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Crohn's disease may involve any part of the digestive tract from mouth to anus, but affects mainly the distal ileum and the,colon. At diagnosis, perianal lesions are observed in 20% of the cases. During the disease course, strictures develop in the majority of patients with ileal disease, while penetrating lesions (fistulas and abscesses) develop in half of the patients. Only one third of patients with colonic involvement will develop structuring or penetrating lesions. Intestinal lesions of ulcerative colitis involve constantly the rectum and may extend continuously throughout the colon. At diagnosis, lesions involve the rectum, the left colon and most of the colon in similar proportions. Subsequent extension of the lesions over 20 years is observed in half of the patients. In Crohn's disease, 40%-50% of the patients require intestinal resection at 10 years. The risk of colectomy in ulcerative colitis is about 1% per year Dysplasia and cancer may complicate longstanding extensive colonic lesions in Crohn's disease and ulcerative colitis. Malignant transformation of chronic inflammatory lesions may also occur in patients with longstanding lesions of the small bowel in Crohn's disease.

Objective: No Crohn's disease (CD) molecular maker has advanced to clinical use, and independent lines of evidence support a central role of the gut microbial community in CD. Here we explore the feasibility of extracting bacterial protein signals relevant to CD, by interrogating myriads of intestinal bacterial proteomes from a small number of patients and healthy controls., Design: We first developed and validated a workflow-including extraction of microbial communities, two-dimensional difference gel electrophoresis (2D-DIGE), and LC-MS/MS-to discover protein signals from CD-associated gut microbial communities. Then we used selected reaction monitoring (SRM) to confirm a set of candidates. In parallel, we used 16S rRNA gene sequencing for an integrated analysis of gut ecosystem structure and functions., Results: Our 2D-DIGE-based discovery approach revealed an imbalance of intestinal bacterial functions in CD. Many proteins, largely derived from Bacteroides species, were over-represented, while under-represented proteins were mostly from Firmicutes and some Prevotella members. Most overabundant proteins could be confirmed using SRM. They correspond to functions allowing opportunistic pathogens to colonise the mucus layers, breach the host barriers and invade the mucosae, which could still be aggravated by decreased host-derived pancreatic zymogen granule membrane protein GP2 in CD patients. Moreover, although the abundance of most protein groups reflected that of related bacterial populations, we found a specific independent regulation of bacteria-derived cell envelope proteins., Conclusions: This study provides the first evidence that quantifiable bacterial protein signals are associated with CD, which can have a profound impact on future molecular diagnosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To explore the risk of new or recurrent cancer among patients with IBD and previous cancer, exposed or not to immunosuppressants., Design: Among the 17 047 patients of the CESAME prospective observational cohort who were enrolled from May 2004 to June 2005, and followed-up until December 2007, we identified 405 patients with cancer diagnosed previous to study entry. We calculated the rates of incident cancer in patients with or without previous cancer, and we assessed by survival analysis and nested case-control study the impact of immunosuppressants on the risk of incident new or recurrent cancer in patients with previous cancer., Results: The rate of incident cancer was 21.1/1000 patient-years (PY) and 6.1/1000 PY in patients with and without previous cancer, respectively. The multivariate-adjusted HR of incident cancer between patients with and without previous cancer was 1.9 (95% CI 1.2 to 3.0, p=0.003). Among patients with previous cancer, the rates of new and recurrent cancers were, respectively, 13.2/1000 PY and 6.0/1000 PY in the 312 patients who were not taking immunosuppressant at the time of study entry, and 23.1/1000 PY and 3.9/1000 PY in the 93 patients treated with immunosuppressants at study entry. There was no significant association between the exposure to immunosuppressants and the risk of new or recurrent cancer., Conclusions: Patients with IBD with a history of cancer are at increased risk of developing any (new or recurrent) cancer, with a predominant incidence of new cancers. Treatment with immunosuppressants has no overall major impact per se on this risk., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Crohn's disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). However, there are no guidelines for the screening and early diagnosis of SBA. Colorectal cancer associated with chronic colitis arises from dysplasia. High-risk patients benefit from surveillance colonoscopies aimed to detect dysplasia. The dysplasia-carcinoma sequence remains poorly documented in CD-associated SBA. Moreover, molecular data about SBA complicating CD and associated dysplasia are very limited. We therefore assessed dysplasia and several key molecular markers of carcinogenesis in SBA and dysplasia developed in patients with CD., Methods: Forty-five SBA complicating CD and 4 specimens with dysplasia without SBA were screened. In SBA, we looked for dysplasia and determined their pathological characteristics (type, grade, distribution). We also stained for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), p53, β-catenin, and p16 and looked for KRAS, BRAF and PIK3CA mutations., Results: All neoplastic lesions, except 1 lesion, were found in inflamed mucosal areas. Dysplasia was found in 20 of 41 patients with SBA (49%). Dysplasia was flat or raised, low grade or high grade, and adjacent or distant to concomitant SBA. Molecular markers of SBA carcinogenesis complicating CD were similar to those observed in chronic colitis-related colorectal cancer (KRAS, BRAF, p53, MSI), although differences were observed for β-catenin and p16. No PIK3CA mutations were observed., Conclusions: These results suggest that there is an inflammation-dysplasia-adenocarcinoma sequence in at least half of CD-related SBA, similar to what is observed in chronic colitis-related colorectal cancer and may have implications for the prevention and treatment of this cancer.

