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      Concise Review: A Safety Assessment of Adipose‐Derived Cell Therapy in Clinical Trials: A Systematic Review of Reported Adverse Events

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          Abstract

          The popularity of adipose‐derived cell therapy has increased over the last decade, and the number of studies published annually is growing. However, concerns regarding safety in the setting of previous malignancy or the use of allogeneic cells have been raised. We therefore aimed to systematically review all clinical studies using adipose‐derived cell therapy to identify reported adverse events with a special focus on risk of thromboembolic, immunological, and oncological safety concerns. Our systematic search resulted in 70 included studies involving more than 1,400 patients that were treated with adipose‐derived cell therapy. Safety assessment method was not described in 32 of the included studies. For studies involving systemic or cardiac administration, one case of pulmonary thromboembolism and cases of both myocardial and cerebral infarctions were described. In the setting of allogeneic cell therapy studies, where the production of specific antibodies toward donor cells was examined, it was noted that 19%–34% of patients develop antibodies, but the consequence of this is unknown. With regard to oncological safety, only one case of breast cancer recurrence was identified out of 121 patients. Adipose‐derived cell therapy has so far shown a favorable safety profile, but safety assessment description has, in general, been of poor quality, and only adverse events that are looked for will be found. We encourage future studies to maintain a strong focus on the safety profile of cell therapy, so its safeness can be confirmed. stem cells translational medicine 2017;6:1786–1794

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          A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation.

          The effective management of fistulas in patients with Crohn's disease presents an extremely challenging problem. Mesenchymal adult stem cells extracted from certain tissues, such as adipose tissue, can differentiate into various cell types. Therefore, we have tried to use such cells to stimulate healing of Crohn's fistulas. We designed a prospective Phase I clinical trial, involving five patients with Crohn's disease, to test the feasibility and safety of autologous stem cells transplantation in the treatment of fistulas. We also studied the expression of various cell markers and the growth rates of the lipoaspirate-derived cells that were used for transplantation. One patient was excluded because of bacterial contamination of cultured cells. We inoculated nine fistulas in four patients with autologous adipose tissue-derived stem cells at Passage 3 or earlier. Eight inoculated fistulas were followed weekly for at least eight weeks. In six fistulas, the external opening was covered with epithelium at the end of Week 8, and, thus, these fistulas were considered healed (75 percent). In the other two fistulas, there was only incomplete closure of the external opening, with a decrease in output flow (not healed; 25 percent). No adverse effects were observed in any patient at the end of the follow-up period (minimum follow-up,12 months; maximum follow-up, 30 months; follow-up average, 22 months). To our knowledge, this is the first report of a clinical trial of cell therapy using autologous stem cells obtained from a lipoaspirate. Our results indicate that our protocol is feasible and safe for the treatment of fistulas in Crohn's disease. The number of patients included and the uncontrolled nature of Phase I clinical trials do not allow demonstration of the effectiveness of the treatment. However, the results of the present study encourage to perform further studies in Phase II.
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            Adipose Mesenchymal Stromal Cell-Based Therapy for Severe Osteoarthritis of the Knee: A Phase I Dose-Escalation Trial.

            : Osteoarthritis (OA) is the most widespread musculoskeletal disorder in adults. It leads to cartilage damage associated with subchondral bone changes and synovial inflammation, causing pain and disability. The present study aimed at evaluating the safety of a dose-escalation protocol of intra-articular injected adipose-derived stromal cells (ASCs) in patients with knee OA, as well as clinical efficacy as secondary endpoint. A bicentric, uncontrolled, open phase I clinical trial was conducted in France and Germany with regulatory agency approval for ASC expansion procedure in both countries. From April 2012 to December 2013, 18 consecutive patients with symptomatic and severe knee OA were treated with a single intra-articular injection of autologous ASCs. The study design consisted of three consecutive cohorts (six patients each) with dose escalation: low dose (2 × 10(6) cells), medium dose (10 × 10(6)), and high dose (50 × 10(6)). The primary outcome parameter was safety evaluated by recording adverse events throughout the trial, and secondary parameters were pain and function subscales of the Western Ontario and McMaster Universities Arthritis Index. After 6 months of follow-up, the procedure was found to be safe, and no serious adverse events were reported. Four patients experienced transient knee joint pain and swelling after local injection. Interestingly, patients treated with low-dose ASCs experienced significant improvements in pain levels and function compared with baseline. Our data suggest that the intra-articular injection of ASCs is a safe therapeutic alternative to treat severe knee OA patients. A placebo-controlled double-blind phase IIb study is being initiated to assess clinical and structural efficacy.
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              Enrichment of autologous fat grafts with ex-vivo expanded adipose tissue-derived stem cells for graft survival: a randomised placebo-controlled trial.

