Marion Chauvenet

Neopterin is a novel reliable fecal marker as accurate as calprotectin for predicting endoscopic disease activity in patients with inflammatory bowel diseases.

Background:Fecal biomarkers have emerged as an important tool for assessing and monitoring disease activity in patients with inflammatory bowel diseases (IBDs). We performed a prospective head-to-head comparison of the diagnostic accuracy of both fecal calprotectin (fCal) and neopterin (fNeo), and serum C-reactive protein in predicting endoscopic disease severity in patients with IBD. Methods:A total of 133 consecutive patients with IBD (78 Crohns disease [CD] and 55 ulcerative colitis [UC]) undergoing a colonoscopy provided fecal samples for the measurement of fCal and fNeo concentrations and a blood sample for the serum C-reactive protein measurement. Endoscopic disease activities were scored independently according to the Simple Endoscopic Score for CD in patients with CD and to the Rachmilewitz Index in patients with UC. The respective performances of the fecal markers with respect to endoscopic disease severity were assessed by computing correlations, sensitivities, specificities, and overall accuracies at adjusted cutoffs and also test operating characteristics. Results:The fCal and fNeo concentrations differed significantly in clinically and endoscopically active IBD when compared with those in patients with inactive disease. Both fCal and fNeo concentrations correlated closer with endoscopic scores in UC (r = 0.75 and r = 0.72, respectively; P < 0.0001 for both) than in CD (r = 0.53 and r = 0.47, respectively; P < 0.0001 for both). Using cutoffs of 250 &mgr;g/g for fCal and 200 pmol/g for fNeo, both fecal markers had similar overall accuracies to predict endoscopic activity in patients with CD (74%) and also a higher and similar accuracies (88% and 90%, respectively) in patients with UC, whereas accuracies of C-reactive protein were slightly lower in patients with CD and UC. Conclusions:The fNeo is a novel reliable surrogate biomarker with the potential to identify patients with IBD with active mucosal lesions and represents an alternative marker as accurate as fCal to predict and monitor the severity of mucosal damages in patients with IBD.

Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab is associated with a profound long-lasting depletion of Foxp3+ regulatory T cells: a mechanistic explanation for ipilimumab-induced severe enterocolitis?

To the Editor: Ipilimumab is a novel fully human immunostimulatory monoclonal antibody (mAb) that abrogates the function of cytotoxic T-lymphocyte antigen-4 (CTLA-4). CTLA-4 is an immune-inhibitory surface molecule expressed on activated T cells that exerts a dampening effect on the immune system. CTLA-4 is highly expressed on regulatory T cells that control T-cell-related immune responses and inflammation. A recent study documented the overall survival benefit for patients with metastatic melanoma treated with ipilimumab plus dacarbazine. However, one of the most frequent drug-related adverse events profile with ipilimumab is primarily immune-related and includes rash, colitis, hypophysitis, thyroiditis, and hepatitis. The mechanism by which these immune-related adverse events (IRAEs), which can be sometimes severe and life-threatening, occurs remains largely unknown. Here we document a patient treated with ipilimumab who developed a severe enterocolitis of the respective proportion of circulating T-lymphocyte subsets and propose, based on these results, that ipilimumab could induce a sustained dysbalance between regulatory and effector T cells, favoring the occurrence of gut inflammation and lesions. A 56-year-old male was referred to our department after a 3-month history of severe diarrhea. His medical history was notable for thoracic melanoma, for which he underwent a complete surgical resection followed by the systemic administration of ipilimumab (10 mg/kg every 3 weeks for eight courses) as an adjuvant immunotherapy regimen. Within a few days of the last infusion, he experienced the onset of profuse watery diarrhea associated with progressive body weight loss, hypoalbuminemia, high levels of fecal calprotectin, and serum C-reactive protein (CRP). Ipilimumab was stopped and the patient was initially treated as an outpatient with stable doses of steroids (intravenous methylprednisolone 2 mg/kg/d). Repeated microbiologic stool and blood samples were negative, including a search for cytomegalovirus (CMV) infection and toxins for Clostridium difficile. A colonoscopy revealed a severe pancolitis featured by extensive, deep, and confluent ulcerations covered with mucopurulent exudates and spontaneous bleeding surrounded by diffusely inflamed mucosa. In addition, lesions were not confined to the colon, since superficial ulcerations were also observed in the terminal ileum. Intestinal exam showed a dense inflammatory infiltrate and the absence of granuloma. Despite longstanding steroid therapy (3 months after onset of diarrhea) and total parenteral nutrition, the diarrhea progressed with up to 10–15 bloody bowel movements per day with persistent abdominal pain. Hence, the patient was considered refractory to steroids and a blood sample was collected and peripheral blood (PB) lymphocytes isolated to characterize the frequency of circulating regulatory Foxp3þ T cells as well as the proportion of ‘‘effector’’ T cells (including interferon-gamma [IFN-c]or interleukin [IL]-17-producing CD4þ T cells and cytotoxic granzyme B expressing CD8þ T cells) before changing the line of therapy. Strikingly, our flow cytometric analysis revealed an unusually low frequency of PB regulatory Foxp3þ CD4þT cells (0.2% of total cells gated on CD3þ cells) that contrasted with that of PB cytotoxic granzyme Bþ T cells (81.0% of total cells gated on CD3þCD8þ cells) and also those of PB IFN-cand IL-17-expressing CD4þ T cells (27.3% and 1.3% of total cells gated on CD3þCD4þ cells, respectively) (Fig. 1). An abdominal CT scan revealed a severe colitis located especially on the transverse and left colon without complications such as intestinal perforation or abscess. The patient received two infusions of infliximab (5 mg/kg at weeks 0 and 2) as second-line therapy and his diarrhea progressively improved to grade 1 with a drop of fecal calprotectin (from 3265 to 1780 lg/g stool) and was completely resolved by 2 months. During the course of enterocolitis, the patient developed also a hypophysitis, a thyroiditis, and a moderate hepatitis; the outcome of all these IRAEs was favorable. Manipulation of the immune system by abrogating CTLA-4, an immune regulatory molecule, represents a new and promising antitumoral strategy to induce better disease control and to prolong survival in patients with advanced melanoma. Rash, colitis, and hepatitis so far represent the most frequent induced IRAEs even if various other organs may be affected, and our observation represents a caricatural picture of the side effects that may occur under ipilimumab. In a recent clinical trial, gastrointestinal IRAEs were reported in 41 (35%) out of 115 patients who experienced diarrhea and/or colitis during treatment with ipilimumab. An onset of gastrointestinal IRAEs usually We thank SFR Biosciences Gerland-Lyon Sud (UMS344/US8) for the contribution of the platform of cytometry. Copyright VC 2011 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.21927 Published online inWiley Online Library (wileyonlinelibrary.com).

