RESUMEN
Early diagnosis of laryngeal squamous cell carcinoma (LSCC) at the stage of dysplasia could greatly improve the outcome of affected patients. For the first time we compared the mutational landscape of non-progressing dysplasia (NPD; n = 42) with progressing dysplasia (PD; n = 24), along with patient-matched LSCC biopsies; a total of 90 samples. Using targeted next-generation sequencing identified non-synonymous mutations in six genes (PIK3CA, FGFR3, TP53, JAK3, MET, FBXW7), and mutations were validated by Sanger sequencing and/or qPCR. Analysis was extended in silico to 530 head and neck (HNSCC) cases using TCGA data. Mutations in PIK3CA and FGFR3 were detected in PD and LSCC cases, as well as other HNSCC cases, but absent in NPD cases. In contrast, mutations in JAK3, MET and FBXW7 were found in NPD cases but not PD, LSCC or other HNSCC cases. TP53 was the most frequently mutated gene in both PD and NPD cases. With the exception of R248W, mutations were mutually exclusive. Moreover, five of seven PD mutations were located in motif H2 of p53, whereas none of the NPD mutations were. In summary, we propose that the mutational profile of laryngeal dysplasia has utility for the early detection of patients at risk of progression.
Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patología , Mutación , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Sustitución de Aminoácidos , Biomarcadores de Tumor , Biología Computacional/métodos , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Reproducibilidad de los Resultados , Medición de Riesgo , Factores de RiesgoRESUMEN
CONCLUSION: The application described in this study appears to be accurate and valid, thus allowing calculation of a hearing handicap and assessment of the pure-tone air conduction threshold with iPhone/iPad devices. OBJECTIVE: To develop and evaluate a newly developed professional, computer-based hearing handicap calculator and a manual hearing sensitivity assessment test for the iPhone and iPad (AudCal). METHODS: Multi-center prospective non-randomized validation study. One hundred and ten consecutive adult participants underwent two hearing evaluations, a standard audiometry and a pure-tone air conduction test using AudCal with an iOS device. The hearing handicap calculation accuracy was evaluated comparing AudCal vs a web-based calculator. RESULTS: Hearing loss was found in 83 and 84 out of 220 standard audiometries and AudCal hearing tests (Cohen's Kappa = 0.89). The mean difference between AudCal and standard audiogram thresholds was -0.21 ± 6.38 dB HL. Excellent reliability and concordance between standard audiometry and the application's hearing loss assessment test were obtained (Cronbach's alpha = 0.96; intra-class correlation coefficient = 0.93). AudCal vs a web-based calculator were perfectly correlated (Pearson's r = 1).
Asunto(s)
Audiología/métodos , Audiometría/instrumentación , Umbral Auditivo/fisiología , Computadoras de Mano/estadística & datos numéricos , Pérdida Auditiva/rehabilitación , Aplicaciones Móviles/estadística & datos numéricos , Diseño de Software , Diseño de Equipo , Pérdida Auditiva/fisiopatología , Humanos , Reproducibilidad de los Resultados , Teléfono Inteligente/estadística & datos numéricosRESUMEN
OBJECTIVES/HYPOTHESIS: Proteins p53 and cyclin D1 play a crucial role in cell cycle control. Protein p53 mutations are one of the most common genetic alterations in human cancer, and cyclin D1 gene amplification has been found to be associated with poor prognosis in different types of tumors. Functional alterations of these proteins may play an important role both in the carcinogenesis of squamous carcinomas of the head and neck and in the clinical evolution of these tumors. The objective of the present study was to evaluate whether the presence of p53 and/or cyclin D1 proteins (detected by immunohistochemical analysis) could serve as relevant variables for the assessment of the prognosis of laryngeal squamous cell carcinoma. STUDY DESIGN: Retrospective multicentric study. METHODS: Paraffin-embedded biopsy specimens from 62 human epidermoid laryngeal carcinomas were randomly selected. The expression of p53 and cyclin D1 was examined by means of immunohistochemical analysis with a view to evaluating whether there is a correlation between the aberrant expression of these proteins and disease prognosis. RESULTS: In the sample, the presence of immunohistochemically detectable p53 is associated with shorter survival and disease-free intervals, as shown in Kaplan-Meier survival curve analysis. Indeed, multivariate statistical analysis revealed that the accumulation of p53 is an independent prognostic factor, which is associated with shorter survival. This association was not evident in the case of cyclin D1. CONCLUSION: A more precise prognosis of patients with laryngeal epidermoid carcinomas could be achieved by taking into account the presence of p53 (as assayed by immunohistochemical analysis) in biopsy tissue