Fat Quantitation in Liver Biopsies Using a Pretrained Classification Based System

Non-Alcoholic Fatty Liver Disease (NAFLD) is a common syndrome that mainly leads to fat accumulation in liver and steatohepatitis. It is targeted as a severe medical condition ranging from 20% to 40% in adult populations of the Western World. Its effect is identified through insulin resistance, which places patients at high mortality rates. An increased fat aggregation rate, can dramatically increase the development of liver steatosis, which in later stages may advance into fibrosis and cirrhosis. During recent years, new studies have focused on building new methodologies capable of detecting fat cells, based on the histology method with digital image processing techniques. The current study, expands previous work on the detection of fatty liver, by identifying once more a number of diverse histological findings. It is a combined study of both image analysis and supervised learning of fat droplet features, with a specific goal to exclude other findings from fat ratio calculation. The method is evaluated in a total set of 40 liver biopsy images with different magnification capabilities, performing satisfyingly (1.95% absolute error)

The Discrete Analysis of the Tissue Biopsy Images with Metamaterial Formalization:Identifying Tumor Locus

Herein, we develop an enhanced and automated methodology for detection of the tumour cells in fixed biopsy samples. Metamaterial formalism (MMF) approach allowing recognition of tumour areas in tissue samples is enhanced by providing an advanced technique to digitize mouse biopsy images. Thus, a colour-based segmentation technique based on the K-means clustering method is used allowing for a precise segmentation of the cells composing the biological tissue sample. Errors occurring at the tissue digitization steps are detected by applying MMF. Doing so, we end up with the robust, fully automated approach with no needs of the human intervention, ready for the clinical applications. The proposed methodology consists of three major steps, i. e. digitization of the biopsy image, analysis of the biopsy image, modelling of the disordered metamaterial. It is worthwhile mentioning, that the technique under consideration allows for the cancer stage detection. Moreover, early stage cancer diagnosis is possible by applying MMF

Deep Learning-based Computer-Aided Diagnosis systems: a contribution to prostate cancer detection in histopathological images

In this work, novel computer-aided diagnosis systems for medical image analysis focusing on prostate cancer are proposed and implemented. First, the histopathology of prostate cancer was studied, along with the Gleason Grading System, which measures the aggressiveness of a tumor through different patterns with the purpose of driving therapies dealing with this disease. Furthermore, a study of Deep Learning techniques, particularly focusing on neural networks applied to medical image analysis, was conducted. Based on these studies, a Deep Learning-based system to detect malignant regions in gigapixel-size whole-slide prostate cancer tissue images was proposed and developed, which is able to report spatial information of the malignant areas. This solution was evaluated in terms of performance and execution time, obtaining promising results when compared to other state-of-the-art methods. Since the implemented system locates malignant regions within the image without providing a global class, a customWide & Deep network was developed to report a slide-level label per image. The proposed system provides a fast screening method for analyzing histopathological images. Next, a neural network was proposed to assign a specific Gleason pattern to the malignant areas of the tissue. Finally, with the purpose of developing a global computeraided diagnosis system for prostate cancer detection and classification, the three aforementioned subsystems were combined, allowing a complete analysis of histopathological images by reporting whether the sample is normal or malignant, and, in the last case, a heatmap of the malignant areas with their corresponding Gleason pattern. The studied algorithms were also used for other medical image analysis tasks. The performance of these systems were evaluated, discussing the obtained results, presenting conclusions and proposing improvements for future works

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

Ultrasound Guided Robot for Human Liver Biopsy using High Intensity Focused Ultrasound for Hemostasis

