Characteristics of a cost-effective blood test for colorectal cancer screening.

BACKGROUND: Blood-based biomarker tests can potentially change the landscape of colorectal cancer (CRC) screening. We characterize the conditions under which blood test screening would be as effective and cost-effective as annual fecal immunochemical testing (FIT) or decennial colonoscopy. METHODS: We used the three CISNET-Colon models to compare scenarios of no screening, annual FIT, decennial colonoscopy, and a blood test meeting CMS coverage criteria (74% CRC sensitivity and 90% specificity). We varied the sensitivity to detect CRC (74%-92%), advanced adenomas (AAs, 10%-50%), screening interval (1-3 years), and test cost ($25-$500). Primary outcomes included quality-adjusted life-years gained (QALYG) from screening and costs for an US average-risk 45-year-old cohort. RESULTS: Annual FIT yielded 125-163 QALYG per 1,000 at a cost of $3,811-5,384 per person, whereas colonoscopy yielded 132-177 QALYG at a cost of $5,375-7,031 per person. A blood test with 92% CRC sensitivity and 50% AA sensitivity yielded 117-162 QALYG if used every three years and 133-173 QALYG if used every year but would not be cost-effective if priced above $125 per test. If used every three years, a $500 blood test only meeting CMS coverage criteria yielded 83-116 QALYG, at a cost of $8,559-9,413 per person. CONCLUSION: Blood tests that only meet CMS coverage requirements should not be recommended to patients who would otherwise undergo screening by colonoscopy or FIT due to lower benefit. Blood tests need higher AA sensitivity (above 40%) and lower costs (below $125) to be cost-effective.

Early-onset Colorectal Cancer Patients Do Not Require Shorter Intervals for Post-surgical Surveillance Colonoscopy.

BACKGROUND & AIMS: Early-onset colorectal cancer (EO-CRC), diagnosed before age 50, is rising in incidence worldwide. Although post-surgical colonoscopy surveillance strategies exist, appropriate intervals in EO-CRC remain elusive, as long-term surveillance outcomes remain scant. We sought to compare findings of surveillance colonoscopies of EO-CRC with patients with average onset colorectal cancer (AO-CRC) to help define surveillance outcomes in these groups. METHODS: Single-institution retrospective chart review identified EO-CRC and AO-CRC patients with colonoscopy and no evidence of disease. Surveillance intervals and time to development of advanced neoplasia (CRC and advanced polyps [adenoma/sessile serrated]) were examined. For each group, 3 serial surveillance colonoscopies were evaluated. Statistical analyses were performed utilizing log-ranked Kaplan-Meier method and Cox proportional hazards. RESULTS: A total of 1259 patients with CRC were identified, with 612 and 647 patients in the EO-CRC and AO-CRC groups, respectively. Compared with patients with AO-CRC, patients with EO-CRC had a 29% decreased risk of developing advanced neoplasia from time of initial surgery to first surveillance colonoscopy (hazard ratio, 0.71; 95% confidence interval, 0.52-1.0). Average follow-up time from surgical resection to first surveillance colonoscopy was 12.6 months for both cohorts. Overall surveillance findings differed between cohorts (P = .003), and patients with EO-CRC were found to have less advanced neoplasia compared with their counterparts with AO-CRC (12.4% vs 16.0%, respectively). Subsequent colonoscopies found that, while patients with EO-CRC returned for follow-up surveillance colonoscopy earlier than patients with AO-CRC, the EO-CRC cohort did not have more advanced neoplasia nor non-advanced adenomas. CONCLUSIONS: Patients with EO-CRC do not have an increased risk of advanced neoplasia compared with patients with AO-CRC and therefore do not require more frequent colonoscopy surveillance than current guidelines recommend.

Clinicopathological Characteristics and Risk Factors of Young-Onset Gastric Carcinoma: A Systematic Review and Meta-analysis.

