tbuckley/cabot-search huggingface dataset:
Association of Cardiac Resynchronization Therapy With Change in Left Ventricular Ejection Fraction in Patients With Chemotherapy-Induced Cardiomyopathy
Authors: Jagmeet P. Singh, Scott D. Solomon, Michael G. Fradley, Ana Barac, Kristina A. Kremer, Christopher A. Beck, Mary W. Brown, Scott McNitt, Susan Schleede, Wojciech Zareba, Ilan Goldenberg, Valentina Kutyifa
Journal: JAMA (2019)

<h3>Importance</h3> The incidence of chemotherapy-induced cardiomyopathy is increasing and is associated with poor clinical outcomes. <h3>Objective</h3> To assess the association of cardiac resynchronization therapy (CRT) with improvement in cardiac function, as well as clinical improvement in patients with chemotherapy-induced cardiomyopathy. <h3>Design, Setting, and Participants</h3> The Multicenter Automatic Defibrillator Implantation Trial–Chemotherapy-Induced Cardiomyopathy was an uncontrolled, prospective, cohort study conducted between November 21, 2014, and June 21, 2018, at 12 tertiary centers with cardio-oncology programs in the United States. Thirty patients were implanted with CRT owing to reduced left ventricular ejection fraction (LVEF≤35%), New York Heart Association class II-IV heart failure symptoms, and wide QRS complex, with established chemotherapy-induced cardiomyopathy and were followed up for 6 months after CRT implantation. The date of final follow-up was February 6, 2019. <h3>Exposures</h3> CRT implantation according to standard of care. <h3>Main Outcomes and Measures</h3> The primary end point was change in LVEF from baseline to 6 months after initiating CRT. Secondary outcomes included all-cause mortality and change in left ventricular end-systolic volume and end-diastolic volume. <h3>Results</h3> Among 30 patients who were enrolled (mean [SD] age, 64 [11] years; 26 women [87%]; 73% had a history of breast cancer; 20% had a history of lymphoma or leukemia), primary end point data were available for 26 patients and secondary end point data were available for 23 patients. Patients had nonischemic cardiomyopathy with left bundle branch block, median LVEF of 29%, and a mean QRS duration of 152 ms. Patients with CRT experienced a statistically significant improvement in mean LVEF at 6 months from 28% to 39% (difference, 10.6% [95% CI, 8.0%-13.3%];<i>P</i> &lt; .001). This was accompanied by a reduction in LV end-systolic volume from 122.7 to 89.0 mL (difference, 37.0 mL [95% CI, 28.2-45.8]) and reduction in LV end-diastolic volume from 171.0 to 143.2 mL (difference, 31.9 mL [95% CI, 22.1-41.6]) (both<i>P</i> &lt; .001). Adverse events included a procedure-related pneumothorax (1 patient), a device pocket infection (1 patient), and heart failure requiring hospitalization during follow-up (1 patient). <h3>Conclusions and Relevance</h3> In this preliminary study of patients with chemotherapy-induced cardiomyopathy, CRT was associated with improvement in LVEF after 6 months. The findings are limited by the small sample size, short follow-up, and absence of a control group. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02164721
Surgical removal of a hepaticogastrostomy stent because of its recurrent dislocation into the esophagus
Authors: Hoonsub So, Jae Hoon Lee, Jin Hee Noh, Sung Woo Ko, Jun Seong Hwang, Dongwook Oh, Tae Jun Song
Journal: Endoscopy (2019)

For endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS), an echoendoscope is advanced to the gastric cardia to puncture the ducts in segment 2 or 3 (B2 or B3) [1]. As proximal migration of a stent can be fatal, endoscopists usually prefer to use a long stent [2] [3]. We describe a case in which an HGS metal stent was surgically removed because of its recurrent dislocation into the esophagus, with accompanying vomiting.
