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C Thiede

Publications and source records attributed to C Thiede.

At least 19 recordsLinked to original sources
PubMed2006

Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease with multiple different cytogenetic and molecular aberrations contributing to leukemic transformation. We compared gene expression profiles of 4608 genes using cDNA-arrays from 20 AML patients (nine with -7/del7q and 11 with normal karyotype) with 23 CD34+ preparations from healthy bone marrow donors. SKI, a nuclear oncogene, was highly up regulated. In a second set of 183 AML patients analyzed with real-time PCR, the highest expression level of SKI in AML with -7/del7q could be confirmed. As previously described, Ski associates with the retinoic acid receptor (RAR) complex and can repress transcription. We wanted to investigate the interference of Ski with RARalpha signaling in AML. Ski was co-immunoprecipitated and colocalized with RARalpha. We also found that overexpression of wild-type Ski inhibited the prodifferentiating effects of retinoic acid in U937 leukemia cells. Mutant Ski, lacking the N-CoR binding, was no more capable of repressing RARalpha signaling. The inhibition by wild-type Ski could partially be reverted by the histone deacetylase blocking agent valproic acid. In conclusion, Ski seems to be involved in the blocking of differentiation in AML via inhibition of RARalpha signaling.

Acute Disease↗
PubMed2006

Reduced intensity conditioning allows for up-front allogeneic hematopoietic stem cell transplantation after cytoreductive induction therapy in newly-diagnosed high-risk acute myeloid leukemia.

There is substantial need to improve the outcome of patients with high-risk acute myeloid leukemia (AML). The clinical trial reported here investigated a new approach of up-front allogeneic hematopoietic stem cell transplantation (HSCT), provided a median of 40 days (range 22-74) after diagnosis, in twenty-six consecutive patients with newly-diagnosed high-risk AML characterized by poor-risk cytogenetics (n = 19) or inadequate blast clearance by induction chemotherapy (IC, n = 7). The median age was 49 years (range 17-68). During IC-induced aplasia after the 1st (n = 11) or 2nd (n = 15) cycle, patients received allogeneic peripheral blood stem cells (PBSC) from related (n = 11) or unrelated (n = 15) donors following a fludarabine-based reduced-intensity regimen. Seventeen patients were not in remission before HSCT with a median marrow blast count of 34% (range 6-70). All patients achieved rapid engraftment and went into remission with complete myeloid and lymphatic chimerism. Grades II to IV acute GvHD occurred in 14 (56%) and extensive chronic GvHD was documented in 8 (35%) patients. The probability of disease-free survival was 61% with only three patients relapsing 5, 6 and 7 months after transplantation, respectively. Up-front allogeneic HSCT as part of primary induction therapy seems to be an effective strategy in high-risk AML patients and warrants further investigation.

Acute Disease↗
PubMed2005

Graft clonogenicity and intensity of pre-treatment: factors affecting outcome of autologous peripheral hematopoietic cell transplantation in patients with acute myeloid leukemia in first remission.

A total of 22 patients with acute myeloid leukemia (AML) in first complete remission receiving autologous blood stem cell transplantation (ABSCT) were investigated in order to determine factors affecting outcome. All but two patients had a normal karyotype and received the same high-dose chemotherapy followed by G-CSF-mobilized peripheral blood stem cells after the second (n=5) or third (n=17) course of induction and post-remission chemotherapy, respectively. With a median follow-up of 30 months, the median disease-free survival is 24.1 months. Univariate analysis showed that three chemotherapy cycles before ABSCT were associated with a significant better disease-free survival (P=0.0018) and overall survival (P=0.0033), whereas the presence of an FLT3-mutation (n=6) showed no impact. The number of megakaryocytic progenitors (CFU-MK) infused tended to correlate with primary platelet engraftment (P=0.07) and were predictive for neutrophil (P=0.011) and platelet counts (P=0.009) 180 days after transplantation. Patients receiving a higher amount of CFU-MK had a better event-free survival (P=0.02). Our data suggest that the content of CFU-MK within the graft predicts the quality of hematological recovery and long-term disease control. Additionally, a minimum of three chemotherapy cycles before ABSCT seems to be associated with an improved outcome.

Adult↗
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗
PubMed2004

Reduced-intensity conditioning with busulfan and fludarabine with or without antithymocyte globulin in HLA-identical sibling transplantation--a retrospective analysis.

