<p>From being a rare disease in the early 1900s, lung cancer is today the most common forms of cancer worldwide. This development is due to the gradual uptake of cigarette smoking in different populations and birth cohorts during the past 75 years. In spite of different modes of treatment, survival is still poor and surgery remains the prerequisite for cure. </p><p>National data from the Swedish Cancer Register for the 35-year period 1958-1994 were analysed to estimate the effects of birth cohort, year of diagnosis (period) and age at diagnosis on the time trends in lung cancers. Early mortality, complications, major morbidity during the first 30 days, quality of life and long term survival after lung cancer surgery were assessed to estimate the significance of pre-surgical and tumour-related risk factors. Also, effects of delay in diagnosis and treatment among patients with non-small cell lung cancer were examined.</p><p>The main results indicate that the overall age-adjusted incidence of lung cancer in Sweden has stabilised in men during the last two decades but has been increasing continuously in women. The fastest rate increase was noted among the youngest women and the incidence of adenocarcinoma is increasing in both sexes. Our results show low early mortality and morbidity after lung cancer surgery. Furthermore, quality of life was comparable with that of CABG patients postoperatively. However, patients with reduced lung capacity and those undergoing pneumonectomy should be treated with great care, as they run a considerable risk of major complications, impaired quality of life or death during the first 30 days postoperatively. Tumour stage (TNM) is the best prognostic indicator for long-term survival following radical surgery, underlying the importance of accurate surgical staging. Factors such as impaired preoperative lung function, older age, and major complications after surgery all negatively influence survival. Current smokers as a group run a significant risk of an adverse outcome (major complication or death), impaired mental health and shortened survival after lung cancer surgery. Waiting time for diagnosis and treatment of lung cancer was longer than recommended; especially among those surgically treated, but prolonged delay did not influence survival adversely.</p>

In Sweden approximately 2800 new lung cancer patients are diagnosed every year. Radiotherapy is used with curative intention in certain groups of patients. The aim of this thesis is to study the basis of differences in radioresistance and the possibility to predict response to radiotherapy. In the first study we investigated, using the comet assay, four lung cancer cell lines with different sensitivity towards radiation. A clear dose-response relationship for radiation-induced DNA single strand and double strand breaks were found. All cell lines showed a remarkably efficient repair of both the DNA single strand and double strand breaks one hour after irradiation. However, further studies in one radioresistant and one radiosensitive cell line demonstrated that repair during the first 15 min had the best accordance with radiosensitivity measured as surviving fraction. In the second and third study, sequencing studies of the p53 gene were performed on cell lines as well as on tumour material. Cell lines that were expressing a mutation in exon 7 were associated with increased radiosensitivity compared with tumor cell lines with mutations in other exons. In the clinical study, 10 patients were found to be mutated in the p53 gene whereas the other 10 patients were not. No correlation to clinical parameters could be drawn. In the fourth study, serum from 67 patients with a confirmed diagnosis of non-small cell lung cancer was investigated for the presence of p53 antibodies. P53 antibodies in sera, taken prior to radiation treatment, were associated with increased survival. The summary of this thesis indicates that the p53 gene has an impact on the effect of radiotherapy in lung cancer. The presence of p53 antibodies might be of clinical interest for predicting survival after radiotherapy. Further studies on the importance of the p53 gene on early repair are of interest.

