Norbert Gattermann

Universitätsklinikum Düsseldorf, Düsseldorf, North Rhine-Westphalia, Germany

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Publications (259)1174.71 Total impact

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    ABSTRACT: Myelodysplastic syndrome (MDS) associated with an acquired, isolated deletion of chromosome 5q (del (5q) MDS), represent a clonal disorder of hematopoiesis and a clinically distinct entity of MDS. Treatment of del (5q) MDS with the drug lenalidomide has significantly improved quality of life leading to transfusion independence and complete cytogenetic response rates (CCR) in the majority of patients. Telomeres are located at the end of eukaryotic chromosomes and are linked to replicative history/potential as well as genetic (in) stability of hematopoietic stem cells. Here, we analyzed telomere length (TL) dynamics before and under lenalidomide treatment in the peripheral blood and/or bone marrow of del (5q) patients enrolled in the LEMON-5 study (NCT01081431). Hematopoietic cells from del (5q) MDS patients were characterized by significantly shortened TL compared to age-matched healthy controls. Telomere loss was more accelerated in patients with longer disease duration (>2 years) and more pronounced cytopenias. Sequential analysis under lenalidomide treatment revealed that previously shortened TL in peripheral blood cells was significantly "elongated" towards normal levels within the first six months suggesting a shift from clonal del (5q) cells towards normal hematopoiesis in lenalidomide treated MDS patients. Taken together our findings suggest that the development of the del (5q) clone is associated with accelerated telomere shortening at diagnosis. However, upon induction of CCR and reoccurrence of normal hematopoiesis, the lack of a persistent TL deficit argues against telomere-mediated genetic instability neither as a disease-promoting event of del (5q) MDS nor for lenalidomide mediated development of secondary primary malignancies of the hematopoietic system in responding patients.
    Leukemia Research 09/2015; DOI:10.1016/j.leukres.2015.09.003 · 2.35 Impact Factor
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    ABSTRACT: Myelodysplastic syndromes (MDS) are oligoclonal hematopoietic disorders characterized by peripheral cytopenias with anemias being the most prevalent feature. The majority of patients will depend on regular transfusions of packed red blood cells (PRBC) during the course of the disease. Particularly patients with MDS and low risk for transformation into acute myeloid leukemia and low risk of early death will receive PRBC transfusions on a regular basis, which puts them at high risk for transfusional iron overload. Transfusion dependence has been associated with negative impact on organ function and reduced life expectancy. Recently, several retrospective but also some prospective studies have indicated, that transfusion dependent patients with MDS might benefit from consequent iron chelation with regard to morbidity and mortality. However, low treatment adherence due to adverse events mainly gastrointestinal in nature is an important obstacle in achieving sufficient iron chelation in MDS patients. Here, we will summarize and discuss the existing data on Deferasirox in low risk MDS published so far and provide recommendations for optimal management of gastrointestinal adverse events during iron chelation aiming at improving treatment compliance and, hence, sufficiently removing excess iron from the patients. Copyright © 2015. Published by Elsevier Ltd.
