Functional Magnetic Resonance Imaging of Breast Cancer

This thesis examines the use of magnetic resonance imaging (MRI) techniques in the detection of breast cancer and the prediction of pathological complete response (pCR) to neoadjuvant chemotherapy (NACT). This thesis compares the diagnostic performance of diffusion-weighted imaging (DWI) models in the breast using a systematic review and meta-analysis. Advanced diffusion models have been proposed that may improve the performance of standard DWI using the apparent diffusion coefficient (ADC) to discriminate between malignant and benign breast lesions. Pooling the results from 73 studies, comparable diagnostic accuracy is shown using the ADC and parameters from the intra-voxel incoherent motion (IVIM) and diffusion tensor imaging (DTI) models. This work highlights a lack of standardisation in DWI protocols and methodology. Conventional acquisition techniques used in DWI often suffer from image artefacts and low spatial resolution. A multi-shot DWI technique, multiplexed sensitivity encoding (MUSE), can improve the image quality of DWI. A MUSE protocol has been optimised through a series of phantom experiments and validated in 20 patients. Comparing MUSE to conventional DWI, statistically significant improvements are shown in distortion and blurring metrics and qualitative image quality metrics such as lesion conspicuity and diagnostic confidence, increasing the clinical utility of DWI. This thesis investigates the use of dynamic contrast-enhanced MRI (DCE-MRI) in the detection of breast cancer and the prediction of pCR. Abbreviated MRI (ABB-MRI) protocols have gained increasing attention for the detection of breast cancer, acquiring a shortened version of a full diagnostic protocol (FDP-MRI) in a fraction of the time, reducing the cost of the examination. The diagnostic performance of abbreviated and full diagnostic protocols is systematically compared using a meta-analysis. Pooling 13 studies, equivalent diagnostic accuracy is shown for ABB-MRI in cohorts enriched with cancers, and lower but not significantly different diagnostic performance is shown in screening cohorts. Higher order imaging features derived from pre-treatment DCE-MRI could be used to predict pCR and inform decisions regarding targeted treatment, avoiding unnecessary toxicity. Using data from 152 patients undergoing NACT, radiomics features are extracted from baseline DCE-MRI and machine learning models trained to predict pCR with moderate accuracy. The stability of feature selection using logistic regression classification is demonstrated and a comparison of models trained using features from different time points in the dynamic series demonstrates that a full dynamic series enables the most accurate prediction of pCR.GE Healthcare funded PhD Studentshi

The impact of tumor edema on T2-weighted 3T-MRI invasive breast cancer histological characterization: a pilot radiomics study

Background: to evaluate the contribution of edema associated with histological features to the prediction of breast cancer (BC) prognosis using T2-weighted MRI radiomics. Methods: 160 patients who underwent staging 3T-MRI from January 2015 to January 2019, with 164 histologically proven invasive BC lesions, were retrospectively reviewed. Patient data (age, menopausal status, family history, hormone therapy), tumor MRI-features (location, margins, enhancement) and histological features (histological type, grading, ER, PgR, HER2, Ki-67 index) were collected. Of the 160 MRI exams, 120 were considered eligible, corresponding to 127 lesions. T2-MRI were used to identify edema, which was classified in four groups: peritumoral, pre-pectoral, subcutaneous, or diffuse. A semi-automatic segmentation of the edema was performed for each lesion, using 3D Slicer open-source software. Main radiomics features were extracted and selected using a wrapper selection method. A Random Forest type classifier was trained to measure the performance of predicting histological factors using semantic features (patient data and MRI features) alone and semantic features associated with edema radiomics features. Results: edema was absent in 37 lesions and present in 127 (62 peritumoral, 26 pre-pectoral, 16 subcutaneous, 23 diffuse). The AUC-classifier obtained by associating edema radiomics with semantic features was always higher compared to the AUC-classifier obtained from semantic features alone, for all five histological classes prediction (0.645 vs. 0.520 for histological type, 0.789 vs. 0.590 for grading, 0.487 vs. 0.466 for ER, 0.659 vs. 0.546 for PgR, and 0.62 vs. 0.573 for Ki67). Conclusions: radiomic features extracted from tumor edema contribute significantly to predicting tumor histology, increasing the accuracy obtained from the combination of patient clinical characteristics and breast imaging data

Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

© 2017 The Author(s). Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis

Tensor based multichannel reconstruction for breast tumours identification from DCE-MRIs

A new methodology based on tensor algebra that uses a higher order singular value decomposition to perform three-dimensional voxel reconstruction from a series of temporal images obtained using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is proposed. Principal component analysis (PCA) is used to robustly extract the spatial and temporal image features and simultaneously de-noise the datasets. Tumour segmentation on enhanced scaled (ES) images performed using a fuzzy C-means (FCM) cluster algorithm is compared with that achieved using the proposed tensorial framework. The proposed algorithm explores the correlations between spatial and temporal features in the tumours. The multi-channel reconstruction enables improved breast tumour identification through enhanced de-noising and improved intensity consistency. The reconstructed tumours have clear and continuous boundaries; furthermore the reconstruction shows better voxel clustering in tumour regions of interest. A more homogenous intensity distribution is also observed, enabling improved image contrast between tumours and background, especially in places where fatty tissue is imaged. The fidelity of reconstruction is further evaluated on the basis of five new qualitative metrics. Results confirm the superiority of the tensorial approach. The proposed reconstruction metrics should also find future applications in the assessment of other reconstruction algorithms

Quantitative Analysis of Dynamic Contrast-Enhanced Magnetic Resonance Breast Images: Optimization of the Time-to-Peak as a Diagnostic Indicator

Dynamic contrast-enhanced MRI (DCE-MRI) has been widely used in the diagnosis of breast cancer and as an aid in the management of this disease. Although DCE-MRI has a high sensitivity for the detection of malignant breast lesions, distinguishing malignant from benign lesions is more challenging for this method and may depend to some extent on how the images are analysed. Although clinical assessment of these images typically involves qualitative assessment by an expert, there is growing interest in the development of quantitative and automated methods to assist the expert assessment. This thesis involves the quantitative analysis of a particular empirical feature of the time evolution of the DCE-MRI signal known as the time-to-peak ( 7 ^ ) . In particular, this thesis investigates die feasibility of applying measures sensitive to 7 ^ heterogeneity as indicators for malignancy in breast DCE-MRI. Breast lesions in this study were automatically segmented by K-means clustering. Voxel- by-voxel 7\u27peak values were extracted using an empirical model. The / 1th percentile values (p = 10, 20...) of the 7’peak distribution within each lesion, as well as the fractional and absolute hot spot volumes were determined, where hot spot volume refers to the volume of tissue with 7 ^ less than a threshold value. Using the area under the receiver operating characteristic curve (AUC), these measures were tested as indicators for differentiating fibroadenomas from invasive lesions and from ductal carcinoma in situ, as well as for differentiating non-fibroadenoma benign lesions from these malignant lesions. For differentiating fibroadenomas from malignant lesions, low percentile values (p = 10) provided high diagnostic performance. At the optimal threshold (3 min), the hot spot volume provided high diagnostic performance. However, non-fibroadenoma benign lesions were quite difficult to distinguish from malignant lesions. This thesis demonstrates that quantitative analysis of the 7’peak distribution can be optimized for diagnostic performance providing indicators sensitive to intra-lesion r peak heterogeneity

