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Infected tracheostomas are frequently associated with high morbidity and mortality rates-especially in patients after neck-oncological surgery with subsequent radiochemotherapy. A 59-year-old male patient with a history of hypopharynx carcinoma, successive laryngectomy and adjuvant radiochemotherapy developed an oesophagotracheal fistula with massive inflammation and periodical bleedings, uncontrollable by regular stent alternations. In a multidisciplinary setting, the decision was made to treat the patient with an anterior mediastinal tracheostomy. Extending usual anterior mediastinal tracheostomy indications, we present an ultimate treatment option for infected tracheostomas and highly advocate this interdisciplinary venture, as it significantly improves quality of life., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Radioresistance is a common feature of head and neck squamous cell carcinoma (HNSCC). We previously showed that the irradiation- activated vascular endothelial growth factor (VEGF)-extracellular signal-regulated kinase (ERK)-axis is fundamental for the survival of resistant tumors. In this study, we examined if treatment with potent multikinase (MK) inhibitors, sorafenib and sunitinib, could radiosensitize tumor cells., Methods: Cultured HNSCC cell lines were treated with inhibitors and subsequently irradiated. Radiosensitizing effects were functionally assessed by annexin-V apoptosis and clonogenic assays and confirmed by Western blot. Additionally, we surveyed human HNSCC tissue microarrays (TMAs) for activated ERK expression., Results: Based on combination indexes, we found that combining irradiation with both inhibitors exerted strong and supra-additive antitumor effects on clonogenic survival. Kinase inhibition enhanced irradiation-induced apoptotic rates and inhibited postradiogenic phospho-ERK-expression. Patients with recurrent HNSCC displayed significantly lower extracellular signal-regulated kinase phosphorylation (pERK) levels than relapse-free patients., Conclusion: We propose further evaluation of sorafenib and sunitinib as potential radiosensitizing agents in HNSCC treatment. © 2017 Wiley Periodicals, Inc. Head Neck 39: 623-632, 2017., (© 2017 Wiley Periodicals, Inc.)

Objective: Systemic chemotherapy for different malignancies occurs alongside various side effects, including reduced sensory function. To date, little is known about the effect of chemotherapeutic agents on olfaction. The aim of this study was to provide new data about changes in sense of smell during chemotherapy among patients with advanced squamous cell carcinomas of the head and neck region., Methods: In a prospective, controlled cohort study of patients undergoing up to three courses of chemotherapy (cis- or carboplatin, 5-fluorouracil and docetaxel), olfaction was evaluated prior to and directly following completing a cycle, as well as 3 weeks later with the beginning of the next cycle. For evaluation of sense of smell, the established Sniffin' Sticks test with a determination of threshold, discrimination and identification (TDI) was used. Thirty-three patients (44-85 years old, 25 men and 8 women) were included in the study. Most malignancies were located in the oropharynx., Results: Among the 28 patients who scored normosmic or hyposmic at the beginning of the study, the mean decrease in TDI-score was 0.72 points (24.0-23.2) in the first cycle, 2.1 points (24.5-22.4) in the second cycle and 0.77 points (24.2-23.4) in the third cycle. The decrease during the second cycle was significant. Age (>55 years) had a significant (negative) influence in the first and the second cycles. Smoking only showed a tendency to decreased TDI-scores in chemotherapy. In-between consecutive cycles an increase in TDI-score was obvious (+1.0 points after the first and +1.5 points after the second cycle)., Conclusion: Chemotherapy with cisplatin, 5-fluorouracil and docetaxel significantly affected sense of smell to a small extent. This effect was more pronounced in elderly patients and smokers. This fact must be taken into account as a possible additional negative effect in usually prevailing malnutrition in these patients. Furthermore, no cumulative effect of the administered therapeutic agents on olfaction could be proven during this study and recovery occurred within a 3-week period., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: The body of knowledge regarding rhinosinusitis(RS) continues to expand, with rapid growth in number of publications, yet substantial variability in the quality of those presentations. In an effort to both consolidate and critically appraise this information, rhinologic experts from around the world have produced the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS)., Methods: Evidence-based reviews with recommendations(EBRRs) were developed for scores of topics, using previously reported methodology. Where existing evidence was insufficient for an EBRR, an evidence-based review (EBR)was produced. The sections were then synthesized and the entire manuscript was then reviewed by all authors for consensus., Results: The resulting ICAR:RS document addresses multiple topics in RS, including acute RS (ARS), chronic RS (CRS)with and without nasal polyps (CRSwNP and CRSsNP), recurrent acute RS (RARS), acute exacerbation of CRS (AECRS), and pediatric RS., Conclusion: As a critical review of the RS literature, ICAR:RS provides a thorough review of pathophysiology and evidence-based recommendations for medical and surgical treatment. It also demonstrates the significant gaps in our understanding of the pathophysiology and optimal management of RS. Too often the foundation upon which these recommendations are based is comprised of lower level evidence. It is our hope that this summary of the evidence in RS will point out where additional research efforts may be directed., (© 2016 ARS-AAOA, LLC.)

Objectives/hypothesis: The efficacy of macrolides in chronic rhinosinusitis (CRS) is still under controversy. To date, only two double-blind, placebo-controlled studies have been published with differing results. None of these studies investigated the possible benefit of macrolides in the postoperative period. We conducted an investigator-initiated clinical trial using 250-mg erythromycin once a day over a period of 3 months, beginning the administration of either erythromycin or placebo 2 weeks after a surgical intervention for CRS., Study Design: Randomized double-blind, placebo-controlled trial., Methods: The concentrations of eosinophilic cationic protein (ECP) and myeloperoxidase in nasal secretion were chosen as primary outcome measures. Additionally, as a secondary outcome measure, changes in the Sino-Nasal Outcome Test-20 score, olfaction, saccharin transit time, nasal endoscopy score, and self-rating of nasal health using a visual analogue scale were evaluated., Results: Sixty-seven patients after surgery for CRS with or without nasal polyps were screened, and 58 patients were randomized to the study groups. For the primary outcomes, the concentrations of ECP changed from 176.4 µl/l ± 79.0 to 226.1 µl/l ± 200.6 in the erythromycin group and from 186.9 µl/l ± 36.0 to 192.9 µl/l ± 189.2 in the placebo group; no statistical differences were found. Of the secondary outcomes, only the nasal endoscopy score showed a statistically significant improvement in the erythromycin group (from 2.6 ± 1.4 to 1.9 ± 1.5 points) compared to the placebo group (from 2.5 ± 1.3 to 2.6 ± 1.5 points). The subgroup of patients without nasal polyps in the erythromycin group showed a tendency to improvement in some secondary outcome criteria., Conclusions: A general recommendation for long-term, low-dose erythromycin treatment after surgery for CRS cannot be given. In patients with CRS without nasal polyps, a tendency to improved parameters was detected., Level of Evidence: Ib., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Tonsillar hypertrophy caused by the progressive accumulation of partially degraded glycosaminoglycans (GAGs) within the cells is a typical symptom in patients with mucopolysaccharidoses (MPS). We studied the tissue of adenoids and tonsils of patients suffering from MPS with special regard to characteristic morphological features serving as possible markers for diagnosis., Methods: Adenoids of 87 patients and tonsils of 4 patients with MPS (2 patients with MPS I, 7 MPS II, 5 MPS IV and 10 MPS VI and 63 controls) and controls were examined. Examinations were repeated in a blinded manner by two pathologists., Results: The key feature observed was a subepithelial "clearing" on scanning magnification, induced by perivascular accumulation of histiocytoid cell forms. Similar agglomerates could sometimes be found at the base of lymphoid follicles. In the blinded assessment a specificity of 92% (100% for adenoids) and a sensitivity of 100% were achieved. The inter-observer-consistency was 92% (100% for adenoids). In tonsillectomy specimens marked subepithelilal fibrosis can lead to a false-negative evaluation., Conclusions: Qualified histological examination could be an option for early diagnosis of MPS., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Fascin is an actin-bundling protein that is associated with cellular motility and cancer-cell invasion. The present study aimed to examine the expression of fascin in head and neck squamous cell carcinoma (HNSCC) and its potential use as a biomarker. In a prospective study with a median follow-up time of 48.8 months, tumor tissues, adjacent healthy tissues and cervical lymph node metastases were collected from 25 patients and analyzed by immunohistochemistry. The specimens were scored according to the intensity of fascin staining and the percentage of tumor cells stained using a semi-quantitative scoring approach; the data were analyzed and correlated with clinical follow-up observations. All of the investigators were blinded to the origin of the specimens. The expression levels of fascin were significantly increased in the tumor tissues (P=0.03) and lymph node metastases (P=0.03) compared with that of the normal tissues. The high expression level of fascin in the tumor tissues was correlated with the N-status, however, not with overall survival. Therefore, fascin may be a suitable marker for the prediction of regional lymphatic metastasis in HNSCC.