    Leukemia research 06/2015; 39(10). DOI:10.1016/j.leukres.2015.06.008 · 2.35 Impact Factor
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    ABSTRACT: This study aimed to determine the extent to which the prognostic advantage of myelodysplastic syndromes (MDS) with del(5q) is due to the more favourable age and sex distribution of patients in that group when compared to other MDS subtypes. A total of 1912 MDS patients from the Duesseldorf registry with less than 5% blasts in the bone marrow were evaluable and had complete covariates. As endpoints, overall survival and progression to acute myeloid leukaemia (AML) were considered. Cox models were computed for both outcomes. A multivariate Cox model for survival confirmed higher age and male sex as risk factors. In addition, we found a survival advantage of 9·1 years for MDS del(5q) patients compared to refractory cytopenia with unilineage dysplasia, while the survival advantage of MDS del(5q) over refractory cytopenia with multilineage dysplasia was 18·6 years. Considering progression to AML, we did not find any significant differences between the World Health Organization classification subtypes. Our analyses show that the higher survival probabilities of MDS del(5q) patients are not only due to age and sex, although higher age and male sex were also important risk factors. Interestingly, it seems that the survival advantage of MDS del(5q) decreases over time. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 05/2015; 170(5). DOI:10.1111/bjh.13496 · 4.71 Impact Factor

  • Leukemia Research 04/2015; 39:S82. DOI:10.1016/S0145-2126(15)30161-2 · 2.35 Impact Factor

  • Leukemia Research 04/2015; 39:S60-S61. DOI:10.1016/S0145-2126(15)30118-1 · 2.35 Impact Factor

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    ABSTRACT: Natural Killer cells are well known to mediate anti-leukemic responses in myeloid leukemia but their role in myelodysplastic syndromes is not well understood. Here, in a cohort of newly diagnosed patients (n=75), widespread structural and functional natural killer cell defects were identified. Firstly, one subgroup of patients (13%) had a selective deficiency of peripheral natural killer cells (count < 10/mm3 blood) with normal frequencies of T and natural killer-like T cells. Natural killer cell-deficient patients were predominantly found in high-risk subgroups and were significantly associated with poor prognosis. In the second subgroup, representing the majority of patients (76%), natural killer cells were present but exhibited poor cytotoxicity. The defect was strongly associated with reduced levels of perforin and granzyme B. Notably, natural killer cell function and arming of cytotoxic granules could be fully reconstituted by in vitro stimulation. Further phenotypic analysis of these patients revealed an immature natural killer cell compartment that was biased towards CD56bright cells. The residual CD56dim cells exhibited a significant increase of the unlicensed NKG2A-KIR- subset and a striking reduction in complexity of the KIR repertoire. Taken together, these results suggests that the widespread defects in natural killer cell function of myelodysplastic patients are mostly due to either unsuccessful or inefficient generation of mature, functionally competent natural killer cells, which might contribute to disease progression due to impaired immune surveillance. Copyright © 2015, Ferrata Storti Foundation.
    Haematologica 02/2015; 100(5). DOI:10.3324/haematol.2014.118679 · 5.81 Impact Factor
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    ABSTRACT: Myelodysplastic syndromes (MDS) present with a normo- or hyperplastic bone marrow in most cases. We aimed at a characterization of patients with different types of cellularity. We assessed marrow cellularity both by histology and cytology in 1270 patients and analysed hematologic, cytogenetic, and prognostic parameters accordingly. The concordance of the assessment of cellularity differed dramatically between histology and cytology as only 36.5% were described as hypocellular by both methods (p<0.0005) (hypocellular 16.4%, normocellular 23.3%, hypercellular 60.3%). There were no major differences with regard to hematopoietic insufficiency. The presence of fibrosis was associated to hypercellular bone marrow. Median survival differed from 38 months in hypocellular, 42 months in normocellular and 25 months in hypercellular MDS (p<0.0005). AML progression rates were 33% for hypercellular MDS after 2 years, whereas hypo- and normocellular had a progression rate of 19% after 2 years (p=0.018). IPSS and IPSS-R were able to identify different risk groups within all three cellularity groups. Based on our data, hypocellular patients obviously do not present as a separate entity, as there were no striking differences with regard to cytogenetics and WHO types. Assessment of cellularity should be performed by histopathology. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 01/2015; 95(3). DOI:10.1111/ejh.12512 · 2.07 Impact Factor
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    ABSTRACT: In Europe, azacitidine is the only hypomethylating agent approved for the treatment of patients with int-2-/high-risk myelodysplastic syndromes, offering significantly improved survival compared with conventional care. However, not all patients treated with azacitidine respond to treatment, and the vast majority of responders subsequently relapse. Currently, no standard care regimens have been established for patients after failure of azacitidine. Here, we discuss treatment options after loss of response or progression on azacitidine. In addition, we briefly consider optimization of first-line treatment along with potential biomarkers for identifying and monitoring response during treatment with azacitidine.
