bluuebunny/crossref_metadata_2025_split huggingface dataset:
SURG-19. EVALUATION OF SERUM NEURON SPECIFIC ENOLASE, INTERFERON-ALPHA, AND INTERFERON-GAMMA IN RESPONSE TO LASER ABLATION OF HIGH GRADE GLIOMAS
Authors: Bartlett Seamus , Nagaraja Tavarekere , Schultz Lonni , Ewing James , Brown Stephen , Knight Robert , Lee Ian 
Published: December 2020

Abstract

BACKGROUND
The blood-brain barrier (BBB) is a formidable obstacle in the treatment of gliomas. It has been speculated that the BBB may be temporarily disrupted in laser ablation, a relatively new treatment used for newly diagnosed and recurrent high grade gliomas (HGG). BBB disruption can be measured non-invasively through serum neuron specific enolase (NSE) levels. In addition to disrupting the BBB, laser ablation could trigger an immune response in brain that has yet to be studied. Interferon-alpha (IFN-α) and interferon-gamma (IFN-ɣ) are cytokines used as serum markers for an immune response.

OBJECTIVE
To measure NSE and IFN-α and IFN-ɣ as serum markers for BBB disruption and brain immune response activation, respectively, in patients undergoing laser ablation for recurrent high grade gliomas.

METHODS
Sixteen patients with recurrent HGG underwent laser ablation from 2/2017 to 12/2019. All 16 patients had gross total ablation of the contrast enhancing mass. Serum levels of NSE, IFN-α, IFN-ɣ were measured pre-operatively and at 24 hours, 2 weeks, and 8-16 weeks post-operatively, depending on adjuvant treatment received post-operatively.

RESULTS
Levels of NSE consistently increased 24 hours post-operatively (2.28±0.37 ng/ml) compared to pre-operative levels (1.62±0.29 ng/ml), p=0.032. Afterwards, NSE decreased and reached baseline by 2 weeks postoperatively (2 weeks- 1.67±0.29 ng/ml, 8 weeks- 1.85±0.91 ng/ml, 12 weeks- 0.81±0.33 ng/ml, 16 weeks- 1.23±0.93 ng/ml). Compared to their pre-operative levels, IFN-α and IFN-ɣ (85.46±35.29 and 1.62±0.47 pg/ml, respectively) did not display a significant difference in their serum levels (p=0.26-0.72 and 0.14-0.60, respectively, for IFN-α and IFN-ɣ) at any post-operative measurement time. Conclusions: Elevated NSE levels following laser ablation in HGG indicate a temporary disruption of the BBB that persists for approximately 2 weeks without eliciting an accompanying immune reaction in brain. Correlation studies with DCE-MRI are on-going.
SURG-22. PATTERN OF RECURRENCE ALONG EXTENT OF RESECTION IN PATIENTS WITH GLIOBLASTOMA, IDH-WILDTYPE: A RETROSPECTIVE STUDY
Authors: Yoo Jihwan , Kang Seok-Gu , Yoon Seon-Jin , Kim Kyung Hwan , Jung Inho , Kim Woohyun , Yoon Hong In , Kim Se Hoon , Moon Ju Hyung , Kim Eui Hyun , Chang Jong Hee 
Published: December 2020

Abstract

OBJECTIVE
The concept for maximal resection of glioblastoma(GBM) is changing to resect not only contrast-enhanced (CE) tumor but non-contrast-enhanced (NCE) tumor. Although maximal resection is associated with longer survival, the pattern of recurrence in glioblastoma, isocitrate dehydrogenase (IDH)-wildtype patient is poorly understood.

METHODS
This retrospective, single-center study included 358 eligible patients through November 1, 2005 to December 31, 2018. Those patients were grouped along extent of resection (subtotal resection (STR, n=123), gross-total resection (GTR, n=194), and supratotal resection (SupTR, n=41)). The pattern of recurrence was classified based on the range of radiation treatment, into infield gross target volume (GTV), infield clinical target volume (CTV), marginal, outfield and CSF seeding.

