PTHrP participates in the bone destruction of middle ear cholesteatoma via promoting macrophage differentiation into osteoclasts induced by RANKL. / PTHrP促进RANKLè¯±å¯¼å·¨å™¬ç»†èƒžåˆ†åŒ–ä¸ºç ´éª¨ç»†èƒžå‚ä¸Žä¸­è€³èƒ†è„‚ç˜¤éª¨ç ´å.

OBJECTIVES: Progressive bone resorption and destruction is one of the most critical clinical features of middle ear cholesteatoma, potentially leading to various intracranial and extracranial complications. However, the mechanisms underlying bone destruction in middle ear cholesteatoma remain unclear. This study aims to explore the role of parathyroid hormone-related protein (PTHrP) in bone destruction associated with middle ear cholesteatoma. METHODS: A total of 25 cholesteatoma specimens and 13 normal external auditory canal skin specimens were collected from patients with acquired middle ear cholesteatoma. Immunohistochemical staining was used to detect the expressions of PTHrP, receptor activator for nuclear factor-kappa B ligand (RANKL), and osteoprotegerin (OPG) in cholesteatoma and normal tissues. Tartrate-resistant acid phosphatase (TRAP) staining was used to detect the presence of TRAP positive multi-nucleated macrophages in cholesteatoma and normal tissues. Mono-nuclear macrophage RAW264.7 cells were subjected to interventions, divided into a RANKL intervention group and a PTHrP+ RANKL co-intervention group. TRAP staining was used to detect osteoclast formation in the 2 groups. The mRNA expression levels of osteoclast-related genes, including TRAP, cathepsin K (CTSK), and nuclear factor of activated T cell cytoplasmic 1 (NFATc1), were measured using real-time polymerase chain reaction (real-time PCR) after the interventions. Bone resorption function of osteoclasts was assessed using a bone resorption pit analysis. RESULTS: Immunohistochemical staining showed significantly increased expression of PTHrP and RANKL and decreased expression of OPG in cholesteatoma tissues (all P<0.05). PTHrP expression was significantly positively correlated with RANKL, the RANKL/OPG ratio, and negatively correlated with OPG expression (r=0.385, r=0.417, r=-0.316, all P<0.05). Additionally, the expression levels of PTHrP and RANKL were significantly positively correlated with the degree of bone destruction in cholesteatoma (r=0.413, r=0.505, both P<0.05). TRAP staining revealed a large number of TRAP-positive cells, including multi-nucleated osteoclasts with three or more nuclei, in the stroma surrounding the cholesteatoma epithelium. After 5 days of RANKL or PTHrP+RANKL co-intervention, the number of osteoclasts was significantly greater in the PTHrP+RANKL co-intervention group than that in the RANKL group (P<0.05), with increased mRNA expression levels of TRAP, CTSK, and NFATc1 (all P<0.05). Scanning electron microscopy of bone resorption pits showed that the number (P<0.05) and size of bone resorption pits on bone slices were significantly greater in the PTHrP+RANKL co-intervention group compared with the RANKL group. CONCLUSIONS: PTHrP may promote the differentiation of macrophages in the surrounding stroma of cholesteatoma into osteoclasts through RANKL induction, contributing to bone destruction in middle ear cholesteatoma.

Efficacy of Otoendoscopy for Residual Cholesteatoma Detection During Microscopic Chronic Ear Surgery.