It is unknown whether the addition of antithymocyte globulin (ATG) to reduced-intensity conditioning with busulfan (BU) and fludarabine (FLU) is beneficial in HLA-identical sibling transplantation. Therefore, we analyzed retrospectively data on 83 patients, who received peripheral blood stem cells from HLA-identical siblings after conditioning with either 8 mg/kg BU and 150 mg/m2 FLU (n=45) or 8 mg/kg BU, 180 mg/m2 FLU and 40 mg/kg ATG (n=38). Graft-versus-host disease (GVHD) prophylaxis consisted of CSA alone (n=32) or a combination with either MTX or MMF (n=51). The median age was 52 years. Graft failure occurred in two patients after BU/FLU and in three after BU/FLU/ATG (P=0.66). After conditioning with BU/FLU, platelet recovery was significantly faster (P=0.017), and less platelet (P<0.001) and red blood cell (P=0.002) support was needed. Incidences of acute GVHD grades II and IV were 46 and 49%, respectively. Limited chronic GVHD occurred more often after BU/FLU compared to BU/FLU/ATG (54 vs 23%, P=0.02). The overall survival, non-relapse and relapse mortality did not differ significantly. We conclude that in peripheral blood stem cell transplantation from HLA-identical siblings after reduced-intensity conditioning with BU and FLU, ATG has no major impact on the rate of graft rejection and acute GVHD, but it reduces the incidence of limited chronic GVHD.

Acute Disease↗
PubMed2004

CD34+ cell dose, conditioning regimen and prior chemotherapy: factors with significant impact on the early kinetics of donor chimerism after allogeneic hematopoietic cell transplantation.

The aim of this study was to define factors that significantly influence the early kinetics of donor chimerism after transplantation. In a retrospective study, the percentage of donor chimerism in peripheral blood measured with sex-chromosome-specific probes and fluorescence-in situ hybridization was analyzed in 184 recipients of allogeneic hematopoietic cells between days 1 and 30. Using a generalized linear model for longitudinal observations, the dose of CD34+ cells infused had a significant impact on the slope of donor chimerism. In multivariate analysis, cell doses of 2-8 x 10(6)/kg (P=0.001) and <2 x 10(6) CD34+ cells/kg (P<0.0001) were associated with slower increase of donor chimerism compared to >8.0 x 10(6) CD34+ cells/kg. In addition, fludarabine-based reduced-intensity conditioning resulted in a significant delay of donor cell increase compared to standard conditioning therapy (P=0.0001). The application of chemotherapy before the start of conditioning (P=0.0003) and the use of antithymocyte globulin (P=0.003) were associated with a faster increase of donor chimerism. The factors identified in this study can be used to predict the kinetics of early donor chimerism for an individual patient.

Adolescent↗
PubMed2004

Evaluation of STR informativity for chimerism testing--comparative analysis of 27 STR systems in 203 matched related donor recipient pairs.

Chimerism analysis has become a routine method to document engraftment and also for detection of residual disease. PCR-based procedures using STR analysis, especially commercially available multiplex assays, are frequently used. However, these assays have been optimized for forensic purposes and do not necessarily fulfil all needs for chimerism analysis. To improve these analyses, data on the level of informativity of STR systems in the context of chimerism analysis would be helpful. We evaluated 27 STR markers for their informativity in 203 patients and their HLA-matched related donors. These STRs included 18 from different multiplex kits, whereas nine were selected from the literature or STR databases. The STR profiles were ranked from Type 1 (not informative) to Type 5 (best suited for chimerism analysis). According to this ranking, the informativity of the STR systems was found highly variable, ranging from 4.4 to 49.0% Type 5 constellations. Among the most informative STRs were Penta E, SE33, D2S1338 and D18S51. Informativity of an STR was correlated with the degree of heterozygosity (r=0.86; P=0.0001), but not with the total number of alleles present. These data indicate that selection of suitable STR markers is important to improve diagnostics based on STR analysis.

Genetic Carrier Screening↗
PubMed2003

Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group.

PURPOSE: To study whether hematopoietic stem-cell transplantation (HSCT) after reduced-intensity conditioning is effective and tolerable in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Thirty patients with advanced B-cell CLL were included into the study. After reduced-intensity conditioning with fludarabine, busulfan, and antithymocyte globulin, patients received a transplant from related (n = 15) or unrelated donors (n = 15). Minimal residual disease (MRD) was monitored with a clone-specific polymerase chain reaction. RESULTS: After a median follow-up of 2 years, 23 patients are alive (to date). Neutrophil and platelet engraftment occurred after a median of 17.5 and 15 days, respectively. Acute graft-versus-host disease (GVHD) grade 2 to 4 was observed in 17 patients (56%), and chronic GVHD was observed in 21 patients (75%). Twelve patients (40%) achieved a complete remission (CR), and 16 patients (53%) achieved a partial remission. Late CR occurred up to 2 years after transplantation. MRD was monitored in eight patients with CR. All patients achieved a molecular CR. At last follow-up, six patients were in ongoing molecular CR. Causes of death were treatment-related complications in four patients and progressive disease in three patients. The probability of overall survival, progression-free survival, and nonrelapse mortality at 2 years was 72% (95% confidence interval [CI], 54% to 90%), 67% (95% CI, 49% to 85%), and 15% (95% CI, 1% to 29%), respectively. CONCLUSION: Treatment-related mortality after reduced-intensity conditioning followed by allogeneic HSCT was low. The procedure induced molecular remissions in patients with advanced CLL. The observation of late remissions provided evidence of a graft-versus-leukemia effect.

Adult↗
PubMed2003

Etiology and therapy of Helicobacter pylori-associated gastric lymphomas.

