Specificity For Colorectal Cancer Research Articles

Effectiveness of fecal DNA syndecan-2 methylation testing for detection of colorectal cancer in a high-risk Chinese population.

Colorectal cancer (CRC) is among the most prevalent and life-threatening malignancies worldwide. Syndecan-2 methylation (mSDC2) testing has emerged as a widely used biomarker for early detection of CRC in stool and serum samples. Cancer (CRC) is among the most prevalent and life-threatening malignancies worldwide. mSDC2 testing has emerged as a widely used biomarker for early detection of CRC in stool and serum samples. To validate the effectiveness of fecal DNA mSDC2 testing in the detection of CRC among a high-risk Chinese population to provide evidence-based data for the development of diagnostic and/or screening guidelines for CRC in China. A high-risk Chinese cohort consisting of 1130 individuals aged 40-79 years was selected for evaluation via fecal mSDC2 testing. Sensitivity and specificity for CRC, advanced adenoma (AA) and advanced colorectal neoplasia (ACN) were determined. High-risk factors for the incidence of colorectal lesions were determined and a logistic regression model was constructed to reflect the efficacy of the test. A total of 1035 high-risk individuals were included in this study according to established criteria. Among them, 16 suffered from CRC (1.55%), 65 from AA (6.28%) and 189 from non-AAs (18.26%); 150 patients were diagnosed with polyps (14.49%). Diagnoses were established based upon colonoscopic and pathological examinations. Sensitivities of the mSDC2 test for CRC and AA were 87.50% and 40.00%, respectively; specificities were 95.61% for other groups. Positive predictive values of the mSDC2 test for CRC, AA and ACN were 16.09%, 29.89% and 45.98%, respectively; the negative predictive value for CRC was 99.79%. After adjusting for other high-risk covariates, mSDC2 test positivity was found to be a significant risk factor for the occurrence of ACN (P < 0.001). Our findings confirmed that offering fecal mSDC2 testing and colonoscopy in combination for CRC screening is effective for earlier detection of malignant colorectal lesions in a high-risk Chinese population.

Colorectal cancer detected by liquid biopsy 2 years prior to clinical diagnosis in the HUNT study.

Colorectal cancer (CRC) is often diagnosed in advanced stages. Circulating tumour DNA (ctDNA) has been proposed as an early diagnostic biomarker. However, as a screening tool, ctDNA has mainly been studied in selected populations at the time of clinical diagnosis. The aim of this study was to detect CRC by known ctDNA markers up to 2 years prior to clinical diagnosis. In this case-control study, methylated ctDNA markers were detected in plasma samples from 106 healthy controls and 106 individuals diagnosed with CRC within 24 months following participation in The Trøndelag Health Study. The most specific single markers were BMP3, FLI1, IKZF1, SFRP1, SFRP2, NPTX2, SLC8A1 and VIM (specificity >70%). When combining these into a panel, the CRC sensitivity was 43% (95% CI 42.7-43.4) and the CRC specificity was 86% (95% CI 85.7-86.2). The findings were reproduced in an independent validation set of samples. Detection of known methylated ctDNA markers of CRC is possible up to 2 years prior to the clinical diagnosis in an unselected population resembling the screening setting. This study supports the hypothesis that some patients could be diagnosed earlier, if ctDNA detection was part of the CRC screening programme.

Incorporating faecal haemoglobin measurement using the faecal immunochemical test (FIT) in the referral, triage and prioritisation pathway for patients with colorectal symptoms.

To derive a colorectal symptom pathway incorporating standard clinical and FIT data to guide referral, triage, and prioritisation of cases in New Zealand. Diagnostic accuracy of FIT to rule out colorectal cancer (CRC) was determined by meta-analysis. Thereafter, the risk of CRC after FIT was estimated for common clinical presentations by Bayesian methodology, using a specifically collated retrospective cohort of symptomatic cases. A symptom/FIT pathway was developed iteratively following multi-disciplinary engagement. Eighteen studies were included in meta-analysis. The sensitivity and specificity for CRC were 89.0% (95%CI 87.0-90.9%) and 80.1% (95%CI 77.7-82.4%) respectively, at a FHb threshold of >10mcg haemoglobin per gram stool, and 95.7% (95%CI 93.2-97.7%) and 60.5% (95%CI 53.8-67.0%) respectively, at the limit of detection. The final pathway was 97% sensitive for CRC, compared with 90% for the current direct access criteria, and requires 47% fewer colonoscopies. Estimated prevalence of CRC among those declined investigation was 0.23%. Incorporating FIT in the new patient symptomatic pathway as presented appears feasible, safe, and allows for resources to be targeted to those at greatest risk of disease. Further work is needed to ensure equity for Māori if this pathway were introduced nationally.

