Exploring Stakeholders' Perspectives on Implementing Universal Germline Testing for Colorectal Cancer: Findings From a Clinical Practice Survey.

PURPOSE: New guidelines recommend considering germline genetic testing for all patients with colorectal cancer (CRC). However, there is a lack of data on stakeholders' perspectives on the advantages and barriers of implementing universal germline testing (UGT). This study assessed the perspectives of members of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) regarding the implementation of UGT for patients with CRC, including readiness, logistics, and barriers. METHODS: A cross-sectional survey was sent to 317 active members of CGA-IGC. The survey included sections on demographics, clinical practice specialty, established institutional practices for testing, and questions pertaining to support of and barriers to implementing UGT for patients with CRC. RESULTS: Eighty CGA-IGC members (25%) participated, including 42 genetic counselors (53%) and 14 gastroenterologists (18%). Forty-seven (59%) reported an academic medical center as their primary work setting, and most participants (56%) had more than 10 years of clinical practice. Although most participants (73%) supported UGT, 54% indicated that changes in practice would be required before adopting UGT, and 39% indicated that these changes would be challenging to implement. There was support for both genetics and nongenetics providers to order genetic testing, and a majority (57%) supported a standardized multigene panel rather than a customized gene panel. Key barriers to UGT implementation included limited genetics knowledge among nongenetics providers, time-consuming processes for obtaining consent, ordering tests, disclosing results, and lack of insurance coverage. CONCLUSION: This study demonstrates wide support among hereditary GI cancer experts for implementation of UGT for patients with CRC. However, alternative service delivery models using nongenetics providers should be considered to address the logistical barriers to UGT implementation, particularly the growing demand for genetic testing.

An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.

OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. CONCLUSION: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.

Current chemoprevention approaches in Lynch syndrome and Familial adenomatous polyposis: a global clinical practice survey.

Background: International chemoprevention preferences and approaches in Lynch syndrome (LS) and APC-associated polyposis, including Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) have not been previously explored. Aim: To describe current chemoprevention strategies for patients with LS or FAP/AFAP (referred to collectively as FAP) practiced by members of four international hereditary cancer societies through administration of a survey. Results: Ninety-six participants across four hereditary gastrointestinal cancer societies responded to the survey. Most respondents (91%, 87/96) completed information regarding their demographics and practice characteristics relating to hereditary gastrointestinal cancer and chemoprevention clinical practices. Sixty-nine percent (60/87) of respondents offer chemoprevention for FAP and/or LS as a part of their practice. Of the 75% (72/96) of survey respondents who were eligible to answer practice-based clinical vignettes based off of their responses to ten barrier questions regarding chemoprevention, 88% (63/72) of those participants completed at least one case vignette question to further characterize chemoprevention practices in FAP and/or LS. In FAP, 51% (32/63) would offer chemoprevention for rectal polyposis, with sulindac - 300 mg (18%, 10/56) and aspirin (16%, 9/56) being the most frequently selected options. In LS, 93% (55/59) of professionals discuss chemoprevention and 59% (35/59) frequently recommend chemoprevention. Close to half of the respondents (47%, 26/55) would recommend beginning aspirin at time of commencement of the patient's first screening colonoscopy (usually at age 25yrs). Ninety-four percent (47/50) of respondents would consider a patient's diagnosis of LS as an influential factor for aspirin use. There was no consensus on the dose of aspirin (≤100 mg, >100 mg - 325 mg or 600 mg) to offer patients with LS and there was no agreement on how other factors, such as BMI, hypertension, family history of colorectal cancer, and family history of heart disease, would affect the recommendation for aspirin use. Possible harm among older patients (>70 years) was identified as the most common reason to discourage aspirin use. Conclusion: Although chemoprevention is widely discussed and offered to patients with FAP and LS by an international group of hereditary gastrointestinal cancer experts, there is significant heterogeneity in how it is applied in clinical practice.

Impact of Cold Snare vs Cold Forceps Resection of Diminutive Adenomas on Segmental Incomplete Resection Rate.

