bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMIC-12. TUMOR EDGE-DESTINED CELLS IN GBM CELLS IN A CELL-INTRINSIC MECHANISM
Authors: Yamashita Daisuke , Minata Mutsuko , Yu Hai , Zhang Soujun , Li Chaoxi , Flanary Victoria , Ghosh Sadashib , Lee Yeri , Cho Heejin , Botta Davide , Guo Xiaoxian , Ozaki Saya , Yamaguchi Shinobu , Komarova Svetlana , Bastola Soniya , Crossman David , Nabors Louis , Markert James , Gu Zhenglong , Skolnick Jeffrey , Zamboni Nicola , Lund Frances , Nam Do-Hyun , Nakano Ichiro 
Published: November 2019

Abstract
The highly infiltrative nature of glioblastoma (GBM) underscores limited response to current therapies and subsequent unfavorable clinical outcome. Despite the gross total resection of tumors located in the enhancing lesions, GBMs inevitably recur from the areas adjacent to the resection cavity that retains tumor cells with tumor-initiating capacity with therapy resistant nature (glioma-initiating cells: GICs). Here, we identified, in clinical GBM tumors, two mutually-exclusive glioma-initiating cell subpopulations in two different regions of GBM tumors, core- and edge-located glioma-initiating cells that co-exist in single tumors (Minata et al. Cell Reports. 2019). Following this observation, we further established patient-derived GBM clones from both tumor core and edge tissues, termed core-GICs and edge-GICs, and uncovered their distinct molecular signatures. Unexpectedly, we found that these two distinct GIC subpopulations retain the spatial identity, meaning that the core GICs locate themselves in the injected site, whereas the edge GICs initiated to form edge-like lesions, when xenografted into mouse brains. Through OMICs analyses, we identified CD38 as a key molecule to determine the edge phenotype both in vitro and in vivo. Collectively, our findings indicate, for the first time, that GBM cells are heterogeneous to be composed of tumor cells destined to be located in distinct regions of the tumors in a molecularly-defined manner.
ACTR-63. PHASE I DOSE ESCALATION STUDY OF PROCASPASE ACTIVATING COMPOUND-1 (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE IN PATIENTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA OR GLIOBLASTOMA
Authors: Holdhoff Matthias , Nicholas Martin , Peterson Richard , Danciu Oana , Maraka Stefania , Hergenrother Paul , Tarasow Theodore , Dudek Arkadiusz 
Published: November 2019

Abstract

BACKGROUND
Procaspase activating compound -1 (PAC-1) is a small molecule that catalyzes conversion of procaspase-3 to caspase-3 which induces apoptosis in cancer cells. Glioblastoma (GBM) is among the tumors with high concentrations of procaspase-3 and low levels of caspase-3. PAC-1 crosses the blood brain barrier and has been shown to synergize with temozolomide (TMZ) in canine malignant glioma and meningioma that arise spontaneously.

METHODS
This is a multicenter phase 1 dose-escalation study to assess the maximum tolerated dose (MTD) of PAC-1 administered days 1–21 in combination with TMZ days 8–12 at a dose of 150 mg/m2 of each 28 day cycle in subjects with recurrent anaplastic astrocytoma (AA) or GBM. A modified Fibonacci 3 + 3 design is used with up to 4 dose levels of PAC-1 (375, 500, 625 and 750 mg/day). Neurologic toxicity, including cognitive function, is closely monitored throughout the trial. INTERIM DATA: A total of 14 subjects have been enrolled to-date. Of these, 7 at dose level 1, PAC-1 375 mg/day (6 GBM, 1 AA; median age 58y, range 25–75) and 7 at dose level 2, PAC-1 500 mg/day (5 GBM, 2 AA; median age 51y, range 35–60). Best responses to-date were 2 subjects with a partial response and 2 with stable disease. Grade 3 (hepatotoxicity) and 4 (cerebral edema) was reported as possibly related to PAC-1 in 1 patient at dose level 1. The median number of cycles received was 4 (range, 1–12+) at dose level 1 and 2 (range, 1–3) at dose level 2. Enrollment to dose level 2 has been completed and data analysis is ongoing. Updated response and toxicity as well as pharmacokinetic data will be presented.
TMIC-16. THE EXPRESSION OF CX43 AND GAP43 AS CELL-TO-CELL LINKING FACTORS WITHIN THE GROUP OF DIFFUSE AND ANAPLASTIC GLIOMAS
Authors: Krigers Aleksandrs , Moser Patrizia , Fritsch Helga , Thomé Claudius , Freyschlag Christian F 
Published: November 2019

Abstract

INTRODUCTION
The diversity of expansion and resistance within the group of diffuse and anaplastic gliomas might be possible due to variations in the cell-to-cell communication, determined by the Cx43- junctional activity and microtubules-defined networking with GAP43 as the main structural component. The aim of our trial was to assess the expression of these crucial proteins in samples of patients.

