Colorectal Cancer Risk Assessment Research Articles

Effect of Behavioral Economic Incentives for Colorectal Cancer Screening in a Randomized Trial

Financial incentives might increase participation in prevention such as screening colonoscopy. We studied whether incentives informed by behavioral economics increase participation in risk assessment for colorectal cancer (CRC) and completion of colonoscopy for eligible adults. Employees of a large academic health system (50-64 y old; n = 1977) were randomly assigned to groups that underwent risk assessment for CRC screening and direct access colonoscopy scheduling (control), or risk assessment, direct access colonoscopy scheduling, a $10 loss-framed incentive to complete risk assessment, and a $25 unconditional incentive for colonoscopy completion (incentive). The primary outcome was the percentage of participants who completed screening colonoscopy within 3 months of initial outreach. Secondary outcomes included the percentage of participants who scheduled colonoscopy and the percentage who completed the risk assessment. At 3 months, risk assessment was completed by 19.5% of participants in the control group (95% CI, 17.0-21.9%) and 31.9% of participants in the incentive group (95% CI, 29.0-34.8%) (P < .001). At 3 months, 0.7% of controls had completed a colonoscopy (95% CI, .2%-1.2%) compared with 1.2% of subjects in the incentive group (95% CI, .5%-1.9%) (P= .25). In a randomized trial of participants who underwent risk assessment for CRC with vs without financial incentive, the financial incentive increased CRC risk assessment completion but did not result in a greater completion of screening colonoscopy. Clinicaltrials.gov no: NCT03068052.

Tumour budding/T cell infiltrates in colorectal cancer: proposal of a novel combined score.

The tumour-node-metastasis classification system is used for prognostication purposes and to guide patient management. However, in colorectal cancer (CRC), additional markers are needed to stratify prognostic subgroups. Two promising markers have emerged from large bodies of research: tumour budding and T cell host response (CD3, CD8 and CD45RO infiltrates). However, attempts to combine these two parameters have been sparse. The aim of this study was to perform an assessment of potential protagonists that could be used in a combined score (budding/T cell score, BTS). This descriptive, retrospective study was performed on a multipunch tissue microarray containing material from 345 patients with stages I-IV CRC. Areas from tumour centre, front and microenvironment were stained for pancytokeratin/CD3, pancytokeratin/CD8 and pancytokeratin/CD45RO. Tumour buds were scored manually and T cell infiltrates digitally using open-source software. Tumour buds, T cell counts and combined BTS were associated with clinicopathological features and overall survival (OS). A higher combined BTS score (buds/CD8, tumour centre) performed better than budding or CD8/CD3 alone in predicting nodal metastases (P<0.0001, OR=1.466, 95% CI=1.115-1.928). Only higher BTS (buds/CD3) were significantly associated with poorer OS on multivariate analysis (P=0.012, hazard ratio=1.218, 95% confidence interval=1.044-1.419). Although CD8+ /CD3+ T cells are predictive of tumour biology in CRC, we found a combined BTS to be stronger in predicting survival and certain features with high clinical relevance, such as nodal metastases, in comparison to budding or T cells alone. Further studies combining T cell infiltrates and tumour budding are necessary to optimise risk assessment of CRC.

Development and Validation of Persian Risk Assessment Tool using National Comprehensive Cancer Network Guideline for Colorectal Cancer Screening

Introduction: Despite evidence that early diagnosis of Colorectal Cancer (CRC) reduces the associated death burden, screening programs are uncommon even in developed countries. Aim: To develop and validate a simple, practical and effcient tool to improve CRC risk assessment by identifying moderateand high-risk disease. Materials and Methods: The National Comprehensive Cancer Network guideline has been used to develop the CRC risk assessment tool. Content validity was assessed by a panel of 10 experts by generating a Content Validity Index (CVI), which was recorded quantitatively as the proportion of experts who agreed that the item was relevant, before calculating the Content Validity Ratio (CVR) per item. Results: The CVI was in the range 0.7-1 and the acceptable CVR was in the range 0.4-1. The overall mean CVI and CVR values were 0.93 and 0.62, respectively. Changes were made according to the experts’ recommendations, and the fnal online Persian questionnaire was assessed for face validity by 15 individuals (general population voluntarily). Only a few items subsequently needed modifcation and expansion. Conclusion: This validated risk assessment tool is simple, quick, and easy to apply to different clinical categories and subcategories of CRC and can even be self-administered. This is the frst translated tool in Persian version, usable in Iran.