Percutaneous liver biopsy is the gold standard among clinician\u27s tool to diagnose and guide subsequent therapy for liver disease. Ultrasound image guidance is being increasingly used to reduce associated procedural risks but post–biopsy complications still persist. The major and most common complication is hemorrhage, which is highly unpredictable and may sometimes lead to death. Though the risk of mortality is low, it is too high for a diagnostic procedure. Post-biopsy care and additional surgical intervention to arrest hemorrhage make liver biopsy a costly procedure for health care delivery systems. Non-invasive methods to stop bleeding exist like electro–cautery, microwave, lasers, radio frequency, argon–beam, and High Intensity Focused Ultrasound (HIFU). All the methods except HIFU require direct exposure of the needle puncture site for hemostasis. HIFU is an ultrasound modality and uses mechanical sound waves for focused energy delivery. Ultrasound waves are minimally affected by tissue attenuation and focus internal targets without direct exposure. Human error in focusing HIFU renders it unusable for a medical procedure especially when noninvasive. In this project we designed and developed an ultrasound guided prototype robot for accurate HIFU targeting to induce hemostasis. The robotic system performs percutaneous needle biopsy and a 7.5 cm focal length HIFU is fired at the puncture point when the needle tip retracts to the liver surface after sample collection. The robot has 4 degrees of freedom (DOF) for biopsy needle insertion, HIFU positioning, needle angle alignment and US probe image plane orientation. As the needle puncture point is always in the needle path, mechanically constraining the HIFU to focus on the needle reduced the required functionality significantly. Two mini c-arms are designed for needle angle alignment and US probe image plane orientation. This reduced the contact foot print of the robot over the patient providing a greater dexterity for positioning the robot. The robot is validated for HIFU hemostasis by a series of experiments on chicken breasts. HIFU initiated hemorrhage control with robotic biopsy ensures arrest of post-biopsy hemorrhage and decreases patient anxiety, hospital stay, morbidity, time of procedure, and cost. This can also be extended to other organs like kidneys, lungs etc. and has widespread implications such as control of hemorrhage in post-biopsies in patients with reduced ability for hemostasis. This research opens a greater scope for research for automation and design making it a physician friendly tool for eventual clinical use

Advancements and Breakthroughs in Ultrasound Imaging

Ultrasonic imaging is a powerful diagnostic tool available to medical practitioners, engineers and researchers today. Due to the relative safety, and the non-invasive nature, ultrasonic imaging has become one of the most rapidly advancing technologies. These rapid advances are directly related to the parallel advancements in electronics, computing, and transducer technology together with sophisticated signal processing techniques. This book focuses on state of the art developments in ultrasonic imaging applications and underlying technologies presented by leading practitioners and researchers from many parts of the world

Fat Quantitation in Liver Biopsies Using a Pretrained Classification Based System

Non-Alcoholic Fatty Liver Disease (NAFLD) is a common syndrome that mainly leads to fat accumulation in liver and steatohepatitis. It is targeted as a severe medical condition ranging from 20% to 40% in adult populations of the Western World. Its effect is identified through insulin resistance, which places patients at high mortality rates. An increased fat aggregation rate, can dramatically increase the development of liver steatosis, which in later stages may advance into fibrosis and cirrhosis. During recent years, new studies have focused on building new methodologies capable of detecting fat cells, based on the histology method with digital image processing techniques. The current study, expands previous work on the detection of fatty liver, by identifying once more a number of diverse histological findings. It is a combined study of both image analysis and supervised learning of fat droplet features, with a specific goal to exclude other findings from fat ratio calculation. The method is evaluated in a total set of 40 liver biopsy images with different magnification capabilities, performing satisfyingly (1.95% absolute error)

A Colour Wheel to Rule them All: Analysing Colour & Geometry in Medical Microscopy

