tbuckley/cabot-search huggingface dataset:
AB0667 SPECIFICITY OF ANTI-TRNA SYNTHETASE AUTOANTIBODIES CORRELATED WITH CLINICAL COURSE AND PROGNOSIS OF MYOSITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE
Authors: Yasushi Kondo, Yoko Nakagome, Kazuki Hirano, Yasushi Koyama, Sho Sasaki, Katayoshi Kurabayashi, Yuto Izumi, Chiho Yamada, Shinji Sato
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Interstitial lung disease (ILD) is associated with mortality among patients with idiopathic inflammatory myopathy (IIM). Anti-aminoacyl-tRNA synthetase (anti-ARS) autoantibodies have been identified highly specific for IIM and coincidence of ILD. It has been identified that non-Jo1 positive anti-ARS patients may have decreased survival rate. However, differences of characteristics and prognosis in myositis-associated ILD with an individual anti-ARS autoantibody have not been clarified. <h3>Objectives:</h3> To compare the characteristics and cumulative survival of myositis-associated ILD with different positivity of anti-ARS antibodies. <h3>Methods:</h3> We investigated retrospectively all consecutive patients with myositis -associated ILD evaluated from 1999-2017.All autoantibodies were screened by using RNA and protein immunoprecipitation assays. Demographic data, laboratory findings and chest computed tomography (CT) images were obtained. <h3>Results:</h3> Among 105 patients with myositis-associated ILD, enrolled, 47 had anti-Jo1 antibody and 58 had non-Jo1 antibody: anti-EJ (n=20), anti-PL12 (n=12), ant-PL7 (n=11), anti-KS (n=8) and anti OJ (n=7). The diagnosis at first visit were polymyositis (PM; n=28), dermatomyositis (DM; n=42), clinically amyopathic dermatomyositis (CADM; n=3) and antisynthetase syndrome (ASS; n=31). Most common causes of death in this study were exacerbation of ILD (n=10, 71.4%). Anti-Jo-1 positive patients had better ILD prognosis than non-Jo1 patients (log rank test, p = 0.03). The prevalence of rapidly progressive ILD (RP-ILD) and upper lung field lesions in CT scans were significantly higher in anti-EJ positive patients (p=0.02 and p=0.05, respectively). Although the prognosis of ILD was not significantly different among 6 anti-ARS antibodies, anti-EJ positive patients had poor ILD prognosis than anti-Jo1 patients with the 5-year unadjusted cumulative survival was 73% and 95%, respectively. <h3>Conclusion:</h3> Our data confirm that the characteristics and outcomes of myositis-associated ILD are distinct by anti-ARS antibodies and highlighted that anti-EJ antibody positivity associated with relatively poor prognosis and RP-ILD. <h3>References</h3> [1] McHugh NJ, Tansley SL. Nat Rev Rheumatol. 2018; 20;14(5):290-302. [2] aggarwal, R. et al. Ann. Rheum. Dis. 2014; 73: 227–232 [3] Shi J. et al. J Rheumatol2017; 44: 1051-1057 [4] Takanashi S, et al. Rheumatology (Oxford). 2019Jan8. doi: 10.1093/rheumatology/key420. <h3>Acknowledgement:</h3> The authors would particularly like to thank Etsuko Iwata and Masui for their assistance <h3>Disclosure of interests:</h3> None declared
Theranostic application of lipiodol for transarterial chemoembolization in a VX2 rabbit liver tumor model
Authors: Johanna Maria Mijntje van Breugel, Jean-François Geschwind, Sahar Mirpour, Lynn Jeanette Savic, Xuchen Zhang, Rafael Duran, MingDe Lin, Milena Miszczuk, Eleni Liapi, Julius Chapiro
Journal: Theranostics (2019)

The goal of this study was to investigate the role of Lipiodol as a tumor-specific imaging biomarker to determine therapeutic efficacy of cTACE and investigate its inter-dependency with tumor perfusion using radiological-pathological correlation in an animal model of liver cancer.A total of N=36 rabbits were implanted in the left lobe of the liver with VX2 tumors, treated with cTACE using doxorubicin suspended in Lipiodol, and randomly sacrificed at 24 h, 7 days, or 20 days post-TACE. Unenhanced and contrast-enhanced CT scans including a perfusion protocol were obtained before cTACE and immediately before sacrifice. Tumor vascularity and Lipiodol deposition within tumors and hepatic tissue (non-target deposits) were quantified using 3D quantitative assessment tools and measurements of arterial flow, portal flow, and perfusion index (PI). After sacrifice histologic staining, including