High incidence of extraadrenal paraganglioma in families with SDHx syndromes detected by functional imaging with [18F]fluorodihydroxyphenylalanine PET.

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.

Reactive oxygen species activation of MAPK pathway results in VEGF upregulation as an undesired irradiation response.

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.

Short-term hearing results after primary stapedotomy with nitinol and teflon-platinum prostheses for otosclerosis.

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.

Treatment for adult idiopathic and Wegener-associated subglottic stenosis.

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.

Impact of ozone exposure on prostaglandin release in nasal polyps.

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.

Analysis of cytogenetic aberrations in sporadic vestibular schwannoma by comparative genomic hybridization.

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.

Analysis of differentially expressed proteins in oral squamous cell carcinoma by MALDI-TOF MS.

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.

Expression analysis suggests a potential cytoprotective role of Birc5 in the inner ear.

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.

Post-operative complications after removal of sporadic vestibular schwannoma via retrosigmoid-suboccipital approach: current diagnosis and management.

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.

Cytogenetic analysis of a malignant triton tumour by comparative genomic hybridization (CGH) and review of the literature.

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.

Long-term functional outcome after unilateral cordectomy.

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.

Relocation of an infected tracheostoma: anterior mediastinal tracheostomy as Mission:Impossible.

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.

First-night-effect on polysomnographic respiratory sleep parameters in patients with sleep-disordered breathing and upper airway pathology.

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.

Correlation of the Epworth Sleepiness Scale with respiratory sleep parameters in patients with sleep-related breathing disorders and upper airway pathology.

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.

Quality of life in sporadic vestibular schwannoma: a review.

Quality of life (QoL) measures are increasingly used as outcome measures in the assessment of different treatment options in clinical practice and as endpoints in clinical trials. Methods and questionnaires currently used for QoL assessment in vestibular schwannoma (VS) patients, studies evaluating QoL before and after treatment, studies on patients managed conservatively and studies evaluating facial-nerve-function-related QoL in VS patients are reviewed. Current methodological controversial issues in QoL studies on VS patients include the lack of a planned prospective comparison between QoL values before and after treatment, a need for the inclusion of additional questions along with standard questionnaires and the need to report on both the statistical and the clinical significance of QoL data. QoL assessments merit being included in more trials along with standardized interpretation and complete reporting of results.

Inducible NO synthase confers chemoresistance in head and neck cancer by modulating survivin.

The dual role of the inducible NO synthase (iNOS) and NO signaling in head and neck squamous cell carcinoma (HNSCC) is a complex and can both promote or inhibit tumor progression. However, the underlying molecular mechanisms are not yet resolved in detail. We show for the first time that conditions, favoring low NO levels conferred resistance against cisplatin/taxol-induced apoptosis in HNSCC cell lines. Cytoprotection was mediated by survivin, because we observed its upregulation subsequent to low doses of the NO donors S-nitroso-N-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) or ectopic expression of physiologic amounts of iNOS. Also, RNAi-mediated depletion of survivin blocked NOs anti-apoptotic effects. Induction of survivin involves activation of the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway, which was antagonized by the PI3K-inhibitor LY294002. Importantly, application of the iNOS-specific inhibitor 1400W combined with RNAi-mediated downregulation of survivin cooperatively enhanced drug-induced cell death. The iNOS/survivin-axis appears to be also of clinical relevance since immunohistochemistry revealed that iNOS expression correlated with enhanced survivin levels in HNSCC specimens. In contrast, high NO concentrations suppressed survivin levels in HNSCC but also in non-malignant cells resulting in apoptosis. Cell death induced by high amounts of SNAP/SNP or by strong overexpression of iNOS involved activation of p38MAP-kinase, which was counteracted by the p38MAP-kinase inhibitor SB202190. Here, we provide evidence for a novel molecular mechanism how NO signaling may contribute to therapy resistance in HNSCC by modulating survivin expression. Our data further suggest pursuing pharmacogenetic iNOS/survivin-targeting approaches as potential therapeutic strategies in head and neck cancer.

Association between surgical steps and intraoperative auditory brainstem response and electrocochleography waveforms during hearing preservation vestibular schwannoma surgery.

