Moshe Leshno

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

Early exposure to cow's milk protein is protective against IgE-mediated cow's milk protein allergy.

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

The Prevalence Rate and Anatomic Location of Colorectal Adenoma and Cancer Detected by Colonoscopy in Average-Risk Individuals Aged 40–80 Years

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

The prevalence and natural course of food protein–induced enterocolitis syndrome to cow’s milk: A large-scale, prospective population-based study

BACKGROUND The diversity in the perceived prevalence, recovery, and risk factors for cows milk allergy (CMA) necessitated a large-scale, population-based prospective study. OBJECTIVE We sought to determine the prevalence, cross-reactivity with soy allergy, and risk factors for the development of CMA. METHODS In a prospective study the feeding history of 13,019 infants was obtained by means of telephone interview (95.8%) or questionnaire (4.2%). Infants with probable adverse reactions to milk were examined, skin prick tested, and challenged orally. RESULTS Ninety-eight percent of the cohort participated in the study. The cumulative incidence for IgE-mediated CMA was 0.5% (66/13,019 patients). The mean age of cows milk protein (CMP) introduction was significantly different (P < .001) between the healthy infants (61.6 +/- 92.5 days) and those with IgE-mediated CMA (116.1 +/- 64.9 days). Only 0.05% of the infants who were started on regular CMP formula within the first 14 days versus 1.75% who were started on formula between the ages of 105 and 194 days had IgE-mediated CMA (P < .001). The odds ratio was 19.3 (95% CI, 6.0-62.1) for development of IgE-mediated CMA among infants with exposure to CMP at the age of 15 days or more (P < .001). Sixty-four patients with IgE-mediated CMA tolerated soy, and none had a proved allergy to soy. CONCLUSIONS IgE-mediated CMA is much less common than generally reported. Early exposure to CMP as a supplement to breast-feeding might promote tolerance. Finally, soy is a reasonable feeding alternative in patients with IgE-mediated CMA.

Chronic urticaria and autoimmunity: Associations found in a large population study

BACKGROUND:The role of screening colonoscopy for colorectal (CR) neoplasia in average-risk population, remains to be determined.OBJECTIVES:To evaluate the prevalence and anatomic location of CR adenoma and carcinoma and the morbidity of colonoscopy in individuals at average risk for CR cancer (CRC).METHODS:A retrospective prevalence study of subjects aged 40–80 yr, with no cancer-related symptoms, personal or family history of CR neoplasia, who underwent a colonoscopy.RESULTS:Enrolled were 1,177 persons; 183 aged 40–49 yr (young), 917 aged 50–75 yr, and 77 aged 76–80 yr (elderly). The prevalence of overall CR neoplasia, advanced neoplasia, and cancer was 20.9%, 6.3%, and 1.1%, respectively. In the 50–75 age group, the prevalence of overall adenoma, advanced neoplasia, and cancer was 21.3%, 6.7%, and 1.2%, respectively. Of the 206 neoplasia cases, 21–43% harbored proximal neoplasia beyond the reach of sigmoidoscopy, without distal lesions. Among the elderly, the prevalence of overall adenoma, advanced neoplasia, and cancer reached 26.0%, 14.3%, and 2.6%, respectively. In the young group, 9.8% had overall neoplasia, 1.1% had advanced adenoma, and none had CRC. Procedure-related morbidity rate was 0.1%, with no perforations, bleedings, or mortality.CONCLUSIONS:Screening colonoscopy in average-risk subjects demonstrated a considerable prevalence of CR neoplasia and proximal lesions beyond the reach of sigmoidoscopy. The morbidity rate was negligible. Primary screening colonoscopy should be considered in health programs for the average-risk population, beginning at the age of 50 yr. The significantly high rate of advanced and proximal neoplasia in the elderly, encourages the inclusion of healthy subjects aged 76–80 yr in future prospective studies.

