Heterogeneity in outcome selection, definition and measurement in studies assessing the treatment of cryptoglandular anal fistula: findings from a systematic review.

BACKGROUND: Treatment for cryptoglandular anal fistula (AF) is challenging and a lack of uniform outcomes in the literature prevents direct comparison of treatments. This can be addressed by developing a core outcome set, a standardised set of outcomes reported in all interventional studies for a specific condition. The aim of this systematic review is to assess the range of outcomes, their definitions, and the measurement instruments currently utilised in interventional studies for adult patients with AF. This will inform the development of an AF core outcome set. METHODS: Medline, Embase and The Cochrane Library were searched to identify all patient- and clinician-reported outcomes in studies assessing medical, surgical or combination treatment of adult patients with AF published from January 2008 to May 2020. The resulting outcomes were categorized according to the Core Outcome Measurement in Effectiveness Trials (COMET) taxonomy to better understand their distribution. RESULTS: In total, 155 studies were included, 552 outcomes were extracted, with a median of three outcomes (interquartile range 2-5) per study. Only 25% of studies demonstrated high-quality outcome reporting. The outcomes were merged into 52 unique outcomes and structured into four core areas and 14 domains, with the majority in the domain of physiological or clinical (gastrointestinal) outcomes. The most commonly reported outcomes were healing (77%), incontinence (63%), and recurrence (40%), with no single outcome assessed across all studies. There was a wide variation in outcome definitions and measurement instruments used. CONCLUSIONS: There is substantial heterogeneity in outcomes, definitions, and measurement instruments reported in interventional studies for cryptoglandular anal fistula. This emphasises the need for standardised outcome reporting and measurement.

The development of a cryptoglandular Anal Fistula Core Outcome Set (AFCOS): an international Delphi study protocol.

PURPOSE: Cryptoglandular anal fistula is a disorder with an incidence of around 1 per 5,000 people per year in European countries. Many studies have been conducted to evaluate the effectiveness of interventions for anal fistula. However, there is considerable heterogeneity in the outcomes assessed and reported in these studies. This limits research quality and complicates evidence synthesis. A solution for heterogeneity in outcome reporting is the development of a Core Outcome Set (COS). This paper describes the protocol for the development of a European COS for Anal Fistula (AFCOS). METHODS: The first step will be a systematic review of the literature to identify potential outcomes that may be included in the COS. Patient interviews will be conducted in The United Kingdom and The Netherlands to ensure that both clinician-important and patient-important outcomes are captured. The outcomes will be categorized using the COMET taxonomy and taken forward to a Delphi consensus exercise. In up to three web-based Delphi surveys the outcomes will be prioritized by patients, clinicians (surgeons, gastroenterologists, and radiologists), and (clinical) researchers. The responses will be summarized and reported anonymously in subsequent round(s) facilitating convergence to a consensus opinion. The final COS will be decided during a face-to-face consensus meeting with patients, clinicians, and (clinical) researchers. DISCUSSION: This study protocol describes the development of a European COS for anal fistula to improve research quality, evidence synthesis, and patient care.

Metabonomics and the Gut Microbiome Associated With Primary Response to Anti-TNF Therapy in Crohn's Disease.

BACKGROUND AND AIMS: Anti-tumour necrosis factor [anti-TNF] therapy is indicated for treatment of moderate to severe inflammatory bowel disease [IBD], but has a primary non-response rate of around 30%. We aim to use metabonomic and metataxonomic profiling to identify predictive biomarkers of anti-TNF response in Crohn's disease. METHODS: Patients with luminal Crohn's disease, commencing anti-TNF therapy, were recruited with urine, faeces, and serum samples being collected at baseline and 3-monthly. Primary response was defined according to a combination of clinical and objective markers of inflammation. Samples were measured using three UPLC-MS assays: lipid, bile acid, and Hydrophillic Interaction Liquid Chromatography [HILIC] profiling with 16S rRNA gene sequencing of faeces. RESULTS: Samples were collected from 76 Crohn's disease patients who were anti-TNF naïve and from 13 healthy controls. There were 11 responders, 37 non-responders, and 28 partial responders in anti-TNF-treated Crohn's patients. Histidine and cysteine were identified as biomarkers of response from polar metabolite profiling [HILIC] of serum and urine. Lipid profiling of serum and faeces found phosphocholines, ceramides, sphingomyelins, and triglycerides, and bile acid profiling identified primary bile acids to be associated with non-response to anti-TNF therapy, with higher levels of phase 2 conjugates in non-responders. Receiver operating curves for treatment response demonstrated 0.94 +/ -0.10 [faecal lipid], 0.81 +/- 0.17 [faecal bile acid], and 0.74 +/- 0.15 [serum bile acid] predictive ability for anti-TNF response in Crohn's disease. CONCLUSIONS: This prospective, longitudinal cohort study of metabonomic and 16S rRNA gene sequencing analysis demonstrates that a range of metabolic biomarkers involving lipid, bile acid, and amino acid pathways may contribute to prediction of response to anti-TNF therapy in Crohn's disease. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Darvadstrocel for the treatment of patients with perianal fistulas in Crohn's disease.

Despite significant advances in medical and surgical therapy for perianal fistulas in Crohn's disease (CD), treatment results are still modest, and a specific need for more effective therapies is a reality. Darvadstrocel is composed of expanded human allogeneic mesenchymal adult stem cells extracted from adipose tissue and constitutes the first stem cell therapy for perianal fistulizing CD to receive approval from the European Medicines Agency (EMA). This therapy is injected in both internal and external openings, as well as inside the fistula tracks, to induce fistula healing. In this monograph, the authors review the preclinical pharmacology of darvadstrocel, as well as pharmacokinetics and metabolism, and cover the main indications and detailed information on the efficacy and safety profile of the agent. Possible interactions with other agents used to treat CD are also explored. Darvadstrocel is a safe and effective therapy for perianal complex fistulas in CD, and represents the beginning of a new era of mesenchymal stem cell therapy in this difficult phenotype of the disease.

