Prevalence of celiac disease in cirrhosis and outcome of cirrhosis on a gluten free diet: a prospective study.

BACKGROUND & AIMS: Current consensus suggests CD to be a multi-systemic disease that could affect any organ system including the liver. It remains under-diagnosed in the US and its prevalence and management in cirrhotic patients has not been studied. Our aim was (1) to estimate the prevalence of CD in cirrhosis, (2) to characterize cirrhotic patients with abnormal celiac serology and normal small bowel biopsy and (3) to evaluate the effect of a GFD on the liver. METHODS: A total of 204 consecutive patients with biopsy proven cirrhosis scheduled for an upper endoscopy (EGD) to assess and treat gastro-esophageal varices (GEV) at the Cleveland Clinic between 5/1/2008 and 5/30/2010 were enrolled in the study and followed for 2 years. RESULTS: CD affects 2.5% of cirrhotic patients and more than twice the prevalence in the general population. Abnormal EMA >1/10 and high hTTG levels >20 IU can be used to diagnose CD in cirrhosis. Sensitivities and specificities are 100% for EMA and 80% and 94% for hTTG, respectively. After a GFD, patients with CD showed a return to normal levels of their celiac serology, small bowel biopsy and liver enzyme abnormalities. CONCLUSIONS: CD is at least twice more common in cirrhotic patients than in the general population and GFD improves liver tests. CD can occur coincidentally with other liver disorders and screening may be warranted during the evaluation of patients with cirrhosis. Abnormal EMA and high hTTG levels can be used to diagnose CD in cirrhosis.

Endoscopic and histologic abnormalities of gastrointestinal tract in patients with hereditary hemochromatosis.

BACKGROUND: Patients with iron overload frequently complained of upper gastrointestinal (GI) symptoms. This study aimed to systemically evaluate the association between hereditary hemochromatosis (HH) and gut inflammation. PATIENTS AND METHODS: HH patients were identified using the ICD-9 codes. Inclusion criteria were patients with primary HH who had esophagogastroduodenoscopy (EGD) and/or colonoscopy with GI biopsies (N=39). Patients undergoing EGD with duodenal biopsy for the indication of "rule out celiac disease" were included in the control group (N=40). GI biopsy specimens were rereviewed and scored. RESULTS: Of the 39 patients with genetically confirmed primary HH in the study group, 28 (71.8%) had liver biopsy and 25 (89.3%) of them showed iron deposition. Twenty-five patients (64.1%) had EGD and 23 (59.0%) had colonoscopy. Histologic inflammation was identified in the esophagus in 2 patients (8.0%), stomach in 11 (44.0%), duodenum in 2 (8.7%), and colon in 3 (13.0%). Duodenal biopsy specimen was available for rereview in 16 patients (41.0%). Patient demographics were comparable between the 16 cases in the study group and the 40 cases in the control group. On histology, the frequency of intraepithelial lymphocytosis of small intestine was 25.5% in the HH cases versus 2.5% in controls (P=0.020). HH patients also had a greater proportion of intraepithelial neutrophil infiltration (31.2% vs. 2.5%, P=0.006) and lamina propria lymphocyte infiltration (31.2% vs. 0%, P=0.001) than controls. CONCLUSIONS: GI inflammation was common in HH patients, which from the different perspective, supports the notion that iron overload may lead to GI inflammation.

Gene expression profiling of serrated polyps identifies annexin A10 as a marker of a sessile serrated adenoma/polyp.