Background & Aims: Treatment with immunosuppressive thiopurines such as azathioprine is associated with an increased risk of leukemogenesis. We assessed the risk of myeloid disorders, such as acute myeloid leukemia and myelodysplastic syndromes, in a large cohort of patients with inflammatory bowel disease (IBD) in France., Methods: We performed a prospective observational study of 19,486 patients with IBD enrolled in the Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France (CESAME) study from May 2004 through June 2005; patients were followed through December 31, 2007. The incidence of myeloid disorders in the general population, which was used for reference, was determined from the French Network of Cancer Registries., Results: During 49,736 patient-years of follow-up, 5 patients were diagnosed with incident myeloid disorders (2 with acute myeloid leukemia and 3 with myelodysplastic syndromes). Four of these patients had been exposed to thiopurines (1 with ongoing treatment and 3 with past exposure). The risk of myeloid disorders was not increased among the overall IBD population, compared with the general population; the standardized incidence ratio (SIR) was 1.80 (95% confidence interval [CI], 0.58-4.20). The risk of myeloid disorders was not increased among patients with IBD and ongoing thiopurine treatment (SIR, 1.54; 95% CI, 0.05-8.54), but patients with past exposures to thiopurines had an increased risk of myeloid disorders (SIR, 6.98; 95% CI, 1.44-20.36)., Conclusions: Past exposure to thiopurines increases the risk of myeloid disorders 7-fold among patients with IBD. This finding should be considered when initiating thiopurine therapy, so risks and benefits can be calculated., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The effects of extra-intestinal cancer on the course of inflammatory bowel disease (IBD) are poorly understood., Aim: To evaluate the impact of cancer and its management on IBD outcomes., Methods: A total 80 IBD patients (51 Crohn's disease, 29 ulcerative colitis; 33 men, median age at cancer diagnosis 48yrs) diagnosed with extra-intestinal cancer were selected from a prospective database. IBD activity and therapeutic requirements (assessed year-by-year) were compared before and after cancer diagnosis, with a control group of patients without cancer matched for gender, birth date, date of IBD diagnosis and IBD phenotype., Results: Paired comparisons of the consecutive periods before and after cancer diagnosis did not show significant changes in median (IQR) percentages of years with active disease (27% [0-50] vs. 19% [0-53]), while the proportion of patient-years on any immunosuppressant remained stable (26% vs. 28%). Chemotherapy had no significant effect on IBD activity. Compared to controls, patients with cancer had a similar IBD activity and use of anti-TNF, but less use of immunomodulators (19% vs. 25%, p<0,001) and an increased rate of surgery (4% vs. 2.5%, p<0,05). Individual variations in IBD activity after cancer diagnosis were not significantly different in patients with cancer and their matched controls., Conclusion: Occurrence of extra-intestinal cancer impacts IBD therapeutic management, with a trend towards less use of immunomodulators and more surgery. In the long-term, cancer diagnoses and treatments do not modify IBD outcomes., (Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Inflammatory bowel diseases can favour the occurrence of colon cancer while their treatments can increase the risk of certain other cancers. The doctor's skill lies in striking the right benefit-risk balance of the treatments.

The incidence of lymphoproliferative disorders (LD) is increasing in developed countries. Patients with inflammatory bowel disease (IBD) exposed to thiopurines are at additional risk of three specific forms of LD: Epstein-Barr-Virus-related post-transplant like LD, hepato-splenic T-cell lymphoma and post-mononucleosis lymphoproliferation. The risk of the two latter forms of LD can be reduced when considering specific immunosuppressive strategies in young males. It is still unclear whether the risk of uterine cervix abnormalities is increased in IBD women, irrespective of the use of immunosuppressants. Given the excess risk demonstrated in various other contexts of immunosuppression, it is currently recommended that all women with IBD, particularly those receiving immunosuppressants, strictly adhere to a screening program of cervical surveillance and undergo vaccination against HPV, when appropriate. Patients with IBD receiving immunosuppressants are at increased risk of skin cancers. The risk of non-melanoma skin cancer is notably increased in patients receiving thiopurines. Recent data suggest that the risk of melanoma is mildly increased in patients exposed to anti-TNF therapy. All IBD patients should adhere to a program of sun protection and dermatological surveillance, whose details should take into account the other non-IBD-related risk factors., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)

In inflammatory bowel disease (IBD) patients, thiopurines promote carcinogenesis of Epstein-Barr Virus (EBV)-related lymphomas, non-melanoma skin cancers and urinary tract cancers, while anti-TNF agents could promote carcinogenesis of melanomas. Patients with IBD and previous cancer are at a higher risk of developing new or recurrent cancer than IBD patients without a history of cancer, irrespective of the use of immunosuppressants. In transplant recipients, the use of thiopurines is associated with a high rate of cancer recurrence, particularly within the first two years following transplantation. In patients with chronic inflammatory disease, limited data suggest that no dramatic incidence of cancer recurrence is associated with the use of thiopurines or anti-TNF agents. However, there is a rationale for a two-year drug holiday from immunosuppressants after the diagnosis and treatment of the majority of incident cancers, as often as possible. Extending the duration of the immunosuppressant drug holiday to 5 years in patients with previous cancers associated with a high risk of recurrence in the post-transplant state should be considered. The immunosuppressants that can be initiated or resumed after cancer treatment should be chosen according to the type of the previous cancer. All individual decisions should be made on a case-by-case basis, together with the oncologist, according to characteristics and expected evolution of the index cancer, expected impact of the immunosuppressants on cancer evolution, and intrinsic severity of IBD, with its associated risks.

