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The rates of serious cardiac, neurologic, and pulmonary events attributable to colonoscopy are poorly characterized, and background event rates are usually not accounted for.We performed a multistate population-based study using changepoint analysis to determine the rates and timing of serious gastrointestinal and nongastrointestinal adverse events associated with screening/surveillance colonoscopy, including analyses by age (45 to55, 55 to65, 65 to75, and ≥75 years). Among 4.5 million persons in the Ambulatory Surgery and Services Databases of California, Florida, and New York who underwent screening/surveillance colonoscopy in 2005-2015, we ascertained serious postcolonoscopy events in excess of background rates in Emergency Department (SEDD) and Inpatient Databases (SID).Most serious nongastrointestinal postcolonoscopy events were expected based on the background rate and not associated with colonoscopy itself. However, associated nongastrointestinal events predominated over gastrointestinal events at ages ≥65 years, including more myocardial infarctions plus ischemic strokes than perforations at ages ≥75 years (361 [95% confidence intervals {CI} 312-419] plus 1,279 [95% CI 1,182-1,384] vs 912 [95% CI 831-1,002] per million). At all ages, the observed-to-expected ratios for days 0-7, 0-30, and 0-60 after colonoscopy were substantially1 for gastrointestinal bleeding and perforation, but minimally1 for most nongastrointestinal complications. Risk periods ranged from 1 to 125 days depending on complication type and age. No excess postcolonoscopy in-hospital deaths were observed.Although crude counts substantially overestimate nongastrointestinal events associated with colonoscopy, nongastrointestinal complications exceed bleeding and perforation risk in older persons. The inability to ascertain modifications to antiplatelet therapy was a study limitation. Our results can inform benefit-to-risk determinations for preventive colonoscopy.

INTRODUCTION Risk stratification has been proposed as a strategy to improve participation in colorectal cancer (CRC) screening, but evidence is lacking. We performed a randomized controlled trial of risk stratification using the National Cancer Institute's Colorectal Cancer Risk Assessment Tool (CCRAT) on screening intent and completion. METHODS A total of 230 primary care patients eligible for first-time CRC screening were randomized to risk assessment via CCRAT or education control. Follow-up of screening intent and completion was performed by record review and phone at 6 and 12 months. We analyzed change in intent after intervention, time to screening, overall screening completion rates, and screening completion by CCRAT risk score tertile. RESULTS Of the patients, 61.7% of patients were aged

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

The incidence of colorectal cancer (CRC) is increasing worldwide. CRC has high mortality when detected at advanced stages, yet it is also highly preventable. Given the difficulties in implementing major lifestyle changes or widespread primary prevention strategies to decrease CRC risk, screening is the most powerful public health tool to reduce mortality. Screening methods are effective but have limitations. Furthermore, many screen-eligible people remain unscreened. We discuss established and emerging screening methods, and potential strategies to address current limitations in CRC screening. A quantum step in CRC prevention might come with the development of new screening strategies, but great gains can be made by deploying the available CRC screening modalities in ways that optimize outcomes while making judicious use of resources.

BACKGROUND & AIMS: Sessile serrated polyps (SSPs) could account for a substantial proportion of colorectal cancers. We aimed to increase clarity on SSP prevalence and clinical features. METHODS: We performed a systematic review of Medline, Web of Science, Embase, and Cochrane databases for original studies published in English since 2000. We included studies of different populations (United States general or similar), interventions (colonoscopy, autopsy), comparisons (world regions, alternative polyp definitions, adenoma), outcomes (prevalence, clinical features), and study designs (cross-sectional). Random-effects regression was used for meta-analysis where possible. RESULTS: We identified 74 relevant colonoscopy studies. SSP prevalence varied by world region, from 2.6% in Asia (95% CI, 0–5.9%) to 10.5% in Australia (95% CI, 2.8%–18.2%). Prevalence values did not differ significantly between the United States and Europe (P=.51); the pooled prevalence was 4.6% (95% CI, 3.4%–5.8%), and SSPs accounted for 9.4% of polyps with malignant potential (95% CI, 6.6%–12.3%). Mean prevalence was higher when assessed through high-performance exams (9.1%; 95% CI, 4.0%–14.2%, P=.04) and with alternative definition of clinically relevant serrated polyps (12.3%; 95% CI, 9.3%–15.4%; P

Rates of incomplete colonoscopy in non-expert settings range up to 13%. Expert colonoscopists can complete ~ 95% colonoscopies when other endoscopists fail; however, a small number remain incomplete even in expert hands, typically due to bowel fixity. Pentax Retroview™ (EC-3490TLi) is a new slim colonoscope with a short turning radius (STR) and greater tip deflection (210°), which allows easy maneuverability across sharply angulated/fixed colonic bends. We evaluated the utility of this colonoscope for completing colonoscopies that fail even in the hands of expert colonoscopists. Retrospective chart review was performed, and main outcomes measured included cecal intubation rate, lesions detected, dosage of sedation used, and complications. Using the STR colonoscope, complete colonoscopy to the cecum was possible in 34/37 patients (91.9%). No loss of lumen/blind advancement was necessary in any of the procedures. No adverse events occurred. Among the completed colonoscopies, 6/34 (17.6%) patients had adenomas, all proximal to the site of prior failure, including one advanced adenoma. All failures (n = 3, 8.1%) had a history of cancer surgeries, with peritoneal carcinomatosis/extensively fixed/frozen bowel (two patients) and an additional diverticular stricture with colo-vesical fistula (one patient). STR colonoscope facilitates completion of a high proportion (91.9%) of colonoscopies that previously failed in expert hands. Its STR allows easy maneuverability across segments of sharp angulation with bowel fixity without need for blind advancement. The use of this colonoscope led to the detection of adenomas in 17.6% of patients, all proximal to the site of prior failed colonoscopy.

