tbuckley/cabot-search huggingface dataset:
ATIM-13. ASUNERCEPT PLUS RADIOTHERAPY IN RELAPSED GLIOBLASTOMA. UPDATE ON FIVE YEARS OVERALL SURVIVAL OF STUDY NCT01071837 AND DEVELOPMENT OF A POPULATION-PK - TUMOR GROWTH INHIBITION - SURVIVAL MODEL
Authors: Harald Ficke, Nina Hanke, Claudia Kunz, Wolfgang Wick, Thorsten Lehr
Journal: Neuro-Oncology (2018)

Asunercept (APG101) is an Fc-fusion protein consisting of the extracellular domain of human CD95 (APO-1/Fas) and the Fc domain of IgG1. Asunercept is in clinical development for glioblastoma (GB). Based on PK-data from study NCT01071837 a population pharmacokinetic (PopPK) - tumor growth inhibition (TGI) model was developed and extended to a survival model describing the effect of radiotherapy (RT) or RT + asunercept on the overall survival (OS) of GB-patients. The objective of the model was to identify the best descriptor (i.e. asunercept exposure, tumor size determined by MRT) for survival and to quantify the effect of CpG2 methylation in the CD95 ligand promoter on patient survival. Model development was performed using non-linear mixed effects modeling with NONMEM 7.3 in a stepwise procedure. Firstly, a PopPK–TGI model was developed. Several tumor growth models were tested (e.g. exponential, sequential exponential-linear). Secondly, a survival model was developed and linked to the PopPK-TGI model. For the PopPK-TGI model, data from 84 patients were available contributing to 314 tumor measurements. Glioblastoma growth was best described by an exponential growth model with an average doubling time of 90 days. Asunercept exposure showed a significant inhibitory effect on the tumor growth rate. Tumor size was identified to significantly influence survival. Incorporation of CpG2 CD95L promotor methylation further improved the model: the survival in asunercept-treated patients was prolonged with lower CpG2 methylation status. A PopPK-TGI-Survival model for asunercept and radiotherapy treated patients was developed. A clear inhibitory effect of asunercept exposure was observable on tumor growth resulting in an increased survival. A recent update on OS of study NCT01071837 revealed that 7% of Asunercept+RT treated 2nd-line GB patients were alive after 5 years compared to 0% in patients treated with RT alone.
New Treatment for Certain Types of Leukemia and Lymphoma
Authors: Rebecca Voelker
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
CSIG-04. A REQUIREMENT FOR RIOK2 CATALYTIC ACTIVITY IN RTK-PI3K DEPENDENT GLIOBLASTOMA
Authors: Nathaniel Boyd, Alexander Chen, Jhomar Marquez, Renee Read
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is a particularly lethal brain neoplasm that accounts for half of malignant and fifteen percent of all primary brain tumors diagnosed in adults. These statistics elevate GBM to a priority in neuro-oncology research, but the tumors remain incurable with an exceptionally poor median survival of fifteen months after diagnosis. In order to promote targeted therapy development, there are ongoing efforts to understand GBM at a molecular level, which involve characterization of these tumors via their transcriptional and mutational profile. Recent studies indicate aberrations in receptor tyrosine kinase (RTKs), including EGFR and PDGFRA, and the Pi-3 kinase (PI3K) signaling pathways are major drivers of tumorigenesis in GBM. Using a Drosophila melanogasterGBM model to locate downstream targets of these pathways, our laboratory has identified right open reading frame 2 (RIOK2) serine-threonine kinase as a downstream effector of aberrant RTK-PI3K signaling in glial tumorigenesis. Subsequent follow-up studies indicate that RIOK2, which is overexpressed in RTK mutant human GBMs, drives survival and proliferation of RTK-PI3K-dependent human GBM cells. In order to understand how RIOK2 functions to promote tumorigenesis through RTK-PI3K signaling, we used a chemical genetics approach in both Drosophilaand cultured human GBM cells to test the effects of catalytic inhibition of RIOK2 in tumorous glia as well as normal glia to find that RIOK2 catalytic activity is essential for the growth of tumor cells, but dispensable for the growth of normal glia. However, the substrates of RIOK2 are unknown. Therefore, through a combination of proteomic and genetic approaches, we are currently seeking to identify potential targets of RIOK2 catalytic activity. Together, our data indicate a role for RIOK2 in promoting GBM tumorigenesis and our ongoing studies reveal an important tumor-specific target signaling pathway for consideration in experimental therapeutics.
