Made available in DSpace on 2014-07-29T15:25:19Z (GMT). No. of bitstreams: 1 Tese Orlando M da Mota.pdf: 619245 bytes, checksum: 8c9d25ddb6ce5f94a96176a085b305f1 (MD5) Previous issue date: 2012-05-10 / Context and Objectives: This thesis was divided into two parts. In the first one risk factors for esophageal cancer were analyzed using data from a case and control study. In the second part the survival of the esophageal cancer patients from the first study was analyzed. The aim of this study was to evaluate the risk factors for esophageal cancer in an area where the incidence is low and survival of patients undergoing treatment in a low-volume hospital. Methods: This is a case-control study hospital based. The analysed variables were: sociodemographic data, habits, (tobacco and alcohol). The sample was analyzed using the chi-square test, Mann-Whitney test and Mantel-Haenszel approach for multivariate analysis. The strength of the risk was calculated using odds ratios (OR) with significance defined at 5% and 95% confidence intervals. Results: It was analysed 99 cases of esophageal cancer and 223 controls. The risk of esophageal cancer was higher in patients &#8805; 55 years (OR = 1.95; P= 0.01). Patients from rural areas had almost five times high risk in comparison with urban. (OR 4.9; P < 0.001). Smoking was a risk factor among cases (OR = 3.8; P < 0.001), exposure to smoke from wood stoves (OR = 4.42; P < 0.001) as well as frequent consumption of apples and pears OR 0,27 (CI95% 0,11 -0,70) and fish OR 0,23 (CI 0,07 0,75), were found as protective factors. We analysed the survival of 99 cases of the esophageal cancer. The average survival was 32.7% for the first year, 25,2% for the second year and 11,0% for the third year. Conclusion: In a region in which the incidence of esophageal cancer is low, the most significant risk factors were living rurally, smoking, exposure to a wood stove and dary products consumption. Survival in patients with esophageal cancer for the third year was 11%, the patients undergoing surgical treatment survival in the third were 19,6%. / Esta pesquisa dividiu-se, em duas partes. Na primeira, avaliou-se os fatores de risco para o câncer do esôfago através de um estudo caso-controle. Na seguinte, analisamos estadiamento e sobrevida dos pacientes portadores de câncer do esôfago selecionados para estudo de casos e controles. Pacientes e Métodos Foram recrutados 99 casos de câncer do esôfago e 223 controles hospitalares não portadores de câncer. Analisaram-se os dados sóciodemográficos, hábitos, estilo de vida e a sobrevida dos 99 pacientes tratados no Hospital Araújo Jorge (HAJ). Os casos e controles foram submetidos à análise estatística pelo teste do qui-quadrado, teste de Mann-Whitney e análise multivariada pelo método Mantel Haenszel. O risco foi calculado por meio da OR com nível de significância de 5% e intervalo de confiança de 95%. Resultados Os pacientes com Idade acima de 55 anos apresentaram maior risco OR 1,95 (IC 95% 1,18 - 3,20 p=0,01), pacientes oriundos de zona rural tiveram OR= 4,9 (IC 95% 2,9 - 8,2 p<0,001). O tabagismo foi fator de risco para os casos OR=3,8 (IC 95%1,9 - 7,8 p<0,001), a exposição à fumaça do fogão à lenha OR=4,42 (IC95% 2,34 - 8,03, p<0,001) também foi significante. Consumo de frutas ricas em vitaminas e minerais (maçãs e peras) OR 0,27 (IC95% 0,11 - 0,70); carne de peixes OR 0,23 (IC95% 0,07 - 0,75) foram fatores de proteção estatisticamente significantes. A análise de sobrevida global dos 99 casos de câncer do esôfago do primeiro ao terceiro ano foram: 32,7%, 25,2% e 11%, respectivamente. Conclusão: Em área de baixa incidência para o câncer do esôfago os fatores de risco mais importantes foram o tabagismo, a procedência rural, a exposição ao fogão à lenha e o consumo de laticínios. A sobrevida global dos pacientes com câncer do esôfago em 3 anos, submetidos a tratamento curativo e paliativo foi 11%, já a sobrevida dos submetidos a tratamento cirúrgico curativo 19,6%.

