Search

Background: The incidence of T1 colorectal cancer (CRC) has increased with the implementation of CRC screening programs. It is unknown whether the outcomes and risk models for T1 CRC based on non-screen-detected patients can be extrapolated to screen-detected T1 CRC. This study aimed to compare the stage distribution and oncologic outcomes of T1 CRC patients within and outside the screening program., Methods: Data from T1 CRC patients diagnosed between 2014 and 2017 were collected from 12 hospitals in the Netherlands. The presence of lymph node metastasis (LNM) at diagnosis was compared between screen-detected and non-screen-detected patients using multivariable logistic regression. Cox proportional hazard regression was used to analyze differences in the time to recurrence (TTR), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival. Additionally, the performance of conventional risk factors for LNM was evaluated across the groups., Results: 1803 patients were included (1114 [62%] screen-detected), with median follow-up of 51 months (interquartile range 30). The proportion of LNM did not significantly differ between screen- and non-screen-detected patients (12.6% vs. 8.9%; odds ratio 1.41; 95%CI 0.89-2.23); a prediction model for LNM performed equally in both groups. The 3- and 5-year TTR, MFS, and CSS were similar for patients within and outside the screening program. However, overall survival was significantly longer in screen-detected T1 CRC patients (adjusted hazard ratio 0.51; 95%CI 0.38-0.68)., Conclusions: Screen-detected and non-screen-detected T1 CRCs have similar stage distributions and oncologic outcomes and can therefore be treated equally. However, screen-detected T1 CRC patients exhibit a lower rate of non-CRC-related mortality, resulting in longer overall survival., Competing Interests: M. Koopman has an advisory role for Eisai, Nordic Farma, Merck-Serono, Pierre Fabre, and Servier and has received institutional grants from Bayer, Bristol Myers Squibb, Merck, Personal Genome Diagnostics (PGDx), Pierre Fabre, Roche, Sirtex, and Servier. G.R. Vink has received institutional grants from BMS, Merck, Servier, Personal Genome, Diagnostics, Bayer, Sirtex, Pierre Fabre, Lilly, and Delfi Diagnostics. F.P. Vleggaar is a consultant for Boston Scientific. L.M.G. Moons is a consultant for Boston Scientific. L. van der Schee, K.J.C. Haasnoot, S.G. Elias, K.M. Gijsbers, Y.A. Alderlieste, Y. Backes, A.-M. van Berkel, F. Boersma, F. ter Borg, E.C.H. Breekveldt, K. Kessels, I. Lansdorp-Vogelaar, M.E. van Leerdam, G. Rasschaert, R.-M. Schreuder, R.W.M. Schrauwen, T.C.J. Seerden, M.B.W.M. Spanier, J.S. Terhaar Sive Droste, E. Toes-Zoutendijk, J.B. Tuynman, W.H. de Vos tot Nederveen Cappel, and M.M. Laclé declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Background: Post-colonoscopy colorectal cancers (PCCRCs) decrease the effect of colorectal cancer (CRC) screening programs. To enable PCCRC incidence reduction in the long-term, we classified PCCRCs diagnosed after colonoscopies performed in a fecal immunochemical test (FIT)-based screening program., Methods: PCCRCs diagnosed after colonoscopies performed between 2014-2016 for a positive FIT in the Dutch CRC screening program were included. PCCRCs were categorized according to the World Endoscopy Organization consensus statement into (a) interval PCCRC (diagnosed before the recommended surveillance); (b) non-interval type A (diagnosed at the recommended surveillance interval); (c) non-interval type B (diagnosed after the recommended surveillance interval); or (d) non-interval type C (diagnosed after the intended recommended surveillance interval, with surveillance not implemented owing to co-morbidity). The most probable etiology was determined by root-cause analysis. Tumor stage distributions were compared between categories., Results: 116362 colonoscopies were performed after a positive FIT with 9978 screen-detected CRCs. During follow-up, 432 PCCRCs were diagnosed. The 3-year PCCRC rate was 2.7%. PCCRCs were categorized as interval (53.5%), non-interval type A (14.6%), non-interval type B (30.6%), and non-interval type C (1.4%). The most common etiology for interval PCCRCs was possible missed lesion with adequate examination (73.6%); they were more often diagnosed at an advanced stage (stage III/IV; 53.2%) compared with non-interval type A (15.9%; P <0.001) and non-interval type B (40.9%; P =0.03) PCCRCs., Conclusions: The 3-year PCCRC rate was low in this FIT-based CRC screening program. Approximately half of PCCRCs were interval PCCRCs. These were mostly caused by missed lesions and were diagnosed at a more advanced stage. This emphasizes the importance of high quality colonoscopy with optimal polyp detection., Competing Interests: P. Wisse has received consulting fees from the National Institute for Public Health and Environment for the evaluation of biobank development for the storage of samples of participants of the Dutch colorectal cancer screening program. G.A. Meijer is co-founder and a board member (CSO) of CRCbioscreen BV; he has a research collaboration with CZ Health Insurances (cash matching to ZonMW grant) and research collaborations with Exact Sciences, Sysmex, Sentinel Ch. SpA, Personal Genome Diagnostics (PGDX), DELFi, and Hartwig Medical Foundation; these companies provide materials, equipment and/or sample/genomic analyses. E. Dekker has endoscopic equipment on loan from Olympus and Fujifilm, and has received a research grant from Fujifilm; she has received honorarium for consultancy from Fujifilm, Tillots, Olympus, GI Supply, Cancer Prevention Pharmaceuticals, PAION, and Ambu, and speakers’ fees from Olympus, Roche, GI Supply, Norgine, IPSEN, PAION, and Fujifilm. M.C.W. Spaander has received research support from Sentinel, Sysmex, Norgine, and Medtronic. S.Y. de Boer, M. Oudkerk Pool, J.S. Terhaar sive Droste, and C. Verveer declare that they have no conflicts of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Background: The role of radiological staging and surveillance imaging is under debate for T1 colorectal cancer (CRC) as the risk of distant metastases is low and imaging may lead to the detection of incidental findings., Objective: The aim of this study was to evaluate the yield of radiological staging and surveillance imaging for T1 CRC., Methods: In this retrospective multicenter cohort study, all patients of 10 Dutch hospitals with histologically proven T1 CRC who underwent radiological staging in the period 2000-2014 were included. Clinical characteristics, pathological, endoscopic, surgical and imaging reports at baseline and during follow-up were recorded and analyzed. Patients were classified as high-risk T1 CRC if at least one of the histological risk factors (lymphovascular invasion, poor tumor differentiation, deep submucosal invasion or positive resection margins) was present and as low-risk when all risk factors were absent., Results: Of the 628 included patients, 3 (0.5%) had synchronous distant metastases, 13 (2.1%) malignant incidental findings and 129 (20.5%) benign incidental findings at baseline staging. Radiological surveillance was performed among 336 (53.5%) patients. The 5-year cumulative incidence of distant recurrence, malignant and benign incidental findings were 2.4% (95% confidence interval (CI): 1.1%-5.4%), 2.5% (95% CI: 0.6%-10.4%) and 18.3% (95% CI: 13.4%-24.7%), respectively. No distant metastatic events occurred among low-risk T1 CRC patients., Conclusion: The risk of synchronous distant metastases and distant recurrence in T1 CRC is low, while there is a substantial risk of detecting incidental findings. Radiological staging seems unnecessary prior to local excision of suspected T1 CRC and after local excision of low-risk T1 CRC. Radiological surveillance should not be performed in patients with low-risk T1 CRC., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization., Methods/design: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate., Discussion: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Trial registration Nederlands Trial Register, NL 7879, 16 July 2019 ( https://trialregister.nl/trial/7879 )., (© 2022. The Author(s).)

