Recommendations for a step-wise comparative approach to the evaluation of new screening tests for colorectal cancer.

BACKGROUND: New screening tests for colorectal cancer continue to emerge, but the evidence needed to justify their adoption in screening programs remains uncertain. METHODS: A review of the literature and a consensus approach by experts was undertaken to provide practical guidance on how to compare new screening tests with proven screening tests. RESULTS: Findings and recommendations from the review included the following: Adoption of a new screening test requires evidence of effectiveness relative to a proven comparator test. Clinical accuracy supported by programmatic population evaluation in the screening context on an intention-to-screen basis, including acceptability, is essential. Cancer-specific mortality is not essential as an endpoint provided that the mortality benefit of the comparator has been demonstrated and that the biologic basis of detection is similar. Effectiveness of the guaiac-based fecal occult blood test provides the minimum standard to be achieved by a new test. A 4-phase evaluation is recommended. An initial retrospective evaluation in cancer cases and controls (Phase 1) is followed by a prospective evaluation of performance across the continuum of neoplastic lesions (Phase 2). Phase 3 follows the demonstration of adequate accuracy in these 2 prescreening phases and addresses programmatic outcomes at 1 screening round on an intention-to-screen basis. Phase 4 involves more comprehensive evaluation of ongoing screening over multiple rounds. Key information is provided from the following parameters: the test positivity rate in a screening population, the true-positive and false-positive rates, and the number needed to colonoscope to detect a target lesion. CONCLUSIONS: New screening tests can be evaluated efficiently by this stepwise comparative approach.

Changing epidemiology of colorectal cancer makes screening sigmoidoscopy less useful for identifying carriers of colorectal neoplasms.

BACKGROUND: There is renewed interest in flexible sigmoidoscopy (FS) colorectal cancer (CRC) screening following trials showing significantly reduced CRC incidence and mortality. AIMS: To evaluate the potential usefulness of FS screening in our population. METHODS: We examined rectosigmoid (RS) cancer epidemiology in our Jewish population using Israel National Cancer Registry data, computed by CRC site, age groups, and gender. We also reviewed endoscopy-screening publications for prevalence of RS and proximal advanced adenomas (AAP) and having both or either. RESULTS: During 1980-2008, there were 64,559 CRCs registered; 31.6 % were RS cancer which has now decreased to 29 % of men's and 26 % of women's CRC (both P < 0.01). In <50 year olds, RS cancer occurred in 42 % of males' and 35 % of females' CRC, and in the last 2 decades this ratio is unchanged. In 50-74 year olds, RS cancer decreased to stable levels of 32 % of males' and 29 % females' CRC (both P < 0.01). In ≥75 year olds, RS cancer progressively decreased to 24 % of males' and 22 % females' CRC (both P < 0.001). From endoscopy screening reports in 40-79 year olds, RS AAPs occurred in 2.0-5.8 %, being least in women, most in men, and not increased with aging. Some 50-57 % of screenees had both RS and proximal AAPs, least when aged 40-49 years at 25 %, women were 35 %, and with aging 40 %, but most in men at 70 %. CONCLUSIONS: With the changing CRC epidemiology, having fewer RS neoplasms but more proximal cancer, the effectiveness of FS screening for identifying significant neoplasms decreases with screenees' age and especially in females. These make FS screening less suitable for our aging and increasingly female population.

Can a gastrointestinal pathologist identify microsatellite instability in colorectal cancer with reproducibility and a high degree of specificity?

Clinical features usually initiate evaluation for Lynch Syndrome (LS) but some colorectal cancer (CRC) histopathology findings are compatible with high microsatellite instability (MSI-H) that also occurs in LS. This led to the suggestion that pathologists request MSI analysis, which is an expensive addition to routine histology. We aimed to see if a Gastrointestinal Pathologist could identify MSI-H features with reproducibility and high (95%) specificity (MSI-H 95%). Histopathology of all CRCs received during 2005 and 4 MSI-H controls were scored using 2 published methods, "MsScore" and "PathScore". MSI analysis was performed on CRCs scored by either method as probable MSI-H 95% and results compared. To examine reproducibility of histopathology, 100 coded slides, including 25 scored MSI-H 95% and 75 scored low, were re-examined to now identify those needing MSI analysis. Costs were evaluated for identifying MSI-H with or without scoring. All 227 CRCs were scored for possible MSI-H 95%; 24 had high scores and MSI analysis. DNA analysis proved 14 MSI-H, PathScore identified 13 (95%), MsPath identified 9 (64%), histopathology alone identified 7 (50%). Reproducibility for identifying histopathology characteristics of MSI-H at re-examination, without scoring, was "moderate agreement" (Kappa statistic = 0.4615). Costs for identifying MSI-H by PathScore were the lowest, $436/identification. Conclusions; PathScore identified the most proven MSI-H CRCs at lowest cost and even an experienced gastrointestinal pathologist has difficulties identify MSI-H without scoring. So, scoring can be facilitated by a computerized evaluation form for routine CRC histology, prompting score computation and recommendation for MSI analysis with high specificity.

