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|Progenitor Cell Therapy for the Treatment of Damaged Myocardium due to Ischemia
|Medical Policy
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/6:2013
|Return to Medical Policy Index
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
Progenitor cell therapy describes the use of multipotent cells of various cell lineages (autologous or allogeneic) for tissue repair and/or regeneration. Progenitor cell therapy is being investigated for the treatment of damaged myocardium resulting from acute or chronic cardiac ischemia.
Ischemia is the most common cause of cardiovascular disease and myocardial damage in the developed world. Despite impressive advances in treatment, ischemic heart disease is still associated with high morbidity and mortality. Current treatments for ischemic heart disease seek to revascularize occluded arteries, optimize pump function, and prevent future myocardial damage. However, current treatments are not able to reverse existing damage to heart muscle. (1, 2) Treatment with progenitor cells (i.e., stem cells) offers potential benefits beyond those of standard medical care, including the potential for repair and/or regeneration of damaged myocardium. The potential sources of embryonic and adult donor cells include skeletal myoblasts, bone marrow cells, circulating blood-derived progenitor cells, endometrial mesenchymal stem cells (MSCs), adult testis pluripotent stem cells, mesothelial cells, adipose-derived stromal cells, embryonic cells, induced pluripotent stem cells, and bone marrow MSCs, all of which are able to differentiate into cardiomyocytes and vascular endothelial cells.
The mechanism of benefit following treatment with progenitor cells is not entirely understood. Differentiation of progenitor cells into mature myocytes and engraftment of progenitor cells into areas of damaged myocardium has been suggested in animal studies using tagged progenitor cells. However, there is controversy concerning whether injected progenitor cells actually engraft and differentiate into mature myocytes in humans to a degree that might result in clinical benefit. It has also been proposed that progenitor cells may improve perfusion to areas of ischemic myocardium. Basic science research also suggests that injected stem cells secrete cytokines with anti-apoptotic and pro-angiogenesis properties. Clinical benefit may result if these paracrine factors are successful at limiting cell death from ischemia or stimulating recovery. For example, myocardial protection can occur through modulation of inflammatory and fibrogenic process. Alternatively, paracrine factors might affect intrinsic repair mechanisms of the heart through neovascularization, cardiac metabolism and contractility, increase in cardiomyocyte proliferation, or activation of resident stem and progenitor cells. The relative importance of these proposed paracrine actions will depend on the age of the infarct, e.g., cytoprotective effects with acute ischemia versus cell proliferation with chronic ischemia. Investigation of the specific factors that are induced by administration of progenitor cells is ongoing.
There are also a variety of potential delivery mechanisms for donor cells, encompassing a wide range of invasiveness. Donor cells can be delivered via thoracotomy and direct injection into areas of damaged myocardium. Injection of progenitor cells into the coronary circulation can also be done using percutaneous, catheter-based techniques. Finally, progenitor cells can be delivered intravenously via a peripheral vein. With this approach, the cells must be able to target damaged myocardium and concentrate at the site of myocardial damage.
Adverse effects of treatment with progenitor cells include the risk of the delivery procedure (e.g., thoracotomy, percutaneous catheter-based, etc.) and the risks of the donor cells themselves. Donor progenitor cells can differentiate into fibroblasts rather than myocytes. This may create a substrate for malignant ventricular arrhythmias. There is also a theoretical risk that tumors, such as teratomas, can arise from progenitor cells, but the actual risk of this occurring in humans is not known at present.
Regulatory Status
U.S. Food and Drug Administration (FDA) approval is not required in situations in which autologous cells are processed on site with existing laboratory procedures and injected with existing catheter devices. However, there are several products that require FDA approval. MyoCell™ (BioHeart, Inc., Sunrise, FL) consists of patient autologous skeletal myoblasts that are expanded ex vivo and supplied as a cell suspension in a buffered salt solution for injection into the area of damaged myocardium. Since the myoblast isolation and expansion occurs at a single reference laboratory (BioHeart), this process is subject to FDA approval. In addition, implantation may require the use of a unique catheter delivery system (MyoCath™) that also requires FDA approval.
An allogeneic human mesenchymal stem cell (hMSC) product (Prochymal®) is being developed by Osiris Therapeutics, Inc. (Baltimore, MD) for treatment of acute myocardial infarction (MI). (3) Prochymal (also referred to as Provacel®) is a highly purified preparation of ex vivo cultured adult hMSCs isolated from the bone marrow of healthy young adult donors. Prochymal has been granted "fast track" status by the FDA for Crohn's disease and graft-versus-host disease (GVHD), and has orphan drug status for GVHD from the FDA and the European Medicines Agency. Prochymal is being studied in Phase II trials for the treatment of acute MI (AMI), pulmonary disease, and type 1 diabetes.
MultiStem® (Athersys) is an allogeneic bone marrow-derived adherent adult stem-cell product. MultiStem has received orphan drug status from the FDA for GVHD and has received authorization from the FDA for a Phase II trial for treatment of acute myocardial infarction with an adventitial delivery system.
Progenitor cell therapy, including but not limited to skeletal myoblasts or hematopoietic stem cells, is considered investigational as a treatment of damaged myocardium.
Infusion of growth factors (i.e., granulocyte colony stimulating factor [GCSF]) is considered investigational as a technique to increase the numbers of circulating hematopoietic stem cells as treatment of damaged myocardium.
Policy Guidelines
There are no specific codes for this procedure, either describing the laboratory component of processing the harvested autologous cells, or for the implantation procedure. In some situations, the implantation may be an added component of a scheduled coronary artery bypass graft (CABG), in other situations, the implantation may be performed as a unique indication for a cardiac catheterization procedure.
Benefit Application
BlueCard/National Account Issues
Progenitor cell implantation/transplantation is a specialized service that may prompt request for an out of network referral.
The evidence review for this policy is derived in part from a 2008 TEC Assessment, (4) with the literature updated annually since the 2008 TEC Assessment using the MEDLINE database. The Assessment was a systematic review that included randomized, controlled trials (RCTs) of progenitor cell therapy versus standard medical care for treatment of either acute or chronic myocardial ischemia. The TEC Assessment focused on the impact of progenitor cell therapy on clinical outcomes but also included data on physiologic outcomes, such as change in left ventricular ejection fraction (LVEF). The most recent literature update since the 2008 TEC Assessment was performed through March 2012.
Acute Ischemia
The 2008 TEC Assessment reviewed a total of 10 publications from 6 unique studies enrolling 556 patients with acute ischemia. (4) These trials had similar inclusion criteria, enrolling patients with acute ST-segment elevation myocardial infarction (MI) treated successfully with percutaneous coronary intervention (PCI) and stenting, with evidence of residual myocardial dysfunction in the region of the acute infarct. Progenitor cell therapy was delivered via an additional PCI procedure within 1 week of the acute event. The REPAIR-AMI trial (described below) is the largest trial included in the TEC Assessment and had the largest number of clinical outcomes reported. (5, 6) The other 5 trials included in the TEC Assessment had very few clinical events, precluding meaningful analysis of clinical outcomes. The primary evidence from these other trials consists of physiologic outcomes measures, such as change in LVEF and change in infarct size. The primary endpoint in all 6 trials was change in LVEF. In each trial, there was a greater increase in the LVEF for the progenitor cell group compared with the control group. In 4 of the 6 studies, this difference reached statistical significance, while in 2 studies there was a nonsignificant increase in favor of the treatment group. The magnitude of the incremental improvement in LVEF was not large in most cases, with 5 of the 6 studies reporting an incremental change of 1% to 6% and the final study reporting a larger incremental change of 18%.
In 2007 Lipinski et al. published a quantitative meta-analysis of studies that estimated the magnitude of benefit of progenitor cell treatment on left ventricular (LV) function and infarct size. (7) This analysis included 10 controlled trials with a total of 698 patients. Results for the primary endpoint, change in LVEF, showed a statistically significant greater improvement of 3% (95% confidence interval [CI]: 1.9–4.1%, p<0.00001) for the progenitor cell group. There was also a statistically significant greater improvement in infarct size for the progenitor cell group with an incremental improvement of -5.6% over the control group (95% CI: -8.7 to -2.5, respectively, p<0.001). At least 4 meta-analyses of bone marrow progenitor cell treatment for acute MI have been published since the 2008 TEC Assessment, each examining between 6 and 13 RCTs. (8-11) All 4 meta-analyses concluded that there was a modest improvement in LVEF for patients treated with progenitor cells. The mean estimated improvement in ejection fraction over control ranged from 2.9–6.1%. The studies also concluded that myocardial perfusion and/or infarct size was improved in the progenitor cell treatment group, although different outcome parameters were used. All 4 of the meta-analyses concluded that there were no demonstrable differences in clinical outcomes for patients treated with progenitor cells.
A 2012 updated Cochrane review included 33 RCTs (39 comparisons with 1,765 participants) on bone marrow-derived stem-cell therapy for acute MI. (12) Twenty-five trials compared stem/progenitor cell therapy with no intervention, and 14 trials compared the active intervention with placebo. There was a high degree of statistical and clinical heterogeneity in the included trials, including variability in the cell dose, delivery and composition. Overall, stem-cell therapy was found to improve LVEF in both the short- (weighted mean difference of 1.78%) and long-term (12 to 61 months, weighted mean difference of 3.07%). Stem-cell treatment reduced left-ventricular end systolic and end-diastolic volumes at certain times and reduced infarct size in long-term follow-up. There were positive correlations between mononuclear cell dose infused and the effect on LVEF and between the timing of stem-cell treatment and the effect on LVEF. Although the quality of evidence on LVEF was rated as high, the clinical significance of the change in LVEF is unclear. The quality of evidence on health outcomes was rated as moderate. Stem/progenitor cell treatment was not associated with statistically significant changes in the incidence of mortality or morbidity (re-infarction, arrhythmias, hospital re-admission, restenosis, and target vessel revascularization), although the studies may have been underpowered to detect differences in clinical outcomes. Due to variability in outcomes measured, it was not possible to combine data on health related quality of life or performance status.
Key studies, including studies published after the literature search was conducted for the 2012 Cochrane review, are described below.