Background: The adenoma detection rate (ADR) is an essential quality indicator for endoscopists performing colonoscopies for colorectal cancer (CRC) screening as it is associated with postcolonoscopy CRCs (PCCRCs). Currently, data on ADRs of endoscopists performing colonoscopies in fecal immunochemical testing (FIT)-based screening, the most common screening method, are scarce. Also, the association between the ADR and PCCRC has not been demonstrated in this setting., Objective: To evaluate the association between the ADR and PCCRC risk in colonoscopies done after a positive FIT result., Design: Population-based cohort., Setting: Dutch, FIT-based, CRC screening program., Participants: Patients undergoing colonoscopy, done by accredited endoscopists, after a positive FIT result., Measurements: Quality indicator performance and PCCRC incidence for colonoscopies in FIT-positive screenees were assessed. The PCCRCs were classified as interval, a cancer detected before recommended surveillance, or noninterval. The association between ADR and interval PCCRC was evaluated with a multivariable Cox regression model and PCCRC incidence was determined for different ADRs., Results: 362 endoscopists performed 116 360 colonoscopies with a median ADR of 67%. In total, 209 interval PCCRCs were identified. The ADR was associated with interval PCCRC, with an adjusted hazard ratio of 0.95 (95% CI, 0.92 to 0.97) per 1% increase in ADR. For every 1000 patients undergoing colonoscopy, the expected number of interval PCCRC diagnoses after 5 years was approximately 2 for endoscopists with ADRs of 70%, compared with more than 2.5, almost 3.5, and more than 4.5 for endoscopists with ADRs of 65%, 60%, and 55%, respectively., Limitation: The relative short duration of follow-up (median, 52 months) could be considered a limitation., Conclusion: The ADR of endoscopists is inversely associated with the risk for interval PCCRC in FIT-positive colonoscopies. Endoscopists performing colonoscopy in FIT-based screening should aim for markedly higher ADRs compared with primary colonoscopy., Primary Funding Source: None.

Background and study aims  A free resection margin (FRM) > 1 mm after local excision of a T1 colorectal cancer (CRC) is known to be associated with a low risk of local intramural residual cancer (LIRC). The risk is unclear, however, for FRMs between 0.1 to 1 mm. This study evaluated the risk of LIRC after local excision of T1 CRC with FRMs between 0.1 and 1 mm in the absence of lymphovascular invasion (LVI), poor differentiation and high-grade tumor budding (Bd2-3). Patients and methods  Data from all consecutive patients with local excision of T1 CRC between 2014 and 2017 were collected from 11 hospitals. Patients with a FRM ≥ 0.1 mm without LVI and poor differentiation were included. The main outcome was risk of LIRC (composite of residual cancer in the local excision scar in adjuvant resection specimens or local recurrence during follow-up). Tumor budding was also assessed for cases with a FRM between 0.1 and 1mm. Results  A total of 171 patients with a FRM between 0.1 and 1 mm and 351 patients with a FRM > 1 mm were included. LIRC occurred in five patients (2.9 %; 95 % confidence interval [CI] 1.0-6.7 %) and two patients (0.6 %; 95 % CI 0.1-2.1 %), respectively. Assessment of tumor budding showed Bd2-3 in 80 % of cases with LIRC and in 16 % of control cases. Accordingly, in patients with a FRM between 0.1 and 1 mm without Bd2-3, LIRC was detected in one patient (0.8%; 95 % CI 0.1-4.4 %). Conclusions  In this study, risks of LIRC were comparable for FRMs between 0.1 and 1 mm and > 1 mm in the absence of other histological risk factors., Competing Interests: Competing interests Dr. Moons is consultant for Boston Scientific., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Introduction: Local full-thickness resections of the scar (FTRS) after local excision of a T1 colorectal cancer (CRC) with uncertain resection margins is proposed as an alternative strategy to completion surgery (CS), provided that no local intramural residual cancer (LIRC) is found. However, a comparison on long-term oncological outcome between both strategies is missing., Methods: A large cohort of patients with consecutive T1 CRC between 2000 and 2017 was used. Patients were selected if they underwent a macroscopically complete local excision of a T1 CRC but positive or unassessable (R1/Rx) resection margins at histology and without lymphovascular invasion or poor differentiation. Patients treated with CS or FTRS were compared on the presence of CRC recurrence, a 5-year overall survival, disease-free survival, and metastasis-free survival., Results: Of 3,697 patients with a T1 CRC, 434 met the inclusion criteria (mean age 66 years, 61% men). Three hundred thirty-four patients underwent CS, and 100 patients underwent FTRS. The median follow-up period was 64 months. CRC recurrence was seen in 7 patients who underwent CS (2.2%, 95% CI 0.9%-4.6%) and in 8 patients who underwent FTRS (9.0%, 95% CI 3.9%-17.7%). Disease-free survival was lower in FTRS strategy (96.8% vs 89.9%, P = 0.019), but 5 of the 8 FTRS recurrences could be treated with salvage surgery. The metastasis-free survival (CS 96.8% vs FTRS 92.1%, P = 0.10) and overall survival (CS 95.6% vs FTRS 94.4%, P = 0.55) did not differ significantly between both strategies., Discussion: FTRS after local excision of a T1 CRC with R1/Rx resection margins as a sole risk factor, followed by surveillance and salvage surgery in case of CRC recurrence, could be a valid alternative strategy to CS., (Copyright © 2022 by The American College of Gastroenterology.)

Background: Endoscopic mucosal resection (EMR) for large colorectal polyps is in most cases the preferred treatment to prevent progression to colorectal carcinoma. The most common complication after EMR is delayed bleeding, occurring in 7% overall and in approximately 10% of polyps ≥ 2 cm in the proximal colon. Previous research has suggested that prophylactic clipping of the mucosal defect after EMR may reduce the incidence of delayed bleeding in polyps with a high bleeding risk., Methods: The CLIPPER trial is a multicenter, parallel-group, single blinded, randomized controlled superiority study. A total of 356 patients undergoing EMR for large (≥ 2 cm) non-pedunculated polyps in the proximal colon will be included and randomized to the clip group or the control group. Prophylactic clipping will be performed in the intervention group to close the resection defect after the EMR with a distance of < 1 cm between the clips. Primary outcome is delayed bleeding within 30 days after EMR. Secondary outcomes are recurrent or residual polyps and clip artifacts during surveillance colonoscopy after 6 months, as well as cost-effectiveness of prophylactic clipping and severity of delayed bleeding., Discussion: The CLIPPER trial is a pragmatic study performed in the Netherlands and is powered to determine the real-time efficacy and cost-effectiveness of prophylactic clipping after EMR of proximal colon polyps ≥ 2 cm in the Netherlands. This study will also generate new data on the achievability of complete closure and the effects of clip placement on scar surveillance after EMR, in order to further promote the debate on the role of prophylactic clipping in everyday clinical practice., Trial Registration: ClinicalTrials.gov NCT03309683 . Registered on 13 October 2017. Start recruitment: 05 March 2018. Planned completion of recruitment: 31 August 2021.

