Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
May-2014 Volume 31 Issue 5

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
May-2014 Volume 31 Issue 5

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Ki-67 as an independent prognostic factor in an unselected cohort of patients with ovarian cancer: Results of an explorative, retrospective study

  • Authors:
    • Marco Johannes Battista
    • Nina Mantai
    • Isabel Sicking
    • Cristina Cotarelo
    • Veronika Weyer
    • Antje Lebrecht
    • Christine Solbach
    • Marcus Schmidt
  • View Affiliations / Copyright

    Affiliations: Department of Gynaecology and Obstetrics, University Medical Centre Mainz, D-55131 Mainz, Germany, Department of Pathology, University Medical Centre Mainz, D-55131 Mainz, Germany, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Centre Mainz, D-55131 Mainz, Germany
  • Pages: 2213-2219
    |
    Published online on: March 11, 2014
       https://doi.org/10.3892/or.2014.3079
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

The identification of prognostic markers has clinical implications in epithelial ovarian carcinoma (EOC). Here, we studied markers for proliferation (Ki-67), endocrine regulation [progesterone receptor (PR), estrogen receptor (ER)], and invasion [urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1)]. All patients with available follow-up information and EOC tissue, who were treated at our institution between 1997 and 2004, were enrolled in the present study. Expression of Ki-67, PR and ER was determined by immunohistochemical analyses. uPA and PAI-1 antigen levels were determined using enzyme‑linked immunosorbent assays. One hundred and eight patients entered the present study. The median follow-up time was 43.3 (range 11.4-68.0) months. In multivariable Cox regression analyses, Ki-67 expression showed an independent negative impact on disease-free survival (DFS) and overall survival (OS) [hazard ratio (HR) for DFS, 11.5; 95% confidence interval (CI), 2.64-49.7; p=0.001 and HR for OS, 21.2; 95% CI, 9.9-113.1; p<0.001]. After cut-off optimization, PR expression showed an independent positive impact on prognosis (HR for DFS, 0.15; 95% CI, 0.03-0.68; p=0.014 and HR for OS, 0.13; 95% CI, 0.03‑0.68; p=0.016). Furthermore, postoperative residual tumor burden and completeness of chemotherapy determined the prognosis. ER, uPA and PAI-1 were not associated with survival. PR and ER, and postoperative residual tumor burden and tumor stage showed a strong correlation in an explorative Spearman's rank correlation coefficient (rho=0.759 and rho=0.426, respectively). Ki-67 and cut-off optimized PR are independently associated with the prognosis of EOC. Further prospective studies are warranted to confirm these associations and to elucidate the underlying mechanisms.
View Figures

Figure 1

Figure 2

View References

1 

Cannistra SA: Cancer of the ovary. N Engl J Med. 351:2519–2529. 2004. View Article : Google Scholar : PubMed/NCBI

2 

Gadducci A, Cosio S, Tana R and Genazzani AR: Serum and tissue biomarkers as predictive and prognostic variables in epithelial ovarian cancer. Crit Rev Oncol Hematol. 69:12–27. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Hanahan D and Weinberg RA: Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Linden MD, Torres FX, Kubus J and Zarbo RJ: Clinical application of morphologic and immunocytochemical assessments of cell proliferation. Am J Clin Pathol. 97(Suppl 1): S4–S13. 1992.PubMed/NCBI

5 

Cattoretti G, Becker MH, Key G, et al: Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 168:357–363. 1992. View Article : Google Scholar

6 

Garzetti GG, Ciavattini A, Goteri G, et al: Ki67 antigen immunostaining (MIB 1 monoclonal antibody) in serous ovarian tumors: index of proliferative activity with prognostic significance. Gynecol Oncol. 56:169–174. 1995. View Article : Google Scholar : PubMed/NCBI

7 

Viale G, Giobbie-Hurder A, Regan MM, et al: Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1–98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol. 26:5569–5575. 2008.PubMed/NCBI

8 

Kritpracha K, Hanprasertpong J, Chandeying V, Dechsukhum C and Geater A: Survival analysis in advanced epithelial ovarian carcinoma in relation to proliferative index of MIB-1 immunostaining. J Obstet Gynaecol Res. 31:268–276. 2005. View Article : Google Scholar : PubMed/NCBI

9 

Margulis V, Lotan Y, Karakiewicz PI, et al: Multi-institutional validation of the predictive value of Ki-67 labeling index in patients with urinary bladder cancer. J Natl Cancer Inst. 101:114–119. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Scambia G, Ferrandina G, Agostino GD, et al: Oestrogen and progesterone receptors in ovarian carcinoma. Endocr Relat Cancer. 3:293–301. 1998. View Article : Google Scholar

