Search

Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

Summary Background Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. Methods HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov , NCT02100696 . Findings HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). Interpretation HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. Funding F Hoffmann-La Roche.

BACKGROUND: There is no information regarding the outcome of Crohn's disease (CD) patients treated with endoscopic balloon dilation (EBD) in non-referral hospitals, nor on the efficacy of EBD in ulcerative colitis (UC). We report herein the results of the largest series published to date.; AIM: To assess the efficacy and safety of EBD for inflammatory bowel disease (IBD) stenosis performed in 19 hospitals with different levels of complexity and to determine factors related to therapeutic success.; METHODS: We identified IBD patients undergoing EBD in the ENEIDA database. Efficacy of EBD was compared between CD and UC and between secondary and tertiary hospitals. Predictive factors of therapeutic success were assessed with multivariate analysis.; RESULTS: Four-hundred dilations (41.2% anastomotic) were performed in 187 IBD patients (13 UC/Indeterminate colitis). Technical and therapeutic success per dilation was achieved in 79.5% and 55.3%, respectively. Therapeutic success per patient was achieved in 78.1% of cases (median follow-up: 40months) with 49.7% requiring more than one dilation. No differences related to either diagnosis or hospital complexity was found. Technical success [OR 4.12 (95%CI 2.4-7.1)] and not receiving anti-TNF at the time of dilation [OR 1.7 (95% CI 1.1-2.6)] were independently related to therapeutic success per dilation. A stricture length=2cm [HR 2.43 (95% CI 1.11-5.31)] was a predictive factor of long-term success per patient. The rate of major complications was 1.3%.; CONCLUSIONS: EBD can be performed with similar efficacy and safety in hospitals with differing levels of complexity and it might be a suitable treatment for UC with short stenosis. To achieve a technical success and the short length of the stenosis seem to be critical for long-term therapeutic success.

The production of antibodies to anti-tumor necrosis factor alpha (TNF) agents is one of the main causes of treatment failure in Crohn’s disease (CD). To date, however, the contribution of genetics to anti-TNF immunogenicity in CD is still unknown. The objective of the present study was to identify genetic variation associated with anti-TNF immunogenicity in CD. We performed a two-stage genome-wide association study in a cohort of 96 and 123 adalimumab-treated patients, respectively. In the discovery stage, we identified a genome-wide significant association between the CD96 locus and the production of antibodies to anti-TNF treatment (P = 1.88e–09). This association was validated in the replication stage (P

Introduction Guidelines for surveillance after polypectomy are lacking in strong evidence. Our aim was to identify some precursors of colorectal cancer lesions at 3 years after polypectomy to improve stratification and surveillance programs. Methods We included patients with high-risk lesions (HRLs), defined as advanced adenoma (AA), large serrated polyps (SPs), and multiplicity (≥3 of any adenomas/SPs). Data on age, sex, cardiovascular risk factors, pharmacological treatment, and the histological characteristics in each individual, and mutations in genes involved in the most advanced index polyp, were collected. Parameters independently associated with a metachronous HRL diagnosis were evaluated through univariate and multivariate analyses. The results are reported as odds ratios and 95% confidence intervals along with P values. Results A total of 537 cases (median age: 60.7 years; 66% male) were included. Dyslipidemia and smoking correlated with metachronous HRLs. Multivariate logistic regression analysis showed that the presence of multiplicity with ≥3 polyps on the index colonoscopy was significantly associated with metachronous HRL, AA, proximal AA, and ≥3 polyps at 3 years. In addition, independent predictors of metachronous proximal AA were increasing age, female sex, and the loss of expression of the MLH1 protein. Discussion Multiplicity was a strong predictor of HRLs at 3 years, although the inclusion of other clinical variables (age, sex, smoking status, and dyslipidemia) improves surveillance recommendations. Without these risk factors, the surveillance could be extended to 5 years; we propose examining the somatic expression of MHL1 in all patients.

Background: Previous studies in mice indicated that Paneth cells and c-Kit-positive goblet cells represent the stem cell niche of the small intestine and colon, respectively, partly by supporting Wnt and Notch activation. Whether these cell populations play a similar role in human intestinal cancer remains unexplored. Methods: We performed histopathological evaluation and immunohistochemical analysis of early colorectal adenomas and carcinoma adenoma from patients at the Hospital del Mar in Barcelona. We then determined the possible correlation between the different parameters analyzed and with patient outcomes. Results: Paneth cells accumulate in a subset of human colorectal adenomas directly associated with Notch and Wnt/β-catenin activation. Adenoma areas containing Paneth cells display increased vessel density in the lamina propria and higher levels of the stem cell marker EphB2. In an in-house cohort of 200 colorectal adenoma samples, we also observed a significant correlation between the presence of Paneth cells and Wnt activation. Kaplan–Meier analysis indicated that early adenoma patients carrying Paneth cell-positive tumors display reduced disease-free survival compared with patients with Paneth cell-free lesions. Conclusions: Our results indicate that Paneth cells contribute to the initial steps of cancer progression by providing the stem cell niche to adenoma cells, which could be therapeutically exploited.

Background and Aims Primary sclerosing cholangitis [PSC] is usually associated with inflammatory bowel disease [IBD]. An increased risk of malignancies, mainly colorectal cancer [CRC] and cholangiocarcinoma [CCA], has been reported in PSC-IBD patients. Our aim was to determine the clinical characteristics and management of PSC in IBD patients, and the factors associated with malignancies. Methods PSC-IBD patients were identified from the Spanish ENEIDA registry of GETECCU. Additional data were collected using the AEG-REDCap electronic data capture tool. Results In total, 277 PSC-IBD patients were included, with an incidence rate of 61 PSC cases per 100 000 IBD patient-years, 69.7% men, 67.5% ulcerative colitis and mean age at PSC diagnosis of 40 ± 16 years. Most patients [85.2%] were treated with ursodeoxycholic acid. Liver transplantation was required in 35 patients [12.6%] after 79 months (interquartile range [IQR] 50–139). It was more common in intra- and extrahepatic PSC compared with small-duct PSC (16.3% vs 3.3%; odds ratio [OR] 5.7: 95% confidence interval [CI] = 1.7–19.3). The incidence rate of CRC since PSC diagnosis was 3.3 cases per 1000 patient-years [95% CI = 1.9–5.6]. Having symptoms of PSC at PSC diagnosis was the only factor related to an increased risk of CRC after IBD diagnosis [hazard ratio= 3.3: 95% CI = 1.1–9.9]. CCA was detected in seven patients [2.5%] with intra- and extrahepatic PSC, with median age of 42 years [IQR 39–53], and presented a lower life expectancy compared with patients without CCA and patients with or without CRC. Conclusions PSC-IBD patients with symptoms of PSC at PSC diagnosis have an increased risk of CRC. CCA was only diagnosed in patients with intra- and extrahepatic PSC and was associated with poor survival.

Purpose Although there is convincing evidence that red and processed meat intake increases the risk of colorectal cancer (CRC), the potential role of meat cooking practices has not been established yet and could partly explain the current heterogeneity of results among studies. Therefore, we aimed to investigate the association between meat consumption and cooking practices and the risk of CRC in a population-based case-control study. Methods A total of 1671 CRC cases and 3095 controls recruited in Spain between September 2008 and December 2013 completing a food frequency questionnaire with a meat-specific module were included in the analyses. Odds ratios (OR) and confidence intervals (CI) were estimated by logistic regression models adjusted for known confounders. Results Total meat intake was associated with increased risk of CRC (OR (T3-T1) 1.41; 95% CI 1.19-1.67; p (trend) < 0.001), and similar associations were found for white, red and processed/cured/organ meat. Rare-cooked meat preference was associated with low risk of CRC in red meat (ORrare vs. medium 0.66; 95% CI 0.51-0.85) and total meat (ORrare vs. medium 0.56; 95% CI 0.37-0.86) consumers, these associations being stronger in women than in men. Griddle-grilled/barbecued meat was associated with an increased CRC risk (total meat: OR 1.45; 95% CI 1.13-1.87). Stewing (OR 1.25; 95% CI 1.04-1.51) and oven-baking (OR 1.18; 95% CI 1.00-1.40) were associated with increased CRC risk of white, but not red, meat. Conclusion Our study supports an association of white, red, processed/cured/organ and total meat intake with an increased risk of CRC. Moreover, our study showed that cooking practices can modulate such risk.

