Marc Ferrante

Universitair Ziekenhuis Leuven, Louvain, Flanders, Belgium

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Publications (102)604.8 Total impact

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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. · 5.12 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.
    12/2014;
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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.
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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; · 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;
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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; · 5.12 Impact Factor
  • Journal of Crohn s and Colitis 02/2014; 8:S8. · 3.39 Impact Factor
  • Journal of Crohn s and Colitis 02/2014; 8:S221-S222. · 3.39 Impact Factor
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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 01/2014; · 3.39 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. 01/2014;
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    ABSTRACT: Matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), a disintegrin and metalloprotease with thrombospondin motifs [ADAM(TS)s] and growth factors are involved in inflammation and tissue damage and repair, all occurring in inflammatory bowel disease (IBD). We studied the impact of anti-inflammatory therapy with infliximab on mucosal expression of these tissue remodeling genes in patients with IBD. Mucosal gene expression of 23 MMPs, 4 TIMPs, 50 ADAM(TS)s, and 158 growth factors was investigated in 61 patients with IBD before and after the first infliximab therapy and in 12 controls, with microarrays and quantitative RT-PCR. Protein localization, mucosal gelatinase levels, and net gelatinolytic activity were investigated by immunohistochemistry, zymography analysis, and gelatin degradation assay, respectively. In patients with active IBD before infliximab versus controls, gene expression of many MMPs, TIMPs, ADAM(TS)s, and growth factors was upregulated, whereas colonic expression of MMP28 and TGFA and ileal expression of ADAMDEC1 and AGT were downregulated. After controlling inflammation with infliximab, most gene dysregulations observed at baseline were restored in responders. Increased ratio of MMP1/TIMP1 expression at baseline in active IBD was restored in responders with colonic mucosal healing. With immunohistochemistry, protein localization differences of MMP1, MMP3, REG1A, and TIMP1 were shown between active IBD and control mucosa. With zymography analysis and gelatin degradation assay, higher gelatinase levels and net gelatinolytic activity were measured before infliximab and levels normalized after infliximab. Our data suggest that suppression of inflammation results in the arrest of epithelial damage and subsequent mucosal healing. Therefore, the therapeutic potential of agents targeting MMPs or growth factors as primary therapy seems rather complex.
    Inflammatory Bowel Diseases 12/2013; · 5.12 Impact Factor
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    Journal of Crohn s and Colitis 12/2013; 7(12):982–1018. · 3.39 Impact Factor
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    ABSTRACT: ABO encodes a glycosyltranferase which determines the major human histo-blood group. The FUT2 fucosyltransferase allows expression of ABO antigens on the gastrointestinal mucosa and in bodily secretions (secretor phenotype). A nonsense allele in FUT2 represents a susceptibility variant for Crohn's disease, and both the secretor and ABO blood group status affect the composition of the gut microbiota. Thus, we evaluated if variants in ABO might represent good candidates as Crohn's disease susceptibility loci. We recruited two case-control cohorts, from Italy (n=1301) and Belgium (n=2331). Subjects were genotyped for one SNP in FUT2 and two variants in ABO. No effect on Crohn's disease risk was detected for ABO variants, whereas an association was observed between the FUT2 polymorphism and Crohn's disease susceptibility in the Belgian sample, but not in the Italian cohort. The effect of histo-blood groups was evaluated using group O as the reference. Most non-O groups had odds ratios (ORs) higher than 1 in both cohorts, and combined analysis of the two samples indicated a predisposing effect for the A and B groups (OR=1.17, 95% CI: 1.02-1.32 and OR=1.33, 95% CI: 1.09-1.58, respectively). In Crohn's disease patients, the non-O blood group and the non-secretor status were associated with higher risk of developing a stricturing or penetrating disease. ABO histo-blood group might confer susceptibility to Crohn's disease and modulate disease severity.
    Journal of Crohn s and Colitis 11/2013; · 3.39 Impact Factor
