Risk prediction for advanced neoplasia using longitudinal adherence measures to fecal immunochemical test-based colorectal cancer screening programs.

BACKGROUND: Patterns of longitudinal adherence may predict advanced neoplasia (AN) detection in subsequent rounds of colorectal cancer (CRC) screening. However, after more than five rounds, it is important to obtain a simplified measure. The aim was to determine the best simplified measure of longitudinal adherence to predict AN detection in CRC screening. METHODS: Individuals with four invitations from a Dutch Fecal immunochemical testing (FIT-)based pilot study and two Italian FIT-based CRC screening programs were included. We calculated AN detection in the fourth round, stratified by prior adherence. Five simplified measures were compared to full information (permutations) using chi-squared goodness-of-fit: adherence previous invitation, consistency, frequency, frequency + adherence previous invitation, and proportion of invitations covered. RESULTS: AN detection in the fourth round was highly dependent on prior adherence behavior. For inconsistent adherence, detection in the fourth round was strongly dependent on frequency and time since last participation. The performance of the simplified measures to capture this variation differed considerably. 'Adherence previous invitation' scored worst in predicting AN detection. 'Frequency+adherence previous invitation' had lowest chi-squared goodness-of-fit. DISCUSSION: The simplified measure 'frequency+adherence previous invitation' is the best measure to reflect patterns of longitudinal adherence and could be used to emphasize to individuals the importance of CRC screening.

Long-Term Follow-up of the Italian Flexible Sigmoidoscopy Screening Trial.

BACKGROUND: Recent reports showed that the protective effect of flexible sigmoidoscopy (FS) screening was maintained up to17 years, although differences were reported by sex. OBJECTIVE: To assess long-term reduction of colorectal cancer (CRC) incidence and mortality after a single FS screening. DESIGN: Parallel randomized controlled trial. (ISRCTN registry number: 27814061). SETTING: 6 centers in Italy. PARTICIPANTS: Persons aged 55 to 64 years expressing interest in having FS screening if invited, recruited from 1995 to 1999 and followed until 2012 (incidence) and 2014 to 2016 (mortality). INTERVENTION: Eligible persons were randomly assigned (1:1 ratio) to either the once-only FS screening group or control (usual care) group. MEASUREMENTS: Incidence and mortality rate ratios (RRs) and rate differences. RESULTS: A total of 34 272 persons (17 136 in each group) were included in the analysis; 9911 participants had screening in the intervention group. Median follow-up was 15.4 years for incidence and 18.8 years for mortality. Incidence of CRC was reduced by 19% (RR, 0.81 [95% CI, 0.71 to 0.93]) in the intention-to-treat (ITT) analysis, comparing the intervention with the control group, and by 33% (RR, 0.67 [CI, 0.56 to 0.81]) in the per protocol (PP) analysis, comparing participants screened in the intervention group with the control persons. Colorectal cancer mortality was reduced by 22% (RR, 0.78 [CI, 0.61 to 0.98]) in the ITT analysis and by 39% (RR, 0.61 [CI, 0.44 to 0.84]) in the PP analysis. Incidence of CRC was statistically significantly reduced among both men and women. Colorectal cancer mortality was statistically significantly reduced among men (ITT RR, 0.73 [CI, 0.54 to 0.97]) but not among women (ITT RR, 0.90 [CI, 0.59 to 1.37]). LIMITATION: Self-selection of volunteers from the general population sample targeted for recruitment may limit generalizability. CONCLUSION: The strong protective effect of a single FS screening for CRC incidence and mortality was maintained up to 15 and 19 years, respectively. PRIMARY FUNDING SOURCE: Italian Association for Cancer Research, Italian National Research Council, Istituto Oncologico Romagnolo, Fondo "E. Tempia," University of Milan, and Local Health Unit ASL-Torino.

Adenoma detection by Endocuff-assisted versus standard colonoscopy in an organized screening program: the "ItaVision" randomized controlled trial.