The aim of this article is to determine the efficacy of otoendoscopy during microscopic cholesteatoma surgery on residual cholesteatoma rates postoperatively. The medical records of patients (aged 4-90) with primary acquired cholesteatoma who underwent microscopic cholesteatoma surgery (exclusively transcanal approach or canal wall-up tympano-mastoidectomy) with subsequent otoendoscopic examination (80 ears) for intraoperative cholesteatoma residues were retrospectively reviewed. All cases with mixed microscopic/endoscopic, fully endoscopic, or fully microscopic dissection were excluded, as well as cases where a canal wall-down technique was used. After microscopic cholesteatoma removal, the otoendoscope was used to inspect the middle ear recesses for intraoperative cholesteatoma residues. The intra- and postoperative cholesteatoma residue rate were evaluated. On endoscopic examination, intraoperative cholesteatoma residues were encountered in 24 patients (30%). A total of 30 foci were detected. Most of them were found in the superior retrotympanum (15 foci). In 9 cases an antral remnant guided the surgeon to convert to a canal wall up tympanomastoidectomy. During the postoperative follow-up period, residual cholesteatoma was detected on postoperative magnetic resonance imaging in 6 patients (7.5%). Adding an otoendoscopic examination to microscopic cholesteatoma surgery reduced the postoperative cholesteatoma residues rate (odds ratio=0.16). A negative otoendoscopic examination led to a cholesteatoma residue-free follow-up period in 95% of cases(NPV=0.95). Otoendoscopy is effective in identifying intraoperative cholesteatoma residues after microscopic cholesteatoma surgery. It reduces the postoperative cholesteatoma residue rate, and a negative otoendoscopic examination increases the likelihood of a cholesteatoma residue-free follow-up.

Identification of miRNA expression profile in middle ear cholesteatoma using small RNA-sequencing.

BACKGROUND: The present study aims to identify the differential miRNA expression profile in middle ear cholesteatoma and explore their potential roles in its pathogenesis. METHODS: Cholesteatoma and matched normal retroauricular skin tissue samples were collected from patients diagnosed with acquired middle ear cholesteatoma. The miRNA expression profiling was performed using small RNA sequencing, which further validated by quantitative real-time PCR (qRT-PCR). Target genes of differentially expressed miRNAs in cholesteatoma were predicted. The interaction network of 5 most significantly differentially expressed miRNAs was visualized using Cytoscape. Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses were processed to investigate the biological functions of miRNAs in cholesteatoma. RESULTS: The miRNA expression profile revealed 121 significantly differentially expressed miRNAs in cholesteatoma compared to normal skin tissues, with 56 upregulated and 65 downregulated. GO and KEGG pathway enrichment analyses suggested their significant roles in the pathogenesis of cholesteatoma. The interaction network of the the 2 most upregulated (hsa-miR-21-5p and hsa-miR-142-5p) and 3 most downregulated (hsa-miR-508-3p, hsa-miR-509-3p and hsa-miR-211-5p) miRNAs identified TGFBR2, MBNL1, and NFAT5 as potential key target genes in middle ear cholesteatoma. CONCLUSIONS: This study provides a comprehensive miRNA expression profile in middle ear cholesteatoma, which may aid in identifying therapeutic targets for its management.

Osteopontin-driven partial epithelial-mesenchymal transition governs the development of middle ear cholesteatoma.

Cholesteatoma is a common disease of the middle ear. Currently, surgical removal is the only treatment option and patients face a high risk of relapse. The molecular basis of cholesteatoma remains largely unknown. Here, we show that Osteopontin (OPN), a predominantly secreted protein, plays a crucial role in the development of middle ear cholesteatoma. Global transcriptome analysis revealed the loss of epithelial features and an enhanced immune response in human cholesteatoma tissues. Quantitative RT-PCR and immunohistochemical staining of middle ear cholesteatoma validated the reduced expression of epithelial markers, as well as the elevated expression of mesenchymal markers including Vimentin and Fibronectin, but not N-Cadherin, α-smooth muscle actin (α-SMA) or ferroptosis suppressor protein 1 (FSP1), indicating a partial epithelial-mesenchymal transition (EMT) state. Besides, the expression of OPN was significantly elevated in human cholesteatoma tissues. Treatment with OPN promoted cell proliferation, survival and migration and led to a partial EMT in immortalized human keratinocyte cells. Importantly, blockade of OPN signaling could remarkably improve the cholesteatoma-like symptoms in SD rats. Our mechanistic study demonstrated that the AKT-zinc finger E-box binding homeobox 2 (ZEB2) axis mediated the effects of OPN. Overall, these findings suggest that targeting the OPN signaling represents a promising strategy for the treatment of middle ear cholesteatoma.

