| | Serum CD44 levels predict survival in patients with low-risk myelodysplastic syndromesAccepted 28 May 2010. published online 28 June 2010.
Corrected Proof 1. Introduction  Myelodysplastic syndromes (MDS) constitute a heterogeneous group of myeloid neoplasms with ineffective hematopoiesis, peripheral cytopenias and the risk of progression to acute myeloid leukaemia (AML) [1], [2], [3], [4]. MDS are preferentially diagnosed in the elderly. The median age at diagnosis is 70+ in epidemiological studies (72 years in the Düsseldorf registry and 76 in the Tyrol registry). The incidence of MDS increases dramatically with advanced age revealing age specific incidences of 9, 25, and 31/100.000/year for the age groups 60–70, 71–80, and 80+, respectively [5]. The large and increasing proportion of elderly MDS patients and the availability of more and more treatment options, imposes an urgent need to develop strategies and algorithms for optimal management and treatment. Of several prognostic models, the International Prognostic Scoring System (IPSS) is the most widely utilized and incorporates bone marrow blast cell count, cytogenetic abnormalities and the degree of cytopenia [6]. However, it is still difficult to predict survival in individual patients. Thus, several refinements of the IPSS have been suggested, such as the integration of elevated serum lactate dehydrogenase (IPSS+LDH) [7], transfusion requirements (WHO-IPSS) [8], distinct cytogenetic aberrations [9] or patient-associated factors such as comorbidities or functional capacities [5], [10]. A scoring model including low platelets, anemia, advanced age, bone marrow blasts and cytogenetics was recently proposed to overcome the limitations of the IPSS and to stratify patients with low-risk disease [11]. Adhesive interactions including cell–cell and cell–matrix interactions are essential in the pathogenesis of various types of solid and hematological malignancies [12]. The adhesion receptor CD44 comprises a family of transmembrane glycoproteins generated by alternative splicing, resulting in proteins that range in size from 80 to 200 kDa [13]. The most widely expressed form is called the “standard” 80–90kDa form (CD44s), whereas “variant” isoforms CD44 (CD44v) display a molecular weight of 160–200kDa and a restricted expression pattern. Evidence that CD44 may be involved in the regulation of early stages of normal hematopoiesis has been suggested by its expression in primitive clonogenic cells and a marked decrease in mature cells after addition of anti-CD44 monoclonal antibodies to long-term marrow cultures (LTC) [14]. Very high levels of CD44 have been reported on both LTC-initiating cells and granulopoietic colony-forming cells. In contrast, primitive erythropoietic progenitors express low CD44 levels [15]. During maturation lineage-associated changes in CD44 were described, displaying a CD44 down-regulation in mature myeloid and erythroid cells [16]. Moreover, CD44 is relevant for B-cell differentiation and function [17]. CD44 mediates the binding of normal progenitors and of leukemic cells to hyaluronan, and its activity has been associated with an unfavorable clinical course in acute myeloid leukaemia [18], [19]. An aberrant expression of CD44 isoforms resulting in an unfavorable clinical course was demonstrated in several types of hematological malignancies including non-Hodgkin's lymphoma [20], B-cell chronic leukaemia [21] and multiple myelomas [22]. In myelodysplastic syndromes immunophenotypic characterization of myelopoiesis revealed elevated expression of CD44 with an increase in the immature myeloid compartment, whereas refractory anemia showed significantly decreased expression of CD44 on gated myeloid cells [23]. CD44 can be shed from the cellular surface by active proteolytic processes and is subsequently released as a soluble molecule (solCD44) [24], [25]. CD44 shedding may have important effects on tumor cell behaviour as CD44-dependent interactions with extracellular matrix and signalling pathways are regulated [26]. Actually, active cleavage of CD44 was demonstrated in several types of malignant cells [27], [28], [29] and elevated serum solCD44 levels correlate with unfavorable prognosis in several types of human tumours [26]. Analyses in small cohorts have demonstrated elevated solCD44 levels in MDS [30], [31]. Aim of this study was to analyze serum levels of soluble CD44 standard isoform (solCD44s) in an expanded group of MDS patients and to evaluate its relevance in the prognostication of MDS patients. 