A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening.

BACKGROUND: Colorectal cancer is the third most diagnosed cancer in adults in the United States. Early detection could prevent more than 90% of colorectal cancer-related deaths, yet more than one third of the screening-eligible population is not up to date with screening despite multiple available tests. A blood-based test has the potential to improve screening adherence, detect colorectal cancer earlier, and reduce colorectal cancer-related mortality. METHODS: We assessed the performance characteristics of a cell-free DNA (cfDNA) blood-based test in a population eligible for colorectal cancer screening. The coprimary outcomes were sensitivity for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions) relative to screening colonoscopy. The secondary outcome was sensitivity to detect advanced precancerous lesions. RESULTS: The clinical validation cohort included 10,258 persons, 7861 of whom met eligibility criteria and were evaluable. A total of 83.1% of the participants with colorectal cancer detected by colonoscopy had a positive cfDNA test and 16.9% had a negative test, which indicates a sensitivity of the cfDNA test for detection of colorectal cancer of 83.1% (95% confidence interval [CI], 72.2 to 90.3). Sensitivity for stage I, II, or III colorectal cancer was 87.5% (95% CI, 75.3 to 94.1), and sensitivity for advanced precancerous lesions was 13.2% (95% CI, 11.3 to 15.3). A total of 89.6% of the participants without any advanced colorectal neoplasia (colorectal cancer or advanced precancerous lesions) identified on colonoscopy had a negative cfDNA blood-based test, whereas 10.4% had a positive cfDNA blood-based test, which indicates a specificity for any advanced neoplasia of 89.6% (95% CI, 88.8 to 90.3). Specificity for negative colonoscopy (no colorectal cancer, advanced precancerous lesions, or nonadvanced precancerous lesions) was 89.9% (95% CI, 89.0 to 90.7). CONCLUSIONS: In an average-risk screening population, this cfDNA blood-based test had 83% sensitivity for colorectal cancer, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. (Funded by Guardant Health; ECLIPSE ClinicalTrials.gov number, NCT04136002.).

Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening.

BACKGROUND: A next-generation multitarget stool DNA test, including assessments of DNA molecular markers and hemoglobin level, was developed to improve the performance of colorectal cancer screening, primarily with regard to specificity. METHODS: In a prospective study, we evaluated a next-generation multitarget stool DNA test in asymptomatic adults 40 years of age or older who were undergoing screening colonoscopy. The primary outcomes were sensitivity of the test for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions). Advanced precancerous lesions included one or more adenomas or sessile serrated lesions measuring at least 1 cm in the longest dimension, lesions with villous histologic features, and high-grade dysplasia. Secondary objectives included the quantification of sensitivity for advanced precancerous lesions and specificity for nonneoplastic findings or negative colonoscopy and comparison of sensitivities for colorectal cancer and advanced precancerous lesions between the multitarget stool DNA test and a commercially available fecal immunochemical test (FIT). RESULTS: Of 20,176 participants, 98 had colorectal cancer, 2144 had advanced precancerous lesions, 6973 had nonadvanced adenomas, and 10,961 had nonneoplastic findings or negative colonoscopy. With the next-generation test, sensitivity for colorectal cancer was 93.9% (95% confidence interval [CI], 87.1 to 97.7), and specificity for advanced neoplasia was 90.6% (95% CI, 90.1 to 91.0). Sensitivity for advanced precancerous lesions was 43.4% (95% CI, 41.3 to 45.6), and specificity for nonneoplastic findings or negative colonoscopy was 92.7% (95% CI, 92.2 to 93.1). With the FIT, sensitivity was 67.3% (95% CI, 57.1 to 76.5) for colorectal cancer and 23.3% (95% CI, 21.5 to 25.2) for advanced precancerous lesions; specificity was 94.8% (95% CI, 94.4 to 95.1) for advanced neoplasia and 95.7% (95% CI, 95.3 to 96.1) for nonneoplastic findings or negative colonoscopy. As compared with FIT, the next-generation test had superior sensitivity for colorectal cancer (P<0.001) and for advanced precancerous lesions (P<0.001) but had lower specificity for advanced neoplasia (P<0.001). No adverse events occurred. CONCLUSIONS: The next-generation multitarget stool DNA test showed higher sensitivity for colorectal cancer and advanced precancerous lesions than FIT but also showed lower specificity. (Funded by Exact Sciences; BLUE-C ClinicalTrials.gov number, NCT04144738.).

Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death.

BACKGROUND: Although colonoscopy is widely used as a screening test to detect colorectal cancer, its effect on the risks of colorectal cancer and related death is unclear. METHODS: We performed a pragmatic, randomized trial involving presumptively healthy men and women 55 to 64 years of age drawn from population registries in Poland, Norway, Sweden, and the Netherlands between 2009 and 2014. The participants were randomly assigned in a 1:2 ratio either to receive an invitation to undergo a single screening colonoscopy (the invited group) or to receive no invitation or screening (the usual-care group). The primary end points were the risks of colorectal cancer and related death, and the secondary end point was death from any cause. RESULTS: Follow-up data were available for 84,585 participants in Poland, Norway, and Sweden - 28,220 in the invited group, 11,843 of whom (42.0%) underwent screening, and 56,365 in the usual-care group. A total of 15 participants had major bleeding after polyp removal. No perforations or screening-related deaths occurred within 30 days after colonoscopy. During a median follow-up of 10 years, 259 cases of colorectal cancer were diagnosed in the invited group as compared with 622 cases in the usual-care group. In intention-to-screen analyses, the risk of colorectal cancer at 10 years was 0.98% in the invited group and 1.20% in the usual-care group, a risk reduction of 18% (risk ratio, 0.82; 95% confidence interval [CI], 0.70 to 0.93). The risk of death from colorectal cancer was 0.28% in the invited group and 0.31% in the usual-care group (risk ratio, 0.90; 95% CI, 0.64 to 1.16). The number needed to invite to undergo screening to prevent one case of colorectal cancer was 455 (95% CI, 270 to 1429). The risk of death from any cause was 11.03% in the invited group and 11.04% in the usual-care group (risk ratio, 0.99; 95% CI, 0.96 to 1.04). CONCLUSIONS: In this randomized trial, the risk of colorectal cancer at 10 years was lower among participants who were invited to undergo screening colonoscopy than among those who were assigned to no screening. (Funded by the Research Council of Norway and others; NordICC ClinicalTrials.gov number, NCT00883792.).

Effectiveness and Cost-Effectiveness of Colorectal Cancer Screening With a Blood Test That Meets the Centers for Medicare & Medicaid Services Coverage Decision.

BACKGROUND & AIMS: A blood-based colorectal cancer (CRC) screening test may increase screening participation. However, blood tests may be less effective than current guideline-endorsed options. The Centers for Medicare & Medicaid Services (CMS) covers blood tests with sensitivity of at least 74% for detection of CRC and specificity of at least 90%. In this study, we investigate whether a blood test that meets these criteria is cost-effective. METHODS: Three microsimulation models for CRC (MISCAN-Colon, CRC-SPIN, and SimCRC) were used to estimate the effectiveness and cost-effectiveness of triennial blood-based screening (from ages 45 to 75 years) compared to no screening, annual fecal immunochemical testing (FIT), triennial stool DNA testing combined with an FIT assay, and colonoscopy screening every 10 years. The CMS coverage criteria were used as performance characteristics of the hypothetical blood test. We varied screening ages, test performance characteristics, and screening uptake in a sensitivity analysis. RESULTS: Without screening, the models predicted 77-88 CRC cases and 32-36 CRC deaths per 1000 individuals, costing $5.3-$5.8 million. Compared to no screening, blood-based screening was cost-effective, with an additional cost of $25,600-$43,700 per quality-adjusted life-year gained (QALYG). However, compared to FIT, triennial stool DNA testing combined with FIT, and colonoscopy, blood-based screening was not cost-effective, with both a decrease in QALYG and an increase in costs. FIT remained more effective (+5-24 QALYG) and less costly (-$3.2 to -$3.5 million) than blood-based screening even when uptake of blood-based screening was 20 percentage points higher than uptake of FIT. CONCLUSION: Even with higher screening uptake, triennial blood-based screening, with the CMS-specified minimum performance sensitivity of 74% and specificity of 90%, was not projected to be cost-effective compared with established strategies for colorectal cancer screening.

