Systematic review with meta-analysis: prevalent vs. incident oesophageal adenocarcinoma and high-grade dysplasia in Barrett's oesophagus.

BACKGROUND: The proportion of oesophageal adenocarcinoma that is detected concurrently with initial Barrett's oesophagus diagnosis is not well studied. AIM: To compare the proportion of prevalent adenocarcinoma vs. incident adenocarcinoma found during surveillance of Barrett's. METHODS: We performed a systematic search of MEDLINE, EMBASE and Web of Science (from their inception to 31 May 2015) for cohort studies in adults with Barrett's (nondysplastic Barrett's ± Barrett's with low-grade dysplasia) with minimum average follow-up of 3 years, and providing numbers of prevalent adenocarcinoma detected (concurrently with Barrett's diagnosis and up to 1 year afterwards) vs. incident adenocarcinoma detected (greater than 1 year after Barrett's diagnosis). Pooled weighted proportions of prevalent and incident adenocarcinoma were calculated, using a random effects model. RESULTS: On meta-analysis of 13 studies reporting on 603 adenocarcinomas in 9657 Barrett's patients, 85.1% of adenocarcinomas were classified as prevalent [95% confidence interval (CI), 78.1-90.2%) and 14.9% as incident (95% CI, 9.8-21.9%), with substantial heterogeneity (I(2) = 66%). Among nine studies reporting on 787 high-grade dysplasia and oesophageal adenocarcinomas in 8098 Barrett's patients, the proportion of prevalent high-grade dysplasia-oesophageal adenocarcinoma was similar at 80.5% (95% CI, 68.1-88.8%, I(2) = 87%). These results remained stable across multiple subgroup analyses including study quality, setting, duration of follow-up and presence of baseline dysplasia. CONCLUSIONS: In our meta-analysis, four of five patients diagnosed with adenocarcinoma or high-grade dysplasia at index endoscopy or within 1 year of Barrett's follow-up were considered to be prevalent cases. Continued efforts are needed to identify patients with Barrett's before the development of adenocarcinoma.

Detection rate and outcome of colonic serrated epithelial changes in patients with ulcerative colitis or Crohn's colitis.

BACKGROUND: Chronic ulcerative colitis (CUC) and colonic Crohn's disease (CD) increase colorectal neoplasia (CRN) risk. While sessile serrated polyp (SSP) is a known cancer precursor, serrated epithelial changes (SEC) are of uncertain prevalence and neoplastic risk. AIM: To assess the serrated lesion detection rates in CUC and CD and documented incidence of subsequent CRN in a retrospective, single-centre cohort study. METHODS: Patients were identified by a central diagnostic index and pathology review confirmed SEC, SSP, CUC and CD diagnoses from 2006-12. Matched controls were identified from among all CUC and CD patients having colonoscopy during the second half of the time period. All were followed for incident CRN, estimated by the Kaplan-Meier method. RESULTS: Between 2006 and 2012, 79 SEC and 10 SSP cases were identified. Detection rates were estimated to be 10/1000 and 2/1000 patients, for SEC and SSP respectively, among 4208 unique CUC or CD patients having colonoscopy from 2010-12. With only 10 cases, SSP patients were not further analysed. Cumulative incidence of subsequent CRN at 1 and 3 years was 12% (95% CI, 0-30%) and 30% (3-57%), respectively, in SEC patients compared to 4% (0-12%) and 9% (0-23%), respectively, in CUC or CD controls (P = 0.047, log-rank). However, this statistical difference was not significant after patients were stratified for history of prior or synchronous dysplasia (P = 0.09). CONCLUSIONS: Serrated epithelial changes and sessile serrated polyps are uncommonly detected by colonoscopy in chronic ulcerative colitis and Crohn's disease patients. Histology with changes of serrated epithelium may be associated with risk of subsequent colorectal neoplasia, however further studies are needed to explore this relationship.

Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease.

