tbuckley/cabot-search huggingface dataset:
P08.65 The mechanisms of oncometabolites in epigenetic control, DNA repair, neural development and gliomagenesis
Authors: Y. Xiong, W. Xu, H. Yang, P. Wang, S. Ma, S. Zhao, D. Ye, K. Guan
Journal: Neuro-Oncology (2017)

Eight genes encoding for subunits of four distinct metabolic enzymes (IDH1, IDH2, SDH and FH) are mutated in various types of human malignancies. Of these 8 genes, IDH1 is the most frequently mutated, in particular in low-grade gliomas. Oncogenic mutation in IDH1 and IDH2 abolish their normal catalytic activity in producing α-ketoglutarate (αKG) and also gain a new function to produce oncometabolite D-2-hydroxyglutarate (D2HG). We previously discovered that D2HG, and its enantiomer, L2HG, act a competitive inhibitor of αKG and inhibit both αKG- dependent JmiC family of histone demethylases and TET family of DNA demethylases. These discoveries provide a molecular basis for the CpG island methylator phenotype (CIMP) observed in IDH-mutant gliomas. More recently, we demonstrated that D2HG also inhibits αKG- dependent alkB homolog (ALKBH) family of DNA repair enzymes, sensitizing IDH1-mutant glioma cells to alkylating agents such as methyl methanesulfonate (MMS), N-methyl-N0- nitro-N-nitrosoguanidine (MNNG) and CCNU/lomustine. These results provide a molecular basis for the clinical benefits seen in IDH-mutant glioma patients who in addition to radiation therapy (RT) received a chemotherapy of procarbazine, CCNU/lomustine, and vincristine (PCV). These results also suggest that impairment of DNA repair may contribute to tumorigenesis driven by IDH mutations and that alkylating agents may merit exploration for treating IDH-mutated cancer patients. Accumulation of D2HG and L2HG are also found in rare neurometabolic disorders and brain tumors, known as 2-hydroxyglutaric aciduria. They are caused by mutations ­targeting genes encoding for either D2HG or L2HG dehydrogenase (D2HGDH and L2HGDH), respectively, that clean up both enantiomers of 2HG. To determine the biochemical and pathophysiological consequences of L2HG accumulation, we created L2hgdh knockout (KO) mice. L2hgdh null mice exhibited a robust increase of L2HG in multiple tissues. The highest L2HG is observed in brain and testis with corresponding increase of histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover, L2hgdh deficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. These observations provide in vivo evidence to support that L2hgdh mutation leads to L2HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thus offering new insights into the pathophysiology of L2HGA and IDH-mutant glioma in human. We will also discuss our recent progress in characterizing the function and regulation of additional αKG-antagonizing oncometabolites in the epigenetic control and oncogenesis.
Abstract 9371: Low In-Treatment HDL Cholesterol Strongly Predicts Incident Atrial Fibrillation: The LIFE Study
Authors: Peter M Okin, Darcy A Hille, Kristian Wachtell, Sverre E Kjeldsen, Björn Dahlöf, Richard B Devereux
Journal: Circulation (2012)

Background: Hypertensive patients are at increased risk of atrial fibrillation (AF). Although low baseline HDL levels have been associated with a higher risk of AF in some analyses, this has not been born out in recent population-based studies; whether changing levels of HDL over time are more strongly related to the risk of new AF has not been examined. Methods: Incident AF was examined in relation to baseline and in-treatment HDL levels prior to development of AF in 8267 hypertensive patients with no history of AF, in sinus rhythm on their baseline ECG, randomly assigned to losartan- or atenolol-based treatment. HDL levels at baseline and each year of testing were categorized into quartiles according to baseline HDL levels. Results: During 4.7±1.1 years follow-up, new AF developed in 645 patients (7.8%). In univariate analyses, compared with HDL &gt;1.78 mMol/L, patients with in-treatment HDL &lt;1.21 entered as a time-varying covariate had a 53% greater risk of new AF; patients with in-treatment HDL in the 2 nd or 3 rd quartiles had intermediate increased risks of AF. Baseline HDL was only a weak predictor of new AF. In multivariate Cox analyses adjusting for multiple AF risk factors, including the previously demonstrated predictive value of in-treatment heart rate and Cornell product LVH, there was no attenuation of the risk of new AF associated with low in-treatment HDL. In-treatment non-HDL cholesterol (p=0.171) and statin use (p=0.626) were not significant predictors of new AF in the multivariate model including in-treatment HDL. Baseline HDL was not a significant predictor of AF in multivariate analysis. Conclusions: Lower in-treatment HDL is strongly associated with risk of new AF, even after adjusting for other potential AF risk factors and treatment effects. These findings suggest that serial assessment of HDL can better estimate AF risk in hypertensive patients. Further study is indicated to determine whether therapies that increase HDL can lower risk of developing AF.
P09.41 Single agent Bevacizumab in recurrent glioblastoma after a second line chemotherapy with Fotemustine. The Italian Association of Neuro Oncology experience
Authors: A. Gonnelli, M. Cantarella, A. Molinari, G. Villani, G. Lombardi, M. Fabrini, A. Pace, A. Fabi, F. Pasqualetti, R. Rudà, R. Soffietti, F. Paiar
Journal: Neuro-Oncology (2017)

