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Mounting evidence suggests that the superposition of anatomical clutter in x-ray chest radiography poses a major impediment to the detectability of subtle lung nodules. Through decomposition of projections acquired using different x-ray energy spectra, dual-energy (DE) imaging offers to dramatically improve lung nodule conspicuity. The development of a high-performance DE chest imaging system is reported, with design and implementation guided by fundamental imaging performance metrics. Analytical and experimental studies of imaging performance guided the optimization of key acquisition technique parameters, including x-ray filtration, allocation of dose between low- and high-energy projections, and peak-kilovoltage selection. To minimize anatomical misregistration between images, a cardiac gating system was designed and implemented to direct x-ray exposures to within the quiescent period of the heart cycle. The instrumentation and optimal imaging techniques have been incorporated in a DE imaging prototype system now deployed in a clinical study to evaluate the diagnostic performance of DE imaging.

Mounting evidence suggests that the superposition of anatomical clutter in x-ray chest radiography poses a major impediment to the detectability of subtle lung nodules. Through decomposition of projections acquired using different x-ray energy spectra, dual-energy (DE) imaging offers to dramatically improve lung nodule conspicuity. The development of a high-performance DE chest imaging system is reported, with design and implementation guided by fundamental imaging performance metrics. Analytical and experimental studies of imaging performance guided the optimization of key acquisition technique parameters, including x-ray filtration, allocation of dose between low- and high-energy projections, and peak-kilovoltage selection. To minimize anatomical misregistration between images, a cardiac gating system was designed and implemented to direct x-ray exposures to within the quiescent period of the heart cycle. The instrumentation and optimal imaging techniques have been incorporated in a DE imaging prototype system now deployed in a clinical study to evaluate the diagnostic performance of DE imaging.

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.

1) Hipòtesi El càncer de pulmó és la neoplàsia més freqüent en el moment actual i és la primera causa de mort per càncer en el món. Aproximadament el 85 % dels pacients presenten CPCNP. Inclús els casos identificats en estadis precoços i en què es pot realitzar un tractament quirúrgic curatiu, tenen un risc de recaiguda global del 60%. A pesar dels avenços en el tractament de la malaltia realitzats durant els darrers anys, la supervivència global continua essent molt baixa, al voltant del 15 % als 5 anys. És per aquest motiu que es fa necessària la troballa de biomarcadors que puguin predir el risc de recaiguda, una vegada realitzada la resecció quirúrgica. Aquests biomarcadors ens permetrien estratificar els pacients pel seu risc i individualitzar el seguiment i el tractament de la malaltia, especialment en els pacients en estadi I que no reben cap tractament adjuvant. La majoria de pacients amb CPNCP són fumadors i durant els últims anys s’ha observat que variants polimòrfiques d’enzims relacionats amb la metabolització de carcinògens del tabac, en gens de reparació del DNA o en gens relacionats amb l’expulsió de carcinògens de la cèl•lula s’han associat a un risc augmentat de càncer de pulmó. No obstant, l’impacte d’aquests SNPs en la recaiguda del CPCNP no ha estat establert. Si tenim en compte que els SNPs són característiques innates dels individus, podríem pensar que la seva presència podria tenir un efecte també en la recaiguda de pacients fumadors que han desenvolupat un càncer de pulmó, ja que les diferencies genotípiques es podrien traduir en diferències en el procés de malignització mediat pel tabac. Aquests SNPs doncs podrien seleccionar-nos individus que han tingut un risc incrementat de càncer de pulmó i que, una vegada realitzat un tractament local quirúrgic, podrien tenir un risc augmentat de recidivar. Per altre banda recentment els miRNAs han esdevingut com a elements claus en el procés de carcinogènesi. Els miRNAs són molècules que controlen la diferenciació i el creixement cel•lular i en diferents tipus tumorals s’associen a l’evolució de la malaltia. Polimorfismes en gens relacionats amb miRNAs implicats en càncer o en els propis miRNAs poden jugar un paper en la progressió tumoral. Més concretament, polimorfismes en gens de la via de processament dels miRNAs o en la seqüència del pri-miRNA o pre-miRNA poden afectar als nivells finals de determinats miRNAs. A més, polimorfismes en les seqüències d’anclatge de miRNAs poden reprimir la inhibició dels gens diana per aquests i per tant, afectar la seva funció. En definitiva, polimorfismes relacionats amb els miRNAs podrien modificar el risc de recaiguda després de la cirurgia en pacients amb CPCNP. Basant-nos en aquestes hipòtesis ens plantegem els següents objectius: 2) Objectiu general Trobar biomarcadors de recaiguda i supervivència global en pacients quirúrgics de CPCNP basant-nos en l’estudi de les variants polimòrfiques del DNA. 3) Objectius específics 1. Analitzar, en una sèrie retrospectiva de pacients amb CPCNP quirúrgics, polimorfismes en gens relacionats amb el metabolisme del tabac (fase I i fase II), gens de reparació del DNA i en el gen MDR1/ABCB1 en pacients amb hàbit tabàquic. 2. Analitzar polimorfismes presents en regions del DNA codificants per miRNAs relacionats amb proliferació, apoptosi, angiogènesi i cicle cel•lular en una sèrie retrospectiva de pacients amb CPCNP quirúrgics. 3. Analitzar polimorfismes presents en els gens que intervenen en el procés de maduració dels miRNAs en una sèrie retrospectiva de pacients amb CPCNP quirúrgics. 4. Analitzar polimorfismes localitzats al lloc d’anclatge del miRNA al mRNA en una sèrie retrospectiva de pacients amb CPCNP quirúrgics. 5. Establir si existeix relació entre els diferents genotips i el temps a la recaiguda o la supervivència global.

