Sascha C. van Doorn

Evaluation of an assay for methylated BCAT1 and IKZF1 in plasma for detection of colorectal neoplasia

BackgroundSpecific genes, such as BCAT1 and IKZF1, are methylated with high frequency in colorectal cancer (CRC) tissue compared to normal colon tissue specimens. Such DNA may leak into blood and be present as cell-free circulating DNA. We have evaluated the accuracy of a novel blood test for these two markers across the spectrum of benign and neoplastic conditions encountered in the colon and rectum.MethodsCirculating DNA was extracted from plasma obtained from volunteers scheduled for colonoscopy for any reason, or for colonic surgery, at Australian and Dutch hospitals. The extracted DNA was bisulphite converted and analysed by methylation specific real-time quantitative PCR (qPCR). A specimen was deemed positive if one or more qPCR replicates were positive for either methylated BCAT1 or IKZF1 DNA. Sensitivity and specificity for CRC were estimated as the primary outcome measures.ResultsPlasma samples were collected from 2105 enrolled volunteers (mean age 62 years, 54 % male), including 26 additional samples taken after surgical removal of cancers. The two-marker blood test was run successfully on 2127 samples. The test identified 85 of 129 CRC cases (sensitivity of 66 %, 95 % CI: 57–74). For CRC stages I-IV, respective positivity rates were 38 % (95 % CI: 21–58), 69 % (95 % CI: 53–82), 73 % (95 % CI: 56–85) and 94 % (95 % CI: 70–100). A positive trend was observed between positivity rate and degree of invasiveness. The colonic location of cancer did not influence assay positivity rates. Gender, age, smoking and family history were not significant predictors of marker positivity. Twelve methylation-positive cancer cases with paired pre- and post-surgery plasma showed reduction in methylation signal after surgery, with complete disappearance of signal in 10 subjects. Sensitivity for advanced adenoma (n = 338) was 6 % (95 % CI: 4–9). Specificity was 94 % (95 % CI: 92–95) in all 838 non-neoplastic pathology cases and 95 % (95 % CI: 92–97) in those with no colonic pathology detected (n = 450).ConclusionsThe sensitivity for cancer of this two-marker blood test justifies prospective evaluation in a true screening population relative to a proven screening test. Given the high rate of marker disappearance after cancer resection, this blood test might also be useful to monitor tumour recurrence.Trial registrationACTRN12611000318987.

A novel colonoscopy reporting system enabling quality assurance

BACKGROUND AND STUDY AIMS The quality of colonoscopy can only be measured if colonoscopy reports include all key quality indicators. In daily practice, reporting is often incomplete and not standardized. This study describes a novel, structured colonoscopy reporting system, which aims to generate standardized and complete reports and to facilitate the automatic analysis of colonoscopy quality indicators. METHODS A new colonoscopy reporting system (EndoALPHA) was developed. The system reports all colonoscopy quality indicators, as well as pathological findings, in a systematic manner using structured terminology. All essential items carry specific codes, which enables statistical analysis and the automatic generation of reports of all quality indicators. The EndoALPHA reporting system was tested with regard to completeness of reporting and evaluation of quality indicators both for individual endoscopists and the endoscopy unit. RESULTS In 2012, all 810 colonoscopies performed at one colonoscopy center were documented using EndoALPHA. Overall, 94 % of performed colonoscopies were reported completely using the encoded terminology. Individual unadjusted cecal intubation rates were above 90 % for all endoscopists (mean 96.7 %), and the adenoma detection rate was above 20 % for all endoscopists (35.4 % for the unit). CONCLUSION The novel EndoALPHA reporting system enables automatic quality assessment on two levels: the completeness of reporting can be evaluated, and if this is adequate, the quality of the colonoscopies can also be assessed. Integrated with feedback, benchmarking and training, the reporting system may facilitate quality improvement for colonoscopy services.

Polyp Morphology: An Interobserver Evaluation for the Paris Classification Among International Experts

OBJECTIVES:The Paris classification is an international classification system for describing polyp morphology. Thus far, the validity and reproducibility of this classification have not been assessed. We aimed to determine the interobserver agreement for the Paris classification among seven Western expert endoscopists.METHODS:A total of 85 short endoscopic video clips depicting polyps were created and assessed by seven expert endoscopists according to the Paris classification. After a digital training module, the same 85 polyps were assessed again. We calculated the interobserver agreement with a Fleiss kappa and as the proportion of pairwise agreement.RESULTS:The interobserver agreement of the Paris classification among seven experts was moderate with a Fleiss kappa of 0.42 and a mean pairwise agreement of 67%. The proportion of lesions assessed as “flat” by the experts ranged between 13 and 40% (P<0.001). After the digital training, the interobserver agreement did not change (kappa 0.38, pairwise agreement 60%).CONCLUSIONS:Our study is the first to validate the Paris classification for polyp morphology. We demonstrated only a moderate interobserver agreement among international Western experts for this classification system. Our data suggest that, in its current version, the use of this classification system in daily practice is questionable and it is unsuitable for comparative endoscopic research. We therefore suggest introduction of a simplification of the classification system.

