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Postcolonoscopy colorectal cancer (PCCRC) can arise from missed cancers, missed premalignant lesions, incomplete resection, and new cancers with an accelerated route to cancer.1.

Immunohistochemistry (IHC) testing for mismatch repair proteins (MMRP) in patients with colorectal cancer can be performed on endoscopic biopsy material or the surgical resection material. Data are continuing to accumulate regarding the deleterious effect of neoadjuvant chemoradiation on MMRP expression. However, despite continuing rise in the use of endoscopic biopsies for IHC, most pathology departments still use mainly the surgical materials for IHC testing. In this study we compared the quality of stains among 96 colon cancer subjects with paired endoscopic and surgical material available for MLH1, MSH2, MSH6, and PMS2 stains (96 × 4, yielding 384 paired stains). Each slide received both a quantitative score (immunoreactivity [0-3] × percent positivity [0-4]) and a qualitative score (absent; weak and focal; strong). The quantitative scores of all MMRP were significantly higher among the endoscopic material (P

Barrett’s esophagus (BE) is a known complication of gastroesophageal reflux disease. In a previous study, we described a high prevalence of intestinal metaplasia (IM) in patients with an irregular Z line. However, the clinical importance of this finding is unclear. To evaluate the long-term development of BE and relevant complications in patients diagnosed with an irregular Z line, with or without IM, on routine esophago-gastro-duodenoscopy (EGD). In our previously described cohort, 166 out of 2000 consecutive patients were diagnosed with an incidental irregular Z line. Of those with irregular Z line, 43% had IM. In this continuation study, patients’ status was reassessed after a median follow-up of 70 months. Patients were divided into two groups: Patients with IM (IM-positive group) and without IM (IM-negative group). The incidence of long-term development of BE, dysplasia, and esophageal adenocarcinoma were compared between groups. At least one follow-up EGD was performed in 102 (61%) patients with an irregular Z line. Endoscopic evidence of BE was found in eight IM-positive patients (8/50 [16%]) and in one IM-negative patient (1/52 [1.9%]). Two (4%) IM-positive patients developed BE with low-grade dysplasia. None of the patients developed high-grade dysplasia, or esophageal adenocarcinoma. Patients with irregular Z line do not develop major BE complication in more than 5 years of follow-up.

Immunohistochemistry (IHC) testing for mismatch repair proteins (MMRP) is currently being used primarily in colorectal cancer resection specimens. We aimed to compare the results of IHC staining performed on biopsy specimens obtained at endoscopy with that performed on surgical specimens after neoadjuvant therapy. Thirty-two rectal cancer subjects had paired preneoadjuvant and postneoadjuvant tissue available for IHC staining (MLH1, MSH2, MSH6, and PMS2), whereas 39 rectosigmoid cancer patients who did not receive neoadjuvant treatment served as controls. Each slide received a qualitative (absent, focal, and strong) and quantitative score (immunoreactivity [0-3] × percent positivity [0-4]). The quantitative scores of MMRP from the operative material were significantly lower in the neoadjuvant group than in the control (P < .05 for all).The scores of all MMRP from endoscopic biopsies were not significantly different between the neoadjuvant and the control groups. Disagreement between the endoscopic biopsy and the operative material was evident in 23 of 128 stains (18.5%) in the neoadjuvant group and in 12 of 156 stains (7.7%) in the control group (P = .009). In the neoadjuvant group, a disagreement pattern of "endoscopic strong operative focal" was observed in 28.1% for PMS2, 12.5% for MSH6, 12.5% for MLH1, and 6.3% for MSH2, and in the control group, this same disagreement pattern was found in 12.8% for PMS2, 7.7% for MSH6, 7.7% for MLH1, and 0% for MSH2. Based on our findings, we suggest that for rectal cancer, the endoscopic material rather than the operative material should serve as the primary material for IHC staining.

There are currently no accepted clinical guidelines for the surveillance of first-degree relatives (FDRs) of gastric cancer patients. The existence of intestinal metaplasia, as well as altered mucin expression, might be associated with an increased risk for gastric cancer. In the present study we aimed to investigate the mucin phenotype of individuals with a family history of gastric cancer.We included FDRs of gastric cancer patients. Individuals with functional chest pain served as controls. Upper endoscopy including extensive biopsy according to the Olga protocol was performed. Immunohistochemical staining for MUC1, MUC2, MUC5AC, and MUC6 was performed. Sera were assayed for pepsinogen I and II. Helicobacter status was determined through Giemsa staining and serological tests.Forty FDRs and eight controls were included; the mean age was 46.7 ± 12.0 years. In both the study group and the control group there were no gross endoscopic findings and no histological evidence of intestinal metaplasia. Superficial MUC1 expression was significantly increased in the study group (47.5 vs. 0%; P=0.01). There was no difference in the expression of deep MUC1, MUC2, MUC5AC, or MUC6 between the groups, nor was there a difference in pepsinogen I/II levels or Helicobacter pylori exposure (35.0 vs. 25.0%; P=0.46).Despite normal appearing mucosa and the absence of intestinal metaplasia according to histological analysis, FDRs of gastric cancer patients show increased expression of MUC1, which may serve as a predictor of future intestinal metaplasia, dysplasia, and cancer. Further studies are needed to verify these findings and their implications.

