tbuckley/cabot-search huggingface dataset:
CADD-35. THE DEVELOPMENT OF PERSONALIZED CAM AVATAR MODEL TO PREDICT CHEMOTHERAPEUTIC DRUG SENSITIVITY/RESISTANCE OF GLIOMAS
Authors: Martine Charbonneau, Laurent-Olivier Roy, Maxime Richer, David Fortin, Claire Dubois
Journal: Neuro-Oncology (2018)

Malignant glial tumors are associated with a poor prognosis, presenting a short median patient survival and a very limited response to therapies. Although the first line therapy is standardized, there exists no consensus as to which second line treatment modality is better. We thus sought to demonstrate the feasibility of transforming our newly established expertise into personalized treatments for glioma patients by developing an advanced in vivo Avatar model developed from patient derived tumors. The typical medical Avatar system entails implantation of patient tumor samples in immunodeficient mice for subsequent test in drug efficacy. As the generation of mouse Avatars is a slow and costly approach, many cancer patients are set to have a significant disease progression before the results from the mouse model become available. We recently developed a rapid and cost-effective, pre-clinical model that is well suited for precision medicine – the ex-ovo chicken embryo ChorioAllantoic Membrane (CAM) assay. We will present data indicating that tumor growth occurs very rapidly in ex ovo CAMs, with measurable tumors obtained within a few days, as opposed to several weeks in mice. Even though tumor sizes are smaller in the CAM than in mice, the engrafting rate is higher and tumor sizes are more uniform. Implantation of glioma tissue fragments from 25 patients led to the successful establishment of CAM xenograft tumors which faithfully recapitulate the histology of the primary tumor for the majority of patients. Furthermore, we observed a significant inhibition of tumor growth in CAMs treated with first and second line chemotherapeutic drugs. This next-generation Avatar model has the potential to become an asset for personalized medicine in gliomas treatment.
Subclinical coronary artery disease in veteran athletes: is a new preparticipation methodology required?
Authors: Hélder Dores, Pedro de Araújo Gonçalves, José Monge, Rogério Costa, Luis Tátá, Aneil Malhotra, Sanjay Sharma, Nuno Cardim, Nuno Neuparth
Journal: British Journal of Sports Medicine (2018)

Preparticipation evaluation of veteran athletes should focus on accurate cardiovascular (CV) risk stratification and subclinical detection of coronary artery disease (CAD), which is the main cause of sudden cardiac death in this population. We aimed to investigate the effectiveness of current preparticipation methodology used to identify veteran athletes with high coronary atherosclerotic burden.A total of 105 asymptomatic male athletes aged ≥40 years old, with low to moderate CV risk (Systematic Coronary Risk Estimation <5%) who trained ≥4 hours/week for at least 5 years, were studied. The screening protocol included clinical evaluation, ECG, transthoracic echocardiogram and exercise testing. Cardiac CT was performed to detect CAD, defined as a high atherosclerotic burden according to coronary artery calcium score and coronary CT angiography.The majority of the athletes (n=88) engaged in endurance sports, with a median volume of exercise of 66 (44; 103) metabolic equivalent task score/hour/week. Exercise testing was abnormal in 13 (12.4%) athletes, 6 (5.7%) with electrocardiographic criteria for myocardial ischaemia and 7 (6.7%) with exercise-induced ventricular arrhythmias. A high coronary atherosclerotic burden was present in 27 (25.7%) athletes, of whom 11 (40.7%) had CV risk factors and 6 had abnormal exercise tests, including 3 who were positive for myocardial ischaemia.Conventional methodology used in preparticipation evaluation of veteran athletes, based on clinical CV risk factors and exercise testing, was poor at identifying significant subclinical CAD. The inclusion of more objective markers, particularly data derived from cardiac CT, is promising for more accurate CV risk stratification of these athletes.
Biphasic effect of alpha benzene hexachloride (α-BHC) on diethylnitrosamine-intiated hepatocarcinogenesis and possible hormesis mechanism in rats.
Authors: Rawiwan Puatanachokchai, Keiichirou Morimura, Hideki Wanibuchi, Anna Kinoshita, Jin Seok Kang, Yoshihiko Funae, Shoji Fukushima
Journal: Cancer Research (2005)