Autonomous Artificial Intelligence vs Artificial Intelligence-Assisted Human Optical Diagnosis of Colorectal Polyps: A Randomized Controlled Trial.

BACKGROUND & AIMS: Artificial intelligence (AI)-based optical diagnosis systems (CADx) have been developed to allow pathology prediction of colorectal polyps during colonoscopies. However, CADx systems have not yet been validated for autonomous performance. Therefore, we conducted a trial comparing autonomous AI to AI-assisted human (AI-H) optical diagnosis. METHODS: We performed a randomized noninferiority trial of patients undergoing elective colonoscopies at 1 academic institution. Patients were randomized into (1) autonomous AI-based CADx optical diagnosis of diminutive polyps without human input or (2) diagnosis by endoscopists who performed optical diagnosis of diminutive polyps after seeing the real-time CADx diagnosis. The primary outcome was accuracy in optical diagnosis in both arms using pathology as the gold standard. Secondary outcomes included agreement with pathology for surveillance intervals. RESULTS: A total of 467 patients were randomized (238 patients/158 polyps in the autonomous AI group and 229 patients/179 polyps in the AI-H group). Accuracy for optical diagnosis was 77.2% (95% confidence interval [CI], 69.7-84.7) in the autonomous AI group and 72.1% (95% CI, 65.5-78.6) in the AI-H group (P = .86). For high-confidence diagnoses, accuracy for optical diagnosis was 77.2% (95% CI, 69.7-84.7) in the autonomous AI group and 75.5% (95% CI, 67.9-82.0) in the AI-H group. Autonomous AI had statistically significantly higher agreement with pathology-based surveillance intervals compared to AI-H (91.5% [95% CI, 86.9-96.1] vs 82.1% [95% CI, 76.5-87.7]; P = .016). CONCLUSIONS: Autonomous AI-based optical diagnosis exhibits noninferior accuracy to endoscopist-based diagnosis. Both autonomous AI and AI-H exhibited relatively low accuracy for optical diagnosis; however, autonomous AI achieved higher agreement with pathology-based surveillance intervals. (ClinicalTrials.gov, Number NCT05236790).

Using Computer Vision to Improve Endoscopic Disease Quantification in Therapeutic Clinical Trials of Ulcerative Colitis.

BACKGROUND & AIMS: Endoscopic assessment of ulcerative colitis (UC) typically reports only the maximum severity observed. Computer vision methods may better quantify mucosal injury detail, which varies among patients. METHODS: Endoscopic video from the UNIFI clinical trial (A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis) comparing ustekinumab and placebo for UC were processed in a computer vision analysis that spatially mapped Mayo Endoscopic Score (MES) to generate the Cumulative Disease Score (CDS). CDS was compared with the MES for differentiating ustekinumab vs placebo treatment response and agreement with symptomatic remission at week 44. Statistical power, effect, and estimated sample sizes for detecting endoscopic differences between treatments were calculated using both CDS and MES measures. Endoscopic video from a separate phase 2 clinical trial replication cohort was performed for validation of CDS performance. RESULTS: Among 748 induction and 348 maintenance patients, CDS was lower in ustekinumab vs placebo users at week 8 (141.9 vs 184.3; P < .0001) and week 44 (78.2 vs 151.5; P < .0001). CDS was correlated with the MES (P < .0001) and all clinical components of the partial Mayo score (P < .0001). Stratification by pretreatment CDS revealed ustekinumab was more effective than placebo (P < .0001) with increasing effect in severe vs mild disease (-85.0 vs -55.4; P < .0001). Compared with the MES, CDS was more sensitive to change, requiring 50% fewer participants to demonstrate endoscopic differences between ustekinumab and placebo (Hedges' g = 0.743 vs 0.460). CDS performance in the JAK-UC replication cohort was similar to UNIFI. CONCLUSIONS: As an automated and quantitative measure of global endoscopic disease severity, the CDS offers artificial intelligence enhancement of traditional MES capability to better evaluate UC in clinical trials and potentially practice.

