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Inflammatory bowel disease remains a difficult disease to effectively treat, especially fistulizing Crohn's disease. Perianal fistulas in the setting of Crohn's disease remain an area of unmet need with significant morbidity in this patient population. Up to one third of Crohn's patients will have perianal fistulizing disease and current medical and surgical interventions are of limited efficacy. Thus, most patients experience significant morbidity, narcotic use, and loss of employment and end up with multiple surgical interventions. Mesenchymal stem cells (MSCs) have shown efficacy in phase 3 clinical trials, but considerable infrastructure challenges make MSCs limited with regard to scalability in clinical practice. Extracellular vesicles, being derived from MSCs and capturing the secretome functionality of MSCs, offer similar physiological utility regarding mechanism, while also providing an off the shelf regenerative medicine product that could be widely used in daily clinical practice., (© 2024. The Author(s).)

Background: Mesenchymal stem cells have been administered via direct injection to treat perianal Crohn's fistulizing disease. We herein sought to determine the safety and durability of treatment response to 12 months with 3 individual phase IB/IIA clinical trials of mesenchymal stem cells for refractory perianal, rectovaginal, and ileal pouch fistulas in the setting of Crohn disease., Methods: Three phase IB/IIA randomized placebo-controlled single-blinded clinical trials were performed for (1) perianal fistulas, (2) rectovaginal fistula, and (3) ileal pouch in situ with anovaginal and/or perianal fistulas. Bone marrow-derived mesenchymal stem cells (75 million in 7.5 mL) were injected at the time of exam under anesthesia on day 0 and month 3. Outcome measures were adverse events and combined clinical and pelvic magnetic resonance imaging healing at month 6 and month 12., Results: Across all 3 trials, 64 patients were enrolled; 49 were treatment and 15 were control. At 6 months, combined clinical and radiographic healing was achieved in 83.3%, 33.3%, and 30.8% of the perianal, rectovaginal, and pouch fistula treatment cohorts, respectively. At 12 months, the treatment response was durable, with 67.7% of perianal, 37.5% of rectovaginal, and 46.2% of peripouch fistulas maintaining complete clinical and radiographic healing. Two patients in the perianal fistula control cohort achieved combined clinical and radiographic healing at 12 months, whereas 0% of rectovaginal and pouch control patients healed., Conclusion: Bone marrow-derived mesenchymal stem cells offer a safe and effective alternative treatment approach for severe perianal, rectovaginal, and peripouch fistulizing Crohn's disease. Treatment results are durable at 12 months., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Crohn-related rectovaginal fistulas are notoriously difficult to treat. Studies of mesenchymal stem cells for the treatment of perianal Crohn fistulizing disease have largely excluded rectovaginal fistulas. The aim of this study was to determine the safety and efficacy of mesenchymal stem cells for refractory rectovaginal fistulizing Crohn disease., Methods: A phase IB/IIA randomized control trial was performed in a 3:1, single-blinded study. Patients included were adult women with an anovaginal/rectovaginal fistula in the setting of Crohn disease. Seventy-five million mesenchymal stem cells were administered with a 22G needle after curettage and primary closure of the fistula tract at day 0 and month 3. Adverse and serious adverse events were recorded at post-procedure day 1, week 2, week 6, month 3, month 6, and month 12, along with clinical healing, magnetic resonance imaging, and patient-reported outcomes., Results: A total of 19 patients were enrolled and treated-15 treatment and 4 control. There were no adverse or serious adverse events related to mesenchymal stem cell therapy. At 6 months, 50% of the treatment group and 0% of the control had complete clinical and radiographic healing; 91.7% of the treatment group had improvement at 6 months with only one patient having a lack of response, whereas only 50% of the control group had improvement at 6 months., Conclusion: Bone marrow-derived mesenchymal stem cells offer a safe alternative treatment approach for rectovaginal fistulas in the setting of Crohn disease. Complete healing was achieved in half of the patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Perianal fistulizing Crohn's disease is notoriously difficult to treat. Recent studies of mesenchymal stem cells have demonstrated safety and efficacy of this novel treatment approach. However, no studies to date have included pediatric patients. We sought to determine safety and efficacy of mesenchymal stem cells for pediatric perianal fistulizing Crohn's disease., Methods: This was a phase I clinical trial to evaluate safety and feasibility of mesenchymal stem cells in pediatric perianal Crohn's patients 13 to 17 years of age. At the time of an exam under anesthesia, following curettage of the fistula tract and closure of the internal opening with absorbable suture, 75 million mesenchymal stem cells were administered with a 22-gauge needle. This was repeated at 3 months if complete clinical and radiographic healing were not achieved. Adverse and serious adverse events at were measured at postprocedure day 1, week 2, week 6, month 3, month 6, and month 12. Clinical healing, radiographic healing per magnetic resonance imaging, and patient-reported outcomes were measured at the same time points., Results: Seven pediatric patients were enrolled and treated (6 male; median age of 16.7 years). There were no adverse or serious adverse events related to the investigational product or injection procedure. At 6 months, 83% had complete clinical and radiographic healing. The perianal Crohn's Disease Activity Index, Wexner incontinence score, and Van Assche score had all decreased at 6 months., Conclusions: Bone marrow-derived mesenchymal stem cells offer a safe, and likely effective, treatment approach for pediatric perianal fistulizing Crohn's disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The leading cause of pouch failure following ileal pouch-anal anastomosis are peri-pouch fistulas and pelvic sepsis., Objective: Determine the overall efficacy of current surgical