bluuebunny/crossref_metadata_2025_split huggingface dataset:
CMET-33. PHASE II STUDY OF PALBOCICLIB IN BRAIN METASTASES HARBORING CDK PATHWAY ALTERATIONS
Authors: Brastianos Priscilla , Cohen Justine , Wang Nancy , Lee Eudocia , Ligibel Jennifer , Chukwueke Ugonma , Keeley Maura , Oh Kevin , White Michael , Gerstner Elizabeth , Batchelor Tracy , Lawrence Donald , Ryan David P , John Iafrate A , Giobbie-Hurder Anita , Flaherty Keith , Santagata Sandro , Carter Scott , Cahill Daniel , Sullivan Ryan 
Published: November 2019

Abstract

BACKGROUND
Up to 25% of all cancer patients will develop brain metastases and prognosis remains poor. In preclinical work, we discovered that more than 50% brain metastases genomically diverge from primary tumors and harbor alterations in genes involved with cell cycle regulation. We thus initiated a phase II study to evaluate the efficacy and safety of the cyclin dependent kinase (CDK) 4/6 inhibitor, palbociclib, in patients with recurrent brain metastases with alterations in the CDK pathway (NCT02896335).

METHODS
The primary endpoint of the trial is the rate of intracranial benefit (defined as CR, PR, or SD, per RANO) at 8 weeks after the start of palbociclib. A Simon two-stage design was used to compare the rate of intracranial benefit for a null rate of 10% against an alternative of 30%. Fifteen patients were to be enrolled in the first stage. If fewer than 2 responders were observed, then the study would stop for insufficient evidence of efficacy. If 6 or more responders were observed among the total of 30, this treatment regimen would be considered worthy of further study. CSF, blood samples and tumor samples were collected to elucidate the genomic determinants of response to CDK inhibitors in the brain.

RESULTS
A total of 14 patients have been accrued (5 with breast cancer, 4 with melanoma, 3 esophageal and 2 with non-small cell lung cancer) thus far. One or more grade-3 or higher adverse events at least possibly related to treatment were seen in six (42%) patients, the majority being hematologic toxicities. At the time of the data analysis, eight (57%) patients had achieved intracranial benefit. Therefore, the study met primary endpoint.

CONCLUSIONS
In this unique, genomically-guided brain metastasis trial, we demonstrate that the CDK 4/6 inhibitor, palbociclib, is well-tolerated and has activity in patients with brain metastases.
COMP-03. QUANTITATIVE IMAGE FEATURE ANALYSIS IN DIFFUSE GLIOMA – A VALUABLE MR IMAGING BIOMARKER FOR PREOPERATIVE IDH MUTATION CLASSIFICATION
Authors: Carver Eric , Snyder James , Griffith Brent , Wen Ning 
Published: November 2019

Abstract

INTRODUCTION
Pre-operative differentiation of IDH mutant gliomas from similar appearing pathologies on imaging prior to definitive surgical diagnosis may aid treatment navigation, maximize the surgical approach, and provide diagnostic support for inoperable tumors. Quantitative image feature analysis offers a potential non-invasive method to identify diagnostic, prognostic, and predictive imaging biomarkers. We investigated the use of radiomic MR imaging features to classify tumors based on IDH mutation status.

METHOD
Pre-operative T1-weighted (T1W), T2-weighted (T2W), T1-contrast enhanced (T1CE), and fluid attenuated inversion recovery (FLAIR) MR brain images, along with patient IDH mutation status (mutant/wildtype) were obtained for 128 glioma patients from The Cancer Genome Atlas (TCGA). Enhancing tumor was delineated by GLISTRboost. GlistrBoost is a hybrid-discriminative model that segments tumors based on an expectation-maximization framework with a classification scheme and uses a probabilistic Bayesian strategy for segmentation refinement. MR studies for 78 glioma patients from six institutions were used for training and 50 glioma patients from a different institution were used for validation. Pre-processing included registration, resampling, and normalization. Cancer Imaging Phenomics Toolkit (CaPTK) extracted 938 radiomic image features per sequence for the enhancing tumor contour. Relevance of each individual feature was determined by the least absolute shrinkage and selection operator (LASSO). The ability of relevant radiomic image features to identify mutation status of IDH was assessed by logistic regression.

