bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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

Abstract
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

Abstract
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

Abstract
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

Abstract

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

Abstract
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

Abstract

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.
NIMG-23. BRAIN TUMOR REPORTING AND DATA SYSTEM (BT-RADS) AND QUANTITATIVE TOOLS TO GUIDE ITS IMPLEMENTATION
Authors: Weinberg Brent , Ramesh Karthik , Gurbani Saumya , Schreibmann Eduard , Kleinberg Lawrence , Shu Hui-Kuo , Shim Hyunsuk 
Published: November 2019

Abstract
Glioblastoma is the most aggressive primary adult brain tumor, with median survival of 15 months despite surgery and chemoradiation. MRI is used to guide treatment decisions, but imaging interpretation is challenging because of subtle findings with overlap between treatment effect and disease progression. The most frequently used quantitative brain tumor assessment metric is the Response Assessment in Neuro-Oncology (RANO), but this scoring system requires manual delineation 2-D metrics which can be subjective and is not directly tied to patient management decisions. The Brain Tumor Reporting and Data System (BT-RADS) is a novel, management-based reporting system developed by the Emory brain tumor team to improve quantitation and reduce bias in imaging assessment. BT-RADS scoring incorporates quantitative volumetric changes in contrast-enhanced T1-weighted (CE-T1w) and fluid attenuation inversion recovery (FLAIR) MRI, patient medications, clinical outcome, and treatment dates, and has been aligned closely with management decisions. To improve repeatability and reliability of scoring, we have begun to develop a cloud platform to help physicians utilizing BT-RADS. Longitudinal MRI data from each patient are automatically co-registered using rigid registration and aligned using trilinear interpolation, enabling voxel-to-voxel comparisons across multiple scans. The platform implements a semi-automated algorithm to segment tumor volumes using curvature flow, thresholding, and morphological filtering which expedites clinical review, as physicians simply edit and confirm segmentation accuracy rather than manual segmenting and measuring 2D images. Additionally, radiation dose maps can be overlaid on clinical images to determine what may be treatment effect and in-field vs. out-of-field recurrence. A secure web interface allows easy use by the entire treatment team, e.g. in a “tumor board” setting. Future plans include incorporating clinical and genomic data and fully automating tumor segmentation. The goal of this work is to provide more quantitative and objective follow-up metrics that can guide clinical decision making in glioblastoma patients.