BACKGROUND: Current approaches to the detection of colorectal neoplasia associated with inflammatory bowel disease (IBD-CRN) are suboptimal. AIM: To test the feasibility of using stool assay of exfoliated DNA markers to detect IBD-CRN. METHODS: This investigation comprised tissue and stool studies. In the tissue study, gene sequencing and methylation assays were performed on candidate genes using tissue DNA from 25 IBD-CRNs and from 25 IBD mucosae without CRN. Mutations on p53, APC, KRAS, BRAF or PIK3CA genes were insufficiently informative, but several aberrantly methylated genes were highly discriminant. In the stool study, we evaluated candidate methylated genes (vimentin, EYA4, BMP3, NDRG4) in a prospective blinded study on buffered stools from 19 cases with known IBD-CRN and 35 age- and sex-matched IBD controls without CRN. From stool-extracted DNA, target genes were assayed using quantitative allele-specific real-time target and signal amplification method. RESULTS: IBD-CRN cases included 17 with ulcerative colitis (UC) and two with Crohn's disease (CD); nine had cancer and 10 had dysplasia. Controls included 25 with UC and 10 with CD. Individually, BMP3, vimentin, EYA4 and NDRG4 markers showed high discrimination in stools with respective areas under the ROC curve of 0.91, 0.91, 0.85 and 0.84 for total IBD-CRN and of 0.97, 0.97, 0.95 and 0.85 for cancer. At 89% specificity, the combination of BMP3 and mNDRG4 detected 9/9 (100%) of CRC and 80% of dysplasia, 4/4 (100%) of high grade and 4/6 (67%) of low grade. CONCLUSION: These findings demonstrate the feasibility of stool DNA testing for non-invasive detection of colorectal neoplasia associated with inflammatory bowel disease.

CT colonography without cathartic preparation: feasibility study.

PURPOSE: To evaluate methods for contrast material labeling of stool in the unprepared colon for computed tomographic (CT) colonography and to determine their sensitivity for polyp detection. MATERIALS AND METHODS: Fifty-six patients with suspected or known polyps were assigned to five groups. Two to seven doses of 225 mL of dilute contrast material were orally administered during 24 or 48 hours. Transverse CT images were assessed for effectiveness of stool labeling. Colonoscopy was performed in all patients and was the standard. Two radiologists blinded to prior imaging and colonoscopic results assessed polyp detection. RESULTS: For each group, average stool labeling scores and ranges were as follows: 24 hour two dose, 16% and 8%-21%; 24 hour five dose, 53% and 27%-66%; 48 hour four dose, 38% and 22%-48%; 48 hour six dose, 68% and 54%-77%; and 48 hour seven dose, 88% and 75%-98%. Sensitivity for the two radiologists for the identification of patients with polyps 1 cm or larger for each group was as follows: 24 hour two dose, 50% and 67%; 24 hour five dose, 100% and 100%; 48 hour four dose, 58% and 75%; 48 hour six dose, 56% and 67%; and 48 hour seven dose, 100% and 80%. CONCLUSION: Ingestion of contrast material adequately labels stool for lesion identification; a 48-hour lead time and multiple doses of contrast material are required. Sensitivity for polyp detection in patients with adequate stool labeling approaches the sensitivity for polyp detection in prepared colons.

A search for germline APC mutations in early onset colorectal cancer or familial colorectal cancer with normal DNA mismatch repair.

