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Simple Summary Colorectal cancer (CRC) is the third most common cancer in the world. The gut microbiome, which includes a collection of microbes, is a potential modifiable risk factor. The study of the microbiome is complex and many issues remain unsolved despite the scientific efforts that have been recently made. The present study aimed to build a CRC predictive model performing a meta-analyses of previously published shotgun metagenomics data, and to validate it in a new study. For that purpose, 156 participants of a CRC screening program were recruited, with an even distribution of CRCs, high-risk colonic precancerous lesions, and a control group with normal colonic mucosa. We have identified a signature of 32 bacterial species that have a good predictive accuracy to identify CRC but not precancerous lesions. This suggests that the identified microbes that were enriched or depleted in CRC are merely a consequence of the tumor. The gut microbiome is a potential modifiable risk factor for colorectal cancer (CRC). We re-analyzed all eight previously published stool sequencing data and conducted an MWAS meta-analysis. We used cross-validated LASSO predictive models to identify a microbiome signature for predicting the risk of CRC and precancerous lesions. These models were validated in a new study, Colorectal Cancer Screening (COLSCREEN), including 156 participants that were recruited in a CRC screening context. The MWAS meta-analysis identified 95 bacterial species that were statistically significantly associated with CRC (FDR < 0.05). The LASSO CRC predictive model obtained an area under the receiver operating characteristic curve (aROC) of 0.81 (95%CI: 0.78-0.83) and the validation in the COLSCREEN dataset was 0.75 (95%CI: 0.66-0.84). This model selected a total of 32 species. The aROC of this CRC-trained model to predict precancerous lesions was 0.52 (95%CI: 0.41-0.63). We have identified a signature of 32 bacterial species that have a good predictive accuracy to identify CRC but not precancerous lesions, suggesting that the identified microbes that were enriched or depleted in CRC are merely a consequence of the tumor. Further studies should focus on CRC as well as precancerous lesions with the intent to implement a microbiome signature in CRC screening programs.

False-positivity rates in faecal immunochemical test (FIT) can be affected by drug exposure. We aimed to assess the association between proton pump inhibitors (PPI) consumption and false positive (FP) results in a colorectal cancer (CRC) screening programme using electronic prescription records. A retrospective cohort study within a population-based screening program for CRC from 2010 to 2016 was performed. Participants with a conclusive FIT result and with prescription electronic data were included. An FP result was defined as having a positive FIT (≥ 20 µg haemoglobin/g faeces) and a follow-up colonoscopy without intermediate or high-risk lesions or CRC. Screening data were anonymously linked to the public data analysis program for health research and innovation (PADRIS) database that recorded patient diseases history and reimbursed medication. PPI exposure was defined as having retrieved at least one dispensation of PPI three months prior to the FIT. A total of 89,199 tests (of 46,783 participants) were analysed, 4824 (5.4%) tested positive and the proportion of FP was 53.5%. Overall, 17,544 participants (19.7%) were PPI users prior to FIT performance. PPI exposure increased the probability of obtaining an FP FIT result from 50.4 to 63.3% (adjusted OR 1.39; 95% CI 1.18–1.65). Nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, antibiotics, and laxatives were also associated with an FP result. The effect of PPI was independent and showed a synergistic interaction with nonsteroidal anti-inflammatory drugs. PPIs increase FIT positivity at the expense of FP results. The recommendation to avoid their use before FIT performance could reduce up to 3% of colonoscopies and 9% of FP results.

Several studies have examined environmental factors and inflammatory bowel diseases (IBD) using traditional approaches; however, provided results are still conflicting. Our aim was to determine whether lifestyle and nutrient exposures, related to IBD in observational meta-analyses, influence IBD risk using a Mendelian randomization (MR) approach. A two-sample MR approach was applied on summary-level genome-wide association results. Genetic variants strongly associated with measures of tobacco smoking, obesity and fat distribution, physical activity, and blood levels of vitamins and fatty acids were evaluated on genetic data from international IBD consortia including a total of 25,042 IBD cases (12,194 cases of Crohn’s disease (CD) and 12,366 cases of ulcerative colitis (UC)) and 34,915 controls. Our results indicated that, among lifestyle exposures, being a smoker was positively associated with CD (OR 1.13, P = 0.02), but it was not associated with UC risk (OR 0.99, P = 0.88). Body-mass index (BMI) and body fat percentage were positively associated with CD (OR 1.11, P = 0.02, per standard deviation (SD) of 4.6 kg/m2; and OR 1.50, P = 3 × 10–10, per SD of 6.6%; respectively); while for UC, BMI was inversely associated (OR 0.85, P = 5 × 10–5; per SD) and body fat percentage showed a OR of 1.11 (P = 0.11; per SD). Additionally, among nutrient exposures, omega-3 fatty acids levels were inversely associated with CD (OR 0.67, P = 2 × 10–6). Our MR results did not support a protective effect for being a smoker on UC risk; however, they are compatible with a risk effect for higher body fat proportion and a protective role for higher levels of omega-3 fatty acids on CD etiology.

