Next-generation sequencing improves precision medicine in hearing loss.

Background: An early etiological diagnosis of hearing loss positively impacts children's quality of life including language and cognitive development. Even though hearing loss associates with extremely high genetic and allelic heterogeneity, several studies have proven that Next-Generation Sequencing (NGS)-based gene panel testing significantly reduces the time between onset and diagnosis. Methods: In order to assess the clinical utility of our custom NGS GHELP panel, the prevalence of pathogenic single nucleotide variants, indels or copy number variants was assessed by sequencing 171 nuclear and 8 mitochondrial genes in 155 Spanish individuals with hearing loss. Results: A genetic diagnosis of hearing loss was achieved in 34% (52/155) of the individuals (5 out of 52 were syndromic). Among the diagnosed cases, 87% (45/52) and 12% (6/52) associated with autosomal recessive and dominant inheritance patterns respectively; remarkably, 2% (1/52) associated with mitochondrial inheritance pattern. Although the most frequently mutated genes in this cohort were consistent with those described in the literature (GJB2, OTOF or MYO7A), causative variants in less frequent genes such as TMC1, FGF3 or mitCOX1 were also identified. Moreover, 5% of the diagnosed cases (3/52) were associated with pathogenic copy number variants. Conclusion: The clinical utility of NGS panels that allows identification of different types of pathogenic variants-not only single nucleotide variants/indels in both nuclear and mitochondrial genes but also copy number variants-has been demonstrated to reduce the clinical diagnostic odyssey in hearing loss. Thus, clinical implementation of genomic strategies within the regular clinical practice, and, more significantly, within the newborn screening protocols, is warranted.

Inner ear drug delivery through a cochlear implant: Pharmacokinetics in a Macaque experimental model.

OBJECTIVES: The method of drug delivery directly into the cochlea with an implantable pump connected to a CI electrode array ensures long-term delivery and effective dose control, and also provides the possibility to use different drugs. The objective is to develop a model of inner ear pharmacokinetics of an implanted cochlea, with the delivery of FITC-Dextran, in the non-human primate model. DESIGN: A preclinical cochlear electrode array (CI Electrode Array HL14DD, manufactured by Cochlear Ltd.) attached to an implantable peristaltic pump filled with FITC-Dextran was implanted unilaterally in a total of 15 Macaca fascicularis (Mf). Three groups were created (5 Mf in each group), according to three different drug delivery times: 2 hours, 24 hours and 7 days. Perilymph (10 samples, 1µL each) was sampled from the apex of the cochlea and measured immediately after extraction with a spectrofluorometer. After scarifying the specimens, x-Rays and histological analysis were performed. RESULTS: Surgery, sampling and histological analysis were performed successfully in all specimens. FITC-Dextran quantification showed different patterns, depending on the delivery group. In the 2 hours injection experiment, an increase in FITC-Dextran concentrations over the sample collection time was seen, reaching maximum concentration peaks (420-964µM) between samples 5 and 7, decreasing in successive samples, without returning to baseline. The 24-hours and 7-days injection experiments showed even behaviour throughout the 10 samples obtained, reaching a plateau with mean concentrations ranging from 2144 to 2564 µM and from 1409 to 2502µM, respectively. Statistically significant differences between the 2 hours and 24 hours groups (p = 0.001) and between the 2 hours and 7 days groups (p = 0.037) were observed, while between the 24 hours and 7 days groups no statistical differences were found. CONCLUSIONS: This experimental study shows that a model of drug delivery and pharmacokinetics using an active pump connected to an electrode array is feasible in Mf. An infusion time ranging from 2 to 24 hours is required to reach a maximum concentration peak at the apex. It establishes then an even concentration profile from base to apex that is maintained throughout the infusion time in Mf. Flow mechanisms during injection and during sampling that may explain such findings may involve cochlear aqueduct flow as well as the possible existence of substance exchange from scala tympani to extracellular spaces, such as the modiolar space or the endolymphatic sinus, acting as a substance reservoir to maintain a relatively flat concentration profile from base to apex during sampling. Leveraging the learnings achieved by experimentation in rodent models, we can move to experiment in non-human primate with the aim of achieving a useful model that provides transferrable data to human pharmacokinetics. Thus, it may broaden clinical and therapeutic approaches to inner ear diseases.

Healthy aging in elderly cochlear implant recipients: a multinational observational study.

