Teun van Gelder

Erasmus MC, Rotterdam, South Holland, Netherlands

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Publications (346)1456.8 Total impact

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    ABSTRACT: Background and objective: Morphine dosing can be challenging in terminally ill adult patients due to the heterogeneous nature of the population and the difficulty of accurately assessing pain during sedation. To determine the pharmacokinetics of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in this population, and to find clinically relevant parameters for dose individualisation, we performed a population pharmacokinetic analysis. Methods: Blood samples were randomly collected from 47 terminally ill patients in both the pre-terminal and terminal phases. Nonlinear mixed-effects modelling (NONMEM) was used to develop a population pharmacokinetic model and perform covariate analysis. Results: The data were accurately described by a two-compartment model for morphine with two one-compartment models for both its metabolites. Typical morphine clearance was 48 L/h and fell exponentially by more than 10 L/h in the last week before death. Decreased albumin levels and a decreased estimated glomerular filtration rate (eGFR) resulted in lower metabolite clearance. Between-subject variability in clearance was 52 % (morphine), 75 % (M3G) and 79 % (M6G), and changed to 53, 29 and 34 %, respectively, after inclusion of the covariates. Conclusions: Our results show that morphine clearance decreased up to the time of death, falling by more than 10 L/h (26 %) in the last week before death, and that M3G and M6G accumulated due to decreased renal function. Further studies are warranted to determine whether dose adjustment of morphine is required in terminally ill patients.
    No preview · Article · Dec 2015 · Clinical Pharmacokinetics
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    ABSTRACT: Background: The aim of this study was to investigate whether pre-transplant tacrolimus (Tac) dose requirements of patients scheduled to undergo living donor kidney transplantation correlate with post-transplantation dose requirements. Methods: The predictive value of Tac dose requirements (defined as the ratio of the Tac predose concentration, C0, divided by the total daily Tac dose, D) pre-transplantation on this same parameter post-transplantation was assessed retrospectively in a cohort of 57 AB0-incompatible kidney transplant recipients. These patients started immunosuppressive therapy 14 days before transplant surgery. All patients were using a stable dose of glucocorticoids and were at steady-state Tac exposure before transplantation. Results: Tac dose requirements immediately before transplantation (C0/Dbefore) explained 63% of the Tac dose requirements on day 3 post-transplantation: r = 0.633 (F (1, 44) = 75.97, p <0.01). No other clinical and demographic variables predicted Tac dose requirements early after transplantation. Conclusions: Steady-state Tac dose requirement before transplantation largely predicted post-transplantation Tac dose requirements in AB0-incompatible kidney transplant recipients. The importance of this finding is that the post-transplantation Tac dose can be individualized based on a patient's pre-transplantation Tac concentration/dose ratio. Pre-transplant Tac phenotyping therefore has the potential to improve transplantation outcomes.
    No preview · Article · Dec 2015 · Therapeutic drug monitoring
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    ABSTRACT: Patients expressing the cytochrome P450 (CYP) 3A5 gene require a higher tacrolimus dose to achieve therapeutic exposure compared with non-expressers. This randomized-controlled study investigated if adaptation of the tacrolimus starting dose according to CYP3A5 genotype increases the proportion of kidney transplant recipients being within the target tacrolimus predose concentration range (10-15 ng/mL) at first steady-state. Two hundred forty living-donor, renal transplant recipients were assigned to either receive a standard, bodyweight-based or a CYP3A5 genotype-based tacrolimus starting dose. At day 3, no difference in the proportion of patients having a tacrolimus exposure within the target range was observed between the standard-dose and genotype-based groups: 37.4% vs. 35.6%, respectively; p = 0.79. The proportion of patients with a sub-therapeutic (i.e. <10 ng/mL) or a supra-therapeutic (i.e. >15 ng/mL) Tac C0 in the two groups was also not significantly different. The incidence of acute rejection was comparable between both groups (p = 0.82). Pharmacogenetic adaptation of the tacrolimus starting dose does not increase the number of patients having therapeutic tacrolimus exposure early after transplantation and does not lead to improved clinical outcome in a low immunological risk population. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · American Journal of Transplantation
