Marc Ferrante

Universitair Ziekenhuis Leuven, Louvain, Flemish, Belgium

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Publications (140)1008.22 Total impact

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    ABSTRACT: Prophylactic azathioprine (AZA) is efficacious in preventing postoperative Crohn's disease (CD) recurrence. However, it is unknown if AZA should be started immediately after surgery. We compared efficacy of systematic versus endoscopy-driven AZA in preventing CD recurrence at week 102. CD patients undergoing curative resection with ileocolonic anastomosis and at higher risk of recurrence were included in this prospective, multicenter trial. Patients were randomized to systematic AZA initiated ≤2 weeks from surgery, or endoscopy-driven AZA where therapy was only initiated in case of endoscopic recurrence (Rutgeerts' score ≥i2) at weeks 26 or 52 following surgery. The primary endpoint was endoscopic remission (i0-i1) at week 102. Secondary endpoints included complete endoscopic remission (i0), and clinical remission. The study was prematurely stopped due to slow recruitment. Between 2005 and 2011, 63 patients (28 male, median age 36 years) were randomized to systematic (n=32) or endoscopy-driven AZA (n=31). Twenty-one patients withdrew prematurely (8 clinical recurrence, 6 adverse reactions to AZA, 7 patient's preference). In the endoscopy-driven AZA group, 14 patients had to initiate AZA (11 at week 26, 3 at week 52). Endoscopic remission was achieved by 50% in the systematic and 42% in the endoscopy-driven AZA group (p=0.521). No difference in secondary endpoints could be determined. Systematic AZA therapy in patients at higher risk of postoperative CD recurrence is not superior to endoscopy-driven treatment. Early postoperative endoscopic evaluation between week 26-52 seems most appropriate to guide further therapy, but larger studies are warranted. (ClinicalTrials.gov, Number NCT02247258). Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Journal of Crohn s and Colitis 04/2015; DOI:10.1093/ecco-jcc/jjv076 · 3.56 Impact Factor
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    ABSTRACT: Dear Editor, We read with great interest the manuscript by Ungar and colleagues describing the temporal evolution of antibodies to infliximab (ATI) in patients with IBD treated with infliximab (IFX).1 By prospectively following 125 patients with IBD, they showed that ATI formation is a dynamic process. Clinically relevant ATI were typically formed within the first 12 months but transient ATI, which are of little clinical significance, can be formed at any time during treatment. They furthermore demonstrated that the evolution of ATI correlates with clinical loss of response and that concomitant immunomodulator use prolonged ATI-free survival, which is in line with previous reports. Nevertheless, patient-related factors possibly influencing ATI formation weren't considered and haven't been studied extensively. We hypothesised that ATI formation may be triggered by HLA-DRB1 alleles, as was shown for immunogenicity to interferon-β therapy in multiple sclerosis.2 We retrospectively analysed 192 patients with IBD: 76 patients developed ATI during IFX maintenance treatment (=ATI+) (44 Crohn's disease (CD), 32 UC) and these were matched with 116 patients (64 CD, 52 UC) who never developed ATI (=ATI−). All patients were antitumour necrosis factor naïve before IFX … [Full text of this article]
    Gut 04/2015; DOI:10.1136/gutjnl-2015-309698 · 13.32 Impact Factor
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    ABSTRACT: Data on immunogenicity to adalimumab (ADL) therapy in patients with IBD is limited. We performed additional analyses on the Karmiris cohort using the homogeneous mobility shift assay (HMSA) focusing on the inter-relationship of serum ADL concentration, antibodies-to-adalimumab (ATA), inflammatory markers and sustained response. 536 prospectively collected serum samples were available for analysis of ADL concentration and ATA using HMSA. We studied the role of week 4 serum ADL concentration and immunomodulator (IMM) use on ATA formation with a Cox proportional hazards model. Mixed model repeated measures analysis was performed to assess the independent effects of serum ADL concentration and ATA on C-reactive protein (CRP) and response. ATA was detected in 20% of patients after a median of 34 (12.4-60.5) weeks. ATA-positive samples correlated with lower serum ADL concentration (p<0.001). Cox regression modelling showed that week 4 ADL concentration of <5 µg/mL significantly increased the future risk of ATA formation (HR=25.1; 95% CI 5.6 to 111.9; p=0.0002) and that IMM co-treatment prevented ATA formation (HR=0.23; 95% CI 0.06 to 0.86; p=0.0293). Regression modelling showed a negative correlation between CRP and ADL concentration (p=0.0001) and a positive one with ATA (p=0.0186). The model revealed that both lower serum ADL concentration and ATA were independently associated with future CRP (p=0.0213 and p=0.0013 respectively). ATA positivity was associated with discontinuation of ADL because of loss or response (OR=3.04; 95% CI 1.039 to 9.093; p=0.034). ATA were detected in 20% of patients. Risk of ATA formation increased with lower early serum ADL concentration and in patients not on IMM. ATA and ADL were strongly associated with higher future CRP level and discontinuation of ADL. 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.