Author(s): Lee, Briton; Keyes, Erin; Rachocki, Carly; Grimes, Barbara; Chen, Ellen; Vittinghoff, Eric; Ladabaum, Uri; Somsouk, Ma | Abstract: Background a aimsReports of mailed fecal immunochemical test (FIT) outreach effectiveness over time are minimal. We aimed to better evaluate a mailed FIT program with longitudinal metrics.MethodsA total of 10,771 patients aged 50 to 75 years not up-to-date with colorectal cancer screening were randomized to intervention or usual care. The intervention arm received an advanced notification call and informational postcard prior to a mailed FIT. Usual care was at the discretion of the primary care provider. Patients were followed for up to 2.5 years. The primary outcome was the difference in cumulative proportion of completed FIT screening between arms. Screening was further examined with the proportion of time up-to-date, consistency of adherence, and frequency of abnormal FIT.ResultsThe cumulative proportion of FIT completion was higher in the outreach intervention (73.2% vs 55.1%; P l .001). The proportion of time covered by screening was higher in the intervention group (46.8% vs 27.3%; Δ19.6%; 95% confidence interval, 18.2%-20.9%). Patients assigned to FIT outreach were more likely to consistently complete FITs (2 completed of 2 offered) (50.1% vs 21.8%; P l .001). However, for patients who did not complete the FIT during the first cycle, only 17.1% completed a FIT during the second outreach cycle. The number and overall proportion of abnormal FIT was significantly higher in the outreach intervention (6.9% Outreach vs 4.1% Usual Care; P l .01).ConclusionsOrganized mailed FIT outreach significantly increased colorectal cancer screening over multiple years in this safety-net health system. Although mailing was overall effective, the effect was modest in patients who did not complete FIT in first cycle of intervention. (ClincialTrials.gov, NCT02613260).

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected patients, leading to colorectal cancer (CRC), and is an ideal model to study early transition to CRC. We performed deep multi-omic profiling of 135 normal mucosal, benign and dysplastic polyps and adenocarcinoma samples from 6 FAP patients who consented to broad data sharing. Whole genome sequencing indicates that spatially separated polyps from the same donor harbor numerous mutations in common, but evolve independently, consistent with a model of polyclonal origin and spreading. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during early hyperplasia, dysplasia and cancer formation. These involve processes such as cell proliferation, immune response, alterations in metabolism (including amino acids, 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/NSAIDs, a common preventative treatment of FAP patients. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in cancer formation and potential mechanisms of pharmaceutical prophylaxis.

To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated 451,886 single-cell chromatin accessibility profiles and 208,557 single-cell transcriptomes from 48 polyps, 27 normal tissues, and 6 CRCs collected from patients with and without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from normal to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T-cells, and a subtype of FOX-regulated pre-cancer associated fibroblasts. In the cancerous state, we observe T-cell exhaustion, RUNX1-regulated cancer associated fibroblasts, and increasing accessibility associated with HNF4A motifs in epithelia. Methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.

Background The adenoma detection rate at screening (ADR) predicts interval colorectal cancer. Monitoring other lesion detection rates and colonoscopy indications has been proposed. We developed a comprehensive, automated colonoscopy audit program based on standardized clinical documentation, explored detection rates across indications, and developed the Adenoma Detection Rate – Extended to all Screening / Surveillance (ADR-ESS) score. Methods In a prospective cohort study, we calculated overall and advanced adenoma and sessile serrated lesion (SSL) detection rates among 15,253 colonoscopies by 35 endoscopists from 4 endoscopy units across all colonoscopy indications. We explored correlations between detection rates, and the precision and stability of ADR-ESS versus ADR. Results The overall “screening, first” ADR was 36.3% (95% confidence interval [CI], 34.5%–38.1%). The adenoma detection rate was lower for “screening, not first” (relative rate [RR], 0.80; 95% CI, 0.74–0.87) and “family history” (RR, 0.84; 95% CI, 0.74–0.96), and higher for “surveillance” (RR, 1.22; 95% CI, 1.15–1.31) and “follow-up, FIT” (RR, 1.21; 95% CI, 1.07–1.37). For “screening, first,” the detection rates for advanced adenoma, SSL, and advanced SSL were 6.7% (95% CI, 5.7%–7.7%), 7.2% (95% CI, 6.2%–8.2%), and 2.6% (95% CI, 2.0%–3.2%), respectively. Adenoma and SSL detection were correlated (r = 0.44; P = .008). ADR-ESS had substantially narrower confidence intervals and less period-to-period variability than ADR, and was not improved by weighting for indication volume and correction for detection by indication. Conclusions Comprehensive, automated colonoscopy audit based on standardized clinical documentation is feasible. Adenoma detection is a fair but imperfect proxy for SSL detection. ADR-ESS increases the precision of adenoma detection assessments and emphasizes quality across colonoscopy indications.

Background and study aims Patients with cirrhosis demonstrate alterations in physiology, hemodynamics, and immunity which may increase procedural risk. There exist sparse data regarding the safety of performing ambulatory colonoscopy in patients with cirrhosis. Patients and methods From a population-based sample of three North American states (California, Florida, and New York), we collected data on 3,590 patients with cirrhosis who underwent ambulatory colonoscopy from 2009 to 2014. We created a control cohort propensity score-matched for cirrhotic severity who did not undergo colonoscopy (N = 3,590) in order to calculate the attributable risk for adverse events. The primary endpoint was the rate of unplanned hospital encounters (UHEs) within 14 days of colonoscopy (or from a synthetic index date for the control cohort). Predictors for UHE were assessed in multivariable regression. Results The attributable risk for any UHE following colonoscopy was 3.1 % (confidence interval [CI] 2.1–4.1 %, P Conclusions There is a moderate though detectable increase in risk for adverse event following ambulatory colonoscopy in patients with cirrhosis. The presence of ascites in particular portends higher risk. These data may guide clinicians when counseling patients with cirrhosis on the choice of colorectal cancer screening modality.

