tbuckley/cabot-search huggingface dataset:
EXTH-30. THERAPEUTIC BENEFIT OF A KETOGENIC DIET THROUGH ALTERED GUT MICROBIOTA IN A MOUSE MODEL OF GLIOMA
Authors: Braden McFarland, Kory Dees, Nathalia Melo, Samuel Fehling, Sara Gibson, Zhaoqi Yan, Ranjit Kumar, Casey Morrow, Etty Benveniste
Journal: Neuro-Oncology (2017)

Like many cancers, glioma cells have an altered metabolic state and utilize glycolysis even in the presence of oxygen, and thus require a large amount of glucose. The ketogenic diet is a high fat, low carbohydrate, low protein diet that limits the amount of glucose, and theoretically starves tumor growth. In addition, recent reports have indicated that the gut microbiome can influence tumor growth as well as the effectiveness of certain therapeutic agents. In this study, we sought to determine if the ketogenic diet is an effective treatment for glioma, and to correlate changes in the healthy gut bacteria in response to the ketogenic diet. In an orthotopic mouse model of glioma, we found that mice fed the ketogenic diet had slightly increased survival compared to mice fed a normal diet. Comparing the composition of gut bacteria from animals on normal versus ketogenic diets, we found significant differences in several key microbes. Interestingly, we observed that there were several long-term ketogenic survivors implanted with intracranial tumors and displayed a significant increase in the percentage of microbes found in the murine gastrointestinal tract (F. rodentium and related microbes). We found that F. rodentium growth does not occur until day 21 on the diet; thus, F. rodentium could be introduced early as a probiotic and enhance anti-tumor effects of the ketogenic diet. Additionally, we found that the ketogenic diet increased the percentage of mature Th17 cells, potentially collaborating with the growth of F. rodentium to decrease tumor growth. No studies have ever evaluated a probiotic for therapeutic efficacy in glioma. As the ketogenic diet is very strict, and can negatively affect quality of life, a ketogenic-diet probiotic (healthy gut bacteria, similar to the probiotics in yogurt) may offer an alternative supplement and patients could possibly eat a modified (less strict) ketogenic diet.
TMOD-44. HGF-AUTOCRINE ACTIVATION OF MET RECEPTOR TYROSINE KINASE INDUCES DE NOVO GLIOMA FORMATION IN MICE
Authors: Jianqun Kou, Johanna Preiszner, Jennifer Johnson, Barbara Tschida, Benjamin Staal, Liang Kang, Kirk Tanner, John Schweitzer, David Largaespada, Qian Xie
Journal: Neuro-Oncology (2017)

Genomic profiling of glioblastoma (GBM) has identified 4 molecular classifications, with the mesenchymal subtype as the most invasive phenotype resulting in short survival. The Met oncogene activation leads to invasive tumor growth and is a mesenchymal marker. Within the same GBMs, elevated MET activation is often accompanied by an increased expression of hepatocyte growth factor (HGF), suggesting a ligand-dependent activation of MET via an HGF-autocrine loop formation. While HGF-autocrine activation is considered a molecular feature determining the vulnerability to MET inhibitors, whether it is causal to glioma initiation is elusive. In this study, using a well-established Sleeping Beauty transposon strategy, we show that mixed injection of human Hgf and Met DNA together with a short hairpin siRNA against p53 into the lateral ventricle of neonatal mice results in de novo glioma formation with invasive phenotypes that resembles human GBM pathology. While neural stem cells (NSC) are hypothetically considered the cell of origin of GBM, the glioma spheres harvested from the tumor models expressed nestin, GFAP, and Sox 2, the markers of NSCs. When transplanted, these neurosphere cells also initiated tumors in mice that were suppressed by a MET small molecule inhibitor. Our results suggest that constitutively MET activation by HGF-autocrine loop may transform NSCs into glioma initiating cells that ultimately result in GBM formation. While Met inhibitors are being evaluated in clinical trials against multiple cancer types, our genetically engineered glioma mouse model driven by human HGF-autocrine activation (SB-hHgf/Met) provides a great tool for studying GBM tumor biology and MET targeting therapeutics.
Locoregional administration of replication-competent retrovirus vector achieves multifocal tumor-restricted propagation and transduction in an immunocompetent model of metastatic colorectal cancer
Authors: Kei Hiraoka, Takahiro Kimura, Christopher Logg, Noriyuki Kasahara
Journal: Cancer Research (2006)

