tbuckley/cabot-search huggingface dataset:
SURG-08. SURVIVAL BENEFIT OF LOBECTOMY FOR PRIMARY GLIOBLASTOMAS IN NON-ELOQUENT REGION: GROSS-TOTAL RESECTION VERSUS SUPRATOTAL RESECTION
Authors: Minkyun Na, Tae Hoon Roh, Ju Hyung Moon, Eui Hyun Kim, Seok-Gu Kang, Jong Hee Chang
Journal: Neuro-Oncology (2018)

This single center retrospective study aims to assess survival benefit of lobectomy compared to gross-total resection without lobectomy for primary glioblastomas (pGBM) in non-eloquent region. The only prognostic factor of glioblastoma that can be determined by the surgeon is the extent of resection. However, glioblastomas are known to infiltrate to a wider extent and are eventually recurred by remaining microscopic tumors. In surgical oncology field, the classic concept of radical resection was wide resection including normal surrounding tissue. Nevertheless, it is not yet known whether further removal of tumor-surrounding tissue may be helpful for survival in pGBM patients. Among the patients who had undergone surgical resection and were diagnosed as glioblastoma by histopathologic examination, we selected patients who had complete resection with the lesion localized on the non-dominant frontal or temporal lobe. Patients were divided into two groups: those who underwent gross-total resection of the tumor without additional tissue resection (GTR group) and those who underwent gross-total resection of the tumor with additional lobectomy (SupTR group). Progression-free survival (PFS), overall survival (OS) and postoperative Karnofsky performance scale (KPS) score were compared between groups. Thirteen of 28 patients underwent complete resection only, and 15 patients underwent complete resection with additional frontal or temporal lobectomy. The median PFS time after surgery was 13.1 months (95% CI 6.4–19.8) in GTR group and 38.3 months (95% CI 11.9–64.7) in SupTR group (p=0.098), respectively. The median OS time after surgery was 14.4 months (95% CI 12.1–16.7) in GTR group and 35.0 months (95% CI 17.4–52.6) in SupTR group (p=0.018), respectively. The mean postoperative KPS score was 73.4 in GTR group and 71.33 in SupTR group (p=0.586), respectively. CONCLUSIONS: In the non-dominant frontal or temporal glioblastomas which were completely resectable, additional lobectomy improved overall survival, without deteriorating performance of the patients.
Inhibitor of apoptosis protein BIRC3 (API2, cIAP2, AIP1) is upregulated by the non-canonical NFKB pathway.
Authors: Peter Simon, Rachel Sargent, Arnold Rabson
Journal: Cancer Research (2007)

5327  The Nuclear Factor kappa B (NF-κB) family of transcription factors regulates genes involved in a diverse range of cellular processes including cell growth, inflammatory response, differentiation and apoptosis. Members of the family are regulated by at least two distinct pathways. In the well-studied classical pathway, numerous stimuli lead to ubiquitin-dependent degradation of the IkBα regulatory protein allowing the functionally active p50/p65 complex to accumulate in the nucleus and stimulate transcription. The non-canonical NF-κB pathway is regulated by the p100 NF-κB2 protein which encodes an IκB-like activity within its C-terminus. p100 is processed to p52 NF-κB2 in response to cellular stimulation through a subset of TNFR family members. Mutations, commonly truncations in the IκB-like domain of the NFKB2 gene, have been found in B-cell non-Hodgkin’s lymphomas, chronic lymphocytic leukemia, multiple myelomas, cutaneous T-cell lymphomas (CTCL), breast and colon cancers. These mutations lead to stimulation-independent processing of NFKB2 to the active p52. To identify potential target genes that might play a role in malignancies associated with activation of the non-canonical NFKB pathway, we cloned the truncated NFKB2 gene (p80) from the HUT 78 human CTCL cell line downstream of a Tetracycline-repressible promoter. This construct was stably integrated into the Jurkat T-lymphocyte cell line and RNA was harvested under conditions of elevated and repressed p80 expression. Whole genome expression analysis using Affymetrix microarrays revealed several genes correlated with p80 expression. One of these genes, BIRC3 (API2, cIAP2, AIP1), is a member of the Inhibitor of Apoptosis family of proteins that has been previously linked to activation by the classical NFKB pathway. We confirmed the microarray results by performing RT-qPCR reactions and show elevated levels of BIRC3 mRNA in cells expressing high levels of p80. Further, in transient transfection assays in Jurkat cells with the BIRC3 promoter cloned upstream of the Luciferase reporter gene, we have shown that plasmids expressing p80, and the processed p52 are capable of stimulating the BIRC3 promoter whereas activation by the wild type p100 was diminished. BIRC3 promoter activity was further stimulated by cotransfection of p80 (or p52) with RELB or p65, indicating possible binding partners in NFKB dimers. Additional work is ongoing to elucidate the similarities and differences in classical and non-canonical NFKB activation of the BIRC3 gene.
Abstract 19788: Comparative Outcomes of Mechanical Thrombectomy for Acute Ischemic Stroke in Patients With and Without Atrial Fibrillation
Authors: Muhammad Bilal Munir, Fahad Alqahtani, Sami Aljohani, Abdulrahman Tarabishy, Abdulrahman Beltagy, Ashwin Bhirud, Mohamad Adnan Alkhouli
Journal: Circulation (2017)

