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Percutaneous Thermal Ablation of Spine Metastasis

  • Alexander Theologis
  • Jack W. Jennings
  • Jacob M. Buchowski
Chapter

Abstract

As patients with cancer are living longer, metastatic spine disease is becoming an ever-increasing burden in the oncology patient. While radiation is the current standard of care for painful metastatic spinal disease without associated mechanical instability or neurologic symptoms, radiation therapy alone may lead to insufficient pain relief and inadequate tumor control and may not prevent vertebral collapse. Furthermore, radiation therapy can lead to complications ranging from mild (e.g., skin irritation) to severe (e.g., postradiation myelopathy). As such, alternative minimally invasive, image-guided treatment strategies that do not interfere with systemic therapies have been developed to improve outcomes for this patient population. Two such modalities, radiofrequency ablation (RFA) and cryoablation, have demonstrated to be particularly useful tools for this endeavor. In this chapter, we will discuss the current indications for RFA and cryoablation in the treatment of spinal metastases and how each technique is performed. We also present the most current evidence regarding each modality’s efficacy in the treatment of patients with spinal metastases and the importance of supplemental cement augmentation. A discussion of their limitations and risk profiles will be provided so as to emphasize that a fundamental working knowledge of ablation principles and technologies is needed to perform these techniques safely.

Keywords

Metastatic tumors Spine Pain Vertebral body Pedicle Radiofrequency ablation (RFA) Cryoablation Vertebroplasty Kyphoplasty Fracture Spinal cord injury Radiculopathy 

References

  1. 1.
    National Cancer Institute. Cancer statistics. National Institutes of Health; 2016.Google Scholar
  2. 2.
    Wallace A, Robinson C, Meyer J, Tran N, Gangi A, Callstrom M, et al. The metastatic spine disease multidisciplinary working group algorithms. Oncologist. 2015;20(10):1205–15.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Hillen T, Anchala P, Friedman M, Jennings J. Treatment of metastatic posterior vertebral body osseous tumors by using a targeted bipolar radiofrequency ablation device: technical note. Radiology. 2014;273(1):261–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Wiltse L, Fonseca A, Amster J, Dimartino P, Ravessoud F. Relationship of the dura, Hofmann’s ligaments, Batson's plexus, and a fibrovascular membrane lying on the posterior surface of the vertebral bodies and attaching to the deep layer of the posterior longitudinal ligament. An anatomical, radiologic, and clin. Spine (Phila Pa 1976). 1993;18(8):1030–43.CrossRefGoogle Scholar
  5. 5.
    Stopeck A, Lipton A, Body J, Steger G, Tonkin K, de Boer R, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813–22.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Henry D, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29(9):1125–32.CrossRefPubMedGoogle Scholar
  8. 8.
    Harrison M, Wong T, Armstrong A, George D. Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease. Cancer Manag Res. 2013;5:1–14.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Quilty P, Kirk D, Bolger J, Dearnaley D, Lewington V, Mason M, et al. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol. 1994;31(1):33–40.CrossRefPubMedGoogle Scholar
  10. 10.
    Serafini A, Houston S, Resche I, Quick D, Grund F, Ell P, et al. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol. 1998;16(4):1574–81.CrossRefPubMedGoogle Scholar
  11. 11.
    Wong M, Stockler M, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2012;2:CD003474.Google Scholar
  12. 12.
    Yuen K, Shelley M, Sze W, Wilt T, Mason M. Bisphosphonates for advanced prostate cancer. Cochrane Database Syst Rev. 2006;4:CD006250.Google Scholar
  13. 13.
    Lopez-Olivo M, Shah N, Pratt G, Risser J, Symanski E, Suarez-Almazor M. Bisphosphonates in the treatment of patients with lung cancer and metastatic bone disease: a systematic review and meta-analysis. Support Care Cancer. 2012;20(11):2985–98.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hortobagyi G, Theriault R, Porter L, Blayney D, Lipton A, Sinoff C, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med. 1996;335(24):1785–91.CrossRefPubMedGoogle Scholar
  15. 15.
    Conte P, Latreille J, Mauriac L, Calabresi F, Santos R, Campos D, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol. 1996;14(9):2552–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Goetz M, Callstrom M, Charboneau J, Farrell M, Maus T, Welch T, et al. Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol. 2004;22(2):300–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Massie M, Holland J. The cancer patient with pain: psychiatric complications and their management. J Pain Symptom Manag. 1992;7(2):99–109.CrossRefGoogle Scholar
  18. 18.