METHODS
Tissue of adult patients with WHO°II and III gliomas, who underwent surgery 2014 to 2018, were selected from institutional biobank. The expression was analyzed using immunohistochemistry and routine findings gained from patient charts.

RESULTS
43 (57%) males and 33 (43%) females with a median age of 47 years (IqR: 35–61) were analyzed. In 15 (20%) patients a diffuse glioma (WHO°II) and in 46 (60%) an anaplastic glioma (WHO°III) was diagnosed. Further 15 patients (20%) were diagnosed with a diffuse glioma showing focal anaplasia. The IDH1 wildtype tumors demonstrated higher Cx43 expression in patients with longer intervals between imaging-based diagnosis and biopsy (p=0.032), whereas this association was absent in IDH1 mutated gliomas (p=0.549). The IDH1 wildtype tumors showed a higher expression of Cx43 (p=0.003) and a trend towards higher expression of GAP43 (p=0.075). Advanced Cx43 expression correlated with lower Ki67 nuclear expression in both IDH1 wildtype (p=0.003) and mutated gliomas (p=0.019).

DISCUSSION
The IDH1 wildtype gliomas showed advanced expression of Cx43 and GAP43 as well as longitudinal increase of Cx43. In the same time, tumors with lower mitosis rate produced more communication proteins, probably due to longer interphase. It can be interpreted as the intercellular networking provides acquired pathogenicity in the tumors with lower, e.g. “favorable”, proliferation rate. Moreover, IDH1 wildtype gliomas showed here advanced results, matching their aggressive behavior and poor outcome. Thus, diffuse and anaplastic gliomas are not homogenic and need to be evaluated considering their genetic profile.
TMIC-18. ELECTRICAL CIRCUIT INTEGRATION OF GLIOMA THROUGH NEURON-GLIOMA SYNAPSES AND POTASSIUM CURRENTS
Authors: Venkatesh Humsa , Morishita Wade , Geraghty Anna , Silverbush Dana , Gillespie Shawn , Arzt Marlene , Tam Lydia , Ponnuswami Anitha , Ni Lijun , Woo Pamelyn , Taylor Kathryn , Agarwal Amit , Regev Aviv , Brang David , Vogel Hannes , Hervey-Jumper Shawn , Bergles Dwight , Suvà Mario , Malenka Robert , Monje Michelle 
Published: November 2019

Abstract
High-grade gliomas are a lethal group of cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors into the tumor microenvironment represents part of the mechanism by which neuronal activity influences glioma growth, but this alone is insufficient to explain the magnitude of the effect that activity exerts on glioma progression. Here, we report that neuron-glioma interactions include electrochemical communication through both bona fide synapses and activity-dependent potassium flux. Single cell transcriptomic analyses revealed unambiguous expression of synaptic genes by malignant glioma cells, and neuron to glioma synaptic structures were evident by electron microscopy. Whole cell patch clamp electrophysiology demonstrated AMPAR-mediated excitatory neurotransmission between pre-synaptic neurons and post-synaptic glioma cells. Millisecond timescale excitatory post-synaptic currents (EPSCs) were found in a subpopulation of glioma cells, reminiscent of the axon-glial synapses between neurons and normal oligodendrocyte precursor cells (OPCs). Neuronal activity also evokes a second, non-synaptic electrophysiological response characterized by a prolonged (>1 sec) depolarization in a subpopulation of glioma cells. These longer duration currents are blocked by tetrodotoxin or barium and induced by potassium, indicating neuronal activity-dependent potassium flux reminiscent of astrocyte currents. The amplitude of the prolonged currents is reduced by gap junction inhibitors, supporting the concept that gap junction-mediated tumor interconnections can function to amplify evoked potassium currents in an electrically coupled network. As membrane depolarization of normal neural precursor cells can regulate proliferation, differentiation and survival, and glioma cells exhibit two distinct mechanisms of neuronal activity-evoked membrane depolarization, we tested the hypothesis that membrane depolarization promotes glioma growth. Using in vivooptogenetic techniques to depolarize xenografted glioma cells, we found that glioma membrane depolarization robustly promoted proliferation, while pharmacologically or genetically blocking electrochemical signaling inhibited glioma xenograft growth and extended mouse survival. Together, these findings indicate that electrical circuit integration promotes glioma progression.
TMIC-34. SENESCENT ASTROCYTE INDUCED INFLAMMATION MAY UNDERLIE SEX DIFFERENCES IN THE AGE-DEPENDENT RISE IN GLIOBLASTOMA INCIDENCE
Authors: Rhee Gina , Broestl Lauren , Grandison Lucia , Warrington Nicole , Kfoury Najla , Sponagel Jasmin , Hill Cameron , Rubin Joshua 
Published: November 2019