Fecal immunochemical testing results and characteristics of colonic lesions

BACKGROUND AND STUDY AIMS Fecal immunochemical tests (FIT) are used to detect blood in feces, which might indicate the presence of colorectal neoplasia. The aim of this study was to investigate whether FIT results vary depending on the characteristics of colonic lesions. PATIENTS AND METHODS This was a retrospective analysis of lesions detected in a cohort of asymptomatic individuals (aged 50 - 75 years) who were invited to participate in a FIT-based screening pilot in The Netherlands. The mean FIT result was compared across subgroups of individuals defined by histopathology of the most advanced lesion detected. In addition, the results were compared with data from a primary colonoscopy screening trial, in which participants also completed a FIT. RESULTS In three rounds of FIT-based screening, a total of 877 FIT-positive individuals underwent colonoscopy. Higher mean FIT results (hemoglobin [Hb]/g feces) were observed in individuals with carcinomas (199 μg Hb/g) and advanced adenomas (87 μg Hb/g) compared with participants with nonadvanced adenomas (50 μg Hb/g) or those with serrated lesions (46 μg Hb/g) (P < 0.001). In the primary colonoscopy trial, 1256 participants completed a FIT test and underwent colonoscopy. The number of participants with nonadvanced adenomas as the most advanced lesion was comparable between this group and the FIT-based screening group (20 % vs. 22 %). CONCLUSION In FIT-based screening, the mean FIT results varied depending on the characteristics of the most advanced colonic lesion. The proportion of participants with a nonadvanced adenoma as the most advanced lesion was similar in the FIT-based screening group and in the primary colonoscopy screening group, suggesting that these lesions are coincidental findings rather than FIT-detected findings. CLINICAL TRIAL REGISTRATION www.trialregister.nl number NTR2755.

Polypectomy skills of gastroenterology fellows: can we improve them?

Background and aims: Currently, most training programs for gastroenterology (GI) fellows lack systematic training in polypectomy. Systematic education and direct feedback with the direct observational polypectomy skills (DOPyS) method is a simple and inexpensive way to train GI fellows in practical endoscopy. Our primary aim was to evaluate whether a lecture-based training course could improve the polypectomy skills of GI fellows. As a secondary aim, the interobserver agreement among the three assessors was evaluated. Participants and methods: We invited GI fellows to record five polypectomies, after which they attended a training course consisting of three lectures on polyps and polypectomy methods given by expert endoscopists. After training, the fellows recorded five polypectomies again. All videos were blindly assessed by three expert endoscopists, who used the DOPyS method. Results: Eight GI fellows participated in this study. There was no significant difference in the median overall competency scores before and after training; before training, 25 % (10/40) of the polypectomies were scored as “pass,” compared with 37.5 % (15/40) after training (P = 0.56). The interobserver agreement among the experts was fair (intraclass correlation coefficient [ICC] 0.34, 95 % confidence interval [CI] 0.14 – 0.52). Conclusions: Our lecture-based training course did not result in an improvement in overall competency scores for the polypectomy skills of GI fellows. Besides, the overall quality of the polypectomy techniques of the fellows was considered low. To optimize polypectomy training and competency, we believe that direct feedback in the endoscopy suite and hands-on training by dedicated teachers are essential.

Quality of colonoscopy and advances in detection of colorectal lesions: a current overview

Colonoscopy is the gold standard for the detection of colorectal cancer and its precursors. Nevertheless multiple studies have demonstrated a significant miss-rate for polyps and, more importantly, demonstrated the occurrence of interval cancers in the years after colonoscopy. This imperfect protection against colorectal cancer can be explained by multiple factors related to both the endoscopist and the equipment. To ensure the quality of colonoscopy, several quality indicators have been described. These include bowel preparation, cecal intubation rate, withdrawal time, adenoma detection rate and complication rate. Measurement of these quality indicators, followed by awareness, benchmarking and additional training will hopefully optimize daily practice. If these basic quality parameters are well taken care of, advanced colonoscopic techniques will aim at further increasing the detection and differentiation of colonic lesions. In this review, the authors discuss the literature on quality indicators for colonoscopy and give a comprehensive overview of the advanced colonoscopic techniques currently available.

Optical diagnosis of malignant colorectal polyps: is it feasible?

