Serum M2-pyruvate kinase: A promising non-invasive biomarker for colorectal cancer mass screening

AIM: To explore the value of serum M2-pyruvate kinase (M2-PK) in colorectal cancer (CRC) mass screening. METHODS: We conducted a molecular epidemiology study in Hangzhou, China, from year 2006 to year 2008. Serum samples were collected from 93 CRC, 41 advanced adenomas, 137 adenomas, 47 non-adenomatous polyps, and 158 normal participants in a community setting. Serum M2-PK and carcinoembryonic antigen (CEA) were measured using Enzyme-linked immuno-sorbent assay. SPSS 16.0 software was used to perform data analysis. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificities were estimated for serum M2-PK in diagnosis of colorectal lesions and compared with CEA. RESULTS: Average serum M2-PK value among 158 normal people was 2.96 U/mL and not affected by gender (P = 0.47) or age (P = 0.59). Average serum M2-PK (U/mL) was 14.75 among stage Ⅲ and 13.10 among stage Ⅰ and Ⅱ CRC patients, about 4 times higher than that among normal people. Average serum M2-PK was 8.58, 6.70, 5.13 and 2.51 U/mL among advanced adenoma, adenomas, non-adenomatous polyps, and inflammatory bowel disease patients, respectively. AUC for serum M2-PK was greater than that for CEA among all colorectal lesions. AUC for serum M2-PK was 0.89 (0.84, 0.94) (95% confidence interval), higher than that for CEA [0.70 (0.62-0.79)] in CRC stageⅠ and Ⅱ, 0.89 (0.84-0.94) vs 0.73 (0.63-0.83) in CRC stage Ⅲ, 0.81 (0.74-0.86) vs 0.63 (0.53 -0.73) in advanced adeno- mas, 0.69 (0.64-0.76) vs 0.54 (0.47-0.60) in adenomas, and 0.69 (0.62-0.78) vs 0.58 (0.48-0.68) in nonadenomatous polyps. The diagnostic sensitivity for all colorectal lesions increased with decrease in the cut-off value of serum M2-PK. The diagnostic sensitivity (%) of serum M2-PK was 100.00 for CRC, 95.12 advanced ad- enoma, 82.48 adenoma, and 82.98 non-adenomatous polyp. There were no CRC cases missed and 40.51% of unnecessary colonoscopies were avoided when the cut-off value was 2.00 U/mL. CONCLUSION: Serum M2-PK can be used as a primary screening test in CRC mass screening. It may be a promising non-invasive biomarker for CRC early detection.     

肿瘤型丙酮酸激酶在结直肠癌血浆中的测定及其临床意义

目的：探讨肿瘤型丙酮酸激酶（tumorM2pyruvatekinase,TUM2-PK）在结直肠癌血浆中的浓度变化,及其作为肿瘤指标的临床应用价值。方法：使用Elisa方法测定16例健康对照组人群血浆TuM2-PK浓度,以及40例结直肠癌患者治疗前血浆TUM2-PK浓度（其中22例追踪测定术后血样浓度,7例追踪肿瘤复发转移后进行XELOX方案化疗1次后血样浓度）。同时期测定血清癌胚抗原（CEA）浓度。结果：结直肠癌患者的血浆TUM2-PK值明显高于正常人（P〈0．01）。血浆TUM2-PK值与Dukes分期较晚（P〈0．01）以及复发远处转移（P〈0．01）明显相关。在接受手术的患者中血浆TUM2-PK在原发肿瘤的病理分级不良（P=0．047）、淋巴转移阳性（P=0．030）、有远处转移（P：0．022）、DukesD期（P=0．048）情况下明显升高。在特异性相同的情况下,血浆TUM2-PK敏感性比血清CEA高（80％VS52．5％）,联合检测的敏感性明显上升。追踪术后及化疗后患者血浆TUM2-PK浓度变化,发现其浓度显著下降（P〈0．01）。结论：血浆TUM2-PK水平在罹患结直肠癌,尤其是发生浸润转移的患者中明显升高,并且在术后及化疗后下降明显,有望成为筛选和提示进展的诊断指标,并在检测疾病动态变化方面有良好的应用价值。     

