263 results on '"Maria Molina-Molina"'
Search Results
102. Preserved Forced Vital Capacity is not Always Representing Early IPF
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José Antonio Rodríguez-Portal, Guillermo Suarez-Cuartin, Jaume Sauleda, Ana Romero, Maria Molina-Molina, Orlando Acosta Fernández, Esteban Cano-Jiménez, Pilar Rivera Ortega, Karina Portillo, Diego Castillo, Eva Balcells, Guadalupe Bermudo Peloche, Claudia Valenzuela, Myriam Aburto, Belén Núñez, Virginia Leiro, Ana Villar, Vanesa Vicens-Zygmunt, Estrella Fernández-Fabrellas, Amalia Moreno, Rosario Laporta, Maria Teresa González-Budiño, and Lurdes Planas-Cerezales
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medicine.medical_specialty ,Vital capacity ,business.industry ,Diagnosis ,Medicine ,Idiopathic pulmonary fibrosis ,business ,Intensive care medicine - Published
- 2020
103. Outcome of hospitalisation for COVID-19 in patients with Interstitial Lung Disease: An international multicentre study
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Philip L. Molyneaux, Maria Molina-Molina, Felix Chua, Siva Mahendran, R K Coker, Pilar Rivera-Ortega, Maria Kokosi, George Margaritopoulos, Alice Packham, Alex West, Suresh Babu, Joanna C. Porter, Nazia Chaudhuri, Elisabeth Bendstrup, Michael Henry, Sharon Sturney, Ewen M Harrison, Tim Wallis, Athol U. Wells, Peter J. M. Openshaw, Louise E. Crowley, Laura Mackay, Elisabetta A. Renzoni, Glenn Hearson, Lisa G. Spencer, Iain A. Stewart, Killian Hurley, Ian Forrest, Diego Castillo Villegas, Sarah Agnew, Thomas M Drake, Simon P. Hart, Gauri Saini, Katherine M.A. O'Reilly, Huzaifa Adamali, Annemarie B Docherty, Jennifer K Quint, J Kenneth Baillie, Muhunthan Thillai, Rachel K. Hoyles, Katie Ward, Melissa Wickremasinghe, Michael A Gibbons, Malcolm G Semple, Davinder Dosanjh, Venerino Poletti, John M. Hutchinson, Helen Parfrey, R. Gisli Jenkins, David R Thickett, Aiden O’Brien, Lucy Howard, Emily Heiden, Michael Kreuter, Shaney L Barratt, Isaric C Investigators, Chris Barber, Anne-Marie Russell, Katherine Groom, S Jones, Stephen Bianchi, Christine A Fiddler, Giulia M. Stella, Anjali Crawshaw, Sarah Haney, Ling-Pei Ho, Helen Stone, William Chang, Peter M. George, Mark Jones, and Felix Woodhead
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education.field_of_study ,Vital capacity ,medicine.medical_specialty ,business.industry ,Population ,Interstitial lung disease ,respiratory system ,medicine.disease ,Comorbidity ,behavioral disciplines and activities ,Confidence interval ,respiratory tract diseases ,body regions ,FEV1/FVC ratio ,Internal medicine ,Cohort ,Medicine ,In patient ,education ,business - Abstract
RationaleThe impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established.ObjectivesTo assess outcomes following COVID-19 in patients with ILD versus those without in a contemporaneous age, sex and comorbidity matched population.MethodsAn international multicentre audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death.Measurements and Main ResultsData from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and comorbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of ConclusionsPatients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.
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- 2020
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104. Real-world clinical effectiveness of rituximab rescue therapy in patients with progressive rheumatoid arthritis-related interstitial lung disease
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Maria Molina-Molina, Joan M. Nolla, Alejandro Robles-Perez, Vanesa Vicens-Zygmunt, Marcos Anibal Yañez, Javier Narváez, Patricio Luburich, and Juan José Alegre
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medicine.medical_specialty ,Pulmonary function testing ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Rescue therapy ,Internal medicine ,medicine ,Humans ,In patient ,030212 general & internal medicine ,030203 arthritis & rheumatology ,business.industry ,Interstitial lung disease ,Retrospective cohort study ,medicine.disease ,Anesthesiology and Pain Medicine ,Treatment Outcome ,Rheumatoid arthritis ,Cohort ,Rituximab ,business ,Lung Diseases, Interstitial ,Immunosuppressive Agents ,medicine.drug - Abstract
To assess the real-world, long-term effectiveness of rituximab (RTX) as a rescue therapy in patients with progressive rheumatoid arthritis-related interstitial lung disease (RA-ILD) in whom more conventional therapy has failed.Longitudinal retrospective observational study of a cohort of patients with RA-ILD that started treatment with RTX due to ongoing progressive ILD despite treatment with glucocorticoids and csDMARDs or immunosuppressants (IS). All patients were treated with two or more cycles of RTX and evaluated for at least 12 months. Ongoing therapy with csDMARDs or IS remained unchanged.Thirty-one patients were analyzed. Before initiation of RTX the mean decline (delta) in %pFVC and %pDLCO from the ILD diagnosis (median 21 months) was -16.5% and -19.7%, respectively. After 1 year of treatment, RTX was able to reverse the decline of pulmonary function test (PFTs) parameters: ∆%pFVC +8.06% compared to baseline (95% CI: -10.9 to -5.2; p0.001) and ∆%pDLCO +12.7% (95% CI: -16.3 to -9.1; p0.001). In addition, there was a significant reduction in the median dose of prednisone, and it could be suspended in 26% of cases. Dividing the population into UIP and non-UIP patterns, we observed a significant increase in PFTs parameters in both groups. In the 25 patients (80.6%) that completed 2 years of treatment, the statistically significant amelioration in PFTs parameters observed at one year was maintained: ∆%pFVC +11.2% (95% CI: -15.6 to -6.8; p0.001) and ∆%pDLCO +14.8% (95% CI: -19.3 to -10.3; p0.001). At the end of the follow-up period (median 32 months; IQR 25th-75th 26-64), only 23 of the 31 patients (74.2%) were still undergoing treatment with RTX: in 3 cases (10%) it was stopped due to adverse events, in another 3 (10%) treatment failed ultimately requiring a lung transplant, and 2 patients (6%) died due to progression of the ILD and infectious complications. The frequency of adverse events reached 32% of cases.Based on our results, RTX appears to be effective as rescue therapy in a considerable proportion of patients with progressive RA-ILD unresponsive to conventional treatment.
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- 2020
105. GSE4-loaded nanoparticles a potential therapy for lung fibrosis that enhances pneumocyte growth, reduces apoptosis and DNA damage
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Lurdes Planas, Beatriz Fernández-Varas, Rosa Guerrero-López, Guillermo Guenechea, Rosario Perona, Elena G Arias-Salgado, Julio Cortijo, Leandro Sastre, Manoli Igartua, Susana P. Egusquiaguirre, Rosa Maria Hernandez, Laura Pintado-Berninches, Cristina Manguan-García, Ana Montes-Worboys, Laura Iarriccio, Maria Molina-Molina, José Luis Pedraz, Adela Serrano, Centro de Investigación Biomédica en Red Cáncer (España), Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Comisión Interministerial de Ciencia y Tecnología, CICYT (España), European Commission, and Centro de Investigación Biomédica en Red Enfermedades Raras (España)
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0301 basic medicine ,Telomerase ,DNA damage ,Apoptosis ,macromolecular substances ,Bleomycin ,telomerase ,Biochemistry ,Pulmonary fibrosis ,Alveolar cells ,03 medical and health sciences ,chemistry.chemical_compound ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Fibrosis ,Genetics ,medicine ,Humans ,Molecular Biology ,Lung ,Nanopartícules ,pulmonary fibrosis ,Chemistry ,technology, industry, and agriculture ,Fibrosi pulmonar ,alveolar cells ,respiratory system ,medicine.disease ,Oxidative Stress ,030104 developmental biology ,medicine.anatomical_structure ,Alveolar Epithelial Cells ,Cancer research ,GSE4 ,Nanoparticles ,Collagen ,Peptides ,030217 neurology & neurosurgery ,Biotechnology ,DNA Damage - Abstract
© 2021 The Authors., Idiopathic pulmonary fibrosis is a lethal lung fibrotic disease, associated with aging with a mean survival of 2-5 years and no curative treatment. The GSE4 peptide is able to rescue cells from senescence, DNA and oxidative damage, inflammation, and induces telomerase activity. Here, we investigated the protective effect of GSE4 expression in vitro in rat alveolar epithelial cells (AECs), and in vivo in a bleomycin model of lung fibrosis. Bleomycin-injured rat AECs, expressing GSE4 or treated with GSE4-PLGA/PEI nanoparticles showed an increase of telomerase activity, decreased DNA damage, and decreased expression of IL6 and cleaved-caspase 3. In addition, these cells showed an inhibition in expression of fibrotic markers induced by TGF-β such as collagen-I and III among others. Furthermore, treatment with GSE4-PLGA/PEI nanoparticles in a rat model of bleomycin-induced fibrosis, increased telomerase activity and decreased DNA damage in proSP-C cells. Both in preventive and therapeutic protocols GSE4-PLGA/PEI nanoparticles prevented and attenuated lung damage monitored by SPECT-CT and inhibited collagen deposition. Lungs of rats treated with bleomycin and GSE4-PLGA/PEI nanoparticles showed reduced expression of α-SMA and pro-inflammatory cytokines, increased number of pro-SPC-multicellular structures and increased DNA synthesis in proSP-C cells, indicating therapeutic efficacy of GSE4-nanoparticles in experimental lung fibrosis and a possible curative treatment for lung fibrotic patients., R.P laboratory was funded by grants P17-01401 (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain supported by FEDER funds), CIBER 576/805_ER16PE06P2016 and MINECO from the Spanish Government (INNPACTO, IPT-2012-0674-090000). M.M-M. laboratory was funded by Instituto de Salud Carlos III PI18/00367, supported by FEDER (Fondos Europeos de Desarrollo Regional (a way to build Europe)), JC received funds from MINECO CICYT SAF2014-55322-P, and GG laboratory was funded by grant SAF2015-68073-R (MINECO/FEDER) supported by FEDER funds. C.MG and R G-L are granted by the CIBERER.