Advanced neoplasia in Veterans at screening colonoscopy using the National Cancer Institute Risk Assessment Tool

BackgroundAdapting screening strategy to colorectal cancer (CRC) risk may improve efficiency for all stakeholders however limited tools for such risk stratification exist. Colorectal cancers usually evolve from advanced neoplasms that are present for years. We applied the National Cancer Institute (NCI) CRC Risk Assessment Tool, which calculates future risk of CRC, to determine whether it could be used to predict current advanced neoplasia (AN) in a veteran cohort undergoing a baseline screening colonoscopy.MethodsThis was a prospective assessment of the relationship between future CRC risk predicted by the NCI tool, and the presence of AN at screening colonoscopy. Family, medical, dietary and physical activity histories were collected at the time of screening colonoscopy and used to calculate absolute CRC risk at 5, 10 and 20 years. Discriminatory accuracy was assessed.ResultsOf 3121 veterans undergoing screening colonoscopy, 94% had complete data available to calculate risk (N = 2934, median age 63 years, 100% men, and 15% minorities). Prevalence of AN at baseline screening colonoscopy was 11 % (N = 313). For tertiles of estimated absolute CRC risk at 5 years, AN prevalences were 6.54% (95% CI, 4.99, 8.09), 11.26% (95% CI, 9.28-13.24), and 14.21% (95% CI, 12.02-16.40). For tertiles of estimated risk at 10 years, the prevalences were 6.34% (95% CI, 4.81-7.87), 11.25% (95% CI, 9.27-13.23), and 14.42% (95% CI, 12.22-16.62). For tertiles of estimated absolute CRC risk at 20 years, current AN prevalences were 7.54% (95% CI, 5.75-9.33), 10.53% (95% CI, 8.45-12.61), and 12.44% (95% CI, 10.2-14.68). The area under the curve for predicting current AN was 0.60 (95% CI; 0.57-0.63, p < 0.0001) at 5 years, 0.60 (95% CI, 0.57-0.63, p < 0.0001) at 10 years and 0.58 (95% CI, 0.54-0.61, p < 0.0001) at 20 years.ConclusionThe NCI tool had modest discriminatory function for estimating the presence of current advanced neoplasia in veterans undergoing a first screening colonoscopy. These findings are comparable to other clinically utilized cancer risk prediction models and may be used to inform the benefit-risk assessment of screening, particularly for patients with competing comorbidities and lower risk, for whom a non-invasive screening approach is preferred.

An electronic family health history tool to identify and manage patients at increased risk for colorectal cancer: protocol for a randomized controlled trial

BackgroundColorectal cancer is the fourth most commonly diagnosed cancer in the United States. Approximately 3–10% of the population has an increased risk for colorectal cancer due to family history and warrants more frequent or intensive screening. Yet, < 50% of that high-risk population receives guideline-concordant care. Systematic collection of family health history and decision support may improve guideline-concordant screening for patients at increased risk of colorectal cancer. We seek to test the effectiveness of a web-based, systematic family health history collection tool and decision support platform (MeTree) to improve risk assessment and appropriate management of colorectal cancer risk among patients in the Department of Veterans Affairs primary care practices.MethodsIn this ongoing randomized controlled trial, primary care providers at the Durham Veterans Affairs Health Care System and the Madison VA Medical Center are randomized to immediate intervention or wait-list control. Veterans are eligible if assigned to enrolled providers, have an upcoming primary care appointment, and have no conditions that would place them at increased risk for colorectal cancer (such as personal history, adenomatous polyps, or inflammatory bowel disease). Those with a recent lower endoscopy (e.g. colonoscopy, sigmoidoscopy) are excluded. Immediate intervention patients put their family health history information into a web-based platform, MeTree, which provides both patient- and provider-facing decision support reports. Wait-list control patients access MeTree 12 months post-consent. The primary outcome is the risk-concordant colorectal cancer screening referral rate obtained via chart review. Secondary outcomes include patient completion of risk management recommendations (e.g. colonoscopy) and referral for genetic consultation. We will also conduct an economic analysis and an assessment of providers’ experience with MeTree clinical decision support recommendations to inform future implementation efforts if the intervention is found to be effective.DiscussionThis trial will assess the feasibility and effectiveness of patient-collected family health history linked to decision support to promote risk-appropriate screening in a large healthcare system such as the Department of Veterans Affairs.Trial registrationClinicalTrials.gov, NCT02247336. Registered on 25 September 2014.