<p>This thesis reports on the development of a novel comprehensive database (Dragon Database of Genes Implicated in Esophageal Cancer, DDEC) as an integrated knowledge database aimed at representing a gateway to esophageal cancer related data. More importantly, it illustrates how the biocurated genes in the database may represent a reliable starting point for divulging transcriptional regulation, diagnostic markers and the biology related to esophageal cancer.</p>

<p>This thesis reports on the development of a novel comprehensive database (Dragon Database of Genes Implicated in Esophageal Cancer, DDEC) as an integrated knowledge database aimed at representing a gateway to esophageal cancer related data. More importantly, it illustrates how the biocurated genes in the database may represent a reliable starting point for divulging transcriptional regulation, diagnostic markers and the biology related to esophageal cancer.</p>

The main objective of this research was to develop a two-stage optical imaging platform to improve detection of cancer in Barrett’s esophagus (BE). BE caused by chronic reflux and patients with BE are at a higher risk for developing esophageal adenocarcinoma (EAC). However, neoplasia in BE is often unidentifiable under standard endoscopy, and studies have shown nearly half of early cancers can go unidentified by this method. Widefield imaging (resolves ~100 microns) allows efficient surveillance of large BE segments. Two widefield imaging techniques were identified to improve contrast between benign and abnormal lesions during an ex vivo 15 patient feasibility study. Cross-polarized imaging (CPI) reduced specular reflection and improved vascular contrast. Vital-dye fluorescence imaging (VFI) using topically-applied proflavine improved visualization of glandular pattern. Moreover, relevant pathologic features visible during VFI were seen in corresponding histology slides as well as high resolution images of the same sites. Based on these results, a cap-based Multispectral Digital Endoscope (MDE) was designed and built. The MDE can image in three different imaging modes: white light imaging, CPI, and VFI. Modifications to a Pentax EPK-i video processor and a Pentax endoscope were made to incorporate these imaging modes into one system. A 21 patient in vivo pilot study with 65 pathologically correlated sites demonstrated the feasibility of using this system in vivo; image criteria were developed to classify neoplasia with a sensitivity and specificity of 100% and 76% respectively. High resolution imaging (resolves ~2-5 micron) may verify the disease presence in suspicious areas identified using widefield techniques. 2-NBDG, a fluorescent metabolic marker, was used as to identify neoplastic biopsies. In a study with 21 patients yielding 38 pathologically correlated biopsies and 158 image sites, 2-NBDG imaging allowed classification of cancerous biopsies with a sensitivity of 96% and specificity of 90%. The unique contributions of these results is the development of a multimodal cap-based endoscopic system to identify suspicious areas in BE, and using a metabolic marker to verify the presence of disease. This application extends beyond esophageal cancer detection and may be explored for cancer detection in other organ sites characterized by columnar epithelium.

<p>This thesis reports on the development of a novel comprehensive database (Dragon Database of Genes Implicated in Esophageal Cancer, DDEC) as an integrated knowledge database aimed at representing a gateway to esophageal cancer related data. More importantly, it illustrates how the biocurated genes in the database may represent a reliable starting point for divulging transcriptional regulation, diagnostic markers and the biology related to esophageal cancer.</p>

<p>This thesis reports on the development of a novel comprehensive database (Dragon Database of Genes Implicated in Esophageal Cancer, DDEC) as an integrated knowledge database aimed at representing a gateway to esophageal cancer related data. More importantly, it illustrates how the biocurated genes in the database may represent a reliable starting point for divulging transcriptional regulation, diagnostic markers and the biology related to esophageal cancer.</p>

Primary esophageal (E) and gastro-esophageal junction (GEJ) cancer xenografts have the potential to become useful pre-clinical models of disease. In this study, we determined that p16 negative tumors that have not been exposed to neo-adjuvant chemo-radiation have higher engraftment chances. Morphological features and expression of certain molecular markers (p53, p16, Ki-67, EGFR, Her-2/neu) suggest that no major changes occur between primary tumors and xenografts or between early passage and late passage xenografts. Global gene expression data supported these results but revealed that approximately 2000 genes differed significantly between passage one xenografts and human tumors. Most of these genes, however, might coincide with stromal signals present in patient tumors but absent in xenografts. Primary E/GEJ cancer xenografts also showed a wide range of chemosensitivities to cisplatin-paclitaxel treatment, confirming the usefulness of these models in drug testing. These models also revealed potential ways to interrogate tumor initiating cell (TIC) dynamics after chemotherapy.