2. Materials and methods 2.1. Patients This study comprised clinical data and serum samples from 130 MDS patients, 66 previously reported and 64 new patients [31]. All patients had given written informed consent prior to any study procedure and the protocol was approved by the local ethics committee. Specimens were obtained after exclusion of ongoing infection and before any kind of treatment was administered. Patients with severely impaired liver or kidney function or elevated C-reactive protein were excluded from the study. Median age of patients was 68 years (range 19–93 years), and female to male ratio was 1:1.36. The patients were diagnosed between 1989 and 2006, and, therefore, MDS subtypes were primarily defined according to the criteria of the French–American–British (FAB) group [32]. Forty-six patients presented with refractory anemia (RA), 14 with RA with ringed sideroblasts (RARS), 29 with RA with excess of blasts (RAEB), 18 with RAEB in transition (RAEB-t), and 17 with chronic myelomonocytic leukaemia (CMML). Six patients displayed overt secondary acute leukaemia (sAML) that developed from MDS (bone marrow blasts>30%). Adoption of the WHO classification 2008 showed 24 patients with sAML (based on bone marrow blasts>19%), 14 with CMML I, 3 with CMML II, 5 with RA, 4 with RARS, 11 with RCMD, 11 with del5q syndrome, 16 with RAEB-I and 11 with RAEB-II. A group of 29 patients with RA or RARS according to FAB remained unclassifiable according to WHO 2008 because of inadequate bone marrow diagnostics. Clinical characteristics of the patients are listed in detail in Table 1. The control group consisted of 63 persons (median age 54 years; range 20–93 years) without any evidence of inflammatory or neoplastic disease. | a The cytogenetic risk group “good risk” includes 55× normal karyotype, 19× del5q, 1× loss of chromosome Y. bThe cytogenetic risk group “intermediate risk” includes 4× trisomy 8, 2× del5q and trisomy 8, 2× marker chromosomes, 1× trisomy 11, 1× trisomy 14, 1× del3q, 1× del5q and del3p, 1× del5q and chromosome 3 inversion, 1× del5q and del 20q, 1× del5q and trisomy 21, 1× del 20q and trisomy 21, 1× translocation t(16;17), 1× −Y and dup1q, 1× −Y and del11q, 1× chromosome X rearrangement, 1× chromosome 7 inversion. cThe cytogenetic risk group “poor risk” includes 4× monosomy 7, 2× del5q and monosomy 7, 1× del7q, 1× −Y and monosomy 7, 7× complex karyotype. |
2.3. Flow cytometric evaluation of surface CD44 in various cellular compartments To determine surface expression of CD44 and its distribution in clonal cells in MDS, we performed multicolor flow cytometry experiments using bone marrow cells obtained from MDS patients, and fluorochrome-labeled antibodies directed against CD14, CD34, CD38, CD44, CD45, and CD123. The following monoclonal antibodies (mAb) were applied: FITC-labeled mAb 581 (CD34), APC-conjugated mAb HIT2 (CD38), PerCP-labled mAb 2D1 (CD45), mAb 515 (PE) against CD44, and an mIgG1 isotype control mAb (MOPC-21) were all from Becton Dickinson Biosciences (San Jose, CA). The FITC-labeled mAb TÜK4 (CD14) was purchased from Dako (Glostrup, Denmark) and the PE-conjugated CD123 mAb 32703 was from R&D systems (Minneapolis, MN). Heparinized bone marrow cells were first incubated with mAbs at room temperature (RT) for 15min. Then, erythrocytes were lysed in FACS Lysing Solution (Becton Dickinson Biosciences). Cells were then washed and analyzed on a FACSCalibur (Becton Dickinson Biosciences) using CellQuest (Becton Dickinson Biosciences) and FlowJo software (TreeStar, Ashland, OR). Neoplastic progenitor cells were defined by their typical forward/side scatter (FSC/SSC) characteristics and their unique phenotype (CD34+, CD45dim+, and CD38−). Monocytes were defined as CD45high+/SSCdim+ and were confirmed to be CD14+ cells in selected samples. Lymphocytes were defined as CD45high+/SSClow cells, and neutrophil granulocytes were defined as CD45dim+ cells and their typical FSC/SSC characteristics. Flow cytometric results were expressed as ratio of median fluorescence intensities (MFI) obtained with specific mAbs and MFI obtained with control mAbs (MFI mAb:MFI control mAb). The following score was applied: MFI ratio>100=+++; MFI ratio 10.01–100=++; MFI ratio 3.01–10=+; MFI ratio 1.2–3.0=+/−; MFI<1.2=−. 