m^(6)A modification of lncRNA in middle ear cholesteatoma

Objective:Middle ear cholesteatoma is a non-tumorous condition that typically leads to hearing loss,bone destruction,and other severe complications.Despite surgery being the primary treatment,the recurrence rate remains high.Therefore,exploring the molecular mechanisms underlying cholesteatoma is crucial for discovering new therapeutic approaches.This study aims to explore the involvement of N6-methyladenosine(m^(6)A)methylation in long non-coding RNAs(lncRNAs)in the biological functions and related pathways of middle ear cholesteatoma.Methods:The m^(6)A modification patterns of lncRNA in middle ear cholesteatoma tissues(n=5)and normal post-auricular skin tissues(n=5)were analyzed using an lncRNA m^(6)A transcriptome microarray.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses were conducted to identify potential biological functions and signaling pathways involved in the pathogenesis of middle ear cholesteatoma.Methylated RNA immunoprecipitation(MeRIP)-PCR was used to validate the m^(6)A modifications in cholesteatoma and normal skin tissues.Results:Compared with normal skin tissues,1525 lncRNAs were differentially methylated in middle ear cholesteatoma tissues,with 1048 showing hypermethylation and 477 showing hypomethylation[fold change(FC)≥3 or<1/3,P<0.05].GO enrichment analysis indicated that hypermethylated lncRNAs were involved in protein phosphatase inhibitor activity,neuron-neuron synapse,and regulation ofα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)receptor activity.Hypomethylated lncRNAs were associated with mRNA methyltransferase activity,secretory granule membrane,and mRNA methylation.KEGG analysis revealed that hypermethylated lncRNAs were mainly associated with 5 pathways:the Hedgehog signaling pathway,viral protein interaction with cytokines and cytokine receptors,mitogen-activated protein kinase(MAPK)signaling pathway,cytokine-cytokine receptor interaction,and adrenergic signaling in cardiomyocytes.Hypomethylated lncRNAs were mainly involved in 4 pathways:Renal cell carcinoma,tumor necrosis factor signaling pathway,transcriptional misregulation in cancer,and cytokine-cytokine receptor interaction.Additionally,MeRIP-PCR confirmed the changes in m^(6)A methylation levels in NR_033339,NR_122111,NR_130744,and NR_026800,consistent with microarray analysis.Real-time PCR also confirmed the significant upregulation of MAPK1 and NF-κB,key genes in the MAPK signaling pathway.Conclusion:This study reveals the m^(6)A modification patterns of lncRNAs in middle ear cholesteatoma,suggests a direction for further research into the role of lncRNA m^(6)A modification in the etiology of cholesteatoma.The findings provide potential therapeutic targets for the treatment of middle ear cholesteatoma.

Congenital cholesteatoma of the middle ear-a report of 10 cases

Objectives To study clinical, imaging features and treatment outcomes of congenital cholesteatoma of middle ear (CCME). Methods This is a retrospective review of 10 CCME cases selected from 952 cholesteatoma cases treated between January 1995 and December 2005 at the Department of Otolaryngology-Head and Neck Surgery, Chinese PLA General Hospital. The main outcome measures were the site of origin, clinical features, surgical findings, imaging characteristics and hearing results. Results The mean age of the 10 patients was 16 years(ranged from 10 to 24 years), with 6 being older than 18 years. There were 7 males and 3 females. The average delay to diagnosis was longer than 2 years. The mean preoperative PTA was 55 dB HL, with a mean ABG of 45 dB. Typical cholesteatomas were seen behind the tympanic membrane in the superoposterior quadrant on otoscopy only in 2 patients. High resolution CT was completed in all patients. Most of the patients(8/10) were diagnosed with otosclerosis or ossicular abnormality before operation. All patients underwent a one-stage tympanoplasty following transmeatal explorative tympanotomy and complete cholesteatoma removal, except one, who underwent a CWU mastoidectomy due to extensive cholesteatoma involvement. The choleasteatoma lesion was confined to the superoposterior mesotympanum in all patients. The mean postoperative PTA was 20 dB HL. All patients were followed-up for at least 1.5 years postoperatively. Revision procedures were performed in 2 patients for hearing deterioration. No residual or recurrence of cholesteatoma was found. Conclusion CCME is a rare disease that often gets delayed diagnosis. Residual lesions and the prognosis mainly depend on the extent of the lesion.