A prospective, cross-sectional, multicentre study to evaluate the clinical performance of the ColoSTAT in vitro diagnostic for the detection of biomarkers associated with colorectal cancer.

3529 Background: Colorectal cancer (CRC) survival rates could be improved if more cancers were detected early. The ColoSTAT blood test and algorithm combines concentrations of 5 protein biomarkers with age and sex to provide an alternative to current CRC screening methods like the faecal immunochemical test (FIT). We compared the performance of ColoSTAT to colonoscopy in detecting CRC. Methods: Patients in this Australian study were either recently diagnosed with CRC using colonoscopy and progressing to surgery or neoadjuvant treatment (Cohort 1) or had no CRC history and were scheduled for colonoscopy (Cohort 2). Due to COVID-19 pandemic-related recruitment delays, the samples from Cohort 1 were supplemented with bio-banked blood samples (BBS) from patients with clinically confirmed CRC. Patients provided a 17 mL blood sample and were followed until start of cancer treatment or colonoscopy. All blood samples were de-identified prior to testing by an independent laboratory. The primary endpoints were ColoSTAT sensitivity of ≥73% (lower 95% confidence limit [LCL] &gt; 60%), and specificity ≥90% (LCL &gt; 80%). Sensitivity by TNM stage was an exploratory endpoint (ACTRN12619000301167). Results: Cohort 1 enrolled 29 patients, Cohort 2 enrolled 768 patients and 192 BBS were included. Patient demographic characteristics were similar in Cohorts 1, 2 and BBS. Overall, the median age of the patients (n = 989) was 64 years (range 40 to 88) and 53.4% were female. Definitive ColoSTAT results were obtained for 22 patients in Cohort 1, 554 in Cohort 2 and 81 in BBS. Overall, the estimated sensitivity of ColoSTAT for detection of CRC compared with colonoscopy was 81.3% (95%CL 73.0%-87.4%) and estimated specificity 91.0% (95%CL 87.7%-93.5%) (Table). Conclusions: The ColoSTAT test met the primary endpoints of performance based on sensitivity and specificity in detecting CRC compared to colonoscopy. ColoSTAT sensitivity and specificity for CRC were comparable with published performance parameters for FIT which range from 74-93% (sensitivity) and 85-96% (specificity).1 Clinical trial information: ACTRN12619000301167 . Clinical trial information: ACTRN12619000301167 . [Table: see text]

The impact of extending CRC screening to the older population: Results from CRC-AIM microsimulation model.

10567 Background: Average-risk screening for colorectal cancer (CRC) is effective and recommended. The U.S. Preventive Services Task Force issued grade A and B recommendations for screening ages 50-75 and 45-49, respectively, however the recommendation for the older population (ages 76-85) is grade C (moderate certainty that the net benefit is small). With emerging blood-based CRC screening, we evaluated the benefits of screening the older population with continued multi-target stool DNA (mt-sDNA) or FIT strategies and/or with a modality shift to blood-based tests after age 75. Methods: Using the validated CRC-AIM microsimulation model, triennial mt-sDNA and annual FIT screening (ages 45-75) followed by four strategies for ages 76-85 (no screening, continued mt-sDNA/FIT, or a modality shift to blood-based screening using either CMS criteria [CMS] or recently reported blood test data from the ECLIPSE study1 [BT; Guardant Health, Inc.] were considered. For CMS criteria and BT, CRC sensitivity were set at 74% and 83%; and adenoma sensitivity was set to 20%, and 13%; and CRC specificity was set to 90% for both tests. Real-world (RWE) adherence for initial screening was set to 80% (CMS, BT), 65.6% (mt-sDNA), and 42.6% (FIT). Adherence for follow-up colonoscopy was set to 72.1% (mt-sDNA, CMS, BT) and 46.0% (FIT). Results: Screening among the population aged 45-85 resulted in 281 life years gained (LYG) with continued mt-sDNA as compared to 193 with continued FIT. Furthermore, mt-sDNA reduced CRC mortality by 70% as compared to 49% by FIT (Table). When screening modality was shifted to CMS (76-85 year olds), mt-sDNA/CMS resulted in 279 LYG as compared to 196 for FIT/CMS. CRC incidence was reduced by 59% (mt-sDNA/CMS) as compared to 38% (FIT/CMS), and mortality declined by 69% (mt-sDNA/CMS) as compared to 51% (FIT/CMS). Reductions in disease burden were lower when modality was switched to BT after age 75 due to reduced test performance. Conclusions: Extending CRC screening to the older population with continued mt-sDNA demonstrated the best health outcomes compared to other modalities. A modality shift after age 75 to blood-based testing resulted in greater LYG as compared to no screening, with performance at CMS criteria yielding better results than BT. Therefore, despite inferior performance, blood-based tests may offer a CRC screening option for older patients who are unable to complete stool testing. [Table: see text]