BACKGROUND: The Endocuff Vision device (Arc Medical Design Ltd., Leeds, UK) has been shown to increase mucosal exposure, and consequently adenoma detection rate (ADR), during colonoscopy. This nationwide multicenter study assessed possible benefits and harms of using Endocuff Vision in a fecal immunochemical test (FIT)-based screening program. METHODS: Patients undergoing colonoscopy after a FIT-positive test were randomized 1:1 to undergo Endocuff-assisted colonoscopy or standard colonoscopy, stratified by sex, age, and screening history. Primary outcome was ADR. Secondary outcomes were ADR stratified by endoscopists' ADR, advanced ADR (AADR), adenomas per colonoscopy (APC), withdrawal time, and adverse events. RESULTS: 1866 patients were enrolled across 13 centers. After exclusions, 1813 (mean age 60.1 years; male 53.8 %) were randomized (908 Endocuff Vision, 905 standard colonoscopy). ADR was significantly higher in the Endocuff Vision arm (47.8 % vs. 40.8 %; relative risk [RR] 1.17, 95 % confidence interval [CI] 1.06-1.30), with no differences between arms regarding size or morphology. When stratifying for endoscopists' ADR, only low detectors (ADR < 33.3 %) showed a statistically significant ADR increase (Endocuff Vision 41.1 % [95 %CI 35.7-46.7] vs. standard colonoscopy 26.0 % [95 %CI 21.3-31.4]). AADR (24.8 % vs. 20.5 %, RR 1.21, 95 %CI 1.02-1.43) and APC (0.94 vs. 0.77; P  = 0.001) were higher in the Endocuff Vision arm. Withdrawal time and adverse events were similar between arms. CONCLUSION: Endocuff Vision increased ADR in a FIT-based screening program by improving examination of the whole colonic mucosa. Utility was highest among endoscopists with a low ADR.

Faecal haemoglobin concentration among subjects with negative FIT results is associated with the detection rate of neoplasia at subsequent rounds: a prospective study in the context of population based screening programmes in Italy.

OBJECTIVE: To estimate the predictive role of faecal haemoglobin (f-Hb) concentration among subjects with faecal immunochemical test (FIT) results below the positivity cut-off for the subsequent risk of advanced neoplasia (AN: colorectal cancer-CRC-or advanced adenoma). DESIGN: Prospective cohort of subjects aged 50-69 years, undergoing their first FIT between 1 January 2004 and 31 December 2010 in four population-based programmes in Italy. METHODS: All programmes adopted the same analytical procedure (OC Sensor, Eiken Japan), performed every 2 years, on a single sample, with the same positivity cut-off (20 µg Hb/g faeces). We assessed the AN risk at subsequent exams, the cumulative AN detection rate (DR) over the 4-year period following the second FIT and the interval CRC (IC) risk following two negative FITs by cumulative amount of f-Hb concentration over two consecutive negative FITs, using multivariable logistic regression models and the Kaplan-Meier method. RESULTS: The cumulative probability of a positive FIT result over the subsequent two rounds ranged between 7.8% (95% CI 7.5 to 8.2) for subjects with undetectable f-Hb at the initial two tests (50% of the screenees) and 48.4% (95% CI 44.0 to 53.0) among those (0.7% of the screenees) with a cumulative f-Hb concentration ≥20 µg/g faeces. The corresponding figures for cumulative DR were: 1.4% (95% CI 1.3 to 1.6) and 25.5% (95% CI 21.4 to 30.2) for AN; 0.17% (95% CI 0.12 to 0.23) and 4.5% (95% CI 2.8 to 7.1) for CRC. IC risk was also associated with cumulative f-Hb levels. CONCLUSION: The association of cumulative f-Hb concentration with subsequent AN and IC risk may allow to design tailored strategies to optimise the utilisation of endoscopy resources: subjects with cumulative f-Hb concentration ≥20 µg/g faeces over two negative tests could be referred immediately for total colonoscopy (TC), while screening interval might be extended for those with undetectable f-Hb.

Flexible Sigmoidoscopy and CT Colonography Screening: Patients' Experience with and Factors for Undergoing Screening-Insight from the Proteus Colon Trial.

