Fetal progenitor cells for treatment of chronic limb ischemia.

04:21 PM Abstract No. 22 A National Surgical Quality Improvement Program database analysis of atherectomy with balloon angioplasty compared with balloon angioplasty alone for the treatment of chronic limb ischemia

Autologous bone marrow mononuclear cell therapy improves symptoms in patients with end-stage peripheral arterial disease and reduces inflammation-associated parameters

Introduction: The journey from single cell to complex being is attributable to stem cells role. Adult stem cells originate during ontogeny & persist in specialized niches within organs. Asymmetric division of each stem cell during differentiation produces : one daughter stem cell & one daughter transit amplifying/intermediate cell having migratory properties. Forced migration of hematopoietic stem/progenitor cells (HSPC) from bone marrow into peripheral blood is called mobilization. Accumulating evidence suggests that attenuation of the chemokine stromal derived factor-1(SDF-1)-CXCR4 axis that plays a pivotal role in retention of HSPC in bone marrow (BM) results in the release of these cells from the BM into peripheral blood. Recently, adult cells have been genetically reprogrammed to an embryonic stem cell like state. Induced pluripotent stem cells (IPSCs) were similar to human embryonic stem cells in morphology, proliferative capacity, expression of cell surface antigens, & gene expression. Treatment of ischemic vascular disease of lower limbs remains a significant challenge. Unfortunately, if medical & surgical salvage procedures fail, amputation is an unavoidable result for those patients. Aim of Work: (Hypothesis) To assess the application of implantation of autologous stem/progenitor cell in the treatment of chronic limb ischemia & to evaluate the safety, efficacy & feasibility of this novel therapeutic approach. Methods: A total of 24 patients with chronic limb ischemia not eligible for arterial reconstruction or endovascular procedures were enrolled & randomized (1:1) to either the implanted group or the control group. Control group: Conventional medical therapy in the form of anti platelet therapy & vasodilators. Implanted group: Subcutaneous injection of 300μ g/day of recombinant human granulocyte colony stimulating factor (G-CSF) for 5 days to mobilize stem/progenitor cells from BM. Total leucocytic count is measured daily to follow up successful mobilization of bone marrow mononuclear cells (BMMNCs). Stem cell Harvesting After 5 days peripheral blood mononuclear cells (PBMNCs) were harvested using a cell separator. Samples from apheresis products are subjected to TLC measurement & immunophenotypic characterization of CD34+ cells by flow cytometry. The collected PBMNCs were implanted by multiple intramuscular injections into ischemic limbs. Results: There was significant increase in pain free walking distance & ankle/brachial index (ABI) & significant decreased rest pain. Effectiveness was documented by : reduced number of amputation, increase ABI & improvement of the quality of life in therapeutic group compared to control group. Conclusion: The novel therapeutic approach of PBMNCs implantation in patients with chronic limb ischemia is safe, feasible & effective in decreasing co-morbidity & rate of amputation. Safety was manifested by absence of complications during G-CSF therapy or during harvesting & injection of the stem cells. Recommendations: 1- Future studies on larger number of patients & longer follow up. 2- Controlled studies using different methods & different cell population (PBMNCs, BMMNCs or MSCs) to compare the outcome of each. 3-Studing the role of endothelial progenitor cell dysfunction in different ischemic diseases to develop successful gene therapy.

Analysis of Outcomes Following Failed Endovascular Treatment of Chronic Limb Ischemia

Due to dramatic advances in endovascular techinques, multiple approaches to the treatment of chronic limb ischemia (CLI) are widely available to a variety of specialists. Although most of these techinques are often succesful in restoring flow to the ischemic extremity, it is unclear if this immediate success translates into long-lasting wound healing, limb salvage and retrun to a pr-morbid level of activity.Traditionally, the “success” of vascular interventions has been measured solely in terms of immediate technical success, patency, freedom from further revascularization, limb salvage and mortality. Outcomes research in CLI is entering a new phase where patient-oriented outcomes are replacing traditional lesion-oriented outcomes.

Stem cell transplant can induce vasculogenesis and improve the blood supply to an ischemic region, offering hope for chronic lower extremity ischemic diseases. Bone marrow mononuclear cells are one of the sources for stem cell transplants. We sought to observe the safety and efficacy of autologous bone marrow mononuclear cells transplant for treating critical limb ischemia. Eligible patients were randomized 1:1 to receive placebo (0.9% NaCl) or 1 × 107 piece/mL bone marrow mononuclear cell transplant. For 6 months, patients' skin ulcers, ankle-brachial index, and rest pain were examined and recorded before and after treatment. Six months after the bone marrow mononuclear cells transplant, clinical symptoms like rest pain and skin ulcers gradually abated (P < .05). Ankle-brachial index also increased after the transplant (P < .01). Autologous bone marrow mononuclear cells transplant for treatment of patients with chronic limb ischemia is safe, effective, and feasible.