REPAIR-AMI: This was a double-blinded trial that infused bone marrow-derived progenitor cells or a placebo control infusion of the patient's own serum and enrolled 204 patients with acute ST-segment elevation MI meeting strict inclusion criteria from 17 centers in Germany and Switzerland. (5, 6) At 12 months of follow-up, there were statistically significant decreases in the progenitor cell group for MI (0 vs. 6, p<0.03) and revascularization (22 vs. 37, p<0.03, both respectively), as well as for the composite outcome of death, MI, and revascularization (24 vs. 42, p<0.009, respectively). Two-year clinical outcomes from the REPAIR-AMI trial, performed according to a study protocol amendment filed in 2006, were reported in 2010. (5, 13) Three of the 204 patients were lost to follow-up (2 patients in the placebo group and 1 in the progenitor cell group). A total of 11 deaths occurred during the 2-year follow-up, 8 in the placebo group and 3 in the progenitor cell group. There was a significant reduction in MI (0% vs. 7%), and a trend toward a reduction in rehospitalizations for heart failure (1% vs. 5%) and revascularization (25% vs. 37% - all respectively) in the active treatment group. Analysis of combined events (all combined events included infarction), showed significant improvement with progenitor cell therapy after acute MI (AMI). There was no increase in ventricular arrhythmia or syncope, stroke, or cancer. It was noted that investigators and patients were unblinded at 12-month follow-up, the sample size of the REPAIR-AMI trial was not powered to definitely answer the question of whether administration of progenitor cells can improve mortality and morbidity after AMI, and the relatively small sample size might limit the detection of infrequent safety events. Thus, this analysis should be viewed as hypothesis-generating, providing the rationale to design a larger trial that addresses clinical endpoints.
HEBE: In 2011, Hirsch et al. reported a multicenter RCT of bone marrow or peripheral blood mononuclear cells compared with standard therapy in 200 patients with acute MI treated with primary percutaneous coronary intervention. (14) Mononuclear cells were delivered between 3 and 8 days after MI. Blinded assessment of the primary endpoint, the percentage of dysfunctional left ventricular segments that had improved segmental wall thickening at 4 months, found no significant difference between either of the treatment groups (38.5% for bone marrow, 36.8% for peripheral blood) and control (42.4%). There was no significant difference between the groups in LVEF, or changes in left ventricular volumes, mass or infarct size, or in rates of clinical events. At 4 months, there was a similar percentage of patients in New York Heart Association (NYHA) class II or higher (19% for bone marrow, 20% for peripheral blood, and 18% for control).
TIME: Investigators from the Cardiovascular Cell Therapy Research Network (CCTRN) reported 2012/2013 results from the randomized, double-blind, controlled, Timing in Myocardial Infarction Evaluation (TIME) trial. (15) One hundred and twenty patients with left ventricular dysfunction were randomized to placebo or to bone marrow mononuclear cell administration in the infarct-related artery at either 3 or 7 days after PCI. At 6 months there was no significant difference in LVEF or left ventricular function (assessed by magnetic resonance imaging, MRI) for the mononuclear cell groups compared to placebo. Rates of major adverse events were low in all treatment groups (11 patients underwent repeat vascularization and 6 received implantable cardioverter-defibrillators).
ASTAMI: Beitnes and colleagues reported the unblinded 3-year reassessment of 97 patients (out of 100) from the randomized ASTAMI trial. (16, 17) The group treated with bone marrow progenitor cells had a larger improvement in exercise time between baseline and 3-year follow-up (1.5 vs. 0.6 minutes, respectively), but there was no difference between groups in change in peak oxygen consumption (3.0 mL/kg/min vs. 3.1 mL/kg/min, respectively), and there was no difference between groups in change of global LVEF or quality of life. Rates of adverse clinical events in both groups were low (3 infarctions and 2 deaths). These 3-year findings are similar to the 12-month results from this trial. (18)
Section Summary: Literature updates since the 2008 TEC Assessment have identified numerous small RCTs that evaluated the impact of bone marrow progenitor cells on outcomes for patients with MI. The majority of these studies treated patients with acute MI and reported the outcomes of LVEF and/or myocardial perfusion at 3–6 months. These studies generally reported small to modest improvements in these intermediate outcomes, although one RCT from 2011 found no benefit of stem-cell treatment for acute MI. None of the trials published after the 2008 TEC Assessment have reported benefits in clinical outcomes, such as mortality, adverse cardiac outcomes, exercise capacity, or quality of life.
Chronic Ischemia
The 2008 TEC Assessment included a total of 6 trials that randomly assigned 231 patients for treatment of chronic ischemic heart disease. (4) Three trials randomly assigned 125 patients to progenitor cell therapy versus standard medical care. The other 3 trials randomly assigned 106 patients undergoing coronary artery bypass grafting (CABG) to CABG plus progenitor cell treatment versus CABG alone. Four trials employed bone marrow-derived progenitor cells as the donor cell source, 1 trial used circulating progenitor cells (CPCs), and the final trial included both a CPC treatment group and a bone marrow-derived treatment group. The primary physiologic measurement reported in these trials was change in LVEF. In all 6 trials there was a greater improvement in LVEF for the treatment group compared with the control group, and in 4 of 6 trials, this difference reached statistical significance. For the 3 trials of progenitor cell treatment versus standard medical care, the range of incremental improvement in LVEF was 2.7–6.0%. For the trials of progenitor cell treatment plus CABG versus CABG alone, the range of improvement in LVEF was 2.5–10.1%. Only 1 trial reported comparative analysis of data on the change in size of ischemic myocardium, finding no difference in size of ischemic myocardium between treatment groups. (19) Only 2 of the 6 studies reported any clinical outcomes, and both trials reported on change in NYHA class between groups. (20, 21)
Assmus et al.: The largest trial on chronic ischemia that was included in the 2008 TEC Assessment was Assmus et al. (REPAIR-AMI Investigators), which was a single-center, unblinded trial that enrolled 75 patients into 3 groups; treatment with bone marrow-derived progenitor cells, treatment with circulating progenitor cells, or usual medical care. (20) Assmus et al. reported an improvement in mean NYHA class of 0.25 (0–4 scale) for the bone-marrow treatment group and an improvement of 0.23 for the CPC group, compared with a worsening of 0.18 for the standard medical therapy group (p<0.01). This publication also reported on adverse cardiac events, but there were extremely small numbers of any of these clinical outcomes and no differences between groups.
Assmus and colleagues also reported in 2013 the CELLWAVE Phase I/II double-blind randomized trial in patients with chronic heart failure. This trial tested the hypothesis that shock wave-facilitated intracoronary cell therapy improves LVEF to a greater degree than does nonshock wave-facilitated cell therapy, due to an effect of shock wave treatment on facilitating the homing ability of progenitor cells to their target. (22) Patients were randomized to low-dose (n=42), high-dose (n=40), or sham (n=21) shock wave pre-treatments of the left ventricle. Twenty-four hours later, patients assigned to receive shock wave treatment were randomized to an intracoronary infusion of either placebo or bone marrow-derived mononuclear cells, and patients assigned to the sham shock wave treatment were given an infusion of bone marrow-derived mononuclear cells. The improvement in LVEF at 4 months was significantly greater in the groups that received shock wave + mononuclear cells (3.2%), compared with the placebo infusion group (1.0%). LVEF improved in 93% of patients receiving shock wave + mononuclear cells compared to 64% of patients who received shock wave + placebo infusion, and 64% of patients who received sham shockwave + mononuclear cells. Regional wall thickening improved significantly in the shock wave-treated mononuclear cell group (3.6%), but not in the placebo infusion group (0.6%). Symptomatic heart failure status assessed by the NYHA class showed a modest improvement with low-dose shock wave + mononuclear cells (-0.3) and with high-dose shock wave + mononuclear cells (-0.4).
STAR-Heart: Results from the acute and long-term effects of intracoronary stem-cell transplantation in 191 patients with chronic heart failure (STAR-heart) study were reported by Strauer et al. in 2010. (23) In this non-randomized open-label trial, 391 patients with chronic heart failure due to ischemic cardiomyopathy were enrolled; 191 patients received intracoronary bone marrow cell (BMC) therapy, and 200 patients who did not accept the treatment but agreed to follow-up testing served as controls. The time between percutaneous coronary intervention for infarction and admission to the tertiary clinic was 8.5 years. For the BMC therapy, mononuclear cells were isolated and identified (included CD34-positive cells, AC133-positive cells, and CD45/CD14-negative cells). Cells were infused directly into the infarct-related artery. Follow-up on all patients was performed at 3, 12, and 60 months and included coronary angiography, biplane left ventriculography, electrocardiogram (ECG) at rest, spiroergometry, right heart catheterization and measurements of late potentials (LPs), short-term heart rate variability (HRV), and 24-hour Holter ECG. At up to 5 years after intracoronary BMC therapy, there was a significant improvement in hemodynamics (LVEF, cardiac index), exercise capacity (NYHA classification), oxygen uptake, and LV contractility compared to controls. There was also a significant decrease in long-term mortality in the BMC-treated patients (0.75% per year) compared to the control group (3.68% per year, p<0.01). These results are encouraging, especially in regard to the mortality outcomes, since this is the first controlled trial that reports a significant mortality benefit for progenitor cell treatment. However, the study is limited by the potential for selection bias due to patient self-selection into treatment groups. For example, there was a 7% difference in baseline ejection fraction between the 2 groups, suggesting that the groups were not comparable on important clinical characteristics. In addition, the lack of blinding raises the possibility of bias in patient-reported outcomes such as NYHA class. RCTs are needed to confirm these health outcome benefits for chronic ischemia.
Section Summary. For chronic ischemic heart disease, there is limited evidence on clinical outcomes. Only a handful of clinical outcome events have been reported across the included studies, too few for meaningful analysis. Other clinical outcomes, such as NYHA class, are confined to very small numbers of patients and not reported with sufficient methodologic rigor to permit conclusions. Therefore, the evidence is insufficient to permit conclusions on the impact of progenitor cell therapy on clinical outcomes for patients with chronic ischemic heart disease.
Refractory Angina
Stem-cell therapy is also being investigated in patients with intractable angina who are not candidates for revascularization.
