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

Background: Individuals with adenomatous colorectal polyps undergo repeated colonoscopy surveillance to identify and remove metachronous adenomas. However, many patients with adenomas do not develop recurrent adenomas. Better methods to evaluate who benefits from increased surveillance are needed. We evaluated the use of altered EVL methylation as a potential biomarker for risk of recurrent adenomas. Methods: Patients with =1 colonoscopy had EVL methylation (mEVL) measured with an ultra-accurate methylation-specific droplet digital PCR assay on normal colon mucosa. The association between EVL methylation levels and adenoma or colorectal cancer was evaluated using three case/control definitions in three models: unadjusted (model 1), adjusting for baseline characteristics (model 2), and an adjusted model excluding patients with colorectal cancer at baseline (model 3). Results: Between 2001 and 2020, 136 patients were included; 74 healthy patients and 62 patients with a history of colorectal cancer. Older age, never smoking, and baseline colorectal cancer were associated with higher levels of mEVL (P = 0.05). Each log base 10 difference in mEVL was associated with an increased risk of adenoma(s) or cancer at/after baseline for model 1 [OR, 2.64; 95% confidence interval (CI), 1.09-6.36], and adenoma(s) or cancer after baseline for models 1 (OR, 2.01; 95% CI, 1.04-3.90) and model 2 (OR, 3.17; 95% CI, 1.30-7.72). Conclusions: Our results suggest that EVL methylation level detected in the normal colon mucosa has the potential to be a biomarker for monitoring the risk for recurrent adenomas. Impact: These findings support the potential utility of EVL methylation for improving the accuracy for assigning risk for recurrent colorectal adenomas and cancer. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is common cancer with a high mortality rate. Low-carbohydrate diet (LCD) score holistically evaluates the LCD pattern from carbohydrate, protein, and fat intake. Epidemiologic data of LCD-colorectal cancer association are sparse. Methods: We evaluated the associations between LCD (i.e., total, animal- and plant-based) and colorectal cancer risk in the Singapore Chinese Health Study, a population-based prospective cohort study including 61,321 Chinese in Singapore who were 45 to 74 years old at baseline. Cox proportional hazard regression model was used to determine the HRs and respective 95% confidence intervals (CI) for colorectal cancer associated with LCD after adjusting for potential confounders, including age, sex, BMI, physical activity, family history of colorectal cancer, etc. Results: After an average of 19.5 years of follow-up, 2,520 participants developed colorectal cancer (1,608 colon cancer and 912 rectal cancer). Overall, the association between total or plant-based LCD scores with the risk of colorectal, colon, or rectal cancer was null (all Ptrend = 0.28). The animal-based LCD was modestly associated with colon cancer risk (Ptrend = 0.02), but not with rectal cancer. Compared with the lowest quartile, HRs (95% CIs) of colon cancer for quartiles 2, 3, and 4 of animal-based LCD were 1.12 (0.98-1.29), 1.27 (1.10-1.46), and 1.14 (0.99-1.31), respectively. Conclusions: A low-level carbohydrate diet with a high level of animal protein and fat was associated with a moderate increase in the risk of colon cancer among Chinese Singaporeans. Impact: High consumption of animal protein/fat and low consumption of carbohydrates may increase colon cancer risk. [ABSTRACT FROM AUTHOR]

Background: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis. Methods: In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer-specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC). Results: A significant association of the TGFBR3 SNP rs7524066 with more favorable colorectal cancer-specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74-0.94; P value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68-0.98; P value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed. Conclusions: Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Biomarkers have a wide range of applications in the clinical management of cancer, including screening and therapeutic management. Tumor DNA released from neoplastic cells has become a particularly active area of cancer biomarker development due to the critical role somatic alterations play in the pathophysiology of cancer and the ability to assess released tumor DNA in accessible clinical samples, in particular blood (i.e., liquid biopsy). Many of the early applications of tumor DNA as a biomarker were pioneered in colorectal cancer due to its well-defined genetics and common occurrence, the effectiveness of early detection, and the availability of effective therapeutic options. Herein, in the context of colorectal cancer, we describe how the intended clinical application dictates desired biomarker test performance, how features of tumor DNA provide unique challenges and opportunities for biomarker development, and conclude with specific examples of clinical application of tumor DNA as a biomarker with particular emphasis on early detection. [ABSTRACT FROM AUTHOR]

Background: Telomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated. Methods: We conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer-specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P values were adjusted using Bonferroni correction. Results: The association between minor allele of rs7200950 (ACD) with colorectal cancer-specific survival varied significantly by smoking pack-years (corrected P = 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or colorectal cancer-specific survival in women but not in men. Conclusions: Our study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted. [ABSTRACT FROM AUTHOR]

