The diagnostic evaluation of ever smokers with pulmonary nodules represents a growing clinical challenge due to the implementation of lung cancer screening. The high false-positive rate of screening frequently results in the use of unnecessary invasive procedures in patients who are ultimately diagnosed as benign, clearly highlighting the need for additional diagnostic approaches. We previously derived and validated a bronchial epithelial gene-expression biomarker to detect lung cancer in ever smokers. However, bronchoscopy is not always chosen as a diagnostic modality. Given that bronchial and nasal epithelial gene-expression are similarly altered by cigarette smoke exposure, we sought to determine if cancer-associated gene-expression might also be detectable in the more readily accessible nasal epithelium. Nasal epithelial brushings were prospectively collected from ever smokers undergoing diagnostic evaluation for lung cancer in the AEGIS-1 (n=375) and AEGIS-2 (n=130) clinical trials and gene-expression profiled using microarrays. The computational framework used to discover biomarkers in these data was formalized and implemented in an open-source R-package. We identified 535 genes in the nasal epithelium of AEGIS-1 patients whose expression was associated with lung cancer status. Using matched bronchial gene-expression data from a subset of these patients, we found significantly concordant cancer-associated gene-expression alterations between the two airway sites. A nasal lung cancer classifier derived in the AEGIS-1 cohort that combined clinical factors and nasal gene-expression had significantly higher AUC (0.81) and sensitivity (0.91) than the clinical-factor model alone in independent samples from the AEGIS-2 cohort. These results support that the airway epithelial field of lung cancer-associated injury extends to the nose and demonstrates the potential of using nasal gene-expression as a non-invasive biomarker for lung cancer detection. The framework for deriving this biomarker was generalized and implemented in an open-source R-package. The package provides a computational pipeline to compare biomarker development strategies using microarray data. The results from this pipeline can be used to highlight the optimal model development parameters for a given dataset leading to more robust and accurate models. This package provides the community with a novel and powerful tool to facilitate biomarker discovery in microarray data.

Until recently it was assumed that the healthy mammalian lung did not harbour a microbiota, unlike other body sites. However, through the use of sequencing based technologies this has been shown to not be the case. Low biomass communities of microbes can be identified in the healthy lung and the lung microbiota in various diseases states has been shown to differ form these 'healthy' communities. The sheep respiratory microbiota is of interest from both an animal health perspective and due to the potential use of the sheep as a large animal model for studying the lung microbiota. In this thesis I seek to characterise the composition and variability of the sheep lung microbiota; the differences between the sheep upper and lower respiratory tract bacterial communities and to assess whether exhaled breath condensate collection can be used as a non-invasive lung microbiota sampling method. To study the bacterial communities present in samples I have used 16S rRNA gene sequencing and analysis. In Chapter 3 I examine the inter-individual and spatial variability present within the sheep lung microbiota. Protected specimen brushings were collected from three lung segments in six animals at three time-points. In a separate sheep a greater number of brushings was taken (n=16) in order to examine the amount of variability over a smaller spatial scale. I find that there can be large differences between the bacterial communities isolated from different locations within the lung, even over short distances. Samples also cluster by the sheep from which they were taken, indicating a host specific influence on the lung microbiota. In Chapter 4 I compare whole lung washes and oropharyngeal swabs from 40 lambs in order to examine the differences between the upper and lower respiratory tract microbiotas. I find that oropharyngeal swabs separate into rumen-like or upper respiratory tract-like bacterial communities. Despite the fact that in humans the upper and lower respiratory microbiotas have been shown to have similar compositions, the sheep lung microbiota samples in this study do not resemble either oropharyngeal samples or reagent only controls. In my first two results chapters, lung sampling methods were used which involved either anaesthesia combined with a bronchoscopic procedure (Chapter 3) or samples being taken from dead animals (Chapter 4). In Chapter 5 I assess whether there is a less invasive way of taking lung microbiota samples from a living individual, both to minimise the procedural stress on animals used as models and to increase the pool of potential volunteers for human lung microbiota studies. I compared samples taken via protected specimen brushings to samples taken via exhaled breath condensate collection, a less invasive sampling technique. I find that condensate samples contain less bacterial DNA and different bacteria than brushing samples, indicating that it is unlikely they could be used as a replacement for invasive sampling methods. In my final results chapter I compare the results across Chapters 3, 4 and 5 to identify bacteria which occur consistently in the sheep lung and could therefore potentially be described as core lung microbiota members. In conclusion, while I have found that there are large differences between the sheep lung microbiota and that which has previously been described in humans, the sheep can still be of use as a model in studies where these differences would not have a significant impact, such as in Chapter 5 of this thesis. I have identified several bacterial members of the core sheep lung microbiota which in future it would be interesting to better characterise and to assess whether they play a role in sheep health.