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    ABSTRACT: Objective: Kidney transplant recipients face many self-management challenges. We aimed to identify profiles of attitudes towards self-management support (SMS) shortly after kidney transplantation. Methods: Profiles were generated using Q-methodology: In face-to-face interviews participants rank-ordered opinion statements on aspects of SMS according to agreement. Socio-demographic and medical characteristics were assessed using a questionnaire. By-person factor analysis was used to analyze the rankings and qualitative data was used to support choice of profiles. The resulting factors represent clusters of patients with similar attitudes towards SMS. Results: Forty-three patients (mean age=56; 77% male) participated. Four profiles were identified: (A) transplant-focused and obedient; (B) holistic and collaborative; (C) life-focused and self-determined; and (D) was bipolar. The positive pole (D+) minimalizing and disengaged and the negative pole (D-) coping-focused and needy represent opposing viewpoints within the same profile. Socio-demographic and medical characteristics were not related to profile membership. Discussion: Each profile represents a specific attitude on post-transplant life, responsibility for health and decision-making, SMS needs, and preferences for SMS. Practical implications: Patients vary in their attitude, needs and preferences for SMS indicating the necessity of providing personalized support after kidney transplantation. Health professionals should explore patients' SMS needs and adapt support accordingly.
    No preview · Article · Nov 2015 · Patient Education and Counseling
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    ABSTRACT: In association with therapeutic drug monitoring (TDM) of immunosuppressive drugs, pharmacogenetics has rapidly emerged as an additional tool to refine dose selection or, more interestingly to select, a priori, the first dose to administer. Pharmacogenetic biomarkers are now readily available in most transplantation centers, at a limited cost and within a limited analytical time frame, which make them compatible with the clinical decision process. However, despite some evidence of clear associations between polymorphisms in genes encoding metabolizing enzymes (CYP3A4/3A5, UGT1A9) or drug transporters (ABCB1, ABCC2, SLCO1B1) and pharmacokinetics of several immunosuppressive drugs, pre-emptive genotyping and selection of the optimal starting dose based on the genetic background of the patient is still rarely performed in clinical practice. The main reason is probably the lack of formal proof that clinical outcome really improves following genotype-based dosing. So far, the only clinical recommendation in relation to pharmacogenetic biomarkers should be a doubling of the starting Tacrolimus (Tac) dose in patients who are CYP3A5 expressers, and even in this case, some authors still do not recommend pre-emptive genotyping but only genotype-based adaptation if the CYP3A5 genotype is already known. However, with the rise of new technologies, as next generation sequencing, allowing to obtain pre-emptive genetic information, one must be aware that the question will no longer be whether to genotype or not, but rather whether or not to use the information already there. There was therefore a need to update the information available in relation to pharmacogenetic biomarkers for calcineurin inhibitors (CNIs), mycophenolic acid (MPA) and mammalian target of rapamycin inhibitors (mTORi).
    No preview · Article · Oct 2015 · Therapeutic drug monitoring
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    ABSTRACT: Background and Objective The anti-oestrogen tamoxifen requires metabolic activation to endoxifen by cytochrome P450 (CYP) enzymes, predominantly CYP2D6. Potent CYP2D6-inhibiting antidepressants can seriously disrupt tamoxifen metabolism, probably influencing the efficacy of tamoxifen. For this reason, paroxetine and fluoxetine are recommended not to be used with tamoxifen in breast cancer patients. We investigated the effects of switching potent CYP2D6-inhibiting antidepressants to weak CYP2D6-inhibiting antidepressants on the plasma pharmacokinetics of tamoxifen. Methods Ten breast cancer patients who were treated with tamoxifen in combination with a potent CYP2D6-inhibiting antidepressant (paroxetine or fluoxetine) for at least 4 weeks were enrolled. Under close supervision by a psychiatrist, patients were switched to treatment with escitalopram or venlafaxine (weak CYP2D6-inhibiting antidepressants). Before and after the switch, pharmacokinetic blood sampling was performed over 24 h. Pharmacokinetic parameters were estimated using noncompartmental analysis. Adverse effects were recorded during the study. Results Endoxifen exposure was ~3-fold higher during escitalopram co-administration than during paroxetine or fluoxetine co-administration (median 387 nM·h [range 159–637 nM·h] versus 99.2 nM·h [range 70.0–210 nM·h]; P = 0.012; Wilcoxon signed-rank test). The ratio of endoxifen to N-desmethyltamoxifen and the ratio of 4-hydroxytamoxifen to tamoxifen increased by 3.3- and ~1.5-fold, reflecting increased CYP2D6 activity. Antidepressant switching did not result in psychiatric problems or antidepressant-related adverse effects. Conclusion In this study, switching to the weak CYP2D6 inhibitor escitalopram was safe and feasible and resulted in clinically relevant rises in endoxifen concentrations. We therefore advise switching paroxetine and fluoxetine to escitalopram in patients using tamoxifen. However, switching should always be weighed in individual patients.
