Skip to main content

Advertisement

SpringerLink
Log in

Regenerative therapy with mesenchymal stem cells at the site of malignant primary bone tumour resection: what are the risks of early or late local recurrence?

  • Original Paper
  • Published:
International Orthopaedics Aims and scope Submit manuscript

Abstract

Purpose

There is concern that regenerative cell-based therapies at the site of malignant primary bone tumours could result in increased risk of local tumour recurrence. We therefore investigated the long-term risks for site-specific recurrences in patients who had received an autologous bone marrow derived mesenchymal stem cell suspension to improve healing at the host-to-allograft bone junction of the reconstruction after bone tumour resection.

Methods

A total of 92 patients were treated from 1993 to 2003 with bone marrow-derived mesenchymal stem cells after bone tumour resection. Patients were monitored for cancer incidence from the date of first operation (1993) until death, or until 31 December 2013. The mean follow-up time was 15.4 years (range ten to 20 years). The average number of MSCs returned to the patient was 234,000 MSCs ± 215,000. The primary outcome was to evaluate the risk of tumorigenesis recurrence at the cell therapy treatment sites with radiographs and/or MRIs. The relative risk of cancer recurrence was expressed as the ratio of observed and expected number of cases according to three different control populations.

Results

Thirteen recurrences were found at the treatment sites among the 92 patients. The expected number of recurrences based on incidence in the three cohort populations was between 15 and 20 for the same cancer, age and sex distribution. The standardized incidence ratio (equal to observed cancers divided by expected cancers) for the entire follow-up period and for all recurrences was between 0.65 and 0.86 (95 % CI 0.60–1.20).

Conclusion

This study found no increased cancer local recurrence risk in patients after application of autologous cell-based therapy using bone marrow-derived mesenchymal stem cells at the treatment site after an average follow-up period of 15.4 years, ranging from ten to 20 years.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Amaral AT, Manara MC, Berghuis D, Ordonez JL, Biscuola M et al (2014) Characterization of human mesenchymal stem cells from Ewing sarcoma patients. Pathogenetic implications. PLoS ONE 9(2):e85814

    Article  PubMed Central  PubMed  Google Scholar 

  2. Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P et al (2000) Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol 18:4016–4027

    CAS  PubMed  Google Scholar 

  3. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S et al (2002) Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 20:776–790

    Article  PubMed  Google Scholar 

  4. Caplan AI (2005) Mesenchymal stem cells: cell-based reconstructive therapy. Tissue Eng 11:1198–1211

    Article  CAS  PubMed  Google Scholar 

  5. CCSS (2014) The Childhood Cancer Survivor Study (CCSS).www.stjude.org/ccss. Accessed 27 May 2014

  6. Centeno CJ, Schultz JR, Cheever M, Freeman M, Faulkner S, Robinson B, Hanson R (2011) Safety and complications reporting update on the reimplantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther 6:368–378

    Article  CAS  PubMed  Google Scholar 

  7. Champlin RE, Andreeff M (2004) Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 96:1593–1603

    Article  PubMed  Google Scholar 

  8. Coleman SR, Saboeiro AP (2007) Fat grafting to the breast revisited: safety and efficacy. Plast Reconstr Surg 119:775–785, discussion 786–777

    Article  CAS  PubMed  Google Scholar 

  9. Coquelin L, Fialaire-legendre A, Roux S, Poignard A, Bierling P, Hernigou P, Chevallier N, Rouard H (2012) In vivo and in vitro comparison of three different allografts vitalized with human mesenchymal stromal cells. Tissue Eng A 18(17–18):1921–1931

    Article  CAS  Google Scholar 

  10. Delepine N, Delepine G, Hernigou P, Desbois JC (1991) Bone union in allografts chemotherapy considerations. Limb Salvage Ed., Springer, pp 117–119

  11. Delepine G, Delepine N, Hernigou P (1991) Allograft with patellar tendon in reconstructive procedures after upper tibial resection. Limb Salvage Ed., Springer, pp 436–437

  12. Djouad F, Bony C, Apparailly F, Louis-Plence P, Jorgensen C et al (2006) Earlier onset of syngeneic tumors in the presence of mesenchymal stem cells. Transplantation 82:1060–1066

    Article  PubMed  Google Scholar 

  13. Demicheli R, Retsky MW, Hrushesky WJ, Baum M (2007) Tumor dormancy and surgery-driven interruption of dormancy in breast cancer: learning from failures. Nat Clin Pract Oncol 4:699–710

    Article  PubMed  Google Scholar 

  14. Ferrari S, Briccoli A, Mercuri M, Bertoni F, Cesari M et al (2006) Late relapse in osteosarcoma. J Pediatr Hematol Oncol 28:418–422

    Article  PubMed  Google Scholar 

  15. Gasparini M, Lombardi F, Ballerini E et al (1994) Long-term outcome of patients with monostotic Ewing’s sarcoma treated with combined modality. Med Pediatr Oncol 23(5):406–412

    Article  CAS  PubMed  Google Scholar 

  16. Gibbs CP, Kukekov VG, Reith JD, Tchigrinova O, Suslov ON et al (2005) Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia 7:967–976

