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The effectiveness of screening for colorectal cancer (CRC) by sex and age in randomized trials is uncertain.To evaluate the 15-year effect of sigmoidoscopy screening on CRC incidence and mortality.Pooled analysis of 4 large-scale randomized trials of sigmoidoscopy screening.Norway, the United States, the United Kingdom, and Italy.Women and men aged 55 to 64 years at enrollment.Sigmoidoscopy screening.Primary end points were cumulative incidence rate ratio (IRR) and mortality rate ratio (MRR) and rate differences after 15 years of follow-up comparing screening versus usual care in intention-to-treat analyses. Stratified analyses were done by sex, cancer site, and age at screening.Analyses comprised 274 952 persons (50.7% women), 137 493 in the screening and 137 459 in the usual care group. Screening attendance was 58% to 84%. After 15 years, the rate difference for CRC incidence was 0.51 cases (95% CI, 0.40 to 0.63 cases) per 100 persons and the IRR was 0.79 (CI, 0.75 to 0.83). The rate difference for CRC mortality was 0.13 deaths (CI, 0.07 to 0.19 deaths) per 100 persons, and the MRR was 0.80 (CI, 0.72 to 0.88). Women had less benefit from screening than men for CRC incidence (IRR for women, 0.84 [CI, 0.77 to 0.91]; IRR for men, 0.75 [CI, 0.70 to 0.81];Data from the U.K. trial were less granular because of privacy regulations.This pooled analysis of all large randomized trials of sigmoidoscopy screening demonstrates a significant and sustained effect of sigmoidoscopy on CRC incidence and mortality for 15 years.Health Fund of South-East Norway.

Background There is continued uncertainty regarding the risks of hepato-pancreato-biliary cancers in patients with inflammatory bowel disease (IBD) with or without concomitant primary sclerosing cholangitis (PSC). Objective To give updated estimates on risk of hepato-pancreato-biliary cancers in patients with IBD, including pancreatic cancer, hepatocellular carcinoma, gall bladder cancer, and intra – and extrahepatic cholangiocarcinoma. Methods In a population-based cohort study, we included all patients diagnosed with IBD in Norway and Sweden from 1987 to 2016. The cohort comprised of 141,960 patients, identified through hospital databases and the National Patient Register. Participants were followed through linkage to national cancer, cause of death, and population registries. We calculated absolute risk and standardized incidence ratios (SIRs) of hepato-pancreato-biliary cancers by PSC and other clinical characteristics. Results Of the 141,960 IBD patients, 3.2% were diagnosed with PSC. During a median follow-up of 10.0 years, we identified 443 biliary tract cancers (SIR 5.2, 95% confidence interval [CI] 4.8–5.7), 161 hepatocellular carcinomas (SIR 2.4, 95% CI 2.0–2.7) and 282 pancreatic cancers (SIR 1.3, 95% CI 1.2–1.5). The relative risks were considerably higher in PSC-IBD patients, with SIR of 140 (95% CI 123–159) for biliary tract, 38.6 (95% CI 29.2–50.0) for hepatocellular, and 9.0 (95% CI 6.3–12.6) for pancreatic cancer. The SIRs were still slightly increased in non-PSC-IBD patients, compared to the general population. For biliary tract cancer, the cumulative probability at 25 years was 15.6% in PSC-IBD patients, and 0.4% in non-PSC-IBD patients. Conclusions The dramatically increased risks of hepato-pancreato-biliary cancers in PSC-IBD patients support periodic surveillance for these malignancies. While much lower, the excess relative risks in non-PSC-IBD patients were not trivial compared to non-IBD related risk factors.

Background: Although colonoscopy is widely used as a screening test to detect colorectal cancer, its effect on the risks of colorectal cancer and related death is unclear. Methods: We performed a pragmatic, randomized trial involving presumptively healthy men and women 55 to 64 years of age drawn from population registries in Poland, Norway, Sweden, and the Netherlands between 2009 and 2014. The participants were randomly assigned in a 1:2 ratio to either receive an invitation to undergo a single screening colonoscopy (the invited group) or to receive no invitation or screening (the usual-care group). The primary end points were the risks of colorectal cancer and related death, and the secondary end point was death from any cause. Results: Follow-up data were available for 84,585 participants in Poland, Norway, and Sweden - 28,220 in the invited group, 11,843 of whom (42.0%) underwent screening, and 56,365 in the usual-care group. A total of 15 participants had major bleeding after polyp removal. No perforations or screening-related deaths occurred within 30 days after colonoscopy. During a median follow-up of 10 years, 259 cases of colorectal cancer were diagnosed in the invited group as compared with 622 cases in the usual-care group. In intention-to-screen analyses, the risk of colorectal cancer at 10 years was 0.98% in the invited group and 1.20% in the usual-care group, a risk reduction of 18% (risk ratio, 0.82; 95% confidence interval [CI], 0.70 to 0.93). The risk of death from colorectal cancer was 0.28% in the invited group and 0.31% in the usual-care group (risk ratio, 0.90; 95% CI, 0.64 to 1.16). The number needed to invite to undergo screening to prevent one case of colorectal cancer was 455 (95% CI, 270 to 1429). The risk of death from any cause was 11.03% in the invited group and 11.04% in the usual-care group (risk ratio, 0.99; 95% CI, 0.96 to 1.04). Conclusions: In this randomized trial, the risk of colorectal cancer at 10 years was lower among participants who were invited to undergo screening colonoscopy than among those who were assigned to no screening. (Funded by the Research Council of Norway and others; NordICC ClinicalTrials.gov number, NCT00883792.).

Background Norway and Sweden have similar populations and health care systems, but different reactions to the COVID-19 pandemic. Norway closed educational institutions, and banned sports and cultural activities; Sweden kept most institutions and training facilities open. We aimed to compare peoples’ attitudes towards authorities and control measures, and perceived impact of the pandemic and implemented control measures on life in Norway and Sweden. Methods Anonymous web-based surveys for individuals age 15 or older distributed through Facebook using the snowball method, in Norway and Sweden from mid-March to mid-April, 2020. The survey contained questions about perceived threat of the pandemic, views on infection control measures, and impact on daily life. We performed descriptive analyses of the responses and compared the two countries. Results 3508 individuals participated in the survey (Norway 3000; Sweden 508). 79% were women, the majority were 30–49 years (Norway 60%; Sweden 47%), and about 45% of the participants in both countries had more than 4 years of higher education. Participants had high trust in the health services, but differed in the degree of trust in their government (High trust in Norway 17%; Sweden 37%). More Norwegians than Swedes agreed that school closure was a good measure (Norway 66%; Sweden 18%), that countries with open schools were irresponsible (Norway 65%; Sweden 23%), and that the threat from repercussions of the mitigation measures were large or very large (Norway 71%; Sweden 56%). Both countries had a high compliance with infection preventive measures (> 98%). Many lived a more sedentary life (Norway 69%; Sweden 50%) and ate more (Norway 44%; Sweden 33%) during the pandemic. Conclusion Sweden had more trust in the authorities, while Norwegians reported a more negative lifestyle during the pandemic. The level of trust in the health care system and self-reported compliance with preventive measures was high in both countries despite the differences in infection control measures.

