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      Predictive Factors for Anastomotic Leakage After Colorectal Surgery: Study Protocol for a Prospective Observational Study (REVEAL Study)


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          Anastomotic leakage (AL) remains the most important complication following colorectal surgery, and is associated with high morbidity and mortality rates. Previous research has focused on identifying risk factors and potential biomarkers for AL, but the sensitivity of these tests remains poor.


          This prospective multicenter observational study aims at combining multiple parameters to establish a diagnostic algorithm for colorectal AL.


          This study aims to include 588 patients undergoing surgery for colorectal carcinoma. Patients will be eligible for inclusion when surgery includes the construction of a colorectal anastomosis. Patient characteristics will be collected upon consented inclusion, and buccal swabs, breath, stool, and blood samples will be obtained prior to surgery. These samples will allow for the collection of information regarding patients’ inflammatory status, genetic predisposition, and intestinal microbiota. Additionally, breath and blood samples will be taken postoperatively and patients will be strictly observed during their in-hospital stay, and the period shortly thereafter.


          This study has been open for inclusion since August 2015.


          An estimated 8-10% of patients will develop AL following surgery, and they will be compared to non-leakage patients. The objectives of this study are twofold. The primary aim is to establish and validate a diagnostic algorithm for the pre-operative prediction of the risk of AL development using a combination of inflammatory, immune-related, and genetic parameters. Previously established risk factors and novel parameters will be incorporated into this algorithm, which will aid in the recognition of patients who are at risk for AL. Based on these results, recommendations can be made regarding the construction of an anastomosis or deviating stoma, and possible preventive strategies. Furthermore, we aim to develop a new algorithm for the post-operative diagnosis of AL at an earlier stage, which will positively reflect on short-term survival rates.

          Trial Registration

          Clinicaltrials.gov: NCT02347735; https://clinicaltrials.gov/ct2/show/NCT02347735 (archived by WebCite at http://www.webcitation.org/6hm6rxCsA)

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          Most cited references48

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          Definition and grading of anastomotic leakage following anterior resection of the rectum: a proposal by the International Study Group of Rectal Cancer.

          Anastomotic leakage represents a major complication after anterior resection of the rectum. The incidence of anastomotic leakage varies considerably among clinical studies in part owing to the lack of a standardized definition of this complication. The aim of the present article was to propose a definition and severity grading of anastomotic leakage after anterior rectal resection. After a literature review a consensus definition and severity grading of anastomotic leakage was developed within the International Study Group of Rectal Cancer. Anastomotic leakage should be defined as a defect of the intestinal wall at the anastomotic site (including suture and staple lines of neorectal reservoirs) leading to a communication between the intra- and extraluminal compartments. Severity of anastomotic leakage should be graded according to the impact on clinical management. Grade A anastomotic leakage results in no change in patients' management, whereas grade B leakage requires active therapeutic intervention but is manageable without re-laparotomy. Grade C anastomotic leakage requires re-laparotomy. The proposed definition and clinical grading is applicable easily in the setting of clinical studies. It should be applied in future reports to facilitate valid comparison of the results of different studies. Copyright 2010 Mosby, Inc. All rights reserved.
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            Increased local recurrence and reduced survival from colorectal cancer following anastomotic leak: systematic review and meta-analysis.

            To examine the long-term oncological impact of anastomotic leakage (AL) after restorative surgery for colorectal cancer using meta-analytical methods. Outcomes evaluated were local recurrence, distant recurrence, and survival. Recurrence after potentially curative surgery for colorectal cancer remains a significant clinical problem and has a poor prognosis. AL may be a risk factor for disease recurrence, however available studies have been conflicting. A meta-analysis was conducted to investigate the impact of AL on disease recurrence and long-term survival. Studies published between 1965 and 2009 evaluating the long-term oncological impact of AL were identified by an electronic literature search. Outcomes evaluated included local recurrence, distant recurrence, and cancer specific survival. Meta-analysis was performed using the DerSimonian-Laird random-effects model to compute odds ratio and 95% confidence intervals. Study heterogeneity was evaluated using Q statistics and I and publication bias assessed with funnel plots and Egger's test. Twenty-one studies comprising 13 prospective nonrandomized studies, 1 prospective randomized, and 7 retrospective studies met the inclusion criteria, yielding a total of 21,902 patients. For rectal anastomoses, the odd ratios (OR) of developing a local recurrence when there was AL was 2.05 (95% CI = 1.51-2.8; P = 0.0001). For studies describing both colon and rectal anastomoses, the OR of local recurrence when there was an AL was 2.9 (95% CI = 1.78-4.71; P < 0.001). The OR of developing a distant recurrence after AL was 1.38 (95% CI = 0.96-1.99; P = 0.083). Long term cancer specific mortality was significantly higher after AL with an OR of 1.75 (95% CI = 1.47-2.1; P = 0.0001). AL has a negative prognostic impact on local recurrence after restorative resection of rectal cancer. A significant association between colorectal AL and reduced long-term cancer specific survival was also noted. No association between AL and distant recurrence was found. @ 2011 Lippincott Williams & Wilkins, Inc.
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              Defunctioning stoma reduces symptomatic anastomotic leakage after low anterior resection of the rectum for cancer: a randomized multicenter trial.

