A quantitative immunochemical faecal occult blood test is more efficient for detecting significant colorectal neoplasia than a sensitive guaiac test.

BACKGROUND: The sensitive guaiac faecal occult blood test, Haemoccult SENSA (HOS; Beckman Coulter, Fullerton, CA, USA), is our standard screening test for significant colorectal neoplasia. We evaluated an automatically-developed, quantified human haemoglobin immunochemical faecal test, OC-MICRO (Eiken Chemical Co., Tokyo, Japan), to improve test specificity and so reduce the colonoscopy burden. AIM: To compare guaiac faecal occult blood test and immunochemical faecal test diagnostic efficacy and costs for identifying significant neoplasia. METHODS: Colonoscopies were performed on patients who prepared three daily guaiac faecal occult blood tests with or without immunochemical faecal tests. RESULTS: Total colonoscopy was performed on 151 subjects who prepared both guaiac and immunochemical faecal tests (group 1) and the positive predictive values (PPV) were also compared to those of 162 subjects undergoing colonoscopy for positive guaiac faecal occult blood tests (group 2). In group 1, comparative sensitivity, specificity, and PPVs for significant neoplasia with guaiac faecal occult blood test were 75%, 34%, and 12% (PPV, 18% for group 2) and with immunochemical faecal test were 75%, 94% and 60% (P < 0.01 for specificity). The number of colonoscopy examinations needed to detect a significant neoplasm because of positive faecal occult blood tests was six to eight with HOS and two with OC-MICRO at 21-31% the cost of evaluating a positive guaiac faecal occult blood test. CONCLUSION: An immunochemical faecal test maintains the high sensitivity of guaiac faecal occult blood test, but significantly reduces the colonoscopy burden and screening costs.

Can quantification of faecal occult blood predetermine the need for colonoscopy in patients at risk for non-syndromic familial colorectal cancer?

BACKGROUND: Patients at risk for non-syndromic (Lynch or polyposis) familial colorectal neoplasia undergo colonoscopic surveillance at intervals determined by clinically ascertained protocols. The quantitative immunochemical faecal occult blood test for human haemoglobin is specific and sensitive for significant colorectal neoplasia (cancer or advanced adenomatous polyp). AIM: To determine immunochemical faecal occult blood test efficacy for identifying significant neoplasia in at-risk patients undergoing elective colonoscopy. METHODS: We retrospectively identified consecutive at-risk patients who provided three immunochemical faecal occult blood tests before colonoscopy. Quantitative haemoglobin analysis was performed by the OC-MICRO automated instrument using the 100 ng Hb/mL threshold to determine positivity. RESULTS: In 252 at-risk patients undergoing colonoscopy; five had cancer, 14 an advanced adenoma and 46 a non-advanced adenoma. The immunochemical faecal occult blood test was positive in 31 patients (12.3%). Sensitivity, specificity, positive and negative predictive values for cancer were: 100%, 90%, 16% and 100%, and for all significant neoplasia: 74%, 93%, 45% and 98%. With 88% fewer colonoscopies, all colorectal cancers and 74% of all significant neoplasia would have been identified by this one-time immunochemical faecal occult blood test screening. CONCLUSIONS: A sensitive, non-invasive, interval screening test might be useful to predetermine the need for colonoscopy in this at-risk population and minimize unnecessary examinations. This favourable retrospective evaluation will be extended to a prospective study.

Effect of a calcium-enriched diet on the colonic epithelial hyperproliferation induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats on a low calcium and fat diet.

