bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-36. THE ROLE OF PD-L1 IN GLIOBLASTOMA-DERIVED EXTRACELLULAR VESICLES IN THE INDUCTION OF IMMUNOSUPPRESSIVE MONOCYTES
Authors: Himes Benjamin , Peterson Timothy , Tyson Jasmine , Lee Helen , deMooij Tristan , Cumba-Garcia Luz , Jung Mi-Yeon , Gustafson Michael , Dietz Allan , Johnson Aaron , Dong Haidong , Maus Rachel , Svetomir Markovic , Lucien-Matteoni Fabrice , Yan David , Uhm Sarah , Abukhadra Mina , Parney Daniel , Parney Ian
Published: November 2019

Glioblastoma (GBM) is the most common and lethal primary brain tumor, and novel therapeutic strategies that make a substantial impact on outcomes are sorely needed. Immunotherapies have shown great promise in the treatment of a number of cancers in recent year, and a concerted effort is being made to apply these treatment paradigms to GBM. However, many GBM patients exhibit profound immunosuppression, likely limiting the efficacy of such approaches. The mechanisms of this immunosuppression are poorly understood, but tumor-derived extracellular vesicles (EVs), may play a role. We demonstrate that GBM-derived EVs induce the development of myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs). We further demonstrate that these EV-induced monocytic cells are immunosuppressive, resulting in impaired T cell proliferation upon co-culture. We found that the immunosuppressive effects of tumor-derived EVs appear to be driven by the induction of these immunosuppressive monocytes, as EV treatment of T cells did not significantly impact T cell proliferation. Further, we sought to characterize the important of programmed death ligand 1 (PD-L1) in the induction of these immunosuppressive monocyte populations. We found PD-L1 to be expressed in the EVs from GBM cell lines, and that modulation in PD-L1 expression via either constitutive overexpression or shRNA-mediated knockdown resulted in concordant changes in expression in tumor-derived EVs. We demonstrate that PD-L1 is important for the induction of NCM but not for MDSCs. Taken together, these findings point to a significant role for tumor-derived EVs in the induction of immunosuppressive monocytes in GBM, and that these cells may be a driving force of systemic immunosuppression. PD-L1 is one factor expressed in EVs that has immunomodulatory properties, but additional EV cargo likely plays a major role in the induction of immunosuppressive cells.
IMMU-37. SINGLE-CELL SYSTEMS NEUROIMMUNOLOGY REVEALS IMMUNOSUPPRESSIVE CORRELATES WITH VENTRICULAR STEM CELL NICHE CONTACT IN HUMAN GLIOBLASTOMA
Authors: Bartkowiak Todd , Barone Sierra , Greenplate Allison , Sinnaeve Justine , Leelatian Nalin , Mistry Akshitkumar , Roe Caroline , Mobley Bret , Chambless Lola , Thompson Reid , Weaver Kyle , Ihrie Rebecca , Irish Jonathan
Published: November 2019

Glioblastomas make up more than 60% of adult primary brain tumors and carry a median survival of less than 15 months despite aggressive standard therapy. Immunotherapy, which is now standard of care for many solid tumors, offers an appealing therapeutic approach that may improve outcomes for glioblastoma patients. Predictive features in glioblastomas that may inform responsiveness to different immunotherapeutic modalities, however, are still lacking. Recent studies have demonstrated that patients whose tumors show radiographic contact with the lateral ventricles, and thus the stem cell niche of the ventricular-subventricular zone (V-SVZ), have reduced survival outcomes compared to patients whose tumors do not contact the V-SVZ. We therefore hypothesized that tumor contact with the V-SVZ engenders a unique, immunosuppressive microenvironment that promotes tumor growth by suppressing anti-tumor immunity. Glioblastoma tumors, obtained in accordance with the Declaration of Helsinki and with institutional IRB approval (#131870, #030372, #181970), were disaggregated into single-cell suspensions and multi-dimensional single-cell mass cytometry was performed to interrogate >30 immune parameters in thirteen immune populations infiltrating human glioblastomas. Using advanced computational dimensionality-reduction tools (Citrus, t-SNE, FlowSOM, and MEM), we identified distinctions among the abundance and phenotypes of tumor-infiltrating immune cells. Firstly, on the basis of tumor contact with the V-SVZ, Citrus identified differential abundance of five T and myeloid cell subsets among glioblastomas. Secondly, differential expression of five functional immune markers was observed in seven distinct immune cell subsets infiltrating glioblastoma tumors. Further, both immune abundance and marker expression correlated with patient outcome. Manual gating analysis and parallel computational pipelines confirmed that comparable cell subsets could be identified with traditional approaches and unsupervised algorithmic analysis. These results provide key insights into the immune microenvironment of glioblastomas. In addition, several clinically actionable immunotherapeutic targets were uncovered that may be used to optimize treatment strategies for glioblastomas based on V-SVZ contact status.
IMMU-47. RNA-NANOPARTICLE VACCINES ARE SAFE AND IMMUNOLOGICALLY ACTIVE IN CLIENT-OWNED CANINES WITH TERMINAL GLIOMAS
Authors: Carrera-Justiz Sheila , Stover Brian , Milner Rowan , Weidert Frances , Huang Jianping , Mitchell Duane , Mendez-Gomez Hector , Sayour Elias
Published: November 2019

BACKGROUND

The lack of appropriate preclinical murine glioblastoma models limits comprehensive toxicity/efficacy evaluation of investigational agents. To overcome this challenge, we evaluated the safety and activity of a new immunotherapeutic technology that we have pioneered (composed of tumor mRNA complexed into a custom lipid-nanoparticle formulation) in client-owned canines (pet dogs) diagnosed with malignant gliomas. OBJECTIVE/

METHODS

Canine malignant gliomas were biopsied for generation of personalized tumor mRNA loaded into our custom lipid-nanoparticle (NP) vector. The patients received RNA-NPs intravenously beginning two weeks after their biopsy once weekly (x3) and no other anti-tumor therapeutic interventions.