The pyruvate kinase isoenzyme M2 (Tu M2-PK) as a tumour marker for renal cell carcinoma

The M2 isoenzyme of pyruvate kinase (M2-PK) is specially expressed by tumour cells (Tu M2-PK) and has been detected in the peripheral blood of patients with renal cell carcinoma (RCC). We analysed the benefit of using Tu M2-PK as a tumour marker for primary detection of RCC by receiver operating characteristic (ROC) analysis. The area under the curve was 0.674, and the sensitivity, specificity and positive predictive value (PPV) were 44.4%, 87.5% and 88%, respectively, at the ROC optimal cut-off of 28.2 kU/L. We examined 71 patients. Since the marker sensitivity for detection of the early stages T1 and T2 was only 47% it is not suggested to use this marker for primary diagnosis of RCC. Its use as part of the confirmatory preoperative evaluation might be considered in view of its high PPV.     

Tumour M2-PK as a stool marker for colorectal cancer: comparative analysis in a large sample of unselected older adults vs colorectal cancer patients

Stool testing based on tumour-derived markers might offer a promising approach for non-invasive colorectal cancer (CRC) screening. The aim of this study was to estimate the potential of a new test for faecal tumour M2-PK to discriminate patients with CRC from a large sample of unselected older adults. Faecal tumour M2-PK concentrations were determined in 65 CRC patients and in a population-based sample of 917 older adults (median age: 65 and 62 years, respectively). Sensitivity and specificity of the test were calculated at different cutoff values, and receiver-operating characteristic curves (ROC) were constructed to visualise the discriminatory power of the test. The median (interquartile range) faecal tumour M2-PK concentration was 8.6 U ml(-1) (2.8-18.0) among CRC patients and <2 U ml(-1) (<2-3.2; P<0.0001) in the population sample. At a cutoff value of 4 U ml(-1), sensitivity (95% confidence interval) was 85% (65-96%) for colon cancer and 56% (41-74%) for rectum cancer. Specificity (95% confidence interval) was estimated to be 79% (76-81%). Given the comparatively high sensitivity of the tumour M2-PK stool test (especially for colon cancer) and its simple analysis, the potential use of the test for early detection of CRC merits further investigation. Possibilities to enhance specificity of the test should be explored.     

The Optimal Cut-Off Level of The Fecal Immunochemical Test For Colorectal Cancer Screening in a Country with Limited Colonoscopy Resources: A Multi-Center Study from Thailand

Background: Selecting the cut-off point for the fecal immunochemical test (FIT) for colorectal cancer (CRC) screening programs is of prime importance. The balance between the test performance for detecting advanced neoplasia and the available colonoscopy resources should be considered. We aimed to identify the optimal cut-off of FIT for advanced neoplasia in order to minimize colonoscopy burden. Methods: We conducted a multi-center study in 6 hospitals from diverse regions of Thailand. Asymptomatic participants, aged 50-75 years, were tested with one-time quantitative FIT (OC-SENSOR, Eiken Chemical Co.,Ltd., Tokyo, Japan) and all participants underwent colonoscopy. We assessed test performance in detecting advanced neoplasia (advanced adenoma and CRC) and measured the burden of colonoscopy with different cut-offs [25 (FIT25), 50 (FIT50), 100 (FIT100), 150 (FIT150), and 200 (FIT200)ng/ml]. Results: Among 1,479 participants, advanced neoplasia and CRC were found in 137 (9.3%) and 14 (0.9%), respectively. From FIT25 to FIT200, the positivity rate decreased from 18% to 4.9%. For advanced neoplasia, an increased cut-off decreased sensitivity from 42.3% to 16.8% but increased specificity from 84.2% to 96.3%. The increased cut-off increased the positive predictive value (PPV) from 21.5% to 31.5%. However, all cut-off points provided a high negative predictive value (NPV) (>90%). For CRC, the miss rate for FIT25 to FIT 150 was the same (n=3, 21%), whereas that with FIT200 increased to 35% (n=5). Conclusions: In a country with limited-colonoscopy resources, using FIT150 may be preferred because it offers both high PPV and NPV for advanced neoplasia detection. It could also decrease colonoscopy workload, while maintaining a CRC miss rate similar to those with lower cut-offs.     

