Review of potential medical treatments for middle ear cholesteatoma

Abstract

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.

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

“…1 F ). To the best of our knowledge, inflammation is an important stimulating factor for the proliferation of cholesteatoma epithelial cells ( 6 , 26 ). Furthermore, our results and recent reports have demonstrated the involvement of autophagy in the pathogenesis and progression of cholesteatoma ( 14 ).…”

Comparison of Tissue Factors in the Ontogenetic Aspects of Human Cholesteatoma

“…NF-κβ is present in almost every activity in human organisms [ 26 ]. It mainly regulates inflammatory processes, cell proliferation, and apoptosis [ 14 , 27 ]. Our data do not show statistically discernible differences between the adult and children groups.…”

“…Cholesteatoma presents with chronic inflammation and often episodes of exacerbation [ 14 ]. The potent pro-inflammatory cytokine is interleukin 1 alfa (IL-1α); this is expressed in various types of cells—macrophages, lymphocytes, neutrophils, fibroblasts, epithelial and endothelial cells, keratinocytes, and other cell types [ 15 ].…”

“…In addition to this, NF-κβ regulates the gene responsible for cell proliferation and apoptosis [ 27 ]. In human cholesteatoma, NF-κβ is associated with cell proliferation and inflammatory processes [ 14 , 28 ].…”

Dynamic Microscopic Optical Coherence Tomography as a New Diagnostic Tool for Otitis Media

“…We underline this theory since we discovered a live cell movement in the peri-matrix, Furthermore, this was assessed by the clinical histopathological evaluation, revealing stacks of keratin and epithelial cells decomposed with immune and inflammatory cells corresponding to the picture of a medium to highgrade inflammatory cholesteatoma. Several studies associate the interaction of the immune system with the cholesteatoma [6,[25][26][27][28][29]36] and even specifically target innate immunoregulatory events [37]. Unfortunately, to date, there are no markers for OCT, which are able to label specific immune cells.…”