UBC Faculty Research and Publications

The relationship between stage 1 and 2 non-small cell lung cancer and lung function in men and women Malhotra, Samir; Lam, Stephen; Man, SF P; Gan, Wen Q; Sin, Don D Feb 1, 2006

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata


52383-12890_2005_Article_41.pdf [ 515.54kB ]
JSON: 52383-1.0132574.json
JSON-LD: 52383-1.0132574-ld.json
RDF/XML (Pretty): 52383-1.0132574-rdf.xml
RDF/JSON: 52383-1.0132574-rdf.json
Turtle: 52383-1.0132574-turtle.txt
N-Triples: 52383-1.0132574-rdf-ntriples.txt
Original Record: 52383-1.0132574-source.json
Full Text

Full Text

ralssBioMed CentBMC Pulmonary MedicineOpen AcceResearch articleThe relationship between stage 1 and 2 non-small cell lung cancer and lung function in men and womenSamir Malhotra1, Stephen Lam1,3, SF Paul Man1,2, Wen Q Gan1,2 and Don D Sin*1,2Address: 1Department of Medicine (Respiratory Division), University of British Columbia, All in Vancouver, British Columbia, Canada, 2The James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul's Hospital, All in Vancouver, British Columbia, Canada and 3British Columbia Cancer Agency, All in Vancouver, British Columbia, CanadaEmail: Samir Malhotra - smalhotra@shaw.ca; Stephen Lam - slam2@bccancer.bc.ca; SF Paul Man - PMan@providencehealth.bc.ca; Wen Q Gan - wgan@mrl.ubc.ca; Don D Sin* - dsin@mrl.ubc.ca* Corresponding author    AbstractBackground: Reduced forced expiratory volume in one second (FEV1) has been linked to non small celllung cancer (NSCLC). However, it is unclear whether all or only certain histological subtypes of NSCLCare associated with reduced FEV1. Moreover, there is little information on whether gender modifies thisrelationship. Using a large tissue registry, we sought to determine the relationship between FEV1 andsubtypes of NSCLC and determine whether this relationship is modified by gender.Methods: We used data from patients who underwent tumor resection for NSCLC at a teaching hospitalin Vancouver and had various pre-operative clinical measurements including FEV1. We divided the cohortinto quartiles of predicted FEV1 and using both logistic and linear regression modeling techniquesdetermined whether FEV1 was related to the occurrence of adeno or squamous cell carcinoma in men andwomen.Results: There were 610 patients in the study (36% females). On average, women were more likely tohave adenocarcinoma than were men (72% of all cases of NSCLC in women versus 40% in men; p < 0.001).In women, there was no significant relationship between FEV1 and the risk of any histological subtypes ofNSCLC. In men, however, there was an inverse relationship between the risk of adenocarcinoma and FEV1such that the lowest quartile of FEV1 was 47% less likely to have adenocarcinoma compared with thehighest FEV1 quartile (adjusted odds ratio, 0.52; 0.28 to 0.98; p for trend, 0.028). The reverse was observedfor squamous cell carcinoma.Conclusion: In individuals undergoing lung resection for NSCLC, the risk of adenocarcinoma andsquamous cell carcinoma of the lung varies as a function of FEV1, independent of smoking intensity in menbut not in women.Clinical Implications: These data indicate that women are much more susceptible to adenocarcinomathan are men especially when they have normal or near normal lung function. It may thus be useful toconduct periodic surveillance chest radiographs in asymptomatic female smokers (or ex-smokers) toascertain peripheral nodules or masses before distant metastases occur since adenocarcinomas tend toPublished: 01 February 2006BMC Pulmonary Medicine 2006, 6:2 doi:10.1186/1471-2466-6-2Received: 31 May 2005Accepted: 01 February 2006This article is available from: http://www.biomedcentral.com/1471-2466/6/2© 2006 Malhotra et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 6(page number not for citation purposes)metastasize earlier in the disease course than squamous cell carcinomas.BMC Pulmonary Medicine 2006, 6:2 http://www.biomedcentral.com/1471-2466/6/2BackgroundLung cancer is now an epidemic in women. Although theincidence of lung