Systematic Review and Meta-analysis: The Three-year Post-colonoscopy Colorectal Cancer Rate as per the World Endoscopy Organization Methodology.

BACKGROUND & AIMS: In 2018, the World Endoscopy Organization (WEO) introduced standardized methods for calculating post-colonoscopy colorectal cancer-3yr rates (PCCRC-3yr). This systematic review aimed to calculate the global PCCRC-3yr according to the WEO methodology, its change over time, and to measure the association between risk factors and PCCRC occurrences. METHODS: We searched 5 databases from inception until January 2024 for PCCRC-3yr studies that strictly adhered to the WEO methodology. The overall pooled PCCRC-3yr was calculated. For risk factors and time-trend analyses, the pooled PCCRC-3yr and odds ratios (ORs) of subgroups were compared. RESULTS: Several studies failed to adhere to the WEO methodology. Eight studies from 4 Western European and 2 Northern American countries were included, totalling 220,106 detected-colorectal cancers (CRCs) and 18,148 PCCRCs between 2002 and 2017. The pooled Western World PCCRC-3yr was 7.5% (95% confidence interval [CI], 6.4%-8.7%). The PCCRC-3yr significantly (P < .05) decreased from 7.9% (95% CI, 6.6%-9.4%) in 2006 to 6.7% (95% CI, 6.1%-7.3%) in 2012 (OR, 0.79; 95% CI, 0.72-0.87). There were significantly higher rates for people with inflammatory bowel disease (PCCRC-3yr, 29.3%; OR, 6.17; 95% CI, 4.73-8.06), prior CRC (PCCRC-3yr, 29.8%; OR, 3.03; 95% CI, 1.34-4.72), proximal CRC (PCCRC-3yr, 8.6%; OR, 1.51; 95% CI, 1.41-1.61), diverticular disease (PCCRC 3-yr, 11.6%; OR, 1.74; 95% CI, 1.37-2.10), and female sex (PCCRC-3yr, 7.9%; OR, 1.15; 95% CI, 1.11-1.20). CONCLUSION: According to the WEO methodology, the Western World PCCRC-3yr was 7.5%. Reassuringly, this has decreased over time, but further work is required to identify the reasons for PCCRCs, especially in higher-risk groups. We devised a WEO methodology checklist to increase its adoption and standardise the categorization of patients in future PCCRC-3yr studies.

Application of Duty of Candour legislation in post-colonoscopy colorectal cancer: a prospective cohort study.

Background & Study Aims The study investigates the application of Duty of Candour (DoC) legislation in the context of post-colonoscopy colorectal cancers (PCCRCs). DoC mandates transparent disclosure of notifiable safety incidents to patients in the English National Health Service, including those leading to severe or moderate harm. This study aims to analyse the application of DoC in PCCRCs, improve understanding of the legislation and identify challenges in its implementation. Patients & Methods A national audit of PCCRCs was conducted between September 2021 to May 2022. PCCRCs were identified using linked administrative datasets and root-cause analyses were performed using a structured template. 1,724 PCCRCs were included. 'Avoidability' and harm categorised into specific levels, with guidance provided to improve consistency in judgments. Results 16% of PCCRCs resulted in major harm or death, of which 27%(75) were at least probably avoidable. Hospitals deemed DoC discharge necessary in only 53% of these cases. When including moderate harm, 11% of all PCCRCs would trigger DoC discharge, yet this was deemed necessary in only 41% of these cases. Conclusions There is inconsistent application of DoC in PCCRC cases. Challenges include determining 'avoidability' and harm, particularly when there is a delay in diagnosis. Clearer guidance and definitions of harm are needed to improve adherence to regulations.

Inflammatory Bowel Disease-Associated Colorectal Cancer Epidemiology and Outcomes: An English Population-Based Study.