Hemoglobin degradation can be affected by ambient temperature and humidity. How this modifies the advanced neoplasia detection rate and interval cancer rate remains understudied. We conducted a retrospective study and analyzed the impact of ambient temperature and humidity on the fecal immunochemical test (FIT) positivity rate, detection rate for advanced neoplasia, and interval colorectal cancer (CRC). The results of our study indicated that at >24 degrees C, the positivity rate was lower, whereas the detection rate of the FIT for advanced neoplasia and the interval cancer detection rate were not affected, probably because we have adopted measures to minimize the impact of ambient temperature on FIT sensitivity. Humidity did not affect FIT sensitivity. The results emphasize the importance of organizational efforts on the procedures along the screening process (such as the cold chain) to minimize the effect of seasonal variations in temperature on the positivity rate. Exposure of the fecal immunochemical test (FIT) to different ambient temperatures and humidity is unavoidable in population-based screening programs in Southern European countries, and it could lead to a decrease in target colorectal lesions. The objective was to evaluate the effect of ambient temperature and humidity on the FIT sensitivity in a population-based screening program for colorectal cancer (CRC) using an ecological design. The retrospective cohort included individuals aged 50-69 years who participated in CRC screening (Barcelona) from 2010-2015, and were followed until 2017 to identify interval CRCs. The positivity rate, and detection rates for advanced polyps and CRC were compared according to ambient temperature, humidity, and quarters of the year. A positive FIT was defined as the detection of >= 20 mu g Hb/g in feces. The monthly ambient temperature and humidity were recorded on the day that the FIT was performed. In total, 92,273 FIT results from 53,860 participants were analyzed. The FIT positivity rate was lower at >24 degrees C than at

Background: A safe and effective colorectal cancer chemoprevention agent remains to be discovered. There is little evidence regarding the protective effect of chondroitin sulphate and glucosamine on colorectal cancer. We aimed to assess the association between colorectal cancer risk and the use of chondroitin sulphate and glucosamine using a large cohort with dispensed data. Methods: We performed a population-based case–control study in Catalonia using primary care reimbursed medication records (SIDIAP database). The study included 25,811 cases with an incident diagnosis of colorectal cancer and 129,117 matched controls between 2010 and 2015. Results: The prevalence of ever use was 9.0% (n = 13,878) for chondroitin sulphate, 7.3% (n = 11,374) for glucosamine, and 35% for regular use of nonsteroidal anti-inflammatory drugs (NSAID; n = 45,774). A decreased risk of colorectal cancer was observed among chondroitin sulphate use [OR: 0.96; 95% confidence interval (CI), 0.91–1.01], glucosamine use (OR: 0.92; 95% CI, 0.87–0.97), and concurrent use of chondroitin sulphate and glucosamine (OR: 0.83; 95% CI, 0.70–0.98). Especially for glucosamine, there was a dose–response association regarding duration and cumulative dose. The analysis stratified by simultaneous use with other NSAIDs showed that these drugs used without other NSAIDs do not reduce risk (OR: 1.06; 95% CI, 0.74–1.51). However, they may have a synergistic protective effect when used with other NSAIDs (OR: 0.80; 95% CI, 0.72–0.88). Conclusions: This study does not provide strong support for an independent protective association of chondroitin sulphate or glucosamine on colorectal cancer risk in our population. However, these drugs may have a synergistic beneficial effect among NSAID users. Impact: Chondroitin sulphate or glucosamine may contribute to the protective effect of NSAID use in colorectal cancer.

Background Irritable bowel syndrome (IBS) is a functional disorder affecting around 11% of the world population, which diagnostic is mainly based on clinical parameters. IBS shares many symptoms with other gastrointestinal disorders such as inflammatory bowel disease (IBD), which makes positive diagnosis a difficult task. Aim This work presents the design of a new test, called RAID‐Dx, which is a mathematical algorithm based on the combination of nine faecal microbial markers capable of diagnosing IBS. Methods A cohort consisting of 165 subjects (52 IBS and 52 IBD patients, and 61 healthy controls) was recruited from the Gastroenterology Department of six hospitals. Each patient provided a stool sample from which DNA was extracted, and microbial markers composing RAID‐Dx were analysed by qPCR. The results obtained were used to define and validate the RAID‐Dx algorithm. Results The abundance of the biomarkers included in the algorithm differed according to the diagnosis. RAID‐Dx shows a high capacity to diagnose IBS with a sensitivity of 82.4% and a specificity of 85.7%. RAID‐Dx also reports higher sensitivity and specificity values than faecal calprotectin for IBS and IBD differentiation. Conclusions RAID‐Dx is a noninvasive tool aimed to diagnose IBS with high sensitivity and specificity. The use of this new tool for IBS diagnosis could significantly improve disease management, minimise its misdiagnosis and increase patients’ quality of life