An update on risk assessment for familial and hereditary colorectal cancer.

Family history risk assessment can identify individuals at increased risk of colorectal cancer (CRC) who would benefit from earlier or more frequent CRC screening. Clinicians should evaluate the patient's family history as well as personal history to identify red flags and patterns that may suggest predisposition to CRC and then use that information to stratify risk into average, increased, and high risk categories to inform genetic counseling recommendations and personalized management.

778a – Randomized Controlled Trial of Personalized Colorectal Cancer Risk Assessment Vs. Education to Promote Uptake of Colorectal Cancer Screening

778a – Randomized Controlled Trial of Personalized Colorectal Cancer Risk Assessment Vs. Education to Promote Uptake of Colorectal Cancer Screening

Validation of the NCI Colorectal Cancer Risk Assessment Tool for baseline advanced neoplasia in a veterans cohort.

521 Background: Tailoring screening strategy to colorectal cancer (CRC) risk may improve efficiency for all stakeholders. We applied the National Cancer Institute (NCI) CRC Risk Assessment Tool, which calculates 5-10-year, and 20-year absolute risk of colorectal cancer to determine whether it could be used to predict baseline risk of colorectal cancer precursors in a Veterans cohort undergoing first screening colonoscopy. Methods: This was a prospective evaluation of whether the NCI CRC Risk Assessment Tool which offers an absolute risk over time, could be used to estimate baseline cancerous precursors (advanced neoplasia) in Veterans undergoing first screening colonoscopy. Family, medical, dietary and physical activity histories were collected at the time of screening colonoscopy and used to calculate absolute 5, 10, and 20-year CRC risk, and to compare estimated CRC risk to observed AN. Sensitivity analyses were performed. Results: Of 3,121 Veterans undergoing screening colonoscopy, 94% had complete data available to calculate risk (N = 2,934, median age 63 years, 100% men, and 15% minorities). 11% (N = 313) were diagnosed with AN on baseline screening colonoscopy. The area under the curve for predicting AN was 0.60 (95% CI; 0.57-0.63, p &lt; 0.0001) at 5 years, 0.60 (95% CI, 0.57-0.63, p &lt; 0.0001) at 10 years and 0.58 (95% CI, 0.54-0.61, p &lt; 0.0001) at 20 years. At 5 years, we calculated the sensitivity (0.18, 95% CI; 0.14-0.22), specificity (0.91, 95% CI; 0.90-0.92) positive predictive value (0.19, 95% CI; 0.15-0.24) and negative predictive value (0.90, 95% CI; 0.89-0.91) considering the top 10th percentile of risk tool scores as a positive result. Conclusions: The NCI CRC Risk Assessment Tool had modest discriminatory function for predicting AN risk at 5, 10 and 20 years. The Tool’s specificity and negative predictive value were quite good, highlighting its usefulness in risk prediction. This tool may beused to inform the benefit-risk assessment of screening colonoscopy for patients with competing comorbidities.

The Effects of the Nurse Navigation Program in Promoting Colorectal Cancer Screening Behaviors: a Randomized Controlled Trial.

Although screening programs are known and recommended for the early detection of colorectal cancer (CRC), the screening rates for the fecal occult blood test (FOBT) and colonoscopy are very low among adult individuals. Navigation programs, also known as individualized counseling, have recently begun to be used for increasing screening rates. The purpose of this study was to compare the efficacy of the Nurse Navigation Program versus usual care on CRC screening participation and movement in stage of adoption for CRC screening and to examine perceived benefits of and barriers to CRC screening. This study was designed in line with a pre- and posttest two-group methodology. A total of 110 participants (55 nurse-navigated and 55 non-navigated patients) were studied. Data were collected using the following three tools: a sociodemographic information form, the Harvard Colorectal Cancer Risk Assessment Tool, and Instruments to Measure Colorectal Cancer Screening Benefits and Barriers. Following the Nurse Navigation Program, the FOBT (82 and 84%, respectively) and colonoscopy completion rates (15 and 22%, respectively) were significantly higher in the nurse-navigated group than in the non-navigated group at 3 and 6months follow-up. Following the program, the benefit perceptions of the nurse-navigated group about CRC screening were improved, and their barrier perceptions were reduced. The results showed that the Nurse Navigation Program had significant effects on CRC screening behavior and health-related beliefs concerning CRC screening. Further assessment of the Nurse Navigation Program in different groups should be performed to observe its effects.

