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 Letters
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-1074 Online ISSN: 1792-1082
Journal Cover
February-2025 Volume 29 Issue 2

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
February-2025 Volume 29 Issue 2

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

  • Supplementary Files
    • Supplementary_Data.pdf
Article Open Access

Intratumoural expression of dihydropyrimidine dehydrogenase is an independent prognostic factor in resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine

  • Authors:
    • Hakon Blomstrand
    • Malin Bodarve
    • Fredrik Groth
    • Peter Naredi
    • Malin Sund
    • Caroline Vilhav
    • Henrik Green
    • Bergthor Björnsson
    • Daniel Öhlund
    • Stina Lindblad
    • Oskar Franklin
    • Nils O. Elander
  • View Affiliations / Copyright

    Affiliations: Division of Surgery, Orthopaedics and Oncology, Department of Biomedical and Clinical Sciences, Linköping University, SE‑58185 Linköping, Sweden, Department of Clinical Pathology, Linköping University Hospital, SE‑58185 Linköping, Sweden, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE‑40530 Gothenburg, Sweden, Department of Diagnostics and Intervention, Umeå University, SE‑90187 Umeå, Sweden, Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Linköping University, SE‑58185 Linköping, Sweden, Department of Diagnostics and Intervention, and Wallenberg Centre for Molecular Medicine, Umeå University, SE‑90187 Umeå, Sweden
    Copyright: © Blomstrand et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 99
    |
    Published online on: December 10, 2024
       https://doi.org/10.3892/ol.2024.14845
  • 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

Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis, and biomarkers to guide treatment decisions in PDAC are generally lacking. Intratumoural expression of dihydropyrimidine dehydrogenase (DPD) is a potential prognostic parameter in patients with PDAC undergoing surgical resection and postoperative chemotherapy. In the present study, DPD was analysed by immunohistochemistry of a tissue microarray platform including a real‑world cohort of 495 patients with PDAC who had undergone resection with curative intent at any of three tertiary centres, including Northern, Western and Southeastern regions of Sweden, between 1993 and 2019. DPD level (high/low) was analysed and overall survival associations were assessed in treatment subgroups using a multivariate Cox regression model accounting for potential confounders. In patients who had not received adjuvant chemotherapy (n=182), the median overall survival time was 11.6 months (95% CI 9.6‑13.5), compared with 28.8 months (25.0‑32.6) among those who had (n=313; log‑rank P<0.001). The most common type of chemotherapy was gemcitabine single agent (Gem, n=239) followed by gemcitabine plus capecitabine (GemCape, n=39). Tumour‑Node‑Metastasis (TNM) stage and DPD expression were statistically significant prognostic parameters in the Gem group (HR 1.19, 95% CI 1.01‑1.41, P=0.036), with high expression of DPD linked with worse survival. In addition, tumour grade and TNM stage were statistically significant prognostic factors in the group that did not receive any chemotherapy (P≤0.001). No statistically significant parameters were identified in the GemCape group. Taken together, intratumoural expression of DPD may be considered a prognostic marker for patients with PDAC treated with adjuvant gemcitabine following surgical resection, with low expression levels predicting better survival. Further studies in larger cohorts of patients receiving multi‑drug or non‑gemcitabine based regimens are warranted.
View Figures

Figure 1

Figure 2

Figure 3

View References

1 

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI

2 

Cancerfonden, . The Swedish Cancer Society Report. Cancerfonden; Stockholm: 2023

3 

Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 350:1200–1210. 2004. View Article : Google Scholar : PubMed/NCBI

4 

Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, et al: Adjuvant chemotherapy with fluorouracil plus folinic acid vs. gemcitabine following pancreatic cancer resection: A randomized controlled trial. JAMA. 304:1073–1081. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, et al: Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): A multicentre, open-label, randomised, phase 3 trial. Lancet. 389:1011–1024. 2017. View Article : Google Scholar : PubMed/NCBI

6 

Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, Choné L, Francois E, Artru P, Biagi JJ, et al: FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 379:2395–2406. 2018. View Article : Google Scholar : PubMed/NCBI

7 

Uesaka K, Boku DN, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, et al: Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: A phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 388:248–257. 2016. View Article : Google Scholar : PubMed/NCBI

8 

Padmanabhan S: Handbook of pharmacogenomics and stratified medicine. Academic Press; Cambridge, MA, USA: pp. 341–364. 2014

