{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:46:04Z","timestamp":1787748364711,"version":"build-2784847793"},"reference-count":27,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T00:00:00Z","timestamp":1690329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Objectives. Despite recent advances in biomolecular research that have improved our knowledge of cholesteatoma pathogenesis, the reasons behind its highly variable clinical course are still not clarified. It has been proposed that biological signaling between peri-matrix and matrix cells could play a critical role in disease homeostasis. The aim of our study was to analyze the expression of inflammatory (IL-1\u03b2), hyper-proliferative (STAT-3, TGF-\u03b2), and angiogenic (VEGF-C, PDGFr) factors in congenital and acquired cholesteatomas (both in adults and children), which might correlate with the clinical features observed. We performed an experimental study on 37 patients (29 males and 8 females, ranging from 4 to 66 years of age) who were diagnosed with cholesteatoma between 2020 and 2021 in our institution. All patients underwent clinical, audiologic, and radiologic assessments. Bone erosion grading and staging of cholesteatoma growth were assessed through preoperative evaluation and intraoperative middle ear findings, according to the PTAM System proposed by the Japan Otological Society (2016). Retro-auricular skin specimens were intraoperatively collected in all patients. Skin and cholesteatoma samples were analyzed through histopathological, western blot, and immunohistochemical evaluations. The expression rate was measured to find out the differences between congenital and acquired cholesteatomas as well as between the adult and pediatric populations. Expression of angiogenic, inflammatory, and proliferative biomarkers is significantly increased in acquired cholesteatomas in children as compared to congenital and acquired forms in adults, in accordance with the higher stage of disease shown by imaging, surgical, and histological features. Our data suggest that pathways already supposed to be involved in the pathogenesis of cholesteatomas could be differently activated in more destructive forms, typically found in children. The identification of potential biomarkers of cholesteatoma aggressiveness could lead to more personalized management (timing of intervention, recurrence prevention) and the future identification of anti-growth\/anti-proliferative agents as non-surgery therapeutic options.<\/jats:p>","DOI":"10.3390\/jpm13081189","type":"journal-article","created":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T01:27:46Z","timestamp":1690421266000},"page":"1189","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Study of Angiogenic, Pro-Apoptotic, and Pro-Inflammatory Factors in Congenital and Acquired Cholesteatomas"],"prefix":"10.3390","volume":"13","author":[{"given":"Rolando","family":"Rolesi","sequence":"first","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8473-8074","authenticated-orcid":false,"given":"Fabiola","family":"Paciello","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Paludetti","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"De Corso","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Sergi","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Fetoni","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Reproductive Sciences and Dentistry-Audiology Section, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"854024","DOI":"10.1155\/2015\/854024","article-title":"Updates and Knowledge Gaps in Cholesteatoma Research","volume":"2015","author":"Kuo","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s00405-013-2852-y","article-title":"Extensive intratemporal cholesteatomas: Presentation, complications and surgical outcomes","volume":"272","author":"Vashishth","year":"2013","journal-title":"Eur. Arch. Oto-Rhino-Laryngol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"168","DOI":"10.7874\/jao.2016.20.3.168","article-title":"Clinical Aspects and Surgical Outcomes of Congenital Cholesteatoma in 93 Children: Increasing Trends of Congenital Cholesteatoma from 1997 through 2012","volume":"20","author":"Cho","year":"2016","journal-title":"J. Audiol. Otol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1097\/00005537-200011000-00023","article-title":"A New Pathogenesis of Mesotympanic (Congenital) Cholesteatoma","volume":"110","author":"Tos","year":"2000","journal-title":"Laryngoscope"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"408","DOI":"10.3109\/00016487809107520","article-title":"Tubal closing failure in retraction type cholesteatoma and adhesive middle ear lesions","volume":"86","author":"Magnuson","year":"1978","journal-title":"Acta Otolaryngol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1177\/019459988409200313","article-title":"Evacuation of the Middle Ear by Sniffing: A Cause of High Negative Pressure and Development of Middle Ear Disease","volume":"92","author":"Falk","year":"1984","journal-title":"Otolaryngol. Neck Surg."