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1.
Otol Neurotol ; 45(4): 376-385, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38361325

RESUMEN

OBJECTIVE: To investigate if pharmacological treatment with prednisone and L-N-acetylcysteine (STE + NAC) influence functional hearing preservation in cochlear implant (CI) surgery. STUDY DESIGNS: Preimplantation and postimplantation longitudinal case-control study. SETTING: Tertiary referral center. PATIENTS: Pediatric and adult recipients of CI with preimplantation functional hearing defined as an average of air-conducted thresholds at 125, 250, and 500 Hz (low-frequency pure-tone average [LFPTA]) <80 dB. INTERVENTIONS: Preimplantation and postimplantation audiometry. Weight-adjusted oral prednisone and L-N-acetylcysteine starting 2 days before surgery (Miami cocktail). Prednisone was continued for 3 days and L-N-acetylcysteine for 12 days after surgery, respectively. Cochlear implantation with conventional length electrodes. MAIN OUTCOME MEASURES: Proportion of patients with LFPTA <80 dB, and LFPTA change at 1-year postimplantation. RESULTS: All 61 patients received intratympanic and intravenous dexamethasone intraoperatively, with 41 patients receiving STE + NAC and 20 patients not receiving STE + NAC. At 1-year postimplantation, the proportion of functional hearing preservation was 83% in the STE + NAC group compared with 55% of subjects who did not receive STE + NAC ( p = 0.0302). The median LFPTA change for STE + NAC-treated and not treated subjects was 8.33 dB (mean, 13.82 ± 17.4 dB) and 18.34 dB (mean, 26.5 ± 23.4 dB), respectively ( p = 0.0401, Wilcoxon rank test). Perioperative STE + NAC treatment resulted in 10 dB of LFPTA better hearing than when not receiving this treatment. Better low-frequency preimplantation hearing thresholds were predictive of postimplantation functional hearing. No serious side effects were reported. CONCLUSION: Perioperative STE + NAC, "The Miami Cocktail," was safe and superior to intraoperative steroids alone in functional hearing preservation 1-year after cochlear implantation.


Asunto(s)
Implantación Coclear , Implantes Cocleares , Adulto , Humanos , Niño , Implantación Coclear/métodos , Estudios de Casos y Controles , Prednisona , Acetilcisteína , Estudios Retrospectivos , Umbral Auditivo , Audiometría de Tonos Puros , Audición , Resultado del Tratamiento
2.
Hum Genomics ; 17(1): 103, 2023 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-37996878

RESUMEN

BACKGROUND: We analyzed the genetic causes of sensorineural hearing loss in racial and ethnic minorities of South Florida by reviewing demographic, phenotypic, and genetic data on 136 patients presenting to the Hereditary Hearing Loss Clinic at the University of Miami. In our retrospective chart review, of these patients, half self-identified as Hispanic, and the self-identified racial distribution was 115 (86%) White, 15 (11%) Black, and 6 (4%) Asian. Our analysis helps to reduce the gap in understanding the prevalence, impact, and genetic factors related to hearing loss among diverse populations. RESULTS: The causative gene variant or variants were identified in 54 (40%) patients, with no significant difference in the molecular diagnostic rate between Hispanics and Non-Hispanics. However, the total solve rate based on race was 40%, 47%, and 17% in Whites, Blacks, and Asians, respectively. In Non-Hispanic Whites, 16 different variants were identified in 13 genes, with GJB2 (32%), MYO7A (11%), and SLC26A4 (11%) being the most frequently implicated genes. In White Hispanics, 34 variants were identified in 20 genes, with GJB2 (22%), MYO7A (7%), and STRC-CATSPER2 (7%) being the most common. In the Non-Hispanic Black cohort, the gene distribution was evenly dispersed, with 11 variants occurring in 7 genes, and no variant was identified in 3 Hispanic Black probands. For the Asian cohort, only one gene variant was found out of 6 patients. CONCLUSION: This study demonstrates that the diagnostic rate of genetic studies in hearing loss varies according to race in South Florida, with more heterogeneity in racial and ethnic minorities. Further studies to delineate deafness gene variants in underrepresented populations, such as African Americans/Blacks from Hispanic groups, are much needed to reduce racial and ethnic disparities in genetic diagnoses.


