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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.

There is considerable variation in the quality of colonoscopy performance. The Norwegian quality assurance programme Gastronet registers outpatient colonoscopies performed in Norwegian endoscopy centres. The aim of Gastronet is long-term improvement of endoscopist and centre performance by annual feedback of performance data.The objective of this article is to perform an analysis of trends of quality indicators for colonoscopy in Gastronet.This prospective cohort study included 73,522 outpatient colonoscopies from 73 endoscopists at 25 endoscopy centres from 2003 to 2012. We used multivariate logistic regression with adjustment for relevant variables to determine annual trends of three performance indicators: caecum intubation rate, pain during the procedure, and detection rate of polyps ≥5 mm.The proportion of severely painful colonoscopies decreased from 14.8% to 9.2% (relative risk reduction of 38%; OR = 0.92 per year in Gastronet; 95% CI 0.86-1.00; p = 0.045). Caecal intubation (OR = 0.99; 95% CI 0.94-1.04; p = 0.6) and polyp detection (OR = 1.03; 95% CI 0.99-1.07; p = 0.15) remained unchanged during the study period.Pain at colonoscopy showed a significant decrease during years of Gastronet participation while caecal intubation and polyp detection remained unchanged - independent of the use of sedation and/or analgesics and level of endoscopist experience. This may be due to the Gastronet audit, but effects of improved endoscopy technology cannot be excluded.

BACKGROUND Questionnaire surveys are important for surveying the health and disease behaviour of the population, but recent years have seen a fall in participation. Our study tested whether incentives can increase participation in these surveys.MATERIAL AND METHOD We sent a questionnaire on risk factors for colorectal cancer (height, weight, smoking, self-reported diagnoses, family medical history) to non-screened participants in a randomised colonoscopy screening study for colorectal cancer: participants who were invited but did not attend for colonoscopy examination (screening-invited) and persons who were not offered colonoscopy (control group). The persons were randomised to three groups: no financial incentive, lottery scratch cards included with the form, or a prize draw for a tablet computer when they responded to the form. We followed up all the incentive groups with telephone reminder calls, and before the prize draw for the tablet computer.RESULTS Altogether 3 705 of 6 795 persons (54.5 %) responded to the questionnaire; 43.5 % of those invited for screening and 65.6 % of the control group (p < 0.001). The proportion that answered was not influenced by incentives, either among those invited for screening (42.4 % in the non-prize group, 45.5 % in the lottery scratch card group and 42.6 % in the prize draw group; p = 0.24), or in the control group (65.6 % in the non-prize group, 66.4 % in the lottery scratch card group and 64.7 % in the prize draw group; p = 0.69). Prior to reminder calls, 39.2 % responded. A further 15.3 % responded following telephone reminder calls (14.1 % of the screening-invited and 16.5 % of the control group; p < 0.001).INTERPRETATION Incentives did not increase participation in this medical questionnaire survey. Use of telephone reminder calls and telephone interviews increased participation, but whether this is more effective than other methods requires further study.

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.

BACKGROUND The post cardiac arrest syndrome (PCAS) is responsible for the majority of in-hospital deaths following cardiac arrest (CA). The major elements of PCAS are anoxic brain injury and circulatory failure. OBJECTIVE This study aimed to investigate the clinical characteristics of circulatory failure and inflammatory responses after out-of-hospital cardiac arrest (OHCA) and to identify patterns of circulatory and inflammatory responses, which may predict circulatory deterioration in PCAS. METHODS This study is a single-center cohort study of 50 patients who receive intensive care after OHCA. The patients are followed for 5 days where detailed information from circulatory variables, including measurements by pulmonary artery catheters (PACs), is obtained in high resolution. Blood samples for inflammatory and endothelial biomarkers are taken at inclusion and thereafter daily. Every 10 min, the patients will be assessed and categorized in one of three circulatory categories. These categories are based on mean arterial pressure; heart rate; serum lactate concentrations; superior vena cava oxygen saturation; and need for fluid, vasoactive medications, and other interventions. We will analyze predictors of circulatory failure and their relation to inflammatory biomarkers. RESULTS Patient inclusion started in January 2016. CONCLUSIONS This study will obtain advanced hemodynamic data with high resolution during the acute phase of PCAS and will analyze the details in circulatory state transitions related to circulatory failure. We aim to identify early predictors of circulatory deterioration and favorable outcome after CA. CLINICALTRIAL ClinicalTrials.gov: NCT02648061; https://clinicaltrials.gov/ct2/show/NCT02648061 (Archived by WebCite at http://www.webcitation.org/6wVASuOla)