    Gut 04/2015; DOI:10.1136/gutjnl-2014-307882 · 13.32 Impact Factor
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    ABSTRACT: Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC. We performed a 1 y, randomized, controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3-7 μg/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n=123) or continued dosing based on TCs (n=128) (maintenance phase). The primary endpoint was clinical and biochemical remission at 1 y after the optimization phase. At screening, 115/263 patients had a TC of infliximab of 3-7 μg/mL (43.7%). Of 76 patients with TCs <3 μg/mL, 69 patients (91%) achieved TCs of 3-7 μg/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P=.020) and a decrease in the median concentration of C-reactive protein, compared to before the dose increase (3.2 vs 4.3 mg/L; P<.001); these changes were not observed in patients with UC. Of 72 patients with TCs >7 μg/mL, 67 patients (93%) achieved TCs of 3-7 μg/mL after dose reduction. This resulted in a 28% reduction in drug cost than before dose reduction (P<.001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary endpoint (P=.686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) (P=.018). Targeting patients' infliximab TCs to 3-7 μg/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 y, but was associated with fewer flares during the course of treatment. ClinicalTrialsRegister.eu number: 2011-002061-38. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Gastroenterology 02/2015; DOI:10.1053/j.gastro.2015.02.031 · 13.93 Impact Factor
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    ABSTRACT: Inflammatory bowel disease (IBD) is recognized as an independent risk factor for thrombosis. First, we investigate whether the concentration of fibrinolysis inhibitors is increased in patients with IBD. Second, we investigate the effect of infliximab induction therapy on the hemostatic profile. This prospective study included 103 patients with IBD starting infliximab therapy and 113 healthy controls. Plasma was collected before the first infliximab infusion (wk 0) and after induction therapy (wk 14). Patients not showing a clinical response on induction were considered as primary nonresponders. Fibrinolysis inhibitors were measured by enzyme-linked immunosorbent assay. Using a clot lysis assay, the area under the curve (global marker for coagulation/fibrinolysis), 50% clot lysis time (marker for fibrinolytic capacity), and amplitude (indicator for clot formation) were determined. Patients with IBD selected for infliximab treatment have higher area under the curve (median 29 [interquartile range, 20-38]) and amplitude (0.4 [0.3-0.5]) compared with healthy controls (18 [13-24] and 0.3 [0.2-0.3], respectively, P < 0.001). Primary nonresponders showed a decrease neither in inflammatory markers nor in hemostatic parameters, whereas in primary responders, a decrease in inflammatory markers was associated with a decrease in both area under the curve (29 [20-38] (wk 0) to 20 [14-28] (wk 14), P < 0.001) and amplitude (0.4 [0.3-0.5] (wk 0) to 0.3 [0.3-0.4] (wk 14), P < 0.001). This is the first prospective study demonstrating that the clot lysis profile differs between patients with IBD and healthy individuals. On infliximab induction treatment, this clot lysis profile normalizes in responders suggesting that infliximab treatment is advisable for patients with IBD with an activated hemostatic profile.
    Inflammatory Bowel Diseases 02/2015; DOI:10.1097/MIB.0000000000000301 · 5.48 Impact Factor
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    ABSTRACT: The role of Aeromonas species as an enteropathogen in patients with and without inflammatory bowel disease (IBD) is still debated. The aim was to explore the significance of positive Aeromonas stool cultures in IBD and patients without IBD. Observational retrospective study including all patients with a stool culture positive for Aeromonas between January 2011 and October 2013 at the Leuven University Hospitals. Demographics, clinical, and endoscopic outcomes and laboratory results were analyzed. A total of 77 patients (11 IBD) were identified. In 37 cases, Aeromonas caused a mild self-limited gastrointestinal infection. Among the 40 patients needing antibiotics, 22 presented a mild-to-moderate gastrointestinal infection; 4 suffered from extraintestinal complications; and 4 were coinfected by Campylobacter spp. A. veronii caused more frequently severe infection than the other species (25% versus 5%; P = 0.046). In 2 patients with ulcerative colitis, Aeromonas triggered a moderate-to-severe flare and 2 cases appeared in the context of de novo Crohn's disease. In contrast, in 1 patient with ulcerative colitis and 2 patients with Crohn's disease, Aeromonas caused a mild gastrointestinal infection not worsening the disease activity and in 4 patients with Crohn's disease, it presented in the context of active disease with no clear pathogenic role. Patients with IBD were treated more often with antibiotics (82 versus 41%, P = 0.012) and had more complications (46 versus 14%, P = 0.024). Aeromonas caused mostly mild infections but also moderate and severe infections. A. veronii was more prevalent in patients with IBD and was associated with worse clinical outcomes. Aeromonas caused milder infections in patients without IBD. Other risk factors for severe infection were not found.