Faecal tumour M2 pyruvate kinase: a new, sensitive screening tool for colorectal cancer

Proliferating cells, especially tumour cells, express a special isoenzyme of pyruvate kinase, termed M2-PK, which can occur in a tetrameric form with a high affinity to its substrate, phosphoenolpyruvate (PEP), and in a dimeric form with a low PEP affinity. In tumour cells, the dimeric form is usually predominant and is therefore termed Tumour M2-PK. The levels of Tumour M2-PK within tumours and in EDTA-plasma correlate with staging and the ability of the tumour cells to metastasise. Since most colorectal tumours grow intraluminally, it appeared interesting to determine whether Tumour M2-PK is detectable in the faeces of tumour patients. Stool samples were tested by ELISA from controls without colorectal cancer and colorectal cancer patients. Whereas Tumour M2-PK levels were low in the control group (mean value+/-s.e.m.: 3.3+/-0.4, n=144), they were high in the case of colorectal cancer (56.1+/-15.3, n=60). At a cutoff value of 4 U ml(-1), the sensitivity was 73%. TNM and Dukes' classification of the tumours revealed a strong correlation between faecal Tumour M2-PK levels and staging. The determination of Tumour M2-PK in faeces provides a new promising screening tool for colorectal tumours.     

Diagnostic value of fecal tumor M2-pyruvate kinase for CRC screening: a systematic review and meta-analysis

The measurement of fecal tumor M2-pyruvate kinase (PKM2), overexpressed in tumor cells, has been proposed as a novel tool for detecting colorectal cancer (CRC). However, the sensitivity and specificity of this test varied among studies. The aim of this meta-analysis was to determine the diagnostic accuracy of fecal PKM2 for CRC and to evaluate its utility in the CRC screening. It was compared to guaiac fecal occult blood test (gFOBT) or immunological fecal occult blood test (iFOBT). Through comprehensive literature search, 10 studies met the inclusion criteria and were included. Summary estimates for sensitivity and specificity were calculated by using the bivariate random effect model. The hierarchical summary receiver operating characteristic curve was also undertaken. The overall sensitivity and specificity of fecal PKM2 for detecting CRC were 79% (95% CI = 75-83%) and 81% (95% CI = 73-87%), respectively. The summary positive predictive value and negative predictive value were 74% (95% CI = 56-87%) and 86% (95% CI = 79-91%), respectively. The pooled diagnostic odds ratio was 16 (95% CI = 10-26). In head-to-head comparison, the diagnostic odds ratio of PKM2 and gFOBT for CRC were 10.167 (95% CI = 5.992-17.250) and 6.557 (95% CI = 3.467-12.403), respectively. The diagnostic odds ratio of PKM2 and iFOBT for CRC were 9.542 (95% CI = 5.893-15.452) and 67.248 (95% CI = 16.194-279.26), respectively. The fecal PKM2 test was a diagnostic tool with moderate sensitivity and specificity for detecting CRC. Its diagnostic efficiency was similar to that of gFOBT. Because of its relatively low specificity and positive predict value, fecal PKM2 was not recommended used alone as a screening tool for CRC.     

反向被动血凝法检测粪便潜血对大肠癌人群筛检的效果评价

Evaluation of reverse passive hemagglutination (RPHA) fecal occult blood (FOB) test in screening for colorectal cancer was carried out in a group of subjects (3034 persons) with history of rectal polyp and ulcer. All subjects were examined by 60 cm fiberoptic colonoscopy, RPHA and benzidine (BT) FOB tests. Among this high risk population, 10 cases of colorectal cancer and 1 case of rectal carcinoid were detected by colonoscopy and pathology. Regarding the findings under fiberoptic colonoscopy as a reference standard, the sensitivity of RPHA and BT in screening for colorectal cancer was 63.6% and 72.7%; the specificity was 81.9% and 61.7%; the general indicator--Youden index was 0.46 and 0.34, respectively. In 7 cases of colorectal cancer with both FOB tests positive, 5 (71%) had lesions in early stages (Dukes A and B). The results indicate that comparing with BT, RPHA has slightly lower sensitivity but higher specificity. RPHA fecal occult blood test could be used as preliminary screening for colorectal cancer.     

