Diagnóstico de esclerosis múltiple mediante análisis de registros de tomografía de coherencia óptica y redes neuronales convolucionales entrenadas con imágenes sintéticas

Antecedentes: La Esclerosis Múltiple (EM) es una enfermedad del sistema nervioso central altamente discapacitante y que se presenta con frecuencia en adultos jóvenes. Para su diagnóstico se utilizan los criterios de McDonald, basados principalmente en evidencias de resonancia magnética, estudio del líquido cefalorraquídeo y el estado clínico del paciente. Sin embargo es conveniente investigar nuevos biomarcadores que permitan un diagnóstico fiable y no invasivo en las primeras fases de la enfermedad, permitiendo de este modo el uso de tratamientos modificadores de la enfermedad, ya que puede suponer una mejor evolución de los pacientes. Objetivos: El objetivo general de la presente tesis doctoral es investigar nuevos métodos de procesamiento y clasificación de imágenes de espesores de diferentes estructuras de la retina, obtenidas mediante Tomografía de Coherencia Óptica de fuente de barrido (SS-OCT) para conseguir un diagnóstico precoz de EM. Métodos: Se dispone de imágenes de espesores de las siguientes estructuras de la retina: retina completa, RNFL, GCL+, GCL++ y coroides, adquiridas por un equipo SS-OCT, en una base de datos formada por 48 sujetos de control y 48 pacientes con EM de diagnóstico reciente. Para la identificación de las estructuras y de las regiones con mayor capacidad discriminante se utiliza el método Relieff de categorización de características. Como clasificador, se utiliza una Red Neuronal Convolucional (RNC), y para evitar problemas de sobreajuste, se generan imágenes sintéticas con Redes Generativas Antagónicas. La comprobación de los métodos de clasificación se realiza mediante validación cruzada dejando uno fuera. Resultados: No existe diferencia significativa entre el grupo de control y el grupo de pacientes ni en edad ni en distribución entre sexos. Los pacientes han tenido un diagnóstico reciente (7,35 ± 1,95 meses). La aplicación del método Relieff detecta que las tres estructuras con mayor capacidad discriminante son GCL+, GCL++ y el espesor de la retina completa. Mediante las Redes Generativas Antagónicas se generan 100 imágenes SS-OCT sintéticas de sujetos de control y 100 imágenes SS-OCT de pacientes EM. Utilizando las imágenes originales en el clasificador RNC se obtiene una precisión de 0,968; en imágenes filtradas con el método Relieff la precisión de es 1,0 y utilizando las imágenes sintéticas para el entrenamiento de la RNC también es 1,0. Si se dispone únicamente del 50% de las imágenes originales, se comprueba la ventaja de disponer datos sintéticos para el entrenamiento de la RNC: la precisión aumenta de 0,66 a 0,96. Conclusiones: Las alteraciones estructurales neurorretinianas en las primeras fases de la EM son adecuadas para implementar un sistema de ayuda al diagnóstico mediante una red neuronal convolucional con un excelente nivel de precisión

Analysis of gamma-band activity from human EEG using empirical mode decomposition

The purpose of this paper is to determine whether gamma-band activity detection is improved when a filter, based on empirical mode decomposition (EMD), is added to the pre-processing block of single-channel electroencephalography (EEG) signals. EMD decomposes the original signal into a finite number of intrinsic mode functions (IMFs). EEGs from 25 control subjects were registered in basal and motor activity (hand movements) using only one EEG channel. Over the basic signal, IMF signals are computed. Gamma-band activity is computed using power spectrum density in the 30–60 Hz range. Event-related synchronization (ERS) was defined as the ratio of motor and basal activity. To evaluate the performance of the new EMD based method, ERS was computed from the basic and IMF signals. The ERS obtained using IMFs improves, from 31.00% to 73.86%, on the original ERS for the right hand, and from 22.17% to 47.69% for the left hand. As EEG processing is improved, the clinical applications of gamma-band activity will expand.Universidad de AlcaláInstituto de Salud Carlos II