INTRODUCTION: The characteristics of gastric carcinoma in young individuals differ from that in older individuals. We conducted a systematic review and meta-analysis to explore the clinicopathological features and risk factors associated with young-onset (younger than 50 years) gastric carcinoma. METHODS: We searched for studies published between January 1, 1990, and September 1, 2023, on patients with young-onset gastric carcinoma in PubMed, EMBASE, Web of Science, and MEDLINE to explore clinicopathological characteristics among this specific patient group. Extracted information included the proportion of patients with symptoms or family history of gastric cancer, tumor location, and histological features such as Lauren or World Health Organization histological classification and degree of differentiation. Additional analyses were conducted on risk factors such as positive family history, Helicobacter pylori infection, or high-risk nutritional or behavioral factors. The estimates were derived using random or fixed-effect models and included subgroup analyses based on different sex and age groups. This study was registered in PROSPERO (CRD42023466131). RESULTS: We identified 5,696 records, 1,292 were included in the quality assessment stage. Finally, 84 studies from 18 countries or regions including 89,447 patients with young-onset gastric carcinoma were included. Young-onset gastric carcinoma has slight female predominance (53.7%, 95% confidence interval [CI]: 51.6-55.7%), with most having symptoms (87.0%, 95% CI: 82.4%-91.7%). Family history was reported in 12.1% (95% CI: 9.5%-14.7%). H. pylori infection was detected in 60.0% of cases (95% CI: 47.1%-72.8%). Most of these carcinomas were in the non-cardia region (89.6%, 95% CI: 82.4%-96.8%), exhibiting Lauren diffuse-type histology (71.1%, 95% CI: 66.8%-75.3%) and poor/undifferentiated features (81.9%, 95% CI%: 79.7-84.2%). A positive family history of gastric cancer was the most important risk factor associated with the development of gastric carcinoma in young individuals (pooled odds ratios 4.0, 95% CI: 2.8-5.2), followed by H. pylori infection (odds ratio 2.3; 95% CI: 1.4-3.2) and dietary and other lifestyle risk factors. DISCUSSION: Young-onset gastric carcinoma exhibits specific clinicopathological characteristics, with positive family history being the most important risk factor. Most of the patients were symptomatic at diagnosis. These findings could help to inform future strategies for the early detection of gastric carcinoma among young individuals.

Nutritional aspects in autoimmune diseases undergoing hematopoietic stem cell transplantation: overview and recommendations on behalf of the EBMT ADWP and Nurses Group.

Autoimmune diseases (ADs) represent a heterogeneous group of conditions affecting 5-10% of the global population. In recent decades, hematopoietic stem cell transplant (HSCT), mainly autologous, has been successfully adopted to treat patients affected by severe/refractory ADs. In this context malnutrition has a detrimental impact on relapse, mortality, infection rate, engraftment, long-term survival, and prolongation of hospitalization. However, in this population, the management of nutrition should be improved since nutritional assessment is partially performed in routine clinical practice. A panel of nurses and physicians from the European Society for Blood and Marrow Transplantation (EBMT) reviewed all available evidence based on current literature and expert practices from centers with extensive experience in HSCT for ADs, on the nutritional management of ADs patients during HSCT procedure. In this context, adequate nutritional status predicts a better response to treatment and improves quality of life. Herein, a systematic and comprehensive monitoring of nutritional status before, during and after HSCT, with adequate nutritional support in the case of ADs patients, in addition to assessing the dietary requirements associated with HSCT has been covered. Moreover, given the singularity of each AD, the underlying disease should be considered for an appropriate approach. The management and evaluation of nutritional status must be carried out by a multidisciplinary team to assess the needs, monitor the effectiveness of each intervention, and prevent complications, especially in complex situations as patients affected by ADs.

Global burden of young-onset gastric cancer: a systematic trend analysis of the global burden of disease study 2019.

