John B A G Haanen

Netherlands Cancer Institute, Amsterdamo, North Holland, Netherlands

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Publications (179)1587.07 Total impact

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    ABSTRACT: Purpose To compare prognostic performance of MSKCC and IMDC risk models in patients with synchronous mRCC. Methods Retrospective analysis of pre-therapeutic MSKCC and IMDC prognostic factors and outcomes in patients with synchronous mRCC treated at a single institute in the targeted therapy era was performed. Cytoreductive nephrectomy (CN) was performed in patients with WHO performance 0–1 and limited metastasis. Results Of 190 patients, only 2 had favourable risk. Overall, 141 patients received targeted therapy and 97 underwent CN. By MSKCC score, 143 (76.1 %) patients were intermediate risk (median OS 16 months) but only 97 (51.9 %) by IMDC (median OS 23 months). Conversely, 46 of the MSKCC intermediate-risk patients (31.2 %) were IMDC poor risk. Only poor risk by MSKCC and ≥4 IMDC factors had similar poor outcome (median OS 5 months and OS 2 years of 4.1 % and 10.4 %, respectively). Following CN, baseline elevated platelets and neutrophils decreased to normal in 61.5 and 75 %, respectively. This suggests that the primary tumour may influence baseline counts resulting in more IMDC poor risk. In both models, CN status was associated with better OS. Conclusion Patients with synchronous mRCC and poor risk by MSKCC or ≥4 IMDC factors have a short survival expectancy, and CN may not be the primary objective in this population. Conversely, with either MSKCC or IMDC intermediate risk the probability to survive 2 years is 38.6–45.7 %, which suggests that a subgroup of patients live long enough to derive a potential benefit of CN.
    No preview · Article · Feb 2016 · World Journal of Urology
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    ABSTRACT: Objective: To analyze if prediction of survival for patients with synchronous metastatic renal cell cancer (mRCC) could be further refined by baseline volume of the primary tumor, the metastases, or the remaining volume after surgery; this study was performed because survival expectancies of patients with intermediate-risk mRCC vary substantially. Material and methods: The predictive value of the different volumes on overall survival (OS) was analyzed retrospectively in patients with intermediate Memorial Sloan-Kettering Cancer Center (MSKCC) risk profile and ≤3 International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) factors, who received sunitinib in our institute. Tumor volumes were calculated on segmented computed tomography using in-house developed software. A multivariate analysis was performed including number of metastatic sites and baseline tumor burden (TB). Results: A total of 68 patients were included. Median OS for patients without cytoreductive nephrectomy (CN) was 6 months (95% CI: 3.0-8.9mo) vs. 31 months (95% CI: 23.1-38.8mo) for those with CN, respectively. More second-line treatment was given after CN (49% vs. 17%, P = 0.125). There was no correlation between tumor volume and TB measured by Response Evaluation Criteria in Solid Tumors. Of all included clinical and volumetric parameters, remaining volume after CN, CN status and 2 vs. 3 IMDC factors were significantly correlated with OS. In the Cox regression analysis, CN was the only remaining significant parameter (P = 0.003). Conclusions: None of the baseline volumetric parameters is an independent prognostic factor in patients with intermediate MSKCC risk mRCC with≤3 IMDC factors receiving sunitinib. Only CN status correlated significantly with prognosis. None of the baseline volumes nor TB by Response Evaluation Criteria in Solid Tumors was associated with CN status, suggesting that extent of disease had no significant influence on the decision to perform surgery.
    No preview · Article · Jan 2016 · Urologic Oncology
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    ABSTRACT: It is well established how effector T cells exit the vasculature to enter the peripheral tissues in which an infection is ongoing. However, less is known regarding how CTLs migrate toward infected cells after entry into peripheral organs. Recently, it was shown that the chemokine receptor CXCR3 on T cells has an important role in their ability to localize infected cells and to control vaccinia virus infection. However, the search strategy of T cells for virus-infected targets has not been investigated in detail and could involve chemotaxis toward infected cells, chemokinesis (i.e., increased motility) combined with CTL arrest when targets are detected, or both. In this study, we describe and analyze the migration of CTLs within HSV-1-infected epidermis in vivo. We demonstrate that activated T cells display a subtle distance-dependent chemotaxis toward clusters of infected cells and confirm that this is mediated by CXCR3 and its ligands. Although the chemotactic migration is weak, computer simulations based on short-term experimental data, combined with subsequent long-term imaging indicate that this behavior is crucial for efficient target localization and T cell accumulation at effector sites. Thus, chemotactic migration of effector T cells within peripheral tissue forms an important factor in the speed with which T cells are able to arrive at sites of infection.