9 

Longley DB, Harkin DP and Johnston PG: 5-fluorouracil: Mechanisms of action and clinical strategies. Nat Rev Cancer. 3:330–338. 2003. View Article : Google Scholar : PubMed/NCBI

10 

Fukui Y, Oka T, Nagayama S, Danenberg PV, Danenberg KD and Fukushima M: Thymidylate synthase, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase mRNA and protein expression levels in solid tumors in large scale population analysis. Int J Mol Med. 22:709–716. 2008.PubMed/NCBI

11 

European Medicines Agency, . EMA recommendations on DPD testing prior to treatment with fluorouracil, capecitabine, tegafur and flucytosine. EMA, Press Release; Amsterdam: 2020

12 

Falvella FS, Cheli S, Martinetti A, Mazzali C, Iacovelli R, Maggi C, Gariboldi M, Pierotti MA, Di Bartolomeo M, Sottotetti E, et al: DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan. Br J Clin Pharmacol. 80:581–588. 2015. View Article : Google Scholar : PubMed/NCBI

13 

Zhang YH, Shi WN, Wu SH, Miao RR, Sun SY, Luo DD, Wan SB, Guo ZK, Wang WY, Yu XF, et al: SphK2 confers 5-fluorouracil resistance to colorectal cancer via upregulating H3K56ac-mediated DPD expression. Oncogene. 39:5214–5227. 2020. View Article : Google Scholar : PubMed/NCBI

14 

Vallböhmer D, Yang DY, Kuramochi H, Shimizu D, Danenberg KD, Lindebjerg J, Nielsen JN, Jakobsen A and Danenberg PV: DPD is a molecular determinant of capecitabine efficacy in colorectal cancer. Int J Oncol. 31:413–418. 2007.PubMed/NCBI

15 

Elander NO, Aughton K, Ghaneh P, Neoptolemos JP, Palmer DH, Cox TF, Campbell F, Costello E, Halloran CM, Mackey JR, et al: Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer. Br J Cancer. 118:947–954. 2018. View Article : Google Scholar : PubMed/NCBI

16 

Kondo N, Murakami Y, Uemura K, Sudo T, Hashimoto Y, Nakashima A and Sueda T: Combined analysis of dihydropyrimidine dehydrogenase and human equilibrative nucleoside transporter 1 expression predicts survival of pancreatic carcinoma patients treated with adjuvant gemcitabine plus S-1 chemotherapy after surgical resection. Ann Surg Oncol. 19 (Suppl 3):S646–S655. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Kuramochi H, Hayashi K, Uchida K, Nakajima G, Hatori T, Danenber KD, Danenberg PV and Yamamoto M: High intratumoral dihydropyrimidine dehydrogenase mRNA levels in pancreatic cancer associated with a high rate of response to S-1. Cancer Chemother Pharmacol. 63:85–89. 2008. View Article : Google Scholar : PubMed/NCBI

18 

Tsukahara S, Shiota M, Takamatsu D, Nagakawa S, Matsumoto T, Kiyokoba R, Yagi M, Setoyama D, Noda N, Matsumoto S, et al: Cancer genomic profiling identified dihydropyrimidine dehydrogenase deficiency in bladder cancer promotes sensitivity to gemcitabine. Sci Rep. 12:85352022. View Article : Google Scholar : PubMed/NCBI

19 

Blomstrand H, Olsson H, Green H, Björnsson B and Elander NO: Impact of resection margins and para-aortic lymph node metastases on recurrence patterns and prognosis in resectable pancreatic cancer-a long-term population-based cohort study. HPB (Oxford). 25:1531–1544. 2023. View Article : Google Scholar : PubMed/NCBI

20 

Schemper M and Smith TL: A note on quantifying follow-up in studies of failure time. Control Clin Trials. 17:343–346. 1996. View Article : Google Scholar : PubMed/NCBI

21 

Tempero M, Pelzer U, O'Reilly EM, Winter J, Oh DY, Li CP, Tortora G, Chang HM, Lopez CD, Bekaii-Saab T, et al: Adjuvant nab-paclitaxel + gemcitabine in resected pancreatic ductal adenocarcinoma: Results from a randomized, open-label, phase III trial. J Clin Oncol. 41:2007–2019. 2023. View Article : Google Scholar : PubMed/NCBI