2985   Colorectal cancer is still one of the leading causes of cancer-related death, and the liver is the most common site of distant metastasis. Many patients present with unresectable multifocal metastases, and adjuvant chemotherapy has had limited success. We are currently developing murine leukemia virus (MLV)-based replication-competent retrovirus (RCR) vectors, which have been demonstrated to achieve efficient and progressive gene transfer in vivo in immunodeficient xenograft models of breast cancer, prostate cancer, and glioma. Compared to other replicating oncolytic viruses, RCR vectors have the unique property of propagating only in actively dividing cells and establishing stable integration in the infected tumor cell genome, which may allow more persistent expression of therapeutic genes such as immunostimulatory cytokines, anti-angiogenic factors, tumor suppressors, and suicide genes. In the present study, the transduction efficiency and replication kinetics of an amphotropic RCR vector (ACE-GFP) carrying the green fluorescent protein (GFP) marker gene was first quantitated in human (WiDr) and murine (CT26) colon cancer cell lines in vitro, by flow cytometric monitoring of GFP transmission. In both cell lines, after ACE-GFP inoculation at low multiplicity of infection (MOI=0.1), the percentage of GFP-positive cells increased rapidly from approximately 10% to >90% within 9 to 11 days. Next, we established a hepatic metastasis model of colorectal cancer by intrasplenic injection of CT26 cells in syngeneic Balb/c mice. After tumor establishment, a total dose of 1 x 10e4 transducing units (TU) of ACE-GFP virus was administered by locoregional infusion via the splenic vein, and the GFP expression was examined by fluorescence imaging. By 4 weeks post-vector infusion, significant increases in the intensity and area of GFP expression were observed in multiple tumor sites. Infected tumors were also digested with collagenase and immediately examined by flow cytometry for more precise quantitation. The level of transduction in the CT26 tumors increased significantly from an average of 9% at 2 weeks to over 53% by 4 weeks post-vector infusion. However, no detectable GFP expression was observed in adjacent normal liver by fluorescence imaging or immunohistochemistry, nor could the vector be detected by genomic PCR in any other normal tissues, including bone marrow, intestine, lung, and kidney. Our results thus demonstrate that RCR vectors can efficiently replicate and achieve significant levels of multifocal tumor transduction even in immunocompetent hosts, and may represent a highly suitable vehicle for delivering therapeutic genes selectively to metastatic tumor cells in the liver by locoregional administration, while sparing normal hepatocytes and other normal tissues.
SCDT-31. ATF5 IS A NEW TARGET FOR GLIOMAS
Authors: James Angelastro
Journal: Neuro-Oncology (2017)

Activating transcription factor 5 (ATF5) has been shown to be highly expressed in gliomas and governs their survival. Loss of ATF5 expression or function promotes apoptosis in gliomas, but spares normal non-neoplastic cells. This selectivity toward causing death in gliomas, but not in non-cancerous tissue has inspired targeted ATF5 drug development. In general transcription factors have been shown not to be druggable, especially by small organic molecules. As an alternative strategy, we have developed a peptide biologic that is a dominant negative form of ATF5 fused to a cell penetrating peptide, penetratin. Our pioneering results show that through systemic injection, this biologic passed through the blood brain barrier and triggered regression of gliomas arisen from genetic manipulation of neural progenitors or from human glioblastoma xenografts. Our biologic is manufactured either as a recombinant protein in bacteria, or by contemporary chemical peptide synthesis. Both manufactured forms target gliomas and are not cytotoxic toward normal brain and other tissue both in cellularity and function. This biologic peptide approach also targets non-neural cancers with promising results. Innovation and early therapeutic results have led to an academic spin-off start-up engaged in launching our biologic toward clinical trials.
PATH-35. MAINTENANCE OF EGFR ABNORMALITIES OVER TIME AND COMPARISON OF MOLECULAR METHODOLOGIES IN GLIOBLASTOMA (GBM)
Authors: Andrew Lassman, Cara Dimino, Mahesh Mansukhani, Vundavalli Murty, Kyle D Holen, Peter J Ansell, Peter Canoll, Nicholas Butowski, Joanna J Phillips, William Yong, Timothy Cloughesy
Journal: Neuro-Oncology (2017)