Twenty percent of colorectal cancers (CRCs) arise in people who have a family history of CRC in at least one other relative. Although a fraction of these CRCs are explained by two well-described autosomal dominant syndromes-5% by hereditary nonpolyposis colorectal cancer (HNPCC) and 1% by familial adenomatous polyposis (FAP)-the cause of the remaining 14% of familial aggregates of CRC is unknown. Many cases of HNPCC are due to germline mutations in DNA mismatch repair genes, leading to the tumor phenotype of microsatellite instability (MSI), and most cases of FAP are caused by germline APC mutations. To date, non-FAP familial CRC aggregates have not been evaluated for germline APC mutations. In this study, we examined the involvement of germline APC mutations in 79 individuals with CRC who had early-age onset of their cancer (age < 50 years) and/or a family history of CRC. Cases with FAP or HNPCC due to defective mismatch repair were excluded from the study. Using conformation-sensitive gel electrophoresis and the protein truncation test as the screening methods, no functionally significant germline mutations were detected for any of the cases. An apparently silent polymorphism resulting in a 1-bp alteration of A --> G (proline --> proline) in exon 4 was observed. Additionally, four intervening sequence (IVS) alterations were detected: IVS2-53t-->c in 3 cases; IVS4-17ins T in 3 cases; IVS5+32t-->c in 16 cases; and IVS5+33g-->a in 1 case. All appeared to be polymorphisms present in similar proportions in an average-risk population. We conclude that germline APC mutations do not account for familial MSS (stable microsatellite) CRC associated with few synchronous polyps.

Fecal occult blood testing for iron deficiency: a reappraisal.

Fecal occult blood (FOB) tests have been evaluated primarily for the application of colorectal cancer screening. Less is known about the performance characteristics of FOB tests for the evaluation of iron deficiency, the most common other application. As most clinically important occult gastrointestinal bleeding arises from the proximal gut, it is critical that FOB tests target analytes that are stable during the enteric transit. Available data indicate that guaiac-type and immunochemical tests are insensitive for the detection of proximal gut bleeding, and their use may confound the evaluation of iron deficiency. In contrast, the heme porphyrin test is sensitive for both proximal and distal sources of occult gastrointestinal bleeding, and this FOB test would appear to be the most rational selection for use in patients with iron deficiency or anemia. Outcome data are needed to better assess the impact of FOB testing on algorithms for evaluation of iron deficiency.

Association of Peutz-Jeghers-like mucocutaneous pigmentation with breast and gynecologic carcinomas in women.

Most reports describe an increased risk of malignancy in Peutz-Jeghers syndrome (PJS). We identified individuals with PJS-like pigmentation but no polyposis, designated as isolated mucocutaneous melanotic pigmentation (IMMP), and 1) characterized their clinical features, 2) assessed them for cancer events, and 3) screened a sample of these subjects for mutations in LKB1, a gene responsible for a portion of PJS cases. Review of Mayo Clinic records from 1945 to 1996 identified 26 patients with IMMP. All were then interviewed or their medical records reviewed to determine if cancer had developed. Conformation-sensitive gel electrophoresis (CSGE) screening for LKB1 mutations was followed by direct sequencing. Ten of these 26 individuals (38%) developed 12 malignancies that arose in the cervix (n = 3), endometrium (n = 3), breast (n = 1), kidney (n = 1), lung (n = 2), colon (n = 1), and lymphatic tissue (n = 1). In females with IMMP, the relative risk for cancer was 3.2 (95% CI, 1.2-6.9), while that for males was not increased. The relative risk for breast and gynecologic cancers was 7.8 (95% CI, 2.5-18.1) in affected females. Of 9 individuals tested, no LKB1 mutations were detected. Classical PJS is associated with an increased cancer risk. Our results indicate that IMMP is another lentiginosis with cancer predisposition. In particular, the relative risk for cancer in females with IMMP was significantly increased, as is true in females with PJS. However, LKB1 mutations did not contribute to the development of IMMP in the patients tested.

Colorectal cancer screening by detection of altered human DNA in stool: feasibility of a multitarget assay panel.