Background: Endoscopic full-thickness resection (eFTR) is a minimally invasive resection technique that allows definite diagnosis and treatment for complex colorectal lesions ≤ 30 mm unsuitable for conventional endoscopic resection. This study reports clinical outcomes from the Dutch colorectal eFTR registry., Methods: Consecutive patients undergoing eFTR in 20 hospitals were prospectively included. The primary outcome was technical success, defined as macroscopic complete en bloc resection. Secondary outcomes were: clinical success, defined as tumor-free resection margins (R0 resection); full-thickness resection rate; and adverse events. RESULTS : Between July 2015 and October 2018, 367 procedures were included. Indications were difficult polyps (non-lifting sign and/or difficult location; n = 133), primary resection of suspected T1 colorectal cancer (CRC; n = 71), re-resection after incomplete resection of T1 CRC (n = 150), and subepithelial tumors (n = 13). Technical success was achieved in 308 procedures (83.9 %). In 21 procedures (5.7 %), eFTR was not performed because the lesion could not be reached or retracted into the cap. In the remaining 346 procedures, R0 resection was achieved in 285 (82.4 %) and full-thickness resection in 288 (83.2 %). The median diameter of resected specimens was 23 mm. Overall adverse event rate was 9.3 % (n = 34/367): 10 patients (2.7 %) required emergency surgery for five delayed and two immediate perforations and three cases of appendicitis. CONCLUSION : eFTR is an effective and relatively safe en bloc resection technique for complex colorectal lesions with the potential to avoid surgery. Further studies assessing the role of eFTR in early CRC treatment with long-term outcomes are needed., Competing Interests: P. Fockens receives personal fees from Cook, Ethicon, and Olympus, and research support from Boston Scientific outside the submitted work. E. Dekker has endoscopic equipment on loan from FujiFilm, and has received a research grant from FujiFilm, consultancy fees from FujiFilm, Olympus, Tillotts, GI Supply, and CPP-FAP, and speaker’s fees from Olympus, Roche, and GI Supply. B. Bastiaansen has received speaker’s fees from Olympus, Tillotts Pharma AG, and Ovesco Endoscopy AG. The remaining authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background and Aims: In contrast to the adverse event (AE) risk of endoscopic resection (ER) of adenomas, the intra- and postprocedural AE risks of ER of T1 colorectal cancer (CRC) are scarcely reported in the literature. It is unclear whether ER of early CRCs, which grow into the submucosal layer and sometimes show incomplete lifting, is associated with an increased AE risk. We aimed to identify the AE rate after ER of T1 CRCs and to identify the risk factors associated with these AEs., Methods: Medical records of patients with T1 CRCs diagnosed between 2000 and 2014 in 15 hospitals in the Netherlands were reviewed. Patients who underwent primary ER were selected. The primary outcome was the occurrence of endoscopy-related AEs. The secondary outcome was the identification of risk factors. Multivariate logistic regression was performed., Results: Endoscopic AEs occurred in 59 of 1069 (5.5%) patients, among which 37.3% were classified as mild, 59.3% as moderate, and 3.4% as severe. AEs were postprocedural bleeding (n = 40, 3.7%), perforation (n = 13, 1.2%), and postpolypectomy electrocoagulation syndrome (n = 6, 0.6%). No fatal AEs were observed. Independent predictors for AEs were age >70 years (odds ratio, 2.11; 95% confidence interval, 1.12-3.96) and tumor size >20 mm (odds ratio, 2.22; 95% confidence interval, 1.05-4.69)., Conclusions: In this large multicenter retrospective cohort study, AE rates of ER of T1 CRC (5.5%) are comparable with reported AE rates for adenomas. Larger tumor size and age >70 years are independent predictors for AEs. This study suggests that endoscopic treatment of T1 CRCs is not associated with an increased periprocedural AE risk., (Copyright © 2020 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Improving patient education focusing on bowel preparation before a colonoscopy leads to cleaner colons. Endoscopy units must obtain informed consent and perform a risk assessment for sedative use prior to a colonoscopy. The current practice in the Netherlands to achieve these goals is nurse counseling in an outpatient setting. This is costly and has disadvantages in terms of uniformity and time consumption for both the patient and the hospital. The hypothesis is that computer-based education with use of video and 3D animations may replace nurse counseling in most cases, without losing quality of bowel cleanliness during colonoscopy. This multicenter, randomized, endoscopist blinded clinical trial evaluates a primary outcome measure (bowel preparation) during colonoscopy. Secondary outcome measures are sickness absence, patient anxiety after instruction and prior to colonoscopy, patient satisfaction and information re-call. The study will be performed in four endoscopy units of different levels (rural, urban, and tertiary). Inclusion criteria are adult age and referral for complete colonoscopy. Exclusion criteria are Dutch illiteracy, audiovisual handicaps or mental disabilities and no (peers with) internet access. This trial aims to establish online computer-based education as tool for patient education prior to a colonoscopy. By choosing a direct comparison with the standard of care (nurse counseling), both endoscopic quality measures and patient related outcome measures can be evaluated.

Background & Aims: Risk stratification for adverse events, such as metastasis to lymph nodes, is based only on histologic features of tumors. We aimed to compare adverse outcomes of pedunculated vs nonpedunculated T1 colorectal cancers (CRC)., Methods: We performed a retrospective study of 1656 patients diagnosed with T1CRC from 2000 through 2014 at 14 hospitals in The Netherlands. The median follow-up time of patients was 42.5 months (interquartile range, 18.5-77.5 mo). We evaluated the association between tumor morphology and the primary composite end point, adverse outcome, adjusted for clinical variables, histologic variables, resection margins, and treatment approach. Adverse outcome was defined as metastasis to lymph nodes, distant metastases, local recurrence, or residual tissue. Secondary end points were tumor metastasis, recurrence, and incomplete resection., Results: Adverse outcome occurred in 67 of 723 patients (9.3%) with pedunculated T1CRCs vs 155 of 933 patients (16.6%) with nonpedunculated T1CRCs. Pedunculated morphology was independently associated with decreased risk of adverse outcome (adjusted odds ratio [OR], 0.59; 95% CI, 0.42-0.83; P = .003). Metastasis, incomplete resection, and recurrence were observed in 5.8%, 4.6%, and 3.9% of pedunculated T1CRCs vs 10.6%, 8.0%, and 6.6% of nonpedunculated T1CRCs, respectively. Pedunculated morphology was independently associated with a reduced risk of metastasis (adjusted OR, 0.62; 95% CI, 0.41-0.94; P = .03), incomplete resection (adjusted OR, 0.57; 95% CI, 0.36-0.91; P = .02), and recurrence (adjusted hazard ratio, 0.52; 95% CI, 0.32-0.85; P = .009). Metastasis, incomplete resection, and recurrence did not differ significantly between low-risk pedunculated vs nonpedunculated T1CRCs (0.8% vs 2.9%, P = .38; 1.5% vs 0%, P = .99; 1.5% vs 0%; P = .99). However, incomplete resection and recurrence were significantly lower for high-risk pedunculated vs nonpedunculated T1CRCs (6.5% vs 12.5%; P = .007; 4.4% vs 8.6%; P = .03)., Conclusions: In a retrospective study of patients with T1CRC, we found pedunculated morphology to be associated independently with a decreased risk of adverse outcome in a T1CRC population at high risk of adverse outcome. Incorporating morphologic features of tumors in risk assessment could help predict outcomes of patients with T1CRC and help identify the best candidates for surgery., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

