No description available.

There is no abstract available for this dissertation. / Department of Counseling Psychology and Guidance Services

Thesis (Ph. D.)--University of Hawaii at Manoa, 2005. / Includes bibliographical references (leaves 68-75). / Also available by subscription via World Wide Web / ix, 75 leaves, bound 29 cm

Thesis (M.S.)--University of Hawaii at Manoa, 2007. / Includes bibliographical references. / viii, 12 leaves, bound ill. 29 cm

Breast cancer is the most feared and common female malignancy in the world. About one in ten women in South Africa will be diagnosed during her lifetime with this disease. The outcome of breast cancer treatment is dependent on early detection and swift subsequent management. A lack of research exists in South Africa about diagnostic and treatment delay factors. A situational analysis is currently underway to improve the breast cancer service in the country. Even less is known about the delays in rural health care. This study examined the delay during the diagnosis and treatment of breast lumps in the Theewaterskloof (TWK) sub district in the Western Cape. The results were compared to Worcester hospital, the secondary referral centre of this district. Three hundred and twenty (322) patients from Caledon hospital and surrounding clinics in the TWK and 322 randomly selected patients from Worcester hospital surgical clinic, who presented during 2007-2010, were retrospectively studied. The mean breast lump diagnostic period at TWK was 45 days versus 16 days at Worcester. Breast cancer diagnostic times were 38 days and 19 days respectively. More alarming was the difference in breast surgery delay of 173 days versus 16 days at TWK Worcester hospital respectively. These time periods were compared to the tertiary institutions in the Western Cape and with international guidelines. Cytological adequacy i.e. Fine Needle Aspiration (FNA) and core needle biopsy between the institutions are also reported. In conclusion it is suggested that regular training in FNA is required to improve the cytological adequacy at TWK. Long delay in surgical waiting periods can be addressed by referring TWK breast cancer patients to Worcester hospital after diagnosis.

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer, with a particularly poor prognosis. Identification of epidemiologic risk factors for IBC might shed light on causes of the disease, and guide screening and perhaps treatment. Previous studies have suggested that race, geographic location, body mass index (BMI), menopausal status, age at menarche, parity, duration of lactation, and exposure to mouse mammary tumor virus may be key risk factors in the development of IBC. This retrospective epidemiologic study examines the risk factors for IBC in predominantly Caucasian patients treated at the Dana Farber Cancer Institute (DFCI) in Boston, MA. The risk factors that were examined in this study include the following: BMI, family history of having breast cancer, comorbidities, duration of symptoms associated with IBC prior to diagnosis, season of diagnosis, and molecular subtypes of breast cancer. Additionally, the descriptive statistics for the mean age of diagnosis, race, menopausal status, genetic predisposition, and the presence of metastases in distant organs were also determined. This study showed that there is some evidence of a hereditary component and seasonal variation to the disease. Furthermore, this study reiterates the association of high body mass index (BMI) and IBC. The data collected from the DFCI IBC patient population suggest that modifiable lifestyle factors, perhaps due to a lack of awareness of the disease, might be crucial in the development of IBC. Further research is needed to explore the unique risk factors in developing IBC elucidated in this study in order to better understand and prevent such an aggressive disease.