Background: Acute ischemic strokes in atrial fibrillation (Afib) patients are associated with higher degree of disability, and worse outcomes than in patients with no AF. Mechanical thrombectomy (MT) has been recently assigned a class IA recommendation for the treatment of ischemic stroke in select group of patients. However, single center reports suggested possible worse outcomes of MT in patients with AF due to the larger and more organized/resistant clots. Methods: We utilized the national database to compare in-hospital outcomes and resource utilization of MT for ischemic stroke in patients with and without AF. Results: Out of 933,659 patients admitted with ischemic stroke between 2003 - 2014, 4627 patients (0.5%) underwent MT. Out of these patients, 1480 (32%) had concomitant AF while remaining patients were categorized as non-AF cohort. AF patients were older (74 vs. 60 years, p< 0.001) and had significantly higher burden of key co-morbidities as compared to non-AF group (Table-1). After propensity ...
GENE-41. LIQUID BIOPSY USING CELL FREE DNA FROM THE CEREBROSPINAL FLUID (CSF) IN GLIOMA
Authors: Jun-ichi Adachi, Tomonari Suzuki, Kazuhiko Mishima, Ryo Nishikawa
Journal: Neuro-Oncology (2018)

Mutation in the IDH1gene is a genetic defect exclusively found in glioma, and has been established as a prognostic factor for WHO Grade 2–4 glioma. Therefore, detecting this mutation is clinically important. In this study, we report the results of analyzing defects in IDH1 mutation by detecting circulating cell free (ccf) DNA in the CSF derived from the tumor tissue of glioma patients. Moreover, MGMTpromoter methylation, H3F3A and BRAFmutation were evaluated for the CSF samples in a subset of glioma patients. Lumbar puncture was performed to obtain CSF from 7 patients with glioma. ccfDNA was extracted from 1 ml of CSF using the Maxwell rapid sample concentrator system. Subsequently, the presence of point mutation of theIDH1gene was screened by real-time PCR/high-resolution melting (HRM) curve analysis, and the mutation was confirmed on the basis of DNA sequencing results. Status in the IDH1gene was also analyzed using the same assay technique for the DNA extracted from the excised fresh tumor tissue, to compare the results with that of CSF-derived ccfDNA. In addition, ccfDNA was also extracted from the plasma in 3 patients to additionally examine the presence of the IDH1gene mutation. MGMTpromoter methylation, H3F3A and BRAFmutation were also performed using the HRM method. CSF-derived ccfDNA was successfully extracted from all patients and analyzed. IDH1gene mutation was detected in 3 of the 7 glioma patients. The results of the IDH1gene analysis of CSF-derived ccfDNA and that of the DNA extracted from the surgically excised tumor tissue were consisted in all patients. Three MGMTpromoter methylation, two H3F3Amutations, and three BRAFmutations were detected, respectively. Gene analysis of ccfDNA from the CSF enabled the evaluation of IDH1 mutation in glioma patients less invasively, without directly obtaining any tumor tissue. Moreover, this technique can be applied to analyze MGMTgene promotor methylation, H3F3A and BRAFmutation.
Hepcidin Suppression By Momelotinib Is Associated with Increased Iron Availability and Erythropoiesis in Transfusion-Dependent Myelofibrosis Patients
Authors: Stephen T Oh, Moshe Talpaz, Aaron T. Gerds, Vikas Gupta, Srdan Verstovsek, Ruben A. Mesa, Carole Brennan Miller, Candido E. Rivera, Angela Fleischman, Swati Goel, Mark L Heaney, Casey O'Connell, Murat Arcasoy, Yafeng Zhang, Jun Kawashima, Tomas Ganz, Carrie Baker Brachmann
Journal: Blood (2018)
Abstract 17709: Interleukin-1 Blockade in Heart Failure With Preserved Ejection Fraction: The Diastolic Heart Failure Anakinra Response Trial 2 (DHART2)
Authors: Benjamin Van Tassell, Justin Canada, Leo Buckley, Salvatore Carbone, Cory Trankle, Marco Del Buono, Dave Dixon, Dinesh Kadariya, Hayley Billingsley, Tae Shik Park, Chau Vo, Sofanit Dessie, Ross Arena, Antonio Abbate
Journal: Circulation (2017)

