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Background: Aspirin may decrease colorectal cancer incidence, but its role as an adjunct to or substitute for screening has not been evaluated.Objective: To examine the potential cost-effectiveness of aspirin chemoprophylaxis in relation to screening.Design: Markov model.Data Sources: Literature on colorectal cancer epidemiology, screening, costs, and aspirin chemoprevention (1980-1999).Target Population: General U.S. population.Time Horizon: 50 to 80 years of age.Perspective: Third-party payer.Intervention: Aspirin therapy in patients screened with sigmoidoscopy every 5 years and fecal occult blood testing every year (FS/FOBT) or colonoscopy every 10 years (COLO).Outcome Measures: Discounted cost per life-year gained.Results Of Base-case Analysis: When a 30% reduction in colorectal cancer risk was assumed, aspirin increased costs and decreased life-years because of related complications as an adjunct to FS/FOBT and cost $149 161 per life-year gained as an adjunct to COLO. In patients already taking aspirin, screening with FS/FOBT or COLO cost less than $31 000 per life-year gained.Results Of Sensitivity Analysis: Cost-effectiveness estimates depended highly on the magnitude of colorectal cancer risk reduction with aspirin, aspirin-related complication rates, and the screening adherence rate in the population. However, when the model's inputs were varied over wide ranges, aspirin chemoprophylaxis remained generally non-cost-effective for patients who adhere to screening.Conclusions: In patients undergoing colorectal cancer screening, aspirin use should not be based on potential chemoprevention. Aspirin chemoprophylaxis alone cannot be considered a substitute for colorectal cancer screening. Public policy should focus on improving screening adherence, even in patients who are already taking aspirin. [ABSTRACT FROM AUTHOR]

Background: Testing has been advocated for all persons with newly diagnosed colorectal cancer to identify families with the Lynch syndrome, an autosomal dominant cancer-predisposition syndrome that is a paradigm for personalized medicine.Objective: To estimate the effectiveness and cost-effectiveness of strategies to identify the Lynch syndrome, with attention to sex, age at screening, and differential effects for probands and relatives.Design: Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers.Data Sources: Published literature.Target Population: All persons with newly diagnosed colorectal cancer and their relatives.Time Horizon: Lifetime.Perspective: Third-party payer.Intervention: Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery.Outcome Measures: Life-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios.Results Of Base-case Analysis: The benefit of all strategies accrued primarily to relatives with a mutation associated with the Lynch syndrome, particularly women, whose life expectancy could increase by approximately 4 years with hysterectomy and salpingo-oophorectomy and adherence to colorectal cancer screening recommendations. At current rates of germline testing, screening, and prophylactic surgery, the strategies reduced deaths from colorectal cancer by 7% to 42% and deaths from endometrial and ovarian cancer by 1% to 6%. Among tumor-testing strategies, immunohistochemistry followed by BRAF mutation testing was preferred, with an incremental cost-effectiveness ratio of $36,200 per life-year gained.Results Of Sensitivity Analysis: The number of relatives tested per proband was a critical determinant of both effectiveness and cost-effectiveness, with testing of 3 to 4 relatives required for most strategies to meet a threshold of $50,000 per life-year gained. Immunohistochemistry followed by BRAF mutation testing was preferred in 59% of iterations in probabilistic sensitivity analysis at a threshold of $100,000 per life-year gained. Screening for the Lynch syndrome with immunohistochemistry followed by BRAF mutation testing only up to age 70 years cost $44,000 per incremental life-year gained compared with screening only up to age 60 years, and screening without an upper age limit cost $88,700 per incremental life-year gained compared with screening only up to age 70 years.Limitation: Other types of cancer, uncertain family pedigrees, and genetic variants of unknown significance were not considered.Conclusion: Widespread colorectal tumor testing to identify families with the Lynch syndrome could yield substantial benefits at acceptable costs, particularly for women with a mutation associated with the Lynch syndrome who begin regular screening and have risk-reducing surgery. The cost-effectiveness of such testing depends on the participation rate among relatives at risk for the Lynch syndrome.Primary Funding Source: National Institutes of Health. [ABSTRACT FROM AUTHOR]

