This thesis examined associations between ecological indicators of residential radon and fine particulate matter air pollution (PM2.5) and lung cancer mortality using data from the American Cancer Society Cancer Prevention Study-II (CPS-II) prospective cohort. Nearly 1.2 million CPS-II participants were recruited in 1982. Mean county-level residential radon concentrations were linked to study participants according to ZIP code information at enrollment (mean (SD) = 53.5 (38.0) Bq/m3). Cox proportional hazards regression models were used to obtain adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for lung cancer mortality associated with radon. After necessary exclusions, a total of 811,961 participants in 2,754 counties were retained for analysis. A significant positive linear trend was observed between categories of radon concentrations and lung cancer mortality (p = 0.02). A 15% (95% CI 1 - 31%) increase in the risk of lung cancer mortality was observed per each 100 Bq/m3 radon. Radon was also positively associated with chronic obstructive pulmonary disease mortality (HR per each 100 Bq/m3 = 1.13, 95% CI 1.05 - 1.21). No clear associations were observed between radon and non-respiratory mortality. In lifelong never smokers (n = 188,699), each 10 µg/m3 increase in mean metropolitan statistical area PM2.5 concentrations was associated with a 15-27% increase in the risk of lung cancer death which strengthened among individuals with a history of asthma or any prevalent chronic lung disease at enrollment (p for interaction < 0.05). There was no association between PM2.5 and mortality from non-malignant respiratory disease. In conclusion, this thesis observed significant positive associations between ecological indicators of residential radon and PM2.5 concentrations and lung cancer mortality. These findings further support efforts to reduce radon concentrations in homes to the lowest possible level and strengthens the evidence that ambient concentrations of PM2.5 measured in recent decades are associated with small but measurable increases in lung cancer mortality. Further research is needed to better understand possible complex inter-relationships between environmental risk factors, chronic lung disease, and lung cancer.

A causal link between radon exposure and lung cancer was previously established through numerous epidemiological studies of miners and residential occupants exposed to radon gas. Although the health detriment to Canadians from residential radon exposure has been estimated in earlier assessments, a comprehensive radon survey by Health Canada in 2011 was the first to sample residences from every health region in the country. Further, this survey yielded higher concentration measurements than previous surveys, with an arithmetic average concentration about twice that of an older survey which was the basis for many of the previous Canadian radon risk assessments. Two exposure-response models from the US NRC were selected for this thesis, along with seasonal adjustment factors for the survey data to compute expected value, rather than conservative, risk estimates. Population-based (population attributable risk, PAR; excess lifetime risk ratio, ELRR; and life-years lost LYL) and individual-based (ELRR and LYL) indices are used to summarize the health detriment. Mean estimates of ELRR, PAR, and LYL for the Canadian population are estimated in the range of 0.31 - 0.48, 0.19 - 0.26, and 0.19 - 0.31, respectively, depending on the model used. Point estimates are also provided for individual provinces and some results are strati ed by risk factors, such as smoking history and floor level of residency. A number of sources of uncertainty in the results are identified, and some are incorporated in a two-dimensional uncertainty analysis using Monte Carlo methods.