2.4. Statistical analysis Statistical analysis was performed using SPSS 15.0 software (SPSS Inc., Chicago, USA). The two-sided Mann–Whitney U-test was used to compare means between different FAB groups. Correlation coefficients were calculated with Spearman's rank correlation. Survival curves were estimated using the Kaplan–Meier (KM) procedure and log-rank test. The observation period lasted a minimum of 1 year. Minimal follow-up information included survival and AML transformation. Cut-off levels for solCD44s were defined as the mean level of healthy persons plus two standard deviations (stdev) [31]. Multivariate survival analysis was performed using the Cox proportional hazard model. 3. Results 3.1. Neoplastic (progenitor) cells in MDS express CD44 As assessed by multicolor flow cytometry, bone marrow leukocytes obtained from all patients with MDS tested, invariably expressed CD44 on their surface, without substantial differences in staining intensities or distribution of CD44 when comparing results obtained in different patients or when comparing normal bone marrow samples with bone marrow cells in MDS. Moreover, in patients with MDS, CD44 was found to be expressed in all types of neoplastic cells, including monocytes, immature CD34+/CD38− progenitor (stem) cells, and more mature CD34+/CD38+ progenitor cells (Table 2 and Fig. 1). The clonal origin of CD34+/CD38− cells was confirmed by high level expression of CD123 (not shown). Taken together, CD44 is expressed abundantly in clonal neoplastic progenitor cells in MDS. 3.2. Increased levels of solCD44s are detectable in patients with MDS Levels of serum CD44s were significantly elevated in patients with MDS (median level 604.8ng/ml, range 301–7961) as compared to healthy donors (median level 460ng/ml, range 280–890) and were characterized by a differential expression in various FAB subgroups, showing the highest levels in CMML and in secondary AML (Fig. 2A). The median level of solCD44s in RA was 585.5ng/ml (range 340.3–1210), in RARS 550.1ng/ml (range 360.4–1188.1), in RAEB 595ng/ml (range 301–1077), in RAEB-t 702.5ng/ml (range 349.7–1138), in CMML 1020.3ng/ml (range 569.8–7961), and in secondary AML transformed from MDS 871.6ng/ml (range 459–1757). On adopting the WHO classification, solCD44s was significantly elevated in the MDS patient cohort including RA, RARS, RCMD, 5q-, RAEB-I, and RAEB-II (Fig. 2B). A group of 29 patients with RA or RARS according to the FAB classification, could due to lack of adequate bone marrow histology not be unequivocally translated into the WHO classification and were thus summarised in a group designated “not further classifiable” (nfc). sAML (blasts>19%), CMML I and II as defined by the WHO classification revealed the highest levels of solCD44s (Fig. 2B). With regard to the solCD44s levels in the various cytogenetic risk groups, box plot analysis revealed the lowest levels in MDS to be associated with isolated del(5q). These patients had significantly lower values than the remaining good cytogenetic risk group, or the intermediate or poor cytogenetic risk group; the latter two groups showed no intergroup difference (data not illustrated). 3.3. Correlation of solCD44s with leukocyte count and months of survival Spearman's Rho rank correlation showed a minor correlation between solCD44 and age (r=0.161, p=0.05, Fig. 3). Consequently, further calculations were adjusted for age using Pearson's partial correlation coefficient. In the total cohort of patients (n=130) no correlation with gender, IPSS, blasts, cytogenetic risk groups (as defined by the IPSS score), hemoglobin, platelets, ferritin, LDH, transfusion requirement, bone marrow fibrosis or duration of dysplastic phase (time interval from initial diagnosis to leukemic transformation) was found. A correlation was observed between solCD44s and logarithm of leukocyte count (r=0.296, p=0.001), logarithm of monocyte count (r=0.449, p<0.001), and months of survival (r=−0.361, p=0.001) (Fig. 3B–D). Correlation analysis without AML and CMML cases shows no correlation with leukocyte count and a mild correlation with monocyte counts (r=0.224, p=0.32). 