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Introducción o motivación de la tesis: Los avances en el conocimiento de las bases moleculares de la respuesta inflamatoria en la rinosinusitis crónica con pólipos nasales (RSCcPN) han conducido el manejo de estos pacientes hacia una medicina personalizada y de precisión. La cirugía de la cavidad nasal se ha posicionado como una alternativa adecuada en aquellos pacientes que no alcanzan el control con el tratamiento médico adecuado, pero las recidivas de la enfermedad siguen siendo una limitación. La aparición de nuevos abordajes quirúrgicos basados en las características específicas de cada paciente y el escaso control de la enfermedad asociado a las formas más severas de la enfermedad hace necesario revisar el papel de la cirugía personalizada y de precisión en el manejo de la RSCcPN. Se espera que esta investigación refuerce las pruebas clínicas disponibles, aporte evidencia sobre los resultados de las técnicas quirúrgicas extendidas y contribuya a proporcionar nuevas recomendaciones quirúrgicas en los pacientes con RSCcPN. Contenido de la investigación: Esta tesis doctoral evalúa el papel los abordajes endoscópicos nasosinusales extendidos en pacientes con RSCcPN, analizando los resultados clínicos, endoscópicos y radiológicos a medio y largo plazo, en comparación con las cirugías más limitadas o localizadas. Por otra parte, examina las mejoras añadidas al uso de la cirugía regenerativa (mucoplastia endonasal), como técnica complementaria, en pacientes con características de la enfermedad más severas y de peor pronóstico. En última instancia recoge una revisión que resume toda la evidencia publicada hasta el momento y posiciona los resultados de esta tesis doctoral en el panorama científico actual. Conclusión: La aplicación de las variantes extendidas de la cirugía endoscópica nasosinusal mejora los resultados clínicos a largo plazo en los pacientes con RSCcPN. La asociación de la mucoplastia endonasal supone una mejora añadida a estos abordajes, con resultados

Introduction: The worldwide incidence rate of laryngeal cancer is declining. However, the 5-year survival for these patients has decreased in recent years from 66% to 63%. This may be due to changes in the treatment of the disease. The present study aimed to evaluate the survival rate of patients with LC according to the stage of the disease and the treatment applied. For this purpose, surgical versus organ preservation protocols (OPP) based on chemoradiotherapy were evaluated. Methods: A retrospective cohort study was conducted in a tertiary hospital. The study included adult patients with a clinical diagnosis of primary LC. Patients with LC and systemic metastases and those with synchronous tumors at diagnosis were excluded. Univariate and multivariate analyses were performed to determine the association between exposure to LC treatment and the time to event (death). Overall survival (OS), cause-specific survival (CSS), and disease-free survival (DFS) were calculated. Results: Patients with advanced tumors (stages III and IV) had almost three times the risk of LC death than those in the initial tumor stages (I and II) [HR CCS = 2.89 (95%CI 1.30–6.39)]; [HR OS = 2.01 (95%CI 1.35–2.98)]. Patients who underwent surgical treatment had a higher chance of survival than those who were treated according to OPP [HR = 0.62; 95%CI (0.38–1.02)] in CSS, 0.74 [95%CI (0.50–1.90)] in OS, and 0.61 [95%CI (0.40–0.91)] in DFS. Discussion: OPP changed the management of patients with advanced stages of LC, establishing CRT as an alternative to surgery. Our data did not reveal clinically relevant differences in OS between patients treated with OPP and those who underwent surgery; however, we reported differences in the DFS rate after five years of follow-up in favor of the surgery-treated group of patients. Conclusion: Surgical treatment improves CSS and DFS at five years in patients with initial LC with respect to radiation therapy alone. Furthermore, surgical treatment associated wit

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a chronic inflammatory disease that affects about 5% of the general global population [...]

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease of the nose and paranasal sinuses characterized by the presence of nasal polyps. The symptoms produced by the presence of nasal polyps such as nasal obstruction, nasal discharge, facial pain, headache, and loss of smell cause a worsening in the quality of life of patients. The source of the nasal polyps remains unclear, although it seems to be due to a chronic inflammation process in the sinonasal mucosa. Fibroblasts, the main cells in connective tissue, are intimately involved in the inflammation processes of various diseases; to this end, we carried out a systematic review to evaluate their inflammatory role in nasal polyps. Thus, we evaluated the main cytokines produced by nasal polyp-derived fibroblasts (NPDF) to assess their involvement in the production of nasal polyps and their involvement in different inflammatory pathways. The results of the review highlight the inflammatory role of NPDF through the secretion of various cytokines involved in the T1, T2, and T3 inflammatory pathways, as well as the ability of NPDF to be stimulated by a multitude of substances. With these findings, the fibroblast is positioned as a new potential therapeutic target in the treatment of CRSwNP.