Background Little is known about the psychological outcomes of germline multigene panel testing, particularly among diverse patients and those with moderate‐risk pathogenic variants (PVs). Methods Study participants (N = 1264) were counseled and tested with a 25‐ or 28‐gene panel and completed a 3‐month postresult survey including the Multidimensional Impact of Cancer Risk Assessment (MICRA). Results The mean age was 52 years, 80% were female, and 70% had cancer; 45% were non‐Hispanic White, 37% were Hispanic, 10% were Asian, 3% were Black, and 5% had another race/ethnicity. Approximately 28% had a high school education or less, and 23% were non–English‐speaking. The genetic test results were as follows: 7% had a high‐risk PV, 6% had a moderate‐risk PV, 35% had a variant of uncertain significance (VUS), and 52% were negative. Most participants (92%) had a total MICRA score ≤ 38, which corresponded to a mean response of “never,” “rarely,” or only “sometimes” reacting negatively to results. A multivariate analysis found that mean total MICRA scores were significantly higher (more uncertainty/distress) among high‐ and moderate‐risk PV carriers (29.7 and 24.8, respectively) than those with a VUS or negative results (17.4 and 16.1, respectively). Having cancer or less education was associated with a significantly higher total MICRA score; race/ethnicity was not associated with the total MICRA score. High‐ and moderate‐risk PV carriers did not differ significantly from one another in the total MICRA score, uncertainty, distress, or positive experiences. Conclusions In a diverse population undergoing genetic counseling and multigene panel testing for hereditary cancer risk, the psychological response corresponded to test results and showed low distress and uncertainty. Further studies are needed to assess patient understanding and subsequent cancer screening among patients from diverse backgrounds. Lay Summary Multigene panel tests for hereditary cancer have become widespread despite concerns about adverse psychological reactions among carriers of moderate‐risk pathogenic variants (mutations) and among carriers of variants of uncertain significance.This large study of an ethnically and economically diverse cohort of patients undergoing panel testing found that 92% “never,” “rarely,” or only “sometimes” reacted negatively to results.Somewhat higher uncertainty and distress were identified among carriers of high‐ and moderate‐risk pathogenic variants, and lower levels were identified among those with a variant of uncertain significance or a negative result.Although the psychological response corresponded to risk, reactions to testing were favorable, regardless of results., Multigene panel tests for hereditary cancer have become widespread despite concerns that carriers of moderate‐risk pathogenic variants or uncertain variants could have adverse psychological reactions. This large cohort study of patients undergoing panel testing has found that the psychological response is favorable, regardless of genetic test results.

Background & Aims Colorectal cancer (CRC) incidence at ages younger than 50 years is increasing, leading to proposals to lower the CRC screening initiation age to 45 years. Data on the effectiveness of CRC screening at ages 45–49 years are lacking. Methods We studied the association between undergoing colonoscopy at ages 45–49 or 50–54 years and CRC incidence in a retrospective population-based cohort study using Florida's linked Healthcare Cost and Utilization Project databases with mandated reporting from 2005 to 2017 and Cox models extended for time-varying exposure. Results Among 195,600 persons with and 2.6 million without exposure to colonoscopy at ages 45–49 years, 276 and 4844 developed CRC, resulting in CRC incidence rates of 20.8 (95% CI, 18.5–23.4) and 30.6 (95% CI, 29.8–31.5) per 100,000 person-years, respectively. Among 660,248 persons with and 2.4 million without exposure to colonoscopy at ages 50–54 years, 798 and 6757 developed CRC, resulting in CRC incidence rates of 19.0 (95% CI, 17.7–20.4) and 51.9 (95% CI, 50.7–53.1) per 100,000 person-years, respectively. The adjusted hazard ratios for incident CRC after undergoing compared with not undergoing colonoscopy were 0.50 (95% CI, 0.44–0.56) at ages 45–49 years and 0.32 (95% CI, 0.29–0.34) at ages 50–54 years. The results were similar for women and men (hazard ratio, 0.48; 95% CI, 0.40–0.57 and hazard ratio, 0.52; 95% CI, 0.43–0.62 at ages 45–49 years, and hazard ratio, 0.35; 95% CI, 0.31–0.39 and hazard ratio, 0.29; 95% CI, 0.26–0.32 at ages 50–54 years, respectively). Conclusions Colonoscopy at ages 45–49 or 50–54 years was associated with substantial decreases in subsequent CRC incidence. These findings can inform screening guidelines.

Cost-effectiveness analysis compares benefits and costs of different interventions to inform decision makers. Alternatives are compared based on an incremental cost-effectiveness ratio reported in terms of cost per quality-adjusted life-year gained. Multiple cost-effectiveness analyses of colorectal cancer (CRC) screening have been performed. Although regional epidemiology of CRC, relevant screening strategies, regional health system, and applicable medical costs in local currencies differ by country and region, several overarching points emerge from literature on cost-effectiveness of CRC screening. Cost-effectiveness analysis informs decisions in ongoing debates, including preferred age to begin average-risk CRC screening, and implementation of CRC screening tailored to predicted CRC risk.

The American Gastroenterological Association's Center for Gastrointestinal Innovation and Technology convened a consensus conference in December 2018, entitled, "Colorectal Cancer Screening and Surveillance: Role of Emerging Technology and Innovation to Improve Outcomes." The goal of the conference, which attracted more than 60 experts in screening and related disciplines, including the authors, was to envision a future in which colorectal cancer (CRC) screening and surveillance are optimized, and to identify barriers to achieving that future. This White Paper originates from that meeting and delineates the priorities and steps needed to improve CRC outcomes, with the goal of minimizing CRC morbidity and mortality. A one-size-fits-all approach to CRC screening has not and is unlikely to result in increased screening uptake or desired outcomes owing to barriers stemming from behavioral, cultural, and socioeconomic causes, especially when combined with inefficiencies in deployment of screening technologies. Overcoming these barriers will require the following: efficient utilization of multiple screening modalities to achieve increased uptake; continued development of noninvasive screening tests, with iterative reassessments of how best to integrate new technologies; and improved personal risk assessment to better risk-stratify patients for appropriate screening testing paradigms.

Research on the communication of genetic test results has focused predominately on non-Hispanic White (NHW) mutation-positive families with high-risk hereditary cancer conditions. Little is known about this process for racially and ethnically diverse individuals or for those with mutations in moderate risk genes. The communication behaviors of study participants who carry a gene mutation were analyzed 3 months after disclosure of genetic test results. Participants were queried about communication of their results, as part of a prospective study of multi-gene panel genetic testing. The responses of particpants who tested positive were analyzed by race/ethnicity and by level of cancer risk (high vs. moderate). Of the 216 mutation-positive study participants, 136 (63%) responded. Self-reported race/ethnicity was 46% NHW, 41% Hispanic, 10% Asian, and 2% Black. The majority (99.0%, n = 135) had shared their results with someone and 96% had told a family member (n = 130). Hispanic respondents were less likely to have told a healthcare provider about their results than NHW (29% vs. 68%, p < .0001). Asian respondents were less likely than NHW to encourage family members to undergo testing (OR = 0.1, p = .03); but Asian family members were more likely to undergo testing (OR = 8.0, p = .03). There were no differences in communication between those with a mutation in a high- or moderate-risk gene. Three months post genetic testing, communication of results was very high; 30% reported a family member underwent genetic testing. Further studies are needed to better understand the communication process in individuals from diverse racial/ethnic backgrounds.

