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US Preventive Services Task Force (USPSTF) guidelines recommend single-cancer screening for select cancers (e.g., breast, cervical, colorectal, lung). Advances in genome sequencing and machine learning have facilitated the development of blood-based multi-cancer early detection (MCED) tests intended to complement single-cancer screening. MCED tests can interrogate circulating cell-free DNA to detect a shared cancer signal across multiple tumor types. We report real-world experience with an MCED test that detected cancer signals in three individuals subsequently diagnosed with cancers of the ovary, kidney, and head/neck that lack USPSTF-recommended screening. These cases illustrate the potential of MCED tests to detect early-stage cancers amenable to cure., (© 2024. The Author(s).)

The incidence of early onset colorectal cancer, or colorectal cancer (CRC) diagnosed before age 50, is increasing. 1 In response, multiple societal guidelines in the United States now recommend initiating CRC screening at age 45 in average-risk individuals (ie, those without high-risk clinical characteristics, such as bleeding, or iron deficiency anemia), inflammatory bowel disease, or family history of colorectal neoplasia. 2 The Veterans Health Administration (VHA) is the largest integrated health system in the United States and is contending with how best to expand CRC screening access to this younger population in the setting of limited colonoscopy resources. Understanding the rate and anatomic location of colorectal neoplasia in Veterans younger than age 50 can inform the expected yield of different screening modalities. Prior work has shown that individuals undergoing colonoscopy for low-risk diagnostic indications have equivalent risk of colorectal neoplasia as those undergoing average-risk screening. 3 This study and a recent meta-analysis 4 reported that 3.6% (95% confidence interval, 1.9%-6.7%) to 3.7% (95% confidence interval, 3.0%-4.7%) of average-risk individuals age 45-49 have advanced colorectal neoplasia (ACN), defined as an advanced polyp or carcinoma; however, data specific to the VHA population are lacking., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The National Comprehensive Cancer Network (NCCN) guidelines have recommended tailored chemotherapy for stage III high-risk (T4 and/or N2) and low-risk (T1-T3 and N1) colon cancer since 2018. Studies have investigated the effect of relative dose intensity (RDI) of FOLFOX on stage III colon cancer survival, however, none has performed a stratified analysis by risk profiles. This study aims to identify the FOLFOX optimal RDI for high-risk and low-risk stage III colon cancer patients., Methods: Data on 407 eligible patients, diagnosed with stage III colon cancer in 2011 who received FOLFOX, were collected by 8 population-based cancer registries. Multivariable Cox model and Fine-Gray competing risks model were employed to explore Optimal RDI defined as the lowest RDI administered without significant differences in either overall or cause-specific death., Results: Among the 168 high-risk patients, the optimal RDI cut-off was 70% (HR = 1.59 with 95% CI: 0.69-3.66 in overall mortality; HR = 1.24 with 95% CI: 0.42-3.64 in cause-specific mortality when RDI < 70% vs. RDI ≥ 70%). Among the 239 low-risk patients, none of the evaluated cut-offs were associated with significant differences in risk of death between comparison groups. The lowest assessed RDI was 45%, HR = 0.80; 95% CI: 0.24 to 2.73 for overall mortality and HR = 0.53; 95% CI: 0.06 to 4.95 for cause-specific mortality, when RDI <45% versus RDI ≥45%., Conclusions: There is no significant harm on the risk of death when reducing RDI by <30% for high-risk patients. For the low-risk patients, we found that RDI as low as 45% did not significantly affect the risk of death., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Outreach, including patient navigation, has been shown to increase the uptake of colorectal cancer (CRC) screening in underserved populations. This analysis evaluates the cost-effectiveness of triennial multi-target stool DNA (mt-sDNA) versus outreach, with or without a mailed annual fecal immunochemical test (FIT), in a Medicaid population. A microsimulation model estimated the incremental cost-effectiveness ratio using quality-adjusted life years (QALY), direct costs, and clinical outcomes in a cohort of Medicaid beneficiaries aged 50-64 years, over a lifetime time horizon. The base case model explored scenarios of either 100% adherence or real-world reported adherence (51.3% for mt-sDNA, 21.1% for outreach with FIT and 12.3% for outreach without FIT) with or without real-world adherence for follow-up colonoscopy (66.7% for all). Costs and outcomes were discounted at 3.0%. At 100% adherence to both screening tests and follow-up colonoscopy, mt-sDNA costed more and was less effective compared with outreach with or without FIT. When real-world adherence rates were considered for screening strategies (with 100% adherence for follow-up colonoscopy), mt-sDNA resulted in the greatest reduction in incidence and mortality from CRC (41.5% and 45.8%, respectively) compared with outreach with or without FIT; mt-sDNA also was cost-effective versus outreach with and without FIT ($32,150/QALY and $22,707/QALY, respectively). mt-sDNA remained cost-effective versus FIT, with or without outreach, under real-world adherence rates for follow-up colonoscopy. Outreach or navigation interventions, with associated real-world adherence rates to screening tests, should be considered when evaluating the cost-effectiveness of CRC screening strategies in underserved populations.