Background Artificial intelligence (AI) for polyp detection is being introduced to colonoscopy, but there is uncertainty how this affects endoscopists’ ability to detect polyps and neoplasms. We performed a video-based study to address whether AI improved the endoscopists’ performance to detect polyps. Methods We established a dataset of 200 colonoscopy videos (length 5 s; 100 without polyps and 100 with one polyp). About 33 early-career endoscopists (50–400 colonoscopies performed) from 10 European countries classified each video as either ‘polyp present’ or ‘polyp not present’. The video assessment was performed twice with a four-week interval. The first assessment was performed without any AI tool, whereas the second was performed with an AI tool for polyp detection. The primary endpoint was early-career endoscopists’ sensitivity to detect polyps. Gold standard for presence and histology of polyps were confirmed by two expert endoscopists and pathologists, respectively. McNemar’s test was used for statistical significance. Results There were 86 neoplastic and 14 non-neoplastic polyps (mean size 5.6 mm) in the 100 videos with polyps. Early-career endoscopists’ sensitivity to detect polyps increased from 86.3% (95% confidence interval [CI]: 85.1–87.5%) to 91.7% (95%CI: 90.7–92.6%) with the AI aid (p

Background: During the first wave of the Covid-19 epidemic, a national lockdown was established in Norway, and inhabitants were asked to contact healthcare only if absolutely necessary. We investigated hospital admissions and mortality due to non-Covid-19 disease during the lockdown compared to previous years. Methods: We compared the number of emergency admissions and in-hospital fatality for diagnoses probably unaffected (acute myocardial infarction, acute abdominal conditions, cerebrovascular diseases) and affected by the lockdown (infections, injuries) in the South-Eastern Health Region of Norway during weeks 12–22, 2020, compared to the mean of the same period in the years 2017–2019. We also compared population mortality March–May 2020, to the mean of the same period in years 2017–2019. Results: A total of 280,043 emergency admissions were observed; 20,911 admissions probably unaffected, and 30,905 admissions probably affected by the lockdown. Admissions due to diagnoses probably unaffected was reduced by 12% (95% confidence interval (CI) 9–15%), compared to 2017–2019. Admissions for diagnoses probably affected was reduced by 30% (95% CI 28–32%). There was a 34% reduction in in-hospital fatality due to acute myocardial infarction (95% CI 4–56%), 19% due to infections (95% CI 1–33%), and no change for the other diagnoses, compared to 2017–2019. The risk of in-hospital mortality to total mortality was lower for acute myocardial infarction (relative risk 0.85, 95% CI 0.73–0.99) and injuries (relative risk 0.83, 95% CI 0.70–0.98). Conclusions: Even though fewer patients were admitted to hospital, there was no increase in in-hospital fatality or population mortality, indicating that those who were most in need still received adequate care.

Background To optimize colorectal cancer (CRC) screening and surveillance, information regarding the time-dependent risk of advanced adenomas (AA) to develop into CRC is crucial. However, since AA are removed after diagnosis, the time from AA to CRC cannot be observed in an ethically acceptable manner. We propose a statistical method to indirectly infer this time in a progressive three-state disease model using surveillance data. Methods Sixteen models were specified, with and without covariates. Parameters of the parametric time-to-event distributions from the adenoma-free state (AF) to AA and from AA to CRC were estimated simultaneously, by maximizing the likelihood function. Model performance was assessed via simulation. The methodology was applied to a random sample of 878 individuals from a Norwegian adenoma cohort. Results Estimates of the parameters of the time distributions are consistent and the 95% confidence intervals (CIs) have good coverage. For the Norwegian sample (AF: 78%, AA: 20%, CRC: 2%), a Weibull model for both transition times was selected as the final model based on information criteria. The mean time among those who have made the transition to CRC since AA onset within 50 years was estimated to be 4.80 years (95% CI: 0; 7.61). The 5-year and 10-year cumulative incidence of CRC from AA was 13.8% (95% CI: 7.8%;23.8%) and 15.4% (95% CI: 8.2%;34.0%), respectively. Conclusions The time-dependent risk from AA to CRC is crucial to explain differences in the outcomes of microsimulation models used for the optimization of CRC prevention. Our method allows for improving models by the inclusion of data-driven time distributions.

Background Artificial intelligence (AI)-based polyp detection systems are used during colonoscopy with the aim of increasing lesion detection and improving colonoscopy quality. Patients and methods: We performed a systematic review and meta-analysis of prospective trials to determine the value of AI-based polyp detection systems for detection of polyps and colorectal cancer. We performed systematic searches in MEDLINE, EMBASE, and Cochrane CENTRAL. Independent reviewers screened studies and assessed eligibility, certainty of evidence, and risk of bias. We compared colonoscopy with and without AI by calculating relative and absolute risks and mean differences for detection of polyps, adenomas, and colorectal cancer. Results Five randomized trials were eligible for analysis. Colonoscopy with AI increased adenoma detection rates (ADRs) and polyp detection rates (PDRs) compared to colonoscopy without AI (values given with 95 %CI). ADR with AI was 29.6 % (22.2 % – 37.0 %) versus 19.3 % (12.7 % – 25.9 %) without AI; relative risk (RR] 1.52 (1.31 – 1.77), with high certainty. PDR was 45.4 % (41.1 % – 49.8 %) with AI versus 30.6 % (26.5 % – 34.6 %) without AI; RR 1.48 (1.37 – 1.60), with high certainty. There was no difference in detection of advanced adenomas (mean advanced adenomas per colonoscopy 0.03 for each group, high certainty). Mean adenomas detected per colonoscopy was higher for small adenomas (≤ 5 mm) for AI versus non-AI (mean difference 0.15 [0.12 – 0.18]), but not for larger adenomas (> 5 – ≤ 10 mm, mean difference 0.03 [0.01 – 0.05]; > 10 mm, mean difference 0.01 [0.00 – 0.02]; high certainty). Data on cancer are unavailable. Conclusions AI-based polyp detection systems during colonoscopy increase detection of small nonadvanced adenomas and polyps, but not of advanced adenomas.

Background Patients who have undergone Roux-en-Y gastric bypass (RYGB) are at increased risk of biliary disease necessitating endoscopic retrograde cholangiopancreatography (ERCP). The most widely used approaches to perform ERCP after RYGB are laparoscopy-assisted ERCP (LA-ERCP) and balloon enteroscopy-assisted ERCP (BEA-ERCP). There are few studies comparing these procedures. We aimed to compare the performance, benefits, and harms of LA-ERCP and BEA-ERCP in RYGB patients. Methods We identified all RYGB patients who underwent ERCP at two tertiary care endoscopy centers in Oslo, Norway between May 2013 and December 2017. One center performed BEA-ERCP, the other LA-ERCP. Procedure success was defined as fulfillment of the therapeutic or diagnostic aim, according to the procedure description. Adverse events were classified according to the Clavien–Dindo grading system. Results During the study period, 40 BEA-ERCP and 39 LA-ERCP procedures were performed in 68 patients. Procedure success rate was 72.5 % for BEA-ERCP and 87.2 % for LA-ERCP (P = 0.14). Adverse events occurred in 18 % of BEA-ERCP and 28 % of LA-ERCP (P = 0.23). Serious adverse events (Clavien–Dindo grade ≥ 3b) occurred in 2.5 % of BEA-ERCP and 7.7 % of LA-ERCP procedures (P = 0.36). Concomitant cholecystectomy was performed in 25 of the 39 LA-ERCP procedures. The median procedure times for LA-ERCP performed with and without concomitant cholecystectomy were 201 minutes and 140 minutes, respectively, and for BEA-ERCP was 125 minutes. Conclusions In experienced hands, both LA-ERCP and BEA-ERCP have high success rates after RYGB. The choice of approach should be individualized according to patient characteristics and available physician competence.

During the COVID-19 pandemic, the need for rapid legal interventions to protect public health has challenged standards of evidence generation and implementation. Investigators have generated high-quality evidence for drugs and vaccines at remarkable speed, but COVID-19 mitigation measures enforced by laws and regulations remain guided by the precautionary principle rather than by empirical evidence. This article discusses new concepts for embedded evidence generation for legal public health interventions in times of crisis.

