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Au travers d’études cliniques et biologiques, de méta-analyses et de revues systématiques de la littérature, nous avons étudié les CBNPC de stade III sur le plan thérapeutique et cherché des facteurs pronostiques pour la survie dans le but d’améliorer la classification internationale et, à terme, de permettre une meilleure prise en charge des patients inclus dans ce groupe hétérogène de tumeurs. Dans le cadre d’essais randomisés, nous avons montré qu’un abord multimodal et multidisciplinaire permettait d’améliorer le pronostic des patients atteints d’un CBNPC de stade III. Le traitement des tumeurs non résécables implique une combinaison de chimiothérapie et de radiothérapie, dont l’administration concomitante doit être proposée aux patients aptes à la tolérer. La chimiothérapie doit être incluse dans le schéma thérapeutique des tumeurs potentiellement résécables. Elle permet une résection chirurgicale complète chez des patients sélectionnés dont la tumeur était initialement non résécable. Nous avons déterminé que des caractéristiques cliniques (l’indice de performance et l’âge), biologiques (les taux sanguins de polynucléaires neutrophiles, d’hémoglobine et de plaquettes, la bilirubinémie) et propres à la tumeur (l’extension locale [T3-4] et ganglionnaire [N3]) avaient une valeur pronostique indépendante pour la survie. Ceci nous a permis d’aboutir à une proposition de modification de la classification internationale concernant les CBNPC de stade III. Bien que pris individuellement, les facteurs biologiques que nous avons étudiés (p53, EGF-R, TTF-1, Mdm2) n’aient pas de valeur pronostique pour la survie, nous avons montré que la combinaison EGF-R+/TTF1- était un facteur pronostique indépendant en analyse multivariée pour la survie spécifique au cancer bronchique. Nous avons finalement évalué le rôle pronostique de la tomodensitométrie par émission de positrons et de la mesure semi-quantitative de captation du 18F-FDG (SUV) sur la survie des patients atteints de CBNPC et montré qu’un SUV élevé était un facteur de mauvais pronostic pour la survie.

Colorectal cancer (CRC) is one of the most common causes of death from malignant disease. Nevertheless, no ideal screening method exists and there is a lack of prognostic and predictive factors to support clinical decisions and to aid the development of a more individualized treatment for patients with CRC. The aim of this thesis was to investigate early detection, prognostic and predictive factors of CRC. In the first paper, a novel method to collect cells for DNA quantification from the rectal mucosa was investigated. The sensitivity and specificity of this test to detect CRC or any pathology in colon and rectum were ultimately too low to be acceptable. In the second paper, the prognostic value of growth differentiation factor 15 (GDF 15) was evaluated in patients curatively operated for colorectal cancer. GDF 15 expression was demonstrated to be associated with a negative prognosis in patients with stages I-III and III disease. In the third paper, the prognostic value of BRAF, PIK3CA KRAS and MSI was evaluated in a cohort of patients with CRC stratified by disease and recurrence. The results indicated that patients with CRC stage III without recurrence have a higher frequency of BRAF mutation compared to stage III patients with recurrence. In the fourth paper, histopathological predictors of pathologic complete response (pCR) as well as the association between pre-treatment carcinoembryonic antigen (CEA) levels and pCR in non-smoking and smoking patients receiving preoperative chemo-radiotherapy for rectal cancer were evaluated. Only in non-smokers was a low CEA level significantly associated with pCR, suggesting that the predictive value of CEA for pCR in rectal cancer in smokers can be limited. In sum, this research has investigated a new method for CRC detection and further evaluated the clinical use of prognostic and predictive markers in CRC.

Because of the failure so far to find effective treatment for patients with advanced stages of melanoma, increasing efforts have been made to find prognostic factors identifying patients in the risk zone for development of metastasis. This thesis investigates the prognostic powers of a few selected serological and immunohistochemical biomarkers. In the first and second study, patients operated on for localized malignant melanoma were investigated regarding the prognostic impact of angiogenic serological markers and circulating levels of S100. We concluded that the S100 assays, especially S100BB, are potential biomarkers in patients with malignant melanoma, correlated to both survival and disease free survival. However, no such conclusion could be drawn from the first study, where we found no correlation to survival and investigated angiogenic markers. In the third and fourth study four new potential immunohistochemical biomarkers where investigated in collaboration with the Swedish Human Protein Atlas Program, and those where TRP-1, galectin-1, DLG5 and syntaxin-7. We found that TRP-1 correlated inversely with tumor stage and galectin-1 correlated to Ki-67. DLG5 showed a significant inverse correlation to Ki67 and the expression of STX7 was inversely correlated to tumor stage, suggesting that decreased expression is associated with more aggressive tumors. None of the investigated markers in study III and IV correlated with disease free survival or overall survival. In the fifth and last study, we examined the expression of SOX10, a transcription factor, in different melanocytic lesions. Also, a proliferation assay was carried out in a human melanoma cell line. The results reveal the presence of SOX10 in different melanocytic lesions, with a weak inverse correlation to survival and a significant inverse correlation to T-stage. A significant decrease in proliferation rate for SOX10 silenced cells was found and our data also suggests an increased migratory response in SOX10 silenced cells.

