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Schiavon, Marco (2013) Clinical, morphological and molecular characterization of cancer phenotypes associated with chronic obstructive pulmonary disease (COPD): new prospective of target therapies. [Ph.D. thesis]

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Abstract (english)

BACKGROUND
Chronic obstructive pulmonary disease (COPD) and lung cancer are two catastrophic diseases, representing leading causes of morbidity and mortality worldwide.
Although the treatment has greatly improved both diseases continue to show increasing frequency and above all an unpredictable progression.
Several studies have firmly established a strict connection between COPD and lung cancer highlighting also the importance of the inflammatory response as a risk factor for both diseases.
The inflammatory paradigm is undoubtedly one of the most fascinating theories to connect COPD and lung cancer and it has acquired new impetus by the recent discoveries in the COPD pathogenesis. Emerging evidence in this context has emphasized the role of adaptive immune responses, possibly with an autoimmune component due to the recognition of pulmonary selfantigens modified by cigarette smoking and to the failure of mechanisms regulating immunological tolerance. In this context, COPD-associated cancers might have specific
pathogenetic and morphological features, differently from tumours arising in non-COPD patients, due to the synergic effect of cigarette smoke and chronic inflammation.
AIM OF THE RESEARCH
This research project focuses on the study of lung cancer in patients with COPD compared to smokers without COPD and never smoker patients in order to identify eventual distinct clinical, morphological and molecular phenotypes.
MATERIALS AND METHODS
From 2010 to 2012, we prospectively enrolled patients with peripheral non small lung cancer submitted to anatomical lung resection (lobectomy, bilobectomy or pneumonectomy) associated with systematic lymphadenectomy. Patients with central airway cancer, secondary lung tumours or previously submitted to inductive treatment were excluded from the study.
According to respiratory functional tests and smoking history patients were then divided in 3 groups: COPD patients, smokers without COPD and never-smoker subjects with normal lung function (FEV1/FVC ratio >70%). Each patient underwent a full clinical and instrumental assessment.
Morphological studies included detailed analysis of growth pattern (according to the latest revision of adenocarcinoma classification), cell proliferation (Ki67/MIB1 expression),
parameters of intra-and peri-tumoral remodelling (inflammation, fibrosis and necrosis) and tumoural detection of interleukin-17 (IL-17) cytokine. Genetic analysis of EGFR and KRAS mutations was also performed in all cases.
RESULTS
In the study period, 66 patients who met the inclusion/exclusion criteria were initially enrolled:16 COPD, 32 smokers without COPD and 18 never smokers.
As the selection criteria affected the predominant histologic profile with a clear predominance of the adenocarcinoma histotype (63% in COPD patients, 71% in smokers and 56% in neversmokers), we performed our investigations only in patients with this histology to obtain results not affected by different histotypes. Therefore the study group was composed of 43 patients (10 COPD, 23 smokers and 10 never-smokers), whose main demographic and functional parameters were comparable except for male/female ratio, reversed in never-smokers, and for lung function, reduced in COPD patients, as expected.
Given the specific aim the comparison of different clinical, morphological and molecular data was mainly performed within the category of smoking patients (COPD patients and smokers without COPD), while never smokers represented control group.
From a clinical point of view the most important differences concern the number of peripheral blood basophils and standard uptake value of positron emission tomography–computed tomography (SUV of PET-CT). COPD patients showed a significant higher number of basophils and lower SUV of PET-CT than smokers without COPD.
Concerning the histological evaluation adenocarcinoma of COPD patients showed a more frequent lepid pattern, less evident solid aspect and lower MIB1/Ki67 index than adenocarcinoma of smokers without COPD. A significant more extensive necrosis was found in adenocarcinoma of COPD and smokers without COPD compared to never-smokers. Finally although not statistically significant a stronger IL17 tissue expression was observed in COPD cases compared to smokers without COPD.
As regards molecular data the most interesting finding was a trend of less frequency of KRAS mutation in adenocarcinoma of COPD patients.
CONCLUSIONS
Adenocarcinoma in COPD patients presents clinical, molecular and morphological features of lower aggressiveness (higher number of basophils, low SUV of PET-CT, increased lepidic
component, reduced solid pattern, lower cell proliferation and less frequent K-RAS mutation) compared to that of smokers without COPD.
Alternative mechanisms of carcinogenesis may be involved in the development/progression of lung cancer in COPD patients. Given the importance of inflammation in the pathogenesis of the disease other mechanisms, such as IL-17 pathway, mainly driving inflammatory mediated carcinogenesis might be crucial.
Additional knowledge of these mechanisms would be of considerable help in the fight against lung cancer especially concerning therapeutic perspectives, providing a rational basis for the development of targeted and more effective treatments.