    No preview · Article · Oct 2015 · Clinical Pharmacokinetics
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    ABSTRACT: Background and objectives: Definition of individual risk profile is the first step to implement strategies to keep the delicate balance between under- and overimmunosuppression after kidney transplantation. Design, setting, participants, & measurements: We used data from the Efficacy Limiting Toxicity Elimination Symphony Study (1190 patients between 2002 and 2004) to model risk of rejection and infection in the first year after kidney transplantation. External validation was performed in a study population from the Fixed-Dose Concentration-Controlled Trial (630 patients between 2003 and 2006). Results: Despite different temporal dynamics, rejections and severe infections had similar overall incidences in the first year after transplantation (23.4% and 25.5%, respectively), and infections were the principal cause of death (43.2% of all deaths). Recipient older age, deceased donor, higher number of HLA mismatches, and high risk for cytomegalovirus disease were associated with infection; deceased donor, higher number of HLA mismatches, and immunosuppressive therapy including cyclosporin A (compared with tacrolimus), with rejection. These factors were integrated into a two-dimensional risk stratification model, which defined four risk groups: low risk for infection and rejection (30.8%), isolated risk for rejection (36.1%), isolated risk for infection (7.0%), and high risk for infection and rejection (26.1%). In internal validation, this model significantly discriminated the subgroups in terms of composite end point (low risk for infection/rejection, 24.4%; isolated risk for rejection and isolated risk for infection, 31.3%; high risk for infection/rejection, 54.4%; P<0.001), rejection episodes (isolated risk for infection and low risk for infection/rejection, 13.0%; isolated risk for rejection and high risk for infection/rejection, 24.2%; P=0.001), and infection episodes (low risk for infection/rejection and isolated risk for rejection, 12.0%; isolated risk for infection and high risk for infection/rejection, 37.6%; P<0.001). External validation confirmed the applicability of the model to an independent cohort. Conclusions: We propose a two-dimensional risk stratification model able to disentangle the individual risk for rejection and infection in the first year after kidney transplantation. This concept can be applied to implement a personalized immunosuppressive and antimicrobial treatment approach.
    No preview · Article · Oct 2015 · Clinical Journal of the American Society of Nephrology
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    ABSTRACT: Background: Low-molecular-weight heparins (LMWHs) have been shown to accumulate in patients with renal insufficiency, especially in therapeutic dosages. Although no appropriate studies have been conducted for prophylactic dosages of nadroparin, dose reduction is sometimes recommended, especially for high prophylactic dosages. We assessed accumulation of a prophylactic dose of 5700 IU subcutaneous nadroparin once daily in patients with renal insufficiency. Methods: We conducted a prospective cohort study and measured peak anti-Xa activity four hours after subcutaneous nadroparin injection on day 1, 3, 5 and if possible day 10 in adults with and without renal insufficiency defined as a glomerular filtration rate (GFR) below or above 50 ml/min/1.73 m2. Patients with a GFR below 10 ml/min/1.73 m2 were excluded. Results: We included 14 patients in each group. In the group with renal failure 12 patients had a GFR between 30 and 50 ml/min/1.73 m2. Peak anti-Xa activity showed a high interindividual variability, but was fairly constant within each patient. There was no rise in peak anti-Xa activity on day 3 and 5 after consecutive administration. In the group with normal renal function, peak anti-Xa activity declined on day 5 compared with day 1 (p = 0.005). Conclusion: Prophylactic dosages of nadroparin showed no accumulation in patients with a GFR between 30-50 ml/ min/1.73 m2. Dose reduction in this group could lead to suboptimal thromboprophylaxis. Due to underrepresentation of patients with a GFR < 30 ml/min/1.73 m2 (n = 2), we cannot give recommendations for this group.
