***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVES Cell therapy is a novel experimental treatment modality for patients with critical limb ischemia ( CLI ) of the lower extremities and no other established treatment options . This study was conducted to assess the safety and clinical efficacy of intramuscular injection of autologous tissue repair cells ( TRCs ) . METHODS A prospect i ve , r and omized double-blinded , placebo controlled , multicenter study ( RESTORE-CLI ) was conducted at 18 centers in the United States in patients with CLI and no option for revascularization . Enrollment of 86 patients began in April 2007 and ended in February 2010 . For the prospect ively planned interim analysis , conducted in February 2010 , 33 patients had the opportunity to complete the trial ( 12 months of follow-up ) , and 46 patients had completed at least 6 months of follow-up . The interim analysis included analysis of both patient population s. An independent physician performed the bone marrow or sham control aspiration . The aspirate was processed in a closed , automated cell manufacturing system for approximately 12 days to generate the TRC population of stem and progenitor cells . An average of 136 ± 41 × 10(6 ) total viable cells or electrolyte ( control ) solution were injected into 20 sites in the ischemic lower extremity . The primary end point was safety as evaluated by adverse events , and serious adverse events as assessed at multiple follow-up time points . Clinical efficacy end points included major amputation-free survival and time to first occurrence of treatment failure ( defined as any of the following : major amputation , death , de novo gangrene , or doubling of wound size ) , as well as major amputation rate and measures of wound healing . RESULTS There was no difference in adverse or serious adverse events between the two groups . Statistical analysis revealed a significant increase in time to treatment failure ( log-rank test , P = .0053 ) and amputation-free survival in patients receiving TRC treatment , ( log-rank test , P = .038 ) . Major amputation occurred in 19 % of TRC-treated patients compared to 43 % of controls ( P = .14 , Fisher exact test ) . There was evidence of improved wound healing in the TRC-treated patients when compared with controls at 12 months . CONCLUSIONS Intramuscular injection of autologous bone marrow-derived TRCs is safe and decreases the occurrence of clinical events associated with disease progression when compared to placebo in patients with lower extremity CLI and no revascularization options This study evaluated the efficacy and safety of intramuscular administration of NV1FGF , a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 ( FGF-1 ) , versus placebo , in patients with critical limb ischemia ( CLI ) . In a double-blind , r and omized , placebo-controlled , European , multinational study , 125 patients in whom revascularization was not considered to be a suitable option , presenting with nonhealing ulcer(s ) , were r and omized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.2 mg/ml on days 1 , 15 , 30 , and 45 ( total 16 mg : 4 x 4 mg ) . The primary end point was occurrence of complete healing of at least one ulcer in the treated limb at week 25 . Secondary end points included ankle brachial index ( ABI ) , amputation , and death .  There were 107 patients eligible for evaluation . Improvements in ulcer healing were similar for use of NV1FGF ( 19.6 % ) and placebo ( 14.3 % ; P = 0.514 ) . However , the use of NV1FGF significantly reduced ( by twofold ) the risk of all amputations [ hazard ratio ( HR ) 0.498 ; P = 0.015 ] and major amputations ( HR 0.371 ; P = 0.015 ) . Furthermore , there was a trend for reduced risk of death with the use of NV1FGF ( HR 0.460 ; P = 0.105 ) . The adverse event incidence was high , and similar between the groups . In patients with CLI , plasmid-based NV1FGF gene transfer was well tolerated , and result ed in a significantly reduced risk of major amputation when compared with placebo OBJECTIVES We have previously reported the results of a dose-finding phase II trial showing that HGF angiogenic gene therapy can increase TcPO2 compared with placebo in patients with critical limb ischemia ( CLI ) . The purpose of this r and omized placebo controlled multi-center trial was to further assess the safety and clinical efficacy of a modified HGF gene delivery technique in patients with CLI and no revascularization options . METHODS Patients with lower extremity ischemic tissue loss ( Rutherford 5 and 6 ) received three sets of eight intramuscular injections every 2 weeks of HGF plasmid under duplex ultrasound guidance . Injection locations were individualized for each patient based on arteriographically defined vascular anatomy . Primary safety end point was incidence of adverse events ( AE ) or serious adverse events ( SAE ) . Clinical end points included change from baseline in toe brachial index ( TBI ) , rest pain assessment by a 10 cm visual analogue scale ( VAS ) as well as wound healing , amputation , and survival at 3 and 6 months . RESULTS R and omization ratio was 3:1 HGF ( n = 21 ) vs placebo ( n = 6 ) . Mean age was 76 ± 2 years , with 56 % male and 59 % diabetic . There was no difference in demographics between groups . There was no difference in AEs or SAEs , which consisted mostly of transient injection site discomfort , worsening of CLI , and intercurrent illnesses . Change in TBI significantly improved from baseline at 6 months in the HGF-treated group compared with placebo ( 0.05 ± 0.05 vs -0.17 ± 0.04 ; P = .047 ) . Change in VAS from baseline at 6 months was also significantly improved in the HGF-treated group compared with placebo ( -1.9 ± 1.3 vs + 0.06 ± 0.2 ; P = .04 ) . Complete ulcer healing at 12 months occurred in 31 % of the HGF group and 0 % of the placebo ( P = .28 ) There was no difference in major amputation of the treated limb ( HGF 29 % vs placebo 33 % ) or mortality at 12 months ( HGF 19 % vs placebo 17 % ) between groups . CONCLUSION HGF gene therapy using a patient vascular anatomy specific delivery technique appears safe , maintained limb perfusion , and decreased rest pain in patients with CLI compared with placebo . A larger study to assess the efficacy of this therapy on more clinical ly relevant end points is warranted Background The aim of the present study was to develop a risk-scoring method for prediction of immediate postoperative outcome after  infrainguinal surgical revascularization for critical limb ischemia . Methods The Finnvasc registry included data on 3,925 infrainguinal surgical revascularization procedures .  