We examined whether hyperproliferation of colonic crypt epithelium during cancer induction by N-methyl-N-nitro-N-nitrosoguanidine (MNNG), in rats on a low fat and calcium diet could be reduced by added calcium p.o. From the age of 4 weeks, 104 male Sprague-Dawley rats received a low fat (3.5%), low calcium (0.05% calcium ion), and low vitamin D (0.4 IU/g) diet. Sixty-four also had calcium salts, derived from either calcium lactate or solubilized calcium carbonate, added to their drinking water; therefore their total calcium intake was about 1% of daily diet. At age 12 weeks the rats were divided into 4 treatment groups: 8 rats, not receiving added calcium, had rectal saline instillations weekly (saline control group) and were sacrificed after a further 28 weeks; 3 groups of 32 rats each received intrarectal MNNG (1.5 mg) weekly. One group, not receiving added calcium, was the MNNG control group; while the second group also received added calcium lactate, and the third group received calcium carbonate. Groups of 24 were sacrificed periodically until 28 weeks of treatment. Rats were sacrificed and epithelial proliferation was estimated, 1 week after the last intrarectal instillation, by in vivo labeling with tritiated thymidine and measuring the ratio of labeled to total colonic crypt epithelial cells. The mean labeling index of the MNNG treated and added calcium groups were significantly higher (8.7-9.5%) than that of the saline controls (2.8%) only at week 28; however, it was then still significantly less than that of the MNNG controls not having added calcium (17.9%). Hyperproliferation, during induction of colonic cancer by MNNG in rats on a low calcium diet, can be reduced by a calcium enriched diet even in the presence of a low fat intake.

Exclusion of PTEN and 10q22-24 as the susceptibility locus for juvenile polyposis syndrome.

Juvenile polyposis syndrome (JPS; MIM 174900) is an autosomal dominant condition with incomplete penetrance characterized by hamartomatous polyps of the gastrointestinal tract and a risk of gastrointestinal cancer. Gastrointestinal hamartomatous polyps are also present in Cowden syndrome (CS; MIM 158350) and Bannayan-Zonana syndrome (BZS; also called Ruvalcaba-Myhre-Smith syndrome; MIM 153480). The susceptibility locus for both CS and BZS has recently been identified as the novel tumor suppressor gene PTEN, encoding a dual specificity phosphatase, located at 10q23.3. A putative JPS locus, JP1, which most likely functions as a tumor suppressor, had previously been mapped to 10q22-24 in both familial and sporadic juvenile polyps. Given the shared clinical features of gastrointestinal hamartomatous polyps among the three syndromes and the coincident mapping of JP1 to the region of PTEN, we sought to determine whether JPS was allelic to CS and BZS by mutation analysis of PTEN and linkage approaches. Microsatellite markers spanning the CS/BZS locus (D10S219, D10S551, D10S579, and D10S541) were used to compute multipoint lod scores in eight informative families with JPS. Lod scores of < -2.0 were generated for the entire region, thus excluding PTEN and any genes within the flanking 20-cM interval as candidate loci for familial JPS under our statistical models. In addition, analysis of PTEN using a combination of denaturing gradient gel electrophoresis and direct sequencing was unable to identify a germline mutation in 14 families with JPS and 11 sporadic cases. Therefore, at least a proportion of JPS cases are not caused by germline PTEN alteration or by an alternative locus at 10q22-24.

Nutritional and lifestyle habits and water-fiber interaction in colorectal adenoma etiology.

Adenomatous polyps are neoplasms that may progress to colorectal cancer. The role of diet and other lifestyle habits in their etiology is now being elucidated. The aim of this study was to evaluate effects of nutritional habits, weight and weight gain, tobacco smoking, and physical activity in adenoma etiology. A quantified dietary history questionnaire was designed to evaluate long-term dietary habits in addition to more recent ones. The study population comprised 196 adenoma patients and matched asymptomatic, screened controls. Statistical analysis used multivariate conditional logistic models, adjusting for total energy intake and physical activity. Odds ratios (ORs) and 95% confidence intervals (CIs) for adenoma associated with highest versus lowest tertiles of mean daily intake were as follows: for energy, OR 3.7 and CI 2.1-6.7; for animal fat, OR 2.4 and CI 1.2-4.7; for tobacco smoking, OR 3.1 and CI 1.1-2.8; and for weight gain, OR 2.2 and CI 1.2-4.1 (P for linear trend for all, < or = 0.01). Significant negative associations were found with intake of total carbohydrates (OR, 0.3; CI, 0.1-0.7) and fluids (OR, 0.4; CI, 0.2-0.8) (P for both < 0.01) as well as for physical activity (OR, 0.6; CI, 0.3-0.9; P = 0.03). Increased risk for adenoma was observed with decreased intake of carotene (OR, 0.6; CI, 0.3-1.0; P = 0.06), vitamin E (OR, 0.6; CI, 0.3-1.0; P = 0.07), and dietary fiber (OR, 0.6; CI, 0.3-1.3; not significant). The OR of interaction between water and dietary fiber was significant (OR, 0.7; CI, 0.6-0.9; P = 0.01), suggesting a synergistic protective effect. Specific dietary and lifestyle habits were identified as independent factors associated with colorectal adenomas; of special interest is the interaction between water and fiber intake. Avoiding these factors might delay or prevent neoplasia.

