tbuckley/cabot-search huggingface dataset:
QOLP-02. INSURANCE STATUS IMPACTS THE ECONOMIC BURDEN AND SURVIVAL OF GLIOBLASTOMA PATIENTS WITH HEALTH INSURANCE
Authors: Ankush Chandra, Jacob Young, Cecilia Dalle Ore, Darryl Lau, Jonathan Rick, Fara Dayani, Alan Nguyen, Joseph Garcia, Michael McDermott, Mitchel Berger, Manish Aghi
Journal: Neuro-Oncology (2018)

Glioblastoma carries a high economic burden for patients and caregivers. We investigated the hospital costs of surgery for newly-diagnosed glioblastoma patients based on insurance status. Retrospective review of GBM patients undergoing first resection at UCSF and corresponding hospital charges from 2010–2015. Of 227 patients (median age= 62; females= 37.9%), 31 (13.7%) had Medicaid, 94 (41.4%) had Medicare, and 102 (44.9%) had private insurance. Medicaid patients had 30% higher mean overall hospital costs for resecting GBM compared to non-Medicaid insurance patients ($50,285 vs $38,800; p= 0.015). Sub-cost analysis revealed Medicaid patients had higher ICU, OR and imaging costs versus non-Medicaid insured patients ($13,400/$16,470/$2,182 vs $9,700/$14,770/$1,357; p= 0.01/p= 0.03/p< 0.0001). Kaplan-Meier survival analysis showed Medicaid patients had the shortest overall survival (10.7 months, Medicare = 12.8 months, Private insurance = 15.8 months; p=0.02). Tumor diameter at diagnosis was largest for Medicaid (4.7 cm) versus Medicare (4.1 cm) and privately insured patients (4.2 cm; p=0.03). Only 67.74% of Medicaid patients had PCPs versus 91.5% and 86.27% of Medicare and privately insured patients, respectively (p=0.004), at their initial visit to our institution. Medicaid patients had longer overall and ICU lengths of stay (6.9 and 2.6 days) versus Medicare (4.0 and 1.5 days) and privately insured (3.9 and 1.8 days; p < 0.01) cohorts. Moreover, Medicaid patients had similar comorbidity rates as Medicare patients (67.8% vs. 67.18%), but both groups had higher comorbidity rates than privately insured patients (40.4%; p< 0.0001). CONCLUSIONS: Despite higher surgical costs and longer lengths of stay, GBM patients with Medicaid have poorer survival. This may reflect that these patients lacking PCPs and, thus, having more comorbidities and presenting later in the disease course with larger tumors consume more hospital resources such as OR time and confer increased operative risk.
Salmonella-induced thrombi in mice develop asynchronously in the spleen and liver and are not effective bacterial traps
Authors: Nonantzin Beristain-Covarrubias, Marisol Perez-Toledo, Adriana Flores-Langarica, Malou Zuidscherwoude, Jessica R. Hitchcock, Will M. Channell, Lloyd D. W. King, Mark R. Thomas, Ian R. Henderson, Julie Rayes, Steve P. Watson, Adam F. Cunningham
Journal: Blood (2018)
Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea
Authors: Stephanie N. Taylor, Jeanne Marrazzo, Byron E. Batteiger, Edward W. Hook, Arlene C. Seña, Jill Long, Michael R. Wierzbicki, Hannah Kwak, Shacondra M. Johnson, Kenneth Lawrence, John Mueller
Journal: New England Journal of Medicine (2018)

Antibiotic-resistant Neisseria gonorrhoeae has prompted the development of new therapies. Zoliflodacin is a new antibiotic that inhibits DNA biosynthesis. In this multicenter, phase 2 trial, zoliflodacin was evaluated for the treatment of uncomplicated gonorrhea.
Unique prostate cancer marker, prostate specific membrane antigen or PSMA and its role in prostate cancer metastasis.
Authors: Arundhati Ghosh, Warren D. Heston
Journal: Cancer Research (2004)

