Justus Duyster

Universitätsklinikum Freiburg, Freiburg an der Elbe, Lower Saxony, Germany

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Publications (166)1280.5 Total impact

  • M Waterhouse · I Bartsch · H Bertz · J Duyster · J Finke
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    ABSTRACT: Central nervous system (CNS) complications have been described in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). Cerebrospinal fluid (CSF) analysis is included in the diagnostic workup in patients with neurological symptoms after alloHCT. CSF donor-recipient chimerism analysis usually is not used to evaluate patients with neurological complications after alloHCT. To assess the potential contribution of CSF donor-recipient chimerism in patients with neurological complications, we analyzed 85 CSF samples from 50 patients with neurological complications after alloHCT. After alloHCT, 21 patients showed the presence of recipient-derived DNA. In 13 of these patients, recurrence of the underlying disease was detected in CSF. There was a moderate correlation between the recipient DNA percentage as detected by short tandem repeat (STR) amplification and the cell concentration in CSF (Spearmann r: 0.66 P=0.004). The percentage of cells with immunophenotypic abnormalities from patients relapsing in the CNS detected by flow cytometry showed a strong correlation with the percentage of recipient-derived DNA in CSF assessed by STR analysis (Spearmann r: 0.83 P=0.0008). Donor-recipient chimerism analysis in CSF in patients with neurological symptoms after alloHCT is a practical, feasible and useful complementary method to the already established methodologies included in the diagnostic workup.Bone Marrow Transplantation advance online publication, 5 October 2015; doi:10.1038/bmt.2015.226.
    Bone marrow transplantation 10/2015; DOI:10.1038/bmt.2015.226 · 3.57 Impact Factor
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    ABSTRACT: Despite major improvements in allogeneic hematopoietic cell transplantation over the last decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Pre-clinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grade III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The ORR was 81.5% (44/54) in SR-aGVHD including 25 CRs (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%,95% CI) and 97.4% (92.3-100%,95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and CMV-reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.Leukemia accepted article preview online, 31 July 2015. doi:10.1038/leu.2015.212.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2015; DOI:10.1038/leu.2015.212 · 10.43 Impact Factor
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    ABSTRACT: Patients often experience bone marrow examinations (BMEs) as frightening and painful. Varying operators and uncertainty about who will perform the BME worsen their anxiety. In our study, clinical nurse specialists (CNSs) were trained to perform BMEs to ensure continuity and to test the feasibility, patient satisfaction, and biopsy quality. This exploratory evaluation assessed 574 BMEs at our tertiary center between January 2012 and February 2013, 398 BMEs performed by CNS and 176 by physicians. Our aims were to determine whether BMEs by CNS yield results similar to those of physicians, analyzing (1) patient satisfaction with the BME (a) consent and (b) performance, (2) induced pain, and (3) quality of aspirates and length of trephine biopsies. When performed by CNS, 100 % of the patients were satisfied with the consent procedure and 99 % with the BME performance (physicians 99 and 91 %, respectively). The median pain score was low when both CNS and physicians performed the BME, with no or only mild pain in 92 and 76 % of patients, respectively. Bone marrow (BM) aspirates by CNS and physicians were assessed as technically evaluable in ~70 %; moreover, the median length of trephine biopsies was similar when performed by CNS or physicians with 12 and 13 mm, respectively. In conclusion, BMEs conducted by motivated CNS and within a structured training program are feasible and yield equal outcomes compared to physicians. The use of adequate pain management during BMEs by trained and experienced operators results in an extremely rare use of sedatives, low pain scores, and high patient satisfaction.
    Annals of Hematology 06/2015; 94(9). DOI:10.1007/s00277-015-2405-0 · 2.63 Impact Factor
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    ABSTRACT: The successful treatment of acute leukemias with allogeneic hematopoietic cell transplantation (allo-HCT) is limited by acute graft versus host disease (GvHD). Because microRNA-155 (miR-155) regulates activation of the innate immune system, we aimed to determine its function in dendritic cells (DCs) during GvHD in an experimental model. We observed that miR-155 deficiency of the recipient led to improved survival, reduced serum levels of pro inflammatory cytokines, and lower GvHD histopathology scores. Additionally, miR-155(-/-) bone marrow chimeric mice receiving allo-HCT and miR-155(-/-) DCs showed that miR-155 deficiency in the DC compartment was responsible for protection from GvHD. Activated miR-155(-/-) DCs displayed lower expression of various purinergic receptors and impaired migration towards ATP. Microarray analysis of LPS/ATP-stimulated miR-155(-/-) DCs revealed MAPK pathway dysregulation and reduced inflammasome-associated gene expression. Consistent with this gene expression data, we observed reduced ERK activation, caspase-1 cleavage, and IL-1β production in miR-155(-/-) DCs. The connection between miR-155 and inflammasome activation was supported by the fact that Nlrp3/miR-155 double knockout allo-HCT recipient mice experienced no increased protection from GvHD compared to Nlrp3(-/-) recipients. This study indicates that during GvHD, miR-155 promotes DC migration towards sites of ATP release accompanied by inflammasome activation. Inhibiting pro-inflammatory miR-155 by antagomir treatment could help to reduce this complication of allo-HCT. Copyright © 2015 American Society of Hematology.