Colonoscopy vs the Fecal Immunochemical Test: Which is Best?

Although there is no debate around the effectiveness of colorectal cancer screening in reducing disease burden, there remains a question regarding the most effective and cost-effective screening modality. Current United States guidelines present a panel of options that include the 2 most commonly used modalities, colonoscopy and stool testing with the fecal immunochemical test (FIT). Large-scale comparative effectiveness trials comparing colonoscopy and FIT for colorectal cancer outcomes are underway, but results are not yet available. This review will separately state the "best case" for FIT and colonoscopy as the screening tool of first choice. In addition, the review will examine these modalities from a health economics perspective to provide the reader further context about the relative advantages of these commonly used tests.

Relative Efficacies of Interventions to Improve the Quality of Screening-Related Colonoscopy: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND & AIMS: Significant variability exists in colonoscopy quality indicators, including adenoma detection rate (ADR). We synthesized evidence from randomized trials in a network meta-analysis on interventions to improve colonoscopy quality. METHODS: We included trials from database inceptions to September 25, 2023, of patients undergoing screening-related colonoscopy and presented efficacies of interventions within domains (periprocedural parameters, endoscopist-directed interventions, intraprocedural techniques, endoscopic technologies, distal attachment devices, and additive substances) compared to standard colonoscopy. The primary outcome was ADR. We used a Bayesian random-effects model using Markov-chain Monte Carlo simulation, with 10,000 burn-ins and 100,000 iterations. We calculated odds ratios with 95% credible intervals and present surface under the cumulative ranking (SUCRA) curves. RESULTS: We included 124 trials evaluating 37 interventions for the primary outcome. Nine interventions resulted in statistically significant improvements in ADR compared to standard colonoscopy (9-minute withdrawal time, dual observation, water exchange, i-SCAN [Pentax Ltd], linked color imaging, computer-aided detection, Endocuff [Olympus Corp], Endocuff Vision [Olympus Corp], and oral methylene blue). Dual observation (SUCRA, 0.84) and water exchange (SUCRA, 0.78) ranked highest among intraprocedural techniques; i-SCAN (SUCRA, 0.95), linked color imaging (SUCRA, 0.85), and computer-aided detection (SUCRA, 0.78) among endoscopic technologies; WingCap (A&A Medical Supply LLC) (SUCRA, 0.87) and Endocuff (SUCRA, 0.85) among distal attachment devices and oral methylene blue (SUCRA, 0.94) among additive substances. No interventions improved detection of advanced adenomas, and only narrow-band imaging improved detection of serrated lesions (odds ratio, 2.94; 95% credible interval, 1.46-6.25). CONCLUSIONS: Several interventions are effective in improving adenoma detection and overall colonoscopy quality, many of which are cost-free. These results can inform endoscopists, unit managers, and endoscopy societies on relative efficacies.

Cold Versus Hot Snare Endoscopic Resection of Large Nonpedunculated Colorectal Polyps: Randomized Controlled German CHRONICLE Trial.

