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  • 1
    Keywords: CANCER ; POPULATION ; RISK ; prevention ; NONSTEROIDAL ANTIINFLAMMATORY DRUGS ; CARDIOVASCULAR-DISEASE ; TASK-FORCE ; AMERICAN-COLLEGE ; OUTPATIENT COLONOSCOPY ; COLORECTAL ADENOMA DETECTION
    Abstract: CONTEXT: Immunochemical fecal occult blood tests (iFOBTs) are potentially promising tools for colorectal cancer screening. Low-dose aspirin use, which increases the likelihood of gastrointestinal bleeding, is common in the target population for colorectal cancer screening. OBJECTIVE: To assess the association of low-dose aspirin use with the performance of 2 quantitative iFOBTs in a large sample of patients undergoing colorectal cancer screening. DESIGN, SETTING, AND PARTICIPANTS: Diagnostic study conducted from 2005 through 2009 at internal medicine and gastroenterology practices in southern Germany including 1979 patients (mean age, 62.1 years): 233 regular users of low-dose aspirin (167 men, 67 women) and 1746 who never used low-dose aspirin (809 men, 937 women). MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values, and area under receiver operating characteristic (ROC) curves in detecting advanced colorectal neoplasms (colorectal cancer or advanced adenoma) with 2 quantitative iFOBTs. RESULTS: Advanced neoplasms were found in 24 users (10.3%) and 181 nonusers (10.4%) of low-dose aspirin. At the cut point recommended by the manufacturer, sensitivities of the 2 tests were 70.8% (95% confidence interval [CI], 48.9%-87.4%) for users compared with 35.9% (95% CI, 28.9%-43.4%) for nonusers and 58.3% (95% CI, 36.6%-77.9%) for users compared with 32.0% (95% CI, 25.3%-39.4%) for nonusers (P = .001 and P = .01, respectively). Specificities were 85.7% (95% CI, 80.2%-90.1%) for users compared with 89.2% (95% CI, 87.6%-90.7%) for nonusers and 85.7% (95% CI, 80.2%-90.1%) for users compared with 91.1% (95% CI, 89.5%-92.4%) for nonusers (P = .13 and P = .01, respectively). The areas under the ROC curve were 0.79 (95% CI, 0.68-0.90) for users compared with 0.67 (95% CI, 0.62-0.71) for nonusers and 0.73 (95% CI, 0.62-0.85) for users compared with 0.65 (95% CI, 0.61-0.69) for nonusers (P = .05 and P = .17, respectively). Among men, who composed the majority of low-dose aspirin users, the areas under the ROC curve were 0.87 (95% CI, 0.76-0.98) for users compared with 0.68 (95% CI, 0.63-0.74) for nonusers and 0.81 (95% CI, 0.68-0.93) for users compared with 0.67 (95% CI, 0.61-0.72) for nonusers (P = .003 and P = .04, respectively). CONCLUSION: For 2 iFOBTs, use of low-dose aspirin compared with no aspirin was associated with a markedly higher sensitivity for detecting advanced colorectal neoplasms, with only a slightly lower specificity.
    Type of Publication: Journal article published
    PubMed ID: 21139112
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  • 2
    Keywords: POPULATION ; PERFORMANCE ; PLASMA ; MARKERS ; CARCINOEMBRYONIC ANTIGEN ; GASTRIC-CANCER ; OCCULT BLOOD-TESTS ; COLORECTAL ADENOMA DETECTION ; AVERAGE RISK ; SERUM PEPSINOGEN
    Abstract: Objectives: In the evaluation of cancer screening tests, cancer-free controls are often matched to cancer cases on factors such as sex and age. We assessed the potential merits and pitfalls of such matching using an example from colorectal cancer (CRC) screening. Study Design and Setting: We compared sex and age distribution of CRC cases and cancer-free people undergoing screening colonoscopy in Germany in 2006 and 2007. We assessed specificity by sex and age of two immunochemical fecal occult blood tests (iFOBTs) in a study among screening colonoscopy participants conducted in the same years, and we assessed the expected impact of matching by sex and age on the validity of specificity estimates at various cut points. Results: In the screening colonoscopy program, the proportion of men and mean age were 59.6% and 68.6 years among 10,324 CRC patients compared with 45.6% and 64.7 years, respectively, among 997,490 cancer-free participants. The specificity of the iFOBTs was higher among women than among men and decreased with age. Matching of cancer-free controls by age and sex would have led to the underestimation of specificity at all cut points assessed. Conclusion: In the evaluation of cancer screening tests, matching of controls may lead to biased estimates of specificity.