Reproducibility studies and effects of bowel preparations on measurements of rectal epithelial proliferation.

Measurements of rectal epithelial proliferation (REP), using tritiated labelled thymidine, correlate with colonic epithelial proliferation, risk for cancer and response to therapies. There have been criticisms regarding its reproducibility and the possible deleterious effects of bowel preparations on this biomarker. We studied paired observations on 7 patients repeated without bowel preparation, 11 repeated after tap-water enema, and 8 repeated after PEG-electrolyte solution or extract of senna purgative and found no significant differences between paired observations. In addition, in a high-risk group for colorectal cancer, 31 persons received PEG or senna preparation and their REP was not significantly different from that of 23 examined without these preparations. Thus, REP is a reproducible biomarker and not affected by several commonly used bowel preparations.

Influence of demographic parameters on rectal epithelial proliferation.

Measurement of rectal epithelial proliferation is now being used as a biomarker for assessing risk for colorectal cancer and response within dietary intervention studies. We examined the possible confounding effects of demographic parameters on the proliferation of 52 healthy middle-aged volunteers without known risk factors for colorectal cancer. No significant effects on proliferation of age, sex or ethnic grouping were found other than marked urban-rural differences amongst men. We hypothesise that these could be explained by differences in dietary habits and their deleterious effects in the older male population. Careful matching of controls are probably needed in order to demonstrate the minor changes in mucosal proliferation that could reflect risk for neoplasia. Further human studies are needed to examine the effects of diet and extremes of age on proliferation.

Rectal epithelial proliferation in persons post sporadic colorectal neoplasia.

Some studies have shown diffuse large bowel epithelial hyperproliferation in persons having colorectal neoplasia. Thus, measurements of rectal epithelial proliferation (REP) could be useful as a screening biomarker of risk for sporadic neoplasia. We examined REP, by autoradiography with tritiated thymidine, in 84 persons: 32 healthy volunteers, 37 who had had sporadic adenomas and 15 post cured sporadic colorectal cancer. Measurements of the labelling index (ratio of labelled to total number of crypt cells) showed a statistically insignificant but increasing gradient of hyperproliferation related to degree and invasiveness of neoplasia. However, this became significant when examining the proportion of labelled crypt compartments in each group and by comparing combined compartments 3 and 4 of cancer patients to non-cancer patients. Gender and age were found to be parameters that influenced the results. Using standard methods of analysis of REP, the lack of clear separation between risk groups limits the usefulness of REP measurements as a screening biomarker of risk for sporadic large bowel neoplasia.

Rectal epithelial proliferation in women recovered from breast cancer.

Women recovered from breast cancer are at increased risk for colorectal neoplasia. The reasons may be genetic, dietary or endogenous hormonal risk factors. Measurements of rectal epithelial proliferation are a useful biomarker of risk for large bowel cancer. This was studied in 12 women after (mean 7.8 years) cured breast cancer, who had a mean % labelling index of 7.5 +/- 3.5 (S.D.) as compared to 5.8 +/- 1.8 (S.D.) in a disease-free comparison group of 25 women. In addition, analysis of labelled crypt compartments demonstrated a significantly higher proportion in the study group with thymidine uptake, mainly in the mid crypt zone, and an extension of crypt cell DNA synthesis towards the surface epithelium. Using proliferative activity as a biomarker of risk in a larger study group, we may learn more about common etiological factors for both malignancies and also identify a higher-risk subgroup for long-term follow-up and possible therapeutic intervention.

Rectal epithelial proliferation characteristics of first degree relatives of sporadic colon cancer patients.