1190  Recently there has been a shift in the prevailing paradigm regarding the dose dependence of carcinogen action with increasing acceptance of hormesis as a phenomenon although underlying mechanisms remain to be established. To ascertain whether α-benzene hexachloride (α-BHC), a non-genotoxic hepatocarcinogen in rodents, might act by biphasic effect, hormesis, male F344 rats were injected with 100 mg/kg bw. of diethylnitrosamine once a week 3 times via ip. and then administered various concentrations of α-BHC ranging from 0.01 to 500 ppm, for 10 and 32 weeks. The end point markers were glutathione S-transferase placental form (GST-P) positive foci, preneoplastic lesions in the rat liver, for medium-term experiment and tumor formation for long-term experiment. The results from medium-term study showed the highest concentration of α-BHC significantly increased the number and area of GST-P positive foci, but a low dose of α-BHC, 0.05 ppm, caused significant reduction, showing a J-shape dose-response curve. The PCNA positive index for GST-P positive foci in the low dose-treated group was significantly reduced and this was concurrent with the induction of TGF-β mRNA expression in low dose treated-group. The dose response curves of CYP450 content, NADPH-P450 reductase activity and 8-OHdG formation revealed the same pattern as GST-P positive foci data. Though, the response curves of CYP2B1 and 3A2 in their catalytic activities, protein and mRNA expression showed threshold, catalytic activity of CYP2C11 exhibited an inverted J-curve. Therefore, CYP2C11 might function in detoxification and CYP2B1 and 3A2 might play a role in bioactivation of α-BHC. The results of long-term study demonstrated 50 and 500 ppm of α-BHC treated-rats significantly increased the incidence and multiplicity of liver tumors. Interestingly, the number of hepatocellular adenoma tends to be declined in the low dose, 0.1 ppm, of α-BHC treated rats. Gene expression analysis data of normal tissues adjacent to tumors showed that c-jun mRNA expression significantly decrease and TGF-β tend to be induced in low dose treated-group. There was no change of TGF-α mRNA level when compared to DEN alone group. Thus, α-BHC may exert hormetic action regarding its early stage of hepatocarcinogenesis and this might involve induction of detoxifying enzymes at low dose, influencing free radical production and oxidative stress and consequently pathological change in the liver. Hormetic effect of α-BHC was not found in long-tem experiment of this study. It might be due to tested chemical concentrations and duration of exposure.
DNA methylation and de-methylation using hybrid site-targeting proteins
Authors: Yong Lei, Yung-Hsin Huang, Margaret A. Goodell
Journal: Genome biology (2018)

DNA methylation plays important roles in determining cellular identity, disease, and environmental responses, but little is known about the mechanisms that drive methylation changes during cellular differentiation and tumorigenesis. Meanwhile, the causal relationship between DNA methylation and transcription remains incompletely understood. Recently developed targeted DNA methylation manipulation tools can address these gaps in knowledge, leading to new insights into how methylation governs gene expression. Here, we summarize technological developments in the DNA methylation editing field and discuss the remaining challenges facing current tools, as well as potential future directions.
Preclinical Development and First-in-Human Imaging of the Integrin αvβ6 with [18F]αvβ6-Binding Peptide in Metastatic Carcinoma
Authors: Sven H. Hausner, Richard J. Bold, Lina Y. Cheuy, Helen K. Chew, Megan E. Daly, Ryan A. Davis, Cameron C. Foster, Edward J. Kim, Julie L. Sutcliffe
Journal: Clinical Cancer Research (2018)

The study was undertaken to develop and evaluate the potential of an integrin αvβ6-binding peptide (αvβ6-BP) for noninvasive imaging of a diverse range of malignancies with PET.The peptide αvβ6-BP was prepared on solid phase and radiolabeled with 4-[18F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired αvβ6-expressing and αvβ6-null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired αvβ6-expressing and αvβ6-null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer.[18F]αvβ6-BP displayed excellent affinity and selectivity for the integrin αvβ6in vitro [IC50(αvβ6) = 1.2 nmol/L vs IC50(αvβ3) >10 μmol/L] in addition to rapid target-specific cell binding and internalization (72.5% ± 0.9% binding and 52.5% ± 1.8%, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [18F]αvβ6-BP was rapid, primarily via the kidneys. In patients, [18F]αvβ6-BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [18F]αvβ6-BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung.The clinical impact of [18F]αvβ6-BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.
PDCT-03. A PHASE II TRIAL OF POLY-ICLC IN THE MANAGEMENT OF RECURRENT OR PROGRESSIVE PEDIATRIC LOW GRADE GLIOMAS. RESULTS FOR THE NEUROFIBROMATOSIS 1 GROUP. (NCT01188096)
Authors: Dolly Aguilera, Tobey MacDonald, Robert Castellino, Anna Janss, Claire Mazewski, Nadja Kadom, Minya Pu, Karen Messer, John Crawford, Erin Connelly, Rachel Gray, Andres Salazar, Donald Durden
Journal: Neuro-Oncology (2018)

