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  • Online Resource  (10)
  • 2005-2009  (10)
  • 2007  (10)
  • Medicine  (10)
  • 1
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2451-2451
    Abstract: In the current WHO classification patients (pts) with therapy-associated MDS are merged into a subgroup of AML, termed “AML with MDS, therapy-related”, regardless of dysplastic features, medullary blast count or cytogenetics. To validate the appropriateness of this approach, we combined the MDS/AML data sets of the Duesseldorf as well as the Goettingen data base. We identified 305 pts with t-MDS or t-AML. There were 138 males and 167 females, median age was 64 (22–90). When classified according to the WHO proposals for primary MDS (pMDS), 38% of the pts had AML (28% blast count & gt;30%, 10% blast count 20–30% (RAEB-T)), 10% had RAEB II, 8% RAEB I, 2% CMML II, 3% CMML I, 6% RA, 1.5% RARS, 20% RCMD, 11% RCMD-RS and 0.5% had 5q- Syndrome. 60% of pts had received chemotherapy only, 12% radiotherapy, and 28% underwent combined radiochemotherapy prior to t-MDS/AML diagnosis. The median latency between treatment and diagnosis was 116 months in pts who received radiotherapy as compared to 81 months in pts treated with chemotherapy alone or in combination with radiation (p= 0.0005). Cytogenetics were available in 192 pts (63%). 58% had an abnormal karyotype, the median number of aberrant chromosomes was 2 (0–12). The most frequent aberrant chromosome was chromosome 5 (18%), followed by 7 (14%), 20 (7%) and 17 (7%). 48% of the pts had a low-risk, 18% an intermediate-risk, and 33% a high-risk karyotype according to IPSS. Median survival of the entire group was 10 months compared to 26 months in pMDS in our registry (p=0.00005). Important prognostic parameters for pMDS, like age, hemoglobin level, platelet count, neutrophile count, as well as classification and scoring systems (FAB, WHO, IPSS) could not show an impact on outcome in t-MDS/AML. Pts with & lt;5% medullary blasts had a median survival of 16 months, with 5–9% of 8 months, with 10–19% of 8 months, with 20–29% of 6 months and pts with a blast count & gt;30% had a median survival of 12months (p=n.s.). When we compared pts with a medullary blast count & lt;5 vs ≥5 months the survival difference (15 vs 7 months) became significant (p=0,013). Pts with an elevated LDH level had a median survival of 7 as compared to 17 months in pts with normal LDH (p=0.0006). The karyotype subgroups (IPSS) showed significant survival differences between each of the groups: low-risk -34 months, intermediate-risk -25 months, high-risk -8 months. In a multivariate analysis only karyotype (p=0,011) and LDH level (p=0,014) remained independent prognostic parameters (blast count: p=0,961). These two variables can be combined in a score: LDH elevated= 1 point, high-risk karyotype= 1 point. This score leads to 3 subgroups (0, 1, or 2 points) with a significantly different prognosis of 42, 15, and 7 months (p=0,01). Our analysis shows that there is no substantial difference in survival between t-MDS and t-AML, justifying the combination of both entities in one AML subgroup. Current morphology based classification systems offer no prognostic information. On the other hand the established karyotype classification according to IPSS remains relevant for prognosis and combining this information with the LDH level leads to a simple score that is able to separate prognostically different risk-groups and thus should be validated further. 0%
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 2
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 16 ( 2007-08-15), p. 4695-4703
    Abstract: Purpose: Amplified MYCN oncogene defines a subgroup of neuroblastomas with poor outcome. However, a substantial number of MYCN single-copy neuroblastomas exhibits an aggressive phenotype similar to that of MYCN-amplified neuroblastomas even in the absence of high MYCN mRNA and/or protein levels. Experimental Design: To identify shared molecular mechanisms that mediate the aggressive phenotype in MYCN-amplified and single-copy high-risk neuroblastomas, we defined genetic programs evoked by ectopically expressed MYCN in vitro and analyzed them in high-risk versus low-risk neuroblastoma tumors (n = 49) using cDNA microarrays. Candidate gene expression was validated in a separate cohort of 117 patients using quantitative PCR, and protein expression was analyzed in