The WHO separates marginal zone B-cell lymphomas (MZBL) of nodal and extranodal type. Both arise from memory B cells of the marginal zone. Extranodal MZBL of the mucosa-associated lymphatic tissue (MALT) have characteristic features such as homing in epithelial tissue, lymphoepithelial destruction, and a very indolent clinical course. They arise in epithelial tissues normally devoid of lymphatic cells, where the lymphatic tissue was acquired after, for instance, a chronic infection. The best example here is infection of the stomach with Helicobacter pylori ( Hp). Besides the classical association with gastric MALT lymphomas, there have been reports in which an association between Hp and diffuse large B-cell lymphoma (DLBCL) has been observed as well. Consequently, cure of Hp infection resulted in remission induction not only in gastric MALT lymphomas, but also in some patients with very limited stages of DLBCL of the stomach. In addition to the association with Hp, progress has been made with regard to MALT lymphoma biology. Translocation t(1;14) involving the Bcl-10 gene, and translocation t(11;18) involving a novel gene called MLT1, both result in activation of the crucial transcription factor NF-kappaB. These genetic events seem specific in that they have been observed only in MALT lymphomas. Once present, at least the more frequently observed translocation t(11;18) renders cells resistant to cure of Hp infection. Another clinically important question is that in many patients in complete remission after cure of Hp infection, detection of minimal residual disease is positive. Whether these cells are normal memory B cells (with the identical B-cell rearrangement as the original lymphoma clone), or dormant lymphoma cells, is unclear at present. In patients not responding to cure of Hp infection, several treatment options are discussed. MALT lymphomas have opened up a new discussion of lymphoma biology and have thus been called a model disease.

Chromosomes, Human, Pair 1↗
PubMed2003

Evidence for a graft-versus-tumor effect in refractory ovarian cancer.

PURPOSE: A 31-year-old woman suffered a 4th relapse of epithelial ovarian cancer refractory to several cytotoxic drugs including platinum, paclitaxel, and topotecan. METHODS: Sequential high-dose chemotherapy with autografting (three courses) led to a minor response of short duration. In order to induce a graft-versus-tumor effect, allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-identical sibling donor, after dose-reduced conditioning, was performed in January 2001. RESULTS: On day +51 the patient developed acute grade II graft-versus-host disease of the skin and gastrointestinal tract, which was successfully treated by prednisolone. Six months after allogeneic HSCT a complete disappearance of the tumor could be seen. Unfortunately, 14 months later a 5th relapse was diagnosed. CONCLUSIONS: This case demonstrates, on the one hand, that allogeneic HSCT is able to induce complete remissions (CR) in chemoresistant ovarian cancer. On the other hand, despite achievement of CR after allografting, the chance of cure remains limited for these patients.

Adult↗
PubMed2003

Immunophenotyping is an independent factor for risk stratification in AML.

BACKGROUND: Chromosomal abnormalities are one of the most important prognostic factors in acute myeloid leukemia (AML). However, only a limited number of patients have such informative chromosomal abnormalities. The prognostic value of immunophenotyping in this disease is still unclear. METHODS: Seven hundred and eighty-three newly diagnosed AML patients treated in the German SHG-AML trials in 1991 and 1996 were analyzed with a panel of 33 antibodies. Expression was correlated to overall survival, complete remission-rate, and complete remission duration, and tested in a multivariate analysis including other clinical and biological markers. RESULTS: With a median follow-up of 4.3 years, patients with AML blasts negative for CD9, CD11b, CD13, CD34, and CD41, or positive for CD15, CD33, CD38, CD64, and MPO had superior overall survival. This effect was associated with a significantly higher complete remission rate (CD13, CD34, CD41, and CD64) or a longer complete remission duration (CD9, CD11b, and CD64). Cox-regression analysis, including cytogenetic, morphologic, and biologic parameters showed CD9, CD13, CD34, and CD64 as independent factors for overall survival. These markers were used for a prognostic score. Patients were pooled in three groups with highly significant differences of overall survival. The prognostic relevance of this score was confirmed in patients with normal karyotype and/or in younger patients </= 60 years. CONCLUSIONS: Immunophenotyping is not only helpful for diagnosis but is of independent significance for prognosis, and may be useful for risk stratification in AML patients.

Acute Disease↗
PubMed2003

Stable molecular remission induced by imatinib mesylate (STI571) in a patient with CML lymphoid blast crisis relapsing after allogeneic stem cell transplantation.

We report the response to the ABL kinase inhibitor imatinib mesylate (STI571) in a patient with chronic myeloid leukemia (CML) who relapsed twice after dose-reduced allogeneic stem cell transplantation (alloSCT) for B lymphoid blast crisis (BC) and failed to develop an antileukemic response despite grade 3 graft-versus-host disease (GvHD). Complete hematologic, cytogenetic and molecular responses were achieved within 9 weeks of therapy and are maintained after 27 months. Extensive chronic skin GvHD necessitating immunosuppressive therapy developed after 14 months. This case illustrates the ability of imatinib to induce sustained hematologic and molecular remissions in some patients relapsing with advanced stage CML after alloSCT.

Adult↗