This data base was r and omly divided into a derivation and a validation data set of similar sizes . Results In the overall series , 30-day postoperative mortality and major amputation rates were 3.1 % and 6.3 % , respectively . The 30-day postoperative mortality and /or limb-loss rate was 9.2 % . Diabetes , coronary artery disease , foot gangrene , and urgent operation were independent predictors of 30-day postoperative mortality and /or major lower-limb amputation . A risk score was developed by assigning 1 point each to the latter risk factors . In the derivation data set , the 30-day postoperative mortality/amputation rates in patients with scores of 0 , 1 , 2 , 3 , and 4 were 7.7 % , 6.4 % , 11.1 % , 20.4 % , and 27.3 % , respectively , ( P < 0.0001 ) ; mortality rates were 1.3 % , 2.3 % , 4.1 % , 7.7 % , and 12.1 % , respectively , ( P < 0.0001 ) ; and major amputation rates were 6.4 % , 4.3 % , 7.1 % , 12.7 % , and 18.2 % , respectively , ( P < 0.0001 ) . In the validation data set , the 30-day postoperative mortality/amputation rates in patients with scores of 0 , 1 , 2 , 3 , and 4 were 4.8 % , 7.5 % , 10.1 % , 15.9 % , and 22.2 % , respectively , ( P < 0.0001 ) ; mortality rates were 0.7 % , 2.3 % , 4.2 % , 5.5 % , and 14.8 % , respectively , ( P < 0.0001 ) ; and major amputation rates were 4.6 % , 5.3 % , 6.4 % , 11.0 % , and 14.0 % , respectively ( P = 0.011 ) . Conclusions This simple risk-scoring method can be useful to stratify the immediate postoperative outcome of patients undergoing infrainguinal surgical revascularization for critical lower-limb ischemia BACKGROUND Patients with critical limb ischaemia have a high rate of amputation and mortality . We tested the hypothesis that non-viral 1 fibroblast growth factor ( NV1FGF ) would improve amputation-free survival . METHODS In this phase 3 trial ( EFC6145/TAMARIS ) , 525 patients with critical limb ischaemia unsuitable for revascularisation were enrolled from 171 sites in 30 countries . All had ischaemic ulcer in legs or minor skin gangrene and met haemodynamic criteria ( ankle pressure < 70 mm Hg or a toe pressure < 50 mm Hg , or both , or a transcutaneous oxygen pressure < 30 mm Hg on the treated leg ) . Patients were r and omly assigned to either NV1FGF at 0·2 mg/mL or matching placebo ( visually identical ) in a 1:1 ratio . R and omisation was done with a central interactive voice response system by block size 4 and was stratified by diabetes status and country . Investigators , patients , and study teams were masked to treatment . Patients received eight intramuscular injections of their assigned treatment in the index leg on days 1 , 15 , 29 , and 43 . The primary endpoint was time to major amputation or death at 1 year analysed by intention to treat with a log-rank test using a multivariate Cox proportional hazard model . This trial is registered with Clinical Trials.gov , number NCT00566657 . FINDINGS 259 patients were assigned to  NV1FGF  and 266 to placebo . All 525 patients were analysed . The mean age was 70 years ( range 50 - 92 ) , 365 ( 70 % ) were men , 280 ( 53 % ) had diabetes , and 248 ( 47 % ) had a history of coronary artery disease . The primary endpoint or components of the primary did not differ between treatment groups , with major amputation or death in 86 patients ( 33 % ) in the placebo group , and 96 ( 36 % ) in the active group ( hazard ratio 1·11 , 95 % CI 0·83 - 1·49 ; p=0·48 ) . No significant safety issues were recorded . INTERPRETATION TAMARIS provided no evidence that NV1FGF is effective in reduction of amputation or death in patients with critical limb ischaemia . Thus , this group of patients remains a major therapeutic challenge for the clinician . FUNDING Sanofi-Aventis , Paris , France Fifty percent of diabetics ( 7 % of general population ) suffer from peripheral arterial occlusive disease , which may lead to amputation due to critical limb ischemia ( CLI ) . The aim of our study was to prevent major limb amputation ( MLA ) in this group of patients using a local application of autologous bone marrow stem cells ( ABMSC ) concentrate . A total of 96 patients with CLI and foot ulcer ( FU ) were r and omized into groups I and II . Patients in group I ( n = 42 , 36 males , 6 females , 66.2 ± 10.6 years ) underwent local treatment with ABMSC while those in group II ( n = 54 , control , 42 males , 12 females , 64.1 ± 8.6 years )  received st and ard medical care .  The frequency of major limb amputation in groups I and II was 21 % and 44 % within the 120 days of follow up , respectively ( p < 0.05 ) . Only in salvaged limbs of group I both toe pressure and toe brachial index increased ( from 22.66 ± 5.32 to 25.63 ± 4.75 mmHg and from 0.14 ± 0.03 to 0.17 ± 0.03 , respectively , mean ± SEM ) . The CD34 + cell counts in bone marrow concentrate ( BMC ) decreased ( correlation , p = 0.024 ) with age , even though there was no correlation between age and healing . An unexpected finding was made of relative , bone marrow lymphopenia in the initial bone marrow concentrates in patients who failed ABMSC therapy ( 21 % of M 
    Output:
    
Meta- analysis of the literature confirmed a difference in amputation rate between patients with tissue loss and rest pain .