3292  Prostate Specific Membrane Antigen, PSMA is a type II transmembrane glycoprotein, overexpressed in prostate carcinoma. PSMA is negatively regulated by androgen. PSMA is a unique cell surface marker for imaging of hormone refractory carcinomas and metastatic foci. PSMA has two important enzymatic function, namely, folate hydrolase and NAALADase. Folate hydrolase function of PSMA is required to cleave terminal gamma-linked glutamates from poly-gamma-glutamated folates and NAALADase activity, where it cleaves the terminal glutamate from neuro-dipeptidase, N-acetyl-aspartyl-glutamate. Apart from its enzymatic function, PSMA also exhibits an endocytic function, where it spontaneously recycles through endocytic vesicles or it can internalize with its own monoclonal antibody. It is not known at this moment, whether PSMA has its own natural ligand. It is not clear whether PSMA has any role in the invasion of prostate cancer cells through extracellular matrix, i.e., in metastasis. For that purpose, we have tried to use PSMA overexpressed cell line PC3-PIP (PC3 cells derived, over-expressing PSMA), as well as other prostate cancer cell lines, which express PSMA endogenously (e.g., LNCaP, C4-2, CWR22, MDAPCa2b etc.), showed reduction in invasion capability compared to PC3, DU145 cells (which do not express PSMA normally) indicates that PSMA has anti-metastatic role, in prostate cancer cell invasion. To rule out the possibility that this reduction in the invasion capability of PSMA expressing cells are due to PSMA expression, not due to intrinsic properties of different prostate cancer cell lines, the PSMA expressing PC3-PIP cells were tested against PC3-FLU cells. We found that PC3-PIP cells expressing PSMA showed about 5-fold reduction in the invasion capability compared to PC3-FLU cells mediated inhibition of invasion. Same observation holds true for other PSMA over-expressing cell lines. We have also observed that different kinds of sugar residues have significant effect on the prostate cancer cells ability to invade though extracellular matrix. We have tried to dissect different biological functions of PSMA whether that has any role in the metastatic progression of prostate cancer cells. We have studied role of sugar modifications as well as the function of internalization motif on the invasion of PSMA expressing prostate cancer cells. We have found that altering sugar residues at various attachment sites has dramatic effect on this novel function of PSMA. Further work is being carried out in which we have knocked off the expression of PSMA in prostate cancer cell lines by RNAi method and analyzing their invasion properties. These interesting findings will be discussed.
NCMP-07. CLINICAL NEUROLOGICAL FEATURES AND ELECTROGRAPHIC PATTERNS OF PATIENTS WITH RELAPSED OR REFRACTORY LARGE B-CELL LYMPHOMA TREATED WITH AXICABTAGENE CILOLEUCEL AT MEMORIAL SLOAN KETTERING CANCER CENTER (MSKCC)
Authors: Alexandra Sequeira, David Mao, Xi Chen, Edward Avila, Elena Mead, Craig S Sauter, Maria Lia Palomba, Parastoo B Dahi, Connie Lee Batlevi, Gunjan L Shah, Jason Chan, Sergio A Giralt, Miguel-Angel Perales, Bianca D Santomasso
Journal: Neuro-Oncology (2018)

