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1.  Ursodeoxycholic acid counteracts celecoxib in reduction of duodenal polyps in patients with familial adenomatous polyposis: a multicentre, randomized controlled trial 
Due to prophylactic colectomy, mortality in patients with familial adenomatous polyposis (FAP) has changed, with duodenal cancer currently being the main cause of death. Although celecoxib reduces duodenal polyp density in patients with FAP, its long-term use may increase the risk of cardiovascular events and alternatives need to be explored. Preclinical studies suggest that the combination of celecoxib with ursodeoxycholic acid (UDCA) is a potentially effective strategy. We performed a randomized, double-blind, placebo-controlled trial to investigate the effect of celecoxib and UDCA co-treatment on duodenal adenomatosis in patients with FAP.
Patients with FAP received celecoxib (400 mg twice daily) and UDCA (1000-2000 mg daily, ~20-30 mg/kg/day, n=19) or celecoxib and placebo (n=18) orally for 6 months. Primary outcome was drug efficacy, assessed by comparing duodenal polyp density at pre- and post-intervention by blinded review of endoscopic recordings. As secondary outcomes, cell proliferation, apoptosis, and COX-2 levels in normal duodenal mucosa were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction.
In intention-to-treat analysis, deceased polyp density was observed after celecoxib/placebo treatment (p=0.029), whereas increased polyp density was observed after celecoxib/UDCA treatment (p=0.014). The difference in change in duodenal polyp density was statistically significant between the groups (p=0.011). No changes in secondary outcomes were observed. Thirty patients (81%) reported one or more adverse events, 16 patients (84%, Common Toxicity Criteria for Adverse Events version 3.0 (CTCAE) grade 1–3) treated with celecoxib/UDCA and 14 patients (78%, CTCAE grade 1–2) treated with celecoxib/placebo. Nine patients (24%) discontinued intervention prematurely, 5 patients (26%) treated with celecoxib/UDCA and 4 patients (22%) treated with celecoxib/placebo.
Celecoxib reduces duodenal polyp density in patients with FAP, and unexpectedly, high dose UDCA co-treatment counteracts this effect. The benefit of long term use of celecoxib for duodenal cancer prevention needs to be weighed against the (risk of) adverse events.
Trial registration, identifier NCT00808743
PMCID: PMC3750541  PMID: 23919274
Familial adenomatous polyposis; Chemoprevention; Celecoxib; Ursodeoxycholic acid; Duodenal adenomatosis; Cell proliferation; Apoptosis; Cyclooxygenase-2
2.  Similar fecal immunochemical test results in screening and referral colorectal cancer 
AIM: To improve the interpretation of fecal immunochemical test (FIT) results in colorectal cancer (CRC) cases from screening and referral cohorts.
METHODS: In this comparative observational study, two prospective cohorts of CRC cases were compared. The first cohort was obtained from 10 322 average risk subjects invited for CRC screening with FIT, of which, only subjects with a positive FIT were referred for colonoscopy. The second cohort was obtained from 3637 subjects scheduled for elective colonoscopy with a positive FIT result. The same FIT and positivity threshold (OC sensor; ≥ 50 ng/mL) was used in both cohorts. Colonoscopy was performed in all referral subjects and in FIT positive screening subjects. All CRC cases were selected from both cohorts. Outcome measurements were mean FIT results and FIT scores per tissue tumor stage (T stage).
RESULTS: One hundred and eighteen patients with CRC were included in the present study: 28 cases obtained from the screening cohort (64% male; mean age 65 years, SD 6.5) and 90 cases obtained from the referral cohort (58% male; mean age 69 years, SD 9.8). The mean FIT results found were higher in the referral cohort (829 ± 302 ng/mL vs 613 ± 368 ng/mL, P = 0.02). Tissue tumor stage (T stage) distribution was different between both populations [screening population: 13 (46%) T1, eight (29%) T2, six (21%) T3, one (4%) T4 carcinoma; referral population: 12 (13%) T1, 22 (24%) T2, 52 (58%) T3, four (4%) T4 carcinoma], and higher T stage was significantly associated with higher FIT results (P < 0.001). Per tumor stage, no significant difference in mean FIT results was observed (screening vs referral: T1 498 ± 382 ng/mL vs 725 ± 374 ng/mL, P = 0.22; T2 787 ± 303 ng/mL vs 794 ± 341 ng/mL, P = 0.79; T3 563 ± 368 ng/mL vs 870 ± 258 ng/mL, P = 0.13; T4 not available). After correction for T stage in logistic regression analysis, no significant differences in mean FIT results were observed between both types of cohorts (P = 0.10).