Background: Although smell and taste disorders are highly prevalent symptoms of COVID 19 infection, the predictive factors leading to long-lasting chemosensory dysfunction are still poorly understood. Methods: 102 out of 421 (24.2%) mildly symptomatic COVID-19 patients completed a second questionnaire about the evolution of their symptoms one year after the infection using visual analog scales (VAS). A subgroup of 69 patients also underwent psychophysical evaluation of olfactory function through UPSIT. Results: The prevalence of chemosensory dysfunction decreased from 82.4% to 45.1% after 12 months, with 46.1% of patients reporting a complete recovery. Patients older than 40 years (OR = 0.20; 95% CI: [0.07, 0.56]) and with a duration of loss of smell longer than four weeks saw a lower odds ratio for recovery (OR = 0.27; 95% CI: [0.10, 0.76]). In addition, 28 patients (35.9%) reported suffering from parosmia, which was associated with moderate to severe taste dysfunction at the baseline (OR = 7.80; 95% CI: [1.70, 35.8]). Among the 69 subjects who underwent the UPSIT, 57 (82.6%) presented some degree of smell dysfunction, showing a moderate correlation with self-reported VAS (r = −0.36, p = 0.0027). Conclusion: A clinically relevant number of subjects reported persistent chemosensory dysfunction and parosmia one year after COVID-19 infection, with a moderate correlation with psychophysical olfactory tests.

Currently, some monoclonal antibodies (mAbs) are being studied for chronic rhinosinusitis with nasal polyps (CRSwNP). Three anti-IL-5 mAb: mepolizumab, reslizumab and benralizumab, have been tested through randomized clinical trials. In this real-life study, we aimed to describe the nasal effects of a cohort of asthmatic adults treated with anti-IL-5 mAb. Methods: We carried out an observational study in adults (≥18 years) on anti-IL-5 mAb treatment. Variables included ACT and SNOT−22 questionnaires, nasal polyps score, blood total IgE levels and blood eosinophil count. Results: Overall, 38 participants were included in the study; 19 patients received mepolizumab, 17 were treated with benralizumab and 2 patients were given reslizumab. There was a statistically significant difference in the ACT and SNOT−22 scores before and after mAb treatment. ACT score increased from 11.05 to 21.5 after treatment (p < 0.001). SNOT−22 decreased from 57 to 37.3 after treatment (p = 0.004). No statistically significant differences between mAb groups were observed regarding the ACT or the SNOT−22 (p = 0.775) response (p = 0.775). In addition, 60.53% of patients obtained a minimal clinically important difference (MCID) in SNOT−22. Conclusions: A significant clinical response based on SNOT−22 score evolution after anti-IL-5 mAb treatment was observed. This study also demonstrated that blood eosinophil count, rather than serum total IgE levels, is the best predictor of asthma symptom improvement, which was assessed through the ACT and SNOT−22 questionnaires.

INTRODUCCIÓN: Actualmente, las guías de práctica clínica consideran equiparables, en términos de supervivencia, el tratamiento quirúrgico frente al tratamiento radioterápico en estadios iniciales y frente a las terapias organopreservadoras en estadios avanzados. OBJETIVOS: El objetivo de esta tesis doctoral ha sido analizar la supervivencia de los pacientes con cáncer de laringe en base a características socio-demográficas, antecedentes personales, características clínicas y tratamiento recibido. MATERIAL Y MÉTODO: Estudio observacional, analítico, de cohortes retrospectivo, sobre la población de referencia del área de influencia sanitaria del Hospital Universitario Virgen Macarena, que han recibido un diagnóstico de cáncer de laringe en el periodo de estudio comprendido entre las fechas 1/1/2006 y 31/12/2017, RESULTADOS: Se han diagnosticado 328 pacientes con cáncer de laringe en el periodo de estudio. El 32,3% de los pacientes han desarrollado una recidiva y el 20,1% han fallecido a causa del cáncer. La realización de cirugía se ha asociado con una disminución del riesgo de fallecimiento por cáncer de laringe. La preservación de la funcionalidad laríngea postradioterapia se ha asociado con una disminución de las probabilidades de fallecimiento. La administración de radioterapia complementaria tras tratamiento quirúrgico se ha asociado con una disminución de las probabilidades de desarrollar recidiva, recurrencia o metástasis. CONCLUSIONES: La realización de cirugía frente a otro tipo de tratamiento se ha asociado con una disminución del riesgo de fallecimiento por cáncer de laringe independientemente del estadiaje tumoral.

The COVID-19 outbreak has spread extensively around the world. Loss of smell and taste have emerged as main predictors for COVID-19. The objective of our study is to develop a comprehensive machine learning (ML) modelling framework to assess the predictive value of smell and taste disorders, along with other symptoms, in COVID-19 infection. A multicenter case-control study was performed, in which suspected cases for COVID-19, who were tested by real-time reversetranscription polymerase chain reaction (RT-PCR), informed about the presence and severity of their symptoms using visual analog scales (VAS). ML algorithms were applied to the collected data to predict a COVID-19 diagnosis using a 50-fold cross-validation scheme by randomly splitting the patients in training (75%) and testing datasets (25%). A total of 777 patients were included. Loss of smell and taste were found to be the symptoms with higher odds ratios of 6.21 and 2.42 for COVID-19 positivity. The ML algorithms applied reached an average accuracy of 80%, a sensitivity of 82%, and a specificity of 78% when using VAS to predict a COVID-19 diagnosis. This study concludes that smell and taste disorders are accurate predictors, with ML algorithms constituting helpful tools for COVID-19 diagnostic prediction.