    Spiegel D, Sands S, Koopman C. Pain and depression in patients with cancer. Cancer. 1994;74(9):2570–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Kim J, Losina E, Bono C, Schoenfeld A, Collins J, Katz J, et al. Clinical outcome of metastatic spinal cord compression treated with surgical excision ± radiation versus radiation therapy alone: a systematic review of literature. Spine (Phila Pa 1976). 2012;37(1):78–84.CrossRefGoogle Scholar
  20. 20.
    Fisher C, DiPaola C, Ryken T, Bilsky M, Shaffrey C, Berven S, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine (Phila Pa 1976). 2010;35(22):E1221–9.CrossRefGoogle Scholar
  21. 21.
    Fourney D, Frangou E, Ryken T, Dipaola C, Shaffrey C, Berven S, et al. Spinal instability neoplastic score: an analysis of reliability and validity from the spine oncology study group. J Clin Oncol. 2011;29(22):3072–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Gerszten P, Burton S, Ozhasoglu C, Welch W. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine (Phila Pa 1976). 2007;32(2):193–9.CrossRefGoogle Scholar
  23. 23.
    Choi C, Adler J, Gibbs I, Chang S, Jackson P, Minn A, et al. Stereotactic radiosurgery for treatment of spinal metastases recurring in close proximity to previously irradiated spinal cord. Int J Radiat Oncol Biol Phys. 2010;78(2):499–506.CrossRefPubMedGoogle Scholar
  24. 24.
    Ahmed K, Stauder M, Miller R, Bauer H, Rose P, Olivier K, et al. Stereotactic body radiation therapy in spinal metastases. Int J Radiat Oncol Biol Phys. 2012;82(5):e803–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Ryu S, Yoon H, Stessin A, Gutman F, Rosiello A, Davis R. Contemporary treatment with radiosurgery for spine metastasis and spinal cord compression in 2015. Radiat Oncol J. 2015;33(1):1–11.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Valesin Filho E, de Abreu L, Lima G, de Cubero D, Ueno F, Figueiredo G, et al. Pain and quality of life in patients undergoing radiotherapy for spinal metastatic disease treatment. Int Arch Med. 2013;6(1):6.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Tong D, Gillick L, Hendrickson F. The palliation of symptomatic osseous metastases; final results of the study by the radiation therapy oncology group. Cancer. 1982;50(5):893–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Madsen E. Painful bone metastasis: efficacy of radiotherapy assessed by the patients: a randomized trial comparing 4 Gy X 6 versus 10 Gy X 2. Int J Radiat Oncol Biol Phys. 1983;9(12):1775–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Blitzer P. Reanalysis of the RTOG study of the palliation of symptomatic osseous metastasis. Cancer. 1985;55(7):1468–72.CrossRefPubMedGoogle Scholar
  30. 30.
    Price P, Hoskin P, Easton D, Austin D, Palmer S, Yarnold J. Prospective randomised trial of single and multifraction radiotherapy schedules in the treatment of painful bony metastases. Radiother Oncol. 1986;6(4):247–55.CrossRefPubMedGoogle Scholar
  31. 31.
    Arcangeli G, Micheli A, Giannarelli D, La Pasta O, Tollis A, Vitullo A, et al. The responsiveness of bone metastases to radiotherapy: the effect of site, histology and radiation dose on pain relief. Radiother Oncol. 1989;14(2):95–101.CrossRefPubMedGoogle Scholar
  32. 32.
    Cole D. A randomized trial of a single treatment versus conventional fractionation in the palliative radiotherapy of painful bone metastases. Clin Oncol (R Coll Radiol). 1989;1(2):59–62.CrossRefGoogle Scholar
  33. 33.
    Poulter C, Cosmatos D, Rubin P, Urtasun R, Cooper J, Kuske R, et al. A report of RTOG 8206: a phase III study of whether the addition of single dose hemibody irradiation to standard fractionated local field irradiation is more effective than local field irradiation alone in the treatment of symptomatic osseous metastases. Int J Radiat Oncol Biol Phys. 1992;23(1):207–14.CrossRefPubMedGoogle Scholar
  34. 34.
    Arcangeli G, Giovinazzo G, Saracino B, D’Angelo L, Giannarelli D, Micheli A. Radiation therapy in the management of symptomatic bone metastases: the effect of total dose and histology on pain relief and response duration. Int J Radiat Oncol Biol Phys. 1998;42(5):1119–26.CrossRefPubMedGoogle Scholar
  35. 35.
