Polyp detection rate and cumulative incidence of post-colonoscopy colorectal cancer in Germany.

Studies have shown that the quality of colonoscopy influences the incidence of post-colonoscopy colorectal cancer (PCCRC). However, data from Germany on this association are lacking. We aimed to assess cumulative incidence of PCCRC in persons undergoing colonoscopy in Germany according to the physician's polyp detection rate (PDR). Using the German Pharmacoepidemiological Research Database (GePaRD) with claims data of ~20% of the German population, we included persons with a baseline colonoscopy between 2008 and 2017 and categorized them according to the procedure at baseline (snare polypectomy, forceps polypectomy, no polypectomy). In each subgroup, we distinguished between persons examined by physicians with a PDR in the lowest quartile vs higher quartiles and described cumulative CRC incidence during follow-up. Overall, 822 715 persons examined by 1752 physicians were included. One quarter of the physicians had a PDR ≤21.8% (lowest quartile). In all subgroups, the 5-year cumulative CRC incidence was statistically significantly higher in persons examined by physicians with a PDR ≤21.8% vs >21.8%: It was 69% higher in persons with snare polypectomy (0.88% vs 0.52%), 87% higher in persons with forceps polypectomy (0.58% vs 0.31%), and 48% higher in persons without polypectomy at baseline (0.31% vs 0.21%). In conclusion, we found a substantially increased PCCRC risk in persons examined by physicians with a low PDR in Germany, irrespective of the baseline findings. Our study highlights the importance of a high-quality colonoscopy to maximize the preventive effect of colonoscopy on CRC incidence.

PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the "Cancer Integrin" αvß6 with Ga-68-Trivehexin.

PURPOSE: To develop a new probe for the αvß6-integrin and assess its potential for PET imaging of carcinomas. METHODS: Ga-68-Trivehexin was synthesized by trimerization of the optimized αvß6-integrin selective cyclic nonapeptide Tyr2 (sequence: c[YRGDLAYp(NMe)K]) on the TRAP chelator core, followed by automated labeling with Ga-68. The tracer was characterized by ELISA for activities towards integrin subtypes αvß6, αvß8, αvß3, and α5ß1, as well as by cell binding assays on H2009 (αvß6-positive) and MDA-MB-231 (αvß6-negative) cells. SCID-mice bearing subcutaneous xenografts of the same cell lines were used for dynamic (90 min) and static (75 min p.i.) µPET imaging, as well as for biodistribution (90 min p.i.). Structure-activity-relationships were established by comparison with the predecessor compound Ga-68-TRAP(AvB6)3. Ga-68-Trivehexin was tested for in-human PET/CT imaging of HNSCC, parotideal adenocarcinoma, and metastatic PDAC. RESULTS: Ga-68-Trivehexin showed a high αvß6-integrin affinity (IC50 = 0.047 nM), selectivity over other subtypes (IC50-based factors: αvß8, 131; αvß3, 57; α5ß1, 468), blockable uptake in H2009 cells, and negligible uptake in MDA-MB-231 cells. Biodistribution and preclinical PET imaging confirmed a high target-specific uptake in tumor and a low non-specific uptake in other organs and tissues except the excretory organs (kidneys and urinary bladder). Preclinical PET corresponded well to in-human results, showing high and persistent uptake in metastatic PDAC and HNSCC (SUVmax = 10-13) as well as in kidneys/urine. Ga-68-Trivehexin enabled PET/CT imaging of small PDAC metastases and showed high uptake in HNSCC but not in tumor-associated inflammation. CONCLUSIONS: Ga-68-Trivehexin is a valuable probe for imaging of αvß6-integrin expression in human cancers.

Value of upper gastrointestinal endoscopy for gastric cancer surveillance in patients with Lynch syndrome.