Association of circulating nucleosomes levels with FIT performance for advanced adenomas in a symptomatic population.

170 Background: The effectiveness of screening using either fecal immunochemical testing (FIT) or colonoscopy in reducing colorectal cancer (CRC) mortality has been demonstrated in previous studies. Nevertheless, the single test sensitivity of FIT for relevant precursor lesions, especially high-risk neoplasms like invasive cancer or advanced adenomas (AA), is a concern. Improving the sensitivity for high-risk neoplasm is critical to improving the effectiveness of screening in reducing CRC incidence and mortality. Dysregulation of histone post-translational modifications (PTMs) has been linked with several cancers including CRC. We investigated the clinical performance of circulating nucleosome levels containing specific histone PTMs in blood, in combination with FIT from symptomatic subjects referred to colonoscopy to evaluate their discriminant power towards CRC and AA. Methods: 10mls whole blood was obtained prior to colonoscopy from 476 patients referred to colonoscopy in National Taiwan University Hospital for surveillance or secondary to bowel symptoms. Patients were classified into 5 groups based on their colonoscopy reports: (i) patient with CRC (n = 67), (ii) patients with AA (n = 60, including 22 with AA≥2cm); (iii) patients with non-AA (n = 123); (iv) patients with non-neoplastic polyps (n = 29); (vi) healthy controls with no endoscopic lesion (n = 197). Plasma samples were analyzed for nucleosome levels using 7 different quantitative immunoassays (Nu.Q assays; Belgian Volition SRL, Belgium) targeting H3.1-nucleosomes or different histone modifications (H3K27Me3-, H3K36Me3-, H3K9Me3-, H3K14Ac-, H3K27Ac- or H3R8Cit-nucleosomes). All study subjects were asked to collect a stool sample at home within 48-hours before the colonoscopy. The fecal samples were assayed with the OC-SENSOR FIT kit (Eiken Chemical Co., Ltd., Tokyo, Japan) for all subjects. Results: At a cut-off of 20µg/g feces, the FIT test showed a sensitivity of 83.5% at 82.1% specificity for CRC +AA vs. Controls. All the CRC patients were detected but 35% of AA were missed, and 7 of which were high-risk adenomas (AA≥2cm). A combination of 2 Nu.Q biomarkers: H3K36Me3 and H3K9Me3 with FIT in a decision tree model showed an improved sensitivity of 98.4% allowing the detection of all CRC patients and 97% of the patients with AA including all high-risk adenomas. The 2 missed AA were one AA below 1cm and one between 1 and 2cm. Unnecessary colonoscopies could be reduced by 28.9% of the control and 20.7% of the non-neoplastic polyps subgroups as both are found negative with this panel of assays. Conclusions: At present, all the symptomatic patients are sent to colonoscopy in clinical practice. Our results indicate that H3K36Me3- and H3K9Me3-nucleosome levels, in combination with FIT in a decision tree model, could detect all CRC patients and all high-risk adenomas and help reduce unnecessary colonoscopies.

Circulating nucleosomes for detection of colorectal cancer and high-risk advanced adenomas.

