tbuckley/cabot-search huggingface dataset:
NIMG-16. FEASIBLITY OF FLUORINE-18 FLUCICLOVINE PET-CT AND MRI FOR MONITORING OF CHEMO-RADIATION IN GLIOBLASTOMA: INITIAL RESULTS FROM A PILOT STUDY
Authors: Susan C Short, Russell Frood, David Broadbent, Sharon Fernandez, Garry McDermott, Bashar Al-Qaisieh, David Buckley, Stuart Currie, Louise Murray, Andrew Scarsbrook
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma has a poor prognosis despite treatment with surgery and chemo-radiotherapy (CRT). Monitoring early response to CRT is challenging and conventional imaging is sub-optimal for stratifying poorly responding patients for novel agents. Also, imaging is not routinely performed during CRT and consequently, personalised treatment through individualised radiation dose adaption is not possible. AIMS: To evalutate the feasibility of Fluorine-18 Fluciclovine PET-CT for early response assessment during and post-treatment in patients with glioblastoma undergoing standard-of-care CRT. METHODS Patients with confirmed glioblastoma and macroscopic residual tumour post-surgery were consented for PET-CT and MRI prior to CRT (scan 1), after completing 2 weeks (10 fractions) of CRT (scan 2) and 6 weeks after completing treatment (scan 3). For each scan, patients were immobilised in a radiotherapy treatment mask. PET-CT and MRI scans were performed at each timepoint within a few days of each other. Patients were treated and followed up according to local guidelines. RESULTS 6 patients were recruited to the study between June 2018 and May 2019. All patients tolerated the additional imaging without problems. 2 patients were unable to attend their post-treatment PET-CT scan due to clinical deterioration. Fluciclovine PET-CT highlighted potentially active disease beyond the surgical cavity pre-radiotherapy (scan 1) in 3 patients. In 4/6, PET signal persisted after 2 weeks of radiotherapy with stable MRI appearances (scan 2). Frank disease progression was seen in 1 patient on both MRI and PET-CT mid-treatment. 3/4 patients with persistent activity at scan 2, showed disease progression post-treatment on both PET-CT and MRI (scan 3). Another had progressive changes on MRI but stable PET-CT appearances possibly representing pseudoprogression. CONCLUSION These preliminary results suggest that Fluciclovine PET-CT could help in monitoring treatment and further work to assess the ability to guide individualised treatment planning in glioblastoma is warranted.
EPID-24. DOES THE LOCATION MATTER? CHARACTERIZATION OF THE ANATOMIC LOCATIONS, MOLECULAR PROFILES, AND CLINICAL FEATURES OF GLIOMAS
Authors: Christopher Mackintosh, Richard Butterfield, Nan Zhang, Bernard Bendok, Richard Zimmerman, Kristin Swanson, Alyx Porter, Maciej Mrugala
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Locations of gliomas may influence clinical presentations, molecular profiles, treatment options, and prognoses. Using the Mayo Clinic Arizona Cancer Center registry, we analyzed the frequency at which gliomas were identified in different regions of the brain. We evaluated molecular profiles, clinical courses and survival by anatomic location. METHODS Registry was queried to include patients with glioma over a 10-year period. Statistical analyses were used to compare demographic, genetic, and clinical characteristics among patients with gliomas in different locations. RESULTS 182 gliomas were identified. Of the tumors confined to a single lobe, there were 51 frontal (28.0%), 50 temporal (27.5%), 22 parietal (12.1%), and 7 occipital tumors (3.8%) identified. Multifocal disease was noted in 38 patients (20.9%). Tumors affecting temporal lobe were associated with reduced overall survival when compared to all other tumors (11.0 months vs. 13.0 months, log-rank p=0.0068). However, this disparity became insignificant when adjusted for tumor grade, age, and surgical approach [HR(95% CI) 1.26(0.87, 1.82), p=0.212]. Out of 82 cases tested for IDH-1, 10 were mutated (5.5%). IDH-1 mutation was present in 6 frontal, 2 temporal, 1 thalamic, and 1 multifocal tumor. Out of 21 cases tested for 1p19q deletions, 12 were co-deleted, 9 of which were frontal lobe tumors. MGMT methylation was assessed in 45 cases; 7 of 14 frontal tumors and 6 of 13 temporal tumors were methylated. ATRX loss was detected in 2/42 assessed cases. CONCLUSION Our results support the hypothesis that the anatomical locations of gliomas influence patients’ clinical courses. Tumors involving the temporal lobe were associated with poorer survival, though this association appeared to be driven by these patients’ more aggressive tumor profiles and higher risk baseline demographics. Molecular analysis was limited by low prevalence of genetic testing in the study sample, highlighting the importance of capturing this information for all gliomas.