    Leukemia Research 09/2014; 38(12). DOI:10.1016/j.leukres.2014.09.008 · 2.35 Impact Factor
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    ABSTRACT: Since 2001, chronic myelomonocytic leukemia (CMML) is classified by the WHO as myeloproliferative/myelodysplastic neoplasm. Herein we tried to better describe CMML patients with regard to hematological characteristics and prognosis using data of the Duesseldorf registry. We created 6 CMML subgroups, by dividing dysplastic and proliferative CMML at the cut-off of white blood cell count of 13,000/μl and splitting these two groups into 3 subgroups: CMML 0 with <5% blasts (n = 101), CMML I with 5%-9% blasts (n = 204) and CMML II with 10%-19% blasts (n = 81). For comparison we included patients with RCMD, RAEB I and II. The newly created CMML 0 group had better prognosis than CMML I and II, median survival times were 31 months (ms), 19 ms and 13 ms, respectively (p < 0.001). Median survival times between the corresponding dysplastic and proliferative subgroups 0 and 1 differed significantly: CMML 0 dysplastic 48 ms and CMML 0 proliferative 17 ms (p = 0.03), CMML I dysplastic 29 ms and CMML I proliferative 15 ms (p = 0.008), CMML II dysplastic 17 ms and CMML II proliferative 10 ms (p = 0.09). Outcome of CMML patients worsens with increasing medullary blasts and when presenting as proliferative type. Therefore it is justified to separate CMML with <5% medullary blasts.
    Leukemia Research 09/2014; 38(12). DOI:10.1016/j.leukres.2014.09.003 · 2.35 Impact Factor
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    David P. Steensma · Norbert Gattermann ·

    Bailli&egrave re s Best Practice and Research in Clinical Haematology 06/2014; 27(2). DOI:10.1016/j.beha.2014.04.008 · 2.12 Impact Factor
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    ABSTRACT: Background Aberrant DNA methylation is frequently found in human malignancies including acute myeloid leukemia (AML). While most studies focus on later disease stages, the onset of aberrant DNA methylation events and their dynamics during leukemic progression are largely unknown. Methods We screened genome-wide for aberrant CpG island methylation in three disease stages of a murine AML model that is driven by hypomorphic expression of the hematopoietic transcription factor PU.1. DNA methylation levels of selected genes were correlated with methylation levels of CD34+ cells and lineage negative, CD127-, c-Kit+, Sca-1+ cells; common myeloid progenitors; granulocyte-macrophage progenitors; and megakaryocyte-erythroid progenitors. Results We identified 1,184 hypermethylated array probes covering 762 associated genes in the preleukemic stage. During disease progression, the number of hypermethylated genes increased to 5,465 in the late leukemic disease stage. Using publicly available data, we found a significant enrichment of PU.1 binding sites in the preleukemic hypermethylated genes, suggesting that shortage of PU.1 makes PU.1 binding sites in the DNA accessible for aberrant methylation. Many known AML associated genes such as RUNX1 and HIC1 were found among the preleukemic hypermethylated genes. Nine novel hypermethylated genes, FZD5, FZD8, PRDM16, ROBO3, CXCL14, BCOR, ITPKA, HES6 and TAL1, the latter four being potential PU.1 targets, were confirmed to be hypermethylated in human normal karyotype AML patients, underscoring the relevance of the mouse model for human AML. Conclusions Our study identified early aberrantly methylated genes as potential contributors to onset and progression of AML.