[Specialist consensus on endoscopic surgery of the middle ear mastoid].

This article discusses otoscopic middle ear mastoid surgery from multiple perspectives. Firstly, it discusses the indications and contraindications for surgery from the nature of the lesion and the imaging manifestations; secondly, it recommends the applicable equipment and describes the surgical approach in detail; finally, it summarizes the principles of the management of the operative cavity of the mastoid process in the middle ear from the perspectives of function and reconstruction. The purpose of this article is to illustrate otoscopic middle ear mastoid surgery with the aim of providing reference or guidance for performing related surgeries.

Congenital cholesteatoma: what radiologists need to know.

Congenital cholesteatoma is a rare, non-neoplastic lesion that causes conductive hearing loss in children. It is underrecognized and often diagnosed only when there is an established hearing deficit. In the pediatric population, hearing deficiency is particularly detrimental because it can impede speech and language development and, in turn, the social and academic well-being of affected children. Delayed diagnosis leads to advanced disease that requires more extensive surgery and a greater chance of recurrence. A need to promote awareness and recognition of this condition has been advocated by clinicians and surgeons, but no comprehensive imaging review dedicated to this entity has been performed. This review aims to discuss the diagnostic utility of high-resolution computed tomography and magnetic resonance imaging in preoperative and postoperative settings in congenital cholesteatoma. Detailed emphasis is placed on the essential preoperative computed tomography findings that facilitate individualized surgical management and prognosis in the pediatric population.

Proto-oncogene mutations in middle ear cholesteatoma contribute to its pathogenesis.

BACKGROUND: Chronic inflammation causes bone destruction in middle ear cholesteatomas (MECs). However, the causes of their neoplastic features remain unknown. The present study demonstrated for the first time that neoplastic features of MEC are based on proto-oncogene mutations. RESULTS: DNA was extracted from MEC and blood samples of five patients to detect somatic mutations using depth-depth exome sequencing. Exons with somatic variants were analyzed using an additional 17 MEC/blood test pairs. Variants detected in MECs but not in blood were considered pathogenic variant candidates. We analyzed the correlation between proto-oncogene (NOTCH1 and MYC) variants and the presence of bone destruction and granulation tissue formation. MYC and NOTCH1 variants were detected in two and five of the 22 samples, respectively. Two of the NOTCH1 variants were located in its specific functional domain, one was truncating and the other was a splice donor site variant. Mutations of the two genes in attic cholesteatomas (n = 14) were significantly related with bone destruction (p = 0.0148) but not with granulation tissue formation (p = 0.399). CONCLUSIONS: This is the first study to demonstrate a relationship between neoplastic features of MEC and proto-oncogene mutations.

High-Resolution Computed Tomography in Middle Ear Cholesteatoma: How Much Do We Need It?

Background and Objectives: The diagnosis of cholesteatoma is usually clinic, and the only efficient treatment is surgical. High-resolution computed tomography (HRCT) is not considered absolutely necessary for the management of an uncomplicated cholesteatoma, but unsuspected situations from a clinical point of view can be discovered using the scans, warning the surgeon. Our objective is to compare HRCT scan information with intraoperative findings in patients with cholesteatoma and analyze the usefulness of a preoperative HRCT scan from a surgical point of view. Materials and Methods: This is a prospective descriptive study conducted in the Department of Otolaryngology, Victor Babes University of Medicine and Pharmacy Timisoara, Romania, from May 2021 to April 2022. It was carried out on 46 patients with a clinical diagnosis of cholesteatoma who were consequently operated on in our department. All patients received full clinical and audiological examinations. In all cases, an HRCT scan was performed preoperatively as a mandatory investigation. Preoperative HRCT scans were analyzed, and their findings were compared to the intraoperative notes. The two sets of observations were analyzed using standard statistical methods. Results: Extensive cholesteatoma was the most common type of disease, involving 46% of the patients, followed by pars flaccida cholesteatoma (35%) and pars tensa cholesteatoma (19%). Eroded scutum was the most frequent lesion involving 70% of the patients, followed by incus erosion (67%). Comparison of the HRCT and intraoperative findings revealed a very good correlation for tegmen tympani erosion, sigmoid plate erosion, scutum and malleus erosion, and a moderate-to-good correlation for lateral semicircular canal erosion, incus and stapes erosion, and fallopian canal erosion. Conclusions: HRCT is a valuable tool in the preoperative assessment of cholesteatoma, helping in making surgical decisions. It can accurately predict the extent of disease and is helpful for detecting unapparent dangerous situations. However, it is not very accurate in detecting fallopian canal and stapes erosion.

