Mammographic Image Contrast Enhancement Through The Use Of Moving Contrast Sweep.

Low contrast in mamographic image has always made detection of subtle signs such as the presence of micro calcification within dense tissue a challenge

Beyond mammography : an evaluation of complementary modalities in breast imaging

Breast cancer is the main cause of cancer death among women worldwide and the goal of mammography screening is to reduce breast cancer-specific mortality. The reduction of the sensitivity of mammography for detecting cancer among women with dense breasts requires the use of complementary methods for this subset of women. Three of the projects in this thesis examine the performance of such complementary methods and a fourth study investigates the association between the biomarker BPE (background parenchymal enhancement) and risk factors for breast cancer. In study 1, we prospectively compared the sensitivity and specificity of Automated Breast Volume Scanner (ABVS) with handheld ultrasound for detection of breast cancer among women with a suspicious mammographic finding who were recalled after attending the population-based mammography screening program. We performed both methods on 113 women and found 26 malignant lesions. Analysis was performed in two categories: breasts with a suspicious screening mammography and breasts with a negative screening mammography. In the first category (n=118) the sensitivity of both methods was 88% (p=1.0), the specificity of handheld ultrasound was 93.5 % and ABVS was 89.2%. The difference in specificity was not statistically significant (p=0.29). For breasts without a suspicious mammographic finding, the sensitivity of handheld ultrasound and ABVS was 100% (p=1.0), the specificity was 100% and 94.1% respectively. The difference in specificity was statistically significant (p=0.03). In summary, ABVS has similar sensitivity to handheld ultrasound, but lower specificity in breasts with a negative mammogram. In study 2, we explored the incremental cancer detection rate when adding a threedimensional infrared imaging (3DIRI) score to screening mammography among women with dense breasts (Volpara volumetric density >6 % on the previous mammography examination) who attended the population-based mammography screening program. Women with a negative mammogram and positive 3DIRI score were triaged for a DCEMRI examination to verify the presence of cancer. Of 1727 participants, 7 women had a mammography-detected breast cancer. Among women with a negative mammogram and a positive infrared imaging (n=219), an additional 6 cancers in 5 women were detected on MRI resulting in an incremental cancer detection rate of 22.5 per 1000. Among women with a negative mammography and infrared examination, one woman was diagnosed with breast cancer during the two-year follow-up. The study does not provide information on the proportion of cancers that might have been detected had MRI been performed among women with a negative mammogram and 3DIRI score. Consequently, this study does not shed light on the diagnostic accuracy of infrared imaging or whether using an infrared risk score is the optimal method for identifying women who would benefit from additional imaging modalities. In study 3, we used MRI examinations of study 2 among women without breast cancer (n=214) to explore the association between BPE at DCE-MRI and a large array of risk factors for breast cancer. Thanks to the Karma database, we had unique access to data from self-reporting questionnaires on risk factors. BPE and mammographic density were assessed visually by three radiologists and BPE was further dichotomized into low and high. We created categorical variables for other risk factors. We calculated the univariable associations between BPE and each risk factor and fitted an adjusted logistic regression model. In the adjusted model, we found a negative association with age (p=0.002), and a positive association with BMI (p=0.03). There was a statistically significant association with systemic progesterone (p=0.03) but since only five participants used progesterone preparations, the result is uncertain. Although the likelihood for high BPE increased with increase in mammographic density, the association was not statistically significant (p=0.23). We were able to confirm earlier findings that BPE is associated with age, BMI and progesterone, but we could not find an association with other risk factors for breast cancer. In study 4, we compared the diagnostic accuracy, reading-time, and inter-rater agreement of an abbreviated protocol (aMRI) to the routine full protocol (fMRI) of contrast-enhanced breast MRI. The MRI examinations were performed before biopsy and among women who were not part of a surveillance program due to an increased familial risk of breast cancer. Analysis was performed on a per breast basis. Aggregated across three readers, the sensitivity and specificity were 93.0% and 91.7% for aMRI, and 92.0% and 94.3% for the fMRI. Using a generalized estimating equations approach to compare the two protocols, the difference in sensitivity was not statistically significant (p=0.840), and the difference in specificity was significant (p=0.003). There was a statistically significant difference in average reading time of 67 seconds for aMRI and 126 seconds for the fMRI (p= 0.000). The inter-rater agreement was 0.79 for aMRI and 0.83 for fMRI. We were able to demonstrate that the abbreviated protocol has similar sensitivity to the full protocol even if MRI is performed before biopsy and the images lack telltale signs of malignancy. In conclusion, this thesis provides new knowledge about the biomarker BPE, broadens our knowledge on the diagnostic accuracy of two different imaging modalities and highlights the importance of good study design for diagnostic accuracy studies

Breast Cancer Detection on Automated 3D Ultrasound with Co-localized 3D X-ray.