Tacrolimus induction followed by maintenance monotherapy is useful in selected patients with moderate-to-severe ulcerative colitis refractory to prior treatment

BACKGROUND Tacrolimus in refractory ulcerative colitis often serves as a bridge to long-term maintenance therapy with thiopurines. Our aim was to review efficacy and safety of tacrolimus in active ulcerative colitis resistant to conventional therapies, including anti-tumour necrosis factor. METHODS Charts of consecutive outpatients with refractory ulcerative colitis, in whom tacrolimus was orally administered as a 12 week-induction (target trough levels 10-15ng/mL) followed by a maintenance therapy (target trough levels 5-10ng/mL), were retrospectively reviewed. Clinical remission and response at weeks 4, 12 and 52 as well as adverse events within 1-year therapy were reported. RESULTS Twelve (40%) and six (20%) of the 30 patients included (14 males, mean age 37.1±1.4 years) achieved a clinical remission and response, respectively, at week 12. Three responders to tacrolimus initiation experienced drug-related adverse events requiring discontinuation. Among the 18 remaining initial responders who tolerated tacrolimus, 8 (27%) were in clinical remission at week 52, whereas the remainder either experienced adverse events requiring drug withdrawal (n=4) or relapsed (n=6). Overall adverse events were recorded in 14 patients (46%), mainly finger tremor and urinary infections. CONCLUSION Oral monotherapy with tacrolimus may be a valuable long-term therapeutic option in selected patients with moderate-to-severe active refractory ulcerative colitis.

Endoscopic and histologic characteristics of serrated lesions

In recent years, a second pathway for colonic carcinogenesis, distinct from the adenomatous pathway, has been explored. This is referred to as serrated pathway and includes three types of polyp, characterised by a serrated appearance of the crypts: hyperplastic polyps (HP), sessile serrated adenomas (SSA) or lesions, and traditional serrated adenomas. Each lesion has its own genetic, as well as macroscopic and microscopic morphological features. Because of their flat aspect, their detection is easier with chromoendoscopy (carmin indigo or narrow-band imaging). However, as we show in this review, the distinction between SSA and HP is quite difficult. It is now recommended to resect in one piece as it is possible the serrated polyps with a control in a delay depending on the presence or not of dysplasia. These different types of lesion are described in detail in the present review in general population, in polyposis and in inflammatory bowel diseases patients. This review highlights the need to improve characterization and understanding of this way of colorectal cancerogenesis.