Potential otogenic complications caused by cholesteatoma of the contralateral ear in patients with otogenic abscess secondary to middle ear cholesteatoma of one ear:A case report

BACKGROUND Otogenic brain abscess caused by middle ear cholesteatoma is a potentially serious and life-threatening complication in the ear,nose,and throat clinic.The mortality rate associated with otogenic brain abscesses is 8%–26.3%.Recently,in China,the incidence of brain abscess secondary to middle ear cholesteatoma has started to increase due to antibiotic resistance.CASE SUMMARY A 55-year-old male presented hearing loss in the right ear and headache for 1 mo in 2018.Computed tomography(CT) showed an area of low density in the right middle ear and mastoid and auditory ossicle defects and a small amount of soft tissue density in the left middle ear.The parietal wall of the right tympanic cavity and the posterior wall of the mastoid sinus were thin and less continuous.Cranial magnetic resonance imaging revealed an area of low intensity encapsulated by an area of high intensity in the right temporal lobe.We diagnosed him with a brain abscess secondary to middle ear cholesteatoma.He received surgery to drain the abscess followed by a modified radical mastoidectomy.The patient visited our department 3 years later because of intermittent otorrhea in the left ear.CT revealed that the area of the soft tissue density in the left middle ear and mastoid was significantly increased.The posterior wall of the mastoid sinus was destroyed,leaving the left middle ear connecting with the brain.The patient underwent a modified radical mastoidectomy in the left ear CONCLUSION Regular follow-up and timely treatment of contralateral ear disease are vital for the prevention of otogenic complications in patients with otogenic abscesses secondary to middle ear cholesteatoma in the unilateral ear.

Middle ear foreign body causing cholesteatoma and external auditory canal granuloma: a case report

Objective Patients with unilateral ear discharge and hearing loss often have external or middle ear diseases. We present a 55-year-old man who suffered from persistent ear discharge and hearing loss in the left ear. Local findings showed that his left ear canal was filled with a large amount of granulation tissue, with purulent, foul-smelling discharge. Computed tomography indicated left middle ear cholesteatoma and mass shadow in the left external auditory canal. Modified radical mastoidectomy was performed. A piece of white plastic stick was found in the middle ear during the operation. Foreign body-induced cholesteatoma and external auditory canal granuloma in adults are very rare. We present this rare case so that these conditions can be better recognized and understood.

Squamous Cell Carcinoma of the Middle Ear: Case Report and Literature Review

Malignant tumors originating from the middle ear are rare. The literature identifies chronic inflammation and Human Papillomavirus (HPV) infection as the most common risk factors. A CT scan to assess bony invasion and an MRI to evaluate soft tissue involvement, depth of invasion, and perineural invasion, followed by a biopsy, are indispensable for diagnosis and treatment. There is no standard treatment for squamous cell carcinoma of the middle ear, however, most reported cases are treated with surgical resection followed by postoperative radiotherapy. Given the challenges of achieving complete surgical excision, radiotherapy plays a crucial role in controlling middle ear cancers, as demonstrated in our case. We present a case of squamous cell carcinoma of the middle ear in a 63-year-old female with a history of chronic suppurative otitis media. The patient underwent a right subtotal petrosectomy without lymph node dissection followed by concurrent chemoradiotherapy. At the one-year follow visit, no recurrence or metastasis was detected.

Bilateral Middle Fossa Floor Meningiomas Invading the Middle Ear

This case is a 49-year-old female patient who presented with suspected eustachian tube dysfunction symptoms that were refractory to medical treatment. She presented with conductive hearing loss and aural fullness on the left. A physical exam revealed an epitympanic fleshy mass in the middle ear with effusion. Imaging with MRI and CT showed opacification of the epitympanum with surrounding bony demineralization bilaterally left greater than right and significant thinning versus dehiscence of the tegmen mastoideum and tympani on the left with only thinning of the tegmen on the right. An MR temporal bone with and without contrast, demonstrated enhancement of the left middle ear extending to the tegmen and corresponding enhancement of the dura along the floor of the left middle cranial fossa as well as extending along foramen ovale into the infratemporal fossa. There was to a lesser degree similar appearance on the right. A biopsy of the middle ear mass on the left revealed meningioma. This case highlights the need to widen your differential with common symptoms when they are refractory to treatment.

