Orientador: Gilberto Uemura / Banca: José Ricardo Paciência Rodrigues / Banca: Helena Cristina da Silva / Resumo: O câncer de mama é um problema de saúde pública, com 49.470 casos em 2005 no Brasil. A mamografia é o método de escolha para rastreamento e diagnóstico precoce do câncer de mama. O sistema BI RADS veio tentar organizar e padronizar os laudos mamográficos. O VPP do Bl-RADS IV varia de 2 a 90% e da categoria V > 90%. Objetivos: avaliar as principais características das lesões mamográficas suspeitas e calcular o VPP da categoria IV e V. Sujeitos e métodos: foram estudados 309 laudos mamográficos de Bl-RADS IV e V e correlacionados com seus resultados de histopatológicos. A análise estatística foi o teste diagnóstico do VPP. Resultados: idade média 54 anos, mama esquerda acometida em 165 (53,4%) pacientes e mama direita em 144 (46,6%) pacientes, BI RADS IV 265 (85,8%), Bl-RADS V 44 (14,2%), lesões benignas 163 (52,8%), lesões proliferativas de risco 48 (15,5%), lesões malignas 98 (31,7%). Os principais achados mamográficos na categoria IV foram as microcalcificações 163 (61,5%) e na categoria V foram os nódulos em 22 (50,0%). A modalidade de biopsia mais usada na categoria IV foi o agulhamento mamário em 188 (70,9%) e na categoria V foi à biopsia per cutânea em 16 (36,4%). O carcinoma ductal infiltrante foi o tipo histológico mais freqüente na categoria IV em 45 (78,9%) e na categoria V em 35 (85,4%) pacientes. O VPP para a categoria IV foi de 39,2% e da categoria V de 95,5%. Conclusão: Concluímos que os principais achados mamográficos na categoria IV foram as microcalcificações, com VPP desta categoria de 39,2%; na categoria V foram os nódulos os principais achados mamográficos, com VPP de 95,5%, valor este que confirma esta categoria como alta probabilidade de malignidade. / Abstract: Breast cancer is a serious world health problem. The mammography is the better method for the screening of earlier breast cancer. The Bl-RADS system was introduced to standardize the report results. Bl-RADS IV has a Positive Predictive Value (PPV) ranged from 2 to 90% and over 90% to category V. Objectives: to evaluate the principal characteristics of the suspicious mammographic lesions and calculate PPV of the Bl-RADS category IV and V. Subjects and methods: it was evaluated 309 reports of mammographic abnormalities classified as Bl-RADS IV and V; and their correlations with biopsies results. Resulted: medium age was 54 years, the lesions occurred in 165 left-sided breast (53.4%) and in 144 right-sided breast (46.6%). Bl-RADS IV pattern was identified in 265 (85.8%) reports and BI-RADS V in 44 (14.2%). Benign lesions were found in 163 reports (52.8%), proliferative risk lesions were found in 48 (15.5%), malign lesions were found in 98 (31.7%). The principal mammographic lesion was the microcalcification in category IV and nodules were in category V. The most used procedure for diagnosis was core biopsy in 204 patients (66%). The invasive ductal carcinoma was the predominant histological type in malignant breast tumors. PPV of 39.2% was observed for BI-RADS IV and for BI-RÃDS V was 95.5%. Conclusion: the principal mammographic pattern lesion in the Bl-RADS IV was the microcalcification, with PPV of 39.2% and the nodules were the principal mammographic pattern lesions in the BI-RADS V with PPV of 95.5%. It confirms the high probability of malignancy in BI-RADS V category. / Mestre