BACKGROUND: While gastric cancer is generally declining globally, the temporal trend of young-onset (< 40 years) gastric cancer remains uncertain. We performed this analysis to determine the temporal trends of young-onset gastric cancer compared to late-onset cancer (≥ 40 years). METHODS: We extracted cross-sectional data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. The burden of gastric cancer from 1990 to 2019 was assessed through indicators including incidence and mortality rates, which were classified at global, national, and regional levels, and according to socio-demographic indexes (SDI) and age or sex groups. Joinpoint regression analysis was used to identify specific years with significant changes. The correlation between AAPC with countries' average SDI was tested by Pearson's Test. RESULTS: The global incidence rate of young-onset gastric cancer decreased from 2.20 (per 100,000) in 1990 to 1.65 in 2019 (AAPC: - 0.95; 95% confidence interval [CI] - 1.25 to - 0.65; P < 0.001). Late-onset cancer incidence also decreased from 59.53 (per 100,000) in 1990 to 41.26 in 2019 (AAPC: - 1.23; 95% CI - 1.39 to - 1.06, P < 0.001). Despite an overall decreasing trend, the incidence rate of young-onset cancer demonstrated a significant increase from 2015 to 2019 (annual percentage change [APC]: 1.39; 95% CI 0.06 to 2.74; P = 0.041), whereas no upward trend was observed in late-onset cancer. Mortality rates of young- and late-onset cancer both exhibited a significant decline during this period (AAPC: - 1.82; 95% CI - 2.15 to - 1.56; P < 0.001 and AAPC: - 1.69, 95% CI - 1.79 to - 1.59; P < 0.001). The male-to-female rate ratio for incidence and mortality in both age groups have been increasing since 1990. While countries with high SDI have had a greater decline in the incidence of late-onset gastric cancer (slope of AAPC change: - 0.20, P = 0.004), it was not observed in young-onset cancer (slope of AAPC change: - 0.11, P = 0.13). CONCLUSIONS: The global incidence and mortality rates of both young- and late-onset gastric cancer have decreased since 1990. However, the incidence rate of young-onset cancer has demonstrated a small but significant upward trend since 2015. There was disparity in the decline in young-onset gastric cancer among male and high SDI countries. These findings could help to inform future strategies in preventing gastric cancer in younger individuals.

Prevalence of Gastric Precursor Lesions in Countries With Differential Gastric Cancer Burden: A Systematic Review and Meta-analysis.

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.

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.

Projected Colorectal Cancer Incidence and Mortality Based on Observed Adherence to Colonoscopy and Sequential Stool-Based Screening.

INTRODUCTION: Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. METHODS: The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. RESULTS: Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8-26.9) and 6.9 (5.0-9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6-2.9] for screening colonoscopy and 2.5 [1.8-3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8-18.5] and 2.9 [2.1-3.9], respectively) than HSgFOBT (20.8 [15.8-28.1] and 3.9 [2.9-5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68-0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. DISCUSSION: Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable-as observed in the national colonoscopy study, microsimulation, comparative effectiveness, screening recommendations.

Persistent SARS-CoV-2 infection: significance and implications.

SARS-CoV-2 causes persistent infections in a subset of individuals, which is a major clinical and public health problem that should be prioritised for further investigation for several reasons. First, persistent SARS-CoV-2 infection often goes unrecognised, and therefore might affect a substantial number of people, particularly immunocompromised individuals. Second, the formation of tissue reservoirs (including in non-respiratory tissues) might underlie the pathophysiology of the persistent SARS-CoV-2 infection and require new strategies for diagnosis and treatment. Finally, persistent SARS-CoV-2 replication, particularly in the setting of suboptimal immune responses, is a possible source of new, divergent virus variants that escape pre-existing immunity on the individual and population levels. Defining optimal diagnostic and treatment strategies for patients with persistent virus replication and monitoring viral evolution are therefore urgent medical and public health priorities.

Survey of white-footed mice in Connecticut, USA reveals low SARS-CoV-2 seroprevalence and infection with divergent betacoronaviruses.

Diverse mammalian species display susceptibility to and infection with SARS-CoV-2. Potential SARS-CoV-2 spillback into rodents is understudied despite their host role for numerous zoonoses and human proximity. We assessed exposure and infection among white-footed mice (Peromyscus leucopus) in Connecticut, USA. We observed 1% (6/540) wild-type neutralizing antibody seroprevalence among 2020-2022 residential mice with no cross-neutralization of variants. We detected no SARS-CoV-2 infections via RT-qPCR, but identified non-SARS-CoV-2 betacoronavirus infections via pan-coronavirus PCR among 1% (5/468) of residential mice. Sequencing revealed two divergent betacoronaviruses, preliminarily named Peromyscus coronavirus-1 and -2. Both belong to the Betacoronavirus 1 species and are ~90% identical to the closest known relative, Porcine hemagglutinating encephalomyelitis virus. Low SARS-CoV-2 seroprevalence suggests white-footed mice may not be sufficiently susceptible or exposed to SARS-CoV-2 to present a long-term human health risk. However, the discovery of divergent, non-SARS-CoV-2 betacoronaviruses expands the diversity of known rodent coronaviruses and further investigation is required to understand their transmission extent.

ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription.

