Determinants of Pouch-Related Symptoms, a Common Outcome of Patients With Adenomatous Polyposis Undergoing Ileoanal Pouch Surgery.

INTRODUCTION: Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is performed in patients with adenomatous polyposis syndromes (APSs). Data regarding pouch outcomes in APS are scarce. The purposes of this study were to determine the prevalence of pouch-related symptoms in patients with APS and to identify the contributing factors. METHODS: This is a prospective cohort study. Demographic, surgical, and clinical data were collected. Endoscopy was performed, and biopsies from the terminal ileum, pouch, and cuff were obtained in all patients and reviewed by a dedicated pathologist. RESULTS: Fifty-one patients with APS after IPAA were followed. Twenty patients (39.2%) had pouch-related symptoms. Single-stage IPAA had better outcomes than 2-stage IPAA: fewer daily bowel movements (42.9% vs 13.8% with ≤5 daily bowel movement, P = 0.02), more solid consistency (52.4% vs 6.9%, P < 0.001), and less abdominal pain (19% vs 48.3%, P = 0.034). Younger age at IPAA (<20) was also associated with better outcomes: fewer daily bowel movement (58.3% vs 17.9% with ≤5 daily bowel movement, P = 0.011), less watery consistency (8.3% vs 53.8%, P = 0.005), and abdominal pain (8.3% vs 43.6%, P = 0.037). Eighteen patients (35.3%) had endoscopic signs of inflammation, and 22 patients (43.1%) had histologic signs of pouchitis. However, no correlation was found between symptoms and endoscopic or histologic findings. The median pouchitis disease activity index was low (2, interquartile range 1-4) and did not correlate with clinical symptoms. DISCUSSION: Pouch-related symptoms are common in patients with APS after IPAA. One-stage IPAA and younger age at surgery are associated with better clinical outcomes. However, symptoms do not correlate well with endoscopic or histologic findings or with pouchitis disease activity index and might be attributed to a functional pouch disorder.

Endoscopic resection of large colorectal adenomas - clinical experience of a tertiary referral centre.

AIM: Colorectal cancer is a leading cause of cancer-related mortality. Adenomatous polyps are typically resected endoscopically to prevent cancer while giant and complex polyps are managed surgically. No criteria clearly define the indications for surgical vs endoscopic resection. Our aim was to evaluate factors associated with the short-term efficacy and safety of endoscopic resection of large (≥ 20 mm) and giant (≥ 40 mm) adenomas. METHOD: Consecutive cases with colonic adenomas larger than 20 mm resected endoscopically were included. Endoscopic, clinical and histological details of polyps were recorded as well as the need for surgical resection. RESULT: A total of 351 resections were included. The average adenoma diameter was 30.34 ± 10.66 mm. Surgery was recommended in 21 (5.98%) cases. In a multivariate analysis for efficacy, two variables were independent risk factors for surgery: adenoma size [OR 1.08 (95% CI: 1.04-1.12)] and caecal location [5.97(1.60-22.33)]. Postpolypectomy complications were documented in 85 (24.2%) cases: bleeding 69 (19.7%), perforations 8(2.3%) and significant discomfort 15(4.3%). Twenty-one patients (6.0%) developed serious complications requiring further hospitalization. In multivariate analysis for safety, independent risk factors for postpolypectomy complications included adenoma size [1.04 (1.06-1.01)], polyp morphology [sessile 2.55 (1.45-4.51), flat 2.40 (1.04-5.52)] and submucosal adrenaline injection [1.87 (1.11-3.20)]. Increments of 1 mm in adenoma diameter beyond 20 mm increased the need for surgery by 8% and the risk of complications by 4%. CONCLUSION: Resection of large or giant adenomas is generally a safe procedure. Although adenoma size and morphology are significant predictors of efficacy and safety, each case should be individually evaluated in a specialist unit for feasibility of endoscopic resection.

Genetic features of Lynch syndrome in the Israeli population.