    Ratanatharathorn V, Powers W, Moss W, Perez C. Bone metastasis: review and critical analysis of random allocation trials of local field treatment. Int J Radiat Oncol Biol Phys. 1999;44(1):1–18.CrossRefPubMedGoogle Scholar
  36. 36.
    Chow E, Harris K, Fan G, Tsao M, Sze W. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol. 2007;25(11):1423–36.CrossRefPubMedGoogle Scholar
  37. 37.
    Chow E, Zeng L, Salvo N, Dennis K, Tsao M, Lutz S. Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol). 2012;24(2):112–24.CrossRefGoogle Scholar
  38. 38.
    Agarawal J, Swangsilpa T, van der Linden Y, Rades D, Jeremic B, Hoskin P. The role of external beam radiotherapy in the management of bone metastases. Clin Oncol (R Coll Radiol). 2006;18(10):747–60.CrossRefGoogle Scholar
  39. 39.
    Lo S, Sahgal A, Hartsell W, Lutz S, Kardamakis D, van der Linden Y, et al. No the treatment of bone metastasis with highly conformal radiation therapy: a brave new world or a costly mistake? Clin Oncol (R Coll Radiol). 2009;21(9):662–4.CrossRefGoogle Scholar
  40. 40.
    Van der Linden Y, Steenland E, van Houwelingen H, Post W, Oei B, Marijnen C, et al. Patients with a favourable prognosis are equally palliated with single and multiple fraction radiotherapy: results on survival in the Dutch Bone Metastasis Study. Radiother Oncol. 2006;78(3):245–53.CrossRefPubMedGoogle Scholar
  41. 41.
    Wallace A, Greenwood T, Jennings J. Radiofrequency ablation and vertebral augmentation for palliation of painful spinal metastases. J Neuro-Oncol. 2015;124(1):111–8.CrossRefGoogle Scholar
  42. 42.
    Greenwood T, Wallace A, Friedman M, Hillen T, Robinson C, Jennings J. Combined ablation and radiation therapy of spinal metastases: a novel multimodality treatment approach. Pain Physician. 2015;18(6):573–81.PubMedGoogle Scholar
  43. 43.
    Chang U, Cho W, Kim M, Cho C, Lee D, Rhee C. Local tumor control after retreatment of spinal metastasis using stereotactic body radiotherapy; comparison with initial treatment group. Acta Oncol. 2012;51(5):589–95.CrossRefPubMedGoogle Scholar
  44. 44.
    Masucci G, Yu E, Ma L, Chang E, Letourneau D, Lo S, et al. Stereotactic body radiotherapy is an effective treatment in reirradiating spinal metastases: current status and practical considerations for safe practice. Expert Rev Anticancer Ther. 2011;11(12):1923–33.CrossRefPubMedGoogle Scholar
  45. 45.
    Anchala P, Irving W, Hillen T, Friedman M, Georgy B, Coldwell D, et al. Treatment of metastatic spinal lesions with a navigational bipolar radiofrequency ablation device: a multicenter retrospective study. Pain Physician. 2014;17(4):317–27.PubMedGoogle Scholar
  46. 46.
    Theodorescu D. Cancer cryotherapy: evolution and biology. Rev Urol. 2004;6(Suppl 4):S9–S19.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Gage A, Baust J. Cryosurgery for tumors. J Am Coll Surg. 2007;205(2):342–56.CrossRefPubMedGoogle Scholar
  48. 48.
    Ullrick S, Hebert J, Davis K. Cryoablation in the musculoskeletal system. Curr Probl Diagn Radiol. 2008;37(1):39–48.CrossRefPubMedGoogle Scholar
  49. 49.
    McGhana J, Dodd G 3rd. Radiofrequency ablation of the liver: current status. AJR Am J Roentgenol. 2001;176(1):3–16.CrossRefPubMedGoogle Scholar
  50. 50.
    Hoffmann R, Jakobs T, Trumm C, Helmberger T, Reiser M. RFA of renal cell carcinoma in a solitary kidney. Abdom Imaging. 2008;33(2):230–6.CrossRefPubMedGoogle Scholar
  51. 51.
    Brace C. Radiofrequency and microwave ablation of the liver, lung, kidney, and bone: what are the differences? Curr Probl Diagn Radiol. 2009;38(3):135–43.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Lane M, Le H, Lee S, Young C, Heran M, Badii M, et al. Combination radiofrequency ablation and cementoplasty for palliative treatment of painful neoplastic bone metastasis: experience with 53 treated lesions in 36 patients. Skelet Radiol. 2011;40(1):25–32.CrossRefGoogle Scholar
  53. 53.
