bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &lt; 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 &lt; 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

Abstract

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 (&lt; 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

Abstract
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

Abstract
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 &gt;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.