Identification of Mycobacterium cosmeticum sp. as a novel colitogenic infectious agent in a nonimmunocompromised patient.

We report here the first case of a nonimmunocompromised patient who developed a severe diffuse granulomatous colitis induced by a nontuberculous mycobacteriosis typed Mycobacterium cosmeticum that had never been identified to date as a colitogenic infectious agent. A 32-year-old Turkish patient was admitted complaining of dull abdominal pain, bloody diarrhea, and fever for 1 month. His personal and familial medical history was unremarkable. He emigrated to France 1 year previously, took no drugs, and had no toxic habits. No professional exposure in metals, including beryllium, was recorded. On admission, physical examination showed abdominal distension, tympanism, and tenderness in the right lower quadrant without abdominal mass and a substantial progressive loss of weight ( 4 kg in the last month). The liver, spleen, and superficial lymph nodes were not palpable. Skin examination failed to detect any lesions. Routine blood analysis showed an iron-deficiency anemia, whereas platelets and white blood cell counts as well as liver function tests were normal. Serum C-reactive protein was elevated (159 mg/L; normal <2 mg/L). Chest radiography and urinary analysis were unremarkable. Blood and stool culture including the use of selective culture media failed to detect any pathogenic bacteria or parasites and repeated tests by enzyme-linked immunosorbent assay (ELISA) for Clostridium difficile cytotoxins A and B were negative. The serologies for HIV, HTLV, HSV, CMV, EBV, and Yersinia, Campylobacter, Salmonella, and Shigella were negative. Abdominal computed tomography (CT) scan revealed a severe transmural segmental colitis located on the ascendant and transverse colon associated with centimetric mesenteric adenomegaly. The chest CT scan was normal. A rectosigmoidoscopy with biopsy revealed no macroscopic and histologic distal colonic lesions. The patient was empirically treated conservatively with intravenous antibiotics (ofloxacine 400 mg/ d and ceftriaxone 1 g/d) and parenteral nutritional support for 1 week without any evidence of clinical improvement. In contrast, the patient remained febrile and presented evident clinical signs of intestinal obstruction confirmed by a CT scan showing a more severe transmural ascendant and right transverse colitis associated with a small bowel distension. Therefore, the scheduled colonoscopy was canceled and the patient underwent an exploratory laparotomy and a segmental ascendant and right transverse colectomy with an ileotransverse anastomosis protected by a temporary loop ileostomy. Histologic analysis of the colon specimen confirmed a severe transmural colitis surprisingly associated with multiple nonnecrotizing epithelioid granulomas characterized by multinucleated Langhans giant cells located both into the colon lamina propria and mesenteric adenomegaly (Fig. 1). Histopathological colonic specimens revealed neither acid-alcohol-resistant bacilli on Ziehl-Neelsen staining nor intestinal parasites (Microsporidia, Cryptosporidia sp., Isospora belli). In addition, intestinal biopsy specimen cultures for mycobacteria, pathogenic bacteria species (Salmonella, Yersinia, Shigella, and Campylobacter) and yeast were negative. After surgery, the clinical outcome was progressively favorable. Cytomegalovirus (CMV) viral load assessed by polymerase chain reaction (PCR) and specific PCR detection for Tropheryma whipplei in colon were also negative. Serum immunoglobulin IgG, IgM, and IgA levels, LDH, b2-microglobulin, and angiotensin-converting enzyme were normal. Neither antinuclear antibodies (ANA) nor anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic antibodies (pANCA) were detectable in serum. A chronic granulomatous disease was excluded by a fluorescence activated-cell sorter (FACS) test using dihydrorhodamine 123. The patients did not manifest evidence of albinism or prolonged bleeding time and platelet dysfunction suggestive of Hermansky– Pudlak syndrome. Early morning urines samples and Mantoux Tb skin test did not demonstrate evidence of tuberculosis. Two months later and before closing the stoma, the patient was asymptomatic and an ileocolonoscopy revealed the presence of discontinuous reddish inflammatory lesions on the colonic mucosa with sometimes superficial erosions. Histopathological analysis of the multiple biopsy specimens performed on the left colon, sigmoid, and rectum showed similar previous microscopic findings, i.e., marked edema, diffuse inflammatory infiltrates, and extensive noncaseous epithelioid cell granulomas. In contrast, endoscopic and systematic histologic examination of the distal ileum was unremarkable. Interestingly, whereas Mycobacteria tuberculosis complex was undetectable, nontuberculous mycobacteria species were identified in colonic biopsies by a LightCycler real-time PCR-based method using our original species-specific probes (Patent WO/2007/034118) with a detection sensitivity of 5.10 CFU/mL. The following specific forward primers used were 50-ACCAACGATGGT GTGTCCAT-30 and reverse primers 50Copyright VC 2011 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.21804 Published online 7 July 2011 inWiley Online Library (wileyonlinelibrary.com).