Follow-up of patients undergoing both semiquantitated immunochemical fecal occult blood and colonoscopy examinations.

The semiquantitated immunochemical fecal occult blood test (I-FOBT) used for colorectal cancer (CRC) screening has had its long-term performance characteristics determined by clinical follow-up or sometimes by colonoscopy as the 'gold standard'. We reanalyzed a file of total colonoscopy patients who also prepared three I-FOBTs, processed by the OC-MICRO instrument, using at least 50 ng Hb/ml buffer threshold to determine a positive test. The performance of both tests was evaluated by the National Cancer Registry follow-up to identify new CRCs and by determining the effects of the number of tests prepared and their thresholds for analysis, sex, and age on results. A total of 1630 patients, mean age 62.7 years, SD 11.9, 50.1% men, having undergone both tests were followed up for a mean of 51.5 months, SD 13.4; 25 CRC patients were registered. At 36 months, I-FOBT sensitivity for CRC was 95.8% (95% confidence interval 87.8, 104), as was initial colonoscopy; within 48 months, it was 92% (95% confidence interval 81.4, 103) and 96%, respectively. I-FOBT identified 70 of the 122 (57.2%) colonoscopy-detected advanced adenoma patients. CRC and advanced adenomatous polyps were more common in men (P<0.01), whose risk increased at 51-73 years (odds ratio 4.639, P=0.056), but not among women (odds ratio 1.952). It then increased significantly (P<0.01) for both sexes aged at least 74 years. I-FOBTs identified most CRCs diagnosed within 36 months of follow-up with sensitivity similar to that of initial colonoscopy, with neither test identifying every CRC patient. Sex and age influence results and need consideration when planning population screening.

Risk for colorectal cancer in elderly persons and possible methodologies for their screening.

OBJECTIVES: Most colorectal cancer (CRC) screening guidelines recommend average-risk screening up to the age of 75 years. However, increasing life span and incidence of proximal CRC could require changes to the age guidelines and adapting screening methodology for the elderly persons. Therefore, we reviewed our CRC epidemiology, international screening age-guidelines, and screening tests for the elderly persons and presented our long-term results of colonoscopy and semi-quantitated immunochemical fecal occult blood tests (I-FOBTs) in individuals that are 75 years or more. MATERIALS AND METHODS: We examined the Israel National Cancer Registry (INCR) data to assess the risk of CRC in individuals aged 75 years or more. We re-examined files of patients aged 75 years or more, who underwent both colonoscopy and three I-FOBTs, and followed them through the INCR to identify new cases of CRC. RESULTS: Nationwide, during 2005 and 2007, 41.3% of all CRCs occurred in individuals aged 75 years or more. Both I-FOBT and colonoscopy were performed on 271 individuals (mean age: 78.5 years, standard deviation: 3.1). Both initial colonoscopy and I-FOBT of at least 50 ngHb/ml buffer in either of the first two tests identified six patients with CRC; INCR registered another stage 1 rectal CRC within 1 year. Therefore, the initial sensitivity to CRC of either test was 85.7% (95% confidence interval: 59.8 and 112), valid during a mean of 44.3 months and a standard deviation of 13.4 at INCR follow-up; 14 of 27 advanced adenomatous polyps were identified by I-FOBT, giving a sensitivity of 58.8% (95% confidence interval: 42.3 and 75.4) for CRC or advanced adenomatous polyps. CONCLUSION: Recently, 41.3% of our CRCs occurred in individuals aged 75 years or more, diagnosed clinically and not by screening. I-FOBT and initial colonoscopic CRC sensitivity were similar, both having false-negative results. Screening age guidelines need reconsideration; our initial results show that semi-quantitated I-FOBT screening is feasible but needs large-scale evaluation in 'healthy' elderly persons.

