Orientadores: Sophie Françoise Mauricette Derchain, Luis Otávio Zanatta Sarian / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-11-07T13:25:01Z (GMT). No. of bitstreams: 1 Moraes_DenisedaRochaPittaLimade_D.pdf: 1846599 bytes, checksum: 5c83c44db1103b63041e2ceb928d48d4 (MD5) Previous issue date: 2012 / Resumo: Objetivo: Avaliar a acurácia da mesotelina, CA125, HE4 e índice ROMA na diferenciação de mulheres brasileiras com tumores malignos de ovário daquelas com tumores benignos e ou mulheres saudáveis, e avaliar se os sintomas específicos relatados pelas mulheres podem ser usados em associação à expressão desses marcadores séricos, na diferenciação pré-operatória de neoplasia maligna de ovário. Sujeitos e Métodos: Neste estudo de corte transversal foram incluídas 199 mulheres com massa anexial (67 com tumores malignos e 132 com tumores benignos) e 150 mulheres saudáveis. Todas as mulheres com massa anexial, atendidas no hospital do Departamento de Obstetrícia e Ginecologia da Faculdade de Medicina da UNICAMP, foram convidadas a participar do estudo. Um grupo-controle, de mulheres saudáveis atendidas nos ambulatórios de menopausa e planejamento familiar no mesmo hospital, foi selecionado. Após uma explicação sobre os métodos e objetivo da pesquisa, todas as mulheres responderam o questionário com relação aos sintomas específicos. Foram coletados dados sobre a idade e índice de massa corpórea e sangue periférico para quantificação da mesotelina, o CA125 e a HE4. Foi usado o algoritmo de particionamento recursivo baseado no modelo de regressão linear para verificar a contribuição da idade e de cada marcador sérico no diagnóstico de tumores malignos. Foram comparadas as áreas sob as curvas (AUCs) obtidas através das curvas ROC (Receiver Operator Characteristics) de cada marcador sérico e índice ROMA, para diferenciar mulheres com tumores malignos. Foi calculada a proporção de mulheres com cada um dos 22 sintomas específicos nos grupos com tumores malignos de ovário, tumores benignos e mulheres saudáveis. O sintoma foi considerado positivo quando ocorria mais que 12 vezes ao mês e por até um ano. A proporção de sintomas foi comparada utilizando teste de qui-quadrado ou teste exato de Fischer, quando apropriado. Os 16 sintomas específicos aplicáveis a toda a coorte e para o qual a periodicidade foi verificada foram submetidos à análise pelo Método de Ward para agrupamento hierárquico. Os agrupamentos de sintomas e sintomas isolados identificados foram: abdômen (abdômen inchado e/ou aumento do volume abdominal); dor (dor pélvica, costas e/ou abdominal); pernas inchadas; digestão (estômago cheio e/ou náusea /vômito); alimentação (dificuldade para comer e/ou empachada); sente alguma massa abdominal; diversos (fadiga e/ou dificuldade para respirar); bexiga (urgência em urinar e/ou urinar frequentemente). Foi avaliada a proporção de mulheres com cada agrupamento de sintomas ou sintomas isolados em mulheres com tumores malignos, tumores benignos e saudáveis, através do teste qui-quadrado para tendências. Utilizou-se um algoritmo de particionamento recursivo para verificar a contribuição da idade da mulher, de cada agrupamento de sintomas ou sintomas isolados, estado menopausal, perda de peso e marcadores séricos no diagnóstico de tumores malignos. Resultados: O CA125 foi o marcador sérico com maior capacidade para discriminar mulheres com tumores malignos (p<0,001). Entre as mulheres com tumores benignos e CA125 positivo, a HE4 foi positiva em apenas um caso e a mesotelina foi positiva em outro. Em mulheres com CA125 negativo, a idade, a mesotelina e a HE4 não contribuíram para a diferenciação entre mulheres com tumores malignos, tumores benignos e saudáveis. Em contrapartida, em mulheres com CA125 positivo, a HE4 contribuiu significantemente para detecção de mulheres com tumores malignos (p<0,01). A AUC da mesotelina foi menor que das AUC dos outros marcadores. O ROMA e o CA125 apresentarm melhores AUCs do que o HE4. A proporção de mulheres com cada um dos agrupamentos de sintomas ou sintomas isolados foi significativamente maior em mulheres com tumores malignos, quando comparadas àquelas com tumores benignos e, destas, comparadas com as mulheres saudáveis (p tendência em todas as comparações <0,01). Após a análise multivarida, as associações mais significativas para detecção de tumores malignos de ovário foram as do agrupamento abdômen (p<0,001), expressão do CA125 (p<0,001), agrupamento dor (p=0,01) e perda de peso (p=0,03). Conclusões: Em mulheres com CA125 negativo, a mesotelina e HE4 não contribuíram para detecção do carcinoma de ovário. Entretanto, em mulheres com CA125 positivo, a HE4 contribuiu para diferenciar aquelas com tumores malignos. Em mulheres com tumores