Resumo: O câncer de mama acomete muitas mulheres em todo o mundo e as metástases são a principal causa de morte. Conhecimentos acerca do comportamento biológico são úteis para aprimorar a abordagem, principalmente terapêutica. Os perfis histológico e imuno-histoquímico podem nos permitir melhor compreensão dos fenômenos que determinam a evolução da doença. Objetivo: Comparar lesões palpáveis e não palpáveis para determinar agressividade biológica, baseado nos parâmetros histopatológicos e imuno-histoquímicos. Metodologia: Foram estudados 296 (duzentos e noventa e seis) casos de câncer de mama, confirmados pela histopatologia, separados em dois grupos: Grupo 1: Lesões não palpáveis, detectadas exclusivamente por mamografia (microcalcificações, nódulo ou distorção arquitetural) ou por achado incidental e Grupo 2: Lesões palpáveis (nódulo, massa ou condensação), em estudo retrospectivo, analítico e horizontal. Foram avaliados critérios histopatológicos (Grau Nuclear, Formação Tubular e Índice Mitótico) e imuno-histoquímicos (Receptores de Estrogênio, Receptores de Progesterona, Ki67, p53 e c-erbB-2) de agressividade, comparando-se os dois grupos, com tratamento estatístico (índice de significância p<0,05). Resultados: Avaliados os dois grupos indistintamente, observou-se que a maior expressão dos Receptores Hormonais (RE e RP) esteve relacionada com Grau Nuclear, Formação Tubular e Índice Mitótico baixos. Super-expressão de Ki67 foi prevalente nos graus histopatológicos mais elevados. c-erbB-2 e p53, embora não estatisticamente significativo, apresentaram a mesma tendência do Ki67 em relação às variáveis histopatológicas. O Grupo 1 apresentou menor incidência de Grau Nuclear, Formação Tubular e Índice Mitótico elevados que o Grupo 2. O Grupo 1 apresentou maior expressão dos Receptores Hormonais (p<0,05), enquanto o Grupo 2 apresentou maior expressão de Ki67(p<0,05) / Abstract: The breast cancer commits many women throughout the world, and the metastases are the main cause of deaths. The knowledge about the biologic aggressiveness is useful to improve the treatment and the histopathological and immunohistochemical profiles can help to understand the events that determine the outcome. Objective: To compare two groups of patients with breast cancer (Group 1: non-palpable lesions; Group 2: palpable lesions), based in histopathological and immunohistochemical parameters to determine the biologic aggressiveness. Methods: We have studied 296 (two hundred ninety six) cases of breast cancer, diagnosed by histopathology, divided in two groups: Group 1- non-palpable lesions, exclusively detected by mammography (microcalcifications, nodule or architectural distortion) or with incidental finding and Group 2- palpable lesions (Nodule or mass), in retrospective, analytical and horizontal analysis. We evaluated histopathological parameters (nuclear grade, tubularity and mitotic counts) and immunohistochemical markers(Estrogen Receptors, Progesterone Receptors, p53, Ki67 and c-erbB-2), comparing the two groups, with statistic analysis (p<0.05). Results: The bigger the expression of estrogen and progesterone receptors the smaller the nuclear grade, tubularity and mitotic counts. On the contrary, the bigger the expression of Ki67 the higher the nuclear grade, tubularity and mitotic counts. We observed that c-erbB-2 and p53 expression showed the same tendency of the Ki67 in relation to the histopathologic parameters. Group 1 showed less incidence of elevated nuclear grade, tubularity and mitotic counts, bigger expression of Estrogen and Progesterone Receptors(p<0.05). Group 2 showed higher expression of Ki67 (p<0.05). The c-erbB-2 expression was a little bit higher in Group 2 than in Group 1(p=0.055). The p53 expression didnot show differences between the groups. / Orientador: Gilberto Uemura / Coorientador: Rogério Estevam Farias / Doutor