O câncer de mama é a neoplasia mais comum entre as mulheres. Sua etiologia é complexa, onde tanto fatores ambientais como genéticos podem contribuir para o desenvolvimento tumoral. Estima-se que 5 a 10% dos casos de carcinomas de mama sejam representados pelos carcinomas de mama familial e 90 a 95% sejam representados pelos carcinomas de mama esporádicos. Independente da etiologia, um dos principais agravantes é consequência da habilidade das células tumorais metastizar. Mutações podem levar a mudança ou perda de expressão de diferentes genes e isto possibilita que as células adquiram particularidades genéticas e fenotípicas que contribuem para a progressão do tumor através da aquisição de vantagens que medeiam a sua sobrevivência. Dentre estas vantagens adquiridas está a capacidade das células tumorais de escaparem da destruição pelas células imunológicas ou, até mesmo, utilizarem estas células a seu favor, na promoção de um microambiente tumoral inflamatório que pode auxiliar o desenvolvimento da angiogênese que posteriormente facilitará a metástase. As características dos carcinomas de mama são as principais ferramentas para avaliação do diagnóstico e prognóstico da doença. Portanto, o objetivo de nosso trabalho foi a análise de quatro variantes polimórficas de genes que codificam importantes moléculas do sistema imunológico, duas relacionadas aos genes que codificam os receptores de quimiocinas, CCR2 e CCR5, e duas relacionadas ao gene HLA-G em 188 mulheres com carcinoma de mama (105 com câncer de mama familial e 83 com câncer de mama esporádico) e em 151 mulheres sem carcinoma e sem história familiar de câncer (grupo controle), como possíveis marcadores de diagnóstico e prognóstico do carcinoma de mama. Para a análise da variante do CCR2, denominada CCR264I, e para a análise de uma das variantes que codifica a molécula de HLA-G, denominada +3142, utilizou-se a técnica PCR-RFLP. Para a análise da variante do gene CCR5, denominada CCR5delta32 e para a análise da outra variante do HLA-G, caracterizada pela inserção de 14pb na região 3’UTR do gene, utilizou-se a técnica PCR. As frequências alélicas, genotípicas e haplotípicas foram estimadas e comparadas entre os grupos de mulheres, usando o Teste Qui-Quadrado ou o Teste Exato de Fisher e, posteriormente, foram relacionadas a fatores de diagnóstico e prognóstico. Observou-se maiores frequências dos alelos selvagens do CCR2, Val (p=0,040, OR 0,61, IC 95% = 0,38 – 0,98) e do CCR5, Wt (p=0,032, OR 0,46, IC 95% = 0,23 – 0,94) e maior frequência do haplótipo duplo selvagem Wt/Val destas mesmas variantes gênicas dos genes CCR2 e CCR5, nas mulheres do grupo controle (p=0,030) em relação às mulheres com câncer de mama familial. Quando as variantes foram avaliadas em conjunto com os parâmetros clínicos, observou-se que as mulheres com carcinoma de mama esporádico apresentavam a doença em idade mais elevada (57,29 ± 8,457 anos e 44,23 ± 12,092 anos para mulheres com câncer de mama esporádico e familial, respectivamente, p < 0.001) e de forma mais agressiva, com maior frequência dos carcinomas invasores (p = 0,001) que as mulheres com carcinoma de mama familial. Além disso, as variantes de inserção/deleção de 14 pb do HLA-G e CCR264I, mostraram relação positiva com a agressividade tumoral nestas mulheres (p = 0,039 e p = 0,005). Nossos dados sugerem que os carcinomas invasores possam estar relacionados a uma maior infiltração de células imunológicas e com o aumento da inflamação no microambiente tumoral, mediados pelo receptor CCR2 e pela molécula HLA-G, respectivamente. / Breast cancer is the most common cancer among women. Its etiology is complex, where genetic, environmental and endocrine factors contribute to tumor development. It is estimated that 5 to 10% of the breast cancers are represented by familial breast cancers and 90 to 95% are represented by sporadic breast cancers. Independent of the etiology, the major aggravating consequence is the ability of tumor cells to metastasize. Mutations can lead to a change or loss of expression a different genes and this allows the appearance of genetic and phenotypic features which contribute to tumor progression. Among these features is the ability of tumor cells to evade from the immune cells or even use immune cells in the promotion of a inflammatory microenvironment promotion which may help angiogenesis and, later, metastasis. The aim of our study was to evaluate four important polymorphic variants of genes which encode important immune system molecules, two related genes encoding chemokine receptors, CCR2 and CCR5, and two related to HLA-G gene in 188 women with breast cancer (105 women with familial breast cancer and 83 with sporadic breast cancer) and 151 women without cancer and family history of cancer (control group), such as potential markers for diagnosis and prognosis of breast cancer. CCR2 polymorphism, CCR264I, and one HLA-G polymorphism, +3142, were genotyped by PCR-RFLP. CCR5delta32 and 14pb HLA-G polymorphism were genotyped by PCR. Allelic, genotypic and haplotypic frequencies were estimated and compared between the groups using the Chi-square test or Fisher's exact test and subsequently were associated to diagnostic and prognostic factors. We observed a higher allelic frequency of the CCR2 wild type allele, Val (p = 0.040, OR 0.61, 95% CI = 0.38 - 0.98) e CCR5 wild type allele, Wt (p = 0.032, OR 0.46, CI 95% = 0.23 - 0.94) and higher haplotype frequency of the double wild type variants (Wt/Val) of these same genes (CCR2 and CCR5) in women in the control group (p = 0.030) compared to women with familial breast cancer. All polymorphisms were evaluated together with the clinical parameters and it was observed that women with breast cancer showed sporadic cancer latter (57.29 ± 8.457 years and 44.23 ± 12.092 years for women with sporadic breast cancer and familial breast cancer, respectively, p < 0.001) and more invasiveness (p = 0.001) as compared to women with familial breast cancer. Moreover, the HLA-G 14pb and CCR264I polymorphism, showed a positive association with tumor aggressiveness in women with sporadic breast cancer (p = 0.039 and p = 0.005, respectively). Our data suggest that invasive cancers may be associated with increased immune cells infiltration and inflammation in the tumor microenvironment mediated by both CCR2 receptor and HLA-G molecule.