In our study, we evaluated the effectiveness of upper gastrointestinal (GI) endoscopy as an instrument for early gastric cancer (GC) detection in Lynch syndrome (LS) patients by analyzing data from the registry of the German Consortium for Familial Intestinal Cancer. In a prospective, multicenter cohort study, 1128 out of 2009 registered individuals with confirmed LS underwent 5176 upper GI endoscopies. Compliance was good since 77.6% of upper GI endoscopies were completed within the recommended interval of 1 to 3 years. Forty-nine GC events were observed in 47 patients. MLH1 (n = 21) and MSH2 (n = 24) mutations were the most prevalent. GCs in patients undergoing regular surveillance were diagnosed significantly more often in an early-stage disease (UICC I) than GCs detected through symptoms (83% vs 25%; P = .0231). Thirty-two (68%) patients had a negative family history of GC. The median age at diagnosis was 51 years (range 28-66). Of all GC patients, 13 were diagnosed at an age younger than 45. Our study supports the recommendation of regular upper GI endoscopy surveillance for LS patients beginning no later than at the age of 30.

Early detection of duodenal cancer by upper gastrointestinal-endoscopy in Lynch syndrome.

Small bowel cancer (SBC) is the malignancy with the highest standardized incidence ratio in Lynch syndrome (LS) patients. Of all SBCs, about 50% are duodenal cancers (DCs), therefore being accessible by esophago-gastro-duodenoscopy (EGD) for surveillance. We asked whether early detection of DC is possible for LS patients undergoing surveillance by EGD and if surveillance should be limited to specific subgroups. Data for LS patients with DC were retrieved from the registry of the German Consortium for Familial Intestinal Cancer. Patients undergoing active surveillance by EGDs (surveillance group) were compared to those who did not (nonsurveillance group) regarding tumor stage at diagnosis. Union for International Cancer Control stages I-IIA were defined as early stage disease and IIB-IV as advanced stage disease. Statistical analysis was performed using Fisher's exact test. Among 2015 patients with pathogenic variants in any mismatch-repair-gene, 47 patients with 49 DCs were identified. In 10% of cases, patients were under 35 years at diagnosis; family and personal tumor history did not correlate with DC diagnosis. Pathogenic germline variants in MSH6, PMS2 or EPCAM were present in 10% of patients. Statistical analysis could be performed on 13 DC patients in the surveillance group and 14 in the nonsurveillance group. Early detection was possible for 71% of patients in the surveillance group and 29% of patients in the nonsurveillance group (P = .021). Early detection of DC by EGD in LS patients is feasible regardless of family history, mutational status and should start no later than 25 years of age.

Post-polypectomy colonoscopy surveillance: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2020.

The following recommendations for post-polypectomy colonoscopic surveillance apply to all patients who had one or more polyps that were completely removed during a high quality baseline colonoscopy. 1: ESGE recommends that patients with complete removal of 1 - 4 < 10 mm adenomas with low grade dysplasia, irrespective of villous components, or any serrated polyp < 10 mm without dysplasia, do not require endoscopic surveillance and should be returned to screening.Strong recommendation, moderate quality evidence.If organized screening is not available, repetition of colonoscopy 10 years after the index procedure is recommended.Strong recommendation, moderate quality evidence. 2: ESGE recommends surveillance colonoscopy after 3 years for patients with complete removal of at least 1 adenoma ≥ 10 mm or with high grade dysplasia, or ≥ 5 adenomas, or any serrated polyp ≥ 10 mm or with dysplasia. Strong recommendation, moderate quality evidence. 3: ESGE recommends a 3 - 6-month early repeat colonoscopy following piecemeal endoscopic resection of polyps ≥ 20 mm.Strong recommendation, moderate quality evidence. A first surveillance colonoscopy 12 months after the repeat colonoscopy is recommended to detect late recurrence.Strong recommendation, high quality evidence. 4: If no polyps requiring surveillance are detected at the first surveillance colonoscopy, ESGE suggests to perform a second surveillance colonoscopy after 5 years. Weak recommendation, low quality evidence.After that, if no polyps requiring surveillance are detected, patients can be returned to screening. 5: ESGE suggests that, if polyps requiring surveillance are detected at first or subsequent surveillance examinations, surveillance colonoscopy may be performed at 3 years. Weak recommendation, low quality evidence.A flowchart showing the recommended surveillance intervals is provided (Fig. 1).