Expression of MMP-14 and its role in bone destruction in middle ear cholesteatoma: A prospective observational study.

Cholesteatoma is a noncancerous cystic lesion caused by an abnormal growth of keratinizing squamous epithelium which is invasive and capable of destroying structures. A prospective study on the expression of membrane type1-matrix metalloproteinases (MMP-14) and its related influencing factors in middle ear cholesteatoma was conducted to fully understand the pathogenesis of cholesteatoma in the molecular level. We examined the expression of MMP-14 by immunohistochemical staining 39 middle ear cholesteatoma specimens and 10 external auditory meatus epithelial cell specimens. The cholesteatoma specimens were divided into 4 groups according to the degree of destruction of the ossicles during surgery. The associated factors affecting MMP-14 expression were analyzed using statistical methods; The positive expression of MMP-14 in the epithelium of the external auditory canal was significantly different between middle ear cholesteatoma and normal patients (P < .05); Gender, age, and the degree of hearing loss had no statistically significant effect on MMP-14 expression (P > .05); The expression of MMP-14 was positively correlated with the severity of bone destruction (R = 0.535, P < .05); MMP-14 plays an important role in the pathological development of the epithelium of cholesteatoma; MMP-14 expression in middle ear cholesteatoma tissue was not strongly correlated with the level of hearing loss, age or gender, but was positively correlated with the degree of middle ear bone destruction.

The Hyperproliferation Mechanism of Cholesteatoma Based on Proteomics: SNCA Promotes Autophagy-Mediated Cell Proliferation Through the PI3K/AKT/CyclinD1 Signaling Pathway.

Cholesteatoma is a chronic inflammatory ear disease with abnormal keratinized epithelium proliferation and tissue damage. However, the mechanism of keratinized epithelium hyperproliferation in cholesteatoma remains unknown. Hence, our study sought to shed light on mechanisms affecting the pathology and development of cholesteatoma, which could help develop adjunctive treatments. To investigate molecular changes in cholesteatoma pathogenesis, we analyzed clinical cholesteatoma specimens and paired ear canal skin with mass spectrometry-based proteomics and bioinformatics. From our screen, alpha-synuclein (SNCA) was overexpressed in middle ear cholesteatoma and might be a key hub protein associated with inflammation, proliferation, and autophagy in cholesteatoma. SNCA was more sensitive to lipopolysaccharide-induced inflammation, and autophagy marker increase was accompanied by autophagy activation in middle ear cholesteatoma tissues. Overexpression of SNCA activated autophagy and promoted cell proliferation and migration, especially under lipopolysaccharide inflammatory stimulation. Moreover, inhibiting autophagy impaired SNCA-mediated keratinocyte proliferation and corresponded with inhibition of the PI3K/AKT/CyclinD1 pathways. Also, 740Y-P, a PI3K activator reversed the suppression of autophagy and PI3K signaling by siATG5 in SNCA-overexpressing cells, which restored proliferative activity. Besides, knockdown of SNCA in RHEK-1 and HaCaT cells or knockdown of PI3K in RHEK-1 and HaCaT cells overexpressing SNCA both resulted in attenuated cell proliferation. Our studies indicated that SNCA overexpression in cholesteatoma might maintain the proliferative ability of cholesteatoma keratinocytes by promoting autophagy under inflammatory conditions. This suggests that dual inhibition of SNCA and autophagy may be a promising new target for treating cholesteatoma.

