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Article History

Received: 6 May 2020

Revised: 21 July 2020

Accepted: 9 September 2020

First Online: 30 September 2020

Compliance with ethical standards

:

: The scientific guarantor of this publication is Mario Silva.

: The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article.

: One of the authors has significant statistical expertise (Federica Sabia, MSc).

: Written informed consent was obtained from each subject recruited in the MILD trial.

: Institutional review board approval was obtained.

: This paper represents a retrospective analysis of the MILD trial, which was a prospective lung cancer screening trial funded in 2005. The trial was registered in a public trial registry (Identifier: NCT02837809). Previous publications from the MILD trial investigated different subjects of lung cancer screening by low-dose CT and circulating biomarkers. The subject and result of those publications do not overlap with the present manuscript submitted to <i>European Radiology</i>. Please find the list of such publications at the bottom of this cover letter (1–32).List of previous papers that included screenees from the MILD lung cancer screening trial:1. Sverzellati N, Calabro E, Randi G, La Vecchia C, Marchiano A, Kuhnigk JM, Zompatori M, Spagnolo P, Pastorino U. Sex differences in emphysema phenotype in smokers without airflow obstruction. <i>The European Respiratory Journal</i> 2009; 33: 1320–1328.2. Marchiano A, Calabro E, Civelli E, Di Tolla G, Frigerio LF, Morosi C, Tafaro F, Ferri E, Sverzellati N, Camerini T, Mariani L, Lo Vullo S, Pastorino U. Pulmonary nodules: volume repeatability at multidetector CT lung cancer screening. <i>Radiology</i> 2009; 251: 919–925.3. Sverzellati N, Ingegnoli A, Calabro E, Randi G, La Vecchia C, Marchiano A, Kuhnigk JM, Hansell DM, Zompatori M, Pastorino U. Bronchial diverticula in smokers on thin-section CT. <i>European Radiology</i> 2010; 20: 88–94.4. Calabro E, Randi G, La Vecchia C, Sverzellati N, Marchiano A, Villani M, Zompatori M, Cassandro R, Harari S, Pastorino U. Lung function predicts lung cancer risk in smokers: a tool for targeting screening programmes. <i>The European Respiratory Journal</i> 2010; 35: 146–151.5. Roz L, Verri C, Conte D, Miceli R, Mariani L, Calabro E, Andriani F, Pastorino U, Sozzi G. Plasma DNA levels in spiral CT-detected and clinically detected lung cancer patients: a validation analysis. <i>Lung Cancer</i> 2009; 66: 270–271.6. Sverzellati N, Guerci L, Randi G, Calabro E, La Vecchia C, Marchiano A, Pesci A, Zompatori M, Pastorino U. Interstitial lung diseases in a lung cancer screening trial. <i>The European Respiratory Journal</i> 2011; 38: 392–400.7. Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabro E, Croce CM, Pastorino U, Sozzi G. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. <i>Proceedings of the National Academy of Sciences of the United States of America</i> 2011; 108: 3713–3718.8. Diciotti S, Sverzellati N, Kauczor HU, Lombardo S, Falchini M, Favilli G, Macconi L, Kuhnigk JM, Marchiano A, Pastorino U, Zompatori M, Mascalchi M. Defining the intra-subject variability of whole-lung CT densitometry in two lung cancer screening trials. <i>Academic Radiology</i> 2011; 18: 1403–1411.9. Sverzellati N, Cademartiri F, Bravi F, Martini C, Gira FA, Maffei E, Marchiano A, La Vecchia C, De Filippo M, Kuhnigk JM, Rossi C, Pastorino U. Relationship and prognostic value of modified coronary artery calcium score, FEV1, and emphysema in lung cancer screening population: the MILD trial. <i>Radiology</i> 2012; 262: 460–467.10. Pastorino U, Rossi M, Rosato V, Marchiano A, Sverzellati N, Morosi C, Fabbri A, Galeone C, Negri E, Sozzi G, Pelosi G, La Vecchia C. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. <i>European Journal of Cancer Prevention: the official journal of the European Cancer Prevention Organisation</i> 2012; 21: 308–315.11. Sverzellati N, Randi G, Spagnolo P, Marchiano A, Silva M, Kuhnigk JM, La Vecchia C, Zompatori M, Pastorino U. Increased mean lung density: another independent predictor of lung cancer? <i>Eur J Radiol</i> 2013; 82: 1325–1331.12. Sverzellati N, Kuhnigk JM, Furia S, Diciotti S, Scanagatta P, Marchiano A, Molinari F, Stoecker C, Pastorino U. CT-based weight assessment of lung lobes: comparison with ex vivo measurements. <i>Diagnostic and Interventional Radiology</i> 2013; 19: 355–359.13. Sverzellati N, Colombi D, Randi G, Pavarani A, Silva M, Walsh SL, Pistolesi M, Alfieri V, Chetta A, Vaccarezza M, Vitale M, Pastorino U. Computed tomography measurement of rib cage morphometry in emphysema. <i>PLoS One</i> 2013; 8: e68546.14. Sozzi G, Boeri M, Rossi M, Verri C, Suatoni P, Bravi F, Roz L, Conte D, Grassi M, Sverzellati N, Marchiano A, Negri E, La Vecchia C, Pastorino U. Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study. <i>Journal of Clinical Oncology: official journal of the American Society of Clinical Oncology</i> 2014; 32: 768–773.15. Fortunato O, Boeri M, Verri C, Conte D, Mensah M, Suatoni P, Pastorino U, Sozzi G. Assessment of circulating microRNAs in plasma of lung cancer patients. <i>Molecules</i> 2014; 19: 3038–3054.16. Pozzi P, Munarini E, Bravi F, Rossi M, La Vecchia C, Boffi R, Pastorino U. A combined smoking cessation intervention within a lung cancer screening trial: a pilot observational study. <i>Tumori</i> 2015; 101: 306–311.17. Hu J, Boeri M, Sozzi G, Liu D, Marchiano A, Roz L, Pelosi G, Gatter K, Pastorino U, Pezzella F. Gene signatures stratify computed tomography screening detected lung cancer in high-risk populations. <i>EBioMedicine</i> 2015; 2: 831–840.18. Sestini S, Boeri M, Marchiano A, Pelosi G, Galeone C, Verri C, Suatoni P, Sverzellati N, La Vecchia C, Sozzi G, Pastorino U. Circulating microRNA signature as liquid-biopsy to monitor lung cancer in low-dose computed tomography screening. <i>Oncotarget</i> 2015; 6: 32868–32877.19. Silva M, Galeone C, Sverzellati N, Marchiano A, Calareso G, Sestini S, La Vecchia C, Sozzi G, Pelosi G, Pastorino U. Screening with low-dose computed tomography does not improve survival of small cell lung cancer. <i>Journal of Thoracic Oncology: official publication of the International Association for the Study of Lung Cancer</i> 2016; 11: 187–193.20. Sverzellati N, Silva M, Calareso G, Galeone C, Marchiano A, Sestini S, Sozzi G, Pastorino U. Low-dose computed tomography for lung cancer screening: comparison of performance between annual and biennial screen. <i>European Radiology</i> 2016; 26: 3821–3829.21. Pastorino U, Boffi R, Marchiano A, Sestini S, Munarini E, Calareso G, Boeri M, Pelosi G, Sozzi G, Silva M, Sverzellati N, Galeone C, La Vecchia C, Ghirardi A, Corrao G. Stopping smoking reduces mortality in low-dose computed tomography screening participants. <i>Journal of Thoracic Oncology: official publication of the International Association for the Study of Lung Cancer</i> 2016; 11: 693–699.22. Sestini S, Boeri M, Marchiano A, Silva M, Calareso G, Galeone C, Sozzi G, Pastorino U. [Lung cancer screening in high-risk subjects: early detection with LDCT and risk stratification using miRNA-based blood test]. <i>Epidemiol Prev</i> 2016; 40: 42–50.23. Infante M, Sestini S, Galeone C, Marchiano A, Lutman FR, Angeli E, Calareso G, Pelosi G, Sozzi G, Silva M, Sverzellati N, Cavuto S, La Vecchia C, Santoro A, Alloisio M, Pastorino U. Lung cancer screening with low-dose spiral computed tomography: evidence from a pooled analysis of two Italian randomized trials. <i>European Journal of Cancer Prevention: the official journal of the European Cancer Prevention Organisation</i> 2016.24. Bozzetti F, Paladini I, Rabaiotti E, Franceschini A, Alfieri V, Chetta A, Crisafulli E, Silva M, Pastorino U, Sverzellati N. Are interstitial lung abnormalities associated with COPD? A nested case-control study. <i>Int J Chron Obstruct Pulmon Dis</i> 2016; 11: 1087–1096.25. Pastorino U, Morelli D, Marchiano A, Sestini S, Suatoni P, Taverna F, Boeri M, Sozzi G, Cantarutti A, Corrao G. Inflammatory status and lung function predict mortality in lung cancer screening participants. <i>European Journal of Cancer Prevention: the official journal of the European Cancer Prevention Organisation</i> 2017.26. Ciompi F, Chung K, van Riel SJ, Setio AAA, Gerke PK, Jacobs C, Th Scholten E, Schaefer-Prokop C, Wille MMW, Marchiano A, Pastorino U, Prokop M, van Ginneken B. Towards automatic pulmonary nodule management in lung cancer screening with deep learning. <i>Sci Rep</i> 2017; 7: 46479.27. Silva M, Sverzellati N, Colombi D, Milanese G, La Vecchia C, Galeone C, Marchiano A, Pastorino U. Pleural plaques in lung cancer screening by low-dose computed tomography: prevalence, association with lung cancer and mortality. <i>BMC Pulm Med</i> 2017; 17: 155.28. Silva M, Schaefer-Prokop CM, Jacobs C, Capretti G, Ciompi F, van Ginneken B, Pastorino U, Sverzellati N. Detection of subsolid nodules in lung cancer screening: complementary sensitivity of visual reading and computer-aided diagnosis. <i>Invest Radiol</i> 2018.29. Silva M, Prokop M, Jacobs C, Capretti G, Sverzellati N, Ciompi F, van Ginneken B, Schaefer-Prokop CM, Galeone C, Marchiano A, Pastorino U. Long-term active surveillance of screening detected subsolid nodules is a safe strategy to reduce overtreatment. <i>Journal of Thoracic Oncology: official publication of the International Association for the Study of Lung Cancer</i> 2018.30. Charbonnier JP, Chung K, Scholten ET, van Rikxoort EM, Jacobs C, Sverzellati N, Silva M, Pastorino U, van Ginneken B, Ciompi F. Automatic segmentation of the solid core and enclosed vessels in subsolid pulmonary nodules. <i>Sci Rep</i> 2018; 8: 646.31. Pastorino U, Silva M, Sestini S, Sabia F, Boeri M, Cantarutti A, Sverzellati N, Sozzi G, Corrao G, Marchiano A. Prolonged lung cancer screening reduced 10-year mortality in the MILD trial. <i>Annals of Oncology: official journal of the European Society for Medical Oncology / ESMO</i> 2019.32. Pastorino U, Sverzellati N, Sestini S, Silva M, Sabia F, Boeri M, Cantarutti A, Sozzi G, Corrao G, Marchiano A. Ten-year results of the MILD trial demonstrate the safety and efficacy of biennial lung cancer screening. <i>European Journal of Cancer</i> Accepted June 2019.<b>Methodology</b>• retrospective• diagnostic or prognostic study• performed at one institution