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- 2020
106. Pirfenidone in Unclassifiable Interstitial Lung Disease (uILD): A Subgroup Analysis Stratified by Concomitant Mycophenolate Mofetil (MMF) Use
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Toby M. Maher, Frank Gilberg, Vincent Cottin, Judit Axmann, Tamera J. Corte, Michael Kreuter, Klaus-Uwe Kirchgaessler, and Maria Molina-Molina
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medicine.medical_specialty ,business.industry ,Internal medicine ,Concomitant ,Interstitial lung disease ,medicine ,Subgroup analysis ,Pirfenidone ,medicine.disease ,Mycophenolate ,business ,Gastroenterology ,medicine.drug - Published
- 2020
107. Proteomic Evaluation of the Lungs of Senescence-Accelerated Prone 8 (SAMP8) Mouse
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C. de la Torre, Annie Pardo, G. Christian, Joan Josep Bech-Serra, Maria Molina-Molina, Yalbi I. Balderas-Martínez, Moisés Selman, and M. Pallàs
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Senescence ,Biology ,Cell biology - Published
- 2020
108. Home Spirometry as a Primary Endpoint in Clinical Trials: Sensitivity Analyses of a Randomized Controlled Trial of Pirfenidone in Patients with Unclassifiable Interstitial Lung Disease (UILD)
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Judit Axmann, Toby M. Maher, Klaus-Uwe Kirchgaessler, Tamera J. Corte, Michael Kreuter, Vincent Cottin, Frank Gilberg, and Maria Molina-Molina
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Spirometry ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Interstitial lung disease ,Pirfenidone ,medicine.disease ,law.invention ,Clinical trial ,Randomized controlled trial ,law ,Internal medicine ,Clinical endpoint ,Medicine ,In patient ,business ,Sensitivity analyses ,medicine.drug - Published
- 2020
109. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial
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Rainer Georg Goeldner, S. Abe, Dirk Skowasch, Romain Kessler, S. Izumi, A. Barczyk, E. Belloli, J. S. Park, H. Takaya, C. Marquette, Neil Ettinger, Krishna Thavarajah, Nina Patel, Manuel Quaresma, Yasuhiko Nishioka, D Koschel, Silvia Quadrelli, M. A. Bergna, J. Sauleda, M. Salinas Fénero, J. Kang, G. Giessel, Oksana A. Shlobin, Kevin K. Brown, T. Kawamura, Ketan P. Buch, W. Randerath, O. Acosta, A. Silva Orellana, L. Wemeau, N. Sakamoto, Bruno Crestani, Sonye K. Danoff, Shane Shapera, S. Stieglitz, M. Reynaud-Gaubert, Tejaswini Kulkarni, P. Elias, Leslie Tolle, Lake Morrison, C. Glazer, Yoshikazu Inoue, Rozsa Schlenker-Herceg, Yolanda Mageto, Anand Devaraj, Zeenat Safdar, H. Hayashi, Y. Kim, Nik Hirani, Srihari Veeraraghavan, Sylvain Marchand-Adam, S. Cerri, J. Golden, D. Hotchkin, Rebecca Bascom, K. Ichikado, Martin Kolb, Nazia Chaudhuri, H. Cai, B. Crestani, J. W. Song, V. Yakusevich, Anoop M. Nambiar, Sergey Moiseev, Y. Kondoh, F. Lebargy, Wim A. Wuyts, Maria Padilla, A. Gamez-Dubuis, Sergey Avdeev, A. León Jiménez, R. Martinez, Luca Richeldi, J. Dematte D'Amico, Teng Moua, E. Bergot, J. Falk, Benjamin Bondue, K. Kishi, Danielle Antin-Ozerkis, L. Gómez Carrera, Francesco Bonella, Vincent Cottin, T. Moua, A. Villar, Stéphane Jouneau, Z. Xu, R. Hallowell, Mary E. Strek, H. Takahashi, Antje Prasse, A. Cantin, M. Okamoto, G. Criner, M. Rossman, M. Schwartz, R. Refini, Myriam Aburto, S. Makino, Y. Inoue, L. Jones, J. Burk, L. Morrow, Shelley L. Schmidt, S. Chaaban, M. Ilkovich, J. A. Rodríguez Portal, Athol U. Wells, S. Blaas, C. Andrews, D. M. Castillo Villegas, Caroline Dahlqvist, Q. Luo, H. Yamauchi, Justin M. Oldham, Julien Guiot, M. Kolb, Nitin Y. Bhatt, Y. Yamada, Maria Otaola, Alberto Pesci, E. Britt, W. Wuyts, E. Jassem, Daniel F. Dilling, Kevin R. Flaherty, H. Kitamura, H. Poonyagariyagorn, Y. Miyazaki, Robert J. Kaner, L. Pitts, Toby M. Maher, Marilyn K. Glassberg, G. Arce, J. Kus, S. Weigt, E. R. Fernández Pérez, Ivan O. Rosas, Michael Kreuter, Claudia Valenzuela, S. Tomassetti, Susanne Stowasser, K. Tomii, C. Kono, Ben Hope-Gill, D. Ziora, B. Sigal, E. Bazdyrev, R. Maturana Rozas, Paul Beirne, T. Saito, F. Varone, T. Suda, M. Arias, A. Cazaux, J. Hetzel, Helen Stone, Maria Molina-Molina, F. Riviere, L. Homik, Mary Beth Scholand, A. Gifford, W. Piotrowski, Carlo Vancheri, T. Takeuchi, H. Sugiura, M. Martínez, and Hilario Nunes
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Diarrhea ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Indoles ,Vital Capacity ,Population ,nintedanib, idiopathic pulmonary fibrosis ,Settore MED/10 - MALATTIE DELL'APPARATO RESPIRATORIO ,behavioral disciplines and activities ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,Idiopathic pulmonary fibrosis ,FEV1/FVC ratio ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,nintedanib ,medicine ,Humans ,030212 general & internal medicine ,education ,Protein Kinase Inhibitors ,Idiopathic interstitial pneumonia ,Aged ,education.field_of_study ,business.industry ,Interstitial lung disease ,Nausea ,Middle Aged ,respiratory system ,Sciences bio-médicales et agricoles ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,body regions ,030228 respiratory system ,chemistry ,Disease Progression ,Female ,Nintedanib ,business ,Hypersensitivity pneumonitis - Abstract
The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis., info:eu-repo/semantics/published
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- 2020
110. Acute exacerbation of idiopathic pulmonary fibrosis: International survey and call for harmonisation
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Julie Morisset, Julia Wälscher, G Calligaro, Carlo Vancheri, Yasuhiro Kondoh, Claudia Valenzuela, Catharina C. Moor, Martin Kolb, Kevin R. Flaherty, Simon L.F. Walsh, Toby M. Maher, Sergey Avdeev, Nazia Chaudhuri, Marlies S. Wijsenbeek, Harold R. Collard, Carlos Alberto de Castro Pereira, António Morais, Vanesa Vicens-Zygmunt, Markus Polke, Wim A. Wuyts, Silvia Quadrelli, Vincent Cottin, Argyrios Tzouvelekis, Moisés Selman, Jürgen Behr, Tamera J. Corte, Manuela Funke-Chambour, Michael Kreuter, Maria Molina Molina, Elisabeth Bendstrup, Johannes Krisam, and Pulmonary Medicine
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Palliative care ,Exacerbation ,medicine.medical_treatment ,610 Medicine & health ,Idiopathic pulmonary fibrosis ,medicine ,Extracorporeal membrane oxygenation ,Humans ,Intensive care medicine ,Lung ,Pulmonologists ,business.industry ,Immunosuppression ,respiratory system ,Prognosis ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,humanities ,respiratory tract diseases ,Vaccination ,Disease Progression ,Steroids ,Tomography, X-Ray Computed ,business ,Complication - Abstract
Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an often deadly complication of IPF. No focussed international guidelines for the management of AE-IPF exist. The aim of this international survey was to assess the global variability in prevention, diagnostic and treatment strategies for AE-IPF.Pulmonologists with ILD expertise were invited to participate in a survey designed by an international expert panel.509 pulmonologists from 66 countries responded. Significant geographical variability in approaches to manage AE-IPF was found. Common preventive measures included antifibrotic drugs and vaccination. Diagnostic differences were most pronounced regarding use of Krebs von den Lungen-6 and viral testing, while high-resolution computed tomography, brain natriuretic peptide and D-dimer are generally applied. High-dose steroids are widely administered (94%); the use of other immunosuppressant and treatment strategies is highly variable. Very few (4%) responders never use immunosuppression. Antifibrotic treatments are initiated during AE-IPF by 67%. Invasive ventilation or extracorporeal membrane oxygenation are mainly used as a bridge to transplantation. Most physicians educate patients comprehensively on the severity of AE-IPF (82%) and consider palliative care (64%).Approaches to the prevention, diagnosis and treatment of AE-IPF vary worldwide. Global trials and guidelines to improve the prognosis of AE-IPF are needed.
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- 2020
111. Characterizing lung resident mesenchymal stem cells in idiopathic pulmonary fibrosis patients
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Ana Garrido Martín, O Gigirey, C Rio Bocos, Cristina Gómez, A F Carvajal, A Jahn, Maria Molina-Molina, C Villena, J Velasco, J Mercader Oliver, J Pons, A Montes, Ernest Sala, and C Crespi
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Cell type ,Lung ,medicine.diagnostic_test ,business.industry ,Cell ,Mesenchymal stem cell ,respiratory system ,medicine.disease ,respiratory tract diseases ,Flow cytometry ,Pathogenesis ,Idiopathic pulmonary fibrosis ,medicine.anatomical_structure ,medicine ,Cancer research ,Bone marrow ,business - Abstract
Introduction: Mesenchymal stem cells (MSCs) are multipotent cells with an impressive potential for regeneration and immunomodulation. The niche of resident MSCs in the lung is believed to play an important role in pulmonary disease; however, most of the studies are focused on MSC from other origin as bone marrow. Here, we performed a comprehensive study of the characteristics of lung MSCs in both donor and in idiopathic pulmonary fibrosis (IPF) patients. Results and methods: MSCs were isolated from donor and IPF human lung tissue and mesenchymality was confirmed by flow cytometry (Stemflow hMSC Analysis) and Rohart MSC in silico test. The differentiation capacity was assessed using the Human MSC Functional Identification kit and both conditions were able to differentiate into osteoblasts and adipocytes after 21 days, although less potential was observed in IPF lung MSCs for the last one. Moreover, functional analyses were performed for migration and proliferation by real-time monitoring cell assay. Notably, profibrotic stimulation by TGF-s induced a significant change by increasing migration and decreasing proliferation in the IPF-lung MSCs when compared to donor. Furthermore, the regenerative ability to close an epithelial wound was significantly reduced in lung MSCs from IPF patients as tested by scratch assay in indirect and direct co-culture. Conclusions: Lung MSCs were successfully isolated from both donor and IPF and could differentiate into other cell types. However, IPF lung MSCs displayed a decreased proliferation and an increased migration profile in response to fibrotic stimulus possibly due to an increased sensibility to profibrotic factors. Moreover, IPF lung MSCs had reduced regenerative potential which might be involved in the impaired repair in IPF pathogenesis.
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- 2020
112. Clinical implications of ANCA positivity in idiopathic pulmonary fibrosis patients
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Maria Molina-Molina and Guillermo Suarez-Cuartin
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Pulmonary and Respiratory Medicine ,lcsh:RC705-779 ,medicine.medical_specialty ,business.industry ,Journal Club ,MEDLINE ,lcsh:Diseases of the respiratory system ,respiratory system ,medicine.disease ,Expert Opinion ,Dermatology ,humanities ,respiratory tract diseases ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,030228 respiratory system ,mental disorders ,Medicine ,030212 general & internal medicine ,business ,Vasculitis ,psychological phenomena and processes - Abstract
The diagnostic process of idiopathic interstitial pneumonias (IIPs) is complex and the underlying mechanisms that participate in these diseases still need to be fully understood. In 2015, the European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-Associated Interstitial Lung Disease introduced the term “interstitial pneumonia with autoimmune features” (IPAF) to identify subjects with IIP and features suggesting background autoimmunity but not characterisable connective tissue disease (CTD) [1]. The need for a proper clinical, serological and morphological assessment of IIP was highlighted to identify potential subjects with IPAF and CTD-ILD. However, the measurement of anti-neutrophil cytoplasmic antibodies (ANCAs) is not included in the definition of IPAF and ANCA serological testing is only recommended in idiopathic pulmonary fibrosis (IPF) when a clinical suspicion of vasculitis exists [2]. As current research evaluates the prognostic relevance of autoimmune features in IIP, the clinical importance of ANCA positivity still needs to be determined., ANCA positivity is uncommon in North American IPF patients. However, women with IPF who areMPO-positive have a considerable risk for developing clinical manifestations of vasculitis. http://bit.ly/2RlsQNP
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- 2020
113. ERS International Congress, Madrid, 2019: highlights from the Interstitial Lung Diseases Assembly
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Francesco Bonella, Hilario Nunes, Marlies S. Wijsenbeek, Maria Molina-Molina, Sebastiano Emanuele Torrisi, Tiago M. Alfaro, Fernanda Hernandez-Gonzalez, Elena Bargagli, Michael Kreuter, Venerino Poletti, Clairelyne Dupin, V Fernandes, Katerina M. Antoniou, Elisabetta A. Renzoni, Paolo Spagnolo, and Pulmonary Medicine
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Lung ,business.industry ,lcsh:R ,Congress Highlights ,lcsh:Medicine ,respiratory system ,medicine.disease ,behavioral disciplines and activities ,respiratory tract diseases ,body regions ,medicine.anatomical_structure ,International congress ,medicine ,Sarcoidosis ,Intensive care medicine ,business ,Idiopathic interstitial pneumonia - Abstract
This article discusses a selection of the scientific presentations in the field of interstitial lung diseases (ILDs) that took place at the 2019 European Respiratory Society International Congress in Madrid, Spain. There were sessions from all four groups within Assembly 12: group 12.01 “Idiopathic interstitial pneumonias”, group 12.02 “ILDs/diffuse parenchymal lung diseases (DPLDs) of known origin”, group 12.03 “Sarcoidosis and other granulomatous ILDs/DPLDs” and group 12.04 “Rare ILDs/DPLDs”. The presented studies brought cutting-edge developments on several aspects of these conditions, including pathogenesis, diagnosis and treatment. As many of the ILDs are individually rare, the sharing of experiences and new data that occur during the Congress are very important for physicians interested in ILDs and ILD patients alike., The 2019 #ERSCongress in Madrid provided novel data on interstitial lung diseases https://bit.ly/3iUKMZY
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- 2020
114. Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis
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Simon P. Hart, Vilmundur Gudnason, Yingze Zhang, Hiroto Hatabu, Rebecca Braybrooke, R. Gisli Jenkins, Shwu-Fan Ma, Michael Ng, Carlos Flores, George T. O'Connor, Ma'en Obeidat, Nik Hirani, Brian D. Hobbs, Megan L. Paynton, Amy Dressen, Ayodeji Adegunsoye, Helen Booth, Dominic Furniss, Philippe Joubert, Eunice Oballa, Ian Sayers, Martin D. Tobin, Krina T. Zondervan, Richard Hubbard, Xuan Li, Yohan Bossé, John D. Newell, Beatriz Guillen-Guio, Ann B. Millar, Wim Timens, Mary E. Strek, Gunnar Gudmundsson, Philip L. Molyneaux, Gary M. Hunninghake, Ani Manichaikul, Tasha E. Fingerlin, Rachel K. Putman, Richard J. Allen, Vidyia Navaratnam, Maria Molina-Molina, Don D. Sin, Helen Parfrey, Luke M. Kraven, Moira K. B. Whyte, Xuting R. Sheng, Phuwanat Sakornsakolpat, David J. Lederer, David C. Nickle, Ian P. Hall, Brian L. Yaspan, Louise V. Wain, Toby M. Maher, Gauri Saini, Ke Hao, Michael Hill, Naftali Kaminski, Andrew P. Morris, Hanfei Xu, Justin M. Oldham, David A. Schwartz, Robin J. McAnulty, Michael H. Cho, Victor E. Ortega, Margaret Neighbors, Imre Noth, William A. Fahy, Action for Pulmonary Fibrosis, National Institute for Health Research, British Lung Foundation, Groningen Research Institute for Asthma and COPD (GRIAC), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland
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Male ,Pathology ,Epidemiology ,Respiratory System ,Kinesins ,Gene Expression ,Genome-wide association study ,Cell Cycle Proteins ,TOR Serine-Threonine Kinases/metabolism ,VARIANTS ,Critical Care and Intensive Care Medicine ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,KIF15 ,TELOMERES ,genetics ,030212 general & internal medicine ,Respiratory system ,11 Medical and Health Sciences ,RISK ,TOR Serine-Threonine Kinases ,Intracellular Signaling Peptides and Proteins ,respiratory system ,Middle Aged ,MAD1L1 ,3. Good health ,medicine.anatomical_structure ,SURVIVAL ,epidemiology ,Female ,Life Sciences & Biomedicine ,Kinesin/genetics ,Signal Transduction ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Spindle Apparatus ,DIAGNOSIS ,Risk Assessment ,REGION ,03 medical and health sciences ,Critical Care Medicine ,General & Internal Medicine ,medicine ,Genetics ,Erfðafræði ,Humans ,Genetic Predisposition to Disease ,Aged ,Cell Cycle Proteins/genetics ,Lungnasjúkdómar ,Lung ,Science & Technology ,DEPTOR ,business.industry ,MUTATIONS ,Case-control study ,Editorials ,RTEL1 ,medicine.disease ,Epithelium ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,Genarannsóknir ,030228 respiratory system ,EVENT ,Case-Control Studies ,GAIN ,business ,Intracellular Signaling Peptides and Proteins/genetics ,Idiopathic Pulmonary Fibrosis/genetics ,Genome-Wide Association Study - Abstract
Publisher's version (útgefin grein), Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Measurements and Main Results: We identified and replicated threenewgenome-wide significant (P, R.J.A. is an Action for Pulmonary Fibrosis Research Fellow. L.V.W. holds a GSK/British Lung Foundation Chair in Respiratory Research. R.G.J. is supported by a National Institute for Health Research (NIHR) Research Professorship (NIHR reference RP-2017-08-ST2-014). I.N. is supported by the NHLBI (R01HL130796). B.G.-G. is funded by Agencia Canaria de Investigación, Innovación y Sociedad de la Información (TESIS2015010057) cofunded by European Social Fund. J.M.O. is supported by the NHLBI (K23HL138190). C.F. is supported by the Spanish Ministry of Science, Innovation and Universities (grant RTC-2017-6471-1; Ministerio de Ciencia e Innovacion/Agencia Estatal de Investigación/Fondo Europeo de Desarrollo Regional, Unión Europea) cofinanced by the European Regional Development Funds “A way of making Europe” from the European Union and by agreement OA17/008 with Instituto Tecnológico y de Energías Renovables to strengthen scientific and technological education, training, research, development and innovation in Genomics, Personalized Medicine and Biotechnology. The Spain Biobank array genotyping service was performed at CEGEN-PRB3-ISCIII, which is supported by PT17/0019, of the PE I+D+i 2013–2016, funded by Instituto de Salud Carlos III, and cofinanced by the European Regional Development Funds. P.L.M. is an Action for Pulmonary Fibrosis Research Fellow. M.O. is a fellow of the Parker B. Francis Foundation and a Scholar of the Michael Smith Foundation for Health Research. B.D.H. is supported by NIH K08 HL136928, Parker B. Francis Research Opportunity Award. M.H.C. and G.M.H. are supported by NHLBI grants R01HL113264 (M.H.C.), R01HL137927 (M.H.C.), R01HL135142 (M.H.C. and G.M.H.), R01111024 (G.M.H.), and R01130974 (G.M.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. T.M.M. is supported by an NIHR Clinician Scientist Fellowship (NIHR Ref: CS-2013-13-017) and a British Lung Foundation Chair in Respiratory Research (C17-3). M.D.T. is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). The research was partially supported by the NIHR Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health. I.P.H. was partially supported by the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. I.S. is supported by Medical Research Council (G1000861) and Asthma UK (AUK-PG-2013-188). D.F. was supported by an Intermediate Fellowship from the Wellcome Trust (097152/Z/11/Z). This work was partially supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. V.N. is funded by an NIHR Clinical Lectureship. G.G. is supported by project grant 141513-051 from the Icelandic Research Fund and Landspitali Scientific Fund A-2016-023, A-2017-029, and A-2018-025. D.J.L. and A.M. are supported by Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SNP Health Association Resource (SHARe) project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California) and the Broad Institute of Harvard and Massachusetts Institute of Technology (Boston, Massachusetts) using the Affymetrix Genome-Wide Human SNP Array 6.0. This work was supported by NIH grants R01 HL131565 (A.M.), R01 HL103676 (D.J.L.), and R01 HL137234 (D.J.L.).