This Individual Research Project (IRP) is the extension research to the group design project (GDP) work which the author has participated in his Msc programme. The GDP objective is to complete the conceptual design of a 200-seat, flying wing civil airliner—FW-11. The next generation aircraft design demands higher reliability, safety and maintainability. With the development of the vehicle hydraulic system technology, the equipment and systems become more and more complex, their reliability and maintenance become more difficult for designers, manufacturers and customers. To improve the mission reliability and reduce life cycle cost, there is strong demand for the application of health management technology into airframe system design. In this research, the author introduced diagnostic, prognostic and health management (DPHM) concept into the aircraft hydraulic power system development. As a brand new technology, it is a challenge to apply the DPHM techniques to on-board system. Firstly, an assumed hydraulic power system was designed for FW-11 by the author and used as the case in his IRP research. Then the crucial components and key parameters needed to be monitored were obtained based on Function Hazard Analysis and Failure Modes Effects Analysis of this system. The writer compared a few diagnostic and prognostic methods in detail, and then selected suitable ones for a hydraulic power system. A diagnostic process was applied to the hydraulic power system using a Case-based reasoning (CBR) approach, whilst a hybrid prognostic method was suggested for the system. After that, a diagnostic, prognostic and health management (DPHM) architecture of the hydraulic power system was designed at system level based on the diagnostic and prognostic research. The whole research work provided a general and practical instruction for hydraulic system design by means of DPHM application.

The Zapatista movement of southern Mexico has received little analytical attention focused on the myriad of writings issued by the movement. To help fill this gap, this study uses David Snow and Robert Benford’s concept of framing as a theoretical basis, and performs a systematic and discursive analysis of the communiqués issued by the Zapatista movement in order to understand how the movement framed itself over its thirteen-year existence. Communiqués were coded by noting evocations of the diagnostic frames of corrupt government, violent government, and neoliberal government and in terms of prognostic framing, general democracy, small-scale democracy, and revolutionary frames. This research concludes that the prognostic frame of general democracy was very high in the initial years of the movement, and shifted towards the small-scale democracy frame after the election of Vicente Fox in 2000. The diagnostic frames dealt with in this research showed a slight downward trend as Mexico democratized, but there is significant inter-year variation in the prevalence diagnostic frames that seems to be related to specific acts of government repression, or other government actions. This research also concludes that a portion of the EZLN’s success and long existence can be attributed to the movement’s ability to modify its diagnostic and prognostic frames to match the changing political and societal context that the movement existed in.

Follicular lymphoma (FL) is an attractive model for discovering biomarkers and elucidating mechanisms of tumour progression. We hypothesized that alterations in the expression of proteins with known roles in cancer biology and hematological cells might correlate with clinical outcome and thereby shed light on biological mechanisms. Sections from a tissue microarray (TMA) containing FL samples from 67 patients were immunostained for candidate biomarkers, including p53, p16INK4a, Bcl-2, Bcl-6, MUM1, PML, phospho-ERK, and p27Kip1. The Kaplan-Meier method and log-rank test were used to identify markers that correlate significantly (p<0.05) with overall survival (OS). The chi-squared or Fisher exact test were used to examine associations between histological markers and baseline clinical features, including the Follicular Lymphoma International Prognostic Index (FLIPI) score. Expression of p16INK4a or p53, or absent CD10 expression correlated with poor survival. Patients with p16INK4a-negative tumours had a median OS of 13.4 years compared to 8.3 years for those with p16INK4a-positive tumours (p=0.006). Expression of p16INK4a was significantly associated with low hemoglobin, elevated serum lactate dehydrogenase (LDH), high histological grade, high cell proliferation index, presence of associated diffuse large B-cell lymphoma (DLBCL) and high-risk FLIPI classification. Our observation of a positive association between p16INK4a expression and indicators of tumour aggressiveness is novel and perhaps surprising since loss of the INK4a tumour suppressor gene is one of the most frequently observed lesions in human cancers, including lymphoma. Expression of p16INK4a may be part of a cellular response to unidentified pro-mitotic mutations, such as deleterious mutations of the RB tumour suppressor gene, associated with more aggressive instances of FL. Immunostaining FL diagnostic biopsies for expression of p16INK4a may serve as an informative prognostic biomarker to aid clinicians managing FL patients. / Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2008-07-04 15:55:16.121

