tbuckley/cabot-search huggingface dataset:
HOUT-35. RETROSPECTIVE ANALYSIS OF OUTCOMES IN HOSPITALIZED MALIGNANT BRAIN NEOPLASM PATIENTS WITH STATUS EPILEPTICUS
Authors: Mina Lobbous, Sahil Gupta, Paula Warren
Journal: Neuro-Oncology (2018)

To investigate the key characteristics and outcomes in patients with Malignant Brain Neoplasm and Status Epilepticus. Epileptic seizures are a major comorbidity in patients with malignant brain neoplasm (MBN), either at presentation or as a sign of progression. Seizures are more challenging to control in this patient population, especially with rapidly growing tumor and often progress to status epilepticus (SE). We conducted this study to investigate the key characteristics and outcomes in patients with MBN and SE. Analysis of National Inpatient Sample data (2003–2013) showed a total of 76,357 patients discharged with a primary diagnosis of MBN, ICD-9 Code 191.X. Among this patient population, 557 patients with SE were identified. We compared age, length of stay (LOS) and total hospital charges between MBN patients with and without SE, as well as the association between MBN and SE with patient race, sex, and disposition status. Analyses revealed that 0.7% of MBN patients were found to have SE. No significant difference was found in age at admission of patients with SE (50.69 vs 51.76 p=0.233). SE was associated with African American (AA) race as compared to non-AA (1.4% vs 0.7%), longer LOS (11.54 vs 6.92 days), higher hospital charges ($113,416 vs $65,159), disposition other than home (69.9% vs 44.7%) and increased mortality (15.5% vs 4.1%). The results suggest SE is associated with increased morbidity and mortality amongst MBN patients. Our results show an association between SE and increased LOS, worse disposition, higher hospital charges, and mortality. Therefore, early identification and aggressive treatment of SE is warranted in hospitalized patients with Malignant Brain Neoplasm. Future prospective studies are needed to investigate different treatment approaches for Status Epilepticus in hospitalized patients with brain tumors.
Induction of human epidermal growth factor receptor 2 degradation by celecoxib and its derivative OSU-03012
Authors: Shu-Chuan Weng, Ching-Shih Chen
Journal: Cancer Research (2008)

3310  Background and Significance. Amplification or overexpression of the human epidermal growth factor receptor 2 (HER2), present in 20 - 30% of human breast cancer, is associated with poor prognosis, frequent disease recurrence, and resistance to hormonal, cytotoxic, and radiation therapies. Consequently, targeting HER2 represents an important strategy for breast cancer therapy. In the course of our investigation of the effect of OSU-03012, a celecoxib-derived, COX-2-inactive phosphoinositide-dependent kinase-1 (PDK-1) inhibitor, on sensitizing HER2-positive breast cancer cells to trastuzumab, we found that OSU-03012, and to a lesser extent, potentiated trastuzumab’s antiproliferative effect, in part, through the downregulation of HER2 expression. Here, we report that celecoxib and OSU-03012 facilitate HER2 endocytosis and degradation through PDK-1-dependent recruitment of NEDD4 (neuronal precursor cell-expressed developmentally downregulated 4).  Methods: HER2-overexpressing SKBR3 human breast cancer cells were used in all assays. Drug effects on the expression level and/or subcellular location of HER2, NEDD4, and biomarkers of endosomes and lysosomes were analyzed by Western blotting, flow cytometry, and immunocytochemistry. Intracellular phosphatidylinostiol 3-phosphates (PI3P) synthesis was detected by immunocytochemistry using the GST-2xFYVE fusion protein.  Results: Immunocytochemical evaluations showed that celecoxib, OSU-03012 and LY294002 (a PI3 kinase inhibitor) induced HER2 endocytosis. Nedd4, an E3 ligase for HER2 that is regulated by protein kinase Akt and Serum and glucocorticoid-inducible kinase (SGK) activities, was activated by PI3K/PDK-1 inhibition. Co-immunoprecipitation data indicated that interaction between HER2 and the AP2 adaptor protein; AP50/μ2 was increased by OSU-03012. Evidences that OSU-03012-induced HER2 down-regulation involves autophagy include the co-localization of internalized HER2 with LAMP-2 positive autolysosomes and MDC positive vacuoles in celecoxib or OSU-03012-treated cells, as well as the attenuation of HER2 down-regulation by the autophagy inhibitors, balifomycin, folimycin and chloroquine. Moreover, OSU-03012- and celecoxib-induced reductions in cell viability, as determined by MTT assay, was also attenuated by chloroquine, suggesting a role for drug-induced autophagic down-regulation of HER2 in mediating the antiproliferative effects of these compounds in cancer cells.  Conclusions: These data indicate that celecoxib and OSU-03012 induce ligand-independent HER2 endocytosis and autophagic degradation through a mechanism that involves PDK-1 pathway inhibition and PI3K activity. This study not only provides new mechanistic insight into the potential therapeutic benefits of celecoxib against HER2 positive breast cancer, but also into the roles of PI3K and PDK-1 pathways in HER2 regulation.
A Phase 3 Study of Ravulizumab (ALXN1210) Versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria Naive to Complement Inhibitors: Results of a Subgroup Analysis with Patients Stratified By Baseline Hemolysis Level, Transfusion History, and Demographics
Authors: Ilene C. Weitz, Aleksandr Kulagin, Shinji Nakao, Caroline I. Piatek, Jeffrey Szer, Scott T. Rottinghaus, Lori Volles, Andrew I. Damokosh, Rasha Aguzzi, Loree Larratt, Antonio M. Risitano
Journal: Blood (2018)
CMET-11. LEPTOMENINGEAL MELANOMA METASTASIS PRESENTING AS INTRAVENTRICULAR AND SUBARACHNOID HEMORRHAGE
Authors: Maya Graham, Radhika Jagannathan, Elayna Rubens, Jedd Wolchok, Synphen Wu
Journal: Neuro-Oncology (2018)

