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1、粒细胞集落刺激因子能增强骨髓源单个核细胞治疗下肢缺血的作用,谷涌泉,郭连瑞,吴英锋,张建,汪忠镐 首都医科大学宣武医院血管外科首都医科大学血管外科研究所,骨髓单个核细胞治疗下肢缺血的临床试验,有利报道越来越多但是骨髓采集量过大：达 0.5 to 1 L 需要全麻对高龄患者仍很危险单个核细胞的采集量只有109,Tateishi-Yuyama,2002;Gu,2003;Huang,2004;Miyamoto,2004;Higashi,2004,粒细胞集落刺激因子(G-CSF),是一种细胞因子能诱导内皮细胞增生和迁移全身给药能促进心梗区域和缺血肢体生成新生血管,Amgen Yamamoto,1996
2、;Powell,2005;Huang,2005；Masuda,2003；Kocher,2001,目 的,G-CSF的预处理能否增加骨髓中单个核细胞的收获量,进而减少采髓量，但却增强其肢体血管新生效应?,回顾性研究,*历史对照,入选标准,重度间歇跛行静息痛溃疡坏疽,入选标准,不适合行介入治疗及外科搭桥手术因为缺乏流出道或缺乏移植物介入或外科治疗失败者一般状况差,排除标准,控制不佳的糖尿病(HbA1C6.5g/dl)五年之内的肿瘤患者,或术前肿瘤标记物明显升高者(CEA,PSA,CA-153)心绞痛器官功能衰竭(心、肝、肾)脓毒血症 肢体大范围坏疽难以保肢者,G-CSF 预处理,300g/d，IH
3、,Qd,for 2 days 白细胞升至23(15 38)109/L预防心梗及脑血管意外LMWH，40-60 mg,IH,Bid Aspirin，100 mg,Qd,采集骨髓单个核细胞,局麻髂后上棘抽取骨髓取出骨渣及红细胞密度梯度离心法（Percol 1.077,400g,20min）,BM-MNC 移植,I M,I A,移植途径,我们既往的研究发现肌注法和动脉腔内移植法两种移植途径的治疗效果没有明显差异。,Gu,et al.Chin J Clin Rehab,2004,8(35)：7970-2.;Guo,et al.Chin J Clin Rehab,2005,9(10):57-9,结果BM
4、-MNC 收获量,每毫升骨髓的单个核细胞收获量提高10.8倍,主观症状的改善移植后2月-,主观症状-疼痛,冷感和麻木感,(P=0.011),95%,84%,完全缓解,改善,总体改善,TcPO2 术后2月,89%),92%),P0.05,踝肱指数增加0.1 术后2月,(P 0.05).,45%,38%,结果（1）-并发症,与使用 G-CSF 相关:轻度发热：1 例 疲乏无力：2 例 均未经处理而自行康复BM-MNC 移植后:心梗：1 例在动员组(术后1周)死于心衰:2 例均在未动员组:(分别于术后第2周和第7周),保肢情况-2月后-,2.3%,12.6%,P0.05,结果（7）间歇跛行距离-术后
5、2月,跛行距离测定:-常速-在病房的楼道,结果（8）-血管造影（术后4-8周）,两组间有显著性差异.,91%,55%,P0.001,术前,术后,术前,8周后,（G-CSF 动员组）,术后,1年随访,结论,G-CSF 能明显增加的收获量.G-CSF预处理能减少骨髓采集量，并增强BM-MNC的促血管新生作用.需要进行多中心前瞻性随机对照研究证实.,谢谢！,Granulocyte Colony-stimulating factor can enhance the angiogenic effect of bone marrow mononuclear cells treating limb isch
6、emia,Guo LR,Gu YQ,Wu YF,Zhang J,Wang ZG*Vascular Surgery Department of Xuanwu Hospital;Capital Medical University，Beijing，China,Clinical Trials of BM-MNCTo Treat Lower limb Ischemia,Favorable reports But:Typically the harvest requires 0.5 to 1 liter Need general anesthesiaRisk to elderly patientsThe
7、 MNC yield is only about a billion cells,Tateishi-Yuyama,2002;Gu,2003;Huang,2004;Miyamoto,2004;Higashi,2004,Granulocyte Colony Stimulating Factor(G-CSF),Cytokine that stimulates the bone marrowInduces endothelial cells to proliferate and migrateReported to enhance neo-vasculogenesis in infracted hea
8、rts and ischemic limbs.,Amgen Yamamoto,1996;Powell,2005;Huang,2005；Masuda,2003；Kocher,2001,Objective,Can pre-treatment with G-CSF enhance the harvest of BM-MNC，then decrease the BM harvest,but enhance the angiogenic efficacy to treat lower limb ischemia?,Retrospective Study,*historical control,Inclu
9、sion criteria,Severe claudicationRest painNon-healing ulcerGangrene,Patients were not candidates for endovascular or vascular surgery duo tolack of either suitable conduit lack of suitable anastomotic targetsPoor medical condition,Exclusion criteria,Poorly-controlled diabetes(HbA1C6.5g/dl)Confirmed
10、malignancy during the past 5 years,or elevated serum tumor markers preoperatively(CEA,PSA,CA-153)AnginaEnd stage organ failure(heart,liver&kidney)Sepsis Limb necrosis requiring amputation independent of blood flow,G-CSF pre-treatment,300g/d IH,Qd,for 2 days WBC increased to 23(15 38)109/LPrecaution
11、against MI,stroke LMWH 40-60 mg,IH,Bid Aspirin 100 mg,Qd,Harvest of BM-MNCs,local anesthesia(1%lidocaine)Aspiration of bone-marrow from the posterior superior iliac crest remove bone spicules and erythrocytesdensity gradient centrifugation（Percol 1.077,400g,20min）,BM-MNC Implantation,I M,I A,Deliver
12、y routes,No significant difference in therapeutic effect has been reported between the delivery routes.,Gu,et al.Chin J Clin Rehab,2004,8(35)：7970-2.;Guo,et al.Chin J Clin Rehab,2005,9(10):57-9,ResultsBM-MNC Harvested,10.8 fold increase in MNC when corrected for each ml of BM harvested,Improvement o
13、f Subjective Symptoms 2 Months Post-op-,Subjective symptoms-Pain,coolness and numbness,(P=0.011),95%,84%,TcPO2 2 Months Post-op,89%),92%),P0.05,Ankle Brachial Index Increase 0.1 2 Months Post-op,(P 0.05).,45%,38%,Results（1）-Complications,of G-CSF administration:mild fever：1 patient transient lassitu
14、de：2 patients All of them recovered without intervention.following BM-MNC implantation:myocardial infarction：1 in Gp1(1 week post-op)died of heart failure:2 pts In Gp 2:(2 and 7 weeks post-op),Limb Salvage 2 months post-op-,2.3%,12.6%,P0.05,Results（7）at 2 mon post-op Improvement of pain-free walking
15、 distance of claudicants,Assessment of pain-free walking distance:-a constant speed-on the same corridor in our ward,Results（8）at 4-8 wks post-op-Angiography,There was significant difference between the two groups.,91%,55%,P0.001,Pre-op,Post-op,Before operation,8 weeks after operation,A patient in G
16、roup 1（with G-CSF pre-treatment）,8 weeks post-op,One-year follow-up,Conclusion,G-CSF increased the yield of BM-MNC 10.8 fold per ml of bone marrow harvested.The angiogenic benefit could be enhanced despite the smaller volume of BM harvested after G-CSF pre-treatment.A prospective,randomized,controlled study should be strongly recommended.,Thank you for your attention！,