Asunto(s)
Pérdida Auditiva Sensorineural , Humanos , Asiático/genética , Negro o Afroamericano/genética , ADN/genética , Florida/epidemiología , Pérdida Auditiva Sensorineural/epidemiología , Pérdida Auditiva Sensorineural/genética , Hispánicos o Latinos/genética , Péptidos y Proteínas de Señalización Intercelular , Estudios Retrospectivos , Blanco/genética
3.
Mol Cancer Ther ; 22(11): 1280-1289, 2023 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-37527526

RESUMEN

Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective nonsurgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase (FAK) family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell-cycle arrest and produced a 44% decrease in tumor growth over a 2-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary VS cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.


Asunto(s)
Antineoplásicos , Neurilemoma , Neurofibromatosis 2 , Humanos , Neurofibromatosis 2/tratamiento farmacológico , Neurofibromatosis 2/genética , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Fosfatidilinositol 3-Quinasas/farmacología , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Dasatinib/farmacología , Fosfatidilinositol 3-Quinasa/farmacología , Fosfatidilinositol 3-Quinasa/uso terapéutico , Neurilemoma/tratamiento farmacológico , Neurilemoma/genética , Antineoplásicos/farmacología , Proliferación Celular
4.
Laryngoscope ; 133(10): 2440-2442, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37435849
5.
Acta Otolaryngol ; 143(7): 551-557, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37354038

RESUMEN

BACKGROUND: Temporal bone paragangliomas are rare tumours with variable presentation that can be hereditary. Identification of clinical and genetic factors of aggressive tumour behaviour is important. OBJECTIVE: To determine the underlying genetic mutations and genotype/phenotype correlations in a multi-ethnic population of South Florida with sporadic temporal bone paragangliomas. METHODS: In a cohort of glomus tympanicum (GT) and glomus jugulare (GJ) cases, we assessed the frequency of pathogenic single nucleotide variants, insertions, deletions, and duplications in coding exons of genes that have been associated with paragangliomas (SDHB, SDHC, SDHD, SDHA, SDHAF2, RET, NF1, VHL, TMEM127, and MAX). RESULTS: None of the 12 GT cases had mutations. Among 13 GJ cases, we identified four mutation carriers (31%); two in SDHC, one in SDHB, and one in SDHD. All patients with pathogenic mutations were of Hispanic ethnicity, presented at a younger age (mean 27.5 versus 52.11 years), and with more advanced disease when compared to mutation-negative GJ cases.Conclusions and Significance: Mutations in the SDH genes are found in 31% of sporadic GJ. SDH-associated GJ had advanced disease and a 50% risk of metastasis. Our data supports emerging recommendations for genetic screening in all populations with GJ tumours as the genetic status informs management.


Asunto(s)
Paraganglioma , Succinato Deshidrogenasa , Humanos , Persona de Mediana Edad , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/metabolismo , Mutación de Línea Germinal , Paraganglioma/genética , Paraganglioma/epidemiología , Mutación , Estudios de Asociación Genética
6.
World Neurosurg ; 168: e297-e308, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36198364

RESUMEN

OBJECTIVE: The purpose of this study is to retrospectively evaluate the clinical and surgical outcomes of a large surgical series of vestibular schwannoma from North America over 20 years. METHODS: After institutional review board approval a retrospective review of the senior author's personal case logs to identify patients who had operations for vestibular schwannoma was performed. The clinical notes, operative record, preoperative and postoperative imagings, and long-term clinical follow-up notes were evaluated. RESULTS: A total of 415 patients who underwent 420 surgeries were identified from the years 1998-2021. The average length of follow-up was 3 years and 9 months. Overall, at last follow-up the rate of "good" facial nerve outcomes (House-Brackmann [HB] score I and II) was 86% and "poor" facial nerve outcomes (HB III-VI) was 14%. The amount of cerebellopontine angle extension (P = 0.023), tumor volume (P = 0.015), facial nerve consistency (P < 0.001), preoperative HB score (P < 0.001), and FN stimulation threshold at the end of the procedure (P < 0.001) were correlated to facial nerve function at the last follow-up. CONCLUSIONS: This study represents one of the largest recently reported surgical series of vestibular schwannoma in North American literature with available long term follow-up. Facial nerve outcomes correlated with cerebellopontine angle extension, tumor volume, facial nerve stimulation threshold, facial nerve consistency, preoperative facial nerve function, and history of a prior resection. Tumor recurrence remains significantly higher after subtotal resection. We believe the data supports a continuation of a strategy of general intent of gross total resection, greatly modifiable by intraoperative findings and judgment.