Sessile serrated adenomas/polyps (SSA/Ps) are precursors of colon cancer, particularly those that exhibit microsatellite instability. Distinguishing SSA/Ps from the related, but innocuous, microvesicular hyperplastic polyp (MVHP) can be challenging. In this study seven gastrointestinal pathologists reviewed 109 serrated polyps and identified 60 polyps with histological consensus. Microarray analysis was performed on six distal consensus MVHPs < 9 mm, six proximal consensus SSA/Ps > 9 mm, and six normal colon biopsies (three proximal, three distal). Comparative gene expression analysis confirmed the close relationship between SSA/Ps and MVHPs as there was overlapping expression of many genes. However, the gene expression profile in SSA/Ps had stronger and more numerous associations with cancer-related genes compared with MVHPs. Three genes (TFF2, FABP6, and ANXA10) were identified as candidates whose expression can differentiate SSA/Ps from MVHPs, and the differences in expression were confirmed by quantitative RT-PCR. As ANXA10 showed the most promise in differentiating these polyps, the expression of ANXA10 was evaluated by immunohistochemistry in consensus SSA/Ps (n = 26), MVHPs (n = 21), and normal colon (n = 9). Immunohistochemical expression of ANXA10 was not identified in separate samples of normal colon or in the normal colonic epithelium adjacent to the serrated polyps. Consistent with the microarray and quantitative RT-PCR experiments, immunohistochemical expression of ANXA10 was markedly increased in SSA/Ps compared to MVHPs (p < 0.0001). An ANXA10 score ≥ 3 has a sensitivity of 73% and a specificity of 95% in the diagnosis of an SSA/P. In conclusion, we show that SSA/Ps and MVHPs have significant overlap in gene expression, but also important differences, particularly in cancer-related pathways. Expression of ANXA10 may be a potential marker of the serrated pathway to colon cancer.

Backwash ileitis and the risk of colon neoplasia in ulcerative colitis patients undergoing restorative proctocolectomy.

BACKGROUND: The significance of backwash ileitis (BWI) relating to the risk of colon neoplasia in ulcerative colitis (UC) patients is controversial. AIM: We investigated the association between BWI and the presence of colon neoplasia in the colectomy specimen. METHODS: From 4,198 UC patients in a prospectively maintained pouch database from 1983 to 2011, patients with extensive colitis and BWI (n = 178) in proctocolectomy were compared with 537 controls [extensive colitis (n = 385) and left-sided colitis (n = 152)] without ileal inflammation. RESULTS: Colon neoplasia (colon dysplasia and/or colon cancer) was seen in 32 (18 %) patients with BWI in contrast to 45 (11.7 %) with extensive colitis and 13 (8.6 %) with left-sided colitis alone (p = 0.03). Of those with BWI, colon cancer was seen in 10 patients (5.6 %), while low grade and high grade dysplasia were seen in 7 (3.9 %) and 15 (8.4 %) patients respectively. On multivariate analysis, the presence of BWI with extensive colitis [odds ratio (OR) = 3.53; 95 % confidence interval (CI) 1.01-12.30, p = 0.04], presence of primary sclerosing cholangitis (PSC) (OR = 5.79, 95 % CI 1.92-17.40, p = 0.002) and moderate to severe disease activity at UC diagnosis (OR 4.29, 95 % CI 2.06-9.01, p < 0.001) were associated with an increased risk for identifying any colon neoplasia. For colon cancer, the presence of PSC (OR = 11.30, 95 % CI 1.54-80.9, p = 0.01) was the only factor independently associated with an increased risk. CONCLUSIONS: The presence of BWI with extensive colitis was associated with the risk of identifying colon neoplasia but not cancer alone in the proctocolectomy specimen.

Radiofrequency ablation in Barrett's esophagus with dysplasia.

BACKGROUND: Barrett's esophagus, a condition of intestinal metaplasia of the esophagus, is associated with an increased risk of esophageal adenocarcinoma. We assessed whether endoscopic radiofrequency ablation could eradicate dysplastic Barrett's esophagus and decrease the rate of neoplastic progression. METHODS: In a multicenter, sham-controlled trial, we randomly assigned 127 patients with dysplastic Barrett's esophagus in a 2:1 ratio to receive either radiofrequency ablation (ablation group) or a sham procedure (control group). Randomization was stratified according to the grade of dysplasia and the length of Barrett's esophagus. Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia. RESULTS: In the intention-to-treat analyses, among patients with low-grade dysplasia, complete eradication of dysplasia occurred in 90.5% of those in the ablation group, as compared with 22.7% of those in the control group (P<0.001). Among patients with high-grade dysplasia, complete eradication occurred in 81.0% of those in the ablation group, as compared with 19.0% of those in the control group (P<0.001). Overall, 77.4% of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3% of those in the control group (P<0.001). Patients in the ablation group had less disease progression (3.6% vs. 16.3%, P=0.03) and fewer cancers (1.2% vs. 9.3%, P=0.045). Patients reported having more chest pain after the ablation procedure than after the sham procedure. In the ablation group, one patient had upper gastrointestinal hemorrhage, and five patients (6.0%) had esophageal stricture. CONCLUSIONS: In patients with dysplastic Barrett's esophagus, radiofrequency ablation was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression. (ClinicalTrials.gov number, NCT00282672.)

