bluuebunny/crossref_metadata_2025_split huggingface dataset:
SURG-29. CLINICAL FACTORS ASSOCIATED WITH RECURRENCE IN ATYPICAL MENINGIOMA: RETROSPECTIVE ANALYSIS OF 99 PATIENTS IN TWO INSTITUTES
Authors: Sung Kyung Soo , Song Young Jin , Zoon Kim Young 
Published: December 2020

Abstract

OBJECTIVE
The objectives of this study were to examine the local control (LC) rate of atypical meningioma after surgical resection with or without adjuvant treatment, to identify risk factors for the recurrence of atypical meningioma, and to compare our results to known factors from the literature.

METHODS
Clinical and radiological records of patients with atypical meningiomas diagnosed at two institutes from January 2000 to December 2018 were reviewed retrospectively. Histopathological features were also reviewed using formalin-fixed paraffin embedded samples from pathological archives.

RESULTS
Of the 99 atypical meningiomas eligible for analysis, 36 (36.4%) recurred during the follow-up period (mean 83.3 months, range 12–232 months). The rate of 3-year LC and 5-year LC was 80.8% and 74.7% respectively. The mean time-to-recurrence was 49.4 months (range 12–150 months). Multivariate analysis using Cox proportional-hazard regression model showed that the extent of resection (Hazard ratio [HR] 4.761, p=0.013), Ki67 index (HR 8.541, p=0.004), mitotic index (HR 3.275, p=0.044), tumor size (HR 3.228, p=0.041), and radiotherapy (HR 3.816, p=0.029) were independently associated with 3-year LC. These factors was also statistically associated with recurrence-free survival. In terms of radiotherapy after surgical resection, the recurrence was not prevented by immediate radiotherapy because of the strong effect of proliferative index on recurrence. Three cases of malignant transformation to WHO grade III meningioma were histopathologically confirmed after repeated surgery. Two out of these three patients succumbed to malignant transformation. The mean Ki67 proliferative index increased for recurrent cases in 18 patients (58.1%) from 7.55% (range 4-16) to 11.81% (range 5-24).

CONCLUSION
The present study suggests that the extent of resection, proliferative index (according to Ki67 expression) and mitotic index, tumor size, and radiotherapy are associated with recurrence of atypical meningiomas. However, our results should be further validated through prospective and randomized clinical trials.
SURG-34. MULTIDISCIPLINARY MANAGEMENT OF A PATIENT WITH OPTIC PATHWAY-HYPOTHALAMIC LANGERHANS CELL HISTIOCYTOSIS: A CASE REPORT
Authors: Emmanuel Custodio John , Ferraris Kevin Paul , Navarro Joseph Erroll , Seng Kenny , Alcazaren Jose Carlos , Dantes Ma Angelle 
Published: December 2020

Abstract
Langerhans cell histiocytosis (LCH) of the Central Nervous System (CNS) is rare. Isolated involvement of the hypothalamic region is much more extremely rare with only 0.04 to 0.6% of the cases. We report a case of a 33 year-old female who presented with a one-year history of amenorrhea and a five-month history of intermittent headache, memory lapse, and somnolence. The patient was of normal body mass index with normal visual acuity and intact visual fields. Laboratory examinations revealed panhypopituitarism with central diabetes insipidus. Cranial magnetic resonance imaging showed a large lobulated mass measuring 1.9 x 2.2 x 2 cm in the suprasellar region which extended to the pituitary infundibulum, hypothalamus and retrochiasmatic region, with surrounding edema. The patient underwent right orbitozygomatic craniotomy and subtotal excision of the mass through subfrontal and transsylvian approaches. Histopathological examination of langerhans cells were observed with positive immunohistochemical stain for CD1a and S100 protein antigen markers establishing a diagnosis of CNS LCH. Thoracoabdominal computed tomography scan and bone scan were done postoperatively and showed no evidence of extracranial lesions. The patient had been receiving prednisone and vinblastine based chemotherapy regimen. She remains to be asymptomatic and on close surveillance. To date, there is no standardized treatment strategy for CNS LCH in the adult population. An accurate histopathologic diagnosis and a specialized multidisciplinary team approach especially involving Oncology, Neurosurgery, Ophthalmology and Endocrinology are critical to optimally tailor possible effective treatment options for patients with this similar disease. Long-term follow-up is crucial due to the increased risk of local recurrence and multisystemic involvement.
SURG-37. SYSTEMATIC REVIEW OF GAMMA-KNIFE RADIOSURGERY AND MICROSURGICAL RESECTION FOR BRAINSTEM CAVERNOUS MALFORMATIONS
Authors: Kondajji Aditya , Nguyen Thien , Sheppard John , Kulinich Daniel , Unterberger Ansley , Evans Audree , Patel Kunal , Yang Isaac 
Published: December 2020