Introduction Because individuals with serrated polyps and adenomas are at increased risk of developing new polyps and colorectal cancer (CRC), surveillance after resection is justified. After adenoma resection, most international guidelines are consistent, but recommendations for surveillance after serrated polyp resection vary. The United States Multi-Society Taskforce on CRC (US-MSTF) base surveillance intervals on serrated polyp subtype (traditional serrated adenoma, sessile serrated polyp, hyperplastic polyps), while the European Society of Gastrointestinal Endoscopy (ESGE) guidelines do not take serrated polyp subtype into account. We evaluated the implications of this difference in a primary colonoscopy screening cohort. Methods We included participants from a large colonoscopy screening trial. In a post-hoc simulation, assuming full protocol adherence, we determined the surveillance interval for each subject based on their polyp burden, using the most recent US-MSTF and ESGE guidelines. Results We included 5323 participants, of whom 1228 had one or more serrated polyps. In 5201 of all participants (98 %; Cohen’s kappa 0.90) and in 1106 of those with serrated polyps (90 %; Cohen’s kappa 0.80), both guidelines recommended identical surveillance intervals. Recommendations for a 3-year surveillance interval were identical between the two guidelines. All 122 subjects with discordant recommendations would receive a follow-up colonoscopy after 10 years using ESGE guidance and after 5 years using US-MSTF guidance. Conclusion Despite the different criteria used to determine surveillance after serrated polyp resection, most individuals are recommended identical colonoscopy surveillance intervals whether following the ESGE or US-MSTF guidelines. This suggests that surveillance recommendations do not need to consider the serrated polyp subtype.

Background: Norway and Sweden are similar countries in terms of socioeconomics and health care. Norway implemented extensive COVID-19 measures, such as school closures and lockdowns, whereas Sweden did not. Aims: To compare mortality in Norway and Sweden, two similar countries with very different mitigation measures against COVID-19. Methods: Using real-world data from national registries, we compared all-cause and COVID-19-related mortality rates with 95% confidence intervals (CI) per 100,000 person-weeks and mortality rate ratios (MRR) comparing the five preceding years (2015–2019) with the pandemic year (2020) in Norway and Sweden. Results: In Norway, all-cause mortality was stable from 2015 to 2019 (mortality rate 14.6–15.1 per 100,000 person-weeks; mean mortality rate 14.9) and was lower in 2020 than from 2015 to 2019 (mortality rate 14.4; MRR 0.97; 95% CI 0.96–0.98). In Sweden, all-cause mortality was stable from 2015 to 2018 (mortality rate 17.0–17.8; mean mortality rate 17.1) and similar to that in 2020 (mortality rate 17.6), but lower in 2019 (mortality rate 16.2). Compared with the years 2015–2019, all-cause mortality in the pandemic year was 3% higher due to the lower rate in 2019 (MRR 1.03; 95% CI 1.02–1.04). Excess mortality was confined to people aged ⩾70 years in Sweden compared with previous years. The COVID-19-associated mortality rates per 100,000 person-weeks during the first wave of the pandemic were 0.3 in Norway and 2.9 in Sweden. Conclusions: All-cause mortality in 2020 decreased in Norway and increased in Sweden compared with previous years. The observed excess deaths in Sweden during the pandemic may, in part, be explained by mortality displacement due to the low all-cause mortality in the previous year.

Background Closed fitness centers during the Covid-19 pandemic may negatively impact health and wellbeing. We assessed whether training at fitness centers increases the risk of SARS-CoV-2 virus infection. Methods In a two-group parallel randomized controlled trial, fitness center members aged 18 to 64 without Covid-19-relevant comorbidities, were randomized to access to training at a fitness center or no-access. Fitness centers applied physical distancing (1 m for floor exercise, 2 m for high-intensity classes) and enhanced hand and surface hygiene. Primary outcomes were SARS-CoV-2 RNA status by polymerase chain reaction (PCR) after 14 days, hospital admission after 21 days. The secondary endpoint was SARS-CoV-2 antibody status after 1 month. Results 3764 individuals were randomized; 1896 to the training arm and 1868 to the no-training arm. In the training arm, 81.8% trained at least once, and 38.5% trained ≥six times. Of 3016 individuals who returned the SARS-CoV-2 RNA tests (80.5%), there was one positive test in the training arm, and none in the no-training arm (risk difference 0.053%; 95% CI − 0.050 to 0.156%; p = 0.32). Eleven individuals in the training arm (0.8% of tested) and 27 in the no-training arm (2.4% of tested) tested positive for SARS-CoV-2 antibodies (risk difference − 0.87%; 95%CI − 1.52% to − 0.23%; p = 0.001). No outpatient visits or hospital admissions due to Covid-19 occurred in either arm. Conclusion Provided good hygiene and physical distancing measures and low population prevalence of SARS-CoV-2 infection, there was no increased infection risk of SARS-CoV-2 in fitness centers in Oslo, Norway for individuals without Covid-19-relevant comorbidities. Trial registration The trial was prospectively registered in ClinicalTrials.gov on May 13, 2020. Due to administrative issues it was first posted on the register website on May 29, 2020: NCT04406909.

Background and aims: Obesity with type-2 diabetes is a global challenge. Lifestyle interventions have limited effect for most patients. Bariatric surgery is highly effective, but resource-demanding, invasive and associated with serious complications. Recently, a new intragastric balloon was introduced, not requiring endoscopy for placement or removal (Elipse™, Allurion Inc., Natick, MA). The balloon is swallowed in a capsule and filled with water once in the stomach. The balloon self-deflates after 4 months and is naturally excreted. The present trial investigated balloon feasibility, safety and efficacy in patients with obesity and type-2 diabetes. Patients and methods: We treated 19 patients, with type-2 diabetes and body mass index (BMI) of 30.0-39.9 kg/m2 at two Norwegian centers with the Elipse balloon. Patient follow-up during balloon treatment mimicked real-world clinical practice, including dietary plan and outpatient visits. The primary efficacy endpoints were total body weight loss (TBWL) and HbA1c at weeks 16 and 52. Results: All patients underwent balloon insertion uneventfully as out-patients. Mean TBWL and HbA1c reduction after 16 and 52 weeks of balloon insertion was 3.9% (95%CI 2.1-5.7) and 0.8% (95%CI 1.9-3.5); and 7 (95%CI 4-10), and 1 (95%CI -6 to 9) mmol/mol, respectively. Adverse events occurred in two patients (10.5%): one developed gastric outlet obstruction, managed by endoscopic balloon removal; the other excessive vomiting and dehydration, managed conservatively. Conclusions: This first Scandinavian real-world clinical trial with a new minimally invasive intragastric balloon system demonstrated good feasibility, but did not confirm expected efficacy for weight loss and diabetes control.

Background Whole body ischemia and reperfusion injury after cardiac arrest leads to the massive inflammation clinically manifested in the post-cardiac arrest syndrome. Previous studies on the inflammatory effect on circulatory failure after cardiac arrest have either investigated a selected patient group or a limited part of the inflammatory mechanisms. We examined the association between cardiac arrest characteristics and inflammatory biomarkers, and between inflammatory biomarkers and circulatory failure after cardiac arrest, in an unselected patient cohort. Methods This was a prospective study of 50 consecutive patients with out-of-hospital cardiac arrest. Circulation was invasively monitored from admission until day five, whereas inflammatory biomarkers, i.e. complement activation, cytokines and endothelial injury, were measured daily. We identified predictors for an increased inflammatory response, and associations between the inflammatory response and circulatory failure. Results We found a marked and broad inflammatory response in patients after cardiac arrest, which was associated with clinical outcome. Long time to return of spontaneous circulation and high lactate level at admission were associated with increased complement activation (TCC and C3bc), pro-inflammatory cytokines (IL-6, IL-8) and endothelial injury (syndecan-1) at admission. These biomarkers were in turn significantly associated with lower mean arterial blood pressure, lower cardiac output and lower systemic vascular resistance, and increased need of circulatory support in the initial phase. High levels of TCC and IL-6 at admission were significantly associated with increased 30-days mortality. Conclusion Inflammatory biomarkers, including complement activation, cytokines and endothelial injury, were associated with increased circulatory failure in the initial period after cardiac arrest.

