bluuebunny/crossref_metadata_2025 huggingface dataset:
SURG-01. OPTIMALTTF-1: FINAL RESULTS OF A PHASE 1 STUDY: FIRST GLIOBLASTOMA RECURRENCE EXAMINING TARGETED SKULL REMODELING SURGERY TO ENHANCE TUMOR TREATING FIELDS STRENGTH
Authors: Korshøj Anders , Mikic Nikola , Lukacova Slavka , Christian Sørensen Jens , Hansen Frederik , Thielscher Axel , Cortnum Søren , Guldberg Trine , Ramshad-Lassen Yasmin , Rahbek Christian , Severinsen Kåre , von Oettingen Gorm
Published: November 2019

BACKGROUND

OptimalTTF-1(open-label phase-1) combines Tumor Treating Fields(TTFields) treatment with targeted skull-remodeling surgery(SR-surgery) aiming to enhance the electric field strength in the tumor(NCT02893137). SR-surgery aims to reduce the electrical impedance of the skull. Pre-clinical modeling indicates that SR-surgery increases the electric field strength. The final analysis examined toxicity and efficacy of TTFields combined with SR-surgery and best-choice-chemotherapy in first glioblastoma recurrence(rGBM).

METHODS

18 patients were screened and 15 (4F/11M) enrolled between Dec2016 and Mar2019. The primary endpoint was frequency of serious adverse events (CTCAEv4.0) and secondary endpoints were overall survival (OS) and progression-free survival (PFS). Eligible patients were ≥18-years, had focal supratentorial rGBM, KPS≥70, and a minimum calculated increase in TTFields strength of ≥25% after SR-surgery. At the time-of-analysis patients were censored for time-to-event endpoints.

RESULTS

Baseline data(median (range)) demonstrated a patient age of 57(39;67), skull defect area=10.6 cm2(7;37), increase in the TTFields strength by 43%(25;59). All tumors were IDH-wt and 4 had MGMT-promoter methylation. In total, 4 patients were excluded from the study prior to TTFields initiation (consent withdrawal, radionecrosis/non-recurrence, postoperative infection and neurodeficit), 11 patients (2F/9M) underwent treatment. Treatment compliance was 90%(48;98), mean treatment duration and follow-up was 6.8 months(2.3;20.4) and 10 months respectively. Grade 1–2 AEs included, headache 60% CI95%=[32;84], fatigue 53%, CI95%=[27;79], skin rash 47%, CI95%=[21;73], and nausea 40%, CI95%=[16;68]. No grade 3 SAEs were related to the intervention (6 seizures, 1 headache, 1 fatigue, 1 TIA, 1 post-op infection, 1 diarrhea and 1 DVT). Efficacy outcomes were PFS6=64%, CI95%=[35;85], PFS=8.8 months, CI95%=[6.2;13.2], OS=15.0 months, CI95%=[9.6;16.2], and OS12=64%, CI95%=[35;85].

CONCLUSION

Targeted SR-surgery combined with TTFields is safe and does not induce additional toxicity. Furthermore, it potentially increases overall survival in rGBM. A phase 2 clinical trial is currently being planned.
SURG-05. EXPERIENCE PROFILING OF FLUORESCENCE-GUIDED SURGERY FOR GLIOMAS
Authors: Young Ji So , Eun Lee Chae , Chowdhury Tamrin , Wook Kim Jin , Park Chul-Kee
Published: November 2019