RESULTS

Within a few hours after administration, tumor specific RNA-NPs elicited margination of peripheral blood mononuclear cells, which increased in the subsequent days/weeks post-treatment; suggesting that RNA-NPs mediate lymphoid honing of immune cell populations before egress. RNA-NPs also elicited increased: 1) serum interferon-α that spiked at 2 hours; 2) CD80 and MHCII on CD11c+ cells (demonstrating activation of peripheral DCs); and 3) interferon-γ + T-cells (i.e. activated T-cells). After receiving weekly RNA-NPs (×3), the canines had a steady course. Aside from low-grade fevers on the vaccination days, personalized tumor RNA-NPs (1x) were well tolerated with stable blood counts, chemistries, and renal/liver function tests. All patients assessed developed immunologic response with pseudoprogression or stable/smaller tumors by MRI. Although we have treated a small cohort, we have observed improvement in median/overall survival in all canine patients with terminal gliomas receiving RNA-NPs (compared with historical controls).

CONCLUSION

RNA-NPs were feasible, safe and immunologically active in client-owned canines with terminal gliomas. We have not appreciated significant toxicities in canines that would preclude investigation in humans at 1x dosing. Although these results need to be validated in larger canine data sets, these results suggest safety and activity of tumor specific RNA-NPs in canines with terminal gliomas.
IMMU-49. THE SELECTIVE ENRICHMENT OF T CELLS TARGETING UNKNOWN BRAIN CANCER ANTIGENS VIA TROGOCYTOSIS
Authors: Moore Ginger , Divita Bayli , Flores Catherine , Mitchell Duane
Published: November 2019

INTRODUCTION

Trogocytosis is the exchange of membrane components from one cell to another. During T cell activation, dendritic cell (DC) and T cell membranes become anchored around the TCR/MHC complex and their costimulatory molecules. Part of the DC membrane is pulled away, taken in, and educates the T cell to recognize foreign antigens. We have utilized this phenomenon to isolate and expand a select population of T cells that have undergone this interaction. HYPOTHESIS: (1) By selecting for cells that have undergone trogocytosis, we are enriching for a tumor-specific population of T cells and can improve anti-tumor responses in the setting of adoptive cellular transfer (ACT). (2) This approach represents a reliable method to detect tumor-specific antigens across numerous types of brain cancers.

METHODS

Murine DCs are pulsed with KR158B glioma RNA and then stained with a proliferation dye such as Cell Trace Violet. These cells are co-cultured overnight with CD3+ splenocytes of vaccinated mice and IL-2. The cells are then sorted into T cells that have undergone trogocytosis (CD3+ CTV+) and those that have not (CD3+CTV-) and placed back into co-culture with fresh dendritic cells for expansion of tumor-specific T cells and/or restimulation assay. Additionally, T cells are spectratyped and phenotyped by flow cytometry.

RESULTS

Cells that had undergone trogocytosis (CD3+CTV+) demonstrated superior IFNγ secretion and enriched for CD4+ and CD8+ central memory and effector subsets compared to cells that had not undergone trogocytosis (CD3+CTV-). Spectratyping analysis revealed CD3+CTV+ cells enriched for Vβ 5.1/5.2 and Vβ 6, two families we have determined to be crucial for anti-tumor efficacy.

CONCLUSIONS

This method of selection and enrichment of tumor-specific T cells has promising implications for the enhancement of ACT. This method can be used to elucidate tumor-specific antigens that are unique to an individual’s cancer fingerprint.
INNV-09. CLINICAL EFFICACY OF TUMOR TREATING FIELDS FOR NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Liu Yang , Strawderman Myla , Warren Kwanza , Richardson Margie , Serventi Jennifer , Mohile Nimish , Milano Michael , Walter Kevin
Published: November 2019

Recent clinical trials demonstrated that adding tumor treating fields (TTF) to radiotherapy and temozolomide chemotherapy (the Stupp protocol) increased survival for glioblastoma (GBM) patients. However, data is lacking on the magnitude of this survival effect when the regimen is used outside of a clinical trial as part of routine clinical practice. In the present study, we retrospectively identified adult patients with newly diagnosed GBM (n = 240) treated with the Stupp protocol at our institution from January 2005 to July 2017. We grouped patients into two time periods for comparison: 2005–2013 (group 1, Stupp protocol) and 2014–2017 (group 2, TTF+ Stupp protocol). Thirty-six percent (37/104) of patients in group 2 received TTF in conjunction with the Stupp protocol. Within group 2, the 37-patients who received TTF + Stupp had increased 6-month and 1-year survival rates compared to the 67-patients who received Stupp alone (97.1% vs. 75.7%, p = 0.006; 67.6% vs. 53.7%, p = 0.170, respectively). The improvement of survival rate at 6-month was further confirmed by a modified Poisson model (RR: 1.23, p = 0.010) adjusting for sex, age, performance status and extent of resection. However, we did not observe improvements in overall survival (OS) with a Cox model with TTF treatment modeled as a time-dependent covariate (HR = 0.87, p = 0.599). Furthermore, we did not find that the addition of TTF as a treatment option in our center significantly improved OS for patients in group 2 when compared to those in group 1 (429.0 vs. 395.0 days, p = 0.138). Therefore, while adding TTF to the Stupp protocol appeared to benefit patients with newly diagnosed GBM, this effect may be largely due to selection bias. Comprehensive studies including large number of patients as well as longer follow-up time are needed to validate our results.
INNV-10. SAFETY OF APIXABAN FOR VENOUS THROMBOEMBOLISM PREVENTION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Thomas Alissa , Wright Heather , Walker Hannah , Prasad Prachi , Chan Kelly , Tipirneni Eswar , Goodwin Andrew , Holmes Chris
Published: November 2019

