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1.	Rutegård, Miriam, et al. (author) 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 2019 In: Cancer Imaging. - : BMC. - 1740-5025 .- 1470-7330. ; 19 Journal article (peer-reviewed)abstract 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.
2.	Rutegård, Miriam, et al. (author) Rectal cancer : a methodological approach to matching PET/MRI to histopathology 2020 In: Cancer Imaging. - : BioMed Central (BMC). - 1740-5025 .- 1470-7330. ; 20:1 Journal article (peer-reviewed)abstract Purpose: To enable the evaluation of locoregional disease in the on-going RECTOPET (REctal Cancer Trial on PET/MRI/CT) study; a methodology to match mesorectal imaging findings to histopathology is presented, along with initial observations.Methods: FDG-PET/MRI examinations were performed in twenty-four consecutively included patients with rectal adenocarcinoma. In nine patients, of whom five received neoadjuvant treatment, a postoperative MRI of the surgical specimen was performed. The pathological cut-out was performed according to clinical routine with the addition of photo documentation of each slice of the surgical specimen, meticulously marking the location, size, and type of pathology of each mesorectal finding. This allowed matching individual nodal structures from preoperative MRI, via the specimen MRI, to histopathology.Results: Preoperative MRI identified 197 mesorectal nodal structures, of which 92 (47%) could be anatomically matched to histopathology. Of the matched nodal structures identified in both MRI and histopathology, 25% were found to be malignant. These malignant structures consisted of lymph nodes (43%), tumour deposits (48%), and extramural venous invasion (9%). One hundred eleven nodal structures (55%) could not be matched anatomically. Of these, 97 (87%) were benign lymph nodes, and 14 (13%) were malignant nodal structures. Five were malignant lymph nodes, and nine were tumour deposits, all of which had a short axis diameter < 5 mm.Conclusions: We designed a method able to anatomically match and study the characteristics of individual mesorectal nodal structures, enabling further research on the impact of each imaging modality. Initial observations suggest that small malignant nodal structures assessed as lymph nodes in MRI often comprise other forms of mesorectal tumour spread.Trial registration: Clinical Trials Identifier: NCT03846882.
3.	Back, Erik, et al. (author) Author response to : Permanent stoma prediction after anterior resection for rectal cancer: risk prediction scoring using preoperative variables 2022 In: British Journal of Surgery. - : Oxford University Press. - 0007-1323 .- 1365-2168. ; 109:2 Journal article (other academic/artistic)
4.	Back, Erik, et al. (author) Mucosal blood flow in the remaining rectal stump is more affected by total than partial mesorectal excision in patients undergoing anterior resection : a key to understanding differing rates of anastomotic leakage? 2021 In: Langenbeck's archives of surgery (Print). - : Springer. - 1435-2443 .- 1435-2451. ; 406:6, s. 1971-1977 Journal article (peer-reviewed)abstract PURPOSE: Anterior resection is the procedure of choice for tumours in the mid and upper rectum. Depending on tumour height, a total mesorectal excision (TME) or partial mesorectal excision (PME) can be performed. Low anastomoses in particular have a high risk of developing anastomotic leakage, which might be explained by blood perfusion compromise. A pilot study indicated a worse blood flow in TME patients in an open setting. The aim of this study was to further evaluate perianastomotic blood perfusion changes in relation to TME and PME in a predominantly laparoscopic context.METHOD: In this prospective cohort study, laser Doppler flowmetry was used to evaluate the perianastomotic colonic and rectal perfusion before and after surgery. The two surgical techniques were compared in terms of mean differences of perfusion units using a repeated measures ANOVA design, which also enabled interaction analyses between type of mesorectal excision and location of measurement. Anastomotic leakage until 90 days after surgery was reported for descriptive purposes.RESULTS: Some 28 patients were available for analysis: 17 TME and 11 PME patients. TME patients had a reduced blood perfusion postoperatively compared to PME patients in the aboral posterior area (mean difference: -57 vs 18 perfusion units; p = 0.010). An interaction between mesorectal excision type and anterior/posterior location was detected at the aboral level (p = 0.007). Two patients developed a minor leakage, diagnosed after discharge.CONCLUSION: Patients operated on using TME have a decreased blood flow in the aboral posterior quadrant of the rectum postoperatively compared to patients operated on using PME. This might explain differing rates of anastomotic leakage.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02401100.
5.	Back, Erik, et al. (author) Permanent stoma rates after anterior resection for rectal cancer : risk prediction scoring using preoperative variables 2021 In: British Journal of Surgery. - : Oxford University Press. - 0007-1323 .- 1365-2168. ; 108:11, s. 1388-1395 Journal article (peer-reviewed)abstract BACKGROUND: A permanent stoma after anterior resection for rectal cancer is common. Preoperative counselling could be improved by providing individualized accurate prediction modelling.METHODS: Patients who underwent anterior resection between 2007 and 2015 were identified from the Swedish Colorectal Cancer Registry. National Patient Registry data were added to determine presence of a stoma 2 years after surgery. A training set based on the years 2007-2013 was employed in an ensemble of prediction models. Judged by the area under the receiving operating characteristic curve (AUROC), data from the years 2014-2015 were used to evaluate the predictive ability of all models. The best performing model was subsequently implemented in typical clinical scenarios and in an online calculator to predict the permanent stoma risk.RESULTS: Patients in the training set (n = 3512) and the test set (n = 1136) had similar permanent stoma rates (13.6 and 15.2 per cent). The logistic regression model with a forward/backward procedure was the most parsimonious among several similarly performing models (AUROC 0.67, 95 per cent c.i. 0.63 to 0.72). Key predictors included co-morbidity, local tumour category, presence of metastasis, neoadjuvant therapy, defunctioning stoma use, tumour height, and hospital volume; the interaction between age and metastasis was also predictive.CONCLUSION: Using routinely available preoperative data, the stoma outcome at 2 years after anterior resection for rectal cancer can be predicted fairly accurately.
6.	Bostrom, Petrus, et al. (author) Arterial ligation in anterior resection for rectal cancer : A validation study of the Swedish Colorectal Cancer Registry 2014 In: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 53:7, s. 892-897 Journal article (peer-reviewed)abstract Background: The level of arterial ligation has been a variable of the Swedish Colorectal Cancer Registry since 2007. The aim of this study is to evaluate the accuracy of this registry variable in relation to anterior resection for rectal cancer.Methods: The operative charts of all cardiovascularly compromised patients who underwent anterior resection during the period 2007-2010 in Sweden were retrieved and compared to the registry. We selected the study population to reflect the common assumption that these patients would be more sensitive to a compromised visceral blood flow. Levels of vascular ligation were defined, both oncologically and functionally, and their sensitivity, specificity, positive and negative predictive values, level of agreement and Cohen's kappa were calculated.Results: Some 744 (94.5%) patients were eligible for analysis. Functional high tie level showed a sensitivity of 80.2% and a specificity of 90.1%. Positive and negative predictive values were 87.7 and 83.8%, respectively. Level of agreement was 85.5% and Cohen's kappa 0.70. The corresponding calculations for oncologic tie level yielded similar results.Conclusion: The suboptimal validity of the Swedish Colorectal Cancer Registry regarding the level of vascular ligation might be problematic. For analyses with rare positive outcomes, such bowel ischaemia, or with minor expected differences in outcomes, it would be beneficial to collect data directly from the operative charts of the medical records in order to increase the chance of identifying clinically relevant differences.
7.	Boström, Petrus, et al. (author) Oncological Impact of High Vascular Tie After Surgery for Rectal Cancer : A Nationwide Cohort Study 2021 In: Annals of Surgery. - : Wolters Kluwer. - 0003-4932 .- 1528-1140. ; 274:3, s. e236-e244 Journal article (peer-reviewed)abstract Objective: The purpose of this study was to investigate the impact of tie level on oncological outcomes in rectal cancer surgery.Summary background data: Theoretically, a high tie of the inferior mesenteric artery could facilitate removal of apical node metastases and improve tumor staging accuracy. However, no appropriately sized randomized controlled trial exists and results from observational studies are not consistent.Methods: All stage I–III rectal cancer patients who underwent abdominal surgery with curative intention in 2007 to 2014 were identified and followed, using the Swedish Colorectal Cancer Registry. Primary outcome was cancer-specific survival, whereas overall and relative survival, locoregional and distant recurrence, and lymph node harvest were secondary outcomes, with high tie as exposure. We used propensity score matching to emulate a randomized controlled trial, and then performed Cox regression analyses to estimate hazard ratios (HRs) with confidence intervals (CIs).Results: Some 8287 patients remained for analysis, of which 37% had high tie surgery. After propensity score matching, the 5-year cancer-specific survival rate was overall 86% and we found no association between the level of tie and cancer-specific (HR 0.92, 95% CI 0.79–1.07) or overall (HR 0.98, 95% CI 0.89–1.08) survival, nor to locoregional (HR 0.85, 95% CI 0.59–1.23) or distant (HR 1.01, 95% CI 0.88–1.15) recurrence, nor to relative survival (HR 1.05, 95% CI 0.85–1.28). Stratification and sensitivity analyses were similarly insignificant, after adjustment for confounding. Total lymph node harvest was, however, increased after high tie surgery (P < 0.01), but no differences were seen regarding positive nodes (P = 0.72).Conclusion: In this nationwide cohort study, the level of tie did not influence any patient-oriented oncological outcome, neither overall nor in node-positive patients. This would allow the patient's anatomical configuration and the surgeon's preferences to determine the level of tie.