therapy for the treatment of perianal and anovaginal fistulizing disease related to Crohn's disease phenotype of the pouch., Design: Retrospective cohort study of a prospectively maintained, IRB-approved database., Settings/patients: Ninety-one (2.3%) patients of 3058 patients with an original diagnosis of ulcerative colitis who underwent proctocolectomy with ileal pouch-anal anastomosis between 2000 and 2021 at the Cleveland Clinic and underwent postoperative surgery for Crohn's-related perianal disease., Interventions: Two hundred thirty-one operations for perianal or anovaginal fistula(s)., Main Outcome and Measures: Healing rate of surgical therapy for peri-pouch fistulizing disease, impact of recurrent interventions on outcomes, and predictors of surgical failure., Results: Overall mean age was 39.1 (± 11.6) years, with a BMI of 25.3 (± 6.3) kg/m 2 . More than half of the patients were female (n = 52, 57.1%). Sixty-three patients (69.2%) had a perianal fistula, 25 (27.5%) had an anovaginal fistula, and 3 (3.3%) patients had both. Overall success rate for healing was 59.3% (n = 54/91) at a mean follow-up of 6.4 (± 4.8) years. Seventeen (18.7%) patients underwent a concomitant diverting loop ileostomy. Among them, eight (47.0%) patients had the ileostomy closure after a mean time of 9.7 (± 2.8) months. In the multivariable logistic regression model, patients who had seton insertions in any operation were significantly less likely to heal (OR 0.11 95%, CI 0.03-0.43, p = 0.001). Overall pouch failure rate was 12.1%., Limitations: Retrospective single-center study which lacks a control arm and consistent long-term follow-up specific to a population-based dataset., Conclusions: Pouch patients who develop perianal disease are difficult to treat, sometimes requiring pouch excision. However, when medical treatment alone is not effective, a multidisciplinary approach including surgical intervention can result in complete fistula healing in more than half of the cases., (© 2023. The Society for Surgery of the Alimentary Tract.)

Background: Mesenchymal stem cells have been used for the treatment of perianal Crohn's fistulizing disease by direct injection. However, no studies to date have included patients with proctitis, anal canal involvement, and multiple branching tracts., Objective: This study aimed to determine safety and efficacy of mesenchymal stem cells for refractory perianal Crohn's disease., Design: Phase IB/IIA randomized controlled trial., Settings: Tertiary IBD referral center., Patients: Adult Crohn's disease patients with perianal fistulizing disease., Intervention: Seventy-five million mesenchymal stem cells were administered with a 22-G needle by direct injection after curettage and primary closure of the fistula tract. A repeat injection of 75 million mesenchymal stem cells at 3 months was given if complete clinical and radiographic healing were not achieved., Main Outcomes Measures: Adverse and serious adverse events occurred at postprocedure day 1, week 2, week 6, month 3, month 6, and month 12. Clinical healing, radiographic healing per MRI, and patient-reported outcomes were collected at the same time points., Results: A total of 23 patients were enrolled and treated; 18 were treatment patients and 5 were control. There were no adverse or serious adverse events reported related to mesenchymal stem cell therapy. At 6 months, 83% of the treatment group and 40% of the control group had complete clinical and radiographic healing. The perianal Crohn's disease activity index, Wexner incontinence score, and VanAssche score had all significantly decreased in treatment patients at 6 months; none significantly decreased in the control group., Limitations: Single institution and single blinded., Conclusions: Bone marrow-derived mesenchymal stem cells offer a safe and effective alternative treatment approach for severe perianal fistulizing Crohn's disease. See Video Abstract at http://links.lww.com/DCR/C128 ., Un Estudio De Fase Ib/iia De Clulas Madre Mesenquimales Derivadas De Mdula Sea Alognica Expandida Ex Vivo Para El Tratamiento De La Enfermedad De Crohn Fistulizante Perianal: ANTECEDENTES:Las células madre mesenquimales se han utilizado para el tratamiento de la enfermedad fistulizante de Crohn perianal mediante inyección dirigida. Sin embargo, ningún estudio hasta la fecha ha incluido pacientes con proctitis, afectación del canal anal y vías de ramificación múltiples.OBJETIVO:Determinar la seguridad y eficacia de las células madre mesenquimales para la enfermedad de Crohn perianal refractaria.DISEÑO:Ensayo de control aleatorizado de fase IB/IIA.AJUSTES:Centro de referencia de enfermedad inflamatoria intestinal terciaria.PACIENTES:Pacientes adultos con enfermedad de Crohn con enfermedad fistulizante perianal.INTERVENCIÓN:Se administraron 75 millones de células madre mesenquimales con una aguja 22G mediante inyección directa después del legrado y cierre primario del trayecto de la fístula. Se administró una inyección repetida de 75 millones de células madre mesenquimales a los 3 meses si no se lograba una curación clínica y radiográfica completa.PRINCIPALES MEDIDAS DE RESULTADOS:eventos adversos y adversos graves en el día 1, la semana 2, la semana 6, el mes 3, el mes 6 y el mes 12 después del procedimiento. Curación clínica, curación radiográfica por imagen de resonancia magnética y resultados informados por el paciente en los mismos puntos de tiempo.RESULTADOS:Un total de 23 pacientes fueron reclutados y tratados; 18 fueron de tratamiento y 5 de control. No se informaron eventos adversos o adversos graves relacionados con la terapia con células madre mesenquimales. A los seis meses, el 83 % del grupo de tratamiento y el 40 % del control tenían una curación clínica y radiográfica completa. El índice de actividad de la enfermedad de Crohn perianal, la puntuación de incontinencia de Wexner y la puntuación de VanAssche habían disminuido significativamente en los pacientes de tratamiento a los seis meses; ninguno disminuyó significativamente en el grupo de control.LIMITACIONES:Institución única y simple ciego.CONCLUSIONES:Las células madre mesenquimales derivadas de la médula ósea ofrecen un d tratamiento alternativo seguro y eficaz para la enfermedad de Crohn fistulizante perianal grave. Consulte Video Resumen en http://links.lww.com/DCR/C128 . (Traducción-Dr Yolanda Colorado )., (Copyright © The ASCRS 2023.)

