The genomics of sporadic and hereditary colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Over the past three decades, extensive efforts have sought to elucidate the genomic landscape of CRC. These studies reveal that CRC is highly heterogeneous at the molecular level, with different subtypes characterised by distinct somatic mutational profiles, epigenetic aberrations and transcriptomic signatures. This review summarises our current understanding of the genomic and epigenomic alterations implicated in CRC development and progression. Particular focus is given to how characterisation of CRC genomes is leading to more personalised approaches to diagnosis and treatment.

Operative blood loss adversely affects short and long-term outcomes after colorectal cancer surgery: results of a systematic review and meta-analysis.

BACKGROUND: The aim of this meta-analysis was to assess the impact of operative blood loss on short and long-term outcomes following colorectal cancer surgery. METHODS: A systematic literature review and meta-analysis were performed, from inception to the 10th of August 2020. A comprehensive literature search was performed on the 10th of August 2020 of PubMed MEDLINE, Embase, Science Citation Index Expanded, and Cochrane Central Register of Controlled Trials. Only studies reporting on operative blood loss and postoperative short term or long-term outcomes in colorectal cancer surgery were considered for inclusion. RESULTS: Forty-three studies were included, reporting on 59,813 patients. Increased operative blood loss was associated with higher morbidity, for blood loss greater than 150-350 ml (odds ratio [OR] 2.09, p < 0.001) and > 500 ml (OR 2.29, p = 0.007). Anastomotic leak occurred more frequently for blood loss above a range of 50-100 ml (OR 1.14, p = 0.007), 250-300 ml (OR 2.06, p < 0.001), and 400-500 ml (OR 3.15, p < 0.001). Postoperative ileus rate was higher for blood loss > 100-200 ml (OR 1.90, p = 0.02). Surgical site infections were more frequent above 200-500 ml (OR 1.96, p = 0.04). Hospital stay was increased for blood loss > 150-200 ml (OR 1.63, p = 0.04). Operative blood loss was significantly higher in patients that suffered morbidity (mean difference [MD] 133.16 ml, p < 0.001) or anastomotic leak (MD 69.56 ml, p = 0.02). In the long term, increased operative blood loss was associated with worse overall survival above a range of 200-500 ml (hazard ratio [HR] 1.15, p < 0.001), and worse recurrence-free survival above 200-400 ml (HR 1.33, p = 0.01). Increased blood loss was associated with small bowel obstruction caused by colorectal cancer recurrence for blood loss higher than 400 ml (HR 1.97, p = 0.03) and 800 ml (HR 3.78, p = 0.02). CONCLUSIONS: Increased operative blood loss may adversely impact short term and long-term postoperative outcomes. Measures should be taken to minimize operative blood loss during colorectal cancer surgery. Due to the uncertainty of evidence identified, further research, with standardised methodology, is required on this important subject.

A systematic review and network meta-analysis comparing energy devices used in colorectal surgery.