Bevacizumab is an anti-VEGF antibody used in the treatment of recurrent glioblastoma (GBM). Despite the available literature, few is known about the best schedule to administer this angiogenesis inhibitor: i) early, at the first recurrence, or ii) later, after a second line of chemotherapy. In this retrospective multicenter study, we reported the results obtained in 51 patients (pts) with recurrent GBM treated with single agent bevacizumab after the failure of a second-line chemotherapy with fotemustine (FTM). In March 2016, at the time of data analysis, 3 patients (5.9%) were still alive with stable disease, whereas 48 patients were dead due to disease progression. Kaplan-Meier estimated median survival from diagnosis of GBM was 28 months (95%CI 22.1-33.9). The median survival measured from the beginning of FTM and bevacizumab therapy were 11.3 (95% CI 8.4-13.6) and 6 (95% CI 3.8-8.1) months, respectively. Six and 12-month PFS rate from the beginning of bevacizumab treatment were 18% and 13%, respectively. Despite the interpretation of this study is limited by the retrospective design, bevacizumab may be a promising approach after failure of second-line FTM therapy.
P04.27 Texture feature analysis to predict overall survival in recurrent glioblastoma treated in the DIRECTOR trial
Authors: A. Vils, H. Wirsching, M. Nesteruk, S. Tanadini-Lang, G. Reifenberger, J. Tonn, M. Guckenberger, W. Wick, N. Andratschke, M. Weller
Journal: Neuro-Oncology (2017)

Introduction: Recently, quantitative radiomics approaches have shown their potential to predict clinical outcome and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in patients with newly diagnosed glioblastoma. However, for recurrent glioblastoma scarce data on the value of quantitative radiomics is available. This study was designed to evaluate the association of clinical outcome with radiomic features in patients with recurrent glioblastoma. Materials and Methods: We analyzed imaging data of the DIRECTOR trial, a prospective randomized multicenter study comparing two dose-intensified temozolomide regimens in recurrent glioblastoma (N=105); data from 54 patients with complete imaging data either with or without repeat surgery were available for image analysis. The contouring of recurrent tumor was performed on gadolinium-enhanced T1-weighted images (T1+Gad MRI). We used a newly developed in-house software for radiomic feature extraction and calculation (43 features describing tumor shape and tumor texture). Radiomic features were first preselected in the principal component analysis and later used in the multivariable analyses. A cox proportional hazard model was trained to predict progression free survival (PFS) and overall survival (OS) and a logistic regression was used to predict MGMT promoter methylation status. Results: Five features correlated with PFS (P < 0.05) and three features correlated with OS (P < 0.05) in the univariable Cox regression analysis of patients with recurrent glioblastoma. In contrast, no parameter correlated with MGMT promoter methylation status (P > 0.05). Upon multivariable analysis, an association between two partially overlapping features and PFS and OS was found (PFS features: sum of entropy and large size high gray-level emphasis (lshge); concordance index (CI), 0.622; Wald test, P = 0.002; OS: features, surface and lshge; CI, 0.615; Wald test, P = 0.024). CONCLUSION: In our analysis, both PFS and OS, but not MGMT promoter methylation status, were associated with texture features on T1+Gad MRI in patients with recurrent glioblastoma treated with alkylating agent chemotherapy. This proof of principle investigation should be validated on an independent external dataset of recurrent glioblastoma patients in order to establish potential imaging biomarkers with predictive potential.
P06.01 Functional analysis of IL13Rα2-specific chimeric antigen receptor T cells in immunocompetent mouse of glioblastoma
Authors: K. C. Pituch, J. Miska, G. Krenciute, G. Li, W. K. Panek, S. Gottschalk, I. V. Balyasnikova
Journal: Neuro-Oncology (2017)