Background: Low serum 25-hydroxyvitamin D [25(OH)D] concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer-specific survival. Methods: Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer-specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer. Results: The 25(OH)D decreasing allele of SNP rs2282679 (GC gene, encodes group-specific component/vitamin D-binding protein) was associated with poorer colorectal cancer-specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall [HR = 1.54; confidence interval (CI), 0.86-2.78] and colorectal cancer-specific mortality (HR = 1.76; 95% CI, 0.86-3.58). A significant increased risk of overall mortality was observed in women (HR = 3.26; 95% CI, 1.45-7.33; Pheterogeneity = 0.01) and normal-weight individuals (HR = 4.14; 95% CI, 1.50-11.43, Pheterogeneity = 0.02). Conclusions: Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer-specific survival, although power might have been an issue. Impact: Further studies are warranted to investigate the association in specific subgroups. [ABSTRACT FROM AUTHOR]

Background: Colonoscopy follow-up recommendations depend on the presence or absence of polyps, and if found, their number, size, and histology. Patients may be responsible for conveying results between primary and specialty care or providing medical information to family members; thus, accurate reporting is critical. This analysis assessed the accuracy of self-reported colonoscopy findings. Methods: 3,986 participants from the Study of Colonoscopy Utilization, an ancillary study nested within the Prostate, Lung, Colorectal, and Ovarian Screening Trial, were included. Self-reports of polyp and adenoma were compared to medical records, and measures of sensitivity and specificity were calculated. Correlates of accurate self-report of polyp were assessed using logistic regression and weighted to account for study sampling. Results: The sensitivity and specificity of self-reported polyp findings were 88% and 85%, respectively, and for adenoma 11% and 99%, respectively. Among participants with a polyp, older age was associated with lower likelihood while polyp severity and non-white race were associated with increased likelihood of accurate recall. Among participants without a polyp, having multiple colonoscopies was associated with lower likelihood while family history of colorectal cancer was associated with increased likelihood of accurate recall. Among both groups, longer time since colonoscopy was associated with lower likelihood of accurate recall. Conclusions: Participants recalled with reasonable accuracy whether they had a prior polyp; however, recall of histology, specifically adenoma, was much less accurate. Impact: Identification of strategies to increase accurate self-report of colonic polyps are needed, particularly for patient-provider communications and patient reporting of results to family members. [ABSTRACT FROM AUTHOR]

Guidelines recommend colonoscopy after an episode of diverticulitis to exclude neoplasia but the effectiveness of testing is uncertain. Patients with complicated diverticulitis may be at higher risk for neoplasia, but most patients have uncomplicated disease. We examined the incidence of colorectal cancer (CRC) and advanced adenoma (AA) in patients with diverticulitis compared with patients undergoing screening colonoscopy. CT scans from January 1, 2008, to May 1, 2013, at the University of Pittsburgh Medical Center (UPMC) were reviewed to identify those with confirmed acute diverticulitis. Subsequent surgical, colonoscopy, and pathology reports were abstracted to identify those with a diagnosis of AA and CRC. The incidence of neoplasia was compared with that reported for screening colonoscopy from a meta-analysis (n = 68,324), and from colonoscopy examinations at UPMC between 2013 and 2015 (n = 28,573). A total of 5167 abdominal/pelvic CT scan reports identified 978 patients with acute diverticulitis, among which 474 (48.5%) patients had undergone at least 1 colonoscopy or gastrointestinal surgery to April 2015. The CRC rate in patients with diverticulitis (13/474, 2.7%) was significantly higher (P <.0001) compared with both the meta-analysis (0.8%) and UPMC (0.3%). The AA rate (19/474, 4.0%) was similar to the rate in the meta-analysis (5.0%, P =.39) but significantly lower than at UPMC (7.7%, P =.003). The incidence of AA or CRC in complicated diverticulitis (10/141, 7.1%) did not differ significantly (P =.85) from the incidence of AA or CRC in uncomplicated diverticulitis (22/332, 6.6%). CRC after diverticulitis was significantly higher than that observed at screening colonoscopy and was not limited to complicated disease. Colonoscopy is advisable after the diagnosis of diverticulitis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The American Cancer Society has recommended initiating colorectal cancer (CRC) screening at age 45 years instead of 50 years. We estimated the cost effectiveness and national effects of adopting this recommendation. We compared screening strategies and alternative resource allocations in a validated Markov model. We based national projections on screening participation rates by age and census data. Screening colonoscopy initiation at age 45 years instead of 50 years in 1000 persons averted 4 CRCs and 2 CRC deaths, gained 14 quality-adjusted life-years (QALYs), cost $33,900/QALY gained, and required 758 additional colonoscopies. These 758 colonoscopies could instead be used to screen 231 currently unscreened 55-year-old persons or 342 currently unscreened 65-year-old persons, through age 75 years. These alternatives averted 13–14 CRC cases and 6–7 CRC deaths and gained 27–28 discounted QALYs while saving $163,700–$445,800. Improving colonoscopy completion rates after abnormal results from a fecal immunochemical test yielded greater benefits and savings. Initiation of fecal immunochemical testing at age 45 years instead of 50 years cost $7700/QALY gained. Shifting current age-specific screening rates to 5 years earlier could avert 29,400 CRC cases and 11,100 CRC deaths over the next 5 years but would require 10.7 million additional colonoscopies and cost an incremental $10.4 billion. Improving screening rates to 80% in persons who are 50–75 years old would avert nearly 3-fold more CRC deaths at one third the incremental cost. In a Markov model analysis, we found that starting CRC screening at age 45 years is likely to be cost effective. However, greater benefit, at lower cost, could be achieved by increasing participation rates for unscreened older and higher-risk persons. [ABSTRACT FROM AUTHOR]