    Full-text · Article · Oct 2015
  • Eric C. T. Geijteman · Henning Tiemeier · Teun van Gelder

    No preview · Article · Oct 2015 · JAMA Internal Medicine

  • No preview · Article · Sep 2015 · European geriatric medicine
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    ABSTRACT: Anti-tumor necrosis factor alpha (TNFα) therapy is effective in pediatric patients with inflammatory bowel disease (IBD) but associated with a risk of developing anti-drug antibodies (ADA) which lower the efficacy. Incorporating measurement of trough levels and ADA (therapeutic drug monitoring) may prevent the development of neutralizing ADA or could contribute to more optimal treatment strategies if ADA are already formed. The aim of this review was to investigate the role of therapeutic drug monitoring in children and adolescents with IBD exposed to anti-TNFα agents. A literature search identified publications that measured anti-TNFα drug trough levels and/or ADA in children or adolescents with IBD. Studies were eligible when (1) article was written in English, (2) original data were available, (3) full text article or abstract was available, (4) measurement of antibodies against anti-TNFα drugs or trough level of anti-TNFα drugs were reported, and (5) levels were measured in pediatric patients with IBD. The search yielded 811 articles, of which 795 articles were excluded based on title or abstract. A total of 14 studies were included in the review. Therapeutic drug monitoring within the pediatric IBD population certainly has a potential benefit. As occurrence of immune reactions to anti-TNFα agents varies widely, incorporating measurement of IFX trough levels at week 8 or week 14 predicts therapy response and allows for dose adjustments to reach therapeutic drug concentrations. However, a clinically relevant cutoff level for ADA has not been defined yet, and the optimal intervention strategy still has to be determined.
    No preview · Article · Sep 2015 · Inflammatory Bowel Diseases
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    ABSTRACT: Background The antipsychotics risperidone, aripiprazole and pipamperone are frequently prescribed for the treatment in children with autism. The aim of this study was to validate an ultra-high performance liquid chromatography-mass spectrometry method for the quantification of these antipsychotics in plasma.Methods An ultra-high performance liquid chromatography-mass spectrometry assay was developed for the determination of the drugs and metabolites. Gradient elution was performed on a reversed phase column with a mobile phase consisting of ammonium acetate, formic acid in methanol or in Milli-Q ultrapure water at a flow rate of 0.5 mL/min.ResultsThe method was validated according to the FDA guidelines. The analytes were found stable enough after reconstitution and injection of only 5 μL improved the accuracy and precision in combination with the internal standard. Calibration curves of all five analytes were linear. All analytes were stable for at least 72 h in the auto-sampler and the QC high of 9-OH-risperidone was stable for 48 h.Conclusions The method allows quantification of all analytes. The advantage of this method is the combination of a minimal injection volume, a short run-time, an easy sample preparation method and the ability to quantify all analytes in one run. This article is protected by copyright. All rights reserved.