Personalized medicine is a rapidly growing field in healthcare that aims to customize medical treatments and preventive measures based on each patient’s unique characteristics, such as their genes, environment, and lifestyle factors. This approach acknowledges that people with the same medical condition may respond differently to therapies and seeks to optimize patient outcomes while minimizing the risk of adverse effects. To achieve these goals, personalized medicine relies on advanced technologies, such as genomics, proteomics, metabolomics, and medical imaging. Digital histopathology, a crucial aspect of medical imaging, provides clinicians with valuable insights into tissue structure and function at the cellular and molecular levels. By analyzing small tissue samples obtained through minimally invasive techniques, such as biopsy or aspirate, doctors can gather extensive data to evaluate potential diagnoses and clinical decisions. However, digital analysis of histology images presents unique challenges, including the loss of 3D information and stain variability, which is further complicated by sample variability. Limited access to data exacerbates these challenges, making it difficult to develop accurate computational models for research and clinical use in digital histology. Deep learning (DL) algorithms have shown significant potential for improving the accuracy of Computer-Aided Diagnosis (CAD) and personalized treatment models, particularly in medical microscopy. However, factors such as limited generability, lack of interpretability, and bias sometimes hinder their clinical impact. Furthermore, the inherent variability of histology images complicates the development of robust DL methods. Thus, this thesis focuses on developing new tools to address these issues. Our essential objective is to create transparent, accessible, and efficient methods based on classical principles from various disciplines, including histology, medical imaging, mathematics, and art, to tackle microscopy image registration and colour analysis successfully. These methods can contribute significantly to the advancement of personalized medicine, particularly in studying the tumour microenvironment for diagnosis and therapy research. First, we introduce a novel automatic method for colour analysis and non-rigid histology registration, enabling the study of heterogeneity morphology in tumour biopsies. This method achieves accurate tissue cut registration, drastically reducing landmark distance and excellent border overlap. Second, we introduce ABANICCO, a novel colour analysis method that combines geometric analysis, colour theory, fuzzy colour spaces, and multi-label systems for automatically classifying pixels into a set of conventional colour categories. ABANICCO outperforms benchmark methods in accuracy and simplicity. It is computationally straightforward, making it useful in scenarios involving changing objects, limited data, unclear boundaries, or when users lack prior knowledge of the image or colour theory. Moreover, results can be modified to match each particular task. Third, we apply the acquired knowledge to create a novel pipeline of rigid histology registration and ABANICCO colour analysis for the in-depth study of triple-negative breast cancer biopsies. The resulting heterogeneity map and tumour score provide valuable insights into the composition and behaviour of the tumour, informing clinical decision-making and guiding treatment strategies. Finally, we consolidate the developed ideas into an efficient pipeline for tissue reconstruction and multi-modality data integration on Tuberculosis infection data. This enables accurate element distribution analysis to understand better interactions between bacteria, host cells, and the immune system during the course of infection. The methods proposed in this thesis represent a transparent approach to computational pathology, addressing the needs of medical microscopy registration and colour analysis while bridging the gap between clinical practice and computational research. Moreover, our contributions can help develop and train better, more robust DL methods.En una época en la que la medicina personalizada está revolucionando la asistencia sanitaria, cada vez es más importante adaptar los tratamientos y las medidas preventivas a la composición genética, el entorno y el estilo de vida de cada paciente. Mediante el empleo de tecnologías avanzadas, como la genómica, la proteómica, la metabolómica y la imagen médica, la medicina personalizada se esfuerza por racionalizar el tratamiento para mejorar los resultados y reducir los efectos secundarios. La microscopía médica, un aspecto crucial de la medicina personalizada, permite a los médicos recopilar y analizar grandes cantidades de datos a partir de pequeñas muestras de tejido. Esto es especialmente relevante en oncología, donde las terapias contra el cáncer se pueden optimizar en función de la apariencia tisular específica de cada tumor. La patología computacional, un subcampo de la visión por ordenador, trata de crear algoritmos para el análisis digital de biopsias. Sin embargo, antes de que un ordenador pueda analizar imágenes de microscopía médica, hay que seguir varios pasos para conseguir las imágenes de las muestras. La primera etapa consiste en recoger y preparar una muestra de tejido del paciente. Para que esta pueda observarse fácilmente al microscopio, se corta en secciones ultrafinas. Sin embargo, este delicado procedimiento no está exento de dificultades. Los frágiles