ACT34-CMI: In 2011, Losordo et al. reported an industry-funded multicenter randomized double-blind Phase II study that included 167 patients with refractory angina and no suitable revascularization options. (24) Patients were randomized to 1 of 2 doses of mobilized autologous CD34+ cells from peripheral blood (1 x 105 or 5 x 105) or to placebo injections. The cell dose was delivered via intramyocardial injection into 10 sites identified as viable, ischemic areas of the myocardium by electromechanical endocardial mapping. One patient died during the procedure. Angina frequency was documented by daily phone calls to an interactive voice responsive system. The primary outcome was weekly angina frequency at 6 months. Angina frequency was significantly lower in the the low-dose group than in placebo-treated patients at both 6 months (6.8 vs. 10.9) and 12 months (6.3 vs. 11.0). Angina frequency in the high-dose group tended to be lower at 6 (8.3) and 12 (7.2) months, but this did not attain statistical significance. Secondary endpoints included exercise tolerance testing, use of antianginal medications, Canadian Cardiovascular Society (CCS) functional class, and health-related quality of life. Improvement in exercise tolerance was signficantly greater in low-dose patients than in placebo-treated patients at 6 (139 vs. 69 seconds) and 12 months (140 vs. 58 seconds). Exercise tolerance in the high-dose group tended to be higher at 6 (110 seconds) and 12 months (103 seconds), but this did not reach statistical significance. The time to onset of angina during treadmill exercise was not significantly different for either the low- or high-dose groups. The percentage of patients who improved on the Seattle Angina Questionnaire was greater in the low- (69.2%) and high-dose groups (67.3%) compared to controls (40.8%), and some of the measures of changes in CCS class were significantly better in both the low- and high-dose groups. Most parameters from single-proton emission computed tomography (SPECT) were not significantly different. Mortality at 12 months was 5.4% in the placebo-treated group with no deaths among cell-treated patients (p=0.107). Interpretation of these results is limited by the trend (p=0.091) for a greater percentage of patients in the control group (41.1%) to have had prior heart failure than the low- (21.8%) or high-dose (28.6%) groups. Additional study in a larger number of subjects is needed to confirm these results.
van Ramshorst et al.: A randomized, double-blind trial of autologous bone marrow-derived mononuclear cells or placebo that included 50 patients with intractable angina despite optimal medical therapy and who were not candidates for revascularization therapy was reported in 2009. (25) The main outcomes were measures of myocardial perfusion derived from SPECT scanning at rest and SPECT after exercise stress at 3 months post-treatment. Secondary outcomes included LVEF, Canadian Cardiovascular Society (CCS) angina class, and Seattle Angina Quality-of-Life Questionnaire measured at 6 months post-treatment. There were modest improvements for most of the outcomes in favor of the experimental group compared to placebo. For the primary outcome, a significantly greater improvement was found in the stress perfusion score for the progenitor cell group (mean difference -2.44; 95% CI: -3.58 to -1.30, p<0.001) but no significant difference in the rest perfusion score (mean difference -0.32; 95% CI: -0.87 to 0.23, p=0.25). There was also a significant decrease in the mean number of ischemic segments for the progenitor cell group (mean decrease 2.4 vs. 0.8, p<0.001). LVEF improved slightly in the progenitor cell group and decreased slightly in the placebo group (mean change 3% +/- 5 vs. -1% +/- 3, respectively, p=0.03). At 6 months, CCS class decreased more for the progenitor cell group (mean difference -0.79; 95% CI: -1.10 to -0.48, p<0.001) and the Seattle Angina Quality-of-Life score increased more for the progenitor cell group (mean increase 12% vs. 6.3%, respectively, p=0.04).
Section Summary. The evidence on stem-cell therapy for refractory angina includes at least 2 RCTs, including a Phase II RCT that examined 2 doses of mononuclear cells compared to placebo. Functional outcomes such as angina frequency and exercise tolerance showed modest improvements with the lower dose of mononuclear cells. Limitations of the literature include the small size of available trials, along with differences between groups at baseline that increase the uncertainty of the findings. Additional studies with a larger number of subjects are needed to determine with greater certainty whether progenitor-cell therapy improves health outcomes in patients with refractory angina.
Ongoing Clinical Trials
A 2010 critical review of cell therapy for the treatment of coronary heart disease by Wollert and Drexler described 20 ongoing cell therapy trials in patients with coronary heart disease. (26) Issues to be resolved in these 2nd and 3rd generation cell therapy trials include patient selection, cell type, procedural details, clinical endpoints, and strategies to enhance cell engraftment and prolong cell survival. Moreover, "a large body of evidence indicates that the beneficial effects of cell therapy are related to the secretion of soluble factors acting in a paracrine manner." The authors suggest that the identification of specific factors promoting tissue regeneration may eventually enable therapeutic approaches based on the application of specific paracrine factors. Updated literature reviews have also identified a number of publications that describe ongoing RCTs.
The rationale and design of the "Swiss multicenter intracoronary stem cells study in acute myocardial infarction" (SWISS-AMI) was reported in 2010. (27) In this trial, 192 patients with AMI will be randomized to control or 1 of 2 groups treated with autologous bone marrow mononuclear cells (5 to 7 days or 3 to 4 weeks after the initial event). The mononuclear cells will be infused directly into the infarct-related coronary artery. The primary endpoint is the change in global LVEF at 4 months; secondary endpoints include changes in infarct size, regional myocardial thickness, and wall motion at 4 and 12 months. Major adverse cardiac events will be assessed at 4, 12, and 24 months.
Taljaard and colleagues reported the rationale and design of what is described as the first randomized placebo-controlled trial of "enhanced" progenitor cell therapy for AMI. (28) The "enhanced angiogenic cell therapy in acute myocardial infarction" trial (ENACT-AMI) is a Phase IIb, double-blind, RCT, using coronary injection of autologous early endothelial progenitor cells for patients who have suffered large MI. A total of 99 patients will be randomly assigned to placebo (Plasma-Lyte A), autologous mononuclear cells, or mononuclear cells transfected with human endothelial nitric oxide synthase delivered by injection into the infarct-related artery. This trial is described as the first to include a strategy to enhance the function of autologous progenitor cells by overexpressing endothelial nitric oxide synthase and the first to use combination gene and cell therapy for the treatment of cardiac disease.
The PERFECT Phase III randomized controlled trial (NCT00950274) will assess intramyocardial bone marrow stem-cell therapy in combination with coronary artery bypass grafting. (29) The trial is expected to enroll 142 patients with completion in December 2013.
BAMI (Effect of Intracoronary Reinfusion of Bone Marrow-derived Mononuclear Cells on All-Cause Mortality in Acute Myocardial Infarction, NCT01569178) is a large Phase II trial that will be conducted in Europe. (30)
The placebo-controlled Allogeneic Heart Stem Cells to Achieve Myocardial Regeneration (ALLSTAR, NCT01458405) will assess the efficacy of allogeneic cardiosphere-derived cells in 270 patients with ventricular dysfunction after MI. (30)
Progenitor cell therapy has been tested in patients with acute ischemia, chronic ischemia, and refractory angina. For all these conditions, there is a similar pattern of outcomes, with modest improvements demonstrated on physiologic outcomes, but limited evidence on clinical outcomes. For acute ischemic heart disease, the limited evidence on clinical outcomes suggests that there may be benefits in improving left ventricular ejection fraction (LVEF), reducing recurrent myocardial infarction (MI), decreasing the need for further revascularization, and perhaps even decreasing mortality. For chronic ischemic heart disease, only a handful of clinical outcome events have been reported across the included studies, too few for meaningful analysis. For refractory angina, evidence from a Phase II randomized controlled trial (RCT) that examined 2 doses of mononuclear cells compared to placebo reported that functional outcomes such as angina frequency and exercise tolerance showed modest improvements with the lower dose of mononuclear cells.
Progenitor cell therapy for the treatment of damaged and ischemic myocardium is a rapidly evolving field, with a number of areas of substantial uncertainty including patient selection, cell type, and procedural details (e.g., timing and mode of delivery). The accumulating evidence on this therapy indicates that progenitor cell therapy is a promising intervention, but that the ultimate effects on health outcomes are still uncertain. The clinical significance of the improvement in the physiologic parameters has yet to be demonstrated, and there is very little evidence demonstrating a benefit in clinical outcome. Moreover, the evidence remains primarily limited to short-term effects; the long-term durability of benefit has not yet been determined. Therefore, progenitor (stem) cell therapy for the treatment of damaged or ischemic myocardium is considered investigational.
Medicare National Coverage
There is no national coverage determination.
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- Hendrikx M, Hensen K, Clijsters C et al. Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation 2006; 114(1 Suppl):I101-7.
- Assmus B, Honold J, Schachinger V et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 2006; 355(12):1222-32.
- Patel AN, Geffner L, Vina RF et al. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective randomized study. J Thorac Cardiovasc Surg 2005; 130(6):1631-8.
- Assmus B, Walter DH, Seeger FH et al. Effect of shock wave-facilitated intracoronary cell therapy on LVEF in patients with chronic heart failure: the CELLWAVE randomized clinical trial. JAMA 2013; 309(15):1622-31.
- Strauer BE, Yousef M, Schannwell CM. The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study. Eur J Heart Fail 2010; 12(7):721-9.
- Losordo DW, Henry TD, Davidson C et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res 2011; 109(4):428-36.
- van Ramshorst J, Bax JJ, Beeres SL et al. Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial. JAMA 2009; 301(19):1997-2004.
- Wollert KC, Drexler H. Cell therapy for the treatment of coronary heart disease: a critical appraisal. Nat Rev Cardiol 2010; 7(4):204-15.
- Surder D, Schwitter J, Moccetti T et al. Cell-based therapy for myocardial repair in patients with acute myocardial infarction: rationale and study design of the SWiss multicenter Intracoronary Stem cells Study in Acute Myocardial Infarction (SWISS-AMI). Am Heart J 2010; 160(1):58-64.
- Taljaard M, Ward MR, Kutryk MJ et al. Rationale and design of Enhanced Angiogenic Cell Therapy in Acute Myocardial Infarction (ENACT-AMI): the first randomized placebo-controlled trial of enhanced progenitor cell therapy for acute myocardial infarction. Am Heart J 2010; 159(3):354-60.
- Donndorf P, Kaminski A, Tiedemann G et al. Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT Phase III randomized multicenter trial: study protocol for a randomized controlled trial. Trials 2012; 13:99.
- Marban E, Malliaras K. Mixed results for bone marrow-derived cell therapy for ischemic heart disease. JAMA 2012; 308(22):2405-6.
|No specific CPT codes
|ICD-9 Diagnosis
|Investigational for all uses
|ICD-10-CM (effective 10/1/14)
|Investigational for all diagnoses
|ICD-10-PCS (effective 10/1/14)
|No specific code found for intracoronary infusion of stem cells
|Transfusion, central vein, percutaneous, embryonic stem cells
|Transfusion, central vein, percutaneous, cord blood and hematopoietic stem cells, code list
|Type of Service
|Place of Service
Cellular Cardiomyoplasty
Policy History
|Add policy to Medicine section, Cardiology subsection
|New policy
|Replace policy
|Policy updated with literature search. No change in policy statement. Reference 13 added
|Replace policy
|Policy updated with literature search. No change in policy statement.
|Replace policy
|Policy updated with literature search; reference numbers 14-20 added; no change in policy statement
|Replace policy
|Description, Rationale, and Reference sections completely revised, based on 2008 TEC Assessment. No change in policy statement
|Replace policy
|Policy updated with literature search; references 29-38 added. No change to policy statements
|Replace policy
|Policy updated with literature search through May 2010; references added, deleted, and reordered; policy statements unchanged
|Replace policy
|Policy updated with literature search through April 2011; references added and reordered; policy statements unchanged
|Replace policy
|Policy updated with literature search through March 2012; references 12, 14, 22 added and references reordered; 1 reference removed; policy statements unchanged
|Replace policy
|Policy updated with literature search through May 15, 2013; references 15, 22, 29 and 30 added and references reordered; policy statements unchanged