Background The ratio of Helicobacter pylori/NSAID-negative gastric ulcers is increasing. Idiopathic gastric ulcers have unique clinical and endoscopic features, and are associated with more bleeding complications and a higher mortality. Alterations in gastric mucin expression and sialylation pattern may be important in ulcer pathogenesis.

Objective To compare the uptake of faecal immunochemical occult blood test (FIT) with guaiac faecal occult blood test (gFOBT) in a screening programme, with specific attention to the demographic and socioeconomic factors that might affect test uptake. Setting The Clalit Health Service screening programme, Israel. Methods Average-risk individuals aged 50–75 years were randomized into a FIT arm or gFOBT arm using a programme based on the socioeconomic status (SES) of their primary care clinics. G-FOBT was performed with Hemoccult SENSA™ (3 evacuations) and FIT with the OC- MICRO™ (3 evacuations, refrigerating mandated). The GLIMMIX model was used. Results There were 5,464 and 10,668 eligible participants in the FIT and gFOBT arms respectively. Compliance in taking the kits was better (but not statistically significantly better) with gFOBT (37.8% vs. 29.3%; odds ratio [OR] 1.43 [95% CI 0.73–2.80]; P = 0.227). Kit return was higher in the FIT arm (65.0% vs. 78.9%; OR 0.45 [95% CI 0.24–0.83], P = 0.021). Overall test uptake was affected by age, gender, being immigrant and SES (determined by whether or not the participant paid national insurance tax, and the SES of the primary care clinic). The overall uptake of gFOBT and FIT was comparable (OR 0.996 [95% CI 0.46–2.17], P = 0.99). Conclusions Overall compliance for test uptake was comparable between the two methods despite the more demanding procedure in the FIT arm. Sociodemographic parameters were the major determinants of compliance. An educational programme, with emphasis on the sociodemographic characteristics of the target population, should be instigated.

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).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 bothor=75 and 100 ngHb/ml of buffer thresholds to determine positivity.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.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.

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 ◦ Co r 20 ◦ Co r 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. (Am J Gastroenterol 2005;100:2519‐2525)

Low or minimal doses of aspirin are widely used for prevention of cardiovascular diseases. Aspirin is known to produce severe adverse gastrointestinal effects, such as bleeding and perforation. Less is known about the risk associated with minidose aspirin. Our aim was to assess the possible association of upper gastrointestinal tract bleeding with minidose aspirin therapy. A retrospective controlled design was used. Patients hospitalized for melena or hematemesis between January 1, 2000, and December 31, 2001, were identified by ICD-9 codes, and their clinical findings were compared to these of patients without upper gastrointestinal bleeding hospitalized during the same period and matched for age and sex. Bleeding was attributed to therapy if patients used a nonsteroidal anti-inflammatory drug or aspirin therapy within 30 days before hospitalization. The study group included 318 patients (59% male), and the control group 141 (65% male). Mean ages were 67 +/- 19 and 64 +/- 19 years, respectively. Study patients had more accompanying diseases, used more medications, and required more blood transfusions than controls (37%, vs. 2% of controls; P0.001). Minidose aspirin was used by 28% of the study group and 18% of the controls (P = 0.03). The average dose was 40 +/- 86 and 21 +/- 55 mg/day, respectively (P = 0.012). Only 26% of the study patients received a gastric protective agent. On multivariate analysis, aspirin consumption was the only independent risk factor for upper gastrointestinal tract bleeding. There appears to be an association between minidose aspirin treatment and hospitalization for upper gastrointestinal tract bleeding. Despite the advanced age of the patients, only one-quarter were treated with gastric protective agent.

Background and Aims The current guidelines for surveillance after polypectomy do not distinguish between diminutive (1-5 mm) and small (6-9 mm) polyps with low-grade dysplasia (LGD). We aimed to evaluate the risk for advanced neoplasia on follow-up colonoscopy. Methods We retrospectively analyzed 443 patients whose worst finding at index colonoscopy was polypectomy of 1 to 5 or 6 to 9 mm polyps with LGD and those who underwent a follow-up colonoscopy. Results During a mean follow-up of 32.0 months (interquartile range 13-48 months), advanced neoplasia was found in 26 patients (5.9%). Among all included patients (n = 443), advanced neoplasia was found in 13 of 310 patients (4.2%) of the 1- to 5–mm group versus 13 of 133 patients (9.8%) of the 6- to 9-mm group (hazard ratio [HR], 3.49; 95% confidence interval [CI], 1.6-7.6). Among the patients with 1 to 2 polyps resected (n = 313), advanced neoplasia was found in 8 of 231 patients (3.5%) of the 1- to 5-mm group versus 8 of 82 patients (9.8%) of the 6- to 9-mm group (HR 3.97; 95% CI, 1.47-10.7). Among the patients with ≥3 polyps resected (n = 130), advanced neoplasia was found in 5 of 79 patients (6.3%) of the 1- to 5-mm group versus 5 of 51 patients (9.8%) of the 6- to 9-mm group (HR 2.4; 95% CI, 0.7-8.36). Fair bowel preparation also was associated with the risk for advanced neoplasia at follow-up (HR 3.87, 95% CI, 1.70-8.82). Conclusions Our findings suggest that among patients with up to 9-mm adenomatous polyps, a polyp size of 6 to 9 mm, >2 polyps, and fair bowel preparation are associated with advanced neoplasia.

