Skip to main content
SpringerLink
Log in

Gene Therapy and Free Flaps for Therapeutic Reconstructive Surgery

  • Chapter
  • First Online:
Gene Therapy in Reconstructive and Regenerative Surgery

  • 292 Accesses

Abstract

Surgery, whether alone or in combination with adjuvant or neoadjuvant therapy, is a major component in the treatment of oncological disease. Patients with ablative defects following surgical resection may undergo reconstructive surgery, with the aim of returning the patient to a premorbid level, for example, a mastectomy for cancer clearance and a breast reconstruction for chest wall reconstruction. However, despite multidisciplinary involvement, aggressive surgical margins, and additional therapy, tumor recurrence may occur. Autologous tissue used for reconstruction may provide a potential therapeutic source to patients and promote long-term tumor eradication by secreting therapeutic factors. This review focuses on gene therapy as a means of ex vivo transduction of autologous tissue and describes how reconstructive tissue can offer both reconstructive and therapeutic roles in the form of therapeutic flaps.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Taylor GI, Daniel RK. The free flap: composite tissue transfer by vascular anastomosis. Aust N Z J Surg. 1971;43(1):1–3.

    Article  Google Scholar 

  2. Daniel RK, Taylor GI. Distant transfer of an island flap by microvascular anastomoses. A clinical technique. Plast Reconstr Surg. 1973;52(2):111–7.

    Article  CAS  PubMed  Google Scholar 

  3. Mathes SJ. Muscle flaps and their blood supply. In: Aston SJ, Beasley RW, Thorne CW, editors. Plastic surgery. 5th ed. New York: Lippincott-Raven; 1997. p. 61–71.

    Google Scholar 

  4. Dempsey MP, Hamou C, Michaels J, Ghali S, Jazayeri L, Grogan RH, Gurtner GC. Using genetically modified microvascular free flaps to deliver local cancer immunotherapy with minimal systemic toxicity. Plast Reconstr Surg. 2008;121(5):1541–53.

    Article  CAS  PubMed  Google Scholar 

  5. Michaels J, Levine JP, Hazen A, Ceradini DJ, Galiano RD, Soltanian H, Gurtner GC. Biologic brachytherapy: ex vivo transduction of microvascular beds for efficient, targeted gene therapy. Plast Reconstr Surg. 2006;118(1):54–65.

    Article  CAS  PubMed  Google Scholar 

  6. Allen RJ, Treece P. Deep inferior epigastric perforator flap for breast reconstruction. Ann Plast Surg. 1994;32:32–8.

    Article  CAS  PubMed  Google Scholar 

  7. Blondeel PN, Boeckx WD. Refinements in free flap breast reconstruction: the free bilateral deep inferior epigastric perforator flap anastomosed to internal mammary artery. Br J Plast Surg. 1994;47:495–501.

    Article  CAS  PubMed  Google Scholar 

  8. Wei FC, Jain V, Celik N, et al. Have we found an ideal soft tissue flap? An experience with 672 anterolateral thigh flaps. Plast Reconstr Surg. 2002;109:2219.

    Article  PubMed  Google Scholar 

  9. Lin F, Grinsell D. Free anterolateral thigh perforator flap for head and neck cancer resection in a nonagenarian. Mod Plast Surg. 2012;2(1):1–4.

    Article  Google Scholar 

  10. Tanzini. Sporo il nito nuova processo di aupertozione della menuelle. Riforma Med. 1906;22:757.

    Google Scholar 

  11. d’Este S. La technique de l’amputation de la mamelle pour carcinome mammaire. Rev Chir. 1912;45:164.

    Google Scholar 

  12. Cheng MH, Saint-Cyr M, Ali RS, Chang KP, Hao SP, Wei FC. Osteomyocutaneous peroneal artery-based combined flap for reconstruction of composite and en bloc mandibular defects. Head Neck. 2009;31(3):361–70.

    Article  PubMed  Google Scholar 

  13. Moon HK, Taylor GI. The vascular anatomy of rectus abdominis musculocutaneous flaps based on the deep superior epigastric system. Plast Reconstr Surg. 1988;82:815–32.

