Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease.

BACKGROUND: Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor ß1 (TGF-ß1) due to high levels of SMAD7, an inhibitor of TGF-ß1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7. METHODS: In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. RESULTS: The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease. CONCLUSIONS: We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.).

Intestinal Surgery for Crohn's Disease: Role of Preoperative Therapy in Postoperative Outcome.

PURPOSES: Patients affected by Crohn's disease (CD) require lifelong medical therapy, but they can also often require abdominal surgery. The effect of CD therapy on postoperative course is still unclear. The aim of this study was to evaluate the effect of preoperative medical therapy on the outcome of intestinal surgery in these patients. METHODS: Data from a consecutive series of 167 patients with CD operated on at the University of Padova Hospital from 2000 to 2013 were retrieved. Data of preoperative therapy during the 6 months before surgery were available for 146 patients who were enrolled in this retrospective study. Clinical data and surgical details were retrieved and postoperative complications and reoperation were considered outcome measures. Univariate and multivariate analysis were performed. RESULTS: No significant difference was observed between patients without data about their preoperative therapy and those with them. Eight patients underwent reoperation in the first 30 postoperative days: two of them for anastomotic leak, three for bleeding, one for obstruction and two for abdominal wound dehiscence. At multivariate analysis, preoperative adalimumab and budesonide resulted to be an independent predictor of reoperation (OR = 7.67 (95% CI = 1.49-39.20), p = 0.01 and OR = 6.7749 (95% CI = 0.98-46.48), p = 0.05, respectively). At multivariate analysis neither pharmacological nor clinical variables resulted to predict anastomotic leak. CONCLUSIONS: In our series, adalimumab seemed to be associated to early reoperation after intestinal surgery. This may be due to a worst disease severity in patients who needed surgery in spite of biological therapy. Preoperative tapering of budesonide dose seems a safe option before elective abdominal surgery for CD.

Lactobacillus crispatus M247-derived H2O2 acts as a signal transducing molecule activating peroxisome proliferator activated receptor-gamma in the intestinal mucosa.

BACKGROUND & AIMS: Accumulating evidence indicates that the peroxisome proliferator activated receptor (PPAR)-gamma is a major player in maintaining intestinal mucosa homeostasis, but whether PPAR-gamma is directly involved in probiotic-mediated effects and the molecular events involved in its activation are not known. METHODS: We investigated the role of PPAR-gamma in the immunomodulatory effects of Lactobacillus crispatus M247 on intestinal epithelial cells (IEC) and the role of probiotic-derived H(2)O(2) on PPAR-gamma activity. RESULTS: L crispatus M247 supplementation in mice significantly increased PPAR-gamma levels and transcriptional activity in the colonic mucosa. L crispatus M247 induced PPAR-gamma nuclear translocation and enhanced transcriptional activity in epithelial (CMT-93) cells, as demonstrated by the increased luciferase activity of a PPAR-gamma-responsive element, PPAR-gamma-responsive gene up-regulation, and reduced activity of an nuclear factor-kappaB-responsive element. Pharmacologic PPAR-gamma inhibition or silencing by small interfering RNA cancelled the L crispatus M247-mediated effects in CMT-93 cells. Because Lactobacillus strains producing little H(2)O(2) failed to activate PPAR-gamma, we investigated the role of L crispatus M247-derived H(2)O(2) in PPAR-gamma activation. L crispatus M247 induced a transient rise in intracellular H(2)O(2) and PPAR-gamma transcriptional activity was cancelled by antioxidant or H(2)O(2) scavenger. Toll-like receptor (TLR)-2 was not required for PPAR-gamma up-regulation mediated by L crispatus M247 in mice, although the protective effects of L crispatus M247 on dextran sodium sulfate-induced colitis were less pronounced in TLR-2(-/-) mice. CONCLUSIONS: L crispatus M247 uses H(2)O(2) as a signal transducing molecule to induce PPAR-gamma activation in IEC, directly modulating epithelial cell responsiveness to inflammatory stimuli.

TGF-beta1 and IGF-1 production and recurrence of Crohn's disease after ileo-colonic resection.