Interval colorectal cancers (CRCs), cancers diagnosed after a screening/surveillance examination in which no cancer is detected, and before the date of next recommended examination, reflect an unprecedented challenge in CRC detection and prevention. To better understand this poorly characterized CRC variant, we examined the clinical and mutational characteristics of interval CRCs in comparison with screen detected CRCs. We included 1175 CRCs documented in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and 3661 CRCs in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Multivariable Cox models were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of death risk. Whole exome sequencing was conducted in 147 PLCO cases and 796 NHS/HPFS cases. A total of 619 deaths (312 CRC-specific) and 2404 deaths (1904 CRC-specific) were confirmed during follow-up of PLCO and NHS/HPFS, respectively. Compared with screen detected CRCs, interval CRCs had a multivariate-adjusted HR (95% CI) of 1.47 (1.21–1.78) for CRC-specific mortality and 1.27 (1.09–1.47) for overall mortality (meta-analysis combining all 3 cohorts). However, we did not observe significant differences in mutational features between interval and screen detected CRCs (false discovery rate adjusted P >.05). Interval CRCs had a significantly increased risk of death compared with screen detected CRCs that were not explained by established clinical prognostic factors, including stage at diagnosis. The survival disadvantage of interval CRCs did not appear to be explained by differences in the genomic landscape of tumors characterized by whole exome sequencing. [Display omitted] Colorectal cancers diagnosed between screening examinations (interval cancers) had significantly increased risk of death than screen detected cancers, although no significant molecular differences were observed between them at a whole exome sequencing level. [ABSTRACT FROM AUTHOR]

Background: Colonoscopy is the predominant method for colorectal cancer screening in the United States. Previous studies have documented variation across physicians in colonoscopy quality as measured by the adenoma detection rate (ADR). ADR is the primary quality measure of colonoscopy examinations and an indicator of the likelihood of subsequent colorectal cancer. There is interest in mechanisms to improve the ADR. In Central Illinois, a local employer and a quality improvement organization partnered to publically report physician colonoscopy quality. Objective: We assessed whether this initiative was associated with an improvement in the ADR. Design: We compared ADRs before and after public reporting at a private practice endoscopy center with 11 gastroenterologists in Peoria, Illinois, who participated in the initiative. To generate the ADR, colonoscopy and pathology reports from examinations performed over 4 years at the endoscopy center were analyzed by using previously validated natural language processing software. Setting: A central Illinois endoscopy center. Results: The ADR in the pre-public reporting period was 34.3% and 39.2% in the post-public reporting period (an increase of 4.9%, P < .001). The increase in the right-sided ADR was 5.1% (P < .01), whereas the increase in the left-sided ADR was 2.1% (P < .05). The increase in the ADR was 7.8% for screening colonoscopies (P < 0.05) and 3.5% for nonscreening colonoscopies (P < .05). All but 1 physician' s ADR increased (range -2.7% to 10.5%). There was no statistically significant change in the advanced ADR (increase of 0.8%, P = .22). Limitations: There was no concurrent control group to assess whether the increased ADR was due to a secular trend. Conclusion: A public reporting initiative on colonoscopy quality was associated with an increase in ADR. [ABSTRACT FROM AUTHOR]