Risk-Index of Colorectal Cancer to Triage for Screening

Colorectal cancer (CRC) is the unregulated growth of one or more adenomatous polyps (most frequently adenocarcinomas) occurring in the colon and/or the rectum. Of all new cancer cases in the US, 8.0% are colorectal. Colorectal cancer claims 8.4% of all cancer-deaths and thus has above-average mortality vs. other cancers. To detect CRC at early stages, the United States Preventative Services Task Force (USPSTF) recommends screening by colonoscopy or sigmoidoscopy for ages 50-75. However, the high false positive rates of these procedures lead to a lot of unnecessary screening. The goal of this study is to develop an artificial neural network (ANN) for colorectal cancer risk prediction usable for triaging people for screening based on their personal health data. The data to train and validate the ANN is the set of 1997-2016 responses (excepting 2004) to the National Health Interview Survey (NHIS) personal health questionnaire, in which colon and/or rectal cancer occurring 4 years or less from the survey date is counted as one instance of CRC. Respondents with 1 or more null entries were discarded. Using 70% of the NHIS data, training uses gradient descent in parameter space to adjust the parameters of a softmax-function and minimize a logistic cost function (regression). The extent to which the parameters are adjusted is calculated using the chain rule of calculus (backpropagation). The validation tests the regression-fitted function upon the remaining 30% of the data. As a binary test, sensitivity (TPR), specificity (SPC), and positive/negative predictive values (PPV/NPV) are calculated and compared with the USPSTF. As a trinary test, three levels of risk-stratification are defined by requiring that no more than 1% of CRC/non-CRC cases be misclassified as low/high-risk. If a person of medium risk having/not having CRC is counted as half of a false negative/positive (e.g., annual/biennial screenings for those of high/medium risk), the trinary test of risk-stratification also has an associated TPR, SPC, PPV, and NPV. As a binary test, the ANN has sensitivity of 0.7, specificity of 0.7, PPV of 0.09, and NPV of 0., all (except for NPV) exceeding the USPSTF guidelines and independent of tumorous advancement. As a trinary test, lowered SPC and PPV are exchanged for higher TPR and NPV.Abstract MO_30_2748; Table 1Performance of USPSTF (entire data set) compared to the ANN (validation-portion of data set, only).CRC, # screenedCRC, # not screenedNo CRC, # screenedNo CRC, # not screenedANN (bi.)517255106,864235,029ANN (tri.)497145142,603.5207,004USPSTF762490232,545297,065TPRSPCPPVNPVANN (bi.)0.6700.6870.009450.997ANN (tri.)0.7740.4080.003470.9993USPSTF0.6090.4390.003270.998 Open table in a new tab CRC risk calculated by ANN from personal health data is noninvasive, insensitive to tumorous advancement, & outperforms USPSTF screening guidelines as a binary and trinary test. In addition, the ANN offers the prospect of CRC risk assessment in real time and on the world map.

Effect of Nurse Navigation Program on Colorectal Cancer Screening Behaviour of the Individuals Aged 50-70

Background: Colorectal cancer (CRC) is the third leading cause of cancer mortality in the world. In Turkey, it is the third most commonly diagnosed cancer and fourth leading cause of cancer death. Cancer screening activities are mostly initiated and implemented at primary health care services. Despite it is known that benefits of screening in reducing CRC incidence and mortality rates CRC screening rates are significantly lower among men and women in Turkey. However there are several interventions have been proposed to identify and remove barriers for increasing CRCS in the literature, navigation programs, also known as individualized counseling, have begun to used as a promising method recently. Aim: The aim of this study is to evaluate effects of Nurse Navigation Program that is administered to individuals aged 50-70 on their screening behavior concerning colorectal cancer (fecal occult blood test and colonoscopy) and their beliefs about this process. Methods: The study was designed experimental pretest-posttest control group design. In the study it is used random assignment to intervention and control groups, with blocking stratified. The participants of the study were 110 individuals aged between 50 and 70 registered to a family health center in İstanbul. The 'Nurse Navigation Program' was administered to the participants. The data were collected through the use of the following three tools: the Demographical Information Form, The Harvard Colorectal Cancer Risk Assessment Tool, Instruments to Measure Colorectal Cancer Screening Benefits and Barriers. The data obtained were analyzed by the descriptive and significance analyses. Results: Following the Nurse Navigation Program the experimental groups FOBT (82% and 84%) and colonoscopy completion rate (15% and 22%) were significantly higher in the control group at 3 and 6 months follow-up. Following the program when compared with the control group it is found that the mean score of the barriers perception of the experimental group was significantly lower and the mean score of the benefits perception of the experimental group was significantly higher. Conclusion: The results show that the Nurse Navigation Program had significant effects on the CRC screening behavior and health-related beliefs concerning the CRC screening. It can be suggested that the Nurse Navigation Program can be further tested on different groups to observe its effects.