Background: Approximately 30% of Crohn's disease-related perianal fistulas heal in the adult population with conventional medical and surgical interventions. This healing rate remains unknown in pediatric patients., Objective: This study aimed to determine the healing rate of pediatric perianal Crohn's fistulas and identify factors associated with healing., Design: Retrospective case series., Setting: A quaternary referral center., Patients: Patients aged <18 years with a Crohn's perianal fistula, seen between January 1, 1991, and August 1, 2021, were included in the study., Interventions: Multivariable logistic regression to identify factors independently associated with perianal fistula healing., Main Outcome Measures: Healing of Crohn's perianal fistula at the date of last clinical encounter, defined as the clinical note reporting a healed fistula or normal perianal examination., Results: A total of 91 patients aged <18 years with a Crohn's disease-related perianal fistula were identified (59% female, 76% white). The mean (SD) age at Crohn's diagnosis was 12 (±4) years. The mean follow-up after Crohn's diagnosis was 10 (±7) years. Overall, 89% of patients had a perianal fistula, 2% had an anovaginal fistula, and 10% had an ileal pouch-associated fistula. Patients underwent a median (interquartile range) of 2 (1-5) operations. A seton was placed in 60% of patients, 47% underwent abscess drainage, and 44% underwent fistulotomy or fistulectomy. Fistula healing occurred in 71% of patients over a median of 1.3 (0.4-2.5) years. Seven patients (7%) underwent proctectomy, and 3 (3%) underwent ileal pouch excision. After multivariable adjustment, younger age at diagnosis of perianal fistula was associated with an increased likelihood of healing (OR 0.56 for each increased year; 95% CI, 0.34-0.92)., Limitations: Retrospective, single institution., Conclusions: Over two-thirds of fistulas heal in pediatric Crohn's disease patients with conventional surgical and medical intervention. Younger age at fistula development is associated with an increased likelihood of healing. See Video Abstract at http://links.lww.com/DCR/C185 ., Resultados a Largo Plazo De Las Fstulas Perianales En La Enfermedad De Crohn En Pacientes Peditricos: ANTECEDENTES:Aproximadamente el 30% de las fístulas perianales relacionadas con la enfermedad de Crohn se curan en la población adulta con intervenciones médicas y quirúrgicas convencionales. Esta tasa de curación sigue siendo desconocida en pacientes pediátricos.OBJETIVO:Determinar la tasa de curación de las fístulas de Crohn perianales en población pediátrica e identificar los factores asociados con la curación.DISEÑO:Serie de casos retrospectiva.ESCENARIO:Un centro de referencia cuaternario.PACIENTES:Pacientes menores de 18 años con fístula(s) perianal(es) por enfermedad de Crohn, atendidos entre el 1 de enero de 1991 y el 1 de agosto de 2021.INTERVENCIONES:Regresión logística multivariable para identificar factores asociados de forma independiente con la cicatrización de la fístula perianal.PRINCIPALES MEDIDAS DE RESULTADO:Curación de la fístula perianal de Crohn en la fecha del último encuentro clínico, definida como la nota clínica que informa una fístula curada o un examen perianal normal.RESULTADOS:Se identificó un total de 91 pacientes <18 años de edad con una fístula perianal relacionada con la enfermedad de Crohn (59% mujeres, 76% blancos). La edad media (DE) al diagnóstico de Crohn fue de 12 (±4) años. El seguimiento medio tras el diagnóstico de Crohn fue de 10 (±7) años. En general, el 89 % de los pacientes tenía fístula perianal, el 2 % tenía fístula anovaginal y el 10 % de los pacientes tenía fístula asociada a reservorio ileal. Los pacientes fueron sometidos a una mediana (RIC) de 2 (1-5) operaciones. En el 60% de los pacientes se colocó sedal, en el 47% se drenó el absceso y en el 44% se realizó fistulotomía o fistulectomía. La curación de la fístula se produjo en el 71% de los pacientes durante una mediana de 1,3 (0,4-2,5) años. Siete pacientes (7%) se sometieron a proctectomía y 3 (3%) se sometieron a escisión del reservorio ileal. Después del ajuste multivariable, la edad más joven en el momento del diagnóstico de la fístula perianal se asoció con una mayor probabilidad de curación (OR 0,56 por cada año de aumento, IC del 95%, 0,34-0,92).LIMITACIONES:Retrospectivo, institución única.CONCLUSIONES:Más de dos tercios de las fístulas se curan en pacientes pediátricos con enfermedad de Crohn con intervención médica y quirúrgica convencional. Una edad más joven en el momento del desarrollo de la fístula se asocia con una mayor probabilidad de curación. Consulte Video Resumen en http://links.lww.com/DCR/C185 . (Traducción--Dr. Felipe Bellolio )., (Copyright © The ASCRS 2023.)

