Symptoms and General Pathology

All Conditions

Neoplasms

Polyps

Adenomatous Polyps

Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

blood or stool samples will be collected from people referred for screening colonoscopy

blood or stool samples will be collected from people with colorectal cancer detected at colonoscopy or resection

blood or stool samples will be collected from people with no polyps or low risk polyps (\<10mm, no villous component or dysplasia) detected at colonoscopy

blood or stool samples will be collected from people with AMN detected at resection

blood or stool samples will be collected from people with SSP detected at resection

Participants with disease that is not colorectal neoplasia. Analysis of this cohort is not a primary endpoint but the investigators will report assay positivity in this group on an opportunistic basis. This cohort will include patients diagnosed with, for example, inflammatory bowel disease or extracolonic cancer.

blood or stool samples will be collected

Michael J Bourke, MBBS FRACP

The purpose of this study is to determine the clinical utility of stool and blood methylation tests for detection of advanced mucosal neoplasia (AMN) and sessile serrated polyps (SSP).

By not only diagnosing colorectal cancer (CRC) at an early stage, but also removing precursor lesions (adenomas), colonoscopy with polypectomy reduces the risk of developing and dying from CRC. Approximately 90% of polyps are less than 10 mm and are easily removed by competent endoscopists. Laterally spreading lesions (LST) and sessile lesions of the colon, also known as advanced mucosal neoplasia (AMN) are underrecognised types of lesions that are more likely to progress to cancer. They include sessile serrated polyps (SSP), an emerging entity of flat polyps with malignant potential. Detection of hemoglobin (a component of blood) in stool is an established validated screening tool for CRC. Its specific role in the prediction of AMN, and particularly SSPs is yet to be defined. Blood tests measuring the level of tumour derived methylated deoxyribonucleic acid (DNA) in blood circulating have been demonstrated to have clinical utility for detection of CRC and AMN. A blood based CRC screening test has the potential to increase compliance. This study aims to determine the clinical utility of stool and blood methylation tests for detection of AMN and SSPs. Stool and blood will be obtained from consenting patients referred for endoscopic removal of known ANM and SSP (study arm) as well as from consenting patients scheduled for colonoscopy screening (control arm). The level of stool hemoglobin and methylated tumour derived DNA in circulation will be measured in the two study groups. Cutoff values will be generated to assess best predictive capability of high risk lesions based on these tests.

2mg of stool per patient 18mL of blood per patient

Non-invasive Risk Stratification of CR AMN/SSP

Evaluation of Stool and Blood Based Tests for Colorectal Advanced Mucosal Neoplasia

Data to adequately describe demographic situations of each participant.

The process will use an automated extraction procedure incorporating state-of-the-art magnetic silica-coated beads on a QIASymphony (Qiagen). The extracted DNA is bisulphite-converted and further purified (automated on a QIACube HT liquid handler) prior to analyzing 12uL of bis-DNA in a multi-plexed (BCAT1, IKZF1, ACTB (control assay)) real-time PCR for measuring the methylation levels of target amplicons.

Suspended stool collected in the HM-JACKarc sampling device will be processed for Hb measurements using commercially available reagents and the bench-top analyser instrument, HM-JACKarc, according to manufacturer recommendation (Kyowa Medex Co Ltd, Japan). Measured haemoglobin concentrations will be reported as ug Hb/g stool. A 20 ug Hb/g stool a cut-off concentration will be used for qualitative reporting.

Data to adequately decribe the clinical situations of each participant.

Professor Michael Bourke

Director of Gastrointestinal Endoscopy

Standard colonoscopy: All optically diagnosed polyps will be removed and sent to the CHUM pathology laboratory for histopathological evaluation according to institutional standards.

Standard Colonoscopy

Daniel von Renteln, MD, PhD

Julie Fleury

Daniel Von Renteln, MD

Roupen Djinbachian, MD

Daniel von Renteln, Md

During colonoscopy, the endoscopist will document colonoscopy indication; BBPS score; withdrawal time; adenoma and polyp detection rate at index and follow-up colonoscopy; completeness of polypectomy; polyp location, size, surface, morphology (Paris classification), histopathology; complications.

Colorectal cancer (CRC) ranks second among worldwide cancer related deaths and third in terms of cancer incidence. Colonoscopy-based screening programs have been established to reduce CRC morbidity and mortality. Multiple guidelines have established surveillance recommendations for repeat colonoscopies based on findings at index colonoscopy. Serrated lesions (SLs), including sessile serrated polyps/adenomas (SSP) and traditional serrated adenomas (TSA) have become of increased interest for their role as precursors of CRC. The optimal timing of follow-up colonoscopies after detection of SLs has been controversial as studies looking into optimal surveillance timing are lacking. The US Multi Society Task Force (USMSTF) 2020 guidelines recommend 5-10y surveillance intervals for detection of 1-2 SSPs, 3-5y for 3-4 SSPs, 3y for \>4 SSPs or TSA. In contrast, the 2020 European Society of Gastrointestinal Endoscopy (ESGE) Guidelines state that 1-10mm SLs do not require follow-up. It is unclear what the appropriate surveillance intervals is for patients with SLs which is evidenced by diverging recommendations from USMSTF/ESGE. High-grade dysplasia (HGD) is an exceedingly rare finding in colorectal polyps. The current literature on the yield of colonoscopy after index HGD is sparse, with conflicting data on risk of metachronous HRA due to low numbers of included HGD leading to high variability in reported outcomes.

The primary aim of this study is to determine the rate of metachronous advanced neoplasia (TMAN) detection after index detection of serrated lesions \[sessile serrated polyps (SSPs), traditional serrated adenomas (TSAs)\], and metachronous high-risk adenoma (HRA) after index detection of high-grade dysplasia (HGD).