Orientador: Laurival Antonio De Luca / Banca: Anete Kinumi Ueda / Banca: Odair Carlito Michelin / Banca: José Costa Andrade / Banca: Angela Marx / Resumo: Foi preocupante o número de biópsias indicadas nas microcalcificações (BIRADS 3 e 4) encontradas em mamografias e o baixo número de casos positivos encontrados. Partindo de pacientes com este diagnóstico radiológico, foi realizada dosagem sé rica de zinco através do método de absorção atômica. Após a realização das biópsias, foi feita a análise estatística dos casos com exame patológico benigno ou neoplasias intra-ductais. Não foram encontradas diferenças entre os grupos quanto a idade, a idade da menarca, a idade da primeira gestação, o número de gestações, nem com o tempo de amamentação. Não foram encontradas diferenças significativas entre os dois grupos, quando relacionados com a classificação BI-RADS. Embora as pacientes com neoplasia intra-ciucta I tenham apresentados níveis séricos de zinco abaixo do grupo controle, este valor não foi significativo (p>O,05), não podendo ser considerado como fator preditivo de risco. / Abstract: The indication of biopsy in the cases of microcalcification (BI-RADS 3 and 4) detected by mammography and the small number of positive results found at these biopsies causes concern among the authors. Thus, serum zinc concentrations were measured by the atomic absorption method in patients with this radiologic diagnosis. Following biopsy performance, the cases of benign pathologic findings or intraductal neoplasia were statistically analyzed. No differences between groups were found in age, age at menarche, age at first pregnancy, number of pregnancies and breastfeeding duration. No significant differences between groups were found regarding BI-RADS c1assification. Although serum zinc concentrations were lower in the patients with intraductal neoplasia than in controls, statistical difference was not significant (p>O,05). Thus, this parameter could not be considered as a predictive risk facto... / Doutor

No description available.

Recently the traditional primary method of treatment for breast carcinoma — the Halsted radical mastectomy — has been challenged. It is felt by some people that other methods may be more appropriate for certain women. Quality of life and the patient's preferences are being considered in addition to the strictly medical aspects of the problem. One procedure that attempts to increase the quality of life for certain women is the selective biopsy. Women who are proven to have lymph node metastases at the biopsy are spared a mastectomy and treated by radiation since surgery cannot remove all of the cancer. A study was undertaken at the British Columbia Cancer Institute of selective biopsy patients diagnosed between 1955 and 1963 in order to assess the procedure in British Columbia. After studying survival for selective biopsy patients and others, it was concluded that the procedure should continue to be recommended. Since only 14% of the patients now referred to BCCI have had a selective biopsy, I decided to try to find a statistical method for assessing the probability of nodal metastases. The problem is one of statistical classification. The literature on the theory of several statistical models was reviewed. Two models were chosen for the problem: linear discriminant analysis and logistic regression. The classification procedure most often used is discriminant analysis. However, the linear discriminant model assumes a normal distribution and common covariance matrix for the vector of observations. Medical data is often non-normal and even discrete. The logistic probability model works well with such data. Both models were then used to study the selective biopsy problem. The patients of the BCCI study were used as a training set to estimate the parameters of the discriminant function and the logistic probability function. Then each estimated function was used to classify the patients as a measure of the goodness of fit of the models. The logistic regression correctly classified slightly more of the patients than the discriminant analysis did. Because of the iterative nature of the logistic regression, the execution time for the logistic regression was longer than for discriminant analysis, but not beyond practical limits. .The variables that were significant in the statistical analyses could be used to help the physician make a clinical assessment of the lymph nodes of a woman with breast carcinoma. The variables indicate areas where further research would be useful. / Science, Faculty of / Mathematics, Department of / Graduate