The ability to balance conflicting functional demands is critical for ensuring organismal survival. The transcription and repair of the mitochondrial genome (mtDNA) requires separate enzymatic activities that can sterically compete1, suggesting a life-long trade-off between these two processes. Here in Caenorhabditis elegans, we find that the bZIP transcription factor ATFS-1/Atf5 (refs. 2,3) regulates this balance in favour of mtDNA repair by localizing to mitochondria and interfering with the assembly of the mitochondrial pre-initiation transcription complex between HMG-5/TFAM and RPOM-1/mtRNAP. ATFS-1-mediated transcriptional inhibition decreases age-dependent mtDNA molecular damage through the DNA glycosylase NTH-1/NTH1, as well as the helicase TWNK-1/TWNK, resulting in an enhancement in the functional longevity of cells and protection against decline in animal behaviour caused by targeted and severe mtDNA damage. Together, our findings reveal that ATFS-1 acts as a molecular focal point for the control of balance between genome expression and maintenance in the mitochondria.

The potential of saliva as an accessible and sensitive sample type for the detection of respiratory pathogens and host immunity.

Despite its prominence in early scientific records, the usefulness of saliva as a respiratory specimen has been de-emphasised over the past century. However, due to its low cost and reliance on specific supply chains and the non-invasive nature of its collection, its benefits over swab-based specimens are again becoming increasingly recognised. These benefits were highlighted over the course of the COVID-19 pandemic, where saliva emerged as a more practical, clinically non-inferior sample type for the detection of SARS-CoV-2 and saw numerous saliva-based diagnostic tests approved for clinical use. Looking forward, as saliva uniquely contains both respiratory secretions and immunological components, it has potentially wide applications, ranging from clinical diagnostics to post-vaccine disease burden and immunity surveillance. This Personal View seeks to summarise the existing evidence for the use of saliva in detecting respiratory pathogens, beyond SARS-CoV-2, as well as detailing methodological factors that can influence sample quality and thus, clinical utility.

High-fat-diet-associated intestinal microbiota exacerbates psoriasis-like inflammation by enhancing systemic γδ T cell IL-17 production.

Although it is known that psoriasis is strongly associated with obesity, the mechanistic connection between diet and skin lesions is not well established. Herein, we showed that only dietary fat, not carbohydrates or proteins, exacerbates psoriatic disease. Enhanced psoriatic skin inflammation was associated with changes in the intestinal mucus layer and microbiota composition by high-fat diet (HFD). Change of intestinal microbiota by vancomycin treatment effectively blocked activation of psoriatic skin inflammation by HFD, inhibited the systemic interleukin-17 (IL-17) response, and led to increased mucophilic bacterial species such as Akkermansia muciniphila. By using IL-17 reporter mice, we could show that HFD facilitates IL-17-mediated γδ T cell response in the spleen. Notably, oral gavage with live or heat-killed A. muciniphila effectively inhibited HFD-induced enhancement of psoriatic disease. In conclusion, HFD exacerbates psoriatic skin inflammation through changing the mucus barrier and the intestine microbial composition, which leads to an enhanced systemic IL-17 response.

Projected long-term effects of colorectal cancer screening disruptions following the COVID-19 pandemic.

The aftermath of the initial phase of the COVID-19 pandemic may contribute to the widening of disparities in colorectal cancer (CRC) outcomes due to differential disruptions to CRC screening. This comparative microsimulation analysis uses two CISNET CRC models to simulate the impact of ongoing screening disruptions induced by the COVID-19 pandemic on long-term CRC outcomes. We evaluate three channels through which screening was disrupted: delays in screening, regimen switching, and screening discontinuation. The impact of these disruptions on long-term CRC outcomes was measured by the number of life-years lost due to CRC screening disruptions compared to a scenario without any disruptions. While short-term delays in screening of 3-18 months are predicted to result in minor life-years loss, discontinuing screening could result in much more significant reductions in the expected benefits of screening. These results demonstrate that unequal recovery of screening following the pandemic can widen disparities in CRC outcomes and emphasize the importance of ensuring equitable recovery to screening following the pandemic.

Factors associated with detection of hereditary diffuse gastric cancer on endoscopy in individuals with germline CDH1 mutations.