Numerous studies reported a usefulness of 5-ALA fluorescence-guided surgery (FGS) in high grade gliomas. However, fluorescence pattern and intensity is variable among gliomas. In this study, we report our extensive experiences of FGS in various gliomas focusing on epidemiological data of fluorescence pattern. A total of 827 histologically proven glioma patients out of 900 brain tumor patients who had undergone FGS using 5-ALA during the period of 8.5 years between July 2010 and January 2019 were analyzed. Indication for FGS in glioma surgery harbored any evidence of possible high-grade foci at presumed gliomas in preoperative magnetic resonance images (MRI). Among the 827 gliomas, the number of cases corresponding to 2016 World Health Organization (WHO) grade IV, III, II, and I are 528 (58.7%), 193 (21.4%), 87 (9.7%) and 19 (2.1%), respectively. In terms of fluorescence rate, grade IV gliomas showed positive fluorescence in 95.4% of cases including strong intensity in 85.6%. Grade III gliomas showed fluorescence in about half of cases (55.0%), while 45.0% of cases did not show any fluorescence. Anaplastic oligodendroglioma had more positive rate (63.9%) than anaplastic astrocytoma (46.2%). Both grade II and I gliomas still showed positive fluorescence in about one-fourths of cases (24.1% and 26.3%, respectively). Among them ependymoma and pilocytic astrocytoma were fluorescence-prone tumors. This epidemiological data of 5-ALA fluorescence in various grades of gliomas provides fundamental reference to clinical application of FGS using 5-ALA in glioma surgery.
SURG-08. SURGICAL OUTCOMES OF PITUITARY ADENOMAS TREATED WITH TRANSSPHENOIDAL SURGERY: A SINGLE INSTITUTION’S EXPERIENCE
Authors: Beom Seo Young , Kim Oh-Lyong
Published: November 2019

We retrospectively analyzed surgical outcomes of transsphenoidal surgery for pituitary adenomas. A total of 366 consecutive patients undergoing transsphenoidal surgery for a pituitary adenoma from December 1990 through May 2017 were included in this study. The most common tumor type was nonfunctioning pituitary adenoma (NFPA) (63.7%), followed by prolactin-secreting adenoma (20.5%), growth hormone-secreting adenoma (13.4%), adrenocorticotropin-secreting adenoma (2.2%), and thyrotropin-secreting adenoma (0.2%). This cohort study consisted of 164 male and 202 female patients. The median patients age was 48 years. The median follow-up duration was 63 months. Gross-total resection (GTR) was achieved in 83.7% of patients with a NFPA, 76% of prolactin-secreting adenomas, 71.4% of growth hormone-secreting adenomas, 75% of adrenocorticotropin-secreting adenomas, 100% of thyrotropin-secreting adenomas. There were 326 macroadenomas (69.1%). Surgical outcome was better in patients with microadenomas than in patients with macroadenomas (100% and 77.9%, respectively). Improvement of visual disturbances occurred in 148 (93.7%) of the 158 cases. Hormonal impairment by pituitary adenoma was improved in 105 (87.5%) of the 120 cases. There were 24 (8.2%) cases of recurrence after GTR; 17 patients underwent second surgery, 5 patients received radiotherapy, and the others continued conservative treatment. The median time interval between TSA and recurrence was 56 months. Postoperative cerebrospinal fluid leakage occurred in seven (1.9%) of 366 patients. Transsphenoidal surgery is an effective and safe treatment modality for most patients with pituitary adenoma.
SURG-20. IDENTIFICATION OF INFILTRATIVE CANCER CELLS AT THE GLIOMA RESECTION CAVITY MARGIN USING STIMULATED RAMAN SCATTERING MICROSCOPY
Authors: Morshed Ramin , Pekmezci Melike , Young Jacob , Aghi Manish , McDermott Mike , Theodosopoulos Philip , Berger Mitchel , Hervey-Jumper Shawn
Published: November 2019

INTRODUCTION

Microscopic residual disease at the tumor margin is the primary barrier to complete resection which impacts outcome. Stimulated Raman scattering microscopy (SRM) has proven effective to classify CNS tumor tissue and detect tumor cells within grossly normal post mortem glioma specimens. In this study, we use SRM for detection of residual glioma cells within the resection cavity margins.