About 5% of colorectal adenomas are estimated to progress to colorectal cancer. However, it is important to identify which adenomas actually carry a high risk of progression, because these serve as intermediate endpoints, for example, in screening programs. In clinical practice, adenomas with a size of ≥10 mm, villous component and/or high-grade dysplasia, called advanced adenomas, are considered high risk, although solid evidence for this classification is lacking. Specific DNA copy number changes are associated with adenoma-to-carcinoma progression. We set out to determine the prevalence of cancer-associated events (CAE) in advanced and nonadvanced adenomas. DNA copy number analysis was performed on archival tissues from three independent series of, in total, 297 adenomas (120 nonadvanced and 177 advanced) using multiplex ligation-dependent probe amplification or low-coverage whole-genome DNA sequencing. Alterations in two or more CAEs were considered to mark adenomas as high risk. Two or more CAEs were overall present in 25% (95% CI, 19.0-31.8) of advanced adenomas; 23% (11/48), 36% (12/33), and 23% (22/96) of the advanced adenomas in series 1, 2, and 3, respectively, and 1.7% (1/58) and 4.8% (3/62) of the nonadvanced adenomas, in series 1 and 2, respectively. The majority of advanced adenomas do not show CAEs, indicating that only a subset of these lesions is to be considered high risk. Nonadvanced adenomas have very low prevalence of CAEs, although those with CAEs should be considered high risk as well. Specific DNA copy number alterations may better reflect the true progression risk than the advanced adenoma phenotype. Cancer Prev Res; 11(7); 403-12. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Metamizole can be used in both short- and long-term pain relief therapies and has a relatively favourable safety profile compared with classic NSAIDs. Metamizole is also infamous because of its potential fatal adverse drug reaction, agranulocytosis. Although this risk varies, it is estimated to occur in less than one million metamizole prescriptions. We describe a case of a 68-year-old patient who developed leukopenia after using metamizole.

Background: Up to 37% of colorectal cancer (CRC) survivors report depressive and anxiety symptoms. The identification of risk factors for depressive or anxiety symptoms might help focus supportive care resources on those patients most in need. The present study aims to explore which factors are associated with heightened anxiety or depression symptom severity., Methods: In this cross-sectional study, individuals diagnosed with CRC 3.5 to 6 years ago completed questionnaires on sociodemographic information, medical comorbidities, anxiety symptoms (Beck Anxiety Inventory), and depressive symptoms (Inventory of Depressive Symptomatology). The general linear model analysis of covariance was used to identify factors associated with heightened anxiety or depressive symptom severity., Results: The sample included 91 CRC survivors, 40.7% women, mean age 69.1 years. A minority of CRC survivors had moderate (3.4%) or severe (2.3%) anxiety symptoms, and moderate (7.7%) or severe (0%) depressive symptoms. Shorter time since diagnosis and higher number of comorbid diseases were associated with higher anxiety symptom severity. Female sex and higher number of comorbid diseases were associated with higher depressive symptom severity., Conclusion: From this explorative study, it follows that survivors with multiple comorbid diseases, shorter time since diagnosis, and female survivors might be at risk for higher anxiety and/or depressive symptom severity. Survivors with these characteristics might need extra monitoring.

Background: Faecal immunochemical tests (FITs) are commonly used in colorectal cancer (CRC) screening. Diagnostic accuracy of FIT differs between males and females. This so far unexplained difference could result in a dissimilarity in screening outcome between both sexes. The aim of this study is to compare sensitivity and specificity of a FIT between males and females, and study potential explanatory variables., Methods: In this cross-sectional study, data were prospectively collected. 3,022 subjects performed a FIT prior to complete colonoscopy. Sensitivity, specificity, and ROC curves were compared for both sexes. Potential explanatory variables of the relation between sensitivity and sex were explored., Results: At all cut-off values, FIT sensitivity for CRC was higher (range 13-23%) and specificity was lower (range 2-4%) in males compared to females. At 75 ng/ml, sensitivity for CRC was 93% in males compared to 71% in females (p = 0.03), and specificity was 90% in males compared to 93% in females (p = <0.05). For advanced adenomas, males had a slightly higher sensitivity and lower specificity (not significant). At 75 ng/ml, sensitivity for advanced adenomas was 33% in males compared to 29% in females (p = 0.46), and specificity was 93% in males compared to 95% in females (p = 0.22). ROC curves were similar for both sexes, and equal combinations of sensitivity and specificity could be achieved by adjusting the cut-off values. For CRC, the difference in sensitivity could not be explained by age or location of the tumour., Conclusions: FIT has a higher sensitivity and a lower specificity for CRC in males than in females. Equal test characteristics can be achieved by allowing separate cut-off values for both sexes. Location and age do not explain the observed differences in sensitivity.

In the course and prognosis of colorectal cancer (CRC), early detection and treatment are essential factors. Fecal immunochemical tests (FITs) are currently the most commonly used non-invasive screening tests for CRC and premalignant (advanced) adenomas, however, with restricted sensitivity. We hypothesized that fecal volatile organic compounds (VOCs) may serve as a diagnostic biomarker of CRC and adenomas. In this proof of concept study, we aimed to assess disease-specific VOC smellprints in fecal gas to distinguish patients with CRC and advanced adenomas from healthy controls. Fecal samples of patients who were scheduled to undergo an elective colonoscopy were collected. An electronic nose (Cyranose 320) was used to measure VOC patterns in fecal gas from patients with histopathologically proven CRC, with advanced adenomas and from controls (no abnormalities seen at colonoscopy). Receiver operator characteristic curves and corresponding sensitivity and specificity for detection of CRC and advanced adenomas were calculated. A total of 157 stool samples (40 patients with CRC, 60 patients with advanced adenomas, and 57 healthy controls) were analyzed by electronic nose. Fecal VOC profiles of patients with CRC differed significantly from controls (area under curve ± 95%CI, p-value, sensitivity, specificity; 0.92 ± 0.03, <0.001, 85%, 87%). Also VOC profiles of patients with advanced adenomas could be discriminated from controls (0.79 ± 0.04, <0.001, 62%, 86%). The results of this proof of concept study suggest that fecal gas analysis by an electronic nose seems to hold promise as a novel screening tool for the (early) detection of advanced neoplasia and CRC., (© 2013 UICC.)

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.

Background: Stool-based molecular tests hold large potential for improving colorectal cancer screening. Here, we investigated the analytical sensitivity of a DNA methylation assay on partial stool samples, and estimated the DNA degradation in stool over time. In addition, we explored the detection of DNA methylation in fecal immunochemical test (FIT) fluid., Materials and Methods: Partial stool samples of colonoscopy-negative individuals were homogenized with stool homogenization buffer, spiked with different numbers of HCT116 colon cancer cells and kept at room temperature for 0, 24, 48, 72 and 144 h before DNA isolation. Analytical sensitivity was determined by the lowest number of cells that yielded positive test results by DNA methylation or mutation analysis. DNA methylation in FIT fluid was measured in 11 CRC patients and 20 control subjects., Results: The analytical sensitivity for detecting DNA methylation was 3000 cells per gram stool, compared to 60000 cells per gram stool for detection of DNA mutations in the same stool samples. No degradation up to 72 h was noted when a conservation buffer was used. DNA methylation was detected in 4/11 CRC FIT samples and in none of the 20 control FIT samples., Conclusions: Methylation based stool DNA testing showed a high analytical sensitivity for tumor DNA in partial stool samples, which was hardly influenced by DNA degradation over time, provided an adequate buffer was used. The feasibility of detecting DNA methylation in FIT fluid demonstrates the opportunity to combine testing for occult blood with DNA methylation in the same collection device.