Purpose To compare the acceptability of computed tomographic (CT) colonography and flexible sigmoidoscopy (FS) screening and the factors predicting CT colonographic screening participation, targeting participants in a randomized screening trial. Materials and Methods Eligible individuals aged 58 years (n = 1984) living in Turin, Italy, were randomly assigned to be invited to screening for colorectal cancer with FS or CT colonography. After individuals who had died or moved away (n = 28) were excluded, 264 of 976 (27.0%) underwent screening with FS and 298 of 980 (30.4%) underwent CT colonography. All attendees and a sample of CT colonography nonattendees (n = 299) were contacted for a telephone interview 3-6 months after invitation for screening, and screening experience and factors affecting participation were investigated. Odds ratios (ORs) were computed by means of multivariable logistic regression. Results For the telephone interviews, 239 of 264 (90.6%) FS attendees, 237 of 298 (79.5%) CT colonography attendees, and 182 of 299 (60.9%) CT colonography nonattendees responded. The percentage of attendees who would recommend the test to friends or relatives was 99.1% among FS and 93.3% among CT colonography attendees. Discomfort associated with bowel preparation was higher among CT colonography than FS attendees (OR, 2.77; 95% confidence interval [CI]: 1.47, 5.24). CT colonography nonattendees were less likely to be men (OR, 0.36; 95% CI: 0.18, 0.71), retired (OR, 0.31; 95% CI: 0.13, 0.75), to report regular physical activity (OR, 0.37; 95% CI: 0.20, 0.70), or to have read the information leaflet (OR, 0.18; 95% CI: 0.08, 0.41). They were more likely to mention screening-related anxiety (mild: OR, 6.30; 95% CI: 2.48, 15.97; moderate or severe: OR, 3.63; 95% CI: 1.87, 7.04), erroneous beliefs about screening (OR, 32.15; 95% CI: 6.26, 165.19), or having undergone a recent fecal occult blood test (OR, 13.69; 95% CI: 3.66, 51.29). Conclusion CT colonography and FS screening are well accepted, but further reducing the discomfort from bowel preparation may increase CT colonography screening acceptability. Negative attitudes, erroneous beliefs about screening, and organizational barriers are limiting screening uptake; all these factors are modifiable and therefore potentially susceptible to interventions. © RSNA, 2017 Online supplemental material is available for this article.

Full-spectrum (FUSE) versus standard forward-viewing colonoscopy in an organised colorectal cancer screening programme.

OBJECTIVE: Miss rate of polyps has been shown to be substantially lower with full-spectrum endoscopy (FUSE) compared with standard forward-viewing (SFV) colonoscopy in a tandem study at per polyp analysis. However, there is uncertainty on whether FUSE is also associated with a higher detection rate of colorectal neoplasia, especially advanced lesions, in per patient analysis. METHODS: Consecutive subjects undergoing colonoscopy following a positive faecal immunochemical test (FIT) by experienced endoscopists and performed in the context of a regional colorectal cancer population-screening programme were randomised between colonoscopy with either FUSE or SFV colonoscopy in seven Italian centres. Randomisation was stratified by gender, age group and screening history. Primary outcomes included detection rates of advanced adenomas (A-ADR), adenomas (ADR) and sessile-serrated polyps (SSPDR). RESULTS: Of 741 eligible subjects, 658 were randomised to either FUSE (n=328) or SFV (n=330) colonoscopy and included in the analysis. Overall, 293/658 and 143/658 subjects had at least one adenoma (ADR 44.5%) and advanced adenoma (A-ADR 21.7%), respectively, while SSP was the most advanced lesion in 18 cases (SSPDR 2.7%). ADR and A-ADR were 43.6% and 19.5% in the FUSE arm, and 45.5% and 23.9% in the SFV arm, with no difference for both ADR (OR for FUSE: 0.96, 95% CI 0.81 to 1.14) and A-ADR (OR for FUSE: 0.82, 95% CI 0.61 to 1.09). No difference in SSPDR or multiplicity was detected between the two arms. In the per polyp analysis, the mean number of adenomas and proximal adenomas per patient was 0.81±1.25 and 0.47±0.93 in the FUSE arm, and 0.85±1.33 and 0.48±0.96 in the SFV colonoscopy arm (p=NS for both comparisons). CONCLUSIONS: No statistically significant difference in ADR and A-ADR between FUSE and SFV colonoscopy was detected in a per patient analysis in FIT-positive patients. TRIAL REGISTRATION NUMBER: ISRCTN10357435.