Purpose Racial/ethnic disparities in cancer survival in the United States are well documented, but the underlying causes are not well understood. We quantified the contribution of tumor, treatment, hospital, sociodemographic, and neighborhood factors to racial/ethnic survival disparities in California. Materials and Methods California Cancer Registry data were used to estimate population-based cancer-specific survival for patients diagnosed with breast, prostate, colorectal, or lung cancer between 2000 and 2013 for each racial/ethnic group (non-Hispanic black, Hispanic, Asian American and Pacific Islander, and separately each for Chinese, Japanese, and Filipino) compared with non-Hispanic whites. The percentage contribution of factors to overall racial/ethnic survival disparities was estimated from a sequence of multivariable Cox proportional hazards models. Results In baseline models, black patients had the lowest survival for all cancer sites, and Asian American and Pacific Islander patients had the highest, compared with whites. Mediation analyses suggested that stage at diagnosis had the greatest influence on overall racial/ethnic survival disparities accounting for 24% of disparities in breast cancer, 24% in prostate cancer, and 16% to 30% in colorectal cancer. Neighborhood socioeconomic status was an important factor in all cancers, but only for black and Hispanic patients. The influence of marital status on racial/ethnic disparities was stronger in men than in women. Adjustment for all covariables explained approximately half of the overall survival disparities in breast, prostate, and colorectal cancer, but it explained only 15% to 40% of disparities in lung cancer. Conclusion Overall reductions in racial/ethnic survival disparities were driven largely by reductions for black compared with white patients. Stage at diagnosis had the largest effect on racial/ethnic survival disparities, but earlier detection would not entirely eliminate them. The influences of neighborhood socioeconomic status and marital status suggest that social determinants, support mechanisms, and access to health care are important contributing factors.

The Hospital Readmissions Reduction Program (HRRP), which was instituted in 2012, may have affected readmission rates for non-target conditions, including colorectal cancer (CRC). We aimed to analyze the nationwide all-cause 30-day readmission rate following CRC surgery in a US nationwide database.We queried the 2010-2015 Nationwide Readmissions Database to estimate readmission rates. All results were weighted for national estimates.Among 616,348 index cases, the overall 2010-2015 30-day readmission rate was 14.7% (95% confidence interval, 14.5%-14.9% [n = 90,555]), with a decreasing trend from 15.5% in 2010 and 2011 to 13.5% in 2015 (p-trend0.001). Rectal resection, longer length of stay, non-invasive cancer, surgery at a metropolitan teaching hospital, non-routine discharge, elective admission, and higher Elixhauser comorbidity score were associated with subsequent readmission.In the US, 30-day readmission rates after CRC surgery showed a decreasing trend during 2010-2015, which could represent a spillover effect of the HRRP.

Background: Global increases in colorectal cancer risk have spurred debate about optimal use of screening resources. We explored the potential clinical and economic impact of colorectal cancer screening tailored to predicted colorectal cancer risk. Methods: We compared screening tailored to predicted risk versus uniform screening in a validated decision analytic model, considering the average risk population's actual colorectal cancer risk distribution, and a risk-prediction tool's discriminatory ability and cost. Low, moderate, and high risk tiers were identified as colorectal cancer risk after age 50 years of ≤3%, >3 to Results: Assuming no colorectal cancer risk misclassification or risk-prediction tool costs, tailored screening was preferred over uniform screening. Tailored colonoscopy was minimally less effective than uniform colonoscopy, but saved $90,200–$889,000/QALY; tailored FIT/colonoscopy yielded more QALYs/person than annual FIT at $10,600–$60,000/QALY gained. Relatively modest colorectal cancer risk misclassification rates or risk-prediction tool costs resulted in uniform screening as the preferred approach. Conclusions: Current risk-prediction tools may not yet be accurate enough to optimize colorectal cancer screening. Impact: Uniform screening is likely to be preferred over tailored screening if a risk-prediction tool is associated with even modest misclassification rates or costs.

Guidelines recommend screening all patients with newly diagnosed colorectal cancer (CRC) for Lynch syndrome (LS). However, the efficiency of universal LS screening in elderly populations has not been well studied.To compare the performance of age-restricted and universal LS screening using reflex mismatch repair (MMR) immunohistochemistry (IHC) of CRC tumors.Retrospective cohort study.A large, diverse, community-based health care system.3891 persons with newly diagnosed CRC who had LS screening between 2011 and 2016.Diagnostic yield of different LS screening strategies.Sixty-three LS cases (diagnostic yield, 1.62%) were identified by universal screening, with only 5 (7.9%) detected after age 70 years and 1 (1.6%) detected after age 80 years. When all patients with CRC who had universal screening were used as the denominator, 58 LS cases (diagnostic yield, 1.49% [95% CI, 1.13% to 1.92%]) were identified in patients with CRC diagnosed at or before age 70 years, 60 LS cases (diagnostic yield, 1.54% [CI, 1.18% to 1.98%]) were identified in those with CRC diagnosed at or before age 75 years, and 62 LS cases (diagnostic yield, 1.59% [CI, 1.22% to 2.04%]) were identified in those with CRC diagnosed at or before age 80 years. Using 75 years as the upper age limit for screening missed 3 of 63 (4.8%) LS cases but resulted in 1053 (27.1%) fewer cases requiring tumor MMR IHC. Using 80 years as the upper age limit missed 1 of 63 (1.6%) LS cases and resulted in 668 (17.2%) fewer cases requiring tumor MMR IHC.Persons who were eligible for but did not complete germline analysis were excluded from calculations of performance characteristics.The incremental diagnostic yield decreased substantially after age 70 to 75 years. Stopping reflex CRC screening for LS after age 80 years may be reasonable because of very low efficiency, particularly in resource-limited settings, but this merits further investigation. Studies evaluating the effect of diagnosing LS in elderly persons on their family members are needed.Kaiser Permanente Northern California Division of Research.