tejidos pueden distorsionarse, desgarrarse o agujerearse, poniendo en peligro la integridad general de la muestra. Una vez que el tejido está debidamente preparado, suele tratarse con tintes de colores característicos. Estos tintes acentúan diferentes tipos de células y tejidos con colores específicos, lo que facilita a los profesionales médicos la identificación de características particulares. Sin embargo, esta mejora en visualización tiene un alto coste. En ocasiones, los tintes pueden dificultar el análisis informático de las imágenes al mezclarse de forma inadecuada, traspasarse al fondo o alterar el contraste entre los distintos elementos. El último paso del proceso consiste en digitalizar la muestra. Se toman imágenes de alta resolución del tejido con distintos aumentos, lo que permite su análisis por ordenador. Esta etapa también tiene sus obstáculos. Factores como una calibración incorrecta de la cámara o unas condiciones de iluminación inadecuadas pueden distorsionar o hacer borrosas las imágenes. Además, las imágenes de porta completo obtenidas so de tamaño considerable, complicando aún más el análisis. En general, si bien la preparación, la tinción y la digitalización de las muestras de microscopía médica son fundamentales para el análisis digital, cada uno de estos pasos puede introducir retos adicionales que deben abordarse para garantizar un análisis preciso. Además, convertir un volumen de tejido completo en unas pocas secciones teñidas reduce drásticamente la información 3D disponible e introduce una gran incertidumbre. Las soluciones de aprendizaje profundo (deep learning, DL) son muy prometedoras en el ámbito de la medicina personalizada, pero su impacto clínico a veces se ve obstaculizado por factores como la limitada generalizabilidad, el sobreajuste, la opacidad y la falta de interpretabilidad, además de las preocupaciones éticas y en algunos casos, los incentivos privados. Por otro lado, la variabilidad de las imágenes histológicas complica el desarrollo de métodos robustos de DL. Para superar estos retos, esta tesis presenta una serie de métodos altamente robustos e interpretables basados en principios clásicos de histología, imagen médica, matemáticas y arte, para alinear secciones de microscopía y analizar sus colores. Nuestra primera contribución es ABANICCO, un innovador método de análisis de color que ofrece una segmentación de colores objectiva y no supervisada y permite su posterior refinamiento mediante herramientas fáciles de usar. Se ha demostrado que la precisión y la eficacia de ABANICCO son superiores a las de los métodos existentes de clasificación y segmentación del color, e incluso destaca en la detección y segmentación de objetos completos. ABANICCO puede aplicarse a imágenes de microscopía para detectar áreas teñidas para la cuantificación de biopsias, un aspecto crucial de la investigación de cáncer. La segunda contribución es un método automático y no supervisado de segmentación de tejidos que identifica y elimina el fondo y los artefactos de las imágenes de microscopía, mejorando así el rendimiento de técnicas más sofisticadas de análisis de imagen. Este método es robusto frente a diversas imágenes, tinciones y protocolos de adquisición, y no requiere entrenamiento. La tercera contribución consiste en el desarrollo de métodos novedosos para registrar imágenes histopatológicas de forma eficaz, logrando el equilibrio adecuado entre un registro preciso y la preservación de la morfología local, en función de la aplicación prevista. Como cuarta contribución, los tres métodos mencionados se combinan para crear procedimientos eficientes para la integración completa de datos volumétricos, creando visualizaciones altamente interpretables de toda la información presente en secciones consecutivas de biopsia de tejidos. Esta integración de datos puede tener una gran repercusión en el diagnóstico y el tratamiento de diversas enfermedades, en particular el cáncer de mama, al permitir la detección precoz, la realización de pruebas clínicas precisas, la selección eficaz de tratamientos y la mejora en la comunicación el compromiso con los pacientes. Por último, aplicamos nuestros hallazgos a la integración multimodal de datos y la reconstrucción de tejidos para el análisis preciso de la distribución de elementos químicos en tuberculosis, lo que arroja luz sobre las complejas interacciones entre las bacterias, las células huésped y el sistema inmunitario durante la infección tuberculosa. Este método también aborda problemas como el daño por adquisición, típico de muchas modalidades de imagen. En resumen, esta tesis muestra la aplicación de métodos clásicos de visión por ordenador en el registro de microscopía médica y el análisis de color para abordar los retos únicos de este campo, haciendo hincapié en la visualización eficaz y fácil de datos complejos. Aspiramos a seguir perfeccionando nuestro trabajo con una amplia validación técnica y un mejor análisis de los datos. Los métodos presentados en esta tesis se caracterizan por su claridad, accesibilidad, visualización eficaz de los datos, objetividad y transparencia. Estas características los hacen perfectos para tender puentes robustos entre los investigadores de inteligencia artificial y los clínicos e impulsar así la patología computacional en la práctica y la investigación médicas.Programa de Doctorado en Ciencia y Tecnología Biomédica por la Universidad Carlos III de MadridPresidenta: María Jesús Ledesma Carbayo.- Secretario: Gonzalo Ricardo Ríos Muñoz.- Vocal: Estíbaliz Gómez de Marisca