NIMG-72. PROGNOSTIC VALUE OF [18F]-FDG POSITRON EMISSION TOMOGRAPHY IN PATIENTS WITH RECURRENT GLIOBLASTOMA RECEIVING BEVACIZUMAB
Authors: Maya Graham, Simone Krebs, Tejus Bale, Kwaku Domfe, Stephanie Lobaugh, Zhigang Zhang, Mark Dunphy, Thomas Kaley, Robert Young
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Bevacizumab is used extensively for the treatment of recurrent glioblastoma, and its modification of contrast-enhanced MRI creates a need for alternate prognostic read-outs. We sought to determine the prognostic value of [18F]-FDG (FDG) PET in glioblastoma patients performed during treatment with bevacizumab. METHODS We performed an institutional review board approved retrospective study on patients who underwent FDG PET within 4 weeks of a dose of bevacizumab for recurrent glioblastoma. Volumes of interest were placed over one reference lesion as defined by MRI. Maximum standardized uptake value (SUVmax) and peak standardized uptake value (SUVpeak) in this volume of interest were measured on PET, and metabolic tumor volume (MTV), total lesion glycolysis (TLG) and lesion-to-normal contralateral white matter ratios (SUVmax/cWM) were calculated. In addition, tumors were divided into 2 groups based on qualitative uptake pattern: (i) FDG non-avid and (ii) FDG avid. Statistical impact of PET parameters on overall survival (OS) was assessed, as was histopathological correlate of PET findings for patients with pathology available within 3 months of PET. RESULTS 31 patients were included. Qualitative uptake pattern was significantly associated with OS (p = 0.005), with a median OS of 9.7 months in FDG non-avid patients versus 4.5 months in FDG avid patients. In univariate analysis, SUVmax, SUVpeak and T/N ratio were also significantly associated with OS (p &lt; 0.001). Dichotomizing our sample using a SUVmax cut-off of 15.3 was also predictive of OS (adjusted p = 0.05). Pathology was available for 7 patients (22.6%) and confirmed PET findings. CONCLUSION FDG PET is a promising imaging biomarker to predict overall survival in recurrent glioblastoma patients on chronic antiangiogenic therapy, offering a tool for guiding assessment of treatment response in this patient population.
Response to Therapy and the Effectiveness of Treatment with Selinexor and Dexamethasone in Patients with Penta-Exposed Triple-Class Refractory Myeloma Who Had Plasmacytomas
Authors: Andrew J. Yee, Carol Ann Huff, Ajai Chari, Dan T. Vogl, Maria Gavriatopoulou, Ajay K Nooka, Philippe Moreau, David Dingli, Craig E. Cole, Sagar Lonial, Meletios A. Dimopoulos, Joshua R Richter, Ravi Vij, Sascha A Tuchman, James E. Hoffman, Luciano J. Costa, Terri L Parker, Philip Vlummens, Chantal Doyen, Noa Biran, David S. Siegel, Jatin Shah, Carla Picklesimer, Jean-Richard Saint-Martin, Lingling Li, Michael G. Kauffman, Sharon Shacham, Paul G. Richardson, Sundar Jagannath
Journal: Blood (2019)
CSIG-29. STRUCTURAL AND FUNCTIONAL STUDIES OF PID1, A NOVEL GROWTH SUPPRESSOR IN BRAIN TUMORS
Authors: Xiuhai Ren, Emi Hirsh, Min Mahdi, Fumiyaki Ito, Xiaojiang Chen, Gregory Shackleford, Anat Erdreich-Epstein
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Brain cancers, including medulloblastomas and gliomas, are a major cause of death in children and adults. We reported that PID1 (Phosphotyrosine Interaction Domain containing 1) is a growth suppressor in medulloblastomas and gliomas (PMID: 24300787). PID1 also enhances the anti-tumor effects of chemotherapy (PMID: 28400607). We are now seeking to better understand the structure and mechanism of PID1, in order to utilize this knowledge to develop innovative PID1-based therapies. METHODS PID1 mutants were expressed in E. coli as MBP fusion proteins, purified and used for MALS analysis. Additional epitope tagged PID1 constructs (HA, V5, tGFP, eGFP) were generated, expressed in mammalian cells and analyzed by western blots, immunoprecipitation, and functional assays. RESULTS We carried out screening and testing of multiple mutants of purified PID1 and characterized them. Experiments in cell culture supported presence of similar findings in mammalian cells. Colony assays in glioma and medulloblastoma cell lines identified a region in PID1 that confers the most robust growth-inhibitory effect. Experiments are underway to further refine the boundaries and characteristics of this growth-inhibitory region. CONCLUSIONS This project, which is focused on better understanding of the structure and function of PID1, is uncovering novel aspects of its molecular function. Insights gained from this work will guide studies to develop innovative PID1-based therapies for gliomas and medulloblastomas.