The changing epidemiology of colorectal cancer and its relevance for adapting screening guidelines and methods.

In many countries at risk for colorectal cancer (CRC), screening guidelines provide average-risk screening for patients aged between the ages of 50 and 75 years. However, an earlier onset of CRC, an increasing life span and an incidence of right-sided CRC have been noted, which could require changes in age guidelines and screening methodology, especially for the elderly. We examined this in our Jewish populations using Israel Cancer Registry data, 1980-2008, computed by age groups, sex, ethnic groups, cancer site, and cancer stage. In patients who were below 50 years of age, there was no significant increase in incidence except for men born in Israel (P=0.05). In patients aged between 50 and 74 or more than 75 years there was an increased incidence (P<0.001 for both). However, the percentage for CRC patients aged between 50 and 74 years decreased but those who were aged more than 75 years increased (P<0.001 for both). Therefore, 45.3% of patients (39.1% aged ≥ 75 years) would not be electively screened. In addition, there was an increased trend (P<0.001) for right-sided (from cecum to and including the splenic flexure) CRC in patients both 50-74 and more than 75 years old. During 1999-2008, as compared with patients aged between 50 and 74 years, those below 50 years were less likely to be diagnosed with stage 1 or 2 CRC and more likely have stage 3 or 4 CRC (P<0.01 for all), whereas those aged more than 75 years were less likely to have stage 3 CRC (P<0.01). These results should influence CRC screening age guidelines, especially for 'healthy' individuals aged 75 years or more, and their need for noninvasive, but sensitive and specific pre-colonoscopy screening methodologies. In addition, the more advanced cancer stage in the patients aged below 50 years needs to make the treating physicians more aware of the fact that CRC can occur even at this age.

Cumulative evaluation of a quantitative immunochemical fecal occult blood test to determine its optimal clinical use.

BACKGROUND: 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. METHODS: Cumulative data were analyzed from a prospective cross-sectional double-blind study of 1682 consecutive, ambulatory, nonbleeding colonoscopy patients who volunteered for IFOBTs, most of above average risk, from 3 ambulatory-endoscopy centers. Fecal Hb was measured in 3 samples and analyzed by an automated instrument, and the highest result >or=50 ng Hb/mL of buffer was related to findings. RESULTS: Colonoscopy identified CRC in 20 patients and advanced APs in 129. Sensitivity for either was best when any of 3 tests had >or=50 ng Hb/mL of buffer; sensitivity was 61.1% (95% confidence interval [CI], 53.2-68.9), and specificity was 87.8% (95% CI, 86.2-89.4). Positive tests identified 100% of CRCs and 55% of advanced APs every 3.1 colonoscopies. Sensitivity of a single test at the commonly used 100-ng Hb/mL threshold was lower at 31.5% (95% CI, 24.1-39.0) (P<.001), but specificity was higher at 96.4% (95% CI, 95.5-97.3) (P<.001). Positive tests identified 65% of CRCs and 26.4% of advanced APs every 2.2 colonoscopies. CONCLUSIONS: The fecal Hb cutoff chosen by the screener and the number of samples collected per patient determine sensitivity and specificity for CRC/advanced AP; these factors determine the number of colonoscopies needed for positive tests and neoplasia yield. This information provides guidelines for IFOBT screening. Limitations are 1-time screening and most examinees not being at average risk for CRC.

A protocol for genetic evaluation of patients with multiple colorectal adenomas and without evidence of APC gene mutation.

BACKGROUND: Patients with multiple (< 100) colorectal adenomatous polyps are at increased risk for colorectal cancer. Genetic evaluation of those patients who test negative forAPCgene mutation is both a clinical and economic burden but is critical for counseling and surveillance. In Israel, this is confounded by the fact that national health insurance does not fully cover genetic evaluation of APC gene exon 16. OBJECTIVES: To perform a comprehensive genetic evaluation of APC gene mutation-negative polyposis patients with the aim of developing a future evaluation protocol. METHODS: Genetic analyses were performed in 29 APC gene mutation-negative Jewish individuals with 5 to > or = 40 colonic adenomas who did not fulfill Amsterdam (clinical) criteria for Lynch syndrome. Analyses included completion of APC gene exon 16 sequencing, analysis for APC gene copy number variations (deletions or duplications), MUTYH gene sequencing, and microsatellite instability in CRC patients fulfilling "Bethesda" (laboratory investigation) criteria for Lynch syndrome. RESULTS: Completion of APC gene exon 16 sequencing revealed one patient with the E1317Q polymorphism. All were normal by APC multiplex ligation-dependent probe amplification analysis. Pathogenic MUTYH mutations were found in three patients, all of North African origin; two additional patients had variants of unknown significance. One of six patients with Bethesda-positive criteria was MSI-High with immunohistology consistent with MLH1 mutation. CONCLUSIONS: Based on this small but well-characterized cohort with multiple colorectal adenomas, Lynch syndrome needs to be excluded if there are compatible criteria; otherwise MUTYH sequencing is probably the first step in evaluating APC-negative patients, especially for Jews of North African descent. Completing APC exon 16 sequencing and copy number variations analysis should probably be the last evaluations.

Familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life. FAP has an incidence at birth of about 1/8,300, it manifests equally in both sexes, and accounts for less than 1% of colorectal cancer (CRC) cases. In the European Union, prevalence has been estimated at 1/11,300-37,600. Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Generally, cancers start to develop a decade after the appearance of the polyps. Nonspecific symptoms may include constipation or diarrhea, abdominal pain, palpable abdominal masses and weight loss. FAP may present with some extraintestinal manifestations such as osteomas, dental abnormalities (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts and odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoid tumors, and extracolonic cancers (thyroid, liver, bile ducts and central nervous system). A less aggressive variant of FAP, attenuated FAP (AFAP), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk. Some lesions (skull and mandible osteomas, dental abnormalities, and fibromas on the scalp, shoulders, arms and back) are indicative of the Gardner variant of FAP. Classic FAP is inherited in an autosomal dominant manner and results from a germline mutation in the adenomatous polyposis (APC) gene. Most patients (~70%) have a family history of colorectal polyps and cancer. In a subset of individuals, a MUTYH mutation causes a recessively inherited polyposis condition, MUTYH-associated polyposis (MAP), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract. Diagnosis is based on a suggestive family history, clinical findings, and large bowel endoscopy or full colonoscopy. Whenever possible, the clinical diagnosis should be confirmed by genetic testing. When the APC mutation in the family has been identified, genetic testing of all first-degree relatives should be performed. Presymptomatic and prenatal (amniocentesis and chorionic villous sampling), and even preimplantation genetic testing is possible. Referral to a geneticist or genetic counselor is mandatory. Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome). Cancer prevention and maintaining a good quality of life are the main goals of management and regular and systematic follow-up and supportive care should be offered to all patients. By the late teens or early twenties, colorectal cancer prophylactic surgery is advocated. The recommended alternatives are total proctocolectomy and ileoanal pouch or ileorectal anastomosis for AFAP. Duodenal cancer and desmoids are the two main causes of mortality after total colectomy, they need to be identified early and treated. Upper endoscopy is necessary for surveillance to reduce the risk of ampullary and duodenal cancer. Patients with progressive tumors and unresectable disease may respond or stabilize with a combination of cytotoxic chemotherapy and surgery (when possible to perform). Adjunctive therapy with celecoxib has been approved by the US Food and Drug Administration and the European Medicines Agency in patients with FAP. Individuals with FAP carry a 100% risk of CRC; however, this risk is reduced significantly when patients enter a screening-treatment program.

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.

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 >or=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.

The changing epidemiology of upper gastrointestinal cancers in Israel: clinical and screening implications.

Western countries and now developing countries have noted a decreasing incidence of upper gastrointestinal (UGI) (esophageal and gastric) cancers, but increasing distal esophageal adenocarcinoma and a shift to fundal-sited gastric cancer. We examined these trends in Israeli Jewish and non-Jewish populations, drawing conclusions on the need to promote prevention and/or screening. Israel Cancer Registry UGI cancer data were computed by ethnicity, immigration after 1990, sex, sites and histology, examining age-standardized rates (ASR)/10 for 2000-2005 and incidence trends during 1980-2005. In Jews, male esophageal cancer incidence has increased (P<0.01) and is highest in European-American-born males (ASR/10, 1.98), but decreasing in the upper two-thirds of esophagus so that in men 89% now occur in the lower one-third. In both sexes this was associated with decreasing squamous cell carcinoma (P<0.01) but increased adenocarcinoma to cause 72.6% of esophageal cancers in men. Gastric cancer incidence is highest in European-American-born males (ASR/10, 11.75); there is a decreasing incidence in both sexes (P<0.01) and gastric site trends are stable. In non-Jews, esophageal cancer incidence is three times higher in men (ASR/10, 0.82); they are only squamous cell cancers and incidence trends are stable. Gastric cancer incidence is twice as high in men (ASR/10, 8.45) and gastric site trends are stable. UGI cancer incidence in Jews and non-Jews, men and women, is low as compared with most developing countries. The important findings are the low but prominent incidence of distal esophageal and gastric adenocarcinoma in male immigrants. This requires attention to possible preventive measures in at-risk groups.