Abstract

BACKGROUND
Although microsurgical resection (MR) remains the gold-standard for the treatment of symptomatic cavernous malformations, some authors have proposed the use of radiosurgical Gamma-Knife Surgery (GKS) for lesions that are deep or eloquent, such as those located in the brainstem.

OBJECTIVE
Here were analyze the literature regarding patient outcomes following MR or GKS for brain stem cavernous malformations.

METHODS
This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic literature review. A database search of PubMed, Scopus, Embase, and Web of Science was conducted in September 2019. This review included studies evaluating the outcomes of MR or GKS for cavernous malformations located in the brainstem.

RESULTS
Gross total resection was achieved in the majority of patients and effectively eliminated the risk of recurrent hemorrhage from the operative lesion in studies following the outcomes of MR. GKS reduces the annual hemorrhage rate for patients, although it does not eliminate the cavernous malformation. Both treatment modalities were effective in reducing prior symptomatology. Unlike resection, GKS only reduces the risk of future hemorrhage and does prevent it.

CONCLUSIONS
Both MR and GKS can improve or stabilize symptoms in patients. However, the therapeutic benefit of GKS may take months to years to take full-effect, resulting in a potential for subsequent hemorrhagic events. MR remains the best treatment option due to its ability to eliminate future bleeding events entirely and should be performed whenever gross total resection is possible.
SURG-41. BLOOD-BRAIN BARRIER DISRUPTION WITH HIGH-FREQUENCY ELECTROPORATION IN VIVO: A PRELIMINARY INVESTIGATION DEMONSTRATING THE EFFECTS OF VARIED PULSE WIDTHS AND INTRA-PHASE DELAYS
Authors: Lorenzo Melvin , Thomas Sean , Verbridge Scott , Robertson John , Rossmeisl John , Davalos Rafael 
Published: December 2020

Abstract

OBJECTIVE
Treatment of CNS disorders suffer from the inability to deliver large therapeutic agents to the brain parenchyma due to protection from the blood-brain barrier (BBB). High-frequency electroporation (HFE) employs a series of high voltage pulsed electric fields to disrupt the BBB and/or ablate tumor tissue while sparring proteinaceous structures. Pulsing parameters pulse width and intra-phase delay can be modulated to reduce excitation of muscle and nervous tissues, though this is inherently accompanied by an increase in thresholds for ablation in non-CNS tissues. Here, we investigate the effects of pulse width and intra-phase delay on intracranial tissue for BBB disruption (BBBD) in an in vivo healthy rodent model.

METHODS
18 male Fisher rats underwent craniectomy procedure and two blunt tipped monopolar electrodes were advanced into the brain for HFE therapy. 200 bursts of HFE were delivered at a voltage-to-distance ratio 600 V/cm. BBBD was verified with contrast enhanced T1W MRI (gadopentetate dimeglumine) and pathologically (Evans blue dye).

RESULTS
Gross pathological sections and contrast enhanced T1W scans demonstrated BBBD for 2-2-2 µs (n = 4, 36.6 ± 9.4 mm3, 36.7 ± 13.0 mm3), 2-5-2 µs (n = 4, 74.1 ± 7.7 mm3, 74.7 ± 9.8 mm3), 5-2-5 µs (n = 4, 53.9 ± 8.1 mm3, 59.2 ± 10.8 mm3), 5-5-5 µs (n = 4, 81.2 ± 7.9 mm3, 84.1 ± 8.7 mm3), and 10-1-10 µs (n = 2, 61.0 ± 2.8 mm3, 60.0 ± 4.2 mm3) HFE. Histologically, tissue damage was restricted to electrode insertion tracks. BBBD was induced with minimal muscle contractions and minimal cell death attributed to HFE. Numerical modeling indicated the threshold for HFE-mediated BBBD as low magnitude electric fields (&lt; 201 V/cm). These data suggest HFE-mediated BBBD is only modestly affected by changes in pulse width and intra-phase delay.
TAMI-05. THE IRRADIATED BRAIN MICROENVIRONMENT SUPPORTS GLIOMA STEMNESS AND SURVIVAL VIA ASTROCYTE-DERIVED TRANSGLUTAMINASE 2
Authors: Berg Tracy , Marques Carolina , Pantazopoulou Vasiliki , Johansson Elinn , von Stedingk Kristoffer , Lindgren David , Pietras Elin , Bergström Tobias , Swartling Fredrik , Governa Valeria , Bengzon Johan , Belting Mattias , Axelson Håkan , Squatrito Massimo , Pietras Alexander 
Published: December 2020