Asunto(s)
Neuroma Acústico , Humanos , Neuroma Acústico/diagnóstico por imagen , Neuroma Acústico/cirugía , Nervio Facial/diagnóstico por imagen , Nervio Facial/cirugía , Estudios de Seguimiento , Estudios Retrospectivos , Procedimientos Neuroquirúrgicos/efectos adversos , Procedimientos Neuroquirúrgicos/métodos , Resultado del Tratamiento , Recurrencia Local de Neoplasia/cirugía , Complicaciones Posoperatorias/cirugía
7.
World Neurosurg ; 168: e490-e499, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36216244

RESUMEN

BACKGROUND: Papaverine, a vasodilator approved for use by the U.S. Food and Drug Administration, has shown efficacy in treating vasospasm in cardiology, urology, and nephrology. The vasodilatory effect of papaverine is also hoped to protect the facial nerve from ischemic damage and nerve manipulation during vestibular schwannoma surgery. Our institution uses intracisternal papaverine irrigation during vestibular schwannoma resection to protect the facial nerve in patients with neuromonitoring changes. Our objective was to investigate the safety and facial nerve outcomes of intracisternal papaverine irrigation during vestibular schwannoma resection. METHODS: We retrospectively reviewed patients who underwent resection of vestibular schwannoma at our institution between 2008 and 2021. Patients received papaverine if the intraoperative facial nerve stimulation threshold increased above 0.05 mA. Postoperative outcomes were compared with control patients who did not receive papaverine. RESULTS: A total of 283 cases were included in our analysis. Patients who received papaverine (n = 60) had lower immediate postoperative House-Brackmann (HB) grades than did control individuals (mean, 1.54 vs. 1.95; P = 0.029) and a lower likelihood of immediate postoperative HB grade >1 (odds ratio, 0.514; P = 0.039). At long-term follow-up, there was no significant difference in HB grade. Papaverine use was not associated with increased rates of perioperative complications (P = 0.24). CONCLUSIONS: The off-label use of intracisternal papaverine irrigation during vestibular schwannoma resection can certainly be used safely for select cases. It is associated with improved immediate postoperative facial nerve outcomes, similar long-term facial nerve outcomes, and no significant increase in complications.


Asunto(s)
Traumatismos del Nervio Facial , Neuroma Acústico , Humanos , Nervio Facial/cirugía , Neuroma Acústico/cirugía , Neuroma Acústico/complicaciones , Papaverina , Estudios Retrospectivos , Traumatismos del Nervio Facial/etiología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología
8.
Otol Neurotol ; 43(7): 789-796, 2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35861647

RESUMEN

OBJECTIVES: To evaluate the utility of intracochlear electrocochleography (ECochG) monitoring during cochlear implant (CI) surgery on postoperative hearing preservation. STUDY DESIGN: Prospective, randomized clinical trial. SETTING: Ten high-volume, tertiary care CI centers. PATIENTS: Adult patients with sensorineural hearing loss meeting the CI criteria who selected an Advanced Bionics CI. METHODS: Patients were randomized to CI surgery either with audible ECochG monitoring available to the surgeon during electrode insertion or without ECochG monitoring. Hearing preservation was determined by comparing preoperative unaided low-frequency (125-, 250-, and 500-Hz) pure-tone average (LF-PTA) to postoperative LF-PTA at CI activation. Pre- and post-CI computed tomography was used to determine electrode scalar location and electrode translocation. RESULTS: Eighty-five adult CI candidates were enrolled. The mean (standard deviation [SD]) unaided preoperative LF-PTA across the sample was 54 (17) dB HL. For the whole sample, hearing preservation was "good" (i.e., LF-PTA change 0-15 dB) in 34.5%, "fair" (i.e., LF-PTA change >15-29 dB) in 22.5%, and "poor" (i.e., LF-PTA change ≥30 dB) in 43%. For patients randomized to ECochG "on," mean (SD) LF-PTA change was 27 (20) dB compared with 27 (23) dB for patients randomized to ECochG "off" ( p = 0.89). Seven percent of patients, all of whom were randomized to ECochG off, showed electrode translocation from the scala tympani into the scala vestibuli. CONCLUSIONS: Although intracochlear ECochG during CI surgery has important prognostic utility, our data did not show significantly better hearing preservation in patients randomized to ECochG "on" compared with ECochG "off."