METHODS

Patients with gliomas undergoing surgical resection were included. Margin samples were taken after the primary surgeon determined the resection cavity wall to be grossly normal and were analyzed using (1) true H&E, (2) SRM pseudo H&E, (3) immunohistochemical stains (IHC) for IDH1-R132H or p53. The sections were scored on a scale of 0–3 by a neuropathologist blinded to the corresponding results from each modality (0=no definite tumor cells; 1=rare tumor cells; 2=moderate tumor cells with preserved neuropil; 3 = abundant tumor cells). Positive and negative predictive values and Spearman correlation coefficients were calculated.

RESULTS

Ninety-one margin samples from 19 patients were included. Tumors were WHO grade II (29.7%), III (38.5%), and IV (31.8%). There was a strong correlation between SRM and H&E (Spearman correlation (r) = 0.76), SRM and IHC (r=0.81), and H&E and IHC scores (r=0.91). PPV of SRM score of 3 was 100%. The presence of tumor cells on SRM (scores 1–3) strongly correlated with the presence of tumor cells on H&E (PPV = 95%) and IHC (PPV = 91%). The absence of tumor cells on SRM correlated with absence of tumor on H&E and IHC only 10% and 50% (NPV) of the time, respectively.

CONCLUSIONS

The PPV of utilizing SRM to detect residual glioma cells in grossly normal resection cavity margins is high however the NPV is low. SRM may have utility as a rapid point-of-care intraoperative tool for identification of infiltrative glioma within resection cavity margins.
SURG-28. RADIOFREQUENCY ABLATION AS AN ADJUNCT FOR PAIN AND TUMOR CONTROL IN SPINAL METASTATIC DISEASE
Authors: Urbisci Tony , Thomas Bryan , Tran Nam
Published: November 2019

BACKGROUND

The spine, particularly the thoracolumbar region is a common site for metastatic spread from a variety of primary cancer types. Radiofrequency ablation (RFA) of these lesions has proven efficacious for pain control, but the addition of adjunctive radiation therapy (XRT) remains the standard of care for pain palliation and to prevent tumor progression.

OBJECTIVE

This study aims to investigate RFA as a standalone intervention to treat and prevent the progression of metastatic vertebral lesions. Study Design: Single center retrospective review of patients receiving RFA for vertebral metastatic lesions between 2013 and 2016. Twenty-nine spinal lesions in nineteen patients were treated with RFA followed by vertebral augmentation. Primary tumors were from prostate, renal cell, breast, lung, laryngeal, multiple myeloma, cervix, thyroid, and colon. The treated levels were then followed with either MRI, PET CT, or CT at varying intervals per the primary oncologist. We compared the duration between the procedure and either first imaging evidence of tumor progression at the treated level or patient death between patients that underwent RFA alone or with the addition of adjunctive XRT.

RESULTS

Our comparison shows no significant difference (p < 0.357) between the time to progression between the group that received RFA alone and the group that received RFA in conjunction with XRT.

CONCLUSION

Radiofrequency ablation is a safely and effectively used in the treatment of vertebral metastatic osseous lesions. Although the sample size is small, and the patient population is heterogenous, there is supporting evidence that targeted RFA is as effective in preventing local tumor progression as the procedure combined with XRT.
SURG-29. LASER INTERSTITIAL THERMAL THERAPY COMPARED TO CRANIOTOMY FOR TREATMENT OF RECURRENT GLIOBLASTOMA
Authors: Palejwala Ali , O’connor Kyle , Glenn Chad , Sughrue Michael
Published: November 2019