Background and Aims: Mesenchymal stem cells [MSCs] have been used for the treatment of perianal Crohn's fistulising disease by direction injection. No studies to date have included patients with an ileal pouch-anal anastomosis [IPAA] in situ., Methods: A phase IB/IIA, randomised, control trial of bone marrow-derived, allogeneic MSCs via direct injection to treat adult patients with a peripouch fistula[s] was conducted; 75 million MSCs were administered with a 22 G needle, with repeat injection at 3 months if complete clinical and radiographic healing was not achieved. Adverse and serious adverse events at post-procedure Day 1, Week 2, Week 6, Month 3, Month 6, and Month 12 were assessed. Clinical healing, radiographic healing per pelvic magnetic resonance imaging [MRI], and patient-reported outcomes were assessed at the same time points., Results: A total of 22 patients were enrolled and treated; 16 were treated and six were controls. There were no adverse or serious adverse events related to MSC therapy. At 6 months, 31% of the treatment group and 20% of the control had complete clinical and radiographic healing. When stratifying the treatment group into perianal [n = 7] and ano-vaginal [n = 8] fistulas, 6-month healing in the treatment groups was 57% and 0%, respectively. The perianal Crohn's disease activity index [PCDAI], Wexner incontinence score, and van Assche score all significantly decreased in treatment patients at 6 months; only the PCDAI decreased in the control group., Conclusion: Bone marrow-derived, allogeneic MSCs offer a safe and effective alternative treatment approach for peripouch fistulas in the setting of a Crohn's like phenotype of the pouch [ClinicalTrials.gov Identifier: NCT04519684.]., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Rectovaginal fistula occurs in up to 10-20% of women with Crohn's disease, significantly affecting their quality of life. We sought to determine outcomes of single and repeat operative interventions., Methods: A retrospective review of all adult patients with a Crohn's-related rectovaginal fistula, who underwent an operation between 1995 and 2021, was performed. Data collected included patient demographics, Crohn's-related medical treatment, surgical intervention, postoperative outcomes, and fistula outcomes., Results: A total of 166 patients underwent 360 operations; mean age was 42.8 [+/-13.2] years; 34 [20.7%] patients were current and 58 [35.4%] former smokers. The most commonly performed procedure was: a local approach [n = 160, 44.5%] using fibrin glue, fistulotomy/fistulectomy, or seton placement; followed by a transvaginal/transanal approach [n = 113, 31.4%] with an advancement flap repair [including Martius advancement flap] and episoproctotomy; a transabdominal approach [n = 98, 27.2%] including proctectomy or re-do anastomosis; and finally gracilis muscle interposition [n = 8, 2.2%]. The median number of operative interventions per patient was 2 [1.0-3.0] procedures. The overall fistula healing rate per patient was 71.7% [n = 119] at a median follow-up of 5.5 [1.2-9.8] years. Factors that impaired healing included former smoking (odds ratio [OR] 0.52, 95% confidence interval [CI] 0.31-0.87, p = 0.014) and seton insertion [OR 0.42, 95% CI 0.21-0.83, p = 0.012]., Conclusion: Over two-thirds of Crohn's-related rectovaginal fistulas can achieve closure with multiple surgical interventions. Smoking and seton usage negatively affect healing rates and should be avoided., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Refractory perianal Crohn's disease remains notoriously difficult to treat. We developed a novel technology using a commercially available bioabsorbable fistula plug to deliver autologous adipose-derived mesenchymal stem cells., Objective: This study aimed to assess therapeutic safety and feasibility in the completed STOMP (stem cells on matrix plugs) phase 1 clinical trial., Design: Prospective single-arm phase I clinical trial., Setting: Tertiary academic medical center., Patients: Adults (aged 18-65 y) with complex single-tract Crohn's disease perianal fistula who have failed conventional therapy were included in this study., Intervention: Autologous adipose-derived mesenchymal stem cells were isolated, ex vivo culture expanded, and seeded onto a commercially available bioabsorbable fistula plug. Six weeks later, patients returned to the operating room for removal of the seton and placement of the stem cell-loaded plug., Main Outcome Measures: Patients were followed up for a total of 8 visits through 12 months. Safety was the primary end point; clinical healing and MRI response were secondary end points., Results: Twenty patients (12 females; mean age 36 y) were treated with the stem cell-loaded plug. Of the 20 patients enrolled, 3 were not included in the 12-month analysis because of study withdrawal. Through 12 months, no patient experienced a serious adverse event related to the stem cell-loaded plug. Four patients experienced 7 serious adverse events and 12 patients experienced 22 adverse events. Complete clinical healing occurred in 14 of 18 patients at 6 months and 13 of 17 patients at 12 months. MRI response was observed in 12 of 18 patients at 6 months., Limitations: The main limitations were the small sample size and restrictive inclusion criteria., Conclusions: A stem cell-loaded plug can safely and effectively deliver cell-based therapy for patients with single-tract fistulizing perianal Crohn's disease. See Video Abstract at http://links.lww.com/DCR/C70 ., Respuesta Duradera Observada En