To determine the expression of membrane-bound mucins and glycan side chain sialic acids in Helicobacter pylori (H. pylori)-associated, non-steroidal inflammatory drug (NSAID)-associated and idiopathic-gastric ulcers.We studied a cohort of randomly selected patients with H. pylori (group 1, n = 30), NSAID (group 2, n = 18), combined H. pylori and NSAID associated gastric ulcers (group 3, n = 24), and patients with idiopathic gastric ulcers (group 4, n = 20). Immunohistochemistry for MUC1, MUC4, MUC17, and staining for Erythrina cristagalli agglutinin and Sambucus nigra agglutinin (SNA) lectins was performed on sections from the ulcer margins.Staining intensity of MUC17 was higher in H. pylori ulcers (group 1) than in idiopathic ulcers (group 4), 11.05 ± 3.67 vs 6.93 ± 4.00 for foveola cells, and 10.29 ± 4.67 vs 8.00 ± 3.48 for gland cells, respectively (P0.0001). In contrast, MUC1 expression was higher in group 4 compared group 1, 9.89 ± 4.17 vs 2.93 ± 5.13 in foveola cells and 7.63 ± 4.60 vs 2.57± 4.50 for glands, respectively (P0.0001). SNA lectin staining was increased in group 4, in parallel to elevated MUC1 expression, indicating more abundant α2-6 sialylation in that group.Cytoplasmic MUC17 staining was significantly decreased in the cases with idiopathic ulcer. The opposite was observed for both MUC1 and SNA lectin. This observation may reflect important pathogenic mechanisms, since different mucins with altered sialylation patterns may differ in their protection efficiency against acid and pepsin.

Aspirin is widely used for its antiplatelet activity, but it harbors a risk of severe adverse gastrointestinal effects, such as bleeding and perforation, especially in elderly people. Our aim to assess the prevalence of upper gastrointestinal lesions and the effect of aspirin on the gastrointestinal mucosa in asymptomatic subjects taking minidose aspirin (100 to 325 mg per day) for more than 3 months. A prospective, open design was used. Patients attending the ophthalmology and cardiology outpatient clinics who had a medical history of more than 3 months of regular aspirin consumption were referred for esophagogastroduodenoscopy (EGD). Of the 90 patients referred for EGD, 44 were symptomatic (epigastric pain or dyspepsia) and were excluded from the study. The 46 asymptomatic patients included 22 men and 24 women of mean age 70 +/- 10 years (range, 36 to 87 years); 32% were current or former smokers. Mean daily aspirin dose was 129.34 +/- 76.61 mg. Only 24% were taking a gastroprotective agent. EGD revealed ulcer or erosions in 47.83% of the patients: erosive gastroduodenitis in 13 patients, gastric ulcer in 14, duodenal ulcer in 2, and gastric and duodenal ulcers in 2. Urease test for Helicobacter pylori infection was positive in 26%. Univariate and multivariate analysis revealed no factor other than aspirin predictive of a positive endoscopy. Minidose aspirin treatment is associated with a high prevalence of ulcerations of the stomach and duodenum.

MUC2 is the primary component of the mucin barrier that separates the intestinal microbiota and the intestinal epithelium. This mucous barrier is affected by both luminal/microbial factors and host/immune factors, both of which have genetic and environmental determinants. The complex interactions between these players in health and disease states are not fully understood. Inflammatory bowel disease (IBD) has both genetic and environmental etiologies that lead to the breakdown of the epithelial barrier. In this review, we explore the up-to-date evidence that implicates mucin in the pathogenesis of IBD. In IBD, quantitative changes in mucin secretion occur, as well as structural changes in mucin's glycoprotein core and the sulfation and sialylation of mucin's oligosaccharide residues. These changes are associated with a diminished functionality of the mucous barrier. We identify the various genetic mutations associated with these changes and outline the animal models that have enhanced the current understanding of the genetic basis for IBD. Further study is needed to better characterize the immune and genetic influences on mucin expression and secretion and role of endoplasmic reticulum stress and a defective unfolded protein response in mediating these changes.