Asunto(s)
Implantación Coclear , Implantes Cocleares , Adulto , Audiometría de Respuesta Evocada/métodos , Cóclea/diagnóstico por imagen , Cóclea/cirugía , Implantación Coclear/métodos , Implantes Cocleares/efectos adversos , Audición , Humanos , Estudios Prospectivos
9.
J Clin Med ; 10(22)2021 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-34830704

RESUMEN

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive, neuromodulating technique for brain hyperexcitability disorders. The objective of this paper is to discuss the mechanism of action of rTMS as well as to investigate the literature involving the application of rTMS in the treatment of tinnitus. The reviewed aspects of the protocols included baseline evaluation, the total number of sessions, frequency and the total number of stimuli, the location of treatment, and the outcome measures. Even with heterogeneous protocols, most studies utilized validated tinnitus questionnaires as baseline and outcome measures. Low frequency (1 Hz) stimulation throughout 10 consecutive sessions was the most widely used frequency and treatment duration; however, there was no consensus on the total number of stimuli necessary to achieve significant results. The auditory cortex (AC) was the most targeted location, with most studies supporting changes in neural activity with multi-site stimulation to areas in the frontal cortex (FC), particularly the dorsolateral prefrontal cortex (DLPFC). The overall efficacy across most of the reviewed trials reveals positive statistically significant results. Though rTMS has proven to impact neuroplasticity at the microscopic and clinical level, further studies are warranted to demonstrate and support the clinical use of rTMS in tinnitus treatment with a standardized protocol.

10.
Otol Neurotol ; 42(4): e503-e511, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33492057

RESUMEN

BACKGROUND: Vestibular schwannoma (VS) are intracranial tumors caused by merlin deficiency. Sodium fluorescein (SF) is a fluorescent compound that accumulates in various intracranial tumors, causing tumors to emit green fluorescence after blue light excitation. HYPOTHESIS: Intravenous SF preferentially deposits in VS, helping surgeons differentiate tumor from surrounding tissue. METHODS: Merlin-deficient Schwann cells were grafted onto cochleovestibular nerves of immunodeficient rats. Rats were randomized to receive SF (7.5 mg/kg; n = 5) or saline (n = 3). Tissues were harvested at 1 hour and photographed in white and blue light. Sixteen surgeons identified and marked the tumor-tissue interfaces on images. Fluorescence was measured on tissue specimens using the IVIS imaging system and on tissue cross-sections obtained with confocal microscopy. Western blot was performed to measure levels of organic anion transporting polypeptide (OATP), a drug transporter specific for SF. RESULTS: Under blue light, tumors from SF rats demonstrated bright green fluorescence under direct visualization, higher fluorescence measurements on tissue specimens (p < 0.001), and more SF deposition on tissue cross-sections (p < 0.001), when compared with surrounding tissues and placebo rats. Surgeons were better able to distinguish the tumor-tissue interfaces in SF rats. Furthermore, the expression level of OATP1C1 was significantly higher in tumors than in surrounding tissues (p < 0.0001). CONCLUSION: In a xenograft model of VS, intravenous SF preferentially deposits in tumors, compared with normal surrounding tissue. Under blue light, tumors emit an intense green fluorescence that can help surgeons differentiate tumor from critical structures nearby, which may improve clinical outcomes in complicated VS surgery.