INTRODUCTION: Polypectomy technique, for diminutive lesion resection, is variable among colonoscopists using either cold snare polypectomy (CSP) or cold forceps polypectomy (CFP). While it is well described that CSP is a preferred technique to resect small lesions, there is little data evaluating the impact resection techniques have on metachronous adenoma burden. The aim of this study was to evaluate the rate of incomplete resection attributable to CSP and CFP of diminutive adenomas. METHODS: This is a 2-center retrospective cohort study evaluating the segmental incomplete resection rate (S-IRR) of diminutive tubular adenomas (TA). S-IRR was calculated by subtracting the segmental metachronous adenoma rate in a specific colonic segment without adenoma from segments with adenoma on index colonoscopy. The primary outcome was the S-IRR of diminutive TA resected by CSP or CFP on index colonoscopy. RESULTS: A total of 1,504 patients were included in the analysis: 1,235 with TA <6 mm and 269 with TA 6-9 mm as the most advanced lesion. The S-IRR in a segment that had a <6-mm TA incompletely resected by CFP on index colonoscopy was 13%. The S-IRR in a segment that had a <6-mm TA incompletely resected by CSP was 0%. Among 12 included colonoscopists, the range of overall S-IRR was 1.1%-24.4% with an average S-IRR of 10.3%. DISCUSSION: S-IRR was 13% higher with CFP resection of diminutive TA than with CSP. A proposed S-IRR metric of <5% is a target goal for all diminutive polyp resection because 3/12 colonoscopists achieved this low rate. S-IRR can be used as a methodology to compare and quantify the difference in segmental metachronous adenoma burden across various polypectomy removal methods.

DNA methylation and miRNA expression in colon adenomas compared with matched normal colon mucosa and carcinomas.

Dysregulation of DNA methylation patterns and non-coding RNA, including miRNAs, has been implicated in colon cancer, and these changes may occur early in the development of carcinoma. In this study, the role of epigenetics as early changes in colon tumorigenesis was examined through paired sample analysis of patient-matched normal, adenoma and carcinoma samples. Global methylation was assessed by genomic 5-methyl cytosine (5-mC) and long interspersed nuclear element-1 (LINE-1) promoter methylation by pyrosequencing. KRAS mutations were also assessed by pyrosequencing. Expression of miRNA, specifically, two microRNA genes-miR-200a and let-7c-was analysed using RT-qPCR. Differences in global methylation in adenomas were not observed, compared with normal tissue. However, LINE-1 methylation was decreased in adenomas (p = .056) and carcinomas (p = .011) compared with normal tissue. Expressions of miRNA, miR-200a and let-7c were significantly higher in adenomas than normal tissues (p = .008 and p = .045 respectively). Thus the significant changes in LINE-1 methylation and microRNA expression in precancerous lesions support an early role for epigenetic changes in the carcinogenic process. Epigenetic characteristics in adenomas may provide potential diagnostic and prognostic therapeutic targets early in cancer development at the adenoma stage.

Risk of total metachronous advanced neoplasia in patients with both small tubular adenomas and serrated polyps.

BACKGROUND AND AIMS: The impact of concomitant small serrated polyps (SPs) on the risk of subsequent neoplasia when small tubular adenomas (TAs) are found is uncertain. METHODS: Patients who on index colonoscopy had ≤2 TAs of <10 mm in size in isolation were compared with those with concomitant ≤2 small-sized SPs. SP was inclusive of polyps described by pathology as sessile serrated lesions (SSLs) or proximal hyperplastic polyps (HPs) <10 mm in size. The primary endpoint was the rate of total metachronous advanced neoplasia (T-MAN) compared among the TAs in the isolation group and the groups inclusive of SPs (SSLs or proximal HPs). RESULTS: For patients with TAs and small SPs found concomitantly, the rate of T-MAN was 9.6% (24/251), which was significantly higher than the rate of T-MAN in patients with isolated small TAs (5.2% [59/1138], P = .011). Within the concomitant SP cohort, the rate of T-MAN in the proximal HP subgroup remained significantly increased (9% [19/212]) compared with the isolated small TA group (P = .037). CONCLUSIONS: When small TAs are found concomitantly with small SPs, there is an increase in the rate of T-MAN in comparison with isolated TAs. This increase in T-MAN also occurs when small TAs are found in conjunction with small proximal HPs. The presence of concomitant small SPs should be considered in determining surveillance intervals when small TAs are identified in colonoscopy screening programs.

Endoscopic polypectomy devices.

Video 1Use of submucosal injection prior to en-bloc endoscopic mucosal resection.Video 2Use of a detachable loop ligating device prior to hot snare resection of a pedunculated polyp.

Correlation of LINE-1 Hypomethylation With Size and Pathologic Extent of Dysplasia in Colorectal Tubular Adenomas.