RESULTS
Tumor recurrence was observed for each group as follows: STR group, 80.5%, GTR group, 75.3%, and SupTR group, 63.4%. Statistical differences in pattern of recurrence among each group were observed in infield GTV (STR group:75.8%, GTR group: 71.9%, and SupTR group: 42.3%, p=0.003) and Outfield (STR group:11.0%, GTR group: 21.2%, SupTR group: 34.6%, p=0.012) recurrence. The survival for SupTR group was significantly longer than that for the STR and GTR in terms of both overall survival (OS) and progression free survival (PFS) (OS, STR: 15.7m, GTR: 21.6m, SupTR: 44.7m, PFS, STR: 10.4m, GTR: 14.3m, SupTR: 35.5m)

CONCLUSIONS
As the extent of resection increased, local recurrence decreased and distant recurrence increased. During treatment of glioblastoma, expectation
SURG-27. TREATING HYDROCEPHALUS IN DIFFUSE MIDLINE GLIOMAS WITH AN H3 K27M MUTATION
Authors: Coombs L , LaRocca R , Hata Jessica , Nickols H , Spalding A , Mutchnick Ian , Moriarity Thomas , Gump William , Sun D 
Published: December 2020

Abstract

BACKGROUND
Diffuse midline gliomas (DMG) are a subset of malignant gliomas that share a characteristic Histone H3K27M mutation. These tumors are centrally located and may cause hydrocephalus on initial presentation. DMG lack characteristic imaging that distinguish from other primary brain tumors in the midline. We conducted this retrospective chart review of 43 consecutive patients presenting with midline tumors to determine: how many had a DMG; whether DMG patients with hydrocephalus were candidates for resection; and what the outcomes of endoscopic third ventriculostomy (ETV) versus ventriculoperitoneal shunt (VPS) placement were, as compared to wild type (WT) tumors.

METHODS
We conducted an IRB approved retrospective chart review of patients presenting with midline tumors from 9/2016-3/2020 to determine H3K27M mutation status, hydrocephalus, and neurosurgery intervention.

RESULTS
The median age of all midline tumor patients was 19.1 years (range 1.1-80.1). 26% (11/43) of midline tumors presented with H3K27M mutation, with a higher rate of hydrocephalus compared to patients without mutation [7/11 (65%) for DMG vs. 6/32 (19%) for WT, p&lt; 0.05]. Of the seven H3K27M patients presenting with hydrocephalus, none were candidates for resection, 5 underwent ETV, and 2 underwent VPS placement as initial management. 4 out of these 5 ETVs failed within an average of 24 days (6-42 days). 2 patients then underwent VP shunt placement; the other 2 underwent secondary ETV but both failed and required VP shunting as well. All 6 WT tumor patients had one procedure (1 ETV, 5 resection) to relieve hydrocephalus, and no patients had recurrent hydrocephalus.

CONCLUSIONS
Both pediatric and adult patients may present with DMG associated with a higher rate of unresectable tumors and hydrocephalus on presentation. Furthermore, these data suggest that neuroendoscopic third ventriculostomy and septum pellucidum fenestration for the management of obstructive hydrocephalus in patients with DMG may be less robust than shunting.
SURG-39. 5-AMINOLEVULINIC ACID FLUORESCENCE (5-ALA) GUIDED RESECTION OF GLIOBLASTOMA, LESSON LEARNED FROM 26 CASES
Authors: Cho Jinmo 
Published: December 2020

Abstract

INTRODUCTION
5-ALA is known as useful tool for high grade glioma resection and the accumulation extent of 5-ALA is known as far beyond gadolinium enhancement. Extent of resection is key factor for favorable outcome and long-term survival for high grade glioma patients and 5-ALA might increase extent of resection. We present our experience of 5-ALA guided glioma surgeries.

MATERIALS AND METHODS
Total 26 patients were performed 5-ALA guided surgery. They ingested 20mg/kg, four hours before craniotomy. We tried to perform supra-total resection rather than gross total resection according to the tumor consistency and if the tumor located relatively non-eloquent area, we tried to perform lobectomy rather than lesionectomy. After tumor resection, we inspect the tumor bed under 5-ALA fluorescence, and we confirmed the complete loss of fluorescence on the tumor resected bed. We check the MRI within 48 hour after operation and assess the extent of resection.