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Orientador: Ricardo de Souza Cavalcante / Resumo: Introdução. A candidemia tem-se tornado cada vez mais frequente nos hospitais e apresentado elevada mortalidade. Conhecer a epidemiologia e os fatores prognósticos permite melhor manejo clínico desta infecção. Diante disto, este estudo teve por objetivo avaliar a incidência da candidemia em um hospital de ensino durante os últimos anos, a mortalidade, a prevalência das espécies causadoras da infecção, bem como os fatores prognósticos. Métodos. Este foi um estudo de coorte não concorrente, com pacientes atendidos no Hospital das Clínicas da Faculdade de Medicina de Botucatu (HCFMB), que apresentaram diagnóstico de candidemia durante sua internação, entre os anos de 2012 e 2019. Os dados clínicos foram obtidos a partir do prontuário médico. Para a avaliação dos fatores associados ao prognóstico, em análise univariada e múltipla, foi utilizado o modelo de Regressão Proporcional de Cox. Foram consideradas significativas as variáveis com valores de p inferiores a 0,05. Resultados. Ocorreram 314 episódios de candidemia em 288 pacientes. A taxa de incidência foi de 1,66/1000 admissões. A espécie mais prevalente foi Candida albicans (38,8%), seguida de complexo C. parapsilosis (20,4%), C. tropicalis (15,3%), C. glabrata (10,8%) e C. krusei (2,5%). Na população pediátrica houve predomínio de complexo C. parapsilosis (p<0,0001) e C. glabrata nos adultos (p=0,002). A taxa de mortalidade em 30 dias foi de 43,4%, sendo maior em adultos do que pacientes pediátricos (19,3% vs 54,0%; p<0,01)... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction. Candidemia has become increasingly frequent in hospitals and has shown high mortality. Knowing the epidemiology and prognostic factors allows better clinical management of this infection. In view of this, this study aimed to evaluate the incidence of candidemia in a teaching hospital during the past few years, mortality, the prevalence of species causing the infection, as well as prognostic factors. Methods. Non-concurrent cohort study was carried out, with inpatients at the Hospital das Clínicas, Faculdade de Medicina de Botucatu (HCFMB), who presented a diagnosis of candidemia during their hospitalization, between the years 2012 and 2019. The clinical data were obtained from the medical records. For the assessment of factors associated with prognosis, in univariate and multiple analysis, the Cox Proportional Regression model was used. Variables with p values below 0.05 were considered significant. Results. There were 314 episodes of candidemia in 288 patients. The incidence rate was 1.66 / 1000 admissions. The most prevalent species was Candida albicans (38.8%), followed by C. parapsilosis complex (20.4%), C. tropicalis (15.3%), C. glabrata (10.8%) and C. krusei (2.5%). In the pediatric population, there was a predominance of the C. parapsilosis complex (p <0.0001) and C. glabrata in adults (p=0.002). The 30-day mortality rate was 43.4%, being higher in adults than pediatric patients (19.3% vs 54.0%; p<0.01). Independent factors of mortality were liver cirrhos... (Complete abstract click electronic access below) / Mestre

Despite mounting evidence, a question still exists as to the true clinical relevance of varying degrees of malnutrition, the role of currently measured nutritional parameters in identifying malnutrition and predicting clinical risk in individual patients, and the efficacy of nutritional therapy. This study was designed to document the usefulness of the Prognostic Nutritional Index (PNI) as a predictor of clinical course. The nutritional assessments and clinical records of 328 subjects in a Veterans Administration Hospital were reviewed, PNI and complication rates were determined for each of the subjects, and the data statistically analyzed. The PNI was found to be a useful indicator of malnutrition and predictor of clinical course. The PNI appeared to be a more sensitive index of clinical outcome than did comparison of individual nutritional parameters to accepted norms, although it accounted for only 17% of the information needed to predict clinical course perfectly.