    Blood 05/2015; 126(1). DOI:10.1182/blood-2014-12-617258 · 10.45 Impact Factor
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    ABSTRACT: IL-33 binding to the receptor suppression of tumorigenicity 2 (ST2) produces pro-inflammatory and anti-inflammatory effects. Increased levels of soluble ST2 (sST2) are a biomarker for steroid-refractory GVHD and mortality. However, whether sST2 has a role as an immune modulator or only as a biomarker during GVHD was unclear. We show increased IL-33 production by non-hematopoietic cells in the GI tract in mice post-conditioning and patients during GVHD. Exogenous IL-33 administration during the peak inflammatory response worsened GVHD. Conversely, GVHD lethality and TNF-α production was significantly reduced in il33(-/-) recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2(-/-) versus wildtype donor T cells had a marked reduction in GvHD lethality and GI histopathology. Alloantigen-induced IL-18 receptor upregulation was lower in st2(-/-) T cells, and linked to reduced IFN-γ production by st2(-/-) versus wildtype T cells during GVHD. Blockade of IL-33/ST2 interactions during allo-hematopoietic cell transplantation by exogenous ST2-Fc infusions had a marked reduction in GVHD lethality indicating a role of ST2 as a decoy receptor modulating GVHD. Together, these studies point to targeting of the IL-33/ST2 axis as a novel and potent target for GVHD therapy. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; 125(20). DOI:10.1182/blood-2014-10-606830 · 10.45 Impact Factor
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    ABSTRACT: FIP1L1-PDGFRA is a constitutively-activated kinase described in chronic eosinophilic leukemia,and hypereosinophilic syndrome. Imatinib is clinically active in FIP1L1-PDGFRA-positive diseases. Using in vitro screening to identify imatinib-resistant mutations, we most frequently detected a Phe to Ser exchange at position 604 (F604S) of FIP1L1-PDGFRA alone or in combination with other exchanges. Surprisingly, FIP1L1-PDGFRA/F604S did not increase the biochemical or cellular IC50 value of imatinib when compared with unmutated FIP1L1-PDGFRA. However, FIP1L1-PDGFRA/F604S more efficiently induced growth factor independence in cell lines and primary mouse bone marrow cells. Pulse chase analysis revealed that the F604S exchange strongly stabilized FIP1L1-PDGFRA/F604S. The F604S mutation creates a binding site for the phosphatase domain of SHP-2 leading to lower autophosphorylation of FIP1L1-PDGFRA/F604S. This is associated with a reduced activation of SRC and CBL by FIP1L1-PDGFRA/F604S compared to the unmutated oncogene. Since SRC inhibition and knock-down resulted in FIP1L1-PDGFRA stabilization this explains the extended half life of FIP1L1-PDGFRA/F604S. Interestingly, FIP1L1-PDGFRA/L629P, a recently identified mutation in an imatinib-resistant CEL patient, also showed protein stabilization similar to that observed with FIP1L1-PDGFRA/F604S. Therefore, resistance mutations in FIP1L1-PDGFRA that do not interfere with drug binding but rather increase target protein stability seem to be one of the drug-resistance mechanism in FIP1L1-PDGFRA-positive disease.Leukemia accepted article preview online, 12 March 2015. doi:10.1038/leu.2015.70.