8.	Boström, Petrus, et al. (author) Population‐based cohort study of the impact on postoperative mortality of anastomotic leakage after anterior resection for rectal cancer 2019 In: BJS Open. - : John Wiley & Sons. - 2474-9842. ; 3:1, s. 106-111 Journal article (peer-reviewed)abstract 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.
9.	Boström, Petrus, 1981- (author) Rectal cancer : the influence of surgical technique on morbidity, mortality and survival 2020 Doctoral thesis (other academic/artistic)abstract Surgery is still the most common treatment for rectal cancer, being the most effective and cost-efficient modality. However, it is not without risk, nor without controversies. This dissertation is an evaluation of the pros and cons of high versus low ligation, whether anastomotic leakage is still prevalent after surgery and associated with increased mortality, and if the risk of leakage could be predicted by early postoperative pain.Study I relied upon case records and registry data to evaluate the causal effect of high ligation on the risk of anastomotic leakage after anterior resection in 722 patients with increased cardiovascular risk. When controlling for confounders, no association was found overall. However, an increased risk for leakage after high ligation was noted for the few patients who suffered from both manifest cardiovascular disease and ASA III–IV (OR 3.66, 95% CI 1.04–12.85) and when performed in a low volume hospital (OR 3.89, 95% 1.58– 9.59). Study II estimated the risk of anastomotic leakage and death after anterior resection today. Among the 6,948 patients, 10.0% suffered from leakage, in whom mortality was 3.9% versus 1.5% for patients without a leak. However, this increased mortality was driven entirely by patients in need of reintervention, who exhibited a 7.5% 90-day mortality, resulting in a significantly increased risk (OR 5.57, 95% CI 3.29–9.44), when controlling for confounders, while conservatively treated leakage was not associated with mortality. Age acted as an effect modifier, as postoperative mortality after leakage was increased in the elderly.Study III returned to high versus low ligation as exposure, to evaluate the long-term oncological benefits of either ligation level, with cancer-specific survival as primary outcome. The final cohort of 8,287 patients who underwent abdominal surgery for rectal cancer, with curative intent, was followed for a minimum of 3.5 years. After propensity score matching, no significant differences were found between high and low ligation for any survival or recurrence analysis, nor in the unmatched cohort, when controlling for confounders. A statistically significant difference was found for lymph node harvest, which was slightly greater in high ligation (17.7 vs 16.7 lymph nodes). Finally, study IV estimated the independent predictive ability of postoperative pain, measured on the numerical rating scale (NRS), on the risk for anastomotic leakage after colorectal cancer surgery. It seems as if increased early pain is an independent predictor for leakage (OR 1.73, 95% CI 1.22– 2.46 for NRS 4–10), with increasing risk of leakage with increasing pain (OR 2.42 for NRS 8–10). In addition, increased pain was more strongly associated with more severe leakage.In summary, the level of ligation seems to be of importance only in a select group of high-risk patients, but offers no obvious oncological advantages. The high incidence and serious sequelae of anastomotic leakage makes it one of the most important clinical challenges in colorectal surgery, with especially detrimental effects in the elderly. A better understanding of the causal pathways behind leakage, and the overall harm and benefit of ligation level and diverting stomas, might allow a better selection of treatment for future patients.
10.	Grahn, Oskar, et al. (author) Concerning our paper on the possible relation of postoperative non-steroidal anti-inflammatory drugs to anastomotic leakage and cancer recurrence 2022 In: Colorectal Disease. - : Wiley-Blackwell Publishing Inc.. - 1462-8910 .- 1463-1318. ; 24:10, s. 1245-1245 Journal article (other academic/artistic)
11.	Grahn, Oskar, et al. (author) Postoperative non-steroidal anti-inflammatory drugs in relation to recurrence, survival and anastomotic leakage after surgery for colorectal cancer 2022 In: Colorectal Disease. - : Blackwell Publishing. - 1462-8910 .- 1463-1318. ; 24:8, s. 933-942 Journal article (peer-reviewed)abstract AIM: To investigate whether non-steroidal 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.METHODS: This is a protocol-based retrospective cohort study on colorectal cancer patients operated between 2007 and 2012 at 21 hospitals in Sweden. The 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 non-radically operated tumours were excluded. Multivariable regression with adjustment for confounders was performed, estimating hazard ratios (HRs) for long-term and odds ratios (ORs) for short-term outcomes, including 95% confidence intervals (CIs).RESULTS: Some 6945 patients remained after exclusion, of which 3996 were treated at hospitals where an 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% 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- 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 improved cancer recurrence and the rate of anastomotic leakage was detected, which may depend on tumour site and anastomotic location.
12.	Holmgren, Klas, et al. (author) Anterior resection for rectal cancer in Sweden : validation of a registry-based method to determine long-term stoma outcome 2018 In: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:12, s. 1631-1638 Journal article (peer-reviewed)abstract 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.
13.	Holmgren, Klas, et al. (author) Defunctioning stomas decrease chances of a stoma-free outcome after anterior resection for rectal cancer Other publication (other academic/artistic)
14.	Holmgren, Klas, et al. (author) Defunctioning stomas may reduce chances of a stoma-free outcome after anterior resection for rectal cancer 2021 In: Colorectal Disease. - : Blackwell Publishing. - 1462-8910 .- 1463-1318. ; 23:11, s. 2859-2869 Journal article (peer-reviewed)abstract 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.
15.	Holmgren, Klas, 1989- (author) Permanent stoma after anterior resection for rectal cancer : prevalence and mechanisms 2019 Doctoral thesis (other academic/artistic)abstract While sphincter-saving surgery constitutes standard treatment for rectal cancer, anterior resection still harbours a significant risk of a permanent stoma in the long run. Although anastomotic leakage plays a major role in this surgical dilemma, the exact mechanisms are not known, while surveys indicate a stoma-free outcome is essential for a majority of patients. To address this issue, the overall aim of the present thesis was to investigate the permanent stoma prevalence in patients undergoing anterior resection for rectal cancer in Sweden, and to identify plausible mechanisms that impede prospects of a stoma-free outcome.In a population-based cohort, chart review of patients who had anterior resection for rectal cancer in the Northern healthcare region in Sweden between 2007 and 2013 showed that 75 out of 316 (24%) patients ended up with a permanent stoma. Of 274 patients (87%) primarily defunctioned with a stoma, 229 underwent stoma closure, 21 (9%) of whom suffered major complications that required return to theatre or worse. A permanent stoma was shown to be more common among patients with anastomotic leakage and an advanced tumour stage.A registry-based method to estimate nationwide stoma outcome after anterior resection for rectal cancer was developed, using data from the Swedish Colorectal Cancer Registry and the National Patient Registry. With a chart-reviewed cohort as reference, stoma outcome was assessed with a positive predictive value of 85.1%, and a negative predictive value of 100.0%. In patients operated in Sweden between 2007 and 2013, the registry-based method determined that 942 out of 4768 (19.8%) had a permanent stoma, while stoma rates varied substantially between different healthcare regions.In a 1:1 matched case-control study of 82 patients who had curative resection for non-disseminated colorectal cancer, a subgroup analysis of 34 patients with rectal cancer displayed biomarker aberrations in serum measured preoperatively in those with anastomotic leakage. Compared to complication-free controls, 15 proteins related to inflammation were elevated, of which two (C-X-C motif chemokine 6, and C-C motif chemokine 11) remained significant after adjustment for multiple testing.Based on a cohort of 4529 patients who had anterior resection, tumour height served as a proxy to determine the extent of mesorectal excision, while long-term stoma outcome was classified using a previously validated registry-based method. Defunctioning stomas significantly decreased chances of a stoma-free outcome, especially in patients undergoing partial mesorectal excision; for these patients, faecal diversion was also least beneficial in terms of reducing anastomotic leakage.In conclusion, every fifth patient undergoing anterior resection for rectal cancer in Sweden eventually ends up with a permanent stoma. Although construction of a defunctioning stoma decreases the risk of symptomatic anastomotic leakage, subsequent takedown surgery carries a substantial risk of major complications, while chances of a long-term stoma-free outcome become significantly reduced. To facilitate selective use of faecal diversion, novel markers to identify high-risk anastomoses prior to surgery have been identified, but require validation in larger prospective settings. Anterior resection without a defunctioning stoma should be considered in appropriately informed patients for whom a stoma-free outcome is of importance. In particular, this holds true for patients eligible for partial mesorectal excision, where anastomotic dehiscence is less frequent and the advantageous effects of a defunctioning stoma are limited.