Leptomeningeal spread of cancer can have protean presentations, increasing the difficulty of making this diagnosis. We present the case of a 77-year-old man with prior metastatic melanoma who presented with spontaneous headache that worsened over several days, and was found to have both intraventricular and cortical subarachnoid hemorrhage on CT head. His neurological exam was unremarkable. MRI of the brain with contrast confirmed the CT findings and did not reveal any evidence of parenchymal or leptomeningeal metastases. MR angiogram followed by a conventional angiogram did not demonstrate any vascular abnormalities. Cerebrospinal fluid examination revealed 110 white blood cells, 34000 red blood cells, and protein of 160. Cytology returned positive for malignant melanoma cells. No additional sites of disease were found on further evaluation with MRI spine and CT of the chest, abdomen and pelvis. In retrospect, the patient had endorsed some fluctuating nausea and fatigue three months prior to presentation, as well as positional vertigo two weeks prior to presentation. His oncologic history was notable for prior immunotherapy with ipilimumab, as well as diagnosis of dural-based brain metastases two years earlier, for which he underwent surgical resection and radiation therapy. He had no evidence of disease for one year prior to this new diagnosis of leptomeningeal involvement. This case highlights an unusual presentation of leptomeningeal metastasis and underscores the importance of maintaining heightened suspicion for this diagnosis when evaluating subarachnoid hemorrhage in a cancer patient, especially in the case of melanoma. It raises the question of whether this particular cancer type or the patient’s prior immunotherapy contributed to his presentation, and emphasizes the need for further elucidation of the biology of leptomeningeal metastasis.
CMET-20. EVIDENCE OF CNS RESPONSE OF PEMBROLIZUMAB FOR LEPTOMENINGEAL CARCINOMATOSIS AT A SINGLE CELL RESOLUTION
Authors: Christopher Alvarez-Breckenridge, Sanjay Prakadan, Eudocia Lee, Sara Tolaney, Lakshmi Nayak, Nancy Lin, Ivanna Bihun, Ugonma Chukwueke, Kevin Oh, Michael White, Elizabeth Gerstner, Donald Lawrence, Justine Cohen, Anita Giobbie-Hurder, Daniel Cahill, Scott Carter, Alex Shalek, Ryan Sullivan, Priscilla Brastianos
Journal: Neuro-Oncology (2018)