Gastric intestinal metaplasia and dysplasia are precursor lesions for adenocarcinoma. The risks of progression to malignancy from these lesions are not well characterized, particularly in the US populations.We identified 4,331 Kaiser Permanente Northern California members who were diagnosed with gastric intestinal metaplasia or dysplasia between 1997 and 2006 and followed them through December 2013. The incident rates of gastric adenocarcinoma, relative risks in comparison with the Kaiser Permanente general population, and predictors of progression to malignancy were investigated.Among 4,146 individuals with gastric intestinal metaplasia and 141 with low-grade dysplasia with 24,440 person-years follow-up, 17 and 6 cases of gastric adenocarcinoma were diagnosed, respectively, after 1 year from the index endoscopy. The incidence rate of gastric adenocarcinoma was 0.72/1,000 person-years in patients with intestinal metaplasia, with a relative risk of 2.56 (95% confidence interval (CI) 1.49-4.10) compared with the Kaiser Permanente member population, and 7.7/1,000 person-years for low-grade dysplasia, with a relative risk of 25.6 (95% CI, 9.4-55.7). The median time for gastric intestinal metaplasia to progress to adenocarcinoma was 6.1 years, and for low-grade dysplasia, 2.6 years. Hispanic race/ethnicity and history of dysplasia were associated with significantly higher risk of progression to gastric adenocarcinoma.Gastric intestinal metaplasia and dysplasia are significant predictors for gastric adenocarcinoma. The low risk for malignancy associated with intestinal metaplasia does not support routine endoscopic surveillance. However, surveillance should be considered in patients at higher risks, including those with suspicious endoscopic features, presence of dysplasia, and Hispanic race/ethnicity.

Persons with a family history (FH) of colorectal cancer (CRC) or adenomas that are not due to known hereditary syndromes have an increased risk for CRC. An understanding of these risks, screening recommendations, and screening behaviors can inform strategies for reducing the CRC burden in these families. A comprehensive review of the literature published within the past 10 years has been performed to assess what is known about cancer risk, screening guidelines, adherence and barriers to screening, and effective interventions in persons with an FH of CRC and to identify FH tools used to identify these individuals and inform care. Existing data show that having 1 affected first-degree relative (FDR) increases the CRC risk 2-fold, and the risk increases with multiple affected FDRs and a younger age at diagnosis. There is variability in screening recommendations across consensus guidelines. Screening adherence is

Background Tailoring screening to colorectal cancer (CRC) risk could improve screening effectiveness. Most CRCs arise from advanced neoplasia (AN) that dwells for years. To date, no available colorectal neoplasia risk score has been validated externally in a diverse population. The authors explored whether the National Cancer Institute (NCI) CRC risk-assessment tool, which was developed to predict future CRC risk, could predict current AN prevalence in a diverse population, thereby allowing its use in risk stratification for screening. Methods This was a prospective examination of the relation between predicted 10-year CRC risk and the prevalence of AN, defined as advanced or multiple (≥3 adenomatous, ≥5 serrated) adenomatous or sessile serrated polyps, in individuals undergoing screening colonoscopy. Results Among 509 screenees (50% women; median age, 58 years; 61% white, 5% black, 10% Hispanic, and 24% Asian), 58 (11%) had AN. The prevalence of AN increased progressively from 6% in the lowest risk-score quintile to 17% in the highest risk-score quintile (P = .002). Risk-score distributions in individuals with versus without AN differed significantly (median, 1.38 [0.90-1.87] vs 1.02 [0.62-1.57], respectively; P = .003), with substantial overlap. The discriminatory accuracy of the tool was modest, with areas under the curve of 0.61 (95% confidence interval [CI], 0.54-0.69) overall, 0.59 (95% CI, 0.49-0.70) for women, and 0.63 (95% CI, 0.53-0.73) for men. The results did not change substantively when the analysis was restricted to adenomatous lesions or to screening procedures without any additional incidental indication. Conclusions The NCI CRC risk-assessment tool displays modest discriminatory accuracy in predicting AN at screening colonoscopy in a diverse population. This tool may aid shared decision-making in clinical practice. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2663-2670. © 2016 American Cancer Society.

Background: Multiplex gene sequencing panels (MGP) are increasingly used for assessment of hereditary breast cancer risk. Compared to testing for BRCA1 and BRCA2 (BRCA1/2) only, testing more genes increases the likelihood of identifying a deleterious mutation (DM) and/or a variant of uncertain significance (VUS), which might cause distress, uncertainty or regret about testing. Little is known about the patient experience of MGP testing. Methods: We conducted a prospective study of MGP testing, using a panel of 25 genes: APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53. Participants were enrolled at three medical centers and were eligible if they met standard genetic testing guidelines or if they had a ≥2.5% probability of a DM in any gene on the panel, as calculated by predictive models (e.g. IBIS, Penn II, MMRPro). Participants were surveyed about their experiences with MGP testing including distress and uncertainty at baseline (before test results disclosure) and three months later. The 25-item Multidimensional Impact of Cancer Risk Assessment (MICRA) scale measured distress, uncertainty and positive experiences at three months after testing. We present a planned interim analysis after enrolling 500 of 2000 total participants. Results: Of 500 participants, 332 (66%) were referred for suspicion of hereditary breast/ovarian cancer syndrome. Of these 332, 97% were female, 79% were white, 43% were Hispanic and 33% were Spanish-speaking only; for 25%, high school was their highest level of education. A total of 48% had breast cancer, 5% had ovarian cancer, and 7% had another cancer: 11% had a DM and 35% had VUS in one or more genes. At study entry most participants thought about cancer rarely or not at all (69%, 95% confidence interval (CI) 58%-77%), and few (7%, CI 3%-14%) had thoughts of cancer that affected their daily lives; results were unchanged three months later, after genetic results disclosure (Chi-squared test, p-value >0.1). MICRA scores at three months were low for distress (mean score 2 out of a possible 30) and uncertainty (mean score 7 out of 45), and high for positive testing experiences (mean score 9 out of 15). Most (82%, CI 72%-88%) participants wanted to know all of their MGP results even if the clinical relevance was not fully understood, and most (87%, CI 79%-93%) never regretted learning their MGP results. Conclusions: Among diverse participants of a prospective, multi-center MGP testing trial, cancer- and genetic testing-related distress were low at entry and remained low three months later. These results provide no evidence for an increase in distress or uncertainty after MGP. Longer-term follow-up in a larger cohort is underway. Citation Format: Kurian AW, Idos G, McDonnell K, Ricker C, Sturgeon D, Culver J, Lowstuter K, Hartman A-R, Allen B, Rowe-Teeter C, Kingham KE, Koff RB, Lebensohn A, Chun NM, Petrovchich IM, Mills MA, Hong C, Ladabaum U, Ford JM, Gruber SB. The patient experience in a prospective trial of multiplex gene panel testing for cancer risk. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-07.

Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, and its incidence is increasing in younger persons. Established CRC screening methods include fecal immunochemical testing, which requires handling of stool, and colonoscopy, which is invasive. Many persons who remain unscreened might accept a blood-based screening test, which could have profound public health impact. DNA methylation is a stable, early, and tissue-specific event in cancer development and progression. Measuring the methylation status of tumor-derived cell-free DNA in plasma could enable identification of early-stage CRC. We first developed a plasma-based methylated DNA panel for all stages of CRC (Study 1). We then validated this panel in a subsequent study with independent samples (Study 2). Methods: Differentially methylated regions (DMRs) were initially selected by analyzing tissue data from The Cancer Genome Atlas (TCGA) database. In Study 1, candidate regions were evaluated in plasma samples of 215 patients (93 CRC, 122 controls including 31 with non-advanced adenoma) using methylation-sensitive restriction enzyme qPCR (MSRE-qPCR). This training set was used for marker evaluation and construction of a prediction model. The most promising methylation markers were selected by a support vector machine (SVM)-based machine learning classifier using a random forest algorithm. In Study 2, the selected markers were validated in an independent validation set of 724 samples collected in Spain, Ukraine, the UK, and the US (152 CRC, 622 controls including 148 with non-advanced adenoma and 52 with non-CRC cancer). Results: Tissue data analysis yielded 180 potential DMRs. In Study 1, a panel consisting of the top 12 methylation markers was selected. In Study 2, the prediction model based on this panel correctly classified 117/152 CRC (77%) patients. Sensitivity improved with CRC stage, ranging from 71% (25/35) for stage I, 76% (37/49) for stage II, 77% (37/48) for stage III, to 100% (14/14) for stage IV. Specificity of the model was 88% (544/622). Among non-CRC cancer cases, specificity was 83% overall (73% [19/26] for lung cancer and 92% [24/26] for breast cancer). Conclusions: We developed a prediction model based on a novel plasma 12-marker methylation panel that demonstrated highly promising test performance characteristics for early-stage CRC detection in a validation study using independent samples. This method could serve as the basis for a highly accurate and minimally invasive blood-based CRC screening test. Citation Format: Kristi Kruusmaa, Marko Bitenc, Walter Pulverer, Andreas Weinhaeusel, José Luis Rodrigo Agudo, Andrés Barrientos Delgado, Andrés Sánchez Yagüe, José Manuel Rodríguez Laiz, Marko Chersicola, Primož Knap, Silvia Schönthaler, Uri Ladabaum. Development and clinical performance of an accurate cell-free DNA (cfDNA) methylation assay for early detection of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A05.

Lynch syndrome is characterized by germline abnormalities in mismatch repair (MMR) genes, leading to predisposition to multiple cancers [1]. A second hit to the unaffected allele is required for tumorigenesis. MMR proteins repair incorrectly paired nucleotides and prevent generation of insertions and deletions at microsatellites [2]. Aberrancies in these MMR proteins can be a result of germline mutations or somatic alterations. Defective MMR results in microsatellite instability (MSI) and a high mutational burden [3]. The clinical implications of MSI are becoming readily apparent, as presence of MSI leads to the generation of neoantigens, stimulating tumor-associated lymphocytes [4, 5]. This has led to the use of programmed cell death protein 1 blockade for MMR-deficient tumors [6]. The U.S. Food and Drug Administration recently approved pembrolizumab for any advanced solid tumor demonstrating MSI and nivolumab for metastatic MSI colorectal cancer. However, the clinical significance of numerous MMR gene variants remains uncertain. The International Society for Gastrointestinal Hereditary Tumors classification system categorizes 2,360 MMR variants, which can be used to gauge pathogenicity [7]. There are many variants of uncertain significance (VUS; or class 3) for which clinicians are unable to provide recommendations. In this study, we employed the combination of germline testing and tumor mutational assessment to help discern the clinical relevance of VUS and guide immunotherapeutic decisions. Key Points A clinical dilemma arises when genomic testing yields variants of uncertain significance (VUS). Germline VUS were identified in two patients with gastrointestinal malignancies, but only one patient had a second-hit mutation in a mismatch repair gene leading to mismatch repair deficiency that conferred response to immunotherapy. The combination of germline testing along with tumor mutational assessment can help discern the clinical relevance of VUS and can help guide therapeutic decision-making toward individualized patient care.

Background & Aims Families with a history of Lynch syndrome often do not adhere to guidelines for genetic testing and screening. We investigated practice patterns related to Lynch syndrome worldwide, to ascertain potential targets for research and public policy efforts. Methods We collected data from the International Mismatch Repair Consortium (IMRC), which comprises major research and clinical groups engaged in the care of families with Lynch syndrome worldwide. IMRC institutions were invited to complete a questionnaire to characterize diagnoses of Lynch syndrome and management practice patterns. Results Fifty-five providers, representing 63 of 128 member institutions (49%) in 21 countries, completed the questionnaire. For case finding, 55% of respondents reported participating in routine widespread population tumor testing among persons with newly diagnosed Lynch syndrome–associated cancers, whereas 27% reported relying on clinical criteria with selective tumor and/or germline analyses. Most respondents (64%) reported using multigene panels for germline analysis, and only 28% reported testing tumors for biallelic mutations for cases in which suspected pathogenic mutations were not confirmed by germline analysis. Respondents reported relying on passive dissemination of information to at-risk family members, and there was variation in follow through of genetic testing recommendations. Reported risk management practices varied—nearly all programs (98%) recommended colonoscopy every 1 to 2 years, but only 35% recommended chemoprevention with aspirin. Conclusions There is widespread heterogeneity in management practices for Lynch syndrome worldwide among IMRC member institutions. This may reflect the rapid pace of emerging technology, regional differences in resources, and the lack of definitive data for many clinical questions. Future efforts should focus on the large numbers of high-risk patients without access to state-of-the-art Lynch syndrome management.