    Type of Publication: Journal article published
    PubMed ID: 23257151
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  • 3
    Keywords: POPULATION ; PERFORMANCE ; PROGRAM ; colonoscopy ; COST-EFFECTIVENESS ANALYSIS ; ADENOMA DETECTION ; AVERAGE RISK ; CUTOFF
    Abstract: Immunochemical faecal occult blood tests (iFOBTs) have been shown to have higher sensitivity to detect colorectal cancer (CRC) and its precursors than traditional guaiac-based faecal occult blood tests, but are more costly and require specific laboratory equipment. A number of qualitative iFOBTs have been developed, but their performance varied widely because of the large variation in positivity thresholds used for test positivity. We aimed to evaluate the performance of qualitative iFOBTs with well adjusted positivity thresholds in the screening setting. In a study of 229 participants who underwent screening colonoscopy in Germany (45 patients with CRC, 65 with advanced adenoma and 119 free of colorectal neoplasms), we evaluated the performance of two qualitative iFOBTs at five different positivity thresholds and compared it with the performance of a quantitative iFOBT. Receiver operating characteristic curves were constructed. The areas under the curve, and the sensitivity and specificity of the tests, were calculated. For both qualitative tests, sensitivities were around 30% for advanced adenoma and 80% for CRC at very high levels of specificity (98-99%). Comparison of results with the receiver operating characteristic curves for the quantitative test indicated that the qualitative tests yielded similarly high levels of sensitivity at comparable levels of specificity. In conclusion, with appropriate adjustment of positivity thresholds ensuring the levels of specificity required in population-based screening, qualitative, office-based iFOBTs can be an economic, qualitatively comparable alternative to quantitative iFOBTs.
    Type of Publication: Journal article published
    PubMed ID: 23702679
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  • 4
    Keywords: neoplasms ; POPULATION ; PERFORMANCE ; UPDATE ; colonoscopy ; OCCULT BLOOD-TESTS ; ADENOMA DETECTION ; AVERAGE RISK ; CUTOFF LEVELS
    Abstract: Background. Faecal immunochemical tests (FITs) for haemoglobin are increasingly used for non-invasive screening for colorectal cancer (CRC) but large scale comparative studies of different FITs for detection of CRC, overall and by stage, are sparse. We aimed to determine and compare performance of different FITs for the detection of CRC, and to assess their stage-specific sensitivities. Material and methods. We assessed sensitivity, specificity and their corresponding 95% confidence intervals for six qualitative FITs among 74 CRC cases (59% stage I or II cancers) and 1480 controls free of colorectal neoplasm. Overall and stage-specific receiver operating characteristic curves were derived for three quantitative FITs. The areas under the curves (AUCs) were calculated and compared. Results. Pairs of overall sensitivity and specificity of the qualitative FITs ranged from 66% and 96% to 92% and 62%, respectively. For the three quantitative tests, AUCs ranged from 0.90 to 0.92, with sensitivities ranging from 80% to 87% at cut-offs yielding 90% specificity. AUCs ranged from 0.85 to 0.92, 0.94 to 0.96, and 0.86 to 0.93 for stage I, stage II and advanced stages (stage III and IV) cancers, respectively. At a specificity of 90%, the tests detected 65%-85% of stage I cancers. Conclusion. The diagnostic performance of FITs regarding detection of CRC is promising, even though the pre-defined cut-offs of some of the qualitative FITs need to be adjusted to limit false-positive rates in screening setting. At cut-off levels yielding 90% specifi city, the quantitative tests detected the vast majority of CRCs, even at early stages.
    Type of Publication: Journal article published
    PubMed ID: 23617541
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  • 5
    Keywords: EXPRESSION ; CELL-PROLIFERATION ; RISK ; PROTEIN ; MESSENGER-RNA ; COLON-CANCER ; STABILITY ; LIVER METASTASES ; POLYPS ; FALSE DISCOVERY RATE
    Abstract: Deregulation of apoptosis is a frequent alteration in early benign lesions of the colon mucosa and is thought to be a major contributor to tumor progression and cancer. Single nucleotide polymorphisms (SNPs) within apoptosis-related genes could affect apoptotic responses and their identification might provide a basis to assess individual risk for development of early lesions. To investigate a possible association between genetic polymorphisms and the occurrence of hyperplastic polyps (HP), we developed a custom DNA chip assay for 1,536 SNPs in the coding and flanking regions of 826 genes with known functional roles in apoptosis or apoptosis-associated (e. g., stress-related) pathways. During a first round of screening, genotypes were determined for 272 endoscopy patients harboring hyperplastic colorectal polyps and for 512 sex and aged-matched controls. A set of 14 candidate SNPs associated with HP (P 〈 0.01) was then evaluated in an independent cohort of patients (n = 38) and controls (n = 38). Following meta-analysis of Stages I and II, a false discovery rate approach was applied. Among the 14 candidate SNPs, eight showed significant association (combined P 〈 0.01) with the occurrence of HP. The SNPs rs4709583 (PARK2) and rs10476823 (HDAC3) were analyzed for potential functional effects on RNA splicing and RNA half-life. Despite its location near a splice site, alternative splicing was not detected for rs4709583 (PARK3). By contrast, cDNA analysis revealed use of a cryptic polyadenylation signal in the 3'UTR of HDAC3 mRNA and a longer mRNA half-life in a cell line heterozygous for rs10476823.