text: Unlock the full version of Boggle and you'll be able to play the orginal Hasbro board game or new versions - Salvo Mode, Super Weapons and custom modes! You'll have access to party games, unlockable items, leaderboards and achievements! This game requires the Xbox 360 hard drive or the 512MB Memory Unit for storage. There are no refunds for this item. Online gameplay is no longer available. For more information, see www.xbox.com/live/accounts.

subset: commoncrawl


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Baroness Lawrence is being mooted as a future Labour candidate to be Mayor of London. The party's policy review chief Jon Cruddas told the Sunday People her potential candidacy was an "interesting idea".
Further to previous correspondence on the above matter, I can report that despite the best efforts of your union's negotiators, Transport for London have continued t...
Mayor of London press release The Mayor of London, Boris Johnson, has launched proposals for a new investment scheme designed to accelerate house building and hel...
It is important to get to the bottom of fraud claims surrounding Tower Hamlets council, the Communities Secretary has said. Eric Pickles called on inspectors to l...
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Drawing, Sketch, & Watercolor Paper Rolls
Yes, you can buy drawing paper in a roll. Borden & Riley 116 Vellum is a good choice for artists who want an archival surface and an expansive sheet. It is a thick 90 pounds and will also accept light washes.
Sign Writer's Bond is more basic. At 20lb, it is lightweight and economical, perfect for sketching or to cover bulletin boards.
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30th Annual All Children's Hospital Telethon Raises $4,154,917
This year's Telethon theme, "Thirty Years of Miracles," celebrated a 30-year tradition of raising funds and friends for All Children's Hospital. Since its first annual broadcast in 1984, more than $84-million has been raised through the Telethon, with every dollar staying right here to support All Children's programs and facilities for youngsters.
The 11 ½ hour broadcast on WFLA-TV News Channel 8 focused on the amazingly strong children and their families who count on All Children's expertise. Stories of youngsters from throughout west central Florida who have benefited from All Children's care were the highlight of the 30th annual fundraiser.


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Big Button Game: Metacity Introduces Flexibility
The current button arrangement redesign in Ubuntu causes numerous bugs in GNOME and Ubuntu. The Metacity team now wants to step in.
The recent hot discussion around the redesign of the three standard window buttons to move them from right to left in the Ubuntu 10.04 window alerted Metacity window manager developers to a problem they've long been grappling with: if a designer includes specific images for the buttons in a developed theme, they can't be moved without breaking the underlying design.
A GNOME user can now freely determine where the buttons go, but themes present a special problem in that the button_layout key specifies their position in the GNOME configuration. The solution is not optimal because button_layout is persisted across themes (the global setting) so that a user can't change the positioning when introducing a new theme.
GNOME developers want to solve this problem so that future themes will overwrite the button_layout setting, which would require a new Themes v3 format. Metacity developer Thomas Thurman in his blog is rather recommending a workaround involving a separate GKeyFile configuration file in the theme directory that would parse the key-value file to set the button layout for any new theme.
Issue 163/2014
Buy this issue as a PDF
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Tag Cloud
KDE Announces Software Compilation 4.13
New release comes with better semantic search and improvements to Kontact.
Coverity: Open Source Code has Fewer Defects
Annual code quality report shows FOSS is more secure at all project size levels.
An Even Smaller Raspberry Pi
The Raspberry Pi Foundation has announced an even smaller version of the tiny computer that will fit into a DIMM slot.
Freaky Privilege Escalation Attack
A new class of problems lets a malicious app pre-configure an invisible privilege update.
Facebook Rolls Out New PHP-like Programming Language
New Hack language adds static typing and other conveniences.
Fedora Announces Innovative Crytography Policy System
New crypto policy system will offer easier configuration and more uniform security.
Shuttleworth Calls for Declarative Firmware
Ubuntu founder denounces insecurity in proprietary, close-source software blobs.
New TLS Attack Takes the S out of HTTPS
Vulnerability affects many Linux web servers
Munich Adopts Kolab
The Bavarian capital shuns Microsoft, Google, and other alternatives to implement an open source groupware solution.
Canonical Announces Ubuntu Smartphones
Phone vendor partnerships bring Mark Shuttleworth's dream of Ubuntu on a phone a step closer to reality.