Patient with SL or HGD diagnosed from 2010-2022 with lack of follow-up will be contacted by phone, then invited to undergo follow-up colonoscopy. Data collected will include patient age; sex; ASA class; past medical history; family history of CRC; procedure date; name of endoscopist; colonoscopy indication; BBPS score; withdrawal time; adenoma and polyp detection rate at index and follow-up colonoscopy; completeness of polypectomy; polyp location, size, surface, morphology (Paris classification), histopathology; complications, immediate and late (14 days).

We expect a higher percentage of high-risk lesions in our study group compared to our retrospective findings due to follow-up delays. As there is no published literature on the subject, our assumptions will be relative to our retrospective cohort. Assuming 60% participation in our study (patients deceased, unable to be contacted, received follow-up elsewhere, do not fit inclusion criteria), we expect 362 out of 603 patients to be enrolled in the SL group and 75 out of 124 in the HGD group. Assuming a 35% high-risk lesion (T-MAN) detection in the SL group compared to 22.1% detected retrospectively, we expect to include 127 cases of T-MAN. Assuming a 40% high-risk lesion (metachronous HRA) detection in the HGD group compared to 23.8% detected retrospectively \[given the longer surveillance delays for these patients (7y) with 1% already with CRC at 1.8y median follow-up\] we expect to include 30 cases of metachronous HRA. To perform univariate regression, we require inclusion of 10 patients with T-MAN in the SL group (minimum sample size: 29) and 10 patients with metachronous HRA in the HGD group (minimum sample size: 25). To perform our multivariate analyses, we require inclusion of 30 patients with T-MAN in the SL group (minimum sample size: 86) and 30 patients with metachronous HRA in the HGD group (minimum sample size: 75). Descriptive analysis with presentation of crude numbers, proportions, or medians with interquartile range will be used to present patient, procedure, and polyp outcomes. The rate of T-MAN in the SL group and metachronous HRA in the HGD group will be reported as proportions with exact 95% confidence intervals (CI). Primary outcomes will be illustrated using Kaplan Meier survival analyses for each group. We will perform COX proportional hazards regression to determine the effects of polyp size, location, and synchronous polyp status (no adenoma, LRA, or HRA) on risk of T-MAN, and effects of polyp size and location on risk of metachronous HRA for the SL and HGD groups respectively. Comparisons will be presented as Hazard ratios (HR) with 95% CI. We will perform multivariate COX regression to determine the effects of confounders on development of T-MAN or metachronous HRA. Our model will be adjusted family history of CRC and smoking status. Further confounders such as age, sex, and aspirin use will be evaluated in sensitivity analyses for possible inclusion in the multivariate analysis. The effect of duration of surveillance delays on risk of T-MAN or metachronous HRA will be evaluated using logistic regression. A two-tailed p\<0.05 will be considered statistically significant for all analyses.

prospective, multi-endoscopist, single center, single group assignment

Effect of Serrated Polyps and High-grade Dysplasia at Index Colonoscopy on Risk of Metachronous High-risk Adenomas

the rate of total metachronous advanced neoplasia (TMAN) detection after index detection of serrated lesions \[sessile serrated polyps (SSPs), traditional serrated adenomas (TSAs)\]

the rate of metachronous high-risk adenoma (HRA) after index detection of high-grade dysplasia (HGD)

The rate of T-MAN detection for concomitant index SSP+low-risk adenoma (LRA); index SSP+ high-risk adenoma (HRA); index SSP alone

The rate of T-MAN detection according to number, size, location, and dysplasia status of index SSPs

The rate of metachronous HRA detection for index HGD alone

The rate of metachronous HRA detection for index HGD according to number, size, location, of index HGD

The rate of metachronous high-risk serrated lesion (SL) for concomitant index SSP+LRA; index SSP+HRA; index SSP alone; index SSP all synchronous findings included; index TSA all synchronous findings included

The rate of metachronous high-risk SL detection according to number, size, location, and dysplasia status of index SSPs

The rate of metachronous HRA for concomitant index SSP+LRA; index SSP+HRA; index SSP alone; index SSP all synchronous findings included; index TSA all synchronous findings included

The rate of metachronous HRA detection according to number, size, location, and dysplasia status of index SSPs

The rate of T-MAN and metachronous HRA detection for the serrated lesion (SL) and HGD groups stratified by number of years of surveillance delay

The rate of metachronous advanced SL and metachronous HRA detection for the serrated lesion (SL) group stratified by number of years of delay at time of endoscopy from surveillance intervals recommended by guidelines

Adenoma detection rates (ADR) and advanced adenoma detection rates at follow-up stratified by number of years of delay at time of endoscopy from surveillance intervals recommended by guidelines

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Non-invasive Risk Stratification of CR AMN/SSP	NCT02476682	Adenomatous Pol...	blood or stool ...	18 Years -	Western Sydney Local Health District
Effect of Serrated Polyps and High-grade Dysplasia at Index Colonoscopy on Risk of Metachronous High-risk Adenomas	NCT05355363	Colorectal Canc... Colon Adenoma	Standard Colono...	45 Years - 80 Years	Centre hospitalier de l'Université de Montréal (CHUM)
Effect of Serrated Polyps and High-grade Dysplasia at Index Colonoscopy on Risk of Metachronous High-risk Adenomas	NCT05355363	Colorectal Canc... Colon Adenoma	Standard Colono...	45 Years - 80 Years	Centre hospitalier de l'Université de Montréal (CHUM)

Spots Global Cancer Trial Database for sessile serrated polyps