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- 2020
115. Prognostic factors of progressive fibrotic hypersensitivity pneumonitis: a large, retrospective, multicentre, observational cohort study
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Esteban Cano-Jiménez, Ana Villar Gómez, Eduardo Velez Segovia, Myriam Aburto Barrenechea, Jacobo Sellarés Torres, Joel Francesqui, Karina Portillo Carroz, Alan Jhunior Solis Solis, Orlando Acosta Fernández, Ana Belén Llanos González, Jaume Bordas-Martinez, Eva Cabrera Cesar, Eva Balcells Vilarnau, Diego Castillo Villegas, Ana Reyes Pardessus, Coral González Fernández, Marta García Moyano, Amaia Urrutia Gajate, Andrés Blanco Hortas, and María Molina-Molina
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Medicine - Abstract
Background Fibrotic hypersensitivity pneumonitis (fHP) is an immune-mediated interstitial lung disease caused by sensitisation to chronic allergen inhalation. This study aimed to determine prognostic indicators of progression and mortality in fHP. Methods This was a retrospective, multicentre, observational, cross-sectional cohort study of consecutive patients diagnosed with fHP from 1 January 2012 to 31 December 2021. Multivariate Cox regression analyses were used to calculate hazard ratios (HRs) with 95% confidence intervals for predictors of progression and survival. Results A total of 403 patients were diagnosed with fHP: median (interquartile range) age 66.5 (14.0) years, 51.9% females and 55.1% never-smokers. The cause of fHP was mainly fungal (39.7%) or avian (41.4%). Lung biopsy was performed in 269 cases (66.7%). In the whole cohort the variables that were related to mortality or lung transplant were older age (HR 1.08; p
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- 2024
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116. Tratamiento actual de la enfermedad pulmonar intersticial asociada a la artritis reumatoide
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Javier Narváez, Alejandro Robles-Perez, and Maria Molina-Molina
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Diseases of the respiratory system ,RC705-779 ,business.industry ,Medicine ,business - Published
- 2021
117. Normativa sobre el tratamiento farmacológico de la fibrosis pulmonar idiopática
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Antoni Xaubet, Estrella Fernández-Fabrellas, José Antonio Rodríguez-Portal, Elena Bollo, Julio Ancochea, Orlando Acosta, Maria Molina-Molina, Claudia Valenzuela, and Diego Castillo
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Poor prognosis ,Lung ,Medical treatment ,business.industry ,Incidence (epidemiology) ,Pirfenidone ,medicine.disease ,Surgery ,Clinical trial ,03 medical and health sciences ,chemistry.chemical_compound ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,medicine.anatomical_structure ,030228 respiratory system ,chemistry ,medicine ,Nintedanib ,030212 general & internal medicine ,Intensive care medicine ,business ,medicine.drug - Abstract
Idiopathic pulmonary fibrosis is defined as chronic fibrosing interstitial pneumonia limited to the lung, with poor prognosis. The incidence has been rising in recent years probably due to improved diagnostic methods and increased life expectancy. In 2013, the SEPAR guidelines for the diagnosis and treatment for idiopathic pulmonary fibrosis were published. Since then, clinical trials and meta-analyses have shown strong scientific evidence for the use of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis. In 2015, the international consensus of 2011 was updated and new therapeutic recommendations were established, prompting us to update our recommendation for the medical treatment of idiopathic pulmonary fibrosis accordingly. Diagnostic aspects and non-pharmacological treatment will not be discussed as no relevant developments have emerged since the 2013 guidelines.
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- 2017
118. Fibrosis pulmonar idiopática
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Antoni Xaubet, Julio Ancochea, and Maria Molina-Molina
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Pathology ,medicine.medical_specialty ,Lung ,business.industry ,General Medicine ,Disease ,medicine.disease ,Transplantation ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,medicine.anatomical_structure ,030228 respiratory system ,Usual interstitial pneumonia ,medicine ,Etiology ,Genetic predisposition ,030212 general & internal medicine ,business ,Survival rate - Abstract
Idiopathic pulmonary fibrosis is a fibrosing interstitial pneumonia associated with the radiological and/or histological pattern of usual interstitial pneumonia. Its aetiology is unknown, but probably comprises the action of endogenous and exogenous micro-environmental factors in subjects with genetic predisposition. Its diagnosis is based on the presence of characteristic findings of high-resolution computed tomography scans and pulmonary biopsies in absence of interstitial lung diseases of other aetiologies. Its clinical evolution is variable, although the mean survival rate is 2-5 years as of its clinical presentation. Patients with idiopathic pulmonary fibrosis may present complications and comorbidities which modify the disease's clinical course and prognosis. In the mild-moderate disease, the treatment consists of the administration of anti-fibrotic drugs. In severe disease, the best therapeutic option is pulmonary transplantation. In this paper we review the diagnostic and therapeutic aspects of the disease.
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- 2017
119. Biomarcadores séricos en las enfermedades pulmonares intersticiales difusas
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Maria Molina-Molina and Jacobo Sellares
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Pulmonary and Respiratory Medicine ,Gynecology ,medicine.medical_specialty ,business.industry ,medicine ,business - Published
- 2020
120. Gender equity in interstitial lung disease
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Marilyn K. Glassberg, Marlies S. Wijsenbeek, Maria Molina-Molina, Kerri A. Johannson, Mary E. Strek, Leticia Kawano-Dourado, and Pulmonary Medicine
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Pulmonary and Respiratory Medicine ,Male ,medicine.medical_specialty ,Gender equity ,Biomedical Research ,business.industry ,Sexism ,Interstitial lung disease ,MEDLINE ,medicine.disease ,Sex Factors ,Sex factors ,Internal medicine ,medicine ,Humans ,Female ,business ,Lung Diseases, Interstitial - Published
- 2020
121. Antifibrotic treatment in progressive non-IPF fibrotic interstitial lung diseases
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Orlando Acosta Fernández, Núria Padullés Zamora, Jose Manuel Palma López, Jordi Dorca Sargatal, Agustín Medina Gonzálvez, Jaume Bordas Martinez, Ramón José Jódar Masanés, Laura Pérez Martín, Guadalupe Bermudo Peloche, Guillermo Suarez-Cuartin, Lurdes Planas-Cerezales, Maria Molina Molina, Vanesa Vicens Zygmunt, Ana Belén Llanos-González, and Sara García Gil
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medicine.medical_specialty ,business.industry ,Pirfenidone ,respiratory system ,medicine.disease ,Gastroenterology ,respiratory tract diseases ,chemistry.chemical_compound ,FEV1/FVC ratio ,Idiopathic pulmonary fibrosis ,chemistry ,DLCO ,Usual interstitial pneumonia ,Internal medicine ,Pulmonary fibrosis ,medicine ,Nintedanib ,business ,Hypersensitivity pneumonitis ,medicine.drug - Abstract
Introduction and Aim: Pirfenidone and nintedanib are anti-fibrotic approved treatments for idiopathic pulmonary fibrosis (IPF). Its efficacy and safety in other fibrotic interstitial lung diseases (ILD) is under study in clinical trials. The aim was to analyse the effect of these drugs in non-IPF progressive fibrotic patients that couldn’t be included in these trials. Methods: Multicenter retrospective study of 34 progressive PF non-IPF patients treated with anti-fibrotic drugs. Demographic, clinical data and treatment-related variables were evaluated. The reason to start off-label anti-fibrotic was disease progression with previous therapy and exclusion from clinical trials. Results: Patients with non-IPF progressive PF were: 38% unclassifiable PF (UPF), 20% familial pulmonary fibrosis (FPF), 18% CTD-ILD, 15% chronic hypersensitivity pneumonitis (CHP) and 9% pneumoconiosis. Mean age was 67±12 years, 74% were male and 47% ex-smokers. 21% of cases had usual interstitial pneumonia HRCT pattern. Mean FVC was 66%±23 and DLCO 45%±12. Co-medications were: low-dose prednisone (20), mycophenolate (5) and sirolimus (1). Twenty-four subjects (71%) received pirfenidone and ten (29%) nintedanib. After one year, a FVC decrease of 5-10% was observed in only 3 patients (1 CHP, 1 pneumoconiosis, 1 UPF), while others showed stability or improvement. Main reported adverse effects were: 20% hypertransaminasemia, 27% diarrhea and 15% weight loss, requiring 5 patients to stop therapy. Conclusion: After one year of anti-fibrotic therapy, most patients with non-IPF progressive PF showed functional stability. Clinical trials are mandatory to evaluate their potential efficacy, but these drugs are a safe option in progressive PF patients.
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- 2019
122. Late Breaking Abstract - Phase II trial of pirfenidone in patients with progressive fibrosing unclassifiable ILD (uILD)
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David J. Lederer, Vincent Cottin, Judit Axmann, Frank Gilberg, Katerina Samara, Tamera J. Corte, Toby M. Maher, Klaus-Uwe Kirchgaessler, Aryeh Fischer, Maria Molina-Molina, and Michael Kreuter
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Spirometry ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Pirfenidone ,Placebo ,03 medical and health sciences ,FEV1/FVC ratio ,Safety profile ,0302 clinical medicine ,030228 respiratory system ,DLCO ,Internal medicine ,Clinical endpoint ,Medicine ,In patient ,030212 general & internal medicine ,business ,medicine.drug - Abstract
Introduction: There are no approved therapies for patients with uILD, who may have irreversible ILD. We evaluated efficacy and safety of pirfenidone in patients with progressive fibrosing uILD. Methods: This was a double-blind, randomised, placebo-controlled Phase II trial (NCT03099187). The primary endpoint was predicted FVC change over 24 weeks measured by daily home spirometry; secondary endpoints included changes in FVC (measured at site visits), DLco and 6MWD. Safety was also assessed. Results: 253 patients were randomised and 251 were treated (n=127 pirfenidone; n=124 placebo). Analysis of the primary endpoint was impacted by high intra-individual variability in home spirometry values in both treatment groups, amplified in patients with short observation periods, which prevented application of the planned statistical model. Median (Q1, Q3) FVC change (home spirometry) over 24 weeks was –87.7 mL (–338.1, 148.6) and –157.1 mL (–370.9, 70.1) in pirfenidone and placebo groups, respectively (Table). FVC change measured at site visits considerably favoured pirfenidone over placebo; results for DLco and 6MWD generally trended towards pirfenidone (Table). AE reporting reflected the known safety profile of pirfenidone. Conclusions: The planned statistical model could not be applied to the primary endpoint data. Results of key secondary endpoints suggest patients with progressive fibrosing uILD benefit from pirfenidone.
