Risk factors for anastomotic leakage in colonic procedures within an ERAS-protocol. A retrospective cohort study from the Swedish part of the international ERAS-database.

BACKGROUND: Research on anastomotic leakage (AL) in colonic procedures within an Enhanced Recovery After Surgery (ERAS) protocol has not yet been conducted. The aim of this study was to identify risk factors for AL after colonic surgery. METHODS: The study included all consecutively recorded patients operated with colonic resection surgery in the Swedish part of the international ERAS® Interactive Audit System (EIAS) between September 2009 and June 2022. The cohort was analyzed and evaluated regarding risk factors for AL. RESULTS: Altogether 10,632 patients were included, 10,219 were without AL and 413 (3.9%) were with AL. After adjusted analysis, male sex (4.6% AL), OR: 1.49; 95% CI (1.16-1.90), obesity (4.8% AL), OR: 1.62; 95% CI (1.18-2.24), previous surgery (4.4% AL), OR: 1.45; 95% CI (1.14-1.86), open surgery (4.4% AL), OR: 1.36; 95% CI (1.02-1.83), anastomosis between small bowel and rectum (13.1% AL), OR: 3.97; 95% CI (2.23-7.10), stapled anastomosis (5.3% AL), OR: 2.46; 95% CI (1.79-3.38), inhalation anesthesia (4.2% AL), OR: 1.80; 95% CI (1.26-2.57), and conversion to open surgery (5.5% AL), OR 1.49; 95% CI (1.02-2.19) were significant risk factors for AL. Although pre and intraoperative compliance to the ERAS-protocol was similar, excess of fluids day 0 was an independent predictor for AL. CONCLUSION: Male sex, obesity, previous surgery, open surgery, stapled anastomotic technique, anastomosis between small bowel and rectum, inhalation anesthesia, conversion to open surgery, and among ERAS interventions, excess of fluids day 0, were significant risk factors for AL.

A Randomized Controlled Clinical Trial of Transanal Irrigation Versus Conservative Treatment in Patients With Low Anterior Resection Syndrome After Rectal Cancer Surgery.

OBJECTIVE: The aim of the study was to evaluate transanal irrigation (TAI) as a treatment for low anterior resection syndrome (LARS). BACKGROUND: LARS is a bowel disorder that is common after sphincter preserving rectal cancer surgery. Despite symptomatic medical treatment of LARS many patients still experience bowel symptoms that may have a negative impact on quality of life (QoL). TAI is a treatment strategy, of which the clinical experience is promising but scientific evidence is limited. MATERIALS AND METHODS: A multicenter randomized trial comparing TAI (intervention) with conservative treatment (control) was performed. Inclusion criteria were major LARS, age above 18 years, low anterior resection with anastomosis and a defunctioning stoma as primary surgery, >6 months since stoma reversal, anastomosis without signs of leakage or stricture, and no signs of recurrence at 1-year follow-up. The primary endpoint was differences in bowel function at 12-month follow-up measured by LARS score, Cleveland Clinic Florida Fecal Incontinence Score, and 4 study-specific questions. The secondary outcome was QoL. RESULTS: A total of 45 patients were included, 22 in the TAI group and 23 in the control group. Follow-up was available for 16 and 22 patients, respectively. At 12 months, patients in the TAI group reported significantly lower LARS scores (22.9 vs 32.4; P =0.002) and Cleveland Clinic Florida Fecal Incontinence Score (6.4 vs 9.2; P =0.050). In addition, patients in the TAI group also scored significantly higher QoL [8 of 16 European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) QoL aspects] compared with the control group. CONCLUSIONS: The results confirm our clinical experience that TAI reduces symptoms included in LARS and improves QoL.