Pancreatic cancer in Israel: the epidemiology, possibilities of prevention, early detection and screening.

Pancreatic cancer is not a common malignancy in Israel, but it is the third most common cause of cancer mortality, attributable to a lack of screening tests, inaccessibility of the pancreas, and late cancer stage at diagnosis. We reviewed the epidemiology, known risk factors and screening methods available in Israel and describe the Israeli national consortium that was established to identify persons at risk and decide on screening methods to detect and treat their early-stage pancreatic cancer. In collaboration with the Israel National Cancer Registry, we evaluated the incidence and trends of the disease in the Jewish and non-Jewish populations. The consortium reviewed known lifestyle risk habits, genetic causes, and screening methodologies used and available in Israel. Overall, there are about 600 new patients per year, with the highest incidence occurring in Jewish men of European birth (age-standardized rate 8.11/10(5) for 2003-06). The 5 year survival is about 5%. The consortium concluded that screening will be based on endoscopic ultrasonography. Pancreatic cancer patients and families at risk will be enrolled, demographic and lifestyle data collected and a cancer pedigree generated. Risk factors will be identified and genetic tests performed as required. This concerted national program to identify persons at risk, recommend which environmental risk factors to avoid and treat, and perform endoscopic ultrasound and genetic screening where appropriate, might reduce the incidence of invasive pancreatic cancer and/or improve its prognosis.

A familial gastrointestinal cancer clinic: organization, aims and activities, 2004-2007.

BACKGROUND: Dedicated, organ-specific screening clinics have been shown to significantly reduce cancer morbidity and mortality. OBJECTIVES: To establish a dedicated clinic for Clalit Health Service patients at high risk for hereditary gastrointestinal cancer and to provide them with clinical and genetic counseling, diagnostic screening and follow-up. RESULTS: During the 3 years of the clinic's activity, 634 high risk families, including 3804 at-risk relatives, were evaluated. The most common conditions were hereditary colorectal syndromes, Lynch syndrome (n=259), undefined young-onset or familial colorectal cancer (n=214), familial adenomatous polyposis (n=55), and others (n=106). They entered follow-up protocols and 52 underwent surgical procedures. CONCLUSIONS: Consistent public and professional education is needed to increase awareness of hereditary colorectal cancer and the possibility of family screening, early diagnosis and therapy. The public health services--i.e., the four health management organizations--should provide genetic testing for these patients who, at present, are required to pay for almost all of these available but costly tests. Dedicated colorectal surgical units are needed to provide the specialized therapeutic procedures needed by patients with familial colorectal cancer. Our future plans include adding psychosocial support for these at-risk patients and their families as well as preventive lifestyle and dietary intervention.

A quantitative immunochemical fecal occult blood test for colorectal neoplasia.