Polyinosinic-Polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC) is a double stranded RNA that acts as a ligand for the Toll Receptor 3 (TLR3) and results in a broad host defense stimulation, including T-cell and natural killer cell activation and cytokine release (interferons alpha, beta, and gamma, interleukins, corticosteroids, and TNF). The goal of this trial is to determine the efficacy of this novel immunotherapy against refractory pediatric low-grade glioma (LGG). Here we present the results for the neurofibromatosis group. Poly-ICLC 20mcg/kg/dose IM was self-administered twice a week at home for up to 24 cycles. Each cycle is 28 days. Endpoints include objective tumor response rate, progression-free survival (PFS), and rate of stabilization/improvement in visual examination in those with optic pathway glioma. Twenty three patients were enrolled, six with NF-1. Of NF1 patients (3 males, 3 females), five were evaluable, ages 1–16 years. Tumor location: 4 optic pathway, one thalamic, one cervico-medullary junction. 5/6 had received more than 2 prior regimens (range 1–7). Responses (PR+SD) were observed in 4/5 (80%), with 2 SD having a decrease in tumor size by 35% and 10%, one of whom had significant improvement on visual field testing, and 2 PR having decrease in tumor size by 50% and 55%. Only low grade toxicities were observed with poly-ICLC, including erythema and pain at site of injection, fever, myalgias, and ALT elevation. One intra-tumoral hemorrhage occurred with complete resolution with medical management alone. All patients are alive. Poly-ICLC is extremely well tolerated in the NF-1 group and the single agent response rate in this small NF1 cohort is encouraging. Expanded phase II testing of poly-ICLC in the NF-1 cohort is planned.
EXTH-49. NOVEL AD-REIC VECTOR WITH THE SUPER GENE EXPRESSION (SGE) SYSTEM (AD-SGE-REIC) AS A PROMISING THERAPEUTIC AGENT FOR MALIGNANT GLIOMA
Authors: Kazuhiko Kurozumi, Tetsuo Oka, Kentaro Fujii, Yasuhiko Hattori, Yusuke Tomita, Toshihiko Shimizu, Atsuhito Uneda, Yuji Matsumoto, Hiromi Kumon, Isao Date
Journal: Neuro-Oncology (2018)

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor and therapeutic gene in many human cancers. We have investigated the anti-glioma effect of the adenovirus vector carrying REIC/Dkk-3 (Ad-CAG-REIC). Recently an Ad-REIC vector with the super gene expression (SGE) system (Ad-SGE-REIC) has been developed for higher protein expression and therapeutic effects than the conventional adenoviral vector (Ad-CAG-REIC). In this study, we evaluated the anti-glioma effect of the Ad-SGE-REIC against malignant glioma. Transcriptome analysis of the differential (exome sequencing-derived) expression levels of REIC was conducted based on using The Cancer Genome Atlas (TCGA) GBM patient dataset (n=349) using the Project Betastasis web platform (http://www.betastasis.com/glioma/tcga_gbm/). To evaluate the anti-glioma effect of the Ad-SGE-REIC, we conducted a cytotoxicity assay to assess treatments with Ad-SGE-REIC, Ad-CAG-REIC, or Ad-LacZ (control) using malignant glioma cells (U87ΔEGFR or GL261) and normal human astrocytes (NHAs). Seven days after implantation of glioma cells into the brain of mice, Ad-SGE-REIC, Ad-CAG-REIC, or Ad-LacZ (control) was injected stereotactically at the tumor inoculation site. The survival of mice in each group was analyzed by the Kaplan–Meier method. Analysis of the TCGA GBM patient dataset revealed that differential expression levels of REIC were lower in all subgroups, including Proneural, Neural, Classical, and Mesenchymal groups, than in the control group. In the cytotoxicity assay, after treatment with Ad-SGE-REIC, the number of malignant glioma cells attached to the bottom of culture wells was significantly reduced in a time-dependent manner. The survival time of the mice treated with Ad-SGE-REIC was significantly longer than those treated with Ad-LacZ or Ad-CAG-REIC. We demonstrated the anti-glioma effect of Ad-SGE-REIC. We are now planning an investigator-initiated clinical trial (phase I/IIa) of Ad-SGE-REIC for the treatment of recurrent malignant glioma.
TMIC-18. IMPACT OF HFE MUTATION ON VIABILITY IN MACROPHAGES EXPOSED TO GLIOBLASTOMA EXOSOMES
Authors: Darya Nesterova, Oliver Mrowczynski, Becky Slagle-Webb, Achuthamangalam Madhankumar, Brad Zacharia, Anne Nixon, James Connor
Journal: Neuro-Oncology (2018)