The incidence of early-onset colorectal cnacer-ie, colorectal cancer diagnosed in patients under the age of 50 years- has been increasing around the world. This Series paper provides a comprehensive review on the topic of early-onset colorectal cancer, including examining the epidemiology of early-onset colorectal cancer around the world, clinical and pathological features, genetic and epigenetic landscapes, and emerging data on the clinical risk factors associated with this malignancy. Evidence-based approaches to prevention and early detection are also presented., Competing Interests: Declaration of interests SGP reports research support from Olympus America and Freenome, and honoraria from Erbe USA. JJK is an Advisor for Exact Sciences and reports Equity position and Chief Medical Officer position at Gastro Girl and GI OnDEMAND. CRB reports honoraria from Ambry Genetics. All other authors declared no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Carcinoids, frequently classified as "colorectal cancer" contribute to rising early-onset colorectal cancer (EOCRC) incidence rates (IR) and have distinct staging distributions compared to often advanced stage adenocarcinomas (screening target). Thus, assessing temporal shifts in early-onset distant stage adenocarcinoma can impact public health., Methods: 2000-2016 Surveillance Epidemiology and End Results (SEER) 18 yearly adenocarcinoma IRs were stratified by stage ( in situ , localized, regional, distant), age (20-29, 30-39, 40-49, 50-54-year-olds), subsite (colorectal, rectal-only, colon-only), and race [non-Hispanic whites, non-Hispanic Blacks (NHB), Hispanics] in 103,975 patients. Three-year average annual IR changes (pooled 2000-2002 IRs compared with 2014-2016) and cancer stage proportions (percent contribution of each cancer stage) were calculated., Results: Comparing 2000-2002 with 2014-2016, the steepest percent increases are in distant stage cancers. Colon-only, distant adenocarcinoma increased most in 30-39-year-olds (49%, 0.75/100,000→1.12/100,00, P < 0.05). Rectal-only, distant stage increases were steepest in 20-29-year-olds (133%, 0.06/100,000→0.14/100,000, P < 0.05), followed by 30-39-year-olds (97%, 0.39/100,000→0.77/100,000, P < 0.05) and 40-49-year-olds (48%, 1.38/100,000→2.04/100,000, P < 0.05). Distant stage proportions (2000-2002 to 2014-2016) increased for colon-only and rectal-only subsites in young patients with the largest increases for rectal-only in 20-29-year-olds (18%→31%) and 30-39-year-olds (20%→29%). By race, distant stage proportion increases were largest for rectal-only in 20-29-year-old NHBs (0%→46%) and Hispanics (28%→41%). Distant colon proportion increased most in 20-29-year-old NHBs (20%→34%)., Conclusions: Youngest patients show greatest burdens of distant colorectal adenocarcinoma. Although affecting all races, burdens are higher in NHB and Hispanic subgroups, although case counts remain relatively low., Impact: Optimizing earlier screening initiatives and risk-stratifying younger patients by symptoms and family history are critical to counteract rising distant stage disease., (©2022 American Association for Cancer Research.)

Colorectal cancer (CRC) incidence and mortality are rising in individuals under age 50, termed early age onset (EAO) CRC. Lower endoscopy is recommended for all patients with unexplained iron deficiency anemia (IDA) or hematochezia to assess the EAO-CRC. For those without symptoms, professional societies recommend decreasing the age to start screening from 50 to 45. Primary care provider (PCP) knowledge and practices around EAO-CRC risk assessment and screening are unknown. We conducted a survey study in May, 2020 of multi-specialty PCPs from three large medical systems to assess PCP knowledge, risk stratification practices and barriers/facilitators they face to offer CRC screening in patients < 50. We conducted univariate analysis to assess factors associated with knowledge and diagnostic practices. Response rate was 27.7% (196/708). Although 77.6% of respondents were aware that EAO-CRC incidence is increasing, only 42.9% knew that EAO-CRC mortality is also increasing. Of note, 91.8% recommend starting average risk screening at age 50. For 40- to 49-year-old patients present with unexplained IDA or hematochezia, 71.9% and 50.5% of respondents, respectively, recommend a diagnostic colonoscopy. Trainees were less likely to be aware of rising EAO-CRC mortality (odds ratio, 0.42; 95% CI, 0.21 to 0.82) and non-internal medicine providers were less likely to recommend CRC screening in those with a first-degree relative with CRC (odds ratio, 0.82; 95% CI, 0.72 to 0.93). Ongoing education efforts will be required to improve recognition and management of high-risk symptoms, particularly among non-internists and trainees., Competing Interests: CONFLICTS OF INTEREST AP: None, CJH: None, JE: None, JJK: Advisor for Exact Sciences, Equity position and Chief Medical Officer for Gastro Girl (virtual health care company) and GI On DEMAND (virtual health care platform), CLL: None, SW: Consultant Boston Scientific, Medtronic, Cernostics, Interpace, Exact Sciences. Supported by NIH/NIDDK U34DK124174 and University of Colorado Department of Medicine Outstanding Early Scholars Award, SGP: Olympus America (research support), Freenome Inc. (research support), ERBE USA (honorarium)., (Copyright © 2021 Korean Society of Cancer Prevention.)