Adenoma detection with blue-water infusion colonoscopy: a randomized trial

Background and aims Colonoscopy is currently the reference method to detect colorectal neoplasia, yet some adenomas remain undetected. The water infusion technique and dying with indigo carmine has shown interesting results for reducing this miss rate. The aim of this study was to compare the adenoma detection rate (adenoma and adenocarcinoma; ADR) and the mean number of adenomas per patient (MAP) for blue-water infusion colonoscopy (BWIC) versus standard colonoscopy. Methods We performed a multicenter, randomized controlled trial in eight units, including patients with a validated indication for colonoscopy (symptoms, familial or personal history, fecal occult blood test positive). Consenting patients were randomized 1:1 to BWIC or standard colonoscopy. All colonoscopies were performed by experienced colonoscopists. All colonoscopy quality indicators were prospectively recorded. Results Among the 1065 patients included, colonoscopies were performed completely for 983 patients (514 men; mean age 59.1). The ADR was not significantly different between the groups; 40.4 % in the BWIC group versus 37.5 % in the standard colonoscopy group (odds ratio [OR] 1.13; 95 % confidence interval [CI] 0.87 - 1.48; P = 0.35). MAP was significantly greater in the BWIC group (0.79) than in the standard colonoscopy group (0.64; P = 0.005). For advanced adenomas, the results were 50 (10.2 %) and 36 (7.3 %), respectively (P = 0.10). The cecal intubation rate was not different but the time to cecal intubation was significantly longer in BWIC group (9.9 versus 6.2 minutes; P < 0.001). Conclusion Despite the higher MAP with BWIC, the routine use of BWIC does not translate to a higher ADR. Whether increased detection ultimately results in a lower rate of interval carcinoma is not yet known. CLINICAL TRIALS REGISTRATION EudraCT 2012-A00548 - 35; NCT01937429.

Chimiothérapie intra-artérielle hépatique et cancer colorectal métastatique : où en sommes-nous en 2017 ?

La maladie metastatique hepatique predominante concerne 30 % des cancers colorectaux. La chimiotherapie systemique (cytotoxiques et therapies ciblees) a considerablement ameliore le pronostic de ces patients. La chimiotherapie intra-arterielle hepatique repose sur la vascularisation preferentielle des metastases hepatiques par le reseau arteriel hepatique, qui permet d’exposer les lesions a une concentration elevee de cytotoxique tout en limitant la toxicite systemique. Elle a demontre son efficacite depuis de nombreuses annees dans les stades avances. Sa place a des stades plus precoces de prise en charge est en cours d’evaluation.

Su1244 Accuracy of Fecal M2-Pyruvate Kinase Compared With Fecal Calprotectin to Assess Endoscopic Severity in Patients With Inflammatory Bowel Diseases

CS+IS therapy (21.5% vs. 12.5%; p<0.001). The proportion of patients who had normal C-reactive protein (CRP) was lower in the anti-TNF group (38.3%) compared to the control group (64.5%; p<0.001). In the univariate analysis, positive TST was associated with age, Bacille Calmette-Guerin vaccination and mesalazine therapy. Negative TST was associated with CS therapy, IS therapy, CS+IS therapy, Crohn s disease vs. ulcerative colitis, anti-TNF group vs. control group and elevated CRP. In the multivariate analysis, positive TST was associated with age while negative TST was associated with CS therapy (OR 0.32; 95% CI 0.15-0.70; p=0.004), IS therapy (OR 0.34; 95% CI 0.180.61; p<0.001) or CS+IS therapy (OR 0.16; 95% CI 0.06-0.40; p<0.001). Conclusions: CS and IM therapy strongly negatively affected TST performance. As a result the likelihood of having a positive TST was lower in patients candidates for anti-TNF therapy than in controls. Therefore, current guidelines for TB screening prior to antiTNF therapy appear inaccurate in patients under CS or IS. Patients should be screened for LTBI prior to initiation of CS or IS therapy. The second TST is useful because it increases detection sensitivity by 22%.