Colorectal Cancer Knowledge, Risk Perception, and Screening Inclination Among Previously Unscreened Adults

Introduction: Colorectal cancer (CRC) remains the 3rd most common cancer in the US. Most CRCs are preventable, but screening participation remains suboptimal. Several factors have been associated with screening compliance, such as perception of CRC risk. Enrollment is complete in our randomized controlled study examining the impact of the National Cancer Institute Colorectal Cancer Risk Assessment Tool (CCRAT) on screening attitudes and behavior. Here we present our study cohort’s baseline CRC knowledge, risk perception, and screening intent based on the transtheoretical model (TTM) of behavioral change. Methods: 229 primary care patients 50-75 years old eligible for first time CRC screening were randomized to risk-assessment with the CCRAT or education control from Oct 2015 to Jan 2018. Baseline data were analyzed in aggregate to preserve blinding before final follow-up on screening behavior through Jan 2019. Based on screening intent, patients were assigned to the pre-contemplation, contemplation or preparation TTM stage. Univariable multinomial models were used to explore predictors of TTM stage. Results: Most patients were Caucasian (54.6%) or Asian (30.1%) with college or higher education (94.3%) and annual incomes $75,000 or more (65.1%) (Table 1). Most heard of colonoscopy (99.1%) and fecal immunochemical tests (74.7%) but rarely other tests. 57.2% expressed fear of finding CRC on screening, 57.2% considered their absolute CRC risk neither likely nor unlikely, and 40.2% considered it unlikely/very unlikely (Table 2). Perception of risk relative to the average person was similar to perception of absolute risk. 9.2% already scheduled screening, 55.9% contemplated screening and 44.1% were pre-contemplative. Those of older age were less likely contemplative (OR 0.95 [95%CI;0.91-0.99]), while those with a family CRC history (OR 11.9 [3.1-45.8]) or perceived high relative CRC risk (OR 14.0 [2.2-91.1]) were more likely preparative(Table 3). Conclusion: Among a cohort of higher socioeconomic status who had not yet received CRC screening, familiarity with leading CRC screening tests was high, fear of finding CRC at screening was common, and perceived absolute CRC risk overestimated true risk. Only a minority had active plans to undergo screening. Those with a family history of CRC and perception of high relative CRC risk had high intent to screen, while older patients were slightly less inclined. The impact of the CCRAT on risk perception, TTM stage, and screening behavior remains to be determined.293_A Figure 1 No Caption available.293_B Figure 2 No Caption available.293_C Figure 3 No Caption available.

Predicting the presence of adenomatous polyps during colonoscopy with National Cancer Institute Colorectal Cancer Risk-Assessment Tool.

AIMTo evaluate the National Cancer Institute (NCI) Colorectal Cancer (CRC) Risk Assessment Tool as a predictor for the presence of adenomatous polyps (AP) found during screening or surveillance colonoscopy.METHODSThis is a retrospective single center observational study. We collected data of adenomatous polyps in each colonoscopy and then evaluated the lifetime CRC risk. We calculated the AP prevalence across risk score quintiles, odds ratios of the prevalence of AP across risk score quintiles, area under curves (AUCs) and Youden’s indexes to assess the optimal risk score cut off value for AP prevalence status.RESULTSThe prevalence of AP gradually increased throughout the five risk score quintiles: i.e., 27.63% in the first and 51.35% in the fifth quintile. The odd ratios of AP prevalence in the fifth quintile compared to the first and second quintile were 2.76 [confidence interval (CI): 1.71-4.47] and 2.09 (CI: 1.32-3.30). The AUC for all patients was 0.62 (CI: 0.58-0.66). Youden’s Index indicated the optimal risk score cutoff value discriminating AP prevalence status was 3.60.CONCLUSIONPatients with the higher NCI risk score have higher risk of AP and subsequent CRC; therefore, measures to increase the effectiveness of CRC detection in these patients include longer withdrawal time, early surveillance colonoscopy, and choosing flexible colonoscopy over other CRC screening modalities.