Pacientes Con Enfermedad De Crohn Perianal Fistulizante Refractaria Mediante El Uso De Clulas Madre Mesenquimales Autlogas En Una Matriz Disoluble Resultados Del Ensayo De Fase I Stem Cell on Matrix Plug: ANTECEDENTES:La enfermedad de Crohn perianal refractaria sigue siendo notoriamente difícil de tratar. Desarrollamos una tecnología novedosa utilizando un tapón de fístula bioabsorbible disponible comercialmente para administrar células madre mesenquimales derivadas de tejido adiposo autólogo.OBJETIVO:Evaluar la seguridad y viabilidad terapéutica en el ensayo finalizado STOMP.DISEÑO:Ensayo clínico prospectivo de fase I de un solo brazo.AJUSTE:Centro médico académico terciario.PACIENTES:Adultos (18-65) con fístula perianal compleja de la enfermedad de Crohn de un solo tracto que han fracasado con la terapia convencional.INTERVENCIÓN:Se aislaron células madre mesenquimales derivadas de tejido adiposo autólogo, se expandieron en cultivo ex vivo y se sembraron en un tapón de fístula bioabsorbible disponible comercialmente. Seis semanas después, los pacientes regresaron al quirófano para retirar el setón y colocar el tapón cargado de células madre.PRINCIPALES MEDIDAS DE RESULTADO:Los pacientes fueron seguidos durante un total de 8 visitas durante 12 meses. La seguridad fue el criterio principal de valoración; la curación clínica y la respuesta a la resonancia magnética fueron criterios de valoración secundarios.RESULTADOS:Veinte pacientes (12 mujeres, edad media 36 años) fueron tratados con el tapón cargado de células madre. De los 20 pacientes inscritos, tres no se incluyeron en el análisis de 12 meses porque se retiraron del estudio. A lo largo de 12 meses, ningún paciente experimentó un evento adverso grave relacionado con el tapón cargado de células madre. Cuatro pacientes experimentaron 7 eventos adversos graves y 12 pacientes experimentaron 22 eventos adversos. La curación clínica completa ocurrió en 14 de 18 pacientes a los 6 meses y en 13 de 17 pacientes a los 12 meses. La respuesta a la resonancia magnética se observó en 12 de 18 pacientes a los 6 meses.LIMITACIONES:Las principales limitaciones son el tamaño pequeño de la muestra y los criterios de inclusión restrictivos.CONCLUSIONES:Un tapón cargado de células madre se puede administrar de manera segura y efectiva, una terapia basada en células para pacientes con enfermedad de Crohn perianal fistulizante de un solo tracto. Consule Video Resumen en http://links.lww.com/DCR/C70 . (Traducción- Dr. Yesenia Rojas-Khalil )., Competing Interests: Financial Disclosure : Dr Lightner is a consultant for Takeda. Mayo Clinic and Drs Faubion, Dozois, and Dietz have a financial interest related to this research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies., (Copyright © The ASCRS 2022.)

Background: Surgical treatment of recurrent rectovaginal fistulas is notoriously difficult. Placement of the gracilis muscle between the vagina and anus is an advanced technique used to close persistent fistulas. We have utilized this procedure for recalcitrant fistulas and hypothesized that a gracilis interposition would offer a good treatment option for patients with refractory rectovaginal fistulas, regardless of underlying etiology., Objective: The purpose of this study was to investigate healing rates of gracilis interposition in patients with refractory rectovaginal fistulas., Design: Following institutional review board approval, a retrospective review of all adult female patients with a diagnosis of rectovaginal fistula between January 2009 and August 2020 was performed; those who underwent gracilis interposition for definitive fistula closure were included for analysis., Settings: The study was conducted at a colorectal surgery department at a tertiary center in the United States., Patients: All patients were adult females with a diagnosis of a rectovaginal fistula who underwent gracilis interposition for definitive closure., Main Outcome Measures: Patient demographics, etiology of rectovaginal fistula, previous surgical intervention, presence of intestinal diversion, operative details, 30-day morbidity, recurrence of fistula, and time to recurrence. Fistula closure was defined as lack of clinical symptoms following stoma closure, negative fistula detection on gastrograffin enema' and absence of an internal opening at examination under anesthesia., Results: Twenty-two patients were included who had a median age of 43 years (range, 19-64 years) and median body mass index of 31 kg/m 2 (range, 22-51). Median time between prior attempted surgical repair and gracilis surgery was 7 months (range, 3-17). The number of previously attempted repairs were 1-2 (n = 8), 3-4 (n = 9), and > 4 (n = 5). The most recent attempted surgical repair was rectal advancement flap (n = 7), transperineal +/- Martius flap (n = 4), episioproctotomy (n = 3), transvaginal repair (n = 2), and other (n = 6). All patients had fecal diversion at the time of gracilis surgery. Thirty-day postoperative surgical site infection at the graft/donor site was 32% (n = 7). At a median follow-up of 22 months (range 2-62), fistula closure was 59% (n = 13). Gracilis interposition was successful in all inflammatory bowel disease patients., Limitations: The study was limited by its retrospective nature., Conclusions: Gracilis interposition is an effective operative technique for reoperative rectovaginal fistula closure. Patients should be counseled regarding the possibility of graft/donor site infection. See Video Abstract at http://links.lww.com/DCR/B763 ., Reparacin Con Colgajo De Gracilis