No description available.

nÃo hà / Introdução: O cÃncer Ãum dos principais problemas mundiais de saÃde e uma das causas mais importantes de morbidade e mortalidade em saÃde pÃblica. Segundo a OrganizaÃÃo Mundial de SaÃde (OMS) Ãa segunda causa de morte no mundo;perdendo apenas para as doenÃas cardiovasculares.Temos alta incidÃncia nacional de pacientes com cÃncer de pulmÃo avanÃado. Hà imprevisibilidade de perfis epidemiolÃgicos e respostas terapÃuticas. A biologia molecular tem sido importante na caracterizaÃÃo sobre a diferenciaÃÃo tumoral e prognÃstico da doenÃa.Novos tratamentos sÃo direcionados por caracterÃsticas farmacogenÃmicas. Pouco se sabe sobre a prevalÃncia desses genes no CearÃe na AmÃrica Latina, bem como sobre caracterÃsticas clÃnicas e desfechos relacionados. Objetivo: Identificar as caracterÃsticas e distribuiÃÃo do perfil epidemiolÃgico dos pacientes portadores de neoplasia de pulmÃo avanÃado, atendidos no ambulatÃrio de oncologia do Hospital de Messejana - Dr. Carlos Alberto Studart. Material e Métodos: Estudo observacional, prospectivo e analítico com inclusão de 135 pacientes portadores de neoplasia de pulmÃo avanÃado, entre 08/2012 a 12/2014; sendo analisados quanto a distribuiÃÃo de frequÃncia por procedÃncia, sexo, raÃa, escolaridade, queixas clinicas, tabagismo e perfil molecular. Resultados: Houve predominÃncia na procedÃncia de pacientes oriundos de cidades do interior do Cearà (69%); pacientes do sexo feminino (51,1%), baixa escolaridade (1o grau ou menos -19%), agricultores (22,4%), Pardos (47,4%) e tabagistas.(79%)O subtipo histolÃgico adenocarcinoma foi predominante (32,5%). DispnÃia foi a principal queixa clinica. O atendimento inicial predominante se deu no perÃodo de internamento (75,5%). Conclusão: Neste grupo de pacientes identificou-se um perfil de caracterÃsticas epidemiolÃgicas prÃprias. Criou-se um registro de cÃncer do hospital.Hà proporcionalidade de resultados com a literatura. / Introduction: Cancer is a leading global health problems and one of the most important causes of morbidity and mortality in public health. According to the World Health Organization (WHO) is the second leading cause of death worldwide, second only to the diseases cardiovasculares.Temos national high incidence of patients with advanced lung cancer. There unpredictability of epidemiological profiles and therapeutic responses. Molecular biology has been important in the characterization of tumor differentiation and prognosis of the disease. New treatments are directed by pharmacogenomic characteristics. Little is known about the prevalence of these genes in CearÃand Latin America as well as on clinical characteristics and outcomes related. Objective: To identify the characteristics and distribution of the epidemiological profile of patients with advanced lung cancer, treated at the oncology clinic at the Messejana Hospital - Dr. Carlos Alberto Studart. Material and Methods: An observational, prospective and analytical study with inclusion of 135 patients with advanced lung cancer, between 08/2012 to 12/2014; being analyzed for the distribution of origin by frequency, sex, race, education, clinical complaints, smoking and molecular profile. Results: There was a predominance in the success of patients from small towns of CearÃ(69%); female patients (51.1%), low education (first degree or less -19%), farmers (22.4%), Pardos (47.4%) and smokers. (79%) The histological subtype was adenocarcinoma predominantly (32.5%). Dyspnea was the main complaint clinica.O predominant initial treatment occurred in hospital stay (75.5%). Conclusion: In this group of patients identified a profile of epidemiological characteristics. Created a hospital cancer registry. There proportionality results with the literature.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Pulmonary complications including acute chest syndrome are leading causes of sickle cell disease related morbidity and mortality. Studies have shown that pulmonary changes can be detected during childhood. Spirometry is the current standard for measuring lung function. Growing evidence suggests that lung clearance index (LCI) is as sensitive as spirometry in identifying pulmonary changes in pediatric patients. Our cross-sectional study compared the sensitivity of LCI to spirometry in the detection of early pulmonary changes in children with sickle cell disease. Our results show that LCI significantly correlates to FEV1% predicted (Spearman’s coefficient -0.44, p = 0.003), FVC % predicted (Spearman’s coefficient -0.44, p = 0.006) and FEF25-75 (Spearman’s coefficient -0.49, p <0.001). Using receiver operating characteristic (ROC) curves, LCI was found to be more sensitive than spirometry, but less specific. The data support LCI’s use as a test to screen for pulmonary changes in children with sickle cell disease. Earlier monitoring of lung function will allow for preventative therapies and delayed progression of pulmonary dysfunction.