              The aim of this randomized multicenter trial was to assess the rate of symptomatic anastomotic leakage in patients operated on with low anterior resection for rectal cancer and who were intraoperatively randomized to a defunctioning stoma or not. The introduction of total mesorectal excision surgery as the surgical technique of choice for carcinoma in the lower and mid rectum has led to decreased local recurrence and improved oncological results. Despite these advances, perioperative morbidity remains a major issue, and the most feared complication is symptomatic anastomotic leakage. The role of the defunctioning stoma in regard to anastomotic leakage is controversial and has not been assessed in any randomized trial of sufficient size. From December 1999 to June 2005, a total of 234 patients were randomized to a defunctioning loop stoma or no loop stoma. Loop ileostomy or loop transverse colostomy was at the choice of the surgeon. Inclusion criteria for randomization were expected survival >6 months, informed consent, anastomosis < or =7 cm above the anal verge, negative air leakage test, intact anastomotic rings, and absence of major intraoperative adverse events. The overall rate of symptomatic leakage was 19.2% (45 of 234). Patients randomized to a defunctioning stoma (n = 116) had leakage in 10.3% (12 of 116) and those without stoma (n = 118) in 28.0% (33 of 118) (odds ratio = 3.4; 95% confidence interval, 1.6-6.9; P < 0.001). The need for urgent abdominal reoperation was 8.6% (10 of 116) in those randomized to stoma and 25.4% (30 of 118) in those without (P < 0.001). After a follow-up of median 42 months (range, 6-72 months), 13.8% (16 of 116) of the initially defunctioned patients still had a stoma of any kind, compared with 16.9% (20 of 118) those not defunctioned (not significant). The 30-day mortality after anterior resection was 0.4% (1 of 234) and after elective reversal a defunctioning stoma 0.9% (1 of 111). Median age was 68 years (range, 32-86 years), 45.3% (106 of 234) were females, 79.1% (185 of 234) had preoperative radiotherapy, the level of anastomosis was median 5 cm, and intraoperative blood loss 550 mL, without differences between the groups. Defunctioning loop stoma decreased the rate of symptomatic anastomotic leakage and is therefore recommended in low anterior resection for rectal cancer.

                Author and article information

                JMIR Res Protoc
                JMIR Res Protoc
                JMIR Research Protocols
                JMIR Publications Inc. (Toronto, Canada )
                Apr-Jun 2016
                09 June 2016
                : 5
                : 2
                : e90
                [1] 1Department of General Surgery Maastricht University Medical Centre MaastrichtNetherlands
                [2] 2NUTRIM School for Nutrition & Translational Research in Metabolism Maastricht University MaastrichtNetherlands
                [3] 3Department of Surgery Maxima Medical Centre VeldhovenNetherlands
                [4] 4Department of Surgery Zuyderland Medical Centre HeerlenNetherlands
                [5] 5Department of Surgery Zuyderland Medical Centre SittardNetherlands
                [6] 6Pediatric Surgical Centre Amsterdam Emma Children's hospital Amsterdam Medical Centre/Vrije Universiteit Medisch Centrum AmsterdamNetherlands
                Author notes
                Corresponding Author: Audrey CHM Jongen a.jongen@ 123456maastrichtuniversity.nl
                Author information
                ©Audrey CHM Jongen, Joanna WAM Bosmans, Serdar Kartal, Tim Lubbers, Meindert Sosef, Gerrit D Slooter, Jan H Stoot, Frederik-Jan van Schooten, Nicole D Bouvy, Joep PM Derikx. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 09.06.2016.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on http://www.researchprotocols.org, as well as this copyright and license information must be included.

                : 23 December 2015
                : 22 January 2016
                : 7 February 2016
                : 7 February 2016

                anastomotic leakage,colorectal surgery,postoperative complications,biomarkers,personalized medicine


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