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.

[QUALYPOLL. Questionnaire which measures the quality of life for patients who have undergone an intestinal or urological ostomy]. / QUALYPOLL. Cuestionario que mide la calidad de vida en los pacientes ostomizados.

The authors publish the first precise, specific, valid questionnaire in Spanish which measures the quality of life related to health for patients who have undergone an intestinal or urological ostomy; furthermore, this questionnaire has been validated in a sample of Spanish population. The OPM Division of B. Braun Medical was the sponsor of the study which led to the creation of this QUALYPOLL questionnaire. Statistical validation of the data complied was performed by Health Outcomes Research Europe which carried out a multi-centric national study to evaluate the measuring properties of the aforementioned QUALYPOLL questionnaire on patients who have undergone an intestinal or urological ostomy.

Treatment of Crohn's-Related Rectovaginal Fistula With Allogeneic Expanded-Adipose Derived Stem Cells: A Phase I-IIa Clinical Trial.

: The aim of this clinical trial was to determine the safety and feasibility of expanded allogeneic adipose-derived stem cells to treat Crohn's-related rectovaginal fistula (CRRVF). We designed a phase I-II clinical trial (https://ClinicalTrials.gov, NCT00999115) to treat 10 patients with CRRVF. Patients receiving biological therapy during follow-up were excluded. Curettage was performed, and a vaginal or rectal flap was added if the surgeon considered it necessary. The therapeutic protocol included intralesional injection of 20 million stem cells in the vaginal walls (submucosal area) and fistula tract. Healing was evaluated 12 weeks later. If the fistula had not healed, a second dose of 40 million stem cells was administered. Patient follow-up was 52 weeks from last cell injection. Healing was defined as re-epithelialization of both vaginal and rectal sides and absence of vaginal drainage. Cytokines and immunological blood tests were monitored. Serious adverse events or rejection issues were not observed. Five patients were excluded because biologic drugs were required to treat a Crohn's disease flare-up during follow-up. Cytokine profiles and immunotoxicity assays showed no statistically significant alterations. Sixty percent of the nonexcluded patients achieved a complete healing. Expanded allogeneic adipose-derived stem-cell injection is a safe and feasible therapy for treating CRRVF, and the healing success rate seems promising (60%). The results of this trial encourage further exploration into this therapy. SIGNIFICANCE: This may be the first publication in which allogeneic stem cells to treat rectovaginal fistula in Crohn´s disease seem to be a feasible and safe treatment. Additional studies are necessary to confirm the efficacy profile of the allogeneic stem cells strategy in a controlled design.

Recurrent anal fistulae: limited surgery supported by stem cells.

AIM: To study the results of stem-cell therapy under a Compassionate-use Program for patients with recurrent anal fistulae. METHODS: Under controlled circumstances, and approved by European and Spanish laws, a Compassionate-use Program allows the use of stem-cell therapy for patients with very complex anal fistulae. Candidates had previously undergone multiple surgical interventions that had failed to resolve the fistulae, and presented symptomatic recurrence. The intervention consisted of limited surgery (with closure of the internal opening), followed by local implant of stem cells in the fistula-tract wall. Autologous expanded adipose-derived stem cells were the main cell type selected for implant. The first evaluation was performed on the 8(th) postoperative week; outcome was classified as response or partial response. Evaluation one year after the intervention confirmed if complete healing of the fistula was achieved. RESULTS: Ten patients (8 male) with highly recurrent and complex fistulae were treated (mean age: 49 years, range: 28-76 years). Seven cases were non-Crohn's fistulae, and three were Crohn's-associated fistulae. Previous surgical attempts ranged from 3 to 12. Two patients presented with preoperative incontinence (Wexner scores of 12 and 13 points). After the intervention, six patients showed clinical response on the 8(th) postoperative week, with a complete cessation of suppuration from the fistula. Three patients presented a partial response, with an evident decrease in suppuration. A year later, six patients (60%) remained healed, with complete reepithelization of the external opening. Postoperative Wexner Scores were 0 in six cases. The two patients with previous incontinence improved their scores from 12 to 8 points and from 13 to 5 points. No adverse reactions or complications related to stem-cell therapy were reported during the study period. CONCLUSION: Stem cells are safe and useful for treating anal fistulae. Healing can be achieved in severe cases, sparing fecal incontinence risk, and improving previous scoring.

First-in-Human Case Study: Pregnancy in Women With Crohn's Perianal Fistula Treated With Adipose-Derived Stem Cells: A Safety Study.

UNLABELLED: The aim of this study was to determine whether treatment with adipose-derived stem cells (ASCs) had any influence on fertility, course of pregnancy, newborn weight, or physical condition of newborns. We performed a retrospective study of patients with a desire to become pregnant after having received intralesional injection of autologous ASCs for the treatment of perianal or rectovaginal fistula associated with Crohn's disease. We collected data on the resulting pregnancies, deliveries, and newborns of these patients. ASCs were expanded in vitro and characterized according to the international guidelines for cell surface markers (clusters of differentiation) and differentiated to adipocytes, chondrocytes, and osteocytes prior to implantation (except first implant in 2002). We analyzed five young women with Crohn's disease treated with ASCs: one for rectovaginal and perianal fistula, two for rectovaginal fistula only, and two for perianal fistula only. All patients received 2 doses of 20 million and 40 million cells at an interval of 3-4 months. Another patient received 2 doses of 6.6 million and 20 million ASCs with 9 months between each dose. Fertility and pregnancy outcomes were not affected by cell therapy treatment. No signs of treatment-related malformations were observed in the neonates by their respective pediatricians. In the patients studied, cell therapy with ASCs did not affect the course of pregnancy or newborn development. SIGNIFICANCE: Local treatment with mesenchymal stem cells derived from adipose tissue seems not to affect the ability to conceive, the course of pregnancy, pregnancy outcomes, or newborns' health in female patients. This is the first publication about pregnancy outcome in women with perianal fistula and Crohn's disease treated with stem cell therapy, and could be of interest for doctors working in cell therapy. This is a very important question for patients, and there was no answer for them until now.

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.