    Type of Publication: Journal article published
    PubMed ID: 24861865
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  • 6
    Keywords: COLON-CANCER ; PROGNOSTIC-SIGNIFICANCE ; PANCREATIC-CANCER ; ANTI-P53 ANTIBODIES ; HUMORAL IMMUNE-RESPONSE ; PROTEOMICS-BASED IDENTIFICATION ; SERUM P53 ANTIBODIES ; CIRCULATING ANTIBODIES ; CANCER/TESTIS ANTIGEN ; AUTOIMMUNE-RESPONSE
    Abstract: Multiple studies have shown that cancer patients produce detectable autoantibodies against certain tumor-associated antigens, which might be promising blood biomarkers for early detection of colorectal cancer (CRC). We aimed to provide an overview of published studies on blood autoantibody markers for early detection of CRC and to summarize their diagnostic performance. A systematic literature search was performed in PubMed, ISI Web of Knowledge and EMBASE to find relevant studies published until 23 July 2013. Relevant information, such as study population characteristics, autoantibodies studied, analytical methods and diagnostic performance characteristics was independently extracted by two reviewers. Overall, 67 studies evaluating 109 autoantibody markers were included. Most individual markers showed low sensitivity (below 25%) for detecting CRC, along with high specificity close to 100%. Occasionally reported higher sensitivities for specific antibodies are yet to be replicated in independent studies. Generally, more promising results were seen for combinations of multiple autoantibody markers. But again, these promising results are yet to be replicated in other samples. In conclusion, autoantibody signatures may become a promising approach to noninvasive CRC screening. Optimized marker panels are yet to be developed, and promising results require validation in large screening populations.
    Type of Publication: Journal article published
    PubMed ID: 24462820
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  • 7
    Keywords: colon ; BREAST ; MARKERS ; MASS-SPECTROMETRY ; proteome ; YIELD ; TISSUE INHIBITOR ; OCCULT BLOOD-TESTS ; STATISTICAL-MODEL ; LRG1
    Abstract: Non-invasive detection of colorectal cancer with blood-based markers is a critical clinical need. Here we describe a phased mass spectrometry-based approach for the discovery, screening, and validation of circulating protein biomarkers with diagnostic value. Initially, we profiled human primary tumor tissue epithelia and characterized about 300 secreted and cell surface candidate glycoproteins. These candidates were then screened in patient systemic circulation to identify detectable candidates in blood plasma. An 88-plex targeting method was established to systematically monitor these proteins in two large and independent cohorts of plasma samples, which generated quantitative clinical datasets at an unprecedented scale. The data were deployed to develop and evaluate a five-protein biomarker signature for colorectal cancer detection.
    Type of Publication: Journal article published
    PubMed ID: 26253081
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  • 8
    Keywords: CANCER ; POPULATION ; NEOPLASIA ; AVERAGE-RISK ; sigmoidoscopy ; PROSPECTIVE MULTICENTER ; COLORECTAL ADENOMA DETECTION ; POLYP
    Abstract: There is increasing evidence that faecal immunochemical tests (FITs) for haemoglobin offer a number of advantages over traditional guaiac based faecal occult blood tests (gFOBTs). However, evidence on diagnostic performance from direct comparisons with colonoscopy findings in all participants in the average risk population is still sparse. We aimed for a head-to-head comparison of three quantitative FITs with a gFOBT among participants of the German screening colonoscopy programme. Pre-colonoscopy stool samples and colonoscopy reports were obtained from 2235 participants of screening colonoscopy in 2005-2009. To enhance comparability of diagnostic performance of the various tests, we assessed sensitivity, specificity, predictive values and likelihood ratios of FITs after adjusting the FIT cut-off haemoglobin (Hb) concentrations in such a way that FIT positivity rates equalled the positivity rate of the gFOBT. Colorectal cancer, advanced adenomas and other adenomas were found in 15 (0.7%), 207 (9.3%) and 398 (17.8%) participants. The gFOBT was positive in 111 (5.0%) participants, with sensitivities (specificities) for detecting colorectal cancer, any advanced neoplasm or any neoplasm of 33.3% (95.2%), 8.6% (95.4%) and 5.5% (95.2%). At the same positivity rate, all three FITs outperformed the gFOBT in all indicators. In particular, all sensitivities of FITs were approximately two to three times higher at increased levels of specificity. All differences were statistically significant, except for some of the performance indicators for colorectal cancer. In conclusion, FITs can detect much larger proportions of colorectal neoplasms even if their cut-offs are set to levels that ensure equally low positivity rates as gFOBT.
