Algorithms and Results of Eye Tissues Differentiation Based on RF Ultrasound

Algorithms and software were developed for analysis of B-scan ultrasonic signals acquired from commercial diagnostic ultrasound system. The algorithms process raw ultrasonic signals in backscattered spectrum domain, which is obtained using two time-frequency methods: short-time Fourier and Hilbert-Huang transformations. The signals from selected regions of eye tissues are characterized by parameters: B-scan envelope amplitude, approximated spectral slope, approximated spectral intercept, mean instantaneous frequency, mean instantaneous bandwidth, and parameters of Nakagami distribution characterizing Hilbert-Huang transformation output. The backscattered ultrasound signal parameters characterizing intraocular and orbit tissues were processed by decision tree data mining algorithm. The pilot trial proved that applied methods are able to correctly classify signals from corpus vitreum blood, extraocular muscle, and orbit tissues. In 26 cases of ocular tissues classification, one error occurred, when tissues were classified into classes of corpus vitreum blood, extraocular muscle, and orbit tissue. In this pilot classification parameters of spectral intercept and Nakagami parameter for instantaneous frequencies distribution of the 1st intrinsic mode function were found specific for corpus vitreum blood, orbit and extraocular muscle tissues. We conclude that ultrasound data should be further collected in clinical database to establish background for decision support system for ocular tissue noninvasive differentiation

Surgical Ophthalmic Oncology

Designed as an easy-to-use, practical guide to tumors of the eye, lids, and orbit, this Open Access book comprehensively addresses surgical treatment and management of diseases related to ophthalmic oncology. Surgical Ophthalmic Oncology: A Collaborative Open Access Reference is an ideal reference for general ophthalmologists, surgeons, fellows and trainees around the world who encounter these diseases in the care of their patients. Notably, this book includes considerations for those ophthalmologists offering subspecialty care in environments with limited access to advanced technology and instrumentation. Individual chapters address diagnostic indications, pre-operative and post-operative concerns, and provide detailed explanations of surgical techniques required to manage various eye cancer ailments with help of ample illustrations. High-quality videos included throughout the book provide readers with the opportunity to review surgical steps in real-time as a learning tool. Chapters thoroughly cover tumors of eyelid, cornea and conjunctiva, orbit as well as intraocular tumors, while later chapters discuss ophthalmic radiation therapy. The book concludes with a section on ophthalmic pathology which details essential guidelines on relevant aspects from specimen collection and transport, to interpretation of the pathology report. Surgical Ophthalmic Oncology: A Collaborative Open Access Reference is a unique and necessary valuable resource for ophthalmologists, trainees, and related medical professionals working in underserved areas in providing quality care for patients suffering from ocular cancers. ; Open Access text that discusses Preferred Practice Guidelines for common surgeries performed on tumors of the eye and adnexa Written for general ophthalmologists providing oncology care and specialists practicing in areas with limited access to advanced technology and instrumentation Includes chapters on eyelid tumors, conjunctival and corneal tumors, intraocular tumors, brachytherapy, and ocular pathology Each chapter includes extensive color pictures and relevant video to assist the clinician in the various surgical procedures discusse

Surgical Ophthalmic Oncology

Designed as an easy-to-use, practical guide to tumors of the eye, lids, and orbit, this Open Access book comprehensively addresses surgical treatment and management of diseases related to ophthalmic oncology. Surgical Ophthalmic Oncology: A Collaborative Open Access Reference is an ideal reference for general ophthalmologists, surgeons, fellows and trainees around the world who encounter these diseases in the care of their patients. Notably, this book includes considerations for those ophthalmologists offering subspecialty care in environments with limited access to advanced technology and instrumentation. Individual chapters address diagnostic indications, pre-operative and post-operative concerns, and provide detailed explanations of surgical techniques required to manage various eye cancer ailments with help of ample illustrations. High-quality videos included throughout the book provide readers with the opportunity to review surgical steps in real-time as a learning tool. Chapters thoroughly cover tumors of eyelid, cornea and conjunctiva, orbit as well as intraocular tumors, while later chapters discuss ophthalmic radiation therapy. The book concludes with a section on ophthalmic pathology which details essential guidelines on relevant aspects from specimen collection and transport, to interpretation of the pathology report. Surgical Ophthalmic Oncology: A Collaborative Open Access Reference is a unique and necessary valuable resource for ophthalmologists, trainees, and related medical professionals working in underserved areas in providing quality care for patients suffering from ocular cancers. ; Open Access text that discusses Preferred Practice Guidelines for common surgeries performed on tumors of the eye and adnexa Written for general ophthalmologists providing oncology care and specialists practicing in areas with limited access to advanced technology and instrumentation Includes chapters on eyelid tumors, conjunctival and corneal tumors, intraocular tumors, brachytherapy, and ocular pathology Each chapter includes extensive color pictures and relevant video to assist the clinician in the various surgical procedures discusse