INTRODUCTION: Conventional adenomas (tubular adenoma [TA] or tubulovillous adenoma) and sessile serrated lesions (SSLs) are neoplastic precancerous lesions frequently detected in patients undergoing average risk screening colonoscopy and polyp surveillance. Metachronous risk stratification of adenomas is currently limited to histologic features and size of polyps. We report long interspersed nucleotide element-1 (LINE-1) methylation levels in SSL in comparison to TA and the impact of TA size and presence of high-grade dysplasia (HGD) on LINE-1 methylation. METHODS: LINE-1 methylation was assessed by pyrosequencing of bisulfite-converted DNA. We compared LINE-1 methylation between TA and SSL, among varying sizes of TA, and between TA with HGD and low-grade dysplasia (LGD). RESULTS: LINE-1 methylation declined with increasing polyp size in TA when comparing those <5 mm (72.31 ± 6.11), 5 to <10 mm (67.50 ± 7.00), and ≥10 mm (66.75 ± 11.89). There were lower LINE-1 methylation levels in TA with LGD (n = 119) compared with SSLs (n = 29) (69.11 ± 8.62 vs 81.41 ± 2.43, P < 0.001). TA containing HGD (n = 26) had lower LINE-1 methylation levels than those with LGD (n = 119) (59.86 ± 7.93 vs 69.11 ± 8.62, P < 0.001). DISCUSSION: HGD and increasing size of TA/tubulovillous adenoma were associated with lower LINE-1 methylation. This supports a hypothesis that LINE-1 hypomethylation in TAs indicates advancement along the CRC tumorigenesis pathway. Lower LINE-1 methylation and greater variance of global DNA methylation was seen in TA compared with SSL. LINE-1 methylation in adenomas correlates with polyp size and degree of dysplasia and deserves further study as a predictor of metachronous colorectal cancer risk.

Devices and techniques for flexible endoscopic management of Zenker's diverticulum (with videos).

BACKGROUND AND AIMS: Zenker's diverticulum (ZD) has traditionally been treated with open surgery or rigid endoscopy. With the advances in endoscopy, alternative flexible endoscopic treatments have been developed. METHODS: This document reviews current endoscopic techniques and devices used to treat ZD. RESULTS: The endoscopic techniques may be categorized as the traditional flexible endoscopic septal division and the more recent submucosal tunneling endoscopic septum division, also known as peroral endoscopic myotomy for ZD. This document also addresses clinical outcomes, safety, and financial considerations. CONCLUSIONS: Flexible endoscopic approaches treat symptomatic ZD with results that are favorable compared with traditional open surgical or rigid endoscopic alternatives.

Segmental metachronous adenoma rate as a metric for monitoring incomplete resection in a colonoscopy screening program.

BACKGROUND AND AIMS: Polypectomy technique has been shown to vary among colonoscopists, and interval colorectal cancer may result from incomplete resection of an adenoma. Methods to monitor polypectomy quality and the size of polyps resected to monitor have not been well defined. The aim of this study was to compare the rate of metachronous adenoma attributable to incomplete resection in polyps 6 to 9 mm versus polyps 10 to 20 mm. METHODS: The segmental metachronous adenoma rate attributable to incomplete resection (SMAR-IR) was calculated by subtracting the rate of metachronous neoplasia (MN) in segments without adenoma from segments with adenoma. The primary outcome of the study was the SMAR-IR in polyps 6 to 9 mm and 10 to 20 mm found on index colonoscopy. RESULTS: Of 337 patients included in the analysis, 146 patients had a tubular adenoma (TA) 10 to 20 mm in size and 191 patients a TA 6 to 9 mm in size as the most advanced lesion. For cases in which an index 10- to 20-mm TA was resected, the SMAR in segments with adenoma was 21.0% and in segments without adenoma 9.6%, so the SMAR-IR was 11.4% (95% confidence interval, 4.5-18.3). For cases in which an index 6- to 9-mm TA was resected, the SMAR in segments with adenoma was 22.0% and in segments without adenoma 8.8%, so the SMAR-IR was 13.2% (95% confidence interval, 7.2-19.4). Among 6 colonoscopists, the SMAR-IR ranged between 7.0% and 15.5% for polyps 6 to 20 mm. CONCLUSIONS: MN rates in segments with a TA 10-20 mm and a TA 6-9 mm are higher than the MN rates in segments without index neoplasia. Incomplete resection of neoplasia appears to be a significant risk factor for MN in 6- to 9-mm lesions as well as larger ones.

Interobserver reliability of methods to determine complete resection of adenomas in colonoscopy.