Endoscopic submucosal dissection for removal of large colorectal neoplasias in an outpatient setting: a single-center series of 660 procedures in Sweden.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is a technique developed in Japan for the removal of large lesions in the GI tract. Because of the complexity of the technique, implementation in Western health care has been slow. An ESD procedure is usually followed by hospital admission. Our aim was to investigate if ESD of colorectal lesions can be performed in an outpatient setting. METHODS: Six hundred sixty colorectal ESD procedures between 2014 and 2020 were evaluated retrospectively. All patients referred to the unit with an early colorectal neoplasm >20 mm without signs of deep invasion were considered eligible for an ESD procedure. RESULTS: Of 660 lesions, 323 (48.9%) were localized in the proximal colon, 102 (15.5%) in the distal colon, and 235 (35.6%) in the rectum. Median lesion size was 38 mm (interquartile range, 30-50) and median procedure duration 70 minutes (interquartile range, 45-115). En-bloc resection was achieved in 620 cases (93.9%). R0 resection was achieved in 492 en-bloc resections (79.4%), whereas the number of Rx and R1 resections was 124 (20.0%) and 4 (.6%), respectively. Low-grade dysplasia was found in 473 cases (71.7%), high-grade dysplasia in 144 (21.8%), and adenocarcinoma in 34 (5.1%). Six hundred twelve procedures (92.7%) were scheduled as outpatient, and 33 of these underwent unplanned admission. Forty-eight cases (7.3%) were planned as inpatient procedures. The rate of full wall perforation was 38 (5.8%), in which 35 (92.1%) were managed endoscopically and 3 patients (7.9%) required emergency surgery. Forty-six patients (7.0%) sought medical attention within 30 days because of bleeding (21 [3.2%]), abdominal tenderness (16 [2.4%]), and other reasons (9 [1.4%]). Twenty-four of these patients were admitted for observation for a median of 2 days (range, 1-7). Ten of these patients were treated with antibiotics, and 6 patients required blood transfusion. None required additional surgery. CONCLUSIONS: ESD of colorectal lesions can be safely performed in an outpatient setting in a well-selected patient.

Computed tomography diagnosed first time diverticulitis and colorectal cancer.

BACKGROUND: Computed tomography (CT) with intravenous contrast is the gold standard for diagnosing diverticulitis. Published results concerning follow-up colonoscopy after an episode of acute diverticulitis to rule out cancer are conflicting. This study aimed to evaluate the risk of underlying colonic malignancy in patients diagnosed with a first time diverticulitis with a state of the art CT investigation with intravenous contrast. METHODS: Retrospective analysis of all patients with a first episode of diverticulitis diagnosed with CT at Danderyds Hospital, Stockholm, between January 1, 2015, and November 16, 2016. Data on modified Hinchey classification, age, sex, laboratory parameters, body mass index, and colonoscopy findings were recorded. RESULTS: The study identified 518 patients with a CT-verified first time diverticulitis. Four hundred twenty-six (82%) of the 518 patients underwent follow-up colonoscopy and constitute our study cohort. CT showed that 402 patients had uncomplicated diverticulitis (modified Hinchey Ia), and 24 patients had complicated diverticulitis (modified Hinchey ≥Ib). Colonoscopy showed cancers in 2 (0.5%) of the 426 patients initially diagnosed as acute diverticulitis. In addition, 13 (3%) patients had advanced adenomas, and 121 (28%) patients had benign adenomas upon follow-up colonoscopy. Patients with CT-verified complicated diverticulitis (modified Hinchey ≥Ib) had a significantly higher risk for colon cancer compared with patients with an uncomplicated first time diverticulitis. CONCLUSION: Our study supports routine follow-up colonoscopy after a first episode of CT-diagnosed complicated diverticulitis. In contrast, we do not find an increased risk for neoplasia in patients with uncomplicated diverticulitis.

Long-Term Results after Anastomotic Leakage following Rectal Cancer Surgery: A Comparison of Treatment with Endo-Sponge and Transanal Irrigation.

OBJECTIVE: We aimed to evaluate long-term results in patients from regular health care treated with endoscopic transanal closure system, that is, endoscopic vacuum-assisted closure system (EVAC) compared to transanal irrigation. METHODS: In this retrospective, medical chart-based, observational study, we included patients with anastomotic leakage after low anterior resection for rectal cancer from 3 Stockholm hospitals 2006-2016 and compared time to first stoma closure in a Kaplan-Meier model and the proportion of patients who were stoma-free at end of follow-up. RESULTS: Anastomotic leakage was found in 81 patients who were followed up in median 5.9 years (min-max: 0.53-13). EVAC was used on 14 (17%) patients and transanal irrigation on 34 (42%) patients. The remaining 33 (41%) patients either got a permanent colostomy or were treated only with antibiotics and percutaneous drainage. Treatment with EVAC or transanal irrigation led to similar rates of stoma closure, both when comparing all patients, and when comparing patients with similar defects. At the end of follow-up, 43% of patients treated with EVAC and 50% of patients treated with repeated irrigation were stoma-free (p = 0.75). CONCLUSIONS: We found no evidence of better outcomes in patients treated with EVAC. The study was, however, limited by small sample size.

Colorectal ESD in day surgery.