A Novel Surgery Classification for Endoscopic Approaches to Middle Ear Cholesteatoma

This study aimed to develop a novel surgery classification for an endoscopic approach to middle ear cholesteatoma.We retrospectively analyzed the surgical approaches and outcomes of patients with middle ear cholesteatoma.Middle ear cholesteatoma surgeries were divided into four types and two special types as follows:type I,attic retraction pocket,which only requires tympanostomy tube placement or retraction pocket resection and cartilage reconstruction;typeⅡ,cholesteatoma which is limited to the attic or in which endoscopy can confirm complete removal of mastoid cholesteatoma lesions,including type Ⅱa,requiring only use of a curette,and type Ⅱ b,requiring use of an electric drill or chisel;type Ⅲ,cholesteatoma not limited to the attic,in which endoscopy cannot confirm complete removal of mastoid cholesteatoma lesions,requiring the combined use of endoscope and microscope to perform endoscopic tympanoplasty and"Canal Wall Up"mastoidectomy;type Ⅳ,extensive involvement of mastoid cavity cholesteatoma lesions and/or cases with a potential risk of complications,removal of which can only be performed under a microscope for"Canal Wall Down"mastoidectomy.In addition,there were two special types:"difficult external auditory canal"and congenital cholesteatoma in children.In our system,type I and type U middle ear cholesteatoma surgery was completely performed under an endoscope alone.However,estimating the extent of the lesions,determining the choice of mastoid opening and reestablishing ventilation are the key points for an endoscopic approach to middle ear cholesteatoma.The classification of endoscopic middle ear cholesteatoma surgery may benefit the selection of surgical indications.

Pediatric Middle Ear Congenital Cholesteatoma: A Case Report

Congenital cholesteatoma（CC）is a rarely seen benign tumor of the temporal bone. There are five general sites of extradural occurrence: the middle ear, external auditory meatus, mastoid, squamous portion and the petrous apex of the temporal bone. CC grows slowly and presents no symptoms at the early stage. Delayed and mis-diagnosis are common with this condition. Case report A 10-year-old boy presented with a 3-month history of hearing loss on right side. There was no history of otorrhea, facial palsy, previous otological procedures or trauma. Otoscopy revealed a bulging posterosuperior quadrant in the otherwise intact right tympanic membrane （Fig.1）. Pure tone audiometry showed an average threshold of 51 dB for 500, 1000, 2000 and 4000Hz, with a 40 dB air-bone gap, suggesting a moderate conductive hearing loss（Fig.4）. CT scan of the temporal bone showed an isolated soft tissue density lesion in the middle ear（Fig.2）.