cancer has stabilized in men, there con-tinues to be a dramatic increase in lung cancer cases in thefemale population. In 2003, an estimated 80,100 womenin the United States (US) were diagnosed with lung cancerand 68,800 died from this disease [1]. In women, lungcancer has surpassed breast cancer as the leading cause ofcancer mortality in 1987 and now accounts for 25% of allcancer deaths [1]. In both men and women, cigarettesmoking is the leading causative factor for lung cancer.Compared to never-smokers, smokers have a 20-foldincrease in the risk for lung cancer [2].Interestingly, reduced forced expiratory volume in onesecond (FEV1), an important indicator of lung function,has also been linked with lung cancer, independent of theeffects of cigarette smoking [3-5]. A study by Wasswa-Kintu et al. [6] found that FEV1, in a severity-dependentmanner, was associated with lung cancer incidence andmortality even after adjustments for smoking intensityues) significantly increased the risk of lung cancer amongcurrent and former female smokers. In men, however, theincrease in risk was much less pronounced. This study,however, did not include information on histological sub-types of lung cancer. It is therefore unclear whether themodifying effects of gender on the relationship betweenFEV1 and lung cancer impacted the risk for adenocarci-noma, squamous cell carcinoma or both. Such informa-tion would be valuable in gaining a better understandingof the potential differences (or similarities) in lung cancersusceptibility between men and women. To investigatethis question, we analyzed data from a large cohort ofindividuals who underwent surgical resection for a smallperipheral tumor.MethodsStudy participantsData were obtained from patients who required surgicaltreatment of Stage 1 and II lung cancers at St. Paul's Hos-pital in Vancouver, Canada between 1978 and 2003. Allresected tumors were examined by board-certified pathol-ogists, who were unaware of the patient's lung functionmeasurements at the time of the histological assessment.The histological subtype was diagnosed on surgical speci-mens according to the World Health Organization classi-fication [7]. Because very few patients with small cellcarcinomas undergo surgical resection, we restricted theanalysis to non-small cell lung cancers (NSCLC). For ana-lytic purposes, bronchoalveolar carcinoma was includedin the adenocarcinoma group.Clinical variablesAs part of their pre-operative work-up, all patients com-pleted a pulmonary function test that met the standards ofthe American Thoracic Society [8]. From this test, FEV1,forced vital capacity (FVC) and transfer coefficient for car-bon monoxide (KCO) were determined. We applied a pre-diction equation to calculate predicted FEV1 values foreach patient [9]. Clinical information including age, gen-der, height, weight, and tobacco smoke exposure werealso collected pre-operatively. Tobacco smoke exposurewas estimated by using current smoking status, and thenumber of cigarettes smoked per day (pack-years of smok-ing). Arterial blood gas measurements on room air werealso obtained in these patients.Statistical analysisContinuous variables were compared using a Student t-test and dichotomous variables were compared using achi-square test. To determine the relationship betweenFEV1 and the risk of adeno and squamous cell carcinomasin both men and women, we divided the groups intoquartiles based on FEV1 within each gender category. WeThe Relative Risk Of Adeno (A) And Squamous Cell Carci-noma (B) According To Baseline FEV1 Measurement In Wom n Who Underwent Tumor Resection For Non-Small Cell Lu g CancerFigur  1The Relative Risk Of Adeno (A) And Squamous Cell Carci-noma (B) According To Baseline FEV1 Measurement In Women Who Underwent Tumor Resection For Non-Small Cell Lung Cancer. Curves were fitted using a spline tech-nique.