BACKGROUND: Recurrence after surgery is a major problem in the treatment of Crohn's disease (CD). Alteration of healing processes may play a role in this phenomenon. Transforming growth factor beta (TGF-beta) and insulin-like growth factor (IGF-1) have pro-fibrogenic properties and are involved in wound-healing mechanisms. The aim of this study was to assess their role in the CD recurrence after ileo-colonic resection. PATIENTS AND METHODS: Twenty patients with CD, who underwent ileo-colonic resection in the period between 1999 and 2005, were enrolled in this study. Tissue samples were obtained from macroscopically diseased and healthy ileum. The TGF-beta1 and IGF-1 mRNAs were quantified by real-time polymerase chain reaction using glyceraldehyde 3-phosphate dehydrogenase as the housekeeping gene. Histological severity of the disease was assessed to quantify the ileal inflammation. Patients' follow-up was investigated. Comparisons and correlations were carried out with nonparametric tests and survival analysis was performed. RESULTS: Histological inflammation was moderately severe in the diseased bowel, while it was absent in healthy segments (P < 0.01). TGF-beta1 production in healthy bowels showed a direct correlation with clinical CD recurrence (tau = 0.43, P = 0.04) and survival analysis showed that patients who expressed high TGF-beta1 mRNA transcripts in healthy intestines had higher cumulative recurrence rates than those who expressed low TGF-beta1 mRNA levels (P = 0.02). CONCLUSION: Our study suggests that the high levels of TGF-beta1 in healthy bowels of patients who undergo ileo-colonic resection for CD are associated with early clinical disease recurrence, while there seems to be no association between IGF-1 and CD recurrence.

Restorative proctocolectomy for inflammatory bowel disease: the Padova prognostic score for colitis in predicting long-term outcome and quality of life.

BACKGROUND: In 10-20% of cases, it is impossible to distinguish between ulcerative colitis and Crohn's colitis, affecting the possibility to predict the long-term outcome after restorative proctocolectomy (RPC). The study aimed to assess the accuracy of a new prognostic score for inflammatory bowel diseases (IBD) colitis [the Padova Prognostic Score for Colitis (PPSC)] in predicting long-term clinical/functional outcome and quality of life after RPC. MATERIALS AND METHODS: The PPSC was created by the integration of histological and clinical information. The accuracy of the PPSC was tested in predicting long-term clinical outcome (i.e. pouch complications/survival) and quality of life of 58 consecutive patients who had undergone RPC in our institute from 1984 to 2004. Clinical outcome was assessed with an ad hoc functional questionnaire and the revision of the hospital and outpatients clinic notes. Quality of life surveys were carried out with the Padova IBD Quality of Life (PIBDQL) and with Cleveland Global Quality of Life (CGQL) scores. RESULTS: The PPSC predicted pouch fistulae (accuracy = 84.5%; sensitivity = 50%; specificity = 90%) and changes in sexual life (accuracy = 71%; sensitivity = 23%; specificity = 87%). The PPSC also predicted the PIBDQL score with an accuracy of 62%, a sensitivity of 28% and a specificity of 97%, whilst it predicted the CGQL score with an accuracy of 29%, a sensitivity of 12% and a specificity of 80%. The PPSC failed to predict pouchitis or pouch failure. CONCLUSIONS: The Padova Prognostic Score for Colitis proved effective in predicting pouch fistulae or abscesses, but not pouchitis and pouch failure. The PPSC was accurate in predicting disease-specific quality of life.

Inflammatory Bowel Disease Therapies Adversely Affect Fertility in Men- A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Sexual functions are sometimes adversely affected by the therapeutic drugs delivered for treating IBD. Much attention has been focused on pregnancy/sexual issues in women. Relatively less attention has been poured in to address this issue in men. This systematic review assesses the drugs having potential detrimental effects on fertility in men. METHODS: Three databases were searched by two researchers independently for potentially relevant publications between 1964 to 2015 and 249 papers were retrieved. Studies that dealt with sexual problems after IBD drugs administration were included in the purview of this review. RESULTS: Fourteen studies with 327 human patients and 110 animals were analysed. Sulphasalazine treated patients had lower spermatozoa count, lower sperm motility and higher risk of oligospermia compared to mesalazine treated ones. Biologics seem to be safe to use while attempting to conceive however, proper clinical studies reporting male fertility problems in IBD patients are lacking. Azathioprine caused oligospermia but a meta-analytical approach was not possible due to heterogeneity in studies. Some animal studies showed methotrexate affects abnormal testis structure and spermatogenesis. CONCLUSION: This study summarises the current literature and safety issues affecting fertility parameters in men and animals treated with IBD therapeutic drugs, which can further assist clinicians in better management of adult male IBD patients.