    Inflammatory Bowel Diseases 01/2015; 21(1):71-78. DOI:10.1097/MIB.0000000000000247 · 5.48 Impact Factor
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    ABSTRACT: Ulcerative colitis (UC) is associated with differential colonic expression of genes involved in immune response (e.g. IL8) and barrier integrity (e.g. cadherins). MicroRNAs (miRNAs) are regulators of gene expression and are involved in various immune-related diseases. In this study, we investigated (1) if miRNA expression in UC mucosa is altered and (2) if any of these changes correlate with mucosal mRNA expression. Integration of mRNA and miRNA expression profiling may allow the identification of functional links between dysregulated miRNAs and their target mRNA. Colonic mucosal biopsies were obtained from 17 UC (10 active and 7 inactive) patients and 10 normal controls. Total RNA was used to analyze miRNA and mRNA expression via Affymetrix miRNA 2.0 and Affymetrix Human Gene 1.0ST arrays, respectively. Both miRNA and gene expression profiles were integrated by correlation analysis to identify dysregulated miRNAs with their corresponding predicted target mRNA. Microarray data were validated with qRT-PCR. Regulation of IL8 and CDH11 expression by hsa-miR-200c-3p was determined by luciferase reporter assays. When comparing active UC patients vs. controls, 51 miRNAs and 1543 gene probe sets gave significantly different signals. In contrast, in inactive UC vs. controls, no significant miRNA expression differences were found while 155 gene probe sets had significantly different signals. We then identified potential target genes of the significantly dysregulated miRNAs and genes in active UC vs. controls and found a highly significant inverse correlation between hsa-miR-200c-3p and IL8, an inflammatory marker, and between hsa-miR-200c-3p and CDH11, a gene related to intestinal epithelial barrier function. We could demonstrate that hsa-miR-200c-3p directly regulates IL8 and CDH11 expression. Differential expression of immune- and barrier-related genes in inflamed UC mucosa may be influenced by altered expression of miRNAs. Integrated analysis of miRNA and mRNA expression profiles revealed hsa-miR-200c-3p for use of miRNA mimics as therapeutics.
    PLoS ONE 12/2014; 9(12):e116117. DOI:10.1371/journal.pone.0116117 · 3.53 Impact Factor
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    ABSTRACT: There are limited data on the effects of discontinuing infliximab therapy for Crohn's disease (CD). We investigated the long-term outcome of patients with CD who discontinued infliximab while in clinical remission, and searched for prognostic markers of continued remission after infliximab cessation. We performed a retrospective, single-center study of 100 patients with CD who discontinued infliximab upon achieving clinical remission; 84 patients continued immunomodulator therapy. Clinical and endoscopic data were retrieved from a medical database in Belgium, and patients were followed through April 2013 (for a median 9.7 ys; interquartile range, 8-11.5 ys). Sustained clinical remission (SCR) was defined as maintenance of disease remission, without escalation in medical therapy or CD-related surgeries, until the end of the follow-up period. We measured trough concentrations of infliximab, antibodies to microbial antigens, and circulating inflammatory markers in serum samples collected before treatment and at the time of infliximab discontinuation. At the end of the follow-up period, 52 patients had SCR. Univariate (log-rank) analysis associated SCR with patients' age at diagnosis (≥25 ys, P=.012) and disease duration (<1 y, P=.017). Among factors evaluated at the time of infliximab discontinuation, infliximab trough concentrations (<6 μg/ml, P=.031), complete mucosal healing (P=.046), and serum positivity for vascular cell adhesion molecule-1 (>0.67 μg/ml, P=.024) were associated with SCR. In multiple Cox proportional hazards regression analysis, only age at diagnosis ≥25 ys was independently associated with SCR (hazard ratio, 1.83; 95% confidence interval, 1.03-3.25; P=.04). In a large, real-life study, 52% of patients with CD who discontinued infliximab upon achieving clinical remission remained in SCR after a median period of approximately 10 ys; most remained on immunomodulator therapy. Although patients with CD have variable responses to infliximab, a subgroup achieves long-term remission after infliximab discontinuation. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Clinical Gastroenterology and Hepatology 12/2014; DOI:10.1016/j.cgh.2014.11.026 · 6.53 Impact Factor
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    ABSTRACT: The disease spectrum and natural course of Crohn's disease and ulcerative colitis are highly variable. The majority of Crohn's disease patients will require surgery at a certain stage in their disease compared to only a fraction of the ulcerative colitis patients. Similarly, some patients are destined to experience an indolent disease course while others will require early intensive therapy. Ideally, these subtypes of patients should be identified as early as possible with the help of reliable prognostic factors in order to guide personalized therapeutic decisions. In this review, the authors focused on the most relevant reports on the use of different prognostic factors to predict disease course, postoperative recurrence and response to therapy in patients with inflammatory bowel disease. The last 15 years have seen a wealth of novel genetic and serological markers of disease severity. Nevertheless, none of these markers have proven to be superior to careful clinical phenotyping and endoscopic features early in the disease course. Future attempts should apply an integrated approach that unites clinical, serological and (epi)genetic information with environmental influences, with a clear focus on the microbiome to ultimately identify molecular-based and clinically relevant subgroups.