Background: Given the increasing burden on colonoscopy capacity, it has been suggested that faecal immunochemical test (FIT) results could guide surveillance colonoscopy intervals. Against this background, we have evaluated the test accuracy of single and double FIT sampling to detect colorectal cancer (CRC) and/or advanced adenomas in an asymptomatic colonoscopy-controlled high-risk population., Methods: Cohort study of asymptomatic high-risk patients (personal history of adenomas/CRC or family history of CRC), who provided one or two FITs before elective colonoscopy. Test accuracy of FIT for detection of CRC and advanced adenomas was determined (cut-off level 50 ng/ml)., Results: 1,041 patients provided a FIT (516 personal history of adenomas, 172 personal history of CRC and 353 family history of CRC). Five CRCs (0.5%) and 101 advanced adenomas (9.7%) were detected by colonoscopy. Single FIT sampling resulted in a sensitivity, specificity, PPV and NPV for CRC of 80%, 89%, 3% and 99.9%, respectively, and for advanced adenoma of 28%, 91%, 24% and 92%, respectively. Double FIT sampling did not result in a significantly higher sensitivity for advanced neoplasia. Simulation of multiple screening rounds indicated that sensitivity of FIT for advanced adenoma could reach 81% after 5 screening rounds., Conclusions: In once-only FIT sampling before surveillance colonoscopy, 70% of advanced neoplasia were missed. A simulation approach indicates that multiple screening rounds may be more promising in detecting advanced neoplasia and could potentially alleviate endoscopic burden.

Background: Colorectal cancer screening by fecal immunochemical tests (FITs) is hampered by frequent false-positive (FP) results and thereby the risk of complications and strain on colonoscopy capacity. Hemorrhoids might be a plausible cause of FP results., Objective: To determine the contribution of hemorrhoids to the frequency of FP FIT results., Design: Retrospective analysis from prospective cohort study., Setting: Five large teaching hospitals, including 1 academic hospital., Patients: All subjects scheduled for elective colonoscopy., Interventions: FIT before bowel preparation., Main Outcome Measurements: Frequency of FP FIT results in subjects with hemorrhoids as the only relevant abnormality compared with FP FIT results in subjects with no relevant abnormalities. Logistic regression analysis to determine colonic abnormalities influencing FP results., Results: In 2855 patients, 434 had positive FIT results: 213 had advanced neoplasia and 221 had FP results. In 9 individuals (4.1%; 95% CI, 1.4-6.8) with an FP FIT result, hemorrhoids were the only abnormality. In univariate unadjusted analysis, subjects with hemorrhoids as the only abnormality did not have more positive results (9/134; 6.7%) compared with subjects without any abnormalities (43/886; 4.9%; P = .396). Logistic regression identified hemorrhoids, nonadvanced polyps, and a group of miscellaneous abnormalities, all significantly influencing false positivity. Of 1000 subjects with hemorrhoids, 67 would have FP results, of whom 18 would have FP results because of hemorrhoids only., Limitations: Potential underreporting of hemorrhoids; high-risk individuals., Conclusions: Hemorrhoids in individuals participating in colorectal cancer screening will probably not lead to a substantial number of false-positive test results., (Copyright © 2012 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Purpose: Early detection of colorectal cancer (CRC) and its precursor lesions is an effective approach to reduce CRC mortality rates. This study aimed to identify novel protein biomarkers for the early diagnosis of CRC., Experimental Design: Proximal fluids are a rich source of candidate biomarkers as they contain high concentrations of tissue-derived proteins. The FabplCre;Apc(15lox/+) mouse model represents early-stage development of human sporadic CRC. Proximal fluids were collected from normal colon and colon tumors and subjected to in-depth proteome profiling by tandem mass spectrometry. Carcinoembryonic antigen (CEA) and CHI3L1 human serum protein levels were determined by ELISA., Results: Of the 2,172 proteins identified, quantitative comparison revealed 192 proteins that were significantly (P < 0.05) and abundantly (>5-fold) more excreted by tumors than by controls. Further selection for biomarkers with highest specificity and sensitivity yielded 52 candidates, including S100A9, MCM4, and four other proteins that have been proposed as candidate biomarkers for human CRC screening or surveillance, supporting the validity of our approach. For CHI3L1, we verified that protein levels were significantly increased in sera from patients with adenomas and advanced adenomas compared with control individuals, in contrast to the CRC biomarker CEA., Conclusion: These data show that proximal fluid proteome profiling with a mouse tumor model is a powerful approach to identify candidate biomarkers for early diagnosis of human cancer, exemplified by increased CHI3L1 protein levels in sera from patients with CRC precursor lesions., (©2012 AACR.)

Using a bioinformatics-based strategy, we set out to identify hypermethylated genes that could serve as biomarkers for early detection of colorectal cancer (CRC) in stool. In addition, the complementary value to a Fecal Immunochemical Test (FIT) was evaluated. Candidate genes were selected by applying cluster alignment and computational analysis of promoter regions to microarray-expression data of colorectal adenomas and carcinomas. DNA methylation was measured by quantitative methylation-specific PCR on 34 normal colon mucosa, 71 advanced adenoma, and 64 CRC tissues. The performance as biomarker was tested in whole stool samples from in total 193 subjects, including 19 with advanced adenoma and 66 with CRC. For a large proportion of these series, methylation data for GATA4 and OSMR were available for comparison. The complementary value to FIT was measured in stool subsamples from 92 subjects including 44 with advanced adenoma or CRC. Phosphatase and Actin Regulator 3 (PHACTR3) was identified as a novel hypermethylated gene showing more than 70-fold increased DNA methylation levels in advanced neoplasia compared with normal colon mucosa. In a stool training set, PHACTR3 methylation showed a sensitivity of 55% (95% CI: 33-75) for CRC and a specificity of 95% (95% CI: 87-98). In a stool validation set, sensitivity reached 66% (95% CI: 50-79) for CRC and 32% (95% CI: 14-57) for advanced adenomas at a specificity of 100% (95% CI: 86-100). Adding PHACTR3 methylation to FIT increased sensitivity for CRC up to 15%. PHACTR3 is a new hypermethylated gene in CRC with a good performance in stool DNA testing and has complementary value to FIT.

