G. Lehnerdt

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.

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 Gαs gene (T393C) correlates with increased Gαs 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.

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 Gαs gene (T393C) correlates with increased Gαs 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.

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.

Association Study of the G-Protein β3 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. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3203–7)

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.

Basosquamöses Karzinom der Haut

BACKGROUND Basosquamous carcinoma (BSC) is a rare malignancy with specific histopathological features of both basal cell (BCC) and squamous cell carcinoma (SCC). Therefore, the histological diagnosis is challenging. Due to its low incidence there is no consensus on the surgical management of BSC. PATIENTS AND METHODS We describe the (immunohistological) diagnostic and therapeutic aspects of nine cases (8 male symbol : 1 female symbol, on average 68.6 years of age (range: 47-81)) of BSC. Of these, seven were located on the pinna, one on the forehead and zygomatic region and one in the retroauricular region. RESULTS Immunochemical staining for epithelial membrane antigen was negative (apart from the typical areas of epithelial pearl formation) and BerEP4 was positive in all cases. Therapy consisted of partial removal of the pinna in four, and total removal in three cases. One patient was treated by partial removal of the auricle with superficial parotidectomy and ipsilateral neck dissection. In the case of the carcinoma on the forehead, a local excision was performed. The median follow-up was 45 months. One patient had a local recurrence. CONCLUSIONS The histological diagnosis of BSC is confirmed by the use of EMA and BerEP4 immunohistological staining. Clinically, BSC is a rare, aggressive skin tumor. Despite the histological similarity to basal cell carcinoma, BSC has an imminent risk of metastasizing. Hence, therapy should be similar to that for SCC, taking into consideration the age and general state of the usually elderly patient.

Cutaneous basosquamous cell carcinoma

BACKGROUND Basosquamous carcinoma (BSC) is a rare malignancy with specific histopathological features of both basal cell (BCC) and squamous cell carcinoma (SCC). Therefore, the histological diagnosis is challenging. Due to its low incidence there is no consensus on the surgical management of BSC. PATIENTS AND METHODS We describe the (immunohistological) diagnostic and therapeutic aspects of nine cases (8 male symbol : 1 female symbol, on average 68.6 years of age (range: 47-81)) of BSC. Of these, seven were located on the pinna, one on the forehead and zygomatic region and one in the retroauricular region. RESULTS Immunochemical staining for epithelial membrane antigen was negative (apart from the typical areas of epithelial pearl formation) and BerEP4 was positive in all cases. Therapy consisted of partial removal of the pinna in four, and total removal in three cases. One patient was treated by partial removal of the auricle with superficial parotidectomy and ipsilateral neck dissection. In the case of the carcinoma on the forehead, a local excision was performed. The median follow-up was 45 months. One patient had a local recurrence. CONCLUSIONS The histological diagnosis of BSC is confirmed by the use of EMA and BerEP4 immunohistological staining. Clinically, BSC is a rare, aggressive skin tumor. Despite the histological similarity to basal cell carcinoma, BSC has an imminent risk of metastasizing. Hence, therapy should be similar to that for SCC, taking into consideration the age and general state of the usually elderly patient.

Chirurgisches Management der persistierenden Speichelfistel nach Salvage-Laryngektomie

Erratum. Laryngo-Rhino-Otol 2013; 92: e1 Erratum N. Rothmeier, T. K. Hoff mann, G. K. Lehnerdt, S. Lang, S. Mattheis Laryngo-Rhino-Otol 2013; 92 (04): 236–243 DOI: 10.1055/s-0033-1333721 Chirurgisches Management der persistierenden Speichelfi stel nach Salvage-Laryngektomie In Heft 4/13 der Laryngo-Rhino-Otol wurde in der Originalarbeit Chirurgisches Management der persistierenden Speichelfi stel nach Salvage-Laryngektomie ein Mitautor falsch benannt. Korrekt muss die Autorenliste lauten: N. Rothmeier, T. K. Hoff mann, G. Lehnerdt, S. Lang, S. Mattheis Dieser Artikel ist ein Erratum zum Beitrag: „Chirurgisches Management der persistierenden Speichelfi stel nach SalvageLaryngektomiein“ der Laryngo-Rhino-Otol 2013; 92 (04): 236–243.

Diagnostic and prognostic biomarkers in head and neck squamous cell carcinoma

Classical prognostic factors for squamous cell carcinoma of the head and neck (HNSCC) are based on general parameters such as tumor stage or histological grading and only allow for a rough estimation of the clinical course. However, predicting individual responses to treatment remains challenging and diverging clinical courses of same-stage HNSCC stage remain obscure. The need for a better understanding of the individual genomic or proteomic signature of HNSCC resulted in a great number of publications on novel biomarkers. Still, in most cancer centres therapy planning and risk appraisal are solely based on the classical factors with only a few exceptions such as HPV status in oropharyngeal carcinoma. Future improvements in biomarker research will probably be achieved with sets of various genomic and proteomic markers as provided by microarray technology. This review highlights the criteria for a successful biomarker candidate, gives an overview on the most important new biomarkers, and introduces the principles of genomic and proteomic biomarker chips.