    No preview · Article · Sep 2015 · Biomedical Chromatography
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    Full-text · Article · Aug 2015 · Intensive Care Medicine

  • No preview · Article · Aug 2015
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    ABSTRACT: Although therapeutic dosages of most low-molecular-weight heparins (LMWHs) are known to accumulate in patients with renal insufficiency, for the lower prophylactic dosages this has not been clearly proven. Nevertheless, dose reduction is often recommended. We conducted a systematic review to investigate whether prophylactic dosages of LMWH accumulate in renal insufficient patients. A comprehensive search was conducted on 17 February 2015 using Embase, Medline, Web of Science, Scopus, Cochrane, PubMed publisher, and Google scholar. The syntax emphasized for LMWHs, impaired renal function, and pharmacokinetics. The search yielded 674 publications. After exclusion by reading the titles, abstracts, and if necessary the full paper, 11 publications remained. For dalteparin and tinzaparin, no accumulation was observed. Enoxaparin, on the other hand, did lead to accumulation in patients with renal insufficiency, although not in patients undergoing renal replacement therapy. Bemiparin and certoparin also did show accumulation. No data were available for nadroparin. In this systematic review, we show that prophylactic dosages of tinzaparin and dalteparin are likely to be safe in patients with renal insufficiency and do not need dose reduction based on the absence of accumulation. However, prophylactic dosages of enoxaparin, bemiparin, and certoparin did show accumulation in patients with a creatinine clearance (CrCl) below 30 ml/min, and therefore, dose reduction is required. The differences in occurrence of accumulation seem to depend on the mean molecular weight of LMWHs.
    Full-text · Article · Jun 2015 · European Journal of Clinical Pharmacology
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    ABSTRACT: The anti-estrogen tamoxifen is characterized by a large variability in response, partly due to pharmacokinetic differences. We examined circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Pharmacokinetic analysis was performed in mice, dosed at six different times (24-h period). Tissue samples were used for mRNA expression analysis of drug-metabolizing enzymes. In patients, a cross-over study was performed. During three 24-h periods, after tamoxifen dosing at 8 a.m., 1 p.m., and 8 p.m., for at least 4 weeks, blood samples were collected for pharmacokinetic measurements. Differences in tamoxifen pharmacokinetics between administration times were assessed. The mRNA expression of drug-metabolizing enzymes showed circadian variation in mouse tissues. Tamoxifen exposure seemed to be highest after administration at midnight. In humans, marginal differences were observed in pharmacokinetic parameters between morning and evening administration. Tamoxifen Cmax and area under the curve (AUC)0–8 h were 20 % higher (P < 0.001), and tamoxifen tmax was shorter (2.1 vs. 8.1 h; P = 0.001), indicating variation in absorption. Systemic exposure (AUC0–24 h) to endoxifen was 15 % higher (P < 0.001) following morning administration. The results suggest that dosing time is of marginal influence on tamoxifen pharmacokinetics. Our study was not designed to detect potential changes in clinical outcome or toxicity, based on a difference in the time of administration. Circadian rhythm may be one of the many determinants of the interpatient and intrapatient pharmacokinetic variability of tamoxifen. Electronic supplementary material The online version of this article (doi:10.1007/s10549-015-3452-x) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jun 2015 · Breast Cancer Research and Treatment
  • Teun van Gelder
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    ABSTRACT: Generic immunosuppressive drugs are available in Europe, Canada, and the United States. Between countries, there are large differences in the market penetration of generic drugs in general, and for immunosuppressive drugs in particular. The registration criteria for generic immunosuppressive drugs are often criticized. However, it is unlikely that the criteria for registration of narrow therapeutic index drugs are going to change, and bioequivalence studies, performed in healthy volunteers, will remain the backbone of the registration process. It would be good if the registration authorities would demand that all generic variants of an innovator drug have the same pill appearance to reduce errors and promote drug adherence.To allow for safe substitution, a number of criteria need to be fulfilled. Generic substitution should not be taken out of the hands of the treating physicians. Generic substitution can only be done safely if initiated by the prescriber, and in well-informed and prepared patients. Payers should refrain from forcing pharmacists to dispense generic drugs in patients on maintenance treatment with innovator drug. Instead, together with transplant societies, they should design guidelines on how to implement generic immunosuppressive drugs into clinical practice. Substitutions must be followed by control visits to check if the patient is taking the medication correctly and if drug exposure remains stable. Inadvertent, uncontrolled substitutions from 1 generic to another, initiated outside the scope of the prescriber, must be avoided as they are unsafe. Repetitive subsequent generic substitutions result in minimal additional cost savings and have an inherent risk of medication errors.