hematoxylin and eosin (H&E), CD31, and Oil Red O (ORO) were performed on tumor and liver samples to evaluate necrosis, microvascular density (MVD), and Lipiodol retention over time. Transmission electron microscopy (TEM) was performed to assess Lipiodol deposition and clearance over time.All cTACE procedures were carried out successfully except for one, which was excluded from further analysis. Twenty-four hours post-TACE, tumor PI (p=0.04) was significantly decreased, which was maintained at 7 days (p=0.003), but not at 20 days (p=0.4). A strong correlation (R2 = 0.894) was found between the volume of enhancing tumor tissue at baseline and Lipiodol-positive tumor volume post-TACE. Both ORO and TEM showed deposition of Lipiodol across all imaging time points within the VX2 tumors. However, gradual and ultimately near-complete Lipiodol washout was observed over time in the non-tumoral liver. MVD decreased between 24 h and 7 days post-TACE, and then increased 20 days post-TACE (both p<0.01).Our data provide radiology-pathology evidence for the function of Lipiodol as a theranostic, tumor-specific drug delivery agent because it is both imageable and tumor-seeking, whereby it is preferentially taken up and retained by tumor cells. Those tumor-specific functions also enable Lipiodol to act as an imaging biomarker for the therapeutic efficacy of cTACE. Together with volumetric quantification of tumor vascularization on CT, Lipiodol could be used as a predictor of a patient's response to cTACE and contribute to the therapeutic management of patients with liver cancer.
Simvastatin Improves Neutrophil Function and Clinical Outcomes in Pneumonia. A Pilot Randomized Controlled Clinical Trial
Authors: Elizabeth Sapey, Jaimin M. Patel, Hannah Greenwood, Georgia M. Walton, Frances Grudzinska, Dhruv Parekh, Rahul Y. Mahida, Rachel C. A. Dancer, Sebastian T. Lugg, Philip A. Howells, Jon Hazeldine, Paul Newby, Aaron Scott, Peter Nightingale, Adam T. Hill, David R. Thickett
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Population studies suggest improved sepsis outcomes with statins, but the results of randomized controlled trials in patients with sepsis and organ dysfunction in critical care settings have broadly been negative. In vitro data suggest that statins modulate age-related neutrophil functions, improving neutrophil responses to infection, but only in older patients and at high doses.Objectives: To determine if high-dose simvastatin improves neutrophil functions and is safe and tolerated in hospitalized older adults with community-acquired pneumonia with sepsis (CAP + S) not admitted to critical care.Methods: We conducted a randomized, double-blind, placebo-controlled pilot study of simvastatin 80 mg or placebo for 7 days for patients with CAP + S aged 55 years or older admitted to a secondary care hospital. The Day 4 primary endpoint was change in neutrophil extracellular trap formation (NETosis). Day 4 secondary endpoints included neutrophil chemotaxis, safety and tolerability, Sequential Organ Failure Assessment score, mortality, readmission, and markers of tissue degradation/inflammation.Measurements and Main Results: Four days of simvastatin adjuvant therapy in patients with CAP + S was associated with improvements in systemic neutrophil function (NETosis and chemotaxis), a reduction in systemic neutrophil elastase burden, and improved Sequential Organ Failure Assessment scores compared with placebo. A post hoc analysis demonstrated that simvastatin therapy was associated with improved hospitalization-free survival compared with placebo. Simvastatin was well tolerated in this elderly and multimorbid patient group with common coprescription of macrolide antibiotics.Conclusions: This pilot study supports high-dose simvastatin as an adjuvant therapy for CAP + S in an older and milder disease cohort than assessed previously. A definitive multicenter study is now warranted in this population to assess the likelihood of benefit and harm.Clinical trial registered with EudraCT (2012-00343-29).
TBCRC 002: A phase II, randomized, open label trial of preoperative letrozole versus letrozole (LET) in combination with bevacizumab (BEV) in post-menopausal women with newly diagnosed stage II/III breast cancer.