CSIG-46. DEVELOPMENT OF A NOVEL GLIOBLASTOMA MODEL TO STUDY THE ROLE OF NOX4 IN DISEASE PATHOGENESIS
Authors: Levi Adams, Yoon-Seong Kim
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM), a cancer of the glial cells in the brain, is the most common and aggressive primary brain tumor and even with aggressive and invasive treatment only has a median survival of about a year. The reactive oxygen species producing NADPH Oxidase 4 (NOX4) has been shown to be significantly increased in GBM and patients with high NOX4 expression have shown reduced progression-free survival. However, the molecular mechanism underlying the functional role of NOX4 in this disease is largely unknown. To study this, we have developed a novel in vivo model of GBM in WT and GFAP-specific NOX4 KO background by injecting a single Cre-inducible lentiviral vector targeting multiple pathways reported in human GBM (classical subtype). This approach allows us to faithfully model the complex contextual signaling events that drive the human pathology, providing a clear picture of relevant pathways and to generate in vivo and in vitro models that phenocopy the human disease. Our preliminary data indicates that NOX4 blockade prevents glioma stem cell (GSC) differentiation, reduces proliferation, induces cell death and slows disease progression, in part through the PI(3)K/Akt signaling pathway. Elucidation of the NOX4 pathway in GBM will improve our understanding of the cellular signaling mechanisms driving this disease and may offer new therapeutic avenues.
PATH-28. THE NATURAL HISTORY OF BRAF V600E-MUTATED GLIOBLASTOMAS IN ADULTS
Authors: Karisa Schreck, Elizabeth Vera, Orwa Aboud, Alvina Acquaye, Lisa Boris, Nicole Briceno, Miranda Brown, Hye-Jung Chung, Sonja Crandon, Nancy Garren, Ming Ji, Jason Levine, Snehal Patel, Martha Quezado, Mark Raffeld, Jennifer Reyes, Carlos Romo, Christine Siegel, Brett Theeler, Liqiang Xi, Mark Gilbert, Stuart Grossman, Terri Armstrong, Jing Wu
Journal: Neuro-Oncology (2018)

BRAF V600E-mutations are rare but noteworthy in primary brain tumors given their potential as a targetable mutation and the lack of efficacious therapies for glioblastoma. BRAF V600E mutations may serve as a prognostic marker in pediatric and low-grade gliomas, and are associated with improved survival in young adults with glioblastoma; however, its prognostic significance in adults >35 years is uncertain given the very small number of patients evaluated to date. Patients aged >18 with WHO III-IV glioma and a BRAF V600E mutation were identified from the National Institutes of Health, the Johns Hopkins Hospital, and a previous publication (PMID:27503138). Paired control cases were identified at each institution based on age, sex, degree of resection, performance status at diagnosis/first encounter, MGMT and IDH status, and first-line treatment. Log-rank test was used to compare survival curves. The present cohort consisted of 23 patients (6 from each institution and 11 from a published cohort) with median age of 39 (range 20–70 years), 78% female, and 87% with a glioblastoma diagnosis. No tumors had an IDH mutation. 39% of patients were aged >50 years. All but one were treated with radiation and temozolomide at diagnosis (exception went into hospice and died shortly thereafter). The median overall survival was 33.4 ± 8.4 months in all patients. For 13 patients aged 35 or older, median survival was 34.5 ± 12.1 months compared to 18.0 ± 3.0 months in case-matched controls (p=0.03). Two patients were treated with dabrafenib and trametinib; one is still on therapy (26 months), the other progressed after 8 months. CONCLUSIONS: Adults aged >35 with BRAF V600E mutation may have improved survival compared with matched controls, similar to results in young adults. BRAF V600E mutations occur in patients with glioblastoma aged >50 years and testing in this population should be considered as well.