Analysis of interpretability methods applied to DCE-MRI of Breasts Images

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Sinais e Imagens Biomédicas), 2022, Universidade de Lisboa; Faculdade de CiênciasO cancro da mama é uma doença que afeta um elevado número de mulheres a uma escala mundial [1]. Os exames físicos e a mamografia são as formas mais eficazes de detetar lesões e nódulos na mama. Contudo, estes métodos podem revelar-se inconclusivos. Uma maneira de solidificar o diagnóstico de cancro da mama é a realização de testes suplementares, tal como a ressonância magnética. O exame de ressonância magnética mais comum para detetar cancro da mama é DCE-MRI, um exame que obtém imagens através da injeção de um agente de contraste [2]. A consolidação do diagnóstico pode também ser realizada via meios de machine learning. Vários métodos de machine learning têm vindo a ajudar técnicos a realizar tarefas como deteção e segmentação de tumores. Apesar destes métodos serem eficazes, as tarefas que este realizam são caracterizadas por um elevado grau de responsabilidade visto que estão diretamente relacionadas com o bem-estar de um ser humano. Isto leva à necessidade de justificar os resultados destes métodos de maneira a aumentar a confiança nos mesmos. As técnicas que tentam explicar os resultados de métodos de machine learning pertencem à área de Explainable Artificial Intelligence [3]. Esta dissertação foca-se em aplicar e analisar métodos state-of-the-art de Explainable Artificial Intelligence a modelos de machine learning. Como estes modelos foram construídos tendo como base imagens de DCE-MR de mamas, os métodos aplicados a estes modelos visam explicar os seus resultados visualmente. Um dos métodos aplicados foi SHAP, SHapley Addictive exPlanations. Este método pode ser aplicado a uma variedade de modelos e baseia-se nos Shapley Values da teoria de jogos para explicar a importância das características da imagem de acordo com os resultados do modelo [4]. Outro método aplicado foi Local Interpretable Model-agnostic Explanations, ou LIME. Este método cria imagens alteradas e testa-as nos modelos criados. Estas imagens perturbadas têm um peso de acordo com o grau das perturbações. Quando testadas nos modelos, LIME calcula quais as perturbações que influenciam a mudança do resultado do modelo e, consequentemente, encontra as áreas da imagem que são mais importantes para a classificação da imagem de acordo com o modelo [5]. O último método aplicado foi o Gradient-weighted Class Activation Mapping, ou Grad-CAM. Este método pode ser aplicado em diversos modelos, sendo uma generalização do método CAM [6], mas apenas pode ser aplicado em tarefas de classificação. O método de Grad-CAM utiliza os valores dos gradientes específicos de classes e as feature maps extraídas de convolutional layers para realçar áreas discriminativas de uma certa classe na imagem. Estas layers são componentes importantes que constituem o corpo dos modelos. Para lá destes métodos, extraiu-se e analisou-se matrizes convolucionais, chamadas de filtros, usadas pelas convolutional layers para obter o output destas layers. Esta tarefa foi realizada para observar os padrões que estão a ser filtrados nestas camadas. Para aplicar estes métodos, foi necessário construir e treinar vários modelos. Nesse sentido, três modelos com a mesma estrutura foram criados para realizar tarefas de regressão. Estes modelos têm uma arquitetura constituída por três convolutional layers seguidas de uma linear layer, uma dropout layer e outra linear layer. Um dos modelos tem como objetivo medir a área do tumor em maximum intensity projections dos volumes. Os outros dois modelos têm como objetivo medir a percentagem de redução do tumor quando introduzido dois maximum intensity projections. A diferença entre estes dois modelos está nas labels criadas para os inputs. Um dos modelos usa valores calculados através da diferença entre a área dos tumores dos duas maximum intensity projections, enquanto o outro modelo usa valores da regressão da área do tumor fornecidos por técnicos. A performance destes modelos foi avaliada através da computação dos coeficientes de correlação de Pearson e de Spearman. Estes coeficientes são calculados usando a covariância e o produto do desvio-padrão de duas variáveis, e diferem no facto de o coeficiente de Pearson apenas captar relações lineares enquanto o coeficiente de Spearman capta qualquer tipo de relação. Do modelo que teve como objetivo medir a área do tumor calculou-se os coeficientes de Pearson e de Spearman de 0.53 e 0.69, respetivamente. O modelo que teve como objetivo calcular a percentagem de redução do tumor e que usou valores calculados como labels teve a melhor performance dos três modelos, com coeficientes de Pearson e de Spearman com valores de 0.82 e 0.87, respetivamente. O último modelo utilizado não conseguiu prever corretamente os valores fornecidos pelos técnicos e, consequentemente, este modelo foi descartado. De seguida, os métodos de visualização de filtros e SHAP foram aplicados aos dois restantes modelos. A técnica de visualização de filtros permitiu demonstrar as partes da imagem que estão a ser filtradas nas convolutional layers, sendo possível observar certos padrões nestes filtros. O método SHAP realçou áreas da mama que contribuíram para as previsões dos modelos. Como ambas as tarefas se focam em calcular algo através da área dos tumores, consideramos imagens SHAP bem-sucedidas aquelas que realçam áreas do tumor. Com isto em mente, as imagens obtidas através do método SHAP tiveram um sucesso de 57% e de 69% para o modelo que mede a área do tumor e para o modelo que mede a percentagem de redução do tumor, respetivamente. Outro modelo foi construído com o objetivo de classificar pares de maximum intensity projections de