A FOLLOW-UP STUDY ON AUTOLOGOUS BONE MARROW MONONUCLEAR CELLS TRANSPLANTATION FOR CRITICAL LOWER ARTERIOSCLEROSIS OBLITERANS IN DIABETIC PATIENTS_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

 DOUYanhua ¹ , ZHAOJin ¹ , ZHANGLi ² , WANGXueying ¹ , YUANHong ³ , YUANChunhui ⁴

1. Department of Endocrinology Jinzhou Central Hospital, Jinzhou Liaoning, 121000, P. R. China;
2. Department of Orthopedics, Jinzhou Central Hospital, Jinzhou Liaoning, 121000, P. R. China;
3. Infection Disease Clinic and Research Center, No. 302 Military Hospital of Chinese PLA;
4. Standardized Clinical Cyto-therapeutic Research Center, Chinese Medical Doctor Association-China Armed Police General Hospital;

Corresponding author：

DOUYanhua, Email: douyanhua62@sohu.com

Keywords：

Bone marrow mononuclear cells transplantation; Diabetes mellitus; Arteriosclerosis oblisterans; Overall survival rate; Amputation-free survival rate

DOI：

10.7507/1002-1892.20150192

Video：

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Objective To assess the long-term effectiveness and safety of autologous bone marrow mononuclear cells (BM-MNC) transplantation in the treatment of critical diabetic lower arteriosclerosis obliterans (ASO). Methods Between January 2007 and January 2010, 61 patients with critical diabetic lower ASO were treated with standard medical therapies in 29 cases (control group) or with standard medical therapies and autologous BM-MNC transplantation in 32 cases (treatment group). There was no significant difference in gender, age, disease duration, Fontatine stage, glucose (GLU), triglyceride (TG), total cholesterol (CHOL), low-density lipoprotein-cholesterol (LDL-C), hemoglobin A1c (HbA1c), systolic blood pressure (SBP), and diastolic blood pressure (DBP) between 2 groups (P>0.05). The endpoints were overall survival (OS) and amputation-free survival (AFS). The risk indexes for ASO were observed and compared between 2 groups before and after treatments. Results The patients were followed up 2-36 months, and no malignant tumor occurred. The OS rate, OS time, AFS rate, and AFS time were 82.76% (24/29), (32.31±9.08) months, 37.50% (9/24), and (21.28±13.35) months in the control group and were 78.13% (25/32), (32.47±6.96) months, 68.00% (17/25), and (28.38±9.48) months in the treatment group;all indexes showed no significant differences (P>0.05). OS rate, OS time, AFS rate, and AFS time showed no significant differences between 2 groups at the other time (P>0.05) except AFS time at 1 year, which was significantly short in the control group than the treatment group (t=2.806, P=0.007). At the endpoint of follow-up, the indexes of GLU, TG, CHOL, LDL-C, HbA1c, SBP, and DBP showed no significant differences between before and after treatments and between 2 groups (P>0.05) in 49 survival patients (24 in control group and 25 in treatment group). Conclusion Autologous BM-MNC transplantation is safe and effective in the treatment of critical diabetic lower ASO, which can significantly improve AFS rate and prolong AFS time with no risks.

Citation： DOUYanhua, ZHAOJin, ZHANGLi, WANGXueying, YUANHong, YUANChunhui. A FOLLOW-UP STUDY ON AUTOLOGOUS BONE MARROW MONONUCLEAR CELLS TRANSPLANTATION FOR CRITICAL LOWER ARTERIOSCLEROSIS OBLITERANS IN DIABETIC PATIENTS. Chinese Journal of Reparative and Reconstructive Surgery, 2015, 29(7): 893-898. doi: 10.7507/1002-1892.20150192 Copy