Background and Aims: Different post-polypectomy guidelines underscore the need for high-quality baseline colonoscopy before appropriate surveillance recommendations can be made. Standards for colonoscopy practice have been advocated by gastrointestinal societies. Our aims were to define standards for the procedural practice of colonoscopy in this particular setting of surveillance and to generate a colonoscopy procedural quality checklist that could be implemented in clinical practice. Methods: This study was based on the Delphi process methodology. The baseline questionnaire included 12 domains and 56 individual statements. A total of three rounds were carried out between September 2015 and March 2016 until consensus or lack of consensus was reached. Results: In total, consensus was reached on 27 statements in nine domains. High levels of agreement and consensus were reached that: (i) colonoscopy should be considered complete only if the whole cecum has been inspected, including the ileocecal valve and the appendiceal orifice (agreement score 4.63; degree of consensus 82%); (ii) quality of the bowel preparation should always be reported (agreement score 4.9, degree of consensus 94%); and (iii) it is preferable to use a segmental validated scale (agreement score 4.36, degree of consensus 86%). Consensus was also reached regarding multiple statements related to documentation of polyps and their resection. Finally, a colonoscopy quality checklist was drafted. Conclusion: Consensus on different statements regarding quality of colonoscopy has been reached. Based on this consensus, we propose a colonoscopy quality checklist that would be helpful for post-polypectomy surveillance recommendations.

Importance There have been substantial improvements in the early detection, treatment, and survival from cancer in the United States, but it is not clear to what extent patients with different types of health insurance have benefitted from these advancements. Objective To examine trends in cancer survival by health insurance status from January 1997 to December 2014. Design, Setting, and Participants California Cancer Registry (a statewide cancer surveillance system) data were used to estimate population-based survival by health insurance status in 3 calendar periods: January 1997 to December 2002, January 2003 to December 2008, and January 2009 to December 2014 with follow-up through 2014. Overall, 1 149 891 patients diagnosed with breast, prostate, colorectal, or lung cancer, or melanoma in California were included in the study. Main Outcomes and Measures Five-year all-cause and cancer-specific survival probabilities by insurance category and calendar period for each cancer site and sex; hazard ratios (HRs) and 95% CIs for each insurance category (none, Medicare, other public) compared with private insurance in each calendar period. Results According to data from 1 149 891 patients diagnosed with breast, prostate, colorectal, or lung cancer, or melanoma gathered from the California Cancer Registry, improvements in survival were almost exclusively limited to patients with private or Medicare insurance. For patients with other public or no insurance, survival was largely unchanged or declined. Relative to privately insured patients, cancer-specific mortality was higher in uninsured patients for all cancers except prostate, and disparities were largest from 2009 to 2014 for breast (HR, 1.72; 95% CI, 1.45-2.03), lung (men: HR, 1.18; 95% CI, 1.06-1.31 and women: HR, 1.32; 95% CI, 1.15-1.50), and colorectal cancer (women: HR, 1.30; 95% CI, 1.05-1.62). Mortality was also higher for patients with other public insurance for all cancers except lung, and disparities were largest from 2009 to 2014 for breast (HR, 1.25; 95% CI, 1.17-1.34), prostate (HR, 1.17; 95% CI, 1.04-1.31), and colorectal cancer (men: HR, 1.16; 95% CI, 1.08-1.23 and women: HR, 1.11; 95% CI, 1.03-1.20). Conclusions and Relevance After accounting for patient and clinical characteristics, survival disparities for men with prostate cancer and women with lung or colorectal cancer increased significantly over time, reflecting a lack of improvement in survival for patients with other public or no insurance. To mitigate these growing disparities, all patients with cancer need access to health insurance that covers all the necessary elements of health care, from prevention and early detection to timely treatment according to clinical guidelines.

This cancer epidemiology study uses SEER program data to describe trends in stage of incident colorectal cancer in adults aged 40-49 years between 1975 and 2015 to understand if apparent increases in incidence are due to earlier detection or true increases in risk.

BACKGROUND Colorectal cancer (CRC) screening is underused by minority populations, and patient navigation increases adherence with screening colonoscopy. In this study, the authors estimated the cost-effectiveness of navigation for screening colonoscopy from the perspective of a payer seeking to improve population health. METHODS A validated model of CRC screening was informed with inputs from navigation studies in New York City (population: 43% African American, 49% Hispanic, 4% white, 4% other; base-case screening: 40% without navigation, 65% with navigation; navigation costs: $29 per colonoscopy completer, $21 per noncompleter, $3 per non-navigated individual). Two analyses compared: 1) navigation versus no navigation for 1-time screening colonoscopy in unscreened individuals aged ≥50 years; and 2) programs of colonoscopy with versus without navigation versus fecal occult blood testing (FOBT) or fecal immunochemical testing (FIT) for individuals ages 50 to 80 years. RESULTS In the base case: 1) 1-time navigation gained quality-adjusted life-years (QALYs) and decreased costs; 2) longitudinal navigation cost $9800 per QALY gained versus no navigation, and, assuming comparable uptake rates, it cost $118,700 per QALY gained versus FOBT but was less effective and more costly than FIT. The results were most dependent on screening participation rates and navigation costs: 1) assuming a 5% increase in screening uptake with navigation, and a navigation cost of $150 per completer, 1-time navigation cost $26,400 per QALY gained; and 2) longitudinal navigation with 75% colonoscopy uptake cost