Background: Even with newer and repurposed anti-TB drugs almost a third of patients with XDR-TB have unfavourable outcomes. In patients with localised disease and adequate pulmonary reserve, surgery is an important adjunctive treatment. However, there are no outcome data from TB endemic countries, and the prognostic significance of pre-operative PET-CT findings remains unknown. Objectives: To report outcomes for resectional surgery in our setting, and to study whether PET activity outside of the resection influences treatment outcomes. Methods: A retrospective study of all XDR-TB patients undergoing surgery at Groote Schuur Hospital (GSH) between July 2010 and December 2016 was performed. PET-CT was performed in a subgroup. Patients were followed up to determine treatment outcomes at 24-months post- surgery. Treatment success and failure, including all-cause mortality, was determined. Results: In total, 35 patients underwent surgery. The mean age was 36, 49% were male and 26% were HIV-infected. Pneumonectomy was the most common procedure (57%). Three patients (9%) were lost to follow up by 24 months. Total all-cause mortality was 34%. Treatment success was achieved in 15/35 (43%). In patients who underwent pre-operative PET-CT, there were no overall radiological features or PET parameters that were found to be prognostic for treatment failure. Conclusion: Resectional surgery for DR-TB in combination with chemotherapy resulted in cure in less than half of patients. Our data do not support the use of PET-CT to preselect patients or prognosticate about their outcome. These data inform clinical practice and underscore the need to support antibiotic stewardship strategies in TB-endemic settings.

An investigation into anthropocentric, socio-economic, racial and environmental factors influencing lung function. In modern clinical practice the data derived from pulmonary function tests are an integral part of the evaluation of pulmonary disease states. Such data may shed light on the nature of the disease state, the extent (severity) of the disease and the degree of functional impairment that is present. It is generally recognized that there is a lack of consistent data regarding "normal" values in pulmonary function. Despite great progress in standardizing instrumentation, methodology and calculation of the lung function test, the interpretation of the test is complicated by the lack of standardized prediction values. The identification of race as a confounding variable is particularly important in an evaluation of appropriateness of currently used pulmonary function reference values. It has been pointed out that reference values for blacks, in particular, have deficiencies and that this issue demands urgent investigation. The study of differences in lung function in different race groups is complex. Race, itself, is a controversial concept and its close relationship to social stratification needs to be explored before differences may be attributed to race itself.