16.	Holmgren, Klas, et al. (author) Preoperative biomarkers related to inflammation identify high-risk anastomoses in surgery for rectal cancer : an explorative study on patients with colorectal cancer Other publication (other academic/artistic)
17.	Holmgren, Klas, et al. (author) Preoperative biomarkers related to inflammation may identify high-risk anastomoses in colorectal cancer surgery : explorative study 2022 In: BJS Open. - : Oxford University Press. - 2474-9842. ; 6:3 Journal article (peer-reviewed)abstract 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.
18.	Kverneng Hultberg, Daniel, 1990- (author) Surgery for rectal cancer : the impact of perioperative factors 2020 Doctoral thesis (other academic/artistic)abstract Rectal cancer is one of the most common and deadly cancer forms worldwide. A large proportion of rectal cancer patients are surgically treated with curative intention, with anterior resection being the most frequently used method today. During surgery, the inferior mesenteric artery is either ligated proximal (high tie) or distal to the left colic artery (low tie). It is not known whether the tie level affects the oncologic nor the functional outcome. Postoperatively, about one in ten patients develop an anastomotic leakage. It is unclear whether treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) affects the risk of leakage, or whether having a leakage influences the functional outcome. The general aims of this dissertation were to increase the knowledge of intra- and postoperative treatment for rectal cancer, with the goal of improving the oncologic and functional outcomes, as well as reducing postoperative complications. National registers, predominantly the Swedish Colorectal Cancer Registry, were used in all of the dissertation’s four retrospective cohort studies to identify and retrieve information regarding patients. Various statistical methods have been used in all studies with the aim of eliminating bias, including confounding.In Study I, high tie slightly increased the total number of harvested lymph nodes in the included 8287 patients, as compared with low tie, while the primary outcome cancer-specific survival, as well as secondary oncologic outcomes, were not affected. This indicates that the oncologic outcome does not have to be considered when the surgeon determines the level of tie.In Study II, investigating the effect of tie level on the functional outcome, the outcome was any defecatory or urogenital symptoms two years after anterior resection, assessed with a mailed questionnaire. With a response rate of 86%, 805 patients were included. High tie did not, except for increasing the need of defecation at night, influence the risk of major dysfunction. Again, this would facilitate the choice of tie level.Study III used the same outcome, and in part the same study population, as Study II, but instead with the exposure anastomotic leakage. With a response rate of 82%, 1180 patients were included. We found that anastomotic leakage increased the risk of reduced sexual activity and increased the use of aid products for fecal incontinence after anterior resection, while the risk of urinary incontinence was unexpectedly decreased. Other outcomes were not clearly affected. In Study IV, in addition to the register, information was gathered from patient records. In the included 1495 patients who had undergone anterior resection, postoperative NSAID treatment was not found to increase the risk of symptomatic anastomotic leakage. There were no differences between non-selective and COX-2 selective NSAIDs. This study does not support that NSAID treatment increases the risk of anastomotic leakage after such surgery.
19.	Kverneng Hultberg, Daniel, et al. (author) The Impact of Anastomotic Leakage on Long-Term Function after Anterior Resection for Rectal Cancer 2020 In: Diseases of the Colon & Rectum. - : American Society of Colon & Rectal Surgeons. - 0012-3706 .- 1530-0358. ; 63:5, s. 619-628 Journal article (peer-reviewed)abstract Background: It is still not clear whether anastomotic leakage after anterior resection for rectal cancer affects long-term functional outcome.Objective: To evaluate how anastomotic leakage following anterior resection for rectal cancer influences defecatory, urinary and sexual function.Design: In this retrospective population-based cohort study, patients were identified through the Swedish Colorectal Cancer Registry, which was also used for information on the exposure variable anastomotic leakage, and covariates.Settings: A nationwide register was used for including patients.Patients: All patients undergoing anterior resection for rectal cancer in Sweden from April 2011– June 2013 were included.Main Outcome Measures: Outcome was any defecatory, sexual or urinary dysfunction, assessed two years after surgery by a postal questionnaire. The association between anastomotic leakage and function was assessed in multivariable logistic and linear regression models, with adjustment for confounding.Results: Response rate was 82%, resulting in 1180 included patients. Anastomotic leakage occurred in 7.5%. A permanent stoma was more common among leak patients (44% vs. 9%; p<0.001). Leakage patients had an increased risk of aid use for fecal incontinence (OR 2.27; 95% CI 1.20-4.30) and reduced sexual activity (90% vs. 82%; p=0.003), while the risk of urinary incontinence was decreased (OR 0.53; 95% CI 0.31-0.90). A sensitivity analysis assuming that a permanent stoma was created due to anorectal dysfunction strengthened the negative impact of leakage on defecatory dysfunction.Limitations: Limitations include the used questionnaire not having been previously validated, underreporting of anastomotic leakage in the register, and small patient numbers in the analysis of sexual symptoms.Conclusions:a Anastomotic leakage was found to statistically significantly increase the risk of aid use due to fecal incontinence and reduced sexual activity, though the impact on defecatory dysfunction might be underestimated, as permanent stomas are sometimes fashioned due to anorectal dysfunction. Further research is warranted, especially regarding urogenital function.
20.	Rutegård, Jörgen, 1943-, et al. (author) Non-steroidal anti-inflammatory drugs in colorectal surgery : a risk factor for anastomotic complications? 2012 In: World Journal of Gastrointestinal Surgery. - : Baishideng Publishing Group Co., Limited. - 1948-9366. ; 4:12, s. 278-280 Journal article (peer-reviewed)abstract In a recent article, Gorissen et al report on 795 patients with primary colorectal anastomosis operated on during the period 2008-2010 for different colorectal conditions at two centres. The leakage rate was significantly higher among patients who were administered non-steroidal anti-inflammatory drugs (NSAIDs) in the perioperative course. A dose-response relationship could also be traced, where longer NSAID use yielded a higher risk of anastomotic breakdown. However, as this study is observational in design, confounding by indication may be present and there is also a risk of residual confounding from unmeasured covariates. Moreover, the question whether different affinity for the cyclooxygenase enzyme is important in different NSAIDs seems to be largely unanswered. The results, conclusions and clinical relevance of the aforementioned study, including the possible effects of different types of NSAIDs, are discussed. While acknowledging that this study represents the best attempt so far in establishing the causal relationship between perioperative NSAID use and anastomotic leakage, the need for further research in this important area is underlined.
21.	Rutegård, Martin, 1982-, et al. (author) Correspondence : The right kind of rectal cancer operation for the right patient requires information on all relevant outcomes 2022 In: Colorectal Disease. - : Blackwell Publishing. - 1462-8910 .- 1463-1318. ; 24:1, s. 136-137 Journal article (other academic/artistic)
22.	Rutegård, Martin, 1982-, et al. (author) Defunctioning loop ileostomy in anterior resection for rectal cancer and subsequent renal failure : nationwide population-based study 2023 In: BJS Open. - : Oxford University Press. - 2474-9842. ; 7:3 Journal article (peer-reviewed)abstract BACKGROUND: Electrolyte disturbances and dehydration are common after anterior resection for rectal cancer with a defunctioning loop ileostomy. High-quality population-based studies on the impact of a defunctioning loop ileostomy on renal failure are lacking.METHODS: This was a nationwide observational study, based on the Swedish Colorectal Cancer Registry of patients undergoing anterior resection for rectal cancer between 2008 and 2016, with follow-up until 2017. Patients with severe co-morbidity, with age greater than 80 years, and with pre-existing renal failure were excluded. Loop ileostomy at index surgery constituted exposure, while a diagnosis of renal failure was the outcome. Acute and chronic events were analysed separately. Inverse probability weighting with adjustment for confounding derived from a causal diagram was employed. Hazards ratios (HRs) with 95 per cent c.i. are reported.RESULTS: A total of 5355 patients were eligible for analysis. At 5-year follow-up, all renal failure events (acute and chronic) were 7.2 per cent and 3.3 per cent in the defunctioning stoma and no stoma groups respectively. In the weighted analysis, a HR of 11.59 (95 per cent c.i. 5.68 to 23.65) for renal failure in ostomates was detected at 1 year, with the largest effect from acute renal failure (HR 24.04 (95 per cent c.i. 8.38 to 68.93)). Later follow-up demonstrated a similar pattern, but with smaller effect sizes.CONCLUSION: Patients having a loop ileostomy in combination with anterior resection for rectal cancer are more likely to have renal failure, especially early after surgery. Strategies are needed, such as careful fluid management protocols, and further research into alternative stoma types or reduction in stoma formation.