CD19-specific chimeric antigen receptor (CAR) T cell therapy is a promising treatment for hematological malignancies however is associated with neurotoxicity. Axicabtagene ciloleucel is approved to treat adult patients with relapsed or refractory large B-cell lymphoma. Here we describe the neurological features and encephalogram (EEG) patterns of patients with refractory lymphoma treated with axicabtagene ciloleucel at Memorial Sloan Kettering Cancer Center (MSKCC). We retrospectively analyzed the neurological features and EEG patterns of the first six patients with refractory lymphoma treated at MSKCC with axicabtagine ciloleucel between February and April 2018. All six patients developed neurotoxicity, with both diffuse encephalopathy and focal neurological features.None of the patients had pre-existing neurological conditions. All patients received prophylatic levetiracetam and had a long-term video EEG performed. Two patients developed neurological findings concerning for focal status epilepticus. One patient had rhythmic right arm movements followed by weakness and the EEG showed left lateralized rhythmic delta activity (LRDA) with sharp waves and attenuation possibly reflecting a post-ictal state. The second patient had right facial and bilateral eye twitching concerning for focal motor status epilepticus. The EEG showed diffuse dysfunction - rhythmic delta activity and triphasic waves. Both patients had clinical improvement with addition of fosphenytoin. The remaining four patients had EEGs showing diffuse cerebral dysfunction. Neuroimaging in all patients was unrevealing for acute or significant structural pathology. Most patients had resolving neurologic symptoms; one patient had prolonged paraparesis. CONCLUSIONS: Axicabtagene ciloleucel can lead to transient diffuse and focal neurological findings of varying severity including focal status epilepticus. EEG is useful in characterizing cerebral dysfunction however is limited in detecting epileptic events. In patients who develop clinical status epilepticus escalation of AEDs may be warranted despite EEG not fulfilling status epilepticus criteria. Further study is needed to determine whether AED escalation can optimize patient outcomes.
Abstract 15072: Long-term results of Catheter Ablation for Supraventricular Tachycardia Involving Twin Atrioventricular Nodes in Patients with Complex Heart Disease
Authors: Daiji Takeuchi, Keiko Toyohara, Morio Shoda, Takeshi Hiramatsu, Toshio Nakanishi
Journal: Circulation (2010)

Background: Supraventricular tachycardia (SVT) involving twin atrioventricular (AV) nodes often affects morbidity in complex heart disease. Although catheter ablation (CA) is performed for such SVT...
Cell Surface Notch Ligand DLL3 is a Therapeutic Target in Isocitrate Dehydrogenase–mutant Glioma
Authors: Marissa Spino, Sylvia C. Kurz, Luis Chiriboga, Jonathan Serrano, Briana Zeck, Namita Sen, Seema Patel, Guomiao Shen, Varshini Vasudevaraja, Aristotelis Tsirigos, Carter M. Suryadevara, Joshua D. Frenster, Kensuke Tateishi, Hiroaki Wakimoto, Rajan Jain, Howard A. Riina, Theodore P. Nicolaides, Erik P. Sulman, Daniel P. Cahill, John G. Golfinos, Kumiko Isse, Laura R. Saunders, David Zagzag, Dimitris G. Placantonakis, Matija Snuderl, Andrew S. Chi
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Isocitrate dehydrogenase (IDH)-mutant glioma is a distinct glioma molecular subtype for which no effective molecularly directed therapy exists. Low-grade gliomas, which are 80%–90% IDH-mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by IHC in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody–drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in IDH-mutant glioma. Experimental Design: We evaluated DLL3 expression by RNA using TCGA data and by IHC in a discovery set of 63 gliomas and 20 nontumor brain tissues and a validation set of 62 known IDH wild-type and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous IDH-mutant glioma tumorspheres was determined by cell viability assay. Results: Compared to IDH wild-type glioblastoma, IDH-mutant gliomas have significantly higher DLL3 RNA (P &amp;lt; 1 × 10−15) and protein by IHC (P = 0.0014 and P &amp;lt; 4.3 × 10−6 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in IDH-mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 nontumor brains. Patient-derived IDH-mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner. Conclusions: DLL3 is selectively and homogeneously expressed in IDH-mutant gliomas and can be targeted with Rova-T in patient-derived IDH-mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.
TMIC-39. UNRAVELLING THE TUMOUR MICROENVIRONMENT OF GLIOMA
Authors: Kelly McKelvey, Amanda Hudson, Helen Wheeler, Connie Diakos, Viive Howell
Journal: Neuro-Oncology (2018)