Active vaccination against interleukin‐5 as long‐term treatment for insect‐bite hypersensitivity in horses
Authors: Antonia Fettelschoss‐Gabriel, Victoria Fettelschoss, Florian Olomski, Katharina Birkmann, Franziska Thoms, Maya Bühler, Martin Kummer, Andris Zeltins, Thomas M. Kündig, Martin F. Bachmann
Journal: Allergy (2018)

Insect-bite hypersensitivity (IBH) in horses is a chronic allergic dermatitis caused by insect bites. Horses suffer from pruritic skin lesions, caused by type-I/type-IV allergic reactions accompanied by prominent eosinophil infiltration into the skin. Interleukin-5 (IL-5) is the key cytokine for eosinophils and we have previously shown that targeting IL-5 by vaccination reduces disease symptoms in horses.Here, we analyzed the potential for long-term therapy by assessing a second follow-up year of the previously published study.The vaccine consisted of equine IL-5 (eIL-5) covalently linked to a cucumber mosaic virus-like particle (VLP) containing a universal T cell epitope (CuMVTT ) using a semi-crossover design to follow vaccinated horses during a second treatment season. Thirty Icelandic horses were immunized with 300 μg of eIL-5-CuMVTT without adjuvant.The vaccine was well tolerated and did not reveal any safety concerns throughout the study. Upon vaccination, all horses developed reversible anti-eIL-5 auto-antibody titers. The mean course of eosinophil levels was reduced compared to placebo treatment leading to significant reduction of clinical lesion scores. Horses in their second vaccination year showed a more pronounced improvement of disease symptoms when compared to first treatment year, most likely due to more stable antibody titers induced by a single booster injection. Hence, responses could be maintained over two seasons and the horses remained protected against disease symptoms.Yearly vaccination against IL-5 may be a long-term solution for the treatment of IBH and other eosinophil-mediated diseases in horses and other species including humans.
EXTH-58. ONC206, AN IMIPRIDONE FAMILY MEMBER, SUPPRESSES GLIOBLASTOMA CELLS VIA BLOCKING CANCER STEMNESS PATHWAYS
Authors: Jinkyu Jung, Tyrone Dowdy, Emeline Tabouret, Brent Reynolds, Joshua Allen, Mioara Larion, Mark Gilbert, Deric Park
Journal: Neuro-Oncology (2018)

Imipridones selectively target G protein-coupled receptors (GPCRs) that control critical signaling pathways in various cancer cells. Aberrant overexpression of GPCRs has been implicated in tumorigenesis. ONC201, a first generation imipridone that directly antagonizes dopamine receptor D2 (DRD2), continues to be evaluated in clinical trials for advanced cancers. The immediate downstream mechanism(s) of DRD2 inhibition and resulting anti-cancer activity remains an area of active study. METHODS & ONC206, an analog of ONC201, shares the same imipridone core chemical structure and selective antagonism of DRD2, potently inhibits treatment-resistant glioblastoma caused by intra-tumoral heterogeneity with clinically achievable concentrations. In silico analysis of a glioma patient database revealed that alteration of DRD2 mRNA expression was directly connected to global gene expression change. Imaging DRD2 expression by immunofluorescence demonstrated heterogeneous expression of DRD2 in the glioblastoma cells. After DRD2 inhibition, global metabolite profiling in patient-derived glioblastoma stem cells (GSCs) compared with differentiated glioblastoma cells (DGCs) demonstrated globally differential effects in their cellular signaling pathways. Cell viability assay showed that exposure to ONC206 in a dose dependent manner preferentially eliminated GSCs with 50 to 200 nM of IC50 ranges, whereas the IC50 of DGCs ranged from 200 to 1000 nM. In vitro limiting dilution and sphere formation assay showed that ONC206 prevented tumor sphere formation and tumor growth. ONC206 down-regulated protein expression of cancer-related stem cell markers in the GSCs; silencing DRD2 expression confirmed the dependency of DRD2 expression on cancer stem cell niches in glioblastoma. ONC206 treatment displays the differential effects on glioblastoma cells, more selectively targeting DRD2 in GSCs (at nanomolar concentrations) compared with DGCs in culture and in xenograft models. This suggests that a therapeutic strategy targeting DRD2-expressing GSCs within glioblastoma may be beneficial for overcoming the therapeutic resistance.