},{"key":"ref_7","first-page":"5","article-title":"Mastoid volume and eustachian tube function in ears with cholesteatoma","volume":"8","author":"Lindeman","year":"1987","journal-title":"Am. J. Otol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1177\/000348947108000312","article-title":"Cellular Differentiation of the Middle Ear Lining","volume":"80","year":"1971","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_9","first-page":"786","article-title":"Pathogenesis of attic cholesteatoma: Clinical and immunohistochemical support for combination of retraction theory and proliferation theory","volume":"21","author":"Sudhoff","year":"2000","journal-title":"Am. J. Otol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1002\/lary.24890","article-title":"Etiopathogenesis of Acquired Cholesteatoma: Prominent Theoriesand Recent Advances in Biomolecular Research","volume":"125","author":"Kuo","year":"2015","journal-title":"Laryngoscope"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1007\/s00405-015-3679-5","article-title":"Pediatric middle ear cholesteatoma: The comparative study of congenital cholesteatoma and acquired cholesteatoma","volume":"273","author":"Morita","year":"2015","journal-title":"Eur. Arch. Oto-Rhino-Laryngol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1017\/S002221511100315X","article-title":"Evaluation of epithelial proliferation in paediatric and adult cholesteatomas using the Ki-67 proliferation marker","volume":"126","author":"Sikka","year":"2011","journal-title":"J. Laryngol. Otol."},{"key":"ref_13","first-page":"987","article-title":"Expression of epidermal growth factor receptor Ki67 and p16 in human middle ear cholesteatoma","volume":"22","author":"Li","year":"2008","journal-title":"Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi"},{"key":"ref_14","first-page":"7","article-title":"Molecular biology of cholesteatoma","volume":"55","author":"Maniu","year":"2014","journal-title":"Rom. J. Morphol. Embryol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1097\/00005537-200303000-00009","article-title":"Osteoclast Stimulating and Differentiating Factors in Human Cholesteatoma","volume":"113","author":"Hamzei","year":"2003","journal-title":"Laryngoscope"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1017\/S0022215113000601","article-title":"Acquired cholesteatoma: Summary of the cascade of molecular events","volume":"127","author":"Louw","year":"2013","journal-title":"J. Laryngol. Otol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1055\/s-0030-1268464","article-title":"Current concepts of the pathogenesis of acquired middle ear cholesteatoma","volume":"90","author":"Welkoborsky","year":"2011","journal-title":"Laryngorhinootologie"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1177\/000348949710600810","article-title":"Localization of transforming growth factor-beta-expressing cells and comparison with major extracellular components in aural cholesteatoma","volume":"106","author":"Lang","year":"1997","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"298","DOI":"10.21053\/ceo.2015.01662","article-title":"Pathogenesis and Bone Resorption in Acquired Cholesteatoma: Current Knowledge and Future Prospectives","volume":"9","author":"Hamed","year":"2016","journal-title":"Clin. Exp. Otorhinolaryngol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1097\/MOO.0b013e32836464bd","article-title":"Management of acquired cholesteatoma in the pediatric population","volume":"21","author":"Dornhoffer","year":"2013","journal-title":"Curr. Opin. Otolaryngol. Head Neck Surg."},{"key":"ref_21","first-page":"7","article-title":"Cholesteatoma: A molecular and cellular puzzle","volume":"19","author":"Albino","year":"1998","journal-title":"Am. J. Otol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/0196-0709(93)90044-8","article-title":"Possible autocrine growth stimulation of cholesteatoma epithelium by transforming growth factor alpha","volume":"14","author":"Schulz","year":"1993","journal-title":"Am. J. Otolaryngol."},{"key":"ref_23","first-page":"793","article-title":"Angiogenesis and angiogenic growth factors in middle ear cholesteatoma","volume":"21","author":"Sudhoff","year":"2000","journal-title":"Am. J. Otol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1177\/019459989010300403","article-title":"Interleukin 1 causing bone destruction in middle ear cholesteatoma","volume":"103","author":"Ahn","year":"1990","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1159\/000319897","article-title":"Expression of IL-17 and Its Role in Bone Destruction in Human Middle Ear Cholesteatoma","volume":"72","author":"Haruyama","year":"2010","journal-title":"ORL J. Otorhinolaryngol. Relat. Spec."},{"key":"ref_26","first-page":"709","article-title":"Activation of the IL-6\/JAK\/STAT3 signaling pathway in human middle ear cholesteatoma epithelium","volume":"7","author":"Liu","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1097\/MLG.0b013e31814faafa","article-title":"Transforming growth factor beta and wound healing in human cholesteatoma","volume":"118","author":"Huisman","year":"2008","journal-title":"Laryngoscope"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/13\/8\/1189\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:19:17Z","timestamp":1760127557000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/13\/8\/1189"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,26]]},"references-count":27,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["jpm13081189"],"URL":"https:\/\/doi.org\/10.3390\/jpm13081189","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,26]]}}}