Durability of radiofrequency ablation in Barrett's esophagus with dysplasia.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett's esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE. METHODS: We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events. RESULTS: After 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1 per 181 patient-years (0.55%/patient-years); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1 per 73 patient-years (1.37%/patient-years). CONCLUSIONS: In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.

Diagnosis and management of dysplasia and cancer of the ileal pouch in patients with underlying inflammatory bowel disease.

Approximately 30% of the patients with ulcerative colitis (UC) would ultimately require colectomy for medically refractory UC or UC-associated neoplasia. Restorative proctocolectomy with ileal pouch-anal anastomosis has become the surgical treatment of choice for these patients. However, this procedure does not completely abolish the risk for neoplasia of the pouch. The main risk factor for pouch neoplasia is a preoperative diagnosis of UC-associated dysplasia or cancer. Although the natural history and prognosis of pouch dysplasia are not clear, mortality associated with pouch cancer, once diagnosed, appears to be high. Conversely, not all pouch neoplasia follows the chronic inflammation-dysplasia-cancer sequence, which makes pouch endoscopy with biopsy, the current gold standard for surveillance, challenging. In addition, the findings that pouch neoplasia is not common and that pouch endoscopy still misses dysplasia lead to controversy on the need and time interval of routine endoscopic surveillance. However, based on reports in the literature and their own experience, the authors recommend surveillance endoscopy to be performed in patients at risk, such as those with a precolectomy diagnosis of UC-associated neoplasia. This review appraises issues in the prevalence and incidence, risk factors, technical aspects of pouch construction, clinical and pathological features, natural history, surveillance examination, diagnosis, and management of pouch neoplasia.

Preoperative colorectal neoplasia increases risk for pouch neoplasia in patients with restorative proctocolectomy.

BACKGROUND & AIMS: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has substantially reduced the risk for ulcerative colitis (UC)-associated dysplasia or cancer (neoplasia). We characterized features, risk factors, and outcomes of pouch neoplasia in patients with inflammatory bowel disease in a historical cohort study. METHODS: A total of 3203 patients with a preoperative diagnosis of inflammatory bowel disease underwent restorative proctocolectomy with IPAA from 1984 to 2009 at the Cleveland Clinic. Demographic, clinical, and endoscopic data were reviewed and samples were examined by histological analyses. Univariable and Cox regression analyses were performed. RESULTS: Cumulative incidences for pouch neoplasia at 5, 10, 15, 20, and 25 years were 0.9%, 1.3%, 1.9%, 4.2%, and 5.1%, respectively. Thirty-eight patients (1.19%) had pouch neoplasia, including 11 (0.36%) with adenocarcinoma of the pouch and/or the anal-transitional zone (ATZ), 1 (0.03%) with pouch lymphoma, 3 with squamous cell cancer of the ATZ, and 23 with dysplasia (0.72%). In the Cox model, the risk factor associated with pouch neoplasia was a preoperative diagnosis of UC-associated cancer or dysplasia, with adjusted hazard ratios of 13.43 (95% confidence interval: 3.96-45.53; P < .001) and 3.62 (95% confidence interval: 1.59-8.23; P = .002), respectively. Mucosectomy did not protect against pouch neoplasia. CONCLUSIONS: Risk for neoplasia in patients with UC and IPAA is small and not eliminated by colectomy or mucosectomy. A preoperative diagnosis of dysplasia or cancer of colon or rectum is a risk factor for pouch dysplasia or adenocarcinoma.

Grading of gastric foveolar-type dysplasia in Barrett's esophagus.