Abstract (italian)

INTRODUZIONE
La BPCO e il tumore polmonare sono due malattie catastrofiche e rappresentano alcune tra le principali cause di morbilità e mortalità in tutto il mondo.
Sebbene il trattamento di queste patologie è notevolmente migliorato negli ultimi anni, esse continuano a presentare una crescente incidenza e soprattutto un andamento clinico non
prevedibile a priori.
Lo stesso termine "tumore polmonare non a piccole cellule (NSCLC)" comprende un gruppo di malattie neoplastiche con caratteristiche cliniche e molecolari estremamente eterogenee.
Diversi studi hanno ormai fermamente stabilito la stretta connessione tra la BPCO e il cancro del polmone evidenziando anche l'importanza della risposta infiammatoria agli stimoli nocivi, in particolare il fumo di sigaretta, come fattore di rischio fondamentale per entrambe le malattie. La
teoria infiammatoria è senza dubbio uno dei paradigmi più affascinanti per collegare la BPCO e il tumore polmonare e ha acquisito un nuovo impulso dalle più recenti scoperte nella patogenesi della BPCO.
Infatti, sono emerse in questo campo evidenze importanti che hanno sottolineato il ruolo fondamentale di risposte immunitarie adattative, anche con una componente autoimmune dovuta sia al riconoscimento di auto-antigeni polmonari modificati dal fumo di sigaretta sia al fallimento
dei meccanismi che regolano la tolleranza immunologica. In questo contesto, le neoplasie a insorgenza in pazienti con BPCO, per effetto sinergico del fumo e di una specifica
infiammazione cronica, potrebbero possedere specifiche caratteristiche patogenetiche e morfologiche, differenti da tumori di altre popolazioni non affette da BPCO.
SCOPO DELLA RICERCA
Questo progetto di ricerca si concentra sullo studio del cancro del polmone nei pazienti con BPCO comparandolo a due gruppi di controllo, composti da fumatori sani e pazienti non
fumatori, al fine di individuare distinti fenotipi neoplastici dal punto di vista bioumorale, morfologico e molecolare.
MATERIALI E METODI
Dal 2010 al 2012, sono stati arruolati nello studio pazienti con NSCLC in sede periferica sottoposti a resezione polmonare anatomica (lobectomia, bilobectomia o pneumonectomia)
associata a linfadenectomia sistematica. I pazienti con neoplasia a carico delle vie aeree centrali, con tumore polmonare secondario o precedentemente sottoposti a trattamento chemioradioterapico sono stati esclusi dal progetto. Ogni paziente è stato sottoposto ad una completa
valutazione clinica e strumentale, che ha compreso i test di funzionalità polmonare polmonari (i criteri GOLD sono stati utilizzati per identificare i pazienti con BPCO), radiografia del
torace/TAC torace/18FDG PET-TC analisi del sangue.
I pazienti sono stati poi divisi in 3 gruppi in base alle prove funzionali respiratorie e alla storia di fumo: pazienti con BPCO, soggetti fumatori e pazienti non fumatori con funzione polmonare normale (rapporto FEV1/FVC> 70%).
Lo studio istologico della neoplasia è stato caratterizzato da: stadiazione pTNM, analisi morfometrica del pattern di crescita (secondo l'ultima revisione della classificazione del cancro
del polmone), proliferazione cellulare (mediante valutazione dell’espressione di Ki67/MIB1), i parametri di rimodellamento intra-e peri-tumorale (infiammazione, fibrosi, necrosi) e la
caratterizzazione del pattern citochinico di IL-17 a livello peri-e intra-tumorale.
Infine è stata eseguita l'analisi genetica delle mutazioni dei geni EGFR e KRAS.
RISULTATI
Nel periodo di studio sono stati inizialmente arruolati 66 pazienti che rispettavano i criteri di inclusione/esclusione, di cui 16 BPCO, 32 fumatori senza BPCO e 18 non fumatori. Poiché i criteri di selezione hanno profondamente condizionato il profilo istologico predominante, con una netta prevalenza dell’istotipo adenocarcinoma (63% nella BPCO, 71% nei fumatori e 56% nei non fumatori), abbiamo deciso di condurre la valutazione neoplastica funzionale, morfologica, molecolare solo nell’ istologia prevalente.
Pertanto, il gruppo di studio è risultato composto da 43 pazienti (10 BPCO, 23 fumatori, 10 non fumatori), che presentavano comparabili dati demografici e funzionali ad eccezione del rapporto maschio/ femmina, invertito nei non fumatori, per la funzione polmonare, ridotta nei pazienti con
BPCO. Dato l'obiettivo specifico, il confronto dei differenti dati clinici, morfologici e molecolari è stato svolto prevalentemente all'interno della categoria dei soggetti fumatori (pazienti affetti da BPCO e fumatori senza BPCO), mentre i pazienti con storia negativa di fumo hanno rappresentato il gruppo di controllo.Da un punto di vista clinico, le più rimarcabili differenze sono emerse a livello del numero di basofili nel sangue periferico e del valore di standard uptake value (SUV) all’indagine PET-TC.
Infatti i pazienti con BPCO hanno mostrato un numero significativamente superiore di basofili e un SUV inferiore rispetto ai soggetti fumatori senza BPCO.
Per quanto riguarda la valutazione istologica, gli adenocarcinomi nei pazienti con BPCO hanno presentato un aumento del pattern lepidico, con riduzione della componente solida e una più bassa espressione del Ki67/MIB1 rispetto ai tumori dello stesso istotipo insorti in soggetti fumatori senza BPCO. Si è evidenziata una maggiore rappresentazione della componente necrotica negli adenocarcinomi dei pazienti fumatori, con o senza BPCO, rispetto al gruppo dei non fumatori. Infine un forte ma non significativo aumento di IL-17 è stato osservata nei casi con BPCO rispetto ai fumatori.
L’analisi molecolare ha permesso di osservare, come dato più rilevante, un trend di ridotta frequenza di mutazione di KRAS negli adenocarcinomi dei pazienti con BPCO rispetto alle
neoplasie del gruppo dei fumatori.
CONCLUSIONI
Gli adenocarcinomi correlati alla BPCO sono emersi presentare caratteristiche cliniche, morfologiche e molecolari di minore aggressività (aumento del numero di basofili, ridotto
SUVmax alla PET-TC, aumento della componente lepidica, ridotti pattern solido e proliferazione cellulare e meno frequente mutazione di K-RAS) rispetto alle neoplasie insorte in pazienti fumatori senza BPCO. Vie alternative di carcinogenesi potrebbero essere coinvolte nello sviluppo/progressione del tumore polmonare dei pazienti con BPCO. Data l'importanza dell'infiammazione nella patogenesi di questa malattia polmonare, altri meccanismi, quale il
pathway di IL-17, potrebbero essere cruciali per lo sviluppo cancerogenetico principalmente mediato dall’infiammazione. La conoscenza di questi meccanismi potrebbe essere di notevole aiuto nella lotta contro il tumore polmonare soprattutto per quanto riguarda nuove prospettive
terapeutiche, fornendo le basi per sviluppare trattamenti mirati e con maggiore efficacia.