INTRODUCTION: Pulmonary embolism (PE) is a major cause of mortality during pregnancy. It is estimated that about 20% of maternal deaths in north america are due to PE. A lung V/Q study in a standard (non-gravid) patient typically consists of a low dosage ventilation study followed by a higher dosage perfusion study. In some centers however, perfusion-only imaging, without accompanying ventilation imaging has been employed. In this method, a several-fold lower dose of radioactivity is used. Perfusion-only imaging has multiple advantages. In addition to reduction of radiation dose to the mother and the fetus, there is decreased cost to the health-care system as well as improved patient convenience and shortened hospital workflow. OBJECTIVES: The present study aimed at assessing the negative predictive value (among other diagnostic accuracy measures) of perfusion-only imaging in a large group of pregnant patients with suspected pulmonary embolism. METHODS: This study was a retrospective cohort study of the entire pregnant patients with suspected PE who underwent V/Q scan at The Ottawa Hospital and their V/Q scans were available in the PACS system. After acquiring REB approval, a comprehensive search in the PACS (Picture Archiving and Communication System) was conducted to find pregnant patients who were assessed for PE in our division since 2004 (the earliest date the V/Q images were available in our system). A statistical consultation was made before the initiation of data collection and at the time of data analysis. All patients who met the inclusion criteria were included. Initially a nuclear medicine resident with 2 years of experience read all the perfusion- only images. The PISAPED criteria were used for image interpretation. Then the results were compared against the reports made by nuclear medicine staffs that were available to us in our electronic system and a final interpretation was made after such comparison. The follow-up clinical notes were used as the gold standard to make a final diagnosis of PE. Finally, diagnostic accuracy measures were calculated. RESULTS: A total of 364 patients were included. Mean maternal age at the time of lung V/Q scan was 30.3 years-old (SD=5.8) ranging from 16 to 51 years-old. From a total of 362 lung perfusion scans, 316/362 (87.3%) scans interpreted as normal, 17/362 (4.7%) scans were interpreted as high probability and 29/362 (8.0%) scans were interpreted as non-diagnostic. Pulmonary embolism was diagnosed in a total of 15 patients directly after performing lung scan. None of the patients with normal perfusion-only scans were diagnosed later with PE, proving a negative predictive value of 100%. The sensitivity and specificity of perfusion-only imaging after including the non-diagnostic studies were 100% (100% to 100%) and 99.1% (88.1% to 94.1%), respectively with a negative predictive value of 100% (100% to 100%) and a positive predictive value of 32.6% (19.1% to 46.2%). Conclusion: The results of the current study show that perfusion-only imaging has a very high negative predictive value for PE in pregnant population and therefore can exclude PE with a very high degree of accuracy.

Radon is a human carcinogen and is an important occupational and public health concern. Radiation protection programs, implemented since the 1950s and 1960s, have significantly reduced radon levels in uranium mines and improved the quality of exposure information. Precise quantification of the risk of lung cancer at low levels of radon exposure and the factors that confound and modify this risk are important for occupational radiation protection. This is a joint cohort study of 408 lung cancer deaths and 394,236 person-years of risk from the Czech, French and Canadian male uranium miners, employed in 1953 or later, with cumulative radon exposures < 100 working level months (WLM). Internal Poisson regression models, stratified by cohort, age at risk and calendar year period at risk were used to calculate the linear excess relative risk (ERR) per unit cumulative radon exposure (lagged five-years). The impact of effect modifiers: time since exposure, attained age, and exposure rate were assessed using an exposure-age-concentration model. Finally, sensitivity analyses assessed the confounding effect of unmeasured tobacco smoking on the radon-lung cancer mortality risk estimate. A statistically significant linear relationship between radon and lung cancer mortality was found, with ERR/WLM = 0.017 (95% confidence intervals (CI): 0.009–0.028) at < 100 WLM cumulative radon exposures. In trend analyses, statistically significant risk was observed at cumulative exposures as low as 10–19 WLM, with RR = 1.64 (95% CI: 1.03–2.65, N = 48 deaths). Radon exposures received in more recent periods (5–14 years previously) had the greatest risk of lung cancer mortality. These risks decreased with increasing time since exposure and attained age. No effect of exposure rate, separate from measures of cumulative exposure, was observed at low radon levels. The confounding effect of unmeasured tobacco smoking was small and did not substantially change the radon-lung cancer mortality risk estimates found. These findings provide strong evidence for an increased risk of lung cancer mortality after long-term low radon exposure among Czech, French and Canadian uranium miners. The results are compatible with other studies of miners restricted to low radon levels and residential radon studies. The results suggest radiation protection measures are of significant importance among modern uranium miners with low radon exposure levels.