Importance: Early-onset colorectal cancer incidence rates are rising faster in White individuals than Black individuals. However, prior National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) racial stratification analyses used smaller SEER 13 databases, combined patients under age 50 years, did not stratify by sex, and did not focus on adenocarcinoma histologic subtypes (screening target)., Objective: To perform a race- and sex-stratified adenocarcinoma incidence rate analysis in individuals aged 40 to 49 years using larger SEER 18 databases with expanded race data to better understand the colorectal cancer burden in those at or approaching screening age., Design, Setting, and Participants: This cross-sectional study used 2000 to 2017 SEER 18 annual age-adjusted colorectal cancer incidence rates stratified by anatomic subsite (colon or rectum), adenocarcinoma histology, race (non-Hispanic Black or non-Hispanic White), and sex for individuals aged 40 to 49 years, and yearly annual percent change (APC) incidence rates were calculated. Annual rate ratios (ARRs) between subgroups were determined. Statistical analysis was performed from January to March 2021., Main Outcomes and Measurements: Early-onset colorectal cancer incidence rates, APCs, and ARRs., Results: In this study, a total of 46 728 colorectal cancer cases were identified in 45 429 patients aged 40 to 49 years from 2000 to 2017. Among the 45 429 patients included in this study, 6480 (14.2%) were Black and 27 426 (60.4%) were White; the mean (SD) age was 45.5 (2.8) years. Among White individuals aged 40 to 49 years, colorectal adenocarcinoma incidence rates increased from 19.6 per 100 000 person-years in 2000 to 25.2 per 100 000 person-years in 2017 (APC, 1.6; 95% CI, 1.3 to 1.9). Among Black individuals aged 40 to 49 years, colorectal adenocarcinoma incidence rates were not significantly changed (26.4 per 100 000 person-years in 2000 and 25.8 per 100 000 person-years in 2017 [APC, -0.03; 95% CI, -0.5 to 0.5]). There were no significant differences in ARRs of absolute colorectal incidence rates between White and Black individuals from 2014 to 2017. Rectal-only absolute adenocarcinoma incidence rates in Black and White individuals remained similar from 2000 to 2008 but significantly diverged in 2009. As of 2017, rectal absolute incidence rates were 39% higher among White individuals than among Black individuals with increasing APC (APC, 2.2; 95% CI, 1.6 to 2.8) whereas rectal adenocarcinoma incidence rates among Black individuals were decreasing, although the APC was not statistically significant (APC, -1.4; 95% CI, -2.6 to 0.1). Absolute colonic adenocarcinoma incidence rates remained higher in Black individuals. The study subgroups with the largest divergence in APCs were rectal adenocarcinoma in White vs Black women (APC of 2.2 [95% CI, 1.6 to 2.8] vs APC of -1.7 [95% CI, -3.6 to 0.3], respectively)., Conclusions and Relevance: This study found that colorectal adenocarcinoma incidence rates in people aged 40 to 49 years were increasing among White individuals but stabilized among Black individuals with absolute incidence rates becoming equivalent. Absolute rectal adenocarcinoma incidence rates were 39% lower in Black individuals with a widening disparity in rectal cancer between White and Black women. Possible contributors include introduction of a screening threshold of age 45 years in Black individuals in 2008. Although the average-risk screening age has now shifted to age 45 years in all racial groups, these data can help motivate real-world implementation of guidelines to maximize screening rates that have historically been suboptimal in younger individuals.