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EPrint type:Ph.D. thesis
Tutor:Schiavon, Marco
Supervisor:Rea, Federico and Calabrese, Fiorella
Ph.D. course:Ciclo 25 > Scuole 25 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE CARDIOVASCOLARI
Data di deposito della tesi:29 January 2013
Anno di Pubblicazione:2013
Key Words:BPCO/COPD Tumore polmonare/Lung tumor KRAS/KRAS IL17/IL17
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/21 Chirurgia toracica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:5728
Depositato il:11 Oct 2013 13:25
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Bibliografia

I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

1) Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Ù Cerca con Google

2) Petty TL. The history of COPD. Int J Chron Obstruct Pulmon Dis. 2006; 1(1):3-14. Cerca con Google

3) Fishman AP. One hundred years of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005; 171(9):941-948. Cerca con Google

4) Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J. 1977; 1(6077):1645-1648. Cerca con Google

5) Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P, Mannino DM, Menezes AM, Sullivan SD, Lee TA, Weiss KB, Jensen RL, Marks GB, Gulsvik A, Nizankowska-Mogilnicka E; BOLD Collaborative Research Group. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet. 2007;370:741-50. Cerca con Google

6) Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006;28:523-32. Cerca con Google

7) Van den Boom G, van Schayck CP, van Möllen MP, Tirimanna PR, den Otter JJ, van Grunsven PM, Buitendijk MJ, van Herwaarden CL, van Weel C. Active detection of chronic obstructive pulmonary disease and asthma in the general population. Results and economic consequences of the DIMCA program. Am J Respir Crit Care Med. 1998;158:1730-8. Cerca con Google

8) Mead J. The lung's "quiet zone". N Engl J Med. 1970;282:1318-9. Cerca con Google

9) O'Donnell DE, Laveneziana P. Dyspnea and activity limitation in COPD: mechanical factors. COPD. 2007;4:225-36. Cerca con Google

10) Chung C, Delaney J and Hodgins R. “Respirology” Toronto Notes (2008) pp.R9. Cerca con Google

11) Rodríguez-Roisin R, Drakulovic M, Rodríguez DA, Roca J, Barberà JA, Wagner PD. Ventilation-perfusion imbalance and chronic obstructive pulmonary disease staging severity. J Appl Physiol. 2009;106:1902-8. Cerca con Google

12) Peto R, Speizer FE, Cochrane AL, Moore F, Fletcher CM, Tinker CM, Higgins IT, Gray RG, Richards SM, Gilliland J, Norman-Smith B. The relevance in adults of air-flow obstruction, but not of mucus hypersecretion, to mortality from chronic lung disease. Results from 20 years of prospective observation. Am Rev Respir Dis. 1983;128:491-500. Cerca con Google

13) Peinado VI, Pizarro S, Barberà JA. Pulmonary vascular involvement in COPD. Chest. 2008;134:808-14. Cerca con Google

14) Celli BR, Barnes PJ. Exacerbations of chronic obstructive pulmonary disease. Eur Respir J. 2007 Jun;29(6):1224-38. Cerca con Google

15) Vestbo J. Systemic inflammation and progression of COPD. Thorax. 2007;62:469-70. Cerca con Google

16) Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175:250-5. Cerca con Google

17) Fabbri LM, Luppi F, Beghé B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J. 2008; 31(1):204-212. Cerca con Google

18) Sin DD, Man JP, Man SF. The risk of osteoporosis in Caucasian men and women with obstructive airways disease. Am J Med. 2003;114:10-4. Cerca con Google

19) Fishman’s Pulmonary Disease and Disorders. McGraw-Hill 2008. Fourth Edition. p 712. Cerca con Google

