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N Engl J Med. 2011 Aug 4;365(5):395-409. doi: 10.1056/NEJMoa1102873. Epub 2011 Jun 29.

Reduced lung-cancer mortality with low-dose computed tomographic screening.

Collaborators (1478)

Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD, Aberle DR, Berg CD, Black WC, Church TR, Fagerstrom RM, Galen B, Gareen IF, Gatsonis C, Goldin JG, Gohagan JK, Hillman B, Jacobs PM, Jaffe C, Kramer BS, Lynch D, Marcus PM, Schnall M, Sullivan DC, Sullivan D, Tatum JL, Zylak CJ, Berg CD, Aberle DR, Fagerstrom RM, Gatsonis C, Gareen IF, Marcus PM, Cagnon C, Cody D, Fletcher G, Flynn MJ, Judy PF, Kruger R, Larke FJ, McNitt-Gray M, Payne T, Seibert JA, Wu X, Abbott G, Aberle DR, Amorosa JK, Barr RG, Black WC, Boiselle PM, Chiles C, Clark R, Coppage L, Falk R, Fishman EK, Gemmel D, Goldin JG, Goodman E, Hart EM, Hazelton T, Johnson E, Judy PF, Kazerooni E, McComb BL, McLennan G, Munden RF, Ravenel J, Sullivan MA, Swensen SJ, Thomas K, Torigian DA, Tung G, Vydareny KH, Worrell JA, Balkin P, Church TR, Fouad M, Freedman MT, Garg K, Gelmann EP, Gierada DS, Hocking W, Inampudi S, Isaacs C, Kvale P, Lynch DA, Mann H, Manor W, Nath H, Reding D, Spizarny DL, Strollo DC, Waltz J, Chen MH, Corle D, Duan F, Izmirilian G, Pinsky P, Prorok PC, Sausville EA, Burke W, Colice G, Edwards B, Emerson S, Harris R, Klein JS, Korn EL, Mayer R, Selby JV, Sturges DW, Turnbull BW, Watson TJ, Fletcher J, Green S, Miller AB, Edelman MJ, Evans WK, Fontana RS, Machtay M, Young RC, Alberts D, DeMets D, Greenwald P, Jacobs PM, McLoud TC, Naidich DP, Tatum JL, Gierada DS, Clark KW, Clingan KL, Fagerstrom RM, Fletcher G, Flynn MJ, Garg K, Larke FJ, Márquez G, Moore SM, Nath H, Ohan P, Payne TJ, Rosenbaum JL, Strollo DC, Wu X, Ford MB, Peace S, Aberle DR, Barr R, Black WC, Goldin JG, Torigian D, Vydareny K, Worrell J, Aberle DR, Baylin S, Caporaso N, Dennis P, Duan F, Dubinett S, Franklin W, Gatsonis C, Grizzle W, Hirsch F, Massion P, McKeeta-Probeck K, Minna J, Patz E, Spitz M, Berg CD, Prorok PC, Fagerstrom RM, Marcus PM, Corle D, Hu P, Izmirlian G, Pinsky P, Márquez G, Sullivan D, Gaegler J, Gohagan JK, Hoffman S, Jackson C, Lange E, Loesch M, Papadopoulos E, Galen B, Jaffe C, Jacobs PM, Tatum JL, Kramer BS, Aberle DR, Gatsonis C, Gareen I, Schnall M, Apgar C, Boyle A, Caldwell T, Fredericks N, Harbison D, Hartfeil D, Jones S, King S, Mahon I, Medina R, Masiejczyk C, Sears L, Zamora P, Brastater H, Iyer V, George J, Gopalakrishnan D, Blair P, Bradley M, Crozier C, Oh M, Spiese N, Steward C, Kelly-Truran M, Thompson T, Cunningham E, Levering A, McMurtrie K, Nahill M, Snowden S, Smith K, Wilton F, Welsh T, Welsh R, Christie W, Clabo S, Clune R, Cunningham N, Downs J, Dymond L, Falcone J, Harris S, Harvey P, Hill J, Hill L, Letizia D, Looney K, McGinley H, Mean A, Moore M, Norton R, Ortico V, Sabina S, Sole R, Stetz J, Ssali A, Stubblefield J, Taylor T, White S, Gatsonis C, Chen MH, Duan F, Lu B, Gareen IF, Duggan M, Souza C, Adams A, Baum S, Blevins M, Fox P, Girardi V, Gorelick J, Hunt E, McMullen Q, Meganathan K, Rendas-Baum R, Sicks JD, Snyder B, Yeh M, Brewer BK, O'Brien B, Cahill J, Ford MB, Rosenbaum JL, Clingan KL, Payte N, Price