Introduction Increased values in the fecal immunochemical test (FIT) are correlated with increasingly severe colorectal neoplasia, but little attention has been given to FIT values below the cut-off point (negative FIT, nFIT). We analysed the relationship between the concentrations of two consecutive nFIT and the risk of following screen-detected advanced neoplasia and interval cancer (IC) in a population-based colorectal cancer screening program. Methods FIT results were categorised into non-detectable nFIT (0–3.8 μg haemoglobin/g feces), low nFIT (3.9–9.9) and high nFIT (10.0–19.9). Multivariable adjusted logistic regression was used to estimate the odds ratios (OR) of advanced neoplasia and IC with the nFIT results in the first two screens. Results More than 90% of the 42,524 persons had non-detectable nFIT in the first and second screen; 4.5% and 5.8% had a low nFIT, respectively, and 2.2% and 2.9% had a high nFIT. The probability of testing positive and being diagnosed of advanced neoplasia or IC rose with increasing values of nFIT. Compared with those with two non-detectable nFIT results, the highest OR were found among those who had two high nFIT results (OR 21.75; 95% confidence interval: 12.44, 38.04) and those with one low nFIT and one high nFIT (ORs around 20). Conclusions Participants with nFIT results above the detection limit of the test had an increased risk of advanced neoplasia and IC in subsequent participations. This information could be used in the design of personalised screening strategies.

Purpose: A recent study reported that 5-fluorouracil (5-FU)-based chemotherapy is less effective in treating patients with advanced colorectal cancer demonstrating hypermethylation of the TFAP2E gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts. Experimental Design: Two cohorts of 783 patients with colorectal cancer: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of TFAP2E methylation and expression as a predictor of response of colorectal cancer patients to 5-FU–based chemotherapy. DNA methylation status of the TFAP2E gene in patients with colorectal cancer was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed. Results: Correlation between TFAP2E methylation status and IHC staining was performed in 607 colorectal cancer samples. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by TFAP2E hypermethylation in stage IV patients [HR, 1.21; 95% confidence interval (CI), 0.79–1.87; log-rank P = 0.6]. In stage II–III cases, disease-free survival was not influenced by TFAP2E hypermethylation status in 5-FU–treated (HR, 0.91; 95% CI, 0.52–1.59; log-rank P = 0.9) as well as in nontreated patients (HR, 0.88; 95% CI, 0.5–1.54; log-rank P = 0.7). Conclusions: TFAP2E hypermethylation does not correlate with loss of its protein expression. Our large, systematic, and comprehensive study indicates that TFAP2E methylation and expression may not play a major role in predicting response to 5-FU–based chemotherapy in patients with colorectal cancer. Clin Cancer Res; 24(12); 2820–7. ©2018 AACR.

Objective The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype's response to chemotherapy. Design This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS). Results Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P < 0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05-2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P < 0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24-3.44, P = 0.005). Conclusion We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy. This work was supported by the Instituto de Salud Carlos III (PI08/0726, INT-09/208, PI11/2630, INT-12-078, INT13-196, PI14/01386), FISABIO-ISABIAL foundation (UGP-13-221, UGP-14-265), and the Asociación Española contra el Cáncer (Fundación Científica GCB13131592CAST). Eva Hernández-Illán received a grant from Instituto de Salud Carlos III (FI12/00233). Mar Giner-Calabuig received a grant from VALi+d. EXP ACIF/2016/002. Miren Alustiza received a predoctoral grant from ISABIAL (UGP-16-138). Other financial support was obtained from Asociación Española de Gastroenterología grants (Gonzalo Miño 2014, Tamarite 2015, Grupo de endoscopia 2016).

Background: The response to thiopurine treatment in inflammatory bowel disease patients differs greatly among individuals and nearly 50% of patients experience no benefit. Several factors have been implicated in determining this response, including individual genetic variation. Methods: Aiming to identify genes involved in the response to thiopurine drugs, a two-stage investigation of 20,000 coding single-nucleotide polymorphisms (cSNPs) in 10,000 genes was performed in a Spanish cohort of 257 individuals, 193 showing steroid free remission versus 64 non responder individuals 12 months after initial dose of the drug. The 20 top cSNPs with lower p-values for the association test identified at the first stage (133 responders/ 34 non responders), were replicated in a second cohort (60 responders/ 30 non responders). Results: Whereas not statistically significant in all of the two analyzed cohorts, the consistent across samples direction of the observed associations and the allelic joined analysis suggest a significant risk for lack of response related to two genes, PION and ZNF673. With a CMH p-value= 4.26x-06, the associated PION cSNP (rs17151692) minor A allele increases risk for treatment failure 4.5 times when all data is combined. Conclusion: These findings might help to understand the biological mechanisms behind thiopurine treatment failure and to tailor treatment for individual inflammatory bowel disease patients.

Background and objective The Colorectal Cancer Screening Program of Barcelona was implemented in December 2009 and involves pharmacies for the distribution and collection of screening tests. The aim of this article is to describe the main indicators of the first round of the Program (2010–2011), based on the ones suggested by the European Union. Material and methods The target population of the Colorectal Cancer Screening Program of Barcelona includes men and women aged 50–69 years who live in the catchment areas of Hospital Clinic and Hospital del Mar . Screening consists of biennial immunochemical fecal occult blood testing, with colonoscopy as confirmatory procedure. Results Target population comprised 197,795 persons. Participation rate was 43.6%, was higher among women and among those aged 60 and older. 2.1% of the eligible population stated to have been already screened for colorectal cancer. Overall positivity rate was 6.2%, higher among men and with a broad variability among health care areas. The detection rates of low- and high-risk adenoma, and of invasive cancer were 9.1‰, 21.7‰ and 3.1‰, respectively. 48.2% of tumors were stage I. Conclusions These results are considered satisfactory and consistent with those obtained in other programs and with European standards. Nevertheless, some areas for improvement have been identified. The high participation rate can be attributed, at least in part, to the type of test and to the involvement of community pharmacies.

Background & Aims Crohn's disease is a highly heterogeneous inflammatory bowel disease comprising multiple clinical phenotypes. Genome-wide association studies (GWASs) have associated a large number of loci with disease risk but have not associated any specific genetic variants with clinical phenotypes. We performed a GWAS of clinical phenotypes in Crohn's disease. Methods We genotyped 576,818 single-nucleotide polymorphisms in a well-characterized cohort of 1090 Crohn's disease patients of European ancestry. We assessed their association with 17 phenotypes of Crohn's disease (based on disease location, disease behavior, disease course, age at onset, and extraintestinal manifestations). A total of 57 markers with strong associations to Crohn's disease phenotypes ( P -4 ) were subsequently analyzed in an independent replication cohort of 1296 patients of European ancestry. Results We replicated the association of 4 loci with different Crohn's disease phenotypes. Variants in MAGI1 , CLCA2 , 2q24.1 , and LY75 loci were associated with a complicated stricturing disease course ( P combined = 2.01 × 10 -8 ), disease location ( P combined = 1.3 × 10 -6 ), mild disease course ( P combined = 5.94 × 10 -7 ), and erythema nodosum ( P combined = 2.27 × 10 -6 ), respectively. Conclusions In a GWAS, we associated 4 loci with clinical phenotypes of Crohn's disease. These findings indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease.

