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Post-Transplant Events

Bone marrow mononuclear cells versus G-CSF-mobilized peripheral blood mononuclear cells for treatment of lower limb ASO: pooled analysis for long-term prognosis

Abstract

In this study, we report the comparative result of long-term clinical prognoses for patients with no-option critical limb ischemia (CLI) caused by arteriosclerosis obliterans, who are implanted with autologous bone marrow mononuclear cells (BMMNC; n=74) or G-CSF-mobilized (M)-PBMNC (n=111), as no information is available on how the two treatments compare in terms of long-term prognosis, such as survival or amputation. We performed pooled analysis using data from two previous cohort studies. All patients had disease of Fontaine classification III or IV. The endpoints were OS and amputation-free survival (AFS). After adjustment for history of dialysis and Fontaine classification, there was no significant difference between the two treatments with respect to OS (hazard ratio (HR)=1.49; 95% confidence interval (CI)=0.74–3.03, P=0.26) or AFS (HR=0.96; 95% CI=0.61–1.51, P=0.87). The negative prognostic factors affecting OS or AFS were the small number of CD34-positive cells collected, history of dialysis, Fontaine classification, male sex and older age. These results suggest that there was no significant difference in long-term prognosis between patients treated with BMMNC and those treated with M-PBMNC. The number of CD34-positive cells collected was an important prognostic factor for amputation and death.

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References

  1. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG et al. Inter-society consensus for the management of peripheral arterial disease (TASC II). Eur J Vasc Endovasc Surg 2007; 33 (Suppl 1): S1–S75.

    Article  Google Scholar 

  2. Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H et al. Therapeutic angiogenesis for patients with limb ischemia by autologous transplantation of bone-marrow cells: a pilot study and a randomized controlled trial. Lancet 2002; 360: 427–435.

    Article  Google Scholar 

  3. Esato K, Hamano K, Li TS, Furutani A, Seyama A, Takenaka H et al. Neovascularization induced by autologous bone marrow cell implantation in peripheral arterial disease. Cell Transplant 2002; 11: 747–752.

    Article  Google Scholar 

  4. Saigawa T, Kato K, Ozawa T, Toba K, Makiyama Y, Minagawa S et al. Clinical application of bone marrow implantation in patients with arteriosclerosis obliterans, and the association between efficacy and the number of implanted bone marrow cells. Circ J 2004; 68: 1189–1193.

    Article  Google Scholar 

  5. Higashi Y, Kimura M, Hara K, Noma K, Jitsuiki D, Nakagawa K et al. Autologous bone-marrow mononuclear cell implantation improves endothelium-dependent vasodilation in patients with limb ischemia. Circulation 2004; 109: 1215–1218.

    Article  Google Scholar 

  6. Miyamoto M, Yasutake M, Takano H, Takagi H, Takagi G, Mizuno H et al. Therapeutic angiogenesis by autologous bone marrow cell implantation for refractory chronic peripheral arterial disease using assessment of neovascularization by 99mTc-tetrofosmin (TF) perfusion scintigraphy. Cell Transplant 2004; 13: 429–437.

    Article  Google Scholar 

  7. Hasebe H, Osada M, Kodama Y, Fujioka D, Sano K, Nakamura T et al. Therapeutic angiogenesis by autologous transplantation of bone-marrow cells in a patient with progressive limb ischemia due to arteriosclerosis obliterans: a case report. J Cardiol 2004; 43: 179–183.

    PubMed  Google Scholar 

  8. Nizankowski R, Petriczek T, Skotnicki A, Szczeklik A . The treatment of advanced chronic lower limb ischaemia with marrow stem cell autotransplantation. Kardiol Pol 2005; 63: 351–360.

    PubMed  Google Scholar 

  9. Kajiguchi M, Kondo T, Izawa H, Kobayashi M, Yamamoto K, Shintani S et al. Safety and efficacy of autologous progenitor cell transplantation for therapeutic angiogenesis in patients with critical limb ischemia. Circ J 2007; 71: 196–201.