Comparing CT colonography and flexible sigmoidoscopy: a randomised trial within a population-based screening programme.

IMPORTANCE AND AIMS: The role of CT colonography (CTC) as a colorectal cancer (CRC) screening test is uncertain. The aim of our trial was to compare participation and detection rate (DR) with sigmoidoscopy (flexible sigmoidoscopy (FS)) and CTC in a screening setting. DESIGN SETTING AND PARTICIPANTS: We conducted two randomised clinical trials (RCTs). (1) Participation RCT: individuals, aged 58 years, living in Turin (Italy), were randomly assigned to be invited to FS or CTC screening; (2) detection RCT: residents in northern Italy, aged 58-60, giving their consent to recruitment, were randomly allocated to CTC or FS. Polyps ≥6 mm at CTC, or 'high-risk' distal lesions at FS, were referred for colonoscopy (TC). MAIN OUTCOME MEASURES: Participation rate (proportion of invitees examined); DR of advanced adenomas or CRC (advanced neoplasia (AN)). RESULTS: Participation was 30.4% (298/980) for CTC and 27.4% (267/976) for FS (relative risk (RR) 1.1; 95% CI 0.98 to 1.29). Among men, participation was higher with CTC than with FS (34.1% vs 26.5%, p=0.011). In the detection RCT, 2673 subjects had FS and 2595 had CTC: the AN DR was 4.8% (127/2673, including 9 CRCs) with FS and 5.1% (133/2595, including 10 CRCs) with CTC (RR 1.08; 95% CI 0.85 to 1.37). Distal AN DR was 3.9% (109/2673) with FS and 2.9% (76/2595) with CTC (RR 0.72; 95% CI 0.54 to 0.96); proximal AN DR was 1.2% (34/2595) for FS vs 2.7% (69/2595) for CTC (RR 2.06; 95% CI 1.37 to 3.10). CONCLUSIONS AND RELEVANCE: Participation and DR for FS and CTC were comparable. AN DR was twice as high in the proximal colon and lower in the distal colon with CTC than with FS. Men were more likely to participate in CTC screening. TRIAL REGISTRATION NUMBER: NCT01739608; Pre-results.

Offering people a choice for colorectal cancer screening.

OBJECTIVES: To assess the population coverage and diagnostic yield of offering an immunochemical faecal occult blood test (FIT) to non-responders to a flexible sigmoidoscopy (FS) invitation. DESIGN: A cohort study conducted in a population-based colorectal cancer (CRC) screening programme. In this programme, eligible men and women aged 58 (Turin; 43,748 subjects) or 60 (Verona; 19,970 subjects) are invited, with a personal letter signed by their general practitioner, to undergo an FS. Bowel preparation is limited to a single enema self-administered at home. Subjects in whom one distal polyp >5 mm (≥ 10 mm in Turin) or at least one adenoma (one advanced adenoma or more than two adenomas in Turin) is detected at FS are referred for colonoscopy. People who do not respond to the invitation to undergo an FS are invited to have an FIT (OC-Sensor; Eiken, Tokyo, Japan; single sample, cut-off 100 ng/ml). Attendance rate and neoplasia yield were analysed in four consecutive birth cohorts. RESULTS: Overall participation rate for the FS invitation was 39.3% in Verona and 29.9% in Turin. Of the eligible non-responders to the FS invitation, 19.3% (95% CI 18.9% to 19.7%) underwent an FIT. As a result, the proportion of people undergoing screening by FS or FIT was 55.2% in Verona and 39.3% in Turin, with no gender differences in either centre. FIT detected 8.3% of all advanced adenomas and 20.4% of all CRCs diagnosed at screening. CONCLUSIONS: A strategy involving the sequential offer of FS and FIT is a feasible and efficient approach. FIT in people not attending for FS increases screening uptake and detection of advanced adenomas and CRCs.