acordo com percentagem de redução de área do tumor. Cada par foi previamente classificado numa de quatro classes, sendo que cada classe corresponde a uma redução incremental de 25%, ou seja, a primeira classe corresponde a uma redução do tumor de 0% a 25%, enquanto a última classe corresponde a uma redução do tumor de 75% a 100%. Este modelo tem uma arquitetura semelhante à de um modelo de Resnet18 [7]. A performance deste modelo foi avaliada através de uma matriz de confusão. Através desta matriz podemos observar um sucesso de 70% no que toca a previsões corretas feitas pelo modelo. De seguida, os três métodos, SHAP, LIME e Grad-CAM, foram aplicados neste modelo. Como o objetivo deste modelo baseia-se em classificar as imagens de acordo com a percentagem de redução de tumor, também se considerou imagens de SHAP com sucesso aquelas que realçam áreas do tumor. Tendo isto em conta, observou-se uma taxa de sucesso de 82% em realçar a zona do tumor nas maximum intensity projections. As perturbações criadas para serem aplicadas no método LIME correspondem a áreas quadradas na imagem. O método LIME cria imagens atribuindo valores nulos a estas áreas aleatoriamente. O método LIME atribui um peso às imagens perturbadas de acordo com o nível de perturbação que estas sofrem. Neste trabalho, duas diferentes perturbações foram criadas, sendo a primeira perturbação áreas quadradas de 10 por 10 pixéis e a segunda áreas quadradas de 25 por 25 pixéis. Após a perturbação das imagens, estas foram inseridas novamente no modelo e as diferenças na previsão do modelo foram aprendidas pelo algoritmo do LIME. Imagens criadas com as perturbações mais pequenas tiveram uma maior taxa de sucesso que as perturbações maiores, realçando perturbações na área do tumor com uma certidão de 48%. Apesar deste facto, as imagens criadas com as perturbações de 25 por 25 pixéis tiveram os resultados mais claros no que toca a localizar o tumor visto que o tamanho das perturbações permitiu englobar todo o tumor. Por último, o método Grad-CAM foi aplicado a todas as importantes convolutional layers do modelo. Este método foi bastante eficaz a localizar as áreas discriminativas de uma certa classe, visto que conseguiu localizar o tumor bastante facilmente quando aplicado na última convolutional layer. Para lá deste facto, foi possível observar as áreas discriminativas de uma certa classe nas imagens quando se aplica este método a convolutional layers intermédias. Concluindo, a aplicação destas técnicas permitiu explicar parte das decisões feitas pelos modelos de machine learning no âmbito da análise de imagens de DCE-MRI de cancro da mama.Computer aided diagnosis has had an exponential growth in medical imaging. Machine learning has helped technicians in tasks such as tumor segmentation and tumor detection. Despite the growth in this area, there is still a need to justify and fully understand the computer results, in order to increase the trust of medical professionals in these computer tasks. By applying explainable methods to the machine learning algorithms, we can extract information from techniques that are often considered black boxes. This dissertation focuses on applying and analyzing state-of-the-art XAI (eXplainable Artificial Intelligence) methods to machine learning models that handle DCE-MR (Dynamic Contrast-Enhanced Magnetic Resonance) breast images. The methods used to justify the model’s decisions were SHAP (SHapley Additive exPlanations) [4], LIME (Local Interpretable Model-agnostic Explanations) [5] and Grad-CAM (Gradient-weighted Class Activation Mapping) [8], which correspond to three visual explanation methods. SHAP uses Shapley Values from game theory to explain the importance of features in the image to the model’s prediction. LIME is a method that uses weighted perturbed images and tests then using the existing models. From the model’s response to these perturbed images, the algorithm can find which perturbations cause the model to change its prediction and, consequently, can find the important areas in the image that lead to the model’s prediction. Grad-CAM is a visual explanation method that can be applied to a variety of neural network architectures. It uses gradient scores from a specific class and feature maps extracted from convolutional layers to highlight classdiscriminative regions in the images. Two neural network models were built to perform regression tasks such as measuring tumor area and measuring tumor shrinkage. To justify the network’s results, filters were extracted from the network’s convolutional layers and the SHAP method was applied. The filter visualization technique was able to demonstrate which parts of the image are being convoluted by the layer’s filters while the SHAP method highlighted the areas of the tumor that contributed most to the model’s predictions. The SHAP method had a success rate of 57% at highlighting the correct area of the breast when applied to the neural network which measured the tumor area, and a success rate of 69% when applied to the neural network which measured the tumor shrinkage. Another model was created using a Resnet18’s architecture. This network had the task of classifying the breast images according to the shrinkage of the tumor and the SHAP, LIME and Grad-CAM methods were applied to it. The SHAP method had a success rate of 82%. The LIME method was applied two times by using perturbations of different sizes. The smaller sized perturbations performed better, having a success rate of 48% at highlighting the tumor area, but the larger sized perturbations had better results in terms of locating the entire tumor, because the area covered was larger. Lastly, the Grad-CAM method excelled at locating the tumor in the breast when applied to the last important convolutional layer in the network