Bakgrund: Lungcancer är en sjukdom som har en dålig prognos och där ett stort antal människor insjuknar årligen. Det är en sjukdom som leder till många och svåra symtom vilket skapar stort lidande. Syfte: Syftet med denna studie var att beskriva patienters upplevelser av att leva med lungcancer i det dagliga livet. Metod: En litteraturbaserad studie genomfördes med en kvalitativ ansats. Tolv vetenskapliga artiklar granskades och analyserades enligt en modell för en litteraturbaserad studie. Resultat: Ur resultatet identifierades sex kategorier: leva med osäkerhet, stigma och skuld, upplevelser av sjukdomsrelaterade symtom, en förändrad självkänsla, att få stöd och bli bekräftad samt pendla mellan hopp och förtvivlan. Diskussion: Det fanns ett behov hos patienterna av att leva så självständig som möjligt, där det sociala stödet och stödet från vårdpersonal var avgörande för att de skulle klara av det. Stöd överhuvudtaget var viktigt för att patienterna skulle kunna hantera de flesta situationer. Genom att sjuksköterskan får kunskap om patienters upplevelser av lungcancer kan patienters lidande lindras med hjälp av stöd från sjuksköterskan. / Background: Lung cancer is a disease with poor prognosis, with many people that falls ill each year. It is a disease which leads to numerous and severe symptoms that create much suffering. Aim: The aim of this study was to describe patients' experiences of living with lung cancer in daily life. Methods: A literature study was conducted with a qualitative approach. Twelve scientific articles were reviewed and analyzed according to a model for a literature study. Results: Six categories were identified: live with uncertainty, stigma and guilt, experience of disease-related symptoms, a changed self-esteem, to get support and be confirmed and thrown between hope and despair. Discussion: There was a need for patients to live as independent as possible, social support and the support from health professionals was crucial for them to cope with it. Support overall was important for patients to be able to handle most situations. By acquiring knowledge about patients' with lung cancers experiences the nurse can be a better support for the patient in order to alleviate patients suffering.

Activated epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations characterize molecular subgroups of non-small cell lung cancer (NSCLC) and have a strong predictive value for response to EGFR inhibitor therapy. Recently, EGFR mutation testing was included in the diagnostic algorithm of NSCLC. However, there is a controversy about the clonal stability of the mutation during the progression of the disease. The aim of this study was to analyze NSCLC tumor tissue for the presence of both EGFR and KRAS mutations in morphologically different parts of the primary tumor. Formaldehyd fixed and paraffin embedded lung cancer specimens from primary resected NSCLC patients were selected; five cases harboring EGFR and five with KRAS mutations. From each tumor, three morphologically different tumor sites were manually micro-dissected and analyzed for the presence of EGFR and KRAS mutations. Additionally, normal lung tissue at a distance from the primary tumor as well as in close vicinity was tested.The EGFR and KRAS status were consistent in the three different areas of the primary tumors of all ten cases. EGFR as well as KRAS mutations were as well detectable in close and in some distant normal lung parenchyma in 7 of 10 analyzed patient samples. In conclusion, we found consistent KRAS and EGFR mutation status in primary NSCLC tumors. This finding is of importance for clinical practice, because it indicates that any part of the tumor, independent of intratumoral histological pattern, is representative for EGFR and KRAS mutation testing.

