Comparison of postoperative urinary complications in laparoscopic-assisted anorectoplasty versus posterior sagittal anorectoplasty for anorectal malformation with rectourethral fistula.

BACKGROUND: Long-term urinary outcomes after anorectal malformation (ARM) repair are affected by surgical approach and sacral anomalies. This study aimed to compare laparoscopic-assisted anorectoplasty (LAARP) and posterior sagittal anorectoplasty (PSARP) in terms of urinary complications. METHODS: Between 2001 and 2022, 45 patients were treated with LAARP or PSARP. The rectourethral fistula and inflow angle between the fistula and rectum was confirmed by preoperative colonography. The incidence of urinary complications and treatment were compared between the two groups. RESULTS: Four patients (14%) had remnant fistula and five patients (17%) had neurogenic bladder dysfunction in LAARP group, while three patients (18%) had urethral injury in PSARP group. All patients with remnant fistula were asymptomatic and followed without treatment. The incidence of remnant fistula improved between earlier decade and later decade. In all cases with urethral injury, suture repair was performed and no postoperative leakage was noted. All five patients with neurogenic bladder dysfunction had spine abnormalities that required clean intermittent catheterization (CIC) and two were free from CIC finally. CONCLUSIONS: It is important to check inflow angle preoperatively to prevent remnant fistula. For PSARP, meticulous dissection is required when separating fistula from urethra because they create common wall. The most contributing factor to neurogenic bladder is sacral anomalies. Preoperative evaluation and postoperative urinary drainage are important.

Predictors of recurrence and long-term patient reported outcomes following surgical repair of anal fistula, a retrospective analysis.

PURPOSE: Surgery for anal fistulas can result in devastating complications, including reoperations and fecal incontinence. There is limited contemporary evidence comparing outcomes since the adoption of the ligation of intersphincteric fistula tract procedure into mainstream practice. The purpose of this study is to compare recurrence rates and long-term outcomes of anal fistula following repair. METHODS: Data was collected from the electronic medical records or patient reported outcomes from patients aged 18 or older with a primary or recurrent cryptoglandular anal fistula. Primary outcome was recurrence defined as the identification of at least one fistula os or a high clinical suspicion of anal fistula. Secondary outcomes included fecal incontinence and postoperative quality of life. RESULTS: A total of 171 patients underwent definitive surgical repairs for their anal fistula. So 66.5% had a simple fistula, and 33.5% had a complex fistula. Of the 171 patients, 12.5% had a recurrence. The recurrence rates were 5.9% for simple fistula and 25.4% for complex fistula. Predictors of recurrence included diabetes mellitus, history of anorectal abscess, complex fistula, and sphincter sparing surgery. LIFT or plug/biologic procedures were both associated with a 50% or greater recurrence rate. No significant differences were found in fecal incontinence or associated quality of life between sphincter sparing or non-sphincter sparing surgical resections. CONCLUSION: The study provides insights into the long-term outcomes of surgical repair for anal fistula. We demonstrate that sphincter sparing operations are associated with increased recurrence, meanwhile, non-sphincter sparing surgeries did not increase the risk of fecal incontinence or worsen quality of life.

Discontinuation of Anti-Tumour Necrosis Factor Therapy in Patients with Perianal Fistulizing Crohn's Disease: Individual Participant Data Meta-Analysis of 309 Patients from 12 Studies.

BACKGROUND: The risk of relapse after anti-tumour necrosis factor [TNF] therapy discontinuation in Crohn's disease patients with perianal fistulas [pCD] is unclear. We aimed to assess this risk. METHODS: A systematic literature search was conducted to identify cohort studies on the incidence of relapse following anti-TNF discontinuation in pCD patients. Individual participant data were requested from the original study cohorts. Inclusion criteria were age ≥16 years, pCD as a (co)indication for start of anti-TNF therapy, more than three doses, and remission of luminal and pCD at anti-TNF discontinuation. The primary outcome was the cumulative incidence of CD relapse using Kaplan-Meier estimates. Secondary outcomes included response to re-treatment and risk factors associated with relapse as assessed by Cox regression analysis. RESULTS: In total, 309 patients from 12 studies in ten countries were included. The median duration of anti-TNF treatment was 14 months [interquartile range 5.8-32.5]. Most patients were treated for pCD without active luminal disease [89%], received first-line anti-TNF therapy [87%], and continued immunomodulatory therapy following anti-TNF discontinuation [78%]. The overall cumulative incidence of relapse was 36% (95% confidence interval [CI] 25-48%) and 42% [95% CI 32-53%] at 1 and 2 years after anti-TNF discontinuation, respectively. Risk factors for relapse included smoking (hazard ratio [HR] 1.5 [1.0, 2.1]) and history of proctitis (HR 1.7 [1.1, 2.5]). The overall re-treatment response rate was 82%. CONCLUSIONS: This individual participant data meta-analysis, on predominantly patients with pCD without active luminal disease and first-line anti-TNF therapy, shows that over half of patients remain in remission 2 years after anti-TNF discontinuation. Therefore, anti-TNF discontinuation may be considered in this subgroup.