3.4. Increased solCD44s correlates with shortened median survival To analyze prognostic relevance, Kaplan–Meier (KM) plots were performed with a cohort of 114 FAB-classified MDS patients, excluding patients with secondary AML (bone marrow blasts>30%) (n=6), patients who underwent stem cell transplantation (n=4) and patients with a follow-up of less than 12 months (n=6). Increased solCD44s (cut-off level 688.6ng/ml) correlated with shortened median survival in the total patient group (12 versus 39 months survival, p<0.001, Fig. 4A) and within the FAB subgroups RA and CMML (24 versus 53 months survival, p=0.003; 5 versus 53 months survival, p=0.013, respectively). Of the 16 CMML patients included for analysis 10 were characterized by hyperproliferative CMML (white blood count>12000/μl); 80% of these patients (n=8) showed elevated solCD44s and worse survival in KM plot. IPSS-defined cytogenetic risk groups (good, intermediate, and poor) revealed a relevant risk stratification (33, 25, and 5 months median survival, respectively; p<0.001). By including solCD44 levels, KM plots showed a significant influence of solCD44s levels on survival of patients with good (39 versus 13 months median survival, p<0.001) or intermediate cytogenetic risk (21 versus 6 months, p=0.002) (data not illustrated). Survival in the subgroup of MDS with 5q- was independent of solCD44s levels. In WHO-classified MDS (n=82), patients revealing high solCD44s were characterized by a median survival of 25 months, whereas persons with solCD44s levels below the cut-off level revealed a median survival of 39 months (p=0.006; Fig. 4B). On multivariate analysis (Cox proportional hazard model) including all FAB-classified MDS patients (except sAML, hyperproliferative CMML, patients with stem cell transplantation or observation period<12 months) solCD44s was confirmed as predictor of survival independent of IPSS, age, gender, and LDH (Table 3). Because of multicollinearity, only non-correlated, non-redundant variables and parameters with established prognostic value were included for multivariate analysis. Multivariate analysis also remained significantly for solCD44s by inclusion of only WHO-classified patients (hazard ratio=1.002, 95% confidence interval=1.000–1.003, p=0.029). Accordingly, an increase in solCD44s from 500 to 1500ng/ml results in an up to 4.5-fold risk of mortality, calculated by hazard ratio(increase in ng/ml). The correlation between AML-free survival and solCD44s levels was calculated within the WHO-classified patient cohort including CMML. Accordingly, sAML was defined by bone marrow blasts>19%. For survival plots the status of sAML (yes/no) and the duration of the dysplastic phase or observation period were inserted. Analysis revealed a tendency to a higher risk for transition to AML in patients with higher solCD44s levels (p=0.063, see Fig. 4C). For calculation of event-free survival, events were defined as either progression to AML or death without progression. With respect to solCD44s, the 3 years event-free survival probability was about 50% for WHO-classified patients without elevated serum levels, but was only around 20% in those with elevated serum levels (p<0.001) (data not illustrated). 