23.	Rutegård, Martin, 1982-, et al. (author) Early postoperative mortality after surgery for rectal cancer in Sweden, 2000-2011 2014 In: Colorectal Disease. - : Wiley-Blackwell. - 1462-8910 .- 1463-1318. ; 16:6, s. 426-432 Journal article (peer-reviewed)abstract Aim: Postoperative mortality has traditionally been defined as death within 30 days of surgery. Such mortality after rectal cancer resection has declined significantly during the last decades. However, it is possible that this decline can be explained merely by a shift towards an increase in 90-day mortality.Method: A nationwide cohort study was based on data from the Swedish Colorectal Cancer Registry and the Swedish Patient Registry concerning patients who had undergone surgical resection for rectal cancer in 2000-2011. Unconditional logistic regression was used to calculate ORs with 95% CIs regarding mortality in different calendar periods (2000-2003, 2004-2007 and 2008-2011) in two different postoperative time periods (0-30 days and 31-90 days).Results: Some 15,437 patients were included in this surgical cohort. Mortality within 30 days of surgery decreased from 2.1% in 2000-2003 to 1.6% in 2008-2011, whilst the corresponding mortality within the 31- to 90-day time window decreased from 2.1% to 1.4%. The adjusted risk of 30-day mortality in 2008-2011 was statistically significantly decreased compared with that in 2000-2003 (OR = 0.67; 95% CI: 0.48-0.93) and mortality in the 31- to 90-day time window was also reduced for 2008-2011 compared with 2000-2003 (OR = 0.71; 95% CI: 0.51-0.99).Conclusion: This population-based, nationwide Swedish study indicates that postoperative mortality, as measured within 30 days and 31-90 days after surgery, has decreased with time. However, no relevant shift from earlier to later postoperative mortality was discerned.
24.	Rutegård, Martin, 1982-, et al. (author) High tie in anterior resection for rectal cancer confers no increased risk of anastomotic leakage 2012 In: British Journal of Surgery. - Malden, MA : Wiley-Blackwell. - 0007-1323 .- 1365-2168. ; 99:1, s. 127-132 Journal article (peer-reviewed)abstract Background: It is controversial whether division of the inferior mesenteric artery close to the aorta influences the risk of anastomotic leakage, especially in the elderly and unfit. This population-based study was carried out to evaluate the independent association between a high arterial ligation and anastomotic leakage in anterior resection for rectal cancer. Methods: All patients who had anterior resection for rectal cancer from 2007 to 2009 inclusive were identified in the Swedish Colorectal Cancer Registry. The association between high tie and anastomotic leakage was evaluated in a logistic regression model, with adjustment for confounders. Stratification was performed for co-morbidity as judged by the American Society of Anesthesiologists (ASA) classification. Results: Symptomatic anastomotic leakage occurred in 81 (9.9 per cent) of 818 patients with a high tie and 108 (9.8 per cent) of 1101 without. Overall, the use of a high tie was not associated with a higher risk of anastomotic leakage (odds ratio (OR) 1.00, 95 per cent confidence interval 0.72 to 1.39). There was no increased risk in patients classifed as ASA grade I or II (OR 0.97, 0.69 to 1.35), or in those graded ASA III or IV (OR 1.26, 0.58 to 2.75). Conclusion: In the present population-based setting, use of a high tie was not associated with an increased rate of symptomatic anastomotic leakage.
25.	Rutegård, Martin, 1982-, et al. (author) 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 2019 In: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 9:5 Journal article (peer-reviewed)abstract 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.
26.	Sörelius, Karl, 1981-, et al. (author) A nationwide study on the incidence of mesenteric ischaemia after surgery for rectal cancer demonstrates an association with high arterial ligation 2019 In: Colorectal Disease. - : Wiley. - 1462-8910 .- 1463-1318. ; 21:8, s. 925-931 Journal article (peer-reviewed)abstract Aim: The incidence of mesenteric ischaemia after resection for rectal cancer has not been investigated in a population-based setting. The use of high ligation of the inferior mesenteric artery might cause such ischaemia, as the bowel left in situ depends on collateral blood supply after a high tie.Method: The Swedish Colorectal Cancer Registry was used to identify all patients subjected to an abdominal resection for rectal cancer during the years 2007-2017 inclusive. Mesenteric ischaemia within the first 30 postoperative days was recorded, classified as either stoma necrosis or colonic necrosis. Multivariable logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for mesenteric ischaemia in relation to high tie, with adjustment for confounding.Results: Some 14 657 patients were included, of whom 59 (0.40%) had a reoperation for any type of mesenteric ischaemia, divided into 34 and 25 cases of stoma necrosis and colonic necrosis, respectively. Compared with patients who did not require reoperation for mesenteric ischaemia following rectal cancer surgery, the proportion having high tie was greater (54.2% vs 38.5%; P = 0.032). The adjusted OR for reoperation due to any mesenteric ischaemia with high tie was 2.26 (95% CI 1.34-3.79), while the corresponding estimates for stoma and colonic necrosis, respectively, were 1.60 (95% CI 0.81-3.17) and 3.69 (95% CI 1.57-8.66).Conclusion: The incidence of reoperation for mesenteric ischaemia after abdominal resection for rectal cancer is low, but the use of a high tie might increase the risk of colonic necrosis demanding surgery.
27.	Axman, Erik, et al. (author) Association between previous inguinal hernia surgery and the risk of anastomotic leakage after colorectal surgery: nationwide registry-based study. 2023 In: BJS open. - : Oxford University Press. - 2474-9842. ; 7:4 Journal article (peer-reviewed)
28.	Boström, Petrus, et al. (author) Early postoperative pain as a marker of anastomotic leakage in colorectal cancer surgery 2021 In: International Journal of Colorectal Disease. - : Springer-Verlag New York. - 0179-1958 .- 1432-1262. ; 36:9, s. 1955-1963 Journal article (peer-reviewed)abstract Purpose: Even though anastomotic leakage after colorectal surgery is a major clinical problem in need of a timely diagnosis, early indicators of leakage have been insufficiently studied. We therefore conducted a population-based observational study to determine whether the patient’s early postoperative pain is an independent marker of anastomotic leakage.Methods: By combining the Swedish Colorectal Cancer Registry and the Swedish Perioperative Registry, we retrieved prospectively collected data on 3084 patients who underwent anastomotic colorectal surgery for cancer in 2014–2017. Postoperative pain, measured with the numerical rating scale (NRS), was considered exposure, while anastomotic leakage and reoperation due to leakage were outcomes. We performed logistic regression to evaluate associations, estimating odds ratios (ORs) and 95% confidence intervals (CIs), while multiple imputation was used to handle missing data.Results: In total, 189 patients suffered from anastomotic leakage, of whom 121 patients also needed a reoperation due to leakage. Moderate or severe postoperative pain (NRS 4–10) was associated with an increased risk of anastomotic leakage (OR 1.69, 95% CI 1.21–2.38), as well as reoperation (OR 2.17, 95% CI 1.41–3.32). Severe pain (NRS 8–10) was more strongly related to leakage (OR 2.38, 95% CI 1.44–3.93). These associations were confirmed in multivariable analyses and when reoperation due to leakage was used as an outcome.Conclusion: In this population-based retrospective study on prospectively collected data, increased pain in the post-anaesthesia care unit is an independent marker of anastomotic leakage, possibly indicating a need for further diagnostic measures.
29.	Boström, Petrus, et al. (author) Early postoperative pain as a predictor of anastomotic leakage in colorectal cancer surgery Other publication (other academic/artistic)
30.	Cook, Michael B., et al. (author) Prediagnostic circulating markers of inflammation and risk of oesophageal adenocarcinoma : a study within the National Cancer Institute Cohort Consortium 2019 In: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 68:6, s. 960-968 Journal article (peer-reviewed)abstract OBJECTIVE: Cross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk.DESIGN: This nested case-control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy.RESULTS: Soluble tumour necrosis factor receptor 2 (sTNFR2) (ORsquartile 4 vs 1=2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker-cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity-oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (p<0.05) mediator of cancer risk.CONCLUSION: This prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of oesophageal adenocarcinoma.