Para La Fstula Rectovaginal Reoperatoria: ANTECEDENTES:El tratamiento quirúrgico de las fístulas rectovaginales recurrentes es muy difícil. La colocación del músculo gracilis entre la vagina y el ano es una técnica avanzada que se utiliza para cerrar las fístulas persistentes. Hemos utilizado este procedimiento para las fístulas recalcitrantes y planteamos la hipótesis de que una interposición del gracilis ofrecería una buena opción de tratamiento para pacientes con fístulas rectovaginales refractarias, independientemente de la etiología subyacente.OBJETIVO:Investigar las tasas de curación de la interposición del gracilis en pacientes con fístulas rectovaginales refractarias.DISEÑO:Tras la aprobación de la junta de revisión institucional, se realizó una revisión retrospectiva de todas las pacientes adultas con un diagnóstico de fístula rectovaginal entre enero de 2009 y agosto de 2020; los que se sometieron a interposición de gracilis para el cierre definitivo de la fístula se incluyeron para el análisis.AJUSTE:Departamento de cirugía colorrectal de un centro terciario en Estados Unidos.PACIENTES:Todas las pacientes adultas con diagnóstico de fístula rectovaginal que se sometieron a interposición de gracilis para cierre definitivo.PRINCIPALES MEDIDAS DE RESULTADO:datos demográficos del paciente, etiología de la fístula rectovaginal, intervención quirúrgica previa, presencia de derivación intestinal, detalles quirúrgicos, morbilidad a los 30 días, recurrencia de la fístula y tiempo hasta la recurrencia. El cierre de la fístula se definió como la ausencia de síntomas clínicos después del cierre del estoma, la detección negativa de la fístula en el enema de gastrograffin y la ausencia de una abertura interna en el examen bajo anestesia.RESULTADOS:Se incluyeron 22 pacientes que tenían una mediana de edad de 43 años (rango 19-64 años) y una mediana de índice de masa corporal de 31 kg / m2 (rango 22-51). La mediana de tiempo entre el intento previo de reparación quirúrgica y la cirugía del gracilis fue de 7 meses (rango 3-17). El número de reparaciones previamente intentadas fue: 1-2 (n = 8), 3-4 (n = 9), y >4 (n = 5). El intento de reparación quirúrgica más reciente fue el colgajo de avance rectal (n = 7), el colgajo transperineal +/- Martius (n = 4), la episioproctotomía (n = 3), la reparación transvaginal (n = 2) y otros (n = 6). Todos los pacientes tenían derivación fecal en el momento de la cirugía gracilis. La infección del sitio quirúrgico posoperatorio a los 30 días en el sitio del injerto / donante fue del 32% (n = 7). Con una mediana de seguimiento de 22 meses (rango 2-62), el cierre de la fístula fue del 59% (n = 13). La interposición de Gracilis fue exitosa en todos los pacientes con enfermedad inflamatoria intestinal.LIMITACIONES:Carácter retrospectivo de los datos.CONCLUSIONES:La interposición de Gracilis es una técnica quirúrgica eficaz para el cierre reoperatorio de la fístula rectovaginal. Se debe asesorar a los pacientes sobre la posibilidad de infección del sitio del injerto / donante. Consulte Video Resumen en http://links.lww.com/DCR/B763 . (Traducción-Dr. Ingrid Melo )., (Copyright © The ASCRS 2021.)

Perianal fistulising Crohn's disease is an aggressive disease phenotype that can have a substantial detrimental impact on patients' quality of life. Current biological understanding of perianal fistulising Crohn's disease remains inadequate and previous classification systems have not provided clear guidance on therapy in clinical practice nor on defining patient cohorts within clinical trials. We propose a new classification system for perianal fistulising Crohn's disease that was developed through a modified nominal group technique expert consensus process. The classification identifies four groups of patients. Key elements include stratification according to disease severity as well as disease outcome; synchronisation of patient and clinician goals in decision making, with a proactive, combined medical and surgical approach, on a treat to patient goal basis; and identification of indications for curative fistula treatment, diverting ostomy, and proctectomy. The new classification retains an element of flexibility, in which patients can cycle through different classes over time. Furthermore, with each specific class comes a paired treatment strategy suggestion and description of clinical trial suitability. The proposed classification system is the first of its kind and is an important step towards tailored standardisation of clinical practice and research in patients with perianal fistulising Crohn's disease., Competing Interests: Declaration of interests JG has served as an advisory board member or speaker for Arena and Janssen. NI is funded by a Royal College of Surgeons research fellowship, sponsored by the Ileostomy & Internal Pouch Association. JFL has served as a speaker for Janssen. SA is supported through an Australian Government Research Training Program Scholarship. CJB has an unrestricted grant from Boehringer Ingelheim and Roche, and has received speaker fees from Takeda, Tillotts, and Galapagos. KBG has received grants from Pfizer Inc and Celltrion; consultancy fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, ImmunicTherapeutics, Janssen Pharmaceuticals, Novartis, Pfizer Inc, Samsung Bioepis, and Takeda, and speaker's honoraria from Celltrion, Ferring, Janssen Pharmaceuticals, Novartis, Pfizer Inc, Samsung Bioepis, Takeda, and Tillotts. ALL has served as a consultant for Takeda. SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB Inc, and Vifor. AS