20) Curtis JL, Freeman CM, Hogg JC. The immunopathogenesis of chronic obstructive pulmonary disease: insights from recent research. Proc Am Thorac Soc. 2007; 4(7):512-521. Cerca con Google

21) Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, Pinto Plata V, Cabral HJ. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350:1005-12. Cerca con Google

22) Travis WD et al. Atlas of nontumour pathology “Non-Neoplastic Disorders of the Lower Respiratory Tract” (2002); pp.435-457. Cerca con Google

23) Ballarin A, Bazzan E, Zenteno RH, Turato G, Baraldo S, Zanovello D, Mutti E, Hogg JC, Saetta M, Cosio MG. Mast Cell Infiltration Discriminates between Histopathological Phenotypes of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2012;186:233-9. Cerca con Google

24) Baugh RJ, Travis J. Human leukocyte granule elastase: rapid isolation and characterization. Biochemistry. 1976; 15(4):836-841. Cerca con Google

25) Hersh CP, DeMeo DL, Silverman EK. National Emphysema Treatment Trial state of the art: genetics of emphysema. Proc Am Thorac Soc. 2008; 5(4):486-493. Cerca con Google

26) Wan ES, Silverman EK. Genetics of COPD and emphysema. Chest. 2009; 136(3):859-866. Cerca con Google

27) Viegi G, Paoletti P, Vellutini M, Carrozzi L, Di Pede F, Baldacci S, Modena P, Pedreschi M, Di Pede C, Giuntini C. Effects of daily cigarette consumption on respiratory symptoms and lung function in a general population sample of north-Italian men. Respiration. 1991;58:282-6. Cerca con Google

28) Sethi JM, Rochester CL. Smoking and chronic obstructive pulmonary disease. Clin Chest Med. 2000;21:67-86. Cerca con Google

29) Balmes J, Becklake M, Blanc P, Henneberger P, Kreiss K, Mapp C, Milton D, Schwartz D, Toren K, Viegi G. Environmental and Occupational Health Assembly, American Thoracic Society. American Thoracic Society Statement: Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med. 2003; 167(5):787-797. Cerca con Google

30) Bruce N, Perez-Padilla R, Albalak R. Indoor air pollution in developing countries: a major environmental and public health challenge. Bull World Health Organ. 2000; 78(9):1078-1092. Cerca con Google

31) Rivera RM, Cosio MG, Ghezzo H, Salazar M, Pérez-Padilla R. Comparison of lung morphology in COPD secondary to cigarette and biomass smoke. Int J Tuberc Lung Dis. 2008; 12(8):972-977. Cerca con Google

32) Lawlor DA, Ebrahim S, Davey Smith G. Association of birth weight with adult lung function: findings from the British Women's Heart and Health Study and a meta-analysis. Thorax. 2005;60:851-8. Cerca con Google

33) Eisner MD, Anthonisen N, Coultas D, Kuenzli N, Perez-Padilla R, Postma D, Romieu I, Silverman EK, Balmes JR; Committee on Nonsmoking COPD, Environmental and Occupational Health Assembly. An official American Thoracic Society public policy statement: Novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;182:693-718. Cerca con Google

34) Crothers K, Huang L, Goulet JL, Goetz MB, Brown ST, Rodriguez-Barradas MC, Oursler KK, Rimland D, Gibert CL, Butt AA, Justice AC. HIV infection and risk for incident pulmonary diseases in the combination antiretroviral therapy era. Am J Respir Crit Care Med. 2011;183:388-95. Cerca con Google

35) Prescott E, Lange P, Vestbo J. Socioeconomic status, lung function and admission to hospital for COPD: results from the Copenhagen City Heart Study. Eur Respir J. 1999;13:1109-14. Cerca con Google

36) Silva GE, Sherrill DL, Guerra S, Barbee RA. Asthma as a risk factor for COPD in a longitudinal study. Chest. 2004;126:59-65. Cerca con Google

37) Vestbo J, Prescott E, Lange P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am J Respir Crit Care Med. 1996;153:1530-5. Cerca con Google

38) Abboud RT, Vimalanathan S. Pathogenesis of COPD. Part I. The role of proteaseantiprotease imbalance in emphysema. Int J Tuberc Lung Dis. 2008; 12(4):361-367. Cerca con Google

39) Baraldo S, Saetta M. To reg or not to reg: that is the question in COPD. Eur Respir J. 2008;31:486-8. Cerca con Google

40) Renda T, Baraldo S, Pelaia G, Bazzan E, Turato G, Papi A, Maestrelli P, Maselli R, Vatrella A, Fabbri LM, Zuin R, Marsico SA, Saetta M. Increased activation of p38 MAPK in COPD. Eur Respir J. 2008;31:62-9. Cerca con Google

41) Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med. 2009; 360(23):2445-2454. Cerca con Google

42) Turato G, Barbato A, Baraldo S, Zanin ME, Bazzan E, Lokar-Oliani K, Calabrese F, Panizzolo C, Snijders D, Maestrelli P, Zuin R, Fabbri LM, Saetta M. Nonatopic children with multitrigger wheezing have airway pathology comparable to atopic asthma. Am J Respir Crit Care Med. 2008;178:476-82. Cerca con Google