BACKGROUND & AIMS: Endoscopic mucosal resection (EMR) is standard therapy for nonpedunculated colorectal polyps ≥20 mm. It has been suggested recently that polyp resection without current (cold resection) may be superior to the standard technique using cutting/coagulation current (hot resection) by reducing adverse events (AEs), but evidence from a randomized trial is missing. METHODS: In this randomized controlled multicentric trial involving 19 centers, nonpedunculated colorectal polyps ≥20 mm were randomly assigned to cold or hot EMR. The primary outcome was major AE (eg, perforation or postendoscopic bleeding). Among secondary outcomes, major AE subcategories, postpolypectomy syndrome, and residual adenoma were most relevant. RESULTS: Between 2021 and 2023, there were 396 polyps in 363 patients (48.2% were female) enrolled for the intention-to-treat analysis. Major AEs occurred in 1.0% of the cold group and in 7.9% of the hot group (P = .001; odds ratio [OR], 0.12; 95% CI, 0.03-0.54). Rates for perforation and postendoscopic bleeding were significantly lower in the cold group, with 0% vs 3.9% (P = .007) and 1.0% vs 4.4% (P = .040). Postpolypectomy syndrome occurred with similar frequency (3.1% vs 4.4%; P = .490). After cold resection, residual adenoma was found more frequently, with 23.7% vs 13.8% (P = .020; OR, 1.94; 95% CI, 1.12-3.38). In multivariable analysis, lesion diameter of ≥4 cm was an independent predictor both for major AEs (OR, 3.37) and residual adenoma (OR, 2.47) and high-grade dysplasia/cancer for residual adenoma (OR, 2.92). CONCLUSIONS: Cold resection of large, nonpedunculated colorectal polyps appears to be considerably safer than hot EMR; however, at the cost of a higher residual adenoma rate. Further studies have to confirm to what extent polyp size and histology can determine an individualized approach. German Clinical Trials Registry (Deutsches Register Klinischer Studien), Number DRKS00025170.

Comparative Effectiveness and Cost-Effectiveness of Colorectal Cancer Screening With Blood-Based Biomarkers (Liquid Biopsy) vs Fecal Tests or Colonoscopy.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening is highly effective but underused. Blood-based biomarkers (liquid biopsy) could improve screening participation. METHODS: Using our established Markov model, screening every 3 years with a blood-based test that meets minimum Centers for Medicare & Medicaid Services' thresholds (CMSmin) (CRC sensitivity 74%, specificity 90%) was compared with established alternatives. Test attributes were varied in sensitivity analyses. RESULTS: CMSmin reduced CRC incidence by 40% and CRC mortality by 52% vs no screening. These reductions were less profound than the 68%-79% and 73%-81%, respectively, achieved with multi-target stool DNA (Cologuard; Exact Sciences) every 3 years, annual fecal immunochemical testing (FIT), or colonoscopy every 10 years. Assuming the same cost as multi-target stool DNA, CMSmin cost $28,500/quality-adjusted life-year gained vs no screening, but FIT, colonoscopy, and multi-target stool DNA were less costly and more effective. CMSmin would match FIT's clinical outcomes if it achieved 1.4- to 1.8-fold FIT's participation rate. Advanced precancerous lesion (APL) sensitivity was a key determinant of a test's effectiveness. A paradigm-changing blood-based test (sensitivity >90% for CRC and 80% for APL; 90% specificity; cost ≤$120-$140) would be cost-effective vs FIT at comparable participation. CONCLUSIONS: CMSmin could contribute to CRC control by achieving screening in those who will not use established methods. Substituting blood-based testing for established effective CRC screening methods will require higher CRC and APL sensitivities that deliver programmatic benefits matching those of FIT. High APL sensitivity, which can result in CRC prevention, should be a top priority for screening test developers. APL detection should not be penalized by a definition of test specificity that focuses on CRC only.

Risk of Cancers Proximal to the Colon in Fecal Immunochemical Test Positive Screenees in a Colorectal Cancer Screening Program.