Introduction: Enhanced inflammation may contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Hypothesis: Interleukin-1 (IL-1) blockade with anakinra may impr...
IMMU-32. RETARGETING IMMUNOEDITED GLIOMA ESCAPE VARIANTS WITH ADOPTIVE CELLULAR THERAPY
Authors: Tyler Wildes, Kyle Dyson, Adam Grippin, Bayli DiVita, Catherine Flores, Duane Mitchell
Journal: Neuro-Oncology (2018)

Adoptive T cell immunotherapy (ACT) leads to extension of median survival and long-term cures of treatment-resistant models of malignant glioma, medulloblastoma, and pontine gliomas. While very promising, tailored strategies to overcome ACT failure are needed. Therefore, we studied the tumors and adoptively-transferred T cells of KR158B glioma-bearing mice after they escaped ACT. The remaining T cells recognized the original KR158B tumor; however, the escaped tumor displayed marked immunoediting rendering it distinct from original tumor. We anticipated that successful strategies would need to be tailored to the new antigenic signature and therefore studied the HYPOTHESIS: That ex vivo-expanded T cells specific for glioma escape variants could successfully retarget immunoedited gliomas, despite the loss of primary antigens. We performed RNAseq on normal brain, primary KR158B and GL261 gliomas, and tumor escape variants from KR158B (TOGA1.1/1.2) to analyze gene expression changes after ACT. We used restimulation co-cultures of T cells with tumor targets and IFN-g ELISAs to determine T cell activation. RNAseq showed parental tumors KR158B and GL261 share many differentially-expressed genes compared to normal brain. The escape variant TOGA1.1 demonstrated loss of ~80% of the genes that were upregulated in the KR158B and GL261 tumors. When we generated TOGA1.1 or TOGA1.2-specific T cells, they efficiently recognized TOGA1.1 or TOGA1.2 tumors but not primary KR158B or the opposite glioma escape variant. Additionally, T cell receptor (TCR)-Vb spectratyping prior to restimulation determined that distinct TCR-Vb families recognized parental tumors and TOGA1.1 and 1.2. Glioma escape variants are antigenically-distinct from primary tumors and other escape variants but retain expression of immunogenic antigens. Generation of ACT with specificity for escape variants provides exquisite antigen-specific recognition of the immunoedited tumors. These studies suggest feasibility of repeated treatment of tumors that have escaped ACT with generation of new, activated T cells targeting immunoedited gliomas.
Chitinase 3‐like 1 protein plays a critical role in respiratory syncytial virus‐induced airway inflammation
Authors: Min Jung Kim, Doo Hee Shim, Hye‐Ran Cha, Kuk‐Young Moon, Chang Mo Yang, Su Jin Hwang, Kyung Won Kim, Jeon Han Park, Chun Geun Lee, Jack A. Elias, Myung Hyun Sohn, Jae Myun Lee
Journal: Allergy (2018)