169 Background: Detection and treatment of early colorectal cancer (CRC) or advanced adenomas (AA) is the key for superior outcomes and fecal immunochemical testing (FIT)-based screening has proven effective in reducing CRC death and the risk of advanced-stage CRC but the discrepancy in the effectiveness was observed between proximal and distal cancers. On the other hand, false-positive results of FIT with 60 % of negative colonoscopy is another concern, considering the burden to the screening participants and the healthcare providers. A blood-based test as an alternative or supplement to FIT has the potential to concurrently enhance the detection of high-risk neoplasms and identify individuals at risk who should then be referred to colonoscopy. We investigated the levels of circulating free nucleosomes containing different epigenetic modifications in patients referred for colonoscopy. Methods: 10mls whole blood was obtained from 520 asymptomatic patients prior to colonoscopy at National Taiwan University Hospital. Patients were classified into 5 groups based on their colonoscopy reports: (i) patient with CRC (n = 33), (ii) patients with AA (n = 123, including 18 with AA &gt; 2cm); (iii) patients with non-AA (n = 168); (iv) patients with non-neoplastic polyps (n = 30); (vi) healthy controls with no endoscopic lesion (n = 166). Plasma samples were analyzed for nucleosome levels using 7 different quantitative immunoassays (Nu.Q assays; Belgian Volition SRL, Belgium) targeting H3.1-nucleosomes or different histone modifications (H3K27Me3-, H3K36Me3-, H3K9Me3-, H3K14Ac-, H3K27Ac- or H3R8Cit-nucleosomes). All study subjects were asked to collect a stool sample at home within 48-hours before the colonoscopy. The fecal samples were assayed with the Eiken OC-SENSOR FIT kit (Eiken Chemical Co., Ltd., Tokyo, Japan) for all study subjects. Results: At a cut-off of 20µg/g feces, the FIT test showed a sensitivity of 92,9% at 17.5% specificity for CRC +AA vs. Controls. All the CRC patients and 83.3% of the high-risk AA (&gt; 2cm) patients were FIT positive. A combination of 2 Nu.Q biomarkers: H3K27Me3 and H3R8Cit with FIT in a logistic regression model showed improved sensitivity of 95% at 20.6% specificity allowing the detection of all CRC patients and 94.3% of AA patients including all the high-risk adenomas. The FIT test detected 46 out of 55 proximal adenomas whereas the combined model could detect 50 proximal adenomas including 3 proximal AA &gt; 2cm not being detected by FIT (p &lt; 0.05). The same combination would reduce unnecessary colonoscopies by 21.8% of the control and 23.3% of the non-neoplastic polyps subgroups compared to 17.5% and 6.7%, respectively with the FIT test alone. Conclusions: Our results indicate that H3K27Me3 and H3R8Cit-nucleosome levels in combination with FIT could improve the detection of proximal high-risk AA and could also provide a non-invasive method to reduce unnecessary colonoscopy.

Methylation of SDC2/TFPI2 and Its Diagnostic Value in Colorectal Tumorous Lesions.

Background: SDC2 methylation is a feasible biomarker for colorectal cancer detection. Its specificity for colorectal cancer is higher than 90%, but the sensitivity is normally lower than 90%. This study aims to improve the sensitivity of SDC2 detection through finding a high positive target from the false-negative samples of SDC2 detection based on analysis of the bowel subsite difference in methylation. Methods: Hypermethylated TFPI2 was identified in SDC2 hypomethylated colorectal cancer samples retrieved from TCGA database with the methylation level lower than 0.2. The methylation-specific PCR assay was developed and then evaluated using tissue samples (184 cancer and 54 healthy control samples) and stool samples (289 cancer, 190 adenoma, and 217 healthy control samples). Results: TFPI2 was hypermethylated in most SDC2 hypomethylated colorectal cancer samples. When the SDC2/TFPI2-combined PCR assay was performed in stool specimens, the AUC value of cancer vs. control was 0.98, with the specificity of 96.40% and sensitivity of 96.60%, and the AUC value of adenoma vs. control was 0.87, with the specificity of 95.70% and the sensitivity of 80.00%. The improvement in sensitivity was the most momentous in the left colon. As the detection index, the Ct value was better in improving the sensitivity of detection than the methylation level based on the 2−ΔΔCt value. Conclusion: TFPI2 can improve the sensitivity of SDC2 methylation–specific detection of colorectal tumorous lesions while maintaining high specificity, in particular reducing the missed detection of left colon cancer and adenoma.

Can FIT rule out colorectal cancer in symptomatic patients? Diagnostic test accuracy results from 9,822 patients in the NICE FIT study.