Risk of Malignancy in Adenomas Detected During Screening Colonoscopy.

BACKGROUND & AIMS: A higher incidence of proximal interval cancers after colonoscopy has been reported in several follow-up studies. One possible explanation for this might be that proximally located adenomas have greater malignant potential. The aim of the present study was to assess the risk of malignancy in proximal versus distal adenomas in patients included in a large screening colonoscopy database; adenoma shape and the patients' age and sex distribution were also analyzed. METHODS: Data for 2007-2012 from the German National Screening Colonoscopy Registry, including 594,614 adenomas identified during 2,532,298 screening colonoscopies, were analyzed retrospectively. The main outcome measure was the rate of high-grade dysplasia (HGD) in adenomas, used as a surrogate marker for the risk of malignancy. Odds ratios (ORs) for the rate of HGD found in adenomas were analyzed in relation to patient- and adenoma-related factors using multivariate analysis. RESULTS: HGD histology was noted in 20,873 adenomas (3.5%). Proximal adenoma locations were not associated with a higher HGD rate. The most significant risk factor for HGD was adenoma size (OR 10.36 ≥1 cm vs <1 cm), followed by patient age (OR 1.26 and 1.46 for age groups 65-74 and 75-84 vs 55-64 years) and sex (OR 1.15 male vs female). In comparison with flat adenomas as a reference lesion, sessile lesions had a similar HGD rate (OR 1.02) and pedunculated adenomas had a higher rate (OR 1.23). All associations were statistically significant (P ≤ .05). CONCLUSIONS: In this large screening database, it was found that the rates of adenomas with HGD are similar in the proximal and distal colon. The presence of HGD as a risk marker alone does not explain higher rates of proximal interval colorectal cancer. We suggest that certain lesions (flat, serrated lesions) may be missed in the proximal colon and may acquire a more aggressive biology over time. A combination of endoscopy-related factors and biology may therefore account for higher rates of proximal versus distal interval colorectal cancer.

Trends in Adenoma Detection Rates During the First 10 Years of the German Screening Colonoscopy Program.

BACKGROUND & AIMS: The adenoma detection rate (ADR) is an important quality indicator of screening colonoscopy; it is inversely associated with risk of interval cancers and colorectal cancer mortality. We assessed trends in the ADR in the first 10 years of the German screening colonoscopy program. METHODS: We calculated age-adjusted and age-specific detection rates of nonadvanced adenomas and advanced adenomas for each calendar year based on 4.4 million screening colonoscopies conducted from 2003 through 2012 and reported to the German screening colonoscopy registry. RESULTS: We observed a steady and strong increase in rate of detection of nonadvanced adenomas in both sexes and all age groups. Age-adjusted rates of detection of nonadvanced adenomas increased from 13.3% to 22.3% among men and from 8.4% to 14.9% among women. This increase was mostly due to an increase in detection rates of adenomas <0.5 cm, and it is partly explained by an innovation effect (higher ADRs among incoming colonoscopists than among leaving colonoscopists, and relatively stable ADRs among continuing colonoscopists). Only modest increases were observed in detection rates of advanced adenomas (from 7.4% to 9.0% among men, and from 4.4% to 5.2% among women) and colorectal cancer. In 2012, overall ADR reached 31.3% and 20.1% in men and women, respectively. CONCLUSIONS: We observed a strong increase in ADRs from 2003 through 2012 in Germany. Although we cannot exclude the effects of secular trends in colorectal neoplasm prevalence, the observed increase was mainly the result of a steady increase in detection of nonadvanced adenomas (especially adenomas <0.5 cm). Further research should address potential implications for defining screening and surveillance intervals.

Colorectal cancer.

