No description available.

Background: Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk. Methods/design: This is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n=75) or placebo (n=75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored. Discussion: The study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases.

<p>Breast cancer is currently the most common non-skin cancer and the second leading cause of cancer-related death in women here in the United States. X-ray mammography is currently the standard clinical imaging modality for breast cancer screening and diagnosis due to its high sensitivity and resolution at a low patient dose. With the advancement of breast imaging from analog to digital, quantitative measurements rather than qualitative assessments can be made from these images. One such measurement, mammographic breast density (i.e. the percentage of the entire breast volume that is taken up by dense glandular tissue), has been shown to be a biomarker well correlated with cancer risk. However, a digital mammogram still suffers from its projective nature. The resulting overlap of normal breast tissue can obscure lesions, limit quantitative measurement accuracy, and present false alarms leading to unnecessary recall studies. To address this key limitation, several 3D imaging techniques have been developed such as breast magnetic resonance imaging (MRI), dedicated breast computed tomography (CT), and digital breast tomosynthesis (tomo). Perhaps the most recently developed modality is tomo, which is a limited-angle cone-beam CT of the breast compressed in the same geometry as mammography. Because tomo retains all the aforementioned advantages of mammography but adds depth information and can be built based on an existing digital mammography device, measuring breast density and extracting other quantitative features from tomo images was a major focus of this study.</p><p>Before attempting to measure breast density and other features from reconstructed tomo image volumes, the quantitative potential of this imaging modality was assessed. First, we explored a slice-by-slice technique that measures tissue density using only the information from a single slice from the reconstructed tomosynthesis volume with geometrically simple tissue-equivalent phantoms. Once this task has been satisfactorily performed, we studied a probabilistic approach toward quantitation of the entire 3D volume. Some work has been done previously in the realm of 2D hidden Markov random fields (HMRFs) to categorize mammograms according to their Wolf pattern, detect mammographic lesions, and segment satellite and mixed media (text/photograph) images. For this project, a 3D hidden Markov model (HMM) method was developed and applied to tomo images under the simplified assumption that the possible tissue type of each tomo voxel is either adipose (fatty) or glandular (dense). Because adipose and glandular tissue is easily distinguished in MR images, patient breast MRIs were used to train, validate, and finally to assess the accuracy of our HMM segmentation algorithm when applied to tomo images by comparing the volumetric breast density to the MRI breast density for the same patient. Because they are so often studied conjunctively, several image texture features were calculated and compared between MRI and tomo as well.</p><p>Another aim of our study was to investigate whether changes in macroscopic 3D imaging features (texture and density) can accurately predict the chemoprevention response that was measured with Random Periareolar Fine Needle Aspiration (RPFNA) cytology for a uniquely young high-risk cohort of women. This aim to investigate the potential of combining multi-modality macroscopic 3D imaging information with a cytological measure of risk and then investigating how response to tamoxifen and other chemoprevention treatment affects each of these risk biomarkers in young, high-risk women is completely novel in the fields of medical physics and biomedical engineering.</p> / Dissertation

Introduction: Breast density is an important independent risk factor for breast cancer and is negatively associated with diagnostic sensitivity of mammography. Measurement of breast density can be used to identify women at increased risk of developing breast cancer and those who would benefit from additional imaging. However, measurement techniques are generally subjective and do not reflect the true three-dimensional nature of the breast and its component tissues.Method: A semi-automated method for determining the volume of glandular tissue from digitised mammograms has been developed in Manchester. It requires a calibration device (stepwedge) to be imaged alongside the breast during mammography, with magnification markers on the compression paddle to accurately determine breast thickness. Improvements to the design of the stepwedge and markers have enabled the method to be applied to the screening population for the first time. 1,289 women had their volumetric breast density measured using this method and additionally completed a questionnaire on breast cancer risk factors.Results: The method has demonstrated excellent intra- and inter-observer agreement. The median percentage breast density in the study cohort was 8.4% (interquartile range 4.9 – 14.2%). There was no significant difference between left and right breasts; the difference between MLO and CC views was significant (CC view was denser), but values were closely correlated (r = 0.92, p < 0.001). The median glandular volume was 60.1cm3 and exhibited no significant variation between left/right breasts or CC/MLO views. A number of breast cancer risk factors were found to be significantly correlated with glandular volume and percentage breast density, including age, weight, BMI, parity, current HRT use and current smoking. The strength of correlation was equal to or greater than that of visually assessed mammographic density. Glandular volume and percentage breast density measurements demonstrated strong relationships with visually assessed mammographic density, which has been shown to be highly correlated with risk.Conclusions: These findings are promising and suggest that volumetric breast density measured using this method should be associated with breast cancer risk. However, further work is required to establish this relationship directly. The method will be used in a large study, known as PROCAS (Predicting Risk Of Cancer At Screening) which aims to develop individualised breast cancer risk prediction models; these have the potential to form the basis of tailored screening intervals. Preliminary work has been undertaken to adapt the method for full field digital mammography, which suggests that it is possible to use the integrated digital detector as the calibration device.

