Shlomo Birkenfeld

A Quantitative Immunochemical Fecal Occult Blood Test for Colorectal Neoplasia

Context Although screening with a guaiac-based fecal occult blood test (FOBT) reduces colorectal cancer mortality, better tests are needed. Contribution In the study, 1000 patients undergoing diagnostic colonoscopy provided fecal samples that a clinical laboratory tested with a quantitative immunochemical test for hemoglobin. Hemoglobin content was highest in samples from people with significant neoplasia, for which sensitivity and specificity were 67% and 91%, respectively. Positive and negative likelihood ratios were 7.8 and 0.36, respectively. Cautions The authors did not compare the immunochemical FOBT with guaiac-based FOBT. The study included people with symptoms. Implications The quantitative immunochemical test for fecal hemoglobin is a promising test that needs evaluation in a screening population. The Editors A colorectal cancer screening test should identify persons with early-stage cancer that is an immediate medical threat and persons with advanced adenomas that could be a future threat. As well as having high sensitivity, the screening test should have high specificity for detecting clinically significant neoplasia, cancer, and advanced adenomas to minimize follow-up colonoscopy examinations (1). The commonly used guaiac-based fecal occult blood tests (FOBTs) have low specificity for detecting human hemoglobin and relatively low sensitivity for identifying clinically significant colorectal neoplasia (18). Office-developed qualitative immunochemical FOBTs are specific for detection of human hemoglobin and have improved test specificity (1, 46, 913). However, the manufacturers designed the test to have sensitivity for measuring hemoglobin similar to that of a sensitive guaiac-based FOBT, which is a limitation. Moreover, we found that doing the actual measuring in the office was not conducive to large-scale screening while maintaining quality control (1, 2, 6). We investigated a clinical laboratorybased immunochemical test that measures the hemoglobin content of a stool sample. Laboratory-based, automated, immunochemical measurement of fecal human hemoglobin eliminates the need for diet restrictions, is specific for human hemoglobin, and allows for quality control. In addition, clinicians can choose a fecal hemoglobin threshold level to perform colonoscopy and can adjust this threshold to take account of the patients risk for advanced neoplasia and the availability of quality colonoscopy (1, 1420). The quantitative immunochemical FOBT has been evaluated in Japan and elsewhere (1422). However, to our knowledge, no English-language publication systematically compares fecal immunochemical hemoglobin content with total colonoscopy findings. We aimed to measure the sensitivity and specificity of different levels of fecal hemoglobin for detecting clinically significant colorectal neoplasia versus colonoscopy, to determine the posttest probability of advanced neoplasia at different fecal hemoglobin threshold values, and to determine the optimal number of fecal samples. Methods Patients We asked consecutive ambulatory persons who were referred for colonoscopy to volunteer to prepare immunochemical FOBTs for research purposes. Some patients were asymptomatic and were invited for elective colonoscopy, some patients were at high risk for colorectal cancer (these patients were from our clinic), and some patients were symptomatic and were referred by their treating physician (Table 1 and Figure 1). We have reported partial findings on the initial 500 patients (20). Table 1. Baseline Characteristics* Figure 1. Study flow diagram. I-FOBT = immunochemical fecal occult blood test; IBD = inflammatory bowel disease. Exclusions were concurrent hospitalization, visible rectal bleeding, known diagnosis of inflammatory bowel disease, hematuria, menstruation at the time of obtaining a stool specimen, and inability to prepare the immunochemical FOBT (Figure 1). We did not exclude patients with long-term use of nonsteroidal anti-inflammatory drugs or anticoagulant therapy that was stopped for colonoscopy. Endoscopy and Lesions We inserted the colonoscope to the cecum or an obstructing carcinoma. We excluded 49 patients with an incomplete colonoscopy. Biopsy was done on lesions or they were removed, and their sites were noted. We classified abnormal findings by number of polyps, polyp sizes, and sites grouped by location (proximal [colon cecum to and including splenic flexure] or distal colon) and by histologic characteristics. The endoscopist estimated polyp size with a calibrated open biopsy forceps. We grouped adenomas and mass lesions by diameter or size (5 mm, 6 to 9 mm, or 10 mm) and by histologic characteristics (tubular, serrated, tubulovillous, or villous). We classified dysplasia as low grade or high grade. Pathologists were blinded to the immunochemical FOBT results. Clinically significant neoplasia includes colorectal cancer or advanced polyps (adenomas 10 mm in diameter, adenomas with 20% villous histologic characteristics, or any high-grade dysplasia regardless of size) (23). We classified patients with more than 1 lesion according to the most advanced lesion. We reexamined all advanced adenomas smaller than 10 mm to confirm their histologic diagnosis (24). Fecal Sampling Participants received an explanation of the test and written instructions on how to prepare the fecal samples. After voiding urine and flushing the toilet before having a bowel movement, participants placed a disposable paper float in the toilet bowl to immobilize the stool for easy sampling (Appendix Figure 1). Each fecal sample tube has a unique bar code. Before preparing the sample, the patient wrote his or her name and the date on the tube. The immunochemical FOBT sampling probe is inserted into an 8-cm2-cm test tubeshaped container. The patient inserts the probe into several different areas of the stool and then reinserts it firmly into the tube to seal it (Appendix Figure 2). The probe tip with the fecal sample is suspended in a standard volume of hemoglobin-stabilizing buffer. According to the manufacturers manual, the amount of stool obtained by this process is semistandardized (but does depend on fecal consistency) at 10 mg (SD, 0.5). According to the manufacturers data, the mean specimen size ranges from 9.03 mg (SD, 0.29) for diarrhea to 11.89 mg (SD, 0.76) for hard stools. Examinees prepared 3 daily or consecutive samples during the week before colonoscopy examination. They observed no dietary or medication restrictions other than stopping aspirin and anticoagulant therapy before endoscopy. Samples were stored in double ziplock bags at 4C until development within 2 weeks (20, 25). We processed the samples by using the OC-MICRO instrument (Eiken Chemical Co., Tokyo, Japan) as described in the Appendix. Appendix Figure 1. Folded paper float opened ( left ) and placed in toilet bowl ( right ). After defecation and fecal sampling, the participant flushes the float into the toilet. Appendix Figure 2. Stool probe and fecal sample storage tube. The patient removes the fecal probe that has a serrated tip that accumulates the fecal sample. The probe is then reinserted deeper into the tube past a scraper and through a membrane that removes excess feces. The bottom compartment of the tube contains a 2-mL buffer solution for stabilizing the fecal specimen in the tip serrations. For pricing the immunochemical FOBT at