Electronic nose can discriminate colorectal carcinoma and advanced adenomas by fecal volatile biomarker analysis: proof of principle study

In the course and prognosis of colorectal cancer (CRC), early detection and treatment are essential factors. Fecal immunochemical tests (FITs) are currently the most commonly used non‐invasive screening tests for CRC and premalignant (advanced) adenomas, however, with restricted sensitivity. We hypothesized that fecal volatile organic compounds (VOCs) may serve as a diagnostic biomarker of CRC and adenomas. In this proof of concept study, we aimed to assess disease‐specific VOC smellprints in fecal gas to distinguish patients with CRC and advanced adenomas from healthy controls. Fecal samples of patients who were scheduled to undergo an elective colonoscopy were collected. An electronic nose (Cyranose 320®) was used to measure VOC patterns in fecal gas from patients with histopathologically proven CRC, with advanced adenomas and from controls (no abnormalities seen at colonoscopy). Receiver operator characteristic curves and corresponding sensitivity and specificity for detection of CRC and advanced adenomas were calculated. A total of 157 stool samples (40 patients with CRC, 60 patients with advanced adenomas, and 57 healthy controls) were analyzed by electronic nose. Fecal VOC profiles of patients with CRC differed significantly from controls (area under curve ± 95%CI, p‐value, sensitivity, specificity; 0.92 ± 0.03, <0.001, 85%, 87%). Also VOC profiles of patients with advanced adenomas could be discriminated from controls (0.79 ± 0.04, <0.001, 62%, 86%). The results of this proof of concept study suggest that fecal gas analysis by an electronic nose seems to hold promise as a novel screening tool for the (early) detection of advanced neoplasia and CRC.     

Sensitivity and specificity of faecal tumour M2 pyruvate kinase for detection of colorectal adenomas in a large screening study

The measurement of faecal tumour M2 pyruvate kinase (tumour M2 PK) has been proposed as a novel approach for early detection of colorectal cancer (CRC). However, as regards the potential of the test to detect precursors to CRC, an issue that is highly relevant to estimate its use in reducing CRC incidence and mortality, the available evidence is scant and controversial. The aim of our study was to determine the performance characteristics of the tumour M2 PK test with respect to colorectal adenomas in the target population of screening. Among 1082 participants of screening colonoscopy in Germany, of whom 30% had any adenoma and 10% had an advanced adenoma, the median (interquartile range) tumour M2 PK level in the whole study population was 1.3 U ml(-1) (0.3-3.3). At a cutoff value of 4 U ml(-1), sensitivity was 22 and 23% for detection of advanced and other adenomas, respectively, whereas specificity was 82%. The area under the receiver-operating characteristics curve (95% confidence interval) was 0.54 (0.51-0.58) and 0.56 (0.52-0.59) for advanced and other adenomas, respectively. In conclusion, the tumour M2 PK test has only very limited potential to distinguish between people bearing precursors to CRC and people with no finding at colonoscopy.     

EVALUATION OF REVERSE PASSIVE HEMAGGLUTINATION （RPHA） FECAL OCCULT BLOOD TEST IN SCREENING OF COLORECTAL NEOPLASIA

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Blood Tests for Early Detection of Colorectal Cancer

Detection of advanced colorectal neoplasia (advanced adenoma or cancer) in the course of screening programs has been proven to reduce both the incidence and mortality of the disease. In the average-risk population, the most extended colorectal cancer (CRC) screening strategies are based either on annual or biennial fecal occult blood tests, with colonoscopy reserved for patients testing positive, or on endoscopic procedures performed as the primary screening tool every 5 (sigmoidoscopy) or 10 (colonoscopy) years. In addition, other screening procedures, such as CT colonography and fecal DNA analysis, are under current investigation. However, several drawbacks associated with these techniques have led to low acceptability and compliance rates in population-based screenings. Therefore, there is a compelling need to identify noninvasive biomarkers to enhance screening acceptance and efficacy in detecting CRC at an earlier and curable stage. Although the analysis of blood biomarkers has not been included among the recommended strategies for CRC screening yet, recent advances in proteomics and genomics suggest that these technologies may represent alternative or complementary approaches to the currently accepted strategies in the near future. However, the accuracy of these techniques in terms of sensitivity, specificity, and predictive values for early detection of CRC must be confirmed in mass screening studies.     