INTRODUCTION: Patients with inflammatory bowel diseases (IBDs) of the colon are at an increased risk of colorectal cancer (CRC). This study investigates the epidemiology of IBD-CRC and its outcomes. METHODS: Using population data from the English National Health Service held in the CRC data repository, all CRCs with and without prior diagnosis of IBD (Crohn's, ulcerative colitis, IBD unclassified, and IBD with cholangitis) between 2005 and 2018 were identified. Descriptive analyses and logistic regression models were used to compare the characteristics of the 2 groups and their outcomes up to 2 years. RESULTS: Three hundred ninety thousand six hundred fourteen patients diagnosed with CRC were included, of whom 5,141 (1.3%) also had a previous diagnosis of IBD. IBD-CRC cases were younger (median age at CRC diagnosis [interquartile range] 66 [54-76] vs 72 [63-79] years [ P < 0.01]), more likely to be diagnosed with CRC as an emergency (25.1% vs 16.7% [ P < 0.01]), and more likely to have a right-sided colonic tumor (37.4% vs 31.5% [ P < 0.01]). Total colectomy was performed in 36.3% of those with IBD (15.4% of Crohn's, 44.1% of ulcerative colitis, 44.5% of IBD unclassified, and 67.7% of IBD with cholangitis). Synchronous (3.2% vs 1.6% P < 0.01) and metachronous tumors (1.7% vs 0.9% P < 0.01) occurred twice as frequently in patients with IBD compared with those without IBD. Stage-specific survival up to 2 years was worse for IBD-associated cancers. DISCUSSION: IBD-associated CRCs occur in younger patients and have worse outcomes than sporadic CRCs. There is an urgent need to find reasons for these differences to inform screening, surveillance, and treatment strategies for CRC and its precursors in this high-risk group.

Efficacy of biological therapies and small molecules in moderate to severe ulcerative colitis: systematic review and network meta-analysis.

OBJECTIVE: Biological therapies and small molecules continue to be evaluated in moderate to severely active ulcerative colitis, but are often studied in placebo-controlled trials, meaning their relative efficacy and safety is unknown. We examined this in a network meta-analysis. DESIGN: We searched the literature to October 2021 to identify eligible trials. We judged efficacy using clinical remission, endoscopic improvement, or clinical response, and according to previous exposure or non-exposure to antitumour necrosis factor (TNF)-α therapy. We also assessed safety. We used a random effects model and reported data as pooled relative risks (RRs) with 95% CIs. Interventions were ranked according to their P-score. RESULTS: We identified 28 trials (12 504 patients). Based on failure to achieve clinical remission, upadacitinib 45 mg once daily ranked first versus placebo (RR 0.73; 95% CI 0.68 to 0.80, P-score 0.98), with infliximab 5 mg/kg and 10 mg/kg second and third, respectively. Upadacitinib ranked first for clinical remission in both patients naïve to anti-TNF-α drugs (RR 0.69; 95% CI 0.61 to 0.78, P-score 0.99) and previously exposed (RR 0.78; 95% CI 0.72 to 0.85, P-score 0.99). Upadacitinib was superior to almost all other drugs in these analyses. Based on failure to achieve endoscopic improvement infliximab 10 mg/kg ranked first (RR 0.61; 95% CI 0.51 to 0.72, P-score 0.97), with upadacitinib 45 mg once daily, second, and infliximab 5 mg/kg third. Upadacitinib was more likely to lead to adverse events, but serious adverse events were no more frequent, and withdrawals due to adverse events were significantly lower than with placebo. Infections were significantly more likely with tofacitinib than placebo (RR 1.41; 95% CI 1.03 to 1.91). CONCLUSION: In a network meta-analysis, upadacitinib 45 mg once daily ranked first for clinical remission in all patients, patients naïve to anti-TNF-α drugs and patients previously exposed. Infliximab 10 mg/kg ranked first for endoscopic improvement. Most drugs were safe and well tolerated.

The Comparative Efficacy of Chlorhexidine Gluconate and Povidone-iodine Antiseptics for the Prevention of Infection in Clean Surgery: A Systematic Review and Network Meta-analysis.