Novel Approaches for the Treatment of Uveal Melanoma

Il melanoma uveale (MU) è il principale tumore intraoculare nella popolazione adulta. Durante il mio dottorato di ricerca, la mia attività scientifica è stata volta allo studio dei meccanismi coinvolti nella progressione del MU, con lo scopo di identificare nuove strategie terapeutiche dirette contro la componente tumorale e stromale. Il sistema dei fattori di crescita dei fibroblasti (FGF) e dei loro recettori (FGFR) è coinvolto nella crescita e nella progressione tumorale. Inoltre, dati clinici evidenziano come l’elevata espressione di ligandi e/o recettori sia associata ad una prognosi peggiore nei pazienti. In questo lavoro di tesi è stato dimostrato per la prima volta come l’inibizione del sistema FGF/FGFR rappresenti una strategia efficace per colpire le cellule staminali tumorali del MU, coinvolte nella disseminazione metastatica, nella resistenza alle terapie e nell’insorgenza di recidive. Inoltre, durante il mio dottorato di ricerca ho partecipato allo sviluppo di un modello ortotopico di MU nell’embrione di zebrafish. Infine, una parte di questo lavoro di tesi è stata volta ad approfondire i meccanismi di escape immunologico messi in atto dal MU per sfuggire al controllo del sistema immunitario. In questo contesto, i linfociti Natural Killer (NK) sono una popolazione di cellule dell’immunità che riveste un ruolo fondamentale nell’immunosorveglianza nei confronti delle cellule tumorali. I nostri dati preliminari dimostrano che il MU esprime elevati livelli del fattore immunosoppressivo TGFb e che è in grado “riprogrammare” i linfociti NK verso un fenotipo pro-tumorale, detto decidual-like, ponendo le basi per ulteriori studiUveal melanoma (UM) is a very aggressive tumor, and it represents the most common primary intraocular malignancy in the adult population. While primary tumors are successfully treated in 90% of cases, almost 50% of patients ultimately develops metastasis, with a median survival after diagnosis spanning from 6 to 12 months. Therefore, effective pharmacological therapies are eagerly required. In this frame, during my PhD I have focused on gaining a better understanding on the mechanisms sustaining tumor progression in the attempt to identify novel therapeutic strategies. In this thesis, I have illustrated our results on alternative approaches aimed at hampering both tumor cells as well as the stromal component. The Fibroblast Growth Factor (FGF)/FGF Receptor (FGFR) system exerts a very important role in UM. Indeed, both clinical and experimental evidence demonstrates the presence of an autocrine FGF/FGFR activation loop, with alterations in the expression of ligands and receptors resulting in a poorer prognosis in patients. In this context, we have previously demonstrated the efficacy of inhibiting the FGF/FGFR system using the pan FGF-trap NSC12 as a strategy to reduce cell proliferation, migration, and survival of UM cell lines. Additionally, FGF-mediated signaling is also involved in the maintenance of Cancer Stem-like Cells (CSCs), a subpopulation of tumor cells responsible for tumorigenesis, metastatic dissemination, therapy resistance, and recurrence. Therefore, eliminating CSCs is a crucial step to achieve a complete tumor eradication. On this premise, we have demonstrated for the first time that the inhibition of the FGF/FGFR system is an effective strategy to hamper the stem-like component due to the enhanced sensitivity of CSCs to FGF-deprivation. In this frame, we have also established an orthotopic model of UM in the zebrafish embryo as a tool for in vivo drug screening. By engrafting tumor cells in proximity to the developing choroidal vasculature of the eye, our model closely mimics the microenvironment in which tumors originate. Additionally, we have developed a reliable and accurate method for assessing xenograft tumor growth by exploiting the bioluminescent signal of tumor cells transduced with firefly luciferase. The advent of immune therapy strategies has failed to improve the clinical management of UM, due to the exploitation of immune escape strategies that are still largely unclear. In this context, Natural Killer (NK) lymphocytes are important regulators of cancer immunosurveillance and their activity is finely controlled by the expression of specific activating and inhibitory receptors that allow them to discriminate and eliminate malignant cells. However, the presence of a pro-tumor and pro-angiogenic subpopulation of decidual-like NK lymphocytes has been recently described in various tumor types. These cells are characterized by the production of pro-angiogenic/pro-inflammatory mediators as well as by an impairment of their cytotoxic functions. On this premise, we have investigated whether decidual-like polarization of NK lymphocytes could be involved in UM, as a process sustaining tumor progression as well as the formation of metastatic lesions. Our data demonstrates that the conditioned media from UM cell can shift NK lymphocytes towards a decidual-like state, characterized by reduced levels of activating receptors and by an impaired cytotoxic activity. These data, together with the evidence that UM cells express the immunosuppressive cytokine TGFb, support the hypothesis that soluble factors produced by cancer cells and accumulated within the tumor microenvironment could favor UM immune escape. Our results set the basis for further studies on the role played by UM-derived TGFb in reprogramming NK lymphocytes and they hint at TGFb as a potential target for the treatment of UM