DNA methylation patterns in blood of patients with colorectal cancer and adenomatous colorectal polyps

Colorectal cancer (CRC) screening rates are currently suboptimal. Blood-based screening could improve rates of earlier detection for CRC and adenomatous colorectal polyps. In this study, we evaluated the feasibility of plasma-based detection of early CRC and adenomatous polyps using array-mediated analysis methylation profiling of 56 genes implicated in carcinogenesis. Methylation of 56 genes in patients with Stages I and II CRC (N=30) and those with adenomatous polyps (N=30) were compared with individuals who underwent colonoscopy and were found to have neither adenomatous changes nor CRC. Composite biomarkers were developed for adenomatous polyps and CRC, and their sensitivity and specificity was estimated using five-fold cross validation. Six promoters (CYCD2, HIC1, PAX 5, RASSF1A, RB1 and SRBC) were selected for the biomarker, which differentiated CRC patients and controls with 84% sensitivity and 68% specificity. Three promoters (HIC1, MDG1 and RASSF1A) were selected for the biomarker, which differentiated patients with adenomatous polyps and controls with sensitivity of 55% and specificity of 65%. Methylation profiling of plasma DNA can detect early CRC with significant accuracy and shows promise as a methodology to develop biomarkers for CRC screening.     

Tumor type M2 pyruvate kinase (TuM2-PK) as a novel plasma tumor marker in melanoma

Proliferating cells express the pyruvate kinase isoenzyme type M2 (M2-PK). This enzyme exists as an active tetramer and an inactive dimer. The dimeric form is predominantly found in tumor cells and is therefore termed Tumor M2-PK (TuM2-PK). TuM2-PK molecules are released into the peripheral blood and may hereby function as a marker of tumor load in cancer patients. Our study was aimed to investigate TuM2-PK as a potential plasma marker in melanoma patients compared to the well-established serum marker S100beta. We measured the concentration of TuM2-PK in plasma and S100beta in corresponding serum samples from 300 melanoma patients and 53 healthy controls using a sandwich ELISA and an immunoluminometric assay, respectively. Plasma concentrations of TuM2-PK were significantly increased in melanoma patients compared to healthy controls (9.30 U/ml vs. 7.20 U/ml; p = 0.0036) and correlated with tumor load (p < 0.0005) and disease stage (p < 0.0005). Patients with elevated plasma TuM2-PK (cut-off = 15 U/ml) presented a reduced overall (p < 0.000005) and progression-free (p = 0.023) survival. Multivariate analysis revealed plasma TuM2-PK and serum S100beta as independent predictors of overall survival in metastasized patients. Neither plasma TuM2-PK nor serum S100beta showed prognostic relevance for tumor-free patients. Although the sensitivity and specificity to predict disease progression or death was higher for serum S100beta compared to plasma TuM2-PK, the combination of both markers improved the estimation of prognosis compared to that of serum S100beta alone.     

Prognostic value of plasmatic tumor M2 pyruvate kinase and carcinoembryonic antigen in the survival of colorectal cancer patients

Colorectal cancer (CRC) can be cured in most cases if diagnosed at an early stage. Carcinoembryonic antigen (CEA) remains the most widely used cancer marker for determining prognosis of CRC. Previous studies have shown that plasmatic tumor M2 pyruvate kinase (Tu M2-PK) is highly sensitive in CRC detection at an early stage and equally as good as the results for established tumor markers with clinical potential for cancer prognosis and monitoring. The aim of this study was to assess the prognostic value of Tu M2-PK in plasma using a survival analysis in combination with CEA in serum in patients newly diagnosed with CRC. The initial study included 183 patients who had a complete diagnostic colonoscopy. This cohort study was designed to evaluate the survival in patients with histologically confirmed gastrointestinal cancers (n = 41). Tu M2-PK concentrations in EDTA plasma were determined immunologically using an ELISA assay. Plasma Tu M2-PK levels were significantly higher in patients with distant metastases, stage IV for TNM score, and advanced stage (C+D) subgroups of Dukes than other subgroups. The univariate Cox’s analysis showed that CEA and Tu M2-PK gave high hazard ratios for risk of death (odds ratio CEA = 3.57 and odds ratioTu M2-PK = 2.23) and comparable values in average survival time. The results for both biomarkers did not overlap. These findings suggest that plasmatic Tu M2-PK levels of more than 20 U/mL may be a predictor of death risk.     