Diagnosis of Lynch syndrome (LS) may be complex. Knowledge of mutation spectrum and founder mutations in specific populations facilitates the diagnostic process. Aim of the study is to describe genetic features of LS in the Israeli population and report novel and founder mutations. Patients were studied at high-risk clinics. Diagnostics followed a multi-step process, including tumor testing, gene analysis and testing for founder mutations. LS was defined by positive mutation testing. We diagnosed LS in 242 subjects from 113 families coming from different ethnicities. We identified 54 different mutations; 13 of them are novel. Sixty-seven (59%) families had mutations in MSH2, 20 (18%) in MSH6, 19 (17%) in MLH1 and 7 (6%) in PMS2; 27% of the MSH2 mutations were large deletions. Seven founder mutations were detected in 61/113 (54%) families. Constitutional mismatch repair deficiency (CMMR-D) was identified in five families. Gene distribution in the Israeli population is unique, with relatively high incidence of mutations in MSH2 and MSH6. The mutation spectrum is wide; however, 54% of cases are caused by one of seven founder mutations. CMMR-D occurs in the context of founder mutations and consanguinity. These features should guide the diagnostic process, risk estimation, and genetic counseling.

The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis-like phenotype and early onset cancer.

Data on the clinical presentation of constitutional mismatch repair deficiency syndrome (CMMRD) is accumulating. However, as the extraintestinal manifestations are often fatal and occur at early age, data on the systematic evaluation of the gastrointestinal tract is scarce. Here we describe 11 subjects with verified biallelic carriage and who underwent colonoscopy, upper endoscopy and small bowel evaluation. Five subjects were symptomatic and in six subjects the findings were screen detected. Two subjects had colorectal cancer and few adenomatous polyps (19, 20 years), three subjects had polyposis-like phenotype (13, 14, 16 years), four subjects had few adenomatous polyps (8, 12-14 years) and two subjects had no polyps (both at age 6). Of the three subjects in the polyposis-like group, two subjects had already developed high-grade dysplasia or cancer and one subject had atypical juvenile polyps suggesting juvenile polyposis. Three out of the five subjects that underwent repeated exams had significant findings during short interval. The gastrointestinal manifestations of CMMRD are highly dependent upon age of examination and highly variable. The polyps may also resemble juvenile polyposis. Intensive surveillance according to current guidelines is mandatory.

Diagnostic yield of colonoscopy for constipation as the sole indication.

AIM: There is controversy over whether constipation as the only symptom should be an indication for routine diagnostic colonoscopy. The study was carried out to assess the prevalence of abnormal pathology on colonoscopy and to assess the risk factors for colonic neoplasia in patients with constipation but without 'high risk symptoms'. METHOD: A cross-sectional, single-centre study was conducted on individuals who underwent colonoscopy for constipation as the sole indication between 2005 and 2008. Standardized endoscopic and pathology reports were reviewed. Univariable and multivariable analyses were performed. RESULTS: A total of 786 patients (595 women, 75.7%; mean age, 57.4±13.5 years) underwent diagnostic colonoscopy for constipation. Forty-three (5.5%) had polyps, of whom 19 (2.4%) had hyperplastic polyps and 19 (2.4%) adenomas. No cancers were found. In patients with adenoma, the detection rate was 2.9% for patients below age 40 years and 1.7% for patients below age 50 years. Older age was associated with a polyp in both univariate and multivariate analysis. Gender, ethnicity and smoking were not associated with polyp or adenoma. CONCLUSION: Colonoscopy for patients with constipation as the sole indication had a lower yield of neoplastic lesions than that for patients undergoing routine screening colonoscopy. Colonoscopy in constipation may only be warranted in patients who are over 50 years of age.

Pyloric gland metaplasia and pouchitis in patients with ileal pouch-anal anastomoses.