RESULTS
Among the 26 patients, 22 patients were confirmed glioblastoma and 3 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. We confirmed all enhancing lesion was completely removed, however, 4 patients show residual non-enhancing lesion in post-operative MRI. Two patients suffered temporary hemiparesis and 2 patients show permanent visual field defect.

CONCLUSION
5-ALA is useful tool for glioma surgery. Resection extent could be increased, however, non-enhancing lesion in the high grade gliomas, might be missed under 5-ALA guidance.
TAMI-01. NEOADJUVANT PD-1 ANTIBODY BLOCKADE REMODELS THE IMMUNE MICROENVIRONMENT OF METASTATIC BRAIN TUMORS
Authors: Sun Lu , Kienzler Jenny , Lee Alexander , Chow Frances , Chavez Carolina , Yong William , Everson Richard , Kim Won , Hugo Willy , Prins Robert 
Published: December 2020

Abstract
Brain metastases (BM) commonly arise in patients with melanoma, lung, and breast cancer. Currently, there are limited options for GBM and BM patients who have failed the first-line standard treatment, underscoring the importance of developing new therapeutic strategies. Last year, we and other groups evaluated the neoadjuvant timing of anti-PD-1 checkpoint blockade therapy in recurrent GBM (rGBM) patients, which resulted in a modest survival benefit. In light of the known effectiveness of anti-PD-1 as a systemic therapy to control melanoma and non-small cell lung cancer BM, we set out to study the anti-tumor immune response of BM patients to anti-PD-1 in the neoadjuvant setting. We posited that neoadjuvant anti-PD-1 in patients with BM would result in a stronger antitumoral immune response, which could be quantified at the single cell level. To test this, we made use of contemporary single cell techniques, including multiplex immunofluorescence, time-of-flight mass cytometry (CyTOF) and single-cell RNA sequencing (scRNAseq), to characterize the intratumoral immune cell populations and their transcriptomic profiles. We found that neoadjuvant anti-PD-1 significantly increased the number of tumor infiltrating T lymphocytes in BM compared to rGBM (2.5 fold in BM, p= 0.02 vs. 1.4 fold in rGBM, p= 0.19). Multiplex immunofluorescence analysis of T cells in BM samples revealed a change from T cell exclusion to a diffusely infiltrating phenotype after anti-PD-1 treatment. Importantly, BM showed a higher fraction of effector/cytotoxic T cells compared to rGBM (7.3% vs. 0.9% of lymphoid cells, p= 0.005) and anti-PD-1 further enhanced this population. In the myeloid compartment of BM, neoadjuvant anti-PD-1 increased the frequency of HLA-DR+CD206- M1-like macrophages, implicating a pro-inflammatory microenvironment. In summary, our study delineated the immune cell subtypes altered by neoadjuvant anti-PD-1 and offers insights into new combination therapies that can help understand the clinical efficacy of immunotherapy for BM and GBM patients.
TAMI-02. ALTERATIONS IN C-X3-C MOTIF CHEMOKINE RECEPTOR 1 (CX3CR1) EXPRESSION INFLUENCE MICROGLIAL AND MACROPHAGE RESPONSE IN DIFFERENT STEPS OF CEREBRAL METASTASIS FORMATION
Authors: Zhang Wenlong , von Mücke-Heim Iven-Alex , Mulazzani Matthias , Karschnia Philipp , Straube Andreas , von Baumgarten Louisa 
Published: December 2020