Purpose:Colorectal cancer is an important cause of mortality in the developed world. Hereditary forms are due to germ-line mutations in APC, MUTYH, and the mismatch repair genes, but many cases present familial aggregation but an unknown inherited cause. The hypothesis of rare high-penetrance mutations in new genes is a likely explanation for the underlying predisposition in some of these familial cases.Methods:Exome sequencing was performed in 43 patients with colorectal cancer from 29 families with strong disease aggregation without mutations in known hereditary colorectal cancer genes. Data analysis selected only very rare variants (0-0.1%), producing a putative loss of function and located in genes with a role compatible with cancer. Variants in genes previously involved in hereditary colorectal cancer or nearby previous colorectal cancer genome-wide association study hits were also chosen.Results:Twenty-eight final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in CDKN1B, XRCC4, EPHX1, NFKBIZ, SMARCA4, and BARD1.Conclusion:We identified new potential colorectal cancer predisposition variants in genes that have a role in cancer predisposition and are involved in DNA repair and the cell cycle, which supports their putative involvement in germ-line predisposition to this neoplasm.Genet Med 17 2, 131-142.

Background. Individuals with a family history of colorectal cancer (CRC) have an increased risk of CRC. We evaluated the diagnostic yield of CCE in the detection of lesions and also two different colon preparations. Methods. A prospective multicenter study was designed to assess CCE diagnostic yield in a cohort of asymptomatic individuals with a family history of CRC. CCE and colonoscopy were performed on the same day by 2 endoscopists who were blinded to the results of the other procedure. Results. Fifty-three participants were enrolled. The sensitivity, specificity, PPV, and NPV of CCE for detecting advanced adenomas were 100%, 98%, 67%, and 100%. Sensitivity, specificity, PPV, and NPV of CCE for the diagnosis of individuals with polyps were 87%, 97%, 93%, and 88%, respectively. CCE identify 100% of individuals with significant or advanced lesions. Overall cleanliness was adequate by 60.7% of them. The PEG-ascorbic boost seems to improve colon cleanliness, with similar colonic transit time. Conclusion. CCE is a promising tool, but it has to be considered as an alternative technique in this population in order to reduce the number of colonoscopies performed. More studies are needed to understand appropriate screening follow-up intervals and optimize the bowel preparation regimen.

The potential protective effect of renin?angiotensin system (RAS) inhibitors is a subject of increasing interest due to their possible role as chemopreventive agents against colorectal cancer (CRC). To evaluate this association, we conducted a case-control study with 2165 cases of colorectal cancer, diagnosed between 2007 and 2012, and 3912 population controls frequency matched (by age, sex and region) fromthe Spanishmulticenter case-control studyMCCSpain. We found a significant protective effect of the angiotensin-converting enzyme Inhibitors (ACEIs) against CRC, limited to the under-65 years group (OR=0.65 95%CI (0.48?0.89)) and to a lesser degree tomen (OR=0.81 95%CI (0.66?0.99). In contrast, the angiotensin receptor blockers (ARBs) did not show a significant effect. Regarding the duration of use, a greater protection was observed in men as the length of consumption increases. In contrast, in the under-65 stratum, the strongest association was found in short-term treatments. Finally, by analyzing ACEIs effect by colon subsite, we found no differences, except for under 65 years old, where the maximum protection was seen in the proximal intestine, descending in the distal and rectum (without statistical significance). In conclusion, our study shows a protective effect on CRC of the ACEis limited to males and people under 65 years old, which increases in proximal colon in the latter. If confirmed, these resultsmay suggest a novel approach to proximal CRC prevention, given the shortcomings of colonoscopy screening in this location. This work was supported by the “Accion Transversal del Cancer”, approved on the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613), PI15/00069, PI15/01032, PI15/00914, by the Fundación Marqués de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) del ISCIII (RD12/0036/0036)), by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the Junta de Andalucía (2009-S0143), by the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), by the Recercaixa (2010ACUP 00310), by the Regional Government of the Basque Country, by the Consejería de Sanidad de la Región de Murcia, by the European Commission grants FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation, by the Catalan Government DURSI grant 2014SGR647, by the Fundación Caja de Ahorros de Asturias and by the University of Oviedo.

Stage II colon cancer (CC) still remains a clinical challenge with patient stratification for adjuvant therapy (AT) largely relying on clinical parameters. Prognostic biomarkers are urgently needed for better stratification. Previously, we have shown that WNT target genes AXIN2, DKK1, APCDD1, ASCL2 and LGR5 are silenced by DNA methylation and could serve as prognostic markers in stage II CC patients using methylation-specific PCR. Here, we have extended our discovery cohort AMC90-AJCC-II (N=65) and methylation was analyzed by quantitative pyrosequencing. Subsequently, we validated the results in an independent EPICOLON1 CC cohort (N=79). Methylation of WNT target genes is negatively correlated to mRNA expression. A combination of AXIN2 and DKK1 methylation significantly predicted recurrences in univariate (area under the curve (AUC)=0.83, confidence interval (CI): 0.72–0.94, PPmethylation: 3.84, 95% CI: 1.14–12.43; HRCMS4: 3.73, 95% CI: 1.22–11.48). CMS4 subtype tumors with WNT target methylation showed worse prognosis. Combining WNT target gene methylation and CMS4 subtype lead to an AUC of 0.89 (0.791–0.982, PAXIN2 and DKK1 were found to be robust markers for recurrence prediction in stage II MSS CC patients. Further validation of these findings in a randomized and prospective manner could pave a way to identify poor prognosis patients of stage II CC for AT.

Background and Aims: Little is known about the risk factors of colectomy in patients with ulcerative colitis (UC) under thiopurine treatment. The aim of the study was to determine the prevalence and the predictive risk factors of colectomy in an extensive cohort of patients with UC treated with thiopurines in Spain. Methods: Among 5753 UC patients, we identified those diagnosed between 1980 and 2009 and treated with azathioprine or mercaptopurine (AZA/MP). We analyzed the age at diagnosis, familial history of IBD, extraintestinal manifestations (ElMs), disease extent, smoking status and treatment requirements (AZA/MP, cyclosporine (CsA) or anti-TNF alpha). Colectomies for dysplasia or cancer were excluded. Survival analysis and Cox proportional hazard regression were performed. Results were reported as hazard ratios (HR) with 95% Cl. Results: Among the 1334 cases included, 119 patients (8.9%) required colectomy after a median time of 26 months (IQR 12-42) after AZA/MP initiation. Independent predictors of colectomy were: Extensive UC (HR 1.7, 95% Cl: 1.1-2.6), ElMs (HR 1.5, 95% CI: 1.0-2.4), need for antiTNF alpha (HR 2.3, 95% CI: 1.5-3.4) and need for CsA (HR 2.4, 95% CI: 1.6-3.7). Patients requiring early introduction of AZA/MP had an increased risk of colectomy with a HR of 4.9 (95% CI: 3.2-7.8) when AZA/MP started in the first 33 months after UC diagnosis. Conclusions: Nearly one-tenth of patients with UC under thiopurines require colectomy. Extensive UC, ElMs, need for CsA or anti-TNF alpha ever and an early need for AZA/MP treatment were associated with a higher risk of colectomy. These risk factors of colectomy could help to stratify risk in further controlled studies in UC. (C) 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