BACKGROUND: Diagnosis and management of chronic antibiotic-refractory pouchitis and Crohn's disease of the pouch can be challenging. Pyloric gland metaplasia is a histological feature indicative of chronic mucosal inflammation. Its value in diagnosis and prognosis of pouch disorders has not been investigated. AIM: To assess the prevalence, diagnostic and prognostic value, and risk factors of pyloric gland metaplasia in pouch patients. METHODS: Patients were identified from our prospectively maintained Pouchitis Database. Pouch biopsy specimens were re-reviewed for pyloric gland metaplasia and other histological features. Two cohorts of patients were studied: a historical cohort (n = 111) and the second, a validation cohort (n = 100). Univariate and multivariate analyses were performed to assess risk factors for pyloric gland metaplasia. RESULTS: The prevalence of pyloric gland metaplasia in the historical cohort and validation cohort was 45 (40.1%) and 24 (24.0%), respectively. The sensitivity and specificity of pyloric gland metaplasia for the diagnosis of chronic antibiotic-refractory pouchitis or Crohn's disease were 70.7% and 92.5%, respectively, for the first cohort and 39.0% and 86.4%, respectively, for the 2nd validation cohort. In multivariate analysis of the first cohort, patients with refractory pouchitis or Crohn's disease were 28 times (95% CI, 7.3-107.1) more likely to have pyloric gland metaplasia than those with a normal pouch or irritable pouch syndrome. The factor of refractory pouchitis or Crohn's disease remained in the model for the 2nd validation cohort with odds ratio of 4.58 (95% CI, 1.6-13.4). CONCLUSIONS: Pyloric gland metaplasia is associated with diagnosis of chronic antibiotic-refractory pouchitis or Crohn's disease of the pouch and appears to be a specific marker for both disease entities.

Triiodothyronine and interleukin-6 (IL-6) induce expression of HGF in an immortalized rat hepatic stellate cell line.

BACKGROUND/AIMS: Despite its being considered a primary mitogen for hepatocytes, triiodothyronine (T3) has no effect on the proliferation of hepatocytes in vitro, and in our studies, induces significant in vivo hepatocyte proliferation only during liver injury. We hypothesized that T3 may affect hepatocytes proliferation indirectly, by inducing other cells in the liver to secrete hepatic mitogens. METHODS: In vivo studies: Lipopolysaccharide, T3 and a combination of the two were injected into rats, and hepatocyte proliferation was determined by PCNA staining and mitotic index. IN VITRO STUDIES: a rat hepatic stellate cell line (HSC-6T) was cultured with T3, IL-6 and a combination of the two, and we assessed the effect of these cytokine/hormone combinations on the cell proliferation and on secretion of IL-6 and HGF, measured by ELISA. Expression of thyroid hormone receptors was assessed by RT-PCR. RESULTS: In vivo: T3, together with lipopolysaccharide, enhances PCNA staining and the mitotic index of hepatocytes in the treated rats. In vitro: the hepatic stellate cell line expresses thyroid hormone receptor alpha 1, but not beta 1. Proliferation of stellate cells is not affected by T3, with or without IL-6. T3 has no effect on secreted levels of IL-6 in the stellate cell line. Hepatic stellate cells cultured with T3 and IL-6 show significantly increased amounts of secreted HGF after 48 h in culture. CONCLUSION: T3 may induce hepatocyte proliferation in vivo during injury by turning on expression of HGF in stellate cells and acting together with IL-6.

Prospective assessment of microsatellite instability in gastrointestinal neoplasia in Ashkenazi and non-Ashkenazi Jews.