From being a rare disease in the early 1900s, lung cancer is today the most common forms of cancer worldwide. This development is due to the gradual uptake of cigarette smoking in different populations and birth cohorts during the past 75 years. In spite of different modes of treatment, survival is still poor and surgery remains the prerequisite for cure. National data from the Swedish Cancer Register for the 35-year period 1958-1994 were analysed to estimate the effects of birth cohort, year of diagnosis (period) and age at diagnosis on the time trends in lung cancers. Early mortality, complications, major morbidity during the first 30 days, quality of life and long term survival after lung cancer surgery were assessed to estimate the significance of pre-surgical and tumour-related risk factors. Also, effects of delay in diagnosis and treatment among patients with non-small cell lung cancer were examined. The main results indicate that the overall age-adjusted incidence of lung cancer in Sweden has stabilised in men during the last two decades but has been increasing continuously in women. The fastest rate increase was noted among the youngest women and the incidence of adenocarcinoma is increasing in both sexes. Our results show low early mortality and morbidity after lung cancer surgery. Furthermore, quality of life was comparable with that of CABG patients postoperatively. However, patients with reduced lung capacity and those undergoing pneumonectomy should be treated with great care, as they run a considerable risk of major complications, impaired quality of life or death during the first 30 days postoperatively. Tumour stage (TNM) is the best prognostic indicator for long-term survival following radical surgery, underlying the importance of accurate surgical staging. Factors such as impaired preoperative lung function, older age, and major complications after surgery all negatively influence survival. Current smokers as a group run a significant risk of an adverse outcome (major complication or death), impaired mental health and shortened survival after lung cancer surgery. Waiting time for diagnosis and treatment of lung cancer was longer than recommended; especially among those surgically treated, but prolonged delay did not influence survival adversely.

The following thesis describes and analyses the representation of lung cancer in the Canadian print media. The thesis employs a theoretical framework comprised of Giddens’ theory of reflexivity and Goffman’s theory of framing, to understand the social dynamics of negotiation behind the disease’s portrayal in the media, in a late modern context. Late modernity was defined by institutional reflexivity and a focus on understanding and mitigating risk. The research was conducted through a content analysis and examined quantitative trends that contributed to a subsequent qualitative interpretation. The results show that the coverage of lung cancer decreased over time. The analysis shows a discourse of a biomedical institution that has unsuccessfully controlled the disease, a lack of patient advocacy, particularly among celebrities, and a continued conflation of smoking behaviour and lung cancer, all of which contributed to the decreasing coverage. The framing processes point to a society focused on understanding risk through studying the disease’s causes, as well as one concerned with legislative debate and behavioural prevention. The emergence of a frame focused on the patient’s lived experience might contribute to an improved representation of the disease.

Lymph node metastasis is a critical prognostic factor for lung cancer. Effective therapy to control lymphatic metastasis may improve survival. The work described in this thesis focuses on the development of a microparticulate lymphatic targeting system, which can be applied as an adjuvant therapy in the control of lymphatic metastasis in lung cancer. The study shows that intrapleural administered colloidal particulates are predominantly taken up by regional lymphatic tissue in rat models including healthy rats, rats bearing orthotopic lung tumours and rats following pneumonectomy. The effect of particle size on lymphatic particle distribution was examined by intrapleural administration of 111In-aminopolystyrene beads. Approximately 2 µm is a suitable size for intrapleural lymphatic targeting. Biodegradable polylactide-co-glycolide (PLGA) microparticles containing the anticancer agent paclitaxel (PTX) were subsequently formulated in the desired size by spray drying. PLGA-PTX microspheres were incorporated into a biodegradable and biocompatible gelatin sponge matrix to form an implantable lymphatic targeted drug delivery system. The system was characterized in vitro and its lymphatic targeting ability was examined in vivo. Fluorescence labeled microspheres embedded within the sponge were selectively taken up by regional lymphatics as the sponge matrix disintegrated following intrapleural implantation. A pharmacokinetic study showed that the total PTX exposure in lymphatic tissue was dramatically higher than that achieved through intravenous administration. The peak plasma drug concentration, which governs systemic toxicity, was significantly reduced. The low but persistent detection of plasma PTX indicates that PTX was control released from the system after intrapleural implantation. In a therapeutic efficacy study performed in the H460 orthotopic lung cancer model, gelatin sponges containing PLGA-PTX microspheres were placed in the pleural cavity as an adjuvant treatment after surgical resection of the primary lung tumour. Trans-lymphatic chemotherapy resulted in a significantly lower incidence of lymphatic tumour recurrence (20%) compared to no treatment and placebo control animals (100%). PLGA-PTX microspheres were seen in regional lymphatic tissue over 4 weeks after the sponge placement. It is concluded that the trans-lymphatic targeting drug delivery system described in this thesis may improve the control of lymphatic metastasis in lung cancer.