To compare two strategies for colorectal cancer screening: one-time colonoscopy versus fecal immunochemical testing (FIT) (and colonoscopy for positive) every 2 years, in order to determine which strategy provides the highest participation and detection rates in groups of sex and age. This analysis was performed with data from the first screening round within the COLONPREV study, a population-based, multicenter, nationwide trial carried out in Spain. Several logistic regression models were applied to identify the influence of the screening test on participation rates and detection of proximal and distal neoplasms, as well to identify the influence of age and sex: women aged 50-59 years, women aged 60-69 years, men aged 50-59 years, and men aged 60-69 years. Participation was higher in women than in men, especially among women aged 50-59 years (25.91 % for colonoscopy and 35.81 % for FIT). Crossover from colonoscopy to FIT was higher among women than men, especially among those aged 60-69 years (30.37 %). In general, detection of any neoplasm and advanced adenoma was higher with colonoscopy than with FIT, but no significant differences were found between the two strategies for colorectal cancer detection. Detection of advanced adenoma in both arms was lower in women [specifically in women aged 50-59 years (OR 0.31; 95 % CI 0.25-0.38) than in men aged 60-69 years]. Women aged 50-59 years in the colonoscopy arm had a higher probability of detection of advanced adenoma (OR 4.49; 95 % CI 3.18-6.35), as well as of detection of neoplasms in proximal and distal locations (proximal OR 19.34; 95 % CI 12.07-31.00; distal OR 11.04; 95 % CI 8.13-15.01) than women of the same age in the FIT arm. These differences were also observed in the remaining groups but to a lesser extent. Women were more likely to participate in a FIT-based strategy, especially those aged 50-59 years. The likelihood of detection of any neoplasm was higher in the colonoscopy arm for all the population groups studied, especially in women aged 50-59 years. Distinct population groups should be informed of the benefits of each screening strategy so that they may take informed decisions.

Introduction Although the conventional treatment of patients with stage IV colorectal cancer involves resection of the primary tumour followed by chemotherapy, several studies suggest that in patients with few symptoms the first and only treatment should be chemotherapy. The objective of this study is to analyse the complications related to the primary tumour in a series of patients with unresectable metastatic colorectal cancer treated with chemotherapy without surgery. Materials and methods Retrospective descriptive study. The study included all patients with unresectable metastatic colorectal cancer treated with chemotherapy without resection of the primary tumour (January 2007–February 2011). Results The mean age of the 61 patients analysed was 67±13 years and the performance status was 0-1 in 53 (87%). Twenty (33%) patients developed complications during follow-up. The most common complication was intestinal obstruction in 15 (25%) patients followed by perforation. Complications required surgery in 6 (10%) cases. We did not find differences in patient characteristics between those who had a complication and those without, although the complication rate in patients with a colonic stent (53%) was twice that of other patients (26%). Conclusions Chemotherapy without surgery is a good option in most patients with unresectable metastatic colorectal cancer. However, although the percentage of patients requiring surgery is low, the total number of complications related to the primary tumour is not negligible. Studies are needed to identify those patients in whom a prophylactic colectomy could be indicated.

Objective To evaluate the effect of aspirin and nonaspirin antiplatelet agents (NAAAs) on the performance of the fecal immunochemical test (FIT). Participants and Methods We performed a post hoc analysis of results from a clinical trial that involved 28,696 asymptomatic average-risk men and women aged 50 to 69 years invited to participate in a colorectal cancer screening program with FIT between November 1, 2008, and June 31, 2011. Results The test was returned by 6390 individuals (22.3%), of whom 5821 (91.1%) reported not using antiplatelet drugs (nonusers group) and 569 (8.9%) reported using these drugs at the time of testing (users group). The FIT result was positive in 48 of 569 users (8.4%) and 365 of 5821 nonusers (6.3%) ( P =.05). A positive FIT result was found in 7.3% (28/384) of aspirin users, 7.1% (10/140) of NAAA users, and 22.2% (10/45) of those undergoing dual antiplatelet therapy (DAPT) (aspirin plus an NAAA). The DAPT subgroup had a significantly higher positive FIT rate than the nonuser group (odds ratio, 3.5; 95% CI, 1.7-7.3; P P = .40). The PPV for AN was 57.0% in aspirin users, 30.0% in NAAA users, and 50.0% in DAPT users, without statistically significant differences between the user and nonuser groups. Conclusion The use of DAPT increased the rate of positive FIT results. Use of aspirin, NAAAs, or both did not modify the PPV for AN in this population-based colorectal screening program. Trial Registration clinicaltrials.gov Identifier: NCT00906997

BACKGROUND Whether current smoking worsens the clinical course of microscopic colitis (MC) is unknown. The aim was to evaluate the impact of smoking on the clinical course of MC. METHODS One hundred and eighty-four patients (72% women; age, 62.4 ± 1.1 years) with MC (118 collagenous colitis (CC) and 66 lymphocytic colitis (LC) were evaluated (39 of them were current smokers). In all the patients, smoking habits and clinical data at presentation, response to therapy, and clinical relapses during follow-up were prospectively recorded. Risk factors for clinical relapse were studied in 160 patients after a mean follow-up of 28 ± 1 months. Cox regression analysis was used to adjust for confounding variables. RESULTS Age at diarrhea onset was 63.0 ± 1.4 years in nonsmokers and 50.4 ± 2.1 years in current smokers (P < 0.001). There was no significant influence of smoking habit on either clinical symptoms at diagnosis or clinical remission rate. Clinical relapse rate was 25.5% for CC and 29.6% for LC, with the mean relapse-free time 28.8 months (95% confidence interval, 26.3-31.4) for CC and 26.9 months (95% confidence interval, 26-30.3) for LC (P = 0.5). Multivariate analysis showed that age at diagnosis (

The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale. © 2013 Macmillan Publishers Limited. All rights reserved 1470-269X/13.

OBJECTIVE: To estimate the long-term need for colonoscopies after a positive fecal immunochemical test (FIT) and post-polypectomy surveillance in the context of a population-based colorectal cancer (CRC) screening program. METHODS: A discrete-event simulation model was built to reproduce the process of CRC screening and post-polypectomy surveillance following European guidelines in a population of 100,000 men and women aged 50-69 years over a 20-year period. Screening consisted of biennial FIT and colonoscopy in participants with positive results. The model was mainly fed using data from the first and second rounds of a Spanish program (2010-2013). Data on post-polypectomy surveillance results were obtained from the literature. A probabilistic multivariate sensitivity analysis was performed on the effect of participation, FIT positivity, and adherence to surveillance colonoscopies. The main outcome variables were the number of colonoscopies after a positive FIT, surveillance colonoscopies, and the overall number of colonoscopies. RESULTS: An average yearly number of 1,200 colonoscopies after a positive FIT were predicted per 100,000 inhabitants with a slight increase to 1,400 at the end of the 20-year period. Surveillance colonoscopies increased to an average of 1,000 per 100,000 inhabitants in the long-term, showing certain stabilization in the last years of the 20-year simulation horizon. The results were highly sensitive to FIT positivity. ONCLUSIONS: Implementing a population-based CRC screening program will increase the demand for colonoscopies, which is expected to double in 20 years, mainly due to an increase in surveillance colonoscopies. Financial support for this study was provided to MC by grant number PI07/90357 from Instituto de Salud Carlos III-FEDER (www.isciii.es/) and number AP94422011 from Fundación Mutua Madrileña (www.fundacionmutua.es/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Roche Diagnostics International Ltd., a commercial company, provided support in the form of salaries for JM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.