3.5. Levels of solCD44s refine IPSS-based risk stratification As expected, IPSS-based risk stratification of FAB-classified MDS patients was highly predictive of survival (p<0.001, Fig. 5A). Patients in the low-risk group had a median survival of 53 months, as compared to 25 months for patients in the intermediate-1-risk group, 3 months for patients in the intermediate-2-risk group and 18 months for patients in the high-risk group. In addition, IPSS-stratified KM analysis revealed prognostically different subgroups in lower risk MDS subjected to solCD44s levels (Fig. 5B–E). When patients were separated according to their solCD44s levels (normal versus elevated), the low- and intermediate-1 IPSS risk groups were divided into two prognostically different subgroups. Within the low-risk group the increased solCD44s revealed four RA patients and one RARS patient with an unfavorable clinical outcome (32 versus 63 months median survival, p=0.037). Nineteen patients in the intermediate-1-risk group characterized by elevated solCD44s showed a median survival of 13 months versus 33 months in patients without elevated solCD44s (p=0.015). Patients with inferior prognosis included patients with RA (n=6), RARS (n=2), RAEB (n=7) and four patients with CMML, otherwise characterized by a favorable karyotype (in 73.3% of cases) and low IPSS score (0–1). Transition to AML occurred in three patients (1× CMML, 2× RAEB). Causes of death were heterogeneous including sepsis, subdural hematoma and heart insufficiency related to siderosis or anemia. Regarding WHO-classified patients and IPSS risk groups, solCD44s also significantly differentiated lower risk MDS (IPSS low and Int-1; n=66) into patients with favorable and those with unfavorable course (52 versus 26 months of median survival, p=0.007; data not illustrated). Within the IPSS low-risk group (n=30), patients with solCD44s above the cut-off level had a median survival of 75 months and those with lower levels 24 months (p=0.045; data not illustrated). Within the IPSS int-1-risk group (n=36) no significant dependence on solCD44s was found. Because of limited sample size (n=8) after removal of RAEB-t and CMML cases, KM plots were not applicable for higher risk groups. The WPSS score was calculated in 44 patients. Within the limited sample size of the various risk groups (3 patients with very low risk, 18× low risk, 6× Int, 14× high risk, and 3 very high) no dependency on solCD44s was verifiable.(as reviewed by Ref. (26); (36)). 4. Discussion Shedding of CD44 plays an important role in the regulation of cell–cell and cell–matrix interaction as well as in signal transduction [34], [35]. Enhanced cleavage of the CD44 ectodomain has been observed in various human cancer tissues, including 58% of gliomas, 67% of breast carcinomas, 45% of non-small cell lung carcinomas, 90% of colon carcinomas, 25% of ovarian carcinomas, and 58% of oral squamous cell carcinomas [27]. Elevated solCD44s levels in serum correlate with tumor burden and metastatic potential of gastric and colon cancer, as well as unfavorable outcome in non-Hodgkin's lymphoma (as reviewed by Ref. [26], [36]). A value of solCD44s as tumor marker has also been reported for patients with head and neck cancer [37]. In breast cancer increased levels of soluble CD44 are associated with increased tumor size, lymph node metastasis [33] and resistance to chemotherapy [38]. Observations in small series of AML and MDS underline the prognostic significance of solCD44, even in myeloid neoplasms [19], [30], [31], [39]. Elevated levels of solCD44s were found in acute myeloid and lymphoid leukaemia, in CML, and in MDS patients [19], [30], [31]. Because of normalisation of levels in complete remission and increase in patients with relapse, serum CD44 was suggested as a marker for monitoring response to treatment and disease progression in acute leukaemia [19], [30]. Similarly, serum concentrations of CD44 were shown to reflect the disease status in pediatric leukaemia patients [39]. Serial analysis of six MDS patients with transition to acute myeloid leukaemia revealed an increase in serum levels of CD44 with MDS progression [30]. Apart from this observation, this study group reported only slightly increased CD44 serum levels in 43 MDS patients, without subgroup analysis and no investigation of its impact on survival [30]. We recently reported first evidence of a prognostic significance of solCD44s in a cohort of 66 MDS patients [31]. The present analysis confirms the increase in solCD44s in MDS patients in comparison to normal persons. Differential expression in various FAB or WHO subtypes, displaying the lowest levels in del5q MDS and the highest levels in RAEB, CMML, and in secondary AML evolved from MDS, is