    Thanos L, Mylona S, Galani P, Tzavoulis D, Kalioras V, Tanteles S, et al. Radiofrequency ablation of osseous metastases for the palliation of pain. Skelet Radiol. 2008;37(3):189–94.CrossRefGoogle Scholar
  54. 54.
    Gevargez A, Groenemeyer D. Image-guided radiofrequency ablation (RFA) of spinal tumors. Eur J Radiol. 2008;65(2):246–52.CrossRefPubMedGoogle Scholar
  55. 55.
    Callstrom M, Charboneau J, Goetz M, Rubin J, Wong G, Sloan J, et al. Painful metastases involving bone: feasibility of percutaneous CT- and US-guided radio-frequency ablation. Radiology. 2002;224(1):87–97.CrossRefPubMedGoogle Scholar
  56. 56.
    Tomasian A, Wallace A, Northrup B, Hillen T, Jennings J. Spine cryoablation: pain palliation and local tumor control for vertebral metastases. AJNR Am J Neuroradiol. 2016;37(1):189–95.CrossRefPubMedGoogle Scholar
  57. 57.
    Prologo J, Passalacqua M, Patel I, Bohnert N, Corn D. Image-guided cryoablation for the treatment of painful musculoskeletal metastatic disease: a single-center experience. Skelet Radiol. 2014;43(11):1551–9.CrossRefGoogle Scholar
  58. 58.
    Thacker P, Callstrom M, Curry T, Mandrekar J, Atwell T, Goetz M, et al. Palliation of painful metastatic disease involving bone with imaging-guided treatment: comparison of patients’ immediate response to radiofrequency ablation and cryoablation. AJR Am J Roentgenol. 2011;197(2):510–5.CrossRefPubMedGoogle Scholar
  59. 59.
    Callstrom M, Atwell T, Charboneau J, Farrell M, Goetz M, Rubin J, et al. Painful metastases involving bone: percutaneous image-guided cryoablation—prospective trial interim analysis. Radiology. 2006;241(2):572–80.CrossRefPubMedGoogle Scholar
  60. 60.
    De Freitas R, de Menezes M, Cerri G, Gangi A. Sclerotic vertebral metastases: pain palliation using percutaneous image-guided cryoablation. Cardiovasc Interv Radiol. 2011;34(Suppl 2):S294–9.CrossRefGoogle Scholar
  61. 61.
    Callstrom M, Dupuy D, Solomon S, Beres R, Littrup P, Davis K, et al. Percutaneous image-guided cryoablation of painful metastases involving bone: multicenter trial. Cancer. 2013;119(5):1033–41.CrossRefPubMedGoogle Scholar
  62. 62.
    McMenomy B, Kurup A, Johnson G, Carter R, McWilliams R, Markovic S, et al. Percutaneous cryoablation of musculoskeletal oligometastatic disease for complete remission. J Vasc Interv Radiol. 2013;24(2):207–13.CrossRefPubMedGoogle Scholar
  63. 63.
    Masala S, Chiocchi M, Taglieri A, Bindi A, Nezzo M, De Vivo D, et al. Combined use of percutaneous cryoablation and vertebroplasty with 3D rotational angiograph in treatment of single vertebral metastasis: comparison with vertebroplasty. Neuroradiology. 2013;55(2):193–200.CrossRefPubMedGoogle Scholar
  64. 64.
    Kurup A, Woodrum D, Morris J, Atwell T, Schmit G, Welch T, et al. Cryoablation of recurrent sacrococcygeal tumors. J Vasc Interv Radiol. 2012;23(8):1070–5.CrossRefPubMedGoogle Scholar
  65. 65.
    Rodriguez Castañeda W, Callstrom M. Effective pain palliation and prevention of fracture for axial-loading skeletal metastases using combined cryoablation and cementoplasty. Tech Vasc Interv Radiol. 2011;14(3):160–9.CrossRefGoogle Scholar
  66. 66.
    Wallace A, Greenwood T, Jennings J. Use of imaging in the management of metastatic spine disease with percutaneous ablation and vertebral augmentation. AJR Am J Roentgenol. 2015;205(2):434–41.CrossRefPubMedGoogle Scholar
  67. 67.
