Jörg Ebmeyer

HPV & head and neck cancer: a descriptive update

The incidence of head and neck squamous cell carcinoma (HNSCC) has been gradually increasing over the last three decades. Recent data have now attributed a viral aetiology to a subset of head and neck cancers. Several studies indicate that oral human papillomavirus (HPV) infection is likely to be sexually acquired. The dominance of HPV 16 in HPV+ HNSCC is even greater than that seen in cervical carcinoma of total worldwide cases. Strong evidence suggests that HPV+ status is an important prognostic factor associated with a favourable outcome in head and neck cancers.Approximately 30 to 40% of HNSCC patients with present with early stage I/II disease. These patients are treated with curative intent using single modality treatments either radiation or surgery alone. A non-operative approach is favored for patients in which surgery followed by either radiation alone or radiochemotherapy may lead to severe functional impairment. Cetuximab, a humanized mouse anti-EGFR IgG1 monoclonal antibody, improved locoregional control and overall survival in combination with radiotherapy in locally advanced tumours but at the cost of some increased cardiac morbidity and mortality.Finally, the improved prognosis and treatment responses to chemotherapy and radiotherapy by HPV+ tumours may suggest that HPV status detection is required to better plan and individualize patient treatment regimes.

Balloon dilatation eustachian tuboplasty: A clinical study†

To assess the feasibility of balloon dilatation eustachian tuboplasty (BET) as an option for treatment of patients with eustachian tube (ET) dysfunction.

Isolation of Novel Multipotent Neural Crest-Derived Stem Cells from Adult Human Inferior Turbinate

Adult human neural crest-derived stem cells (NCSCs) are of extraordinary high plasticity and promising candidates for the use in regenerative medicine. Here we describe for the first time a novel neural crest-derived stem cell population within the respiratory epithelium of human adult inferior turbinate. In contrast to superior and middle turbinates, high amounts of source material could be isolated from human inferior turbinates. Using minimally-invasive surgery methods isolation is efficient even in older patients. Within their endogenous niche, inferior turbinate stem cells (ITSCs) expressed high levels of nestin, p75(NTR), and S100. Immunoelectron microscopy using anti-p75 antibodies displayed that ITSCs are of glial origin and closely related to nonmyelinating Schwann cells. Cultivated ITSCs were positive for nestin and S100 and the neural crest markers Slug and SOX10. Whole genome microarray analysis showed pronounced differences to human ES cells in respect to pluripotency markers OCT4, SOX2, LIN28, and NANOG, whereas expression of WDR5, KLF4, and c-MYC was nearly similar. ITSCs were able to differentiate into cells with neuro-ectodermal and mesodermal phenotype. Additionally ITSCs are able to survive and perform neural crest typical chain migration in vivo when transplanted into chicken embryos. However ITSCs do not form teratomas in severe combined immunodeficient mice. Finally, we developed a separation strategy based on magnetic cell sorting of p75(NTR) positive ITSCs that formed larger neurospheres and proliferated faster than p75(NTR) negative ITSCs. Taken together our study describes a novel, readily accessible source of multipotent human NCSCs for potential cell-replacement therapy.

Balloon dilation eustachian tuboplasty: a feasibility study.

Objective: To assess the feasibility and safety of balloon dilation Eustachian tuboplasty (BET) as an option for treatment of patients with Eustachian tube dysfunction. Patients and Interventions: A cadaveric study of 5 temporal human bones was performed. Each bone underwent transnasal balloon dilation Eustachian tuboplasty (BET) with computed tomography and post-dilation histology. The procedure involved the dilation of the cartilaginous and bony portion of the Eustachian tube with a balloon catheter. Results: BET is technically easy to perform. No damage to essential structures, particularly the carotid canal, was found. Conclusion: This newly introduced method seems to be a feasible and safe procedure to dilate the Eustachian tube.

Zoledronic acid inhibits osteoclastogenesis in vitro and in a mouse model of inflammatory osteolysis

This study assessed effects of the bisphosphonate zoledronic acid (ZLNA) on osteoclastogenesis. To assess the effect of ZLNA on osteoclast formation in vitro, we cultured mouse bone marrow cells under conditions that promote osteoclastogenesis. Administered at concentrations from 10−6 to 10−9 mol/L, ZLNA led to a dose-dependent inhibition of osteoclastogenesis. Combined TUNEL staining and histochemical staining for tartrate-resistant acid phosphatase showed that ZLNA induced apoptosis in osteoclasts and monocytic precursor cells. To study the effects of ZLNA in vivo, we placed keratin particles onto the surface of the parietal bone of mice to induce localized inflammatory bone resorption. Three experimental groups received daily subcutaneous injections of ZLNA (1, 3, or 10 μg/kg body weight) from 4 days before surgery until 5 days after keratin implantation. The ZLNA significantly reduced osteoclast recruitment in a dose-dependent manner, but did not affect the degree of inflammation or the mineral apposition rate.