Asunto(s)
Neoplasias Encefálicas , Neuroma Acústico , Animales , Fluoresceína , Microscopía Confocal , Ratas , Células de Schwann
11.
J Otol ; 16(1): 40-46, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33505449

RESUMEN

BACKGROUND: Congenital hearing loss is remarkably heterogeneous, with over 130 deafness genes and thousands of variants, making for innumerable genotype/phenotype combinations. Understanding both the pathophysiology of hearing loss and molecular site of lesion along the auditory pathway permits for significantly individualized counseling. Electrophysiologic techniques such as electrocochleography (ECochG) and electrically-evoked compound action potentials (eCAP) are being studied to localize pathology and estimate residual cochlear vs. neural health. This review describes the expanding roles of genetic and electrophysiologic evaluation in the precision medicine of congenital hearing loss.The basics of genetic mutations in hearing loss and electrophysiologic testing (ECochG and eCAP) are reviewed, and how they complement each other in the diagnostics and prognostication of hearing outcomes. Used together, these measures improve the understanding of insults to the auditory system, allowing for individualized counseling for CI candidacy/outcomes or other habilitation strategies. CONCLUSION: Despite tremendous discovery in deafness genes, the effects of individual genes on neural function remain poorly understood. Bridging the understanding between molecular genotype and neural and functional phenotype is paramount to interpreting genetic results in clinical practice. The future hearing healthcare provider must consolidate an ever-increasing amount of genetic and phenotypic information in the precision medicine of hearing loss.

13.
Otol Neurotol ; 41(9): 1163-1174, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32925832

RESUMEN

: This combined American Neurotology Society, American Otological Society, and American Academy of Otolaryngology - Head and Neck Surgery Foundation document aims to provide guidance during the coronavirus disease of 2019 (COVID-19) on 1) "priority" of care for otologic and neurotologic patients in the office and operating room, and 2) optimal utilization of personal protective equipment. Given the paucity of evidence to inform otologic and neurotologic best practices during COVID-19, the recommendations herein are based on relevant peer-reviewed articles, the Centers for Disease Control and Prevention COVID-19 guidelines, United States and international hospital policies, and expert opinion. The suggestions presented here are not meant to be definitive, and best practices will undoubtedly change with increasing knowledge and high-quality data related to COVID-19. Interpretation of this guidance document is dependent on local factors including prevalence of COVID-19 in the surgeons' local community. This is not intended to set a standard of care, and should not supersede the clinician's best judgement when managing specific clinical concerns and/or regional conditions.Access to otologic and neurotologic care during and after the COVID-19 pandemic is dependent upon adequate protection of physicians, audiologists, and ancillary support staff. Otolaryngologists and associated staff are at high risk for COVID-19 disease transmission based on close contact with mucosal surfaces of the upper aerodigestive tract during diagnostic evaluation and therapeutic procedures. While many otologic and neurotologic conditions are not imminently life threatening, they have a major impact on communication, daily functioning, and quality of life. In addition, progression of disease and delay in treatment can result in cranial nerve deficits, intracranial and life-threatening complications, and/or irreversible consequences. In this regard, many otologic and neurotologic conditions should rightfully be considered "urgent," and almost all require timely attention to permit optimal outcomes. It is reasonable to proceed with otologic and neurotologic clinic visits and operative cases based on input from expert opinion of otologic care providers, clinic/hospital administration, infection prevention and control specialists, and local and state public health leaders. Significant regional variations in COVID-19 prevalence exist; therefore, physicians working with local municipalities are best suited to make determinations on the appropriateness and timing of otologic and neurotologic care.


Asunto(s)
Infecciones por Coronavirus/epidemiología , Otoneurología/organización & administración , Otorrinolaringólogos , Otolaringología/organización & administración , Neumonía Viral/epidemiología , Corticoesteroides/uso terapéutico , Betacoronavirus , COVID-19 , Centers for Disease Control and Prevention, U.S. , Humanos , Quirófanos , Pandemias , Equipo de Protección Personal/normas , Guías de Práctica Clínica como Asunto , Calidad de Vida , Medición de Riesgo , SARS-CoV-2 , Estados Unidos
14.
Otol Neurotol ; 40(9): 1167-1177, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31318786