Approximately 8% of patients with cancer develop leptomeningeal carcinomatosis (LMD). LMD is associated with approximately 4 week median survival and a paucity of treatment options beyond palliative shunting. We performed a phase II study of the PD-1 inhibitor pembrolizumab in LMD from any solid tumor malignancy (NCT02886585). The primary endpoint is the rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Serial CSF, blood samples and tumor samples were collected to elucidate the genomic and transcriptional determinants of response to immunotherapy in central nervous system lesions. A total of 18 patients were accrued and the median follow-up of patients still alive was 6.8 months (range: 2.2 to 7.6 months). At the time of data retrieval, 11 patients (61%) were alive at three months after enrollment (OS3). Therefore, the study met its primary endpoint. Whole exome sequencing of tissue samples and cell-free DNA from CSF and blood, as well as single-cell RNA sequencing of CSF, were carried out to decipher tumor evolution, track immune cell recruitment, and identify biomarkers of response. Analysis of 7877 tumor and immune cells across 6 patients demonstrated patient-specific tumor clustering and evidence of T cell and antigen presenting cells recruited to the CSF following pembrolizumab treatment. Longitudinal CSF samples demonstrated genetic and transcriptomic differences in tumor and immune cells suggesting response to treatment in patients that reached OS3 compared with those that did not. These findings suggest that pembrolizumab has activity in LMD and that CSF provides an opportunity to monitor the clonal evolution of the tumor and immune microenvironment in LMD.
Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic
Authors: T.A. Chan, M. Yarchoan, E. Jaffee, C. Swanton, S.A. Quezada, A. Stenzinger, S. Peters
Journal: Annals of Oncology (2018)

Treatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required.
STEM-13. HYPOXIC INDUCTION OF VASORIN MEDIATES GLIOMA STEM CELL-ENDOTHELIAL CELL INTERACTIONS IN THE PERIVASCULAR NICHE
Authors: Jennifer Yu, Xingjiang Yu, Amy Burrows, Shideng Bao
Journal: Neuro-Oncology (2018)

Glioma stem-like cells (GSCs) have been recognized to play an important role in tumor progression. GSCs are highly resistant to radiation and chemotherapy and have a high capacity to self-renew and differentiate into multiple lineages. GSCs preferentially reside within niches including the hypoxic and perivascular niches that help to support their undifferentiated state. Interactions between GSCs and different cell types in these niches, including endothelial cells, help to maintain GSCs and facilitate tumor migration, invasion and angiogenesis. We previously identified that the transmembrane protein Vasorin (VASN) is a critical node in GSC maintenance. Little is known about this protein (< 20 papers), but we have found that VASN is overexpressed in about 80% of GBM and is associated with poor prognosis. VASN is preferentially induced in GSCs in hypoxia and binds Notch1 to stabilize it at the cell membrane. This interaction effectively functions as a switch to amplify Notch signaling in GSCs in hypoxia to promote their survival. We now build upon these studies and find that VASN is expressed in GSCs not just in the hypoxic niche but also the perivascular niche. GSCs are abundant in the perivascular niche and endothelial cells can provide Notch ligands that help to maintain GSCs self-renewal properties. We have found that VASN is frequently expressed in hypoxic, CD44+ and Olig2+ tumor cells in the perivascular niche in GBM, and that VASN is expressed in a subset of tumor-associated endothelial cells. Our data suggest that reciprocal Notch signaling mediated by VASN between endothelial cells and GSCs in the perivascular niche helps to maintain GSCs. These data suggest that VASN may also play an important role in perivascular niche interactions between GSCs and endothelial cells through Notch signaling.
Biomarkers: to be or not to be
Authors: Sule Yavuz, Lars Rönnblom
Journal: Annals of the Rheumatic Diseases (2018)

We read with great interest the article by van den Hoogen et al 1 describing galectin-9 (Gal-9) as a novel, easy-to-measure biomarker for the interferon (IFN) signature in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). We support the views expressed by the authors that IFN signature is an important biomarker in disease activity in SLE and there is certainly a need for easier to measure biomarkers for IFN signature, but to suggest that Gal-9 could aid in clinical decision making in steering anti-IFN therapy seems premature. We know that the common …
EXTH-54. Bcl-2/Bcl-xL INHIBITION SYNERGISTICALLY ENHANCES THE ANTI-NEOPLASTIC ACTIVITY OF CUSP9 AGAINST GLIOBLASTOMA CELLS IN VITRO
Authors: Marc-Eric Halatsch, Richard Eric Kast, Annika Dwucet, Christian Rainer Wirtz, Markus Siegelin, Georg Karpel-Massler
Journal: Neuro-Oncology (2018)