    Genome Medicine 04/2014; 6(4):34. DOI:10.1186/gm551 · 5.34 Impact Factor
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    ABSTRACT: Fragestellung. Unser Ziel war die Beurteilung der Mikrovaskularisation und des antiangiogenetischen Effektes einer Thalidomidtherapie mittels dynamischer kontrastverstärkter MRT (d-MRT) bei unterschiedlichen hämatologischen Erkrankungen. Methodik. Bei 20 Normalpersonen, 20 Patienten mit Myelodysplastischen Syndromen (MDS), 10 Patienten mit Osteomyelofibrose (OMF) und 10 Patienten mit Multiplem Myelom (MM) wurde eine schnelle Gradientenechosequenz (Turbo fast low angle shot 2D) mit pumpengesteuerter Gd-DTPA-Applikation vor und bei 18 davon durchschnittlich 4,3 Monate nach Therapiebeginn mit Thalidomid durchgeführt. Zwei Perfusionsparameter (Amplitude und Austauschratenkonstante) wurden berechnet und es erfolgten ein statistischer Vergleich der Werte zwischen Probanden und Patienten sowie eine Korrelation der klinischen Verlaufsparameter der Patienten mit den d-MRT-Ergebnissen. Ergebnisse. Bei den Patienten wurden im Vergleich zu den Normalpersonen durchschnittlich höhere Amplituden (Normalpersonen 14,4±5,2; MDS 24,8±8,1; OMF 35,9±4,3; MM 23,4±3,6) und Austauschratenkonstanten (Normalpersonen 0,124±0,042; MDS 0,136±0,036; OMF 0,144±0,068; MM 0,131±0,034) gemessen. Bei 14 von 18 im Verlauf untersuchten Patienten konnte eine signifikante (p<0,005) Reduktion der Perfusionsparameter in der d-MRT unter Thalidomidtherapie nachgewiesen werden. Klinisch zeigten sämtliche dieser Patienten eine Krankheitsremission. Schlussfolgerungen. Bei den untersuchten hämatologischen Erkrankungen liegen im Vergleich zu Normalpersonen signifikant höhere d-MRT-Perfusionsparameter der Lendenwirbelsäule vor. Unter antiangiogenetischer Therapie mit Thalidomid kommt es im Falle eines Therapieansprechens zum Abfall dieser Werte. Purpose. The aim of the study was to measure microcirculation parameters by dynamic contrast-enhanced MRI (d-MRI) and to evaluate the anti-angiogentic effects during treatment with thalidomide in different hematologic malignancies. Methods. In 20 healthy normal persons, 20 patients with myelodysplastic syndromes (MDS), 10 patients with multiple myeloma (MM) and 10 with myelofibrosis (MF) a fast gradient echo sequence (Turbo fast low angle shot 2D) with a pump controlled bolus infusion of gadolinium-DTPA was performed before and in 18 of these after beginning (average of 4,3 months) of a thalidomide therapy. Two pharmacokinetic parameters – the amplitude and exchange-rate-constant – were calculated and a statistical comparison of these values between healthy persons and patients as well as a correlation with the clinical course was executed. Results. Compared with the normal controls the patients showed a higher amplitude (normal persons 14.4±5.2, MDS 24.8±8.1, MF 35.9±4.3, MM 23.4±3.6) and exchange-rate-constant (normal persons 0.124±0.042, MDS 0.136±0.036, MF 0.144±0.068, MM 0.131±0.034). In the d-MRI-follow-up examinations a significant (p<0.005) reduction of the amplitude and exchange rate constant values was evident in 14 of 18 patients undergoing a thalidomide therapy. Clinically all of these patients showed a therapy responding with complete or partial diseases remission. Conclusions. In patients with hematologic malignancies significantly higher d-MRI-microcirculation parameters of the lumbar spine can be demonstrated than in normal persons. During anti-angiogenetic treatment with thalidomide a decrease of these values was observed in case of a responding to therapy.