Context: Mutations in the four subunits of succinate dehydrogenase (SDH) are the cause for the hereditary paraganglioma (PGL) syndrome types 1-4 and are associated with multiple and recurrent pheochromocytomas and PGLs. SDHC mutations most frequently result in benign, nonfunctional head-and neck PGLs (HNPGLs). The malignant potential of SDHC mutations remains unclear to date., Objectives: We report a patient with malignant PGL carrying a SDHC mutation and compare her case with two others of the same genotype but presenting with classic benign HNPGLs. Loss of heterozygosity (LOH) was demonstrated in the malignant PGL tissue., Design: In three unrelated patients referred for routine genetic testing, SDHB, SDHC, and SDHD genes were sequenced, and gross deletions were excluded by multiplex ligation-dependent probe amplification (MLPA). LOH was determined by pyrosequencing-based allele quantification and SDHB immunohistochemistry., Results: In a patient with a nonfunctioning thoracic PGL metastatic to the bone, the lungs, and mediastinal lymph nodes, we detected the SDHC mutation c.397C>T predicting a truncated protein due to a premature stop codon (p.Arg133*). We demonstrated LOH and loss of SDHB protein expression in the malignant tumor tissue. The two other patients also carried c.397C>T, p.Arg133*; they differed from each other with respect to their tumor characteristics, but both showed benign HNPGLs., Conclusions: We describe the first case of a malignant PGL with distant metastases caused by a SDHC germline mutation. The present case shows that SDHC germline mutations can have highly variable phenotypes and may cause malignant PGL, although malignancy is probably rare.

In the present article we report a cholesteatoma of the hypotympanum extending to the jugular foramen in a 16-year-old male with Treacher Collins syndrome. Preoperative imaging excluded jugular paraganglioma and set the diagnosis of cholesteatoma. We discuss the operative treatment via a large hypotympanotomy and creation of an open hypotympanic cavity. To the authors' knowledge this is the first description of hypotympanal cholesteatoma with such an extension, being treated through this approach., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated., Design and Methods: Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC., Results: Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression., Conclusions: These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.

Background: Radioresistance limits the effectiveness of radiotherapy in head and neck squamous cell carcinoma. We previously demonstrated post-radiogenic mitogen-activated protein kinase (MAPK) pathway activation and vascular endothelial growth factor (VEGF) release resulting in reduced tumor cell response. Here, we examined the association of this mechanism with the induction of reactive oxygen species (ROS) under irradiation (IR)., Methods: Intracellular ROS after IR were measured. We modeled radiation-induced ROS by exposure of two SCC lines to H2 O2 and evaluated the impact of irradiation and ROS on ERK phosphorylation by Western blot, immunohistochemistry, and ELISA., Results: We found elevated pERK levels after treatment with IR and H2 O2 , which could be distinctly suppressed by U0126. Immunohistochemistry and ELISA revealed increased intracellular VEGF levels after H2 O2 application., Conclusions: Our data show that irradiation-induced ROS activate the MAPK pathway and release of VEGF. As VEGF is known to be released after cellular distress resulting in cytoprotection, the described mechanism is potentially of importance for therapy success., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The aim of this study is to determine differences in postoperative air-bone gap (ABG) after placement of teflon-platinum or nitinol middle ear prostheses in primary stapedotomy patients with otosclerosis. Thirty otosclerosis patients (24 female, 6 male; age 10-61 years) with primary stapedotomy were studied prospectively. Before and after surgery, the mean and standard deviations of the ABG were measured at eight frequencies (0.25-4 kHz). Patients were randomized into one of two groups receiving either teflon-platinum or nitinol prostheses. Hearing results were assessed 1 year after surgery. To assess the joint influence of treatment and frequency on ABG reduction, a linear mixed model was used (significance level was p = 5%). The Tukey-Kramer method was used to adjust for multiple comparisons. Significant differences were found between treatment groups (p < 0.0001) and between frequencies within the same treatment group (p < 0.0001) but no interaction (p = 0.7963), i.e. the reduction of the conductive components over frequencies was nearly parallel in both groups. Overall, patients in the Teflon group had a larger reduction of conductive components, on average 8.0 dB more reduction, than patients in the nitinol group. However, after adjusting for multiple comparisons, we could not identify a single frequency with a significant difference in reduction of conductive components. Use of the teflon-platinum prosthesis results in statistically non-significant better ABG closure at 0.25-4 kHz 1 year postoperatively than the use of the nitinol prosthesis.

Objectives/hypothesis: To report on the clinical course and management of sinonasal paragangliomas (PGLs)., Study Design and Methods: Retrospective chart review of six patients with PGLs of the nasal cavity and paranasal sinuses., Results: Three patients had tumors with malignant clinical behavior with cerebral metastases or infiltration of brain and local recurrence, despite surgery and/or radiotherapy, while three patients demonstrated a benign course., Conclusion: Sinonasal paragangliomas are frequently malignant. If malignant, they are very aggressive, with rapid local spread as well as high metastatic potential despite surgical resection; and they have a poor prognosis. Malignancy cannot be diagnosed on histology, but only on the basis of clinical behavior. Intracranial metastasis is commonly expected. Long-term follow-up, with particular emphasis put on the intracranial structures, is mandatory as recurrences or metastasis may occur even after a long time interval., (© 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

Hypothesis: The purpose of this study is to offer new data about facial nerve malformations in the tympanic cavity., Background: Prospective anatomic study of newborns to demonstrate the submacroscopic anatomy of the intratympanic facial nerve and its surrounding structures by malformations., Methods: Step-by-step microdissection of 12 newborn temporal bones and histologic evaluation of 4 middle ears showing multiple malformations., Results: Four of 12 temporal bones presented malformation in the middle ear. All 4 temporal bones showed developmental failures of the stapes, and 3 of them had malposition of the tympanic portion of the facial nerve. In 3 cases, there was an oval window atresia, and in 1 case, the rim of the oval window was not ossified and was positioned medial to the stapes., Conclusion: Malformation or displacement of the stapes can be an indirect sign for facial nerve malformation. The most common site for facial nerve malformation is the tympanic portion. The tympanic segment of the nerve is devoid of bony covering in association with these anomalies of the stapes.