Neural network prediction analysis: The bankruptcy case

BACKGROUND The prevalence and natural history for food protein-induced enterocolitis syndrome (FPIES) have not been determined. OBJECTIVE We sought to determine the prevalence, clinical manifestations, and rate of recovery for FPIES in a large-scale, population-based prospective study. METHODS In a prospective study the feeding history of 13,019 infants was obtained. Infants with probable adverse reactions to cows milk protein (CMP) were clinically examined, skin prick tested, and challenged orally. Diagnostic criteria for CMP-induced FPIES included age less than 9 months, delayed recurrent vomiting (usually with nausea), and lethargy after exposure to CMP in the absence of other IgE-mediated symptoms, such as rash, urticaria, and respiratory symptoms. In addition, a positive challenge response to milk resulted in the above-mentioned gastrointestinal symptoms, removal of milk from the diet resulted in the resolution of those symptoms, or both. RESULTS Ninety-eight percent of the cohort participated in the study. The cumulative incidence for FPIES was 0.34% (44/13,019 patients). The most common symptoms were recurrent vomiting (100%), lethargy (77%) diarrhea (25%), pallor (14%), and bloody diarrhea (4.5%). All patients had FPIES within the first 6 months of life. By the age of 3 years, 90% of the patients had recovered. We did not detect any concomitant reaction to soy. Eight patients with FPIES had IgE-mediated cows milk allergy (IgE-CMA). CONCLUSIONS The prevalence of FPIES is significant, and its clinical presentation is distinct from that of IgE-CMA. Most patients with FPIES recover, although a proportion might convert to IgE-CMA. The likelihood for a cross-reactivity to soy in this population was less than previously estimated.

Re-evaluation of serum alanine aminotransferase upper normal limit and its modulating factors in a large-scale population study

BACKGROUND Chronic urticaria (CU) is a common disease in which most cases were considered to be idiopathic. Recent evidence indicates that at least a subset of cases of chronic idiopathic urticaria are autoimmune in origin. OBJECTIVE We aimed to characterize the association between CU, autoimmune diseases, and autoimmune/inflammatory serologic markers in a large unselected population. METHODS Data on 12,778 patients given a diagnosis of CU by either allergy or dermatology specialists during 17 years in a large health maintenance organization in Israel were collected. For each patient, we collected information on diagnosis of major, well-defined autoimmune diseases and autoimmunity- and inflammatory-related serologic markers. Similar data were collected for a control group comprised of 10,714 patients who visited dermatologists, family physicians, or allergy specialists and had no indication of CU. RESULTS Having CU was associated with an increased odds ratio for hypothyroidism, hyperthyroidism, and antithyroid antibodies. Female patients with CU had a significantly higher incidence of rheumatoid arthritis, Sjögren syndrome, celiac disease, type I diabetes mellitus, and systemic lupus erythematosus, mostly diagnosed during the 10 years after the diagnosis of CU. High mean platelet volume, positive rheumatoid factor, and antinuclear antibodies were all significantly more prevalent in patients with CU. CONCLUSIONS A strong association was found between CU and major autoimmune diseases. A common pathogenic mechanism is implied by the high prevalence of autoantibodies and the existence of a chronic inflammatory process expressed by the high mean platelet volume. These findings have implications for the diagnosis, management, and prognosis of patients with CU.

Cost-Effectiveness Analysis of Screening for Celiac Disease in the Adult Population

Abstract In this paper we evaluate the prediction capability of various neural network models. The models examined in this study differ on the following parameters: data span, learning technique and number of iterations. The neural net prediction capabilities are also compared to results obtained by classical discriminant analysis models. The specific case evaluated is bankruptcy prediction. The common assumption of all bankruptcy prediction models is that fundamental economic factors and the characteristics of a firm are reflected in its financial statements. Therefore, using analytic tools and data from the firms financial reports, one can evaluate and predict its future financial status. Since the number of bankrupt firms is limited, we used examples (financial statements) from various periods preceding the bankruptcy event. Although the financial statements from the bankruptcy period convey more information, financial statements form distinct periods always improved the models. The prediction capability of the models is improved by using enhanced learning techniques. However, if the enhancement learning technique is too ‘strong’, the model becomes too specific for the training data set and thus loses its prediction capabilities.

Natural Course and Risk Factors for Persistence of IgE-Mediated Cow's Milk Allergy

Abstract: Background: The upper normal limit (ULN) of serum alanine‐aminotrasferase (ALT) normal range was recently challenged, because patients diagnosed with liver diseases may have ‘normal’ or near‐‘normal’ ALT levels, and because possible modulators are often ignored in determining normal range.

Sesame food allergy and sensitization in children: the natural history and long-term follow-up.

Background . Celiac disease (CD) is common and, when undiagnosed, may result in increased mortality, suggesting that mass screening could be justified. The authors examined the cost-effectiveness (CE) of such an approach, assuming a higher mortality rate in undiagnosed CD and that adhering to a gluten-free diet (GFD) reduces the mortality rate. Methods . The authors developed a state transition Markov model, evaluating the CE of screening an entire population at the age of 18. Screening strategies included no screening v. screening by IgA antiendomysial antibodies (EMA), IgA human antitissue transglutaminase antibodies (TTG), and TTG verified by EMA. All strategies were examined with and without evaluation for IgA deficiency, and they all included an intestinal biopsy. Effects of variables were examined using sensitivity analysis. Effectiveness was assessed by life expectancy for each strategy and the incremental average CE ratio for each. Results . Base-case analysis revealed US