Introduction: The Louisiana Acadian region (population 1.2 million), home of the Cajuns, has among the highest US colorectal cancer (CRC) rates. Although Cajuns are a known genetic founder population, studies assessing for hereditary CRC have not been performed., Methods: A retrospective review of 2 hospital cancer registries was performed to identify young (<55) Cajun CRC patients in Lafayette, Louisiana (the Acadian region population center), diagnosed from 2003 to 2016. Men were studied because of the higher likelihoods of retaining Cajun surnames for ancestry identification compared with women. Immunohistochemistry for mismatch repair proteins associated with the Lynch syndrome (LS) was performed on tumors. Germline sequencing was performed on adjacent normal tissue of these archived formalin-fixed paraffin-embedded surgical resection specimens for pathogenic variants underlying CRC-associated syndromes, including LS, familial adenomatous polyposis, and others., Results: Of 9 young Cajuns, a germline analysis revealed LS in 2 (MLH1 frameshift, MLH1 missense pathogenic variants). Both had immunohistochemistry-deficient MLH1. Two others had the same adenomatous polyposis coli variant of unknown significance (2 algorithms predicting deleterious and probably damaging change), making this a potential familial adenomatous polyposis founder effect candidate., Discussion: This is the first study assessing for hereditary CRC in a large US regional founder population. This small study did not identify clear Cajun founder pathogenic variants. However, larger studies are warranted, which could also help clarify the clinical significance of the adenomatous polyposis coli variant of unknown significance. This study is important because it demonstrates that a retrospective tumor analysis can be used to ascertain the prevalence of genetic susceptibility in specific populations., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Colorectal cancer-screening models commonly assume 100% adherence, which is inconsistent with real-world experience. The influence of adherence to initial stool-based screening [fecal immunochemical test (FIT), multitarget stool DNA (mt-sDNA)] and follow-up colonoscopy (after a positive stool test) on colorectal cancer outcomes was modeled using the Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model. Average-risk individuals without diagnosed colorectal cancer at age 40 undergoing annual FIT or triennial mt-sDNA screening from ages 50 to 75 were simulated. Primary analyses incorporated published mt-sDNA (71%) or FIT (43%) screening adherence, with follow-up colonoscopy adherence ranging from 40% to 100%. Secondary analyses simulated 100% adherence for stool-based screening and colonoscopy follow-up (S1), published adherence for stool-based screening with 100% adherence to colonoscopy follow-up (S2), and published adherence for both stool-based screening and colonoscopy follow-up after positive mt-sDNA (73%) or FIT (47%; S3). Outcomes were life-years gained (LYG) and colorectal cancer incidence and mortality reductions (per 1,000 individuals) versus no screening. Adherence to colonoscopy follow-up after FIT had to be 4%-13% higher than mt-sDNA to reach equivalent LYG. The theoretical S1 favored FIT versus mt-sDNA (LYG 316 vs. 297; colorectal cancer incidence reduction 68% vs. 64%; colorectal cancer mortality reduction 76% vs. 72%). The more realistic S2 and S3 favored mt-sDNA versus FIT (S2: LYG 284 vs. 245, colorectal cancer incidence reduction 61% vs. 50%, colorectal cancer mortality reduction 69% vs. 59%; S3: LYG 203 vs. 113, colorectal cancer incidence reduction 43% vs. 23%, colorectal cancer mortality reduction 49% vs. 27%, respectively). Incorporating realistic adherence rates for colorectal cancer screening influences modeled outcomes and should be considered when assessing comparative effectiveness. PREVENTION RELEVANCE: Adherence rates for initial colorectal cancer screening by FIT or mt-sDNA and for colonoscopy follow-up of a positive initial test influence the comparative effectiveness of these screening strategies. Using adherence rates based on published data for stool-based testing and colonoscopy follow-up yielded superior outcomes with an mt-sDNA versus FIT-screening strategy., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Early-onset colorectal cancer (EOCRC) incidence rates (IRs) are rising, according to previous cancer registry analyses. However, analysis of histologic subtypes, including adenocarcinoma (the focus of CRC screening and diagnostic testing) and carcinoid tumors (which are classified as "colorectal cancer" in SEER [Surveillance, Epidemiology, and End Results] databases but have a distinct pathogenesis and are managed differently from adenocarcinoma), has not been reported., Objective: To assess EOCRC IRs and changes in IRs over time, stratified by histology., Design: Retrospective analysis., Setting: Yearly IRs according to SEER 18 data from 2000 to 2016 on age-specific colon-only, rectal-only, and combined-site CRC cases, stratified by histology ("overall" CRC [all histologic subtypes], adenocarcinoma, and carcinoid tumors) and age., Patients: 119 624 patients with CRC., Measurements: IRs per 100 000 population, changes in 3-year average annual IRs (pooled IRs from 2000 to 2002 vs. those from 2014 to 2016), and annual percentage change (APC) in persons aged 20 to 29, 30 to 39, 40 to 49, and 50 to 54 years., Results: The steepest changes in adenocarcinoma 3-year average annual IRs were for rectal-only cases in persons aged 20 to 29 years (+39% [0.33 to 0.46 per 100 000]; P < 0.050) and 30 to 39 years (+39% [1.92 to 2.66 per 100 000]; P < 0.050) and colon-only cases in those aged 30 to 39 years (+20% [3.30 to 3.97 per 100 000]; P < 0.050). Corresponding APCs were 1.6% ( P < 0.050), 2.2% ( P < 0.050), and 1.2% ( P < 0.050), respectively. In persons aged 40 to 49 years, 3-year average annual IRs increased in both colon-only (+13% [12.21 to 13.85 per 100 000]; P < 0.050) and rectal-only (+16% [7.50 to 8.72 per 100 000]; P < 0.050) subsites. Carcinoid tumors were common, representing approximately 4% to 20% of all colorectal and 8% to 34% of all rectal cancer cases, depending on age group and calendar year. Colon-only carcinoid tumors were rare. Colorectal carcinoid tumor IRs increased more steeply than adenocarcinoma in all age groups, thus affecting the contribution of carcinoid tumors to overall cancer cases over time. These changes were driven by rectal subsites and were most pronounced in persons aged 50 to 54 years, in whom rectal carcinoid tumors increased by 159% (2.36 to 6.10 per 100 000) between 2000 to 2002 and 2014 to 2016, compared with 10% for adenocarcinoma (18.07 to 19.84 per 100 000), ultimately accounting for 22.6% of all rectal cancer cases., Limitation: Population-based data., Conclusion: These findings underscore the importance of assessing histologic CRC subtypes independently. Doing so may lead to a better understanding of the drivers of temporal changes in overall CRC incidence and a more accurate measurement of outcomes from efforts to reduce adenocarcinoma risk, and can guide future research., Primary Funding Source: None.

Aim: Multiple screening strategies are guideline-endorsed for average-risk colorectal cancer (CRC). The impact of real-world adherence rates on the cost-effectiveness of non-invasive stool-based CRC screening strategies remains undefined., Methods: This cost-effectiveness analysis from the perspective of Medicare as a primary payer used the Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model (CRC-AIM) to estimate cost and clinical outcomes for triennial multi-target stool DNA (mt-sDNA), annual fecal immunochemical test (FIT) and annual fecal occult blood test (FOBT) screening strategies in a simulated cohort of US adults aged 65 years, who were assumed to either be previously unscreened or initiating screening upon entry to Medicare. Reported real-world adherence rates for initial stool-based screening and colonoscopy follow up (after a positive stool test result) were defined as 71.1% and 73.0% for mt-sDNA, 42.6% and 47.0% for FIT, and 33.4% and 47.0% for FOBT, respectively. The incremental cost-effectiveness ratio using quality-adjusted life years (QALY) was defined as the primary outcome of interest; other cost and clinical outcomes were also reported in secondary analyses. Multiple sensitivity and scenario analyses were conducted., Results: When reported real-world adherence rates were included only for initial stool-based screening, mt-sDNA was cost-effective versus FIT ($62,814/QALY) and FOBT ($39,171/QALY); mt-sDNA also yielded improved clinical outcomes. When reported real-world adherence rates were included for both initial stool-based screening and follow-up colonoscopy (when indicated), mt-sDNA was increasingly cost-effective compared to FIT and FOBT ($31,725/QALY and $28,465/QALY, respectively), with further improved clinical outcomes., Limitations: Results are based on real-world cross-sectional adherence rates and may vary in the context of other types of settings. Only guideline-recommended stool-based strategies were considered in this analysis., Conclusion: Comparisons of the effectiveness and benefits of specific CRC screening strategies should include both test-specific performance characteristics and real-world adherence to screening tests and, when indicated, follow-up colonoscopy.