Background: Mastocytosis is a heterogeneous disease characterized by mast cell accumulation in 1 or more organs. Gastrointestinal manifestations of systemic mastocytosis have been previously studied in small cohorts of patients, and no specific histologic description is available., Objective: We sought to assess the clinical and pathologic features of gastrointestinal manifestations in patients with mastocytosis., Methods: Medical history and gastrointestinal symptoms of patients with mastocytosis (n = 83) were compared with those of matched healthy subjects (n = 83) by means of patient questionnaire. Data were analyzed for epidemiologic, clinical, biological, and genetic factors associated with gastrointestinal symptoms for patients with mastocytosis. A comparative analysis of gastrointestinal histology from patients with mastocytosis (n = 23), control subjects with inflammatory bowel disease (n = 17), and healthy subjects (n = 19) was performed., Results: The following gastrointestinal symptoms occurred more frequently and were more severe in patients with mastocytosis than in healthy subjects: bloating (33% vs 7.2%, P < .0001), abdominal pain (27.3% vs 4.8%, P < .0001), nausea (23% vs 8.4%, P = .02), and diarrhea (33.85% vs 1.2%, P < .0001). Patients with mastocytosis had a significantly higher incidence of personal history of duodenal ulcer (P = .02). Wild-type (WT) c-Kit was associated with diarrhea (P = .03). Specific histologic lesions were present in patients with mastocytosis but were not correlated with clinical symptoms., Conclusion: Gastrointestinal manifestations in patients with mastocytosis are highly prevalent and often severe. Clinical symptoms do not correspond to histologic findings, are nonspecific, and can simulate irritable bowel syndrome., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response against the tumor and immunosuppression is known to increase the risk for certain tumors.This article reviews current literature on the role of inflammation in cancer and the cancer risk in immune-mediated inflammatory diseases (IMIDs). We discuss the effect on cancer risk of different drug classes used in the treatment of IMIDs treatment, including biologicals such as tumor necrosis factor (TNF) inhibitors.Overall cancer incidence and mortality risk are similar to the general population in inflammatory bowel disease (IBD), and slightly increased for rheumatoid arthritis and psoriasis, with risk profiles differing for different tumor types. Increased risk for non-melanoma skin cancer is associated with thiopurine treatment in IBD, with the combination of anti-TNF and methotrexate in rheumatoid arthritis and with PUVA, cyclosporine and anti-TNF treatment in psoriasis. Data on the safety of using biologic or immunosuppressant therapy in IMID patients with a history of cancer are scarce.This review provides clinicians with a solid background to help them in making decisions about treatment of immune-mediated diseases in patients with a tumor history.This article is related to another review article in Molecular Cancer: http://www.molecular-cancer.com/content/12/1/86.

Background: Patients with Crohn's disease (CD) of the colon are at risk for colorectal cancer and should be screened for dysplasia and cancer of the colon. Small bowel adenocarcinoma (SBA) is a complication of small bowel CD and carries a poor prognosis. However, there is no screening test for SBA in patients with small bowel CD. The aim of this study was to assess the risk and incidence of SBA in a large prospective cohort of patients with small bowel CD and to compare it with the risk of colorectal cancer in patients with CD involving the colon, recruited in the same cohort., Methods: In a nationwide French cohort, 11,759 patients with CD were enrolled by 680 gastroenterologists. The SBA risk was obtained by dividing the observed cases in our cohort to the expected cases in the general population., Results: At baseline, 8222 (69.9%) patients had small bowel CD (either alone or associated with colonic CD); their median follow-up was 35 months (interquartile range, 29-40). Five new cases of SBA were diagnosed, all in patients with small bowel CD, within inflamed areas. Among the 5 patients with incident SBA, 4 died of SBA and 1 is in remission 7 years after the diagnosis of SBA. The incidence rates of SBA were 0.235 per 1000 patient-years (95% confidence interval [CI], 0.076-0.547) among patients with small bowel CD and 0.464 per 1000 patient-years (95% CI, 0.127-1.190) among those with small bowel CD for >8 years. This accounted for approximately 30% of the risk of colorectal cancer in patients with CD of the colon. Patients with small bowel CD and small bowel CD for >8 years had an SBA standardized incidence ratio of 34.9 (95% CI, 11.3-81.5) and 46.0 (95% CI, 12.5-117.8), respectively., Conclusions: SBA in patients with small bowel CD carries a poor prognosis, and its risk is approximately 30% of colorectal cancer risk in patients with CD of the colon. Further studies should determine if small bowel endoscopic screening in high-risk patients is feasible and effective.

