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Chrysarobin

A diagnostic device measuring syndecan 2(SDC2) methylation status in stool DNA to detect colorectal cancer

Stool-based SDC2 DNA methylation test

A diagnostic device using immunoturbidimetric methods to measure fecal hemoglobin concentration

quantitative Fecal immunochemical test

Zhaoshen Li, MD

to determine screening value of stool-based SDC2 DNA methylation test for advanced colorectal neoplasia in the asymptomatic Chinese community population.

In China, colorectal cancer (CRC) remains to be the leading cancer of the digestive system. According to nationwide cancer statistics using population-based cancer registry data in China, age-standardized incidence rate of CRC and age-standardized mortality rate increased significantly from 2000 to 2015. It induces a substantial financial burden in terms of healthcare utilization and quality-adjusted life years (QALY) lost. Fecal Occult Blood Tests (FOBT) and colonoscopy have been proposed as the main primary screening modalities for asymptomatic subjects by international guidelines and Asia Pacific Consensus Statements. Nevertheless, shortage and uneven distribution of colonoscopy resources combined with huge population base consisted of the current situation in China. Previous population-based CRC screening programs usually employed questionnaires and/or FOBT to assess high-risk groups and recommended colonoscopy. This algorithm faced difficulties such as complex traditional questionnaires, low colonoscopy adherence, and a high false-positive rate. When the Coronavirus disease 2019 pandemic further limited the implementation of colonoscopy, the contradictions developed more acute.

A Hong Kong group had designed and validated a colorectal cancer risk scoring system based on age, gender, smoking history, and family history through the results of screening in 11 Asia-Pacific cities. The Asia-Pacific Colorectal Screening (APCS) score was more concise and divided the population into three categories: low risk, intermediate risk, and high risk. Compared with the low-risk population, the probability of advanced colorectal neoplasia in intermediate-risk and high-risk population increased by 2.6 times and 4.3 times respectively. Because of simplicity and efficiency, it was recommended by Asia-Pacific screening guidelines and several guidelines in China. Another APCS related multi-center study indicated that by selecting high-risk subjects and low/average-risk subjects with a positive fecal immunochemical test (FIT) for colonoscopy, the colonoscopy workload could be reduced by 50% compared with the strategy of primary colonoscopy in those same subjects. All these experiences deserved to be drawn on during the post-pandemic era.

The recent decade has witnessed a rapid development of non-invasive biomarkers to detect CRC. Stool DNA(sDNA) Testing is a novel screening test for CRC, using molecular techniques to identify CRC-relevant biomarkers in stool. One of its toolkits, Multitarget Stool DNA Testing (FIT-DNA), was first approved by the FDA in 2014 for its application in clinical practice, which has been widely promoted in the United States. Subsequently, it was endorsed by multiple societies as one of the recommended screening tests.

Recently, a stool test of methylated Syndecan-2(SDC2) has been developed as a fecal-DNA product targeted to improve the diagnostic accuracy of CRC screening. A meta-analysis of previous clinical studies reporting the accuracy of stool DNA methylation tests in detecting CRC included 46 studies totaling 16,149 patients. The most accurate single gene was found to be SDC2 with a pooled sensitivity of 83.1% (72.6%, 90.2%) and a specificity of 91.2% (88.6%, 93.2%). A recent study involving 1,110 subjects from 2017 to 2018 by three Chinese tertiary hospitals assessed the performance of the SDC2 sDNA test. The sensitivity of the SDC2 sDNA test was 301/359 (83.8%) for CRC, 16/38 (42.1%) for advanced adenomas, and 134/154 (87.0%) for early-stage CRC (stage I-II), while maintaining a specificity of 699/713 (98.0%). Nevertheless, there were limitations in the design of these original studies. For instance, most involved small, hospital-based CRC cases and controls that might not fill the knowledge gap between population screening. Additional clinical trials are required to further validate its diagnostic accuracy in other populations, especially community-setting.

Potential participates would be recruited via community public communication. The subjects would be asked to fill in a concise questionnaire obtained through a public WeChat account after informed consent. Basic information would be acquired while APCS score and correspondent risk categories would be calculated automatically. After sampling education, stool collection devices of sDNA and quantitative fecal immunochemical test (qFIT) would be distributed to all subjects. Two samples of stool from single defecation would be requested to put into the two collection devices according to instructions respectively by the subjects themselves at home.

Efforts would be made by the public WeChat account and the community staff to urge samples recover from subjects as quickly as possible (prefer within 24h after defecation). Community staff would deliver the samples qualified in the initial evaluation to the standardized laboratory for testing as quickly as possible. If APCS be evaluated high-risk or any of qFIT or sDNA tests positive, the risk of the subject would be considered increased. Colonoscopy would be strongly recommended, and priority and rapid arrangement would be made in the corresponding center. For subjects with low/intermediate-risk APCS and negative qFIT and sDNA, the project team also encourages the subjects to accept colonoscopy on the basis of a clear understanding of benefits and risks. We would help to arrange colonoscopy as early as possible.