BACKGROUND: Microsatellite instability (MSI) is a useful marker of replication errors in neoplasia, resulting from mutations in the mismatch repair (MMR) genes. Nearly all hereditary non-polyposis colorectal cancer (HNPCC) and about 15% of sporadic colorectal cancers (CRC) exhibit high MSI (MSI-H). The use of the Amsterdam criteria for HNPCC diagnosis may fail to identify many HNPCC cases. Genetic screening of mutations in the MMR genes is laborious, time-consuming, expensive and limited by a low detection rate. Hence, MSI testing is a feasible and cost-effective method to select suspected HNPCC patients for genetic analysis. MSI has not been used routinely or prospectively in the assessment of newly diagnosed CRC. AIMS: To prospectively evaluate MSI status in a cohort of patients seen at the Gastrointestinal Oncology Unit of the Tel Aviv Medical Center. METHODS: Ninety-eight consecutive patients with colonic or gastric neoplasia were included. Samples from neoplastic and normal mucosa were obtained at the time of diagnostic endoscopy. MSI was determined based on five Bethesda markers using standard polymerase chain reaction procedures. RESULTS: The overall incidence of MSI was 20.4%. MSI-H was detected in 22.2% of CRC, 20% of colonic adenomas and 18.2% of gastric neoplasia. MSI-positive neoplasia tended to display multiple colonic sites, moderate-well differentiated tumors, and a higher rate of familial gastrointestinal neoplasia. CONCLUSIONS: MSI may be involved in the early stages of some colorectal tumorigenesis pathways since it may be detected in adenomas. MSI may serve as a cost-effective, reliable and important tool in the selection of HNPCC-suspected families for genetic testing. A small study population, referral bias or ethnic variation might explain the higher MSI rate. It is suggested that, similar to familial adenomatous polyposis, a state of attenuated HNPCC may exist. Hence, the clinical approach in positive patients, and their family members, should be conducted as for families with genetically proven HNPCC.

The changing epidemiology of leptospirosis in Israel.

We reviewed all serologically confirmed cases of leptospirosis from 1985 to 1999 in Israel, where the disease is endemic. There were 59 cases, with an average annual incidence of 0.05/100,000. The dominant serogroup, Leptospira icterohemorrhagica, occurred in 29% of patients; in an earlier study (1970-1979), it accounted for only 2%. Serogroups that occurred mainly in rural areas accounted previously for 79% but had declined to 32%.

Systemic vasculitis presenting as a tumorlike lesion. Four case reports and an analysis of 79 reported cases.

Systemic vasculitis might present as a tumorlike lesion that initially could misdirect the correct diagnosis and the appropriate medical treatment. The aim of the present study is to summarize all reported cases of tumorlike presentation in systemic vasculitides, in order to have comprehensive data on the characteristics of this unusual phenomenon. We report 4 cases of systemic vasculitis presenting as a tumorlike lesion. In addition, we performed a MEDLINE search of all English-language papers published from 1966 to 1999, looking for vasculitis presenting as tumorlike lesion. Details were included concerning vasculitis classification, specific characteristics, location of the "tumor," the presence or absence of systemic involvement, and whether surgery was performed before diagnosis. Seventy-nine cases of vasculitis presenting as a tumorlike lesion were found in the literature, in addition to the 4 new cases described. The average age of the reported cases was 50.5 +/- 15.8 years, and 51% were female. In 82% of the cases the "tumor" was associated with constitutional symptoms and elevated erythrocyte sedimentation rate (ESR). The most common vasculitis categories with tumorlike presentation were Wegener granulomatosis (WG; 28 cases) and giant cell arteritis (GCA; 17 cases). In almost half the patients, surgery was performed before diagnosis. All patients with GCA presented with either a breast or an ovarian tumor. The most common location of a tumorlike lesion was the breast (22%), followed by central nervous system lesions (16%). Other frequent locations were the ovary (10%), caused exclusively by GCA and polyarteritis nodosa (PAN), and the male genitourinary system, almost all caused by PAN. Including vasculitis in the differential diagnosis of a tumorlike lesion might lead to an earlier diagnosis and consequently to prompt and appropriate treatment, avoiding needless operations. Constitutional symptoms and elevated ESR should alert clinicians to the possible diagnosis of vasculitis rather than a tumor. The association of GCA with ovarian pseudotumor is distinct and has not been emphasized before. We therefore suggest that GCA should be included in the list of differential diagnosis of an ovarian or breast tumor in an elderly woman, particularly when systemic symptoms and parameters of inflammation are present.

Simulation of the hepatic metabolism of stilbene and its tricyclic derivatives by Fenton and Ruff reagents: models for cytochrome P-450 activation of chemical carcinogens.