Dietary components potentially influence breast cancer risk factors, including breast density (BD) and estrogen metabolism (EM). Tamoxifen (TAM) is a commonly prescribed anti-estrogen adjuvant cancer treatment to reduce breast cancer risk, partially through modulation of BD and EM. Epidemiological evidence has suggested a potential protective effect from dietary intakes of fiber and vegetables in breast cancer recurrence in women on TAM as well as an independent influence on BD and EM. The relationship between dietary intake BD and EM in women prescribed TAM is not fully understood. A cross-sectional analysis using baseline data collected from 130 pre- and post-menopausal women taking TAM and enrolled in the Diindolylmethane Efficacy (DIME) Study was conducted. Participants completed the Arizona Food Frequency Questionnaire to assess dietary intake. TAM metabolites were analyzed through HPLC. BD was measured from digital mammograms and urinary EM was analyzed using LC/MS. Unadjusted linear regression between diet and four TAM metabolites indicated significant association between endoxifen and caffeine. 4-hydroxyTAM had significant inverse associations with fat intake, including monounsaturated, polyunsaturated and saturated fats. Linear regression adjusted for BMI revealed a statistically significant positive association with caffeine intake and BD, with no other dietary associations observed. The highest amount of correlations was observed between 2OHE and energy, total fat, MUFA, PUFA, protein and carbohydrate intake, though weak. Correlations were seen between 4OHE, 16αOHE and total isoflavones. Cholesterol was weakly positively correlated with 2mOHE, E1 and approached significance with E2. Dietary intake shows little association with BD or EM in women taking TAM therapy. Alternate preventive mechanisms for diet in women on TAM therapy should be investigated.

Breast cancer is the most common and the second most fatal cancer among women in the U.S. Current knowledge indicates that there is a relationship between high breast density (measured by mammography) and increased breast cancer risk. However, the biology behind this relationship is not well understood. This may be due to the limited information provided by mammography which only yields information on the relative amount of fibroglandular to adipose tissue in the breast. In our studies, breast density is assessed using quantitative MRI, in which MRI-based tissue-dependent parameters are derived voxel-wise by mathematically modeling the acquired MRI signals. Specifically, we use data from a radial gradient- and spin-echo imaging technique, previously developed in our group, to assess fat fraction and T₂ of the water component in relation to breast density. In addition, we use diffusion-weighted imaging to obtain another parameter, apparent diffusion coefficient (ADC) of the water component in the breast. Each parametric map provides a different type of information: fat fraction gives the amount of fat present in the voxel, the T₂ of water spin relaxation is sensitive to the water component in the tissue, and the ADC of water yields other type of information, such as tissue cellularity. The challenge in deriving these parameters from breast MRI data is the presence of abundant fat in the breast, which can cause artifacts in the images and can also affect the parameter estimation. We approached this problem by modifying the imaging sequence (as in the case of diffusion-weighted imaging) and by exploring new signal models that describe the MRI signal accounting for the presence of fat. In this work, we present the improvements made in the imaging sequence and in the parametric mapping algorithms using simulation and phantom experiments. We also present preliminary results in vivo in the context of breast density-related tissue characterization.