More than 1·2 million patients are diagnosed with colorectal cancer every year, and more than 600,000 die from the disease. Incidence strongly varies globally and is closely linked to elements of a so-called western lifestyle. Incidence is higher in men than women and strongly increases with age; median age at diagnosis is about 70 years in developed countries. Despite strong hereditary components, most cases of colorectal cancer are sporadic and develop slowly over several years through the adenoma-carcinoma sequence. The cornerstones of therapy are surgery, neoadjuvant radiotherapy (for patients with rectal cancer), and adjuvant chemotherapy (for patients with stage III/IV and high-risk stage II colon cancer). 5-year relative survival ranges from greater than 90% in patients with stage I disease to slightly greater than 10% in patients with stage IV disease. Screening has been shown to reduce colorectal cancer incidence and mortality, but organised screening programmes are still to be implemented in most countries.

Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: a comprehensive analysis of 3,671 families.

Carriers of mismatch repair (MMR) gene mutations have a high lifetime risk for colorectal and endometrial cancers, as well as other malignancies. As mutation analysis to detect these patients is expensive and time-consuming, clinical criteria and tumor-tissue analysis are widely used as pre-screening methods. The aim of our study was to evaluate the performance of commonly applied clinical criteria (the Amsterdam I and II Criteria, and the original and revised Bethesda Guidelines) and the results of tumor-tissue analysis in predicting MMR gene mutations. We analyzed 3,671 families from the German HNPCC Registry and divided them into nine mutually exclusive groups with different clinical criteria. A total of 680 families (18.5%) were found to have a pathogenic MMR gene mutation. Among all 1,284 families with microsatellite instability-high (MSI-H) colorectal cancer, the overall mutation detection rate was 53.0%. Mutation frequencies and their distribution between the four MMR genes differed significantly between clinical groups (p < 0.001). The highest frequencies were found in families fulfilling the Amsterdam Criteria (46.4%). Families with loss of MSH2 expression had higher mutation detection rates (69.5%) than families with loss of MLH1 expression (43.1%). MMR mutations were found significantly more often in families with at least one MSI-H small-bowel cancer (p < 0.001). No MMR mutations were found among patients under 40-years-old with only colorectal adenoma. Familial clustering of Lynch syndrome-related tumors, early age of onset, and familial occurrence of small-bowel cancer were clinically relevant predictors for Lynch syndrome.

Controversies in colorectal cancer screening.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide and a good candidate for screening programmes. However, there is controversy concerning which of the available screening tests should be used. SUMMARY: There is general agreement that screening for CRC in the asymptomatic population should begin at the age of 50. Several different screening methods are available which can be separated into those that mainly detect cancers: faecal occult blood tests [guaiac (FOBT) and immunochemical (FIT)], genetic stool tests, blood tests and the M2-pyruvate kinase (M2-PK) test. Methods that detect cancers and polyps are colonoscopy, sigmoidoscopy, CT-colonography (CT-C) and colon capsule endoscopy. The only tests for which a reduction in CRC mortality compared to no screening have been proven in randomized trials are FOBT and sigmoidoscopy. Several trials suggest that FIT are superior to FOBT in terms of detection rates of cancers and advanced adenomas and possibly compliance. There is indirect evidence suggesting efficacy of colonoscopy as a screening test. The role of CT-C is controversial. There is data suggesting a good sensitivity for neoplasia >9 mm with a lower sensitivity for smaller neoplasia. However, radiation exposure is considered a major limitation in some countries. Unresolved questions include the lesion cut-off for referral to colonoscopy and work-up of extracolonic findings. For other methods, like genetic stool testing using newer markers, blood tests, capsule endoscopy and M2-PK, there is currently insufficient data on screening of the asymptomatic population. Key Messages: Colorectal screening is recommended and should be performed in the form of an organized programme. If detection of early-stage cancers is the aim of a screening programme, FIT seem to be superior to FOBT. If detection and removal of adenomas is the aim of a screening programme, endoscopic methods seem to be good alternatives. Sigmoidoscopy is easier to perform but will likely only have an effect on distal cancers. Colonoscopy is more invasive but enables inspection of the whole colon. The role of CT-C, capsule endoscopy, genetic stool tests, blood tests and M2-PK is currently unknown.