Imaging guidance for cholesteatoma surgery using tissue autofluorescence.

Significance: Cholesteatoma is an expansile destructive lesion of the middle ear and mastoid, which can result in significant complications by eroding adjacent bony structures. Currently, there is an inability to accurately distinguish cholesteatoma tissue margins from middle ear mucosa tissue, causing a high recidivism rate. Accurately differentiating cholesteatoma and mucosa will enable a more complete removal of the tissue. Aim: Develop an imaging system to enhance the visibility of cholesteatoma tissue and margins during surgery. Approach: Cholesteatoma and mucosa tissue samples were excised from the inner ear of patients and illuminated with 405, 450, and 520 nm narrowband lights. Measurements were made with a spectroradiometer equipped with a series of different longpass filters. Images were obtained using a red-green-blue (RGB) digital camera equipped with a long pass filter to block reflected light. Results: Cholesteatoma tissue fluoresced under 405 and 450 nm illumination. Middle ear mucosa tissue did not fluoresce under the same illumination and measurement conditions. All measurements were negligible under 520 nm illumination conditions. All spectroradiometric measurements of cholesteatoma tissue fluorescence can be predicted by a linear combination of emissions from keratin and flavin adenine dinucleotide. We built a prototype of a fluorescence imaging system using a 495 nm longpass filter in combination with an RGB camera. The system was used to capture calibrated digital camera images of cholesteatoma and mucosa tissue samples. The results confirm that cholesteatoma emits light when it is illuminated with 405 and 450 nm, whereas mucosa tissue does not. Conclusions: We prototyped an imaging system that is capable of measuring cholesteatoma tissue autofluorescence.

Is pre-operative audiometry a reliable predictor of ossicular chain condition?

OBJECTIVE: Investigation of ossicular chain (OC) status before surgery is important for preoperative patient consultation. This research aimed to investigate the relationship between pre-operative audiometric values and intra-operative OC condition in a relatively large population of chronic otitis media (COM) surgeries. METHODS: In this descriptive-analytic cross-sectional study, we evaluated 694 patients who underwent COM surgeries. We analyzed pre-operative audiometric data and intraoperative findings including ossicular anatomy, ossicular mobility, and the condition of middle ear mucosa. RESULTS: The optimal cut-off values of pre-operative speech reception threshold (SRT), mean air-conduction (AC), and mean air-bone gap (ABG) for predicting OC discontinuity were 37.5 dB, 37.2 dB, and 28.4 dB, respectively. For the prediction of OC fixation, the optimal cut-off points of SRT, mean AC, and mean ABG were 37.5 dB, 40.3 dB, and 32.8 dB, respectively. The computing of Cohen's d (95 % confidence interval) demonstrated the greater mean ABG in ears with OC discontinuity in comparison with ears with normal ossicles in all types of pathologies. There was a descending trend of Cohen's d from cholesteatoma to tympanosclerosis and then to granulation tissue and hypertrophic mucosa. There was a substantial relation between the type of pathology and OC status (P < 0.001). Ears with tympanosclerosis plaque had the most fixed OC among all types of pathologies (40 ears, 30.8 %), and ears with no pathology had the most normal OC (135 ears, 83.3 %). CONCLUSIONS: The results supported the view that pre-operative hearing is a key determining factor for the prediction of OC status.

The impact of fusion imaging technique on middle ear cholesteatoma surgery: a prospective comparative study.