The use of bisphosphonates has been associated with a decrease in the risk of colorectal cancer (CRC) in observational studies, but with controversial results and difficult to interpret because of routine concomitant use of calcium and vitamin D. We aimed to assess the association between CRC risk and outpatient exposure to antiosteoporotic drugs using a large cohort with prescription data in Catalonia. A case-control study was performed using the Information System for Development of Primary Care Research (SIDIAP) which is a primary care medical record database that has linked data on reimbursed medication. The study included 25,836 cases with an incident diagnosis of CRC between 2010 and 2015 and 129,117 matched controls by age (+/- 5 years), sex and healthcare region. A multivariable model was built adjusting for known risk factors and comorbidities that were significantly associated to CRC in the dataset, and a propensity score for bisphosphonates. Tests for interaction for multiple drug use and stratified analysis for tumour location were prospectively planned. Overall 18,230 individuals (11.5%) were users of bisphosphonates. A significant but modest protective effect on CRC was observed for bisphosphonates (OR 0.95, 95% CI 0.91-0.99), that was no longer significant when adjusted for calcium and vitamin D (OR 0.98, 95% CI 0.93-1.03). Bisphosphonates, however, showed a dose-response effect with duration of use even when adjusted for calcium and vitamin D (OR for use > 40 months: 0.90, 95% CI 0.81-1.00, P value for trend: 0.018). The use of bisphosphonates was associated with a modest decrease in the risk of CRC, but this effect was essentially explained by concomitant use of calcium or vitamin D. The observed protective effect was stronger for long durations of use, which deserves further study.

Background: The aim of this study was to estimate the cumulative risk of a false-positive (FP) result in a fecal occult blood test (FOBT) through 7 screening rounds and to identify its associated factors in a population-based colorectal cancer screening program. Methods: Retrospective cohort study, which included participants ages 50 to 69 years of a colorectal cancer screening program in Catalonia, Spain. During this period, 2 FOBTs were used (guaiac and immunochemical). A discrete-time survival model was performed to identify risk factors of receiving a positive FOBT with no high-risk adenoma or colorectal cancer in the follow-up colonoscopy. We estimated the probability of having at least 1 FP over 7 screening rounds. Results: During the period of 2000 to 2017, the cumulative FP risk was 16.3% (IC95%: 14.6%–18.3%), adjusted by age, sex, and type of test. The median number of screens was 2. Participants who began screening at age 50 years had a 7.3% [95% confidence interval (CI), 6.35–8.51] and a 12.4% (95% CI, 11.00–13.94) probability of an FP with 4 screening rounds of guaiac-based test and immunochemical test, respectively. Age, the fecal immunochemical test, first screening, and number of personal screens were factors associated with an FP result among screenees. Conclusions: The cumulative risk of an FP in colorectal screening using FOBT seems acceptable as the colonoscopy, with its high accuracy, lengthens the time until additional colorectal screening is required, while complication rates remain low. Impact: It is useful to determine the cumulative FP risk in cancer screening for both advising individuals and for health resources planning.

Background Different risk-based colorectal cancer (CRC) screening strategies, such as the use of polygenic risk scores (PRS), have been evaluated to improve effectiveness of these programs. However, few studies have previously assessed its usefulness in a fecal immunochemical test (FIT)-based screening study. Methods A PRS of 133 single nucleotide polymorphisms was assessed for 3619 participants: population controls, screening controls, low-risk lesions (LRL), intermediate-risk (IRL), high-risk (HRL), CRC screening program cases, and clinically diagnosed CRC cases. The PRS was compared between the subset of cases (n = 648; IRL+HRL+CRC) and controls (n = 956; controls+LRL) recruited within a FIT-based screening program. Positive predictive values (PPV), negative predictive values (NPV), and the area under the receiver operating characteristic curve (aROC) were estimated using cross-validation. Results The overall PRS range was 110–156. PRS values increased along the CRC tumorigenesis pathway (Mann-Kendall P value 0.007). Within the screening subset, the PRS ranged 110-151 and was associated with higher risk-lesions and CRC risk (ORD10vsD1 1.92, 95% CI 1.22–3.03). The cross-validated aROC of the PRS for cases and controls was 0.56 (95% CI 0.53–0.59). Discrimination was equal when restricted to positive FIT (aROC 0.56), but lower among negative FIT (aROC 0.55). The overall PPV among positive FIT was 0.48. PPV were dependent on the number of risk alleles for positive FIT (PPVp10-p90 0.48–0.57). Conclusions PRS plays an important role along the CRC tumorigenesis pathway; however, in practice, its utility to stratify the general population or as a second test after a FIT positive result is still doubtful. Currently, PRS is not able to safely stratify the general population since the improvement on PPV values is scarce.