RESULTS
LASSO identified one highly informative radiomic imaging feature, the minimum of the mean absolute histogram deviation on T1 MR images, which was able to predict IDH mutation status with an accuracy of 0.74, precision of 1.0, and recall of 0.32.

CONCLUSION
Non-invasive prediction of IDH mutation status from pre-surgical MR images offers potential diagnostic, therapeutic, and prognostic benefits for glioma patients. Quantitative image feature analysis is a feasible method for identifying potential radiomic imaging features.
COMP-14. MOLECULAR PROFILING AND CELLULAR DECONVOLUTION OF GLIOBLASTOMA BRAIN TUMORS USING CHROMATIN RUN-ON AND SEQUENCING
Authors: Chu Tinyi , Rice Edward , Salamanca Hans , Wang Zhong , Longo Sharon , Corona Robert , Viapiano Mariano , Chin Lawrence , Danko Charles 
Published: November 2019

Abstract
Glioblastoma is among the most heterogeneous malignancies, making difficult the identification of clinically-relevant interactions between tumor cells and their supportive tumor microenvironment. Moreover, whether the heterogeneity of tumor cells is reflected by changes in the composition of the tumor microenvironment remains poorly defined. To further understand the cellular heterogeneity of GBM, we used our previously validated chromatin run-on and sequencing (ChRO-seq) method to analyze 61 GBMs from a retrospective cohort of patients banked at the State University of New York (Upstate Medical Center) between 1987 and 2007 (characteristics: Male:Female ratio= 2:1; median age at diagnosis= 59 years; median KPS=80; median overall survival= 343 days). We developed a new Bayesian statistical model that uses transcription at cell-type specific enhancers to identify the cellular composition of the tumor microenvironment in each patient. We validated our tool using simulations and scATAC-seq data from the same specimens, showing large improvements in sensitivity and accuracy compared with CYBERSORT. Integrative analysis of cellular composition and matching clinical data revealed correlations between the presence of specific cell types in the tumor mass and clinical variables. Finally, our analysis allowed us to identify transcription factors (e.g., NF-kB, C/EBPB) that control gene expression changes, revealing which cell types are controlled by each transcription factor in the GBM microenvironment. Our study uncovers new insights into the cellular heterogeneity of GBM and its impact on clinical progression and survival.
COMP-17. LARGE-SCALE TRANSCRIPTOMIC CHARACTERIZATION OF PRIMARY AND RECURRENT GLIOBLASTOMA IDENTIFIES GENE EXPRESSION SIGNATURE OF TUMOR RESPONSE TO STANDARD THERAPY
Authors: Dhawan Andrew , Lathia Justin , Peereboom David , Barnett Gene , Yeaney Gabrielle , Ahluwalia Manmeet 
Published: November 2019

Abstract
A near-universal phenomenon in glioblastoma is disease recurrence following surgical resection and chemoradiotherapy. Development of biomarkers predictive of therapeutic response to better guide care and inform future targeted therapies is crucial. In this work, a total of 84 glioblastoma surgical specimens involving 44 primary tumors and 40 matched samples at time of re-resection, were characterized utilizing RNA-sequencing. Transcriptomic analysis was carried out with the goal of identifying underlying differences between those patients with prolonged response to standard therapy and delayed time to re-resection. We examined individual gene expression, gene coexpression networks, and well-known gene pathways in this dataset that showed consistent association with time to re-resection in both primary and progressed specimens, independent of tumor molecular subtype. Leveraging this large, well-characterized dataset, and using a novel computational methodology based on a seed-gene approach, we identified a predictive gene signature for therapeutic response. Our analyses revealed a striking degree of heterogeneity among gene expression associated with response to standard therapy and time to re-resection, adding to the complexity of signature derivation. The novel signature we obtained for response showed components involving genes such as those in the IGF pathway (IGF2BP2, IGF2BP3) and PDGF-signalling pathway (MYC, FLI1, ARHGAP4, JAK3) predictive of poor response to therapy. Likewise, predictors of positive response to therapy included genes involved in the apoptosis and RAS pathways (RAB4A, CHUK) and DNA replication pathways (SSBP2). In sum, this is among the largest cohorts of well-characterized clinical tumor samples for which there is transcriptomic information from primary and re-resected samples from matched patients. Our results not only highlight an innovative computational method for gene signature derivation in the setting of significant underlying heterogeneity, but also result in a predictive gene signature, offering the potential to give therapy to those who stand to benefit most.
DDIS-02. DEVELOPMENT OF NOVEL SPRAY-TYPE FLUORESCENT PROBES FOR GLIOBLASTOMA DETECTION
Authors: Kitagawa Yosuke , Tanaka Shota , Kuriki Yugo , Yamamoto Kyoko , Nejo Takahide , Takahashi Satoshi , Nomura Masashi , Hana Taijun , Koike Tsukasa , Kushihara Yoshihiro , Yamazawa Erika , Takayanagi Shunsaku , Mukasa Akitake , Kamiya Mako , Urano Yasuteru , Saito Nobuhito 
Published: November 2019