1.	Graziani L,Piaggesi A.Indication and clinical outcomes for below knee endovascular therapy:review article.Catheter Cardiac Interven,2010,75:433-443.
2.	Setacci C, Sirignano P, Galzerano G, et al.Endovascular first as "preliminary approach" for critical limb ischemia and diabetic foot.J Cardiovasc Surg (Torino), 2013,54(6):679-684.
3.	Naoum JJ, Arbid EJ.Endovascular techniques in limb salvage:infrapopliteal angioplasty.Methodist Debakey Cardiovasc J, 2013,9(2):103-107.
4.	Kota SK,Kota SK,Meher LK,et al.Surgical revascularization techniques for diabetic foot.J Cardiovasc Dis Res,2013,4(2):79-83.
5.	Lawall H,Bramlage P,Amann B.Treatment of peripheral arterial disease using stem and progenitor therapy.J Vasc Surg,2011,53(2):445-453.
6.	Tateishi-Yuyama E,Matsubara H,Murohara T,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(9331):427-435.
7.	Hoshino J,Ubara Y,Hara S,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(8):1193-1198.
8.	Saigawa T,Kato K,Ozawa T,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(12):1189-1193.
9.	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 Translat,2011,46(2):278-284.
10.	Sugihara S,Yamamoto Y,Matsubara K,et al.Autoperipheral blood mononuclear cell transplantation improved giant ulcers due to chronic arteriosclerosis obliterans.Heart Vessels,2006,21(4):258-262.
11.	Yang SS,Kim NR,Park KB,et al.A phase I study of human cord blood-derived mesenchymal stem cell therapy in patients with peripheral arterial occlusive disease.Int J Stem Cells,2013,6(1):37-44.
12.	姚克纯,李德芬,贺如意.彩色及脉冲多普勒超声在糖尿病下肢动脉病变诊断中的应用.中国超声医学杂志,1990,6(3):162-165.
13.	谷涌泉,齐立行,郭连瑞,等.自体骨髓干细胞移植治疗严重下肢缺血5例.中国康复医学杂志,2004,19(9):687-688.
14.	Lambert MA,Belch JJ.Medical management of critical limb ischaemia:where do we stand today.J Intern Med,2013,274(4):295-307.
15.	Ness J,Aronow WS.Prevalence of coexistence of coronary artery disease,ischemic stroke,and peripheral arterial disease in older persons,mean age 80 years,in an academic hospital-based geriatrics practice.J Am Geriatr Soc,1999,47(10):1255-1256.
16.	Norgren L,Hiatt WR,Dormandy JA,et al.Inter-society consensus for the management of peripheral arterial disease (TASC Ⅱ).Eur J Vasc Endovasc Surg,2007,33 Suppl 1:S1-75.
17.	Amato B,Compagna R,Della Corte GA,et al.Peripheral blood mono-nuclear cells implantation in patients with peripheral arterial disease:a pilot study for clinical and biochemical outcome of neoangiogenesis.BMC Surg,2012,12 Suppl 1:S1.
18.	Lawall H,Bramlage P,Amann B.Treatment of peripheral arterial disease using stem and progenitor therapy.J Vasc Surg,2011,53(2):445-453.
19.	Bartel RL,Booth E,Cramer C,et al.From bench to bedside:review of gene and cell-based therapies and the slow advancement into phase 3 clinical trials,with a focus on Aastrom's Ixmyelocel-T.Stem Cell Rev and Rep,2013,9(3):373-383.
20.	Yang M,Sheng L,Zhang TR,et al.Stem cell therapy for lower extremity diabetic ulcers:where do we stand? Biomed Res Int,2013,2013:462179.
21.	Matoba S,Tatsumi T,Murohara T,et al.Long-term clinical outcome after intramuscular implantation of bone marrow mononuclear cells (Therapeutic Angiogenesis by Cell Transplantation[TACT]trial) in patients with chronic limb ischemia.Am Heart J,2008,156(5):1010-1008.
22.	赵锦,徐艳,王卓,等.自体骨髓干细胞移植治疗严重下肢动脉硬化闭塞症15例.中国组织工程研究与临床康复,2009,13(40):7959-7963.
23.	Gupta PK,Chullikana A,Parakh R,et al.A double blind randomized placebo controlled phase I/Ⅱ study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia.J Transl Med,2013,11:143.
24.	Bertoluci MC,Pimazoni-Netto A,Pires AC,et al.Diabetes and cardiovascular disease:from evidence to clinical practice-position statement 2014 of Brazilian Diabetes Society.Diabetol Metab Syndr,2014,6:58.
25.	Jonsson TB,Larzon T,Arfvidsson B,et al.Adverse events during treatment of critical limb ischemia with autologous peripheral blood mononuclear cell implant.Int Angiol,2012,31(1):77-84.