43) Joosten LA, Netea MG, Kim SH, Yoon DY, Oppers-Walgreen B, Radstake TR, Barrera P, van de Loo FA, Dinarello CA, van den Berg WB. IL-32, a proinflammatory cytokine in rheumatoid arthritis. Proc Natl Acad Sci USA. 2006; 103:3298–3303. Cerca con Google

44) Shioya M, Nishida A, Yagi Y, Ogawa A, Tsujikawa T, Kim-Mitsuyama S, Takayanagi A, Shimizu N, Fujiyama Y, Andoh A. Epithelial overexpression of interleukin-32alpha in inflammatory bowel disease. Clin Exp Immunol. 2007; 149:480–486. Cerca con Google

45) Baraldo S, Lokar-Oliani K, Turato G, Zuin R, Saetta M. The Role of Lymphocytes in the Pathogenesis of Asthma and COPD. Curr Med Chem. 2007;14:2250-6. Cerca con Google

46) Zanini A, Chetta A, Saetta M, Baraldo S, D'Ippolito R, Castagnaro A, Neri M and Olivieri D. Chymase-positive mast cells play a role in the vascular component of airway remodeling in asthma. J Allergy Clin Immunol. 2007;120:329-33. Cerca con Google

47) Jemal A, Siegel R, Ward E. Cancer statistics, 2009. CA Cancer J Clin. 2009; 59(4):225. Cerca con Google

48) Travis WD, Brambilla E, Mulller –Hermellink HK, Harris CC. Tumors of the Lung, Pleura, Thymus and Heart. WHO. 2004. Cerca con Google

49) Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6(2):244-85. Cerca con Google

50) Youlden DR, Cramb SM, Baade PD: The international epidemiology of lung cancer: geographical distribution and secular trends. J Thorac Oncol 2008; 3: 819–831. Cerca con Google

51) Egleston BL, Meireles SI, Flieder DB, Clapper ML: Population-based trends in lung cancer incidence in women. Semin Oncol 2009; 36: 506–515. Cerca con Google

52) Scagliotti GV, Longo M, Novello S: Nonsmall cell lung cancer in never smokers. Curr Opin Oncol 2009; 21: 99–104. Cerca con Google

53) Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating Mutations in the Epidermal Growth Factor Receptor Underlyng Responsiveness of Non.Small-Cell Lung Cancer to Gefitinib. The New England Journal of Medicine 2004; 350; 21: 2129-2138. Cerca con Google

54) Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR Mutations in Lung Cancer: correlations with Clinical Response to Gefitinib Theraphy. Science 2004; 304: 1497-1500. Cerca con Google

55) Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. PNAS 2004; 101: 13306-13311. Cerca con Google

56) Riely GJ, Pao W, Pham D, Li AR, Rizvi N, Venkatraman ES, Zakowski MF, Kris MG, Ladanyi M, Miller VA. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res 2006; 12: 839–844. Cerca con Google

57) Kalemkerian GP, Pass HI. Present Concepts in the Molecular Biology of Lung Cancer in Shields TW. General Thoracic Surgery, 6th Edition.©2005 Lippincott Williams & Wilkins. Cerca con Google

58) Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989; 49(17): 4682-9. Cerca con Google

59) Cho JY, Kim JH, Lee YH, et al. Correlation between K-ras gene mutation and prognosis of patients with nonsmall cell lung carcinoma. Cancer. 1997; 79(3): 462-7. Cerca con Google

60) Bidoli P, Robustelli della Cuna e Pastorino U: Neoplasie del polmone. In: Medicina Oncologica. Bonadonna G, Robustelli della Cuna, Valagusa. MASSON, Milano, 2003. Cerca con Google

61) Schrump DS, Altorki NA, Henschke CL, Cartier D, Turrisi AT, Gutierrez M. Non-Small Cell Lung Cancer. In: CANCER Principles and Practice of Oncology. De Vita V, Hellman S, Rosemberg SA eds. Lippincott Williams and Wilkins Publ, Philadelphia, 2005, pp 753-810. Cerca con Google

62) Singhal S, Shrager JB, Kaiser LR. Multimodality Therapy for Non-Small-Cell Lung Cancer in Shields TW. General Thoracic Surgery, 6th Edition.©2005 Lippincott Williams & Wilkins. Cerca con Google

63) Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002. 346, 92-98. Cerca con Google

64) Jackman DM, Yeap BY, Sequist LV, Lindeman N, Holmes AJ, Joshi VA, Bell DW, Huberman MS, Halmos B, Rabin MS, Haber DA, Lynch TJ, Meyerson M, Johnson BE, Jänne PA. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res. 2006; 12: 3908–3914. Cerca con Google

65) Suzuki M, Shigematsu H, Iizasa T, Hiroshima K, Nakatani Y, Minna JD, Gazdar AF, Fujisawa T. Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer. Cancer 2006;106:2200 –2207. Cerca con Google

66) Vallières E, Shepherd FA, Crowley J. The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol. 2009 Sep;4(9):1049-59. Cerca con Google