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- 2019
123. Could chest ultrasound replace chest X-ray for the diagnosis of pneumothorax after pulmonary cryobiopsy?
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Noelia Cubero De Frutos, Salud Santos Perez, Jordi Dorca Sargatal, Maria Molina Molina, Marta Diez Ferrer, Pere Trias Sabria, Rosa Lopez Lisbona, Yuliana Pascual González, Antonia Bonet Burguera, and Vanesa Vicens Zygmunt
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Chest ultrasound ,medicine.medical_specialty ,Lung ,business.industry ,medicine.medical_treatment ,medicine.disease ,Chest tube ,medicine.anatomical_structure ,Pneumothorax ,Medicine ,In patient ,Radiology ,Complication ,business ,Prospective cohort study ,Hospital stay - Abstract
Background: Transbronchial lung cryobiopsy (TBLC) has been established as a common and safe procedure in the diagnosis of diffuse interstitial lung diseases (ILD). The patient can be discharged after a few hours under observation, except if a complication is presented, mainly bleeding or pneumothorax (PTX). Chest X-ray (CXR) is the conventional examination performed to detect PTX, but sometimes the delay in carrying it out may lengthen the patient’s hospital stay. Chest ultrasound (US) is more sensitive in the detection of PTX. Objective: to assess if chest US could replace CXR to detect PTX. Methods: prospective study in patients with indication of TBLC for the study of ILD from April 2018 to February 2019. Chest US was performed 1 hour after the procedure in the recovery area and a CXR was performed 4 hours after the procedure in the Radiology department, except if the patient had symptoms or if the US showed PTX, performing CXR earlier. Results: 32 patients were included,57.3% males.94% of the biopsies were performed in lower lobes.24 patients did not present PTX on US and this was confirmed with CXR, except in one patient who presented late PTX on the CXR.4 patients presented PTX on US and it was also confirmed with CXR. US detected 1 PTX that was not visible in CXR. In 3 cases there were doubts in the US image due to a bad window, of which 1 had PTX and another 2 did not. About the patients who presented PTX (22%), only two (6.2%) required a chest tube. The rest were discharged after 24-72 hours of observation. Conclusions: Chest US can replace conventional CXR in a large number of patients, allowing early discharge, although the possibility of late PTX (3.1%) must be taken into account.
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- 2019
124. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial
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Tamera J. Corte, Michael Kreuter, Katerina Samara, Toby M. Maher, Judit Axmann, Aryeh Fischer, Maria Molina-Molina, Klaus-Uwe Kirchgaessler, Vincent Cottin, David J. Lederer, Frank Gilberg, National Institute for Health Research, and British Lung Foundation
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Male ,Pulmonary Fibrosis ,Respiratory System ,Vital Capacity ,law.invention ,0302 clinical medicine ,Randomized controlled trial ,law ,Clinical endpoint ,030212 general & internal medicine ,Lung ,education.field_of_study ,medicine.diagnostic_test ,Pirfenidone ,Middle Aged ,Progression-Free Survival ,Respiratory Function Tests ,Europe ,Treatment Outcome ,Tolerability ,Drug Therapy, Combination ,Female ,Life Sciences & Biomedicine ,medicine.drug ,Pulmonary and Respiratory Medicine ,Spirometry ,medicine.medical_specialty ,Pyridones ,Population ,Placebo ,CLASSIFICATION ,1117 Public Health and Health Services ,03 medical and health sciences ,FEV1/FVC ratio ,Critical Care Medicine ,Double-Blind Method ,Internal medicine ,General & Internal Medicine ,medicine ,Humans ,education ,Aged ,Science & Technology ,business.industry ,1103 Clinical Sciences ,Mycophenolic Acid ,030228 respiratory system ,UPDATE ,IDIOPATHIC PULMONARY-FIBROSIS ,business ,Lung Diseases, Interstitial ,FORCED VITAL CAPACITY ,1199 Other Medical and Health Sciences - Abstract
Summary Background At present, no approved pharmacotherapies are available for unclassifiable interstitial lung disease (ILD), which is characterised by progressive fibrosis of the lung. We aimed to assess the efficacy and safety of pirfenidone in patients with progressive fibrosing unclassifiable ILD. Methods We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 70 centres in Australia, Belgium, Canada, Czech Republic, Denmark, Germany, Greece, Ireland, Israel, Italy, Poland, Portugal, Spain, and the UK. Eligible patients (aged ≥18–85 years) had progressive fibrosing unclassifiable ILD, a percent predicted forced vital capacity (FVC) of 45% or higher and percent predicted carbon monoxide diffusing capacity (DLco) of 30% or higher, more than 10% fibrosis on high-resolution CT, and a high-resolution CT from the previous 12 months. Patients were randomly assigned (1:1) to 2403 mg oral pirfenidone daily or placebo using a central validated interactive voice or web-based response system, stratified by concomitant mycophenolate mofetil use and presence or absence of interstitial pneumonia with autoimmune features. Investigators, site personnel, and patients were masked to treatment assignment. The primary endpoint was mean predicted change in FVC from baseline over 24 weeks, measured by daily home spirometry. Secondary endpoints were change in FVC measured by site spirometry, proportion of patients who had a more than 5% or more than 10% absolute or relative decline in percent predicted FVC measured by clinic-based spirometry, change in percent predicted DLco, change in 6-min walk distance (6MWD), change in University of California San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) score, change in Leicester Cough Questionnaire score, change in cough visual analogue scale, and changes in total and subscores of the St George's Respiratory Questionnaire (SGRQ), all of which were compared with baseline. Additional secondary endpoints included proportion of patients who had non-elective hospitalisation (respiratory and all-cause) and acute exacerbations, and progression-free survival. Efficacy was analysed in the intention-to-treat (ITT) population, which included all randomly assigned patients. Safety was assessed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT03099187 , and is no longer recruiting. Findings Between May 15, 2017, and June 5, 2018, 253 patients were randomly assigned to receive 2403 mg pirfenidone (n=127) or placebo (n=126) and were included in the ITT analysis set. Analysis of the primary endpoint was affected by intraindividual variability in home spirometry values, which prevented application of the prespecified statistical model. Over 24 weeks, predicted median change in FVC measured by home spirometry was −87·7 mL (Q1–Q3 −338·1 to 148·6) in the pirfenidone group versus −157·1 mL (−370·9 to 70·1) in the placebo group. Over 24 weeks, predicted mean change in FVC measured by site spirometry was lower in patients given pirfenidone than placebo (treatment difference 95·3 mL [95% CI 35·9 to 154·6], p=0·002). Compared with the placebo group, patients in the pirfenidone group were less likely to have a decline in FVC of more than 5% (odds ratio [OR] 0·42 [95% CI 0·25 to 0·69], p=0·001) or more than 10% (OR 0·44 [0·23 to 0·84], p=0·011). At week 24, mean change in DLco from baseline was −0·7% (SD 7·1) for the pirfenidone group and −2·5% (8·8) for the placebo group, and mean change in 6MWD from baseline was −2·0 m (68·1) for the pirfenidone group and −26·7 m (79·3) for the placebo group. Changes from baseline in UCSD-SOBQ, Leicester Cough Questionnaire score, cough visual analogue scale, and SGRQ scores were similar between the pirfenidone and placebo groups at week 24. Analysis of acute exacerbations, hospital admissions, and time to death from respiratory causes during the study yielded no meaningful results due to a small number of events. No differences in progression-free survival were identified between the pirfenidone and placebo groups, irrespective of the definition of progression-free survival used. Treatment-emergent adverse events were reported in 120 (94%) of 127 patients in the pirfenidone group and 101 (81%) of 124 patients in the placebo group. Serious treatment-emergent adverse events were reported in 18 (14%) patients in the pirfenidone group and 20 (16%) patients in the placebo group. The most common treatment-related treatment-emergent adverse events were gastrointestinal disorders (60 [47%] in the pirfenidone group vs 32 [26%] in the placebo group), fatigue (16 [13%] vs 12 [10%]), and rash (13 [10%] vs nine [7%]). Interpretation Although the planned statistical model could not be applied to the primary endpoint data, analysis of key secondary endpoints suggests that patients with progressive fibrosing unclassifiable ILD could benefit from pirfenidone treatment, which has an acceptable safety and tolerability profile. These findings support further investigation of pirfenidone as an effective treatment for patients with progressive fibrotic unclassifiable ILD. Funding F Hoffmann-La Roche.
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- 2019
125. Serum Biomarkers in Diffuse Interstitial Lung Diseases
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Maria Molina-Molina and Jacobo Sellares
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Pathology ,medicine.medical_specialty ,Lung ,medicine.anatomical_structure ,business.industry ,Serum biomarkers ,medicine ,Humans ,General Medicine ,business ,Lung Diseases, Interstitial ,Biomarkers - Published
- 2019
126. Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis
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Pearce G. Wilcox, Joel M. Guthridge, Oliver Eickelberg, Mary E. Strek, Michael P. Keane, Yasunari Miyazaki, Doris Rassl, Osamu Narumoto, Moisés Selman, Jonathan A. Kropski, Maryl Kreider, Seamus C. Donnelly, Joao A. de Andrade, Geoffrey J. Laurent, Claudia Ravaglia, Michelle E. Armstong, Peter Saunders, Edwin K. Silverman, Yuben Moodley, Sydney B. Montesi, Tsukasa Okamoto, John S. Sundy, Tasha E. Fingerlin, Julie Powers, Jonathan Cardwell, Masaki Hirose, John Sembrat, Joyce S. Lee, Ho Cheol Kim, Yoshikazu Inoue, Karin A. Pacheco, David A. Schwartz, Tarik Walker, Ivana V. Yang, Camille M. Moore, Roberto Carbone, Martina Vasakova, Steven D. Nathan, Vivi Danchel, Michael Henry, Thomas G. O'Riordan, Helen Parfrey, Annie Pardo, Merte Lemma WoldeHanna, Nesrin Mogulkoc, Francesco Bonella, Philip L. Molyneaux, Alvaro Aranda, Martina Sterclova, Yingze Zhang, Ian Glaspole, Toby M. Maher, Barry S. Shea, Tejaswini Kulkarni, Peter Doran, Maria Molina-Molina, Namrata Patel, Haruhiko Furusawa, Dong Soon Kim, Kenneth B. Beckman, Svetlana Baltic, Feng Li, Drew C. Venuto, Harold R. Collard, Avram D Walts, Venerino Poletti, Shwu Fan Ma, Maho Suzukawa, Tracy Luckhardt, Nikhil Hirani, Wonjun Ji, Bruno Crestani, Kevin K. Brown, R. Gisli Jenkins, Caroline Kannengiesser, Christopher J. Ryerson, Aoife McElroy, Pamela Russell, Marvin I. Schwarz, Jin Woo Song, Ana Montes Worboys, Rachel Z. Blumhagen, Gauri Saini, Gunnar Gudmundsson, James D. Crapo, Paul J. Wolters, Sara Tomassetti, Christine A Fiddler, Lisa A. Maier, Carol Bair, Nurdan Kokturk, James E. Loyd, Rebecca Braybrooke, Shinobu Akagawa, Raphael Borie, Mauricio Rojas, Jürgen Behr, Tamera J. Corte, Michael H. Cho, Joy D. Cogan, Mark P. Steele, Susan K. Mathai, Francesco Puppo, Toru Arai, Kevin F. Gibson, Makenna Bishop, Isis E. Fernandez, Mary K. Porteous, Imre Noth, Jeffrey J. Swigris, Anna J. Podolanczuk, Brian Vestal, Cecilia M. Prêle, Ken Ohta, David J. Lederer, Deborah A. Nickerson, Elisabeth Bendstrup, Helgi J Isaksson, Cheryl Markin, Judith A. James, Carlos Machahua, Daniel J. Kass, Azin S. Poon, Ege Üniversitesi, National Institute for Health Research, and British Lung Foundation
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Male ,Genetic variants ,Respiratory System ,Cell ,Medizin ,LOCI ,Disease ,MUC5B PROMOTER POLYMORPHISM ,SUSCEPTIBILITY ,Critical Care and Intensive Care Medicine ,DISEASE ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Medicine ,030212 general & internal medicine ,Promoter Regions, Genetic ,Telomerase ,Cellular Senescence ,11 Medical and Health Sciences ,Pulmonary Surfactant-Associated Protein A ,GTPase-Activating Proteins ,High-Throughput Nucleotide Sequencing ,ASSOCIATION ,Targeted resequencing ,respiratory system ,idiopathic pulmonary fibrosis ,Mucin-5B ,Pulmonary Surfactant-Associated Protein C ,GENOME ,medicine.anatomical_structure ,Host-Pathogen Interactions ,Female ,DNA Sequence Analysis ,Life Sciences & Biomedicine ,Pulmonary and Respiratory Medicine ,Senescence ,EXPRESSION ,Telomere-Binding Proteins ,macromolecular substances ,03 medical and health sciences ,Critical Care Medicine ,General & Internal Medicine ,Humans ,disease risk alleles ,Genetic Predisposition to Disease ,Gene ,Science & Technology ,business.industry ,Host (biology) ,MUTATIONS ,genetic variants ,DNA Helicases ,Editorials ,Genetic Variation ,rare variants ,Rare variants ,Sequence Analysis, DNA ,targeted resequencing ,medicine.disease ,Logistic Models ,030228 respiratory system ,Case-Control Studies ,Exoribonucleases ,Immunology ,RNA ,ATP-Binding Cassette Transporters ,business ,Disease risk alleles ,Genome-Wide Association Study - Abstract
EgeUn###, Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 3 102295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence. Copyright © 2019 by the American Thoracic Society, Háskóli Íslands, HI University of Chicago University of Ulsan, UOU Monash University, MU University of Nottingham University of Edinburgh University of Colorado Denver Universitat de Barcelona University of Pittsburgh, Pitt Harvard School of Dental Medicine Massachusetts General Hospital, MGH University of Pennsylvania, Penn University College Cork, UCC City, University of London, City University of California, San Francisco, UCSF School of Medicine, Vanderbilt University Ege Üniversitesi University of Virginia, UV Aarhus Universitetshospital Central Manchester University Hospitals NHS Foundation Trust Columbia University Novartis Sunovion COPD Foundation Pfizer National Heart, Lung, and Blood Institute, NHLBI: R01-HL097163, UH3-HL123442, P01-HL092870 U.S. Department of Defense, DOD: W81XWH-17-1-0597, U01 HL089897, U01 HL089856 AstraZeneca Siemens Foundation North Carolina GlaxoSmithKline Foundation, 1National Jewish Health, Denver, Colorado; 2School of Public Health; 3Department of Medicine, and 54Department of Immunology, University of Colorado Denver, Denver, Colorado; 4Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; 5Brigham and Women’s Hospital, Harvard School of Medicine, Boston, Massachusetts; 6Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;7Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 8MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom; 9Respiratory Medicine Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; 10Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom; 11Royal Brompton Hospital and Imperial College, London, United Kingdom; 12Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania; 13Department of Medicine, University of California, San Francisco, San Francisco, California; 14Gilead Sciences, Foster City, California; 15Department of Medicine, University of Chicago, Chicago, Illinois; 16Department of Medicine, University of Virginia, Charlottesville, Virginia; 17Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; 18National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; 19National Hospital Organization Tokyo National Hospital, Tokyo, Japan; 20Helmholtz Zentrum München, Neuherberg, Germany; 21University Hospital Munich, Munich, Germany; 22Department of Pulmonology, Ege University Hospital, Bornova, Izmir, Turkey; 23Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia; 24Alfred Hospital and Monash University, Melbourne, Australia; 25Pulmonary Medicine, GB Morgagni Hospital, Forlì, Italy; 26Department of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy; 27Université Paris Diderot and Hôpital Bichat, Paris, France; 28Royal Papworth Hospital and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 29Respiratory Department, University Hospital of Bellvitge, University of Barcelona, Barcelona, Spain; 30National University Hospital of Iceland, University of Iceland, Reykjavik, Iceland; 31Department of Medicine, Columbia University Irving Medical Center, New York, New York; 32Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts; 33Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 34Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas,” México City, México; 35Universidad Nacional Autónoma de México, México City, México; 36Cork University Hospital and University College Cork, Cork, Ireland; 37St. Vincent’s University Hospital, Dublin, Ireland; 38School of Medicine, University College Dublin, Dublin, Ireland; 39Department of Respiratory Medicine, First Faculty of Medicine Charles University and Thomayer Hospital, Prague, Czech Republic; 40University of British Columbia, Vancouver, Canada; 41Tokyo Medical and Dental University, Tokyo, Japan; 42Institute for Respiratory Health and; 43Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Perth, Australia; 44Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island; 45Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia; 46Department of Pulmonary Medicine, Gazi University School of Medicine, Ankara, Turkey; 47Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; 48Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany; 49Department of Medicine, Tallaght University Hospital, Trinity College Dublin, Dublin, Ireland; 50CardioPulmonary Reserach Center, Alliance Pulmonary Group, Guaynabo, Puerto Rico; 51Department of Internal Medicine, University of Genoa, Genoa, Italy; 52Biomedical Genomics Center, University of Minnesota; Minneapolis, Minnesota; and 53Northwest Genomics Center, University of Washington, Seattle, Washington -- This research was supported by grants from the NHLBI (R01-HL097163, P01-HL092870, and UH3-HL123442) and the Department of Defense (W81XWH-17-1-0597). The COPDGene project was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the NHLBI. The COPDGene project was also supported by the COPD Foundation through contributions made to an industry advisory board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.