Objective To compare the effectiveness of flexible sigmoidoscopy in screening for colorectal cancer by patient sex and age. Design Pooled analysis of randomised trials (the US Prostate, Lung, Colorectal and Ovarian cancer screening trial (PLCO), the Italian Screening for Colon and Rectum trial (SCORE), and the Norwegian Colorectal Cancer Prevention trial (NORCCAP)). Data sources Aggregated data were pooled from each randomised trial on incidence of colorectal cancer and mortality stratified by sex, age at screening, and colon subsite (distal v proximal). Eligibility criteria for selecting studies Invited individuals aged 55-74 (PLCO), 55-64 (SCORE), and 50-64 (NORCCAP). Individuals were randomised to receive flexible sigmoidoscopy screening once only (SCORE and NORCCAP) or twice (PLCO), or receive usual care (no intervention). Results 287 928 individuals were included in the pooled analysis; 115 139 randomised to screening and 172 789 to usual care. Compliance rates were 58%, 63%, and 87% in SCORE, NORCCAP, and PLCO, respectively. Median follow-up was 10.5 to 12.1 years. Screening reduced the incidence of colorectal cancer in men (relative risk 0.76; 95% confidence interval 0.70 to 0.83) and women (0.83; 0.75 to 0.92). No difference in the effect of screening was seen between men younger than 60 and those older than 60. Screening reduced the incidence of colorectal cancer in women younger than 60 (relative risk 0.71; 95% confidence interval 0.59 to 0.84), but not significantly in those aged 60 or older (0.90; 0.80 to 1.02). Colorectal cancer mortality was significantly reduced in both younger and older men, and in women younger than 60. Screening reduced colorectal cancer incidence to a similar extent in the distal colon in men and women, but there was no effect of screening in the proximal colon in older women with a significant interaction between sex and age group (P=0.04). Conclusion Flexible sigmoidoscopy is an effective tool for colorectal cancer screening in men and younger women. The benefit is smaller and not statistically significant for women aged over 60; alternative screening methods that more effectively detect proximal tumours should be considered for these women.

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.

Fecal Microbiota for Clostridium difficile Clostridium difficile is the leading cause of nosocomial infectious diarrhea. New treatment strategies are needed. In this letter, preliminary data on fecal therapy as primary treatment are assessed.

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.

Colonoscopes with gradual stiffness have recently been developed to enhance cecal intubation.We aimed to determine if the performance of gradual stiffness colonoscopes is noninferior to that of magnetic endoscopic imaging (MEI)-guided variable stiffness colonoscopes.Consecutive patients were randomized to screening colonoscopy with Fujifilm gradual stiffness or Olympus MEI-guided variable stiffness colonoscopes. The primary endpoint was cecal intubation rate (noninferiority limit 5%). Secondary endpoints included cecal intubation time. We estimated absolute risk differences with 95% confidence intervals (CIs).We enrolled 475 patients: 222 randomized to the gradual stiffness instrument, and 253 to the MEI-guided variable stiffness instrument. Cecal intubation rate was 91.7% in the gradual stiffness group versus 95.6% in the variable stiffness group. The adjusted absolute risk for cecal intubation failure was 4.3% higher in the gradual stiffness group than in the variable stiffness group (upper CI border 8.1%). Median cecal intubation time was 13 minutes in the gradual stiffness group and 10 minutes in the variable stiffness group (The study is inconclusive with regard to noninferiority because the 95% CI for the difference in cecal intubation rate between the groups crosses the noninferiority margin. (ClinicalTrials.gov identifier: NCT01895504).

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).

In randomized trials, the most commonly reported method of effect estimation is intention-to-treat (ITT), and to a lesser extent the per-protocol. The ITT is preferred because it is an unbiased estimator of the effect of treatment assignment. However, if there is any non-adherence the ITT is a biased estimate of the treatment effect, defined as the contrast between the potential outcome if treated versus the potential outcome if not treated. The treatment effect is most relevant to patients. Principal stratification is a framework for estimating treatment effects that combines potential outcomes and latent adherence strata. It yields an unbiased estimator of the complier average causal effect (CACE) for a difference in means or proportions, in the setting of all-or-nothing adherence. This paper addresses estimation of the causal hazard ratio for the compliers in a setting of right censoring of a time-to-event. We propose a novel approach to operationalizing principal stratification using weights. We report the results of simulations that vary the amount of adherence and selection bias that show the hazard ratio estimators we propose have minimal bias compared to the ITT, and per-protocol estimators. We demonstrate the approach using a population based randomized controlled trial of colorectal cancer screening subject to a high frequency of nonadherence in the screening arm.

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)

We thank Doherty and Hawkins for their responses to our article.123 Our paper is a meta-analysis, so we adhered to the PRISMA guidelines.4 The CONSORT guidelines, as mentioned by Doherty, are for individual randomised trials and do not apply to our paper. The …

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).

Background Denmark and Norway are the best countries to study effects of mammography screening, because they are the only countries with stepwise introduction of nationwide mammography screening, enabling comparative effectiveness studies of high quality. Although Denmark and Norway are countries with similar populations and health care systems, reported reductions in breast cancer mortality (incidence-based) caused by screening differed vastly; 25% in Denmark versus 10% in Norway. This study explores reasons for this difference. Patients and Methods We compared two published studies from the Danish and Norwegian screening programs (Olsen et al., 2005; Kalager et al., 2010) investigating biennial mammography screening for women age 50–69 years. Four comparison groups of women were constructed (‘current’ and ‘historical screening groups’; ‘current’ and ‘historical nonscreening groups’) based on county of residence. We calculated incidence-based breast cancer mortality in the current versus the historical period for screening and nonscreening groups, using mortality rate ratios (MRR) in the two countries, accounting for concomitant changes in breast cancer mortality. Results In the screening groups, similar reductions in breast cancer mortality were found when periods preceding and following start of screening were compared, in Denmark [25%; MRR 0.75; 95% confidence interval (CI) 0.64% to 0.88%] and in Norway (28%; MRR 0.72; 95% CI 0.63% to 0.81%). However, mortality increased in Denmark in the current nonscreening group compared with the historical nonscreening group; for women >59 years, breast cancer mortality increased by 14% (MRR 1.14, 95% CI 1.07–1.22), whereas in Norway a 19% reduction was seen (MRR 0.81, 95% CI 0.72–0.92). This increase accounts for the different relative effect of screening in Denmark and Norway; 25% breast cancer mortality reduction in Denmark, 10% in Norway. Conclusions The seemingly larger effect of screening in Denmark may not be solely attributable to screening itself, but to increased breast cancer mortality in women older than 59 years not invited to screening.

The authors discuss concerns about the updated recommendations for colorectal cancer screening from the USPSTF. They advocate for integration of high-quality clinical trials into ongoing screening ...

Background Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality. A well-defined precursor lesion (adenoma) and a long preclinical course make CRC a candidate for screening. This paper reviews the current evidence for the most important tests that are widely used or under development for population-based screening. Material and methods In this narrative review, we scrutinized all papers we have been aware of, and carried out searches in PubMed and Cochrane library for relevant literature. Results Two screening methods have been shown to reduce CRC mortality in randomised trials: repetitive faecal occult blood testing (FOBT) reduces CRC mortality by 16%; once-only flexible sigmoidoscopy (FS) by 28%. FS screening also reduces CRC incidence (by 18%), FOBT does not. Colonoscopy screening has a potentially larger effect on CRC incidence and mortality, but randomised trials are lacking. New screening methods are on the horizon but need to be tested in large clinical trials before implementation in population screening. Conclusions FS screening reduces CRC incidence and CRC mortality by removal of adenomas; FOBT reduces CRC mortality by early detection of cancer. Several other tests are available, but none has been evaluated in randomised trials. Screening strategies differ considerably across countries.