BACKGROUND & AIMS: Assay of altered DNA exfoliated into stool represents an intriguing approach to screen for colorectal neoplasia, but multiple markers must be targeted because of genetic heterogeneity. We explored the feasibility of a stool assay panel of selected DNA alterations in discriminating subjects with colorectal neoplasia from those without. METHODS: Freezer-archived stools were analyzed in blinded fashion from 22 patients with colorectal cancer, 11 with adenomas > or =1 cm, and 28 with endoscopically normal colons. After isolation of human DNA from stool by sequence-specific hybrid capture, assay targets included point mutations at any of 15 sites on K-ras, p53, and APC genes; Bat-26, a microsatellite instability marker; and highly amplifiable DNA. RESULTS: Analyzable human DNA was recovered from all stools. Sensitivity was 91% (95% confidence interval, 71%-99%) for cancer and 82% (48%-98%) for adenomas > or =1 cm with a specificity of 93% (76%-99%). Excluding K-ras from the panel, sensitivities for cancer were unchanged but decreased slightly for adenomas to 73% (39%-94%), while specificity increased to 100% (88%-100%). CONCLUSIONS: Assay of altered DNA holds promise as a stool screening approach for colorectal neoplasia. Larger clinical investigations are indicated.

Fecal calprotectin levels predict colorectal inflammation among patients with chronic diarrhea referred for colonoscopy.

OBJECTIVE: Chronic diarrhea is a relatively common condition with multiple diverse etiologies. Stool testing may serve as a diagnostic aid to discriminate the presence or absence of organic pathology, such as colorectal inflammation. Calprotectin (a leukocyte-derived protein) and hemoglobin can be measured quantitatively from stool and represent candidate inflammation biomarkers. The aim of this study was to assess and compare the screening performance of fecal calprotectin and fecal hemoglobin among colonoscopy referral patients with chronic diarrhea of unknown origin or chronic colitis of unknown activity. METHODS: All subjects were identified prospectively and each submitted a single stool sample before purgation. Fecal calprotectin (PhiCal; Nycomed Pharma, Oslo, Norway) and fecal hemoglobin (HemoQuant; Mayo Medical Laboratories, Rochester, MN) assays were performed in separate laboratories by masked technicians. Colonoscopic and histological findings served as criterion standards for establishing the presence or absence of colorectal inflammation. RESULTS: Among 110 subjects who provided complete fecal assay data, 29 (26%) had and 81 (74%) did not have colorectal inflammation. Increased fecal calprotectin levels were significantly (p = 0.0001) associated with the presence of colorectal inflammation, whereas fecal hemoglobin levels were not (p = 0.61). Direct comparison of the fecal assays revealed that calprotectin was a more sensitive biomarker for colorectal inflammation at all specificity levels (p = 0.0001). CONCLUSIONS: In this study of colonoscopy referral patients, colorectal inflammation was reflected by fecal calprotectin but not by fecal hemoglobin levels. Assay of fecal calprotectin holds promise as a triage tool to identify inflammatory causes of chronic diarrhea.

Optimization of CT colonography technique: prospective trial in 180 patients.

PURPOSE: To assess the added benefits of prone positioning in addition to supine positioning and oral iodinated contrast medium for help in the detection of colonic polyps at computed tomographic (CT) colonography. MATERIALS AND METHODS: CT colonography was performed in prone and supine positions in 180 patients with polyps or risk factors for colonic neoplasia. Patients were randomly assigned to receive a standard bowel preparation or a standard preparation plus oral iodinated contrast medium. One radiologist interpreted supine images alone, and another analyzed supine and prone images. All patients subsequently underwent colonoscopy. RESULTS: At colonoscopy, 121 large (> or =1-cm-diameter) polyps and 142 smaller (0.5-0.9-cm) polyps were identified. Prone positioning resulted in increased sensitivity for identification of patients with large (> or =1-cm) polyps (increase from 70% to 85%, P: =.004) and of patients with polyps 0.5 cm or larger (increase from 75% to 88%, P: <.005), with no change in specificity. Use of oral contrast medium did not significantly improve polyp detection even in the subset of patients in whom colonic fluid attenuation was markedly increased. CONCLUSION: Acquisition and review of supine and prone CT colonographic images significantly improves the ability to identify patients with polyps 0.5 cm in diameter or larger. Administration of oral iodinated contrast medium does not significantly improve polyp detection.

Immunodiscrimination of colorectal neoplasia using MUC1 antibodies: discrepant findings in tissue versus stool.