DDIS-01. NEW DRUG DISCOVERY WITH DRUG RE-POSITIONING SYSTEM TOWARD GBM TREATMENT
Authors: Hiroyuki Michiue, Nobushige Tsuboi, Keiichiro Hayashi, Hideki Matsui, Kazuhiko Kurozumi
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Invasion of Glioblastoma (GBM) cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM cells. Therefore, we hypothesized that the inhibition of actin polymerization with existing medication could lead to clinical GBM treatment directly in short time. The Drug Repositioning system is also known as drug repurposing or drug reprofiling and understood as the process of redeveloping a compound for use in a different disease. In this time, we would show the new direction of drug development with drug repositioning. MATERIALS AND METHODS We adopted a drug repositioning system for screening with a pyrene-actin-based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood–brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity. RESULTS Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing FAK signaling. Fluvoxamine showed no drug toxicity. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same doze of anti-depressant effect. CONCLUSIONS The SSRI group has big potential for clinical GBM treatment with low cost, short time and low side effect.
Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer
Authors: Harm Westdorp, Jeroen H. A. Creemers, Inge M. van Oort, Gerty Schreibelt, Mark A. J. Gorris, Niven Mehra, Michiel Simons, Anna L. de Goede, Michelle M. van Rossum, Alexandra J. Croockewit, Carl G. Figdor, J. Alfred Witjes, Erik H. J. G. Aarntzen, Roel D. M. Mus, Mareke Brüning, Katja Petry, Martin Gotthardt, Jelle O. Barentsz, I. Jolanda M. de Vries, Winald R. Gerritsen
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC)<b>.</b> We investigated the immunological response and clinical outcome of vaccination with blood-derived CD1c<sup>+</sup> myeloid dendritic cells (mDCs; cDC2) and plasmacytoid DCs (pDCs). <h3>Methods</h3> In this randomized phase IIa trial<b>,</b> 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and overall survival. Radiological responses were assessed by MRIs and contrast-enhanced <sup>68</sup>Ga-prostate-specific membrane antigen PET/CT, according to RECIST 1.1, PCWG2 criteria and immune-related response criteria. <h3>Results</h3> Both tetramer/dextramer-positive (dm<sup>+</sup>) and IFN-γ-producing (IFN-γ<sup>+</sup>) antigen specific T cells were detected more frequently in skin biopsies of patients with radiological non-progressive disease (5/13 patients; 38%) compared to patients with progressive disease (0/8 patients; 0%). In these patients with vaccination enhanced dm<sup>+</sup> and IFN-γ<sup>+</sup> antigen-specific T cells median rPFS was 18.8 months (<i>n</i>&nbsp;= 5) vs. 5.1 months (<i>n</i>&nbsp;= 16) in patients without IFN-γ-producing antigen-specific T cells (<i>p</i>&nbsp;= 0.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1–2 toxicity. <h3>Conclusions</h3> Immunotherapy with blood-derived DC subsets was feasible and safe and induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with an improved clinical outcome. <h3>Trial registration</h3> ClinicalTrials.gov identifier NCT02692976, registered 26 February 2016, retrospectively registered.