Introduction Colonoscopy of asymptomatic, healthy individuals for colorectal cancer screening rarely causes complications and adverse events. Thus, quality of life (QOL) of the participants should not be affected by the procedure. Aim The aim of the study was to isolate the influence of colonoscopy, by investigation QOL before and after the procedure in a cohort of consecutive patients with different indications. Methods This study is a prospective, longitudinal study, designed to compare the potential influence of colonoscopy on QOL. For a cohort of consecutive patients undergoing colonoscopy for various reasons and indications, we filled a QOL short form-36 and a short feedback questionnaire before, immediately after, and a month after the procedure. We also measured the quality of the endoscopy, the outcome in patients, and acceptability among patients. Results There was no significant change before and immediately after colonoscopy in any of the short form-36 parameters. Physical functioning, role limitation physical, pain, general health, vitality, social functioning, role limitation mental, and mental health had very similar scores before and 2-3 h after the procedure. There was a decrease in the physical functioning a month after the procedure (P=0.01). The same was found for non-inflammatory bowel disease patients, but not for inflammatory bowel disease patients. Conclusion Colonoscopy did not affect QOL in the short or the long duration after the procedure. As such, colonoscopy may be suitable as a part of screening programs. We believe that QOL estimation should be an integral part of assessment of a screening program.

The ratio of Helicobacter pylori/NSAID-negative gastric ulcers is increasing. Idiopathic gastric ulcers have unique clinical and endoscopic features, and are associated with more bleeding complications and a higher mortality. Alterations in gastric mucin expression and sialylation pattern may be important in ulcer pathogenesis.The purpose of this study was to determine the expression pattern of membrane-bound mucins and side chain sugars in H. pylori associated-, NSAID-, and idiopathic-gastric ulcers.We randomly selected 92 patients with H. pylori (group 1, n = 30), NSAID (group 2, n = 18), combined H. pylori and NSAID associated gastric ulcers (group 3, n = 24), and patients with idiopathic gastric ulcers (group 4, n = 20). Immunohistochemistry for T-cell CD4/CD8, MUC1, MUC4, MUC17, and ECA and SNA lectins staining was performed on sections from the ulcer margins. Inflammation score was assessed according to the Sydney system.Bleeding and mortality rates were significantly higher in group 4. CD4 positive T cell count was higher in H. pylori positive patients (P = 0.009). Staining intensity of MUC17 was higher in group 1 than in group 4, foveola and glands alike, with 11.50 ± 3.47 versus 6.80 ± 4.02, and 9.61 ± 4.26 versus 7.59 ± 3.26, respectively (P0.0001). This was a mirror image with MUC1. SNA lectin staining was increased in group 4, in parallel to MUC1 expression, indicating more abundant α2-6 sialylation in that group.Cytoplasmic MUC17 staining was significantly decreased in the cases with idiopathic ulcer. The opposite was demonstrated for MUC1. This observation might be important, since different mucins with altered sialylation patterns likely differ in their protection efficiency against acid and pepsin.

Barret's esophagus (BE) is defined as a situation in which the distal esophageal squamous epithelium was replaced by columnar epithelium, with or without goblet cells. BE is considered a significant risk factor for the development of esophageal cancer, however, screening is recommended only for high risk patients. The new guidelines determine the proper terminology of the endoscopic appearance of BE and the way that biopsies should be taken. After BE is confirmed, surveillance is extremely important as its performance has been shown to prevent cancer and death. The surveillance is based on the endoscopic and pathological findings, highlighting the importance of advanced endoscopy and specialized pathology expertise. The guidelines determine the place of the endoscopic ablative technology and specialized surgery in these patients.

Genetic background is suspected in about 20% of colorectal cancer (CRC) cases, in which either genetic polymorphisms or Mendelian heritable factors are involved. Currently known CRC syndromes include various polyposis syndromes (1% of total CRC cases) and Lynch syndrome (LS), previously termed hereditary nonpolyposis colorectal cancer (HNPCC, comprises 3-5% of all CRC cases). LS is caused by dominantly inherited mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and results in a very high lifetime risk (approximately 80%) for CRC and significantly increased risk for extracolonic tumors in regions such as the endometrium, ovary, urinary tract, lymphoma, stomach, pancreas small bowel and brain. Carriers are advised to undergo specific medical and intense endoscopic surveillance. Diagnosis of carriers is mandatory for providing appropriate recommendations for surveillance, which was shown to decrease morbidity, mortality and health costs. Diagnosis of LS dictates preventive surgical procedures for the colon endometrium and ovaries, and assists in decisions regarding CRC chemotherapy. Family members' screening and surveillance is determined by mutation testing. Diagnosis is performed, based on the clinical selection criteria of Amsterdam and Bethesda and according to typical histology of tumor tissue. Initially, tumor testing is performed by either microsatellite instability (MSI), immunohistochemistry (IHC) or both. Certain Jewish ethnical subgroups may undergo founder mutation testing. Ultimate identification of the mutation by sequencing and MLPA is performed according to the IHC results. In families with hereditary CRC criteria, in which workup for LS is negative, the surveillance protocol will be determined by an experienced multidisciplinary team, including a formal genetic consultation.