Abstract
Metastasis to the brain is a frequent complication in lung cancer and is still associated with a dismal prognosis. Current treatment strategies not only target tumor cells but also focus on cells of the tumor microenvironment like tumor associated microglia/macrophages (TAMs). The interactions between tumor cells and TAMs during different steps of cerebral metastasis formation of lung cancer brain metastasis are poorly characterized. Moreover, the role of CX3CR1 in this process remains unclear. We established a syngeneic cerebral metastasis mouse model by combining a chronic cranial window and two-photon laser scanning microscopy (TPLSM), which allows the tracking of single fluorescent metastasizing tumor cells and the tumor microenvironment on a cellular resolution in vivoover time for a period of weeks. Transgenic CX3CR1 proficient and deficient mice (CX3CRGFP/wt and CX3CR1GFP/GFP) were injected with red fluorescent Lewis lung carcinoma cells. During different steps of metastasis formation (extravasation, formation of micro- and macrometastasis) the density and cell body volume of TAMs, their interaction with tumor cells and possible influence on the fate of single metastatic tumor cells were investigated using serial TPLSM. We found that during metastasis formation TAM density was significantly lower in CX3CR1 deficient mice. However, activation as assessed by TAM morphology did not differ in the absence of CX3CR1. Strikingly, CX3CR1 deficiency was associated with a significant increase of tumor cells successfully extravasating the cerebral vasculature. However, subsequent steps (mirco- and macrometastasis formation) were observed less frequent in CX3CR1 deficient mice. In summary, our results highlight a complex role of CX3CR1 for TAMs during cerebral metastasis formation, indicating anti-tumorous properties of CX3CR1 at early steps and possible pro-tumorous effects at later stages (micro- and macrometastasis formation).
TAMI-06. PRECLINICAL MODELS REVEAL BRAIN-MICROENVIRONMENT SPECIFIC METABOLIC DEPENDENCIES IN GLIOBLASTOMA
Authors: Minami Jenna , Bayley Nicholas , Tse Christopher , Zhu Henan , Morrow Danielle , Yong William , Liau Linda , Cloughesy Timothy , Graeber Thomas , Nathanson David 
Published: December 2020

Abstract
Metabolic reprogramming is a hallmark of cancer, and malignant cells must acquire metabolic adaptations to fuel neoplastic progression. Mutations or changes in metabolic gene expression can impose nutrient dependencies in tumors, and even in the absence of metabolic defects, cancer cells can become auxotrophic for particular nutrients or metabolic byproducts generated by other cells in the tumor microenvironment (TME). Conventional cell lines do not recapitulate the metabolic heterogeneity of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology. Additionally, these systems are under strong selective pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells. Here, we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) and gliomaspheres that reveal a subset of gliomas that, while able to form in vivo, cannot survive in vitro. RNA sequencing of tumors that can form both in vivo and in vitro (termed “TME-Indifferent”) compared to that of tumors that can only form in vivo (termed “TME-Dependent”) revealed transcriptional changes associated with altered nutrient availability, emphasizing the unique metabolic programs impacted by the tumor microenvironment. Furthermore, TME-dependent tumors lack metabolic signatures associated with nutrient biosynthesis, thus indicating a potential dependency of these tumors on scavenging specific nutrients from the extracellular milieu. Collectively, these data emphasize the metabolic heterogeneity within GBM, and reveal a subset of gliomas that lack metabolic plasticity, indicating a potential brain-microenvironment specific metabolic dependency that can be targeted for therapy.
TAMI-13. IMPORTANCE OF CD38 INHIBITION IN PRE-RECURRENT GLIOBLASTOMA
Authors: Hirte Renee , Olson Ian E , Rahman Masum , Mansour Moustafa , Casabella Amanda Munoz , Burns Terry C 
Published: December 2020