Chitinase 3-like 1 protein (CHI3L1) (YKL-40 in humans and breast regression protein [BRP]-39 in mice) is required for optimal allergen sensitization and Th2 inflammation in various chronic inflammatory diseases including asthma. However, the role of CHI3L1 in airway inflammation induced by respiratory viruses has not been investigated. The aim of this study was to investigate the relationship between CHI3L1 and airway inflammation caused by respiratory syncytial virus (RSV) infection. We measured YKL-40 levels in human nasopharyngeal aspirate (NPA) from hospitalized children presenting with acute respiratory symptoms. Wild-type (WT) and BRP-39 knockout (KO) C57BL/6 mice were inoculated with live RSV (A2 strain). Bronchoalveolar lavage fluid and lung tissue samples were obtained on day 7 after inoculation to assess lung inflammation, airway reactivity, and expression of cytokines and BRP-39. In human subjects, YKL-40 and IL-13 levels in NPA were higher in children with RSV infection than in control subjects. Expression of BRP-39 and Th2 cytokines, IL-13 in particular, was increased following RSV infection in mice. Airway inflammation caused by RSV infection was reduced in BRP-39 KO mice as compared to WT mice. Th2 cytokine levels were not increased in the lungs of RSV-infected BRP-39 KO mice. BRP-39 regulated M2 macrophage activation in RSV-infected mice. Additionally, treatment with anti-CHI3L1 antibody attenuated airway inflammation and Th2 cytokine production in RSV-infected WT mice. These findings suggest that CHI3L1 could contribute to airway inflammation induced by RSV infection. CHI3L1 could be a potential therapeutic candidate for attenuating Th2-associated immunopathology during RSV infection.
STEM-22. UPTAKE OF P-BORONO-PHENYLALANINE BY BRAIN TUMOR STEM LIKE CELLS ANALYZED BY MASS CYTOMETRY
Authors: Natsuko Kondo, Masaki HIkida, Mitsutoshi Nakada, Minoru Suzuki
Journal: Neuro-Oncology (2018)

Because of chemo- and radio-resistance of brain tumor stem cells, they could be the origins of recurrent malignant glioma. We have used boron neutron capture therapy (BNCT) to treat patients with either recurrent or newly diagnosed malignant glioma resulting in a significant increase in median survival of patients. BNCT is a form of tumor-selective particle radiation therapy consisting of two components. First, a boron-10 (10B)-containing drug is administered, followed by irradiation with epithermal neutrons. The resulting 10B(n,α)7Li capture reaction produces alpha particles whose short path length (5–9 µm) results in the selective killing of tumor cells with a concomitant sparing of adjacent normal tissues. P-borono-phenylalanine (BPA) is a chemical compound used in clinical trials in BNCT. BPA accumulates preferentially in growing cells rather than in quiescent cells of the tumor. Here, we investigate whether brain tumor stem like cells take up BPA or not using mass cytometry (Cytof). We used brain tumor stem like cells (SLC) and the cells differentiated by fetal bovine serum from them (DC). After exposure to BPA for 24 hours at the concentration of 25ppm in 5% CO2 incubator, we immune-stained them using twenty stem cell markers, anti-Ki-67, anti-BPA and anti-CD98 (heterodimer that forms the large neutral amino acid transporter to take up BPA) antibody and analyzed with Cytof. Two to three times larger number of SLC were BPA or CD98 (+) than DC. In BPA or CD98 (+) cells in SLC, although the number of Ki-67 (+) cells were only two to three times larger than negative cells, that of stem cell marker (Oct3, Nestin, Sox2, and PDGFRa) (+) cells were two to six times larger than negative cells Stemness may influence the uptake of BPA. In following experiments, effect of tumor micro-environment on BPA uptake is to be cleared.
Is Upcoding Anesthesia Time the Tip of the Iceberg in Insurance Fraud?
Authors: Alberto Coustasse, Mike Frame, Avinandan Mukherjee
Journal: JAMA Network Open (2018)

