European Journal of Dermatology

, Volume 26, Issue 5, pp 452–459 | Cite as

Immunohistochemical markers of advanced basal cell carcinoma: CD56 is associated with a lack of response to vismodegib

  • Jean-Marie Castillo
  • Anne-Chantal Knol
  • Jean-Michel Nguyen
  • Amir Khammari
  • Mélanie Saint-Jean
  • Brigitte Dreno
Investigative report



Vismodegib is an effective treatment for advanced basal cell carcinoma (BCC), but primary resistance to vismodegib remains to be elucidated. Alternative approaches are warranted to help selecting patients most likely to be responsive to treatment. The identification of immunohistochemical markers may support this perspective, as well as better understanding of resistance mechanisms.


To determine the level of expression of CD56, PDGF-R, CD117, MMP9, TIMP3, and CXCR4 in advanced BCC, and explore whether expression levels are associated with non-response to vismodegib.

Materials and methods

A cross-sectional study was conducted. Immunohistochemical markers were selected based on their roles in tumour proliferation and/or migration in skin tumours. Tissue samples included pretreatment advanced BCC samples from patients treated with vismodegib, with an available response after six months of treatment. Regression optimised models were used to build hypotheses regarding a possible association between expression levels and non-response to vismodegib, whichwas then tested by logistic regression.


Twenty-three patients were included. The percentage of samples expressing markers ranged from 43.5% (CD117) to 91.3% (CXCR4). CD56 expression was significantly associated with an increased risk of non-response to vismodegib (OR = 5.5; CI 95%: 3.4-29.8; p = 0.0488); a similar association was suggested for CXCR4 (p = 0.066), but not identified for other markers.


These results provide a better understanding of the expression of immunohistochemical markers in advanced BCC. Further detailed analysis of CD56 expression may provide insights into guiding further investigation of the correlation between this marker and non-response to vismodegib.

Key words

basal cell carcinoma immunohistochemistry treatment response vismodegib 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Madan V, Lear JT, Szeimies R-M. Non-melanoma skin cancer. Lancet 2010; 375: 673–85.CrossRefPubMedGoogle Scholar
  2. 2.
    Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: incidence. J Am Acad Dermatol 1994; 30: 774–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 2010; 146: 283–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Dreier J, Felderer L, Barysch M, Rozati S, Dummer R. Basal cell carcinoma: a paradigm for targeted therapies. Expert Opin Pharmacother 2013; 14: 1307–18.CrossRefPubMedGoogle Scholar
  5. 5.
    Walling HW, Fosko SW, Geraminejad PA, Whitaker DC, Arpey CJ. Aggressive basal cell carcinoma: presentation, pathogenesis, and management. Cancer Metastasis Rev 2004; 23: 389–402.CrossRefPubMedGoogle Scholar
  6. 6.
    Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med 2005; 353: 2262–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Kovarik CL, Stewart D, Barnard JJ. Lethal basal cell carcinoma secondary to cerebral invasion. J Am Acad Dermatol 2005; 52: 149–51.CrossRefPubMedGoogle Scholar
  8. 8.
    Wadhera A, Fazio M, Bricca G, Stanton O. Metastatic basal cell carcinoma: a case report and literature review. How accurate is our incidence data? Dermatol Online J 2006; 12: 7.PubMedGoogle Scholar
  9. 9.
    Pfeiffer P, Hansen O, Rose C. Systemic cytotoxic therapy of basal cell carcinoma. A review of the literature. Eur J Cancer 1990; 26: 73–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Lear JT. Oral hedgehog-pathway inhibitors for basal-cell carcinoma. N Engl J Med 2012; 366: 2225–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Hoff(Von-) DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 2009; 361: 1164–72.CrossRefGoogle Scholar
  12. 12.
    Cirrone F, Harris CS. Vismodegib and the hedgehog pathway: a new treatment for basal cell carcinoma. Clin Ther 2012; 34: 2039–50.CrossRefPubMedGoogle Scholar
  13. 13.
    Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366: 2171–9.CrossRefPubMedGoogle Scholar
  14. 14.
    LoRusso PM, Rudin CM, Reddy JC, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res 2011; 17: 2502–11.CrossRefPubMedGoogle Scholar
  15. 15.
    Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012; 366: 2180–8.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sekulic A, Midgen M, Basset-Seguin N, et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma (aBCC): 18-month update of the pivotal ERIVANCE BCC study, 2013 ASCO Annual Meeting. J Clin Oncol 2013; 31: 9037.Google Scholar
  17. 17.
    Grob J, Kunstfeld R, Dreno B, et al. Vismodegib, a Hedgehog pathway inhibitor (HPI), in advanced basal cell carcinoma (aBCC): STEVIE study interim analysis in 300 patients, 2013 ASCO Annual Meeting. J Clin Oncol 2013; 31: 9036.Google Scholar
  18. 18.
    Chang ALS, Solomon JA, Hainsworth JD, et al. Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib. J Am Acad Dermatol 2014; 70: 60–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Dreno B, Basset-Seguin N, Caro I, Yue H, Schadendorf D. Clinical benefit assessment of vismodegib therapy in patients with advanced basal cell carcinoma. The Oncologist 2014; 19: 790–6.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–16.CrossRefPubMedGoogle Scholar
  21. 21.
    Chebassier N, El Houssein O, Viegas I, Dréno B. In vitro induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 expression in keratinocytes by boron and manganese. Exp Dermatol 2004; 13: 484–90.CrossRefPubMedGoogle Scholar
  22. 22.
    Nguyen J-M, Gaultier A, Antonioli D. Le Titanic revu par ROP, une nouvelle méthode de régression non paramétrique combinée à une classification. Rev Epidémiologie Santé Publique 2014; 62: 45–6.CrossRefGoogle Scholar
  23. 23.
    Nguyen J, Gaultier A. Abilities of statistical models to identify subjects with ghost prognosis factors. J Health Educ Res Dev 2015; 03: 03.Google Scholar
  24. 24.