Authors: Andres Forero-Torres, Hope S. Rugo, Christos Vaklavas, Nancy U. Lin, Lisa A. Carey, Minetta C. Liu, Rita Nanda, Shannon Puhalla, Anna Maria Storniolo, Helen Krontiras, Mansoor N. Saleh, Yufeng Li, Albert F. LoBuglio, Jennifer F. De Los Santos
Journal: Journal of Clinical Oncology (2013)

527 Background: A study from UAB Breast SPORE showed that expression of vascular endothelial growth factor (VEGF) in MCF7 breast tumor xenografts imparts tamoxifen resistance, increases tumor growth and metastatic potential. We postulated that anti-VEGF therapy would enhance anti-estrogen therapy. Methods: Randomized 2:1 phase II selection trial of LET (2.5 mg/day) with/without BEV (anti-VEGF monoclonal antibody; 15 mg/kg q3 weeks) for 24 weeks prior to surgery in post-menopausal patients with stage II/III, ER+/HER2- breast cancer. Primary objective was pathologic complete remission (pCR). Secondary objectives included response rates, down-staging, and toxicity. The trial was not powered to compare arms, but sized to estimate pCR rates to a certain precision (SE&lt;5% for combination, SE&lt;2% for single agent). Biopsies of the tumor and circulating tumor cells were collected. Results: 75 patients were randomized; 50 in the combination and 25 in the LET alone arm; 45 and 24 patients underwent surgery, respectively. Median age was 61 and 65 years, respectively. 5 patients in the combination arm had a pCR (11%; CI 1.9-20.1%) (no evidence of invasive cancer) , and 3 a near pCR (7%; 0%-14.5%) (microscopic disease only); thus pCR/near pCR rate 18% (6.8-29.2%). No patient treated with LET alone achieved a pCR/near pCR. The objective response rate was 64.5% in the combination arm and 37.5% in the single agent arm. 45% of the patients in the combination arm attained stage 0/I; 25% in the letrozole alone arm attained stage I, none attained stage 0. Therapy was well tolerated in both arms with no grade 4/5 toxicity. The most common AEs in the letrozole arm were hot flashes, fatigue, arthralgias/stiffness, myalgias, nausea/vomiting, and night sweats; in the combination arm they were hypertension, arthralgias/stiffness, hot flashes, headache, fatigue, proteinuria, dyspnea, rash, and myalgias. Conclusions: Neoadjuvant therapy with LET and BEV was well-tolerated and resulted in increased objective responses and down-staging. “Next-Gen” genomic analysis of the biopsies will allow for a trial with a targeted patient enrolment. Clinical trial information: F061229006.
FRI0394 MAINTAINED CLINICAL REMISSION IN ANKYLOSING SPONDYLITIS PATIENTS SWITCHED FROM REFERENCE INFLIXIMABTO ITS BIOSIMILAR. AN 18-MONTH COMPARATIVE OPEN-LABEL STUDY
Authors: Evripidis Kaltsonoudis, Eleftherios Pelechas, Paraskevi Voulgari, Alexandros Drosos
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> switching from reference infliximab (RI) to biosimilar infliximab (BI) had no detrimental effects on efficacy and safety compared to continuous RI. However, long-term follow-up data is missing. Objectives: the aim of this study was to evaluate if BI is equivalent to RI to maintain patients with Ankylosing Spondylitis (AS) in clinical remission, in a long-term fashion. Methods: one hundred and nine consecutive unselected AS patients were investigated. All, followed-up at predefined times receiving RI (5mg/kg/8 weeks) and were naïve to other biologics. Patients who were in clinical remission were asked to switch from RI to BI using the same therapeutic dose. Patients switched to BI were compared with a match control group receiving continuous RI. During follow-up the demographic, clinical, laboratory parameters and comorbidities were all recorded for at least 18 months. Disease activity was measured using the Bath Ankylosing Spondylitis activity index (BASDAI), and the Ankylosing Spondylitis disease activity score (ASDAS), using the C-reactive protein. Remission was defined if patients achieved BASDAI &lt;4 and ASDAS &lt;1.3. Results: twenty-one patients were excluded, nine because had no clinical remission and twelve because refused to switch. Thus, 88 were evaluated. From those, 45 switched to BI, while 43 continued receiving RI. There were no differences between groups regarding demographic, clinical and laboratory parameters. All patients were in clinical remission (BASDAI &lt;4 and ASDAS &lt;1.3). During follow-up, five patients from the switched group and three from the maintenance group discontinued the study. Four patients receiving BI presented nocebo effects and were switched back to the RI. Three responded well, while the fourth did not. After 18 months of treatment, all patients in both groups remained in clinical remission. No significant adverse events were noted between groups. <h3>Conclusion</h3> BI is equivalent to RI in maintaining AS in clinical remission for at least 18 months. <h3>Acknowledgement</h3> We have no acknowledegement for this abstract <h3>Disclosure of Interests</h3> None declared