neuroblastoma tumors by immunoblotting and immunohistochemistry. Results: We identified a genetic signature characterized by a subset of MYCN/MYC and E2F targets, including Skp2, encoding the F-box protein of the SCFSkp2 E3-ligase, to be highly expressed in high-risk neuroblastomas independent of amplified MYCN. We validated the findings for Skp2 and analyzed its expression in relation to MYCN and E2F-1 expression in a separate cohort (n = 117) using quantitative PCR. High Skp2 expression proved to be a highly significant marker of dire prognosis independent of both MYCN status and disease stage, on the basis of multivariate analysis of event-free survival (hazard ratio, 3.54; 95% confidence interval, 1.56-8.00; P = 0.002). Skp2 protein expression was inversely correlated with expression of p27, the primary target of the SCFSkp2 E3-ligase, in neuroblastoma tumors. Conclusion: Skp2 may have a key role in the progression of neuroblastomas and should make an attractive target for therapeutic approaches.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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  • 3
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3170-3170
    Abstract: During the last decade, chronic myeloid leukemia (CML) has been mainly characterized by the reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the protooncogene BCR-ABL. This constitutively active tyrosine kinase is widely considered as the cause of the disease. Even though BCR-ABL transcripts are found in every dividing hematopoietic cell and thus, the disease is likely to originate from a primitive stem cell, the “cell of origin” is still a matter of debate. Despite the active “leukemia stem cell” discussion, very few characteristics of the “cancer stem cell” are established to date. In order to get further molecular insights into CML stem and progenitor cells, we examined CD34+ cell subsets obtained from bone marrow of 7 patients with CML in chronic phase in comparison with 5 healthy volunteers. CD34+ cells were immunomagnetically selected and high-speed cell sorting of lineage-negative, CD34+, CD38−, hematopoietic stem cells and myeloid progenitors was performed. Progenitors were further subdivided by anti-IL-3Ralpha and anti-CD45RA staining. Following RNA extraction, a two-cycle amplification procedure was used to generate cDNA for the hybridization with Affymetrix U133A2.0 arrays. After performing smoothening spline normalization, we applied the perfect match-mismatch difference model algorithm to calculate expression values (dChip). Hierarchical cluster analysis was performed using a correlation based centroid linkage algorithm. Hereby we could discriminate the HSCs, CMPs, and MEP subsets. Corroboration of RNA expression was performed by real-time RT-PCR for selected genes. Comparing the HSC subsets of CML patients with healthy controls we found 98 differentially expressed genes. 87 genes had a lower expression level in CML HSCs whereas 11 genes had a higher one. Among the downregulated genes in CML were transcriptions factors involved in myelogenesis and proliferation and several adhesion molecules associated with homing and migration of the HSCs. On the other hand, the Leptin receptor and BCR-ABL downstream targets were found to be upregulated. Within the common myeloid progenitor (CMP) compartment 37 genes were significantly differentially regulated. Twenty genes had a higher expression level in CML CMPs, 17 genes were downlegulated. Hematopoietic cell-specific cell cycle inhibitor MS4A3 was among the significantly downregulated genes whereas genes of the retinoblastoma and E2F families as well as inhibitors of the Wnt-signaling pathway were upregulated. Looking at megakaryocte-erythrocyte progenitors (MEP) in CML, key mediators of G2-M cell cycle transition were downregulated indicating a lower proliferative capacity of this subset. No transcriptional differences have been observed between granulocyte-macrophage progenitors from CML patients and healthy volunteers. Interestingly, among all other subsets myeloperoxidase (MPO) was downregulated in the CML samples and the Leptin receptor was upregulated. Our results provide novel insights into the biology of CML and potentially provide the basis for the characterization of a candidate CML stem cell.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 17 ( 2007-09-01), p. 8406-8411
