co-cultures. These data uncover a new role for TTCC Cav3.2 in promoting neuron-GBM interactions and GBM growth.
CNSC-12. NEURONAL DIFFERENTIATION DRIVES THE ANTI-TUMOR EFFICACY OF MEK INHIBITION IN GLIOBLASTOMA
Authors: Khan Sabbir , Martinez-Ledesma Emmanuel , Park Soon Young , Dong Jianwen , Piao Yuji , Harrison Erin , Koul Dimpy , Balasubramaniyan Veerakumar , de Groot John , Yung W K Alfred
Published: November 2022

Multiple genomic aberrations and distinct molecular subtypes of glioblastoma (GBM) have been identified through multi-omics analyses including single-cell genomic and epigenomic analysis. Epidermal Growth Factor Receptor (EGFR) amplification is found in nearly 50% of GBM tumors. Several EGFR inhibitors have been tested in GBM but failed to demonstrate long-term therapeutic benefit, presumably due to target heterogeneity, escape signal pathways, and acquired resistance. Therefore, we investigated downstream signaling, mitogen-activated protein kinase (MEK1/2) as a potential therapeutic target for GBM. We utilized an unbiased high-throughput screening with a panel of glioma stem-like cells (GSCs) and identified that GBM cells harboring EGFR amplification showed anti-proliferative and apoptotic cell death (sensitive) to multiple MEK inhibitors. RNA-seq analysis of cells pre- and post-treatment with trametinib, a potent MEK inhibitor, revealed an upregulation of neurogenesis and neuronal differentiation genes such as β-III tubulin, ASCL1, DLL1, DLL3, NeuroD4, PAX6 and NCAM1. In addition, downregulation of the several MEK targets including erythroblast transformation specific (ETS) family genes, particularly ETV5 was observed. We demonstrated that MEK inhibition increased neuronal differentiation demonstrated by immunofluorescence, western blot, and RT-qPCR experiments using selected differentiation markers (β-III tubulin, ASCL1, DLL3, and NeuroD4). In addition, ETV-5 knockout in GSCs by CRISPR/Cas-9 promoted the expression of neuronal differentiation genes. Oral treatment of trametinib in an orthotopic GSC xenograft model significantly improved animal survival, in which 25-30% of mice are long-term survivors. This was accompanied by decreased MEK/ERK signal and cell proliferation in tumor tissues. Thus, we demonstrated here that MEK1/2 inhibition by trametinib induces neuronal differentiation mediated through downregulation of ETV-5 in GBM, a potential novel mechanism of action of MEK1/2 signal inhibition.
CNSC-16. BIDIRECTIONAL SIGNALING BETWEEN GLIOBLASTOMA AND NEURAL PROGENITORS EXPLORED WITH CELL-SPECIFIC PROTEOMICS RESULTS IN INCREASED TUMOR MALIGNANCY AND ALTERED NEUROGENESIS IN THE SUBVENTRICULAR ZONE
Authors: Norton Emily , Whaley Lauren , Jones Vanessa , Brooks Mieu , Zarco Natanael , Russo Marissa , Schiapparelli Paula , Sanchez Guadalupe , Ramos-Fresnedo Andres , Rossoll Wilfried , Chaichana Kaisorn , Anastasiadis Panos , Quiñones-Hinojosa Alfredo , Guerrero-Cazares Hugo
Published: November 2022