All colonoscopy examinations will be performed by experienced endoscopists while monitoring quality of colonoscopy (bowel preparation, cecal intubation rate and withdrawal time). Full-time recording personnel would be arranged to follow up and record the relevant information of colonoscopy. For the subjects diagnosed with colorectal cancer, the postoperative diagnosis and tumor-node-metastasis (TNM) staging of the subjects would be retrieved.

A Stool DNA Test for Detection of Advanced Colorectal Neoplasia in Asymptomatic Chinese Community Population

Detection of Advanced Colorectal Neoplasia for Stool DNA in Asymptomatic Chinese Population : A Multi-central Community-based Screening Study

Advanced colorectal neoplasia is defined as a colorectal adenoma or sessile serrated lesion ≥10 mm, adenoma or sessile serrated lesion with tubulovillous or villous histology, adenoma with high-grade dysplasia, traditional serrated adenoma, or presence of colorectal cancer.

The compliance rate of colonoscopy was calculated as the number of recieving colonoscopy divdied the number of accomplishing primary evaluation of APCS, stool DNA or FIT.

Lesions will be confirmed as malignant by histopathologic examination.

Advanced colorectal neoplasia is defined as a colorectal adenoma or sessile serrated lesion, traditional serrated adenoma, hyperplastic polyp ≥10 mm, or colorectal cancer.

Lesions will be confirmed as malignant or precancerous by histopathologic examination.

High-risk subgroup: APCS calculated high-risk or qFIT positive. A diagnostic colonoscopy procedure is the reference method. Lesions will be confirmed as malignant or precancerous by histopathologic examination.

Low-risk subgroup: APCS calculated low or medium risk, and qFIT negative. A diagnostic colonoscopy procedure is the reference method. Lesions will be confirmed as malignant or precancerous by histopathologic examination.

Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Gongli Hospital of Shanghai Pudong New Area

Shanghai Songjiang District Central Hospital

Shanghai Jing'an District Central Hospital

Shanghai Yangpu District Central Hospital

People's Hospital of Qingyuan

Guangdong Provincial Hospital of Traditional Chinese Medicine

900 Hospital of the Joint Logistics Team

First Affiliated Hospital of Suzhou Medical College

Affiliated Hospital of Jiangnan University

Traditional Chinese Medicine Hosipital of Kunshan

Ankang Central Hospital

Shandong Cancer Hospital and Institute

Ningjin County Hospital

Changhai Hospital

MD,Director, Head of Department of Gastroenterology and Digestive Endoscopy Center, Principal Investigator, Clinical Professor

Colonoscopy performed with Endocuff for mucosal inspection and interventions (eg. polypectomy).

Endocuff colonoscopy

control

Colorectal cancer (CRC) is a leading cause of morbidity and mortality worldwide, especially in Western countries. CRC is currently considered a preventable disease and screening has been endorsed by several societies, since it has been shown that screening and surveillance are effective in reducing both CRC incidence and mortality. However, recently, concern has risen regarding colonoscopy effectiveness, especially in the right colon. The most accepted explanation for this effectiveness variability is attributed to sessile serrated lesions (SSL), which are more frequent in the proximal colon, more difficult to detect because of their flat morphology and associated with interval CRC, which is the occurrence of CRC after screening colonoscopy and before the next scheduled procedure. Several techniques are emerging to increase the sensitivity of colonoscopy for pre-cancerous lesions, especially adenomas. Recently an endoscopic cap, the Endocuff, was developed to improve adenoma detection. Several studies demonstrated improved adenoma detection with Endocuff-assisted colonoscopy when compared with conventional colonoscopy. Still, the available data for its' role in detecting SSL is very limited. The aim of this randomized controlled trial is to evaluate the effectiveness of Endocuff-assisted colonoscopy in detection of colorectal SSL.

Serrated Lesions Detection With Endocuff-assisted Colonoscopy

Serrated Lesions Detection With Endocuff-assisted Colonoscopy - A Randomized Controlled Trial

Average number of serrated lesions ≥ 10 mm detected per colonoscopy

Number of patients with at least one serrated lesion/total number of participants

Average number of serrated lesions \< 10 mm detected per colonoscopy

Average number of adenomas detected per colonoscopy

Number of patients with at least one adenoma/total number of participants

Number of patients with at least one adenocarcinoma/total number of participants

Proportion of colonoscopies with cecal intubation x100

time from the cecum to the rectum in minutes

Hospital Beatriz Ângelo

Symptoms and General Pathology

Polyps

Herbal and Botanical

Cola

Participants will be evaluated by same endoscopist, back-to-back tandem colonoscopy. It consists of two withdrawal from the cecum to sigmoid colon using firstly High Definition White Light Endoscopy (WLE) and secondly Narrow Band Imaging (NBI). All detected polyps will be classified macroscopically and resected in each withdrawal.