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127. Diagnostic likelihood thresholds that define a working diagnosis of idiopathic pulmonary fibrosis
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Venerino Poletti, Marlies S. Wijsenbeek, David J. Lederer, Yasuhiro Kondoh, Ian Glaspole, Fernando J. Martinez, Tamera J. Corte, Hiroyuki Taniguchi, Maria Molina-Molina, Juergen Behr, Sara Tomassetti, Margaret L. Wilsher, Wim A. Wuyts, Athol U. Wells, Elisabeth Bendstrup, Kevin K. Brown, Simon L.F. Walsh, António Morais, Yoshikazu Inoue, Hilario Nunes, Carlo Vancheri, Dominique Valeyre, Moisés Selman, Ganesh Raghu, Kerri A. Johannson, Kevin R. Flaherty, Luca Richeldi, Brett Ley, Jan C. Grutters, Toby M. Maher, Bruno Crestani, Martin Kolb, Richard Nusser, Michael Kreuter, Katerina M. Antoniou, Christopher J. Ryerson, Vincent Cottin, Paolo Spagnolo, and Pulmonary Medicine
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Respiratory System ,Settore MED/10 - MALATTIE DELL'APPARATO RESPIRATORIO ,Practice Patterns ,INTERSTITIAL LUNG-DISEASE ,Critical Care and Intensive Care Medicine ,Antifibrotic therapy ,Clinical practice guidelines ,Idiopathic pulmonary fibrosis ,Surgical lung biopsy ,Working diagnosis ,0302 clinical medicine ,Antifibrinolytic agent ,Diagnosis ,Medicine ,CRITERIA ,030212 general & internal medicine ,Respiratory system ,Practice Patterns, Physicians' ,11 Medical and Health Sciences ,medicine.diagnostic_test ,Interstitial lung disease ,respiratory system ,Prognosis ,Antifibrinolytic Agents ,AGREEMENT ,BIOPSY ,Radiology ,Life Sciences & Biomedicine ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Clinical Decision-Making ,Lung biopsy ,surgical lung biopsy ,Diagnosis, Differential ,03 medical and health sciences ,Critical Care Medicine ,General & Internal Medicine ,Biopsy ,Humans ,Physicians' ,Science & Technology ,business.industry ,MORTALITY ,Patient Selection ,Editorials ,medicine.disease ,respiratory tract diseases ,030228 respiratory system ,Differential ,Differential diagnosis ,business - Abstract
Rationale: The level of diagnostic likelihood at which physicians prescribe antifibrotic therapy without requesting surgical lung biopsy (SLB) in patients suspected of idiopathic pulmonary fibrosis (IPF) is unknown. Objectives: To determine how often physicians advocate SLB in patient subgroups defined by IPF likelihood and risk associated with SLB, and to identify the level of diagnostic likelihood at which physicians prescribe antifibrotic therapy with requesting SLB. Methods: An international cohort of respiratory physicians evaluated 60 cases of interstitial lung disease, giving: 1) differential diagnoses with diagnostic likelihood; 2) a decision on the need for SLB; and 3) initial management. Diagnoses were stratified according to diagnostic likelihood bands described by Ryerson and colleagues. Measurements and Main Results: A total of 404 physicians evaluated the 60 cases (24,240 physician-patient evaluations). IPF was part of the differential diagnosis in 9,958/24,240 (41.1%) of all physician-patient evaluations. SLB was requested in 8.1%, 29.6%, and 48.4% of definite, provisional high-confidence and provisional low-confidence diagnoses of IPF, respectively. In 63.0% of provisional high-confidence IPF diagnoses, antifibrotic therapy was prescribed without requesting SLB. No significant mortality difference was observed between cases given a definite diagnosis of IPF (90-100% diagnostic likelihood) and cases given a provisional high-confidence IPF diagnosis (hazard ratio, 0.97; P = 0.65; 95% confidence interval, 0.90-1.04). Conclusions: Most respiratory physicians prescribe antifibrotic therapy without requesting an SLB if a provisional high-confidence diagnosis or "working diagnosis" of IPF can be made (likelihood>70%). SLB is recommended in only a minority of patients with suspected, but not definite, IPF.
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128. Assessing quality of life of idiopathic pulmonary fibrosis patients: the INSTAGE study
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Maria Molina-Molina and Guillermo Suarez-Cuartin
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Pulmonary and Respiratory Medicine ,Quality of life ,medicine.medical_specialty ,Sildenafil ,Journal Club ,MEDLINE ,Pulmonary fibrosis ,03 medical and health sciences ,chemistry.chemical_compound ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Internal medicine ,medicine ,030212 general & internal medicine ,lcsh:RC705-779 ,business.industry ,Fibrosi pulmonar ,lcsh:Diseases of the respiratory system ,respiratory system ,medicine.disease ,Expert Opinion ,humanities ,respiratory tract diseases ,030228 respiratory system ,chemistry ,Qualitat de vida ,cardiovascular system ,Nintedanib ,business - Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by progressive lung interstitial fibrosis of unknown cause [1]. IPF incidence increases with older age and clinical manifestations include dry cough, exertional dyspnoea and overall progressive deterioration of patient quality of life (QOL) [1]. In the past decade, new treatment options have become available to treat IPF, such as nintedanib, an intracellular tyrosine kinase inhibitor. The INPULSIS trials evaluated the efficacy and safety of nintedanib versus placebo in 1066 IPF patients with a diffusing capacity of the lung for carbon monoxide (DLCO) of 30–79% of the predicted value [2]. These trials showed that treatment with nintedanib slowed the rate of forced vital capacity (FVC) decline but no significant difference was observed in the St George's Respiratory Questionnaire (SGRQ) score [2]., The addition of sildenafil to nintedanib treatment does not improve outcomes to a greater extent than monotherapy with nintedanib, and it is not recommended for IPF subjects http://ow.ly/Gaq530o9kEg
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129. Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis
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George T. O'Connor, Gauri Saini, Helen Booth, Dominic Furniss, William A. Fahy, Ke Hao, Beatriz Guillen-Guio, Vilmundur Gudnason, Brian L. Yaspan, Imre Noth, Hanfei Xu, Hiroto Hatabu, Brian D. Hobbs, Ma'en Obeidat, Nik Hirani, Justin M. Oldham, Victor E. Ortega, David A. Schwartz, Simon P. Hart, Ani Manichaikul, Richard Hubbard, Xuan Li, Philippe Joubert, Michael Hill, Michael Ng, Ann B. Millar, Vidyia Navaratnam, Richard J. Allen, Rebecca Braybrooke, Ian Sayers, Ian P. Hall, Shwu-Fan Ma, Philip L. Molyneaux, Carlos Flores, Tasha E. Fingerlin, Martin D. Tobin, Gunnar Gudmundsson, Rachel K. Putman, Gary M. Hunninghake, Krina T. Zondervan, Moira K. B. Whyte, Robin J. McAnulty, Louise V. Wain, Andrew P. Morris, Michael H. Cho, David C. Nickle, Don D. Sin, Helen Parfrey, Toby M. Maher, Yohan Bossé, Maria Molina-Molina, John D. Newell, Eunice Oballa, Phuwanat Sakornsakolpat, David J. Lederer, R. Gisli Jenkins, Amy Dressen, Wim Timens, Luke M. Kraven, and Megan L. Paynton
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0303 health sciences ,Lung ,business.industry ,Genome-wide association study ,Disease ,respiratory system ,medicine.disease ,DEPTOR ,MAD1L1 ,respiratory tract diseases ,3. Good health ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,medicine.anatomical_structure ,030228 respiratory system ,Immunology ,Medicine ,business ,Gene ,030304 developmental biology ,Genetic association - Abstract
RationaleIdiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.ObjectivesTo improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations.Methods and measurementsWe performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Main resultsWe identified and replicated three new genome-wide significant (P-8) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility.ConclusionsNovel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.
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130. Differences in the Approach to Acute Exacerbation of Idiopathic Pulmonary Fibrosis (AE IPF) Between Expert Centres and General Pulmonologists: Results from an International Survey
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Marlies S. Wijsenbeek, Martin Kolb, Argyris Tzouvelekis, Carlos Alberto de Castro Pereira, Toby M. Maher, Simon L.F. Walsh, Julia Wälscher, Vincent Cottin, Julie Morisset, Wim A. Wuyts, G Calligaro, Tamera J. Corte, Harold R. Collard, Juergen Behr, Sergey Avdeev, Nazia Chaudhuri, Markus Polke, Kevin R. Flaherty, Silvia Quadrelli, Elisabeth Bendstrup, Maria Molina-Molina, António Morais, Manuela Funke-Chambour, Michael Kreuter, M Selman, Claudia Valenzuela, Carlo Vancheri, Y. Kondoh, V. Vicens Zygmunt, and Karen Moor
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medicine.medical_specialty ,Idiopathic pulmonary fibrosis ,Exacerbation ,business.industry ,Internal medicine ,International survey ,Medicine ,business ,medicine.disease ,Pulmonologists - Published
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131. Pirfenidone treatment in individuals with idiopathic pulmonary fibrosis: Impact of timing of treatment initiation
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Klaus-Uwe Kirchgaessler, Toby M. Maher, Maria Molina-Molina, Stéphane Jouneau, Paul W. Noble, Judit Axmann, Elisabeth Bendstrup, David J. Lederer, Lake Morrison, Lisa Lancaster, Ute Petzinger, Frank Gilberg, Imperial College London, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Duke University Medical Center, Columbia University Medical Center (CUMC), Columbia University [New York], Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Aarhus University Hospital, F. Hoffmann-La Roche [Basel], Cedars-Sinai Medical Center, Medical writing support was provided by RebekahWaters, Ph.D. (CMC Affinity, a division of McCann Health MedicalCommunications, Ltd., Manchester, UK), funded by F. Hoffmann-LaRoche, Ltd., and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
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Male ,Vital Capacity ,Treatment outcome ,Respiratory System ,Severity of Illness Index ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,NINTEDANIB ,law.invention ,chemistry.chemical_compound ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Randomized controlled trial ,law ,030212 general & internal medicine ,Anti-Inflammatory Agents, Non-Steroidal ,Pirfenidone ,Middle Aged ,respiratory system ,Prognosis ,3. Good health ,Survival Rate ,Treatment Outcome ,Female ,Nintedanib ,Life Sciences & Biomedicine ,medicine.drug ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Pyridones ,Time to treatment ,Risk Assessment ,Drug Administration Schedule ,Time-to-Treatment ,03 medical and health sciences ,Double-Blind Method ,Internal medicine ,Severity of illness ,medicine ,Humans ,Letters ,Survival rate ,Aged ,Science & Technology ,Dose-Response Relationship, Drug ,business.industry ,1103 Clinical Sciences ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,medicine.disease ,EFFICACY ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,030228 respiratory system ,chemistry ,business - Abstract
International audience; Idiopathic pulmonary fibrosis (IPF) is a debilitating, progressive, fatal, fibrosing lung disease. Pirfenidone and nintedanib are oral antifibrotics with demonstrated efficacy in reducing lung function decline in individuals with IPF, independent of baseline lung function. Intervention with an antifibrotic as early as possible in the disease course might be the most appropriate strategy to preserve lung capacity. However, many physicians are reluctant to initiate antifibrotics at diagnosis, and delay treatment until disease progression is observed. Furthermore, certain countries do not reimburse antifibrotic treatment for individuals with preserved lung function (% predicted forced vital capacity [FVC] > 80%). These post hoc analyses aimed to assess: 1) FVC decline during long-term pirfenidone treatment in RECAP in individuals with IPF categorized by baseline % predicted FVC; and 2) the impact of deferring pirfenidone treatment on annual FVC decline in individuals with IPF during CAPACITY and RECAP.