Diagnosis of multiple sclerosis using multifocal ERG data feature fusion

The purpose of this paper is to implement a computer-aided diagnosis (CAD) system for multiple sclerosis (MS) based on analysing the outer retina as assessed by multifocal electroretinograms (mfERGs). MfERG recordings taken with the RETI?port/scan 21 (Roland Consult) device from 15 eyes of patients diagnosed with incipient relapsing-remitting MS and without prior optic neuritis, and from 6 eyes of control subjects, are selected. The mfERG recordings are grouped (whole macular visual field, five rings, and four quadrants). For each group, the correlation with a normative database of adaptively filtered signals, based on empirical model decomposition (EMD) and three features from the continuous wavelet transform (CWT) domain, are obtained. Of the initial 40 features, the 4 most relevant are selected in two stages: a) using a filter method and b) using a wrapper-feature selection method. The Support Vector Machine (SVM) is used as a classifier. With the optimal CAD configuration, a Matthews correlation coefficient value of 0.89 (accuracy = 0.95, specificity = 1.0 and sensitivity = 0.93) is obtained. This study identified an outer retina dysfunction in patients with recent MS by analysing the outer retina responses in the mfERG and employing an SVM as a classifier. In conclusion, a promising new electrophysiological-biomarker method based on feature fusion for MS diagnosis was identified.Agencia Estatal de InvestigaciónInstituto de Salud Carlos II

Differential study of retinal thicknesses in the eyes of Alzheimer’s patients, multiple sclerosis patients and healthy subjects

Multiple sclerosis (MS) and Alzheimer’s disease (AD) cause retinal thinning that is detectable in vivo using optical coherence tomography (OCT). To date, no papers have compared the two diseases in terms of the structural differences they produce in the retina. The purpose of this study is to analyse and compare the neuroretinal structure in MS patients, AD patients and healthy subjects using OCT. Spectral domain OCT was performed on 21 AD patients, 33 MS patients and 19 control subjects using the Posterior Pole protocol. The area under the receiver operating characteristic (AUROC) curve was used to analyse the differences between the cohorts in nine regions of the retinal nerve fibre layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL) and outer nuclear layer (ONL). The main differences between MS and AD are found in the ONL, in practically all the regions analysed (AUROCFOVEAL = 0.80, AUROCPARAFOVEAL = 0.85, AUROCPERIFOVEAL = 0.80, AUROC_PMB = 0.77, AUROCPARAMACULAR = 0.85, AUROCINFERO_NASAL = 0.75, AUROCINFERO_TEMPORAL = 0.83), and in the paramacular zone (AUROCPARAMACULAR = 0.75) and infero-temporal quadrant (AUROCINFERO_TEMPORAL = 0.80) of the GCL. In conclusion, our findings suggest that OCT data analysis could facilitate the differential diagnosis of MS and AD

Differential Study of Retinal Thicknesses in the Eyes of Alzheimer"s Patients, Multiple Sclerosis Patients and Healthy Subjects

Multiple sclerosis (MS) and Alzheimer"s disease (AD) cause retinal thinning that is detectable in vivo using optical coherence tomography (OCT). To date, no papers have compared the two diseases in terms of the structural differences they produce in the retina. The purpose of this study is to analyse and compare the neuroretinal structure in MS patients, AD patients and healthy subjects using OCT. Spectral domain OCT was performed on 21 AD patients, 33MS patients and 19 control subjects using the Posterior Pole protocol. The area under the receiver operating characteristic (AUROC) curve was used to analyse the differences between the cohorts in nine regions of the retinal nerve fibre layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL) and outer nuclear layer (ONL). The main differences between MS and AD are found in the ONL, in practically all the regions analysed (AUROCFOVEAL = 0.80, AUROCPARAFOVEAL = 0.85, AUROCPERIFOVEAL = 0.80, AUROC_PMB = 0.77, AUROCPARAMACULAR = 0.85, AUROCINFERO_NASAL = 0.75, AUROCINFERO_TEMPORAL = 0.83), and in the paramacular zone (AUROCPARAMACULAR = 0.75) and infero-temporal quadrant (AUROCINFERO_TEMPORAL = 0.80) of the GCL. In conclusion, our findings suggest that OCT data analysis could facilitate the differential diagnosis of MS and AD

Personalized monitoring of circulating tumor DNA with a specific signature of trackable mutations after chimeric antigen receptor T-cell therapy in follicular lymphoma patients