Background & Aims: Saccharomyces boulardii is a probiotic yeast that has been shown to have beneficial effects on the intestinal epithelial barrier and digestive immune system. There is preliminary evidence that S boulardii could be used to treat patients with Crohn's disease (CD). We performed a randomized, placebo-controlled trial to evaluate the effects of S boulardii in patients with CD who underwent remission during therapy with steroids or aminosalicylates., Methods: We performed a prospective study of 165 patients who achieved remission after treatment with steroids or salicylates; they were randomly assigned to groups given S boulardii (1 g/day) or placebo for 52 weeks. The primary end point was the percentage of patients in remission at week 52. Time to relapse, Crohn's disease activity index scores, and changes in parameters of inflammation were secondary end points., Results: CD relapsed in 80 patients, 38 in the S boulardii group (47.5%) and 42 in the placebo group (53.2%, a nonsignificant difference). The median time to relapse did not differ significantly between patients given S boulardii (40.7 weeks) vs placebo (39.0 weeks). There were no significant differences between groups in mean Crohn's disease activity index scores or erythrocyte sedimentation rates or in median levels of C-reactive protein. In a post hoc analysis, nonsmokers given S boulardii were less likely to experience a relapse of CD than nonsmokers given placebo, but this finding requires confirmation., Conclusions: Although the probiotic yeast S boulardii is safe and well tolerated, it does not appear to have any beneficial effects for patients with CD in remission after steroid or salicylate therapies., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: There is an unclear risk of colonic high-grade dysplasia (HGD) and colorectal cancer (CRC) among patients with inflammatory bowel disease (IBD) treated with immunosuppressants. We analyzed data on CRC development among patients with IBD enrolled in the observational cohort Cancers et Surrisque Associé aux Maladies Inflammatoires Intestinales En France (CESAME)., Methods: We followed and collected data from 19,486 patients with IBD (60.3% with Crohn's disease, 30.1% receiving thiopurine therapy) enrolled in CESAME from May 2004 and June 2005, and followed them until December 2007. When the study began, 2841 patients (14.6%) were characterized as having long-standing extensive colitis (ie, >10 years and involving ≥50% of the colon). Early lesions (HGD and CRC) were defined as those diagnosed within 10 years after diagnosis of IBD., Results: Thirty-seven patients developed CRC during the follow-up period, and 20 developed colorectal HGD. The standardized incidence ratios of CRC were 2.2 for all IBD patients (95% confidence interval [CI]: 1.5-3.0; P < .0001), 7.0 for patients with long-standing extensive colitis (95% CI: 4.4-10.5; P < .001), and 1.1 for patients without long-standing extensive colitis (95% CI: 0.6-1.8; P = .84). Among patients with long-standing extensive colitis, the multivariate adjusted hazard ratio for colorectal HGD and cancer was 0.28 for those who received thiopurines compared with those who never received thiopurine therapy (95% CI: 0.1-0.9; P = .03). Twenty-two patients developed early lesions; 7 of these were related to IBD, based on histologic analysis., Conclusions: Patients with IBD and long-standing extensive colitis are at increased risk for CRC, although the risk is lower among patients receiving thiopurine therapy. Patients without long-standing extensive colitis have a risk for CRC similar to that of the general population, but they can develop IBD-related lesions within 10 years after diagnosis of IBD., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Little is known about the long-term outcomes of patients with Crohn's disease (CD) who have a complete response to therapy with azathioprine. We assessed the long-term effects of azathioprine in responders., Methods: We collected data from the MICISTA registry (a database from the Rothschild and Saint-Antoine Hospitals, Paris, France) on consecutive CD patients treated with azathioprine from 1987 to 1999 who responded to therapy (steroid-free clinical remission at 1 y); they were followed up until 2011 (n = 220; 86 men; median age, 32 y; median follow-up period, 12.6 y). Data were compared with those from 440 matched patients with CD who did not receive immunosuppressants during the same inclusion period (controls)., Results: The cumulative rate of sustained remission 10 years after treatment with azathioprine was 38%. Among patients exposed to azathioprine during a prospective follow-up period (1995-2011, 1936 patient-years), the percentage of patient-years with active disease (flare or complication during the calendar year) was 17.6%. Compared with the control group, at baseline, responders were more often active smokers with significantly more extensive disease, perianal lesions, and extradigestive manifestations. During follow-up evaluation, responders had a significantly reduced risk of intestinal surgery (adjusted odds ratio, 0.69; 95% confidence interval, 0.52-0.91) and perianal surgery (adjusted odds ratio, 0.36; 95% confidence interval, 0.27-0.46). A significantly higher percentage of responders developed cancers, including nonmelanoma skin cancers, compared with controls (9.5% vs 4.1%; P < .01). Survival rates after 20 years were 92.8% ± 2.3% of responders vs 97.9% ± 0.8% of controls (P = .01)., Conclusions: Based on a study at a single center, patients with CD who responded to azathioprine had a smaller proportion of patient-years with active disease, and were less likely to be hospitalized or undergo intestinal surgery, than patients with CD who did not receive immunosuppressants. These benefits, however, could be offset by an increased risk of malignancies., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Gut microbiota metabolises bile acids (BA). As dysbiosis has been reported in inflammatory bowel diseases (IBD), we aim to investigate the impact of IBD-associated dysbiosis on BA metabolism and its influence on the epithelial cell inflammation response., Design: Faecal and serum BA rates, expressed as a proportion of total BA, were assessed by high-performance liquid chromatography tandem mass spectrometry in colonic IBD patients (42) and healthy subjects (29). The faecal microbiota composition was assessed by quantitative real-time PCR. Using BA profiles and microbiota composition, cluster formation between groups was generated by ranking models. The faecal BA profiles in germ-free and conventional mice were compared. Direct enzymatic activities of BA biotransformation were measured in faeces. The impact of BA on the inflammatory response was investigated in vitro using Caco-2 cells stimulated by IL-1β., Results: IBD-associated dysbiosis was characterised by a decrease in the ratio between Faecalibacterium prausntizii and Escherichia coli. Faecal-conjugated BA rates were significantly higher in active IBD, whereas, secondary BA rates were significantly lower. Interestingly, active IBD patients exhibited higher levels of faecal 3-OH-sulphated BA. The deconjugation, transformation and desulphation activities of the microbiota were impaired in IBD patients. In vitro, secondary BA exerted anti-inflammatory effects, but sulphation of secondary BAs abolished their anti-inflammatory properties., Conclusions: Impaired microbiota enzymatic activity observed in IBD-associated dysbiosis leads to modifications in the luminal BA pool composition. Altered BA transformation in the gut lumen can erase the anti-inflammatory effects of some BA species on gut epithelial cells and could participate in the chronic inflammation loop of IBD.

Acute diarrhea is defined as an abnormally frequent discharge of semisolid or fluid fecal matter from the bowel, lasting less than 14 days. More than three millions cases of acute diarrhea, presumably due to intestinal infections, are seen in general practice every year in France. Most of the cases are benign and resolve under symptomatic treatment within 3 days, without need for biological tests or antibiotics. In special contexts (septicemic syndrome, visible blood in stools, severe dehydration, patients at risk of severe sepsis [valvulopathy]), biologic tests and probabilist antibiotic treatment are required. Hygiene, rehydration and diet recommendations are always part of the treatment of acute diarrhea, in addition to the symptomatic treatment of diarrhea and other digestive symptoms. Antibiotic-associated diarrhea is clinically benign in most cases, and attributed to transient dysbiosis of gut microbiota. In the remaining cases, diarrhea is the clinical expression of intestinal infection by Clostridium difficile, that should be treated with metronidazole, or the clinical expression of a Klebsiella oxytoca-associated colitis that usually spontaneously resolves after stopping antibiotics., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Thiopurines promote Epstein-Barr virus-related lymphomas, nonmelanoma skin cancers and acute myeloid leukemias. Anti-tumor necrosis factor (anti-TNF) agents may inhibit or activate carcinogenesis according to the cellular pathways that are activated. A mild increase in the risk of melanoma has been reported in patients exposed to anti-TNF agents. Transplanted patients with previous history of cancer are at high risk of cancer recurrence when receiving posttransplant immunosuppressive therapy, particularly within the first 2 years of treatment. Few data exist for patients with chronic inflammatory disease. In the CESAME cohort that included essentially patients receiving thiopurines, there was no excess incidence of recurrent or new cancer associated with exposure to immunosuppressive therapy in the patients with previous cancer at cohort entry. In clinical practice, the decision to start or resume immunosuppressive therapy in inflammatory bowel disease (IBD) patients with recent cancer should be discussed case by case with cancer specialists. However, taken into account the experience of transplant specialists, it could be suggested not to consider a waiting period for women with adequately treated uterine high-grade cervical dysplasia. For invasive cancers, a waiting period of 2 years should be considered if possible. During this period, treatment of IBD should be restricted to 5-aminosalicylic acid, steroids, nutritional therapy, or surgery, except in case of aggressive IBD that cannot be controlled by these methods. A longer waiting period of 5 years could be recommended for the most aggressive forms of cancers, such as melanomas, aggressive breast cancers, sarcomas, urinary tract cancers, and myelomas., (© 2013 S. Karger AG, Basel.)