malignos de ovário, os sintomas específicos, abdômen e dor foram significantemente mais frequentes. Podem ser utilizados em associação ao CA125 na diferenciação de tumores malignos em mulheres com massa anexial / Abstract: Objective: To evaluate the accuracy of mesothelin, CA125, HE4 and ROMA index in the differentiation of Brazilian women with ovarian malignant tumors from those with benign tumors or healthy women; and to evaluate whether the prevalence of specific self-reported symptoms can be used in association to the expression of serum markers for the preoperative differentiation of ovarian malignant tumors. Study Design: For this cross sectional study, 199 women with adnexal mass (67 with malignant tumors and 132 with benign tumors) and 150 healthy women were included. All women with adnexal masses, attending the hospital of the Department of Obstetrics and Gynecology of the Unicamp School of Medicine were invited to participate in the study. A control group of healthy women attending menopause and family planning clinics at the same hospital were selected. After an explanation about the study research methods and purpose all women answered a survey regarding specific symptoms. There were also collected data on age and body mass index. Peripheral blood was collected for serum measurements of mesotelina, CA125 and HE4. A recursive partitioning algorithm, based on a linear regression model was used to confirm the contribution of age and each of the serum markers to the diagnosis of malignant tumors. Comparison of Area Under the Curve (AUC) obtained through Receiver Operator Characteristics (ROC) curves for each of the serum markers and ROMA index were used to differentiating women with malignant tumors. We next calculated the proportion of women with each of the 22 specific symptoms in the groups of women with ovarian malignant tumors, benign tumors and healthy women. We considered a symptom positive if it occurred more than 12 times per month and for less than one year. The proportions were pairwise compared using chi-square or the Fisher exact test where appropriate. The 16 specific symptoms which applied to the entire cohort and for which the periodicity had been ascertained were further subjected to the Ward's Hierarchical Clustering Method. Clusters of symptoms and isolated symptoms were: abdomen (abdominal bloating and/or increased abdomen size); pain (pelvic, back and/or abdominal pain); leg swelling; digestion (indigestion and/or nauseas /vomiting); eating (unable to eat normally and/or feeling full quickly); able to feel abdominal mass; miscellaneous (fatigue and/or difficulty breathing); bladder (urinary urgency and/or frequent urination). We evaluated the trend in proportion of women with each cluster of symptoms in the groups of women with malignant tumors, benign tumors and healthy women using the chi-squared test for trend in proportions. Another recursive partitioning algorithm was used to confirm the contribution of patient age, clusters of symptoms, menopausal status, weight loss and the serum markers to the diagnosis of malignant tumors Results: CA125 was the serum marker that had the greatest capacity to discriminate women with malignant tumors (p<0.001). Among the women with benign tumors and positive CA125, HE4 was positive in only one case and mesothelin in another case. In women with negative CA125 neither age nor mesothelin nor HE4 contributed any further to the differentiation between women with malignant, tumors benign tumors and healthy women. In contrast, for women with positive CA125, HE4 contributed significantly to the detection of women with malignant tumors (p<0.01). The AUC for mesothelin was smaller than that for all the other curves, and ROMA and CA125 had better AUC than HE4. The proportion of women with each of the clusters of symptoms and isolated symptoms decreased significantly from the group of women with malignant tumors to that with benign tumors and from this group to the healthy women (p for trends in all comparisons= <0.01). After a multivariate analysis the association that contributed the most to the detection of malignant ovarian tumors was that of the abdomen cluster (p<0.001), CA125 expression (p<0.001), pain cluster (p=0.01) and weight loss (p=0.03). Conclusion: In women with negative CA125 neither mesothelin nor HE4 contributed to detect ovarian carcinoma. HE4 was helpful to differentiate malignant tumors when CA125 is positive. Specific symptoms, abdomen and pain were significantly higher in women with malignant ovarian tumors and may be used along with the CA125 to select women with ovarian malignancy among those with adnexal masses / Doutorado / Oncologia Ginecológica e Mamária / Doutora em Ciências da Saúde