Fistula development after anal abscess drainage-a multicentre retrospective cohort study.

PURPOSE: Anal abscesses are common and, despite correct treatment with surgical drainage, carry the risk of developing fistulas. Studies identifying risk factors for the development of anal fistulas are sparse. This study aimed to identify the risk factors for anal fistulas after anal abscess surgery. METHODS: This was a multicentre, retrospective cohort study of patients undergoing acute surgery for anal abscesses in the Capital Region of Denmark between 2018 and 2019. The patients were identified using ICD-10 codes for anal abscesses. Predefined clinicopathological factors and postoperative courses were extracted from patient records. RESULTS: A total of 475 patients were included. At a median follow-up time of 1108 days (IQR 946-1320 days) following surgery, 164 (33.7%) patients were diagnosed with an anal fistula. Risk factors for developing fistulas were low intersphincteric (OR 2.77, 95CI 1.50-5.06) and ischioanal (OR 2.48, 95CI 1.36-4.47) abscesses, Crohn's disease (OR 5.96, 95CI 2.33-17.2), a history of recurrent anal abscesses (OR 4.14, 95CI 2.47-7.01) or repeat surgery (OR 5.96, 95CI 2.33-17.2), E. coli-positive pus cultures (OR 4.06, 1.56-11.4) or preoperative C-reactive protein (CRP) of more than 100 mg/L (OR 3.21, 95CI 1.57-6.71). CONCLUSION: Several significant clinical risk factors were associated with fistula development following anal abscess surgery. These findings are clinically relevant and could influence the selection of patients for specialised follow-up, facilitate expedited diagnosis, and potentially prevent unnecessarily long treatment courses.

Surgical treatment trends and outcomes for anal fistula: fistulotomy is still accurate and safe. Results from a nationwide observational study.

PURPOSE: The aim of the present study was to analyse current surgical treatment preferences for anal fistula (AF) and its subtypes and nationwide results in terms of success and complications. METHODS: A retrospective multicentre observational cohort study was conducted. The study period was 1 year (2019), with a follow-up period of at least 1 year. A descriptive analysis of patient characteristics and trends regarding technical options was performed. Univariate and multivariate Cox regression models were used to analyse factors associated with healing and faecal incontinence (FI). RESULTS: Fifty-one hospitals were involved, providing data on 1628 patients with AF. At a median follow-up of 18.3 (9.9-28.3) months, 1231 (75.9%) patients achieved healing, while 390 (24.1%) did not; failure was catalogued as persistence in 279 (17.2.0%) patients and as recurrence in 111 (6.8%). On multivariate analysis, factors associated with healing were fistulotomy (OR 5.5; 95% CI 3.8-7.9; p < 0.001), simple fistula (OR 2.1; 95% CI 1.5-2.8; p < 0.001), single tract (HR 1.9; 95% CI 1.3-2.8; p < 0.001) and number of preparatory surgeries (none vs. 3; HR 1.8; 95% CI 1.2-2.8; p = 0.006). Regarding de novo FI, in the multivariate analysis previous anal surgery (OR 1.5, 95% CI 1.0-2.4, p = 0.037), age (OR 1.02, 95% CI 1.00-1.04, p = 0.002) and being female (OR 1.7, 95% CI 1.1-2.5, p = 0.008) were statistically related. CONCLUSIONS: Anal fistulotomy is the most used procedure for AF, especially for simple AF, with a favourable overall balance between healing and continence impairment. Sphincter-sparing or minimally invasive sphincter-sparing techniques resulted in lower rates of healing. In spite of their intended sphincter-sparing design, a certain degree of FI was observed for several of these techniques.