Dysplasia is the gold standard biomarker of cancer risk in Barrett's esophagus, but its diagnosis remains difficult. This is due in part to its multitude of histological appearances. One aspect receiving little attention concerns gastric-type Barrett's dysplasia, which is distinctly different from the well-established intestinal variant. Recognition of gastric-type dysplasia and development of separate grading criteria are required. The prevalence, diagnostic criteria, and natural history of gastric-type Barrett's dysplasia were systematically evaluated in 1854 endoscopic biopsies from a cohort of 200 consecutive Barrett's dysplasia patients. Goblet cells were present in all cases, confirming the utility of this defining feature of Barrett's esophagus. The prevalence of Barrett's gastric-type dysplasia was 15% at the patient level (30 of 200 patients) and 20% at the biopsy level (166 of 852 dysplastic biopsies). Gastric-type dysplasia uniformly showed non-stratified, basally oriented nuclei as the major criterion for distinguishing it from intestinal-type Barrett's dysplasia. As such, loss of nuclear polarity, as the most objective criterion to distinguish intestinal-type low- and high-grade dysplasia, cannot be applied to gastric-type dysplasia. Rather, discriminatory features included increased nuclear size with a high-grade dysplasia cutoff by receiver operating characteristic (ROC) analysis approximating 3-4 times the size of a mature lymphocyte, providing an optimal sensitivity, specificity, and area under the curve of 0.78, 0.90, and 0.90 (95% CI: (0.87, 0.93)), respectively. Crowded, irregular glandular architecture (P<0.001) was more common in high-grade lesions (P<0.001), as was eosinophilic and oncocytic cytoplasm relative to the mucinous cytoplasm (P<0.001), prominent nucleoli (P<0.001), mild nuclear pleomorphism (P<0.001), and villiform architecture (P<0.001). During follow-up, 64% (7 of 11) of patients with pure gastric and 26% (5 of 19) with mixed gastric and intestinal dysplasia underwent neoplastic progression. The recognition of Barrett's gastric-type dysplasia and use of the proposed grading criteria should promote better diagnostic classification of the Barrett's neoplastic spectrum.

The efficacy and tolerability of AST-120 (spherical carbon adsorbent) in active pouchitis.

OBJECTIVES: Although a majority of patients with pouchitis respond favorably to antibiotic therapy, many relapse frequently, and nonabsorbable and non-antibiotic-based agents are desirable for reducing bacterial resistance and the systemic adverse effects associated with long-term antibiotic exposure. AST-120 (a spherical carbon adsorbent) comprises highly adsorptive, porous carbon microspheres with the ability to adsorb small-molecular-weight toxins, inflammatory mediators,and harmful bile acids. The aim of this pilot trial was to evaluate the efficacy and tolerability of AST-120 in the treatment of active pouchitis. METHODS: Eligible patients were recruited from two subspecialty pouchitis clinics. Inclusion criteria were(i) ileal pouch-anal anastomosis performed for ulcerative colitis; (ii) active pouchitis with Pouchitis Disease Activity Index (PDAI) scores > or =7; and (iii) discontinuation of antibiotic therapy for at least 2 weeks. Exclusion criteria included Crohn's disease of the pouch, isolated cuffitis, pouch strictures, abscess, and sinuses. All eligible patients received AST-120 in 2-g sachets (oral) open label, thrice a day for 4 weeks. The primary efficacy end point was remission as defined by a PDAI score of < 7 points; the main secondary end point was clinical response, defined by a reduction of the PDAI score of > or =3 points. RESULTS: Nineteen of 20 patients completed the trial. Eleven patients (55.0 % ) had a clinical response to the therapy and 10 patients (50.0 % ) entered remission. Median reduction in the PDAI symptom, endoscopy, and histology subscores, and PDAI total scores after 4 weeks were -2( P = 0.002), -2 ( P = 0.003), 0 ( P = 0.32), and -4 ( P = 0.001) points, respectively. The agent was well tolerated; one patient experienced transient mild elevation of alkaline phosphatase of uncertain significance and one patient experienced an upper respiratory infection after taking one dose of AST-120 and was excluded from the fi nal analysis for the calculation of pre- and post-trial PDAI scores. CONCLUSIONS: AST-120 seems to be effective and well tolerated in treating patients with active pouchitis.A randomized, placebo-controlled trial is warranted for assessing the long-term efficacy and safety of AST-120 in the disease.