Abstract
Glioblastoma multiforme (GBM) is the most aggressive CNS neoplasm with a mere 15 month progression-free survival following current standards-of-care. Furthermore, conventional therapies have been effective, in part, by inducing a senescent-like phenotype in at least a proportion of glioma, as well as within the tumor-adjacent, healthy brain cells. Through an N-glyco-capture large-scale screening method, we were able to identify 25 genes exclusively overexpressed on glioma cell surfaces. Of those 25 targets, CD38 was an attractive target due to pre-existing FDA approved therapeutics. Recent studies have shown, however, that senescent cells, such as those induced via chemo- and radiotherapies, secrete a pro-inflammatory array of cytokines, known collectively as senescence associated secretory phenotype (SASP), that are capable of increasing CD38 expression in monocytes. CD38 functions as an ectoenzyme to convert extracellular NAD+ to nicotinamide (required for glioma cell salvage pathway NAD+ synthesis) and ADPR/cADPR (a cellular proliferation signal). To examine the effects of radiation on human glioma tissue, we performed reverse cyclase assays (RCA) on paired primary and recurrent human glioma tissue samples and found an increase in CD38 activity in post-irradiated tissues (recurrent glioma) compared to pre-irradiated (primary glioma). Through proliferation assays, we also found an increase in glioma cell growth following treatment with cADPR compared to untreated. Our results demonstrate that CD38 activity is tumorgenic, and furthermore that conventional chemo- and radiotherapies increase this CD38 activity. This indicates that treating CD38 with previously FDA approved therapeutics may provide hope for increasing progression free survival in our GBM patient population, and moreover emphasize the importance of leveraging novel large scale screening methods for identifying additional opportunities for treatment.
TAMI-15. THE EFFECT OF INTERSTITIAL FLUID FLOW AND ASTROCYTES / MICROGLIA ON INVASION, PROLIFERATION AND STEMNESS OF PATIENT-DERIVED GLIOMA STEM CELLS
Authors: Atay Naciye , Yuan Jessica , Cornelison Chase , Munson Jennifer 
Published: December 2020

Abstract

SIGNIFICANCE
Glioblastoma is a highly infiltrative, malignant, and deadly glioma that can be classified into subtypes based on molecular classification. Treatment resistant glioma stem cells (GSCs) depend on the tumor microenvironment (TME) to drive recurrence. Cellular composition and interstitial fluid flow (IFF) are significant aspects of the TME. IFF and astrocyte and microglia (A+M) presence have independently been shown to mediate invasion. This study’s goal is to expand our knowledge of IFF and A+M effects on invasion to proliferation and stemness.

METHODS
Seven patient-derived GSC lines were tested in an in vitro 3D model, which consists of GSCs ± A+M resuspended in 0.2% hyaluronan / 0.12% rat tail collagen I gel. The gel was applied to an 8um pore 96-well transwell system. Flow and static conditions were modeled with and without a pressure head above the gel, respectively. Cells beyond the transwell membrane after 18 hrs of incubation were considered invaded. Stemness and proliferation were determined via flow cytometry for CD71 and Ki67, respectively.

RESULTS/CONCLUSIONS
The three mesenchymal GSC lines tested exhibited the largest IFF fold increases in stemness, proliferation, and invasion with averages of 23.9, 19.1, and 2.1, respectively. CD44+ cell populations, highest in mesenchymal cells, had a strong correlation with proliferation (R=0.8439) and stemness (R=0.7829) under flow. Furthermore, depending on the cell line/subtype, the addition of A+M either amplified, reduced, reversed, mitigated, or kept constant the effect of IFF on invasion and proliferation. Incorporating A+M never amplified the effect of IFF on stemness. Adding A+M had a strong effect on the IFF fold change of at least one parameter in six of the cell lines. This is the first presentation showing that IFF, patient-specific, and context-specific factors contribute to both increased proliferation, and maintenance of stem-like phenotypes in glioma.
TAMI-16. BIOMATERIAL MATRICES TO STUDY GLIOBLASTOMA INVASION
Authors: Sohrabi Alireza , Guivatchian Elnaz , Xiao Weikun , Liang Jesse , Ehsanipour Arshia , Condro Michael , Kornblum Harley , Seidlits Stephanie 
Published: December 2020

Abstract

INTRODUCTION
Glioblastoma (GBM) is a highly infiltrative and lethal brain cancer. Previous studies have suggested that GBM tumors are stiffer than healthy brain tissues. We posit that local changes in the mechanical microenvironment near the tumor/tissue interface promote migration of GBM cells away from primary tumors. These studies seek to improve our understanding of how mechanical changes to the microenvironment of GBM tumors and surrounding brain tissue drive GBM progression using an in vitro, 3D model incorporating patient-derived primary GBM cells and a brain matrix-mimetic scaffold in which mechanical modulus can be varied.