Performance Characteristics and Evaluation of an Automated-Developed and Quantitative, Immunochemical, Fecal Occult Blood Screening Test

20, we used the local agents price for 3 tests and added administrative costs. In comparison, the authorized pricing (from Israels Ministry of Health) is

Psoriasis associated with ulcerative colitis and Crohn's disease

13 for screening with 3 guaiac-based FOBTs. The ethics committee of the Rabin Medical Center, Tel Aviv, Israel, approved the study in 2004. All participants gave written informed consent for the immunochemical FOBT and colonoscopy examination. Statistical Analysis We recorded each patients most severe pathologic finding (histologic characteristics, polyp size, and number of polyps) and the highest amount of fecal hemoglobin measured in that patients 3 immunochemical FOBT samples. We classified persons with only small rectal hyperplastic polyps as not having neoplasia. We analyzed fecal hemoglobin measurements according to the number of adenomas (<3 adenomas or 3 adenomas), lesion size, site in the colon (proximal or distal), and histology. We analyzed colorectal cancer and advanced adenoma separately and together as clinically significant colorectal neoplasia. Since the study sample was heterogeneous, we compared the sensitivity and specificity of the immunochemical FOBT in the 3 main categories of reason for referral (Appendix Table 1) by using the chi-square test and Fisher exact test. Appendix Table 1. Immunochemical Fecal Occult Blood Test and Endoscopy Results for Cancer or Clinically Significant Neoplasia, by Reasons for Colonoscopy* To classify a patients fecal hemoglobin level as normal or abnormal, we used 2 thresholds: the published and manufacturer-suggested threshold of 100 ng/mL of buffer and a threshold of 75 ng/mL, which we thought would give a higher sensitivity for detecting clinically significant neoplasia (14, 15, 20). We also repeated these analyses at different thresholds in increments of 25 ng/mL, ranging from 50 ng/mL to 200 ng/mL. We measured the diagnostic value of the immunochemical FOBT for detecting clinically significant neoplasia by using 5 criteria: sensitivity, specificity, likelihood ratios, and posttest probability after a negative and positive result. We compared sensitivity and specificity by using threshold values of 75 ng/mL or greater and 100 ng/mL or greater for abnormal findings and the McNemar test for symmetry. We reported polyp sizes and fecal hemoglobin measurements as means (SDs) and by quartiles. We also reported 95% CIs for means and likelihood ratios (26). Since the distribution of fecal hemoglobin measurements was not normally distributed, we used 1) a parametric test for log2-transformed data (since log of 0 is not defin

