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Royal Oak, MI, United States

Baschnagel A.M.,University of Wisconsin - Madison | Wobb J.L.,William Beaumont Hospital | Dilworth J.T.,William Beaumont Hospital | Williams L.,William Beaumont Hospital | And 4 more authors.
Radiotherapy and Oncology | Year: 2015

Objectives To investigate the relationship between FDG-PET maximum standard uptake value (SUVmax), p16, EGFR, GLUT1 and HK2 expression in head and neck squamous cell carcinomas (HNSCC). Materials and methods Immunohistochemical staining of p16, EGFR, GLUT1 and HK2 was performed on primary tumor tissue from 97 locally advanced HNSCC patients treated with definitive chemoradiation. SUVmax along with p16, EGFR, GLUT1 and HK2 expression were analyzed for associations including local control, locoregional control and disease free survival. Results Pretreatment SUVmax in primary tumors did not differ when stratified by p16, EGFR or GLUT1 expression but SUVmax was significantly higher in HK2 expressing tumors (p = 0.021) and in tumors with higher T-stage (p = 0.022). GLUT1 expression was significantly higher in p16 negative (p < 0.001) and EGFR positive tumors (p < 0.01). HK2 expressing tumors were associated with EGFR positive tumors (p = 0.022) but not with p16 or GLUT1 expression. EGFR positive, p16 negative and high GLUT1 expressing tumors were associated with worse local control and disease free survival on univariate analyses. After adjusting for patient and treatment characteristics p16 status was the only factor that predicted for outcome on multivariate analysis. Conclusions High GLUT1 expression was associated with EGFR positive and p16 negative HNSCC tumors. GLUT1 maybe an important biomarker in HNSCC but its expression appears dependent on p16 status. © 2015 Elsevier Ireland Ltd. All rights reserved. Source

Swanson T.A.,University of Texas Medical Branch | Krueger S.A.,William Beaumont Hospital | Galoforo S.,William Beaumont Hospital | Thibodeau B.J.,Beaumont BioBank | And 3 more authors.
Prostate | Year: 2011

PURPOSE/OBJECTIVES The androgen regulated transmembrane serine protease (TMPRSS2) and ETS transcription factor (ERG) gene fusion is a strong prognostic factor for disease recurrence following prostatectomy. Expression of TMPRSS2/ETS-related gene (ERG) fusion gene transcripts is linked with tumor proliferation, invasion, and an aggressive phenotype. The aim of this study was to define the effect of TMPRSS2/ERG fusion gene expression on chemo- and radiosensitivity in prostate tumor cell lines. MATERIALS/METHODS Clonogenic survival of PC3 and DU145 cells stably expressing TMPRSS2/ERG Types III and VI fusion genes was measured after X-irradiation (0-8Gy) and Paclitaxel. Cell cycle changes and DNA double-strand break induction and repair were assessed. Differential gene expression was measured by microarray analysis. ERG signaling pathway interactions were studied using Ariadne Pathway Studio. RESULTS Expression of the TMPRSS2/ERG fusions in PC3 cells increased radiation sensitivity and decreased paclitaxel sensitivity. Increased radiosensitivity was associated with persistent DNA breaks 24hr post-irradiation, down-regulation of genes involved in DNA repair and mitosis and up-regulation of ETV, an ETS transcription factor. However, DU145 Types III and VI demonstrated a different sensitivity phenotype and gene expression changes. Pathway analysis of ERG signaling further illustrated the variation between the PC3 and DU145 cell lines containing TMPRSS2/ERG fusions. CONCLUSIONS The effect of TMPRSS2/ERG gene fusions had differing effects on radiosensitivity and chemosensitivity depending on cell line and fusion type. Further work is needed with clinical samples to establish whether TMPRSS2/ERG gene fusions affect radio- and chemosensitivity in vivo. © 2011 Wiley-Liss, Inc. Source

Nagar S.,3811 West 13 Mile Road | Ahmed S.,Beaumont BioBank | Peeples C.,3811 West 13 Mile Road | Urban N.,3811 West 13 Mile Road | And 6 more authors.
American Journal of Surgery | Year: 2014