The outstanding efficacy of T cells modified to express chimeric antigen receptors (CAR) for hematological malignancies promises hope that they can be programmed to target and kill solid tumors. As the current standard of care for glioblastoma (GBM) only extends patient survival minimally, CARs can provide an exciting new option for the treatment of this incurable disease. We have generated a CAR expressing the specific single chain antibody (scFv47) against interleukin-13 receptor α 2, (IL13Rα2), a tumor associated antigen expressed highly by glioma tissues. In our recent studies, we have demonstrated that scFv47 CAR T cells are efficacious in killing human glioma cells in vitro and in vivo in athymic mice. Understanding how these CAR T cells behave in the GBM microenvironment and interact with the host immune system is critical for the development of successful CAR T cell therapies. Therefore, in our studies, we generated and compared the efficacy of mouse CAR T cells equipped with two different linkers, short (SL, mouse IgG hinge domain) and long (LL, extracellular domain of murine CD28), connecting scFv47 with transmembrane domains and signaling domains of CD28 and CD3ζ. Interestingly, the linker type was critical to the efficacy of the CAR, as the in vitro51Cr release/killing assay showed that SL-CD28ζ CAR T cells were more effective in lysing GBM cells. This further translated to the in vivo studies, where SL- S CD28ζ CAR T cells significantly extended the survival of mice bearing syngeneic GL261 or SMA560 gliomas modified to express human IL13Rα2. Multicolor flow analysis of tumor tissues showed that SL-CD28ζ CAR T cells persisted at three and seven days after intracranial injection into established GBMs. Interestingly, we observed a reduction of host Tregs at the three day time point, with minimal contribution of CARs to the overall CD4 compartment in the tumor. There was a significantly increased presence of host CD8α+ DC in the brain in response to SL-CD28ζ CAR and not controls suggesting that CARs can enhance recruitment of functional DCs to the tumor. Furthermore, there was a reduced presence of granulocytic myeloid-derived suppressor cells (MDSCs) in the brain and spleen of SL-CD28ζ CAR treated mice. The systemic reduction of MDSCs by functional CARs suggests they are influencing the chemotactic signals used by the tumor to recruit immunosuppressive cells. In conjunction with our data of IL13Rα2-CAR T cell immunotherapy in an immune-compromised model, our study of IL13Rα2-CAR T cells in an immune-competent model shows great promise for the improvement of GBM immunotherapy. We showed that IL13Rα2-CAR T cells are efficacious in killing GBM both in vitro and in vivo. Furthermore, for the first time, we showed that CAR T cell therapy positively modulates the immune landscape of the glioma bearing mice, likely contributing to the antitumor activity of CAR T cells.
OS03.7 Does improved intracranial control from whole brain radiation therapy translate to improved overall survival in patients with limited competing risk from systemic disease? A secondary analysis of EORTC 22952–26001.
Authors: T. Churilla, E. Handorf, S. Collette, L. Collette, Y. Dong, A. Aizer, M. Kocher, R. Soffietti, B. Alexander, S. Weiss
Journal: Neuro-Oncology (2017)