Background Endoscopic screening with polypectomy has been shown to reduce colorectal cancer incidence in randomized trials. Incomplete polyp removal and subsequent development of post-colonoscopy cancers may attenuate the effect of screening. This study aimed to quantify the extent of incomplete polyp removal. Methods We included patients aged 50–75 years with nonpedunculated polyps ≥ 5 mm removed during colonoscopy at four hospitals in Norway. To evaluate completeness of polyp removal, biopsies from the resection margins were obtained after polypectomy. Logistic regression models were fitted to identify factors explaining incomplete resection. Results 246 patients with 339 polyps underwent polypectomy between January 2015 and June 2017. A total of 12 polyps were excluded due to biopsy electrocautery damage, and 327 polyps in 246 patients (mean age 67 years [range 42–83]; 52 % male) were included in the analysis. Overall, 54 polyps (15.9 %) in 54 patients were incompletely resected. Histological diagnosis of the polyp (sessile serrated lesions vs. adenoma, odds ratio [OR] 10.9, 95 % confidence interval [CI] 3.9–30.1) and polyp location (proximal vs. distal colon, OR 2.8, 95 %CI 1.0–7.7) were independent risk factors for incomplete removal of polyps 5–19 mm. Board-certified endoscopists were not associated with lower rates of incomplete resection compared with trainees (14.0 % vs. 14.2 %), OR 1.0 (95 %CI 0.5–2.1). Conclusion Incomplete polyp resection was frequent after polypectomy in routine clinical practice. Serrated histology and proximal location were independent risk factors for incomplete resection. The performance of board-certified gastroenterologists was not superior to that of trainees.

Colonoscopy surveillance after adenoma removal is an increasing burden in many countries. Surveillance recommendations consider characteristics of removed adenomas, but not colonoscopist performance. We investigated the impact of colonoscopist performance on colorectal cancer risk after adenoma removal.We compared colorectal cancer risk after removal of high-risk adenomas, low-risk adenomas, and after negative colonoscopy for all colonoscopies performed by colonoscopists with low vs high performance quality (adenoma detection rate20% vs ≥20%) in the Polish screening program between 2000 and 2011, with follow-up until 2017. Findings were validated in the Austrian colonoscopy screening program.A total of 173,288 Polish colonoscopies were included in the study. Of 262 colonoscopists, 160 (61.1%) were low performers, and 102 (38.9%) were high performers; 11.1% of individuals had low-risk and 6.6% had high-risk adenomas removed at screening; 82.2% had no adenomas. During 10 years of follow-up, 443 colorectal cancers were diagnosed. For low-risk adenoma individuals, colorectal cancer incidence was 0.55% (95% confidence interval [CI] 0.40-0.75) with low-performing colonoscopists vs 0.22% (95% CI 0.14-0.34) with high-performing colonoscopists (hazard ratio [HR] 2.35; 95% CI 1.31-4.21; P = .004). For individuals with high-risk adenomas, colorectal cancer incidence was 1.14% (95% CI 0.87-1.48) with low-performing colonoscopists vs 0.43% (95% CI 0.27-0.69) with high-performing colonoscopists (HR 2.69; 95% CI 1.62-4.47; P.001). After negative colonoscopy, colorectal cancer incidence was 0.30% (95% CI 0.27-0.34) for individuals examined by low-performing colonoscopists, vs 0.15% (95% CI 0.11-0.20) for high-performing (HR 2.10; 95% CI 1.52-2.91; P.001). The observed trends were reproduced in the Austrian validation cohort.Our results suggest that endoscopist performance may be an important contributor in addition to polyp characteristics in determining colorectal cancer risk after colonoscopy screening.

Background There is concern but no solid evidence that morcellation during laparoscopic or vaginal hysterectomy may cause abdominal spread and thereby impaired prognosis of incidental uterine sarcomas. Objective Our purpose was to compare survival among patients with uterine sarcomas who underwent hysterectomy with or without morcellation to test the hypothesis that morcellation impairs prognosis. Study design We identified all women in Norway diagnosed with uterine sarcoma between 1953 and 2012 through national registries and retrieved data on surgical technique and morcellation by evaluation of patient files. Patients were categorised into abdominal, laparoscopic or vaginal hysterectomy with or without morcellation. Vaginal and laparoscopic hysterectomies were introduced in 1991; our main comparison is from 1991 to 2012. We compared age-adjusted disease-specific survival of sarcoma patients treated with or without morcellation and calculated age-adjusted hazard ratios (HRs) and subdistribution HR (accounting for competing risk) with 95% confidence intervals (CIs). Results Among 1367 patients with uterine sarcoma between 1953 and 2012 in Norway, 653 were diagnosed after 1991, and 23 of these patients (3.5%) underwent morcellation. Uterine sarcoma prevalence was 3.6 per 1000 laparoscopic hysterectomies. Mean follow-up was 6.0 years in the morcellated group and 6.9 years in the non-morcellated group. The risk of dying from uterine sarcoma after morcellation was 1.5 per 1000 procedures. Sarcoma mortality was higher in the morcellated group than in the non-morcellated group (age-adjusted HR 1.90, CI 1.05–3.44; multivariate HR, 2.50, 95% CI 0.57–10.9). Age-adjusted 10-year uterine sarcoma survival was 32.2% for women treated with morcellation compared with 57.2% for non-morcellated group (difference 25.5%; CI −55.7 to 18.1). All-cause 10-year survival was 32.2% in the morcellated group and 44.1% in the non-morcellated group (difference 11.9%; CI −40.9 to 32.7). Conclusion Our results strengthen the evidence that morcellation during hysterectomy in patients with incidental uterine sarcoma may cause impaired survival. These results can guide shared decision-making in clinical practice.

ObjectiveTo estimate overdiagnosis of colorectal cancer (CRC) for screening with sigmoidoscopy and faecal occult blood testing (FOBT).DesignSimulation study using data from randomised trials.SettingPrimary screening, UK, NorwayParticipants152 850 individuals from the Nottingham trial and 98 678 individuals from the Norwegian Colorectal Cancer Prevention (NORCCAP) trial.InterventionCRC screening.Outcome measureWe estimated overdiagnosis using long-term data from two randomised trials: the Nottingham trial comparing FOBT screening every other year to no-screening, and the NORCCAP trial comparing once-only sigmoidoscopy screening to no-screening. To estimate the natural growth of adenomas to CRC, we used the following microsimulation models: (i) the Microsimulation Screening Analysis; (ii) the CRC Simulated Population model for Incidence and Natural history; (iii) the Simulation Model of Colorectal Cancer; (iv) a model derived by the German Cancer Research Center. We defined overdiagnosed cancers as the difference between the observed number of CRCs in the no-screening arm and the expected number of cancers in screening arm (sum of observed and prevented by adenoma removal). The amount of overdiagnosis is defined as the number of overdiagnosed cancers over the number of cancers observed in the no-screening arm.ResultsOverdiagnosis estimates were highly dependent on model assumptions. For FOBT screening with 2354 cancers observed in control arm, four out of five models predicted overdiagnosis, range 2.0% (2400 cancers expected in screening) to 7.6% (2533 cancers expected in screening). For sigmoidoscopy screening with 452 cancers observed in control arm, all models predicted overdiagnosis, range 25.2% (566 cancers expected in screening) to 128.1% (1031 cancers expected in screening).ConclusionsThe amount of overdiagnosis estimated based on the microsimulation models varied substantially. Microsimulation models may not give reliable estimates of the preventive effect of adenoma removal, and should be used with caution to inform guidelines.

Improved understanding of the subsequent risk death from colorectal cancer (CRC) among individuals who had adenomas removed is needed. We aimed to quantify this risk using prospectively collected data from population-based cohorts.Using Norwegian and Swedish registries, a cohort of 90,864 individuals with colorectal adenomas removed between 1980 and 2013 was identified. Surveillance was only recommended for high-risk adenomas. The validity of the registry data did not allow classification into low- and high-risk adenomas. Virtually complete follow-up was achieved through linkage to nationwide registers. We calculated incidence-based standardised mortality ratios (SMRs) with 95% confidence intervals (CI).The median follow-up was 7.2 years; 48,058 individuals were followed for more than 10 years. We observed 819 deaths (0.9%) from CRC and expected 731 CRC deaths (0.8%), corresponding to an absolute excess risk of 88 cases (0.1%) and a relative risk of 12% (SMR 1.12; 95%CI 1.05-1.20). The relative risk of CRC death following adenoma removal was slightly higher in Sweden (SMR 1.22; 95%CI 1.11-1.34) than in Norway (SMR 1.03; 95%CI 0.93-1.14), and higher in women (SMR 1.24; 95%CI 1.12-1.36) than in men (SMR 1.02; 95%CI 0.93-1.13). Among individuals with more than 10 years of follow-up, the estimates were similar to the overall cohort, absolute excess risk 0.1% (SMR 1.15; 95%CI 1.06-1.24).The excess risk of CRC death following adenoma removal is small. Optimal surveillance recommendations should be tested in randomised trials.

The view, that rapidly growing tumours are more likely than slow-growing tumours to metastasize and become lethal, has remained almost axiomatic for decades. Unaware of any solid evidence supporting this view, we undertook an exhaustive system-level analysis of intra- and intercellular signalling networks. This analysis indicated that rapid growth and metastasis are often different outcomes of complex integrated molecular events. Evidence from humans can be derived chiefly from screening interventions because interval cancers that surface clinically shortly after a negative screening test are, on average, more rapidly growing than cancers not detected by screening. We reviewed all available data limited to cancers of the breast, cervix and large bowel. The evidence from humans provides no support for the theory that rapidly growing cancers are more prone to metastasize. These findings indicate that the prevailing view should be reconsidered, as should the impact of length-biased sampling in cancer screening, and the findings provide no support for treating interval cancers more aggressively than non-interval cancers.

SummaryBackground Both aspirin use and screening with flexible sigmoidoscopy or guaiac faecal occult blood testing (FOBT) may reduce mortality from colorectal cancer, but comparative effectiveness of these interventions is unknown. Aim To compare aspirin to guaiac FOBT screening with regard to incidence and mortality of colorectal cancer in a network meta-analysis. Methods We searched Medline, EMBASE and the COCHRANE central register (CENTRAL) for relevant randomised trials identified until 31 October 2015. Randomised trials in average-risk populations that reported colorectal cancer mortality, colorectal cancer incidence, or both, with a minimum follow-up of 2 years, and more than 100 randomised individuals were included. Three investigators independently extracted data. We calculated relative risks [RR with 95% predictive intervals (PrIs)] for the comparison of the interventions by frequentist network meta-analyses. Results The effect of aspirin on colorectal cancer mortality was similar to FOBT (RR 1.03; 95% PrI 0.76–1.39) and flexible sigmoidoscopy (RR 1.16; 95% PrI 0.84–1.60). Aspirin was more effective than FOBT (RR 0.36; 95% PrI 0.22–0.59) and flexible sigmoidoscopy (RR 0.37; 95% PrI 0.22–0.62) in preventing death from or cancer in the proximal colon. Aspirin was equally effective as screening in reducing colorectal cancer incidence, while flexible sigmoidoscopy was superior to FOBT (RR 0.84; 95% PrI 0.72–0.97). Conclusions Low-dose aspirin seems to be equally effective as flexible sigmoidoscopy or guaiac FOBT screening to reduce colorectal cancer incidence and mortality, and more effective for cancers in the proximal colon. A randomised comparative effectiveness trial of aspirin vs. screening is warranted.

Background & Aims Recommendation of surveillance colonoscopy should be based on risk of colorectal cancer and death after adenoma removal. We aimed to develop a risk classification system based on colorectal cancer incidence and mortality following adenoma removal. Methods We performed a multicenter population-based cohort study of 236,089 individuals (median patient age, 56 years; 37.8% male) undergoing screening colonoscopies with adequate bowel cleansing and cecum intubation at 132 centers in the Polish National Colorectal Cancer Screening Program, from 2000 through 2011. Subjects were followed for a median 7.1 years and information was collected on colorectal cancer development and death. We used recursive partitioning and multivariable Cox models to identify associations between colorectal cancer risk and patient and adenoma characteristics (diameter, growth pattern, grade of dysplasia, and number of adenomas). We developed a risk classification system based on standardized incidence ratios, using data from the Polish population for comparison. The primary endpoints were colorectal cancer incidence and colorectal cancer death. Results We identified 130 colorectal cancers in individuals who had adenomas removed at screening (46.5 per 100,000 person-years) vs 309 in individuals without adenomas (22.2 per 100,000 person-years). Compared with individuals without adenomas, adenomas ≥20 mm in diameter and high-grade dysplasia were associated with increased risk of colorectal cancer (adjusted hazard ratios 9.25; 95% confidence interval [CI] 6.39–13.39, and 3.58; 95% CI 1.96–6.54, respectively). Compared with the general population, colorectal cancer risk was higher or comparable only for individuals with adenomas ≥20 mm in diameter (standardized incidence ratio [SIR] 2.07; 95% CI 1.40–2.93) or with high-grade dysplasia (SIR 0.79; 95% CI 0.39–1.41), whereas for individuals with other adenoma characteristics the risk was lower (SIR 0.35; 95% CI 0.28–0.44). We developed a high-risk classification based on adenoma size ≥20 mm or high-grade dysplasia (instead of the current high-risk classification cutoff of ≥3 adenomas or any adenoma with villous growth pattern, high-grade dysplasia, or ≥10 mm in diameter). Our classification system would reduce the number of individuals classified as high-risk and requiring intensive surveillance from 15,242 (36.5%) to 3980 (9.5%), without increasing risk of colorectal cancer in patients with adenomas (risk difference per 100,000 person-years, 5.6; 95% CI –10.7 to 22.0). Conclusions Using data from the Polish National Colorectal Cancer Screening Program, we developed a risk classification system that would reduce the number of individuals classified as high risk and require intensive surveillance more than 3-fold, without increasing risk of colorectal cancer in patients with adenomas. This system could optimize the use of surveillance colonoscopy.

Colorectal cancer (CRC) screening programs are far from perfect. Many crucial questions remain, yet expensive CRC screening services are implemented throughout the world without a plan on how to evaluate and improve the service. The time is ripe for improving the design of CRC screening programs.

Background: Current guidelines recommend surveillance colonoscopies after polyp removal depending on the number and characteristics of polyps, but there is a lack of evidence supporting the recommendations. This report outlines the rationale and design of two randomized trials and one observational study investigating evidence-based surveillance strategies following polyp removal. Study design and endpoints: The EPoS studies started to recruit patients in April 2015. EPoS study I randomizes 13 746 patients with low-risk adenomas (1-2 tubular adenomas size = 10mm in diameter, or adenoma with high-grade dysplasia, or >25% villous features) to surveillance after 3, 5, and 10 years, or 5 and 10 years only. EPoS study III offers surveillance after 5 and 10 years to patients with serrated polyps >= 10mm in diameter at any location, or serrated polyps >= 5mm in diameter proximal to the splenic flexure. All polyps are removed before patients enter the trials. The primary end point is colorectal cancer incidence after 10 years. We assume a colorectal cancer risk of 1% for patients in EPoS I, and 2% for patients in EPoS II. Using a noninferiority hypothesis with an equivalence interval of 0.5% for EPoS I and 0.7% for EPoS II, the trials are 90% powered to uncover differences larger than the equivalence intervals. For EPoS III, no power analyses have been performed. Conclusions: The present trials aim to develop evidence-based strategies for polyp surveillance, thereby maximizing effectiveness and minimizing resources.

The long-term effects of sigmoidoscopy screening on colorectal cancer (CRC) incidence and mortality in women and men are unclear.To determine the effectiveness of flexible sigmoidoscopy screening after 15 years of follow-up in women and men.Randomized controlled trial. (ClinicalTrials.gov: NCT00119912).Oslo and Telemark County, Norway.Adults aged 50 to 64 years at baseline without prior CRC.Screening (between 1999 and 2001) with flexible sigmoidoscopy with and without additional fecal blood testing versus no screening. Participants with positive screening results were offered colonoscopy.Age-adjusted CRC incidence and mortality stratified by sex.Of 98 678 persons, 20 552 were randomly assigned to screening and 78 126 to no screening. Adherence rates were 64.7% in women and 61.4% in men. Median follow-up was 14.8 years. The absolute risks for CRC in women were 1.86% in the screening group and 2.05% in the control group (risk difference, -0.19 percentage point [95% CI, -0.49 to 0.11 percentage point]; HR, 0.92 [CI, 0.79 to 1.07]). In men, the corresponding risks were 1.72% and 2.50%, respectively (risk difference, -0.78 percentage point [CI, -1.08 to -0.48 percentage points]; hazard ratio [HR], 0.66 [CI, 0.57 to 0.78]) (P for heterogeneity = 0.004). The absolute risks for death from CRC in women were 0.60% in the screening group and 0.59% in the control group (risk difference, 0.01 percentage point [CI, -0.16 to 0.18 percentage point]; HR, 1.01 [CI, 0.77 to 1.33]). The corresponding risks for death from CRC in men were 0.49% and 0.81%, respectively (risk difference, -0.33 percentage point [CI, -0.49 to -0.16 percentage point]; HR, 0.63 [CI, 0.47 to 0.83]) (P for heterogeneity = 0.014).Follow-up through national registries.Offering sigmoidoscopy screening in Norway reduced CRC incidence and mortality in men but had little or no effect in women.Norwegian government and Norwegian Cancer Society.

Background & Aims Screening for colorectal cancer (CRC) with sigmoidoscopy reduces CRC incidence by detecting and removing adenomas. The number needed to screen is a measure of screening efficiency, but is not directly associated with adenoma removal. We propose the following 2 new metrics for quantifying the relationship between adenoma removal and CRC prevented: number of adenomas needed to remove (NNR) and adenoma dwell time avoided (DTA). Methods We collected data from 4 randomized trials of sigmoidoscopy screening (1 in the United States and 3 in Europe) to assess NNR and DTA. For each trial, NNR was computed as the number of adenomas removed from subjects in the intervention group, divided by the number of CRCs prevented. DTA was computed similarly but taking into account the timing of adenoma removal. Combined results across trials were assessed using standard meta-analytic techniques. Results The estimated NNR for the PLCO (Prostate, Lung, Colorectal and Ovarian) trial was 74 (95% confidence interval [CI], 56–110), for the NORCCAP (Norwegian Colorectal Cancer Prevention) trial was 71 (95% CI, 44–174), for the SCORE (Screening for Colon Rectum) trial was 27 (95% CI, 14–135), and for the UKFSST (UK Flexible Sigmoidoscopy Screening Trial) was 36 (95% CI, 28–52). The combined estimate (meta-analysis) of NNR was 52 (95% CI, 36–93) assuming heterogeneity (P for heterogeneity = .014). DTA estimates among trials ranged from 278 to 730 years, with a combined estimate of 500 (95% CI, 344–833) years assuming heterogeneity (P for heterogeneity = .035), or 2 CRC cases prevented per 1000 adenoma dwell years avoided. The combined estimates of NNR and DTA restricted to advanced adenomas were 13 (95% CI, 9–22) and 122 (95% CI, 90–190) years, respectively. Conclusions We collected data from 4 randomized trials of sigmoidoscopy screening for CRC to develop metrics of endoscopic efficiency, NNR and DTA, which are directly linked to adenoma detection and removal. They can be used to compare screening among endoscopic modalities and to more precisely measure adenoma to carcinoma transition rates.

Background Colonoscopy performance varies between endoscopists, but little is known about the impact of endoscopy assistants on key performance indicators. We used a large prospective colonoscopy quality database to perform an exploratory study to evaluate differences in selected quality indicators between endoscopy assistants. Methods All colonoscopies reported to the Norwegian colonoscopy quality assurance register Gastronet can be used to trace individual endoscopy assistants. We analyzed key quality indicators (cecum intubation rate, polyp detection rate, colonoscopies rated as severely painful, colonoscopies with sedation or analgesia, and satisfaction with information) for colonoscopies performed between 1 January 2013 and 31 December 2014. Differences between individual assistants were analyzed by fitting multivariable logistic regression models, with the best performing assistant at each participating hospital as reference. All models were adjusted for the endoscopist. Results 63 endoscopy assistants from 12 hospitals assisted in 15 365 colonoscopies. Compared with their top performing peers from the same hospital, one assistant was associated with cecum intubation failure, four with poor polyp detection, nine with painful colonoscopy, 16 with administration of sedation or analgesics during colonoscopy, and three with patient dissatisfaction about information given relating to the colonoscopy. The number of procedures during the study period or lifetime experience as an endoscopy assistant were not associated with any quality indicator. Conclusion In this exploratory study, there was little variation on important colonoscopy quality indicators between endoscopy assistants. However, there were differences among assistants that may be clinically important. Endoscopy assistants should be subject to quality surveillance similarly to endoscopists.

Objective There is uncertainty whether cancer screening affects participant incentives for favourable lifestyle. The present study investigates long-term effects of colorectal cancer (CRC) screening on lifestyle changes. Design In 1999–2001, men and women drawn from the population registry were randomised to screening for CRC by flexible sigmoidoscopy (‘invited-to-screening’ arm) or to no-screening (control arm) in the Norwegian Colorectal Cancer Prevention trial. A subgroup of 3043 individuals in the ‘invited-to-screening’ and 2819 in the control arm, aged 50–55 years, randomised during 2001 had their lifestyle assessed by a questionnaire at inclusion and after 11 years (42% of cohort). The outcome was 11-year changes in lifestyle factors (body weight, smoking status, physical exercise, selected dietary habits) and in total lifestyle score (0–4 points, translating to the number of lifestyle recommendations adhered to). We compared outcomes in the two randomisation arms and attendees with positive versus negative findings. Results Total lifestyle scores improved in both arms. The improvement was smaller in the ‘invited-to-screening’ arm (score 1.43 at inclusion; 1.58 after 11 years) compared with the control arm (score 1.49 at inclusion; 1.67 after 11 years); adjusted difference −0.05 (95% CI −0.09 to −0.01; p=0.03). The change in the score was less favourable in screening attendees with a positive compared with negative screening result; adjusted difference −0.16 (95% CI −0.25 to −0.08; p Conclusions The present study suggests that possible unfavourable lifestyle changes after CRC screening are modest. Lifestyle counselling may be considered as part of cancer screening programmes. Trial registration number NCT00119912.

Background & Aims Endoscopic screening for colorectal cancer (CRC) is performed at longer time intervals than the fecal occult blood test or screenings for breast or prostate cancer. This causes concerns about interval cancers, which have been proposed to progress more rapidly. We compared outcomes of patients with interval CRCs after sigmoidoscopy screening vs outcomes of patients with CRC who had not been screened. Methods We performed a secondary analysis of a randomized sigmoidoscopy screening trial in Norway with 98,684 participants (age range, 50–64 years) who were randomly assigned to groups that were (n = 20,552) or were not (n = 78,126) invited for sigmoidoscopy screening from 1999 through 2001; participants were followed up for a median 14.8 years. We compared CRC mortality and all-cause mortality between individuals who underwent screening and were diagnosed with CRC 30 days or longer after screening (interval cancer group, n = 163) and individuals diagnosed with CRC in the nonscreened group (controls, n = 1740). All CRCs in the control group were identified when they developed symptoms (clinically detected CRCs). Analyses were stratified by cancer site. We used Cox regression to estimate hazard ratio (HRs), adjusted for age and sex. Results Over the follow-up period, 43 individuals in the interval cancer group died from CRC; among controls, 525 died from CRC. CRC mortality (adjusted HR, 0.98; 95% confidence interval, 0.72–1.35; P = .92), rectosigmoid cancer mortality (adjusted HR, 1.10; 95% confidence interval, 0.63–1.92; P = .74), and all-cause mortality (adjusted HR, 0.99; 95% confidence interval, 0.76–1.27; P = .91) did not differ significantly between the interval cancer group and controls. Conclusions In this randomized sigmoidoscopy screening trial, mortality did not differ significantly between individuals with interval CRCs and unscreened patients with clinically detected CRCs. ClinicalTrials.gov identifier: NCT00119912 .

Surveillance is recommended for various GI cancers, and substantial resources are invested. However, little is known about the effect of surveillance, neither for good, nor for bad. Most evidence stems from observational studies, but observational studies of surveillance can be subject to various biases that may severely influence the results. In this chapter we discuss challenges related to various research questions, study designs, choice of endpoints, and how to deal with different forms of bias. We hope this chapter will be helpful for researchers when performing high-quality studies of surveillance, and to enable physicians and policy-makers to understand the possibilities and limitations of current evidence.

Background and study aims: Colonoscopy is frequently performed with opioid analgesia, but the impact of drug delivery timing has not been studied in detail. Low-dose opioids administered before the procedure may provide better pain control than on-demand administration when the patient experiences pain. Patients and methods: A total of 119 outpatients were randomized to receive 50 μg of fentanyl either before colonoscopy (routine group) or on demand if needed during the colonoscopy (on-demand group). Additional fentanyl or midazolam was allowed in both groups if required. The primary outcome was pain measured on both a 100-mm visual analog scale (VAS; 0 = no pain, 100 = worst possible pain) and a four-point Likert scale (no, slight, moderate, or severe pain) immediately after the procedure. Results: A total of 61 patients in the routine group and 58 patients in the on-demand group were included in the study. Mean VAS pain scores were 27.4 mm in the routine group and 30.5 mm in the on-demand group (mean difference – 3.2 mm; 95 % confidence interval – 11.9 to 5.5; P = 0.5). On the Likert scale, moderate or severe pain was experienced by 25.0 % and 31.5 % of patients in the routine and on-demand groups, respectively (p = 0.5). Cecal intubation rate and time to reach the cecum were similar between the groups. More patients in the on-demand group (81.0 %) than in the routine group (62.3 %) were able to leave the clinic without the need for recovery time (P = 0.03). Conclusion: Routine administration of fentanyl did not provide better analgesia during colonoscopy than on-demand fentanyl, and more patients needed time for recovery. Trial registration: ClinicalTrials.gov (NCT01786434).

IMPORTANCE Although some countries have implemented widespread colonoscopy screening, most European countries have not introduced it because of uncertainty regarding participation rates, procedure-related pain and discomfort, endoscopist performance, and effectiveness. To our knowledge, no randomized trials on colonoscopy screening currently exist. OBJECTIVE To investigate participation rate, adenoma yield, performance, and adverse events of population-based colonoscopy screening in several European countries. DESIGN, SETTING, AND POPULATION A population-based randomized clinical trial was conducted among 94959 men and women aged 55 to 64 years of average risk for colon cancer in Poland, Norway, the Netherlands, and Sweden from June 8, 2009, to June 23, 2014. INTERVENTIONS Colonoscopy screening or no screening. MAIN OUTCOMES AND MEASURES Participation in colonoscopy screening, cancer and adenoma yield, and participant experience. Study outcomes were compared by country and endoscopist. RESULTS Of 31 420 eligible participants randomized to the colonoscopy group, 12 574 (40.0%) underwent screening. Participation rates were 60.7% in Norway (5354 of 8816), 39.8% in Sweden (486 of 1222), 33.0% in Poland (6004 of 18 188), and 22.9% in the Netherlands (730 of 3194) (P < .001). The cecum intubation rate was 97.2%(12 217 of 12 574), with 9726 participants (77.4%) not receiving sedation. Of the 12 574 participants undergoing colonoscopy screening, we observed 1 perforation (0.01%), 2 postpolypectomy serosal burns (0.02%), and 18 cases of bleeding owing to polypectomy (0.14%). Sixty-two individuals (0.5%) were diagnosed with colorectal cancer and 3861 (30.7%) had adenomas, of which 1304 (10.4%) were high-risk adenomas. Detection rates were similar in the proximal and distal colon. Performance differed significantly between endoscopists; recommended benchmarks for cecal intubation (95%) and adenoma detection (25%) were not met by 6 (17.1%) and 10 of 35 endoscopists (28.6%), respectively. Moderate or severe abdominal pain after colonoscopy was reported by 601 of 3611 participants (16.7%) examined with standard air insufflation vs 214 of 5144 participants (4.2%) examined with carbon dioxide (CO2) insufflation (P < .001). CONCLUSIONS AND RELEVANCE Colonoscopy screening entails high detection rates in the proximal and distal colon. Participation rates and endoscopist performance vary significantly. Postprocedure abdominal pain is common with standard air insufflation and can be significantly reduced by using CO2.

Mammography screening for breast cancer is widely available in many countries. Initially praised as a universal achievement to improve women's health and to reduce the burden of breast cancer, the benefits and harms of mammography screening have been debated heatedly in the past years. This review discusses the benefits and harms of mammography screening in light of findings from randomized trials and from more recent observational studies performed in the era of modern diagnostics and treatment. The main benefit of mammography screening is reduction of breast-cancer related death. Relative reductions vary from about 15 to 25% in randomized trials to more recent estimates of 13 to 17% in meta-analyses of observational studies. Using UK population data of 2007, for 1,000 women invited to biennial mammography screening for 20 years from age 50, 2 to 3 women are prevented from dying of breast cancer. All-cause mortality is unchanged. Overdiagnosis of breast cancer is the main harm of mammography screening. Based on recent estimates from the United States, the relative amount of overdiagnosis (including ductal carcinoma in situ and invasive cancer) is 31%. This results in 15 women overdiagnosed for every 1,000 women invited to biennial mammography screening for 20 years from age 50. Women should be unpassionately informed about the benefits and harms of mammography screening using absolute effect sizes in a comprehensible fashion. In an era of limited health care resources, screening services need to be scrutinized and compared with each other with regard to effectiveness, cost-effectiveness and harms.

Background The per-protocol effect is the effect that would have been observed in a randomized trial had everybody followed the protocol. Though obtaining a valid point estimate for the per-protocol effect requires assumptions that are unverifiable and often implausible, lower and upper bounds for the per-protocol effect may be estimated under more plausible assumptions. Strategies for obtaining bounds, known as “partial identification” methods, are especially promising in randomized trials. Results We estimated bounds for the per-protocol effect of colorectal cancer screening in the Norwegian Colorectal Cancer Prevention trial, a randomized trial of one-time sigmoidoscopy screening in 98,792 men and women aged 50–64 years. The screening was not available to the control arm, while approximately two thirds of individuals in the treatment arm attended the screening. Study outcomes included colorectal cancer incidence and mortality over 10 years of follow-up. Without any assumptions, the data alone provide little information about the size of the effect. Under the assumption that randomization had no effect on the outcome except through screening, a point estimate for the risk under no screening and bounds for the risk under screening are achievable. Thus, the 10-year risk difference for colorectal cancer was estimated to be at least −0.6 % but less than 37.0 %. Bounds for the risk difference for colorectal cancer mortality (–0.2 to 37.4 %) and all-cause mortality (–5.1 to 32.6 %) had similar widths. These bounds appear helpful in quantifying the maximum possible effectiveness, but cannot rule out harm. By making further assumptions about the effect in the subpopulation who would not attend screening regardless of their randomization arm, narrower bounds can be achieved. Conclusions Bounding the per-protocol effect under several sets of assumptions illuminates our reliance on unverifiable assumptions, highlights the range of effect sizes we are most confident in, and can sometimes demonstrate whether to expect certain subpopulations to receive more benefit or harm than others. Trial registration Clinicaltrials.gov identifier NCT00119912 (registered 6 July 2005)

Although colonoscopic surveillance of patients after removal of adenomas is widely promoted, little is known about colorectal-cancer mortality among these patients.Using the linkage of the Cancer Registry and the Cause of Death Registry of Norway, we estimated colorectal-cancer mortality among patients who had undergone removal of colorectal adenomas during the period from 1993 through 2007. Patients were followed through 2011. We calculated standardized incidence-based mortality ratios (SMRs) using rates for the Norwegian population at large for comparison. Norwegian guidelines recommended colonoscopy after 10 years for patients with high-risk adenomas (adenomas with high-grade dysplasia, a villous component, or a size ≥10 mm) and after 5 years for patients with three or more adenomas; no surveillance was recommended for patients with low-risk adenomas. Polyp size and exact number were not available in the registry. We defined high-risk adenomas as multiple adenomas and adenomas with a villous component or high-grade dysplasia.We identified 40,826 patients who had had colorectal adenomas removed. During a median follow-up of 7.7 years (maximum, 19.0), 1273 patients were given a diagnosis of colorectal cancer. A total of 398 deaths from colorectal cancer were expected and 383 were observed, for an SMR of 0.96 (95% confidence interval [CI], 0.87 to 1.06) among patients who had had adenomas removed. Colorectal-cancer mortality was increased among patients with high-risk adenomas (expected deaths, 209; observed deaths, 242; SMR, 1.16; 95% CI, 1.02 to 1.31), but it was reduced among patients with low-risk adenomas (expected deaths, 189; observed deaths, 141; SMR, 0.75; 95% CI, 0.63 to 0.88).After a median of 7.7 years of follow-up, colorectal-cancer mortality was lower among patients who had had low-risk adenomas removed and moderately higher among those who had had high-risk adenomas removed, as compared with the general population. (Funded by the Norwegian Cancer Society and others.).

Colorectal cancer is a major health burden. Screening is recommended in many countries.To estimate the effectiveness of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality in a population-based trial.Randomized clinical trial of 100,210 individuals aged 50 to 64 years, identified from the population of Oslo city and Telemark County, Norway. Screening was performed in 1999-2000 (55-64-year age group) and in 2001 (50-54-year age group), with follow-up ending December 31, 2011. Of those selected, 1415 were excluded due to prior colorectal cancer, emigration, or death, and 3 could not be traced in the population registry.Participants randomized to the screening group were invited to undergo screening. Within the screening group, participants were randomized 1:1 to receive once-only flexible sigmoidoscopy or combination of once-only flexible sigmoidoscopy and fecal occult blood testing (FOBT). Participants with positive screening test results (cancer, adenoma, polyp ≥10 mm, or positive FOBT) were offered colonoscopy. The control group received no intervention.Colorectal cancer incidence and mortality.A total of 98,792 participants were included in the intention-to-screen analyses, of whom 78,220 comprised the control group and 20,572 comprised the screening group (10,283 randomized to receive a flexible sigmoidoscopy and 10,289 to receive flexible sigmoidoscopy and FOBT). Adherence with screening was 63%. After a median of 10.9 years, 71 participants died of colorectal cancer in the screening group vs 330 in the control group (31.4 vs 43.1 deaths per 100,000 person-years; absolute rate difference, 11.7 [95% CI, 3.0-20.4]; hazard ratio [HR], 0.73 [95% CI, 0.56-0.94]). Colorectal cancer was diagnosed in 253 participants in the screening group vs 1086 in the control group (112.6 vs 141.0 cases per 100,000 person-years; absolute rate difference, 28.4 [95% CI, 12.1-44.7]; HR, 0.80 [95% CI, 0.70-0.92]). Colorectal cancer incidence was reduced in both the 50- to 54-year age group (HR, 0.68; 95% CI, 0.49-0.94) and the 55- to 64-year age group (HR, 0.83; 95% CI, 0.71-0.96). There was no difference between the flexible sigmoidoscopy only vs the flexible sigmoidoscopy and FOBT screening groups.In Norway, once-only flexible sigmoidoscopy screening or flexible sigmoidoscopy and FOBT reduced colorectal cancer incidence and mortality on a population level compared with no screening. Screening was effective both in the 50- to 54-year and the 55- to 64-year age groups.clinicaltrials.gov Identifier: NCT00119912.

Objective Although serrated polyps may be precursors of colorectal cancer (CRC), prospective data on the long-term CRC risk in individuals with serrated polyps are lacking. Design In a population-based randomised trial, 12 955 individuals aged 50–64 years were screened with flexible sigmoidoscopy, while 78 220 individuals comprised the control arm. We used Cox models to estimate HRs with 95% CIs for CRC among individuals with ≥1 large serrated polyp (≥10 mm in diameter), compared with individuals with adenomas at screening, and to population controls, and multivariate logistic regression to assess polyp risk factors for CRC. Results A total of 103 individuals had large serrated polyps, of which 81 were included in the analyses. Non-advanced adenomas were found in 1488 individuals, advanced adenomas in 701. Median follow-up was 10.9 years. Compared with the control arm, the HR for CRC was 2.5 (95% CI 0.8 to 7.8) in individuals with large serrated polyps, 2.0 (95% CI 1.3 to 2.9) in individuals with advanced adenomas and 0.6 (95% CI 0.4 to 1.1) in individuals with non-advanced adenomas. A large serrated polyp was an independent risk factor for CRC, adjusted for histology, size and multiplicity of concomitant adenomas (OR 3.3; 95% CI 1.3 to 8.6). Twenty-three large serrated polyps found at screening were left in situ for a median of 11.0 years. None developed into a malignant tumour. Conclusions Individuals with large serrated polyps have an increased risk of CRC, comparable with individuals with advanced adenomas. However, this risk may not be related to malignant growth of the serrated polyp. Trial registration number The Norwegian Colorectal Cancer Screening trial is registered at clinicaltrials.gov (NCT00119912).