Participants will be evaluated by same endoscopist, back-to-back tandem colonoscopy. It consists of two withdrawal from the cecum to sigmoid colon using firstly Narrow Band Imaging (NBI) and secondly High Definition White Light Endoscopy (WLE). All detected polyps will be classified macroscopically and resected in each withdrawal.

Withdrawal from cecum to sigmoid colon with Narrow Band Imaging (NBI, Evis Exera III, Olympus)

Withdrawal from cecum to sigmoid colon with High Definition White Light Endoscopy (WLE)

Fausto Riu, MD

This study is designed to evaluate the utility of Narrow Band Imaging (NBI) compared with High Definition White Light colonoscopy (WLE) in subjects with serrated lesions who do not fulfill the diagnostic criteria of Serrated Polyposis Syndrome (SPS).

Colorectal cancer (CRC) is the second leading cause of cancer death in western countries. Conventional polyps were considered the precursor lesions of all cases of sporadic colon cancer. Recently, serrated lesions and especially the Sessile Serrated Adenoma (SSA), are responsible of interval CRC between 20% to 35% of all CRC cases. These polyps are difficult to identify at endoscopy because they are located in the right colon, they are sessile or flat morphology and are pale color with mucus capping.

According to the WHO, SPS is defined with one of the following criteria: (1) at least 5 serrated polyps proximal to the sigmoid colon, 2 of which are greater than 10 mm in diameter; (2) any number of serrated polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis; or (3) more than 20 serrated polyps of any size distributed throughout the colon. Therefore, patients with SPS are considered to be at increased risk of CRC. Considering the substantial risk of polyp recurrence, it is mandatory to follow up an annual surveillance.

Narrow-Band Imaging (NBI, Olympus) selectively uses certain wavelengths of the visible light leading to a shift in the excitation spectrum towards blue light. Blood vessels will appear dark, allowing an improved visibility and identification of the surface and vascular structures. In contrast to conventional chromoendoscopy, it is easily activated by pressing a button on the endoscope. A pilot study in patients with SPS showed significantly lower polyp miss rate with NBI compared with WLE. Furthermore, the European Society of Gastrointestinal Endoscopy (ESGE) has recently published the first Guideline of Advanced Endoscopic Imaging for the detection and differentiation of colorectal neoplasia and recommends conventional chromoendoscopy or NBI in patients with SPS (strong recommendation, low quality evidence).

The hypothesis is that NBI could improve the detection rate of serrated polyps compared with WLE in patients who do not accomplish the SPS criteria.

The investigators will perform a randomised, cross-over trial of tandem colonoscopy using NBI and WLE. The main goal is to compare the rate of detected polyps between both techniques and, if it is necessary, reassessing the diagnosis for an appropriate surveillance interval.

Study of Narrow Band Imaging in the Characterization of Serrated Lesions

Randomised Tandem Colonoscopy of Narrow Band Imaging (NBI) and White Light Endoscopy in Patients With Serrated Lesions

Efficacy of NBI in detecting serrated polyps compared with WLE

Compare the number of missed lesions on the index examination based on the colonoscopy findings (NBI and WLE)

Accuracy in detecting adenomas endoscopically compared with histopathology (gold standard)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Stool DNA Test for Detection of Advanced Colorectal Neoplasia in Asymptomatic Chinese Community Population	NCT04786704	Colorectal Canc... Colorectal Neop... Advanced Adenom... Adenoma Serrated Lesion	Stool-based SDC... quantitative Fe...	45 Years - 75 Years	Changhai Hospital
Serrated Lesions Detection With Endocuff-assisted Colonoscopy	NCT03856957	Serrated Lesion Adenoma Colorectal Canc...	Endocuff colono... control	40 Years - 80 Years	Hospital Beatriz Ângelo
A Stool DNA Test for Detection of Advanced Colorectal Neoplasia in Asymptomatic Chinese Community Population	NCT04786704	Colorectal Canc... Colorectal Neop... Advanced Adenom... Adenoma Serrated Lesion	Stool-based SDC... quantitative Fe...	45 Years - 75 Years	Changhai Hospital
Study of Narrow Band Imaging in the Characterization of Serrated Lesions	NCT02406547	Serrated Polyps Sessile Serrate... Colorectal Neop...	NBI WLE	50 Years -	Parc de Salut Mar

Spots Global Cancer Trial Database for serrated lesion