Claus Wittekindt

Parotidectomy for benign parotid disease at a university teaching hospital: outcome of 963 operations.

Objective/Hypothesis: The objective of this study was to analyze the perioperative and long‐term complications after standardized lateral and total parotidectomy for benign parotid tumors and chronic parotitis with special regard on the training skill of the surgeons at a university teaching center. All teaching operations were performed under strict microscopic control and supervision of experienced surgeons.

Recurrent pleomorphic adenoma of the parotid gland: Analysis of 108 consecutive patients

Surgery for recurrent parotid pleomorphic adenoma is a challenging problem.

COMPLICATIONS OF SUSPENSION LARYNGOSCOPY

Although suspension laryngoscopy (SL) is routinely used in operative laryngology, no prospectively gathered data on the complications of this procedure have so far been available. We prospectively analyzed 339 consecutive procedures for ***intervention-related complications. The survey included preoperative dental status and assessment of postoperative dental, mucosal, and nerve injuries. Minor mucosal lesions were found in 75% of all patients. All healed spontaneously within a few days. Dental injuries occurred in 6.5% of all patients. These were more frequent in therapeutic laryngoscopy than in diagnostic procedures (6.8% versus 6.0%). Highly significant correlations were found between dental injury rate and preoperative dental disease (p < .04) and grade of periodontitis (p < .001). Temporary nerve lesions were observed in 13 patients (9 of the lingual nerve and 4 of the hypoglossal nerve). Although minor complications frequently occur during SL, it is a relatively safe procedure with a low risk of significant morbidity.

Expression of p16 protein is associated with human papillomavirus status in tonsillar carcinomas and has implications on survival.

Our recent analysis of papillomavirus (HPV) DNA in different malignant head and neck tumors revealed that HPV infections occurred most frequently in tonsillar carcinomas (58%) and that 84% of positive cases contained the highly oncogenic HPV type 16. We could also present data in favor of the hypothesis that in view of their clinical behavior and the involved risk factors HPV-positive and HPV-negative tonsillar carcinomas may represent two separate tumor entities. Looking for a surrogate marker, which in further epidemiological studies could replace the laborious and expensive HPV detection/typing we analyzed p16 protein expression in 34 tonsillar carcinomas for their correlation with HPV status. p16 is an inhibitor of cyclin-dependent kinases 4 and 6 which activate the negative cell cycle regulator protein pRB which in turn downregulates p16 expression. It could be shown that in neoplastic cells of the cervix uteri E7 protein of the high-risk HPVs can interfere with this regulatory circuit by its virtue to inactivate pRB and thus lead to the overexpession of p16. We found 53% of the tested tonsillar carcinomas to be HPV positive. 56% of all tumors tested were immunohistochemically positive for the p16 protein. In 16 of 18 of the HPV-positive carcinomas diffuse p16 expression was observed. In contrast, only 1 of the HPV-negative carcinomas showed focal p16 staining (p < 0.001). Clinical outcome analysis revealed a significant correlation of p16 expression with increased disease-free survival (p = 0.02). These data indicate that p16 is a technically simple immunohistological marker, applicable for routine pathological histology, and its prognostic value for survival is fully equivalent to HPV DNA detection.

Textured polydimethylsiloxane elastomers in the human larynx : Safety and efficiency of use

For the treatment of unilateral laryngeal paralysis with glottic insufficiency injection laryngoplasty is a popular modality of treatment. This procedure augments the volume of the paralyzed vocal fold by endoscopic injection. However, the ideal substance has not yet been found for that purpose. We report for the first time the systematic application and long-term results of vulcanized polydimethylsiloxane (PDMS) particles in the treatment of glottic insufficiency in the human larynx. Of 10 patients treated with PDMS in the early 1990s, 7 patients could be retrieved for reevaluation. Laryngeal function was assessed by videostroboscopy, expert rating, and further characterized by the objective parameters of voice profile and maximum phonation time. In a standardized questionnaire, all patients were asked for their personal impression of the results. Mean follow-up time was 88.4 months (range 69-102 months). Glottic closure was complete in 5 of 7 patients. There were no signs of granuloma formation or other pathologic changes of the injected vocal folds. In 4 cases, voices were rated normal or near-normal; 2 voices were rated as fair; 1 usable. All the patients reported significant and lasting voice improvement. None of the patients reported any problems related to PDMS. PDMS particles provide permanent augmentation of human vocal fold volume without complications. Their use is a valuable and safe alternative when a definitive one-step procedure seems advantageous. However, further studies are needed to assess voice improvement in comparison to other materials.

Immunohistochemical expression of VEGF and VEGF receptors in nasal polyps as compared to normal turbinate mucosa

Abstract. The factors involved in the development of chronic inflammation and edema in nasal polyps remain to be clarified. The expression of vascular endothelial growth factor (VEGF) has been described in plasma cells, suggesting that plasma cells may play a major role in the development of edema in nasal polyps through the production of VEGF. We performed immunohistochemical analysis using specific antibodies to VEGF and to the known VEGF receptors, VEGFR-1 and VEGFR-2, on paraffin sections of human nasal polyps (n=11) and controls of human mucosa of the normal middle turbinates (n=6). In normal turbinate mucosa, sporadic immunostaining for VEGF was observed throughout the endothelial cells of the small veins and arteries. VEGFR-1 and VEGFR-2 expression was faint in the healthy turbinates. In nasal polyp tissues, strong immunostaining for VEGF was found in the endothelium of blood vessels and in the infiltrating perivascular inflammatory cells. Fibroblasts also stained for VEGF. Strong immunolabeling to VEGFR-1 was evident in the vascular endothelium, whereas weak to moderate VEGFR-1-staining was generally confined to scattered mononuclear round cells. Mononuclear round cells and the endothelium of capillaries revealed immunoreactivity to VEGFR-2. These findings support a role for VEGF and its receptors, VEGFR-1 and VEGFR-2, in the development and perpetuation of edema and angiogenesis in nasal polyps.

High risk for bilateral Warthin tumor in heavy smokers – review of 185 cases

Conclusions. We identified smoking as a significant risk factor for multilocular Warthin tumor development. Therefore, we recommend taking history of smoking into account when making the decisions for surgical strategy. Objectives. Warthin tumor is a common benign neoplasm of the parotid gland. Risk factors for multilocular development have not been defined. Patients and methods. A total of 185 consecutive patients treated for Warthin tumor were included. Charts were reviewed for symptoms, risk factors, and diagnostic and surgical procedures. Patients were followed for facial function and recurrence. Risk factors were evaluated. Results. Overall, in 203 parotid operations, a lateral parotidectomy (77%) was performed in most cases; 94% were primary surgery and 6% were revision surgery. In 89% of patients swelling was the only symptom. Bilateral Warthin tumor was seen in 17% of patients. Of these cases synchronous and metachronous bilateral tumors were observed in 61% and 39%, respectively. The median time period for second contralateral tumor development was 7 years. Postoperative transient facial dysfunction was observed in 31%, which recovered within 3 months in all cases. Evaluation of risk factors revealed that 89% of the subjects were smokers and 66% were heavy smokers. The risk for bilateral Warthin tumors correlated significantly with the amount of nicotine intake (p=0.003).

Permeabilität der runden Fenstermembran für Prednisolon-21-Hydrogensuccinat Prednisolongehalt der Perilymphe nach lokaler Applikation vs. systemischer Injektion

ZusammenfassungHintergrund und Fragestellung. Zur Behandlung vestibulokochleärer Störungen gehört systemisch appliziertes Prednisolon zur Therapie der Wahl. Die in den Labyrinthflüssigkeiten zu erreichenden Konzentrationen sind wegen unerwünschter Nebenwirkungen limitiert. Eine direkte Applikation im Bereich der runden Fenstermembran könnte höhere therapeutische Wirkspiegel im Erfolgsorgan erzielen. Ziel der Studie war daher die Bestimmung der Permeabilität der runden Fenstermembran beim Meerschweinchen nach lokal appliziertem Prednisolon. Methodik. Die Applikation von Prednisolon-21-Hydrogensuccinat (5 mg in 0,1 ml) erfolgte unmittelbar in die runde Fensternische auf die Fenstermembran. Als Vergleich dienten Perilymphproben nach intraperitonealer Applikation von 60 mg/kg KG Prednisolon-21-Hydrogensuccinat. Perilymphproben wurden jeweils nach 15, 20, 80, 180, 330 und 960 min (n=60) nach Präparation der Kochlea und Eröffnung der Apex cochleae entnommen. Der Prednisolonspiegel in den Perilymphproben wurde durch eine isokratische Hochdruckflüssigkeitschromatographie (HPLC) quantitativ bestimmt. Ergebnisse. Die höchste Prednisolonkonzentration mit 952,3 (±382,7) mg/l fand sich 180 min nach lokaler Applikation. Nach 960 min betrug die Konzentration 18,7 (±16,9) mg/l. Nach systemischer Applikation wurden Konzentrationen von maximal 14,7 (±7,1) mg/l gemessen. Schlussfolgerung. Durch eine einmalige, lokale Applikation werden hohe Konzentrationen von Prednisolon in kochleärer Perilymphe erzielt. Messbare Prednisolonkonzentrationen fanden sich bis zu 16 h nach einmaliger Applikation.AbstractBackground and objective. Prednisolone is the drug of first choice for the treatment of cochleovestibular disorders, such as sudden hearing loss. Because of the known side effects, the efficient drug levels to be achieved within inner ear fluids are limited by intravenous administration. The aim of the study was to determine the concentration in the perilymph of prednisolone-21-hydrogen succinate applied into the round window niche in comparison to the concentration after intraperitoneal application. Methods. Application of prednisolone-21-hydrogen succinate (5 mg in 0.1 ml) on the round window membrane was performed after sedation under microscopic view directly into the round window niche of the guinea pig. In order to compare the results, perilymph samples after systemic application of 60 mg/kg body weight prednisolone were used. The time between application and taking specimens of perilymph from the cochlea varied. Specimens of perilymph were obtained after 15, 20, 80, 180, 330, and 960 min (10 specimens in each group, n=60) by dissecting the cochlea and opening the apex cochleae. Levels of prednisolone-21-hydrogen succinate in perilymph were measured by isocratic high-pressure liquid chromatography (HPLC). Results. The highest levels of prednisolone-21-hydrogen succinate were found after 180 min: 952.3 mg/l (95% confidence interval: 382.7). After 960 min the level was 18.72 mg/l (95% confidence interval: 16.9). In the group with systemic application, the levels measured were below 14.71 mg/l (95% confidence interval: 7.05). Conclusion. The results demonstrate that high levels of prednisolone-21-hydrogen succinate in perilymph are achievable by local application of a single dose into the round window niche. After application of 5 mg, the levels of prednisolone are measurable up to 16 h.

Basics of tumor development and importance of human papilloma virus (HPV) for head and neck cancer.

Head and Neck Squamous Cell Carcinomas (HNSCC) are the 6th most common cancers worldwide. While incidence rates for cancer of the hypopharynx and larynx are decreasing, a significant increase in cancer of the oropharynx (OSCC) is observed. Classical risk factors for HNSCC are smoking and alcohol. It has been shown for 25 to 60% of OSCC to be associated with an infection by oncogenic human papilloma viruses (HPV). The development of “common” cancer of the head and neck is substantially enhanced by an accumulation of genetic changes, which lead to an inactivation of tumor suppressor genes or activation of proto-oncogenes. A more or less uniform sequence of different DNA-damages leads to genetic instability. In this context, an early and frequent event is deletion on the short arm of chromosome 9, which results in inactivation of the p16-gene. In contrast, for HPV-induced carcinogenesis, expression of the viral proteins E6 and E7 is most important, since they lead to inactivation of the cellular tumor-suppressor-proteins p53 and Rb. The natural route of transoral infection is a matter of debate; peroral HPV-infections might be frequent and disappear uneventfully in most cases. Smoking seems to increase the probability for developing an HPV-associated OSCC. The association of HNSCC with HPV can be proven with established methods in clinical diagnostics. In addition to classical prognostic factors, diagnosis of HPV-association may become important for selection of future therapies. Prognostic relevance of HPV probably surmounts many known risk-factors, for example regional metastasis. Until now, no other molecular markers are established in clinical routine. Future therapy concepts may vary for the two subgroups of patients, particularly patients with HPV-associated OSCC may take advantage of less aggressive treatments. Finally, an outlook will be given on possible targeted therapies.

Nuclear survivin expression is associated with HPV-independent carcinogenesis and is an indicator of poor prognosis in oropharyngeal cancer

The relationship between expression of the inhibitor of apoptosis protein survivin and the presence of high-risk human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC) remains unclear. This also accounts for its role as a predictor of survival. Therefore, we conducted a multicentre retrospective study on 106 consecutive oropharyngeal cancer patients. Human papillomavirus sequences were detected by nested PCR protocols. Survivin and p16 expression as a surrogate marker for HPV status were analysed by immunohistochemistry. Sequences of high-risk HPV were detected in 29% of cases. Prominent cytoplasmatic expression of survivin was found in 58% of cases and nuclear expression of survivin was found in 19% of the survivin-positive tumours. Nuclear expression of survivin was significantly correlated with HPV-negative tumours (P=0.023) and with a poor disease-free survival rate with an estimated 3-year disease-free survival probability of 35% for tumours with nuclear expression of survivin vs 78% for tumours with non-nuclear expression of survivin (hazard ratio=8.264; 95% confidence interval (95% CI)=2.510–27.210; P<0.001). In multivariate analysis, p16 expression status as well as nuclear expression of survivin were strong independent and opposing prognostic indicators of disease-free survival (hazard ratio=0.068; 95% CI=0.005–0.892; P=0.041 and hazard ratio=15.975; 95% CI=2.377–107.360; P=0.004, respectively). Our data show that nuclear accumulation of survivin correlates with HPV-independent carcinogenesis and is an independent predictor of poor survival in patients with OSCC.