BackgroundCART therapy has produced a paradigm shift in the treatment of relapsing FL patients. Strategies to optimize disease surveillance after these therapies are increasingly necessary. This study explores the potential value of ctDNA monitoring with an innovative signature of personalized trackable mutations.MethodEleven FL patients treated with anti-CD19 CAR T-cell therapy were included. One did not respond and was excluded. Genomic profiling was performed before starting lymphodepleting chemotherapy to identify somatic mutations suitable for LiqBio-MRD monitoring. The dynamics of the baseline mutations (4.5 per patient) were further analyzed on 59 cfDNA follow-up samples. PET/CT examinations were performed on days +90, +180, +365, and every six months until disease progression or death.ResultsAfter a median follow-up of 36 months, all patients achieved a CR as the best response. Two patients progressed. The most frequently mutated genes were CREBBP, KMT2D and EP300. Simultaneous analysis of ctDNA and PET/CT was available for 18 time-points. When PET/CT was positive, two out of four ctDNA samples were LiqBio-MRD negative. These two negative samples corresponded to women with a unique mesenteric mass in two evaluations and never relapsed. Meanwhile, 14 PET/CT negative images were mutation-free based on our LiqBio-MRD analysis (100%). None of the patients had a negative LiqBio-MRD test by day +7. Interestingly, all durably responding patients had undetectable ctDNA at or around three months after infusion. Two patients presented discordant results by PET/CT and ctDNA levels. No progression was confirmed in these cases. All the progressing patients were LiqBio-MRD positive before progression.ConclusionThis is a proof-of-principle for using ctDNA to monitor response to CAR T-cell therapy in FL. Our results confirm that a non-invasive liquid biopsy MRD analysis may correlate with response and could be used to monitor response. Harmonized definitions of ctDNA molecular response and pinpointing the optimal timing for assessing ctDNA responses are necessary for this setting. If using ctDNA analysis, we suggest restricting follow-up PET/CT in CR patients to a clinical suspicion of relapse, to avoid false-positive results

La vuelta al día en 24 mundos

El trabajo obtuvo un Premio Tomás García Verdejo a las buenas prácticas educativas en la Comunidad Autónoma de Extremadura para el curso académico 2015/2016. Modalidad ASe presenta un proyecto llevado a cabo entre varios centros educativos de la provincia de Cáceres que consistió en hacer actividades de fomento y animación a la lectura ligadas a los continentes del globo terrestre. Los objetivos del proyecto fueron: fomentar la relación y convivencia entre los centros; promover el trabajo colaborativo; propiciar ambientes que fomenten valores como la responsabilidad, el esfuerzo, la igualdad entre géneros y el respesto; conocer y disfrutar las diferentes formas literarias como relatos, poemas y obras dramáticas a través de la lectura, la escucha y la propia creación y recreación; comprender y respetar las diferentes culturas y las diferencias entre las personas; iniciarse en el uso de las nuevas tecnologías desarrollando un espíritu crítico ante los mensajes que reciben y elaboran y utilizar diferentes representaciones y expresiones artísticas e iniciarse en la construcción de propuestas visuales y audiovisualesExtremaduraES

Table_1_Personalized monitoring of circulating tumor DNA with a specific signature of trackable mutations after chimeric antigen receptor T-cell therapy in follicular lymphoma patients.xlsx

BackgroundCART therapy has produced a paradigm shift in the treatment of relapsing FL patients. Strategies to optimize disease surveillance after these therapies are increasingly necessary. This study explores the potential value of ctDNA monitoring with an innovative signature of personalized trackable mutations.MethodEleven FL patients treated with anti-CD19 CAR T-cell therapy were included. One did not respond and was excluded. Genomic profiling was performed before starting lymphodepleting chemotherapy to identify somatic mutations suitable for LiqBio-MRD monitoring. The dynamics of the baseline mutations (4.5 per patient) were further analyzed on 59 cfDNA follow-up samples. PET/CT examinations were performed on days +90, +180, +365, and every six months until disease progression or death.ResultsAfter a median follow-up of 36 months, all patients achieved a CR as the best response. Two patients progressed. The most frequently mutated genes were CREBBP, KMT2D and EP300. Simultaneous analysis of ctDNA and PET/CT was available for 18 time-points. When PET/CT was positive, two out of four ctDNA samples were LiqBio-MRD negative. These two negative samples corresponded to women with a unique mesenteric mass in two evaluations and never relapsed. Meanwhile, 14 PET/CT negative images were mutation-free based on our LiqBio-MRD analysis (100%). None of the patients had a negative LiqBio-MRD test by day +7. Interestingly, all durably responding patients had undetectable ctDNA at or around three months after infusion. Two patients presented discordant results by PET/CT and ctDNA levels. No progression was confirmed in these cases. All the progressing patients were LiqBio-MRD positive before progression.ConclusionThis is a proof-of-principle for using ctDNA to monitor response to CAR T-cell therapy in FL. Our results confirm that a non-invasive liquid biopsy MRD analysis may correlate with response and could be used to monitor response. Harmonized definitions of ctDNA molecular response and pinpointing the optimal timing for assessing ctDNA responses are necessary for this setting. If using ctDNA analysis, we suggest restricting follow-up PET/CT in CR patients to a clinical suspicion of relapse, to avoid false-positive results.</p