    Article  CAS  PubMed  Google Scholar 

  14. Saint-Cyr M, Schaverien M, Arbique G, et al. Three- and four-dimensional computed tomographic angiography and venography for the investigation of the vascular anatomy and perfusion of perforator flaps. Plast Reconstr Surg. 2008;121:772–80.

    Article  CAS  PubMed  Google Scholar 

  15. Blondeel PN, Beyens G, Verhaeghe R, et al. Doppler flowmetry in the planning of perforator flaps. Br J Plast Surg. 1998;51(3):202–9.

    Article  CAS  PubMed  Google Scholar 

  16. Rozen WM, Ribuffo D, Atzeni M, et al. Current state of the art in perforator flap imaging with computed tomographic angiography. Surg Radiol Anat. 2009;31:631–9.

    Article  PubMed  Google Scholar 

  17. Pacifico MD, See MS, Cavale N, et al. Preoperative planning for DIEP breast reconstruction: early experience of the use of computerised tomography angiography with VoNavix 3D software for perforator navigation. J Plast Reconstr Aesthet Surg. 2009;62(11):1464–9.

    Article  CAS  PubMed  Google Scholar 

  18. Dean C, Chetty U, Forrest AP. Effects of immediate breast reconstruction on psychosocial morbidity after mastectomy. Lancet. 1983;1:459–62.

    Article  CAS  PubMed  Google Scholar 

  19. Elder EE, Brandberg Y, Bjorklund T, et al. Quality of life and patient satisfaction in breast cancer patients after immediate breast reconstruction: a prospective study. Breast. 2005;14:201–8.

    Article  PubMed  Google Scholar 

  20. Vile RG, Russell SJ, Lemoine NR. Cancer gene therapy: hard lessons and new courses. Gene Ther. 2000;7:2–8.

    Article  CAS  PubMed  Google Scholar 

  21. Check E. Gene therapy: a tragic setback. Nature. 2002;420:116–8.

    Article  CAS  PubMed  Google Scholar 

  22. Check E. Cancer fears cast doubts on future of gene therapy. Nature. 2003;421:678.

    Article  CAS  PubMed  Google Scholar 

  23. Gene therapy clinical trials worldwide. Hoboken, NJ: John Wiley and Sons; 2007. www.wiley.com/legacy/wileychi/genmed/clinical

  24. Kootstra NA, Verma IM. Gene therapy with viral vectors. Annu Rev Pharmacol Toxicol. 2003;43:413–39.

    Article  CAS  PubMed  Google Scholar 

  25. Blacklow NR, Hoggan MD, Sereno MS, et al. A seroepidemiologic study of adenovirus-associated virus infection in infants and children. Am J Epidemiol. 1971;94:359–66.

    Article  CAS  PubMed  Google Scholar 

  26. Bantel-Schaal U. Adeno-associated parvoviruses inhibit growth of cells derived from malignant human tumors. Int J Cancer. 1990;45:190–4.

    Article  CAS  PubMed  Google Scholar 

  27. Hermonat PL. Adeno-associated virus inhibits human papillomavirus type 16: a viral interaction implicated in cervical cancer. Cancer Res. 1994;54:2278–81.

    PubMed  CAS  Google Scholar 

  28. Walz CM, Anisi TR, Schlehofer JR, et al. Detection of infectious adeno-associated virus particles in human cervical biopsies. Virology. 1998;247:97–105.

    Article  CAS  PubMed  Google Scholar 

  29. Michaels J, Dobryansky M, Galiano RD, et al. Ex vivo transduction of microvascular free flaps for localized peptide delivery. Ann Plast Surg. 2004;52:581–4.

    Article  PubMed  Google Scholar 

  30. Johnson-Saliba M, Jans DA. Gene therapy: optimising DNA delivery to the nucleus. Curr Drug Targets. 2001;2:371–99.

    Article  CAS  PubMed  Google Scholar 

  31. Wells DJ. Electroporation and ultrasound enhanced non-viral gene delivery in vitro and in vivo. Cell Biol Toxicol. 2010;26:21–8.

    Article  CAS  PubMed  Google Scholar 

  32. Wolff JA, Budker V. The mechanism of naked DNA uptake and expression. Adv Genet. 2005;54:3–20.

    PubMed  CAS  Google Scholar 

  33. Ghali S, Bhatt KA, Dempsey MP, Jones DM, Singh S, Aarabi S, Butler PE, Gallo RL, Gurtner GC. Treating chronic wound infections with genetically modified free flaps. Plast Reconstr Surg. 2009;123(4):1157–68.