    Brümmendorf T, Lemmon V. Immunoglobulin superfamily receptors: cis-interactions, intracellular adapters and alternative splicing regulate adhesion. Curr Opin Cell Biol 2001; 13: 611–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Walmod PS, Kolkova K, Berezin V, Bock E. Zippers make signals: NCAM-mediated molecular interactions and signal transduction. Neurochem Res 2004; 29: 2015–35.CrossRefPubMedGoogle Scholar
  26. 26.
    Amoureux MC, Cunningham BA, Edelman GM, Crossin KL. NCAM binding inhibits the proliferation of hippocampal progenitor cells and promotes their differentiation to a neuronal phenotype. J Neurosci 2000; 20: 3631–40.PubMedGoogle Scholar
  27. 27.
    Cambon K, Venero C, Berezin V, Bock E, Sandi C. Post-training administration of a synthetic peptide ligand of the neural cell adhesion molecule, C3d, attenuates long-term expression of contextual fear conditioning. Neuroscience 2003; 122: 183–91.CrossRefPubMedGoogle Scholar
  28. 28.
    Ditlevsen DK, Køhler LB, Pedersen MV, et al. The role of phosphatidylinositol 3-kinase in neural cell adhesion molecule-mediated neuronal differentiation and survival. J Neurochem 2003; 84: 546–56.CrossRefPubMedGoogle Scholar
  29. 29.
    Prag S, Lepekhin EA, Kolkova K, et al. NCAM regulates cell motility. J Cell Sci 2002; 115: 283–92.PubMedGoogle Scholar
  30. 30.
    Abbott JJ, Amirkhan RH, Hoang MP. Malignant melanoma with a rhabdoid phenotype: histologic, immunohistochemical, and ultrastructural study of a case and review of the literature. Arch Pathol Lab Med 2004; 128: 686–8.PubMedGoogle Scholar
  31. 31.
    Johnson JP. Cell adhesion molecules in the development and progression of malignant melanoma. Cancer Metastasis Rev 1999; 18: 345–57.CrossRefPubMedGoogle Scholar
  32. 32.
    Pujol JL, Simony J, Demoly P, et al. Neural cell adhesion molecule and prognosis of surgically resected lung cancer. Am Rev Respir Dis 1993; 1484: 1071–5.CrossRefGoogle Scholar
  33. 33.
    Cho EY, Choi Y, Chae SW, Sohn JH, Ahn GH. Immunohistochemical study of the expression of adhesion molecules in ovarian serous neoplasms. Pathol Int 2006; 56: 62–70.CrossRefPubMedGoogle Scholar
  34. 34.
    Choi Y-L, Xuan YH, Shin YK, et al. An immunohistochemical study of the expression of adhesion molecules in gallbladder lesions. J Histochem Cytochem 2004; 52: 591–601.CrossRefPubMedGoogle Scholar
  35. 35.
    Zołtowska A, Stepiński J, Lewko B, et al. Neural cell adhesion molecule in breast, colon and lung carcinomas. Arch Immunol Ther Exp (Warsz) 2001; 49: 171–4.Google Scholar
  36. 36.
    Daniel L, Bouvier C, Chetaille B, et al. Neural cell adhesion molecule expression in renal cell carcinomas: relation to metastatic behavior. Hum Pathol 2003; 34: 528–32.CrossRefPubMedGoogle Scholar
  37. 37.
    Terada T. Expression of NCAM (CD56), chromogranin A, synaptophysin, c-KIT (CD117) and PDGFRA in normal non-neoplastic skin and basal cell carcinoma: an immunohistochemical study of 66 consecutive cases. Med Oncol 2013; 30: 1.Google Scholar
  38. 38.
    Brechbiel J, Miller-Moslin K, Adjei AA. Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer. Cancer Treat Rev 2014; 40: 750–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Ditlevsen DK, Povlsen GK, Berezin V, Bock E. NCAM-induced intracellular signaling revisited. J Neurosci Res 2008; 86: 727–43.CrossRefPubMedGoogle Scholar
  40. 40.
    Schnidar H, Eberl M, Klingler S, et al. Epidermal growth factor receptor signaling synergizes with hedgehog/GLI in oncogenic transformation via activation of the MEK/ERK/JUN pathway. Cancer Res 2009; 69: 1284–92.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Eberl M, Klingler S, Mangelberger D, et al. Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells: hedgehog-EGFR cooperation response genes in cancer. EMBO Mol Med 2012; 4: 218–33.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Basile J, Thiers B, Maize J, Lathers DMR. Chemokine receptor expression in non-melanoma skin cancer. J Cutan Pathol 2008; 35: 623–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Scala S, Giuliano P, Ascierto PA, et al. Human melanoma metastases express functional CXCR4. Clin Cancer Res 2006; 12: 2427–33.CrossRefPubMedGoogle Scholar
  44. 44.