RESUMEN

HYPOTHESIS: Application of localized, mild therapeutic hypothermia during cochlear implantation (CI) surgery is feasible for residual hearing preservation. BACKGROUND: CI surgery often results in a loss of residual hearing. In preclinical studies, local application of controlled, mild therapeutic hypothermia has shown promising results as a hearing preservation strategy. This study investigated a suitable surgical approach to deliver local hypothermia in patients utilizing anatomical and radiologic measurements and experimental measurements from cadaveric human temporal bones. METHODS: Ten human cadaveric temporal bones were scanned with micro-computed tomography and anatomical features and measurements predicting round window (RW) visibility were characterized. For each bone, the standard facial recess and myringotomy approaches for delivery of hypothermia were developed. The St. Thomas Hospital (STH) classification was used to record degree of RW visibility with and without placement of custom hypothermia probe. Therapeutic hypothermia was delivered through both approaches and temperatures recorded at the RW, RW niche, over the lateral semicircular canal and the supero-lateral mastoid edge. RESULTS: The average facial recess area was 13.87 ±â€Š5.52 mm. The introduction of the cooling probe through either approach did not impede visualization of the RW or cochleostomy as determined by STH grading. The average temperatures at RW using the FR approach reduced by 4.57 ±â€Š1.68 °C for RW, while using the myringotomy approach reduced by 4.11 ±â€Š0.98 °C for RW. CONCLUSION: Local application of therapeutic hypothermia is clinically feasible both through the facial recess and myringotomy approaches without limiting optimal surgical visualization.


Asunto(s)
Implantación Coclear/métodos , Hipotermia Inducida/métodos , Ventana Redonda/cirugía , Canales Semicirculares/cirugía , Cadáver , Femenino , Humanos , Apófisis Mastoides/cirugía , Hueso Temporal/cirugía , Microtomografía por Rayos X , Adulto Joven
15.
Neuro Oncol ; 21(4): 486-497, 2019 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-30615146

RESUMEN

BACKGROUND: Neurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas. METHODS: Mouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns. RESULTS: Trametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance. CONCLUSION: MEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.


Asunto(s)
Azetidinas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Neuroma Acústico , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/farmacología , Pirimidinonas/farmacología , Animales , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , Ratones , Neurofibromatosis 2/complicaciones , Neuroma Acústico/etiología
16.
Otol Neurotol ; 39(7): e550-e556, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29957670

RESUMEN

HYPOTHESIS: The retrofacial approach is a feasible approach to the round window niche and that the Round window-Sigmoid sinus line will help determine the feasibility of retrofacial approach for cochlear implantation unless there is a very high jugular bulb. BACKGROUND: When the round window cannot be visualized by facial recess approach during cochlear implantation, other conservative techniques can be used to improve visualization such as the retrofacial approach. METHODS: Thirteen adult dry cadaveric temporal bones were studied. Computed tomography (CT) scan was obtained on all temporal bones. An imaginary Round window-Sigmoid sinus line was drawn on the axial images. We assessed whether this line is anterior (including intersection) or posterior to the facial nerve (FN). The following closest distances were measured on CT scans: 1) posterior semicircular canal (PSC)-FN, 2) PSC-Stapedius muscle, 3) PSC-Jugular bulb, 4) lateral semicircular canal (LSC)-Jugular bulb, 5) sigmoid sinus-FN. A canal wall-up mastoidectomy, facial recess, and retrofacial approach were performed in all specimens. We have noted whether we need a standard or an extended mastoidectomy. RESULTS: The Round window-Sigmoid sinus line was posterior to the FN in all specimens. The retrofacial approach was feasible and the round window was visualized in all specimens. Extended mastoidectomy was required in seven specimens and the PSC-FN was ≤ 3 mm in five of them. CONCLUSION: Retrofacial approach is feasible in cochlear implantation when the Round window-Sigmoid sinus line is posterior to the FN and the jugular bulb is not obstructing the round window.


Asunto(s)
Implantación Coclear/métodos , Ventana Redonda/cirugía , Cadáver , Estudios de Factibilidad , Humanos
17.
Otolaryngol Clin North Am ; 51(2): 429-440, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29502727

RESUMEN

Diagnosis and treatment of advanced otosclerosis can be controversial. In 1961, House and Sheehy defined advanced otosclerosis as hearing loss in air conduction threshold by 85 dB with nonmeasurable bone conduction. Recently, the definition of advanced otosclerosis is mostly based on the decrease of speech recognition. There are some treatment modalities: stapes surgery and hearing aids, cochlear implantation, or direct acoustic cochlear implant. The authors propose a new algorithm for treatment. If the patient is treated with cochlear implantation, the surgeon should be cautious for facial nerve stimulation after surgery because it is the most prevalent complication.