Although adenomas and serrated polyps are the preneoplastic lesions of colorectal cancer, only few of them will eventually progress to cancer. This review provides a comprehensive overview of the present and future of post-polypectomy colonoscopy surveillance. Post-polypectomy surveillance guidelines have recently been updated and all share the aim towards more selective and less frequent surveillance. We have examined these current guidelines and compared the recommendations of each of them. To improve the diagnostic yield of post-polypectomy surveillance it is important to find predictors of metachronous polyps that better identify high-risk individuals of developing advanced neoplasia. For this reason, we have also conducted a literature review of the molecular biomarkers of metachronous advanced colorectal polyps. Finally, we have discussed future directions of post-polypectomy surveillance and identified possible strategies to improve the use of endoscopic resources with the COVID-19 pandemic.

Background and Aims Genome-wide association studies [GWAS] for inflammatory bowel disease [IBD] have identified 240 risk variants. However, the benefit of understanding the genetic architecture of IBD remains to be exploited. Transcriptome-wide association studies [TWAS] associate gene expression with genetic susceptibility to disease, providing functional insight into risk loci. In this study, we integrate relevant datasets for IBD and perform a TWAS to nominate novel genes implicated in IBD genetic susceptibility. Methods We applied elastic net regression to generate gene expression prediction models for the University of Barcelona and University of Virginia RNA sequencing project [BarcUVa-Seq] and correlated expression and disease association research [CEDAR] datasets. Together with Genotype-Tissue Expression project [GTEx] data, and GWAS results from about 60 000 individuals, we employed Summary-PrediXcan and Summary-MultiXcan for single and joint analyses of TWAS results, respectively. Results BarcUVa-Seq TWAS revealed 39 novel genes whose expression in the colon is associated with IBD genetic susceptibility. They included expression markers for specific colon cell types. TWAS meta-analysis including all tissues/cell types provided 186 novel candidate susceptibility genes. Additionally, we identified 78 novel susceptibility genes whose expression is associated with IBD exclusively in immune (N = 19), epithelial (N = 25), mesenchymal (N = 22) and neural (N = 12) tissue categories. Associated genes were involved in relevant molecular pathways, including pathways related to known IBD therapeutics, such as tumour necrosis factor signalling. Conclusion These findings provide insight into tissue-specific molecular processes underlying IBD genetic susceptibility. Associated genes could be candidate targets for new therapeutics and should be prioritized in functional studies.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P, Reporting Summary. Further information on experimental design is available in the Life Sciences Reporting Summary linked to this article.

Background Short message service (SMS) based interventions are widely used in healthcare and have shown promising results to improve cancer screening programs. However, more research is still needed to implement SMS in the screening process. We present a study protocol to assess the impact on health and economics of three targeted SMS-based interventions in population-based cancer screening programs. Methods/Design The M-TICs study is a randomized controlled trial with a formal process evaluation. Participants aged 50–69 years identified as eligible from the colorectal cancer (CRC) and breast cancer (BC) screening program of the Catalan Institute of Oncology (Catalonia, Spain) will be randomly assigned to receive standard invitation procedure (control group) or SMS-based intervention to promote participation. Two interventions will be conducted in the CRC screening program: 1) Screening invitation reminder: Those who do not participate in the CRC screening within 6 weeks of invite will receive a reminder (SMS or letter); 2) Reminder to complete and return fecal immunochemical test (FIT) kit: SMS reminder versus no intervention to individuals who have picked up a FIT kit at the pharmacy and they have not returned it after 14 days. The third intervention will be performed in the BC screening program. Women who had been screened previously will receive an SMS invitation or a letter invitation to participate in the screening. As a primary objective we will assess the impact on participation for each intervention. The secondary objectives will be to analyze the cost-effectiveness of the interventions and to assess participants’ perceptions. Expected results The results from this randomized controlled trial will provide important empirical evidence for the use of mobile phone technology as a tool for improving population-based cancer screening programs. These results may influence the cancer screening invitation procedure in future routine practice. Trial registration Registry: NCT04343950 (04/09/2020); clinicaltrials.gov.

Background & Aims The association of genetic variation with tissue-specific gene expression and alternative splicing guides functional characterization of complex trait-associated loci and may suggest novel genes implicated in disease. Here, our aims were as follows: (1) to generate reference profiles of colon mucosa gene expression and alternative splicing and compare them across colon subsites (ascending, transverse, and descending), (2) to identify expression and splicing quantitative trait loci (QTLs), (3) to find traits for which identified QTLs contribute to single-nucleotide polymorphism (SNP)-based heritability, (4) to propose candidate effector genes, and (5) to provide a web-based visualization resource. Methods We collected colonic mucosal biopsy specimens from 485 healthy adults and performed bulk RNA sequencing. We performed genome-wide SNP genotyping from blood leukocytes. Statistical approaches and bioinformatics software were used for QTL identification and downstream analyses. Results We provided a complete quantification of gene expression and alternative splicing across colon subsites and described their differences. We identified thousands of expression and splicing QTLs and defined their enrichment at genome-wide regulatory regions. We found that part of the SNP-based heritability of diseases affecting colon tissue, such as colorectal cancer and inflammatory bowel disease, but also of diseases affecting other tissues, such as psychiatric conditions, can be explained by the identified QTLs. We provided candidate effector genes for multiple phenotypes. Finally, we provided the Colon Transcriptome Explorer web application. Conclusions We provide a large characterization of gene expression and splicing across colon subsites. Our findings provide greater etiologic insight into complex traits and diseases influenced by transcriptomic changes in colon tissue.