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132. The Future of Pharmacological Treatment in Idiopathic Pulmonary Fibrosis
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Maria Molina-Molina
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medicine.medical_specialty ,business.industry ,General Medicine ,Disease ,Pirfenidone ,Precision medicine ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,Clinical trial ,03 medical and health sciences ,chemistry.chemical_compound ,Therapeutic approach ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,030228 respiratory system ,chemistry ,Pulmonary fibrosis ,medicine ,Humans ,Nintedanib ,Drug Therapy, Combination ,Intensive care medicine ,business ,medicine.drug ,Forecasting - Abstract
The therapeutic approach in idiopathic pulmonary fibrosis has changed substantially over the past 5 years. National and international guidelines for the pharmacological treatment of IPF recommend 2antifibrotic drugs, nintedanib and pirfenidone. The use of both these drugs is supported by high-level evidence, with benefits including not only slower disease progression but also a reduction in the annual risk of death. Currently, the therapeutic management of these patients prioritizes both the use of drugs that act on the pathogenic mechanisms of the disease, and the positive effect of improving quality of life with integrated multidisciplinary support, including nutrition, physical activity, education, emotional support, and palliation of symptoms. The overall aim is to ensure that the patient remains as well as possible for as long as possible after diagnosis. However, the goal of the new antifibrotic combinations that are currently under evaluation in clinical trials is to use the potential antifibrotic synergy to enhance the therapeutic benefit or completely halt disease progression, by acting simultaneously on different pathogenic pathways. Another line of investigation involves markers that might be useful for identifying patients who may benefit more from certain antifibrotics than from others, which would make it possible to optimize resources and take the first steps toward precision medicine in pulmonary fibrosis. Below, we review the main potential areas for improvement in the pharmacological treatment of idiopathic pulmonary fibrosis in the short, medium, and long term.
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133. Ein globaler Blick auf akute Exazerbationen der idiopathischen Lungenfibrose (AE-IPF): Ergebnisse einer internationalen Umfrage
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Nazia Chaudhuri, Kevin R. Flaherty, Maria Molina-Molina, Juergen Behr, Martin Kolb, Vanesa Vicens-Zygmunt, Y. Kondoh, Marlies S. Wijsenbeek, Wim A. Wuyts, Carlo Vancheri, Tamera J. Corte, Elisabeth Bendstrup, Harold R. Collard, Argyrios Tzouvelekis, Julia Wälscher, Carlos Alberto de Castro Pereira, Markus Polke, Michael Kreuter, Manuela Funke, António Morais, Silvia Quadrelli, M Selman, K Moor, Julie Morisset, G Calligaro, Sergey Avdeev, Simon L.F. Walsh, Vincent Cottin, and Toby M. Maher
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134. Interstitial Lung Diseases in Developing Countries
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Maria Molina-Molina and Pilar Rivera-Ortega
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Asbestosis ,Infectious and parasitic diseases ,RC109-216 ,Review ,Health Services Accessibility ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Prevalence ,030212 general & internal medicine ,Connective Tissue Diseases ,medicine.diagnostic_test ,030503 health policy & services ,Pneumoconiosis ,Incidence ,Interstitial lung disease ,General Medicine ,respiratory system ,Països en vies de desenvolupament ,Malalties pulmonars ,Public aspects of medicine ,RA1-1270 ,0305 other medical science ,Hypersensitivity pneumonitis ,Alveolitis, Extrinsic Allergic ,Spirometry ,medicine.medical_specialty ,Developing countries ,03 medical and health sciences ,Sarcoidosis, Pulmonary ,Internal medicine ,Air Pollution ,Occupational Exposure ,medicine ,Genetic predisposition ,Pulmonary diseases ,Humans ,Idiopathic Interstitial Pneumonias ,Developing Countries ,business.industry ,Asbestos ,Environmental Exposure ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,Years of potential life lost ,business ,Lung Diseases, Interstitial ,Tomography, X-Ray Computed - Abstract
More than 100 different conditions are grouped under the term interstitial lung disease (ILD). A diagnosis of an ILD primarily relies on a combination of clinical, radiological, and pathological criteria, which should be evaluated by a multidisciplinary team of specialists. Multiple factors, such as environmental and occupational exposures, infections, drugs, radiation, and genetic predisposition have been implicated in the pathogenesis of these conditions. Asbestosis and other pneumoconiosis, hypersensitivity pneumonitis (HP), chronic beryllium disease, and smoking-related ILD are specifically linked to inhalational exposure of environmental agents. The recent Global Burden of Disease Study reported that ILD rank 40th in relation to global years of life lost in 2013, which represents an increase of 86% compared to 1990. Idiopathic pulmonary fibrosis (IPF) is the prototype of fibrotic ILD. A recent study from the United States reported that the incidence and prevalence of IPF are 14.6 per 100,000 person-years and 58.7 per 100,000 persons, respectively. These data suggests that, in large populated areas such as Brazil, Russia, India, and China (the BRIC region), there may be approximately 2 million people living with IPF. However, studies from South America found much lower rates (0.4-1.2 cases per 100,000 per year). Limited access to high-resolution computed tomography and spirometry or to multidisciplinary teams for accurate diagnosis and optimal treatment are common challenges to the management of ILD in developing countries.
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135. Research highlights from the 2018 ERS International Congress: interstitial lung diseases
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Elena Bargagli, Veronica Alfieri, Francesco Bonella, Florence Jeny, Elisabetta A. Renzoni, Hilario Nunes, Venerino Poletti, Marlies S. Wijsenbeek, Maria Molina-Molina, Katerina M. Antoniou, Catharina C. Moor, Paolo Spagnolo, Tiago M. Alfaro, Michael Kreuter, and Pulmonary Medicine
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Pulmonary and Respiratory Medicine ,Parenchymal lung disease ,medicine.medical_specialty ,Etiology ,Epidemiology ,Congress Highlights ,Medizin ,lcsh:Medicine ,030204 cardiovascular system & hematology ,behavioral disciplines and activities ,03 medical and health sciences ,0302 clinical medicine ,Diagnòstic ,International congress ,Diagnosis ,medicine ,Pulmonary diseases ,Epidemiologia ,Idiopathic interstitial pneumonia ,Lung ,business.industry ,lcsh:R ,Interstitial lung disease ,respiratory system ,medicine.disease ,Dermatology ,respiratory tract diseases ,medicine.anatomical_structure ,030228 respiratory system ,Etiologia ,Sarcoidosis ,business - Abstract
This article reviews a selection of the scientific presentations on interstitial lung disease (ILD)/diffuse parenchymal lung disease (DPLD) that were made at the 2018 European Respiratory Society (ERS) International Congress in Paris. A number of advances in the epidemiology, pathogenesis, diagnosis and treatment of these disorders were presented and discussed by clinicians and researchers. The research topics span over all four groups of ERS Assembly 12: Interstitial Lung Diseases (Group 12.01: Idiopathic interstitial pneumonias; Group 12.02: ILD/DPLD of known origin; Group 12.03: Sarcoidosis and other granulomatous ILD/DPLD; Group 12.04: Rare ILD/DPLD)., A selection of the scientific presentations on interstitial lung disease from the 2018 #ERSCongress in Paris http://ow.ly/LAbD30nmsFs
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136. Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes
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Julián Sevilla, Mónica Martínez-Gallo, Laura Iarriccio, Elena Vallespín, Maria-Luz Uria, Lurdes Planas-Cerezales, Luis Ignacio Gonzalez-Granado, Virginia Leiro-Fernandez, Rosario Perona, Claudia Valenzuela, Albert Català, Sara Martín, Isabel Badell-Serra, Maria Molina-Molina, Carmen Rodríguez-Vigil, Pablo Lapunzina, Belén López-Muñiz, P. Martínez, Elena G Arias-Salgado, Guiomar Perez de Nanclares, Mariana Bastos-Oreiro, Leandro Sastre, Jaime Carrillo, Ana Maria Galera-Miñarro, Anna Ruiz-Llobet, Cristina Diaz-Heredia, Eva M. Galvez, Andrea Martín-Nalda, Laura Pintado-Berninches, Instituto de Salud Carlos III, CSIC - Unidad de Recursos de Información Científica para la Investigación (URICI), Federación Española de Enfermedades Raras, Sastre, Leandro, Sastre, Leandro [0000-0003-3613-5938], Institut Català de la Salut, [Arias-Salgado EG, Pintado-Berninches L] Instituto de Investigaciones Biomedicas CSIC/UAM, IDIPaz, Madrid, Spain. Advanced Medical Projects, Madrid, Spain. [Galvez E] Hematología y Hemoterapia, Hospital Niño Jesús, Madrid, Spain. [Planas-Cerezales L] Unitat ILD, Departament de Pneumologia, Hospital de Universitari de Bellvtige, Barcelona, Spain. Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain. Universitat de Barcelona, Barcelona, Spain. [Vallespin E, Martinez P] Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Madrid, Spain. [Martín-Nalda A, Martínez-Gallo M, Uria ML, Diaz-Heredia C] Unitat de Patologia Infecciosa i Immunodeficiències de Pediatria, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Vall d’Hebron Institut de Recerca, Barcelona, Spain. Departament de Biologia Cel•lular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Male ,0301 basic medicine ,DNA repair ,lcsh:Medicine ,Anèmia ,Cells::Cellular Structures::Intracellular Space::Cell Nucleus::Cell Nucleus Structures::Intranuclear Space::Chromosomes::Chromosome Structures::Telomere [ANATOMY] ,030105 genetics & heredity ,Exon ,0302 clinical medicine ,Respiratory Tract Diseases::Lung Diseases::Lung Diseases, Interstitial::Idiopathic Interstitial Pneumonias::Idiopathic Pulmonary Fibrosis [DISEASES] ,Pharmacology (medical) ,enfermedades respiratorias::enfermedades pulmonares::enfermedades pulmonares intersticiales::neumonías intersticiales idiopáticas::fibrosis pulmonar idiopática [ENFERMEDADES] ,Child ,Telomerase ,Telomere Shortening ,Genetics (clinical) ,Pulmonary fibrosis ,Genetics ,Sanger sequencing ,Telòmer ,Otros calificadores::Otros calificadores::/genética [Otros calificadores] ,Dyskeratosis congenita ,Telomeropathies ,Anemia, Aplastic ,Anèmia aplàstica - Aspectes genètics ,Fibrosi pulmonar ,Anemia ,Exons ,General Medicine ,Telomere ,Pedigree ,Other subheadings::Other subheadings::/pathology [Other subheadings] ,Child, Preschool ,symbols ,Female ,Otros calificadores::Otros calificadores::/patología [Otros calificadores] ,Aplastic anemia ,Adult ,Hemic and Lymphatic Diseases::Hematologic Diseases::Anemia::Anemia, Aplastic [DISEASES] ,Adolescent ,Biology ,Young Adult ,03 medical and health sciences ,symbols.namesake ,Other subheadings::Other subheadings::/genetics [Other subheadings] ,medicine ,Humans ,Fibrosi pulmonar - Aspectes genètics ,enfermedades hematológicas y linfáticas::enfermedades hematológicas::anemia::anemia aplásica [ENFERMEDADES] ,Gene ,Southern blot ,Research ,lcsh:R ,Infant ,medicine.disease ,Human genetics ,RNA ,células::estructuras celulares::espacio intracelular::núcleo celular::estructuras del núcleo celular::espacio intranuclear::cromosomas::estructuras cromosómicas::telómero [ANATOMÍA] ,030217 neurology & neurosurgery - Abstract
[Background]: Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients., [Methods]: This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes., [Results]: Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT, TERC, RTEL1, CTC1 and ACD. In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening., [Conclusion]: Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed., Funded by grants PI14–01495 and PI17–01401 (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain supported by FEDER funds) and by one ACCI project from CIBERER and one grant to the FPI cohort from CIBERES., We acknowledge support of the publication fee by the CSIC Open Access Publication Support initiative through its Unit of Information Resources for Research (URICI).
