Judith Neukirchen

Incidence and prevalence of myelodysplastic syndromes: Data from the Düsseldorf MDS-registry

Population-based data on patients with MDS are scarce. Here we report the incidence and prevalence of MDS based on data from the Düsseldorf MDS Registry. Cases in the city of Düsseldorf in the study period were identified from the MDS Registry. We calculated crude, calendar-year, age- and sex-specific and European Standard Population age-standardized incidence rates as well as point prevalences per 100,000 The crude incidence rate was 4.15/100,000/year and the point prevalence per 100,000 persons of 7. We found that the incidence and prevalence of MDS was higher in men than women and increased sharply with increasing age.

Improved survival in MDS patients receiving iron chelation therapy – A matched pair analysis of 188 patients from the Düsseldorf MDS registry

MDS patients are prone to develop transfusional iron overload. Iron overload may partly explain why transfusion dependency is associated with a decreased likelihood of survival. Our matched-pair analysis included 94 patients on long-term chelation therapy and 94 matched patients without it. All patients had iron overload, defined as serum ferritin (SF) above 1000 ng/ml or a history of multiple transfusions and SF ≥ 500 ng/ml. Median SF was 1954 ng/ml in chelated and 875 ng/ml in non-chelated patients. The difference in median survival (74 vs. 49 months, respectively; p=0.002) supports the idea that iron chelation therapy is beneficial for MDS patients.

Gene expression profiling for molecular distinction and characterization of laser captured primary lung cancers

MethodsWe examined gene expression profiles of tumor cells from 29 untreated patients with lung cancer (10 adenocarcinomas (AC), 10 squamous cell carcinomas (SCC), and 9 small cell lung cancer (SCLC)) in comparison to 5 samples of normal lung tissue (NT). The European and American methodological quality guidelines for microarray experiments were followed, including the stipulated use of laser capture microdissection for separation and purification of the lung cancer tumor cells from surrounding tissue.ResultsBased on differentially expressed genes, different lung cancer samples could be distinguished from each other and from normal lung tissue using hierarchical clustering. Comparing AC, SCC and SCLC with NT, we found 205, 335 and 404 genes, respectively, that were at least 2-fold differentially expressed (estimated false discovery rate: < 2.6%). Different lung cancer subtypes had distinct molecular phenotypes, which also reflected their biological characteristics. Differentially expressed genes in human lung tumors which may be of relevance in the respective lung cancer subtypes were corroborated by quantitative real-time PCR.Genetic programming (GP) was performed to construct a classifier for distinguishing between AC, SCC, SCLC, and NT. Forty genes, that could be used to correctly classify the tumor or NT samples, have been identified. In addition, all samples from an independent test set of 13 further tumors (AC or SCC) were also correctly classified.ConclusionThe data from this research identified potential candidate genes which could be used as the basis for the development of diagnostic tools and lung tumor type-specific targeted therapies.

Platelet counts and haemorrhagic diathesis in patients with myelodysplastic syndromes

Objectives:  Most patients with myelodysplastic syndromes (MDS) present with single or multiple lineage cytopenias in peripheral blood despite a hypercellular bone marrow. Thrombocytopenia, attributable to ineffective platelet production by dysfunctional megakaryocytes, has been estimated to occur in 40–65% of patients. However, there are hardly any studies on the clinical relevance of low platelet counts in MDS.

Validation of the revised International Prognostic Scoring System (IPSS-R) in patients with myelodysplastic syndrome: A multicenter study

The revised IPSS (IPSS-R) was developed aiming at a better prognostication, taking into account patients treated with best supportive care. We herein validated this model on the basis of data from 1314 patients who received BSC only as well as patients who underwent induction chemotherapy (n=214) or allogeneic transplantation (n=167). We could demonstrate a clear distinction of the IPSS-R risk categories with regard to survival and risk of AML evolution in all patient cohorts. When comparing IPSS-R, IPSS, WHO prognostic scoring system (WPSS) and Duesseldorf score, the best results regarding the ability to predict survival were obtained by the IPSS-R.

Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias

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), 19ms and 13ms, respectively (p<0.001). Median survival times between the corresponding dysplastic and proliferative subgroups 0 and 1 differed significantly: CMML 0 dysplastic 48ms and CMML 0 proliferative 17ms (p=0.03), CMML I dysplastic 29ms and CMML I proliferative 15ms (p=0.008), CMML II dysplastic 17ms and CMML II proliferative 10ms (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.

The proteasome inhibitor bortezomib acts differently in combination with p53 gene transfer or cytotoxic chemotherapy on NSCLC cells

In this report, the effects of a combined treatment with the proteasome inhibitor bortezomib and either a recombinant adeno-associated virus type 2 (rAAV-2)-mediated p53 gene transfer or chemotherapeutic agents, docetaxel and pemetrexed, were tested on p53 positive and p53negative non-small cell lung cancer (NSCLC) cell lines. The combination of bortezomib and rAAV-p53 led to a significant synergistic inhibition of cell growth between 62–82% depending on the p53 status of the cell line and drug concentration. Surviving cells of the combined treatment showed a significant reduced ability to form colonies. Enhanced cell toxicity was associated with a 5.3–14.4-fold increase of the apoptotic rate and intracellular p53 level up to 50.4% following vector-mediated p53 restoration and bortezomib treatment. In contrast, an antagonistic effect on tumor cell growth and colony formation was observed for the combination of bortezomib and docetaxel or pemetrexed as a reduction of cell growth between 31 and 48% was found in comparison to 50% using the single agents. Lower cytotoxic effects were associated with significantly reduced apoptosis and an increase of clonogenic growth. The observed antagonistic effects between bortezomib and docetaxel or pemetrexed might influence clinical trials using these compounds. Conversely, p53 restoration and bortezomib treatment led to enhanced, synergistic tumor cell toxicity.

Proposed score for survival of patients with myelodysplastic syndromes

Patient selection for various therapies in myelodysplastic syndromes (MDS) is based on prognostic factors, scoring systems and the individual life expectancy. However, most established risk scores include mainly disease‐related parameters and thus focus on leukaemia‐transformation rather than survival.

The myelodysplastic syndrome- comorbidity index provides additional prognostic information on patients stratified according to the revised international prognostic scoring system

The myelodysplastic syndromes are a heterogeneous group of disorders of the hematopoietic stem cell and stem cell niche.[1][1] The revised version of the International Prognostic Scoring System (IPSS-R), which is based on disease-related factors, was recently published.[2][2] In 2010, the MDS-

Cellularity, characteristics of hematopoietic parameters and prognosis in myelodysplastic syndromes

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.