    Article  CAS  Google Scholar 

  34. Ghali S, Dempsey MP, Jones DM, Grogan RH, Butler PE, Gurtner GC. Plastic surgical delivery systems for targeted gene therapy. Ann Plast Surg. 2008;60:323–32.

    Article  CAS  PubMed  Google Scholar 

  35. Brunetti-Pierri N, Palmer DJ, Beaudet AL, Carey KD, Finegold M, Ng P. Acute toxicity after high-dose systemic injection of helper-dependent adenoviral vectors into nonhuman primates. Hum Gene Ther. 2004;15:35.

    Article  CAS  PubMed  Google Scholar 

  36. Sung M, Chen SH, Thung SM, et al. Intratumoral delivery of adenovirus-mediated interleukin-12 gene in mice with metastatic cancer in the liver. Hum Gene Ther. 2002;13:731.

    Article  CAS  PubMed  Google Scholar 

  37. Portielje JE, Gratama JW, van Ojik HH, Stoter G, Kruit WH. IL-12: a promising adjuvant for cancer vaccination. Cancer Immunol Immunother. 2003;52:133.

    PubMed  CAS  Google Scholar 

  38. Stiefeld SM, Graziani AL, MacGregor RR, Esterhai JL Jr. Toxicities of antimicrobial agents used to treat osteomyelitis. Orthop Clin North Am. 1991;22:439–65.

    PubMed  CAS  Google Scholar 

  39. Holtom PD, Patzakis MJ. Newer methods of antimicrobial delivery for bone and joint infections. Instr Course Lect. 2003;52:745–9.

    PubMed  Google Scholar 

  40. Hiemenz JW, Walsh TJ. Lipid formulations of amphotericin B: recent progress and future directions. Clin Infect Dis. 1996;22(S2):S133–44.

    Article  CAS  PubMed  Google Scholar 

  41. Henry SL, Galloway KP. Local antibacterial therapy for the management of orthopaedic infections: pharmacokinetic considerations. Clin Pharmacokinet. 1995;29:36–45.

    Article  CAS  PubMed  Google Scholar 

  42. Moehring HD, Gravel C, Chapman MW, Olsen SA. Comparison of antibiotic beads and intravenous antibiotics in open fractures. Clin Orthop. 2000;372:254–61.

    Article  Google Scholar 

  43. Hedstrom SA, Lidgren L, Torholm C, Onnerfalt R. Antibiotic containing bone cement beads in the treatment of deep muscle and skeletal infections. Acta Orthop Scand. 1980;51:863–9.

    Article  CAS  PubMed  Google Scholar 

  44. Carretero M, Del Río M, García M, et al. A cutaneous gene therapy approach to treat infection through keratinocyte-targeted overexpression of antimicrobial peptides. FASEB J. 2004;18(15):1931–3.

    Article  CAS  PubMed  Google Scholar 

  45. Munro AJ. An overview of randomised controlled trials of adjuvant chemotherapy in head and neck cancer. Br J Cancer 1995;71:83–91.

    Google Scholar 

  46. Clayman GL, el-Naggar AK, et al. In vivo molecular therapy with p53 adenovirus for microscopic residual head and neck squamous carcinoma. Cancer Res. 1995;55(1):1–6.

    PubMed  CAS  Google Scholar 

  47. Clayman GL, Frank DK, et al. Adenovirus-mediated wild-type p53 gene transfer as a surgical adjuvant in advanced head and neck cancers. Clin Cancer Res. 1999;5(7):1715–22.

    PubMed  CAS  Google Scholar 

  48. Peng Z. Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther. 2005;16(9):1016–27.

    Article  CAS  PubMed  Google Scholar 

  49. Wilson JM. Gendicine: the first commercial gene therapy product. Hum Gene Ther. 2005;16(9):1014–5.

    Article  CAS  PubMed  Google Scholar 

  50. Ganly I, Kirn D, Eckhardt SG, et al. A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res. 2000;6(3):798–806.

    PubMed  CAS  Google Scholar 

  51. Nemunaitis J, Khuri F, Ganly I, et al. Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer. J Clin Oncol. 2001;19(2):289–98.