We report the findings and outputs of an international expert opinion process to develop a definition of early Crohn's disease (CD) that could be used in future disease-modification trials. Nineteen experts on inflammatory bowel diseases held an international expert opinion meeting to discuss and agree on a definition for early CD to be used in disease-modification trials. The process included literature searches for the relevant basic-science and clinical evidence. A published preliminary definition of early CD was used as the basis for development of a proposed definition that was discussed at the expert opinion meeting. The participants then derived a final definition, based on best current knowledge, that it is hoped will be of practical use in disease-modification trials in CD.

Background & Aims: New therapeutic strategies are needed for patients with refractory Crohn's disease (CD). We evaluated data from the Crohn's And Treg Cells Study (CATS1) to determine the safety and efficacy of antigen-specific T-regulatory (Treg) cells for treatment of patients with refractory CD., Methods: We performed a 12-week, open-label, multicenter, single-injection, escalating-dose, phase 1/2a clinical study in 20 patients with refractory CD. Ovalbumin-specific Treg cells (ova-Tregs) were isolated from patients' peripheral blood mononuclear cells (PBMCs), exposed to ovalbumin, and administrated intravenously. Safety and efficacy were assessed using clinical and laboratory parameters. We evaluated proliferation of PBMCs in response to ovalbumin., Results: Injections of ova-Tregs were well tolerated, with 54 adverse events (2 related to the test reagent) and 11 serious adverse events (3 related to the test reagent, all recovered). Overall, a response, based on a reduction in Crohn's Disease Activity Index (CDAI) of 100 points, was observed in 40% of patients at weeks 5 and 8. Six of the 8 patients (75%) who received doses of 10(6) cells had a response at weeks 5 and 8, with a statistically significant reduction in CDAI. In this group, remission (based on CDAI ≤150) was observed in 3 of 8 patients (38%) at week 5 and 2 of 8 patients (25%) at week 8., Conclusions: Administration of antigen-specific Tregs to patients with refractory CD (CATS1) was well tolerated and had dose-related efficacy. The ovalbumin-specific immune response correlated with clinical response, supporting immune-suppressive mechanisms of ova-Tregs. The consistency of results among different assessment methods supports the efficacy of ova-Tregs; this immune therapy approach warrants further clinical and mechanistic studies in refractory CD. Eudract, Number: 2006-004712-44., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: It remains to be shown whether inflammatory bowel disease (IBD) is associated with an increased risk of primary intestinal lymphoproliferative disorders (PILD). We assessed this risk in the CESAME French nationwide prospective observational cohort., Methods: In all, 680 gastroenterologists enrolled 19,486 patients with IBD (Crohn's disease in 60.3%) from May 2004 to June 2005. Follow-up ended on 31 December 2007. Available biopsy samples and surgical specimens from patients with PILD (n = 14) were centralized for review. The reference incidence of PILD in the general population was obtained from the Côte d'Or registry and was used as a comparator to assess the standardized incidence ratio (SIR). The influence of thiopurine exposure was explored in a nested case-control study., Results: In the CESAME population the crude incidence of PILD was 0.12/1000 patient-years, with a corresponding SIR of 17.51 (95% confidence interval [CI], 6.43-38.11; P < 0.0001). The risk was highest in patients exposed to thiopurines (SIR 49.52, 95% CI 13.49-126.8; P < 0.0001), while it did not reach statistical significance in patients naïve to thiopurines (SIR 4.83, 95% CI, 0.12-26.91; P = 0.37). The odds ratio associated with ongoing thiopurine exposure (vs. naïve) was 2.97 (95% CI, 0.30-infinity; P = 0.38). All 14 cases of PILD were non-Hodgkin's B-cell LD, 78.6% occurred in males, 85.7% arose in IBD lesions, and 45.5% were Epstein-Barr virus-positive. Eleven cases occurred in patients with Crohn's disease. Mean (SD) age at PILD diagnosis was 55.1 (5.6) years and the median time since IBD onset was 8.0 years (interquartile range, 3.0-15.8)., Conclusions: Patients with IBD have an increased risk of developing PILD., (Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.)

Patients with extensive or complicated Crohn's disease (CD) at diagnosis should be treated straightaway with immunosuppressive therapy according to the most recent guidelines. In patients with localized and uncomplicated CD at diagnosis, early use of immunosuppressive therapy is debated for preventing disease progression and limiting the disabling clinical impact. In this context, there is a need for predictors of benign or unfavourable subsequent clinical course, in order to avoid over-treating with risky drugs those patients who would have experienced spontaneous mid-term asymptomatic disease without progression towards irreversible intestinal lesions. At diagnosis, an age below 40 years, the presence of perianal lesions and the need for treating the first flare with steroids have been consistently associated with an unfavourable subsequent 5-year or 10-year clinical course. The positive predictive value of unfavourable course in patients with 2 or 3 predictors ranges between 0.75 and 0.95 in population-based and referral centre cohorts. Consequently, the use of these predictors can be integrated into the elements that influence individual decisions. In the CD postoperative context, keeping smoking and history of prior resection are the strongest predictors of disease symptomatic recurrence. However, these clinical predictors alone are not as reliable as severity of early postoperative endoscopic recurrence in clinical practice. In ulcerative colitis (UC), extensive colitis at diagnosis is associated with unfavourable clinical course in the first 5 to 10 years of the disease, and also with long-term colectomy and colorectal inflammation-associated colorectal cancer. In patients with extensive UC at diagnosis, a rapid step-up strategy aiming to achieve sustained deep remission should therefore be considered. At the moment, no reliable serological or genetic predictor of inflammatory bowel disease clinical course has been identified.