The Reelin gene located on the human chromosome region 7q22, encodes an extracellular matrix glycoprotein, a ligand for ApoER2 and low-density lipoprotein receptors (LDL) Receptor, is required for mediating the correct positioning of neurons during embryonic brain development1. In the current study, first we applied RT-PCR and immunohistochemistry analysis (IHC) analysis on tissue microarrays (TMA) to verify the Reelin expression patterns in a variety of adult tissues, suggesting additional roles for Reelin in stabling the cyto-architecture and controlling the remodeling of many organs during development. Second, we report the Reelin expression status in tumorigenesis. We discover that the loss of Reelin expression is associated with multiple types of cancers, including more than 80% of both breast and colorectal cancers. Interestingly, our study also found suspension small cell lung cancer (SCLC) cell lines that grow as large aggregates retained high Reelin expression, whereas attached non small cell lung cancer cultures do not. That may imply the Reelin expression may be also associated with cell culture morphology and growth characteristics in the in vitro culture system for lung cancers. Our results here also demonstrated that epigenetic silencing of Reelin expression by DNA hypermethylation in tumors directly correlates with loss of Reelin expression in many cancers. Reelinmethylation was reversed and expression restored by treating tumor cell lines with the demethylating agent 5-aza-2-deoxycytidine. In conclusion, from the molecular basis of Reelingene inactivation in human cancer here, we propose that the Reelinvariation in more than 80% of breast and colorectal cancers makes it a significant novel tumor marker.

Tyrosine kinases regulate fundamental signal pathways in cells including cell proliferation, motility, and differentiation. The kinase activity is tightly controlled in normal cells but is usually excessive activated in cancers. Several tyrosine kinase inhibitors are used in cancer therapies nowadays. Our novel tyrosine kinase inhibitor, 1J-309, is a multiple kinase inhibitor that targets several receptors including vascular endothelial growth factor receptors (VEGFRs). We find 1J-309 dramatically reduces cell proliferation of VEGFR3+/VEGF-C+ A549 human lung cancer cells by decreasing the expression of CDK1 and cyclin B1 following growth arrest at G2/M phase. After long term drug treatment, 1J-309 causes cell death. Moreover, 1J-309 represses CDK1 expression at early stage but it does not change CDK1 RNA expression and protein stability. Additionally, 1J-309 significantly decreases the migration ability of A549 cells. 1J-309 also reduces gelatin-related invasion potency. The AKT and p38 MAPK activity are significantly repressed by 1J-309 and it dramatically drives the expression of tumor suppressor, p53, at low-dose treatment. Our results demonstrate that 1J-309 significantly attenuates cell proliferation by inducing G2/M growth arrest, reduces the invasion and migration potency, and promotes a dramatic increase of p53 in A549 cells.

Several computer-aided diagnostic (CAD) methods for solitary pulmonary nodules (SPNs) have been proposed, which can be divided into two major categories: (1) the morphometric CT method, and (2) the perfusion CT method. The first goal of this work is to introduce a neural network-based CAD method of lung nodule diagnosis by combining morphometry and perfusion characteristics by perfusion CT. The proposed approach has the following distinctive features. Firstly, this work develops a very efficient semi-automatic procedure to segment entire nodules. Secondly, reliable nodule classification can be achieved by using only two time-point perfusion CT feature measures (precontrast and 90 s). This greatly reduces the amount of radiation exposure to patients and the data processing time. As demonstrated in previous work, classification tuberculomas from malignancies has been considered to be a challenging task. However the diagnosis accuracy for tuberculomas reaches 92.9% by applying the proposed CAD method. Another goal of this work is, by investigating the relative merits of 2D and 3D methods, to develop a two-stage approach that combines the simplicity of 2D and the accuracy of 3D methods. Experimental results show statistically significant differences between the diagnostic accuracy of 2D and 3D methods. The results also show that with a very minor drop in diagnostic performance the two-stage approach can significantly reduce the number of nodules needed to be processed by the 3D method and thus alleviates the computational demand.