BACKGROUND: The fusion of computed tomography images with non-echo planner diffusion-weighted magnetic resonance images may overcome the limitations of each individual modality. OBJECTIVES: This study aimed to assess the ability of the 'fusion' technique to predict the location of middle ear cholesteatoma by evaluating Its impact on preoperative surgical planning and postoperative results. METHODOLOGY: Eighty-three adults with cholesteatoma underwent preoperative CT scans and non-EPI-DW-MRI with or without the 'fusion' technique. We evaluated cholesteatoma localization in both groups, selecting the most appropriate surgical technique, and correlating it with the intraoperative findings. Both groups were compared in terms of residual/recurrent cholesteatoma at one, six and twelve months after surgery. RESULTS: The 'fusion' technique's sensitivity, specificity, and accuracy in predicting the location of cholesteatoma were 97.5. 97.4, and 97.5%, respectively, versus 97.59, 57.69, and 73.21% of CT alone. There was a total operators agreement after the evaluation of the 'fusion' images with the adopted surgical technique. A statistically significant decrease in residual and recurrence cholesteatoma rates was found in group A. CONCLUSIONS: The 'fusion' technique provides the surgeon with the precise cholesteatoma location, guiding him in making the correct surgical decision, contributing to the decrease in postoperative residual and recurrence rates.

Morphopathogenesis of Adult Acquired Cholesteatoma.

Background and Objectives. The aim of this study was to compare the distribution of proliferation markers (Ki-67, NF-κß), tissue-remodeling factors (MMP-2, MMP-9, TIMP-2, TIMP-4), vascular endothelial growth factor (VEGF), interleukins (IL-1 and IL-10), human beta defensins (HßD-2 and HßD-4) and Sonic hedgehog gene protein in cholesteatoma and control skin. Methods. Nineteen patient cholesteatoma tissues and seven control skin materials from cadavers were included in the study and stained immunohistochemically. Results. Statistically discernible differences were found between the following: the Ki-67 in the matrix and the Ki-67 in the skin epithelium (p = 0.000); the Ki-67 in the perimatrix and the Ki-67 in the connective tissue (p = 0.010); the NF-κß in the cholesteatoma matrix and the NF-κß in the epithelium (p = 0.001); the MMP-9 in the matrix and the MMP-9 in the epithelium (p = 0.008); the HßD-2 in the perimatrix and the HßD-2 in the connective tissue (p = 0.004); and the Shh in the cholesteatoma's perimatrix and the Shh in the skin's connective tissue (p = 0.000). Conclusion. The elevation of Ki-67 and NF-κß suggests the induction of cellular proliferation in the cholesteatoma. Intercorrelations between VEGF, NF-κß and TIMP-2 induce neo-angiogenesis in adult cholesteatoma. The similarity in the expression of IL-1 and IL-10 suggests the dysregulation of the local immune status in cholesteatoma. The overexpression of the Sonic hedgehog gene protein in the cholesteatoma proves the selective local stimulation of perimatrix development.

A micro-computed tomography study of the sinus tympani variation in humans.

BACKGROUND: The posterior part of the tympanic cavity comprises a depression called the sinus tympani (ST). The said structure is of outmost importance, e.g. in surgical procedures involving the middle ear, as a pathology (microbial biofilm or cholesteatoma) present in this difficult to access location might hinder its effective treatment. The aim of the study was to evaluate anatomical variants of the ST in human adult petrous bones. For this purpose, three-dimensional (3D) models of the ST were recreated from micro-computed tomography (CT) scans of 44 dry petrous bone samples (19 female, 25 male), applying 3D Slicer, Meshmixer and MeshLab software. MATERIALS AND METHODS: Anatomical variants of the ST were classified in terms of both shape and surface configuration. The internal configuration of the ST was classified as heterogeneous - containing small bony trabeculae and crests up to 1.0 mm in size, contrasting to homogeneous ST that characterizes a relatively smooth interior, or mere presence of minor depressions and mild folds. Female STs were more bowl-shaped (57.9%) than saccular (42.1%), and had heterogeneous surface configuration (52.6%) compared to homogeneous (47.4%). On the contrary, male STs were more saccular (52.0%) rather than bowl-shaped (48.0%), and predominantly had a heterogeneous surface (84.0%) over homogeneous (16.0%). RESULTS AND CONCLUSIONS: A complex combination of ST features comprised of a saccular shape and heterogeneous surface occurred in 52.0% of males and in 15.8% of females (a statistically significant difference; p = 0.0254, Fisher's exact test) seems to be clinically important because of its potential negative implication on health outcomes after surgery in the case of, for example, cholesteatoma, and it may also favour chronic pathological processes.