Background: There is no information on the impact of age and gender on the diagnostic yield of different positivity thresholds for the fecal immunochemical test for hemoglobin (FIT). Objectives: To evaluate the performance of this test at distinct positivity cut-offs in a population -based colorectal cancer (CRC) screening program. Methods: CRC detection rate (DR), and analysis of resources were evaluated retrospectively, at different cut-offs of FIT (20, 25, 30, 35 and 40 tig Hb/g) respect to a reference value (15 tig Hb/g), according to age and gender, in a screening population of 10,611 participants of the ColonPrev study (Quintero. NEJM 2013). Results: At the reference cut-off value, 36 CRC and 252 advanced adenomas (AA) were diagnosed. Increasing the cut-off in women 60 years increasing cut-off at 25-30 tig Hb/g. In men >60 years, all increases in the cut-off affected the CRC DR, especially when the cut-off was increased from 35 to 40 tig Hb/g (CRC miss rate 25%). Conclusions: To improve the performance of FIT in CRC screening programs, FIT cut-offs could be individualized by age and gender. (C) 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

We describe an association between TGFBR1 polymorphism rs868 and mismatch repair proficient hereditary colorectal cancers. This polymorphism results in more binding of TGFBR1 to let-7b-5p miRNA, which would result in lower expression of TGFBR1 and thus higher colorectal cancer risk.The purpose of this study was to identify novel colorectal cancer (CRC)-causing alleles in unexplained familial CRC cases. In order to do so, coding regions in five candidate genes (MGMT, AXIN2, CTNNB1, TGFBR1 and TGFBR2) were sequenced in 11 unrelated microsatellite-stable hereditary non-polyposis CRC (MSS HNPCC) cases. Selected genetic variants were genotyped in a discovery set of 27 MSS HNPCC cases and 85 controls. One genetic variant, rs67687202, in TGFBR1 emerged as significant (P = 0.002), and it was genotyped in a replication set of 87 additional MSS HNPCC-like cases and 338 controls where it was also significantly associated with MSS HNPCC cases (P = 0.041). In the combined genotype data, rs67687202 was associated with a moderate increase in CRC risk (OR = 1.68; 95% CI = 1.13-2.50; P = 0.010). We tested a highly correlated SNP rs868 in 723 non-familial CRC cases compared with 629 controls, and it was not significantly associated with CRC risk (P = 0.370). rs868 is contained in a let-7 miRNA binding site in the 3'UTR of TGFBR1, which might provide a functional basis for the association in MSS HNPCC. In luciferase assays, the risk-associated allele for rs868 was associated with half the luciferase expression in the presence of miRNA let-7b-5p compared with protective allele, suggesting more binding of let-7b-5p and less TGFBR1 expression. Thus, rs868 potentially is a CRC risk-causing allele. Our results support the concept that rs868 is associated with lower TGFBR1 expression thereby increasing CRC risk.

Colonoscopy and fecal immunochemical testing (FIT) are accepted strategies for colorectal-cancer screening in the average-risk population. METHODS: In this randomized, controlled trial involving asymptomatic adults 50 to 69 years of age, we compared one-time colonoscopy in 26,703 subjects with FIT every 2 years in 26,599 subjects. The primary outcome was the rate of death from colorectal cancer at 10 years. This interim report describes rates of participation, diagnostic findings, and occurrence of major complications at completion of the baseline screening. Study outcomes were analyzed in both intention-to-screen and as-screened populations. RESULTS: The rate of participation was higher in the FIT group than in the colonoscopy group (34.2% vs. 24.6%, P, Supported by grants from Asociación Española contra el Cáncer (Fundación Científica and Junta de Barcelona), Instituto de Salud Carlos III (PI08/90717), FEDER funds, and Agència de Gestió d’Ajuts Universitaris i de Recerca (2009SGR849). Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is funded by Instituto de Salud Carlos III. In the Basque Country, the study received additional grants from Obra Social de Kutxa, Diputación Foral de Gipuzkoa (DFG 07/5), Departamento de Sanidad del Gobierno Vasco, EITB-Maratoia (BIO 07/ CA/19), and Acción Transversal contra el Cáncer del CIBERehd (2008). In Galicia, this work was supported by Dirección Xeral de Innovación e Xestión da Saúde Pública, Conselleria de Sanidade, and Xunta de Galicia. Eiken Chemical of Japan and its Spanish representatives, Palex Medical and Biogen Diagnóstica, donated supplies and automated analyzers used for FIT

The EPICOLON consortium was initiated in 1999 by the Gastrointestinal Oncology Group of the Spanish Gastroenterology Association. It recruited consecutive, unselected, population-based colorectal cancer (CRC) cases and control subjects matched by age and gender without personal or familial history of cancer all over Spain with the main goal of gaining knowledge in Lynch syndrome and familial CRC. This epidemiological, prospective and multicentre study collected extensive clinical data and biological samples from ∼2000 CRC cases and 2000 controls in Phases 1 and 2 involving 25 and 14 participating hospitals, respectively. Genetic susceptibility projects in EPICOLON have included candidate-gene approaches evaluating single-nucleotide polymorphisms/genes from the historical category (linked to CRC risk by previous studies), from human syntenic CRC susceptibility regions identified in mouse, from the CRC carcinogenesis-related pathways Wnt and BMP, from regions 9q22 and 3q22 with positive linkage in CRC families, and from the mucin gene family. This consortium has also participated actively in the identification 5 of the 16 common, low-penetrance CRC genetic variants identified so far by genome-wide association studies. Finishing their own pangenomic study and performing whole-exome sequencing in selected CRC samples are among EPICOLON future research prospects. © 2012 The Author.

Background: The selection of patients for genetic testing to rule out Lynch syndrome is currently based on fulfilment of at least one of the revised Bethesda criteria followed by mismatch repair (MMR) status analysis. A study was undertaken to compare the present approach with universal MMR study-based strategies to detect Lynch syndrome in a large series of patients with colorectal cancer (CRC). Methods: 2093 patients with CRC from the EPICOLON I and II cohorts were included. Immunohistochemistry for MMR proteins and/or microsatellite instability (MSI) analysis was performed in tumour tissue. Germline MLH1 and MSH2 mutation analysis was performed in patients whose tumours showed loss of MLH1 or MSH2 staining, respectively. MSH6 genetic testing was done in patients whose tumours showed lack of MSH6 expression or a combined lack of MSH2 and MSH6 expression but did not have MSH2 mutations. PMS2 genetic testing was performed in patients showing isolated loss of PMS2 expression. In patients with MSI tumours and normal or not available MMR protein expression, all four MMR genes were studied. Results: A total of 180 patients (8.6%) showed loss of expression of some of the MMR proteins and/or MSI. Four hundred and eighty-six patients (23.2%) met some of the revised Bethesda criteria. Of the 14 (0.7%) patients who had a MMR gene mutation, 12 fulfilled at least one of the revised Bethesda criteria and two (14.3%) did not. Conclusions: Routine molecular screening of patients with CRC for Lynch syndrome using immunohistochemistry or MSI has better sensitivity for detecting mutation carriers than the Bethesda guidelines. Instituto de Salud Carlos III (INT09/208 and PI08/0726). Fundación de la CV para la Investigación en el Hospital General Universitario de Alicante. Grant SAF 07-64873 from the Ministerio de Educación y Ciencia. Funds from the AGAUR (2009 SGR 849) Instituto de Salud Carlos III (FI07/00303) CIBERehd is funded by the Instituto de Salud Carlos III. Grant from Conselleria d’Educació de la Generalitat Valenciana (VALi+d).

Background & Aims 5-Fluorouracil (5-FU)–based adjuvant chemotherapy does not increase survival times of patients with colorectal tumors with microsatellite instability. We determined the response of patients with colorectal tumors with the CpG island methylator phenotype (CIMP) to 5-FU–based therapy. Methods We analyzed a population-based cohort of 302 patients with colorectal cancer (CRC) for a median follow-up time of 50.7 months. CIMP status was determined by analysis of the CACNAG1 , SOCS1 , RUNX3 , NEUROG1 , and MLH1 promoters; tumors were considered to be CIMP positive if at least 3 promoters were methylated. Results Tumors from 29.5% of patients (89/302) were CIMP positive; CIMP status did not influence disease-free survival (DFS; log-rank = 0.3). Of tumors of TNM stages II–III (n = 196), 32.7% were CIMP positive. Among patients with stages II–III CRC who did not receive adjuvant 5-FU chemotherapy, those with CIMP-positive tumors had longest times of DFS (log-rank = 0.04); In patients who received chemotherapy, those with CIMP-positive tumors had shorter times of DFS (log-rank = 0.02). In patients with CIMP-negative tumors, adjuvant 5-FU chemotherapy significantly increased time of DFS (log-rank = 0.00001). However, in patients with CIMP-positive tumors, adjuvant 5-FU chemotherapy did not affect time of DFS (log-rank = 0.7). Multivariate analysis showed a significant, independent interaction between 5-FU treatment and CIMP status (hazard ratio [HR], 0.6; 95% confidence interval [CI], 0.5–0.8). Among patients with CIMP-positive tumors, adjuvant chemotherapy was not an independent predictor of outcome (HR, 0.8; 95% CI, 0.3–2.0). In patients who did not receive adjuvant 5-FU chemotherapy, CIMP status was the only independent predictor of survival (HR, 2.0; 95% CI, 1.1–3.8). Conclusions Patients with CIMP-positive colorectal tumors do not benefit from 5-FU–based adjuvant chemotherapy.