O câncer de mama é a neoplasia mais comum entre as mulheres. Sua etiologia é complexa, onde tanto fatores ambientais como genéticos podem contribuir para o desenvolvimento tumoral. Estima-se que 5 a 10% dos casos de carcinomas de mama sejam representados pelos carcinomas de mama familial e 90 a 95% sejam representados pelos carcinomas de mama esporádicos. Independente da etiologia, um dos principais agravantes é consequência da habilidade das células tumorais metastizar. Mutações podem levar a mudança ou perda de expressão de diferentes genes e isto possibilita que as células adquiram particularidades genéticas e fenotípicas que contribuem para a progressão do tumor através da aquisição de vantagens que medeiam a sua sobrevivência. Dentre estas vantagens adquiridas está a capacidade das células tumorais de escaparem da destruição pelas células imunológicas ou, até mesmo, utilizarem estas células a seu favor, na promoção de um microambiente tumoral inflamatório que pode auxiliar o desenvolvimento da angiogênese que posteriormente facilitará a metástase. As características dos carcinomas de mama são as principais ferramentas para avaliação do diagnóstico e prognóstico da doença. Portanto, o objetivo de nosso trabalho foi a análise de quatro variantes polimórficas de genes que codificam importantes moléculas do sistema imunológico, duas relacionadas aos genes que codificam os receptores de quimiocinas, CCR2 e CCR5, e duas relacionadas ao gene HLA-G em 188 mulheres com carcinoma de mama (105 com câncer de mama familial e 83 com câncer de mama esporádico) e em 151 mulheres sem carcinoma e sem história familiar de câncer (grupo controle), como possíveis marcadores de diagnóstico e prognóstico do carcinoma de mama. Para a análise da variante do CCR2, denominada CCR264I, e para a análise de uma das variantes que codifica a molécula de HLA-G, denominada +3142, utilizou-se a técnica PCR-RFLP. Para a análise da variante do gene CCR5, denominada CCR5delta32 e para a análise da outra variante do HLA-G, caracterizada pela inserção de 14pb na região 3’UTR do gene, utilizou-se a técnica PCR. As frequências alélicas, genotípicas e haplotípicas foram estimadas e comparadas entre os grupos de mulheres, usando o Teste Qui-Quadrado ou o Teste Exato de Fisher e, posteriormente, foram relacionadas a fatores de diagnóstico e prognóstico. Observou-se maiores frequências dos alelos selvagens do CCR2, Val (p=0,040, OR 0,61, IC 95% = 0,38 – 0,98) e do CCR5, Wt (p=0,032, OR 0,46, IC 95% = 0,23 – 0,94) e maior frequência do haplótipo duplo selvagem Wt/Val destas mesmas variantes gênicas dos genes CCR2 e CCR5, nas mulheres do grupo controle (p=0,030) em relação às mulheres com câncer de mama familial. Quando as variantes foram avaliadas em conjunto com os parâmetros clínicos, observou-se que as mulheres com carcinoma de mama esporádico apresentavam a doença em idade mais elevada (57,29 ± 8,457 anos e 44,23 ± 12,092 anos para mulheres com câncer de mama esporádico e familial, respectivamente, p < 0.001) e de forma mais agressiva, com maior frequência dos carcinomas invasores (p = 0,001) que as mulheres com carcinoma de mama familial. Além disso, as variantes de inserção/deleção de 14 pb do HLA-G e CCR264I, mostraram relação positiva com a agressividade tumoral nestas mulheres (p = 0,039 e p = 0,005). Nossos dados sugerem que os carcinomas invasores possam estar relacionados a uma maior infiltração de células imunológicas e com o aumento da inflamação no microambiente tumoral, mediados pelo receptor CCR2 e pela molécula HLA-G, respectivamente. / Breast cancer is the most common cancer among women. Its etiology is complex, where genetic, environmental and endocrine factors contribute to tumor development. It is estimated that 5 to 10% of the breast cancers are represented by familial breast cancers and 90 to 95% are represented by sporadic breast cancers. Independent of the etiology, the major aggravating consequence is the ability of tumor cells to metastasize. Mutations can lead to a change or loss of expression a different genes and this allows the appearance of genetic and phenotypic features which contribute to tumor progression. Among these features is the ability of tumor cells to evade from the immune cells or even use immune cells in the promotion of a inflammatory microenvironment promotion which may help angiogenesis and, later, metastasis. The aim of our study was to evaluate four important polymorphic variants of genes which encode important immune system molecules, two related genes encoding chemokine receptors, CCR2 and CCR5, and two related to HLA-G gene in 188 women with breast cancer (105 women with familial breast cancer and 83 with sporadic breast cancer) and 151 women without cancer and family history of cancer (control group), such as potential markers for diagnosis and prognosis of breast cancer. CCR2 polymorphism, CCR264I, and one HLA-G polymorphism, +3142, were genotyped by PCR-RFLP. CCR5delta32 and 14pb HLA-G polymorphism were genotyped by PCR. Allelic, genotypic and haplotypic frequencies were estimated and compared between the groups using the Chi-square test or Fisher's exact test and subsequently were associated to diagnostic and prognostic factors. We observed a higher allelic frequency of the CCR2 wild type allele, Val (p = 0.040, OR 0.61, 95% CI = 0.38 - 0.98) e CCR5 wild type allele, Wt (p = 0.032, OR 0.46, CI 95% = 0.23 - 0.94) and higher haplotype frequency of the double wild type variants (Wt/Val) of these same genes (CCR2 and CCR5) in women in the control group (p = 0.030) compared to women with familial breast cancer. All polymorphisms were evaluated together with the clinical parameters and it was observed that women with breast cancer showed sporadic cancer latter (57.29 ± 8.457 years and 44.23 ± 12.092 years for women with sporadic breast cancer and familial breast cancer, respectively, p < 0.001) and more invasiveness (p = 0.001) as compared to women with familial breast cancer. Moreover, the HLA-G 14pb and CCR264I polymorphism, showed a positive association with tumor aggressiveness in women with sporadic breast cancer (p = 0.039 and p = 0.005, respectively). Our data suggest that invasive cancers may be associated with increased immune cells infiltration and inflammation in the tumor microenvironment mediated by both CCR2 receptor and HLA-G molecule.