Le cancer bronchique non à petites cellules (CBNPC) est particulièrement chimiorésistant. Aucun marqueur robuste de chimiorésistance n'a été validé dans ce type de cancer. Nous avons cherché à décrire dans ce travail des marqueurs innovants de résistance à la chimiothérapie à base de platine dans les CBNPC. Après avoir étudié les caractéristiques cliniques et moléculaires habituelles des patients réfractaires à la chimiothérapie, nous avons étudié le rôle de la voie Sonic Hedgehog (Shh) dans le CBNPC et son impact en termes de chimiorésistance. Nous avons ainsi montré que cette voie de signalisation, connue comme liée aux cellules souches cancéreuses, est corrélée au caractère réfractaire à la chimiothérapie. L'expression de Gli2 est associée à la progression tumorale, à la survie sans progression et à la survie globale. Nous avons également démontré une corrélation entre l'activation de la voie Shh et la transition épithélio-mésenchymateuse, qui est liée à l'agressivité tumorale, le pouvoir métastasiant et la chimiorésistance. Nous avons aussi validé le rôle de la voie Shh dans la prolifération tumorale et la chimiorésistance dans un autre modèle de cancer thoracique, le mésothéliome pleural malin. Enfin, nous nous sommes intéressés à l'expression de hPAF1C (human polymerase II-associated factor 1 complex), facteur suractivé dans les cellules souches cancéreuses et lié à l'activation de la voie Shh. Nous avons montré que l'expression de hPAF1C est associée à un mauvais pronostic et à la prolifération tumorale par interaction avec c-Myc. Ces résultats soulignent le rôle important de la voie Shh dans le CBNPC en termes de chimiorésistance et d'agressivité tumorale. / Non-small cell lung cancer (NSCLC) is known to be chemoresistant. Few robust markers of chemoresistance have been validated so far in this type of cancer. We have described in this work new innovative markers of resistance to cisplatin-based chemotherapy in NSCLC. After the study of usual clinical and molecular caracteristics of patients who were refractory to chemotherapy, we have then explored the role of the Sonic Hedgehog (Shh) pathway in NSCLC and its impact in term of chemoresistance. We have shown that Shh pathway, closely linked with cancer stem cells, was correlated with the refractory property to chemotherapy. Positive Gli2 immunohistochemistry score was associated with tumor progression et progression-free survival. We have also demonstrated a correlation between Shh activation and epithelial-mesenchymal transition, known to be linked with tumor aggressiveness, metastatic ability and chemoresistance. We have then validated the great role of Shh pathway in tumor proliferation and chemoresistance in another thoracic cancer, known to be chemoresistant, the malignant pleural mesothelioma. At last, the impact of ceancer stem cells on tumor aggressiveness and prognosis has been demonstrated through the study of the expression of hPAF1C (human polymerase II-associated factor 1 complex), described as overactivated in cancer stem cells and linked to Shh pathway activation. We have shown that hPAF1C expression was associated with poor prognosis and with tumor proliferation through an interaction with c-Myc. These results underline the major role of Shh pathway and cancer stem cells in SNCLC in term of chemoresistance and tumor aggressiveness.