Short-term efficacy and safety of three novel sphincter-sparing techniques for anal fistulae: a systematic review.

BACKGROUND: The surgical treatment of complex anal fistulae, particularly those involving a significant portion of the anal sphincter in which fistulotomy would compromise continence, is challenging. Video-assisted anal fistula treatment (VAAFT), fistula tract laser closure (FiLaC™) and over-the-scope clip (OTSC®) proctology system are all novel sphincter-sparing techniques targeted at healing anal fistulae. In this study, all published articles on these techniques were reviewed to determine efficacy, feasibility and safety. METHODS: A systematic search of major databases was performed using defined terms. All studies reporting on experience of these techniques were included and outcomes (fistula healing and safety) evaluated. RESULTS: Eighteen studies (VAAFT-12, FiLaC™-3, OTSC®-3) including 1245 patients were analysed. All were case series, and outcomes were heterogeneous with follow-up ranging from 6 to 69 months and short-term (< 1 year) healing rates of 64-100%. Morbidity was low with only minor complications reported. There was one report of minor incontinence following the first reported study of FiLaC™, and this was treated successfully at 6 months with rubber band ligation of hypertrophied prolapsed mucosa. There are inconsistencies in the technique in studies of VAAFT and FiLaC™. CONCLUSIONS: All three techniques appear to be safe and feasible options in the management of anal fistulae, and short-term healing rates are acceptable with no sustained effect on continence. There is, however, a paucity of robust data with long-term outcomes. These techniques are thus welcome additions; however, their long-term place in the colorectal surgeon's armamentarium, whether diagnostic or therapeutic, remains uncertain.

Natural history of anorectal sepsis.

BACKGROUND: Progression from anorectal abscess to fistula is poorly described and it remains unclear which patients develop a fistula following an abscess. The aim was to assess the burden of anorectal abscess and to identify risk factors for subsequent fistula formation. METHODS: The Hospital Episode Statistics database was used to identify all patients presenting with new anorectal abscesses. Cox regression analysis was undertaken to identify factors predictive of fistula formation. RESULTS: A total of 165 536 patients were identified in the database as having attended a hospital in England with an abscess for the first time between 1997 and 2012. Of these, 158 713 (95·9 per cent) had complete data for all variables and were included in this study, the remaining 6823 (4·1 per cent) with incomplete data were excluded from the study. The overall incidence rate of abscess was 20·2 per 100 000. The rate of subsequent fistula formation following an abscess was 15·5 per cent (23 012 of 148 286) in idiopathic cases and 41·6 per cent (4337 of 10 427 in patients with inflammatory bowel disease (IBD) (26·7 per cent coded concurrently as ulcerative colitis; 47·2 per cent coded as Crohn's disease). Of all patients who developed a fistula, 67·5 per cent did so within the first year. Independent predictors of fistula formation were: IBD, in particular Crohn's disease (hazard ratio (HR) 3·51; P < 0·001), ulcerative colitis (HR 1·82; P < 0·001), female sex (HR 1·18; P < 0·001), age at time of first abscess 41-60 years (HR 1·85 versus less than 20 years; P < 0·001), and intersphincteric (HR 1·53; P < 0·001) or ischiorectal (HR 1·48; P < 0·001) abscess location compared with perianal. Some 2·9 per cent of all patients presenting with a new abscess were subsequently diagnosed with Crohn's disease; the median time to diagnosis was 14 months. CONCLUSION: The burden of anorectal sepsis is high, with subsequent fistula formation nearly three times more common in Crohn's disease than idiopathic disease, and female sex is an independent predictor of fistula formation following abscess drainage. Most fistulas form within the first year of presentation with an abscess.

Risk of metachronous colorectal cancer following colectomy in Lynch syndrome: a systematic review and meta-analysis.

AIM: Lynch syndrome (LS) accounts for 2-4% of all colorectal cancer (CRC) cases, and is associated with an increased risk of developing metachronous colorectal cancer (mCRC). The role of extended colectomy in LS CRC is controversial. There are limited studies comparing the risk of mCRC following segmental colectomy and extended colectomy. The objective of this systematic review is to evaluate the risk of developing mCRC following segmental and extended colectomy for LS CRC and endoscopic compliance. METHOD: A systematic review of major databases was performed using predefined terms. All original articles published in English comparing the risk of mCRC in LS patients after segmental and extended colectomy from 1950 to January 2016 were included. RESULTS: The search retrieved 324 studies. Six studies involving 871 patients met the inclusion criteria. Of these, 705 (80.9%) underwent segmental colectomy and 166 (19.1%) extended colectomy. Average follow-up was 91.2 months. The mCRC rate was 22.8% and 6% in the segmental and extended colectomy groups, respectively. The segmental group were over four times more likely to develop mCRC (OR 4.02, 95% CI: 2.01-8.04, P < 0.0001). mCRC occurred in patients after segmental colectomy despite 1-2-yearly postoperative endoscopic surveillance. CONCLUSION: This result suggests that extended colectomy reduces the risk of mCRC by over four-fold compared with segmental colectomy. mCRC occurred in the segmental group despite postoperative endoscopic surveillance. This needs to be borne in mind when deciding on the appropriate surgical management of LS patients with CRC. We recommend that extended colectomy should be considered for patients with confirmed LS CRC.