O câncer de mama é a neoplasia mais comum entre as mulheres. Sua etiologia é complexa, onde tanto fatores ambientais como genéticos podem contribuir para o desenvolvimento tumoral. Estima-se que 5 a 10% dos casos de carcinomas de mama sejam representados pelos carcinomas de mama familial e 90 a 95% sejam representados pelos carcinomas de mama esporádicos. Independente da etiologia, um dos principais agravantes é consequência da habilidade das células tumorais metastizar. Mutações podem levar a mudança ou perda de expressão de diferentes genes e isto possibilita que as células adquiram particularidades genéticas e fenotípicas que contribuem para a progressão do tumor através da aquisição de vantagens que medeiam a sua sobrevivência. Dentre estas vantagens adquiridas está a capacidade das células tumorais de escaparem da destruição pelas células imunológicas ou, até mesmo, utilizarem estas células a seu favor, na promoção de um microambiente tumoral inflamatório que pode auxiliar o desenvolvimento da angiogênese que posteriormente facilitará a metástase. As características dos carcinomas de mama são as principais ferramentas para avaliação do diagnóstico e prognóstico da doença. Portanto, o objetivo de nosso trabalho foi a análise de quatro variantes polimórficas de genes que codificam importantes moléculas do sistema imunológico, duas relacionadas aos genes que codificam os receptores de quimiocinas, CCR2 e CCR5, e duas relacionadas ao gene HLA-G em 188 mulheres com carcinoma de mama (105 com câncer de mama familial e 83 com câncer de mama esporádico) e em 151 mulheres sem carcinoma e sem história familiar de câncer (grupo controle), como possíveis marcadores de diagnóstico e prognóstico do carcinoma de mama. Para a análise da variante do CCR2, denominada CCR264I, e para a análise de uma das variantes que codifica a molécula de HLA-G, denominada +3142, utilizou-se a técnica PCR-RFLP. Para a análise da variante do gene CCR5, denominada CCR5delta32 e para a análise da outra variante do HLA-G, caracterizada pela inserção de 14pb na região 3’UTR do gene, utilizou-se a técnica PCR. As frequências alélicas, genotípicas e haplotípicas foram estimadas e comparadas entre os grupos de mulheres, usando o Teste Qui-Quadrado ou o Teste Exato de Fisher e, posteriormente, foram relacionadas a fatores de diagnóstico e prognóstico. Observou-se maiores frequências dos alelos selvagens do CCR2, Val (p=0,040, OR 0,61, IC 95% = 0,38 – 0,98) e do CCR5, Wt (p=0,032, OR 0,46, IC 95% = 0,23 – 0,94) e maior frequência do haplótipo duplo selvagem Wt/Val destas mesmas variantes gênicas dos genes CCR2 e CCR5, nas mulheres do grupo controle (p=0,030) em relação às mulheres com câncer de mama familial. Quando as variantes foram avaliadas em conjunto com os parâmetros clínicos, observou-se que as mulheres com carcinoma de mama esporádico apresentavam a doença em idade mais elevada (57,29 ± 8,457 anos e 44,23 ± 12,092 anos para mulheres com câncer de mama esporádico e familial, respectivamente, p < 0.001) e de forma mais agressiva, com maior frequência dos carcinomas invasores (p = 0,001) que as mulheres com carcinoma de mama familial. Além disso, as variantes de inserção/deleção de 14 pb do HLA-G e CCR264I, mostraram relação positiva com a agressividade tumoral nestas mulheres (p = 0,039 e p = 0,005). Nossos dados sugerem que os carcinomas invasores possam estar relacionados a uma maior infiltração de células imunológicas e com o aumento da inflamação no microambiente tumoral, mediados pelo receptor CCR2 e pela molécula HLA-G, respectivamente. / Breast cancer is the most common cancer among women. Its etiology is complex, where genetic, environmental and endocrine factors contribute to tumor development. It is estimated that 5 to 10% of the breast cancers are represented by familial breast cancers and 90 to 95% are