SIED-GISCOR recommendations for colonoscopy in screening programs: Part I - Diagnostic.

The implementation of FIT programs reduces incidence and mortality from CRC in the screened subjects. The ultimate efficacy for CRC morbidity and mortality prevention in a FIT program depends on the colonoscopy in FIT+ subjects that has the task of detecting and removing these advanced lesions. Recently, there has been growing evidence on factors that influence the quality of colonoscopy specifically withing organized FIT programs, prompting to dedicated interventions in order to maximize the benefit/harm ratio of post-FIT colonoscopy. This document focuses on the diagnostic phase of colonoscopy, providing indications on how to standardise colonoscopy in FIT+ subjects, regarding timing of examination, management of antithrombotic therapy, bowel preparation, competence and sedation.

Management of Pt1 tumours removed by endoscopy during colorectal cancer screening: Outcome and treatment quality indicators.

INTRODUCTION: Limited information is available about outcomes of patients with malignant adenomas endoscopically resected at screening. The aim of the study was to evaluate diagnostic and therapeutic quality indicators and to correlate them with clinical and surgical outcomes. MATERIALS AND METHODS: We reviewed endoscopic and histology characteristics of all pT1 tumours endoscopically removed at the time of colonoscopy assessment in subjects with a positive screening test result in the context of a population-based program. RESULTS: 392 pT1 tumours were completely removed by endoscopy (en-bloc = 86.7%, piecemeal = 13.3%) and the histology report was considered complete in 83.2% of cases. Treatment was limited to endoscopic excision for 120 patients (30.7%, Group 1), 272 (69.3%, Group 2) underwent radicalisation surgery. In patients who had at least 1 lymph node examined, the rate of nodal involvement was 5.4% (13/239); no metastatic node was found in the 21 (27.6%) out of 76 patients with low-risk adenomas, who underwent surgery. CONCLUSION: Risk of nodal involvement in colorectal pT1 tumours is well predicted by known histologic features also in a screening setting, although it was lower than among patients from clinical series. Surgical overtreatment is still significantly present and there is ample room for improvement regarding diagnostic and therapeutic flow-chart.

Gastroenterology today: between certainties and news.

This special article reports on two crucial issues discussed during a meeting. The first was the updated management of Helicobacter pylori (H. pylori) infection. This was approached taking into account the recent European Guidelines, with a focus on novelties in treatment. In particular, considering the increasing H. pylori antibiotic resistance to clarithromycin, in countries with a high clarithromycin resistance rate, the bismuth-containing quadruple therapies should be preferred. The new formulation, with bismuth, metronidazole, and tetracycline contained in a single capsule (three-in-one), has shown exciting results both in naive and in non-responder patients. Levofloxacin- and rifabutin-containing triple therapies should be proposed to patients who experienced H. pylori treatment failures. Another key message on H. pylori management was that, after one or more failures, standard antimicrobial susceptibility testing should be considered before prescribing a further treatment. The second issue concerned the novelties on dysbiosis of intestinal microbiota and its clinical consequences. Among the latter, the focus was on both constipation-predominant irritable bowel syndrome (IBS-C) and microscopic colitis. Since the number of microorganisms inhabiting the gastrointestinal (GI) tract is estimated to be about 10 times higher than that of human cells, it is not surprising to foresee the clinical consequences of dysbiosis. However, to date the role of dysbiosis in IBS-C and in microscopic colitis is poorly known and major efforts are needed to understand if manipulating microbiota could improve the treatment of these and other diseases both within and outside the GI tract. At a meeting held in Turin, Italy, on May 27, 2017 two crucial issues of modern gastroenterology were discussed: the updated management of Helicobacter pylori (H. pylori) infection and the novelties regarding the dysbiosis of intestinal microbiota and its clinical consequences. Among the latter, a focus was made on both constipation-predominant irritable bowel syndrome (IBS-C) and microscopic colitis. In this special article we report the most recent salient advances discussed during this meeting.