Background: Although early-onset colorectal cancer (EOCRC) incidence rates (IRs) are increasing, geographic and intra-racial IR disparities are not well defined., Methods: 2000-2015 Surveillance, Epidemiology, and End Results (SEER) program CRC IR Analysis (170,434 cases) was performed from ages 30 to 60 in four US regions, 18 individual registries, metropolitan and nonmetropolitan locations and stratified by race. Analyses were conducted in 1-year and 5-year age increments., Results: Wide US regional EOCRC IR variations exist: For example, age 45 IRs in the south are 26.8/100,000, 36.0% higher than the West, 19.7/100,000 (p < 0.0001). Disparities magnify between individual registries: EOCRC IRs in highest risk registries were 177-348% (Alaska Natives), 75-200% (Hawaii), 76-128% (Louisiana), and 61-125% (Kentucky) higher than lowest risk registries depending on age. EOCRC IRs are 18.2%-25.6% higher in nonmetropolitan versus metropolitan settings. Wide geographic intra-racial disparities exist. Within the White population, the greatest IR difference (78.8%) was between Kentucky (5.9/100,000) and Los Angeles (3.3/100,000) in 30- to 34-year-olds (p < .0001). Within the Black population, the greatest difference (136.2%) was between rural Georgia (30.7/100,000) and California excluding San Francisco-Oakland/San Jose-Monterey/Los Angeles (13/100,000) in 40- to 44-year-olds (p = 0003)., Conclusion: Marked geographic EOCRC disparities exist with disproportionately high IRs in Alaska Natives, Hawaii, and southern registries. Geographic intra-racial disparities are present within White and Black populations. In Blacks, there are disproportionately high EOCRC IRs in rural Georgia. Although vigilance is required in all populations, attention must be paid to these higher risk populations. Potential interventions include assuring early investigation of symptoms, targeting modifiable risk factors and utilizing earlier age 45 screening options supported by some guidelines., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Colorectal cancer screening is essential to detect and remove premalignant lesions to prevent the development of colorectal cancer. Multiple screening modalities are available, including colonoscopy and stool-based testing. Colonoscopy remains the gold standard for detection and removal of premalignant colorectal lesions. Screening guidelines by the American Cancer Society now recommend initiating screening for all average-risk adults at 45 years old. Family history of colorectal cancer, other cancers, and advanced colon polyps are strong risk factors that must be considered in order to implement earlier testing. Epidemiologic studies continue to show disparities in colorectal cancer incidence and mortality and wide variability in screening rates., Competing Interests: Disclosure J.J. Karlitz serves as consultant to Exact Sciences Corporation as well as being a consultant and part of the speakers bureau for Myriad Genetics. Dr J.J. Karlitz has an equity position in Gastro Girl., (Published by Elsevier Inc.)

Importance: Early-onset colorectal cancer incidence rates among patients aged 45 to 49 years have been considered much lower compared with the rates among patients aged 50 to 54 years, prompting debate about earlier screening benefits at 45 years. However, the observed incidence rates in the Surveillance, Epidemiology, and End Results (SEER) registries may underestimate colorectal cancer case burdens in those younger than 50 years compared with those older than 50 years because average-risk screening is generally not performed to detect preclinical cases of colorectal cancer. Finding steep incidence increases of invasive stage (beyond in situ) cases of colorectal cancer from age 49 to 50 years would be consistent with high rates of preexisting, undetected cancers in younger patients ultimately receiving a diagnosis of colorectal cancer after undergoing screening at 50 years., Objective: To assess the preclinical burden of colorectal cancer by analyzing its incidence in 1-year age increments, focusing on the transition between ages 49 and 50 years., Design, Setting, and Participants: Data from the SEER 18 registries, representing 28% of the US population, were used to conduct a cross-sectional study of colorectal cancer incidence rates from January 1, 2000, to December 31, 2015, in 1-year age increments (ages 30-60 years) stratified by US region (South, West, Northeast, and Midwest), sex, race, disease stage, and tumor location. Statistical analysis was conducted from November 1, 2018, to December 15, 2019., Main Outcomes and Measures: Incidence rates of colorectal cancer., Results: A total of 170 434 cases of colorectal cancer were analyzed among 165 160 patients (92 247 men [55.9%]; mean [SD] age, 51.6 [6.7] years). Steep increases in the incidence of colorectal cancer in the SEER 18 registries were found from 49 to 50 years of age (46.1% increase: 34.9 [95% CI, 34.1-35.8] to 51.0 [95% CI, 50.0-52.1] per 100 000 population). Steep rate increases from 49 to 50 years of age were also seen in all US regions, men and women, white and black populations, and in colon and rectal cancers. The rate ratio incidence increase in the SEER 18 registries from 49 to 50 years of age (1.46 [95% CI, 1.43-1.51]) was significantly higher than earlier 1-year age transitions. Steep rate increases in the SEER 18 registries were found from 49 to 50 years of age in localized-stage (75.9% increase: 11.2 [95% CI, 10.7-11.7] to 19.7 [95% CI, 19.0-20.3] per 100 000) and regional-stage (30.3% increase: 13.2 [95% CI, 12.7-13.8] to 17.2 [95% CI, 16.7-17.8] per 100 000) colorectal cancers. A total of 8799 of the 9474 cases (92.9%) of colorectal cancer in the SEER 18 registries from 2000 to 2015 that were diagnosed among individuals aged 50 years were invasive., Conclusions and Relevance: Steep incidence increases between 49 and 50 years of age are consistent with previously undetected colorectal cancers diagnosed via screening uptake at 50 years. These cancers are not reflected in observed rates of colorectal cancer in the SEER registries among individuals younger than 50 years. Hence, using observed incidence rates from 45 to 49 years of age alone to assess potential outcomes of earlier screening may underestimate cancer prevention benefits.