This position paper of the Section of Gastrointestinal Oncology of the Israeli Gastroenterological Association recommends specific guidelines for colorectal cancer surveillance in patients with inflammatory bowel disease. Colorectal cancer (CRC) is a severe complication of inflammatory bowel disease (IBD), generally developing into a longstanding disease. The Lifetime prevalence of CRC in ulcerative colitis (UC) patients is estimated to be 2% after 10 years, 8% after 20 years, and even 18% after 30 years of extensive disease. Screening colonoscopy should be initiated 8-10 years after onset of symptoms in extensive UC patients (pancolitis), and after 15 years in patients with left-sided colitis (UC or Crohn's). Surveillance should continue periodically at an interval of every 1 to 2 years. Surveillance colonoscopies should be performed in combination with an extensive biopsy protocol. High-grade dysplasia (HGD) in flat mucosa or a dysplasia associated Lesion or mass (DALM) is considered an indication for colectomy when the pathological findings are confirmed by a second experienced pathologist. Further research is directed toward improving detection of dysplasia during colonoscopy through the use of novel endoscopic imaging techniques which are hoped to impact the approach to cancer prevention in patients with IBD.

Fecal immunochemical test (FIT) is gaining popularity as a screening tool for colorectal cancer. The introduction of capsule endoscopy (CE) enables an assessment of the relationship between small bowel (SB) lesions and FIT results.To determine whether SB lesions found by CE are associated with an increased rate of positive FIT.Consecutive patients undergoing CE for obscure occult gastrointestinal bleeding also underwent FIT. CE was performed using the PillCam SB and FIT was performed with OC-Micro (three samples, threshold 75 and 100 ng/ml).Fifty-one patients were included; the mean lowest hemoglobin was 9.1 ± 2.1 g/dl. Twenty-six patients (51.0%) had SB lesions identified by CE and were classified as the probable or suspected source of bleeding. At the threshold of 75 and 100 ng/ml, 12 of 26 (46.1%) and 10 of 26 (38.4%), respectively had a positive FIT. In contrast, only two of 25 (8.0%) patients without SB lesions had a positive FIT at both thresholds (P=0.002 and 0.010 respectively). The mean fecal hemoglobin in patients with SB lesions classified as probable or suspected source of bleeding versus patients with normal SB was 345.6 ± 773 and 25.0 ± 37.7 ng/ml, respectively (P=0.025).A positive FIT can be explained by significant SB lesions detected by CE. Further studies are still needed to evaluate whether asymptomatic patients with positive FIT and nonexplanatory colonoscopy should undergo further study of the SB.

Approximately 30% of colorectal cancers exhibit familial clustering. Currently, we recognize a number of different types of polyps and polyposis syndromes that are classified according to the histology of the typical polyp. We differentiate between adenomas, hyperplastic, and hamartomatous polyps as well as between syndromes that are manifested by 10-100 or above 100 polyps. It is essential to distinguish between these syndromes as each has a different mode of presentation, spectrum of signs and symptoms and cancer risk associated with them. With the knowledge accumulating, we now have the tools to lower the risk of cancer by performing specific screening programs that are tailored to each syndrome. In these guidelines we focus on the non-adenomatous polyps, hyperplastic and hamartomatous polyposis syndromes. We outline the importance of multi-sector team work that includes the family practitioner, gastroenterologist, pathologist, genetic counselor, surgeon, and social worker.

Approximately 30% of colorectal cancers exhibit familial clustering. We recognize different types of polyps and polyposis syndromes that are classified according to the histological diagnosis. We differentiate between adenomas, hyperplastic, and hamartomatous polyps as well as between syndromes that are manifested by 10-100 or above 100 polyps. Only about 1% of colorectaL cancers (CRCs) are due to adenomatous polyposis syndrome. It is essential to distinguish between these syndromes as each has a different mode of presentation, spectrum of signs and symptoms and cancer risk. With the knowledge that is accumulating we now have the tools to lower the risk of cancer by performing specific screening programs that are tailored to each syndrome specifically. We present the Israeli guidelines for management of adenomatous polyposis, based on the American and European experience and consensus. We outline the importance of mutti-sectorial team work that includes the family practitioner, gastroenterologist, pathologist, genetic counselor, surgeon and social worker.

The position paper of the GastrointestinaL Oncology Section of the Israeli Gastroenterological Association recommends specific guidelines for surveillance after polypectomy and curative resection of colorectal cancer. Periodic colonoscopy is necessary for early detection of metachronous lesions or cancer recurrence. After polypectomy of a simple hyperplasic polyp, colonoscopy is repeated in 10 years. Small adenoma dictates colonoscopy after 5-10 years. In the case of advanced adenoma, repeat coLonoscopy is to be conducted after 3 years. The personal impression of the colonoscopists may advance procedures to an earlier colonoscopy, especially after piecemeal polypectomy of a large sessile polyp. Fecal occult blood test or any other screening procedures are not needed after polypectomy. Colonoscopy, carcinoembrionic antigen examination (CEA) and liver imaging are necessary for surveillance after curative resection of colorectal cancer, and improve survival. Total colonoscopy should be performed before the operation or in cases with obstructive carcinoma, colonic imaging should be completed with virtual colonoscopy. Total colonoscopy should be performed 3-6 months after surgery if not conducted previously. The next follow-up is needed 3 and 5 years after the operation. After low anterior resection, the recurrence rate may be high and patients who have not undergone radiation therapy nor mesorectal resection should undergo sigmoidoscopy every 3-6 months for 2-3 years after surgery.