Purpose: Knowledge of the genetic backgrounds of hereditary syndromes, which are increasingly being characterized, enables genetic screening of family members of affected patients. Upon detection of a mutation, genetic counselling and clinical screening including imaging modalities and biochemical analyses are commonly performed., Methods: Unaffected, mutation-positive relatives of index patients with hereditary paraganglioma syndromes were offered PET imaging with [(18)F]fluorodihydroxyphenylalanine and the incidence of pathological findings was retrospectively analysed in relation to mutations of the succinate dehydrogenase enzyme complex. PET only or PET/CT was performed in 21 individuals from eight families with SDHD, one family with SDHC and two families with SDHB mutations. Screening was offered every 2 to 5 years., Results: Of the 21 individuals, 14 showed paraganglioma during screening. In particular, in only 2 of 15 patients with a SDHD mutation were the findings completely unremarkable on PET screening. However, false-negative lesions for abdominal manifestations in two SDHD-positive patients were detected., Conclusion: FDOPA PET is a sensitive imaging modality which should be offered to patients with a detected SDHx (SDHD) mutation, preferably using a hybrid technique.

The aim of the study is to present the results of combination treatment for adult non-traumatic subglottic stenosis (SGS). This is a retrospective chart review of 12 female patients (age range 32-76 years) with idiopathic SGS (eight patients) and Wegener's granulomatosis. All patients had a hard and 11 a short (less than 1 cm) stenosis. Eleven patients were treated with endoscopic CO(2) laser, one with Nd-YAG laser. Topical triamcinolone was applied to all. In 10 patients, topical mitomycin C (MMC) was additionally applied. Symptom severity and airway resistance (AR) were evaluated pre- and post-interventionally. Postoperatively, oral steroids (and/or methotrexate) and proton pump inhibitors (PPI) were prescribed. Follow-up period ranged between 7 and 115 months. All patients reported a significant improvement in obstructive symptoms. Average AR preoperatively was 1.004 kPa/(L/s) and postoperatively 0.526 kPa/(L/s). Three patients underwent surgery once, 2 required a second surgery, 5 were operated 3 times, one 5 times, and one 7 times. The latter two patients had not received local MMC treatment. Endoscopic laser surgery combined with local MMC and triamcinolone application and postoperative oral steroid/methotrexate and PPI therapy provides a treatment option that results in prolongation of the symptom-free time intervals and avoidance of open surgery in patients with idiopathic and Wegener-associated hard and short SGS.

Background: Irradiation-induced signaling via the 2 pathways, Raf-MEK-ERK and PI3K-Akt, is known to be closely associated with a limited response to radiotherapy. In the present study we analyzed the relevance of constitutively active K-Ras for postradiogenic pathway stimulation and the option of coordinated inhibition to overcome these rescue mechanisms., Methods: We used 2 epithelial tumor cell lines as a model system, one of them harboring a G12S K-Ras mutation. Cells were irradiated and the effect of combined treatment with ionizing radiation and inhibitors on the expression of pERK and pAkt was determined by Western blotting. Additionally, clonogenic assays were performed to functionally analyze survival of the cell lines., Results: Compared with the nonmutated cells we observed the G12S cell line showing a clearly reduced response to inhibitor treatment under irradiation. In the case of pharmacologic inhibition of 1 of the pathways a compensatory upregulation of the second cascade leading to increased clonogenic survival seems feasible. However, there was a good functional response of this cell line to double inhibition with both compounds represented by minimized colony forming ability. The activation of ERK and Akt after irradiation was confirmed in xenotransplants showing elevated postradiogenic protein levels., Conclusion: With our data we confirmed our hypothesis of postradiogenic constitutive activation of the 2 pathways both required for Ras-mediated radioresistance in epithelial cells. If this effect should prove itself as a general mechanism in Ras-mutated tumors, application of specific inhibitors to block both cascades in parallel could contribute to enhance radiosensitivity in these types of cancer., (Copyright © 2012 Wiley Periodicals, Inc.)

The emergence of radioresistance is a significant issue in the treatment of squamous cell carcinoma. We recently demonstrated that post-radiogenic extracellular signal-regulated kinase (ERK) signaling might decrease radiosensitivity in this cancer type. To further elucidate how tumor-organizing cell types respond to irradiation and ERK pathway inhibition, we analyzed one oral squamous cell carcinoma and one lung cancer cell line (HNSCCUM-02T, A549), fibroblasts (NIH3T3), primary normal and cancer-associated fibroblasts (CAFs) in vitro. Irradiated cells treated with mitogen-activated protein kinase (MAPK) inhibitor U0126 were screened for pERK levels. Post-radiogenic cellular responses were functionally analyzed by proliferation and colony assays. We found analogous pERK expression, proliferation and survival of tumor and normal fibroblast cells. CAFs did not show any response to treatment. We hypothesized that radiation and MAPK inhibition have no dose-limiting effect on tumor-surrounding normal tissue. As CAFs are considered to influence the radioresponse of the entire tumor, but are not affected by treatment themselves, potential CAF-mediated tumor protection should be considered in further studies.

Background: A derailed balance of cell proliferation and apoptosis is presumed to result in cell hyperplasia as a typical feature of nasal polyps. Survivin, a protein of the inhibitors of the apoptosis family is proposed to promote polyp formation. However, studies concerning survivin expression in chronic rhinosinusitis (CRS) with nasal polyps are rare and the specificity of the survivin expression in nasal polyps from individuals with aspirin-exacerbated respiratory disease (AERD) has not been investigated., Methods: Immunohistochemical survivin expression analysis was performed. Samples were taken from the ethmoid sinus of individuals with CRS with nasal polyps with and without AERD during sinus surgery and control specimens of the inferior turbinate from individuals without CRS. Cell cultures were stimulated with recombinant vascular endothelial growth factor (VEGF(165)) and the resulting survivin expression was analyzed by Western blot., Results: The survivin expression of 61 specimens was analyzed by quantitative immunohistochemistry and a potential VEGF-dependant stimulation of survivin in cell cultures was investigated. The survivin expression in nasal polyps from individuals with AERD was increased compared with the controls (median, 1194 versus 927 arbitrary units [A.U.]; p = 0.054). Western blot analysis revealed in vitro a VEGF-dependant regulation of survivin in nasal polyps from individuals without AERD, but not in those with AERD (p = 0.05)., Conclusion: Enhanced survivin expression might result in decreased apoptosis and cellular hyperplasia as a part of the largely unknown pathophysiology of nasal polyp formation. Furthermore, we hypothesize a pathological, VEGF-independent constitutive survivin expression in nasal polyps of individuals with AERD.

A dysregulation of the cyclooxygenases and a leukotriene/prostaglandin imbalance are assumed to be part of the pathogenesis of the aspirin (ASA) intolerance syndrome. Ozone is an air pollutant with known proinflammatory effects on exposed epithelia, however, its impact on the expression of the cyclooxygenases 1 and 2 (cox1/2) and prostaglandin E(2) (PGE(2)) in the nasal mucosa is not well known. Therefore, we analyzed cox expression and PGE(2) levels after ozone exposure in nasal mucosa and in nasal polyps considering ASA intolerance. Isolated epithelial nasal cells from control subjects without chronic rhinosinusitis (CRS), and those from patients with nasal polyps with and without ASA intolerance were cultured and exposed in vitro to ozone. Cox1/2 expression levels were analyzed by immunohistochemistry and PGE(2) release by ELISA. After ozone exposure cox1/2 expression remained unchanged in all the three groups. PGE(2) release was lowered in cell cultures from controls and from polyps of ASA tolerant but not in those of ASA intolerant patients after ozone exposure. In the latter, PGE(2) expression remained unchanged. Our in vitro data suggest that aspirin tolerant patients with polyps might be more affected by ozone compared to aspirin intolerant ones. The potential clinical impact of impaired PGE(2) expression caused by ozone on the functions of respiratory epithelia remains to be clarified.