Asthma is the most common chronic disease in children and the effects of air pollution exposure on asthma and respiratory health in children have been a growing concern over recent decades. Although a number of epidemiological studies have been carried out in this field, these have produced conflicting results. The aim of this study was to assess the effects of long term exposure to nitrogen dioxide (NO2) and particulate matter (PM10) on asthma prevalence and lung function in children. To achieve this, a novel exposure model was developed and evaluated, which allowed retrospective exposure assessment of children participating in a population based birth cohort study – the Manchester Asthma and Allergy Study (MAAS). MAAS is a prospective birth cohort study comprising 1185 children specifically designed to study asthma and allergies. Clinical follow up took place at ages 3, 5, 8 and 11 years. At each follow up parents completed questionnaires on asthma diagnosis and symptoms and children underwent skin prick tests for common allergens. Children’s specific airways resistance (sRaw, at ages 3, 5, 8, 11) and forced expiratory volume in one second (FEV1, at ages 5, 8, 11) were measured. At ages 5 and 11 years FEV1 was measured at baseline and after bronchodilator treatment. The exposure model developed during this study incorporated outdoor and indoor air pollution, spatio-temporal variation in air pollution and time-activity patterns of children. The model was based on the concept of microenvironmental exposure. It modelled personal exposure based on PM10 and NO2 concentrations in children’s home, school and journey microenvironments (MEs) and the length of time they spend in these MEs. Land use regression (LUR) models were used to model PM10 and NO2 concentrations in outdoor MEs. These LUR models were specifically developed for the Greater Manchester area. A novel method was used to develop the LUR models, which used the output from an air dispersion model as dependent variables in the regression analysis. Furthermore, a novel approach was used to obtain annual concentration of PM10 and NO2 from 1996 to 2010, which involved the recalibration of the LUR models for each year. A mass balance model and indoor to outdoor ratios were used to model concentrations in indoor MEs. The performance of the exposure model was evaluated through a personal monitoring study in schoolchildren attending a local secondary school. Children wore personal NO2 monitors for two consecutive days in four seasons. Parental questionnaires and time-activity diaries were used to obtain information for the exposure model and to model NO2 exposure for the same time period. The results showed good agreement between monitored and modelled NO2 concentrations (Normalised mean bias factor=-0.04). Multiple linear regression and generalised estimating equations (GEE) were used to assess the cross-sectional and longitudinal effect of modelled exposure on sRaw and FEV1 (as % predicted). Multiple logistic regression and GEE were used to assess the effect of modelled exposure on the prevalence of asthma and current wheeze.The longitudinal analyses showed significant associations between PM10 and NO2 exposure and % predicted FEV1 (PM10: B=-1.37, p=0.019; NO2: B=-0.83, p=0.003), but no association with sRaw (PM10: B=0.009, p=0.37; NO2: B=-0.007, p=0.16). The cross-sectional analyses showed no association between pollutant exposure during the summer or winter prior to age 11 and any of the lung function measures (p>0.05). Long term PM10 or NO2 exposure were not associated with asthma or current wheeze (p>0.05).This study developed and evaluated a novel air pollution exposure model for epidemiological research. The results of this study suggest a negative impact of long term exposure to NO2 and PM10 on growth in FEV1 during primary school age. However, no evidence of an association between long term exposure to NO2 and PM10 and childhood asthma was found.

This study was designed to examine the hypothesis that the amount of amniotic fluid present during gestation is critical to normal lung growth and maturation. On day 16 of gestation the amniotic sacs of the right or left uterine horns of timed pregnant Sprague-Dawley rats were punctured with a 20 gauge needle. The fetuses of the opposite horn served as controls. On day 21 of gestation (one day prior to natural delivery) the fetuses were delivered by Cesarean section. An unbalanced, mixed model analysis of variance was performed on the data collected from each fetus. Probability values of less than 0.05 between control and experimental animals were considered significant. Amniotic sac puncture resulted in a significant loss of amniotic fluid as indicated by reduced amniotic fluid volume on day 21. Experimental body weight was significantly reduced indicating fetal growth retardation. Lung growth was also retarded as indicated by significantly reduced lung weight to body weight ratios and lung volume to body weight ratios following amniotic sac puncture. There was a reduction in the amount of fluid present within the experimental lungs. There appeared to be no significant effect on the structural units of the lung as indicated by no significant difference between control and experimental fetal lungs in terms of cell number, cell size, total protein to body weight ratio, maturation of type II cells, volume fraction of saccular air, saccular wall, conducting air and nonparenchyma, airspace size, saccular surface area to body weight ratio and surface to volume ratio. Thus, loss of amniotic fluid significantly affected lung growth, more than it affected overall body growth, without having an effect on lung maturation. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Objetivo: O câncer de pulmão é a primeira causa de morte relacionada ao câncer quando considerados ambos os sexos. Os grandes esforços para a redução do tabagismo e para a introdução do filtro de cigarro mudaram a epidemiologia do câncer de pulmão. Em países desenvolvidos, a ascensão do adenocarcinoma e o declínio do epidermoide são de notório conhecimento. Outra característica é o aumento da incidência da doença entre mulheres. Um entendimento melhor da atual epidemiologia do câncer de pulmão é necessário para o desenvolvimento de estratégias de saúde pública de prevenção, diagnóstico e tratamento. Métodos: Análise retrospectiva de todos os pacientes com CPNPC tratados com ressecção pulmonar entre 1986 e 2010 em um hospital universitário do Sul do Brasil. As análises foram divididas em três períodos: 1986-1990, 1991-2000 e 2001-2010. O mesmo grupo de patologistas realizou o diagnóstico, e os estágios foram atualizados para a nova classificação da IASLC, 7ª edição. Todas as análises foram realizadas utilizando o programa SAS, versão 13. Resultados: Foram estudados 817 pacientes submetidos à ressecção pulmonar por CPNPC entre 1986 e 2010. Setenta por cento eram homens, média de idade de 61,4 anos, 44,2% carcinoma epidermoide e 40% adenocarcinoma, 26,7% estágio IIIA. A proporção de mulheres apresentou um aumento de 22% no primeiro período para 36% na última década. A idade média no momento da cirurgia era de 52,7 anos para mulheres e 57,3 para homens no primeiro período, e 60,1 para mulheres e 63,9 para homens no último período (p<0.001). A proporção de carcinoma epidermoide modificou de 49,1% inicialmente para 38,7% no último período (p=0.017). Em comparação, a prevalência do adenocarcinoma cresceu de 35,4% para 39,6% e, mais recentemente, para 41,2%. Em relação ao número total de pessoas acometidas pela doença, mulheres com adenocarcinoma representavam 9,4% no primeiro período, 12,5% no segundo e 16,8% no último período. Pacientes com estágio IIIA representavam 27,9% na última década. O tipo de cirurgia predominante foi a lobectomia. A pneumonectomia foi o procedimento cirúrgico em 21,9%, 18,8% e 16,8% dos casos em cada período, em ordem crescente, respectivamente (p<0.03). Conclusão: Neste estudo de pacientes no Sul do Brasil, a análise de gênero demonstrou que a taxa de câncer de pulmão entre as mulheres está aumentando nas últimas três décadas, mas ainda não chegou a ultrapassar a taxa masculina. A proporção de adenocarcinoma em mulheres aumentou. O significativo declínio da quantidade proporcional de pneumonectomia provavelmente reflete a mudança da indicação e técnica cirúrgica. A idade média de pacientes submetidos a tratamento cirúrgico aumentou tanto para homens quanto para mulheres, mas não alcançou a média de países desenvolvidos de 71 anos. A mudança da proporção do tipo histológico e de mulheres está de acordo com os dados de países desenvolvidos. / Objective: Lung cancer is the leading cause of cancer-related death worldwide when considering both genders. The great effort to reduce smoking and to introduce the usage of cigarette filter has changed lung cancer epidemiology. In developed countries, the increasing incidence of adenocarcinoma and the decrease of squamous cell carcinoma are well known. Other characteristic reported is the rising number of women with the disease. Better understanding of current lung cancer epidemiology is necessary for the appropriate design of public health strategies for prevention, diagnosis and treatment. Methods: Retrospective analysis of all patients with non-small cell lung cancer (NSCLC) treated with lung resection between 1986 and 2010 in a university hospital of Southern Brazil. Analysis was divided in three periods: 1986-1990, 1991-2000 and 2001-2010. The same pathology group performed histological diagnosis and all staging was updated according to the new IASLC, 7th edition. All analyses were performed using the SAS program, version 13. Results: We studied 817 patients who underwent lung resection for NSCLC from 1986 to 2010. Seventy percent were males, average age 61.4 years old, 44.2% squamous cell carcinoma and 40% adenocarcinoma, 26.7% stage IIIA. The female proportion increased from 22% in the first period to 36% in the last decade. Mean age at surgery treatment was 52.7 years old for women and 57.3 years old for men in the first period, and 60.1 for women and 63.9 for men in the last period (p<0.001). The proportion of squamous cell changed from 49.1% initially to 38.7% in the last period (p=0.017). In comparison, the adenocarcinoma prevalence increased from 35.4% to 39.6% and, most recently, to 41.21%. Of the total NSCLC patients, females with adenocarcinoma represented 9.4% in the first period, 12.5% in the second and 16.8% in last period. Patients with stage IIIA represented 27.9% in the last decade. Lobectomy was the predominant type of surgery. Pneumonectomy was the surgical procedure in 21.9%, 18.8% and 16.8% of the cases in each period, respectively (p<0.03). Conclusions: In this cohort of patients in Southern Brazil, gender analysis shows that rates of lung cancer in females are rising over the last three decades, but have not surpassed men rates. The proportion of adenocarcinoma in females has increased. The significant decrease of pneumonectomy rates probably reflects changes on surgical management techniques and indication. The mean age of patients undergoing surgical treatment has increased for both men and women, but has not reached the average age reported in developed countries, 71 years old. The histological and gender findings for lung cancer are in accordance with the data of developed countries.