Metastatic uveal melanoma : The final frontier

Publisher Copyright: © 2022Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10–13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95–100% and 83–100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma.Peer reviewe

Towards Interpretable Machine Learning in Medical Image Analysis

Over the past few years, ML has demonstrated human expert level performance in many medical image analysis tasks. However, due to the black-box nature of classic deep ML models, translating these models from the bench to the bedside to support the corresponding stakeholders in the desired tasks brings substantial challenges. One solution is interpretable ML, which attempts to reveal the working mechanisms of complex models. From a human-centered design perspective, interpretability is not a property of the ML model but an affordance, i.e., a relationship between algorithm and user. Thus, prototyping and user evaluations are critical to attaining solutions that afford interpretability. Following human-centered design principles in highly specialized and high stakes domains, such as medical image analysis, is challenging due to the limited access to end users. This dilemma is further exacerbated by the high knowledge imbalance between ML designers and end users. To overcome the predicament, we first define 4 levels of clinical evidence that can be used to justify the interpretability to design ML models. We state that designing ML models with 2 levels of clinical evidence: 1) commonly used clinical evidence, such as clinical guidelines, and 2) iteratively developed clinical evidence with end users are more likely to design models that are indeed interpretable to end users. In this dissertation, we first address how to design interpretable ML in medical image analysis that affords interpretability with these two different levels of clinical evidence. We further highly recommend formative user research as the first step of the interpretable model design to understand user needs and domain requirements. We also indicate the importance of empirical user evaluation to support transparent ML design choices to facilitate the adoption of human-centered design principles. All these aspects in this dissertation increase the likelihood that the algorithms afford interpretability and enable stakeholders to capitalize on the benefits of interpretable ML. In detail, we first propose neural symbolic reasoning to implement public clinical evidence into the designed models for various routinely performed clinical tasks. We utilize the routinely applied clinical taxonomy for abnormality classification in chest x-rays. We also establish a spleen injury grading system by strictly following the clinical guidelines for symbolic reasoning with the detected and segmented salient clinical features. Then, we propose the entire interpretable pipeline for UM prognostication with cytopathology images. We first perform formative user research and found that pathologists believe cell composition is informative for UM prognostication. Thus, we build a model to analyze cell composition directly. Finally, we conduct a comprehensive user study to assess the human factors of human-machine teaming with the designed model, e.g., whether the proposed model indeed affords interpretability to pathologists. The human-centered design process is proven to be truly interpretable to pathologists for UM prognostication. All in all, this dissertation introduces a comprehensive human-centered design for interpretable ML solutions in medical image analysis that affords interpretability to end users

Next-Generation Sequencing in the Identification of Biomarkers in Cutaneous Melanoma According to the Etiopathogenic Development Pathway and their Potential Clinical Relevance