The gut microbiome has a fundamental role in human health and disease. However, studying the complex structure and function of the gut microbiome using next generation sequencing is challenging and prone to reproducibility problems. Here, we obtained cross-sectional colon biopsies and faecal samples from nine participants in our COLSCREEN study and sequenced them in high coverage using Illumina pair-end shotgun (for faecal samples) and IonTorrent 16S (for paired feces and colon biopsies) technologies. The metagenomes consisted of between 47 and 92 million reads per sample and the targeted sequencing covered more than 300 k reads per sample across seven hypervariable regions of the 16S gene. Our data is freely available and coupled with code for the presented metagenomic analysis using up-to-date bioinformatics algorithms. These results will add up to the informed insights into designing comprehensive microbiome analysis and also provide data for further testing for unambiguous gut microbiome analysis., Measurement(s)genome •rRNA_16STechnology Type(s)DNA sequencingFactor Type(s)sex •age •Smoking •Weight •Height •Diet •MedicationSample Characteristic - OrganismHomo sapiensSample Characteristic - Environmentfeces •colon Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.11902236

Dyslipidemia and statin use have been associated with colorectal cancer (CRC), but prospective studies have shown mixed results. We aimed to determine whether dyslipidemia is causally linked to CRC risk using a Mendelian randomization approach and to explore the association of statins with CRC. A casecontrol study was performed including 1336 CRC cases and 2744 controls (MCC-Spain). Subjects were administered an epidemiological questionnaire and were genotyped with an array which included polymorphisms associated with blood lipids levels, selected to avoid pleiotropy. Four genetic lipid scores specific for triglycerides (TG), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), or total cholesterol (TC) were created as the count of risk alleles. The genetic lipid scores were not associated with CRC. The ORs per 10 risk alleles, were for TG 0.91 (95%CI: 0.72–1.16, p = 0.44), for HDL 1.14 (95%CI: 0.95–1.37, p = 0.16), for LDL 0.97 (95%CI: 0.81–1.16, p = 0.73), and for TC 0.98 (95%CI: 0.84–1.17, p = 0.88). The LDL and TC genetic risk scores were associated with statin use, but not the HDL or TG. Statin use, overall, was a non-significant protective factor for CRC (OR 0.84; 95%CI: 0.70–1.01, p = 0.060), but lipophilic statins were associated with a CRC risk reduction (OR 0.78; 95%CI 0.66–0.96, p = 0.018). Using the Mendelian randomization approach, our study does not support the hypothesis that lipid levels are associated with the risk of CRC. This study does not rule out, however, a possible protective effect of statins in CRC by a mechanism unrelated to lipid levels., This work was supported by the ‘Acción Transversal del Cancer’, approved by the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III, co-founded by FEDER funds –‘a way to build Europe’ [grants PI08/1770, PI08/0533, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/00613, PI17/00092 and PI15/00069]. Support was also provided by the Fundación Marqués de Valdecilla (grant API 10/09]; the Junta de Castilla y León [grant LE22A10-2]; the Consejería de Salud of the Junta de Andalucía [2009-S0143]; the Conselleria de Sanitat of the Generalitat Valenciana [grant AP 061/10]; the Recercaixa [grant 2010ACUP 00310]; the Regional Government of the Basque Country; the Consejería de Sanidad de la Región de Murcia; European Commission grants FOOD-CT-2006-036224-HIWATE; the Spanish Association Against Cancer (AECC) Scientific Foundation; the Catalan Government DURSI [grants 2017SGR723 and 2014SGR850]; the Fundación Caja de Ahorros de Asturias; the University of Oviedo; Societat Catalana de Digestologia; and COST action CA17118 Transcoloncan.

The gut microbiome has a fundamental role in human health and disease. However, studying the complex structure and function of the gut microbiome using next generation sequencing is challenging and prone to reproducibility problems due to the heterogeneity of sample sets. Here, we obtained cross-sectional colon biopsies and faecal samples from nine participants in our COLSCREEN study and sequenced them in high coverage using Illumina pair-end shotgun (for faecal samples) and IonTorrent 16S (for paired feces and colon biopsies) technologies. The metagenomes consisted of between 47 and 92 million reads per sample and the targeted sequencing covered more than 300K reads per sample across seven hypervariable regions of the 16S gene. Our data is freely available and coupled with code for the presented metagenomic analysis using up-to-date bioinformatics algorithms. These results will add up to the informed insights into designing comprehensive microbiome analysis and also provide data for further testing for unambiguous gut microbiome analysis.