Objective: To assess the survival benefit of whole brain radiotherapy (WBRT) for patients with controlled extra-cranial disease and those with favorable diagnosis-specific graded prognostic assessment (dsGPA) scores within EORTC 22952. Methods: In the EORTC 22952 trial, patients with 1–3 brain metastases with stable systemic disease or asymptomatic primary tumors were randomized to WBRT versus observation prior to stereotactic radiosurgery (SRS) or after surgical resection. We performed exploratory analyses using cox regression, the Kaplan-Meier method, and landmark analysis to evaluate overall survival according to receipt of WBRT accounting for 1) extracranial progression in all patients and 2) calculated dsGPA score (unfavorable = [0.5–2.0] or favorable = [2.5–4.0]) for non-small cell lung cancer (NSCLC) patients. We adjusted for performance status, primary site, metastases number, and initial presence of extracranial disease in multivariable analysis including time to extracranial progression as a time-dependent covariate. For landmark analysis, we examined survival in the subset of patients who survived without extracranial progression to at least 6 months and compared groups according to the receipt of WBRT. Results: A total of 329 patients treated per-protocol were included for analysis. 115 (35 %) patients had no extracranial progression, while 70 (21 %) patients had extracranial progression < 90 days, 65 (20 %) patients between 90 and 180 days, and 79 (24 %) patients > 180 days from randomization. There was no difference in the model-based risk of death in the WBRT group before (HR [95%CI] = 0.70 [0.45–1.11], p = 0.133), or after (HR [95%CI] = 1.20 [0.89–1.61], p = 0.214) extracranial progression. Landmark analysis confirmed no impact of WBRT on survival among patients with controlled disease at 6 months (p = 0.51). 175 of 177 NSCLC patients had data for dsGPA calculation. There was no overall survival benefit to WBRT among patients with favorable dsGPA scores (HR [95%CI] = 1.10 [0.68–1.79]) or unfavorable dsGPA scores (HR [95%CI] = 1.11 [0.71–1.76]). Conclusion: After careful patient selection, we were unable to find a subset of patients with controlled extracranial disease or favorable dsGPA scores that benefited from the addition of WBRT. This secondary analysis of phase III data further supports the omission of WBRT for patients with 1–3 brain metastases undergoing SRS or surgery and close surveillance.
In pre-clinical models of colorectal or head and neck carcinoma, palifermin does not alter the anti-tumor efficacy of chemotherapy or Cetuximab alone or in combination
Authors: Rachael L. Brake, Luis Borges, Robert Radinsky, Charlie Starnes
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1170 

Mucositis is a common, painful, dose-limiting toxicity of chemotherapy and radiation therapy for cancer. The disorder is characterized by breakdown of the mucosa that results in the formation of ulcerative lesions. Mucositis affects up to 75 percent of patients who undergo hematopoietic stem-cell transplantation and 77 percent of patients with head and neck cancer who receive such treatment. Numerous studies in animals and humans have tried to find a means of preventing and treating mucositis. Kepivance™ (palifermin; ΔN23KGF) is approved in the United States to decrease the incidence and duration of severe oral mucositis in patients with hematological malignancies receiving myelotoxic therapy followed by hematopoietic stem cell transplantation (HSCT). The safety and efficacy of palifermin has not been established in patients with non - hematological malignancies. Here we report studies designed to determine if palifermin alters the anti-tumor activities of a relevant chemotherapy (5FU or cisplatin), Cetuximab, or the combination thereof in a model of colorectal (HT29) or head and neck carcinoma (Fadu). Cetuximab is an anti-epidermal growth factor receptor (EGFR) antibody approved for the treatment of colorectal carcinoma in combination with chemotherapy. The use of Cetuximab, and palifermin is currently being evaluated in patients with various solid tumors in separate clinical trials. The HT-29 and Fadu cell lines were chosen for detailed analysis as they express both the KGF and EGF receptors. The functionality of these receptors was then assessed by phosphorylation of Akt upon in vitro stimulation. Finally these cell lines were used to establish tumor xenograft models where the question of altered efficacy of the anti-tumor agents in the presence of palifermin was assessed. The studies demonstrated that in the presence of a functional KGF receptor on the tumor cells, palifermin had no effect on the growth of either tumor type compared to the vehicle treated control (p ≥ 0.8622). Comparisons between the combination of chemotherapy and Cetuximab versus chemotherapy, Cetuximab and palifermin, also found no statistically significant growth difference in either the HT-29 (p=>0.9999) or the Fadu (p = 0.7441) tumor xenograft models. In addition in the HT-29 tumors, the experiment was established such that comparisons could be made between each of the anti-tumor agents as single agents or in combination with palifermin. The comparison of 5FU alone or in combination with palifermin failed to demonstrate statistical significance (p = >0.9999) as did the same comparison using Cetuximab (p = 0.9985). These studies suggest that palifermin may have therapeutic potential in the treatment of mucositis in solid tumor settings in addition to HSCT, without negatively impacting anti-tumor activities of the relevant chemotherapy.
P08.13 A single pharmaceutic agent for molecular resection of Glioblastoma
Authors: P. Sonawane, D. Herpai, S. Ferluga, S. B. Tatter, W. Debinski
Journal: Neuro-Oncology (2017)