31.	COVIDSurg Collaborative, (author) Delaying surgery for patients with a previous SARS-CoV-2 infection 2020 In: British Journal of Surgery. - : John Wiley & Sons. - 0007-1323 .- 1365-2168. ; 107:12, s. e601-e602 Journal article (peer-reviewed)
32.	Gadan, Soran, et al. (author) Defunctioning stoma and short- and long-term outcomes after low anterior resection for rectal cancer : a nationwide register-based cohort study 2021 In: International Journal of Colorectal Disease. - : Springer. - 0179-1958 .- 1432-1262. ; 36:7, s. 1433-1442 Journal article (peer-reviewed)abstract PURPOSE: A defunctioning stoma reduces the risk of symptomatic anastomotic leakage after low anterior resection for rectal cancer and mitigates the consequences when a leakage occurs, but the impact on mortality and oncological outcomes is unclear. The aim was to investigate the associations of a defunctioning stoma with short- and long-term outcomes in patients undergoing low anterior resection for rectal cancer.METHODS: Data from all patients who underwent curative low anterior resection for rectal cancer between 1995 and 2010 were obtained from the Swedish Colorectal Cancer Register. A total of 4130 patients, including 2563 with and 1567 without a defunctioning stoma, were studied. Flexible parametric models were used to estimate hazard ratios for all-cause mortality, 5-year local recurrence, and distant metastatic disease in relation to the use of defunctioning stoma, adjusting for confounding factors and accounting for potential time-dependent effects.RESULTS: During a median follow-up of 8.3 years, a total of 2169 patients died. In multivariable analysis, a relative reduction in mortality was observed up to 6 months after surgery (hazard ratio = 0.82: 95% CI 0.67-0.99), but not thereafter. After 5 years of follow-up, 4.2% (173/4130) of the patients had a local recurrence registered and 17.9% (741/4130) had developed distant metastatic disease, without difference between patients with and without defunctioning stoma.CONCLUSION: A defunctioning stoma is associated with a short-term reduction in all-cause mortality in patients undergoing low anterior resection for rectal cancer without any difference in long-term mortality and oncological outcomes, and should be considered as standard of care.
33.	Gadan, S., et al. (author) What is the risk of permanent stoma beyond 5 years after low anterior resection for rectal cancer? : A 15-year follow-up of a randomized trial 2020 In: Colorectal Disease. - : John Wiley & Sons. - 1462-8910 .- 1463-1318. ; 22:12, s. 2098-2104 Journal article (peer-reviewed)abstract Aim: Low anterior resection of the rectum for cancer (LAR) entails a risk of symptomatic anastomotic leakage as well as impaired anorectal function, both of which may eventually result in the need for a permanent stoma (PS). The aim was to investigate the incidence of and risk factors for PS beyond 5 years following LAR.Methods: Patients undergoing LAR and included in a multicentre trial with randomization to defunctioning stoma or not were followed for a median of 15 years. The reasons for a PS up to 5 years (PS <= 5 years) and beyond 5 years (PS > 5 years) were identified and compared. Risk factors for PS were analysed.Results: Of all patients, 25% (57/232) had a PS. PS <= 5 years occurred in 19% (44/232) at a median of 12.5 months and PS > 5 years in 6% (13/232) at a median of 118 months following LAR. The main reason for PS <= 5 years was impaired anorectal function in 55% (24/44) and the main reason for PS > 5 years was pelvic sepsis related to the colorectal anastomosis in 46% (6/13). The major risk factor for PS was symptomatic anastomotic leakage, which occurred in 56% (32/57) of patients with PS and 10% (17/175) of patients without PS (P < 0.001).Conclusion: One-fourth of the patients who ended up with a PS had it fashioned beyond 5 years at a median of 10 years following LAR. Symptomatic anastomotic leakage was the major risk factor for PS, and impaired anorectal function was the main overall reason for a PS.
34.	Gerdin, Anders, et al. (author) Preoperative beta blockers and other drugs in relation to anastomotic leakage after anterior resection for rectal cancer 2024 In: Colorectal Disease. - : John Wiley & Sons. - 1462-8910 .- 1463-1318. ; 26:5, s. 974-986 Journal article (peer-reviewed)abstract Aim: Previous research has indicated that preoperative beta blocker therapy is associated with a decreased risk of complications after surgery for rectal cancer. This is thought to arise because of the anti-inflammatory activity of the drug. These results need to be reproduced and analyses extended to other drugs with such properties, as this information might be useful in clinical decision-making. The main aim of this work was to replicate previous findings of beta blocker use as a prognostic marker for postoperative leakage. We also investigated whether drug exposure might induce anastomotic leaks.Method: This is a retrospective multicentre cohort study, comprising 1126 patients who underwent anterior resection for rectal cancer between 2014 and 2018. The use of any preoperative beta blocker was treated as the primary exposure, while anastomotic leakage within 12 months of surgery was the outcome. Secondary exposures comprised angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins and metformin. Using multivariable regression, we performed a replication analysis with a predictive aim for beta blockers only, while adjustment for confounding was done in more causally oriented analyses for all drugs. We estimated incidence rate ratio (IRR) and relative risk (RR) with 95% confidence intervals (CIs).Results: Anastomotic leakage occurred in 20.6% of patients. Preoperative beta blockers were used by 22.7% of the cohort, while the leak distribution was almost identical between exposure groups. In the main replication analysis, no association could be detected (IRR 0.95, 95% CI 0.68–1.33). In the causally oriented analyses, only metformin affected the risk of leakage (RR 1.59, 95% Cl 1.31–1.92).Conclusion: While previous research has suggested that preoperative beta blocker use could be prognostic of anastomotic leakage, this study could not detect any such association. On the contrary, our results indicate that preoperative beta blocker use neither predicts nor causes anastomotic leakage after anterior resection for rectal cancer.
35.	Golshani, P., et al. (author) The modified Glasgow Prognostic Score indicates an increased risk of anastomotic leakage after anterior resection for rectal cancer 2023 In: International Journal of Colorectal Disease. - : Springer. - 0179-1958 .- 1432-1262. ; 38:1 Journal article (peer-reviewed)abstract BackgroundPreoperative inflammation might cause and also be a marker for anastomotic leakage after anterior resection for rectal cancer. Available biomarker indices such as the modified Glasgow Prognostic Score (mGPS) or the C-reactive protein-to-albumin ratio (CAR) may be clinically useful for leakage assessment.MethodsPatients who underwent anterior resection for rectal cancer during 2014-2018 from a multicentre retrospective cohort were included. Data from the Swedish Colorectal Cancer registry and chart review at each hospital were collected. In a subset of patients, preoperative laboratory assessments were available, constituting the exposures mGPS and CAR. Anastomotic leakage within 12 months was the outcome. Causally oriented analyses were conducted with adjustment for confounding, as well as predictive models.ResultsA total of 418 patients were eligible for analysis. Most patients had mGPS = 0 (84.7%), while mGPS = 1 (10.8%) and mGPS = 2 (4.5%) were less common. mGPS = 2 (OR: 4.11; 95% CI: 1.69-10.03) seemed to confer anastomotic leakage, while this was not seen for mGPS = 1 (OR 1.09; 95% CI: 0.53-2.25). A cut off point of CAR > 0.36 might be indicative of leakage (OR 2.25; 95% CI: 1.21-4.19). Predictive modelling using mGPS rendered an area-under-the-curve of 0.73 (95% CI: 0.67-0.79) at most.DiscussionPreoperative inflammation seems to be involved in the development of anastomotic leakage after anterior resection for cancer. Inclusion into prediction models did not result in accurate leakage prediction, but high degrees of systemic inflammation might still be important in clinical decision-making.