BACKGROUND: A major health priority is to increase colorectal cancer screening, and colonoscopy has become an increasingly important method of screening. The Medicare program began coverage for colonoscopy for average risk individuals in 2001. OBJECTIVES: We sought to examine whether overall colorectal cancer screening increased over time and whether these increases were a result of increased utilization of all methods or a result of greater use of colonoscopy but reduced use of other methods, whether the enactment of Medicare coverage was associated with an increase in colonoscopy among Medicare enrollees, and whether these trends equally affected subpopulations. METHODS: We used nationally representative data from the 2000 and 2003 National Health Interview Surveys and analyzed data using used chi, difference-in-differences tests, and logistic regression analyses to examine whether screening rates differed between 2000 and 2003. RESULTS: The percentage of individuals being screened for colorectal cancer using any method increased modestly from 2000 to 2003 (3%), with increases a result of increased use of colonoscopy and a reduction in the use of other methods. Increases in colonoscopy use were significant among all populations except the insured, non-Medicare population with low incomes. Among Medicare enrollees with high/middle incomes, colonoscopy use increased 14% from 2000 to 2003 compared with an increase of only 7% among low-income groups, which was a significant difference (P < 0.01). Similarly, among insured, non-Medicare enrollees with high/middle incomes, colonoscopy use increased 11% from 2000 to 2003 compared with an increase of only 4% among low-income groups, which also was a significant difference (P < 0.01). CONCLUSIONS: Colorectal cancer screening utilization increased modestly from 2000 to 2003, with the increases that primarily were the result of increased colonoscopy use. Increases in colonoscopy use, however, were primarily among high/middle income groups. Although Medicare coverage may have indirectly facilitated the increase in colonoscopy, we could not determine that coverage directly increased screening rates. Screening rates remain modest and lower income individuals continue to be screened less. Topics for future research include approaches to facilitating screening among low-income individuals and evaluating the impact of policy coverage decisions. [ABSTRACT FROM AUTHOR]

Abstract Visceral hypersensitivity may contribute to symptoms in functional dyspepsia. Selective serotonin reuptake inhibitors (SSRIs) may be beneficial in functional gastrointestinal disorders. The aim of this study was to determine whether the SSRI sertraline affects gastric sensitivity and compliance in healthy humans. Ten healthy humans completed a 6-week randomized, double-blind, crossover trial of sertraline (50 mg day -1 ) vs. placebo. After each 2-week treatment, fullness, pain and nausea were rated at increasing gastric barostat distending pressures. Sensation thresholds above minimal distending pressure (MDP) were determined with a tracking method. Somatic sensory testing was performed by hand immersion in ice water. No differences were found between sertraline and placebo for symptoms as a function of distending pressure (fullness, P = 0.72; pain, P = 0.79; nausea, P = 0.41), gastric compliance (P = 0.15), median and interquartile range thresholds for first sensation [4.1 (3.5–5.7) vs. 6.2 (3.3–10.0) mmHg above MDP, P = 0.19] and pain [15.2 (8.3–21.0) vs. 15.3 (10.3–19.8) mmHg above MDP, P = 0.85], and median tolerance times for hand ice water immersion [27 (19–99) vs. 29 (20–180) s, P = 0.73]. In conclusion, sertraline had no effect on gastric sensitivity or compliance, or somatic pain tolerance in healthy humans. Studies are needed to assess the effects of SSRIs on visceral sensation and clinical symptoms in patients with functional dyspepsia. [ABSTRACT FROM AUTHOR]

Abstract Visceral hypersensitivity may contribute to symptoms in functional dyspepsia. Selective serotonin reuptake inhibitors (SSRIs) may be beneficial in functional gastrointestinal disorders. The aim of this study was to determine whether the SSRI sertraline affects gastric sensitivity and compliance in healthy humans. Ten healthy humans completed a 6-week randomized, double-blind, crossover trial of sertraline (50 mg day -1 ) vs. placebo. After each 2-week treatment, fullness, pain and nausea were rated at increasing gastric barostat distending pressures. Sensation thresholds above minimal distending pressure (MDP) were determined with a tracking method. Somatic sensory testing was performed by hand immersion in ice water. No differences were found between sertraline and placebo for symptoms as a function of distending pressure (fullness, P = 0.72; pain, P = 0.79; nausea, P = 0.41), gastric compliance (P = 0.15), median and interquartile range thresholds for first sensation [4.1 (3.5–5.7) vs. 6.2 (3.3–10.0) mmHg above MDP, P = 0.19] and pain [15.2 (8.3–21.0) vs. 15.3 (10.3–19.8) mmHg above MDP, P = 0.85], and median tolerance times for hand ice water immersion [27 (19–99) vs. 29 (20–180) s, P = 0.73]. In conclusion, sertraline had no effect on gastric sensitivity or compliance, or somatic pain tolerance in healthy humans. Studies are needed to assess the effects of SSRIs on visceral sensation and clinical symptoms in patients with functional dyspepsia. [ABSTRACT FROM AUTHOR]