BACKGROUND & AIMS: In more than half of the colorectal cancer screening participants with a positive fecal immunochemical test (FIT) result, no advanced neoplasia (AN) is detected at colonoscopy. The positive FIT result could also be generated by cancers located proximal to the colon: upper gastrointestinal, oral cavity, nose, and throat cancers. We evaluated screenees' risk of being diagnosed with a cancer proximal to the colon within the 3 years and compared risks between those with a positive vs those with a negative FIT. METHODS: Data of Dutch colorectal cancer screening participants who underwent biennial FIT-based screening 2014-2018 were collected from the national screening database and linked to the National Cancer Registry. Screenees were classified into 3 groups: FIT-positives with AN (FIT+/AN+), FIT-positives without AN (FIT+/AN-), and FIT-negatives (FIT-). We compared the cumulative incidence of cancers proximal to the colon in each group 3 years after FIT. A Cox regression analysis with left truncation and right censoring, using FIT positivity as time-dependent variable and stratified for sex, was performed to compare the hazard of cancers proximal to the colon in participants who were FIT-positive vs FIT-negative. RESULTS: Three-year cumulative incidence of cancers proximal to the colon in FIT+/AN+ (n = 65,767), FIT+/AN- (n = 50,661), and FIT- (n = 1,831,647) screenees was 0.7%, 0.6%, and 0.4%, respectively (P < .001). FIT-positives were older and more frequently male than FIT-negatives (P < .001). Significantly more cancers proximal to the colon were detected among FIT-positives (P < .001; hazard ratio, 1.55; 95% CI, 1.44-1.67). CONCLUSION: FIT-positive screenees were at significantly increased risk of being diagnosed with a cancer proximal to the colon within 3 years after FIT, although the 3-year cumulative incidence was still less than 1%.

Rapid Endoscopic Diagnosis of Benign Ulcerative Colorectal Diseases With an Artificial Intelligence Contextual Framework.

BACKGROUND & AIMS: Benign ulcerative colorectal diseases (UCDs) such as ulcerative colitis, Crohn's disease, ischemic colitis, and intestinal tuberculosis share similar phenotypes with different etiologies and treatment strategies. To accurately diagnose closely related diseases like UCDs, we hypothesize that contextual learning is critical in enhancing the ability of the artificial intelligence models to differentiate the subtle differences in lesions amidst the vastly divergent spatial contexts. METHODS: White-light colonoscopy datasets of patients with confirmed UCDs and healthy controls were retrospectively collected. We developed a Multiclass Contextual Classification (MCC) model that can differentiate among the mentioned UCDs and healthy controls by incorporating the tissue object contexts surrounding the individual lesion region in a scene and spatial information from other endoscopic frames (video-level) into a unified framework. Internal and external datasets were used to validate the model's performance. RESULTS: Training datasets included 762 patients, and the internal and external testing cohorts included 257 patients and 293 patients, respectively. Our MCC model provided a rapid reference diagnosis on internal test sets with a high averaged area under the receiver operating characteristic curve (image-level: 0.950 and video-level: 0.973) and balanced accuracy (image-level: 76.1% and video-level: 80.8%), which was superior to junior endoscopists (accuracy: 71.8%, P < .0001) and similar to experts (accuracy: 79.7%, P = .732). The MCC model achieved an area under the receiver operating characteristic curve of 0.988 and balanced accuracy of 85.8% using external testing datasets. CONCLUSIONS: These results enable this model to fit in the routine endoscopic workflow, and the contextual framework to be adopted for diagnosing other closely related diseases.

Texture and Color Enhancement Imaging Improves Colonic Adenoma Detection: A Multicenter Randomized Controlled Trial.

The global burden of colorectal cancer is expected to increase more than 60% by 2030; however, compelling evidence now shows that the implementation of population screening programs in developed countries has led to a substantial reduction in incidence and mortality.1,2 Despite this, patients continue to develop preventable colorectal cancers, in part because of high rates of interval colon cancer diagnosed after screening or surveillance colonoscopies.3.