67) Berghmans T, Dusart M, Paesmans M, Hossein-Foucher C, Buvat I, Castaigne C, Scherpereel A, Mascaux C, Moreau M, Roelandts M, Alard S, Meert AP, Patz EF Jr, Lafitte JJ, Sculier JP; European Lung Cancer Working Party for the IASLC Lung Cancer Staging Project. Primary tumor standardized uptake value (SUVmax) measured on fluorodeoxyglucose positron emission tomography (FDG-PET) is of prognostic value for survival in non-small cell lung cancer (NSCLC): a systematic review and meta-analysis (MA) by the European Lung Cancer Working Party for the IASLC Lung Cancer Staging Project. J Thorac Oncol. 2008 Jan;3(1):6-12. Cerca con Google

68) Punturieri A, Szabo E, Croxton TL, Shapiro SD, Dubinett SM: Lung cancer and chronic obstructive pulmonary disease: needs and opportunities for integrated research. J Natl Cancer Inst. 2009; 101: 554–559. Cerca con Google

69) Ben-Zaken CS, Pare PD, Man SF, Sin DD. The growing burden of chronic obstructive pulmonary disease and lung cancer in women: examining sex differences in cigarette smoke metabolism. Am J Respir Crit Care Med. 2007; 176: 113–120. Cerca con Google

70) Turner MC, Chen Y, Krewski D, Calle EE, Thun MJ. Chronic obstructive pulmonary disease is associated with lung cancer mortality in a prospective study of never smokers. Am J Respir Crit Care Med. 2007;176:285–90. Cerca con Google

71) Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med. 2005; 142: 233–239. Cerca con Google

72) Yao H, Rahman I. Current concepts on the role of inflammation in COPD and lung cancer. Curr Opin Pharmacol. 2009; 9: 375– 383. Cerca con Google

73) Papi A, Casoni G, Caramori G, Guzzinati I, Boschetto P, Ravenna F, Calia N, Petruzzelli S, Corbetta L, Cavallesco G, Forini E, Saetta M, Ciaccia A, Fabbri LM. COPD increases the risk of squamous histological subtype in smokers who develop non-small cell lung carcinoma. Thorax. 2004 ; 59(8): 679 – 681. Cerca con Google

74) Spitz MR, Wei Q, Dong Q, Amos CI, Wu X. Genetic susceptibility to lung cancer: the role of DNA damage and repair. Cancer Epidemiol Biomarkers Prev. 2003;12:689–98. Cerca con Google

75) Ocak S, Sos ML, Thomas RK, Massion PP. High-throughput molecular analysis in lung cancer: insights into biology and potential clinical applications. Eur Respir J. 2009;34:489–506. Cerca con Google

76) Cohen BH, Ball WC Jr, Bias WB, Brashears S, Chase GA, Diamond EL, Hsu SH, Kreiss P, Levy DA, Menkes HA, Permutt S, Tockman MS. A genetic-epidemiologic study of chronic obstructive pulmonary disease. I. Study design and preliminary observations. Johns Hopkins Med J. 1975 ; 137 ( 3 ): 95 – 104. Cerca con Google

77) Cohen BH, Diamond EL, Graves CG, Kreiss P, Levy DA, Menkes HA, Permutt S, Quaskey S, Tockman MS. A common familial component in lung cancer and chronic obstructive pulmonary disease. Lancet. 1977; 2( 8037 ): 523 – 526. Cerca con Google

78) Schwartz AG, Ruckdeschel JC. Familial lung cancer: genetic susceptibility and relationship to chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006 ; 173 ( 1 ): 16 – 22. Cerca con Google

79) Yang P, Wentzlaff KA, Katzmann JA, Marks RS, Allen MS, Lesnick TG, Lindor NM, Myers JL, Wiegert E, Midthun DE, Thibodeau SN, Krowka MJ.. Alpha1-antitrypsin defi ciency allele carriers among lung cancer patients. Cancer Epidemiol Biomarkers Prev. 1999; 8( 5 ): 461 – 465. Cerca con Google

80) Yang P, Bamlet WR, Sun Z, Ebbert JO, Aubry MC, Krowka MJ, Taylor WR, Marks RS, Deschamps C, Swensen SJ, Wieben ED, Cunningham JM, Melton LJ, de Andrade M. Alpha1-antitrypsin and neutrophil elastase imbalance and lung cancer risk. Chest. 2005; 128 (1): 445 – 452. Cerca con Google

81) Sun Z, Yang P. Role of imbalance between neutrophil elastase and alpha 1-antitrypsin in cancer development and progression. Lancet Oncol. 2004; 5 ( 3 ): 182 – 190. Cerca con Google

82) Bowman RV, Yang IA, Semmler AB, Fong KM. Epigenetics of lung cancer. Respirology. 2006; 11 ( 4 ): 355 – 365. Cerca con Google

83) Kagan J, Srivastava S, Barker PE, Belinsky SA, Cairns P. Towards clinical application of methylated DNA sequences as cancer biomarkers: a joint NCI’s EDRN and NIST workshop on standards, methods, assays, reagents and tools. Cancer Res. 2007; 67(10): 4545 – 4549. Cerca con Google

84) Adcock IM, Tsaprouni L, Bhavsar P, Ito K. Epigenetic regulation of airway inflammation. Curr Opin Immunol. 2007; 19 ( 6 ): 694 – 700. Cerca con Google