A higher detection rate for colorectal cancer and advanced adenomatous polyp for screening with immunochemical fecal occult blood test than guaiac fecal occult blood test, despite lower compliance rate. A prospective, controlled, feasibility study

OBJECTIVES:Guaiac fecal occult blood colorectal cancer (CRC) screening tests (FOBT) are faulted for low sensitivity and nonspecificity for human hemoglobin (Hb). Automated-developed, immunochemical, human Hb FOBT (I-FOBT) is specific, eliminates diet restrictions, and Hb quantification allows selection of a threshold for colonoscopy. Aims were to determine 1) test reproducibility; 2) test stability; 3) intrapatient daily I-FOBT variation; 4) test sensitivity and specificity for neoplasia in 500 symptomatic/high-risk patients undergoing colonoscopy; and 5) to correlate fecal Hb measurements with findings.METHODS:The desktop instrument OC-Sensor (Eiken, Japan) automatically develops and quantitates 50 tests/h for Hb. Patients prepared three tests, which were quantified and then 1) repeatedly re-examined; 2) stored at 4°C or 20°C or 28°C and repeatedly examined; and 3) fecal Hb levels were correlated with colonoscopic findings.RESULTS:Five I-FOBTs re-examined five times in 1 day had no significant measurement changes. Thirty tests stored for 21 or more days had a decay/day of 0.3%± 0.4 at 4°C (NS), 2.2%± 1.7 at 20°C (NS), and 3.7%± 1.8 at 28°C (p < 0.05). There were intrapatient variations between the three daily I-FOBTs (NS). At the recommended 100 ng Hb/mL threshold, all six cases of CRCs and 20 out of 28 cases of advanced adenomas were detected; evaluated together their sensitivity and specificity were 76.5% and 95.3%.CONCLUSIONS:Desktop, automated-developed, quantitative I-FOBT is now available. Refrigerated OC-Sensor samples are stable for 21 days, easy to prepare and develop and, at the 100 ng Hb/mL threshold, have high sensitivity, specificity, and negative predictive values for significant neoplasia. Suitability for population CRC screening awaits further evaluation.

Coeliac disease associated with psoriasis

Background  Numerous reports have demonstrated the epidemiological, pathogenic, and genetic association between psoriasis and Crohns disease. Nevertheless, the association between psoriasis and ulcerative colitis was rarely described.

Sensitivity, but Not Specificity, of a Quantitative Immunochemical Fecal Occult Blood Test for Neoplasia Is Slightly Increased by the Use of Low-Dose Aspirin, NSAIDS, and Anticoagulants

