Association Between Polyp Detection Rate and Post-Colonoscopy Cancer Among Patients Undergoing Diagnostic Colonoscopy.

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

Association between time to colonoscopy after a positive guaiac fecal test result and risk of colorectal cancer and advanced stage disease at diagnosis.

We evaluated time to colonoscopy after a positive guaiac-based fecal occult blood test (gFOBT) result and its association with the risk of overall colorectal cancer (CRC) and advanced-stage disease at diagnosis. We conducted a retrospective cohort study (2011-2013) within the Clalit Health Services, Israel. Participants were patients between 50 and 74 years old with a positive gFOBT result who had follow-up colonoscopies within 24 months. The exposure was time to colonoscopy, and the main outcome measure was a risk for overall and advanced CRC (defined as Stages III-IV). Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for patient demographics and baseline risk factors. Of the 17,958 patients with positive gFOBT results (median age, 61 years [interquartile range, 56-67 years]; women, 52.2%), there were 685 cases of CRC and 156 cases of an advanced-stage disease diagnosed. The rate of cancer diagnosis at 0-3, 4-6, 7-9, 10-12 and 13-24 months was 3.9%, 2.5%, 3.5%, 4.2% and 7.3%, respectively (p < 0.001). Compared to colonoscopy follow-up within 0-3 months, risks for any CRC and advanced stage disease were higher for a follow-up of 12-24 months: OR, 1.97 (95% CI, 1.51-2.56) and 1.88 (95% CI, 1.43-2.46), respectively. For right-sided cancer (n = 194), an increased risk starts at 10 months, OR, 1.91 (95% CI 1.03-3.56). A result of 3-6 positive fields was significantly associated diagnosis of cancer (OR, 5.52; 95% CI, 4.71-6.46) and advanced stage disease (OR, 8.07; 95% CI, 5.74-11.36). Encouraging an early uptake of colonoscopy and targeting those with 10-24 months delay and a 3-6 positive fields is warranted.

Risk of Neoplastic Progression Among Patients with an Irregular Z Line on Long-Term Follow-Up.

BACKGROUND: 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. GOALS: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: Patients with irregular Z line do not develop major BE complication in more than 5 years of follow-up.

Risk of advanced lesions at the first follow-up colonoscopy after polypectomy of diminutive versus small adenomatous polyps of low-grade dysplasia.

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.

Mucin function in inflammatory bowel disease: an update.

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.

Presence of JC virus DNA in the tumor tissue and normal mucosa of patients with sporadic colorectal cancer (CRC) or with positive family history and Bethesda criteria.

INTRODUCTION: 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. AIM: 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. METHODS: 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. RESULTS: 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 < 0.001). Immunohistochemistry for hMLH1, hMSH2, hMSH6, and PMS2 was performed in all of the Group A and B patients. All patients of Group A (100%) showed expression of these proteins, while only 19 patients of Group B did so (73.1%), P = 0.009. JCV T Ag DNA was found in 20, 28.5, and 42.1% of the tumors in Group A, Group B with negative staining for DNA repair genes, and Group B with a positive staining, respectively (NS). CONCLUSION: CRC patients with positive family history have a higher incidence of JCV T Ag, but this did not correlate with specific DNA repair gene mutations. We could not conclude that, on the background of genetic mutation in one of the DNA repair genes, JCV acts as the missing link in the chain of events leading to CRC.

Membrane-bound mucins and mucin terminal glycans expression in idiopathic or Helicobacter pylori, NSAID associated peptic ulcers.

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. AIMS: 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. METHODS: 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. RESULTS: 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 (P < 0.0001). 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. CONCLUSIONS: 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.

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

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.

[The Israeli recommendations for diagnosis, management, follow-up and prevention of colorectal cancer (CRC) in familial adenomatous polyposis].

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.

[Surveillance of patients with inflammatory bowel diseases].

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.

[Surveillance of patients with Barrett's esophagus].

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.

[Guidelines for diagnosis, treatment, surveillance and prevention of cancer in patients with familial non-adenomatous polyposis].

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.

[Management of hereditary non-polyposis syndrome (Lynch syndrome)].

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.

Dose-dependent association of proton pump inhibitors use with gastric intestinal metaplasia among Helicobacter pylori-positive patients.