Abstract
The highest-grade gliomas invariably recur as incurable tumors following standard of care comprising surgery, radiotherapy, and chemotherapy. The majority of the recurrent tumors form within the area of the brain receiving high-dose irradiation during treatment of the primary tumor, indicating that the recurrent tumor forms in an irradiated microenvironment. The tumor microenvironment has been demonstrated to influence the therapeutic response and stemness characteristics of tumor cells, but the influence of radiation on the microenvironment and its subsequent consequences for tumor cells are incompletely understood. Here, we used genetically engineered glioma mouse models and human glioma samples to characterize the impact of standard of care radiotherapy on the brain tumor microenvironment. We found that tumor-associated astrocytes subjected to radiation in vitro could enhance tumor cell stemness and survival of co-cultured glioma cells. More aggressive gliomas formed in vivo when mouse brains were irradiated prior to tumor cell implantation, suggesting that the irradiated brain microenvironment supports tumor growth. We isolated the effect of irradiated astrocytes to extracellular matrix secreted by these cells, and specifically found that astrocyte-derived transglutaminase 2 (TGM2) is a stromal promoter of glioma stemness and radioresistance. TGM2 levels were increased after radiation in glioma mouse models. Recombinant TGM2 enhanced, and TGM2 inhibitors blocked, glioma cell stemness. In human GBM tissue, TGM2 levels were increased in recurrent vs. primary tumors. In summary, in addition to supporting TGM2 as a potential therapeutic target in glioma, our data indicate that radiotherapy results in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.
TAMI-07. THE IMMUNE MICROENVIRONMENT IN LOWER GRADE GLIOMAS
Authors: Kumar Anupam , Chen Katharine , Petritsch Claudia , Nicolaides Theodore , Santi-Vicini Mariarita , Perry Arie , Bollen Andrew , Solomon David , Molinaro Annette M , Phillips Joanna 
Published: December 2020

Abstract
The determinants of the tumor-associated immune response in brain tumors are poorly understood. Using tumor samples from two molecularly distinct subtypes of lower grade glioma, MAPK-driven glioma with biallelic inactivation of CDKN2A (n=30) and IDH-mutant, 1p/19q-intact astrocytoma (n=29), we demonstrate qualitative and quantitative differences in the tumor-associated immune response and we investigate the molecular mechanisms involved. Histologically the MAPK-driven gliomas were comprised of pleomorphic xanthoastrocytoma (PXA) (n=11) and anaplastic PXA (n=19). Seven patients had paired samples from two sequential surgeries. Immune cell populations and their activity were determined by quantitative multiplex immunostaining and Digital Spatial Profiling and gene expression was analyzed by Nanostring. Functional studies were performed using established cell lines and two new patient-derived lines from MAPK-driven LGGs. MAPK-driven tumors exhibited an increased number of CD8+ T cells and tumor-associated microglial/macrophage (TAMs), including CD163+ TAMs, as compared to IDH-mutant astrocytoma. In contrast, IDH-mutant tumors had increased FOXP3+ immunosuppressive T regulatory cells. Transcriptional and protein level analyses in MAPK-driven tumors suggested an active cytotoxic T cell response with robust expression of granzyme B, present on 27% of CD8+ T cells, increased MHC class I expression, and altered cytokine profiles. Interestingly, MAPK-driven tumors also had increased expression of immunosuppressive molecules, including CXCR4, PD-L1, and VEGFA. Expression differences for cell surface and secreted proteins were confirmed in patient-derived tumor lines and functional relationships between altered chemokine expression and immune cell infiltration was investigated. Our data provide novel insights into the immune contexture of MAPK driven LGGs and suggest MAPK driven gliomas with biallelic inactivation of CDKN2A may be particularly vulnerable to immunotherapeutic modulation
TAMI-10. CIRCULATING ANGIOGENIC CELLS (CACS) IN GLIOBLASTOMA: TOWARDS DEFINING CRUCIAL FUNCTIONAL DIFFERENCES IN CAC-INDUCED NEOPLASTIC VERSUS REACTIVE NEOVASCULARIZATION
Authors: Huizer Karin , Sacchetti Andrea , Swagemakers Sigrid , van der Spek Peter , Mustafa Dana , Kros Johan M 
Published: December 2020