CONCLUSION: Differences in T stage distribution largely explain differences in FIT results between screening and referral cohorts. Therefore, FIT results should be reported according to T stage.
PMCID: PMC3471108  PMID: 23082056
Screening population; Referral cohort; Fecal immunochemical test; Tumor stage distribution; Colorectal cancer
3.  Progression of duodenal adenomatosis in familial adenomatous polyposis: due to ageing of subjects and advances in technology 
Familial Cancer  2011;10(3):491-499.
Familial adenomatous polyposis patients are at risk of duodenal cancer. Surveillance is indicated and the extent of duodenal polyposis is quantified by the Spigelman staging system. We noticed an impressive increase in high Spigelman stages over the years and therefore decided to investigate whether this increase might be due to the time-lapse since the inception of surveillance or related to improvements in endoscopic imaging and/or changes in dysplasia-reporting. Patients who were investigated by the same endoscopist since 1980 in at least 2 different episodes of technical improvements were eligible. The period 1980–2009 was divided into 4 episodes using the following landmarks: replacement of fibre-endoscopes by video-endoscopes in 1987, change in processors in 1995, change in image resolution in 2000, and change in dysplasia-reporting in 2006. An increase in Spigelman stages from low stages (0–II 100%) to high stages (III 28.1%, IV 43.8%) was seen (median follow-up: 19.5 years). In patients who progressed, a median of 4 years elapsed before progression by one stage occurred and 7 years to progress by two stages. In a mixed-model analysis, both time-lapse and technical improvements were determinant factors for duodenal disease progression. When both factors were introduced in the model, the time-lapse as well as the change in image resolution and dysplasia-ranking contributed consistently in increasing Spigelman scores and stages. The impressive increase in severity of duodenal polyposis is determined by time-lapse, technological advances and change in dysplasia-reporting. These results might call for a revised Spigelman classification.
PMCID: PMC3175343  PMID: 21416262
Familial adenomatous polyposis; FAP; Duodenal adenomatosis; Spigelman staging system; Endoscopy
4.  Study protocol: population screening for colorectal cancer by colonoscopy or CT colonography: a randomized controlled trial 
BMC Gastroenterology  2010;10:47.
Colorectal cancer (CRC) is the second most prevalent type of cancer in Europe. Early detection and removal of CRC or its precursor lesions by population screening can reduce mortality. Colonoscopy and computed tomography colonography (CT colonography) are highly accurate exams and screening options that examine the entire colon. The success of screening depends on the participation rate. We designed a randomized trial to compare the uptake, yield and costs of direct colonoscopy population screening, using either a telephone consultation or a consultation at the outpatient clinic, versus CT colonography first, with colonoscopy in CT colonography positives.
Methods and design
7,500 persons between 50 and 75 years will be randomly selected from the electronic database of the municipal administration registration and will receive an invitation to participate in either CT colonography (2,500 persons) or colonoscopy (5,000 persons) screening. Those invited for colonoscopy screening will be randomized to a prior consultation either by telephone or a visit at the outpatient clinic. All CT colonography invitees will have a prior consultation by telephone. Invitees are instructed to consult their general practitioner and not to participate in screening if they have symptoms suggestive for CRC. After providing informed consent, participants will be scheduled for the screening procedure. The primary outcome measure of this study is the participation rate. Secondary outcomes are the diagnostic yield, the expected and perceived burden of the screening test, level of informed choice and cost-effectiveness of both screening methods.
This study will provide further evidence to enable decision making in population screening for colorectal cancer.
Trial registration
Dutch trial register: NTR1829
PMCID: PMC2889851  PMID: 20482825
5.  Polyp measurement based on CT colonography and colonoscopy: variability and systematic differences 
European Radiology  2009;20(6):1404-1413.
To assess the variability and systematic differences in polyp measurements on optical colonoscopy and CT colonography.
Gastroenterologists measured 51 polyps by visual estimation, forceps comparison and linear probe. CT colonography observers randomly assessed polyp size two-dimensionally (abdominal and intermediate window) and three-dimensionally (manually and semi-automatically). Linear mixed models were used to assess the variability and systematic differences between CT colonography and optical colonoscopy techniques.
The variability of forceps and linear probe measurements was comparable and both showed less variability than measurement by visual assessment. Measurements by linear probe were 0.7 mm smaller than measurements by visual assessment or by forceps. The variability of all CT colonography techniques was lower than for measurements by forceps or visual assessment and sometimes lower (only 2D intermediate window and manual 3D) compared with measurements by linear probe. All CT colonography measurements judged polyps to be larger than optical colonoscopy, with differences ranging from 0.7 to 2.3 mm.