Reactions of trans-stilbene, cis-stilbene, 5H-dibenzo [a,d] cyclo-heptene 5-one and 5H-dibenz [b,f] azepine (iminostilbene) with Fenton reagent [Fe (II)/H2O2] clearly simulate their hepatic metabolism. Expoxidation on the corresponding ethylenic linkage was found to be a common pathway of these compounds. Epoxides of trans-stilbene, cis-stilbene, and 5H-dibenzo[a,d]cycloheptene 5-one were further oxidized to dihydrodiols, alpha-hydroxyketones, diketones, and finally cleavage of the ethylenic bonds to the formation of the corresponding aldehydes. However, the unstable epoxide of iminostilbene gave 9-acridinecarbaldehyde that is further oxidized to 9-acridone. Reaction of both trans- and cis-stilbene with Ruff reagent [Fe III)/H2O2] gave the same oxidative products to that obtained from Fenton reagent. The radical scavenger 2,6 bis (1,1-dimethylethyl)-4-methyl phenol (BHT) decreases the total yield conversion and increases the formation ratio of both cis-epoxide and d,l-hydrobenzoin from cis-stilbene.

Biomimetic models for monooxygenases.

The microsomal mixed function oxidase system contains the cytochrome P-450 oxidative drug metabolizing family of enzymes. The catalytic cycle of cytochrome P-450 is believed to involve the formation of an active iron-oxygen species which is responsible for oxygen transfer to the substrate. This assumption is supported by the fact that a number of peroxidative agents can replace NADPH, the reductase, and oxygen as co-reactants in most oxidative reactions of microsomal cytochrome P-450. We have found that a mixture of either ferrous or ferric ions with hydrogen peroxide (Fenton and Ruff reagents) can serve as biomimetic models for cytochrome P-450 in hydroxylation, exposidation, sulfoxidation, and N-demethylation of various drugs. The existance of an iron-oxo active species in both Fenton and Ruff type reactions has been postulated and provides reaction cycles similar to those of cytochrome p-450. Other model systems for the hepatic hydroxylation and epoxidation using transition metal complexes with porphyrin are also discussed. The present paper reviews the various biomimetic models of the heme cytochrome P-450 and emphasizes their simulation of hepatic drug metabolism and their potential medical and industrial applications.

The role of iron chelates on the selectivity of Fenton reagent in hydroxylation, N-demethylation, and sulfoxidation of cimetidine: a novel biomimetic model for the regioselectivity of cytochrome P-450.

The effect of iron chelates on the reaction of cimetidine with Fenton reagent [Fe(II)/H2O2] has been investigated. Iron chelates with high affinity to ferrous ions inhibited this reaction. However, iron chelates with high affinity to ferric ions selectively promote either hydroxylation, N-demethylation, or sulfoxidation of cimetidine. These results indicate that the oxidation of cimetidine with hydrogen peroxide activated by various chelated ferrous ions serves as a biomimetic model for the regioselectivity of multiple forms of cytochrome P-450 in the metabolism of cimetidine.

Reactions of theophylline, theobromine and caffeine with Fenton's reagent--simulation of hepatic metabolism.

Theophylline and caffeine undergo N-demethylation and hydroxylation by Fenton's reagent to give uric acid derivatives; theophylline is oxidized mainly to 1-methyluric acid, and 1,3-dimethyluric acid and 1-methyluric acid are the major products obtained from caffeine. Theobromine undergoes predominantly N-demethylation to give 7-methylxanthine. The nature of the products indicate that these reactions simulate hepatic drug metabolism.

Reaction of cimetidine with Fenton reagent. A biomimetic model for the mixed-function oxidase drug metabolism.

Cimetidine sulfoxide, N-desmethylcimetidine, N-desmethylcimetidine sulfoxide, cimetidine guanylurea, and the 5-hydroxymethylimidazole derivative of cimetidine sulfoxide were isolated from the reaction of cimetidine with Fenton reagent. The product distribution from the reaction of cimetidine with Fenton reagent clearly simulates the metabolism of cimetidine by the mixed-function oxidase.