Balloon Eustachian Tuboplasty (BET) in Children: A Retrospective Multicenter Analysis.

OBJECTIVE: Generation of pilot data for planning of prospective BET-studies for treatment of dilatory Eustachian tube (ET) dysfunction in children. STUDY DESIGN: Retrospective multicenter analysis. SETTING: Nine ENT departments at tertiary care teaching hospitals. PATIENTS: 4-12-year-old children with chronic otitis media with effusion (COME) for more than 3 months or more than 3 episodes of acute otitis media during the last year, having failed standard surgical therapy at least once. INTERVENTION: BET with or without paracentesis, ventilation tube insertion, or tympanoplasty. MAIN OUTCOME MEASURES: Tympanic membrane appearance, tympanometry, and hearing threshold. RESULTS: Two hundred ninety-nine ETs of 167 children were treated. Mean age was 9.1 years (95% confidence interval [95% CI]: 8.7-9.4 yr). In 249 ears (83.3%), COME and/or retraction of the tympanic membrane were the indication for BET. Median hearing threshold was 20 dB HL (95% CI: 0-46 dB). One hundred fifty-five ears (51.8%, 95% CI: 46.1-57.4%) showed a tympanogram type B. Treatment consisted of BET without other interventions ("BET-only") in 70 children, 128 ears. Median length of follow-up for 158 (94.6%) children was 2.6 months (95% CI: 0.3-16.1 mo). After treatment, the tympanic membrane appeared normal in 196 ears (65.6%, 95% CI: 60.0-70.8%, p < 0.001). Median hearing threshold improved to 10 dB HL (95% CI: 0-45 dB, p < 0.001). Tympanograms shifted toward type A and C (type A: 39.1%, 95% CI: 33.7-44.7, p < 0.001). These improvements were also observed in subgroup analyses of "BET-only" treatment and the indication of "COME" respectively. CONCLUSION: BET is improving a variety of dilatory ET dysfunction-related ear diseases in children. This study provides detailed data for design and planning of prospective studies on BET in children.

EGFR-specific T cell frequencies correlate with EGFR expression in head and neck squamous cell carcinoma.

BACKGROUND: In head and neck squamous cell carcinoma (HNSCC), expression levels of the epidermal growth factor receptor (EGFR) correlate with poor prognosis and decreased survival rates. As the mechanisms responsible for cellular immune response to EGFR in vivo remain unclear, the frequency and function of EGFR-specific cytotoxic T cells (CTL) was determined in HNSCC patients. METHODS: The frequency of CTL specific for the HLA-A2.1-restricted EGFR-derived YLN peptide (YLNTVQPTCV) and KLF peptide (KLFGTSGQKT) was determined in 16 HLA-A2.1+ HNSCC patients and 16 healthy HLA-A2.1+ individuals (NC) by multicolor flow cytometry. Patients' results were correlated to EGFR expression obtained by immunohistochemistry in corresponding tumor sections. Proliferation and anti-tumor activity of peptide-specific CTL was demonstrated by in vitro stimulation with dendritic cells pulsed with the peptides. RESULTS: Frequency of EGFR-specific CTL correlated significantly with EGFR expression in tumor sections (p = 0.02, r2 = 0.6). Patients with elevated EGFR scores (> 7) had a significantly higher frequency of EGFR-specific CTL than NC and patients with low EGFR scores (< 7). EGFR-specific CTL from cancer patients were expanded ex vivo and produced IFN-γ upon recognition of EGFR+ target cells. CONCLUSION: EGFR expressed on HNSCC cells induces a specific immune response in vivo. Strategies for expansion of EGFR-specific CTL may be important for future immunotherapy of HNSCC patients.

Hyperfractionated accelerated radiotherapy versus conventional fractionation both combined with chemotherapy in patients with locally advanced head and neck carcinomas: a retrospective analysis of a monoinstitutional series.