Hyperproliferation of rectal epithelium is characteristic of families at high genetic risk for large bowel neoplasia, but has not been well-documented in families of sporadic colorectal cancer patients. This was studied in 119 such first degree relatives and 44 comparison subjects without this family history. All screened negative for large bowel neoplasia. Within the family group proliferation was significantly higher in the men and those aged less than 45 years, also higher (insignificantly) in non-Europeans and those having greater than 1 first degree colorectal cancer relative. In comparison to the nonfamily group the labelling index (LI) of the relatives showed a significant negative correlation with age (R = -0.20, P = 0.03). Within this family group the probability of having an elevated LI (greater than 6.0%) was greatest in the young (less than 50 years old) men (odds ratio = 2.0). Measurements of rectal epithelial proliferation (REP) in these first degree relatives, at a young age, might help delineate a high risk subgroup for prospective primary and secondary intervention.

Increased expression of a putative adenoma-associated antigen in pre-colonoscopic effluent of patients with colorectal cancer.

A monoclonal antibody Adnab-9, was raised against antigens derived from benign polyps of the colon. Adnab-9 was tested against pre-colonoscopic effluent material obtained from groups of patients with a macroscopically normal colonscopic examination, histologically confirmed adenomatous polyps and patients with colorectal cancer (CRC). The resultant binding levels displayed little overlap between the CRC group and the normal, and the difference was statistically significant. Since this putative early neoplasia associated antigen is essentially not expressed in CRC extracts, it may originate from a region of the colon predisposed to neoplasia, increasing in expression as the tendency to malignancy progresses, useful in the diagnosis of early stage malignancy.

Familial adenomatous polyposis at the Tel Aviv Medical Center: demographic and clinical features.

UNLABELLED: Familial adenomatous polyposis (FAP) is an uncommon, but widespread genetic disorder that develops multiple colonic adenomatous polyps and, if untreated, can lead to large bowel cancer. Little is known about its occurrence and characteristics in the Israeli population. AIMS: To evaluate FAP prevalence, phenotypic manifestations and compliance for diagnosis and follow-up in our registry. METHODS: Since 1993 approximately one-half of FAP patients in Israel have been seen and followed-up by us before and/or after colectomy. They and their families were encouraged to have mutation analysis, genetic and/or endoscopic screening. RESULTS: 37 pedigrees were identified, including 2 non-Jewish. The Jewish ethnic distribution was similar to that of the general population and the point prevalence rate estimated as 28.4/one million Jewish inhabitants. There were 461 first-degree relatives at-risk for FAP. Genetic screening was completed and successful in 28 pedigrees (87.5%), and 73 FAP patients entered the registry. Marked intra- familial phenotypic variations with minimal disease manifestation were noted in 11 patients belonging to 4 pedigrees. Cancer occurred in 15.1% (11 patients), in 10 before FAP diagnosis or during follow- up elsewhere, but one non-compliant patient developed duodenal cancer. One other patient died from a massive, neglected, intra- abdominal desmoid. Compliance for evaluation and follow-up of pedigree members and individual FAP patients was inadequate in 29% and 27%, respectively. CONCLUSIONS: FAP occurs in the Israeli Jewish population at the expected rate, but is inadequately recognized in non-Jews. The inadequate compliance for screening and post-surgical follow-up needs to be addressed by educating the public, health care workers and Health Insurers.

A sensitive guaiac faecal occult blood test is less useful than an immunochemical test for colorectal cancer screening in a Chinese population.