BACKGROUND: The aim of this study was to compare energy devices used for intraoperative hemostasis during colorectal surgery. METHODS: A systematic literature review and Bayesian network meta-analysis performed. MEDLINE, EMBASE, Science Citation Index Expanded, and Cochrane were searched from inception to August 11th 2021. Intraoperative outcomes were operative blood loss, operative time, conversion to open, conversion to another energy source. Postoperative outcomes were mortality, overall complications, minor complications and major complications, wound complications, postoperative ileus, anastomotic leak, time to first defecation, day 1 and 3 drainage volume, duration of hospital stay. RESULTS: Seven randomized controlled trials (RCTs) were included, reporting on 680 participants, comparing conventional hemostasis, LigaSure™, Thunderbeat® and Harmonic®. Harmonic® had fewer overall complications compared to conventional hemostasis. Operative blood loss was less with LigaSure™ (mean difference [MD] = 24.1 ml; 95% confidence interval [CI] - 46.54 to - 1.58 ml) or Harmonic® (MD = 24.6 ml; 95% CI - 42.4 to - 6.7 ml) compared to conventional techniques. Conventional hemostasis ranked worst for operative blood loss with high probability (p = 0.98). LigaSure™, Harmonic® or Thunderbeat® resulted in a significantly shorter mean operative time by 42.8 min (95% CI - 53.9 to - 31.5 min), 28.3 min (95% CI - 33.6 to - 22.6 min) and 26.1 min (95% CI - 46 to - 6 min), respectively compared to conventional electrosurgery. LigaSure™ resulted in a significantly shorter mean operative time than Harmonic® by 14.5 min (95% CI 1.9-27 min) and ranked first for operative time with high probability (p = 0.97). LigaSure™ and Harmonic® resulted in a significantly shorter mean duration of hospital stay compared to conventional electrosurgery of 1.3 days (95% CI - 2.2 to - 0.4) and 0.5 days (95% CI - 1 to - 0.1), respectively. LigaSure™ ranked as best for hospital stay with high probability (p = 0.97). Conventional hemostasis was associated with more wound complications than Harmonic® (odds ratio [OR] = 0.27; CI 0.08-0.92). Harmonic® ranked best with highest probability (p = 0.99) for wound complications. No significant differences between energy devices were identified for the remaining outcomes. CONCLUSIONS: LigaSure™, Thunderbeat® and Harmonic® may be advantageous for reducing operative blood loss, operative time, overall complications, wound complications, and duration of hospital stay compared to conventional techniques. The energy devices result in comparable perioperative outcomes and no device is superior overall. However, included RCTs were limited in number and size, and data were not available to compare all energy devices for all outcomes of interest.

Right hemicolectomy with complete mesocolic excision is safe, leads to an increased lymph node yield and to increased survival: results of a systematic review and meta-analysis.

BACKGROUND: The introduction of complete mesocolic excision (CME) for right colon cancer has raised an important discussion in relation to the extent of colic and mesenteric resection, and the impact this may have on lymph node yield. As uncertainty remains regarding the usefulness of and indications for right hemicolectomy with CME and the benefits of CME compared with a traditional approach, the purpose of this meta-analysis is to compare the two procedures in terms of safety, lymph node yield and oncological outcome. METHODS: We performed a systematic review of the literature from 2009 up to March 15th, 2020 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two hundred eighty-one publications were evaluated, and 17 met the inclusion criteria and were included. Primary endpoints analysed were anastomotic leak rate, blood loss, number of harvested lymph nodes, 3- and 5-year oncologic outcomes. Secondary outcomes were operating time, conversion, intraoperative complications, reoperation rate, overall and Clavien-Dindo grade 3-4 postoperative complications. RESULTS: In terms of safety, right hemicolectomy with CME is not inferior to the standard procedure when comparing rates of anastomotic leak (RR 0.82, 95% CI 0.38-1.79), blood loss (MD -32.48, 95% CI -98.54 to -33.58), overall postoperative complications (RR 0.82, 95% CI 0.67-1.00), Clavien-Dindo grade III-IV postoperative complications (RR 1.36, 95% CI 0.82-2.28) and reoperation rate (RR 0.65, 95% CI 0.26-1.75). Traditional surgery is associated with a shorter operating time (MD 16.43, 95% CI 4.27-28.60) and lower conversion from laparoscopic to open approach (RR 1.72, 95% CI 1.00-2.96). In terms of oncologic outcomes, right hemicolectomy with CME leads to a higher lymph node yield than traditional surgery (MD 7.05, 95% CI 4.06-10.04). Results of statistical analysis comparing 3-year overall survival and 5-year disease-free survival were better in the CME group, RR 0.42, 95% CI 0.27-0.66 and RR 0.36, 95% CI 0.17-0.56, respectively. CONCLUSIONS: Right hemicolectomy with CME is not inferior to traditional surgery in terms of safety and has a greater lymph node yield when compared with traditional surgery. Moreover, right-sided CME is associated with better overall and disease-free survival.

Appraisal of the current guidelines for the management of diverticular disease using the Appraisal of Guidelines Research and Evaluation II (AGREE II) instrument.