With the incidence and mortality of brain cancer almost equivocal there is a vital need to understand the intricacies of the glioma microenvironment. This study details the temporal and spatial localisation of immune cell populations and mediators during glioma development using the murine orthotopic Gl261 glioma model. Male C57Bl/6 mice were stereo-tactically inoculated with 1x106 Gl261 cells at AP0.1mm, ML1.0mm, DV2.4mm Bregma. Immune cell populations were assessed at D0, D1, D3, D7, D14, D21 post-inoculation by veterinary haematological analyser (Coulter Ac·Tdiff™) and 16-parameter flow cytometry (Fortessa™). Significant temporal changes were observed in all immune cell populations among the splenic, bone marrow and peripheral blood systemic compartments: WBCs, RBCs, platelets, CD3+ T cell, CD3+CD4+ Th, CD3+CD4+CD25+ Treg, CD3+CD8+ Tc, NK1.1+ NK, NK1.1+CD3+ NK/T, CD115+CD11b+ monocyte, CD115+CD11b+CD80+ M1, CD115+CD11b+CD206+ M2, CD115-CD11b+ DC, CD115-CD11b+Ly6ChighLy6G- M-MDSC, CD115-CD11b+Ly6C+Ly6G+ PMN-MDSC, CD117+ HSC and CD19+ B cell (Kruskal-Wallis with Dunn’s multiple comparison test; p=0.02- p< 0.0001). Analysis of plasma coagulation and inflammatory mediators, and histopathology of the tumour microenvironment is to be completed. The data derived provides baseline characteristics to study the changes associated with radiation, chemotherapy and immunotherapy treatment and to sequence therapies to maintain immune modulation. This information will contribute to identifying those immunotherapies which will have maximal benefit among the glioma patient population, where currently anti-CTLA-4 and anti-PD-1 immunotherapies have had little impact. KM is supported by a Matt Callander Beanie for Brain Cancer HMRI Fellowship funded by the Mark Hughes Foundation, and grants from The Brain Cancer Group and Sydney Vital Translational Cancer Centre; AH is supported by a The Brain Cancer Group Fellowship.
Dual carrier-cargo hydrophobization and charge ratio optimization improve the systemic circulation and safety of zwitterionic nano-polyplexes
Authors: Meredith A. Jackson, Sean K. Bedingfield, Fang Yu, Mitchell E. Stokan, Rachel E. Miles, Elizabeth J. Curvino, Ella N. Hoogenboezem, Rachel H. Bonami, Shrusti S. Patel, Peggy L. Kendall, Todd D. Giorgio, Craig L. Duvall
Journal: Biomaterials (2018)
PATH-37. LIQUID BIOPSY FOR IDENTIFICATION OF NEWLY DIAGNOSED GLIOMA
Authors: Ian Lee, Lisa Scarpace, Kevin Nelson, Darshana Patil, Vineet Datta, Dadasaheb Akolkar, Sachin Apurva, Pooja Fulmali, Sneha Puranik, James Snyder, Houtan Noushmehr, Pradeep Devhare, Ana deCarvalho, Rajan Datar, Tobias Walbert, Steven Kalkanis
Journal: Neuro-Oncology (2018)

In patients with newly diagnosed intracerebral lesions based on MRI, gliomas are often suspected, but MRI is rarely definitive thus necessitating biopsy. For non-enhancing lesions involving eloquent or deep-seated structures, diagnosis can be especially challenging as biopsy may be relatively risky or undesirable to the patient. In this study, analysis of plasma isolated cell-free DNA and exosome mRNA and miRNA from newly diagnosed glioma patients and from cancer-free volunteers was used to predict disease. Blood was drawn from 40 patients with newly diagnosed gliomas (28 high grade glioma (HGG), 12 low grade (LGG)) and 10 healthy volunteers without documented history of cancer. High quality DNA and RNA was isolated and sequenced using Next Generation Sequencing and Digital Droplet PCR was used for detection and verification of trace molecular artefacts. Multianalyte processing yielded data that was harmonized and interpreted through an Artificial Intelligence based algorithm to assess for possible glioma and to assign grade. EGFRviii and IDH1 mutations were also analyzed and compared to molecular testing from tumor specimens. 97.5% (39 of 40) of glioma patients were deemed to have gliomas by plasma testing. 96% of HGG patients and 67% of the LGG patients were correctly graded. Of the 10 healthy controls, 8 were concluded to be cancer-free. Two of the patients were suspicious for malignancy, of which one was possible glioma. IDH1 and EGFRviii mutation had concordance at 74 % (26/35) and 59% (12/16), respectively. CONCLUSIONS: Analysis of plasma cell free tumor derived DNA and RNA was highly sensitive for detecting glioma with high agreement in grading as well. In patients with newly diagnosed intracerebral lesions, this may be a useful screening test to determine the need for more invasive testing, i.e. biopsy/resection. Further testing in blinded samples from brain tumor patients and healthy subjects will follow.
Anti-neuropilin-1 antibodies block the binding of a tuftsin-antagonist peptide, TKPPR, to neuropilin-1 on receptor-positive cells
Authors: Mathew von Wronski, Natarajan Raju, Nancy Bogdan, Michael Tweedle, Adrian Nunn
Journal: Cancer Research (2007)