There is extensive debate regarding the protective effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on colorectal cancer (CRC). We aimed to assess the association between CRC risk and exposure to statins using a large cohort with prescription data. We carried out a case-control study in Catalonia using the System for Development of Primary Care Research (SIDIAP) database that recorded patient diseases history and linked data on reimbursed medication. The study included 25 811 cases with an incident diagnosis of CRC between 2010 and 2015 and 129 117 frequency-matched controls. Subjects were classified as exposed to statins if they had ever been dispensed statins. Analysis considering mean daily defined dose, cumulative duration and type of statin were performed. Overall, 66 372 subjects (43%) were exposed to statins. There was no significant decrease of CRC risk associated to any statin exposure (OR = 0.98; 95% CI: 0.95–1.01). Only in the stratified analysis by location a reduction of risk for rectal cancer was observed associated to statin exposure (OR = 0.87; 95% CI: 0.81–0.92). This study does not support an overall protective effect of statins in CRC, but a protective association with rectal cancer merits further research.

Simple Summary The number of interval colorectal cancers is an intermediate measure of the effectiveness of a population-screening programme in decreasing colorectal cancer mortality. Differences between interval and screen-detected cancers have been reported. Better characterization of colorectal cancer to differentiate false-negative faecal immunochemical test results from true interval cancers would help determine whether to focus more on the organizational aspects of a screening programme or on stratifying colorectal cancer risk. This review provides a comprehensive overview of the epidemiological, clinical, and molecular characteristics of interval colorectal cancers. Abstract Tumors that are not detected by screening tests are known as interval cancers and are diagnosed clinically after a negative result in the screening episode but before the next screening invitation. Clinical characteristics associated with interval colorectal cancers have been studied, but few molecular data are available that describe interval colorectal cancers. A better understanding of the clinical and biological characteristics associated with interval colorectal cancer may provide new insights into how to prevent this disease more effectively. This review aimed to summarize the current literature concerning interval colorectal cancer and its epidemiological, clinical, and molecular features.

Background The most common side effect in population screening programmes is a false-positive result which leads to unnecessary risks and costs. Aims To identify factors associated with false-positive results in a colorectal cancer screening programme with the faecal immunochemical test (FIT). Methods Cross-sectional study of 472 participants with a positive FIT who underwent colonoscopy for confirmation of diagnosis between 2013 and 2014. A false-positive result was defined as having a positive FIT (≥20 μg haemoglobin per gram of faeces) and follow-up colonoscopy without intermediate/high-risk lesions or cancer. Results Women showed a two-fold increased likelihood of a false-positive result compared with men (adjusted OR, 2.3; 95%CI, 1.5–3.4), but no female-specific factor was identified. The other variables associated with a false-positive result were successive screening (adjusted OR, 1.5; 95%CI, 1.0–2.2), anal disorders (adjusted OR, 3.1; 95%CI, 2.1–4.5) and the use of proton pump inhibitors (adjusted OR, 1.8; 95%CI, 1.1–2.9). Successive screening and proton pump inhibitor use were associated with FP in men. None of the other drugs were related to a false-positive FIT. Conclusion Concurrent use of proton pump inhibitors at the time of FIT might increase the likelihood of a false-positive result. Further investigation is needed to determine whether discontinuing them could decrease the false-positive rate.

The aim of this study was to analyse false-negative (FN) results of the faecal immunochemical test (FIT) and its determinants in a colorectal cancer screening programme in Catalonia. We carried out a cross-sectional study among 218 screenees with a negative FIT result who agreed to undergo a colonoscopy. A false-negative result was defined as the detection, at colonoscopy, of intermediate/high-risk polyps or colorectal cancer in a patient with a previous negative FIT (