Computed tomography before balloon Eustachian tuboplasty--a true necessity?

Objective Since the introduction of balloon Eustachian tuboplasty the necessity of preoperative high-resolution CT scans of the temporal bone has been a topic of debate. This study investigated the informative value of preoperative CT scanning in predicting intraoperative or postoperative difficulties and complications. Special focus was laid on the existence of carotid canal dehiscences for fear of intraprocedural injury. Study Design Retrospective. Setting Tertiary referral center. Patients and Interventions Approximately 284 patients (510 Eustachian tubes) with intractable Eustachian tube dysfunction undergoing unilateral or bilateral balloon Eustachian tuboplasty with preoperative high-resolution CT scans of the temporal bone from January 1, 2009, to December 31, 2012. Results Carotid canal dehiscences were found in 18 patients (6.3%). In 3 patients (4 Eustachian tubes, 1.1% of patients) balloon dilatation could not be performed because of difficulties advancing the balloon catheter. Of these 3 patients, one had bilateral carotid canal dehiscences, whereas the other two had unremarkable CT scans. Postoperative complications occurred in 3 patients (1.1%): 2 soft tissue emphysemas and 1 unilateral hypoglossal paresis. All 3 patients had unremarkable CT scans, and all complications resolved completely without further sequelae. Conclusion Preoperative high-resolution CT scan of the temporal bone does not seem to be suitable to predict intraoperative or postoperative difficulties of balloon Eustachian tuboplasty. Being extremely cautious during balloon catheter insertion into the Eustachian tube and using a device that is designed with a built-in stop mechanism preventing too deep insertion, the data presented suggest that fear of injury to the internal carotid artery during balloon dilatation might be disproportionate. Nevertheless, for inexperienced surgeons, HR-CT scans of the temporal bone may help to understand the relation between internal carotid artery and the Eustachian tube.

Identification of Novel Cholesteatoma-Related Gene Expression Signatures Using Full-Genome Microarrays

Background Cholesteatoma is a gradually expanding destructive epithelial lesion within the middle ear. It can cause extensive local tissue destruction in the temporal bone and can initially lead to the development of conductive hearing loss via ossicular erosion. As the disease progresses, sensorineural hearing loss, vertigo or facial palsy may occur. Cholesteatoma may promote the spread of infection through the tegmen of the middle ear and cause meningitis or intracranial infections with abscess formation. It must, therefore, be considered as a potentially life-threatening middle ear disease. Methods and Findings In this study, we investigated differentially expressed genes in human cholesteatomas in comparison to regular auditory canal skin using Whole Human Genome Microarrays containing 19,596 human genes. In addition to already described up-regulated mRNAs in cholesteatoma, such as MMP9, DEFB2 and KRT19, we identified 3558 new cholesteatoma-related transcripts. 811 genes appear to be significantly differentially up-regulated in cholesteatoma. 334 genes were down-regulated more than 2-fold. Significantly regulated genes with protein metabolism activity include matrix metalloproteinases as well as PI3, SERPINB3 and SERPINB4. Genes like SPP1, KRT6B, PRPH, SPRR1B and LAMC2 are known as genes with cell growth and/or maintenance activity. Transport activity genes and signal transduction genes are LCN2, GJB2 and CEACAM6. Three cell communication genes were identified; one CDH19 and two from the S100 family. Conclusions This study demonstrates that the expression profile of cholesteatoma is similar to a metastatic tumour and chronically inflamed tissue. Based on the investigated profiles we present novel protein-protein interaction and signal transduction networks, which include cholesteatoma-regulated transcripts and may be of great value for drug targeting and therapy development.

Treatment of the patulous Eustachian tube with soft-tissue bulking agent injections.