In Glioblastoma (GBM), the tumor microenvironment is critical to cancer development and progression. Glioblastoma Extracellular Vesicles (GBM-EVs) have been shown to promote a tumor-supporting phenotype in macrophages, leading to surrounding immunosuppression and enhanced tumor growth. Microglia and macrophages contribute to iron homeostasis, essential for cellular energy production in rapidly dividing cells. The HFE mutation is associated with altered cellular iron homeostasis. It is the most common autosomal recessive polymorphism found in Caucasians and may be linked to worse patient prognosis in GBM. Our lab showed that HFE mutation confers phenotypic differences between HFE and wild-type (WT) macrophages, with HFE macrophages displaying increased migration and phagocytosis. How these phenotypic differences may present in response to GBM exosomes has not yet been explored. Primary macrophage cultures isolated from bone marrow of WT and HFE mutant knock-in mice were exposed to exosomes from different patient-derived cancer stem cells. Significant differences in macrophage viability 24 hours after exosome exposure were observed in response to GBM exosomes (p= 0.001). When exposed to GBM exosomes, WT macrophage viability consistently decreased while the viability of macrophages with the HFE mutation increased. There was no significant difference between the two genotype macrophage groups when exposed to U87 exosomes, supporting that the stem cells are modulating macrophage phenotype. These data suggest that genotypic differences in iron handling pay a critical role in macrophage response to GBM exosomes and may be responsible for differences seen in disease severity in patients with HFE mutations.
ACTR-59. IMPROVING THE INTRA-OPERATIVE DIAGNOSIS OF HIGH-GRADE GLIOMA USING A FLUORESCENCE BIOMARKER – RESULT OF THE GALA-BIDD STUDY
Authors: Colin Watts, Keyoumars Ashkan, Michael Jenkinson, Kathreena Kurian, Wendi Qian, Stephen Price, Tomasz Matys, Gail Doughton, Andrea Machin, Josephine Jung, Ibrahim Jalloh, Chloe Harman, Katrina Gatley, Gemma Young, Richard Hardy, Alimu Dayimu
Journal: Neuro-Oncology (2018)

Correctly distinguishing gliomas as low or high grade (LGG or HGG) during surgery can influence the surgical procedure, enhancing resection and improving survival. The UK NCRI GALA-BIDD study was designed to prospectively investigate whether the presence of visible fluorescence is a pragmatic intra-operative diagnostic surgical biomarker of high-grade disease within a tumour mass in real time during surgery. Patients with suspected intrinsic glioma discussed at neuro-oncology Multidisciplinary Team meetings and suitable for fluorescence guided cytoreductive surgery were eligible. 5-aminolevulinic acid (5-ALA) was used to generate visible fluorescence. Samples of fluorescent tissue were sent for peri-operative histopathological analysis to establish an intra-operative diagnosis of LGG or HGG. These data were compared with the final central pathological diagnosis. From Feb 2015 to March 2017 in the UK, 106 patients were recruited: median age 59 (range 23–77); 59% male; 25% WHO radiological grade II transforming to a higher grade and 55% grade IV. 5-ALA were given for 103 patients with a median dose of 1500mg (range 960-2200mg). 67% of patients classified as HGG at local peri-operative diagnosis were confirmed by the central review (weighted Kappa 0.37 (95%CI=0.21–0.54)). 88 patients were evaluable for the primary endpoint: 81 had visible fluorescence of the tumour with central histopathology diagnosis as 1 LGG, 78 HGG (a 99% concordance in HGG classification with the 99%CI=91%-99.9%) and 2 not assessed; 7 patients had no visible fluorescence and were diagnosed as 6 LGG and 1 HGG. CONCLUSION: There is an urgent need to improve the local peri-operative diagnosis. The presence of visible fluorescence can be used as an additional pragmatic intra-operative diagnostic surgical biomarker of high-grade disease within a tumour mass. Use for assessment of low-grade disease needs further investigation.
RARE-08. GRADING CONSIDERATIONS FOR MENINGEAL SOLITARY FIBROUS TUMOR/HEMANGIOPERICYTOMA
Authors: Karen Fritchie, Kassandra Jensch, Sarah Jenkins, Michael Link, Paul D Brown, Fausto Rodriguez, Andrew Guajardo, Daniel Brat, Jose’ Velazquez Vega, Arie Perry, Ashley Wu, David Raleigh, Sandro Santagata, David Louis, Priscilla Brastianos, Alexander Kaplan, Brian Alexander, Sabrina Rossi, Fabio Ferrarese, Florian Haller, Caterina Giannini
Journal: Neuro-Oncology (2018)

Meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) is a rare tumor with propensity for recurrence and metastasis. We compared the WHO 2016 CNS tumor classification (CNS-G), a 3-tier system based on histopathologic phenotype and mitotic count, to the WHO 2013 Soft Tissue classification (ST-G), a 2-tier system based on mitotic count alone, in a cohort of 133 patients (59 female, 74 male; mean age 54 years [range 20–87]) with meningeal SFT/HPC. Tumors were pathologically confirmed through review of the first tumor resection (n=97), local recurrence (n=35) or distant metastasis (n=1). STAT6 immunostain showed nuclear expression in 132 cases. NAB2-STAT6 fusion was detected in 99 (of 111) successfully tested tumors (89%) including the lone STAT6 immunonegative tumor. Tumors were classified as grade 1 (n=43), 2(n=41) or 3 (n=49) using the CNS-G, and SFT (n=84) or malignant SFT (n=49) by using the ST-G. Necrosis was present in 16 cases (12%). On followup, 42 patients had at least 1 subsequent recurrence, including 8 with metastases. 29 patients died. On univariate analysis necrosis (p=0.0018) and CNS-G or ST-G (p-value respectively 0.014, 0.0041) were significantly associated with recurrence-free (RFS) but not overall survival (OS). NAB2-STAT6 fusion type was not associated with RFS or OS. Ten-year RFS was 61, 58 and 34% for CNS-G 1,2 and 3 versus 59 and 34% for ST-G SFT and malignant SFT, respectively. Ten-year RFS was 0% and 56% for tumors with and without necrosis. Our data suggest that SFT/HPC are better stratified using a two-tiered grading scheme. On multivariate analysis, necrosis was an independent predictor of RFS (HR 2.9, p=0.016) while ST-G was not quite significant (HR=1.9, p=0.062), suggesting necrosis should be reintroduced among SFT/HPC grading criteria.
ATIM-41. PHASE II TRIAL OF A SURVIVIN VACCINE (SurVaxM) For Newly Diagnosed Glioblastoma
Authors: Manmeet Ahluwalia, David Reardon, Ajay Abad, William Curry, Eric Wong, David Peereboom, Ahmed Belal, Jingxin Qiu, Kathleen Mogensen, Cathy Schilero, Danielle Casucci, Laszlo Mechtler, Erik Uhlmann, Michael Ciesielski, Robert Fenstermaker
Journal: Neuro-Oncology (2018)

Survivin is an anti-apoptotic protein that is highly expressed in glioblastoma (GBM). We conducted a single-arm, multi-center phase II trial in newly diagnosed GBM (nGBM) to determine 6-month progression-free survival (PFS-6), 12-month overall survival (OS-12) and immunologic response in patients treated with surgery, chemoradiation, adjuvant temozolomide (TMZ) and survivin-targeted immunization. Patients with nGBM who hadwith HLA-A*02, -A*03, -A*11 and -A*24 haplotypes and, Karnofsky performance status ≥70 were included. Following craniotomy (3 residual contrast enhancement) and chemoradiation, patients received 4 prime-boost doses of SurVaxM (500 mcg) every 2 weeks, followed by adjuvant TMZ and maintenance SurVaxM every 12 weeks until progression. Immunogenicity of SurVaxM was assessed by measuring anti-survivin antibody levels and survivin-specific CD8+ T-cells using multimers. Sixty-three patients, median age 60 years (range, 20–82), including 38 males were treated. Survivin expression was detectable in all patients (1–40% ([median = 12%]) of tumor cells by immunohistochemistry). The vaccine was highly immunogenic and produced survivin-specific CD8+ T-cells and antibody (IgG) titers. The regimen was well-tolerated and immunogen-related adverse events were mild with no regimen limiting toxicity attributable to SurVaxM. PFS-6 was 96.7% (C.I. = 87.6%- 99.1%) and OS-12 was 94.2% (C.I. =83.0%-98.1%) as measured from diagnosis. In MGMT methylated, PFS6 of 96.9% (C.I. = 99.6% to 79.8%); OS12 of 98.1% (C.I. = 99.0% to 97.2%) and in unmethylated tumors, PFS6 of 96.6% (C.I. = 99.6% to 78%); OS12 of 88.9% (C.I. = 99% to 77.2%) was observed. Methylated patients with higher survivin levels had significantly better PFS-6 than those with low survivin levels (r = 0.4). SurVaxM is safe and a promising adjunct therapy in nGBM. Compared to historical matched controls, addition of SurVaxM improved PFS-6 and OS-12 in nGBM. Patients with poor prognostic factors (unmethylated MGMT, higher survivin levels) treated with SurVaxM achieved better survival than expected.