Venous thromboembolism (VTE) impacts an estimated one in every three patients with malignant glioma (MG), resulting in increased morbidity and mortality. Despite the high prevalence and serious consequences of VTE, there is no outpatient standard of care prevention strategy. There have been three prospective clinical trials of VTE prophylaxis in patients with newly diagnosed MG, all of which used an injectable low molecular weight heparin (LMWH) product. We performed an open-label safety study of apixaban, a direct oral anticoagulant (DOAC), for VTE prevention in patients with newly diagnosed MG. All patients had surgery or biopsy two to twenty-one days prior to enrollment in the study. Patients were treated with apixaban 2.5 mg twice daily for up to 6 months. Peak and trough apixaban concentrations were measured at the beginning and end of treatment. Thirteen patients consented to the study and ten enrolled (2 screen-fail, 1 withdrawal). The patients have completed a mean of 4.5 cycles of apixaban (range 2 to 6, with 2 patients still undergoing treatment). There were no bleeding events while receiving apixaban. There were no hematologic or non-hematologic treatment-related adverse events. There were no VTE events observed in patients receiving apixaban. Two patients who came off treatment early due to disease progression developed VTEs after stopping prophylactic apixaban. Quality of life analysis is ongoing. In this pilot study we found that prophylactic dosing of 2.5 mg twice daily of apixaban was safe in the post-operative period for patients with newly diagnosed MG. Our preliminary results suggest that this may be a safe and effective prevention strategy for VTE prophylaxis in this high risk group of patients.
INNV-17. INNOVATIVE EDUCATIONAL APPROACHES TO ENHANCE PATIENT AND CAREGIVER UNDERSTANDING OF TTFIELDS FOR GLIOBLASTOMA
Authors: Shackelford Melissa , Frongillo Peggy , Certo Jeanine
Published: November 2019

INTRODUCTION

The most common, aggressive malignant brain tumor is Glioblastoma (GBM) with patient median survival of 15–21 months. Patients with GBM face devastation of diagnosis, disease-burden, and hardship of seeking accurate information regarding treatment options. Evolving technology-enhanced methods of learning challenge traditional ways patients with cancer are educated and create an educational paradigm shift. The device manufacturer of Tumor Treating Fields (TTFields)) has developed innovative supplementary educational platforms to compliment healthcare provider (HCP) education of patients-caregivers with GBM treated with TTFields. This report aimed to evaluate these supplementary educational platforms.

METHODS

Emerging technology methods were employed to address patient-caregiver frequently asked questions, which included queries regarding treatment overview, mechanism of action, treatment initiation, and management to potentially ease the emotional burden of patients-caregivers seeking TTFields information. The TTFields educational platforms included incorporation of Web program, Buddy Program, Open-House Program (live and webinar), Chalk-Talk Video, and Facebook.

RESULTS

Educational platforms connecting potential and current TTFields patients-caregivers via live/webinar Open-House events ensured patient support. The phone-based Buddy Program allowed for direct 1:1 discussions between potential and current TTFields patients-caregivers. Patient-caregiver surveys revealed 100% would recommend the program to others (n=91); 98% were satisfied with the call experience (n=90); 76% felt the most valuable takeaway was speaking to someone who understands their situation (n=82). Of ambassadors, 98% felt they helped address registrants’ concerns (n=150). A dedicated TTFields Facebook page and first-ever, industry-led Facebook Live event (national broadcast; patients-caregivers discussed unique issues) were launched. Additionally, vignettes (eg, videos, written stories) were shared through a dedicated patient-caregiver website and YouTube channel.

CONCLUSIONS

In an ever-growing information age, it is important that HCPs become aware of innovative ways to reach and provide education for patients with brain cancer. Emerging technology utilization may improve GBM supportive care, by improving communication channels and potentially easing burden.
INNV-19. SURVEYING BIAS IN NEURO-ONCOLOGY AND SOCIETY FOR NEURO ONCOLOGY (SNO) MEMBERS: GENDER AND BEYOND
Authors: Kumthekar Priya , Brastianos Priscilla , Dunbar Erin , Peters Katherine , Porter Alyx
Published: November 2019

BACKGROUND

The face of neuro-oncology providers has evolved over the century. We sought to evaluate if its culture has evolved concurrently. Women in NeuroOncology (“WiN.”) is a SNO subcomittee that identifies the needs of women in neuro-oncology and promotes advancement of the careers of women in neuro-oncology. We created this survey to examine bias within our field with the goal to implement future change.

METHODS

Following IRB approval, we surveyed both male and female SNO members and analyzed de-identified responses.

RESULTS

Of the 206 respondents, 25% identified as male, 84.9% were in academics, 73.7% were primarily research focused (69% clinical), and 59% were medical neuro-oncology focused. The majority of respondents were 36–45 years old (47%), followed by 46–55 (32%), and 21% aged 56+. 69.8% self-identified as white, followed by 22% Asian, 7.8% Latin, and 2.9% Black. The majority reported general professional bias at least “not infrequently”, with 11.7% reporting it “very commonly.” 59.9% reported “not being invited to participate and or being considered for an opportunity”, followed by 46.1% “being minimized, teased or disrespected”, 44.3% “being passed over for professional opportunities”, and 41.9% salary disparity. Furthermore, of those reporting general professional bias, 42.9% reported a lack of effective mentorship and 94% reported some frequency of burnout, with 34% “commonly, very commonly”, followed by 28.3% “not infrequently.” Notably, although only 25% of responders were men, 82.4% of total respondents reported some frequency of gender bias in the workplace, with “not infrequently” being the most commonly reported (48%).