Glioblastoma (GBM) is the most common and aggressive primary neoplasm of the central nervous system. The location of GBM contributes significantly to patient outcomes, where tumors contacting the lateral ventricles (LVs) have increased expression of stem cell genes, increased incidence of distal recurrence, and decreased overall survival. While the reasons for these findings are not fully understood, we hypothesize they arise due to interactions with the subventricular zone (SVZ), the largest neurogenic niche in mammals. We examined bidirectional signals between GBM cells and neural progenitor cells (NPCs) in vitro and in vivo using a combination of patient-derived intraoperative samples, preclinical animal models, and the methionine tRNA synthetase L274G (MetRS*) nascent proteomic labeling system, which allows for cell-specific proteomics analysis from complex in vivo systems. In co-culture with NPCs, GBM cells increase their viability, proliferation, migration, and expression of malignancy-promoting proteins, including migratory proteins such as TAGLN, PALLD, and STAT1. In vivo, tumor proximity to the SVZ results in increased proliferation, increased expression of stemness markers, decreased survival, and altered tumor-specific proteome. We then examined the reciprocal effect of GBM cells on NPC biology. In vitro and in vivo, GBM cells decreased NPC proliferation and induced decreased neuronal maturation of NPCs. To determine NPC proteomic changes in vivo, we created a transgenic mouse line Nestin-CreERT2; STOPflox R26-MetRS L274G, where upon tamoxifen administration Nestin+ NPCs express GFP and MetRS*. Our results indicate that LV-proximal GBM induces decreased expression of neuronal maturation proteins such as Eml1, VGLUT1, and EAAT2, and an increase in pro-migratory factors such as Lamc1 in NPCs. In conclusion, there are bidirectional proteomic interactions between GBM cells and NPCs that contributes to altered neurogenesis and increased tumor malignancy of LV-proximal GBM. The signaling factors identified in our studies will result in identification of novel therapeutic targets for GBM.
CNSC-17. GLIOMA SYNAPSES RECRUIT MECHANISMS OF ADAPTIVE PLASTICITY
Authors: Taylor Kathryn , Barron Tara , Zhang Helena , Hui Alexa , Hartmann Griffin , Ni Lijun , Venkatesh Humsa , Du Peter , Mancusi Rebecca , Yalçin Belgin , Chau Isabelle , Ponnuswami Anitha , Aziz-Bose Razina , Monje Michelle
Published: November 2022

The nervous system plays an increasingly appreciated role in the regulation of cancer. In malignant gliomas, neuronal activity drives tumor progression not only through paracrine signaling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF), but also through electrophysiologically functional neuron-to-glioma synapses. Malignant synapses are mediated by calcium-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors in both pediatric and adult high-grade gliomas, and consequent depolarization of the glioma cell membrane drives tumor proliferation. The nervous system exhibits plasticity of both synaptic connectivity and synaptic strength, contributing to neural circuit form and functions. In health, one factor that promotes plasticity of synaptic connectivity and strength is activity-regulated secretion of the neurotrophin BDNF. Here, we show that malignant synapses exhibit similar plasticity regulated by BDNF-TrkB (tropomyosin receptor kinase B) signaling. Signaling through the receptor TrkB, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. This potentiation of malignant synaptic strength shares mechanistic features with the long-term potentiation (LTP) that is thought to contribute to memory and learning in the healthy brain. BDNF-TrkB signaling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of TrkB in human glioma cells exerts growth inhibitory effects in vivo and in neuron:glioma co-cultures that cannot be explained by classical growth factor signaling alone. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of pediatric glioblastoma and diffuse intrinsic pontine glioma (DIPG). Taken together, these findings indicate that BDNF-TrkB signaling promotes malignant synaptic plasticity and augments tumor progression. While targeting Trk signaling is presently being explored for NTRK-fusion brain tumors, these findings indicate that BDNF-TrkB signaling may also represent an important therapeutic target for NTRK2 wildtype gliomas.
CNSC-19. GLIOMA-INDUCED NEURONAL REMODELING PROMOTES REGIONAL IMMUNOSUPPRESSION
Authors: Nejo Takahide , Krishna Saritha , Young Jacob S , Yamamichi Akane , Jimenez Christian , Chen Tiffany , Watchmaker Payal , Choudhury Abrar , Diebold David , Ogino Hirokazu , Raleigh David , Hervey-Jumper Shawn L , Okada Hideho
Published: November 2022