    Type of Publication: Journal article published
    PubMed ID: 23706981
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  • 9
    Keywords: PROTEIN ; COLORECTAL-CANCER ; SQUAMOUS-CELL CARCINOMA ; MALIGNANT-TUMORS ; ANTI-P53 ANTIBODIES ; HUMORAL IMMUNE-RESPONSE ; TUMOR-ASSOCIATED ANTIGEN ; POTENTIAL BIOMARKER ; PROTEOMICS-BASED IDENTIFICATION ; P53 ANTIBODY
    Abstract: Antibodies against tumor-associated antigens have been found in serum of patients with various types of cancers and may serve as biomarkers for early detection of gastric cancer as well. This systematic review aims to give an overview about known autoantibodies and their diagnostic value in gastric cancer. We conducted a systematic literature search in two databases to identify studies which performed serological testing for autoantibodies in gastric cancer patients and controls. Data on study characteristics and results were extracted independently by two reviewers. Overall, 39 articles reporting the detection of 34 different autoantibodies met the inclusion criteria for this review. The most common antibody detection method was enzyme-linked immunosorbent assay and the most frequently assessed autoantibody was anti-p53, which was tested in 13 studies. Most antibodies were assessed in only one study and only few authors have evaluated the diagnostic value of combinations of multiple autoantibodies. For single autoantibodies, specificity was generally very high (median: 99.15%), but sensitivity was mostly rather low (median: 12.35%). For some autoantibody combinations, substantially higher sensitivity at reasonably high levels of specificity could be achieved. Development of extended and optimized multimarker panels of autoantibodies might be a promising approach for gastric cancer early detection.
    Type of Publication: Journal article published
    PubMed ID: 24615018
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  • 10
    Keywords: PROTECTION ; MODEL ; prognosis ; colon ; TARGET ; chemotherapy ; microsatellite instability ; tumor marker ; inflammation ; tissue microarray ; cancer prognosis ; INFLAMMASOME ; CYTOPLASMIC DNA ; DSDNA ; interferon (IFN)
    Abstract: Functional studies on colorectal cancer cells indicated a protective role of the interferon-inducible dsDNA sensor Absent in Melanoma 2 (AIM2) in cancer progression. Given that a high mutation rate and lack of AIM2 expression was previously detected in a subset of colorectal cancers, we here investigated the association of AIM2 expression in tumor cells and patient prognosis (5-year follow-up). A tissue microarray analysis of 476 matched tissue pairs (colorectal tumor and adjacent normal colon epithelium) was performed by two independent observers. Samples from 62 patients were excluded because of missing follow-up information or due to neo-adjuvant therapy before tissue sampling. Out of the remaining 414 tissue pairs, 279 (67.4%) displayed reduced AIM2 expression in cancer cells when compared to epithelial cells of their normal counterpart. Thirty-eight patients (9.18%) had completely lost AIM2 expression in tumor cells. After adjustment for sex, age, cancer stage, tumor site, tumor grade and chemotherapy, complete lack of AIM2 expression was associated with an up to 3-fold increase in overall mortality (HR=2.40; 95% CI=1.44-3.99) and disease specific mortality (HR=3.14; 95% CI=1.75-5.65) in comparison to AIM2-positive tumor samples. Our results demonstrate that lack of AIM2 expression is closely associated with poor outcome in colorectal cancer. The data thus strongly substantiate a protective role of AIM2 against progression of colorectal tumors. Further studies are required to assess whether lack of AIM2 expression may be used as a biomarker for the identification of colorectal cancer patients with poor prognosis
    Type of Publication: Journal article published
    PubMed ID: 24729378
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