OBJECTIVE: Hyperfractionated accelerated radiotherapy (HART) has been combined with chemotherapy (CC) for locally advanced head and neck cancer, but no data from randomized trials are available for a comparison with conventionally fractionated radiotherapy (CFRT) and CC. METHODS: This monoinstitutional retrospective study compares the results of both treatment schedules: 315 patients with locally advanced carcinoma (UICC stage III and IV) of the oral cavity and the orohypopharynx were treated from January 1990 to March 2006 with a radiochemotherapy combination based on mitomycin C and fluorouracil (HART-CC: 203 patients, CFRT-CC: 112 patients, total dose: 70-72 Gy) with curative intent. RESULTS: Two- and 4-year survival was 60 and 42 (HART-CC) and 59 and 42% (CFRT-CC; p = 0.82, log-rank test), respectively. Using multivariate Cox regression, pretreatment hemoglobin level, N stage, tumor site but not the year of treatment, gender and T stage were significant prognosticators for survival. For locoregional control, only N stage was significant. The prognostic value of these pretreatment factors did not variate with the fractionation schedule used. CONCLUSIONS: In combination with CC, there was no trend towards an improved efficacy of HART in comparison with CFRT.

The GNAS1 T393C polymorphism predicts survival in patients with advanced squamous cell carcinoma of the larynx.

OBJECTIVES/HYPOTHESIS: In previous studies, we have demonstrated that the T-allele of a specific single nucleotide polymorphism (SNP) in the Galphas gene (T393C) correlates with increased Galphas expression and hence apoptosis. The T-allele was associated with a favorable outcome in a variety of human cancers, for example, carcinoma of the urinary bladder, kidney, colorectal, oro- and hypopharynx. STUDY DESIGN: The prognostic value of the T393C SNP was retrospectively evaluated in an unselected series of patients treated with curative intent for laryngeal squamous cell carcinomas including all tumor stages with different therapeutic regimens. METHODS: DNA analysis was performed using DNA from paraffin-embedded tissue samples from 157 patients (142 men, 15 women) with a median follow-up of 68 (3-143) months. The various genotypes were correlated with the overall survival. RESULTS: Survival was significantly dependent on the T393C genotype in advanced American Joint Committee on Cancer (AJCC) stages (III-IV) with an apparent gene-dose effect (P = .0437). Five-year survival rates were 76% for TT, 49% for TC, and 43.5% for CC. In multivariate analysis including age at diagnosis, AJCC stage, grade, gender, and T393C genotypes, patients with CC genotype displayed a higher risk for death with a hazard ratio of 2.59 (95% confidence interval: 1.01-6.64, P = .047) compared with the reference group consisting of T393 homozygous individuals. CONCLUSIONS: The T393C SNP is a prognostic marker that could help to identify high risk patients suffering from head and neck cancer.

Association study of the G-protein beta3 subunit C825T polymorphism with disease progression an overall survival in patients with head and neck squamous cell carcinoma.

The T-allele of a common C825T single nucleotide polymorphism (SNP) in the gene GNB3, encoding the G3 subunit of heterotrimeric G-proteins, is associated with a truncated form of the G3 protein that imparts a greater signaling capacity than the alternative C-allele encoding a nontruncated protein. We analyzed the C825T-allele status with regard to disease progression in patients with head and neck squamous cell carcinoma (HNSCC). The prognostic value of the SNP was evaluated in an unselected series of 341 patients treated with curative intent for HNSCC including all tumor stages with different therapeutic regimens. Genotype analysis was done by Pyrosequencing using DNA from paraffin-embedded tissue samples. Genotypes were correlated with relapse-free and overall survival. Proportions of 5-year relapse-free intervals were 62% for CC, 60% for TC, and 42% for TT genotypes. Kaplan-Meier curves revealed a significant genotype-dependent relapse-free interval (P = 0.036). In multivariate analysis with stage, localization, grade, gender, and smoking habits as covariates, GNB3 825T homozygous patients displayed a higher risk for relapse than C825 homozygous patients (TT versus CC, hazard ratio; 95% confidence interval, 1.4-4.8; P = 0.002). The same genotype effect was found for overall survival, TT genotypes were at higher risk for death compared with CC genotypes (hazard ratio, 2.6; 95% confidence interval, 1.6-4.3; P < 0.001), and 5-year survival proportions were 60% for CC, 52% for TC, and 33% for TT. The GNB3 C825T SNP thus represents a host derived prognostic marker in HNSCC, which allows identifying high-risk patients, which could benefit from novel and/or more aggressive therapeutic regimes.

Overall and relapse-free survival in oropharyngeal and hypopharyngeal squamous cell carcinoma are associated with genotypes of T393C polymorphism of the GNAS1 gene.