There is controversy surrounding the frequency with which EGFR abnormalities are maintained as therapeutic targets in serial GBM samples. In addition, there are multiple methods used to detect EGFRamp and EGFRvIII. Finally, a recent analysis suggested EGFR amp may be less common in GBMs in Asian patients. We retrospectively compared the frequency of EGFR abnormalities in serial samples of GBMs and compared results among multiple assays. We also assessed potential correlations of EGFR abnormalities with self-reported gender and race. 222 GBMs from 145 patients (63% men, 37% women; median age 59 years, range 20-83 years) who underwent 1 (145), 2 (61), 3 (15), or 4 (1) surgeries at Columbia University Medical Center were analyzed for EGFR abnormalities and other biomarkers. EGFR amp was assessed and detected in 43% of newly diagnosed cases, and maintained in 75% of recurrent tumors that were tested at 2 or more time points. EGFRvIII was assessed and detected in 31% of newly diagnosed tumors, exclusively (97%) in cases with EGFR amp (90%) or chromosome 7 polysomy (7%). The frequency of EGFR amp did not differ by gender; there were too few non-whites to assess racial variations in this initial analysis. Comparison of NGS vs. FISH/CISH for detection of EGFR amp, other methodological comparisons, and pooled analyses from the University of California, San Francisco and Los Angeles will be presented to increase the sample size. EGFRamp was maintained in most cases analyzed at multiple time points. Comparison of test methodologies is ongoing.
Despite My Best Intentions
Authors: James S. Kahn
Journal: JAMA (2017)

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QLIF-37. SURVIVORSHIP IN BRAIN METASTASES PATIENTS: THE ROLE OF THE NEURO-ONCOLOGY TEAM IN ADDRESSING EDUCATIONAL NEEDS IN NON-NEURO-ONCOLOGY PROFESSIONALS?
Authors: Catherine McBain, Sara Robson, Elizabeth Molloy, Julie Emerson, Charlotte Smith, James Leggate, Rovel Colaco, Gillian Whitfield
Journal: Neuro-Oncology (2017)

Outcomes of patients treated for brain metastases are improving, with growing numbers of long-term survivors following surgery and stereotactic radiosurgery (SRS). Most patients continue longer-term care predominantly under their site-specific oncology team (breast, lung etc). It was proposed that survivorship in brain metastases patients might be enhanced by addressing neuro-oncology-specific educational needs in less specialised health professionals. AIMS: To identify educational needs of health care professionals caring for patients following treatment for brain metastases. To provide a comprehensive educational package to meet needs identified. Educational needs were evaluated via a baseline survey addressing confidence in managing neuro-oncology problems. The questionnaire was electronically disseminated to an unselected, diverse group of health professionals including primary care physicians, nurses and allied health professionals in hospital and community settings. The results were collated to inform the content of the training. Surveys of attendees’ confidence in managing aspects of care were completed at registration, end of day and 5 weeks later. A two-sample Wilcoxon rank-sum (Mann-Whitney) test was applied to compare the data. 266 responses were received, although as it was disseminated electronically, response rate cannot be calculated. A whole-day training event was designed around the responses. Topics covered the acute and late toxicity of brain metastases treatments, management of epilepsy, emergencies and the role of rehabilitation in preserving function and enhancing quality of life. Results from the 90 attendees showed statistically significant improvement in confidence above baseline across all aspects at both time-points (end of day and 5 weeks later), suggesting that the attendees benefitted on the day and that benefit was retained. Significant unmet educational need was demonstrated in the confidence of non-neuro-oncology professionals caring for brain metastases patients. Targeted educational intervention achieved durable, measurable improvement. Further work to addressing survivorship in brain metastases populations is warranted.
TMOD-23. ESTABLISHMENT AND CHARACTERIZATION OF IDH1-MUTANT HYPERMUTATED GLIOMA CELL LINES
Authors: Lindsey Jones, Tali Mazor, Matthew Grimmer, Chloe Najac, Joydeep Mukherjee, Tracy Chow, Russel Pieper, Sabrina Ronen, Joanna J Phillips, Susan Chang, Joseph Costello
Journal: Neuro-Oncology (2017)