Background: Poorly coordinated diurnal cortisol and circadian rest-activity rhythms predict earlier mortality in metastatic breast and colorectal cancer, respectively. We examined the prognostic value of the diurnal cortisol rhythm in lung cancer. Methods: Lung cancer patients (. n=. 62, 34 female) were within 5. years of diagnosis and had primarily non small-cell lung cancer, with disease stage ranging from early to advanced. Saliva collected over two days allowed calculation of the diurnal cortisol slope and the cortisol awakening response (CAR). Lymphocyte numbers and subsets were measured by flow cytometry. Survival data were obtained for 57 patients. Cox Proportional Hazards analyses were used to test the prognostic value of the diurnal cortisol rhythm on survival calculated both from study entry and from initial diagnosis. Results: The diurnal cortisol slope predicted subsequent survival over three years. Early mortality occurred among patients with higher slopes, or relatively " flat" rhythms indicating lack of normal diurnal variation (Cox Proportional Hazards p=. .009). Cortisol slope also predicted survival time from initial diagnosis (. p=. .012). Flattened profiles were linked with male gender (. t=. 2.04, df=. 59, p=. .046) and low total and cytotoxic T cell lymphocyte counts (. r=. -.39 and -.30, p=. .004 and .035, respectively). After adjustment for possible confounding factors, diurnal slope remained a significant, independent predictor of survival. Conclusions: Flattening of the diurnal cortisol rhythm predicts early lung cancer death. Data contribute to growing evidence that circadian disruption accelerates tumor progression.

Background: Poorly coordinated diurnal cortisol and circadian rest-activity rhythms predict earlier mortality in metastatic breast and colorectal cancer, respectively. We examined the prognostic value of the diurnal cortisol rhythm in lung cancer. Methods: Lung cancer patients (. n=. 62, 34 female) were within 5. years of diagnosis and had primarily non small-cell lung cancer, with disease stage ranging from early to advanced. Saliva collected over two days allowed calculation of the diurnal cortisol slope and the cortisol awakening response (CAR). Lymphocyte numbers and subsets were measured by flow cytometry. Survival data were obtained for 57 patients. Cox Proportional Hazards analyses were used to test the prognostic value of the diurnal cortisol rhythm on survival calculated both from study entry and from initial diagnosis. Results: The diurnal cortisol slope predicted subsequent survival over three years. Early mortality occurred among patients with higher slopes, or relatively " flat" rhythms indicating lack of normal diurnal variation (Cox Proportional Hazards p=. .009). Cortisol slope also predicted survival time from initial diagnosis (. p=. .012). Flattened profiles were linked with male gender (. t=. 2.04, df=. 59, p=. .046) and low total and cytotoxic T cell lymphocyte counts (. r=. -.39 and -.30, p=. .004 and .035, respectively). After adjustment for possible confounding factors, diurnal slope remained a significant, independent predictor of survival. Conclusions: Flattening of the diurnal cortisol rhythm predicts early lung cancer death. Data contribute to growing evidence that circadian disruption accelerates tumor progression.

Lung cancer has been the leading cause of cancer death in women forthe past three decades. Although smoking is the most important riskfactor for lung cancer, not all lung cancer deaths in American womenare attributed to smoking and the role of dietary exposures remainunclear.In particular, the effect of coffee consumption and teaconsumption on lung cancer risk remains inconclusive. Therefore weassessed these associations prospectively in 83,777 women between theages of 50-79 who did not have a previous history of cancer. Dailycoffee and tea consumption (cups/d) were assessed via a baselinequestionnaire while the 1,038 lung cancer cases included in analysiswere self-reported and verified by outcome assessors. Cox proportionalhazard models, adjusted for important lung cancer risk factors, wereused to model the associations. 71% of women reported drinking coffeedaily while only 26% of participants drank tea. Preliminary resultssuggested a significant increase in lung cancer risk for caffeinated(HR=1.47, 95% CI 1.21-1.79), decaffeinated (HR=1.56, 95% CI 1.17-2.07)and total coffee (HR= 1.58, 95% CI 1.29-1.93) when comparing those inthe highest consumption categories to non-drinkers, but no significantresults were observed in these consumption groups in an analysisconducted with only non-smokers. Daily tea consumption wassignificantly associated with a reduction of risk (HR= 0.82, 95% CI0.71-0.96). Our data suggests that there is no association betweencoffee consumption and lung cancer risk or tea consumption and lungcancer risk.