Background and study aims: As colorectal cancer screening programs are being implemented worldwide, an increasing number of early (T1) cancers are being diagnosed. These cancers should be recognized during colonoscopy because they require a specific therapeutic approach. Several studies have shown that Asian experts can reliably recognize T1 cancers during colonoscopy. In daily practice, however, accurate endoscopic diagnosis of T1 cancers still seems challenging. We evaluated the performance of optical diagnosis of T1 cancers by European colonoscopy experts, general gastroenterologists and gastrointestinal fellows. Patients and methods: We collected endoscopic images of 43 colonic lesions: 19 T1 cancers (excluding intramucosal carcinoma) and 24 benign polyps ranging from 7 mm to 30 mm in size. Seven colonoscopy experts, 7 general gastroenterologists, and 14 gastrointestinal fellows assessed these images. We calculated sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) and their 95 % confidence intervals for optical diagnosis of T1 cancers. Results: Overall sensitivity for correct diagnosis of T1 cancers was 60 % (95 % CI;45 – 72). Sensitivity was highest for experts (67 %: 95 %CI; 48 – 81), when compared to general gastroenterologists (53 %: 95 %CI; 37 – 69) and gastrointestinal fellows (59 %: 95 %CI;45 – 72). The overall NPV was 75 % (95 %CI;60 – 86); NPV was lowest for general gastroenterologists 72 % (95 %CI;57 – 83) vs 78 % (95 %CI;63 – 89) for experts and 75 % (95 %CI;60 – 85) for gastrointestinal fellows. Conclusions: In this image-based study, both sensitivity for the optical diagnosis of a T1 cancer and NPV for excluding a T1 cancer were insufficient. Experts performed best with a sensitivity of 67 % and a NPV of 78 %, while the performance of fellows in the last year of training was comparable to that of experts. Our study indicates that training for endoscopic diagnosis for T1 cancers is urgently needed to ensure optimal clinical practice for treatment of these lesions.

The accuracy of polyp assessment during colonoscopy in FIT-screening is not acceptable on a routine basis

Background: During colonoscopy, correct assessment of polyps is important. Recognition of early carcinomas is needed for tailor-made treatment and avoidance of unnecessary complications. Moreover, accurate diagnosis of diminutive lesions could result in a safe resect and discard strategy. We assessed the accuracy of polyp assessment by general endoscopists without specific training or experience in image-enhanced endoscopy during routine colonoscopies within a fecal immunochemical test (FIT)-based screening program. Methods: Data were collected in the third round of a FIT-based colorectal cancer screening pilot program. Patients diagnosed as FIT-positive (318) underwent colonoscopy using Olympus (160 and 180 series) endoscopes without magnification or routine use of (virtual) chromoendoscopy. Endoscopists received no special training. They made an on-site evaluation and classified detected polyps as hyperplastic, adenoma, carcinoma. Samples of resected lesions were sent for histopathology. Sensitivity and specificity were calculated. We differentiated for fellows and consultants. Results: In the 318 patients with a positive FIT-screening result, 683 lesions were detected; 564 lesions were included in the analyses. The pathologist classified these lesions as 141 hyperplastic polyps, 349 adenomas, 16 carcinomas, and 58 other. Sensitivity for diagnosis of adenomas was 88 % (95 %CI 84 – 91); specificity 49 % (95 %CI 42 – 55). Of the 16 colorectal carcinomas, endoscopists diagnosed four incorrectly (sensitivity 75 % [95 %CI 44 – 89]; specificity 99 % [95 %CI 98 – 100]), including three stage I cancers and one stage III cancer. There were no differences in accuracy of diagnosis that related to different sizes of lesions or the experience of the endoscopist. Conclusion: In a routine FIT-based screening setting and without specific training or routine use of (digital) chromoendoscopy, endoscopic prediction of the histopathology of colonic lesions is inaccurate when the procedure is performed by general endoscopists.

Mo1184 Changes in FIT result Are More Predictive Than Absolute FIT Values in Colorectal Cancer Screening

routine service, the establishment of more accessible screening infrastructure to screening participants, and educational initiatives on the details and safety of the screening tests are therefore needed. Since the screening participants who have the associated factors identified in this study were more likely to encounter psychological obstacles of CRC screening, they should receive more thorough explanation of the nature of screening tests.

Mo1187 Can Endoscopists Correctly Predict Polyp Histopathology in FIT Based Screening

G A A b st ra ct s 16), were 3.7 for CRCs (95%CI= 2.8 to 4.6, p ,.0001 vs. SNADs), 2.3 for CAs (95%CI= 1.7 to 3.0, p,.0001 vs. SNADs), 1.3 for LPGDs (95%CI= 0.8 to 1.8, p=.0001 vs. SNADs), and 0.3 for SNADs (95%CI= 0.2 to 0.5), respectively. Conclusion: Fecal DNA methylation strategy can robustly detect a variety of gastrointestinal tumors, including pancreatic cancers. Our improved fecal DNA methylation assay provides an effective and promising tool for the non-invasive screening of not only for CRC but also for LPGDs, highlighting its tremendous clinical utility in reducing the mortality and morbidity associated with these malignancies.