Abstract
PURPOSE: ALA is commonly used as an intraoperative tool in malignant glioma surgery, which has been proven effective for radical tumor resection and extended progression-free survival. However, there are some limitations in its use, such as false positivity, false negativity, and inability of re-administration. We aim to develop a novel fluorescent labeling system which can be repeatedly administered by spray during surgery, using hydroxymethyl rhodamine green (HMRG) as fluorescent scaffold originally designed at our university for cancer detection. [Methods]Primary probe screening was performed using the homogenized glioblastoma (GBM) samples with the fluorescent probe library comprised of more than 320 kinds of HMRG fluorescent scaffold combined with various types of dipeptides. Second probe screening was performed using fresh GBM specimens and the selected probes in primary screening. To identify the responsible enzymes, diced electrophoresis gel (DEG) assay was performed. This method utilizes the combination of two dimensional electrophoresis (isoelectric point and molecular weight) and a multiwell-plate-based fluorometric assay to find protein spots with the specified activities. [Results] The prominent probes were selected based upon the above two-step screenings. We identified two enzymes by proteome analysis and experiments using inhibitors, which was further confirmed with real-time PCR and western blotting. [Discussion] This screening methodology is innovative in that it is based on selecting probes from the probe library that respond to clinical samples rather than creating probes from the responsible enzymes. Practical fluorescent probes can be established even for low-grade gliomas, which would be a breakthrough for rapid intraoperative diagnosis in glioma surgery. [Conclusion] HMRG-based aminopeptidase fluorescent probes may be effective for GBM detection.
DDIS-04. INTERFERON-β SENSITIZES HUMAN GLIOBLASTOMA CELLS TO THE CYCLIN-DEPENDENT KINASE INHIBITOR, TG02
Authors: Le Rhun Emilie , Lohmann Birthe , Epskamp Mirka , Weller Michael 
Published: November 2019

Abstract
Novel treatments for glioblastoma, the most common malignant primary brain tumor, are urgently needed. Type I interferons (IFN) are natural cytokines primarily involved in defense against viral infections, but may also play a role in the control of cancer, notably in the suppression of the cancer stem cell phenotype. TG02 is a novel orally available cyclin-dependent kinase 9 inhibitor which induces glioma cell apoptosis without profound caspase activation and is currently being explored in early clinical trials in newly diagnosed and recurrent glioblastoma. Here we used human glioma-initiating cell line models to explore whether IFN-β modulate the anti-glioma activity of TG02. Pre-exposure to IFN-β sensitized human glioma models to a variable extent to subsequent exposure to TG02. Combination treatment was associated with increased DEVD-amc cleaving activity that was blocked by BCL2. However, BCL2 did not protect from the synergistic effects of IFN and TG02 on glioma cell growth, furthermore, although IFN strongly induced pro-apoptotic XIAP-associated factor (XAF) expression, disrupting XAF expression did not abrogate the synergy with TG02 either. Consistent with that, caspase 3 gene silencing did not abrogate effects of TG02 or IFN-β alone or in combination. Finally, we observed that IFN-β may indeed modulate the effects of TG02 up-stream in the signaling cascade since inhibition of RNA polymerase II phosphorylation, a direct readout of TG02 pharmacodynamic activity, was facilitated in glioma cells pre-exposed to IFN-β. In summary, these data suggest that type I IFN may be combined with TG02 to limit glioblastoma growth but the well characterized effects of IFN and TG02 on apoptotic signaling are dispensable for synergistic control of tumor growth. Instead, exploring how IFN signaling primes glioma cells for TG02-mediated direct target inhibition may help to design novel, more effective pharmacological approaches to glioblastoma.
DDIS-25. PENTAMIDINE; A NEW CHEMOTHERAPY TARGETING ON GLIOMA STEM LIKE CELLS
Authors: Tamai Sho , Jiapaer Shabierjiang , Zhang Guangtao , Zhang Jiakang , Wang Yi , Sabit Hemragul , Tanaka Shingo , Kinoshita Masashi , Hirao Atsushi , Nakada Mitsutoshi 
Published: November 2019