36.	Grahn, Oskar, 1985- (author) Modulating the inflammatory response after colorectal cancer surgery : friend or foe? 2024 Doctoral thesis (other academic/artistic)abstract Colorectal cancer was the second most deadly and third most common cancer globally in 2020. In Sweden, more than 5,000 new colonic cancer cases and more than 2,000 rectalcancer cases were reported in 2021, making colorectal cancer the third most common in Sweden (excluding skin malignancies).Anastomotic leakage after colorectal cancer surgery is a feared complication that confers substantial morbidity, including a higher risk of permanent stoma and cardiovascular morbidity, but can also impart an increased risk of recurrence and mortality; the reason why leakage might cause this is not established. Perioperative inflammation including upregulation of cyclooxygenase-enzymes, which is further increased by anastomotic leakage, can possibly modulate both anastomotic healing as well as impact minimal residual disease. Non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibiting COX-enzymes and can be part of a postoperative multimodal analgesia protocol. However, their postoperative use has been debated, with fears of NSAIDs possibly increasing anastomotic leakage rates.Study I was a retrospective cohort study on 1,341 patients who had undergone anterior resection for rectal cancer. Exposure was at least two days with NSAIDs during the first postoperative week, and the primary outcome was recurrence-free survival. A Cox regression model could not demonstrate a significant association with a hazard ratio (HR) of 1.02 (95% confidence interval (CI): 0.79–1.33) and neither did a propensity score-matched analysis. An instrumental variable analysis displayed a tentative improvement in recurrence-free survival in the NSAID-exposed (HR 0.61; 95% CI 0.38–0.99), but the core assumptions to perform such an analysis were not fully satisfied.Study II was a protocol-based retrospective cohort study with a total of 6,945 patients resected for colorectal cancer with a primary anastomosis formed. NSAID-exposure was determined by each individual hospital’s postoperative analgesia protocol, while patient data and outcomes were retrieved from the Swedish colorectal cancer registry. Some 3,996 (58%) patients were treated at a hospital with NSAIDs included in their postoperative analgesia protocol. No significant association with recurrence-free survival was seen (HR 0.97, 95% CI0.87–1.09). However, a reduction in cancer recurrence was demonstrated (HR 0.83, 95% CI0.72‒0.95), with an increased risk reduction for locoregional (HR 0.68, 95% CI 0.48–0.97) in comparison to distant recurrence (HR 0.85, 95% CI 0.74–0.98). Anastomotic leakage was less frequent as well, mainly because of a reduction in the group with colorectal or ileorectal anastomoses (HR 0.47, 95% CI 0.33–0.68).In Study III, the aim was to explore proteomic and biological pathway alterations in patients with peritoneal infection. This was a 1:1 matched cohort study on patients resected for colorectal cancer with a primary anastomosis formed, including 32 cases who suffered a postoperative peritoneal infection matched with 32 controls with a complication-free postoperative stay. Serum samples were retrieved from their first postoperative visit and at one year postoperatively. Out of a total of 270 proteins tested, 77 were differentially expressed at the first postoperative visit at a median sampling time of 41 days after surgery. Many of the top hub proteins are known actors in colorectal cancer progression, including survival and invasiveness, potentially enhancing minimal residual disease. Over-represented pathways were related to cardiomyopathy, cell-adhesion, extracellular matrix, phosphatidylinositol-3-kinase/Akt (PI3K-Akt) and transforming growth factor beta (TGF-Beta) signalling.In Study IV, the aim was to evaluate the frequency of a known polymorphism of the COX-2 gene promotor -765G>C in a Swedish cohort of colorectal cancer patients, and whether a previously reported association between this gene variant with an increase in anastomotic leakage could be reproduced. This was a 1:1 matched case-control study on a total of 94 patients who were resected for colorectal cancer with a subsequent primary anastomosis, with cases suffering a peritoneal infection. Preoperative blood and serum samples were genotyped and analysed using pre-defined protein panels. Of the 94 patients in total, one in each group were homozygous for the minor allele C/C, and ten cases and 14 controls were heterozygous with G/C and the rest were homozygous for the major allele. Thus, there were fewer individuals with the minor allele in the case group, with a non-significant odds ratio of 0.71(p=0.413), ultimately not replicating the finding of the previous study. The protein quantitative trait loci analysis rendered no associations of interest.In conclusion, no statistically significant effects on recurrence-free survival from postoperative NSAIDs in patients resected for colorectal cancer could be demonstrated in study I, whereas significant associations between NSAID use and reduction in frequency of anastomotic leaks as well as cancer recurrence could be shown in study II. In study III, numerous proteins were differentially expressed in patients suffering a postoperative peritoneal infection, even after more than a month’s duration, potentially stimulating minimal residual disease. The over-representation analysis found pathways related to cardiomyopathy, which could help explain the increase in cardiovascular morbidity in patients suffering anastomotic leakage. Study IV could not reproduce the potentially marked increase in anastomotic leak frequency in carriers of the COX-2 gene promotor -765G>C polymorphism in a Swedish sample. Whether to include NSAIDs or not in postoperative multimodal analgesia is a question still not answered, and it may depend on the genotype, the patient’s preoperative inflammatory state, tumour location, the specific NSAID used, and whether a leak has already occurred. NSAIDs might have effects on both morbidity including cardiovascular and anastomotic leakage as well as minimal residual disease including recurrence and mortality. This thesis suggests potential protective effects regarding both anastomotic leakage as well as cancer recurrence, but it seems to depend on at least some of the aforementioned factors. The proteomic landscape regarding postoperative peritoneal infection has been investigated, and where it has also been demonstrated that the duration of said alterations can be greater than was earlier suspected. Finally, even if a replication attempt was not successful considering the relation between a COX-2 gene promotor polymorphism and anastomotic leakage, it could be worthwhile to attempt further replication studies.
37.	Grahn, Oskar, et al. (author) Mutation of the cyclooxygenase 2 gene promoter and anastomotic leakage in colorectal cancer patients : retrospective cohort study 2024 In: BJS Open. - : Oxford University Press. - 2474-9842. ; 8:1 Journal article (peer-reviewed)abstract Anastomotic leakage after surgery for colorectal cancer is a serious complication, causing an increased morbidity rate and mortality rate1,2.There is a debate and conflicting evidence on whether non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of leak3,4. NSAIDs act by inhibiting cyclooxygenase (COX) enzymes, which can be subdivided into isoenzymes COX-1 and COX-2. In a seminal study by Reisinger et al.5, knocking out the COX-2 gene resulted in an increase of colonic anastomotic leaks in mice. In a complementary cohort of colorectal cancer patients5, an increased frequency of anastomotic leaks was demonstrated among those homozygous for the COX-2 gene promoter mutation −765G > C (also known as rs20417). This finding could potentially be translated into clinical use following external validation.Biological effects might not only be present among those homozygous for the minor allele of −765C/C. For example, the heterozygous state of −765G/C has been associated with a decreased postoperative inflammatory response6.The present study aimed to evaluate the prevalence of the polymorphism 765G > C in a Swedish cohort of colorectal cancer patients, and its association with postoperative peritoneal infection.
38.	Grahn, Oskar, et al. (author) Peritoneal infection after colorectal cancer surgery induces substantial alterations in postoperative protein levels : an exploratory study Other publication (other academic/artistic)abstract Purpose: Peritoneal infection, due to anastomotic leakage, after resection for colorectal cancer have been shown to associate with increased cancer recurrence and mortality, as well as cardiovascsular morbidity. Alterations in circulating protein levels could help shed light on the underlying mechanisms, prompting this exploratory study of 64 patients operated for colorectal cancer with anastomosis.Methods: Thirty-two cases who suffered a postoperative peritoneal infection were matched with 32 controls who had a complication-free postoperative stay. Proteins in serum samples at their first postoperative visit and at one year after surgery were analysed using proximity extension assays and enzyme-linked immunosorbent assays. Multivariate projection methods, adjusted for multiple testing, were used to compare levels between groups, and enrichment and network analyses were performed.Results: Seventy-seven proteins, out of 270 tested, were differentially expressed at a median sampling time of 41 days after surgery. Many of the differentially expressed top hub proteins have known involvement in cancer progression, survival, invasiveness and metastasis. Over-represented pathways were related to cardiomyopathy, cell-adhesion, extracellular matrix, phosphatidylinositol-3-kinase/Akt (PI3K/Akt) and transforming growth factor beta (TGF-β) signaling.Conclusion: These affected proteins and pathways could provide clues as to why these patients might suffer increased cancer recurrence, mortality and cardiovascular morbidity.
39.	Grahn, Oskar, et al. (author) Postoperative non-steroidal anti-inflammatory drug use and oncological outcomes of rectal cancer 2021 In: BJS open. - : Oxford University Press (OUP). - 2474-9842. ; 5 Journal article (peer-reviewed)abstract Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are known to suppress the inflammatory response after surgery and are often used for pain control. This study aimed to investigate NSAID use after radical surgical resection for rectal cancer and long-term oncological outcomes. Methods: A cohort of patients who underwent anterior resection for rectal cancer between 2007 and 2013 in 15 hospitals in Sweden was investigated retrospectively. Data were obtained from the Swedish Colorectal Cancer Registry and medical records; follow-up was undertaken until July 2019. Patients who received NSAID treatment for at least 2 days after surgery were compared with controls who did not, and the primary outcome was recurrence-free survival. Cox regression modelling with confounder adjustment, propensity score matching, and an instrumental variables approach were used; missing data were handled by multiple imputation. Results: The cohort included 1341 patients, 362 (27.0 per cent) of whom received NSAIDs after operation. In analyses using conventional regression and propensity score matching, there was no significant association between postoperative NSAID use and recurrence-free survival (adjusted hazard ratio (HR) 1.02, 0.79 to 1.33). The instrumental variables approach, including individual hospital as the instrumental variable and clinicopathological variables as co-variables, suggested a potential improvement in the NSAID group (HR 0.61, 0.38 to 0.99). Conclusion: Conventional modelling did not demonstrate an association between postoperative NSAID use and recurrence-free survival in patients with rectal cancer, although an instrumental variables approach suggested a potential benefit.