Background: Epidemiologic data suggest that smoking increases the risk and the severity of Crohn's disease (CD), although it may protect patients with ulcerative colitis (UC). To investigate this paradox, we evaluated the effect of cigarette smoke in the function of blood mononuclear cells from healthy subjects and patients with CD or UC in flare up., Methods: The production of mediators associated with inflammation but also with protective functions was evaluated by enzyme-linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA), following either in vivo or in vitro exposure to cigarette smoke., Results: We found that mononuclear cells from smokers with CD were functionally impaired. These cells secreted lower levels of chemokines and cytokines as compared with nonsmoker counterparts, whereas healthy smokers or smokers with UC were not affected. Similar findings were noted after in vitro exposure to cigarette smoke extract. In addition, cells from patients with CD who smoke presented a defective sensitivity to antiinflammatory or antioxidant protection, and particularly synthesized lower levels of cytoprotective Hsp70. The effects observed were not due to diminished cell viability. Our experiments suggest that cigarette smoke-related responses were largely dependent on oxidative stress generated, and not on the nicotine component., Conclusions: Overall, our data point out the presence of biological differences between blood mononuclear cells from patients with CD and UC toward cigarette smoke that might support its opposite role in both diseases., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Background & Aims: Recent studies reported a role for more than 70 genes or loci in the susceptibility to Crohn's disease (CD). However, the impact of these associations in clinical practice remains to be defined. The aim of the study was to analyse the relationship between genotypes and phenotypes for the main 53 CD-associated polymorphisms., Method: A cohort of 798 CD patients with a median follow up of 7 years was recruited by tertiary adult and paediatric gastroenterological centres. A detailed phenotypic description of the disease was recorded, including clinical presentation, response to treatments and complications. The participants were genotyped for 53 CD-associated variants previously reported in the literature and correlations with clinical sub-phenotypes were searched for. A replication cohort consisting of 722 CD patients was used to further explore the putative associations., Results: The NOD2 rare variants were associated with an earlier age at diagnosis (p = 0.0001) and an ileal involvement (OR = 2.25[1.49-3.41] and 2.77 [1.71-4.50] for rs2066844 and rs2066847, respectively). Colonic lesions were positively associated with the risk alleles of IL23R rs11209026 (OR = 2.25 [1.13-4.51]) and 6q21 rs7746082 (OR = 1.60 [1.10-2.34] and negatively associated with the risk alleles of IRGM rs13361189 (OR = 0.29 [0.11-0.74]) and DEFB1 rs11362 (OR = 0.50 [0.30-0.80]). The ATG16L1 and IRGM variants were associated with a non-inflammatory behaviour (OR = 1.75 [1.22-2.53] and OR = 1.50 [1.04-2.16] respectively). However, these associations lost significance after multiple testing corrections. The protective effect of the IRGM risk allele on colonic lesions was the only association replicated in the second cohort (p = 0.03)., Conclusions: It is not recommended to genotype the studied polymorphisms in routine practice.

Most of the immunosuppressive therapy-associated excess lymphomas in IBD are due to a loss of control of Epstein-Barr virus (EBV) infection. Systemic EBV viral-load monitoring and preemptive treatments are extensively used in the posttransplant setting, but these methods have not yet been evaluated in IBD patients and cannot therefore be recommended in this context. However, the systemic EBV viral load should be measured in cases of unexplained fever, lymphadenopathy or hemophagocytic syndrome, in order to optimize the diagnostics of early EBV-related lymphoproliferations. The risk of hepatosplenic T cell lymphoma can, theoretically, be limited by avoiding prolonged combination therapy with thiopurines and anti-tumor necrosis factor (anti-TNF) beyond 2 years in young males. Young males seronegative for EBV are at risk for fatal forms of primary EBV infection, with postmononucleosis lymphoproliferation. This incidence could be limited by considering avoiding treatment with thiopurines in this subgroup of patients. There is a marked excess risk of nonmelanoma skin cancer in IBD patients currently or previously treated with thiopurines, which justifies lifelong sun protection and dermatological screening in these patients. The level of risk is still unclear for monotherapies with anti-TNF. An excess of human papilloma virus (HPV)-related uterine cervix dysplasia and cancer has been reported in various populations of women with IBD, but the proper role of immunosuppressive therapy remains to be quantified. However, yearly screening for uterine cervix abnormalities is recommended for all female IBD patients, along with HPV vaccination in young girls., (Copyright © 2012 S. Karger AG, Basel.)

Background & Aims: Patients with inflammatory bowel disease (IBD) who have been exposed to thiopurines might have an increased risk of skin cancer. We assessed this risk among patients in France., Methods: We performed a prospective observational cohort study of 19,486 patients with IBD, enrolled from May 2004 to June 2005, who were followed up until December 31, 2007. The incidence of nonmelanoma skin cancer (NMSC) in the general population, used for reference, was determined from the French Network of Cancer Registries., Results: Before the age of 50 years, the crude incidence rates of NMSC among patients currently receiving or who previously received thiopurines were 0.66/1000 and 0.38/1000 patient-years, respectively; these values were 2.59/1000 and 1.96/1000 patient-years for the age group of 50 to 65 years and 4.04/1000 and 5.70/1000 patient-years for patients older than 65 years. Among patients who had never received thiopurines, the incidence of NMSC was zero before the age of 50 years, 0.60/1000 for the ages of 50 to 65 years, and 0.84/1000 for those older than 65 years. A multivariate Cox regression model stratified by propensity score quintiles showed that ongoing thiopurine treatment (hazard ratio [HR], 5.9; 95% confidence interval [CI], 2.1-16.4; P = .0006) and past thiopurine exposure (HR, 3.9; 95% CI, 1.3-12.1; P = .02) were risk factors for NMSC. They also identified age per 1-year increase as a risk factor for NMSC (HR, 1.08; 95% CI, 1.05-1.11; P < .0001)., Conclusions: Ongoing and past exposure to thiopurines significantly increases the risk of NMSC in patients with IBD, even before the age of 50 years. These patients should be protected against UV radiation and receive lifelong dermatologic screening., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Nodular regenerative hyperplasia (NRH) is a rare hepatic disorder that may lead to severe portal hypertension. Cases of NRH have been reported in patients receiving thiopurines for inflammatory bowel disease (IBD). Since azathioprine (AZA) is used more and more frequently as a maintenance treatment in IBD, the risk of NRH must be known. The objective of this study was to evaluate the prevalence of NRH and its predictive factors in IBD patients treated with AZA., Materials and Methods: From the same tertiary referral center, 1888 consecutive IBD patients treated with AZA were studied. Clinical diagnosis of NRH was proven by liver biopsy in all cases except one. The cumulative risk of NRH was estimated with the Kaplan-Meier method. Factors associated with NRH were tested independently with the log-rank method and multivariate proportional hazards model with time-dependent covariates., Results: Fifteen patients developed NRH in a median treatment duration of 52.4 months (SE 1.6). The cumulative incidence of NRH was 1.28±0.45% at 10 years. Only two variables were independently associated with NRH occurrence: male gender (P=0.0001, hazard ratio [HR] 8.5, 95% confidence interval [CI] 1.9-37.9) and small bowel resection≥50 cm (P<0.0001, HR 6.6, 95% CI 2.2-20.0), either prior to or after AZA initiation., Conclusions: The risk of developing NRH during AZA treatment is low. This study suggests that male patients with small bowel resection≥50 cm constitute the group with the higher risk of developing NRH while treated with AZA.