X-ray mammography is the gold standard for detecting breast cancer while B-mode ultrasound is employed as its diagnostic complement. This dissertation aimed at acquiring a high quality, high-resolution 3D automated ultrasound image of the entire breast at current diagnostic frequencies, in the same geometry as mammography and its 3D equivalent, digital breast tomosynthesis, and to extend and help test its utility with co-localization. The first objective of this work was to engineer solutions to overcome some challenges inherent in acquiring complete automated ultrasound of the breast and minimizing patient motion during scans. Automated whole-breast ultrasound that can be registered to X-Ray imaging eliminates the uncertainty associated with hand-held ultrasound. More than 170 subjects were imaged using superior coupling agents tested during the course of this study. At least one radiologist rated the usefulness of X-Ray and ultrasound co-localization as high in the majority of our study cases. The second objective was to accurately register tomosynthesis image volumes of the breast, making the detection of tissue growth and deformation over time a realistic possibility. It was found for the first time to our knowledge that whole breast digital tomosynthesis image volumes can be spatially registered with an error tolerance of 2 mm, which is 10% of the average size of cancers in a screening population. The third and final objective involved the registration and fusion of 3D ultrasound image volumes acquired from opposite sides of the breast in the mammographic geometry, a novel technique that improves the volumetric resolution of high frequency ultrasound but poses unique problems. To improve the accuracy and speed of registration, direction-dependent artifacts should be eliminated. Further, it is necessary to identify other regions, usually at greater depths, that contain little or misleading information. Machine learning, principal component analysis and speckle reducing anisotropic diffusion were tested in this context. We showed that machine learning classifiers can identify regions of corrupted data accurately on a custom breast-mimicking phantom, and also that they can identify specific artifacts in-vivo. Initial registrations of phantom image sets with many regions of artifacts removed provided robust results as compared to the original datasets.Ph.D.Biomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/78947/1/sumedha_1.pd

Breast Cancer : automatic detection and risk analysis through machine learning algorithms, using mammograms