TMIC-54. THE IMPACT OF GLIOMA CANCER CELL STEMNESS ON EXOSOME PHENOTYPE
Authors: Oliver Mrowczynski, A B Madhankumar, Jeffrey Sundstrom, Yuanjun Zhao, Yuka Imamura-Kawasawa, Becky Slagle-Webb, Elias Rizk, Brad Zacharia, James Connor
Journal: Neuro-Oncology (2018)

Glioblastoma is the most common central nervous system malignancy in adults with a median survival of only 14 months. The current arsenal of treatment modalities including surgical resection and combination chemoradiation have been largely ineffective. One reason proposed for the ineffectiveness of our current therapeutic regimen is the resistance of glioma stem cells (GSCs) within the tumor and tumor borders. We investigated the hypothesis that the communication of GSCs to their microenvironment through exosomes is a key factor underlying the enhanced cellular proliferation and the development of resistance to therapeutics. Exosomes are nanometer sized vesicles released by cancer cells that contain DNA, RNA, and protein critical to the interaction of a cell with its microenvironment. Two properties of exosomes were analyzed: 1) exosome function and 2) exosome profile. Exosomes secreted by patient derived-glioma stem cells (GSC-exosomes) increased cellular proliferation, radiation resistance, temozolomide resistance, and doxorubicin resistance. We further profiled the GSC-exosomes to begin to probe the underlying mechanism of this phenomenon. Profiling showed specific changes to RNA and protein favoring therapeutic resistance and cellular proliferation. For example, GSC exosomes have increased expression of proteins involved in radiation and chemotherapeutic resistance (Ex. CDK4 and Notch), cellular proliferation (Ex. Cyclin B1 and Cyclin D2), angiogenesis (Ex. VEGF-A and EGFR), glioma cell stemness and de-differentiation (Ex. EPHA2, Cathepsin B), and cell invasion and metastasis (Ex. ITGA3, COL4A2). The results of our study suggest a novel exosome-based mechanism by which glioma stem cells alter therapeutic resistance and increase cellular proliferation. TUMOR MODELS
NIMG-72. A NOVEL ARRAY LAYOUT FOR DELIVERING TTFIELDS TO THE WHOLE BRAIN
Authors: Ofir Yesharim, Ariel Naveh, Zeev Bomzon
Journal: Neuro-Oncology (2018)

INTRODUCTION: Tumor Treating Fields (TTFields) is an antimitotic cancer treatment approved for the treatment of Glioblastoma Multiforme. TTFields are delivered using 2 pairs of transducer arrays. When treating Glioblastoma, the array positioning on the head is planned to maximize TTFields dose delivered to the tumor. This results in an increased dose of TTFields at the tumor, whilst reducing the intensity of the field in other regions. In some clinical scenarios, such as treatment of multiple brain metastases, it might be desirable to deliver TTFields at therapeutic intensities to the entire brain, thereby ensuring that even microscopic lesions receive a therapeutic dose of TTFields. Here we present novel transducer array layouts designed to deliver a uniform distribution of TTFields to the entire brain. Methods Computer simulations were used to calculate the field distributions generated by different array layouts. The simulations utilized a realistic computerized head model of a 40+ years old human mal. Delivery of TTFields using pairs of array layouts placed at different locations on the head and neck was simulated using Sim4Life V3.0 (ZMT Zurich). To analyze the field distributions, the brain was divided into five regions: 1) the cerebellum, brain stem and other infra-tentorial anatomical regions; 2–5) four quadrant of the cerebrum. The mean and median field intensities in the five regions generated by each layout were calculated and compared. Results A layout in which one pair of arrays is placed on the right temple, and left scapula and the second pair placed on the left temple and right scapula yielded a uniform intensity distribution within the brain. (median intensities between 1.5 V/cm to 1.7 V/cm within all regions). Conclusion We have identified a novel TTFields array layout that will be beneficial in clinical scenarios where treatment of the entire brain with TTFields is desired.