JC virus (JCV) may infect the gastrointestinal tract in childhood, and, by encoding a gene for T-antigen (T Ag), can initiate chromosomal instability in epithelial cells. We looked for JCV DNA in the cancer tissue of patients with sporadic colorectal cancer (CRC, Group A) and with positive family history and Bethesda criteria (Group B). We hypothesized that the role of JCV may be different between these two groups. Fifty-six patients were randomly selected from our database, 30 in Group A and 26 in Group B. DNA was isolated from the tumor, normal mucosa, and plasma, and JCV DNA sequences were looked for with specific polymerase chain reaction (PCR) assays for T Ag primers. Immunohistochemistry for hMLH1, hMSH2, hMSH6, and PMS2 was performed on paraffin-embedded tissue. In Group A, T Ag was demonstrated in 6 (20.00%) and 3 (10.00%) of the tumors and adjacent normal mucosa, respectively (P = 0.094). In Group B, the corresponding observations were 10 (38.46%) and 6 (23.07%), respectively (P

Objectives Patients with positive fecal occult blood test and unrevealing colonoscopy are often advised to undergo esophago-gastro-duodenoscopy (EGD) to exclude a bleeding source in the upper gastrointestinal tract. In this study, we evaluated EGD findings in patients with positive immunochemical fecal occult blood test (I-FOBT) not explained by colonoscopy. Methods Out of 1221 consecutive patients having total colonoscopy after preparing I-FOBT (OC-MICRO, with threshold of 75 or 100 ngHb/ml), we included only patients without colorectal cancer or advanced adenomatous polyp on colonoscopy, who also underwent EGD within 4 months of the fecal blood testing. Findings on EGD were classified as those lesions which are likely or unlikely to bleed. Results EGD was performed in 160 patients after a negative colonoscopy. The procedure was performed 1.6 ± 1.4 months after the I-FOBT. Lesion with a bleeding potential was found in 24 patients (15%). In three (12.5%) and two (8.3%) of these patients I-FOBT was positive at the 75 and 100 ngHb/ml threshold, respectively. In 136 patients EGD was normal, and I-FOBT was similarly positive in 16 (11.7%) and 13 patients (9.5%), respectively. The mean fecal hemoglobin was also similar between the groups. Conclusion Immunological FOBT positivity was not correlated with the finding of lesions, which are likely to bleed on EGD. Thus, EGD is probably not indicated in patients with positive I-FOBT and unrevealing colonoscopy.

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.

Background Hypermethylation of tumor suppressor genes' promoter and JC virus infection may be etiologic factors in the development of colorectal cancer (CRC). Objectives To look at both JC virus T antigen and hMLH1 promoter methylation in CRC tissue in Israeli ethnic groups with different incidence of CRC. Methods Twenty-four consecutive patients with sporadic CRC were included in the study. Genomic DNA was isolated from paraffin-embedded microdomains removed from five slides of 7 μm by deparaffinizing in multiple xylene washes. Isolated DNA was used as a template for PCR to amplify DNA sequences coding the amino terminus of JC virus T antigen. Methylation-specific PCR was performed on bisulfite-modified DNA templates from CRC tissue materials to study methylation status of hMLH1 promoter, using two sets of primers specific for amplification of methylated and unmethylated alleles. Results hMLH1 promoter methylation was observed in five patients (20.8%) who were also positive for JC virus T antigen, with even distribution among the ethnic groups. JC virus T antigen DNA was found in cancer tissues of 20 of the 24 patients; 50, 90.9, and 100% of Asia–Africa-born Jews, Europe–America-born Jews, and Israeli Arabs, respectively (P = 0.036 between the first group to the other). Conclusion Evidence for higher JC virus infection was shown among Europe-America-born Jews and Israeli Arabs. hMLH1 promoter methylation was evenly distributed between different ethnic groups in Israel.