has served as speaker for Takeda, Johnson and Johnson, and Pfizer. MC has served as speaker for Pfizer. AD'H has served as speaker for Johnson & Johnson and Takeda. SV has received grants from AbbVie, J&J, Pfizer, and Takeda; and has received consulting and/or speaking fees from AbbVie, Arena Pharmaceuticals, Avaxia, Boehringer Ingelheim, Celgene, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, Hospira, Janssen, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Takeda, Theravance, and Tillots Pharma AG. AH has served as consultant, advisory board member or speaker for AbbVie, Arena, Atlantic, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Ferring, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire, and Takeda, and serves on the global steering committee for Genentech. PT has acted as speaker and/or served on advisory boards for Takeda and Ferring. All other authors declared no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Perianal fistulas affect approximately 2 in 10,000 people, causing symptoms such as pain and discharge, which can have a debilitating effect on a patient's quality of life. Surgical treatment, which can offer a potential cure or palliation of symptoms, must be considered carefully in cases with extensive sphincter involvement. In complex cases, the use of preoperative magnetic resonance imaging (MRI) can help to determine the best course of operative action. This review describes common and contemporary surgical procedures for perianal fistula, highlighting technical features, as well as important surgical considerations associated with each method and how these can be assessed radiologically. We focus on the anatomical features and MRI findings that take procedural elements into account and help determine the most appropriate method of treatment. The aim of this article is to provide a basis for informed and focused discussion between surgeons and radiologists to ensure the most appropriate procedure is selected for each case, with the ultimate aim of obtaining the most favourable outcomes for patients., (Copyright © 2021. Published by Elsevier Ltd.)

Perianal disease is a particularly morbid phenotype of Crohn's disease, affecting up to one third of patients, with a significantly diminished quality of life. Conventional medical therapy and surgical interventions have limited efficacy. Medical treatment options achieve long-term durable remission in only a third of patients. Therefore, most patients undergo an operation, leaving them with a chronic seton or at risk of incontinence with multiple interventions. Mesenchymal stem cell therapy is an emerging therapy without risk of incontinence and improved efficacy as compared with conventional therapy. Laser therapy is another new intervention. Unfortunately, up to 40% of patients still require a stoma related to perianal fistulizing disease.

Aim: Restorative proctocolectomy has been widely adopted as the procedure of choice for restoring gastrointestinal continuity following proctocolectomy. It is often associated with improved quality of life and high patient satisfaction; however, the development of a pouch anal fistula can cause significant morbidity. Pouch fistulas are notoriously difficult to treat and there is great heterogeneity in the management reported of these fistulas. A lack of classification, and the assumption that fistulas originating from completely different aetiologies will behave and respond similarly to a particular treatment strategy, precludes meaningful comparison of management outcomes. We aim to introduce consistency in the reporting of pouch fistulas using a novel classification system., Methods: A consensus process involving clinicians experienced in the management of pouch fistulas from two high volume tertiary centres was performed., Results: We propose that pouch anal fistulas should be classified into four distinct groups according to their aetiology: group 1, anastomotic related; group 2, inflammatory bowel disease related, with sub-classifications Crohn's (type A) and non-Crohn's (type B) in origin; group 3, cryptoglandular related; and group 4, malignancy related., Conclusion: Classification of pouch fistulas according to their aetiology will provide consistency in the literature and improve the quality of prospective evidence for the management of pouch fistulas., (© 2020 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

The use of mesenchymal stem cells has resulted in a breakthrough for the treatment of complex perianal fistulas in Crohn's disease. This novel treatment is associated with a minimally invasive surgical technique that can be well defined. However, our previous experience has taught us that neglecting any of the critical steps in the operation can result in frequent treatment failure. We have put together a comprehensive guide, a stepwise algorithm, for our minimally invasive approach to identify common pitfalls and reduce treatment failures. Using data we have collected over the past 15 years from drug development, execution of clinical trials, and enacting an advanced educational training program, we spelt out each stage of the minimally invasive surgical intervention for stem cell delivery for perianal Crohn's disease. In this article, we provide 21 tips for a correct approach during the five major phases of the surgical procedure. To optimize the efficacy of mesenchymal stem cells for perianal Crohn's disease, a standardized minimally invasive technique including a reliable and reproducible series of key steps should be utilized.

