Safety and efficacy of granulocyte–colony-stimulating factor administration following autologous intramuscular implantation of bone marrow mononuclear cells: a randomized controlled trial in patients with advanced lower limb ischemia

Zafarghandi, Mohammad Reza; Ravari, Hassan; Aghdami, Nasser; Namiri, Mehrnaz; Moazzami, Kasra; Taghiabadi, Ehsan; Fazel, Abdorreza; Pournasr, Behshad; Farrokhi, Ali; Sharifian, Ramezan Ali; Salimi, Javad; Moini, Majıd; Baharvand, Hossein

doi:10.3109/14653240903518163

Cited by 24 publications

(15 citation statements)

References 29 publications

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“…Of note, most of our patients suffered from diabetes mellitus, with the high prevalence of mediasclerosis [22/27 subjects (81%) in the responders group], where noncompressible ankle arteries precluded meaningful determination of the ABI. Importantly, the prevalence of limb salvage 73% in the present study was similar to that of other studies reporting the effects of cell therapy at 6 months (15,37).…”

Section: Discussionsupporting

confidence: 89%

No Difference in Intra-Arterial and Intramuscular Delivery of Autologous Bone Marrow Cells in Patients with Advanced Critical Limb Ischemia

Klepanec

Mistrík

Altaner³

et al. 2012

Cell Transplant

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Stem cell therapy has been proposed to be an alternative therapy in patients with critical limb ischemia (CLI), not eligible for endovascular or surgical revascularization. We compared the therapeutic effects of intramuscular (IM) and intra-arterial (IA) delivery of bone marrow cells (BMCs) and investigated the factors associated with therapeutic benefits. Forty-one patients (mean age, 66 ± 10 years; 35 males) with advanced CLI (Rutherford category, 5 and 6) not eligible for revascularization were randomized to treatment with 40 ml BMCs using local IM (n = 21) or selective IA infusion (n = 20). Primary endpoints were limb salvage and wound healing. Secondary endpoints were changes in transcutaneous oxygen pressure (tcpO 2 ), quality-of-life questionnaire (EQ5D), ankle-brachial index (ABI), and pain scale (0-10). Patients with limb salvage and wound healing were considered to be responders to BMC therapy. At 6-month follow-up, overall limb salvage was 73% (27/37) and 10 subjects underwent major amputation. Four patients died unrelated to stem cell therapy. There was significant improvement in tcpO 2 (15 ± 10 to 29 ± 13 mmHg, p < 0.001), pain scale (4.4 ± 2.6 to 0.9 ± 1.4, p < 0.001), and EQ5D (51 ± 15 to 70 ± 13, p < 0.001) and a significant decrease in the Rutherford category of CLI (5.0 ± 0.2 to 4.3 ± 1.6, p < 0.01). There were no differences among functional parameters in patients undergoing IM versus IA delivery. Responders (n = 27) were characterized by higher CD34 + cell counts in the bone marrow concentrate (CD34 + 29 ± 15×10 6 vs. 17 ± 12×10

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Section: Discussionsupporting

confidence: 89%

No Difference in Intra-Arterial and Intramuscular Delivery of Autologous Bone Marrow Cells in Patients with Advanced Critical Limb Ischemia

Klepanec

Mistrík

Altaner³

et al. 2012

Cell Transplant

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“…Also, unlike rodent models, there are significant differences between the muscle mass/subcutaneous fat ratios in patients, which can affect delivery location. Prior clinical trials have delivered the therapeutic agent via blind intramuscular injections 1.5–2.5 cm deep into the thigh and calf [41, 42]. Because of the differences in body habitus, some patients received the agent deep within the muscle, while others received the agent in the subcutaneous fat.…”

Section: Discussionmentioning

confidence: 99%

X-Ray-Visible Microcapsules Containing Mesenchymal Stem Cells Improve Hind Limb Perfusion in a Rabbit Model of Peripheral Arterial Disease