PURPOSE: In previous studies, we have shown that the T allele of a specific single-nucleotide polymorphism (SNP) in the Galphas gene (T393C) correlates with increased Galphas expression and hence apoptosis. The T allele was associated with a favorable outcome in a variety of human cancers, e.g., carcinoma of the urinary bladder, kidney, and colorectum. EXPERIMENTAL DESIGN: The prognostic value of the T393C SNP was evaluated in an unselected series of patients treated with curative intent for oropharyngeal and hypopharyngeal squamous cell carcinomas, including all tumor stages with different therapeutic regimens. Genotype analysis was done using DNA from paraffin-embedded tissue samples from 202 patients (162 men, 40 women) with a median follow-up of 38 months (1-133 months). The various genotypes were correlated with relapse-free and overall survival. RESULTS: GNAS1 393C homozygous patients displayed a higher risk for disease progression than T393 homozygous patients (hazard ratio CC versus TT, 1.9; 95% confidence interval, 1.1-3.2; P = 0.019). The same genotype effect was observed for overall survival with CC genotypes at higher risk for death compared with TT genotypes (hazard ratio, 1.7; 95% confidence interval, 1.1-2.9; P = 0.015). Multivariate analysis showed that, besides American Joint Committee on Cancer stage, tumor localization, and gender, the T393C polymorphism was an independent prognostic factor for disease progression and death. CONCLUSION: The T393C SNP could be considered as a genetic marker to predict the clinical course of patients suffering from oropharyngeal and hypopharyngeal cancer.

Immunohistochemical evidence of BMP-2, -4 and -7 activity in otospongiosis.

CONCLUSION: This study is the first to show that bone morphogenetic proteins (BMP)-2, -4 and -7 play a role in active phase otosclerotic bone remodelling (otospongiosis). OBJECTIVES: The role of BMPs in various tissue growth and repair mechanisms is an ongoing topic in the literature. BMP-2, -4 and -7 are known to be of major importance in bone formation and repair. Their role in otosclerotic bone transformation has not been analysed previously. The main goal of this study was to perform an immunohistological analysis of BMP-2, -4 and -7 in otoclerosis. MATERIALS AND METHODS: Parts of the stapedial footplates, collected during partial stapedectomies in 30 patients with clinical otosclerosis, were analysed for histological otosclerotic lesions after staining haematoxylin and eosin. Immunohistochemical analysis was performed using polyclonal IgG antibodies for BMP-2, -4 and -7, as well as biotinylated secondary antibodies, avidin-biotin-peroxidase complex reaction and alkaline phosphatase staining. RESULTS: In all, 14 specimens contained otosclerosis; 3 of these were otospongiotic, 8 fibrotic, 2 sclerotic and 1 had both sclerotic and fibrotic lesions. Thus in total 14/30 specimens (47%) showed histological otosclerosis. Only the multiple osteoblasts and osteoclasts in those specimens exhibiting an otospongiotic phase showed distinct immunochemical staining for BMP-2, -4 and -7.

Lidocaine: neurobiological targets and effects on the auditory system.

Lidocaine, a local anesthetic and anti-arrhythmic agent, is also known both as a tinnitus- and as a pain-suppressing drug. The sites of action in tinnitus suppression are in the cochlea as well as in the central auditory nervous system. In the present study, audiological and brain imaging studies in humans were used to identify the anatomical structure where lidocaine has its action on tinnitus. Molecular studies were used to elucidate the action of lidocaine on the cellular level. Various ion channels and receptors (e.g. voltage-gated Na(+), K(+) and Ca(2+) channels, glutamate, GABA, glycine and vanilloid receptors), found in the auditory system and possibly connected to tinnitus, are affected by lidocaine. Identification of molecular structures involved in expression of neuroplasticity in the auditory system in tinnitus and modeling the binding sites of local anesthetics could lead to the design of subtype-specific inhibitors that could provide new pharmacological targets for treatment.

Signaling by way of type IB and II bone morphogenetic protein receptors regulates bone formation in otospongiosis.