Background and Aims: Few studies have been conducted addressing the safety of thiopurine treatment in pregnant women with inflammatory bowel disease (IBD). The aim of this study was to evaluate the pregnancy outcome of women with IBD who have been exposed to thiopurines., Methods: 215 pregnancies in 204 women were registered and documented in the CESAME cohort between May 2004 and October 2007. Physicians documented the following information from the women: last menstrual date, delivery term, details of pregnancy outcome, prematurity, birth weight and height, congenital abnormalities, medication history during each trimester, smoking history and alcohol ingestion. Data were compared between three groups: women exposed to thiopurines (group A), women receiving a drug other than thiopurines (group B) and women not receiving any medication (group C)., Results: Mean age at pregnancy was 28.3 years. 75.7% of the women had Crohn's disease and 21.8% had ulcerative colitis, with a mean disease duration of 6.8 years at inclusion. Of the 215 pregnancies, there were 138 births (142 newborns), and the mean birth weight was 3135 g. There were 86 pregnancies in group A, 84 in group B and 45 in group C. Interrupted pregnancies occurred in 36% of patients enrolled in group A, 33% of patients enrolled in group B, and 40% of patients enrolled in group C; congenital abnormalities arose in 3.6% of group A cases and 7.1% of group B cases. No significant differences were found between the three groups in overall pregnancy outcome., Conclusions: The results obtained from this cohort indicate that thiopurine use during pregnancy is not associated with increased risks, including congenital abnormalities.

Myeloid differentiation (MD)-2 is linked to the cell surface as a Toll-like receptor (TLR) 4-bound protein though may also function as a soluble receptor to enable the lipopolysaccharide (LPS)-driven response. We recently demonstrated the importance of MD-2 either as a cell-associated or as a soluble receptor in the control of intestinal epithelial cell response toward LPS. High levels of circulating MD-2 were recently proposed as a risk factor for infectious/ inflammatory diseases as septic shock. We hypothesized that MD-2 might be present in sera from patients with inflammatory bowel disease and have pathogenic consequences. We analysed MD-2 activity in sera from patients with inflammatory bowel disease or from healthy subjects. We measured MD-2 activity as the capacity to mediate LPS-driven stimulation of intestinal epithelial cells (HT29). We found that sera from patients with inflammatory bowel disease, particularly Crohn's disease, endowed HT29 cells with a markedly higher LPS-dependent stimulating capacity as compared to sera from healthy subjects. The effect of sera was specific for LPS activation and was reduced in the presence of anti-MD-2, and anti-TLR4 antibodies. We conclude that sera from patients with inflammatory bowel disease might contain increased MD-2. This might result in higher local availability of the protein leading to a loss of tolerance toward gut microbiota.

Gastrointestinal symptoms occurring in patients with Crohn's disease (CD) can be related to disease activity or to intercurrent infection. Absence of appropriate stool work-up can lead to misdiagnosis and wrong treatment. We report here two cases of acute cryptosporidiosis in patients with CD. This microorganism can trigger IBD flare or cause severe infections in immunocompromised host. Adding specific search for oocysts of Cryptosporidium parvum using the Ziehl-Neelsen technique to the microbiologic work-up from stools in patients with Crohn's disease seeking medical intervention for sudden exacerbation of digestive symptoms seems to be recommended., (Copyright © 2010. Published by Elsevier B.V.)

Objectives: Colorectal cancer (CRC), developing from dysplastic lesions, is the main long-term complication of pancolitis. The aims of the present study were to assess the risks for neoplasia and advanced neoplasia (AN), respectively, in ulcerative colitis (UC) and Crohn's disease (CD) patients with pancolitis, and to search for protective and risk factors for colorectal neoplasia., Methods: A total of 855 inflammatory bowel disease (IBD) patients with longstanding pancolitis (276 UC, 56 IBD unclassified (IBDu), and 523 CD) had pathological examination of a proctocolectomy specimen (n=255) or multiple biopsy samples from a surveillance colonoscopy (n=600) after median disease duration of 115 months. Risk factors for low-grade dysplasia (LGD) and AN, respectively, were searched for in the whole group of patients and in a case-control comparison after matching for IBD phenotype., Results: A total of 75 patients eventually developed colorectal neoplasia: 14 adenomas, 28 nonadenomatous LGD, and 33 ANs. The 25-year cumulative risks for neoplasia and AN, respectively, were 32.8±5.7% and 25.9±5.7% in UC and IBDu vs. 12.1±2.7% and 3.9±2.0% in CD (P<0.0001). In CD, patients with UC-like endoscopic appearance (n=126) had an increased risk for AN compared with those with discrete lesions (at 25 years, 10.6±7.2 vs. 1.5±0.9%). In the case-control comparison, factors associated with an increased risk of AN were primary sclerosing cholangitis (hazard ratio (HR) 4.72 (1.54-14.52)) and family history of CRC (HR 3.37 (1.02-11.14)), whereas previous segmental colectomy was protective (HR 0.25 (0.07-0.88))., Conclusions: The risk of AN in longstanding pancolitis is higher in UC or IBDu than in CD. In CD, this risk is significantly increased in patients with UC-like endoscopic lesions. The surveillance program should focus on these latter patients.