OBJECTIVE: There is uncertainty around preoperative skin antisepsis in clean surgery. Network meta-analysis provides more precise estimates than standard pairwise meta-analysis and can rank interventions by efficacy, to better inform clinical decisions. BACKGROUND: Infection is the most common and costly complication of surgery. The relative efficacy of CHG and PVI based skin antiseptics in clean surgery remains unclear. METHODS: We searched for randomized or nonrandomized studies comparing the effect of different preparations of CHG and PVI on the dichotomous outcome of surgical site infection. We included studies of adults undergoing clean surgery. We excluded studies concerning indwelling vascular catheters, blood sampling, combination antiseptics or sequential applications of different antiseptics. We performed a network meta-analysis to estimate the relative efficacy of interventions using relative risks (RR). RESULTS: We included 17 studies comparing 5 antiseptics in 14,593 individuals. The overall rate of surgical site infection was 3%. Alcoholic CHG 4%-5% was ranked as the most effective antiseptic as it halved the risk of surgical site infection when compared to aqueous PVI [RR 0.49 (95% confidence interval 0.24, 1.02)] and also to alcoholic PVI, although uncertainty was larger [RR 0.51 (95% confidence interval 0.21, 1.27)]. Adverse events related to antiseptic application were only observed with patients exposed to PVI. CONCLUSIONS: Alcoholic formulations of 4%-5% CHG seem to be safe and twice as effective as PVI (alcoholic or aqueous solutions) in preventing infection after clean surgery in adults. Our findings concur with the literature on contaminated and clean-contaminated surgery, and endorse guidelines worldwide which advocate the use of alcoholic CHG for preoperative skin antisepsis. REGISTRATION: PROSPERO ID CRD42018113001.

Causes of Post-Colonoscopy Colorectal Cancers Based on World Endoscopy Organization System of Analysis.

BACKGROUND & AIMS: Postcolonoscopy colorectal cancer (PCCRC) is CRC diagnosed after a colonoscopy in which no cancer was found. A consensus article from the World Endoscopy Organization (WEO) proposed an approach for investigating and categorizing PCCRCs detected within 4 years of a colonoscopy. We aimed to identify cases of PCCRC and the factors that cause them, test the WEO system of categorization, quantify the proportion of avoidable PCCRCs, and propose a target rate for PCCRCs detected within 3 years of a colonoscopy that did not detect CRC. METHODS: We performed a retrospective analysis of 107 PCCRCs identified at a single medical center in England from January 1, 2010, through December 31, 2017 using coding and endoscopy data. For each case, we reviewed clinical, pathology, radiology, and endoscopy findings. Using the WEO recommendations, we performed a root-cause analysis of each case, categorizing lesions as follows: possible missed lesion, prior examination adequate; possible missed lesion, prior examination inadequate; detected lesion, not resected; or likely incomplete resection of previously identified lesion. We determined whether PCCRCs could be attributed to the colonoscopist for technical or decision-making reasons, and whether the PCCRC was avoidable or unavoidable, based on the WEO categorization and size of tumor. The endoscopy reporting system provided performance data for individual endoscopists. RESULTS: Of the PCCRCs identified, 43% were in high-risk patients (those with inflammatory bowel disease, previous CRC, previous multiple large polyps, or hereditary cancer syndromes) and 66% were located distal to the hepatic flexure. There was no correlation between postcolonoscopy colorectal tumor size and time to diagnosis after index colonoscopy. Bowel preparation was poor in 19% of index colonoscopies, and only 36% of complete colonoscopies had adequate photodocumentation of completion. Development of 73% of PCCRCs was determined to be affected by technical endoscopic factors, 17% of PCCRCs by administrative factors (follow-up procedures delayed/not booked by administrative staff), and 27% of PCCRCs by decision-making factors. Twenty-seven percent of PCCRCs were categorized as possible missed lesion, prior examination adequate; 58% as possible missed lesion, prior examination inadequate; 8% as detected lesion, not resected; and 7% as incomplete resection of previously observed lesion; 89% were deemed to be avoidable. CONCLUSIONS: In a retrospective analysis of PCCRCs, using the WEO system of categorization, we found 43% to occur in high-risk patients; this might be reduced with more vigilant surveillance. Measures are needed to reduce technical, decision-making, and administrative factors. We found that 89% of PCCRCs may be avoidable. If half of avoidable PCCRCs could be prevented, the target rate of 2% for the PCCRC-3y (cancer diagnosed between 6 and 36 months after index colonoscopy) benchmark would be achievable.