    Current Gastroenterology Reports 11/2014; 16(11):416. DOI:10.1007/s11894-014-0416-y
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    ABSTRACT: Background A long-lasting good functional outcome of the pelvic pouch and a subsequent satisfying quality of life (QoL) are mandatory. Long-term functional outcome and QoL in a single-center cohort were assessed. Patients and methods A questionnaire was sent to all patients with an IPAA for UC, operated between 1990 and 2010 in our department. Pouch function was assessed using the Öresland Score (OS) and the ‘Pouch Functional Score’ (PFS). QoL was assessed using a Visual Analogue Score (VAS). Results 250 patients (42% females) with a median age at surgery of 38 years (interquartile range (IQR): 29–48 years) underwent restorative proctocolectomy. Median follow‐up was 11 years (IQR: 6–17 years). Response rate was 81% (n = 191). Overall pouch function was satisfactory with a median OS of 6/15 (IQR: 4–8) and a median PFS of 6/30 (IQR: 3–11). 24-hour bowel movement is limited to 8 times in 68% of patients (n = 129), while 55 patients (29%) had less than 6 bowel movements. 12 patients (6.5%) were regularly incontinent for stools, while 154 patients (82%) reported a good fecal continence. Fecal incontinence during nighttime was more common (n = 72, 39%). Pouch function had little impact on social activity (4/10; IQR: 2–6) and on professional activity (3/10; IQR: 1–6). 172 patients (90%) reported to experience an overall better health condition since their operation. The OS and the PFS correlated well (Pearson's correlation coefficient = 0.83). Overall pouch function was stable over time. Conclusion Majority of patients report a good pouch function on the long-term with limited impact on QoL.
    Journal of Crohn s and Colitis 10/2014; 8(10). DOI:10.1016/j.crohns.2014.03.001 · 3.56 Impact Factor
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    ABSTRACT: Background Data for adalimumab in ulcerative colitis after prior use of infliximab are scarce.AimsTo study adalimumab response rates and predictors of response in ulcerative colitis, including drug concentrations.Methods In this single centre cohort study 73 UC patients, previously exposed to infliximab, were assessed for response to adalimumab at weeks 12 and 52. Serum samples prior to week 12 were available and included in multivariate analysis to predict response.ResultsOverall clinical response at week 12 and 52 were 75% and 52%, respectively. Adalimumab was continued without need for dose escalation throughout year 1 in 16 patients, 22 needed dose escalation and 35 discontinued treatment within 1 year. Prior response to infliximab and early serum concentrations correlated with response. Receiver operator characteristic curve analysis yielded optimal adalimumab concentrations of 4.58 μg/mL for week 12 and 7.0 μg/mL for week 52. Independent predictors for response at week 12 were primary response to infliximab [odds ratio (OR) 8.33; 95% confidence interval (CI) 1.8–33.3; P = 0.006] and an adalimumab concentration ≥4.58 μg/mL at week 4 (OR 4.85; 95% CI 1.3–18.6; P = 0.009). Positive predictors for week 52 response were primary response to infliximab (OR 5.2; 95% CI 1.14–23.8; P = 0.034) and adalimumab concentration at week 4 of ≥7 μg/mL (OR 3.56; 95% CI 1.17–10.79; P = 0.025).Conclusion Prior response to infliximab and high early adalimumab serum concentrations predict week 12 and year 1 responses to adalimumab in ulcerative colitis.