Background: The adenoma detection rate (ADR) is a validated and widely used measure of colonoscopy quality. There is uncertainty in the published literature as to which colonoscopy examinations should be excluded when measuring a physician's ADR. Objective: To examine the impact of varying the colonoscopy exclusion criteria on physician ADR. Design: We applied different exclusion criteria used in 30 previous studies to a dataset of endoscopy and pathology reports. Under each exclusion criterion, we calculated physician ADR. Setting: A private practice colonoscopy center affiliated with the University of Illinois College of Medicine. Patients: Data on 20,040 colonoscopy examinations performed by 11 gastroenterologists from July 2009 to May 2013 and associated pathology notes. Main Outcome Measurements: ADRs across all colonoscopy examinations, each physician's ADR, and ADR ranking. Results: There were 28 different exclusion criteria used when measuring the ADR. Each study used a different combination of these exclusion criteria. The proportion of all colonoscopy examinations in the dataset excluded under these combinations of exclusion criteria ranged from 0% to 92.2%. The mean ADR across all colonoscopy examinations was 39.1%. The change in mean ADR after applying the 28 exclusion criteria ranged from -5.5 to +3.0 percentage points. However, the exclusion criteria affected each physician's ADR relatively equally, and therefore physicians' rankings via the ADR were stable. Limitations: ADR assessment was limited to a single private endoscopy center. Conclusion: There is wide variation in the exclusion criteria used when measuring the ADR. Although these exclusion criteria can affect overall ADRs, the relative rankings of physicians by ADR were stable. A consensus definition of which exclusion criteria are applied when measuring ADR is needed. [ABSTRACT FROM AUTHOR]

Background & Aims Anemia is a common manifestation of inflammatory bowel disease (IBD) that can greatly affect patients' quality of life. We performed a prospective study of a large cohort of patients with IBD to determine if patterns of anemia over time are associated with aggressive or disabling disease. Methods We performed a longitudinal analysis of demographic, clinical, laboratory, and treatment data from a registry of patients with IBD at the University of Pittsburgh Medical Center from 2009 through 2013. Patients with a complete follow-up evaluation (at least 1 annual visit with laboratory results) were included. Anemia was defined by World Health Organization criteria. Disease activity scores (the Harvey–Bradshaw Index or the ulcerative colitis activity index) and quality-of-life scores (based on the short IBD questionnaire) were determined at each visit; laboratory data, including levels of C-reactive protein and erythrocyte sedimentation rates, as well as patterns of IBD-related health care use, were analyzed. Results A total of 410 IBD patients (245 with Crohn’s disease, 165 with ulcerative colitis; 50.5% female) were included. The prevalence of anemia in patients with IBD was 37.1% in 2009 and 33.2% in 2013. Patients with IBD and anemia required significantly more health care and had higher indices of disease activity, as well as a lower average quality of life, than patients without anemia ( P < .0001). Anemia (persistent or recurrent) for 3 or more years was correlated independently with hospitalizations ( P < .01), visits to gastroenterology clinics ( P < .001), telephone calls ( P < .004), surgeries for IBD ( P = .01), higher levels of C-reactive protein (in patients with ulcerative colitis, P = .001), and a higher erythrocyte sedimentation rate ( P < .0001). Anemia was correlated negatively with quality-of-life scores ( P < .03). Conclusions Based on a longitudinal analysis of 410 patients, persistent or recurrent anemia correlates with more aggressive or disabling disease in patients with IBD. [ABSTRACT FROM AUTHOR]

There is a need to develop a colorectal cancer (CRC) screening test that is noninvasive, cost effective, and sensitive enough to detect preneoplastic lesions. This case-control study examined the feasibility of using circulating extracellular microRNAs (miRNAs) to differentiate a spectrum of colorectal neoplasia of various severity and hence for early detection of colorectal neoplasia. Archived serum samples of 10 normal controls and 31 cases, including 10 with nonadvanced adenoma, 10 with advanced adenoma, and 11 with CRC, were profiled for circulating miRNAs using next-generation sequencing. Multiple linear regression, adjusting for age, gender, and smoking status, compared controls and the 3 case groups for levels of 175 miRNAs that met stringent criteria for miRNA sequencing analysis. Of the 175 miRNAs, 106 miRNAs were downregulated according to severity of neoplasia and showed a relative decrease in the expression from controls to nonadvanced adenoma to advanced adenoma to CRC (P trend < 0.05). Pairwise group comparisons showed that 39 and 80 miRNAs were differentially expressed in the advanced adenoma and CRC groups compared with the controls, respectively. Differences in miRNA levels between the nonadvanced adenoma group and controls were modest. Our study found that expression of many miRNAs in serum was inversely correlated with the severity of colorectal neoplasia, and differential miRNA profiles were apparent in preneoplastic cases with advanced lesions, suggesting circulating miRNAs could serve as potential biomarkers for CRC screening. [ABSTRACT FROM AUTHOR]

The article looks at a study done in order to investigate gene-calcium interactions from genome-wide analysis of colorectal cancer risk. Topics discussed include role of calcium intake in reducing the risk of colorectal cancer, interaction between calcium intake and single nucleotide polymorphism (SNPs) in calcium-related pathways, and none role of genetic variants in modifying the association between calcium intake and colorectal cancer.