Risk factors for low bone mass in patients with ulcerative colitis following ileal pouch-anal anastomosis.

OBJECTIVES: Bone mineral density (BMD) can be adversely affected by the chronic nature of inflammatory bowel disease. Ileal pouch-anal anastomosis (IPAA) is the surgical treatment of choice for patients with ulcerative colitis (UC) who require proctocolectomy. There are few data on BMD in UC patients with IPAA. The aim of the study was to assess the prevalence and risk factors associated with low BMD in UC patients after IPAA. METHODS: A total of 327 eligible patients with UC and IPAA from the Pouchitis Clinic were enrolled. Dual-energy X-ray absorptiometry was performed. Patients were classified as having normal or low BMD, based on the criteria by the International Society for Clinical Densitometry. A total of 39 demographic and clinical variables were evaluated with logistic regression models. RESULTS: Of 327 patients with a median of 4 years after IPAA, 105 (32.1%) had low BMD. Fragility fracture was documented in 11 patients (10.5%) in the low BMD group and in 13 of 222 patients (5.9%) in the normal BMD group (P=0.14). In the multivariable analysis, covariate-adjusted factors associated with a low BMD were advanced age (odds ratio (OR) =1.64 per 5 years; 95% CI, 1.44-1.87), low body mass index (OR=0.43 per 5 kg/m(2); 95% CI, 0.30-0.62), and non-use of daily calcium supplement (OR=0.53; 95% CI, 0.29-0.96). Pouch-associated factors were not found to be significantly associated with the bone loss. CONCLUSIONS: Low BMD was common in patients with UC, even after colectomy and IPAA. Low BMD in this patient population was associated with certain risk factors, some of which may be modifiable.

Association between immune-associated disorders and adverse outcomes of ileal pouch-anal anastomosis.

OBJECTIVES: Autoimmune disorders (ADs) frequently coexist with inflammatory bowel disease. The aim of the study was to determine whether coexisting AD in patients with ileal pouches increases the risk for chronic antibiotic-refractory pouchitis (CARP) and other inflammatory conditions of the pouch. METHODS: A total of 622 patients seen in our Pouchitis Clinic were enrolled. We compared the prevalence of adverse outcomes of the pouch (including CARP, Crohn's disease of the pouch, and pouch failure) in patients with or without concurrent AD and assessed the factors for these adverse outcomes. RESULTS: There were seven pouch disease categories: normal (N=60), irritable pouch syndrome (N=112), active pouchitis (N=131), CARP (N=67), Crohn's disease (N=131), cuffitis (N=83), surgical complications (N=36), and anismus (N=2). The prevalence of AD in these pouch disease categories was 4.5%, 12.5%, 9.2%, 13.4%, 10.7%, 3.8%, 1.5%, and 0%, respectively. The presence of at least one AD at time of pouch surgery was shown to be associated with a twofold increase in the risk for CARP (hazard ratio=2.29; 95% CI: 1.52, 3.46; P<0.001) and for pouch-associated hospitalization (hazard ratio=2.39; 95% CI: 1.59, 3.58; P<0.001). The presence of AD was not associated with increased risk for irritable pouch syndrome, active pouchitis, Crohn's disease, cuffitis, surgical complications, or pouch failure. Patients with Crohn's disease of the pouch had a 2.42 times higher risk for pouch failure (P=0.042) than these without. Active smoking or a history of smoking was shown to be associated with an increased risk for pouch-associated hospitalization and pouch failure. CONCLUSIONS: AD appears to be associated with an increased risk for CARP, and the presence of the association between these AD and pouch disorders may stimulate further research on the link of these organ systems on an immunological basis.

Fundic gland polyp dysplasia is common in familial adenomatous polyposis.

