Peter-Martin Krarup

A nationwide study on anastomotic leakage after colonic cancer surgery

Aim  Anastomotic leakage (AL) is a major challenge in colorectal cancer surgery due to increased morbidity and mortality. Possible risk factors should be investigated differentially, distinguishing between rectal and colonic surgery in large‐scale studies to avoid selection bias and confounding.

Anastomotic leak increases distant recurrence and long-term mortality after curative resection for colonic cancer: a nationwide cohort study.

Objective:To investigate the impact of anastomotic leak (AL) on disease recurrence and long-term mortality in patients alive 120 days after curative resection for colonic cancer. Background:There is no solid data as to whether AL after colonic cancer surgery increases the risk of disease recurrence. Methods:This was a nationwide cohort study of 9333 patients, prospectively registered in the database of the Danish Colorectal Cancer Group and merged with data from the Danish Pathology Registry and the National Patient Registry. Multivariable Cox regression analysis was used to adjust for confounding. Results:The incidence of AL was 6.4%, 744 patients died within 120 days. Of the remaining 8589 patients, 861 (10.0%) developed local recurrence with no association to AL [adjusted hazard ratio (HR) = 0.78; 95% confidence interval (CI): 0.55–1.12; P = 0.184]. Distant recurrence developed in 1281 (14.9%) patients and more frequently after AL (adjusted HR = 1.42; 95% CI: 1.13–1.78; P = 0.003). AL was also associated with increased long-term mortality (adjusted HR = 1.20; 95% CI: 1.01–1.44; P = 0.042). In 2841 patients with stage III cancer, AL was associated with both decreased likelihood of receiving adjuvant chemotherapy (adjusted HR = 0.58; 95% CI: 0.45–0.74; P < 0.001) and a delay to initial administration (16 days; 95% CI: 12–20 days; P < 0.001). Conclusions:AL was significantly associated with increased rates of distant recurrence and long-term all-cause mortality. Cancelled or delayed administration of adjuvant chemotherapy may partly account for these findings.

Management of Anastomotic Leakage in a Nationwide Cohort of Colonic Cancer Patients

BACKGROUND The mortality associated with anastomotic leakage (AL) after colonic cancer surgery is high and management often results in permanent fecal diversion. Preservation of bowel continuity in combination with proximal loop diversion (salvage) may reduce the number of permanent ostomies without jeopardizing safety. STUDY DESIGN This nationwide study used prospective data from the database of the Danish Colorectal Cancer Group, the National Patient Registry, and patient files. Patients with AL requiring surgery (grade C) were categorized according to the type of surgical treatment as anastomotic takedown with an end-ostomy or salvage. Thirty-day mortality, long-term mortality, and permanent ostomy rates were analyzed using multivariable logistic and Cox regression analyses. RESULTS Anastomotic leakage occurred in 593 of 9,333 patients (6.4%), of whom 507 with grade C were included. Takedown and salvage were undertaken in 433 (85.4%) and 74 (14.6%) patients, respectively. Salvage was performed more frequently for Hinchey I-II or minor anastomotic defects and resulted in increased likelihood of stoma reversal (adjusted hazard ratio 3.24, 95% CI 2.04 to 5.16, p < 0.001), corresponding to a risk of permanent fecal diversion of 16.8%, compared with 54.5% after takedown. Adjusted mortality rates were comparable between the groups. A second episode of AL after stoma reversal occurred more frequently in patients with end-ileostomies (10 of 64) than in patients with end-colostomies (1 of 64) or loop-ileostomies (3 of 36), p = 0.017. CONCLUSIONS Patients with Hinchey I-II and small anastomotic defect were safely managed by anastomotic salvage, which reduced the risk of permanent fecal diversion. Anastomotic salvage is a viable option for this subset of patients.

Pharmacological interventions for improved colonic anastomotic healing: A meta-analysis

AIM To identify pharmaceuticals for the prophylaxis of anastomotic leakage (AL), we systematically reviewed studies on anastomosis repair after colorectal surgery. METHODS We searched PubMed and EMBASE for articles published between January 1975 and December 2012. We included studies in English with the primary purpose of promoting healing of anastomoses made in the colon or rectum under uncomplicated conditions. We excluded studies on adverse events from interventions, nutritional interventions or in situ physical supporting biomaterials. The primary outcome was biomechanical strength or AL. We performed meta-analyses on therapeutic agents investigated by three or more independent research groups using the same outcome. The DerSimonian-Laird method for random effects was applied with P < 0.05. RESULTS Of the 56 different therapeutic agents assessed, 7 met our inclusion criteria for the meta-analysis. The prostacyclin analog iloprost increased the weighted mean of the early bursting pressure of colonic anastomoses in male rats by 60 mmHg (95%CI: 30-89) vs the controls, and the immunosuppressant tacrolimus increased this value by 29 mmHg (95%CI: 4-53) vs the controls. Erythropoietin showed an enhancement of bursting pressure by 45 mmHg (95%CI: 14-76). The anabolic compound growth hormone augmented the anastomotic strength by 21 mmHg (95%CI: 7-35), possibly via the up-regulation of insulin-like growth factor-1, as this growth factor increased the bursting pressure by 61 mmHg (95%CI: 43-79) via increased collagen deposition. Hyperbaric oxygen therapy increased the bursting pressure by 24 mmHg (95%CI: 13-34). Broad-spectrum matrix metalloproteinase inhibitors increased the bursting pressure by 48 mmHg (95%CI: 31-66) on postoperative days 3-4. In the only human study, the AL incidence was not significantly reduced in the 103 colorectal patients treated with aprotinin (11.7%) compared with the 113 placebo-treated patients (9.7%). CONCLUSION This systematic review identified only one randomized clinical trial and seven therapeutic agents from pre-clinical models that could be explored further for the prophylaxis of AL after colorectal surgery.

Occurrence and survival of synchronous pulmonary metastases in colorectal cancer: A nationwide cohort study

OBJECTIVE To investigate the occurrence of synchronous colorectal cancer metastases (SCCM) confined to the lungs, risk factors for these metastases and their impact on survival. METHODS In a nationwide cohort study of 26,200 patients data were prospectively entered into the Danish Colorectal Cancer Groups (DCCGs) database between May 2001 and December 2011. The recorded data were merged with data from the Danish Pathology Registry and the National Patient Registry. Multivariable logistic- and extended Cox regression analyses were used to adjust for confounding variables. RESULTS In total, 1970 patients (7.5%) had pulmonary SCCM of whom 736 (37%) had metastases exclusively in the lungs. Advanced age, recent years of diagnosis and a rectal index cancer were significantly associated with pulmonary SCCM. Adjustment for excess use of thoracic CT scans in rectal cancer patients did not alter this association (adjusted OR=1.81 (95% CI: 1.46-2.25, P<0.001)). Patients subjected to pulmonary metastasectomy, resection of primary tumour and chemotherapy had a superior overall survival compared with non-treated patients, especially when these therapeutic modalities were combined. CONCLUSIONS The occurrence of pulmonary SCCM was higher than previously reported and had a severe impact on survival. Our analyses suggest that pulmonary metastasectomy, resection of the primary tumour and chemotherapy may be a sound strategy in patients with confined pulmonary SCCM, but the risk of selection bias and consequent exaggeration of the treatment effect should be kept in mind. This study may serve as a reliable un-biased reference for future evaluation on detection strategies and potential therapeutic interventions.

Association of Comorbidity with Anastomotic Leak, 30-day Mortality, and Length of Stay in Elective Surgery for Colonic Cancer: A Nationwide Cohort Study.

BACKGROUND: Comorbidity has a negative influence on the long-term prognosis in patients with colorectal cancer, whereas its impact on the postoperative course is less clear. OBJECTIVES: The aim of this study was to investigate the influence of comorbidity on anastomotic leak and short-term outcomes after resection for colonic cancer. DESIGN: This is a retrospective nationwide cohort study SETTING: Data were obtained from the Danish Colorectal Cancer Group and the National Patient Registry. PATIENTS: Patients with colonic cancer undergoing elective resection between 2001 and 2008 were selected. MAIN OUTCOME MEASURES: The primary outcome was the ability of comorbidity to predict anastomotic leak. Secondary outcomes were 30-day mortality and length of stay. Comorbidity was assessed by the Charlson Comorbidity Index. Multivariable logistic regression and receiver operating characteristics curves were used to adjust for confounding. RESULTS: The rate of anastomotic leak was 535/8597 (6.2%). The mean (95% CI) Charlson score was 0.83 (0.72–0.94) and 0.63 (0.61–0.66) for patients with and without anastomotic leak, p < 0.001. The Charlson score, as assessed in the multivariable analysis (adjusted OR, 1.07; 95% CI, 0.99–1.15; p = 0.077) and by receiver operating characteristics curves (area under the curve = 0.548), failed to predict anastomotic leak. Thirty-day mortality was 425/8587 (4.9%). In patients with anastomotic leakage, a Charlson score of ≥2 was associated with increased mortality in comparison with a Charlson score of <2 (adjusted HR, 1.58; 95% CI, 1.00–2.51; p = 0.047). Mean length of stay was 8.7 days (95% CI, 8.4–9.2 days) for patients without an anastomotic leak in comparison with 23.3 days (95% CI, 21.5–25.1 days) for patients with anastomotic leak and 25.5 days (95% CI, 21.7–29.3 days) in patients with anastomotic leak and a Charlson score of >2, p < 0.001. LIMITATIONS: This study is limited by the accuracy of the coding used to generate the Charlson Comorbidity Index and the retrospective study design. CONCLUSION: Comorbidity failed to predict anastomotic leak, but it was associated with an inferior short-term outcome in patients with this surgical complication.

Therapeutic improvement of colonic anastomotic healing under complicated conditions: A systematic review

AIM To identify therapeutic agents for the prophylaxis of gastrointestinal anastomotic leakage (AL) under complicated conditions. METHODS The PubMed and EMBASE databases were searched for English articles published between January 1975 and September 2014. Studies with the primary purpose of improving anastomotic healing in the colon or rectum under complicated preoperative and/or intraoperative conditions were included. We excluded studies investigating the adverse effects or risk assessment of an active intervention. Furthermore, investigations of biophysical materials, sealants, electrical stimulation and nutrients were excluded. The primary study outcome was biomechanical anastomotic strength or AL. The meta-analysis focused on therapeutic agents that were investigated in one animal model using the same outcome by at least three independent research groups. RESULTS The 65 studies included were divided into 7 different complicated animal models: Bowel ischemia, ischemia/reperfusion, bowel obstruction, obstructive jaundice, peritonitis, chemotherapy and radiotherapy. In total, 48 different therapeutic compounds were examined. The majority of investigated agents (65%) were reported as beneficial for anastomotic healing. Twelve of the agents (25%) were tested more than once in the same model, whereas 13 (27%) of the agents were tested in two or more models of complicated healing. Two therapeutic agents met our inclusion criteria for the meta-analysis. Postoperative hyperbaric oxygen therapy significantly increased anastomotic bursting pressure in ischemic colon anastomoses by a mean of 28 mmHg (95%CI: 17 to 39 mmHg, P < 0.00001). Granulocyte macrophage-colony stimulating factor failed to show a significant increase in anastomotic bursting pressure (95%CI: -20 to 21 mmHg, P = 0.97) vs controls in experimental chemotherapeutic models. CONCLUSION This systematic review identified potential therapeutic agents, but more studies are needed before concluding that any of these are useful for AL prophylaxis.

Mismatch repair status and synchronous metastases in colorectal cancer: A nationwide cohort study.

The causality between the metastatic potential, mismatch repair status (MMR) and survival in colorectal cancer (CRC) is complex. This study aimed to investigate the impact of MMR in CRC on the occurrence of synchronous metastases (SCCM) and survival in patients with SCCM on a national basis. A nationwide cohort study of 6,692 patients diagnosed with CRC between 2010 and 2012 was conducted. Data were prospectively entered into the Danish Colorectal Cancer Groups database and merged with data from the Danish Pathology Registry and the National Patient Registry. Multivariable and multinomial logistic‐ and Cox‐regression and proportional excess hazards analyses were used for confounder adjustment and to adjust for the general population mortality. In total, 983 of 6,692 patients (14.7%) had dMMR and 935 (14.0%) had SCCM. dMMR was associated with a decreased risk of SCCM, adjusted Odds Ratio (aOR) = 0.54 (95% confidence interval (CI):0.40–0.70, p < 0.001). The association only applied to confined hepatic metastases (aOR = 0.30, 95%CI: 0.18–0.49, p < 0.001), whereas the presence of confined pulmonary metastases (aOR = 0.71, 95% CI: 0.39–1.29, p = 0.258) or synchronous hepatic and pulmonary metastases (aOR = 0.69, 95% CI:0.26–1.29, p = 0.436) were unaffected by MMR. MMR in patients with SCCM had no impact on survival (Cox: adjusted Hazard Ratio (aHR) = 0.76, 95% CI: 0.54–1.06, p = 0.101; Proportional excess hazards: aHR = 0.73, 95% CI: 0.50–1.07, p = 0.111) when adjusting for other prognostic factors. The metastatic pattern varied according to MMR status. MMR had no impact on survival in patients with UICC Stage IV CRC. These findings may be important for the understanding of the metastatic processes and thus for optimizing staging and treatment in CRC patients.

Treatment of Complex Fistula-in-Ano With a Nitinol Proctology Clip

BACKGROUND: The treatment of complex anocutaneous fistulas remains a major therapeutic challenge balancing the risk of incontinence against the chance of permanent closure. OBJECTIVE: The purpose of this study was to investigate the efficacy of a nitinol proctology clip for closure of complex anocutaneous fistulas. DESIGN: This is a single-center cohort study with retrospective analysis of all of the treated patients. SETTINGS: Data were obtained from patient records and MRI reports, as well as follow-up telephone calls and clinical follow-up with endoanal ultrasonography. PATIENTS: All of the patients were treated for high transsphincteric and suprasphincteric anocutaneous fistulas at the Digestive Disease Center, Bispebjerg Hospital, between May 2013 and February 2015. INTERVENTIONS: All of the patients were treated with the nitinol proctology clip. MAIN OUTCOME MEASURES: Primary outcome was fistula healing after proctology clip placement, as evaluated through clinical examination, endoanal ultrasonography, and MRI. RESULTS: The fistula healing rate 1 year after the clip procedure was 54.3% (19 of 35 included patients). At the end of follow-up, 17 (49%) of 35 patients had persistent closure of the fistula tracks. No impairment of continence function was observed. Treatment outcome was not found to be statistically associated with any clinicopathological characteristics. LIMITATIONS: The study is limited by its retrospective and nonrandomized design. Selection bias may have occurred, because treatment options other than the clip were available during the study period. The small number of patients means that there is a nonnegligible risk of type II error in the conclusion, and the follow-up may be too short to have detected all of the failures. CONCLUSIONS: Healing rates were comparable with those of other noninvasive, sphincter-sparing techniques for high-complex anocutaneous fistulas, with no risk of incontinence. Predictive parameters for fistula healing using this technique remain uncertain. See Video Abstract at http://links.lww.com/DCR/A347.

GM6001 Increases Anastomotic Leakage following Colonic Obstruction Possibly by Impeding Epithelialization

BACKGROUND Emergency operations performed on an obstructed colon are accompanied by an increased risk of anastomotic insufficiency. Tissue-destructive matrix metalloproteinase (MMP) activity is elevated in the obstructed colon and contributes to a loss of suture-holding submucosal collagen, which may be mediated by tumor necrosis factor (TNF)-α. Our aim was to study the effect of the non-selective MMP and TNF-α converting enzyme (TACE) inhibitor GM6001 (30 mg/kg) on anastomosis repair in obstructed left colon. GM6001 has been proved to be highly efficacious in elective anastomosis rodent models. METHODS A partial obstruction of the distal colon was induced in male Sprague-Dawley rats. After 4 d the obstructed colonic segment was resected, and an end-to-end anastomosis was constructed. Seven days later, the anastomoses were evaluated for clinical leakage. Histopathological and immunohistochemical assessments were also performed. Finally, the direct effect of GM6001 on epithelialization was studied in cultured colonic epithelial cells. RESULTS Unlike the robust beneficial effect on anastomosis under uncomplicated conditions, here GM6001 had a negative impact on anastomotic wound healing following colonic obstruction and substantially (p=0.004) more rats in the GM6001 group (75%) than in the control group (11%) had developed anastomotic leakage. In the anastomotic wounds, the myofibroblast abundance and cell proliferation were similar in the two groups. Histologically, GM6001 treatment resulted in wider and minimally epithelialized wounds that were commonly necrotic on the luminal side and infiltrated with numerous granulocytes. In vitro, GM6001 also delayed (p=0.026) epithelialization of denuded intestinal epithelium grown on type I collagen. CONCLUSIONS Non-selective MMP/TACE inhibition with GM6001 increased the anastomotic complications following colon obstruction. Inhibition of epithelialization is one possible mechanism responsible for the increased leakage following GM6001 treatment.