The United States has seen progress with colorectal cancer with both falling incidence and mortality rates. Factoring into this decline, the significance of early detection and removal of precancerous lesions through screening must be underscored. With the advancement of screening modalities, attention has been directed towards optimizing the quality of screening and detecting adenomas. Colorectal cancer screening has been a major agenda item for national gastroenterology societies, culminating in a major victory with passage of the Balanced Budget Act that allowed for Medicare coverage of colorectal cancer screening. Colonoscopy as the primary screening modality was solidified in the 1990s after landmark studies demonstrated its superiority over modalities for detecting precancerous polyps. Despite progress, colorectal cancer screening disparities between race and gender continue to exist. Legislative efforts are on-going and include the SCREEN Act and Dent Act that aim to further improve access to screening. The National Colorectal Cancer Roundtable has launched colorectal cancer screening initiatives targeting at risk populations. Today, the current goal of these initiatives is to reach colorectal screening rate of 80% of eligible patients by 2018. With these initiatives, efforts to narrow the gaps in screening disparities and lower overall mortality have been prioritized and continued by the medical community. This review article details colorectal cancer screening progress to date and highlights major studies and initiatives that have solidified its success in the United States., (Published by Elsevier Inc.)

Objective: Although widely recommended, Lynch syndrome (LS) testing with tumor microsatellite instability (MSI) and/or immunohistochemistry (IHC) is infrequently performed in early-onset colorectal cancer (CRC), and CRC generally. Reasons are poorly understood. Hence, we conducted a national survey focusing on gastroenterologists, as they are frequently first to diagnose CRC, assessing testing barriers and which specialist is felt responsible for ordering MSI/IHC. Additionally, we assessed factors influencing timing of MSI/IHC ordering; testing on colonoscopy biopsy, opposed to post-operative surgical specimens, assists decisions on preoperative germline genetic testing and extent of colonic resection (ECR)., Methods: A 21-question web-based survey was distributed through an American College of Gastroenterology email listing., Results: In total 509 completed the survey. 442 confirmed gastroenterologists were analyzed. Only 33.4% felt gastroenterologists were responsible for MSI/IHC ordering; pathologists were believed most responsible (38.6%). Cost, unfamiliarity interpreting results and unavailable genetic counseling most commonly prevented routine ordering (33.3%, 29.2%, 24.9%, respectively). In multivariable analysis, non-academic and rural settings were associated with cost and genetic counseling barriers. Only 46.1% felt MSI/IHC should always be performed on colonoscopy biopsy. Guideline familiarity predicted whether respondents felt surgical resection should be delayed until results returned given potential effect on ECR decisions., Conclusion: Inconsistencies in who is felt should order MSI/IHC may lead to diffusion of responsibility, preventing consistent testing, including preoperatively. Assuring institutional universal testing protocols are in place, with focus on timing of testing, can optimize care. Strategies addressing cost barriers and genomic service availability in rural and non-academic settings can enhance testing. Greater emphasis on guideline familiarity is required.

Purpose: KRAS mutations and tumor location have been associated with response to targeted therapy among patients with stage IV colorectal cancer (CRC) in various trials. This study performed the first population-based examination of associations between KRAS mutations, tumor location, and survival, and assessed factors associated with documented KRAS testing. Methods: Patients with stage IV adenocarcinoma of the colon/rectum diagnosed from 2010 to 2013 were extracted from SEER data. Analyses of patient characteristics, KRAS testing, and tumor location were conducted using logistic regression. Cox proportional hazards models assessed relationships between KRAS mutations, tumor location, and risk of all-cause death. Results: Of 22,542 patients, 30% received KRAS testing, and 44% of these had mutations. Those tested tended to be younger, married, and metropolitan area residents, and have private insurance or Medicare. Rates of KRAS testing also varied by registry (range, 20%-46%). Patients with right-sided colon cancer (vs left-sided) tended to be older, female, and black; have mucinous, KRAS -mutant tumors; and have a greater risk of death (hazard ratio [HR], 1.27; 95% CI, 1.22-1.32). KRAS mutations were not associated with greater risk of death in the overall population; however, they were associated with greater risk of death among patients with left-sided colon cancer (HR, 1.19; 95% CI, 1.05-1.33). Conclusions: This large population-based study showed that among patients initially diagnosed with stage IV CRC, right-sided colon cancer was associated with greater risk of death compared with left-sided cancer, and KRAS mutations were only associated with risk of death in left-sided colon cancer. An unexpected finding was that among patients with stage IV disease, right-sided cancer was more commonly seen in black patients versus whites. Future studies should further explore these associations and determine the role of biology versus treatment differences. In addition, use of KRAS testing is increasing, but there is wide geographic variation wherein disparities related to insurance coverage and rurality may warrant further study., (Copyright © 2017 by the National Comprehensive Cancer Network.)