Colon Polyp Surveillance: Separating the Wheat From the Chaff.

One goal of colorectal cancer (CRC) screening is to prevent CRC incidence by removing precancerous colonic polyps, which are detected in up to 50% of screening examinations. Yet, the lifetime risk of CRC is 3.9%-4.3%, so it is clear that most of these individuals with polyps would not develop CRC in their lifetime. It is, therefore, a challenge to determine which individuals with polyps will benefit from follow-up, and at what intervals. There is some evidence that individuals with advanced polyps, based on size and histology, benefit from intensive surveillance. However, a large proportion of individuals will have small polyps without advanced histologic features (ie, "nonadvanced"), where the benefits of surveillance are uncertain and controversial. Demand for surveillance will further increase as more polyps are detected due to increased screening uptake, recent United States recommendations to expand screening to younger individuals, and emergence of polyp detection technology. We review the current understanding and clinical implications of the natural history, biology, and outcomes associated with various categories of colon polyps based on size, histology, and number. Our aims are to highlight key knowledge gaps, specifically focusing on certain categories of polyps that may not be associated with future CRC risk, and to provide insights to inform research priorities and potential management strategies. Optimization of CRC prevention programs based on updated knowledge about the future risks associated with various colon polyps is essential to ensure cost-effective screening and surveillance, wise use of resources, and inform efforts to personalize recommendations.

Recent progress in Lynch syndrome and other familial colorectal cancer syndromes.

The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape-altering discoveries revealed that there were distinct forms of familial cancer, and most were related to genes previously not known to be involved in human disease. This review largely focuses on advances in our understanding of Lynch syndrome because of the unique relationship of this disease to defective DNA mismatch repair and the clinical implications this has for diagnostics, prevention, and therapy. Recent advances have occurred in our understanding of the epidemiology of this disease, and the advent of broad genetic panels has altered the approach to germline and somatic diagnoses for all of the familial colorectal cancer syndromes. Important advances have been made toward a more complete mechanistic understanding of the pathogenesis of neoplasia in the setting of Lynch syndrome, and these advances have important implications for prevention. Finally, paradigm-shifting approaches to treatment of Lynch-syndrome and related tumors have occurred through the development of immune checkpoint therapies for hypermutated cancers. CA Cancer J Clin 2018;68:217-231. © 2018 American Cancer Society.

Polyketide synthase positive Escherichia coli one-time measurement in stool is not informative of colorectal cancer risk in a screening setting.

Environmental factors like the pathogenicity island polyketide synthase positive (pks+) Escherichia coli (E. coli) could have potential for risk stratification in colorectal cancer (CRC) screening. The association between pks+ E. coli measured in fecal immunochemical test (FIT) samples and the detection of advanced neoplasia (AN) at colonoscopy was investigated. Biobanked FIT samples were analyzed for both presence of E. coli and pks+ E. coli and correlated with colonoscopy findings; 5020 CRC screening participants were included. Controls were participants in which no relevant lesion was detected because of FIT-negative results (cut-off ≥15 µg Hb/g feces), a negative colonoscopy, or a colonoscopy during which only a nonadvanced polyp was detected. Cases were participants with AN [CRC, advanced adenoma (AA), or advanced serrated polyp (ASP)]. Existing DNA isolation and quantitative polymerase chain reaction (qPCR) procedures were used for the detection of E. coli and pks+ E. coli in stool. A total of 4542 (90.2%) individuals were E. coli positive, and 1322 (26.2%) were pks+ E. coli positive. The prevalence of E. coli in FIT samples from individuals with AN was 92.9% compared to 89.7% in FIT samples of controls (p = 0.010). The prevalence of pks+ E. coli in FIT samples from individuals with AN (28.6%) and controls (25.9%) was not significantly different (p = 0.13). The prevalences of pks+ E. coli in FIT samples from individuals with CRC, AA, or ASP were 29.6%, 28.3%, and 32.1%, respectively. In conclusion, the prevalence of pks+ E. coli in a screening population was 26.2% and did not differ significantly between individuals with AN and controls. These findings disqualify the straightforward option of using a snapshot measurement of pks+ E. coli in FIT samples as a stratification biomarker for CRC risk. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Gastroenterology/Hepatology: What You May Have Missed in 2023.