Objective A patulous Eustachian tube ([ET] tuba aperta) may cause symptoms as autophony, breath synchronous tinnitus, pressure sensation, and conductive hearing loss and thus lead to an enormous cutback in quality of life. In combination with “sniffing,” it can trigger the development of cholesteatoma. Because of the ambiguous symptoms, the diagnosis can be challenging. A patulous ET can only be diagnosed through a well-structured examination, including patient history, physical examination with thorough observation of the movements of the tympanic membrane, and tympanometry with reflex-decay. Study Design and Methods Transnasal endoscopic injection of injectable soft-tissue bulking agent into the torus tubarius was performed in 20 patients as a new treatment option for patulous ET. All patients were followed up 6 weeks and 6 and 12 months after treatment. For each intervention, 0.8 to 2 mL of injectable soft-tissue bulking agent was used. Results In nine patients, more than one procedure was necessary. On follow-up, 10 out of 15 patients were satisfied with the result. Only three out of 15 patients reported no improvement of their symptoms. The procedure was minimally invasive, fast, and easy to perform. Conclusion There is no gold standard for the therapy of patulous ET. The injection of soft-tissue bulking agent in the torus tubarius is a new minimally invasive therapeutic approach, but much more clinical experience is needed. Level of Evidence IV.

1,8-Cineol Reduces Mucus-Production in a Novel Human Ex Vivo Model of Late Rhinosinusitis

Inflammatory diseases of the respiratory system such as rhinosinusitis, chronic obstructive pulmonary disease, or bronchial asthma are strongly associated with overproduction and hypersecretion of mucus lining the epithelial airway surface. 1,8-cineol, the active ingredient of the pharmaceutical drug Soledum, is commonly applied for treating such inflammatory airway diseases. However, its potential effects on mucus overproduction still remain unclear.In the present study, we successfully established ex vivo cultures of human nasal turbinate slices to investigate the effects of 1,8-cineol on mucus hypersecretion in experimentally induced rhinosinusitis. The presence of acetyl-α-tubulin-positive cilia confirmed the integrity of the ex vivo cultured epithelium. Mucin-filled goblet cells were also detectable in nasal slice cultures, as revealed by Alcian Blue and Periodic acid-Schiff stainings. Treatment of nasal slice cultures with lipopolysaccharides mimicking bacterial infection as observed during late rhinosinusitis led to a significantly increased number of mucin-filled goblet cells. Notably, the number of mucin-filled goblet cells was found to be significantly decreased after co-treatment with 1,8-cineol. On a molecular level, real time PCR-analysis further showed 1,8-cineol to significantly reduce the expression levels of the mucin genes MUC2 and MUC19 in close association with significantly attenuated NF-κB-activity. In conclusion, we demonstrate for the first time a 1,8-cineol-dependent reduction of mucin-filled goblet cells and MUC2-gene expression associated with an attenuated NF-κB-activity in human nasal slice cultures. Our findings suggest that these effects partially account for the clinical benefits of 1,8-cineol-based therapy during rhinosinusitis. Therefore, topical application of 1,8-cineol may offer a novel therapeutic approach to reduce bacteria-induced mucus hypersecretion.

Reconstitution of the mast cell population in W/Wv mice.

Hypothesis: Intravenous injection of cultured mast cells (MCs) can reconstitute the MC population in MC-deficient mice. We hypothesize that injected culture-derived MCs do not repopulate all tissues equally. Background: Mast cells are central elements not only in anaphylaxis and allergy but also in immune reactions to bacteria and other pathogens. Their broad involvement in innate immunity requires extensive research in the future. Studies of MC function often use MC-deficient mice to compare with wild-type animals. A very elegant method to prove that the observed changes are due to the lack of MCs is to compare results in wild-type mice, MC-deficient mice, and MC-deficient mice that have been reconstituted with cultured MCs. Reconstitution of the MC population can be achieved by intravenous injection of MCs into MC-deficient mice. Whether the injected MCs repopulate the desired tissues has to be proven before this model is used. Also, the time frame of the reconstitution has to be demonstrated. Methods: Mast cell-deficient mice were injected with bone marrow-derived cultured MCs, and the mucosa of middle ear (MEs), nose, and tracheobronchial system was analyzed for MCs 4, 6, 8, 10, and 20 weeks after injection. Results: Reconstitution of the ME mucosa was complete and persistent for more than 20 weeks. Reconstitution failed in nasal mucosa. In bronchial mucosa, reconstitution was incomplete and transient. Conclusion: This model can be used to investigate effects of MCs in various immune reactions in the ME. Studies should use the time frame 6 to 8 weeks after reconstitution of the MC population. However, the model has limitations for investigations in the respiratory tract.