Background & Aims No therapy has been proven to prevent the recurrence of diverticulitis. Mesalamine has shown efficacy in preventing relapse in inflammatory bowel disease, and there is preliminary evidence that it might be effective for diverticular disease. We investigated the efficacy of mesalamine in preventing recurrence of diverticulitis in 2 identical but separate phase 3, randomized, double-blind, placebo-controlled, multicenter trials (identical confirmatory trials were conducted for regulatory reasons). Methods We evaluated the efficacy and safety of multimatrix mesalamine vs placebo in the prevention of recurrent diverticulitis in 590 (PREVENT1) and 592 (PREVENT2) adult patients with ≥1 episodes of acute diverticulitis in the previous 24 months that resolved without surgery. Patients received mesalamine (1.2 g, 2.4 g, or 4.8 g) or placebo once daily for 104 weeks. The primary end point was the proportion of recurrence-free patients at week 104. Diverticulitis recurrence was defined as surgical intervention at any time for diverticular disease or presence of computed tomography scan results demonstrating bowel wall thickening (>5 mm) and/or fat stranding consistent with diverticulitis. For a portion of the study, recurrence also required the presence of abdominal pain and an increase in white blood cells. Results Mesalamine did not reduce the rate of diverticulitis recurrence at week 104. Among patients in PREVENT1, 53%−63% did not have disease recurrence, compared with 65% of those given placebo. Among patients in PREVENT2, 59%−69% of patients did not have disease recurrence, compared with 68% of those given placebo. Mesalamine did not reduce time to recurrence, and the proportions of patients requiring surgery were comparable among treatment groups. No new adverse events were identified with mesalamine administration. Conclusions Mesalamine was not superior to placebo in preventing recurrent diverticulitis. Mesalamine is not recommended for this indication. ClinicalTrials.gov ID: NCT00545740 and NCT00545103 . [ABSTRACT FROM AUTHOR]

Background: It is unclear whether the higher burden from colorectal cancer among blacks is due to an increased biological susceptibility. Objective: To determine whether non-Hispanic blacks (blacks) have a higher risk of adenoma recurrence than non-Hispanic whites (whites) after removal of colorectal adenoma. Design: Secondary analysis of the Polyp Prevention Trial (PPT) data. Setting: United States. Patients: Patients were 1668 self-identified whites and 153 blacks who completed the 4-year trial. Of these, 688 whites and 55 blacks enrolled in a posttrial, passive Polyp Prevention Trial Continued Follow-up Study (PPT-CFS) and underwent another colonoscopy. Main Outcome Measurements: Recurrence and location of the adenoma and advanced adenoma by race-ethnicity during PPT and cumulative recurrence over a mean follow-up of 8.3 years (range, 4.9-12.4 years) among PPT-CFS enrollees. Results: Blacks had similar risk of recurrence of adenoma (39.2% vs 39.4%; incidence risk ratio [RR] = .98; 95% CI, .80-1.20) and advanced adenoma (8.5% vs 6.4%; RR = 1.18; 95% CI, .68-2.05) as whites at the end of PPT. Recurrence risk did not differ by colon subsite. Among PPT-CFS enrollees, the cumulative recurrence rate over a maximal follow-up period of 12 years was similar for blacks and whites for adenoma (67.3% vs 67.0%; RR = 1.01; 95% CI, .84-1.21) and advanced adenoma (14.5% vs 16.9%; RR = 1.03; 95% CI, .60-1.79). Limitation: There were few blacks in the long-term follow-up study. Conclusions: Adenoma and advanced adenoma recurrence did not differ by race. Our study does not support more frequent surveillance colonoscopies for blacks with a personal history of adenoma as an intervention to reduce colorectal cancer disparity. [Copyright &y& Elsevier]

Background & Aims: Low rates of adenoma detection by colonoscopy have been associated with increased rates of interval colorectal cancer. We evaluated the relationship between the rate of adenoma detection by flexible sigmoidoscopy and interval distal colorectal cancer. Methods: We analyzed data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer screening trial, which used flexible sigmoidoscopy as a colorectal cancer screening modality (46,835 subjects; 66,711 examinations by 93 examiners). An adenoma detection rate was defined for each examiner as the number of examinations that identified adenomas (confirmed by pathology analysis) divided by the total number of screening examinations. Interval cancers were defined as cancers presumed detectable but not detected, which was based on the stage at diagnosis and the elapsed time from screening to diagnosis. Results: The Prostate, Lung, Colorectal, and Ovarian Cancer study identified 32 interval distal cancers. The incidence of interval cancer for individuals screened by examiners in the lowest quartile of distal adenoma detection (2.0%–7.2%) was 9.0/10,000 examinations, whereas the incidence of interval cancers was lower among individuals whose examiners were in higher quartiles of adenoma detection, ranging from 3.0 to 5.4/10,000 examinations. The odds of interval distal cancer were significantly increased for patients of examiners in the lowest quartile of distal adenoma detection (<7.2%), with an adjusted odds ratio of 2.4 (95% confidence interval, 1.1–5.0; P = .02). Conclusions: Lower levels of adenoma detection by flexible sigmoidoscopy increase the risk for interval distal cancer. Detection of distal adenomas is a marker of the performance quality of flexible sigmoidoscopy. The parent study is registered under ClinicalTrials.gov, number NCT00002540. [ABSTRACT FROM AUTHOR]