CONCLUSIONS

In this survey, we identified SNO members who have experienced bias. Based on quantitative and qualitative responses, many reported bias manifesting as missing academic opportunities, salary disparity, burnout, and lack of mentorship. As we cultivate the next generation, we will use these results to engage those in leadership to promote unbiased equality.
INNV-20. A SYSTEMATIC REVIEW OF TUMOR TREATING FIELDS THERAPY FOR PRIMARY FOR RECURRENT AND GLIOBLASTOMA
Authors: Shah Pavan , White Taija , Price Carrie , Mukherjee Debraj
Published: November 2019

BACKGROUND

Glioblastoma is an aggressive primary central nervous system malignancy with poor prognosis and limited treatment options. Tumor treating fields (TTFs) are a novel treatment modality utilizing alternating electric fields that have demonstrated promise in randomized clinical trials for primary and recurrent glioblastomas. In addition to these studies, a multitude of smaller investigations have been performed examining their efficacy in a variety of combination therapies. This systematic review of available literature aims to summarize and evaluate the efficacy and safety of TTFs for primary and recurrent glioblastoma patients.

METHODS

A systematic review of the literature was performed according to PRISMA guidelines from database inception through 2/27/2019. Databases queried include PubMed, Embase, Cochrane, Scopus, Web of Science, and ClinicalTrials.gov. 856 unique studies were initially identified in this search, 9 of which met final inclusion criteria. 2 authors independently performed the screening and data extraction of the studies.

RESULTS

Excluding historical controls, 1569 patients were identified in these studies, 1191 of which received TTFs therapy. TTFs were evaluated in single-arm clinical trials (n = 2), randomized clinical trials (n = 2), and retrospective studies (n = 5). These 9 studies are presented based on treatments provided, baseline patient characteristics, and patient outcomes. No adverse events appear to be associated with TTFs other than adverse skin reactions. Given the heterogeneity in the presented studies, a quantitative meta-analysis was not performed.

CONCLUSIONS

TTFs are a novel treatment modality that have demonstrated safety and efficacy in a number of settings and study designs. However, further investigation is needed to continue characterizing treatment outcomes and assessing TTFs interactions with various drug regimens.
INNV-26. IN VITRO CHEMO RESISTANCE PROFILES OF CIRCULATING GLIAL CELLS REPLICATE CHEMO CHARACTERISTICS OF TUMOR TISSUE
Authors: Akolkar Dadasaheb , Patil Sanket , Mhase Vishakha , Devhare Pradip , Fulmali Pooja , Patil Revati , Srinivasan Ajay , Datta Vineet , Schuster Stefan , Bhatia Jatinder , Datar Rajan
Published: November 2019

Survival of high-grade glioma patients remains dismal due to onset of resistance to even the limited systemic treatment option currently available. Except for indirect prediction of alkylating agent Temozolomide response through MGMT promotor methylation and NTRK fusions for larotrectinib, there are no biomarkers available for drug response prediction. Cell based, in vitro chemosensitivity assays can interrogate the efficacy of an array of cytotoxic drugs. However, the unavailability of live tumor cells for such assays pose challenges in clinical practice. Repeat biopsies are neither advisable nor feasible. Access to Circulating Glial Cells (CGCs) can provide real time insight into the chemo dynamics of the tumor. In this study, we show for the first time that CGCs can be harvested from peripheral blood of glioma patients for chemo response and resistance profiles (CRR) of cytotoxic drugs. CGCs were harvested from 15 ml of peripheral blood from high grade GBM patients (n=9) out of whom cells derived from surgically excised tumor tissue were also available for comparison in 2 patients. CellWizard™ process was adopted for enrichment of CGCs which is based upon epigenetically active media with paradoxical chemo-toxicity that selectively induces lethality in normal cells. This paradoxical cytotoxicity of the medium leads to selective elimination of most leukocytes thus facilitating a label free negative enrichment of CGCs. In vitro chemo sensitivity assay performed on live CGCs and cell death events were determined to evaluate response to different class of chemotherapy drugs. Evaluation of drug response showed very high concordance between tumor derived cells and CGCs in both patients where live tissue was available. In 7 patients where CGCs alone could be evaluated, the response showed replication between in vitro profile compared to treatment antecedents in 5 patients. 2 patients were treatment naïve and the response reflected high sensitivity to Temozolomide.
MNGI-06. EFFICACY OF 177LU-DOTATATE THERAPY IN RECURRENT ANAPLASTIC MENINGIOMA
Authors: Kizilbash Sani , Johnson Derek
Published: November 2019

BACKGROUND

177Lu-Dotatate (177Lu-DOTA0-Tyr3-Octreotate) is a beta-particle emitting somatostatin analog recently FDA approved for the treatment of somastatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Somatostatin receptors are highly expressed in almost all meningiomas, therefore 177Lu-Dotatate may be a reasonable treatment strategy for this disease. Furthermore, the short path length of the beta particle should allow for treatment of previously radiated patients with low risk of cerebral radiation necrosis. CASE STUDY: A 61 year-old male presented with a history of atypical meningioma (WHO grade II), recurrent as anaplastic meningioma (WHO grade III). His previous treatments included multiple surgical resections, fractionated radiation therapy, stereotactic radiosurgery, everolimus/octreotide LAR, bevacizumab and hydroxyurea. MRI imaging revealed rapid volumetric progression over the prior nine months with a near tripling in size from 29.9 cm3 to 80.4 cm3. In-111 octreotide confirmed the presence of somatostatin receptors within the tumor. 177Lu-Dotatate was administered intravenously at a dose of 200 millicuries per dose, every eight weeks for four cycles. Treatment was tolerated very well, with no significant adverse events. Tumor volume initially increased to 98.3 cm3 after cycle 1 of treatment, and subsequently decreased to 91.2 cm3 after cycle 2. Eight months after treatment onset, the tumor volume remained stable (93.4 cm3).