BACKGROUND: Colorectal endoscopic submucosal dissection (ESD) was developed in Japan and is growing in popularity in Europe. Patients undergoing a colorectal ESD procedure in Japan are hospitalized for several days. In this study, we investigated the feasibility of colorectal ESD as an outpatient procedure in a European setting. METHODS: A prospective cohort of all patients undergoing colorectal ESD at Danderyds Hospital, Stockholm, Sweden from April 2014 to December 2015 were studied. Data on patient demographics, procedural outcome and 30-day readmissions were studied. Data are presented as median (range), mean ± SD or true numbers as appropriate. RESULTS: A total of 182 patients underwent a colorectal ESD during the study period. Of the 182 these, 11 were scheduled for an in-hospital procedure and of 171 patients scheduled for a day-procedure and 15 were admitted for observation. The remaining 156 patients were discharged after 2-4 h of observation and comprise the study cohort. Mean age was 69 years. Median lesion size was 28 (10-120) mm, and median resection time was 65 (10-360) min. Lesions were located as follows: anal canal 1 (0.6%), rectum 52 (33.3%), sigmoid 17 (10.9%), descending 3 (1.9%), transverse 24 (15.4%), ascending 29 (18.6%), and cecum 30 (19.2%). Eight (5.1%) of the 156 day surgery patients returned for medical attention during the postoperative 30-day period. Three of them were admitted for in-hospital observation. None of the day surgery patients required any surgical intervention. CONCLUSION: Uncomplicated colorectal ESD can safely be carried out in a day surgery setting.

Emergency management with resection versus proximal stoma or stent treatment and planned resection in malignant left-sided colon obstruction.

BACKGROUND: Emergency surgery for colon cancer, as a result of obstruction, has been vitiated by a high frequency of complications and poor survival. The concept of "bridge to surgery" includes either placement of self-expanding metallic stents (SEMS) or diverting stoma of an obstructing tumour and subsequent planned resection. The aim of this study was to compare acute resection with stoma or stent and later resection regarding surgical and oncological outcomes and total hospital stay. METHODS: This is a retrospective cohort study. All 2424 patients diagnosed with colorectal cancer during 1997-2013 were reviewed. All whom underwent acute surgery with curative intention for left-sided malignant obstruction were included in the study. RESULTS: One hundred patients fulfilled the inclusion criteria. Among them, 57 patients were treated with acute resection and 43 with planned resection after either acute diverting colostomy (n = 23) or stent placement (n = 20). The number of harvested lymph nodes in the resected specimen was higher in the planned resection group compared with acute resection group (21 vs. 8.7; p = 0.001). Fewer patients were treated with adjuvant chemotherapy in the acute resection group than in the stoma group (14 % (8/57 patients) vs. 43 %, (10/23 patients; p = 0.024)). Patients operated with acute resection had a higher 30-day mortality rate and were more frequently left with a permanent stoma. CONCLUSIONS: Decompression of emergency obstructive left colon cancer with stent or stoma and subsequent curative resection appears safer and results in a higher yield of lymph node harvest, and fewer patients are left with a permanent stoma.

The thioredoxin and glutaredoxin systems in smoking cessation and the possible relation to postoperative wound complications .

UNLABELLED:  Background. Smoking cessation prior to surgery has proven to be an effective means of reducing wound complications. The underlying mechanisms are poorly characterized. The present study is the first to investigate how short-term smoking cessation affects the thioredoxin and glutaredoxin systems. METHODS: A total of 21 daily smokers scheduled for surgery were enrolled and randomized to smoking cessation intervention or control group. The main outcome measure was changes in plasma levels of thioredoxin (Trx) and glutaredoxin (Grx) following smoking cessation. Secondary outcomes were changes in plasma levels of TNF-a, IL-1b, and IL-6. RESULTS: Glutaredoxin levels in plasma increased after smoking cessation. The mean Grx difference between sample 2 and sample 1 among abstainers was 11.4 ng/mL; among smokers it was 0.6 ng/mL (P = 0.05). Among those with a postoperative complication there was a slight decrease (-0.9 ng/mL in mean) in glutaredoxin, which was not statistically significant (P = 0.27). A change in thioredoxin levels in plasma after smoking cessation was not evident. Changes in cytokine levels before and after smoking cessation were not significant. CONCLUSION: Short-term smoking cessation seems to increase plasma levels of Grx. The Trx system seems to be more robust against smoking toxicity. Fewer wound complications occurred in the smoking cessation group and glutaredoxin might be involved in the underlying mechanism .

Requirements for the different cysteines in the chemotactic and desensitizing activity of human thioredoxin.