              Autologous fat grafting is increasingly used in reconstructive surgery. However, resorption rates ranging from 25% to 80% have been reported. Therefore, methods to increase graft viability are needed. Here, we report the results of a triple-blind, placebo-controlled trial to compare the survival of fat grafts enriched with autologous adipose-derived stem cells (ASCs) versus non-enriched fat grafts. Healthy participants underwent two liposuctions taken 14 days apart: one for ASC isolation and ex-vivo expansion, and another for the preparation of fat grafts. Two purified fat grafts (30 mL each) taken from the second liposuction were prepared for each participant. One graft was enriched with ASCs (20 × 10(6) cells per mL fat), and another graft without ASC enrichment served as a control. The fat grafts were injected subcutaneously as a bolus to the posterior part of the right and left upper arm according to the randomisation sequence. The volumes of injected fat grafts were measured by MRI immediately after injection and after 121 days before surgical removal. The primary goal was to compare the residual graft volumes of ASC-enriched grafts with those of control grafts. This study is registered at www.clinicaltrialsregister.eu, number 2010-023006-12. 13 participants were enrolled, three of whom were excluded. Compared with the control grafts, the ASC-enriched fat grafts had significantly higher residual volumes: 23·00 (95% CI 20·57-25·43) cm(3) versus 4·66 (3·16-6·16) cm(3) for the controls, corresponding to 80·9% (76·6-85·2) versus 16·3% (11·1-21·4) of the initial volumes, respectively (p<0·0001). The difference between the groups was 18·34 (95% CI 15·70-20·98) cm(3), equivalent to 64·6% (57·1-72·1; p<0·0001). No serious adverse events were noted. The procedure of ASC-enriched fat grafting had excellent feasibility and safety. These promising results add significantly to the prospect of stem cell use in clinical settings, and indicate that ASC graft enrichment could render lipofilling a reliable alternative to major tissue augmentation, such as breast surgery, with allogeneic material or major flap surgery. Danish Cancer Society, Centre of Head and Orthopaedics Rigshospitalet, and Moalem Weitemeyer Bendtsen. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Navid.m.toyserkani@rsyd.dk
                Journal
                Stem Cells Transl Med
                Stem Cells Transl Med
                10.1002/(ISSN)2157-6580
                SCT3
                Stem Cells Translational Medicine
                John Wiley and Sons Inc. (Hoboken )
                2157-6564
                2157-6580
                19 July 2017
                September 2017
                : 6
                : 9 ( doiID: 10.1002/sct3.2017.6.issue-9 )
                : 1786-1794
                Affiliations
                [ 1 ] Department of Plastic Surgery Odense University Hospital Odense Denmark
                [ 2 ] The Danish Centre for Regenerative Medicine Odense University Hospital Denmark
                [ 3 ] Clinical Institute, Odense University Hospital Odense Denmark
                [ 4 ] Laboratory of Molecular and Cellular Cardiology, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital Odense Denmark
                [ 5 ] Institute of Molecular Medicine, University of Southern Denmark Odense C Denmark
                Author notes
                [*] [* ]Correspondence: Navid Mohamadpour Toyserkani, M.D., Department of Plastic Surgery, Odense University Hospital, Sdr. Boulevard 29, Odense C, Denmark. Telephone: +45 6541 4679; e‐mail: Navid.m.toyserkani@ 123456rsyd.dk
                Author information
                https://orcid.org/http://orcid.org/0000-0001-5619-4711
                Article
                SCT312192
                10.1002/sctm.17-0031
                5689766
                28722289
                6f3b4642-3b63-4b1f-b707-48436132496a
                © 2017 The Authors S tem C ells T ranslational M edicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 10 February 2017
                : 09 June 2017
                Page count
                Figures: 2, Tables: 2, Pages: 10, Words: 7693
                Product
                Categories
                Standards, Policies, Protocols, and Regulations for Cell‐Based Therapies
                Adipose Stem Cells/VSF
                Adult Stem Cells
                Perivascular Stem/Progenitor Cells
                Mesenchymal Stem Cells
                Clinical Trials
                Clinical Application / Translation
                Standards, Protocols, Policies, and Regulations for Cell‐Based Therapies
                Translational Research Articles and Reviews
                Standards, Protocols, Policies, and Regulations for Cell‐Based Therapies
                Custom metadata
                2.0
                sct312192
                September 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.4.1 mode:remove_FC converted:09.11.2017

                adipose‐derived stromal cells,stromal vascular fraction,safety,adverse events,complications

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