Abstract

INTRODUCTION
Glioblastoma (GBM) is the most common primary malignant brain tumors. Despite aggressive therapies, median overall survival of patients who suffered from GBM is only 18 months. Furthermore, there is no effective therapy for glioma stem cells (GSCs), which act as forming tumors. Herein, we newly identified pentamidine, an antiprotozoal drug, is effective for GSCs by using drug repositioning approach.

METHOD
We used patient-derived glioma stem like cell lines KGS01, KGS07 which were established at Kanazawa University. We investigated proliferation ability, stemness and intracellular signal change by proliferation assay, sphere forming assay and western blotting, respectively. RESULT: Proliferation ability was prohibited by pentamidine in both cell lines. The half maximal inhibitory concentration was 1 - 5 μM. Sphere forming assay revealed that size and number of spheres were reduced in both cell lines, depending on concentration of pentamidine. Phosphorylation of extracellular signal-related kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) were suppressed by pentamidine.

DISCUSSION
Pentamidine is known as the therapeutic drug for pneumocystis jirovecii. In this study, pentamidine suppressed proliferation activity and stemness in both glioma stem cell lines. Previous papers revealed pentamidine had anti-tumor effects for some types of tumor cell lines, however, therapeutic effect for tumor stem cells have never been mentioned.

CONCLUSION
These results suggest that pentamidine would be therapeutic drug for GSCs by suppressing phosphorylation of ERK and STAT3.
DDIS-36. BTP-7, A NOVEL PEPTIDE FOR THERAPEUTIC TARGETING OF MALIGNANT BRAIN TUMORS
Authors: von Spreckelsen Niklas , Ghotmi Yarah , Fadzen Colin , Wolfe Justin , Hartrampf Nina , Bergmann Sonja , Qu Yuan , Murrell Emily , Bononi Fernanda , Luyt Leonard , Lamfers Martine , Ligon Keith , Chiocca Ennio , Viapiano Mariano , Pentelute Bradley L , Lawler Sean , Cho Choi-Fong 
Published: November 2019

Abstract
High-grade gliomas are deadly cancers, and current standard-of-care has demonstrated limited success. The ability to specifically target glioma cells allows for the development of safer and more efficacious brain cancer therapy strategies. Brevican, a CNS-specific extracellular matrix protein is upregulated in glioma cells and its expression correlates with tumor progression. Particularly, a brevican isoform lacking glycosylation, B/bΔg is a unique glioma marker and not expressed in non-cancerous tissues. Therefore, B/bΔg represents a valuable target for anti-cancer strategies. Here, we describe the utilization of state-of-the-art platforms to screen a one-bead-one-compound combinatorial peptide library to discover a novel “B/bΔg-Targeting Peptides”, called BTP-7 that can bind B/bΔg with high affinity and specificity. BTP-7 displayed 260 nanomolar affinity for recombinant B/bΔg protein. Binding to a specific site on B/bΔg was confirmed in a competitive binding assay using BTP-7 functionalized with a UV-crosslinker and BTP-7 had little association with the fully glycosylated isoform of brevican (control). Scrambling of the BTP-7 sequence led to complete abrogation of B/bΔg binding. Furthermore, BTP-7 is preferentially taken up by B/bΔg-expressing glioma cells compared with non-expressing cells. We also discovered that BTP-7 can cross the blood-brain barrier in both the in vitro BBB organoid model and in mice. BTP-7 displayed 10x greater binding to intracranial GBM-6 tumors than control peptides, and 4x higher tumor uptake than in normal brain tissues. Conjugation of BTP-7 to camptothecin (an anti-tumor drug) via a cleavable linker led to increased DNA damage in intracranial GBM-6 tumors and prolonged survival in tumor-bearing mice. Our results show the potential of BTP-7 for the development of next-generation targeted therapeutics that could greatly benefit the outcome of patients with advanced brain cancer.
EPID-03. HISTOLOGY-SPECIFIC BRAIN TUMOR INCIDENCE AND SURVIVAL VARIES BY SEX
Authors: Dong Michelle , Cioffi Gino , Kruchko Carol , Ostrom Quinn , Lathia Justin , Rubin Joshua , Berens Michael , Connor James , Barnholtz-Sloan Jill 
Published: November 2019