Efficacy of pharmacological therapies in patients with IBS with diarrhoea or mixed stool pattern: systematic review and network meta-analysis.

OBJECTIVE: Over half of patients with IBS have either diarrhoea (IBS-D) or a mixed stool pattern (IBS-M). The relative efficacy of licenced pharmacological therapies is unclear in the absence of head-to-head trials. We conducted a network meta-analysis to resolve this uncertainty. DESIGN: We searched MEDLINE, Embase, Embase Classic, the Cochrane central register of controlled trials, and Clinicaltrials.gov through January 2019 to identify randomised controlled trials (RCTs) assessing the efficacy of licenced pharmacological therapies (alosetron, eluxadoline, ramosetron and rifaximin) in adults with IBS-D or IBS-M. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of all pharmacological therapies were reported as a pooled relative risk with 95% CIs to summarise the effect of each comparison tested. Treatments were ranked according to their p score. RESULTS: We identified 18 eligible RCTs (seven alosetron, five ramosetron, two rifaximin and four eluxadoline), containing 9844 patients. All were superior to placebo for the treatment of IBS-D or IBS-M at 12 weeks, according to the Food and Drug Administration (FDA)-recommended endpoint for trials in IBS. Alosetron 1 mg twice daily was ranked first for efficacy, based on the FDA-recommended composite endpoint of improvement in both abdominal pain and stool consistency, effect on global symptoms of IBS and effect on stool consistency. Ramosetron 2.5µg once daily was ranked first for effect on abdominal pain. Total numbers of adverse events were significantly greater with alosetron 1 mg twice daily and ramosetron 2.5µg once daily, compared with placebo. Rifaximin 550 mg three times daily ranked first for safety. Constipation was significantly more common with all drugs, except rifaximin 550 mg three times daily. CONCLUSION: In a network meta-analysis of RCTs of pharmacological therapies for IBS-D and IBS-M, we found all drugs to be superior to placebo, but alosetron and ramosetron appeared to be the most effective.

Relative Efficacy of Tegaserod in a Systematic Review and Network Meta-analysis of Licensed Therapies for Irritable Bowel Syndrome With Constipation.

Irritable bowel syndrome (IBS) is a chronic functional bowel disorder affecting 1 in 10 people and associated with poor psychological health, reduced quality of life, and increased health care expenditure.1 The etiology is complex and incompletely understood.2 Approximately one-third of patients have IBS with constipation (IBS-C),1 for which there are licensed therapies available in the United States. We summarized comparative efficacy of these in a recent network meta-analysis of randomized controlled trials (RCTs).3 Tegaserod, a 5-hydroxytryptamine-4 receptor agonist, approved by the Food and Drug Administration (FDA) for IBS-C, was withdrawn in 2007 after a small excess number of cerebrovascular and cardiovascular ischemic events in patients taking the drug.4 However, since our network meta-analysis, it has been reintroduced in the United States. It is therefore important to understand its efficacy relative to other available licensed therapies for IBS-C.

Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and network meta-analysis.

OBJECTIVE: Opioids are increasingly prescribed in the West and have deleterious GI consequences. Pharmacological therapies to treat opioid-induced constipation (OIC) are available, but their relative efficacy is unclear. We performed a systematic review and network meta-analysis to address this deficit in current knowledge. DESIGN: We searched MEDLINE, EMBASE, EMBASE Classic and the Cochrane central register of controlled trials through to December 2017 to identify randomised controlled trials (RCTs) of pharmacological therapies in the treatment of adults with OIC. Trials had to report a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of pharmacological therapies was reported as a pooled relative risk (RR) with 95% CIs to summarise the effect of each comparison tested and ranked treatments according to their P-score. RESULTS: Twenty-seven eligible RCTs of pharmacological therapies, containing 9149 patients, were identified. In our primary analysis, using failure to achieve an average of ≥3 bowel movements (BMs) per week with an increase of ≥1 BM per week over baseline or an average of ≥3 BMs per week, to define non-response, the network meta-analysis ranked naloxone first in terms of efficacy (RR=0.65; 95% CI 0.52 to 0.80, P-score=0.84), and it was also the safest drug. When non-response to therapy was defined using failure to achieve an average of ≥3 BMs per week, with an increase of ≥1 BM per week over baseline, naldemedinewas ranked first (RR=0.66; 95% CI 0.56 to 0.77, P score=0.91) and alvimopan second (RR=0.74; 95% CI 0.57 to 0.94, P-score=0.71). CONCLUSION: In network meta-analysis, naloxone and naldemedine appear to be the most efficacious treatments for OIC. Naloxone was the safest of these agents.

Decreasing Risk of First and Subsequent Surgeries in Patients With Crohn's Disease in England From 1994 through 2013.

BACKGROUND & AIMS: Gastrointestinal (GI) surgery is an important part of the treatment algorithm for patients with Crohn's disease (CD) that is complicated or does not respond to medical therapy. Cohort studies from Denmark and Canada have shown that the risk of primary surgery is decreasing but there is a lack of contemporary data on subsequent resections. We examined trends in first and second GI resections in patients with CD. METHODS: We performed a retrospective cohort study using the United Kingdom primary care database ResearchOne, collecting data from patients with Crohn's disease from 1994 through 2013. We compared rates of first and second GI resections with etiological factors. RESULTS: Among 3059 incident cases of CD, 13%, 21%, and 26% of the patients underwent surgical resections after 1, 5, and 10 years, respectively. Of patients with an initial resection, 20% required an additional operation when followed for 10 years after the initial resection. We found a significant reduction in first surgery, from 44% to 21% after 10 years of disease, from 1994 to 2003 (χ2 for trend, P < .05). There was a significant reduction in second resections, in a 10-year follow-up period, from 40% in 1994 to 17% in 2003 (χ2 for trend, P < .05). Duration of disease, younger age at diagnosis, smoking, and immunomodulator use were positively associated with first surgeries. Duration of disease was significantly associated with the risk of undergoing a second resection. CONCLUSION: In a retrospective analysis of a United Kingdom primary care database, we observed a significant reduction in first and subsequent GI surgeries among patients with CD over the past 20 years in England.

Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis.

BACKGROUND & AIMS: Several secretagogues have been approved for the treatment of irritable bowel syndrome with constipation (IBS-C). However, their relative efficacy is unclear because there have been no head-to-head randomized controlled trials. We conducted a network meta-analysis to compare their efficacies in patients with IBS-C. METHODS: We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane Central Register of Controlled Trials through June 2018 to identify randomized controlled trials assessing the efficacy of secretagogues in adults with IBS-C. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random-effects model. Efficacy and safety of secretagogues were reported as a pooled relative risk with 95% confidence interval to summarize the effect of each comparison tested, and treatments were ranked according to their P score. RESULTS: We identified 15 eligible randomized controlled trials of secretagogues that included 8462 patients. Linaclotide, lubiprostone, plecanatide, and tenapanor were superior to placebo for the treatment of IBS-C. Linaclotide (290 µg once daily) was ranked first in efficacy based on the end point recommended by the Food and Drug Administration for trials in IBS-C, the primary end point used in each trial, abdominal pain, and complete spontaneous bowel movements. Tenapanor (50 mg twice daily) was ranked first for decreasing bloating. Total numbers of adverse events were significantly larger with linaclotide (290 and 500 µg once daily) and plecanatide (3 mg once daily) compared with placebo. However, plecanatide 6 mg once daily ranked first for safety. Diarrhea was significantly more common with all drugs, except lubiprostone (8 µg twice daily). Nausea was significantly more common in patients who received lubiprostone. CONCLUSIONS: In a network analysis of randomized controlled trials of secretagogues for IBS-C, we found all drugs to be superior to placebo. Efficacy was similar among individual drugs and dosages for most end points. However, data were extracted at the 12-week time point, so the long-term relative efficacy of these drugs is unknown.

Increasing Prescription of Opiates and Mortality in Patients With Inflammatory Bowel Diseases in England.

BACKGROUND & AIMS: The prescription of opiate medications is increasing. Individuals with inflammatory bowel diseases (IBD) can develop serious complications from opiate use, but few data are available on the prescription of these drugs to patients with IBD. We examined trends in prescriptions of opiates and their association with all-cause mortality in individuals with IBD. METHODS: We performed a retrospective cohort study of 3517 individuals with Crohn's disease (CD) and 5349 with ulcerative colitis (UC) using the primary care database ResearchOne, which holds de-identified clinical and administrative information from the health records of approximately 6 million persons (more than 10% of the total population) in England. We explored trends in prescriptions of all opiates, codeine, tramadol, or strong opiates, separately from 1990 through September 14, 2014. Associations between opiates and all-cause mortality were examined using propensity score-matched analysis. RESULTS: There was a statistically significant increase in the prescription of opiate medications, with 10% of subjects receiving an opiate prescription from 1990 through 1993 compared to 30% from 2010 through 2013 (chi-square for trend, P < .005). Prescription of strong opiates was significantly associated with increased premature mortality of patients with CD (heavy use) or UC (moderate or heavy use). There was a significant association between heavy use of any opiate or codeine alone and premature mortality of patients with UC. Use of tramadol alone, or in combination with codeine, was not associated with premature mortality in patients with CD or UC. CONCLUSIONS: In an analysis of primary care patients with IBD in England, we found prescriptions for opiate drugs to have increased significantly from 1990 through 2013. Heavy use of strong opiates among patients with IBD associates with increased all-cause premature mortality.

A randomised, single blinded trial, assessing the effect of a two week preoperative very low calorie diet on laparoscopic cholecystectomy in obese patients.

BACKGROUND: Laparoscopic cholecystectomy (LC) can be technically challenging in the obese. The primary aim of the trial was to establish whether following a Very Low Calorie Diet (VLCD) for two weeks pre-operatively reduces operation time. Secondary outcomes included perceived operative difficulty and length of hospital stay. METHODS: A single-blinded, randomized controlled trial of consecutive patients with symptomatic gallstones and BMI >30 kg/m(2) 46 patients were randomized to a VLCD or normal diet for two weeks prior to LC. Food diaries were used to document dietary intake. The primary outcome measure was operation time. Secondary outcomes were length of stay, weight change operative complications, day case rates and perceived difficulty of operation. RESULTS: The VLCD was well tolerated and had significantly greater preoperative weight loss (3.48 kg vs. 0.98 kg; p < 0.0001). Median operative time was significantly reduced by 6 min in the VLCD group (25 vs. 31 min; p = 0.0096). There were no differences in post-operative complications, length of stay, or day case rates between the groups. Dissection of Calot's triangle was deemed significantly easier in the VLCD group. CONCLUSION: A two week VLCD prior to elective laparoscopic cholecystectomy in obese patients is safe, well tolerated and was shown to significantly reduce pre-operative weight and operative time. ISRCTN: 61630192. http://www.isrctn.com/ISRCTN61630192 Trial registration.