The most exciting area in current cancer research is immuno-oncology, which aims to develop immunotherapy that activates the human immune system to attack cancers. However, we still lack broadly effective drugs and drug targets for this promising new cancer treatment modality. In an attempt to seek new immuno-oncology drugs that particularly target the antitumor innate immunity, our lab had previously screened traditional Chinese herbal medicine and found that water extract from a medicinal plant, Alocasia Cucullata (AC), has strong anticancer activity in mouse solid tumor models and acts partly by promoting antitumor, proinflammatory macrophages. However, the active components responsible for this exciting immuno-oncology activity and the corresponding immune targets are unknown. Therefore, the aim of my PhD study is to develop chemical biology strategies to isolate and purify the active components of AC from the crude water extract and identify the corresponding cellular targets and mechanisms. Results from my study identified two separable activities and active components, one smaller than 3K and the other larger than 100K, which work synergistically to simulate antitumor macrophages. Further analysis revealed the >100K active component is a large polysaccharide that binds to multiple Toll-like Receptors (TLRs) critical for activating proinflammatory M1-type macrophages. Identity of the Nonetheless, I was able to clean up this fraction by 50 fold and perform RNAseq to examine the innate immune targets of this intriguing drug lead and found it acts to differentiate monocytes to macrophages. Overall my PhD thesis has explored new chemical biology strategies to purify and characterize active components from traditional Chinese medicine towards new drug development and developed a variety of cell-based immune activity assays for identifying and characterizing novel innate immune drug targets and mechanisms

In this study, we searched for significant hypo and hyper methylation CpG (5'-C-phosphate-G-3') probes from The Cancer Genome Atlas (TCGA) datasets. First, the relationship between hypo and hypermethylation pattern in significantly expressed genes associated in pancreatic ductal adenocarcinoma (PDAC) was analyzed using computational methodologies in R package. This was done by combining DNA methylation (DM) and gene expression (GE) information, and their corresponding metadata (i.e., clinical data and molecular subtypes) and saved as R files. Next, examination of differentially methylated CpG sites (DMCs) between two groups (normal vs tumor) was identified gene sets. From this analysis, we found nine (09) overexpressed hypomethylated and six (06) under expressed hypermethylated genes near significant CpG probes. Results from this work will shed light on the relationship between CpG methylation and gene expression associated with PDAC.

Tumour initiation and progression is thought to be driven by a small population of tumor initiating cells (TICs) or cancer stem cells (CSCs), which have the capacity to migrate and cause metastases and contribute to tumour relapse. These cells possess properties that are similar to those of normal tissue stem cells, which include the capacity to undergo self-renewal as well as the capacity to give rise to more differentiated progenitor cells, which comprise the bulk of the tumour cell population. Thus far, the clinical significance of these cells in breast cancers has not been extensively explored with regard to their relationship with tumour pathology or patient survival. In this thesis we evaluate the presence of these cells in terms of clinicopathological tumour characteristics and patient outcome, as well as assess potential markers of breast CSCs for prognostic significance. Through the quantification of breast CSCs in primary breast tumours using in vivo xenografts assays we show that their presence correlates with aggressive tumour characteristics. In addition, we propose that markers of breast CSCs may differ based on the molecular subtype of the tumour, and that these markers have prognostic significance in patients. / Thesis / Master of Science (MSc)

No description available.

This thesis explores the role of values in risk assessment for breast cancer. Why? First, breast cancer poses a serious health threat to women, yet currently has no known cause. This means the discussion of risk becomes central to this disease. Second, K.S. Shrader-Frechette has shown that values enter in at each stage of risk assessment. These stages are the choice of topics, methods, and evaluation. By using Shrader-Frechette's framework for analysis of such areas of breast cancer as mammography, prophylactic mastectomy, tamoxifen and the role of estrogen, research routes, and prevention, it can be shown that certain values dominate the risk assessment. These values are the technological imperative, individual causation of disease, and reductionism. This thesis argues that the dominance of these values has led to a narrow and biased view of breast cancer risk. This view leaves women with fewer legitimate choices for the management of breast cancer risk and in many ways excluded altogether from its risk discourse. As breast cancer advocacy groups have gained in strength, attention has been drawn to the fact that there are competing values which can be used in risk assessment for this disease. These competing values are a low-tech/high-preventative, holistic, care-oriented approach to disease. These values can provide a viable alternative assessment of risk in breast cancer. Furthermore, this alternative risk picture is more desirable than the current one, because it helps to redirect and widen the focus on risk in breast cancer and gives women a central role in its risk discourse. / Thesis / Master of Arts (MA)