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Hayes FA, Thompson EI, Kumar M, Hustu HO (1987) Long-term survival in patients with Ewing’s sarcoma relapsing after completing therapy. Med Pediatr Oncol 15(5):254–256

    Article  CAS  PubMed  Google Scholar 

  18. Hernigou P, Delepine G, Goutallier D, Julieron A (1993) Massive allografts sterilised by irradiation (clinical results). J Bone Joint Surg (BR) 75 B, n° 6, 904-913

  19. Hernigou P, Beaujean F (1997) Autologous bone marrow to stimulate bone healing. J Cell Eng 2(3):113–116

    Google Scholar 

  20. Hernigou P, Gras G, Marinello G, Dormont D (2000) Inactivation of HIV by application of heat and radiation. Acta Orthop Scand 71(5):508–512

    Article  CAS  PubMed  Google Scholar 

  21. Hernigou P, Gras G, Marinello G, Dormont D (2000) Influence of irradiation on the risk of transmission of HIV in bone grafts obtained from appropriately screened donors and followed by radiation sterilization. Cell Tissue Bank 1:279–289

    Article  PubMed  Google Scholar 

  22. Hernigou P, Poignard A, Beaujean F, Rouard H (2005) Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am 87:1430–1437

    Article  PubMed  Google Scholar 

  23. Hernigou P, Homma Y, Flouzat-Lachaniette CH, Poignard A, Chevallier N, Rouard H (2013) Cancer risk is not increased in patients treated for orthopaedic diseases with autologous bone marrow cell concentrate. J Bone Joint Surg Am 95(24):2215–2221

    Article  PubMed  Google Scholar 

  24. Hernigou P, Homma Y, Flouzat Lachaniette CH, Poignard A, Allain J, Chevallier N, Rouard H (2013) Benefits of small volume and small syringe for bone marrow aspirations of mesenchymal stem cells. Int Orthop 37(11):2279–2287

    Article  PubMed  Google Scholar 

  25. Hernigou P, Pariat J, Queinnec S, Homma Y, Lachaniette CH, Chevallier N, Rouard H (2014) Supercharging irradiated allografts with mesenchymal stem cells improves acetabular bone grafting in revision arthroplasty. Int Orthop 2014 Feb 9 [Epub ahead of print]

  26. Homma Y, Kaneko K, Hernigou P (2013) Supercharging allografts with mesenchymal stem cells in the operating room during hip revision. Int Orthop 2013 Dec 10 [Epub ahead of print]

  27. Institut National du Cancer (2011) [The situation of cancer in France in 2011]. Collection rapports & syntheses, ouvrage collectif edité par l’INCA, Boulonge- Billancourt. www.e-cancer.fr. [In French]

  28. Kinsella TJ, Miser JS, Waller B et al (1991) Long-term follow-up of Ewing’s sarcoma of bone treated with combined modality therapy. Int J Radiat Oncol Biol Phys 20(3):389–395

    Article  CAS  PubMed  Google Scholar 

  29. Koksal Y, Akyuz C, Varan A, Atilla B, Gedikoglu G et al (2008) Late recurrence in primary region of parosteal osteosarcoma: a case report. Pediatr Hematol Oncol 25:83–88

    Article  PubMed  Google Scholar 

  30. Kubista B, Klinglmueller F, Bilban M, Pfeiffer M, Lass R, Giurea A, Funovics PT, Toma C, Dominkus M, Kotz R, Thalhammer T, Trieb K, Zettl T, Singer CF (2011) Microarray analysis identifies distinct gene expression profiles associated with histological subtype in human osteosarcoma. Int Orthop 35(3):401–411

  31. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ (2012) Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One 7:e47559

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Lau TW, Wong JW, Yip DK, Chien EP, Shek TW, Wong LL (2004) Local recurrence of parosteal osteosarcoma adjacent to a prosthesis after 20 years: a case report. J Orthop Surg (Hong Kong) 12(2):263–266

    CAS  Google Scholar 

  33. Lazennec G, Jorgensen C (2008) Concise review: adult multipotent stromal cells and cancer: risk or benefit? Stem Cells 26:1387–1394

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Le BH, Buchanan MR, Steer C, de Boer R (2007) Late recurrence of osteosarcoma. Intern Med J 37(6):420–422

    Article  CAS  PubMed  Google Scholar 

  35. Lee OK, Coathup MJ, Goodship AE, Blunn GW (2005) Use of mesenchymal stem cells to facilitate bone regeneration in normal and chemotherapy treated rats. Tissue Eng 11:1727–1735

    Article  CAS  PubMed  Google Scholar 

  36. Leotot J, Coquelin L, Bodivit G, Bierling P, Hernigou P, Rouard H, Chevallier N (2013) Platelet lysate coating on scaffolds directly and indirectly enhances cell migration, improving bone and blood vessel formation. Acta Biomater 9(5):6630–6640

    Article  CAS  PubMed  Google Scholar 

  37. Li X, Moretti VM, Ashana AO, Lackman RD (2012) Impact of close surgical margin on local recurrence and survival in osteosarcoma. Int Orthop 36:131–137. doi:10.1007/s00264-011-1230-x

