New diagnostic markers in salivary gland tumors.

Parotid gland tumors are a rare and heterogeneous entity. Molecular markers are sparse. The aim of the study was to identify new diagnostic markers in benign and malignant salivary tumors. A tissue microarray was constructed with 158 tumor samples. Expression of 21 tumor antigens involved in tumor cell survival and known for prognostic potential was assessed immunohistochemically in all parotid gland samples. CEA, Cox-1, Cox-2, Sigma, beta-Catenin, WISP-1 and PDGF-beta were differently regulated in benign and malignant parotid tumors. Subsequently, these seven proteins entered the step-wise logistic regression analysis. As a second step, we defined a score for differentiating benign versus malignant parotid lesions: 4*CEA+15*Cox-1+4*Cox-2+4*Sigma+3*PDGF-beta+10*beta-Catenin+14*Wisp1. Sensitivity and specificity of 94 and 83% were reached. Besides routine hematoxylin and eosin staining, definition of new diagnostic markers and subsequently a new diagnostic score are an attempt to create an additional tool for the diagnosis of parotid gland tumors.

The clinical perspective on late-onset depression in European real-world treatment settings.

The clinical phenotype of the so-called late-onset depression (LOD) affecting up to 30% of older adults and yielding heterogeneous manifestations concerning symptoms, severity and course has not been fully elucidated yet. This European, cross-sectional, non-interventional, naturalistic multicenter study systematically investigated socio-demographic and clinical correlates of early-onset depression (EOD) and LOD (age of onset ≥ 50 years) in 1410 adult in- and outpatients of both sexes receiving adequate psychopharmacotherapy. In a total of 1329 patients (94.3%) with known age of disease onset, LOD was identified in 23.2% and was associated with unemployment, an ongoing relationship, single major depressive episodes, lower current suicidal risk and higher occurrence of comorbid hypertension. In contrast, EOD was related to higher rates of comorbid migraine and additional psychotherapy. Although the applied study design does not allow to draw any causal conclusions, the present results reflect broad clinical settings and emphasize easily obtainable features which might be characteristic for EOD and LOD. A thoughtful consideration of age of onset might, hence, contribute to optimized diagnostic and therapeutic processes in terms of the globally intended precision medicine, ideally enabling early and adequate treatment allocations and implementation of respective prevention programs.

Expression of the tetraspanins CD9, CD37, CD63, and CD151 in Merkel cell carcinoma: strong evidence for a posttranscriptional fine-tuning of CD9 gene expression.

Tetraspanins including CD9, CD37, CD63, and CD151 are linked to cellular adhesion, cell differentiation, migration, carcinogenesis, and tumor progression. The aim of the study was to detect, quantify, and evaluate the prognostic value of these tetraspanins in Merkel cell carcinoma and to study the regulation of CD9 mRNA expression in Merkel cell carcinoma cell lines in detail. Immunohistochemical staining of 28 Merkel cell carcinoma specimens from 25 patients showed a significant correlation of CD9 (P=0.03) and CD151 (P=0.043) expression to overall survival. CD9 and CD63 expression correlated significantly to patients' disease-free interval (P=0.017 and P=0.058). Of primary Merkel cell carcinoma tumors, 42% were CD9 positive in contrast to only 21% of the subcutaneous in-transit metastases. Characterization of the 5' untranslated region (UTR) of the CD9 mRNA from two cultured Merkel cell carcinoma cell lines revealed the presence of two major RNA species differing only in the length of their 5' termini (183 versus 102 nucleotides). In silico analysis of the long CD9 mRNA predicted a 5' UTR folding pattern blocking ribosomal scanning and translation. Quantitative data by real-time RT-PCR not only indicated a reduction of CD9 mRNA but also a distinct quantitative shift toward the long 5' UTR in CD9 receptor negative cells. These observations provide an example for a posttranscriptional fine-tuning of CD9 gene expression in tumor cells.

Down-regulation of Mcl-1 with antisense technology alters the effect of various cytotoxic agents used in treatment of squamous cell carcinoma of the head and neck.

Antisense oligonucleotides have recently been identified as new anticancer agents. Since human head and neck cancer cells highly express the antiapoptotic protein myeloid cell leukemia-1 (Mcl-1), the aim of this study was to explore the efficacy of the Mcl-1 suppression in combination with various cytotoxic agents in the head and neck cancer cell line SCC9. After oligonucleotide transfection and/or treatment with cisplatin, 5-fluorouracil (5-FU), gemcitabine, paclitaxel or cetuximab, proliferation assays were performed to determine cell viability. The expression patterns of Mcl-1, Bax and Bak were assessed by Western blot analysis and the apoptotic cells were determined by immunohistochemistry using the M30 antibody. A combined Mcl-1 antisense oligonucleotide treatment with paclitaxel, cetuximab and gemcitabine led to a significant reduction in the viable cells. However, the combination with cisplatin and 5-FU showed only moderate synergistic cytotoxic effects. According to the cytotoxic data, distinct apoptosis rates were observed after the combined treatment with the different substances. Western blot analysis also showed a significant suppression of the Mcl-1 synthesis. Our data show that the Mcl-1 antisense oligonucleotide in combination with certain cytotoxic agents has the potential to significantly decrease cell viability in vitro.

Expression of the Sonic hedgehog pathway in squamous cell carcinoma of the skin and the mucosa of the head and neck.

BACKGROUND: Activation of the hedgehog pathway may contribute to carcinogenesis. This study characterizes the expression pattern in squamous cell carcinoma of the skin and the head and neck. METHODS: Tissue microarrays were constructed with samples of squamous cell carcinoma of the skin and the head and neck. All tissue samples were immunohistochemically stained for 7 Hedgehog pathway molecules. RESULTS: Significant (p < .0001) overexpression of all evaluated molecules could be observed in the tumor samples compared with healthy control tissues. Expression of Gli-2 showed significant upregulation and that of Smoothened and Patched significant downregulation in head and neck compared with skin carcinoma. High expression of Sonic hedgehog correlates significantly (p = .001) with poor overall survival in patients with head and neck cancer. CONCLUSIONS: Hedgehog signaling is differentially regulated in squamous cell carcinomas of the skin and the head and neck. Sonic hedgehog expression may serve as a prognostic factor in patients with head and neck cancer.