    No preview · Article · Nov 2015 · The Journal of Immunology
  • M.H. Geukes Foppen · M. Donia · I.M. Svane · J.B.A.G. Haanen
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    ABSTRACT: Over the past few years melanoma incidence has been rising steadily, resulting in an increase in melanoma related mortality. Until recently, therapeutic options for metastatic melanoma were scarce. Chemotherapy and, in some countries, IL-2 were the only registered treatment modalities. In the last five years, treatment with immunotherapy (anti CTLA-4, anti PD-1, or the combination of these antibodies) has shown very promising results and was able to improve survival in patients with metastatic melanoma. Adoptive cell therapy using tumor-infiltrating lymphocytes is yet another, but highly promising, immunotherapeutic strategy for patients with metastatic melanoma. This review will discuss the development of TIL as a treatment option for melanoma, its mode of action and simplification over time, and the possibilities to expand this therapy to other types of cancer. Also, the future directions of TIL based therapies will be highlighted.
    No preview · Article · Oct 2015 · Molecular oncology
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    ABSTRACT: Background: Abiraterone Acetate (AA) and Enzalutamide (Enz) are effective hormonal treatments in mCRPC patients. Retrospective studies suggested clinical cross-resistance between Enz and AA. However, 12.8-39.1% of patients previously treated with docetaxel (Doc) and AA do respond to Enz. These responders have not been characterized. Methods: 102 Enz treated mCRPC patients after AA and Doc treatment were included in this study. Differences in patient characteristics and previous treatment outcomes between PSA responders and non-responders on Enz were evaluated. Results: Median Progression-Free Survival was 12.2 weeks (95%CI 11.7-14.3) and Overall Survival 43.5 weeks (95%CI 37.4-61.2). There were 26 (25%) Enz-responders and 76 (75%) non-responders. Significant higher percentages of Gleason scores ≥8 and PSA doubling times (PSA-DT) <3 months were found in Enz responders than in non-responders. The interval between end of AA and start of Enz treatment (IAE) for responders was 24.6 weeks (IQR 4.0-48.1) and 8.9 weeks for non-responders (IQR 3.7-25.9) (P = 0.08). In an IAE <40 days subgroup (34 patients), Enz responses were related to AA non-responsiveness, while univariate and logistic regression analysis of baseline criteria of a subgroup of patients with an IAE≥40 (68 patients) revealed significant differences in baseline PSA levels, PSA-DT <3 months, Gleason scores ≥8 and IAE's between Enz responders and non-responders. Conclusions: PSA response to Enz after previous AA and Doc treatment was associated with a longer IAE, a higher Gleason score and a PSA-DT <3 months. Identification of these patients might be of value for sequencing of treatment options. Prostate © 2015 Wiley Periodicals, Inc.
    No preview · Article · Sep 2015 · The Prostate
  • John B A G Haanen · Caroline Robert
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    ABSTRACT: Undoubtedly the discovery of immune checkpoints such as CTLA-4 and PD-1 has been crucial to the development of cancer immunotherapy. Although these molecules were originally discovered as molecules playing a role in T cell activation or apoptosis, subsequent preclinical research showed their important role in the maintenance of peripheral immune tolerance. Mice deficient of the immune checkpoints CTLA-4 or PD-1 develop autoimmune-like diseases that occur early after birth and are lethal in the case of CTLA-4 deficiency, or become apparent much later in life in the case of PD-1 deficiency. Blockade of CTLA-4 and PD-1 resulted in the development of antitumor immune responses that were effective as single agents or required additional treatment depending on the preclinical model. Therefore, it was surprising that single-agent anti-CTLA-4 and anti-PD-1 are so effective anticancer treatments in humans. These therapies have revolutionized cancer immunotherapy as they showed for the first time in many years of research in metastatic melanoma, which is considered one of the most immunogenic human cancers, an improvement in overall survival, with an increasing group of patients benefitting long-term from these treatments. In this chapter we discuss the discovery of immune checkpoints, the clinical application of their inhibitors and the future directions of this highly interesting class of molecules.
    No preview · Article · Sep 2015