This article summarizes clinically important gastroenterology developments from 2023 for internal medicine specialists. In colorectal cancer screening, a new RNA fecal screening test is on the horizon, as well as a new analysis on the benefits of using artificial intelligence in screening colonoscopy to detect more polyps. There is new evidence for management of gastrointestinal bleeding, a new drug for treatment of recurrent small-intestinal angiodysplasia, and a new endoscopic treatment method in patients with gastrointestinal tumor bleeding. The authors feature a randomized trial about amitriptyline as treatment for patients with irritable bowel syndrome by primary care providers and bring you news about new biologic agents for inflammatory bowel disease and eosinophilic esophagitis. Finally, they review 2 important articles on new terminology and management of metabolic dysfunction-associated fatty liver disease.

Computer-Aided Diagnosis for Leaving Colorectal Polyps In Situ : A Systematic Review and Meta-analysis.

BACKGROUND: Computer-aided diagnosis (CADx) allows prediction of polyp histology during colonoscopy, which may reduce unnecessary removal of nonneoplastic polyps. However, the potential benefits and harms of CADx are still unclear. PURPOSE: To quantify the benefit and harm of using CADx in colonoscopy for the optical diagnosis of small (≤5-mm) rectosigmoid polyps. DATA SOURCES: Medline, Embase, and Scopus were searched for articles published before 22 December 2023. STUDY SELECTION: Histologically verified diagnostic accuracy studies that evaluated the real-time performance of physicians in predicting neoplastic change of small rectosigmoid polyps without or with CADx assistance during colonoscopy. DATA EXTRACTION: The clinical benefit and harm were estimated on the basis of accuracy values of the endoscopist before and after CADx assistance. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. The outcome measure for benefit was the proportion of polyps predicted to be nonneoplastic that would avoid removal with the use of CADx. The outcome measure for harm was the proportion of neoplastic polyps that would be not resected and left in situ due to an incorrect diagnosis with the use of CADx. Histology served as the reference standard for both outcomes. DATA SYNTHESIS: Ten studies, including 3620 patients with 4103 small rectosigmoid polyps, were analyzed. The studies that assessed the performance of CADx alone (9 studies; 3237 polyps) showed a sensitivity of 87.3% (95% CI, 79.2% to 92.5%) and specificity of 88.9% (CI, 81.7% to 93.5%) in predicting neoplastic change. In the studies that compared histology prediction performance before versus after CADx assistance (4 studies; 2503 polyps), there was no difference in the proportion of polyps predicted to be nonneoplastic that would avoid removal (55.4% vs. 58.4%; risk ratio [RR], 1.06 [CI, 0.96 to 1.17]; moderate-certainty evidence) or in the proportion of neoplastic polyps that would be erroneously left in situ (8.2% vs. 7.5%; RR, 0.95 [CI, 0.69 to 1.33]; moderate-certainty evidence). LIMITATION: The application of optical diagnosis was only simulated, potentially altering the decision-making process of the operator. CONCLUSION: Computer-aided diagnosis provided no incremental benefit or harm in the management of small rectosigmoid polyps during colonoscopy. PRIMARY FUNDING SOURCE: European Commission. (PROSPERO: CRD42023402197).

CRC screening with sigmoidoscopy extends life by 110 d; other cancer screening tests do not extend life.

SOURCE CITATION: Bretthauer M, Wieszczy P, Løberg M, et al. Estimated lifetime gained with cancer screening tests: a meta-analysis of randomized clinical trials. JAMA Intern Med. 2023;183:1196-1203. 37639247.