Analysis of U2 small nuclear RNA fragments in the bile differentiates cholangiocarcinoma from primary sclerosing cholangitis and other benign biliary disorders.

BACKGROUND AND OBJECTIVES: Up to now the diagnosis of early stage cholangiocarcinoma (CC) has remained difficult, with low sensitivities reported for current diagnostic methods. Based on recent promising findings about circulating U2 small nuclear RNA fragments (RNU2-1f) as novel blood-based biomarkers for pancreatic and colorectal adenocarcinoma, we studied the utility of RNU2-1f as a diagnostic marker of CC in bile fluid. METHODS: Bile fluid was collected from patients with CC (n = 12), controls (patients with choledocholithiasis) (n = 11) and with primary sclerosing cholangitis (PSC; n = 11). RNU2-1f levels were measured by real-time polymerase chain reaction normalized to cel-54. RESULTS: Measurement of RNU2-1f levels in bile fluids enabled the differentiation of patients with CC from controls in all cases. Furthermore, RNU2-1f levels in bile fluids of patients with CC were significantly higher than in patients with PSC, resulting in a receiver-operating characteristic curve area of 0.856, with sensitivity of 67 % and specificity of 91 %. CONCLUSIONS: Our data suggest that the measurement of RNU2-1 fragments detected in the bile fluid can be used as a diagnostic marker for CC and should be included in future prospective diagnostic studies for this disease entity.

Efficacy of a nationwide screening colonoscopy program for colorectal cancer.

BACKGROUND & AIMS: Screening colonoscopy examinations for colorectal cancer are offered in the United States and some European countries. Data on results and adverse effects of screening colonoscopy are limited. In autumn 2002, colonoscopy was introduced as part of a nationwide cancer screening program in Germany; it was offered to the general population for individuals 55 years of age or older. We collected and analyzed data from this program. METHODS: We performed a prospective cross-sectional study, collecting results from 2,821,392 screening colonoscopies performed at more than 2100 practices by highly qualified endoscopists in Germany from January 2003 to December 2008. Data on participation, colorectal adenoma and cancer detection, and complications were collected using standardized documentation forms. The data generated were centrally processed and evaluated. RESULTS: The cumulative participation rate was 17.2% of eligible women and 15.5% of eligible men 55-74 years old. The adenoma detection rate (ADR) was 19.4%, with a higher rate in men (25.8% vs 16.7% in women). Advanced adenomas were found in 6.4% of patients. Carcinomas were detected in 25,893 subjects (0.9%); most were of an early UICC stage (I, 47.3%; II, 22.3%; III, 20.7%; IV, 9.6%). The ADRs for gastroenterologists and nongastroenterologists were 25.1% and 22.3%, respectively (adjusted odds ratio, 1.18; 95% confidence interval, 1.16-1.21). The overall complication rate was 2.8/1000 colonoscopies, and the rate of serious complications was 0.58/1000 colonoscopies. CONCLUSIONS: A nationwide colonoscopy screening program that uses highly qualified endoscopists can detect a significant number of adenomas and early-stage carcinomas. The ADR for gastroenterologists was higher than for nongastroenterologists.