Repurposing represents a promising approach to safely accelerate the clinical application of therapeutics with anti-cancer activity. In this study, we examined whether inhibition of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL enhances the biological effects of the repurposed CUSP9 regimen in an in vitro setting of glioblastoma. We applied MTT assays to assess cellular proliferation. Annexin V/PI and TMRE staining were used to examine apoptosis. Western blotting, RT-PCR and specific knockdown experiments using siRNA were employed to examine molecular mechanisms of action. Bcl-2/Bcl-xL inhibition by the BH3 mimetic ABT263, yielded synergistic anti-proliferative effects across a wide panel of established and primary cultured glioblastoma cells when combined with CUSP9 which had been reduced to only one tenth of its original concentration (CUSP9 1/10). The combination treatment also led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases. On the molecular level, CUSP9 1/10 counteracted ABT263-mediated upregulation of Mcl-1. Silencing of Mcl-1 enhanced ABT263-mediated apoptosis, indicating that Mcl-1 is crucial for the induction of cell death conveyed by the combination treatment. Levels of Mcl-1 mRNA were not decreased following combination therapy, and co-treatment with cycloheximide showed reduced protein stability, pointing towards a post-translational mechanism of action. These data suggest that Bcl-2/Bcl-xL inhibition enhances the susceptibility of glioblastoma cells towards CUSP9, allowing dramatic dose reduction and potentially decreased toxicity when applied clinically. A clinical trial involving the original CUSP doses (CUSP9v3) is currently ongoing in our institution (NCT02770378). The Bcl-2/Bcl-xL inhibitor ABT263 is in clinical trials and might represent a valuable adjunct to the original CUSP.
Abstract 17036: Uncontrolled Apparent Treatment Resistant Hypertension is Associated With Increased Hospitalization and Increased Total Hospital Reimbursements
Authors: Sreekanth Vemulapalli, Luqin Deng, Manesh Patel, Meredith L Kilgore, Lesley H Curtis, Ryan Irvin, Laura P Svetkey, Daichi Shimbo, David A Calhoun, Paul Muntner
Journal: Circulation (2015)

Background: Apparent treatment resistant hypertension (aTRH) is defined as uncontrolled BP with three or more antihypertensives or controlled BP with 4 or more antihypertensives. ATRH is associated with increased adverse cardiovascular outcomes, however, little is known about healthcare utilization and expenses in those with aTRH. Methods: The study included participants 65 years and older in the nationwide Reasons for Geographic and Racial Differences in Stroke (REGARDS) study with fee for service Medicare insurance. ATRH was defined as treatment with three or more antihypertensives of different classes. Participants were categorized as hypertensive without aTRH (no aTRH), controlled aTRH (BP ≤140/90), and uncontrolled aTRH (BP ≥ 140/90). Healthcare expenses were determined using diagnoses in Medicare parts A and B claims. Results: At baseline, 3933 (84.5%) had no aTRH, 247 (5.3%) had controlled aTRH, and 474 (10.2%) had uncontrolled aTRH. Compared to participants with no aTRH, those with uncontrolled aTRH and controlled aTRH were more likely to be male (45.7%, 50.4%, 53.8%) and black (48.5%, 47.0%, 35.6%), respectively. Participants with uncontrolled and controlled aTRH also had a higher prevalence of atrial fibrillation, stroke, and coronary artery disease compared to those with no aTRH. Adjusted annual median outpatient total reimbursements per patient were similar between those with uncontrolled aTRH, controlled aTRH, and no aTRH ($5248 [IQR $2904, $10006], $5697 [IQR $3104, $9930], $4525 [IQR $2587, $7923]). Uncontrolled aTRH, but not controlled aTRH was associated with an increased adjusted annual rate of hospitalizations as compared to no aTRH (risk ratio=1.13; 95% CI [IQR 1.03 - 1.24]; p=0.01). Among patients with any hospitalizations, uncontrolled aTRH was associated with the highest median annual inpatient total reimbursements ($6324 [IQR 3149, 16238]; controlled aTRH = $5507 [IQR 2197, 13884]; no aTRH $4968 [IQR 2252, 10882]). Conclusions: Uncontrolled aTRH is associated with an increased rate of hospitalizations and higher charges per hospitalization. Efforts to improve blood pressure control among patients with uncontrolled aTRH may also result in reduced hospitalizations and hospital charges.
NIMG-45. MULTIVARIATE PATTERN ANALYSIS OF DE NOVO GLIOBLASTOMA PATIENTS OFFERS IN VIVO EVALUATION OF O6-METHYLGUANINE-DNA-METHYLTRANSFERASE (MGMT) PROMOTER METHYLATION STATUS, COMPENSATING FOR INSUFFICIENT SPECIMEN AND ASSAY FAILURES
Authors: Saima Rathore, Spyridon Bakas, MacLean Nasrallah, Hamed Akbari, Stephen Bagley, Sung Min Ha, Elizabeth Mamourian, Christopher Watt, Zev Binder, Donald O’Rourke, Christos Davatzikos
Journal: Neuro-Oncology (2018)