  • No preview · Article · Aug 2015 · Cancer Research

  • No preview · Article · Aug 2015 · Asia-Pacific Journal of Clinical Oncology
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    ABSTRACT: Immunotherapy has now been clinically validated as an effective treatment for many cancers. There is tremendous potential for synergistic combinations of immunotherapy agents and for combining immunotherapy agents with conventional cancer treatments. Clinical trials combining blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) may serve as a paradigm to guide future approaches to immuno-oncology combination therapy. In this Review, we discuss progress in the synergistic design of immune-targeting combination therapies and highlight the challenges involved in tailoring such strategies to provide maximal benefit to patients.
    No preview · Article · Jul 2015 · Nature Reviews Cancer
  • Andrea van Elsas · Hans van Eenennaam · John B A G Haanen
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    ABSTRACT: T-cell checkpoint inhibitors treat the cancer patient's immune system potentially inducing significant long-term survival. Pembrolizumab demonstrates clinical activity in patients diagnosed with melanoma and other cancers. Its mode of action suggests a rationale for combination with other treatment modalities, urging oncologists to brush up their knowledge of immunology. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Jul 2015 · Clinical Cancer Research
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    ABSTRACT: To analyze the clinical characteristics of a serous retinopathy associated with mitogen-activated protein kinase kinase (MEK) inhibition with binimetinib treatment for metastatic cutaneous melanoma (CM) and uveal melanoma (UM), and to determine possible pathogenetic mechanisms that may lead to this retinopathy. Prospective observational, cohort-based, cross-sectional study. Thirty CM patients and 5 UM patients treated with the MEK inhibitor binimetinib (CM) or a combination of binimetinib and the protein kinase C inhibitor sotrastaurin (UM). Extensive ophthalmic examination was performed, including Early Treatment of Diabetic Retinopathy Study best-corrected visual acuity, applanation tonometry, slit-lamp examination, indirect ophthalmoscopy, digital color fundus photography, and optical coherence tomography (OCT). In selected cases, additional examinations were performed, including visual field testing and electro-oculography (EOG). Blood samples were obtained from 3 CM patients and 3 UM patients to analyze the presence of autoantibodies against retinal and retinal pigment epithelium (RPE) proteins. Visual symptoms, visual acuity, fundus appearance, characteristics on OCT, fundus autofluorescence (FAF), and EOG. Six CM patients (20%) and 2 UM patients (40%) reported visual symptoms during the study. The median time to the onset of symptoms, which were all mild and transient, was 3.5 days (range, <1 hour to 3 weeks). On OCT, subretinal fluid (SRF) was detected in 77% of CM patients and 60% of UM patients. In the 26 patients with SRF, the fovea was affected in 85%. After the start of the medication, an EOG was performed in 19 eyes of 11 patients; 16 of these eyes (84%) developed SRF on OCT. Fifteen of these eyes (94%) showed an abnormal Arden ratio (<1.65). A broad pattern of anti-retinal antibodies was found in 3 CM patients and 2 UM patients tested, whereas anti-RPE antibodies were detected in all 6 tested patients. A time-dependent and reversible serous retinopathy can develop both in patients with metastatic CM and UM treated with binimetinib. A minority of patients develop visual symptoms, which are generally mild and transient. A cause of binimetinib-associated serous retinopathy may be toxicity of medication, but autoantibodies also may be involved. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Ophthalmology
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    ABSTRACT: Targeted therapy with sunitinib, pazopanib or everolimus has improved treatment outcome for patients with metastatic renal cell carcinoma patients (RCC). However, despite considerable efforts in sequential or combined modalities, durable remissions are rare. Immunotherapy like cytokine therapy with interleukin-2, T cell checkpoint blockade or adoptive T cell therapies can achieve long-term benefit and even cure. This raises the question of whether combining targeted therapy with immunotherapy could also be an effective treatment option for RCC patients. Sunitinib, one of the most frequently administered therapeutics in RCC patients has been implicated in impairing T cell activation and proliferation in vitro. In this work, we addressed whether this notion holds true for expansion of tumor-infiltrating lymphocytes (TILs) in sunitinib-treated patients. We compared resected primary RCC tumor material of patients pretreated with sunitinib with resection specimen from sunitinib-naïve patients. We found improved TIL expansion from sunitinib-pretreated tumor digests. These TIL products contained more PD-1 expressing TIL, while the regulatory T cell infiltration was not altered. The improved TIL expansion was associated with reduced intratumoral myeloid-derived suppressor cell (MDSC) content. Depletion of MDSCs from sunitinib-naïve RCC tissue-digest improved TIL expansion, proving the functional relevance of the MDSC alteration by sunitinib. Our in vivo results do not support previous in vitro observations of sunitinib inhibiting T cell function, but do provide a possible rationale for the combination of sunitinib with immunotherapy.
    No preview · Article · Jun 2015 · Cancer Immunology and Immunotherapy
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    ABSTRACT: The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of BRAF(V600E) metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole-exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug-resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAF(V600E), we identified a new activating insertion in MEK1. This MEK1(T55delins) (RT) mutation could be traced back to a fraction of the pre-treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient-derived xenografts (PDX) from therapy-refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter- and intra-tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    Full-text · Article · Jun 2015 · EMBO Molecular Medicine
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    ABSTRACT: We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials. Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on-2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice. A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15-17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8-10.0) and 18.7 months (95% CI: 17.5-19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand-foot syndrome (each 7%). Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.British Journal of Cancer advance online publication, 18 June 2015; doi:10.1038/bjc.2015.196 www.bjcancer.com.
    Full-text · Article · Jun 2015 · British Journal of Cancer
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    Full-text · Dataset · Jun 2015