FRI0255 Polymyositis and dermatomyositis: a review of 47 cases
Authors: CC Ben Taarit, S Turki, E Abderrahim, H Ben Maiz
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Polymyositis (PM) and Dermatomyositis (DM) are a multisystem disease characterised by acute and chronic nonsuppurative inflammation of striated muscle and skin. <h3>Objectives</h3> Objectives of this study is to describe the clinical profile, course and treatment of 47 cases of PM and DM observed over a period of 26 years. <h3>Methods</h3> Retrospective review of 47 cases with PM and DM. <h3>Results</h3> There were 36 women and 11 men with a mean age of 35 years. The classification showed: 21 cases of PM and 16 cases of DM, one case of DM was associated with a malignancy, one case of DM in children and 8 cases of an overlapping syndrome. Muscle weakness and myalgia were constant, non destructive arthritis or arthralgia were observed in 32 cases, calcinosis in 2 patients (1 DM in children and 1 overlapping syndrome with scleroderma). Results of biological tests, erythrocyte sedimentation rate and serum enzyme determination were abnormal in respectively 29 cases and 46 cases. The electromyogram was generally of a myogenic type with spontaneous activity (39/41). Steroïd therapy is prescribed in all cases and additional immunosuppressive drug (methotrexate, cyclophosphamide) is performed in 15 cases. <h3>Conclusion</h3> DM and PM are a multisystemic disease with good response to only steroïd therapy associated to immunosuppressive drugs.
Reproducing human and cross-species drug toxicities using a Liver-Chip
Authors: Kyung-Jin Jang, Monicah A. Otieno, Janey Ronxhi, Heng-Keang Lim, Lorna Ewart, Konstantia R. Kodella, Debora B. Petropolis, Gauri Kulkarni, Jonathan E. Rubins, David Conegliano, Janna Nawroth, Damir Simic, Wing Lam, Monica Singer, Erio Barale, Bhanu Singh, Manisha Sonee, Anthony J. Streeter, Carl Manthey, Barry Jones, Abhishek Srivastava, Linda C. Andersson, Dominic Williams, Hyoungshin Park, Riccardo Barrile, Josiah Sliz, Anna Herland, Suzzette Haney, Katia Karalis, Donald E. Ingber, Geraldine A. Hamilton
Journal: Science Translational Medicine (2019)

A rat, dog, and human Liver-Chip designed using microengineered Organs-on-Chips technology recapitulates species-specific drug toxicities.
Expression of the Fractalkine Receptor (CX3CR1) Is Significantly Increased in Immune Cells of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma patients with Active Disease
Authors: Marzia Palma, Tom A. Mulder, Kia Heimersson, Li-Sophie Rathje, Thomas Olin, Johan Schultz, Håkan Mellstedt, Anders Österborg
Journal: Blood (2019)
Interstitial macrophage-derived thrombospondin-1 contributes to hypoxia-induced pulmonary hypertension
Authors: Rahul Kumar, Claudia Mickael, Biruk Kassa, Linda Sanders, Daniel Hernandez-Saavedra, Daniel E Koyanagi, Sushil Kumar, Steve C Pugliese, Stacey Thomas, Jazalle McClendon, James P Maloney, William J Janssen, Kurt R Stenmark, Rubin M Tuder, Brian B Graham
Journal: Cardiovascular Research (2019)

Transforming growth factor-β (TGF-β) signalling is required for chronic hypoxia-induced pulmonary hypertension (PH). The activation of TGF-β by thrombospondin-1 (TSP-1) contributes to the pathogenesis of hypoxia-induced PH. However, neither the cellular source of pathologic TSP-1 nor the downstream signalling pathway that link activated TGF-β to PH have been determined. In this study, we hypothesized that circulating monocytes, which are recruited to become interstitial macrophages (IMs), are the major source of TSP-1 in hypoxia-exposed mice, and TSP-1 activates TGF-β with increased Rho-kinase signalling, causing vasoconstriction.Flow cytometry revealed that a specific subset of IMs is the major source of pathologic TSP-1 in hypoxia. Intravenous depletion and parabiosis experiments demonstrated that these cells are circulating prior to recruitment into the interstitium. Rho-kinase-mediated vasoconstriction was a major downstream target of active TGF-β. Thbs1 deficient bone marrow (BM) protected against hypoxic-PH by blocking TGF-β activation and Rho-kinase-mediated vasoconstriction.In hypoxia-challenged mice, BM derived and circulating monocytes are recruited to become IMs which express TSP-1, resulting in TGF-β activation and Rho-kinase-mediated vasoconstriction.