The number of women diagnosed with the breast cancer continues to rise year on year. Breast cancer is now the most common type of cancer in the UK, with over 55000 cases reported last year. In most cases, mammography is the first step towards diagnosing breast cancer. However, it continues to have many practical limitations as compared to more sophisticated modalities such as MRI. The relatively low cost of mammography, together with the ever increasing risk of women contracting the disease, has led to many developed countries having a breast screening program. These routine breast screens are taken at different points in time and are called temporal mammograms. Currently, a radiologist tends to qualitatively assess temporal mammograms and look for any abnormalities or suspicious regions that might be of a concern. In this thesis, we develop an automatic shape analysis model that can detect and quantify such changes inside the breast. This will not only help in early diagnosis of the disease, which is key to survival, but will potentially aid prognosis and post treatment care. The core to this thesis is the use of Circular Integral Invariants. We explore its multi-scale properties and use it for image smoothing to reduce image noise and enhance features for segmentation. We implement, modify and enhance a segmentation method which previously has been successfully used to acquire breast regions of interest. We applied such Integral Invariants for shape description, to be used for shape matching as well as for subdividing shapes into sub-regions and quantifying the differences between two such shapes. We combine boundary information with the information from inside a shape, thus eccentrically transforming shapes before describing their structure. We develop a novel false positives reduction method based on Integral Invariants scale space. A second aspect of the thesis is the evaluation of and emphasis on the use of breast density maps against the commonly used intensity maps or x-rays. We find density maps sufficient to use in clinical practice. The methods developed in this thesis aim to help clinicians in making diagnostic decision at the point of case. Our shape analysis model is easy to compute, fast and very general in nature that could be deployed in a wide range of applications, beyond mammography.

Mammographic breast density (MBD) is a strong risk factor for developing breast cancer. MBD is typically estimated by manually selecting the area occupied by the dense tissue on a mammogram. There is interest in measuring the volume of dense tissue, or volumetric breast density (VBD), as it could potentially be a stronger risk factor. This dissertation presents and validates an algorithm to measure the VBD from digital mammograms. The algorithm is based on an empirical calibration of the mammography system, supplemented by physical modeling of x-ray imaging that includes the effects of beam polychromaticity, scattered radation, anti-scatter grid and detector glare. It also includes a method to estimate the compressed breast thickness as a function of the compression force, and a method to estimate the thickness of the breast outside of the compressed region. The algorithm was tested on 26 simulated mammograms obtained from computed tomography images, themselves deformed to mimic the effects of compression. This allowed the determination of the baseline accuracy of the algorithm. The algorithm was also used on 55 087 clinical digital mammograms, which allowed for the determination of the general characteristics of VBD and breast volume, as well as their variation as a function of age and time. The algorithm was also validated against a set of 80 magnetic resonance images, and compared against the area method on 2688 images. A preliminary study comparing association of breast cancer risk with VBD and MBD was also performed, indicating that VBD is a stronger risk factor. The algorithm was found to be accurate, generating quantitative density measurements rapidly and automatically. It can be extended to any digital mammography system, provided that the compression thickness of the breast can be determined accurately.