Objectives/hypothesis: Chronic rhinosinusitis (CRS) is a multifactorial disease that probably arises as a result of genetic diversity and environmental factors. SPINK5 is a serine protease inhibitor, which is supposed to be an important regulator of epithelial barrier maintenance. The role of SPINK5 polymorphisms and expression in CRS, especially in individuals with aspirin intolerance, is unclear., Study Design: SPINK5 single-nucleotide polymorphisms (SNPs) and SPINK5 expression levels were correlated with CRS without (CRSsNP) and with nasal polyps (CRSwNP), aspirin intolerance, asthma, and allergies., Methods: One hundred four nasal tissue samples, 15 from patients with CRSsNP, 59 from patients with CRSwNP, and 30 from healthy controls of the inferior turbinate, were analyzed for their SPINK5 status. Genotypes of four SPINK5 single nucleotide polymorphism (SNPs; G1258A, G2475T, A2915G, and A1103G), as well as SPINK5 mRNA expression levels, were determined by polymerase chain reaction., Results: No correlation between any SPINK5 SNP and CRSsNP, CRSwNP, or allergies and asthma was observed. The heterozygous SNPs G1258A and A1103G were observed more frequently in aspirin-intolerant patients; the homozygous (A/A) genotype of SNP 1258 and the homozygous (G/G) genotype SNP 1103 were less frequent. There was no correlation between the analyzed SNPs and the level of SPINK5 expression. It was noted that in individuals with CRSwNP, aspirin intolerance, and allergies, SPINK5 expression was lowered., Conclusions: G1258A and A1103G polymorphisms are distinctive for the aspirin intolerance syndrome. Lowered SPINK5 expression might be a contributing factor leading to CRS, and appears to be characteristic for patients suffering from aspirin intolerance and from allergies., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Novel strategies of cancer therapy combine irradiation and anti-angiogenic active compounds. However, little is known concerning the undesired cellular and molecular effects caused by this novel treatment concept. We used a mouse squamous cell carcinoma (SCC) xenotransplantation model to evaluate the potential undesired effects which compromise the success of this therapeutic combination. SCCs were subcutanously implanted in nude mice. Animals were treated with a fractionated irradiation scheme (5x4 Gy) alone or in combination with daily injections of anti-vascular endothelial growth factor (VEGF) antibodies. Controls remained untreated. Before and after treatment, resonance imaging (MRI), ultrasound and near-infrared spectrometry were used to evaluate tumor vessel integrity. Finally, tumors were explanted and VEGF, basic fibroblast growth factor (bFGF), vessel density, proliferation and apoptotic activity were analyzed by immunohistochemistry. Irradiation caused VEGF release and we found evidence for VEGF-mediated vessel protection. In the tumors derived from the combined treatment, blood volume was decreased, and apoptotic indices were increased. Remarkably, bFGF levels and proliferative indices were also increased. Combined irradiation/anti-VEGF treatment resulted in the desired VEGF depletion and increased tumor cell apoptosis. Nonetheless, bFGF and proliferation also increased, possibly suggesting a compensatory response. The application of additional targeted drugs may help develop more effective SCC treatments.

Background: Attention of the otorhinolaryngologist needs to be drawn to the versatile aspects of head and neck paragangliomas (PGLs)., Methods: This study is a retrospective, nonrandomized clinical study of all 175 individuals with PGLs treated in our department between 1989 and 2010. A genetic analysis was performed on 86 patients., Results: The 175 patients presented 224 head and neck PGLs as well as 2 thyroid papillary carcinomas. Genetic analysis resulted in 1 patient positive for a von Hippel-Lindau (VHL) gene mutation and 34 for succinate dehydrogenase (SDH) gene mutations (22 SDHD, 7 SDHC, and 5 SDHB), 12 of the latter carrying a novel mutation. Thirty-three patients (18.9%) had multiple PGLs and 11 patients (6.3%) had a malignant paraganglioma. SDH-mutation carriers had multiple tumors in 64.7% and malignant paragangliomas in 20.6%., Conclusions: Multifocal occurrence, potential malignancy, genetic aspects, possible coincidence of thyroid carcinoma, and hormone production have to be considered in patients with head and neck PGLs., (Copyright © 2011 Wiley Periodicals, Inc.)

Promoter hypermethylation of tumor suppressor genes (TSGs) is a common feature of primary cancer cells. However, to date the somatic epigenetic events that occur in head and neck squamous cell carcinoma (HNSCC) tumorigenesis have not been well-defined. In the present study, we analyzed the promoter methylation status of the genes mutL homolog 1 (MLH1), Ras-association domain family member 1 (RASSF1A) and O-6-methylguanine-DNA methyltransferase (MGMT) in 23 HNSCC samples, three control tissues and one HNSCC cell line (UM-SCC 33) using methylation-specific PCR (MSP). The expression of the three proteins was quantified by semi-quantitative immunohistochemical analysis. The cell line was treated with the demethylating agent 5-azacytidine (5-Aza) and the methylation status after 5-Aza treatment was analyzed by MSP and DNA sequencing. Proliferation was determined by Alamar blue staining. We found that the MGMT promoter in 57% of the analyzed primary tumor samples and in the cell line was hypermethylated. The MLH promoter was found to be methylated in one out of 23 (4%) tumor samples while in the examined cell line the MLH promoter was unmethylated. The RASSF1A promoter showed methylation in 13% of the tumor samples and in the cell line. MGMT expression in the group of tumor samples with a hypermethylated promoter was statistically significantly lower compared to the group of tumors with no measured hypermethylation of the MGMT promoter. After treatment of the cell line with the demethylating agent 5-Aza no demethylation of the methylated MGMT and RASSF1A genes were determined by MSP. DNA sequencing verified the MSP results, however, increased numbers of unmethylated CpG islands in the promoter region of MGMT and RASSF1A were observed. Proliferation was significantly (p<0.05) reduced after treatment with 5-Aza. In summary, we have shown promoter hypermethylation of the tumor suppressor genes MGMT and RASSF1A in HNSCC, suggesting that this epigenetic inactivation of TSGs may play a role in the development of HNSCC. 5-Aza application resulted in partial demethylation of the MGMT and RASSF1A TSGs and reduced proliferation of the tumor cells suggesting further evaluation of 5-Aza for HNSCC treatment.

Aberrant inactivation of tumor suppressor genes by promoter hypermethylation has been recognized as a crucial step of tumor development and is related to aggressiveness and therapy resistance. To identify potential novel treatment strategies, we evaluated pharmacological genome demethylation for the increase of irradiation treatment effectiveness in head and neck squamous cell carcinoma (HNSCC) in this in vitro study. HNSCC cells were cultured with 2 different concentrations of 5-azacytidine (5-Aza) for 72 h, followed by a single fraction irradiation with 4 or 50 Gy, respectively. To show successful genome demethylation, the methylation status of the tumor suppressor gene hic1 (hypermethylated in cancer) promoter was analyzed by methylation specific PCR (MSP) as well as hic1 transcription by quantitative RT-PCR. Survival, apoptosis, viability, and migration of the tumor cells were analyzed as functional parameters of combined treatment response. After 5-Aza treatment the hic1 promoter was demethylated and gene transcription restored demonstrating genome demethylation. 5-Aza treated cells tended to be less viable and showed decreased survival indicated by lower colony numbers. Apoptosis and migration were not affected. The combined application of irradiation and 5-Aza significantly reduced survival compared to the single treatments. Accordingly, apoptosis was strongly increased after combined 4 Gy/5-Aza treatment. Viability was not additionally affected by combined treatment. Migration was affected weakly by combined high dosage irradiation/5‑Aza treatment. Our data show that the combined application of 5-Aza and irradiation is effective in vitro. A demethylating concept prior to irradiation should be further evaluated for its potential to reduce irradiation resistance.