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kobe,paul or lebron that is the question? who will win the MVP? all are outstanding players. duh they are there in the NBA arent they? just kidding!!
but who is the real MVP. once again the question is kobe, lebron or paul?
lebron is having an outstanding season the cavs are 34-26 and are in second place behind the pistons!! he is averaging 30ppg and 7 apg!!! now that he has some help, who knos they might win a nba championship game!!
paul is a having a great year to. the hornets are 39-19 and are in second place behind the spurs in there division. paul is averaing a solid 20ppg 4 rpg and 10apg. pretty good stats! but wait do you kno wat they both hav in common. ill tell u. both their teams are in second
do you kno whos team is not in second... none other than the LA Lakers. which kobe is on and their record is 42-18!!! kobe is also averaging 28ppg and 5 apg. and the lakers are on their way to nba champioship.
last of all the MVP award goe to Kobe Bryant of the LA Lakers!!! congrats
thank you everyone 4 watching the MVP award show


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The Reiki Association is a community of people initiated into Reiki and is part of the worldwide Reiki community. The Association exists to enable people with Reiki to connect and share experiences with each other, to learn, support and find friendship with others who are exploring a life with Reiki. For many, being a member of TRA brings a valuable sense of being part of the wider Reiki community.
What is Reiki? Find out more here
To join TRA or renew subscriptions go here
To read more about Touch magazine go here
If you would like to donate to TRA online go here
The CNHC Reiki register is now open!
On 14 May 2012 the Complementary and Natural Healthcare Council opened its register for Reiki practitioners. The Reiki Association is one of the verifying organisations Read more...
Booking will soon be open for our 2014 Gathering which wil be held at Hothorpe Hall in Leicestershire! Dates for your diary are the 16th to 18th of May 2014. We are thrilled to have Paul and Susan Mitchell facilitating at the event.
This magazine is now available to everyone! If you are not a member of TRA you can still subscribe to this excellent magazine. See here for more details.


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BOISE -- We've learned overnight that the University of Washington Huskies' star tight end Austin Seferian-Jenkins has been suspended, and will not play against Boise State on Saturday night.
The story is making headlines courtesy the Seattle Times, which reports that Seferian-Jenkins will be suspended for the August 31 game after pleading guilty to drunk driving in July.
The pre-season All-American holds every record for a tight end at the University of Washington. Seferian-Jenkins made 69 catches for 850 yards in 2012, scoring 7 touchdowns for the team, according to the Seattle Times.
The 6-foot-6, 276-pound junior is also a projected first-round NFL draft pick.
No word on the Broncos' reaction to the suspension.
Stay with KTVB.COM for updates.


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Greater Oklahoma City is in the geographic center of North America equidistant from the east and west coasts and major trade partners of Canada and Mexico. The ten county region is at the crossroads of the U.S., sitting at the heart of three major national highways on the NAFTA corridor.
There's a reason Greater Oklahoma City is such a great place for business: Location. The ten county region is positioned within a day's drive of the rapidly-growing south-central region (OK, TX, AR, LA) projected to grow more than 44% during the next 25 years.
Explore the counties and cities of Greater Oklahoma City including major employers and higher education. The ten county region boasts an average commute time of 20 minutes and a skilled workforce over half a million strong.
The Oklahoma City Thunder have done more than take the NBA by storm as ESPN has named them the top franchise in all of pro sports. The magazine looked at a host of factors to see what franchises offered the most to their fan base. The Thunder scored particularly high in fan relations and the likability of its players.
(October 18, 2012)
Bricktown visitors will have a new place to satisfy their sweet tooth when Bricktown Candy Co. opens Friday.
The shop will sell many kinds of bulk candy - chocolate, sours, bubble gum, licorice, hard candy, jaw breakers and more - plus bottled soft drinks. In a few weeks, expect gelato to be added to the inventory, owner Justin Thomas said. "We'll have a little bit of everything."
Thomas said he's wanted to open a candy store in Bricktown for years and added he isn't worried about the economy affecting business.
"Candy is a recession-proof industry," he said. "People actually buy more candy during a recession to make them feel good."
Thomas, 40, grew up in Muskogee but has called Oklahoma City home for 20 years. The husband and father (of a 2-year-old and expecting a new baby in October) said he's looking forward to adding more family-friendly retail to Bricktown.
The store opens Friday at 100 E California, above Jazmo'z Bourbon Street Cafe.


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Your Satisfaction is Guaranteed:
In this literary classic, saintly Prince Myshkin returns to Russia from a Swiss sanitorium and finds himself a stranger in a society obsessed with wealth, power and sexual conquest. He soon becomes entangled in a love triangle with a notorious kept woman, Nastasya, and a beautiful young girl, Aglaya.
BookHints: Book Lovers Recommend...
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Carlisle, Henry; Arad, Ron
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Book Description: Penguin, 2006. Hardcover. Book Condition: As New. Dust Jacket Condition: As New. One of the five beautiful 'Designer Classics' released to celebrate Penguin Classics' Diamond Anniversary. Dust jacket is designed by Ron Arad and housed in a perspex slipcase. #801 of 1000. Still in its shrink-wrap. Heavy item - may require extra postage. Bookseller Inventory # 000101
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Book Description: London, England: Penguin/Penguin Designer Classics, 2006. Hardcover. Book Condition: As New. Dust Jacket Condition: As New. 1st Edition. 1st Printing. Signed. 704 pages. Published in 2006. Artist Book. One of the most stunningly beautiful Artist Book interpretations of the classic ever created. Limited Edition of one numbered and signed copy. Should not be confused with the Limited Edition of 1000 copies. A brilliant production by Ron Arad: Oversize-volume format. Text by Fyodor Dostoyevsky. Art by Ron Arad. White cardboard box. Printed on archival acid-free stock paper in the United Kingdom to absolutely the highest standards. In transparent Plexiglas ("Perspex") box, which serves as the book's DJ. Rather than just an outer slipcase, it is completely integral to the book. Published on the occasion of Penguin Book's 60th Anniversary, "The Idiot" is one of five classics that the publisher issued in a Limited Edition by commissioning five of the world's most important artists in their respective fields. The other titles are Gustave Flaubert's "Madame Bovary", D. H. Lawrence's "Lady Chatterley's Lover", F. Scott Fitzgerald's "Tender Is The Night: A Romance", and Fyodor Dostoyevsky's "Crime And Punishment" (he is the only novelist to be honored with not one, but two, masterpieces in the Series). "Arad's book has no cover so the reader will pick it up and read the author's first words. It is stripped back to show the glue and thread in the spine which is visible through an acrylic slipcase with a fresnel lens so the text appears to move as the lid is removed" (Publisher's blurb). "By not wanting to have a cover, it ended with the book becoming an amazing object that is alive, but which maintains its transparency. It becomes a glorious box with a book inside, almost like a monument" (Ron Arad). Said like a true architect who has worked for the Metropolitan Museum of Art New York, the Centre Georges Pompidou Paris, the Vitra Design Museum Germany, and the Victoria & Albert Museum London. The ultimate book-as-object, the literary classic-as-work-of-art, worthy of this auspicious celebration and posterity. A "must-have" edition for Fyodor Dostoyevsky and art/graphic design collectors. This copy is Number 1, indicated as such on the Back Limitation Page, and is very prominently and beautifully signed in black ink-pen on the first page by Ron Arad. By special arrangement with Penguin, Arad numbered and signed only the first copy of the Limited Edition, which is now highly collectible. This is the only numbered and signed copy available anywhere and has no flaws, a pristine beauty. A rare, one-of-a-kind signed copy thus. One of the greatest novels of all time, re-interpreted by one of the finest living architect/designers. A flawless collectible copy. (SEE ALSO OTHER PENGUIN DESIGNER CLASSIC TITLES IN OUR CATALOG) ISBN 0713999659. Signed by Author. Bookseller Inventory # 11378
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Clayton >Dry Cleaning & Laundry Services > Al's Wydown Laundry & Cleaners
7620 Wydown Blvd, St Louis, MO | Directions 6310538.642860 -90.333843
Mon - Fri, 7am - 6pm; Sat, 8am - 5pm; Sun, closed
Neighborhoods: Clayton, Saint Louis
I brought a few items to Al's and not one came back undamaged. They put safety pins in all of my skirts in the FRONT. You can see holes in all of them now. There are also stains on most of the clothes I brought in. They also charged me almost twice as much as other places. I would not recommend Al's.
After reading a few of the older posts below, I almost can't believe that they're describing the place I trust to care for all my dry cleaning needs. I am extremely selective about clothing and those places I use to clean it. I've been using Al's forever, and I have trusted them to clean everything including my wife's wedding dress, Zegna, Ferragamo, and even my blue jeans. I have never been disappointed when I have special requests like stain removal or speedy turnaround, and I have never questioned the value of the service they provide. Getting in and out is quick and easy, and the staff is careful to make sure that my order, no matter how big or small, is correct. I highly recommend Al's and question this forum's effectiveness given that this page only rates the shop 1/4. That's wrong! They're 100% in my book!
I Greatly Recommend – This store does great work! It is family run and very dependable. The work is fast and always comes back on time. Al's is also environmentally friendly. They use green bags to give laundry back instead of wasting plastic bags. They work with all kinds of clothes and have even started to do repairs and shine shoes. The employees are nice and very respectful. The prices are reasonable and the store also has a great tailor. Overall, Al's cleaners is a great place to go!
Destroyed all my clothing – After an incident that required me to have my entire wardrobe washed, I made the enormous mistake of trusting this place with my personal property. For starters, all of my laundered clothes were returned in wadded up balls like used Kleenex. What's worse, though, is that after I ironed and hung up the clothing that they had so kindly crumpled up like toilet paper, I quickly noticed that EVERYTHING had been shrunk--skirts and shirts were a hopeless mess of puckered seams, tops were too short, hems were shorter on one side than the other. I have about three wearable outfits to my name now. What's more, when I called to ask what happened, they were obnoxious and rude, scolded me for "bringing in all this stuff", and said it was my fault for not telling them how to wash my clothes. If they need a customer to instruct them on how to carry on the basic functions of their jobs, I say at least send the customer a payroll check for providing the establishment with the supervisory guidance that the management is too incompetent to provide. That's fair, right? Anyhow, if you enjoy wearable clothing and basic respect, this is definitely NOT the place for you. And besides, you don't want to bother them with "bringing in all your stuff."
Nice place Nice people – I've been going there for over a year and have not had any broken buttons which is huge with me because I travel. They recycle my hangers and have reusable garmet bags instead of plastic another plus.
Little money stealer – Watch out for the little girl working the men over at the cleaners. She will charm her way into you pockets and over charge you everytime! I caught her over charging me 2 times and she just smiled and said :opps my bad baby" to try and make it go away. Fool me once shame on you, fool me twice I'll write a review! I might not of minded had the price not been jacked sky high to begin with. There are 2 other very cheep GREAT cleaners right by this one!
ruined my wedding dress!!! – DO NOT take any garments that you value to this shop. I had many positive experiences at Al's, so after my wedding, I chose to use their gown cleaning service. My gown returned with snagged lace and yellow spots where it appeared that someone had tried to glue down lace that had come detached from the dress. They offered to try to clean it again in an attempt to solve the problem. I accepted, but when I picked up my dress, there was further damage. Someone had tried to cut off snags in the lace, but the damage was still visible. The manager claimed the damage was due to wear and engaged us in what deteriorated into a yelling match, including moments in which he leaned over the counter in a threatening manner. In the end he refused to pay for any damage to the dress or to refund cleaning costs. I have never had an experience like this with any other place of business.
Terrible Service – This dry cleaners has terrible service. The staff are rude and unhelpful, and the first thing they always say is that they themselves are not responsible for the poor cleaning or the broken buttons/zippers/etc. The staff have even told me that I was rude to them when I told them I wanted my money back. This place is not worth your time OR money -- go somewhere else!
All good things come to an end – it sadness me to say but this please is not worth going to anymore. Ever since the old owner Al left the new owner his son just does not care. The work is horribly sloppy now and it seems the only time the new owner is there is to jack up the prices. They have had 5 prices increase in the last year and it almost seems the raise them now just to make up for lost business. 18 dollars to have a suit pressed is highway robbery. Also stay away from house accounts they always seemed to have mysterious charges on there that are never explainable. His new staff does not have a clue what they are doing and do not seem to care either. SO sad...
AVOID THIS PLACE! This dry cleaning business (1) attempts to overbill upon pick-up as if the receipt the customer receives upon drop-off is an "estimate"; (2) damages clothing and tries to convince customers it is somehow not responsible for the damage, and (3) has terrible customer service.
Bottom line: With so many good dry cleaning businesses within a few miles, it's just not worth the hassle.
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Total 1068 pages , Current Page: 908
Into The Wild Green Yonder
Mount Argent Skytalon, fly to Point and use skill01(Grab Captured Crusader) Rescue 3 Captured Argent Crusaders from Scourgeholme then use skill02(Drop Off Captured Crusader) drop them off at Point the Vanguard Infirmary at the center of the Argent Vanguard. Report to Highlord Tirion Fordring should you succeed. Flying speed can be raised up by using Skill03(Soar).