Endoscopic ear surgery in middle ear cholesteatoma

Objective:Endoscope has been used as diagnostic tool for recidivism and as an adjunct to microscopic technique in the management of cholesteatoma.At present transcanal endoscopic ear surgery(TEES)is being used as a minimally invasive alternative for microscopic approach.We aim to evaluate the feasibility,structural,functional and quality of life outcomes of endoscopic technique in middle ear cholesteatoma.Method:This prospective study was conducted at a tertiary care hospital from January 2017 to January 2018 including 32 adult patients who were treated by TEES for middle ear cholesteatoma.Feasibility of endoscopic technique was assessed by the conversion rates,visualization of middle ear structures and complications.Structural outcomes were evaluated in terms of graft uptake at the third month follow-up and presence of residual or recurrent disease.Functional outcomes were evaluated in terms of postoperative air-bone gap closure at third month follow-up.Patient outcomes in terms of post-operative pain,cosmetic score,day of return to daily activities and patient comfort scores were evaluated.The quality of life outcomes were evaluated using chronic ear survey(CES)and short form questionnaire12 version 2(SF-12V2)which are disease specific and general quality of life assessment tools respectively.Result:Out of 32 patients,endoscopic intact canal wall mastoidectomy was done for 28 and endoscopic canal wall down mastoidectomy in 4 patients.One(3.1%)patient had to be converted to microscopic technique.Median follow-up period was 32.8 months(9e46 months).There were no post-operative complications in any of our patients.The mean middle ear structural visibility index score was 8.4±1.4 with the use of zero-degree endoscope.Graft uptake rate at third month follow-up was 100%.Two(6.3%)patients had recurrent disease at 6 months follow-up and were treated by revision endoscopic surgery.The air conduction(51.3±20.2 dB vs.34.5±20.4 dB,p<0.001),and air-bone gap(33.5±11.1 dB vs.16.9±11.8 dB,p<0.001)has been significantly improved.The mean pain score at 0 hours,6 hours and 24 hours after surgery were 2.5/10,1.6/10 and 0.75/10 respectively.At the discharge,the mean patient comfort score was 9.3±0.6 out of 10.Mean cosmetic score was 9.3±0.5 at the third month follow-up.There was significant post-operative improvement in the sub-scale and total scores of CES and SF-12V2.Conclusion:Endoscopic approach to middle ear cholesteatoma is feasible and confers excellent structural,functional as well as patient related quality of life outcomes.

Voltage property analysis of piezoelectric floating mass actuator used in middle ear implant

Aiming at a kind of middle ear implant（MEI）, the driving voltage of a piezoelectric floating mass actuator is analyzed using a 0. 7Pb （Mg1/3Nb2/3） O3-0. 3PbTiO3 （ PMN- 30% PT）stack as a new type of vibrator. For the purpose of facilitating the analysis, a simplified coupling model of the ossicular chain and the piezoelectric actuator is constructed. First, a finite element model of a human middle ear is constructed by reverse engineering technology, and the validity of this model is confirmed by comparing the simulated motion of the stapes footplate obtained by this model with experimental measurements. Then the displacement impedance of the incus long process is analyzed, and a single mass-spring-damper equivalent model of the ossicular chain attached with the clamp is derived. Finally, a simplified coupling model of the ossicular chain and the piezoelectric actuator is established and used to analyze the driving voltage property of the actuator. The results show that the required driving voltage decreases with the increase in the frequency, and the maximum required driving voltage is 20. 9 V in the voice frequencies. However, in the mid-high frequencies where most sensorineural hearing loss occurs, the maximum required driving voltage is 3.8 V, which meets the low-voltage and low-power requirements of the MEI.

Middle ear osteoma causing Eustachian tube obstruction:A case report and literature review

Middle ear osteoma is an extremely rare benign tumor of the middle ear.Due to its very slow growth rate and benign nature,osteoma of the middle ear can be found incidentally without causing any symptoms.The most common clinical signs are conductive hearing loss,the sense of fullness in the ear,tinnitus,and otorrhea.Small-sized osteomas can be misdiagnosed as otosclerosis without showing any signs other than conductive hearing loss.When the mass becomes very large,and symptoms caused by the tumor increase,treatment also becomes difficult.In this paper,we report a case of middle ear osteoma causing conductive hearing loss and effusion due to the effect of pressure on the middle ear ossicles and the Eustachian tube.We also present a review of the pertinent literature.

Middle Ear Implants:Historical and futuristic perspective

Technological advancements are continuously changing the paradigm of human existence.Human beings are constantly engaging in various measures to reduce the extent of sensory and motor impairment.This has been in the form of various devices,e.g.orthopedic prosthesis,visual aids (spectacles) and hearing aids.Countless attempts throughout the centuries have been made in an effort to improve sound amplification in patients.This article seeks to highlights the technological journey of one such implant,the middle ear implant,from its inception to the more technological advanced futuristic proposals.While there are many amplification devices available presently,there still remains a group of patients who have not experienced adequate amplification for their hearing loss and this subset may gain the greatest benefit from middle ear implants.