Treatments for Poststroke Motor Deficits and Mood Disorders: A Systematic Review for the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Guidelines for Stroke Rehabilitation
Authors: Kristen E. D'Anci, Stacey Uhl, Jeffrey Oristaglio, Nancy Sullivan, Amy Y. Tsou
Journal: Annals of Internal Medicine (2019)

Early rehabilitation after stroke is essential to help reduce disability.To summarize evidence on the benefits and harms of nonpharmacologic and pharmacologic treatments for motor deficits and mood disorders in adults who have had stroke.English-language searches of multiple electronic databases from April 2009 through July 2018; targeted searches to December 2018 for studies of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors.19 systematic reviews and 37 randomized controlled trials addressing therapies for motor deficits or mood disorders in adults with stroke.One investigator abstracted the data, and quality and GRADE assessment were checked by a second investigator.Most interventions (for example, SSRIs, mental practice, mirror therapy) did not improve motor function. High-quality evidence did not support use of fluoxetine to improve motor function. Moderate-quality evidence supported use of cardiorespiratory training to improve maximum walking speed and repetitive task training or transcranial direct current stimulation to improve activities of daily living (ADLs). Low-quality evidence supported use of robotic arm training to improve ADLs. Low-quality evidence indicated that antidepressants may reduce depression, whereas the frequency and severity of antidepressant-related adverse effects was unclear. Low-quality evidence suggested that cognitive behavioral therapy and exercise, including mind-body exercise, may reduce symptoms of depression and anxiety.Studies were of poor quality, interventions and comparators were heterogeneous, and evidence on harms was scarce.Cardiorespiratory training, repetitive task training, and transcranial direct current stimulation may improve ADLs in adults with stroke. Cognitive behavioral therapy, exercise, and SSRIs may reduce symptoms of poststroke depression, but use of SSRIs to prevent depression or improve motor function was not supported.U.S. Department of Veterans Affairs, Veterans Health Administration.
Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry
Authors: Karin Hohloch, Christine Windemuth-Kieselbach, Pier Luigi Zinzani, Roberto E. Cacchione, Wojciech Jurczak, Cheolwon Suh, Lorenz Truemper, Christian W Scholz
Journal: Blood (2019)
Development of a Personalized 3D Carotid Model for Cerebral Vasculopathy Monitoring in Sickle Cell Disease
Authors: Nguyen-Peyre Kim-Anh, Laurène Lenoir, Valentin Amar, Frédéric Segonds, Nuriye Akçay, Seguin Marion, Philippe Connes, France Pirenne, Jean-Frédéric Gerbeau, Irène Vignon-Clémentel, Suzanne Verlhac, Pablo Bartolucci
Journal: Blood (2019)
NIMG-68. FEDERATED LEARNING IN NEURO-ONCOLOGY FOR MULTI-INSTITUTIONAL COLLABORATIONS WITHOUT SHARING PATIENT DATA
Authors: Micah Sheller, Brandon Edwards, G Anthony Reina, Jason Martin, Spyridon Bakas
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Training deep learning algorithms requires large amounts of data, which is a significant challenge in the medical domain, and particularly in neuro-oncology, where ample data can only be found in multi-institutional collaborations. The current paradigm for multi-institutional collaborations is based on pooled datasets that has always faced privacy, legal, technical, and data-ownership concerns. In this study we evaluate the hypothesis that federated learning can provide a method to overcome these concerns and facilitate a shift in the paradigm of multi-institutional collaborations without sharing patient data. We attempt to investigate this hypothesis in a feasibility study of automatically delineating the glioblastoma extent in T2-FLAIR scans. METHODS We identified a retrospective cohort of 165 glioblastoma patients with available clinically acquired pre-operative multi-parametric structural MRI (mpMRI) scans (i.e., T1, T1Gd, T2, T2-FLAIR), with corresponding expert tumor boundary annotations, from 10 independent institutions. We implemented a 3D deep learning algorithm (3D-UNet) to predict the boundaries of the whole tumor extent, by virtue of the abnormal hyper-intense signal of T2-FLAIR scans. We compare the performance of this 3D-UNet model resulting from federated learning with the performance of the same 3D-UNet model generated by sharing data to a single location where centralized/traditional training occurs. RESULTS Our quantitative results on federated learning (Dice:85.2%) across individual contributions from the 10 institutions demonstrate final model quality reaching 99% of the model quality achieved by sharing data (Dice:86.2%). CONCLUSIONS Translation and adoption of federated learning in a clinical configuration for multi-institutional collaborations is expected to have a catalytic impact towards precision and personalized medicine. The performance of computer-aided analytics and assistive diagnostics is expected to see a precipitous rise, as new models are trained on datasets of unprecedented size through such data-private collaborations.