BACKGROUND: Guaiac-based fecal occult blood tests (FOBTs) for colorectal cancer screening are not specific for human hemoglobin and have low sensitivity. Automated-development, immunochemical FOBT is quality-controlled, is specific for human hemoglobin, and does not require diet restriction. OBJECTIVES: To measure the sensitivity and specificity of quantitative immunochemical fecal hemoglobin measurements for detection of cancer and advanced adenoma in patients undergoing colonoscopy, to determine fecal hemoglobin thresholds that give the highest posttest probability for neoplasia, and to determine the number of immunochemical FOBTs needed. DESIGN: Prospective, cross-sectional study. SETTING: Ambulatory endoscopy services of the main health medical organization in Tel Aviv, Israel. PARTICIPANTS: 1000 consecutive ambulatory patients--some asymptomatic but at increased risk for colorectal neoplasia and some symptomatic--who were undergoing elective colonoscopy and volunteered to prepare immunochemical FOBTs. INTERVENTION: The hemoglobin content of 3 bowel movements was measured, and the highest value was compared with colonoscopy findings. MEASUREMENTS: Sensitivity, specificity, predictive values, likelihood ratios, and 95% CIs of fecal hemoglobin measurements for clinically significant neoplasia, their relationship to the amount of fecal hemoglobin measured, and the number of immunochemical FOBTs performed. RESULTS: Colonoscopy identified clinically significant neoplasia in 91 patients (cancer in 17 patients and advanced adenomas in 74 patients). Using 3 immunochemical FOBTs and a hemoglobin threshold of 75 ng/mL of buffer, sensitivity and specificity were 94.1% (95% CI, 82.9% to 100.0%) and 87.5% (CI, 85.4% to 89.6%), respectively, for cancer and 67% (CI, 57.4% to 76.7%) and 91.4% (CI, 89.6% to 93.2%), respectively, for any clinically significant neoplasia. LIMITATIONS: The fecal sampling method is standardized, but the sample size depends on fecal consistency. Some patients were tested while discontinuing aspirin and anticoagulant therapies. Study patients were at increased risk, and results might not apply to average-risk populations. CONCLUSIONS: Quantitative immunochemical FOBT has good sensitivity and specificity for detection of clinically significant neoplasia. Test performance in screening average-risk populations is not known.

Changing sites of colorectal cancer in the Israeli Jewish ethnic populations and its clinical implications.

Countries at risk for colorectal cancer noted an increase in right-sided colorectal cancer. We examined this in the Israeli Jewish populations. Israel Cancer Registry data, 1982-2001, were computed by sex, age, ethnic group and colorectal cancer site: 'rectal cancer' included the recto-sigmoid junction, 'right-sided' colorectal cancer included proximal colon up to and including the splenic flexure. In both sexes, colorectal cancer trends increased significantly owing to colonic cancer (P<0.01) whereas rectal cancer decreased (P<0.01). Left and right colorectal cancer trends decreased in Israel born people (P<0.01), but in Asia-Africa born people increases were seen at both sites in the male (P=0.02 and 0.06, respectively) and female (P=0.03 and 0.01, respectively) population. In those > or =65 years old, right colorectal cancer trends increased in all men (P=0.05) and women (P=0.01). On comparing data from 1982-1986 with that from 1997-2001 right colorectal cancer showed an increase in both sexes (P<0.01): to 32.7% of male colorectal cancer and 57.6% of female colorectal cancer. In the period 1997-2001, the total male population > or =65 years had increased relatively by 7.5% (P<0.01), and women by 22.6% (P<0.01) and the proportion of right colorectal cancer in > or =65 years olds increased relatively by 10.9% in the male population, and 18.2% in the female population, with one-third of this increase occurring in Russian immigrants arriving after 1990. In conclusion, there is a trend for right colorectal cancer in Jews aged > or =65 years. The proportion and amount of colorectal cancer increased most significantly in older women, which was partially explained by their increasing numbers and by colorectal cancer occurring in recent immigrants from Russia, who were at high-risk for colorectal cancer. These results should influence colorectal cancer screening and diagnostic methodologies used.

The changing incidence and sites of colorectal cancer in the Israeli Arab population and their clinical implications.

Israeli Arabs have been at low risk for colorectal cancer (CRC) and had mainly proximal cancer, but increasing CRC is now noted. We examined this trend and CRC site and compared them to the total Jewish population and to the low-risk Jews of Asian-African origin. Israel Cancer Registry CRC data, 1982-2002, for Arabs and Jews was computed by gender, age and site: rectal cancer included recto-sigmoid junction; "right-sided" CRC included the proximal colon up to and also the splenic flexure. During 1982-2002, Arab CRC trends increased significantly in both sexes due to left-sided CRC (women, p = 0.01; men, p = 0.02) and rectal cancers (p = 0.05). Left-sided CRC increased significantly in both men and women aged > or = 65 years (p = 0.02). Comparing 1982-1984 to 2000-2002, the proportion of right-sided CRC decreased in both genders (p < 0.01) from 39.4 to 27.1% of male CRC, and from 44.8 to 31.3% in females. In general, this pattern of increasing rectal and left-sided CRC had been seen over a decade earlier in Jews of Asian-African origin and then their trend reversed during the last decade. In conclusion, there is a recent trend for left-sided CRC in Israeli Arabs, probably related to their changing life style. These results should influence their cancer preventive lifestyle recommendations, and CRC screening and diagnostic methodologies used.

Familial adenomatous polyposis: The practical applications of clinical and molecular screening.