Kedziorek

Hofmann

et al. 2012

Stem Cells

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The therapeutic goal in peripheral arterial disease (PAD) patients is to restore blood flow to ischemic tissue. Stem cell transplantation offers a new avenue to enhance arteriogenesis and angiogenesis. Two major problems with cell therapies are poor cell survival and the lack of visualization of cell delivery and distribution. To address these therapeutic barriers, allogeneic bone marrow-derived mesenchymal stem cells (MSCs) were encapsulated in alginate impregnated with a radiopaque contrast agent (MSC-Xcaps.) In vitro MSC-Xcap viability by a fluorometric assay was high (96.9% ± 2.7% at 30 days postencapsulation) and as few as 10 Xcaps were visible on clinical x-ray fluoroscopic systems. Using an endovascular PAD model, rabbits (n = 21) were randomized to receive MSC-Xcaps (n = 6), empty Xcaps (n = 5), unencapsulated MSCs (n = 5), or sham intramuscular injections (n = 5) in the ischemic thigh 24 hours postocclusion. Immediately after MSC transplantation and 14 days later, digital radiographs acquired on a clinical angiographic system demonstrated persistent visualization of the Xcap injection sites with retained contrast-to-noise. Using a modified TIMI frame count, quantitative angiography demonstrated a 65% improvement in hind limb perfusion or arteriogenesis in MSC-Xcap-treated animals versus empty Xcaps. Post-mortem immunohistopathology of vessel density by anti-CD31 staining demonstrated an 87% enhancement in angiogenesis in Xcap-MSC-treated animals versus empty Xcaps. MSC-Xcaps represent the first x-ray-visible cellular therapeutic with enhanced efficacy for PAD treatment.

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“…However, clinical trials testing the therapeutic effects of these cytokines alone have not been successful for peripheral artery disease(44), stroke(45) and myocardial infarction(46-48). Alternatively, intramuscular administration of cytokine mobilized leukapheresis cell product has demonstrated some benefit in subjects with refractory CLI using unfractionated mononuclear cells(49-52), selected CD34+ cells(18, 24), and mesenchymal stem cells(53). Two small trials demonstrated that single-limb, intramuscular administration of autologous peripheral blood acquired CD133+ cells in subjects with CLI is feasible but efficacy could not be assessed as these trials were uncontrolled(54, 55).…”

Section: Discussionmentioning

confidence: 99%

Bilateral administration of autologous CD133+ cells in ambulatory patients with refractory critical limb ischemia: lessons learned from a pilot randomized, double-blind, placebo-controlled trial

et al. 2014

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Introduction CD133+ cells confer angiogenic potential and may be beneficial for the treatment of critical limb ischemia (CLI). However, patient selection, blinding methods and endpoints for clinical trials is challenging. We hypothesized that bilateral intramuscular administration of cytokine mobilized CD133+ cells in ambulatory patients with refractory CLI would be feasible and safe. Methods In this double-blind, randomized, sham-controlled trial, subjects received subcutaneous injections of granulocyte colony stimulating factor (10 mcg/kg/d) for 5 days, followed by leukapheresis, and intramuscular administration of 50-400 million sorted CD133+ cells delivered into both legs. Control subjects received normal saline injections, sham leukapheresis and intramuscular injection of placebo buffered solution. Subjects were followed for 1 year. An aliquot of CD133+ cells was collected from each subject to test for genes associated with cell senescence. Results 70 subjects were screened, of whom 10 were eligible. Subject enrollment was suspended due to a high rate of mobilization failure in subjects randomized to treatment. Of 10 subjects enrolled (7 randomized to treatment, 3 randomized to control), there were no differences in serious adverse events at 12 months and blinding was preserved. There were non-significant trends toward improved amputation free survival, 6 minute walk distance, walking impairment questionnaire and quality of life in subjects randomized to treatment. Successful CD133+ mobilizers expressed fewer senescence associated genes compared to poor mobilizers. Conclusion Bilateral administration of autologous CD133+ cell in ambulatory CLI subjects was safe and blinding was preserved. However, poor mobilization efficiency combined with high CD133+ senescence suggests futility in this approach.

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Safety and efficacy of granulocyte–colony-stimulating factor administration following autologous intramuscular implantation of bone marrow mononuclear cells: a randomized controlled trial in patients with advanced lower limb ischemia

Cited by 24 publications

References 29 publications

No Difference in Intra-Arterial and Intramuscular Delivery of Autologous Bone Marrow Cells in Patients with Advanced Critical Limb Ischemia

No Difference in Intra-Arterial and Intramuscular Delivery of Autologous Bone Marrow Cells in Patients with Advanced Critical Limb Ischemia

X-Ray-Visible Microcapsules Containing Mesenchymal Stem Cells Improve Hind Limb Perfusion in a Rabbit Model of Peripheral Arterial Disease

Bilateral administration of autologous CD133+ cells in ambulatory patients with refractory critical limb ischemia: lessons learned from a pilot randomized, double-blind, placebo-controlled trial

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