Accuracy of Self-Checked Fecal Occult Blood Testing for Colorectal Cancer in Thai Patients

Purpose: Colorectal cancer (CRC) screening with fecal occult blood testing (FOBT) has been associatedwith a reduction in CRC incidence and CRC-related mortality. However, a conventional FOBT requires stoolcollection and handling, which may be inconvenient for participants. The EZ-DetectTM (Siam PharmaceuticalThailand) is a FDA-approved chromogen-substrate based FOBT which is basically a self-checked FOBT (nostool handling required). This study aimed to evaluate the accuracy of EZ-Detect for CRC detection. Methods:This prospective study was conducted in the Faculty of Medicine, Siriraj Hospital, Bangkok, Thailand betweenNovember 2013 and May 2014. Some 96 patients with histologically-proven CRC and 101 patients with normalcolonoscopic findings were invited to perform self-checked FOBT according to the manufacturer’s instructions.Results were compared with endoscopic and pathologic findings. Sensitivity, specificity, positive predictive value(PPV), and negative predictive value (NPV) for CRC detection were calculated. Results: The present studyrevealed the sensitivity, specificity, PPV and NPV of this self-checked FOBT for CRC detection to be 41% (95%CI: 31-51), 97% (95% CI: 92-99), 93% (95% CI: 81-98) and 63% (95% CI: 55-70), respectively. The overallaccuracy of the self-checked FOBT for identifying CRC was 70%. The sensitivity for CRC detection based on7th AJCC staging was 29% for stage I, 32% for stage II and 50% for stage III/IV (P=0.19). The sensitivity was33% for proximal colon and 42% for distal colon and rectal cancer (P=0.76). Notably, none of nine infiltrativelesions gave a positive FOBT. Conclusions: The self-checked FOBT had an acceptable accuracy of CRC detectionexcept for infiltrative tumors. This home-administrated or ‘DIY’ do-it-yourself FOBT could be considered asone non-invasive and convenient tool for CRC screening.     

Tumor M2 pyruvate kinase in plasma of patients with urological tumors.

The M2 isoenzyme of pyruvate kinase (M2-PK) is specifically expressed in tumor cells (TU M2-PK) and may therefore provide a tumor marker for malignancies. We have investigated the plasma concentrations of TU M2-PK in patients with renal cell carcinoma (RCC), transitional cell carcinoma of the bladder (BCA), prostate cancer (PCA) and benign prostatic hyperplasia (BPH). TU M2-PK was quantified with a commercially available enzyme-linked immunosorbent assay (ELISA) kit. Using this ELISA kit, plasma samples of 57 healthy individuals were compared to 63 patients with RCC, 36 patients with BCA, 58 patients with PCA and 28 patients with BPH. Patients with carcinomas were subdivided into those patients with nonmetastatic and those with metastatic disease. Only patients with RCC (nonmetastatic and metastatic) showed significantly increased concentrations of TU M2-PK compared to normal individuals. In metastatic RCC, TU M2-PK levels were highest and were also significantly enhanced compared to nonmetastatic RCC. The sensitivity for nonmetastatic RCC was 27.5% and for metastatic RCC 66.7% at the 95% reference value of the control group. In BCA, PCA and BPH, no significant differences could be detected. Our results indicate that TU M2-PK concentrations in plasma may be a potential biomarker of advanced RCC.     

Diagnostic Value of Fecal Calprotectin as a Screening Biomarker for Gastrointestinal Malignancies