Post-polypectomy colonoscopy surveillance: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

MAIN RECOMMENDATIONS: The following recommendations for post-polypectomy endoscopic surveillance should be applied only after a high quality baseline colonoscopy with complete removal of all detected neoplastic lesions.1 In the low risk group (patients with 1 - 2 tubular adenomas < 10 mm with low grade dysplasia), the ESGE recommends participation in existing national screening programmes 10 years after the index colonoscopy. If no screening programme is available, repetition of colonoscopy 10 years after the index colonoscopy is recommended (strong recommendation, moderate quality evidence). 2 In the high risk group (patients with adenomas with villous histology or high grade dysplasia or ≥10 mm in size, or ≥ 3 adenomas), the ESGE recommends surveillance colonoscopy 3 years after the index colonoscopy (strong recommendation, moderate quality evidence). Patients with 10 or more adenomas should be referred for genetic counselling (strong recommendation, moderate quality evidence). 3 In the high risk group, if no high risk adenomas are detected at the first surveillance examination, the ESGE suggests a 5-year interval before a second surveillance colonoscopy (weak recommendation, low quality evidence). If high risk adenomas are detected at first or subsequent surveillance examinations, a 3-year repetition of surveillance colonoscopy is recommended (strong recommendation, low quality evidence).4 The ESGE recommends that patients with serrated polyps < 10 mm in size with no dysplasia should be classified as low risk (weak recommendation, low quality evidence). The ESGE suggests that patients with large serrated polyps (≥ 10 mm) or those with dysplasia should be classified as high risk (weak recommendation, low quality evidence).5 The ESGE recommends that the endoscopist is responsible for providing a written recommendation for the post-polypectomy surveillance schedule (strong recommendation, low quality evidence).

ß-Catenin, Cox-2 and p53 immunostaining in colorectal adenomas to predict recurrence after endoscopic polypectomy.

BACKGROUND: Endoscopic polypectomy significantly reduces the incidence of colorectal cancer, but recurrence rates are high, especially for adenomas with advanced histology. The present guidelines recommend re-colonoscopy 3 to 5 years later. Due to limited resources, more precise predictions of adenoma recurrence are required. DESIGN: Lesions from 109 patients with colorectal adenomas recruited into a randomized, placebo-controlled chemoprevention trial with mesalazine were included. Formalin-fixed paraffin-embedded tissue sections were stained for ß-catenin, cyclooxygenase-2 (Cox-2), and p53 and scored. Adenoma recurrence rates were recorded after 3 years and associated with clinical and immunohistochemical parameters by contingency table analysis. RESULTS: After 3 years, adenomas recurred in 51.4% of patients. Out of 109 adenomas, 95 met at least one criterion of advanced adenoma (size >1 cm, villous histology, high-grade intraepithelial neoplasia). There was no influence of age, sex, size or villous histology on adenoma reappearance, whilst the number of adenomas at baseline was positively associated with recurrence (p = 0.003). In contrast, ß-catenin nuclear localisation, Cox-2 expression and p53 nuclear expression were significantly associated with adenoma recurrence after 3 years (ß-catenin: p = 0.002; Cox-2: p = 0.001; p53: p = 0.001). Combining these three markers led to a negative predictive value of 88.5% and a sensitivity of 94.6%. (OR = 13.54) CONCLUSIONS: Scoring each single parameter and, more strongly, the combination of all three parameters of the expression of ß-catenin, Cox-2 and p53 in colorectal adenoma tissue may be a useful negative predictor for adenoma recurrence in patients with advanced colorectal adenomas.

[Checkpoint inhibitors in colorectal carcinoma: are we entering a new era?] / Checkpointinhibitoren beim kolorektalen Karzinom ­ eine neue Ära?