Experimental cholesteatoma: a comparison between spontaneous and induced models.

OBJECTIVE: To compare the incidence and the histopathological aspect of spontaneous and two induced Mongolian gerbils' models of cholesteatoma: External Auditory Canal (EAC) obliteration model and the Auditory Tube (AT) cauterization model. METHODS: Fifty-four ears of 27 animals were divided into EAC obliteration, AT cauterization, and control groups and histologically assessed for cholesteatoma incidence and classification at intervals of 2, 4, 8, and 16 weeks. RESULTS: Cholesteatoma was diagnosed in 30 of the 53 ears evaluated with a significantly higher incidence in groups that received some type of intervention (p<0.0001). It was not possible to histologically distinguish cholesteatomas of the same stage between the study groups. CONCLUSION: Although we observed a significant increase in cholesteatoma incidence with the two methods used when compared to the control group, all developed cholesteatomas were apparently identical from a histological point of view.

Clinical Analysis of 85 Cases of External Auditory Canal Cholesteatoma Surgery under Specialized Endoscopy.

Objective: To investigate the clinical characteristics, surgical experience, and surgical outcomes of external auditory canal cholesteatoma (EACC) surgery under endoscopic otolaryngoscopy. Methods: A retrospective analysis of 85 EACC cases admitted to the Department of Otolaryngology, Renji Hospital, Shanghai Jiaotong University School of Medicine, from January 2016 to February 2021 was performed, followed by retrospective analysis of clinical data to explore the feasibility and clinical characteristics of all-oral endoscopic EACC surgery. A total of 85 EACC patients (90 ears) with a mean age of 49.93 ± 14.87 years were included in the study. According to Udayabhanu staging, 43 ears (47.78%) were stage I, 40 ears (44.44%) were stage II, and 7 ears (7.78%) were stage III. All patients underwent transendoscopic surgery. Results: 79 ears (87.78%) underwent endoscopic EACC resection alone (+external auditory canal tumor resection/tympanostomy tube insertion), 9 ears (10%) underwent endoscopic EACC resection+tympanostomy+tympanoplasty, 1 ear (1.11%) underwent endoscopic EACC resection+tympanoplasty, and 2 ears (2.22%) underwent EACC resection+otolaryngotomy+tympanoplasty+auditory chain reconstruction endoscopically. Of these, 7 ears (7.78%) underwent auricular cartilage-chondroplasty and 2 ears (2.22%) underwent auricular cartilage membrane repair. All patients were reviewed at 1 week, 2 weeks, 1 month, 3 months, 6 months, and 1 year postoperatively. One patient with stage II external auditory atresia had a recurrence after 6 months and underwent endoscopic ear surgery (ESS) again. One patient with stage 2 atresia recurred after 1 year and again underwent endoscopic ear surgery. The rest of the patients recovered well after the surgery, and the grafts healed well. Conclusion: EACC surgery through the external ear canal under a dedicated endoscope is a safe, reliable, and effective method. Patients with stage I and II external auditory canal cholesteatoma surgery under endoscopy have a rapid postoperative recovery with significant hearing improvement, and stage IIIA patients can also achieve good results under strict evaluation of indications.

Review of potential medical treatments for middle ear cholesteatoma.

