Purpose: The epidermal growth factor receptor (EGFR) inhibitor gefitinib (Iressa) has shown antitumor activity in clinical trials against cancers, such as non^small cell lung cancer and head and neck squamous cell carcinoma (HNSCC). Research on non^small cell lung cancer has elucidated factors that may predict response to gefitinib. Less is known about molecular markers that may predict response to gefitinib in HNSCC patients. Experimental Design: We analyzed possible associations of responsiveness to gefitinib with molecular markers of the EGFR/ErbB receptor family signaling pathway using 10 established HNSCC lines in vitro. IC 50 of gefitinib sensitivity was determined using clonogenic survival assays. ErbB signaling was assessed byWestern and real-time reverse transcription-PCR analyses of EGFR, ErbB2, ErbB3, and ErbB4 expression levels as well as by phosphorylation analysis of pEGFR, pErbB2, pErbB3, pAkt, and pErk. EGFR sequences encoding kinase domain and EGFR gene copy numbers were determined by cDNA sequencing and real-time PCR, respectively. Finally, responsiveness to gefitinib was compared with responsiveness to the anti-EGFR antibody cetuximab (Erbitux). Results: Expression levels of pErbB2 (P = 0.02) and total ErbB3 protein (P = 0.02) associated with resistance to gefitinib. Combining gefitinib with pertuzumab (Omnitarg), an antibody targeting ErbB2 heterodimerization, provided additional growth-inhibitory effect over gefitinib alone on relatively gefitinib-resistant HNSCC cell lines. The same markers did not predict resistance to cetuximab. In contrast, a similar trend suggesting association between EGFR gene copy number and drug sensitivity was observed for both gefitinib (P = 0.0498) and cetuximab (P = 0.053). No activating EGFR mutations were identified. Conclusions: EGFR amplification may predict sensitivity to gefitinib in HNSCC. However, other EGFR/ErbB receptor family members than EGFR may contribute to resistance to gefitinib. ErbB2 and ErbB3 may have potential as predictive markers and as therapeutic targets for combination therapy in treatment of HNSCC with gefitinib.

No abstract

The cell adhesion molecule syndecan-1 expression is induced during keratinocyte differentiation and reduced during the formation of squamous cell carcinomas (SCCs). A significant correlation between decreased syndecan-1 expression in head and neck SCC measured from frozen sections with immuohistochemical methods and clinical outcome are reported. The clinical relevance of the cellular proliferation marker Ki-67 is controversial in SCC of the head and neck. The purpose of this study was to determine the expression of syndecan-1 and Ki-67 in SCC of the larynx and correlate the results with known prognostic factors and clinical outcome. Paraffin-embedded samples of 100 patients with laryngeal SCC (44 glottic, 36 supraglottic, 20 transglottic) treated at Turku University Central Hospital were re-examined and divided into four histological grades of differentiation, four grades of keratinisation, and four grades of 104-9 (syndecan-1) immunostaining. The mitotic index was analysed as the number of mitoses per volume corrected high power fields. The relative number of Ki-67 positive cells was evaluated. The patients mean age was 64 years and the 5-year survival was 69%. In univariate analysis, intermediate or strong staining for syndecan-1 was associated with higher overall survival than those tumours with no or little syndecan-1 expression (p = 0.048). Nodal status (p = 0.0001), tumour size (p = 0.0004) and localisation (p = 0.0008), general condition (p = 0.0001), histological grade (p = 0.02) and patient age (p = 0.03) correlated with overall survival whereas the Ki-67 index (p = 0.093), mitotic index (p = 0.23) and grade of keratinisation (p = 0.90) failed to do so. The results suggest that syndecan-1 could be a useful prognostic factor in SCC of the larynx.

Dysphagia is a common symptom in various neurological disorders affecting pharyngeal functions. Cricopharyngeal dysfunction is one of the major findings in these patients. The most effective treatment for restoring normal swallowing function in persistent cricopharyngeal dysfunction is cricopharyngeal myotomy, especially when mechanical obstruction or a well-localized neuromuscular dysfunction, such as a cricopharyngeal muscle spasm, is present. However, when there is a more diffuse neurological disorder present the results of surgery are more disappointing. In unclear cases, or in patients with temporary problems, no good method other than swallowing training, bougienage, and tube feeding are available. During the past decade, botulinum toxin has been found to be of therapeutic value in the treatment of a variety of neurological disorders associated with inappropriate muscular contractions such as torticollis and spasmodic dysphonia. Recently, injections of botulinum toxin in patients with cricopharyngeal muscle dysfunction have been reported to result in marked relief of dysphagia. In this article we describe our experiences with botulinum toxin injections to treat four patients suffering from deglutition problems and cricopharyngeal dysphagia of different origins. Botulinum toxin was injected into the cricopharyngeus muscle that was identified by endoscopy under general anesthesia. In this study, no major side effects were observed. Three patients obtained a significant improvement of esophageal symptoms after the first injection. The treatment had limited effect in one patient who had reflux disease and only slight cricopharyngeus dysfunction.

Bioactive glass S53P4 is a noteworthy material in mastoid obliteration surgery.