Respiratory gating in lung PET imaging to compensate for respiratory motion artifacts is a current research issue with broad potential impact on quantitation, diagnosis and clinical management of lung tumors. However, PET images collected at discrete bins can be significantly affected by noise as there are lower activity counts in each gated bin unless the total PET acquisition time is prolonged, so that gating methods should be combined with imaging-based motion correction and registration methods. The aim of this study was to develop and validate a fast and practical solution to the problem of respiratory motion for the detection and accurate quantitation of lung tumors in PET images. This included: (1) developing a computer-assisted algorithm for PET/CT images that automatically segments lung regions in CT images, identifies and localizes lung tumors of PET images; (2) developing and comparing different registration algorithms which processes all the information within the entire respiratory cycle and integrate all the tumor in different gated bins into a single reference bin. Four registration/integration algorithms: Centroid Based, Intensity Based, Rigid Body and Optical Flow registration were compared as well as two registration schemes: Direct Scheme and Successive Scheme. Validation was demonstrated by conducting experiments with the computerized 4D NCAT phantom and with a dynamic lung-chest phantom imaged using a GE PET/CT System. Iterations were conducted on different size simulated tumors and different noise levels. Static tumors without respiratory motion were used as gold standard; quantitative results were compared with respect to tumor activity concentration, cross-correlation coefficient, relative noise level and computation time. Comparing the results of the tumors before and after correction, the tumor activity values and tumor volumes were closer to the static tumors (gold standard). Higher correlation values and lower noise were also achieved after applying the correction algorithms. With this method the compromise between short PET scan time and reduced image noise can be achieved, while quantification and clinical analysis become fast and precise.

Lung cancer is the second most prevalent cancer in men and women in the United States and the overall leading cause of cancer-related deaths. Due to this high prevalence, lung cancer screening is a critical procedure in all Family Medicine practices. However, screening is particularly important in rural Appalachian clinics, as this area experiences especially high rates of mortality due to lung cancer. The United States Preventive Services Task Force recommends annual low-dose computed tomography (LDCT) lung cancer screening in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. The goal of this project is assess readiness of clinical providers of the risks and benefits of lung cancer screening, to encourage screening when appropriate, and ultimately increase then number of LDCT annual screenings. Provider knowledge was assessing using a lung cancer screening knowledge and practice survey. Participants then attended an educational sessions that provided information on the importance of screening and when it is appropriate to administer LDCT. Finally, a second survey was administered, again to assess knowledge and practice. Data analysis is currently in process. A t-test will be executed to determine if there is a statistically significant difference between survey scores before and after the educational session. It is expected that the educational program will lead to increases in provider knowledge and more appropriate screenings. The results of this study have important ramifications for this area; because Appalachia has disproportionately high mortality due to lung cancer, it is imperative that the disease be identified as early as possible to ensure the most effective treatment. This project illustrates a method to increase screenings.