A terapia hormonal na menopausa tem sido objeto de muita contradição nos últimos anos, pois trabalhos mostram resultados contraditórios quanto a benefícios e riscos para as usuárias. Ficou demonstrada, em alguns trabalhos, a maior incidência de carcinoma de mama em usuárias de terapia hormonal clássica e, portanto, existe uma constante busca no que diz respeito ao refinamento de métodos diagnósticos e avaliação dos efeitos das novas drogas na mama. Dentre as drogas mais modernas, a tibolona vem se destacando por apresentar poucos efeitos colaterais, principalmente relacionados à mama. Esta droga apresenta três metabólitos com ação tecidual específica. Assim, efeitos androgênicos, estrogênicos ou progesterônicos podem ser observados na dependência do órgão alvo estudado. Os objetivos de nosso estudo foram avaliar um método de análise computadorizada da densidade mamográfica e, ao mesmo tempo, avaliar os efeitos da tibolona na densidade dessas mamografias. Em nosso estudo, foram avaliadas 26 pacientes na pós menopausa e que tinham indicação do uso de terapia hormonal oral, de acordo com o protocolo vigente no Setor de Endocrinologia Ginecológica do Centro de Saúde Escola da Faculdade de Medicina de Ribeirão Preto-USP. Essas pacientes receberam tibolona na dose de 2,5 mg/dia por 24 semanas. Todas foram submetidas à mamografia antes a após o uso da droga sendo, durante a realização do exame, colocado sobre a plataforma de compressão da mama (Buck) um objeto de referência (escala em acrílico confeccionada para essa finalidade) na intenção de normalizar os exames pré e pós-tratamento. Além disto, as mamografias foram submetidas à avaliação de dois examinadores com o intuito de verificar variações da densidade mamográfica. Essas mesmas mamografias, após normalização pelo objeto de referência, também foram submetidas à análise computadorizada da densidade. Foram realizadas comparações entre os resultados da avaliação da densidade da mama antes e após o uso da tibolona tanto nos laudos dos examinadores, quanto nas imagens digitalizadas. Foi feito também comparação inter-examinadores. As análises comparativas das densidades das grafias antes a após o uso da tibolona não mostraram variações significativas tanto na análise dos examinadores quanto na análise computadorizada. A análise comparativa inter-examinadores mostrou uma tendência à variação entre as classificações da densidade mamográfica, apesar de não ser estatisticamente significante. Podemos concluir que a tibolona, se administrada a pacientes na pós menopausa, na dose de 2,5 mg/dia por 24 semanas não causa variação da densidade mamográfica. Desta forma, a avaliação computadorizada da densidade mamográfica pode ser usada como método auxiliar aos radiologistas, em casos de mamas mais densas permitindo uma melhor avaliação desses casos. / Over the last few years, hormonal therapy has been subject of much controversy since various studies have shown contradictory results regarding the risks and benefits for users. A higher incidence of breast carcinoma among users of classical hormonal therapy has been demonstrated in some studies and therefore there is a constant search regarding the refinement of diagnostic methods and the evaluation of the effects of new drugs on the breast. Among the more modern drugs, tibolone is particularly outstanding because it has few side effects, especially related to the breast. This drug has three metabolites with specific tissue action. Therefore, androgenic, estrogenic or progestogenic effects can be achieved, depending on the organ evaluated. The objectives of the present study were to assess a computerized method for the analysis of mammographic density. The author evaluated 26 menopausal women with an indication for oral hormonal therapy according to the protocol of the sector of gynecologic endocrinology of the Faculty of Medicine of Ribeirão Preto, USP. Tibolone at the dose of 2.5 mg/day was administered to these patients for 24 weeks. The patients were submitted to mammography before and after the use of the drug. During the exam, a reference object (an acrylic scale prepared for this purpose) was placed on the platform for breast compression (Buck) in order to normalize the pre- and post-treatment exams. In addition, two examiners evaluated the mammographies in order to determine variations in mammographic density. After normalization according to the reference object, these same mammographies were submitted to computerized density analysis. The mamographic density results obtained before and after the use of tibolone are compared in the digitalized images and in the examiners evaluation. In the same way, an inter-examiners analysis was done. The comparative analyses of the mammographic densities before and after the use of tibolone did not show significant variations in the analyses of the examiners or in the computerized analysis. Inter-examiner analysis showed a tendency to variation in the classification of mammographic density, although the difference was not statistically significant. The author concluded that tibolone, when administered to menopausal women at the dose of 2.5 mg/day for 24 weeks, did not cause a variation in mammographic density. Computerized evaluation of mammographic density can be used as an auxiliary method to radiologists, in cases of high density breast mammography, allowing a more confident evaluation of these cases.