Familial adenomatous polyposis (FAP) is an autosomal dominant condition mostly due to a mutation of the APC gene on the chromosome 5q. Carriers have an almost 100% chance of developing colorectal cancer after having multiple (typically 100s to 1000s) of adenomatous polyps. It is usually readily identified through this phenotype of multiple adenomas. Correlations between the location of the family-specific mutation on the APC gene and clinical manifestations of the disease are of some assistance in clinical management, though there is heterogeneity in clinical course even between family members with the same mutation. FAP is important to recognize, as there are disease-specific management implications with respect to offering mutational analysis of the APC (and perhaps other) genes for predictive testing of other family members, endoscopic diagnostic procedures, surveillance planning, and surgical management. Extra-colonic manifestations, including duodenal polyposis, desmoid disease and other tumours, can dominate clinical care after colectomy. The inheritable and lethal nature of the disease, together with the availability of effective treatment strategies, makes a sensitive clinical and psychosocial approach important to maximize compliance and good outcomes for all members of affected families.

Germ line mutations of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients with small bowel cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study.

PURPOSE: The aim of study was to determine the clinical characteristics and mutational profiles of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients with small bowel cancer (SBC). EXPERIMENTAL DESIGN: A questionnaire was mailed to 55 members of the International Society for Gastrointestinal Hereditary Tumours, requesting information regarding patients with HNPCC-associated SBC and germ line mismatch repair gene mutations. RESULTS: The study population consisted of 85 HNPCC patients with identified mismatch repair gene mutations and SBCs. SBC was the first HNPCC-associated malignancy in 14 of 41 (34.1%) patients for whom a personal history of HNPCC-associated cancers was available. The study population harbored 69 different germ line mismatch repair gene mutations, including 31 mutations in MLH1, 34 in MSH2, 3 in MSH6, and 1 in PMS2. We compared the distribution of the mismatch repair mutations in our study population with that in a control group, including all pathogenic mismatch repair mutations of the International Society for Gastrointestinal Hereditary Tumours database (excluding those in our study population). In patients with MSH2 mutations, patients with HNPCC-associated SBCs had fewer mutations in the MutL homologue interaction domain (2.9% versus 19.9%, P = 0.019) but an increased frequency of mutations in codons 626 to 733, a domain that has not previously been associated with a known function, versus the control group (26.5% versus 2.8%, P < 0.001). CONCLUSIONS: In HNPCC patients, SBC can be the first and only cancer and may develop as soon as the early teens. The distribution of MSH2 mutations found in patients with HNPCC-associated SBCs significantly differed from that found in the control group (P < 0.001).

Evaluation of a desk top instrument for the automated development and immunochemical quantification of fecal occult blood.

BACKGROUND: The guaiac fecal occult blood test (FOBT) for colorectal cancer (CRC) screening is user dependent and not specific for human hemoglobin (Hb). The automated-developed, quantitative, immunochemical human Hb FOBT (I-FOBT) is specific, allows for quality control and selection of a suitable Hb level, with optimal sensitivity and specificity, for colonoscopy. MATERIAL/METHODS: We evaluated a desktop instrument, OC-MICRO (Eiken, Japan), which automatically develops and quantifies 50 fecal tests/hr for Hb; for ease of use, test reproducibility and stability and intra-patient daily I-FOBT variation; clinical evaluation included sensitivity and specificity for neoplasia in patients undergoing colonoscopy. RESULTS: Five hundred patients prepared 3 fecal tests which were quantified for Hb, I-FOBT samples were: (1) repeatedly re-examined; (2) stored at 4 degrees C or 20 degrees C or 28 degrees C and re-examined; (3) I-FOBT levels correlated with colonoscopic findings. Five I-FOBTs re-examined 6 times had no significant changes; 30 tests stored > or = 21 days had a decay/day of: 0.3%+/-0.4 at 4 degrees C (NS), 2.2%+/-1.7 at 20 degrees C (NS) and 3.7%+/-1.8 at 28 degrees C (P<0.05). Receiver operator characteristic curve analysis showed that at the 100 ng Hb/mL I-FOBT level 76.5% of CRCs and advanced adenomas were detected with a specificity of 95.3%. CONCLUSIONS: The instrument provided reproducible results and refrigerated I-FOBT samples were stable 21 days. An I-FOBT level can be chosen to provide optimal sensitivity and specificity for significant neoplasia.