Background: Calprotectin in feces seems to be a more sensitive marker for gastrointestinal (GI) cancers thanfecal occult blood, but its specificity may be too low for screening average risk populations. This study aims atevaluating the diagnostic value of fecal calprotectin as a screening biomarker for GI malignancies. Materialsand Methods: In a case-control study, 100 patients with GI malignancies (50 patients with colorectal cancer and50 patients with gastric cancer) and 50 controls were recruited in Tabriz Imam Reza and Sina hospitals duringa 24-month period. One to two weeks after the last endoscopy/colonoscopy, fecal specimens were collected bythe patients and examined by ELISA method for quantitative measurement of calprotectin content. The resultswere compared between the three groups. Results: The mean fecal calprotectin level was 109.1±105.3 (2.3-454.3,median:74), 241.1±205.2 (3.4-610.0, median:19.3) and 45.9±55.1μg/g (1.3-257.1, median:19.3) in gastric cancer,colorectal cancer and control group, respectively, the differences being significant (p<0.001) and remaining afteradjustment for age. The optimal cut-off point for fecal calprotectin was ≥75.8μg/g for distinguishing colorectalcancer from normal cases (sensitivity and specificity of 80% and 84%, respectively). This value was ≥41.9μg/gfor distinguishing gastric cancer from normal cases (sensitivity and specificity of 62%). Conclusions: Our resultsrevealed that fecal calprotectin might be a useful and non-invasive biomarker for distinguishing colorectal cancerfrom non-malignant GI conditions. However, due to low sensitivity and specificity, this biomarker may not helpphysicians distinguishing gastric cancer cases from healthy subjects.     

Strong subsite‐specific variation in detecting advanced adenomas by fecal immunochemical testing for hemoglobin

Fecal immunochemical tests (FITs) for hemoglobin are increasingly recommended and used in colorectal cancer (CRC) screening. We aimed to provide a detailed assessment of the sensitivity of FIT according to type and subsite of neoplasms in a true screening setting. A quantitative FIT (FOB Gold, Sentinel Diagnostics, Milano, Italy) was applied prior to colonoscopy by 3,466 participants of the German screening colonoscopy program. Subsite specific sensitivity for various types of colorectal neoplasms was derived by comparing FIT results with findings at screening colonoscopy. The most advanced finding at colonoscopy was CRC, advanced adenoma, and nonadvanced adenoma in 29, 354 and 686 cases, respectively. Per‐adenoma sensitivity for large advanced adenomas (>1 cm) strongly varied by location (p < 0.001): cecum: 0/14 (0%), ascending colon and right flexure: 11/43 (26%), transverse colon and left flexure: 2/14 (14%), descending colon: 7/12 (58%), sigmoid colon: 47/92 (51%), rectum: 14/39 (36%). By contrast, the FIT detected all of 5 proximal CRC and 23 out of 24 (96%) distal CRCs, whereas per‐adenoma sensitivity of both proximal (17/259, 7%) and distal nonadvanced adenomas (20/237, 8%) essentially equaled the false positivity rate among those without neoplasms (152/2,397, 6%). In conclusion, we found a very large gradient of subsite specific FIT sensitivity for detecting large advanced adenomas ranging from 0% for advanced adenomas located in the cecum to >50% for those located in the descending or sigmoid colon. By contrast, FIT sensitivity was uniformly excellent for CRC and uniformly poor for nonadvanced adenomas, regardless of their location.     

Multitarget stool DNA for colorectal cancer screening: A review and commentary on the United States Preventive Services Draft Guidelines

Multitarget stool DNA (mt-sDNA) testing was approved for average risk colorectal cancer (CRC) screening by the United States Food and Drug Administration and thereafter reimbursed for use by the Medicare program (2014). The United States Preventive Services Task Force (USPSTF) October 2015 draft recommendation for CRC screening included mt-sDNA as an “alternative” screening test that “may be useful in select clinical circumstances”, despite its very high sensitivity for early stage CRC. The evidence supporting mt-sDNA for routine screening use is robust. The clinical efficacy of mt-sDNA as measured by sensitivity, specificity, life-years gained (LYG), and CRC deaths averted is similar to or exceeds that of the other more specifically recommended screening options included in the draft document, especially those requiring annual testing adherence. In a population with primarily irregular screening participation, tests with the highest point sensitivity and reasonable specificity are more likely to favorably impact CRC related morbidity and mortality than those depending on annual adherence. This paper reviews the evidence supporting mt-sDNA for routine screening and demonstrates, using USPSTF’s modeling data, that mt-sDNA at three-year intervals provides significant clinical net benefits and fewer complications per LYG than annual fecal immunochemical testing, high sensitivity guaiac based fecal occult blood testing and 10-year colonoscopy screening.