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 175-190).

Epithelial ovarian cancer (EOC) is difficult to detect in early stage disease, resulting in a high mortality rate. The molecular events underlying EOC development remain largely unknown. Chromosome 3 exhibits frequent deletions and rearrangements in EOC by cytogenetic analysis. In addition, loss of heterozygosity (LOH) mapping of matched ovarian tumour and constitutional DNA samples exhibits specific regions of chromosome 3 loss involving distinct regions: 3p25-p26, 3p24 and a region proximal to 3p14. Thus, chromosome 3p loss points to the location of tumour suppressor genes (TSG) implicated in tumourigenesis, based on Knudson's 'two-hit' model and the paradigm of the classical TSG. The dissertation hypothesis states at least one TSG implicated in EOC is located on chromosome 3p. A novel complementation approach based on the transfer of normal chromosome 3 fragments into OV-90, a tumourigenic EOC cell line harbouring LOH of the 3p arm, was used to generate functional evidence for chromosome 3p TSGs. Three hybrids exhibited complete suppression of tumourigenic potential based on the inability to form colonies in soft agarose, spheroids in cell culture, and tumours in nude mice xenograft models. While all hybrids had acquired various chromosome 3 regions, they all shared in common a 3p12-pcen interval, suggesting at least one common gene may have affected the suppression of tumourigenicity in the OV-90-derived hybrids. Twelve known/hypothetical genes mapping to 3p12-pcen region were characterized based on gene expression and mutation analysis following a classical model for TSG inactivation. To establish the relevance to EOC, gene expression of candidates was investigated in primary cultures of normal ovarian surface epithelial cells and both malignant serous and benign serous tumour samples. The gene expression and genetic analysis identified seven TSG candidates, none of which appeared to be mutated or transcriptionally silenced based on classical mechanisms of TSG inactivation in OV-90, thus suppression of tumourigenicity may have resulted from the functional complementation of one more haploinsufficient 3p12-pcen genes. Several genes (GBE1, VGLL3, ZNF654 ) appeared underexpressed in malignant tumours and these findings suggest the intriguing possibility that more than one 3p12-pcen gene was involved in the suppression of tumourigenicity in OV-90, and by extension, EOC.

Thesis (M.Sc. (Medical Technology))--Mahidol University,

Thesis (M.S.)--University of Alabama at Birmingham, 2009. / Title from first page of PDF file (viewed on June 11, 2009). Includes bibliographical references (p. 44-54).

Thesis (Ph. D.)--University of Michigan, 2005. / Includes bibliographical references.

Thesis (Ph. D.)--University of Michigan, 2005. / Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 53-56).