BACKGROUND AND AIMS: Individuals with germline pathogenic CDH1 variants have a high risk of hereditary diffuse gastric cancer. The sensitivity of EGD in detecting signet ring cell carcinoma (SRCC) in this population is low. We aimed to identify endoscopic findings and biopsy practices associated with detection of SRCC. METHODS: This retrospective cohort included individuals with a germline pathogenic/likely pathogenic CDH1 variant undergoing at least 1 EGD at Memorial Sloan Kettering Cancer Center between January 1, 2006, and March 25, 2022. The primary outcome was detection of SRCC on EGD. Findings on gastrectomy were also assessed. The study included periods before and after implementation of the Cambridge protocol for endoscopic surveillance, allowing for assessment of a spectrum of biopsy practices. RESULTS: Ninety-eight CDH1 patients underwent at least 1 EGD at our institution. SRCC was detected in 20 (20%) individuals on EGD overall and in 50 (86%) of the 58 patients undergoing gastrectomy. Most SRCC foci were detected in the gastric cardia/fundus (EGD, 50%; gastrectomy, 62%) and body/transition zone (EGD, 60%; gastrectomy, 62%). Biopsy results of gastric pale mucosal areas were associated with detection of SRCC (P < .01). The total number of biopsy samples taken on EGD was associated with increased detection of SRCC (P = .01), with 43% detected when ≥40 samples were taken. CONCLUSIONS: Targeted biopsy sampling of gastric pale mucosal areas and increasing number of biopsy samples taken on EGD were associated with detection of SRCC. SRCC foci were mostly detected in the proximal stomach, supporting updated endoscopic surveillance guidelines. Further studies are needed to refine endoscopic protocols to improve SRCC detection in this high-risk population.

Randomized Trial of Facilitated Adherence to Screening Colonoscopy vs Sequential Fecal-Based Blood Test.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening guidelines include screening colonoscopy and sequential high-sensitivity fecal occult blood testing (HSgFOBT), with expectation of similar effectiveness based on the assumption of similar high adherence. However, adherence to screening colonoscopy compared with sequential HSgFOBT has not been reported. In this randomized clinical trial, we assessed adherence and pathology findings for a single screening colonoscopy vs sequential and nonsequential HSgFOBTs. METHODS: Participants aged 40-69 years were enrolled at 3 centers representing different clinical settings. Participants were randomized into a single screening colonoscopy arm vs sequential HSgFOBT arm composed of 4-7 rounds. Initial adherence to screening colonoscopy and sequential adherence to HSgFOBT, follow-up colonoscopy for positive HSgFOBT tests, crossover to colonoscopy, and detection of advanced neoplasia or large serrated lesions (ADN-SERs) were measured. RESULTS: There were 3523 participants included in the trial; 1761 and 1762 participants were randomized to the screening colonoscopy and HSgFOBT arms, respectively. Adherence was 1473 (83.6%) for the screening colonoscopy arm vs 1288 (73.1%) for the HSgFOBT arm after 1 round (relative risk [RR], 1.14; 95% CI, 1.10-1.19; P ≤ .001), but only 674 (38.3%) over 4 sequential HSgFOBT rounds (RR, 2.19; 95% CI, 2.05-2.33). Overall adherence to any screening increased to 1558 (88.5%) in the screening colonoscopy arm during the entire study period and 1493 (84.7%) in the HSgFOBT arm (RR, 1.04; 95% CI, 1.02-1.07). Four hundred thirty-six participants (24.7%) crossed over to screening colonoscopy during the first 4 rounds. ADN-SERs were detected in 121 of the 1473 participants (8.2%) in the colonoscopy arm who were adherent to protocol in the first 12 months of the study, whereas detection of ADN-SERs among those who were not sequentially adherent (n = 709) to HSgFOBT was subpar (0.6%) (RR, 14.72; 95% CI, 5.46-39.67) compared with those who were sequentially adherent (3.3%) (n = 647) (RR, 2.52; 95% CI, 1.61-3.98) to HSgFOBT in the first 4 rounds. When including colonoscopies from HSgFOBT patients who were never positive yet crossed over (n = 1483), 5.5% of ADN-SERs were detected (RR, 1.50; 95% CI, 1.15-1.96) in the first 4 rounds. CONCLUSIONS: Observed adherence to sequential rounds of HSgFOBT was suboptimal compared with a single screening colonoscopy. Detection of ADN-SERs was inferior when nonsequential HSgFOBT adherence was compared with sequential adherence. However, the greatest number of ADN-SERs was detected among those who crossed over to colonoscopy and opted to receive a colonoscopy. The effectiveness of an HSgFOBT screening program may be enhanced if crossover to screening colonoscopy is permitted. CLINICALTRIALS: gov, Number: NCT00102011.