    Leukemia 03/2015; 29(8). DOI:10.1038/leu.2015.70 · 10.43 Impact Factor
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    ABSTRACT: ABL tyrosine kinase inhibitors (TKI) like Imatinib, Dasatinib and Nilotinib are the gold standard in conventional treatment of CML. However, the emergence of resistance remains a major problem. Alternative therapeutic strategies of ABL TKI-resistant CML are urgently needed. We asked whether dual inhibition of BCR-ABL and Aurora kinases A-C could overcome resistance mediated by ABL kinase mutations. We therefore tested the dual ABL and Aurora kinase inhibitors PHA-739358 and R763/AS703569 in Ba/F3- cells ectopically expressing wild type (wt) or TKI-resistant BCR-ABL mutants. We show that both compounds exhibited strong anti-proliferative and pro-apoptotic activity in ABL TKI resistant cell lines including cells expressing the strongly resistant T315I mutation. Cell cycle analysis indicated polyploidisation, a consequence of continued cell cycle progression in the absence of cell division by Aurora kinase inhibition. Experiments using drug resistant variants of Aurora B indicated that PHA-739358 acts on both, BCR-ABL and Aurora Kinase B, whereas Aurora kinase B inhibition might be sufficient for the anti-proliferative activity observed with R763/AS703569. Taken together, our data demonstrate that dual ABL and Aurora kinase inhibition might be used to overcome ABL TKI resistant CML.
    PLoS ONE 11/2014; 9(11):e112318. DOI:10.1371/journal.pone.0112318 · 3.23 Impact Factor
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    ABSTRACT: Multiple myeloma (MM) is a plasma cell neoplasm that results from clonal expansion of an Ig-secreting terminally differentiated B cell. Advanced MM is characterized by tissue damage that involves bone, kidney, and other organs and is typically associated with recurrent genetic abnormalities. IL-6 signaling via the IL-6 signal transducer GP130 has been implicated as an important driver of MM pathogenesis. Here, we demonstrated that ectopic expression of constitutively active GP130 (L-GP130) in a murine retroviral transduction-transplantation model induces rapid MM development of high penetrance. L-GP130-expressing mice recapitulated all of the characteristics of human disease, including monoclonal gammopathy, BM infiltration with lytic bone lesions, and protein deposition in the kidney. Moreover, the disease was easily transplantable and allowed different therapeutic options to be evaluated in vitro and in vivo. Using this model, we determined that GP130 signaling collaborated with MYC to induce MM and was responsible and sufficient for directing the plasma cell phenotype. Accordingly, we identified Myc aberrations in the L-GP130 MM model. Evaluation of human MM samples revealed recurrent activation of STAT3, a downstream target of GP130 signaling. Together, our results indicate that deregulated GP130 activity contributes to MM pathogenesis and that pathways downstream of GP130 activity have potential as therapeutic targets in MM.
    Journal of Clinical Investigation 11/2014; 124(12). DOI:10.1172/JCI69094 · 13.22 Impact Factor
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    ABSTRACT: Patients with BRAFV600E/K-driven melanoma respond to the BRAF inhibitor vemurafenib due to subsequent deactivation of the proliferative RAS/RAF/MEK/ERK pathway. In BRAF WT cells and those with mutations that activate or result in high levels of the BRAF activator RAS, BRAF inhibition can lead to ERK activation, resulting in tumorigenic transformation. We describe a patient with malignant melanoma who developed chronic lymphocytic leukemia (CLL) in the absence of RAS mutations during vemurafenib treatment. BRAF inhibition promoted patient CLL proliferation in culture and in murine xenografts and activated MEK/ERK in primary CLL cells from additional patients. BRAF inhibitor-driven ERK activity and CLL proliferation required B cell antigen receptor (BCR) activation, as inhibition of the BCR-proximal spleen tyrosine kinase (SYK) reversed ERK hyperactivation and proliferation of CLL cells from multiple patients, while inhibition of the BCR-distal Bruton tyrosine kinase had no effect. Additionally, the RAS-GTP/RAS ratio in primary CLL cells exposed to vemurafenib was reduced upon SYK inhibition. BRAF inhibition increased mortality and CLL expansion in mice harboring CLL xenografts; however, SYK or MEK inhibition prevented CLL proliferation and increased animal survival. Together, these results suggest that BRAF inhibitors promote B cell malignancies in the absence of obvious mutations in RAS or other receptor tyrosine kinases and provide a rationale for combined BRAF/MEK or BRAF/SYK inhibition.