Background: Colorectal cancer (CRC) screening requires sufficient endoscopic resources. The present study aims to determine the Dutch endoscopic production and manpower for 2009, evaluate trends since 2004, determine additional workload which would be caused by implementation of a CRC screening program, and inventory colonoscopy rates performed in other European countries., Methods: All Dutch endoscopy units (N = 101) were surveyed for manpower and the numbers of endoscopy procedures performed in 2009. Based on calculations in the report issued by the Dutch Health Council, future additional workload caused by faecal immunochemical test (FIT) screening was estimated. The number of colonoscopies performed in Europe was evaluated by a literature search and an email-inquiry., Results: Compared to 2004, there was a 24% increase in total endoscopies (N = 505,226 in 2009), and a 64% increase in colonoscopies (N = 191,339 in 2009) in The Netherlands. The number of endoscopists had increased by 4.6% (N = 583 in 2009). Five years after stepwise implementation of FIT-based CRC screening, endoscopic capacity needs to be increased an additional 15%. A lack of published data on the number of endoscopies performed in Europe was found. Based on our email-inquiry, the number of colonoscopies per 100,000 inhabitants ranged from 126 to 3,031 in 15 European countries., Conclusions: Over the last years, endoscopic procedures increased markedly in The Netherlands without a corresponding increase in manpower. A FIT-based CRC screening program requires an estimated additional 15% increase in endoscopic procedures. It is very likely that current colonoscopy density varies widely across European countries., (© 2012 van Turenhout et al;)

Background: A single sampled faecal immunochemical test (FIT) has moderate sensitivity for colorectal cancer and advanced adenomas. Repeated FIT sampling could improve test sensitivity. The aim of the present study is to determine whether any of three different strategies of double FIT sampling has a better combination of sensitivity and specificity than single FIT sampling., Methods: Test performance of single FIT sampling in subjects scheduled for colonoscopy was compared to double FIT sampling intra-individually. Test positivity of double FIT sampling was evaluated in three different ways: 1) "one of two FITs+" when at least one out of two measurements exceeded the cut-off value, 2) "two of two FITs+" when both measurements exceeded the cut-off value, 3) "mean of two FITs+" when the geometric mean of two FITs exceeded the cut-off value. Receiver operator curves were calculated and sensitivity of single and the three strategies of double FIT sampling were compared at a fixed level of specificity., Results: In 124 of 1096 subjects, screen relevant neoplasia (SRN) were found (i.e. early stage CRC or advanced adenomas). At any cut-off, "two of two FITs+" resulted in the lowest and "one of two FITs+" in the highest sensitivity for SRN (range 35-44% and 42%-54% respectively). ROC's of double FIT sampling were similar to single FIT sampling. At specificities of 85/90/95%, sensitivity of any double FIT sampling strategy did not differ significantly from single FIT (p-values 0.07-1)., Conclusion: At any cut off, "one of two FITs+" is the most sensitive double FIT sampling strategy. However, at a given specificity level, sensitivity of any double FIT sampling strategy for SRN is comparable to single FIT sampling at a different cut-off value. None of the double FIT strategies has a superior combination of sensitivity and specificity over single FIT., (© 2011 Oort et al; licensee BioMed Central Ltd.)

Background: Adjusting the threshold for positivity of quantitative fecal immunochemical tests (FIT) allows for controlling the number of follow-up colonoscopies in a screening program. However, it is unknown to what extent higher cutoff levels affect detection rates of screen-relevant neoplasia. This study aimed to assess the effect of higher cutoff levels of a quantitative FIT on test positivity rate and detection rate of early-stage colorectal cancers (CRC)., Methods: Subjects above 40 years old scheduled for colonoscopy in 5 hospitals were asked to sample a single FIT (OC sensor) before colonoscopy. Screen-relevant neoplasia were defined as advanced adenoma or early-stage cancer (stage I and II). Positivity rate, sensitivity, and specificity were evaluated at increasing cutoff levels of 50 to 200 ng/mL., Results: In 2,145 individuals who underwent total colonoscopy, 79 patients were diagnosed with CRC, 38 of which were with early-stage disease. Advanced adenomas were found in 236 patients. When varying cutoff levels from ≥ 50 to ≥ 200 ng/mL, positivity rates ranged from 16.5% to 10.2%. With increasing cutoff levels, sensitivity for early-stage CRCs and for screen-relevant neoplasia ranged from 84.2% to 78.9% and 47.1% to 37.2%, respectively., Conclusions: Higher FIT cutoff levels substantially decrease test positivity rates with only limited effects on detection rates of early-stage CRCs. However, spectrum bias resulting in higher estimates of sensitivity than would be expected in a screening population may be present., Impact: Higher cutoff levels can reduce strain on colonoscopy capacity with only a modest decrease in sensitivity for curable cancers., (©2010 AACR.)

Background and Study Aims: Cecal intubation is not achieved in 2 - 23 % of colonoscopies. The efforts made by physicians to visualize the remaining colon and the number of missed significant lesions are unknown. This study evaluates 1) the reasons for incomplete colonoscopy, 2) the rates of complete colonic evaluation after incomplete colonoscopy, and 3) the number of (pre-) malignant lesions missed by incomplete colonoscopy., Patients and Methods: In this population-based cohort study index colonoscopies were performed between September and December 2005. Prospectively collected data from consecutive patients with an incomplete colonoscopy were analyzed. For up to 18 months after the index colonoscopy, any further examinations performed in these patients were identified retrospectively. These secondary examinations included: repeat colonoscopy, computed tomography (CT) colonography, barium enema, abdominal CT scan, and surgery involving the colorectum., Results: Of 5278 colonoscopies, 511 were incomplete (9.7 %). The most frequent causes of incomplete colonoscopy were looping of the scope (20.4 %), patient discomfort (15.3 %), and obstructing tumor (13.9 %). Secondary examination was performed in 278 patients (54.4 %) after incomplete colonoscopy. Patients undergoing surveillance after colorectal cancer (CRC) (78.9 %) and those with anemia (73.1 %) most frequently received a secondary examination. Incomplete colonoscopies due to stenosis (78.9 %), severe inflammation (77.8 %) or an obstructing tumor (74.6 %) were most frequently followed by a secondary examination. In all of the follow-up examinations, CRC was diagnosed in 18 patients (3.5 %) and advanced adenoma in four patients (0.8 %)., Conclusions: In 4.3 % of the patients, advanced neoplasia was missed by incomplete colonoscopy. Our data therefore suggest that additional imaging is obligatory to visualize the remaining colon adequately., (Copyright Georg Thieme Verlag KG Stuttgart . New York.)

Background: Diagnosing colorectal cancer (CRC) at an early stage improves survival. To what extent any delay affects outcome once patients are symptomatic is still unclear.Our objectives were to evaluate the association between diagnostic delay and survival in symptomatic patients with early stage CRC and late stage CRC., Methods: Prospective population-based observational study evaluating daily clinical practice in Northern Holland. Diagnostic delay was determined through questionnaire-interviews. Dukes' stage was classified into two groups: early stage (Dukes A or B) and late stage (Dukes C or D) cancer. Patients were followed up for 3.5 years after diagnosis., Results: In total, 272 patients were available for analysis. Early stage CRC was present in 136 patients while 136 patients had late stage CRC. The mean total diagnostic delay (SE) was 31 (1.5) weeks in all CRC patients. No significant difference was observed in the mean total diagnostic delay in early versus late stage CRC (p = 0.27).In early stage CRC, no difference in survival was observed between patients with total diagnostic delay shorter and longer than the median (Kaplan-Meier, log-rank p = 0.93).In late stage CRC, patients with a diagnostic delay shorter than the median had a shorter survival than patients with a diagnostic delay longer than the median (log-rank p = 0.01). In the multivariate Cox regression model with survival as dependent variable and median delay, age, open access endoscopy, number and type of symptoms as independent variables, the odd's ratio for survival in patients with long delay (>median) versus short delay (