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3 of the strangest birth hoaxes ever produced.
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A New York writer has won this year's PEN/Faulkner Award for Fiction.
Deborah Eisenberg's collection of short stories, "The Collected Stories of Deborah Eisenberg," published by Picador in 2010, beat out more than three hundred books to win. Her 992-page collection gathers short stories from four of her books: "Transactions in a Foreign Currency," "Under the 82nd Airborne," "All Around Atlantis," and "Twilight of the Superheroes."
She is one of only six women to win the prestigious $15,000 prize. The other female writers who won it are Kate Christensen for "The Great Man" (2008), Sabina Murray for "The Caprices" (2003), Ann Patchett for "Bel Canto" (2002), Gina Berriault for "Women in Their Beds: New and Selected Stories" (1997) and Annie Proulx for "Postcards" (1993).
Eisenberg has won, among other awards, a Guggenheim Fellowship (1987-88), the REA Award for the Short Story in 2000, and in 2009, a MacArthur "Genius" award.
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Raise your glasses: last week we toasted to the 3rd anniversary of our colossal Entertainment Building Flagship in..
Rising Sun Launch: MCM Lands in Japan
In celebration of MCM's highly-anticipated Grand Opening in Tokyo, we painted the town 'Cognac' celebrating all th..
Spring Fever with Harods & Paradiso
Attention shoppers: the UK's premier locale for luxury, Harrods are offering an exclusive Paradiso POUCH with a va..
MCM x Li Xiao Ran Photoshoot in Modern Weekly China
China's most beloved soap opera star Li Xiao Ran features on the cover of Modern Weekly China in celebration of ou..
Spotted at the Independent Spirit Awards: Frauke Ludwig x MCM
German TV presenter Frauke Ludowig flaunts her glam-rock credentials at the Independent Spirit Awards 2014 in a go..
iAPM Grand Opening Highlights
The wait is over: from black tie highlights to handbags & heels, on 7 Friday we rolled out the red carpet to the f..
Sporty-Chic with Keana & Fashion Has It
From casual to couture, our latest SS14 Keana Collection makes bold style-statements that makes heads turn. Disco..
SS14 White Day Gift + Style Guide featuring Ji-Hye Han & Hae-Jin Park
Exciting times ahead: some of our SS14 products were recently featured in editorials in Cholsun Ilbo and The Star,..
Fashion Has It: Style Diary With MCM
Claire and Vasia from Fashion Has It take us on a European travel whirlwind from Greece to France and Switzerland...
Buzzing in Busan: MCM Opens in Shinsegae Centum City
We've just expanded our boutique inside the world's largest department store. Take a look at our state-of-the-art ..
Berlin Flagship Cocktail Party with Kelis & Marcel Djeng
In celebration of our latest Spring / Summer '14 collection, MCM hosted an exclusive cocktail reception at our Ber..
Keana: Inspiration & Style File
Today's new star is Keana... With its beautiful handcrafted shrunken lamb leather body and cowhide lining, the Kea..
MCM Opens in Jelmoli, Zurich's Historical Department Store
It's official: after the success of our Swiss Flagship debut in 2013, we're pleased to inaugurate our latest retai..
Valentine's Day Gift Guide with Selfridges
Valentine Day is almost here, so Mademoiselle Robot compiled a little Valentine's Day Gift guide based on what she..
MCM Opens in Shanghai iAPM
Introducing MCM's latest Flagship Boutique at the Shanghai iPAM mall ? MCM's hottest landmark for 'luxe is a retai..
MCM Opens in Taipei Breeze Centre
With Chinese New Year around the corner, we're rearing to celebrate the Year of the Horse in style. To kick off t..
May Stylescope with the Stark Collection
Fashionistas and urbanites, it is time for a brand new StyleScope! The lovely month of May brings in many changes and wonderful opportunities abound for everyone. The StyleScope for May comes to you in association with the Stark collection. Find out which star signs best suit our favourite products from the range, and what's in the stars for them in May...
If you are Libra, Sagittarius, Capricorn, Aquarius or Virgo, you were born under a lucky Stark!
Libra, this month is all about power and money... You are not one to scrimp usually and it isn't going to start now. This month you feel like a million dollars and you might well be on your way to also earn a million dollars. Follow your instinct and invest in that business you meant to invest in! Sure enough you will need a gorgeous wallet to keep all those notes in: the Large Stark Wallet in Blue (for serenity) will be perfect!
This month will be all about your health and fitness regime. Forget about your jet-setting ways for a while and use your energy to go to the gym, change your diet and perhaps improve your work/life balance. You will enjoy your upcoming trips even more. And knowing you, there will be many trips to come! Be prepared with the studded Stark Two-Pocket Messenger... It will take you from the gym to the airport and back!
The first half of the month might have made you feel like you wanted to hibernate for the rest of your life, Aquarius, but don't worry, things are looking up! Romance is lurking around the corner and with it will no doubt come an array of Spring invitations to picnics, weddings and aperitivos. Be prepared for anything with the Stark Small Messenger in bright, bubbly apple green. Trust us, May is going to surprise you!
May most definitely puts the "GO" in Virgo as you embark on one of the most exciting months of the year. Travel is on the agenda for you and who knows where your wings will take you. You could be watching the sunset in Seoul, drinking Pastis in Paris or navigating New York. The world truly is your oyster. You might need to pack your overnight kit in the Stark Weekender.
Capricorn, why so sullen? This month forget about your responsibilities and usual Capricorn worries and let your hair down. Take your Stark backpack and go for a little adventure. There is a time to be a responsible grown-up, of course, but now you need to have as much fun as you possibly can. Go out dancing, travel, flirt, anything, just don't come back until you are all funned out!
Traduction - L'horoscope de Mai selon Stark
Love from Mademoiselle Robot
Stark , Style , Scope , Astro , Backpack
Mikey84 says :
Totally in love with studded Stark Two-Pocket Messenger, where can i get it??? Any online store??? Thx!
Lindsay Lohan Wears MCM @ the Coachella Festival
Style Slicker's Instagram Roundup
MCM Blogger Makeover in Chelsea, London - Behind-The-Scenes
Style Slicker's Instagram Roundup: Elda