Abstract 5057: Exposure to highly energetic charged (hze) particle radiation is associated with higher colitis and colorectal cancer incidence in IL10-/- mice

Abstract Epidemiological data from atom-bomb survivors and from radiotherapy patients have highlight an underlying risk of colitis and colorectal cancer (CRC) after ionizing radiation-exposure. In contrast, astronauts planning to undertake deep space exploration such as mission to Mars have risk of radiation exposure from highly energetic charged (HZE) particles present in galactic cosmic radiation (GCR) and risk of colitis and CRC after HZE-exposure is yet to be determined. Therefore, animal studies are warranted to address existing uncertainties in colitis and CRC risk prediction after exposure to HZE radiation. Here we report IL10-/- mice as a suitable mouse model for assessment of colitis and CRC risk after exposure to space radiation. Male mice (n=12 mice/group) were whole-body exposed to sham-radiation, γ-rays and 28Si-ion (300 MeV/n; 70 keV/μm; 1.4 Gy). Mice were sacrificed three months after irradiation, and colon swiss-rolls sections were analyzed for colitis and CRC grade was noted in hematoxylin and eosin stained sections. Immunohistochemistry (β-catenin, Cyclin-D1, phospho-H3, iNOS, phoshoNfKβ-p65, and Cox2) was also performed to assess HZE-induced proliferative and inflammatory signaling. Further, inflammation-associated gene-expression analysis was also conducted in both radiation-induced tumor and adjoining normal tissue area. Here we report that relative to controls and γ-ray, colitis score, colon tumor incidence, size and grade was significantly higher after space (28Si-ion) radiation exposure. Higher number of phospho-H3 positive cells in 28Si-ion exposed mouse colon demonstrated increased proliferative index and in increased colon tumors of higher grade, could be due to greater activation of β-catenin and its downstream effector cyclin D1. In addition, higher accumulation of iNOS, phoshoNfKβ-p65, and Cox2 in stromal and epithelial cells after space radiation exposure clearly indicates upregulation of both immune and epithelial inflammation as drivers of colitis and CRC development. Inflammation associated protein markers and gene expression signatures were more pronounced after 28Si-ion exposure. Significant up-regulation of GATA4, ICAM1, ITGA2 and EGFR were exclusive to 28Si-ion exposed mouse colon, however PTGES and TGFβ1 were upregulated in both γ and 28Si-ion exposed mice. Overall, this study suggests that IL10-/- mouse are a suitable model to assess IR-induced colitis and CRC risk, and that space radiation carries higher risk of colitis and CRC incidence, relative to γ-rays at comparable doses. This study has implications for risk prediction in astronauts planning for deep space mission and also for cancer patients planning to undergo particle radiotherapy. Citation Format: Shubhankar Suman, Bo-Hyun Moon, Albert J. Fornace, Kamal Datta. Exposure to highly energetic charged (hze) particle radiation is associated with higher colitis and colorectal cancer incidence in IL10-/- mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5057.

Serrated epithelial colorectal polyps (hyperplastic polyps, sessile serrated adenomas) with perineurial stroma: Clinicopathological and molecular analysis of a new series.