Colorectal tumor-associated antigens are attractive targets for novel stool-screening assays. MUC1, a glycoprotein antigen, is aberrantly expressed in transformed colorectal mucosa and represents a candidate fecal biomarker. In this study, tissue staining and stool testing were performed to further clarify the discriminant potential of MUC1 in markedly different biologic media. One anti-MUC1 monoclonal antibody (MA5) was used for immunohistochemistry and two commercially available MUC1 assay kits (ELSA-CA 15-3 and Truquant BR) were used for stool detection. On tissue staining, MUC1 expression was strong in 40/40 (100%) adenocarcinomas, moderate in 42/55 (76%) adenomas, faint in 8/28 (29%) juxtatumoral mucosa specimens, and absent in 15/15 (0%) nonadjacent mucosa specimens. Conversely MUC1 levels in stool testing did not differ between colorectal cancer cases (N = 14) and controls (N = 14). Based on these results, MUC1 appears to be a functional tumor biomarker in colorectal tissue but not in stool. Bacterial metabolism within stool may unmask the core antigen of MUC1 and account for this discordance in immunoreactivity.

Gastric mucosal responses to intrahepatic portosystemic shunting in patients with cirrhosis.

BACKGROUND & AIMS: The response of gastric mucosal lesions in cirrhotic patients with portal hypertension, namely, portal hypertensive gastropathy (PHG) and gastric vascular ectasia (GVE), to transjugular intrahepatic portosystemic shunts (TIPS) is not known. METHODS: Clinical and laboratory evaluation, upper gastrointestinal endoscopy, and Doppler ultrasonography were performed before placement of TIPS and 6 weeks, 3 months, and 6 months after TIPS in 54 patients. Thirty patients had mild PHG, 10 had severe PHG, and 14 had GVE. RESULTS: Approximately 75% of the patients with severe PHG responded to TIPS as shown by improvement in endoscopic findings and by a decrease in transfusion requirements; 89% of patients with mild PHG had endoscopic resolution. Patients with GVE had neither endoscopic resolution nor a decrease in transfusion requirements after TIPS. There was no difference in mortality between the 2 groups. CONCLUSIONS: The results support the position that severe PHG and GVE may be different lesions. Mild and severe PHG respond to TIPS. Because GVE does not respond to TIPS, we recommend that TIPS be avoided for the treatment of gastrointestinal bleeding associated with GVE.

Morphometric analysis of the "mucocellular layer" overlying colorectal cancer and normal mucosa: relevance to exfoliation and stool screening.

Characterization of shed cell elements entrapped within the colorectal surface mucus would be valuable to the study of exfoliation and candidate stool screening markers. Yet, surprisingly little is known about the cellular composition of this "mucocellular layer" (MCL). Our aim was to describe and compare the histomorphometry of the MCL that overlies colorectal cancer (CRC) and normal mucosa. From tissue archives, 20 resected CRC specimens yielding perpendicular cuts of both tumor surface and adjacent normal mucosa were consecutively selected. MCL thickness and cell number were determined in triplicate using an ocular micrometer. Cellular elements within the MCL were characterized on paraffin sections by immunohistochemistry. Mean cell density was much greater in the MCL over CRC (2,639 +/- 2,178 per mm2) than over normal mucosa (184 +/- 395 per mm2), p < .001. Robust-appearing colonocytes and inflammatory cells predominated in the hypercellular MCL of CRC; the former retained expression of tumor-associated antigens. In contrast, the sparsely scattered cells within the normal MCL were typically apoptotic and of indeterminate lineage. Based on direct observations from this first descriptive study of the colorectal MCL, luminal shedding appears to be much greater from CRC than from normal mucosa.