    Journal of Clinical Investigation 10/2014; 124(11). DOI:10.1172/JCI76539 · 13.22 Impact Factor
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    ABSTRACT: The SH2-containing adaptor protein Grb10 was first identified in a yeast-screen as a new binding partner for BCR-ABL and associates with BCR-ABL in a tyrosine-dependent manner. However, its function in BCR-ABL-mediated leukemogenesis in vivo is still unknown. Here we describe an important role of Grb10 in BCR-ABL-induced leukemia by using a versatile system for efficient oncogene expression and simultaneous Grb10-knockdown from a single vector. Primary BM cells coexpressing Grb10-miR/BCR-ABL showed a significant decrease in colony formation and cell cycle progression. Transplantation of Grb10miR/BCR-ABL- or control-miR/BCR-ABL transduced BM lead to a CML/B-ALL-like phenotype with significantly delayed disease onset and progression resulting in prolonged overall survival in Grb10-miR transplanted mice. Methylcellulose experiments exhibit additive effects of Imatinib treatment and Grb10-knockdown. Cell Cycle analysis suggests an antiproliferative effect of Grb10-knockdown in BCR-ABL(+) primary BM cells. However, Grb10 abrogation was not capable of completely abolishing the BCR-ABL-induced disease. Our findings were confirmed in the human BCR-ABL(+) cell-line K562, where we demonstrate reduced viability, cell cycle progression and induction of apoptosis by stable Grb10 microRNA expression. Taken together, our results suggest, that Grb10-knockdown in vivo leads to impaired proliferation, longer survival and reduced colony-formation suggesting an important role of Grb10 in BCR-ABL-mediated leukemogenesis.Leukemia accepted article preview online, 24 September 2014. doi:10.1038/leu.2014.283.
    Leukemia 09/2014; 29(4). DOI:10.1038/leu.2014.283 · 10.43 Impact Factor
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    ABSTRACT: Acute graft-versus-host disease (GvHD) limits the success of allogeneic hematopoietic cell transplantation (allo-HCT), therefore a better understanding of its biology may improve therapeutic options. We observed miR-146a upregulation in T cells of mice developing acute GvHD compared to untreated mice. Transplanting miR-146a(-/-) T cells caused increased GvHD severity, elevated TNF serum levels and reduced survival. TNF receptor-associated factor 6(TRAF6), a verified target of miR-146a, was upregulated in miR-146a(-/-) T cells following alloantigen stimulation. Higher TRAF6 levels translated into increased NF-κB activity and TNF production in miR-146a(-/-) T cells. Conversely, the detrimental effect of miR-146a deficiency in T cells was antagonized by TNF blockade, while phytochemical induction of miR-146a or its overexpression using a miR-146a mimic reduced GvHD severity. In humans, the minor genotype of the SNP rs2910164 in HCT donors, which reduces expression of miR-146a, was associated with severe acute GvHD (grade III/IV). We show that miR-146a functions as a negative regulator of donor T cells in GvHD by targeting TRAF6, leading to reduced TNF transcription. Since miR-146a expression can be exogenously enhanced, our results provide a novel, targeted molecular approach to mitigate GvHD.
    Blood 09/2014; 124(16). DOI:10.1182/blood-2014-04-569046 · 10.45 Impact Factor
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    ABSTRACT: The spleen tyrosine kinase (SYK) was identified as an oncogenic driver in a broad spectrum of hematologic malignancies. The in vivo comparison of three SYK containing oncogenes, SYK(wt), TEL-SYK and IL-2-inducible T-cell kinase (ITK)-SYK revealed a general myeloexpansion and the establishment of three different hematologic (pre)diseases. SYK(wt) enhanced the myeloid and T-cell compartment, without leukemia/lymphoma development. ITK-SYK caused lethal T-cell lymphomas and the cytoplasmic TEL-SYK fusion induced an acute panmyelosis with myelofibrosis-type acute myeloid leukemia (AML) with up to 50% immature megakaryoblasts infiltrating bone marrow, spleen and liver, additional MPN features (myelofibrosis and granulocyte expansion) and MDS stigmata with megakaryocytic and erythroid dysplasia. LKS cells were reduced and all subsets (LT/ST/MPP) showed reduced proliferation rates. SYK inhibitor treatment (R788) of diseased TEL-SYK mice reduced leukocytosis, spleen and liver infiltration, enhanced the hematocrit and prolonged survival time, but could not significantly reduce myelofibrosis. Stat5 was identified as a major downstream mediator of TEL-SYK in vitro as well as in vivo. Consequently, targeted deletion of Stat5 in vivo completely abrogated TEL-SYK-induced AML and myelofibrosis development, proving Stat5 as a major driver of SYK-induced transformation. Our experiments highlight the important role of SYK in AML and myelofibrosis and prove SYK and STAT5 inhibitors as potent treatment options for those diseases.