Intraoperative monitoring of the auditory pathway by means of either electrocochleography or auditory brainstem response audiometry is valuable during hearing preservation vestibular schwannoma (VS) surgery. A more than 75% intraoperative reduction of the amplitude of these evoked auditory potentials was thought to be related with clear hearing compromise of hearing. We identified 22 patients who satisfied this intraoperative criterion in a cohort of 86 consecutive patients who had attempted hearing preservation VS surgery. The surgical step that temporally coincided with the above event was considered to be the most critical step for hearing monitoring during this kind of surgery. Most frequently, drilling of the internal auditory canal and direct tumor resection were associated with the aforementioned changes, but also drilling of the cortical temporal bone at the very beginning of surgery or the opening of the dura could be implicated. This profound intraoperative amplitude decrease was associated with a profound postoperative hearing impairment in 84% of the cases.

Cochlear implantation after surgery for bilateral jugular foramen paragangliomas: a case report.

This paper describes a case of cochlear implantation for deafness due to bilateral glomus jugulare tumors (paragangliomas) as well as an unusual complication after cochlear implantation in a 31-year-old male. A 31-year-old male with profound sensorineural hearing loss on the right side and deafness on the left side, caused by bilateral jugular foramen paragangliomas, was implanted with a multi-channel cochlear implant (Combi 40+, Med-El) on the right side during subtotal petrosectomy for removal of the right-sided glomus jugulare tumor. No postoperative medical complications were observed. The patient responded to acoustic stimuli. Postoperative computed tomography (CT) did not show any misplacement of the electrode. Three years after implantation, an acute, rapidly progressive hearing impairment with pain to acoustic stimuli was observed. A CT scan at that time showed cochlear bone resorption. No radiologic evidence of paraganglioma recurrence was observed. The implant was removed and a biopsy of the cochlea was performed which on histologic examination showed fibrosis without any sign of any tumor recurrence. Cochlear implantation can restore hearing in deafness due to bilateral glomus jugulare tumors. Cochlear resorption may occur as a late complication in the implanted side in the patients.

Successful rigid endoscopic removal of an esophageal subtotally covered nitinol stent 11 months after initial placement.

Formation of granulation tissue and stricture at the stent's ends are well-known long-term complications of esophageal subtotally covered externally self-expandable metal stents (SEMS). Removal is associated with an increased risk of mucosal injury, severe bleeding, mediastinis, and consecutive stenosis. We report on a case of successful endoscopic removal of an esophageal SEMS 11 months after original placement to cover an iatrogenic esophageal perforation created during rigid esophagoscopy in a patient with cancer of unknown primary (CUP) syndrome. This case shows that safe SEMS late removal is achievable and at the same time illustrates the disadvantages of using SEMS for benign esophageal pathology. Particularly in cases of accidental esophageal injury during endoscopy, esophageal SEMS placement should be considered as a therapeutic option only if conventional surgery is contraindicated.

Cochlear implant and hearing aid: a new approach to optimizing the fitting in this bimodal situation.

More and more patients with residual hearing on the contralateral side are becoming candidates for cochlear implants (CI) surgery due to increasing CI. The major benefits of regular binaural hearing are spatial hearing, localization, and signal source discrimination in both quiet and noisy surroundings. In most of the reports, hearing aid fitting was carried out without balancing both the devices. Twelve children and eight adults with residual hearing on the non-operated side were binaurally fitted. Our fitting procedure for the hearing aid was based on the desired sensation level [i/o] method. A loudness scaling was used to adjust the loudness perception monaurally and to balance the volume of both devices. Speech audiometry in quiet and noisy surroundings was conducted both monaurally and in the bimodal mode. The fitting was modified according to the respective test results. In all children and six adults, a measurable gain and/or a subjective improvement of speech perception was achieved. Two adult patients did not accept the new fitting. In seven younger children, loudness scaling was impossible to perform because of age. This was also the case with speech audiometry for two children. A structured bimodal fitting using loudness scaling for both the cochlear implant and the hearing aid results in a subjective and objective amelioration of the patient's hearing and speech perception.