Low-grade gliomas can undergo hypermutation (HM) and malignant progression after treatment with temozolomide (TMZ). We and others have demonstrated that TMZ-associated HM is characterized by predominant C>T/G>A nucleotide transitions and mutation of mismatch repair (MMR) and PI3K pathway genes. Well-characterized models of HM glioma are needed to better understand the biology of HM tumors. We established three IDH1-mutant HM glioma cell lines from two post-treatment surgical specimens, two from an ATRX- and P53-mutant HM astrocytoma (P137), and one from a TERT promoter-mutant, 1p/19q co-deleted HM oligodendroglioma (P278). P137 cultures were established in serum-free conditions on laminin (GNS) and in 10% serum (ML). HM status was determined by exome sequencing. P137 GNS and P137 ML have 4,722 and 2,946 mutations, respectively, and represent independent HM events compared to each other and both spatially distinct and adjacent samples of uncultured tissue. MMR genes MSH4, MSH5, and MSH6 and PI3K pathway gene AKT3 have C>T/G>A mutations in P137 ML. In P137 GNS, MSH4, MSH5, MSH6, MLH1, MTOR, RPTOR, PIK3CA, and PTEN have C>T/G>A mutations. Both P137 ATRX-mutant lines are positive for alternative lengthening of telomeres, as measured by c-circle assay. Phylogenetic analysis shows that an independent tumor sample of P137 shares 524 mutations with the cell lines and has 1,872 private mutations. An immediately spatially adjacent piece of tumor shares 1,081 mutations with the GNS culture, only 47 mutations with the ML culture, and has 2,865 private mutations. P278 was established in serum-free conditions, has 5,752 mutations, and shares 4,875 of these mutations with two independent pieces of the tumor, including C>T/G>A mutations in MLH1, MSH2, MTOR, RPTOR, and PIK3R1. All cell lines maintain an IDH1 R132H heterozygous mutation through months of in vitro growth, produce 2-hydroxyglutarate, and demonstrate anchorage-independent growth. These cell lines provide novel tools for modeling hypermutated oligodendroglioma and astrocytoma.
IMMU-08. THERAPEUTIC POTENTIAL OF CHLOROTOXIN-REDIRECTED CAR-T CELLS AGAINST HETEROGENEOUS GLIOBLASTOMAS
Authors: Dongrui Wang, Sarah Wright, Wen-Chung Chang, Renate Starr, Xin Yang, Brenda Aguilar, Alfonso Brito, Aniee Sarkissian, Behnam Badie, Stephen Forman, Michael Barish, Christine Brown
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is one of the most lethal cancers with standard approaches of surgery, radiation and chemotherapy only moderately increasing patient survival. Immunotherapies employing chimeric antigen receptor (CAR)-redirected T cells are being applied for the treatment of many cancers including GBM, with early indications of clinical promise. One of the challenges of CAR therapy for the treatment of GBM and other solid tumors is the heterogeneity of cells within a given tumor, which allows for escape of antigen-negative cells and tumor recurrence. Therefore, future progress in the application of CAR T cell therapy to GBM requires identification of tumor-associated antigens broadly expressed on the majority of tumor cells. Such antigens, when targeted, would potentially limit opportunities for antigen escape. Previous studies have established that the scorpion toxin-derived peptide chlorotoxin (CLTX) binds to a wide-range of brain tumors, and we show that fluorescently-labeled CLTX binds a panel of primary GBM cells and low-passage GBM spheres with negligible binding to normal cells derived from neural and other tissues. Here, we report the development of a new class of CAR exploiting the GBM-binding potential of CLTX. T cells expressing this novel toxin-based CAR using CLTX as the targeting domain are activated in the presence of GBM cells. Moreover, these CAR-T cells are able to eradicate GBM cells of varying TCGA subtype and displaying a variety of antigen expression patterns in both in vitro co-culture and in vivo orthotopic models. Notably, CLTX binds mouse GBM cells, yet CLTX-CAR T cells caused no pathological alterations of normal mouse tissues, indicating that these cells have few or no off-target effects. Taken together, these studies support the potential utility of CLTX-CAR T cells to effectively target GBM while overcoming GBM heterogeneity and thus limiting antigen escape.
OA 17.02 Updated Efficacy Results From the BIRCH Study: First-Line Atezolizumab Therapy in PD-L1–Selected Patients With Advanced NSCLC
Authors: E. Carcereny, E. Felip, M. Reck, J. Patel, R. Heist, A. Balmanoukian, L. Chow, L. Paz-Ares, J. Qiu, S. Coleman, S. Mocci, A. Sandler, T. Kurata, F. Shepherd
Journal: Journal of Thoracic Oncology (2017)
Internet, una herramienta sencilla y práctica para el cribado de Chlamydia trachomatis en la población joven
Authors: D Novak, A C Edman, M. Jonsson, R B Karlsson
Journal: Eurosurveillance (2003)