Tese de Mestrado Integrado, Engenharia Biomédica e Biofísica (Engenharia Clínica e Instrumentação Médica), 2021, Universidade de Lisboa, Faculdade de CiênciasCom 2.3 milhões de casos diagnosticados em todo o Mundo, durante o ano de 2020, o cancro da mama tornou-se aquele com maior incidência, nesse mesmo ano, considerando ambos os sexos. Anualmente, em Portugal, são diagnosticados aproximadamente sete mil (7000) novos casos de cancro da mama, com mil oitocentas (1800) mulheres a morrerem, todos os anos, devido a esta doença - indicando uma taxa de mortalidade de aproximadamente 5 mulheres por dia. A maior parte dos diagnósticos de cancro da mama ocorrem ao nível de programas de rastreio, que utilizam mamografia. Esta técnica de imagem apresenta alguns problemas: o facto de ser uma imagem a duas dimensões leva a que haja sobreposição de tecidos, o que pode mascarar a presença de tumores; e a fraca sensibilidade a mamas mais densas, sendo estas caraterísticas de mulheres com risco de cancro da mama mais elevado. Como estes dois problemas dificultam a leitura das mamografias, grande parte deste trabalhou focou-se na verificação do desempenho de métodos computacionais na tarefa de classificar mamografias em duas classes: cancro e não-cancro. No que diz respeito à classe “não cancro” (N = 159), esta foi constituída por mamografias saudáveis (N=84), e por mamografias que continham lesões benignas (N=75). Já a classe “cancro” continha apenas mamografias com lesões malignas (N = 73). A discriminação entre estas duas classes foi feita com recurso a algoritmos de aprendizagem automática. Múltiplos classificadores foram otimizados e treinados (Ntreino=162, Nteste = 70), recorrendo a um conjunto de características previamente selecionado, que descreve a textura de toda a mamografia, em vez de apenas uma única Região de Interesse. Estas características de textura baseiam-se na procura de padrões: sequências de pixéis com a mesma intensidade, ou pares específicos de pixéis. O classificador que apresentou uma performance mais elevada foi um dos Support Vector Machine (SVM) treinados – AUC= 0.875, o que indica um desempenho entre o bom e o excelente. A Percent Mammographic Density (%PD) é um importante fator de risco no que diz respeito ao desenvolvimento da doença, pelo que foi estudado se a sua adição ao set de features selecionado resultaria numa melhor performance dos classificadores. O classificador, treinado e otimizado utilizando as features de textura e os cálculos de %PD, com maior capacidade discriminativa foi um Linear Discriminant Analysis (LDA) – AUC = 0.875. Uma vez que a performance é igual à obtida com o classificador que utiliza apenas features de textura, conclui-se que a %PD parece não contribuir com informação relevante. Tal pode ocorrer porque as próprias características de textura já têm informação sobre a densidade da mama. De forma a estudar-se de que modo o desempenho destes métodos computacionais pode ser afetado por piores condições de aquisição de imagem, foi simulado ruído gaussiano, e adicionado ao set de imagens utilizado para testagem. Este ruído, adicionado a cada imagem com quatro magnitudes diferentes, resultou numa AUC de 0.765 para o valor mais baixo de ruído, e numa AUC de 0.5 para o valor de ruído mais elevado. Tais resultados indicam que, para níveis de ruído mais baixo, o classificador consegue, ainda assim, manter uma performance satisfatória – o que deixa de se verificar para valores mais elevados de ruído. Estudou-se, também, se a aplicação de técnicas de filtragem – com um filtro mediana – poderia ajudar a recuperar informação perdida aquando da adição de ruído. A aplicação do filtro a todas as imagens ruidosas resultou numa AUC de 0.754 para o valor mais elevado de ruído, atingindo assim um desempenho similar ao set de imagens menos ruidosas, antes do processo de filtragem (AUC=0.765). Este resultados parecem indicar que, na presença de más condições de aquisição, a aplicação de um filtro mediana pode ajudar a recuperar informação, conduzindo assim a um melhor desempenho dos métodos computacionais. No entanto, esta mesma conclusão parece não se verificar para valores de ruído mais baixo onde a AUC após filtragem acaba por ser mais reduzida. Tal resultado poderá indicar que, em situações onde o nível de ruído é mais baixo, a técnica de filtragem não só remove o ruído, como acaba também por, ela própria, remover informação ao nível da textura da imagem. De modo a verificar se mamas com diferentes densidades afetavam a performance do classificador, foram criados três sets de teste diferentes, cada um deles contendo imagens de mamas com a mesma densidade (1, 2, e 3). Os resultados obtidos indicam-nos que um aumento na densidade das mamas analisadas não resulta, necessariamente, numa diminuição da capacidade em discriminar as classes definidas (AUC = 0.864, AUC = 0.927, AUC= 0.905; para as classes 1, 2, e 3 respetivamente). A utilização da imagem integral para analisar de textura, e a utilização de imagens de datasets diferentes (com dimensões de imagem diferentes), poderiam introduzir um viés na classificação, especialmente no que diz respeito às diferentes áreas da mama. Para verificar isso mesmo, utilizando o coeficiente de correlação de Pearson, ρ = 0.3, verificou-se que a área da mama (e a percentagem de ocupação) tem uma fraca correlação com a classificação dada a cada imagem. A construção do classificador, para além de servir de base a todos os testes apresentados, serviu também o propósito de criar uma interface interativa, passível de ser utilizada como ficheiro executável, sem necessidade de instalação de nenhum software. Esta aplicação permite que o utilizador carregue imagens de mamografia, exclua background desnecessário para a análise da imagem, extraia features, teste o classificador construído e dê como output, no ecrã, a classe correspondente à imagem carregada. A análise de risco de desenvolvimento da doença foi conseguida através da análise visual da variação dos valores das features de textura ao longo dos anos para um pequeno set (N=11) de mulheres. Esta mesma análise permitiu descortinar aquilo que parece ser uma tendência apresentada apenas por mulheres doentes, na mamografia imediatamente anterior ao diagnóstico da doença. Todos os resultados obtidos são descritos profundamente ao longo deste documento, onde se faz, também, uma referência pormenorizada a todos os métodos utilizados para os obter. O resultado da classificação feita apenas com as features de textura encontra-se dentro dos valores referenciados no estado-da-arte, indicando que o uso de features de textura, por si só, demonstrou ser profícuo. Para além disso, tal resultado serve também de indicação que o recurso a toda a imagem de mamografia, sem o trabalho árduo de definição de uma Região de Interesse, poderá ser utilizado com relativa segurança. Os resultados provenientes da análise do efeito da densidade e da área da mama, dão também confiança no uso do classificador. A interface interativa que resultou desta primeira fase de trabalho tem, potencialmente, um diferenciado conjunto de aplicações: no campo médico, poderá servir de auxiliar de diagnóstico ao médico; já no campo da análise computacional, poderá servir para a definição da ground truth de potenciais datasets que não tenham legendas definidas. No que diz respeito à análise de risco, a utilização de um dataset de dimensões reduzidas permitiu, ainda assim, compreender que existem tendências nas variações das features ao longo dos anos, que são especificas de mulheres que desenvolveram a doença. Os resultados obtidos servem, então, de indicação que a continuação desta linha de trabalho, procurando avaliar/predizer o risco, deverá ser seguida, com recurso não só a datasets mais completos, como também a métodos computacionais de aprendizagem automática.Two million and three hundred thousand Breast Cancer (BC) cases were diagnosed in 2020, making it the type of cancer with the highest incidence that year, considering both sexes. Breast Cancer diagnosis usually occurs during screening programs using mammography, which has some downsides: the masking effect due to its 2-D nature, and its poor sensitivity concerning dense breasts. Since these issues result in difficulties reading mammograms, the main part of this work aimed to verify how a computer vision method would perform in classifying mammograms into two classes: cancer and non-cancer. The ‘non-cancer group’ (N=159) was composed by images with healthy tissue (N=84) and images with benign lesions (N=75), while the cancer group (N=73) contained malignant lesions. To achieve this, multiple classifiers were optimized and trained (Ntrain = 162, Ntest = 70) with a previously selected ideal sub-set of features that describe the texture of the entire image, instead of just one small Region of Interest (ROI). The classifier with the best performance was Support Vector Machine (SVM), (AUC = 0.875), which indicates a good-to-excellent capability discriminating the two defined groups. To assess if Percent Mammographic Density (%PD), an important risk factor, added important information, a new classifier was optimized and trained using the selected sub-set of texture features plus the %PD calculation. The classifier with the best performance was a Linear Discriminant Analysis (LDA), (AUC=0.875), which seems to indicate, once it achieves the same performance as the classifier using only texture features, that there is no relevant information added from %PD calculations. This happens because texture already includes information on breast density. To understand how the classifier would perform in worst image acquisition conditions, gaussian noise was added to the test images (N=70), with four different magnitudes (AUC= 0.765 for the lowest noise value vs. AUC ≈ 0.5 for the highest). A median filter was applied to the noised images towards evaluating if information could be recovered. For the highest noise value, after filtering, the AUC was very close to the one obtained for the lowest noise value before filtering (0.754 vs 0.765), which indicates information recovery. The effect of density in classifier performance was evaluated by constructing three different test sets, each containing images from a density class (1,2,3). It was seen that an increase in density did not necessarily resulted in a decrease in performance, which indicates that the classifier is robust to density variation (AUC = 0.864, AUC= 0.927, AUC= 0.905 ; for class 1, 2, and 3 respectively). Since the entire image is being analyzed, and images come from different datasets, it was verified if breast area was adding bias to classification. Pearson correlation coefficient provided an output of ρ = 0.22, showing that there is a weak correlation between these two variables. Finally, breast cancer risk was assessed by visual texture feature analysis through the years, for a small set of women (N=11). This visual analysis allowed to unveil what seems to be a pattern amongst women who developed the disease, in the mammogram immediately before diagnosis. The details of each phase, as well as the associated final results are deeply described throughout this document. The work done in the first classification task resulted in a state-of-the-art performance, which may serve as foundation for new research in the area, without the laborious work of ROI definition. Besides that, the use of texture features alone proved to be fruitful. Results concerning risk may serve as basis for future work in the area, with larger datasets and the incorporation of Computer Vision methods