Abstract
Sex differences in the rates of glioblastoma increase with age. There are likely to be multiple biological mechanisms underlying these sex differences. Here, we focused on the changes that occur with aging in the secretomes of male and female astrocytes to determine whether sex differences in chemokine and cytokine secretion, and inflammatory cell recruitment, could be one of those mechanisms. We focused on glioblastoma (GBM) and the role that senescent astrocytes might play in the age-dependent widening of the gap between male and female GBM cases. We found that the senescence associated secretory phenotype of male and female astrocytes significantly differed, notably in the enrichment of Fractalkine (1.33:1 (F:M)), the primary chemoattractant for microglia, in female compared to male SASP. This was in contrast to the greater abundance of tumorigenic growth factors like bFGF (1.25:1 (M:F)), in the male SASP. Implantation of either male or female senescent astrocytes into the brains of mice resulted in the recruitment of microglia to the injection site. Regardless of the recipient mouse sex, female astrocyte implantation resulted in significantly larger microglial infiltrates (2-fold) and greater astrocyte activation, as compared to the injection of equal numbers of male senescent cells. We propose a model for how sex differences in astrocyte SASP could result in lower rates of GBM with age in females: greater microglial attraction to senescent cells results in their enhanced clearance and consequently a reduction in senescence-associated GBM promotion.
TMIC-36. ALDH1A2 AS A NOVEL PUTATIVE MARKER OF MACROPHAGE DIFFERENTIATION IN GBM
Authors: Sanders Stephanie , Herpai Denise , Miller Lance , Debinski Waldemar 
Published: November 2019

Abstract
Tumor-associated macrophages (TAM) are abundant in glioblastoma (GBM), composing up to 30% of the total tumor mass. However, their genotype/phenotype and exact role in tumor progression and immune suppression are not fully understood. Macrophages are believed to be polarized along a spectrum spanning from M0, M1, and M2 states. M1 TAMs are proinflammatory while M2 TAMs are associated with anti-inflammatory, pro-tumor responses. For example, using gelatin zymography we saw an increase in MMP 2 and 9 activities in co-culture of GBM cells and M2 polarized macrophages. In search for factors determining M2 type TAMs, we found Aldehyde Dehydrogenase 1 family A2 (ALDH1A2) to be highly over-expressed in M2 polarized THP1 cells using a gene expression array. We also performed single cell sequencing on CD45+ cells isolated from GBM tumors using antibody-conjugated magnetic beads. Monocytic/macrophage cells were found in 2 clusters and ALDH1A2 expression was increased in 2.1% of CD68+/CD163+ cells in Cluster 1 and 2.7% of CD68+/CD163+ cells in Cluster 2. Notably, ALDH1A2 was not detected in peripheral blood mononuclear cells. Analysis of the single cell sequencing data has led to identification of several genes whose expression is increased in ALDH1A2+ cells compared to ALDH1A2- cells. These genes are associated with lipid metabolism, regulation of neoplastic transformation, and insulin growth factor signaling. To further validate these results, we co-stained GBM tumor sections for CD163 and ALDH1A2 and observed that ALDH1A2 is co-localized in M2 macrophages. We have noticed a propensity of ALDH1A2+ cells to be associated with tumor neovasculature. Being that ALDH1A2 is the main enzyme in retinoic acid (RA) synthesis, it is plausible that this could represent another possible function of these enzyme-positive TAMs. Taken together these data suggest a role for ALDH1A2 as a novel putative marker of a subset of M2 TAM phenotype and function in GBM.
TMIC-40. YKL-40 AS MODULATOR OF CANCER STEM CELL PHENOTYPIC TRANSITIONS IN HUMAN GLIOBLASTOMAS
Authors: Guetta-Terrier Charlotte , Akosman Bedia , Kamle Suchitra , Fajardo Eduardo , Fiser Andras , Lee Chun G , Toms Steven A , Elias Jack A , Tapinos Nikos 
Published: November 2019