El objetivo de este estudio fue evaluar un nuevo metodo de cribado de C. trachomatis basado en la toma de muestras en casa utilizando Internet como herramienta para que los participantes obtengan los resultados de su analisis. Se diseno un estudio de despistaje poblacional en un entorno de atencion primaria de Umea, Suecia. En el se incluyeron exclusivamente varones de 22 anos (n=1074), residentes de Umea, una ciudad con 100.000 habitantes. La tasa de participacion fue del 38,5%. En el grupo estudiado, el 1,1% de los participantes estaba infectado con C. trachomatis. Los participantes obtuvieron sus resultados en Internet y las tres cuartas partes de los varones infectados con C. trachomatis solicitaron atencion medica de forma independiente. La cantidad de veces que se visito Internet excedio el numero de muestras de orina analizadas. La estrategia de cribado de C. trachomatis por Internet consiguio la maxima tasa de participacion de varones que se conoce hasta la fecha, y tambien llego hasta varones jovenes no pertenecientes a los grupos de alto riesgo.
SURG-30. DOES LEVETIRACETAM ACT AS A TEMOZOLOMIDE CHEMOSENSITIZER IN PATIENTS WITH GLIOBLASTOMA?
Authors: Tae-Hoon Roh, Se-Hyuk Kim, Seok-Gu Kang, Eui Hyun Kim, Jaeho Cho, Chang Ok Suh, Se Hoon Kim, Jong Hee Chang
Journal: Neuro-Oncology (2017)

In a recent study, patients with glioblastoma (GBM) who administered Levetiracetam (LEV) during chemoradiotherapy were reported to have survival benefit. However, the effect of LEV on survival of glioblastoma patients is not well known. From 2004 to 2016, 340 patients with surgically resected and pathologically confirmed glioblastoma treated with Temozolomide-based chemoradiotherapy were studied. Patients were divided into two groups according to whether LEV was included in the anticonvulsant used during chemotherapy. Progression-free survival and overall survival were compared between groups. Overall survival was 28.1 months and 24.3 months (log-rank test, p=0.057), and progression free survival was 17.3 months and 14.6 months (p=0.048) in LEV group and in No LEV group, respectively. Subgroup analysis was performed based on MGMT methylation and extent of resection. The benefit of LEV was the most prominent in MGMT methylated and incomplete resection group (p=0.048). In multivariate analysis including extents of resection, age, sex, MGMT methylation, and IDH1 mutation, this benefit was insignificant (p=0.200). Adverse events more than CTCAE grade 3 were less in LEV group than in no LEV group (p=0.034). Progression-free survival was significantly longer when LEV was used during Temozolomide-based chemoradiotherapy in our study. This benefit was prominent for the MGMT methylation type with remnant tumors. In addition, the toxicity of Temozolomide was low in the group using levetiracetam. Therefore, the use of levetiracetam as an AED for CCRT in GBM patients is recommended and further studies are needed to determine if this affects survival.