BACKGROUND & AIMS: Fundic gland polyps (FGPs) are common in familial adenomatous polyposis (FAP) but have been considered nonneoplastic. Gastric carcinoma arises from FGPs in FAP presumably from a dysplasia-carcinoma pathway. Our study examined the prevalence of FGPs and FGP dysplasia in FAP and identified endoscopic or demographic features associated with FGPs and dysplasia. METHODS: Demographic and endoscopic information were obtained prospectively from 75 consecutive subjects undergoing upper-endoscopic surveillance for FAP. Systematic biopsy specimens of FGPs, normal-appearing fundic mucosa, and antral mucosa for Helicobacter pylori were obtained. Multivariable analysis assessed the association of demographic or endoscopic factors with the presence of FGP or FGP dysplasia. RESULTS: FGPs were detected in 88% of subjects and were dysplastic in 41% (38% low grade, 3% high grade). H pylori infection was rare in subjects with vs without FGPs (1.5% vs 33.3%, P = .005). In the multivariable analysis larger FGP size (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.1-14.4), higher stage of duodenal polyposis (OR, 2.3; 95% CI, 1.2-4.5), and antral gastritis (OR, 11.2; 95% CI, 1.2-103.9) were associated with FGP dysplasia. Exposure to acid-suppressive medications was associated with a marked decrease in dysplastic FGPs (OR, 0.14; 95% CI, 0.03-0.64). CONCLUSIONS: The majority of FAP patients have FGPs and nearly half will have dysplastic FGPs. There is an inverse relationship between H pylori and FGPs. FGP dysplasia is associated with larger polyp size, increased severity of duodenal polyposis, and antral gastritis. Acid-suppressive therapy use appears protective against dysplasia in FGPs.

Clostridium difficile infection in patients with ileal pouch-anal anastomosis.

BACKGROUND & AIMS: There has been an increase in the incidence and severity of Clostridium difficile-associated diarrhea in the U.S. The importance of C difficile infection in patients with ileal pouch-anal anastomosis (IPAA) is unknown. This study was designed to determine risk of acquiring C difficile infection in pouch disorders. METHODS: Consecutive ulcerative colitis patients (n = 115) with IPAA undergoing pouch endoscopy were enrolled from May 2005-March 2006. Fecal specimens of pouch aspirate were collected during pouch endoscopy and analyzed for C difficile toxin A and B by enzyme-linked immunosorbent assay. Nineteen clinical, endoscopic, and histologic variables were assessed with stepwise selection methods. Two multivariate logistic regression models were constructed. RESULTS: Twenty-one patients (18.3%) were positive for C difficile infection. Adjusting for other factors in the model, men were 5.12 (95% confidence interval, 1.38-20.46) times more likely to have C difficile infection than women. Compared with patients with pancolitis, those with preoperative left-sided colitis were 8.4 (95% confidence interval, 1.25-56.4) times more likely to have C difficile infection. Six of 6 patients with C difficile infection (3 with refractory pouchitis, 2 with Crohn's disease, and 1 with irritable pouch syndrome) with repeat clinical, endoscopic, and laboratory evaluation after anti-C difficile therapy experienced clinical remission and disappearance of C difficile toxin from stools, with 4 showing decreased mucosal inflammation. CONCLUSIONS: C difficile infection involving IPAA is common, characteristically occurring with or without previous receipt of antibiotics. Treatment of C difficile infection in patients with IPAA might improve the clinical outcome.

Poor interobserver agreement in the distinction of high-grade dysplasia and adenocarcinoma in pretreatment Barrett's esophagus biopsies.