Background and Objective: Diagnosis of colorectal cancer after negative findings on endoscopic evaluation raises concern about the effectiveness of endoscopic screening. We contrast screening-detected cancers with cancers not detected by screening among participants assigned to flexible sigmoidoscopy (FSG) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to determine the reasons for the lack of detection of prevalent lesions. Design: Cancers detected within 1 year of a screening FSG with abnormal findings were classified as screening detected. All other cancers were categorized, based on cancer stage and years until detection, as either not detectable or prevalent but not detected at the time of screening. Setting/Patients: A total of 77,447 subjects in the multicenter PLCO trial. Main Outcome Measurements: A total of 977 colorectal cancers were diagnosed with a mean follow-up of 11.5 years. Results: A total of 243 (24.9%) cancers were screening detected, 470 (48.1%) were not detectable at screening, and 264 (27.0%) were considered prevalent but not detected. Among prevalent nondetected lesions, 35.6% (n = 94) were attributed to problems in patient compliance (58 never screened, 34 delayed colonoscopy follow-up, and 2 inadequate bowel preparation), 43.9% (n = 116) were attributable to a limitation in the FSG procedure (97 beyond the reach of the sigmoidoscope and 19 inadequate depth of insertion on FSG), and 20.5% (n = 54) were caused by endoscopist limitation (33 missed on FSG, 21 missed at initial colonoscopy) (P < .0001). Had colonoscopy instead of FSG been used for screening, an additional 15.6% and as many as 19.0% of cancers may have been screening-detected. Limitations: These estimates are reasonable approximations, but biological variability precludes precise determinations. Conclusions: Prevalent nondetected cancers were more often attributable to problems with patient compliance or limitations in the FSG procedure than to missed lesions. Colonoscopy instead of FSG could have moderately increased the detection of cancer via screening. [Copyright &y& Elsevier]

Background: Colonoscopy may be less efficacious in reducing colorectal cancer mortality in the proximal compared with the distal colon. A greater likelihood for missed and recurrent adenomas in the proximal colon may contribute to this phenomenon. Objective: To examine whether a proximal adenoma is associated with the risk and location of missed and recurrent adenomas. Design: Prospective. Setting: Polyp Prevention Trial. Participants: A total of 1864 patients with an adenoma at baseline underwent a follow-up colonoscopy 4 years later (adenoma recurrence). Of these, 1731 underwent a clearing colonoscopy 1 year after the baseline examination (missed adenoma). Main Outcome Measurements: Association of baseline adenoma location with the risk and location of adenomas found at colonoscopy performed 1 year and 4 years later. Results: At the year 1 colonoscopy, 598 patients (34.6%) had an adenoma (missed adenoma). Compared with those with a distal-only adenoma at baseline, patients with a proximal-only adenoma at baseline were more likely to have any missed adenomas (relative risk [RR] 1.28; 95% CI, 1.09-1.49) and a proximal-only missed adenoma (RR 2.05; 95% CI, 1.49-2.80). At the year 4 colonoscopy, 733 patients (39.3%) had adenoma recurrence. Patients with a baseline proximal-only adenoma were more likely to have any adenoma recurrence (RR 1.14; 95% CI, 1.00-1.31) and a proximal-only adenoma recurrence (RR 1.52; 95% CI, 1.15-2.02). Sensitivity analyses involving missed adenomas did not materially affect the risk or location of recurrent adenomas at year 4 colonoscopy. Limitation: Lesions may still be missed on repeated colonoscopies. Conclusions: Missed and recurrent adenomas are more likely to be in the proximal colon. [Copyright &y& Elsevier]