BACKGROUND: Colorectal cancer screening by guaiac faecal occult blood test has been shown to reduce the incidence and mortality of colorectal cancer in Western populations. The optimal faecal occult blood test, whether guaiac or immunochemical, for colorectal cancer screening in the Chinese population remains to be defined. AIM: To compare the performance characteristics of a sensitive guaiac-based faecal occult blood test (Hemoccult SENSA) and an immunochemical faecal occult blood test (FlexSure OBT) in a Chinese population referred for colonoscopy. METHODS: One hundred and thirty-five consecutive patients who were referred for colonoscopy and who met the study inclusion criteria took samples for the two faecal occult blood tests simultaneously from three successive stool specimens, with no dietary restrictions. All tests were developed and interpreted by a single experienced technician who was blind to the clinical diagnosis. The sensitivity, specificity and positive predictive value for the detection of colorectal adenomas and cancers were estimated for the two tests. RESULTS: The sensitivity, specificity and positive predictive value for the detection of significant colorectal neoplasia (adenomas > or = 1.0 cm and cancers) were 91%, 70% and 18% for Hemoccult SENSA and 82%, 94% and 47% for FlexSure OBT. The specificity and positive predictive value were significantly higher for FlexSure OBT than for Hemoccult SENSA (P < 0.001 and P = 0.016, respectively). Combining the positive results from both faecal occult blood tests did not improve the accuracy. CONCLUSION: The positive predictive value of the immunochemical faecal occult blood test for the detection of significant colorectal neoplasia was 29% better than that of the sensitive guaiac-based test. This may relate to the Chinese diet and requires further study. The poor specificity of the sensitive guaiac-based test, without dietary restriction, makes it less useful for colorectal cancer screening in a Chinese population.

Cancer of the gastrointestinal tract: early detection or early prevention?

Gastrointestinal cancer is a major medical and economic burden worldwide. Oesophageal and gastric cancers are most common in the non-industrialized countries, while colorectal cancer is the predominant gastrointestinal malignancy in westernized countries. Their aetiology is mainly related to correctable and preventable lifestyle habits; namely diet (including obesity), physical activity, alcohol and tobacco intake, and sanitation. Prevention and/or treatment of Helicobacter pylori infection would significantly reduce the prevalence of gastric cancer. Screening for cancer, its early detection and treatment requires medical facilities, endoscopic expertise and a major investment of national financial resources. This is only feasible in affluent industrialized countries such as Japan for gastric cancer, some western countries for oesophageal and colorectal cancer. Only population screening for colorectal cancer has been proven feasible and cost-beneficial.

An evaluation of rectal epithelial proliferation measurement as biomarker of risk for colorectal neoplasia and response in intervention studies.

Colorectal carcinogenesis is preceded by a phase of epithelial hyperproliferation. Detection and measurement of this hyperproliferation could be useful as a marker of risk for neoplasia or a measure of response to intervention therapy. Today, bromodeoxyuridine labelling and immunohistology is the easiest to perform and most standardized technique for evaluating proliferation in experimental and human studies. In general, measurement of proliferation has fulfilled expectation in experimental studies, however, in humans it has been less conclusive. The reasons are multifactorial and include: limitations in obtaining tissue samples and sampling error, the type of labelling technique used, lack of an objective method for quantifying proliferation and confounding factors influencing the degree of proliferation. The use of matched controls, sophisticated statistical analysis and the search for trends and not just statistical significance, is to be recommended. At present, evaluation of rectal epithelial proliferation is of limited value in assessing risk for colorectal neoplasia in the individual. On the other hand, it seems a useful biomarker of response within the context of a matched control intervention trial.

Evaluation and comparison of an immunochemical and a guaiac faecal occult blood screening test for colorectal neoplasia.

Guaiac tests for faecal occult blood are used for colorectal neoplasia screening. Specificity may be improved by using an immunochemical test for human blood. We evaluated and compared, within an endoscopic study, an immunochemical test for human stool albumin, BM-Test Colon Albumin, with the guaiac test, Hemoccult SENSA. Both tests were given to 527 screenees who had had a low-peroxidase diet before and during the tests. All had a colonoscopic (59%) or flexible sigmoidoscopic (41%) examination. Both tests were easy to perform and develop. They were of similar sensitivity (35-30%) for adenomas > or = 1.0 cm in diameter or cancers, but Colon Albumin had a higher specificity (90%) than Hemoccult (85%; P < 0.05). The latter, however, had a higher sensitivity for neoplasia of all sizes (25% vs 20%; NS) but lower specificity (85% vs 90%; P < 0.05). Colon Albumin was positive in 11.2%, while Hemoccult SENSA was positive in 16.7% and appears very sensitive to dietary peroxidases. Positivity was reduced to 7% by changing the methodology protocol. Overall, the guaiac test is more sensitive but less specific than the immunochemical test for colorectal neoplasia. However, the technical and diagnostic limitations of these tests must be appreciated, and because of their high positivity rate neither is suitable for mass screening. A more specific test for neoplasia is needed.