Asunto(s)
Implantación Coclear/métodos , Implantes Cocleares , Perdida Auditiva Conductiva-Sensorineural Mixta/terapia , Otosclerosis/terapia , Cirugía del Estribo/métodos , Conducción Ósea/fisiología , Terapia Combinada , Humanos , Imagen por Resonancia Magnética , Otosclerosis/diagnóstico por imagen , Otosclerosis/patología , Percepción del Habla , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
19.
Otol Neurotol ; 39(3): 299-305, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29342054

RESUMEN

OBJECTIVE: To demonstrate the safety and effectiveness of the MED-EL Electric-Acoustic Stimulation (EAS) System, for adults with residual low-frequency hearing and severe-to-profound hearing loss in the mid to high frequencies. STUDY DESIGN: Prospective, repeated measures. SETTING: Multicenter, hospital. PATIENTS: Seventy-three subjects implanted with PULSAR or SONATA cochlear implants with FLEX electrode arrays. INTERVENTION: Subjects were fit postoperatively with an audio processor, combining electric stimulation and acoustic amplification. MAIN OUTCOME MEASURES: Unaided thresholds were measured preoperatively and at 3, 6, and 12 months postactivation. Speech perception was assessed at these intervals using City University of New York sentences in noise and consonant-nucleus-consonant words in quiet. Subjective benefit was assessed at these intervals via the Abbreviated Profile of Hearing Aid Benefit and Hearing Device Satisfaction Scale questionnaires. RESULTS: Sixty-seven of 73 subjects (92%) completed outcome measures for all study intervals. Of those 67 subjects, 79% experienced less than a 30 dB HL low-frequency pure-tone average (250-1000 Hz) shift, and 97% were able to use the acoustic unit at 12 months postactivation. In the EAS condition, 94% of subjects performed similarly to or better than their preoperative performance on City University of New York sentences in noise at 12 months postactivation, with 85% demonstrating improvement. Ninety-seven percent of subjects performed similarly or better on consonant-nucleus-consonant words in quiet, with 84% demonstrating improvement. CONCLUSION: The MED-EL EAS System is a safe and effective treatment option for adults with normal hearing to moderate sensorineural hearing loss in the low frequencies and severe-to-profound sensorineural hearing loss in the high frequencies who do not benefit from traditional amplification.


Asunto(s)
Estimulación Acústica/instrumentación , Implantes Cocleares , Audífonos , Pérdida Auditiva Sensorineural/cirugía , Resultado del Tratamiento , Adolescente , Adulto , Anciano , Implantación Coclear , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Percepción del Habla/fisiología , Encuestas y Cuestionarios , Adulto Joven
20.
Acta Otolaryngol ; 138(11): 1051-1056, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30776269

RESUMEN

BACKGROUND: Precise techniques to find the facial nerve (FN) and recess are lacking. OBJECTIVES: We aimed to define incus-spine and incus-FN angles which can be used to localize the FN and recess during mastoidectomy. MATERIAL AND METHODS: Thirty adult cadaveric temporal bones were studied. Canal-wall up mastoidectomy with a facial recess approach was performed. The temporal bones and microscope were positioned differently to change the visual angle. The following distances were measured: (1) Short process of the incus (SPI)-FN; (2) Body of the incus-FN. Photographs were taken. Three lines were drawn on the photographs between the SPI, FN, and the spine of Henle. The angles were created and measured. RESULTS: Three of the temporal bones were excluded due to the absence of the spine of Henle and two of them due to the displacement of the SPI. The mean of the incus-spine angle in 25 temporal bones was 90.12° and the mean of the Incus-FN angle was 135.96°. The mean distances of the SPI-FN and body of incus-FN were 4.85 and 9.26 mm, respectively. CONCLUSIONS AND SIGNIFICANCE: The incus-spine and the incus-FN angles along with the distances can help localize the FN and recess.


Asunto(s)
Puntos Anatómicos de Referencia , Nervio Facial/anatomía & histología , Hueso Temporal/anatomía & histología , Adulto , Cadáver , Disección , Nervio Facial/cirugía , Traumatismos del Nervio Facial/prevención & control , Femenino , Humanos , Yunque , Masculino , Mastoidectomía/métodos , Sensibilidad y Especificidad , Hueso Temporal/cirugía
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