Serrated colorectal fibroblastic polyps (FPs) are rare benign mucosal lesions composed of serrated epithelial crypts separated and distorted by intimately associated bland spindle cell proliferations with perineurial-like phenotype. We herein describe 21 new FPs affecting 10 females and 9 males aged 45 to 80 yrs. (mean, 62 yrs). Lesions originated in the sigmoid colon/rectosigmoid junction (n = 16), rectum (n = 2), and other parts of the colon (n = 3). Most patients had additional synchronous or metachronous polyps: classical adenomas (12 patients), sessile serrated adenoma/SSA (1 patient), hyperplastic polyps/HPs (7 patients), both HPs and adenomas (6 patients) and colorectal cancer (2 patients). Size of the lesions varied from 1 to 6 mm (mean: 3 mm). Histologically, all lesions were composed of serrated epithelial crypts that were separated and distorted by spindle cell stromal proliferations (consistently EMA+, claudin-1+ and GLUT-1+). The epithelial component displayed features of HPs (n = 17) and SSA (n = 4). Laser-microdissection-guided molecular testing was successful for 13 epithelial and 9 stromal components (9 paired samples). The BRAF V600E mutation was detected in 54% of the epithelial but in none of the stromal components. In conclusion, colorectal FPs represent genuine serrated epithelial polyps corresponding either to HP or (less frequently) SSA and should be better classified as such with a note on the presence of the stromal component. A more concise terminology reflecting their epithelial nature is needed to fulfill the requirements for colorectal cancer risk assessment and hence adopt appropriate follow-up strategies.

Early genetic aberrations in patients with sporadic colorectal cancer.

Chromosome instability (CIN) is widely observed in both sporadic and hereditary colorectal cancer (CRC). Defects in APC and WNT signaling are primarily associated with CIN in hereditary CRC, but the genetic causes for CIN in sporadic CRC remain elusive. Using high-density SNP array and exome data from The Cancer Genome Atlas (TCGA), we characterized loss of heterozygosity (LOH) and copy number variation (CNV) in the peripheral blood, normal colon, and corresponding tumor tissue in 15 CRC patients with proficient mismatch repair (MMR) and 24 CRC patients with deficient MMR. We found a high frequency of 18q LOH in tumors and arm-specific enrichment of genetic aberrations on 18q in the normal colon (primarily copy neutral LOH) and blood (primarily copy gain). These aberrations were specific to the sporadic, pMMR CRC. Though in tumor samples genetic aberrations were observed for genes commonly mutated in hereditary CRC (eg, APC, CTNNB1, SMAD4, BRAF), none of them showed LOH or CNV in the normal colon or blood. DCC located on 18q21.1 topped the list of genes with genetic aberrations in the tumor. In an independent cohort of 13 patients subjected to Whole Genome Sequencing (WGS), we found LOH and CNV on 18q in adenomatous polyp and tumor tissues. Our data suggests that patients with sporadic CRC may have genetic aberrations preferentially enriched on 18q in their blood, normal colon epithelium, and non-malignant polyp lesions that may prove useful as a clinical marker for sporadic CRC detection and risk assessment.

The Association of Low-Penetrance Variants in DNA Repair Genes with Colorectal Cancer: A Systematic Review and Meta-Analysis.

Objectives:Approximately 35% of colorectal cancer (CRC) risk is attributable to heritable factors known hereditary syndromes, accounting for 6%. The remainder may be due to lower penetrance polymorphisms particularly of DNA repair genes. DNA repair pathways, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), direct reversal repair (DRR), and double-strand break repair are complex, evolutionarily conserved, and critical in carcinogenesis. Germline mutations in these genes are associated with high-penetrance CRC syndromes such as Lynch syndrome. However, the association of low-penetrance polymorphisms of DNA repair genes with CRC risk remains unclear.Methods:A systematic literature review of PubMed, Embase, and HuGENet databases was conducted. Pre-specified criteria determined study inclusion/exclusion. Per-allele, pooled odds ratios disclosed the risk attributed to each variant. Heterogeneity was investigated by subgroup analyses for ethnicity and tumor location; funnel plots and Egger’s test assessed publication bias.Results:Sixty-one polymorphisms in 26 different DNA repair genes were identified. Meta-analyses for 22 polymorphisms in 17 genes revealed that six polymorphisms were significantly associated with CRC risk within BER (APE1, PARP1), NER (ERCC5, XPC), double-strand break (RAD18), and DRR (MGMT), but none within MMR. Subgroup analyses revealed significant association of OGG1 rs1052133 with rectal cancer risk. Egger’s test revealed no publication bias.Conclusions:Low-penetrance polymorphisms in DNA repair genes alter susceptibility to CRC. Future studies should therefore analyze whole-genome polymorphisms and any synergistic effects on CRC risk.Translational impact:This knowledge may enhance CRC risk assessment and facilitate a more personalized approach to cancer prevention.