    Nour S, Aschoff A, Mitchell I, Emancipator S, Duerk J, Lewin J. MR imaging-guided radio-frequency thermal ablation of the lumbar vertebrae in porcine models. Radiology. 2002;224(2):452–62.CrossRefPubMedGoogle Scholar
  68. 68.
    Froese G, Das R, Dunscombe P. The sensitivity of the thoracolumbar spinal cord of the mouse to hyperthermia. Radiat Res. 1991;125(2):173–80.CrossRefPubMedGoogle Scholar
  69. 69.
    Letcher F, Goldring S. The effect of radiofrequency current and heat on peripheral nerve action potential in the cat. J Neurosurg. 1968;29(1):42–7.CrossRefPubMedGoogle Scholar
  70. 70.
    Dupuy D, Hong R, Oliver B, Goldberg S. Radiofrequency ablation of spinal tumors: temperature distribution in the spinal canal. AJR Am J Roentgenol. 2000;175(5):1263–6.CrossRefPubMedGoogle Scholar
  71. 71.
    Yamane T, Tateishi A, Cho S, Manabe S, Yamanashi M, Dezawa A, et al. The effects of hyperthermia on the spinal cord. Spine (Phila Pa 1976). 1992;17(11):1386–91.CrossRefGoogle Scholar
  72. 72.
    Van der Linden E, Kroft L, Dijkstra P. Treatment of vertebral tumor with posterior wall defect using image-guided radiofrequency ablation combined with vertebroplasty: preliminary results in 12 patients. J Vasc Interv Radiol. 2007;18(6):741–7.CrossRefPubMedGoogle Scholar
  73. 73.
    Nakatsuka A, Yamakado K, Takaki H, Uraki J, Makita M, Oshima F, et al. Percutaneous radiofrequency ablation of painful spinal tumors adjacent to the spinal cord with real-time monitoring of spinal canal temperature: a prospective study. Cardiovasc Interv Radiol. 2009;32(1):70–5.CrossRefGoogle Scholar
  74. 74.
    Kurup A, Morris J, Boon A, Strommen J, Schmit G, Atwell T, et al. Motor evoked potential monitoring during cryoablation of musculoskeletal tumors. J Vasc Interv Radiol. 2014;25(11):1657–64.CrossRefPubMedGoogle Scholar
  75. 75.
    Rybak L, Gangi A, Buy X, La Rocca Vieira R, Wittig J. Thermal ablation of spinal osteoid osteomas close to neural elements: technical considerations. AJR Am J Roentgenol. 2010;195(4):W293–8.CrossRefPubMedGoogle Scholar
  76. 76.
    Wallace A, Vyhmeister R, Hsi A, Robinson C, Chang R, Jennings J. Delayed vertebral body collapse after stereotactic radiosurgery and radiofrequency ablation: case report with histopathologic-MRI correlation. Interv Neuroradiol. 2015;21(6):742–9.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Grönemeyer D, Schirp S, Gevargez A. Image-guided radiofrequency ablation of spinal tumors: preliminary experience with an expandable array electrode. Cancer J. 2002;8(1):33–9.CrossRefPubMedGoogle Scholar
  78. 78.
    Ha K, Kim Y, Yoo T. Intraoperative radiofrequency ablation for metastatic spine disease: report of 4 cases and review. Eur J Orthop Surg Traumatol. 2013;23(Suppl 2):S129–34.CrossRefPubMedGoogle Scholar
  79. 79.
    Bagla S, Sayed D, Smirniotopoulos J, Brower J, Neal RJ, Dick B, et al. Multicenter prospective clinical series evaluating radiofrequency ablation in the treatment of painful spine metastases. Cardiovasc Interv Radiol. 2016;39(9):1289–97.CrossRefGoogle Scholar
  80. 80.
    Zwart J, Sand T, Unsgaard G. Warm and cold sensory thresholds in patients with unilateral sciatica: C fibers are more severely affected than A-delta fibers. Acta Neurol Scand. 1998;97(1):41–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Alexander Theologis
    • 1
  • Jack W. Jennings
    • 2
  • Jacob M. Buchowski
    • 3
  1. 1.Department of Orthopaedic SurgeryUniversity of California—San Francisco (UCSF)San FranciscoUSA
  2. 2.Department of RadiologyMallinckrodt Institute of Radiology, Washington University School of Medicine, Barnes-Jewish HospitalSt. LouisUSA
  3. 3.Department of Orthopaedic SurgeryBJC Institute of Health, Washington University in St. Louis—School of MedicineSt. LouisUSA

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