HYPOTHESIS: The main goal of this study was to perform an immunohistologic analysis of bone morphogenetic protein receptors (BMPR) in otospongiosis. BACKGROUND: BMP-2, -4, and -7 play an essential role in bone formation and repair. They do so as well in otosclerosis. It has been shown that these BMPs are traceable in osteocytes and osteoclasts in the active phase of otosclerosis (otospongiosis). The role of the different BMP receptors in otosclerotic bone transformation has not been previously analyzed. METHODS: The posterior parts of the stapes footplates, collected during partial stapedectomies in 35 patients with clinical otosclerosis, were analyzed for histologic otosclerotic lesions after hematoxylin staining. Immunohistochemical analysis was performed using polyclonal immunoglobulin G antibodies for BMPR-IA, -IB, and -II, as well as biotinylated secondary antibodies, avidin-biotin-peroxidase complex reaction, and alkaline phosphatase staining with nitroblue-tetrazolium-chloride. RESULTS: Seventeen of 35 (49%) specimens contained otosclerosis, but only 5 of these exhibited an otospongiotic phase. The abundant osteoblasts and osteoclasts in these cases showed distinct immunochemical staining for BMP-2, -4, and -7. In two cases, there could also be found an immense positive staining for BMPR-IB and modest staining for BMPR-II, whereas BMPR-1A always remained negative. CONCLUSION: It was demonstrated for the first time that in otospongiosis, the actions of the BMPs are mediated through BMPR-IB and BMPR-II. To determine this role in detail, further investigations, especially for the phosphorylated Smad proteins within the BMP dependent mediator cascade, will be necessary.

Laser-tonsillotomy for treatment of obstructive tonsillar hyperplasia in early childhood: a retrospective review.

INTRODUCTION: Tonsillar hyperplasia leading to dyspnea, dysphagia and other symptoms of obstruction represents a common problem especially in young children where tonsillectomy should be avoided in order to preserve the immunological function of the tonsils. Aim of the study was to assess carbon-dioxide-laser-tonsillotomy as a considered alternative procedure to reduce the tonsillar volume in these children. METHODS: Between 1993 and 2004, 109 children with tonsillar hyperplasia without former episodes of tonsillitis received laser-tonsillotomy mostly (n=98) combined with adenoidectomy. The protruding part of the tonsil was reduced by a CO2-laser. Seventy-five children were available for follow-up with a standard questionnaire. Five patients required a subsequent tonsillectomy due to a recurrence of tonsillar hyperplasia. Histological investigations were performed. Twenty-two children were reevaluated by clinical examination. RESULTS: Most of the patients were relieved from obstructive symptoms. There was no occurrence of postoperative hemorrhage or peritonsillar abscesses. The histological investigations on the specimens from later performed tonsillectomy (n=5) showed no evidence of inflammation or scar formations, but open and deep crypts. The clinical examination did not reveal any signs of chronic infections. CONCLUSION: In this retrospective study tonsillotomy with CO2-laser in early childhood leads to a long-term elimination of obstructive symptoms due to tonsillar hyperplasia with minimal discomfort for the patient while preserving normally functioning immunocompetent tonsillar tissue. Further prospective studies are planned.

Management of an "Ear Camp" for children in Namibia.

OBJECTIVE: In this publication, we present our experiences with managing an "Ear Camp" in northern Namibia, where the population is predominantly black. Medical coverage for ear problems is poor in this part of the country. METHODS: Within 10 days, 38 children (median age 12 years) were operated mainly for (sub) total defects of the tympanic membrane. In two cases, an open cavity had to be created because of a cholesteatoma. We performed a tympanoplasty type I in 18 cases and a tympanoplasty type III in 20 cases. Additionally, in 8 cases an antrotomy and in another 8 cases a mastoidectomy was performed. The ossicular chain was reconstructed with a titanium-PORP (14 cases), a titanium-TORP, interposition of the head of the malleus or a cartilage columella (one case each) or by placing the reconstructed tympanic membrane directly onto the head of the stapes (three cases). The tympanic membrane was reconstructed by the use of tragal cartilage with overlapping perichondrium in underlay-technique. RESULTS: Thirty-one children could be followed up. A defect of the tympanic membrane was found in five cases because of continuous purulent discharge. The average improvement of air conduction thresholds in the frequencies between 250 and 4000 Hz was 15 dB. CONCLUSIONS: Surgical techniques, antibiotic treatment and perioperative management have to be adapted to limited possibilities of pre-treatment and aftercare. As development aid should support people to look after themselves, we started to instruct local doctors with regard to pre- and postoperative care in ear surgery. Training of the local doctors will be continued in our next "Ear Camp" in 2004.