Does immunological remission, defined as disappearance of autoantibodies, occur with current treatment strategies? A long-term follow-up study in rheumatoid arthritis patients who achieved sustained DMARD-free status
Authors: Debbie M Boeters, Leonie E Burgers, René EM Toes, Annette van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2019)

Sustained disease-modifying antirheumatic drug (DMARD)-free status, the sustained absence of synovitis after cessation of DMARD therapy, is infrequent in autoantibody-positive rheumatoid arthritis (RA), but approximates cure (ie, disappearance of signs and symptoms). It was recently suggested that immunological remission, defined as disappearance of anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF), underlies this outcome. Therefore, this long-term observational study determined if autoantibodies disappear in RA patients who achieved sustained DMARD-free remission.We studied 95 ACPA-positive and/or RF-positive RA patients who achieved DMARD-free remission after median 4.8 years and kept this status for the remaining follow-up (median 4.2 years). Additionally, 21 autoantibody-positive RA patients with a late flare, defined as recurrence of clinical synovitis after a DMARD-free status of ≥1 year, and 45 autoantibody-positive RA patients who were unable to stop DMARD therapy (during median 10 years) were studied. Anti-cyclic citrullinated peptide 2 (anti-CCP2) IgG, IgM and RF IgM levels were measured in 587 samples obtained at diagnosis, before and after achieving DMARD-free remission.13% of anti-CCP2 IgG-positive RA patients had seroreverted when achieving remission. In RA patients with a flare and persistent disease this was 8% and 6%, respectively (p=0.63). For anti-CCP2 IgM and RF IgM, similar results were observed. Evaluating the estimated slope of serially measured levels revealed that RF levels decreased more in patients with than without remission (p<0.001); the course of anti-CCP2 levels was not different (p=0.66).Sustained DMARD-free status in autoantibody-positive RA was not paralleled by an increased frequency of reversion to autoantibody negativity. This form of immunological remission may therefore not be a treatment target in patients with classified RA.
SAT0363 ENTHESITIS BUT NOT DACTYLITIS CONTRIBUTES TO BURDEN OF DISEASE IN PSA PATIENTS: DATA FROM THE BEPAS REAL LIFE COHORT
Authors: Kurt de Vlam, Rik Lories, Serge Steinfeld, Filip van den Bosch, Adrien Nzeusseu Toukap, Hermine Leroi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Psoriatic arthritis (PsA) significantly impacts physical function and quality of life. Limited data are available to specifically evaluate the impact of the different disease domains such as arthritis, axial involvement, skin disease, enthesitis and dactylitis. The BEPAS cohort, a prospective daily life cohort of PsA patients allows to study the impact of enthesitis and dactylitis on disease activity, disability and quality of life in PsA patients. <h3>Objectives</h3> 1) to measure the impact of enthesitis and dactylitis on health-related quality of life in PsA patients in Belgium. <h3>Methods</h3> At the inclusion visit, a cross-sectional analysis of dactylitis and enthesitis was performed among 462 patients from the BEPAS cohort and impact of enthesitis and/or dactylitis was studied. Patients were evaluated for the demographics, clinical disease manifestations, disability, disease global assessment and inflammatory markers at inclusion. Differences of tested variables between patients with and without dactylitis and/or enthesitis were evaluated by T-test or Chi –square testing. <h3>Results</h3> 462 patients (273 males and 189 females) with a mean disease duration of 8.53 years (SD: 9.25yrs) were recruited in 17 BEPAS centers from December 2012 to July 2014. 111 patients had enthesitis and 63 patients had dactylitis at inclusion. 17 patients had both enthesitis and dactylitis. Results are summarized in the table below: <h3>Conclusion</h3> Enthesitis has a larger impact on Quality of Life and Health Status than dactylitis in PsA. Patients with enthesitis and dactylitis have higher joint scores but not higher markers of systemic inflammation than those without. <h3>Acknowledgement</h3> This study is financially supported by MSD Belgium <h3>Disclosure of Interests</h3> Kurt de Vlam Consultant for: Pfizer Inc, Consultant for: Johnson &amp; Johnson, Rik Lories Consultant for: Abbvie, Celgene, Eli-Lilly, Janssen, Merck, Novartis, Pfizer, UCB, Serge Steinfeld: None declared, Filip van den Bosch Consultant for: AbbVie, BMS, Galapagos, Janssen, Lilly, Merck, Novartis, Pfizer and UCB, Speakers bureau: AbbVie, BMS, Janssen, Lilly, Merck, Novartis, Pfizer and UCB., Adrien Nzeusseu Toukap: None declared, Hermine Leroi Employee of: HL is a employee of MSD Belgium