    Article  CAS  PubMed  Google Scholar 

  52. Khuri FR, Nemunaitis J, Ganly I, et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med. 2000;6(8):879–85.

    Article  CAS  PubMed  Google Scholar 

  53. Li QF, Reis ED, Zhang WX, Silver L, Fallon JT, Weinberg H. Accelerated flap prefabrication with vascular endothelial growth factor. J Reconstr Microsurg. 2000;16:45.

    Article  CAS  PubMed  Google Scholar 

  54. Zhang F, Fischer K, Komorowska-Timek E, et al. Improvement of skin paddle survival by application of vascular endothelial growth factor in a rat TRAM flap model. Ann Plast Surg. 2001;46:314.

    Article  CAS  PubMed  Google Scholar 

  55. Lu F, Mizuno H, Uysal CA, Cai X, Ogawa R, Hyakusoku H. Improved viability of random pattern skin flaps through the use of adipose-derived stem cells. Plast Reconstr Surg. 2008;121(1):50–8.

    Article  CAS  PubMed  Google Scholar 

  56. Gomez-Navarro J, Arafat W, Xiang J. Gene therapy for carcinoma of the breast. Pro-apoptotic gene therapy. Breast Cacner Res. 2000;2:32–44.

    Article  CAS  Google Scholar 

  57. Elledge RM, Allred DC. The p53 tumor suppressor gene in breast cancer. Breast Cancer Res Treat. 1994;32:39–47.

    Article  CAS  PubMed  Google Scholar 

  58. Berns EM, De Witte HH, Klijn JG, et al. Prognostic value of TP53 protein accumulation in human primary breast cancer: an analysis by luminometric immunoassay on 1491 tumor cytosols. Anticancer Res. 1997;17:3003–6.

    PubMed  CAS  Google Scholar 

  59. White E. Tumor biology. p53, guardian of Rb. Nature. 1994;371:21–2.

    Article  CAS  PubMed  Google Scholar 

  60. Wu J. Apoptosis and angiogenesis: two promising tumor markers in breast cancer. Anticancer Res. 1996;16:2233–9.

    PubMed  CAS  Google Scholar 

  61. Sierra A, Lloveras B, Castellsague X, et al. Bcl-2 expression is associated with lymph node metastasis in human ductal breast carcinoma. Int J Cancer. 1995;60:54–60.

    Article  CAS  PubMed  Google Scholar 

  62. Vakkala M, Lahteenmaki K, Raunio H, Paakko P, Soini Y. Apoptosis during breast carcinoma progression. Clin Cancer Res. 1999;5:319–24.

    PubMed  CAS  Google Scholar 

  63. Thornberry NA, Lazebnik Y. Caspases: enemies within. Science. 1998;281:1312–6.

    Article  CAS  PubMed  Google Scholar 

  64. Takamiya Y, Short MP, Ezzeddine ZD, et al. Gene therapy of malignant brain tumors: a rat glioma line bearing the herpes simplex virus type 1-thymidine kinase gene and wild type retrovirus kills other tumor cells. J Neurosci Res. 1992;33:493–503.

    Article  CAS  PubMed  Google Scholar 

Download references

Contributors

All authors contributed to the design, writing, and editing of this manuscript and granted approval of the final version.

Conflicts of Interest

None of the authors have any conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine, Stanford, CA, USA

    Christopher R. Davis, Peter A. Than & Geoffrey C. Gurtner

Authors
  1. Christopher R. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter A. Than
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Geoffrey C. Gurtner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Geoffrey C. Gurtner .

Editor information

Editors and Affiliations

  1. Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Giorgio Giatsidis

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Davis, C.R., Than, P.A., Gurtner, G.C. (2018). Gene Therapy and Free Flaps for Therapeutic Reconstructive Surgery. In: Giatsidis, G. (eds) Gene Therapy in Reconstructive and Regenerative Surgery. Springer, Cham. https://doi.org/10.1007/978-3-319-78957-6_7

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-78957-6_7

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-78956-9

  • Online ISBN: 978-3-319-78957-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation