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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.

ObjectiveHigh-quality colonoscopy (adequate bowel preparation, whole-colon visualisation and removal of all neoplastic polyps) is a prerequisite to start polyp surveillance, and is ideally achieved in one colonoscopy. In a large multinational polyp surveillance trial, we aimed to investigate clinical practice variation in number of colonoscopies needed to enrol patients with low-risk and high-risk adenomas in polyp surveillance.DesignWe retrieved data of all patients with low-risk adenomas (one or two tubular adenomas ResultsThe study comprised 15 581 patients from 38 endoscopy centres in five European countries; 6794 patients had low-risk and 8787 had high-risk adenomas. 961 patients (6.2%, 95% CI 5.8% to 6.6%) underwent two or more colonoscopies before surveillance began; 101 (1.5%, 95% CI 1.2% to 1.8%) in the low-risk group and 860 (9.8%, 95% CI 9.2% to 10.4%) in the high-risk group. Main reasons were poor bowel preparation (21.3%) or incomplete colonoscopy/polypectomy (14.4%) or planned second procedure (27.8%). Need of repeat colonoscopy varied between study centres ranging from 0% to 11.8% in low-risk adenoma patients and from 0% to 63.9% in high-risk adenoma patients. On the second colonoscopy, the two most common reasons for a repeat (third) colonoscopy were piecemeal resection (26.5%) and unspecified reason (23.9%).ConclusionThere is considerable practice variation in the number of colonoscopies performed to achieve complete polyp removal, indicating need for targeted quality improvement to reduce patient burden.Trial registration numberNCT02319928.

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 Endoscopic screening with polypectomy reduces the incidence of colorectal cancer (CRC). Incomplete polyp removal may attenuate the effect of screening. This randomized trial compared cold snare polypectomy (CSP) with hot snare polypectomy (HSP) in terms of complete polyp resection. Methods We included patients ≥ 40 years of age at eight hospitals in four countries who had at least one non-pedunculated polyp of 4–9 mm detected at colonoscopy. Patients were randomized 1:1 to CSP or HSP. Biopsies from the resection margins were obtained systematically after polypectomy in both groups. We hypothesized that CSP would be non-inferior to HSP, with a non-inferiority margin of 5 %. Logistic regression models were fitted to identify the factors explaining incomplete resection. Results 425 patients, with 601 polyps, randomized to either CSP or HSP were included in the analysis. Of 318 polyps removed by CSP and 283 polyps removed by HSP, 34 (10.7 %) and 21 (7.4 %) were incompletely resected, respectively, with an adjusted risk difference of 3.2 % (95 %CI −1.4 % to 7.8 %). There was no difference between the groups in terms of post-polypectomy bleeding, perforation, or abdominal pain. Independent risk factors for incomplete removal were serrated histology (odds ratio [OR] 3.96; 95 %CI 1.63 to 9.66) and hyperplastic histology (OR 2.52; 95 %CI 1.30 to 4.86) in adjusted analyses. Conclusion In this randomized trial, non-inferiority for CSP could not be demonstrated. Polyps with serrated histology are more prone to incomplete resection compared with adenomas. CSP can be used safely for small polyps in routine colonoscopy practice.

Background Women and men with colorectal adenomas are at increased risk of colorectal cancer and colonoscopic surveillance is recommended. However, the long-term cancer risk remains unknown. Aims To investigate colorectal cancer incidence and mortality after adenoma removal in women and men METHODS: We identified all individuals who had adenomas removed in Norway from 1993 to 2007, with follow-up through 2018. We calculated standardized incidence ratios (SIR) and incidence-based mortality ratios (SMR) with 95% confidence intervals (CI) for colorectal cancer in women and men using the female and male population for comparison. We defined high-risk adenomas as ≥2 adenomas, villous component, or high-grade dysplasia. Results The cohort comprised 40 293 individuals. During median follow-up of 13.0 years, 1079 women (5.5%) and 866 men (4.2%) developed colorectal cancer; 328 women (1.7%) and 275 men (1.3%) died of colorectal cancer. Colorectal cancer incidence was more increased in women (SIR 1.64, 95% CI 1.54-1.74) than in men (SIR 1.12, 95% CI 1.05-1.19). Colorectal cancer mortality was increased in women (SMR 1.13, 95% CI 1.02-1.26) and reduced in men (SMR 0.79, 95% CI 0.71-0.89). Women with high-risk adenomas had an increased risk of colorectal cancer death (SMR 1.37, 95% CI 1.19-1.57); women with low-risk adenomas (SMR 0.90, 95% CI 0.76-1.07) and men with high-risk adenomas had a similar risk (SMR 0.89, 95% CI 0.76-1.04), while men with low-risk adenomas had reduced risk (SMR 0.70, 95% CI 0.59-0.84). Conclusions After adenoma removal, women had an increased risk of colorectal cancer death, while men had reduced risk, compared to the general female and male populations. Sex-specific surveillance recommendations after adenoma removal should be considered.

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.).

Repeated rounds of faecal immunochemical testing (FIT) for occult blood is a common method for screening for colorectal cancer (CRC). However, the time interval between FIT rounds is not thoroughly investigated. In a CRC screening trial in South-Eastern Norway, individuals were invited for biennial FIT between 2012 and 2019. The positivity threshold was15 mcg haemoglobin/g faeces (mcg/g). Due to organizational challenges, the interval between screening rounds randomly varied between 1.5 and 3.5 years, forming a natural experiment. We investigated the detection rate of CRC and advanced neoplasia (AN: CRC or advanced adenoma) at the subsequent round (FIT

ObjectiveTo estimate the risk of non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL) in patients with inflammatory bowel disease (IBD).DesignWe undertook a two-country population cohort study with all patients diagnosed with IBD in Norway and Sweden from 1987 and 1993 through 2015 and 2016, respectively, and analysed the risk of NHL and HL. In Sweden, we also analysed prescriptions of thiopurines and anti-tumour necrosis factor (TNF)-α therapy from 2005. We calculated standardised incidence ratios (SIRs) with 95% CIs using the general populations as reference.ResultsAmong 131 492 patients with IBD with a medium follow-up of 9.6 years, we identified 369 cases of NHL and 44 cases of HL. The SIR of NHL was 1.3 (95% CI 1.1 to 1.5) in ulcerative colitis and 1.4 (95% CI 1.2 to 1.7) in Crohn’s disease. We found no compelling heterogeneity in analyses stratified by patient characteristics. We found a similar pattern and magnitude of excess risks for HL. At 10 years, cumulative incidence was 0.26% (95% CI 0.23% to 0.30%) and 0.06% (95% CI 0.04% to 0.08%) for NHL and HL, respectively. Higher excess risks were found among patients with NHL with concomitant primary sclerosing cholangitis (SIR 3.4; 95% CI 2.1 to 5.2) and in those prescribed thiopurines alone (SIR 2.8; 95% CI 1.4 to 5.7) or with anti-TNF-α agents (SIR 5.7; 95% CI 2.7 to 11.9).ConclusionPatients with IBD have a statistically significant increased risk of malignant lymphomas compared with the general population, but the absolute risk remains low.

Artificial intelligence (AI) tools aimed at improving polyp detection have been shown to increase the adenoma detection rate during colonoscopy. However, it is unknown how increased polyp detection rates by AI affect the burden of patient surveillance after polyp removal.We conducted a pooled analysis of 9 randomized controlled trials (5 in China, 2 in Italy, 1 in Japan, and 1 in the United States) comparing colonoscopy with or without AI detection aids. The primary outcome was the proportion of patients recommended to undergo intensive surveillance (ie, 3-year interval). We analyzed intervals for AI and non-AI colonoscopies for the U.S. and European recommendations separately. We estimated proportions by calculating relative risks using the Mantel-Haenszel method.A total of 5796 patients (51% male, mean 53 years of age) were included; 2894 underwent AI-assisted colonoscopy and 2902 non-AI colonoscopy. When following U.S. guidelines, the proportion of patients recommended intensive surveillance increased from 8.4% (95% CI, 7.4%-9.5%) in the non-AI group to 11.3% (95% CI, 10.2%-12.6%) in the AI group (absolute difference, 2.9% [95% CI, 1.4%-4.4%]; risk ratio, 1.35 [95% CI, 1.16-1.57]). When following European guidelines, it increased from 6.1% (95% CI, 5.3%-7.0%) to 7.4% (95% CI, 6.5%-8.4%) (absolute difference, 1.3% [95% CI, 0.01%-2.6%]; risk ratio, 1.22 [95% CI, 1.01-1.47]).The use of AI during colonoscopy increased the proportion of patients requiring intensive colonoscopy surveillance by approximately 35% in the United States and 20% in Europe (absolute increases of 2.9% and 1.3%, respectively). While this may contribute to improved cancer prevention, it significantly adds patient burden and healthcare costs.

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 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.

Introduction: In colorectal cancer (CRC) surveillance, adenoma characteristics such as size, number of adenomas, dysplasia, and villous components, are used as indicators for risk of developing metachronous cancer and guide the surveillance interval. The current risk groups (e.g., advanced adenomas) cannot optimally distinguish high risk from low risk, which may result in suboptimal surveillance strategies. Specific DNA copy number aberrations are associated with risk of colorectal adenoma-to-carcinoma progression, but these aberrations are present in only a subset of advanced adenomas. Therefore, we hypothesize that specific DNA copy number aberrations may better predict the risk of CRC than advanced adenoma. Aim: To evaluate whether a molecularly-defined high-risk adenoma is a better risk factor for CRC than the presently used advanced adenoma. Materials and methods: DNA copy number profiles were determined, by means of low-coverage whole genome sequencing, on a series of 529 adenomas, selected from a Norwegian adenoma cohort. We retrieved detailed information on adenoma characteristics and whether adenoma patients were subsequently diagnosed with CRC or not. By univariate and multivariate regression analysis we estimated the odds ratio for association between the development of CRC and baseline presence of advanced adenoma versus presence of a molecularly-defined high-risk adenoma, respectively. Results: Molecular high-risk features were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. The odds ratio for developing metachronous CRC was 3.58 (p=2.84E-8) and 1.90 (p=0.012), when an advanced adenoma or molecular high-risk adenoma was detected at the baseline colonoscopy, respectively. In the multivariate regression analysis only advanced adenoma was as a significant risk factor for CRC. Conclusion: Molecularly-defined high-risk adenomas are associated with an increased risk of CRC. However, the advanced adenoma is a stronger predictor for risk of CRC. Citation Format: Henriette C. Jodal, Eddymurphy U. Akwiwu, Leticia G. Leon, Margriet Lemmens, Pien Delis-van Diemen, Dagmar Klotz, Meike de Wit, Remond Fijneman, Monique van Leerdam, Evelien Dekker, Manon C. W. Spaander, Gerrit A. Meijer, Michael Bretthauer, Magnus Løberg, Veerle M. H. Coupé, Mette Kalager, Beatriz Carvalho. Molecular adenoma features to predict metachronous colorectal cancer risk: A nested-case control study [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A004.

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: Observational studies are increasingly used to estimate the effectiveness of cancer screening. However, the validity of such studies remains uncertain. Methods: 98,678 individuals were included in the Norwegian Colorectal Cancer Prevention trial, a randomized sigmoidoscopy screening trial. We used the trial data and designed case-control studies nested among individuals randomized to sigmoidoscopy and compared the results with those from intention-to-treat and per-protocol analyses to test the validity of the case-control design to estimate screening effect on colorectal cancer incidence and mortality, and all-cause mortality. We analyzed the case-control studies with the following methodologies: The logistic regression method, where we adjusted for self-selection in multivariable regression models including age, sex, comorbidity, socioeconomics and ethnicity; and the self-selection method where we adjusted for self-selection by different unscreened groups: regional - and national reference population. The trial is registered with ClinicalTrials.gov, NCT00119912. Findings: In intention-to-treat analysis of the randomized trial, sigmoidoscopy screening reduced colorectal cancer mortality by 19% (relative risk (RR) 0.81; 95% CI 0.67-0.99). When the same data were analyzed with a case-control design, the reductions varied between 44% (RR 0.56; 95% CI 0.33-0.97) and 67% (odds ratio (OR) 0.33; 95% CI 0.22-0.51) depending on the method used. While the intention-to-treat analysis showed no screening benefit on all-cause mortality (RR 1.00; 95% CI 0.97-1.03), the case-control studies suggested a benefit between 22% (RR 0.78; 95% CI 0.71-0.85) and 57% (OR 0.42; 95% CI 0.39-0.45) depending on the method used. Interpretation: Observational studies may overestimate the benefits of cancer screening and should therefore not guide screening policies. Clinical Trials: ClinicalTrials.gov, NCT00119912 Funding: The study received intramural funding from the University of Oslo and Oslo University Hospital. No external funding was provided. Declaration of Interest: None to declare. Ethical Approval: The NORCCAP trial was approved by the Ethics Committee of South-East Norway (project ID S-98052) and the Norwegian Data Protection Authority (Project ID 98/1408). The current study was approved by the NORCCAP steering committee.

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.

ObjectivesNorway and Sweden are similar countries regarding ethnicity, socioeconomics and health care. To combat Covid-19, Norway implemented extensive measures such as school closures and lock-downs, while Sweden has been criticised for relaxed measures against Covid-19. We compared the effect of the different national strategies on all-cause and Covid-19 associated mortality.DesignRetrospective cohort.SettingThe countries Norway and Sweden.ParticipantsAll inhabitants.Main outcome measuresWe calculated weekly mortality rates (MR) with 95% confidence intervals (CI) per 100,000 individuals as well as mortality rate ratios (MRR) comparing the epidemic year (29th July, 2019 to 26th July, 2020) to the four preceding years (July 2015 to July 2019). We also compared Covid-19 associated deaths and mortality rates for the weeks of the epidemic in Norway and Sweden (16th March to 26th July, 2020).ResultsIn Norway, mortality rates were stable during the first three 12-month periods of 2015/16; 2016/17 and 2017/18 (MR 14.8 to 15.1 per 100,000), and slightly lower in the two most recent periods including during epidemic period (2018/19 and 2019/20; 14.5 per 100,000). In Sweden, all-cause mortality was stable during the first three 12-month periods of 2015/16; 2016/17 and 2017/18 (MR 17.2 to 17.5 per 100,000), but lower in the year 2018/19 immediately preceding the epidemic (16.2 per 100,000). Covid-19 associated mortality rates were 0.2 per 100,000 (95%CI 0.1 to 0.4) in Norway and 2.9 (95%CI 1.9 to 3.9) in Sweden. The increase in mortality was confined to individuals in 70 years or older.ConclusionsAll-cause mortality remained unaltered in Norway. In Sweden, the observed increase in all-cause mortality during Covid-19 was partly due to a lower than expected mortality preceding the epidemic and the observed excess mortality, was followed by a lower than expected mortality after the first Covid-19 wave. This may suggest mortality displacement.Strengths and limitations of this studyCompares two similar contries in all aspects but the handling of the Covid-19 epidemicEvaluates the mortality for several years before and during the epidemicProvides a possible explanation of the observed mortality changesDiscusses the socioeconomic effects of the different strategies in the two countriesDoes not evaluate cause-specific mortality

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.

Background: The risk of hepatobiliary and pancreatic cancer in patients with inflammatory bowel disease (IBD) with or without concomitant primary sclerosing cholangitis (PSC) has not been reliably quantified in large, prospective studies with long-term follow-up. Methods: We performed a population cohort study of all patients diagnosed with IBD in Norway and Sweden from 1987 to 2015. Participants were followed through linkage to national cancer, cause of death and population registers. We calculated standardized incidence ratios (SIR) with 95% confidence intervals (CIs) and absolute risk of hepatobiliary and pancreatic cancer by PSC status and other clinical characteristics. Results: We identified 141,960 IBD patients, 4,548 (3.2%) of these with concomitant PSC. During a median follow-up time of 10.0 years, we identified 479 biliary tract cancers (SIR 5.2, 95% CI 4.7-5.7), 127 hepatocellular carcinomas (SIR 2.1, 95% CI 1.8-2.5) and 282 pancreatic cancers (SIR 1.3, 95% CI 1.2-1.5). The relative risks were considerably higher in patients with PSC, with SIRs of 142 (95% CI 125-160) for biliary tract, 27.7 (95% CI 19.4-38.5) for hepatocellular, and 9.0 (95% CI 6.3-12.6) for pancreatic cancer. For IBD patients without PSC, we found SIRs of 2.5 (95% CI 2.2-2.9), 1.5 (1.2-1.8), and 1.2 (1.1-1.4) for biliary tract cancer, hepatocellular carcinoma, and pancreatic cancer, respectively. Conclusion: Patients with IBD experience a substantially increased risk of biliary tract cancer. Although the risk is largely confined to patients with concomitant PSC, non-PSC patients also confer a moderate excess risk. Citation Format: Jingru Yu, Erle Refsum, Lise M. Helsingen, Trine Folseraas, Alexander Ploner, Paulina Wieszczy, Ishita Barua, Henriette C. Jodal, Espen Melum, Magnus Løberg, Johannes Blom, Michael Bretthauer, Hans-Olov Adami, Mette Kalager, Weimin Ye. Risk of hepatobiliary & pancreatic cancer in inflammatory bowel disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 841.

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.