SCIDOT-36. PREDICTIVE CED INFUSION VOLUMES FOR SURGICAL PLANNING AND INFUSION REGIME STRATEGIES
Authors: Clare Killick-Cole, Max Woolley, David Johnson, Owen Lewis, Paul Skinner, Alison Bienemann, Steven Gill
Journal: Neuro-Oncology (2019)

Abstract Previous research and clinical trials have highlighted the utility of convection-enhanced delivery (CED) to directly administer therapeutics to the brain. This method bypasses the blood-brain barrier, which is a major obstacle in systemic drug delivery. The Renishaw Neuroinfuse™ recessed step catheter has been developed to utilise a mechanism we have termed “controlled reflux” to maximise distribution within brain targets, whereby the infusate tracks to a flow inhibiting feature. Once in contact with this feature, the flow pathway is initiated radially along the step region, facilitating a low-pressure infusion profile that minimises fast flow-rate tissue damage at the catheter tip whilst maximising coverage. This can be demonstrated through in vitro studies, in vivo preclinical work and humanitarian cases treating DIPG. The controlled reflux mechanism provides a level of infusion prediction, which can be used for catheter placement planning in order to optimize infusion distribution within a chosen target area. The Neuroinfuse™ catheter is delivered through an implantable guide tube whereby the guide tube and the catheter lengths are cut to provide bespoke features within the controlled reflux zone. By manipulating catheter step lengths this way, catheters can be designed to achieve target distribution volumes within an individual’s unique brain anatomy. Here we will present data demonstrating the utility of the acute catheter system, and its additional use as a modular component of the chronic drug delivery system. This modularisation strategy provides attributes for catheter placement and infusion distribution planning that spans across multiple indications for neuro-oncology and neurodegenerative diseases.
DDIS-07. IDENTIFICATION OF DRUGGABLE MOLECULAR TARGETS IN MENINGIOMA
Authors: Anh Tran, Lyndsee Zhang, Felix Sahm, Denise Scholtens, Craig Horbinski
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Meningioma is the most common primary intracranial tumor, with nearly 30,000 new cases in the US every year. Many meningiomas invade the brain, recur, and become radioresistant, causing severe disability and lethality. Prior work by Sahm et al. showed that meningiomas have consistent patterns of global CpG methylation, and that those patterns are better at prognostic stratification than traditional WHO grading (Lancet Oncol. 2017 May;18(5):682–694). In this study, we hypothesized that specific methylation events could provide further insights as to the signaling pathways driving more aggressive behavior, and identify druggable targets. METHODS We analyzed the Illumina 450k CpG methylation profiles of 493 meningiomas that were published in Lancet Oncology, searching for associations between methylation at individual CpG sites and progression-free survival (PFS). Pathway enrichment analyses were performed using gProfiler and Reactome for genes closest to significant CpG sites, followed by screening for candidate drugs targeting the pathways that were linked with malignant behavior using the ReactomeFIViz Cytoscape Plugin. RESULTS Our analyses revealed 981 genes in which methylation of mapped CpG sites was consistently associated with either shorter PFS (positive hazard ratios (HRs)) or longer PFS (negative HRs) at FDR-adjusted p&lt; 0.05. Methylation of genes encoding proteins involved in G-protein coupled receptor (GPCR) signaling pathways, especially G-alpha (s) and olfactory signaling pathways, showed pronounced association with PFS. We identified 134 anticancer drugs that target the GPCR pathway, including docetaxel and raloxifene hydrochloride, which specifically target G alpha (s) subcomponents. Both are FDA-approved, but no published data exist on their use in meningiomas. CONCLUSIONS This project is advancing our understanding of the molecular pathways driving aggressive behavior in meningioma, and is identifying existing drugs that can be repurposed to treat this tumor.
Restoring Innate and Adaptive Immune Repertoire in Multiple Myeloma for Therapeutic Application
Authors: Rafael Alonso Fernández, Laetitia Pierre-Louis, Rao Prabhala, Yan Xu, Joaquin Martinez-Lopez, Takahiro Miyazaki, Mehmet Kemal Samur, Loui Madakamutil, Mariateresa Fulciniti, Nikhil C. Munshi
Journal: Blood (2019)