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  • 1
    Keywords: EXPRESSION ; tumor ; carcinoma ; CELL ; Germany ; TYROSINE KINASE ; screening ; SITE ; SITES ; DISTINCT ; microarray ; PROTEIN ; TISSUE ; TUMORS ; primary ; GROWTH-FACTOR RECEPTOR ; FREQUENCY ; FREQUENCIES ; STAGE ; PROGRESSION ; immunohistochemistry ; ABERRATIONS ; HEAD ; ONCOPROTEIN ; CARCINOMAS ; NECK ; squamous cell carcinoma ; GREECE ; gene amplification ; head and neck ; laryngeal carcinoma ; OROPHARYNGEAL ; C-MYC ; CANCER PATIENTS ; CYCLIN D1 OVEREXPRESSION ; cytogenetic aberration ; head and neck squamous cell carcinoma (HNSCC) ; immunohistochemistry (IHC) ; MICROARRAY ANALYSIS ; oncoprotein overexpression ; OVEREXPRESSION ; POOR-PROGNOSIS ; tissue microarray (TMA) ; tumor classification
    Abstract: Background: Tissue microarray (TMA) analysis is a high-throughput approach that allows the screening of large tumor collectives for cytogenetic aberrations. In this study, a TMA of a large collection of clinically well-defined primary squamous cell carcinomas of the head and neck (HNSCC) was used to determine the expression of several oncoproteins. Materials and Methods: A TMA containing 547 primary HNSCC was used for the analysis of cyclinD1, c-myc, erbb1 and erbb2 expression by immunohistochemistry (IHC). Results: CyclinD1 and c-myc were overexpressed at higher frequencies in primary pharyngeal and laryngeal carcinomas compared with primary oral carcinomas (p 〈 0.001 and p 〈 0.001), while erbb1 and erbb2 overexpression was associated with oral site (p 〈 0.001 and p = 0.04, respectively). Furthermore, cyclinD1 overexpression correlated with stage IV primary carcinomas (p = 0.04). Conclusion: HNSCC is a heterogenous group of tumors, which, depending on anatomic sites and clinical stage, shows variable expressions of the oncoproteins described. This indicates a specific pathogenic role of these oncoproteins in different subtypes of HNSCC and may have therapeutic implications
    Type of Publication: Journal article published
    PubMed ID: 14666705
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  • 2
    Keywords: CANCER ; CELLS ; tumor ; carcinoma ; Germany ; THERAPY ; TUMORS ; PATIENT ; treatment ; 5-FLUOROURACIL ; ASSAY ; chemotherapy ; EPITHELIAL-CELLS ; HEAD ; NECK ; squamous cell carcinoma ; PREDICTION ; sensitivity ; head and neck carcinoma ; HNSCC ; INFUSION ; SOLID TUMORS ; COLONY FORMATION ; chemosensitivity testing ; head and neck squamous cell carcinoma ; SPECIMENS ; 5-FU ; drug combinations ; tumor stroma
    Abstract: Previous studies focusing on response prediction to chemotherapy by chemosensitivity testing of tumor explants has focused on the response determination of single cytostatic drugs, in contrast to the common clinical application of cytostatic drug combinations. Therefore, the present study was aimed at determining the quantitative ex vivo chemoreactivity of epithelial cells from head and neck squamous cell carcinoma (HNSCC) specimens to cytostatic drug combinations. Specimens from 12 histologically-confirmed HNSCC were investigated. According to a previously established ex vivo colony formation assay, the individual cellular chemoreactivity was determined quantitatively for combinations of 4 cytostatic drugs: cis-platinum (cis-DDP), carboplatin (CBDCA), 5-Fluorouracil (5-FU) and docetaxel (DTX). The tests were performed using drug combinations according to recent clinical therapy regimens in the treatment of solid tumors: i) cis-DDP + 5FU, ii) CBDCA + 5FU, iii) cis-DDP + DTX and iv) CBDCA + DTX The approach provides individual drug response patterns of epithelial as well as of stromal cells. Individual, selective sensitivities were found for each drug combination tested. The stromal and epithelial chemoreactivity profiles differed in most of the specimens. Moreover, stromal cell chemoresistance dominated selective epithelial chemosensitivities in the majority of cases. The determination of the epithelial ex vivo chemoreactivity identified individual chemosensitivities which were verified by the clinical history of the patient. Therefore, the described protocol to determine the ex vivo chemoresponse of HNSCC specimens to cytostatic drug combinations may help to provide clinicaly useful information concerning the individual chemoresponse of HNSCC with regard to individualization of oncological decision making
    Type of Publication: Journal article published
    PubMed ID: 16619587
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  • 3