Design of Floating Mass Type Piezoelectric Actuator for Implantable Middle Ear Hearing Devices

To overcome some of the problems inherent in conventional heating aids such as low gain at high fi＇equencies due to acoustic feedback, discomfort in occlusion of the extemal ear canal and so on, implantable middle ear hearing devices （IMEHDs） have been developed over the past two decades. For such kinds of IMEHDs, this paper presents the design of a floating mass piezoelectric actuator using a PMN-30%PT stack as a new type of vibrator. The proposed piezoelectric actuator consists of only three components of a piezoelectric stack, a metal case and a clamp. For the purpose of aiding the design of this actuator, a coupling biomechanics model of human middle ear and the piezoelectric actuator was constructed. This model was built based on a complete set of computerized tomography section images of a healthy volunteer＇s left ear by reverse engineering technology. The validity of this model was confirmed by comparing the motion of the tympanic membrane and stapes footplate obtained by this model with published experimental measurements on human temporal bones. It is shown that the designed actuator can be implanted on the incus long process by a simple surgical operation, and the stapes footplate displacement by its excitation at 10.5 V root-mean-square（RMS） voltage was equivalent to that from acoustic stimulation at 100 dB sound pressure level（SPL）, which is adequate stimulation to the ossicular chain. The corresponding power consumption is 0.04 mW per volt of excitation at 1 kHz, which is low enough for the transducer to be used in an implantable middle ear device.

Classification of facial nerve aberration in congenital malformation of middle ear:Implications for surgery of hearing restoration

Objectives: Facial nerve aberration is the most troublesome situation in congenital malformations of middle ear.The aim of our study is to investigate its imaging and clinical features as well as relevant choice of surgical techniques for hearing improvement.Methods: A retrospective study involving review of clinical data of 227 patients(256 ears) with congenital middle ear anomaly was undertaken, including preoperative computed tomography(CT) data, surgical records and videos.Results: Aberration involving intratemporal facial nerve was found in 82/256 ears(32.03%) with congenital middle ear anomaly. The most common forms of aberration included overhanging over the oval window(50/82 ears, 60.98%), bifurcation(3/82 ears, 3.66%) and transverse over the promontory(3/82 ears, 3.66%), counting for 68.29%(56/82) of the cases with facial nerve aberration. Concomitant stapes malformation was found in 76/82 ears(92.68%) and atresia or stenosis of the oval window in 27/82 ears(32.93%). In 9/82 ears(10.98%) both stapes and oval window was absent. Elective surgeries for the purpose of hearing improvement included stapodotomy + piston implantation, labyrinthotomy, labyrinthotomy + total ossicular replacement prosthesis(TORP) implantation and Vibrant Soundbridge(VSB) implantation.Conclusion: The majority of facial nerve aberration in congenital malformation of middle ear involves displacement of facial nerve, in addition to concomitant malformations of the stapes and/or oval window, which may influence the choice of surgery for hearing improvement. VSB implantation may be considered as a useful option.

Intra-operative hearing monitoring methods in middle ear surgeries

Hearing loss is a condition affecting millions of people worldwide. Conductive hearing loss (CHL) is mainly caused by middle ear diseases. The low frequency area is the pivotal part of speech frequencies and most frequently impaired in patients with CHL. Among various treatments of CHL, middle ear surgery is efficient to improve hearing. However, variable success rates and possible needs for prolonged revision surgery still frustrate both surgeons and patients. Nowadays, increasing numbers of researchers explore various methods to monitor the efficacy of ossicular reconstruction intraoperatively, including electrocochleography (ECochG), auditory brainstem response (ABR), auditory steady state response (ASSR), distortion product otoacoustic emissions (DPOAE), subjective whisper test, and optical coherence tomography (OCT). Here, we illustrate several methods used clinically by reviewing the literature.