40.	Greijdanus, Nynke G., et al. (author) Stoma-free survival after anastomotic leak following rectal cancer resection : worldwide cohort of 2470 patients 2023 In: British Journal of Surgery. - : Oxford University Press. - 0007-1323 .- 1365-2168. ; 110:12, s. 1863-1876 Journal article (peer-reviewed)abstract BACKGROUND: The optimal treatment of anastomotic leak after rectal cancer resection is unclear. This worldwide cohort study aimed to provide an overview of four treatment strategies applied.METHODS: Patients from 216 centres and 45 countries with anastomotic leak after rectal cancer resection between 2014 and 2018 were included. Treatment was categorized as salvage surgery, faecal diversion with passive or active (vacuum) drainage, and no primary/secondary faecal diversion. The primary outcome was 1-year stoma-free survival. In addition, passive and active drainage were compared using propensity score matching (2 : 1).RESULTS: Of 2470 evaluable patients, 388 (16.0 per cent) underwent salvage surgery, 1524 (62.0 per cent) passive drainage, 278 (11.0 per cent) active drainage, and 280 (11.0 per cent) had no faecal diversion. One-year stoma-free survival rates were 13.7, 48.3, 48.2, and 65.4 per cent respectively. Propensity score matching resulted in 556 patients with passive and 278 with active drainage. There was no statistically significant difference between these groups in 1-year stoma-free survival (OR 0.95, 95 per cent c.i. 0.66 to 1.33), with a risk difference of -1.1 (95 per cent c.i. -9.0 to 7.0) per cent. After active drainage, more patients required secondary salvage surgery (OR 2.32, 1.49 to 3.59), prolonged hospital admission (an additional 6 (95 per cent c.i. 2 to 10) days), and ICU admission (OR 1.41, 1.02 to 1.94). Mean duration of leak healing did not differ significantly (an additional 12 (-28 to 52) days).CONCLUSION: Primary salvage surgery or omission of faecal diversion likely correspond to the most severe and least severe leaks respectively. In patients with diverted leaks, stoma-free survival did not differ statistically between passive and active drainage, although the increased risk of secondary salvage surgery and ICU admission suggests residual confounding.
41.	Greijdanus, Nynke G., et al. (author) Stoma-free survival after rectal cancer resection with anastomotic leakage : development and validation of a prediction model in a large international cohort 2023 In: Annals of Surgery. - : Wolters Kluwer. - 0003-4932 .- 1528-1140. ; 278:5, s. 772-780 Journal article (peer-reviewed)abstract Objective: To develop and validate a prediction model (STOMA score) for 1-year stoma-free survival in patients with rectal cancer (RC) with anastomotic leakage (AL).Background: AL after RC resection often results in a permanent stoma.Methods: This international retrospective cohort study (TENTACLE-Rectum) encompassed 216 participating centres and included patients who developed AL after RC surgery between 2014 and 2018. Clinically relevant predictors for 1-year stoma-free survival were included in uni and multivariable logistic regression models. The STOMA score was developed and internally validated in a cohort of patients operated between 2014 and 2017, with subsequent temporal validation in a 2018 cohort. The discriminative power and calibration of the models' performance were evaluated.Results: This study included 2499 patients with AL, 1954 in the development cohort and 545 in the validation cohort. Baseline characteristics were comparable. One-year stoma-free survival was 45.0% in the development cohort and 43.7% in the validation cohort. The following predictors were included in the STOMA score: sex, age, American Society of Anestesiologist classification, body mass index, clinical M-disease, neoadjuvant therapy, abdominal and transanal approach, primary defunctioning stoma, multivisceral resection, clinical setting in which AL was diagnosed, postoperative day of AL diagnosis, abdominal contamination, anastomotic defect circumference, bowel wall ischemia, anastomotic fistula, retraction, and reactivation leakage. The STOMA score showed good discrimination and calibration (c-index: 0.71, 95% CI: 0.66-0.76).Conclusions: The STOMA score consists of 18 clinically relevant factors and estimates the individual risk for 1-year stoma-free survival in patients with AL after RC surgery, which may improve patient counseling and give guidance when analyzing the efficacy of different treatment strategies in future studies.
42.	Hemmingsson, Oskar, 1975-, et al. (author) Author response to: Excision and suture in the midline versus Karydakis flap surgery for pilonidal sinus: randomized clinical trial 2022 In: BJS Open. - : Oxford University Press. - 2474-9842. ; 6:4 Journal article (other academic/artistic)
43.	Hemmingsson, Oskar, 1975-, et al. (author) Excision and suture in the midline versus Karydakis flap surgery for pilonidal sinus : randomized clinical trial 2022 In: BJS Open. - : Oxford University Press. - 2474-9842. ; 6:2 Journal article (peer-reviewed)abstract BACKGROUND: There are several surgical options for the management of pilonidal disease, including midline and off midline closure, but prospective studies are rare. The study hypothesis was that Karydakis flap surgery would result in shorter wound healing and fewer recurrences than excision of pilonidal sinus and suture in the midline.METHODS: A randomized clinical trial was conducted in two hospitals in Sweden between 2006 and 2015 to compare excision and suture in the midline with Karydakis flap surgery. Adult patients with a chronic pilonidal sinus disease were randomized 1:1 at the outpatient clinic without blinding. Power calculation based on recurrence of 2 per cent for Karydakis flap and 10 per cent for excision and primary closure in the midline required 400 patients with 90 per cent statistical power at 5 per cent significance assuming 10 per cent loss during follow-up. Participants were followed up until complete wound healing; late follow-up after 6-13 years was performed by telephone by two blinded assessors. The two co-primary outcomes were time to complete wound healing and recurrence rate.RESULTS: The study was terminated early at a planned interim analysis due slow recruitment and a significant difference in primary outcome. In total, 125 patients were randomized, of whom 116 were available for the present analysis. Median wound healing time was 49 days (95 per cent confidence interval (c.i.) 32 to 66) for excision with suture in the midline and 14 days (95 per cent c.i. 12 to 20) for Karydakis flap surgery (P < 0.001). There were five recurrences in each group, after a median follow-up of 11 years (P = 0.753).CONCLUSION: Karydakis flap surgery for pilonidal sinus disease led to a shorter wound healing time than excision and suture in the midline but no difference in recurrence rates.Registration number: NCT00412659 (http://www.clinicaltrials.gov).
44.	Ielpo, B., et al. (author) Global attitudes in the management of acute appendicitis during COVID-19 pandemic : ACIE Appy Study 2020 In: British Journal of Surgery. - : John Wiley & Sons. - 0007-1323 .- 1365-2168. Journal article (peer-reviewed)abstract BACKGROUND: Surgical strategies are being adapted to face the COVID-19 pandemic. Recommendations on the management of acute appendicitis have been based on expert opinion, but very little evidence is available. This study addressed that dearth with a snapshot of worldwide approaches to appendicitis.METHODS: The Association of Italian Surgeons in Europe designed an online survey to assess the current attitude of surgeons globally regarding the management of patients with acute appendicitis during the pandemic. Questions were divided into baseline information, hospital organization and screening, personal protective equipment, management and surgical approach, and patient presentation before versus during the pandemic.RESULTS: Of 744 answers, 709 (from 66 countries) were complete and were included in the analysis. Most hospitals were treating both patients with and those without COVID. There was variation in screening indications and modality used, with chest X-ray plus molecular testing (PCR) being the commonest (19·8 per cent). Conservative management of complicated and uncomplicated appendicitis was used by 6·6 and 2·4 per cent respectively before, but 23·7 and 5·3 per cent, during the pandemic (both P < 0·001). One-third changed their approach from laparoscopic to open surgery owing to the popular (but evidence-lacking) advice from expert groups during the initial phase of the pandemic. No agreement on how to filter surgical smoke plume during laparoscopy was identified. There was an overall reduction in the number of patients admitted with appendicitis and one-third felt that patients who did present had more severe appendicitis than they usually observe.CONCLUSION: Conservative management of mild appendicitis has been possible during the pandemic. The fact that some surgeons switched to open appendicectomy may reflect the poor guidelines that emanated in the early phase of SARS-CoV-2.