Objective: To study differences between aspirin-tolerant patients and aspirin-intolerant patients concerning vascular endothelial growth factor (VEGF) expression. Recent publications strongly suggest the involvement of VEGF and its receptors in the pathophysiologic process of nasal polyps., Design: We subjected 43 polyp specimens to semiquantitative immunohistochemical analysis. We quantified VEGF and its receptors (Flk, Flt, and neuropilin) in all samples. To gain insight into potential VEGF-mediated cellular responses, we determined proliferative (Ki67) and apoptotic (caspase 3) indices., Patients: Polyp samples were obtained from 22 aspirin-intolerant patients and from 21 aspirin-tolerant patients, and control specimens were obtained from 24 subjects with healthy nasal respiratory mucosa., Setting: Laboratory; Department of Otorhinolaryngology-Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany., Main Outcome Measures: Expression levels of VEGF, VEGF receptors. and proliferative and apoptotic indices., Results: We found higher expressed levels of VEGF and neuropilin and stronger proliferation in nasal polyps from aspirin-tolerant and aspirin-intolerant patients compared with controls. In polyps from aspirin-intolerant patients, VEGF was expressed at considerably higher levels compared with those from aspirin-tolerant subjects. Apoptotic activity remained unchanged in all 3 groups., Conclusions: Nasal polyps from aspirin-tolerant and aspirin-intolerant patients are characterized by strong proliferation and high levels of VEGF and neuropilin expression. Nasal polyps from aspirin-intolerant patients show distinctly increased VEGF levels. The relevance of these findings for future therapeutic approaches is yet to be determined.

Objective: Gentamicin application is an important therapeutic option to control vertigo spells in Ménière's disease. However, even in the case of low-dose intratympanic application, gentamicin might contribute to a pathological NO-increase leading to cochlear damage and hearing impairment. The study was performed to evaluate the nitric oxide (NO) reducing capacity of doxycycline in the inner ear after NO-induction by gentamicin., Methods: In a prospective animal study, a single dose of gentamicin (10mg/kg body weight) was injected intratympanically into male guinea pigs (n=48). The auditory brainstem responses (ABRs) were recorded prior to application and 3, 5 and 7 days afterwards. The organ of Corti and the lateral wall of 42 animals were isolated after 7 days and incubated separately for 6h in cell culture medium. Doxycycline was adjusted to organ cultures of 5 animals. Two NOS inhibitors, N(G)-Nitro-l-arginine methyl ester (l-NAME) and NG-monomethyl-l-arginine monoacetate (l-NMMA), were applied in three different concentrations to the organ cultures of 30 animals in total (5 animals per concentration). As controls, seven animals received no further substance except gentamicin. The NO-production was quantified by chemiluminescence. Additional six gentamicin-treated animals were used for immunohistochemical studies., Results: The ABRs declined continuously from the first to the seventh day after gentamicin application. Doxycycline reduced NO-production in the lateral wall by 54% (p=.029) comparable to the effect of the applied nitric oxide inhibitors. In the organ of Corti, NO-production was reduced by about 41% showing no statistical significance in respect to great inter-animal variations., Conclusion: The application of doxycycline might offer a new therapeutic approach to prevent NO-induced cochlea damage through ototoxic substances., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Irradiation plays a pivotal role in head and neck squamous cell carcinoma (HNSCC) treatment. However, especially recurrent tumors frequently show increased radioresistance. We analyzed irradiation-stimulated mitogen-activated protein kinase (MAPK) signaling pathways to define cellular rescue mechanisms., Methods: Irradiated HNSCC cells were screened for MAPK activation and results were confirmed and refined by functional analyses. Extracellular signal-regulated kinase (ERK) inhibitor U0126 application enabled us to specify postradiogenic cellular responses. Vascular endothelial growth factor (VEGF) levels were analyzed additionally., Results: We observed a pronounced and time-dependent ERK stimulation. Pathway inhibition resulted in decreased radioresistance. Likewise, we found a decrease of VEGF release after inhibitor treatment. ERK activation was confirmed in xenotransplants showing elevated postradiogenic phospho-ERK (pERK) and VEGF levels., Conclusions: Our data give evidence for induction of ERK and successive VEGF release in HNSCC during radiotherapy, which might be partially explained by autoregulated cytoprotection maintained by pERK and potentially VEGF. In conclusion, targeting the ERK-VEGF axis might enhance the efficiency of radiotherapy., (Copyright © 2010 Wiley Periodicals, Inc.)

In biological fluids, proteins associate with nanoparticles, leading to a protein "corona" defining the biological identity of the particle. However, a comprehensive knowledge of particle-guided protein fingerprints and their dependence on nanomaterial properties is incomplete. We studied the long-lived ("hard") blood plasma derived corona on monodispersed amorphous silica nanoparticles differing in size (20, 30, and 100 nm). Employing label-free liquid chromatography mass spectrometry, one- and two-dimensional gel electrophoresis, and immunoblotting the composition of the protein corona was analyzed not only qualitatively but also quantitatively. Detected proteins were bioinformatically classified according to their physicochemical and biological properties. Binding of the 125 identified proteins did not simply reflect their relative abundance in the plasma but revealed an enrichment of specific lipoproteins as well as proteins involved in coagulation and the complement pathway. In contrast, immunoglobulins and acute phase response proteins displayed a lower affinity for the particles. Protein decoration of the negatively charged particles did not correlate with protein size or charge, demonstrating that electrostatic effects alone are not the major driving force regulating the nanoparticle-protein interaction. Remarkably, even differences in particle size of only 10 nm significantly determined the nanoparticle corona, although no clear correlation with particle surface volume, protein size, or charge was evident. Particle size quantitatively influenced the particle's decoration with 37% of all identified proteins, including (patho)biologically relevant candidates. We demonstrate the complexity of the plasma corona and its still unresolved physicochemical regulation, which need to be considered in nanobioscience in the future., (© 2011 American Chemical Society)

Malignant triton tumour (MTT) is a rare, highly malignant neoplasm, characterized by a mixture of cells with nerve sheath and skeletal muscle differentiation. Cytogenetic analyses of this neoplasm are rare to date and none comparative genomic hybridisation (CGH) analysis has been published. In the present study we report about the genomic imbalances of a MMT analysed by CGH, in a 39-year-old male patient without neurofibromatosis. We observed the amplifications at chromosomal location 1p, 6p, 16p, 16q, 17p, 17q, 19p, 19q, 20p, and 22q. Comparing our results with those of previous studies, we found evidence for recurrent genomic aberrations at the chromosomes 1, 16, 17, 19, and 22 suggesting the involvement of several oncogenes in the genesis of MTT.

Objective: To evaluate differences in effectiveness (hearing recovery rates) between idiopathic sudden sensorineural hearing loss (ISSNHL) patients treated with intravenous therapy alone and patients treated with a combination of intravenous and intratympanic therapy., Study Design: Retrospective case review., Setting: Tertiary referral hospital center., Patients and Interventions: Ninety-four patients with moderate ISSNHL treated with an intravenous steroid and vasoactive regimen (duration of therapy, 9 ± 2.76 d) and 76 patients with severe ISSNHL treated with a combination regimen of intravenous and intratympanic therapy (duration of therapy, 10 ± 2.71 d) were reviewed. In the latter patients' group, a series of 3 intratympanic injections of a dexamethasone/hyaluronic acid mix solution were applied every 2 days., Main Outcome Measure: Pure-tone audiometric thresholds at 0.5, 1, 2, 4, and 8 kHz were compared between groups using the Wilcoxon test., Results: Combination therapy in severe ISSNHL did not show any statistically significant difference in effectiveness to intravenous therapy in moderate ISSNHL (p > 0.05)., Conclusion: In patients with severe ISSNHL, starting intratympanic steroid therapy as an adjunct early in the course of intravenous steroid and vasoactive therapy improves hearing to a level which is obtained in patients with less severe (moderate) ISSNHL treated with intravenous therapy alone.

Vestibular schwannomas (VS) are benign tumors of the nervous system that are usually sporadic but also occur in the inherited disorder neurofibromatosis type 2 (NF2). The NF2 gene is a tumor suppressor gene located on chromosome 22. Loss of the NF2 protein product, Merlin, is universal in both sporadic and NF2-related schwannomas and the loss or mutation of the gene is the only established causative event underlying schwannoma formation. Comparative genomic hybridization (CGH) was used to screen 20 sporadic VS to identify additional chromosomal regions that may harbor genes involved in VS-tumorigenesis. The most common change were losses on chromosome 22q. Additionally, losses were observed on chromosome 9p indicating a possible participation of the CDKN2A tumor suppressor gene in the genesis of VS. Gains were observed on 17q, 19p and 19q, which have been reported before in malignant peripheral nerve sheath tumors that are associated with neurofibromatosis type 1. Importantly, high level amplifications have been observed on 16p and 16q as well as on 9q, suggesting the possible involvement of several oncogenes in the tumorigenesis of VS. Our data suggest the involvement of various oncogenes and tumor suppressor genes might play a role in the genesis of the vestibular schwannomas apart from the inactivation of the NF2 gene.

Background: The "Candy Smell Test" (CST) has been introduced as a new testing method for the evaluation of the human sense of smell. In contrast to other established orthonasal smell tests, the CST addresses the retronasal application of odors, typical for food aroma effects during mastication and swallowing. The aim of this study was to evaluate the CST in a clinical setting in patients with olfactory dysfunction and normal controls against the Sniffin' Sticks test. Furthermore, cutoff points for normal and pathological results in the CST should be determined., Methods: The olfactory performance of 96 patients presenting with olfactory disorders and 71 healthy controls was evaluated with the CST-comprised of 23 different aromatized smell candies and the extended Sniffin' Sticks test (threshold, discrimination, and identification). The control group was gender matched but included also younger persons., Results: The tested subjects could easily understand the procedures and were motivated to participate. The CST correlated well with the Sniffin' Sticks for all tested subjects and for patients (n = 96) and controls (n = 71). The proposed cutoff value to differentiate normosmia from hyposmia in the CST was a score of <16 (i.e., 16 correctly identified odors) of 23. A score below 13 in the CST was the cutoff value for anosmia., Conclusion: The CST is an easy-to-handle reliable tool to investigate retronasal olfaction suited for clinical determination of normosmia, hyposmia, and ansomia. In addition, it can be used for investigation where self-application is necessary such as in large survey studies.

Background: Intersinus connections and accessory ostia of the maxillary sinus are well known to rhinologic surgeons but are less known for the remaining paranasal sinuses. Probing and dilatation of the natural ostia of diseased sinuses is being popularized currently by the clinical value of balloon catheter dilation (BCD). Although short-term high success rates with treatment of the dilated ostia/duct have been reported with this technique, the potential impact of fractures of adjacent bony septae on accessory sinus ostia, on mucosally lined surfaces, and on intersinus drainage pathways still has not been considered. The aim of this study was to review the literature on accessory sinus ostia, intersinus connections, and mucociliary drainage pathways for the entire sinus system that are relevant to BCD., Methods: A literature review was performed., Results: Accessory sinus ostia exist for each paranasal sinus. Many sinuses drain not only directly into the nasal cavity but also indirectly through adjacent sinuses. Of note, one major drainage pathway of the frontal sinus is over the ethmoid sinuses and via the ethmoids into the maxillary sinus and subsequently into the nose. Drainage of the sphenoid sinus exists both through posterior ethmoidal cells and directly into the nasopharynx., Conclusion: Accessory ostia are not only common for the maxillary sinus but also for the entire paranasal sinus system. BCD may potentially inadvertently impair mucociliary clearance of the sinuses through effects on secondary drainage pathways.

Objectives/hypothesis: Keloids are often refractive to treatment, and recurrences occur quite frequently. Radiofrequency tissue volume reduction (RFTVR) is a surgical technology that induces extensive fibrosis at the target tissues., Methods: We applied RFTVR in 14 patients (19 auricles, 5 patients treated bilaterally; 9 female, 5 male; range, 10-66 years) with keloids of the auricle. Keloids were located at the earlobe in 4 patients (5 auricles), helix in 9 patients (12 auricles), and at both earlobe and helix in 1 patient (2 auricles). In 6 patients (8 auricles) RFTVR was the sole treatment modality applied, and in 7 patients (10 auricles) intralesional steroid injection was also performed. Patients underwent one to seven sessions of RFTVR. Patients were followed up between 2 and 92 months postoperatively (median, 24.5 months)., Results: Good cosmetic results were achieved in 10 of 14 patients (13 auricles). Three patients (5 auricles) were refractive to treatment, and 1 patient (1 auricle) showed progressive disease despite treatment., Conclusions: Radiofrequency tissue volume reduction may be considered as a new, minimally invasive treatment option for keloids of the auricle., (Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.)

Conclusions: Data from 50 patients suggest that the SONATATI(100) cochlear implant (CI) is a safe and effective device., Objective: MED-EL has developed and tested a CI with titanium housing (the SONATATI(100)), which has the same internal components as the PULSARCI(100). Implant surgery should be less traumatic, as with these CIs smaller incisions and less drilling are involved. The study aimed to assess surgical issues pertaining to the implantation of the device, patient compatibility with the titanium of the implant housing, and other patient-related issues., Methods: Fifty patients were recruited into this multicenter study. In phase 1, 30 adults and in phase 2, 20 children received a SONATATI(100) cochlear implant. An intraoperative survey was completed by the surgeons for all patients. A postoperative survey was completed by the audiologists/fitting engineers at first fitting and 3 and 6 months after the first fitting to evaluate the safety and the efficacy of the device., Results: The device was proven to be effective in that it was stable in the implant bed and that minimally invasive surgery could be carried out. The device was proven to be safe after medium-term use and no unexpected adverse events were reported.