    Article  PubMed Central  PubMed  Google Scholar 

  38. Lucarelli, Bellotti C, Mantelli M, Antonietta M, Avanzini, Maccario R et al (2014) In vitro biosafety profile evaluation of multipotent mesenchymal stem cells derived from the bone marrow of sarcoma patients. J Transl Med 12:95

    Article  PubMed Central  PubMed  Google Scholar 

  39. Mankin HJ, Hornicek FJ, Rosenberg AE, Harmon DC, Gebhardt MC (2004) Survival data for 648 patients with osteosarcoma treated at one institution. Clin Orthop 429:286–291

    Article  PubMed  Google Scholar 

  40. Mishra PJ, Mishra PJ, Humeniuk R, Medina DJ, Alexe G, Mesirov JP, Ganesan S, Glod JW, Banerjee D (2008) Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res 68:4331–4339

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Morishita T, Honoki K, Ohgushi H, Kotobuki N, Matsushima A, Takakura Y (2006) Tissue engineering approach to the treatment of bone tumors: three cases of cultured bone grafts derived from patients’ mesenchymal stem cells. Artif Organs 30:115–118

    Article  PubMed  Google Scholar 

  42. Nakamura K, Ito Y, Kawano Y, Kurozumi K, Kobune M et al (2004) Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther 11:1155–1164

    Article  CAS  PubMed  Google Scholar 

  43. Naumov GN, Bender E, Zurakowski D, Kang SY, Sampson D et al (2006) A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst 98:316–325

    Article  PubMed  Google Scholar 

  44. Nilbert M, Saeter G, Elomaa I, Monge OR, Wiebe T, Alvegard TA (1998) Ewing’s sarcoma treatment in Scandinavia 1984–1990—ten-year results of the Scandinavian Sarcoma Group Protocol SSGIV. Acta Oncol 37(4):375–378

    Article  CAS  PubMed  Google Scholar 

  45. Perrot P, Rousseau J, Bouffaut A-L, Rédini F, Cassagnau E, Deschaseaux F, Heymann MF, Heymann D, Duteille F, Trichet V, Gouin F (2010) Safety concern between autologous fat graft, mesenchymal stem cell and osteosarcoma recurrence. PLoS One 5(6):e10999. doi:10.1371/journal.pone.0010999

    Article  PubMed Central  PubMed  Google Scholar 

  46. Strauss SJ, McTiernan A, Whelan JS (2004) Late relapse of osteosarcoma: implications for follow-up and screening. Pediatr Blood Cancer 43(6):692–697

    Article  PubMed  Google Scholar 

  47. Tolar J, Nauta AJ, Osborn MJ, Panoskaltsis Mortari A, McElmurry RT, Bell S, Xia L, Zhou N, Riddle M, Schroeder TM, Westendorf JJ, McIvor RS, Hogendoorn PCW, Szuhai K, Oseth L, Hirsch B, Yant SR, Kay MA, Peister A, Prockop DJ, Fibbe WE, Blazar BR (2007) Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 25:371–379

    Article  CAS  PubMed  Google Scholar 

  48. Thariat J, Italiano A, Peyrade F et al (2008) Very late local relapse of Ewing’s sarcoma of the head and neck treated with aggressive multimodal therapy. Sarcoma 2008:854141

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Varani J, Lovett EJ 3rd, Lundy J (1981) A model of tumor cell dormancy: effects of anesthesia and surgery. J Surg Oncol 17:9–14

    Article  CAS  PubMed  Google Scholar 

  50. Welck M, Gikas P, Pearce P, Bhumbra R, Briggs T, Cannon S (2009) Local recurrence of osteosarcoma after 17 years. Ann R Coll Surg Engl 91:1–3

    Article  Google Scholar 

  51. Wasilewski-Masker K, Liu Q, Yasui Y, Leisenring W, Meacham LR, Hammond S, Meadows AT, Robison LL, Mertens AC (2009) Late recurrence in pediatric cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 101:1709–1720

    Article  PubMed Central  PubMed  Google Scholar 

  52. Xu WT, Bian ZY, Fan QM, Li G, Tang TT (2009) Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis. Cancer Lett 281:32–41

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Ted Sand and Richard Suzuki and the other members of Celling Biosciences for reviewing the final manuscript and for their help in translation.

Author information

Authors and Affiliations

  1. Orthopaedic Surgery, Hopital Henri Mondor, Créteil, France

    Philippe Hernigou, Charles Henri Flouzat Lachaniette, Jerome Delambre, Nathalie Chevallier & Helene Rouard

Authors
  1. Philippe Hernigou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles Henri Flouzat Lachaniette
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jerome Delambre
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nathalie Chevallier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Helene Rouard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philippe Hernigou.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hernigou, P., Flouzat Lachaniette, C.H., Delambre, J. et al. Regenerative therapy with mesenchymal stem cells at the site of malignant primary bone tumour resection: what are the risks of early or late local recurrence?. International Orthopaedics (SICOT) 38, 1825–1835 (2014). https://doi.org/10.1007/s00264-014-2384-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00264-014-2384-0

Keywords

Search

Navigation