Ioannis Psallidas1, Nikolaos I Kanellakis2, Stephen Gerry3, Marie Laëtitia Thézénas4, Philip D Charles4, Anastasia Samsonova5, Herbert B Schiller6, Roman Fischer4, Rachelle Asciak2, Robert J Hallifax2, Rachel Mercer2, Melissa Dobson7, Tao Dong8, Ian D Pavord9, Gary S Collins3, Benedikt M Kessler4, Harvey I Pass10, Nick Maskell11, Georgios T Stathopoulos12, Najib M Rahman13. 1. Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Laboratory of Pleural and Lung Cancer Translational Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford Respiratory Trials Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address: ioannis.psallidas@ndm.ox.ac.uk. 2. Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Laboratory of Pleural and Lung Cancer Translational Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford Respiratory Trials Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 3. Centre for Statistics in Medicine, Botnar Research Centre, University of Oxford, Oxford, UK. 4. Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 5. Bioinformatics Core, Department of Oncology, University of Oxford, Oxford, UK; Institute of Translational Biomedicine, St Petersburg State University, St Petersburg, Russia. 6. Comprehensive Pneumology Center and Institute for Lung Biology and Disease, University Hospital, Ludwig-Maximilian University, Munich, Bavaria, Germany; Helmholtz Center Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany. 7. Laboratory of Pleural and Lung Cancer Translational Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 8. Centre for Translational Immunology, CAMS-Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. 9. Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. 10. Department of Cardiothoracic Surgery New York University Langone Medical Center, New York, NY, USA. 11. Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Bristol, UK. 12. Comprehensive Pneumology Center and Institute for Lung Biology and Disease, University Hospital, Ludwig-Maximilian University, Munich, Bavaria, Germany; Helmholtz Center Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Patras, Greece. 13. Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Laboratory of Pleural and Lung Cancer Translational Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford Respiratory Trials Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK; National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
Abstract
BACKGROUND: The prevalence of malignant pleural effusion is increasing worldwide, but prognostic biomarkers to plan treatment and to understand the underlying mechanisms of disease progression remain unidentified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion and build a score that predicts survival. METHODS: In this multicohort study, we used five separate and independent datasets from randomised controlled trials to investigate potential biomarkers of survival and pleurodesis. Mass spectrometry-based discovery was used to investigate pleural fluid samples for differential protein expression in patients from the discovery group with different survival and pleurodesis outcomes. Clinical, radiological, and biological variables were entered into least absolute shrinkage and selection operator regression to build a model that predicts 3-month mortality. We evaluated the model using internal and external validation. FINDINGS: 17 biomarker candidates of survival and seven of pleurodesis were identified in the discovery dataset. Three independent datasets (n=502) were used for biomarker validation. All pleurodesis biomarkers failed, and gelsolin, macrophage migration inhibitory factor, versican, and tissue inhibitor of metalloproteinases 1 (TIMP1) emerged as accurate predictors of survival. Eight variables (haemoglobin, C-reactive protein, white blood cell count, Eastern Cooperative Oncology Group performance status, cancer type, pleural fluid TIMP1 concentrations, and previous chemotherapy or radiotherapy) were validated and used to develop a survival score. Internal validation with bootstrap resampling and external validation with 162 patients from two independent datasets showed good discrimination (C statistic values of 0·78 [95% CI 0·72-0·83] for internal validation and 0·89 [0·84-0·93] for external validation of the clinical PROMISE score). INTERPRETATION: To our knowledge, the PROMISE score is the first prospectively validated prognostic model for malignant pleural effusion that combines biological and clinical parameters to accurately estimate 3-month mortality. It is a robust, clinically relevant prognostic score that can be applied immediately, provide important information on patient prognosis, and guide the selection of appropriate management strategies. FUNDING: European Respiratory Society, Medical Research Funding-University of Oxford, Slater & Gordon Research Fund, and Oxfordshire Health Services Research Committee Research Grants.
BACKGROUND: The prevalence of malignant pleural effusion is increasing worldwide, but prognostic biomarkers to plan treatment and to understand the underlying mechanisms of disease progression remain unidentified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion and build a score that predicts survival. METHODS: In this multicohort study, we used five separate and independent datasets from randomised controlled trials to investigate potential biomarkers of survival and pleurodesis. Mass spectrometry-based discovery was used to investigate pleural fluid samples for differential protein expression in patients from the discovery group with different survival and pleurodesis outcomes. Clinical, radiological, and biological variables were entered into least absolute shrinkage and selection operator regression to build a model that predicts 3-month mortality. We evaluated the model using internal and external validation. FINDINGS: 17 biomarker candidates of survival and seven of pleurodesis were identified in the discovery dataset. Three independent datasets (n=502) were used for biomarker validation. All pleurodesis biomarkers failed, and gelsolin, macrophage migration inhibitory factor, versican, and tissue inhibitor of metalloproteinases 1 (TIMP1) emerged as accurate predictors of survival. Eight variables (haemoglobin, C-reactive protein, white blood cell count, Eastern Cooperative Oncology Group performance status, cancer type, pleural fluid TIMP1 concentrations, and previous chemotherapy or radiotherapy) were validated and used to develop a survival score. Internal validation with bootstrap resampling and external validation with 162 patients from two independent datasets showed good discrimination (C statistic values of 0·78 [95% CI 0·72-0·83] for internal validation and 0·89 [0·84-0·93] for external validation of the clinical PROMISE score). INTERPRETATION: To our knowledge, the PROMISE score is the first prospectively validated prognostic model for malignant pleural effusion that combines biological and clinical parameters to accurately estimate 3-month mortality. It is a robust, clinically relevant prognostic score that can be applied immediately, provide important information on patient prognosis, and guide the selection of appropriate management strategies. FUNDING: European Respiratory Society, Medical Research Funding-University of Oxford, Slater & Gordon Research Fund, and Oxfordshire Health Services Research Committee Research Grants.
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