represented by sporadic breast cancers. Independent of the etiology, the major aggravating consequence is the ability of tumor cells to metastasize. Mutations can lead to a change or loss of expression a different genes and this allows the appearance of genetic and phenotypic features which contribute to tumor progression. Among these features is the ability of tumor cells to evade from the immune cells or even use immune cells in the promotion of a inflammatory microenvironment promotion which may help angiogenesis and, later, metastasis. The aim of our study was to evaluate four important polymorphic variants of genes which encode important immune system molecules, two related genes encoding chemokine receptors, CCR2 and CCR5, and two related to HLA-G gene in 188 women with breast cancer (105 women with familial breast cancer and 83 with sporadic breast cancer) and 151 women without cancer and family history of cancer (control group), such as potential markers for diagnosis and prognosis of breast cancer. CCR2 polymorphism, CCR264I, and one HLA-G polymorphism, +3142, were genotyped by PCR-RFLP. CCR5delta32 and 14pb HLA-G polymorphism were genotyped by PCR. Allelic, genotypic and haplotypic frequencies were estimated and compared between the groups using the Chi-square test or Fisher's exact test and subsequently were associated to diagnostic and prognostic factors. We observed a higher allelic frequency of the CCR2 wild type allele, Val (p = 0.040, OR 0.61, 95% CI = 0.38 - 0.98) e CCR5 wild type allele, Wt (p = 0.032, OR 0.46, CI 95% = 0.23 - 0.94) and higher haplotype frequency of the double wild type variants (Wt/Val) of these same genes (CCR2 and CCR5) in women in the control group (p = 0.030) compared to women with familial breast cancer. All polymorphisms were evaluated together with the clinical parameters and it was observed that women with breast cancer showed sporadic cancer latter (57.29 ± 8.457 years and 44.23 ± 12.092 years for women with sporadic breast cancer and familial breast cancer, respectively, p < 0.001) and more invasiveness (p = 0.001) as compared to women with familial breast cancer. Moreover, the HLA-G 14pb and CCR264I polymorphism, showed a positive association with tumor aggressiveness in women with sporadic breast cancer (p = 0.039 and p = 0.005, respectively). Our data suggest that invasive cancers may be associated with increased immune cells infiltration and inflammation in the tumor microenvironment mediated by both CCR2 receptor and HLA-G molecule.

Breast cancer is the most frequently diagnosed cancer in women worldwide.A treatment regime, both effective and safe and can only be achieved once more effective chemotherapeutic agents are discovered or identified. These “drugs” must selectively induce cell death such as apoptosis or necroptosis in the cancer cells. Apoptotic cell death allows a cell to “commit suicide” in genetically- controlled or programmed mechanism(s). The microenvironment of the tumour is important since a nurturing malignant environment is required for tumour maintenance, progression and ultimately the development of metastasis. Due to the correlation of the tumour microenvironment to aggressive tumour progression, emphasis should be placed on the constituents of the tumour’s microenvironment. In recent years, the understanding of intracellular pathways in cancer cells has increased rapidly, contributing to the development of drugs with more specific targets such as growth factors, signalling molecules, cell adhesion proteins, proteases, cell-cycle proteins, modulators of apoptosis and molecules that promote angiogenesis and metastasis. The main aim of this study was thus to identify a few potential or active compounds from a library of synthetically-derived compounds as possible alternative breast cancer treatment candidates.