Lymph node metastasis is a critical prognostic factor for lung cancer. Effective therapy to control lymphatic metastasis may improve survival. The work described in this thesis focuses on the development of a microparticulate lymphatic targeting system, which can be applied as an adjuvant therapy in the control of lymphatic metastasis in lung cancer. The study shows that intrapleural administered colloidal particulates are predominantly taken up by regional lymphatic tissue in rat models including healthy rats, rats bearing orthotopic lung tumours and rats following pneumonectomy. The effect of particle size on lymphatic particle distribution was examined by intrapleural administration of 111In-aminopolystyrene beads. Approximately 2 µm is a suitable size for intrapleural lymphatic targeting. Biodegradable polylactide-co-glycolide (PLGA) microparticles containing the anticancer agent paclitaxel (PTX) were subsequently formulated in the desired size by spray drying. PLGA-PTX microspheres were incorporated into a biodegradable and biocompatible gelatin sponge matrix to form an implantable lymphatic targeted drug delivery system. The system was characterized in vitro and its lymphatic targeting ability was examined in vivo. Fluorescence labeled microspheres embedded within the sponge were selectively taken up by regional lymphatics as the sponge matrix disintegrated following intrapleural implantation. A pharmacokinetic study showed that the total PTX exposure in lymphatic tissue was dramatically higher than that achieved through intravenous administration. The peak plasma drug concentration, which governs systemic toxicity, was significantly reduced. The low but persistent detection of plasma PTX indicates that PTX was control released from the system after intrapleural implantation. In a therapeutic efficacy study performed in the H460 orthotopic lung cancer model, gelatin sponges containing PLGA-PTX microspheres were placed in the pleural cavity as an adjuvant treatment after surgical resection of the primary lung tumour. Trans-lymphatic chemotherapy resulted in a significantly lower incidence of lymphatic tumour recurrence (20%) compared to no treatment and placebo control animals (100%). PLGA-PTX microspheres were seen in regional lymphatic tissue over 4 weeks after the sponge placement. It is concluded that the trans-lymphatic targeting drug delivery system described in this thesis may improve the control of lymphatic metastasis in lung cancer.

<p>We present a new x-ray imaging technique, Correlation Imaging (CI), for improved breast and lung cancer detection. In CI, multiple low-dose radiographic images are acquired along a limited angular arc. Information from unreconstructed angular projections is directly combined to reduce the effect of overlying anatomy - the largest bottleneck in diagnosing cancer with projection imaging. In addition, CI avoids reconstruction artifacts that otherwise limit the performance of tomosynthesis. This work involved assessing the feasibility of the CI technique, its optimization, and its implementation for breast and chest imaging.</p><p>First a theoretical model was developed to determine the diagnostic information content of projection images using a mathematical observer. The model was benchmarked for a specific application in assessing the impact of reduced dose in mammography. Using this model, a multi-factorial task-based framework was developed to optimize the image acquisition of CI using existing low-dose clinical data. The framework was further validated using a CADe processor. Performance of CI was evaluated on mastectomy specimens at clinically relevant doses and further compared to tomosynthesis. Finally, leveraging on the expected improvement in breast imaging, a new hardware capable of CI acquisition for chest imaging was designed, prototyped, evaluated, and experimentally validated.</p><p>The theoretical model successfully predicted diagnostic performance on mammographic backgrounds, indicating a possible reduction in mammography dose by as much as 50% without adversely affecting lesion detection. Application of this model on low-dose clinical data showed that peak CI performance may be obtained with 15-17 projections. CAD results confirmed similar trends. Mastectomy specimen results at higher dose revealed that the performance of optimized breast CI may exceed that of mammography and tomosynthesis by 18% and 8%, respectively. Furthermore, for both CI and tomosynthesis, highest dose setting and maximum angular span with an angular separation of 2.75o was found to be optimum, indicating a threshold in the number of projections per angular span for optimum performance. </p><p>Finally, for the CI chest imaging system, the positional errors were found to be within 1% and motion blur to have minimal impact on the system MTF. The clinical images had excellent diagnostic quality for potentially improved lung cancer detection. The system was found to be robust and scalable to enable advanced applications for chest radiography, including novel tomosynthesis trajectories and stereoscopic imaging.</p> / Dissertation