  • No preview · Article · Jun 2015 · Human gene therapy. Clinical development
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    Full-text · Article · Jun 2015 · Human gene therapy. Clinical development
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    ABSTRACT: Background: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. Methods: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here. Results: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. Conclusions: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
    Full-text · Article · May 2015 · New England Journal of Medicine
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    ABSTRACT: Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. GlaxoSmithKline. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · May 2015 · The Lancet
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    ABSTRACT: Here, we describe a fatal Serious Adverse Event observed in a patient infused with autologous T cell receptor (TCR) transduced T cells. This TCR, originally obtained from a melanoma patient, recognizes the well-described HLA-A*0201 restricted 26-35 epitope of MART-1, and was not affinity enhanced. Patient 1 with metastatic melanoma experienced a cerebral hemorrhage, epileptic seizures and a witnessed cardiac arrest 6 days after cell infusion. Three days later, the patient died from multiple organ failure and irreversible neurologic damage.After T cell infusion, levels of IL-6, IFN-γ, CRP and procalcitonin increased to extreme levels, indicative of a cytokine release syndrome or T cell mediated inflammatory response. Infused T cells could be recovered from blood, broncho-alveolar lavage, ascites, and after autopsy from tumor sites and heart tissue. High levels of NT-proBNP indicate semi-acute heart failure. No cross reactivity of the modified T cells towards a beating cardiomyocyte culture was observed. Together, these observations suggest that high levels of inflammatory cytokines alone or in combination with semi-acute heart failure and epileptic seizure may have contributed substantially to the occurrence of the acute and lethal event. Protocol modifications to limit the risk of T cell activation-induced toxicity are discussed.Molecular Therapy (2015); doi:10.1038/mt.2015.60.
    No preview · Article · Apr 2015 · Molecular Therapy

Publication Stats

11k Citations
1,587.07 Total Impact Points

Institutions

  • 1999-2015
    • Netherlands Cancer Institute
      • • Department of Medical Oncology
      • • Division of Immunology
      Amsterdamo, North Holland, Netherlands
  • 2010-2014
    • Leiden University
      Leyden, South Holland, Netherlands
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2011
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
    • Leiden University Medical Centre
      • Department of Clinical Oncology
      Leyden, South Holland, Netherlands
  • 2006
    • VU University Amsterdam
      • Department of Medical Oncology
      Amsterdamo, North Holland, Netherlands
  • 2005
    • Johns Hopkins University
      Baltimore, Maryland, United States