Risk of anorectal cancer in patients with Crohn's disease and perianal fistula: a nationwide Danish cohort study.

AIM: Patients with Crohn's disease (CD) often suffer from perianal fistulizing disease. Their risk of anorectal cancer remains uncertain. We aimed to examine the long-term risk of anorectal cancer in a population-based cohort of CD patients with anorectal fistula. METHOD: Our study population covered all individuals (n = 7 987 520) aged 15+ years living in Denmark from 1978 to 2018. We identified all patients with CD and anorectal fistula in the Danish National Patient Register (NPR) and 50 matched noninflammatory bowel disease (IBD) individuals from the general population. Using Cox regression analyses, we examined the risk of anorectal cancer in CD fistula patients versus non-IBD individuals. All patients with CD were identified using codes from the International Classification of Diseases and their data extracted from the NPR. The main outcome measure was cases of anorectal cancer. RESULTS: A total of 2786 CD patients with anorectal fistula and 139 300 non-IBD individuals were followed for 1 553 917 person-years. During follow-up, anorectal cancer was observed in 19 CD patients (0.68%) and 340 non-IBD individuals (0.24%), corresponding to a 2.9-fold increased hazard ratio (HR) of anorectal cancer in CD fistula patients (95% CI 1.80-4.53), with a particularly high risk of anal cancer (HR 15.13, 95% CI 6.88-33.31) and a mean time from CD fistula diagnosis to anorectal cancer of 6.7 (SD 6.5) years. The risk was slightly higher in women than men and had no apparent relation to treatment with tumour necrosis factor-α inhibitors. Sensitivity analyses using CD nonfistula patients for comparison revealed similar results. Individual data on smoking and infection with human papilloma virus were not available. CONCLUSION: Patients with CD and anorectal fistula have a three-fold increased risk of anorectal cancer compared with the general population. The number needed to surveil to detect one case of anorectal cancer in this patient population was 2160 patients per year in patients with long-standing fistula (>6 years).

Indocyanine green fluorescence imaging localization: A helpful addition to laparoscopic dissection and division of rectourethral fistulae.

BACKGROUND: Rectourethral fistulae (RUF) are the most prevalent type of anorectal malformations in boys, with various surgical treatment methods investigated in recent years. Currently, research is focused on preventing urethral damage or urethral diverticulum formation caused by imprecise dissection during the laparoscopically assisted anorectal pull-through (LAARP) technique. This study aimed to determine the efficacy of indocyanine green (ICG) fluorescence imaging to improve the localization and separation of the RUF during laparoscopic surgery. METHODS: ICG was intrarectally injected through a pre-inserted gastric tube at the distal enterostomy port to locate the fistula. This retrospective analysis included children with RUF who were treated surgically with ICG fluorescence imaging localization-assisted LAARP between January and June 2022. We investigated the patient demographics, perioperative conditions, and subsequent follow-up results. RESULTS: Four patients underwent ICG-assisted LAARP. Their median age was 80 days (range, 63-120) and the median duration of each procedure was 145 min (range, 120-165). Postoperatively, the duration of catheter retention and hospital stay was eight days. The children's prognosis was based on the follow-up outcomes of gastrointestinal, urinary tract function, and imaging examination. None of the included patients was diagnosed with urinary diverticulum, urinary tract injury, anal stricture, or rectal prolapse. CONCLUSIONS: Injection of ICG at the end of the rectum during LAARP surgery is a feasible adjunct for locating the RUF, providing a greater degree of accuracy for laparoscopic separation and resection of fistulae, thereby decreasing the risk of urological complications.

Deep remission improves the quality of life of patients with Crohn's disease and anoperineal fistula treated with darvadstrocel: results of a French pilot study.