Estrategias de mejora en el diagnóstico del cáncer de mama por imagen de resonancia magnética: Avances en la secuencia potenciada en difusión

Desde la introducción de la imagen eco-planar para la obtención de la imagen potenciada en difusión (IPD), esta secuencia se utiliza cada vez más en la práctica clínica para la detección y caracterización de las lesiones mamarias. La IPD eco-planar de disparo único carece de una alta resolución espacial y es sensible al movimiento y a la falta de homogeneidad del campo magnético lo que puede generar artefactos en la imagen que a menudo dificultan una adecuada delimitación de las lesiones, en especial aquellas de menor tamaño. Las secuencias de difusión eco-planares de disparo múltiple ofrecen una mayor resolución espacial, pero son susceptibles a errores de fase inducidos por el movimiento, ya que cada disparo individual puede tener una dirección de codificación diferente. Esto produce artefactos tipo fantasma, registro erróneo de pixeles y una baja resolución de imagen con pobre contraste de difusión en las imágenes generadas. Además, los valores del coeficiente de difusión aparente (CDA) pueden verse alterados arrojando medidas inexactas que pueden afectar al diagnóstico. Una de las técnicas más prometedoras para corregir los errores de fase inducidos por el movimiento es la imagen potenciada en difusión decodificación de sensibilidad multiplexada (IPDCSM). Esta técnica utiliza el método de imagen paralela llamado de codificación de sensibilidad (SENSE por sus siglas en inglés) multiplexado logrando una mejor relación señal ruido(RSR). La IPDCSM reduce los artefactos y las distorsiones geométricas sin necesidad de ecos de navegación o modificaciones en la secuencia de pulsos. Esto genera imágenes de alta resolución con tiempos de adquisición cortos que permiten su aplicabilidad clínica. Este trabajo constituye la primera experiencia de esta secuencia aplicada a la imagen mamaria..

Assessment of the Spatial Heterogeneity of Breast Cancers: Associations Between Computed Tomography and Immunohistochemistry.

Background Tumour heterogeneity is considered an important mechanism of treatment failure. Imaging-based assessment of tumour heterogeneity is showing promise but the relationship between these mathematically derived measures and accepted 'gold standards' of tumour biology such as immunohistochemical measures is not established.Methods A total of 20 women with primary breast cancer underwent a research dynamic contrast-enhanced computed tomography prior to treatment with data being available for 15 of these. Texture analysis was performed of the primary tumours to extract 13 locoregional and global parameters. Immunohistochemical analysis associations were assessed by the Spearman rank correlation.Results Hypoxia-inducible factor-1α was correlated with first-order kurtosis (r = -0.533, P = .041) and higher order neighbourhood grey-tone difference matrix coarseness (r = 0.54, P = .038). Vascular maturity-related smooth muscle actin was correlated with higher order grey-level run-length long-run emphasis (r = -0.52, P = .047), fractal dimension (r = 0.613, P = .015), and lacunarity (r = -0.634, P = .011). Micro-vessel density, reflecting angiogenesis, was also associated with lacunarity (r = 0.547, P = .035).Conclusions The associations suggest a biological basis for these image-based heterogeneity features and support the use of imaging, already part of standard care, for assessing intratumoural heterogeneity