BACKGROUND: Forceps margin biopsy and polypectomy specimen margins have both been used to assess for polypectomy resection adequacy. The interobserver reliability of the two methods has not been well described. METHODS: The interpretability of polypectomy specimens for presence of residual neoplasia at the margin was assessed by two blinded pathologists. Next, the concordance of forceps margin biopsy interpretations between three blinded pathologists was evaluated by calculation of interobserver κ. RESULTS: Rates of polypectomy specimen margin interpretability were low: 24/92 (26 %) for pathologist A, 28/92 (30.4 %) for pathologist B. Concordance of forceps margin biopsy interpretations (n = 129) between pathologists was high. Two internal pathologists showed substantial agreement in margin biopsy interpretations (κ 0.779; 95 %CL 0.543, 0.912). The concordance remained strong after biopsies were reviewed by a third, external pathologist (κ 0.829; 95 %CL 0.658, 0.924). There was complete agreement on 123/129 (95.3 %) between all three pathologists for presence of neoplasia. CONCLUSION: The majority of polypectomy specimen margins were uninterpretable by pathologists for presence of residual neoplasia. Forceps margin biopsy shows strong interobserver reliability in adenomatous lesions.

Metachronous Advanced Neoplasia on Surveillance Colonoscopy in Patients With Young- vs Older-onset of Colorectal Cancer.

The incidence of colorectal cancer (CRC) and cancer-related mortality has increased in patients <55 years old.1 Consensus on optimal intervals for post-CRC surveillance colonoscopy in young patients is lacking. The primary endpoint of this study was comparison of rates of metachronous advanced neoplasia (AN) in patients diagnosed with CRC at <50 and 50-75 years. The secondary aim was to evaluate risk factors of metachronous AN.

Enhanced EUS imaging (with videos).

BACKGROUND AND AIMS: EUS remains a primary diagnostic tool for the evaluation of pancreaticobiliary disease. Although EUS combined with FNA or biopsy sampling is highly sensitive for the diagnosis of neoplasia within the pancreaticobiliary tract, limitations exist in specific clinical settings such as chronic pancreatitis. Enhanced EUS imaging technologies aim to aid in the detection and diagnosis of lesions that are commonly evaluated with EUS. METHODS: We reviewed technologies and methods for enhanced imaging during EUS and applications of these methods. Available data regarding efficacy, safety, and financial considerations are summarized. RESULTS: Enhanced EUS imaging methods include elastography and contrast-enhanced EUS (CE-EUS). Both technologies have been best studied in the setting of pancreatic mass lesions. Robust data indicate that neither technology has adequate specificity to serve as a stand-alone test for pancreatic malignancy. However, there may be a role for improving the targeting of sampling and in the evaluation of peritumoral lymph nodes, inflammatory pancreatic masses, and masses with nondiagnostic FNA or fine-needle biopsy sampling. Further, novel applications of these technologies have been reported in the evaluation of liver fibrosis, pancreatic cysts, and angiogenesis within neoplastic lesions. CONCLUSIONS: Elastography and CE-EUS may improve the real-time evaluation of intra- and extraluminal lesions as an adjunct to standard B-mode and Doppler imaging. They are not a replacement for EUS-guided tissue sampling but provide adjunctive diagnostic information in specific clinical situations. The optimal clinical use of these technologies continues to be a focus of ongoing research.

Artificial intelligence in gastrointestinal endoscopy.

BACKGROUND AND AIMS: Artificial intelligence (AI)-based applications have transformed several industries and are widely used in various consumer products and services. In medicine, AI is primarily being used for image classification and natural language processing and has great potential to affect image-based specialties such as radiology, pathology, and gastroenterology (GE). This document reviews the reported applications of AI in GE, focusing on endoscopic image analysis. METHODS: The MEDLINE database was searched through May 2020 for relevant articles by using key words such as machine learning, deep learning, artificial intelligence, computer-aided diagnosis, convolutional neural networks, GI endoscopy, and endoscopic image analysis. References and citations of the retrieved articles were also evaluated to identify pertinent studies. The manuscript was drafted by 2 authors and reviewed in person by members of the American Society for Gastrointestinal Endoscopy Technology Committee and subsequently by the American Society for Gastrointestinal Endoscopy Governing Board. RESULTS: Deep learning techniques such as convolutional neural networks have been used in several areas of GI endoscopy, including colorectal polyp detection and classification, analysis of endoscopic images for diagnosis of Helicobacter pylori infection, detection and depth assessment of early gastric cancer, dysplasia in Barrett's esophagus, and detection of various abnormalities in wireless capsule endoscopy images. CONCLUSIONS: The implementation of AI technologies across multiple GI endoscopic applications has the potential to transform clinical practice favorably and improve the efficiency and accuracy of current diagnostic methods.