OBJECTIVE: Grading Barrett's dysplasia at the lower end of the metaplasia-dysplasia spectrum (negative, indefinite, and low-grade dysplasia) suffers from poor interobserver agreement, even among gastrointestinal pathologists. Data evaluating interobserver agreement in Barrett's mucosal biopsies with changes at the upper end of the dysplasia spectrum (high-grade dysplasia, intramucosal, and submucosal adenocarcinoma) have not been published. The accurate categorization of pretreatment biopsies drives therapeutic decision making, but if the diagnostic distinction between cancer and high-grade dysplasia in Barrett's biopsies is inconsistent, then the use of these diagnoses to make management decisions is suspect. To this end, our aim was to assess interobserver reproducibility among a group of gastrointestinal pathologists in the interpretation of preresection biopsies. METHODS: All study pathologists agreed upon the histologic criteria distinguishing four diagnostic categories, including high-grade dysplasia; high-grade dysplasia with marked distortion of glandular architecture, cannot exclude intramucosal adenocarcinoma; intramucosal adenocarcinoma; and submucosally invasive adenocarcinoma. The histologic criteria were used to independently review preresection biopsies from 163 consecutive Barrett's esophagus patients with at least high-grade dysplasia who ultimately underwent esophagectomy. Reviewers recorded the specific histologic criteria used to categorize each case and Kappa statistics were calculated to assess interobserver agreement. RESULTS: Using kappa statistics, the overall agreement was only fair (kappa= 0.30). Agreement for high-grade dysplasia was moderate (kappa= 0.47), while agreement for high-grade dysplasia with marked architectural distortion, cannot exclude intramucosal adenocarcinoma and intramucosal adenocarcinoma were only fair (kappa= 0.21 and 0.30, respectively) and agreement for submucosal adenocarcinoma was poor (kappa= 0.14). CONCLUSIONS: The overall poor interobserver reproducibility among gastrointestinal pathologists who see a high volume of Barrett's cases calls into question treatment regimens based on the assumption that high-grade dysplasia, intramucosal adenocarcinoma, and submucosal adenocarcinoma can reliably be distinguished in biopsy specimens.

Long-Term Outcomes in Indeterminate Colitis Patients Undergoing Ileal Pouch-Anal Anastomosis: Function, Quality of Life, and Complications.

INTRODUCTION: It is uncertain whether the outcomes of patients with indeterminate colitis (IC) undergoing ileal pouch-anal anastomosis (IPAA) deteriorate over time. The aim of this study was to determine the long-term pouch function, quality of life, complications, and incidence of Crohn's disease after IPAA for patients with IC compared to ulcerative colitis (UC). METHODS: A case matched analysis was performed on patients undergoing IPAA for pathologically confirmed IC or UC, between 1985 and 2014. Patients were case matched for age ± 5 years, gender, date of surgery ± 3 years, type of anastomosis and presence of a diverting loop ileostomy. All patients were followed up for greater than six months. RESULTS: 448 patients were case matched, the average age was 36.8 year old and 52.7 % of patients were male. Mean follow-up was 122.06 months (+/- 80.77 months). There were statistically and clinically comparable number of daytime bowel movements (5.7 v 5.5, p = 0.45), rates of incontinence (26.1 % v 18.3 %, p = 0.09) and nighttime seepage in patients (23.1 % v 28.4 %, p = 0.28) with IC and UC. Quality of life markers and patient restrictions were comparable between the two groups. Rates of pelvic sepsis (IC 8.5 %, UC 8.5 %, p = 0.99) and anastomotic leak (IC 3.1 %, UC 4.0 %, p = 0.61) were similar but fistula formation (IC 15.6 %, UC 8.0 %, p = 0.01) and IPAA Crohn's disease rates (IC 6.7 %, UC 2.7 %, p = 0.04) were significantly increased in IC patients. There was no statistically significant difference in pouch failure rates for IC and UC (5.8 % vs.4.9 %, p = 0.58). CONCLUSION: Patients undergoing IPAA for IC have a higher risk of post-operative fistulae and development of Crohn's disease, but comparable morbidity, functional outcomes, quality of life scores and pouch failure rates when compared to UC patients. Long-term data confirms that IPAA is a good surgical option in patients with IC.

Analytical performance of a formalin-fixed paraffin-embedded tissue-based 634-probe prognostic assay for predicting outcome of patients with stage II colon cancer.