Therapeutic Angiogenesis by Cell Transplantation (TACT) study is the first randomized controlled angiogenic cell therapy by intramuscular injection of autologous bone marrow mononuclear cells (BM-MNCs) in the patients with critical limb ischemia. The feasibility of TACT was reported in the Lancet (2002). Objective and Results The present study was designed to assess the 3-year safety and clinical outcomes of this angiogenic cell therapy by investigating the mortality and leg amputation-free interval as primary endpoints. Three year overall survival rates were 80% in patients with peripheral artery disease (PAD) (11 died in 74 patients) and 100% (no death) in 41 patients with thromboangiitis obliterans (TAO, Buerger’s disease). Three-year amputation-free rate was 60% in PAD and 91% in TAO patients (Fig ). These mortality and amputation-free rate were lower than the historical data from the conventional therapies. The multi-variate analysis revealed that the severity of rest pain and repeated experience of bypass surgery are the prognostic factors negatively affecting amputation-free interval. The significant improvement in the rest pain, ulcer size and walking distance was maintained during at least 2 year after the therapy. Conclusions The present study demonstrates that the angiogenic cell therapy using BM-MNCs has an ability to induce a long-term efficient increase in the regional perfusion in ischemic limbs, leading to extension of amputation-free interval. The safety and efficacy are superior to the conventional revascularization therapies. The severity of rest pain and the history of bypass surgery negatively influence the responsiveness to this cell therapy.

Eversion Femoral Endarterectomy for Iliofemoral Occlusive Disease: A Description of Technique and Series of Cases

Analysis of 17 years of surgical treatment for chronic limb ischemia in a Chinese National Clinical Center for Geriatric Disorders (2002 to 2018)

The purpose of this study was to assess the safety of continuous subcutaneous therapy with treprostinil sodium (Remodulin), a prostacyclin analog, and its effect on ischemic rest pain and ischemic wound healing in subjects with critical limb ischemia (CLI) and no planned revascularization procedure. This was a 12-week, open-label, single-center pilot study enrolling 10 subjects (mean age 82.4 years) with Fontaine stage III to IV (Rutherford class 4-6) peripheral arterial disease and ankle brachial indices less than 0.55. The primary end point was safety, and the secondary end points were the effects of treatment on ischemic rest pain, limb salvage, and wound healing. There was a 62% reduction in mean worst rest pain and a 57% reduction in mean average rest pain at week 12, with most subjects using less pain medication. Three subjects experienced complete healing of their wounds. No subject developed a new wound during the trial. Treprostinil was generally well tolerated. Subcutaneous infusion-site pain was the most frequently reported side effect, with one subject withdrawing from the study as a result. Jaw pain was reported by two subjects. One subject experienced two serious adverse events considered unrelated to treprostinil (cholecystitis and congestive heart failure). This study demonstrates that chronic, continuous subcutaneous treprostinil is safe and can be useful in the treatment of ischemic pain and wounds in subjects with CLI. Future controlled studies are needed to evaluate these effects and determine appropriate patient selection.

LEA 15. Role of Monocytes in the Treatment of Chronic Limb Ischemia and “Hard to Heal” Ulcers

Treatment with autologous, bone marrow mononuclear stem cells has shown effects in patients with chronic limb ischaemia in one randomized clinical study. The aim of the study was to test the potential effect of stem cell treatment in a strict defined group of patients with stable critical limb ischaemia (CLI). A prospective, combined-centre pilot study. Eight patients with CLI of the lower extremities, and without any other treatment options. Bone marrow cells were harvested from the patient's iliac crest and, after separation, injected into the calf muscles of the affected leg. Outcome was evaluated by digital subtraction angiography (DSA), visual analogue scale (VAS) and several non-invasive circulatory physiological tests. There were no complications from the procedures. Two patients were amputated two months after cell injection. Five patients reported pain relief after four months. Five patients could be evaluated at eight months. According to VAS and physiological tests, they were all either stable or showed improvement. This method seems to be a safe option for treating patients with CLI. Inclusion of patients took a long time, mainly because many patients with CLI are offered endovascular treatment in our institution. While symptomatic improvement was found in individual patients, larger trials are required to investigate efficacy. This will probably require multi-centre participation.

Long-term clinical outcome after intramuscular implantation of bone marrow mononuclear cells (Therapeutic Angiogenesis by Cell Transplantation [TACT] trial) in patients with chronic limb ischemia

Background and Aims: Treatment with autologous, bone marrow mononuclear stem cells has shown effects in patients with chronic limb ischaemia. The aim of the study was to test the potential effect of stem cell treatment in a strict defined group of patients with non reconstructable critical limb ischaemia (CLI). Material: Twenty patients with non recontructable CLI of the lower extremities, who received medical treatment in the form of prostavasine. Methods: Bone marrow cells were harvested from the patient’s iliac crest and, after separation, injected into the calf muscles of the affected leg. Outcome was evaluated by digital subtraction angiography (DSA), visual analogue scale (VAO) one patient was amputated two months after cell injection. Two patients reported relief of pain after four months. Conclusion: This method seems to be a safe option for treating patients with non reconstructable CLI.

Long-term Results of Stem Cell Therapy for Acute and Chronic Limb Ischemia