    Der Radiologe 03/2014; 42(3):222-230. DOI:10.1007/s00117-002-0721-6 · 0.43 Impact Factor
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    ABSTRACT: Introduction: Myelodysplastic syndromes (MDS) are heterogeneous diseases of the hematopoietic stem cell, with a median age of 70 years at diagnosis. In this age it is likely to have comorbid diseases. The MDS-specific comorbidity index (MDS-CI) is an easy to use tool for assessing comorbidities in MDS patients. We herein examined if the MDS-CI adds independent prognostic information to the lately revised International Prognostic Scoring System (IPSS-R). Methods: We retrospectively analyzed 1161 patients from the Duesseldorf MDS-Registry according to the MDS-CI. The IPSS-R was available in 506 patients. Results: The most frequent diseases were cardiac diseases, which were even more frequent in male patients 42% vs. 30% in female patients (p<0.001), followed by solid tumors, third are pulmonary diseases 9% (11% in males vs. 6% in females (p=0.002)), fourth and fifth are renal and hepatic comorbidities, which showed no difference in distribution to gender. Overall, male patients had more comorbidities than female patients (p=0.001). The three MDS-CI risk groups differed in terms of survival (39 months (ms) vs. 24ms vs. 15ms, (p<0.001)). The MDS-CI was able to separate three groups within the IPSS-R low risk group, (92 ms vs. 63 ms vs. 36 ms, (p < 0.0001)). After lumping very low und low risk patients together (n=221) median survival times also differed significantly (98ms, 70ms and 45ms, respectively (p=0.005)). In the group consisting of intermediate, high and very high risk patients (n=285) corresponding median survival times differed significantly, (22ms, 21ms and 7ms, respectively (p=0.017)). The causes of death differed between the MDS-CI groups, as in the low risk group more patients died not disease related than in the high risk group. Conclusion The MDS-CI adds significantly independent prognostic information to the IPSS-R. Our data prompted us to make a call for assessing comorbidities prospectively in clinical day to day practice and particularly in clinical trials in order to find out if patients with relevant comorbidities benefit from earlier therapy and if it is reasonable not to treat patients with a high comorbidity score and finally to make MDS patient population better comparable.
    Haematologica 01/2014; 99(3). DOI:10.3324/haematol.2013.101055 · 5.81 Impact Factor
  • Norbert Gattermann · Rainer Haas · Corinna Strupp · Andrea Kündgen · Esther Zipperer ·

    Novel Insights into Pathophysiology, Diagnostics and Treatment of Myelodysplastic Syndromes, 01/2014: pages 86-105; , ISBN: 978-1-78084-432-9
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    David P Steensma · Norbert Gattermann ·
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    ABSTRACT: Iron overload in MDS starts even before patients become red-blood cell transfusion dependent, because disease-associated ineffective erythropoiesis suppresses hepcidin production in the liver and thus causes unrestrained iron absorption in the duodenum. However, the main cause of iron overload is regular transfusion therapy, which in MDS is associated with a risk of unclear magnitude for iron-related complications. Iron deposition in tissues can now be detected with non-invasive techniques such as T2* MRI. Iron toxicity in MDS may not only depend on the degree of tissue iron accumulation but also on the extent of chronic exposure to non-transferrin-bound iron (NTBI), including labile plasma iron (LPI) and intracellular labile iron pools, which increase the level of oxidative stress. Iron chelation therapy (ICT) can rapidly lower NTBI and LPI and more slowly mobilizes tissue iron stores. Further studies, including the ongoing TELESTO controlled trial, will more clearly define the role of ICT in MDS, including any effect on specific morbidities or mortality in the MDS setting.
    Best practice & research. Clinical haematology 12/2013; 26(4):431-444. DOI:10.1016/j.beha.2013.09.009 · 2.12 Impact Factor
  • Ulrich Germing · Guido Kobbe · Rainer Haas · Norbert Gattermann ·
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    ABSTRACT: Myelodysplastic syndromes (MDS) are malignant stem-cell diseases that are usually diagnosed in elderly patients who present with anemia or, less commonly, bi- or pancytopenia. Their incidence in persons over age 80 is above 50 new cases per 100 000 persons per year. Their clinical course is highly variable. About one-quarter of all patients with MDS develop acute leukemia. The median survival time from the moment of diagnosis is about 30 months. We selectively searched the PubMed database for pertinent articles and guidelines from the years 2000-2013. We used the search term "myelodysplastic syndromes." MDS are diagnosed by cytology, with consideration of the degree of dysplasia and the percentage of blast cells in the blood and bone marrow, and on a cytogenetic basis, as recommended in the WHO classification. In particular, chromosomal analysis is necessary for prognostication. The Revised International Prognosis Scoring System (IPSS-R) enables more accurate prediction of the course of disease by dividing patients into a number of low- and highrisk groups. The median survival time ranges from a few months to many years. The approved treatments, aside from transfusion therapy, include iron depletion therapy for low-risk patients, lenalidomide for low-risk patients with a deletion on the long arm of chromosome 5, and 5-azacytidine for high-risk patients. High-risk patients up to age 70 who have no major accompanying illnesses should be offered allogenic stem-cell transplantation with curative intent. The cure rates range from 30% to 50%. Mucositis, hemorrhages, infections, and graft-versus-host diseases are the most common complications of this form of treatment. Myelodysplastic syndromes are treated on an individualized, riskadapted basis after precise diagnostic evaluation and after assessment of the prognosis. More studies are needed so that stage-adapted treatment can be improved still further.