Tis work was supported by the ‘Acción Transversal del Cancer’, approved by the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III, co-founded by FEDER funds –‘a way to build Europe’ (grants PI08/1770, PI08/0533, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/00613, and PI15/00069). Support was also provided by the Fundación Marqués de Valdecilla (grant API 10/09); the Junta de Castilla y León (grant LE22A10–2); the Consejería de Salud of the Junta de Andalucía (2009-S0143); the Conselleria de Sanitat of the Generalitat Valenciana (grant AP 061/10); the Recercaixa (grant 2010ACUP 00310); the Regional Government of the Basque Country; the Consejería de Sanidad de la Región de Murcia; European Commission grants FOOD-CT-2006-036224-HIWATE; the Fundación Científca Asociación Española Contra el Cáncer (AECC); the Catalan Government DURSI (grant This work was supported by the 'Accion Transversal del Cancer', approved by the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III, co-founded by FEDER funds -'a way to build Europe' (grants PI08/1770, PI08/0533, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/00613, and PI15/00069). Support was also provided by the Fundacion Marques de Valdecilla (grant API 10/09); the Junta de Castilla y Leon (grant LE22A10-2); the Consejeria de Salud of the Junta de Andalucia (2009-S0143); the Conselleria de Sanitat of the Generalitat Valenciana (grant AP 061/10); the Recercaixa (grant 2010ACUP 00310); the Regional Government of the Basque Country; the Consejeria de Sanidad de la Region de Murcia; European Commission grants FOOD-CT-2006-036224-HIWATE; the Fundacion Cientifica Asociacion Espanola Contra el Cancer (AECC); the Catalan Government DURSI (grant 2014SGR647); the Fundacion Caja de Ahorros de Asturias; the University of Oviedo; Societat Catalana de Digestologia; and COST action BM1206 Eucolongene., Ibáñez-Sanz, G., Díez-Villanueva, A., Vilorio-Marqués, L., Gracia, E., Aragonés, N., Olmedo-Requena, R., Llorca, J., Vidán, J., Amiano, P., Nos, P., Fernández-Tardón, G., Rada, R., Chirlaque, M.D., Guinó, E., Dávila-Batista, V., Castaño-Vinyals, G., Pérez-Gómez, B., Mirón-Pozo, B., Dierssen-Sotos, T., Etxeberria, J., Molinuevo, A., Álvarez-Cuenllas, B., Kogevinas, M., Pollán, M., Moreno, V.

Scientific Reports 7: Article number: 43263; published online: 24 February 2017; updated: 17 May 2017 The original version of this Article contained a typographical error in the spelling of the author Pablo Fernández-Navarro, which was incorrectly given as Pablo Fernández Navarro. This has now been corrected in both the PDF and HTML versions of the Article.

The presence of cirrhosis increases the mortality of patients with peptic ulcer bleeding (PUB). Both acute variceal bleeding (AVB) and PUB are associated with substantial mortality in cirrhosis. This multicenter cohort study was performed to assess whether the mortality of patients with cirrhosis with PUB is different from that of those with AVB. Patients with cirrhosis and acute gastrointestinal bleeding were consecutively included and treated with somatostatin and proton pump inhibitor infusion from admission and with antibiotic prophylaxis. Emergency endoscopy with endoscopic therapy was performed within the first 6 hours. 646 patients with AVB and 144 with PUB were included. There were baseline differences between groups, such as use of gastroerosive drugs or β-blockers. Child-Pugh and Model for End-Stage Liver Disease MELD scores were similar. Further bleeding was more frequent in the AVB group than those in the PUB group (18% vs. 10%; odds ratio [OR] = 0.50; 95% confidence interval [CI] = 0.29-0.88). However, mortality risk at 45 days was similar in both groups (19% in the AVB group vs. 17% in the PUB group; OR = 0.85; 95% CI = 0.55-1.33; P = 0.48). Different parameters, such as Child-Pugh score, acute kidney injury, acute on chronic liver failure, or presence of shock or bacterial infection, but not the cause of bleeding, were related to the risk of death. Only 2% of the PUB group versus 3% of the AVB group died with uncontrolled bleeding (P = 0.39), whereas the majority of patients in either group died from liver failure or attributed to other comorbidities. Conclusion Using current first-line therapy, patients with cirrhosis and acute peptic ulcer bleeding have a similar survival than those with variceal bleeding. The risk of further bleeding is higher in patients with variceal hemorrhage. However, few patients in both groups died from uncontrolled bleeding, rather the cause of death was usually related to liver failure or comorbidities. (Hepatology 2018;67:1458-1471).