2086   Tuftsin is a short immunostimulatory peptide with the sequence TKPR. Its receptor was believed to be restricted mainly to certain immune cells, and a radiolabeled tuftsin analog has been used to image inflammation in man. We previously reported that the tuftsin antagonist peptide TKPPR binds neuropilin-1 (NP-1), a dual receptor for VEGF and class 3 semaphorins on endothelial and receptor-positive tumor cells, in a VEGF-competitive manner. In addition, particles such as 2-micron diameter beads or microbubbles coated with TKPPR bound specifically to NP-1 on cells. Moreover, at the subcellular level, quantum dots (Qdots) multivalently conjugated with the TKPPR peptide produced immunofluorescence-quality imaging of the apparent distribution of neuropilin-1 on endothelial cells. It was not clear however, whether binding to NP-1 could account for all of the TKPPR-conjugated particle association with endothelial cells or whether an additional receptor may be playing a significant role. We have now tested an anti-neuropilin-1 antibody that blocks VEGF’s interaction with NP-1 and found that it prevents almost all TKPPR-conjugated Qdot binding to HUVEC and the majority of binding to the neuropilin-1-positive PC-3 prostate adenocarcinoma cell line. These results confirm that TKPPR Qdots bind specifically to neuropilin-1 and suggest that in at least some cells neuropilin-1 provides the sole or primary TKPPR peptide binding site and that this peptide can be used to deliver imaging and therapeutic moieties to sites with increased NP-1 expression, such as in cancer, angiogenesis, and inflammation.
Abstract O.04: Kawasaki Disease With Down Syndrome:low Risk For Ivig Resistance And Coronary Artery Abnormalities
Authors: Shinichi Takatsuki, Masato Yokozawa, Masae Ono, Masako Fujiwara, Horoyuki Ida, Hideki Motomura, Horoyuki Moriuchi, Mio Taketazu, Junichi Oki, Shigeaki Nonoyama, Tatsuya Kawano, Kenji Ihara, Sachiko Kido, Junko Shiono, Shiro Tsuchiya, Keiji Tsuchiya, Teruhumi Goushi, Shuhei Ogata, Masahiro Ishii, Fukiko Ichida, Tsutomu Saji
Journal: Circulation (2015)

Background: Japanese nationwide survey reported that Down syndrome (DS) is less-frequently occurring comorbidity in Kawasaki disease (KD). Thus, no studies have focused treatment response and risk for coronary artery abnormalities (CAAs) in KD with DS. The aim of this study was to evaluate clinical manifestations, treatment response and incidence of CAAs in KD with DS. Methods: We retrospectively reviewed the medical records of KD with DS from 2005 through 2012. Data were collected according to survey questionnaires from 16 hospitals. Results: The response rate was 80% and the survey questionnaires from 16 KD patients (11 boys and 5 girls) with DS were collected. Age at diagnosis was 3 years (8 months to 12 years). Eight children (50%) were diagnosed incomplete KD. Five children had previous history of repaired congenital heart disease (AVSD 2, VSD+ASD 1, ASD 2, PDA 1). Of all, 8 children were classified as high risk group based on Kobayashi score. Twelve children received IVIG and 3 children were treated with only high dose aspirin. All 15 children were responded to initial treatment. In the remaining one girl with incomplete KD, the clinical symptoms spontaneously resolved. CAAs were not detected by echocardiography during follow-up. Conclusions: All DS children with KD were responded to initial IVIG or aspirin therapy despite the high risk of IVIG resistance and none of children had CAAs. Therefore, our finding suggested DS is not a risk factor for IVIG resistance and developing CAAs in KD.
Abstract 15531: Nicotinamide Inhibits NAMPT Release and Improves Outcomes in a Murine Model of Cardiac Arrest
Authors: Xiangdong Zhu, Jing Li, Chunpei Lee, Huashan Wang, Terry Vander Hoek
Journal: Circulation (2017)