A multicenter, randomized, double-blind trial of everolimus versus azathioprine and placebo to maintain steroid-induced remission in patients with moderate-to-severe active Crohn's disease.

OBJECTIVES: A prospective study was undertaken to compare the efficacy of everolimus versus azathioprine or placebo in maintaining steroid-induced remission in active Crohn's disease (CD) and assess the safety and pharmacokinetics of everolimus. METHODS: This was a randomized, double-blind, placebo-controlled, proof-of-concept study in adults with moderate-to-severe active CD. The patients received oral steroids for a rapid induction of remission plus everolimus 6 mg/day, azathioprine 2.5 mg/kg/day, or placebo as maintenance treatment. The main outcome measure was the treatment success, defined as a steroid-free remission by the end of month 3 and maintained until study cutoff without the use of prohibited efficacy treatments. RESULTS: Following an interim analysis, the study was terminated before enrollment was completed due to the lack of efficacy. The full intent-to-treat population comprised 138 patients. Only 96 patients who entered the study > or =7 months prior to data cutoff were included in the primary efficacy population. The treatment success was achieved in 13 of 38 everolimus patients, 22 of 36 azathioprine patients, and 8 of 22 placebo patients. Using the Kaplan-Meier estimates at month 7, the incidence of treatment success was 22.0% with everolimus group (95% confidence interval [CI] 6.7-37.3%, P= 0.610 vs placebo), 38.3% with azathioprine group (95% CI 20.6-55.9%, P= 0.500 vs placebo), and 28.8% with placebo group (95% CI 7.7-49.9%). The type and incidence of adverse events in the everolimus cohort were similar to those reported in the approved transplantation indications. CONCLUSIONS: The safety and tolerability of everolimus (6 mg/day) in patients with active CD were comparable to azathioprine. At this dose, everolimus is not more efficacious in achieving a steroid-free remission in active CD than the comparators.

Restorative proctocolectomy for ulcerative colitis: impact on lipid metabolism and adipose tissue and serum fatty acids.

The aim of this prospective study was to evaluate the changes of the metabolism of circulating and storage lipids in patients with ulcerative colitis after restorative proctocolectomy. Fifteen consecutive patients and 15 sex- and age-matched healthy controls were enrolled. Disease activity, diet, inflammatory parameters, plasma lipoprotein concentrations, and fatty acids (FA) of serum phospholipids and of the subcutaneous adipose tissue were assessed at colectomy and at ileostomy closure. In ulcerative colitis patients, total cholesterol and docosahexaenoic acid were lower than in healthy subjects (p < 0.01 and p < 0.05). The median interval between colectomy and ileostomy closure was 6 (range 2-9) months. During that interval, the inflammatory parameters improved, high-density lipoproteins (HDL) cholesterol increased (p < 0.01), and low-density (LDL) cholesterol decreased (p = 0.01). At ileostomy closure, serum arachidonic acid levels were increased (p = 0.04), whereas serum oleic acid level was decreased (p = 0.02). In this interval, no significant alteration, either in serum n-3 FA precursors or in the FA of subcutaneous adipose tissue, was observed. The increase of serum arachidonic acid after colectomy might suggest a lower utilization for inflammatory process. The reduction of LDL cholesterol is an index of malabsorption probably due to the accelerated transit and to the exclusion of the terminal ileum caused by the covering ileostomy.

Health-related quality of life after ileocolonic resection for Crohn's disease: long-term results.