≤40 50 60 70 80 90 ≥100% predicted FEV10.000.200.400.600.801.00RelativeProbabilityofSquamousCellCarcinomainWomen≤40 50 60 70 80 90 ≥100% predicted FEV1ABPage 2 of 6(page number not for citation purposes)and status. Importantly, they found that even a very mod-est reduction in FEV1 (within the "normal" range of val-arbitrarily defined quartile 1 as the category with the high-est predicted FEV1 and quartile 4 as the category with theBMC Pulmonary Medicine 2006, 6:2 http://www.biomedcentral.com/1471-2466/6/2lowest predicted FEV1. Using quartile 1 as the referent, wecompared the odds of adenocarcinoma (or squamous cellcarcinoma) across the quartiles of FEV1 in a logistic regres-sion model. To the crude model, we added age, body massindex (BMI) and pack-years of smoking as covariates asthey were significantly related to FEV1 and the risk of ade-nocarcinoma (and squamous cell carcinoma). These vari-ables were included as both categorical and continuousvariables. As there was no material difference in theresults, for simplicity, we included them as continuousvariables in the final model. To test for a linear increase(or decrease) in the odds ratios (OR) across the quartilesof FEV1, we used a chi-square test for trend, whichadjusted for age, BMI and pack-years of smoking. We alsoperformed a linear regression analysis in which we consid-ered predicted FEV1 as a continuous variable rather than asquartiles to test the robustness of the data. We constructedfitted curves using a cubic spline method to visualize theresults (figures 1 and 2). Similar analyses were performedusing squamous cell carcinomas as the dependent varia-ble. All analyses were conducted using SAS software ver-were considered significant. Continuous variables areexpressed as mean ± SD, unless otherwise specified.ResultsIn total, there were 640 patients during the study period,who were diagnosed with NSCLC and who providedinformed consent to use their lung tissue for research pur-poses. Twenty-two patients (3% of total) were excludedbecause they had undifferentiated tumors that could notbe confidently classified into one of the two major histo-logical subtypes of NSCLC. Additionally, eight patientswere excluded due to insufficient information on the clin-ical variables of interest (e.g. FEV1). This left 610 patientsfor analysis.The baseline characteristics of these patients are summa-rized in Table 1. There was a significant difference in thegender distribution of adenocarcinoma (40% in men vs.73% in women; p < 0.001) and squamous cell carcinomas(57% in men vs. 24% in women; p < 0.001). Smoking sta-tus at the time of surgery was similar between male andfemale patients (p = 0.082), though overall, men hadhigher pack years of smoking compared with women (p <0.001). Similarly, there was no difference in age betweenmen and women (p = 0.496). Male patients had slightlylower FEV1, FVC and arterial oxygen tension (PaO2) thandid female patients (Table 1).Table 2 summarizes the unadjusted and adjusted oddsratios (controlling for covariates which included age, BMIand cigarette smoking) for adenocarcinoma and squa-mous cell carcinoma in women across quartiles of FEV1.In women, at all levels of FEV1, the odds of adenocarci-noma were much higher than that of squamous cell carci-noma (figure 1a and 1b). However, the odds did not varyas a function of FEV1.In contrast, in men, the histological subtype varied signif-icantly across the FEV1 quartiles (Table 3). Reduced FEV1was associated with higher odds for squamous cell carci-noma, while at higher FEV1 values, adenocarcinomas pre-dominated. These data did not change significantly whenFEV1 was evaluated as a continuous rather than as a cate-gorical variable (Figures 2a and 2b). Neither forced vitalcapacity nor transfer coefficient for carbon monoxide wassignificantly related to NSCLC histological subtypes ineither men or women.DiscussionThe most important and novel finding of the presentstudy was that in women the risk for adenocarcinoma didnot vary as a function of FEV1. At all levels of FEV1, aden-ocarcinomas predominated, constituting ~70% of allThe Relative Risk Of Adeno (A) And Squamous Cell Carci-noma (B) According To Baseline FEV1 Measurement In Men Who Underwent Tum r Resectio  For Non-S all Cell Lu g CancerFigur  2The Relative Risk Of Adeno (A) And Squamous Cell Carci-noma (B) According To Baseline FEV1 Measurement In Men Who Underwent Tumor Resection For Non-Small Cell Lung Cancer. Curves were fitted using a spline technique.