Objective: JC virus (JCV) is thought to infect approximately 80% of the human population. Antibodies against JCV can be found in the sera of many people with and without colorectal carcinoma (CRC). We hypothesized that JCV antibody titer will be higher in CRC patients than in healthy controls. Aim: To evaluate this hypothesis in a cohort of patients undergoing colonoscopy. We compared JCV antibody titers in patients with simple adenoma, advanced adenomatous polyp (AAP), CRC, and healthy controls, and evaluated JCV DNA in the tissue. Methods: Ninety-seven patients undergoing colonoscopy offered to participate in the study. Normal colonoscopy, simple adenoma, AAP, and CRC were found in 41, 19, 12, and 25 cases, respectively. A blood sample was taken for JCV DNA isolation and serology. In 18 patients with CRC or AAP tissue samples were taken for JCV DNA isolation and T-antigen (T-Ag) detection. Results: A positive correlation was found between a JCV antibody titer and advanced colonic pathology. The average titer for normal controls, simple polyp, AAP, and CRC was 2.61 ± 0.72, 2.95 ± 0.77, 3.33 ± 0.76, and 3.30 ± 0.50 log, respectively (P < 0.001). Viral DNA could not be shown in the serum. The presence of neoplastic tissue T-Ag (in 33.3% of the patients) was not associated with a difference in the log titer of serum antibody. Conclusions: In this study we showed that patients with advanced neoplasia, compared with patients with normal colonoscopy, harbor a higher JCV antibody titer in the serum. If confirmed, our finding may serve as a marker for CRC or for an earlier stage of AAP.

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 ≥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 ≥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

Barrett's esophagus is a well-known complication of gastroesophageal reflux disease (GERD) and is associated with dysplasia and esophageal adenocarcinoma. Data on the prevalence of specialized intestinal metaplasia (SIM) in biopsy taken from an incidental irregular Z line are scarce.To determine the prevalence of SIM in biopsies taken from an incidental irregular Z line in consecutive patients undergoing upper endoscopy.During the study period, we identified all adult patients who underwent an upper endoscopy with biopsies from an incidental finding of an irregular Z line. Demographic characteristics, prevalence of endoscopic findings, and major complaints were compared between those with SIM and those without.A total of 166 out of 2000 (8.3%) consecutive patients were identified. Specialized intestinal metaplasia was found in 43.5% of all cases. Male sex and the presence of hiatus hernia were predictors of SIM (P=0.043 and 0.001, respectively), with relative risks of 2.02 (95% confidence interval: 1.01-4.0) and 3.31 (95% confidence interval: 1.66-6.58), respectively.In this endoscopic and histological study, SIM was found to be a common finding in patients with irregular Z line. Male sex and the presence of diaphragmatic hernia were significantly associated with the presence of SIM.

BACKGROUND: The molecular mechanisms that underlie colorectal cancer (CRC) include microsatellite instability (MSI), chromosomal instability, and the CpG island methylator phenotype. There is evidence to suggest that CRC incidence varies among different ethnic populations worldwide. The authors of this report hypothesized that environmental factors and lifestyle differences among various ethnic groups may differentially influence the epigenetic regulation of tumor suppressor genes in CRC. METHODS: In the current study, microdissection and DNA extraction were performed on 128 samples of CRC from Israeli patients (85 Jews and 43 Arabs). MSI analysis, mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) protein expression levels, and MLH1 promoter methylation were investigated by combined bisulfite restriction analysis. The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) valine-to-glutamic acid mutation at residue 600 was investigated by direct DNA sequencing. RESULTS: High MSI (MSI-H), MLH1 methylation, and BRAF mutations were observed in 11.6%, 9.4%, and 23.5% of Jews, respectively, and in 16.2%, 17.6%, and 20.9% of Arabs, respectively (P value nonsignificant). MLH1 promoter methylation was observed in 22.6% of microsatellite-stable (MSS) tumors and in 53.8% of MSI-H tumors (P < .015). Extensive methylation (covering both 5′ and 3′ promoter regions) was present in all MSI-H tumors with loss of MLH1 expression. BRAF mutation was observed in 15.6% and 46.1% of MSS tumors and MSI-H tumors, respectively (P < .007). BRAF mutation was observed in 66%, 22.2%, and 14.7% of patients who had tumors with extensive MLH1 promoter methylation, methylation of the 5′ region alone, or without methylation, respectively (P < .006). CONCLUSIONS: There was no difference in molecular signatures examined between Jewish and Arab patients with CRC in Israel. Extensive promoter methylation was associated with MLH1 inactivation, MSI, and BRAF mutation. Cancer 2009. © 2009 American Cancer Society.

Dedicated, organ-specific screening clinics have been shown to significantly reduce cancer morbidity and mortality.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.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.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.

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.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.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 storedor = 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 (P0.05). 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%.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.

Mucin is a high-molecular-weight glycoprotein that is synthesized, stored, and secreted by epithelial mucosal cells, especially goblet cells. Mucin proteins are derived from many different genes, termed MUC genes. Several lines of evidence point to a biological role for mucin in cholesterol gallstone formation. Mucin serves as a pronucleating agent in experimental and human gallstone disease, and the hydrophobic binding sites in the polypeptide core of mucin may provide a favorable environment for nucleation of cholesterol monohydrate from supersaturated bile. Mucin hypersecretion is prominent in many animal models of gallstone formation, thus contributing by its pronucleating quality to gallstone formation. According to some research, mucin hypersecretion may also contribute to the formation of brown pigment stones. This may be explained in part by the findings that lipopolysaccharides derived from certain bacteria are effective stimulants of mucin secretion. Aspirin and nonsteroidal anti-inflammatory drugs inhibit gallbladder mucin secretion and prevent gallstone formation in animal models. Expanding our knowledge on mucin research may improve our understanding of the natural history of gallstone formation and enable the development of new treatment strategies.