Care of patients and their families with familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is a dominantly inherited disorder that is typically characterized by the appearance of multiple colorectal adenomas usually by the teenage years, with a risk of early colorectal cancer approaching 100%. Genetic testing can help determine which family members have the disorder and require surveillance endoscopy. Astute physicians may detect unsuspected FAP in patients with extraintestinal manifestations such as hard or soft cutaneous tumors. Colectomy will prevent cancer but is often necessary before the patient is 20 years old. Postoperative lifelong surveillance is indicated to screen for associated duodenal, thyroid, and rectal or ileal neoplasms. Attenuated FAP variants are less typical and may be confused with other types of familial colorectal neoplasia. Chemoprevention, regression, and other treatment strategies are being developed to improve the management of extracolonic neoplasms and desmoid tumors. A better understanding of the natural history of these FAP-associated phenomena will facilitate the rational selection of interventions. Management guidelines that were recently developed at Mayo Clinic Rochester to provide for uniform care and surveillance are discussed.

Colorectal cancer screening: a community case-control study of proctosigmoidoscopy, barium enema radiography, and fecal occult blood test efficacy.

OBJECTIVE: To examine the effectiveness of screening proctosigmoidoscopy, barium enema radiography, and the fecal occult blood test (FOBT) in decreasing colorectal cancer mortality in a community setting. PATIENTS AND METHODS: In this population-based case-control study, cases comprised 218 Rochester, Minn, residents who died of colorectal cancer between 1970 and 1993. Controls were 435 age- and sex-matched residents who did not have a diagnosis of colorectal cancer. Screening proctosigmoidoscopy, barium enema radiography, and FOBT results were documented for the 10 years prior to and including the date of diagnosis of fatal colorectal cancer in cases and for the same period in matched controls. History of general medical examinations and hospitalizations was also recorded. RESULTS: Within the 10 years prior to diagnosis, the percentages of cases vs controls with at least 1 screening proctosigmoidoscopy were 23 (10.6%) of 218 cases vs 43 (9.9%) of 435 controls; at least 1 screening barium enema radiographic study was done in 12 (5.5%) of 218 vs 25 (5.7%) of 435. Within 3 years prior to diagnosis, the percentages of cases vs controls with at least 1 screening FOBT were 27 (12.4%) of 218 vs 44 (10.1%) of 435. Adjusted odds ratios were 1.04 (95% confidence interval [CI], 0.21-5.13) for proctosigmoidoscopy (distal rectosigmoid cancers only), 0.67 (95% CI, 0.31-1.48) for barium enema radiography, and 0.83 (95% CI, 0.45-1.52) for FOBT over the above time periods. CONCLUSION: In this case-control study within a community setting, a colorectal cancer-specific mortality benefit could not be demonstrated for screening by FOBT, proctosigmoidoscopy, or barium enema radiography. Screening frequency was low, which may have contributed to the lack of measurable effects.

Familial predisposition for colorectal cancer in chronic ulcerative colitis: a case-control study.

BACKGROUND & AIMS: Familial predisposition as a risk for colorectal cancer in ulcerative colitis has not been rigorously explored. The aim of this study was to compare colorectal cancer frequency among kindreds of patients who had ulcerative colitis and colorectal cancer with that of control patients who had ulcerative colitis but no cancer. METHODS: Questionnaires were mailed to subjects to assess cancer occurrence among relatives. Eligible cases included 174 ulcerative colitis patients with colorectal cancer seen at Mayo Clinic in 1976-1994; 174 contemporaneous ulcerative colitis controls without cancer were matched on birth year, sex, and extent and duration of colitis. RESULTS: The responding 147 case and 150 control subjects reported on 1044 and 1090 first-degree relatives, respectively. Colorectal cancer occurred in 14.3% case kindreds and 6.7% control kindreds (P = 0.03). By logistic regression, a family history of sporadic colorectal cancer was an independent risk factor for cancer in ulcerative colitis (odds ratio, 2.33; 95% confidence interval, 1.06-5.14; P = 0.03). CONCLUSIONS: A familial association exists between colorectal cancers occurring with ulcerative colitis and those in the general population. Colorectal cancer in persons with ulcerative colitis represents a risk factor for colorectal cancer in their noncolitic relatives. Likewise, a family history of sporadic colorectal cancer increases the risk of colorectal cancer with ulcerative colitis.