A rapid and simple in vitro method for evaluating human colorectal epithelial proliferation.

Assessment of colonic epithelial proliferation is a biomarker of risk for large-bowel neoplasia. Until now, in vitro labeling of S-phase crypt cells was usually performed by incorporation of tritiated thymidine. Its major disadvantage is the lengthy period of autoradiography before results can be evaluated. The thymidine analogue bromodeoxyuridine, which is detectable by immunohistochemical examination, allows evaluation of epithelial proliferation within 3 days. Pinch rectal biopsy specimens, from the unprepared bowel, are incubated under 1 atm additional pressure in a medium containing bromodeoxyuridine. The tissue is then fixed in 70% ethanol and embedded in paraffin, and the slides are prepared. The labeled nuclei are revealed using indirect immunoperoxidase staining and are easily counted by light microscopy. Assessment of proliferation is rapidly available for determining cancer risk and response in ongoing experimental and human dietary intervention studies.

Gastric polypoid lesions--an eight-year study.

We have reviewed the eight years of experience with gastric polypoid lesions of a university hospital serving the Tel Aviv area, and analyzed 188 polyps. No clinical or endoscopic findings were able to distinguish the polyp variants prior to histological examination. The most frequent type of polyp was the hyperplastic polyp (45.2%), followed by the inflammatory type (29.3%). There were six cases of adenoma and ten cases of gastric carcinoma. The polyps were distributed equally within the body (44.7%) and antrum (48.9%), while the fundus was rarely involved (6.3%). Our findings are compatible with the statement that in general there is no distinction between the histological types classified by sex, age, location, symptoms or endoscopic appearance. Nevertheless, this is the first report of a higher incidence of gastric polyps among Ashkenazi Jews than non-Ashkenazi Jews with identical sex distribution.

Epidemiology of ulcerative colitis in the Jewish population of central Israel 1970-1980.

The epidemiology of ulcerative colitis (UC) was studied in the Jewish population of central Israel in a densely populated urban area of more than 1,400,000 inhabitants. The mean annual incidence for the years 1970-80 was 3.86/100,000, 3.94 in males, and 3.79 in females. The incidence rose from 2.67 in 1970 to 5.09 in 1979, the rise being similar in both sexes. This rise in incidence was found in 3 separate localities in the study area inhabited by communities of different extraction and age composition. The disease started most frequently between the ages of 25 and 29. The crude prevalence of UC in 1980 was 55.2/100,000. The age-adjusted prevalence in Israel-born Jews was 45.8, in Asia-Africa-born 48.5 and in Europe-America-born 52.7/100,000. Compared with our previous study in 1960-70 in the city of Tel Aviv-Yafo, the prevalence of UC was increased and the differences between the community groups have narrowed. This suggests an effect of environmental factors in the causation of ulcerative colitis.

Exfoliative colonic cytology. A simplified method of collection and initial results.

Exfoliative colonic cytology for the diagnosis of colorectal cancer has been largely abandoned due to (1) the widespread use of colonoscopy, (2) the cumbersome methods of cell collection and (3) the occasional difficulty of interpreting the cytologic findings in the presence of inflammatory bowel disease or adenomas. This paper describes a newly formulated bowel preparation for routine colonoscopy, based on imbibing 2 L to 4 L of a balanced electrolyte solution, in which the recovered precolonoscopic effluent (using a convenient disposable collecting kit) yielded cells for cytologic evaluation from 70% of a group of 80 patients at high risk for large bowel neoplasia. Cytology demonstrated neoplastic cells in most cases of endoscopically proven cancer. These results suggest that colonic exfoliative cytology may be useful as a supplemental test to routine colonoscopy. This could be enhanced by further methodologic modifications to the collecting and cytologic methods; large long-term studies are needed to evaluate the potential usefulness of colonic exfoliative cytology.