Introduction: NAMPT is the rate-limiting enzyme in the NAD+ salvage pathway that converts nicotinamide (NAM) to nicotinamide mononucleotide to enable NAD+ biosynthesis. Tissue release of Nampt is a...
Abstract 15760: Inhibition of PI3kα Overcomes Apoptosis Resistance of Smooth Muscle Cells in Pulmonary Hypertension and Thereby Reverses Established Vascular Remodeling
Authors: Marius Vantler, Eva M Berghausen, Arnica Behringer, Rajkumar Savai, Soni Savai Pullamsetti, Stephan Baldus, Stephan Rosenkranz
Journal: Circulation (2016)

Pulmonary hypertension (PH) is hallmarked by vascular remodeling in pulmonary arterioles. Therapeutic reversal of established vascular remodeling is impeded by apoptosis resistance of pulmonary art...
CSIG-27. DIFFERENTIAL ELEVATION OF TERT ACTIVITY AND SENSITIVITY TO TEMOZOLOMIDE BY TYPE OF TERT MUTATION IN MGMT PROMOTER-METHYLATED GLIOBLASTOMA
Authors: Manuela Silginer, Alexandros Papachristodolou, Bettina Hentschel, Dorothee Gramatzki, Jörg Felsberg, Markus Löffler, Gabriele Schackert, Manfred Westphal, Jörg-Christian Tonn, Andreas von Deimling, Torsten Pietsch, Guido Reifenberger, Patrick Roth, Michael Weller
Journal: Neuro-Oncology (2018)

Benefit from temozolomide chemotherapy in glioblastoma is essentially limited to patients with tumors that exhibit O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Recent retrospective clinical analyses indicate that the impact of the MGMT status on chemosensitivity may be modulated by telomerase reverse transcriptase (TERT) promoter mutations. These commonly affect two regions of the TERT promoter, C228T and C250T. TERT promoter mutation status and TERT activity were determined and correlated with sensitivity to irradiation or temozolomide in long term and glioma-initiating cell lines. TERT status alterations were induced using sh-mediated gene TERT silencing or wildtype TERT overexpression. TERT mutation and MGMT promoter methylation status were also determined in a clinical patient cohort from the German Glioma Network. C228T-mutant glioma cell lines (n=8) show higher TERT mRNA expression (mean 0.046 ± 0.012 vs 0.012 ± 0.004 arbitrary units, p=0.049) and higher TERT catalytic activity (mean 122 ± 16 vs 53 ± 11 arbitrary units, p=0.022) than C250T-mutant glioma cell lines (n=5). C228T-mutant glioma cell lines are also more sensitive to irradiation (mean ED90 4.6 ± 0.7 versus 7.1 ± 0.8 Gy, p=0.039) or temozolomide (mean EC50 101.6 ± 58.5 versus 295.2 ± 53.8 µM, p=0.045) in vitro. Targeted alterations of TERT status affect sensitivity to irradiation or temozolomide: TERT gene silencing confers protection whereas TERT overexpression confers sensitization. Consistent with these preclinical observations, patients with C228T TERT mutation and MGMT promoter methylation may derive more benefit from temozolomide chemoradiotherapy (median overall survival 26.5 months, 95% CI 20.3–32.7) than patients with the C250T mutation (median overall survival 16.2 months, 95% CI 8.5–23.8) or patients without TERT mutation (median overall survival 23.7 months, 95% CI 18.7–28.8). These results confirm a link between TERT promoter status and sensitivity to irradiation and temozolomide and illustrate how TERT and MGMT might interact to determine outcome in human glioblastoma. They allow to design future targeted interventions focusing on TERT and MGMT to improve the treatment of glioblastoma.