Faculty Bibliography

BACKGROUND AND AIMS/OBJECTIVE:Growing evidence suggests that the gut microbiome plays a role in carcinogenesis for early-onset colorectal cancer (EOCRC). The novel Ring Finger Protein 213 (RNF213) gene has broad antimicrobial properties. Our study aimed to compare RNF213 mutation rates in EOCRC and late-onset colorectal cancer using data from the cBioPortal for Cancer Genomics. METHODS:All participants from the cBioPortal with CRC samples that profiled the RNF213 gene were included. Multivariable logistic regression was used to assess the association between EOCRC and primary tumor RNF213 mutation. Cox proportional hazards models were used to evaluate the influence of RNF213 mutation on all-cause mortality risk. All tests were two-sided. RESULTS:OR 1.61, 95% CI 0.72, 3.22). There was no significant difference in all-cause mortality risk by RNF213 mutation status. CONCLUSIONS:Primary tumor mutations in exon 29 of the RNF213 gene are associated with significantly increased odds of EOCRC diagnosis in a multicohort sample of participants with CRC. Future studies of germline and precancerous RNF213 mutations are needed to elucidate its possible role in EOCRC tumorigenesis.

OBJECTIVES/OBJECTIVE:Post-colonoscopy colorectal cancer (PCCRC) represents an important real-world colonoscopy quality indicator. Using a national database, we evaluated predictors of PCCRC in fecal immunochemical test (FIT)-positive individuals, determined the PCCRC 3-year rate (PCCRC-3y), and performed a root cause analysis (RCA). METHODS:This retrospective cohort study evaluated FIT-positive patients who underwent colonoscopy from January 2015 to July 2022. Data was collected from the Veterans Affairs (VA) national database. PCCRC was defined as CRC detected ≥6 months after colonoscopy. CRC was identified using SNOMED codes and the VA Cancer Registry. The World Endoscopy Organization methodology was used to perform the RCA and calculate the PCCRC-3y rate. RESULTS:We identified 132 PCCRCs among 52,167 FIT-positive individuals. The PCCRC-3y rate was 6.4% (95% CI, 5.0-7.7%). PCCRC locations were proximal colon (43.2%), distal colon (34.8%), and rectum (22%). Root causes were likely new CRC (17.4%), missed lesions with adequate (31.2%) or inadequate (9.8%) examination, incomplete polyp resection (22%), and detected but unresected lesions (19.7%). 16.7% of patients with PCCRC had poor bowel preparation on index colonoscopy. The cecal intubation rate was 88.6% and rectal retroflexion rate was 84.5%. In 14.4% of cases, recommended surveillance intervals did not adhere to established guidelines. Independent predictors of PCCRC were ages 70-79 (HR 7.86; 95% CI, 1.08-57.39), age ≥80 (HR 10.18; 95% CI, 1.06-97.98), tubulovillous adenoma (HR 3.98; 95% CI, 2.52-6.29), and adenoma with high-grade dysplasia (HR 10.15; 95% CI, 5.91-17.42). CONCLUSIONS:Among FIT-positive individuals, the PCCRC-3y rate was 6.4%, with missed lesions and incomplete resection as key contributors. These findings provide useful information on quality metrics in FIT-based CRC screening programs.

BACKGROUND:The benefits of achieving endoscopic remission among older adults with inflammatory bowel disease (IBD) who have mild persistent disease activity are unknown. METHODS:This was a retrospective study of adults ≥ 60 with IBD who had mild or no disease activity on endoscopy from January 1, 2018-January 1, 2023. The primary outcome was a composite of major IBD-specific adverse events (hospitalizations, surgery, and prescription of corticosteroids for IBD-related symptoms) within 1 year of endoscopic assessment. Our secondary outcome was a composite of 1-year morbidity-related events (mortality, all-cause hospitalization, infection requiring antibiotics, venous thromboembolism, cardiovascular events, and osteoporotic fractures). We also assessed outcomes at 5 years. RESULTS:Among 504 patients, 192 (38.1%) had mild endoscopic disease and 312 (61.9%) were in endoscopic remission, with a median disease duration of 11 years. On multivariable analysis, mild endoscopic disease activity increased the odds of a 1-year adverse IBD-specific outcome (aOR 4.16, 95% CI 2.10-8.24), with similar results at 5 years. Furthermore, mild endoscopic disease was associated with increased odds of experiencing an adverse morbidity-related outcome within 1 year as compared to endoscopic remission (aOR 1.56, 95% CI 1.01-2.43). CONCLUSIONS:Among older adults with prevalent IBD, mild endoscopic disease activity, as compared to endoscopic remission, was associated with increased odds of adverse IBD-specific and morbidity-related outcomes at 1 year, with this risk persisting for IBD-specific outcomes at 5 years. These findings highlight the importance of achieving endoscopic remission, which may confer both short- and longer-term benefits in this population.