BACKGROUND: The injection of allogeneic adipose tissue-derived mesenchymal stem cells (MSC) into anal fistulas in patients with Crohn's disease has never been evaluated in "real-life" conditions in France. METHODS: We prospectively studied the first patients receiving MSC injections at our center and undergoing 12 months of follow-up. The primary endpoint was the clinical and radiological response rate. The secondary endpoints were symptomatic efficacy, safety, anal continence, quality of life (Crohn's anal fistula-quality of life scale, CAF-QoL), and predictive factors of success. RESULTS: We included 27 consecutive patients. The complete clinical and radiological response rates at M12 were 51.9% and 50%, respectively. The combined complete clinical-radiological response (deep remission) rate was 34.6%. No major adverse effects or changes in anal continence were reported. The perianal disease activity index decreased from 6.4 to 1.6 (p < 0.001) for all patients. The CAF-QoL score also decreased from 54.0 to 25.5 (p < 0.001). At the end of the study, M12, the CAF-QoL score was significantly lower only in patients with a complete combined clinical-radiological response relative to those without a complete clinical-radiological response (15.0 versus 32.8, p = 0.01). Having a multibranching fistula and infliximab treatment were associated with a combined complete clinical-radiological response. CONCLUSIONS: This study confirms reported efficacy data for the injection of MSC for complex anal fistulas in Crohn's disease. It also shows a positive impact on the quality of life of patients, particularly those for whom a combined clinical-radiological response was achieved.

[Implantation metastasis of colorectal adenocarcinoma in an anal fistula]. / Colorectalis adenocarcinoma implantációs áttéte végbélsipolyban.

In our case report, we describe a rare form of metastatic colorectal carcinoma, in which tumor cells spread intraluminally and metastasis occurs with implantation mechanism far from the primary tumor. A 43-year-old male patient developed perianal abscess. After surgical intervention a fistula-in-ano appeared at the site of the abscess. Fistulotomy was performed in another hospital. A few months later, we admitted him to our department with an abnormal tissue proliferation appearing in the surgical area. Histology confirmed adenocarcinoma. Colonoscopy detected tissue proliferation in the sigmoid colon, causing a subtotal stenosis. Laparoscopic rectosigmoid resection and per anum tumor excision were performed. Detailed histological examination confirmed the same mucinous adenocarcinoma in the colon and the anorectal malformation. In this case, implantation mechanism is likely in the development of a synchronous tumor at the site of the fistula-in-ano. Implantation metastasis is considered rare, only a few cases have been reported in the international literature so far. We are not aware of any similar case reported from Hungary. Orv Hetil. 2023; 164(3): 110-113.

Pediatric perianal Crohn's disease behavior in the era of biologic therapy. / Comportamiento de la afectación perianal en pacientes pediátricos con enfermedad de Crohn en la era de la terapia biológica.

AIM OF THE STUDY: To describe perianal Crohn's disease behavior and the role of biological therapy in a sample of pediatric patients. METHODS: A retrospective study of pediatric patients with Crohn's disease (CD) treated in our institution from 2017 to 2021, with a minimum follow up period of 6 months, was conducted. Patients were divided whether they had perianal disease (PD) or not. Baseline characteristics, extension of disease, growth failure rate, aggressive pattern rate, use of biological therapy and need for surgery, among other variables, were compared between both groups. Clinical and/or radiological improvement in the last 6 months of follow up was considered good control of PD. RESULTS: Seventy eight pediatric patients with CD were included. Median age at diagnosis was 10.5 years, and median follow up time was 3.8 years. 64.1% patients were male. Of all, 15 (19.2%) had perianal disease, of which 10 had fistulizing findings and 5 had non fistulizing findings. PD was presented at diagnosis in 8 patients, and the rest developed it in a median time of 1 year from diagnosis. PD was associated with growth failure (p = 0.003), use of biological therapies (p = 0.005), and need for second line of biologics (p = 0.005). Most patients (12/15, 80%) had good control of PD with the treatment received. CONCLUSIONS: CD patients with PD seem to need a more aggressive treatment, with biological therapies playing a key role for its handling nowadays. These patients require close nutritional evaluation that ensures proper development and growth.