1. Graziani L,Piaggesi A.Indication and clinical outcomes for below knee endovascular therapy:review article.Catheter Cardiac Interven,2010,75:433-443.
2. Setacci C, Sirignano P, Galzerano G, et al.Endovascular first as "preliminary approach" for critical limb ischemia and diabetic foot.J Cardiovasc Surg (Torino), 2013,54(6):679-684.
3. Naoum JJ, Arbid EJ.Endovascular techniques in limb salvage:infrapopliteal angioplasty.Methodist Debakey Cardiovasc J, 2013,9(2):103-107.
4. Kota SK,Kota SK,Meher LK,et al.Surgical revascularization techniques for diabetic foot.J Cardiovasc Dis Res,2013,4(2):79-83.
5. Lawall H,Bramlage P,Amann B.Treatment of peripheral arterial disease using stem and progenitor therapy.J Vasc Surg,2011,53(2):445-453.
6. Tateishi-Yuyama E,Matsubara H,Murohara T,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(9331):427-435.
7. Hoshino J,Ubara Y,Hara S,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(8):1193-1198.
8. Saigawa T,Kato K,Ozawa T,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(12):1189-1193.
9. 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 Translat,2011,46(2):278-284.
10. Sugihara S,Yamamoto Y,Matsubara K,et al.Autoperipheral blood mononuclear cell transplantation improved giant ulcers due to chronic arteriosclerosis obliterans.Heart Vessels,2006,21(4):258-262.
11. Yang SS,Kim NR,Park KB,et al.A phase I study of human cord blood-derived mesenchymal stem cell therapy in patients with peripheral arterial occlusive disease.Int J Stem Cells,2013,6(1):37-44.
12. 姚克纯,李德芬,贺如意.彩色及脉冲多普勒超声在糖尿病下肢动脉病变诊断中的应用.中国超声医学杂志,1990,6(3):162-165.
13. 谷涌泉,齐立行,郭连瑞,等.自体骨髓干细胞移植治疗严重下肢缺血5例.中国康复医学杂志,2004,19(9):687-688.
14. Lambert MA,Belch JJ.Medical management of critical limb ischaemia:where do we stand today.J Intern Med,2013,274(4):295-307.
15. Ness J,Aronow WS.Prevalence of coexistence of coronary artery disease,ischemic stroke,and peripheral arterial disease in older persons,mean age 80 years,in an academic hospital-based geriatrics practice.J Am Geriatr Soc,1999,47(10):1255-1256.
16. Norgren L,Hiatt WR,Dormandy JA,et al.Inter-society consensus for the management of peripheral arterial disease (TASC Ⅱ).Eur J Vasc Endovasc Surg,2007,33 Suppl 1:S1-75.
17. Amato B,Compagna R,Della Corte GA,et al.Peripheral blood mono-nuclear cells implantation in patients with peripheral arterial disease:a pilot study for clinical and biochemical outcome of neoangiogenesis.BMC Surg,2012,12 Suppl 1:S1.
18. Lawall H,Bramlage P,Amann B.Treatment of peripheral arterial disease using stem and progenitor therapy.J Vasc Surg,2011,53(2):445-453.
19. Bartel RL,Booth E,Cramer C,et al.From bench to bedside:review of gene and cell-based therapies and the slow advancement into phase 3 clinical trials,with a focus on Aastrom's Ixmyelocel-T.Stem Cell Rev and Rep,2013,9(3):373-383.
20. Yang M,Sheng L,Zhang TR,et al.Stem cell therapy for lower extremity diabetic ulcers:where do we stand? Biomed Res Int,2013,2013:462179.
21. Matoba S,Tatsumi T,Murohara T,et al.Long-term clinical outcome after intramuscular implantation of bone marrow mononuclear cells (Therapeutic Angiogenesis by Cell Transplantation[TACT]trial) in patients with chronic limb ischemia.Am Heart J,2008,156(5):1010-1008.
22. 赵锦,徐艳,王卓,等.自体骨髓干细胞移植治疗严重下肢动脉硬化闭塞症15例.中国组织工程研究与临床康复,2009,13(40):7959-7963.
23. Gupta PK,Chullikana A,Parakh R,et al.A double blind randomized placebo controlled phase I/Ⅱ study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia.J Transl Med,2013,11:143.
24. Bertoluci MC,Pimazoni-Netto A,Pires AC,et al.Diabetes and cardiovascular disease:from evidence to clinical practice-position statement 2014 of Brazilian Diabetes Society.Diabetol Metab Syndr,2014,6:58.
25. Jonsson TB,Larzon T,Arfvidsson B,et al.Adverse events during treatment of critical limb ischemia with autologous peripheral blood mononuclear cell implant.Int Angiol,2012,31(1):77-84.

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Chinese Journal of Reparative and Reconstructive Surgery

A FOLLOW-UP STUDY ON AUTOLOGOUS BONE MARROW MONONUCLEAR CELLS TRANSPLANTATION FOR CRITICAL LOWER ARTERIOSCLEROSIS OBLITERANS IN DIABETIC PATIENTS

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