BACKGROUND: Crohn's disease (CD) is a chronic illness that interferes with the daily life of those affected. The aim of the present study was to evaluate long-term health-related quality of life (HRQL) outcome and its clinical predictors in CD patients who have had ileocolonic resection. METHODS: Ninety-seven CD patients, with a mean follow-up of 47.1 months (95% CI, 40.7-53.5 months) after ileocolonic resection, were interviewed by telephone and responded to the generic Cleveland Global Quality of Life (CGQL) questionnaire, and 63 of them also agreed to come to our outpatient clinic to have a Crohn's Disease Activity Index (CDAI) assessment and blood test and to answer the disease-specific Padova Inflammatory Bowel Diseases Quality of Life (PIBDQL) questionnaire. Control groups also were enrolled. RESULTS: The CGQL scores of the 97 CD patients were similar to those of 69 healthy controls. Only the item on current quality of health was scored significantly lower by patients with CD. In contrast, the PIBDQL item and total scores of the CD patients were all significantly lower than those of the respective healthy controls (P < 0.05). Multivariate analysis showed that the CGQL and PIBDQL scores both had a strong linear relationship with number of daily stools and with CDAI score (P < 0.05). CONCLUSIONS: Despite CD patients who have undergone ileocolonic resection having an apparently normal quality of life with a good energy level, as shown by the CGQL, their long-term HRQL is still affected by a significantly impaired quality of health. In fact, the PIBDQL questionnaire showed significant impairment of bowel and systemic symptom domains with important consequences for emotional and social functions. HRQL seems to be significantly related only to current disease activity.

Quality of life after restorative proctocolectomy for ulcerative colitis: different questionnaires lead to different interpretations.

BACKGROUND: According to some researchers, health-related quality-of-life scores for patients who undergo restorative proctocolectomy (RPC) for ulcerative colitis (UC) are comparable to those of healthy control subjects. Other studies show evidence that patients who undergo RPC experience a health-related quality of life similar to patients with mild UC or UC in remission. HYPOTHESIS: The discrepancy in health-related quality-of-life scores among studies may be due to different health-related quality-of-life analyses. DESIGN: Cross-sectional study. SETTING: Outpatient clinic of a tertiary care center. PATIENTS: In the first phase of the study, we consecutively enrolled 24 patients with UC, 24 patients with Crohn disease, and 24 healthy controls. In the second phase of the study, 40 patients who underwent RPC, 43 patients with UC, and 44 controls were consecutively enrolled. INTERVENTIONS: We administered an Italian version of the Cleveland Global Quality of Life (CGQL) instrument, the Padova Inflammatory Bowel Disease Quality of Life instrument, and the Italian 36-Item Short-Form Health Survey. MAIN OUTCOME MEASURES: We evaluated the construct validity, internal consistency, test-retest reliability, sensitivity to change, and discriminant ability of the Italian CGQL instrument. We compared its discriminative ability with that of the Padova Inflammatory Bowel Disease Quality of Life instrument. RESULTS: The Italian CGQL instrument obtained good construct validity, internal consistency, test-retest reliability, and sensitivity to change. The Italian CGQL score did not distinguish patients who underwent RPC from healthy controls and those with mild UC or UC in remission, while the Padova Inflammatory Bowel Disease Quality of Life instrument reported similar scores for patients who underwent RPC and those with mild UC or UC in remission, and showed a difference vs healthy controls. CONCLUSIONS: We validated an Italian version of the CGQL score. The different results obtained with the CGQL and the Padova Inflammatory Bowel Disease Quality of Life instruments can be attributed to the different discriminative ability of the 2 questionnaires.

Enzymes in feces: useful markers of chronic inflammatory bowel disease.

BACKGROUND: Ulcerative colitis and Crohn's disease are characterized by a chronic intestinal inflammation. Since the precise etiology is still unknown, current therapies are aimed at reducing or eliminating inflammation. METHODS: Endoscopy and histology on biopsy specimens remain the gold standard methods for detecting and quantifying bowel inflammation. These technique are expensive, invasive and not well tolerated by patients since the need of repeated examinations affects their quality of life. Although disease activity scores and laboratory inflammatory markers are widely used they showed unreliable relations with endoscopy and histology. Fecal markers have been investigated in inflammatory bowel disease (IBD) by many authors for diagnostic purposes, to assess disease activity and of risk of complications, to predict relapse or recurrence, and to monitor the effect of therapy. Many inflammatory mediators have been detected in the feces such as leukocytes, cytokines and proteins from neutrophil activation. Some of these, particularly lactoferrin and calprotectin, have been demonstrated to be useful in detecting active inflammatory bowel disease, in predicting recurrence of disease after surgery or monitoring the effects of medical therapy. Calprotectin and lactoferrin are remarkably stable and easily detect in stool using ELISA so they appear to be equally recommendable as inflammation markers in the lower gastrointestinal tract especially in IBD patients. CONCLUSION: Fecal markers are non-invasive, simple, cheap, sensitive and specific parameters and are useful to detect strointestinal inflammation.