The ultimate objective of this research was to develop a low cost, reliable system that would lead to early detection of lung cancer. Tests involved the quantitation of gaseous metabolic emissions from immortalized lung cancer cell lines in order to correlate the chemical markers to be of cancerous origin. The specific aims of the project were the study of gas emissions in selected cancer cell lines and identification of volatile organic compounds (VOCs) in them. Disadvantages of earlier studies were that the measurements were not real time or state specific so that molecular identification was often inconclusive. Furthermore the methods of study used in the past were not quantitative, which limited their practicality for medical applications. We felt the need to prove or disprove these earlier results using a new technique. The method we proposed is different and unique when compared to previous methods because cell lines have not been studied extensively for cancer markers. We have studied cancer cell lines which are adherent, immortalized cultures originating from primary tumors obtained from patients with no prior treatment for lung cancer. We have used an alternative method for the spectrometric analysis and quantitation of the selected chemical markers. The pre-concentration method involved a Purge and Trap unit with a thermal desorber where the vapor concentration was enhanced. The concentrated head space gases were analyzed using a Gas Chromatograph ?? Mass Spectrometer setup. This setup eliminated the bulky apparatus used in earlier studies. It is simpler in design and more comprehensive so that external factors such as patient??s diet, habitat and lifestyle do not contribute to our study of recognition of cancer markers. Based on the results obtained in the above experiments, a more comprehensive, inexpensive study of lung cancer related markers could be made. The first section, after giving an introduction to lung cancer, goes on to explain the background work done by other researchers on cancer. The third section gives a detailed explanation of the experimental setup. This is followed by all the tests conducted with corresponding results. The final section deals with the conclusions drawn from all experiments.

The objectives of this research were to test treatment and survival differences between women and men with lung cancer as there is minimal investigation in the literature. Three research questions were developed with statistical testing for gender differences based on similar cancer type, stage, treatment assignment and survival. Data for 44,863 primary lung cancer cases were collected from eight U.S. state-based cancer registries to investigate the research questions. The lung cancer incidence data included the morphological cell-types of adenocarcinoma (AC); squamous cell carcinoma (SCC); large cell carcinoma (LCC) and small cell carcinoma (SCC). Stage, grade, treatment type, as well as, individual characteristics such as gender, age at diagnosis, marital status at diagnosis and race were other variables obtained to be included in the statistical models. Reporting the overall effect for lung cancer gender specific treatment differences or survival has not been demonstrated in the literature to the author's knowledge. By convention, main effects and interaction effects are reported in the literature; without including an evaluation the overall effect of a variable on the outcome, possible misinterpretations could be made. For example, utilizing the Cox's Proportional Hazards model when the interaction effect of gender and treatment type received was examined, females were at an increased risk for death by as much 29% as compared to males (HR = 1.18, 95% CI 1.09 - 1.29). But when the gender effect on survival was assessed, there was an increase in females survivorship as compared to males by as much as 28% (HR = 0.80, 95% CI 0.72 - 0.97 ). In conclusion, by using a unique statistical approach, statistically significant Odds Ratios and Hazard Ratios were demonstrated for the research data set when the overall interaction effect on the outcome was examined. Recommendations to health care practitioners include adhering to current guidelines, e.g. American Medical Association, for lung cancer treatments. Standard treatment protocols were not always followed for early stage disease, e.g. females versus males with stage I lung cancer were 1.71 times more likely to receive chemotherapy in combination with radiation therapy versus a standard first treatment course of surgery (OR = 1.71, 95% CI 1.06 - 2.78). Also, depending on the lung cancer morphology and lung cancer treatment, females as compared to males could exhibit an increase in survivorship by as much as 28%. To improve the results of medical care decisions for lung cancer, clinicians may find the information presented in this study useful and encourage further research on which treatment increases survival for both men and women.