Background: Guaiac-based faecal occult blood tests (g-FOBTs) are most commonly used in colorectal cancer (CRC) screening programmes. Faecal immunochemical tests (FITs) are thought to be superior., Aim: To compare performance of a g-FOBT and a quantitative FIT for detection of CRCs and advanced adenomas in a colonoscopy-controlled population., Methods: We assessed sensitivity and specificity of both FIT (OC-sensor) and g-FOBT (Hemoccult-II) prior to patients' scheduled colonoscopies., Results: Of the 62 invasive cancers detected in 1821 individuals, g-FOBT was positive in 46 and FIT in 54 (74.2% vs. 87.1%, P = 0.02). Among 194 patients with advanced adenomas, g-FOBT was positive in 35 and FIT in 69 (18.0% vs. 35.6%, P < 0.001). Sensitivity for screen relevant tumours (197 advanced adenomas and 28 stage I or II cancers) was 23.0% for g-FOBT and 40.5% for FIT (P < 0.001). Specificity of g-FOBT compared to FIT for the detection of cancer was 95.7% vs. 91.0%, P < 0.001) and for advanced adenomas (97.4% vs. 94.2%, P < 0.001)., Conclusions: Faecal immunochemical test is more sensitive for CRC and advanced adenomas. Sensitivity of FIT for screen relevant tumours, early-stage cancers and advanced adenomas, is significantly higher. Specificity of g-FOBT is higher compared with FIT.

Background: MicroRNAs are small non-coding RNA molecules, which regulate central mechanisms of tumorigenesis. In colorectal tumours, the combination of gain of 8q and 13q is one of the major factors associated with colorectal adenoma to adenocarcinoma progression. Functional studies on the miR-17-92 cluster localised on 13q31 have shown that its transcription is activated by c-myc, located on 8q, and that it has oncogenic activities. We investigated the contribution of the miR-17-92 cluster during colorectal adenoma to adenocarcinoma progression., Methods: Expression levels of the miR-17-92 cluster were determined in 55 colorectal tumours and in 10 controls by real-time RT-PCR. Messenger RNA c-myc expression was also determined by real-time RT-PCR in 48 tumours with array comparative genomic hybridisation (aCGH) data available., Results: From the six members of the miR-17-92 cluster, all except miR-18a, showed significant increased expression in colorectal tumours with miR-17-92 locus gain compared with tumours without miR-17-92 locus gain. Unsupervised cluster analysis clustered the tumours based on the presence of miR-17-92 locus gain. Significant correlation between the expression of c-myc and the six miRNAs was also found., Conclusion: Increased expression of miR-17-92 cluster during colorectal adenoma to adenocarcinoma progression is associated to DNA copy number gain of miR17-92 locus on 13q31 and c-myc expression.

In addition to genetic changes, the occurrence of epigenetic alterations is associated with accumulation of both genetic and epigenetic events that promote the development and progression of human cancer. Previously, we reported a set of candidate genes that comprise part of the emerging "cancer methylome". In the present study, we first tested 23 candidate genes for promoter methylation in a small number of primary colon tumor tissues and controls. Based on these results, we then examined the methylation frequency of Oncostatin M receptor-beta (OSMR) in a larger number of tissue and stool DNA samples collected from colon cancer patients and controls. We found that OSMR was frequently methylated in primary colon cancer tissues (80%, 80/100), but not in normal tissues (4%, 4/100). Methylation of OSMR was also detected in stool DNA from colorectal cancer patients (38%, 26/69) (cut-off in TaqMan-MSP, 4). Detection of other methylated markers in stool DNA improved sensitivity with little effect on specificity. Promoter methylation mediated silencing of OSMR in cell lines, and CRC cells with low OSMR expression were resistant to growth inhibition by Oncostatin M. Our data provide a biologic rationale for silencing of OSMR in colon cancer progression and highlight a new therapeutic target in this disease. Moreover, detection and quantification of OSMR promoter methylation in fecal DNA is a highly specific diagnostic biomarker for CRC.

Aim: To assess the prevalence and location of advanced neoplasia in patients undergoing colonoscopy, and to compare the yield per indication., Methods: In a multicenter colonoscopy survey (n = 18 hospitals) in the Amsterdam area (Northern Holland), data of all colonoscopies performed during a three month period in 2005 were analyzed. The location and the histological features of all colonic neoplasia were recorded. The prevalence and the distribution of advanced colorectal neoplasia and differences in yield between indication clusters were evaluated. Advanced neoplasm was defined as adenoma > 10 mm in size, with > 25% villous features or with high-grade dysplasia or cancer., Results: A total of 4623 eligible patients underwent a total colonoscopy. The prevalence of advanced neoplasia was 13%, with 281 (6%) adenocarcinomas and 342 (7%) advanced adenomas. Sixty-seven percent and 33% of advanced neoplasia were located in the distal and proximal colon, respectively. Of all patients with right-sided advanced neoplasia (n = 228), 51% had a normal distal colon, whereas 27% had a synchronous distal adenoma. Ten percent of all colonoscopies were performed in asymptomatic patients, 7% of whom had advanced neoplasia. In the respective procedure indication clusters, the prevalence of right-sided advanced neoplasia ranged from 11%-57%., Conclusion: One out of every 7-8 colonoscopies yielded an advanced colorectal neoplasm. Colonoscopy is warranted for the evaluation of both symptomatic and asymptomatic patients.

Objective: This study aimed to identify the oncogenes at 20q involved in colorectal adenoma to carcinoma progression by measuring the effect of 20q gain on mRNA expression of genes in this amplicon., Methods: Segmentation of DNA copy number changes on 20q was performed by array CGH (comparative genomic hybridisation) in 34 non-progressed colorectal adenomas, 41 progressed adenomas (ie, adenomas that present a focus of cancer) and 33 adenocarcinomas. Moreover, a robust analysis of altered expression of genes in these segments was performed by microarray analysis in 37 adenomas and 31 adenocarcinomas. Protein expression was evaluated by immunohistochemistry on tissue microarrays., Results: The genes C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5, mapping at 20q, were significantly overexpressed in carcinomas compared with adenomas as a consequence of copy number gain of 20q., Conclusion: This approach revealed C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5 genes to be important in chromosomal instability-related adenoma to carcinoma progression. These genes therefore may serve as highly specific biomarkers for colorectal cancer with potential clinical applications.

Objective: To map the locations of advanced colorectal neoplasia in patients referred for colonoscopy or sigmoidoscopy and to compare the yield of advanced neoplasia and the distribution of advanced neoplasia per indication for endoscopy., Design: Observational., Method: In a multicentre survey in North Holland, the Netherlands (n = 18 hospitals), data on all colonoscopies and sigmoidoscopies performed during a three-month period in 2005 were analyzed. The locations and the histological features of all colonic neoplasia and the indications for endoscopy were recorded. Advanced neoplasm was defined as adenoma >or=10 mm in size, an adenoma with any villous features, or high-grade dysplasia or adenocarcinoma., Results: A total of 4623 patients underwent a total colonoscopy and 3004 patients underwent sigmoidoscopy. The prevalence of advanced neoplasia was 13% on colonoscopy and 6% on sigmoidoscopy. Of the advanced neoplasia found on colonoscopy, 67% were located in the distal colon and 33% in the proximal colon. Of the patients with advanced neoplasia in the proximal colon (n = 228), 51% had no abnormalities in the distal colon. The percentage of advanced neoplasia in the proximal colon varied from 23% in patients younger than 50 years to 41% in patients aged 80 years and older. Depending on the indication for endoscopy, the prevalence of advanced neoplasia in the proximal colon varied from 11-57%., Conclusion: Of the advanced colorectal neoplasms 33% were located in the proximal colon. With increasing age, a shift in tumour localization occurs from distal to proximal in the colon. Colonoscopy is the preferred method for the endoscopic diagnosing of colorectal neoplasia.