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On Web's 25th birthday, a call for Net Bill of Rights
... (VentureBeat) The World Wide Web is 25 years old today. It's time, says its inventor, Sir Tim ... ." His memo to create the WWW was filed on this day in 1989. (You can extend your birthday ... can't be achieved "without an open, universal Web." To battle laws that restrict
Obama skipped intel briefings prior to attacks
... /president/2012-09-06 9/7/2012-http://www.whitehouse.gov/schedule/president/2012-09-07 9/8/2012 ... /schedule/president/2012-09-09 9/10/2012-http://www.whitehouse.gov/schedule/president/2012-09-10 9/11 ... Chris Stevens and three American members of his staff: 9/6/2012-http://www.whitehouse.gov/schedule
Asteroid whizzing between moon, Earth
... its closest approach at 21:07 GMT on Wednesday at a blistering speed of 14.85 km/s (32,076 mph ... ). Although the space rock poses no threat to earth, it highlights the earth's susceptibility to near ... 5. The 98-foot-wide space rock is expected to come within 218,000 miles of earth (0.9 lunar
The meaning and mystery of numbers
... and PBS take us to celebrations across the globe, beginning at some remote island in the South Pacific ... not stay up long enough to see the new year arrive in Los Angeles, or Honolulu, which was probably ... the last major city on earth to finally come into the year 2000. It was amazing to see the delirium
Phony e-mails say Gingrich forced abortion on ex
... . The fake press release, which you can see above, came from an email address in which the "1" in 2012 ... registered "newt20l2.org" (with the lowercase L) today. Their name was withheld. The fake release
My plan to save a quick $100 billion
... the next several years. I would cut that out of the budget quicker than you can count down from 10 ... . Why? Do I not like the space program? Do I not see value from American exploration of space ... The U.S. government is planning to spend $100 billion on the international space station over
The next great U.S. land grab?
... are we stealing today," Young would ask sarcastically at the beginning of committee meetings. His ... constituents cheered and returned him to Congress year after year figuring they could count on him ... of the $4 billion to $5 billion oil and gas revenues generated every year from drilling on the outer
Eclipsing China's shadow
... and other objects into outer space, as well as detonating a nuclear weapon. The idea that China ... stands barefoot in front of the 368-foot Shwedagon Pagoda in Rangoon, Burma, Nov. 19, 2012. All visitors ... When President Obama visited Myanmar in late 2012, a relaxation of tensions was in the air
Meeting set with 'someone more powerful' than D.C.
... to cover it. You see, this event isn't for media attention. I've said it all along: our goal isn't ... p.m. at the Lincoln Memorial in Washington, D.C. "Throughout our history, beginning with George ... . Turn off your television, shut off your computer and open His Word. Spend time with God like you
Big nuke terror drill on tap in U.S. today
... nuclear bomb detonated on U.S. soil. Dubbed "Noble Resolve '07," the series of tests ... building in Baghdad in virtual space, is using that same technology in the Tidewater area of southern ... scenario involves a 10-kiloton nuclear bomb headed to Virginia from a foreign country. "It's


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Fargo, ND (WDAY TV) - A life-changing amount of cash is up for grabs tonight, enough to give every person in the United States a dollar, and you'd still have millions left over.
With the top prize unclaimed for eleven weeks straight, the Mega Millions might have its highest jackpot ever, but the odds of winning are not in your favor.
Read the article: Tuesday's Mega Millions has locals hopeful


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Bourne >Food & Dining > Lobster Trap Co Inc
290 Shore Rd, Buzzards Bay, MA | Directions 0253241.728935 -70.613861
This place discriminates against children with disabilities. I have a son who has a tree nut/peanut allergy. When we inquired as to if their hot dog on the kids meal was made in a facility that processes nuts he said no, which is good. We then asked if the person that cooks their food could change their gloves when they cook his kids meal to prevent cross contamination from other foods he may have cooked that have traces of nuts on them. The manager says no, absolutely not. I can't have them do that as it would take extra time. He then tells us to leave as he doesn't want us to eat there because we have a child that needs a slight accommodation in cooking his food. When we asked his name he became very rude and aggressive and he said his name was Frank Sinatra and we should go somewhere else to eat. I have never ran into this type of discrimination and rudeness since we have been dealing with this allergy for my young son and we eat out a few times a week. I would recommend anyone who has kids or an allergy stay far away from this restaurant as they are rude and insensitive with no regards to their customers' needs.
Awesome place to eat! – This place is great for families and friends. They have so much to offer I have never had a bad meal !!
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3105 Capital Blvd., Raleigh
The Outback of Capital Blvd in Raleigh has been notorious for years. I have discussed this with a number of people (including employees at other Outbacks in the area), and everyone…
3601 New Bern Ave, Raleigh
AWFUL!!!!...from time I sat to being served was 45 mins to get "steamed" veggies which were canned mixed vegetables complete with a hair. Steak overcooked. $1.90 for soda, then…
3111 Capital Blvd, Raleigh
Totally bad food for dinner. Wait staff was good but what came out on the plates was the worst. What are they thinking. This is the Lake Boone location. I don't know about the…
3210 Yonkers Rd, Raleigh
I am wanting to get a job serving there...But I have never worked in a establishment such as gentelmens club..For the men and women who go there..So you think that maybe I would be…
6700 Knightdale Blvd, Knightdale
71 Plz Pkwy, Lexington
Food and service are all excellent
3601 Capital Blvd, Raleigh
star karaoke
: karaoke, music, studio, sing, song, fun, late, night,
: カラオケ 、音楽、スタジオ、歌、歌う、夜遊び、ビール、日本酒
: el karaoke, música, estudio, canta, canción, diversión, atrasada,…
4000 Atlantic AveSte 180, Raleigh
New to me...wow!
1911 Sego Ct, Raleigh
Finally something different in Raleigh. Scooter's is a biker bar like none you have ever seen before. Sexy motorcycles and a first class restaurant & bar with an outdoor patio. You…
3914 Atlantic Ave, Raleigh
Great place to shag


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|Welcome to GetTheLabel's SALE page. Here we have many items from top brands at rock bottom prices! Filter by gender and brand to find your bargain!
Displaying 1 - 7 of 7 products
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Because I hate iTunes with a passion. And to make matters worse iTunes crashed my computer this after noon and, upon reboot I was greeted with this:
How in the hell does it lose my whole library? I looked in all the folders for a data backup and all of them are blank. I fucking hate this program.


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Although the weather has improved there are some roads closed due to surface damage. View the road closures page. If you or your business have been affected by flooding visit the what to do after flooding page.
To view the location of a road on a map, enter the road number in the Explore Herefordshire map search box.
* indicates the latest changes to this page.
This information is based on the latest available reports from council and police sources but is not necessarily comprehensive. Conditions are liable to change at short notice. We advise motorists to take care on all routes and to comply with warning signs.
If works on the highway, or some large deliveries or events, require the closure of a road, the highway authority must issue a traffic regulation order. These events are likely to be more disruptive to traffic so they require higher levels of coordination and communication.
Herefordshire Council is the highway authority for the majority of the county's roads. This is except for the trunk roads and motorways (A49T, A40T (Ross-on-Wye to Monmouth) and the M50), which are managed by the Highways Agency.
To apply for a temporary road closure, please complete the temporary road closure application form.
If your street party requires partial or complete closure of a road, you need to apply in advance to our contractor using the application for a temporary road closure form and include the reason for the road closure.
Please give as much notice as possible. This will allow us to properly assess your application and coordinate your closure with any others.
If you are organising a street party, we advise you to consider obtaining public liability insurance.
Normally, the council does not provide insurance for street parties. However, if the street party is for a national celebration, such as a royal wedding or jubilee, we may provide insurance.
Yes, if your street party involves a bar, band or dancing, you may also require a temporary event notice (cost £21).
This covers up to 500 people attending and you must apply 12 working days in advance of the event.
You can apply online for a temporary event notice.