Extreme heterogeneity in CARD15 and DLG5 Crohn disease-associated polymorphisms between German and Norwegian populations.

The first gene associated with Crohn disease (CD) has been identified as CARD15 (16q12). Three variants, R702W, G908R and 1007fsinsC are strongly and independently associated with the disease. A second gene, conveying a smaller risk for inflammatory bowel disease (IBD), has been identified as DLG5 (10q23). We assess the frequency of the CARD15 SNPs and of the R30Q mutation in DLG5 and their contribution to the development of CD in a cohort of unrelated IBD patients (151 CD, 325 ulcerative colitis (UC)) and healthy controls (236) from South-east Norway (IBSEN cohort). Genotype-based tests of population differentiation using 23 SNPs across CARD15, together with estimates of F(ST), indicated that the German and Norwegian background populations could be differentiated at the CARD15 locus. The Norwegian and German CD samples exhibited particularly strong differentiation at the three predisposing loci and those marking their background haplotype. There were significantly lower frequencies of the CARD15 SNPs and no significant association with CD in the Norwegian samples. Only a marginal association was observed for the subphenotypes ileitis and ileocolitis vs colitis (P=0.048). The population attributable risk percentage (PAR%) for CARD15 variants in the Norwegian cohort is the lowest reported for a European population (1.88%), except Iceland. Similarly, the DLG5 variant showed no association with CD or IBD, however, there was a negative correlation with stricture (P=0.035). The present results are consistent with an emerging pattern of a low frequency of the CARD15 variants in Northern countries where the prevalence of IBD is greatest.

Beneficial effect of auto-aggregating Lactobacillus crispatus on experimentally induced colitis in mice.

We tested the therapeutic relevance of auto aggregation in lactobacilli by comparing the effect on DSS induced colitis of viable Lactobacillus crispatus M247, isolated from healthy humans, to L. crispatus MU5, an isogenic spontaneous mutants of M247, the latter lacking the auto aggregation phenotype which allows the adhesion to human mucus. Aggregating L. crispatus M247, but not the non-aggregating MU5, was retrievable from mice feces and adherent to the colonic mucosa. Daily administration of L. crispatus M247, but not heat killed L. crispatus M247 or aggregation deficient L. crispatus MU5, dose-dependently reduced the severity of DSS colitis. Indeed, L. crispatus MU5 administered in a 30% sucrose solution, known to restore the aggregation phenotype, had a protective effect comparable to mice receiving L. crispatus M247. These results indicate that a surface-mediated property such as aggregation may play a pivotal role in the protective effects obtained by dietary supplementation with L. crispatus M247 during colitis.

Persistence of high CD40 and CD40L expression after restorative proctocolectomy for ulcerative colitis.

AIM: To focus on the role of CD40 and CD40L in their pathogenesis. METHODS: We analyzed by immunohistochemistry the CD40 and CD40L expression in the pouch mucosa of 28 patients who had undergone RPC for UC, in the terminal ileum of 6 patients with UC and 11 healthy subjects. We also examined by flow cytometry the expression of CD40 by B lymphocytes and monocytes in the peripheral blood of 20 pouch patients, 15 UC patients and 11 healthy controls. RESULTS: Ileal pouch mucosa leukocytes presented a significantly higher expression of CD40 and CD40L as compared to controls. This alteration correlated with pouchitis, but was also present in the healthy pouch and in the terminal ileum of UC patients. CD40 expression of peripheral B lymphocytes was significantly higher in patients with UC and pouch, respect to controls. Increased CD40 levels in blood B cells of pouch patients correlated with the presence of spondyloarthropathy, but not with pouchitis, or inflammatory indices. CONCLUSION: High CD40 expression in the ileal pouch mucosa could be implied in the pathogenesis of pouchitis following proctocolectomy for UC, whereas its increased levels on peripheral blood B lymphocytes are associated with the presence of extraintestinal manifestations.

CD80-CD28 signaling controls the progression of inflammatory colorectal carcinogenesis.