    Blood Cancer Journal 08/2014; 4(8):e240. DOI:10.1038/bcj.2014.53 · 3.47 Impact Factor
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    ABSTRACT: Almost 30% of all acute myeloid leukemias (AML) are associated with an internal tandem duplication (ITD) in the juxtamembrane domain of FLT3. Patients with FLT3-ITD mutations tend to have a poor prognosis. MicroRNAs (miRNAs) play a pivotal role in myeloid differentiation and leukemia. miR-155 was found to be upregulated in FLT3-ITD associated AMLs. In this study, we discovered that FLT3-ITD signaling induces the oncogenic miR-155. We show in vitro and in vivo that miR-155 expression is regulated by FLT3-ITD downstream targets NF-κB (p65) and STAT5. Further, we demonstrate that miR-155 targets the myeloid transcription factor PU.1. Knockdown of miR-155 or overexpression of PU.1 blocks proliferation and induces apoptosis of FLT3-ITD associated leukemic cells. Our data demonstrate a novel network in which FLT3-ITD signaling induces oncogenic miR-155 by p65 and STAT5 in acute myeloid leukemia thereby targeting transcription factor PU.1.Leukemia accepted article preview online, 5 August 2014; doi:10.1038/leu.2014.231.
    Leukemia 08/2014; 29(3). DOI:10.1038/leu.2014.231 · 10.43 Impact Factor
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    ABSTRACT: BACKGROUND Little is known about the factors that predict for gastrointestinal stromal tumor (GIST) recurrence in patients treated with adjuvant imatinib.METHODS Risk factors for GIST recurrence were identified, and 2 risk stratification scores were developed using the database of the Scandinavian Sarcoma Group (SSG) XVIII trial, where 358 patients with high-risk GIST with no overt metastases were randomly assigned to adjuvant imatinib 400 mg/day either for 12 or 36 months after surgery. The findings were validated in the imatinib arm of the American College of Surgeons Oncology Group Z9001 trial, where 359 patients with GIST were randomized to receive imatinib and 354 were to receive placebo for 12 months.RESULTSFive factors (high tumor mitotic count, nongastric location, large size, rupture, and adjuvant imatinib for 12 months) were independently associated with unfavorable recurrence-free survival (RFS) in a multivariable analysis in the SSGXVIII cohort. A risk score based on these 5 factors had a concordance index with GIST recurrence of 78.9%. When a simpler score consisting of the 2 strongest predictive factors (mitotic count and tumor site) was devised, the groups with the lowest, intermediate high, and the highest risk had 5-year RFS of 76.7%, 47.5%, and 8.4%, respectively. Both scores were strongly associated with RFS in the validation cohort (P < .001 for each comparison).CONCLUSIONS The scores generated were effective in stratifying the risk of GIST recurrence in patient populations treated with adjuvant imatinib. Patients with nongastric GIST with a high mitotic count are at a particularly high risk for recurrence. Cancer 2014 © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
    Cancer 08/2014; 120(15). DOI:10.1002/cncr.28669 · 4.89 Impact Factor
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    Chuanjiang Yu · Rama Krishna Kancha · Justus Duyster
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    ABSTRACT: FLT3 is the most frequently mutated kinase in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) in the juxta-membrane region constitute the majority of activating FLT3 mutations. Several FLT3 kinase inhibitors were developed and tested in the clinic with significant success. However, recent studies have reported the development of secondary drug resistance in patients treated with FLT3 inhibitors. Since FLT3-ITD is an HSP90 client kinase, we here explored if targeting the stability of drug-resistant FLT3 mutant protein could be a potential therapeutic option. We observed that HSP90 inhibitor treatment resulted in the degradation of inhibitor-resistant FLT3-ITD mutants and selectively induced toxicity in cells expressing FLT3-ITD mutants. Thus, HSP90 inhibitors provide a potential therapeutic choice to overcome secondary drug resistance following TKI treatment in FLT3-ITD positive AML.
    PLoS ONE 05/2014; 9(5):e97116. DOI:10.1371/journal.pone.0097116 · 3.23 Impact Factor

Publication Stats

6k Citations
1,280.50 Total Impact Points


  • 2013–2015
    • Universitätsklinikum Freiburg
      • Department of Internal Medicine I
      Freiburg an der Elbe, Lower Saxony, Germany
  • 2013–2014
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1998–2013
    • Technische Universität München
      • Medizinische Klinik und Poliklinik III - Hämatologie/Onkologie
      München, Bavaria, Germany
  • 2004
    • Philipps University of Marburg
      Marburg, Hesse, Germany
  • 2001
    • Robert-Bosch Krankenhaus
      Stuttgart, Baden-Württemberg, Germany
  • 2000
    • Institut für klinische Pharmakologie
      Stuttgart, Baden-Württemberg, Germany
  • 1998–2000
    • Universität Ulm
      • Department of Internal Medicine
      Ulm, Baden-Württemberg, Germany