CONCLUSION

177Lu-Dotatate may be a safe and effective strategy for the treatment of somastatin receptor-positive meningioma. The transient increase in tumor volume after the first dose in this case may have represented delayed treatment effect or pseudoprogression. A phase II clinical trial is currently being activated to determine the progression-free survival associated with 177Lu-Dotatate in patients with recurrent meningioma.
MNGI-09. MENINGIOMA WITH MULTIPLE DRIVERS: GENOMIC LANDSCAPE AND CLINICAL CORRELATIONS
Authors: Li Chang , Tyrtova Evgeniya , Youngblood Mark , Miyagishima Danielle , Duran Daniel , Montejo Julio , Özduman Koray , Sheth Amar , Zhao Amy , Fomchenko Elena , Clark Victoria , Sohrabi Sadaf , Koljaka Sarah , Li Xuejun , Necmettiin Pamir M , Avşar Timuçin , Kilic Türker , Zhu Hongda , Gong Ye , Bayri Yasar , Amankulor Nduka , Bilgüvar Kaya , Omay Sacit , Huttner Anita , Simon Matthias , Krischek Boris , Kalamarides Michel , Moliterno Jennifer , Zeynep Erson-Omay E , Günel Murat
Published: November 2019

BACKGROUND

Previous studies have established several meningioma genomic subgroups, defined by the mutually exclusive genomic drivers. However, we distinguished a small subset of meningiomas simultaneously harboring multiple drivers from different genomic subgroups, thus referred to as “multiple-driver meningiomas”, that has not been previously investigated. We aimed to characterize the genomic landscape and clinical features of multiple-driver meningiomas.

METHODS

We identified 42 cases of multiple-driver meningiomas from a cohort of 3,016 cases screened for genomic drivers via molecular inversion probe sequencing (MIPS) and/or whole-exome sequencing (WES) previously in our laboratory. All driver mutations were validated via Sanger sequencing and chromosome 22 loss was accessed with qPCR. Clinical information was collected and genome-to-clinical correlations were statistically analyzed. We selected 10 multiple-driver meningioma cases for tumor-normal WES for further characterization of genomic architecture.

RESULTS

Multiple-driver meningiomas were significantly enriched for NF2 alteration (p< 0.001), had significantly higher WHO grade (p= 0.005) and proportion of recurrent tumors (p= 0.007) when compared with “single-driver meningiomas”, i.e. harboring driver alterations from a single genomic subgroup. Among female cases, those with multiple drivers were nearly four times more likely to be high-grade (II or III) compared to single-driver female samples (48.6% vs. 12.6%, p< 0.001). Among tumors harboring NF2 alteration, multiple-driver meningiomas demonstrated skull base predilection compared with single-driver meningiomas (50.0% vs. 27.9%, p= 0.005). WES analysis of 10 multiple-driver meningiomas identified 1p and/or 14q loss in 60% of cases. Clonality analysis revealed the presence of sub-clonal cell populations in 9 cases with all driver mutations clustered into the founding clone in 7 cases, suggesting their acquisition in the early phase of tumor development.

CONCLUSION

Multiple-driver meningiomas demonstrate distinct genomic and clinical features that distinguish them as clinically aggressive. They frequently occur in surgically challenging skull base locations, and are more prevalent among high-grade and recurrent cases.
MNGI-10. ATYPICAL MENINGIOMA: EARLY OUTCOMES WITH OR WITHOUT POSTOPERATIVE RADIATION
Authors: Pan Peter , Pisapia David , Ramakrishna Rohan , Schwartz Theodore , Stieg Philip , Fine Howard , Pannullo Susan , Knisely Jonathan , Chiang Gloria , Ivanidze Jana , Liechty Benjamin , Brandmaier Andrew , Magge Rajiv
Published: November 2019

BACKGROUND

Adjuvant radiotherapy (RT) in atypical meningioma, especially for gross-totally resected tumors, remains controversial.

METHODS

We retrospectively identified histologically-confirmed cases of WHO Grade II atypical meningioma at a large academic institution from 2004–2018. Clinicodemographic, surgical, radiation therapy (RT), and histopathologic data were collected, as well as imaging and clinical outcomes, with a median follow-up time of 26 months (IQR 32). Patients were stratified by resection status and whether or not upfront RT was administered. Additionally, subanalyses were performed to compare external beam RT (EBRT) and stereotactic radiosurgery (SRS). Progression was defined by radiology report.

RESULTS

Of 122 patients, 45 were excluded for lacking adequate records of previous treatment, less than 3 months follow-up, or lacking MR imaging. Of 77 patients analyzed, 57% (44/77) were female; median 59-years-old. 48% (24/50) of gross-total-resections (GTR) received upfront RT – only a single case progressed, at 39 months. Of 26 GTR patients without upfront RT, 8/26 (31%) progressed at median 19.5 months – of these, 2 were lost to follow-up, 5 received salvage RT, and 1 had surgery alone. Adjuvant RT was associated with superior progression free survival (PFS) in GTR (Cox proportional hazard ratio 0.15, likelihood-ratio p=0.025; median PFS not reached). Of 15 subtotal resections (STR) receiving upfront RT, 11 received EBRT and 4 received SRS – 6 progressed (median 37 months), all after EBRT. Upfront SRS demonstrated superior PFS over EBRT following STR (p=0.036). Across the cohort there was one confirmed death, a GTR patient (without RT) who suffered an ischemic stroke at 11 months.