    Keywords: carcinoma ; Germany ; VIVO ; SITE ; SITES ; PATIENT ; culture ; TRIAL ; LESIONS ; ASSAY ; chemotherapy ; HEAD ; NECK ; squamous cell carcinoma ; sensitivity ; CISPLATIN ; MULTICENTER ; PHASE-II ; CELL CARCINOMA ; GEMCITABINE ; ORGAN PRESERVATION ; ADVANCED LARYNGEAL-CANCER ; head and neck carcinoma ; HNSCC ; head and neck squamous cell carcinoma ; SPECIMENS ; predictive testing ; RECURRENT HEAD ; vinca alkaloids ; vinorelbine
    Abstract: Background: Vinorelbine has been identified as an effective cytostatic drug in head and neck squamous cell carcinoma (HNSCC). To predict the individual chemo-response, the application of an ex vivo assay to quantify the response of HNSCC to vinorelbine is presented. Patients and Methods: Twelve biopsies from primary HNSCC sites and five biopsies from metastatic lesions were analyzed (n=17). The specimens were investigated ex vivo for the overall, epithelial and stromal chemoresponse to vinorelbine. Results: By selective evaluation of the epithelial chemoresponse, the applied assay identified three specimens as vinorelbine-sensitive (18%), including one de novo sensitivity in a metastatic lesion of a vinorelbine-resistant hypopharyngeal carcinoma. Conclusion: Applying flavin protecting culture methods and with careful correction for the stromal cell effect, the assay generated reliable data for the assessment of the individual chemoresponse of HNSCC specimens to vinorelbine. The assay may, therefore, facilitate the implementation of individualized chemotherapy protocols
    Type of Publication: Journal article published
    PubMed ID: 16821617
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  • 4
    Keywords: ANGIOGENESIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; INHIBITOR ; INVASION ; tumor ; BLOOD ; CELL ; Germany ; IN-VIVO ; INHIBITION ; MODEL ; THERAPY ; VIVO ; imaging ; TISSUE ; SKIN ; fibroblasts ; PROGRESSION ; REQUIRES ; skin cancer ; EXTRACELLULAR-MATRIX ; INHIBITORS ; CYTOKINE ; ONCOLOGY ; fibroblast ; MATRIX METALLOPROTEINASES ; STROMAL CELLS ; matrix metalloproteinase ; MATRIX-METALLOPROTEINASE INHIBITORS ; EPITHELIAL TUMOR PHENOTYPE ; MMP inhibition
    Abstract: Tumor invasion requires intense interactions with stromal cells and a profound extracellular matrix remodelling by matrix metalloproteinases (MMPs). Here, we assessed the specific contribution of fibroblasts to tumor invasion, MMPs, tissue inhibitors of MMPs and angiogenesis-related cytokine expression in organotypic cultures of highly malignant HaCaT-ras A-5RT3 cells, with and without MMP inhibition. Collagen degradation, the hallmark of tumor invasion, was dependent on fibroblasts and active MMP-2. Additionally, MMP blockade down-regulated VEGF-A and up-regulated PDGF-BB. These results were paralleled in xenotransplants in vivo, demonstrating strong inhibitory effects of MMP blockade on tumor invasion and vascularization, as shown by the almost complete absence of VEGF-A and MMP-14 and by the decrease in relative blood volume. MMP blockade also increased the fraction of mature vessels, as demonstrated by an increased mean tumor vessel diameter and a higher ratio of Ng2-positive vessels. Thus, this study highlights the importance of targeting the tumor stroma to defeat cancer
    Type of Publication: Journal article published
    PubMed ID: 20392987
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  • 5
    Abstract: AIM: The effect of combining sodium butyrate (NaB), a histone deacetylase inhibitor, and 7-hydroxy-staurosporine (UCN-01) on cytotoxicity in human cervical carcinoma cells was evaluated. MATERIALS AND METHODS: HeLa and CaSki cells were treated using NaB alone or in combination with staurosporine (STS) or its analog UCN-01. Cytotoxicity was determined by flow cytometry and morphological assays. Apoptotic pathways were characterized by Western blotting and immunostaining. CaSki cells were also xenografted into nude mice to assess the in vivo effects of NaB/UCN-01 combination. RESULTS: Treatment with NaB and STS or UCN-01 resulted in enhanced apoptosis of cancer cells. Apoptosis involved mitochondrial pathways and overexpression of p53 and p73. In concordance, co-treatment modulated some p53/p73 downstream targets such as p21, BAX, BCL-2 and BCL-X(L), leading to increased caspase-3 and poly(ADP-ribose) polymerase cleavage. In vivo, NaB/UCN-01 combination exerted a substantial tumour growth suppression effect compared with single treatment. CONCLUSION: UCN-01 was shown to be a potentiator of NaB therapy for cervical cancer cells.