4093 Background: The faecal immunochemical test (FIT) is a non-invasive quantitative test that measures occult blood in faeces (faecal haemoglobin, FHb). FIT is already used worldwide in colorectal cancer (CRC) screening programmes. Bowel symptoms have low specificity for CRC; to diagnose one patient with CRC, a large number of symptomatic patients require investigation. A negative FIT test, when blood is not detected, could be used to rule out CRC in symptomatic patients without invasive investigations such as colonoscopy. We report on the largest diagnostic accuracy study to date of FIT in symptomatic patients. Methods: Patients were eligible for recruitment if they experienced bowel symptoms meeting national high-risk criteria and were triaged to investigation with colonoscopy. Patients were excluded from analysis if they did not provide a valid FIT or did not undergo complete colonoscopy. Colonoscopy results were compared to FIT measurements of FHb, and the conduct of the tests was double-blinded. Quality assurance of endoscopy and clinical data was performed by senior clinicians. External statisticians analysed anonymised data. Results: 9822 patients from 50 sites across England participated in the study between October 2017 to March 2019. The most common colonoscopy finding was absence of any colorectal disease (31%). The prevalence of CRC at colonoscopy was 3.3%. The sensitivity of FIT at FHb thresholds of 2, 10 and 150 μg/g significantly decreased from 97.0% to 90.9% and 70.8% respectively (p &lt; 0.01). FIT positivity rate at these thresholds increased from 7.6%, to 19% and 37.2% respectively (p &lt; 0.01). The positive predictive value of FIT for CRC at FHb thresholds of 2, 10 and 150 μg/g was 8.7%, 16.1% and 31.1% respectively and the negative predictive value of FIT at these thresholds was 99.8%, 99.6% and 98.9% respectively. Conclusions: The results of this study support the use of FIT at the threshold of detectable blood (2μg/g) as an initial CRC rule-out test to triage patients with high risk CRC symptoms, reducing the number of unnecessary investigations. This is the first study to report that at the lowest threshold of detectable blood, FIT sensitivity is equivalent to the current gold standard investigation of colonoscopy. Clinical trial information: ISRCTN49676259 .

Quantitative immunochemical fecal occult blood test for neoplasia in colon cancer screening.

To investigate the performance of the quantitative immunochemical fecal occult blood test (qFIT) and to determine the association between the fecal hemoglobin (Hb) level and the location and size of adenomas and the stages of colorectal cancer (CRC). A total of 692 participants were included in the study. Their fecal Hb level was measured using an OC-SENSA MICRO qFIT. The colonoscopy results, including the location, size, and histological features of the adenomas, as well as the relationship between the Hb level and different characteristics were analyzed. Performance of the qFIT at various thresholds of fecal Hb levels was evaluated. Advanced colorectal neoplasia (ACRN) was identified in 76 patients based on the colonoscopic and pathological examinations. Large adenomas (≥10 mm) had a higher fecal Hb level than small adenomas (<10 mm). Advanced adenomas located on the left side of the colon presented with a higher fecal Hb level than those on the right side (P = 0.022). Stage III-IV CRC patients had a significantly higher Hb level than stage I-II patients (P = 0.013). The sensitivity and specificity of qFIT for ACRN was 51.3% and 86.4%，respectively, with the best cut-off level of 400 ng/mL. The sensitivity and specificity for CRC was 61.0% and 89.1%, with the best cut-off level of 500 ng/mL. qFIT has an acceptable sensitivity and specificity for ACRN detection. Furthermore, the qFIT results are associated with the location and size of adenomas as well as the grade of CRC.

Early Detection and Staging of Colorectal Cancer Using a Panel of Micro RNAs

The present invention provides compositions, methods and kits for diagnosing cancer, specifically the diagnosis of colorectal cancer (CRC). More specifically, the invention provides simple assays, with high sensitivity and specificity for CRC, wherein a panel of microRNA (miRNA) are used as biomarkers.

A Blood Test for Methylated BCAT1 and IKZF1 vs. a Fecal Immunochemical Test for Detection of Colorectal Neoplasia.

Objectives:To compare the performance of a new blood test for colorectal cancer (CRC) to an established fecal immunochemical test (FIT) in a study population with the full range of neoplastic and non-neoplastic pathologies encountered in the colon and rectum.Methods:Volunteers were asked to complete a FIT prior to colonoscopy. Blood was collected after bowel preparation but prior to colonoscopy, and plasma was assayed for the presence of methylated BCAT1 and IKZF1 DNA using a multiplex real-time PCR assay. Sensitivity and specificity estimates for the blood test were calculated from true- and false-positive rates for neoplasia and compared with FIT at a range of fecal hemoglobin (Hb) concentration positivity thresholds.Results:In total, 1,381 volunteers (median age 64 years; 49% male) completed both tests prior to colonoscopy. Estimated sensitivity of the BCAT1/IKZF1 blood test for CRC was 62% (41/66; 95% confidence interval 49–74%) with a specificity of 92% (1207/1315; 90–93%). FIT returned the same specificity at a cutoff of 60 μg Hb/g, at which its corresponding sensitivity for cancer was 64% (42/66; 51–75%). In the range of commonly used FIT cutoffs, respective cancer sensitivity and specificity estimates with FIT were: 59% (46–71%) and 93% (92–95%) at 80 μg Hb/g, and 79% (67–88%) and 81% (78–83%) at 10 μg Hb/g. Although estimated sensitivities were not significantly different between the two tests for any stage of cancer, FIT showed a significantly higher sensitivity for advanced adenoma at the lower cutoffs. Specificity of FIT, but not of the BCAT1/IKZF1 blood test, deteriorated substantially in people with overt blood in the feces. When combining FIT (cutoff 10 μg Hb/g) with the BCAT1/IKZF1 blood test, sensitivity for cancer was 89% (79–96%) at 74% (72–77%) specificity.Conclusions:A test based on detection of methylated BCAT1/IKZF1 DNA in blood has comparable sensitivity but better specificity for CRC than FIT at the commonly used positivity threshold of 10 μg Hb/g. Further evaluation of the new test relative to FIT in the population screening context is now required to fully understand the potential advantages and disadvantages of these biomarkers in screening.