miR-541 potentiates the response of human hepatocellular carcinoma to sorafenib treatment by inhibiting autophagy
Authors: Wen-Ping Xu, Jin-Pei Liu, Ji-Feng Feng, Chang-Peng Zhu, Yuan Yang, Wei-Ping Zhou, Jin Ding, Chen-Kai Huang, Ya-Lu Cui, Chen-Hong Ding, Xin Zhang, Bin Lu, Wei-Fen Xie
Journal: Gut (2019)

Objective Autophagy participates in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib. We investigated the feasibility of sensitising HCC cells to sorafenib by modulating miR-541-initiated microRNA-autophagy axis. Design Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the malignant properties and autophagy of human HCC cells. Autophagy was quantified by western blotting of LC3, transmission electron microscopy analyses and confocal microscopy scanning of mRFP-GFP-LC3 reporter construct. Luciferase reporter assays were conducted to confirm the targets of miR-541. HCC xenograft tumours were established to analyse the role of miR-541 in sorafenib-induced lethality. Results The expression of miR-541 was downregulated in human HCC tissues and was associated with malignant clinicopathologic phenotypes, recurrence and survival of patients with HCC. miR-541 inhibited the growth, metastasis and autophagy of HCC cells both in vitro and in vivo. Prediction software and luciferase reporter assays identified autophagy-related gene 2A (ATG2A) and Ras-related protein Rab-1B (RAB1B) as the direct targets of miR-541. Consistent with the effects of the miR-541 mimic, inhibition of ATG2A or RAB1B suppressed the malignant phenotypes and autophagy of HCC cells. Furthermore, siATG2A and siRAB1B partially reversed the enhancement of the malignant properties and autophagy in HCC cells mediated by the miR-541 inhibitor. More interestingly, higher miR-541 expression predicted a better response to sorafenib treatment, and the combination of miR-541 and sorafenib further suppressed the growth of HCC cells in vivo compared with the single treatment. Conclusions Dysregulation of miR-541-ATG2A/RAB1B axis plays a critical role in patients’ responses to sorafenib treatment. Manipulation of this axis might benefit survival of patients with HCC, especially in the context of the highly pursued strategies to eliminate drug resistance.