    Article  Google Scholar 

  10. Arai M, Misao Y, Nagai H, Kawasaki M, Nagashima K, Suzuki K et al. Granulocyte colony-stimulating factor: a noninvasive regeneration therapy for treating atherosclerotic peripheral artery disease. Circ J 2006; 70: 1093–1098.

    Article  CAS  Google Scholar 

  11. Matoba S, Tatsumi T, Murohara T, Imaizumi T, Katsuda Y, Ito M et al. Long-term clinical outcome after intramuscular implantation of bone marrow mononuclear cells (TACT Trial) in patients with chronic limb ischemia. Am Heart J 2008; 156: 1010–1018.

    Article  Google Scholar 

  12. Tateno K, Minamino T, Toko H, Akazawa H, Shimizu N, Takeda S et al. Critical roles of muscle-secreted angiogenic factors in therapeutic neovascularization. Circ Res 2006; 98: 1194–1202.

    Article  CAS  Google Scholar 

  13. Sugihara S, Yamamoto Y, Matsubara K, Ishida K, Matsuura T, Ando F et al. Autoperipheral blood mononuclear cell transplantation improved giant ulcers due to chronic arteriosclerosis obliterans. Heart Vessels 2006; 21: 258–262.

    Article  Google Scholar 

  14. Kawamura A, Horie T, Tsuda I, Ikeda A, Egawa H, Imamura E et al. Prevention of limb amputation in patients with limb ulcers by autologous peripheral blood mononuclear cell implantation. Ther Apher Dial 2005; 9: 59–63.

    Article  Google Scholar 

  15. Kawamura A, Horie T, Tsuda I, Abe Y, Yamada M, Egawa H et al. Clinical study of therapeutic angiogenesis by autologous peripheral blood stem cell (PBSC) transplantation in 92 patients with critically ischemic limbs. J Artif Organs 2006; 9: 226–233.

    Article  Google Scholar 

  16. Hoshino J, Ubara Y, Hara S, Sogawa Y, Suwabe T, Higa Y et al. Quality of life improvement and long-term effects of peripheral blood mononuclear cell transplantation for severe arteriosclerosis obliterans in diabetic patients on dialysis. Circ J 2007; 71: 1193–1198.

    Article  Google Scholar 

  17. Huang PP, Yang XF, Li SZ, Wen JC, Zhang Y, Han ZC . Randomised comparison of G-CSF-mobilized peripheral blood mononuclear cells versus bone marrow-mononuclear cells for the treatment of patients with lower limb arteriosclerosis obliterans. Thromb Haemost 2007; 98: 1335–1342.

    Article  CAS  Google Scholar 

  18. Horie T, Onodera R, Akamastu M, Ichikawa Y, Hoshino J, Kaneko E et al. Long-term clinical outcomes for patients with lower limb ischemia implanted with G-CSF-mobilized autologous peripheral blood mononuclear cells. Atherosclerosis 2010; 208: 461–466.

    Article  CAS  Google Scholar 

  19. Inaba S, Egashira K, Komori K . Peripheral-blood or bone-marrow mononuclear cells for therapeutic angiogenesis? Lancet 2002; 360: 2083.

    Article  Google Scholar 

  20. Kawamoto A, Katayama M, Handa N, Kinoshita M, Takano H, Horii M et al. Intramuscular transplantation of G-CSF-mobilized CD34(+) cells in patients with critical limb ischemia: a phase I/IIa, multicenter, single-blinded, dose-escalation clinical trial. Stem Cells 2009; 27: 2857–2864.

    Article  CAS  Google Scholar 

  21. Burt RK, Testori A, Oyama Y, Rodriguez HE, Yaung K, Villa M et al. Autologous peripheral blood CD133+ cell implantation for limb salvage in patients with critical limb ischemia. Bone Marrow Transplant 2010; 45: 111–116.

    Article  CAS  Google Scholar 

  22. Fadini GP, Agostini C, Avogaro A . Autologous stem cell therapy for peripheral arterial disease meta-analysis and systematic review of the literature. Atherosclerosis 2010; 209: 10–17.