    Type of Publication: Journal article published
    PubMed ID: 21036719
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  • 6
    Keywords: APOPTOSIS ; CANCER ; GROWTH ; KINASE ; MODELS ; PATHWAY ; DISEASE ; GENE ; LINES ; CYCLE ; ASSAY ; HEAD ; CELL CARCINOMA ; pharmacogenomics ; macrophage ; CYTOTOXIC ACTIVITY ; natural product ; head and neck squamous cell carcinoma HNSCC ; oral cavity squamous cell carcinoma OCSCC ; APIACEAE ; Levisticum officinale lovage ; POLYACETYLENES
    Abstract: Background: Oral squamous cell carcinoma (OSCC) is a challenging disease with a high mortality rate. Natural products represent a valuable source for the development of novel anticancer drugs. We investigated the cytotoxic potential of essential oil from the leaves of a medicinal plant, Levisticum officinale (lovage) on head and neck squamous carcinoma cells (HNSCC). Materials and Methods: Cytotoxicity of lovage essential oil was investigated on the HNSCC cell line, UMSCC1. Additionally, we performed pharmacogenomics analyses. Results: Lovage essential oil extract had an IC50 value of 292.6 mu g/ml. Genes involved in apoptosis, cancer, cellular growth and cell cycle regulation were the most prominently affected in microarray analyses. The three pathways to be most significantly regulated were extracellular signal-regulated kinase 5 (ERK5) signaling, integrin-linked kinase (ILK) signaling, virus entry via endocytic pathways and p53 signaling. Conclusion: Levisticum officinale essential oil inhibits human HNSCC cell growth
    Type of Publication: Journal article published
    PubMed ID: 21273597
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  • 7
    Keywords: CANCER ; GROWTH ; IN-VITRO ; KINASE ; PATHWAY ; TOXICITY ; DEATH ; GENE ; COMPONENTS ; LINES ; CYCLE ; ASSAY ; HEAD ; CELL CARCINOMA ; pharmacogenomics ; natural product ; ESSENTIAL PLANT OILS ; head and neck squamous cell carcinoma HNSCC ; oral cavity squamous cell carcinoma OCSCC ; Thymus vulgaris L.(thyme)
    Abstract: Background: Oral cavity squamous cell carcinoma (OCSCC) accounts for 2% to 3% of all malignancies and has a high mortality rate. The majority of anticancer drugs are of natural origin. However, it is unknown whether the medicinal plant Thymus vulgaris L. (thyme) is cytotoxic towards head and neck squamous cell carcinoma (HNSCC). Materials and Methods: Cytotoxicity of thyme essential oil was investigated on the HNSCC cell line, UMSCC1. The IC50 of thyme essential oil extract was 369 mu g/ml. Moreover, we performed pharmacogenomics analyses. Results: Genes involved in the cell cycle, cell death and cancer were involved in the cytotoxic activity of thyme essential oil at the transcriptional level. The three most significantly regulated pathways by thyme essential oil were interferon signaling, N-glycan biosynthesis and extracellular signal-regulated kinase 5 (ERK5) signaling. Conclusion: Thyme essential oil inhibits human HNSCC cell growth. Based on pharmacogenomic approaches, novel insights into the molecular mode of anticancer activity of thyme are presented
    Type of Publication: Journal article published
    PubMed ID: 21273584
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  • 8
  • 9
    Keywords: MONOCLONAL-ANTIBODY ; HER2 ; LAPATINIB PLUS CAPECITABINE ; ANTIBODY-DRUG CONJUGATE ; TRASTUZUMAB EMTANSINE
    Abstract: AIM: To compare results of trastuzumab-emtansine (T-DM1) treatment in our clinical practice with data from phase III clinical trials. PATIENTS AND METHODS: A retrospective chart review of all 23 patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who were started on T-DM1 until April 2014 was performed. RESULTS: Four patients (17.4%) received T-DM1 as first-line, three (13.0%) as second-line, six (26.0%) as third-line, and 10 (43.5%) as fifth- or further-line therapy. Overall, the response rate (ORR) was 26.0%, disease control rate 78.3% and median progression-free survival (PFS) 8.4 months. The only toxicities of grade 3 or more were fatigue (21.7%), thrombocytopenia (4.3%) and elevation of liver enzymes (8.7%). ORR and PFS were similar to the TH3RESA and EMILIA trials. Compared to the EMILIA study, we recorded higher rates of newly-diagnosed cerebral metastasis and cerebral progression in patients with stable peripheral metastases. CONCLUSION: T-DM1 is effective and well-tolerated even in intensively pre-treated patients.
    Type of Publication: Journal article published
    PubMed ID: 26254411
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  • 10
    Abstract: BACKGROUND: Tumor necrosis factor (TNF) receptor family members play a key role in the regulation of biological functions such as differentiation, proliferation and apoptosis of various cell types. MATERIALS AND METHODS: We studied co-expression profiles of death receptors from the TNF family [TNF-related apoptosis-inducing ligand receptor (TRAILR) 1 to 3, TNF receptor 1 (TNFR1) and FAS receptor (FAS)] on peripheral blood blasts from 46 patients with acute myeloid leukemia (AML) at first diagnosis by flow cytometry and correlated the obtained specific fluorescence indices (SFI) with morphological, cytogenetic and clinical parameters. RESULTS: We found that the expression of TRAILR2 and R3 was significantly increased in unfavorable risk groups, according to the National Comprehensive Cancer Network. Additionally, cut-off analyses for TRAILR2 and TNFR1 showed significantly shorter overall survival, earlier disease onset, higher proportions of cases with unfavorable prognosis and higher probability of relapse when SFIs were above the established cut-off. CONCLUSION: We demonstrate that high co-expression of death receptors on blasts is an independent predictor of poor prognosis in AML.
    Type of Publication: Journal article published
    PubMed ID: 26124353
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