Lentiviral Hematopoietic Stem and Progenitor Cell Gene Therapy for Wiskott-Aldrich Syndrome (WAS): Up to 8 Years of Follow up in 17 Subjects Treated Since 2010
Authors: Francesca Ferrua, Maria Pia Cicalese, Stefania Galimberti, Stefania Giannelli, Francesca Dionisio, Federica Barzaghi, Maddalena Migliavacca, Maria Ester Bernardo, Valeria Calbi, Francesca Tucci, Andrea A. Assanelli, Jacopo Peccatori, Elena Albertazzi, Alessandra G. Clerici, Federica A. Salerio, Serena Scala, Luca Basso-Ricci, Sabina Cenciarelli, Daniele Canarutto, Federico Fraschetta, Antonella Bartoli, Hermann M. Wolf, Paolo Silvani, Salvatore Gattillo, Milena Coppola, Luca Santoleri, Anna Villa, Russell Jones, Chris Dott, Maria Grazia Valsecchi, Fabio Ciceri, Luigi Naldini, Alessandro Aiuti
Journal: Blood (2019)
SCIDOT-35. A NOVEL MODEL FOR THE OPTIMIZATION OF DRUG-DEVICE COMBINATIONS FOR THE TREATMENT OF BRAIN TUMORS
Authors: Clare Killick-Cole, Max Woolley, David Johnson, Owen Lewis, Patrick Moore, Julia Fletcher, Paul Skinner, Alison Bienemann, Steven Gill
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Failure of many brain tumor treatments has been attributed to the inability of a compound to cross the blood-brain barrier. Convection-enhanced delivery (CED) offers a method to administer drugs directly to the tumor site, thereby mitigating this limitation. CED has been used in several preclinical and clinical studies, though an approved treatment is yet to come to fruition. A medical device suitable for repeated intraparenchymal delivery is valuable for brain tumor treatment strategies, but a lack of appropriate preclinical models capable of infusing clinically relevant volumes has hindered progress in clinical translation. Currently utilized preclinical models include porcine, which have limited use due to their growth rates and canine and non-human primates, which are restricted by ethical considerations. This study investigates the functional characteristics and stability of the Renishaw clinical Neuroinfuse™ drug delivery system in an ovine model. METHODS A head fixation frame was refined for ovine stereotactic surgery. Eight Romney ewes were implanted with the drug delivery system, comprising of four catheters and a transcutaneous port allowing chronic re-access infusions without repeated surgery. A maximum of four infusions were performed per subject, at four to eight-week intervals. RESULTS The implantation of the Neuroinfuse™ drug delivery system was well-tolerated in all subjects, without serious device related adverse events. Artificial CSF/gadolinium infusions were performed on five subjects. Three subjects were maintained for a follow-up study. Putaminal and thalamic distribution volumes remained stable over the re-access period of up to six months post-implantation. CONCLUSION Romney ewes are suitable for the stereotactic implantation of the Neuroinfuse™ chronic drug delivery system. Transcutaneous ports remained integrated for the study duration, allowing repeated intraparenchymal delivery. This novel preclinical model provides a stable platform for infusion regime optimization of drug-device combinations for chronic CED, which will undoubtably de-risk clinical translation in the neuro-oncology CED field.
Fc-modified HIT-like monoclonal antibody as a novel treatment for sepsis
Authors: Kandace Gollomp, Amrita Sarkar, Sanjiv Harikumar, Steven H. Seeholzer, Gowthami M. Arepally, Kristin Hudock, Lubica Rauova, M. Anna Kowalska, Mortimer Poncz
Journal: Blood (2019)
Demographic Characteristics of Participants in Rheumatoid Arthritis Randomized Clinical Trials
Authors: Adrienne Strait, Francine Castillo, Sonam Choden, Jing Li, Evans Whitaker, Titilola Falasinnu, Gabriela Schmajuk, Jinoos Yazdany
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Racial/ethnic minority groups, women, and elderly people experience a disproportionate burden of disease in rheumatoid arthritis (RA), making it particularly important to examine drug therapies in these populations. Despite a national health agenda to improve representation of diverse populations in randomized clinical trials (RCTs), there have been few large-scale analyses examining RCT demographic characteristics within rheumatology and none focusing on RA. <h3>Objective</h3> To characterize the representation of racial/ethnic minority groups, women, and elderly people through a comprehensive systematic review of RA RCTs. <h3>Data Sources</h3> A literature search of PubMed's MEDLINE database was conducted to identify RA RCTs in adults 19 years and older published in English between January 1, 2008, and January 1, 2018. <h3>Study Selection</h3> Randomized double-blind RCTs examining any systemic, disease-modifying therapy were included. Secondary analyses of previously published RCTs were excluded. Of 1195 identified records, 240 articles (20.1%) met final selection criteria. The analysis focused on RCTs with at least 1 US-based site. <h3>Data Extraction and Synthesis</h3> Data were extracted and synthesized according to the PRISMA guidelines for systematic reviews. Studies were screened for eligibility criteria. Demographic data on the age, sex, and race/ethnicity of RCT participants were extracted. Data analysis was conducted from October 25, 2018, to March 15, 2019. <h3>Main Outcomes and Measures</h3> Representation of race/ethnicity and sex, defined as the proportion of total participants that belonged to each racial/ethnic group or sex. Trends in proportions over time were examined and compared with US demographic data. <h3>Results</h3> A total of 240 RCTs with 77 071 participants were included. Of 126 RCTs with at least 1 US-based site (52.5%), the enrollment of minority racial/ethnic groups was significantly lower than their representation within the US Census population (16% vs 40%;<i>P</i> &lt; .001), and the enrollment of men was significantly lower than the incidence of RA in men nationally (20.4% vs 28.6%;<i>P</i> &lt; .001). There was no trend toward improved representation of racial/ethnic minority groups or men over time. <h3>Conclusions and Relevance</h3> Given the disproportionate burden of RA among racial/ethnic minority groups, it is imperative that policy makers better incentivize the inclusion of racial/ethnic minority groups in RA RCTs.
