Long-term follow-up of patients undergoing adipose-derived adult stem cell administration to treat complex perianal fistulas.

PURPOSE: In patients with perianal fistulas, administration of adult stem cells (ASCs) derived from liposuction samples has proved a promising technique in a preceding phase II trial. We aimed to extend follow-up of these patients with this retrospective study. METHOD: Patients who had received at least one dose of treatment (ASCs plus fibrin glue or fibrin glue alone) were included. Adverse events notified since the end of the phase II study were recorded. Clinical and magnetic resonance imaging (MRI) criteria were used to determine whether recurrence of the healed fistula had occurred. RESULTS: Data were available for 21 out of 24 patients treated with ASCs plus fibrin glue and 13 out of 25 patients treated with fibrin glue in the phase II study. Follow-up lasted a mean of 38.0 and 42.6 months, respectively. Two adverse events unrelated to the original treatment were reported, one in each group. There were no reports of anal incontinence associated with the procedure. Of the 12 patients treated with ASCs plus fibrin glue who were included in the retrospective follow-up in the complete closure group, only 7 remained free of recurrence. MRI was done in 31 patients. No relationship was detected between MRI results and the clinical fistula status, independent of the treatment received. CONCLUSIONS: Long-term follow-up reaffirmed the very good safety profile of the treatment. Nevertheless, a low proportion of the stem cell-treated patients with closure after the procedure remained free of recurrence after more than 3 years of follow-up.

Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial.

PURPOSE: The feasibility and safety of stem cell-based therapy with expanded adipose-derived stem cells (ASCs) has been investigated in a phase I clinical trial. The present study was designed as a phase II multicenter, randomized controlled trial to further investigate the effectiveness and safety of ASCs in the treatment of complex perianal fistulas. METHODS: Patients with complex perianal fistulas (cryptoglandular origin, n = 35; associated with Crohn's disease, n = 14) were randomly assigned to intralesional treatment with fibrin glue or fibrin glue plus 20 million ASCs. Fistula healing and quality of life (SF-12 questionnaire) were evaluated at eight weeks and one year. If healing was not seen at eight weeks, a second dose of fibrin glue or fibrin glue plus 40 million ASCs was administered. RESULTS: Fistula healing was observed in 17 (71 percent) of 24 patients who received ASCs in addition to fibrin glue compared with 4 (16 percent) of 25 patients who received fibrin glue alone (relative risk for healing, 4.43; confidence interval, 1.74-11.27); P < 0.001). The proportion of patients with healing was similar in Crohn's and non-Crohn's subgroups. ASCs were also more effective than fibrin glue alone in patients with a suprasphincteric fistulous tract (P = 0.001). Quality of life scores were higher in patients who received ASCs than in those who received fibrin glue alone. At one year follow-up, the recurrence rate in patients treated with ASCs was 17.6 percent. Both treatments were well tolerated. CONCLUSION: Administration of expanded ASCs (20 to 60 million cells) in combination with fibrin glue is an effective and safe treatment for complex perianal fistula and appears to achieve higher rates of healing than fibrin glue alone.

Treatment of enterocutaneous fistula in Crohn's Disease with adipose-derived stem cells: a comparison of protocols with and without cell expansion.

BACKGROUND: Expanded adipose-derived stem cells (ASC) have been shown to be effective in treating Crohn's patients with enterocutaneous fistulas. It is possible that unexpanded cells corresponding to the stromal vascular fraction (SVF) may also be effective. MATERIALS AND METHODS: A subpopulation of patients from a previous proof-of-concept phase I study with enterocutaneous fistulas received autologous expanded ASCs. The same selection criteria for inclusion were applied to patients who underwent SVF implantation to treat enterocutaneous fistulas. After tract curettage, cell suspensions (either SVF cells from lipoaspirate or expanded ASCs) were injected into the tract walls, and the fistulous tract was sealed with fibrin adhesive (with or without cells). RESULTS: In the series that received ASCs, four fistulas could be evaluated, and cure was achieved in three out of four cases. In the series that received SVF cells, four fistulas were evaluated, with cure achieved in one out of four cases. CONCLUSIONS: Although a comparison of case series cannot be considered firm evidence, a therapeutic protocol that uses expansion prior to implantation does seem to be more effective than one that uses SVF cells directly from a lipoaspirate sample.

Expanded adipose-derived stem cells for the treatment of complex perianal fistula including Crohn's disease.

BACKGROUND: Complex perianal fistulising disease is a distressing condition. In patients without Crohn's disease, surgery is the mainstay treatment but faecal incontinence and recurrence are high. Infliximab is used in Crohn's patients but not all respond to therapy. OBJECTIVE: After an evaluation of the current treatment options, we discuss studies of adipose-derived stem cell (ASC) therapy, a novel approach for treating complex perianal fistulas. METHODS: ASCs are obtained from a liposuction procedure and a subsequent expansion process. They are administered according to a strict protocol which involves infusion of the cells into the target lesion along with fibrin glue. RESULTS/CONCLUSIONS: A Phase IIb study comparing ASC and fibrin glue therapy with fibrin glue therapy alone showed that ASCs were effective at inducing healing in complex perianal fistulas.

An assessment of the incidence of fistula-in-ano in four countries of the European Union.

BACKGROUND AND AIMS: In spite of its long history, fistula-in-ano is generally considered to be relatively uncommon. Nevertheless, no comprehensive analysis of its incidence in developed countries is available. Our goal was to determine the actual incidence of fistula-in-ano based on the study of incidence in four countries of the European Union (EU). MATERIALS AND METHODS: We performed a search of hospital inpatient databases in five different countries. We obtained valid data from four European countries, namely, England (UK; Hospital Episodes Statistics), Germany (German hospitals' databases), Italy (Scheda di Dimissione Ospedaliera), and Spain (Conjunto Mínimo Básico de Datos by Insalud-Spanish National Health Institute). RESULTS: The incidence of fistula-in-ano varied among the different populations in the EU. In the four countries examined, it ranged from 1.04 per 10,000/year in Spain to 2.32 per 10,000/year in Italy. A statistical comparison of rates from the different countries studied gives a confidence interval from 1.20 up to 2.80. The population that we studied represents almost 51% of the total population of the EU. CONCLUSION: This study attempts to determine the actual incidence of fistula-in-ano in the European Community, which was previously uncertain despite its major negative effects on quality of life and the high cost of treatment. Our findings indicate that the incidence of fistula-in-ano in the four countries of the EU studied is significantly higher than that in the only previously published report of the incidence of fistula-in-ano in Europe. Nevertheless, our findings confirm the general perception that fistula-in-ano is a relatively uncommon disease.

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

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.