Background: Despite regular colonoscopy, interval colorectal cancer (CRC) may occur. Long-term studies examining CRC rates in patients with previous colonoscopy are lacking. Objective: We examined the rate of interval CRC in the Polyp Prevention Trial Continued Follow-up Study (PPT-CFS), an observational study of PPT participants that began after the PPT ended. Design: Prospective. Setting: A national U.S. community-based polyp prevention trial. Main Outcome Measurements: Medical records of patients with CRC were collected, reviewed, and abstracted in a standardized fashion. Results: Among 2079 PPT participants, 1297 (62.4%) agreed to participate in the PPT-CFS. They were followed for a median of 6.2 years after 4.3 years of median follow-up in the main PPT. Nine cases of CRC were diagnosed over 7626 person-years of observation (PYO), for an incidence rate of 1.2/1000 PYO. The ratio of CRCs observed compared with that expected by Surveillance, Epidemiology, and End Results was 0.64 (95% CI, 0.28-1.06). Including all CRCs (N = 22) since the beginning of the PPT, the observed compared with expected rate by Surveillance, Epidemiology, and End Results was 0.74 (95% CI, 0.47-1.05). Of patients in whom CRC developed in the PPT-CFS, 78% had a history of an advanced adenoma compared with only 43% of patients who remained cancer free (P = .04). Limitation: A relatively small number of interval cancers were detected. Conclusions: Despite frequent colonoscopy during the PPT, in the years after the trial, there was a persistent ongoing risk of cancer. Subjects with a history of advanced adenoma are at increased risk of subsequent cancer and should be followed closely with continued surveillance. [Copyright &y& Elsevier]

Background & Aims: The recommended timing of surveillance colonoscopy for individuals with adenomatous polyps is based on adenoma histology, size, and number. The burden and cost of surveillance colonoscopy are significant. The aim of this study was to examine the use of surveillance colonoscopy on a community-wide basis. Methods: We retrospectively queried participants in the Prostate, Lung, Colorectal, and Ovarian Cancer screening trial in 9 US communities about use of surveillance colonoscopy. Subjects whose initial colonoscopy showed advanced adenoma (AA), nonadvanced adenoma (NAA), or no adenoma (NA) findings were included. Colonoscopy examinations were confirmed by reviewing colonoscopy reports. Results: Of 3876 subjects selected for inquiry, 3627 (93.6%) responded. The cumulative probability of a surveillance colonoscopy within 5 years was 58.4% (n = 1342) in the AA group, 57.5% in those with ≥3 NAAs (n = 117), 46.7% in those with 1–2 NAAs (n = 905), and 26.5% (n = 1263) in subjects with NAs. Within 7 years, 33.2% of subjects with AAs received ≥2 surveillance examinations versus 26.9% for those with ≥3 NAAs, 18.2% for those with 1 or 2 NAAs, and 10.4% for those with NAs. Incomplete colonoscopy, family history of colorectal cancer, or interval adenomatous findings could explain only a minority of surveillance colonoscopy in low-risk subjects. Conclusions: In community practice, there is substantial overuse of surveillance colonoscopy among low-risk subjects and underuse among subjects with AAs. Interventions to better align use of surveillance colonoscopy with risk for advanced lesions are needed. [Copyright &y& Elsevier]

Background: Aberrant crypt foci (ACF) have emerged as a putative precursor to colorectal adenoma, with potential use as a biomarker of colorectal cancer. However, there are wide differences in ACF prevalence, dysplasia, and histologic confirmation rates across studies. These differences may, in part, be because of variability in identification of endoscopic criteria. Objective: To systematically evaluate the accuracy and reliability of various endoscopic criteria used to identify ACF when using magnification chromoendoscopy (MCE). Design: Images obtained via MCE were shown to participating endoscopists who diagnosed them as ACF or not and who assessed them for the endoscopic characteristics used to identify ACF in the literature. Main Outcome Measurements: The predictive ability of the endoscopic criteria (crypt number, staining, margin, crypt size, epithelial thickness, and lumen shape) for histologic confirmation of ACF, and their reliability across endoscopists. The accuracy of the examiners in identifying ACF that were histologically confirmed was also assessed. Results: The interrater agreement rate for all except one of the endoscopic criteria (crypt number) was low and did not improve with training. None of the criteria could significantly predict histologic confirmation of ACF. Despite training exercises, accuracy of endoscopists to correctly identify a histologically proven ACF remained low. Limitations: Still images with ×40 optical magnification were analyzed rather than real-time endoscopy. All ACF samples were hyperplastic; none were dysplastic. Conclusions: No endoscopic criteria evaluated by our study predicted histologic confirmation of ACF. MCE had low accuracy and poor reliability. [Copyright &y& Elsevier]