    No preview · Article · Jun 2015 · Transplantation
  • Yun-Ying Shi · Dennis A. Hesselink · Teun van Gelder
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    ABSTRACT: Elderly patients are a fast growing population among transplant recipients over the past decades. Both the innate and adaptive immune reactivity decrease with age, which is believed to contribute to the decreased incidence of acute rejection and increased infectious death rate in elderly transplant recipients. In contrast to recipient age, donor age is associated with a higher incidence of acute rejection. Pharmacokinetic studies in renal transplant recipients show that CNI troughs are >5% higher in elderly compared to younger patients given the same dose normalized by body weight. This may impact the starting dose of tacrolimus and cyclosporine. Possibly in elderly patients the intracellular (in lymphocyte) concentrations are relatively high in relation to the whole blood concentration, resulting in a stronger pharmacodynamic effect at the same whole blood trough concentration. For cyclosporine this has been shown, but it is not clear if the same is true for other immunosuppressive drugs. Pharmacodynamic studies have compared the inhibition of target enzymes, or more downstream effects of immunosuppressive drugs, in younger and older patients. Measurement of nuclear factor of activated T-cell (NFAT)-regulated gene expression (RGE), a pharmacodynamic read-out of CNI, is a promising biomarker of immunosuppression. Low levels of NFAT RGE are associated with increased risk of infection and non-melanoma skin cancer in elderly patients. Clinical trials to evaluate the safety and efficacy of immunosuppression regimens in this specific patient population, which is underrepresented in published trials, are lacking. More studies in elderly patients are needed to investigate the impact of age on the pharmacokinetics or pharmacodynamics of immunosuppressive drugs, and to decide on the optimal regimen and target levels for elderly transplant recipients. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · May 2015 · Transplantation Reviews
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    ABSTRACT: Introduction: Starting doses of tacrolimus and ciclosporin are typically chosen on a calculated mg/kg bodyweight basis. After initiation of treatment, doses are adjusted with therapeutic drug monitoring (TDM). This trial-and-error approach has been accepted by most physicians and pharmacists involved in the care of transplanted patients. Areas covered: Dosing algorithms have only fairly recently been proposed to better individualize the starting dose. This review provides an overview of all the currently available dosing algorithms in adult and children for the starting dose of ciclosporin, tacrolimus and mycophenolic acid. In these algorithms, multiple other covariates influencing the starting dose, such as age, hematocrit, comedication and genotype are taken into account. After selecting the starting dose with an algorithm and after initiation of treatment, TDM will, however, remain necessary. Whether or not implementation of such algorithms will improve clinical outcome remains to be demonstrated. Expert opinion: First of all an algorithm needs to be validated, against an independent dataset. Second, in a prospective study the algorithm should prove to reduce the time to reach the target concentration, and to reduce the number of patients with drug concentrations (far) outside the therapeutic window. Finally, a clinical trial demonstrating a benefit on clinical outcome will be crucial in achieving broad acceptance of calculating starting dose using individualized dosing algorithms.
    No preview · Article · Apr 2015 · Expert Opinion on Drug Metabolism & Toxicology
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    Full-text · Article · Apr 2015 · Annals of Oncology

Publication Stats

8k Citations
1,456.80 Total Impact Points

Institutions

  • 2002-2015
    • Erasmus MC
      • Department of Internal Medicine
      Rotterdam, South Holland, Netherlands
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 1989-2015
    • Erasmus Universiteit Rotterdam
      • • Department of Internal Medicine
      • • Department of Medical Oncology
      Rotterdam, South Holland, Netherlands
  • 2007
    • Georg-August-Universität Göttingen
      Göttingen, Lower Saxony, Germany
  • 2000-2004
    • Stanford Medicine
      • Department of Cardiothoracic Surgery
      Stanford, California, United States
  • 1999-2002
    • Stanford University
      • Department of Cardiothoracic Surgery
      Stanford, California, United States
  • 2001
    • University of California, San Francisco
      • School of Pharmacy
      San Francisco, California, United States
  • 1999-2001
    • Leiden University
      Leyden, South Holland, Netherlands