Colorectal cancer (CRC) screening of the average risk population is only indicated according to age. We aim to elaborate a model to stratify the risk of CRC by incorporating environmental data and single nucleotide polymorphisms (SNP). The MCC-Spain case-control study included 1336 CRC cases and 2744 controls. Subjects were interviewed on lifestyle factors, family and medical history. Twenty-one CRC susceptibility SNPs were genotyped. The environmental risk model, which included alcohol consumption, obesity, physical activity, red meat and vegetable consumption, and nonsteroidal anti-inflammatory drug use, contributed to CRC with an average per factor OR of 1.36 (95% CI 1.27 to 1.45). Family history of CRC contributed an OR of 2.25 (95% CI 1.87 to 2.72), and each additional SNP contributed an OR of 1.07 (95% CI 1.04 to 1.10). The risk of subjects with more than 25 risk alleles (5th quintile) was 82% higher (OR 1.82, 95% CI 1.11 to 2.98) than subjects with less than 19 alleles (1st quintile). This risk model, with an AUROC curve of 0.63 (95% CI 0.60 to 0.66), could be useful to stratify individuals. Environmental factors had more weight than the genetic score, which should be considered to encourage patients to achieve a healthier lifestyle., Biological samples were stored at the biobanks supported by Instituto de Salud Carlos III- FEDER: Parc de Salut MAR Biobank (MARBiobanc) (RD09/0076/00036), 'Biobanco La Fe' (RD 09 0076/00021) and FISABIO Biobank (RD09 0076/00058), as well as at the Public Health Laboratory of Gipuzkoa, the Basque Biobank, the ICOBIOBANC (sponsored by the Catalan Institute of Oncology), the IUOPA Biobank of the University of Oviedo, and the ISCIII Biobank. SNP genotyping services were provided by the Spanish 'Centro Nacional de Genotipado' (CEGEN-ISCIII). We thank all the subjects who participated in the study and all MCC-Spain collaborators. This work was supported by the 'Accion Transversal del Cancer', approved by the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III, co-founded by FEDER funds-'a way to build Europe' (grants PI08/1770, PI08/0533, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/00613, and PI15/00069). Support was also provided by the Fundacion Marques de Valdecilla (grant API 10/09); the Junta de Castilla y Leon (grant LE22A10-2); the Consejeria de Salud of the Junta de Andalucia (2009-S0143); the Conselleria de Sanitat of the Generalitat Valenciana (grant AP 061/10); the Recercaixa (grant 2010ACUP 00310); the Regional Government of the Basque Country; the Consejeria de Sanidad de la Region de Murcia; European Commission grants FOOD-CT-2006-036224-HIWATE; the Spanish Association Against Cancer (AECC) Scientific Foundation; the Catalan Government DURSI (grant 2014SGR647); the Fundacion Caja de Ahorros de Asturias; the University of Oviedo; Societat Catalana de Digestologia; and COST action BM1206 Eucolongene.

Background and aim: The aim of this study was to evaluate the efficacy of endoscopic band ligation (EBL) in carefully selected patients who would benefit from this method of resection. Methods: Patients with early upper gastrointestinal and small (< 15 mm) lesions treated with EBL (Duette® Multi-Band Mucosectomy) were prospectively recruited and retrospectively analyzed between 2010 and 2015. All cases were discussed in a multidisciplinary cancer committee and it was concluded that, owing to patient conditions, surgery was not possible and that not conducting histology would not change the clinical management. A first endoscopic control with biopsies was planned at 4-8 weeks. If there was no persistence of the lesion, new controls were programmed at 6 and 12 months. Results: The group (n = 12) included 5 esophagus lesions (adenosquamous carcinoma, n = 1; carcinoma squamous, n = 2; adenocarcinoma, n = 2); 4 gastric lesions (high grade dysplasia, n = 1; adenocarcinoma, n = 2; neuroendocrine tumor [NET], n = 1), and 3 duodenal lesions (NETs) (n = 3). The mean tumor diameter was 9.6 ± 2.8 mm (range 4-15). Only one minor adverse event was described. At first follow-up (4-8 weeks), there was 91.6% and 75% of endoscopic and histological remission, respectively. At 6-month follow-up there was 70% of both endoscopic remission and negative biopsies. And at 12 months, there was 100% and 75% of endoscopic and histological remission, respectively. Persisting lesions were T1 cancers. The median follow-up was 30.6 months. Conclusion: EBL without resection is an easy and safe technique that should be considered in patients with multiple morbidities and small superficial UGI lesions.

Background The faecal immunochemical test (FIT) is used in colorectal cancer (CRC) screening and for the detection of advanced colorectal neoplasia (AN) in symptomatic patients, but its accuracy could be improved. Our objective was to assess the impact of proton pump inhibitors (PPI) on the accuracy of the FIT in the detection of AN, namely advanced colorectal adenoma and CRC. Methods and findings We performed a prospective study of 1002 individuals referred for a diagnostic colonoscopy at Bellvitge University Hospital from September 2011 through to October 2012. An exhaustive interview was performed by a gastroenterologist, prescription drug dispensing database was reviewed and the patient was given a FIT prior to colonoscopy. The positivity threshold of FIT used was ≥ 20 μg Hb/g feces and the main outcome was AN. AN was detected in 13.2% (133) of patients. The accuracy of FIT for detecting AN in the PPI users and non-PPI users were: sensitivity 43.0% vs 65.6%, P = 0.009; specificity 86.9% vs 92.3%, P = 0.010; and, predictive positive value 34.4% vs 55.5%, P = 0.007, respectively. In multivariate analysis, adjusting for potential confounders, PPIs were associated with false positives in AN detection by FIT (OR 1.63 CI 95% 1.02–2.59, P < 0.037). The ROC curve for the FIT in the detection of AN in the PPI users and non-PPI users was 0.68 (CI 95% 0.61–0.76) and 0.85 (CI 95% 0.79–0.90). Conclusions PPI therapy reduces the accuracy of FIT for detecting AN in symptomatic patients.