Objectives: Response to epidermal growth factor receptor inhibitors is poorer among stage IV colorectal cancer (CRC) patients with KRAS mutations; thus KRAS testing is recommended before treatment. KRAS testing was collected by Surveillance, Epidemiology, and End Results (SEER) registries for 2010 CRC cases, and our goal was to provide the first population-based estimates of testing in the United States., Methods: SEER CRC cases diagnosed in 2010 were evaluated (n=30,351). χ tests and logistic regression were conducted to determine patient characteristics associated with KRAS testing, stratified by stages I-III versus stage IV. Log-rank tests were used to examine survival by testing status., Results: KRAS testing among stage IV cases ranged from 39% in New Mexico to 15% in Louisiana. In the model, younger age, being married, living in a metropolitan area, and having primary site surgery were associated with greater odds of receiving KRAS testing. Those who received testing had significantly better survival than those who did not (P<0.0001). Among those who received testing, there was no significant difference in survival by mutated versus wild-type KRAS. Five percent of stage I-III cases received testing., Conclusions: Wide variation in documented KRAS testing for stage IV CRC patients exists among SEER registries. Age remained highly significant in multivariate models, suggesting that it plays an independent role in the patient and/or provider decision to be tested. Further research is needed to determine drivers of variation in testing, as well as reasons for testing in stage I-III cases where it is not recommended.

Background: The adoption of sorafenib into oncology practice as a first-line systemic treatment for advanced hepatocellular carcinoma (HCC) is not well understood. We examined sorafenib use since Food and Drug Administration (FDA) approval in 2007 and associated survival for individuals diagnosed with advanced HCC, conducting a population-based evaluation of treatment patterns and outcomes for this newly approved drug in the US over time., Methods: We identified individuals diagnosed with Barcelona Clinic Liver Cancer Stage C from the 2007 and 2012 National Cancer Institute Patterns of Care study. We examined trends in use as well as patient and clinical factors associated with receiving sorafenib using multivariate logistic regression analysis. We then evaluated the association between sorafenib use and overall hazard of death using multivariate Cox proportional hazards regression., Results: Among 550 individuals diagnosed with advanced HCC, we found no significant increase in the proportion of patients treated with sorafenib from 2007 to 2012 (26.3 vs. 30.4%). After adjusting for patient and clinical characteristics, non-Hispanic Blacks (compared to non-Hispanic Whites) and those with a lower Child-Pugh score remained more likely to receive sorafenib. Individuals receiving systemic chemotherapy only, radiation therapy only, or no treatment at all experienced a higher risk of death than those treated with sorafenib, while those receiving a transplant experienced a lower risk of death., Conclusions: Sorafenib has not been widely adopted into oncology practice since FDA approval for advanced HCC. Few factors apart from Child-Pugh score and race/ethnicity predict sorafenib use in clinical practice, although sorafenib treatment is associated with a lower risk of death.

Objectives: Early-onset colorectal cancer (CRC) incidence rates are rising. This group is susceptible to heritable conditions (i.e., Lynch syndrome (LS)) and inflammatory bowel disease (IBD) with high metachronous CRC rates after segmental resection. Hence, extended colonic resection (ECR) is often performed and considered generally in young patients. As there are no population-based studies analyzing resection extent in early-onset CRC, we used CDC Comparative Effectiveness Research (CER) data to assess state-wide operative practices., Methods: Using CER and Louisiana Tumor Registry data, all CRC patients aged ≤50 years, diagnosed in Louisiana in 2011, who underwent surgery in 2011-2012 were retrospectively analyzed. Prevalence of, and the factors associated with operation type (ECR including subtotal/total/proctocolectomy vs. segmental resection) were evaluated., Results: Of 2,427 CRC patients, 274 were aged ≤50 years. In all, 234 underwent surgery at 53 unique facilities and 6.8% underwent ECR. Statistically significant ECR-associated factors included age ≤45 years, polyposis, synchronous/metachronous LS-associated cancers, and IBD. Abnormal microsatellite instability (MSI) was not ECR-associated. ECR was not performed in sporadic CRC., Conclusions: ECR is performed in the setting of clinically obvious associated high-risk features (polyposis, IBD, synchronous/metachronous cancers) but not in isolated/sporadic CRC. However, attention must be paid to patients with seemingly lower risk characteristics (isolated CRC, no polyposis), as LS can still be present. In addition, the presumed sporadic group requires further study as metachronous CRC risk in early-onset sporadic CRC has not been well-defined, and some may harbor undefined/undiagnosed hereditary conditions. Abnormal MSI (LS risk) is not associated with ECR; abnormal MSI results often return postoperatively after segmental resection has already occurred, which is a contributing factor.

Objectives: As there are no US population-based studies examining Lynch syndrome (LS) screening frequency by microsatellite instability (MSI) and immunohistochemistry (IHC), we seek to quantitate statewide rates in patients aged ≤50 years using data from a Centers for Disease Control and Prevention-funded Comparative Effectiveness Research (CER) project and identify factors associated with testing. Screening rates in this young, high-risk population may provide a best-case scenario as older patients, potentially deemed lower risk, may undergo testing less frequently. We also seek to determine how frequently MSI/IHC results are available preoperatively, as this may assist with decisions regarding colonic resection extent., Methods: Data from all Louisiana colorectal cancer (CRC) patients aged ≤50 years diagnosed in 2011 were obtained from the Louisiana Tumor Registry CER project. Registry researchers and physicians analyzed data, including pathology and MSI/IHC., Results: Of the 2,427 statewide all-age CRC patients, there were 274 patients aged ≤50 years, representing health care at 61 distinct facilities. MSI and/or IHC were performed in 23.0% of patients. Testing-associated factors included CRC family history (P<0.0045), urban location (P<0.0370), and care at comprehensive cancer centers (P<0.0020) but not synchronous/metachronous CRC or MSI-like histology. Public hospital screening was disproportionately low (P<0.0217). Of those tested, MSI and/or IHC was abnormal in 21.7%. Of those with abnormal IHC, staining patterns were consistent with LS in 87.5%. MSI/IHC results were available preoperatively in 16.9% of cases., Conclusions: Despite frequently abnormal MSI/IHC results, LS screening in young, high-risk patients is low. Provider education and disparities in access to specialized services, particularly in underserved populations, are possible contributors. MSI/IHC results are infrequently available preoperatively.