45.	Jutesten, Henrik, et al. (author) High Risk of Low Anterior Resection Syndrome in Long-term Follow-up After Anastomotic Leakage in Anterior Resection for Rectal Cancer 2022 In: Diseases of the Colon and Rectum. - : Lippincott Williams & Wilkins. - 0012-3706 .- 1530-0358. ; 65:10, s. 1264-1273 Journal article (peer-reviewed)abstract BACKGROUND: Low anterior resection syndrome is common after sphincter-sparing surgery, but it is unclear to what extent anastomotic leakage after anterior resection contributes to this condition. OBJECTIVE: The aim of this study is to assess the long-term effect of anastomotic leakage on the occurrence of major low anterior resection syndrome. DESIGN: This is a retrospective observational cohort study evaluating low anterior resection syndrome 4 to 11 years after index surgery. After propensity score-matching using the covariates sex, age, tumor stage, comorbidity, neoadjuvant treatment, extent of mesorectal excision, and defunctioning stoma at index surgery, the effect of anastomotic leakage on low anterior resection syndrome was investigated using relative risk and 95% CI. SETTINGS: This multicenter study included patients from 15 Swedish hospitals between 2007 and 2013. PATIENTS: Patients who underwent anterior resection for rectal cancer were included. MAIN OUTCOME MEASURES: Outcome measures included patient-reported major low anterior resection syndrome, obtained via a postal questionnaire that included a question on stoma status. RESULTS: Among 1099 patients, 653 (59.4%) responded in at a median of 83.5 (interquartile range 66 to 110) months postoperatively. After excluding patients with residual stoma or incomplete responses, 544 remained; of these, 42 had anastomotic leakage. Patients with anastomotic leakage were more likely to have major low anterior resection syndrome (66.7% [28/42]) than patients without leakage (45.8% [230/502]). After matching, anastomotic leakage was significantly related to major low anterior resection syndrome (relative risk 2.3; 95% CI 1.4-3.9) and the individual symptom of urgency (relative risk 2.1; 95% CI 1.1-4.1). LIMITATIONS: This study was limited by its retrospective observational study design. CONCLUSIONS: In long-term follow-up, major low anterior resection syndrome is common after anterior resection for rectal cancer. Anastomotic leakage appears to increase the risk of major low anterior resection syndrome, with urgency as a major contributing symptom. See Video Abstract at http://links.lww.com/DCR/B868.
46.	Li, Xingru, et al. (author) A Detailed Flow Cytometric Analysis of Immune Activity Profiles in Molecular Subtypes of Colorectal Cancer 2020 In: Cancers. - : MDPI. - 2072-6694. ; 12:11 Journal article (peer-reviewed)abstract The local anti-tumour immune response has important prognostic value in colorectal cancer (CRC). In the era of immunotherapy, a better understanding of the immune response in molecular subgroups of CRC may lead to significant advances in personalised medicine. On this note, microsatellite instable (MSI) tumours have been characterised by increased immune infiltration, suggesting MSI as a marker for immune inhibitor checkpoint therapy. Here, we used flow cytometry to perform a comprehensive analysis of immune activity profiles in tumour tissues, adjacent non-malignant tissues and blood, from a cohort of 69 CRC patients. We found several signs of immune suppression in tumours compared to adjacent non-malignant tissues, including T cells more often expressing the immune checkpoint molecules programmed cell death protein (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). We further analysed immune cell infiltration in molecular subgroups of CRC. MSI tumours were indeed found to be associated with increased immune infiltration, including increased fractions of PD-1+ T cells. No correlation was, however, found between MSI and the fraction of CTLA-4+ T cells. Interestingly, within the group of patients with microsatellite stable (MSS) tumours, some also presented with increased immune infiltration, including comparably high portions of PD-1+ T cells, but also CTLA-4+ T cells. Furthermore, no correlation was found between PD-1+ and CTLA-4+ T cells, suggesting that different tumours may, to some extent, be regulated by different immune checkpoints. We further evaluated the distribution of immune activity profiles in the consensus molecular subtypes of CRC. In conclusion, our findings suggest that different immune checkpoint inhibitors may be beneficial for selected CRC patients irrespective of MSI status. Improved predictive tools are required to identify these patients.
47.	Lindmark, Gudrun, et al. (author) qRT-PCR analysis of CEACAM5, KLK6, SLC35D3, MUC2 and POSTN in colon cancer lymph nodes : An improved method for assessment of tumor stage and prognosis 2024 In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 154:3, s. 573-584 Journal article (peer-reviewed)abstract One fourth of colorectal cancer patients having curative surgery will relapse of which the majority will die. Lymph node (LN) metastasis is the single most important prognostic factor and a key factor when deciding on postoperative treatment. Presently, LN metastases are identified by histopathological examination, a subjective method analyzing only a small LN volume and giving no information on tumor aggressiveness. To better identify patients at risk of relapse we constructed a qRT-PCR test, ColoNode, that determines levels of CEACAM5, KLK6, SLC35D3, MUC2 and POSTN mRNAs. Combined these biomarkers estimate the tumor cell load and aggressiveness allocating patients to risk categories with low (0, −1), medium (1), high (2) and very high (3) risk of recurrence. Here we present result of a prospective, national multicenter study including 196 colon cancer patients from 8 hospitals. On average, 21 LNs/patient, totally 4698 LNs, were examined by both histopathology and ColoNode. At 3-year follow-up, 36 patients had died from colon cancer or lived with recurrence. ColoNode identified all patients that were identified by histopathology and in addition 9 patients who were undetected by histopathology. Thus, 25% of the patients who recurred were identified by ColoNode only. Multivariate Cox regression analysis proved ColoNode (1, 2, 3 vs 0, −1) as a highly significant risk factor with HR 4.24 [95% confidence interval, 1.42-12.69, P =.01], while pTN-stage (III vs I/II) lost its univariate significance. In conclusion, ColoNode surpassed histopathology by identifying a significantly larger number of patients with future relapse and will be a valuable tool for decisions on postoperative treatment.
48.	Lu, Sai San Moon, et al. (author) Antibiotics use up to 4.5 years before colorectal cancer surgery is associated with an elevated risk of surgical site infections, including anastomotic leakage, particularly in colon cancer : a Swedish nationwide study Other publication (other academic/artistic)
49.	Lu, Sai San Moon, et al. (author) Prediagnostic prescription antibiotics use and survival in patients with colorectal cancer : a swedish national register-based study 2023 In: Cancer Epidemiology, Biomarkers and Prevention. - : American Association For Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 32:10, s. 1391-1401 Journal article (peer-reviewed)abstract BACKGROUND: Antibiotics use is associated with higher colorectal cancer risk, but little is known regarding any potential effects on survival.METHODS: We conducted a nationwide cohort study, using complete-population data from Swedish national registers between 2005 and 2020, to investigate prediagnostic prescription antibiotics use in relation to survival in colorectal cancer patients.RESULTS: We identified 36,061 stage I-III and 11,242 stage IV colorectal cancer cases diagnosed between 2010 and 2019. For stage I-III, any antibiotics use (binary yes/no variable) was not associated with overall or cancer-specific survival. Compared with no use, moderate antibiotics use (total 11-60 days) was associated with slightly better cancer-specific survival [adjusted HR (aHR) = 0.93; 95% confidence interval (CI), 0.86-0.99)], whereas very high use (>180 days) was associated with worse survival [overall survival (OS) aHR = 1.42; 95% CI, 1.26-1.60, cancer-specific survival aHR = 1.31; 95% CI, 1.10-1.55]. In analyses by different antibiotic types, although not statistically significant, worse survival outcomes were generally observed across several antibiotics, particularly macrolides and/or lincosamides. In stage IV colorectal cancer, inverse relationships between antibiotics use and survival were noted.CONCLUSIONS: Overall, our findings do not support any substantial detrimental effects of prediagnostic prescription antibiotics use on cancer-specific survival after colorectal cancer diagnosis, with the possible exception of very high use in stage I-III colorectal cancer. Further investigation is warranted to confirm and understand these results.IMPACT: Although the study findings require confirmation, physicians probably do not need to factor in prediagnostic prescription antibiotics use in prognosticating patients with colorectal cancer.
50.	Murphy, Neil, et al. (author) A prospective evaluation of plasma polyphenol levels and colon cancer risk 2018 In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 143:7, s. 1620-1631 Journal article (peer-reviewed)abstract Polyphenols have been shown to exert biological activity in experimental models of colon cancer; however, human data linking specific polyphenols to colon cancer is limited. We assessed the relationship between pre-diagnostic plasma polyphenols and colon cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition study. Using high pressure liquid chromatography coupled to tandem mass spectrometry, we measured concentrations of 35 polyphenols in plasma from 809 incident colon cancer cases and 809 matched controls. We used multivariable adjusted conditional logistic regression models that included established colon cancer risk factors. The false discovery rate (qvalues ) was computed to control for multiple comparisons. All statistical tests were two-sided. After false discovery rate correction and in continuous log2 -transformed multivariable models, equol (odds ratio [OR] per log2 -value, 0.86, 95% confidence interval [95% CI] = 0.79-0.93; qvalue = 0.01) and homovanillic acid (OR per log2 -value, 1.46, 95% CI = 1.16-1.84; qvalue = 0.02) were associated with colon cancer risk. Comparing extreme fifths, equol concentrations were inversely associated with colon cancer risk (OR = 0.61, 95% CI = 0.41-0.91, ptrend = 0.003), while homovanillic acid concentrations were positively associated with colon cancer development (OR = 1.72, 95% CI = 1.17-2.53, ptrend < 0.0001). No heterogeneity for these associations was observed by sex and across other colon cancer risk factors. The remaining polyphenols were not associated with colon cancer risk. Higher equol concentrations were associated with lower risk, and higher homovanillic acid concentrations were associated with greater risk of colon cancer. These findings support a potential role for specific polyphenols in colon tumorigenesis.

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