Gliomas remodel neuronal circuits and distinct intratumoral regions maintain functional connectivity through a subpopulation of synaptogenic malignant cells expressing Thrombospondin-1 (TSP-1, encoded by the Thbs1 gene). Single-cell RNA sequencing analyses of primary patient samples identified a significant downregulation of immune response in myeloid cells and lymphoid cells in high functionally connected intratumoral regions characterized by upregulated TSP-1. Understanding the functional significance of immunosuppression within functionally connected intratumoral regions may uncover therapeutic vulnerabilities. Here, we investigate glioma-neuronal-immune crosstalk across clinical tumor specimens and preclinical syngeneic models through bulk and single-cell RNA sequencing (13,670 cells), flow cytometry, and spatial transcriptomics. Using an SB28 murine glioma cell line with endogenous Thbs1 stably expressed, we generated a CRISPR Thbs1-knock-out (KO) cell line. Bulk RNA-sequencing demonstrated that Thbs1-WT tumors exhibited gene expression programming consistent with synapse-associated genes and synaptogenic factors, recapitulating enriched connectivity in primary patient samples. Flow cytometry of brain-infiltrating leukocytes revealed that macrophages isolated from Thbs1-KO tumors were more frequently polarized into the pro-inflammatory “M1-like” phenotype (median M1/M2 ratio = 0.6 [WT] vs 1.34 [KO], p < 0.006). Unbiased gene expression program analysis using spatial transcriptomics for in vivo tumor-harboring mouse brains demonstrated a significant spatial overlap of signatures of synaptogenesis (represented by Ntng1 and Nlgn3 genes) and downregulated immune response (represented by Nfkb1 and Cd83 genes). SB28-Thbs1-KO syngeneic models demonstrated slower tumor growth and significantly longer survival compared to Thbs1-WT counterparts (19 days [WT] vs 25 days [KO], p < 4.5E-5). The survival difference was abrogated in the B6-SCID immunodeficient mice, indicating the critical role of adaptive immunity in the survival advantage associated with TSP-1 inhibition. Our results identify previously unknown immunosuppression mechanisms in the context of glioma-induced intratumoral connectivity via Thbs1. Future therapeutic strategies targeting this glioma-neuronal-immune crosstalk may open up new avenues for glioblastoma immunotherapy.
SURG-39. SURGICAL RESULTS AND LONG-TERM OUTCOME IN SUPRATENTORIAL INTRAVENTRICULAR TUMORS
Authors: Teske Nico , Chiquillo-Domínguez Mariana , Skrap Benjamin , von Baumgarten Louisa , Kunz Mathias , Tonn Joerg-Christian , Thon Niklas , Karschnia Philipp
Published: November 2022

BACKGROUND

Intraventricular tumors (IVTs) are rare lesions of various entities, which pose a surgical challenge. We aimed to elaborate on surgical approaches and outcomes, postoperative morbidity, and elucidate whether preoperative hydrocephalus necessitates shunting despite surgical resection.

METHODS

We retrospectively searched the institutional database for patients with supratentorial intraventricular tumours that were treated in the Department of Neurosurgery of the Ludwig-Maximilians-University Munich, Germany between 2014 and 2022.

RESULTS

We identified 59 patients with supratentorial intraventricular tumors comprising over 15 different tumor entities, most often subependymoma (8/59 patients, 14%). Median age at diagnosis was 41.4 years (range 0-86 years) with 31 male patients (53%) and 28 female patients (48%). Microsurgical tumor resection was completed in 46/59 patients (78%) with incomplete tumor resection (≥ 1ml postoperative tumor volume) in 13/46 patients (28%) and complete tumor resection (< 1ml postoperative tumor volume) in 33/46 patients (72%). In cases where neurosurgical tumor resection was not feasible, stereotactic biopsy was provided in 13/59 patients (22%), often combined with stereotactic internal shunt implantation (5/59 patients, 8%). Mean follow-up was 24 months; median overall survival was not reached. Postoperative persistent hydrocephalus necessitating ventriculoperitoneal shunt placement was rare (5/59 patients, 8%). Ventriculocisternostomy was performed in one patient. New postoperative focal neurological deficits – mostly transient – were encountered in 16/59 patients (27%) at discharge with mild to moderate permanent focal neurological deficits at 3 months in 3/59 patients (5%).

CONCLUSION

Complete resection of IVT can often be achieved and forms the basis for favourable outcome. Permanent neurological deficits are rare, and hydrocephalus can almost always be alleviated which prevents the need for long-term shunting. If microsurgical resection is not feasible, stereotactic biopsy along with internal shunting represents an effective approach to establish diagnosis and ameliorate symptoms.
SURG-40. SINGLE-STAGE RECONSTRUCTION FOLLOWING ONCOLOGIC RESECTION OF BRAIN TUMORS WITH SKULL INVASION
Authors: Ben-Shalom Netanel , Anthony Asemota , Micah Belzberg , Harnof Sagi , Huang Judy , Lim Michael , Brem Henry , Gordon Chad
Published: November 2022