    Abstract: DNA pooling in combination with high-throughput sequencing was done as a part of the Sequenom-Genefinder project. In the pilot study, we tested 83,715 single nucleotide polymorphisms (SNP), located primarily in gene-based regions, to identify polymorphic susceptibility variants for lung cancer. For this pilot study, 369 male cases and 287 controls of both sexes (white Europeans of Southern German origin) were analyzed. The study identified a candidate region in 22q12.2 that contained numerous SNPs showing significant case-control differences and that coincides with a region that was shown previously to be frequently deleted in lung cancer cell lines. The candidate region overlies the seizure 6-like (SEZ6L) gene. The pilot study identified a polymorphic Met430Ile substitution in the SEZ6L gene (SNP rs663048) as the top candidate for a variant modulating risk of lung cancer. Two replication studies were conducted to assess the association of SNP rs663048 with lung cancer risk. The M. D. Anderson Cancer Center study included 289 cases and 291 controls matched for gender, age, and smoking status. The Liverpool Lung Project (a United Kingdom study) included 248 cases and 233 controls. Both replication studies showed an association of the rs663048 with lung cancer risk. The homozygotes for the variant allele had more than a 3-fold risk compared with the wild-type homozygotes [combined odds ratio (OR), 3.32; 95% confidence interval (95% CI), 1.81–7.21]. Heterozygotes also had a significantly elevated risk of lung cancer from the combined replication studies with an OR of 1.15 (95% CI, 1.04–1.59). The effect remained significant after adjusting for age, gender, and pack-years of tobacco smoke. We also compared expression of SEZ6L in normal human bronchial epithelial cells (n = 7), non–small cell lung cancer (NSCLC; n = 52), and small cell lung cancer (SCLC; n = 22) cell lines by using Affymetrix HG-U133A and HG-U133B GeneChips. We found that the average expression level of SEZ6L in NSCLC cell lines was almost two times higher and in SCLC cell lines more than six times higher when compared with normal lung epithelial cell lines. Using the National Center for Biotechnology Information Gene Expression Omnibus database, we found a ∼2-fold elevated and statistically significant (P = 0.004) level of SEZ6L expression in tumor samples compared with normal lung tissues. In conclusion, the results of these studies representing 906 cases compared with 811 controls indicate a role of the SEZ6L Met430Ile polymorphic variant in increasing lung cancer risk. [Cancer Res 2007;67(17):8406–11]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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  • 5
    In: Brain Research, Elsevier BV, Vol. 1147 ( 2007-05), p. 25-33
    Type of Medium: Online Resource
    ISSN: 0006-8993
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2007
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  • 6
    In: Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 81, No. 4 ( 2007-04-01), p. 990-1001
    Abstract: The way the MHC II-associated proteolytic system of APC handles exogenous antigen is key to the stimulation of the T cell in infections and immunotherapy settings. Using a cell-impermeable, activity-based probe (ABP) for papain cathepsins, the most abundant type of endocytic proteases, we have simulated the encounter between exogenous antigen and endocytic proteases in live human monocyte-derived dendritic cells (MO-DC). Although cathepsin S (CatS), -B, -H, and -X were active in DC-derived endocytic fractions in vitro, the peptide-size tracer was routed selectively to active CatS after internalization by macropinocytosis. Blocking of the vacuolar adenosine triphosphatase abolished this CatS-selective targeting, and LPS-induced maturation of DC resulted in degradation of active CatS. Conjugation of the ABP to a protein facilitated the delivery to endocytic proteases and resulted in labeling of sizable amounts of CatB and CatX, although CatS still remained the major protease reached by this construct. Conjugation of the probe to a cell-penetrating peptide (CPP) routed the tracer to the entire panel of intracellular cathepsins, independently from endocytosis or LPS stimulation. Thus, different means of internalization result in differential targeting of active cathepsins in live MO-DC. CPP may serve as vehicles to target antigen more efficiently to protease-containing endocytic compartments.