ANGI-03. PHARMACOLOGICAL TARGETING OF APELIN/APLNR SIGNALING BLUNTS THERAPY RESISTANCE TO VEGFA/VEGFR2 ANTI-ANGIOGENIC TREATMENT IN GLIOBLASTOMA
Authors: Roland Kälin, Giorgia Mastrella, Mengzhuo Hou, Min Li, Veit Stoecklein, Nina Zdouc, Marie Volmar, Hrvoje Miletic, Sören Reinhard, Christel Herold-Mende, Susanne Kleber, Katharina Eisenhut, Gaetano Gargiulo, Michael Synowitz, Angelo Vescovi, Patrick Harter, Josef Penninger, Ernst Wagner, Michel Mittelbronn, Rolf Bjerkvig, Dolores Hambardzumyan, Ulrich Schüller, Joerg-Christian Tonn, Josefine Radke, Rainer Glass
Journal: Neuro-Oncology (2019)

Abstract Anti-angiogenic therapy of glioblastoma with bevacizumab, a vascular endothelial growth factor-A (VEGFA) blocking antibody, may accelerate tumor cell invasion and induce alternative angiogenic pathways. We investigated the roles of the pro-angiogenic receptor APLNR and its cognate ligand apelin in VEGFA/VEGFR2 anti-angiogenic therapy against distinct subtypes of glioblastoma. In proneural glioblastoma, apelin levels were downregulated by VEGFA or VEGFR2 blockade by use of bevacizumab or ramucirumab, respectively. A central role for apelin/APLNR in controlling glioblastoma vascularization was corroborated in a serial implantation model of the angiogenic switch that occurs in human glioblastoma. Apelin and APLNR are broadly expressed in human glioblastoma, and knockdown or knockout of APLN in orthotopic models of proneural or classical glioblastoma subtypes massively reduced glioblastoma vascularization as compared with controls. What is more, direct infusion of the bioactive peptide apelin-13 was able to rescue this vascular loss-of-function phenotype, demonstrating the specific control of tumor vascularization by apelin/APLNR signaling. While high levels of apelin correlated with reduced tumor cell invasiveness, the reduction in apelin expression led to accelerated glioblastoma cell invasion. Analysis of stereotactic glioblastoma biopsies from patients as well as from in vitro and in vivo experiments revealed increased dissemination of APLNR-positive tumor cells when apelin levels were reduced. Most interestingly, application of apelin-F13A, a mutant APLNR ligand, blocked both tumor angiogenesis and glioblastoma cell invasion. Furthermore, co-targeting VEGFR2 and APLNR synergistically improved survival of mice bearing proneural glioblastoma. In summary, we show that apelin/APLNR signaling controls glioblastoma angiogenesis and invasion directly, and that both pathological features are blunted by apelin-F13A. We suggest that apelin-F13A can improve the efficiency and reduce the side effects of established anti-angiogenic treatments for distinct glioblastoma subtypes.