The promise of personalized medicine rests on individualized management with emphasis on the twin goals of prevention when possible, and treatment when necessary. In the case of Lynch syndrome (LS), the paradigm of identifying persons at high risk for serious disease, and intervening to improve outcomes, can be realized. LS, one of the most common inherited cancer predisposition syndromes, is caused by germline mutations that affect DNA mismatch repair (MMR) genes [1]. Persons with LS are at much higher risk for colorectal, endometrial, gastric, ovarian and other cancers than is the general population. Since most people with LS are unaware of their condition, the initial diagnosis is often based on analysis of preventable cancers. In persons diagnosed with LS, close colonoscopic surveillance [2] and prophylactic hysterectomy–oophorectomy once child-bearing is completed [3] can substantially decrease cancer incidence and mortality; furthermore, chemoprevention with aspirin may reduce the overall risk of cancer [4]. When an individual with LS is identified, testing at-risk relatives can determine who also carries the family’s LS-causing mutation and should be offered intensive management. Unaffected relatives can follow average-risk screening recommendations. In this issue of Digestive Diseases and Sciences, GouldSuarez et al. [5] use decision analytic modeling to compare the cost-effectiveness of several strategies to diagnose LS among patients presenting with colorectal cancer. The strategies considered rely on first applying the revised Bethesda guidelines (RBG), or first testing colorectal cancers for features suggestive of LS [abnormal immunohistochemistry (IHC) or microsatellite instability (MSI)], or proceeding directly to germline testing for mutations in the DNA MMR genes. The primary clinical effectiveness measure in the study was the number of true LS cases detected. The primary economic outcome was the mean cost to detect one case of LS with each strategy. Decision analytic modeling can address questions that cannot be answered directly with a definitive, controlled clinical trial—although a prospective randomized controlled trial of competing strategies to identify LS, with long enough follow-up to ascertain relevant clinical outcomes, is unlikely to ever be performed, such a trial can be simulated based on best estimates for probabilities and costs derived from the literature. Key features of a decision analysis include the time horizon and the degree to which downstream clinical and economic consequences are considered. The analysis by Gould-Suarez et al. focuses on the number of LS cases detected; it does not attempt to estimate the downstream consequences of detecting these cases. This short-term analysis has the advantage of needing a simpler model that requires fewer assumptions and model inputs than would be needed for a longer-term analysis. It has the limitation that the measure of cost-effectiveness (cost per case detected) can be difficult to interpret. Deciding what is ‘‘cost-effective’’ usually requires a judgment about willingness to pay for an incremental improvement in clinical outcome. When one strategy is more effective and less costly than another (that is, it is dominant), then the choice between strategies is straightforward. But when one strategy is more effective and more costly than another one, then the acceptability of the more U. Ladabaum (&) Gastrointestinal Cancer Prevention Program, and Clinical Cancer Genetics Program, Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Alway Bldg Rm M211, Stanford, CA 94305-5187, USA e-mail: uri.ladabaum@stanford.edu

BACKGROUND Socioeconomic status (SES) plays an important role in colorectal cancer (CRC) mortality, although the independent and joint effects with nativity and neighborhood factors have yet to be evaluated. METHODS With nearly one-third of all US Hispanics residing in California, the authors obtained information from the California Cancer Registry to examine the associations between neighborhood SES and mortality in all 33,146 Hispanic individuals diagnosed with CRC from 1988 through 2010, with a particular focus on associations among US-born and foreign-born Hispanics. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CI) for overall and CRC-specific mortality. RESULTS Hispanics residing in lower SES neighborhoods demonstrated a higher rate of overall and CRC-specific mortality than those residing in high SES neighborhoods (SES quintile 1[low] vs quintile 5 [high]: HR, 1.15 [95% CI, 1.05-1.26] and HR, 1.16 [95% CI, 1.03-1.30], respectively). Nativity modified the associations between SES and mortality (P for interaction, .02 for overall and P for interaction, .01 for CRC-specific mortality) such that the SES associations were observed only among US-born (P for trend

Background and study aims: Colorectal cancer (CRC) screening strategies in Germany include guaiac-based fecal occult blood testing (gFOBT) starting at age 50 and a switch to colonoscopy at age 55 or continued gFOBT testing, but screening utilization is limited. Blood-based biomarkers, such as methylated Septin 9 DNA ( m SEPT9), may improve screening rates. We performed a cost-effectiveness analysis of current and emerging CRC screening strategies in Germany. Methods: Using a validated Markov model, we compared annual gFOBT for ages 50 through 54 followed by biennial testing until age 75 (FOBT) or by colonoscopy at ages 55 and 65 (FOBT/COLO 55,65), substitution of fecal immunochemical testing (FIT) for gFOBT (FIT, FIT/COLO 55,65), and annual or biennial plasma m SEPT9 testing. We also considered persons who utilize only colonoscopy and varied age at colonoscopy utilization. Results: The current strategies were more effective and less costly than no screening. FIT was more effective and less costly than m SEPT9 testing. FIT/COLO 55,65 cost €12 200 per quality-adjusted life-years gained in comparison with FIT. m SEPT9-based screening was cost-effective in comparison with no screening but was dominated by other cost-saving strategies. Differential screening utilization and adherence greatly affected incremental results between strategies. In probabilistic analyses, FIT was preferred in 49 % and FIT/COLO 55,65 in 47 % of iterations. Conclusion: Currently available CRC screening strategies in Germany, including hybrid fecal testing/colonoscopy, are likely to be cost-saving. Current strategies appear superior to m SEPT9-based screening. The impact of blood-based biomarkers is likely to depend on utilization and adherence as much as on test performance characteristics and cost.

After decades of research, testing for occult blood in faeces is firmly established as a method to screen for colorectal cancer (CRC). Such testing is based on the relatively simple premise that asymptomatic CRCs, and some CRC precursors, may lose small amounts of blood into faeces. The provocative study by Libby et al in Gut ,1 which reports the associations between a positive guaiac faecal occult blood test (gFOBT) result and all-cause as well as non-CRC mortality in the National Health Service Tayside Board area of Scotland, suggests that occult blood in faeces may be telling us more than we might have thought. If the eye is the window to the soul, is a faecal test the window to general health? The current study confirms and expands on the observations of Chen et al , who reported a gradient relationship between all-cause mortality and faecal haemoglobin (f-Hb) concentration in population-based screening programmes in Keelung and Tainan, Taiwan.2 Chen et al and Libby et al found associations between occult blood in faeces and CRC mortality, which is not surprising. However, in the study by Chen et al , with median follow-up of 3.5 years and longest follow-up of 8 years, the adjusted HRs for all-cause mortality ranged from 1.15 (95% CI 1.07 to 1.24) to 1.67 (95% CI 1.54 to 2.07) for persons with f-Hb concentrations of 20–49 and ≥450 ng Hb/mL, respectively (trend test p