Numerical Modeling of Human Middle Ear Biomechanics Using Finite Element Method

An accurate finite element （ FE ） model of the human middle ear can provide better understanding of the mechanics of middle ear, and can be used for aiding the design of the implantable middle ear hearing devices. In this paper, a threedimensional （3D） FE model of the human middle ear was constructed, including the tympanic membrane, ossicular bones, and middle ear suspensory ligaments/museles. This model was constructed based on a complete set of computerized tomography section images of a healthy volunteer＇s left ear by reverse engineering technology. The validity of this model was confirmed by comparing the motions of the tympanic membrane and stapes footplate obtained by this model with published experimental measurements on human temporal bones. The result shows that the model is reasonable in predicting the biomechanics of the human middle ear.

Static analysis of tympanic membrane in aero-otitis media by three-dimensional model of the middle ear

The three-dimensional(3D)model of the middle ear is of great significance to the research of middle ear related diseases.The particular focus of this work is to simulate the impact of aircraft altitude and speed changes on the tympanic membrane(TM)during the descent phase,so as to analyze the pathogenesis of aero-otitis media and the mechanical response characteristics of TM under static pressure.The simulations showed that the stress and strain of TM increase as the altitude difference and speed of the aircraft increase,and the maximum stress and strain areas are consistent with the clinical observation of TM hyperemia.Therefore,among many prevention and treatment measures of aero-otitis media,it is a therapeutic method to directly balance the pressure difference between the inner and outer TM.

First branchial cleft cyst accompanied by external auditory canal atresia and middle ear malformation:A case report

BACKGROUND We report a rare case of first branchial cleft anomaly(FBCA)accompanied by bony atresia of the external auditory canal,middle ear malformation,and location malformation of the facial nerve according to the intraoperative findings.CASE SUMMARY A 19-year-old male patient presented to our department with a mass behind the right earlobe and recurrent postauricular swelling and pain since childhood,he also had severe hearing loss in the right ear since birth.The patient underwent surgery including mass removal,mastoidectomy,and simultaneous meatoplasty and ossiculoplasty under microscopy.No facial palsy or recurrence was noted during postoperative follow-up.CONCLUSION FBCAs are rare,and to our knowledge,this is the first report of FBCA accompanied by external auditory canal bony atresia,middle ear malformation,and location malformation of the facial nerve.An effective postauricular approach under microscopy facilitated complete lesion removal and simultaneous otologic reconstruction.

Carcinoid Tumors in the Middle Ear:a Case Report and Literature Review

Middle ear carcinoid tumor (MEC T) is rare. Only 46 cases of MECT have been reported in the literature since the first case of MECT was described in 1980. We present here a case of primary MECT initially diagnosed as inflammatory aural polyp. The case was a 43-year-old women complaining of right ear chronic otorrhea and hearing loss over a period of five years, with a blockage sensation in the right ear for two years. Audiometry showed conductive hearing loss in the right ear. Physical examination and CT scans showed a mass in the right external auditory canal and middle ear, surrounding the ossicular chain. Pathologic study of surgically removed specimen revealed features of carcinoid tumor with positive staining to chromogranin A and synaptophysin in tumor cells. Local radiation of 60 Gy was applied. The patient has been followed up for more than one year. Postoperative histopathological examination showed no evidence of MECT recurrence one year after surgery, but inflammatory changes in the middle ear. Relevant literatures were reviewed. Clinical, histopathological, immunohistochemical and ultrastructural features of MECT, and strategies in MECT diagnosis and management are discussed.

Inflammatory responses to Hydroxyapatite implants in middle ear in rats

Objective To study local inflammatory response after implantation of hydroxyapatite synthetic ossicular prosthesis. Methods Hydroxyapatite granules were implanted in the bulla in 32 rats. Sham surgical procedures were performed in 10 rats as the control. Animals were sacrificed at 1 to 300 days after surgery. Bulla sections, stained with HE and Mallory’s azan, were examined for numbers and percentages of various inflammatory cell types. Results Slightly more inflammatory reaction was seen in animals with the implant than in the controls, mostly during the early stage following the implantation procedure. Few inflammatory cells were observed at later times. There were satisfactory fibrosis in both implanted and control ears. Conclusion The results indicate that hydroxyapatite synthetic prosthesis is a biocompatible implantation material in the middle ear. Nonetheless, the presence of inflammatory reaction immediately following implantation implies that control of infection is important in the early times after the implantation procedure.