demonstrated. These data are in accordance with observations from Refs. [19], [30], [39], demonstrating elevated solCD44 levels in untreated AML followed by a significant decrease after induction of complete remission (CR). An increase in solCD44 was observed when MDS transformed into AML [30]. These results and the observation that solCD44 is shed by human myeloid cells [40] suggest that solCD44 reflects the tumor burden and serves as a reliable tumor marker in myeloid neoplasms including MDS. This concept is supported by the correlation between solCD44 levels and the leukocyte and monocyte count in the whole group of MDS and AML, which emerged from this analysis, as well as in a small series of AML patients [19]. Our flow cytometry experiments clearly show that surface CD44 is expressed on neoplastic cells including CD34+ cells and even CD34+/CD38−/CD123+ progenitor cells in all MDS patients analyzed. However, in this study we did not clarify whether CD34+ progenitor cells in MDS are also capable of secreting CD44 into the extracellular space. Moreover, it appears that not only MDS cells but also normal bone marrow cells express CD44. The lack of correlation between solCD44 and bone marrow blasts and the prognostic importance of solCD44 in low-risk MDS, which are in general not characterized by elevated leukocyte counts, suggest that solCD44 levels might be also increased by intrinsic mechanisms that are not directly correlated with leukocyte counts. An active and highly regulated ectodomain cleavage of CD44 is prevalent in several types of human tumors [26], suggesting that a differential regulation of CD44 cleavage might be plausible, even in myeloid neoplasms. However, mechanisms of CD44 cleavage have not been analyzed so far in myeloid cells. CD44 shedding by active proteolysis has important effects on tumor cell behavior as CD44-dependent interactions with extracellular matrix and signaling pathways are regulated. Soluble CD44 retains biological functions [25], [41], competes with cell-bound CD44 in ligand binding and in cellular activation [42] and induces apoptosis and inhibits tumor growth [41]. Transfection with soluble CD44 resulted in increased cell proliferation and resistance to apoptosis, suggesting that soluble CD44 could serve as decoy receptor in cancer cells [42]. Cleavage of external CD44 can be followed by cleavage of cytoplasmic CD44 by presenilin-dependent gamma-secretase, which after entering the nucleus can act as a transcription factor of various genes including CD44, thereby mediating cellular signaling cascades [28]. Thus, it is tempting to speculate that CD44 cleavage is involved in the modification of CD44-mediated mechanisms that are essential in the biology of myeloid neoplasms, like cellular proliferation, differentiation and apoptosis [43], [44], and in leukemic stem cell (LSC) function and homing to the bone marrow microenvironment [45]. Notably, CD44 is a well-characterized stem cell homing receptor and has been discussed as a potential cellular target in myeloid leukaemias. As also shown in this study, MDS cells including CD34+ cells and even CD34+/CD38− progenitor cells express membrane-bound CD44, suggesting that CD44 may also play a role as a stem cell homing receptor or target in MDS cells. The effect of solCD44 levels in CD44-targeting therapeutic concepts [46], [47], as possible interactions between solCD44 and therapeutic anti-CD44 mAbs might alter their efficacy in clinical application, remains unclear. In this analysis, data on the prognostic significance of solCD44 reported in the literature are extended as solCD44s is identified for the first time as an independent prognostic factor for survival in MDS in univariate and in multivariate analysis. Moreover, inclusion of solCD44s resulted in an expanded prognostication of patients from IPSS low- and intermediate-1-risk groups. This is of major importance for decision algorithms in MDS. Whereas treatment decisions in high-risk MDS are based on the unfavorable clinical course observed in the majority of patients, the situation in low-risk MDS as defined by the IPSS [6] or WPSS [48] is more complex and demands additional prognostic