Validation of the NCI colorectal cancer risk assessment tool in the CSP 380 veterans cohort.

e15135 Background: Refining screening to colorectal cancer (CRC) risk may promote screening effectiveness. We applied the National Cancer Institute (NCI) CRC Risk Assessment Tool to estimate 5- and 10-year CRC risk in an average-risk Veterans cohort undergoing screening colonoscopy with follow-up. Methods: This was a prospective evaluation of predicted to actual risk of CRC using the NCI CRC Risk Assessment Tool in male Veterans undergoing screening colonoscopy with a median follow-up of 10 years.Family, medical, dietary and physical activity histories were collected at enrollment and used to calculate absolute 5- and 10-year CRC risk, and to compare tertiles of expected to observed CRC risk. Sensitivity analyses were performed. Results: For 2,934 male Veterans with complete data (average age 62.4 years, 15% minorities), 1.3% (N=30) and 1.7% (N=50) were diagnosed with CRC within 5 and 10 years of survey completion. The area under the curve for predicting CRC was 0.69 (95% CI; 0.61-0.78) at 5 years and 0.67 (95% CI, 0.59-0.75) at 10 years. We calculated the sensitivity (0.60, 95% CI; 0.45-0.73), specificity (0.67, 95% CI; 0.65-0.69) positive predictive value (0.031, 95% CI; 0.02-0.04) and negative predictive value (0.99, 95% CI; 0.98-0.99). Conclusions: The NCI CRC Risk Assessment Tool was well-calibrated at 5 years and overestimated CRC risk at 10 years, had modest discriminatory function, and a high NPV in a cohort of ethnically diverse male Veterans. This tool reliably excludes 10-year CRC in low-scoring individuals and may inform patient-provider decision making when the benefit of screening is uncertain. [Table: see text]

Potential biomarkers associated with oxidative stress for risk assessment of colorectal cancer.

Cells are continuously threatened by the damage caused by reactive oxygen/nitrogen species (ROS/RNS), which are produced during physiological oxygen metabolism. In our review, we will summarize the latest reports on the role of oxidative stress and oxidative stress-induced signaling pathways in the etiology of colorectal cancer. The differences in ROS generation may influence the levels of oxidized proteins, lipids, and DNA damage, thus contributing to the higher susceptibility of colon. Reactive species (RS) of various types are formed and are powerful oxidizing agents, capable of damaging DNA and other biomolecules. Increased formation of RS can promote the development of malignancy, and the "normal" rates of RS generation may account for the increased risk of cancer development in the aged. In this review, we focus on the role of oxidative stress in the etiology of colorec-tal cancer and discuss free radicals and free radical-stimulated pathways in colorectal carcinogenesis.

Family history in colonoscopy patients: feasibility and performance of electronic and paper-based surveys for colorectal cancer risk assessment in the outpatient setting

Family history is crucial in stratifying patients' risk for colorectal cancer (CRC). Previous risk assessment tools developed for use in clinic or endoscopy settings have demonstrated suboptimal specificity for identifying patients with hereditary cancer syndromes. Our aim was to test the feasibility and performance of 2 family history surveys (paper and electronic) in individuals presenting for outpatient colonoscopy. Patients presenting for outpatient colonoscopy at a tertiary care center were asked to complete a 5-question paper risk assessment survey (short paper survey) either alone or in conjunction with a second, comprehensive electronic family risk assessment survey (comprehensive tablet survey). Each subject's survey results, along with the electronic medical record, were reviewed, and 10 high-risk criteria and PREMM1,2,6 model scores (a predictive model for carrying a Lynch syndrome-associated gene mutation) were used to identify patients warranting genetic evaluation for suspected hereditary cancer syndromes. Six hundred patients completed the short paper survey (cohort 1), with an additional 100 patients completing both the short paper and comprehensive tablet survey (cohort 2). Using 10 high-risk criteria and/or a PREMM1,2,6 score≥5%, we identified 10% and 9% of patients as high risk for CRC in cohorts 1 and 2, respectively. Of the 69 high-risk subjects, 23 (33%) underwent genetic evaluations and 7 (10%) carried germline mutations associated with cancer predisposition. Both patients and endoscopists reported the tools were user-friendly and helpful for CRC risk stratification. Systematic assessment of family history in colonoscopy patients is feasible and can help endoscopists identify high-risk patients who would benefit from genetic evaluation.