≤40.0 50.0 60.0 70.0 80.0 90.0 ≥ predicted≤40.0 50.0 60.0 70.0 80.0 90.0 ≥ predictedABPage 3 of 6(page number not for citation purposes)sion 9.1 (SAS Institute, Carey, N.C.) and SPSS version11.0 (Chicago, IL). Two-tailed P-values less than 0.05NSCLCs in the female population. In men, however, FEV1made a material difference to the risk for adeno and squa-BMC Pulmonary Medicine 2006, 6:2 http://www.biomedcentral.com/1471-2466/6/2mous cell carcinomas. At reduced FEV1, men were farmore likely to develop squamous cell carcinoma thanadenocarcinomas; the reverse was true when FEV1 was inthe normal or near normal range.These results are consistent with those reported by Papi etal. [10] who found that individuals with chronic obstruc-tive pulmonary disease (COPD) with mildly impairedFEV1 (~70% of predicted) had a four-fold increase in therisk for squamous cell carcinoma compared to those withnormal lung function (FEV1, ~93% of predicted). How-ever, this study could not comment on the potential mod-ifying effects of gender because they had only 18 femalesubjects (representing 13% of the total subjects). Weextend their findings by demonstrating that the risk ofsquamous cell carcinoma increases with decreasing FEV1in men but not in women.The mechanism(s) responsible for the apparent increasein the risk of adenocarcinoma in women are largelyunknown. However, several possibilities exist. Firstly,there may be differences in genetic susceptibility. Forinstance, women for unknown reasons have more fre-quent mutations and transversions in the p53 gene thando men and aberrations in this gene have been associatedwith increased risk of adenocarcinoma [11]. Secondly,hormonal differences may impart differential risk of lungcancer between men and women. NSCLCs have beenassociated with increased expression of estrogen receptorlatter gene encodes for an enzyme that has an integral rolein the production of polycyclic aromatic hydrocarbons(Phase 1 enzymes), which may be carcinogenic [13]. Con-sistent with this notion, female smokers have increasedexpression of CYP1A1 than do male smokers [14]. Furtherinvestigation is required to investigate if estrogen has acausal link to adenocarcinoma by promoting carcinogen-esis through increased CYP1A1 or other related pathways.Thirdly, inflammation may play a primary role in theincreased susceptibility of women to adenocarcinoma.Inflammation has been incited as an important part of thepathogenesis of certain types of lung cancer. Ardies [15]suggests that infection or toxic chemicals can incite a vig-orous inflammatory reaction in the airways, producingcertain by-products that may promote carcinogenesis. InNSCLC, cyclo-oxygenase 2 (COX-2) gene is over-expressed in nearly all stages of disease progression [16]and downstream enzymes of the COX-2 pathwayinvolved in prostanoid synthesis such as prostaglandin E2synthase is also up-regulated [17]. This inflammatorypathway has been implicated in the progression of lungcancer by inhibiting apoptosis, promoting angiogenesisand facilitating microinvasion of tumor to adjacent tissue,leading to tumor growth and metastasis [18,19]. Moreo-ver, COX-2 activity has been associated with poorer prog-nosis in NSCLC [20]. Interestingly, Szczeklik andcolleagues showed that in the asthmatic population,women were five times more likely to have a polymor-Table 1: A Comparison of Baseline Characteristics Between Men and Women With Non-Small Cell Lung Cancer, Who Underwent SurgeryContinuous variables are expressed as mean ± SD and dichotomous variables are expressed as % of column totals.Men N = 388 Women N= 222 P valueAge (years) 64 ± 9 64 ± 10 0.432BMI (kg/m2) 26 ± 4 24 ± 5 <0.001PaCO2 (mm Hg) 41 ± 8 40 ± 7 <0.001PaO2 (mm Hg) 80 ± 22 86 ± 30 <0.001Pre-bronchodilator FEV1(% predicted) 74 ± 19 85 ± 20 <0.001Post-bronchodilator FEV1 (% predicted) 