    Article  CAS  Google Scholar 

  23. Maldonado G, Greenland S . Simulation study of confounder-selection strategies. Am J Epidemiol 1993; 138: 923–936.

    Article  CAS  Google Scholar 

  24. Shigematsu H, Yasuda K, Tanabe T . Clinical outcomes and diagnostic standard in patients with critical leg ischemia in Japan. Ther Res 1992; 13: 4099–4109.

    Google Scholar 

  25. Koch M, Trapp R, Kulas W, Grabensee B . Critical limb ischaemia as a main cause of death in patients with end-stage renal disease: a single-centre study. Nephrol Dial Transplant 2004; 19: 2547–2552.

    Article  Google Scholar 

  26. Biancari F, Kantonen I, Mätzke S, Albäck A, Roth WD, Edgren J et al. Infrainguinal endovascular and bypass surgery for critical leg ischemia in patients on long-term dialysis. Ann Vasc Surg 2002; 16: 210–214.

    Article  Google Scholar 

  27. Schanzer A, Mega J, Meadows J, Samson RH, Bandyk DF, Conte MS . Risk stratification in critical limb ischemia: derivation and validation of a model to predict amputation-free survival using multicenter surgical outcomes data. J Vasc Surg 2008; 48: 1464–1471.

    Article  Google Scholar 

  28. Fadini GP, Sartore S, Albiero M, Baesso I, Murphy E, Menegolo M et al. Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol 2006; 26: 2140–2146.

    Article  CAS  Google Scholar 

  29. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001; 89: e1–e7.

    Article  CAS  Google Scholar 

  30. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003; 348: 593–600.

    Article  Google Scholar 

  31. Choi JH, Kim KL, Huh W, Kim B, Byun J, Suh W et al. Decreased number and impaired angiogenic function of endothelial progenitor cells in patients with chronic renal failure. Arterioscler Thromb Vasc Biol 2004; 24: 1246–1252.

    Article  CAS  Google Scholar 

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Correspondence to R Onodera.

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Appendix

Appendix

BMMNC follow-up study investigators

Kyoto Prefectural University of Medicine: Satoaki Matoba, Tetsuya Tatsumi, Hiroaki Matsubara. Nagoya University Graduate School of Medicine: Toyoaki Murohara, Takahisa Kondo. Kurume University School of Medicine: Tsutomu Imaizumi, Yousuke Katsuda, Yasuyuki Toyama. Gunma University School of Medicine: Shigeru Saito, Saiseikai Wakayama Hospital: Hiroyoshi Komai. Mie University Graduate School of Medicine: Masaaki Ito, Hitoshi Iwasaki. Nara Medical University: Yoshihiko Saito, Satoshi Okayama. Showa University School of Medicine: Hiroshi Suzuki, Teruko Hayada. Osaka City University Graduate School of Medicine: Shinya Fukumoto. Kochi University School of Medicine: Hironori Maeda. Tottori University Graduate School of Medical Science: Yasutaka Yamamoto.

M-PBMNC follow-up study investigators

Department of Surgery, Sapporo Hokuyu Hospital: Takashi Horie, Akio Kawamura. Department of Hemodialysis and Aphaeresis, Itabashi Chuo Hospital: Makoto Akamastu. Kanagawa Cardiovascular and Respiratory Center: Yukio Ichikawa. Kidney Center, Toranomon, Hospital: Junichi Hoshino. Department of Geriatrics and Vascular medicine, Tokyo Medical and Dental University: Eiji Kaneko. Department of Surgery, National Hospital Organization Chiba-East Hospital: Chikara Iwashita. Department of Transfusion Medicine and Cell Therapy, Faculty of Medicine, Keio University: Akaru Ishida. Hemodialysis and Aphaeresis Center, Kitano Hospital, The Tazuke Kofukai Medical Research Institute: Tatsuo Tsukamoto.

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Onodera, R., Teramukai, S., Tanaka, S. et al. Bone marrow mononuclear cells versus G-CSF-mobilized peripheral blood mononuclear cells for treatment of lower limb ASO: pooled analysis for long-term prognosis. Bone Marrow Transplant 46, 278–284 (2011). https://doi.org/10.1038/bmt.2010.110

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