METHODS
GBM xenografts were explanted and vibratome sectioning of fresh tissues for AFM. Hydrogels were fabricated by crosslinking thiolated hyaluronic acid (HA-SH), 8-arm polyethylene glycol (PEG)-norbornene and 4-arm PEG-thiol in the presence of photoinitiator UV light. Mechanical properties were measured using both rheology and AFM. Patient-derived GBM cells were maintained in 3D culture and migration monitored.

RESULTS AND DISCUSSION
AFM measurements of xenograft and brain tissue suggest that modulus is highest near the tumor center, decreases near the tumor border and is lowest in surrounding brain tissue. Hydrogels were tuned to match in vivo mechanics by altering total thiol content while matrix composition and effective pore size remained constant. GBM cells invaded readily in soft hydrogels, but were not able to migrate in stiff hydrogels. When cultured in platforms including defined regions in which moduli were varied, GBM cells seeded in stiffer regions readily migrated towards softer regions, while cells seeded into a softer matrix did not migrate to stiffer regions. Mechanical properties of the microenvironment appear to have marked effects on tumor cell migration and may drive GBM migration into surrounding tissues. In the long-term, we expect these studies to inform development of new therapeutics targeting GBM tumor invasion through improved understanding of underlying mechanisms.
TAMI-19. METABOLIC INTERACTIONS BETWEEN TUMOR CELLS AND THE IMMUNE SYSTEM IN GBM: A POTENTIAL ACHILLES HEEL OF GBM FOR NOVEL THERAPEUTICS
Authors: Tian Guimei , Yang Changlin , Andrews Michael , Karachi Aida , Dajac Mariana , Doshi Devshri , Mendez-Gomez Hector , Moore Ginger , Flores-Toro Joseph , Rahman Maryam , Huang Jianping , Sayour Elias , Harrison Jeffrey , Mitchell Duane , Deleyrolle Loic 
Published: December 2020

Abstract

INTRODUCTION
Glioblastoma (GBM) contains cell populations with distinct metabolic requirements, with fast-cycling cells harnessing aerobic glycolysis, and treatment-resistant slow-cycling cells (SCCs) preferentially engaging lipid metabolism. How the different tumor cells interact with immune cells and how this metabolic heterogeneity shapes the immune landscape in GBM has yet to be understood.

OBJECTIVES
The objectives are to unravel the various molecular signals and metabolic link that underlie the interaction of SCCs with the GBM microenvironment, in particular with the suppressive immune compartment, and to effectively target these interactions for better therapeutics.

METHODS
Multiple murine glioma cell lines were used to establish metabolic heterogeneity and communications, while various genetic and pharmacological approaches were applied to assess the effect of disrupting the metabolic interplay between SCCs and the immune system.

RESULTS
We determined that SCCs exhibit distinct metabolic dependencies, involving preferential lipid metabolism supported by enhanced fatty acid uptake. We also found that tumor progression is regulated by the interaction of SCCs with the immune system and established that SCCs recruit immune suppressive M2-like macrophages to the tumor microenvironment, which in turn work against tumor immune rejection by inhibiting T cell anti-tumor activity. The immune microenvironment shaped by SCCs is marked by specific metabolic features enhancing lipid exchange capacities that are exploited by SCCs to support their survival and functions. Importantly, disrupting lipid metabolic exchange sensitized tumors to chemotherapy.

CONCLUSION
Our results reveal that metabolic interactions between SCCs and tumor-associated macrophages within the GBM microenvironment play a critical role in the development of drug and immune resistant tumors. This study delineates these metabolic communications and assesses the potential therapeutic effect of disrupting these interactions to treat GBM. The insights generated from this project uncover fundamental principles of the emerging connections between the tumor microenvironment, cell metabolism, anti-tumor immunity, and associated therapeutic vulnerabilities.