Ventilation imaging using 4D-CT is a convenient and cost effective functional imaging methodology which might be of value in radiotherapy treatment planning to spare functional lung volumes. To calculate ventilation imaging from 4D-CT we must use deformable image registration (DIR). This study validates the DIR methods and investigates the dependence of calculated ventilation on DIR methods and ventilation algorithms. The first hypothesis is if ventilation algorithms are robust then they will be insensitive to the precise DIR used provided the DIR is accurate. The second hypothesis is that the change in Houndsfield Unit (HU) method is less dependent on the DIR used and depends more on the CT image quality due to the inherent noise of HUs in normal CT imaging. DIR of the normal end expiration and inspiration phases of the 4D-CT images was used to correlate the voxels between the two respiratory phases. All DIR algorithms were validated using a 4D pixel-based and point-validated breathing thorax model, consisting of a 4D-CT image data set along with associated landmarks. Three different DIR algorithms, Optical Flow (OF), Diffeomorphic Demons (DD) and Diffeomorphic Morphons (DM), were retrospectively applied to the same group of 10 esophagus and 10 lung cancer cases all of which had associated 4D-CT image sets that encompassed the entire lung volume. Three different ventilation calculation algorithms were compared (Jacobian, ΔV, and HU) using the Dice similarity coefficient comparison. In the validation of the DIR algorithms, the average target registration errors with one standard deviation for the DIR algorithms were 1.6 ± 0.7 mm, maximum 3.1 mm for OF, 1.3 ± 0.6 mm, maximum 3.3 mm for DM, 1.3 ± 0.6 mm, maximum 2.8 mm for DD, indicating registration errors were within 2 voxels. Dependence of ventilation images on the DIR was greater for the ΔV and the Jacobian methods than for the HU method. The Dice similarity coefficient for 20% of low ventilation volume for ΔV was 0.33 ± 0.03 between OF and DM, 0.44 ± 0.05 between OF and DD and 0.51 ± 0.04 between DM and DD. The similarity comparisons for Jacobian was 0.32 ± 0.03, 0.44 ± 0.05 and 0.51 ± 0.04 respectively, and for HU 0.53 ± 0.03, 0.56 ± 0.03 and 0.76 ± 0.04 respectively. Dependence of ventilation images on the ventilation method used showed good agreement between the ΔV and Jacobian methods but differences between these two and the HU method were significantly greater. Dice similarity coefficient for using OF as DIR was 0.86 ± 0.01 between ΔV and Jacobian, 0.28 ± 0.04 between ΔV and HU and 0.28 ± 0.04 between Jacobian and HU respectively. When using DM or DD as DIR, similar values were obtained when comparing the different ventilation calculation methods. The similarity values for 20% of the high ventilation volume were close to those found for the 20% low ventilation volume. Mean target registration error for all three DIR methods was within one voxel suggesting that the registration done by either of the methods is quite accurate. Ventilation calculation from 4D-CT demonstrates some degree of dependency on the DIR algorithm employed. Similarities between ΔV and Jacobian are higher than between ΔV and HU and Jacobian and HU. This shows that ΔV and Jacobian are very similar, but HU is a very different ventilation calculation method.