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- 2019
137. Effectiveness and safety of tocilizumab for the treatment of refractory systemic sclerosis associated interstitial lung disease: a case series
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Judit LLuch, Juan José Alegre Sancho, Ivan Castellví, Javier Narváez, Joan M. Nolla, and Maria Molina-Molina
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0301 basic medicine ,medicine.medical_specialty ,Cyclophosphamide ,Immunology ,Antibodies, Monoclonal, Humanized ,Placebo ,General Biochemistry, Genetics and Molecular Biology ,Scleroderma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Tocilizumab ,Rheumatology ,Refractory ,Internal medicine ,Pulmonary fibrosis ,medicine ,Humans ,Immunology and Allergy ,skin and connective tissue diseases ,030203 arthritis & rheumatology ,Scleroderma, Systemic ,integumentary system ,business.industry ,Interstitial lung disease ,medicine.disease ,030104 developmental biology ,chemistry ,Lung Diseases, Interstitial ,business ,Complication ,medicine.drug - Abstract
We read with great interest the results of the double-blind phase 2 faSScinate clinical trial,1 in which there was encouraging (although not statistically significant) numerical improvement in skin thickening and evidence of less decline in lung function in patients with systemic sclerosis (SSc) treated with tocilizumab (TCZ) compared with those receiving placebo. Initial investigations with TCZ in patients with SSc demonstrated improvements in skin sclerosis and polyarthritis.2 3 Scleroderma-associated interstitial lung disease (SSc-ILD) is a severely debilitating complication with high mortality in extensive disease. There is no approved disease-modifying treatment, and few effective treatment options are available. One of the most urgent needs is to determine which drugs can be useful as a rescue treatment in patients who do not respond to conventional immunosuppressants (cyclophosphamide (CYC) or mycophenolate mofetil (MMF)). In this sense, TCZ appears as one of the most promising candidates and an ongoing 2-year randomised phase 3 trial of TCZ-SC 162 mg in SSc …
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- 2019
138. Telomere-related gene mutations and lung diseases: Pulmonary fibrosis, emphysema and lung cancer
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Maria Molina-Molina, Rosario Perona Abellón, Leandro Sastre, Federación Española de Enfermedades Raras, and Instituto de Salud Carlos III
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Senescence ,Emphysema ,Telomerase ,Lung ,business.industry ,General Engineering ,medicine.disease ,Telomere ,Pulmonary fibrosis ,medicine.anatomical_structure ,Cancer research ,General Earth and Planetary Sciences ,Medicine ,Related gene ,Lung cancer ,business ,General Environmental Science - Abstract
In this review, we will approach the role of the regulation of telomere length and telomerase activity in different lung diseases. Telomeres are nucleo-protein structures located at the end of chromosomes that protect them from degradation. In the absence of telomerase activity, telomeres are shortened after each round of deoxyribonucleic acid (DNA) replication. When a critical size is reached, there is an induction in cell apoptosis or senescence. Telomere replication is also involved in the acquisition of the unlimited proliferative capacity that characterises tumour cells. Several diseases of lung tissue are associated either with a deficit or overactivation of telomerase activity. Idiopathic pulmonary fibrosis is associated with germinal mutations in telomerase-genes resulting in premature senescence of lung tissue accelerating the onset of the disease. Somatic mutations or polymorphisms in telomere reverse transcriptase (TERT) promoter have also been associated with upregulation of telomerase activity and lung cancer., Funded by grant PI17-01401 (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain supported by FEDER funds).
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- 2019
139. Tolerance and efficacy of antifibrotic treatments in IPF patients carriying telomere related gene mutations
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Martine Reynaud-Gaubert, Antoine Froidure, Anne Gondouin, Stéphane Jouneau, Claire Andrejak, Benjamin Bondue, Anne-Sophie Gamez, Effrosyni D. Manali, Jean-Marc Naccache, Aurélien Justet, Bruno Crestani, Manuela Funke-Chambour, Maria Molina Molina, Sandrine Hirschi, Caroline Kanengiesser, Dymph Klay, Hilario Nunes, Gregoire Prevost, Raphael Borie, Coline H.M. van Moorsel, Cécile Tromeur, Liwine Wemeau, Philippe Bonniaud, Vincent Cottin, Sylvain Marchand-Adam, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de pneumologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), St. Antonius Hospital [Nieuwegein], Infections Virales et Pathologie Comparée - UMR 754 (IVPC), Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Nord [CHU - APHM], Sorbonne Université (SU), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de recherche clinique Biomarqueurs Théranostiques des Cancers Bronchiques Non à Petites Cellules (GRC 4 - Theranoscan), University of Athens Medical School [Athens], Cliniques Universitaires Saint-Luc [Bruxelles], École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Amiens-Picardie, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Les Hôpitaux Universitaires de Strasbourg (HUS), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Institut Henri Beaufour (IPSEN), IPSEN-BEAUFOUR, Hôpital Bretonneau, Bern University Hospital [Berne] (Inselspital), and Hôpital Lapeyronie [Montpellier] (CHU)
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medicine.medical_specialty ,business.industry ,[SDV]Life Sciences [q-bio] ,Pirfenidone ,medicine.disease ,Gastroenterology ,Telomere ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,FEV1/FVC ratio ,chemistry.chemical_compound ,0302 clinical medicine ,030228 respiratory system ,chemistry ,DLCO ,Internal medicine ,Pulmonary fibrosis ,medicine ,Nintedanib ,030212 general & internal medicine ,Related gene ,business ,medicine.drug - Abstract
Telomere related gene (TRG) mutations are found in approximately 20% of patients with familial pulmonary fibrosis and are associated with hepatic, cutaneous and hematologic manifestations. Pirfenidone and nintedanib have been shown to slow the decline of FVC of patients with idiopathic pulmonary fibrosis (IPF). There is limited evidence of efficacy and safety of these treatments in IPF patients carrying a TRG mutation. The objective of this retrospective multicenter study was to analyze the efficacy and safety of antifibrotic drugs in IPF patients carrying a TRG mutation. We identified 103 IPF patients carrying a mutation in TERT (n=74), TERC (n=17), RTEL1 (n=10) or PARN (n=3). from 6 countries (France, Netherlands, Belgium, Spain, Greece and Switzerland) Forty-four patients received nintedanib, 59 received pirfenidone. The mean age at diagnosis was 57.9 ± 13.6 years and the median delay between diagnosis and treatment initiation was 6.0 months [3.0-15.1]. At initiation of treatment, the FVC was 80.8% ± 20.2% and the DLCO was 44.0% ± 13.7%. The median duration of treatment was 10.8 months [6.5-18.1]. Antifibrotic treatment was terminated in 18 patients because of progression of the disease and in 15 patients due to intolerable side effects, mainly digestive (nintedanib, n = 9, pirfenidone, n = 6). The median decline in FVC prior to initiation of treatment was 24.5 mL [10.5-30.1] per month. After initiation of treatment, the median decline in FVC was 18.0 mL [9.0-27.0] per month in patients treated with nintedanib and 25.4 mL per month [14.7-36.7] in patients treated with pirfenidone. This retrospective series shows that antifibrotic therapies are well tolerated in IPF patients with TRG mutations. Further analyses are needed to evaluate the efficacy.
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- 2019
140. Gaps in care of patients living with pulmonary fibrosis: a joint patient and expert statement on the results of a Europe-wide survey
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Francesco Bonella, Antje Prasse, Elisabetta Balestro, Ron Flewett, Michel Viegas, Marlies S. Wijsenbeek, Davide Biondini, Guenther Wanke, Wim A. Wuyts, Helmut Prosch, Benjamin Bondue, Maria Molina-Molina, Steve Jones, Vincent Cottin, Catharina C. Moor, Michael Kreuter, Lurdes Planas-Cerezales, Liam Galvin, Anne-Marie Russell, and Pulmonary Medicine
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,IMPACT ,Respiratory System ,Psychological intervention ,MEDLINE ,lcsh:Medicine ,INTERSTITIAL LUNG-DISEASE ,NEEDS ,Interstitial Lung Disease ,Unmet needs ,PALLIATIVE CARE ,Idiopathic pulmonary fibrosis ,Quality of life ,STAGE ,Pulmonary fibrosis ,Patient experience ,medicine ,Intensive care medicine ,Science & Technology ,business.industry ,lcsh:R ,OF-LIFE ,Interstitial lung disease ,EARLY-DIAGNOSIS ,Original Articles ,respiratory system ,Sciences bio-médicales et agricoles ,medicine.disease ,respiratory tract diseases ,IPF ,CAREGIVERS ,business ,BURDEN ,Life Sciences & Biomedicine - Abstract
Introduction Pulmonary fibrosis (PF) and its most common form, idiopathic pulmonary fibrosis (IPF), are chronic, progressive diseases resulting in increasing loss of lung function and impaired quality of life and survival. The aim of this joint expert and patient statement was to highlight the most pressing common unmet needs of patients with PF/IPF, putting forward recommendations to improve the quality of life and health outcomes throughout the patient journey. Methods Two online surveys for patients and healthcare professionals (HCPs) were conducted by the European Idiopathic Pulmonary Fibrosis and Related Disorders Federation (EU-IPFF) in 14 European countries. Results The surveys were answered by 286 patients and 69 HCPs, including physicians and nurses. Delays in diagnosis and timely access to interstitial lung disease specialists and pharmacological treatment have been identified as important gaps in care. Additionally, patients and HCPs reported that a greater focus on symptom-centred management, adequate information, trial information and increasing awareness of PF/IPF is required. Conclusions The surveys offer important insights into the current unmet needs of PF/IPF patients. Interventions at different points of the care pathway are needed to improve patient experience., This joint expert and patient statement highlights the most pressing common unmet needs of patients with pulmonary fibrosis, and puts forward recommendations to improve the quality of life and health outcomes throughout the patient journey http://bit.ly/34cTOeo
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- 2019
141. The characterisation of interstitial lung disease multidisciplinary team meetings: a global study
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Luca Richeldi, Naomi Launders, Fernando Martinez, Simon L.F. Walsh, Jeffrey Myers, Bonnie Wang, Mark Jones, Alison Chisholm, Kevin R. Flaherty, REG IPF/ILD Working Group collaborators, Aileen David-Wang, Antonio Morais, Arata Azuma, Bruno Crestani, Carlo Vancheri, Carole Youakim, Charlene D. Fell, Christopher J. Ryerson, Demosthenes Bouros, Elisabeth Bendstrup, Ferran Morell, Francesco Bonella, Ganesh Raghu, George Christoff, Giovanni Ferrara, Ian Glaspole, Ivan Rosas, Jürgen Behr, Kaissa DeBoer, Katerina M. Antoniou, Keertan Dheda, Kevin Brown, Lurdes Planas-Cerezales, Magnus Sköld, Manuela Funke, Maria Molina-Molina, Mariano Mazzei, Martin Kolb, Moises Selman, Paola Rottoli, Paolo Spagnolo, Pilar Rivera-Ortega, Sergey Avdeev, Silvia Quandrelli, Tamera J. Corte, Toby M. Maher, Vincent Cottin, Wim Wuyts, and Zuo Jun Xu
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Settore MED/09 - MEDICINA INTERNA ,Gold standard ,lcsh:R ,Interstitial lung disease ,Medizin ,lcsh:Medicine ,Original Articles ,Routine practice ,respiratory system ,Multidisciplinary team ,medicine.disease ,Interstitial Lung Disease ,respiratory tract diseases ,Patient management ,body regions ,Family medicine ,Healthcare settings ,medicine ,business ,Routine care - Abstract
Multidisciplinary team (MDT) diagnosis of interstitial lung disease (ILD) has been proposed as a gold standard, but there are no formal recommendations for MDT process or composition and limited knowledge regarding prevalence in routine practice. We performed a systematic evaluation of ILD diagnostic practice across a range of healthcare settings around the world. Electronic questionnaires were distributed across all global regions via society and collaborators networks. Responses from 457 unique centres across 64 countries were included in the analysis. Of the 350 (76.6%) centres holding formal meetings, the majority held face-to-face MDT meetings (80%), for a minimum of 30 min (93%), and discussed diagnosis (96.9%) and patient management (94.9%) at the meetings. Compared with non-academic and academic non-ILD centres, ILD academic centres reported a higher ILD caseload, held more formal MDT meetings, and were more likely to include histopathology and rheumatology specialists in their diagnostic team. Of the centres holding MDT meetings, 5.5% routinely discussed all new cases at such meetings. An MDT approach to ILD diagnosis is consistently interpreted and widely implemented across a range of routine care settings around the world. This observation will inform future ILD diagnostic agreement studies and diagnostic pathway recommendations., In real-world practice, ILD diagnosis uses a multidisciplinary team approach, irrespective of country or healthcare setting http://ow.ly/I1Di30nMNTX
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- 2018
142. Experience With Nintedanib in Severe Pulmonary Fibrosis Associated With Systemic Sclerosis: A Case Series
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Guillermo Suarez-Cuartin, Ana Belén Llanos-González, Jaume Bordas-Martinez, Maria Molina-Molina, Jordi Dorca, Vanesa Vicens-Zygmunt, Ramon Jodar-Masanes, Guadalupe Bermudo, and Patricio Luburich
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lcsh:RC705-779 ,medicine.medical_specialty ,chemistry.chemical_compound ,chemistry ,business.industry ,Internal medicine ,Pulmonary fibrosis ,medicine ,Nintedanib ,lcsh:Diseases of the respiratory system ,medicine.disease ,business ,Gastroenterology - Published
- 2021
143. Inflammatory markers and circulating extracellular matrix proteins in patients with chronic obstructive pulmonary disease and left ventricular diastolic dysfunction
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Daniel Huertas, Mariana Muñoz-Esquerre, Marta López-Sánchez, Ana Montes, Jordi Dorca, Salud Santos, F. Manresa, and Maria Molina-Molina
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Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Inflammation ,030204 cardiovascular system & hematology ,Doppler echocardiography ,Fibrinogen ,Gastroenterology ,Pulmonary function testing ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Immunology and Allergy ,Interleukin 6 ,Genetics (clinical) ,COPD ,biology ,medicine.diagnostic_test ,business.industry ,C-reactive protein ,medicine.disease ,030228 respiratory system ,biology.protein ,Myocardial fibrosis ,medicine.symptom ,business ,medicine.drug - Abstract
Background Left ventricular diastolic dysfunction (LVDD) is a frequent condition in chronic obstructive pulmonary disease (COPD). Tenascin-C (Tn-C) and matrix metalloproteinase-9 (MMP-9) are extracellular matrix proteins associated with myocardial fibrosis and wall remodeling because of inflammation. Objective To determine whether the circulating levels of inflammatory markers, Tn-C and MMP-9 are associated with LVDD in COPD patients. Methods Forty-two severe stable COPD patients (64 ± 8 years, 88% male, FEV1% 38 ± 5.7) and a control group (n = 11) were included. Pulmonary function tests and a Doppler echocardiography were performed on COPD patients. Baseline serum levels of C-reactive protein (CRP), leukocytes, fibrinogen, interleukins (IL) 6 and 8, Tn-C and MMP-9 were analyzed in all participants. Results COPD patients were classified in two groups: LVDD (n = 35) and non-LVDD (n = 7). Serum levels of IL-6 and CRP were higher in the LVDD group compared to the non-LVDD group [median(IQR)] [3.46 pg/mL (2.36–4.74) vs 1.87 pg/mL (1.10–3.28), P = 0.045] and [6.0 mg/L (3.0–13.0) vs 1.0 mg/L (1.0–2.3), P = 0.001], respectively. The same trend was observed in the analysis adjusted by age and BMI, being significant for CRP (P = 0.04). Circulating IL-6 was associated with the type of LVDD, being higher in the type-II (P = 0.046). Obese patients with COPD-LVDD showed a higher level of inflammatory markers (P = 0.021). Tn-C were significantly higher in patients with LVDD type-II compared to type-I [1422 ng/mL (826–1948) vs 781 ng/mL (640–1139), P = 0.015], without differences in MMP-9. Conclusions Severe COPD patients with LVDD showed a different inflammatory pattern, suggesting a link between low-grade inflammation and the presence of LVDD. In COPD, high levels of Tn-C are related to LVDD type-II.