factors [1]. SolCD44 is a disease-specific variable that might be a helpful prognostic discriminator in lower risk MDS and, as such, one that should be further applied in therapeutic algorithms. In conclusion, this is the first study providing evidence for a prognostic value of solCD44 in a representative group of MDS patients. Elevated levels of sCD44 were correlated with shorter survival and reflected prognostic significance independent of the International Prognostic Scoring System (IPSS). SolCD44 is a helpful prognostic discriminator in lower risk MDS and should be further tested in risk stratification models and prospective studies. Understanding of solCD44-mediated processes will offer an important clue toward defining mechanisms responsible for tumor propagation in MDS and AML and will provide the rationale for therapeutic strategies directed at CD44-mediated interactions by MoAbs or chimeric proteins. Conflict of interest J. Loeffler-Ragg, U. Germing, W.R. Sperr, P. Valent, H. Zwierzina, H. Ulmer, and R. Stauder: No conflict of interest. Reviewers Dr. Argiris S. Symeonidis, University of Patras Medical School, Department of Internal Medicine, Hematology Division, Rion of Patras, Greece. Dr. Jaroslav Cermak, Institute of Hematology and Blood Transfusion, Prague, Czech Republic. Acknowledgments The excellent assistance in sample collection, storage and analysis provided by Manfred Herold, Brigitte Kircher, Michael Steurer, Sergej Skvortsov, Silvia Blunder and Petra Schumacher are gratefully acknowledged. This study was supported by a grant from “Tiroler Verein zur Foerderung der Krebsforschung an der Universitätsklinik Innsbruck (RS)”, “Österr. Krebshilfe Tirol, 2006 (RS)”, “Senioren-Krebshilfe” (RS), “Katholnigg-Stiftung für MDS (HZ)” and the Austrian National Bank, Project No. 10135 (HZ). References [1]. [1]Valent P, Hofmann W, Büsche G, et al. Meeting report: Vienna 2008 workshop of the German–Austrian working group for studying prognostic factors in myelodysplastic syndromes. Ann Hematol. 2009;. [2]. [2]Nimer S. Myelodysplastic syndromes. Blood. 2008;111(10):4841–4851.
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[48]. [48]Malcovati L, Nimer S. Myelodysplastic syndromes: diagnosis and staging. Cancer Control. 2008;15(Suppl. 4):4–13. Reinhard Stauder received his doctoral degree in Medicine from the University of Innsbruck in 1981 and a master's degree in Health Sciences from the University of Health Sciences, Medical Informatics and Technology, Hall in Tirol, Austria, in 2006. From 1994 to 1996 he was Scientific Member of the Basel Institute for Immunology, Basel, Switzerland. R.S. is a Specialist in Internal Medicine, a Certified Specialist in Hematology and Oncology and Associate Professor of Medicine at Innsbruck Medical University, Austria. His main clinical and scientific focus is geriatric oncology as well as myelodysplastic syndromes. R.S. is a member of the EORTC Leukaemia Group, of the EORTC Task Force Cancer in the Elderly and the European Leukaemia Net (ELN). He is a board member of the Austrian Society for Hematology and Oncology as well as chairman of the MDS Group and chairman of the Geriatric Oncology Group of the Austrian Society for Hematology and Oncology. R.S. is the National Representative for Austria to the International Society of Geriatric Oncology (SIOG) and founder and chairman of the Austrian “Aid for Elderly Cancer Patients” (Verein Senioren-Krebshilfe). a Department of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria b Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany c Department of Internal Medicine I, Division of Hematology and Hemostaseology, Vienna Medical University, Vienna, Austria d Ludwig Boltzmann Cluster Oncology, Vienna, Austria e Department of Biostatistics and Documentation, Innsbruck Medical University, Innsbruck, Austria f Department of Internal Medicine V (Hematology and Oncology), Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria  Corresponding author. Tel.: +43 512 504 23255.
PII: S1040-8428(10)00140-X doi:10.1016/j.critrevonc.2010.05.008 © 2010 Elsevier Ireland Ltd. All rights reserved. | |
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