Back ground: Deep enteroscopy for the evaluation and treatment of small bowel pathology has undergone significant technology advancements over the last ten years. Studies directly comparing single (SBE) and double balloon enteroscopy (DBE) with spiral enteroscopy (SE) are few but suggest that the three techniques are comparable. Method: Retrospective review of Spirus® small bowel endoscopy cases over 12 months Results: A single experienced endoscopist completed all cases. The patient characteristics are listed in Table 1. Two patients had strictures (one was dilated) and one had multiple arteriovenous malformations (coagulated with Argon Plasma). Two patients experienced complications. Case 1: A 77 year old female with remote radiation treatment for endometrial carcinoma being evaluated for anemia had several slightly narrowed areas; all judged to be spacious enough to accommodate the overtube except one. The last area appeared tight and the overtube was unlocked as soon as it engaged the location and the scope alone was advanced further. Surprisingly the cecum was reached without difficulty. Upon endoscope withdrawal, bleeding was noted and a perforation was suspected. A tense abdomen was decompressed with a needle, rapidly stabilizing a low blood pressure. Perforation was identified and the segment with several strictures was resected. Case 2: A 44 year old female with cirrhosis secondary to primary sclerosing cholangitis status post hepaticojejunostomy had recurrent anastomotic strictures. On SE assisted ERCP, a perforation was suspected on radiography. ERCP was completed and exam was continued under water without gas insufflation. The perforation was found on the biliary limb and was not favorable for endoclip closure. The spilled intestinal contents were suctioned and pneumoperitoneum was decompressed allowing the patient to be comfortable and stable until laparotomy. A guidewire was placed endoscopically which allowed easy identification of the site during surgery (Figure 1). Conclusion: Patients with known or occult small bowel strictures and surgically altered anatomy with possible adhesional fixation may be at a higher risk of complications and we suggest caution with use of SE in these scenarios. When perforations occur, early recognition and immediate management are of benefit. Despite suffering complications, both patients benefited from their procedures. In case 1, the resection of the diseased intestine led to resolution of anemia. In Case 2, the bile duct stricture was successfully treated and she was bridged to transplant. Table 1: Patient characteristics

sion in the esophagus at three critical stages, specification, metaplasia and maturation. The esophagi were isolated from wild-type, Nrf2-/-, Keap1-/-, or Nrf2-/-;Keap1-/embryos or young adults. Array data were statistically analyzed for differentially expressed genes and pathways. Histochemical and immunohistochemical staining were used to verify potential involvement of the Wnt pathway, PPARβ/δ and the PI3K/Akt pathway in the development of esophageal epithelium. Results Dynamic gene expression pattern accompanied the morphological changes of the developing esophagus at the critical stages. Particularly, the Nrf2/ Keap1 pathway had a baseline activity in the metaplasia phase and was further activated in the maturation phase. The Wnt pathway was active early and became inactive later in the metaplasia stage. In addition, global transcript profiling of the esophagus isolated from Keap1-/mice showed increased expression of Nrf2 downstream targets and genes involved in keratinization. Microarray data also suggested that esophageal hyperkeratosis in the Keap1-/mice was due to activation of PPARβ/δ and the PI3K/Akt pathway. Conclusions Morphological changes of the esophageal epithelium are associated with dynamic changes in gene expression. The activity of Nrf2/Keap1 pathway is required for the maturation of the esophagus.

To determine the pattern of secreted mucin expression in Helicobacter pylori (H. pylori)-related, nonsteroidal anti-inflammatory drug (NSAID)-related and idiopathic gastric ulcers.We randomly selected 92 patients with H. pylori-associated (n = 30), NSAID-associated (n = 18), combined H. pylori and NSAID-associated gastric ulcers (n = 24), and patients with idiopathic gastric ulcers (n = 20). Immunohistochemistry for T-cell CD4/CD8, and for mucin 5AC (MUC5AC) and mucin 6 (MUC6), was performed on sections of the mucosa from the ulcer margin. Inflammation score was assessed according to the Sydney system.MUC5AC was expressed on the surface epithelium (98.9%) and neck glands (98.9%) with minimal expression in the deep glands (6.5%). MUC6 was strongly expressed in the deep glands (97.8%), variable in the neck glands (19.6%) and absent in the surface epithelium (0%). The pattern of mucin expression in idiopathic ulcer margins was not different from the expression in ulcers associated with H. pylori, NSAIDs, or combined H. pylori and NSAIDs. CD4/CD8 ratio was higher in H. pylori-positive patients (P = 0.009). Idiopathic ulcers are associated with hospitalized patients and have higher bleeding and mortality rates.Idiopathic ulcers have a unique clinical profile. Gastric mucin expression in idiopathic gastric ulcers is unchanged compared with H. pylori and/or NSAID-associated ulcers.