Purpose: To explore the presence of differentially expressed proteins in OSCC for discrimination of tumour and normal mucosa to establish potential biomarkers and therapeutic targets., Experimental Design: Paired protein samples of 12 individuals (tongue cancer and non-cancerous mucosa) were separated by two-dimensional polyacrylamid gel electrophoresis. The protein patterns were compared pairwise and protein spots were quantified. We identified about 70 regulated proteins which we subsequently identified by MALDI-TOF mass spectrometry., Results: Cancerous and non-cancerous tissues could be most precisely distinguished by a panel of proteins. They include the heat shock proteins (hsp)70 and 90, keratins (ck) 5, 6, 13, 14, 16, 17 and 19, beta globin, alpha-2-actin, stratifin, tropomyosin, calreticulin precursor, beta-2-tubulin, galectin7, thioredoxin, involucrin, adenylyl-cyclase-associated protein, disulfide isomerase-associated protein, thyrosine 3-monooxygenase, MYL2 and the s100 calcium binding protein. MYL3, cardiac muscle alpha actin 1 proprotein and transferrin were under-represented in OSCC. Six biomarkers, ck6 und ck13, beta globin, alpha-2-actin, hsp70 and hsp90 discriminated best between cancerous and non-cancerous oral tissues. All over-expressed proteins were analysed by STRING-analysis to highlight experimentally determined and computationally predicted interactions between the proteins. Especially involucrin, hsp70, calreticulin precursor, stratifin, (ck) 5, 6, 14, 19, tyrosine 3-monooxygenase, beta-2-tubulin and disulfide isomerase associated protein showed multiple relations., Conclusion: We identified six proteins which are differentially expressed in most OSCC compared to healthy tissues. Of those, by string analysis, multiple interaction partners are assumed for hsp70. This protein is supposed to be the most promising candidate as marker molecule and target for OSCC therapy., (© 2010 John Wiley & Sons A/S.)

The retrosigmoid (suboccipital) approach is one of four surgical approaches for the treatment of vestibular schwannomas (acoustic neuromas). It is increasingly used by otologic surgeons, and in experienced hands is associated with improved results and more limited complications. Mortality rates are minimal and often zero, while postoperative sequelae, on the other hand, are not rare. In order to not only save the patient's life, but also to assure good quality of life after the surgery, one must consider many different aspects of management of the respective complications. In this review the issues of current management of CSF leak and meningitis, facial paresis, headache, hearing loss, unsteadiness, disequilibrium, vertigo, tinnitus, cerebellar and brain stem injuries or abscess, vascular complications and venous air embolism after retrosigmoid approach for removal of vestibular schwannomas are presented., (© Springer-Verlag 2011)

Objective: We postulate, that glomus tympanicum tumors (GTTs) may be safely removed without interference with the ossicular chain via a hypotympanotomy approach., Study Design: Prospective, nonrandomized anatomic and clinical study., Setting: Tertiary referral center., Patients: All 17 patients between 1989 and 2009 with GTTs without involvement of the lumen of the jugular bulb., Interventions: We used a modified hypotympanotomy approach. Our technique is a modification of the one first published by Shambaugh (1955). Pure-tone audiograms were performed in all patients. Preoperative and postoperative audiograms were modeled in a linear mixed model evaluating hearing threshold for air and bone conduction and air-bone gap at 500, 1,000, 2,000, and 3,000 Hz. In an effort to preserve the normal sound conducting apparatus and hearing, we used a retroauricular approach, exposing widely the jugular bulb, the carotid artery, the protympanum, and even the bony part of the Eustachian tube via a hypotympanotomy. Three formalin-fixed and one macerated temporal bones were dissected step by step under the operating microscope to demonstrate the approach in cadaver dissections., Main Outcome Measure: To evaluate if GTTs can be completely resected without interference with the ossicular chain to improve conductive hearing loss., Results: We found a substantial improvement of hearing threshold after surgery at all frequencies in air conduction. For bone conduction, there was only a slight gain within random variation. The air-bone gap decreased significantly after surgery., Conclusion: Our approach demonstrated a safe avenue for complete tumor removal without interference with the continuity of the ossicular chain.

Purpose of the Study: Our aim was to longitudinally analyze the vocal outcome after endoscopic CO(2) laser resection of early glottic carcinoma., Procedures: Sixteen patients treated with laser surgery for T1 or T2 tumors of the vocal cords received voice therapy and were examined 1, 2, 3, 4.5, 6 and 12 months postoperatively. Besides videolaryngostroboscopy, each examination included history, phonetogram of the speaking and the singing voice, language-specific hoarseness diagram and a questionnaire (Voice Handicap Index 12 in German)., Results: Objective parameters demonstrated a broad variability with a slight tendency of improvement over time. For the maximal phonation time a nearly constant improvement was seen. After an initial improvement deterioration for subjective assessment in the Voice Handicap Index was noted in most patients 3-6 months postoperatively., Conclusions: The functional outcome after cordectomy is variable. MESSAGE OF THE PAPER: Discrepancies between objective findings and patient satisfaction over time have to be considered after cordectomy., (Copyright © 2010 S. Karger AG, Basel.)

Background: The guinea pig is widely used as a model to study (patho)physiological processes, such as neurodegenerative disorders. Survivin's dual function as an apoptosis inhibitor and a mitotic regulator is crucial not only for ordered development but its modulation seems crucial also under disease conditions. However, data on the expression and function of the guinea pig Survivin protein (Survivin(Gp)) are currently lacking., Results: Here, we here report the cloning and functional characterization of Survivin(Gp). The respective cDNA was cloned from spleen mRNA, containing a 426 bp open reading frame encoding for a protein of 142aa. Survivin(Gp) displays a high homology to the human and murine orthologue, especially in domains critical for function, such as binding sites for chromosomal passenger complex (CPC) proteins and the nuclear export signal (NES). Notably, phylogenetic analyses revealed that Survivin(Gp) is more related to humans than to rodents. Ectopic expression studies of a Survivin(Gp)-GFP fusion confirmed its dynamic intracellular localization, analogous to the human and murine counterparts. In interphase cells, Survivin(Gp)-GFP was predominantly cytoplasmic and accumulated in the nucleus following export inhibition with leptomycin B (LMB). A typical CPC protein localization during mitosis was observed for Survivin(Gp)-GFP. Microinjection experiments together with genetic knockout demonstrated that the NES is essential for the anti-apoptotic and regulatory role of Survivin(Gp) during cell division. In vivo protein interaction assays further demonstrated its dimerization with human Survivin and its interaction with human CPC proteins. Importantly, RNAi-depletion studies show that Survivin(Gp) can fully substitute for human Survivin as an apoptosis inhibitor and a mitotic effector. Immunohistochemistry, immunofluorescence, and western blotting were employed to detect Survivin expression in guinea pig tissues. Besides its expression in proliferating tissues, such as spleen and liver, we also found Survivin in terminally differentiated cell types. Importantly, Survivin was detectable also in the cochlea, suggesting a potential role for Survivin in the auditory system., Conclusions: We provide the first experimental evidence for the expression of Survivin in the guinea pig. As Survivin(Gp) can substitute for known functions of human Survivin, the guinea pig model will now also allow investigating Survivin's (patho)physiological role and to test Survivin-directed potential therapeutic strategies., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Hearing impairment is a worldwide health problem. Employing semi-quantitative immunological detection methods, we found that the apoptosis inhibitor protein Birc5 is expressed in cell types critical for hearing perception. In the guinea pig model, moderate noise exposure causing only a temporary mean hearing impairment of 33dB significantly enhanced Birc5 expression in the spiral ligament, nerve fibers and the organ of Corti. In contrast, intratympanic gentamicin injection inducing permanent cell damage and mean hearing loss of 24dB correlated with a significant Birc5 downregulation in the ligament, nerve fibers and the organ of Corti. The cytoprotective activity of the guinea pig and human Birc5 protein was confirmed by cloning of the gene and by subsequent ectopic expression and challenging studies against the ototoxin gentamicin in epithelial and auditory cell models. As the mammalian cochlea is unable to regenerate upon damage, these data suggest that modulation of Birc5 expression may represent a novel physiological mechanism to protect the inner ear against stress-induced cell damage. Hence, the targeted modulation of Birc5 levels may lead to novel otoprotective therapeutic strategies., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The aim of the study was to test whether a correlation between the Epworth Sleepiness Scale (ESS) and respiratory sleep parameters recorded by polysomnography (PSG) in patients with sleep-related breathing disorders and upper airway pathology exists. The PSG records of 130 patients (average age 52.6 +/- 10.7 years) with upper airway pathology suspected of having obstructive sleep apnea (OSA) have been retrospectively evaluated. Upper airway pathology included deviation of the nasal septum, inferior nasal turbinate hypertrophy, soft palate webbing, elongated uvula, tonsillar hypertrophy, macroglossia, hypertrophy of the tongue base, unfavorable palate position relative to the tongue base. To test for a possible correlation in this patient population between ESS score and arithmetic values of AHI, SPO(2), ODI and Arousal Index, the Spearman's correlation coefficient was calculated. No correlation between ESS and AHI, minimal SpO(2) and ODI was proven and only a weak positive correlation between Arousal Index and ESS was found in this particular patient population. We concluded that in patients with upper airway pathology, it is not possible to predict solely on the basis of the ESS score the existence of OSA or of other disturbances in Arousal Index, minimal SpO(2) and ODI. Nevertheless, historical data evaluated by questionnaires, such as the ESS provide for additional information combined with the clinical findings to select patients who are candidates for further detailed sleep studies.