Tesis por compendio[ES] El melanoma es el tipo de cáncer de piel más mortífero y peligroso, ya que tumores de pequeño tamaño pueden generar metástasis. Hasta la fecha, se ha tratado de clasificar desde el punto de vista clínico, epidemiológico y molecular, empleándose actualmente el nivel de exposición solar y la localización del tumor como criterios principales para dividir en distintos grupos a los pacientes de melanoma. En 1998, David Whiteman y colaboradores propusieron un "modelo de vías divergentes" para el desarrollo del melanoma. Este presentaba dos vías: una vinculada a la proliferación melanocítica (nevogénica) y otra relacionada con la exposición solar crónica (CSD). Corroborado desde el punto de vista clínico y epidemiológico, todavía no se ha aportado una caracterización molecular en profundidad. A nivel general se habían identificado genes cuyas mutaciones eran relevantes para el desarrollo del melanoma, como por ejemplo KIT. Sin embargo, todavía se había de estudiar con más detalle la distribución de estas mutaciones entre los distintos subgrupos de melanoma, así como su posible valor pronóstico. En esta tesis se han empleado técnicas de secuenciación - masiva y tradicional - para caracterizar los perfiles mutacionales de las poblaciones del modelo de vías divergentes. Encontramos diferencias tanto en el número de mutaciones como en los genes afectados. También hemos visto cómo los melanomas con mutaciones en KIT parecen desarrollarse por una vía independiente de la etiopatogenia conocida, careciendo el estatus mutacional de este gen de valor pronóstico para la supervivencia de los pacientes.[CA] El melanoma és el tipus de càncer de pell més mortífer i perillós, ja que fins els tumors de menor mida poden acabar generant metàstasi. Al llarg dels anys, s'ha tractat de classificar des del punt de vista clínic, epidemiològic i molecular. Les classificacions actuals utilitzen el nivell d'exposició solar i la localització tumoral per dividir en diferents grups als pacients de melanoma. Al 1998, David Whiteman i col·laboradors proposaren un model de desenvolupament del melanoma que anomenaren "model de vies divergents". Aquest presentava dos vies per la melanomagènesi: una vinculada a la proliferació melanocítica (nevogènica) i l'altra relacionada amb l'exposició solar crònica (CSD). Malgrat aquest model fou corroborat des del punt de vista clínic i epidemiològic, encara no s'ha aportat una caracterització molecular en profunditat. A nivell general s'havien identificat gens les mutacions dels quals eren rellevants per al desenvolupament del melanoma, com el gen KIT. Però, encara s'havia d'estudiar amb més cura la distribució d'estes mutacions entre els distints subgrups de melanoma, així com el seu possible valor pronòstic. En aquesta tesi s'han emprat tècniques de seqüenciació -massiva i tradicional- per caracteritzar els perfils mutacionals de les dues poblacions proposades pel model de vies divergents, trobant diferències tant al nombre de mutacions com als gens afectats. També hem vist com els melanomes mutats en KIT semblen desenvolupar-se per una via independent de l'etiopatogènia coneguda, mancant l'estatus mutacional d'aquest gen de valor pronòstic per la supervivència dels pacients.[EN] Melanoma is the deadliest and most dangerous type of skin cancer, given that a small tumor can spread and result in metastasis. Over the years, classifications have been made either from a clinical, epidemiological or molecular point of view. Current classifications use the degree of solar exposure and tumoral location to divide into different melanoma groups. In 1998, David Whiteman and collaborators proposed the divergent pathway model for melanoma development. This presented two pathways to melanomagenesis: one related to melanocytic proliferation (nevogenic) and the other related to chronic sun exposure (CSD). Despite corroborations of this model from the clinic and epidemiology, it is yet to be molecularly characterized in depth. At a general level, different genes had been identified with relevant mutations for the development of melanoma, as is the gene KIT. However, there was a lack of knowledge on how these mutations were distributed among different melanoma subgroups, as well as the potential prognostic value. In this thesis we have implemented sequencing techniques - both massive and traditional - to characterize the mutational profile of the two populations proposed by the divergent pathways model. We found differences both in the number of mutations and in the genes carrying the mutations. We have also seen how melanomas harboring KIT mutations seem to develop in a way which is independent from the known etiology, and how the mutational status of this gene lacks prognostic value on the outcome of the patients.Millán Esteban, D. (2022). Next-Generation Sequencing in the Identification of Biomarkers in Cutaneous Melanoma According to the Etiopathogenic Development Pathway and their Potential Clinical Relevance [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182977Compendi