Middle ear cholesteatoma (MEC), is a destructive, and locally invasive lesion in the middle ear driven by inflammation with an annual incidence of 10 per 100,000. Surgical extraction/excision remains the only treatment strategy available and recurrence is high (up to 40%), therefore developing the first pharmaceutical treatments for MEC is desperately required. This review was targeted at connecting the dysregulated inflammatory network of MEC to pathogenesis and identification of pharmaceutical targets. We summarized the numerous basic research endeavors undertaken over the last 30+ years to identify the key targets in the dysregulated inflammatory pathways and judged the level of evidence for a given target if it was generated by in vitro, in vivo or clinical experiments. MEC pathogenesis was found to be connected to cytokines characteristic for Th1, Th17 and M1 cells. In addition, we found that the inflammation created damage associated molecular patterns (DAMPs), which further promoted inflammation. Similar positive feedback loops have already been described for other Th1/Th17 driven inflammatory diseases (arthritis, Crohn's disease or multiple sclerosis). A wide-ranging search for molecular targeted therapies (MTT) led to the discovery of over a hundred clinically approved drugs already applied in precision medicine. Based on exclusion criteria designed to enable fast translation as well as efficacy, we condensed the numerous MTTs down to 13 top drugs. The review should serve as groundwork for the primary goal, which is to provide potential pharmaceutical therapies to MEC patients for the first time in history. Video Abstract.

Middle ear cholesteatoma (MEC) is a destructive and locally invasive ulcerated lesion in the middle ear driven by inflammation which occurs in 10 out of 100,000 people annually. Surgical extraction/excision is the only treatment strategy available and recurrence is high (up to 40% after ten years), therefore developing the first pharmaceutical treatments for MEC is desperately required. This review is focused on the connections between inflammation and MEC pathogenesis. These connections can be used as attack points for pharmaceuticals. For this we summarized the results of research undertaken over the last 30 + years. MEC pathogenesis can be described by specific inflammatory dysregulation already known from arthritis, Crohn's disease or multiple sclerosis. A hallmark of this dysregulation are positive feedback loops of the inflammation further amplifying itself in a vicious circle-like manner. We have identified over one hundred drugs which are already used in clinic to treat other inflammatory diseases, and could potentially be repurposed to treat MEC. To improve and expedite clinical success rates, we applied certain criteria based on our literature searches and condensed these drugs down to the 13 top drugs. We hope the review will serve as groundwork for the primary goal, which is to provide potential pharmaceutical therapies to MEC patients for the first time in history.

Residual Cholesteatoma After Endoscopic-Assisted Canal Wall-Up Tympanomastoidectomy: A Randomized Controlled Trial.

OBJECTIVE: This study aimed to determine the effectiveness of using endoscopes in reducing recidivism secondary to residual cholesteatoma after canal wall-up tympanomastoidectomy. STUDY DESIGN: Randomized clinical trial. SETTING: Tertiary referral center. PATIENTS: Patients with cholesteatoma, aged 7 to 70 years. INTERVENTIONS: Subjects were randomly allocated into two groups: endoscopic-assisted canal wall-up (EACWU; group 1) and conventional canal wall-up (CWU; group 2) techniques. Pars flaccida and pars tensa subgroups were analyzed according to the anatomic location of cholesteatoma origin. MAIN OUTCOME MEASURES: Presence or absence of residual cholesteatoma, based on second look surgery, diffusion-weighted magnetic resonance imaging, or video-otoscopy at 12 and 18 months after surgery. RESULTS: In total, 57 ears were analyzed: 29 in group 1 and 28 in group 2. Group 1 revealed residual disease in 17.2% of ears, whereas group 2 had residual disease in 35.7% (p > 0.05) of the ears. In the pars tensa cholesteatoma subgroup, the incidence of residual disease was 13.3% for EACWU and 47.1% for the CWU technique (p < 0.05). A tendency of reduced incidence was observed for cholesteatoma due to residual disease using EACWU. In addition, a statistically significant reduction in the residual disease was observed in the subgroup of pars tensa cholesteatomas. In this subgroup, the relative risk was 0.28, and the number needed to treat was 4.6. CONCLUSION: The use of the endoscope reduces the incidence of recidivism secondary to residual disease in pars tensa cholesteatomas. Endoscopic-assisted surgery may be useful in cases with an indication for canal wall-up tympanomastoidectomy. LEVEL OF EVIDENCE: 1b.