Abstract
In order to identify suitable therapeutic targets for glioma anti-angiogenic therapy, the process of neovascularization mediated by circulating angiogenic cells (CACs) needs to be scrutinized. In the present study we compared the expression of neovascularization-related genes by three circulating CAC subsets (HPCs, CD34+ and KDR+ cells; internal controls: PBMCs and circulating endothelial cells) of treatment-naïve patients with glioblastoma (GBM) to those of patients undergoing reactive neovascularization (myocardial infarction (MI). CACs from umbilical cord (representing developmental neovascularization) and healthy subjects served as controls. Fluorescent activated cell sorting was used to isolate CACs, RT-PCR to determine the expression levels of a panel of 48 neovascularization-related genes, Luminex assays to measure plasma levels of 21 CAC-related circulating molecules. We found essential differences in gene expression between GBM and MI CACs. GBM CACs had a higher expression of pro-angiogenic factors (esp. KITL, CXCL12 and JAG1); growth factor and chemotactic receptors (IGF1R, TGFbR2, CXCR4 and CCR2); adhesion receptor monomers (ITGA5 and ITGA6) and matricellular factor POSTN. In addition, we found major differences in the levels of neovascularization-related plasma factors. A strong positive correlation between plasma MMP9 levels and expression of CXCR4 in the CAC subset of hematopoietic progenitor cells (HPCs) was found in GBM patients. Our findings indicate that CAC-mediated neovascularization in GBM is characterized by more efficient CAC homing to target tissue and a more potent pro-angiogenic response than in physiologic tissue repair in MI. Our findings can aid in selecting targets for therapeutic strategies acting against GBM-specific CACs.
TAMI-11. IMPACT OF oHSV ACTIVATED NOTCH SIGNALING IN TUMOR MICROENVIRONMENT, AND ITS IMPACT ON ANTI-TUMOR IMMUNITY
Authors: Otani Yoshihiro , Yoo Ji Young , Chao Samantha , Shimizu Toshihiko , Lewis Cole , Murphy Sara , Pineda Josue , Caraballo Kimberly Rivera , Hong Bangxing , Banasavadi-Siddegowda Yeshavanth Kumar , Heiss John , Yan Yuanqing , Olson Scott , Pei Guangsheng , Zhao Zhongming , Kaur Balveen 
Published: December 2020

Abstract
NOTCH signaling is a method of cell-cell communication where membrane bound NOTCH ligands on signal-sending cells can bind to and initiate cleavage of the NOTCH receptor, releasing NICD which can initiate signal transduction in adjacent “signal-receiving” cells. We have recently shown that oHSV treatment of GBM cells induces NICD cleavage and NOTCH activation in adjacent uninfected glioma cells. RNA sequencing of GBM cells post-infection also uncovered Gene Ontology NOTCH signaling pathway to be significantly upregulated. This activation was induced by viral miRNA-H16, which represses FIH-1 expression. FIH-1 was found to be a negative regulator of Mib1, a ubiquitin ligase, which activates NOTCH ligand-mediated activation of adjacent signal-receiving cells bearing the NOTCH receptor (Otani et al Clin. Can. Res. 2020). Here we have investigated the impact of oHSV-induced NOTCH signaling on the tumor microenvironment. Treatment of brain tumors in immune competent mice with oHSV and NOTCH blocking gamma secretase inhibitor (GSI) induced an anti-tumor memory immune response. Long term survivors in mice treated with the combination also completely rejected subsequent tumor re-challenge in the other hemisphere. UMAP of flow cytometry of tumor-bearing hemispheres and functional analysis of isolated cellular fractions from treated mice showed a significant influx of MDSC cells after oHSV treatment that was rescued in mice treated with oHSV and GSI. Ongoing mechanistic studies are uncovering a significant induction of NOTCH in tumor associated macrophages that aids in recruitment of MDSC cells. Overall these studies have uncovered a significant impact of oHSV therapy on GBM tumor microenvironment and presents opportunities for combination therapies that can help improve therapeutic benefit and anti-tumor immunity.
TAMI-12. CANCER STEM CELL ENRICHMENT AND METABOLIC SUBSTRATE ADAPTABILITY ARE DRIVEN BY HYDROGEN SULFIDE SUPPRESSION IN GLIOBLASTOMA
Authors: Silver Daniel , Roversi Gustavo , Bithi Nazmin , Neumann Chase K , Troike Katie , Ahuja Grace , Reizes Ofer , Brown J Mark , Hine Christopher , Lathia Justin 
Published: December 2020