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Superior Lighting. The projector lenses light up the road ahead with a bright focused beam of light that not only looks great, but improves your night visibility. The integrated Accent Halo's give your Mustang an exotic flair that separates it from the boring herd of look-a-likes.
Full Warranty. Raxiom features an "Industry Leading 2 Year Full Warranty".
DOT Approved. This pair of Mustang Headlights are DOT (Department of Transportation) approved for legal street use under compliance # QR1200174.
Application. Raxiom Chrome HID Halo Projector Headlights are designed to fit the 2013 to 2014 V6, and GT model Mustangs that are equipped with factory HID lighting. Does not fit Shelby GT500 Mustangs.
Bulb application. These Raxiom Projector Headlights retain the factory HID lighting by reusing the stock D3S style HID bulbs.
Technical Note. Not intended for use with vehicles equipped with Daytime Running Lights or Aftermarket HID Kits.
Mustang Fitment: 2013, 2014 Details >>


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- Bob Vila TV Shows >
- Manhattan Remodel and Cape Cod Affordable > Episode 8: Installing Drop Ceilings, Custom Windows, and Mechanicals
Individual Zone Heating and Cooling
It's time for doors, windows, ceilings, and mechanicals in the Manhattan Brownstone. Bob joins Chris Vila, the project manager, for a look at the ceiling that had to be reopened to run refrigerant lines for the air conditioning and the plaster walls that are now wired for the plasma screen television above the hearth. In the front rooms, ductwork is in place for the heating-and-cooling system and a Chicago-bar drop ceiling is installed to hide the ductwork. Fire batts are used to prevent noise transfer through the ceilings. Pella French doors are installed on the balcony while the surrounding masonry is rebuilt with weep holes to divert water and moisture from behind the brick. Oversized Pella double-hung windows are framed out and installed to bring in light and air. The Mitsubishi City Multi HVAC system is set up to deliver customized individual-zone heat and air conditioning throughout the apartment.
- Part 1: Installing a Drop Ceiling to Hide Duct Work
- Part 2: French Doors and Weep Holes on the Balcony and Installing Oversized Double-Hung Windows on a Historic Property
- Part 3: Individual Zone Heating and Cooling
- Bob meets with Meredith Schelp from Mitsubishi Electric HVAC to learn about the City-Multi HVAC system that will heat and cool the Manhattan Brownstone floor-through apartment. This system allows for simultaneous heating and cooling of separate zones throughout the apartment, so that a busy kitchen can be cooled while a quiet den or bedroom receives heat. The system uses outdoor and indoor units with variable drives to accommodate delivery demands. There will be three units installed in the apartment, each above the ceiling in vestibules where the ceilings can be dropped to hide them. Joseph Yannaco of Polar Mechanical Corporation explains that the interior units control the temperature and delivery of the conditioned air. The thermostatic controls run on sensors, so there's no need to keep the panels mounted visibly on interior walls. Ducts carry the heated or cooled air throughout the apartment.
This project deals with two very different notions of home. Bob begins on New York City's Upper West Side, where an 1890s Brownstone is revitalized through high-quality craftsmanship and sensitive design. New York's past meets its present, as the entire floor is recaptured and refurbished to create a spacious urban apartment on the doorstep of Central Park.
At the same time, Bob works with a Cape Cod developer to apply Massachusetts land use statute 40B to create affordable housing, and a neighborhood of homes in Mashpee, MA. These Energy Star certified homes show how quality building practices and reasonable asking prices can work together to provide livable, affordable homes and neighborhoods to those who work in our communities.
At the same time, Bob works with a Cape Cod developer to apply Massachusetts land use statute 40B to create affordable housing, and a neighborhood of homes in Mashpee, MA. These Energy Star certified homes show how quality building practices and reasonable asking prices can work together to provide livable, affordable homes and neighborhoods to those who work in our communities.
Also from Manhattan Remodel and Cape Cod Affordable
Episode 1 - A New Lift for a Manhattan BrownstoneDescription:
Bob is on Manhattan's Upper West Side to renew a 2,000-square-foot Brownstone apartment. First, he looks at what made Brownstones significant, including their details and façades.

 Inside the building, Bob shows how the space was cut up in the 1940s to make a warren of rooms. These walls and finishes will be removed as the space is gutted to prepare for new studs, walls, plumbing, and finishes.

 Pieces will be salvaged for architectural resale, including the pink sink from the bathroom and the retro cabinets in the kitchen, but everything else will go. Bob also visits Central Park, its caretakers, trees, and monuments.
Episode 2 - Demolition in the Manhattan BrownstoneDescription:
The big story is the cornice molding found in tact when the drop ceiling came down. The molding will set a tone for the main living space, where the bricks have been removed to install a flue liner and drafting fireplace. All of the 40s wall, surface, and ceiling treatments are gone, along with the lath and plaster, leaving the bare brick and exposed joists from the original construction. Remodels have cut into the joist work or damaged it, so some reworking will be necessary to build up for the floors and ceilings. The floor joists are sistered to make a level, solid footing for the Georgia-Pacific Plytanium subflooring that goes under the wood floor. Laser levels allow the carpenters to set level lines throughout the apartment horizontally for the floor and vertically for the new steel studs they are installing. Finally, a flexible flue liner is run through the wall, and up the chimney for the new fireplace.
Episode 3 - Building Affordable Homes on Cape CodDescription:
Affordable housing is the story in this project as Bob heads to Mashpee, Massachusetts on Cape Cod, where a state law is helping put higher density, affordable housing in place for four families who live and work in the community. Bob meets Pat Fiero of the Housing Assistance Corporation who explains the hurdles faced by families needing to live near their workplaces in a town where the average home price is $450,000. Bob visits Mashpee Commons and looks at mixed-use development that is providing a town center, housing, commercial property, recreational space, and a new church as a start to this new town development. Bob also meets the developer, Joe Valle, who explains the challenges in developing affordable housing and how this project was made possible by invoking Massachusetts? 40B land use and development law. On site, Bob Bevilaqua moves the earth to prepare the sites, shows the tie-offs for electrical and phone lines, and explains the drainage plan.
Episode 4 - Falmouth's Model for Quality Affordable Housing
Episode 9 - Paneling the Kitchen, Installing Hot Water, and Hanging Doors
Episode 10 - Cladding, Insulating, and Zoning for an Affordable Home
Episode 13 - Installing Pre-Hung Doors, Hardwood Floors, and Gutters
Episode 14 - Affordable HVAC, Painting, Kitchen Cabinets and Counters
Episode 15 - Installing Glazed Wall Tile and a Pedestal Sink
Episode 16 - Refurbishing Wrought Iron, Custom Kitchen Cabinets, Profile Molding
Episode 17 - Kitchens, Feng Shui, and Energy Star Homes
Episode 18 - Finishing Details in the Manhattan Brownstone
- 15 Old House Features We Were Wrong to Abandon
- 17 Tiny Bathrooms We Love
- 20 Insanely Easy 60-Minute Home Improvements
- 70 Gardening Tricks and Ideas for Total Beginners
- 16 Inventive Beds You Can Make Yourself
- Top 10 Classic DIY Projects for the Outdoors
- 15 Once-Popular Household Items That Are Vanishing
- 159 Smart Storage Ideas for the Whole House
- 30 Things Every Adult Should Know How to Do
- 10 Wise Ways to Get Rid of Pests and Critters
- Before and After: 9 Totally Amazing Mobile Home Makeovers
- Top Tips for Keeping Countertops Like New
- 15 Amazing Things You Can Make with $0 Scrap Wood
- 14 Ways to Get More Kitchen Counter Space
- Assembly Required: 15 DIY Kit Homes
- 18 Bathroom Updates You Can Do in 1 Day
- 9 Tried-and-True Methods of Eliminating Weeds
- Picture-Perfect Patios: 10 Outdoor Spaces to Love
- 11 Clever Alternatives to Kitchen Cabinets
- 7 Easy Budget-Friendly Backyard Makeovers


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Stevens-Johnson syndrome
Other Names for this Disease
- Erythema multiforme major
See Disclaimer regarding information on this site. Some links on this page may take you to organizations outside of the National Institutes of Health.
On this page
Clinical Trials & Research for this Disease
- ClinicalTrials.gov lists trials that are studying or have studied Stevens-Johnson syndrome. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.


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CHENEY, WA -- An Eastern Washington University student is training to run his way into the Guinness Book of World Records. The Spokane man hopes to set the record for the number of miles run in a 24-hour period on a treadmill.
In two weeks, 28-year-old David Reese will get on a treadmill at the EWU rec center and not get off for the entire day. He plans on running nearly 7 miles per hour. He will eat 300 calories an hour and will drink on the run.
Reese hopes to break the world record of 161 miles run on a treadmill in 24 consecutive hours.
He says breaking the record is second to what he really wants, to raise money for a charity called "Partners in Health." Reese wants to raise at least $500 for the organization.
For information on how to donate, click here: act.pih.org/page/outreach/view/athleticchallenge/24