NIMG-44. QUANTITATIVE MULTI-PARAMETRIC IMAGE PROFILING REVEALS REMARKABLE HETEROGENEITY WITHIN IDH-WILDTYPE GLIOBLASTOMA, OFFERING PROGNOSTIC STRATIFICATION BEYOND CURRENT WHO CLASSIFICATIONS
Authors: Saima Rathore, Hamed Akbari, MacLean Nasrallah, Spyridon Bakas, Zev Binder, Martin Rozycki, Sung Min Ha, Elizabeth Mamourian, Michel Bilello, Donald O’Rourke, Christos Davatzikos
Journal: Neuro-Oncology (2018)

PURPOSE: The current WHO classifies astrocytomas by IDH mutational status given the significantly poorer prognosis of IDH-wildtype tumors, representing ~95% of de novo glioblastoma. Our previous studies revealed remarkable heterogeneity of these tumors, dividing them in three distinct radiographic subtypes (Rad-S). In this study, we hypothesize that this heterogeneity expands in Rad-S within IDH-wildtype glioblastoma, subdividing them further according to prognosis. We analyzed pre-operative multi-parametric magnetic resonance imaging (mpMRI) data (T1,T1-Gd,T2,T2-FLAIR,DTI,DSC) of a retrospective cohort of pathology-proven de novo IDH-wildtype glioblastoma (n=76). Comprehensive quantitative imaging phenomic (QIP) features were extracted from distinct cancerous sub-regions (enhancing, non-enhancing, edematous), using the Cancer Imaging Phenomics Toolkit (CaPTk-www.cbica.upenn.edu/captk). QIP features comprised intensity histogram, volumetric, morphological, statistical, and textural descriptors. Unsupervised clustering of these features alone revealed tumor Rad-S, based on unambiguous clustering assignments across 1000 permutations, that were evaluated through survival and molecular characteristics. Three Rad-S were identified within IDH-wildtype glioblastoma, with statistically significant survival differences (long-:intermediate-:short-survival, median(months)=19.4:12.3:7.0, distribution=19.7%:34.2%:46.1%) measured by Kaplan-Meier analysis (P<0.001,log-rank) and Cox-Model (hazard-ratio=3.21,95%CI:2.51–4.61). Rad-S correlate with survival independent of age, resection-status, post-surgical therapy, additional genetic alterations, and MGMT promoter methylation status. Importantly, long-survival Rad-S, compared to others, showed statistically significant (P<0.001,Kruskal-Wallis) central hypo-intense non-enhancing region surrounded by hyper-intense rim (T1-Gd), lower angiogenesis/neovascularization (DSC) and cell-density (DTI), and higher water concentration (T2). CONCLUSIONS: Quantitative analysis of mpMRI yields three distinct Rad-S within IDH-wildtype glioblastoma offering complementary stratification beyond current WHO classification, which is independent of any factor known to affect prognosis. These Rad-S provide an additional prognostic indicator as a component of precision diagnostics that may impact choice/timing of surgery, chemotherapy, bevacizumab and radiation, allowing personalized treatment. Further, our current understanding in clinical setting is insufficient to explain prognostic differences among the Rad-S. These results provide guidance for ongoing investigation to elucidate pathologic mechanism and consequently targeted therapeutic strategies.
RDNA-10. HISTOPATHOLOGICAL AND GENOMIC CHARACTERIZATION OF GLIOBLASTOMA (GBM) RESECTED AFTER TUMOR TREATING FIELDS (TTFIELDS) THERAPY
Authors: Sharon Michelhaugh, Sam Kiousis, Sandeep Mittal
Journal: Neuro-Oncology (2018)

TTFields are FDA-approved for treatment of newly-diagnosed and recurrent glioblastoma. In this study, GBMs from one patient pre- and post-TTFields monotherapy were analyzed by immunohistochemistry (IHC) and array comparative genomic hybridization (aCGH) to examine potential TTFields-induced alterations. Pre-TTFields (insular) and post-TTFields (anterior temporal and insular) GBMs were collected from a 38-yo male patient one year apart. Formalin-fixed tissues were studied by IHC utilizing the Vectastain ABC Elite kit (Vector Labs). Extracted DNA from GBMs was quantified and aCGH performed with Agilent SurePrint arrays (G3 ISCA CGH+SNP 180K) using a commercially-available, genetically-normal DNA standard. Bioinformatic analysis was performed with Agilent CytoGenomics Edition 2.5.8.1. Both pre- and post-TTFields tumors had mutated IDH1 and unmethylated MGMT promoter. Ki-67 stained 20–25% of tumor cells in the pre-treatment tumor, and 10–15% in the post-treatment insular tumor. CD133 staining was strong in the pre-treatment tumor with >50% cells stained, while CD133 staining in both post-treatment tumors was reduced in intensity and percent cells stained (<50%). MGMT intensity and number of stained cells was similar across all specimens. Overall, the aCGH analysis identified a small number of copy number gains in all three specimens, with far greater copy number losses. One notable difference between the pre- and post TTFields samples was a loss of the cytoband 13q12.12-q14.3 that was not found in the pre-treatment tumor (log2 fold change=-0.7496 to -0.8628; p=1.41E-283). This cytoband contains tumor suppressor genes retinoblastoma 1 (RB1) and breast and ovarian cancer susceptibility protein 2 (BRCA2). CONCLUSIONS: GBM specimens demonstrated reduced staining for Ki-67 and the stem cell marker CD133, and losses of RB1 and BRCA2 after TTFields therapy. Further studies are warranted as it is uncertain if these represent TTFields-induced changes, or typical GBM evolution.