    Alimentary Pharmacology & Therapeutics 09/2014; 40(11). DOI:10.1111/apt.12968 · 4.55 Impact Factor
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    ABSTRACT: Infliximab is effective for patients with refractory ulcerative colitis (UC), but few factors have been identified that predict long-term outcome of therapy. We aimed to identify a panel of markers associated with outcome of infliximab therapy, to help physicians make personalized treatment decisions.
    Clinical Gastroenterology and Hepatology 08/2014; 13(3). DOI:10.1016/j.cgh.2014.07.055 · 6.53 Impact Factor
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    ABSTRACT: Background & Aims The addition of immunomodulators increases the efficacy of maintenance therapy with infliximab, for up to 1 year, in patients with Crohn’s disease who have not been previously treated with immunomodulators. However, there are questions about the effect of withdrawing immunomodulator therapy from these patients. We studied the effects of treatment with infliximab and immunomodulators (co-treatment) and then immunomodulator withdrawal on long-term outcomes of patients, as well as trough levels of infliximab and formation of anti-infliximab antibodies (ATI). Methods In a retrospective study with the median follow-up period of 34 months (inter-quartile range, 19–58 months), we analyzed data from 223 patients treated for Crohn's disease between May 1999 and December 2010 at the University Hospitals, Leuven, Belgium (65 received infliximab monotherapy, 158 received infliximab and an immunomodulator). Trough levels of infliximab and levels of ATI were measured in blood samples collected from 117 patients throughout co-treatment, as well as the time of immunomodulator withdrawal and after withdrawal. Results Patients receiving co-treatment had higher trough levels of infliximab (adjusted mean increase of 1.44-fold) than those receiving infliximab monotherapy (95% confidence interval [CI], 1.07–1.92; P=.02). A smaller percentage of patients receiving co-treatment developed ATI (35/158, 22%) than those receiving infliximab monotherapy (25/65, 38%; P=.01). Among co-treated patients, levels of infliximab remained stable after immunomodulators were withdrawn (before: 3.2 μg/ml; 95% CI, 1.6–5.8 μg/ml and after: 3.7 μg/ml; 95% CI, 1.3–6.3 μg/ml; P=.70). After withdrawal of immunomodulators, 45/117 patients (38%) required increasing doses of infliximab and 21/117 (18%) discontinued infliximab. At the time of immunomodulator withdrawal, trough levels of infliximab and c-reactive protein were most strongly associated with response to infliximab thereafter. Conclusions In a retrospective analysis, we confirmed that withdrawal of immunomodulators after at least 6 months (median 13 months) of co-treatment with infliximab does not reduce the trough levels of infliximab in patients with Crohn's disease. Detectable trough levels of infliximab at the time of immunomodulator withdrawal are associated with long-term response.
    Clinical Gastroenterology and Hepatology 07/2014; 13(3). DOI:10.1016/j.cgh.2014.07.027 · 6.53 Impact Factor
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    ABSTRACT: The current standard for the assessment of mucosal healing after therapy in inflammatory bowel diseases is endoscopy. However, a high need exists for noninvasive, accurate surrogate markers.
    Inflammatory Bowel Diseases 05/2014; DOI:10.1097/MIB.0000000000000068 · 5.48 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-572. DOI:10.1016/S0016-5085(14)62074-6 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-239. DOI:10.1016/S0016-5085(14)60841-6 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-579. DOI:10.1016/S0016-5085(14)62095-3 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-648. DOI:10.1016/S0016-5085(14)62354-4 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-428. DOI:10.1016/S0016-5085(14)61538-9 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-875-S-876. DOI:10.1016/S0016-5085(14)63186-3 · 13.93 Impact Factor

Publication Stats

3k Citations
1,008.22 Total Impact Points

Institutions

  • 2005–2015
    • Universitair Ziekenhuis Leuven
      • Department of Gastroenterology
      Louvain, Flemish, Belgium
    • The Catholic University of America
      Washington, Washington, D.C., United States
  • 2014
    • The University of Edinburgh
      • Institute of Immunology and Infection Research
      Edinburgh, Scotland, United Kingdom
    • Tel Aviv Sourasky Medical Center
      Tell Afif, Tel Aviv, Israel
  • 2004–2013
    • University of Leuven
      • Translational Research Center for Gastrointestinal Disorders (TARGID)
      Louvain, Flemish, Belgium
  • 2012
    • Nagasaki University
      • Department of Pathology
      Nagasaki, Nagasaki, Japan
  • 2008
    • University of Pennsylvania
      • Department of Medicine
      Filadelfia, Pennsylvania, United States