Primary esophageal (E) and gastro-esophageal junction (GEJ) cancer xenografts have the potential to become useful pre-clinical models of disease. In this study, we determined that p16 negative tumors that have not been exposed to neo-adjuvant chemo-radiation have higher engraftment chances. Morphological features and expression of certain molecular markers (p53, p16, Ki-67, EGFR, Her-2/neu) suggest that no major changes occur between primary tumors and xenografts or between early passage and late passage xenografts. Global gene expression data supported these results but revealed that approximately 2000 genes differed significantly between passage one xenografts and human tumors. Most of these genes, however, might coincide with stromal signals present in patient tumors but absent in xenografts. Primary E/GEJ cancer xenografts also showed a wide range of chemosensitivities to cisplatin-paclitaxel treatment, confirming the usefulness of these models in drug testing. These models also revealed potential ways to interrogate tumor initiating cell (TIC) dynamics after chemotherapy.

Several members of the lysyl oxidase family of copper-dependent amine oxidases have been implicated in tumor development. The Iysyl oxidase (LOX) and LOX-like 2 (LOXL2) genes have been mapped to chromosomal regions affected by loss of heterozygosity (LOH) in several cancers, including those of the colon and esophagus. Indeed, there have been numerous reports of reduced LOX and a few reports of reduced LOXL2 expression in various cancers. Identification of microsatellite markers within the LOX locus and the LOXL2 gene allowed for evaluation ofthe status of these gene alleles in colon and esophageal tumors. There was significant LOH of the LOX locus in colon tumors that was accompanied by reduced mRNA expression and a spectrum of alterations and mutations affecting the LOX gene. This study demonstrated, for the first time, that genetic events, namely LOH, deletions and mutations ofthe LOX gene, were responsible, at least partly, for the reduction of LOX gene expression. There was also significant LOH of the LOXL2 gene in both colon and esophageal tumors. However, instead of a reduction of LOXL2 expression, there was increased expression that correlated with less differentiated tumors and absent elastosis, both indicators of poor prognosis. Further studies indicated that both LOX and LOXL2 are absent in non-invasive tumor cell lines but re-expressed in invasive cell lines, likely as part of the thelial-mesenchymal transition that occurs in the last steps of tumorigenesis to facilitate metastasis. The results presented and research strategy outlined in this dissertation will define the importance of LOXL2 amine oxidase activity and protein interactions in the critical but poorly understood process oftumor cell migration and invasion.

Philosophiae Doctor - PhD / Esophageal cancer (EC) ranks among the ten most frequent cancers worldwide. Mortality rates associated with EC are very similar to the incidence rates due to the relatively late stage of diagnosis and the poor efficacy of treatment. The aim of this study was to enhance our insights of putative transcriptional circuitry of EC genes, thereby potentially positively impacting our knowledge of therapeutic targets, providing indications as to more appropriate lines of treatment, and additionally allowing for the determination of putative candidate diagnostic markers for the early stage detection of EC. This thesis reports on the development of a novel comprehensive database (Dragon Database of Genes Implicated in Esophageal Cancer, DDEC) as an integrated knowledge database aimed at representing a gateway to esophageal cancer related data. More importantly, it illustrates how the biocurated genes in the database may represent a reliable starting point for divulging transcriptional regulation, diagnostic markers and the biology related to esophageal cancer. DDEC contains known and novel information for 529 differentially expressed EC genes compiled using scientific publications from PubMed and is freely accessible for academic and non-profit users at http://apps.sanbi.ac.za/ddec/. The novel information provided to users of the DDEC is the lists of putative transcription factors that potentially control the 529 manually curated genes. The value of the information accessible through the database was further refined by providing precompiled text-mined and data-mined reports about each of these genes to allow for easy exploration of information about associations of EC-implicated genes with other human genes and proteins, metabolites and enzymes, toxins, chemicals with pharmacological effects, disease concepts and human anatomy. This feature has the capacity to display potential associations that are rarely reported and thus difficult to identify, and it enables the inspection of potentially new ‘association hypotheses’ generated based on the precompiled reports. This study further illustrates how the biocurated esophageal squamous cell carcinoma (ESCC) genes in the database may represent a reliable starting point for exploring beyond current knowledge of the transcriptional circuitry of estrogen related hormone therapy. The genes were used to develop a method that identified 44 combinations of transcription factors (TFs) that characterize the promoter sequence of estrogen responsive genes implicated in ESCC. These significantly over-represented combinations of TFs were then used to increase confidence in the 47 novel putative estrogen response genes that may be related to ESCC too. Coincidently, two of the novel putative estrogen response genes were verified by current (2009), experimental publications. / South Africa