INTRODUCTION: Diverticular disease is one of the most frequent reasons for attending emergency departments and surgical causes of hospital admission. In the past decade, many surgical and gastroenterological societies have published guidelines for the management of diverticular disease. The aim of the present study was to appraise the methodological quality of these guidelines using the Appraisal of Guidelines Research and Evaluation II (AGREE II) tool. METHODS: PubMed, Embase, Cochrane Library and Google Scholar databases were searched systematically. The methodological quality of the guidelines was appraised independently by five appraisers using the AGREE II instrument. FINDINGS: A systematic search of the literature identified 12 guidelines. The median overall score of all guidelines was 68%. Across all guidelines, the highest score of 85% was demonstrated in the domain 'Scope and purpose'. The domains 'Clarity and presentation' and 'Editorial independence' both scored a median of 72%. The lowest scores were demonstrated in the domains 'Stakeholder involvement' and 'Applicability' at 46% and 40%, respectively. Overall, the National Institute for Health and Care Excellence (NICE) guidelines performed consistently well, scoring 100% in five of six domains; NICE was one of the few guidelines that specifically reported stakeholder involvement, scoring 97%. Generally, the domain of 'Stakeholder involvement' ranked poorly with seven of twelve guidelines scoring below 50%, with the worst score in this domain demonstrated by Danish guidelines at 25%. CONCLUSION: Six of twelve guidelines (NICE, American Society of Colon & Rectal Surgeons (ASCRS), European Society of Coloproctology (ESCP), American Gastroenterological Association, German Society of Gastroenterology/German Society for General and Visceral Surgery (German), Netherlands Society of Surgery) scored above 70%. Only three, NICE, ASCRS and ESCP, scored above 75% and were voted unanimously by the appraisers for use as they are. Therefore, use of AGREE II may help improve the methodological quality of guidelines and their future updates.

A single centre evaluation of risk prediction models and imaging modalities in acute appendicitis.

INTRODUCTION: Patients with suspected appendicitis remain a diagnostic challenge. The aim of this study was to validate risk prediction models, and to investigate diagnostic accuracy of ultrasonography and computed tomography (CT) in adults undergoing appendicectomy. METHODS: A retrospective case review was performed of patients aged 16-45 years having an appendicectomy between January 2019 and January 2020 at a tertiary referral centre. Primary outcomes were the accuracy of a high risk appendicitis risk score and ultrasonography and CT imaging modalities compared with histological reports following appendicectomy. RESULTS: A total of 206 patients (52% female) were included in the study. Removal of a histologically normal appendix was equally likely in men and women (13.1% vs 11.2% respectively, relative risk: 1.17, 95% confidence interval: 0.56-2.44, p=0.674). A high risk appendicitis score correctly identified 84.0% (79/94) of cases in men and 85.9% (67/78) of cases in women. Ultrasonography was reported as equivocal in 85.7% (18/21) of low risk women and 59.0% (23/39) of high risk women. CT correctly detected or excluded appendicitis in 75.0% (6/8) of low risk women and 88.5% (23/26) of high risk women. CONCLUSIONS: This study suggests that risk prediction models may be useful in both women and men to identify appendicitis. Ultrasonography gave high rates of equivocal results and should not be relied on for the diagnosis of appendicitis. CT is a highly accurate diagnostic tool and could be considered in those at low risk where clinical suspicion remains to reduce negative appendicectomy rates.

A dynamic baseline for dissolved methane in English groundwater.

Elevated dissolved methane (CH4) concentrations in groundwater are an environmental concern associated with hydraulic fracturing for shale gas. Therefore, determining dissolved CH4 baselines is important for detecting and understanding any potential environmental impacts. Such baselines should change in time and space to reflect ongoing environmental change and should be able to predict the probability that a change in dissolved CH4 concentration has occurred. We considered four dissolved CH4 concentration datasets of English groundwater using a Bayesian approach: two national datasets and two local datasets from shale gas exploration sites. The most sensitive national dataset (the previously published British Geological Survey CH4 baseline) was used as a strong prior for a larger (2153 measurements compared to 439) but less sensitive (detection limit 1000 times higher) Environment Agency dataset. The use of the strong prior over a weak prior improved the precision of the Environment Agency dataset by 75%. The expected mean dissolved CH4 concentration in English groundwater based on the Bayesian approach is 0.24 mg/l, with a 95% credible interval of 0.11 to 0.45 mg/l, and a Weibull distribution of W(0.35 ± 0.01, 0.34 ± 0.16). This result indicates the amount of CH4 degassing from English groundwater to the atmosphere equates to between 0.7 and 3.1 kt CH4/year, with an expected value of 1.65 kt CH4/year and a greenhouse gas warming potential of 40.3 kt CO2eq/year. The two local monitoring datasets from shale gas exploration sites, in combination with the national datasets, show that dissolved CH4 concentrations in English groundwater are generally low, but locations with concentrations greater than or equal to the widely used risk action level of 10.0 mg/l do exist. Statistical analyses of groundwater redox conditions at these locations suggest that it may be possible to identify other locations with dissolved CH4 concentrations ≥10.0 mg/l using redox parameters such as Fe concentration.