BACKGROUND: Checkpoint-inhibitors have shown high response rates in some tumours such as melanomas. OBJECTIVES: This article describes the data concerning the efficacy of checkpoint inhibitors in patients with colorectal cancer (CRC). CURRENT DATA: Efficacy for the use of checkpoint inhibitors in CRC has only been shown for tumours with high microsatellite instability (MSI-H) or a deficient mismatch repair system (dMMR). The proportion of patients with MSI-H/dMMR cancers is 10-12% in colon cancers and 3% in rectal cancers. In cohort studies with patients that had progressed under at least one chemotherapy a response rate of 33% could be shown for pembrolizumab and 65% for the combination nivolumab and ipilimumab. In many patients the response was long-lasting. After 2 years between 55 and 75% of patients were still alive. In a randomized study comparing first-line therapy with pembrolizumab and chemotherapy progression-free survival was much longer for the pembrolizumab group (16.5 vs. 8.2 months). In a small series of patients with MSI-H/dMMR rectal cancers treatment with dostarlimab resulted in complete remission in all patients with no regrowth during an admittedly short follow-up. A series of patients with locally advanced MSI-H/dMMR colon cancers showed a treatment response in nearly all patients with 67% experiencing complete remission. In patients with microsatellite-stable (MSS) cancers checkpoint inhibitors showed no effect, the combination with chemotherapy at most a modest effect. CONCLUSIONS: Checkpoint inhibitors are the first-choice palliative treatment in patients with MSI-H/dMMR CRC and have replaced chemotherapy as the first option. Early data show a high response rate for the neoadjuvant treatment of MSI-H/dMMR rectal and colon cancers.

Colorectal Cancer After Screening Colonoscopy: 10-Year Incidence by Site and Detection Rate at First Repeat Colonoscopy.

INTRODUCTION: We aimed to describe cumulative colorectal cancer (CRC) incidence after screening colonoscopy stratified by tumor location, age, and sex as well as CRC detection rate at first repeat colonoscopy. METHODS: Using the German Pharmacoepidemiological Research Database, we included persons with screening colonoscopy and assessed cumulative CRC incidence after baseline screening colonoscopy with snare polypectomy (cohort 1) and without polypectomy (cohort 2). We also determined the CRC detection rate at first repeat colonoscopy by time since screening colonoscopy. RESULTS: Overall, 1,095,381 persons were included. The 10-year cumulative CRC incidence was 1.5% in cohort 1 and 0.6% in cohort 2. The proportion of proximal CRC increased with age: In women of cohort 1, 47% of CRCs in the age group 55-64 years were proximal (men: 42%) while in the age group 65-74 years, this proportion was 55% (men: 49%). In cohort 2, similar patterns were observed. In cohort 1, the CRC detection rate at first repeat colonoscopy among persons examined within 6-8 years after screening colonoscopy was more than twice as high compared with those examined within 4-6 years (1.7% vs 0.8%). DISCUSSION: Among persons followed up after screening colonoscopy, we observed a steadily increasing predominance of proximal CRC, and this shift showed distinct patterns by age and sex. Because our study suggests higher CRC detection rates among persons with a later repeat colonoscopy, the role of delayed surveillance and the benefit of a reminder system should be explored.

The influence of 5-aminosalicylic acid on the progression of colorectal adenomas via the ß-catenin signaling pathway.

Surveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-aminosalicylate (ASA) (mesalazine) is discussed as a chemopreventive agent as it reduces the cancer risk in ulcerative colitis patients. The current study analyses the effect of 5-ASA on Wnt/ß-catenin signaling in vitro and in vivo in colon epithelial cells. The effect of 5-ASA was determined using a ß-catenin/T-cell factor (TCF)-reporter assay and by western blotting in cultured colon cancer cells. Formalin fixed paraffin embedded material from 227 polyps removed from a subgroup of 56 patients, who participated in a randomized placebo-controlled 3-year prevention trial with 5-ASA was evaluated according to histomorphological characteristics and expression of ß-catenin and target genes Cox2, cyclin D1 and E-cadherin as well as ornithine decarboxylase (ODC). Patients were grouped into a low-risk and a high-risk group according to the number of adenomas at initial colonoscopy. ß-catenin/TCF signaling activity was significantly reduced by 5-ASA treatment possibly through a reduction in ß-catenin levels. Moreover, 5-ASA significantly reduced ß-catenin levels and nuclear localization in patients' adenomas. In addition, 5-ASA also significantly changed expression of the downstream targets Cox2, cyclin D1 and E-cadherin, correlating with ß-catenin status. Moreover, 5-ASA significantly reduced levels of ODC in vivo. Expression of p53 was unaltered by the 5-ASA treatment. Our study shows a significant in vitro and long-term in vivo effect of 5-ASA on ß-catenin signaling as a key signaling pathway in the development of colorectal adenoma. Therefore, we suggest the use of 5-ASA as a promising drug for prevention of sporadic colorectal carcinoma.