A linear probe does not reduce the measurement variability of endoscopists compared with the forceps. Measurement differences between observers on CT colonography were usually smaller than at optical colonoscopy. Polyps appeared larger when using various CT colonography techniques than when measured during optical colonoscopy.
PMCID: PMC2861761  PMID: 20033180
CT colonography; Colon; Colonoscopy; Measurement; Cancer; 2D; 3D
6.  CT colonography with limited bowel preparation for the detection of colorectal neoplasia in an FOBT positive screening population 
Abdominal Imaging  2009;35(6):661-668.
Aim was to evaluate the accuracy of computed tomography colonography (CTC) for detection of colorectal neoplasia in a Fecal Occult Blood Test (FOBT) positive screening population.
In three different institutions, consecutive FOBT positives underwent CTC after laxative free iodine tagging bowel preparation followed by colonoscopy with segmental unblinding. Each CTC was read by two experienced observers. For CTC and for colonoscopy the per-polyp sensitivity and per-patient sensitivity and specificity were calculated for detection of carcinomas, advanced adenomas, and adenomas.
In total 22 of 302 included FOBT positive participants had a carcinoma (7%) and 137 had an adenoma or carcinoma ≥10 mm (45%). CTC sensitivity for carcinoma was 95% with one rectal carcinoma as false negative finding. CTC sensitivity for advanced adenomas was 92% (95% CI: 88–96) vs. 96% (95% CI: 93–99) for colonoscopy (P = 0.26). For adenomas and carcinomas ≥10 mm the CTC per-polyp sensitivity was 93% (95% CI: 89–97) vs. 97% (95% CI: 94–99) for colonoscopy (P = 0.17). The per-patient sensitivity for the detection of adenomas and carcinomas ≥10 mm was 95% (95% CI: 91–99) for CTC vs. 99% (95% CI: 98–100) for colonoscopy (P = 0.07), while the per-patient specificity was 90% (95% CI: 86–95) and 96% (95% CI: 94–99), respectively (P < 0.001).
CTC with limited bowel preparation performed in an FOBT positive screening population has high diagnostic accuracy for the detection of adenomas and carcinomas and a sensitivity similar to that of colonoscopy for relevant lesions.
PMCID: PMC2980629  PMID: 19888629
CT colonography; Colorectal neoplasia; Advanced adenoma; Colorectal cancer; FOBT
7.  CT colonography with limited bowel preparation: prospective assessment of patient experience and preference in comparison to optical colonoscopy with cathartic bowel preparation 
European Radiology  2009;20(1):146-156.
The purpose of this study was to prospectively compare participant experience and preference of limited preparation computed tomography colonography (CTC) with full-preparation colonoscopy in a consecutive series of patients at increased risk of colorectal cancer. CTC preparation comprised 180 ml diatrizoate meglumine, 80 ml barium and 30 mg bisacodyl. For the colonoscopy preparation 4 l of polyethylene glycol solution was used. Participants’ experience and preference were compared using the Wilcoxon signed rank test and the chi-squared test, respectively. Associations between preference and experience parameters for the 173 participants were determined by logistic regression. Diarrhoea occurred in 94% of participants during CTC preparation. This side effect was perceived as severely or extremely burdensome by 29%. Nonetheless, the total burden was significantly lower for the CTC preparation than for colonoscopy (9% rated the CTC preparation as severely or extremely burdensome compared with 59% for colonoscopy; p < 0.001). Participants experienced significantly more pain, discomfort and total burden with the colonoscopy procedure than with CTC (p < 0.001). After 5 weeks, 69% preferred CTC, 8% were indifferent and 23% preferred colonoscopy (p < 0.001). A burdensome colonoscopy preparation and pain at colonoscopy were associated with CTC preference (p < 0.04). In conclusion, participants’ experience and preference were rated in favour of CTC with limited bowel preparation compared with full-preparation colonoscopy.
PMCID: PMC2803752  PMID: 19626326
CT colonography; Gastrointestinal; Colon; Bowel preparation; Patient acceptance; Side effects; Contrast; Faecal tagging
8.  CT colonography polyp matching: differences between experienced readers 
European Radiology  2009;19(7):1723-1730.
The purpose of this study was to investigate if experienced readers differ when matching polyps shown by both CT colonography (CTC) and optical colonoscopy (OC) and to explore the reasons for discrepancy. Twenty-eight CTC cases with corresponding OC were presented to eight experienced CTC readers. Cases represented a broad spectrum of findings, not completely fulfilling typical matching criteria. In 21 cases there was a single polyp on CTC and OC; in seven there were multiple polyps. Agreement between readers for matching was analyzed. For the 21 single-polyp cases, the number of correct matches per reader varied from 13 to 19. Almost complete agreement between readers was observed in 15 cases (71%), but substantial discrepancy was found for the remaining six (29%) probably due to large perceived differences in polyp size between CT and OC. Readers were able to match between 27 (71%) and 35 (92%) of the 38 CTC detected polyps in the seven cases with multiple polyps. Experienced CTC readers agree to a considerable extent when matching polyps between CTC and subsequent OC, but non-negligible disagreement exists.