Background Fine-needle aspiration (FNA) aids in the diagnosis of thyroid nodules. The expression of previously implicated genes was examined to potentially discriminate between benign and malignant thyroid samples. Methods Patients included for study had cytology demonstrating follicular cells of undetermined significance, atypical cells of undetermined significance, follicular neoplasm, or suspicion of malignancy with one of the following postoperative diagnoses: follicular thyroid adenomas, follicular thyroid carcinomas, or follicular variant of papillary thyroid carcinomas (FV-PTCs). FNA and tumor expression of human telomerase reverse transcriptase (hTERT), high-mobility group A2 (HMGA2), and trefoil factor 3/3-galactoside-binding lectin (T/G ratio) were analyzed. Results T/G ratios were not significantly different in the malignant and benign groups. HMGA2 was overexpressed in carcinoma states; however, only FV-PTCs were significant (P =.006). Tumor hTERT expression was detected in 25% of follicular thyroid carcinomas, whereas 5% of FV-PTCs and 10% of follicular thyroid adenomas had expression. FNA aspirates showed similar results. Conclusions Although HMGA2 and hTERT showed differential expression, they did not consistently differentiate benign from malignant. Further study based on global gene expression is needed to identify markers that could serve as a diagnostic tool. © 2014 Elsevier Inc. All rights reserved. Source

Baschnagel A.M.,William Beaumont Hospital | Williams L.,William Beaumont Hospital | Hanna A.,William Beaumont Hospital | Chen P.Y.,William Beaumont Hospital | And 4 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2014

Purpose To examine the prognostic significance of c-Met expression in relation to p16 and epidermal growth factor receptor (EGFR) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with definitive concurrent chemoradiation. Methods and Materials Archival tissue from 107 HNSCC patients treated with chemoradiation was retrieved, and a tissue microarray was assembled. Immunohistochemical staining of c-Met, p16, and EGFR was performed. c-Met expression was correlated with p16, EGFR, clinical characteristics, and clinical endpoints including locoregional control (LRC), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS). Results Fifty-one percent of patients were positive for p16, and 53% were positive for EGFR. Both p16-negative (P≤.001) and EGFR-positive (P=.019) status predicted for worse DFS. Ninety-three percent of patients stained positive for c-Met. Patients were divided into low (0, 1, or 2+ intensity) or high (3+ intensity) c-Met expression. On univariate analysis, high c-Met expression predicted for worse LRC (hazard ratio [HR] 2.27; 95% CI, 1.08-4.77; P=.031), DM (HR 4.41; 95% CI, 1.56-12.45; P=.005), DFS (HR 3.00; 95% CI, 1.68-5.38; P<.001), and OS (HR 4.35; 95% CI, 2.13-8.88; P<.001). On multivariate analysis, after adjustment for site, T stage, smoking history, and EGFR status, only high c-Met expression (P=.011) and negative p16 status (P=.003) predicted for worse DFS. High c-Met expression was predictive of worse DFS in both EGFR-positive (P=.032) and -negative (P=.008) patients. In the p16-negative patients, those with high c-Met expression had worse DFS (P=.036) than did those with low c-Met expression. c-Met expression was not associated with any outcome in the p16-positive patients. Conclusions c-Met is expressed in the majority of locally advanced HNSCC cases, and high c-Met expression predicts for worse clinical outcomes. High c-Met expression predicted for worse DFS in p16-negative patients but not in p16-positive patients. c-Met predicted for worse outcome regardless of EGFR status. © 2014 Elsevier Inc. Source

Baschnagel A.M.,University of Wisconsin - Madison | Galoforo S.,William Beaumont Hospital | Thibodeau B.J.,Beaumont BioBank | Ahmed S.,Beaumont BioBank | And 3 more authors.
Anticancer Research | Year: 2015

Aim: Mesenchymal-epithelial transition factor (MET), a receptor tyrosine kinase, is expressed in head and neck squamous cell carcinomas (HNSCC) and is involved in tumor progression and associated with poor prognosis. MET can be inhibited by crizotinib, a potent ATP-competitive kinase inhibitor. We examined the effects of combining crizotinib and radiation in a pre-clinical HNSCC model. Materials and Methods: Nine HNSCC cell lines were screened for MET expression, copy-number amplification and mutational status. The in vitro effects of crizotinib and radiation were assessed with clonogenic survival assays. MET signaling proteins were assessed with western blot and receptor tyrosine kinase array. Tumor growth-delay experiments with UT-SCC-14 and UTSCC-15 oral tongue xenografts were used to assess in vivo tumor radiosensitivity. Results: All nine HNSCC cell lines showed a varying degree of MET protein and RNA expression. Increased MET copy number was not present. MET was expressed after irradiation both in vitro and in vivo. Crizotinib alone inhibited phosphorylation of MET and inhibited cell growth in vitro but did not inhibit phosphorylation of downstream signaling proteins: MAPK, AKT or c-SRC. When combined with radiation in vitro, crizotinib demonstrated radiation enhancement in only one cell line. Crizotinib did not enhance the effect of radiation in either UT-SCC-14 or UTSCC-15 tumors grown as xenografts. Conclusion: MET is overexpressed in HNSCC cell lines, however, crizotinib failed to enhance the radiation response and failed to inhibit MET downstream signaling proteins in this HNSCC model. Source

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