There are few treatment options available for glioblastoma (GBM) patients, and the outcome is poor. Interlukin-13 receptor alpha 2 (IL-13RA2), and A2, A3 and B2 receptors of the Eph family of receptors tyrosine kinase are over-expressed in GBM tumors, but not in normal brain. These receptors are involved in principal mechanisms involved in GBM tumor progression and resistance to therapies. They are present and functional in stem-like and differentiated tumor cells, infiltrating tumor cells, monocytic immune cells infiltrating tumors, but not T or dendritic cells, and in tumor-associated neovasculature. Each patient with GBM over-expresses at least one of these four receptors and more than 90% over-express a combination of at least two of them. We have attempted to target all the four receptors at once and deliver cytotoxic load leading to necrotic cell death. To this end, we have constructed a multivalent, bi-functional protein based on a human IgG1 scaffold. The targeting protein (eA5M-Fc-IL-13M) consists of proteolysis-resistant mutated ephrin-A5 (eA5, which is as a ligand for EphA2, EphA3, EphB2 receptors), the Fc region of IgG1 followed by a modified IL-13, which binds IL-13RA2, but not its physiological receptor; it is termed QUAD. The multivalent protein was expressed in Sf9 cells and purified to homogeneity using affinity Protein G column. The QUAD was then conjugated to a derivative of Pseudomonas exotoxin A, PE38QQR, a highly potent toxin to eukaryotic cells to generate QUAD-CTX. The SDS-PAGE and western blots showed the expected size bands of the purified protein of 125 kDa and, e g., 165 kDa of the 1:1 ligand:toxin conjugate. The binding and function of QUAD was tested in ELISA for specific targeted proteins, flow cytometry, neutralization of targeted cell killing using a PMS/MTS cell viability assay and receptor responses in vitro in GBM cells. The QUAD protein demonstrated specific binding to the three Eph receptors evoking the expected biological effects, such as activation of the receptors, and in that mimicking the property of eA5 alone. We also determined that the multivalent protein was effectively competing for the IL-13RA2 binding sites. Of importance, the QUAD-CTX killed GBM cells very potently while being neutral to various normal cells. Thus, we have successfully generated a multivalent agent capable of recognizing four receptor targets: IL-13RA2, EphA2, EphA3 and EphB2 that are over-expressed in most of the pathobiologically important tumor compartments and virtually in all GBM patients. The cytotoxic conjugate is also expected to have an in situ-vaccination effect due to the necrotic cell death it is causing to the targeted cells that in turn produces danger signal. Therefore, a single pharmaceutic agent under investigation offers potential for effecting molecular resection of GBM tumors with subsequent activation of the immune system.
OS04.5 Radiomics features can characterize the glioblastoma progression on preoperative multimodal MRI
Authors: J. Yan, A. van der Hoorn, C. Li, T. Matys, S. J. Price
Journal: Neuro-Oncology (2017)

Introduction: The identification of the glioblastoma invasive margin in the peritumoral zone outside of the contrast enhancing MRI is difficult, which leads to the failure of local treatment control. We aimed to use radiomics features to characterize the peri-tumoral areas, focusing on the difference between the tumor progression area and non-progression area by using preoperative multi-modal MRIs. And further identify the invasive margin of the glioblastoma. Methods: We retrospectively included 51 newly diagnosed cerebral glioblastoma patients. All patients were treated with 5-aminolevulinic acid (5-ALA) fluorescence guidance surgery and standard postoperative concomitant chemoradiotherapy. Preoperative MRI data acquisition was performed using a 3T MRI. Imaging included volumetric post contrast T1-weighted, perfusion MR, and DTI. DTI was decomposed into isotropic (p) component and anisotropic (q) components. The peritumoral progression areas were obtained by coregistration of the known progression images to the preoperative MRI by using a two stage semi-automatic coregistration method. A total number of 294 voxel based radiomics features were extracted from difference sequences, included first order features, and texture features by using an in-house Matlab program. 37 patients were used to train the classifier, and the other 20 patients were used as an independent validation cohort. Results: In the peritumoral progression area, compare to non-progression area within 10 mm around the contrast enhancing lesion, there were higher signal intensity in FLAIR (p = 0.02), rCBV (p = 0.038), and T1C (p = 0.0004), and there were lower intensity in ADC (p = 0.029) and p (p = 0.001). Radiomics features 35 first order features and 77 second order features were found significantly different between progression and non-progression area. By using supervised convoluted neural network, there was an overall accuracy of 92.4% in the training set (n = 37) and 78.5% in the validation set Conclusion: Multimodal MR imaging, particularly diffusion tensor imaging, can demonstrate distinct characteristics in areas of potential progression on preoperative MRI. Besides, radiomics features can be a potential useful tool to further identify the tumor invasive margin.