BACKGROUND:Protocols for standardized assessment of complete colorectal polyp resection are lacking. This may contribute to divergent quality standards and hinder reliable comparison of incomplete resection rates (IRRs) across resection devices, techniques, endoscopists and institutions. To inform the development of such protocols, we aimed to review available methods. METHODS:We systematically searched the MEDLINE, Embase, Web of Science, and Cochrane Library databases from inception to July 30, 2024. Studies describing the use or validation of methods for assessing completeness of polyp resections were included. Studies using recurrence detected at follow-up or histopathological resection specimen margin assessment as outcome measure were excluded, unless used as a reference standard for evaluation of other methods. RESULTS:Forty-five eligible studies were identified. Methods proposed to assist in visual confirmation of complete resection included the use of image enhancement techniques (n=6), artificial intelligence (n=1), and resection defect diameter (n=1). Methods for measuring IRRs based on a histopathological reference standard involved biopsy sampling (n=29) and extended margin resection (n=8). IRR measurement protocols differed in terms of factors such as location and number of biopsies (1-8), and widths of extended resections (1-3 mm). IRRs exceeding 10% were observed for all polyp size categories and almost all resection techniques, with considerable variability in IRRs reported across studies (biopsy sampling: 0-24.2%; extended resection: 0-61.1%). CONCLUSIONS:Different methods are available to assist in visual confirmation of complete resection and measuring IRRs, with considerable variability in their application. This review highlights the need for standardized assessment of complete colorectal polyp resection.

BACKGROUND AND AIMS/OBJECTIVE:Most colorectal cancer (CRC) screening tests, including fecal immunochemical (FIT) and multitarget stool DNA tests, require patients to scrape a stool sample at home before mailing it to a central lab. This requirement not only deters screening adherence but can also introduce risks of human error, environmental exposure, and transit-related issues. The multitarget stool RNA test (mt-sRNA), which comprises a FIT component and an RNA molecular component, is the only FDA-approved stool-based test for the detection of both CRC and advanced adenomas (AA) that does not require patients to perform an at-home FIT. Instead, trained technicians complete the FIT in the laboratory after the sample is received. This study evaluates the comparability of at-home and in-laboratory FIT in relation to mt-sRNA test performance. METHODS:To assess comparability between the 2 FIT methods, banked residual stool samples from the mt-sRNA test pivotal clinical trial (CRC-PREVENT) were used. As part of clinical trial requirements, subjects were required to collect a stool sample using the mt-sRNA collection kit and complete an at-home FIT swab before shipping the sample back to the laboratory. Patients were subsequently required to complete a screening colonoscopy. Residual stool was sampled using the in-laboratory FIT. Both FIT collection methods (at-home and in-laboratory) were analyzed identically. FIT results were compared with each other and with colonoscopy, to assess concordance, sensitivity, and specificity. RESULTS:A total of 1079 stool samples were tested using both at-home and in-laboratory FIT methods. Overall concordance was 93%. Among 20 CRC cases, the sensitivity for both methods was 75% (n=15). For 231 AA cases, sensitivity for the at-home and in-laboratory FIT was 33% and 38%, respectively. Positive percent agreement (PPA) for colorectal neoplasia was 87%. Among 791 subjects with negative findings, specificity for the at-home and in-laboratory FIT was 94% and 95%, respectively. For subjects with negative findings, the negative percent agreement (NPA) was 98%. When incorporating the in-laboratory FIT into the mt-sRNA test, method-calibrated CRC and AA sensitivities were 94% and 48%, respectively. Method-calibrated specificity for no lesions on colonoscopy was 90%. CONCLUSIONS:Our findings suggest that in-laboratory FIT performance may enhance the diagnostic accuracy of the mt-sRNA test. The in-laboratory method may also reduce inadequate sampling and improve patient ease of use.

The performance of a CRC screening blood test was validated in a prospective, multicenter, observational study (PREEMPT CRC). The composition of the clinical study population can impact performance measures, potentially affecting the generalizability of the observed outcomes. We conducted a prespecified post-stratification adjustment analysis in which PREEMPT CRC performance values were adjusted to US Census age and sex distribution. The PREEMPT CRC evaluable cohort had a higher proportion of younger individuals and females than the census population. Compared to observed values, census adjustment demonstrated nominally higher CRC sensitivity (81.1% [95% confidence interval or CI, 71.3-88.1%] vs 79.2% [95% CI, 68.4-86.9%]) and advanced precancerous lesion sensitivity (13.7% [95% CI, 12.4-15.0%] vs 12.5% [95% CI, 11.3-13.8%]), with lower advanced colorectal neoplasia specificity (90.4% [95% CI, 90.0-90.7%) vs 91.5% [95% CI, 91.2-91.9%]). Negative and positive predictive values were consistent across age groups, highlighting consistent clinical interpretability of test results regardless of patient age.