OBJETIVO DEL ESTUDIO: Describir el comportamiento de la enfermedad de Crohn perianal y el papel de la terapia biológica en una muestra de pacientes pediátricos. METODOS: Estudio retrospectivo de pacientes pediátricos con enfermedad de Crohn (EC) tratados en nuestro centro entre 2017 y 2021, con un seguimiento mínimo de seis meses. Los pacientes se dividieron en función de si tenían enfermedad perianal (EP) o no. Se compararon entre ambos grupos las características iniciales, la extensión de la enfermedad, el índice de retraso en el crecimiento, el índice de patrón agresivo, el empleo de terapia biológica y la necesidad de cirugía, entre otras variables. Se consideró un buen control de la EP una mejoría clínica o radiológica en los 6 últimos meses de seguimiento. RESULTADOS: Se incluyeron 78 pacientes pediátricos con EC. La edad mediana en el momento del diagnóstico fue de 10,5 años, y el tiempo mediano de seguimiento fue de 3,8 años. El 64,1% de los pacientes eran varones. Del total, 15 (19,2%) tenían enfermedad perianal, de los cuales 10 presentaban hallazgos fistulizantes y 5 no fistulizantes. La EP estaba presente en el momento del diagnóstico en 8 pacientes, y el resto la desarrolló en una mediana de 1 año desde el diagnóstico. La EP se asoció con retraso en el crecimiento (p = 0,003), empleo de terapias biológicas (p = 0,005) y necesidad de una segunda línea de terapia biológica (p = 0,005). La mayoría de los pacientes (12/15, 80%) tuvieron un buen control de la EP con el tratamiento recibido. CONCLUSIONES: Los pacientes de EC con EP parecen necesitar un tratamiento más agresivo, en el que las terapias biológicas desempeñan hoy en día un papel fundamental. Estos pacientes precisan de una estrecha evaluación nutricional que garantice su correcto crecimiento y desarrollo.

Efficacy of Anal Sphincter Division During Fistulotomy in Anal Fissure-Associated Fistula.

BACKGROUND: A subset of chronic anal fissures beget focal infection, leading to concomitant fistula. The optimal management of fissure-associated fistula is unknown. OBJECTIVE: This study aimed to characterize healing rates and effects of fistulotomy in fissure-associated fistula. DESIGN: Retrospective study. SETTING: Urban tertiary center. PATIENTS: Adults who underwent fistulotomy for a fistula associated with a chronic anal fissure were included in the study. However, those with Crohn's disease, a history of lateral internal sphincterotomy, and a fistula not amenable to fistulotomy were excluded. INTERVENTIONS: Patients were managed with fistulotomy. Fissures were otherwise managed conservatively with a step-up approach. MAIN OUTCOME MEASURES: The primary end point was healing, defined as resolution of symptoms and both fistula and fissure wounds within 1 year. Subgroup analysis compared those who underwent subcutaneous fistulotomy (group A) with those who underwent fistulotomy involving anal sphincter fibers (group B). RESULTS: Twenty-four of 38 patients (63%) healed with a median overall follow-up of 6.6 months (4.2-14.1). The overall median time to healing was 4.4 months (2.2-6.0). No clinical or pathologic factors predicted healing. In subgroup analysis, overall subcutaneous fistulotomy healing rates were nonstatically lower at 46% (6/13) compared to fistulotomy involving anal sphincter fibers at 72% (18/25; p = 0.16). There was no difference in time to healing (subcutaneous fistulotomy, 6.7 mo [5.2-8.4] vs fistulotomy involving sphincter, 5.1 mo [2.1-7.0]; p = 0.36). LIMITATIONS: The limitations include treatment bias, with increased utilization of chemical sphincter-relaxing agents in those who did not heal. Findings are not applicable to complex fistulas, Crohn's disease, or atypical fissures. CONCLUSIONS: Patients presenting with chronic fissure and associated subcutaneous, intersphincteric, or low transphincteric fistula are successfully managed with fistulotomy. Patients with a subcutaneous fistula tract exhibited nonstatistically significantly lower rates of healing. See Video Abstract at http://links.lww.com/DCR/C145 . EFICACIA DE LA DIVISIN ESFINTRICA DURANTE LA FISTULOTOMA EN CASOS DE FSTULA ASOCIADA A FISURA ANAL: ANTECEDENTES: Ciertos subgrupos de fisuras anales crónicas ocasionan infección localizada, induciendo la aparición de una fístula anal concomitante. Se desconoce el manejo óptimo de la fístula concomitante a una fisura anal.OBJETIVO: Se trata de caracterizar las tasas de curación y el efecto de la fistulotomía en el tratamiento de la fístula concomitante a la fisura anal.DISEÑO: Estudio retrospectivo.EMPLAZAMIENTO: Centro terciario urbano.PACIENTES: Adultos sometidos a fistulotomía por una fístula concomitante a una fisura anal crónica. Se excluyeron la enfermedad de Crohn, el antecedente de una esfinterotomía lateral interna y las fístulas no susceptibles de fistulotomía.INTERVENCIONES: Los pacientes fueron manejados con una fistulotomía clasica. Por lo demás, las fisuras se trataron de forma conservadora con un enfoque médico escalonado.PRINCIPALES MEDIDAS DE RESULTADO: El criterio principal de valoración fué la cura definitiva, determinada como la resolución completa de los síntomas y de las heridas tanto de la fístula como de la fisura en el plazo de un año. El análisis de los subgrupos comparó los que se sometieron a una fistulotomía subcutánea (grupo A) versus una fistulotomía que involucró las fibras del esfínter anal interno (grupo B).RESULTADOS: 24/38 pacientes (63%) curaron con una mediana de seguimiento global de 6,6 meses (4,2-14,1). El tiempo medio general de curación fue de 4,4 meses (2,2-6,0). Ningún factor clínico o patológico predijo la cura. En el análisis de subgrupos, las tasas generales de cura de la fistulotomía subcutánea no fueron estadísticamente más bajas de 46 % (6/13) comparados con la fistulotomía que involucró las fibras del esfínter anal interno en 72 % (18/25; p = 0,16). No hubo diferencia en el tiempo de cicatrización [fistulotomía subcutánea 6,7 meses (5,2-8,4) conparada a la fistulotomía y esfínterotomía parcial interna a 5,1 meses (2,1-7,0); p = 0,36].LIMITACIONES: Sesgo del tratamiento, con mayor utilización de agentes químicos relajantes de la musculatura esfínteriana en aquellos pacientes que no sanaron. No aplicable a fístulas complejas, enfermedad de Crohn o fisuras atípicas.CONCLUSIÓNES: Los pacientes que presentan fisura crónica y fístula subcutánea, inter-esfintérica o trans-esfintérica baja concomitante se manejan con éxito con una fistulotomía. Los pacientes con un trayecto de fístula subcutánea exhibieron tasas de curación más bajas y no estadísticamente significativas. Consulte Video Resumen en http://links.lww.com/DCR/C145 . (Traducción-Dr. Xavier Delgadillo ).

Ligation of Intersphincteric Fistulous Tract vs Endorectal Advancement Flap for High-Type Fistula in Ano: A Randomized Controlled Trial.

BACKGROUND: This study aimed to compare the postoperative outcomes and success rate of the endorectal advancement flap and ligation of intersphincteric fistulous tract (LIFT) in high-type fistula in ano. STUDY DESIGN: This randomized control trial included patients with high-type fistula in ano of cryptoglandular origin. The primary endpoint was complete fistula healing at the end of 6 months. However, the patients were followed up for 2 years. Other parameters studied were perioperative complications, duration of surgery, postoperative pain, hospital stay in hours, continence, and quality of life at 6 months. RESULTS: A total of 84 patients were recruited (42 in each group). The healing rate in the LIFT arm was better than that in the endorectal advancement flap arm (76.2.% vs 54.7%, p = 0.039). Four patients in the endorectal advancement flap group and two in the LIFT group had flatus incontinence at the end of 6 months, but all were continent at 2 years. At the end of the first week, the Visual Analog Scale score and quality of life at 6 months were better in the LIFT arm (3.7 ± 1.16 vs 4.7 ± 0.81 and 0.7 vs 0.6, p < 0.05). The mean duration of surgery was significantly less in the LIFT group (46.43 ± 9.32 vs 89.29 ± 10.90 minutes). None had any postoperative complications, and >80% were discharged within 24 hours. CONCLUSIONS: The shorter operative duration, better quality of life at 6 months, and higher healing rate make LIFT a superior treatment option for high fistula in ano. However, studies with a large sample size will be needed to verify these results.

Dysfunctional Extracellular Matrix Remodeling Supports Perianal Fistulizing Crohn's Disease by a Mechanoregulated Activation of the Epithelial-to-Mesenchymal Transition.

BACKGROUND AND AIMS: Perianal fistula represents one of the most disabling manifestations of Crohn's disease (CD) due to complete destruction of the affected mucosa, which is replaced by granulation tissue and associated with changes in tissue organization. To date, the molecular mechanisms underlying perianal fistula formation are not well defined. Here, we dissected the tissue changes in the fistula area and addressed whether a dysregulation of extracellular matrix (ECM) homeostasis can support fistula formation. METHODS: Surgical specimens from perianal fistula tissue and the surrounding region of fistulizing CD were analyzed histologically and by RNA sequencing. Genes significantly modulated were validated by real-time polymerase chain reaction, Western blot, and immunofluorescence assays. The effect of the protein product of TNF-stimulated gene-6 (TSG-6) on cell morphology, phenotype, and ECM organization was investigated with endogenous lentivirus-induced overexpression of TSG-6 in Caco-2 cells and with exogenous addition of recombinant human TSG-6 protein to primary fibroblasts from region surrounding fistula. Proliferative and migratory assays were performed. RESULTS: A markedly different organization of ECM was found across fistula and surrounding fistula regions with an increased expression of integrins and matrix metalloproteinases and hyaluronan (HA) staining in the fistula, associated with increased newly synthesized collagen fibers and mechanosensitive proteins. Among dysregulated genes associated with ECM, TNFAI6 (gene encoding for TSG-6) was as significantly upregulated in the fistula compared with area surrounding fistula, where it promoted the pathological formation of complexes between heavy chains from inter-alpha-inhibitor and HA responsible for the formation of a crosslinked ECM. There was a positive correlation between TNFAI6 expression and expression of mechanosensitive genes in fistula tissue. The overexpression of TSG-6 in Caco-2 cells promoted migration, epithelial-mesenchymal transition, transcription factor SNAI1, and HA synthase (HAs) levels, while in fibroblasts, isolated from the area surrounding the fistula, it promoted an activated phenotype. Moreover, the enrichment of an HA scaffold with recombinant human TSG-6 protein promoted collagen release and increase of SNAI1, ITGA4, ITGA42B, and PTK2B genes, the latter being involved in the transduction of responses to mechanical stimuli. CONCLUSIONS: By mediating changes in the ECM organization, TSG-6 triggers the epithelial-mesenchymal transition transcription factor SNAI1 through the activation of mechanosensitive proteins. These data point to regulators of ECM as new potential targets for the treatment of CD perianal fistula.

Association of Neutrophil Extracellular Traps with Fistula Healing in Patients with Complex Perianal Fistulizing Crohn's Disease.

BACKGROUND AND AIMS: Perianal fistulizing Crohn's disease [pfCD] is a disabling phenotype of Crohn's disease [CD] with suboptimal outcomes. We assessed neutrophil extracellular traps [NETs] in perianal fistulas and implicated their roles in pfCD healing. METHODS: Patients with complex pfCD who developed preplaced seton drainage were recruited during the verified maintenance of remission in CD. Fistula tracts were sampled during definitive surgery plus seton removal. Patient demographics, CD classification, medication strategy and healing of pfCD were recorded. RNA sequencing was applied for transcriptomic profile analysis. NET components, including myeloperoxidase [MPO], neutrophil elastase [NE] and citrullinated histone H3 [CitH3], were identified using immunofluorescence. Serum infliximab [IFX], anti-IFX antibodies, and tissue levels of IFX, adalimumab [ADA], MPO and CitH3 were determined using enzyme-linked immunosorbent assays. Peptidyl arginine deiminase IV [PAD4], tumour necrosis factor [TNF]-α, and NE were detected using immunohistochemistry. Gene expression levels of PAD family members were assessed with quantitative PCR. RESULTS: Twenty-one patients were included, 15 of whom adopted IFX as maintenance treatment. RNA-sequencing revealed differences in neutrophil associated pathways between unhealed and healed fistulas. NET components [MPO/NE/CitH3] were detectable in the fistulas and were parallel with the levels of PAD4. Eleven of 21 [52%] patients experienced complete healing of the pfCD 108 weeks post-operatively. Fistula NETs were significantly increased in patients with unhealed pfCD. Increased NETs were associated with abundant TNF-α production and the absence of IFX in fistulas. CONCLUSIONS: NETs exist in pfCD fistulas, which are associated with unhealed post-operative fistulas in pfCD, suggesting their prognostic roles in pfCD.

Fistulectomy and primary sphincteroplasty in complex anal fistula treatment: a hospital-based long-term follow-up study.

BACKGROUND: Currently, there is no agreement on the best treatment for complex anal fistulas with the least recurrence and lowest complication rate. The aim of this study was to evaluate the long-term recurrence and incontinence after fistulectomy and primary sphincteroplasty (FIPS) in a group of patients with complex perianal fistula. METHODS: This prospective observational study was done at the colorectal ward of Taleghani Hospital of Tehran from January 2010 to December 2020. Patients with anal fistula who underwent FIPS were studied. After surgery, patients were evaluated regularly by a colorectal surgeon for fistula recurrence and incontinence. Recurrence was described as a new fistula tract formation after the initial cure and failure of healing in the operation site or any purulent discharge from the fistula tract and openings. In addition, the patient's continence was assessed based on the Wexner score. RESULTS: There were 335 patients (66 men and 269 women, mean age 42.74 ± 12.44 years), 191 of them with low fistula and 144 with high fistula. Thirteen patients (3.90%) experienced recurrence (all had a low fistula). Thirty-nine patients (11.64%), 19 patients with high and 20 patients with low fistula, had a Wexner score ≥ 3 during the follow-up. Fifteen patients were lost to follow-up. Male patients (OR = 2.67, 95% CI 0.84, 8.45, p = 0.094, adjusted OR = 4.41, 95% CI 1.05, 18.48, p = 0.042), patients with low fistula (p = 0.001), and recurrent cases had a significantly higher rate of recurrence (OR = 10.38, 95% CI 3.24-33.20 p ≤ 0.001, adjusted OR = 23.36, 95% CI 4.35-125.39, p ≤ 0.001). A significant correlation between body mass index > 35 kg/m2 and incontinence was found (OR = 4.40, 95% CI 1.35, 14.33, p = 0.014). CONCLUSIONS: In the present study, an acceptable healing rate and a low percentage of complications following FIPS were seen in patients with complex anal fistula. Randomized clinical trials with appropriate follow-up duration and sample size comparing different surgical methods in these patients are needed to confirm these results.

Does presence of a VACTERL anomaly predict an associated gynecologic anomaly in females with anorectal malformations?: A Pediatric Colorectal and Pelvic Learning Consortium Study.

BACKGROUND: VACTERL association is defined by the presence of 3 or more anomalies in any of the following systems: vertebral, anorectal, cardiac, trachea-esophageal, renal, or limb. This study hypothesized that the presence of VACTERL association would correlate with an increased risk of gynecologic anomalies in patients with anorectal malformation (ARM). METHODS: This study is a cross-sectional, retrospective analysis from the prospectively collected, multicenter registry of the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC). The 834 female patients with ARM who were enrolled in the registry by January 1, 2020 were included in this study. The relationship of VACTERL association with presence of a gynecologic anomaly was evaluated with Fisher's exact test. The relationship of each VACTERL system with presence of a gynecologic anomaly was assessed in patients with cloaca, rectovestibular fistulas and rectoperineal fistulas. P-values reported were based on a 2-sided alternative and considered significant when less than 0.05. RESULTS: 834 patients with ARM underwent VACTERL screening and gynecologic evaluation with the three most common subtypes being cloaca (n = 215, 25.8%), rectovestibular fistula (n = 191, 22.9%) and rectoperineal fistula (n = 194, 23.3%). A total of 223 (26.7%) patients with ARM had gynecologic anomalies. VACTERL association was seen in 380 (45.6%) of patients with ARM. Gynecologic anomalies were present in 149 (39.1%) vs. 74 (16.3%) of subjects with vs. without VACTERL association (p < 0.001). VACTERL association did not significantly increase the risk of gynecologic anomaly in patients with cloaca and VACTERL (n = 88, 61.5%) vs. cloaca without VACTERL (n = 39, 54.2% p = 0.308). VACTERL association increased the risk of gynecologic anomalies in patients with rectoperineal fistulas (n = 7, 14.9% vs n = 9, 6.1% p = 0.014) and rectovestibular fistulas (n = 19, 31.1% vs. n = 13, 10.0% p<0.001). In patients with ARM who had a VACTERL association, when one of the associated anomalies was renal, there was an even higher risk of having an associated gynecologic anomaly (n = 138, 44.2% vs. n = 85, 16.3% p<0.001). CONCLUSIONS: VACTERL association in patients with rectoperineal and rectovestibular fistulas correlates with an increased risk of gynecologic anomalies. The presence of VACTERL associated findings, especially renal, should prompt a thorough evaluation of the gynecologic system. LEVEL OF EVIDENCE: III. Retrospective comparative study.