The promoter methylation status of the gene encoding for the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) indicates increased efficacy of current standard of care therapy, which is concomitant adjuvant chemoradiotherapy with temozolomide. The MGMT promoter methylation status (MGMTpms) is typically determined as MGMT-methylated or MGMT-unmethylated by tissue-based polymerase chain reaction assays, which can be limited by inadequate specimen or assay failures. Thus, we investigate the hypothesis that integration of subtle, yet distinctive, quantitative imaging phenomic (QIP) features using machine learning may lead to non-invasive determination of MGMTpms. We identified a retrospective cohort of 122 (46 MGMT-methylated) pathology-proven de novo glioblastoma patients with available baseline pre-operative multi-parametric magnetic resonance imaging (mpMRI) data (T1, T1-Gd, T2, T2-FLAIR, DSC, DTI). MGMTpms was obtained through MGMT methylation testing (pyrosequencing across 4 CpG sites in the MGMT promoter). Following delineation of distinct abnormal sub-regions (enhancing, non-enhancing, edematous), comprehensive and diverse QIP features were extracted using the Cancer Imaging Phenomics Toolkit (CaPTk, www.cbica.upenn.edu/captk), capturing intensity, volume, morphology, statistics, and texture of each sub-region. A support vector machine multivariately integrated these features towards a non-invasive marker of MGMTpms. The cross-validated accuracy of our MGMT marker in classifying the mutation status in individual patients was 84.43% (sensitivity=80.43%, specificity=86.84%, area under the curve [AUC]=0.85). Our marker revealed MGMT-methylated tumors with lower neovascularization and cell density, when compared with MGMT-unmethylated tumors, and a distinct spatial distribution pattern between MGMT-methylated and MGMT-unmethylated tumors, with the latter being more lateralized to the right hemisphere. Multivariate integrative analysis of QIP features extracted from mpMRI yields an accurate, non-invasive marker of MGMTpms in glioblastoma. The proposed non-invasive MGMT marker may contribute to (i) MGMTpms determination for patients with inadequate tissue/inoperable tumors, (ii) stratification of patients into clinical trials, (iii) patient selection for targeted therapy, and (iv) personalized treatment planning. *equal contribution
RTHP-02. IMPACT OF 18F-DOPA PET ON RADIOTHERAPY TARGET VOLUMES FOR NEWLY DIAGNOSED MGMT UNMETHYLATED GLIOBLASTOMA PATIENTS; PRELIMINARY RESULTS OF A PHASE II DOSE-ESCALATION TRIAL
Authors: Debra Brinkmann, Deanna Pafundi, Christopher Hunt, Val Lowe, Elizabeth Yan, Paul D Brown, Mark Zakhary, Yan Zhang, Maasa Seaberg, Hok seum Wan Chan Tseung, Jann Sarkaria, Nadia Laack
Journal: Neuro-Oncology (2018)

Multiple studies have demonstrated that amino acid PET tracers identify aggressive disease beyond what is contrast enhancing on T1-weighted conventional MR (T1CE). In this study, we explored discrepancies between 18F-DOPA PET and conventional MR for defining target volumes in newly diagnosed glioblastoma (GBM) radiotherapy patients. In an ongoing NCI-funded trial (NCT:R01CA178200), 18F-DOPA PET was acquired prior to chemoradiation for newly diagnosed GBM patients and incorporated prospectively into the target volumes, modifying low and high dose target volumes, and guiding dose escalation to the most aggressive disease. Based on the results of our pilot biopsy-validation study, two 18F-DOPA PET volumes were defined, one with a T/N threshold >2.0 (PET_high) depicting the most aggressive disease and another with a T/N threshold default of ≥1.5 (PET_low) with modifications if needed by a Nuclear Medicine physician. Both PET volumes were compared with the T1CE+cavity MR volumes for 30 MGMT unmethylated newly diagnosed GBM patients. The PET_low volume extended beyond T2-FLAIR signal abnormality for all patients, and extended beyond standard CTV expansion in 60% of patients. Sixty-seven per cent of patients had at least 20% of the PET_high uptake outside the T1CE volume, and would not have been covered by standard CTV expansion in 8% of patients. The average (range) Dice Similarity Coefficient comparing T1CE with PET_high was 0.3(0.0–0.7). The average (range) Haursdorff maximum distance (cm) between PET uptake and T1CE was found to be 2.4(0.9–7.1). CONCLUSIONS: 18F-DOPA-PET identified regions of biologically active disease outside the T1CE in 67% of patients with significant discordance in volumes. Evaluation of the impact prospective 18F-DOPA PET guidance for dose escalated radiation therapy is under investigation in the ongoing trial.