Objectives:To perform a radio-anatomical evaluation of the nasal cavity floor freemucosal graft (endonasal extended mucoplasty, EEM) to repair mucosal defects afteran extended ethmoid-sphenoidotomy.Methods:A human cadaveric study (radiological and anatomical dissection) and anin vivo study in surgical patients with CRSwNP were performed. The EEM areaswere compared between 3D reconstruction from CT scans and anatomical/surgicaldissections, both in cadaver specimens and in patients. Feasibility was assessed bycorrelation between the EEM area on CT scans and when harvested in cadaversand when grafted in patients. Usefulness was assessed by the degree of coverageof the EEM in the surface exposed after an extended ethmoid-sphenoidotomy.Both feasibility and usefulness were assessed in cadaveric specimens (n = 15) andpatients (n = 4).Results:Fifteen cadaveric specimens and 4 patients with bilateral CRSwNP wereincluded. The mean (SD) areas obtained in the cadaveric radiological and anatomicalstudies were 9.44 (2.07) cm2and 8.03 (1.36) cm2, respectively (intraclass correlationcoefficient 0.59, moderate correlation), and in 3D reconstruction for operatedpatients were 10.32 (0.98) cm2and 11.27 (2.44) cm2, respectively. The coverage ofthe ethmoidal roof in the cadaveric dissection study was 100%, from the anteriorethmoidal artery to the posterior ethmoidal artery, covering the planun sphenoidaleup to 75% in the case series. In 87.5% of the cases, up to 50% of the papiracea lam-ina was covered. Conclusion: The EEM have shown to be a feasible and useful grafting technique to repair skull base defects after performing an extended ethmoid-sphenoidotomy dur ing surgery for CRSwNP. Level of Evidence: NA.

Blood-derived endothelial colony-forming cells (ECFCs) have robust vasculogenic potential that can be exploited to bioengineer long-lasting human vascular networks in vivo. However, circulating ECFCs are exceedingly rare in adult peripheral blood. Because the mechanism by which ECFCs are mobilized into circulation is currently unknown, the reliability of peripheral blood as a clinical source of ECFCs remains a concern. Thus, there is a need to find alternative sources of autologous ECFCs. Here we aimed to determine whether ECFCs reside in the vasculature of human white adipose tissue (WAT) and to evaluate if WAT-derived ECFCs have equal clinical potential to blood-derived ECFCs. We isolated the complete endothelial cell (EC) population from intact biopsies of normal human subcutaneous WAT by enzymatic digestion and selection of CD31+ cells. Subsequently, we extensively compared WAT-derived EC phenotype and functionality to bonafide ECFCs derived from both umbilical cord blood and adult peripheral blood. We demonstrated that human WAT is indeed a dependable source of ECFCs with indistinguishable properties to adult peripheral blood ECFCs, including hierarchical clonogenic ability, large expansion potential, stable endothelial phenotype, and robust in vivo blood vessel-forming capacity. Considering the unreliability and low rate of occurrence of ECFCs in adult blood and that biopsies of WAT can be obtained with minimal intervention in an ambulatory setting, our results indicate WAT as a more practical alternative to obtain large amounts of readily available autologous ECFCs for future vascular cell therapies.

Mediante el empleo de la correlación genotipo-haplotipo-fenotipo en mujeres con hiperandrogenemia y el gen CAPN10, se ha demostrado recientemente una asociación entre el haplotipo 1111 del gen CAPN10 y la aparici&oacu te;n de cáncer (p=0.0005, González y cols. 2003)292. Sorprendentemente, analizando los diferentes tipos tumorales que aparecían en las familias portadoras de este haplotipo de riesgo, se identificó una alta prevalencia del carcinoma de laringe. Estos datos sugieren que el gen CAPN10 podría estar relacionado con una mayor susceptibilidad a padecer cáncer de laringe o a la agregación familiar de cáncer de este tipo tumoral. A partir de aquí se decidió conformar un grupo de pacientes con cáncer de laringe para estudiar la distribución por alelos, genotipos y haplotipos, y compararlos con la distribución de un grupo control. Posteriormente se analizaría la posible repercusión de la distribución genotípica de los pacientes del grupo de casos sobre la supervivencia a los 5 años, porque de esta manera, su análisis podría proporcionar información relevante en el estudio, tratamiento y pronóstico del cáncer de laringe. OBJETIVOS 1.- Realizar un análisis comparativo y efectuar un estudio de asociación entre los distintos polimorfismos (UCSNPs-44,-43,-19,-63) del gen CAPN10 y la existencia de cáncer de laringe en los grupos analizados. 2.-Llevar a cabo un análisis por genotipos del grupo de pacientes con cáncer de laringe e investigar una eventual asociación con la supervivencia.