Background: Cell-free DNA blood tests (cf-bDNA) and next-generation stool tests could change colorectal cancer (CRC) screening., Objective: To estimate the clinical and economic impacts of novel CRC screening tests., Design: Cost-effectiveness analysis using MOSAIC (Model of Screening and Surveillance for Colorectal Cancer)., Data Sources: Published data., Target Population: Average-risk persons., Time Horizon: Ages 45 to 100 years., Perspective: Health sector., Intervention: Novel versus established CRC screening tests., Outcome Measures: Incidence and mortality of CRC, quality-adjusted life-years (QALYs), costs., Results of Base-Case Analysis: For colonoscopy every 10 years, annual fecal immunochemical test (FIT), and triennial next-generation multitarget stool DNA, FIT-RNA, cf-bDNA (Guardant Shield), or cf-bDNA (Freenome), the relative rates (RRs) and 95% uncertainty intervals (UIs) versus no screening for CRC incidence were 0.21 (0.19 to 0.22), 0.29 (0.27 to 0.31), 0.33 (0.32 to 0.36), 0.32 (0.30 to 0.34), 0.58 (0.55 to 0.61) and 0.58 (0.55 to 0.60), respectively; the RRs for CRC death were 0.19 (0.17 to 0.20), 0.25 (0.23 to 0.27), 0.28 (0.27 to 0.30), 0.28 (0.26 to 0.30), 0.44 (0.42 to 0.47), and 0.46 (0.44 to 0.49), respectively. The cf-bDNA test (Shield; list price $1495) cost $89 600 ($74 800 to $102 300) per QALY gained versus no screening; alternatives were less costly and more effective., Results of Sensitivity Analysis: Incremental costs exceeded incremental benefits when novel test intervals were shortened to 2 or 1 years. The cf-bDNA test matched FIT's impact on CRC mortality at 1.35 (1.30 to 1.40)-fold FIT's uptake rate, assuming equal colonoscopy follow-up. If persons who accept colonoscopy or stool tests shifted to cf-bDNA, CRC deaths increased. This adverse effect was overcome if every 3 such substitutions were counterbalanced by cf-bDNA uptake by 2 or more persons refusing alternatives, assuming equal colonoscopy follow-up., Limitation: Longitudinal test-specific participation patterns are unknown., Conclusion: First-generation cf-bDNA tests may deliver net benefit or harm, depending on the balance between achieving screening in persons who decline alternatives versus substituting cf-bDNA for more effective alternatives., Primary Funding Source: The Gorrindo Family Fund., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant inherited genetic disorder that greatly increases the risk of developing several types of cancer, including young children and young adults. LFS is primarily caused by specific mutations in the tumor suppressor gene TP53. In this study, we successfully generated two human induced pluripotent stem cell (iPSC) lines derived from patients diagnosed with LFS, each carrying a distinct heterozygous mutation in the TP53 gene. These LFS patient-derived iPSC lines exhibited robust expression of key pluripotency markers, demonstrated the capacity to differentiate into all three germ layers (endoderm, mesoderm, and ectoderm), and maintained a normal karyotype. The establishment of these iPSC lines provides a valuable tool for modeling LFS in vitro, enabling researchers to investigate the underlying pathological mechanisms associated with the disease across various cell types and tissues., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JCW is a co-founder and scientific advisory board member of Greenstone Biosciences. The other authors confirm that they do not possess any known competing financial interests or personal relationships that could have influenced the work presented in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Colorectal cancer (CRC) is the third leading cause of cancer mortality in the United States. Familial adenomatous polyposis (FAP) is a hereditary syndrome that raises the risk of developing CRC, with total colectomy as the only effective prevention. Even though FAP is rare (0.5% of all CRC cases), this disease model is well suited for studying the early stages of malignant transformation as patients form many polyps reflective of pre-cancer states. In order to spatially profile and analyze the pre-cancer and tumor microenvironment, we have performed single-cell multiplexed imaging for 52 samples: 12 normal mucosa,16 FAP mucosa,18 FAP polyps, 2 FAP adenocarcinoma, and 4 sporadic colorectal cancer (CRCs) using Co-detection by Indexing (CODEX) imaging platform. The data revealed significant changes in cell type composition occurring in early stage polyps and during the malignant transformation of polyps to CRC. We observe a decrease in CD4+/CD8+ T cell ratio and M1/M2 macrophage ratio along the FAP disease continuum. Advanced dysplastic polyps show a higher population of cancer associated fibroblasts (CAFs), which likely alter the pre-cancer microenvironment. Within polyps and CRCs, we observe strong nuclear expression of beta-catenin and higher number neo-angiogenesis events, unlike FAP mucosa and normal colon counterparts. We identify an increase in cancer stem cells (CSCs) within the glandular crypts of the FAP polyps and also detect Tregs, tumor associated macrophages (TAMs) and vascular endothelial cells supporting CSC survival and proliferation. We detect a potential immunosuppressive microenvironment within the tumor 'nest' of FAP adenocarcinoma samples, where tumor cells tend to segregate and remain distant from the invading immune cells. TAMs were found to infiltrate the tumor area, along with angiogenesis and tumor proliferation. CAFs were found to be enriched near the inflammatory region within polyps and CRCs and may have several roles in supporting tumor growth. Neighborhood analyses between adjacent FAP mucosa and FAP polyps show significant differences in spatial location of cells based on functionality. For example, in FAP mucosa, naive CD4+ T cells alone tend to localize near the fibroblast within the stromal compartment. However, in FAP polyp, CD4+T cells colocalize with the macrophages for T cell activation. Our data are expected to serve as a useful resource for understanding the early stages of neogenesis and the pre-cancer microenvironment, which may benefit early detection, therapeutic intervention and future prevention., Competing Interests: Competing interests MPS is a cofounder and scientific advisor of Crosshair Therapeutics, Exposomics, Filtricine, Fodsel, iollo, InVu Health, January AI, Marble Therapeutics, Mirvie, Next Thought AI, Orange Street Ventures, Personalis, Protos Biologics, Qbio, RTHM, SensOmics. MPS is a scientific advisor of Abbratech, Applied Cognition, Enovone, Jupiter Therapeutics, M3 Helium, Mitrix, Neuvivo, Onza, Sigil Biosciences, TranscribeGlass, WndrHLTH, Yuvan Research. MPS is a cofounder of NiMo Therapeutics. MPS is an investor and scientific advisor of R42 and Swaza. MPS is an investor in Repair Biotechnologies. W.J.G. is a consultant and equity holder for 10x Genomics, Guardant Health, Quantapore and Ultima Genomics, and cofounder of Protillion Biosciences, and is named on patents describing ATAC-seq. EDE is an employee and stockholder of Labcorp Genetics and an advisor and stockholder of Taproot Health, Exir Bio, and ROMTech. The remaining authors declare no competing interests.

Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC). We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation. These involve processes such as cell proliferation, immune response, metabolic alterations (including amino acids and lipids), hormones and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin and other nonsteroidal anti-inflammatory drugs, a preventative treatment under investigation in persons with FAP. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in CRC formation and potential mechanisms of pharmaceutical prophylaxis., Competing Interests: Competing interests: M.P.S. is a cofounder and scientific advisor of Personalis, SensOmics, Qbio, January AI, Fodsel, Filtricine, v Protos, RTHM, Iollo, Marble Therapeutics, Crosshair Therapeutics, NextThought and Mirvie. He is a scientific advisor of Jupiter, Neuvivo, Swaza, Mitrix, Yuvan, TranscribeGlass and Applied Cognition. A. Kundaje has affiliations with Biogen (consultant), SerImmune (scientific advisory board (SAB)), RavelBio (scientific cofounder and SAB) and PatchBio (SAB). K.C. is currently an AstraZeneca employee. W.J.G. has affiliations with Guardant Health (consultant and SAB), Protillion Biosciences (scientific cofounder) and 10x and has licenced patents associated with ATAC-seq. E.D.E. is an employee and stockholder of Labcorp, and advisor and stockholder of Taproot Health, Exir Bio and ROMTech. The other authors declare no competing interests., (© 2024. The Author(s).)

Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects. Genes with high promoter-enhancer (P-E) connectivity in unaffected mucosa were not linked to elevated baseline expression but tended to be upregulated in advanced stages. Inhibiting highly connected promoters preferentially represses gene expression in CRC cells compared to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P-E connectivity from a redundant state to a rate-limiting one for transcriptional levels, highlighting the intricate interplay between 3D genome architecture and gene regulation during early CRC progression., Competing Interests: Competing interests: G.K., A.J., D.L. and Z.S. are employees and shareholders of Ultima Genomics. M.P.S is a cofounder and scientific advisor of Personalis, Qbio, SensOmics, January AI, Mirvie, Protos, NiMo and Onza and is on the advisory board of Genapsys. E.D.E. is an employee and stockholder of Invitae and an advisor and stockholder of Taproot Health and Exir Bio. W.J.G. has affiliations with Guardant Health (consultant and scientific advisory board), Protillion Biosciences (Scientifica cofounder) and 10x and has licensed patents associated with ATAC-seq. All other authors declare no competing interests., (© 2024. The Author(s).)

Competing Interests: U. Ladabaum is an advisory board member for UniversalDx, Lean Medical, Vivante/Cylinder Health, and Kohler Ventures, and a consultant for Medtronic, Clinical Genomics, Guardant Health, Freenome, and Neptune Medical.

Background & Aims: Whether gastric cancer (GC) precursor lesions progress to invasive cancer at similar rates globally remains unknown. We conducted a systematic review and meta-analysis to determine the progression of precursor lesions to GC in countries with low versus medium/high incidence., Methods: We searched relevant databases for studies reporting the progression of endoscopically confirmed precursor lesions to GC. Studies were stratified by low (<6 per 100,000) or medium/high (≥6 per 100,000) GC incidence countries. Random-effects models were used to estimate the progression rates of atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia to GC per 1000 person-years., Results: Among the 5829 studies identified, 44 met our inclusion criteria. The global pooled estimates of the progression rate per 1000 person-years were 2.09 (95% confidence interval, 1.46-2.99), 2.89 (2.03-4.11), and 10.09 (5.23-19.49) for AG, IM, and dysplasia, respectively. The estimated progression rates per 1000 person-years for low versus medium/high GC incidence countries, respectively, were 0.97 (0.86-1.10) versus 2.47 (1.70-2.99) for AG (P < .01), 2.37 (1.43-3.92) versus 3.47 (2.13-5.65) for IM (P = .29), and 5.51 (2.92-10.39) versus 14.80 (5.87-37.28) for dysplasia (P = .08). There were no differences for progression of AG between groups when high-quality studies were compared., Conclusions: Similar progression rates of IM and dysplasia were observed among low and medium/high GC incidence countries. This suggests that the potential benefits of surveillance for these lesions in low-risk regions may be comparable with those of population-wide interventions in high-risk regions. Further prospective studies are needed to confirm these findings and inform global screening and surveillance guidelines., (Copyright © 2024 AGA Institute. All rights reserved.)