The RNA-binding protein ESRP1 promotes human colorectal cancer progression.

Epithelial splicing regulatory protein 1 (ESRP1) is an epithelial cell-specific RNA binding protein that controls several key cellular processes, like alternative splicing and translation. Previous studies have demonstrated a tumor suppressor role for this protein. Recently, however, a pro-metastatic function of ESRP1 has been reported. We thus aimed at clarifying the role of ESRP1 in Colorectal Cancer (CRC) by performing loss- and gain-of-function studies, and evaluating tumorigenesis and malignancy with in vitro and in vivo approaches. We found that ESRP1 plays a role in anchorage-independent growth of CRC cells. ESRP1-overexpressing cells grown in suspension showed enhanced fibroblast growth factor receptor (FGFR1/2) signalling, Akt activation, and Snail upregulation. Moreover, ESRP1 promoted the ability of CRC cells to generate macrometastases in mice livers. High ESRP1 expression may thus stimulate growth of cancer epithelial cells and promote colorectal cancer progression. Our findings provide mechanistic insights into a previously unreported, pro-oncogenic role for ESRP1 in CRC, and suggest that fine-tuning the level of this RNA-binding protein could be relevant in modulating tumor growth in a subset of CRC patients.

Once-only sigmoidoscopy in colorectal cancer screening: follow-up findings of the Italian Randomized Controlled Trial--SCORE.

BACKGROUND: A single flexible sigmoidoscopy at around the age of 60 years has been proposed as an effective strategy for colorectal cancer (CRC) screening. METHODS: We conducted a randomized controlled trial to evaluate the effect of flexible sigmoidoscopy screening on CRC incidence and mortality. A questionnaire to assess the eligibility and interest in screening was mailed to 236,568 men and women, aged 55-64 years, who were randomly selected from six trial centers in Italy. Of the 56,532 respondents, interested and eligible subjects were randomly assigned to the intervention group (invitation for flexible sigmoidoscopy; n = 17,148) or the control group (no further contact; n = 17,144), between June 14, 1995, and May 10, 1999. Flexible sigmoidoscopy was performed on 9911 subjects. Intention-to-treat and per-protocol analyses were performed to compare the CRC incidence and mortality rates in the intervention and control groups. Per-protocol analysis was adjusted for noncompliance. RESULTS: A total of 34,272 subjects (17,136 in each group) were included in the follow-up analysis. The median follow-up period was 10.5 years for incidence and 11.4 years for mortality; 251 subjects were diagnosed with CRC in the intervention group and 306 in the control group. Overall incidence rates in the intervention and control groups were 144.11 and 176.43, respectively, per 100,000 person-years. CRC-related death was noted in 65 subjects in the intervention group and 83 subjects in the control group. Mortality rates in the intervention and control groups were 34.66 and 44.45, respectively, per 100,000 person-years. In the intention-to-treat analysis, the rate of CRC incidence was statistically significantly reduced in the intervention group by 18% (rate ratio [RR] = 0.82, 95% confidence interval [CI] = 0.69 to 0.96), and the mortality rate was non-statistically significantly reduced by 22% (RR = 0.78; 95% CI = 0.56 to 1.08) compared with the control group. In the per-protocol analysis, both CRC incidence and mortality rates were statistically significantly reduced among the screened subjects; CRC incidence was reduced by 31% (RR = 0.69; 95% CI = 0.56 to 0.86) and mortality was reduced by 38% (RR = 0.62; 95% CI = 0.40 to 0.96) compared with the control group. CONCLUSION: A single flexible sigmoidoscopy screening between ages 55 and 64 years was associated with a substantial reduction of CRC incidence and mortality.

Video capsule enteroscopy in the diagnosis of celiac disease: a multicenter study.