85) David H . Rudolf Virchow and modern aspects of tumor pathology . Pathol Res Pract . 1988 ; 183 ( 3 ): 356 – 364. Cerca con Google

86) Sin DD, Wu L, Anderson JA, Anthonisen NR, Buist AS, Burge PS, Calverley PM, Connett JE, Lindmark B, Pauwels RA, Postma DS, Soriano JB, Szafranski W, Vestbo J. Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax. 2005; 60 ( 12 ): 992 – 997. Cerca con Google

87) Parimon T, Chien JW, Bryson CL, McDonell MB, Udris EM, Au DH. Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007; 175 ( 7 ): 712 – 719. Cerca con Google

88) Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, Conway WA Jr, Enright PL, Kanner RE, O'Hara P, et al.. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA. 1994; 272 ( 19 ): 1497 – 1505. Cerca con Google

89) McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax. 2007; 62 ( 5 ): 411 – 415. Cerca con Google

90) Palmer MT, Weaver CT. Autoimmunity: increasing suspects in the CD4+ T cell line up. Nat. Immunol. 2010; 11, 36–40. Cerca con Google

91) Dubin PJ, Kolls JK. Th17 cytokines and mucosal immunity. Immunol. Rev. 2008; 226, 160–171. Cerca con Google

92) Perera WR, Hurst JR, Wilkinson TM, Sapsford RJ, Müllerova H, Donaldson GC, Wedzicha JA. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur. Respir. J. 2007; 29, 527–534. Cerca con Google

93) Steinman L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell-mediated tissue damage. Nat. Med. 2007; 13, 139–145. Cerca con Google

94) Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity. 2004; 21, 467–476. Cerca con Google

95) Aggarwal S, Gurney AL. IL-17: prototype member of an emerging cytokine family. J. Leukocyte Biol. 2002; 71, 1–8. Cerca con Google

96) Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat. Rev. Immunol. 2009; 9, 556–567. Cerca con Google

97) Weng NP, Liu K, Catalfamo M, Li Y, Henkart PA. IL-15 is a growth factor and an activator of CD8 memory T cells. Ann. N.Y. Acad. Sci. 2002; 975, 46–56. Cerca con Google

98) Lindemann MJ, Hu Z, Benczik M, Liu KD, Gaffen SL. Differential regulation of the IL-17 receptor by γ c cytokines: inhibitory signaling by the phosphatidylinositol 3-kinase pathway. J. Biol. Chem. 2008; 283, 14100–1410. Cerca con Google

99) Bettelli E, Carrier Y, Gao W, Korn T, Strom TB. Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature. 2006; 44, 235–238. Cerca con Google

100) Bettelli E, Korn T, Kuchroo VK. Th17: the third member of the effector T cell trilogy. Curr. Opin. Immunol. 2007; 19, 652–657. Cerca con Google

101) Miossec P, Korn T, Kuchroo VK. Interleukin-17 and Type17 helper T cells. N. Engl. J. Med. 2009; 361, 888–898. Cerca con Google

102) Lane N, Robins RA, Corne J, Fairclough L. Regulation in chronic obstructive pulmonary disease: the role of regulatory T-cells and Th17 cells. Clin Sci. 2010 Apr 20;119(2):75-86. Cerca con Google

103) Miyahara Y, Odunsi K, Chen W, Peng G, Matsuzaki J, Wang RF. Generation and regulation of human CD4+IL-17-producing T cells in ovarian cancer. Proc Natl Acad Sci U S A. 2008; 105: 15505–10. Cerca con Google

104) Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, Wu C, Li SP, Zheng L. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol. 2009; 50: 980–9.9 Cerca con Google

105) Numasaki M, Watanabe M, Suzuki T, Takahashi H, Nakamura A, McAllister F, Hishinuma T, Goto J, Lotze MT, Kolls JK, Sasaki H. IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. J Immunol. 2005; 175: 6177–89. Cerca con Google

106) Numasaki M, Fukushi J, Ono M, Narula SK, Zavodny PJ, Kudo T, Robbins PD, Tahara H, Lotze MT. Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2003; 101:2620-7. Cerca con Google

107) Li Y, Cao ZY, Sun B, Wang GY, Fu Z, Liu YM, Kong QF, Wang JH, Zhang Y, Xu XY, Li HL. Effects of IL-17A on the occurrence of lung adenocarcinoma. Cancer Biol Ther. 2011. 1;12(7):610-6. Cerca con Google

108) Liu L, Ge D, Ma L, Mei J, Liu S, Zhang Q, Ren F, Liao H, Pu Q, Wang T, You Z. Interleukin-17 and prostaglandin E2 are involved in formation of an M2 macrophage-dominant microenvironment in lung cancer. J Thorac Oncol. 2012;7(7):1091-100. Cerca con Google

109) ATS/ERS Task Force: Standardisation of lung function testing. Eur Respir J. 2005;26. Cerca con Google

110) Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008; 5;359(13):1367-80. Cerca con Google

111) Ellis PM, Blais N, Soulieres D, Ionescu DN, Kashyap M, Liu G, Melosky B, Reiman T, Romeo P, Shepherd FA, Tsao MS, Leighl NB. A systematic review and Canadian consensus recommendations on the use of biomarkers in the treatment of non-small cell lung cancer. J Thorac Oncol. 2011;6(8):1379-91. Cerca con Google