Background and Aims: Serrated polyps (SPs) are precursors to 15% to 20% of colorectal cancers (CRCs). However, there are uncertainties regarding which SPs require surveillance and at what intervals, with recommendations adapted from those for adenomas in the absence of solid evidence. Our aim was to assess which SP risk characteristics relate to a higher risk of metachronous CRC or advanced polyps., Methods: We systematically searched PubMed, Embase, and Cochrane for cohort studies, case-control studies, and clinical trials from inception to December 31, 2023, of CRC or advanced polyps (advanced adenoma [AA] or advanced SP) incidence at surveillance stratified by baseline SP size, dysplasia, location, and multiplicity. We defined advanced SPs as those ≥10 mm or with dysplasia. CRC and advanced polyp incidence per 1000 person-years were estimated. We performed a meta-analysis by calculating pooled relative risks (RRs) using a random-effects model., Results: A total of 5903 studies were reviewed, and 14 were included with 493,949 patients (mean age, 59.5 years; 55% men). The mean follow-up was 4.9 years. CRC incidence per 1000 person-years was 2.09 (95% confidence interval [CI], 1.29-2.90) for advanced SPs, 1.52 (95% CI, 0.78-2.25) for SPs of ≥10 mm, 5.86 (95% CI, 2.16-9.56) for SPs with dysplasia, 1.18 (95% CI, 0.77-1.60) for proximal SPs, 0.52 (95% CI, 0.08-1.12) for ≥3 SPs, 0.50 (95% CI, 0.35-0.66) for nonadvanced SPs, and 0.44 (95% CI, 0.41-0.46) for normal colonoscopy findings. Metachronous CRC risk was higher in advanced SPs versus nonadvanced SPs (RR, 1.84; 95% CI, 1.11-3.04) and versus normal colonoscopy findings (RR, 2.92; 95% CI, 2.26-3.77), in SPs of ≥10 mm versus <10 mm (RR, 2.61; 95% CI, 1.43-4.77) and versus normal colonoscopy findings (RR: 3.52; 95% CI, 2.17-5.69); and in SPs with dysplasia versus normal colonoscopy findings (RR: 2.71; 95% CI, 2.00-3.67). No increase in CRC or advanced polyp risk was found in patients with proximal versus distal SPs, nor in ≥3 SPs versus 1 or 2 SPs., Conclusions: CRC risk is significantly higher in patients with baseline advanced SPs after 4.9 years of follow-up, with risk magnitudes similar to those described for AA, supporting the current recommendation for 3-year surveillance in patients with advanced SPs., Competing Interests: Disclosure The following authors disclosed financial relationships: U. Ladabaum: Advisor for UniversalDx, Lean Medical, Vivante, and Kohler Ventures; consultant for Medtronic, Clinical Genomics, Guardant Health, Freenome and CheckCap. C. Hassan: Consultant for ERBE, Fujifilm, Odin, and Olympus; R. Jover: Advisor for MSD, Norgine, Alpha.Sigma, and GI Supply. All other authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Colorectal cancers (CRCs) arise from adenomas, which can produce fecal occult blood and can be detected endoscopically, or sessile serrated lesions (SSLs), which rarely bleed and may be more challenging to detect. Models informing CRC screening policy should reflect both pathways, accounting for uncertainty., Methods: Novel decision-analytic model of the adenoma and serrated pathways for CRC (ANSER) to compare current and emerging screening strategies, accounting for differential test sensitivities for adenomas and SSLs, and uncertainty. Strategies included colonoscopy every 10 years, stool-DNA/FIT (sDNA-FIT) every 1-3 years, or fecal immunochemical testing (FIT) every year from age 45 to 75 years. Outcomes included CRC cases and deaths, cost-effectiveness (cost/quality-adjusted life-year [QALY] gained), and burden-benefit (colonoscopies/life-year gained), with 95% uncertainty intervals (UIs)., Results: ANSER predicted 62.5 (95% UI = 58.8-66.3) lifetime CRC cases and 24.1 (95% UI = 22.5-25.7) CRC deaths/1000 45-year-olds without screening, and 78%-87% CRC mortality reductions with screening. The tests' outcome distributions overlapped for QALYs gained but separated for required colonoscopies and costs. All strategies cost less than $100 000/QALY gained vs no screening. Colonoscopy was the most effective and cost-effective, costing $9300/life-year gained (95% UI = $500-$21 900) vs FIT. sDNA-FIT cost more than $500 000/QALY gained vs FIT. As more CRCs arose from SSLs, colonoscopy remained preferred based on clinical benefit and cost-effectiveness, but cost-effectiveness improved for a next-generation sDNA-FIT., Conclusion: When the serrated pathway is considered, modeling suggests that colonoscopy is cost-effective vs FIT. In contrast, modeling suggests that sDNA-FIT is not cost-effective vs FIT despite its greater sensitivity for SSLs, even if a substantial minority of CRCs arise from SSLs., (© The Author(s) 2024. Published by Oxford University Press.)

Background & Aims: The prevalence of precursor lesions for gastric cancer (GC) and the differential burden between countries of varying GC risk is not well-understood. We conducted a systematic review and meta-analysis to estimate the global prevalence of precursor lesions., Methods: We estimated the prevalence of atrophic gastritis (AG), gastric intestinal metaplasia (IM), and dysplasia in regions with low, medium, and high GC incidence. Because IM is an advanced manifestation of AG, we assessed the prevalence of less advanced precursors, regardless of the presence of more advanced lesions. Prevalence was sub-stratified by Helicobacter pylori infection, symptomatology, and period (<2000, 2000-2010, and >2010)., Results: Among the 582 articles that underwent full-text review, 166 studies met inclusion criteria. The global prevalence estimates of AG, IM, and dysplasia were 25.4%, 16.2%, and 2.0%, respectively, on the basis of 126 studies that reported the prevalence of less advanced precursors, regardless of the presence of more advanced lesions. The prevalence of all precursor lesions was higher in high and medium compared with low GC incidence countries (P < .01). Prevalence of AG and IM was significantly higher among H pylori-infected individuals (P < .01) but not statistically different between symptomatic and asymptomatic individuals (P > .17). All precursors demonstrated a secular decrease in prevalence over time., Conclusions: Gastric precursor lesions have differences in prevalence in regions with differential GC incidence and are associated with H pylori infection. Because of the substantial prevalence of precursor lesions in both symptomatic and asymptomatic individuals, symptomatic evaluation may not be sufficient to identify individuals at risk. These estimates provide important insights for tailoring GC prevention strategies., (Copyright © 2024 AGA Institute. All rights reserved.)