Capnographic monitoring reduces the incidence of arterial oxygen desaturation and hypoxemia during propofol sedation for colonoscopy: a randomized, controlled study (ColoCap Study).

OBJECTIVES: The aim of this randomized study was to determine whether intervention based on additional capnographic monitoring reduces the incidence of arterial oxygen desaturation during propofol sedation for colonoscopy. METHODS: Patients (American Society of Anesthesiologists classification (ASA) 1-3) scheduled for colonoscopy under propofol sedation were randomly assigned to either a control arm with standard monitoring (standard arm) or an interventional arm in which additional capnographic monitoring (capnography arm) was available. In both study arms, detection of apnea or altered respiration induced withholding propofol administration, stimulation of the patient, chin lift maneuver, or further measures. The primary study end point was the incidence of arterial oxygen desaturation (defined as a fall in oxygen saturation (SaO(2)) of ≥5% or <90%); secondary end points included the occurrences of hypoxemia (SaO(2) <90%), severe hypoxemia (SaO(2) ≤85%), bradycardia, hypotension, and the quality of sedation (patient cooperation and patient satisfaction). RESULTS: A total of 760 patients were enrolled at three German endoscopy centers. The intention-to-treat analysis revealed a significant reduction of the incidence of oxygen desaturation in the capnography arm in comparison with the standard arm (38.9% vs. 53.2%; P<0.001). The numbers of patients with a fall in SaO(2) <90% and ≤85% were also significantly different (12.5% vs. 19.8%; P=0.008 and 3.7 vs. 7.8%; P=0.018). There were no differences regarding the rates of bradycardia and hypotension. Quality of sedation was similar in both groups. Results of statistical analyses were maintained for the per-protocol population. CONCLUSIONS: Additional capnographic monitoring of ventilatory activity reduces the incidence of oxygen desaturation and hypoxemia during propofol sedation for colonoscopy.

Colon cancer screening: which non-invasive filter tests?

The following non-invasive stool tests for colorectal cancer (CRC) screening exist: guaiac or immunochemical fecal occult blood testing (FOBT), genetic stool tests and the M2-PK. Currently the most widely used tests are guaiac-based (gFOBT). Several randomized controlled trials have shown that gFOBT are able to achieve a reduction in CRC-related mortality. This reduction is achieved by detecting asymptomatic cancers at an early stage with a better prognosis. However, gFOBT have a low sensitivity for colorectal adenomas and are thus unlikely to be able to reduce the incidence of CRC. Furthermore, gFOBT are not specific for human blood and can be influenced by external factors. Immunochemical tests (iFOBT) only detect human blood in the stool. In two recent randomized studies from the Netherlands comparing guaiac and immunochemical tests in the asymptomatic population, iFOBT were found to detect more cancers than gFOBT. Furthermore, iFOBT were able to detect more advanced adenomas thus having the potential to be able to reduce the incidence of CRC as well as CRC-related mortality. In the recently released European CRC screening guidelines, iFOBT are considered the screening test of choice. Several questions remain however. It is currently unknown what the optimal cut-off value for an iFOBT to be considered positive should be and what the number of stool samples is that are required. Genetic stool tests detect mutations in stool that can be found in CRC. The original test testing for 21 genetic changes was found to be superior to gFOBT for the detection of cancers. However, the sensitivity was moderate (51.6%) and the sensitivity for advanced adenomas was low. In the meantime the test has been modified improving DNA extraction and reducing the number of mutations tested for as well as including a methylation marker. The efficacy of the modified test in the screening population is unknown. M2-PK is an isomer of the enzyme pyruvate kinase that is involved in glycolysis. Studies have found a good sensitivity for cancers, a low sensitivity for advanced adenomas with a specificity of around 80%. Further studies in the screening population are required.