Objectives/hypothesis: Intratympanic application of gentamicin is an important therapeutic option to control vertigo spells in Ménière's disease. Low doses eliminate the function of semicircular canal ampullae (SCCA) and saccule in most patients, although utricular function is maintained in many cases. Local alteration in free radical production might be responsible for these differences. Therefore, the gentamicin-induced nitric oxide (NO) production was determined in an animal model using separate organ cultures of SCCA, saccule, and utricle., Study Design: Prospective pilot study in male guinea pigs., Methods: SCCA, saccule, and utricle of 28 guinea pigs were isolated and incubated separately for 6 hours in cell culture medium. Gentamicin was administered in two different concentrations (0.4 mg/mL and 0.8 mg/mL) to organ cultures of 16 animals. Tissues from 12 animals were used as controls. Nitric oxide was quantified by chemiluminescence., Results: Gentamicin led to an NO increase of about 70% in the saccule, an NO reduction of more than 70% in SCCA, and an NO reduction of 36% in the utricle., Conclusions: The selective effects of gentamicin on the NO production in the different sensory areas of the vestibular organ have to be taken into account in the therapy of Ménière's disease.

Promoter hypermethylation of tumor suppressor genes is a common feature of primary cancer cells. However, at date the somatic epigenetic events that occur in head and neck squamous cell carcinoma (HNSCC) tumorigenesis are not yet been well defined. In the present study we analysed the methylation status of the gene hypermethylated in cancer-1 (hic1), a gene located on chromosome 17p13.3, a region frequently lost in HNSCC. We analysed 22 HNSCC samples and three cell lines using methylation specific PCR (MSP). We found hic1 methylated in 21 out of 22 samples and in all three cell lines. Treatment of the cell lines with the demethylating agent 5-Azacytidin (5-Aza) resulted in the demethylation of the hic1 promoter and reactivation of hic1 expression as determined by MSP, qPCR and Western blot. Functional analyses revealed decreased proliferative activity and colony forming ability of treated cells. In summary, we found in HNSCC hic1 regulated by promoter methylation. 5-Aza application resulted in the reexpression of hic1 and was followed by decreased aggressiveness of the cancer cells. Our data indicate that hic1 might be a player in HNSCC development and suggest further evaluation of 5-Aza for HNSCC treatment., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The objective of this study is to test whether there is a difference between the polysomnographic (PSG) values of Apnea-hypopnea index (AHI), minimal oxygen saturation (SpO(2)), oxygen desaturation index (ODI) and arousal index recorded on two consecutive nights (so-called "first night effect") in patients with sleep-disordered breathing (SDB) and concomitant upper airway pathology. Retrospective case-control study of polysomnographical recordings of 130 patients (112 males, 18 females, age range 23-80 years) with SDB and upper airway pathology who were tested on two consecutive nights in a hospital sleep laboratory was conducted. Only patients with upper airway pathology without other medical conditions causing SDB were included. AHI, minimal SpO(2), ODI and arousal index values of the first night were compared to those of the second night using Wilcoxon's test. There were no significant statistical differences between AHI, SpO(2), ODI and arousal index values (P = 0.130, P = 0.640, P = 0.052, and P = 0.692, respectively) between the two nights. However, 15% of the patients showed significant variability in the AHI between the two recordings and in 6% of the patients, a diagnosis of severe OSA (AHI > 10/h) would have been missed if only one night of sleep study had been performed. In general, one night of sleep study is sufficient to lead to a clear diagnosis of severe OSA in patients with sleep-disordered breathing and upper airway pathology but may still not diagnose 6% of the patients with severe OSA. Additionally, 15% of the patients showed a significant variability in the AHI between the two nights.

Objectives/hypothesis: Spontaneous nasal cerebrospinal fluid (CSF) fistula represents a rare clinical entity. The possible etiology and the localization of the rhinorrhea remain an ongoing clinical challenge. The purpose of this study was to evaluate the localization of spontaneous CSF fistula and to correlate it with anatomical studies., Study Design: Retrospective clinical study, prospective anatomical study., Methods: Twenty-nine patients with spontaneous CSF rhinorrhea were retrospectively studied, 10 males and 19 females. Ages ranged from 10 to 92 years (mean, 50 years). In addition, 48 human skulls from newborns to adults were examined for the postnatal development of the anterior and middle cranial fossa., Results: In our study isolated cribriform plate defects were found in four patients. The lateral lamina of the ethmoid bone showed defects in three patients. In nine patients the bony defect could be found in the region of the fovea ethmoidalis. The bony defect between the extra- and intracranial space was found in the lateral recess of the sphenoid sinus in eight patients. Five patients had special sites (e.g., supraorbital recess and frontal recess)., Conclusions: This study supports the theory that bony dehiscence in the lateral lamina of the ethmoid bone can be congenital and can also be spontaneously acquired later. The bony dehiscence in the lateral wall of the sphenoid sinus can only develop during pneumatization.

Unlabelled: Smoking and alcohol abuse cause squamous cell carcinoma of the head and neck (SCCHN) through smoke-induced mutations, which are counteracted by O(6)-methylguanine-DNA methyltransferase (MGMT). This study aimed at elucidating the role of MGMT in SCCHN and its precursor lesions (SIN). MGMT was also determined in the normal mucosa (NM) and blood lymphocytes (PBLCs)., Results: a) MGMT was lower in NM than in PBLCs. b) Smoking reduced MGMT in NM but had no effect in PBLCs. c) MGMT activity increased in the sequence NM

Arachnoid cysts are benign intracranial lesions that are typically diagnosed incidentally. They are divided into two types: congenital and acquired. Acquired arachnoid cysts are rare and usually arise after trauma, infection, or haemorrhage. In this report, a rare case of an iatrogenic multiloculated arachnoid cyst as an unusual complication of a skull base defect is presented. It extended extracranially into the sphenoid sinus, the ethmoid, the infratemporal fossa, the nasopharynx and the nasal cavity, as well as into the pterygomaxillary and retromaxillary space, appearing with a distinct clinical picture. We discuss the differential diagnosis and the potential causes of the lesion and provide a brief review of the literature., (Copyright (c) 2009 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)