A terapia hormonal na menopausa tem sido objeto de muita contradição nos últimos anos, pois trabalhos mostram resultados contraditórios quanto a benefícios e riscos para as usuárias. Ficou demonstrada, em alguns trabalhos, a maior incidência de carcinoma de mama em usuárias de terapia hormonal clássica e, portanto, existe uma constante busca no que diz respeito ao refinamento de métodos diagnósticos e avaliação dos efeitos das novas drogas na mama. Dentre as drogas mais modernas, a tibolona vem se destacando por apresentar poucos efeitos colaterais, principalmente relacionados à mama. Esta droga apresenta três metabólitos com ação tecidual específica. Assim, efeitos androgênicos, estrogênicos ou progesterônicos podem ser observados na dependência do órgão alvo estudado. Os objetivos de nosso estudo foram avaliar um método de análise computadorizada da densidade mamográfica e, ao mesmo tempo, avaliar os efeitos da tibolona na densidade dessas mamografias. Em nosso estudo, foram avaliadas 26 pacientes na pós menopausa e que tinham indicação do uso de terapia hormonal oral, de acordo com o protocolo vigente no Setor de Endocrinologia Ginecológica do Centro de Saúde Escola da Faculdade de Medicina de Ribeirão Preto-USP. Essas pacientes receberam tibolona na dose de 2,5 mg/dia por 24 semanas. Todas foram submetidas à mamografia antes a após o uso da droga sendo, durante a realização do exame, colocado sobre a plataforma de compressão da mama (Buck) um objeto de referência (escala em acrílico confeccionada para essa finalidade) na intenção de normalizar os exames pré e pós-tratamento. Além disto, as mamografias foram submetidas à avaliação de dois examinadores com o intuito de verificar variações da densidade mamográfica. Essas mesmas mamografias, após normalização pelo objeto de referência, também foram submetidas à análise computadorizada da densidade. Foram realizadas comparações entre os resultados da avaliação da densidade da mama antes e após o uso da tibolona tanto nos laudos dos examinadores, quanto nas imagens digitalizadas. Foi feito também comparação inter-examinadores. As análises comparativas das densidades das grafias antes a após o uso da tibolona não mostraram variações significativas tanto na análise dos examinadores quanto na análise computadorizada. A análise comparativa inter-examinadores mostrou uma tendência à variação entre as classificações da densidade mamográfica, apesar de não ser estatisticamente significante. Podemos concluir que a tibolona, se administrada a pacientes na pós menopausa, na dose de 2,5 mg/dia por 24 semanas não causa variação da densidade mamográfica. Desta forma, a avaliação computadorizada da densidade mamográfica pode ser usada como método auxiliar aos radiologistas, em casos de mamas mais densas permitindo uma melhor avaliação desses casos. / Over the last few years, hormonal therapy has been subject of much controversy since various studies have shown contradictory results regarding the risks and benefits for users. A higher incidence of breast carcinoma among users of classical hormonal therapy has been demonstrated in some studies and therefore there is a constant search regarding the refinement of diagnostic methods and the evaluation of the effects of new drugs on the breast. Among the more modern drugs, tibolone is particularly outstanding because it has few side effects, especially related to the breast. This drug has three metabolites with specific tissue action. Therefore, androgenic, estrogenic or progestogenic effects can be achieved, depending on the organ evaluated. The objectives of the present study were to assess a computerized method for the analysis of mammographic density. The author evaluated 26 menopausal women with an indication for oral hormonal therapy according to the protocol of the sector of gynecologic endocrinology of the Faculty of Medicine of Ribeirão Preto, USP. Tibolone at the dose of 2.5 mg/day was administered to these patients for 24 weeks. The patients were submitted to mammography before and after the use of the drug. During the exam, a reference object (an acrylic scale prepared for this purpose) was placed on the platform for breast compression (Buck) in order to normalize the pre- and post-treatment exams. In addition, two examiners evaluated the mammographies in order to determine variations in mammographic density. After normalization according to the reference object, these same mammographies were submitted to computerized density analysis. The mamographic density results obtained before and after the use of tibolone are compared in the digitalized images and in the examiners evaluation. In the same way, an inter-examiners analysis was done. The comparative analyses of the mammographic densities before and after the use of tibolone did not show significant variations in the analyses of the examiners or in the computerized analysis. Inter-examiner analysis showed a tendency to variation in the classification of mammographic density, although the difference was not statistically significant. The author concluded that tibolone, when administered to menopausal women at the dose of 2.5 mg/day for 24 weeks, did not cause a variation in mammographic density. Computerized evaluation of mammographic density can be used as an auxiliary method to radiologists, in cases of high density breast mammography, allowing a more confident evaluation of these cases.