A formalin-fixed paraffin-embedded tissue-based prognostic assay to assess the risk for recurrence in stage II colon cancer has recently been clinically validated. This study describes the analytical performance and quality control measures of the assay. The reportable range was determined to be [-1.129, 1.414] in risk score units. The accuracy was evaluated with a split sample comparison within the production lab and between the production lab and a reference lab. The concordance between the replicates within the production lab was 79% (95% confidence interval, 64%-91%). There was no evidence of bias, and the concordance was 78% (95% confidence interval, 61%-90%) between the labs. The lab-to-lab concordance was further evaluated by simulating risk scores from the full reportable range. The simulation suggested a higher concordance. The sensitivity study demonstrated that the percentage of tumor tissue did not impact the risk score and that RNA concentration of 9.5 ng/µL was a conservative determination of the analyte lower limit of quantification. From the precision study, the repeatability and reproducibility estimates were 0.1267 and 0.0548 in risk score units, respectively. Furthermore, multifaceted quality control measures were implemented, such as proper tissue processing steps, high-risk and low-risk controls, nontemplate control, and a gene expression-based classifier to evaluate the cDNA amplification kit, a key reagent in the assay. In conclusion, this study demonstrates the strong analytical performance of the assay and further supports its use as an objective standardized prognostic test for stage II colon cancer.

Serrated lesions of the appendix frequently harbor KRAS mutations and not BRAF mutations indicating a distinctly different serrated neoplastic pathway in the appendix.

Appendiceal serrated polyps often morphologically resemble their colorectal counterparts and most pathologists employ colorectal diagnostic terminology when evaluating appendiceal serrated lesions. We analyzed 132 appendiceal lesions for mutations in the RAS/RAF/MAPK pathway in an attempt to (1) determine the frequency of these mutations in appendiceal serrated lesions and (2) correlate the histopathologic features with molecular alterations. The study group of appendiceal serrated lesions (n = 46) was divided into a non-dysplastic group (28/46, subclassified as 7 hyperplastic polyps and 21 sessile serrated adenoma/polyps (SSA/P) using colorectal diagnostic terminology) and dysplastic group (18/46, subclassified as 9 SSA/Ps with cytological dysplasia, 7 traditional serrated adenomas, and 2 adenomas with prominent serrations). Appendiceal non-serrated dysplastic lesions (n = 86) comprised the control group. Of the 123 lesions analyzed, KRAS mutations were identified in 64 (52%) appendiceal lesions. No significant difference in the presence of KRAS mutations were identified between serrated non-dysplastic lesions (13/25, 52%), serrated dysplastic lesions (7/14, 50%) and the control group of non-serrated dysplastic lesions (44/84, 52%) (P = 1.0). Importantly, KRAS mutations were identified in lesions that were histologically identical to colorectal hyperplastic polyps (2/6, 33%), SSA/Ps (11/19, 58%), and SSA/Ps with cytological dysplasia (4/7, 57%). Of the 126 lesions tested, BRAF V600E mutations were identified in only 5 (4%) appendiceal lesions. Our results indicate that serrated lesions of the appendix often harbor KRAS mutations rather than BRAF mutations and suggest that the serrated pathway in the appendix is likely different than in the colon and rectum.

De novo inflammatory bowel disease and its mimics after organ transplantation.

Diarrhea is a common symptom after solid organ transplantation or hematopoietic stem cell transplantation, with a reported prevalence up to 72%. One of the uncommon causes for diarrhea in the posttransplant setting is development of de novo inflammatory bowel disease (IBD). The incidence of posttransplantation de novo IBD was shown to be higher than that in the general population (206 versus 20 per 100,000 cases annually). The frequency seems to be much higher following orthotopic liver transplantation than the transplantation of other solid organs. De novo IBD has also been described in the setting of bone marrow transplantation though not as commonly as after SOT. While IBD is considered an immune-mediated disorder and responds favorably to immunosuppressive, de novo IBD or IBD-like conditions can occur in the posttransplant period despite antirejection immunosuppressive therapy. Damage or pathogen-associated molecular pattern molecules and their associated ongoing inflammation within the transplanted organ and the recipients' intestine have been implicated as possible etiologies. Various viral, bacterial, and protozoal infections can mimic IBD in postorgan transplantation. Common IBD mimickers in the postbone marrow transplant setting are graft-versus-host disease, infectious enteritis/colitis, and less commonly "cord colitis" that is described in detail below. In this article, we discuss the epidemiology, clinical features, and outcomes of de novo IBD after transplantation and highlight their differences in presentation, diagnosis, and management.