Abstract
Glioblastoma (GBM) is one of the most aggressive human tumors. Recent studies have shown that GBM “aggressiveness” is mainly due to populations of glioma stem cells (GSCs) within the tumor mass, which exhibit high migratory potential [3–5], form secondary tumors and can resist chemotherapy and radiation [6]. GSCs exhibit remarkable plasticity, are able to transition between immature and differentiated stages as well as reversibly express various phenotypic markers depending on the tumor microenvironment [7, 8]. Given such challenging features, GSCs have been subject of extensive research. YKL-40 (or Chitinase 3-like1) is a secreted glycoprotein normally expressed by numerous cell types including neutrophils and macrophages [11]. YKL-40 is highly expressed in numerous types of cancer such as breast, colon, lung, ovary, prostate, rectum and GBM [12–15]. RNA-seq on patient-derived GBMs and TCGA database analysis, showed that YKL-40 is one of the highest expressed genes in GBM. YKL-40 expression is associated with the invasiveness, therapy resistance and low survival rate of patients [16]. Here, we aim to elucidate the mechanistic function of YKL-40 in the microenvironment of human glioblastomas and determine its role as a new therapeutic target. We hypothesize that YKL-40 regulates transitions of GSCs phenotypes that underlie glioblastoma invasiveness and aggression. Our preliminary data show that incubation of patient-derived GSCs with YKL-40 induces a marked phenotypic change of GSCs from CD133+/Sox2+ to CD44+/YKL40+. We also performed RNA-seq and ATAC-seq to study the role of YKL-40 in gene expression and chromatin accessibility and identified the YKL-40-modulated transcriptional regulatory network that drives the phenotypic “switch” of GSCs. Finally, we used a novel humanized monoclonal antibody against YKL-40 to treat orthotopic glioblastoma xenografts and show significant reduction of tumor volume. Our work implicates YKL-40 as a microenvironment modulator of GSC phenotypic transitions and demonstrates pre-clinical efficacy of targeting YKL-40 to reduce tumor burden.
TMIC-45. RADIATION THERAPY-INDUCED EPIGENETIC REWIRING PROMOTES GLIOMA PHENOTYPIC PLASTICITY
Authors: Deepthi Muthukrishnan Sree , Wang Qing , Qin Yue , Kawaguchi Riki , Johnson Maverick , Prasad Rachna , Condro Michael , Kornblum Harley 
Published: November 2019

Abstract
Therapeutic failure and relapse of glioblastoma (GBM) tumors is attributed to a fraction of chemo- and radiation-resistant glioma stem cells (GSCs). Growing evidence indicates that GSCs and tumor cells elicit phenotypic plasticity in response to radiation-therapy (RT) such as de-differentiation and acquisition of a GSC-like state, and epithelial-to- mesenchymal transition (EMT) leading to more aggressive tumors and relapse. Preliminary findings from our laboratory indicate that RT also promotes vascular transdifferentiation of glioma cells, and the transdifferentiated vascular cells are essential for tumor growth in vivo. Together, these studies suggest that RT alters the dynamic equilibrium between “stemness” and “differentiation” states of the tumor cells. Transition between different cellular states or phenotypes required global alterations in chromatin landscape and associated transcriptional changes, and this epigenetic rewiring process is observed in several stages of oncogenesis and metastatic transformation. We hypothesized that epigenetic rewiring occurs in GBM tumor cells that survive radiation-induced DNA damage altering their cell fate that leads to diverse phenotypic outcomes such as EMT, acquisition of stem-like state and vascular transdifferentiation. Preliminary findings from bulk ATAC- and RNA-sequencing of patient-derived gliomasphere lines show that RT increases chromatin accessibility, and reduces expression of several histone components and their chaperones. Gene ontology and transcription factor motif analyses of open chromatin regions showed an enrichment of factors and terms related to pluripotency, vascular specification and stem cell differentiation. Furthermore, single-cell RNA-sequencing of radiated and control tumor cells also showed an increase in vascular markers expressing-clusters, and reduction in expression of histone components post radiation supporting our hypothesis that RT causes epigenetic rewiring in glioma cells leading to diverse phenotypic outcomes including vascular transdifferentiation. Ongoing experiments are aimed at determining the precise molecular mechanism by which RT causes chromatin rewiring, and identifying candidates involved in this process for therapeutic targeting.
ACTR-67. PATTERNS OF CARE AND IMPACT ON SURVIVAL OF FIRST SALVAGE THERAPY IN HIGH-RISK GRADE II GLIOMAS FOLLOWING INITIAL TEMOZOLOMIDE
Authors: Pellerino Alessia , Bello Lorenzo , Conti Nibali Marco , Bruno Francesco , Mo Francesca , Pronello Edoardo , Soffietti Riccardo , Rudà Roberta 
Published: November 2019

Abstract

BACKGROUND
No standard treatment is validated at first progression in high-risk low-grade gliomas, thus the optimal salvage therapy at recurrence and the factors that influence the PFS and OS are being investigated.