The endocannabinoid system is an important regulatory system of multiple functions of the body in all vertebrates. There are 2 specific receptors, CB1 and CB2, through which the cannabinoids exert their effect. CB1-receptors mainly express themselves in myenteric plexuses and submucosal epithelium of the gastrointestinal tract, suggesting their implication in the inhibition of the peristalsis and gastrointestinal contraction. CB2-receptors are expressed in the tissue and immune cells, such as T and B-lymphocytes, monocytes and polymorphonuclear neutrophils, exerting an immunomodulator effect. The role of the endocannabinoid system is not completely known, but there is enough evidence that confirms an important role in the decrease of inflammation through the reduction of the release of pro-inflammatory cytokines. Therefore, it may exert a protective role in many of the points where the homeostasis breaks in inflammatory bowel disease. Research about the mechanisms and effects of the endocannabinoid system in the gastrointestinal tract will allow advancing in the therapy of this illness.

In the last two decades, the incidence of esophageal cancer has progressively increased, especially that of adenocarcinomas localized in the esophagogastric junction. The incidence of gastric cancer has decreased in the last few decades, although this decrease shows wide geographical variations. Thus, the prevalence of gastric cancer continues to be high in countries such as Chile, Colombia and Ireland and this disease remains the most frequent neoplasm in both sexes in China and Japan. In the meeting of the American Gastroenterological Association, notable among all the studies presented on the prevention and treatment of esophageal and gastric cancer were the following contributions: the use of clinical practice guidelines for the prevention and surveillance of Barrett's esophagus (BE) should be improved; treatment with proton pump inhibitors does not seem to reduce the risk of esophageal cancer; endoscopic therapy of intramucosal cancer through complete mucosal resection is effective; Helicobacter pylori eradication prevents the development of metachronous gastric cancer in patients treated for a first intramucosal adenocarcinoma through endoscopic resection; the risk of developing gastric cancer is 6 times higher in patients with mucosa-associated lymphoid tissue (MALT) lymphoma than in the general population; and photodynamic therapy may be an alternative for the treatment of "invisible" gastric adenocarcinoma, which should be followed-up endoscopically.

Background & Aims: Mismatch repair (MMR) deficiencies are the hallmark of tumors arising in Lynch syndrome, however, in approximately 15% of sporadic colorectal cancers (CRC) these deficiencies most often are associated with somatic methylation of the MMR gene MLH1. Recently, an oncogenic mutation in the BRAF gene has been involved in sporadic CRC showing MMR deficiencies as a result of MLH1 promoter methylation. The aim of this study was to evaluate the contribution of BRAF V600E mutation analysis in the identification of MSH2/MLH1 gene mutation carriers in newly diagnosed CRC patients. Methods:BRAF V600E mutation was analyzed in CRC patients with MMR deficiencies (microsatellite instability and/or lack of MLH1/MSH2 protein expression) in the EPICOLON population-based study. The effectiveness and efficiency of different strategies were evaluated with respect to the presence of MSH2/MLH1 germline mutations. Results: MMR deficiencies were detected in 119 of the 1222 CRC patients with tumors showing either microsatellite instability (n = 111) or loss of protein expression (n = 81). BRAF mutation was detected in 22 (18.5%) of the patients. None of the patients with unambiguous germline mutation had BRAF mutation. Regardless of the strategy used to identify MSH2/MLH1 gene carriers, the introduction of BRAF analysis in these patients slightly improves their effectiveness. The introduction of BRAF mutation analysis as a step before germline genetic testing in patients with MMR deficiencies achieved a significant reduction in costs per mutation detected. Conclusions: Detection of BRAF V600E mutation could simplify and improve the cost effectiveness of genetic testing for hereditary nonpolyposis colorectal cancer, especially in patients whose family history is incomplete or unknown.

Patients with colorectal cancer have a high risk of developing metachronous neoplasms. Identification of predictive factors associated with such conditions would allow individualized follow-up strategies in these patients. This study was designed to identify individual and familial factors associated with the development of metachronous colorectal neoplasms in patients with colorectal cancer. In the context of a prospective, multicenter, general population-based study—the EPICOLON project—all patients with colorectal cancer attended in ten Spanish hospitals during a one-year period were included. Patients with familial adenomatous polyposis or inflammatory bowel disease were excluded. All patients were monitored by colonoscopy within two years of the diagnoses. Demographic, clinical, pathologic, molecular (microsatellite instability status and immunohistochemistry for MSH2 and MLH1), and familial characteristics (fulfillment of Amsterdam I or II criteria, and revised Bethesda guidelines) were analyzed. A total of 353 patients were included in the study. At two years of follow-up, colonoscopy revealed the presence of adenomas in 89 (25 percent) patients and colorectal cancer in 14 (3.9 percent) patients, in 7 cases restricted to anastomosis. Univariate analysis demonstrated that development of metachronous neoplasm (adenoma or colorectal cancer) was associated with personal history of previous colorectal cancer (odds ratio, 5.58; 95 percent confidence interval, 1.01–31.01), and presence of previous or synchronous adenomas (odds ratio, 1.77; 95 percent confidence interval, 1.21–3.17). Although nonstatistical significance was achieved, metachronisms were associated with gender (P

ARLTS1 was recently identified in chromosome 13q14 as a tumor suppressor gene of the ADP-ribosylation factor family with pro-apoptotic characteristics. Additionally, one of its genetic variants (W149X) was hypothesized to be a polymorphism associated with familial cancer. We performed a large case-control association study within the EPICOLON project aimed at evaluating the sporadic and familial colorectal cancer (CRC) risk associated with ARLTS1 genetic variants. Whereas P131L and W149X did not seem to affect CRC risk, C148R did show, for the first time in CRC, statistically significant differences between cases and controls [odds ratio (OR) = 1.45, 95% confidence interval (95% CI) = 1.13-1.86, P = 0.003], sporadic cases and controls (OR = 1.59, 95% CI = 1.13-2.23, P = 0.007) and familial cases and controls (OR = 1.55, 95% CI = 1.10-2.19, P = 0.01) in agreement with a hypothetical moderate increase of the cancer risk linked to the C148R ARLTS1 variant, both in sporadic and familial CRC cases.

Background & Aims: Whereas it has conclusively been demonstrated that biallelic MutY human homolog (MYH) mutations confer a significant risk for colorectal cancer (CRC), the influence of monoallelic mutations remains controversial. Characterization of MYH-associated CRC is critical to identify individuals who might benefit from preventive strategies. This prospective, multicenter, case-control, population-based study was aimed at (1) establishing the CRC risk associated with specific germline MYH mutations and (2) devising a set of clinical criteria to identify MYH carriers among newly diagnosed CRC. Methods: Genotyping for Y165C and G382D was performed by TaqMan technology. Single-stranded conformation polymorphism analysis was performed in heterozygotes to screen for mutations in the entire gene. All individuals were re-screened for any additional pathogenic variant. Results: Biallelic and monoallelic MYH mutations were found in 8 (0.7%) and 19 (1.7%) of 1116 CRC patients, respectively. None of the 934 control subjects carried biallelic mutations, whereas 22 (2.3%) of them were monoallelic carriers. In a meta-analysis including all previous case-control studies, monoallelic MYH carriers were not at increased risk for CRC (odds ratio, 1.11; 95% confidence interval, 0.90–1.37), although a significant association was found with the Y165C mutation in either homozygotes or heterozygotes (odds ratio, 1.67; 95% confidence interval, 1.17–2.40). Furthermore, presence of more than 15 synchronous colorectal adenomas or CRC diagnosed before the age of 50 years was the most effective set of criteria for the identification of biallelic MYH mutation carriers. Conclusions: This study proposes the first set of clinical criteria designed to identify CRC patients with biallelic MYH mutations, and it argues against an increased risk for monoallelic carriers.