CONCLUSION

This large single-center retrospective analysis indicates adjuvant RT improves PFS in GTR atypical meningiomas, in concordance with prior studies. It is limited by short median follow-up, possibly related to long-term stability in treated patients. In STR tumors, SRS may contribute to improved PFS compared to EBRT.
PATH-12. IDENTIFYING MOLECULAR PROGNOSTIC MARKERS IN IDHwt GLIOBLASTOMA
Authors: Alnahhas Iyad , Giglio Pierre , Gonzalez Javier , Puduvalli Vinay
Published: November 2019

BACKGROUND

Despite our deeper understanding of the genomic alterations associated with glioblastoma (GBM), only a few genetic and epigenetic modifications have been proven to be meaningful in clinical practice. We have identified molecular parameters of prognostic relevance in IDHwt GBM using patient data from the Ohio State University (OSU) and the publicly available MSK-IMPACT database.

METHODS

A clinically annotated database of glioma patients at OSU- whose tumors were analyzed through Foundation One genomic testing- was utilized to examine mutation and copy number variation (CNV) data. 73 patients with IDHwt GBM were included in this study cohort along with 200 similar patients from the MSK-IMPACT cohort. Data from the MSKCC group was extracted from the cBioPortal database. Altered genes were correlated with clinical outcomes using Cox proportional hazards models. Univariate and multivariate analyses were applied, and variables included: MDM/P53, CDKN2A/B, CDK/CCND, RB1, EGFR/ ERBB, FGFR, PDGFR/KIT, NF1, PI3K, PI3K class 2, MYC and TERT promoter mutations.

RESULTS

Using univariate and multivariate analyses, EGFR activating alterations (amplification, mutations) and RB1 alterations (deletion, mutations) showed significant correlation with favorable outcome in IDHwt GBM: HR 0.496 for EGFR (p< 0.0001) and 0.454 for RB1 (p=0.025). Furthermore, the presence of PDGFR alterations, in EGFR altered tumors only, carried a significantly worse survival in univariate and multivariate analyses: HR 5.094 (p=0.004). This suggests an interaction between EGFR and PDGFR that could be of therapeutic relevance.

CONCLUSIONS

We found that GBM tumors harboring EGFR and/or RB1 alterations have better survival compared to tumors that are EGFR/RB1 wild-type. Moreover, PDGFR alterations worsens survival in EGFR altered GBM. This data provides further insights that might guide targeted therapies in IDHwt GBM.
PATH-14. IMMUNOHISTOCHEMICAL ANALYSIS OF TUMOR ASSOCIATED MACROPHAGE INDUCED AFTER CARMUSTINE WAFER IMPLANTATION IN HUMAN GLIOBLASTOMA
Authors: Shibahara Ichiyo , Miyasaka Kazuhiro , Sato Sumito , Inukai Madoka , Yasui Yoshie , Hide Takuichiro , Kumabe Toshihiro
Published: November 2019

The carmustine (BCNU) wafer, a biodegradable polymer, currently is the only drug that is able to be placed at the surgical site to treat malignant tumors. Biomaterials to treat cancers hold therapeutic potential; however, how they behave inside the tumor microenvironment requires further study. We previously investigated the tumor microenvironment after BCNU wafer implantation, and found that CD68-positive macrophage was significantly introduced around the wafer (Shibahara et al. J Neurooncol 2018). Recent studies demonstrated the importance of tumor-associated macrophage (TAM). However, we could not clarify whether the increased macrophage around the wafer was pro-tumor or anti-tumor phenotype. In the present study, we immunohistochemically examined expressions of CD68, IBA1, CD163, TMEM119, BIN1, CD31, and VEGF to investigate TAM after the wafer implantation. Quantitative evaluation revealed that CD68+ cells were significantly increased (P = 0.0009), whereas TMEM119+ cells were significantly decreased (P = 0.0081) after wafer implantation compared to tissue from cases without wafer implantation. CD163, a known marker of poor prognosis in glioblastoma, did not differ with and without wafer implantation. Among factor analyzed, BCNU wafer did not induce protumor TAM, but reduced microglial marker, TMEM 119. In addition to the aspect of chemotherapy, BCNU wafer may have potential to modify the tumor microenvironment such as TAM.
PATH-22. MULTIPLEXED IMMUNOHISTOCHEMISTRY AND THE IMMUNE MICROENVIRONMENT OF PRIMARY CENTRAL NERVOUS SYSTEM TUMORS
Authors: Bullis Carli , Han Seunggu , Davare Monika
Published: November 2019