In patients with ulcerative colitis (UC) the cumulative risk of colon cancer is lower than the actual rate of dysplasia suggesting an efficient immune surveillance mechanism. Since the co-stimulatory molecule CD80 is overexpressed in dysplastic colonic mucosa of UC patients and T-cell activation entails effective costimulation, we aimed to evaluate the functional implication of CD80 signaling in colonic UC-associated carcinogenesis. In humans, we observed that the percentage of CD80+ and HLA-A+ IEC was increased in the dysplastic colonic mucosa of UC patients. In vitro, IEC activated CD8+ T-cells through a CD80-dependent pathway. Finally, in the AOM/DSS-induced colonic adenocarcinoma model CD80 signaling inhibition significantly increased the frequency and extension of high-grade dysplasia, whereas enhancing CD80 activity with an anti-CTLA4 antibody significantly decreased colonic dysplasia. In conclusion, CD80 signaling between IEC and T-cells represents a key factor controlling the progression from low to high grade dysplasia in inflammatory colonic carcinogenesis.

A protective effect of the synthetic coumarine derivative Cloricromene against DNB-colitis in the rat.

Biologic therapies, namely antibodies against tumor necrosis factor-alpha (TNF- alpha) or its receptors, have been recently introduced for the treatment of patients with inflammatory bowel disease (IBD). In the present study the effects of cloricromene, an agent with known antithrombotic actions and with demonstrated anti-TNF- alpha activity were investigated in a rat model of experimental colitis induced with dinitrobenzenesulphonic acid (DNB)/ethanol. We investigated three experimental groups: (i) sham-colitis with vehicle-treatment (controls, n = 6), (ii) colitis with vehicle-treatment (saline, 0.1 ml s.c., daily) (DNB-V, n = 7), (iii) colitis with cloricromene-treatment (10 mg/kg/day s.c.; DNB-C, n = 8). After 7 days, the weight gain, colon wet weight, macroscopic damage score, coagulation parameters, colon mucosal myeloperoxidase activity (MPO), and tissue concentrations of TNF- alpha and of macrophage inhibitory peptide-2 (MIP-2) were assessed. The macroscopic damage scores, colon wet weights, and tissue MIP-2 levels were significantly increased in untreated and in cloricromene-treated rats compared with controls. Cloricromene treatment was associated with a minor body weight loss (p < 0.025) and significantly reduced tissue concentrations of MPO and TNF-alpha (p < 0.02, both). Blood coagulation parameters were not affected by treatment. In the DNB-model treatment with cloricromene effectively reduces tissue levels of TNF- alpha and of myeloperoxidase, whereas MIP-2 concentrations were not influenced. Blood coagulation parameters remained unchanged indicating safety of treatment. Since biological therapies frequently fail to improve disease course of IBD, other therapies with similar targets should be further investigated.

Time trends and outcome of gastrointestinal bleeding in the Veneto region: a retrospective population based study from 2001 to 2010.

BACKGROUND: Gastrointestinal bleeding is the most frequent emergency for gastroenterologists. Despite advances in management, an improvement in mortality is still not evident. AIM: Determining time trends of gastrointestinal bleeding hospitalization and outcomes from 2001 to 2010 in the Veneto Region (Italy). PATIENTS AND METHODS: Data of patients admitted with gastrointestinal bleeding from Veneto regional discharge records were retrospectively evaluated. Chi-squared and multivariate logistic regression model were used. RESULTS: Overall, 44,343 patients (mean age 64.2 ± 8.6 years) with gastrointestinal bleeding were analysed: 23,450 (52.9%) had upper, 13,800 (31.1%) lower, and 7093 (16%) undefined gastrointestinal bleeding. Admission rate decreased from 108.0 per 100,000 in 2001 to 80.7 in 2010, mainly owing to a decrease in upper gastrointestinal bleeding (64.4 to 35.9 per 100,000, p<0.05). Reductions in hospital fatality rate (from 5.3% to 3%, p<0.05), length of hospital stay (from 9.3 to 8.7 days, p<0.05), and need for surgery (from 5.6% to 5%, p<0.05) were observed. Surgery (OR: 2.97, 95% CI: 2.59-3.41) and undefined gastrointestinal bleeding (OR: 2.89, 95% CI: 2.62-3.19) were found to be risk factors for mortality. CONCLUSIONS: Patient admissions for gastrointestinal bleeding decreased significantly over the years, owing to a decrease in upper gastrointestinal bleeding. Improved outcomes could be related to regional dedicated clinical gastroenterological management.

HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants.

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

Mucosal immune environment in colonic carcinogenesis: CD80 expression is associated to oxidative DNA damage and TLR4-NFκB signalling.

BACKGROUND: CD80 has been thought to play an active role in immunosurveillance as it has been found to be up-regulated in ulcerative colitis (UC) patients with dysplasia. The aim of the present study was to analyse early events in UC-related and non-inflammatory carcinogenesis with reference to CD80 expression to clarify what stimuli are involved in its up-regulation in these patients. PATIENTS AND METHODS: Sixty-two patients affected with UC, UC with dysplasia, UC and cancer, colonic adenoma, or colonic cancer and 11 healthy subjects were enroled in our study. Tissue samples were taken from surgical specimens during colonic resection or during colonoscopy. Mucosal mRNA expression of Toll-like receptor-4 (TLR4) and nuclear factor-kappaB (NF-κB) was quantified with Real Time RT-PCR. TLR4, ß-catenin and p53 expressions were analysed by immunohistochemistry. Mucosal levels of activated NF-κB were measured with immunometric assays while 8-Hydroxydeoxyguanosine (8-OHdG) levels were quantified by high-performance liquid chromatography with electrochemical detection (HPLC-ED). Non-parametric tests were used for statistical analysis. RESULTS: 8-OHdG mucosal levels were higher in the patients with UC + dysplasia with respect to those in the patients with UC only (p=0.03). CD80 mRNA mucosal levels were directly correlated with 8-OHdG mucosal levels (τ=0.26, p=0.04), TLR4 protein expression (τ=0.45, p<0.01) and NF-κB mRNA expression and activity (τ=0.24, p=0.02; τ=0.34, p=0.02, respectively). CD80 protein expression, instead, was directly correlated with 8-OHdG mucosal levels (τ=0.19, p=0.05) and inversely correlated with TLR4 mRNA expression (τ=-0.25, p=0.03). CONCLUSION: Oxidative DNA damage peaked in UC-related dysplasia and was found to be directly correlated to CD80 expression. The direct correlation between TLR4 protein expression and CD80 mRNA and the indirect correlation between CD80 protein and TLR4 mRNA expressions give substance to the hypothesis that they play a role in immunosurveillance. No significant correlations between CD80 expression and p53 and ß-catenin accumulation during oncogenesis were, instead, observed.

Mucosal immune environment in colonic carcinogenesis: CD80 up-regulation in colonic dysplasia in ulcerative colitis.

BACKGROUND: In patients with ulcerative colitis (UC) the inconsistency between the rate of dysplasia and actual cancer incidence suggests the presence of an immunosurveillance mechanism. The aim of our study was to analyse the expression of CD80 and CD86 during the different stages of UC-associated and in non-inflammatory carcinogenesis. PATIENTS AND METHODS: Sixty-two patients affected with UC, UC with colonic dysplasia, UC and cancer, colonic adenoma, or colonic cancer and 11 healthy subjects were enrolled in our study. Tissue samples were taken from surgical specimens during colonic resection or during colonoscopy. Mucosal mRNA expression of CD80 and CD86 was quantified with real time polymerase chain reaction (RT-PCR). CD80, CD86 and p53 expressions and lamina propria mononuclear cell populations (CD3, CD20 and CD68) were analysed by immunohistochemistry. Mucosal levels of IL-1ß, IL-2 and IFN-γ were measured with immunometric assays. RESULTS: Among UC patients, CD80 protein expression was higher in those with dysplasia (p=0.017). In non-inflammatory carcinogenesis pathway CD80 protein and mRNA expressions were lower compared to the corresponding steps in the UC pathway. CD80 expression was directly correlated with the lamina propria mononuclear cell populations (T and B lymphocytes and monocytes). CD80 protein, but not CD80 mRNA, expression was significantly and directly correlated with IL-2 expression. CONCLUSION: CD80 resulted to be up-regulated in UC with dysplasia, while it was down-regulated in cancer. CD80 mucosal levels correlate with lamina propria T-cell and with IL-2 expression suggesting that it may elicit an active role in the immunosurveillance mechanism.