Evaluation of an assay for methylated BCAT1 and IKZF1 in plasma for detection of colorectal neoplasia

BackgroundSpecific genes, such as BCAT1 and IKZF1, are methylated with high frequency in colorectal cancer (CRC) tissue compared to normal colon tissue specimens. Such DNA may leak into blood and be present as cell-free circulating DNA. We have evaluated the accuracy of a novel blood test for these two markers across the spectrum of benign and neoplastic conditions encountered in the colon and rectum.MethodsCirculating DNA was extracted from plasma obtained from volunteers scheduled for colonoscopy for any reason, or for colonic surgery, at Australian and Dutch hospitals. The extracted DNA was bisulphite converted and analysed by methylation specific real-time quantitative PCR (qPCR). A specimen was deemed positive if one or more qPCR replicates were positive for either methylated BCAT1 or IKZF1 DNA. Sensitivity and specificity for CRC were estimated as the primary outcome measures.ResultsPlasma samples were collected from 2105 enrolled volunteers (mean age 62 years, 54 % male), including 26 additional samples taken after surgical removal of cancers. The two-marker blood test was run successfully on 2127 samples. The test identified 85 of 129 CRC cases (sensitivity of 66 %, 95 % CI: 57–74). For CRC stages I-IV, respective positivity rates were 38 % (95 % CI: 21–58), 69 % (95 % CI: 53–82), 73 % (95 % CI: 56–85) and 94 % (95 % CI: 70–100). A positive trend was observed between positivity rate and degree of invasiveness. The colonic location of cancer did not influence assay positivity rates. Gender, age, smoking and family history were not significant predictors of marker positivity. Twelve methylation-positive cancer cases with paired pre- and post-surgery plasma showed reduction in methylation signal after surgery, with complete disappearance of signal in 10 subjects. Sensitivity for advanced adenoma (n = 338) was 6 % (95 % CI: 4–9). Specificity was 94 % (95 % CI: 92–95) in all 838 non-neoplastic pathology cases and 95 % (95 % CI: 92–97) in those with no colonic pathology detected (n = 450).ConclusionsThe sensitivity for cancer of this two-marker blood test justifies prospective evaluation in a true screening population relative to a proven screening test. Given the high rate of marker disappearance after cancer resection, this blood test might also be useful to monitor tumour recurrence.Trial registrationACTRN12611000318987.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1674-2) contains supplementary material, which is available to authorized users.

The accuracy of circulating microRNA-21 in the diagnosis of colorectal cancer: a systematic review and meta-analysis.

The accuracy and clinical value of circulating microRNA-21 (miR-21) were assessed as a novel diagnostic biomarker of colorectal cancer (CRC). Medline/PubMed, EMBASE, the Cochrane Library databases and grey literature(Google scholar; British Library) were searched up to 29 September 2014 for eligible studies of the association between blood-based miR-21 and a diagnosis of CRC. Quality Assessment of Diagnostic Accuracy Studies (QUADAS) was employed to assess the quality of the included studies by two investigators. Stata12.0 and Meta-DiSc1.4 software were applied to test the heterogeneity using Cochran's Q test and I(2) statistics and to perform the meta-analysis. Seven studies with 676 CRC patients and 417 controls were included in the meta-analysis. All were of high quality (QUADAS scores 12 or 13). For miR-21, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio to predict CRC were 75% [95% confidence interval (CI) 63-83%], 84% (95% CI 79-87%), 4.61 (95% CI 3.38-6.29), 0.30 (95% CI 0.20-0.46) and 16.89 (95% CI 7.56-37.73) after using a random-effects model analysis. The area under the summary receiver operating characteristic curve was 0.86 (95% CI 0.83-0.89). The results suggest that circulating miR-21 is a biomarker with moderate sensitivity and specificity for CRC.