OBJECTIVES: Duodenal biopsy is the current gold standard for diagnosis of celiac disease. Videocapsule endoscopy examines the entire small bowel and allows visualization of mucosal villi. We evaluated the potential of videocapsule endoscopy in assessing the severity and extent of mucosal changes in patients with suspected celiac disease. METHODS: Consecutive patients with signs/symptoms suggesting celiac disease and positive anti-gliadin and/or anti-endomysial and/or anti-tissue transglutaminase antibodies underwent upper gastrointestinal endoscopy and videocapsule endoscopy. Duodenal biopsies were classified according to modified Marsh's criteria. Capsule findings were evaluated for the presence of lesions compatible with celiac disease (scalloping of duodenal folds, fissures, flat mucosa, and mosaic appearance). RESULTS: Forty-three patients were studied. Duodenal histology was normal in 11 and compatible with celiac disease in 32. Using duodenal histology as the gold standard, the performance characteristics of capsule endoscopy for the diagnosis of celiac disease were: sensitivity 87.5% (95% CI 76.1-98.9%), specificity 90.9% (95% CI 81.0-100%), positive predictive value 96.5% (95% CI 90.1-100%), negative predictive value 71.4% (95% CI 55.8-87%), positive and negative likelihood ratios 9.6 and 0.14, respectively. Eighteen patients had mucosal changes extending beyond the duodenum, involving the entire small bowel in three. These patients tended to have more severe symptoms, but the difference was not statistically significant. Interobserver agreement for the diagnosis of celiac disease by capsule endoscopy ranged between 79.2 and 94.4%; kappa values ranged between 0.56 and 0.87. CONCLUSIONS: Videocapsule endoscopy shows good sensitivity and excellent specificity for the detection of villous atrophy in patients with suspected celiac disease.

Randomized trial of different screening strategies for colorectal cancer: patient response and detection rates.

BACKGROUND: Although there is general consensus concerning the efficacy of colorectal cancer screening, there is a lack of agreement about which routine screening strategy should be adopted. We compared the participation and detection rates achievable through different strategies of colorectal cancer screening. METHODS: From November 1999 through June 2001 we conducted a multicenter, randomized trial in Italy among a sample of 55-64 year olds in the general population who had an average risk of colorectal cancer. People with previous colorectal cancer, adenomas, inflammatory bowel disease, a recent (< or =2 years) colorectal endoscopy or fecal occult blood test (FOBT), or two first-degree relatives with colorectal cancer were excluded. Eligible subjects were randomly assigned, within the roster of their general practitioner, to 1) biennial FOBT (delivered by mail), 2) biennial FOBT (delivered by general practitioner or a screening facility), 3) patient's choice of FOBT or "once-only" sigmoidoscopy, 4) "once-only" sigmoidoscopy, or 5) sigmoidoscopy followed by biennial FOBT. An immunologic FOBT was used. Participation and detection rates of the strategies tested were compared using multivariable logistic regression models that adjusted for age, sex, and screening center. All statistical tests were two-sided. RESULTS: Of 28 319 people sampled, 1637 were excluded and 26 682 were randomly assigned to a screening arm. After excluding undelivered letters (n = 427), the participation rates for groups 1, 2, 3, 4, and 5 were 30.1% (682/2266), 28.1% (1654/5893), 27.1% (970/3579), 28.1% (1026/3650), and 28.1% (3049/10 867), respectively. Of the 2858 subjects screened by FOBT, 122 (4.3%) had a positive test result, 10 (3.5 per 1000) had colorectal cancer, and 39 (1.4%) had an advanced adenoma. Among the 4466 subjects screened by sigmoidoscopy, 341 (7.6%) were referred for colonoscopy, 18 (4 per 1000) had colorectal cancer, and 229 (5.1%) harbored an advanced adenoma. CONCLUSIONS: The participation rates were similar for sigmoidoscopy and FOBT. The detection rate for advanced neoplasia was three times higher following screening by sigmoidoscopy than by FOBT.

High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis.