Immunochemical fecal occult blood test (FIT) is a new colorectal cancer (CRC) screening method already recommended by the American screening guidelines. We aimed to test the feasibility of FIT as compared to guaiac fecal occult blood test (G‐FOBT) in a large urban population of Tel Aviv. Average‐risk persons, aged 50–75 years, were offered FIT or G‐FOBT after randomization according to the socioeconomic status of their clinics. Participants with positive tests underwent colonoscopy. Participants were followed through the Cancer Registry 2 years after the study. Hemoccult SENSA™ and OC‐MICRO™ (three samples, 70 ng/ml threshold) were used. FIT was offered to 4,657 persons (Group A) and G‐FOBT to 7,880 persons (Group B). Participation rate was 25.9% and 28.8% in Group A and B, respectively (p < 0.001). Positivity rate in Group A and B was 12.7% and 3.9%, respectively (p < 0.001). Cancer found in six (0.49%) and eight (0.35%) patients of Group A and B, respectively (NS). Cancer registry follow‐up found missed cancer in five (0.22%) cases of Group B and none in Group A (NS). The sensitivity, specificity, negative and positive predictive value for cancer in Group A and B were 100%, 85.9%, 100%, 3.9% and 61.5%, 96.4%, 99.8%, 9.1%, respectively. There was increased detection of advanced adenomatous polyp (AAP) by FIT, irrespective of age, gender, and socioeconomic status (Per Protocol: odds ratio 2.69, 95% confidence interval 1.6–4.5; Intention to Screen: odds ratio 3.16, 95% confidence interval 1.8–5.4). FIT is feasible in urban, average‐risk population, which significantly improved performance for detection of AAP and CRC, despite reduced participation.

Quantitative colonoscopic evaluation of relative efficiencies of an immunochemical faecal occult blood test and a sensitive guaiac test for detecting significant colorectal neoplasms

Background  Psoriasis is a chronic inflammatory disorder of the skin reported to be associated with systemic comorbidities.

Cumulative Evaluation of a Quantitative Immunochemical Fecal Occult Blood Test to Determine Its Optimal Clinical Use

OBJECTIVES:We evaluated the effect of the use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), and anticoagulants on the performance of immunochemical fecal occult blood test (I-FOBT).METHODS:A prospective, cross-sectional study of 1,221 ambulatory patients having total colonoscopy after preparing three I-FOBTs. Information regarding the use of medications was collected from the health medical organization (HMO) database. I-FOBT was analyzed with the OC-MICRO instrument using both ≥75 and 100 ngHb/ml of buffer thresholds to determine positivity.RESULTS:Colorectal cancer (CRC) was found in 17 and advanced adenomatous polyp (AAP) in 97 patients. A total of 212 patients were using aspirin/NSAIDS at the time of I-FOBT testing. Qualitative analysis for the detection of AAP/CRC reveals a trend for an increased sensitivity with aspirin/NSAIDS use. At the threshold 75 ng/ml for positivity, the sensitivity for the detection of AAP/CRC was 66.7% for aspirin/NSAIDS use vs. 51.2% for nondrug takers (P=0.20), and at the threshold of 100 ng/ml, the sensitivity was 66.7 vs. 46.5% (P=0.09). The specificity, however, was not affected by the use of aspirin/NSAIDS. At the threshold of 75 ng/ml for positivity, the specificity for the detection of AAP/CRC was 89.5% for aspirin/NSAIDS use vs. 91.2% for nondrug takers (P=0.47), and at the threshold of 100 ng/ml, the specificity was 92.17 vs. 93.0% (P=0.69). A total of 33 patients were using antithrombotics/coagulants at the time of I-FOBT testing. This group was small; however, it appears that their use was also associated with a trend for increased sensitivity and no change in specificity.CONCLUSIONS:The use of aspirin/NSAIDS and anticoagulants was associated with a trend for increased sensitivity with no change in specificity for the detection of AAP/CRC. This study suggests that there is no need to stop these agents before I-FOBT testing.

Identification of colorectal adenomas by a quantitative immunochemical faecal occult blood screening test depends on adenoma characteristics, development threshold used and number of tests performed

Background  The guaiac faecal occult blood test (G‐FOBT), HemoccultSENSA, is sensitive for significant neoplasms [colorectal cancer (CRC), advanced adenomatous polyps (AAP)], but faulted by non‐specificity for human haemoglobin (Hb). Quantified, Hb‐ specific, immunochemical faecal occult blood tests (I‐FOBT) are now used.

Psoriasis Associated with Hepatitis C but Not with Hepatitis B

Quantified, human hemoglobin (Hb)‐specific, immunochemical fecal occult blood test (IFOBT) measurements are now used for colorectal cancer (CRC) screening. The objective was to evaluate sensitivity and specificity for CRC and advanced adenomatous polyps (APs) by the fecal Hb threshold used to determine a positive test and the number of IFOBTs prepared per test, so as to determine the least number of colonoscopies required to detect a neoplasm.