BACKGROUND: Craniectomies requiring skull reconstruction are indicated following oncological resection of masses involving the underlying brain and/or skull. Immediate cranioplasties have previously been performed using suboptimal hand-bending or molding techniques using ‘‘off – the – shelf’’ products. Today with computer – aided design, customized craniofacial implants have become widely available for personalized reconstruction of resected bone and soft tissue. We present the largest series to date of single stage reconstruction using alloplastic biomaterials in consecutive patient series with oversized customized implants.In total, 56 patients underwent resection of skull neoplasms and subsequent cranioplasty reconstruction using customized implants. The most common neoplasms were meningiomas (39%). The most common complications seen among patients were dehiscence – (7%), and extrusion of implant – (3.5%). There was no significant difference in the incidence of postoperative complications between patients who had postoperative chemotherapy/radiotherapy versus those that did not (22.2% versus 13.1%, P 0.39). One-year follow-up revealed acceptable cranial contour and symmetry in all 56 cases.
SURG-41. MACHINE LEARNING PREDICTS THE INFLUENCE OF FRAILTY ON THE CLINICAL MANAGEMENT OF NEUROFIBROMATOSIS TYPE 1: A MIXED-EFFECTS MODELING STUDY USING THE NATIONWIDE READMISSIONS DATABASE
Authors: Shahrestani Shane , Brown Nolan , Gendreau Julian , Zada Gabriel
Published: November 2022

Recent literature has highlighted the association of frailty with significantly higher rates of morbidity and mortality in patients with CNS neoplasms. However, there is a paucity of research regarding the effects of frailty as it relates to neurocutaneous disorders, namely NF1. In this study we evaluated the role of frailty in NF1 patients and compared its predictive utility to that of the Elixhauser Comorbidity Index (ECI). Namely, we used the Nationwide Readmissions Database from 2016 to 2017 to select for those patients with a diagnosis of NF1 who underwent neurosurgical resection of an intracranial tumor. Patient frailty was queried through the use of the Johns Hopkins Adjusted Clinical Groups (JHACG) frailty-defining indicator. ECI scores were collected for these patients for measurement of comorbidities. Propensity score matching was performed for age, sex, ECI, insurance type, median income by ZIP code, and yielded 60 frail and 60 non-frail patients. Receiver operating characteristic (ROC) curves were created for relevant complications, including mortality, non-routine discharge, cost in top quartile, length of stay [LOS] in top quartile, and readmission, using comorbidity indices as predictor values. The area under the curve (AUC) of each ROC served as a proxy for model performance. Following matching of the groups, frail patients still had an increased average hospital cost ($85,441.67±$59,201.09) compared to non-frail patients ($49,321.77±$50,705.80)(p=0.010). Similar trends were also found for LOS between frail (23.1±14.2 days) and non-frail patients (10.7±10.5 days)(p=0.0020). For each complication of interest, ROC curves plotted showed frailty performing as well as ECI and the combination of Frailty+ECI (p >0.05). Frailty+ECI (AUC: 0.924)outperformed the model using only ECI (AUC: 0.842, p=0.027). These findings suggest that frailty is as efficacious as ECI in predicting complications including mortality, non-routine discharge, readmission, and high cost in patients who underwent resection of intracranial lesions associated with NF1.
TMET-02. THERAPEUTIC EFFICACY OF A NOVEL BRAIN PENETRANT SCD INHIBITOR ON BREAST CANCER BRAIN METASTASES
Authors: Sammarco Alessandro , Eyme Katharina , Jha Roshani , Silva Willian Das Neves , Neustadt Rudolph , Ford Ian , Bensinger Steven J , Zappulli Valentina , Breakefield Xandra , Badr Christian E
Published: November 2022