    Deutsches Ärzteblatt International 11/2013; 110(46):783-90. DOI:10.3238/arztebl.2013.0783 · 3.52 Impact Factor
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    ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2013; 28(3). DOI:10.1038/leu.2013.325 · 10.43 Impact Factor
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    ABSTRACT: Myelodysplastic syndromes (MDS) is a disease of predominantly elderly patients with a median age of >70 yrs. However, data on the management of these patients outside of clinical trials are scarce. To assess patterns of MDS management in routine patient care with regard to the impact of age, we conducted a multicenter, representative survey of MDS health services in Germany. Data of 269 patients treated at 57 institutions were collected from preplanned chart reviews and were analyzed retrospectively. At diagnosis, median age was 70 yrs, 50% of patients had a Karnofsky index (KI) of 90%, and 12% had a comorbidity index ≥ 3 according to Sorror et al. (J Clin Oncol, 25, 2007, 4246). Cytogenetic analysis and International Prognostic Scoring System (IPSS) risk assessment were performed significantly less frequently in patients >75 yrs than in patients ≤75 yrs (P < 0.001 and P = 0.019). In bivariate analysis, potential predictors for performing IPSS risk assessment were age ≤75 yrs (y/n, P = 0.019), diagnosis at a university hospital (y/n, P = 0.001), WHO subtypes RCUD (y/n, P = 0.028), RARS (y/n, P = 0.002), or RAEB II (y/n, P = 0.037). Patients ≤75 yrs were more likely to receive active therapies (i.e., chemotherapy, immunomodulatory therapy, or epigenetic therapy) than patients >75 yrs (51% vs. 37%, P = 0.007). In bivariate analysis age ≤75 yrs (y/n, P = 0.007) was a significant predictor for active treatment with no correlation with the other predictors [IPSS risk score int-2 or high (y/n, P = 0.005), WHO subtypes RCUD (y/n, P < 0.001), RCMD (y/n, P = 0.003), RAEB II (y/n, P < 0.001), or CMML I (y/n, P = 0.020)]. This survey confirms the impact of age on the thoroughness of MDS diagnosis and the decision for active treatment. As cytogenetic analysis and risk assessment are essential for the choice of appropriate therapy, elderly patients in particular may not be receiving adequate treatment.
    European Journal Of Haematology 09/2013; 91(6). DOI:10.1111/ejh.12196 · 2.07 Impact Factor
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    ABSTRACT: Within the MDS work-package of the European LeukemiaNet, an Expert Panel was selected according to the framework elements of the NIH Consensus Development Program. A systematic review of the literature was performed including indexed original papers, indexed reviews and educational papers, and abstracts of conference proceedings. Guidelines were developed based on a list of patient- and therapy-oriented questions, and recommendations were formulated and ranked according to the supporting level of evidence. MDS should be classified according to the 2008 WHO criteria. An accurate risk-assessment requires not only the evaluation of disease-related factors, but also of those related to extra-hematological comorbidity. The assessment of individual risk enables the identification of fit patients with a poor prognosis, who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation. A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life. A number of new agents are being developed, for which the available evidence is not sufficient to recommend routine use. The inclusion of patients into prospective clinical trials is strongly recommended.
    Blood 08/2013; 122(17). DOI:10.1182/blood-2013-03-492884 · 10.45 Impact Factor

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10k Citations
1,174.71 Total Impact Points

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  • 2003-2015
    • Universitätsklinikum Düsseldorf
      • Klinik für Hämatologie, Onkologie und Klinische Immunologie
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1991-2015
    • Heinrich-Heine-Universität Düsseldorf
      • • Klinik für Hämatologie, Onkologie und Klinische Immunologie
      • • Faculty of Medicine
      • • Hautklinik
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2007
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany