Preoperative biomarkers related to inflammation may identify high-risk anastomoses in colorectal cancer surgery : explorative study

Anastomotic leakage is a major complication after colorectal surgery, presumed to correspond with a process of failed wound healing, involving inflammation. Circulating levels of inflammation-related biomarkers were investigated in preoperative samples from 41 patients with leakage, who had elective treatment with a primary anastomosis for non-disseminated colorectal cancer, matched to 41 complication-free controls. A total of 15 inflammation-related proteins were elevated before surgery in patients with rectal cancer with leakage, of which C-X-C motif chemokine 6 and C-C motif chemokine 11 remained significantly increased after controlling for multiplicity. As a corresponding expression pattern difference did not emerge when tissue adjacent to the anastomosis was evaluated with immunohistochemistry, findings may reflect a systemic rather than a local host response. While these findings require validation before implementation into surgical practice, they highlight the need for further translational investigations as a promising research area to help decrease leakage rates. Background Colorectal anastomotic leakage can be considered a process of failed wound healing, for which related biomarkers might be a promising research area to decrease leak rates. Methods Patients who had elective surgery with a primary anastomosis for non-metastatic colorectal cancer, at two university hospitals between 1 January 2010 and 31 December 2015 were included. Patients with an anastomotic leak were identified and matched (1:1) to complication-free controls on the basis of sex, age, tumour stage, tumour location, and operating hospital. Preoperative blood samples were analysed by use of protein panels associated with systemic or enteric inflammation by proteomics, and enzyme-linked immunosorbent assays. Multivariable projection methods were used in the statistical analyses and adjusted for multiple comparisons to reduce false positivity. Rectal cancer tissue samples were evaluated with immunohistochemistry to determine local expression of biomarkers that differed significantly between cases and controls. Results Out of 726 patients undergoing resection, 41 patients with anastomotic leakage were matched to 41 controls. Patients with rectal cancer with leakage displayed significantly elevated serum levels of 15 proteins related to inflammation. After controlling for a false discovery rate, levels of C-X-C motif chemokine 6 (CXCL6) and C-C motif chemokine 11 (CCL11) remained significant. In patients with colonic cancer with leakage, levels of high-sensitivity C-reactive protein (hs-CRP) were increased before surgery. Local expression of CXCL6 and CCL11, and their receptors, were similar in rectal tissues between cases and controls. Conclusion Patients with anastomotic leakage could have an upregulated inflammatory response before surgery, as expressed by elevated serological levels of CXCL6 and CCL11 for rectal cancer and hs-CRP levels in patients with colonic cancer respectively. Preoperative inflammation-related serum proteins were evaluated in a case-control study of 41 patients with anastomotic leakage matched 1:1 with 41 complication-free controls. The chemokines C-X-C motif chemokine 6 and C-C motif chemokine 11 were significantly increased before surgery in patients with rectal cancer and leakage, a finding requiring further validation.Peer reviewe

Anastomotic leakage in rectal cancer surgery : The role of blood perfusion

Anastomotic leakage after anterior resection for rectal cancer remains a common and often devastating complication. Preoperative risk factors for anastomotic leakage have been studied extensively and are used for patient selection, especially whether to perform a diverting stoma or not. From the current literature, data suggest that perfusion in the rectal stump rather than in the colonic limb may be more important for the integrity of the colorectal anastomosis. Moreover, available research suggests that the mid and upper rectum is considerably more vascularized than the lower part, in which the posterior compartment seems most vulnerable. These data fit neatly with the observation that anastomotic leaks are far more frequent in patients undergoing total compared to partial mesorectal excision, and also that most leaks occur dorsally. Clinical judgment has been shown to ineffectively assess anastomotic viability, while promising methods to measure blood perfusion are evolving. Much interest has recently been turned to near-infrared light technology, enhanced with fluorescent agents, which enables intraoperative perfusion assessment. Preliminary data are promising, but large-scale controlled trials are lacking. With maturation of such technology, perfusion measurements may in the future inform the surgeon whether anastomoses are at risk. In high colorectal anastomoses, anastomotic revision might be feasible, while a diverting stoma could be fashioned selectively instead of routinely for low anastomoses

Multicentre, randomised trial comparing acellular porcine collagen implant versus gluteus maximus myocutaneous flap for reconstruction of the pelvic floor after extended abdominoperineal excision of rectum : study protocol for the Nordic Extended Abdominoperineal Excision (NEAPE) study

Introduction: Different surgical techniques are used to cover the defect in the floor of the lesser pelvis after an ‘extralevator’ or ‘extended’ abdominoperineal excision for advanced rectal cancer. However, these operations are potentially mutilating, and the reconstruction method of the pelvic floor has been studied only sparsely. We aim to study whether a porcine-collagen implant is superior or equally beneficial to a gluteus maximus myocutaneous flap as a reconstruction method. Methods and analysis: This is a multicentre non-blinded randomised controlled trial with the experimental arm using a porcine-collagen implant and the control arm using a gluteus maximus muscle and skin rotation flap. Considered for inclusion are patients with rectal cancer, who are operated on with a wide abdominoperineal rectal excision including most of the levator muscles and where the muscle remnants cannot be closed in the midline with sutures. Patients with a primary or recurrent rectal cancer with an estimated survival of more than a year are eligible. The randomisation is computer generated with a concealed sequence and stratified by participating hospital and preoperative radiotherapy regimen. The main outcome is physical performance 6 months after surgery measured with the timed-stands test. Secondary outcomes are perineal wound healing, surgical complications, quality of life, ability to sit and other outcomes measured at 3, 6 and 12 months after surgery. To be able to state experimental arm non-inferiority with a 10% margin of the primary outcome with 90% statistical power and assuming 10% attrition, we aim to enrol 85 patients from May 2011 onwards. Ethics and dissemination: The study has been approved by the Regional Ethical Review board at Umeå University (protocol no: NEAPE-2010-335-31M). The results will be disseminated through patient associations and conventional scientific channels

Population‐based cohort study of the impact on postoperative mortality of anastomotic leakage after anterior resection for rectal cancer

Background: Anastomotic leakage following anterior resection for rectal cancer may result in death. The aim of this study was to yield an updated, population‐based estimate of postoperative mortality and evaluate possible interacting factors. Methods: This was a retrospective national cohort study of patients who underwent anterior resection between 2007 and 2016. Data were retrieved from a prospectively developed database. Anastomotic leakage constituted exposure, whereas outcome was defined as death within 90 days of surgery. Logistic regression analyses, using directed acyclic graphs to evaluate possible confounders, were performed, including interaction analyses. Results: Of 6948 patients, 693 (10·0 per cent) experienced anastomotic leakage and 294 (4·2 per cent) underwent reintervention due to leakage. The mortality rate was 1·5 per cent in patients without leakage and 3·9 per cent in those with leakage. In multivariable analysis, leakage was associated with increased mortality only when a reintervention was performed (odds ratio (OR) 5·57, 95 per cent c.i. 3·29 to 9·44). Leaks not necessitating reintervention did not result in increased mortality (OR 0·70, 0·25 to 1·96). There was evidence of interaction between leakage and age on a multiplicative scale (P = 0·007), leading to a substantial mortality increase in elderly patients with leakage. Conclusion: Anastomotic leakage, in particular severe leakage, led to a significant increase in 90‐day mortality, with a more pronounced risk of death in the elderly

Anterior resection for rectal cancer in Sweden : validation of a registry-based method to determine long-term stoma outcome

Background: A permanent stoma after anterior resection for rectal cancer is common. Nationwide registries provide sufficient power to evaluate factors influencing this phenomenon, but validation is required to ensure the quality of registry-based stoma outcomes. Methods: Patients who underwent anterior resection for rectal cancer in the Northern healthcare region of Sweden between 1 January 2007 and 31 December 2013 were reviewed by medical records and followed until 31 December 2014 with regard to stoma outcome. A registry-based method to determine nationwide long-term stoma outcomes, using data from the National Patient Registry and the Swedish Colorectal Cancer Registry, was developed and internally validated using the chart reviewed reference cohort. Accuracy was evaluated with positive and negative predictive values and Kappa values. Following validation, the stoma outcome in all patients treated with an anterior resection for rectal cancer in Sweden during the study period was estimated. Possible regional differences in determined stoma outcomes between the six Swedish healthcare regions were subsequently evaluated with the χ2 test. Results: With 312 chart reviewed patients as reference, stoma outcome was accurately predicted through the registry-based method in 299 cases (95.8%), with a positive predictive value of 85.1% (95% CI 75.8%-91.8%), and a negative predictive value of 100.0% (95% CI 98.4%-100.0%), while the Kappa value was 0.89 (95% CI 0.82-0.95). In Sweden, 4768 patients underwent anterior resection during the study period, of which 942 (19.8%) were determined to have a permanent stoma. The stoma rate varied regionally between 17.8-29.2%, to a statistically significant degree (p = .001). Conclusion: Using data from two national registries to determine long-term stoma outcome after anterior resection for rectal cancer proved to be reliable in comparison to chart review. Permanent stoma prevalence after such surgery remains at a significant level, while stoma outcomes vary substantially between different healthcare regions in Sweden

Defunctioning stomas may reduce chances of a stoma-free outcome after anterior resection for rectal cancer

Aim: To investigate the conflicting consequences of faecal diversion on stoma outcomes and anastomotic leakage in anterior resection for rectal cancer, including interaction effects determined by the extent of mesorectal excision. Method: Anterior resections between 2007 and 2016 were identified using the Swedish Colorectal Cancer Registry. National Patient Registry data were added to determine stoma outcome 2 years after surgery. Tumour distance from the anal verge constituted a proxy for extent of mesorectal excision [total mesorectal excision (TME): ≤10 cm; partial mesorectal excision (PME): 13–15 cm]. With confounder-adjusted probit regression, the total effect of defunctioning stoma on permanent stoma, and the interaction effect of extent of mesorectal excision, were estimated together with the indirect effect through anastomotic leakage. Baseline risks, risk differences (RDs) and relative risks (RRs) were reported. Results: The main study cohort included 4529 patients. Defunctioning stomas influenced the absolute permanent stoma risk (TME: RD 0.11 [95% CI 0.09–0.13]; PME: RD 0.15 [95% CI 0.13–0.16]). The baseline risk was higher in TME, with a resulting greater RR in PME (2.23 [95% CI 1.43–3.02] vs 4.36 [95% CI 3.05–5.68]). The indirect reduction in permanent stoma rates, due to the alleviating effect of faecal diversion on anastomotic leakage, was small (TME: 0.89 [95% CI 0.81–0.96]; PME: 0.96 [95% CI 0.91–1.00]). Conclusion: In anterior resection for rectal cancer, defunctioning stomas may reduce chances of a stoma-free outcome. Considering leakage reduction benefits, consequences of routine diversion in TME might be fairly balanced, while this seems questionable in PME

Patient-reported and doctor-reported symptoms when faecal immunochemical tests are requested in primary care in the diagnosis of colorectal cancer and inflammatory bowel disease : a prospective study

Background: Rectal bleeding and a change in bowel habits are considered to be alarm symptoms for colorectal cancer and they are also common symptoms for inflammatory bowel disease. However, most patients with these symptoms do not have any of these diseases. Faecal immunochemical tests (FITs) for haemoglobin are used as triage tests in Sweden and other countries but little is known about the symptoms patients have when FITs are requested. Objective: Firstly, to determine patients’ symptoms when FITs are used as triage tests in primary care and whether doctors record the symptoms that patients report, and secondly to evaluate the association between symptoms, FIT results and possible prediction of colorectal cancer or inflammatory bowel disease. Methods and materials: This prospective study included 364 consecutive patients for whom primary care doctors requested a FIT. Questionnaires including gastrointestinal symptoms were completed by patients and doctors. Results: Concordance between symptoms reported from patients and doctors was low. Rectal bleeding was recorded by 43.5% of patients versus 25.6% of doctors, FITs were negative in 58.3 and 52.7% of these cases respectively. The positive predictive value (PPV) of rectal bleeding recorded by patients for colorectal cancer or inflammatory bowel disease was 9.9% (95% confidence interval [CI] 5.2–14.7); for rectal bleeding combined with a FIT the PPV was 22.6% (95% CI 12.2–33.0) and the negative predictive value (NPV) was 98.9% (95% CI 96.7–100). For patient-recorded change in bowel habits the PPV was 6.1% (95% CI 2.4–9.8); for change in bowel habits combined with a FIT the PPV was 18.2% (95% CI 9.1–30.9) and the NPV 100% (95% CI 90.3–100). Conclusions: Doctors should be aware that, during consultations, they do not record all symptoms experienced by patients. FITs requested in primary care, when found positive, may potentially be of help in prioritising referrals, also when patients present with rectal bleeding or change in bowel habits

Postoperative nonsteroidal anti-inflammatory drugs in relation to recurrence, survival and anastomotic leakage after surgery for colorectal cancer

Aim: The aim of this work was to investigate whether nonsteroidal anti-inflammatory drugs (NSAIDs) could be beneficial or harmful when used perioperatively for colorectal cancer patients, as inflammation may affect occult disease and anastomotic healing. Method: This is a protocol-based retrospective cohort study on colorectal cancer patients operated on between 2007 and 2012 at 21 hospitals in Sweden. NSAID exposure was retrieved from postoperative analgesia protocols, while outcomes and patient data were retrieved from the Swedish Colorectal Cancer Registry. Older or severely comorbid patients, as well as those with disseminated or nonradically operated tumours were excluded. Multivariable regression with adjustment for confounders was performed, estimating hazard ratios (HRs) for long-term outcomes and odds ratios (ORs) for short-term outcomes, including 95% confidence intervals (CIs). Results: Some 6945 patients remained after exclusion, of whom 3996 were treated at hospitals where a NSAID protocol was in place. No association was seen between NSAIDs and recurrence-free survival (HR 0.97, 95% CI 0.87–1.09). However, a reduction in cancer recurrence was detected (HR 0.83, 95% CI 0.72–0.95), which remained significant when stratifying into locoregional (HR 0.68, 95% CI 0.48–0.97) and distant recurrences (HR 0.85, 95% CI 0.74–0.98). Anastomotic leakage was less frequent (HR 0.69%, 95% CI 0.51–0.94) in the NSAID-exposed, mainly due to a risk reduction in colo-rectal and ileo-rectal anastomoses (HR 0.47, 95% CI 0.33–0.68). Conclusion: There was no association between NSAID exposure and recurrence-free survival, but an association with reduced cancer recurrence and the rate of anastomotic leakage was detected, which may depend on tumour site and anastomotic location

PET/MRI and PET/CT hybrid imaging of rectal cancer - description and initial observations from the RECTOPET (REctal Cancer trial on PET/MRI/CT) study

PurposeThe role of hybrid imaging using F-18-fluoro-2-deoxy-D-glucose positron-emission tomography (FDG-PET), computed tomography (CT) and magnetic resonance imaging (MRI) to improve preoperative evaluation of rectal cancer is largely unknown. To investigate this, the RECTOPET (REctal Cancer Trial on PET/MRI/CT) study has been launched with the aim to assess staging and restaging of primary rectal cancer. This report presents the study workflow and the initial experiences of the impact of PET/CT on staging and management of the first patients included in the RECTOPET study.MethodsThis prospective cohort study, initiated in September 2016, is actively recruiting patients from Region Vasterbotten in Sweden. This pilot study includes patients recruited and followed up until December 2017. All patients had a biopsy-verified rectal adenocarcinoma and underwent a minimum of one preoperative FDG-PET/CT and FDG-PET/MRI examination. These patients were referred to the colorectal cancer multidisciplinary team meeting at Umea University Hospital. All available data were evaluated when making management recommendations. The clinical course was noted and changes consequent to PET imaging were described; surgical specimens underwent dedicated MRI for anatomical matching between imaging and histopathology.ResultsTwenty-four patients have so far been included in the study. Four patients were deemed unresectable, while 19 patients underwent or were scheduled for surgery; one patient was enrolled in a watch-and-wait programme after restaging. Consequent to taking part in the study, two patients were upstaged to M1 disease: one patient was diagnosed with a solitary hepatic metastasis detected using PET/CT and underwent metastasectomy prior to rectal cancer surgery, while one patient with a small, but metabolically active, lung nodulus experienced no change of management. PET/MRI did not contribute to any recorded change in patient management.ConclusionsThe RECTOPET study investigating the role of PET/CT and PET/MRI for preoperative staging of primary rectal cancer patients will provide novel data that clarify the value of adding hybrid to conventional imaging, and the role of PET/CT versus PET/MRI.Trial registrationNCT03846882

Nonsteroidal anti-inflammatory drugs and the risk of anastomotic leakage after anterior resection for rectal cancer

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in colorectal surgery due to their opioid-sparing effect. However, several studies have indicated an increased risk of anastomotic leakage following NSAID treatment, although conflicting results exist. The primary goal of this study was to further examine whether postoperative NSAIDs are independently associated with anastomotic leakage after anterior resection for rectal cancer. Methods: Patients who underwent anterior resection for rectal cancer during 2007-2013 in 15 different hospitals in three healthcare regions in Sweden were included in the study. Registry data and information from patient records were retrieved. The association between NSAID treatment (for at least two days in the first postoperative week) and symptomatic anastomotic leakage (within 90 days) was evaluated with multiple logistic regression, with adjustment for pertinent confounding factors. Results: Some 1495 patients were included in the study. Of these, 27% received postoperative NSAIDs for at least two days in the first postoperative week. Symptomatic anastomotic leakage occurred in 11% and 14% in the NSAID and non-NSAID group, respectively. With adjustment for confounders, the odds ratio for leakage among patients who received NSAIDs compared with those who did not was 0.88 (95% CI 0.65-1.20). No differences were seen between non-selective and COX-2-selective NSAIDs. Conclusion: Postoperative NSAID treatment does not seem to increase the risk of symptomatic anastomotic leakage after anterior resection for rectal cancer. NSAID use appears to be safe, but a well-powered randomized clinical trial is warranted