Abstract
Glioblastoma (GBM) remains among the deadliest of human malignancies. The emergence of the cancer stem cell (CSC) phenotype represents a major challenge to disease management and durable treatment response. The extrinsic, environmental, and lifestyle factors that result in CSC enrichment are not well understood. The CSC state endows cells with a fluid metabolic profile, enabling the utilization of multiple nutrient sources. Therefore, to test the impact of diet on CSC enrichment, we evaluated disease progression in tumor-bearing mice fed an obesity-inducing high-fat diet (HFD) versus an energy-balanced, low-fat control diet. HFD consumption resulted in hyper-aggressive disease that was accompanied by CSC enrichment and shortened survival. HFD consumption also drove intracerebral accumulation of saturated fats, which in turn inhibited the production and signaling of the gasotransmitter hydrogen sulfide (H2S). H2S is an endogenously produced bio-active metabolite derived from sulfur amino acid catabolism. It functions principally through protein S-sulfhydration and regulates a variety of programs including mitochondrial bioenergetics and cellular metabolism. Inhibition of H2S synthesis resulted in increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to cytotoxicity and death of cultured GBM cells. Compared to non-cancerous controls, patient GBM specimens were reduced in overall protein S-sulfhydration, which was primarily lost from proteins regulating cellular metabolism. These findings support the hypothesis that diet-regulated H2S signaling serves to suppress GBM by restricting metabolic adaptability, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.
TAMI-17. RELATIONSHIP BETWEEN IRON METABOLISM, IMMUNE CELL INFILTRATION AND SEX-BASED SURVIVAL DIFFERENCES IN GLIOMAS
Authors: Nesterova Darya , Lee Sang , Zacharia Brad , Proctor Elizabeth , Lathia Justin , Rubin Joshua , Berens Michael , Barnholtz-Sloan Jill S , Connor James 
Published: December 2020

Abstract
Iron plays a central role in cellular metabolism, both in normal cellular functioning and in tumorigenesis. Recent evidence has shown sex-based survival differences in glioblastoma (GBM) may be related to differential expression of metabolism genes. We previously reported the iron regulating gene, HFE, was shown to have a sex-based survival impact in both low-grade gliomas and GBM. We additionally found that females with low HFE expressing tumors have significantly higher survival than males in GBM. To evaluate the relationship between iron gene expression and sex-based survival differences in GBM, we analyzed TCGA GBM gene expression and clinical data. We first analyzed the impact of iron genes on sex-based survival. In addition to HFE, FTL, TFRC, TF, and SLC39A8 (ZIP8), also showed sex-based survival differences. We then compared correlations of HFE and other iron genes to identify whether male and female GBMs differ in iron regulation and metabolism. HFE expression is significantly positively correlated with HMOX1, SLC25A28, SLC11A2, FTH1, HAMP, and TFR2 only in females. Alternatively, HFE expression is negatively correlated with ACO2 (mitochondrial aconitase) in males and ACO1 (cytoplasmic aconitase) in females. We noted that the expression of certain iron genes was highly associated with immune cell infiltration based on sex. TFR2, LRP1, and XIST expression were negatively correlated with low immune cell infiltration in females, but not males. Alternatively, in males, SLC11A2, ACO2, FOXO1, HIF1a, and HAMP genes were negatively correlated with immune infiltration. This suggests that differences in iron regulation between males and females may be contributing to differences in immune function and subsequent survival in GBM. These data suggest that the iron signature of a tumor reflects and possibly drives the metabolic and immune landscape of the tumor microenvironment thereby directly impacting survival differences between male and female GBMs.