Background and Aims: There are conflicting data concerning the association between diverticular disease and colorectal carcinoma (CRC). This study was performed to determine the prevalence and association of diverticulosis, diverticulitis, polyps, and CRC., Materials and Methods: In a cross-sectional, retrospective study, we analyzed the colonoscopy reports of complete colonoscopies and patho-histological results of all patients referred for colonoscopy in a period of 3 months in 18 hospitals in The Netherlands. Diverticulosis was defined as three or more diverticula present and diverticulitis as diverticulosis with inflammation. Polyps were also coded according to localization and size. Advanced neoplastic lesions were defined as polyps >or=10 mm in diameter and/or villous architecture and/or adenomas with high grade dysplasia and/or invasive cancer. Actual and previous described CRC were registered., Results: A total of 4,241 patients were included in the study [1,996 (47%) male], mean age of 59 and range 18-95. Diverticula, diverticulitis, and polyps were seen in 1,052 (25%), 75 (2%), and 1,282 (30%) patients, respectively. No association was found between patients with polyps and those with and without diverticulosis (p=0.478). Invasive adenocarcinoma and adenomas >or=10 mm were most frequently observed. CRC was present in 372 (9%) patients. Negative relation between diverticulosis and CRC and invasive adenocarcinoma was observed. No association was found between polyps and CRC and patients with diverticulitis and CRC. In conclusion, there is no relation between patients with diverticulosis and higher incidence of polyps or CRC when using age-stratified analysis. No increased risk for polyps or CRC was found in patients with diverticulitis.

Background: Future colorectal cancer (CRC) screening programmes should not (greatly) interfere with regular health care. Hence, we analysed the Dutch endoscopic practice to provide a clear insight into endoscopic workload and manpower with a special emphasis on the current ability to facilitate a successful implementation of a faecal occult blood test (FOBT)-based nationwide CRC screening programme., Methods: A questionnaire was sent to all Dutch endoscopy units (n = 100) in the spring of 2005. The questionnaire included topics ranging from the numbers and specifications of endoscopies performed in 2004 and the numbers of endoscopists per unit to expected vacancies for gastroenterologists and waiting times., Results: The response rate was 98%, representing a total of 49,253 hospital beds. overall, a 26% increase in the number of endoscopies from 325,000 in 1999 to almost 410,000 in 2004 was found, accompanied by a 25% increase in manpower. The total number of endoscopists was 598. regional differences were observed in the number of endoscopists, the total number of endoscopies and colonoscopies, and the number of endoscopies per endoscopist. A biannual FOBT-based screening programme would yield an additional workload of 25,385 colonoscopies a year amounting to a 22% increase in the total number of colonoscopies performed. However, the workload per unit would only have to increase by five extra colonoscopies a week., Conclusion: Whereas an FOBT-based CRC screening programme is currently feasible without strongly interfering with regular health care, future plans regarding the scale and preferred mode of screening should incorporate solid data on the (regional) endoscopic capacity and manpower needed for a successful implementation.

Aim: To find out whether there are differences in attitudes about colorectal cancer (CRC) screening among gastrointestinal (GI) specialists and general practitioners (GPs) and which method is preferred in a national screening program., Methods: Four hundred and twenty Dutch GI specialists in the Netherlands and 400 GPs in Amsterdam were questioned in 2004. Questions included demographics, affiliation, attitude towards screening both for the general population and themselves, methods of screening, family history and individual risk., Results: Eighty-four percent of the GI specialists returned the questionnaire in comparison to 32% of the GPs (P < 0.001). Among the GI specialists, 92% favoured population screening whereas 51% of GPs supported population screening (P < 0.001). Of the GI specialists 95% planned to be screened themselves, while 30% of GPs intended to do so (P < 0.001). Regarding the general population, 72% of the GI specialists preferred colonoscopy as the screening method compared to 27% of the GPs (P < 0.001). The method preferred for personal screening was colonoscopy in 97% of the GI specialists, while 29% of the GPs favoured colonoscopy (P < 0.001)., Conclusion: Screening for CRC is strongly supported by Dutch GI specialists and less by GPs. The major health issue is possibly misjudged by GPs. Since GPs play a crucial role in a successful national screening program, CRC awareness should be realized by increasing knowledge about the incidence and mortality, thus increasing awareness of the need for screening among GPs.

Our study aimed to evaluate the oral cavity as a reservoir from where Helicobacter pylori may be transmitted. Histology and PCR amplification were performed. Eighty-four percent of the stomach biopsies tested positive; however, H. pylori was not detected in dental samples, indicating the absence of H. pylori within the oral cavity.

Colorectal cancer (CRC) is still a disease with a high incidence and mortality. Prevention of (pre-) cancerous lesions of CRC by endoscopic screening is promising, but costs are high and identification of high-risk populations is difficult. Since screening both average-risk and high-risk populations for CRC has its logistic and financial limitations, new primary prevention strategies are sought. Substantial evidence has shown that non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors can reduce the incidence and mortality of CRC. However, long-term use of NSAIDs is associated with substantial gastrointestinal toxicity and may cause an exacerbation in IBD patients. Selective COX-2 inhibitors, with a better toxicity profile and no flare-up in IBD disease activity, are therefore attractive candidates for prevention. Chemoprevention with low-dose aspirin can be considered for individuals carrying a high risk for CRC. Folate supplementation is beneficial to the folate-depleted patients, since significant risk reductions for CRC are reported. Moreover, it might be applicable to the general population because it is safe, inexpensive and protects against vascular diseases. In line with drugs beneficial for multiple disease entities, statins have recently been proposed to reduce CRC risk. Ursodeoxycholic acid has been shown to decrease the incidence of colonic dysplasia in patients with ulcerative colitis and PSC and possibly reduces recurrence rates of polyps in general. Unfortunately, prospective randomized trials, in both high-risk and general population, are not available and the evidence is still controversial. Furthermore, cumulative epidemiological and observational data suggest the potential role of hormones as a chemoprotective agent. An increase in CRC in females with an early menopause, as well as a decrease of CRC in women with hormone replacement therapy justify further research into this issue. In IBD patients, both the severity and duration of the inflammation are the most evident risk factors for the development of dysplasia and subsequently cancer. Remission of inflammation, clinically, endoscopically and histologically, in IBD is the major goal. Long-term use of 5-aminosalicylates (5-ASA) has been shown to decrease the incidence of CRC and may hold the best promise as a chemoprotective agent in IBD. In parallel with primary prevention strategies in vascular medicine, the aim might be to postpone adenoma formation, for instance for 10 years, thereby achieving a significant risk reduction for CRC. In current practice, folate supplementation along with low-dose aspirin use in high-risk patients may be most attractive candidates, while future studies will have to clarify the role of these and other chemoprotective agents.