Background Colorectal tumors caused by failure of the DNA mismatch repair system commonly show microsatellite instability. Our goals were to compare the performance of two panels of markers (a panel previously recommended by the National Cancer Institute [NCI] and a pentaplex of mononucleotide repeats) and to devise the simplest diagnostic strategy for identification of patients with colorectal cancer characterized by defects in mismatch repair. Methods We recruited 1058 patients who were newly diagnosed with colorectal cancer. DNA from fresh-frozen and paraffin-embedded tumors was tested for microsatellite instability, using the NCI-recommended panel of microsatellite markers and the pentaplex panel of mononucleotide repeats , respectively, as templates for polymerase chain reactions (PCRs). Microsatellite instability in fresh-frozen tumors was also assessed using the pentaplex panel of mononucleotides in a crossover analysis. The expression of mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) in the tumors was determined immunohistochemically. The sensitivity and specificity with which the marker panels identified tumors with deficiencies in the expression of mismatch repair proteins were calculated. All statistical tests were two-sided. Results The sensitivity and positive predictive value of the NCI panel were 76.5% (95% confidence interval [CI] = 61% to 92%) and 65.0% (95% CI = 49% to 81%), respectively; corresponding values for the mononucleotide pentaplex panel were 95.8% (95% CI = 89% to 103%) and 88.5% (95% CI = 79% to 98%), respectively. A panel consisting of the mononucleotide repeat markers BAT26 and NR24 alone had the same predictive value as the pentaplex panel of mononucleotide repeats. Conclusions The pentaplex panel of mononucleotide repeats performs better than the NCI panel for the detection of mismatch repair – deficient tumors. Simultaneous assessment of the instability of BAT26 and NR24 is as effective as use of the pentaplex panel for diagnosing mismatch repair deficiency. J Natl Cancer Inst 2007;99: 244 – 52

Anorectal pressure studies have demonstrated internal anal sphincter (IAS) hypertonia in patients with chronic anal fissure. It is unknown however, if these changes in IAS function are associated with any abnormality in sphincter morphology. The first aim was to investigate the clinical characteristics and the manometric and endosonographic findings of the IAS in a cohort of patients with chronic anal fissure. The second aim was to investigate the association between these findings and the outcome with topical Glyceryl trinitrate (GTN) therapy.All patients who presented with chronic anal fissure from November 1999 to May 2004 were included after failure of conservative therapy. Anorectal manometry and anal endosonography were performed before treatment with 0.2% GTN ointment twice daily was initiated. Patients were evaluated after 8 weeks.One hundred and twenty-four patients (66 women, mean age, 45.2 +/- 14.8 years) were included. Hypertonia of the IAS was found in 84 (68%) patients. The mean maximum IAS thickness was 3.6 +/- 0.76 mm (1.6-5.5). An abnormally thick IAS, adjusted by age, was observed in 113 (91.1%) patients. We found no correlation between resting pressure and IAS thickness (r = 0.074; p = 0.41). At 8 weeks, 52 patients (42%) had healed with complete symptoms resolution. No statistically significant differences were observed when clinical features and manometric and endosonographic findings were compared between healing and no-healing fissures.The majority of patients with chronic anal fissure present an abnormally thick IAS. Clinical, manometric and endosonographic features had no association with outcome after GTN treatment.

Background The prevalence of MLH1 constitutional epimutations in the general population is unknown. We sought to analyse the prevalence of MLH1 constitutional epimutations in unselected and selected series of patients with colorectal cancer (CRC). Methods Patients with diagnoses of CRC (n=2123) were included in the unselected group. For comparison, a group of 847 selected patients with CRC who fulfilled the revised Bethesda guidelines (rBG) were also included. Somatic and constitutional MLH1 methylation was assayed via methylation-specific multiplex ligation-dependent probe amplification of cases lacking MLH1 expression. Germline alterations in mismatch-repair (MMR) genes were assessed via Sanger sequencing and methylation-specific multiplex ligation-dependent probe amplification. Results Loss of MLH1 expression occurred in 5.5% of the unselected series and 12.5% of the selected series (p

Mutation V600E of BRAF, a kinase-encoding gene from the RAS/RAF/MAPK pathway, in colorectal carcinoma (CRC) suggests a sporadic origin of the disease, providing an exclusion criterion for hereditary nonpolyposis colorectal cancer. Here we describe detection of this mutation by real-time chemistry TaqMan MGB probes, confirmed by direct DNA sequencing as the gold standard. DNA was extracted from paraffin-embedded tissue from 112 tumors obtained from the EPICOLON study. Seventy-two tumors were CRC with defective DNA mismatch repair (MMR; microsatellite instability and/or loss of protein expression by immunohistochemical analysis), and 40 were proficient MMR controls. BRAF mutation was detected in 20/72 (27.8%) CRC with defective MMR and in 3/40 (7.5%) proficient MMR controls (P = 0.011). BRAF mutation was detected in 19/51 (37.3%) tumors with loss of MLH1 expression and in none of the tumors with loss of MSH2 expression (0/13). BRAF mutation was not found in cases with germline mutation of MLH1 (4/112) or MSH2 (3/112) genes. The sensitivity and specificity of our real-time chemistry were both 100% for detecting the V600E mutation. Because real-time chemistry methodology has advantages in cost, time, and labor, we consider it a valuable alternative to automatic direct sequencing, particularly for serial measurements.

Identification of individuals who should undergo hereditary nonpolyposis colorectal cancer (HNPCC) genetic testing is a critical and difficult issue. For this purpose, the National Cancer Institute outlined a set of recommendations, the Bethesda guidelines, which have recently been revised.To compare the clinical performance of original and revised Bethesda guidelines for the detection of MSH2/MLH1 gene carriers in patients with colorectal cancer.A total of 1,222 patients with newly diagnosed colorectal cancer were included in the EPICOLON study, a prospective, multicenter, nationwide epidemiology survey aimed at establishing the incidence of HNPCC in Spain (JAMA 2005; 293:1986-1994). Performance characteristics of the original and revised Bethesda guidelines were assessed with respect to the presence of MSH2/MLH1 germline mutations. Logistic regression analysis was performed to establish the most effective strategy.Original or revised Bethesda guidelines were equivalent strategies in terms of sensitivity (100%vs 100%; ns), specificity (98.1%vs 97.9%; ns), and overall accuracy (98.1%vs 97.9%; ns), as well as positive (25.8%vs 24.2%) and negative predictive values (100%vs 100%). The most discriminating individual variables were criteria number 1 (i.e., fulfillment of the Amsterdam criteria; RR = 34.14; 95% CI = 6.85-170.16; p0.001) and number 2 (i.e., individuals with two HNPCC-related neoplasms; RR = 35.63; 95% CI = 4.83-262.6; p0.001) of the original guidelines, and criterion number 1 of the revised guidelines (i.e., colorectal cancer diagnosed under 50 yr of age; RR = 29.34; 95% CI = 3.81-225.96; p= 0.001). The aggregation of these three criteria was equivalent to both Bethesda guidelines in terms of sensitivity (100%) and negative predictive value (100%), but superior to the revised criteria regarding specificity (98.5%; p0.05), overall accuracy (98.5%; p0.05), and positive predictive value (30.8%).Original and revised Bethesda guidelines are equivalent, highly effective criteria for the identification of MSH2/MLH1 gene mutation carriers in patients with newly diagnosed colorectal cancer. A new set of recommendations, based on a combination of some of their individual criteria, may provide additional advantages in terms of effectiveness.

Background: Cyclooxygenase 2 (COX-2) overexpression is a frequent but not universal event in colorectal cancer. It has been suggested that COX-2 protein expression is reduced in colorectal cancer with a defective mismatch repair (MMR) system, a phenomenon commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC) but also present in up to 15% of sporadic tumors. Aim: To assess COX-2 expression in a large series of fully characterized colorectal cancer patients with respect to the MMR system and to dissect the mechanisms responsible for altered COX-2 expression in this setting. Patients and Methods: MMR-deficient colorectal cancer were identified in a nationwide, prospective, multicenter study (EPICOLON project). Control MMR-proficient colorectal cancer patients were randomly selected. COX-2 expression was evaluated by immunohistochemistry. Personal and familial characteristics, as well as MSH2/MLH1 expression and germ line mutations, were evaluated. Results: One hundred fifty-three patients, 46 with MMR deficiency and 107 with MMR proficiency, were included in the analysis. Overall, tumor COX-2 overexpression was observed in 107 patients (70%). COX-2 overexpression was observed in 85 patients (79%) with a MMR-proficient system, but only in 22 patients (48%) with a MMR-deficient colorectal cancer (P < 0.001). The lack of COX-2 overexpression was independently associated with a MMR-deficient system (odds ratio, 3.89; 95% confidence interval, 1.78-8.51; P = 0.001) and a poor degree of differentiation (OR, 3.83; 95% CI, 1.30-11.31; P = 0.015). In the subset of patients with a MMR-deficient colorectal cancer, lack of COX-2 overexpression correlated with a poor degree of differentiation, no fulfillment of Amsterdam II criteria, absence of MSH2/MLH1 germ line mutations, presence of tumor MSH2 expression, and lack of tumor MLH1 expression. CpG island promoter hypermethylation of COX2 was observed in 6 of 18 (33%) tumors lacking COX-2 expression in comparison with 2 of 28 (7%) tumors expressing this protein (P = 0.04). Conclusions: Up to half of MMR-deficient colorectal cancer do not show COX-2 overexpression, a fact observed almost exclusively in patients with sporadic forms. COX2 hypermethylation seems to be responsible for gene silencing in one third of them. These results suggest the potential utility of nonsteroidal anti-inflammatory drugs in HNPCC chemoprevention and may explain the lack of response of this approach in some sporadic tumors.

The Rockall score is used to assess the prognosis of patients with upper gastrointestinal bleeding.To assess the applicability of the Rockall score in patients undergoing endoscopic therapy for upper gastrointestinal bleeding.Retrospective evaluation of the Rockall score in the period 1995-2001. To evaluate the applicability of the Rockall system, two groups were created: group I (Rockallor=5 points) and group II (Rockallor=6 points).Two hundred and twenty-two patients were included. The median age of patients was 65 +/ -17 years. Hypotension and associated diseases were present in 20 and 50% of patients, respectively. Re-bleeding occurred in 50 patients (23%) whose median score was 7, whereas the median score of patients without re-bleeding was 6 (p=0.14). There were 20 deaths (9%) with a median score of 8, whilst the median score of surviving patients was 6 (p0.001). Sixteen patients in group I (18.4%) and 34 in group II (25.2%) re-bled (p=0.25). All the patients who died belong to group II with a Rockall scoreor=6 (15% versus 0% in groups II and I, respectively, p0.001).The Rockall score can be used in patients who undergo therapeutic endoscopy for upper gastrointestinal bleeding to identify those with high risk for mortality.

Colorectal cancer (CRC) is one of the most common neoplasms and a leading cause of death related to cancer worldwide. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent autosomal dominant predisposition to the development of CRC, accounting for approximately 2.5% of the total CRC burden in Spain. Genomic rearrangements in the MSH2 and MLH1 genes have been reported to account for an important proportion of the mutation spectrum in HNPCC, and DNA dosage techniques have been developed facilitating molecular screening of such deletions/duplications. We screened for MSH2 and MLH1 genomic rearrangements by multiplex ligation-dependent probe amplification (MLPA) in 142 Spanish patients at risk for HNPCC prior to the exon-by-exon mutation scanning and found a deletion encompassing exons 9-16 of MSH2 and a duplication encompassing exons 11-16 of MSH2, both only in one case. These results showed that MSH2/MLH1 rearrangements in Spanish patients at risk for HNPCC seem to be a less frequent mutational event than in other populations.

Colorectal cancer is the third leading cause of cancer mortality in Western countries. Hereditary nonpolyposis colorectal cancer is the most common type of hereditary colorectal cancer, but its incidence remains controversial, ranging from 1 to 5%.This present prospective, multicentre, nationwide study was aimed at compiling prominent epidemiological and clinical data with respect to hereditary non-polyposis colorectal cancer and other familial colorectal cancer forms in Spain, where information is lacking.All patients with a de-novo diagnosis of colorectal cancer and who attended between November 2000 and October 2001 in 25 hospitals all over Spain were registered. Demographic, clinical and tumour-related characteristics of probands, and detailed family history, were obtained.A total of 1872 colorectal cancer patients were included. Clinical diagnosis of hereditary non-polyposis colorectal cancer was established in 46 (2.5%) patients according to the Amsterdam II criteria. Comparison between patients fulfilling either the Amsterdam I or the Amsterdam II criteria revealed no differences with respect to demographic, clinical and tumour-related characteristics. A total of 504 (27.0%) patients had a family history of hereditary non-polyposis colorectal cancer-related neoplasm not fulfilling the Amsterdam criteria (familial colorectal cancer), while 360 (19.2%) patients fulfilled at least one of the Bethesda's criteria.These clinicoepidemiological data provide a more accurate characterization of hereditary non-polyposis colorectal cancer and other familial colorectal cancer forms in Spain, with potential implications in preventive strategies.

Instruments that enable to select individuals that will benefit most from bariatric surgery (BS) are necessary to increase its cost-efficiency. Our goal was to assess if intake capacity, measured with a standardized test, predicts response to BS. Patients with criteria for BS were randomly allocated to laparoscopic gastric bypass (LRYGB) or sleeve gastrectomy (LSG). We measured caloric intake capacity before and 1 year after surgery using a standardized nutrient drink test. We evaluated if pre-surgery satiation could predict satiation and weight loss (%) 1 year after surgery using multiple regression modeling. Descriptive statistics are given as mean ± SD. Fourteen women (48 ± 9 years old, BMI 41 ± 3 kg/m2) were evaluated before and 11 ± 2.6 months after surgery (seven LRYGB, seven LSG). Caloric intake capacity diminished after surgery (−950 ± 85 kcal on average [70 ± 8 % decrease over basal intake capacity]; p = 0.002) and similarly in both LRYGB (72 ± 7 % decrease) and LSG groups (68 ± 8 % decrease); p = 0.5. There was a significant weight reduction after surgery (-32 ± 10 kg [30 ± 8 % of total basal weight]) with a mean post-surgery BMI of 29 ± 2 kg/m2. The best predictive model of weight loss (%) after surgery (R 2 = 89 %, p = 0.0009) included: BMI (p = 0.0004), surgery type (p = 0.01) and pre-surgery intake capacity (p = 0.006). Weight loss was higher in heavier patients and those undergoing LRYGB. Patients with higher intake capacity had a poorer outcome independently of basal BMI and surgery type. Caloric intake capacity, as measured by a standard nutrient drink test, helps to predict weight loss after bariatric surgery. This test might be useful in algorithms of obesity treatment decision.