Objective. To describe the stroke characteristics of patients with a history of inflammatory bowel disease (IBD). Background. A hypercoagulable state associated with IBD has been frequently implicated as a risk factor for ischemic stroke. Variable mechanisms and infrequent occurrence limit prospective clinical research on the association between IBD and stroke. Methods. We retrospectively reviewed consecutive patients with acute ischemic stroke presenting to our medical center from 7/2008 to 9/2013. Patients with a history of IBD were identified. Clinical variables were abstracted from our prospective stroke registry. Results. Over the period of five years we identified only three patients with a documented history of IBD. Each of these patients presented three times to our hospital with new strokes. Patients presented outside the window for intravenous tPA treatment on 8/9 admissions. Each one of our patients had posterior strokes on at least two separate occasions. Hypercoagulation panel showed elevated factor VIII with or without concomitant elevation of Von Willebrand factor (vWF) during almost every admission (8/9 admissions). Only one admission was associated with IBD flare. Conclusion. The association between IBD and posterior strokes is a novel finding. Factor VIII elevation may serve as a biomarker of a peristroke hypercoagulable state in patients with IBD.

Objectives: Determine whether colorectal cancer (CRC) rates are disproportionately high in the French-Acadian region (population 1.2 million) of Louisiana, home of the Cajuns, a founder population., Methods: 2005-2009 cancer incidence rates were stratified by age/race/gender in the 18 Acadian parish region and 9-parish subgroup with higher proportions of French speakers and compared with Louisiana and United States rates. Parishes were identified through language census data. A total of 3,288 CRC cases were identified in the Acadian region and 11,737 in Louisiana., Results: CRC rates in whites and white males in the 18 parishes were statistically significantly higher than both Louisiana and US rates. In the 9 parishes, rates increased further; whites had an incidence of 56.1/100,000, 13% higher than Louisiana (P<0.0003) and 23% higher than US rates (P<0.0001). In white males, incidence was 72.6/100,000, 19% higher than Louisiana (P<0.0002) and 37% higher than US rates (P<0.0001). If the 9-parish regions were considered a "state," white males would have the highest CRC incidence in the United States by 11% (P<0.0175) compared with other white male populations., Conclusions: CRC rates are among the highest in the United States, increasing with the proportion of French speakers, a marker for the Cajun population. This appears to be the first study identifying a high rate of cancer in a large, regional, US founder population, raising the possibility of a genetic predisposition. Alternatively, an unidentified, robust environmental risk factor may be present. Future studies are needed to identify genetic and/or other risk factors in this population.

Background: A 30-year-old immunocompetent male with an unremarkable medical history presented with 2 months of lower abdominal bloating and loose, bloody, mucoid bowel movements. He was clinically suspected to have IBD. Due to the progression of his symptoms, he ultimately required hospitalization for further investigation and care., Investigations: Full medical history and physical examination, routine blood analyses, stool studies, hepatitis serologic tests, abdominal CT, colonoscopy, PCR analysis and light microscopy and immunoperoxidase staining of colonic biopsy samples., Diagnosis: Epstein-Barr virus (EBV)-associated lymphoproliferative disorder with diffuse colonic involvement (EBV colitis) in an immunocompetent adult., Management: Inpatient supportive care.

Randomized controlled trials of hepatitis C virus (HCV) therapy with pegylated interferon and ribavirin have demonstrated sustained viral response rates (SVRs) of 54%-63% (efficacy). Treatment results in clinical practice (effectiveness) may not be equivalent. The goal of this study was to assess the effectiveness of HCV treatment with pegylated interferon and ribavirin in a treatment-naïve, human immunodeficiency virus (HIV)-negative, United States urban population with many ethnic minority patients. We evaluated 2,370 outpatients for HCV therapy from 2001 to 2006 in the Faculty Practice of the Albert Einstein College of Medicine or the attending-supervised Montefiore Medical Center Liver Clinic. Care was supervised by one experienced physician under conditions of everyday clinical practice, and appropriate ancillary resources were made available to all patients. Two hundred fifty-five patients were treated with a mean age of 50 years (60% male, 40% female; 58% Hispanic, 20% African American, 9% Caucasian, 13% other; 68% genotype 1, the remainder genotypes 2 or 3). Patients had at least one liver biopsy. Intention-to-treat analysis (ITT) showed SVR in 14% of genotype 1 patients and 37% in genotype 2/3 patients (P < 0.001). SVR was significantly higher in faculty practice (27%) than in clinic patients (15%) by intention-to-treat (P = 0.01) but not per-protocol analysis (46% faculty practice, 34% clinic). 3.3% of 1,656 treatment-naïve, HIV antibody-negative individuals ultimately achieved SVR. Current hepatitis C therapies may sometimes be unavailable to, inappropriate for, and ineffective in United States urban patients. Treatment with pegylated interferon and ribavirin was less effective in this population than is implied by multinational phase III controlled trials. New strategies are needed to care for such patients.