PS927 PHOSPHOCHROMATOME ANALYSIS UNCOVERS UNEXPECTED ROLES OF CDK6 IN REGULATING TRANSCRIPTION
Authors: S. Nebenfuehr, F. Bellutti, K. Kollmann, M. Farlik, A.C. Müller, V. Sexl
Journal: HemaSphere (2019)

Background: Cyclin‐dependent kinase 6 (CDK6) together with its close homologue CDK4 enables the progression of cells through the early G1 phase of the cell cycle. CDK4/6‐cyclin D complexes phosphorylate members of the retinoblastoma (Rb) protein family, allowing for the release of E2F transcription factors that induce genes required for cell cycle progression and DNA replication. Alterations of the CDK4/6‐Rb pathway are frequently observed in human malignancies. Recent studies focusing on acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) have uncovered a novel role for CDK6 in regulating transcription. Our group has identified CDK6 as part of chromatin‐bound complexes which drive transcription of disease–relevant genes including the cell cycle inhibitor p16 INK4a , the angiogenesis‐promoting factor VEGF‐A (vascular endothelial factor A) and the proto‐oncogene FLT3 (Fms like tyrosine kinase 3). Aims: The aim of this study is to identify novel binding partners of CDK6 on chromatin and to investigate their target gene sets. A better understanding of CDK6 functionality in tumor formation and promotion may help in the design and selection of adequate treatment options. Methods: For further investigation of CDK6́s role in transcription, we transduced murine Cdk6 +/+ and Cdk6 −/− primary bone marrow with the oncogene Bcr/Abl p185 . To systematically gain insights on how CDK6 takes influence on chromatin‐binding and activity of transcription factors we performed RNA‐seq paralleled by mass spectrometry‐based phosphoproteomics of chromatin‐bound proteins (Phospho‐Chromatome). Results: RNA‐seq analysis of Cdk6 +/+ and Cdk6 −/− BCR‐ABL transformed cells identified more than 1700 genes that are differentially expressed. Phospho‐Chromatome studies performed in parallel revealed significant changes in the phosphorylation status of the transcription factors ZBTB7A, EBF1 and YY1. In vitro kinase assays verified a direct phosphorylation of ZBTB7A and EBF1 by active CDK6/CyclinD3 complexes. Summary/Conclusion: We show that CDK6 is broadly associated with chromatin where it fulfils different tasks: beside its well‐known role in the E2F‐release it enhances the phosphorylation of various transcription factors and chromatin‐regulating enzymes. This results in pronounced changes in associated gene expression. Therefor our data indicate that the function of CDK6 is not limited to cell cycle progression but regulates a plethora of tumor‐relevant transcriptional programs. Future therapies may consider this unexpected role and even exploit it to improve personalized and cancer‐specific treatment protocols.
AB0231 Pharmacoeconomic analysis of the treatment of rheumatoid arthritis with leflunomide in comparison with the combination of infliximab and methotrexate
Authors: C Rubio-Terrés, F Romero, A Domínguez-Gil
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To carry out a pharmacoeconomic analysis to compare the efficiency of two rheumatoid arthritis treatments in Spain. <h3>Methods</h3> The study consisted of a systematic review of efficacy and toxicity as well as a cost-minimization analysis, carried out using a pharmacoeconomic model, comparing the treatment with leflunomide and the combination of infliximab and methotrexate during one year. <h3>Results</h3> Clinical trials directly comparing both treatments are not available. The response rate ACR20 combined, after one year, was 53.0% (CI95%: 49.2%-56.4%) with Leflunomide and 42.0% (CI95%: 31.2%-52.5%) with the combination of Infliximab and Methotrexate (P = 0.051). There were no statistically significant differences in the ACR50 response (27.0 vs 21.0, respectively; P = 0.19). There were fewer infections with Leflunomide than with the combination, both respiratory (15.0% and 34.0%, respectively; P = 0.0003) as well as urinary (0.0% and 3.0%, respectively; P = 0.10). In the basic case, the cost per patient of a yearly treatment with Leflunomide or with Infliximab and Methotrexate is estimated to be 315,023 Ptas (Spanish pesetas) (1,893 euros, ?) and 2,596,286 Ptas (15,604 ?), respectively. Therefore, the incremental cost of the combined treatment would be 2,281,263 Ptas (13,711 ?). The sensitivity analysis was carried out using the minimum and maximum costs given by the standard deviations of the unit costs and by modifying other variables, as no significant differences compared to the basic case were found. <h3>Conclusion</h3> The cost per patient after one year of treatment is higher with the combination of Infliximab and Methotrexate compared to Leflunomide, this is basically due to the higher acquisition cost of Infliximab.