Molecular differences of adipose-derived mesenchymal stem cells between non-responders and responders in treatment of transphincteric perianal fistulas.

BACKGROUND: Injection of autologous adipose tissue (AT) has recently been demonstrated to be an effective and safe treatment for anal fistulas. AT mesenchymal stem cells (AT-MSCs) mediate the healing process, but the relationship between molecular characteristics of AT-MSCs of the injected AT and fistula healing has not been adequately studied. Thus we aimed to characterize the molecular and functional properties of AT-MSCs isolated from autologous AT injected as a treatment of cryptogenic high transsphincteric perianal fistulas and correlate these findings to the healing process. METHODS: 27 patients (age 45 ± 2 years) diagnosed with perianal fistula were enrolled in the study and treated with autologous AT injected around the anal fistula tract. AT-MSCs were isolated for cellular and molecular analyses. The fistula healing was evaluated by MRI scanning after 6 months of treatment. AT-MSC phenotype was compared between responders and non-responders with respect to fistula healing. RESULTS: 52% of all patients exhibited clinical healing of the fistulas as evaluated 6 months after last injection. Cultured AT-MSCs in the responder group had a lower short-term proliferation rate and higher osteoblast differentiation potential compared to non-responder AT-MSCs. On the other hand, adipocyte differentiation potential of AT-MSCs was higher in non-responder group. Interestingly, AT-MSCs of responders exhibited lower expression of inflammatory and senescence associated genes such as IL1B, NFKB, CDKN2A, TPB3,TGFB1. CONCLUSION: Our data suggest that cellular quality of the injected AT-MSCs including cell proliferation, differentiation capacity and secretion of proinflammatory molecules may provide a possible mechanism underlying fistula healing. Furthermore, these biomarkers may be useful to predict a positive fistula healing outcome. TRIAL REGISTRATION: NTC04834609, Registered 6 April 2021. https://clinicaltrials.gov/ct2/show/NCT04834609.

Effectiveness of infliximab treatment of complex idiopathic anal fistulas.

OBJECTIVES: To investigate the effects of infliximab treatment in patients with complex idiopathic anal fistulas refractory to standard surgical treatment. MATERIALS AND METHODS: We retrospectively evaluated the effects ofinfliximab treatmentin patients with complex idiopathic anal fistulas refractory to standard surgical intervention. The primary outcome was achievement of substantial clinical improvement defined as sustained, reduced inflammatory activity at perioperativeevaluation, i.e., only minimal-to-moderate secretion and induration and a reduction of fistula size of a magnitude that would make it possible to perform a lay-open or sphincter-sparring closure procedure. Secondary outcomes weresymptom improvement, adverse treatment events and fistula healing after the surgical procedure in those achieving the primary outcome. RESULTS: Twenty-two patients were included (18 high transsphincteric, 3complex low transsphincteric, 1 suprasphincteric fistula). Fistulas had been present for a median of 24 [interquartile range, IQR: 12-33] months. In total, 16 patients (73%) achieved the primary outcome of substantial clinical improvement. Median time from infliximab initiation to patients achieved the primary outcome was 11 [IQR: 8-22] months. Sixteen of the patients responding to infliximab received subsequent lay-open or sphincter-sparring closure procedure surgery. Of these, ten (63%) achieved fistula healing. No serious infectious complications to infliximab treatment were seen. One patient developed a new abscess. One patient developed psoriasis (pustolosispalmoplantaris). CONCLUSIONS: Infliximab treatment may be considered a supplement to repeated curettage and setondrainage in the management of selected, complex idiopathic anal fistulas. Such combined treatment may make otherwise refractory fistulas amenable to definitive closure attempts.

Treatment of chronic anal fissure: a feasibility study on Levorag® Emulgel versus Diltiazem gel 2.

PURPOSE: To compare the standard treatment, diltiazem gel 2%, with Levorag® Emulgel for chronic anal fissures. METHODS: This was a single-blinded, randomised, controlled, clinical trial with a non-inferiority design. Patients with a chronic anal fissure were randomised to treatment with diltiazem or Levorag® Emulgel twice daily for 8 weeks. Primary endpoint was complete healing of the anal fissure after 12 weeks. Secondary endpoints included incidence of adverse events and efficacy on pain relief. RESULTS: In total, 55 patients were included. Inclusion was terminated prematurely due to a slow inclusion rate. Complete fissure healing at 12 weeks follow-up was overall achieved in 31 of 55 (56%) patients, 18 of 29 (62%) in the diltiazem group compared with 13 of 26 (50%) in the Levorag® Emulgel group (P = 0.424). Pain relief was significantly better at day seven in patients treated with diltiazem (P = 0.040) compared with Levorag® Emulgel, whereas there were no differences in early (3 days) or late (12 weeks) pain relief. Three patients (10.3%) developed severe perianal exanthema during diltiazem treatment, whereas no side effects were observed in the Levorag® Emulgel group. CONCLUSION: The study demonstrated statistical non-inferiority of Levorag® Emulgel compared with diltiazem in the treatment of chronic anal fissure. Diltiazem resulted in a more prompt pain relief and also in a substantial number of local allergic reactions. Levorag® Emulgel may therefore be an alternative in these patients. TRIAL REGISTRATION: Clinicaltrials.gov no. NCT02158013.

Efficacy of Injection of Freshly Collected Autologous Adipose Tissue Into Perianal Fistulas in Patients With Crohn's Disease.

BACKGROUND & AIMS: Perianal fistulas are common in patients with Crohn's disease (CD). Injections of cultured autologous and allogeneic adipose tissue-derived stem cells have been shown to heal CD-associated fistulas. Unfortunately, this treatment is time consuming and expensive. We investigated the effects of injecting freshly collected autologous adipose tissue into perianal fistulas in patients with CD. METHODS: In a prospective interventional study, freshly collected autologous adipose tissues were injected into complex perianal fistulas of 21 patients with CD, from March 2015 through June 2018. The primary endpoint was complete fistula healing (no symptoms of discharge, no visible external fistula opening in the perineum, and no internal opening detected by rectal digital examination) 6 months after the last injection. We performed pelvic magnetic resonance imaging to confirm fistula resolution in patients with intersphincter and transsphincter fistulas who showed complete healing at clinical examination. Patients without complete fistula healing after 6 weeks and those with later relapse were offered additional injections. No control individuals were included. RESULTS: Six months after the last adipose tissue injection, 12 patients (57%) had complete fistula healing. Three patients (14%) had ceased fistula secretion, and 1 patient (5%) reported reduced secretion. Among 10 patients with trans-sphincter or inter-sphincter fistulas, magnetic resonance imaging showed complete fistula resolution in 9 patients and a markedly reduced gracile fistula in the remaining patient. Of the 12 patients with complete fistula healing, 9 (43%) required 1 injection, 2 (10%) required 2 injections, and 1 (5%) required 3 injections. The predominant adverse effect was postprocedure proctalgia lasting a few days. Two patients developed small abscesses, 1 had urinary retention, and 1 had minor bleeding during liposuction. CONCLUSION: In a study of 21 patients with CD and perianal fistulas, we found injection of recently collected autologous adipose tissue to be safe and to result in complete fistula healing in 57% of patients. ClinicalTrials.gov, Number: NCT03803917.

Elective surgery after successful endoscopic decompression of sigmoid volvulus may be considered.

INTRODUCTION: Volvulus is an axial twist of any part of the gastrointestinal tract along its mesentery. If it goes unattended, it will cause bowel obstruction and bowel ischaemia with gangrene and perforation. The primary treatment is endoscopic desufflation, but the place for elective surgery is controversial. Volvulus is a rare condition in Western Europe and North America that most often affects elderly of either gender. MATERIAL AND METHODS: We reviewed all records on patients admitted to our hospital during an 11-year period. Age at first admission, co-morbidity and number of readmissions were registered. The results of primary endoscopic treatment and any surgery were registered together with complications, 30-day and one-year moratality rates. RESULTS: A total of 41 patients were treated. The mean age at first admission was 70 years. Significant co-morbidity was found in 33 patients (81%). Thirty patients (73%) were treated for recurrence. Fourteen patients were treated with decompression alone, and 27 patients were operated (14 acute and 13 elective cases). The 30-day mortality was 43% after acute operation and 8% after elective operation (p < 0.05). In the group of patients with decompression alone, the one-year mortality was 50%. CONCLUSION: Elective surgery should be considered because of a high recurrence rate and one-year mortality after initially successful decompression. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.