Thioredoxin (Trx) is a protein disulfide oxidoreductase that can be secreted and act as a chemoattractant for leukocytes. Like chemokines, it causes desensitization of monocytes against its chemotactic activity and that of monocyte chemoattractant protein-1 (MCP-1). To investigate the role of the redox properties of Trx, and particularly of some of its five cysteines, in its chemotactic and desensitizing action, we tested different mutants, including Trx80, a truncated form, and various mutants lacking specific cysteines: Trx C62S/C73S and the redox-inactive mutant Trx C32S/C35S. Of the mutants, only Trx80 maintained the chemotactic activity of wild-type Trx toward both monocytes and polymorphonuclear neutrophils, all of them desensitized monocytes against wild-type Trx or MCP-1, but not chemotactic peptide formyl-methionyl-leucil peptide. These data indicate that different redox-active cysteines are important for Trx chemotactic action, whereas its desensitizing action does not have these requirements, suggesting a redox-independent mechanism.

Truncated thioredoxin (Trx80) exerts unique mitogenic cytokine effects via a mechanism independent of thiol oxido-reductase activity.

Recently we discovered that a naturally occurring C-terminally truncated thioredoxin (Trx80) is a potent mitogenic cytokine stimulating IL-12 production from CD40(+) monocytes. To further characterise Trx80 we have engineered cysteine to serine mutants of Trx80 corresponding to the active site cysteines of Trx (Trx80SGPS) and to the structural cysteine at position 72 (Trx80C72S). Trx80SGPS and Trx80C72S retained the cell stimulatory activity of Trx80 and increased peripheral blood mononuclear cell (PBMC) proliferation three- to five-fold in vitro (P<0.01, n=18). Both Trx80SGPS and Trx80C72S significantly stimulated IL-12 and IFN-gamma secretion from PBMCs in the same manner as Trx80 (P<0.01, n=9 and 10). The previously described Trx80 dimer is caused by non-covalent interactions, and not by any intermolecular disulphide bonds.

Truncated thioredoxin: physiological functions and mechanism.

Human cytosolic thioredoxin (Trx), which is the 12-kDa protein disulfide reductase with the Cys-Gly-Pro-Cys active site and a key component of cellular redox biochemistry and regulation, acts as cocytokine upon leaderless secretion. A 10-kDa C-terminally truncated thioredoxin (Trx80) comprising the 80 or 84 N-terminal amino acids is also secreted and present in plasma, where it originally was purified and identified as eosinophilic cytotoxicity enhancing factor. Recombinant Trx80 was discovered to be a potent mitogenic cytokine that stimulates growth of resting human peripheral blood mononuclear cells (PBMC) in a synthetic medium, an effect that Trx lacks. Trx80 is very different from Trx because it is a dimer lacking reductase activity and the cytokine activity is not dependent on the Cys residues of the Trx active-site motif. The primary targets of Trx80 in PBMC are monocytes that are activated to proliferate and increase expression of CD14, CD40, CD54, and CD86. Trx80 induces secretion of interleukin (IL)-12 in CD40+ monocytes from PBMC. Trx80 and IL-2 together were strongly synergistic to induce secretion of interferon-gamma in PBMC. Trx80 is a potent cytokine for monocytes directing the immune system to a Th1 response via IL-12 production.

Truncated thioredoxin (Trx80) induces differentiation of human CD14+ monocytes into a novel cell type (TAMs) via activation of the MAP kinases p38, ERK, and JNK.

Thioredoxin truncated at its carboxy terminal (Trx80) acts as a cytokine that stimulates monocytes and eosinophils. In the present study, Trx80 was shown to induce differentiation of human CD14(+) monocytes into a cell type not described previously, which we designate as Trx80-activated monocytes (TAMs). TAMs resemble immature dendritic cells (iDCs) generated in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) in that both these cell populations exhibit increased proportions of CD1a(+) and mannose receptor (MR)(+) cells. However, in contrast to iDCs, TAMs express high proportion of CD14 and lower proportion of CD83 and HLA-DR. Functional assays revealed that, in comparison to iDCs, TAMs 1) exhibit a higher pinocytic capacity; 2) release significantly higher amounts of the proinflammatory cytokines tumor necrosis factor-alpha (TNF alpha), IL-1 beta, and IL-6 and of the anti-inflammatory cytokine IL-10; and 3) induce a significantly lower proliferative response in allogeneic peripheral blood mononuclear cells (PBMCs). Indeed, Trx80 appears to be the first endogenous substance shown to have the capacity on its own to induce IL-10 production by monocytes. Analysis of the mitogen-activated protein (MAP) kinase signaling pathway revealed that Trx80 induces phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). We propose that Trx80 is an early signal in response to danger, and that TAMs may play a major role in triggering innate immune responses.