112) Skillrud DM, Offord KP, Miller RD. Higher risk of lung cancer in chronic obstructive pulmonary disease. A prospective, matched, controlled study. Ann Intern Med. 1986;105(4):503-7. Cerca con Google

113) Sin DD, Man SF. Impact of cancers and cardiovascular diseases in chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2008;14(2):115-21. Cerca con Google

114) Caramori G, Casolari P, Cavallesco GN, Giuffrè S, Adcock I, Papi A. Mechanisms involved in lung cancer development in COPD. Int J Biochem Cell Biol. 2011;43(7):1030-44. Cerca con Google

115) Gabrielson E. Worldwide trends in lung cancer pathology. Respirology. 2006; 11( 5 ): 533 – 538. Cerca con Google

116) KAY, A. B. (1980) The role of the eosinophil in physiological and pathological processes. In Recent Advance8 in Olin. Immunology 2(Ed. Thompson), Edinburgh: Churchill Livingstone. Cerca con Google

117) Kolb E, Müller E. Local responses in primary and secondary human lung cancers. II. Clinical correlations. Br J Cancer. 1979;40(3):410-6. Cerca con Google

118) Al-Sarraf N, Gately K, Lucey J, Aziz R, Doddakula K, Wilson L, McGovern E, Young V. Clinical implication and prognostic significance of standardised uptake value of primary non-small cell lung cancer on positron emission tomography: analysis of 176 cases. Eur J Cardiothorac Surg. 2008;34(4):892-7. Cerca con Google

119) Nair VS, Gevaert O, Davidzon G, Napel S, Graves EE, Hoang CD, Shrager JB, Quon A, Rubin DL, Plevritis SK. Prognostic PET 18F-FDG uptake imaging features are associated with major oncogenomic alterations in patients with resected non-small cell lung cancer. Cancer Res. 2012. 1;72(15):3725-34. Cerca con Google

120) Vesselle H, Schmidt RA, Pugsley JM, Li M, Kohlmyer SG, Vallires E, Wood DE. Lung cancer proliferation correlates with [F-18]fluorodeoxyglucose uptake by positron emission tomography. Clin Cancer Res. 2000;6(10):3837-44. Cerca con Google

121) Lee HY, Lee KS, Han J, Kim BT, Cho YS, Shim YM, Kim J. Mucinous versus nonmucinous solitary pulmonary nodular bronchioloalveolar carcinoma: CT and FDG PET findings and pathologic comparisons. Lung Cancer. 2009; 65(2):170-5. Cerca con Google

122) Miyake H, Matsumoto A, Terada A, Yoshida S, Takaki H, Mori H. Mucin-producing tumour of the lung: CT findings. J Thorac Imaging. 1995 Spring;10(2):96-8. Cerca con Google

123) Casali C, Rossi G, Marchioni A, Sartori G, Maselli F, Longo L, Tallarico E, Morandi U. A single institution-based retrospective study of surgically treated bronchioloalveolar adenocarcinoma of the lung: clinicopathologic analysis, molecular features, and possible pitfalls in routine practice. J Thorac Oncol. 2010;5(6):830-6. Cerca con Google

124) Hata A, Katakami N, Fujita S, Kaji R, Imai Y, Takahashi Y, Nishimura T, Tomii K, Ishihara K. Frequency of EGFR and KRAS mutations in Japanese patients with lung adenocarcinoma with features of the mucinous subtype of bronchioloalveolar carcinoma. J Thorac Oncol. 2010; 5(8):1197-200. Cerca con Google

125) Sica GL, Yoshizawa AK, Downey RJ, et al. Reassessment of the histologic spectrum of mucinous bronchioloalveolar carcinoma (mBAC). Mod Pathol 2008;21:351A Cerca con Google

126) Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M, Haller A, Lothaire P, Meert AP, Noel S, Lafitte JJ and Sculier JP. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with metaanalysis. Br J Cancer. 2005; 92: 131-139. Cerca con Google

127) Garassino MC, Borgonovo K, Rossi A, Mancuso A, Martelli O, Tinazzi A, Di Cosimo S, La Verde N, Sburlati P, Bianchi C, Farina G, Torri V. Biological and clinical features in predicting efficacy of epidermal growth factor receptor tyrosine kinase inhibitors: a sistematic review and meta-analysis. Anticancer Res. 2009;29(7):2691-7. Cerca con Google

128) Bonanno L, Schiavon M, Nardo G, Bertorelle R, Bonaldi L, Galligioni A, Indraccolo S, Pasello G, Rea F, Favaretto A. Prognostic and predictive implications of EGFR mutations, EGFR copy number and KRAS mutations in advanced stage lung adenocarcinoma. Anticancer Res. 2010;30(12):5121-8. Cerca con Google

129) Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol 2007; 148:32-46. Cerca con Google

130) Zhu X, Mulcahy LA, Mohammed RA, Lee AH, Franks HA, Kilpatrick L, et al. IL-17 expression by breast-cancer-associated macrophages: IL-17 promotes invasiveness of breast cancer cell lines. Breast Cancer Res 2008; 10:95. Cerca con Google

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