77 ± 18 88 ± 20 <0.001Pre-bronchodilator FVC(% predicted) 86 ± 16 94 ± 18 <0.001Post-bronchodilator FVC, (% predicted) 90 ± 15 96 ± 18 <0.001KCO (% predicted) 78 ± 23 75 ± 22 <0.001Current Smokers (%) 57 64 0.082Pack Years of Smoking* 45 ± 2 37 ± 2 <0.001Adenocarcinoma (%) 40 73 <0.001Squamous cell carcinoma (%) 57 24 <0.001Size of the tumors (cm) 3.6 ± 1.3 2.7 ± 1.0 0.008Upper Lobe (%) 56 58 0.153Middle Lobe or Lingula (%) 3 7 0.153Lower lobe (%) 28 29 0.153Multiple lobes (%) 5 3 0.153* Expressed as geometric mean ± standard deviationAbbreviations: BMI, body mass index, PaCO2, arterial carbon dioxide tension; PaO2, arterial oxygen tension, FEV1, forced expiratory volume in one second, FVC, forced vital capacity; KCO, transfer coefficient for carbon monoxidePage 4 of 6(page number not for citation purposes)β in chromosome 14 [12]. Stimulation of this receptormay have a role in the up-regulation of CYP1A1 gene. Thisphism in the COX-2 promoter region, -765G>C, com-pared to men (5% versus 1% frequency). ThisBMC Pulmonary Medicine 2006, 6:2 http://www.biomedcentral.com/1471-2466/6/2polymorphism is associated with increased production ofprostaglandin (PG) E2 and D2 [21]. Indeed, monocytescultivated from individuals with the C-C genotype pro-duce levels of PGE2 and PGD2 that are 25 to 34 foldhigher than that obtained from individuals with the G-Ggenotype [22]. The importance of this promoter polymor-phism in the genesis of NSCLC is unknown.Gender differences in the incidence of subtypes of NSCLCmay also reflect subtle yet important differences in airwaybiology. In an experiment by Van Winkle et al. [23],female mice exposed to naphthalene, a chemical found inmainstream and sidestream smoke, were more likely tosuffer airway damage than were male mice. Interestingly,for largely unclear reasons, the naphthalene-induced lungdamage occurred predominantly in the distal airways,which is the usual site of adeno but not squamous cell car-cinomas.Adenocarcinomas tend be more peripherally located thanare squamous cell carcinomas [2]. As such, patients areoften asymptomatic until distant metastases occur. Unfor-tunately, by then, curative resection is not feasible. Ourdata indicate that women are much more susceptible toadenocarcinoma than are men especially when they havenormal or near normal lung function. It may thus be use-ful to conduct periodic surveillance chest radiographs inasymptomatic female smokers (or ex-smokers) to ascer-tain peripheral nodules or masses before distant metas-tases occur. A large clinical study is needed to validate thisnotion and to determine the cost-effectiveness of thisapproach.There are several limitations to the current study. Firstly,because individuals with severely impaired FEV1 do notusually undergo surgical resection for their lung cancer,the relationship between FEV1 and various cell types oflung cancer in individuals with FEV1 less than 50% of pre-dicted remains unknown. Secondly, we did not have datafor individuals with advanced stage lung cancers as thesepatients usually do not undergo surgery for their disease.However, there is no material reason to believe that inclu-sion or exclusion of such patients would change the find-ings of this study. Thirdly, we did not have data on smallcell carcinoma because this type of lung cancer metasta-sizes very early on in the disease course and as such is notusually amenable to surgical resection. The effect of gen-der on the relationship between small cell carcinoma andFEV1 remains unknown.In summary, the present study demonstrates that the riskof adeno- and squamous cell carcinoma of the lung variesas a function of FEV1, independent of smoking intensityin men but not in women. In women undergoing lungTable 2: The Relative Odds for Adeno and Squamous Cell Carcinoma In Women Across Different Categories of Lung FunctionThe cells contain odds ratio (OR) and the 95% confidence intervalsQuartile of FEV1 1 2 3 4 Trend Test (p value)†Range of FEV1 (% predicted) 103 to 149 88 to 102 74 to 88 43 to 74Number of subjects 55 56 55 56Unadjusted Odds