BACKGROUND: Gastric intestinal metaplasia is a pre-cancerous condition associated with multiple factors. OBJECTIVE: We evaluated whether cumulative proton pump inhibitor dose is associated with the diagnosis of gastric intestinal metaplasia while controlling for multiple variables. METHODS: We retrospectively identified patients who underwent upper endoscopy with gastric biopsy between 2005 and 2014. Covariate data retrieved included age, sex, ethnicity, smoking status, Helicobacter pylori status (based on clarithromycin-amoxicillin-proton pump inhibitor issued), cumulative proton pump inhibitor issued within 10 years (quartiles [PPI-Q1-4 ] of daily drug dose), anti-parietal cell antibodies, body mass index and comorbidity index. RESULTS: Of the 14,147 included patients (median age 63.4 years; women 54.4%; Helicobacter pylori-positive 29.0%), 1244 (8.8%) had gastric intestinal metaplasia. Increasing age, Helicobacter pylori infection, smoking, anti-parietal cell antibodies and proton pump inhibitor use were all associated with the diagnosis of gastric intestinal metaplasia. Upper quartiles of cumulative proton pump inhibitor doses (PPI-Q4 and PPI-Q3 vs. PPI-Q1 ) were associated with the diagnosis of gastric intestinal metaplasia: adjusted odds ratios 1.32 (95% confidence interval [CI] 1.111.57) and 1.27 (95% CI 1.07-1.52), respectively, for the whole cohort (Ptotal 0.007, Ptrend 0.013), 1.69 (95% CI 1.23-2.33) and 1.40 (95% CI 1.04-1.89), respectively, for Helicobacter pylori-positive patients (Ptotal 0.004, Ptrend 0.005) and 1.21 (95% CI 0.98-1.49) and 1.20 (95% CI 0.96-1.49), respectively, for Helicobacter pylori-negative patients (Ptotal 0.288, Ptrend 0.018). Upper quartiles of proton pump inhibitor dose were associated with a 5-10-fold increased risk of low-grade dysplasia. CONCLUSIONS: Among Helicobacter pylori-positive patients, proton pump inhibitor use appears to be associated with a dose-dependent increased likelihood of gastric intestinal metaplasia.

Patients with sporadic colorectal cancer or advanced adenomatous polyp have elevated anti-JC virus antibody titer in comparison with healthy controls: a cross-sectional study.

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.

JC virus T-Antigen DNA in gastrointestinal mucosa of immunosuppressed patients: a prospective, controlled study.

BACKGROUND: JC virus (JCV), a polyoma virus, is the etiological agent of progressive multifocal leukoencephalopathy in immunosuppressed patients. JCV T-Ag has proven oncogenic potential and is expressed in colonic polyps and carcinomas. We proposed that the prevalence of JCV T-Ag DNA is higher in the normal gastrointestinal (GI) mucosa of immunosuppressed patients compared with their immunocompetent counterparts. AIMS: To look for JCV T-Ag DNA in the normal gastrointestinal mucosa of immunosuppressed patients compared with immunocompetent controls. METHODS: Macroscopically normal samples of upper and lower GI mucosa were obtained from 38 immunosuppressed patients. A control group included samples from 19 immunocompetent inflammatory bowel disease (IBD) and 29 non-IBD cases. DNA was extracted and polymerase chain reaction (PCR) was performed using primers specific for T-Ag. RESULTS: JCV T-Ag DNA was found in nine of the immunosuppressed patients (23.7%) and in three of the controls (6.3%; P = 0.02). Transplant recipients had a particularly high prevalence of JCV T-Ag DNA (35.3%). Patients with IBD receiving immunosuppressive drugs had a higher prevalence of JCV T-Ag DNA in comparison with IBD patients who did not receive immunosuppression (22.2% versus 10.5%, respectively), but this difference was not statistically significant (P = 0.574). CONCLUSION: JCV T-Ag DNA is more prevalent in the upper and lower GI mucosa of immunosuppressed patients, possibly indicating that the virus resides in these patients. This may account for the higher prevalence of GI carcinomas in immunosuppressed patients.

[Surveillance of patients after colonoscopic polypectomy and curative resection of colorectal cancer].

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.

Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer.

BACKGROUND & AIMS: Colorectal cancers (CRCs) with the CpG island methylator phenotype (CIMP) often associate with epigenetic silencing of hMLH1 and an activating mutation in the BRAF gene. However, the current CIMP criteria are ambiguous and often result in an underestimation of CIMP frequencies in CRCs. Because BRAF and KRAS belong to same signaling pathway, we hypothesized that not only mutations in BRAF but mutant KRAS may also associate with CIMP in CRC. METHODS: We determined the methylation status in a panel of 14 markers (7 canonical CIMP-related loci and 7 new loci), microsatellite instability status, and BRAF/KRAS mutations in a collection of 487 colorectal tissues that included both sporadic and Lynch syndrome patients. RESULTS: Methylation analysis of 7 CIMP-related markers revealed that the mean number of methylated loci was highest in BRAF-mutated CRCs (3.6) vs KRAS-mutated (1.2, P < .0001) or BRAF/KRAS wild-type tumors (0.7, P < .0001). However, analyses with 7 additional markers showed that the mean number of methylated loci in BRAF mutant tumors (4.4) was the same as in KRAS mutant CRCs (4.3, P = .8610). Although sporadic microsatellite instability high tumors had the highest average number of methylated markers (8.4), surprisingly, Lynch syndrome CRCs also demonstrated frequent methylation (5.1). CONCLUSIONS: CIMP in CRC may result from activating mutations in either BRAF or KRAS, and the inclusion of additional methylation markers that correlate with mutant KRAS may help clarify CIMP in future studies. Additionally, aberrant DNA methylation is a common event not only in sporadic CRC but also in Lynch syndrome CRCs.

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.

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.