Sensitivity and specificity of CT colonography for the detection of colonic neoplasia after positive faecal occult blood testing: systematic review and meta-analysis

CT colonography (CTC) is recommended after positive faecal occult blood testing (FOBt) when colonoscopy is incomplete or infeasible. We aimed to estimate the sensitivity and specificity of CTC for colorectal cancer and adenomatous polyps following positive FOBt via systematic review. The MEDLINE, EMBASE, AMED and Cochrane Library databases were searched for CTC studies reporting sensitivity and specificity for colorectal cancer and adenomatous polyps. Included subjects had tested FOBt-positive by guaiac or immunochemical methods. Per-patient detection rates were summarized via forest plots. Meta-analysis of sensitivity and specificity was conducted using a bivariate random effects model and the average operating point calculated. Of 538 articles considered, 5 met inclusion criteria, describing results from 622 patients. Research study quality was good. CTC had a high per-patient average sensitivity of 88.8 % (95 % CI 83.6 to 92.5 %) for ≥6 mm adenomas or colorectal cancer, with low between-study heterogeneity. Specificity was both more heterogeneous and lower, at an average of 75.4 % (95 % CI 58.6 to 86.8 %). Few studies have investigated CTC in FOBt-positive individuals. CTC is sensitive at a ≥6 mm threshold but specificity is lower and variable. Despite the limited data, these results suggest that CTC may adequately substitute for colonoscopy when the latter is undesirable. • FOBt is the most common mass screening test for colorectal cancer. • Few studies evaluate CT colonography after positive FOBt. • CTC is approximately 89 % sensitive for ≥6 mm adenomas/cancer in this setting. • Specificity is lower, at approximately 75 %, and more variable. • CT colonography is a good alternative when colonoscopy is undesirable.

Abstract 3511: The translation of epigenetic colorectal cancer tissue based diagnostic biomarkers into both faecal and blood based diagnostic biomarkers.

Abstract Colorectal cancer (CRC) is the 3rd most common cancer with &amp;gt;1 million new cases diagnosed annually. It is estimated that there could be up to 20,000 fewer deaths from CRC over the next 20 years if 60% of those eligible undertook bowel screening. In the UK, the current primary screening tool is the faecal occult blood test (FOBt). This test determines the presence of blood within a patients stool. It does not diagnose CRC directly, a positive test directs patients for further clinical evaluation. This potentially leads to invasive tests such as colonoscopy; however, the presence of blood in the faeces can be due to many factors and thus for every 10 people who undergo a colonoscopy, 7 individuals will have a ‘normal’ result. The poor positive predictive value of the FOBt test leads to unnecessary concern for the patient, has associated morbidity effects and has a huge cost implication for the healthcare system. Consequently, there is a need for a robust preventive strategy that can stratify patients into appropriate screening programmes for the early detection of CRC. There is growing evidence for aberrant hypermethylation of CpG islands in patients who suffer from CRC. Molecular diagnostics companies are exploiting the detection of aberrant DNA hypermethylation of Vimentin in faeces and Septin-9 in blood to develop assays for CRC diagnosis. Both tests are currently undergoing clinical trials. Here we present data from a panel of 12 genes with hypermethylated CpG sites that have been successfully validated in tissue samples. A subset (6 markers) of this panel has previously been shown to have extremely high sensitivity (94%) and specificity (98%) for carcinoma tissues, and importantly this performance is not eroded when tissue from pre-malignant adenoma samples are analysed (sensitivity 93%, specificity 98%). The areas under the Receiver Operating Characteristic curves were 0.984 for carcinomas and 0.968 for adenomas1. We have developed and translated these 12 tissue markers, culminating in a multiplex method for the analysis of all 12 markers in both blood and faecal samples. Here we present the application of this multiplexed method for the detection of carcinomas in faecal/blood samples with high sensitivity and specificity. The resulting method is suitable for a population-based screening approach which provides enhanced sensitivities and specificities over the current FOBt test. 1. G. Lind et al., Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas, Molecular Cancer, vol. 10, 2011. Citation Format: Graham Speight, Nicholas Workman, Pooja Agashe, Richard Stark, Stuart Ball, Andrew Rogers, Will Colón, John Anson. The translation of epigenetic colorectal cancer tissue based diagnostic biomarkers into both faecal and blood based diagnostic biomarkers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3511. doi:10.1158/1538-7445.AM2013-3511