BACKGROUND: Given an increase in the aging population and its impact on healthcare systems, policy makers for provision of health and social services are aiming to keep older adults in good health for longer, in other words towards 'healthy aging'. Our study objective is to show that rehabilitation with cochlear implant treatment in the elderly with hearing impairment improves the overall health-related quality of life and general well-being that translate into healthy aging. METHODS: The multicentre, prospective, repeated measures, single-subject, clinical observational study will accrue 100 elderly, first-time, unilateral CI recipients (≥ 60 years) and analyze changes on specific measurement tools over ca. 20 months from preimplant to postimplant. Evaluations will consist of details collected through case history and interview questionnaires by clinicians, data logging, self-report questionnaires completed by the recipients and a series of commonly used audiometric measures and geriatric assessment tools. The primary indicator of changes in overall quality of life will be the HUI-3. DISCUSSION: The protocol is designed to make use of measurement tools that have already been applied to the hearing-impaired population in order to compare effects of CI rehabilitation in adults immediately before their implantation, (pre-implant) and after gaining 1-1.5 years of experience (post-implant). The broad approach will lead to a greater understanding of how useful hearing impacts the quality of life in elderly individuals, and thus improves potentials for healthy aging. Outcomes will be described and analyzed in detail. TRIAL REGISTRATION: This research has been registered in ClinicalTrials.gov (http://www.clinicaltrials.gov/), 7 March 2017 under the n° NCT03072862 .

Surgical findings and auditory performance after cochlear implant revision surgery.

The objective of this study was to review cochlear reimplantation outcomes in the tertiary hospital and analyze whether facts such as type of failure, surgical findings, or etiology of deafness have an influence. A retrospective study including 38 patients who underwent cochlear implant revision surgery in a tertiary center is performed. Auditory outcomes (pure tone audiometry, % disyllabic words) along with etiology of deafness, type of complication, issues with insertion, and cochlear findings are included. Complication rate is 2.7 %. Technical failure rate is 57.9 % (50 % hard failure and 50 % soft failure), and medical failure (device infection or extrusion, migration, wound, or flap complication) is seen in 42.1 % of the cases. Management of cochlear implant complications and revision surgery is increasing due to a growing number of implantees. Cases that require explantation and reimplantation of the cochlear implant are safe procedures, where the depth of insertion and speech perception results are equal or higher in most cases. Nevertheless, there must be an increasing effort on using minimally traumatic electrode arrays and surgical techniques to improve currently obtained results.

[Guidelines for cochlear implant indication in Navarre]. / Guía clínica para la indicación de implantes cocleares en la Comunidad Foral de Navarra.

Cochlear implants are indicated in severe to profound hearing loss with no benefit with hearing aids. Since the beginning of cochlear implants 30 years ago, auditory outcomes have been improving due to changes introduced in differ-ent areas: electrode design, strategy, surgical technique... Given good results within this period of time, cochlear implant indication has varied too. The aim of this paper is to show an update on indication criteria for cochlear implantation in Navarre, for application in daily practice. The indications are established by consensus amongst the hospitals of the region.

Guía clínica para la indicación de implantes cocleares en la Comunidad Foral de Navarra / Guidelines for cochlear implant indication in Navarre

La colocación de un implante coclear es una medida útil para paliar la hipoacusia neurosensorial de grado severo-profundo en aquellos casos en los que el beneficio del audífono es escaso. Desde su inicio hace 30 años los resultados auditivos han mejorado gracias a los progresivas mejoras que se han adoptado en distintos ámbitos: su diseño, estrategia, técnica quirúrgica... Dados los buenos resultados en este periodo, las indicaciones también han variado. El objetivo de este trabajo es revisar los criterios establecidos y emergentes de indicación de implante coclear, estableciendo de manera consensuada, entre los centros sanitarios de la Comunidad Foral de Navarra, unos criterios actualizados para la indicación del mismo en dicha área territorial, de forma que pueden servir de referencia en situaciones clínicas diferenciadas (AU)

Cochlear implants are indicated in severe to profound hearing loss with no benefit with hearing aids. Since the beginning of cochlear implants 30 years ago, auditory outcomes have been improving due to changes introduced in different areas: electrode design, strategy, surgical technique... Given good results within this period of time, cochlear implant indication has varied too. The aim of this paper is to show an update on indication criteria for cochlear implantation in Navarre, for application in daily practice. The indications are established by consensus amongst the hospitals of the region (AU)

Cardiotoxicity associated with trastuzumab in normal clinical practice.