The Centers for Medicare & Medicaid Services (CMS) defines fraud as making false statements to obtain benefit or payment for which no entitlement would otherwise exist.Medicare and Medicaid fraud was estimated in 2014 to range from $82 billion to $272 billion and involved spending $1.4 billion to combat it. 1Examples of Medicare fraud include but are not limited to billing for services not furnished, billing for services not necessary, misrepresenting the diagnosis to justify payment, and upcoding. 2An unknown number of health care professionals, hospitals, and other health care organizations have probably upcoded for many years.For example, it has been reported that 10 000 of 60 000 annual paid claims for infections that were present at admission were actually hospitalacquired infections that were upcoded to present at admission to avoid financial penalties and claim compensation. 3Examples of Medicare fraud that involves physicians have included cardiologists knowingly submitting claims for consultation services that were not supported by patient medical records and did not meet the criteria for a consultation and endocrinologists who billed routine blood sample collection as critical care blood sample collection. 4
PATH-36. IDH AND TERT PROMOTER MUTATIONS IN NON-DIAGNOSTIC BIOPSIES FROM GLIOMA PATIENTS
Authors: Marc Barritault, Thiebaud Picart, Delphine Poncet, Tanguy Fenouil, Jacques Guyotat, Emmanuel Jouanneau, Bastien Joubert, Alexandre Vasiljevic, Jerôme Honnorat, David Meyronet, Francois Ducray
Journal: Neuro-Oncology (2018)

Non-diagnostic biopsies are a recurrent issue in patients with a suspected brain tumor. Herein, in order to explore the utility of molecular testing in this setting, we determined whether IDH and TERT promoter (pTERT) mutations can be detected in non-diagnostic biopsies from glioma patients. Using Snapshot PCR, we retrospectively assessed IDH and pTERT mutation status in 28 adult glioma patients in whom a first non-diagnostic biopsy had led to perform a second biopsy. Median age at diagnosis was 65 years and median delay between the first and second biopsy 21 days. The first biopsy consisted of not characterizable infiltrated glial cells (n=19), hemorrhage (n=4), necrosis (n=2) or normal tissue (n=3). The second biopsy demonstrated an IDH-wildtype glioblastoma (n=22), an IDH-wildtype astrocytoma (n=4), an IDH-mutant oligodendroglioma (n=1) and an IDH-mutant astrocytoma (n=1). A pTERT mutation was present in 21 cases. Retrospectively, the same IDH and pTERT mutations were identified in the non-diagnostic biopsies of the 2 patients with an IDH-mutant glioma and of 12 out of 21 patients with a pTERT-mutant glioma (57%). Overall an IDH and/or a pTERT mutation were detected in the non-diagnostic biopsies of 13 out of the 22 IDH-mutant and/or pTERT-mutant gliomas (59%) and in 13 out of the 28 cases included in the present series (46%). IDH and pTERT mutations can be detected in a high percentage of non-diagnostic biopsies from glioma patients supporting a role for molecular testing in the interpretation of non-diagnostic biopsies from patients with a suspected brain tumor.
Why are diabetics prone to kidney infections?
Authors: Michael Zasloff
Journal: Journal of Clinical Investigation (2018)

People with diabetes mellitus are at higher risk of developing serious ascending infections of the urinary tract. The traditional explanation has focused on the role of glycosuria in promoting bacterial growth. Using mouse models, Murtha et al. demonstrate that when the intracellular insulin signaling pathway is compromised, antimicrobial defenses are compromised too, and the mice are unable to effectively handle uropathogenic E. coli introduced experimentally into the urinary tract. These observations strongly support the hypothesis that the antimicrobial defenses of the kidney are dependent on insulin, and the urinary tract infections associated with diabetes occur due to reduced expression of these key effectors of innate immunity.
GENE-05. UPREGULATION OF ODZ1-MEDIATED INVASION IN THE HYPOXIC TUMOR MICROENVIRONMENT IN GLIOBLASTOMA
Authors: Carlos Velásquez, Sheila Mansouri, Pilar Molinedo, Juan Martino, Yasin Mamatjan, Ana Talamillo, Shirin Karimi, Nuria Terán, Kenneth Aldape, Gelareh Zadeh, José Fernández-Luna
Journal: Neuro-Oncology (2018)