Immunochemical Fecal Occult Blood Test for Detection of Advanced Colonic Adenomas and Colorectal Cancer: Comparison with Colonoscopy Results

Background. Fecal immunochemical tests (FITs) have been used for colorectal cancer (CRC) screening in several countries. There is lack of information concerning diagnostic performances of this method in Brazil. Methods. Patients scheduled for elective colonoscopy provided one stool sample one week before colonoscopy. The accuracy of a qualitative FIT for detection of CRC and advanced adenomas was determined. Results. Overall 302 patients completed the study. Among them, 53.5% were high risk patients referred for screening or surveillance. Nine (3%) CRCs and 11 (3.6%) advanced adenomas were detected by colonoscopy. Sensitivity and specificity for CRC were, respectively, 88.9% and 87.6%. For advanced adenomas, sensitivity was 63.6% and specificity 87.6%. Conclusion. Our results showed good sensitivity and specificity of the FIT for detecting advanced neoplasias. This method may be a valuable tool for future screening programs in Brazil.

P-0150 Comparative Efficiency of Colorectal Cancer Detection by 2 Different Screening Protocols

ABSTRACT Introduction The OC-Sensor™ (Eiken, Tokyo, Japan) immunochemical fecal occult blood test (I-FOBT) with automated processing, provides a semi-quantitated outcome as the positive cut-off point. This makes it possible to search for the optimal balance between sensitivity and specificity for colorectal cancer (CRC) while providing the balance between optimal efficiency, minimal cost, least demand on resources and inconvenience to the screenee. Methods 5210 patients (Group 1) aged 50-74 years at average risk for CRC were screened with 2 consecutive tests and 13,140 patients (Group 2) of similar age and CRC risk, with a single test. Those with an IFOBT value ≥100-ngHb/mL of buffer underwent colonoscopy. Detection rates of neoplasms were calculated as % of participants with pathology-confirmed CRC (TNM stages I-IV) or carcinoma-in-situ (CIS) or adenoma. Comparative efficiency of these two groups was calculated by two-tailed statistical test. Results More women participated than men, (69%) in Group 1 and 61.8% in Group 2. A positive IFOBT was found in 456 subjects of Group 1 (8.8%) and 972 of Group 2 (7.4%). CRC was detected in 18 (4.0%) and in 38 (3.9%); CIS in 8 (1.8%) and 13 (1.3%); adenomas in 96 (21.1%) and 230 (23.7%) of Group 1 & 2, respectively. These results were not significantly different, CRC [OR=1.010;CI (0.5699-1.790); P=1.000], CIS [OR=1.317;CI (0.5420-3.2020); P=0.6376] & adenoma [OR=0.8603;CI (0.6571-1.126); P=0.2802]. Conclusion The efficiency of CRC or adenoma screening by single semi-quantitated IFOBT (value ≥100-ngHb/mL of buffer) is not significant different from screening by 2 consecutive tests. The single semi-quantitated IFOBT is an effective, easy to use screening tool for clinical practice, with less demand on screenee and cheaper.

Identification of a new protein biomarker for colorectal cancer diagnosis

As one of the most common cancers, colorectal cancer (CRC) is a major public health issue worldwide. Thus, the identification of novel biomarkers to aid in the early diagnosis of CRC is crucial. The aim of the present study was to identify a novel protein biomarker for CRC, and to identify its structure. In this study, a total of 99 serum samples from 73 CRC patients and 26 healthy controls were collected and analyzed by SELDI-TOF-MS. The biomarkers were separated using HPLC and detected with MALDI-TOF-MS. The qualified peaks were ranked by p-value of non-parametric tests and the top 10 peaks displaying significant differences were selected. Among the 10 protein biomarkers, the concentration of a 3.9‑kDa protein in the serum of the CRC patients was much lower than that in the healthy controls. Therefore, the 3.9‑kDa protein was selected as a biomarker for CRC and its separation and purification were performed. The structure of the 3.9-kDa protein biomarker was determined by LC-MS/MS, and was confirmed to be a fragment of serine/theonine kinase 4 (MST1/STK4). The 3.9‑kDa protein biomarker had high sensitivity and specificity for CRC, and its potential clinical application warrants further investigation.

FIT to be Tried

FIT to be Tried