OBJECTIVE: To evaluate the incidence of cardiotoxicity associated with treatment with trastuzumab in clinical practice by describing its characteristics, progress and associated risk factors. METHODS: Retrospective observational study of patients with HER2-positive breast cancer treated with trastuzumab in the fi rst quarter of 2007 in a tertiary hospital. Follow-up was performed from start of treatment until the end of March 2008. The data sources used were the oncological computer program Oncowin® from the pharmacy department and the patient clinical history. We gathered variables related to patient baseline characteristics, treatment and safety. RESULTS: The study included 61 patients. 19 women (32.8%) presented cardiotoxicity, which was the second most common adverse affect of those frequently attributed to the treatment. The average time for toxicity to appear was 7 months, with an average FEVI decrease of 15.6 +/- 9.1 points. In 63.2% of the patients it was symptomatic, and its most frequent manifestation was stress-induced dyspnoea, with a single case of congestive heart failure. Cardiotoxicity led to suspension of treatment in 22.9% of the total patients, which was definitive for 7 out of the 14 patients who interrupted the treatment. No statistically significant differences were found for the possible risk factors. CONCLUSIONS: The incidence of cardiotoxicity in clinical practice is much higher than expected. The important clinical implication of this information and the increasing use of trastuzumab mean that there is a new challenge for the optimal treatment of HER2-positive breast cancer.

Cardiotoxicidad asociada a trastuzumab en la práctica clínica asistencial / Cardiotoxicity associated with trastuzumab in normal clinical practice

Objetivo: Evaluar la incidencia de cardiotoxicidad asociada al tratamiento con trastuzumab en la práctica clínica asistencial, describiendo sus características, su manejo y los factores de riesgo asociados.Método: Estudio observacional retrospectivo que incluyó a pacientes con cáncer de mama HER-2 positivo en tratamiento con trastuzumab durante el primer trimestre de 2007 en un hospital de tercer nivel. Se realizó un seguimiento desde el inicio del tratamiento hasta fi nales de marzo de 2008. Las fuentes de datos utilizadas fueron el programa informático de oncología del servicio de farmacia, Oncowin®, y la historia clínica del paciente. Se recogieron variables relacionadas con las características basales del paciente, con el tratamiento y con la seguridad.Resultados: Se incluyó a 61 pacientes en el estudio; 19 (32,8 %) mujeres presentaron cardiotoxicidad, que supuso el segundo efecto adverso atribuido el tratamiento en frecuencia. La mediana de tiempo de aparición de la toxicidad fue de 7 meses, con un descenso medio de fracción de eyección del ventrículo izquierdo (FEVI) de 15,6 ± 9,1 puntos. En el 63,2 % fue sintomática, la manifestación más frecuente fue la disnea de esfuerzo y hubo un único caso de fallo cardíaco congestivo. La cardiotoxicidad supuso la suspensión del tratamiento en el 22,9 % del total de pacientes, y fue de forma defi nitiva en 7 de las 14 pacientes que interrumpieron el tratamiento. No se hallaron diferencias estadísticamente signifi cativas en cuanto a los posibles factores de riesgo.Conclusiones: La incidencia de cardiotoxicidad en la práctica clínica asistencial se muestra mucho más elevada que la esperada. Su importante implicación clínica y el uso creciente de trastuzumab hacen que suponga un nuevo reto para el tratamiento óptimo del cáncer de mama HER-2 positivo (AU)

Objective: To evaluate the incidence of cardiotoxicity associated with treatment with trastuzumab in clinical practice by describing its characteristics, progress and associated risk factors.Methods: Retrospective observational study of patients with HER2-positive breast cancer treated with trastuzumab in the fi rst quarter of 2007 in a tertiary hospital. Follow-up was performed from start of treatment until the end of March 2008. The data sources used were the oncological computer program Oncowin® from the pharmacy department and the patient clinical history. We gathered variables related to patient baseline characteristics, treatment and safety.Results: The study included 61 patients. 19 women (32.8 %) presented cardiotoxicity, which was the second most common adverse affect of those frequently attributed to the treatment. The average time for toxicity to appear was 7 months, with an average FEVI decrease of 15.6 ± 9.1 points. In 63.2 % of the patients it was symptomatic, and its most frequent manifestation was stress-induced dyspnoea, with a single case of congestive heart failure. Cardiotoxicity led to suspension of treatment in 22.9 % of the total patients, which was defi nitive for 7 out of the 14 patients who interrupted the treatment. No statistically signifi cant differences were found for the possible risk factors.Conclusions: The incidence of cardiotoxicity in clinical practice is much higher than expected. The important clinical implication of this information and the increasing use of trastuzumab mean that there is a new challenge for the optimal treatment of HER2-positive breast cance (AU)