PMCID: PMC2691532  PMID: 19224220
CT colonography; Colorectal neoplasia; Colorectal polyps; Polyp matching; Colonoscopy
9.  Implementation of population screening for colorectal cancer by repeated fecal occult blood test in the Netherlands 
BMC Gastroenterology  2009;9:28.
Colorectal cancer (CRC) is the third most prevalent type of cancer in the world. Its prognosis is closely related to the disease stage at the time of diagnosis. Early detection of symptomless CRC or precursor lesions through population screening could reduce CRC mortality. However, screening programs are only effective if enough people are willing to participate. This study aims to asses the uptake of a second round of fecal occult blood test (FOBt) based screening and to explore factors that could potentially increase this uptake.
Methods and design
Two years after the first screening round, 10.000 average risk persons, aged 50 to 75, will again receive an invitation to participate in immunohistochemical FOBt (iFOBt) based screening. Eligible persons will be recruited through a city population database. Invitees will be randomized to receive either an iFOBt with a faeces collection paper or an iFOBt without a collection paper. The iFOBts will be analyzed in a specialized laboratory at the Academic Medical Centre. Positive iFOBts will be followed by a consultation at our outpatient clinic and, in the absence of contra-indications and after informed consent, by a colonoscopy. The primary outcome measure is the participation rate. Secondary outcome measures are the effect of the addition of a collection paper on the participation rate, reasons for participation and non-participation, measures of informed choice and psychological consequences of screening and measures of psychological and physical burden associated with the iFOBt and the colonoscopy. Another secondary outcome measure is the diagnostic yield of the program.
In order to implement population screening for colorectal cancer in the Netherlands, information is needed on the uptake of repeated rounds of FOBt-based screening and on factors that could potentially increase this uptake in the future since effectiveness of such a program depends on the willingness of persons to participate. This study will provide information on the actual uptake and perception of a second round of iFOBt-based screening. The results of this study will contribute to the future implementation of a national colorectal screening program in the Netherlands.
Trial registration
Dutch Trial register: NTR1327
PMCID: PMC2680893  PMID: 19393087
10.  Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study) 
BMC Surgery  2009;9:4.
Recent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications.
The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas.
Multicenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma ≥ 3 cm, located between 1–15 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane in a piecemeal fashion, and patients will be discharged from the hospital. Residual adenoma that is visible during the first surveillance endoscopy at 3 months will be removed endoscopically in both treatment strategies and is considered as part of the primary treatment.
Primary outcome measure is the proportion of patients with recurrence after 3 months. Secondary outcome measures are: 2) number of days not spent in hospital from initial treatment until 2 years afterwards; 3) major and minor morbidity; 4) disease specific and general quality of life; 5) anorectal function; 6) health care utilization and costs. A cost-effectiveness and cost-utility analysis of EMR against TEM for large rectal adenomas will be performed from a societal perspective with respectively the costs per recurrence free patient and the cost per quality adjusted life year as outcome measures.
Based on comparable recurrence rates for TEM and EMR of 3.3% and considering an upper-limit of 10% for EMR to be non-inferior (beta-error 0.2 and one-sided alpha-error 0.05), 89 patients are needed per group.
The TREND study is the first randomized trial evaluating whether TEM or EMR is more cost-effective for the treatment of large rectal adenomas.
Trial registration number
( NTR1422
PMCID: PMC2664790  PMID: 19284647
11.  The Significance of Detail 
Gastroenterology & Hepatology  2008;4(10):724-726.
PMCID: PMC3104184  PMID: 21960893
12.  Colorectal cancer: what the clinician wants to know 
Cancer Imaging  2005;5(Spec No A):S127-S132.
Colorectal cancer is a common and lethal disease. The adenoma-carcinoma sequence offers a window of opportunity in which the precursor lesion or early carcinoma can be removed endoscopically to prevent systemic disease. New and advanced techniques to improve endoscopic detection of precursor lesions are being developed. Other, less invasive screening methods are currently being developed and may become of use for population-based screening in the near future. Recently, important developments in the treatment (both surgical and chemotherapeutic) of colorectal cancer have occurred. The extent of the disease (stage) forms the basis for therapeutic decisions and accurate imaging is crucial.
PMCID: PMC1665312  PMID: 16361128
Colorectal cancer; polyps; diagnosis; treatment

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