Mechanoresponsive drug delivery materials

Stimuli-responsive drug delivery materials release their payloads in response to physiological or external cues and are widely reported for stimuli such as pH, temperature, ionic strength, electrical potential, or applied magnetic field. While a handful of reports exist on materials responsive to mechanical stimuli, this area receives considerably less attention. This dissertation therefore explores three-dimensional networks and polymer-metal composites as mechanoresponsive biomaterials by using mechanical force to either trigger the release of entrapped agents or change the conformation of implants. At the nanoscale, shear is demonstrated as a mechanical stimulus for the release of a monoclonal antibody from nanofibrous, low molecular weight hydrogels formed from bio-inspired small molecule gelators. Using their self-healing, shear-thinning properties, mechanoresponsive neutralization of tumor necrosis factor alpha (TNFα) in a cell culture bioassay is achieved, suggesting utility for treating rheumatoid arthritis. Reaching the microscale, mechanical considerations are incorporated within the design of cisplatin-loaded meshes for sustained local drug delivery, which are fabricated through electrospinning a blend of polycaprolactone and poly(caprolactone-co-glycerol monostearate). These meshes are compliant, amenable to stapling/suturing, and they exhibit bulk superhydrophobicity (i.e., extraordinary resistance to wetting), which sustains release of cisplatin >90 days in vitro and significantly delays tumor recurrence in an in vivo murine lung cancer resection model. This polymer chemistry/processing strategy is then generalized by applying it to the poly(lactide-co-glycolide) family of biomedical polymers. As a macroscopic approach, a tunable, tension-responsive multilayered drug delivery device is developed, which consists of a water-absorbent core flanked by two superhydrophobic microparticle coatings. Applied strain initiates coating fracture to cause core hydration and subsequent drug release, with rates dependent on strain magnitude. Finally, macroscopic, shape-changing polymer-composite materials are developed to improve the current functionality of breast biopsy markers. This shape change provides a means to prevent marker migration from its intended site—a current clinical problem. In summary, mechanoresponsive systems are described, ranging from the nano- to macroscopic scale, for applications in drug delivery and biomedical devices. These studies add to the nascent field of mechanoresponsive biomedical materials and the arsenal of drug delivery techniques required to combat cancer and other medical ailments.2017-10-27T00:00:00

Advances in Biomedical Applications and Assessment of Ultrasound Nonrigid Image Registration.

Image volume based registration (IVBaR) is the process of determining a one-to-one transformation between points in two images that relates the information in one image to that in the other image quantitatively. IVBaR is done primarily to spatially align the two images in the same coordinate system in order to allow better comparison and visualization of changes. The potential use of IVBaR has been explored in three different contexts. In a preliminary study on identification of biometric from internal finger structure, semi-automated IVBaR-based study provided a sensitivity and specificity of 0.93 and 1.00 respectively. Visual matching of all image pairs by four readers yielded 96% successful match. IVBaR could potentially be useful for routine breast cancer screening and diagnosis. Nearly whole breast ultrasound (US) scanning with mammographic-style compression and successful IVBaR were achieved. The image volume was registered off-line with a mutual information cost function and global interpolation based on the non-rigid thin-plate spline deformation. This Institutional Review Board approved study was conducted on 10 patients undergoing chemotherapy and 14 patients with a suspicious/unknown mass scheduled to undergo biopsy. IVBaR was successful with mean registration error (MRE) of 5.2±2 mm in 12 of 17 ABU image pairs collected before, during or after 115±14 days of chemotherapy. Semi-automated tumor volume estimation was performed on registered image volumes giving 86±8% mean accuracy compared with a radiologist hand-segmented tumor volume on 7 cases with correlation coefficient of 0.99 (p<0.001). In a reader study by 3 radiologists assigned to mark the tumor boundary, significant reduction in time taken (p<0.03) was seen due to IVBaR in 6 cases. Three new methods were developed for independent validation of IVBaR based on Doppler US signals. Non-rigid registration tools were also applied in the field of interventional guidance of medical tools used in minimally invasive surgery. The mean positional error in a CT scanner environment improved from 3.9±1.5 mm to 1.0±0.3 mm (p<0.0002). These results show that 3D image volumes and data can be spatially aligned using non-rigid registration for comparison as well as quantification of changes.Ph.D.Applied PhysicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/64802/1/gnarayan_1.pd

Analysis of Dynamic Magnetic Resonance Breast Images

Dynamic Magnetic Resonance Imaging is a non-invasive technique that provides an image sequence based on dynamic information for locating lesions and investigating their structures. In this thesis we develop new methodology for analysing dynamic Magnetic Resonance image sequences of the breast. This methodology comprises an image restoration step that reduces random distortions affecting the data and an image classification step that identifies normal, benign or malignant tumoral tissues. In the first part of this thesis we present a non-parametric and a parametric approach for image restoration and classification. Both methods are developed within the Bayesian framework. A prior distribution modelling both spatial homogeneity and temporal continuity between neighbouring image pixels is employed. Statistical inference is performed by means of a Metropolis-Hastings algorithm with a specially chosen proposal distribution that out-performs other algorithms of the same family. We also provide novel procedures for estimating the hyper-parameters of the prior models and the normalizing constant so making the Bayesian methodology automatic. In the second part of this thesis we present new methodology for image classification based on deformable templates of a prototype shape. Our approach uses higher level knowledge about the tumour structure than the spatio-temporal prior distribution of our Bayesian methodology. The prototype shape is deformed to identify the structure of the malignant tumoral tissue by minimizing a novel objective function over the parameters of a set of non-affine transformations. Since these transformations can destroy the connectivity of the shape, we develop a new filter that restores connectivity without smoothing the shape. The restoration and classification results obtained from a small sample of image sequences are very encouraging. In order to validate these results on a larger sample, in the last part of the thesis we present a user friendly software package that implements our methodology