22 

Miyake K, Imura S, Yoshizumi T, Ikemoto T, Morine Y and Shimada M: Role of thymidine phosphorylase and orotate phosphoribosyltransferase mRNA expression and its ratio to dihydropyrimidine dehydrogenase in the prognosis and clinicopathological features of patients with pancreatic cancer. Int J Clin Oncol. 12:111–119. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Oba A, Ban D, Kirimura S, Akahoshi K, Mitsunori Y, Matsumura S, Ochiai T, Kudo A, Tanaka S and Minoru T: Clinical application of the biomarkers for the selection of adjuvant chemotherapy in pancreatic ductal adenocarcinoma. J Hepatobiliary Pancreat Sci. 23:480–488. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Aughton K, Elander NO, Evans A, Jackson R, Campbell F, Costello E, Halloran CM, Mackey JR, Scarfe AG, Valle JW, et al: hENT1 predicts benefit from gemcitabine in pancreatic cancer but only with low CDA mRNA. Cancers (Basel). 13:57582021. View Article : Google Scholar : PubMed/NCBI

25 

Wei CH, Gorgan TR, Elashoff DA, Hines OJ, Farrell JJ and Donahue TR: A meta-analysis of gemcitabine biomarkers in patients with pancreaticobiliary cancers. Pancreas. 42:1303–1310. 2013. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Blomstrand H, Bodarve M, Groth F, Naredi P, Sund M, Vilhav C, Green H, Björnsson B, Öhlund D, Lindblad S, Lindblad S, et al: Intratumoural expression of dihydropyrimidine dehydrogenase is an independent prognostic factor in resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine. Oncol Lett 29: 99, 2025.
APA
Blomstrand, H., Bodarve, M., Groth, F., Naredi, P., Sund, M., Vilhav, C. ... Elander, N.O. (2025). Intratumoural expression of dihydropyrimidine dehydrogenase is an independent prognostic factor in resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine. Oncology Letters, 29, 99. https://doi.org/10.3892/ol.2024.14845
MLA
Blomstrand, H., Bodarve, M., Groth, F., Naredi, P., Sund, M., Vilhav, C., Green, H., Björnsson, B., Öhlund, D., Lindblad, S., Franklin, O., Elander, N. O."Intratumoural expression of dihydropyrimidine dehydrogenase is an independent prognostic factor in resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine". Oncology Letters 29.2 (2025): 99.
Chicago
Blomstrand, H., Bodarve, M., Groth, F., Naredi, P., Sund, M., Vilhav, C., Green, H., Björnsson, B., Öhlund, D., Lindblad, S., Franklin, O., Elander, N. O."Intratumoural expression of dihydropyrimidine dehydrogenase is an independent prognostic factor in resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine". Oncology Letters 29, no. 2 (2025): 99. https://doi.org/10.3892/ol.2024.14845
Copy and paste a formatted citation
x
Spandidos Publications style
Blomstrand H, Bodarve M, Groth F, Naredi P, Sund M, Vilhav C, Green H, Björnsson B, Öhlund D, Lindblad S, Lindblad S, et al: Intratumoural expression of dihydropyrimidine dehydrogenase is an independent prognostic factor in resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine. Oncol Lett 29: 99, 2025.
APA
Blomstrand, H., Bodarve, M., Groth, F., Naredi, P., Sund, M., Vilhav, C. ... Elander, N.O. (2025). Intratumoural expression of dihydropyrimidine dehydrogenase is an independent prognostic factor in resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine. Oncology Letters, 29, 99. https://doi.org/10.3892/ol.2024.14845
MLA
Blomstrand, H., Bodarve, M., Groth, F., Naredi, P., Sund, M., Vilhav, C., Green, H., Björnsson, B., Öhlund, D., Lindblad, S., Franklin, O., Elander, N. O."Intratumoural expression of dihydropyrimidine dehydrogenase is an independent prognostic factor in resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine". Oncology Letters 29.2 (2025): 99.
Chicago
Blomstrand, H., Bodarve, M., Groth, F., Naredi, P., Sund, M., Vilhav, C., Green, H., Björnsson, B., Öhlund, D., Lindblad, S., Franklin, O., Elander, N. O."Intratumoural expression of dihydropyrimidine dehydrogenase is an independent prognostic factor in resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine". Oncology Letters 29, no. 2 (2025): 99. https://doi.org/10.3892/ol.2024.14845
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