MATERIAL AND METHODS
We evaluated 71 patients with grade II glioma (WHO 2016) who progressed following surgery and initial chemotherapy with TMZ. Thirty-two (45.1%) patients were oligodendrogliomas IDH 1/2 mutated and 1p19q codeleted, 11 (15.5%) were diffuse astrocytomas IDH mutant, and 28 (39.4%) were diffuse astrocytomas IDH wild-type. Median follow up was 144 months (range 23–180).

RESULTS
Thirty-one patients (43.7%) underwent second surgery, 24 (33.8%) second-line chemotherapy, and 16 (22.5%) radiotherapy with a median PFS of 58 months (IC 95% 49–116). Median PFS was 60 months after second surgery (IC95% 43–116) and chemotherapy (IC95% 51–69), and 38 months after radiotherapy (IC95% 15–64) (p 0.09). No significant benefit in PFS was achieved in oligodendrogliomas undergoing second surgery (60 months) as compared with oligodendrogliomas treated with radiation or chemotherapy (58 months, p 0.11). PFS of astrocytomas IDH wild-type following second surgery (53 months) did not differ from those patients treated with adjuvant treatments (65 months, p 0.28). Median OS from the first salvage therapy was 117 months (IC95% 93 – 123+): 120 months (IC95% 108–140+) after second surgery, 94 months (IC95% 75–117+) after chemotherapy, and 62 months (IC95% 27–112) after radiotherapy (p 0.04). Median OS (123 months, IC95% 106–154) was prolonged in oligodendrogliomas receiving second surgery as compared to those receiving radiotherapy or chemotherapy (93 months, IC 95% 61–112, p 0.07), while median OS in astrocytomas IDH wild-type did not differ between those who received second surgery or radiotherapy or chemotherapy.

CONCLUSION
Reoperation as first salvage treatment in grade II gliomas seems to offer a probability of a longer OS, and this could hold true especially for oligodendrogliomas.
TMIC-46. GLIOMA-INDUCED SYNAPTOGENESIS IS ENRICHED WITHIN FUNCTIONAL CONNECTIVITY NETWORK HUBS AND INFLUENCES LANGUAGE PROCESSING IN ADULT IDH WT GLIOBLASTOMA
Authors: Krishna Saritha , Kakaizada Sofia , Valdivia Claudia , Seo Kyounghee , Raleigh David , Findlay Anne , Almeida Nyle , Sudharshan Rasika , Choudhury Abrar , Brang David , Nagarajan Srikantan , Berger Mitchel , Monje Michelle , Hervey-Jumper Shawn 
Published: November 2019

Abstract

INTRODUCTION
Little is known about the mechanisms by which gliomas integrate into functional neural networks and influence complex cognitive processes such as language. Glioma-neuron interactions are bidirectional, with increased neuronal activity promoting tumor growth and the latter in turn influencing neuronal excitability and synaptic connections. It remains unknown whether glioma-neuron interactions play a role in maintaining long-range neural networks subserving cognition in humans. We test the hypothesis that glioma-neuron interactions (“synaptogenic glioma cells”) are enriched within intratumoral high functional connectivity (FC) network hubs, thereby influencing language processing via release of synaptogenic factors into the tumor microenvironment.

METHODS
We employed magnetoencephalography imaginary coherence measures to identify intratumoral high (HFC) and low (LFC) functional connectivity network hubs in newly diagnosed glioblastoma patients. Primary patient samples and cultures from HFC and LFC sites were assessed for pre and post-synaptic marker expression (IF), cocultured with murine hippocampal neurons, and induced neuron organoids. ECOG Field recordings were performed on HFC/LFC tumors. Secreted proteins were measured from patient serum and LFC/HFC culture supernatant. Language assessments were performed to correlate task performance with FC measures.

RESULTS
Primary patient samples from HFC regions are enriched for glioblastoma cells with a synaptogenic profile as characterized by pre- and post-synaptic marker expression at both tissue and cellular level (coculture with mouse hippocampal neuron and organoid models). RNA sequencing and proteomic analyses from HFC samples revealed a neurogenic signature including thrombospondin 1 (TSP1). Overexpression of TSP1 in LFC primary patient cultures rescues the synaptogenic and proliferative phenotype. Importantly, we found a linear relationship between intratumoral HFC with patient serum TSP1 (ELISA) with a further correlation with language task performance.

CONCLUSION
An enriched population of synaptogenic glioma cells are organized within intratumoral high network connectivity regions. Glioma-induced neuronal synaptogenesis contributes to the microenvironment in support of network connectivity through secretion of TSP1.