Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial

Panés, Julián; Garcı́a-Olmo, Damián; Assche, Gert Van; Colombel, Jean Fréd́eric; Reinisch, Walter; Baumgart, Daniel C.; Dignaß, Axel; Nachury, Maria; Ferrante, Marc; Kazemi-Shirazi, Lili; Grimaud, J. C.; Portilla, Fernando de la; Goldin, Eran; Richard, M; Leselbaum, Anne; Danese, Silvio

doi:10.1016/s0140-6736(16)31203-x

Cited by 796 publications

(714 citation statements)

References 35 publications

Supporting

Mentioning

671

Contrasting

Unclassified

Order By: Relevance

“…8,12,17,19 Studies of surgical treatment have also struggled to identify a robust, objective measure of radiological improvement. 20 The present study has shown that volume of perianal fistula in patients with CD can be reliably measured by MRI with very good inter-and intra-observer agreement.…”

Section: Discussionsupporting

confidence: 59%

Volume assessment magnetic resonance imaging technique for monitoring perianal Crohn’s fistulas

Lung

Sahnan

Burling

et al. 2018

Therap Adv Gastroenterol

View full text Add to dashboard Cite

Background: Perianal Crohn's fistula and their response to anti-tumour necrosis factor (TNF) therapies are best assessed with magnetic resonance imaging (MRI), but radiologist reporting is subjective and variable. This study investigates whether segmentation software could provide precise and reproducible objective measurements of fistula volume. Methods: Retrospective analysis of patients with perianal Crohn's fistula at our institution between 2007 and 2013. Pre-and post-biologic MRI scans were used with varying time intervals. A total of two radiologists recorded fistula volumes, mean signal intensity and time taken to measure fistula volumes using validated Open Source segmentation software. A total of three radiologists assessed fistula response to treatment (improved, worse or unchanged) by comparing MRI scans. Results: A total of 18 cases were reviewed for this pilot study. Inter-observer variability was very good for volume and mean signal intensity; intra-class correlation (ICC) 0.95 [95% confidence interval (CI) 0.91-0.98] and 0.95 (95% CI 0.90-0.97) respectively. Intra-observer variability was very good for volume and mean signal intensity; ICC 0.99 (95% CI 0.97-0.99) and 0.98 (95% CI 0.95-0.99) respectively. Average time taken to measure fistula volume was 202 s and 250 s for readers 1 and 2. Agreement between three specialist radiologists was good [kappa 0.69 (95% CI 0.49-0.90)] for the subjective assessment of fistula response. Significant association was found between objective percentage volume change and subjective consensus agreement of response (p = 0.001). Median volume change for improved, stable or worsening fistula response was −67% [interquartile range (IQR): −78, −47], 0% (IQR: −16, +17), and +487% (IQR: +217, +559) respectively. Conclusion: Quantification of fistula volumes and signal intensities is feasible and reliable, providing an objective measure of perianal Crohn's fistula and response to treatment.

show abstract

Section: Discussionsupporting

confidence: 59%

Volume assessment magnetic resonance imaging technique for monitoring perianal Crohn’s fistulas

Lung

Sahnan

Burling

et al. 2018

Therap Adv Gastroenterol

View full text Add to dashboard Cite

show abstract

“…Clinically, local administration of allogeneic, expanded MSCs in initial trials was not associated with severe adverse events in patients with Crohn's disease who had perianal fistulas and seemed to promote healing. A large random ized trial subsequently showed that allogeneic MSCs (120 million Cx601 cells) induced remission (closure of external openings of fistulas and absence of collections >2 cm) more frequently than placebo 145 . Furthermore, a phase I-IIa study suggested potential beneficial effects of MSCs in rectovaginal fistulas in Crohn's disease, suggest ing that MSCs might be broadly applicable for fistula therapy in patients with Crohn's disease 146 .…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

484

367

View full text Add to dashboard Cite

Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

show abstract

“…It should be noted that a number of feasibility studies were performed, particularly in relation to local stem cell therapy. Since searches for this review were performed, a randomized trial of stem cells has been reported80. A randomized trial of advancement flap versus seton drainage in the context of protocolled medical therapy is underway81.…”

Section: Discussionmentioning

confidence: 99%

Systematic review of surgical interventions for Crohn's anal fistula

Lee

Heywood²,

Adegbola

et al. 2017

BJS Open

View full text Add to dashboard Cite

BackgroundAnal fistula occurs in approximately one in three patients with Crohn's disease and is typically managed through a multimodal approach. The optimal surgical therapy is not yet clear. The aim of this systematic review was to identify and assess the literature on surgical treatments of Crohn's anal fistula.MethodsA systematic review was conducted that analysed studies relating to surgical treatment of Crohn's anal fistula published on MEDLINE, Embase and Cochrane databases between January 1995 and March 2016. Studies reporting specific outcomes of patients treated for Crohn's anal fistula were included. The primary outcome was fistula healing rate. Bias was assessed using the Cochrane ROBINS‐I and ROB tool as appropriate.ResultsA total of 1628 citations were reviewed. Sixty‐three studies comprising 1584 patients were ultimately selected in the analyses. There was extensive reporting on the use of setons, advancement flaps and fistula plugs. Randomized trials were available only for stem cells and fistula plugs. There was inconsistency in outcome measures across studies, and a high degree of bias was noted.ConclusionData describing surgical intervention for Crohn's anal fistula are heterogeneous with a high degree of bias. There is a clear need for standardization of outcomes and description of study cohorts for better understanding of treatment options.

show abstract

Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial

Cited by 796 publications

References 35 publications

Volume assessment magnetic resonance imaging technique for monitoring perianal Crohn’s fistulas

Volume assessment magnetic resonance imaging technique for monitoring perianal Crohn’s fistulas

Current and emerging therapeutic targets for IBD

Systematic review of surgical interventions for Crohn's anal fistula

Contact Info

Product

Resources

About