Background & Aims: Aberrant crypt foci (ACF) are the putative precursor of colorectal adenomas. However, there are limited data available on the prevalence and risk factors for ACF. Methods: Subjects from the Prostate, Lung, Colorectal and Ovarian cancer screening trial were recruited for an ACF study, with subjects with adenoma history being oversampled. By using a standardized protocol of magnified chromoendoscopy with methylene blue staining (up to the middle rectal fold), ACF were photo-documented and removed for histologic evaluation. Results: A total of 505 (66% male; 55% ≥70 y) subjects from 4 institutions were examined; 42% had no adenoma, 32% had nonadvanced distal adenoma, and 25% had advanced distal adenoma at the baseline Prostate, Lung, Colorectal and Ovarian cancer screening trial examination (8.2 years before ACF examination on average). A total of 68% of this population had 1 or more ACF, 43% had 1 to 3, 19% had 4 to 6, and 5% had 7 or more. Baseline adenoma status was not associated with ACF prevalence (range, 66%–69%) or mean number of ACF (range, 3.1–3.5). Of 143 endoscopic ACF examined histologically, 68.5% were confirmed to be ACF. In a logistic model, current (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.2–5.6) and former smoking (OR, 1.6; 95% CI, 1.1–2.5) were associated with higher ACF prevalence; a body mass index greater than 30 was associated with lower prevalence (OR, 0.53; 95% CI, 0.35–0.8). Age, sex, family history of colorectal cancer, and aspirin/nonsteroidal anti-inflammatory drug use were not associated significantly with ACF prevalence. Conclusions: ACF prevalence and number were not associated with adenoma history, and only 68.5% of endoscopic ACF were confirmed histologically. These results raise concern about the use of ACF as a surrogate marker of colorectal cancer risk. [Copyright &y& Elsevier]

Background and Aims: Prospective information on the use and yield of surveillance colonoscopy is limited. We examined the use and yield of surveillance colonoscopy among participants in the Polyp Prevention Trial (PPT) after the 4-year dietary intervention trial ended. Methods: We followed a cohort of 1297 participants. We calculated the cumulative probability of posttrial colonoscopy and investigated the yield and predictive factors for adenoma and advanced adenoma recurrence over a mean time of 5.9 years. Results: Seven-hundred seventy-four subjects (59.7%) had a repeat colonoscopy. Among 431 subjects with low-risk adenomas (1–2 nonadvanced adenomas) at baseline and no adenoma recurrence at the end of the PPT (lowest-risk category), 30.3% underwent a repeat colonoscopy within 4 years. Among 55 subjects who had high-risk adenomas (advanced adenoma and/or ≥3 nonadvanced adenomas) at baseline and again at the final PPT colonoscopy (highest-risk category), 41.3% had a colonoscopy within 3 years and 63.5% had an examination within 5 years. The cumulative yield of advanced adenoma through 6 years was 3.6% for the lowest-risk category, 38.9% for the highest-risk category, and ranged from 6.6% to 13.8% for intermediate-risk categories. An advanced adenoma at the final PPT colonoscopy was associated significantly with an advanced adenoma recurrence during surveillance (hazard ratio, 6.2; 95% confidence interval, 2.5–15.4). Conclusions: Surveillance colonoscopy was overused for low-risk subjects and underused for high-risk subjects. Advanced adenoma yield corresponded with the adenoma risk category. Resource consumption can be better managed by aligning use with the risk of adenoma recurrence. [Copyright &y& Elsevier]

Background and Aims: Recent studies have suggested that some hyperplastic polyps may be associated with an increased risk of colorectal cancer. Prospective information on the risk of adenoma recurrence associated with hyperplastic polyps is limited. We sought to investigate whether the coexistence of hyperplastic polyps with adenomas increases the risk of adenoma recurrence. Methods: We used unconditional logistic regression models to examine the association between baseline hyperplastic polyps and subsequent adenoma recurrence during a 3-year follow-up evaluation, among 1637 participants in the Polyp Prevention Trial. Results: A total of 437 participants (26.7%) had hyperplastic polyps coexisting with adenomas at baseline. Of these, 132 (30.2%) had at least one hyperplastic polyp in the proximal colon, whereas 305 (69.8%) had only distal hyperplastic polyps. When compared with subjects without any hyperplastic polyps at baseline, there was no statistically significant association between the presence of baseline hyperplastic polyps and recurrence of any adenoma (odds ratio [OR], 1.19; 95% confidence interval [CI], 0.94–1.51) or advanced adenoma (OR, 1.25; 95% CI, 0.78–2.03). Also, there was no association between hyperplastic polyp location and adenoma recurrence (OR, 1.01; 95% CI, 0.69–1.48) for any proximal hyperplastic polyp (OR, 1.26; 95% CI, 0.96–1.65) and for distal hyperplastic polyps. Conclusions: The coexistence of hyperplastic polyps with adenomas, irrespective of location, does not confer an increased risk of adenoma recurrence beyond that of adenomas alone within 3 years of follow-up evaluation. Prospective long-term studies on adenoma recurrence risk associated with hyperplastic polyps in screening populations are needed. [Copyright &y& Elsevier]