Background: This study sought to re-estimate the cumulative incidence of perianal or rectovaginal fistulas and the associated proctectomy rate in the prebiologic era vs the biologic era using a population-based cohort of Crohn's disease (CD) patients., Methods: The medical records of 414 residents of Olmsted County, Minnesota, who were diagnosed with CD between 1970 and 2010 were reviewed. The cumulative incidence of perianal or rectovaginal fistulas from time of CD diagnosis and the cumulative rate of proctectomy from date of first perianal or rectovaginal fistula diagnosis were estimated using the Kaplan-Meier method., Results: Eighty-five patients (20.5%) diagnosed with CD between 1970 and 2010 had at least 1 perianal or rectovaginal fistula episode between January 1, 1970, and June 30, 2016. The cumulative incidence of perianal or rectovaginal fistulas was 18% after 10 years, 23% after 20 years, and 24% after 30-40 years from CD diagnosis. The cumulative incidence of perianal or rectovaginal fistulas was significantly lower in patients diagnosed in 1998 or after than in patients diagnosed before 1998 (P = 0.03, log-rank). Among 85 patients developing perianal or rectovaginal fistulas, 16 patients (18.8%) underwent proctectomy for the treatment of perianal or rectovaginal fistulas during follow-up., Conclusions: In a population-based inception cohort of CD, one-fifth of patients were diagnosed with at least 1 perianal or rectovaginal fistula. The cumulative probability of perianal or rectovaginal fistulizing disease has decreased over time., (© 2018 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Management of transsphincteric cryptoglandular fistulas remains a challenging problem and the optimal surgical approach remains elusive. Mesenchymal stem cells, increasingly being utilized for perianal Crohn's disease, offer a novel therapy to treat cryptoglandular fistulas., Objectives: This study aimed to determine safety and feasibility of using an autologous mesenchymal stem cell-coated fistula plug in patients with transsphincteric cryptoglandular fistulas., Design: This study is a phase I clinical trial., Setting: This study was conducted at a tertiary academic medical center., Patients: Adult (>18 years) male and female patients with transsphincteric cryptoglandular fistulas were selected., Main Outcomes Measures: The primary outcomes measured were the safety, feasibility, and efficacy of a mesenchymal stem cell-coated fistula plug in patients with transsphincteric fistulas., Results: Fifteen patients (8 women, mean age 39.8 years) with a single-tract transsphincteric fistula received a mesenchymal stem cell-loaded fistula plug and were followed for 6 months. Duration of disease at the time of study enrollment was a median of 3.0 years (range, 1-13 years) with a median of 3.5 (range, 1-20) prior surgical interventions. Adverse events included 1 plug extrusion, 1 abdominal wall seroma, 3 perianal abscesses requiring drainage, and 1 patient with perianal cellulitis. There were no serious adverse events. At 6 months, 3 patients had complete clinical healing, 8 had partial healing, and 4 patients showed no clinical improvement. Radiographic improvement was seen in 11 of 15 patients., Limitations: This study was limited by the small cohort and short follow-up., Conclusions: Autologous mesenchymal stem cell-coated fistula plug treatment of transsphincteric cryptoglandular fistulas was safe and feasible and resulted in complete or partial healing in a majority of patients. See Video Abstract at http://links.lww.com/DCR/A897.

Background: The management of complex perianal fistulas in Crohn's disease (CD) represents a challenge for patients, gastroenterologists and colorectal surgeons. There are clear limitations with current medical and surgical options, and healing rates remain far from what is expected. A multidisciplinary approach with optimized medical therapy, usually anti-TNF agents, associated with setons and additional surgical techniques is currently the best strategy to aim fistula healing., Methods: A comprehensive review of the literature was conducted on the use of mesenchymal stem cells (MSCs)., Results: The use of mesenchymal stem cells (MSCs) has recently emerged as a promising new therapeutic strategy for complex fistulas in CD patients. This review summarizes the evidence of the use of MSCs in complex CD fistulas, by exploring in detail the types of cells that can be used and their modes of delivery. Additionally, the results of the most recent phase III randomized trial with local MSCs injection are described, and future challenges of this therapeutic option are discussed., Conclusion: The use of MSCs represents hope for better outcomes in patients with CD-related perianal fistulas. More research in the field will help to position this specific therapy in treatment algorithms., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Anal fistula is a challenging condition both for surgeons and patients. Recurrent fistula, Crohn's disease, or autoimmune disorders add further complexity to this situation. Numerous clinical trials have now demonstrated that cell-based therapy appears to be a good complement to fistulous surgery. As in any new treatment, especially that involving living cells, appropriate application is paramount to achieve optimal outcomes. As stem cell-based treatments are gaining a strong foothold in fistula management worldwide, we herein aim to share our mesenchymal stem cell surgical protocol. With the goal of optimizing results of this emerging therapy, we have improved and refined our protocol over the past 17 years of working with stem cells in clinical trials. The protocol consists of nine reproducible steps for mesenchymal stem cell application inside the fistulous tract, and has proven to be safe and effective in several studies, including international phase III clinical trials.

Perianal disease is a common manifestation of Crohn disease (CD) that results in significant morbidity and decreased quality of life. Despite several medical and surgical options, complex perianal CD remains difficult to treat. Before the advent of biologic therapy, antibiotics were the mainstay of medical treatment. Infliximab remains the most well-studied medical therapy for perianal disease. Surgical interventions are limited by the risk of nonhealing wounds and potential incontinence. When treatment options fail, fecal diversion or proctectomy may be necessary. Stem cell therapies may offer improved results and seem to be safe, but are not yet widely used., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In patients with Crohn's disease, perianal fistulas recur frequently, causing substantial morbidity. We performed a 12-patient, 6-month, phase 1 trial to determine whether autologous mesenchymal stem cells, applied in a bioabsorbable matrix, can heal the fistula. Fistula repair was not associated with any serious adverse events related to mesenchymal stem cells or plug placement. At 6 months, 10 of 12 patients (83%) had complete clinical healing and radiographic markers of response. We found placement of mesenchymal stem cell-coated matrix fistula plugs in 12 patients with chronic perianal fistulas to be safe and lead to clinical healing and radiographic response in 10 patients. ClinicalTrials.gov Identifier: NCT01915927., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)