Differentiation of GBM stem-like cells activates an ODZ1-associated pathway, involving activation of the RhoA-ROCK cascade, leading to cytoskeletal remodelling and invasion into the surrounding environment. Clinically, ODZ1 is associated with decreased survival rates. Nevertheless, the association of the ODZ1-mediated invasion pathway with hypoxia, a major hallmark of GBM related to tumor invasion, has not been previously described. In this study, we evaluated expression of ODZ1 and its promoter methylation status under hypoxic conditions in vitro using glioma cell lines, and in vivo by administering pimonidazole (PIMO) to 14 GBM patients. Expression of ODZ1 mRNA was elevated in vitro and its protein expression in tumor samples was increased in regions staining positive for PIMO based on immunohistochemical analysis. ODZ1-promoter methylation status was assessed in DNA extracted from cells exposed to hypoxia and patient tumors using DNA extracted from PIMO-positive and –negative regions by immune-guided laser capture microdissection (LCM) and analyzed on the Illumina Human Methylation EPIC array platform. Hypoxic conditions led to a higher migratory capacity of GBM cells in-vitro, which correlated with an increase in ODZ1 mRNA level. A significant association between ODZ1-positivity and PIMO uptake (pODZ1-promoter was found to be hypomethylated in PIMO-positive regions compared to PIMO-negative regions, in addition to cells grown under hypoxia. Our data suggest that up-regulation of ODZ1 expression and ODZ1-mediated GBM invasion is associated with the hypoxic tumor microenvironment. It is likely that hypoxia leads to increased transcription of ODZ1mRNA through epigenetic regulation. ODZ1 expression within hypoxic tumor microenvironment may serve as a prognostic marker and therapeutic target in GBM.
EXTH-68. ZIKA VIRUS ONCOTROPISM TOWARDS GLIOBLASTOMA PROGENITOR CELLS IS MEDIATED BY THE TYROSINE KINASE RECEPTOR Axl
Authors: Richard Rovin, Parvez Akhtar, Samuel Zwernik, Amin Kassam
Journal: Neuro-Oncology (2018)

An oncolytic virus must display tropism for the target cancer. This oncotropism is mediated by cell surface receptors that are differentially expressed by the cancer cell. Recent research into the mechanism of Zika virus (ZV) induced microcephaly demonstrated that ZV has neurotropism for fetal neural progenitor cells, and this is mediated by Axl. Axl is a member of the TAM (Tyro3, Axl, Mer) family of tyrosine kinase receptors. Additional research showed that Axl is overexpressed in 60% of glioblastoma (GBM). We therefore hypothesized that ZV could target GBM progenitor cells through the Axl receptor. Using Western blot, we discovered that there is a range of Axl expression in commercially available cell lines (5 GBM, 2 breast cancer) and in 11 patient derived GBM progenitor cell lines. Using flow cytometry and immunofluorescence microscopy, we confirmed that ZV cell entry correlates with Axl expression. ZV did not enter nor productively infect Axl negative cell lines. While at 24 hours post exposure, the number of intracellular viral particles increased as Axl expression increased. We next demonstrated that ZV entry was abrogated by the Axl inhibitor R428 in a dose dependent manner, and, anti-Axl antibody treatment also prevented ZV entry. These findings were again confirmed with both flow cytometry and immunofluorescence microscopy. We therefore conclude that ZV is oncotropic towards GBM progenitor cells and this is mediated by the Axl receptor. Thus, ZV meets the first requirement for a GBM oncolytic virus: receptor mediated oncotropism.