    Mori T, Kim J, Yamano T, et al. Epigenetic up-regulation of C-C chemokine receptor 7 and C-X-C chemokine receptor 4 expression in melanoma cells. Cancer Res 2005; 65: 1800–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Xu C-Z, Wang P-H, Yan X-J, et al. Expression of CXCR4 is associated with progression and invasion in patients with nasal-surface basal cell carcinoma. ORL J Otorhinolaryngol Relat Spec 2013; 75: 332–41.CrossRefPubMedGoogle Scholar
  46. 46.
    Chen G-S, Yu H-S, Lan C-CE H-S, et al. CXC chemokine receptor CXCR4 expression enhances tumorigenesis and angiogenesis of basal cell carcinoma. Br J Dermatol 2006; 154: 910–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Chu C-Y, Sheen Y-S, Cha S-T, et al. Induction of chemokine receptor CXCR4 expression by transforming growth factor-β1 in human basal cell carcinoma cells. J Dermatol Sci 2013; 72: 123–33.CrossRefPubMedGoogle Scholar
  48. 48.
    Li X, Ma Q, Xu Q, et al. SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway. Cancer Lett 2012; 322: 169–76.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Williams LT. Signal transduction by the platelet-derived growth factor receptor. Science 1989; 243: 1564–70.CrossRefPubMedGoogle Scholar
  50. 50.
    Xie J, Aszterbaum M, Zhang X, et al. A role of PDGFR alpha in basal cell carcinoma proliferation. Proc Natl Acad Sci USA 2001; 98: 9255–9.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Heldin C-H. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal CCS 2013; 11: 97.CrossRefPubMedGoogle Scholar
  52. 52.
    Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev 2008; 22: 1276–312.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Sabbatino F, Wang Y, Wang X, et al. PDGFRα up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. Oncotarget 2014; 5: 1926–41.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Pontén F, Ren Z, Nistér M, Westermark B, Pontén J. Epithelialstromal interactions in basal cell cancer: the PDGF system. J Invest Dermatol 1994; 102: 304–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Miettinen M, Lasota J. KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. Appl Immunohistochem Mol Morphol 2005; 13: 205–20.CrossRefPubMedGoogle Scholar
  56. 56.
    Fan H, Yuan Y, Wang J, et al. CD117 expression in operable oesophageal squamous cell carcinomas predicts worse clinical outcome. Histopathology 2013; 62: 1028–37.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Kitamura Y, Hirotab S. Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci 2004; 61: 2924–31.CrossRefPubMedGoogle Scholar
  58. 58.
    Carlino MS, Todd JR, Rizos H. Resistance to c-Kit inhibitors in melanoma: insights for future therapies. Oncoscience 2014; 1: 423–6.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Medinger M, Kleinschmidt M, Mross K, et al. c-kit (CD117) expression in human tumors and its prognostic value: an immunohistochemical analysis. Pathol Oncol Res 2010; 16: 295–301.CrossRefPubMedGoogle Scholar
  60. 60.
    Zhao F, Chen Y, Wu Q, Wang Z, Lu J. Prognostic value of CD117 in cancer: a meta-analysis. Int J Clin Exp Pathol 2014; 7: 1012–21.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Groblewska M, Siewko M, Mroczko B, Szmitkowski M. The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer. Folia Histochem Cytobiol 2012; 50: 12–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Liu Z, Li L, Yang Z, et al. Increased expression of MMP9 is correlated with poor prognosis of nasopharyngeal carcinoma. BMC Cancer 2010; 10: 270.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Li H, Cao D, Liu Y, et al. Prognostic value of matrix metalloproteinases (MMP-2 and MMP-9) in patients with lymph node-negative breast carcinoma. Breast Cancer Res Treat 2004; 88: 75–85.CrossRefPubMedGoogle Scholar
  64. 64.
    Ye L, Sun P-H, Martin TA, Sanders AJ, Mason MD, Jiang WG. Psoriasin (S100A7) is a positive regulator of survival and invasion of prostate cancer cells. Urol Oncol Semin Orig Investig 2013; 31: 1576–83.CrossRefGoogle Scholar
  65. 65.
    Wang B-Q, Zhang C-M, Gao W, Wang X-F, Zhang H-L, Yang P-C. Cancer-derived matrix metalloproteinase-9 contributes to tumor tolerance. J Cancer Res Clin Oncol 2011; 137: 1525–33.CrossRefPubMedGoogle Scholar