Total extraperitoneal endoscopic hernioplasty (TEP) versus Lichtenstein hernioplasty: a systematic review by updated traditional and cumulative meta-analysis of randomised-controlled trials.

BACKGROUND-PURPOSE: Totally extraperitoneal (TEP) endoscopic hernioplasty and Lichtenstein hernioplasty are the most commonly used approaches for inguinal hernia repair. However, current evidence on which is the preferred approach is inconclusive. This updated meta-analysis was conducted to track the accumulation of evidence over time. METHODS: Studies were identified by a systematic literature search of the EMBASE, PubMed, Cochrane Library, and Google Scholar databases. Fixed- and random-effects models were used to cumulatively assess the accumulation of evidence over time. RESULTS: The TEP cohort showed significantly higher rates of recurrences and vascular injuries compared to the Lichtenstein cohort; [Peto Odds ratio (OR) = 1.58 (1.22, 2.04), p = 0.005], [Peto OR = 2.49 (1.05, 5.88), p = 0.04], respectively. In contrast, haematoma formation rate, time to return to usual activities, and local paraesthesia were significantly lower in the TEP cohort compared to the Lichtenstein cohort; [Peto OR = 0.26 (0.16, 0.41), p ≤ 0.001], [mean difference = - 6.32 (- 8.17, - 4.48), p ≤ 0.001], [Peto OR = 0.26 (0.17, 0.40), p ≤ 0.001], respectively. CONCLUSIONS: This study, which is based on randomised-controlled trials (RCTs) of high quality, showed significantly higher rates of recurrences and vascular injuries in the TEP cohort than in the Lichtenstein cohort. In contrast, rate of postoperative haematoma formation, local paraesthesia, and time to return to usual activities were significantly lower in the TEP cohort than in the Lichtenstein cohort. Future multicentre RCTs with strict adherence to the standards recommended in the Consolidated Standards of Reporting Trials guidelines will shed further light on the topic.

Sigmoid resection for diverticular disease - to ligate or to preserve the inferior mesenteric artery? Results of a systematic review and meta-analysis.

AIM: In colorectal cancer, ligation of the inferior mesenteric artery (IMA) is a standard surgical approach. In contrast, ligation of the IMA is not mandatory during treatment of diverticular disease. The object of this meta-analysis was to assess if preservation of the IMA reduces the risk of anastomotic leakage. METHOD: A search was performed up to August 2018 using the following electronic databases: MEDLINE/PubMed, ISI Web of Knowledge and Scopus. The measures of treatment effect utilized risk ratios for dichotomous variables with calculation of the 95% CI. Data analysis was performed using the meta-analysis software Review Manager 5.3. RESULTS: Eight studies met the inclusion criteria and were included in the meta-analysis: two randomized controlled trials (RCTs) and six non-RCTs with 2190 patients (IMA preservation 1353, ligation 837). The rate of anastomotic leakage was higher in the IMA ligation group (6%) than the IMA preservation group (2.4%), but this difference was not statistically significant [risk ratio (RR) 0.59, 95% CI 0.26-1.33, I2  = 55%]. The conversion to laparotomy was significantly lower in the IMA ligation group (5.1%) than in the IMA preservation group (9%) (RR 1.74, 95% CI 1.14-2.65, I2  = 0%). Regarding the other outcomes (anastomotic bleeding, bowel injury and splenic damage), no significant differences between the two techniques were observed. CONCLUSION: This meta-analysis failed to demonstrate a statistically significant difference in the anastomotic leakage rate when comparing IMA preservation with IMA ligation. Thus, to date there is insufficient evidence to recommend the IMA-preserving technique as mandatory in resection for left-sided colonic diverticular disease.