Studying the immune microenvironment of primary CNS tumors is critical for the development of novel immunotherapies. At this time, immunotherapy is likely underused and may have a promising future in their treatment. Current limitations in studying the TME of the CNS are the small amount of tissue often available and the laborious, time consuming process of testing for individual markers. Multiplexed immunohistochemistry (mIHC) is a process of evaluating multiple tumor biomarkers on a single piece of tissue. This process has been validated in some non-CNS tumors, including papillary thyroid carcinomas, mesothelioma, and breast and pancreatic tumors, but has not yet been validated in CNS tumors. Our aim in this study is to validate the use of mIHC to study the CNS TME for the development of future immunotherapies. Tissue samples from 5 astrocytomas, 4 neuroblastomas, and 4 medulloblastomas, as well as 2 tissue microarrays (TMAs) were analyzed. The mIHC process was performed as detailed in the paper by Coussens et al. Briefly, the tissues were put through a process of deparaffinization, counterstained with hematoxylin, and incubated with a series of antibodies. They were then scanned and registered into the computer, where color deconvolution and detailed cellular analysis was performed. Two antibody panels were used with the following markers: 1) myeloid panel: CD45, CD66b, CD68, CD163, CSF1, DCLAMP, DCSIGN, MHCII, PANCK, PDL1; 2) lymphoid panel: TBET, CD3, CD8, CD45, GATA3, NKP46, PANCK, PD1, PDL1, RORGT. Populations of macrophages, microglia, T-cells, natural killer cells, and tumor cells were all identified. Macrophages were CD45+CD66b-CD68+. Microglia were CD45+CD66-CD68+CSF1+. Granulocytes were CD45+CD66b+. T-cells were CD45+CD3+. Natural killer cells were CD45+CD3-NKP46+. Tumor cells were CD45-PDL1+. We conclude that mIHC is an efficient and novel way of studying CNS TME. This may have implications in the development of future immunotherapies.
PATH-37. PROGNOSTIC ROLE OF TERT PROMOTER MUTATIONS IMPROVES THE STRATIFICATION OF IDH-MUTATED LOWER GRADE GLIOMA
Authors: Arita Hideyuki , Matsushita Yuko , Ohno Makoto , Miyake Yohei , Saito Kuniaki , Tanaka Shota , Nakamura Taishi , Tamura Kaoru , Higuchi Fumi , Sandika Eriel , Sabit Hemragul , Hattori Yasuhiko , Yamaguchi Shigeru , Okita Yoshiko , Sakamoto Daisuke , Fukai Junya , Uda Takehiro , Hata Nohuhiro , Shofuda Tomoko , Sasayama Takashi , Mori Kanji , Kurozumi Kazuhiko , Kanamori Masayuki , Sasaki Hikaru , Kishima Haruhiko , Kanemura Yonehiro , Nakada Mitsutoshi , Sonoda Yukihiko , Nagane Motoo , Ueki Keisuke , Nishikawa Ryo , Narita Yoshitaka , Ichimura Koichi
Published: November 2019

TERT promoter mutation is associated with 1p/19q codeletion and favorable prognosis in IDH-mutated gliomas. Prognostic and diagnostic significance of TERT promoter mutation is well-recognized in IDH-wildtype glioblastomas, but not in IDH-mutated gliomas. We investigated prognostic efficacy of TERT mutation in a cohort of 560 Japanese IDH-mutated adult gliomas. The molecular status of IDH, TERT and 1p/19q and patient clinical data including Karnofsky performance status (KPS) were collected in all cases. TERT mutations and 1p/19q codeletions were found in 303 and 285 cases, respectively. The patient cohort was divided into four groups by a combination of the 1p/19q and TERT status. The characteristics of 1p/19q intact-TERT mutated group (Astro-TERT group, n=24) were compared with those of 1p/19q intact-TERT wild (Astro-group, n=251) or 1p/19q codeleted-TERT mutated (Oligo-group, n=279) cases. Astro-TERT group with any grade showed intermediate overall survival between the Oligo-group and Astro-group although the survival differences were not statistically significant (median overall survival (OS) not reached (NR) versus NR, and 106 months, respectively. p >0.05). We further conducted subgroup analysis by adjusting KPS and WHO grade as Cox regression analysis for survival indicated the unfavorable survival impact of KPS < 90 and WHO grade IV. In the subgroup with favorable KPS (90–100) and grade II-III (n=438), The OS of Astro-TERT group (median NR) was significantly longer survival than that of Astro-group (median 120.2 months, p=0.032), and was comparable with that of the Oligo-group (median NR, p >0.05). On the other hand, OS of none of the molecular groups significantly differ in poorer KPS subgroups (p >0.05). In grade IV tumors, the OS of the Astro-TERT group (NR) was comparable with that of Astro-group (29 months, p=0.19) rather than Oligo-group (NR, p=0.051). Thus, TERT promoter status provides a valuable prognostic information for IDH-mutated grade II-III gliomas in the current molecular diagnostic system.
NCOG-01. NEUROCOGNITIVE FUNCTION (NCF) AND QUALITY OF LIFE (QOL) RESULTS FROM A PHASE II STUDY OF TEMOZOLOMIDE-BASED CHEMORADIOTHERAPY REGIMEN FOR HIGH RISK LOW-GRADE GLIOMAS
Authors: Wefel Jeffrey , Pugh Stephanie , Choucair Ali , Fisher Barbara , Fox Sherry , Meyers Christina , Ashby Lynn , Mikkelsen Tom , Glass Jon , Yu Michael , Howard Steven , Movsas Benjamin , Mehta Minesh
Published: November 2019

BACKGROUND

RTOG 0424 reported a 73.5% 3-year overall survival (OS) rate. This secondary analysis describes changes in NCF and QOL after therapy.

METHODS

Patients with HR-LGG were treated with radiation and concurrent and adjuvant temozolomide. Standardized NCF tests were performed at baseline, 6 and 12 months (mos). Rates of NCF decline were examined using the reliable change index on Hopkins Verbal Learning Test (HVLT), Trail Making Test (TMT), and Controlled Oral Word Association. Relationships between NCF and subjective cognitive concerns (MOS-Cognitive Function [MOS-CF] scale) were evaluated with Wilcoxon Rank Sum Test. QOL was assessed using FACT-Brain. Longitudinal modeling using maximum likelihood estimation evaluated predictors of change in QOL. Cox models assessed the association of baseline NCF with OS after adjusting for age, anticonvulsants, number of high risk factors, EORTC OS risk group, and tumor crossing the midline.