Abstract

BACKGROUND
Significant sex differences exist in cancer, and males have higher incidence and lower survival compared to females for most cancers. No large-scale studies have systematically examined sex differences in incidence and survival across all primary brain histologies. We performed a comprehensive investigation of the differences in incidence and survival in patients diagnosed with primary malignant brain and other CNS tumors by specific histologies.

METHODS
Age-adjusted incidence rate ratios (IRR) and 95% confidence intervals (945% CI) were generated from the United States Cancer Statistics (USCS) Public Use Database. Data from the Surveillance, Epidemiology, and End-Results (SEER) program were used to calculate overall survival. Data was restricted to patients with histologically or radiologically confirmed, primary malignant tumors diagnosed between 2001 and 2015. Histological groupings were categorized based on the Central Brain Tumor Registry of the United States (CBTRUS). Cox proportional hazards models were used to calculate hazard ratios (HR) adjusted for age for males as compared to females.

RESULTS
Males exhibited higher incidence than females in all brain histologies except meningioma (IRR=0.83; 95% CI 0.73–0.93) and other neuroepithelial tumors (i.e. polar spongioblastomas and astroblastomas) (IRR=0.48; 95% CI 0.26–0.88). Males experienced better overall survival in germ cell tumors, cysts and heterotopias (HR=0.68; 95% CI 0.49–0.94) compared to females, but were observed to have lower survival in all other histologies. Survival was lowest for males among patients with nerve sheath tumors (HR=2.32; 95% CI 1.31–4.12) and other neoplasms related to the meninges (e.g. chondrosarcomas and chordomas) (HR=2.23; 95% CI 1.24–3.99). Survival in meningioma patients was significantly higher in females (HR=1.49; 95% CI 1.25–1.77). Patients with glioblastomas, had a slightly worse survival outcome in males (HR=1.02, 95% CI 1.00–1.05).

CONCLUSION
Understanding the role of sex differences is critical for addressing sex based inequalities and needs to be taken into account in clinical paradigms.
EPID-09. PROGNOSTIC FACTORS IN ADULT PATIENTS WITH PRIMARY INTRACRANIAL EPENDYMOMAS: A POPULATION-BASED STUDY
Authors: Yang Helen , Malik Abdullah , Das Sunit 
Published: November 2019

Abstract

BACKGROUND
Outcomes for patients with intracranial ependymoma remain poor in the current era of cancer treatment. This study aims to investigate the prognostic value of demographic and clinical variables to predict survival using the largest current database of patients with intracranial ependymoma.

METHODS
The Surveillance, Epidemiology and End Results (SEER) registry was queried for prognostic factors and survival outcomes of adult (≥18 years) patients diagnosed with intracranial ependymoma from 2004–2016. Survival was estimated using Kaplan Meier curves. Cox proportional hazards modeling was used to identify correlates of survival.

RESULTS
We identified a cohort of 229 primary intracranial ependymoma patients. The cohort showed a slight male predominance (52%) and had a mean age of 43 ± 17 years. 107 patients (47%) had WHO grade II tumors and 122 patients (53%) had WHO grade III tumors. One year survival was 85% for the entire cohort. Increasing age at diagnosis (HR: 1.05, 95% CI: 1.03–1.07) and WHO grade III tumor (HR: 4.20, 95% CI: 2.02–8.75) were independently associated with mortality after adjusting for age, sex, tumor location, extent of surgery, use of radiation therapy, and use of chemotherapy. Use of radiation therapy was associated with better one-year survival in cases of gross total resection (GTR) and subtotal resection (STR). Use of chemotherapy was not associated with mortality in the adjusted analysis (HR: 2.16, 95% CI: 0.96–4.84).

CONCLUSION
Our results suggest that age at diagnosis and tumor grade are independent factors associated with mortality in adult patients with intracranial ependymoma. Furthermore, use of chemotherapy was not shown to decrease mortality. These findings help guide future prognostic model making and therapeutic strategies designed by health care professionals.