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- 2016
144. A global perspective on acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF): results from an international survey
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Tamera J. Corte, Carlo Vancheri, Kevin R. Flaherty, Marlies S. Wijsenbeek, Y. Kondoh, Harold R. Collard, Maria Molina Molina, Simon L.F. Walsh, Michael Kreuter, Karen Moor, Markus Polke, Silvia Quadrelli, Elisabeth Bendstrup, Argyrios Tzouvelekis, António Morais, Vincent Cottin, Julie Morisset, Toby M. Maher, Julia Waelscher, Moisés Selman, Greg Calligero, Martin Kolb, Juergen Behr, Sergey Avdeev, Manuela Funke, Nazia Chaudhuri, Vanesa Vicens-Zygmunt, Carlos Alberto de Castro Pereira, and Wim A. Wuyts
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medicine.medical_specialty ,Palliative care ,Exacerbation ,business.industry ,medicine.medical_treatment ,International survey ,Immunosuppression ,respiratory system ,medicine.disease ,respiratory tract diseases ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,030228 respiratory system ,medicine ,030212 general & internal medicine ,Intensive care medicine ,Global international ,Complication ,business ,Pulmonologists - Abstract
Background: AE-IPF is a deadly complication of IPF, for which no international guidelines exist, resulting in global variability in prevention, diagnosis and treatment strategies. Methods: Pulmonologists with ILD expertise were invited to participate in a survey designed by an international expert panel. Results: 469 pulmonologists responded (66 countries, 64% experts). Significant geographical variability in approach to managing AE-IPF was found (figure). Common preventive measures include antifibrotics and antacids. Diagnostic differences are most pronounced regarding use of KL-6 and viral testing, while HRCT, BNP and d-dimer are broadly used. High dose steroids are widely administered (92%), but use of immunosuppressant and other strategies is highly variable (fig). Very few (4%) responders never use immunosuppression. Antifibrotics are initiated during AE-IPF by 66%. Invasive ventilation or ECMO are mainly used as a bridge to transplantation. Most physicians educate patients comprehensively on the severity of AE-IPF (82%) and consider palliative care (63%). Conclusion: International approaches to the prevention, diagnosis and treatment of AE-IPF are diverse. Global international guidelines and trials to evaluate these approaches are needed.
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- 2018
145. Role of serum AGE/RAGEs in the differential diagnosis of pulmonary fibrosis
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Carlos Machahua, Ana Montes-Worboys, Raquel Buendia-Flores, Maria Molina-Molina, Lurdes Planas-Cerezales, and Vanesa Vicens-Zygmunt
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medicine.medical_specialty ,Lung ,business.industry ,Disease ,respiratory system ,medicine.disease ,Gastroenterology ,respiratory tract diseases ,Idiopathic pulmonary fibrosis ,FEV1/FVC ratio ,medicine.anatomical_structure ,DLCO ,Internal medicine ,Pulmonary fibrosis ,Medicine ,Differential diagnosis ,business ,Hypersensitivity pneumonitis - Abstract
Background: Previous reports showed an imbalance of the soluble receptor for advanced glycation end-products (sRAGE), an immunoglobulin implicated in the maintenance of alveolar structures, with its ligand (AGE), in lung samples from idiopathic pulmonary fibrosis (IPF). The finding of a non-invasive serum biomarker would help in the early diagnosis and prognosis of IPF and would distinguish it from other fibrotic interstitial lung diseases, such as fibrotic nonspecific interstitial pneumonia (fNSIP) or chronic hypersensitivity pneumonitis (cHP). Aims: We analysed the role of AGE and RAGE levels and the ratio of both molecules in serum samples as possible biomarkers that distinguish different fibrotic interstitial lung entities. Method: Serum samples were collected from 48 IPF patients, 15 cHP, 15 fNSIP, and 12 healthy age matched controls. Patient characteristics (age, sex, smoke habits, and pulmonary functional test (PFT)) were recorded. AGEs and sRAGE level were assessed by ELISA following the manufacture’s recommendation. Patient’s data and serum determinations were analysed with SPSS statistic software. Results: Our study demonstrated a decrease in sRAGE together with an increment of AGEs levels in serum in IPF and cHP samples compared with control and fNSIP, which did not show significant differences between them. AGEs levels resulted negative correlated with sRAGE in IPF samples. Moreover, low levels of sRAGE correlates with worse PFT (FVC and DLCO). Conclusions: This findings demonstrate that the imbalance in AGE/sRAGE levels in serum samples could differentiate IPF and cHP from NSIP. Furthermore, the correlation between sRAGE measurements and patient’s PFT could reflect the severity of the disease.
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- 2018
146. Molecular characterization of novel PiS-like alleles identified in Spanish patients with Alpha-1 antitrypsin deficiency
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Igor Iturbe, Irene Gonzalo, Maria Molina-Molina, Sheila Ramos, Alejandra Damian, Cristina Esquinas, Javier Rivera De la Rosa, Nerea Matamala, Gema Gomez-Mariano, Raquel Saez, Ignacio Blanco, Virginia Aquino, Francisco Casas-Maldonado, María Del Puerto Cano, Selene Martínez, and Beatriz Martinez-Delgado
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Genetics ,Alpha 1-antitrypsin deficiency ,business.industry ,Medicine ,Allele ,business ,medicine.disease - Published
- 2018
147. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: design of a double-blind, randomised, placebo-controlled phase II trial
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David J. Lederer, Aryeh Fischer, Judit Axmann, Maria Molina-Molina, Klaus-Uwe Kirchgaessler, Vincent Cottin, Toby M. Maher, Tamera J. Corte, and Michael Kreuter
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Vital capacity ,interstitial pneumonia with autoimmune features ,Placebo ,Drug design ,Pulmonary fibrosis ,03 medical and health sciences ,FEV1/FVC ratio ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Internal medicine ,medicine ,unclassifiable interstitial lung disease ,030212 general & internal medicine ,Progression-free survival ,Disseny de medicaments ,business.industry ,antifibrotic ,Interstitial lung disease ,Fibrosi pulmonar ,Guideline ,Pirfenidone ,medicine.disease ,030228 respiratory system ,pirfenidone ,business ,medicine.drug - Abstract
IntroductionDespite extensive multidisciplinary team (MDT) assessment, some patients have interstitial lung disease (ILD) that is considered unclassifiable (uILD), for which there are currently no approved treatments. This study will assess the efficacy and safety of the antifibrotic pirfenidone in treating uILD.Methods and analysisThis double-blind, randomised, placebo-controlled phase II trial is enrolling adults with fibrosing ILD, including uILD that fulfils proposed research criteria for interstitial pneumonia with autoimmune features (IPAF), that cannot be classified with moderate or high confidence to any category of ILD following MDT discussion. Study participants must have >10% fibrosis on high-resolution CT scan within the previous 12 months, forced vital capacity (FVC) ≥45% and diffusing capacity of the lung for carbon monoxide ≥30% of predicted values. Study participants will be randomised to receive 801 mg pirfenidone or placebo three times daily for 24 weeks. The efficacy of pirfenidone vs placebo will be assessed by daily measurement of FVC using a handheld spirometer over the treatment period. Other functional parameters, patient-reported outcomes, samples for biomarker analysis and safety endpoints will be collected. Additionally, the study will assess the efficacy and safety of pirfenidone with and without concomitant mycophenolate mofetil treatment and in study participants with or without IPAF.Ethics and disseminationThis trial is being conducted in accordance with the International Conference on Harmonisation E6 guideline for Good Clinical Practice, Declaration of Helsinki and local laws for countries in which the research is conducted.Trial registration numberNCT03099187.
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- 2018
148. Clinical implications of telomere dysfunction in lung fibrosis
- Author
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Maria Molina-Molina and Raphael Borie
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Telomerase ,Cirrhosis ,Gene mutation ,Bioinformatics ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Pulmonary fibrosis ,medicine ,Humans ,Survival rate ,Telomere Shortening ,business.industry ,Bone marrow failure ,Telomere ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,Survival Rate ,030104 developmental biology ,030228 respiratory system ,Mutation ,business - Abstract
Purpose of review Telomere attrition has been proposed as one of the aging hallmarks in pulmonary fibrosis. Telomere shortening and telomerase gene mutations have been widely evaluated in recent years. Reduced telomere length may be identified in a quarter of patients with sporadic idiopathic pulmonary fibrosis (IPF) and half of those cases with family aggregation. However, telomere studies have not transferred from the research field to the clinic. This review is focused on our current understanding of the pathogenic implication of telomere dysfunction in lung fibrosis and its relevance in the clinical setting. Recent findings The most prevalent clinical expression of telomere dysfunction is IPF. Disease onset is usually seen at a younger age and family aggregation is frequently present. Short telomere syndrome is associated in a minority of cases and includes premature hair greying, bone marrow failure and liver cirrhosis. However, patients often present with some extrapulmonary associated telomeric features and related comorbidities that may help to suspect telomere defects. Telomere shortening confers a poor prognosis and reduced lung-transplant free survival time in IPF and other nonidiopathic pulmonary fibrotic entities. Summary Telomere dysfunction associates some common clinical features that could modify patient management in pulmonary fibrosis.
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- 2018
149. Importance of early diagnosis and treatment in idiopathic pulmonary fibrosis
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Maria Molina-Molina, Carlos Lines, Myriam Aburto, Jaume Sauleda, Julio Ancochea, Antoni Xaubet, Orlando Acosta, and José Antonio Rodríguez-Portal
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Interstitial lung fibrosis ,early treatment ,Gastroenterology ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,nintedanib ,Immunology and Allergy ,030212 general & internal medicine ,business.industry ,Public Health, Environmental and Occupational Health ,Pirfenidone ,respiratory system ,medicine.disease ,Early diagnosis ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,IPF ,030228 respiratory system ,chemistry ,Nintedanib ,pirfenidone ,business ,Rare disease ,medicine.drug - Abstract
Idiopathic pulmonary fibrosis (IPF) is a rare disease characterized by chronic, progressive, and irreversible interstitial lung fibrosis of unknown cause [1,2]. Main symptoms and signs include dysp...
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- 2018
150. Anti-fibrotic effects of pirfenidone and rapamycin in primary IPF fibroblasts and human alveolar epithelial cells
- Author
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Maria Molina-Molina, Roger Llatjós, Ignacio Escobar, P. Luburich-Hernaiz, Vanesa Vicens-Zygmunt, E. Sala-Llinas, Jordi Dorca, Ana Montes-Worboys, and C. Machahua-Huamani
- Subjects
0301 basic medicine ,humanos ,Pirfenidone ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Cell Movement ,Pulmonary fibrosis ,Myofibroblasts ,biology ,Fibrosi pulmonar ,Extracellular matrix ,Matriu extracel·lular ,Extracellular Matrix ,medicine.anatomical_structure ,Extracellular matrix proteins ,030220 oncology & carcinogenesis ,fibrosis pulmonar idiopática ,Myofibroblast ,Research Article ,medicine.drug ,Pulmonary and Respiratory Medicine ,Epithelial-Mesenchymal Transition ,Pyridones ,Therapeutics ,matriz extracelular ,Fibroblast migration ,Transforming Growth Factor beta1 ,transición epiteliomesenquimatosa ,03 medical and health sciences ,medicine ,Humans ,Cell migration ,Rapamycin ,Fibroblast ,Sirolimus ,lcsh:RC705-779 ,A549 cell ,business.industry ,factor de crecimiento transformador beta1 ,miofibroblastos ,lcsh:Diseases of the respiratory system ,Terapèutica ,medicine.disease ,Fibronectin ,030104 developmental biology ,A549 Cells ,Alveolar Epithelial Cells ,movimiento celular ,biology.protein ,Cancer research ,piridonas ,business ,Biomarkers - Abstract
Background: Pirfenidone, a pleiotropic anti-fibrotic treatment, has been shown to slow down disease progression of idiopathic pulmonary fibrosis (IPF), a fatal and devastating lung disease. Rapamycin, an inhibitor of fibroblast proliferation could be a potential anti-fibrotic drug to improve the effects of pirfenidone. Methods: Primary lung fibroblasts from IPF patients and human alveolar epithelial cells (A549) were treated in vitro with pirfenidone and rapamycin in the presence or absence of transforming growth factor beta 1 (TGF-beta). Extracellular matrix protein and gene expression of markers involved in lung fibrosis (tenascin-c, fibronectin, collagen I (COM Al], collagen III [COL3A1] and alpha-smooth muscle actin [alpha-SMA]) were analyzed. A cell migration assay in pirfenidone, rapamycin and TGF-beta-containing media was performed. Results: Gene and protein expression of tenascin-c and fibronectin of fibrotic fibroblasts were reduced by pirfenidone or rapamycin treatment Pirfenidone-rapamycin treatment did not revert the epithelial to mesenchymal transition pathway activated by TGF-beta. However, the drug combination significantly abrogated fibroblast to myofibroblast transition. The inhibitory effect of pirfenidone on fibroblast migration in the scratch-wound assay was potentiated by rapamycin combination. Conclusions: These findings indicate that the combination of pirfenidone and rapamycin widen the inhibition range of fibrogenic markers and prevents fibroblast migration. These results would open a new line of research for an anti-fibrotic combination therapeutic approach., This study was supported by Proyectos de Investigacion en Salud del Instituto de Salud Carlos III (FIS PI 15/00710), Hoffmann-La Roche.
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- 2018
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