RESULTS

From 1/2005 to 8/2009, 129 evaluable patients were accrued, and 93 (72%) completed at least one NCF/QOL measurement with completers having better neurologic function than noncompleters (p=0.04). Compliance across measures was 55–59% and 54–57% at 6 and 12mos. Deterioration occurred in 50%/40% at 6mos/12mos, respectively, and was most frequent on HVLT (21%/20%), TMTA (29%/20%), and TMTB (22%/14%). Patients with HVLT deterioration at 12mos, compared to patients without deterioration, had significantly greater decrease in MOS-CF (p=0.01). No NCF test at baseline was independently associated with OS. FACT Emotional (p=0.02) and Functional Well-Being (p=0.004) subscales improved over time. EORTC OS high-risk group was associated with worse QOL on all subscales (p< 0.05 to 0.001) except Emotional Well-Being, tumor crossing the midline was associated with worse Emotional Well-Being (p=0.04), and unmethylated MGMT status was associated with better Physical Well-Being (p=0.05).

CONCLUSIONS

Approximately half of patients with HR-LGG experience NCF decline in the first year after treatment with temozolomide-based concurrent chemoradiation. QOL remained stable or improved.
NCOG-10. RELATIONSHIP BETWEEN COGNITIVE FUNCTION, MOOD, AND FUNCTIONING IN GLIOMA SURVIVORS
Authors: Van Dyk Kathleen , Heimberg Brandon F , Choi Justin , Raymond Catalina , Wang Chencai , Lai Albert , Cloughesy Timothy , Ellingson Benjamin , Leia Nghiemphu P
Published: November 2019

Ensuring optimal quality of life and functioning is a clinical priority in treating glioma survivors. Cognitive function and mood symptoms are prevalent in this population after treatment and it’s reasonable to consider these as significant contributors to patients’ functioning at work and in daily life. However, it’s unclear the degree to which these symptoms contribute to such outcomes. To address this question, we examined the relationships between cognitive tests (i.e., a neuropsychological battery) and mood measures (i.e., the Beck Depression Inventory-II, and the Beck Anxiety Inventory) and work and daily functioning (i.e., Work Productivity and Activity Impairment Questionnaire). Partial correlation of cognitive tests and regression models also included age and IQ (i.e., Test of Premorbid Functioning). Of the 11 participants who were currently working, worse work productivity was significantly associated with worse processing speed (Stroop color naming r=-.74,p=.03, Stroop color word r=-.78,p=.02). Similarly, worse ability in daily activities was also associated with worse processing speed and executive function (Stroop color naming, r=-.52,p=.04; Stroop color word, r=-.55,p=.03; Trails B, r=-.53,p=.03). Greater depression symptoms were strongly correlated with both worse work productivity (r=.83,p=.002), and worse ability in daily activities (r=.55,p=.01). Depression symptoms were generally uncorrelated with cognitive scores. In linear regression models that included both depression symptoms and cognitive scores, only depression emerged as a significant predictor of work productivity and ability to conduct daily activities. In sum, glioma survivors face multiple threats to work and daily functioning by way of tumor and treatment related symptoms. Our analyses suggest that both cognitive function and mood symptoms are important to consider in optimizing functioning, but depression appears to vastly outweigh cognitive function in this regard. These preliminary findings highlight the importance of careful attention to these symptoms in survivorship and point to future research directions elaborating on these relationships.
NIMG-16. FEASIBLITY OF FLUORINE-18 FLUCICLOVINE PET-CT AND MRI FOR MONITORING OF CHEMO-RADIATION IN GLIOBLASTOMA: INITIAL RESULTS FROM A PILOT STUDY
Authors: Short Susan C , Frood Russell , Broadbent David , Fernandez Sharon , McDermott Garry , Al-Qaisieh Bashar , Buckley David , Currie Stuart , Murray Louise , Scarsbrook Andrew
Published: November 2019

BACKGROUND

Glioblastoma has a poor prognosis despite treatment with surgery and chemo-radiotherapy (CRT). Monitoring early response to CRT is challenging and conventional imaging is sub-optimal for stratifying poorly responding patients for novel agents. Also, imaging is not routinely performed during CRT and consequently, personalised treatment through individualised radiation dose adaption is not possible. AIMS: To evalutate the feasibility of Fluorine-18 Fluciclovine PET-CT for early response assessment during and post-treatment in patients with glioblastoma undergoing standard-of-care CRT.

METHODS

Patients with confirmed glioblastoma and macroscopic residual tumour post-surgery were consented for PET-CT and MRI prior to CRT (scan 1), after completing 2 weeks (10 fractions) of CRT (scan 2) and 6 weeks after completing treatment (scan 3). For each scan, patients were immobilised in a radiotherapy treatment mask. PET-CT and MRI scans were performed at each timepoint within a few days of each other. Patients were treated and followed up according to local guidelines.

RESULTS

6 patients were recruited to the study between June 2018 and May 2019. All patients tolerated the additional imaging without problems. 2 patients were unable to attend their post-treatment PET-CT scan due to clinical deterioration. Fluciclovine PET-CT highlighted potentially active disease beyond the surgical cavity pre-radiotherapy (scan 1) in 3 patients. In 4/6, PET signal persisted after 2 weeks of radiotherapy with stable MRI appearances (scan 2). Frank disease progression was seen in 1 patient on both MRI and PET-CT mid-treatment. 3/4 patients with persistent activity at scan 2, showed disease progression post-treatment on both PET-CT and MRI (scan 3). Another had progressive changes on MRI but stable PET-CT appearances possibly representing pseudoprogression.

CONCLUSION

These preliminary results suggest that Fluciclovine PET-CT could help in monitoring treatment and further work to assess the ability to guide individualised treatment planning in glioblastoma is warranted.