BACKGROUND & AIMS: Inherited colorectal polyposis has been linked to constitutive mutations of the APC tumor suppressor gene. Recently, germline mutations in the base excision repair gene MYH have been associated with a recessively inherited form of the disease. The aim of this study was to evaluate germline mutation frequencies of both MYH and APC susceptibility genes in Italian patients with attenuated familial adenomatous polyposis. METHODS: The analysis was performed in 14 unrelated patients by using the protein truncation test for APC and genomic DNA sequencing for MYH. RESULTS: Overall, we identified 7 of 14 (50%) mutation carriers. Two patients were heterozygotes for an APC truncating mutation (2 of 14 [14%]), whereas 5 proved to be homozygotes or compound heterozygotes for MYH gene alterations (5 of 14 [36%]). Two MYH missense mutations, Y165C and G382D, already found to be frequent among patients from northern Europe, were also preponderant in our survey. Individuals with APC-associated syndrome showed a dominant family history of polyposis, whereas patients with MYH-associated disease were either apparently sporadic cases or had a family history consistent with recessive inheritance. MYH biallelic mutation carriers were up to 60% (5 of 8) among patients showing at least 30 adenomas and a family history with no vertical transmission of polyposis. CONCLUSIONS: On the basis of our data, patients with attenuated familial adenomatous polyposis with >30 adenomas and no obvious vertical transmission of the disease should be considered for MYH gene testing.

Germline APC mutation on the beta-catenin binding site is associated with a decreased apoptotic level in colorectal adenomas.

Germline mutations in APC tumor suppressor gene are responsible for familial adenomatous polyposis (FAP). A major role of these genetic changes is the constitutive activation of beta-catenin-Tcf-4 mediated transcription of nuclear target genes, but other cellular functions can be misregulated. To assess how different APC mutations can drive the early steps of colonic tumorigenesis, we studied the effect of 10 different germline-truncating alterations on the phenotype of the corresponding adenomas. A significant reduction of apoptosis, uncoupled with an increased c-myc and cyclin-D1 expression, was seen with a frameshift mutation on codon 1383, in the 20-aa repeats of the beta-catenin degradation domain, independent of a somatic alteration on the wild-type allele. The decreased apoptotic level was associated with a higher incidence of cancerization. No other APC mutation was linked with a similar effect, even in presence of a somatic allelic loss. These findings suggest that mutations in critical sites of the beta-catenin degradation domain of APC gene can convey a selective advantage to the colonic neoplastic clones by altering the apoptotic surveillance rather than enhancing the beta-catenin-Tcf-4 transcription of growth-promoting genes.

Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas.

Biallelic germline mutations in the base excision repair gene MYH have been reported in patients with multiple colorectal adenomas and cancer and in sporadic FAP patients not showing a detectable APC germline mutation. In this study, the prevalence of the common Y165C and G382D germline variants of the MYH gene was examined in 70 FAP/AAPC patients with no detectable APC mutation and a family history compatible with recessive inheritance. In addition, 141 normal-population adenoma patients (mean number of adenomas, 2.8; range, 1-9) and 52 clean colon controls were studied. The entire coding region of the MYH gene was analyzed in Y165C or G382D heterozygous patients. Since the same second mutational event (a 3 bp deletion in exon 14, 1395delGGA) was detected in 3 patients, the prevalence of this variant was also examined in all groups. In all, 14 of 70 patients in the FAP/AAPC group (20%; 95% CI = 11.7-31.6%) had biallelic germline MYH variants and 3 were heterozygotes (4.3%). None of the 141 normal-population adenoma patients carried biallelic germline MYH variants (95% CI = 0.06-4.1%) and 3 were heterozygotes (2.1%). In the control group, no MYH variants were detected. These results indicated that MYH-associated polyposis (MAP) is present in about 20% of Italian FAP/AAPC patients, in whom no germline APC mutation is detectable and showing a family history compatible with recessive inheritance, and in a small fraction of patients with colorectal adenomas in the general population. In addition, our data suggest that mutation 1395delGGA is a subpolymorphic MYH mutational event in some Caucasian populations.