11 

Zhao D, Zhang F, Zhang W, He J, Zhao Y and Sun J: Prognostic role of hormone receptors in ovarian cancer: a systematic review and meta-analysis. Int J Gynecol Cancer. 23:25–33. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Bizzi A, Codegoni AM, Landoni F, et al: Steroid receptors in epithelial ovarian carcinoma: relation to clinical parameters and survival. Cancer Res. 48:6222–6226. 1988.PubMed/NCBI

13 

Geisler JP, Wiemann MC, Miller GA and Geisler HE: Estrogen and progesterone receptor status as prognostic indicators in patients with optimally cytoreduced stage IIIc serous cystadenocarcinoma of the ovary. Gynecol Oncol. 60:424–427. 1996. View Article : Google Scholar : PubMed/NCBI

14 

Lee P, Rosen DG, Zhu C, Silva EG and Liu J: Expression of progesterone receptor is a favorable prognostic marker in ovarian cancer. Gynecol Oncol. 96:671–677. 2005. View Article : Google Scholar : PubMed/NCBI

15 

Sinn BV, Darb-Esfahani S, Wirtz RM, et al: Evaluation of a hormone receptor-positive ovarian carcinoma subtype with a favourable prognosis by determination of progesterone receptor and oestrogen receptor 1 mRNA expression in formalin-fixed paraffin-embedded tissue. Histopathology. 59:918–927. 2011. View Article : Google Scholar

16 

Andreasen PA, Kjøller L, Christensen L and Duffy MJ: The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer. 72:1–22. 1997. View Article : Google Scholar : PubMed/NCBI

17 

Nykjaer A, Conese M, Christensen EI, et al: Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. EMBO J. 16:2610–2620. 1997. View Article : Google Scholar : PubMed/NCBI

18 

van der Burg ME, Henzen-Logmans SC, Berns EM, van Putten WL, Klijn JG and Foekens JA: Expression of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in benign, borderline, malignant primary and metastatic ovarian tumors. Int J Cancer. 69:475–479. 1996.PubMed/NCBI

19 

Konecny G, Untch M, Pihan A, et al: Association of urokinase-type plasminogen activator and its inhibitor with disease progression and prognosis in ovarian cancer. Clin Cancer Res. 7:1743–1749. 2001.PubMed/NCBI

20 

Chen Z, Gerhold-Ay A, Gebhard S, et al: Immunoglobulin kappa C predicts overall survival in node-negative breast cancer. PloS One. 7:e447412012. View Article : Google Scholar : PubMed/NCBI

21 

Anttila BM, Kosma V, Ji H, et al: Clinical significance of alpha-catenin, collagen IV, and Ki-67 expression in epithelial ovarian cancer. J Clin Oncol. 16:2591–2600. 1998.PubMed/NCBI

22 

Schmidt M, Bremer E, Hasenclever D, et al: Role of the progesterone receptor for paclitaxel resistance in primary breast cancer. Br J Cancer. 96:241–247. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Remmele W and Stegner H: Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 8:138–140. 1987.(In German).

24 

Steiner E, Pollow K, Hasenclever D, et al: Role of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) for prognosis in endometrial cancer. Gynecol Oncol. 108:569–576. 2008. View Article : Google Scholar : PubMed/NCBI

25 

Aune G, Stunes AK, Tingulstad S, Salvesen O, Syversen U and Torp SH: The proliferation markers Ki-67/MIB-1, phosphohistone H3, and survivin may contribute in the identification of aggressive ovarian carcinomas. Int J Clin Exp Pathol. 4:444–453. 2011.PubMed/NCBI

26 

Harlozińska A, Bar JK, Sedlaczek P and Gerber J: Expression of p53 protein and Ki-67 reactivity in ovarian neoplasms. Correlation with histopathology. Am J Clin Pathol. 105:334–340. 1996.PubMed/NCBI

27 

Korkolopoulou P, Vassilopoulos I, Konstantinidou AE, et al: The combined evaluation of p27Kip1 and Ki-67 expression provides independent information on overall survival of ovarian carcinoma patients. Gynecol Oncol. 85:404–414. 2002.

28 

Kerns BJ, Jordan PA, Faerman LL, Berchuck A, Bast RC Jr and Layfield LJ: Determination of proliferation index with MIB-1 in advanced ovarian cancer using quantitative image analysis. Am J Clin Pathol. 101:192–197. 1994.PubMed/NCBI

29 

Silverberg SG: Histopathologic grading of ovarian carcinoma: a review and proposal. Int J Gynecol Pathol. 19:7–15. 2000. View Article : Google Scholar : PubMed/NCBI

30 

Lenhard M, Tereza L, Heublein S, et al: Steroid hormone receptor expression in ovarian cancer: progesterone receptor B as prognostic marker for patient survival. BMC Cancer. 12:5532012. View Article : Google Scholar : PubMed/NCBI

31 

Kommoss F, Pfisterer J, Thome M, Schäfer W, Sauerbrei W and Pfleiderer A: Steroid receptors in ovarian carcinoma: immunohistochemical determination may lead to new aspects. Gynecol Oncol. 47:317–322. 1992. View Article : Google Scholar : PubMed/NCBI