  66. 66.
    Pazzaglia L, Ponticelli F, Magagnoli G, et al. Activation of metalloproteinases-2 and-9 by interleukin-1 alpha in S100A4-positive liposarcoma cell line: correlation with cell invasiveness. Anticancer Res 2004; 24: 967–72.PubMedGoogle Scholar
  67. 67.
    Giannopoulos G, Pavlakis K, Parasi A, et al. The expression of matrix metalloproteinases-2 and-9 and their tissue inhibitor 2 in pancreatic ductal and ampullary carcinoma and their relation to angiogenesis and clinicopathological parameters. Anticancer Res 2008; 28: 1875–81.PubMedGoogle Scholar
  68. 68.
    Kubben FJGM, Sier CFM, Meijer MJW, et al. Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer. Br J Cancer 2006; 95: 744–51.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Zhu L, Kohda F, Nakahara T, et al. Aberrant expression of S100A6 and matrix metalloproteinase 9, but not S100A2, S100A4, and S100A7, is associated with epidermal carcinogenesis. J Dermatol Sci 2013; 72: 311–9.CrossRefPubMedGoogle Scholar
  70. 70.
    Poswar FO, Fraga CAC, Farias LC, et al. Immunohistochemical analysis of TIMP-3 and MMP-9 in actinic keratosis, squamous cell carcinoma of the skin, and basal cell carcinoma. Pathol Res Pract 2013; 209: 705–9.CrossRefPubMedGoogle Scholar
  71. 71.
    El-Khalawany MA, Abou-Bakr AA. Role of cyclooxygenase-2, ezrin and matrix metalloproteinase-9 as predictive markers for recurrence of basal cell carcinoma. J Cancer Res Ther 2013; 9: 613–7.CrossRefPubMedGoogle Scholar
  72. 72.
    Furudate S, Fujimura T, Tojo G-I, Haga T, Aiba S. Basal cell carcinoma arising from xeroderma pigmentosum: a case report and an immunohistochemical study. Case Rep Dermatol 2013; 5: 64–8.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 2010; 1803: 55–71.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Baker AH, George SJ, Zaltsman AB, Murphy G, Newby AC. Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3. Br J Cancer 1999; 79: 1347–55.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Ahonen M, Baker AH, Kähäri VM. Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res 1998; 58: 2310–5.PubMedGoogle Scholar
  76. 76.
    Baker AH, Zaltsman AB, George SJ, Newby AC. Divergent effects of tissue inhibitor of metalloproteinase-1,-2, or-3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. TIMP-3 promotes apoptosis. J Clin Invest 1998; 101: 1478–87.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Spurbeck WW, Ng CYC, Strom TS, Vanin EF, Davidoff AM. Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model. Blood 2002; 100: 3361–8.CrossRefPubMedGoogle Scholar
  78. 78.
    Leco KJ, Khokha R, Pavloff N, Hawkes SP, Edwards DR. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrixassociated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem 1994; 269: 9352–60.PubMedGoogle Scholar
  79. 79.
    Apte SS, Olsen BR, Murphy G. The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J Biol Chem 1996; 271: 2874.PubMedGoogle Scholar
  80. 80.
    Anand-Apte B, Bao L, Smith R, et al. A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth. Biochim Biol Cell 1996; 74: 853–62.CrossRefGoogle Scholar
  81. 81.
    Das AM, Seynhaeve ALB, Rens JAP, et al. Differential TIMP3 expression affects tumor progression and angiogenesis in melanomas through regulation of directionally persistent endothelial cell migration. Angiogenesis 2014; 17: 163–77.CrossRefPubMedGoogle Scholar
  82. 82.
    Qi JH, Ebrahem Q, Moore N, et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 2003; 9: 407–15.CrossRefPubMedGoogle Scholar

Copyright information

© John Libbey Eurotext 2016

Authors and Affiliations

  • Jean-Marie Castillo
    • 1
  • Anne-Chantal Knol
    • 2
  • Jean-Michel Nguyen
    • 2
    • 3
  • Amir Khammari
    • 2
    • 4
  • Mélanie Saint-Jean
    • 4
  • Brigitte Dreno
    • 2
    • 4
    • 5
  1. 1.Family Medicine DepartmentNantes Medical SchoolNantesFrance
  2. 2.CRCNA, INSERM U892, CNRS 6299NantesFrance
  3. 3.PIMESP-SEBHôpital St JacquesNantesFrance
  4. 4.Dermato-Cancerology DepartmentCHU Hôtel-DieuNantesFrance
  5. 5.Unité de Thérapie Cellulaire et Génique (UTCG)CHU Hôtel-DieuNantesFrance

Personalised recommendations