Unequal Outcomes in Transplant Eligible Patients with Multiple Myeloma in Latin America: Differences between Public and Private Centers
Authors: Camila Peña, Natalia Paola Schutz, Virginia Bove, Fiorella Villano, Rocío Osorio, Mauricio Chandia, Cecilia Beltran, Javier Schulz, Daniela Cardemil, Carolina Contreras, Carmen Gloria Vergara, Javiera Donoso, Marcela Espinoza, Gabriel La Rocca, Hernán López-Vidal, Pilar León, Christine Rojas, Pablo Soto, Sandra Aranda, Vivianne Torres, Paola Ochoa, Patricio Duarte, Guillermina Remaggi, Sebastian Yantorno, Ariel Corzo, Soledad Zabaljauregui, Claudia Shanley, Sergio Lopresti, Sergio Orlando, Veronica Verri, Luis Darío Quiroga, Carlos García, Vanesa Fernandez, Dorotea Fantl, Jhoanna Ramirez, Alicia Molina, Pilar Papilco, Alex Mite, Ines Reyes, Brener Sabando, Francisca M. Ramirez Aspiazu, Claudia Lucia Sossa, Virginia Abello, Henry Idrobo, Kenny Galvez, Domingo Saavedra, Guillermo Quintero, Raimundo Gazitua, Lina Gaviria, Rigoberto Gomez, Monica Osuna Pérez, Alicia Henao-Uribe, Luz del Carmen Tarín Arzaga, Omar Cantú-Martínez, David Gomez-Almaguer, Yarely Itzayana García-Navarrete, Antonio Cruz-Mora, Yahveth Cantero-Fortiz, Guillermo J. Ruiz-Arguelles, Macarena Roa, Eloisa Riva
Journal: Blood (2019)
PATH-32. GENOMIC LANDSCAPE AND BIOLOGY OF MEDULLOBLASTOMA IN ADULTS
Authors: Tobias Goschzik, Anja zur Mühlen, Evelyn Dörner, Andreas Waha, Carsten Friedrich, Peter Hau, Torsten Pietsch
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Medulloblastoma (MB) is a rare disease in adults. Only few cohorts have been studied so far. METHODS Histological features were evaluated and tumors were annotated to WNT-MB, SHH-MB, and non-WNT/non-SHH-MB by immunohistochemistry. Copy number alterations were analyzed by genome-wide molecular inversion probe array. MB-related genes were screened by NGS panel and Sanger sequencing in WNT- and SHH-MB. RESULTS The cohort of 117 tumors contained 14.5% WNT-MB, 63.2% SHH-MB, and 22.2% non-WNT/non-SHH-MB. Classic histology was found in WNT-MB, non-WNT/non-SHH-MB and 22% of SHH-MB; 78% of SHH-MB showed desmoplastic/nodular histology. In WNT-MB, CTNNB1 mutations were found in 88.2% and monosomy 6 in 52.9% of cases. In SHH-MB, PTCH1 mutations were present in 40% of cases and chromosome 9q loss including the PTCH1 locus was the most frequent copy number event in SHH-MB (50%), while SMO and SUFU mutations were found only in 15.4% and 7.7%, respectively. TERT promoter mutations were present in 92.3% of SHH-MBs. Only 2 (3%) of SHH-MB were TP53-mutated (1.7% of whole cohort). In non-WNT/non-SHH-MB, isochromosome 17q was the most frequent chromosomal alteration (84.6%). A previously published whole chromosomal aberration (WCA) signature with ≥1 WCA was found in 69.2% of cases. For 87 cases, survival data were available. WNT-MB, SHH-MB with wildtype TP53 and non-WNT/non-SHH-MB showed similar outcomes (5-year OS: 75%, 78.1% and 69.1%, respectively). Both SHH-MB patients with mutant TP53 died of disease. Patients with non-WNT/non-SHH-MB characterized by the cytogenetic WCA phenotype showed – as described in pediatric standard-risk MB – significant better overall survival compared to patients with tumors lacking WCA (p=0.02). CONCLUSIONS Adult MB represents four defined biological/genomic entities. While in our cohort WNT-MB and SHH-MB-TP53wt were standard risk, non-WNT/non-SHH-MB patients could be divided into two risk-groups according to the presence or absence of WCA in the tumors as previously published for childhood standard-risk MB.