Brain metastases are a significant therapeutic challenge and are associated with high morbidity and mortality. Recent evidence suggests that brain metastases have increased fatty acid synthesis compared to extracranial tumors. The enzyme stearoyl-CoA desaturase (SCD), which converts saturated long-chain fatty acids into monounsaturated fatty acids, is often upregulated in breast cancer brain metastasis (BCBM) and is considered a promising therapeutic target. However, the lack of brain penetrant SCD inhibitors limited their use in patients. This study aimed to investigate the therapeutic efficacy of a clinical-stage brain penetrant inhibitor of SCD to treat BCBM. We found that pharmacologic inhibition of SCD in multiple breast cancer cell lines induced significant cytotoxicity, mainly by apoptosis. Gas chromatography/mass spectrometry confirmed that the fatty acid desaturation index, which measures SCD activity, was significantly lower after treatment. SCD inhibition triggered endoplasmic reticulum (ER) stress and increased DNA damage due to a higher production of reactive oxygen species. Further, SCD inhibition decreased DNA damage repair by inhibiting homology-directed repair in vitro and in a mouse model of breast cancer. Notably, inhibition of SCD led to a significant decrease in tumor growth in a subcutaneous mouse model of breast cancer and a significant increase in overall survival in a BCBM mouse model. Cytotoxicity was enhanced when this SCD inhibitor was combined with either a DNA damage-inducing agent (temozolomide or radiation) or with a PARP inhibitor (Niraparib). Finally, we observed that combination therapy of SCD inhibition and Niraparib significantly increased overall survival in a BCBM mouse model. Our results suggest that inhibition of SCD alone or in combination with a PARP inhibitor is a promising therapeutic strategy to treat BCBM.
TMET-04. DETECTING DYNAMIC PYRUVATE TUMOR METABOLISM IN PATIENTS WITH GLIOMA USING HYPERPOLARIZED CARBON-13 METABOLIC IMAGING
Authors: Li Yan , Lupo Janine , Autry Adam , Vaziri Sana , Gordon Jeremy , Lafontaine Marisa , Hsin-Yu Chen , Kim Yaewon , Hu Jasmine , Ma Wendy , Villanueva-Meyer Javier , Larson Peder , Xu Duan , Bush Nancy Ann Oberheim , Clarke Jennifer , Vigneron Daniel , Chang Susan M
Published: November 2022

INTRODUCTION

Hyperpolarized carbon-13 (HP-13C) MR enables rapid dynamic imaging of metabolic pathways in the human brain using non-toxic, non-radioactive metabolites as tracers. This study presents our unique experience on the benefit of using [1-13C]pyruvate and [2-13C]pyruvate MR for evaluating patients with glioma.

METHODS

132 scans (71 using an integrated 13C /1H coil) including steady-state 1H-MRSI (~10 min) and dynamic HP-13C imaging (60 sec) following injection of HP [1-13C]pyruvate (N=125) or [2-13C]pyruvate (N=7) were acquired from 46 patients with glioma (18F/28M; 15 IDH-mutant, 27 IDH-wildtype, 4 IDH-status-unknown). Maps of temporally-summed 13C-metabolite signals, ratios, and kinetic rate constants were calculated for contrast-enhancing, nonenhancing, and normal-appearing-white-matter (NAWM) regions and compared to steady-state metabolic metrics.

RESULTS

The only adverse event, in a single patient, was a burning sensation after the injection that resolved after saline flush. The mean time-to-injection of HP probes was 58.6±14.0 sec. Signal-to-noise ratios of [1-13C]lactate and [13C]bicarbonate within the NAWM from the HP [1-13C]pyruvate data were 53±39 and 13±6, respectively. The SD/mean of repeated injections (N=3) for lactate/pyruvate and pyruvate-to-lactate conversion rates were 3.8±3.1% and 6.5±3.1% in the NAWM, respectively. Patients with progressive GBM had significantly higher lactate/pyruvate and lower bicarbonate/lactate (p< 0.05) in contrast- and non-enhancing lesions compared to NAWM. Significantly elevated lactate/pyruvate and reduced bicarbonate/lactate (p< 0.01) were found in contrast-enhancing compared to nonenhancing regions, whereas choline/NAA and steady-state 1H-lactate levels were similar. HP [2-13C]pyruvate data showed reduced glutamate/pyruvate and pyruvate-to-glutamate conversion rates in T2 lesions compared to contralateral normal-appearing brain in IDH-mutant gliomas, consistent with known metabolic reprogramming.

CONCLUSION

This study demonstrates the potential benefit of dynamic HP-13C MRI for evaluating patients with glioma, which provides unique and spatially distinct contrast compared to steady-state metabolic imaging. Ongoing studies will further characterize dynamic metabolism in specific glioma subtypes and provide biomarkers for evaluating responses to treatment.