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    ABSTRACT: Introduction: The advent of tumor necrosis factor (TNF) antagonists represented a radical change in the management of inflammatory bowel disease (IBD). Both in short- and long-term, anti-TNF therapy has been shown to reduce symptoms, heal mucosal ulcers, reduce hospitalizations and surgeries and spare corticosteroids. Areas covered: A literature search to August 2013 was performed to identify the most relevant reports on the use of TNF antagonists in IBD. First, the authors focused on the mechanism of action of TNF antagonists. Second, they evaluated different indications, contraindications, the optimal time to start and the role of combining TNF antagonists with immunomodulators. Third, they explored the importance of mucosal healing, followed by the controversial topic on when TNF antagonists should be stopped. This is followed by the subjects of treatment failure, immunogenicity and therapeutic drug monitoring. Last, they analyzed safety issues including exposure to TNF antagonists during pregnancy. Expert opinion: TNF antagonists have become indispensable in the management of IBD. Efforts to focus on treatment of inflammatory signs only and on optimization of treatment with therapeutic drug monitoring are underway. The advent of several new compounds and "biosimilars" will further challenge the position of TNF antagonists in the treatment algorithm of IBD.
    Expert opinion on biological therapy 11/2013; · 3.22 Impact Factor
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    Journal of Gastroenterology 11/2013; 145:978-986. · 3.79 Impact Factor
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    ABSTRACT: Introduction: The introduction of antibodies directed against tumor necrosis factor (anti-TNF) has dramatically changed our concept of treating both patients with Crohn's disease (CD) and patients with rheumatoid arthritis (RA). Subcutaneous injections with certolizumab pegol (CZP) have been shown efficacious for both CD and RA. In this review, the authors focus on the safety of CZP among other anti-TNF agents. Areas covered: A literature search till June 2013 was performed to identify all trials studying CZP in patients with CD and RA. In addition, abstracts of major congresses were assessed. The authors first focused on the mechanism of action of CZP, and evaluated the efficacy of this drug in both CD and RA. Next, they explored the available safety data on CZP, including infection and malignancy risk, injection site reactions, the development of antibodies against CZP, as well as its use during pregnancy. Expert opinion: Based on the provided literature, CZP seems to have a similar safety profile to other anti-TNF agents. However, in young females considering pregnancy, CZP may be advocated over other anti-TNF agents as it does not actively cross the placenta.
    Expert Opinion on Drug Safety 10/2013; · 2.74 Impact Factor
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    ABSTRACT: Several aspects of the management of Crohn's disease (CD) are shared between patients. The goal of all therapies should be to achieve clinical and endoscopic remission in a timely manner to avoid disease progression and abdominal resections. The way this goal is achieved may differ and predicting how the disease will evolve, what the most appropriate therapy with the highest chance of success will be, how long a therapy needs to be continued, and what the intensity of follow-up should be are more difficult questions and require an individualised approach. Clinical parameters have been suggested to aid in the therapeutic decision process but lack specificity. Although much promise has been put in molecular markers, these have not yet found their way to the clinic. More recently, clinicians have started to gain interest in drug level monitoring to adapt doses of immunomodulators and/or anti-tumour necrosis factor antibodies in an individualised manner. An increasing number of studies show that therapeutic drug monitoring can help physicians to improve and personalise the management of their patients. What is needed now are pharmaco-economic studies showing that personalised management of CD is cost effective.
    Gut 10/2013; 62(10):1511-5. · 10.73 Impact Factor
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    ABSTRACT: Bacteria play an important role in the onset and perpetuation of intestinal inflammation in inflammatory bowel disease (IBD). Unlike in Crohn's disease (CD), in which dysbiosis has been better characterised, in ulcerative colitis (UC), only small cohorts have been studied and showed conflicting data. Therefore, we evaluated in a large cohort if the microbial signature described in CD is also present in UC, and if we could characterise predominant dysbiosis in UC. To assess the functional impact of dysbiosis, we quantified the bacterial metabolites. The predominant microbiota from 127 UC patients and 87 age and sex-matched controls was analysed using denaturing gradient gel electrophoresis (DGGE) analysis. Differences were quantitatively validated using real-time PCR. Metabolites were quantified using gas chromatography-mass spectrometry. Based on DGGE analysis, the microbial signature previously described in CD was not present in UC. Real-time PCR analysis revealed a lower abundance of Roseburia hominis (p<0.0001) and Faecalibacterium prausnitzii (p<0.0001) in UC patients compared to controls. Both species showed an inverse correlation with disease activity. Short-chain fatty acids (SCFA) were reduced in UC patients (p=0.014), but no direct correlation between SCFA and the identified bacteria was found. The composition of the fecal microbiota of UC patients differs from that of healthy individuals: we found a reduction in R hominis and F prausnitzii, both well-known butyrate-producing bacteria of the Firmicutes phylum. These results underscore the importance of dysbiosis in IBD but suggest that different bacterial species contribute to the pathogenesis of UC and CD.