32 

Langdon SP, Hirst GL, Miller EP, et al: The regulation of growth and protein expression by estrogen in vitro: a study of 8 human ovarian carcinoma cell lines. J Steroid Biochem Mol Biol. 50:131–135. 1994. View Article : Google Scholar : PubMed/NCBI

33 

Akahira J, Inoue T, Suzuki T, et al: Progesterone receptor isoforms A and B in human epithelial ovarian carcinoma: immunohistochemical and RT-PCR studies. Br J Cancer. 83:1488–1494. 2000. View Article : Google Scholar : PubMed/NCBI

34 

Kuhn W, Pache L, Schmalfeldt B, et al: Urokinase (uPA) and PAI-1 predict survival in advanced ovarian cancer patients (FIGO III) after radical surgery and platinum-based chemotherapy. Gynecol Oncol. 55:401–409. 1994. View Article : Google Scholar : PubMed/NCBI

35 

Ahlgren JD, Ellison NM, Gottlieb RJ, et al: Hormonal palliation of chemoresistant ovarian cancer: three consecutive phase II trials of the Mid-Atlantic Oncology Program. J Clin Oncol. 11:1957–1968. 1993.PubMed/NCBI

36 

Papadimitriou CA, Markaki S, Siapkaras J, et al: Hormonal therapy with letrozole for relapsed epithelial ovarian cancer. Long-term results of a phase II study. Oncology. 66:112–117. 2004. View Article : Google Scholar : PubMed/NCBI

37 

Kommoss S, du Bois A, Schmidt D, Parwaresch R, Pfisterer J and Kommoss F: Chemotherapy may be more effective in highly proliferative ovarian carcinomas - a translational research subprotocol of a prospective randomized phase III study (AGO-OVAR 3 protocol). Gynecol Oncol. 103:67–71. 2006. View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Battista MJ, Mantai N, Sicking I, Cotarelo C, Weyer V, Lebrecht A, Solbach C and Schmidt M: Ki-67 as an independent prognostic factor in an unselected cohort of patients with ovarian cancer: Results of an explorative, retrospective study. Oncol Rep 31: 2213-2219, 2014.
APA
Battista, M.J., Mantai, N., Sicking, I., Cotarelo, C., Weyer, V., Lebrecht, A. ... Schmidt, M. (2014). Ki-67 as an independent prognostic factor in an unselected cohort of patients with ovarian cancer: Results of an explorative, retrospective study. Oncology Reports, 31, 2213-2219. https://doi.org/10.3892/or.2014.3079
MLA
Battista, M. J., Mantai, N., Sicking, I., Cotarelo, C., Weyer, V., Lebrecht, A., Solbach, C., Schmidt, M."Ki-67 as an independent prognostic factor in an unselected cohort of patients with ovarian cancer: Results of an explorative, retrospective study". Oncology Reports 31.5 (2014): 2213-2219.
Chicago
Battista, M. J., Mantai, N., Sicking, I., Cotarelo, C., Weyer, V., Lebrecht, A., Solbach, C., Schmidt, M."Ki-67 as an independent prognostic factor in an unselected cohort of patients with ovarian cancer: Results of an explorative, retrospective study". Oncology Reports 31, no. 5 (2014): 2213-2219. https://doi.org/10.3892/or.2014.3079
Copy and paste a formatted citation
x
Spandidos Publications style
Battista MJ, Mantai N, Sicking I, Cotarelo C, Weyer V, Lebrecht A, Solbach C and Schmidt M: Ki-67 as an independent prognostic factor in an unselected cohort of patients with ovarian cancer: Results of an explorative, retrospective study. Oncol Rep 31: 2213-2219, 2014.
APA
Battista, M.J., Mantai, N., Sicking, I., Cotarelo, C., Weyer, V., Lebrecht, A. ... Schmidt, M. (2014). Ki-67 as an independent prognostic factor in an unselected cohort of patients with ovarian cancer: Results of an explorative, retrospective study. Oncology Reports, 31, 2213-2219. https://doi.org/10.3892/or.2014.3079
MLA
Battista, M. J., Mantai, N., Sicking, I., Cotarelo, C., Weyer, V., Lebrecht, A., Solbach, C., Schmidt, M."Ki-67 as an independent prognostic factor in an unselected cohort of patients with ovarian cancer: Results of an explorative, retrospective study". Oncology Reports 31.5 (2014): 2213-2219.
Chicago
Battista, M. J., Mantai, N., Sicking, I., Cotarelo, C., Weyer, V., Lebrecht, A., Solbach, C., Schmidt, M."Ki-67 as an independent prognostic factor in an unselected cohort of patients with ovarian cancer: Results of an explorative, retrospective study". Oncology Reports 31, no. 5 (2014): 2213-2219. https://doi.org/10.3892/or.2014.3079
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team