Orientador: Carmen Silvia Passos Lima / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-12T08:37:32Z (GMT). No. of bitstreams: 1 Sagarra_ReginaAparecidaMartinho_D.pdf: 4367587 bytes, checksum: 8cb3760d80526b8901dd10650326920b (MD5) Previous issue date: 2008 / Resumo: Já é conhecida a dependência do crescimento, invasão e a disseminação de tumores sólidos na angiogênese, incluindo o carcinoma de ovário (CO). O CO está associado à produção de proteínas estimuladoras da angiogênese, como o fator de crescimento endotelial vascular (VEGF), produto do gene VEGF, e inibidoras da angiogênese, como a endostatina, produto do gene COL18A1. O CO está também associado à exposição da mulher ao estrogênio endógeno, que é metabolizado junto a outros carcinógenos pelas enzimas da família glutationa S-transferase (GSTM1, GSTT1 e GSTP1). Os genes VEGF, COL18A1, GSTM1, GSTT1 e GSTP1 são polimórficos em humanos e foram associados à origem de diferentes cânceres. O objetivo do estudo foi analisar os papéis dos polimorfismos C936T do gene VEGF, D104N do gene COL18A1, GSTM1, GSTT1 e IleVal do gene GSTP1 na ocorrência do CO e de suas associações a aspectos clínicos das pacientes e do tumor. Foram avaliadas 137 pacientes com CO e 137 controles. A genotipagem foi realizada por meio da reação em cadeia da polimerase e digestão enzimática em amostras de sangue periférico. O significado estatístico das diferenças entre grupos foi calculado por meio do teste da probabilidade exata de Fisher ou qui-quadrado e as determinações dos riscos de ocorrência do CO foram obtidas por meio das razões de Odds (RO). Observamos que as freqüências dos genótipos variantes do gene VEGF e do gene GSTP1 foram menores em pacientes do que em controles. Indivíduos com os genótipos variantes estiveram sob menor risco de ocorrência do CO do que aqueles com os genótipos selvagens dos genes. Freqüências similares dos genótipos distintos dos genes COL18A1, GSTM1 e GSTT1 foram observados em pacientes e controles. Entretanto, a freqüência da deleção homozigótica do gene GSTT1 foi maior em pacientes com tumor de estágios avançados do que aquelas com tumores localizados. Esses resultados sugerem que os polimorfismos C936T do gene VEGF e Ile/Val do gene GSTP1 influenciam o risco de ocorrência do CO e a deleção homozigótica do gene GSTT1 influencia a agressividade do tumor em mulheres de nossa região. / Abstract: Angiogenesis has been established as an important factor in human carcinogenesis influencing tumor growth and invasion, including ovarian carcinoma (OC). OC has been associated with angiogenic proteins like vascular endothelial growth factor (VEGF), produced by VEGF gene, and antiangiogenic agents, like endostatin, produced by COL18A1 gene. There is a clear association between the excessive exposure of endogen estrogen metabolized by glutathione S-transferase (GST) family as like others carcinogens. The VEGF, COL18A1, GSTM1, GSTT1 and GSTP1 genes are polymorphic in humans and they have been involved in the development of tumors. It was conducted a case-control study to investigate the importance of the C936T polymorphism VEGF gene, D104N polymorphism COL18A1 gene, GSTM1, GSTT1 and Ile105Val GSTP1 polymorphisms GST genes and the risk of OC. Therefore, the result was related to clinical aspects of the patients and pathological aspects of the tumor. The study included 137 OC patients and 137 healthy controls. The genomic DNA from peripheral blood was analyzed using polymerase chain reaction followed by restriction endonuclease digestion. Cases and controlswere compared using chi-squared test. Odds ratio and 95% confidence interval were calculated by logistic regression analysis. We observed a lower frequency of variants genotypes in OC patients than controls related to VEGF gene (12,5% versus 24,1% respectively) and GSTP1 gene (31,8% versus 44,5%, respectively). Women with the variants genotypes were under lower risk of OC when compared to those with the wild genotype related to VEGF gene (P= 0,01) and GSTP1 gene (P= 0,02). Similar frequencies of COL18A1 gene, GSTM1 and GSTT1 genes were seen in patients and controls. However, the homozygous deletion frequency of the GSTT1 was higher in advanced tumors patients rather than early stages. This result suggests that C936T polymorphism of VEGF gene and Ile/Val polymorphism of GSTP1 gene are associated with OC risk and homozygous deletion of the GSTT1 is associated with the aggressiveness of the tumor in women at our region. / Doutorado / Clinica Medica / Doutor em Clínica Médica

AimsParticipant drop out is a major barrier to high-quality patient-reported outcome (PRO) data analysis in cancer research as patients with worsening health are more likely to dropout. To test the hypothesis that ovarian cancer patients with worse PROs would drop out earlier, we examined how patients differed by time of dropout on health-related quality of life (HRQOL), anxiety, depression, optimism and insomnia. MethodsThis analysis included 619 participants, stratified by time of dropout, from the Australian Ovarian Cancer Study - Quality of Life substudy, in which participants completed PRO questionnaires at three-monthly intervals for 21 months. Trends in PROs over time were examined. Pearson correlations examined the relationship between time of dropout and baseline PROs. Multiple linear regression models including age, disease stage and time since diagnosis examined relationships between baseline and final PRO scores, and final PRO scores and dropout group. ResultsParticipants who dropped out earlier had significantly worse baseline HRQOL (p<0.0001) and higher depression (p<0.0001). For all five PROs, final scores were significantly associated with baseline scores (p<0.0001). Time of dropout was significantly associated with final HRQOL (p=0.003), anxiety (p=0.05), depression (p=0.02) and optimism (p=0.02) scores. Depression, HRQOL and anxiety worsened at a faster rate overtime in dropouts than study completers. ConclusionsPoorer HRQOL and higher depression at baseline, and final HRQOL, anxiety, depression and optimism scores were predictive of time of dropout. These results highlight the importance of collecting auxiliary data to inform careful and considered handling of missing PRO data during analysis, interpretation and reporting.