    Type of Medium: Online Resource
    ISSN: 0741-5400 , 1938-3673
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    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2007
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  • 7
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1974-1974
    Abstract: BACKGROUND HLA-C epitopes can be grouped in C1C1, C1C2 or C2C2 ligands and mediate NK cell dependent immune response. Especially in haploidentical allogeneic stem cell transplantation a HLA-C ligand mismatch improves event free survival (EFS) in patients with AML known as Velardi effect. Recently, we could show in 109 CML patients that those with a C1C1 phenotype showed better overall survival (OS) and lower rates of treatment related mortality (TRM) (Fischer JC et al. J Immunology. 2007). But, the role of HLA-C ligands in allogeneic transplantations remains controversial. PATIENTS AND METHODS In this study we retrospectively analyzed a group of 88 patients with AML or CML (n=34), MDS (n=21) or lymphoid malignancies (Non-Hodgkin-Lymphoma or ALL) (n=31) receiving unrelated allogeneic blood stem cell transplantation after myeloablative and non-myeloablative conditioning regimens. HLA-C alleles were determined by DNA-based direct sequencing of all donors and recipients included into this study. RESULTS Looking at the group of 34 patients with AML or CML, the 13 recipients with a C1C1 phenotype showed increased OS compared to those with C1C2 and C2C2 phenotypes (all patients alive with a median follow-up of 154 days, range 90 to 665 days vs. a mean survival of 381 days, respectively; p=0.049). All recipients with a C1C1 phenotype received grafts with matched HLA-C alleles. Within the subgroup of patients with C1C2 or C2C2 phenotypes 6 patients had a HLA-C mismatch which was associated with significantly (p=0.016) increased OS (all patients alive with a median follow-up of 575 days, range 133 to 899) compared to matched HLA-C phenotypes (median survival of 254 days). In recipients with C1C1 phenotype the risk for TRM following HLA-C matched hematopoietic stem cell transplantation was reduced as reflected by an odds ratio of 0.13. In turn, the group receiving HLA-C mismatched grafts had a lower incidence of relapse. This effect was independent from the direction of the mismatch, graft vs. host or host vs. graft. The effects described above were not observed in patients with MDS, ALL or lymphoid malignancy. CONCLUSION The beneficial effects of a C1C1 HLA-C phenotype could be confirmed for patients with CML and AML in our patient cohort. Our data also suggest that patients with myeloid malignancies and an unfavourable C1C2 or C2C2 HLA-C phenotype benefit from a donor with HLA-C ligand mismatch.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 8
    Online Resource
    Online Resource
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 2776-2776
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2776-2776
    Abstract: In patients with iron overload from chronic blood (RBC) transfusion a new era of chelation treatment has been started with the availability of 3 chelators, their combinations, and other potential modifiers of tissue iron distribution. The decision about the chelator type and its dose would be facilitated if a mean chelation response could be forecasted. With the knowledge of a chelator’s molar efficacy, one could calculate the dose necessary to compete with the iron influx from blood transfusions. An open compartment model as developed for deferoxamine (DFO) and deferiprone (DFP) (Brit J Haematol2003;121:938–48) would additionally allow to forecast the total body iron store for a given blood transfusion and chelator dose rate over time, also for deferasirox. In a prospective study of the oral chelator deferasirox (DSX, Exjade®), 17 patients with b-thalassemia (age: 4 – 32 y) have been followed for 8 to 38 months by SQUID biomagnetic liver susceptometry in intervals of 6 to 12 months. Retrospectively, the same patients were followed in the past during s.c. DFO treatment. Liver iron concentration LIC, liver volumes, RBC transfusion and chelation dose rates were assessed. Of major importance was the stability of the hematocrit in the RBC units used in our department of 60 ± 3% over more than 6 years. Total body iron stores were calculated from total liver iron taking into account that 80 ± 10% of the total body storage iron is accumulated in the liver. For each measurement interval, molar efficacies were calculated from the daily iron input rate due to RBC plus the change in total body iron stores per interval time, and the molar dose rate of DFO or DSX. Additionally, total body iron elimination (TBIE) rate constants were calculated for each interval and fitted as function of the chelatable iron pool. LIC values, liver volumes, and ferritin levels were measured in the range of 498–8009 μg/g-liver, 654-3208 ml, and between 787 and 14866 μg/l. During DSX and DFO treatment, molar chelation efficacies of 11.2–53.1% and 6.1–23.7% were found for mean dose rates of 0.5–3.2 mmol/d (21–39 mg/kg/d) and 0.9–5.2 mmol/d (25–53 mg/kg/d) applied to iron influx rates of 7.6–30.6 mg/d and 9.7–28.5 mg/d from blood transfusion, respectively. In 6/17 (13/15 for DFO) patients with at least 3 treatment intervals, the intraindividual the molar efficacy ranged from 13.3±1.9% to 39.0±7.2% for DSX and from 7.8±2.0% to 19.4±2.9% for DFO in the same patients. Compliance assessed from tablet count protocols ( 〉 90%) did not influence these data significantly. The mean molar efficacies of 29±10% and 15±5% in our patient group agreed with reference values (Blood2005;106(11):#2690 and Brit J Haematol2003;121:938–48) for DSX and DFO, respectively. In contrast to DFO and DFP, the compartment model calculations resulted in a linear function of the TBIE rate constant for DSX with no saturation effect over the whole range of chelator doses and LIC. In summary, deferasirox was as efficient as deferoxamine at only half the molar dose even on an intraindividual patient basis. Once the individual molar efficacy has been assessed, a minimum chelator dose can be calculated to compete with the daily iron input from blood transfusions. The compartment model parameters of the total body iron elimination rate constant for deferasirox may allow to forecast the gross time pattern of liver iron concentration changes for practical treatment periods.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 9
    In: The Journal of Infectious Diseases, Oxford University Press (OUP), Vol. 196, No. 2 ( 2007-07-15), p. 313-320
    Type of Medium: Online Resource
    ISSN: 0022-1899 , 1537-6613
    URL: Issue
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    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2007
    detail.hit.zdb_id: 1473843-0
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  • 10
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4920-4920
    Abstract: Mobilized peripheral blood stem and progenitor cells are nowadays widely used for transplantation of hematopoietic stem and progenitor cells (PBSCT). These cells can be mobilized into the peripheral blood with cytotoxic chemotherapy, cytokines or both. Currently, G-CSF is most frequently used due to its high efficacy and lack of serious toxicity. However, a serious patient-to-patient variation in the yield of peripheral blood stem and progenitor cells is a feature common of all mobilizations schemes. Therefore, factors determining the collection efficacy have been identified for G-CSF mobilization. Recently a polyethylenglycole-conjugated G-CSF (Peg-G-CSF) has been introduced which has a 12-fold longer half-life than the original compound and therefore leads to long-lasting G-CSF serum-levels after a single injection. Studies on Peg-G-CSF included only small cohorts and no attempts have been made to identify factors influencing the mobilization of blood stem and progenitor cells. Therefore, we retrospectively analyzed 101 unselected patients (66 with multiple myeloma, 26 with non-Hodgkin-lymphoma, 7 with Hodgkin’s disease, 1 with Ewing sarcoma, 1 with malignant germ cell tumor). 27% of patients had active disease, while all others where at least in partial remission after conventional chemotherapy. Patients were treated with a broad range of chemotherapy regimens. The number of cytotoxic chemotherapy cycles administered prior to the mobilization therapy ranged from 1 to 11 (median 4). Mobilization chemotherapy was followed by 6 mg or 12 mg Peg-G-CSF (median 6 mg). Median peripheral blood CD34+ cell maximum in all patients was 65.3/μl (range 0.2–1084 per μl). 12 mg Peg-G-CSF led to a significantly earlier CD34+ cell maximum in the peripheral blood compared to 6 mg Peg-G-CSF (median 13 days vs 15 days, respectively; p=0.01). Overall, a median yield of 8.5 x 10^6 CD34+ cells/kg bodyweight (range 0.2–72.4 x 10^6) was reached with a single apheresis (median, range 1–4). To search for predictors of hematopoietic stem and progenitor cell mobilization, multiple regression analysis was used and revealed CD34+ cell count/μl peripheral blood at the day of apheresis and the processed blood volume during apheresis as predictors for the CD34+ cell yield per kilogram bodyweight. Age, sex, disease type and status were not significantly related to the CD34+ cell count/μl peripheral blood nor the CD34+ cell yield. Interestingly, the number of previous chemotherapy cycles was correlated with the CD34+ cell maximum (p=0.027) with fewer chemotherapy cycles leading to a higher peripheral blood CD34+ cell count and vice versa. In contrast, radiation therapy prior to CD34+ cell mobilization led to a significantly later occurrence of the CD34+ cell maximum in the peripheral blood. Our results confirm the feasibility and efficacy of PBPC mobilization with single dose Peg-G-CSF after cytotoxic chemotherapy shown in previous clinical trials analyzing the largest patient cohort to date and predictors for successful stem cell mobilization with Peg-G-CSF could be identified.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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