H, Keating KJ, Galbraith M, Lawler-Heavner J, Devereux G, Peace S, Chanapatna R, Florczyk M, Morgan A, Ohan P, Tiet L, Martinusen LE, DeBaugh RA, Narayanaswami V, McSwain J, Rosario R, Singh J, Lewis T, Roberts LM, Lake W Jr, Clapp JD, Riley T, Austin J, Jones GC, Rathmell JM, Xu F, Young M, Goodman AS, Irons B, Wright P, Kibic C, Hawkins LL, Sheridan P, Kadish N, Moline D, Phillips R, Adkinson M, Creed D, DeCoste T, Gembala D, Hurst S, King E, Knowles J, McBride P, Pangburn P, Preston J, Stokes K, Tesch P, Wenmoth S, Galocy L, Mandley D, McBride P, Orvis G, Gelmann EP, Isaacs C, Freedman MT, Dial A, Clark L, Cohen L, Gerber J, Jamis-Dow C, Makariou E, Smith E, Garrett A, McGuire C, Neff S, Riley T, Barriera A, Cantrell S, Marsh G, Wray C, Yondonsambuu B, Giles U, Ford M, Brown V, Evangelista AL, Hammond T, Nickel J, Brangan M, Lee M, Lin C, Adkins EC, Armah G, Blue C, Cooke V, Gray N, Gustitis M, Hawkins L, Isaacs G, Kim M, King M, Kumbalasiri K, Laura R, McDaniel K, Mulugeta A, Riley L, Sorrell S, Thomas W, Woodard L, Kvale P, Johnson CC, Tammemagi M, Spizarny D, Zylak CJ, Flynn M, Griesemer E, Kwit B, Fantuz P, McLellan B, Simmons D, Hafeez Y, Maddy N, Davis L, Estell R, Kozakowski S, Rowe J, Stanley M, Zhang X, Frebes ME, Paquette M, Tecmire M, Tye C, Young L, Jacobsen G, Sankey S, Schultz L, Albertsen K, Broski K, Kucera G, Poler K, Spoutz-Ryan C, Thomas D, Greene D, Hill C, Young K, Bellware K, Bohn K, Caird N, Fink H, Fiarman S, Houston M, Jolly A, Krzeczkowski C, Mack C, Murray L, Nanovski A, Rempinski D, Tumberlinson H, William D, Eldridge-Smith E, Graves V, Szabo N, Reding D, Hocking W, Manor W, Crump J, Kruger R, Greenlee R, Lappe K, Multerer D, Kriescher D, Vieth A, Wein S, Fuehrer D, Gjertson C, Krebsbach J, Kuhlka C, Luttrop K, Netzer J, Wegner J, Fischer V, Mathiesen-Viergutz K, Kofka K, Jablonsky N, Johnson B, Kitchner T, Mueller L, Rueth A, Wachholz S, Bohman K, Bruger M, Kramer KR, Kuenhold K, Mueller C, Mueller C, Multerer L, Zahradka S, Alkilidar J, Bhattacharjee N, Cangelosi C, Carlson R, Coppens A, Cousins M, Edelstein B, Gerndt K, Heffernon J, Hinke T, Hinson M, Hutchins L, Lieberman K, Manor W, Mulligan G, Omoba E, Risa T, Sheflin J, Swan T, Warner J, Williams A, Yokochi L, Balkin P, Adaniya R, Glanz K, Navin J, Shambaugh V, Tabrah F, Willcox B, Williams P, He Q, Jenkins V, Bow K, Tsukamoto J, Hyun S, Turner L, Hino G, Chung A, Brown E, Morrow H, Stryker K, Shiratori H, Lau P, Au D, Francis W, Dolan L, Brooke J, Calulot M, Chun V, Rabanal K, Tani J, Lewis C, Morfit J, Brunst A, Elbon-Copp C, Huynh W, Johnson M, Nakano E, Villaruz L, Fouad MN, Nath H, Bailey WC, Garver R, Wu X, Brawner D, Malcomb I, Morgan D, Sanders PC, Sandy A, Schwartz M, Singh S, Dransfield M, Higgins D, Moore A, Acemgil A, Blake T, Lee J, Quattlebaum S, Schach J, Martin T, Khatri R, Gendi W, Powell B, Johnson C, Sears J, Jordan S, Prayer V, Walker C, Johnson M, Thompson J, Crawford ED, Bunn P Jr, Gamito E, Lynch DA, Ogden S, Larke FJ, Pretzel S, Ramsay L, Vaughn C, Whiton C, Sammons D, Springhetti L, Tenorio S, Cadez N, Laster S, O'Donnell C, Garg K, Hughes J, Livingston JG, Morrison G, Moss W, Mullennix M, Peters M, Sahin H, Slear M, Burck M, Hill C, Jewitt E, Pena R, Ordonez E, Sammons G, Hernandez J, Reyes A, Somoza A, Church TR, Oken M, Inampudi S, Day D, Edelman K, Fox T, Gaerte S, Myra-Bloom K, Plunkett M, Olson F, Rust P, Schneider L, Trombley B, Vahey T, Payne TJ, Bangerter A, David-Schlegel T, DesMarais D, Frederickson S, Geisser M, Portnov N, Silverman G, Strahan F, Vuong S, Watt G, Woodside J, Zirbes A, Breer S, Haselhuhn C, Longen C, Mueller C, Rice M, Warren D, Collins S, Levi S, Manual J, Matous L, Olsson P, Peterson S, Rogers C, Steele ML, Beckmann P, Jurjans L, Terrian S, Fraki S, Fronheiser M, Heinrichs L, Kirby D, Seivert J, Steinberg C, Watry M, Boyle K, Burnside A, Kiffmeyer R, Mosiman W, Bailey A, Byrnes P, Stark L, Weston M, Whistler D, Cordes J, Engelhard D, Becker J, Bradley P, Fisher J, Lee R, McLaughlin H, Mendez AM, Meyer G, Miller D, Palmquist K, Ronan R, Sigal B, Weissfeld JL, Salerno MD, Schragin J, Strollo DC, Warfel TE, Wolfe PW, Antico DA, Bee MT, Bittner DF, Corey WT, Hawkins RA, Herbick WT, Karwat MP, Leonard KJ, Petrochko CN, Pickering SF, Smart PE, Walters PJ, Zehner JA, Schragin J, Augustine K, Misko S, Richel M, Riley MA, Warren L, McDonough K, Rozanok B, Schragin J, Helms J, Olson P, Uttecht S, Wirth M, Atkins R, Clement L, Gurtner D, Jones L, Buys SS, Mann H, Drosten R, Murray K, Nowers K, Jenkins P, Tripp D, Herron G, Van Stam E, Varner J, O'Toole K, Olson C, Omori D, Andersen A, Argyle N, Avrin J, Bacon J, Broschinsky M, Montalbo C, Nolan K, Randall A, Schleip K, Sheltra SJ, Tischner R, Toyn C, Turner K, Whittaker B, Wicklander E, Wolf J, Dalton C, Doi B, Childs J, Gren L, Randall A, Watson D, Varner J, Jones T, Neilson B, Ahumada H, Bourija H, Brown C, Ferris B, Hadfield L, Hansen K, Koford J, Kopesec S, Lloyd A, Lofthouse M, Matinkhah S, May V, Nichols S, Nieves A, Oviatt M, Richardson N, Rowley AL, Sandberg E, Scholl D, Seguin SL, Shea D, Smith S, Street PA, Walters M, Weiben R, Wilcox L, Zisumbo R, Beck TM, Waltz JS, Ball S, Burt TB, Daniel EN, DeMordaunt QA, Fisher MT, Fuchs MA, Hubler BE, Jennings CJ, Lane RH, Leymaster CE, Macey LC, Marx SV, Maxwell JR, Nelson BD, Fairbanks J, Wohlers B, Heinz J, Berreth K, Marshall R, Brekke J, Jones K, Barrow A, Bashford D, Clot B, Cook T, Dobson L, Hamilton-Foss A, Hanson W, Hyder JE, Lewis-Burke C, Mitchell S, Osterhout M, Patella K, Peterson P, Schornak-Curtis S, Sirianni L, Stoller L, Vigeant K, Whistle C, Yates J, Andriole G, Gierada DS, Anderson DC, Bhalla S, Bierhals AJ, Bronfman J, Glazer HS, Gutierrez FR, Geisse G, Kotner LM, Javidan-Nejad C, Rezai K, Sagel SS, Semenkovich JW, Siegel MJ, Sorrel D, Woodard PK, Engelhart D, Fletcher G, Haverman R, Campbell A, Gardner V, Gherardini D, Hoese L, Holdener R, Ledbetter L, Nieters P, Reiners C, Wade J, Wiseman M, Rueweler P, Williams R, Chi D, Budd T, Laster S, Webb J, Stolin C, Garrett K, Fleming E, Freesmeier E, Frye J, Graham D, Kaemmerer H, Nevilles J, Taylor K, Blaine J, Clark K, Gierada D, Koppel P, Maffitt D, Moore S, Moulton J, Phillips S, Prior F, Wolfsberger M, Cosas A, Kim S, Kim M, Liang Y, Rueweler P, Williams R, Pilgram T, Haas A, Hartwell D, Roeshe D, Lowery A, Meese S, Naughton K, Yoffie R, Blaine J, Clark K, Koppel P, Maffitt D, Moore S, Prior F, Phillips S, Smith K, Boiselle PM, Schwartzstein R, Lin PJ, Parritt TA, Grady EA, Damon L, Gard S, Griggs R, Potemkin A, Pollock MM, Mc Clellan S, Laron M, Owens T, Costello P, Jacobson FL, Judy PF, Hunsaker AR, Spirn PW, Trotman-Dickenson B, Christopoulos VE, Kazda IK, MacDougall RC, Walsh A, Nawfel RD, Berger R, Chan P, Delano M, Geiger J, Krinopol C, McGinnis AD, McLaughlin AM, Weatherby R, Abbott G, Tung G, Maineiro M, Camara L, Cobb C, Smith W, Foley S, Morrell E, Romano D, Guillette D, Amorosa JK, Aisner J, Backer M, Bramwitt M, de Caravalho V, Epstein R, Joyce P, Langenfeld JE, Reinert A, DeMarco K, Lutzker S, Musanti R, Shiff S, Wolfsohn T, Furlong M, Hudak C, Hugill A, Konduri S, Weslowsky E, Carmen S, Foster DL, Hansen K, Pennetta B, White LV, Tokarz R, Trotta M, Birofka A, Black WC, Kasales CJ, Lewis PJ, Weaver JB, Lenz SB, Barrett AC, Dauphinais RX, Heinz JR, Siemionko MK, Taplin A, Wasson LS, DeAlmeida L, Longacre S, Meagher K, Moser CM, Lawlor JK 3rd, O'Quinn C, Black NE, Bradley HL, Bronson JK, Cosgrove T, Haron MK, King D, Mazuerk PM, O'Donnell NF, Pluta DJ, Sackett TJ, Turgeon GD, Albano H, Bell C, Bergen J, Bizer G, Carmichael NM, Cimis C, Davis S, DeAngelis T, Fellows G, Fenton C, Ferola J, Gankiewicz N, Hastings D, Howell C, Johnson ME, Krisk M, Lancor H, Leary C, LeBlanc M, Leming A, Leming M, Mead D, Milacek M, Mood J, Nordstrom H, Palazzolo C, Pierce J, Remitz RP, Rider J, Robbins KA, Sleasman B, Spaulding J, Vashel C, Welch A, White L, Whitty M, Vydareny KH, Williams AM, Karellas A, Grayson L, McCalister-Cross C, Mesquita S, Nguyen A, Myers LN, Deaton E, Falk R, Maxfield S, Thomas K, Brenzel L, Allen P, Brooks D, Chadwell C, Couch E, DeVore A, Flores R, Francis M, Landes S, Mattingly J, Oechsli M, Pitino B, Sams S, Soukhanova O, Bland P, Bube S, Hoffa T, McElsain B, Johnson D, Francow C, Johnson S, Senn P, Fishman EK, Horton KM, Lawler LP, Bradford L, Christensen G, Bishop J, Motley L, Robertson D, Stewart R, Mahesh M, Blake HB, Bradford H, Bradford J, Burner J, Christensen J, Christensen J, Guzman C, Kasecamp J, Kaufmann JB, Kimball D, Lewis Z, Moesinger S, Walsh S, Taylor K, Yung R, Zeng M, Gambill G, Merrill S, McComb BL, Johnson EA, Jolles HI, Kuzo RS, Morin RL, Abaya R, Chewar D, Shwarts P, Allen S, Manning S, Adams M, Awan Z, Beagle L, Cape D, Zeiger T, Amendolare L, Bahr N, Belyea M, Berg T, Burkhard M, Cottrell L, DeAngelis K, Dvorak M, Gay LH, Hatton K, Jacoby S, Kennedy V, Krach K, Laughren M, Lavergne C, Lawrence M, Lynch J, McDonald A, Mestas F, Moody J, O'Brien C, Pitts J, Polding B, Richardson L, Robinson K, Warren A, Washburn H, Wilson E, Zagarra L, Batton KM, Chellini D, DeWitt K, Fleming DR, Newton-Foster C, Krach K, MacDonald R, O'Brien C, Ott J, Peterson J, Sallas M, Teepe M, Thomas R, Torrence K, Zagarra L, Hildestad J, Swensen SJ, Hartman TE, Jett JR, McCollough CH, Midthun DE, Andrist BR, Hanson NE, Sathre CL, Schroeder LD, Sheeran JR, Walters LC, Andrist CL, Bungum AO, Bornhorst CL, Deno DM, Krpata TS, Lambrecht AM, McKey CM, Prudoehl DK, Richter HR, Ravenel J, Costello P, Brisendine A, Adrales-Bentz T, Arnold K, Benjamin B, Dodd A, Keller J, Saunders T, Shannon S, Bailey L, Comer H, Espiritu J, Helwi S, Mack-Pipkin B, Spicker P, Clark R, Coppage L, Hazelton T, Tockman M, Evans B, Wadhwa N, Baptiste N, Eysmans C, Vera-Gonzalez N, Hamm L, Harjani V, Sear A, Blackwell S, Fernandez A, Williams E, Coleman KA, Afiat J, Kirchoff L, Bowman R, Brothers C, Cohen B, Fields N, Guzman R, Monje C, Sterling W, Thorpe L, White K, Williams B, Hart EM, Nekervis E, Franco A, Glick I, Grigolo M, Harts Y, Migo A, Rockwell KP, Stein A, Weyls R, Berns E, Biringer MT, Del Pino A, Dubbs P, Fehrmann GM, Goodwin AL, Granger L, Haglage J, Hirschy J, King M, Kristopher JW, Mac NM, Mahony G, Markarian A, Ramirez M, Taylor M, West KM, Sullivan MA, Matthews CC, Jones J, Cole A, Dow P, Fearon J, Fodera B, Ginther B, McCall RL, Williams S, Young S, Juul C, LaFleur A, Schmidt A, Wright S, Lohmann K, Pineda L, Greenup S, McNulty K, Pawlak S, Porter H, Lanning T, Loria D, Barr RG, Gemmel D, Cook A 2nd, Hallsky JA, DuChateau A, Engartner C, Evans DM, Love C, Schuler P, Boulos A, Dalal P, Dickstein B, Evans J, Evans K, Gemmel M, Hallsky S, Hoffman P, Hritz C, Kerchum L, Kolich M, Kolich M, Kolich M, Kumar N, Lobaugh J, Love D, Love M, Marchese M, Nelson D, Petkus C, Petruzzi M, Raver C, Schuler E, Schultz D, Kobistek R, Jackson J, Ziegler J, Fleischer J, Welch LL, Acerra M, Brittain B, Conklin L, Cyphert C, Delfosse B, Franceshelli L, Fuller J, Garland D, Gocala PJ, Grunenwald M, Kowalik D, Kurjan SL, Lavernick P, Maderitz J, Metz R, Quinn R, Semansky M, Smith S, St Claire A, Taybus P, Wisler D, Zubena K, Goldin JG, Aberle DR, Duda C, Kay P, Trapnell P, Vlachou M, Cagnon C, McNitt-Gray M, Bigby BB, Gallego A, Hamm G, Spivak J, Pollard M, Brown E, Campa O, Carter B, Clark S, Flores M, Ho J, Lee T, Lewis B, McMahon J, Momongan L, Ngo J, Perryman A, Rivas N, Romo C, Sookpisal K, Stone L, Voight B, Williams C, Adams K, Do P, Engber K, Henry L, Khalili M, Morales S, O'Carroll C, Quijano J, Borgheian S, Inatomi R, Lorenzo A, Lorenzo D, Nyborg G, Salazar V, Woo M, Goodman E, Beck P, Beerman P, Jacobsen J, Phillips R, Vranceanu A, Voight K, Allman E, Chen S, Farkas C, Forter I, Kulkarni G, Low L, Marcus P, Matthews L, Silva-Gietzen J, Sturgeon E, Varner G, McLennan G, Thomas K, Mullen B, Stanford W, Hoffman E, Sprenger K, Chapman A, Crawford K, Marietta J, Kmetty L, Meier J, Pirotte P, Rathmell L, Hudson M, Sieren J, Kazerooni E, Cronin P, Gross B, Kelly A, Patel S, Pernicano P, Holloway L, Chalom G, Harper T, Henricks E, Pool J, Shepherd D, Zapolski D, Goodsitt M, Hooks H, Torigian DA, Gefter W, Werner DL, Smith CE, Choi BK, Lee JK, Holland C, Matuza J, Nosker HC, Russell W, Cupp S, O'Shea M, Munden R, Cates M, Sanchez E, Aganon-Acheta M, Black M, Blalock D, Brown C, Cromwell H, Dunnington J, Erasmus J, Gladish G, Gupta S, Haynes MW, Hensley T, Iyer RB, Madewell J, Malbari T, Marom EM, Morice R, Rao S, Read C, Sabloff B, Scully NF, Tekchandani S, Truong M, Wicks D, Cody D, Geiser WR, Montague JL, Patel M, Robinson T, Worrell JA, Donnelly EF, Massion P, Thielke E, Bell AM, Pickens DR, Bowman WA, Herron T, Shone D, Chin B, Chiles C, Chen M, Harmon L, Hinshaw L, Nelson C, Biracree D, Boyles D, Burrough A, Davis A, Drake E, Frost E, Long A, Bowman E, Dyer S, Peacock P.

Abstract

BACKGROUND:

The aggressive and heterogeneous nature of lung cancer has thwarted efforts to reduce mortality from this cancer through the use of screening. The advent of low-dose helical computed tomography (CT) altered the landscape of lung-cancer screening, with studies indicating that low-dose CT detects many tumors at early stages. The National Lung Screening Trial (NLST) was conducted to determine whether screening with low-dose CT could reduce mortality from lung cancer.

METHODS:

From August 2002 through April 2004, we enrolled 53,454 persons at high risk for lung cancer at 33 U.S. medical centers. Participants were randomly assigned to undergo three annual screenings with either low-dose CT (26,722 participants) or single-view posteroanterior chest radiography (26,732). Data were collected on cases of lung cancer and deaths from lung cancer that occurred through December 31, 2009.

RESULTS:

The rate of adherence to screening was more than 90%. The rate of positive screening tests was 24.2% with low-dose CT and 6.9% with radiography over all three rounds. A total of 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false positive results. The incidence of lung cancer was 645 cases per 100,000 person-years (1060 cancers) in the low-dose CT group, as compared with 572 cases per 100,000 person-years (941 cancers) in the radiography group (rate ratio, 1.13; 95% confidence interval [CI], 1.03 to 1.23). There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group, representing a relative reduction in mortality from lung cancer with low-dose CT screening of 20.0% (95% CI, 6.8 to 26.7; P=0.004). The rate of death from any cause was reduced in the low-dose CT group, as compared with the radiography group, by 6.7% (95% CI, 1.2 to 13.6; P=0.02).

CONCLUSIONS:

Screening with the use of low-dose CT reduces mortality from lung cancer. (Funded by the National Cancer Institute; National Lung Screening Trial ClinicalTrials.gov number, NCT00047385.).

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PMID:
21714641
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