There have been publications that propose the use of laser interstitial thermal therapy (LITT) as a viable alternative to craniotomy for the treatment of glioblastoma (GBM). The aim of this study was to retrospectively compare outcomes after LITT versus craniotomy for patients with recurrent GBM. To adequately match the cohorts, we included only pre-treatment tumor volumes of under 15 cc. We retrospectively collected data on all patients presenting with recurrent GBM, with a recurrence volume under 15 cc. These patients were either treated with LITT or craniotomy by the senior author. Data included demographics, tumor location and volume, tumor markers, perioperative complications, re-initiation of adjuvant chemotherapy, and long-term follow up data. We performed 23 LITT treatments and 34 craniotomies for recurrent GBM in patients that met selection criteria. There was no significant difference in the patients’ age, tumor volume (6.38 for craniotomy versus 5.765 cc for LITT), location, and post-procedure KPS. Patients that underwent LITT had significantly reduced inpatient stays in comparison to craniotomy (1.7 versus 4.2 days). They also had less perioperative complications (13.0% versus 32.3% for craniotomy). It was found that 28 out of the 34 patients that underwent craniotomy were able to undergo adjuvant therapy; in comparison, 15 out of the 23 patients who underwent LITT had undergone adjuvant therapy. Of these patient’s that underwent adjuvant therapy, 87% of patients were able to receive bevacizumab or a clinical trial versus 42% after craniotomy. Progression-free survival (PFS) and overall survival (OS) after procedure were similar for LITT versus craniotomy, respectively: % PFS-survival at 6 months = 23.5% versus 21.7%. Overall survival did not significantly differ at 9 months versus 9.9 months respectively. LITT appears to be safe and may be as efficacious as craniotomy in achieving progression free survival for small to moderate volume recurrent GBM.
SURG-34. CLINICAL PREDICTORS OF TUMOR RECURRENCE AFTER PITUITARY ADENOMA RESECTION
Authors: Jackson Christina , Vo Chau , Daniels Marcus , Chaichana Kaisorn
Published: November 2019

INTRODUCTION

Repeat surgery after tumor recurrence after pituitary adenoma resection can be challenging due to formation of scar tissue and loss of surgical landmarks, which can lead to increased rates of postoperative complications. Identification of clinical predictors of tumor recurrence would allow for appropriate stratification of patients to optimize preoperative counseling and postoperative management.

METHODS

We conducted a retrospective review of 349 patients who underwent pituitary adenoma resection at Johns Hopkins Hospital between 2003 and 2017. We used unadjusted and adjusted logistic regression to identify predictors of tumor recurrence. Factors which were associated with tumor recurrence in univariable models (p< 0.1), were included in our multivariable model. Factors that remained significantly associated with tumor recurrence (p< 0.05) in our multivariable model were considered predictors of recurrence.

RESULTS

59 (16.9%) patients developed tumor recurrence at the time of our study. Patients who had surgery through one nare, transcranial surgery, visual field deficit, larger tumor volume, bilateral cavernous sinus invasion, carotid artery invasion, and postoperative cerebral spinal fluid (CSF) leak were more likely to have tumor recurrence. Conversely, patients who are younger in age, had sphenoid packing, and gross total resection were less likely to have tumor recurrence. In our multivariable model, only age (adjusted odds ratio[aOR]: 0.96), surgery through one nare (aOR: 2.05), gross total resection(aOR: 0.21), and presence of CSF leak(aOR: 4.43) remained significantly associated with tumor recurrence.

CONCLUSIONS

We identified several predictors of tumor recurrence after pituitary adenoma resection. Notably, having gross total resection of the primary tumor had the most significant protective effect on tumor recurrence. Given the increased complication associated with repeat surgery, gross total resection should be attempted in all patients, if feasible. Patients with other predictors of tumor recurrence should be monitored more frequently to allow for early detection of recurrence to optimize treatment strategies.
TMIC-01. THE DYSTROGLYCAN RECEPTOR MAINTAINS GLIOMA STEM CELLS IN THE VASCULAR NICHE
Authors: Day Bryan , Lathia Justin , Bruce Zara , Ensbey Kathleen , Chieh Lim Yi , Jamieson Paul , D’Souza Rochelle , Akgul Seckin , Offenhauser Carolin , Baumgartner Ulrich , Smith Fiona , Li Yuchen , Jurd Courtney , Stringer Brett , Robertson Thomas , Jeffree Rosalind , Johns Terrance , Bhat Krishna , Rich Jeremy , Campbell Kevin , Boyd Andrew
Published: November 2019