    Gut 09/2013; · 10.73 Impact Factor
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    ABSTRACT: Mucosal healing might alter mid- and long-term outcomes of patients with Crohn's disease (CD) and has become an important endpoint in clinical trials. However, the minimal degree of mucosal improvement (endoscopic response) required to alter mid-term outcomes is not known. We aimed to determine the best definition of endoscopic response by evaluating the simple endoscopic score for CD (SES-CD) and the CD endoscopic index of severity (CDEIS) from the study of biologic- and immunomodulator-naive patients in CD (SONIC trial). We analyzed data from 172 patients who participated in the SONIC trial, were found to have endoscopic lesions at baseline, and underwent a second endoscopic examination at week 26 of treatment with infliximab, azathioprine, or both. Mucosal healing was defined as absence of ulcers. A central reader calculated SES-CD and CDEIS results. Different cut-off values were set for endoscopic response, based on the SES-CD or CDEIS. The diagnostic ability of these different cut-off values were evaluated using receiver operating characteristic (ROC) curves and positive (PLR) and negative likelihood ratios (NLR). Corticosteroid-free clinical remission (CFREM) at week 50 was used as a binary classifier. Based on analyses of ROC curves, PLR, and NLR, endoscopic response was defined as a decrease from baseline in SES-CD of at least 50%. At week 26, mucosal healing and endoscopic response were achieved in 48% and 65% of patients, respectively. Mucosal healing at week 26 was associated with CFREM at week 50, with 56% sensitivity, 65% specificity, a PLR of 1.60, and an NLR of 0.67. Endoscopic response at week 26 was associated with CFREM at week 50, with 74% sensitivity, 48% specificity, a PLR of 1.42, and an NLR of 0.54. Endoscopic response, defined as a decrease from baseline in CDEIS of at least 50%, yielded similar results. In patients with CD, mucosal healing and endoscopic response (defined as a decrease from baseline in SESCD or CDEIS of at least 50%) at week 26 of treatment identified those most likely to be in CFREM at week 50. The ability of the proposed endoscopic response cut-off value to predict mid-term CFREM should be validated in an independent, prospective cohort. Its correlation with changes in long-term disease progression requires demonstration. Clinical trials.gov, Number: NCT00094458.
    Gastroenterology 08/2013; · 12.82 Impact Factor
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    ABSTRACT: Introduction: Chronically relapsing inflammation, tissue remodeling and fibrosis are hallmarks of inflammatory bowel diseases. The aim of this study was to investigate changes in connective tissue in a chronic murine model resulting from repeated cycles of dextran sodium sulphate (DSS) ingestion, to mimic the relapsing nature of the human disease. Materials and Methods: C57BL/6 mice were exposed to DSS in drinking water for 1 week, followed by a recovery phase of 2 weeks. This cycle of exposure was repeated for up to 3 times (9 weeks in total). Colonic inflammation, fibrosis, extracellular matrix proteins and colonic gene expression were studied. In vivo MRI T2 relaxometry was studied as a potential non-invasive imaging tool to evaluate bowel wall inflammation and fibrosis. Results: Repeated cycles of DSS resulted in a relapsing and remitting disease course, which induced a chronic segmental, transmural colitis after 2 and 3 cycles of DSS with clear induction of fibrosis and remodeling of the muscular layer. Tenascin expression mirrored its expression in Crohn’s colitis. Microarray data identified a gene expression profile different in chronic colitis from that in acute colitis. Additional recovery was associated with upregulation of unique genes, in particular keratins, pointing to activation of molecular pathways for healing and repair. In vivo MRI T2 relaxometry of the colon showed a clear shift towards higher T2 values in the acute stage and a gradual regression of T2 values with increasing cycles of DSS. Conclusions: Repeated cycles of DSS exposure induce fibrosis and connective tissue changes with typical features, as occurring in Crohn’s disease. Colonic gene expression analysis revealed unique expression profiles in chronic colitis compared to acute colitis and after additional recovery, pointing to potential new targets to intervene with the induction of fibrosis. In vivo T2 relaxometry is a promising non-invasive assessment of inflammation and fibrosis.
    PLoS ONE 07/2013; 8(7):e68876. · 3.53 Impact Factor

Publication Stats

2k Citations
604.80 Total Impact Points

Institutions

  • 2004–2014
    • Universitair Ziekenhuis Leuven
      • Department of Gastroenterology
      Louvain, Flanders, Belgium
  • 2013
    • McGill University Health Centre
      Montréal, Quebec, Canada
  • 2012
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
  • 2004–2012
    • University of Leuven
      Louvain, Flanders, Belgium
  • 2010
    • University of Otago
      Taieri, Otago Region, New Zealand
  • 2005
    • The Catholic University of America
      Washington, Washington, D.C., United States