for Adenocarcinoma 1 (reference) 0.83 (0.33–2.05) 0.35 (0.14–0.81) 0.75 (0.31–1.84) 0.216Adjusted Odds for Adenocarcinoma* 1 (reference) 0.94 (0.36–2.48) 0.44 (0.18–1.09) 0.88 (0.34–2.32) 0.4481 (reference)Unadjusted Odds for Squamous Cell Carcinoma 1 (reference) 0.86 (0.32–2.32) 3.00 (1.25–7.18) 1.23 (0.48–3.13) 0.1941 (reference)Adjusted Odds for Squamous Cell Carcinoma* 1 (reference) 0.71 (0.25–2.06) 2.19 (0.85–5.61) 0.92 (0.33–2.54) 0.567*Adjusted for age, body mass index and pack-years†p-value for linear trend of increasing (or decreasing) odds ratio from quartile 1 to quartile 4Table 3: The Relative Odds for Adeno and Squamous Cell Carcinoma In Men Across Different Categories of Lung FunctionThe cells contain odds ratio (OR) and the 95% confidence intervalsQuartile of FEV1 1 2 3 4 Trend Test (p value)†Range of FEV1 (% predicted) 89 to 120 78 to 89 64 to 78 27 to 64Number of Subjects 97 97 97 97Unadjusted Odds for Adenocarcinoma 1 (reference) 0.88 (0.50–1.55) 0.55 (0.31–1.00) 0.48 (0.27–0.86) 0.004Adjusted Odds for Adenocarcinoma* 1 (reference) 0.78 (0.43–1.44) 0.59 (0.32–1.09) 0.52 (0.28–0.98) 0.028Unadjusted Odds for Squamous Cell Carcinoma 1 (reference) 1.28 (0.73–2.25) 1.79 (1.01–3.17) 2.35 (1.31–4.20) <0.001Adjusted Odds for Squamous Cell Carcinoma* 1 (reference) 1.43 (0.78–2.63) 1.65 (0.90–3.03) 2.09 (1.12–3.90) 0.019Page 5 of 6(page number not for citation purposes)*Adjusted for BMI, age and pack-years†p-value for linear trend of increasing (or decreasing) odds ratio from quartile 1 to quartile 4Publish with BioMed Central   and  every scientist can read your work free of charge"BioMed Central will be the most significant development for disseminating the results of biomedical research in our lifetime."Sir Paul Nurse, Cancer Research UKYour research papers will be:available free of charge to the entire biomedical communitypeer reviewed and published immediately upon acceptancecited in PubMed and archived on PubMed Central BMC Pulmonary Medicine 2006, 6:2 http://www.biomedcentral.com/1471-2466/6/2resection for cancer, adenocarcinoma predominatesacross all levels of FEV1. These data raise the possibilitythat there are fundamental differences in the airway biol-ogy between women and men, which confer increasedsusceptibility of adenocarcinoma for female smokers.Given that the incidence of lung cancers continue to risein women, it is imperative to further investigate these gen-der differences such as the role of inflammation as well ashormonal, molecular and the genetic factors to explainwhy women are more prone to develop adenocarcinoma.Competing interestsThe author(s) declare that they have no competing inter-ests.Authors' contributionsSM and DDS participated in data acquisition, performedstatistical analysis and drafted the manuscript. WG partic-ipated in data analysis and drafting of manuscript. SL pro-vided important intellectual input to the analysis and indrafting of the manuscript. SFP participated in data inter-pretation, analysis and drafting of the manuscript. Allauthors read and approved the final manuscript.AcknowledgementsThe authors wish to thank Dr. Mark Elliott for collating the data files for this project. DDS is supported by a Canada Research Chair (Respiration) and a Michael Smith/St. Paul's Hospital Foundation Professorship in COPD.References1. Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, FeuerEJ, Thun MJ: Cancer Statistics 2004.  CA Cancer J Clin 2004,54:8-29.2. Alberg AJ, Samet JM: Epidemiology of Lung Cancer.  Chest 2003,123(1 Supp):21S-49S.3. Skillurd DM, Offord KP, Miller RD: Higher risk of lung cancer inchronic pulmonary disease: a prospective, matched, control-led study.  Ann Intern Med 1986, 105:503-507.4. Tockman MS, Anthonisen NR, Wright EC, Donithan MG: Airwaysobstruction and the risk for lung cancer.  Ann Intern Med 1987,106:512-518.5. Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P: Ventilatoryfunction and chronic mucus hypersecretion as predictors ofdeath from lung cancer.  