Glioblastomas (GBMs) are malignant central nervous system (CNS) neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumourigenic glioma stem cells (GSCs) in a complex heterogeneous microenvironment. One proposed GSC niche is the extracellular matrix (ECM)-rich perivascular bed of the tumour. Here, we report that the ECM binding alpha (α) subunit of the dystroglycan (DG) receptor is expressed and functionally glycosylated on GSCs residing in the vascular niche. Glycosylated αDG is also expressed highly on the most aggressive mesenchymal-like GBM tumour tissue. Furthermore, we found that DG acts to maintain a de-differentiated stem cell-like phenotype via tight control of MAPK activation. Antibody-based blockade of αDG induces robust ERK-mediated differentiation leading to reduced GSC potential. DG was shown to be required for tumour initiation, with constitutive loss significantly delaying or preventing tumourigenic potential in-vivo. These findings reveal a central role of the DG receptor not only as a structural element but also as a critical factor in the maintenance of GSCs in the GBM vascular niche.
TMIC-02. JUNCTIONAL ADHESION MOLECULE-A (JAM-A) DEFICIENCY DRIVES SEX-SPECIFIC DIFFERENCES IN GLIOBLASTOMA PROGRESSION VIA DIFFERENTIAL MICROGLIA RESPONSES IN THE TUMOR MICROENVIRONMENT
Authors: Turaga Soumya , Silver Daniel , Paouri Evi , Bayik Defne , Peng Sen , Connor James , Barnholtz-Sloan Jill , Rubin Joshua , Berens Michael , Davalos Dimitrios , Lathia Justin
Published: November 2019

Despite the male preponderance for developing glioblastoma (GBM) and better survival outcomes in females, current treatment paradigms do not account for biological sex as a biological or clinical variable. Sex-specific molecular alterations that drive tumor cell growth and therapy response have been documented, however, sex-specific extrinsic differences in the tumor microenvironment have yet to be identified. Based on well-established sex-specific gene signatures and functional differences in microglia, we interrogated influences of male and female microglia in driving GBM growth. Specifically, manipulation of JAM-A expression, a tight junction protein on microglia, was exploited as a paradigm for determining effects on in vivo syngeneic GBM mouse models. Male and female JAM-A KO mice that received orthotopic injection of syngeneic GBM cells presented differential overall survival distinct from their wildtype counterparts. Wild-type male mice phenocopied human males, presenting shorter overall survival than females, this trend was reversed in JAM-A KO mice. Compared to the other genotypes, female JAM-A KO mice presented the greatest number of phagocytic, tumor-promoting, activated microglia. RNA-sequencing of tumors from JAM-A KO and WT mice revealed that female JAM-A KO mice had increased expression of Ifi202b (interferon activated gene 202b), a member of the Activity-regulated Inhibitor of Death (AID) gene family that contributes to mitochondrial resistance to cellular stress. Ifi202b has a role in sex-specific inflammatory diseases, which is consistent with our observation. Female KO microglia had enhanced Ifi202b expression, along with the secretion of Ifi202b associated cytokines, including interleukin-6. Treatment of wild-type female microglia with a JAM-A function blocking antibody demonstrated an increase in Ifi202b levels, confirming direct regulation of Ifi202b expression by neutralizing JAM-A. While cell intrinsic, sex-specific differences have been reported in GBM, our findings demonstrate that differences in the GBM tumor microenvironment also drive sexually dimorphic tumor growth.
TMIC-11. ENHANCED B7-H4 EXPRESSION IN GLIOMAS WITH LOW PD-L1 EXPRESSION IDENTIFIES COLD TUMORS
Authors: Chen Di , Li Gaopeng , Ji Chunxia , Lu Qiqi , Qi Ying , Tang Chao , Xiong Ji , Hu Jian , Hoon Dave S B , Zhang Yan , Yao Yu , Zhou Liangfu
Published: November 2019