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 (CMS min ) (CRC sensitivity 74%, specificity 90%) was compared with established alternatives. Test attributes were varied in sensitivity analyses., Results: CMS min 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, CMS min 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. CMS min 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: CMS min 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., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Colorectal cancer (CRC) incidence at ages <50 years is increasing worldwide. Screening initiation was lowered to 45 years in the United States. The cost-effectiveness of initiating CRC screening at 45 years in Israel was assessed with the aim of informing national policy and addressing internationally relevant questions., Methods: A validated CRC screening model was calibrated to Israeli data and examined annual fecal immunochemical testing (FIT) or colonoscopy every 10 years from 45 to 74 years (FIT45-74 or Colo45-74) versus from 50 to 74 years (FIT50-74 or Colo50-74). The addition of a fourth colonoscopy at 75 years was explored, subanalyses were performed by sex/ethnicity, and resource demands were estimated., Results: FIT50-74 and Colo50-74 reduced CRC incidence by 57% and 70% and mortality by 70% and 77%, respectively, versus no screening, with greater absolute impact in Jews/Other versus Arabs but comparable relative impact. FIT45-74 further reduced CRC incidence and mortality by an absolute 3% and 2%, respectively. With Colo45-74 versus Colo50-74, CRC cases and deaths increased slightly as three colonoscopies per lifetime shifted to 5 years earlier but mean quality-adjusted life-years gained (QALYGs) per person increased. FIT45-74 and Colo45-74 cost 23,800-53,900 new Israeli shekels (NIS)/QALYG and 110,600-162,700 NIS/QALYG, with the lowest and highest values among Jewish/Other men and Arab women, respectively. A fourth lifetime colonoscopy cost 48,700 NIS/QALYG. Lowering FIT initiation to 45 years with modest participation required 19,300 additional colonoscopies in the first 3 years., Conclusions: Beginning CRC screening at 45 years in Israel is projected to yield modest clinical benefits at acceptable costs per QALYG. Despite different estimates by sex/ethnicity, a uniform national policy is favored. These findings can inform Israeli guidelines and serve as a case study internationally., (© 2024 American Cancer Society.)

Introduction: Artificial intelligence (AI) could minimize the operator-dependent variation in colonoscopy quality. Computer-aided detection (CADe) has improved adenoma detection rate (ADR) and adenomas per colonoscopy (APC) in randomized controlled trials. There is a need to assess the impact of CADe in real-world settings., Methods: We searched MEDLINE, EMBASE, and Web of Science for nonrandomized real-world studies of CADe in colonoscopy. Random-effects meta-analyses were performed to examine the effect of CADe on ADR and APC. The study is registered under PROSPERO (CRD42023424037). There was no funding for this study., Results: Twelve of 1,314 studies met inclusion criteria. Overall, ADR was statistically significantly higher with vs without CADe (36.3% vs 35.8%, risk ratio [RR] 1.13, 95% confidence interval [CI] 1.01-1.28). This difference remained significant in subgroup analyses evaluating 6 prospective (37.3% vs 35.2%, RR 1.15, 95% CI 1.01-1.32) but not 6 retrospective (35.7% vs 36.2%, RR 1.12, 95% CI 0.92-1.36) studies. Among 6 studies with APC data, APC rate ratio with vs without CADe was 1.12 (95% CI 0.95-1.33). In 4 studies with GI Genius (Medtronic), there was no difference in ADR with vs without CADe (RR 0.96, 95% CI 0.85-1.07)., Discussion: ADR, but not APC, was slightly higher with vs without CADe among all available real-world studies. This difference was attributed to the results of prospective but not retrospective studies. The discrepancies between these findings and those of randomized controlled trials call for future research on the true impact of current AI technology on colonoscopy quality and the subtleties of human-AI interactions., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)