Am Rev Respir Dis 1990, 141:613-617.6. Wasswa-Kintu S, Gan WQ, Man SF, Pare PD, Sin DD: The relation-ship between reduced forced expiratory volume in one sec-ond and the risk of lung cancer: A systematic review andmeta-analysis.  Thorax 2005, 60:570-575.7. World Health Organization: Histological Typing of Lung Tumours 2ndedition. Geneva, World Health Organization; 1981. 8. American Thoracic Society Official Statement: Lung FunctionTesting: Selection of Reference Values and InterpretativeStrategies.  Am Rev Respir Dis 1991, 144:1202-1218.9. Crapo RO, Morris AH, Gardner RM: Reference spirometric val-ues using techniques and equipment that meet ATS recom-mendations.  Am Rev Respir Dis 1981, 123:659-664.10. 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 his-tological subtype in smokers who develop non-small cell lungcarcinoma.  Thorax 2004, 59:679-681.11. Kure EH, Ryberg D, Hewer A, Phillips DH, Skaug V, Baera R, HaugenA: p53 Mutations in lung tumours: relationship to gender andand cells derived from normal lung express both estrogenreceptors alpha and beta at AP1 sites.  Science 1997,277:1508-1510.13. McLemore TL, Adelberg S, Liu MC, McMahon NA, Yu SJ, HubbardWC, Czerwinski M, Wood TG, Storeng R, Lubet RA: Expression ofCYPA1 gene in patients with lung cancer: evidence for ciga-rette smoke-induced gene expression in normal lung tissueand for altered gene regulation in primary pulmonary carci-nomas.  J Natl Cancer Inst 1990, 82:1333-1339.14. Mollerup S, Ryberg D, Hewer A, Phillips DH, Haugen A: Sex differ-ences in lung CYP1A1 expression and DNA adduct levelsamong lung cancer patients.  Cancer Res 1999, 59:3317-3320.15. Ardies CM: Inflammation as a cause of scar cancers of thelung.  Integrative Cancer Therapies 2003, 3:238-246.16. Achiwa H, Yatabe Y, Hida T, Kuroishi T, Kozaki K, Nakamura S,Ogawa M, Sugiura T, Mitsudomi T, Takahashi T: Prognostic signifi-cance of elevated cyclooxygenase 2 expression in primary,resected lung adenocarcinomas.  Clin Cancer Res 1999,5:1001-1005.17. Ermert L, Dierkes C, Ermert M: Immunohistochemical expres-sion of cyclooxygenase isoenzymes and downstreamenzymes in human lung tumors.  Clin Cancer Res 2003,9:1604-1610.18. Yao R, Rioux N, Castonguay A, You M: Inhibition of COX-2 andinduction of apoptosis: two determinants of nonsteroidalanti-inflammatory drugs' chemopreventive efficacies inmouse lung tumorigenesis.  Exp Lung Res 2000, 26:731-742.19. Folkman J: Seminars in Medicine of the Beth Israel Hospital,Boston. Clinical applications of research on angiogenesis.  NEngl J Med 1995, 333:1757-1763.20. Brabender J, Park J, Metzger R, Schneider PM, Lord RV, Holscher AH,Danenberg KD, Danenberg PV: Prognostic significance ofcyclooxygenase 2 mRNA expression in non-small cell lungcancer.  Ann Surg 2002, 235:440-443.21. Szczeklik W, Sanak M, Szczeklik A: Functional effects and genderassociation of COX-2 gene polymorphism G-765C in bron-chial asthma.  J Allergy Clin Immunol 2004, 114:248-253.22. Papafili A, Hill MR, Brull DJ, McAnulty RJ, Marshall RP, Humphries SE,Laurent GJ: Common promoter variant in cyclooxygenase-2represses gene expression: evidence of role in acute-phaseinflammatory response.  Arterioscler Thromb Vasc Biol 2002,22:1631-1636.23. Van Winkle LS, Gunderson AD, Shimizu J, Baker GL, Brown CD:Gender differences in naphthalene metabolism and naphtha-lene induced lung-injury.  Am J Physiol Lung Cell Mol Physiol 2002,282:L1122-L1134.Pre-publication historyThe pre-publication history for this paper can be accessedhere:http://www.biomedcentral.com/1471-2466/6/2/prepubyours — you keep the copyrightSubmit your manuscript here:http://www.biomedcentral.com/info/publishing_adv.aspBioMedcentralPage 6 of 6(page number not for citation purposes)lung DNA adduct levels.  Carcinogenesis 1996, 17:2201-2205.12. Stabile LP, Davis AL, Gubish CT, Hopkins TM, Luketich JD, ChristieN, Finkelstein S, Siegfried JM: Human non-small cell lung tumors


Citation Scheme:


Citations by CSL (citeproc-js)

Usage Statistics



Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            async >
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:


Related Items