The expression profiles of different immune checkpoint molecules are promising for triaging personalized targeted immunotherapy. Gliomas have been shown as potential targets for immune checkpoint inhibitors. Our study was performed to determine co-expression levels of two major B7 immune molecules PD-L1 and B7-H4 in gliomas in which both have demonstrated to inhibit anti-tumor host immunity. We assessed tumor issues from primary gliomas stage II–IV(n=505) by immunohistochemistry (IHC) for protein levels of both PD-L1 and B7-H4. Gene co-expression analysis assessing clusters based on extent of PD-L1/B7-H4 classifier genes expression were investigated in two transcriptome datasets (TCGA and CGGA) to validate IHC expression profiles. Here, we found that 61% and 54% of patient samples were positive for PD-L1 and B7-H4 respectively, whereby high-expression of either protein was limited to 23% and 20% respectively. Co-expression of PD-L1 and B7-H4 in high levels was limited to 2%. Comparable results were seen in RNA-seq datasets when PD-L1 mRNA expression level corelated negatively with B7-H4. Gene co-expression modules clustered in each grade gliomas without Double-High modules (glioma cluster with high mRNA expression of both PD-L1 and B7-H4 classifier genes) also verified restricted co-expression pattern. B7-H4 mRNA expression level had negative correlation with extent of immune cell infiltration, including tumor-infiltrating lymphocytes (TILs), and High-B7-H4 module gliomas (high B7-H4 but low PD-L1 classifier genes expression) were related to a cold tumor with less TILs. The majority of gliomas express PD-L1 or B7-H4, however, co-expression of both at high levels is minimal. The High-B7-H4 module was significantly lacking in TILs, suggesting that B7-H4 might inhibit T cell trafficking into the central nervous system (CNS). This study demonstrates that PD-L1 expression alone is not fully informative in gliomas for immune targeted or active-specific immunotherapy, and PD-L1 and B7-H4 probably inhibit different aspects of the T cell functions.
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

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

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

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

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

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

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

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

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

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

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.
TMIC-52. REACTIVE ASTROCYTES AID THE EVOLUTION OF IMMUNOSUPPRESSIVE ENVIRONMENT AND DRIVE ONCOGENIC SIGNALING IN GLIOBLASTOMA
Authors: Heiland Dieter , Ravi Vidhya , Behringer Simon P , Wurm Julian , Beck Juergen , Schnell Oliver
Published: November 2019

Reactive astrocytes are caused by multiple pathologies of the central nervous system, whereby they undergo distinct transcriptomic re-programming. Although the role of reactive astrocytes in some inflammatory diseases has been investigated, many central questions regarding the immunoregulatory functions of tumor-associated astrocytes and their crosstalk to microglia remain poorly understood. In our presented study, we purified astrocytes from various pathologies and different brain tumors to map the transcriptional landscape of reactive astrocytes. We identified the marker genes CHI3L1 and CD274 highly enriched in reactive astrocytes of the marginal astrogliosis scar at the tumor boarder. Human neocortical slices along with a microglia loss-of-function model were used to explore the crosstalk of microglia and reactive astrocytes within the tumor environment. Our results revealed that the reactive phenotype mutually arises from both, microglia and tumor cells. This interaction caused JAK/STAT signalling in reactive astrocytes along with a large release of anti-inflammatory cytokines such as TGFß and IL10. Additionally, inhibition of the JAK/STAT pathway recovered the release of anti-inflammatory cytokines and resulted in a pro-inflammatory environment. Besides the immunosuppressive properties, we found evidence that reactive astrocytes drove AKT and MAPK signaling in the tumor through astrocytic released CHI3L1 and consequential binding to IL13RA2. Our findings revealed increased malignant properties arising from astrocytic-tumor interaction, which were rescued by IL13RA2 inhibition. In a nutshell, reactive astrocytes have decisive regulatory tasks in the microenvironment of CNS tumors. Along with microglia, reactive astrocytes cause the evolution of an immunosuppressive environment and support malignant properties of the tumor.