Mastocytosis is a rare and heterogeneous disease characterized by various biological and clinical features with different prognosis and treatments. The disease is usually divided into 2 categories: a pure cutaneous and a systemic disease. Clinical features can be related to mast cells' mediators release or to pathological mast cells infiltration. The diagnosis of mastocytosis is based on clinical, biological, histological, and molecular international criteria. Among all manifestations of the disease, gastrointestinal (GI) symptoms are common and can significantly impair the quality of life. The aim of this article is to review the data regarding GI involvement in mastocytosis. Articles dealing with clinical, pathophysiological, and therapeutic aspects of mastocytosis GI tract involvement were searched for using PubMed. GI manifestations in mastocytosis are reviewed. Pathogenesis of GI symptoms in systemic mastocytosis and their treatment are critically discussed. The most frequent GI symptoms are abdominal pain, diarrhea, nausea, and vomiting. GI lesions may involve all the digestive tract, from the esophagus to the rectum. The histological diagnosis of GI involvement is difficult. The treatment of GI symptoms aims to prevent and limit mast cells degranulation and/or its consequences and more rarely to control tumoral mast cells infiltration. The high prevalence of GI symptoms in mastocytosis and their important functional impact deserves better characterization and treatment in order to improve patients' quality of life. Diagnosis of mastocytosis GI manifestations should be evoked in the case of unexplained severe GI disorders.

Background: Childhood-onset Crohn's disease (CD) might reflect a more severe form of disease. To test this hypothesis we analyzed the long-term natural history of CD in an adult cohort of patients with childhood-onset compared to adult-onset CD., Methods: We selected 206 childhood-onset CD patients among 2992 adult patients with a diagnosis of CD established before December 31, 2000. Disease characteristics were prospectively assessed during follow-up until December 2007 and compared to adult-onset CD patients matched 2 to 1 on gender, year of CD diagnosis, and disease location., Results: Compared to adult-onset CD, patients with childhood-onset CD were more likely to have a severe disease, with an increased year-by-year disease activity index (37% of patient-years in childhood-onset group versus 31% in the adult-onset group, P < 0.001). Immunosuppressant requirement was also increased with a 10-year cumulative risk of 54 +/- 3% in childhood-onset CD group versus 45 +/- 2%, in the adult-onset CD group (P < 0.001). Cumulative risks of stricturing and penetrating complications and surgical resections were not statistically different between groups. Accordingly, these events occurred at a younger age in the childhood-onset CD group. At the age of 30 years the actuarial risk of having undergone an extensive intestinal resection was 48 +/- 5% in the childhood-onset group versus 14 +/- 2% in the adult-onset group (P < 0.001)., Conclusions: Patients with childhood-onset CD exhibit a more active disease and require more immunosuppressive therapy. This feature is observed irrespective of the disease location, suggesting an intrinsic more severe phenotype.

Antibiotic-associated diarrhea (AAD) is associated with altered intestinal microflora and other symptoms that may lead to possibly death. In critically ill patients, diarrhea increases rates of morbimortality. Assessing diarrhea risks is thus important for clinicians. For this reason, we conducted a hypothesis-generating study focused on AAD to provide insight into methods of prevention. We evaluated the hypothesis of predisposing factors within the resident intestinal microbiota in a cohort of outpatients receiving antibiotherapy. Among the pool of tested variables, only those related to bacterial 16S rRNA genes were found to be relevant. Complex statistical analyses provided further information: amid the bacteria 16S rRNA genes, eight were determined to be essential for diarrhea predisposition and characterized from the most important to the least. Using these markers, AAD risk could be estimated with an error of 2%. This molecular analysis offers new perspectives for clinical applications at the level of prevention.

Aim: To evaluate whether crypt abscesses from inflammatory bowel disease (IBD) patients contain bacteria and to establish their nature., Methods: We studied 17 ulcerative colitis patients, 11 Crohn's disease patients, 7 patients with acute self-limited colitis (ASLC) and normal colonic biopsies from 5 subjects who underwent colonoscopy for colon cancer screening. A fluorescent in situ hybridization technique was applied to colonic biopsies to assess the microbiota composition of the crypts and crypt abscesses., Results: Crypts colonized by bacteria were observed in 42.9% and 3.6% of ASLC and IBD patients, respectively (P = 0.019). Crypt abscesses colonized by bacteria were observed in 28.6% and 0.0% of ASLC and IBD patients, respectively (P = 0.035)., Conclusion: These results do not support the hypothesis that crypt abscesses in IBD are the result of localized dysbiosis arising from persistence of living bacteria colonizing the crypts.

The delivery of bioactive molecules directly to damaged tissues represents a technological challenge. We propose here a new system based on virus-like particles (VLP) from rotavirus, with a marked tropism for the gut to deliver bio-active molecules to intestinal cells. For this, nonreplicative VLP nanoparticles were constructed using a baculovirus expression system and used to deliver an exogenous biomolecule, the green fluorescent protein (GFP), into either MA104 cells or intestinal cells from healthy and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-treated mice. Our results show that expression of rotavirus capsid proteins in baculovirus led to the auto assembly of VLP that display similar properties to rotavirus. In vitro experiments showed that VLP were able to enter into MA104 cells and deliver the reporter protein. Intragastric administration of fluorescent VLP in healthy and TNBS-treated mice resulted in the detection of GFP and viral proteins in intestinal samples. Our results demonstrate an efficient entry of non-replicative rotavirus VLP into the epithelial cell line MA104 and provide the first in vivo evidence of the potential of these nanoparticles as a promising safe candidate for drug delivery to intestinal cells.